Title of Invention	TETRAHYDROCARBAZOLE DERIVATIVES .
Abstract	The present invention relates to novel tetrahydrocarbarzole derivatives which are effective as ligands for G-protein coupled receptors (GPCR), especially as antagonists of gonadotropin-releasing hormone (GnRH). The present invention also relates to a pharmaceutical composition comprising these novel tetrahydrocarbazole derivates and to a method for preparing the novel tetrahydrocarbazole derivatives. Furthermore, the present invention also relates to the administration of tetrahydrocarbazole derivatives for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH, to mammals, in particular humans, requiring such an administration, and to the use of tetrahydrocarbazole derivatives for producing a pharmaceutical remedy for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH.

Title of Invention

TETRAHYDROCARBAZOLE DERIVATIVES .

Abstract

The present invention relates to novel tetrahydrocarbarzole derivatives which are effective as ligands for G-protein coupled receptors (GPCR), especially as antagonists of gonadotropin-releasing hormone (GnRH). The present invention also relates to a pharmaceutical composition comprising these novel tetrahydrocarbazole derivates and to a method for preparing the novel tetrahydrocarbazole derivatives. Furthermore, the present invention also relates to the administration of tetrahydrocarbazole derivatives for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH, to mammals, in particular humans, requiring such an administration, and to the use of tetrahydrocarbazole derivatives for producing a pharmaceutical remedy for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH.

Full Text	TETRYDROCARBAZO DERIVATIVES AS LGANDS FOR PROTEIN COUPLED RECEPTORS (GPCR) The present invention relates to novel tetrahydro- carbazole derivatives which are ligands of G-protein coupled receptors, and especially antagonists of gonadotropin-releasing hormone, to the preparation thereof, to the use thereof, and to the pharmaceutical compositions- which include these tetrahydrocarbazole derivatives. The present invention also relates to a method for treating pathological states mediated by G- protein coupled receptors in a mammal, in particular a human. Technical background The structural element which is common to all members of the family of G-protein coupled receptors (GPCR) is the presence of seven transmembrane alpha-helical segments which are connected together by alternating intra- and extracellular loops, with the amino terminus being located on the extracellular side and the carboxy terminus being located on the intracellular side. The family of GPCRs can be divided into a plurality of subfamilies (essentially family A, B and C) with further sequence homologies within these subfamilies. Since GPCRs are mainly involved in signal reception and transduction, a large number of physiological functions are influenced by them. GPCR ligands are therefore potentially suitable as medicaments for the therapy and prophylaxis of a large number of pathological states. A brief survey of diseases which can be treated with GPCR ligands is given in S. Wilson et al., Pharmaceutical' News 2000, 7(3) in Table 1. The majority of known GPCR ligands has a peptide structure. However, peptide receptor ligands frequently have some serious disadvantages such as, for example, low bioavailability and metabolic instability. This is why there has recently been an intensified search for ligands in the form of small, non-peptide molecules. A special part is played in the search for novel, non- 5 peptide receptor ligands by so-called "privileged structures'". These "privileged structures" are the basic molecular structures which provide ligands for a large number of different receptors. The term "privileged structures" was used for the first time by 1.0 Evans et al. in connection with benzodiazepine-based CCK (cholecys-tokinin) A antagonists from the natural product asperlicin (B.E. Evans et al. , J. Med. Chem. 1988, 31, 2235) . For proteases for example it has been known for some time that certain structural classes can 15 serve as inhibitors of various enzymes. Whereas descriptions in the past were in particular of mechanism-based inhibitors of various proteases, however, more recently the frequency of examples of compounds which, by reason of their three-dimensional 20 structure, fit well into the active binding region of various enzymes has increased (cf. M. Whittaker, Cur. Opin. Chem. Biol. 1998, 2, 386; A.S. Ripka et al. , ibid., 441). Such "privileged structures" have already been described for GPCRs too. Examples thereof are, 25 besides the aforementioned benzodiazepines, also peptoids, 4-substituted 4-arylpiperidines, but also specific rigidized β-turnimetics (B.A. Bunin et al. , Ann. Rep. Med. Chem. 1999, 34, 267; R.N. Zuckermann et al., J. Med. Chem. 1994, 37, 2678; G.C.B. Harriman, 30 Tetrahedron Lett. 2000, 41, 8853) . A review of this is to be found in A.A. Patchett et al. , Ann. Rep. Med. Chem. 1999, 35, 289. The tetrahydrocarbazole derivatives of the present invention provide a further class of "privileged structures" for GPCRs. 35 Although the present invention provides ligands for GPCRs in general, the compounds provided by the present invention are suitable in particular as ligands for a particular representative of the class of GPCRs, namely gonadotropin-releasing hormone receptor (GnRH receptor). GnRH receptor can be assigned to subfamily A of GPCRs (cfU.Gether et al., Endocrine Reviews 2000, 21(1), 90). GnRH is a hormone which is synthesized predominantly, but not exclusively, in mammals by nerve cells of the hypothalamus, is transported via the portal vein into the pituitary and is delivered in a controlled mannerto gonadotropic cells. Interaction of GnRH with its receptor having seven transmembrane domains stimulates the production and release of gonadotropic hormones by means of me second messenger inositol 1,4, 5- trisphosphate and Ca24 ions. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are gonadotropins released by GnRH, stimulate the production of sex steroidsd and gamete maturation in both sexes. In addition to GnRH ( also referred to as GnRHl), there are two further forms of GnRH, namely GnRH2 and 3. the GnRH receptor is used as pharmacological target in a number of disorders which depend on functioning sex hormone production, for example prostrate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or antagonists can be employed successfully for these disorders. A further possible indication is, in particular, male fertility control in combination with a replacement dose of androgens. One advantage of GnRH antagonists compared with GnRH superagonists is (heir direct activity in blocking gonadotropoin secretion. Superagonists initially bring about overstimulation of the pituitary, leading to increased gonadotropin release and sex steroid release. This hormonal response is terminated only after a certain delay on the basis of desensitization and downregulation of GnRH receptor concentrations. It is therefore possible that GnRH superagonists, both alone and in combination with testosterone, are unable effectively to suppress sperm production in men and are thus unsuitable for male fertility control. In contrast to this, peptide GnRH antagonists, especially in combination with a replacement dose of androgen, are able to induce a significant oligozoospermia in humans. However, peptide GnRH antagonists have a number of disadvantages. Thus, they have a considerably lower activity as superagonists and must accordingly be administered in considerably higher dosages. In addition, their oral bioavailability is low, so that they must be administered by injection. Repeated injections in turn lead to a reduction in compliance. Furthermore, the synthesis of peptide GnRH antagonists is complicated and costly by comparison with non- peptide compounds. Quinoline derivatives are disclosed as non-peptide GnRH antagonists for example in WO 97/14682. However, it has not been possible to date to put any non-peptide GnRH antagonists on the market. Technical problem The problem on which the present invention is based is to provide novel compounds which are suitable for the treatment of GPCR-mediated pathological states and display in particular a GnRH-inhibiting (GnRH- antagonistic) effect. The novel GPCR ligands, preferably GnRH antagonists, ought where possible to be superior to known peptide compounds and represent an effective alternative or improvement in relation to known non-peptide compounds. The novel GPCR ligands, especially GnRH antagonists, should in particular have high activity and, where possible, a high oral bioavailability. Their synthesis ought moreover to be possible simply and at minimal cost. The present invention also provides pharmaceutical compositions - 5 - comprising the novel non-peptide GPCR ligands, in particular GnRH antagonists. A further problem on which the present invention is based is to provide novel GPCR ligands, preferably GnRH antagonists, for use as pharmaceutical remedy and for use for producing pharmaceutical remedies, comprising the GPCR ligands, preferably GnRH antagonists. In addition,, it is an object of the present invention to provide a method for the treatment of GPCR-mediated pathological states, in particular for inhibiting GnRH, in a mammal, in particular a human. All these problems are surprisingly solved by the provision of the novel tetrahydrocarbazole derivatives, of the pharmaceutical compositions which comprise these tetrahydrocarbazole derivatives, of the method for preparing these tetrahydrocarbazole derivatives, and of the method for the treatment of GPCR-mediated pathological states, preferably for inhibition of GnRH, in a mammal, in particular a human, through administration of the tetrahydrocarbazole derivatives or the use of the tetrahydrocarbazole derivatives for producing pharmaceutical remedies for the treatment of GPCR-mediated pathological states, in particular for GnRH inhibition. Summary of the invention In a first aspect, the present invention provides novel tetrahydrocarbazole derivatives of the general formula (I). In a second aspect, pharmaceutical compositions which comprise at least one of the novel tetrahydrocarbazole derivatives of the general formula (I) are provided. In a third aspect, the present invention provides tetrahydrocarbazole derivatives of the general formula (I) for use as pharmaceutical remedy. In a further aspect, the present invention relates to the use of a tetrahydrocarbazole derivative of the general formula (I) for producing a pharmaceutical remedy for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH. The present invention likewise relates to a method for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH, in a mammal, preferably a human, where an effective amount of a compound of the invention of the general formula (I) is administered to the mammal, preferably the human, requiring such a treatment. The present invention additionally provides a method for preparing tetrahydrocarbazole derivatives of the general formula (I) . This method comprises for example the steps of condensation of a cyclohexanone derivative, which is tethered to a solid phase and is expediently substituted, with a suitably substituted phenylhydrazine derivative, a subsequent derivatization depending on the desired structure of the final compound, and finally elimination from the solid phase and isolation of the product. Detailed description of the invention In a first aspect of the present invention there is provision of novel tetrahydrocarbazole compounds of the general formula (I) (0 in which the radical R! is a hydrogen atom, aC2-C* alkenyl or a Ct-Q alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR11, where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of-NOa, -CHs, -CF3, - OCH3, -OCF3 and halogen atoms, and the radical R!l is a hydrogen atom, a C1-Q2 allqfl, a C1-C12 aralkyl, an aryl, hetaryl, radical or the group -COCH3 and may optionally be substituted by one substituent selected from the group consisting of-CONHa.-COCH3, - COOCH3>-S02CH3 and aryl radicals; me radicals R2, R3, R4 and R5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -COWh, -CF% -OCF% -N02> -CNS a Ci-Q alkyl, a (C2-C6 alkenyl, a Ct-Q alkosy, a Ci-Ct2 aralkyl, an aryl or hetaryl radical; me radical R6 is me group -CONR8, - COOR8, -CHaNR^^CHsR8, -Cr^OR8 or a C2-Q2 alkenyl radical which is optionally substituted by the radicals R* and R9, where the radicals R and R are each independently of one another a hydrogen atom, a Ci-Cn alkyl, a Q-C12 aralkyl, a C1-Q2 heteralkyl, an aryl or heterayl radical, each of which may be substituted by one or more subatituents selected from the group consisting of- OHrNH2, -CONHR10, -COOR10, -NH-C (=NH) -NHa and halogen atoms, where the radical R10 is a hydrogen atom, a C1-C12 alkyl, a C1-C12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R11)2, or where the radicals R8 and RJ may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms andheteroatoms; the radical R7 is a C2-C12 alkyl, a C2-C12 alkenyl, a C2-C12 aralkyi, an aryl or hetaryi radical, me group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR14 or - NHSO2R14 and may optionally be substituted by one or more substituents selected from the group consisting of-OH, -NH2, -CONH2, -COOH and halogen atoms, the radicals R12 and R13 are each independently of one another a hydrogen atom, a C2- Ce alkenyl or a C2-C12 alkyl radical and may optionally be substituted by one or more aryl or hetaryi radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -NOa.-CH3, CF3, -OCH5- OCF3 and halogen atoms, and me radical R14 is a hydrogen atom, a C2-C12 alkyl, aC2-C12 alkenyl, a C2-C12 aralkyi, an aiyl or hetaryi radical which may optionally be substituted by one or more substituents selected from the group consisting of -NO3, - CH3, -OR11, -CF3, -OCF3, -OH, -N(R11)2, -OCOR11, -COOH, -CONH2, -NHCONHR11, - NHCOOR11 and halogen atoms; and the radicals R\ Rb, Re, Rd, Re and Rf are each independently of one another a hydrogen atom, a halogen atom, the group -€OOH, -CONH2, -CF% OCF3, -NO2, -CN, a Ci-Cg alkyl, Ci-Cs alkoxy, an aryl or hetaryi radical; with the proviso that the compound of the general formula (I) is not selected from the group consisting of 3-ammo-l,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3- carboxylic acid, 3-amino-6-benzyloxy-l,2,3 , 4- tetrahydrocarbazole-3-carboxylic acid, 3-acetamido- 1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl 5 3-acetamido-l, 2,3., 4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3- carboxylate or 3-tert-butoxycarbonylamino-l,2,3,4- tetrahydrocarbazole-3-carboxylic acid. 10 One embodiment of the . invention are compounds of the general formula- (I) as indicated above with all the meanings indicated above for the radicals contained in (I), where the radical R11 is a heteroalkyl or a hetarylalkyl radical. 15 The basic tetrahydrocarbazole structures of those compounds which are specifically excluded above from the compounds falling within the definition of the general formula (I) were introduced by Y. Maki et al. 20 in Chem. Pharm. Bull. 1973, 21 (11), 2460-2465 and by R. Millet et al. in Letters In Peptide Science 1999, 6, 221-233. The terms indicated for explanation of the compounds of 2 5 the general formula (I) have in particular the following meaning: C1-C6 or C2-C12 "alkyl radical" means a branched or unbranched, cyclic or acyclic, optionally substituted 3 0 alkyl group having 1 to 6 or 1 to 12 carbon atoms, respectively. Representative examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, n-pentyl, 2,2- dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, n- 35 octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl groups, and cyclic groups, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups, 1-cyclopropyl-, 1-cyclobutyl-, 1-cyclopentyl-, 1-cyclohexyl-, 1-cycloheptylethyl-, 2-cyclopropyl-, 2- cyelobutyl-, 2-cyclopentyl-, 2-cyclohexyl-, 2- cycloheptylethyl groups and the like, but are not restricted to these. C2-C6 "alkenyl radical" means a branched or unbranched, cyclic or acyclic, optionally substituted, mono- or polyunsaturated alkenyl group having 2 to 6 carbon atoms. Representative examples of such alkenyl groups include vinyl, allyl, prop-1-enyl, but-1-enyl, but-2- enyl, but-3-enyl, buta-1,3-dienyl, pent-1-enyl, pent-2- enyl, pent-3-enyl, pent-4-enyl, penta-1,3-dienyl, penta-1,4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1- enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, hexa-1,5-dienyl, hexa-2,4-dienyl, hexa-2,5-dienyl, hexa-1,4-dienyl, hexa-1,3,5-trienyl groups and the like, but are not restricted to these. C2-C6 "alkoxy radical" means a branched or unbranched, cyclic or acyclic, optionally substituted alkoxy group having 2 to 6 carbon atoms. Representative examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n- pentoxy, n-hexoxy, cyclohexyloxy groups and the like, but are not restricted to these. C2-C12 "aralkyl radical" means an alkyl radical having 1 to 12 carbon atoms which is substituted by one or more aryl radicals. Representative examples of such aralkyl groups for the purposes of the present invention include benzyl, 1-phenylethyl, 1-phenylpropyl, 1- phenylbutyl, 1-phenylhexyl, 1-phenyl-2-methylethyl, 1- phenyl-2-ethylethyl, l-phenyl-2,2-dimethylethyl, benzhydryl, triphenylmethyl, 2- or 3-naphthylmethyl, 2- phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5- phenylpentyl groups and the like, but are not restricted to these. Correspondingly, a "hetaralkyl radical" is an alkyl radical substituted by a heteroaryl radical. "Aryl radical" means an optionally substituted mono- or polycyclic aromatic group. Representative examples of such aryl groups- include phenyl, naphthyl groups and the like, but are not restricted to these. The term "hetaryl radical" is identical with the term "heteroaryl radical" and represents an aryl group as defined above which includes in its structure one or more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. Representative examples of such hetaryl or heteroaryl groups include unsubstituted hetaryl radicals and substituted hetaryl radicals, in particular imidazolyl, pyridyl, quinolinyl groups and the like, but are not restricted to these. The term "cyclic structure" includes optionally substituted mono- or polycyclic cyclic structures with a varying number of ring members, in particular five-, six- and seven-membered cyclic structures. These cyclic structures may include besides carbon atoms also one or more heteroatoms such as, in particular, nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. The cyclic structures may include saturated, but also partially or completely unsaturated, structural elements. Representative examples of such cyclic structures include aza-, oxa-, thia-, phosphacyclopentane-, -cyclohexane-, -cycloheptane-, diaza-, dioxa-, dithia-, diphosphacyclopentane, -cyclohexane, -cycloheptane basic cyclic structures and the like, and basic cyclic structures with mixed heteroatom exchange, but are not restricted to these. "Halogen atoms" include in particular fluorine, chorine, bromine and iodine atoms, particularly preferably chlorine acorns. Reference may also be made at this point to the fact that, besides the compounds of the general formula (I), as defined above, which are mentioned per se, the present invention also encompasses physiologically tolerated derivatives or analogs, especially also salts of these compounds. It may further be remarked at this point that the term "receptor ligand" or "ligand" is intended for the purposes of the present invention to designate any compound which binds in any manner to a receptor (in the present invention, the receptor is a GPCR receptor, preferably a GnRH receptor) and induces either an activation, inhibition or other conceivable effect on this receptor. The term "ligand" thus includes agonists, antagonists, partial agonists/antagonists and other ligands which elicit on the receptor an effect which resembles the effect of agonists, antagonists or partial agonists/antagonists. The compounds of the invention of the general formula (I) are preferably GnRH antagonists. One embodiment of the present invention are novel tetrahydrocarbazole derivatives of the invention of the general formula (I) in which the radical R7 is not a hydrogen atom when the radical R6 is at the same time an alkyl radical. A further embodiment of the present invention are compounds of the general formula (I) in which the radical R7 is not in any case a hydrogen atom. Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula. (I) are those compounds in which the radicals Ra, RD, Rc, Rd, Re and Rf are hydrogen atoms. Likewise preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are those compounds in which the radical R1 is a hydrogen atom. Preferred novel tetrahydroearbazole derivatives of the invention of the general formula (I) are additionally those compounds in which the radicals R2, R3, R4 and/or RJ are not hydrogen atoms. Particularly preferred compounds of the general formula (I) in this connection are those in which the radicals R2, R3, R4 and Rs are independently of one another methyl, chloro or methoxy radicals. Very particularly preferred compounds of the general formula (I) in this connection are those in which at least the radical R2 is not a hydrogen atom, especially the compounds. Phenylmethyl[(lS,2S)-l-[[[(3R)-3[[[(lS)-l-(animocaitonyl)-2-methylpropyl]amino] carbonyl] -2,3,4,9-tetrahydro-8-methyl- lH-carbazol-3 -yl]amino] carbonyl] -2-methylbutyl] carbamate (compound no. 150a in the examples) phenylmethyl [ (1S92S)-1- [ [ [ (3R)-3-[ [ [ (lS)-l-(aminocarbonyl)-2-mettiylpropyl] an3d^o]carbonyl]-6-cMoro-2,3,4,94etrahydro-lH-carbazol-3-yl]amino]carbonyl3-2- niethyl-butyl] carbamate (148a). phenylmethyl [(lS,2S)-l-[ [ [ (3R))-3- [ [ [ (1S) -l-(aminocarbonyl)-2-memylpropyl] ammo]cart)onyl]-2,3,4,94etrahyoVo-8-memo^-lH-carbazol-3-yl]ammo]carbonyl]-2- methylbutyl]carbamate (147a). Preferred novel tetrahydrocarbazole derivatives of me invention of the general formula (I) are also those compounds in which R6 is a hydrophobic radical which includes alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system at a distance of from two to tour single bonds, counting from the carbon atom substituted by the radicals R6 and R7. Particularly preferred compounds of the general formula Q) are those where the radical R6 is a carbonyi-phenylalanylamide residue, in particular the compound phenylmethyl [ (1S,2S)-1- [ [ [ (3R)-3- [ [ [ (lS)-2-amkto-2-oxo-l- (phenyhnettiyl) ethyl] amino] carbonyl] 2,3,4,9-tetrahydro-lH-carbazol-3-y]amino] carbonyt]-2-methyl-butyl]carbamate (66), is a carbonyl isoleucylamide residue, in particular the compound phenylmethyl [ (1$,2S) -1-[[[ (3R)-3- [ [ [ (1S)-1- (ammGca&ooyl)-2-methylmethy[(1s,2s)-1-[[[(3R)-3-[[[(1S)-1- yl]amnio]carbony1]-2-methyl-bulyl] carbamate (64), is a carbonyl vaiyl-4- aminobenzamide residue, in particular the compound phenylmethyl [ (1S,2S)-1- [ [ [ (1S) -l-[ [ [ (3R)-3« [ [ [ (1S)-1- [ [ [ 4-(ammocarbonyl)phenyl]amino] carbonyl3-2-memyl- propyl]amino]carbonyl]-2,3,4,9-tetrahydro- lH-carbazol-3 -yi]amino]carbonyl j -2- methylbutyl]carbamate (45). is a carbonyl valyl-N-methylamide residue, in particular the compound phenylmethyl [(lS,2S)-2-methyi-l-[ [ [ (3R)- 2,3,4,9-tetrahydro-3- [ [ [ (1S)- 2-methyi-l-[ (methylamino)-carbonyl]propyl]amino]carbonyl]-lH-carbazol-3-yl] amino] carbonyl]butyl]carbamate (222a), is a methyloxymetbyl-4-pyridyl radical, in particular the compound 2, 3, 4, 9-tetrabydro-3-(3-phenylpropyl)-0- (4-pyridinylmethyl)-lH- carbazole-3-methanol (287), is a carboxyl radical, in particular me compound 2,3,4,9- tetrahydro-3-(3-phenylpropyl)-lH-carba2ole-3- carboxylic acid (273), or is an ethyl propenoate radical, in particular the compound ethyl 3-[2,3,4,9-tetrahydro-3-(3- phenylpropyl)-lH-carbazol-3-yl]-2-propenoate (289). Likewise particularly preferred are compounds of the general formula (I) in which the radical R6 is a carbonylvalylamide residue, in particular the compound phenylmethyl [(lS,2S)-l-[ [ [ (3R)-[ [ [ (1S)-1- (aminocarbonyl)-2-methylpropyl]amino]carbonyl [(1s,2s)-1-[[[(3R)-[[[(1S)-1- yl]amino]carbonyl]-2-methylbutyl]carbamate (58), is a carbonylmrenolylamide residue, in particular the compound phenylmethyl [ (1S,2S)-1- [ [ [ (3R)-3- [ [ [ (1S,2R)-1- (aminocarbonyl)-2-hydroxypropyl]amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3- yl]amino3carbonyl]-2-memylbutyl]carbamate, - 15 - is a cyclic carboxamide residue (such as, for example, a carbonylprolylamide radical, in particular the compound phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[(2S)-2- (aminocarbony1)-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetra- hydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate (181a), or a carbonyloctahydroindolyl-2-carboxamide residue, in particular the compound phenylmethyl [(1S,2S)-1- [ [ [ (3R)-3-[ [ (.2S) -2- (aminocarbonyl)octahydrc-lH-indol-l- yl]carbonyl]-2,3,4,9-tetrahydro-lH-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate (190a)), is a 4-carboxamidophenylcarboxamide residue, in particular the compound phenylmethyl [(1S,2S)-1- [t[(3R)-3-[[[4-(aminocarbony1)phenyl]amino]carbonyl] - 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate (62), is a methylaminomethyl-2-pyridyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N- (2-pyridinylmethyl)-lH-carbazole-3-methanamine (279), is a carbonylvalinol residue, in particular the compounds phenylmethyl [(IS,2S)-1-[[[(3S)-3-[[[(1S)-1- (hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl- butyl] carbamate (267b) and 2,3,4, 9-tetrahydro-AT- [ (1S) -1- (hydroxymethyl) -2- methylpropyl] -3- (3-phenylpropyl) -lff-carbazole-3- carboxamide (276) - or is a methylvalinol residue, in particular the compound (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3- phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-1-butanol (284) . Preferred novel tetrahydrocarbazole derivatives of the invention of general formula (I) are also compounds in which R7 is a hydrophobic radical comprising alkyl, aryl and/or hetaryl structures. Particular preference is given in this connection to compounds of the general formula (I) in which the radical R is a 2,3-biphenyl- propionylamino radical, in particular the compound N-[ [ (3R)-2,3,4,9-tetrahydro-3-[ (l-oxo-2,3-diphenyl-propy)amino)-lH-carbazol-S-yl ] carbonyl]-L-valyl-L-aspartamide (18), is an indanoylamino radical, in particular the compound (3R)-N-[(lS)-l-(aminocarbonyl)-2-melhylpropyI]-3- [[(2,3-dihydro-lH- inden-1-yl)carbonyl]amino]-2,3,4,9.-tetrahydro-lH-carbazole-3-carboxaniide (162a). is an indolylacetylamino radical, in particular the compound (3S)-N- { (1S)-1- (aminocarbonyl)-2-methyl-propyl]-2,3,4,9tetrabydro-3-[ (lH-indol-3-ylacetyl)-amino] - lH-carbazole-3-carboxamide (164b), is a 2-naphthyIacetylamino radical, in particular the compound (3S)-N-[(lS)-l-(aminocari)onyl)-2-methyl-propy0-2,3,4>9-tetrahydro-3-[2- naphtiialinylacetyl)-amino]-lH-carbazole-3-carboxaniide (161b) or is a 3- propionyiamino radical. A former preferred compound is N-[ [ (3R)-2,3,4,9-tetrahydro-3-[ [ (2S,3S)-3-memyl-l- oxo-2-[(l-oxo-3-penylpropyl)atnino]pentyl]-amino]-lH-carbazol-3y1]carbonyl]-L-valyl- L-aspartamide (22). Likewise particularly preferred are compounds of (be general formula (I) in which R7 is a phenylmethylcarboxamide residue substituted on the aromatic system, in particular the compounds (3R)-N-[(lS)-l-(amino-carbonyl)-2- memylpropyl]-2,3,4,9-tetrahydro-3-[ [ (4-methylphenyl) acetyl] amino] -lH-carbazole-3- carboxamide(165a), N-[(lS)-l-aminocarboityl)-2-meurylpro\|l]-2>3,4>9-tetrahydro-3-[ [ (4-methoxyphenyl)- acetyl]amino]-lH-carbazole-3-carboxamide (175), (3R)-N-[ (lS)-l-(aminocarbonyl)-2-methylpropyl]-3-[ [ (3-bromophenyl) acetyl]amino]- 2>3>4,9-tetrahydro-lH-carbazole-3-carboxamide(96), (3R)-N-[(lS)-l-ammocarbonyl)-2-methylpropyl]-3-[[(4-fluorophenyl)acetyl]amino]- 2,3,4,9tetrahyhydro-lH-carbazole-3-carboxamide9l), (3R)-N-[(lS)-l-(aminocarbom?l)-2-methyllpropyl]-3-[[(4-chlorophenyl)acetyl]amino]- 2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide(167a), is a phenylhexylamine residue, in particular the compound (3R)-N-[(1S)-1-(aminocarbonyl)-2-methy1- propyl]-2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-1H- carbazole-3-carboxamide (234a) or is a .phenylpropyl radical, in particular the compounds 6, 8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl- propyl)-lH-carbazole-3-carboxylic acid (275) and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazole-3-carboxylate (272). Also preferred are those novel compounds of the invention of the general formula (I) which are in the R configuration at the carbon atom substituted by the radicals R6 and R7 when the radicals R6 and R7 together form an alpha-amino carboxylic acid structural element. Most preferred for the purposes of the present invention are the compounds phenylmethyl [(1S,2S)-1- [[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]- amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-lH- carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (184a), phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(1S)-1- (hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl- butyl] carbamate (267a), (2S)-l-[[(3R)-3-[[(4-chloro- phenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy-lH- carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a) and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)- N- (2-pyridinylmethyl)-lH-carbazole-3-methanamine (283) . Further representatives of novel compounds of the invention of the general formula (I), including their preparation, are indicated in the examples. The novel tetrahydrocarbazole derivatives (I) of the invention, as defined above, are ligands of GPCR and can be employed in particular for the inhibition, i.e. as antagonists, of gonadotropin-releasing hormone for example for male fertility control, fox' hormone therapy, for the treatment of female sub- or infertility, for female contraception and for tumor control. In male fertility control, the compounds of the invention bring about a reduction in spermatogenesis. Combined administration with androgens, e.g. testosterbne or testosterone derivatives such as, for example, testosterone esters, is preferred. The testosterone derivatives can in this case be administered for example by injection, e.g. by intra- muscular depot injection. The compounds (I) of the invention can also be employed where appropriate in combination with other hormones, e.g. estrogens or/and progestins, in hormone therapy, for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids. Combinations of the GnRH antagonists of the invention and tissue-selective partial estrogen agonists such as Raloxifen are particularly preferred. In addition, the compounds of the invention can be employed in hormones replacement therapy. The compounds (I) of the invention can moreover be employed to increase female fertility, for example by inducing ovulation, and for the treatment of sterility. On the other hand, the novel compounds (I) of the invention are also suitable for contraception in women. Thus, the GnRH antagonist of the invention can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very small estrogen dosages. On days 16 to 21 of the cycle of intake, progestagen is added to the estrogen/GnRH antagonist combination. The GnRH antagonist of the invention can be administered continuously throughout the cycle. It is possible in this way to reduce the hormone dosages and thus achieve a reduction in the side effects of nonphysiological hormone levels. It. is additionally possible to achieve advantageous effects in women suffering from polycystic ovary syndrome and androgen-dependent disorders such as acne, seborrhea and hirsutism. An improved control of the cycle by - comparison with previous administration methods is also to be expected. Further indications are benign prostate hyperplasia, gonadal protection during chemotherapy, controlled ovary stimulation/assisted reproduction techniques, infantile development disorders, e.g. precocious puberty and polycystic ovaries. Finally, the compounds (I) of the invention, as defined above, can also be employed for the treatment of hormone-dependent neoplastic diseases such as premenopausal cancer, prostate cancer, ovarian cancer and endometrial cancer, by suppressing endogenous sex steroid hormones. The novel compounds (I) of the invention, as defined above, are, as GPCR ligands, m particular GnRH antagonists, suitable for the treatment of the pathological states detailed above for administration to mammals, in particular humans, but also for veterinary medical purposes, e.g.. in pets and productive livestock, but also in wild animals. Administration is possible in a known manner, for example orally or non-orally, in particular topically, rectally, intravaginally, nasally or by injection or implantation. Oral administration is preferred. The novel compounds (I) of the invention are converted into a form capable of administration and, where appropriate, mixed with pharmaceutically acceptable carriers or diluents. Suitable excipients and carriers are described for example in Ullman's Encyclopedia of Technical Chemistry, Vol. 4 (1953), 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v. Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie und angrenzende Gebiete" , Pharm. Ind. 2, 1961, 72ff; Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe filr Pharmazie, Kosmetik und angrenzende Gebiete", Cantor KG, Aulendorf in Wiirttemberg, 1971. Oral administration can take place for example in solid form as tablet, capsule, gel capsule, coated tablet, granulation or powder, but also in the form of a drinkable solution. For oral administration, the novel compounds of the invention of the general formula (I), as defined above, can be combined with known and conventionally used, physiologically tolerated excipients and carriers such as, for example, gum arabic, talc, starch, sugars such as, for example, mannitol, methylcellulose, lactose, gelatin, surface- active agents, magnesium stearate, cyclodextrins, aqueous or nonaqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors (e.g. essential oils). The compounds of the invention can also be dispersed in a microparticulate, e.g. nano- particulate, composition. Non-oral administration can take place for example by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by means of implants or by ointments, creams or suppositories. Administration as extended-release form is also possible where appropriate. Implants may contain inert materials, e.g. biodegradable polymers or synthetic silicones such as, for example, silicone rubber. Intravaginal administration is possible for example by means of pessaries. Intrauterine administration is possible for example by means of diaphragms, etc. In addition, transdermal administration, in particular by means of a formulation suitable for this purpose and/or suitable means such as, for example, patches, is also provided. As already explained above, the novel compounds (I) of the invention can also be combined with other active pharmaceutical ingredients. During a combination therapy, the individual active ingredients can be administered simultaneously or separately, in particular either by the same route (e.g. orally) or by separate routes (e.g. orally and as injection). They may be present and administered in identical or different amounts in a unit dose. It is also possible to apply a particular dosage regimen where this appears expedient. It is also possible in this way to combine a plurality of the novel compounds (I) of the invention together. The dosage may vary within a wide range depending on the nature of the indication, the severity of the disorder, the mode of administration, the age, sex, body weight and sensitivity of the subject to be treated. It is within the abilities of a skilled worker to determine a "pharmacologically effective amount" of the combined pharmaceutical composition. Unit doses of from 1 μg to 100 μg, particularly preferably from 1 fig to 10 mg and most preferably from 1 μg to 1 mg, per kg of body weight of the subject to be treated are preferred. Administration can take place in a single dose or a plurality of separate dosages. In a further aspect of the present. invention, accordingly, the present invention also encompasses pharmaceutical compositions as described above, comprising at least one of the novel compounds (I) of the invention, as defined above, and where appropriate pharmaceutically acceptable carriers and/02: excipients. Preferred and particularly preferred pharmaceutical compositions are those comprising at; least one of the aforementioned preferred or particularly preferred novel compounds (I) of the invention, in particular the compounds mentioned by name above. In pharmaceutical compositions according to the present invention it is possible, besides the at least, one compound of the general formula (I), as defined above, for other active pharmaceutical ingredients also to be present, as already described in detail above. At least - one of the novel compounds (I) of the invention, as defined above, is present in the pharmaceutical compositions of the invention in one of the unit doses mentioned above as preferred, particularly preferred or most preferred, specifically and preferably in an administration form which makes oral administration possible. In addition, in a further aspect, the present invention provides compounds of the general formula (I) as defined above for use as pharmaceutical remedy. Preferred tetrahydrocarbazole compound of the invention of the general formula (I) , as defined above, for use as pharmaceutical remedy are in turn those compounds mentioned above as preferred and particularly preferred compounds, in particular the preferred compounds of the invention mentioned by name, and the compounds mentioned in the examples. Concerning pharmaceutical compositions comprising compounds (I) of the invention, and concerning compounds (I) of the invention for use as pharmaceutical remedy, reference may be made in relation to the possibilities for use and administration to what has already been said concerning the novel compounds (I) of the invention, as defined above. In another aspect, the present invention also provides the use of at least one tetrahydrocarbazole derivative of the invention of the general formula (I), as defined above, with - as defined at the outset - the tetra- hydrocarbazoles disclosed in the publications by Millet et al. and Maki et al. being excluded from the meaning of the general formula (I), for producing a pharmaceutical remedy for the treatment of GPCR- mediated diseases, in particular for inhibition of gonadotropin-releasing hormone (GnRH). In addition, the present invention provides in a further aspect the use of at least one compound of the invention of the general formula (I) as defined above, but including the compounds previously excluded by name from the. publications of Millet et al. and Maki et al. , namely 3-aminp-l,2,3,4-tetrahydrocarbazole~3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3- carboxylic acid, 3-amino-6-benzyloxy-l,2,3,4-tetra- hydrocarbazole-3-carboxylic acid, 3-acetamido-l,2 , 3 , 4- tetrahydrocarbazole-3-carboxylic acid, methyl 3- acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3- carboxylate and 3-tert-butoxycarbonylamino-l,2,3,4- tetrahydrocarbazole-3-carboxylic acid, for producing a pharmaceutical remedy for inhibiting GnRH, preferably for male fertility control, for hormone therapy, for the treatment of female sub- and infertility, for female contraception and for tumor control. Stated more clearly, the term "a compound of the general formula (I) as defined above, but including the compounds excluded above by name" means a compound of the general formula (I) in which the radical R1 is a hydrogen atom, a C2 - C6 alkenyl or a C1 - C6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR11, where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms, and the radical R11 is a hydrogen atom, a C1 - C15 alkyl, a C1 - C12 aralkyl, an aryl, hetaryl radical or the group -COCH3 and may optionally be substituted by one substituent selected from the group consisting of -CONH2, -COCH3, -COOCH3, -SO2CH3 and aryl radicals; the radicals R2, R3, R4 and R5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1 - C6 alkyl, a C1 - C6 alkenyl, a C1 - C6 alkoxy, a C1 - C12 aralkyl, an aryl or hetaryl radical; the radical R6 is the group -CONR8R9, -COOR8,. -CH2NR8R9, -CH2R8, -CH2OR8 or a Ci - C;L2 alkenyl radical which is optionally substituted by the radicals R8 and R9, where the radicals R8 and R9 are each independently of one another a hydrogen atom, a Ci - C12 alkyl, a Ci - C12 -aralkyl, a Ci - C12 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONHR10, -COOR10, -NH-C (=NH) -NH2 and halogen atoms, where the radical R1D is a hydrogen atom, a Ci - C12 alkyl, a Ci - Ci2 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R11)2, or where the radicals R8 and R9 may together form a cyclic structure which consists however exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; the radical R7 is a hydrogen atom, a C1 - C12 alkyl, a C1 - C12 alkenyl, aC1 - C12 aralkyl, an aryl or hetaryl radical, the group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR14 or -NHS02R14 and may optionally be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONH2, -COOH and halogen atoms, the radicals R12 and R13 are each independently of one another a hydrogen atom,, a C2 - C6 alkenyl or a CS - Ci2 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms, and the radical R14 is a hydrogen atom, a C1 - C12 alkyl, a C1 - C12 alkenyl, a C1 - C12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of -N02, -CH3, -OR11, -CF3, -OCF3, -OH, -N(RU)2, -OCOR11, -COOH, -CONH2, -NHCONHR11, -NHCOOR11 and halogen atoms; and the radicals Ra, Rb, Rc, Rd, Re and Rf are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1 - C6 alkyl, a C1 - C6 alkoxy, an aryl or hetaryl radical. The indications already mentioned in connection with the novel compounds of the invention of the general formula (I), as defined above (i.e. excluding the compound disclosed in the publications of Maki et al . and Millet et al. and mentioned above by name) have already been given above in relation to the novel compounds (I) of the invention. The compounds which are preferred and particularly preferred in the use of the compounds just defined for producing a pharmaceutical remedy for inhibiting GnRH are identical to the preferred and particularly preferred compounds already mentioned above in connection with the novel compounds of the invention of the general formula (I) , as defined above. The "present invention provides in a further aspect the use of a compound (I) of the invention as defined abbve, but likewise including the compounds excluded by name at the outset, for male fertility control or for female contraception. Preferred and particularly preferred compounds of the invention for this use are those compounds already mentioned at the outset as preferred or particularly preferred compounds of the invention of general formula (I) as defined above. In addition, the present invention provides a method for male fertility control or for female contraception, comprising the administration of an amount, effective for male fertility control or for female contraception, of a compound of the invention as defined in the immediately preceding paragraph, to a subject, preferably a mammal, particularly preferably a human. In another aspect, the present invention relates to a method for the treatment of pathological states mediated by GPCR. The method comprises the administration of at least one compound (I) of the invention, as defined above, to a mammal, in particular a human, when such a treatment is necessary. The administration normally takes place in a pharmaceutically effective amount. As already explained above in relation to the novel compounds (I) of the invention and the pharmaceutical compositions of the invention, it is the task of the expert knowledge of a skilled worker to determine a pharmaceutically effective amount, depending on the specific requirements of the individual case. However, the compounds (I) of the invention are preferably administered in a unit dose of from 1 μg to 100 mg, particularly preferably from 1 μq to 10 mg and most preferably from 1 μg to 1 μg per body weight of subject to be treated. The preferred administration form is oral administration. The administration of one or more of the compounds (I) of the invention in combination with at least one further active ingredient, as already explained above, is also provided. In addition, the present invention also relates to a method for inhibiting. GnRH in a patient, comprising administration of a pharmaceutically effective amount of a compound of the general formula (I) , as defined above, but including compounds excluded by name above, to a patient requiring such a treatment. The method is preferably used in male fertility control, hormone therapy, female contraception, treatment of female sub- or infertility and tumor control. Finally, the present invention provides in a last aspect also a method for the production of the novel tetrahydrocarbazole derivatives of the invention of the general formula (I). The method for the preparation of the compounds of the invention of the general formula (I) can be carried out in various ways, e.g. in liquid phase or as partial or complete solid-phase synthesis. The choice of the suitable synthesis conditions for preparing individual representatives of compounds of the general formula (I) can be made by a skilled worker on the basis of his common general knowledge. One method of the invention for the preparation of compounds of the invention of the general formula (I) is firstly described generally below. A specific variant of the method, namely a solid-phase method, is then described. For further illustration of the present invention, the examples listed thereafter include numerous representatives of compounds of the general formula (I). One method for the preparation of the compounds of the invention of the general formula (I) is preferably carried out in the following way: The central tetrahydrocarbazole structure can be obtained by a Fischer- indole synthesis known per se. For this purpose, a suitably substituted cyclohexanone derivative provided where appropriate with protective groups is condensed with the phenylhydrazine derivative -which is desired in each case and is likewise suitably substituted and provided where appropriate with protective groups, (e.g. as described by Britten & Lockwood, J.C.S. Perkin I 1974, 1824 or as described by Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In particular, the cyclohexanone structure is substituted in positions 3,3', 5,5' and 6,6' via the radicals Ra to Rf, and in positions 4,4' via the radicals, or where appropriate by precursors of the radicals, R6 and R7. The phenylhydrazine structure is optionally substituted by the radicals R2 to R5. Phenylhydrazine derivatives which are not commercially available can be prepared by methods known to the skilled worker. Positional isomers which result where appropriate in the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chromatographic methods such as, for example, HPLC. After the synthesis of the central tetrahydrocarbazole structure, the radical R1 can be introduced by N-alkylation of the nitrogen atom in position 9 with appropriate R1halides with use of base (e.g. as described by Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or else as described by Mooradian et al . , J. Med. Chem. 1970, 13, 327). The radicals R6 and R7 can, as already indicated above, be introduced in various ways depending on their nature, which is explained in detail below. a-Aminocarboxylic acid structures in these radicals can be obtained by treating ketones with NH4(CO)3 and KCN under Schotten-Baumann conditions known per se, and subsequent alkaline hydrolysis of the hydantoin which is formed (Britten & Lockwood, J.C.S. Perkin I 1974, 1824) . Amide residues are preferably generated using methods known per se from peptide chemistry. For this purpose, the acid component is activated with an activating reagent such as DCC or. else HATU (Tetrahedron Lett. 1994, 35, 2279) and condensed in the presence of a base such as DIPEA and/or DMAP with the amino component. Ester residues can also be obtained by using the desired alcohols under analogous conditions. The solvent used in this case is preferably anhydrous. Secondary or tertiary amide residues are obtained from primary amines either by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes/ ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synth. Conrm. 1994, 609) . Sulfonamide residues are obtained from the corresponding amides by reaction with sulfonyl chlorides. Urea residues are obtained by reacting the amines with appropriate isocyanates. Urethane residues can be prepared by preactivacing the appropriate alcohols with carbonyldihydroxybenzo- triazole ((HOBt)2CO) and subsequently reacted with amines (Warass et al., LIPS 1998, 5, 125). Alcohols can be obtained from carboxylic es:ers by reduction with LiAlH4. Aldehyde residues are obtained from alcohol precursors by oxidation for example under Swern conditions known per se with DMSO/oxalyl chloride (Pansavath et al.. Synthesis 1998, 436). Substituted amine residues are obtained by reductive amination of amines with aldehydes (J. Org. Chem. 1996, 61, 3489). Ether residues can be obtained by deprotonating the alcohol precursor with a base such as NaH under Williams conditions known per se and subsequently reacting with an alkyl halide. Double bonds in the radicals can be introduced by reacting an aldehyde or ketone precursor with appropriate phosphonylides under Wittig conditions known per se. A solid-phase method for the preparation or compounds of the invention of formula (I) preferably includes steps (a) to (d) explained in detail below: Step (a) proceeds essentially in analogy to a Fischer indole synthesis, e.g. as described by Britten & Lockwood, J.C.S. Perkin I 1974, 1824; Mak i et. al., Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869 and comprises the condensation of a cyclohexanone derivative {'.'.) which contains the group G and is tethered to a solid phase SP via a linker L suitable tor f o: :v.: ncj the radical Rb where, in the case where the radical R7 is a hydrogen atom, a alkyl, a C1 - C12 aralkyl or a hetaryl radical, the group G is equal to the radical R7, and in the case where the radical R7 has another one of the meanings indicated for R7 in formula (I), the group G is equal to a group -NH-Pg, where Pg is a protective group, with a phenylhydrazine derivative (III) substituted by R2 to R5 On) in the presence of an acid, preferably acetic acid, and of a metal salt, preferably ZnCl2. DMF is preferred as solvent. The radicals Ra to Rf are defined as indicated above in formula (I). Certain substituents or groups may, where appropriate, also be present in protected form, in which case the protective groups are removed again by methods known per se at a suitable time during the synthesis. Particularly suitable solid phase SP for the purposes of the present invention are Rink amide-resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard et al. , Int. J. Peptide Protein Res. 1982, 20, 451), Wang resins (Lu et al. , J. Org. Chem. 1981, 46, 3433) or chlorotrityl-resins (Barlos et al . , Int. J. Peptide Protein Res. 1991, 38, 562), where the cyclohexanone derivative (II) is to be tethered to the solid phase SP by means of an (amino) carboxylic acid. Alcohol precursors of the cyclohexanone derivative (II) can be tethered by using the DHP linker (Liu & Elman, J. Org. Chem. 1995, 60, 7712). Traceless tethering of aromatic precursors of the cyclohexanone derivative (II) to triazine resins is possible (Brase et al. , Angew. Chem. Int. Ed. 1998, 37, 3413). The protective group Pg which is included where appropriate in the group G and protects an a-amino group -NH2 is preferably a "Fmoc" (9- fluorenylmethoxycarbonyl) protective group, but may also be another customary amino protective group, e.g. from the series of the alkoxycarbonyl protective groups (such as, for example the "Z" (benzyloxycarbonyl) or the "Boc" (tert-butoxycarbonyl) group) or another suitable protective group, e.g. a "trityl" (triphenylmethyl) protective group. The constitution of the linker L is such that appropriate derivatization (steps (b) and (c)) and workup (step (d)) result in the desired radical R6 with one of the meanings indicated above for R6 in the final product, the tetrahydrocarbazole derivative of the general formula (I). To illustrate the constitution of the linker L, this may be explained below by way of example for the case where R6 equals the group -CONR8R9. In the case where the radical Rb in the product of the invention of the formula (I) has the meaning -CONR8R9, firstly a compound Pg-N(R8) -R9'-COOH forming the linker L is tethered by means of an activating reagent such as DCC (dicyclohexylcarbodiimide) or HATU (0-(7- azabenzotriazol-1-yl) -N,N-N' , N' -tetramethyluronium hexafluorophosphate) to the solid phase SP via free amino groups of the SP, where Pg and SP have the meaning indicated above, and R9' forms part of the later radical R9. The protective group Pg is subsequently eliminated, e.g. in the case of a Fmoc protective group by means of piperidine/DMF. This results in a compound HR8N-R9'-CONH-SP. The latter compound is then in turn reacted with a precursor of the cyclohexanone derivative (II), namely the cyclohexanone carboxylic acid (II') using an activating reagent such as DCC or HATU, finally resulting in the cyclohexanone derivative (II) as defined above. The meaning of the linker L in the case just described is -CONR8-R9'-CONH-SP. Any resulting isomers of whatever type (enantiomers, diastereomers or positional isomers) can be fractionated - as also elsewhere during the described preparation process - in a known manner by means of HPLC. The actual step (a), i.e. the condensation of the cyclohexanone derivative (II) with the substituted phenylhydrazine derivative (III) and, where appropriate, elimination of the protective group Pg in the group G by means of, for example, piperidine (in the case of a Fmoc protective group) then takes place, so that a free a-amino group is produced again at this point. In the case where the radical R7 is bhe group -NHCOR14, -NHS02R14, -NR12R13 (where R12 and R:3 are not both hydrogen atoms), -NHCONHR14 or -NHCOOR14, a derivatization of the now unprotected a-amino group of the resin-bound cyclohexanone derivative (II) finally takes place in step (b) , so that the various alternative radicals R' defined above can be performed. Depending on the nature of the desired radical R7 in the tetrahydrocarbozole final product (I) of the invention, the procedure for this is as follows: In the case where R7 is the group -NHCOR14, the reaction product from step (a) is reacted with a carboxylic acid R14COOH in the presence of an activating reagent such as, for example, DCC or HATU and in the presence of a base such as, for example, DIPEA (diisopropyl- ethylamine) or DMAP (4-dimethylaminopyridine) by known processes' for forming peptide linkages (cf., for example, Tetrahedron Lett. 1994, 35, 22 7 9; alternative (i))- In the case where R7 is a sulfonamide group -NHS02R14, the reaction product from step (a) is reacted with a sulfonic acid derivative R14So2X, where X is a leaving group, preferably a halogen atom, in particular a chlorine atom, in the presence of a base such as, for example, DMAP or DIPEA (cf., for example, Gennari et al., EJOC 1998, 2437; alternative (ii)). In the case where R7 is the group -NR12R13 (where R12 and R13 are not both hydrogen atoms) , in the case where the radical R12 is a hydrogen atom, the reaction product from step (a) is reacted with a reagent R13X, where X is a leaving group such as, for example, a halide atom, in particular a chloride atom, in the presence of a base such as, for example, DBU or DIPEA (cf. Green, JOC 1995, 60, 4287 or JOC 1996, 61, 3849) or with an aldehyde R13CH0 in the presence of a reducing agent such as, for example, NaH/B(OAc)3. In the case where neither of the radicals R12 and R13 is a hydrogen atom, the reaction product from step (a) is a reacted with a ketone R12COR13 in the presence of a reducing agent (cf. Ellmann et al. , JOC 1997, 62, 1240 or Synth. Commun. 1994, 609; alternative (iii)) . In the; case where both radicals R12 and R13 in R7 equals -NR12R13 are hydrogen atoms, alternative (vi) below applies. In the case where R7 is the group -NHCONHR14 (a urea derivative), the reaction product from step (a) is reacted with an isocyanate R14NCO (cf. Brown et al. , JACS 1997, 119, 3288; alternative (iv)). In the case where R7 is a carbamate or urethane group -NHCOOR14, the reaction product from step (a) is reacted with an alcohol HOR14 which has been preactivated by carbonyldihydroxybenzotriazole ((H0Bt)2C0) (cf. Warass et al., LIPS 1998, 5, 125; alternative (v)). In the case where R7 is a hydrogen atom, a C1 - C12 alkyl, C1 - C12 aralkyl, an aryl, a hetaryl radical or the group -NH2 (i.e. both radicals R12 and R13 in R7 equals -NR12R13 are hydrogen atoms) , step (b) is omitted because no further derivatization is necessary (alternative (vi)). Step (c) , i.e. the derivatization on the indole nitrogen atom, also corresponds, in analogy to step (b) explained above, to various alternatives which are explained in detail below: For cases (i) to (v) defined above in step (b) , a deprotonation of the reaction product obtained in (b) takes place by means of a base such as, for example, NaH or NaHMDS and subsequent derivatization by means of a group R:X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom (cf. Collini & Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et al., J. Med. Chem. 1970, 13, 327). For case (vi) defined above in step (b), i.e. when step (b) is omitted, in analogy to the above description a deprotonation of the reaction product obtained in (a) takes place by means of a base such as, for example NaH or NaHMDS and subsequent derivatization by means of a group R1X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom. Step (d) finally substantially includes the elimination 5 of the reaction product obtained in (c) from the solid phase SP. In the case of Wang, trityl, DHP and Rink amide resins, elimination of the reaction product obtained in (c) takes place with the aid of an acid, in particular with TFA (trifluoroacetic acid). In the case ) of an aminolytic elimination from an HMB resin, the eliminating reagent used is, for example, ammonia in methanol. The desired product is then isolated in a conventional way. i Exemplary embodiments of the preparation of tetrahydrocarbazole derivatives of the invention are detailed below. Examples i I. General synthetic methods for compounds of the invention A Coupling of carboxylic acids to the Rink amide- resin : 0.1 mmol of Fmoc-protected Rink amide-resin (166 mg, loading 0.6 mmol/g) are preswollen with 1.5 ml of DMF in a vessel with bottom frit for 20 min. After aspiration, 1.5 ml of 20% piperidine/DMF are added and stirred for 5 min. After aspiration, a further 1.5 ml of 20% piperidine/DMF are added and stirred for 15 min. Aspiration is followed by washing four times with DMF. Then 675 μa.1 of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 67 5 ul of HATU solution (0.267 M in DMF) and 150 ul of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added and stirred at 40°C for 4 h. After aspiration, the same reagents are again added and stirred at 40°C for 4 h. This is followed by aspiration and washing four times with DMF. B Coupling of carboxylic acids to the trityl-resin: 2.98 inmol of Fmoc protected aminocarboxylic acid are dissolved in 3 0 ml of dry dichloromethane, mixed with 14.3 mmol (2.45 ml) of DIPEA and added to 2.98 mmol of 2-chlorotrityl chloride-resin (2 g, loading 1.49 mmol/g of resin). After shaking for two hours, the resin is filtered off with suction through a frit and washed three times with 20 ml of dichloromethane/MeOH/DIPEA 17:2:1. This is followed by washing three times with 20 ml of dichloromethane, three times with methanol and three times with 2 0 ml of ether and drying in vacuo. A resin with a loading of 0.5 to 1 mmol of amino carboxylic acid per g of resin is obtained. C Coupling of carboxylic acids to the HMB-resin: 21.3 mmol of amino carboxylic acid and 21.3 mmol of HATU are dissolved in 60 ml of DMF and mixed with 63.9 mmol (10.9 ml) of DIPEA. After 5 minutes, 5 g of polystyrene-HMB-resm (loading 0.71 mmol/g of resin) are added and shaken at RT for 5 minutes. Then 21.3 mmol (2.6 g) of DMAP are added and shaken at RT for 1 h. The resin is subsequently filtered off with suction and washed once each with 100 ml of DMF, DCM and DMF. The resin is mixed with 100 ml of 10% Ac20 (acetic anhydride)/DMF/5% DMAP and shaken for 15 min. Aspiration is followed by washing three times each with 100 ml of DCM and ether and drying in vacuo. D Coupling of carboxylic acids to the Wang resin: 54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of DIC are dissolved in 500 ml of dry DCM, and stirred at RT for 10 min. After the precipitated urea has been filtered off, the solution is evaporated to dryness and the residue is dissolved in 160 ml of dry DMF. The solution is added to 4.55 mmol (5 g, loading 0.91 mmol/g of resin) of Wang resin preswollen in DMF, and 4.55 mmol (556 mg) of DMAP are added. After shaking at RT for 1.5 hours, the resin is filtered off with suction and taken up in 100 ml of 10% Ac20/DMF/5% DMAP and shaken for 15 min. Aspiration is followed by- washing three times each with 100 ml of DCM and ether and drying in vacuo. i E Coupling of an alcohol to the DHP-resin: 0.5 mmol of DHP-resin (0.5 g, loading density 1 mmol/g) are preswollen in 2 ml of dichloroethane for 15 min. To this are added 2 ml of a solution of 0.75 M i alcohol/0.37 M pyridinium paratoluenesulfonate and stirred at 80°C for 16 h. Cooling to RT is followed by addition of 5 ml of pyridine, briefly shaking with inversion and filtration with suction. Washing is carried out twice each with 5 ml of DMF, DCM and hexane. F Deprotection of a resin-bound Fmoc protective group: 1.5 ml of 20% piperidine/DMF are added to 0.1 mmol of resin-bound Fmoc group and stirred for 5 min. After aspiration, 1.5 ml of 20% piperidine/DMF are again added and stirred for 15 min. Aspiration is followed by washing four times with DMF. G Coupling of a carboxylic acid to resin-bound amino functions: 675 ul of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 675 ul of HATU solution (0.267 M in DMF) and 150 ul of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added to 0.1 mmol of resin-bound amino functions and stirred at 40°C for 4 h. After aspiration, the same reagents are added again and stirred at 40°C for 4 h. This is followed by aspiration and washing four times with DMF. H Coupling of acetic acid to resin-bound amino functions: 1.5 ml of a solution of 10% acetic anhydride in DMF are added to 0.1 mmol of resin-bound amino functions and stirred at RT for 15 min. This is followed by- aspiration and washing four times with DMF. J Synthesis of tetrahydrocarbazoles starting from resin-bound cyclohexanones: Before the reaction, .0.1 mmol of cyclohexanone-resin are washed twice with 2 ml of DMF and twice with 2 ml of acetic acid. Then 1 ml of DMF and 2 ml of 0.5 M hydrazine/0.5 M ZnCl2 in acetic acid are added to the resin and stirred at 70°C for 20 h. This is followed by aspiration and washing twice with 2 ml of acetic acid and 2 ml of DMF. J Synthesis of sulfonamides starting from resin- bound amides: The resin is washed twice with 2 ml each of DMF and DCE. 1 ml of 0.5 M sulfonyl chloride in DCE and 400 ul of 2.5 M NMM/1 eq. of 0.25 M DMAP in DMF are added to 0.1 mmol of resin-bound amine. Stirring at 60°C for 12 h is followed by aspiration and repetition of the coupling. Aspiration is followed by washing four times with 2000 ml of DMF. K Synthesis of ureas by reaction of resin-bound amine with isocyanates: 2 ml of 0.5 M isocyanate in DCM are added to 0.1 mmol of resin-bound amine and stirred at RT for 18 h. Aspiration is followed by washing four times with DMF. L Synthesis of carbamates by reaction of resin-bound amine with preactivated alcohols: For the preactivation, 0.4 M alcohol and 0.39 M dibenzotriazolyl carbonate and 0.39 M pyridine are stirred in DMF at 40°C for 15 min. 1 mmol of resin- bound amine is mixed with 1 ml of preactivated alcohol, and 167 ml of 2.4 M NMM in DMF are added. Stirring at 60°C for 4 h is followed by aspiration and washing four times with DMF. M Synthesis of N-alkylamines by N-alkylation of resin-bound amines with alkyl halides and catalytic KI: 1 ml of 0.5 M halide/0.05 M KI in DMF and 416 ul of 2.4 M DIPEA in DMF are added to 0.1 mmol of resin-bound i amine and stirred at 90°C for 12 h. After aspiration, the resin is washed four times with 2 ml of DMF. N N-alkylation of resin-bound indole nitrogens with halide/NaH in DMF: 1 ml of DMF and 0.5 mmol of NaH (55% suspension in oil) are added to 0.1 mmol of resin-bound amine. After stirring at RT for 30 min, 1 ml of 0.5 M halide in DMF are added and stirred at 45°C for 8 h. This is followed by aspiration and washing twice each with 2 ml of methanol, DMF, methanol and DMF. O Elimination from the Wang, trityl, DHP, Rink amide-resin: 2 ml of 95% TFA/5% H20 solution are added to 0.1 mmol of resin and shaken at RT for 3 h. The resin is then filtered off and washed with a further 2 ml of TFA. The combined TFA solutions are evaporated to dryness and afford the crude products. P Aminolytic elimination from the HMB-resin: 2 ml of DMF and 2 ml of 7 M NH3 in methanol are added to 0.1 mmol of resin and shaken at RT for 18 h. The resin is then filtered off and washed with DMF. The combined solutions are evaporated to dryness and afford the crude product. Preparation of required starting compounds: 3- [ [ (9H-Fluoren-9-ylmethoxy) carbonyl ]amino] -2,3,4,9- tetrahydro-lH-carbazole-3-carboxylic acid 1 38.4 mmol (6.0 g) of 4,4-ethylenedioxycyclohexanone and 3 9.8 mmol (4.3 g) of phenylhydrazine are dissolved separately in 50 ml and 10 ml, respectively, of water, and then mixed. The milky emulsion resulting after stirring for 10 min is extracted five times with ethyl acetate, dried with MgSo4 and evaporated to dryness. Yield: 9.2 g of orange oil. 9.2 g of the unpurified phenylhydrazone are dissolved in 240 ml of toluene at RT, and 4.9 g of freshly ground ZnCl2 are added. After refluxing with a water trap for 90 min, most of the toluene is distilled off, an excess of 2 N NaOH is added, and the mixture is extracted three times with ethyl acetate. The extract is washed with brine and dried with MgS04, and the solvent is distilled off. The remaining black oil is purified on silica gel with ethyl acetate/hexane 1:9. Yield: 2.7 g of beige solid. 11.6 mmol (2.7 g) of 1,2,4,9-tetrahydrospiro[3H- carbazole-3 , 2 ' - [1, 3 ] dioxolane] and 640 mg of p- toluenesulfonic acid are taken up in 70 ml of acetone and stirred at RT for 2.5 h. The solution is added to NaHCC>3 solution, extracted with ethyl acetate, washed with brine, dried with MgSo4 and concentrated. 2.13 g of red-brown solid remain. Recrystallization from ether results in 1.1 g of beige-colored solid. 60.2 mmol (11.1 g) of 1,2,4,9-tetrahydrospiro-3H- carbazol-3-one, 8.3 g of KCN and 22.0 g of (NH4)2C03 are heated in 5 50 ml of 60% ethanol in an autoclave at 80°C for 3 h. After cooling to room temperature, the reaction mixture is added to ice-water, and the precipitated solid is filtered off. Yield: 10.1 g of gray solid. 44.2 mmol (11.3 g) of 1,2,4,9-tetrahydrospiro[3H- carbazole-3,4'-imidazolidine]-2',5'-dione is heated with 62 g of Ba(0H)2 x 8 H20 in 145 ml of H20 at 150°C for 13 h. After cooling to room temperature, the viscous mass is mixed with 37 g of (NH4)?C03 with stirring and heated at 100°C for 30 min. Cooling to room temperature is followed by filtration, washing with water and evaporation of the filtrate to dryness. Yield: 7.7 g of beige solid. 26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-lH- carbazole-3-carboxylic acid in 2 6 ml of 1 N NaOH and 26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile are combined at room temperature and diluted with 130 ml of acetonitrile/H20 1:1. After two hours, the pH is readjusted to 9 with NEt3 (1.5 ml) and the mixture is stirred at room temperature overnight. Then a further 6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of acetonitrile are added, and stirring is continued for two hours while controlling the pH. Removal of the acetonitrile by distillation is followed by acidification with 0.01 M HC1 and extraction with ethyl acetate. The extract is washed until neutral, dried with Na2S04 and evaporated to dryness in a rotary evaporator. Recrystallization takes place from ether/hexane. Yield: 10.7 g. XH NMR (d6 DMSO): 5 = 2.07 ppm (m, 1H) ; 2.50 (m, 1H) ; 2.70 (bs; 2H) ; 3.04 (q, 2H) ; 4.17 (m, 2H) ; 4.28 (m, 2H); 6.92 (tr, 2H) ; 6.99 (tr, 2H); 7.23 (tr, 2H); 7.24- 7.35 (m, 3H) ; 7.38 (tr, 2H) ; 7.62 (s, 1H) ; 7.68 (dd, 2H) ; 7.87 (d, 2H) ; 10.71 (s, 1H) . Melting point: 119°C Fractionation into the two enantiomers takes place by chiral HPLC. (R) -3- [ [ (9H-Fluoren-9-ylmethoxy) carbonyl]amino] - 2,3,4,9-tetrahydro-lH-carbazole-3-carboxylic acid 1M tR = 6.4 min (Chiralcel OD 10 urn LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) (S) -3- [ [ (9H-Fluoren-9-ylmethoxy) carbonyl]amino] - 2, 3, 4, 9-tetrahydro-lH-carbazole-3-carboxylic acid 1b tR = 7.5 min (Chiralcel OD 10 um LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) 1 - [ [ (9H-Fluoren-9-ylmethoxy) carbonyl]amino] -4-oxocyclo- hexanecarboxylic acid 2 320 inmol (50 g) of 4,4-ethylenedioxycyclohexanone are suspended in 800 ml of 50% EtOH, and 1500 mmol' (144.5 g) of (NH4)2C03 and 640 mmol (41.7 g) of KCN are added. After stirring at 60°C for 5 h, the ethanol is removed in vacuo, and the aqueous residue after cooling - with ice is filtered off, washed with water and dried. Yield: 72.4 g of 4,4-1,4-dioxa-9,11-diazadi- spiro[4.2.4.2]tetradecane-10,12-dione. 295 mmol (66.8 g) of 4,4-1,4-dioxa-9,11-diazadi- spiro[4.2.4.2]tetradecane-10,12-dione and 826 mmol (260.6 g) of Ba(0H)2 x 8 H20 are stirred in 2.5 1 at 150°C in an autoclave for 6 h. After cooling to room temperature, 1032 mmol (99.2 g of (NH4)2C03 are added to the solution and stirred at 60°C for 1 h. The suspension is filtered and washed, and the filtrate is lyophilized. The residue is recrystallized from H20/MeOH. Yield: 45.4 g of 8-amino-l,4-dioxa- spiro [4,5]decane-8-carboxylic acid. 213 mmol (42.9 g) of 8-amino-l,4-dioxaspiro[4,5]decane- 8-carboxylic acid in 213 ml of 1 N NaOH and 213 mmol (71.9 g) of Fmoc-ONSu in 240 ml of acetonitrile are combined and diluted with 1000 ml of acetonitrile/H20 1:1. Adjustment of the pH to 9 is followed by stirring at room temperature overnight. Removal of the acetonitrile in a rotary evaporator is followed by acidification with 0.01 M HCl and extraction with ethyl acetate. The extract is washed until neutral, dried with Na2S04 and evaporated to dryness. The residue is recrystallized from ethyl acetate/hexane. Yield: 79.0 g of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1,4- dioxaspiro[4,5]decane-8-carboxylic acid. 187 mmol (79 g) of 8-[[ (9H-fluoren-9-ylmethoxy)- carbonyl]amino-1,4-dioxaspiro[4,5]decane-8-carboxylic acid are taken up in 3.5 1 of acetone/0.1 M HC1 1:1 and stirred at room temperature for 4 h. The acetone is stripped off in a rotary evaporator, and the precipitated product is filtered off, washed with water and dried. Yield: 68.7 g of 2. 1H NMR (d6 DMSO) : 5 = 1.52-1.73 (m, 4H) ; 1.82-2.14 (m, 4H) ; 4.27 (m, 3H) ; 7.85 (tr, 2H) ; 7.42 (tr, 2H) ; 7 ..67 (s, 1H); 7.75 (d, 2H); 7.91 (d, 2H) Melting point: 157°C 4-0xocyclohexanecarboxylic acid 3 2 0 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate are suspended in 40 ml of 2% H2SO4 and stirred at 90°C for 2 h. This is followed by extraction four times with ethyl acetate, drying with Na2So4 and removal of the solvent. Recrystallization from ether/hexane affords 2.9 g of white solid 3 lH NMR (d5 DMSO): 5 = 1.72 (m, 2H) ; 2.08-2.18 (m, 2H) ; 2.19-2.47 (m, 4H) ; 2.72 (m, 1H) ; 12.23 (bs, 1H) . 4-Chloro-3- [ [ (phenyl amino) carbonyl ] amino] benzeneacetic acid £ 18.55 mmol (2.21 g) of SOCl2 are slowly added to 18.55 mmol (4 g) of 4-chloro-3-nitrobenzeneacetic acid in 50 ml of MeOH while cooling in ice and stirring. After stirring for 30 min, the mixture is allowed to warm to RT and a further 3.71 mmol (0.44 g) of S0C12 are added. Stirring overnight is followed by heating to reflux for 30 min. Stripping off the solvent is followed by recrystallization from ether/hexane. Yield: 3.43 g of methyl 4-chloro-3-nitrobenzeneacetate as yellowish solid. 13.07 mmol (3.0 g) of methyl 4-chloro-3- nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust are heated to reflux in 500 ml of MeOH for 10 min. Then, under reflux, 13 ml of cone. HC1 are added dropwise, and refluxing is continued for 30 min. The suspension is filtered hot, the methanol is distilled off, and the residue is adjusted to pH 14 with a NaHC03 solution. Extraction with ethyl acetate, drying with Na2S04 and removal of the solvent by distillation affords 2.3 g of methyl 3-amino-4-chlorobenzeneacetate as beige solid. 2.08 mmol • (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are dissolved in 40 ml of DCM and, at 0°C, 0.83 mmol (246.3 mg) of triphosgene and 0. 6 ml of pyridine are added. After stirring at 0°C for one hour, 10.4 mmol (1.11 g) of benzylamine are added, and stirring is continued at room temperature overnight. Extraction is carried out with DCM/H2O, the organic phase is dried, and the solvent is removed. Yield: 727 mg of methyl 4-chloro-3-[[(phenylamino)- carbonyl]amino]benzeneacetate. 2.98 mmol (990 mg) of methyl 4-chloro-3- [[ (phenyl- amino) carbonyl]amino]benzeneacetate are taken up in 10 ml of methanol, and 6 mmol of 1 N NaOH are added. After stirring at RT for 2 h, the methanol is distilled off and the residue is acidified to pH 2-3 with 1 M HC1. Extraction is carried out with ethyl acetate, and drying with Na2SO Recrystallization takes place from boiling isopropanol. Yield: 830 mg of white solid £. 1H NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.92 (d, 1H) ; 6.99 (tr, 1H) ; 7.35-7.50 (m, 3H) ; 8.10 (s, 1H) ; 8.30 (s, 1H); 9.42 (s, 1H); 12.40 (bs, 1H). 4~Chloro-3-[[[(phenylmethyl)amino]carbonyl] amino]- benzeneacetic acid 5 2.08 mmol (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are mixed with 10.4 mmol (969 mg) of aniline as described under 4.) and worked up analogously. Yield: 662 mg of solid. For the ester cleavage, 2.47 mmol (790 mg) of methyl 4- chloro-3- [ [ [ (phenylmethyl) amino ]carbonyl] amino ]benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product !5 is obtained without recrystallization. Yield: 693 mg of yellowish solid. ES-MS: 3-19 (M+H+) 4-Chloro-3- [ [ (4-pyridinylamino) carbonyl]amino] benzeneacetic acid £ 2.08 mmol (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 4-aminopyridine as described under 4.) and worked up analogously. Yield: 664 mg of solid. For the ester cleavage, 2.63 mmol (840 mg) of methyl 4- chloro-3-[ [ (4-pyridinylamino)carbonyl]amino] benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product is obtained without recrystallization. Yield: 481 mg of yellowish solid. XH NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.94 (d, 1H) ; 7.40 (m, 3H) ; 8.05 (s, 1H) ; 8.35 (d, 2H) ; 8.50 (s, 1H) ; 9.92 (s, 1H); 12.40 (bs, 1H) 4-Chloro-3- [ [ (2-pyri dinylamino) carbonyl ]amino] benzeneacetic acid 7 2.08 mmol (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 2-aminopyridine as described under 4.) and worked up analogously. Yield: 617 mg of solid. For the ester cleavage, 2.47 mmol (790 mg) of methyl 4- chloro-3-[[(2- pyridinylamino)carbonyl]amino]benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 1_ is obtained without recrystallization. Yield: 693 mg of yellowish solid. 1H NMR (d6 DMSO) : b = 3.59 (s, 2H) ; 6.94 (dd, 1H) ; 7.03 (dd, 1H) ; 7.22 (d, 1H) ; 7.42 (d, 1H) ; 7.78 (dtr, 1H) ; 8.29 (m, 2H); 10.02 (s, 1H); 11.82 (bs, 1H); 12.50 (s, 1H) . XI. Examples of compounds (I) of the invention Example 1: 0.3 mmol (42.6 mg) of 4rOxocyclohexanecarboxylic acid are dissolved in 1 ml of acetic acid and added to a suspension of 0.3 mmol (43.3 g) of phenylhydrazine hydrochloride and 0.3 mmol (40.0 mg) of ZnCl2 in 1 ml of acetic acid. Stirring at 70°C for 20 h is followed by dilution with 20 ml of water and extraction with ethyl acetate. The ethyl acetate phase is washed with water, dried over Na2S04 and evaporated to dryness. Yield: 65.6 mg (100%) of white solid. Name Number Mfnd Mcdlc 2,3,4,9-Tetrahydro-lK-carbazole- 3-carboxylic acid 8 215 215.2507 The column headings (name, number of the compound, Mfnd (measured molecular mass), Mcaic (calculated molecular mass)) which are introduced here also apply to the following examples and are therefore not repeated again. Example 2: Synthesis takes place on the 0.2 mmol scale by methods A, I and O. 2,3,4,9-Tetrahydro-ltf-carbazoie- 3-carboxamide 9_ 214 2 14.2bnb Example 3: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I and O. N-[(1S)-1-(Aminocarbonyl)-2-methyl propyl]-(3S)-2,3,4,9-tetrahydro-lH- carbazole-3-carboxamide 10a 314 313.3987 N- [(1S)-1-(Aminocarbonyl)-2-methyl propyl]-(3R)-2,3,4,9-tetrahydro-ltf- carbazole-3-carboxamide 10b 314 313.3987 N-(2-Amino-2-oxoethyl)-2,3,4,9- tetrahydro-lfl-carbazole-3- carboxamide 11 271 271.3183 Example 4: Synthesis takes place on the 0.2 mmol scale by methods D, F, G, F, G, I and O. N-[(3S)-(2,3,4,9-Tetrahydro-lH- carbazol-3-yl)carbonyl]-L-valyl-L- glutamine 12a 442 442.513 N-[ (3R) -(2,3,4,9-Tetrahydro-lH- carbazol-3-yl)carbonyl]-L-valyl-L- glutamine. Isomer B 12b 442 442.513 Exampl e 5 .- Synthesis takes place on the 0.2 mmol scale by methods D, F, G, I, F and O: N-[[(3S)-3-Amino-2,3,4,9-tetrahydro- lH-carbazol-3-yl)carbonyl]-L- alanine 13_ 301 3vi . 3441 Example 6: 0.1 mmol of carboxylic acid, 0.1 mmol of MOB'. and 0.15 mmol of amine component are dissolved in i':> ml of - 49 - dry DMF (also THF, DCM) , and, while cooling in ice and stirring, 0.5 mmol of NMM is added. After about 15-min, 0.15 mmol of EDCI x HCl is added, and the mixture is stirred for one hour, warmed to room temperature and stirred .overnight.. For workup, the solvent is stripped off, and the product is dissolved in ethyl acetate and washed twice each with 0.1 N HCl and saturated NaCl solution. Drying and stripping off the solvent are followed if necessary by recrystallization. 9H-Fluoren-9-ylmethyl[(3S)-3-1[[(4- bromophenyl)methyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl] carbamate 14 620 620.5439 Methyl N- [[(3S)-3-[[(9tf-fluoren-9-yl methoxy)carbonyl]amino]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]carbonyl]- L-alaninate 15 537 537.6129 Exampl e 7: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G, F, G and O. Yield after evaporation and preparative HPLC: 65 mg of ethyl 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-ltf- carbazole-3-carboxylate 268. ES-MS: 362 (M+H+) 80 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3- phenylpropyl)-lff-carbazole-3-carboxylate 272 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 430 (M+H+) Example 36: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-ltf-carbazole-3- carboxylic acid 273 3.94 mmol (1.31 g) of 269 are stirred in 50 ml of methanol and 30 ml of 50% sodium hydroxide solution at 60°C for 4 h. The mixture is acidified with dilute HC1 and extracted with ether. Drying with Na2S04 and evaporation affords 1.02 g (85%) of white solid 8-(3- phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid 274. 65 mg of 274 are first deprotected with HC1 and then reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparative HPLC: 15 mg of 273. ES-MS: 334 (M+H+) 39 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl- propyl )-lH-carbazole-3-carboxylic acid 275 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 478 (M+H+) Example 37: 2, 3, 4, 9-Tetrahydro-N- [ (1S) -1- (hydroxymethyl) -2- methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3- carboxamide 276 0.66 mmol (200 mg) of 274 are reacted with 1.5 equivalents of valinol in analogy to Example 6. 277 mg of white solid N- [(15) -1-(hydroxymethyl)-2- methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]- decane-8-carboxamide 277 are obtained. Then 0.3 mmol (117 mg) of 277 are first deprotected with HC1 and subsequently reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparative HPLC: 15 mg of 276. ES-MS: 418 (M+H+) 25 mg of 6, 8-dichloro-2 , 3 , 4 , 9-tetrahydro-iV- [ (15) -1- (hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H- carbazole-3-carboxamide 278 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 486 (M+H+) Example 38: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-N- (2-pyridinyl- methyl)-lH-carbazole-3-methanamine 279 54 ml of a 1 M solution of LiAlH4 in dry THF are cautiously added to a solution of 18 mmol (6 g) of 270 in 250 ml of dry THF under argon at room temperature. After heating to reflux for 3 h, cautious hydrolysis is carried out with 300 ml of saturated NH4CI solution, and 250 ml of ether are; added. The aluminum salts are filtered off and washed with ether. Drying of the ether phase with Na2S04 and evaporation of the solvent afford 3.4 g of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]decane- 8-methanol 280. 5.86 mmol (1.7 g) of 280 are dissolved in 60 ml of dry DCM and 20 ml of dry DMSO. Under nitrogen at room temperature, firstly 44 mmol (6.1 ml) of TEA and - then cautiously 17.6 mmol (2.8 g) of S03-pyridine complex are added, and the mixture is stirred for one hour. Subsequently 200 ml of saturated NH4CI solution are added and extraction is carried out with 150 ml of ether. Drying of the ether, phase with Na2SC>4. and evaporation of the solvent afford 1.9 g of 8-(3- phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carbaldehyde 281 as colorless oil. 0.719 mmol of sodium triacetoxyborohydride are added to a mixture of 0.359 mmol (103 mg) of 281 and 0.359 mmol (37 ml) of 2-pyridinemethanamine in 2.5 ml of 1,2- dichloroethane. The mixture is stirred under N2 at room temperature for 3 h. Saturated NaHC03 solution is added, and the mixture is extracted with ether. The dried and evaporated ether extract affords 101 mg (76%) of white solid N-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec-8- yl]-2-pyridinemethanamine 282. Subsequently, 101 mg of 282 are first deprotected with HCl and then reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparation HPLC: 71 mg of 279. ES-MS: 410 (M+H+) 54 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl- propyl) -N- (2-pyridinylmethyl)-lH-carbazole-3- methanamine 283 are prepared analogously using 2,4- dichlorophenylhydrazine. ES-MS: 478 (M+H+) Example 39: (2S)-3-Methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenyl- propyl) -lH-carbazol-3-yl]methyl]amino]-1-butanol 284 0.368 mmol (106 mg) of 281 and 0.368 mmol (38 mg) of valinol are dissolved in 1.5 ml of dry methanol and stirred at room temperature for 30 min. After cooling to 0°C, 0.557 mmol (21 mg) of NaBH4 are added and stirred at room temperature' for 1 h. 0.437 mmol (25 ul) of acetic acid is added, and stirring is continued at pH 6 for 2 h. Saturated NaHC03 solution is added, and the mixture is extracted with ether. Drying of the organic phase with Na2SC>4 and evaporation affords 106 mg (77%) of colorless oil for 270 and 271. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 18 mg of white solid 284. ES-MS: 405 (M+H+) 17 mg of (2S)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -lff-carbazol-3-yl]methyl] amino] -3- methyl-1-butanol 286 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 473 (M+H+) Example 40: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinyl- methyl)-lH-carbazole-3-methanol 287 0.689 mmol of NaH (as 55% suspension in mineral oil) are added to a solution of 0.344 mmol (100 mg) of 280 in 10 ml of dry DMF at 0°C under an N2 atmosphere. The mixture is allowed to reach room temperature and is stirred for 30 min. 1.377 mmol of 4- (chloromethyl)pyridine are added, and the mixture is stirred at 95-100°C overnight. Cooling to room temperature is followed by hydrolysis with 2 ml of water and extraction with ether. Drying of the solvent and evaporation affords 115 mg of yellow oil 288. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 14 mg of white solid 287. ES-MS: 411 (M+H) Example 41: Ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazol-3-yl]-2-propenoate 289 0.347 mmol of 281 in 0.5 ml of THF are added dropwise to a solution of 0.378 mmol of ethyl (triphenylphosphoranylidene)acetate in 1 ml of absolute THF while cooling in ice. After the addition is complete, the mixture is allowed to warm to room temperature and is stirred for a further 2 days. It is then hydrolyzed with water and extracted with ether. Na2S04 is used for drying, phosphane oxide and desiccant are filtered off, and the solvent is removed. Yield 80% of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec- 8-yl]-2-propenoate 290. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 9 mg of white solid 289. ES-MS: 388 (M+H) In addition, the compounds of the invention Nos. 293 to 300, 302 and 304 to 306, which are covered by the general formula (I), are obtained on the 0.2 mmol scale by methods A, F, G, F, G and 0, the compound 301 by methods B, F, G, F, G and 0, and the compound 303 by methods A, F, G, F, G, F, L and 0. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 14 mg of white solid 287. ES-MS: 411 (M+H) Example 41: Ethyl 3-[2, 3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazol-3-yl]-2-propenoate 289 0.347 mmol of 281 in 0.5 ml of THF are added dropwise to a solution of 0.378 mmol of ethyl (triphenylphosphoranylidene)acetate in 1 ml of absolute THF while .cooling in ice. After the addition is complete, the mixture is allowed to warm to room temperature and is stirred for a further 2 days. It is then hydrolyzed with water and extracted with ether. Na2S04 is used for drying, phosphane oxide and desiccant are filtered off, and the solvent is removed. Yield 80% of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec - 8-yl]-2-propenoate 290. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 9 mg of white solid 289. ES-MS: 388 (M+H) In addition, the compounds of the invention Nos. 293 to 300, 302 and 304 to 306, which are covered by the general formula (I), are obtained on the 0.2 mmol scale by methods A, F, G, F, G and 0, the compound 301 by methods B, F, G, F, G and 0, and the compound 303 by methods A, F, G, F, G, F, L and 0. Ill Demonstration of the GnRH-antagon a st : ' eot of compounds (I) of the invention Materials: Buserelin is purchased from Weldincr 'T '>■'■■ ■ n, Germany) . The compound is labeled witn he chloramine T method and Na125I (4000 \ . .•. ■■ s■?-■■ ™- Buchler, Brunswick, Germany). The lai. ■ ;)C is purified by reverse phase HPLC on a n-'.^r OD: II column (250 x 4 mm, particle size 3 j.ii- ■ n ' th 50% acetonitrile/0.15% trif luoroacet: ■ ■. ': i -ow rate of 0.5 ml/min. The specific' ac / is 2000 Ci/mmol- All other chemicals are purchased from commercial source in the highest available purity. Cell culture: Alpha T3-1 cells (Bilezikjian et al., Mol. Endocrinol 5 (1991), 347-355) are cultivated in DMEM medium (Gibco- BRL, Eggenstein-Lepoldshafen, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/1) and 10% fetal calf serum (FCS; PAA Laboratories, Coelbe, Germany) on plastic tissue culture plates (Nunc, 245 x 245 x 20 mm) . CHO-3 cells (Schmid et al. , J. Biol. Chem. 275 (2000), 9193-9200) are cultivated under identical conditions apart from the use of Ham's F12 medium (Gibco-BRL). 10 confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS). The cells are harvested by scraping off with a rubber policeman into 5 ml of PBS and sedimented by centrifugation at 800 rpm for 10 min in a laboratory centrifuge (Heraeus) . The cell pellet is resuspended in 5 ml of 0.25 mol/1 sucrose/0.01 mol/1 triethanolamine, pH 7.4. The cells are lysed by three cycles of freezing in dry ice/ethanol bath and thawing at room temperature. The lysate is centrifuged at 900 rpm for 10 min, and the sediment is discarded. The supernatant is centrifuged at 18 000 rpm in a Sorvall SS34 rotor for 30 min. The pellet (cell membranes) is suspended in 5 ml of assay buffer (0.25 mol/1 sucrose, 0.01 mol/1 triethanolamine, pH 7.5, 1 mg/ml ovalbumin) in a Potter, and stored in 200 ul aliquots at -20°C. Protein is determined by the method of Bradford (Anal. Biochem. 72 (1976), 248-254). Receptor assay: Binding studies for competition plots are carried out as triplicates. A test sample contains 60 fil of cell membrane suspension (10 ug of protein for aT3-l-cells or 40 μg of protein for CH03 cells) , 20 μl of 125I labeled Buserelin (100 000 ipm per sample for competition plots and between 1500 and 200 000 ipm for saturation experiments) and 20 μl of test buffer or test compound solution. The test compounds are dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10"6 mol/1 to 5 x 10"12 mol/1) are prepared in test buffer. The nonspecific binding is determined in the presence of an excess of an unlabeled Buserelin (10~6 mol/1) . The test samples are incubated at room temperature for 30 min. Bound and free ligand are separated by filtration (Whatman GF/C filter 2.5 cm diameter) using an Amicon lOx collecting apparatus and washed twice with 5 ml of 0.02 mol/1 Tris/HCl, pH 7.4. The filters are moistened with 0.3% polyethyleneimine (Serva, Heidelberg, Germany) for 3 0 min in order to reduce the nonspecific binding. The radioactivity retained by the filters is determined in a 5-channel gamma counter (Wallac-LKB 1470 Wizard) . The IC50 values obtained for the preferred compounds, as defined above, are indicated in the table which follows. The compounds of numbers 293 to 306 are tested by the methods indicated below: Receptor binding assay Materials: "-"i-Triptorelin [125I- (D) -Trp6-GnRH] is purchased from Biotrend (Cologne, Germany). The specific activity is in each case 2.13 Ci/mmol. All other chemicals are purchased from commercial sources in the highest purity available. Cell culture: Transfected LTK' cells (ATCC No. CCL 1.3) are cultivated in DMEM medium (Invicrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 moi/i) and 10% fetal calf serum (FCS; Tnvitroqer. Lite Technologies, Germany) on plastic tissue culture platr.es (Nunc, Germany, 245 * 245 x 20 mm). Testing: 80% confluent cell culture plates ate washed twice with 50 ml of phosphate-buffered saline (PBS) and then detached with 0.01 M EDTA solution. The cells are pelleted by centrifugation at 200xg for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet is resuspended in 3 ml of binding medium (DMEM; 10 mM Hepes; 0.5% BSA; 0.1% NaN3; 1 g/1 Bacitracin (add fresh, stock 100x) ; 0.1 g/1 SBTI (add fresh, stock lOOOx) and the cell count is determined by Trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted with binding medium to a concentration of 5 > 10s cells/0.05 ml. Binding studies for competition plots are carried out as duplicates. The test substances are employed as 10 mM DMSO solutions. They are diluted to 4 times the final concentration employed with binding medium. 25 ul of the substance dilution are mixed with 25 ul of tracer solution (25I-triptorel in) . The tracer concentration is adjusted to approx. 50 000 cpm (measured in a Cobra II, y counter, PE Liefe Science, Germany) in the final reaction volume of 100 ul. 200 ul of silicone/liquid paraffin mixture (84%:16%) are introduced into 650 ul conical tubes (Roth, Germany) . 50 ul of the cell suspension are pipetted thereon, followed by 50 ul of the test substance/tracer mixture. The tubes are capped and incubated with vertical rotation in an incubator at. 37°C for 60 min. After incubation, the samples are centrifuged in a centrifuge (Kendro, Germany) at 900 rpm and subsequently shock-frozen in liquid N. . The tip with the cell pellet is cut off and transferred into prepared counting vials (Roth, Germany) . The remainder of t.he conical tube with the remaining supernatant is likewise transferred into a counting vial. '?ho measurement takes place in a y counter for 1 min/sample. Evaluation of the samples takes place after calf.:] at ion of the specific binding compared with ur.trcored cel,.r>, after subtraction of the nonspecLi.c binding (excess ot unlabeled ligand, 1 μm) by means of GraphPad Prism (GraphPad Software Inc., USA) Functional reporter gene assay Materials: All chemicals are purchased from commercial sources in the highest purity available. Cell culture: Stably transfected LTK cells (ATCC No. CCL-1.3) which harbor the GnRH receptor and have heterologous expression of cAMP-responsive elements and a CMV minimal promoter-driven luciferase reporter gene are employed to carry out functional investigations. The cells are cultivated in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/1) and 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany) on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm). Testing: 80% confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS) and then detached with trypsin EDTA solution (Invitrogen Life Technologies, Germany). The cells are pelleted by centrifugation at 200xg for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet is resuspended in 3 ml of assay medium (Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/1) and 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany), and the cell count is determined by Trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted to a concentration of lxlO4 cells/100 ul with assay medium. The cells are set out on white ' 96-well microtiter plates (Costar, Germany) and incubated in an incubator for 18 h. To carry out the test, test substances are diluted as 10 mM DMSO solutions ' in assay medium to 6 times the final concentration employed. 2 5 ul of the test substance are added to 100 ul of cells and incubated at 37°C, 5% C02 for 60 min. Triptorelin (D-Trp6~GnRH)/Rolipram solution (6 nM/6 uM) is then added, followed by incubation again at 3 7°C, 5% C02 for 6 h. Incubation is followed by addition of 50 (0.1 of lysis/detection buffer (LucLite, PE Life Science) and measurement in a Lumistar luminometer (BMG Labtechnologies GmbH, Germany). Evaluation of the samples takes place after calculation of the inhibition compared with untreated stimulated cells, after subtraction of the unstimulated control, by means of GraphPad Prism (GraphPad Software Inc., USA) or alternatively by means of OMMM (Accelrys, Germany) software. The EC50 values obtained for compounds 2 93 to 3 06 are indicated in the table below. m which (0 me radical R1 is a hydrogen atom, a C2-Cg alkenyl or a Cj-Q alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -€OORu, where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -NO?, -CH3, -CF3, -OCH3, - OCFj and halogen atoms, and me radical Rn is a hydrogen atom, a Ci-Ci2 alkyl, a CI-CQ aralkyl, an aryl, hetaryl radical or the group -COCH3 and may optionally be substituted by one substituent selected from the group consisting of-CONIfc, -COCEfe, -COOCH3, - SO2CH3 and aryl radicals; the radicals R2, R3„ R4 and R5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONEfe, -CF3, -OCF3, -NOz, -CN, a CrQ alkyl, a C2- Q alkenyl, a CpQ alkoxy, a Q-C12 arafltyl, an aryl or hetaryl radical; the radical R6 is the group -CONRsR9' -COOR8(-CH2NR8R9rCHbR8-CKbOR8 or a C2-C12 alkenyl radical which is optionally substituted by the radicals Rs and R9, where the radicals R8 and R9 are each independently of one another a hydrogen atom, a C1-C12 alkyl, a C2-C12 aralkyl, a C2-C12 hetaralkyl, an aryl or hetaryi radical, each of which may substituted by one or more substituents selected from the group consisting of-OH, -NHa, -CQNHR10, -COOR!0,-NH-C(=NH)-NH2 and halogen atoms, where the radical R10 is a hydrogen atom, a C1-Q2 alkyl, a QQ2 aralkyl, an aryl or hetaryi radical and is optionally substituted by the group -CON(R")2, or where the radicals R8 and R9 may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroafoms; the radical R7 is a C1-C12 alkyl, a C2-C12 alkenyl, a C1-C12 aralkyl, an aryl or hetaryi radical, the group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR54 or -NHSO2R14 and may optionally be substituted by one or more substituents selected from the group consisting of-OH, -NHa, -CONH2, -COOH and halogen atoms, 10 12 the radicals R and R are each independently of one another a hydrogen atom, a C2-C4 alkenyl or a C2-C12 a&yl radical and may optionally be substituted by one or more aryl or hetaryi radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -NO2, -CH3,-CFs, -OCHs, - OCF3 and halogen atoms, and the radical R14 is a hydrogen atom, a Ci-C12 alkyl, a C2-C12 alkenyl, a C2-C12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of -NO2, -CH3/ -OR11, -CF3, -OCF3, -OH, -N(R11}2, -OCOR11, -COOH, -CONH2, -NHCONHR11, -NHCOOR11 and halogen atoms; and the radicals Ra, Rb, Rc, Rd, Re and Rf are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3# -OCF3, -N02, -CN, a C2-C6alkyl, C1-C6 alkoxy, an aryl or hetaryl radical; with the proviso that the compound of the general formula (I) is not selected from the group consisting of 3~amino-l,2,3,4-tetrahydrocarbazole- 3-carboxylic acid, 3-amino-6-methoxy-l,2,3 , 4- tetrahydrocarbazole-3-carboxylic acid, 3-amino-6- benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-l,2,3,4-tetrahydrocarbazole-3- carboxylic acid, methyl 3-acetamido-l,2,3,4- tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3- acetamido-1,2,3,4-tetrahydrocarbazole-3-carbox- ylate or 3-tert-butoxycarbonylamino-l,2,3,4-tetra- hydrocarbazole-3-carboxylic acid. 2. The compound as claimed in claim 1, where the radicals Ra, Rb, Rc, Rd, Re and R£ are hydrogen atoms. 3. The compound as claimed in claim 1 or 2, where the radical R1 is a hydrogen atom. 4. The compound as claimed in any of claims 1 to 3, where the radicals R2, R3, R4 and/or RD are not hydrogen atoms. 5. The compound as claimed in claim 4, where me radicals R2, R3, R4 and R5 are independently of one another me group -CH3. -CI or -OCH3. 6. The compound as claimed in claim S, where the compound is selected from the group consisting of phenylmemyi [(lS,2S)-l-[ [ [ (3R)-3-[ [ [ (1S)-1- (aminocarbonyl)-2-methylpropoyl]ammo]ea^ carba2»l-3-yl]afiiko]c8ri)onyl]-2-metiiylbu^^ [[[(3R)-3-[[[ (lS)-l-(amkoearbonyl)-2-memylpropyl]anuno]c te phenylmemyi [(lS,2S)-l-[ [ [(lS)-l-(3R)-3-[[[(lS)-l-aminocarbonyl)-2-memylpropyI] aminojcarbonylJ-U^jP-tetrahydro-S-memoxy-lH-carbaEol-S-yl] amino] carbonyl]-2- methylbutyljcarbamate. 7. The compound as claimed in any of claims 1 to 5, where the radical R6 is a hydrophobic radical which includes alkyl, aryl and/or hetaryl structurese and which carries a hydrogen bond donor-acceptor system at a distance of from two to four single bonds, counting from me carbon atom substituted by the radicals R* and R7. 8. The compound as claimed in claim 7, where the radical R6 is selected from the group consisting of a carbonyl phenylalanylamide residue, a carbonyl isoleucylamide residue, a carbonyi vaiyi-4-aminobenzamide residue, a carbonyl valyl-N-methylamide residue, a memylosymethyl-4- pyridyl radical, a carboxyl radical, an ethyl propenoate residue, a carbonylvalylamide residue a carbonylthreonylamide residue, a cyclic carboxmide residue, a 4-carboxamidophenyl- carboxamide residue, a meftylammomemyl-2-pyridyl radical, a carbonylvaiinoi residue and amethylvalinol residue. The compound as claimed in claim 8, where the compound is selected from the group consisting of phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(1S)-2-amino- 2-oxo-l-(phenylmethyl)ethyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(IS,2S)-1- (aminocarbonyl)-2-methylbutyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [ (lS,2S)-l-[[[(3R)-3-[[[(lS)-l-[[ [4- (aminocarbonyl)phenyl]amino]carbonyl]-2- methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro- lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl] carbamate., phenylmethyl [(IS,2S)-2-methyl-l-[[[(3R)-2,3,4,9- tetrahydro-3-[[[(1S)-2-methyl-l-[(methylamino)- carbonyl]propyl]amino]carbonyl]-lH-carbazol-3- yl]amino]carbonyl]butyl]carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-0-(4- pyridinylmethyl)-lH-carbazole-3-methanol, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazole-3-carboxylic acid, ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazol-3-yl]-2-propenoate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] - 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [ (IS, 2S)-l-[ [ [ (3R) -3- [ [ [ (IS, 2J?)-1- (aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]- 2,3,4,9-tetrahydro-ltf-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[(2S)-2- (aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate, phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[(2S)-2- (aminocarbonyl)octahydro-lH-indol-1-yl]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate), phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[4- (aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N- (2- pyridinylmethyl)-lH-carbazole-3-methanamine, phenylmethyl [(lS,2S)-l-[[[(3S)-3-[[[(1S)-1- (hydroxymethyl)-2-methylpropyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, 2,3,4,9-tetrahydro-W- [(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3- carboxamide and (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3- phenylpropyl)-IH-carbazol-3-yl]methyl]amino]-1- butanol. The compound as claimed in any of claims 1 to 5, 7 or 8, where the radical R7 is a hydrophobic radical including alkyl, aryl and/or hetaryl structures. The compound as claimed in claim 10, where the radical R7 is selected from the group consisting of a 2, 3-biphenylpropionylamino radical, an indanoylamino radical, an indolylacetylamino radical, a 2-naphthylacetylamino radical, a 3- propionylamino radical, a phenylmethylcarboxamide residue which is substituted on the aromatic system, a phenylhexylamine residue and a phenylpropyl radical. The compound as claimed in claim 11, where the compound is selected from the group consisting of dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3-yl]amino]carbonyl]-3- phenylpropyl]carbamate,phenylmethyl[(1S)-l-[[[(3R)-3-[[[(lS,2S)-l- (aminoocarbonyl)-2-methylbutyl]amino-carbonyl]-6,8-dichloro-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-3-met±iylbutyl]carbamate, phenylmethyl[(lS)-l-[[[(3R)-3-[[[(lS)-l-aminocarbonyl)-3- methylbutyl]amino]carbonyl]-6,8-dichloro-2>3,4,9-tetrahydro-lH- carbazol-3-yl]amino]carbonyl]-3-methylbutyl]carbamate. 19. A method of preparing a compound as claimed in claim 18, comprising the steps of coupling Fmoc protected amino carboxylic acid to the Rink amide-resin in the presence of an activating agent and a base, followed by deprotection of the resin-bound Fmoc protective group using piperidine / DMF, coupling the Fmoc-protective carboxylic acid to resin bound amino functions followed by a further step of deprotection of the Fmoc protective amino group and coupling the Fmoc protected carboxylic acid to resin bound amino functions and elimination of the reaction product from the resin by treatment with trifluoroacetic acid. 20. The compound as claimed in claim 18, for use as pharmaceutical remedy. Dated this 8th DAY OF JUNE, 2004. (T) The invention relates to novel tetrahydrocarbozole derivatives acting as ligands for G-protein coupled receptors (GPCR), especially as antagonists of gonadotropin-releasing hormone (GnRH). The invention also relates to a pharmaceutical composition containing said novel tetrahydrocarbozole derivatives, and to a method for producing the same. Furthermore, the invention relates to the administration of tetrahydrocarbozole derivatives for the treatment of pathological conditions mediated by GPCR, especially for the inhibition of GnRH, to mammals, especially humans, requiring such treatment, and to the use of tetrahydrocarbozole derivatives for producing a pharmaceutical agent for treating pathological conditions mediated by GPCR, especially for the inhibition of GnRH. IN THE MATTER OF an Application for a German Patent in the name of SCHERTNG AKTIENGESELLSCHAFT filed under No. 101 64 564.3, and IN THE MATTER OF an Application for an Indian Patent. KW5 uroup no, oi turopa nouse, Marsnam Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages is a true and correct translation of the Patent Application filed under No. 101 64 564.3 by SCHERTNG AKTIENGESELLSCHAFT in Germany on 14 December 2001 for "Tetrahydrocarbazole derivatives as ligands for G-protein coupled receptors (GPCR)" and the Official Certificate attached thereto. Date: 15 July 2004 C. E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd FEDERAL REPUBLIC OF GERMANY [Eagle crest] Priority Certificate for the filing of a Patent Application File Reference: 101 64 564.3 Filing date: 14 December 2001 Applicant/Proprietor: SCHERING AKTIENGESELLSCHAFT, Berlin/DE Title: Tetrahydrocarbazole derivatives as ligands for G-protein coupled receptors (GPCR) IPC: C07D,A61K The attached documents are a correct and accurate reproduction of the original submission for this Application. Munich, 11 March 2003 German Patent and Trademark Office The President [Seal of the German Patent pp and Trademark Office] [signature] Joost TETRAHYDROCARBAZOLE DERIVATIVES AS LIGANDS FOR G- PROTEIN COUPLED RECEPTORS (GPCR) The present invention relates to novel tetrahydro- carbazole derivatives which are ligands of G-protein coupled receptors, and especially antagonists of gonadotropin-releasing hormone, to the preparation thereof, to the use thereof, and to the pharmaceutical compositions which include these tetrahydrocarbazole derivatives. The present invention also relates to a method for treating pathological states mediated by G- protein coupled receptors in a mammal, in particular a human. Technical background The structural element which is common to all members of the family of G-protein coupled receptors (GPCR) is the presence of seven transmembrane alpha-helical segments which are connected together by alternating intra- and extracellular loops, with the amino terminus being located on the extracellular side and the carboxy terminus being located on the intracellular side. The family of GPCRs can be divided into a plurality of subfamilies (essentially family A, B and C) with further sequence homologies within these subfamilies. Since GPCRs are mainly involved in signal reception and transduction, a large number of physiological functions are influenced by them. GPCR ligands are therefore potentially suitable as medicaments for the therapy and prophylaxis of a large number of pathological states. A brief survey of diseases which can be treated with GPCR ligands is given in S. Wilson et al., Pharmaceutical News 2000, 7(3) in Table 1. The majority of known GPCR ligands has a peptide structure. However, peptide receptor ligands frequently have some serious disadvantages such as, for example, low bioavailability and metabolic instability. This is why there has recently been an intensified search for ligands in the form of small, non-peptide molecules. A special part is played in the search for novel, non- peptide receptor ligands by so-called "privileged structures". These "privileged structures" are the basic molecular structures which provide ligands for a large number of different receptors. The term "privileged structures" was used for the first time by Evans et al. in connection with benzodiazepine-based CCK (cholecystokinin) A antagonists from the natural product asperlicin (B.E. Evans et al., J. Med. Chem. 1988, 31, 2235) . For proteases for example it has been known for some time that certain structural classes can serve as inhibitors of various enzymes. Whereas descriptions in the past were in particular of mechanism-based inhibitors of various proteases, however, more recently the frequency of examples of compounds which, by reason of their three-dimensional structure, fit well into the active binding region of various enzymes has increased (cf. M. Whittaker, Cur. Opin. Chem. Biol. 1998, 2, 386; A.S. Ripka et al., ibid., 441). Such "privileged structures" have already been described for GPCRs too. Examples thereof are, besides the aforementioned benzodiazepines, also peptoids, 4-substituted 4-arylpiperidines, but also specific rigidized p-turn mimetics (B.A. Bunin et al. , Ann. Rep. Med. Chem. 1999, 34, 267; R.N. Zuckermann et al., J. Med. Chem. 1994, 37, 2678; G.C.B. Harriman, Tetrahedron Lett. 2000, 41, 8853). A review of this is to be found in A.A. Patchett et al., Ann. Rep. Med. Chem. 1999, 35, 289. The tetrahydrocarbazole derivatives of the present invention provide a further class of "privileged structures" for GPCRs. Although the present invention provides ligands for GPCRs in general, the compounds provided by the present invention are suitable in particular as ligands for a particular representative of the class of GPCRs, namely gonadotropin-releasing hormone (GnRH). GnRH can be assigned to subfamily A of GPCRs (cf. U. Gether et al., Endocrine Reviews 2000, 21(1), 90). GnRH is a hormone which is synthesized predominantly, but not exclusively, in mammals by nerve cells of the hypothalamus, is transported via the portal vein into the pituitary and is delivered in a controlled manner to the gonadotrophic cells. Interaction of GnRH with its receptor having seven transmembrane domains stimulates the production and release of gonadotropic hormones by means of the second messenger inositol 1,4,5-trisphosphate and Ca2+ ions. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are gonadotropins released by GnRH, stimulate the production of sex steroids and gamete maturation in both sexes. In addition to GnRH (also referred to as GnRHl), there are two further forms of GnRH, namely GnRH2 and 3. The GnRH receptor is used as pharmacological target in a number of disorders which depend on functioning sex hormone production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or antagonists can be employed successfully for these disorders. A further possible indication is, in particular, male fertility control in combination with a replacement dose of androgens. One advantage of GnRH antagonists compared with GnRH superagonists is their direct activity in blocking gonadotropin secretion. Superagonists initially bring about overstimulation of the pituitary, leading to increased gonadotropin release and sex steroid release. This hormonal response is terminated only after a certain delay on the basis of desensitization and downregulation of GnRH receptor concentrations. It is therefore possible that GnRH superagonists, both alone and in combination with testosterone, are unable effectively to suppress sperm production in men and are thus unsuitable for male fertility control. In contrast to this, peptide GnRH antagonists, especially in combination with a replacement dose of androgen, are able to induce a significant oligozoospermia in humans. However, peptide GnRH antagonists have a number of disadvantages. Thus, they have a considerably lower activity as superagonists and must accordingly be administered in considerably higher dosages. In addition, their oral bioavailability is low, so that they must be administered by injection. Repeated injections in turn lead to a reduction in compliance. Furthermore, the synthesis of peptide GnRH antagonists is complicated and costly by comparison with non- peptide compounds. Quinoline derivatives are disclosed as non-peptide GnRH antagonists for example in WO 97/14682. However, it has not been possible to date to put any non-peptide GnRH antagonists on the market. Technical problem The problem on which the present invention is based is to provide novel compounds which are suitable for the treatment of GPCR-mediated pathological states and display in particular a GnRH-inhibiting (GnRH- antagonistic) effect. The novel GPCR ligands, preferably GnRH antagonists, ought where possible to be superior to known peptide compounds and represent an effective alternative or improvement in relation to known non-peptide compounds. The novel GPCR ligands, especially GnRH antagonists, should in particular have high activity and, where possible, a high oral bioavailability. Their synthesis ought moreover to be possible simply and at minimal cost. The present invention also provides pharmaceutical compositions comprising the novel non-peptide GPCR ligands, in particular GnRH antagonists. A further problem on which the present invention is based is to provide novel GPCR ligands, preferably GnRH antagonists, for use as pharmaceutical remedy and for use for producing pharmaceutical remedies, comprising the GPCR ligands, preferably GnRH antagonists. In addition, it is an object of the present invention to provide a method for the treatment of GPCR-mediated pathological states, in particular for inhibiting GnRH, in a mammal, in particular a human. All these problems are surprisingly solved by the provision of the novel tetrahydrocarbazole derivatives, of the pharmaceutical compositions which comprise these tetrahydrocarbazole derivatives, of the method for preparing these tetrahydrocarbazole derivatives, and of the method for the treatment of GPCR-mediated pathological states, preferably for inhibition of GnRH, in a mammal, in particular a human, through administration of the tetrahydrocarbazole derivatives or the use of the tetrahydrocarbazole derivatives for producing pharmaceutical remedies for the treatment of GPCR-mediated pathological states, in particular for GnRH inhibition. Summary of the invention In a first aspect, the present invention provides novel tetrahydrocarbazole derivatives of the general formula (I). In a second aspect, pharmaceutical compositions which comprise at least one of the novel tetrahydrocarbazole derivatives of the general formula (I) are provided. In a third aspect, the present invention provides tetrahydrocarbazole derivatives of the general formula (I) for use as pharmaceutical remedy. In a further aspect, the present invention relates to the use of a tetrahydrocarbazole derivative of the general formula (I) for producing a pharmaceutical remedy for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH. The present invention likewise relates to a method for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH, in a mammal, preferably a human, where an effective amount of a compound of the invention of the general formula (I) is administered to the mammal, preferably the human, requiring such a treatment. The present invention additionally provides a method for preparing tetrahydrocarbazole derivatives of the general formula (I). This method comprises for example the steps of condensation of a cyclohexanone derivative, which is tethered to a solid phase and is expediently substituted, with a suitably substituted phenylhydrazine derivative, a subsequent derivatization depending on the desired structure of the final compound, and finally elimination from the solid phase and isolation of the product. Detailed description of the invention In a first aspect of the present invention there is provision of novel tetrahydrocarbazole compounds of the general formula (I) in which the radical R1 is a hydrogen atom, a C2-C6 alkenyl or a Ci-C6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR11, where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -N02, -CH3, -CF3/ -OCH3, -OCF3 and halogen atoms, and the radical R11 is a hydrogen atom, a C2-C12 alkyl, a C2-C12 aralkyl, an aryl, hetaryl radical or the group -COCH3 and may optionally be substituted by one substituent selected from the group consisting of -CONH2, -COCH3, -COOCH3, -S02CH3 and aryl radicals; the radicals R2, R3, R4 and R5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, ~CF3, -OCF3, -N02, -CN, a Ci-C6 alkyl, a Ci-C6 alkenyl, a Ci-C6 alkoxy, a C2-C12 aralkyl, an aryl or hetaryl radical; the radical R6 is the group -CONR8R9, -COOR8, -CH2NR8R9, -CH2R8, -CH2OR8 or a C2-C12 alkenyl radical which is optionally substituted by the radicals R8 and R9, where the radicals R8 and R9 are each independently of one another a hydrogen atom, a C2-C12 alkyl, a C2-C12 aralkyl, a C2-C12 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONHR10, --COOR10, -NH-C (=NH)-NH2 and halogen atoms, where the radical R10 is a hydrogen atom, a C2-C12 alkyl, a C2-C12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -C0N(R1X)2, or where the radicals R8 and R9 may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; the radical R7 is a. hydrogen atom, a C2-C12 alkyl, a C2-C12 alkenyl, a C2-C12 aralkyl, an aryl or hetaryl radical, the group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR14 or -NHS02R14 and may optionally be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONH2, -COOH and halogen atoms, the radicals R12 and R13 are each independently of one another a hydrogen atom, a C2-C6 alkenyl or a C2-C12 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms, and the radical R14 is a hydrogen atom, a C2-C12 alkyl, a C2-C12 alkenyl, a C2-C12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of -N02, -CH3, -OR11, -CF3, -OCF3, -OH, -N(Ru)2f -OCOR11, -COOH, -CONH2, -NHCONHR11, -NHCOOR11 and halogen atoms; and the radicals Ra, Rb, Rc, Rd, Re and Rf are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a Ci-C6 alkyl, Ci-C6 alkoxy, an aryl or hetaryl radical; with the proviso that the compound of the general formula (I) is not selected from the group consisting of 3-amino-l,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3- carboxylic acid, 3-amino-6-benzyloxy-l,2,3,4- tetrahydrocarbazole-3-carboxylic acid, 3-acetamido- 1, 2, 3, 4-tetrahydrocarbazole-3-carboxylic acid, methyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3- carboxylate or 3-tert-butoxycarbonylamino-l,2,3,4- tetrahydrocarbazole-3-carboxylic acid. The basic tetrahydrocarbazole structures of those compounds which are specifically excluded above from the compounds falling within the definition of the general formula (I) were introduced by Y. Maki et al. in Chem. Pharm. Bull. 1973, 21 (11), 2460-2465 and by R. Millet et al. in Letters in Peptide Science 1999, 6, 221-233. The terms indicated for explanation of the compounds of the general formula (I) have in particular the following meaning: C1-C6 or C2-C12 "alkyl radical" means a branched or unbranched, cyclic or acyclic, optionally substituted alkyl group having 1 to 6 or 1 to 12 carbon atoms, respectively. Representative examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, n-pentyl, 2,2- dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl groups, and cyclic groups, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups, 1-cyclopropyl-, 1-cyclobutyl-, 1-cyclopentyl-, 1-cyclohexyl-, 1-cycloheptylethyl-, 2-cyclopropyl-, 2- cyclobutyl-, 2-cyclopentyl-, 2-cyclohexyl-, 2- cycloheptylethyl groups and the like, but are not restricted to these. C2-C6 "alkenyl radical" means a branched or unbranched, cyclic or acyclic, optionally substituted, mono- or polyunsaturated alkenyl group having 2 to 6 carbon atoms. Representative examples of such alkenyl groups include vinyl, allyl, prop-1-enyl, but-1-enyl, but-2- enyl, but-3-enyl, buta-1,3-dienyl, pent-1-enyl, pent-2- enyl, pent-3-enyl, pent-4-enyl, penta-1,3-dienyl, penta-1,4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1- enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, hexa-1,5-dienyl, hexa-2,4-dienyl, hexa-2,5-dienyl, hexa-1,4-dienyl, hexa-1,3,5-trienyl groups and the like, but. are not restricted to these. C2-C6 "alkoxy radical" means a branched or unbranched, cyclic or acyclic, optionally substituted alkoxy group having 2 to 6 carbon atoms. Representative examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n- pentoxy, n-hexoxy, cyclohexyloxy groups and the like, but are not restricted to these. C2-C12 "aralkyl radical" means an alkyl radical having 1 to 12 carbon atoms which is substituted by one or more aryl radicals. Representative examples of such aralkyl groups for the purposes of the present invention include benzyl, 1-phenylethyl, 1-phenylpropyl, 1- phenylbutyl, 1-phenylhexyl, l-phenyl-2-methylethyl, 1- phenyl-2-ethylethyl, l-phenyl-2,2-dimethylethyl, benzhydryl, triphenylmethyl, 2- or 3-naphthylmethyl, 2- phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5- phenylpentyl groups and the like, but are not restricted to these. Correspondingly, a "hetaralkyl radical" is an alkyl radical substituted by a heteroaryl radical. "Aryl radical" means an optionally substituted mono- or polycyclic aromatic group. Representative examples of such aryl groups include phenyl, naphthyl groups and the like, but are not restricted to these. The term "hetaryl radical" is identical with the term "heteroaryl radical" and represents an aryl group as defined above which includes in its structure one or more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. Representative examples of such hetaryl or heteroaryl groups include unsubstituted hetaryl radicals and substituted hetaryl radicals, in particular imidazolyl, pyridyl, quinolinyl groups and the like, but are not restricted to these. The term "cyclic structure" includes optionally substituted mono- or polycyclic cyclic structures with a varying number of ring members, in particular five-, six- and seven-membered cyclic structures. These cyclic structures may include besides carbon atoms also one or more heteroatoms such as, in particular, nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. The cyclic structures may include saturated, but also partially or completely unsaturated, structural elements. Representative examples of such cyclic structures include aza-, oxa-, thia-, phosphacyclopentane-, -cyclohexane-, -cycloheptane-, diaza-, dioxa-, dithia-, diphosphacyclopentane, -cyclohexane, -cycloheptane basic cyclic structures and the like, and basic cyclic structures with mixed heteroatom exchange, but are not restricted to these. "Halogen atoms" include in particular fluorine, chorine, bromine and iodine atoms, particularly preferably chlorine atoms. Reference may also be made at this point to the fact that, besides the compounds of the general formula (I), as defined above, which are mentioned per se, the present invention also encompasses physiologically tolerated derivatives or analogs, especially also salts of these compounds. It may further be remarked at this point that: the term "receptor ligand" or "ligand" is intended for the purposes of the present invention to designate any compound which binds in any manner to a receptor (in i the present invention, the receptor is a GPCR receptor, preferably a GnRH receptor) and induces either an activation, inhibition or other conceivable effect on this receptor. The term "ligand" thus includes agonists, antagonists, partial agonists/antagonists and 1 other ligands which elicit on the receptor an effect which resembles the effect of agonists, antagonists or partial agonists/antagonists. The compounds of the invention of the general formula (I) are preferably GnRH antagonists. Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are those compounds in which the radicals Ra, Rb, Rc, Rd, Re and Rf are hydrogen atoms. Likewise preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are those compounds in which the radical R1 is a hydrogen atom. Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are additionally those compounds in which the radicals R2, R3, R4 and/or R5 are not hydrogen atoms. Particularly preferred i compounds of the general formula (I) in this connection are those in which the radicals R2, R3, R4 and R5 are independently of one another methyl, chloro or methoxy radicals. Very particularly preferred compounds of the general formula (I) in this connection are those in i which at least the radical R2 is not a hydrogen atom, especially the compounds phenylmethyl [(1S,2S)-l-[[[(3R)-3-[[[(1S)-1-(aminocar- bonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9- tetrahydro-8-methyl-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate (compound no. 150a in the examples) phenylmethyl [(lS,2S)-l-[[[(3R)-3-[t[(1S)-1-(aminocar- bonyl)-2-methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl- butyl]carbamate (148a), phenylmethyl [ (1S,2S)-1-[[[(3R)-3-[[[ (1S)-1- (aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9- tetrahydro-8-methoxy--lH-carbazol-3-yl]amino]carbonyl]- 2-methylbutyl]carbamate (147a). Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are also those compounds in which R6 is a hydrophobic radical which includes alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system at a distance of from two to four single bonds, counting from the carbon atom substituted by the radicals R6 and R7. Particularly preferred compounds of the general formula (I) are those where the radical R6 is a phenylalanylamide residue, in particular the compound phenylmethyl [(IS, 2S) -1-[[[(3R)-3-[[[(1S)-2-amino-2- oxo-1- (phenylmethyl) ethyl] amino] carbonyl] -2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl- butyl] carbamate (66) , is an isoleucylamide residue, in particular the compound phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[[(1S)-1- (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-2,3,4,9- tetrahydro-lH-carbazcl-3-yl]amino]carbonyl]-2-methyl- butyl] carbamate (64) , is a valyl-4-aminobenzamide residue, in particular the compound phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[[(1S)-1- [[[4-(aminocarbonyl)phenyl]amino]carbonyl]-2-methyl- propyl] amino] carbonyl]-2,3,4,9-tetrahydro-lH-carbazol- 3-yl] amino] carbonyl]-2-methylbutyl] carbamate (45_) , is a valyl-N-methylamide residue, in particular the compound phenylmethyl [(IS, 2S)-2-methyl-l-[[[(3R)- 2,3,4,9-tetrahydro-3-[[[(1S)-2-methyl-l-[(methylamino)- carbonyl]propyl]amino]carbonyl]-lH-carbazol-3- yl]amino]carbonyl]butyl]carbamate (222a), is a methyloxymethyl-4-pyridyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl) -O- (4-pyridinylmethyl)-lH-carbazole-3-methanol (287), is a carboxyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-lH-carbazole-3- carboxylic acid (273) ,, or is an ethyl propenoate radical, in particular the compound ethyl 3-[2,3,4,9-tetrahydro-3- (3- phenylpropyl)-lff-carbazol-3-yl]-2-propenoate (289). Likewise particularly preferred are compounds of the general formula (I) in which the radical R6 is a carbonylvalylamide residue, in particular the compound phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1-(aminocar- bonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetra- hydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate (58), is a carbonylthreonylamide residue, in particular the compound phenylmethyl [ (IS, 2S) -1- [ [ [ (3JR) -3- [ [ [ (IS, 2R) - 1-(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]- 2,3,4, 9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2- methylbutyl]carbamate, is a cyclic carboxamide residue (such as, for example, a carbonylprolylamide radical, in particular the compound phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[(2S)-2- (aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetra- hydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate (181a), or a carbonyloctahydroindolyl-2-carboxamide residue, in particular the compound phenylmethyl [(1S,2S)-1- [ [ [ (3R) -3- [ [ (2S) -2- (aminocarbonyl) octahydro-l.H-indol-1- yl]carbonyl]-2,3,4,9-tetrahydro-lH-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate (190a)), is a 4-carboxamidophenylcarboxamide residue, in particular the compound phenylmethyl [(1S,2S)-1- [ [ [ (3R) -3-[[[4-(aminocarbonyl)phenyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate (62), is a methylaminomethyl-2-pyridyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N- (2-pyridinylmethyl)-lff-carbazole-3-methanamine (279), is a carbonylvalinol residue, in particular the compounds phenylmethyl [ (IS,2S)-1-[[[(3S)-3-[ [ [ (1S)-1- (hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl- butyl]carbamate (267b) and 2,3,4,9-tetrahydro-W-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3- carboxamide (276) or is a methylvalinol residue, in particular the compound (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3- phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-1-butanol (284). Preferred novel tetrahydrocarbazole derivatives of the invention of general formula (I) are also compounds in which R7 is a hydrophobic radical comprising alkyl, aryl and/or hetaryl structures. Particular preference is given in this connection to compounds of the general formula (I) in which the radical R7 is a 2,3-biphenyl- propionylamino radical, in particular the compound N- [[(3R)-2,3,4,9-tetrahydro-3-[(l-oxo-2,3-diphenyl- propyl)amino]-ltf-carbazol-3-yl]carbonyl]-L-valyl-L- aspartamide (18) is an indanoylamino radical, in particular the compound (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3- [[(2,3-dihydro-lH-inden-l-yl)carbonyl]amino]-2,3,4,9- tetrahydro-lH-carbazole-3-carboxamide (162a), is an indolylacetylamino radical, in particular the compound (3S)-N-[(1S)-1-(aminocarbonyl)-2-methyl- propyl] -2,3,4,9-tetrahydro-3-[(lH-indol-3-ylacetyl)- amino]-lH-carbazole-3-carboxamide (164b), is a 2-naphthylacetylamino radical, in particular the compound (3S)-N-[(1S)-1-(aminocarbonyl)-2-methyl- propyl] -2, 3,4,9-tetrahydro-3-[(2-naphthalinylacetyl)- amino]-lH-carbazole-3-carboxamide (161b) or is a 3-propionylamino radical, in particular the - 16 - compound N- [ [ (3.R)-2, 3, 4, 9-tetrahydro-3-[ [ (2S,3S)-3- methyl-l-oxo-2-[(l-oxo-3-phenylpropyl)amino]pentyl]- amino]-lif-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide (22) . Likewise particularly preferred are compounds of the general formula (I) in which R1 is a phenylmethyl- carboxamide residue substituted on the aromatic system, in particular the compounds (3R)-N-[(1S)-1-(amino- carbonyl) -2-methylpropyl] -2, 3,4,9-tetrahydro-3-[[(4- methylphenyl)acetyl]amino]-lH-carbazole-3-carboxamide (165a), N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9- tetrahydro-3-[[(4-methoxyphenyl)-acetyl]amino]--1H- carbazole-3-carboxamide (175), (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[ [ (3- bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-lH- carbazole-3-carboxamide (96_) , (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(4- fluorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-lH- carbazole-3-carboxamide (91_) , (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(4- chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-lH- carbazole-3-carboxamide (167a), is a phenylhexylamine residue, in particular the compound (3R)-N-[(1S)-1-(aminocarbonyl)-2-methyl- propyl] -3-[bis(3-phenylpropyl)amino]-2,3,4,9- tetrahydro-lH-carbazole-3-carboxamide (234a) or is a phenylpropyl radical, in particular the compounds 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl- propyl) -lH-carbazole-3-carboxylic acid (275) and 6,8- dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazole-3-carboxylate (272). Also preferred are those novel compounds of the invention of the general formula (I) which are in the R configuration at the carbon atom substituted by the radicals R6 and R7 when the radicals R6 and R7 together form an alpha-amino carboxylic acid structural element. Most preferred for the purposes of the present invention are the compounds phenylmethyl [(1S,2S)-1- [[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]- amino]carbonyl]-6,8-dichloro-2,3,4, 9-tetrahydro-lH- carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (184a), phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(1S)-1- (hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl- butyl] carbamate (267a), (2S)-l-[[(3R)-3-[[(4-chloro- phenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy-lH- carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a) and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)- N- (2-pyridinylmethyl)-lH-carbazole-3-methanamine (283) . Further representatives of novel compounds of the invention of the general formula (I), including their preparation, are indicated in the examples. The novel tetrahydrocarbazole derivatives (I) of the invention, as defined above, are ligands of GPCR and can be employed in particular for the inhibition, i.e. as antagonists, of gonadotropin-releasing hormone for example for male fertility control, for hormone therapy, for the treatment of female sub- or infertility, for female contraception and for tumor control. In male fertility control, the compounds of the invention bring about a reduction in spermatogenesis. Combined administration with androgens, e.g. testosterone or testosterone derivatives such as, for example, testosterone esters, is preferred. The testosterone derivatives can in this case be administered for example by injection, e.g. by intra- muscular depot injection. The compounds (I) of the invention can also be employed where appropriate in combination with other hormones, e.g. estrogens or/and progestins, in hormone therapy, for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids. Combinations of the GnRH antagonists of the invention and tissue-selective partial estrogen agonists such as Raloxifen" are particularly preferred. In addition, the compounds of the invention can be employed in hormone replacement therapy. The compounds (I) of the invention can moreover be employed to increase female fertility, for example by inducing ovulation, and for the treatment of sterility. On the other hand, the novel compounds (I) of the invention are also suitable for contraception in women. Thus, the GnRH antagonist of the invention can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very small estrogen, dosages. On days 16 to 21 of the cycle of intake, progestagen is added to the estrogen/GnRH antagonist combination. The GnRH antagonist of the invention can be administered continuously throughout the cycle. It is possible in this way to reduce the hormone dosages and thus achieve a reduction in the side effects of nonphysiological hormone levels. It is additionally possible to achieve advantageous effects in women suffering from, polycystic ovary syndrome and androgen-dependent disorders such as acne, seborrhea and hirsutism. An improved control of the cycle by comparison with previous administration methods is also to be expected. Further indications are benign prostate hyperplasia, gonadal protection during chemotherapy, controlled ovary stimulation/assisted reproduction techniques, infantile development disorders, e.g. precocious puberty and polycystic ovaries. Finally, the compounds (I) of the invention, as defined above, can also be employed for the treatment of hormone-dependent neoplastic diseases such as premenopausal cancer, prostate cancer, ovarian cancer and endometrial cancer, by suppressing endogenous sex steroid hormones. The novel compounds (I) of the invention, as defined above, are, as GPCR ligands, in particular GnRH antagonists, suitable for the treatment of the pathological states detailed above for administration to mammals, in particular humans, but also for veterinary medical purposes, e.g. in pets and productive livestock,, but also in wild animals. Administration is possible in a known mariner, for example orally or non-orally, in particular topically, rectally, intravaginally, nasally or by injection or implantation. Oral administration is preferred. The novel compounds (I) of the invention are converted into a form capable of administration and, where appropriate, mixed with pharmaceutically acceptable carriers or diluents. Suitable excipients and carriers are described for example in Ullman's Encyclopedia of Technical Chemistry, Vol. 4 (1953), 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v. Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie und angrenzende Gebiete", Pharm. Ind. 2, 1961, 72ff; Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende Gebiete", Cantor KG, Aulendorf in Wlirttemberg, 1971. Oral administration can take place for example in solid form as tablet, capsule, gel capsule, coated tablet, granulation or powder, but also in the form of a drinkable solution. For oral administration, the novel compounds of the invention of the general formula (I), as defined above, can be combined with known and conventionally used, physiologically tolerated excipients and carriers such as, for example, gum arabic, talc, starch, sugars such as, for example, mannitol, methylcellulose, lactose, gelatin, surface- active agents, magnesium stearate, cyclodextrins, aqueous or nonaqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors (e.g. essential oils) . The compounds of the invention can also be dispersed in a microparticulate, e.g. nano- particulate, composition. Non-oral administration can take place for example by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by means of implants or by ointments, creams or suppositories. Administration as extended-release form is also possible where appropriate. Implants may contain inert materials, e.g. biodegradable polymers or synthetic silicones such as, for example, silicone rubber. Intravaginal administration is possible for example by means of pessaries. Intrauterine administration is possible for example by means of diaphragms, etc. In addition, transdermal administration, in particular by means of a formulation suitable for this purpose and/or suitable means such as, for example, patches, is also provided. As already explained above, the novel compounds (I) of the invention can also be combined with other active pharmaceutical ingredients. During a combination therapy, the individual active ingredients can be administered simultaneously or separately, in particular either by the same route (e.g. orally) or by separate routes (e.g. orally and as injection). They may be present and administered in identical or different amounts in a unit dose. It is also possible to apply a particular dosage regimen where this appears expedient. It is also possible in this way to combine a plurality of the novel compounds (I) of the invention together. The dosage may vary within a wide range depending on the nature of the indication, the severity of the disorder, the mode of administration, the age, sex, body weight and sensitivity of the subject to be treated. It is within the abilities of a skilled worker to determine a "pharmacologically effective amount" of the combined pharmaceutical composition. Unit doses of from 1 ug to 100 mg, particularly preferably from 1 ug to 10 mg and most preferably from 1 ug to 1 mg, per kg of body weight of the subject to be treated are preferred. Administration can take place in a single dose or a plurality of separate dosages. In a further aspect of the present invention, accordingly, the present invention also encompasses pharmaceutical compositions as described above, comprising at least one of the novel compounds (I) of the invention, as defined above, and where appropriate pharmaceutically acceptable carriers and/or excipients. Preferred and particularly preferred pharmaceutical compositions are those comprising at least one of the aforementioned preferred or particularly preferred novel compounds (I) of the invention, in particular the compounds mentioned by name above. In pharmaceutical compositions according to the present invention it is possible, besides the at least one compound of the general formula (I), as defined above, for other active pharmaceutical ingredients also to be present, as already described in detail above. At least one of the novel compounds (I) of the invention, as defined above, is present in the pharmaceutical compositions of the invention in one of the unit doses mentioned above as preferred, particularly preferred or most preferred, specifically and preferably in an administration form which makes oral administration possible. In addition, in a further aspect, the present invention provides compounds of the general formula (I) as defined above for use as pharmaceutical remedy. Preferred tetrahydrocarbazole compound of the invention of the general formula (I) , as defined above, for use as pharmaceutical remedy are in turn those compounds mentioned above as preferred and particularly preferred compounds, in particular the preferred compounds of the invention mentioned by name, and the compounds mentioned in the examples. Concerning pharmaceutical compositions comprising compounds (I) of the invention, and concerning compounds (I) of the invention for use as pharmaceutical remedy, reference may be made in relation to the possibilities for use and administration to what has already been said concerning the novel compounds (I) of the invention, as defined above. In another aspect, the present invention also provides the use of at least one tetrahydrocarbazole derivative of the invention of the general formula (I), as defined above, with - as defined at the outset - the tetra- hydrocarbazoles disclosed in the publications by Millet et al. and Maki et al. being excluded from the meaning of the general formula (I), for producing a pharmaceutical remedy for the treatment of GPCR- mediated diseases, in particular for inhibition of gonadotropin-releasing hormone (GnRH). In addition, the present invention provides in a further aspect the use of at least one compound of the invention of the general formula (I) as defined above, but including the compounds previously excluded by name from the publications of Millet et al. and Maki et al., namely 3-amino-l,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3- carboxylic acid, 3-amino-6-benzyloxy-l,2,3,4-tetra- hydrocarbazole-3-carboxylic acid, 3-acetamido-l,2,3,4- tetrahydrocarbazole-3-carboxylic acid, methyl 3- acetamido-1,2,3, 4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3- carboxylate and 3-tert-butoxycarbonylamino-l,2,3,4- tetrahydrocarbazole-3-carboxylic acid, for producing a pharmaceutical remedy for inhibiting GnRH, preferably for male fertility control, for hormone therapy, for the treatment of female sub- and infertility, for female contraception and for tumor control. Stated more clearly, the term "a compound of the general formula (I) as defined above, but including the compounds excluded above by name" means a compound of the general formula (I) (0 in which the radical R1 is a hydrogen atom, a C2 - C6 alkenyl or a Ci - C6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR11, where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms, and the radical R11 is a hydrogen atom, a C1 - C12 alkyl, a C2-C12 aralkyl, an aryl, hetaryl radical or the group -COCH3 and may optionally be substituted by one substituent selected from the group consisting of -CONH2, -COCH3, -COOCH3, -SO2CH3 and aryl radicals; the radicals R2, R3, R4 and R5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1- C6 alkyl, a Ci - C6 alkenyl, a Ci - C6 alkoxy, a C2-C12 aralkyl, an aryl or hetaryl radical; the radical R6 is the group -CONR8R9, -COOR8, -CH2NR8R9, -CH2R8, -CH2OR8 or a C2-C12 alkenyl radical which is optionally substituted by the radicals R8 and R9, where the radicals R8 and R9 are each independently of one another a hydrogen atom, a C2-C12 alkyl, a Ci - Ci2 aralkyl, a C1-C12 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONHR10, -COOR10, -NH-C (=NH) -NH2 and halogen atoms, where the radical R10 is a hydrogen atom, a C1 - C12 alkyl, a C1 - C12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R1:L)2? or where the radicals R8 and R9 may together form a cyclic structure which consists however exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; the radical R7 is a hydrogen atom, a C1 - C12 alkyl, a C1 - C12 alkenyl, a C1 - C12 aralkyl, an aryl or hetaryl radical, the group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR14 or -NHS02R14 and may optionally be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONH2, -COOH and halogen atoms, the radicals R12 and R13 are each independently of one another a hydrogen atom, a C2 - C6 alkenyl or a C1 - C12 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms, and the radical R14 is a hydrogen atom, a C1 - C12alkyl, a C1 - C12 alkenyl, a C1 - C12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of -N02, -CH3; -OR11, -CF3, -OCF3, -OH, -N(R11)2, -OCOR11, -COOH, -CONH2, -NHCONHR11, -NHCOOR11 and halogen atoms; and the radicals Rd, Rb, Rc, Rd, Re and Rf are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1 - C6 alkyl, a C1 - C6 alkoxy, an aryl or hetaryl radical. The indications already mentioned in connection with the novel compounds of the invention of the general formula (I), as defined above (i.e. excluding the compound disclosed in the publications of Maki et al. and Millet et al. and mentioned above by name) have already been given above in relation to the novel compounds (I) of the invention. The compounds which are preferred and particularly preferred in the use of the compounds just defined for producing a pharmaceutical remedy for inhibiting GnRH are identical to the preferred and particularly preferred compounds already mentioned above in connection with the novel compounds of the invention of the general formula (I), as defined above. The present invention provides in a further aspect the use of a compound (I) of the invention as defined above, but likewise including the compounds excluded by name at the outset, for male fertility control or for female contraception. Preferred and particularly preferred compounds of the invention for this use are those compounds already mentioned at the outset as preferred or particularly preferred compounds of the invention of general formula (I) as defined above. In addition, the present invention provides a method for male fertility control or for female contraception, comprising the administration of an amount, effective for male fertility control or for female contraception, of a compound of the invention as defined in the immediately preceding paragraph, to a subject, preferably a mammal, particularly preferably a human. In another aspect, the present invention relates to a method for the treatment of pathological states mediated by GPCR. The method comprises the administration of at least one compound (I) of the invention, as defined above, to a mammal, in particular a human, when such a treatment is necessary. The administration normally takes place in a pharmaceutically effective amount. As already explained above in relation to the novel compounds (I) of the invention and the pharmaceutical compositions of the invention, it is the task of the expert knowledge of a skilled worker to determine a pharmaceutically effective amount, depending on the specific requirements of the individual case. However, the compounds (I) of the invention are preferably administered in a unit dose of from 1 ug to 100 mg, particularly preferably from 1 ug to 10 mg and most preferably from 1 ug to 1 mg per body weight of subject to be treated. The preferred administration form is oral administration. The administration of one or more of the compounds (I) of the invention in combination with at least one further active ingredient, as already explained above, is also provided. In addition, the present invention also relates to a method for inhibiting GnRH in a patient, comprising administration of a pharmaceutically effective amount of a compound of the general formula (I), as defined above, but including compounds excluded by name above, to a patient requiring such a treatment. The method is preferably used in male fertility control, hormone therapy, female contraception, treatment of female sub- or infertility and tumor control. Finally, the present invention provides in a last aspect also a method for the production of the novel tetrahydrocarbazole derivatives of the invention of the general formula (I) .. The method for the preparation of the compounds of the invention of the? general formula (I) can be carried out in various ways, e.g. in liquid phase or as partial or complete solid-phase synthesis. The choice of the suitable synthesis conditions for preparing individual representatives of compounds of the general formula (I) can be made by a skilled worker on the basis of his common general knowledge. One method of the invention for the preparation of compounds of the invention of the general formula (I) is firstly described generally below. A specific variant of the method, namely a solid-phase method, is then described. For further illustration of the present invention, the examples listed thereafter include numerous representatives of compounds of the general formula (I). One method for the preparation of the compounds of the invention of the general formula (I) is preferably carried out in the following way: The central tetrahydrocarbazole structure can be obtained by a Fischer indole synthesis known per se. For this purpose, a suitably substituted cyclohexanone derivative provided where appropriate with protective groups is condensed with the phenylhydrazine derivative which is desired in each case and is likewise suitably substituted and provided where appropriate with protective groups (e.g. as described by Britten & Lockwood, J.C.S. Perkin I 1974, 1824 or as described by Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In particular, the cyclohexanone structure is substituted in positions 3,3', 5,5' and 6,6' via the radicals Ra to Rf, and in positions 4,4' via the radicals, or where appropriate by precursors of the radicals, Rb and R7. The phenylhydrazine structure is optionally substituted by the radicals R2 10 R5. Phenylhydrazine derivatives which are not commercially available can be prepared by methods known to the skilled worker. Positional isomers which result where appropriate in the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chromatographic methods such as, for example, HPLC. After the synthesis of the central tetrahydrocarbazole structure, the radical R1 can be introduced by N-alkylation of the nitrogen atom in position 9 with appropriate R1-halides with use of base (e.g. as described by Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or else as described by Mooradian et al., J. Med. Chem. 1970, 13, 327). The radicals R6 and R7 can, as already indicated above, be introduced in various ways depending on their nature, which is explained in detail below. a-Aminocarboxylic acid structures in these radicals can be obtained by treating ketones with NH4 (CO) 3 and KCN under Schotten-Baumann conditions known per se, and subsequent alkaline hydrolysis of the hydantoin which is formed (Britten & Lockwood, J.C.S. Perkin I 1974, 1824) . Amide residues are preferably generated using methods known per se from peptide chemistry. For this purpose, the acid component is activated with an activating reagent such as DCC or else HATU (Tetrahedron Lett. 1994, 35, 2279) and condensed in the presence of a base such as DIPEA and/or DMAP with the amino component. Ester residues can also be obtained by using the desired alcohols under analogous conditions. The solvent used in this case is preferably anhydrous. Secondary or tertiary amide residues are obtained from primary amines either by nucieophiiic substitution of alkyl halides or by reductive amination of aldehydes/ ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synth. Comm. 1994, 609). Sulfonamide residues are obtained from the corresponding amides by reaction with sulfonyl chlorides. Urea residues are obtained by reacting the amines with appropriate isocyanates. Urethane residues can be prepared by preactivating the appropriate alcohols with carbonyldihydroxybenzo- triazole ((HOBt)2CO) and subsequently reacted with amines (Warass et al.., LIPS 1998, 5, 125). Alcohols can be obtained from carboxylic esters by reduction with LiAlH4. Aldehyde residues are obtained from alcohol precursors by oxidation for example under Swern conditions known per se with DMSO/oxalyl chloride (Pansavath et al., Synthesis 1998, 436). Substituted amine residues are obtained by reductive amination of amines with aldehydes (J. Org. Chem. 1996, 61, 3489) . Ether residues can be obtained by deprotonating the alcohol precursor with a base such as NaH under Williams conditions known per se and subsequently reacting with an alkyl halide. Double bonds in the radicals can be introduced by reacting an aldehyde or ketone precursor with appropriate phosphonylides under Wittig conditions known per se. A solid-phase method for the preparation of compounds of the invention of formula (I) preferably includes steps (a) to (d) explained in detail below: Step (a) proceeds essentially in analogy to a Fischer indole synthesis, e.g. as described by Britten & Lockwood, J.C.S. Perkin I 1974, 1824; Maki et al., Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869 and comprises the condensation of a cyclohexanone derivative (II) which contains the group G and is tethered to a solid phase SP via a linker L suitable for forming the radical R6 where, in the case where the radical R7 is a hydrogen atom, a C1 - C12 alkyl, a C1 - C12 aralkyl or a hetaryl radical, the group G is equal to the radical R7, and in the case where the radical R7 has another one of the meanings indicated for R7 in formula (I), the group G is equal to a group --NH-Pg, where Pg is a protective group, with a phenylhydrazine derivative (III) substituted by R2 to R5 in the presence of an acid, preferably acetic acid, and of a metal salt, preferably ZnCl2. DMF is preferred as solvent. The radicals Ra to Re are defined as indicated above in formula (I) . Certain substituents or groups may, where appropriate, also be present in protected form, in which case the protective groups are removed again by methods known per se at a suitable time during the synthesis. Particularly suitable solid phase SP for the purposes of the present invention are Rink amide-resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard et al., Int. J. Peptide Protein Res. 1982, 20, 451), Wang resins (Lu et al., J. Org. Chem. 1981, 46, 3433) or chlorotrityl-resins (Barlos et al., Int. J. Peptide Protein Res. 1991, 38, 562), where the cyclohexanone derivative (II) is to be tethered to the solid phase SP by means of an (amino) carboxylic acid. Alcohol precursors of the cyclohexanone derivative (II) can be tethered by using the DHP linker (Liu & Elman, J. Org. Chem. 1995, 60, 7712). Traceless tethering of aromatic precursors of the cyclohexanone derivative (II) to triazine resins is possible (Brase et al., Angew. Chem. Int. Ed. 1998, 37, 3413) . The protective group Pg which is included where appropriate in the group G and protects an a-amino group -NH2 is preferably a "Fmoc" (9- fluorenylmethoxycarbonyl) protective group, but may also be another customary amino protective group, e.g. from the series of the alkoxycarbonyl protective groups (such as, for example the "z" (benzyloxycarbonyl) or the "Boc" (tert-butoxycarbonyl) group) or another suitable protective group, e.g. a "trityl" (triphenylmethyl) protective group. The constitution of the linker L is such that appropriate derivatization (steps (b) and (c)) and workup (step (d)) result in the desired radical R6 with one of the meanings indicated above for R6 in the final product, the tetrahydrocarbazole derivative of the general formula (I). To illustrate the constitution of the linker L, this may be explained below by way of example for the case where R6 equals the group -CONR8R9. In the case where the radical R6 in the product of the invention of the formula (I) has the meaning -CONR8R9, firstly a compound Pg-N (R8) -R9' -COOH forming the linker L is tethered by means of an activating reagent such as DCC (dicyclohexylcarbodiimide) or HATU (0-(7- azabenzotriazol-1-yl)-N,N-N',N'-tetramethyluronium hexafluorophosphate) to the solid phase SP via free amino groups of the SP, where Pg and SP have the meaning indicated above, and R9' forms part of the later radical R9. The protective group Pg is subsequently eliminated, e.g. in the case of a Fmoc protective group by means of piperidine/DMF. This results in a compound HR8N-R9'-CONH-SP. The latter compound is then in turn reacted with a precursor of the cyclohexanone derivative (II), namely the cyclohexanone carboxylic acid (II') using an activating reagent such as DCC or HATU, finally resulting in the cyclohexanone derivative (II) as defined above. The meaning of the linker L in the case just described is -CONR8-R9'-CONH-SP. Any resulting isomers of whatever type (enantiomers, diastereomers or positional isomers) can be fractionated - as also elsewhere during the described preparation process - in a known manner by means of HPLC. The actual step (a), i.e. the condensation of the cyclohexanone derivative (II) with the substituted phenylhydrazine derivative (III) and, where appropriate, elimination of the protective group Pg in the group G by means of, for example, piperidine (in the case of a Fmoc protective group) then takes place, so that a free a-amino group is produced again at this point. In the case where the radical R7 is the group -NHCOR14, -NHS02R14, -NR12R13 (where R12 and R13 are not both hydrogen atoms), -NHCONHR14 or -NHCOOR14, a derivatization of the now unprotected a-amino group of the resin-bound cyclohexanone derivative (II) finally takes place in step (b) , so that the various alternative radicals R7 defined above can be performed. Depending on the nature of the desired radical R7 in the tetrahydrocarbozole final product (I) of the invention, the procedure for this is as follows: In the case where R7 is the group -NHCOR14, the reaction product from step (a) is reacted with a carboxylic acid R COOH in the presence of an activating reagent such as, for example, DCC or HATU and in the presence of a base such as, for example, DIPEA (diisopropyl- ethylamine) or DMAP (4-dimethylaminopyridine) by known processes for forming peptide linkages (cf., for example, Tetrahedron Lett. 1994, 35, 2279; alternative (i)) • In the case where R' is a sulfonamide group -NHS02R14, the reaction product from step (a) is reacted with a sulfonic acid derivative R14S02X, where X is a leaving group, preferably a halogen atom, in particular a chlorine atom, in the presence of a base such as, for example, DMAP or DIPEA (cf., for example, Gennari et al., EJOC 1998, 2437; alternative (ii)). In the case where R7 is the group -NR12R13 (where R12 and R13 are not both hydrogen atoms) , in the case where the radical R12 is a hydrogen atom, the reaction product from step (a) is reacted with a reagent R13X, where X is a leaving group such as, for example, a halide atom, in particular a chloride atom, in the presence of a base such as, for example, DBU or DIPEA (cf. Green, JOC 1995, 60, 4287 or JOC 1996, 61, 3849) or with an aldehyde R13CHO in the presence of a reducing agent such as, for example, NaH/iB (OAc) 3. In the case where neither of the radicals R12 and R13 is a hydrogen atom, the reaction product from step (a) is a reacted with a ketone R12COR13 in the presence of a reducing agent (cf. Ellmann et al., JOC 1997, 62, 1240 or Synth. Commun. 1994, 609; alternative (iii) ) . In the case where both radicals R12 and R13 in R7 equals -NR12R13 are hydrogen atoms, alternative (vi) below applies. In the case where R' is the group -NHCONHR14 (a urea derivative) , the reaction product, from step (a) is reacted with an isocyanate R14NCO (cf. Brown et al., JACS 1997, 119, 3288; alternative (iv)). In the case where R7 is a carbamate or urethane group -NHCOOR14, the reaction product from step (a) is reacted with an alcohol HOR14 which has been preactivated by carbonyldihydroxybenzotriazole ((HOBt)2CO) (cf. Warass et al., LIPS 1998, 5r 125; alternative (v)). In the case where R7 is a hydrogen atom, a C1 - C12 alkyl, C1 - C12 aralkyl, an aryl, a hetaryl radical or the group -NH2 (i.e. both radicals R12 and R13 in R7 equals -NR12R13 are hydrogen atoms), step (b) is omitted because no further derivatization is necessary (alternative (vi)) . Step (c) , i.e. the derivatization on the indole nitrogen atom, also corresponds, in analogy to step (b) explained above, to various alternatives which are explained in detail below: For cases (i) to (v) defined above in step (b) , a deprotonation of the reaction product obtained in (b) takes place by means of a base such as, for example, NaH or NaHMDS and subsequent derivatization by means of a group R1X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom (cf. Collini & Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et al., J. Med. Chem. 1970, 13, 327). For case (vi) defined above in step (b) , i.e. when step (b) is omitted, in analogy to the above description a deprotonation of the reaction product obtained in (a) takes place by means of a base such as, for example NaH or NaHMDS and subsequent derivatization by means of a group R1X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom. Step (d) finally substantially includes the elimination of the reaction product obtained in (c) from the solid phase SP. In the case of Wang, trityl, DHP and Rink amide resins, elimination of the reaction product obtained in (c) takes place with the aid of an acid, in particular with TFA (trifluoroacetic acid). In the case of an aminolytic elimination from an HMB resin, the eliminating reagent used is, for example, ammonia in methanol. The desired product is then isolated in a conventional way. Exemplary embodiments of the preparation of tetrahydrocarbazole derivatives of the invention are detailed below. Examples I. General synthetic methods for compounds of the invention A Coupling of carboxylic acids to the Rink amide- resin : 0.1 mmol of Fmoc-protected Rink amide-resin (166 mg, loading 0.6 mmol/g) are preswollen with 1.5 ml of DMF in a vessel with bottom frit for 20 min. After aspiration, 1.5 ml of 20% piperidine/DMF are added and stirred for 5 min. After aspiration, a further 1.5 ml of 20% piperidine/DMF are added and stirred for 15 min. Aspiration is followed by washing four times with DMF. Then 675 f.i.1 of a 0.267 M solution of Fmoc- protected amino carboxylic acid in DMF, 675 \|il of HATU solution (0.267 M in DMF) and 150 fal of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added and stirred at 40°C for 4 h. After aspiration, the same reagents are again added and stirred at 40°C for 4 h. This is followed by aspiration and washing tour times with DMF. B Coupling of carboxylic acids to the trityl-resin: 2.98 mmol of Fmoc protected aminocarboxylic acid are dissolved in 30 ml of dry dichloromethane, mixed with 14.3 mmol (2.45 ml) of DIPEA and added to 2.98 mmol of 2-chlorotrityl chloride-resin (2 g, loading 1.49 mmol/g of resin). After shaking for two hours, the resin is filtered off with suction through a frit and washed three times with 2 0 ml of dichloromethane/MeOH/DIPEA 17:2:1. This is followed by washing three times with 20 ml of dichloromethane, three times with methanol and three times with 20 ml of ether and drying in vacuo. A resin with a loading of 0.5 to 1 mmol of amino carboxylic acid per g of resin is obtained. C Coupling of carboxylic acids to the HMB-resin: 21.3 mmol of amino carboxylic acid and 21.3 mmol of HATU are dissolved in 60 ml of DMF and mixed with 63.9 mmol (10.9 ml) of DIPEA. After 5 minutes, 5 g of polystyrene-HMB-resin (loading 0.71 mmol/g of resin) are added and shaken at RT for 5 minutes. Then 21.3 mmol (2.6 g) of DMAP are added and shaken at RT for 1 h. The resin is subsequently filtered off with suction and washed once each with 100 ml of DMF, DCM and DMF. The resin is mixed with 100 ml of 10% Ac20 (acetic anhydride)/DMF/5% DMAP and shaken for 15 min. Aspiration is followed, by washing three times each with 100 ml of DCM and ether and drying in vacuo. D Coupling of carboxylic acids to the Wang resin: 54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of DIC are dissolved in 500 ml of dry DCM, and stirred at RT for 10 min. After the precipitated urea has been filtered off, the solution is evaporated to dryness and the residue is dissolved in 160 ml of dry DMF. The solution is added to 4.55 mmol (5 g, loading 0.91 mmol/g of resin) of Wang resin preswollen in DMF, and 4.55 mmol (556 nig) of DMAP are adaed. After shaking at RT for 1.5 hours, the resin is filtered off with suction and taken up in 100 ml of 10% Ac20/DMF/5% DMAP and shaken for 15 min. Aspiration is followed by washing three times each with 100 ml of DCM and ether and drying in vacuo. E Coupling of an alcohol to the DHP-resin: 0.5 mmol of DHP-resin (0.5 g, loading density 1 mmol/g) are preswollen in 2 ml of dichloroethane for 15 min. To this are added 2 ml of a solution of 0.75 M alcohol/0.37 M pyridinium paratoluenesulfonate and stirred at 80°C for 16 h. Cooling to RT is followed by addition of 5 ml of pyridine, briefly shaking with inversion and filtration with suction. Washing is carried out twice each with 5 ml of DMF, DCM and hexane. F Deprotection of a resin-bound Fmoc protective group: 1.5 ml of 20% piperidine/DMF are added to 0.1 mmol of resin-bound Fmoc group and stirred for 5 min. After aspiration, 1.5 ml of 20% piperidine/DMF are again added and stirred for 15 min. Aspiration is followed by washing four times with DMF. G Coupling of a carboxylic acid to resin-bound amino functions: 675 nl of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 675 μl of HATU solution (0.267 M in DMF) and 150 μl of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added to 0.1 mmol of resin-bound amino functions and stirred at 40°C for 4 h. After aspiration, the same reagents are added again and stirred at 40°C for 4 h. This is followed by aspiration and washing four times with DMF. H Coupling of acetic acid to resin-bound amino functions: 1.5 ml of a solution of 10% acetic anhydride in DMF are added to 0.1 mmol of resin-bound amino functions and stirred at RT for 15 min. This is followed by aspiration and washing four times with DMF. 1 Synthesis of tetrahydrocarbazoles starting from resin-bound cyclohexanones: Before the reaction, 0.1 mmol of cyclohexanone-resin are washed twice with 2 ml of DMF and twice with 2 ml of acetic acid. Then 1 ml of DMF and 2 ml of 0.5 M hydrazine/0.5 M ZnCl2 in acetic acid are added to the resin and stirred at 70°C for 20 h. This is followed by aspiration and washing twice with 2 ml of acetic acid and 2 ml of DMF. J Synthesis of sulfonamides starting from resin- bound amides: The resin is washed twice with 2 ml each of DMF and DCE. 1 ml of 0.5 M sulfonyl chloride in DCE and 400 jal of 2.5 M NMM/1 eq. of 0.25 M DMAP in DMF are added to 0.1 mmol of resin-bound amine. Stirring at 60 °C for 12 h is followed by aspiration and repetition of the coupling. Aspiration is followed by washing four times with 2000 ml of DMF. K Synthesis of ureas by reaction of resin-bound amine with isocyanates: 2 ml of 0.5 M isocyanate in DCM are added to 0.1 mmol of resin-bound amine and stirred at RT for 18 h. Aspiration is followed by washing four times with DMF. L Synthesis of carbamates by reaction of resin-bound amine with preactivated alcohols: For the preactivation, 0.4 M alcohol and 0.39 M dibenzotriazolyl carbonate and 0.39 M pyridine are stirred in DMF at 40°C for 15 min. 1 mmol of resin- bound amine is mixed with 1 ml of preactivated alcohol, and 167 ml of 2.4 M NMM in DMF are added. Stirring at 60°C for 4 h is followed by aspiration and washing four times with DMF. M Synthesis of N-alkylamines by N-alkylation of resin-bound amines with alkyl halides and cazalytic KI: 1 ml of 0.5 M halide/0.05 M KI in DMF and 416 \xl of 2.4 M DIPEA in DMF are added to 0.1 mmol of resin-bound amine and stirred at 90°C for 12 h. After aspiration, the resin is washed four times with 2 ml of DMF. N N-alkylation of resin-bound indole nitrogens with halide/NaH in DMF: 1 ml of DMF and 0.5 mmol of NaH (55% suspension in oil) are added to 0.1 mmol of resin-bound amine. After stirring at RT for 30 min, 1 ml of 0.5 M halide in DMF are added and stirred at 45°C for 8 h. This is followed by aspiration and washing twice each with 2 ml of methanol, DMF, methanol and DMF. 0 Elimination from the Wang, trityl, DHP, Rink amide-resin: 2 ml of 95% TFA/5% H20 solution are added to 0.1 mmol of resin and shaken at RT for 3 h. The resin is then filtered off and washed with a further 2 ml of TFA. The combined TFA solutions are evaporated to dryness and afford the crude products. P Aminolytic elimination from the HMB-resin: 2 ml of DMF and 2 ml of 7 M NH3 in methanol are added to 0.1 mmol of resin and shaken at RT for 18 h. The resin is then filtered off and washed with DMF. The combined solutions are evaporated to dryness and afford the crude product. Preparation of required starting compounds: 3-[[(9H-Fluoren-9-ylmethoxy) carbonyl]amino]-2,3,4,9- tetrahydro-lH-carbazole-3-carboxylic acid 1 38.4 mmol (6.G g) of 4,4-ethylenedioxycyclohexanone and 39.8 mmol (4.3 g) of phenylhydrazine are dissolved separately in 50 ml and 10 ml, respectively, of water, and then mixed. The milky emulsion resulting after stirring for 10 min is extracted five times with ethyl acetate, dried with MgS04 and evaporated to dryness. Yield: 9.2 g of orange oil. 9.2 g of the unpurified phenylhydrazone are dissolved in 240 ml of toluene at RT, and 4.9 g of freshly ground ZnCl2 are added. After refluxing with a water trap for 90 min, most of the toluene is distilled off, an excess of 2 N NaOH is added, and the mixture is extracted three times with ethyl acetate. The extract, is washed with brine and dried with MgS04, and the solvent is distilled off. The remaining black oil is purified on silica gel with ethyl acetate/hexane 1:9. Yield: 2.7 g of beige solid. 11.6 mmol (2.7 g) of 1,2, 4,9-tetrahydrospiro[3H- carbazole-3,2'-[1,3]dioxolane] and 640 mg of p- toluenesulfonic acid are taken up in 70 ml of acetone and stirred at RT for 2.5 h. The solution is added to NaHC03 solution, extracted with ethyl acetate, washed with brine, dried with MgS04 and concentrated. 2.13 g of red-brown solid remain. Recrystallization from ether results in 1.1 g of beige-colored solid. 60.2 mmol (11.1 g) of 1, 2, 4, 9-tetrahydrospiro-3H- carbazol-3-oner 8.3 g of KCN and 22.0 g of (NH4)2C03 are heated in 550 ml of 60% ethanol in an autoclave at 80°C for 3 h. After cooling to room temperature, the reaction mixture is added to ice-water, and the precipitated solid is filtered off. Yield: 10.1 g of gray solid. 44.2 mmol (11.3 g) of 1,2,4,9-tetrahydrospiro[3H- carbazole-3,4'-imidazolidine]-2',5'-dione is heated with 62 g of Ba(OH)2 x 8 H20 in 145 ml of H20 at 150°C for 13 h. After cooling to room temperature, the viscous mass is mixed with 37 g of (NH,)2C03 with stirring and heated at 100°C for 30 min. Cooling to room temperature is followed by filtration, washing with water and evaporation of the filtrate to dryness. Yield: 7.7 g of beige solid. 26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-lH- carbazole-3-carboxylic acid in 2 6 ml of 1 N NaOH and 26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile are combined at room temperature and diluted with 130 ml of acetonitrile/H20 1:1. After two hours, the pH is readjusted to 9 with NEt3 (1.5 ml) and the mixture is stirred at room temperature overnight. Then a further 6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of acetonitrile are added, and stirring is continued for two hours while controlling the pH. Removal of the acetonitrile by distillation is followed by acidification with 0.01 M HC1 and extraction with ethyl acetate. The extract, is washed until neutral, dried with Na2S04 and evaporated to dryness in a rotary evaporator. Recrystallization takes place from ether/hexane. Yield: 10.7 g. XH NMR (d6 DMSO) : 5 = 2.07 ppm (m, 1H) ; 2.50 (m, 1H) ; 2.70 (bs; 2H) ; 3.04 (q, 2H) ; 4.17 (m, 2H) ; 4.28 (m, 2H); 6.92 (tr, 2H); 6.99 (tr, 2H); 7.23 (tr, 2H); 7.24- 7.35 (m, 3H) ; 7.38 (tr, 2H) ; 7.62 (s, 1H) ; 7.68 (dd, 2H); 7.87 (d, 2H); 10.71 (s, 1H) . Melting point: 119°C Fractionation into the two enantiomers takes place by chiral HPLC. (R)-3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]- 2,3,4,9-tetrahydro-lH-carbazole-3~carboxylic acid la. tR = 6.4 min (Chiralcel OD 10 (am LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) (S) -3-[[(9H-Fluoren-9-ylmethoxy)carbony1]amino]- 2, 3,4, 9-tetrahydro-lH-carbazole-3-carboxylic acid lb tR = 7.5 rnin (Chiralcel OD 10 um LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) 1-[[(9H-Fluoren-9~ylmethoxy)carbonyl]amino]-4-oxocyclo- hexanecarboxylic acid 2 320 mmol (50 g) of 4,4-ethylenedioxycyclohexanone are suspended in 800 ml of 50% EtOH, and. 1500 mmol (144.5 g) of (NH4)2C03 and 640 mmol (41.7 g) of KCN are added. After stirring at 60°C for 5 h, the ethanol is removed in vacuo, and the aqueous residue after cooling with ice is filtered off, washed with water and dried. Yield: 72.4 g of 4,4-1,4-dioxa-9,11-diazadi- spiro[4.2.4.2]tetradecane-10,12-dione. 295 mmol (66.8 g) of 4 , 4-1,4-dioxa-9,11-diazadi- spiro[4.2.4.2]tetradecane-10,12-dione and 826 mmol (260.6 g) of Ba(OH)2 x 8 H20 are stirred in 2.5 1 at 150°C in an autoclave for 6 h. After cooling to room temperature, 1032 mmol (99.2 g of (NH4)2C03 are added to the solution and stirred at 60°C for 1 h. The suspension is filtered and washed, and the filtrate is lyophilized. The residue is recrystallized from H20/MeOH. Yield: 45.4 g of 8-amino-l,4-dioxa- spiro[4,5]decane-8-carboxylic acid. 213 mmol (42.9 g) of 8-amino-l,4-dioxaspiro[4,5]decane- 8-carboxylic acid in 213 ml of IN NaOH and 213 mmol (71.9 g) of Fmoc-ONSu in 240 ml of acetonitrile are combined and diluted with 1000 ml of acetonitrile/H20 1:1. Adjustment of the pH to 9 is followed by stirring at room temperature overnight. Removal of the acetonitrile in a rotary evaporator is followed by acidification with 0.01 M HC1 and extraction with ethyl acetate. The extract is washed until neutral, dried with Na2S04 and evaporated to dryness. The residue is recrystallized from ethyl acetate/hexane. Yield: 79.0 g of 8- [ [ (9H-fluoren-9-ylmethoxy)carbonyl]amino]-1, 4- dioxaspiro[4,5]decane-8-carboxylic acid. 187 mmol (79 g) of 8-[[(9H-fluoren-9-ylmethoxy)- carbonyl]amino-1,4-dioxaspiro[4,5]decane-8-carboxylic acid are taken up in 3.5 1 of acetone/0.1 M HC1 1:1 and stirred at room temperature for 4 h. The acetone is stripped off in a rotary evaporator, and the precipitated product is filtered off, washed with water and dried. Yield: 68.7 g of 2. 1H NMR (d6 DMSO) : 8 = 1.52-1.73 (m, 4H) ; 1.82-2.14 (m, 4H) ; 4.27 (m, 3H) ; 7.85 (tr, 2H) ; 7.42 (tr, 2H) ; 7.67 (s, 1H) ; 7.75 (d, 2H) ,- 7.91 (d, 2H) Melting point: 157°C 4-0xocyclohexanecarboxylic acid 3 20 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate are suspended in 40 ml of 2% H2S04 and stirred at 90°C for 2 h. This is followed by extraction four times with ethyl acetate, drying with Na2S04 and removal of the solvent. Recrystallization from ether/hexane affords 2.9 g of white solid 3 XH NMR (d6 DMSO): 8 = 1.72 (m, 2H) ; 2.08-2.18 (m, 2H) ; 2.19-2.47 (m, 4H); 2.72 (m, 1H); 12.23 (bs, 1H). 4-Chloro-3-[[ (phenylamino)carbonyl]amino]benzeneacetic acid 4 18.55 mmol (2.21 g) of S0C12 are slowly added to 18.55 mmol (4 g) of 4-chloro-3-nitrobenzeneacetic acid in 50 ml of MeOH while cooling in ice and stirring. After stirring for 30 min, the mixture is allowed to warm to RT and a further 3.71 mmol (0.44 g) of S0C12 are added. Stirring overnight is followed by heating to reflux for 30 min. Stripping off the solvent is followed by recrystallization from ether/hexane. Yield: 3.43 g of methyl 4-chloro-3-nitrobenzeneacetate as yellowish solid. 13.07 mmol (3.0 g) of methyl 4-chloro-3- nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust are heated to reflux in 500 ml of MeOH for 10 min. Then, under reflux, 13 ml of cone. HC1 are added dropwise, and refluxing is continued for 30 min. The suspension is filtered hot, the methanol is distilled off, and the residue is adjusted to pH 14 with a NaHC03 solution. Extraction with ethyl acetate, drying with Na2S04 and removal of the solvent by distillation affords 2.3 g of methyl 3-amino-4~chlorobenzeneacetate as beige solid. 2.08 mmol (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are dissolved in 40 ml of DCM and, at 0°C, 0.83 mmol (24 6.3 mg) of triphosgene and 0.6 ml of pyridine are added. After stirring at 0°C for one hour, 10.4 mmol (1.11 g) of benzylamine are added, and stirring is continued at room temperature overnight. Extraction is carried out with DCM/H2O, the organic phase is dried, and the solvent is removed. Yield: 727 mg of methyl 4-chloro-3-[[(phenylamino)- carbonyl]amino]benzeneacetate. 2.98 mmol (990 mg) of methyl 4-chloro-3-[[ (phenyl- amino) carbonyl] amino ] benzeneacetate are taken up in 10 ml of methanol, and 6 mmol of 1 N NaOH are added. After stirring at RT for 2 h, the methanol is distilled off and the residue is acidified to pH 2-3 with 1 M HC1. Extraction is carried out with ethyl acetate, and drying with Na2S04, and the solvent is removed. Recrystallization takes place from boiling isopropanol. Yield: 830 mg of white solid £. XH NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.92 (d, 1H) ; 6.99 (tr, 1H) ; 7.35-7.50 (m, 3H) ; 8.10 (s, 1H) ; 8.30 (s, 1H); 9.42 (s, 1H); 12.40 (bs, 1H). 4-Chloro-3-[ [ [ (phenylmethyl) amino] carbonyl] ammo] - benzeneacetic acid 5 2.08 mmol (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are mixed with 10.4 mmol (969 mg) of aniline as described under 4.) and worked up analogously. Yield: 662 mg of solid. For the ester cleavage, 2.47 mmol (790 mg) of methyl 4- chloro-3- [[[(phenylmethyl)amino]carbonyl]amino]benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 5 is obtained without recrystallization. Yield: 693 mg of yellowish solid. ES-MS: 319 (M+H+) 4-Chloro-3-[[(4-pyridinylamino)carbonyl]amino] benzeneacetic acid 6_ 2.08 mmol (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are mixed with 10.4 mmol (97 9 mg) of 4-aminopyridine as described under 4.) and worked up analogously. Yield: 664 mg of solid. For the ester cleavage, 2.63 mmol (840 mg) of methyl 4- chloro-3-[[(4-pyridinylamino)carbonyl]amino] benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 6> is obtained without recrystallization. Yield: 481 mg of yellowish solid. XH NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.94 (d, 1H) ; 7.40 (m, 3H) ; 8.05 (s, 1H) ; 8.35 (d, 2H) ; 8.50 (s,r 1H) ; 9.92 (s, 1H); 12.40 (bs, 1H) 4-Chloro-3- [ [ (2-pyridinylamino) carbonyl ] amino '] benzeneacetic acid _7 2.08 mmol (415 mg) of methyl 3-amino-4- chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 2-aminopyridine as described under 4.) and worked up analogously. Yield: 617 mg of solid. For the ester cleavage, 2.47 mmol (790 mg) of methyl 4- chloro-3-[[(2- pyridinylaraino)carbonyl]amino]benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 7 is obtained without recrystallization. Yield: 693 mg of yellowish solid. XH NMR (d6 DMSO) : 6 = 3.59 (s, 2H) ; 6.94 (dd, 1H) ; 7.03 (dd, 1H); 7.22 (d, 1H); 7.42 (d, 1H) ; 7.78 (dtr, 1H) ; 8.29 (m, 2H); 10.02 (s, 1H) ; 11.82 (bs, 1H) ; 12.50 (s, 1H) . II. Examples of compounds (I) of the invention Example 1; 0.3 mmol (42.6 mg) of 4-oxocyclohexanecarboxylic acid are dissolved in 1 ml of acetic acid and added to a suspension of 0.3 mmol (43.3 g) of phenylhydrazine hydrochloride and 0.3 mmol (40.0 mg) of ZnCl2 in 1 ml of acetic acid. Stirring at 70°C for 20 h is followed by dilution with 20 ml of water and extraction with ethyl acetate. The ethyl acetate phase is washed with water, dried over Na2S04 and evaporated to dryness. Yield: 65.6 mg (100%) of white solid. Name Number Mfnd Mcaie 2,3,4,9-Tetrahydro-lH-carbazole- 3-carboxylic acid 8 215 215.2507 The column headings (name, number of the compound, Mfnd (measured molecular mass) , Mcaic (calculated molecular mass) ) which are introduced here also apply to the following examples and are therefore not repeated again. Example 2: Synthesis takes place on the 0.2 mmol scale by methods A, I and O. 2,3,4,9-Tetrahydro-lH-carbazole- 3-carboxamide 9 214 214.2666 Example 3: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I and 0. N-[(1S)-1-(Aminocarbonyl)-2-methyl propyl]-(35)-2,3,4,9-tetrahydro-lH- carbazole-3-carboxamide 10a 314 313.3987 N-[(15)-1-(Aminocarbonyl)-2-methyl propyl]-(3R)-2,3,4,9-tetrahydro-lH- carbazole-3-carboxamide 10b 314 313.3987 N- (2-Amino-2-oxoethyl)-2, 3,4, 9- tetrahydro-lH-carbazole-3- carboxamide _11 271 271.3183 Example 4: Synthesis takes place on the 0.2 mmol scale by methods D, F, G, F, G, I and 0. N- [(35)-(2,3,4,9-Tetrahydro-lH- carbazol-3-yl)carbonyl]-L-valyl-L- glutamine 12a 442 442.513 N-[(3R)-(2,3,4,9-Tetrahydro-lH- carbazol-3-yl)carbonyl]-L-valyl-L- glutamine, Isomer B 12b 442 442.513 Example 5: Synthesis takes place on the 0.2 mmol scale by methods D, F, G, I, F and O: N-[[(35)-3-Amino-2,3,4,9-tetrahydro- lH-carbazol-3-yl)carbonyl]-L- alanine 13 301 301.3441 Example 6: 0.1 mmol of carboxylic acid, 0.1 mmol of HOBt and 0.15 mmol of amine component are dissolved in 15 ml of dry DMF (also THF, DCM) , and, while cooling in ice and stirring, 0.5 mmol of NMM is added. After about 15 min, 0.15 mmol of EDCI x HC1 is added, and the mixture is stirred for one hour, warmed to room temperature and stirred overnight. For workup, the solvent is stripped off, and the product is dissolved in ethyl acetate and washed twice each with 0.1 N HC1 and saturated NaCl solution. Drying and stripping off the solvent are followed if necessary by recrystallization. 9H-Fluoren-9-ylmethyl[(3S)-3-[[[(4- bromophenyl)methyl]amino]carbonyl]- 2,3,4, 9-tetrahydro-lH-carbazol-3-yl] carbamate 1± 62 0 62 0.54 39 Methyl N-[[(35)-3-[[(9H-fluoren-9-yl methoxy)carbonyl]amino]-2,3,4,9- tetrahydro-l.ff-carbazol-3-yl] carbonyl] - L-alaninate 15 537 537.6129 Example 7; Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G, F, G and 0. - 54 - Example 8: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G and 0. refluxed in dry toluene with a water trap for 2 4 h. The solvent is removed and the residue is taken up in ethyl acetate/water. The organic phase is washed with water, dried and evaporated to dryness. The product is distilled in a Kugelrohr apparatus under high vacuum at 120°C and 0.03 mbar. Yield: 1.52 g of 4-ethyl 1,4-dioxaspiro[4,5]decane-8- carboxylate 269. 85 \|il of diisopropylamine in 500 \|il of dry THF are added dropwise to 0.6 mmol of a 1.6 molar solution of butyllithium in heptane at -20 °C under argon and then stirred for 10 min. After cooling to -70°C, 0.5 mmol (107 mg) of 269 in 200 μ1 of dry THF are added dropwise, allowed to reach 0°C over the course of one hour and stirred for a further 30 min. After cooling to -70°C, 0.7 mmol (106 JJ.1) of l-bromo-3-phenylpropane in 300 p.1 of dry THF are added, and the mixture is stirred for 30 min. It is allowed to reach RT and then stirred for 1 hour. The saturated NH4C1 solution and n-hexane are cautiously added to the organic phase, which is stirred for 10 min. The organic phase is separated and washed with water. Filtration through a Whatman filter is followed by evaporation to dryness. Yield: 165 mg of ethyl 8-(3-phenylpropyl)-1,4- dioxaspiro[4,5]decane-8-carboxylate 270. 0.6 mmol (200 mg) of 270 are taken up in. 25 ml of acetone/0.1 M HC1 1:1 and stirred with catalytic amounts of pTsOH at 50°C for 48 h. The acetone is stripped off in a rotary evaporator, and the precipitated product is filtered off, washed, with water and dried. Yield: 156 mg of ethyl 4-oxo-8-(3-phenylpropyl)cyclo- hexanecarboxylate 271. The indolization takes place as described in Example 1 using phenylhydrazine. Yield after evaporation and preparative HPLC: 65 mg of ethyl 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazole-3-carboxylate 268. ES-MS: 362 (M+H+) 80 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3- phenylpropyl)-lH-carbazole-3-carboxylate 272 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 430 (M+H+) Example 36: 2,3,4, 9-Tetrahydro-3-(3-phenylpropyl)-lH-carbazole-3- carboxylic acid 273 3.94 mmol (1.31 g) of 269 are stirred in 50 ml of methanol and 30 ml of 50% sodium hydroxide solution at 60°C for 4 h. The mixture is acidified with dilute HC1 and extracted with ether. Drying with Na2S04 and evaporation affords 1.02 g (85%) of white solid 8-(3- phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid 274. 65 mg of 274 are first deprotected with HC1 and then reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparative HPLC: 15 mg of 273. ES-MS: 334 (M+H+) 39 mg of 6, 8-dichloro-2,3, 4,9-tetrahydro-3-(3-phenyl- propyl) -lH-carbazole-3-carboxylic acid 275 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 478 (M+H+) Example 31: 2,3,4,9-Tetrahydro-W-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3- carboxamide 276 0.66 mmol (200 mg) of 274 are reacted with 1.5 equivalents of valinol in analogy to Example 6. 277 mg of white solid N-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]- decane-8-carboxamide 277 are obtained. Then 0.3 mmol (117 mg) of 277 are first deprotected with HC1 and subsequently reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparative HPLC: 15 mg of 276. ES-MS: 418 (M+H+) 25 mg of 6,8-dichloro-2,3,4,9-tetrahydro-N-[(1S)-1- (hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H- carbazole-3-carboxamide 278 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 486 (M+H+) Example 38: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-N- (2-pyridinyl- methyl)-lH-carbazole-3-methanamine 279 54 ml of a 1 M solution of LiAlH4 in dry THF are cautiously added to a solution of 18 mmol (6 g) of 270 in 250 ml of dry THF under argon at room temperature. After heating to reflux for 3 h, cautious hydrolysis is carried out with 300 ml. of saturated NH4C1 solution, and 250 ml of ether are added. The aluminum salts are filtered off and washed with ether. Drying of the ether phase with Na2S04 and evaporation of the solvent afford 3.4 g of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]decane- 8-methanol 280. 5.86 mmol (1.7 g) of 280 are dissolved in 60 ml of dry DCM and 20 ml of dry DMSO. Under nitrogen at room temperature, firstly 44 mmol (6.1 ml) of TEA and then cautiously 17.6 mmol (2.8 g) of S03-pyridine complex are added, and the mixture is stirred for one hour. Subsequently 200 ml of saturated NH4C1 solution are added and extraction is carried out with 150 ml of ether. Drying of the ether phase with Na2S04 and evaporation of the solvent afford 1.9 g of 8-(3- phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carbaldehyde 281 as colorless oil.. 0.719 mmol of sodium triacetoxyborohydride are added to a mixture of 0.359 mmol (103 mg) of 281 and 0.359 mmol (37 ml) of 2-pyridinemethanamine in 2.5 ml of 1,2- dichloroethane. The mixture is stirred under N2 at room temperature for 3 h. Saturated NaHCCb solution is added, and the mixture is extracted with ether. The: dried and evaporated ether extract affords 101 mg (76%) of white solid N-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec-8- yl]-2-pyridinemethanamine 282. Subsequently, 101 mg of 282 are first deprotected with HC1 and then reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparation HPLC: 71 mg of 279. ES-MS: 410 (M+H+) 54 mg of 6, 8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl- propyl) -N-(2-pyridinylmethyl)-lH-carbazole-3- methanamine 283 are prepared analogously using 2,4- dichlorophenylhydrazine. ES-MS: 478 (M+H+) Example 39: (2S)-3-Methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenyl- propyl) -l#-carbazol-3-yl]methyl]amino]-1-butanol 284 0.368 mmol (106 mg) of 281 and 0.368 mmol (38 mg) of valinol are dissolved in 1.5 ml of dry methanol and stirred at room temperature for 30 min. After cooling to 0°C, 0.557 mmol (21 mg) of NaBH4 are added and stirred at room temperature for 1 h. 0.437 mmol (25 ul) of acetic acid is added, and stirring is continued at pH 6 for 2 h. Saturated NaHC03 solution is added, and the mixture is extracted with ether. Drying of the organic phase with Na2SC>4 and evaporation affords 106 mg (77%) of colorless oil for 270 and 271. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 18 mg of white solid 284. ES-MS: 405 (M+H+) 17 mg of (2S)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-3- methyl-1-butanol 286 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 473 (M+H+) Example 40: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-0-(4-pyridinyl- methyl)-lH-carbazole-3-methanol 287 0.689 mmol of NaH (as 55% suspension in mineral oil) are added to a solution of 0.344 mmol (100 mg) of 280 in 10 ml of dry DMF at 0°C under an N2 atmosphere. The mixture is allowed to reach room temperature and is stirred for 30 min. 1.377 mmol of 4- (chloromethyl)pyridine are added, and the mixture is stirred at 95-100°C overnight. Cooling to room temperature is followed by hydrolysis with 2 ml of water and extraction with ether. Drying of the solvent and evaporation affords 115 mg of yellow oil 288. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 14 mg of white solid 287. ES-MS: 411 (M+H+) Example 41: Ethyl 3-[2, 3, 4, 9-tetrahydro-3-(3-phenylpropyl)-1H- carbazol-3-yl]-2-propenoate 289 0.347 mmol of 281 in 0.5 ml of THF are added dropwise to a solution of 0.378 mmol of ethyl (triphenylphosphoranylidene)acetate in 1 ml of absolute THF while cooling in ice. After the addition is complete, the mixture is allowed to warm to room temperature and is stirred for a further 2 days. It is then hydrolyzed with water and extracted with ether. Na2SC>4 is used for drying, phosphane oxide and desiccant are filtered off, and the solvent is removed.. Yield 80% of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec- 8-yl]-2-propenoate 290. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 9 mg of white solid 289. ES-MS: 388 (M+H+) III Demonstration of the GnRH-antagonistic effect of compounds (I) of the invention Materials: Buserelin is purchased from Welding (Frankfurt/Main, Germany) . The compound is labeled with 125I by using the chloramine T method and Na125I (4000 Ci/mmol; Amersham- Buchler, Brunswick, Germany). The labeled substance is purified by reverse phase HPLC on a Spherisorb ODS II column (250 x 4 mm, particle size 3 μm) by elution with 50% acetonitrile/0.15% trifluoroacetic acid at a flow rate of 0.5 ml/min. The specific activity is 2000 Ci/mmol. All other chemicals are purchased from commercial source in the highest available purity. Cell culture: Alpha T3-1 cells (Bilezikjian et al., Mol. Endocrinol 5 (1991), 347-355) are cultivated in DMEM medium (Gibco- BRL, Eggenstein-Lepoldshafen, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/1) and 10% fetal calf serum (FCS; PAA Laboratories, Coelbe, Germany) on plastic tissue culture plates (Nunc, 245 x 245 x 20 mm) . CHO-3 cells (Schmid et al. , J. Biol. Chem. 275 (2000), 9193-9200) are cultivated under identical conditions apart from the use of Ham's F12 medium (Gibco-BRL). 10 confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS). The cells are harvested by scraping off with a rubber policeman into 5 ml of PBS and sedimented by centrifugation at 800 rpm for 10 min in a laboratory centrifuge (Heraeus) . The cell pellet is resuspended in 5 ml of 0.25 mol/1 sucrose/0.01 mol/1 triethanolamine, pH 7.4. The cells are lysed by three cycles of freezing in dry ice/ethanol bath and thawing at room temperature. The lysate is centrifuged at 900 rpm for 10 min, and the sediment is discarded. The supernatant is centrifuged at 18 000 rpm in a Sorvall SS34 rotor for 30 min. The pellet (cell membranes) is suspended in 5 ml of assay buffer (0.25 mol/1 sucrose, 0.01 mol/1 triethanolamine, pH 7.5, 1 mg/ml ovalbumin) in a Potter, and stored in 200 \xl aliquots at -20CC. Protein is determined by the method of Bradford (Anal. Biochem. 72 (1976), 248-254). Receptor assay: Binding studies for competition plots are carried out as triplicates. A test sample contains 60 f.il of cell membrane suspension (10 μg of protein for αT3-l-cells or 40 ug of protein for CH03 cells), 20 ul of 125I labeled Buserelin (100 000 ipm per sample for competition plots and between 1500 and 200 000 ipm for saturation experiments) and 20 ul of test buffer or test compound solution. The test compounds are dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10"6 mol/1 to 5 x 10"12 mol/1) are prepared in test buffer. The nonspecific binding is determined in the presence of an excess of an unlabeled Buserelin (10~6 mol/1). The test samples are incubated at room temperature for 3 0 min. Bound and free ligand are separated by filtration (Whatman GF/C filter 2.5 cm diameter) using an Amicon lOx collecting apparatus and washed twice with 5 ml of 0.02 mol/1 Tris/HCl, pH 7.4. The filters are moistened with 0.3% polyethyleneimine (Serva, Heidelberg, Germany) for 3 0 min in order to reduce the nonspecific binding. The radioactivity retained by the filters is determined in a 5-channel gamma counter (Wallac-LKB 1470 Wizard). The IC5o values obtained for the preferred compounds, as defined above, are indicated in the table which follows. in which the radical R1 is a hydrogen atom, a C2-C6 alkenyl or a C1-C6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR11, where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms, and the radical R11 is a hydrogen atom, a C1-C12 alkyl, a C1-C12 aralkyl, an aryl, hetaryl radical or the group -COCH3 and may optionally be substituted by one substituent selected from the group consisting of -CONH2, -COCH3, -COOCH3, -SO2CH3 and aryl radicals; the radicals R2, R3, R4 and R5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1-C6 alkyl, a C1-C6 alkenyl, a C1-C6 alkoxy, a C1-C12 aralkyl, an aryl or hetaryl radical; the radical R6 is the group -CONR8R9, -COOR8, -CH2NR8R9, -CH2R8, -CH2OR8 or a C1-C12 alkenyl radical which is optionally substituted by the radicals R8 and R9, where the radicals R8 and R9 are each independently of one another a hydrogen atom, a C1-C12 alkyl, a C1-C12 aralkyl, a C1-C12 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONHR10, -COOR10, -NH-C(=NH)-NH2 and halogen atoms, where the radical R10 is a hydrogen atom, a C1-C12 alkyl, a C1-C12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R11)2, or where the radicals R8 and R9 may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; the radical R7 is a hydrogen atom, a C1-C12 alkyl, a C1-C12 alkenyl, a C1-C12 aralkyl, an aryl or hetaryl radical, the group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR14 or -NHS02R14 and may optionally be substituted by one or more substituents selected from the group consisting of -OH, -NH2, -CONH2, -COOH and halogen atoms, the radicals R12 and R13 are each independently of one another a hydrogen atom, a C2-C6 alkenyl or a C1-C12 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms, - 101 - and the radical R14 is a hydrogen atom, a C1-C12 alkyl, a C1-C12 alkenyl, a C1-C12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of -N02, -CH3, -OR11, -CF3, -OCF3, -OH, -NCR11) 2, -OCOR11, -COOH, -CONH2, -NHCONHR11, -NHCOOR11 and halogen atoms; and the radicals Ra, Rb, Rc, Rd, Re and Rf are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1-C6 alkyl, C1-C6 alkoxy, an aryl or hetaryl radical; with the proviso that the compound of the general formula (I) is not selected from the group consisting of 3-amino-1,2,3,4-tetrahydrocarbazole- 3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4- tetrahydrocarbazole-3-carboxylic acid, 3-amino-6- benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-l ,2,3, 4-tetrahydrocarbazole-3- carboxylic acid, methyl 3-acetamido-l,2,3,4- tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3- acetamido-1,2,3,4-tetrahydrocarbazole-3-carbox- ylate or 3-tert-butoxycarbonylamino-l,2,3,4-tetra- hydrocarbazole-3-carboxylic acid. The compound as claimed in claim 1, where the radicals Ra, Rb, Rc, Rd, Re and Rf are hydrogen atoms. The compound as claimed in claim 1 or 2, where the radical R1 is a hydrogen atom. The compound as claimed in any of claims 1 to 3, where the radicals R2, R3, R4 and/or R5 are not hydrogen atoms. The compound as claimed in claim 4, where the radicals R2, R3, R4 and R5 are independently of one another the group -CH3, -CI or -OCH3. The compound as claimed in claim 5, where the compound is selected from the group consisting of phenylmethyl [(is, 2S)-1-[[[(3R)-3-[[[ (1S)-1- (aminocarbonyl) --2-methylpropyl] amino] carbonyl] - 2,3,4,9-tetrahydro-8-methyl-lH-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1- (aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6- chloro-2,3,4,9-tetrahydro-lH-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate, and phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1- (aminocarbonyl)-2-methylpropyl]amino]carbonyl]- 2,3,4,9-tetrahydro-8-methoxy-lH-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate. The compound as claimed in any of claims 1 to 5, where the radical R6 is a hydrophobic radical which includes alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system at a distance of from two to four single bonds, counting from the carbon atom substituted by the radicals R6 and R7. The compound as claimed in claim 7, where the radical R6 is selected from the group consisting of a phenylalaninylamide residue, an isoleucylamide residue, a valyl-4-aminobenzamide residue, a valyl-N-methylaroide residue, a methyloxymethyl-4- pyridyl radical, a carboxyl radical, an ethyl propenoate residue, a carbonylvalylamide residue, a carbonylthreonylamide residue, a cyclic carboxamide residue, a 4-carboxamidophenyl- carboxamide residue, a methylaminomethyl-2-pyridyl radical, a carbonylvalinol residue and a methylvalinol residue. The compound as claimed in claim 8, where the compound is selected from the group consisting of phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-2-amino- 2-oxo-l-(phenylmethyl)ethyl]amino]carbonyl]- 2,3,4, 9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S,2S)-1- (aminocarbonyl)-2-methylbutyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l-[ [ [4- (aminocarbonyl)phenyl]amino]carbonyl]-2- methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro- lH-carbazol~3-yl]amino]carbonyl]-2- methylbutyl]carbamate, phenylmethyl [(IS, 2S)-2-methyl-l-[[[(3R)-2,3,4,9- tetrahydro-3-[[[(1S)-2-methyl-l-[(methylamino)- carbonyl]propyl]amino]carbonyl]-lH-carbazol-3- yl]amino]carbonyl]butyl]carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-O-(4- pyridinylmethyl)-lH-carbazole-3-methanol, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazole-3-carboxylic acid, ethyl 3-[2, 3,4,9-tetrahydro-3-(3-phenylpropyl)-1H- carbazol-3-yl]-2-propenoate, phenylmethyl [(lS,2S)-l-[[[(3R)-3~[[[(1S)-1- (aminocarbonyl)-2-methylpropyl]amino]carbonyl]- 2,3,4, 9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [ (IS, 2S)-1-[ [ [ (3R)-3-[[[ (1S,2R)-1- (aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]- 2,3,4, 9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[(2S)-2- (aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate, phenylmethyl [ (is,2S)-1- [ [ [ (3R)-3-[[ (2S) -2- (aminocarbonyl)octahydro-lH-indol-1-yl]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate), phenylmethyl [(is,2S)-1-[[[(3R)-3-[[[4- (aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N- (2- pyridinylmethyl) -lH-carbazole-3-methanamine, phenylmethyl [(IS,2S)-1-[[[(3S)-3-[[[ (1S)-1- (hydroxymethyl)-2-methylpropyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, 2,3,4,9-tetrahydro-N-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3- carboxamide and (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3- phenylpropyl) -l/f-carbazol-3-yl] methyl] amino] -1- butanol. The compound as claimed in any of claims 1 to 5, 7 or 8, where the radical R7 is a hydrophobic radical including alkyl, aryl and/or hetaryl structures. The compound as claimed in claim 10, where the radical R7 is selected from the group consisting of a 2,3-biphenylpropionylamino radical, an indanoylamino radical, an indolylacetylamino radical, a 2-naphthylacetylamino radical, a 3- propionylamino radical, a phenylmethylcarboxamide residue which is substituted on the aromatic system, a phenylhexylamine residue and a phenylpropyl radical. The compound as claimed in claim 11, where the compound is selected from the group consisting of N-[[(31?)-2,3,4,9-tetrahydro-3-[(l-oxo-2, 3- diphenylpropyl)amino]-lH-carbazol-3-yl]carbonyl]- L-valyl-L-aspartamide, (3R)-N-[(1S)-1- (aminocarbonyl)-2-methylpropyl]-3- [[(2,3-dihydro-lH-inden-l-yl)carbonyl]amino]- 2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide, (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]- 2,3,4,9-tetrahydro-3-[(lH-indol-3-ylacetyl)amino]- lH-carbazole-3-carboxamide, (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]- 2,3,4,9-tetrahydro-3-[(2-naphthalinylacetyl)- amino]-lH-carbazole-3-carboxamide, N-[ [ (3£)-2,3,4, 9-tetrahydro-3-[ [ (2S, 3S) -3-methyl- l-oxo-2-[(l-oxo-3-phenylpropyl)amino]pentyl]- amino]-lH-carbazol-3-yl]carbonyl]-L-valyl-L- aspartamide, (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]- 2,3,4,9-tetrahydro-3-[[(4-methylphenyl)acetyl]- amino]-lH-carbazole-3-carboxamide, N- [(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9- tetrahydro-3-[[(4-methoxyphenyl)acetyl]amino]-1H- carbazole-3-carboxamide, (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3- [[(3-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro- lH-carbazole-3-carboxamide, (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3- [[(4-fluorophenyl)acetyl]amino]-2,3,4,9- tetrahydro-lH-carbazole-3-carboxamide, (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3- [[(4-chlorophenyl)acetyl]amino]-2,3,4,9- tetrahydro-lH-carbazole-3-carboxamide, (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3- [bis(3-phenylpropyl)amino]-2,3,4,9-tetrahydro-lH- carbazole-3-carboxamide, 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl- propyl) -lH-carbazole-3-carboxylic acid and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3- phenylpropyl)-LH-carbazole-3-carboxylate. The compound as claimed in any of claims 1 to 5, 7, 8, 10 or 11, where the compound is in the R configuration at the carbon atom substituted by the radicals R& and R7 when the radicals R6 and R7 together form an alpha-amino carboxylic acid structural element. The compound as claimed in claim 1, where the compound is selected from the group consisting of [ (lS,2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)-2- methylpropyl]amino]carbonyl]-6,8-dichloro-2, 3,4,9- tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate, phenylmethyl [(1S,2S) -1-[[[(3R)-3-[[[(1S) -1- (hydroxymethyl)-2-methylpropyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]- carbonyl]-2-methylbutyl]carbamate, (2S)-l-[[[(3R)-3-[[(4-chlorophenyl)acetyl]amino]- 2,3,4,9-tetrahydro-8-methoxy-lH-carbazol-3- yl]carbonyl]-2-pyrrolidinecarboxamide and 6, 8-dichloro-2, 3,4,9-tetrahydro-3-(3-phenyl- propyl)-N-(2-pyridinylmethyl)-lH-carbazole-3- methanamine. A pharmaceutical composition comprising at least one compound as claimed in any of claims 1 to 14. The pharmaceutical composition as claimed in claim 15, where the compound is present in a unit dose of from 1 \xq to 100 mg per kg of a patient's body weight. The pharmaceutical composition as claimed in claim 15 or 16, where the compound is present in combination with at least one further active pharmaceutical ingredient and/or pharmaceutically acceptable carrier in the composition. - 107 - A method for preparing a compound as claimed in any of claims 1 to 14. The compound as claimed in any of claims 1 to 14, for use as pharmaceutical remedy. The use of a compound as claimed in any of claims 1 to 14 for producing a pharmaceutical remedy for the treatment of pathological states mediated by G protein-coupled receptors. The use of a compound as defined in claim 1, but including the compounds specifically excluded in claim 1, for producing a pharmaceutical remedy for inhibiting gonadotropin-releasing hormone. The use as claimed in claim 20 or 21 in male fertility control, in hormone therapy,, treatment of female subfertility or infertility, female contraception and tumor control. The use of a compound as defined in claim 1, but including the compounds specifically excluded in claim 1, for male fertility control or for female contraception. The present invention relates to novel tetrahydrocarbarzole derivatives which are effective as ligands for G-protein coupled receptors (GPCR), especially as antagonists of gonadotropin-releasing hormone (GnRH). The present invention also relates to a pharmaceutical composition comprising these novel tetrahydrocarbazole derivates and to a method for preparing the novel tetrahydrocarbazole derivatives. Furthermore, the present invention also relates to the administration of tetrahydrocarbazole derivatives for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH, to mammals, in particular humans, requiring such an administration, and to the use of tetrahydrocarbazole derivatives for producing a pharmaceutical remedy for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH.

Full Text

TETRYDROCARBAZO DERIVATIVES AS LGANDS FOR
PROTEIN COUPLED RECEPTORS (GPCR)
The present invention relates to novel tetrahydro-
carbazole derivatives which are ligands of G-protein
coupled receptors, and especially antagonists of
gonadotropin-releasing hormone, to the preparation
thereof, to the use thereof, and to the pharmaceutical
compositions- which include these tetrahydrocarbazole
derivatives. The present invention also relates to a
method for treating pathological states mediated by G-
protein coupled receptors in a mammal, in particular a
human.
Technical background
The structural element which is common to all members
of the family of G-protein coupled receptors (GPCR) is
the presence of seven transmembrane alpha-helical
segments which are connected together by alternating
intra- and extracellular loops, with the amino terminus
being located on the extracellular side and the carboxy
terminus being located on the intracellular side. The
family of GPCRs can be divided into a plurality of
subfamilies (essentially family A, B and C) with
further sequence homologies within these subfamilies.
Since GPCRs are mainly involved in signal reception and
transduction, a large number of physiological functions
are influenced by them. GPCR ligands are therefore
potentially suitable as medicaments for the therapy and
prophylaxis of a large number of pathological states. A
brief survey of diseases which can be treated with GPCR
ligands is given in S. Wilson et al., Pharmaceutical'
News 2000, 7(3) in Table 1.
The majority of known GPCR ligands has a peptide
structure. However, peptide receptor ligands frequently
have some serious disadvantages such as, for example,

low bioavailability and metabolic instability. This is
why there has recently been an intensified search for
ligands in the form of small, non-peptide molecules. A
special part is played in the search for novel, non-
5 peptide receptor ligands by so-called "privileged
structures'". These "privileged structures" are the
basic molecular structures which provide ligands for a
large number of different receptors. The term
"privileged structures" was used for the first time by
1.0 Evans et al. in connection with benzodiazepine-based
CCK (cholecys-tokinin) A antagonists from the natural
product asperlicin (B.E. Evans et al. , J. Med. Chem.
1988, 31, 2235) . For proteases for example it has been
known for some time that certain structural classes can
15 serve as inhibitors of various enzymes. Whereas
descriptions in the past were in particular of
mechanism-based inhibitors of various proteases,
however, more recently the frequency of examples of
compounds which, by reason of their three-dimensional
20 structure, fit well into the active binding region of
various enzymes has increased (cf. M. Whittaker, Cur.
Opin. Chem. Biol. 1998, 2, 386; A.S. Ripka et al. ,
ibid., 441). Such "privileged structures" have already
been described for GPCRs too. Examples thereof are,
25 besides the aforementioned benzodiazepines, also
peptoids, 4-substituted 4-arylpiperidines, but also
specific rigidized β-turnimetics (B.A. Bunin et al. ,
Ann. Rep. Med. Chem. 1999, 34, 267; R.N. Zuckermann et
al., J. Med. Chem. 1994, 37, 2678; G.C.B. Harriman,
30 Tetrahedron Lett. 2000, 41, 8853) . A review of this is
to be found in A.A. Patchett et al. , Ann. Rep. Med.
Chem. 1999, 35, 289. The tetrahydrocarbazole
derivatives of the present invention provide a further
class of "privileged structures" for GPCRs.
35
Although the present invention provides ligands for
GPCRs in general, the compounds provided by the present
invention are suitable in particular as ligands for a
particular representative of the class of GPCRs, namely

gonadotropin-releasing hormone receptor (GnRH receptor). GnRH receptor can be
assigned to subfamily A of GPCRs (cfU.Gether et al., Endocrine Reviews 2000, 21(1),
90).
GnRH is a hormone which is synthesized predominantly, but not exclusively, in
mammals by nerve cells of the hypothalamus, is transported via the portal vein into the
pituitary and is delivered in a controlled mannerto gonadotropic cells. Interaction of
GnRH with its receptor having seven transmembrane domains stimulates the production
and release of gonadotropic hormones by means of me second messenger inositol 1,4, 5-
trisphosphate and Ca24 ions. Luteinizing hormone (LH) and follicle-stimulating hormone
(FSH), which are gonadotropins released by GnRH, stimulate the production of sex
steroidsd and gamete maturation in both sexes. In addition to GnRH ( also referred to as
GnRHl), there are two further forms of GnRH, namely GnRH2 and 3.
the GnRH receptor is used as pharmacological target in a number of disorders which
depend on functioning sex hormone production, for example prostrate cancer,
premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or
antagonists can be employed successfully for these disorders. A further possible
indication is, in particular, male fertility control in combination with a replacement dose
of androgens.
One advantage of GnRH antagonists compared with GnRH superagonists is (heir
direct activity in blocking gonadotropoin secretion. Superagonists initially bring
about overstimulation of the pituitary, leading to increased gonadotropin release and
sex steroid release. This hormonal response is terminated only after a certain delay
on the basis of desensitization and downregulation of GnRH receptor
concentrations. It is therefore possible that GnRH superagonists, both alone

and in combination with testosterone, are unable
effectively to suppress sperm production in men and are
thus unsuitable for male fertility control. In contrast
to this, peptide GnRH antagonists, especially in
combination with a replacement dose of androgen, are
able to induce a significant oligozoospermia in humans.
However, peptide GnRH antagonists have a number of
disadvantages. Thus, they have a considerably lower
activity as superagonists and must accordingly be
administered in considerably higher dosages. In
addition, their oral bioavailability is low, so that
they must be administered by injection. Repeated
injections in turn lead to a reduction in compliance.
Furthermore, the synthesis of peptide GnRH antagonists
is complicated and costly by comparison with non-
peptide compounds.
Quinoline derivatives are disclosed as non-peptide GnRH
antagonists for example in WO 97/14682. However, it has
not been possible to date to put any non-peptide GnRH
antagonists on the market.
Technical problem
The problem on which the present invention is based is
to provide novel compounds which are suitable for the
treatment of GPCR-mediated pathological states and
display in particular a GnRH-inhibiting (GnRH-
antagonistic) effect. The novel GPCR ligands,
preferably GnRH antagonists, ought where possible to be
superior to known peptide compounds and represent an
effective alternative or improvement in relation to
known non-peptide compounds. The novel GPCR ligands,
especially GnRH antagonists, should in particular have
high activity and, where possible, a high oral
bioavailability. Their synthesis ought moreover to be
possible simply and at minimal cost. The present
invention also provides pharmaceutical compositions

- 5 -
comprising the novel non-peptide GPCR ligands, in
particular GnRH antagonists.
A further problem on which the present invention is
based is to provide novel GPCR ligands, preferably GnRH
antagonists, for use as pharmaceutical remedy and for
use for producing pharmaceutical remedies, comprising
the GPCR ligands, preferably GnRH antagonists.
In addition,, it is an object of the present invention
to provide a method for the treatment of GPCR-mediated
pathological states, in particular for inhibiting GnRH,
in a mammal, in particular a human.
All these problems are surprisingly solved by the
provision of the novel tetrahydrocarbazole derivatives,
of the pharmaceutical compositions which comprise these
tetrahydrocarbazole derivatives, of the method for
preparing these tetrahydrocarbazole derivatives, and of
the method for the treatment of GPCR-mediated
pathological states, preferably for inhibition of GnRH,
in a mammal, in particular a human, through
administration of the tetrahydrocarbazole derivatives
or the use of the tetrahydrocarbazole derivatives for
producing pharmaceutical remedies for the treatment of
GPCR-mediated pathological states, in particular for
GnRH inhibition.
Summary of the invention
In a first aspect, the present invention provides novel
tetrahydrocarbazole derivatives of the general
formula (I).
In a second aspect, pharmaceutical compositions which
comprise at least one of the novel tetrahydrocarbazole
derivatives of the general formula (I) are provided.

In a third aspect, the present invention provides
tetrahydrocarbazole derivatives of the general formula
(I) for use as pharmaceutical remedy.
In a further aspect, the present invention relates to
the use of a tetrahydrocarbazole derivative of the
general formula (I) for producing a pharmaceutical
remedy for the treatment of GPCR-mediated pathological
states, in particular for inhibition of GnRH. The
present invention likewise relates to a method for the
treatment of GPCR-mediated pathological states, in
particular for inhibition of GnRH, in a mammal,
preferably a human, where an effective amount of a
compound of the invention of the general formula (I) is
administered to the mammal, preferably the human,
requiring such a treatment.
The present invention additionally provides a method
for preparing tetrahydrocarbazole derivatives of the
general formula (I) . This method comprises for example
the steps of condensation of a cyclohexanone
derivative, which is tethered to a solid phase and is
expediently substituted, with a suitably substituted
phenylhydrazine derivative, a subsequent derivatization
depending on the desired structure of the final
compound, and finally elimination from the solid phase
and isolation of the product.
Detailed description of the invention
In a first aspect of the present invention there is
provision of novel tetrahydrocarbazole compounds of the
general formula (I)

(0
in which the radical R! is a hydrogen atom, aC2-C* alkenyl or a Ct-Q alkyl radical and
may optionally be substituted by an aryl, hetaryl radical or the group -COOR11, where
the aryl or hetaryl radical may be substituted by up to three substituents which are
selected independently of one another from the group consisting of-NOa, -CHs, -CF3, -
OCH3, -OCF3 and halogen atoms, and the radical R!l is a hydrogen atom, a C1-Q2 allqfl,
a C1-C12 aralkyl, an aryl, hetaryl, radical or the group -COCH3 and may optionally be
substituted by one substituent selected from the group consisting of-CONHa.-COCH3, -
COOCH3>-S02CH3 and aryl radicals;
me radicals R2, R3, R4 and R5 are each independently of one another a hydrogen atom,
a halogen atom, the group -COOH, -COWh, -CF% -OCF% -N02> -CNS a Ci-Q alkyl, a
(C2-C6 alkenyl, a Ct-Q alkosy, a Ci-Ct2 aralkyl, an aryl or hetaryl radical;
me radical R6 is me group -CONR8, - COOR8, -CHaNR^^CHsR8, -Cr^OR8 or a
C2-Q2 alkenyl radical which is optionally substituted by the radicals R* and R9, where
the radicals R and R are each independently of one another a hydrogen atom, a Ci-Cn
alkyl, a Q-C12 aralkyl, a C1-Q2 heteralkyl, an aryl or heterayl radical, each of which
may be substituted by one or more subatituents selected from the group consisting of-
OHrNH2, -CONHR10, -COOR10, -NH-C (=NH) -NHa and halogen atoms, where the
radical R10 is a hydrogen atom, a C1-C12 alkyl, a C1-C12 aralkyl, an aryl or hetaryl radical

and is optionally substituted by the group -CON(R11)2, or where the radicals R8 and RJ
may together form a cyclic structure which consists either exclusively of carbon atoms or
a combination of carbon atoms andheteroatoms;
the radical R7 is a C2-C12 alkyl, a C2-C12 alkenyl, a C2-C12 aralkyi, an aryl or hetaryi
radical, me group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR14 or - NHSO2R14
and may optionally be substituted by one or more substituents selected from the group
consisting of-OH, -NH2, -CONH2, -COOH and halogen atoms,
the radicals R12 and R13 are each independently of one another a hydrogen atom, a C2-
Ce alkenyl or a C2-C12 alkyl radical and may optionally be substituted by one or more aryl
or hetaryi radicals which in turn may be substituted by up to three substituents selected
independently of one another from the group consisting of -NOa.-CH3, CF3, -OCH5-
OCF3 and halogen atoms, and me radical R14 is a hydrogen atom, a C2-C12 alkyl, aC2-C12
alkenyl, a C2-C12 aralkyi, an aiyl or hetaryi radical which may optionally be
substituted by one or more substituents selected from the group consisting of -NO3, -
CH3, -OR11, -CF3, -OCF3, -OH, -N(R11)2, -OCOR11, -COOH, -CONH2, -NHCONHR11, -
NHCOOR11 and halogen atoms;
and the radicals R\ Rb, Re, Rd, Re and Rf are each independently of one another a
hydrogen atom, a halogen atom, the group -€OOH, -CONH2, -CF% OCF3, -NO2, -CN, a
Ci-Cg alkyl, Ci-Cs alkoxy, an aryl or hetaryi radical;
with the proviso that the compound of the general formula (I) is not selected from the
group consisting of 3-ammo-l,2,3,4-tetrahydrocarbazole-3-carboxylic

acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3-
carboxylic acid, 3-amino-6-benzyloxy-l,2,3 , 4-
tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-
1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl
5 3-acetamido-l, 2,3., 4-tetrahydrocarbazole-3-carboxylate,
(-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3-
carboxylate or 3-tert-butoxycarbonylamino-l,2,3,4-
tetrahydrocarbazole-3-carboxylic acid.
10 One embodiment of the . invention are compounds of the
general formula- (I) as indicated above with all the
meanings indicated above for the radicals contained in
(I), where the radical R11 is a heteroalkyl or a
hetarylalkyl radical.
15
The basic tetrahydrocarbazole structures of those
compounds which are specifically excluded above from
the compounds falling within the definition of the
general formula (I) were introduced by Y. Maki et al.
20 in Chem. Pharm. Bull. 1973, 21 (11), 2460-2465 and by
R. Millet et al. in Letters In Peptide Science 1999, 6,
221-233.
The terms indicated for explanation of the compounds of
2 5 the general formula (I) have in particular the
following meaning:
C1-C6 or C2-C12 "alkyl radical" means a branched or
unbranched, cyclic or acyclic, optionally substituted
3 0 alkyl group having 1 to 6 or 1 to 12 carbon atoms,
respectively. Representative examples of such alkyl
groups include methyl, ethyl, n-propyl, isopropyl, n-
butyl, isobutyl, tert-butyl, n-pentyl, 2,2-
dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, n-
35 octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl
groups, and cyclic groups, in particular cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
groups, 1-cyclopropyl-, 1-cyclobutyl-, 1-cyclopentyl-,
1-cyclohexyl-, 1-cycloheptylethyl-, 2-cyclopropyl-, 2-

cyelobutyl-, 2-cyclopentyl-, 2-cyclohexyl-, 2-
cycloheptylethyl groups and the like, but are not
restricted to these.
C2-C6 "alkenyl radical" means a branched or unbranched,
cyclic or acyclic, optionally substituted, mono- or
polyunsaturated alkenyl group having 2 to 6 carbon
atoms. Representative examples of such alkenyl groups
include vinyl, allyl, prop-1-enyl, but-1-enyl, but-2-
enyl, but-3-enyl, buta-1,3-dienyl, pent-1-enyl, pent-2-
enyl, pent-3-enyl, pent-4-enyl, penta-1,3-dienyl,
penta-1,4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1-
enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl,
hexa-1,3-dienyl, hexa-1,4-dienyl, hexa-1,5-dienyl,
hexa-2,4-dienyl, hexa-2,5-dienyl, hexa-1,4-dienyl,
hexa-1,3,5-trienyl groups and the like, but are not
restricted to these.
C2-C6 "alkoxy radical" means a branched or unbranched,
cyclic or acyclic, optionally substituted alkoxy group
having 2 to 6 carbon atoms. Representative examples of
such alkoxy groups include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-
pentoxy, n-hexoxy, cyclohexyloxy groups and the like,
but are not restricted to these.
C2-C12 "aralkyl radical" means an alkyl radical having 1
to 12 carbon atoms which is substituted by one or more
aryl radicals. Representative examples of such aralkyl
groups for the purposes of the present invention
include benzyl, 1-phenylethyl, 1-phenylpropyl, 1-
phenylbutyl, 1-phenylhexyl, 1-phenyl-2-methylethyl, 1-
phenyl-2-ethylethyl, l-phenyl-2,2-dimethylethyl,
benzhydryl, triphenylmethyl, 2- or 3-naphthylmethyl, 2-
phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-
phenylpentyl groups and the like, but are not
restricted to these. Correspondingly, a "hetaralkyl
radical" is an alkyl radical substituted by a
heteroaryl radical.

"Aryl radical" means an optionally substituted mono- or
polycyclic aromatic group. Representative examples of
such aryl groups- include phenyl, naphthyl groups and
the like, but are not restricted to these.
The term "hetaryl radical" is identical with the term
"heteroaryl radical" and represents an aryl group as
defined above which includes in its structure one or
more heteroatoms, in particular nitrogen, phosphorus,
oxygen, sulfur and arsenic atoms. Representative
examples of such hetaryl or heteroaryl groups include
unsubstituted hetaryl radicals and substituted hetaryl
radicals, in particular imidazolyl, pyridyl, quinolinyl
groups and the like, but are not restricted to these.
The term "cyclic structure" includes optionally
substituted mono- or polycyclic cyclic structures with
a varying number of ring members, in particular five-,
six- and seven-membered cyclic structures. These cyclic
structures may include besides carbon atoms also one or
more heteroatoms such as, in particular, nitrogen,
phosphorus, oxygen, sulfur and arsenic atoms. The
cyclic structures may include saturated, but also
partially or completely unsaturated, structural
elements. Representative examples of such cyclic
structures include aza-, oxa-, thia-,
phosphacyclopentane-, -cyclohexane-, -cycloheptane-,
diaza-, dioxa-, dithia-, diphosphacyclopentane,
-cyclohexane, -cycloheptane basic cyclic structures and
the like, and basic cyclic structures with mixed
heteroatom exchange, but are not restricted to these.
"Halogen atoms" include in particular fluorine,
chorine, bromine and iodine atoms, particularly
preferably chlorine acorns.
Reference may also be made at this point to the fact
that, besides the compounds of the general formula (I),

as defined above, which are mentioned per se, the
present invention also encompasses physiologically
tolerated derivatives or analogs, especially also salts
of these compounds.
It may further be remarked at this point that the term
"receptor ligand" or "ligand" is intended for the
purposes of the present invention to designate any
compound which binds in any manner to a receptor (in
the present invention, the receptor is a GPCR receptor,
preferably a GnRH receptor) and induces either an
activation, inhibition or other conceivable effect on
this receptor. The term "ligand" thus includes
agonists, antagonists, partial agonists/antagonists and
other ligands which elicit on the receptor an effect
which resembles the effect of agonists, antagonists or
partial agonists/antagonists. The compounds of the
invention of the general formula (I) are preferably
GnRH antagonists.
One embodiment of the present invention are novel
tetrahydrocarbazole derivatives of the invention of the
general formula (I) in which the radical R7 is not a
hydrogen atom when the radical R6 is at the same time an
alkyl radical.
A further embodiment of the present invention are
compounds of the general formula (I) in which the
radical R7 is not in any case a hydrogen atom.
Preferred novel tetrahydrocarbazole derivatives of the
invention of the general formula. (I) are those
compounds in which the radicals Ra, RD, Rc, Rd, Re and Rf
are hydrogen atoms.
Likewise preferred novel tetrahydrocarbazole
derivatives of the invention of the general formula (I)
are those compounds in which the radical R1 is a
hydrogen atom.

Preferred novel tetrahydroearbazole derivatives of the invention of the general formula
(I) are additionally those compounds in which the radicals R2, R3, R4 and/or RJ are not
hydrogen atoms. Particularly preferred compounds of the general formula (I) in this
connection are those in which the radicals R2, R3, R4 and Rs are independently of one
another methyl, chloro or methoxy radicals. Very particularly preferred compounds of the
general formula (I) in this connection are those in which at least the radical R2 is not a
hydrogen atom, especially the compounds.
Phenylmethyl[(lS,2S)-l-[[[(3R)-3[[[(lS)-l-(animocaitonyl)-2-methylpropyl]amino]
carbonyl] -2,3,4,9-tetrahydro-8-methyl- lH-carbazol-3 -yl]amino] carbonyl] -2-methylbutyl]
carbamate (compound no. 150a in the examples)
phenylmethyl [ (1S92S)-1- [ [ [ (3R)-3-[ [ [ (lS)-l-(aminocarbonyl)-2-mettiylpropyl]
an3d^o]carbonyl]-6-cMoro-2,3,4,94etrahydro-lH-carbazol-3-yl]amino]carbonyl3-2-
niethyl-butyl] carbamate (148a).
phenylmethyl [(lS,2S)-l-[ [ [ (3R))-3- [ [ [ (1S) -l-(aminocarbonyl)-2-memylpropyl]
ammo]cart)onyl]-2,3,4,94etrahyoVo-8-memo^-lH-carbazol-3-yl]ammo]carbonyl]-2-
methylbutyl]carbamate (147a).
Preferred novel tetrahydrocarbazole derivatives of me invention of the general formula
(I) are also those compounds in which R6 is a hydrophobic radical which includes alkyl,
aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system
at a distance of from two to tour single bonds, counting from the carbon atom substituted
by the radicals R6 and R7. Particularly preferred compounds of the general formula Q) are
those where the radical R6 is a carbonyi-phenylalanylamide residue, in particular the
compound phenylmethyl [ (1S,2S)-1- [ [ [ (3R)-3- [ [ [ (lS)-2-amkto-2-oxo-l-
(phenyhnettiyl) ethyl] amino] carbonyl] 2,3,4,9-tetrahydro-lH-carbazol-3-y]amino]
carbonyt]-2-methyl-butyl]carbamate (66), is a carbonyl isoleucylamide residue, in

particular the compound phenylmethyl [ (1$,2S) -1-[[[ (3R)-3- [ [ [ (1S)-1-
(ammGca&ooyl)-2-methylmethy[(1s,2s)-1-[[[(3R)-3-[[[(1S)-1-
yl]amnio]carbony1]-2-methyl-bulyl] carbamate (64), is a carbonyl vaiyl-4-
aminobenzamide residue, in particular the compound phenylmethyl [ (1S,2S)-1- [ [ [ (1S)
-l-[ [ [ (3R)-3« [ [ [ (1S)-1- [ [ [ 4-(ammocarbonyl)phenyl]amino] carbonyl3-2-memyl-
propyl]amino]carbonyl]-2,3,4,9-tetrahydro- lH-carbazol-3 -yi]amino]carbonyl j -2-
methylbutyl]carbamate (45). is a carbonyl valyl-N-methylamide residue, in particular the
compound phenylmethyl [(lS,2S)-2-methyi-l-[ [ [ (3R)- 2,3,4,9-tetrahydro-3- [ [ [ (1S)-
2-methyi-l-[ (methylamino)-carbonyl]propyl]amino]carbonyl]-lH-carbazol-3-yl] amino]
carbonyl]butyl]carbamate (222a), is a methyloxymetbyl-4-pyridyl radical, in particular
the compound 2, 3, 4, 9-tetrabydro-3-(3-phenylpropyl)-0- (4-pyridinylmethyl)-lH-
carbazole-3-methanol (287), is a carboxyl radical, in particular me compound 2,3,4,9-
tetrahydro-3-(3-phenylpropyl)-lH-carba2ole-3- carboxylic acid (273), or is an ethyl
propenoate radical, in particular the compound ethyl 3-[2,3,4,9-tetrahydro-3-(3-
phenylpropyl)-lH-carbazol-3-yl]-2-propenoate (289). Likewise particularly preferred are
compounds of the general formula (I) in which the radical R6 is a carbonylvalylamide
residue, in particular the compound phenylmethyl [(lS,2S)-l-[ [ [ (3R)-[ [ [ (1S)-1-
(aminocarbonyl)-2-methylpropyl]amino]carbonyl [(1s,2s)-1-[[[(3R)-[[[(1S)-1-
yl]amino]carbonyl]-2-methylbutyl]carbamate (58), is a carbonylmrenolylamide residue,
in particular the compound phenylmethyl [ (1S,2S)-1- [ [ [ (3R)-3- [ [ [ (1S,2R)-1-
(aminocarbonyl)-2-hydroxypropyl]amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-
yl]amino3carbonyl]-2-memylbutyl]carbamate,

- 15 -
is a cyclic carboxamide residue (such as, for example,
a carbonylprolylamide radical, in particular the
compound phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[(2S)-2-
(aminocarbony1)-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetra-
hydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate (181a),
or a carbonyloctahydroindolyl-2-carboxamide residue, in
particular the compound phenylmethyl [(1S,2S)-1-
[ [ [ (3R)-3-[ [ (.2S) -2- (aminocarbonyl)octahydrc-lH-indol-l-
yl]carbonyl]-2,3,4,9-tetrahydro-lH-carbazol-3-
yl]amino]carbonyl]-2-methylbutyl]carbamate (190a)),
is a 4-carboxamidophenylcarboxamide residue, in
particular the compound phenylmethyl [(1S,2S)-1-
[t[(3R)-3-[[[4-(aminocarbony1)phenyl]amino]carbonyl] -
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate (62),
is a methylaminomethyl-2-pyridyl radical, in particular
the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-
(2-pyridinylmethyl)-lH-carbazole-3-methanamine (279),
is a carbonylvalinol residue, in particular the
compounds phenylmethyl [(IS,2S)-1-[[[(3S)-3-[[[(1S)-1-
(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl-
butyl] carbamate (267b)
and 2,3,4, 9-tetrahydro-AT- [ (1S) -1- (hydroxymethyl) -2-
methylpropyl] -3- (3-phenylpropyl) -lff-carbazole-3-
carboxamide (276) -
or is a methylvalinol residue, in particular the
compound (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3-
phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-1-butanol
(284) .
Preferred novel tetrahydrocarbazole derivatives of the
invention of general formula (I) are also compounds in
which R7 is a hydrophobic radical comprising alkyl, aryl
and/or hetaryl structures. Particular preference is
given in this connection to compounds of the general
formula (I) in which the radical R is a 2,3-biphenyl-
propionylamino radical, in particular the compound

N-[ [ (3R)-2,3,4,9-tetrahydro-3-[ (l-oxo-2,3-diphenyl-propy)amino)-lH-carbazol-S-yl ]
carbonyl]-L-valyl-L-aspartamide (18), is an indanoylamino radical, in particular the
compound (3R)-N-[(lS)-l-(aminocarbonyl)-2-melhylpropyI]-3- [[(2,3-dihydro-lH-
inden-1-yl)carbonyl]amino]-2,3,4,9.-tetrahydro-lH-carbazole-3-carboxaniide (162a). is
an indolylacetylamino radical, in particular the compound (3S)-N- { (1S)-1-
(aminocarbonyl)-2-methyl-propyl]-2,3,4,9tetrabydro-3-[ (lH-indol-3-ylacetyl)-amino] -
lH-carbazole-3-carboxamide (164b), is a 2-naphthyIacetylamino radical, in particular the
compound (3S)-N-[(lS)-l-(aminocari)onyl)-2-methyl-propy0-2,3,4>9-tetrahydro-3-[2-
naphtiialinylacetyl)-amino]-lH-carbazole-3-carboxaniide (161b) or is a 3-
propionyiamino radical.
A former preferred compound is N-[ [ (3R)-2,3,4,9-tetrahydro-3-[ [ (2S,3S)-3-memyl-l-
oxo-2-[(l-oxo-3-penylpropyl)atnino]pentyl]-amino]-lH-carbazol-3y1]carbonyl]-L-valyl-
L-aspartamide (22). Likewise particularly preferred are compounds of (be general
formula (I) in which R7 is a phenylmethylcarboxamide residue substituted on the
aromatic system, in particular the compounds (3R)-N-[(lS)-l-(amino-carbonyl)-2-
memylpropyl]-2,3,4,9-tetrahydro-3-[ [ (4-methylphenyl) acetyl] amino] -lH-carbazole-3-
carboxamide(165a),
N-[(lS)-l-aminocarboityl)-2-meurylpro|l]-2>3,4>9-tetrahydro-3-[ [ (4-methoxyphenyl)-
acetyl]amino]-lH-carbazole-3-carboxamide (175),
(3R)-N-[ (lS)-l-(aminocarbonyl)-2-methylpropyl]-3-[ [ (3-bromophenyl) acetyl]amino]-
2>3>4,9-tetrahydro-lH-carbazole-3-carboxamide(96),
(3R)-N-[(lS)-l-ammocarbonyl)-2-methylpropyl]-3-[[(4-fluorophenyl)acetyl]amino]-
2,3,4,9tetrahyhydro-lH-carbazole-3-carboxamide9l),
(3R)-N-[(lS)-l-(aminocarbom?l)-2-methyllpropyl]-3-[[(4-chlorophenyl)acetyl]amino]-
2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide(167a),

is a phenylhexylamine residue, in particular the
compound (3R)-N-[(1S)-1-(aminocarbonyl)-2-methy1-
propyl]-2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-1H-
carbazole-3-carboxamide (234a)
or is a .phenylpropyl radical, in particular the
compounds 6, 8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl-
propyl)-lH-carbazole-3-carboxylic acid (275) and ethyl
6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazole-3-carboxylate (272).
Also preferred are those novel compounds of the
invention of the general formula (I) which are in the R
configuration at the carbon atom substituted by the
radicals R6 and R7 when the radicals R6 and R7 together
form an alpha-amino carboxylic acid structural element.
Most preferred for the purposes of the present
invention are the compounds phenylmethyl [(1S,2S)-1-
[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]-
amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-lH-
carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate
(184a), phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(1S)-1-
(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl-
butyl] carbamate (267a), (2S)-l-[[(3R)-3-[[(4-chloro-
phenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy-lH-
carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a)
and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-
N- (2-pyridinylmethyl)-lH-carbazole-3-methanamine (283) .
Further representatives of novel compounds of the
invention of the general formula (I), including their
preparation, are indicated in the examples.
The novel tetrahydrocarbazole derivatives (I) of the
invention, as defined above, are ligands of GPCR and
can be employed in particular for the inhibition, i.e.
as antagonists, of gonadotropin-releasing hormone for
example for male fertility control, fox' hormone

therapy, for the treatment of female sub- or
infertility, for female contraception and for tumor
control.
In male fertility control, the compounds of the
invention bring about a reduction in spermatogenesis.
Combined administration with androgens, e.g.
testosterbne or testosterone derivatives such as, for
example, testosterone esters, is preferred. The
testosterone derivatives can in this case be
administered for example by injection, e.g. by intra-
muscular depot injection.
The compounds (I) of the invention can also be employed
where appropriate in combination with other hormones,
e.g. estrogens or/and progestins, in hormone therapy,
for example for the treatment of endometriosis, uterine
leiomyomas and uterine fibroids. Combinations of the
GnRH antagonists of the invention and tissue-selective
partial estrogen agonists such as Raloxifen are
particularly preferred. In addition, the compounds of
the invention can be employed in hormones replacement
therapy. The compounds (I) of the invention can
moreover be employed to increase female fertility, for
example by inducing ovulation, and for the treatment of
sterility.
On the other hand, the novel compounds (I) of the
invention are also suitable for contraception in women.
Thus, the GnRH antagonist of the invention can be
administered on days 1 to 15 of the cycle together with
estrogen, preferably with very small estrogen dosages.
On days 16 to 21 of the cycle of intake, progestagen is
added to the estrogen/GnRH antagonist combination. The
GnRH antagonist of the invention can be administered
continuously throughout the cycle. It is possible in
this way to reduce the hormone dosages and thus achieve
a reduction in the side effects of nonphysiological
hormone levels. It. is additionally possible to achieve

advantageous effects in women suffering from polycystic
ovary syndrome and androgen-dependent disorders such as
acne, seborrhea and hirsutism. An improved control of
the cycle by - comparison with previous administration
methods is also to be expected. Further indications are
benign prostate hyperplasia, gonadal protection during
chemotherapy, controlled ovary stimulation/assisted
reproduction techniques, infantile development
disorders, e.g. precocious puberty and polycystic
ovaries.
Finally, the compounds (I) of the invention, as defined
above, can also be employed for the treatment of
hormone-dependent neoplastic diseases such as
premenopausal cancer, prostate cancer, ovarian cancer
and endometrial cancer, by suppressing endogenous sex
steroid hormones.
The novel compounds (I) of the invention, as defined
above, are, as GPCR ligands, m particular GnRH
antagonists, suitable for the treatment of the
pathological states detailed above for administration
to mammals, in particular humans, but also for
veterinary medical purposes, e.g.. in pets and
productive livestock, but also in wild animals.
Administration is possible in a known manner, for
example orally or non-orally, in particular topically,
rectally, intravaginally, nasally or by injection or
implantation. Oral administration is preferred. The
novel compounds (I) of the invention are converted into
a form capable of administration and, where
appropriate, mixed with pharmaceutically acceptable
carriers or diluents. Suitable excipients and carriers
are described for example in Ullman's Encyclopedia of
Technical Chemistry, Vol. 4 (1953), 1-39; Journal of
Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v.
Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie und
angrenzende Gebiete" , Pharm. Ind. 2, 1961, 72ff;

Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe filr
Pharmazie, Kosmetik und angrenzende Gebiete",
Cantor KG, Aulendorf in Wiirttemberg, 1971.
Oral administration can take place for example in solid
form as tablet, capsule, gel capsule, coated tablet,
granulation or powder, but also in the form of a
drinkable solution. For oral administration, the novel
compounds of the invention of the general formula (I),
as defined above, can be combined with known and
conventionally used, physiologically tolerated
excipients and carriers such as, for example, gum
arabic, talc, starch, sugars such as, for example,
mannitol, methylcellulose, lactose, gelatin, surface-
active agents, magnesium stearate, cyclodextrins,
aqueous or nonaqueous carriers, diluents, dispersants,
emulsifiers, lubricants, preservatives and flavors
(e.g. essential oils). The compounds of the invention
can also be dispersed in a microparticulate, e.g. nano-
particulate, composition.
Non-oral administration can take place for example by
intravenous, subcutaneous or intramuscular injection of
sterile aqueous or oily solutions, suspensions or
emulsions, by means of implants or by ointments, creams
or suppositories. Administration as extended-release
form is also possible where appropriate. Implants may
contain inert materials, e.g. biodegradable polymers or
synthetic silicones such as, for example, silicone
rubber. Intravaginal administration is possible for
example by means of pessaries. Intrauterine
administration is possible for example by means of
diaphragms, etc. In addition, transdermal
administration, in particular by means of a formulation
suitable for this purpose and/or suitable means such
as, for example, patches, is also provided.
As already explained above, the novel compounds (I) of
the invention can also be combined with other active

pharmaceutical ingredients. During a combination
therapy, the individual active ingredients can be
administered simultaneously or separately, in
particular either by the same route (e.g. orally) or by
separate routes (e.g. orally and as injection). They
may be present and administered in identical or
different amounts in a unit dose. It is also possible
to apply a particular dosage regimen where this appears
expedient. It is also possible in this way to combine a
plurality of the novel compounds (I) of the invention
together.
The dosage may vary within a wide range depending on
the nature of the indication, the severity of the
disorder, the mode of administration, the age, sex,
body weight and sensitivity of the subject to be
treated. It is within the abilities of a skilled worker
to determine a "pharmacologically effective amount" of
the combined pharmaceutical composition. Unit doses of
from 1 μg to 100 μg, particularly preferably from 1 fig
to 10 mg and most preferably from 1 μg to 1 mg, per kg
of body weight of the subject to be treated are
preferred. Administration can take place in a single
dose or a plurality of separate dosages.
In a further aspect of the present. invention,
accordingly, the present invention also encompasses
pharmaceutical compositions as described above,
comprising at least one of the novel compounds (I) of
the invention, as defined above, and where appropriate
pharmaceutically acceptable carriers and/02: excipients.
Preferred and particularly preferred pharmaceutical
compositions are those comprising at; least one of the
aforementioned preferred or particularly preferred
novel compounds (I) of the invention, in particular the
compounds mentioned by name above. In pharmaceutical
compositions according to the present invention it is
possible, besides the at least, one compound of the
general formula (I), as defined above, for other active

pharmaceutical ingredients also to be present, as
already described in detail above.
At least - one of the novel compounds (I) of the
invention, as defined above, is present in the
pharmaceutical compositions of the invention in one of
the unit doses mentioned above as preferred,
particularly preferred or most preferred, specifically
and preferably in an administration form which makes
oral administration possible.
In addition, in a further aspect, the present invention
provides compounds of the general formula (I) as
defined above for use as pharmaceutical remedy.
Preferred tetrahydrocarbazole compound of the invention
of the general formula (I) , as defined above, for use
as pharmaceutical remedy are in turn those compounds
mentioned above as preferred and particularly preferred
compounds, in particular the preferred compounds of the
invention mentioned by name, and the compounds
mentioned in the examples.
Concerning pharmaceutical compositions comprising
compounds (I) of the invention, and concerning
compounds (I) of the invention for use as
pharmaceutical remedy, reference may be made in
relation to the possibilities for use and
administration to what has already been said concerning
the novel compounds (I) of the invention, as defined
above.
In another aspect, the present invention also provides
the use of at least one tetrahydrocarbazole derivative
of the invention of the general formula (I), as defined
above, with - as defined at the outset - the tetra-
hydrocarbazoles disclosed in the publications by Millet
et al. and Maki et al. being excluded from the meaning
of the general formula (I), for producing a

pharmaceutical remedy for the treatment of GPCR-
mediated diseases, in particular for inhibition of
gonadotropin-releasing hormone (GnRH).
In addition, the present invention provides in a
further aspect the use of at least one compound of the
invention of the general formula (I) as defined above,
but including the compounds previously excluded by name
from the. publications of Millet et al. and Maki et al. ,
namely 3-aminp-l,2,3,4-tetrahydrocarbazole~3-carboxylic
acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3-
carboxylic acid, 3-amino-6-benzyloxy-l,2,3,4-tetra-
hydrocarbazole-3-carboxylic acid, 3-acetamido-l,2 , 3 , 4-
tetrahydrocarbazole-3-carboxylic acid, methyl 3-
acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate,
(-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3-
carboxylate and 3-tert-butoxycarbonylamino-l,2,3,4-
tetrahydrocarbazole-3-carboxylic acid, for producing a
pharmaceutical remedy for inhibiting GnRH, preferably
for male fertility control, for hormone therapy, for
the treatment of female sub- and infertility, for
female contraception and for tumor control. Stated more
clearly, the term "a compound of the general
formula (I) as defined above, but including the
compounds excluded above by name" means a compound of
the general formula (I)

in which the radical R1 is a hydrogen atom, a C2 - C6
alkenyl or a C1 - C6 alkyl radical and may optionally be
substituted by an aryl, hetaryl radical or the group
-COOR11, where the aryl or hetaryl radical may be
substituted by up to three substituents which are
selected independently of one another from the group
consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen
atoms, and
the radical R11 is a hydrogen atom, a C1 - C15 alkyl, a
C1 - C12 aralkyl, an aryl, hetaryl radical or the group
-COCH3 and may optionally be substituted by one
substituent selected from the group consisting of
-CONH2, -COCH3, -COOCH3, -SO2CH3 and aryl radicals;
the radicals R2, R3, R4 and R5 are each independently of
one another a hydrogen atom, a halogen atom, the group
-COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1 - C6 alkyl, a
C1 - C6 alkenyl, a C1 - C6 alkoxy, a C1 - C12 aralkyl, an
aryl or hetaryl radical;
the radical R6 is the group -CONR8R9, -COOR8,. -CH2NR8R9,
-CH2R8, -CH2OR8 or a Ci - C;L2 alkenyl radical which is
optionally substituted by the radicals R8 and R9, where
the radicals R8 and R9 are each independently of one
another a hydrogen atom, a Ci - C12 alkyl, a Ci - C12
-aralkyl, a Ci - C12 hetaralkyl, an aryl or hetaryl
radical, each of which may be substituted by one or
more substituents selected from the group consisting of
-OH, -NH2, -CONHR10, -COOR10, -NH-C (=NH) -NH2 and halogen
atoms,
where the radical R1D is a hydrogen atom, a Ci - C12
alkyl, a Ci - Ci2 aralkyl, an aryl or hetaryl radical
and is optionally substituted by the group -CON(R11)2,
or where the radicals R8 and R9 may together form a
cyclic structure which consists however exclusively of
carbon atoms or a combination of carbon atoms and
heteroatoms;

the radical R7 is a hydrogen atom, a C1 - C12 alkyl, a
C1 - C12 alkenyl, aC1 - C12 aralkyl, an aryl or hetaryl
radical, the group -NR12R13, -NHCOR14, -NHCONHR14,
-NHCOOR14 or -NHS02R14 and may optionally be substituted
by one or more substituents selected from the group
consisting of -OH, -NH2, -CONH2, -COOH and halogen
atoms,
the radicals R12 and R13 are each independently of one
another a hydrogen atom,, a C2 - C6 alkenyl or a CS - Ci2
alkyl radical and may optionally be substituted by one
or more aryl or hetaryl radicals which in turn may be
substituted by up to three substituents selected
independently of one another from the group consisting
of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms,
and the radical R14 is a hydrogen atom, a C1 - C12 alkyl,
a C1 - C12 alkenyl, a C1 - C12 aralkyl, an aryl or
hetaryl radical which may optionally be substituted by
one or more substituents selected from the group
consisting of -N02, -CH3, -OR11, -CF3, -OCF3, -OH,
-N(RU)2, -OCOR11, -COOH, -CONH2, -NHCONHR11, -NHCOOR11 and
halogen atoms;
and the radicals Ra, Rb, Rc, Rd, Re and Rf are each
independently of one another a hydrogen atom, a halogen
atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a
C1 - C6 alkyl, a C1 - C6 alkoxy, an aryl or hetaryl
radical.
The indications already mentioned in connection with
the novel compounds of the invention of the general
formula (I), as defined above (i.e. excluding the
compound disclosed in the publications of Maki et al .
and Millet et al. and mentioned above by name) have
already been given above in relation to the novel
compounds (I) of the invention. The compounds which are
preferred and particularly preferred in the use of the
compounds just defined for producing a pharmaceutical
remedy for inhibiting GnRH are identical to the
preferred and particularly preferred compounds already

mentioned above in connection with the novel compounds
of the invention of the general formula (I) , as defined
above.
The "present invention provides in a further aspect the
use of a compound (I) of the invention as defined
abbve, but likewise including the compounds excluded by
name at the outset, for male fertility control or for
female contraception. Preferred and particularly
preferred compounds of the invention for this use are
those compounds already mentioned at the outset as
preferred or particularly preferred compounds of the
invention of general formula (I) as defined above.
In addition, the present invention provides a method
for male fertility control or for female contraception,
comprising the administration of an amount, effective
for male fertility control or for female contraception,
of a compound of the invention as defined in the
immediately preceding paragraph, to a subject,
preferably a mammal, particularly preferably a human.
In another aspect, the present invention relates to a
method for the treatment of pathological states
mediated by GPCR. The method comprises the
administration of at least one compound (I) of the
invention, as defined above, to a mammal, in particular
a human, when such a treatment is necessary. The
administration normally takes place in a
pharmaceutically effective amount. As already explained
above in relation to the novel compounds (I) of the
invention and the pharmaceutical compositions of the
invention, it is the task of the expert knowledge of a
skilled worker to determine a pharmaceutically
effective amount, depending on the specific
requirements of the individual case. However, the
compounds (I) of the invention are preferably
administered in a unit dose of from 1 μg to 100 mg,
particularly preferably from 1 μq to 10 mg and most

preferably from 1 μg to 1 μg per body weight of subject
to be treated. The preferred administration form is
oral administration. The administration of one or more
of the compounds (I) of the invention in combination
with at least one further active ingredient, as already
explained above, is also provided.
In addition, the present invention also relates to a
method for inhibiting. GnRH in a patient, comprising
administration of a pharmaceutically effective amount
of a compound of the general formula (I) , as defined
above, but including compounds excluded by name above,
to a patient requiring such a treatment. The method is
preferably used in male fertility control, hormone
therapy, female contraception, treatment of female sub-
or infertility and tumor control.
Finally, the present invention provides in a last
aspect also a method for the production of the novel
tetrahydrocarbazole derivatives of the invention of the
general formula (I). The method for the preparation of
the compounds of the invention of the general
formula (I) can be carried out in various ways, e.g. in
liquid phase or as partial or complete solid-phase
synthesis. The choice of the suitable synthesis
conditions for preparing individual representatives of
compounds of the general formula (I) can be made by a
skilled worker on the basis of his common general
knowledge. One method of the invention for the
preparation of compounds of the invention of the
general formula (I) is firstly described generally
below. A specific variant of the method, namely a
solid-phase method, is then described. For further
illustration of the present invention, the examples
listed thereafter include numerous representatives of
compounds of the general formula (I).
One method for the preparation of the compounds of the
invention of the general formula (I) is preferably

carried out in the following way:
The central tetrahydrocarbazole structure can be
obtained by a Fischer- indole synthesis known per se.
For this purpose, a suitably substituted cyclohexanone
derivative provided where appropriate with protective
groups is condensed with the phenylhydrazine derivative
-which is desired in each case and is likewise suitably
substituted and provided where appropriate with
protective groups, (e.g. as described by Britten &
Lockwood, J.C.S. Perkin I 1974, 1824 or as described by
Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In
particular, the cyclohexanone structure is substituted
in positions 3,3', 5,5' and 6,6' via the radicals Ra to
Rf, and in positions 4,4' via the radicals, or where
appropriate by precursors of the radicals, R6 and R7.
The phenylhydrazine structure is optionally substituted
by the radicals R2 to R5. Phenylhydrazine derivatives
which are not commercially available can be prepared by
methods known to the skilled worker. Positional isomers
which result where appropriate in the condensation of
the cyclohexanone derivative and the phenylhydrazine
derivative can be separated by chromatographic methods
such as, for example, HPLC.
After the synthesis of the central tetrahydrocarbazole
structure, the radical R1 can be introduced by
N-alkylation of the nitrogen atom in position 9 with
appropriate R1halides with use of base (e.g. as
described by Pecca & Albonico, J. Med. Chem. 1977, 20,
487 or else as described by Mooradian et al . , J. Med.
Chem. 1970, 13, 327).
The radicals R6 and R7 can, as already indicated above,
be introduced in various ways depending on their
nature, which is explained in detail below.
a-Aminocarboxylic acid structures in these radicals can
be obtained by treating ketones with NH4(CO)3 and KCN

under Schotten-Baumann conditions known per se, and
subsequent alkaline hydrolysis of the hydantoin which
is formed (Britten & Lockwood, J.C.S. Perkin I 1974,
1824) .
Amide residues are preferably generated using methods
known per se from peptide chemistry. For this purpose,
the acid component is activated with an activating
reagent such as DCC or. else HATU (Tetrahedron Lett.
1994, 35, 2279) and condensed in the presence of a base
such as DIPEA and/or DMAP with the amino component.
Ester residues can also be obtained by using the
desired alcohols under analogous conditions. The
solvent used in this case is preferably anhydrous.
Secondary or tertiary amide residues are obtained from
primary amines either by nucleophilic substitution of
alkyl halides or by reductive amination of aldehydes/
ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synth.
Conrm. 1994, 609) .
Sulfonamide residues are obtained from the
corresponding amides by reaction with sulfonyl
chlorides.
Urea residues are obtained by reacting the amines with
appropriate isocyanates.
Urethane residues can be prepared by preactivacing the
appropriate alcohols with carbonyldihydroxybenzo-
triazole ((HOBt)2CO) and subsequently reacted with
amines (Warass et al., LIPS 1998, 5, 125).
Alcohols can be obtained from carboxylic es:ers by
reduction with LiAlH4.
Aldehyde residues are obtained from alcohol precursors
by oxidation for example under Swern conditions known

per se with DMSO/oxalyl chloride (Pansavath et al..
Synthesis 1998, 436).
Substituted amine residues are obtained by reductive
amination of amines with aldehydes (J. Org. Chem. 1996,
61, 3489).
Ether residues can be obtained by deprotonating the
alcohol precursor with a base such as NaH under
Williams conditions known per se and subsequently
reacting with an alkyl halide.
Double bonds in the radicals can be introduced by
reacting an aldehyde or ketone precursor with
appropriate phosphonylides under Wittig conditions
known per se.
A solid-phase method for the preparation or compounds
of the invention of formula (I) preferably includes
steps (a) to (d) explained in detail below:
Step (a) proceeds essentially in analogy to a Fischer
indole synthesis, e.g. as described by Britten &
Lockwood, J.C.S. Perkin I 1974, 1824; Mak i et. al.,
Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman,
Tetrahedron Lett. 1996, 37, 4869 and comprises the
condensation of a cyclohexanone derivative {'.'.) which
contains the group G and is tethered to a solid
phase SP via a linker L suitable tor f o: :v.: ncj the
radical Rb

where, in the case where the radical R7 is a hydrogen
atom, a alkyl, a C1 - C12 aralkyl or a hetaryl
radical, the group G is equal to the radical R7, and in
the case where the radical R7 has another one of the
meanings indicated for R7 in formula (I), the group G is
equal to a group -NH-Pg, where Pg is a protective
group, with a phenylhydrazine derivative (III)
substituted by R2 to R5

On)
in the presence of an acid, preferably acetic acid, and
of a metal salt, preferably ZnCl2. DMF is preferred as
solvent. The radicals Ra to Rf are defined as indicated
above in formula (I). Certain substituents or groups
may, where appropriate, also be present in protected
form, in which case the protective groups are removed
again by methods known per se at a suitable time during
the synthesis.
Particularly suitable solid phase SP for the purposes
of the present invention are Rink amide-resins (Rink,
Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard
et al. , Int. J. Peptide Protein Res. 1982, 20, 451),
Wang resins (Lu et al. , J. Org. Chem. 1981, 46, 3433)
or chlorotrityl-resins (Barlos et al . , Int. J. Peptide
Protein Res. 1991, 38, 562), where the cyclohexanone
derivative (II) is to be tethered to the solid phase SP
by means of an (amino) carboxylic acid. Alcohol
precursors of the cyclohexanone derivative (II) can be
tethered by using the DHP linker (Liu & Elman, J. Org.

Chem. 1995, 60, 7712). Traceless tethering of aromatic
precursors of the cyclohexanone derivative (II) to
triazine resins is possible (Brase et al. , Angew. Chem.
Int. Ed. 1998, 37, 3413).
The protective group Pg which is included where
appropriate in the group G and protects an a-amino
group -NH2 is preferably a "Fmoc" (9-
fluorenylmethoxycarbonyl) protective group, but may
also be another customary amino protective group, e.g.
from the series of the alkoxycarbonyl protective groups
(such as, for example the "Z" (benzyloxycarbonyl) or
the "Boc" (tert-butoxycarbonyl) group) or another
suitable protective group, e.g. a "trityl"
(triphenylmethyl) protective group.
The constitution of the linker L is such that
appropriate derivatization (steps (b) and (c)) and
workup (step (d)) result in the desired radical R6 with
one of the meanings indicated above for R6 in the final
product, the tetrahydrocarbazole derivative of the
general formula (I). To illustrate the constitution of
the linker L, this may be explained below by way of
example for the case where R6 equals the group -CONR8R9.
In the case where the radical Rb in the product of the
invention of the formula (I) has the meaning -CONR8R9,
firstly a compound Pg-N(R8) -R9'-COOH forming the linker
L is tethered by means of an activating reagent such as
DCC (dicyclohexylcarbodiimide) or HATU (0-(7-
azabenzotriazol-1-yl) -N,N-N' , N' -tetramethyluronium
hexafluorophosphate) to the solid phase SP via free
amino groups of the SP, where Pg and SP have the
meaning indicated above, and R9' forms part of the later
radical R9. The protective group Pg is subsequently
eliminated, e.g. in the case of a Fmoc protective group
by means of piperidine/DMF. This results in a compound
HR8N-R9'-CONH-SP. The latter compound is then in turn
reacted with a precursor of the cyclohexanone

derivative (II), namely the cyclohexanone carboxylic
acid (II')

using an activating reagent such as DCC or HATU,
finally resulting in the cyclohexanone derivative (II)
as defined above. The meaning of the linker L in the
case just described is -CONR8-R9'-CONH-SP. Any resulting
isomers of whatever type (enantiomers, diastereomers or
positional isomers) can be fractionated - as also
elsewhere during the described preparation process - in
a known manner by means of HPLC.
The actual step (a), i.e. the condensation of the
cyclohexanone derivative (II) with the substituted
phenylhydrazine derivative (III) and, where
appropriate, elimination of the protective group Pg in
the group G by means of, for example, piperidine (in
the case of a Fmoc protective group) then takes place,
so that a free a-amino group is produced again at this
point.
In the case where the radical R7 is bhe group -NHCOR14,
-NHS02R14, -NR12R13 (where R12 and R:3 are not both
hydrogen atoms), -NHCONHR14 or -NHCOOR14, a
derivatization of the now unprotected a-amino group of
the resin-bound cyclohexanone derivative (II) finally
takes place in step (b) , so that the various
alternative radicals R' defined above can be performed.

Depending on the nature of the desired radical R7 in the
tetrahydrocarbozole final product (I) of the invention,
the procedure for this is as follows:
In the case where R7 is the group -NHCOR14, the reaction
product from step (a) is reacted with a carboxylic acid
R14COOH in the presence of an activating reagent such
as, for example, DCC or HATU and in the presence of a
base such as, for example, DIPEA (diisopropyl-
ethylamine) or DMAP (4-dimethylaminopyridine) by known
processes' for forming peptide linkages (cf., for
example, Tetrahedron Lett. 1994, 35, 22 7 9; alternative
(i))-
In the case where R7 is a sulfonamide group -NHS02R14,
the reaction product from step (a) is reacted with a
sulfonic acid derivative R14So2X, where X is a leaving
group, preferably a halogen atom, in particular a
chlorine atom, in the presence of a base such as, for
example, DMAP or DIPEA (cf., for example, Gennari et
al., EJOC 1998, 2437; alternative (ii)).
In the case where R7 is the group -NR12R13 (where R12 and
R13 are not both hydrogen atoms) , in the case where the
radical R12 is a hydrogen atom, the reaction product
from step (a) is reacted with a reagent R13X, where X is
a leaving group such as, for example, a halide atom, in
particular a chloride atom, in the presence of a base
such as, for example, DBU or DIPEA (cf. Green, JOC
1995, 60, 4287 or JOC 1996, 61, 3849) or with an
aldehyde R13CH0 in the presence of a reducing agent such
as, for example, NaH/B(OAc)3. In the case where neither
of the radicals R12 and R13 is a hydrogen atom, the
reaction product from step (a) is a reacted with a
ketone R12COR13 in the presence of a reducing agent (cf.
Ellmann et al. , JOC 1997, 62, 1240 or Synth. Commun.
1994, 609; alternative (iii)) . In the; case where both
radicals R12 and R13 in R7 equals -NR12R13 are hydrogen
atoms, alternative (vi) below applies.

In the case where R7 is the group -NHCONHR14 (a urea
derivative), the reaction product from step (a) is
reacted with an isocyanate R14NCO (cf. Brown et al. ,
JACS 1997, 119, 3288; alternative (iv)).
In the case where R7 is a carbamate or urethane group
-NHCOOR14, the reaction product from step (a) is reacted
with an alcohol HOR14 which has been preactivated by
carbonyldihydroxybenzotriazole ((H0Bt)2C0) (cf. Warass
et al., LIPS 1998, 5, 125; alternative (v)).
In the case where R7 is a hydrogen atom, a C1 - C12 alkyl,
C1 - C12 aralkyl, an aryl, a hetaryl radical or the group
-NH2 (i.e. both radicals R12 and R13 in R7 equals -NR12R13
are hydrogen atoms) , step (b) is omitted because no
further derivatization is necessary (alternative (vi)).
Step (c) , i.e. the derivatization on the indole
nitrogen atom, also corresponds, in analogy to step (b)
explained above, to various alternatives which are
explained in detail below:
For cases (i) to (v) defined above in step (b) , a
deprotonation of the reaction product obtained in (b)
takes place by means of a base such as, for example,
NaH or NaHMDS and subsequent derivatization by means of
a group R:X, where X is a leaving group, e.g. a halide
atom, in particular a chloride atom (cf. Collini &
Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca &
Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et
al., J. Med. Chem. 1970, 13, 327).
For case (vi) defined above in step (b), i.e. when step
(b) is omitted, in analogy to the above description a
deprotonation of the reaction product obtained in (a)
takes place by means of a base such as, for example NaH
or NaHMDS and subsequent derivatization by means of a

group R1X, where X is a leaving group, e.g. a halide
atom, in particular a chloride atom.
Step (d) finally substantially includes the elimination
5 of the reaction product obtained in (c) from the solid
phase SP. In the case of Wang, trityl, DHP and Rink
amide resins, elimination of the reaction product
obtained in (c) takes place with the aid of an acid, in
particular with TFA (trifluoroacetic acid). In the case
) of an aminolytic elimination from an HMB resin, the
eliminating reagent used is, for example, ammonia in
methanol. The desired product is then isolated in a
conventional way.
i Exemplary embodiments of the preparation of
tetrahydrocarbazole derivatives of the invention are
detailed below.
Examples
i
I. General synthetic methods for compounds of the
invention
A Coupling of carboxylic acids to the Rink amide-
resin :
0.1 mmol of Fmoc-protected Rink amide-resin (166 mg,
loading 0.6 mmol/g) are preswollen with 1.5 ml of DMF
in a vessel with bottom frit for 20 min. After
aspiration, 1.5 ml of 20% piperidine/DMF are added and
stirred for 5 min. After aspiration, a further 1.5 ml
of 20% piperidine/DMF are added and stirred for 15 min.
Aspiration is followed by washing four times with DMF.
Then 675 μa.1 of a 0.267 M solution of Fmoc-protected
amino carboxylic acid in DMF, 67 5 ul of HATU solution
(0.267 M in DMF) and 150 ul of NMM solution (2.4 M in
DMF) and 0.01 mmol of DMAP are added and stirred at
40°C for 4 h. After aspiration, the same reagents are
again added and stirred at 40°C for 4 h. This is
followed by aspiration and washing four times with DMF.

B Coupling of carboxylic acids to the trityl-resin:
2.98 inmol of Fmoc protected aminocarboxylic acid are
dissolved in 3 0 ml of dry dichloromethane, mixed with
14.3 mmol (2.45 ml) of DIPEA and added to 2.98 mmol of
2-chlorotrityl chloride-resin (2 g, loading 1.49 mmol/g
of resin). After shaking for two hours, the resin is
filtered off with suction through a frit and washed
three times with 20 ml of dichloromethane/MeOH/DIPEA
17:2:1. This is followed by washing three times with
20 ml of dichloromethane, three times with methanol and
three times with 2 0 ml of ether and drying in vacuo. A
resin with a loading of 0.5 to 1 mmol of amino
carboxylic acid per g of resin is obtained.
C Coupling of carboxylic acids to the HMB-resin:
21.3 mmol of amino carboxylic acid and 21.3 mmol of
HATU are dissolved in 60 ml of DMF and mixed with
63.9 mmol (10.9 ml) of DIPEA. After 5 minutes, 5 g of
polystyrene-HMB-resm (loading 0.71 mmol/g of resin)
are added and shaken at RT for 5 minutes. Then
21.3 mmol (2.6 g) of DMAP are added and shaken at RT
for 1 h. The resin is subsequently filtered off with
suction and washed once each with 100 ml of DMF, DCM
and DMF. The resin is mixed with 100 ml of 10% Ac20
(acetic anhydride)/DMF/5% DMAP and shaken for 15 min.
Aspiration is followed by washing three times each with
100 ml of DCM and ether and drying in vacuo.
D Coupling of carboxylic acids to the Wang resin:
54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of
DIC are dissolved in 500 ml of dry DCM, and stirred at
RT for 10 min. After the precipitated urea has been
filtered off, the solution is evaporated to dryness and
the residue is dissolved in 160 ml of dry DMF. The
solution is added to 4.55 mmol (5 g, loading
0.91 mmol/g of resin) of Wang resin preswollen in DMF,
and 4.55 mmol (556 mg) of DMAP are added. After shaking
at RT for 1.5 hours, the resin is filtered off with

suction and taken up in 100 ml of 10% Ac20/DMF/5% DMAP
and shaken for 15 min. Aspiration is followed by-
washing three times each with 100 ml of DCM and ether
and drying in vacuo.
i
E Coupling of an alcohol to the DHP-resin:
0.5 mmol of DHP-resin (0.5 g, loading density 1 mmol/g)
are preswollen in 2 ml of dichloroethane for 15 min. To
this are added 2 ml of a solution of 0.75 M
i alcohol/0.37 M pyridinium paratoluenesulfonate and
stirred at 80°C for 16 h. Cooling to RT is followed by
addition of 5 ml of pyridine, briefly shaking with
inversion and filtration with suction. Washing is
carried out twice each with 5 ml of DMF, DCM and
hexane.
F Deprotection of a resin-bound Fmoc protective
group:
1.5 ml of 20% piperidine/DMF are added to 0.1 mmol of
resin-bound Fmoc group and stirred for 5 min. After
aspiration, 1.5 ml of 20% piperidine/DMF are again
added and stirred for 15 min. Aspiration is followed by
washing four times with DMF.
G Coupling of a carboxylic acid to resin-bound amino
functions:
675 ul of a 0.267 M solution of Fmoc-protected amino
carboxylic acid in DMF, 675 ul of HATU solution
(0.267 M in DMF) and 150 ul of NMM solution (2.4 M in
DMF) and 0.01 mmol of DMAP are added to 0.1 mmol of
resin-bound amino functions and stirred at 40°C for
4 h. After aspiration, the same reagents are added
again and stirred at 40°C for 4 h. This is followed by
aspiration and washing four times with DMF.
H Coupling of acetic acid to resin-bound amino
functions:
1.5 ml of a solution of 10% acetic anhydride in DMF are
added to 0.1 mmol of resin-bound amino functions and

stirred at RT for 15 min. This is followed by-
aspiration and washing four times with DMF.
J Synthesis of tetrahydrocarbazoles starting from
resin-bound cyclohexanones:
Before the reaction, .0.1 mmol of cyclohexanone-resin
are washed twice with 2 ml of DMF and twice with 2 ml
of acetic acid. Then 1 ml of DMF and 2 ml of 0.5 M
hydrazine/0.5 M ZnCl2 in acetic acid are added to the
resin and stirred at 70°C for 20 h. This is followed by
aspiration and washing twice with 2 ml of acetic acid
and 2 ml of DMF.
J Synthesis of sulfonamides starting from resin-
bound amides:
The resin is washed twice with 2 ml each of DMF and
DCE. 1 ml of 0.5 M sulfonyl chloride in DCE and 400 ul
of 2.5 M NMM/1 eq. of 0.25 M DMAP in DMF are added to
0.1 mmol of resin-bound amine. Stirring at 60°C for
12 h is followed by aspiration and repetition of the
coupling. Aspiration is followed by washing four times
with 2000 ml of DMF.
K Synthesis of ureas by reaction of resin-bound
amine with isocyanates:
2 ml of 0.5 M isocyanate in DCM are added to 0.1 mmol
of resin-bound amine and stirred at RT for 18 h.
Aspiration is followed by washing four times with DMF.
L Synthesis of carbamates by reaction of resin-bound
amine with preactivated alcohols:
For the preactivation, 0.4 M alcohol and 0.39 M
dibenzotriazolyl carbonate and 0.39 M pyridine are
stirred in DMF at 40°C for 15 min. 1 mmol of resin-
bound amine is mixed with 1 ml of preactivated alcohol,
and 167 ml of 2.4 M NMM in DMF are added. Stirring at
60°C for 4 h is followed by aspiration and washing four
times with DMF.

M Synthesis of N-alkylamines by N-alkylation of
resin-bound amines with alkyl halides and catalytic KI:
1 ml of 0.5 M halide/0.05 M KI in DMF and 416 ul of
2.4 M DIPEA in DMF are added to 0.1 mmol of resin-bound
i amine and stirred at 90°C for 12 h. After aspiration,
the resin is washed four times with 2 ml of DMF.
N N-alkylation of resin-bound indole nitrogens with
halide/NaH in DMF:
1 ml of DMF and 0.5 mmol of NaH (55% suspension in oil)
are added to 0.1 mmol of resin-bound amine. After
stirring at RT for 30 min, 1 ml of 0.5 M halide in DMF
are added and stirred at 45°C for 8 h. This is followed
by aspiration and washing twice each with 2 ml of
methanol, DMF, methanol and DMF.
O Elimination from the Wang, trityl, DHP, Rink
amide-resin:
2 ml of 95% TFA/5% H20 solution are added to 0.1 mmol of
resin and shaken at RT for 3 h. The resin is then
filtered off and washed with a further 2 ml of TFA. The
combined TFA solutions are evaporated to dryness and
afford the crude products.
P Aminolytic elimination from the HMB-resin:
2 ml of DMF and 2 ml of 7 M NH3 in methanol are added to
0.1 mmol of resin and shaken at RT for 18 h. The resin
is then filtered off and washed with DMF. The combined
solutions are evaporated to dryness and afford the
crude product.
Preparation of required starting compounds:
3- [ [ (9H-Fluoren-9-ylmethoxy) carbonyl ]amino] -2,3,4,9-
tetrahydro-lH-carbazole-3-carboxylic acid 1
38.4 mmol (6.0 g) of 4,4-ethylenedioxycyclohexanone and
3 9.8 mmol (4.3 g) of phenylhydrazine are dissolved
separately in 50 ml and 10 ml, respectively, of water,

and then mixed. The milky emulsion resulting after
stirring for 10 min is extracted five times with ethyl
acetate, dried with MgSo4 and evaporated to dryness.
Yield: 9.2 g of orange oil.
9.2 g of the unpurified phenylhydrazone are dissolved
in 240 ml of toluene at RT, and 4.9 g of freshly ground
ZnCl2 are added. After refluxing with a water trap for
90 min, most of the toluene is distilled off, an excess
of 2 N NaOH is added, and the mixture is extracted
three times with ethyl acetate. The extract is washed
with brine and dried with MgS04, and the solvent is
distilled off. The remaining black oil is purified on
silica gel with ethyl acetate/hexane 1:9. Yield: 2.7 g
of beige solid.
11.6 mmol (2.7 g) of 1,2,4,9-tetrahydrospiro[3H-
carbazole-3 , 2 ' - [1, 3 ] dioxolane] and 640 mg of p-
toluenesulfonic acid are taken up in 70 ml of acetone
and stirred at RT for 2.5 h. The solution is added to
NaHCC>3 solution, extracted with ethyl acetate, washed
with brine, dried with MgSo4 and concentrated. 2.13 g of
red-brown solid remain. Recrystallization from ether
results in 1.1 g of beige-colored solid.
60.2 mmol (11.1 g) of 1,2,4,9-tetrahydrospiro-3H-
carbazol-3-one, 8.3 g of KCN and 22.0 g of (NH4)2C03 are
heated in 5 50 ml of 60% ethanol in an autoclave at 80°C
for 3 h. After cooling to room temperature, the
reaction mixture is added to ice-water, and the
precipitated solid is filtered off. Yield: 10.1 g of
gray solid.
44.2 mmol (11.3 g) of 1,2,4,9-tetrahydrospiro[3H-
carbazole-3,4'-imidazolidine]-2',5'-dione is heated
with 62 g of Ba(0H)2 x 8 H20 in 145 ml of H20 at 150°C
for 13 h. After cooling to room temperature, the
viscous mass is mixed with 37 g of (NH4)?C03 with
stirring and heated at 100°C for 30 min. Cooling to

room temperature is followed by filtration, washing
with water and evaporation of the filtrate to dryness.
Yield: 7.7 g of beige solid.
26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxylic acid in 2 6 ml of 1 N NaOH and
26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile
are combined at room temperature and diluted with
130 ml of acetonitrile/H20 1:1. After two hours, the pH
is readjusted to 9 with NEt3 (1.5 ml) and the mixture is
stirred at room temperature overnight. Then a further
6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of
acetonitrile are added, and stirring is continued for
two hours while controlling the pH. Removal of the
acetonitrile by distillation is followed by
acidification with 0.01 M HC1 and extraction with ethyl
acetate. The extract is washed until neutral, dried
with Na2S04 and evaporated to dryness in a rotary
evaporator. Recrystallization takes place from
ether/hexane. Yield: 10.7 g.
XH NMR (d6 DMSO): 5 = 2.07 ppm (m, 1H) ; 2.50 (m, 1H) ;
2.70 (bs; 2H) ; 3.04 (q, 2H) ; 4.17 (m, 2H) ; 4.28 (m,
2H); 6.92 (tr, 2H) ; 6.99 (tr, 2H); 7.23 (tr, 2H); 7.24-
7.35 (m, 3H) ; 7.38 (tr, 2H) ; 7.62 (s, 1H) ; 7.68 (dd,
2H) ; 7.87 (d, 2H) ; 10.71 (s, 1H) .
Melting point: 119°C
Fractionation into the two enantiomers takes place by
chiral HPLC.
(R) -3- [ [ (9H-Fluoren-9-ylmethoxy) carbonyl]amino] -
2,3,4,9-tetrahydro-lH-carbazole-3-carboxylic acid 1M
tR = 6.4 min (Chiralcel OD 10 urn LC50 250 x 4.6 cm,
hexane/isopropanol 75:25, 80 ml/min)
(S) -3- [ [ (9H-Fluoren-9-ylmethoxy) carbonyl]amino] -
2, 3, 4, 9-tetrahydro-lH-carbazole-3-carboxylic acid 1b
tR = 7.5 min (Chiralcel OD 10 um LC50 250 x 4.6 cm,
hexane/isopropanol 75:25, 80 ml/min)

1 - [ [ (9H-Fluoren-9-ylmethoxy) carbonyl]amino] -4-oxocyclo-
hexanecarboxylic acid 2
320 inmol (50 g) of 4,4-ethylenedioxycyclohexanone are
suspended in 800 ml of 50% EtOH, and 1500 mmol'
(144.5 g) of (NH4)2C03 and 640 mmol (41.7 g) of KCN are
added. After stirring at 60°C for 5 h, the ethanol is
removed in vacuo, and the aqueous residue after cooling -
with ice is filtered off, washed with water and dried.
Yield: 72.4 g of 4,4-1,4-dioxa-9,11-diazadi-
spiro[4.2.4.2]tetradecane-10,12-dione.
295 mmol (66.8 g) of 4,4-1,4-dioxa-9,11-diazadi-
spiro[4.2.4.2]tetradecane-10,12-dione and 826 mmol
(260.6 g) of Ba(0H)2 x 8 H20 are stirred in 2.5 1 at
150°C in an autoclave for 6 h. After cooling to room
temperature, 1032 mmol (99.2 g of (NH4)2C03 are added to
the solution and stirred at 60°C for 1 h. The
suspension is filtered and washed, and the filtrate is
lyophilized. The residue is recrystallized from
H20/MeOH. Yield: 45.4 g of 8-amino-l,4-dioxa-
spiro [4,5]decane-8-carboxylic acid.
213 mmol (42.9 g) of 8-amino-l,4-dioxaspiro[4,5]decane-
8-carboxylic acid in 213 ml of 1 N NaOH and 213 mmol
(71.9 g) of Fmoc-ONSu in 240 ml of acetonitrile are
combined and diluted with 1000 ml of acetonitrile/H20
1:1. Adjustment of the pH to 9 is followed by stirring
at room temperature overnight. Removal of the
acetonitrile in a rotary evaporator is followed by
acidification with 0.01 M HCl and extraction with ethyl
acetate. The extract is washed until neutral, dried
with Na2S04 and evaporated to dryness. The residue is
recrystallized from ethyl acetate/hexane. Yield: 79.0 g
of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1,4-
dioxaspiro[4,5]decane-8-carboxylic acid.
187 mmol (79 g) of 8-[[ (9H-fluoren-9-ylmethoxy)-
carbonyl]amino-1,4-dioxaspiro[4,5]decane-8-carboxylic

acid are taken up in 3.5 1 of acetone/0.1 M HC1 1:1 and
stirred at room temperature for 4 h. The acetone is
stripped off in a rotary evaporator, and the
precipitated product is filtered off, washed with water
and dried. Yield: 68.7 g of 2.
1H NMR (d6 DMSO) : 5 = 1.52-1.73 (m, 4H) ; 1.82-2.14 (m,
4H) ; 4.27 (m, 3H) ; 7.85 (tr, 2H) ; 7.42 (tr, 2H) ; 7 ..67
(s, 1H); 7.75 (d, 2H); 7.91 (d, 2H)
Melting point: 157°C
4-0xocyclohexanecarboxylic acid 3
2 0 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate
are suspended in 40 ml of 2% H2SO4 and stirred at 90°C
for 2 h. This is followed by extraction four times with
ethyl acetate, drying with Na2So4 and removal of the
solvent. Recrystallization from ether/hexane affords
2.9 g of white solid 3
lH NMR (d5 DMSO): 5 = 1.72 (m, 2H) ; 2.08-2.18 (m, 2H) ;
2.19-2.47 (m, 4H) ; 2.72 (m, 1H) ; 12.23 (bs, 1H) .
4-Chloro-3- [ [ (phenyl amino) carbonyl ] amino] benzeneacetic
acid £
18.55 mmol (2.21 g) of SOCl2 are slowly added to
18.55 mmol (4 g) of 4-chloro-3-nitrobenzeneacetic acid
in 50 ml of MeOH while cooling in ice and stirring.
After stirring for 30 min, the mixture is allowed to
warm to RT and a further 3.71 mmol (0.44 g) of S0C12 are
added. Stirring overnight is followed by heating to
reflux for 30 min. Stripping off the solvent is
followed by recrystallization from ether/hexane.
Yield: 3.43 g of methyl 4-chloro-3-nitrobenzeneacetate
as yellowish solid.
13.07 mmol (3.0 g) of methyl 4-chloro-3-
nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust
are heated to reflux in 500 ml of MeOH for 10 min.
Then, under reflux, 13 ml of cone. HC1 are added

dropwise, and refluxing is continued for 30 min. The
suspension is filtered hot, the methanol is distilled
off, and the residue is adjusted to pH 14 with a NaHC03
solution. Extraction with ethyl acetate, drying with
Na2S04 and removal of the solvent by distillation
affords 2.3 g of methyl 3-amino-4-chlorobenzeneacetate
as beige solid.
2.08 mmol • (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are dissolved in 40 ml of DCM and,
at 0°C, 0.83 mmol (246.3 mg) of triphosgene and 0. 6 ml
of pyridine are added. After stirring at 0°C for one
hour, 10.4 mmol (1.11 g) of benzylamine are added, and
stirring is continued at room temperature overnight.
Extraction is carried out with DCM/H2O, the organic
phase is dried, and the solvent is removed.
Yield: 727 mg of methyl 4-chloro-3-[[(phenylamino)-
carbonyl]amino]benzeneacetate.
2.98 mmol (990 mg) of methyl 4-chloro-3- [[ (phenyl-
amino) carbonyl]amino]benzeneacetate are taken up in
10 ml of methanol, and 6 mmol of 1 N NaOH are added.
After stirring at RT for 2 h, the methanol is distilled
off and the residue is acidified to pH 2-3 with 1 M
HC1. Extraction is carried out with ethyl acetate, and
drying with Na2SO Recrystallization takes place from boiling isopropanol.
Yield: 830 mg of white solid £.
1H NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.92 (d, 1H) ; 6.99
(tr, 1H) ; 7.35-7.50 (m, 3H) ; 8.10 (s, 1H) ; 8.30 (s,
1H); 9.42 (s, 1H); 12.40 (bs, 1H).
4~Chloro-3-[[[(phenylmethyl)amino]carbonyl] amino]-
benzeneacetic acid 5
2.08 mmol (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are mixed with 10.4 mmol (969 mg)
of aniline as described under 4.) and worked up
analogously. Yield: 662 mg of solid.

For the ester cleavage, 2.47 mmol (790 mg) of methyl 4-
chloro-3-
[ [ [ (phenylmethyl) amino ]carbonyl] amino ]benzeneacetate
are hydrolyzed with 1 N NaOH in analogy to the above
method. The product !5 is obtained without
recrystallization. Yield: 693 mg of yellowish solid.
ES-MS: 3-19 (M+H+)
4-Chloro-3- [ [ (4-pyridinylamino) carbonyl]amino]
benzeneacetic acid £
2.08 mmol (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are mixed with 10.4 mmol (979 mg)
of 4-aminopyridine as described under 4.) and worked up
analogously. Yield: 664 mg of solid.
For the ester cleavage, 2.63 mmol (840 mg) of methyl 4-
chloro-3-[ [ (4-pyridinylamino)carbonyl]amino]
benzeneacetate are hydrolyzed with 1 N NaOH in analogy
to the above method. The product is obtained without
recrystallization. Yield: 481 mg of yellowish solid.
XH NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.94 (d, 1H) ; 7.40
(m, 3H) ; 8.05 (s, 1H) ; 8.35 (d, 2H) ; 8.50 (s, 1H) ; 9.92
(s, 1H); 12.40 (bs, 1H)
4-Chloro-3- [ [ (2-pyri dinylamino) carbonyl ]amino]
benzeneacetic acid 7
2.08 mmol (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are mixed with 10.4 mmol (979 mg)
of 2-aminopyridine as described under 4.) and worked up
analogously. Yield: 617 mg of solid.
For the ester cleavage, 2.47 mmol (790 mg) of methyl 4-
chloro-3-[[(2-
pyridinylamino)carbonyl]amino]benzeneacetate
are hydrolyzed with 1 N NaOH in analogy to the above
method. The product 1_ is obtained without
recrystallization. Yield: 693 mg of yellowish solid.

1H NMR (d6 DMSO) : b = 3.59 (s, 2H) ; 6.94 (dd, 1H) ; 7.03
(dd, 1H) ; 7.22 (d, 1H) ; 7.42 (d, 1H) ; 7.78 (dtr, 1H) ;
8.29 (m, 2H); 10.02 (s, 1H); 11.82 (bs, 1H); 12.50 (s,
1H) .
XI. Examples of compounds (I) of the invention
Example 1:
0.3 mmol (42.6 mg) of 4rOxocyclohexanecarboxylic acid
are dissolved in 1 ml of acetic acid and added to a
suspension of 0.3 mmol (43.3 g) of phenylhydrazine
hydrochloride and 0.3 mmol (40.0 mg) of ZnCl2 in 1 ml of
acetic acid. Stirring at 70°C for 20 h is followed by
dilution with 20 ml of water and extraction with ethyl
acetate. The ethyl acetate phase is washed with water,
dried over Na2S04 and evaporated to dryness. Yield:
65.6 mg (100%) of white solid.
Name Number Mfnd Mcdlc
2,3,4,9-Tetrahydro-lK-carbazole-
3-carboxylic acid 8 215 215.2507
The column headings (name, number of the compound, Mfnd
(measured molecular mass), Mcaic (calculated molecular
mass)) which are introduced here also apply to the
following examples and are therefore not repeated
again.
Example 2:
Synthesis takes place on the 0.2 mmol scale by methods
A, I and O.
2,3,4,9-Tetrahydro-ltf-carbazoie-
3-carboxamide 9_ 214 2 14.2bnb

Example 3:
Synthesis takes place on the 0.2 mmol scale by methods
A, F, G, I and O.
N-[(1S)-1-(Aminocarbonyl)-2-methyl
propyl]-(3S)-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxamide 10a 314 313.3987
N- [(1S)-1-(Aminocarbonyl)-2-methyl
propyl]-(3R)-2,3,4,9-tetrahydro-ltf-
carbazole-3-carboxamide 10b 314 313.3987
N-(2-Amino-2-oxoethyl)-2,3,4,9-
tetrahydro-lfl-carbazole-3-
carboxamide 11 271 271.3183
Example 4:
Synthesis takes place on the 0.2 mmol scale by methods
D, F, G, F, G, I and O.
N-[(3S)-(2,3,4,9-Tetrahydro-lH-
carbazol-3-yl)carbonyl]-L-valyl-L-
glutamine 12a 442 442.513
N-[ (3R) -(2,3,4,9-Tetrahydro-lH-
carbazol-3-yl)carbonyl]-L-valyl-L-
glutamine. Isomer B 12b 442 442.513
Exampl e 5 .-
Synthesis takes place on the 0.2 mmol scale by methods
D, F, G, I, F and O:
N-[[(3S)-3-Amino-2,3,4,9-tetrahydro-
lH-carbazol-3-yl)carbonyl]-L-
alanine 13_ 301 3vi . 3441
Example 6:
0.1 mmol of carboxylic acid, 0.1 mmol of MOB'. and
0.15 mmol of amine component are dissolved in i':> ml of

- 49 -
dry DMF (also THF, DCM) , and, while cooling in ice and
stirring, 0.5 mmol of NMM is added. After about 15-min,
0.15 mmol of EDCI x HCl is added, and the mixture is
stirred for one hour, warmed to room temperature and
stirred .overnight.. For workup, the solvent is stripped
off, and the product is dissolved in ethyl acetate and
washed twice each with 0.1 N HCl and saturated NaCl
solution. Drying and stripping off the solvent are
followed if necessary by recrystallization.
9H-Fluoren-9-ylmethyl[(3S)-3-1[[(4-
bromophenyl)methyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]
carbamate 14 620 620.5439
Methyl N- [[(3S)-3-[[(9tf-fluoren-9-yl
methoxy)carbonyl]amino]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]carbonyl]-
L-alaninate 15 537 537.6129
Exampl e 7:
Synthesis takes place on the 0.2 mmol scale by methods
A, F, G, F, G, F, G and O.

Yield after evaporation and preparative HPLC: 65 mg of
ethyl 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-ltf-
carbazole-3-carboxylate 268.
ES-MS: 362 (M+H+)
80 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-
phenylpropyl)-lff-carbazole-3-carboxylate 272 are
prepared analogously using 2,4-dichlorophenylhydrazine.
ES-MS: 430 (M+H+)
Example 36:
2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-ltf-carbazole-3-
carboxylic acid 273
3.94 mmol (1.31 g) of 269 are stirred in 50 ml of
methanol and 30 ml of 50% sodium hydroxide solution at
60°C for 4 h. The mixture is acidified with dilute HC1
and extracted with ether. Drying with Na2S04 and
evaporation affords 1.02 g (85%) of white solid 8-(3-
phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic
acid 274.
65 mg of 274 are first deprotected with HC1 and then
reacted with phenylhydrazine for the indolization as
described for 270 and 271.
Yield after evaporation and preparative HPLC: 15 mg of
273.
ES-MS: 334 (M+H+)
39 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl-
propyl )-lH-carbazole-3-carboxylic acid 275 are prepared
analogously using 2,4-dichlorophenylhydrazine.
ES-MS: 478 (M+H+)
Example 37:

2, 3, 4, 9-Tetrahydro-N- [ (1S) -1- (hydroxymethyl) -2-
methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3-
carboxamide 276
0.66 mmol (200 mg) of 274 are reacted with 1.5
equivalents of valinol in analogy to Example 6. 277 mg
of white solid N- [(15) -1-(hydroxymethyl)-2-
methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]-
decane-8-carboxamide 277 are obtained.
Then 0.3 mmol (117 mg) of 277 are first deprotected
with HC1 and subsequently reacted with phenylhydrazine
for the indolization as described for 270 and 271.
Yield after evaporation and preparative HPLC: 15 mg of
276.
ES-MS: 418 (M+H+)
25 mg of 6, 8-dichloro-2 , 3 , 4 , 9-tetrahydro-iV- [ (15) -1-
(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H-
carbazole-3-carboxamide 278 are prepared analogously
using 2,4-dichlorophenylhydrazine.
ES-MS: 486 (M+H+)
Example 38:
2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-N- (2-pyridinyl-
methyl)-lH-carbazole-3-methanamine 279
54 ml of a 1 M solution of LiAlH4 in dry THF are
cautiously added to a solution of 18 mmol (6 g) of 270
in 250 ml of dry THF under argon at room temperature.
After heating to reflux for 3 h, cautious hydrolysis is
carried out with 300 ml of saturated NH4CI solution, and
250 ml of ether are; added. The aluminum salts are
filtered off and washed with ether. Drying of the ether
phase with Na2S04 and evaporation of the solvent afford
3.4 g of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]decane-
8-methanol 280.

5.86 mmol (1.7 g) of 280 are dissolved in 60 ml of dry
DCM and 20 ml of dry DMSO. Under nitrogen at room
temperature, firstly 44 mmol (6.1 ml) of TEA and - then
cautiously 17.6 mmol (2.8 g) of S03-pyridine complex are
added, and the mixture is stirred for one hour.
Subsequently 200 ml of saturated NH4CI solution are
added and extraction is carried out with 150 ml of
ether. Drying of the ether, phase with Na2SC>4. and
evaporation of the solvent afford 1.9 g of 8-(3-
phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carbaldehyde
281 as colorless oil.
0.719 mmol of sodium triacetoxyborohydride are added to
a mixture of 0.359 mmol (103 mg) of 281 and 0.359 mmol
(37 ml) of 2-pyridinemethanamine in 2.5 ml of 1,2-
dichloroethane. The mixture is stirred under N2 at room
temperature for 3 h. Saturated NaHC03 solution is added,
and the mixture is extracted with ether. The dried and
evaporated ether extract affords 101 mg (76%) of white
solid N-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec-8-
yl]-2-pyridinemethanamine 282.
Subsequently, 101 mg of 282 are first deprotected with
HCl and then reacted with phenylhydrazine for the
indolization as described for 270 and 271. Yield after
evaporation and preparation HPLC: 71 mg of 279.
ES-MS: 410 (M+H+)
54 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl-
propyl) -N- (2-pyridinylmethyl)-lH-carbazole-3-
methanamine 283 are prepared analogously using 2,4-
dichlorophenylhydrazine.
ES-MS: 478 (M+H+)
Example 39:
(2S)-3-Methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenyl-
propyl) -lH-carbazol-3-yl]methyl]amino]-1-butanol 284

0.368 mmol (106 mg) of 281 and 0.368 mmol (38 mg) of
valinol are dissolved in 1.5 ml of dry methanol and
stirred at room temperature for 30 min. After cooling
to 0°C, 0.557 mmol (21 mg) of NaBH4 are added and
stirred at room temperature' for 1 h. 0.437 mmol (25 ul)
of acetic acid is added, and stirring is continued at
pH 6 for 2 h. Saturated NaHC03 solution is added, and
the mixture is extracted with ether. Drying of the
organic phase with Na2SC>4 and evaporation affords 106 mg
(77%) of colorless oil for 270 and 271.
Deprotection and indolization are then carried out as
described for 270 and 271. Yield after evaporation and
preparative HPLC: 18 mg of white solid 284.
ES-MS: 405 (M+H+)
17 mg of (2S)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3-
(3-phenylpropyl) -lff-carbazol-3-yl]methyl] amino] -3-
methyl-1-butanol 286 are prepared analogously using
2,4-dichlorophenylhydrazine.
ES-MS: 473 (M+H+)
Example 40:
2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinyl-
methyl)-lH-carbazole-3-methanol 287
0.689 mmol of NaH (as 55% suspension in mineral oil)
are added to a solution of 0.344 mmol (100 mg) of 280
in 10 ml of dry DMF at 0°C under an N2 atmosphere. The
mixture is allowed to reach room temperature and is
stirred for 30 min. 1.377 mmol of 4-
(chloromethyl)pyridine are added, and the mixture is
stirred at 95-100°C overnight. Cooling to room
temperature is followed by hydrolysis with 2 ml of
water and extraction with ether. Drying of the solvent
and evaporation affords 115 mg of yellow oil 288.

Deprotection and indolization are then carried out as
described for 270 and 271. Yield after evaporation and
preparative HPLC: 14 mg of white solid 287.
ES-MS: 411 (M+H*)
Example 41:
Ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazol-3-yl]-2-propenoate 289
0.347 mmol of 281 in 0.5 ml of THF are added dropwise
to a solution of 0.378 mmol of ethyl
(triphenylphosphoranylidene)acetate in 1 ml of absolute
THF while cooling in ice. After the addition is
complete, the mixture is allowed to warm to room
temperature and is stirred for a further 2 days. It is
then hydrolyzed with water and extracted with ether.
Na2S04 is used for drying, phosphane oxide and desiccant
are filtered off, and the solvent is removed. Yield 80%
of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec-
8-yl]-2-propenoate 290.
Deprotection and indolization are then carried out as
described for 270 and 271.
Yield after evaporation and preparative HPLC: 9 mg of
white solid 289.
ES-MS: 388 (M+H*)
In addition, the compounds of the invention Nos. 293 to
300, 302 and 304 to 306, which are covered by the
general formula (I), are obtained on the 0.2 mmol scale
by methods A, F, G, F, G and 0, the compound 301 by
methods B, F, G, F, G and 0, and the compound 303 by
methods A, F, G, F, G, F, L and 0.

Deprotection and indolization are then carried out as
described for 270 and 271. Yield after evaporation and
preparative HPLC: 14 mg of white solid 287.
ES-MS: 411 (M+H*)
Example 41:
Ethyl 3-[2, 3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazol-3-yl]-2-propenoate 289
0.347 mmol of 281 in 0.5 ml of THF are added dropwise
to a solution of 0.378 mmol of ethyl
(triphenylphosphoranylidene)acetate in 1 ml of absolute
THF while .cooling in ice. After the addition is
complete, the mixture is allowed to warm to room
temperature and is stirred for a further 2 days. It is
then hydrolyzed with water and extracted with ether.
Na2S04 is used for drying, phosphane oxide and desiccant
are filtered off, and the solvent is removed. Yield 80%
of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec -
8-yl]-2-propenoate 290.
Deprotection and indolization are then carried out as
described for 270 and 271.
Yield after evaporation and preparative HPLC: 9 mg of
white solid 289.
ES-MS: 388 (M+H*)
In addition, the compounds of the invention Nos. 293 to
300, 302 and 304 to 306, which are covered by the
general formula (I), are obtained on the 0.2 mmol scale
by methods A, F, G, F, G and 0, the compound 301 by
methods B, F, G, F, G and 0, and the compound 303 by
methods A, F, G, F, G, F, L and 0.

Ill Demonstration of the GnRH-antagon a st : ' eot of
compounds (I) of the invention
Materials:
Buserelin is purchased from Weldincr 'T '>■'■■ ■ n,
Germany) . The compound is labeled witn he
chloramine T method and Na125I (4000 \ . .•. ■■ s■?-■■ ™-
Buchler, Brunswick, Germany). The lai. ■ ;)C is
purified by reverse phase HPLC on a n-'.^r OD: II
column (250 x 4 mm, particle size 3 j.ii- ■ n ' th
50% acetonitrile/0.15% trif luoroacet: ■ ■. ': i -ow
rate of 0.5 ml/min. The specific' ac / is
2000 Ci/mmol-

All other chemicals are purchased from commercial
source in the highest available purity.
Cell culture:
Alpha T3-1 cells (Bilezikjian et al., Mol. Endocrinol 5
(1991), 347-355) are cultivated in DMEM medium (Gibco-
BRL, Eggenstein-Lepoldshafen, Germany) with penicillin
(100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine
(0.01 mol/1) and 10% fetal calf serum (FCS; PAA
Laboratories, Coelbe, Germany) on plastic tissue
culture plates (Nunc, 245 x 245 x 20 mm) . CHO-3 cells
(Schmid et al. , J. Biol. Chem. 275 (2000), 9193-9200)
are cultivated under identical conditions apart from
the use of Ham's F12 medium (Gibco-BRL).
10 confluent cell culture plates are washed twice with
50 ml of phosphate-buffered saline (PBS). The cells are
harvested by scraping off with a rubber policeman into
5 ml of PBS and sedimented by centrifugation at 800 rpm
for 10 min in a laboratory centrifuge (Heraeus) . The
cell pellet is resuspended in 5 ml of 0.25 mol/1
sucrose/0.01 mol/1 triethanolamine, pH 7.4. The cells
are lysed by three cycles of freezing in dry
ice/ethanol bath and thawing at room temperature. The
lysate is centrifuged at 900 rpm for 10 min, and the
sediment is discarded. The supernatant is centrifuged
at 18 000 rpm in a Sorvall SS34 rotor for 30 min. The
pellet (cell membranes) is suspended in 5 ml of assay
buffer (0.25 mol/1 sucrose, 0.01 mol/1 triethanolamine,
pH 7.5, 1 mg/ml ovalbumin) in a Potter, and stored in
200 ul aliquots at -20°C. Protein is determined by the
method of Bradford (Anal. Biochem. 72 (1976), 248-254).
Receptor assay:
Binding studies for competition plots are carried out
as triplicates. A test sample contains 60 fil of cell
membrane suspension (10 ug of protein for aT3-l-cells
or 40 μg of protein for CH03 cells) , 20 μl of 125I

labeled Buserelin (100 000 ipm per sample for
competition plots and between 1500 and 200 000 ipm for
saturation experiments) and 20 μl of test buffer or
test compound solution. The test compounds are
dissolved in distilled water or 50% ethanol. Serial
dilutions (5 x 10"6 mol/1 to 5 x 10"12 mol/1) are
prepared in test buffer. The nonspecific binding is
determined in the presence of an excess of an unlabeled
Buserelin (10~6 mol/1) . The test samples are incubated
at room temperature for 30 min. Bound and free ligand
are separated by filtration (Whatman GF/C filter 2.5 cm
diameter) using an Amicon lOx collecting apparatus and
washed twice with 5 ml of 0.02 mol/1 Tris/HCl, pH 7.4.
The filters are moistened with 0.3% polyethyleneimine
(Serva, Heidelberg, Germany) for 3 0 min in order to
reduce the nonspecific binding. The radioactivity
retained by the filters is determined in a 5-channel
gamma counter (Wallac-LKB 1470 Wizard) .
The IC50 values obtained for the preferred compounds, as
defined above, are indicated in the table which
follows.

The compounds of numbers 293 to 306 are tested by the
methods indicated below:
Receptor binding assay
Materials:
"-"i-Triptorelin [125I- (D) -Trp6-GnRH] is purchased from
Biotrend (Cologne, Germany). The specific activity is
in each case 2.13 Ci/mmol. All other chemicals are
purchased from commercial sources in the highest purity
available.
Cell culture:
Transfected LTK' cells (ATCC No. CCL 1.3) are
cultivated in DMEM medium (Invicrogen Life
Technologies, Germany) with penicillin (100 I.U./ml),
streptomycin (0.1 mg/ml) and glutamine (0.01 moi/i) and
10% fetal calf serum (FCS; Tnvitroqer. Lite
Technologies, Germany) on plastic tissue culture platr.es
(Nunc, Germany, 245 * 245 x 20 mm).

Testing:
80% confluent cell culture plates ate washed twice with
50 ml of phosphate-buffered saline (PBS) and then
detached with 0.01 M EDTA solution. The cells are
pelleted by centrifugation at 200xg for 5 min in a
laboratory centrifuge (Kendro, Germany). The cell
pellet is resuspended in 3 ml of binding medium (DMEM;
10 mM Hepes; 0.5% BSA; 0.1% NaN3; 1 g/1 Bacitracin (add
fresh, stock 100x) ; 0.1 g/1 SBTI (add fresh, stock
lOOOx) and the cell count is determined by Trypan blue
staining in a Neubauer counting chamber. The cell
suspension is adjusted with binding medium to a
concentration of 5 > 10s cells/0.05 ml.
Binding studies for competition plots are carried out
as duplicates. The test substances are employed as
10 mM DMSO solutions. They are diluted to 4 times the
final concentration employed with binding medium. 25 ul
of the substance dilution are mixed with 25 ul of
tracer solution (*25I-triptorel in) . The tracer
concentration is adjusted to approx. 50 000 cpm
(measured in a Cobra II, y counter, PE Liefe Science,
Germany) in the final reaction volume of 100 ul.
200 ul of silicone/liquid paraffin mixture (84%:16%)
are introduced into 650 ul conical tubes (Roth,
Germany) . 50 ul of the cell suspension are pipetted
thereon, followed by 50 ul of the test substance/tracer
mixture. The tubes are capped and incubated with
vertical rotation in an incubator at. 37°C for 60 min.
After incubation, the samples are centrifuged in a
centrifuge (Kendro, Germany) at 900 rpm and
subsequently shock-frozen in liquid N. . The tip with the
cell pellet is cut off and transferred into prepared
counting vials (Roth, Germany) . The remainder of t.he
conical tube with the remaining supernatant is likewise
transferred into a counting vial. '?ho measurement takes
place in a y counter for 1 min/sample.
Evaluation of the samples takes place after calf.:] at ion
of the specific binding compared with ur.trcored cel,.r>,
after subtraction of the nonspecLi.c binding (excess ot

unlabeled ligand, 1 μm) by means of GraphPad Prism
(GraphPad Software Inc., USA)
Functional reporter gene assay
Materials:
All chemicals are purchased from commercial sources in
the highest purity available.
Cell culture:
Stably transfected LTK cells (ATCC No. CCL-1.3) which
harbor the GnRH receptor and have heterologous
expression of cAMP-responsive elements and a CMV
minimal promoter-driven luciferase reporter gene are
employed to carry out functional investigations.
The cells are cultivated in DMEM medium (Invitrogen
Life Technologies, Germany) with penicillin
(100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine
(0.01 mol/1) and 10% fetal calf serum (FCS; Invitrogen
Life Technologies, Germany) on plastic tissue culture
plates (Nunc, Germany, 245 x 245 x 20 mm).
Testing:
80% confluent cell culture plates are washed twice with
50 ml of phosphate-buffered saline (PBS) and then
detached with trypsin EDTA solution (Invitrogen Life
Technologies, Germany). The cells are pelleted by
centrifugation at 200xg for 5 min in a laboratory
centrifuge (Kendro, Germany). The cell pellet is
resuspended in 3 ml of assay medium (Invitrogen Life
Technologies, Germany) with penicillin (100 I.U./ml),
streptomycin (0.1 mg/ml) and glutamine (0.01 mol/1) and
10% fetal calf serum (FCS; Invitrogen Life
Technologies, Germany), and the cell count is
determined by Trypan blue staining in a Neubauer
counting chamber. The cell suspension is adjusted to a
concentration of lxlO4 cells/100 ul with assay medium.
The cells are set out on white ' 96-well microtiter

plates (Costar, Germany) and incubated in an incubator
for 18 h.
To carry out the test, test substances are diluted as
10 mM DMSO solutions ' in assay medium to 6 times the
final concentration employed. 2 5 ul of the test
substance are added to 100 ul of cells and incubated at
37°C, 5% C02 for 60 min.
Triptorelin (D-Trp6~GnRH)/Rolipram solution (6 nM/6 uM)
is then added, followed by incubation again at 3 7°C, 5%
C02 for 6 h.
Incubation is followed by addition of 50 (0.1 of
lysis/detection buffer (LucLite, PE Life Science) and
measurement in a Lumistar luminometer (BMG
Labtechnologies GmbH, Germany).
Evaluation of the samples takes place after calculation
of the inhibition compared with untreated stimulated
cells, after subtraction of the unstimulated control,
by means of GraphPad Prism (GraphPad Software Inc.,
USA) or alternatively by means of OMMM (Accelrys,
Germany) software.
The EC50 values obtained for compounds 2 93 to 3 06 are
indicated in the table below.

m which (0
me radical R1 is a hydrogen atom, a C2-Cg alkenyl or a Cj-Q alkyl radical and may
optionally be substituted by an aryl, hetaryl radical or the group -€OORu, where the aryl
or hetaryl radical may be substituted by up to three substituents which are selected
independently of one another from the group consisting of -NO?, -CH3, -CF3, -OCH3, -
OCFj and halogen atoms, and me radical Rn is a hydrogen atom, a Ci-Ci2 alkyl, a CI-CQ
aralkyl, an aryl, hetaryl radical or the group -COCH3 and may optionally be substituted
by one substituent selected from the group consisting of-CONIfc, -COCEfe, -COOCH3, -
SO2CH3 and aryl radicals;
the radicals R2, R3„ R4 and R5 are each independently of one another a hydrogen atom, a
halogen atom, the group -COOH, -CONEfe, -CF3, -OCF3, -NOz, -CN, a CrQ alkyl, a C2-
Q alkenyl, a CpQ alkoxy, a Q-C12 arafltyl, an aryl or hetaryl radical;
the radical R6 is the group -CONRsR9' -COOR8(-CH2NR8R9rCHbR8-CKbOR8 or a

C2-C12 alkenyl radical which is optionally substituted by the radicals Rs and R9, where
the radicals R8 and R9 are each independently of one another a hydrogen atom, a C1-C12
alkyl, a C2-C12 aralkyl, a C2-C12 hetaralkyl, an aryl or hetaryi radical, each of which may
substituted by one or more substituents selected from the group consisting of-OH, -NHa,
-CQNHR10, -COOR!0,-NH-C(=NH)-NH2 and halogen atoms, where the radical R10 is a
hydrogen atom, a C1-Q2 alkyl, a QQ2 aralkyl, an aryl or hetaryi radical and is optionally
substituted by the group -CON(R")2, or where the radicals R8 and R9 may together form
a cyclic structure which consists either exclusively of carbon atoms or a combination of
carbon atoms and heteroafoms;
the radical R7 is a C1-C12 alkyl, a C2-C12 alkenyl, a C1-C12 aralkyl, an aryl or hetaryi
radical, the group -NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR54 or -NHSO2R14
and may optionally be substituted by one or more substituents selected from the group
consisting of-OH, -NHa, -CONH2, -COOH and halogen atoms,
10 1*2
the radicals R and R are each independently of one another a hydrogen atom, a C2-C4
alkenyl or a C2-C12 a&yl radical and may optionally be substituted by one or more aryl or
hetaryi radicals which in turn may be substituted by up to three substituents selected
independently of one another from the group consisting of -NO2, -CH3,-CFs, -OCHs, -
OCF3 and halogen atoms,

and the radical R14 is a hydrogen atom, a Ci-C12
alkyl, a C2-C12 alkenyl, a C2-C12 aralkyl, an aryl
or hetaryl radical which may optionally be
substituted by one or more substituents selected
from the group consisting of -NO2, -CH3/ -OR11,
-CF3, -OCF3, -OH, -N(R11}2, -OCOR11, -COOH, -CONH2,
-NHCONHR11, -NHCOOR11 and halogen atoms;
and the radicals Ra, Rb, Rc, Rd, Re and Rf are each
independently of one another a hydrogen atom, a
halogen atom, the group -COOH, -CONH2, -CF3# -OCF3,
-N02, -CN, a C2-C6alkyl, C1-C6 alkoxy, an aryl or
hetaryl radical;
with the proviso that the compound of the general
formula (I) is not selected from the group
consisting of 3~amino-l,2,3,4-tetrahydrocarbazole-
3-carboxylic acid, 3-amino-6-methoxy-l,2,3 , 4-
tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-
benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic
acid, 3-acetamido-l,2,3,4-tetrahydrocarbazole-3-
carboxylic acid, methyl 3-acetamido-l,2,3,4-
tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-
acetamido-1,2,3,4-tetrahydrocarbazole-3-carbox-
ylate or 3-tert-butoxycarbonylamino-l,2,3,4-tetra-
hydrocarbazole-3-carboxylic acid.
2. The compound as claimed in claim 1, where the
radicals Ra, Rb, Rc, Rd, Re and R£ are hydrogen
atoms.
3. The compound as claimed in claim 1 or 2, where the
radical R1 is a hydrogen atom.
4. The compound as claimed in any of claims 1 to 3,
where the radicals R2, R3, R4 and/or RD are not
hydrogen atoms.

5. The compound as claimed in claim 4, where me radicals R2, R3, R4 and R5 are
independently of one another me group -CH3. -CI or -OCH3.
6. The compound as claimed in claim S, where the compound is selected from
the group consisting of phenylmemyi [(lS,2S)-l-[ [ [ (3R)-3-[ [ [ (1S)-1-
(aminocarbonyl)-2-methylpropoyl]ammo]ea^
carba2»l-3-yl]afiiko]c8ri)onyl]-2-metiiylbu^^
[[[(3R)-3-[[[ (lS)-l-(amkoearbonyl)-2-memylpropyl]anuno]c
te phenylmemyi [(lS,2S)-l-[ [ [(lS)-l-(3R)-3-[[[(lS)-l-aminocarbonyl)-2-memylpropyI]
aminojcarbonylJ-U^jP-tetrahydro-S-memoxy-lH-carbaEol-S-yl] amino] carbonyl]-2-
methylbutyljcarbamate.
7. The compound as claimed in any of claims 1 to 5, where the radical R6 is a
hydrophobic radical which includes alkyl, aryl and/or hetaryl structurese and which
carries a hydrogen bond donor-acceptor system at a distance of from two to four single
bonds, counting from me carbon atom substituted by the radicals R* and R7.
8. The compound as claimed in claim 7, where the radical R6 is selected from the group
consisting of a carbonyl phenylalanylamide residue, a carbonyl isoleucylamide residue, a
carbonyi vaiyi-4-aminobenzamide residue, a carbonyl valyl-N-methylamide residue, a
memylosymethyl-4- pyridyl radical, a carboxyl radical, an ethyl propenoate residue, a
carbonylvalylamide residue a carbonylthreonylamide residue, a cyclic carboxmide
residue, a 4-carboxamidophenyl- carboxamide residue, a meftylammomemyl-2-pyridyl
radical, a carbonylvaiinoi residue and amethylvalinol residue.

The compound as claimed in claim 8, where the
compound is selected from the group consisting of
phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(1S)-2-amino-
2-oxo-l-(phenylmethyl)ethyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(IS,2S)-1-
(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [ (lS,2S)-l-[[[(3R)-3-[[[(lS)-l-[[ [4-
(aminocarbonyl)phenyl]amino]carbonyl]-2-
methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-
lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl] carbamate.,
phenylmethyl [(IS,2S)-2-methyl-l-[[[(3R)-2,3,4,9-
tetrahydro-3-[[[(1S)-2-methyl-l-[(methylamino)-
carbonyl]propyl]amino]carbonyl]-lH-carbazol-3-
yl]amino]carbonyl]butyl]carbamate,
2,3,4,9-tetrahydro-3-(3-phenylpropyl)-0-(4-
pyridinylmethyl)-lH-carbazole-3-methanol,
2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazole-3-carboxylic acid,
ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazol-3-yl]-2-propenoate,
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1-
(aminocarbonyl) -2-methylpropyl] amino] carbonyl] -
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [ (IS, 2S)-l-[ [ [ (3R) -3- [ [ [ (IS, 2J?)-1-
(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]-
2,3,4,9-tetrahydro-ltf-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[(2S)-2-
(aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate,

phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[(2S)-2-
(aminocarbonyl)octahydro-lH-indol-1-yl]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-
yl]amino]carbonyl]-2-methylbutyl]carbamate),
phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[4-
(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate,
2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N- (2-
pyridinylmethyl)-lH-carbazole-3-methanamine,
phenylmethyl [(lS,2S)-l-[[[(3S)-3-[[[(1S)-1-
(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
2,3,4,9-tetrahydro-W- [(1S)-1-(hydroxymethyl)-2-
methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3-
carboxamide and
(2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3-
phenylpropyl)-IH-carbazol-3-yl]methyl]amino]-1-
butanol.
The compound as claimed in any of claims 1 to 5, 7
or 8, where the radical R7 is a hydrophobic radical
including alkyl, aryl and/or hetaryl structures.
The compound as claimed in claim 10, where the
radical R7 is selected from the group consisting of
a 2, 3-biphenylpropionylamino radical, an
indanoylamino radical, an indolylacetylamino
radical, a 2-naphthylacetylamino radical, a 3-
propionylamino radical, a phenylmethylcarboxamide
residue which is substituted on the aromatic
system, a phenylhexylamine residue and a
phenylpropyl radical.
The compound as claimed in claim 11, where the
compound is selected from the group consisting of

dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3-yl]amino]carbonyl]-3-
phenylpropyl]carbamate,phenylmethyl[(1S)-l-[[[(3R)-3-[[[(lS,2S)-l-
(aminoocarbonyl)-2-methylbutyl]amino-carbonyl]-6,8-dichloro-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-3-met±iylbutyl]carbamate,
phenylmethyl[(lS)-l-[[[(3R)-3-[[[(lS)-l-aminocarbonyl)-3-
methylbutyl]amino]carbonyl]-6,8-dichloro-2>3,4,9-tetrahydro-lH-
carbazol-3-yl]amino]carbonyl]-3-methylbutyl]carbamate.
19. A method of preparing a compound as claimed in claim 18,
comprising the steps of coupling Fmoc protected amino carboxylic acid to
the Rink amide-resin in the presence of an activating agent and a base,
followed by deprotection of the resin-bound Fmoc protective group using
piperidine / DMF,
coupling the Fmoc-protective carboxylic acid to resin bound amino
functions
followed by a further step of deprotection of the Fmoc protective amino
group and coupling the Fmoc protected carboxylic acid to resin bound
amino functions and elimination of the reaction product from the resin
by treatment with trifluoroacetic acid.
20. The compound as claimed in claim 18, for use as pharmaceutical
remedy.
Dated this 8th DAY OF JUNE, 2004.

(T)
The invention relates to novel tetrahydrocarbozole derivatives acting as ligands for G-protein
coupled receptors (GPCR), especially as antagonists of gonadotropin-releasing hormone
(GnRH). The invention also relates to a pharmaceutical composition containing said novel
tetrahydrocarbozole derivatives, and to a method for producing the same. Furthermore, the
invention relates to the administration of tetrahydrocarbozole derivatives for the treatment of
pathological conditions mediated by GPCR, especially for the inhibition of GnRH, to mammals,
especially humans, requiring such treatment, and to the use of tetrahydrocarbozole derivatives for
producing a pharmaceutical agent for treating pathological conditions mediated by GPCR,
especially for the inhibition of GnRH.

IN THE MATTER OF an Application

for a German Patent
in the name of
SCHERTNG AKTIENGESELLSCHAFT
filed under No. 101 64 564.3, and
IN THE MATTER OF an Application
for an Indian Patent.
KW5 uroup no, oi turopa nouse, Marsnam Way, Gerrards Cross, Buckinghamshire,
England, hereby solemnly and sincerely declares that to the best of its knowledge and belief,
the following document, prepared by one of its translators competent in the art and conversant
with the English and German languages is a true and correct translation of the Patent
Application filed under No. 101 64 564.3
by SCHERTNG AKTIENGESELLSCHAFT
in Germany on 14 December 2001
for "Tetrahydrocarbazole derivatives as ligands for G-protein coupled receptors (GPCR)"
and the Official Certificate attached thereto.
Date: 15 July 2004
C. E. SITCH
Deputy Managing Director - UK Translation Division
For and on behalf of RWS Group Ltd

FEDERAL REPUBLIC OF GERMANY
[Eagle crest]
Priority Certificate
for the filing of a Patent Application
File Reference: 101 64 564.3
Filing date: 14 December 2001
Applicant/Proprietor: SCHERING AKTIENGESELLSCHAFT, Berlin/DE
Title: Tetrahydrocarbazole derivatives as ligands for G-protein coupled
receptors (GPCR)
IPC: C07D,A61K
The attached documents are a correct and accurate reproduction of the original
submission for this Application.
Munich, 11 March 2003
German Patent and Trademark Office
The President
[Seal of the German Patent pp
and Trademark Office]
[signature]
Joost

TETRAHYDROCARBAZOLE DERIVATIVES AS LIGANDS FOR G-
PROTEIN COUPLED RECEPTORS (GPCR)
The present invention relates to novel tetrahydro-
carbazole derivatives which are ligands of G-protein
coupled receptors, and especially antagonists of
gonadotropin-releasing hormone, to the preparation
thereof, to the use thereof, and to the pharmaceutical
compositions which include these tetrahydrocarbazole
derivatives. The present invention also relates to a
method for treating pathological states mediated by G-
protein coupled receptors in a mammal, in particular a
human.
Technical background
The structural element which is common to all members
of the family of G-protein coupled receptors (GPCR) is
the presence of seven transmembrane alpha-helical
segments which are connected together by alternating
intra- and extracellular loops, with the amino terminus
being located on the extracellular side and the carboxy
terminus being located on the intracellular side. The
family of GPCRs can be divided into a plurality of
subfamilies (essentially family A, B and C) with
further sequence homologies within these subfamilies.
Since GPCRs are mainly involved in signal reception and
transduction, a large number of physiological functions
are influenced by them. GPCR ligands are therefore
potentially suitable as medicaments for the therapy and
prophylaxis of a large number of pathological states. A
brief survey of diseases which can be treated with GPCR
ligands is given in S. Wilson et al., Pharmaceutical
News 2000, 7(3) in Table 1.
The majority of known GPCR ligands has a peptide
structure. However, peptide receptor ligands frequently
have some serious disadvantages such as, for example,

low bioavailability and metabolic instability. This is
why there has recently been an intensified search for
ligands in the form of small, non-peptide molecules. A
special part is played in the search for novel, non-
peptide receptor ligands by so-called "privileged
structures". These "privileged structures" are the
basic molecular structures which provide ligands for a
large number of different receptors. The term
"privileged structures" was used for the first time by
Evans et al. in connection with benzodiazepine-based
CCK (cholecystokinin) A antagonists from the natural
product asperlicin (B.E. Evans et al., J. Med. Chem.
1988, 31, 2235) . For proteases for example it has been
known for some time that certain structural classes can
serve as inhibitors of various enzymes. Whereas
descriptions in the past were in particular of
mechanism-based inhibitors of various proteases,
however, more recently the frequency of examples of
compounds which, by reason of their three-dimensional
structure, fit well into the active binding region of
various enzymes has increased (cf. M. Whittaker, Cur.
Opin. Chem. Biol. 1998, 2, 386; A.S. Ripka et al.,
ibid., 441). Such "privileged structures" have already
been described for GPCRs too. Examples thereof are,
besides the aforementioned benzodiazepines, also
peptoids, 4-substituted 4-arylpiperidines, but also
specific rigidized p-turn mimetics (B.A. Bunin et al. ,
Ann. Rep. Med. Chem. 1999, 34, 267; R.N. Zuckermann et
al., J. Med. Chem. 1994, 37, 2678; G.C.B. Harriman,
Tetrahedron Lett. 2000, 41, 8853). A review of this is
to be found in A.A. Patchett et al., Ann. Rep. Med.
Chem. 1999, 35, 289. The tetrahydrocarbazole
derivatives of the present invention provide a further
class of "privileged structures" for GPCRs.
Although the present invention provides ligands for
GPCRs in general, the compounds provided by the present
invention are suitable in particular as ligands for a
particular representative of the class of GPCRs, namely

gonadotropin-releasing hormone (GnRH). GnRH can be
assigned to subfamily A of GPCRs (cf. U. Gether et al.,
Endocrine Reviews 2000, 21(1), 90).
GnRH is a hormone which is synthesized predominantly,
but not exclusively, in mammals by nerve cells of the
hypothalamus, is transported via the portal vein into
the pituitary and is delivered in a controlled manner
to the gonadotrophic cells. Interaction of GnRH with
its receptor having seven transmembrane domains
stimulates the production and release of gonadotropic
hormones by means of the second messenger inositol
1,4,5-trisphosphate and Ca2+ ions. Luteinizing hormone
(LH) and follicle-stimulating hormone (FSH), which are
gonadotropins released by GnRH, stimulate the
production of sex steroids and gamete maturation in
both sexes. In addition to GnRH (also referred to as
GnRHl), there are two further forms of GnRH, namely
GnRH2 and 3.
The GnRH receptor is used as pharmacological target in
a number of disorders which depend on functioning sex
hormone production, for example prostate cancer,
premenopausal breast cancer, endometriosis and uterine
fibroids. GnRH superagonists or antagonists can be
employed successfully for these disorders. A further
possible indication is, in particular, male fertility
control in combination with a replacement dose of
androgens.
One advantage of GnRH antagonists compared with GnRH
superagonists is their direct activity in blocking
gonadotropin secretion. Superagonists initially bring
about overstimulation of the pituitary, leading to
increased gonadotropin release and sex steroid release.
This hormonal response is terminated only after a
certain delay on the basis of desensitization and
downregulation of GnRH receptor concentrations. It is
therefore possible that GnRH superagonists, both alone

and in combination with testosterone, are unable
effectively to suppress sperm production in men and are
thus unsuitable for male fertility control. In contrast
to this, peptide GnRH antagonists, especially in
combination with a replacement dose of androgen, are
able to induce a significant oligozoospermia in humans.
However, peptide GnRH antagonists have a number of
disadvantages. Thus, they have a considerably lower
activity as superagonists and must accordingly be
administered in considerably higher dosages. In
addition, their oral bioavailability is low, so that
they must be administered by injection. Repeated
injections in turn lead to a reduction in compliance.
Furthermore, the synthesis of peptide GnRH antagonists
is complicated and costly by comparison with non-
peptide compounds.
Quinoline derivatives are disclosed as non-peptide GnRH
antagonists for example in WO 97/14682. However, it has
not been possible to date to put any non-peptide GnRH
antagonists on the market.
Technical problem
The problem on which the present invention is based is
to provide novel compounds which are suitable for the
treatment of GPCR-mediated pathological states and
display in particular a GnRH-inhibiting (GnRH-
antagonistic) effect. The novel GPCR ligands,
preferably GnRH antagonists, ought where possible to be
superior to known peptide compounds and represent an
effective alternative or improvement in relation to
known non-peptide compounds. The novel GPCR ligands,
especially GnRH antagonists, should in particular have
high activity and, where possible, a high oral
bioavailability. Their synthesis ought moreover to be
possible simply and at minimal cost. The present
invention also provides pharmaceutical compositions

comprising the novel non-peptide GPCR ligands, in
particular GnRH antagonists.
A further problem on which the present invention is
based is to provide novel GPCR ligands, preferably GnRH
antagonists, for use as pharmaceutical remedy and for
use for producing pharmaceutical remedies, comprising
the GPCR ligands, preferably GnRH antagonists.
In addition, it is an object of the present invention
to provide a method for the treatment of GPCR-mediated
pathological states, in particular for inhibiting GnRH,
in a mammal, in particular a human.
All these problems are surprisingly solved by the
provision of the novel tetrahydrocarbazole derivatives,
of the pharmaceutical compositions which comprise these
tetrahydrocarbazole derivatives, of the method for
preparing these tetrahydrocarbazole derivatives, and of
the method for the treatment of GPCR-mediated
pathological states, preferably for inhibition of GnRH,
in a mammal, in particular a human, through
administration of the tetrahydrocarbazole derivatives
or the use of the tetrahydrocarbazole derivatives for
producing pharmaceutical remedies for the treatment of
GPCR-mediated pathological states, in particular for
GnRH inhibition.
Summary of the invention
In a first aspect, the present invention provides novel
tetrahydrocarbazole derivatives of the general
formula (I).
In a second aspect, pharmaceutical compositions which
comprise at least one of the novel tetrahydrocarbazole
derivatives of the general formula (I) are provided.

In a third aspect, the present invention provides
tetrahydrocarbazole derivatives of the general formula
(I) for use as pharmaceutical remedy.
In a further aspect, the present invention relates to
the use of a tetrahydrocarbazole derivative of the
general formula (I) for producing a pharmaceutical
remedy for the treatment of GPCR-mediated pathological
states, in particular for inhibition of GnRH. The
present invention likewise relates to a method for the
treatment of GPCR-mediated pathological states, in
particular for inhibition of GnRH, in a mammal,
preferably a human, where an effective amount of a
compound of the invention of the general formula (I) is
administered to the mammal, preferably the human,
requiring such a treatment.
The present invention additionally provides a method
for preparing tetrahydrocarbazole derivatives of the
general formula (I). This method comprises for example
the steps of condensation of a cyclohexanone
derivative, which is tethered to a solid phase and is
expediently substituted, with a suitably substituted
phenylhydrazine derivative, a subsequent derivatization
depending on the desired structure of the final
compound, and finally elimination from the solid phase
and isolation of the product.
Detailed description of the invention
In a first aspect of the present invention there is
provision of novel tetrahydrocarbazole compounds of the
general formula (I)

in which the radical R1 is a hydrogen atom, a C2-C6
alkenyl or a Ci-C6 alkyl radical and may optionally be
substituted by an aryl, hetaryl radical or the group
-COOR11, where the aryl or hetaryl radical may be
substituted by up to three substituents which are
selected independently of one another from the group
consisting of -N02, -CH3, -CF3/ -OCH3, -OCF3 and halogen
atoms, and
the radical R11 is a hydrogen atom, a C2-C12 alkyl, a
C2-C12 aralkyl, an aryl, hetaryl radical or the group
-COCH3 and may optionally be substituted by one
substituent selected from the group consisting of
-CONH2, -COCH3, -COOCH3, -S02CH3 and aryl radicals;
the radicals R2, R3, R4 and R5 are each independently of
one another a hydrogen atom, a halogen atom, the group
-COOH, -CONH2, ~CF3, -OCF3, -N02, -CN, a Ci-C6 alkyl, a
Ci-C6 alkenyl, a Ci-C6 alkoxy, a C2-C12 aralkyl, an aryl
or hetaryl radical;
the radical R6 is the group -CONR8R9, -COOR8, -CH2NR8R9,
-CH2R8, -CH2OR8 or a C2-C12 alkenyl radical which is
optionally substituted by the radicals R8 and R9,
where the radicals R8 and R9 are each independently of
one another a hydrogen atom, a C2-C12 alkyl, a C2-C12
aralkyl, a C2-C12 hetaralkyl, an aryl or hetaryl
radical, each of which may be substituted by one or

more substituents selected from the group consisting of
-OH, -NH2, -CONHR10, --COOR10, -NH-C (=NH)-NH2 and halogen
atoms,
where the radical R10 is a hydrogen atom, a C2-C12 alkyl,
a C2-C12 aralkyl, an aryl or hetaryl radical and is
optionally substituted by the group -C0N(R1X)2, or where
the radicals R8 and R9 may together form a cyclic
structure which consists either exclusively of carbon
atoms or a combination of carbon atoms and heteroatoms;
the radical R7 is a. hydrogen atom, a C2-C12 alkyl, a
C2-C12 alkenyl, a C2-C12 aralkyl, an aryl or hetaryl
radical, the group -NR12R13, -NHCOR14, -NHCONHR14,
-NHCOOR14 or -NHS02R14 and may optionally be substituted
by one or more substituents selected from the group
consisting of -OH, -NH2, -CONH2, -COOH and halogen
atoms,
the radicals R12 and R13 are each independently of one
another a hydrogen atom, a C2-C6 alkenyl or a C2-C12
alkyl radical and may optionally be substituted by one
or more aryl or hetaryl radicals which in turn may be
substituted by up to three substituents selected
independently of one another from the group consisting
of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms,
and the radical R14 is a hydrogen atom, a C2-C12 alkyl, a
C2-C12 alkenyl, a C2-C12 aralkyl, an aryl or hetaryl
radical which may optionally be substituted by one or
more substituents selected from the group consisting of
-N02, -CH3, -OR11, -CF3, -OCF3, -OH, -N(Ru)2f -OCOR11,
-COOH, -CONH2, -NHCONHR11, -NHCOOR11 and halogen atoms;
and the radicals Ra, Rb, Rc, Rd, Re and Rf are each
independently of one another a hydrogen atom, a halogen
atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a
Ci-C6 alkyl, Ci-C6 alkoxy, an aryl or hetaryl radical;
with the proviso that the compound of the general
formula (I) is not selected from the group consisting
of 3-amino-l,2,3,4-tetrahydrocarbazole-3-carboxylic

acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3-
carboxylic acid, 3-amino-6-benzyloxy-l,2,3,4-
tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-
1, 2, 3, 4-tetrahydrocarbazole-3-carboxylic acid, methyl
3-acetamido-l,2,3,4-tetrahydrocarbazole-3-carboxylate,
(-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3-
carboxylate or 3-tert-butoxycarbonylamino-l,2,3,4-
tetrahydrocarbazole-3-carboxylic acid.
The basic tetrahydrocarbazole structures of those
compounds which are specifically excluded above from
the compounds falling within the definition of the
general formula (I) were introduced by Y. Maki et al.
in Chem. Pharm. Bull. 1973, 21 (11), 2460-2465 and by
R. Millet et al. in Letters in Peptide Science 1999, 6,
221-233.
The terms indicated for explanation of the compounds of
the general formula (I) have in particular the
following meaning:
C1-C6 or C2-C12 "alkyl radical" means a branched or
unbranched, cyclic or acyclic, optionally substituted
alkyl group having 1 to 6 or 1 to 12 carbon atoms,
respectively. Representative examples of such alkyl
groups include methyl, ethyl, n-propyl, isopropyl, n-
butyl, isobutyl, tert-butyl, n-pentyl, 2,2-
dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, n-
octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl
groups, and cyclic groups, in particular cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
groups, 1-cyclopropyl-, 1-cyclobutyl-, 1-cyclopentyl-,
1-cyclohexyl-, 1-cycloheptylethyl-, 2-cyclopropyl-, 2-
cyclobutyl-, 2-cyclopentyl-, 2-cyclohexyl-, 2-
cycloheptylethyl groups and the like, but are not
restricted to these.
C2-C6 "alkenyl radical" means a branched or unbranched,
cyclic or acyclic, optionally substituted, mono- or

polyunsaturated alkenyl group having 2 to 6 carbon
atoms. Representative examples of such alkenyl groups
include vinyl, allyl, prop-1-enyl, but-1-enyl, but-2-
enyl, but-3-enyl, buta-1,3-dienyl, pent-1-enyl, pent-2-
enyl, pent-3-enyl, pent-4-enyl, penta-1,3-dienyl,
penta-1,4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1-
enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl,
hexa-1,3-dienyl, hexa-1,4-dienyl, hexa-1,5-dienyl,
hexa-2,4-dienyl, hexa-2,5-dienyl, hexa-1,4-dienyl,
hexa-1,3,5-trienyl groups and the like, but. are not
restricted to these.
C2-C6 "alkoxy radical" means a branched or unbranched,
cyclic or acyclic, optionally substituted alkoxy group
having 2 to 6 carbon atoms. Representative examples of
such alkoxy groups include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-
pentoxy, n-hexoxy, cyclohexyloxy groups and the like,
but are not restricted to these.
C2-C12 "aralkyl radical" means an alkyl radical having 1
to 12 carbon atoms which is substituted by one or more
aryl radicals. Representative examples of such aralkyl
groups for the purposes of the present invention
include benzyl, 1-phenylethyl, 1-phenylpropyl, 1-
phenylbutyl, 1-phenylhexyl, l-phenyl-2-methylethyl, 1-
phenyl-2-ethylethyl, l-phenyl-2,2-dimethylethyl,
benzhydryl, triphenylmethyl, 2- or 3-naphthylmethyl, 2-
phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-
phenylpentyl groups and the like, but are not
restricted to these. Correspondingly, a "hetaralkyl
radical" is an alkyl radical substituted by a
heteroaryl radical.
"Aryl radical" means an optionally substituted mono- or
polycyclic aromatic group. Representative examples of
such aryl groups include phenyl, naphthyl groups and
the like, but are not restricted to these.

The term "hetaryl radical" is identical with the term
"heteroaryl radical" and represents an aryl group as
defined above which includes in its structure one or
more heteroatoms, in particular nitrogen, phosphorus,
oxygen, sulfur and arsenic atoms. Representative
examples of such hetaryl or heteroaryl groups include
unsubstituted hetaryl radicals and substituted hetaryl
radicals, in particular imidazolyl, pyridyl, quinolinyl
groups and the like, but are not restricted to these.
The term "cyclic structure" includes optionally
substituted mono- or polycyclic cyclic structures with
a varying number of ring members, in particular five-,
six- and seven-membered cyclic structures. These cyclic
structures may include besides carbon atoms also one or
more heteroatoms such as, in particular, nitrogen,
phosphorus, oxygen, sulfur and arsenic atoms. The
cyclic structures may include saturated, but also
partially or completely unsaturated, structural
elements. Representative examples of such cyclic
structures include aza-, oxa-, thia-,
phosphacyclopentane-, -cyclohexane-, -cycloheptane-,
diaza-, dioxa-, dithia-, diphosphacyclopentane,
-cyclohexane, -cycloheptane basic cyclic structures and
the like, and basic cyclic structures with mixed
heteroatom exchange, but are not restricted to these.
"Halogen atoms" include in particular fluorine,
chorine, bromine and iodine atoms, particularly
preferably chlorine atoms.
Reference may also be made at this point to the fact
that, besides the compounds of the general formula (I),
as defined above, which are mentioned per se, the
present invention also encompasses physiologically
tolerated derivatives or analogs, especially also salts
of these compounds.

It may further be remarked at this point that: the term
"receptor ligand" or "ligand" is intended for the
purposes of the present invention to designate any
compound which binds in any manner to a receptor (in
i the present invention, the receptor is a GPCR receptor,
preferably a GnRH receptor) and induces either an
activation, inhibition or other conceivable effect on
this receptor. The term "ligand" thus includes
agonists, antagonists, partial agonists/antagonists and
1 other ligands which elicit on the receptor an effect
which resembles the effect of agonists, antagonists or
partial agonists/antagonists. The compounds of the
invention of the general formula (I) are preferably
GnRH antagonists.
Preferred novel tetrahydrocarbazole derivatives of the
invention of the general formula (I) are those
compounds in which the radicals Ra, Rb, Rc, Rd, Re and Rf
are hydrogen atoms.
Likewise preferred novel tetrahydrocarbazole
derivatives of the invention of the general formula (I)
are those compounds in which the radical R1 is a
hydrogen atom.
Preferred novel tetrahydrocarbazole derivatives of the
invention of the general formula (I) are additionally
those compounds in which the radicals R2, R3, R4 and/or
R5 are not hydrogen atoms. Particularly preferred
i compounds of the general formula (I) in this connection
are those in which the radicals R2, R3, R4 and R5 are
independently of one another methyl, chloro or methoxy
radicals. Very particularly preferred compounds of the
general formula (I) in this connection are those in
i which at least the radical R2 is not a hydrogen atom,
especially the compounds
phenylmethyl [(1S,2S)-l-[[[(3R)-3-[[[(1S)-1-(aminocar-
bonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-
tetrahydro-8-methyl-lH-carbazol-3-yl]amino]carbonyl]-2-

methylbutyl]carbamate (compound no. 150a in the
examples)
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[t[(1S)-1-(aminocar-
bonyl)-2-methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl-
butyl]carbamate (148a),
phenylmethyl [ (1S,2S)-1-[[[(3R)-3-[[[ (1S)-1-
(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-
tetrahydro-8-methoxy--lH-carbazol-3-yl]amino]carbonyl]-
2-methylbutyl]carbamate (147a).
Preferred novel tetrahydrocarbazole derivatives of the
invention of the general formula (I) are also those
compounds in which R6 is a hydrophobic radical which
includes alkyl, aryl and/or hetaryl structures and
which carries a hydrogen bond donor-acceptor system at
a distance of from two to four single bonds, counting
from the carbon atom substituted by the radicals R6 and
R7. Particularly preferred compounds of the general
formula (I) are those where the radical R6 is a
phenylalanylamide residue, in particular the compound
phenylmethyl [(IS, 2S) -1-[[[(3R)-3-[[[(1S)-2-amino-2-
oxo-1- (phenylmethyl) ethyl] amino] carbonyl] -2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl-
butyl] carbamate (66) ,
is an isoleucylamide residue, in particular the
compound phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[[(1S)-1-
(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazcl-3-yl]amino]carbonyl]-2-methyl-
butyl] carbamate (64) ,
is a valyl-4-aminobenzamide residue, in particular the
compound phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[[(1S)-1-
[[[4-(aminocarbonyl)phenyl]amino]carbonyl]-2-methyl-
propyl] amino] carbonyl]-2,3,4,9-tetrahydro-lH-carbazol-
3-yl] amino] carbonyl]-2-methylbutyl] carbamate (45_) ,
is a valyl-N-methylamide residue, in particular the
compound phenylmethyl [(IS, 2S)-2-methyl-l-[[[(3R)-
2,3,4,9-tetrahydro-3-[[[(1S)-2-methyl-l-[(methylamino)-

carbonyl]propyl]amino]carbonyl]-lH-carbazol-3-
yl]amino]carbonyl]butyl]carbamate (222a),
is a methyloxymethyl-4-pyridyl radical, in particular
the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl) -O-
(4-pyridinylmethyl)-lH-carbazole-3-methanol (287),
is a carboxyl radical, in particular the compound
2,3,4,9-tetrahydro-3-(3-phenylpropyl)-lH-carbazole-3-
carboxylic acid (273) ,,
or is an ethyl propenoate radical, in particular the
compound ethyl 3-[2,3,4,9-tetrahydro-3- (3-
phenylpropyl)-lff-carbazol-3-yl]-2-propenoate (289).
Likewise particularly preferred are compounds of the
general formula (I) in which the radical R6 is a
carbonylvalylamide residue, in particular the compound
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1-(aminocar-
bonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetra-
hydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate (58),
is a carbonylthreonylamide residue, in particular the
compound phenylmethyl [ (IS, 2S) -1- [ [ [ (3JR) -3- [ [ [ (IS, 2R) -
1-(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]-
2,3,4, 9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-
methylbutyl]carbamate,
is a cyclic carboxamide residue (such as, for example,
a carbonylprolylamide radical, in particular the
compound phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[(2S)-2-
(aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetra-
hydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate (181a),
or a carbonyloctahydroindolyl-2-carboxamide residue, in
particular the compound phenylmethyl [(1S,2S)-1-
[ [ [ (3R) -3- [ [ (2S) -2- (aminocarbonyl) octahydro-l.H-indol-1-
yl]carbonyl]-2,3,4,9-tetrahydro-lH-carbazol-3-
yl]amino]carbonyl]-2-methylbutyl]carbamate (190a)),
is a 4-carboxamidophenylcarboxamide residue, in
particular the compound phenylmethyl [(1S,2S)-1-
[ [ [ (3R) -3-[[[4-(aminocarbonyl)phenyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate (62),

is a methylaminomethyl-2-pyridyl radical, in particular
the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-
(2-pyridinylmethyl)-lff-carbazole-3-methanamine (279),
is a carbonylvalinol residue, in particular the
compounds phenylmethyl [ (IS,2S)-1-[[[(3S)-3-[ [ [ (1S)-1-
(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl-
butyl]carbamate (267b)
and 2,3,4,9-tetrahydro-W-[(1S)-1-(hydroxymethyl)-2-
methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3-
carboxamide (276)
or is a methylvalinol residue, in particular the
compound (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3-
phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-1-butanol
(284).
Preferred novel tetrahydrocarbazole derivatives of the
invention of general formula (I) are also compounds in
which R7 is a hydrophobic radical comprising alkyl, aryl
and/or hetaryl structures. Particular preference is
given in this connection to compounds of the general
formula (I) in which the radical R7 is a 2,3-biphenyl-
propionylamino radical, in particular the compound
N- [[(3R)-2,3,4,9-tetrahydro-3-[(l-oxo-2,3-diphenyl-
propyl)amino]-ltf-carbazol-3-yl]carbonyl]-L-valyl-L-
aspartamide (18)
is an indanoylamino radical, in particular the compound
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-
[[(2,3-dihydro-lH-inden-l-yl)carbonyl]amino]-2,3,4,9-
tetrahydro-lH-carbazole-3-carboxamide (162a),
is an indolylacetylamino radical, in particular the
compound (3S)-N-[(1S)-1-(aminocarbonyl)-2-methyl-
propyl] -2,3,4,9-tetrahydro-3-[(lH-indol-3-ylacetyl)-
amino]-lH-carbazole-3-carboxamide (164b),
is a 2-naphthylacetylamino radical, in particular the
compound (3S)-N-[(1S)-1-(aminocarbonyl)-2-methyl-
propyl] -2, 3,4,9-tetrahydro-3-[(2-naphthalinylacetyl)-
amino]-lH-carbazole-3-carboxamide (161b)
or is a 3-propionylamino radical, in particular the

- 16 -
compound N- [ [ (3.R)-2, 3, 4, 9-tetrahydro-3-[ [ (2S,3S)-3-
methyl-l-oxo-2-[(l-oxo-3-phenylpropyl)amino]pentyl]-
amino]-lif-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide
(22) .
Likewise particularly preferred are compounds of the
general formula (I) in which R1 is a phenylmethyl-
carboxamide residue substituted on the aromatic system,
in particular the compounds (3R)-N-[(1S)-1-(amino-
carbonyl) -2-methylpropyl] -2, 3,4,9-tetrahydro-3-[[(4-
methylphenyl)acetyl]amino]-lH-carbazole-3-carboxamide
(165a),
N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-
tetrahydro-3-[[(4-methoxyphenyl)-acetyl]amino]--1H-
carbazole-3-carboxamide (175),
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[ [ (3-
bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxamide (96_) ,
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(4-
fluorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxamide (91_) ,
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(4-
chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxamide (167a),
is a phenylhexylamine residue, in particular the
compound (3R)-N-[(1S)-1-(aminocarbonyl)-2-methyl-
propyl] -3-[bis(3-phenylpropyl)amino]-2,3,4,9-
tetrahydro-lH-carbazole-3-carboxamide (234a)
or is a phenylpropyl radical, in particular the
compounds 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl-
propyl) -lH-carbazole-3-carboxylic acid (275) and 6,8-
dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazole-3-carboxylate (272).
Also preferred are those novel compounds of the
invention of the general formula (I) which are in the R
configuration at the carbon atom substituted by the
radicals R6 and R7 when the radicals R6 and R7 together
form an alpha-amino carboxylic acid structural element.

Most preferred for the purposes of the present
invention are the compounds phenylmethyl [(1S,2S)-1-
[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]-
amino]carbonyl]-6,8-dichloro-2,3,4, 9-tetrahydro-lH-
carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate
(184a), phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(1S)-1-
(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl-
butyl] carbamate (267a), (2S)-l-[[(3R)-3-[[(4-chloro-
phenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy-lH-
carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a)
and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-
N- (2-pyridinylmethyl)-lH-carbazole-3-methanamine (283) .
Further representatives of novel compounds of the
invention of the general formula (I), including their
preparation, are indicated in the examples.
The novel tetrahydrocarbazole derivatives (I) of the
invention, as defined above, are ligands of GPCR and
can be employed in particular for the inhibition, i.e.
as antagonists, of gonadotropin-releasing hormone for
example for male fertility control, for hormone
therapy, for the treatment of female sub- or
infertility, for female contraception and for tumor
control.
In male fertility control, the compounds of the
invention bring about a reduction in spermatogenesis.
Combined administration with androgens, e.g.
testosterone or testosterone derivatives such as, for
example, testosterone esters, is preferred. The
testosterone derivatives can in this case be
administered for example by injection, e.g. by intra-
muscular depot injection.
The compounds (I) of the invention can also be employed
where appropriate in combination with other hormones,
e.g. estrogens or/and progestins, in hormone therapy,

for example for the treatment of endometriosis, uterine
leiomyomas and uterine fibroids. Combinations of the
GnRH antagonists of the invention and tissue-selective
partial estrogen agonists such as Raloxifen" are
particularly preferred. In addition, the compounds of
the invention can be employed in hormone replacement
therapy. The compounds (I) of the invention can
moreover be employed to increase female fertility, for
example by inducing ovulation, and for the treatment of
sterility.
On the other hand, the novel compounds (I) of the
invention are also suitable for contraception in women.
Thus, the GnRH antagonist of the invention can be
administered on days 1 to 15 of the cycle together with
estrogen, preferably with very small estrogen, dosages.
On days 16 to 21 of the cycle of intake, progestagen is
added to the estrogen/GnRH antagonist combination. The
GnRH antagonist of the invention can be administered
continuously throughout the cycle. It is possible in
this way to reduce the hormone dosages and thus achieve
a reduction in the side effects of nonphysiological
hormone levels. It is additionally possible to achieve
advantageous effects in women suffering from, polycystic
ovary syndrome and androgen-dependent disorders such as
acne, seborrhea and hirsutism. An improved control of
the cycle by comparison with previous administration
methods is also to be expected. Further indications are
benign prostate hyperplasia, gonadal protection during
chemotherapy, controlled ovary stimulation/assisted
reproduction techniques, infantile development
disorders, e.g. precocious puberty and polycystic
ovaries.
Finally, the compounds (I) of the invention, as defined
above, can also be employed for the treatment of
hormone-dependent neoplastic diseases such as
premenopausal cancer, prostate cancer, ovarian cancer
and endometrial cancer, by suppressing endogenous sex

steroid hormones.
The novel compounds (I) of the invention, as defined
above, are, as GPCR ligands, in particular GnRH
antagonists, suitable for the treatment of the
pathological states detailed above for administration
to mammals, in particular humans, but also for
veterinary medical purposes, e.g. in pets and
productive livestock,, but also in wild animals.
Administration is possible in a known mariner, for
example orally or non-orally, in particular topically,
rectally, intravaginally, nasally or by injection or
implantation. Oral administration is preferred. The
novel compounds (I) of the invention are converted into
a form capable of administration and, where
appropriate, mixed with pharmaceutically acceptable
carriers or diluents. Suitable excipients and carriers
are described for example in Ullman's Encyclopedia of
Technical Chemistry, Vol. 4 (1953), 1-39; Journal of
Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v.
Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie und
angrenzende Gebiete", Pharm. Ind. 2, 1961, 72ff;
Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe fiir
Pharmazie, Kosmetik und angrenzende Gebiete",
Cantor KG, Aulendorf in Wlirttemberg, 1971.
Oral administration can take place for example in solid
form as tablet, capsule, gel capsule, coated tablet,
granulation or powder, but also in the form of a
drinkable solution. For oral administration, the novel
compounds of the invention of the general formula (I),
as defined above, can be combined with known and
conventionally used, physiologically tolerated
excipients and carriers such as, for example, gum
arabic, talc, starch, sugars such as, for example,
mannitol, methylcellulose, lactose, gelatin, surface-
active agents, magnesium stearate, cyclodextrins,
aqueous or nonaqueous carriers, diluents, dispersants,

emulsifiers, lubricants, preservatives and flavors
(e.g. essential oils) . The compounds of the invention
can also be dispersed in a microparticulate, e.g. nano-
particulate, composition.
Non-oral administration can take place for example by
intravenous, subcutaneous or intramuscular injection of
sterile aqueous or oily solutions, suspensions or
emulsions, by means of implants or by ointments, creams
or suppositories. Administration as extended-release
form is also possible where appropriate. Implants may
contain inert materials, e.g. biodegradable polymers or
synthetic silicones such as, for example, silicone
rubber. Intravaginal administration is possible for
example by means of pessaries. Intrauterine
administration is possible for example by means of
diaphragms, etc. In addition, transdermal
administration, in particular by means of a formulation
suitable for this purpose and/or suitable means such
as, for example, patches, is also provided.
As already explained above, the novel compounds (I) of
the invention can also be combined with other active
pharmaceutical ingredients. During a combination
therapy, the individual active ingredients can be
administered simultaneously or separately, in
particular either by the same route (e.g. orally) or by
separate routes (e.g. orally and as injection). They
may be present and administered in identical or
different amounts in a unit dose. It is also possible
to apply a particular dosage regimen where this appears
expedient. It is also possible in this way to combine a
plurality of the novel compounds (I) of the invention
together.
The dosage may vary within a wide range depending on
the nature of the indication, the severity of the
disorder, the mode of administration, the age, sex,
body weight and sensitivity of the subject to be

treated. It is within the abilities of a skilled worker
to determine a "pharmacologically effective amount" of
the combined pharmaceutical composition. Unit doses of
from 1 ug to 100 mg, particularly preferably from 1 ug
to 10 mg and most preferably from 1 ug to 1 mg, per kg
of body weight of the subject to be treated are
preferred. Administration can take place in a single
dose or a plurality of separate dosages.
In a further aspect of the present invention,
accordingly, the present invention also encompasses
pharmaceutical compositions as described above,
comprising at least one of the novel compounds (I) of
the invention, as defined above, and where appropriate
pharmaceutically acceptable carriers and/or excipients.
Preferred and particularly preferred pharmaceutical
compositions are those comprising at least one of the
aforementioned preferred or particularly preferred
novel compounds (I) of the invention, in particular the
compounds mentioned by name above. In pharmaceutical
compositions according to the present invention it is
possible, besides the at least one compound of the
general formula (I), as defined above, for other active
pharmaceutical ingredients also to be present, as
already described in detail above.
At least one of the novel compounds (I) of the
invention, as defined above, is present in the
pharmaceutical compositions of the invention in one of
the unit doses mentioned above as preferred,
particularly preferred or most preferred, specifically
and preferably in an administration form which makes
oral administration possible.
In addition, in a further aspect, the present invention
provides compounds of the general formula (I) as
defined above for use as pharmaceutical remedy.
Preferred tetrahydrocarbazole compound of the invention

of the general formula (I) , as defined above, for use
as pharmaceutical remedy are in turn those compounds
mentioned above as preferred and particularly preferred
compounds, in particular the preferred compounds of the
invention mentioned by name, and the compounds
mentioned in the examples.
Concerning pharmaceutical compositions comprising
compounds (I) of the invention, and concerning
compounds (I) of the invention for use as
pharmaceutical remedy, reference may be made in
relation to the possibilities for use and
administration to what has already been said concerning
the novel compounds (I) of the invention, as defined
above.
In another aspect, the present invention also provides
the use of at least one tetrahydrocarbazole derivative
of the invention of the general formula (I), as defined
above, with - as defined at the outset - the tetra-
hydrocarbazoles disclosed in the publications by Millet
et al. and Maki et al. being excluded from the meaning
of the general formula (I), for producing a
pharmaceutical remedy for the treatment of GPCR-
mediated diseases, in particular for inhibition of
gonadotropin-releasing hormone (GnRH).
In addition, the present invention provides in a
further aspect the use of at least one compound of the
invention of the general formula (I) as defined above,
but including the compounds previously excluded by name
from the publications of Millet et al. and Maki et al.,
namely 3-amino-l,2,3,4-tetrahydrocarbazole-3-carboxylic
acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3-
carboxylic acid, 3-amino-6-benzyloxy-l,2,3,4-tetra-
hydrocarbazole-3-carboxylic acid, 3-acetamido-l,2,3,4-
tetrahydrocarbazole-3-carboxylic acid, methyl 3-
acetamido-1,2,3, 4-tetrahydrocarbazole-3-carboxylate,
(-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3-

carboxylate and 3-tert-butoxycarbonylamino-l,2,3,4-
tetrahydrocarbazole-3-carboxylic acid, for producing a
pharmaceutical remedy for inhibiting GnRH, preferably
for male fertility control, for hormone therapy, for
the treatment of female sub- and infertility, for
female contraception and for tumor control. Stated more
clearly, the term "a compound of the general
formula (I) as defined above, but including the
compounds excluded above by name" means a compound of
the general formula (I)

(0
in which the radical R1 is a hydrogen atom, a C2 - C6
alkenyl or a Ci - C6 alkyl radical and may optionally be
substituted by an aryl, hetaryl radical or the group
-COOR11, where the aryl or hetaryl radical may be
substituted by up to three substituents which are
selected independently of one another from the group
consisting of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen
atoms, and
the radical R11 is a hydrogen atom, a C1 - C12 alkyl, a
C2-C12 aralkyl, an aryl, hetaryl radical or the group
-COCH3 and may optionally be substituted by one
substituent selected from the group consisting of
-CONH2, -COCH3, -COOCH3, -SO2CH3 and aryl radicals;
the radicals R2, R3, R4 and R5 are each independently of
one another a hydrogen atom, a halogen atom, the group

-COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a C1- C6 alkyl, a
Ci - C6 alkenyl, a Ci - C6 alkoxy, a C2-C12 aralkyl, an
aryl or hetaryl radical;
the radical R6 is the group -CONR8R9, -COOR8, -CH2NR8R9,
-CH2R8, -CH2OR8 or a C2-C12 alkenyl radical which is
optionally substituted by the radicals R8 and R9, where
the radicals R8 and R9 are each independently of one
another a hydrogen atom, a C2-C12 alkyl, a Ci - Ci2
aralkyl, a C1-C12 hetaralkyl, an aryl or hetaryl
radical, each of which may be substituted by one or
more substituents selected from the group consisting of
-OH, -NH2, -CONHR10, -COOR10, -NH-C (=NH) -NH2 and halogen
atoms,
where the radical R10 is a hydrogen atom, a C1 - C12
alkyl, a C1 - C12 aralkyl, an aryl or hetaryl radical
and is optionally substituted by the group -CON(R1:L)2?
or where the radicals R8 and R9 may together form a
cyclic structure which consists however exclusively of
carbon atoms or a combination of carbon atoms and
heteroatoms;
the radical R7 is a hydrogen atom, a C1 - C12 alkyl, a
C1 - C12 alkenyl, a C1 - C12 aralkyl, an aryl or hetaryl
radical, the group -NR12R13, -NHCOR14, -NHCONHR14,
-NHCOOR14 or -NHS02R14 and may optionally be substituted
by one or more substituents selected from the group
consisting of -OH, -NH2, -CONH2, -COOH and halogen
atoms,
the radicals R12 and R13 are each independently of one
another a hydrogen atom, a C2 - C6 alkenyl or a C1 - C12
alkyl radical and may optionally be substituted by one
or more aryl or hetaryl radicals which in turn may be
substituted by up to three substituents selected
independently of one another from the group consisting
of -N02, -CH3, -CF3, -OCH3, -OCF3 and halogen atoms,
and the radical R14 is a hydrogen atom, a C1 - C12alkyl,
a C1 - C12 alkenyl, a C1 - C12 aralkyl, an aryl or
hetaryl radical which may optionally be substituted by

one or more substituents selected from the group
consisting of -N02, -CH3; -OR11, -CF3, -OCF3, -OH,
-N(R11)2, -OCOR11, -COOH, -CONH2, -NHCONHR11, -NHCOOR11 and
halogen atoms;
and the radicals Rd, Rb, Rc, Rd, Re and Rf are each
independently of one another a hydrogen atom, a halogen
atom, the group -COOH, -CONH2, -CF3, -OCF3, -N02, -CN, a
C1 - C6 alkyl, a C1 - C6 alkoxy, an aryl or hetaryl
radical.
The indications already mentioned in connection with
the novel compounds of the invention of the general
formula (I), as defined above (i.e. excluding the
compound disclosed in the publications of Maki et al.
and Millet et al. and mentioned above by name) have
already been given above in relation to the novel
compounds (I) of the invention. The compounds which are
preferred and particularly preferred in the use of the
compounds just defined for producing a pharmaceutical
remedy for inhibiting GnRH are identical to the
preferred and particularly preferred compounds already
mentioned above in connection with the novel compounds
of the invention of the general formula (I), as defined
above.
The present invention provides in a further aspect the
use of a compound (I) of the invention as defined
above, but likewise including the compounds excluded by
name at the outset, for male fertility control or for
female contraception. Preferred and particularly
preferred compounds of the invention for this use are
those compounds already mentioned at the outset as
preferred or particularly preferred compounds of the
invention of general formula (I) as defined above.
In addition, the present invention provides a method
for male fertility control or for female contraception,
comprising the administration of an amount, effective

for male fertility control or for female contraception,
of a compound of the invention as defined in the
immediately preceding paragraph, to a subject,
preferably a mammal, particularly preferably a human.
In another aspect, the present invention relates to a
method for the treatment of pathological states
mediated by GPCR. The method comprises the
administration of at least one compound (I) of the
invention, as defined above, to a mammal, in particular
a human, when such a treatment is necessary. The
administration normally takes place in a
pharmaceutically effective amount. As already explained
above in relation to the novel compounds (I) of the
invention and the pharmaceutical compositions of the
invention, it is the task of the expert knowledge of a
skilled worker to determine a pharmaceutically
effective amount, depending on the specific
requirements of the individual case. However, the
compounds (I) of the invention are preferably
administered in a unit dose of from 1 ug to 100 mg,
particularly preferably from 1 ug to 10 mg and most
preferably from 1 ug to 1 mg per body weight of subject
to be treated. The preferred administration form is
oral administration. The administration of one or more
of the compounds (I) of the invention in combination
with at least one further active ingredient, as already
explained above, is also provided.
In addition, the present invention also relates to a
method for inhibiting GnRH in a patient, comprising
administration of a pharmaceutically effective amount
of a compound of the general formula (I), as defined
above, but including compounds excluded by name above,
to a patient requiring such a treatment. The method is
preferably used in male fertility control, hormone
therapy, female contraception, treatment of female sub-
or infertility and tumor control.

Finally, the present invention provides in a last
aspect also a method for the production of the novel
tetrahydrocarbazole derivatives of the invention of the
general formula (I) .. The method for the preparation of
the compounds of the invention of the? general
formula (I) can be carried out in various ways, e.g. in
liquid phase or as partial or complete solid-phase
synthesis. The choice of the suitable synthesis
conditions for preparing individual representatives of
compounds of the general formula (I) can be made by a
skilled worker on the basis of his common general
knowledge. One method of the invention for the
preparation of compounds of the invention of the
general formula (I) is firstly described generally
below. A specific variant of the method, namely a
solid-phase method, is then described. For further
illustration of the present invention, the examples
listed thereafter include numerous representatives of
compounds of the general formula (I).
One method for the preparation of the compounds of the
invention of the general formula (I) is preferably
carried out in the following way:
The central tetrahydrocarbazole structure can be
obtained by a Fischer indole synthesis known per se.
For this purpose, a suitably substituted cyclohexanone
derivative provided where appropriate with protective
groups is condensed with the phenylhydrazine derivative
which is desired in each case and is likewise suitably
substituted and provided where appropriate with
protective groups (e.g. as described by Britten &
Lockwood, J.C.S. Perkin I 1974, 1824 or as described by
Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In
particular, the cyclohexanone structure is substituted
in positions 3,3', 5,5' and 6,6' via the radicals Ra to
Rf, and in positions 4,4' via the radicals, or where
appropriate by precursors of the radicals, Rb and R7.
The phenylhydrazine structure is optionally substituted

by the radicals R2 10 R5. Phenylhydrazine derivatives
which are not commercially available can be prepared by
methods known to the skilled worker. Positional isomers
which result where appropriate in the condensation of
the cyclohexanone derivative and the phenylhydrazine
derivative can be separated by chromatographic methods
such as, for example, HPLC.
After the synthesis of the central tetrahydrocarbazole
structure, the radical R1 can be introduced by
N-alkylation of the nitrogen atom in position 9 with
appropriate R1-halides with use of base (e.g. as
described by Pecca & Albonico, J. Med. Chem. 1977, 20,
487 or else as described by Mooradian et al., J. Med.
Chem. 1970, 13, 327).
The radicals R6 and R7 can, as already indicated above,
be introduced in various ways depending on their
nature, which is explained in detail below.
a-Aminocarboxylic acid structures in these radicals can
be obtained by treating ketones with NH4 (CO) 3 and KCN
under Schotten-Baumann conditions known per se, and
subsequent alkaline hydrolysis of the hydantoin which
is formed (Britten & Lockwood, J.C.S. Perkin I 1974,
1824) .
Amide residues are preferably generated using methods
known per se from peptide chemistry. For this purpose,
the acid component is activated with an activating
reagent such as DCC or else HATU (Tetrahedron Lett.
1994, 35, 2279) and condensed in the presence of a base
such as DIPEA and/or DMAP with the amino component.
Ester residues can also be obtained by using the
desired alcohols under analogous conditions. The
solvent used in this case is preferably anhydrous.
Secondary or tertiary amide residues are obtained from

primary amines either by nucieophiiic substitution of
alkyl halides or by reductive amination of aldehydes/
ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synth.
Comm. 1994, 609).
Sulfonamide residues are obtained from the
corresponding amides by reaction with sulfonyl
chlorides.
Urea residues are obtained by reacting the amines with
appropriate isocyanates.
Urethane residues can be prepared by preactivating the
appropriate alcohols with carbonyldihydroxybenzo-
triazole ((HOBt)2CO) and subsequently reacted with
amines (Warass et al.., LIPS 1998, 5, 125).
Alcohols can be obtained from carboxylic esters by
reduction with LiAlH4.
Aldehyde residues are obtained from alcohol precursors
by oxidation for example under Swern conditions known
per se with DMSO/oxalyl chloride (Pansavath et al.,
Synthesis 1998, 436).
Substituted amine residues are obtained by reductive
amination of amines with aldehydes (J. Org. Chem. 1996,
61, 3489) .
Ether residues can be obtained by deprotonating the
alcohol precursor with a base such as NaH under
Williams conditions known per se and subsequently
reacting with an alkyl halide.
Double bonds in the radicals can be introduced by
reacting an aldehyde or ketone precursor with
appropriate phosphonylides under Wittig conditions
known per se.

A solid-phase method for the preparation of compounds
of the invention of formula (I) preferably includes
steps (a) to (d) explained in detail below:
Step (a) proceeds essentially in analogy to a Fischer
indole synthesis, e.g. as described by Britten &
Lockwood, J.C.S. Perkin I 1974, 1824; Maki et al.,
Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman,
Tetrahedron Lett. 1996, 37, 4869 and comprises the
condensation of a cyclohexanone derivative (II) which
contains the group G and is tethered to a solid
phase SP via a linker L suitable for forming the
radical R6

where, in the case where the radical R7 is a hydrogen
atom, a C1 - C12 alkyl, a C1 - C12 aralkyl or a hetaryl
radical, the group G is equal to the radical R7, and in
the case where the radical R7 has another one of the
meanings indicated for R7 in formula (I), the group G is
equal to a group --NH-Pg, where Pg is a protective
group, with a phenylhydrazine derivative (III)
substituted by R2 to R5

in the presence of an acid, preferably acetic acid, and
of a metal salt, preferably ZnCl2. DMF is preferred as
solvent. The radicals Ra to Re are defined as indicated
above in formula (I) . Certain substituents or groups
may, where appropriate, also be present in protected
form, in which case the protective groups are removed
again by methods known per se at a suitable time during
the synthesis.
Particularly suitable solid phase SP for the purposes
of the present invention are Rink amide-resins (Rink,
Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard
et al., Int. J. Peptide Protein Res. 1982, 20, 451),
Wang resins (Lu et al., J. Org. Chem. 1981, 46, 3433)
or chlorotrityl-resins (Barlos et al., Int. J. Peptide
Protein Res. 1991, 38, 562), where the cyclohexanone
derivative (II) is to be tethered to the solid phase SP
by means of an (amino) carboxylic acid. Alcohol
precursors of the cyclohexanone derivative (II) can be
tethered by using the DHP linker (Liu & Elman, J. Org.
Chem. 1995, 60, 7712). Traceless tethering of aromatic
precursors of the cyclohexanone derivative (II) to
triazine resins is possible (Brase et al., Angew. Chem.
Int. Ed. 1998, 37, 3413) .
The protective group Pg which is included where
appropriate in the group G and protects an a-amino
group -NH2 is preferably a "Fmoc" (9-
fluorenylmethoxycarbonyl) protective group, but may
also be another customary amino protective group, e.g.

from the series of the alkoxycarbonyl protective groups
(such as, for example the "z" (benzyloxycarbonyl) or
the "Boc" (tert-butoxycarbonyl) group) or another
suitable protective group, e.g. a "trityl"
(triphenylmethyl) protective group.
The constitution of the linker L is such that
appropriate derivatization (steps (b) and (c)) and
workup (step (d)) result in the desired radical R6 with
one of the meanings indicated above for R6 in the final
product, the tetrahydrocarbazole derivative of the
general formula (I). To illustrate the constitution of
the linker L, this may be explained below by way of
example for the case where R6 equals the group -CONR8R9.
In the case where the radical R6 in the product of the
invention of the formula (I) has the meaning -CONR8R9,
firstly a compound Pg-N (R8) -R9' -COOH forming the linker
L is tethered by means of an activating reagent such as
DCC (dicyclohexylcarbodiimide) or HATU (0-(7-
azabenzotriazol-1-yl)-N,N-N',N'-tetramethyluronium
hexafluorophosphate) to the solid phase SP via free
amino groups of the SP, where Pg and SP have the
meaning indicated above, and R9' forms part of the later
radical R9. The protective group Pg is subsequently
eliminated, e.g. in the case of a Fmoc protective group
by means of piperidine/DMF. This results in a compound
HR8N-R9'-CONH-SP. The latter compound is then in turn
reacted with a precursor of the cyclohexanone
derivative (II), namely the cyclohexanone carboxylic
acid (II')

using an activating reagent such as DCC or HATU,
finally resulting in the cyclohexanone derivative (II)
as defined above. The meaning of the linker L in the
case just described is -CONR8-R9'-CONH-SP. Any resulting
isomers of whatever type (enantiomers, diastereomers or
positional isomers) can be fractionated - as also
elsewhere during the described preparation process - in
a known manner by means of HPLC.
The actual step (a), i.e. the condensation of the
cyclohexanone derivative (II) with the substituted
phenylhydrazine derivative (III) and, where
appropriate, elimination of the protective group Pg in
the group G by means of, for example, piperidine (in
the case of a Fmoc protective group) then takes place,
so that a free a-amino group is produced again at this
point.
In the case where the radical R7 is the group -NHCOR14,
-NHS02R14, -NR12R13 (where R12 and R13 are not both
hydrogen atoms), -NHCONHR14 or -NHCOOR14, a
derivatization of the now unprotected a-amino group of
the resin-bound cyclohexanone derivative (II) finally
takes place in step (b) , so that the various
alternative radicals R7 defined above can be
performed.

Depending on the nature of the desired radical R7 in the
tetrahydrocarbozole final product (I) of the invention,
the procedure for this is as follows:
In the case where R7 is the group -NHCOR14, the reaction
product from step (a) is reacted with a carboxylic acid
R COOH in the presence of an activating reagent such
as, for example, DCC or HATU and in the presence of a
base such as, for example, DIPEA (diisopropyl-
ethylamine) or DMAP (4-dimethylaminopyridine) by known
processes for forming peptide linkages (cf., for
example, Tetrahedron Lett. 1994, 35, 2279; alternative
(i)) •
In the case where R' is a sulfonamide group -NHS02R14,
the reaction product from step (a) is reacted with a
sulfonic acid derivative R14S02X, where X is a leaving
group, preferably a halogen atom, in particular a
chlorine atom, in the presence of a base such as, for
example, DMAP or DIPEA (cf., for example, Gennari et
al., EJOC 1998, 2437; alternative (ii)).
In the case where R7 is the group -NR12R13 (where R12 and
R13 are not both hydrogen atoms) , in the case where the
radical R12 is a hydrogen atom, the reaction product
from step (a) is reacted with a reagent R13X, where X is
a leaving group such as, for example, a halide atom, in
particular a chloride atom, in the presence of a base
such as, for example, DBU or DIPEA (cf. Green, JOC
1995, 60, 4287 or JOC 1996, 61, 3849) or with an
aldehyde R13CHO in the presence of a reducing agent such
as, for example, NaH/iB (OAc) 3. In the case where neither
of the radicals R12 and R13 is a hydrogen atom, the
reaction product from step (a) is a reacted with a
ketone R12COR13 in the presence of a reducing agent (cf.
Ellmann et al., JOC 1997, 62, 1240 or Synth. Commun.
1994, 609; alternative (iii) ) . In the case where both
radicals R12 and R13 in R7 equals -NR12R13 are hydrogen
atoms, alternative (vi) below applies.

In the case where R' is the group -NHCONHR14 (a urea
derivative) , the reaction product, from step (a) is
reacted with an isocyanate R14NCO (cf. Brown et al.,
JACS 1997, 119, 3288; alternative (iv)).
In the case where R7 is a carbamate or urethane group
-NHCOOR14, the reaction product from step (a) is reacted
with an alcohol HOR14 which has been preactivated by
carbonyldihydroxybenzotriazole ((HOBt)2CO) (cf. Warass
et al., LIPS 1998, 5r 125; alternative (v)).
In the case where R7 is a hydrogen atom, a C1 - C12 alkyl,
C1 - C12 aralkyl, an aryl, a hetaryl radical or the group
-NH2 (i.e. both radicals R12 and R13 in R7 equals -NR12R13
are hydrogen atoms), step (b) is omitted because no
further derivatization is necessary (alternative
(vi)) .
Step (c) , i.e. the derivatization on the indole
nitrogen atom, also corresponds, in analogy to step (b)
explained above, to various alternatives which are
explained in detail below:
For cases (i) to (v) defined above in step (b) , a
deprotonation of the reaction product obtained in (b)
takes place by means of a base such as, for example,
NaH or NaHMDS and subsequent derivatization by means of
a group R1X, where X is a leaving group, e.g. a halide
atom, in particular a chloride atom (cf. Collini &
Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca &
Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et
al., J. Med. Chem. 1970, 13, 327).
For case (vi) defined above in step (b) , i.e. when step
(b) is omitted, in analogy to the above description a
deprotonation of the reaction product obtained in (a)
takes place by means of a base such as, for example NaH
or NaHMDS and subsequent derivatization by means of a

group R1X, where X is a leaving group, e.g. a halide
atom, in particular a chloride atom.
Step (d) finally substantially includes the elimination
of the reaction product obtained in (c) from the solid
phase SP. In the case of Wang, trityl, DHP and Rink
amide resins, elimination of the reaction product
obtained in (c) takes place with the aid of an acid, in
particular with TFA (trifluoroacetic acid). In the case
of an aminolytic elimination from an HMB resin, the
eliminating reagent used is, for example, ammonia in
methanol. The desired product is then isolated in a
conventional way.
Exemplary embodiments of the preparation of
tetrahydrocarbazole derivatives of the invention are
detailed below.
Examples
I. General synthetic methods for compounds of the
invention
A Coupling of carboxylic acids to the Rink amide-
resin :
0.1 mmol of Fmoc-protected Rink amide-resin (166 mg,
loading 0.6 mmol/g) are preswollen with 1.5 ml of DMF
in a vessel with bottom frit for 20 min. After
aspiration, 1.5 ml of 20% piperidine/DMF are added and
stirred for 5 min. After aspiration, a further 1.5 ml
of 20% piperidine/DMF are added and stirred for
15 min. Aspiration is followed by washing four times
with DMF. Then 675 f.i.1 of a 0.267 M solution of Fmoc-
protected amino carboxylic acid in DMF, 675 |il of HATU
solution (0.267 M in DMF) and 150 fal of NMM solution
(2.4 M in DMF) and 0.01 mmol of DMAP are added and
stirred at 40°C for 4 h. After aspiration, the same
reagents are again added and stirred at 40°C for 4 h.

This is followed by aspiration and washing tour times
with DMF.
B Coupling of carboxylic acids to the trityl-resin:
2.98 mmol of Fmoc protected aminocarboxylic acid are
dissolved in 30 ml of dry dichloromethane, mixed with
14.3 mmol (2.45 ml) of DIPEA and added to 2.98 mmol of
2-chlorotrityl chloride-resin (2 g, loading 1.49 mmol/g
of resin). After shaking for two hours, the resin is
filtered off with suction through a frit and washed
three times with 2 0 ml of dichloromethane/MeOH/DIPEA
17:2:1. This is followed by washing three times with
20 ml of dichloromethane, three times with methanol and
three times with 20 ml of ether and drying in vacuo. A
resin with a loading of 0.5 to 1 mmol of amino
carboxylic acid per g of resin is obtained.
C Coupling of carboxylic acids to the HMB-resin:
21.3 mmol of amino carboxylic acid and 21.3 mmol of
HATU are dissolved in 60 ml of DMF and mixed with
63.9 mmol (10.9 ml) of DIPEA. After 5 minutes, 5 g of
polystyrene-HMB-resin (loading 0.71 mmol/g of resin)
are added and shaken at RT for 5 minutes. Then
21.3 mmol (2.6 g) of DMAP are added and shaken at RT
for 1 h. The resin is subsequently filtered off with
suction and washed once each with 100 ml of DMF, DCM
and DMF. The resin is mixed with 100 ml of 10% Ac20
(acetic anhydride)/DMF/5% DMAP and shaken for 15 min.
Aspiration is followed, by washing three times each with
100 ml of DCM and ether and drying in vacuo.
D Coupling of carboxylic acids to the Wang resin:
54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of
DIC are dissolved in 500 ml of dry DCM, and stirred at
RT for 10 min. After the precipitated urea has been
filtered off, the solution is evaporated to dryness and
the residue is dissolved in 160 ml of dry DMF. The
solution is added to 4.55 mmol (5 g, loading
0.91 mmol/g of resin) of Wang resin preswollen in DMF,

and 4.55 mmol (556 nig) of DMAP are adaed. After shaking
at RT for 1.5 hours, the resin is filtered off with
suction and taken up in 100 ml of 10% Ac20/DMF/5% DMAP
and shaken for 15 min. Aspiration is followed by
washing three times each with 100 ml of DCM and ether
and drying in vacuo.
E Coupling of an alcohol to the DHP-resin:
0.5 mmol of DHP-resin (0.5 g, loading density 1 mmol/g)
are preswollen in 2 ml of dichloroethane for 15 min. To
this are added 2 ml of a solution of 0.75 M
alcohol/0.37 M pyridinium paratoluenesulfonate and
stirred at 80°C for 16 h. Cooling to RT is followed by
addition of 5 ml of pyridine, briefly shaking with
inversion and filtration with suction. Washing is
carried out twice each with 5 ml of DMF, DCM and
hexane.
F Deprotection of a resin-bound Fmoc protective
group:
1.5 ml of 20% piperidine/DMF are added to 0.1 mmol of
resin-bound Fmoc group and stirred for 5 min. After
aspiration, 1.5 ml of 20% piperidine/DMF are again
added and stirred for 15 min. Aspiration is followed by
washing four times with DMF.
G Coupling of a carboxylic acid to resin-bound amino
functions:
675 nl of a 0.267 M solution of Fmoc-protected amino
carboxylic acid in DMF, 675 μl of HATU solution
(0.267 M in DMF) and 150 μl of NMM solution (2.4 M in
DMF) and 0.01 mmol of DMAP are added to 0.1 mmol of
resin-bound amino functions and stirred at 40°C for
4 h. After aspiration, the same reagents are added
again and stirred at 40°C for 4 h. This is followed by
aspiration and washing four times with DMF.
H Coupling of acetic acid to resin-bound amino
functions:

1.5 ml of a solution of 10% acetic anhydride in DMF are
added to 0.1 mmol of resin-bound amino functions and
stirred at RT for 15 min. This is followed by
aspiration and washing four times with DMF.
1 Synthesis of tetrahydrocarbazoles starting from
resin-bound cyclohexanones:
Before the reaction, 0.1 mmol of cyclohexanone-resin
are washed twice with 2 ml of DMF and twice with 2 ml
of acetic acid. Then 1 ml of DMF and 2 ml of 0.5 M
hydrazine/0.5 M ZnCl2 in acetic acid are added to the
resin and stirred at 70°C for 20 h. This is followed by
aspiration and washing twice with 2 ml of acetic acid
and 2 ml of DMF.
J Synthesis of sulfonamides starting from resin-
bound amides:
The resin is washed twice with 2 ml each of DMF and
DCE. 1 ml of 0.5 M sulfonyl chloride in DCE and 400 jal
of 2.5 M NMM/1 eq. of 0.25 M DMAP in DMF are added to
0.1 mmol of resin-bound amine. Stirring at 60 °C for
12 h is followed by aspiration and repetition of the
coupling. Aspiration is followed by washing four times
with 2000 ml of DMF.
K Synthesis of ureas by reaction of resin-bound
amine with isocyanates:
2 ml of 0.5 M isocyanate in DCM are added to 0.1 mmol
of resin-bound amine and stirred at RT for 18 h.
Aspiration is followed by washing four times with DMF.
L Synthesis of carbamates by reaction of resin-bound
amine with preactivated alcohols:
For the preactivation, 0.4 M alcohol and 0.39 M
dibenzotriazolyl carbonate and 0.39 M pyridine are
stirred in DMF at 40°C for 15 min. 1 mmol of resin-
bound amine is mixed with 1 ml of preactivated alcohol,
and 167 ml of 2.4 M NMM in DMF are added. Stirring at

60°C for 4 h is followed by aspiration and washing four
times with DMF.
M Synthesis of N-alkylamines by N-alkylation of
resin-bound amines with alkyl halides and cazalytic KI:
1 ml of 0.5 M halide/0.05 M KI in DMF and 416 \xl of
2.4 M DIPEA in DMF are added to 0.1 mmol of resin-bound
amine and stirred at 90°C for 12 h. After aspiration,
the resin is washed four times with 2 ml of DMF.
N N-alkylation of resin-bound indole nitrogens with
halide/NaH in DMF:
1 ml of DMF and 0.5 mmol of NaH (55% suspension in oil)
are added to 0.1 mmol of resin-bound amine. After
stirring at RT for 30 min, 1 ml of 0.5 M halide in DMF
are added and stirred at 45°C for 8 h. This is followed
by aspiration and washing twice each with 2 ml of
methanol, DMF, methanol and DMF.
0 Elimination from the Wang, trityl, DHP, Rink
amide-resin:
2 ml of 95% TFA/5% H20 solution are added to 0.1 mmol of
resin and shaken at RT for 3 h. The resin is then
filtered off and washed with a further 2 ml of TFA. The
combined TFA solutions are evaporated to dryness and
afford the crude products.
P Aminolytic elimination from the HMB-resin:
2 ml of DMF and 2 ml of 7 M NH3 in methanol are added to
0.1 mmol of resin and shaken at RT for 18 h. The resin
is then filtered off and washed with DMF. The combined
solutions are evaporated to dryness and afford the
crude product.
Preparation of required starting compounds:
3-[[(9H-Fluoren-9-ylmethoxy) carbonyl]amino]-2,3,4,9-
tetrahydro-lH-carbazole-3-carboxylic acid 1

38.4 mmol (6.G g) of 4,4-ethylenedioxycyclohexanone and
39.8 mmol (4.3 g) of phenylhydrazine are dissolved
separately in 50 ml and 10 ml, respectively, of water,
and then mixed. The milky emulsion resulting after
stirring for 10 min is extracted five times with ethyl
acetate, dried with MgS04 and evaporated to dryness.
Yield: 9.2 g of orange oil.
9.2 g of the unpurified phenylhydrazone are dissolved
in 240 ml of toluene at RT, and 4.9 g of freshly ground
ZnCl2 are added. After refluxing with a water trap for
90 min, most of the toluene is distilled off, an excess
of 2 N NaOH is added, and the mixture is extracted
three times with ethyl acetate. The extract, is washed
with brine and dried with MgS04, and the solvent is
distilled off. The remaining black oil is purified on
silica gel with ethyl acetate/hexane 1:9. Yield: 2.7 g
of beige solid.
11.6 mmol (2.7 g) of 1,2, 4,9-tetrahydrospiro[3H-
carbazole-3,2'-[1,3]dioxolane] and 640 mg of p-
toluenesulfonic acid are taken up in 70 ml of acetone
and stirred at RT for 2.5 h. The solution is added to
NaHC03 solution, extracted with ethyl acetate, washed
with brine, dried with MgS04 and concentrated. 2.13 g of
red-brown solid remain. Recrystallization from ether
results in 1.1 g of beige-colored solid.
60.2 mmol (11.1 g) of 1, 2, 4, 9-tetrahydrospiro-3H-
carbazol-3-oner 8.3 g of KCN and 22.0 g of (NH4)2C03 are
heated in 550 ml of 60% ethanol in an autoclave at 80°C
for 3 h. After cooling to room temperature, the
reaction mixture is added to ice-water, and the
precipitated solid is filtered off. Yield: 10.1 g of
gray solid.
44.2 mmol (11.3 g) of 1,2,4,9-tetrahydrospiro[3H-
carbazole-3,4'-imidazolidine]-2',5'-dione is heated
with 62 g of Ba(OH)2 x 8 H20 in 145 ml of H20 at 150°C

for 13 h. After cooling to room temperature, the
viscous mass is mixed with 37 g of (NH,)2C03 with
stirring and heated at 100°C for 30 min. Cooling to
room temperature is followed by filtration, washing
with water and evaporation of the filtrate to dryness.
Yield: 7.7 g of beige solid.
26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxylic acid in 2 6 ml of 1 N NaOH and
26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile
are combined at room temperature and diluted with
130 ml of acetonitrile/H20 1:1. After two hours, the pH
is readjusted to 9 with NEt3 (1.5 ml) and the mixture is
stirred at room temperature overnight. Then a further
6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of
acetonitrile are added, and stirring is continued for
two hours while controlling the pH. Removal of the
acetonitrile by distillation is followed by
acidification with 0.01 M HC1 and extraction with ethyl
acetate. The extract, is washed until neutral, dried
with Na2S04 and evaporated to dryness in a rotary
evaporator. Recrystallization takes place from
ether/hexane. Yield: 10.7 g.
XH NMR (d6 DMSO) : 5 = 2.07 ppm (m, 1H) ; 2.50 (m, 1H) ;
2.70 (bs; 2H) ; 3.04 (q, 2H) ; 4.17 (m, 2H) ; 4.28 (m,
2H); 6.92 (tr, 2H); 6.99 (tr, 2H); 7.23 (tr, 2H); 7.24-
7.35 (m, 3H) ; 7.38 (tr, 2H) ; 7.62 (s, 1H) ; 7.68 (dd,
2H); 7.87 (d, 2H); 10.71 (s, 1H) .
Melting point: 119°C
Fractionation into the two enantiomers takes place by
chiral HPLC.
(R)-3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]-
2,3,4,9-tetrahydro-lH-carbazole-3~carboxylic acid la.
tR = 6.4 min (Chiralcel OD 10 (am LC50 250 x 4.6 cm,
hexane/isopropanol 75:25, 80 ml/min)

(S) -3-[[(9H-Fluoren-9-ylmethoxy)carbony1]amino]-
2, 3,4, 9-tetrahydro-lH-carbazole-3-carboxylic acid lb
tR = 7.5 rnin (Chiralcel OD 10 um LC50 250 x 4.6 cm,
hexane/isopropanol 75:25, 80 ml/min)
1-[[(9H-Fluoren-9~ylmethoxy)carbonyl]amino]-4-oxocyclo-
hexanecarboxylic acid 2
320 mmol (50 g) of 4,4-ethylenedioxycyclohexanone are
suspended in 800 ml of 50% EtOH, and. 1500 mmol
(144.5 g) of (NH4)2C03 and 640 mmol (41.7 g) of KCN are
added. After stirring at 60°C for 5 h, the ethanol is
removed in vacuo, and the aqueous residue after cooling
with ice is filtered off, washed with water and dried.
Yield: 72.4 g of 4,4-1,4-dioxa-9,11-diazadi-
spiro[4.2.4.2]tetradecane-10,12-dione.
295 mmol (66.8 g) of 4 , 4-1,4-dioxa-9,11-diazadi-
spiro[4.2.4.2]tetradecane-10,12-dione and 826 mmol
(260.6 g) of Ba(OH)2 x 8 H20 are stirred in 2.5 1 at
150°C in an autoclave for 6 h. After cooling to room
temperature, 1032 mmol (99.2 g of (NH4)2C03 are added to
the solution and stirred at 60°C for 1 h. The
suspension is filtered and washed, and the filtrate is
lyophilized. The residue is recrystallized from
H20/MeOH. Yield: 45.4 g of 8-amino-l,4-dioxa-
spiro[4,5]decane-8-carboxylic acid.
213 mmol (42.9 g) of 8-amino-l,4-dioxaspiro[4,5]decane-
8-carboxylic acid in 213 ml of IN NaOH and 213 mmol
(71.9 g) of Fmoc-ONSu in 240 ml of acetonitrile are
combined and diluted with 1000 ml of acetonitrile/H20
1:1. Adjustment of the pH to 9 is followed by stirring
at room temperature overnight. Removal of the
acetonitrile in a rotary evaporator is followed by
acidification with 0.01 M HC1 and extraction with ethyl
acetate. The extract is washed until neutral, dried
with Na2S04 and evaporated to dryness. The residue is
recrystallized from ethyl acetate/hexane. Yield: 79.0 g

of 8- [ [ (9H-fluoren-9-ylmethoxy)carbonyl]amino]-1, 4-
dioxaspiro[4,5]decane-8-carboxylic acid.
187 mmol (79 g) of 8-[[(9H-fluoren-9-ylmethoxy)-
carbonyl]amino-1,4-dioxaspiro[4,5]decane-8-carboxylic
acid are taken up in 3.5 1 of acetone/0.1 M HC1 1:1 and
stirred at room temperature for 4 h. The acetone is
stripped off in a rotary evaporator, and the
precipitated product is filtered off, washed with water
and dried. Yield: 68.7 g of 2.
1H NMR (d6 DMSO) : 8 = 1.52-1.73 (m, 4H) ; 1.82-2.14 (m,
4H) ; 4.27 (m, 3H) ; 7.85 (tr, 2H) ; 7.42 (tr, 2H) ; 7.67
(s, 1H) ; 7.75 (d, 2H) ,- 7.91 (d, 2H)
Melting point: 157°C
4-0xocyclohexanecarboxylic acid 3
20 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate
are suspended in 40 ml of 2% H2S04 and stirred at 90°C
for 2 h. This is followed by extraction four times with
ethyl acetate, drying with Na2S04 and removal of the
solvent. Recrystallization from ether/hexane affords
2.9 g of white solid 3
XH NMR (d6 DMSO): 8 = 1.72 (m, 2H) ; 2.08-2.18 (m, 2H) ;
2.19-2.47 (m, 4H); 2.72 (m, 1H); 12.23 (bs, 1H).
4-Chloro-3-[[ (phenylamino)carbonyl]amino]benzeneacetic
acid 4
18.55 mmol (2.21 g) of S0C12 are slowly added to
18.55 mmol (4 g) of 4-chloro-3-nitrobenzeneacetic acid
in 50 ml of MeOH while cooling in ice and stirring.
After stirring for 30 min, the mixture is allowed to
warm to RT and a further 3.71 mmol (0.44 g) of S0C12 are
added. Stirring overnight is followed by heating to
reflux for 30 min. Stripping off the solvent is
followed by recrystallization from ether/hexane.
Yield: 3.43 g of methyl 4-chloro-3-nitrobenzeneacetate
as yellowish solid.

13.07 mmol (3.0 g) of methyl 4-chloro-3-
nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust
are heated to reflux in 500 ml of MeOH for 10 min.
Then, under reflux, 13 ml of cone. HC1 are added
dropwise, and refluxing is continued for 30 min. The
suspension is filtered hot, the methanol is distilled
off, and the residue is adjusted to pH 14 with a NaHC03
solution. Extraction with ethyl acetate, drying with
Na2S04 and removal of the solvent by distillation
affords 2.3 g of methyl 3-amino-4~chlorobenzeneacetate
as beige solid.
2.08 mmol (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are dissolved in 40 ml of DCM and,
at 0°C, 0.83 mmol (24 6.3 mg) of triphosgene and 0.6 ml
of pyridine are added. After stirring at 0°C for one
hour, 10.4 mmol (1.11 g) of benzylamine are added, and
stirring is continued at room temperature overnight.
Extraction is carried out with DCM/H2O, the organic
phase is dried, and the solvent is removed.
Yield: 727 mg of methyl 4-chloro-3-[[(phenylamino)-
carbonyl]amino]benzeneacetate.
2.98 mmol (990 mg) of methyl 4-chloro-3-[[ (phenyl-
amino) carbonyl] amino ] benzeneacetate are taken up in
10 ml of methanol, and 6 mmol of 1 N NaOH are added.
After stirring at RT for 2 h, the methanol is distilled
off and the residue is acidified to pH 2-3 with 1 M
HC1. Extraction is carried out with ethyl acetate, and
drying with Na2S04, and the solvent is removed.
Recrystallization takes place from boiling isopropanol.
Yield: 830 mg of white solid £.
XH NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.92 (d, 1H) ; 6.99
(tr, 1H) ; 7.35-7.50 (m, 3H) ; 8.10 (s, 1H) ; 8.30 (s,
1H); 9.42 (s, 1H); 12.40 (bs, 1H).

4-Chloro-3-[ [ [ (phenylmethyl) amino] carbonyl] ammo] -
benzeneacetic acid 5
2.08 mmol (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are mixed with 10.4 mmol (969 mg)
of aniline as described under 4.) and worked up
analogously. Yield: 662 mg of solid.
For the ester cleavage, 2.47 mmol (790 mg) of methyl 4-
chloro-3-
[[[(phenylmethyl)amino]carbonyl]amino]benzeneacetate
are hydrolyzed with 1 N NaOH in analogy to the above
method. The product 5 is obtained without
recrystallization. Yield: 693 mg of yellowish solid.
ES-MS: 319 (M+H+)
4-Chloro-3-[[(4-pyridinylamino)carbonyl]amino]
benzeneacetic acid 6_
2.08 mmol (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are mixed with 10.4 mmol (97 9 mg)
of 4-aminopyridine as described under 4.) and worked up
analogously. Yield: 664 mg of solid.
For the ester cleavage, 2.63 mmol (840 mg) of methyl 4-
chloro-3-[[(4-pyridinylamino)carbonyl]amino]
benzeneacetate are hydrolyzed with 1 N NaOH in analogy
to the above method. The product 6> is obtained without
recrystallization. Yield: 481 mg of yellowish solid.
XH NMR (d6 DMSO) : 5 = 3.57 (s, 2H) ; 6.94 (d, 1H) ; 7.40
(m, 3H) ; 8.05 (s, 1H) ; 8.35 (d, 2H) ; 8.50 (s,r 1H) ; 9.92
(s, 1H); 12.40 (bs, 1H)
4-Chloro-3- [ [ (2-pyridinylamino) carbonyl ] amino ']
benzeneacetic acid _7
2.08 mmol (415 mg) of methyl 3-amino-4-
chlorobenzeneacetate are mixed with 10.4 mmol (979 mg)
of 2-aminopyridine as described under 4.) and worked up
analogously. Yield: 617 mg of solid.

For the ester cleavage, 2.47 mmol (790 mg) of methyl 4-
chloro-3-[[(2-
pyridinylaraino)carbonyl]amino]benzeneacetate
are hydrolyzed with 1 N NaOH in analogy to the above
method. The product 7 is obtained without
recrystallization. Yield: 693 mg of yellowish solid.
XH NMR (d6 DMSO) : 6 = 3.59 (s, 2H) ; 6.94 (dd, 1H) ; 7.03
(dd, 1H); 7.22 (d, 1H); 7.42 (d, 1H) ; 7.78 (dtr, 1H) ;
8.29 (m, 2H); 10.02 (s, 1H) ; 11.82 (bs, 1H) ; 12.50 (s,
1H) .
II. Examples of compounds (I) of the invention
Example 1;
0.3 mmol (42.6 mg) of 4-oxocyclohexanecarboxylic acid
are dissolved in 1 ml of acetic acid and added to a
suspension of 0.3 mmol (43.3 g) of phenylhydrazine
hydrochloride and 0.3 mmol (40.0 mg) of ZnCl2 in 1 ml of
acetic acid. Stirring at 70°C for 20 h is followed by
dilution with 20 ml of water and extraction with ethyl
acetate. The ethyl acetate phase is washed with water,
dried over Na2S04 and evaporated to dryness. Yield:
65.6 mg (100%) of white solid.
Name Number Mfnd Mcaie
2,3,4,9-Tetrahydro-lH-carbazole-
3-carboxylic acid 8 215 215.2507
The column headings (name, number of the compound, Mfnd
(measured molecular mass) , Mcaic (calculated molecular
mass) ) which are introduced here also apply to the
following examples and are therefore not repeated
again.
Example 2:
Synthesis takes place on the 0.2 mmol scale by methods
A, I and O.

2,3,4,9-Tetrahydro-lH-carbazole-
3-carboxamide 9 214 214.2666
Example 3:
Synthesis takes place on the 0.2 mmol scale by methods
A, F, G, I and 0.
N-[(1S)-1-(Aminocarbonyl)-2-methyl
propyl]-(35)-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxamide 10a 314 313.3987
N-[(15)-1-(Aminocarbonyl)-2-methyl
propyl]-(3R)-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxamide 10b 314 313.3987
N- (2-Amino-2-oxoethyl)-2, 3,4, 9-
tetrahydro-lH-carbazole-3-
carboxamide _11 271 271.3183
Example 4:
Synthesis takes place on the 0.2 mmol scale by methods
D, F, G, F, G, I and 0.
N- [(35)-(2,3,4,9-Tetrahydro-lH-
carbazol-3-yl)carbonyl]-L-valyl-L-
glutamine 12a 442 442.513
N-[(3R)-(2,3,4,9-Tetrahydro-lH-
carbazol-3-yl)carbonyl]-L-valyl-L-
glutamine, Isomer B 12b 442 442.513
Example 5:
Synthesis takes place on the 0.2 mmol scale by methods
D, F, G, I, F and O:
N-[[(35)-3-Amino-2,3,4,9-tetrahydro-
lH-carbazol-3-yl)carbonyl]-L-
alanine 13 301 301.3441

Example 6:
0.1 mmol of carboxylic acid, 0.1 mmol of HOBt and
0.15 mmol of amine component are dissolved in 15 ml of
dry DMF (also THF, DCM) , and, while cooling in ice and
stirring, 0.5 mmol of NMM is added. After about 15 min,
0.15 mmol of EDCI x HC1 is added, and the mixture is
stirred for one hour, warmed to room temperature and
stirred overnight. For workup, the solvent is stripped
off, and the product is dissolved in ethyl acetate and
washed twice each with 0.1 N HC1 and saturated NaCl
solution. Drying and stripping off the solvent are
followed if necessary by recrystallization.
9H-Fluoren-9-ylmethyl[(3S)-3-[[[(4-
bromophenyl)methyl]amino]carbonyl]-
2,3,4, 9-tetrahydro-lH-carbazol-3-yl]
carbamate 1± 62 0 62 0.54 39
Methyl N-[[(35)-3-[[(9H-fluoren-9-yl
methoxy)carbonyl]amino]-2,3,4,9-
tetrahydro-l.ff-carbazol-3-yl] carbonyl] -
L-alaninate 15 537 537.6129
Example 7;
Synthesis takes place on the 0.2 mmol scale by methods
A, F, G, F, G, F, G and 0.

- 54 -
Example 8:
Synthesis takes place on the 0.2 mmol scale by methods
A, F, G, F, G and 0.

refluxed in dry toluene with a water trap for 2 4 h. The
solvent is removed and the residue is taken up in ethyl
acetate/water. The organic phase is washed with water,
dried and evaporated to dryness. The product is
distilled in a Kugelrohr apparatus under high vacuum at
120°C and 0.03 mbar.
Yield: 1.52 g of 4-ethyl 1,4-dioxaspiro[4,5]decane-8-
carboxylate 269.
85 |il of diisopropylamine in 500 |il of dry THF are
added dropwise to 0.6 mmol of a 1.6 molar solution of
butyllithium in heptane at -20 °C under argon and then
stirred for 10 min. After cooling to -70°C, 0.5 mmol
(107 mg) of 269 in 200 μ1 of dry THF are added
dropwise, allowed to reach 0°C over the course of one
hour and stirred for a further 30 min. After cooling to
-70°C, 0.7 mmol (106 JJ.1) of l-bromo-3-phenylpropane in
300 p.1 of dry THF are added, and the mixture is stirred
for 30 min. It is allowed to reach RT and then stirred
for 1 hour. The saturated NH4C1 solution and n-hexane
are cautiously added to the organic phase, which is
stirred for 10 min. The organic phase is separated and
washed with water. Filtration through a Whatman filter
is followed by evaporation to dryness.
Yield: 165 mg of ethyl 8-(3-phenylpropyl)-1,4-
dioxaspiro[4,5]decane-8-carboxylate 270.
0.6 mmol (200 mg) of 270 are taken up in. 25 ml of
acetone/0.1 M HC1 1:1 and stirred with catalytic
amounts of pTsOH at 50°C for 48 h. The acetone is
stripped off in a rotary evaporator, and the
precipitated product is filtered off, washed, with water
and dried.
Yield: 156 mg of ethyl 4-oxo-8-(3-phenylpropyl)cyclo-
hexanecarboxylate 271.
The indolization takes place as described in Example 1
using phenylhydrazine.

Yield after evaporation and preparative HPLC: 65 mg of
ethyl 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazole-3-carboxylate 268.
ES-MS: 362 (M+H+)
80 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-
phenylpropyl)-lH-carbazole-3-carboxylate 272 are
prepared analogously using 2,4-dichlorophenylhydrazine.
ES-MS: 430 (M+H+)
Example 36:
2,3,4, 9-Tetrahydro-3-(3-phenylpropyl)-lH-carbazole-3-
carboxylic acid 273
3.94 mmol (1.31 g) of 269 are stirred in 50 ml of
methanol and 30 ml of 50% sodium hydroxide solution at
60°C for 4 h. The mixture is acidified with dilute HC1
and extracted with ether. Drying with Na2S04 and
evaporation affords 1.02 g (85%) of white solid 8-(3-
phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic
acid 274.
65 mg of 274 are first deprotected with HC1 and then
reacted with phenylhydrazine for the indolization as
described for 270 and 271.
Yield after evaporation and preparative HPLC: 15 mg of
273.
ES-MS: 334 (M+H+)
39 mg of 6, 8-dichloro-2,3, 4,9-tetrahydro-3-(3-phenyl-
propyl) -lH-carbazole-3-carboxylic acid 275 are prepared
analogously using 2,4-dichlorophenylhydrazine.
ES-MS: 478 (M+H+)
Example 31:

2,3,4,9-Tetrahydro-W-[(1S)-1-(hydroxymethyl)-2-
methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3-
carboxamide 276
0.66 mmol (200 mg) of 274 are reacted with 1.5
equivalents of valinol in analogy to Example 6. 277 mg
of white solid N-[(1S)-1-(hydroxymethyl)-2-
methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]-
decane-8-carboxamide 277 are obtained.
Then 0.3 mmol (117 mg) of 277 are first deprotected
with HC1 and subsequently reacted with phenylhydrazine
for the indolization as described for 270 and 271.
Yield after evaporation and preparative HPLC: 15 mg of
276.
ES-MS: 418 (M+H+)
25 mg of 6,8-dichloro-2,3,4,9-tetrahydro-N-[(1S)-1-
(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H-
carbazole-3-carboxamide 278 are prepared analogously
using 2,4-dichlorophenylhydrazine.
ES-MS: 486 (M+H+)
Example 38:
2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-N- (2-pyridinyl-
methyl)-lH-carbazole-3-methanamine 279
54 ml of a 1 M solution of LiAlH4 in dry THF are
cautiously added to a solution of 18 mmol (6 g) of 270
in 250 ml of dry THF under argon at room temperature.
After heating to reflux for 3 h, cautious hydrolysis is
carried out with 300 ml. of saturated NH4C1 solution, and
250 ml of ether are added. The aluminum salts are
filtered off and washed with ether. Drying of the ether
phase with Na2S04 and evaporation of the solvent afford
3.4 g of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]decane-
8-methanol 280.

5.86 mmol (1.7 g) of 280 are dissolved in 60 ml of dry
DCM and 20 ml of dry DMSO. Under nitrogen at room
temperature, firstly 44 mmol (6.1 ml) of TEA and then
cautiously 17.6 mmol (2.8 g) of S03-pyridine complex are
added, and the mixture is stirred for one hour.
Subsequently 200 ml of saturated NH4C1 solution are
added and extraction is carried out with 150 ml of
ether. Drying of the ether phase with Na2S04 and
evaporation of the solvent afford 1.9 g of 8-(3-
phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carbaldehyde
281 as colorless oil..
0.719 mmol of sodium triacetoxyborohydride are added to
a mixture of 0.359 mmol (103 mg) of 281 and 0.359 mmol
(37 ml) of 2-pyridinemethanamine in 2.5 ml of 1,2-
dichloroethane. The mixture is stirred under N2 at room
temperature for 3 h. Saturated NaHCCb solution is added,
and the mixture is extracted with ether. The: dried and
evaporated ether extract affords 101 mg (76%) of white
solid N-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec-8-
yl]-2-pyridinemethanamine 282.
Subsequently, 101 mg of 282 are first deprotected with
HC1 and then reacted with phenylhydrazine for the
indolization as described for 270 and 271. Yield after
evaporation and preparation HPLC: 71 mg of 279.
ES-MS: 410 (M+H+)
54 mg of 6, 8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl-
propyl) -N-(2-pyridinylmethyl)-lH-carbazole-3-
methanamine 283 are prepared analogously using 2,4-
dichlorophenylhydrazine.
ES-MS: 478 (M+H+)
Example 39:
(2S)-3-Methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenyl-
propyl) -l#-carbazol-3-yl]methyl]amino]-1-butanol 284

0.368 mmol (106 mg) of 281 and 0.368 mmol (38 mg) of
valinol are dissolved in 1.5 ml of dry methanol and
stirred at room temperature for 30 min. After cooling
to 0°C, 0.557 mmol (21 mg) of NaBH4 are added and
stirred at room temperature for 1 h. 0.437 mmol (25 ul)
of acetic acid is added, and stirring is continued at
pH 6 for 2 h. Saturated NaHC03 solution is added, and
the mixture is extracted with ether. Drying of the
organic phase with Na2SC>4 and evaporation affords 106 mg
(77%) of colorless oil for 270 and 271.
Deprotection and indolization are then carried out as
described for 270 and 271. Yield after evaporation and
preparative HPLC: 18 mg of white solid 284.
ES-MS: 405 (M+H+)
17 mg of (2S)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3-
(3-phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-3-
methyl-1-butanol 286 are prepared analogously using
2,4-dichlorophenylhydrazine.
ES-MS: 473 (M+H+)
Example 40:
2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-0-(4-pyridinyl-
methyl)-lH-carbazole-3-methanol 287
0.689 mmol of NaH (as 55% suspension in mineral oil)
are added to a solution of 0.344 mmol (100 mg) of 280
in 10 ml of dry DMF at 0°C under an N2 atmosphere. The
mixture is allowed to reach room temperature and is
stirred for 30 min. 1.377 mmol of 4-
(chloromethyl)pyridine are added, and the mixture is
stirred at 95-100°C overnight. Cooling to room
temperature is followed by hydrolysis with 2 ml of
water and extraction with ether. Drying of the solvent
and evaporation affords 115 mg of yellow oil 288.

Deprotection and indolization are then carried out as
described for 270 and 271. Yield after evaporation and
preparative HPLC: 14 mg of white solid 287.
ES-MS: 411 (M+H+)
Example 41:
Ethyl 3-[2, 3, 4, 9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazol-3-yl]-2-propenoate 289
0.347 mmol of 281 in 0.5 ml of THF are added dropwise
to a solution of 0.378 mmol of ethyl
(triphenylphosphoranylidene)acetate in 1 ml of absolute
THF while cooling in ice. After the addition is
complete, the mixture is allowed to warm to room
temperature and is stirred for a further 2 days. It is
then hydrolyzed with water and extracted with ether.
Na2SC>4 is used for drying, phosphane oxide and desiccant
are filtered off, and the solvent is removed.. Yield 80%
of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec-
8-yl]-2-propenoate 290.
Deprotection and indolization are then carried out as
described for 270 and 271.
Yield after evaporation and preparative HPLC: 9 mg of
white solid 289.
ES-MS: 388 (M+H+)
III Demonstration of the GnRH-antagonistic effect of
compounds (I) of the invention
Materials:
Buserelin is purchased from Welding (Frankfurt/Main,
Germany) . The compound is labeled with 125I by using the
chloramine T method and Na125I (4000 Ci/mmol; Amersham-
Buchler, Brunswick, Germany). The labeled substance is
purified by reverse phase HPLC on a Spherisorb ODS II
column (250 x 4 mm, particle size 3 μm) by elution with
50% acetonitrile/0.15% trifluoroacetic acid at a flow

rate of 0.5 ml/min. The specific activity is
2000 Ci/mmol.
All other chemicals are purchased from commercial
source in the highest available purity.
Cell culture:
Alpha T3-1 cells (Bilezikjian et al., Mol. Endocrinol 5
(1991), 347-355) are cultivated in DMEM medium (Gibco-
BRL, Eggenstein-Lepoldshafen, Germany) with penicillin
(100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine
(0.01 mol/1) and 10% fetal calf serum (FCS; PAA
Laboratories, Coelbe, Germany) on plastic tissue
culture plates (Nunc, 245 x 245 x 20 mm) . CHO-3 cells
(Schmid et al. , J. Biol. Chem. 275 (2000), 9193-9200)
are cultivated under identical conditions apart from
the use of Ham's F12 medium (Gibco-BRL).
10 confluent cell culture plates are washed twice with
50 ml of phosphate-buffered saline (PBS). The cells are
harvested by scraping off with a rubber policeman into
5 ml of PBS and sedimented by centrifugation at 800 rpm
for 10 min in a laboratory centrifuge (Heraeus) . The
cell pellet is resuspended in 5 ml of 0.25 mol/1
sucrose/0.01 mol/1 triethanolamine, pH 7.4. The cells
are lysed by three cycles of freezing in dry
ice/ethanol bath and thawing at room temperature. The
lysate is centrifuged at 900 rpm for 10 min, and the
sediment is discarded. The supernatant is centrifuged
at 18 000 rpm in a Sorvall SS34 rotor for 30 min. The
pellet (cell membranes) is suspended in 5 ml of assay
buffer (0.25 mol/1 sucrose, 0.01 mol/1 triethanolamine,
pH 7.5, 1 mg/ml ovalbumin) in a Potter, and stored in
200 \xl aliquots at -20CC. Protein is determined by the
method of Bradford (Anal. Biochem. 72 (1976), 248-254).
Receptor assay:
Binding studies for competition plots are carried out
as triplicates. A test sample contains 60 f.il of cell

membrane suspension (10 μg of protein for αT3-l-cells
or 40 ug of protein for CH03 cells), 20 ul of 125I
labeled Buserelin (100 000 ipm per sample for
competition plots and between 1500 and 200 000 ipm for
saturation experiments) and 20 ul of test buffer or
test compound solution. The test compounds are
dissolved in distilled water or 50% ethanol. Serial
dilutions (5 x 10"6 mol/1 to 5 x 10"12 mol/1) are
prepared in test buffer. The nonspecific binding is
determined in the presence of an excess of an unlabeled
Buserelin (10~6 mol/1). The test samples are incubated
at room temperature for 3 0 min. Bound and free ligand
are separated by filtration (Whatman GF/C filter 2.5 cm
diameter) using an Amicon lOx collecting apparatus and
washed twice with 5 ml of 0.02 mol/1 Tris/HCl, pH 7.4.
The filters are moistened with 0.3% polyethyleneimine
(Serva, Heidelberg, Germany) for 3 0 min in order to
reduce the nonspecific binding. The radioactivity
retained by the filters is determined in a 5-channel
gamma counter (Wallac-LKB 1470 Wizard).
The IC5o values obtained for the preferred compounds, as
defined above, are indicated in the table which
follows.

in which
the radical R1 is a hydrogen atom, a C2-C6 alkenyl
or a C1-C6 alkyl radical and may optionally be
substituted by an aryl, hetaryl radical or the
group -COOR11, where the aryl or hetaryl radical
may be substituted by up to three substituents
which are selected independently of one another
from the group consisting of -N02, -CH3, -CF3,
-OCH3, -OCF3 and halogen atoms, and
the radical R11 is a hydrogen atom, a C1-C12 alkyl,
a C1-C12 aralkyl, an aryl, hetaryl radical or the
group -COCH3 and may optionally be substituted by
one substituent selected from the group consisting
of -CONH2, -COCH3, -COOCH3, -SO2CH3 and aryl
radicals;
the radicals R2, R3, R4 and R5 are each
independently of one another a hydrogen atom, a
halogen atom, the group -COOH, -CONH2, -CF3, -OCF3,
-N02, -CN, a C1-C6 alkyl, a C1-C6 alkenyl, a C1-C6

alkoxy, a C1-C12 aralkyl, an aryl or hetaryl
radical;
the radical R6 is the group -CONR8R9, -COOR8,
-CH2NR8R9, -CH2R8, -CH2OR8 or a C1-C12 alkenyl radical
which is optionally substituted by the radicals R8
and R9,
where the radicals R8 and R9 are each independently
of one another a hydrogen atom, a C1-C12 alkyl, a
C1-C12 aralkyl, a C1-C12 hetaralkyl, an aryl or
hetaryl radical, each of which may be substituted
by one or more substituents selected from the
group consisting of -OH, -NH2, -CONHR10, -COOR10,
-NH-C(=NH)-NH2 and halogen atoms,
where the radical R10 is a hydrogen atom, a C1-C12
alkyl, a C1-C12 aralkyl, an aryl or hetaryl radical
and is optionally substituted by the group
-CON(R11)2,
or where the radicals R8 and R9 may together form a
cyclic structure which consists either exclusively
of carbon atoms or a combination of carbon atoms
and heteroatoms;
the radical R7 is a hydrogen atom, a C1-C12 alkyl, a
C1-C12 alkenyl, a C1-C12 aralkyl, an aryl or hetaryl
radical, the group -NR12R13, -NHCOR14, -NHCONHR14,
-NHCOOR14 or -NHS02R14 and may optionally be
substituted by one or more substituents selected
from the group consisting of -OH, -NH2, -CONH2,
-COOH and halogen atoms,
the radicals R12 and R13 are each independently of
one another a hydrogen atom, a C2-C6 alkenyl or a
C1-C12 alkyl radical and may optionally be
substituted by one or more aryl or hetaryl
radicals which in turn may be substituted by up to
three substituents selected independently of one
another from the group consisting of -N02, -CH3,
-CF3, -OCH3, -OCF3 and halogen atoms,

- 101 -
and the radical R14 is a hydrogen atom, a C1-C12
alkyl, a C1-C12 alkenyl, a C1-C12 aralkyl, an aryl
or hetaryl radical which may optionally be
substituted by one or more substituents selected
from the group consisting of -N02, -CH3, -OR11,
-CF3, -OCF3, -OH, -NCR11) 2, -OCOR11, -COOH, -CONH2,
-NHCONHR11, -NHCOOR11 and halogen atoms;
and the radicals Ra, Rb, Rc, Rd, Re and Rf are each
independently of one another a hydrogen atom, a
halogen atom, the group -COOH, -CONH2, -CF3, -OCF3,
-N02, -CN, a C1-C6 alkyl, C1-C6 alkoxy, an aryl or
hetaryl radical;
with the proviso that the compound of the general
formula (I) is not selected from the group
consisting of 3-amino-1,2,3,4-tetrahydrocarbazole-
3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4-
tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-
benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic
acid, 3-acetamido-l ,2,3, 4-tetrahydrocarbazole-3-
carboxylic acid, methyl 3-acetamido-l,2,3,4-
tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-
acetamido-1,2,3,4-tetrahydrocarbazole-3-carbox-
ylate or 3-tert-butoxycarbonylamino-l,2,3,4-tetra-
hydrocarbazole-3-carboxylic acid.
The compound as claimed in claim 1, where the
radicals Ra, Rb, Rc, Rd, Re and Rf are hydrogen
atoms.
The compound as claimed in claim 1 or 2, where the
radical R1 is a hydrogen atom.
The compound as claimed in any of claims 1 to 3,
where the radicals R2, R3, R4 and/or R5 are not
hydrogen atoms.

The compound as claimed in claim 4, where the
radicals R2, R3, R4 and R5 are independently of one
another the group -CH3, -CI or -OCH3.
The compound as claimed in claim 5, where the
compound is selected from the group consisting of
phenylmethyl [(is, 2S)-1-[[[(3R)-3-[[[ (1S)-1-
(aminocarbonyl) --2-methylpropyl] amino] carbonyl] -
2,3,4,9-tetrahydro-8-methyl-lH-carbazol-3-
yl]amino]carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1-
(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6-
chloro-2,3,4,9-tetrahydro-lH-carbazol-3-
yl]amino]carbonyl]-2-methylbutyl]carbamate, and
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S)-1-
(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-
2,3,4,9-tetrahydro-8-methoxy-lH-carbazol-3-
yl]amino]carbonyl]-2-methylbutyl]carbamate.
The compound as claimed in any of claims 1 to 5,
where the radical R6 is a hydrophobic radical which
includes alkyl, aryl and/or hetaryl structures and
which carries a hydrogen bond donor-acceptor
system at a distance of from two to four single
bonds, counting from the carbon atom substituted
by the radicals R6 and R7.
The compound as claimed in claim 7, where the
radical R6 is selected from the group consisting of
a phenylalaninylamide residue, an isoleucylamide
residue, a valyl-4-aminobenzamide residue, a
valyl-N-methylaroide residue, a methyloxymethyl-4-
pyridyl radical, a carboxyl radical, an ethyl
propenoate residue, a carbonylvalylamide residue,
a carbonylthreonylamide residue, a cyclic
carboxamide residue, a 4-carboxamidophenyl-
carboxamide residue, a methylaminomethyl-2-pyridyl
radical, a carbonylvalinol residue and a
methylvalinol residue.

The compound as claimed in claim 8, where the
compound is selected from the group consisting of
phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-2-amino-
2-oxo-l-(phenylmethyl)ethyl]amino]carbonyl]-
2,3,4, 9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S,2S)-1-
(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l-[ [ [4-
(aminocarbonyl)phenyl]amino]carbonyl]-2-
methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-
lH-carbazol~3-yl]amino]carbonyl]-2-
methylbutyl]carbamate,
phenylmethyl [(IS, 2S)-2-methyl-l-[[[(3R)-2,3,4,9-
tetrahydro-3-[[[(1S)-2-methyl-l-[(methylamino)-
carbonyl]propyl]amino]carbonyl]-lH-carbazol-3-
yl]amino]carbonyl]butyl]carbamate,
2,3,4,9-tetrahydro-3-(3-phenylpropyl)-O-(4-
pyridinylmethyl)-lH-carbazole-3-methanol,
2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazole-3-carboxylic acid,
ethyl 3-[2, 3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-
carbazol-3-yl]-2-propenoate,
phenylmethyl [(lS,2S)-l-[[[(3R)-3~[[[(1S)-1-
(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-
2,3,4, 9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [ (IS, 2S)-1-[ [ [ (3R)-3-[[[ (1S,2R)-1-
(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]-
2,3,4, 9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[(2S)-2-
(aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate,

phenylmethyl [ (is,2S)-1- [ [ [ (3R)-3-[[ (2S) -2-
(aminocarbonyl)octahydro-lH-indol-1-yl]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-
yl]amino]carbonyl]-2-methylbutyl]carbamate),
phenylmethyl [(is,2S)-1-[[[(3R)-3-[[[4-
(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate,
2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N- (2-
pyridinylmethyl) -lH-carbazole-3-methanamine,
phenylmethyl [(IS,2S)-1-[[[(3S)-3-[[[ (1S)-1-
(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
2,3,4,9-tetrahydro-N-[(1S)-1-(hydroxymethyl)-2-
methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3-
carboxamide and
(2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3-
phenylpropyl) -l/f-carbazol-3-yl] methyl] amino] -1-
butanol.
The compound as claimed in any of claims 1 to 5, 7
or 8, where the radical R7 is a hydrophobic radical
including alkyl, aryl and/or hetaryl structures.
The compound as claimed in claim 10, where the
radical R7 is selected from the group consisting of
a 2,3-biphenylpropionylamino radical, an
indanoylamino radical, an indolylacetylamino
radical, a 2-naphthylacetylamino radical, a 3-
propionylamino radical, a phenylmethylcarboxamide
residue which is substituted on the aromatic
system, a phenylhexylamine residue and a
phenylpropyl radical.
The compound as claimed in claim 11, where the
compound is selected from the group consisting of

N-[[(31?)-2,3,4,9-tetrahydro-3-[(l-oxo-2, 3-
diphenylpropyl)amino]-lH-carbazol-3-yl]carbonyl]-
L-valyl-L-aspartamide,
(3R)-N-[(1S)-1- (aminocarbonyl)-2-methylpropyl]-3-
[[(2,3-dihydro-lH-inden-l-yl)carbonyl]amino]-
2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide,
(3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-
2,3,4,9-tetrahydro-3-[(lH-indol-3-ylacetyl)amino]-
lH-carbazole-3-carboxamide,
(3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-
2,3,4,9-tetrahydro-3-[(2-naphthalinylacetyl)-
amino]-lH-carbazole-3-carboxamide,
N-[ [ (3£)-2,3,4, 9-tetrahydro-3-[ [ (2S, 3S) -3-methyl-
l-oxo-2-[(l-oxo-3-phenylpropyl)amino]pentyl]-
amino]-lH-carbazol-3-yl]carbonyl]-L-valyl-L-
aspartamide,
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-
2,3,4,9-tetrahydro-3-[[(4-methylphenyl)acetyl]-
amino]-lH-carbazole-3-carboxamide,
N- [(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-
tetrahydro-3-[[(4-methoxyphenyl)acetyl]amino]-1H-
carbazole-3-carboxamide,
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-
[[(3-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-
lH-carbazole-3-carboxamide,
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-
[[(4-fluorophenyl)acetyl]amino]-2,3,4,9-
tetrahydro-lH-carbazole-3-carboxamide,
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-
[[(4-chlorophenyl)acetyl]amino]-2,3,4,9-
tetrahydro-lH-carbazole-3-carboxamide,
(3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-
[bis(3-phenylpropyl)amino]-2,3,4,9-tetrahydro-lH-
carbazole-3-carboxamide,
6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl-
propyl) -lH-carbazole-3-carboxylic acid and
ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-
phenylpropyl)-LH-carbazole-3-carboxylate.

The compound as claimed in any of claims 1 to 5,
7, 8, 10 or 11, where the compound is in the R
configuration at the carbon atom substituted by
the radicals R& and R7 when the radicals R6 and R7
together form an alpha-amino carboxylic acid
structural element.
The compound as claimed in claim 1, where the
compound is selected from the group consisting of
[ (lS,2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)-2-
methylpropyl]amino]carbonyl]-6,8-dichloro-2, 3,4,9-
tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-
methylbutyl]carbamate,
phenylmethyl [(1S,2S) -1-[[[(3R)-3-[[[(1S) -1-
(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-
2,3,4,9-tetrahydro-lH-carbazol-3-yl]amino]-
carbonyl]-2-methylbutyl]carbamate,
(2S)-l-[[[(3R)-3-[[(4-chlorophenyl)acetyl]amino]-
2,3,4,9-tetrahydro-8-methoxy-lH-carbazol-3-
yl]carbonyl]-2-pyrrolidinecarboxamide and
6, 8-dichloro-2, 3,4,9-tetrahydro-3-(3-phenyl-
propyl)-N-(2-pyridinylmethyl)-lH-carbazole-3-
methanamine.
A pharmaceutical composition comprising at least
one compound as claimed in any of claims 1 to 14.
The pharmaceutical composition as claimed in claim
15, where the compound is present in a unit dose
of from 1 \xq to 100 mg per kg of a patient's body
weight.
The pharmaceutical composition as claimed in claim
15 or 16, where the compound is present in
combination with at least one further active
pharmaceutical ingredient and/or pharmaceutically
acceptable carrier in the composition.

- 107 -
A method for preparing a compound as claimed in
any of claims 1 to 14.
The compound as claimed in any of claims 1 to 14,
for use as pharmaceutical remedy.
The use of a compound as claimed in any of claims
1 to 14 for producing a pharmaceutical remedy for
the treatment of pathological states mediated by G
protein-coupled receptors.
The use of a compound as defined in claim 1, but
including the compounds specifically excluded in
claim 1, for producing a pharmaceutical remedy for
inhibiting gonadotropin-releasing hormone.
The use as claimed in claim 20 or 21 in male
fertility control, in hormone therapy,, treatment
of female subfertility or infertility, female
contraception and tumor control.
The use of a compound as defined in claim 1, but
including the compounds specifically excluded in
claim 1, for male fertility control or for female
contraception.

The present invention relates to novel
tetrahydrocarbarzole derivatives which are effective as
ligands for G-protein coupled receptors (GPCR),
especially as antagonists of gonadotropin-releasing
hormone (GnRH). The present invention also relates to a
pharmaceutical composition comprising these novel
tetrahydrocarbazole derivates and to a method for
preparing the novel tetrahydrocarbazole derivatives.
Furthermore, the present invention also relates to the
administration of tetrahydrocarbazole derivatives for
the treatment of GPCR-mediated pathological states, in
particular for inhibition of GnRH, to mammals, in
particular humans, requiring such an administration,
and to the use of tetrahydrocarbazole derivatives for
producing a pharmaceutical remedy for the treatment of
GPCR-mediated pathological states, in particular for
inhibition of GnRH.

Documents:

779-kolnp-2004-granted-abstract.pdf

779-kolnp-2004-granted-claims.pdf

779-kolnp-2004-granted-correspondence.pdf

779-kolnp-2004-granted-description (complete).pdf

779-kolnp-2004-granted-examination report.pdf

779-kolnp-2004-granted-form 1.pdf

779-kolnp-2004-granted-form 18.pdf

779-kolnp-2004-granted-form 2.pdf

779-kolnp-2004-granted-form 26.pdf

779-kolnp-2004-granted-form 3.pdf

779-kolnp-2004-granted-form 5.pdf

779-kolnp-2004-granted-reply to examination report.pdf

779-kolnp-2004-granted-specification.pdf

779-kolnp-2004-granted-translated copy of priority document.pdf

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Patent Number

226493

Indian Patent Application Number

779/KOLNP/2004

PG Journal Number

51/2008

Publication Date

19-Dec-2008

Grant Date

17-Dec-2008

Date of Filing

08-Jun-2004

Name of Patentee

ZENTARIS GMBH

Applicant Address

WEISMULLERSTRASSE 45 60314 FRANKFURT

Inventors:

#	Inventor's Name	Inventor's Address
1	KOPPITZ, MARCUS	SCHARNHORSTR. 28, 10115 BERLIN
2	MUHN, HANS, PETER	MAARKGRAFENSTR. 61 13465 BERLIN
3	SHAW, KEN	4 BADDY LANE, BROOKSIDE, NJ 07926
4	HESSTUMPP, HOGER	WILDGANSSTEIG 97, 13503 BERLIN
5	PAULINI, KLAUS	IN DER MAINAUE 1, 63477 MAINTAL

PCT International Classification Number

C07F 7/00

PCT International Application Number

PCT/EP02/14344

PCT International Filing date

2002-12-16

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/341,878	2001-12-21	Germany
2	10164564	2001-12-14	Germany