Indian Patents. 225599:DISUBSTITUTED PIPERIDINE COMPOUNDS

Title of Invention	DISUBSTITUTED PIPERIDINE COMPOUNDS
Abstract	ABSTRACT IN/PCT/200Q/00621/CHE "DISUBSTITUTED PIPERIDINE COMPOUNDS" The present invention relates to novel compounds, in particular 4, 4-disubstituted and 3, 3-disubstituted piperidine compounds, compositions containing them, and their use for treating medical disorders resuhing from a deficiency in growth hormone.

Full Text	FIELD OF INVENTION The present invention relates to novel compounds, in particular 4,4-disubstituted and 3,3-disubsiituted piperidine compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone. BACKGROUND OF THE INVENTION Growth hormone is a hormone which stimulates growth of all tissues capable'uf growing. In addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilisation and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism. Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine, L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP (pituitary adenyiyl cyclase activating peptide), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus. In disorders or conditions where increased levels of growth hormone is desired, the protein nature of growth hormone makes anything but parenteral administration non-viable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason parenteral administration is preferred. The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed, e.g. in EP 18 072, EP 83 864, WO 89/07110, WO 89/01711, WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711, WO 93/04081, WO 9517422, WO 9517423, WO 9514666, W09419367, W09534311, WO9602530, W09615148, W09613265, W09622997, W09635713, W09638471, W09632943, WO9700894, WO9706803, WO9709060, WO9707117, W09711697, WO9722620, WO9723508, W09724369, and WO9734604. The composition of growth hormone releasing compounds is important for their growth hor¬mone releasing potency as well as their bioavailability. It is therefore an object of the present invention to provide novel compounds with growth hormone releasing properties. Moreover, it is an object to provide novel growth hormone releasing compounds (growth hormone secre¬tagogues) which are specific and/or selective and have no or substantially no side-effects, such as e.g. release of LH, FSH, TSH, ACTH, vasopressin, oxytocin, Cortisol and/or prolactin, it is also an object to provide compounds which have good oral bioavailability. SUMMARY OF THE INVENTION In accordance with the present invention there is provided novel compounds which act directfy on the pituitary cells under normal experimental conditions in vitro to release growth hormone therefrom. These growth hormone releasing compounds can be utilized in vitro as unique research tools for understanding, inter alia, how growth hormone secretion is regulated at the pituitary level. Moreover, the growth hormone releasing compounds of the present invention can also be administered in vivo to increase endogenous growth hormone release. DESCRIPTION OF THE INVENTION Accordingly, in a broad aspect the present invention relates to a compound of general for¬mula I wherein R2, R3, R4 and Rs are independently hydrogen or CM a'kyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl; or RJand R'or R2and R or R* and R4 may optionally form -(CHzJi-U-fCH2,-, wherein i and j are independently 1 or 2 and U is -0-, -S- or a valence bond; h and f are independently 0,1,2, or 3; g and e are independently 0 or 1; M is a valence bond, -CR'sCR7-, arylene, hetaryiene, -O- or -S-; R* and R7 are independently hydrogen, or C1-4-alkyl optionally substituted with one or more aryl or hetaryl; wherein Ra, R9, R10, R11, R12, R13, Ru, R1S, R'8 and R'7 independently of each other are hydrogen, halogen, aryt, hetaryl, C1-4-alkyl or C,2-alkoxy; k and I are independently 0, 1 or 2; E is -CONR,BR'9, -COOR'9, -(CH2m-NH,tS02R10, -{CH2Jrn-NRuCOR2t,, -(CH2-OR19, -(CH2-OCOR20, -CH(R")R191 -(CH2-NR2-CS-NR2R21 or -{CH2-NR2-CO-NR1221; or E is -CONR22NR"R24, wherein R22 is hydrogen, C1-4-alkyl optionally substituted with one or more aryt or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; R° is C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or C,_racyl; and R24 is hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl; or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; or R22 and R23 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxy), aryl or hetaryl; or R22 and Rw together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or Raand R3* together with the nitrogen atom to which they are attached may form a heterocyclic system optionally substituted with one or more CM-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; wherein misO, 1,2 or 3, R18, R1S and R2' independently are hydrogen or C1-4-aikyl optionally substituted with halogen, -NfR2R26, wherein Ra and R28 are independently hydrogen or CM aJkyl; hydroxy), C1-4-aikoxy, Ca-alkoxycarbonyl, C1-4-alkylcarbonytoxy or aryl; wherein R2, R3, R4and Rs are independently hydrogen or CM alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl; or R2 and R3 or R2 and R* or R3 and R* may optionally form -(CHjJrlHCHj);-, wherein i and j are independently 1 or 2 and U is -O-, -S- or a valence bond; h and f are independently 0,1, 2, or 3; g and e are independently 0 or 1; M is -CRe=CR7-, aryiene, hetarylene, -O- or -S-; Ra and R7 are independently hydrogen, or Cs-alkyt optionalJy substituted with one or more aryi or hetaryl; G is -0-(CH2)k-Ra, E is -CONR2NR2R24, wherein R23 is hydrogen, C1-4-alkyi optionally substituted with one or more aryl or hetaryl, or aryl or hetaryi optionally substituted with one or more C1-4-alkyl; R23 is C,2-alkyl optionally substituted with one or more aryl or hetaryl, or CVracyl; and R2* is hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl; or aryl or hetaryl optionally substituted with one or more C1JS-alkyi; or Raand R23 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more Cva-alkyl, halogen, amino, hydroxy), aryl or hetaryl; or R22 and R24 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or R23 and R24 together with the nitrogen atom to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; wherein m is 0,1,2 or 3, R1B, R19 and R21 independently are hydrogen or Cw-alkyl optionally substituted with halogen, -NfR2JR28, wherein R25 and R26 are independently hydrogen or Ct.# alkyl; hydroxyl, C1-4-alkoxy, C,2-aIkoxycarbonyl, C1-4-alkylcarbonyloxy or aryl; one or more chiral carbon atoms are present such chiral center or centers may be in the R-and/or S-configuration, or a mixture of R and S. Furthermore, the compounds of formula I may have one or more carbon-carbon double bonds with the possibility of geometric isomeri, and it is intended that possible stereoisomers (E or Z isomers) are included in the scope of the invention, unless a special geometric isomer is specified. In one embodiment of the compound of formula I R1 is hydrogen. In another embodiment of the compound of formula I R1 is C1-4-alkyt, such as CM-alkyl, in particular methyl. In a further embodiment of the compound of formula I a is 1. In a still further embodiment of the compound of formula I d is 1. In a further embodiment of the compound of formula I b is 1. In a still further embodiment of the compound of formula I b is 2. In a further embodiment of the compound of formula I b is 3. In a still further embodiment of the compound of formula I c is 1. In a further embodiment of the compound of formula I c is 2. In a still further embodiment of the compound of formula I c is 3. In a particular embodiment of the compound of formula I b+c is 4. in a further embodiment of the compound of formula I D is wherein R2, R3, R4and R5 are independently hydrogen or CM alky! optionally substituted with one or more halogen, amino, hydroxy!, aryl or hetaryl; or R2and R3or R2and R4 or R3 and H4 may optionally form -(CI-yrLHCH;),-, wherein i andj are independently 1 or 2 and U is -O-, -S- or a valence bond. h and f are independently 0, 1,2, or 3; g and e are independently 0 or 1; M is -CRa=CR7-, arylene, hetaryiene, -O- or -S-; wherein Rs and R7 are independently hydrogen, or C1-4-alkyl. In one embodiment R2 is hydrogen. In a second embodiment R3 is hydrogen. In a third embodiment R3 is d* alkyl, in particular methyl. In a further embodiment R4 is hydrogen. In a still further embodiment R4 is CM alkyl, in particular methyl. In a further embodiment R3 and R4 form - In a still further embodiment In a further embodiment of the compound of formula I D is wherein R2, R3, R4 and R* are independently hydrogen or CM alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl; or R2 and R3 or R2 and R4 or R3 and R4 may optionally form -(CHI)i-U-(CH2)r, wherein i and j are independently 1 or 2 and U is -0-, -S- or a valence bond, h and f are independently 0,1,2, or 3; g and e are independently 0 or 1; M is a valence bond. In one embodiment R2 is hydrogen. In a second embodiment R3 is hydrogen. In a third embodiment R3 is Cw alkyl, in particular methyl. In a further embodiment R4 is hydrogen. In a still further embodiment R4 is CM alkyl, in particular methyl. In a further embodiment R3 and R" form -(CHJrU-fCHJj-. In a still further embodiment i is 1. In a further embodiment i is 2. In a still further embodiment j is 1. In a further embodiment j is 2. In a still further embodiment U is a valence bond. In a further embodiment R3 and R4 form -(CH2)3-. In a further embodiment h is 0. In a still further embodiment f is 0. in a further embodiment f is 1. In a further embodiment g is 0. In a still further embodiment e is 0. In a further embodiment e is 1. In a preferred embodiment of the compound of formula ID is (1E)-4-amino-4-methylpent-1-enyl, (1E)-4-amino-2,4-dimethyipent-1-enyl, (1EV3-0-aminocyc!obutyl)prop-1-enyi, 1-amino-1-methylethyl, or 3-aminomethyfphenyl. In a still further embodiment of the compound of formula J G is wherein R8, RB, R10, R" and R" independently of each other are hydrogen, halogen, aryl, hetaryl, C1-4-alkyl or C1-4-alkoxy; k is 0,1 or 2. In a further embodiment R8, R9, R'°, R11 and R'2 are independently of each other hydrogen. In a still further embodiment one of R8, R9. R10, R" and R1! is phenyf and the others are hydrogen, in particular R10 is phenyl. In a further embodiment R8 is phenyl, in a still further embodiment k is 1. In a still further embodiment G is phenyl, 1-naphthyl or 2-naphthyl, preferably phenyl or 2-naphthyl. In a further embodiment G is benzyloxy. In a still further embodiment G is 1H-indol. In a further embodiment G is biphenyl-4-yl. In the above compound of formula IG is preferably 2-naphthyi, benzyloxy, 1H-indol or biphenyl-4-yi. In a further embodiment of the compound of formula I J is In a still further embodiment of the compound of formula I E is -CONR1BR19, -COOR'9 or -(CH2)m-OR,&, wherein m is 0,1, 2 or 3, R18 and R19 independently are hydrogen or C1-4-alkyl optionally substituted by halogen, -N(Ra)RH wherein Ra and R28 are independently hydrogen or Ct In another embodiment E is -CONR2NR2R24, wherein R22 is hydrogen, Cs-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; R23 is C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or Cw- acyl; and R24 is hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl; or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; or R2and R" together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more G2-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or R2and R24 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more Cn-aikyl, halogen, amino, hydroxyl, aryl or hetaryl; or R°and R24 together with the nitrogen atom to which they are attached may form a heterocyclic system optionally substituted with one or more CM-alkyl, halogen, amino, hydroxy!, aryl or hetaryl. In a still further embodiment R22 is hydrogen. In another embodiment R22 is C1-4-alkyl, such as C,_4-alkyi, in particular methyl, in a further embodiment R23 is d2-alkyl, such as C,_(-alkyl, in particular methyl. In another embodiment R23 is C,.racyi, such as CM-acyl, in particular acetyl. In a still further embodiment ofthe compound of formula I R24 is hydrogen. In another embodiment of the compound of formula I R24 is C1-4aikyl, such as Cw-alkyl, in particular methyl. In a special embodiment R22 is hydrogen and R23 and R24 are C1-4aikyl, such as CM-alkyl, in particular methyl. In a further embodiment R2and R23 may together with the nitrogen atoms to which they are attached form a heterocyclic system, which is optionally substituted with one or more C1-4-aikyl, halogen, amino, hydroxyl, aryl or hetaryl. Such heterocycfic system, including R22 and R23, may be aromatic or non-aromatic and may be selected from e.g. pyrazoie, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, or pyrazoline. In a still further embodiment R22 and R24 together with the nitrogen atoms to which they are attached form a heterocyclic system, which is optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryi. Such heterocyclic system, including R22 and R:\ may be aromatic or non-aromatic and may be selected from e.g. pyrazoie, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, or pyrazoline. In a further embodiment of the compound of formula I R23 and R24 together with the nitrogen atom to which they are attached form a heterocyclic system, which is optionally substituted with one or more C1-4-aikyl, halogen, amino, hydroxyl, aryl or hetaryl. Such heterocyclic system, including R2and R23, may be aromatic or non-aromatic and may be selected from e.g. aziridine, dtthiazine, pyrrol, imidazoi, pyrazoie, isoindole, indole, indazole, purine, pyrrolidine, pyrroline, imidazoline, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, indoline, isoindoline, or morpholine. In a particular embodiment R23 and R24 together with the nitrogen atom to which they are attached form pyrrolidine. When Raand R23 form a heterocyclic system R2and R24 may simultaneously also form a heterocyclic system or R2* may be hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-4-alkyl. When R22 and R24 form a heterocyclic system R23 and R24 may simultaneously also form a heterocyclic system or R23 may be C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or C,.7-acyl. In the above compound of formula I E is preferably (methyiamino)carbonyl, N,N-dimethylhydrazinocarbonyl, ethoxycarbonyl, or (pyrrolidin-l-yl)aminocarbonyl. Preferred compounds of formula I of the invention are: H{2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxyiic acid methylamide ■ 1-{(2R}-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylanitno]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid methylamide 2-Amino-W4(1R)-2-[(3R)-3-benzyl-3-(N',N,-dimethyl-hydrazinocarbonyl)-piperidin-1-yl]-1-benzyloxymethyl-2-oxo-ethyl)-2-methyl-proptonamide 1-{(2R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-z-enoyi;-m-meinyiaminoi-j-(Dipnenyi-4-yl)proptonyfH-benzylpiperidine-4-carboxylic acid ethyl ester (3S)-1-[(2R)-2-((2E)-5-Am(no-5-methylhex-2-enoylamJno>-3-{1H-inc(ol-3-y/)praptony(i-3-benzylpiperidine-3-carboxylic acid ethyl ester dimethylhydi2inacarbonyl)-piperidin-1-yl]-1-((2-naphthyl)rnethyl)-2-oxoethyl}-N-methyl- amide 2-Amino-N2(1R)-2-p-ben2yM-{N\N'-dimethylhydraz(nocarbonyl)p(peridin-1-ylJ-1-((bipheny/-4-yl)methyl)-2-oxoethyl}-2-methylprapionamide 2-Aminc>-N22-[3-ben2yl-3-(N'2imethylhydrazinocart)onyl)piperidin-1-yl]-1-(benzyloxymethyl)-2-oxoethyl}-2-methylpropionamide 2-Amino-N-{(1R)-2-[3-benzyl-3-(N,N',N"-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(benzyloxymethyl)-2-oxoethyl}-2-methylpropionamide The procedures used in this patent and illustrated in above scheme I are based on peptide couplings well known in the art, and should in no way be interpreted as limiting the invention in any way. In the first step an amine (1) and a carboxyiic acid is coupied to an amide by a coupling agent such as a carbodiimide and hydroxyazabenzoetriazole (HOAt). Prior to the next coupling a suitable protecting group such as tert butyloxycarbonyl (Boc) can be re¬moved with methods well known to those skilled in the art, thereby producing compound (2). It is also possible to avoid the use of protecting groups. Hereafter (2) is coupled to a carbox¬yiic acid of formula D-COOH by a coupling agent, thereby producing compound (3). Compounds of the general structure I containing a hydrazine in the C-term'tnal may be pre¬pared as illustrated above in scheme II. The procedures used in this patent and illustrated in above scheme It are based on peptide couplings well known in the art, and should in no way be interpreted as limiting the invention in any way. In the first step a mono-, di- or tri-substituted hydrazine or hydrazone (4) and an appropriate protected amino acid are coupled to form a compound (5) using a suitable coupling reagent such as 1 -ethy!-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole or another cou¬pling reagent known in the art of peptide coupling in an appropriate solvent such as di-methylformamid or dichloromethane.. Hereafter, the amide (5) and a carboxyiic acid is cou¬pled by a coupling agent, thereby producing compound (6). Hereafter (6) is coupled to a car¬boxyiic acid of formula D-COOH by a coupling agent, thereby producing compound (7). In the procedure, prior to the next coupling a suitable protecting group such as tert butyloxy-carbonyl (Boc) can be removed with methods well known to those skilled in the art. It is also possible to avoid the use of protecting groups. The appropriate amino acids may be pro- tected and deprotected by methods known in the art and described by e.g. T.W. Green (Protective Groups in Organic Synthesis, 2. Ed., John Wiley and Sons, New York 1991). The compounds of formula I exhibit an improved resistance to proteolytic degradation by enzymes because they are non-natural, in particular because the natural amide bonds are replaced by non-natural amide bond mimetics. The increased resistance to proteolytic degradation of the compounds of the invention in comparison with known hormone releasing peptides is expected to improve their bioavailability compared to that of the peptides suggested in the prior literature. In the above structural formulas and throughout the present specification, the following terms have the indicated meanings: The C1-4-alkyl, C1-4-alkyiene, C1-4-alkyl or CM-alkylene groups specified above are intended to include those alkyl or alkylene groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl, and hexyl and their corresponding divalent moieties, such as ethylene. Examples of branched alkyf are isopropyl, sec-butyl, tert-butyi, isopentyi, and isohexyl and their corresponding divalent moie¬ties, such as tsopropylene. Examples of cyclic alkyl are C„-cycloalkyl such as cyclopropyl, cy-clobutyl, cyclopentyl and cyclohexyl and their corresponding divalent moieties, such as cyclo-propylene. The C1-4-alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alk¬oxy are methoxy, ethoxy, propoxy, butoxy, pentoxy. and hexoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cyclic alkoxy are cyciopropyloxy, cydobutyloxy, cyclopentyfoxy and cyclohexyloxy. The Cracyl groups specified above are intended to include those acyl groups of the desig¬nated length in either a linear or branched or cyclic configuration. Examples of linear acyl are formyi, acetyl, propionyl, butyryl, vaieryl, etc. Examples of branched are rsobutyryl, isovaleryl, pivaloyl, etc. Examples of cyclic are cyclopentylcarbonyl, cyclohexylcarbonyl, etc. In the present context, the term "aryl" is intended to include monovalent carbocyciic aromatic ring moieties, being either monocyclic, bicyclic or polycycfic, e.g. selected from the group con¬sisting of phenyl and naphthyl, optionally substituted with one or more C1-4-alkyl, C1-4-alkoxy, halogen, amino or aryl. In the present context, the term "arytene" is intended to include divalent carbocyciic aromatic ring moieties, being either monocyclic, bicyclic or polycydic, e.g. selected from the group con¬sisting of phenylene and naphthylene, optionally substituted with one or more C1-4-alkyl, C,2-alkoxy, halogen, amino or aryl. \n the present context, the term "hetaryl" is intended to include monovalent heterocyclic aro¬matic ring moieties, being either monocyclic, bicyclic or poiycyclic, e.g. selected from the group consisting of pyridyl, 1-H-tetrazol-5-yl, thiazolyf, imidazolyl, indolyl, pyrimidinyl, thiadiazoiyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, quinolinyl, pyrazinyl, or isothiazolyl, option¬ally substituted by one or more Cu-alkyl, Craikoxy, halogen, amino or aryl. In the present context, the term "hetarylene" is intended to include divalent heterocyclic aro¬matic ring moieties, being either monocyclic, bicyclic or poiycyclic, e.g. selected from the group consisting of pyridinediyl, 1-H-tetrazolediyl, thiazoldiyl, imidazolediyl, indolediyl, pyrimidinediyl, thiadiazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl, thiophenediyl, quinolin-ediyl, pyrazinediyl, or isothiazolediyl, optionally substituted by one or more Chalky!, Cr¬aikoxy, halogen, amino or aryl. In the present context, the term "heterocyclic system" is intended to include aromatic as well as non-aromatic ring moieties, which may be monocyclic, bicyclic or polycycfic, and contain in their ring structure at least one, such as one, two or three, nitrogen atom(s), and optionally one or more, such as one or two, other hetero atoms, e.g. suipher or oxygen atoms. The heterocyclic system is preferably selected from pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, pyrazoline, aziridine, drthiazine, pyrrol, imidazol, pyrazole, isoindole, indole, indazole, purine, pyrrolidine, pyrroline, imidazotidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, indoline, isoindoline, or morpholine. The term "halogen" is intended to include chlorine (CI), fluorine (F), bromine (Br) and iodine (I). The compounds of the present invention may have one or more asymmetric centres (chiral carbon atoms) and it is intended that stereoisomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention. The compounds of the present invention may optionally be on a pharmaceutically acceptable salt form such as the pharmaceutically acceptable acid addition salts of compounds of fomiula I which include those prepared by reacting the compound of formula I with an inorganic or or¬ganic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, man-delic phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesul-fonic, trifluoracetic, sulfamic or fumaric acid and/or water. The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammc-nium salt Such salt forms are believed to exhibit approximately the same order of activity as the free base forms. In another aspect, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions containing a compound of the present invention may be pre¬pared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences. 1985 or in Remington: The Science and Practice of Pharmacy, 19th Edition (1995). The com¬positions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications. The pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, cydodextrin, talc, gelatin, agar, pec¬tin, acada, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty adds, fatty add amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier wilt vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 100mg Colloidal silicon dioxide (Aerosil) 1.5mg Cellulose, microcryst. (Avicel) 70mg Modified cellulose gum (Ac-Di-Sol) 7.5mg Magnesium stearate Coating: HPMC approx. 9mg 'Mywacett 9-40 T approx. 0,9mg Acyiated monogiyceride used as plasticizer for film coating. For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The car¬rier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, ab¬sorption enhancers such as lecithin (phosphatidylcholine) or cycfodextrin, or preservatives such as parabenes. Generally, the compounds of the present invention are dispensed in unit dosage form com¬prising 50-200 mg of active ingredient together with a pharmaceuticaliy acceptable earner per unit dosage. The dosage of the compounds according to this invention is suitably 0.01-500 mg/day, e.g. from about 5 to about 50 mg, such as about 10 mg per dose, when administered to patients, e.g. humans, as a drug. in a further aspect the present invention relates to a pharmaceutical composition in unit dose form, comprising as an active ingredient from about 10 to about 200 mg of the compound of the general fomiuia I or a pharmaceuticaliy acceptable salt thereof. It has been demonstrated that compounds of the general formula I possess the ability to re¬lease endogenous growth hormone in vivo. The compounds may therefore be used in the treatment of conditions which require increased plasma growth hormone levels such as in growth hormone deficient humans or in elderly patients or livestock. Thus, in a particular aspect, the present invention relates to a pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceuticaliy acceptable salt thereof together with a pharmaceuticaliy acceptable carrier or diluent In a further aspect, the present invention relates to a method of stimulating the release of growth hormone from the pituitary, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula I or a pharmaceuticaliy ac¬ceptable salt thereof. In a still further aspect, the present invention relates to the use of a compound of the general formula I or a pharmaceuticaliy acceptable salt thereof for the preparation of a medicament for stimulating the release of growth hormone from the pituitary. To those skilled in the art, it is well known that the current and potential uses of growth hor¬mone in humans are varied and multitudinous. Thus, compounds of formula t can be adminis- tered for purposes stimulating release of growth hormone from the pituitary and would then have similar effects or uses as growth hormone itself. Compounds of formula I are useful for stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glu¬cocorticoids, prevention and/or treatment of osteoporosis, treatment of chronic fatigue syndrorr tCFS), treatment of acute fatigue syndrom and muscle loss following election surgery, stimula¬tion of the immune system, acceleration of wound healing, accelerating bone fracture repair, accelerating complicated fractures, e.g. disctraction osteogenesis, treatment of wasting secon¬dary to fractures, treatment of growth retardation, treating of growth retardation resulting from renal failure or insufficiency, treatment of cardiomyopathy, treatment of chronic liver disease, treatment of thrombocytopenia, treatment of Crohn's disease, treatment of short bowel syn¬drome, treatment of chronic obstructive pulmonary disease (COPD), treatment of complica¬tions associated with transplantation, treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness, treatment of obe¬sity and growth retardation associated with obesity, treatment of anorexia, treating growth re¬tardation associated with the Prader-Willi syndrome and Turner's syndrome; increasing the growth rate of a patient having partial growth hormone insensitive syndrome, accelerating the recovery and reducing hospitalization of bum patients; treatment of intrauterine growth retarda¬tion, skeletal dysplasia, hypercortisoiism and Cushing's syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients, treatment of osteo-chondrodysplasias, Noonan's syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and ventilator dependency, treatment of cardiac failure or related vascular dysfunction, treatment of impaired cardiac function, treatment or prevention of myocardial infarction, lowering blood pressure, protection against ventricular dysfunction or prevention of reperfusion events, treat¬ment of adults in chronic dialysis, attenuation of protein catabolic responses after major sur¬gery, reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treat¬ment of hyperinsuiinemia including nesidioblastosis, adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function, treat¬ment of immunosuppressed patients, treatment of sarcopenia, treatment of wasting in connec¬tion with AIDS, improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly, stimulation of osteoblasts, bone remodelling and cartilage growth, regulation of food intake, stimulation of the immune system in companion animals and treatment of disorder of aging in companion animals, promoting growth in livestock and stimulation of wool growth in sheep, treatment of metabolic syndrom (syndrom X), treatment of insulin resistance, including NIDDM, in mammals, e.g. humans, im¬provement of sleep quality and correction of the relative hyposomatotropism of senescence due to high increase in REM sleep and a decrease in REM latency, and treatment of hypo¬thermia. Treatment is also intended to include prophylactic treatment. For the above indications the dosage will vary depending an the compound of formula I em¬ployed, on the mode of administration and on the therapy desired. However, generally dosage levels between 0.0001 and 100 mg/kg body weight daily are administered to patients and ani¬mals to obtain effective release of endogenous growth hormone. Morever the compounds of formula I have no or substantially no side-effects, when administered in the above dosage lev¬els, such side-effects being e.g. release of LH, FSH, TSH, ACTH, vasopressin, oxytocin, Corti¬sol and/or prolactin. Usually, dosage forms suitable for oral, nasal, pulmonat or transdermal administration comprise from about 0.0001 mg to about 100 mg, preferably from about 0.001 mg to about 50 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent. Optionally, the pharmaceutical composition of the invention may comprise a compound of for¬mula I combined with one or more compounds exhibiting a different activity, e.g., an antibiotic or other pharmacologically active material. The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or par¬enteral, the oral route being preferred. Apart from the pharmaceutical use of the compounds of formula I, they may be useful in vitro tools for investigating the regulation of growth hormone release. Compounds of formula I may also be useful in vivo tools for evaluating the growth hormone releasing capability of the pituitary. For example, serum samples taken before and after ad¬ministration of these compounds to humans can be assayed for growth hormone. Comparison of the growth hormone in each serum sample would directly determine the ability of the pa¬tients pituitary to release growth hormone. Compounds of formula I may be administered to commercially important animals to increase their rate and extent of growth, and to increase milk production. A further use of growth hormone secretagogue compounds of formula I is in combination with other secretagogues such as GHRP (2 or 6), GHRH and its analogues, growth hormone and its analogues or somatomedins including IGF-1 and IGF-2. Pharmacological Methods Compounds of formula I may be evaluated in vitro for their efficacy and potency to release growth hormone in rat pituitary primary cultures, and such evaluation may be performed as de¬scribed below. The isolation of rat pituitary cells is a modification of O. Sartor et al.. Endocrinology 116.1985, pp. 952-957. Mate albino Sprague-Dawley rats (250 +/- 25 grams) were purchased from Mellegaard, Lille Skensved, Denmark. The rats were housed in group cages (four ani¬mals/cage) and placed in rooms with 12 hour light cycle. The room temperature varied from 19-24"C and the humidity from 30 - 60%. The rats were decapitated and the pituitaries dissected. The neurointermediate lobes were re¬moved and the remaining tissue was immediately placed in icecold isolation buffer (Gey's me¬dium (Gibco 041-04030) supplemented with 0.25% D-glucose, 2% non-essential amino acids (Gibco 043-01140) and 1 % bovine serum albumine (BSA) (Sigma A-4503)). The tissue was cut into small pieces and transferred to isolation buffer supplemented with 3.8 mg/ml of trypsin (Worthington #3707 TRL-3) and 330 mg/ml of DNase (Sigma D-4527). This mixture was incu¬bated at 70 rotations/min for 35 min at 37"C in a 95/5% atmosphere of OJ/COJ. The tissue was then washed three times in the above buffer. Using a standard pasteur pipette, the tissue was then aspirated into single cells. After dispersion, cells were filtered through a nylon filter (160 mm) to remove undigested tissue. The cell suspension was washed 3 times with isolation buffer supplemented with trypsin inhibitor (0.75 mg/ml, Worthington #2829) and finally resu-spended in culture medium; DMEM (Gibco 041-01965) supplemented with 25 mM HEPES (Sigma H-3375), 4 mM glutamine (Gibco 043-05030H), 0.075% sodium bicarbonate (Sigma S-8875), 0.1% non-essential amino acid. 2.5% fetal calf serum (FCS, Gibco 011-06290), 3% horse serum (Gibco 034-06050), 10% fresh rat serum, 1 nM T3 (Sigma T-2752) and 40 mg/l dexamethasone (Sigma D-4902) pH 7.3, to a density of 2 x 103 cells/ml. The cells were seeded into microtiter plates (Nunc, Denmark), 200 ml/well, and cultured for 3 days at 37°C and 8% CO;. Compound testing After culturing, the cells were washed twice with stimulation buffer (Hanks Balanced Salt Solu¬tion (Gibco 041-04020) supplemented with 1% BSA (Sigma A-4503), 0.25% D-g!ucose (Sigma G-5250) and 25 mM HEPES (Sigma H-3375) pH 7.3) and preincubated for 1 hour at 37°C. The buffer was exchanged with 90 ml stimulation buffer (37°C). Ten ml test compound solution was added and the plates were incubated for 15 min at 37°C and 5% COj. The medium was de¬canted and analyzed for GH content in an rGH SPA test system. All compounds were tested in doses ranging from 10 pM to 100 mM. A dose-response relation was constructed using the Hill equation (Fig P, Biosoft). The efficacy (maximal GH released, E2 was expressed in % of the £„.,, of GHRP-6. The potency (ECR,) was determined as the concentration inducing half maximal stimulation of the GH release. Compounds of formula I may be evaluated for their metabolic stability using the procedure de¬scribed below: Compounds is dissolved at a concentration of 1 mg/ml in water. 25 ml of this solution is added to 175 ml of the respective enzyme-solution (resulting in an enzyme:substrate ratio (w/w) of approximately 1:5). The solution is left at 37°C overnight. 10 ml of the various degradation so¬lutions is analyzed against a corresponding zero-sample using flow injection eiectrospray mass spectrometry (ESMS) with selected ion monitoring of the molecular ion. If the signal has de¬creased more than 20% compared to the zero-sample, the remainder of the solution is ana¬lyzed by HPLC and mass spectrometry in order to identify the extent and site(s) of degradation precisely. Several standard peptides (ACTH 4-10, Angiotensin 1-14 and Glucagon) have been included in the stability tests in order to verify the ability of the various solutions to degrade peptides. Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) were purchased from Sigma, MO, USA) Enzymes (trypsin, chymotrypsin, elastase aminopeptidase M ana carpoxypeptiaase Y ana u) were all purchased from Boehringer Mannheim GmbH (Mannheim, Germany) Pancreatic enzyme mix: trypsin, chymotrypsin and elastase in 100 mM ammoniumbicarbonate pH 8.0 (all concentrations 0.025 mg/ml). Carboxypeptidase mix: carboxypeptidase Y and B in 50 mM ammoniumacetate pH 4.5 (all concentrations 0.025 mg/ml). Aminopeptidase M solution: aminopeptidase M (0.025 mg/ml) in 100 mM ammoniumbicarbon¬ate pH 8.0 Mass spectrometric analysis was performed using two different mass spectrometers. A Sciex API IIJ triple quadrupole LC-MS instrument (Sciex instruments, Thomhill, Ontario) equipped with an electrospray ion-source and a Bio-ion 20 time-of-fiight Plasma Desorption instrument (Bio-Ion Nordic AS, Uppsala, Sweden). Quantification of the compounds (before and after degradation) was done on the API III in¬strument using single ion monitoring of the molecular ion in question with flow injection of the analyte. The liquid flow (MeOH:water 1:1) of 100ml/min was controlled by an ABI 140BHPLC unit (Perkin-Bmer Applied Biosystems Divisions, Foster City, CA). The instrument parameters were set to standard operation conditions, and SIM monitoring was performed using the most intense molecular ion (in most cases this corresponded to the doubly charged molecular ion). Identification of degradation products furthermore involved the use of plasma desorption mass spectrometry (PDMS) with sample application on nitrocellulose coated targets and standard instrumental settings. The accuracy of the hereby determined masses is generally better than 0.1%. Separation and isolation of degradation products was done using a HY-TACH C-18 reverse phase 4.6x105 mm HPLC column (Hewlett-Packard Company, Palo Aito, CA) with a standard acetonitril: TFA separation gradient. The HPLC system used was HP1090M (Hewlett-Packard Company, Palo Alto, CA). +: Stable (less than 20% decrease in SIM signal after 24 h in degradation solution) -: Unstable (more than 20% decrease in SIM signal after 24 h in degradation solution) Any novel feature or combination of features described herein is considered essential to this invention. EXAMPLES; The process for preparing compounds of formula I and preparations containing them is fur¬ther illustrated in the following examples, which however, are not to be construed as limiting. The structures of the compounds are confirmed by either High Performance Liquid Chro¬matography (HPLC), nuclear magnetic resonance (NMR, Bruker 400 MHz) or Liquid Chro-matography-Mass Spectrometry (LC-MS). NMR shifts (d) are given in parts per million (ppm) and only selected peaks are given, mp is melting point and is given in °C. Column chroma¬tography was carried out using the technique described by W.C. Still et al, J. Org. Chem. 1978,43, 2923-2925 on Merck silica gel 60 (Art 9385). Compounds used as starting materi¬als are either known compounds or compounds which can readily be prepared by methods known perse. The methanol/ammonia solution used is a 10% ammonia solution in metha¬nol. HPLC-Analysis: Method A1. The RP-analysis was performed using UV detections at 214, 254, 276, and 301 nm on a 218TP54 4.6 mm x 250 mm 5m C-18 silica column (The Separations Group, Hesperia), which was eluted at 1 mL/min at 42°C. The column was equilibrated with 5% acetonitriie in a buffer consisting of 0.1 M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid, after injection the sample was eluted by a gradient of 5% to 60% acetonitriie in the same buffer during 50 min. Method B1. The RP-analysis was performed using UV detections at 214, 254, 276, and 301 nm on a 218TP54 4.6 mm x 250 mm 5m C-18 silica column (The Seperations Group, Hesperia), which was eluted at 1 mL/min at 42°C. The column was equilibrated with 5% (acetonitriie + 0.1 % TFA) in an aqueous solution of TFA in water (0.1%). After injection the sample was eluted by a gradient of 5% to 60% (acetonitriie + 0.1 % TFA) in the same aqueous buffer during 50 min. LC-MS-Analysis: The LC-MS analyses were performed on a PE Sciex AP1100 LC/MS System using a Wa¬ters® 3 mm x 150 mm 3.5 m C-18 Symmetry column and positive ionspray with a flow rate of 20 ml/min. The column was eluted with a linear gradient of 5-90% acetonitrile, 85-0% wa¬ter and 10 % trifluoroacetic acid (0.1%)/ water in 15 min at a flow rate of 1 ml/min. Abbrevations: TLC: thin layer chromatography DMSO: dimethylsulfoxide min: minutes h: hours Boc: tert butyloxycarbonyl DMF: dimethylformamide THF: tetrahydrofuran EDAC: N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride HOAt: 1-hydroxy-7-azabenzotriazole DIEA: diisopropylethylamine TFA: trifluoroacetic acid Buiidingblocks: N-methylated aminoacids used in the following examples were prepared as in Can. J. Chem. 1977. 55, 906. Step A N-tert-butyloxycarbony(-4-ben2ylpiperidine-4-carboxyIicacid N-tert-butyloxycarbonyl-4-ben2ylpiperidine-4-carboxylic acid ethyl ester (prepared as in Gilli-gan et al J. Med. Chem. 1994, 364-370 using benzyl bromide as the alkylating agent) (11.0 g; 32 mmol) was refluxed for 7 h. in a mixture of ethanol (190 ml) and aqueous sodium hy¬droxide (18% 190 ml). The volume was reduced to a -rird in vacuo and pH was adjusted to 3 with sodium hydrogen sulphate. Water (300 ml) was added and the mixture was extracted with ethylacetate (2 x 250 ml). The combined organic phases were evaporated to afford 8.6 g of N-terf-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid. 'H-NMR: d (CDCI3) 1.45 (s, 9H); 1.5 (m(br); 2H); 2.08 (m(br); 2H); 2.88 (m(br); 2H); 2.89 (s. 2H); 3.95 (m(br); 2H); 7.09-7.30 (5 arom. H). Step B 4-Benzyf-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester N-terf-butyloxycarbonyf-42benzylpiperidine-4-carboxylic acid (3.0 g; 9.0 mmol) was dissolved in methylene chloride (25 ml) and EDAC (1.8 g; 9.0 mmol) and HOAt (1.3 g; 9.0 mmol) was added. The mixture was stirred for 15 min, then methyl amine (33% in ethanol; 2.3 ml; 18 mmol) and DIEA (1.6 mi; 9.0 mmol) was added and the mixture was stirred overnight. Meth¬ylene chloride (100 ml) was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and a aqueous solution of sodium hydrogen-sulphate (10%, 50 ml), dried (MgSO,) and evaporated in vacuo. The residue was chroma-tographed on silica (90 g) using a mixture of aqueous ammonia/ethanol/methylene chloride (1:7:92) as eluent to afford 2.8 g of 4-benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester. 1H-NMR: d (CDCI3) 1.44 (s, 9H); 1.55 (m(br); 2H); 1.98 (m(br); 2H); 2.70 (d, 3H); 2.98 (m(br); 2H); 2.89 (s, 2H); 3.87 (m(br); 2H); 5.15 (q(br); 1H); 7.01-7.32 (5 arom. H). StepC 4-Benzylpiperidine-4-carboxylic acid methyfamide 4-Benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester {2.8 g) was dis¬solved in a mixture of TFA and methylene chloride and stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in water (30 ml) and pH was adjusted to 13 with aqueous sodium hydroxide (1N). The aquoues phase was extracted with methylene chloride (3 x 75 ml) and the combined organic phases were dried (MgS04) and evaporated in vacuo to afford 1.50 g of 4-benzylpiperidine-4-carboxylic acid methylamide. 'H-NMR: d (CDCIj) 1.80 (td; 2H); 2.14 (d(br), 2H); 2.70 (d, 3H); 2.81 (s, 2H); 2.85 (dt; 2H); 3.21 (dt, 2H); 5.25 (t, 1H); 7.00-7.35 (5 arom. H). StepD 4-Benzyt-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylicacid meth¬ylamide (2R)-2-tert-Butyloxycarbonylamino-N-methyl-3-(2-naphthyl)propionic acid (709 mg; 2.15 mmol), HOAt (293 mg 2.25 mmol) and EDAC (412 mg; 2.25 mmol) were dissolved in meth¬ylene chloride (5ml) and stirred for 15 min. 4-Benzylpiperidine-4-carboxylic acid methylamide (500 mg; 2.25 mmol) and DIEA (0.35 ml) were added and the mixture was stirred overnight. Methylene chloride (30 ml) was added and the mixture was washed with a saturated aque¬ous solution of sodium hydrogen carbonate (20 ml) and a aqueous solution of sodium hydro-gensulphate (10%, 20 ml), dried (MgS04) and evaporated in vacuo. The residue was chro-matographed on silica (40 g) using ethyl acetate as eluentto afford 810 mg of 4-benzyl-1-((2R)-2-(N-methyl-fert-butyloxycarbonylamino)-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid methylamide which was dissolved in TFA/methylene chiond& (8+8 ml) and stirred for 40 min at RT. The solvent was removed in vacuo and the residue was neutralised with a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate (50 ml). The organic phase was dried (MgSO«) and evaporated to afford 729 mg of 4-benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid methylamide. StepE 4-Benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylicacid meth-ylamide (360 mg; 0.82 mmole) was coupled to (2E)-5-(fert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid using the same coupling procedure as in step D. Removal of the N-terminal Boc group was performed as in step D but at -10 "C. The crude product was purified on a RP-18-Seppak® (5 g; Waters) using a gradient from 0.1%TFA in water/acetonitrile 100/0 to 0.1% TFA in 60/40 water/acetonitrile to afford 306 mg of the title compound as a trifluoroacetate. 'H-NMR5 (MeOH) (selected peaks for major rotamer) 1.30 (s,3H); 1.31 (a, 3H);2.10(AB-syst, 2H); 2.55 (s, 3H); 5.81 (m, 1H). HPLC: r, = 31.88 min(A1) r, = 33.30 min(B1) ESMS: m/z: 569.4 (M+H). The compound was prepared as in example 1 using (2E)-5-(tert-butyloxycarbonylamino)-5,3-dimethyl-2-hexencic acid instead of (2E)-5-(fert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid in step E HPLC: r,= 33.70 min (A1) r, = 34.22 min(B1) ESMS: m/z: 583.4 (M+H). Example 3 H(2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyi}-4-benzylpiperidine-4-carboxylic acid methytamide This compound was prepared as in example 1 using (2R)-2-terf-Butyloxycarbonylamino-N-methyl-3-(4-biphenylyl)propionic acid instead cf (2R)-2-/ert-Butyioxycarbonylamino-N-methyl-3-(2-naphthyl)propionic acid in step D. HPLC: r, = 34.53 min ESMS: m/z : 595.4 (M+H)+. This compound was prepared as in example 1 using (2R)-2-tert-Butyloxycarbonylamino-N-methyl-3-(4-biphenytyi)propionic acid instead of (2R)-2-tert-Butyloxycarbonylamino-N-methyl-3-(2-naphthyl)proptonic acid in step D and using (2E)-5- HPLC: rt= 35.15 min(A1) r, = 36.83 min(B1) ESMS: m/z : 609.4 (M+H). Example 5 1- This compound was prepared as in example 1 using {2R)-2-tert-Butyloxycarbonylamina-N-methyl-3-(4-biphenylyl)propionic acid instead of (2R)-2-terf-Butyloxycarbonylamino-N-methyl-3-(2-naphthyl)propionic acid in step D and using {2E)-4-(1-(tert-butyloxycarbonylamino)cyciobutyl)but-2-enoic acid instead of (2E)-5-(tert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid in step E. To a solution of 4-faenzylpiperidine-1,4-dicarboxyiic acid 1-terf-butyf ester (0.75 g, 2.35 mmol) (prepared as in Gilligan etalA. Med. Chem. 1994, 364-370) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.32 mg, 2.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol) and the mixture was stirred for 30 min. Then W'W'-dimethylhydrazine (0.27 ml, 3.53 mmol) and diisopropyiethy-lamine (0.52 ml, 3.06 mmol) was added and the mixture was stirred for 2 days. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgS04), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with heptane/ethyl acetate (1:2) to give 0.76 g of 4-benzyl-4-(W'A/'-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester as a colorless oil. To a solution of 4-ben2yl-4-(W,A/'-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tort-butyl ester (0.76 g, 2.02 mmoi) in methylene chloride (2 ml) at 0°C was added trifluoroacetic acid (5 ml) and the mixture was stirred for 60 min. The mixture was quenched with ethanol {20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 4-benzylpiperidine-4-carboxylic acid A/'A/'-dimethylhydrazide in quantitative yield. To a solution of 2-torf-butoxycarbonylaminc-3-(1 H-indole-3-yl)propionic acid (0.37 g, 1.2 mmol) in methylene chloride (15 ml) and dimethylformamid (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.16 mg, 1.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.20 mmol) and the mixture was stirred for 30 min. Then 4-benzylpiperidine-4-carboxylic acid N'/V'-dimethylhydrazide (0.26g, 1.0 mmol) and diisopro-pylethylamine (0.69 ml, 4.0 mmol) was added and the mixture was stirred overnight. Methyl¬ene chloride (100 mi) was added and the mixture was washed with saturated aqueous so¬dium hydrogencarbonate (20 ml), water (20 ml), dried (MgS04), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chloride/(10% ammonia in methanol) (9:1) to give 0.43 g of (2-(4-benzyl-4-(A/',JV-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indole-3-ylmethyl)-2-oxoethyl)carbamic acid tert-butyl ester as a colorless oil. To a solution of (2-{4-benzyM-(A/',A/'-dimethylhydrazinocarbonyf)piperidine-1-yl}-1-(1/-/-indole-3-ylmethyl)-2-oxoethyt)carbamic acid tert-butyl ester (0.40 g, 0.73 mmol) in methylene chloride (3 ml) at 0°C was added triftuoroacetic acid (3 ml) and the mixture was stirred for 30 min. The mixture was quenched with ethanol {20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 0.63 g of 1- HPLC: R, = 7.52min (H8) LC-MS: R, = 7.61 min, m/z = 448.4 (m+1) (122-(4-Benzyl2(W'N'Kiimetnylhydra2inocarbonyf)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyl)carbamic acid tert-butyl ester To a solution of 2-ferf-butoxycarbonylamino-2-methytpropionic acid (0.18 g, 0.88 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazoIe (0.12 mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropy[)carbodiimide hydrochloride (0.12 g, 0.88 mmol) and the mixture was stirred for 30 min. Then 1-(2-amino-3-(1H-indol-3-yl)propionyi)-4-benzylpiperidine-4-carboxylic acid W'A/'-dimethylhydrazide (0.46 g, 0.73 mmol) and diisopro-pylethytamine (0.50 ml, 2.92 mmol) was added and the mixture was stirred overnight. Meth¬ylene chloride (100 ml) was added and the mixture was washed with saturated aqueous so¬dium hydrogencarbonate (20 mi), water (20 ml), dried (MgS04), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chioride/(10% ammonia in methanol) (9:1) to give 0.31 g of (1-(2-(4-benzyl-4-(A/',W-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyfjcarbamic acid terf-butyl ester as a colorless oil. HPLC:R, = 10.25 min (H8) LC-MS: R, = 9.66 min, m/z = 633.2 (m+1) 2-Amino-/V-[(1R)-2-[4-benzyl-4-(W',W-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methyfpropionamide To a solution of (1-{2-(4-benzyM-(W;/V'-dimethylhydra2inocarbonyl)piperidine-1-yl)-l-{iH-indol-3-ylmethy[)-2-oxoethylcarbamoyl)-1-methylethyi)carbamic acid tert-butyi ester {0.29 g, 0.46 mmol) in methylene chloride (3 ml) at 0°C was added trifiuoroacetic acid (3 ml) and the mixture was stirred for 30 min. The mixture was quenched with ethanol {20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 0.25 g of 2-amino-A/-[(1 R)-2-[42enzyl2{N;W'Hdimethylhydrazinocarbonyl)piperidin-1-yl]-1-{(1H-indoI-3-yl)methyl)-2-oxoethyl]-2-methytpropionamide as a white amorph powder. HPLC: R, = 24.56 min (A1), R, = 24.95 min (B1), R, = 7.73 min (H8) LC-MS: R, = 7.74 min, m/z = 533.4 (m+1) Example 7 2-Amino-W2(1R)-2-[(3R)-3-benzyl-3-(W',W'-dimethyl-hydrazinocarbonyl)-piperidin-1-yl]-1-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide 2-Amino-W-[(1R)-2-[(3R)-3-benzyl-3-(WV2imemylhydrazinocarbonyl)-piperidin-1-yl]-1-((iH-indol-3-yl)methyl)-2-oxoethyn-2-methylpropionamide Example 9 1-{(2R)-2-£N-((2E)-S-Amino-5-methyJhex-2-enoyO-N-methylamino)-3-(biphenyM-yOpropionylH-benzytpiperidine-4-carboxyfic acid ethyl ester LC-MS: Rt = 12.36 min, m/z: 624.4 (M+H) HPLC:Rt = 42.785 min (A1) HPLCrRt = 45.148 min (B1) LC-MS: Rt = 11.92 min, m/z: 584.4 (M+H) HPLC:Rt = 39.893 min (A1) HPI_C:Rt = 42.046 min (B1) Example 12 H(2R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpipejidine-4-cai,boxylic acid ethyl ester LC-MS: Rt = 12.21 min, m/z: 598.2 (M+H) HPLC:Rt= 40.541 min (A1) HPLC: Rt = 42.780 min (B1) Example 14 (3S)-1-E(2R)-2-((2E)-5-Amino-3,5-dimethylhex-2-enoylamino)-3-(1H-indol-3-yl)propiony!]-3-benzylpiperidine-3-carboxylic acid ethyl ester LC-MS: Rt = 10.42 min, m/z: 573.2 (M+H) HPLC:Rt = 36.680 min (A1) HPLC:Rt = 38.563 min (B1) Example 15 (3S)-1-[(2R)-2-{3-{Aminomethyl)ben2oyiamino)-3-{1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid ethyl ester LC-MS: Rt = 10.24 min, m/z: 567.4 (M+H) HPLC:Rt = 36.118 min(A1) HPLC:Rt = 38.052 min (B1) Example 16 HPLC: Rt = 31.198 min(B1) Example 17 (2E)-5-Amino-5-methylhex-2-enoic acid N-[(1 R)-2-[3-benzyl-3-(N',N'-dimethylhydra2inocarbonyl)-piperidtn-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethylJamide Example 19 (2E)-5-Amino-5-methylhex-2-enoicacid{(1R)-2-[3-benzyl-3-(N',N'-dimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-{benzyloxymethyl)-2-oxoethyl}amide HPLC: Rt = 33.297 / 33.640 min (B1) Example 22 2-Amino-N-{(1R)-2-t3-benzyl-3-(N',N'-dimethylhydra2inocarbonyl)piperidin-1-yl]-l.((iH-indol-3-yl)methyl)-2-oxoethyl}-2-methylproptonamide WE CLAIM: I. A compound selected from the group consisting of: l-{(2R)-2-[N-((2F)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(2-naphthy])propiony){-4-benzylpipcridinc-4-carboxylic acid methylamide l-{(2R)-2-\|N--((2E)-5-Amino-5-melhy!hex-2-cnoyl)-N-mcthylaminoJ-3-(biphenyl-4-yl)propion;lI-4-benzylpiperidine-4-carboxylic acid metliylamide l-{(2R)-2-[N-((2H)-5-Amino-3,5-dimethylhex-2-enoyl)-N-melhylamino\|-3-(biphenyI-4-yl)propionyl j -4-benzylpiperidinc-4-carboxylic acid methylamide l-((2R}-2-!N-\|(2E)-4-(l-Aminocyclobut\'l)but-2-enoylJ-N-methy!aminoj-3-(biphenyl-4-yl)propionyl)-4-beiizylpiperidine-4-carboxylic acid methylamide 2-Amino-N-f(lR)-2-[4-benzyI-4-(N'.N'-dimelhylhydra7inocarbon\[)piperidin-l-yl]-l-((lH-indo!-3-yl)melliyl)-2-oxocthyl\|-2-methylpropionamidc 2-AminowV" {(] R)-2-[(3R)-3-bcn/yl-3-(.V', ,V'-dimethyl--hydrazinocarbonyI)-piperidin-1 -yl]-1 -benzy!oxymelhyI-2-oxo-clh> i! -2-methyl-propionamidc 2-Amino-A'-\|(lR)-2-[{3R)-3-bt;nzyl-3-(,'VW--dimethylhydrazinocarbonyl)-piperidin-l-yl]-l-((l//-indol-3-yl)methyl)-2-Gxocthyl]-2-mcthylpropionamide l-{(2R)-2-\|N-((2E)o-Amino-5-mcthylhex-2-enoyi)-N-methylaminoJ-3-(biphenyl-4-yl)propionyl\|-4-bcn/ylpiperidine-4-carboxylic acid ethyl ester l-{(2R)-2-fN-((2E)-5-Amino-3.5-dimelhylhex-2-enoyl)-N-methylaminol-3-{biphenyl-4-yl)propionyij-4-bt;nzylpiperidine-4-carboxylic acid ethyl ester l-{{2R)-2-[N-((2E)-5-Amino-5-methylhex-2-cnoyl)-N-methylamino]-3-{2-naphthyl)propionyl!-4-benzylpipcridine-4-earboxylic acid ethyl ester l-{(2R)-2-[N-((2H)-5-Amino-3.5-dimcthylhex-2-enoyl)-N-methylammo]-3-(2-naphthyl)propionyl)-4-benzyipipcridine-4-carboxylic acid elhyl eslcr (3S)-l-[(2R)-2-{(2E)-5-Amino-5-melhylhex-2-enoylamino)-3-(lH-indol-3-yl)propionyl\|-3-benzylpiperidine-3~carboxylic acid ethyl ester (3S)-l-[(2R)-2-((2r-)-5-Amino-3.5-dimethyllicx-2-enoylamino)-3-{lH-indol-3-yI)propionyl]-3-benzylpiperidinc-3-carboxyiic acid ethyl ester (3S)-l-[(2R)-2-(3-(Aminomelhyl)bcn7oylamino)-3-(lH-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid ethyl ester {2E)-5-Amino-5-mcthy!hex-2-cnoic acid N-\|(lR)-2-\|4-bcn/.yl-4-(N^N'-dimethylhydra/inocarbon^■l)pipcridin-■]-yl]-l-((2-naphthyl)mcthyl)-2-oxoethyl}-N-methylamide (2E) 5-Amino-5-mcthylhcx-2-cnoicacidN-[(lRV2-[3-bcn7yl-3-(N',N'-dimethylhydrazinocarbonyl)-pipt;ridin-1 -yl]-1 -({1 H-indol-3-yl)methyi)-2-oxoethyljamide (2E)-5-Amino-5-melhylhex-2-enoic acid N-({lR)-2-[3-benzyl-3-(N^N'-dimethylhydl'azinocarbonyl)-pipcridin- 1 -yl \|-1 -((2-naphthyl)methyl)-2-oxoethyl}-N-methyl-amide (2E)-5-Amino-5-mcthylhex-2-t;noic acid {(1 K)-2-l3-benzyl-3-{N'.N■-dinlethyl-hydrazinocarbonyl)pipc^idin- I -y 11-1 -(bt;nzyloxymelhyl)-2-oxoethyl i amide 2-Amino-N-\|2-\|3-bcn7yl-3-(N\N'-dimcthylhydrazinocarbonyl)piperidin-l-yl]-l-((2-naphthyl)melhyl)-2-oxo-ethyl ] -2-methyl-prapionamide 2-Amino-N-{{lR)-2-[3-benzyl-3-(N'.N'-dimL;diylhydra/.inocarbonyl)pipcridin-l-yl]-l-((biphenyl-4-yl)mcthyl)-2-oxocthyl]-2-mcthylpropionamide 2-Amino-N'\|( lR)-2-[3-benyl 1-3-1 N'.N-dimcthylhydrazinocarbonyOpipcridin-1-yl]-l-((lH-indol'3-yl)melhyl)-2-oxoclhyll-2-methylpropionamidt; 2-Amino-N-{2-\|3-benzyl-3-(N'-methylhydrazinocarbonyl)piperidin-l-yl]-l-(benzyIoxymcthyl)-2-oxoethy!i-2-mcthylpropionamide 2-Amino-N-{(lR)-2-[3-ben2yl-3-(N'-methylhydra2inocarbonyl)piperidin-l-yl]-l-{(lH-indol-3-yl)nicthyl)-2-oxoelhyl}-2-melhylpropionamidc l-[(2R)-2-(2-Amino-2-methylpropionylamino)-3-(l-H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid {pyrrolidin-l-yl)amide 2-Amino-N-{(lR)-2-[3-benzyl-3-(N,N,,N,-trimethylhydrazinocarbonyl)piperidin-l-yl]-l-({lH-indol-3-yl)methyl)-2-oxoethyl)-2-methylpropionamide and pharmaceutically acceptable salts thereof.

Full Text

FIELD OF INVENTION
The present invention relates to novel compounds, in particular 4,4-disubstituted and 3,3-disubsiituted piperidine compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.
BACKGROUND OF THE INVENTION
Growth hormone is a hormone which stimulates growth of all tissues capable'uf growing. In addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilisation and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine, L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP (pituitary adenyiyl cyclase activating peptide), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
In disorders or conditions where increased levels of growth hormone is desired, the protein nature of growth hormone makes anything but parenteral administration non-viable.

Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason parenteral administration is preferred.
The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed, e.g. in EP 18 072, EP 83 864, WO 89/07110, WO 89/0*1711, WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711, WO 93/04081, WO 9517422, WO 9517423, WO 9514666, W09419367, W09534311, WO9602530, W09615148, W09613265, W09622997, W09635713, W09638471, W09632943, WO9700894, WO9706803, WO9709060, WO9707117, W09711697, WO9722620, WO9723508, W09724369, and WO9734604.
The composition of growth hormone releasing compounds is important for their growth hor¬mone releasing potency as well as their bioavailability. It is therefore an object of the present invention to provide novel compounds with growth hormone releasing properties. Moreover, it is an object to provide novel growth hormone releasing compounds (growth hormone secre¬tagogues) which are specific and/or selective and have no or substantially no side-effects, such as e.g. release of LH, FSH, TSH, ACTH, vasopressin, oxytocin, Cortisol and/or prolactin, it is also an object to provide compounds which have good oral bioavailability.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided novel compounds which act directfy on the pituitary cells under normal experimental conditions in vitro to release growth hormone therefrom.
These growth hormone releasing compounds can be utilized in vitro as unique research tools for understanding, inter alia, how growth hormone secretion is regulated at the pituitary level.
Moreover, the growth hormone releasing compounds of the present invention can also be administered in vivo to increase endogenous growth hormone release.

DESCRIPTION OF THE INVENTION
Accordingly, in a broad aspect the present invention relates to a compound of general for¬mula I

wherein R2, R3, R4 and Rs are independently hydrogen or CM a'kyl optionally substituted with
one or more halogen, amino, hydroxyl, aryl or hetaryl; or
RJand R'or R2and R* or R* and R4 may optionally form -(CHzJi-U-fCH2,-, wherein i and j are
independently 1 or 2 and U is -0-, -S- or a valence bond;
h and f are independently 0,1,2, or 3;
g and e are independently 0 or 1;
M is a valence bond, -CR'sCR7-, arylene, hetaryiene, -O- or -S-;
R* and R7 are independently hydrogen, or C1-4-alkyl optionally substituted with one or more aryl
or hetaryl;

wherein Ra, R9, R10, R11, R12, R13, Ru, R1S, R'8 and R'7 independently of each other are hydrogen, halogen, aryt, hetaryl, C1-4-alkyl or C,2-alkoxy; k and I are independently 0, 1 or 2;
E is -CONR,BR'9, -COOR'9, -(CH2m-NH,tS02R10, -{CH2Jrn-NRuCOR2t,, -(CH2-OR19, -(CH2-OCOR20, -CH(R")R191 -(CH2-NR2-CS-NR2R21 or -{CH2-NR2-CO-NR1221; or
E is -CONR22NR"R24, wherein R22 is hydrogen, C1-4-alkyl optionally substituted with one or more aryt or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; R° is C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or C,_racyl; and R24 is hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl; or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; or

R22 and R23 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxy), aryl or hetaryl; or
R22 and Rw together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or
Raand R3* together with the nitrogen atom to which they are attached may form a heterocyclic system optionally substituted with one or more CM-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein misO, 1,2 or 3,
R18, R1S and R2' independently are hydrogen or C1-4-aikyl optionally substituted with halogen, -NfR2R26, wherein Ra and R28 are independently hydrogen or CM aJkyl; hydroxy), C1-4-aikoxy, Ca-alkoxycarbonyl, C1-4-alkylcarbonytoxy or aryl;

wherein R2, R3, R4and Rs are independently hydrogen or CM alkyl optionally substituted with
one or more halogen, amino, hydroxyl, aryl or hetaryl; or
R2 and R3 or R2 and R* or R3 and R* may optionally form -(CHjJrlHCHj);-, wherein i and j are
independently 1 or 2 and U is -O-, -S- or a valence bond;
h and f are independently 0,1, 2, or 3;
g and e are independently 0 or 1;
M is -CRe=CR7-, aryiene, hetarylene, -O- or -S-;
Ra and R7 are independently hydrogen, or Cs-alkyt optionalJy substituted with one or more aryi
or hetaryl;
G is -0-(CH2)k-Ra,

E is -CONR2NR2R24, wherein R23 is hydrogen, C1-4-alkyi optionally substituted with one or more aryl or hetaryl, or aryl or hetaryi optionally substituted with one or more C1-4-alkyl; R23 is C,2-alkyl optionally substituted with one or more aryl or hetaryl, or CVracyl; and R2* is hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl; or aryl or hetaryl optionally substituted with one or more C1JS-alkyi; or

Raand R23 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more Cva-alkyl, halogen, amino, hydroxy), aryl or hetaryl; or
R22 and R24 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or
R23 and R24 together with the nitrogen atom to which they are attached may form a heterocyclic system optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0,1,2 or 3,
R1B, R19 and R21 independently are hydrogen or Cw-alkyl optionally substituted with halogen, -NfR2JR28, wherein R25 and R26 are independently hydrogen or Ct.# alkyl; hydroxyl, C1-4-alkoxy, C,2-aIkoxycarbonyl, C1-4-alkylcarbonyloxy or aryl;

one or more chiral carbon atoms are present such chiral center or centers may be in the R-and/or S-configuration, or a mixture of R and S.
Furthermore, the compounds of formula I may have one or more carbon-carbon double bonds with the possibility of geometric isomeri, and it is intended that possible stereoisomers (E or Z isomers) are included in the scope of the invention, unless a special geometric isomer is specified.
In one embodiment of the compound of formula I R1 is hydrogen. In another embodiment of the compound of formula I R1 is C1-4-alkyt, such as CM-alkyl, in particular methyl.
In a further embodiment of the compound of formula I a is 1.
In a still further embodiment of the compound of formula I d is 1.
In a further embodiment of the compound of formula I b is 1. In a still further embodiment of the compound of formula I b is 2. In a further embodiment of the compound of formula I b is 3.
In a still further embodiment of the compound of formula I c is 1. In a further embodiment of the compound of formula I c is 2. In a still further embodiment of the compound of formula I c is 3.
In a particular embodiment of the compound of formula I b+c is 4.
in a further embodiment of the compound of formula I D is

wherein R2, R3, R4and R5 are independently hydrogen or CM alky! optionally substituted with one or more halogen, amino, hydroxy!, aryl or hetaryl; or
R2and R3or R2and R4 or R3 and H4 may optionally form -(CI-yrLHCH;),-, wherein i andj are independently 1 or 2 and U is -O-, -S- or a valence bond.

h and f are independently 0, 1,2, or 3; g and e are independently 0 or 1;
M is -CRa=CR7-, arylene, hetaryiene, -O- or -S-; wherein Rs and R7 are independently hydrogen, or C1-4-alkyl. In one embodiment R2 is hydrogen. In a second embodiment R3 is hydrogen. In a third embodiment R3 is d* alkyl, in particular methyl. In a further embodiment R4 is hydrogen. In a still further embodiment R4 is CM alkyl, in particular methyl. In a further embodiment R3 and R4 form - In a still further embodiment In a further embodiment of the compound of formula I D is

wherein R2, R3, R4 and R* are independently hydrogen or CM alkyl optionally substituted with
one or more halogen, amino, hydroxyl, aryl or hetaryl; or
R2 and R3 or R2 and R4 or R3 and R4 may optionally form -(CHI)i-U-(CH2)r, wherein i and j are
independently 1 or 2 and U is -0-, -S- or a valence bond,
h and f are independently 0,1,2, or 3;
g and e are independently 0 or 1;
M is a valence bond. In one embodiment R2 is hydrogen. In a second embodiment R3 is
hydrogen. In a third embodiment R3 is Cw alkyl, in particular methyl. In a further embodiment
R4 is hydrogen. In a still further embodiment R4 is CM alkyl, in particular methyl. In a further
embodiment R3 and R" form -(CHJrU-fCHJj-. In a still further embodiment i is 1. In a further
embodiment i is 2. In a still further embodiment j is 1. In a further embodiment j is 2. In a still
further embodiment U is a valence bond. In a further embodiment R3 and R4 form -(CH2)3-. In a

further embodiment h is 0. In a still further embodiment f is 0. in a further embodiment f is 1. In a further embodiment g is 0. In a still further embodiment e is 0. In a further embodiment e is 1. In a preferred embodiment of the compound of formula ID is (1E)-4-amino-4-methylpent-1-enyl,
(1E)-4-amino-2,4-dimethyipent-1-enyl, (1EV3-0-aminocyc!obutyl)prop-1-enyi, 1-amino-1-methylethyl, or 3-aminomethyfphenyl.
In a still further embodiment of the compound of formula J G is

wherein R8, RB, R10, R" and R" independently of each other are hydrogen, halogen, aryl, hetaryl, C1-4-alkyl or C1-4-alkoxy; k is 0,1 or 2. In a further embodiment R8, R9, R'°, R11 and R'2 are independently of each other hydrogen. In a still further embodiment one of R8, R9. R10, R" and R1! is phenyf and the others are hydrogen, in particular R10 is phenyl. In a further embodiment R8 is phenyl, in a still further embodiment k is 1. In a still further embodiment G is phenyl, 1-naphthyl or 2-naphthyl, preferably phenyl or 2-naphthyl. In a further embodiment G is benzyloxy. In a still further embodiment G is 1H-indol. In a further embodiment G is biphenyl-4-yl.
In the above compound of formula IG is preferably 2-naphthyi, benzyloxy, 1H-indol or biphenyl-4-yi.
In a further embodiment of the compound of formula I J is

In a still further embodiment of the compound of formula I E is -CONR1BR19, -COOR'9 or -(CH2)m-OR,&, wherein m is 0,1, 2 or 3, R18 and R19 independently are hydrogen or C1-4-alkyl optionally substituted by halogen, -N(Ra)RH wherein Ra and R28 are independently hydrogen or Ct In another embodiment E is -CONR2NR2R24, wherein R22 is hydrogen, Cs-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; R23 is C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or Cw-

acyl; and R24 is hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl; or aryl or hetaryl optionally substituted with one or more C1-4-alkyl; or R2and R" together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more G2-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or
R2and R24 together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more Cn-aikyl, halogen, amino, hydroxyl, aryl or hetaryl; or
R°and R24 together with the nitrogen atom to which they are attached may form a heterocyclic system optionally substituted with one or more CM-alkyl, halogen, amino, hydroxy!, aryl or hetaryl. In a still further embodiment R22 is hydrogen. In another embodiment R22 is C1-4-alkyl, such as C,_4-alkyi, in particular methyl, in a further embodiment R23 is d2-alkyl, such as C,_(-alkyl, in particular methyl. In another embodiment R23 is C,.racyi, such as CM-acyl, in particular acetyl. In a still further embodiment ofthe compound of formula I R24 is hydrogen. In another embodiment of the compound of formula I R24 is C1-4aikyl, such as Cw-alkyl, in particular methyl. In a special embodiment R22 is hydrogen and R23 and R24 are C1-4aikyl, such as CM-alkyl, in particular methyl. In a further embodiment R2and R23 may together with the nitrogen atoms to which they are attached form a heterocyclic system, which is optionally substituted with one or more C1-4-aikyl, halogen, amino, hydroxyl, aryl or hetaryl. Such heterocycfic system, including R22 and R23, may be aromatic or non-aromatic and may be selected from e.g. pyrazoie, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, or pyrazoline. In a still further embodiment R22 and R24 together with the nitrogen atoms to which they are attached form a heterocyclic system, which is optionally substituted with one or more C1-4-alkyl, halogen, amino, hydroxyl, aryl or hetaryi. Such heterocyclic system, including R22 and R:\ may be aromatic or non-aromatic and may be selected from e.g. pyrazoie, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, or pyrazoline. In a further embodiment of the compound of formula I R23 and R24 together with the nitrogen atom to which they are attached form a heterocyclic system, which is optionally substituted with one or more C1-4-aikyl, halogen, amino, hydroxyl, aryl or hetaryl. Such heterocyclic system, including R2and R23, may be aromatic or non-aromatic and may be selected from e.g. aziridine, dtthiazine, pyrrol, imidazoi, pyrazoie, isoindole, indole, indazole, purine, pyrrolidine, pyrroline, imidazoline, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, indoline, isoindoline, or morpholine. In a

particular embodiment R23 and R24 together with the nitrogen atom to which they are attached form pyrrolidine.
When Raand R23 form a heterocyclic system R2and R24 may simultaneously also form a heterocyclic system or R2* may be hydrogen, C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C1-4-alkyl.
When R22 and R24 form a heterocyclic system R23 and R24 may simultaneously also form a heterocyclic system or R23 may be C1-4-alkyl optionally substituted with one or more aryl or hetaryl, or C,.7-acyl.
In the above compound of formula I E is preferably (methyiamino)carbonyl, N,N-dimethylhydrazinocarbonyl, ethoxycarbonyl, or (pyrrolidin-l-yl)aminocarbonyl.

Preferred compounds of formula I of the invention are:
H{2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpiperidine-4-carboxyiic acid methylamide

■
1-{(2R}-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylanitno]-3-(biphenyl-4-yl)propionyl}-4-benzylpiperidine-4-carboxylic acid methylamide

2-Amino-W4(1R)-2-[(3R)-3-benzyl-3-(N',N,-dimethyl-hydrazinocarbonyl)-piperidin-1-yl]-1-benzyloxymethyl-2-oxo-ethyl)-2-methyl-proptonamide

1-{(2R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-z-enoyi;-m-meinyiaminoi-j-(Dipnenyi-4-yl)proptonyfH-benzylpiperidine-4-carboxylic acid ethyl ester

(3S)-1-[(2R)-2-((2E)-5-Am(no-5-methylhex-2-enoylamJno>-3-{1H-inc(ol-3-y/)praptony(i-3-benzylpiperidine-3-carboxylic acid ethyl ester

dimethylhydi2inacarbonyl)-piperidin-1-yl]-1-((2-naphthyl)rnethyl)-2-oxoethyl}-N-methyl-
amide

2-Amino-N2(1R)-2-p-ben2yM-{N\N'-dimethylhydraz(nocarbonyl)p(peridin-1-ylJ-1-((bipheny/-4-yl)methyl)-2-oxoethyl}-2-methylprapionamide

2-Aminc>-N22-[3-ben2yl-3-(N'2imethylhydrazinocart)onyl)piperidin-1-yl]-1-(benzyloxymethyl)-2-oxoethyl}-2-methylpropionamide

2-Amino-N-{(1R)-2-[3-benzyl-3-(N,N',N"-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(benzyloxymethyl)-2-oxoethyl}-2-methylpropionamide

The procedures used in this patent and illustrated in above scheme I are based on peptide couplings well known in the art, and should in no way be interpreted as limiting the invention in any way. In the first step an amine (1) and a carboxyiic acid is coupied to an amide by a coupling agent such as a carbodiimide and hydroxyazabenzoetriazole (HOAt). Prior to the next coupling a suitable protecting group such as tert butyloxycarbonyl (Boc) can be re¬moved with methods well known to those skilled in the art, thereby producing compound (2). It is also possible to avoid the use of protecting groups. Hereafter (2) is coupled to a carbox¬yiic acid of formula D-COOH by a coupling agent, thereby producing compound (3).

Compounds of the general structure I containing a hydrazine in the C-term'tnal may be pre¬pared as illustrated above in scheme II. The procedures used in this patent and illustrated in above scheme It are based on peptide couplings well known in the art, and should in no way be interpreted as limiting the invention in any way. In the first step a mono-, di- or tri-substituted hydrazine or hydrazone (4) and an appropriate protected amino acid are coupled to form a compound (5) using a suitable coupling reagent such as 1 -ethy!-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole or another cou¬pling reagent known in the art of peptide coupling in an appropriate solvent such as di-methylformamid or dichloromethane.. Hereafter, the amide (5) and a carboxyiic acid is cou¬pled by a coupling agent, thereby producing compound (6). Hereafter (6) is coupled to a car¬boxyiic acid of formula D-COOH by a coupling agent, thereby producing compound (7). In the procedure, prior to the next coupling a suitable protecting group such as tert butyloxy-carbonyl (Boc) can be removed with methods well known to those skilled in the art. It is also possible to avoid the use of protecting groups. The appropriate amino acids may be pro-

tected and deprotected by methods known in the art and described by e.g. T.W. Green (Protective Groups in Organic Synthesis, 2. Ed., John Wiley and Sons, New York 1991).
The compounds of formula I exhibit an improved resistance to proteolytic degradation by enzymes because they are non-natural, in particular because the natural amide bonds are replaced by non-natural amide bond mimetics. The increased resistance to proteolytic degradation of the compounds of the invention in comparison with known hormone releasing peptides is expected to improve their bioavailability compared to that of the peptides suggested in the prior literature.
In the above structural formulas and throughout the present specification, the following terms have the indicated meanings:
The C1-4-alkyl, C1-4-alkyiene, C1-4-alkyl or CM-alkylene groups specified above are intended to include those alkyl or alkylene groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl, and hexyl and their corresponding divalent moieties, such as ethylene. Examples of branched alkyf are isopropyl, sec-butyl, tert-butyi, isopentyi, and isohexyl and their corresponding divalent moie¬ties, such as tsopropylene. Examples of cyclic alkyl are C„-cycloalkyl such as cyclopropyl, cy-clobutyl, cyclopentyl and cyclohexyl and their corresponding divalent moieties, such as cyclo-propylene.
The C1-4-alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alk¬oxy are methoxy, ethoxy, propoxy, butoxy, pentoxy. and hexoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cyclic alkoxy are cyciopropyloxy, cydobutyloxy, cyclopentyfoxy and cyclohexyloxy.
The Cracyl groups specified above are intended to include those acyl groups of the desig¬nated length in either a linear or branched or cyclic configuration. Examples of linear acyl are formyi, acetyl, propionyl, butyryl, vaieryl, etc. Examples of branched are rsobutyryl, isovaleryl, pivaloyl, etc. Examples of cyclic are cyclopentylcarbonyl, cyclohexylcarbonyl, etc.

In the present context, the term "aryl" is intended to include monovalent carbocyciic aromatic ring moieties, being either monocyclic, bicyclic or polycycfic, e.g. selected from the group con¬sisting of phenyl and naphthyl, optionally substituted with one or more C1-4-alkyl, C1-4-alkoxy, halogen, amino or aryl.
In the present context, the term "arytene" is intended to include divalent carbocyciic aromatic ring moieties, being either monocyclic, bicyclic or polycydic, e.g. selected from the group con¬sisting of phenylene and naphthylene, optionally substituted with one or more C1-4-alkyl, C,2-alkoxy, halogen, amino or aryl.
\n the present context, the term "hetaryl" is intended to include monovalent heterocyclic aro¬matic ring moieties, being either monocyclic, bicyclic or poiycyclic, e.g. selected from the group consisting of pyridyl, 1-H-tetrazol-5-yl, thiazolyf, imidazolyl, indolyl, pyrimidinyl, thiadiazoiyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, quinolinyl, pyrazinyl, or isothiazolyl, option¬ally substituted by one or more Cu-alkyl, Craikoxy, halogen, amino or aryl.
In the present context, the term "hetarylene" is intended to include divalent heterocyclic aro¬matic ring moieties, being either monocyclic, bicyclic or poiycyclic, e.g. selected from the group consisting of pyridinediyl, 1-H-tetrazolediyl, thiazoldiyl, imidazolediyl, indolediyl, pyrimidinediyl, thiadiazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl, thiophenediyl, quinolin-ediyl, pyrazinediyl, or isothiazolediyl, optionally substituted by one or more Chalky!, Cr¬aikoxy, halogen, amino or aryl.
In the present context, the term "heterocyclic system" is intended to include aromatic as well as non-aromatic ring moieties, which may be monocyclic, bicyclic or polycycfic, and contain in their ring structure at least one, such as one, two or three, nitrogen atom(s), and optionally one or more, such as one or two, other hetero atoms, e.g. suipher or oxygen atoms. The heterocyclic system is preferably selected from pyrazole, pyridazine, triazine, indazole, phthalazine, cinnoline, pyrazolidine, pyrazoline, aziridine, drthiazine, pyrrol, imidazol, pyrazole, isoindole, indole, indazole, purine, pyrrolidine, pyrroline, imidazotidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, indoline, isoindoline, or morpholine.
The term "halogen" is intended to include chlorine (CI), fluorine (F), bromine (Br) and iodine (I).

The compounds of the present invention may have one or more asymmetric centres (chiral carbon atoms) and it is intended that stereoisomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention.
The compounds of the present invention may optionally be on a pharmaceutically acceptable salt form such as the pharmaceutically acceptable acid addition salts of compounds of fomiula I which include those prepared by reacting the compound of formula I with an inorganic or or¬ganic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, man-delic phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesul-fonic, trifluoracetic, sulfamic or fumaric acid and/or water.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammc-nium salt Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
In another aspect, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
Pharmaceutical compositions containing a compound of the present invention may be pre¬pared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences. 1985 or in Remington: The Science and Practice of Pharmacy, 19th Edition (1995). The com¬positions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
The pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, cydodextrin, talc, gelatin, agar, pec¬tin, acada, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty adds, fatty add amines, polyoxyethylene or water.

Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier wilt vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
Core:
Active compound (as free compound or salt thereof) 100mg
Colloidal silicon dioxide (Aerosil) 1.5mg
Cellulose, microcryst. (Avicel) 70mg
Modified cellulose gum (Ac-Di-Sol) 7.5mg
Magnesium stearate
Coating:
HPMC approx. 9mg
'Mywacett 9-40 T approx. 0,9mg
*Acyiated monogiyceride used as plasticizer for film coating.
For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The car¬rier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, ab¬sorption enhancers such as lecithin (phosphatidylcholine) or cycfodextrin, or preservatives such as parabenes.

Generally, the compounds of the present invention are dispensed in unit dosage form com¬prising 50-200 mg of active ingredient together with a pharmaceuticaliy acceptable earner per unit dosage.
The dosage of the compounds according to this invention is suitably 0.01-500 mg/day, e.g. from about 5 to about 50 mg, such as about 10 mg per dose, when administered to patients, e.g. humans, as a drug.
in a further aspect the present invention relates to a pharmaceutical composition in unit dose form, comprising as an active ingredient from about 10 to about 200 mg of the compound of the general fomiuia I or a pharmaceuticaliy acceptable salt thereof.
It has been demonstrated that compounds of the general formula I possess the ability to re¬lease endogenous growth hormone in vivo. The compounds may therefore be used in the treatment of conditions which require increased plasma growth hormone levels such as in growth hormone deficient humans or in elderly patients or livestock.
Thus, in a particular aspect, the present invention relates to a pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceuticaliy acceptable salt thereof together with a pharmaceuticaliy acceptable carrier or diluent
In a further aspect, the present invention relates to a method of stimulating the release of growth hormone from the pituitary, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula I or a pharmaceuticaliy ac¬ceptable salt thereof.
In a still further aspect, the present invention relates to the use of a compound of the general formula I or a pharmaceuticaliy acceptable salt thereof for the preparation of a medicament for stimulating the release of growth hormone from the pituitary.
To those skilled in the art, it is well known that the current and potential uses of growth hor¬mone in humans are varied and multitudinous. Thus, compounds of formula t can be adminis-

tered for purposes stimulating release of growth hormone from the pituitary and would then have similar effects or uses as growth hormone itself. Compounds of formula I are useful for stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glu¬cocorticoids, prevention and/or treatment of osteoporosis, treatment of chronic fatigue syndrorr tCFS), treatment of acute fatigue syndrom and muscle loss following election surgery, stimula¬tion of the immune system, acceleration of wound healing, accelerating bone fracture repair, accelerating complicated fractures, e.g. disctraction osteogenesis, treatment of wasting secon¬dary to fractures, treatment of growth retardation, treating of growth retardation resulting from renal failure or insufficiency, treatment of cardiomyopathy, treatment of chronic liver disease, treatment of thrombocytopenia, treatment of Crohn's disease, treatment of short bowel syn¬drome, treatment of chronic obstructive pulmonary disease (COPD), treatment of complica¬tions associated with transplantation, treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness, treatment of obe¬sity and growth retardation associated with obesity, treatment of anorexia, treating growth re¬tardation associated with the Prader-Willi syndrome and Turner's syndrome; increasing the growth rate of a patient having partial growth hormone insensitive syndrome, accelerating the recovery and reducing hospitalization of bum patients; treatment of intrauterine growth retarda¬tion, skeletal dysplasia, hypercortisoiism and Cushing's syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients, treatment of osteo-chondrodysplasias, Noonan's syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and ventilator dependency, treatment of cardiac failure or related vascular dysfunction, treatment of impaired cardiac function, treatment or prevention of myocardial infarction, lowering blood pressure, protection against ventricular dysfunction or prevention of reperfusion events, treat¬ment of adults in chronic dialysis, attenuation of protein catabolic responses after major sur¬gery, reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treat¬ment of hyperinsuiinemia including nesidioblastosis, adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function, treat¬ment of immunosuppressed patients, treatment of sarcopenia, treatment of wasting in connec¬tion with AIDS, improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly, stimulation of osteoblasts, bone remodelling and cartilage growth, regulation of food intake, stimulation of the immune system in companion animals and treatment of disorder of aging in companion animals, promoting

growth in livestock and stimulation of wool growth in sheep, treatment of metabolic syndrom (syndrom X), treatment of insulin resistance, including NIDDM, in mammals, e.g. humans, im¬provement of sleep quality and correction of the relative hyposomatotropism of senescence due to high increase in REM sleep and a decrease in REM latency, and treatment of hypo¬thermia. Treatment is also intended to include prophylactic treatment.
For the above indications the dosage will vary depending an the compound of formula I em¬ployed, on the mode of administration and on the therapy desired. However, generally dosage levels between 0.0001 and 100 mg/kg body weight daily are administered to patients and ani¬mals to obtain effective release of endogenous growth hormone. Morever the compounds of formula I have no or substantially no side-effects, when administered in the above dosage lev¬els, such side-effects being e.g. release of LH, FSH, TSH, ACTH, vasopressin, oxytocin, Corti¬sol and/or prolactin. Usually, dosage forms suitable for oral, nasal, pulmonat or transdermal administration comprise from about 0.0001 mg to about 100 mg, preferably from about 0.001 mg to about 50 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
Optionally, the pharmaceutical composition of the invention may comprise a compound of for¬mula I combined with one or more compounds exhibiting a different activity, e.g., an antibiotic or other pharmacologically active material.
The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or par¬enteral, the oral route being preferred.
Apart from the pharmaceutical use of the compounds of formula I, they may be useful in vitro tools for investigating the regulation of growth hormone release.
Compounds of formula I may also be useful in vivo tools for evaluating the growth hormone releasing capability of the pituitary. For example, serum samples taken before and after ad¬ministration of these compounds to humans can be assayed for growth hormone. Comparison of the growth hormone in each serum sample would directly determine the ability of the pa¬tients pituitary to release growth hormone.

Compounds of formula I may be administered to commercially important animals to increase their rate and extent of growth, and to increase milk production.
A further use of growth hormone secretagogue compounds of formula I is in combination with other secretagogues such as GHRP (2 or 6), GHRH and its analogues, growth hormone and its analogues or somatomedins including IGF-1 and IGF-2.

Pharmacological Methods
Compounds of formula I may be evaluated in vitro for their efficacy and potency to release growth hormone in rat pituitary primary cultures, and such evaluation may be performed as de¬scribed below.
The isolation of rat pituitary cells is a modification of O. Sartor et al.. Endocrinology 116.1985, pp. 952-957. Mate albino Sprague-Dawley rats (250 +/- 25 grams) were purchased from Mellegaard, Lille Skensved, Denmark. The rats were housed in group cages (four ani¬mals/cage) and placed in rooms with 12 hour light cycle. The room temperature varied from 19-24"C and the humidity from 30 - 60%.
The rats were decapitated and the pituitaries dissected. The neurointermediate lobes were re¬moved and the remaining tissue was immediately placed in icecold isolation buffer (Gey's me¬dium (Gibco 041-04030) supplemented with 0.25% D-glucose, 2% non-essential amino acids (Gibco 043-01140) and 1 % bovine serum albumine (BSA) (Sigma A-4503)). The tissue was cut into small pieces and transferred to isolation buffer supplemented with 3.8 mg/ml of trypsin (Worthington #3707 TRL-3) and 330 mg/ml of DNase (Sigma D-4527). This mixture was incu¬bated at 70 rotations/min for 35 min at 37"C in a 95/5% atmosphere of OJ/COJ. The tissue was then washed three times in the above buffer. Using a standard pasteur pipette, the tissue was then aspirated into single cells. After dispersion, cells were filtered through a nylon filter (160 mm) to remove undigested tissue. The cell suspension was washed 3 times with isolation buffer supplemented with trypsin inhibitor (0.75 mg/ml, Worthington #2829) and finally resu-spended in culture medium; DMEM (Gibco 041-01965) supplemented with 25 mM HEPES (Sigma H-3375), 4 mM glutamine (Gibco 043-05030H), 0.075% sodium bicarbonate (Sigma S-8875), 0.1% non-essential amino acid. 2.5% fetal calf serum (FCS, Gibco 011-06290), 3% horse serum (Gibco 034-06050), 10% fresh rat serum, 1 nM T3 (Sigma T-2752) and 40 mg/l dexamethasone (Sigma D-4902) pH 7.3, to a density of 2 x 103 cells/ml. The cells were seeded into microtiter plates (Nunc, Denmark), 200 ml/well, and cultured for 3 days at 37°C and 8%
CO;.

Compound testing
After culturing, the cells were washed twice with stimulation buffer (Hanks Balanced Salt Solu¬tion (Gibco 041-04020) supplemented with 1% BSA (Sigma A-4503), 0.25% D-g!ucose (Sigma G-5250) and 25 mM HEPES (Sigma H-3375) pH 7.3) and preincubated for 1 hour at 37°C. The buffer was exchanged with 90 ml stimulation buffer (37°C). Ten ml test compound solution was added and the plates were incubated for 15 min at 37°C and 5% COj. The medium was de¬canted and analyzed for GH content in an rGH SPA test system.
All compounds were tested in doses ranging from 10 pM to 100 mM. A dose-response relation was constructed using the Hill equation (Fig P, Biosoft). The efficacy (maximal GH released, E2 was expressed in % of the £„.,, of GHRP-6. The potency (ECR,) was determined as the concentration inducing half maximal stimulation of the GH release.
Compounds of formula I may be evaluated for their metabolic stability using the procedure de¬scribed below:
Compounds is dissolved at a concentration of 1 mg/ml in water. 25 ml of this solution is added to 175 ml of the respective enzyme-solution (resulting in an enzyme:substrate ratio (w/w) of approximately 1:5). The solution is left at 37°C overnight. 10 ml of the various degradation so¬lutions is analyzed against a corresponding zero-sample using flow injection eiectrospray mass spectrometry (ESMS) with selected ion monitoring of the molecular ion. If the signal has de¬creased more than 20% compared to the zero-sample, the remainder of the solution is ana¬lyzed by HPLC and mass spectrometry in order to identify the extent and site(s) of degradation precisely.
Several standard peptides (ACTH 4-10, Angiotensin 1-14 and Glucagon) have been included in the stability tests in order to verify the ability of the various solutions to degrade peptides.
Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) were purchased from Sigma, MO, USA)

Enzymes (trypsin, chymotrypsin, elastase aminopeptidase M ana carpoxypeptiaase Y ana u) were all purchased from Boehringer Mannheim GmbH (Mannheim, Germany)
Pancreatic enzyme mix: trypsin, chymotrypsin and elastase in 100 mM ammoniumbicarbonate pH 8.0 (all concentrations 0.025 mg/ml).
Carboxypeptidase mix: carboxypeptidase Y and B in 50 mM ammoniumacetate pH 4.5 (all concentrations 0.025 mg/ml).
Aminopeptidase M solution: aminopeptidase M (0.025 mg/ml) in 100 mM ammoniumbicarbon¬ate pH 8.0
Mass spectrometric analysis was performed using two different mass spectrometers. A Sciex API IIJ triple quadrupole LC-MS instrument (Sciex instruments, Thomhill, Ontario) equipped with an electrospray ion-source and a Bio-ion 20 time-of-fiight Plasma Desorption instrument (Bio-Ion Nordic AS, Uppsala, Sweden).
Quantification of the compounds (before and after degradation) was done on the API III in¬strument using single ion monitoring of the molecular ion in question with flow injection of the analyte. The liquid flow (MeOH:water 1:1) of 100ml/min was controlled by an ABI 140BHPLC unit (Perkin-Bmer Applied Biosystems Divisions, Foster City, CA). The instrument parameters were set to standard operation conditions, and SIM monitoring was performed using the most intense molecular ion (in most cases this corresponded to the doubly charged molecular ion).
Identification of degradation products furthermore involved the use of plasma desorption mass spectrometry (PDMS) with sample application on nitrocellulose coated targets and standard instrumental settings. The accuracy of the hereby determined masses is generally better than 0.1%.
Separation and isolation of degradation products was done using a HY-TACH C-18 reverse phase 4.6x105 mm HPLC column (Hewlett-Packard Company, Palo Aito, CA) with a standard acetonitril: TFA separation gradient. The HPLC system used was HP1090M (Hewlett-Packard Company, Palo Alto, CA).

+: Stable (less than 20% decrease in SIM signal after 24 h in degradation solution) -: Unstable (more than 20% decrease in SIM signal after 24 h in degradation solution)
Any novel feature or combination of features described herein is considered essential to this invention.
EXAMPLES;
The process for preparing compounds of formula I and preparations containing them is fur¬ther illustrated in the following examples, which however, are not to be construed as limiting.

The structures of the compounds are confirmed by either High Performance Liquid Chro¬matography (HPLC), nuclear magnetic resonance (NMR, Bruker 400 MHz) or Liquid Chro-matography-Mass Spectrometry (LC-MS). NMR shifts (d) are given in parts per million (ppm) and only selected peaks are given, mp is melting point and is given in °C. Column chroma¬tography was carried out using the technique described by W.C. Still et al, J. Org. Chem. 1978,43, 2923-2925 on Merck silica gel 60 (Art 9385). Compounds used as starting materi¬als are either known compounds or compounds which can readily be prepared by methods known perse. The methanol/ammonia solution used is a 10% ammonia solution in metha¬nol.
HPLC-Analysis:
Method A1.
The RP-analysis was performed using UV detections at 214, 254, 276, and 301 nm on a 218TP54 4.6 mm x 250 mm 5m C-18 silica column (The Separations Group, Hesperia), which was eluted at 1 mL/min at 42°C. The column was equilibrated with 5% acetonitriie in a buffer consisting of 0.1 M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid, after injection the sample was eluted by a gradient of 5% to 60% acetonitriie in the same buffer during 50 min.
Method B1.
The RP-analysis was performed using UV detections at 214, 254, 276, and 301 nm on a 218TP54 4.6 mm x 250 mm 5m C-18 silica column (The Seperations Group, Hesperia), which was eluted at 1 mL/min at 42°C. The column was equilibrated with 5% (acetonitriie + 0.1 % TFA) in an aqueous solution of TFA in water (0.1%). After injection the sample was eluted by a gradient of 5% to 60% (acetonitriie + 0.1 % TFA) in the same aqueous buffer during 50 min.
LC-MS-Analysis:
The LC-MS analyses were performed on a PE Sciex AP1100 LC/MS System using a Wa¬ters® 3 mm x 150 mm 3.5 m C-18 Symmetry column and positive ionspray with a flow rate

of 20 ml/min. The column was eluted with a linear gradient of 5-90% acetonitrile, 85-0% wa¬ter and 10 % trifluoroacetic acid (0.1%)/ water in 15 min at a flow rate of 1 ml/min.
Abbrevations:
TLC: thin layer chromatography
DMSO: dimethylsulfoxide
min: minutes
h: hours
Boc: tert butyloxycarbonyl
DMF: dimethylformamide
THF: tetrahydrofuran
EDAC: N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride
HOAt: 1-hydroxy-7-azabenzotriazole
DIEA: diisopropylethylamine
TFA: trifluoroacetic acid
Buiidingblocks:
N-methylated aminoacids used in the following examples were prepared as in Can. J. Chem.
1977. 55, 906.

Step A
N-tert-butyloxycarbony(-4-ben2ylpiperidine-4-carboxyIicacid
N-tert-butyloxycarbonyl-4-ben2ylpiperidine-4-carboxylic acid ethyl ester (prepared as in Gilli-gan et al J. Med. Chem. 1994, 364-370 using benzyl bromide as the alkylating agent) (11.0 g; 32 mmol) was refluxed for 7 h. in a mixture of ethanol (190 ml) and aqueous sodium hy¬droxide (18% 190 ml). The volume was reduced to a -rird in vacuo and pH was adjusted to 3 with sodium hydrogen sulphate. Water (300 ml) was added and the mixture was extracted with ethylacetate (2 x 250 ml). The combined organic phases were evaporated to afford 8.6 g of N-terf-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid.
'H-NMR: d (CDCI3) 1.45 (s, 9H); 1.5 (m(br); 2H); 2.08 (m(br); 2H); 2.88 (m(br); 2H); 2.89 (s. 2H); 3.95 (m(br); 2H); 7.09-7.30 (5 arom. H).
Step B
4-Benzyf-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester
N-terf-butyloxycarbonyf-42benzylpiperidine-4-carboxylic acid (3.0 g; 9.0 mmol) was dissolved in methylene chloride (25 ml) and EDAC (1.8 g; 9.0 mmol) and HOAt (1.3 g; 9.0 mmol) was added. The mixture was stirred for 15 min, then methyl amine (33% in ethanol; 2.3 ml; 18 mmol) and DIEA (1.6 mi; 9.0 mmol) was added and the mixture was stirred overnight. Meth¬ylene chloride (100 ml) was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and a aqueous solution of sodium hydrogen-sulphate (10%, 50 ml), dried (MgSO,) and evaporated in vacuo. The residue was chroma-tographed on silica (90 g) using a mixture of aqueous ammonia/ethanol/methylene chloride (1:7:92) as eluent to afford 2.8 g of 4-benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester.
1H-NMR: d (CDCI3) 1.44 (s, 9H); 1.55 (m(br); 2H); 1.98 (m(br); 2H); 2.70 (d, 3H); 2.98 (m(br); 2H); 2.89 (s, 2H); 3.87 (m(br); 2H); 5.15 (q(br); 1H); 7.01-7.32 (5 arom. H).

StepC
4-Benzylpiperidine-4-carboxylic acid methyfamide
4-Benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester {2.8 g) was dis¬solved in a mixture of TFA and methylene chloride and stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in water (30 ml) and pH was adjusted to 13 with aqueous sodium hydroxide (1N). The aquoues phase was extracted with methylene chloride (3 x 75 ml) and the combined organic phases were dried (MgS04) and evaporated in vacuo to afford 1.50 g of 4-benzylpiperidine-4-carboxylic acid methylamide.
'H-NMR: d (CDCIj) 1.80 (td; 2H); 2.14 (d(br), 2H); 2.70 (d, 3H); 2.81 (s, 2H); 2.85 (dt; 2H);
3.21 (dt, 2H); 5.25 (t, 1H); 7.00-7.35 (5 arom. H).
StepD
4-Benzyt-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylicacid meth¬ylamide
(2R)-2-tert-Butyloxycarbonylamino-N-methyl-3-(2-naphthyl)propionic acid (709 mg; 2.15 mmol), HOAt (293 mg 2.25 mmol) and EDAC (412 mg; 2.25 mmol) were dissolved in meth¬ylene chloride (5ml) and stirred for 15 min. 4-Benzylpiperidine-4-carboxylic acid methylamide (500 mg; 2.25 mmol) and DIEA (0.35 ml) were added and the mixture was stirred overnight. Methylene chloride (30 ml) was added and the mixture was washed with a saturated aque¬ous solution of sodium hydrogen carbonate (20 ml) and a aqueous solution of sodium hydro-gensulphate (10%, 20 ml), dried (MgS04) and evaporated in vacuo. The residue was chro-matographed on silica (40 g) using ethyl acetate as eluentto afford 810 mg of 4-benzyl-1-((2R)-2-(N-methyl-fert-butyloxycarbonylamino)-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid methylamide which was dissolved in TFA/methylene chiond& (8+8 ml) and stirred for 40 min at RT. The solvent was removed in vacuo and the residue was neutralised with a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate (50 ml). The organic phase was dried (MgSO«) and evaporated to afford 729 mg of 4-benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid methylamide.

StepE
4-Benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylicacid meth-ylamide (360 mg; 0.82 mmole) was coupled to (2E)-5-(fert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid using the same coupling procedure as in step D. Removal of the N-terminal Boc group was performed as in step D but at -10 "C. The crude product was purified on a RP-18-Seppak® (5 g; Waters) using a gradient from 0.1%TFA in water/acetonitrile 100/0 to 0.1% TFA in 60/40 water/acetonitrile to afford 306 mg of the title compound as a trifluoroacetate.
'H-NMR5 (MeOH) (selected peaks for major rotamer) 1.30 (s,3H); 1.31 (a, 3H);2.10(AB-syst, 2H); 2.55 (s, 3H); 5.81 (m, 1H).
HPLC: r, = 31.88 min(A1) r, = 33.30 min(B1)
ESMS: m/z: 569.4 (M+H)*.

The compound was prepared as in example 1 using (2E)-5-(tert-butyloxycarbonylamino)-5,3-dimethyl-2-hexencic acid instead of (2E)-5-(fert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid in step E
HPLC: r,= 33.70 min (A1) r, = 34.22 min(B1)
ESMS: m/z: 583.4 (M+H)*.
Example 3
H(2R)-2-[N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(biphenyl-4-yl)propionyi}-4-benzylpiperidine-4-carboxylic acid methytamide

This compound was prepared as in example 1 using (2R)-2-terf-Butyloxycarbonylamino-N-methyl-3-(4-biphenylyl)propionic acid instead cf (2R)-2-/ert-Butyioxycarbonylamino-N-methyl-3-(2-naphthyl)propionic acid in step D.
HPLC: r, = 34.53 min ESMS: m/z : 595.4 (M+H)+.

This compound was prepared as in example 1 using (2R)-2-tert-Butyloxycarbonylamino-N-methyl-3-(4-biphenytyi)propionic acid instead of (2R)-2-tert-Butyloxycarbonylamino-N-methyl-3-(2-naphthyl)proptonic acid in step D and using (2E)-5- HPLC: rt= 35.15 min(A1) r, = 36.83 min(B1)
ESMS: m/z : 609.4 (M+H)*.
Example 5
1-

This compound was prepared as in example 1 using {2R)-2-tert-Butyloxycarbonylamina-N-methyl-3-(4-biphenylyl)propionic acid instead of (2R)-2-terf-Butyloxycarbonylamino-N-methyl-3-(2-naphthyl)propionic acid in step D and using {2E)-4-(1-(tert-butyloxycarbonylamino)cyciobutyl)but-2-enoic acid instead of (2E)-5-(tert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid in step E.

To a solution of 4-faenzylpiperidine-1,4-dicarboxyiic acid 1-terf-butyf ester (0.75 g, 2.35 mmol) (prepared as in Gilligan etalA. Med. Chem. 1994, 364-370) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.32 mg, 2.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol) and the mixture was stirred for 30 min. Then W'W'-dimethylhydrazine (0.27 ml, 3.53 mmol) and diisopropyiethy-lamine (0.52 ml, 3.06 mmol) was added and the mixture was stirred for 2 days. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgS04), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with heptane/ethyl acetate (1:2) to give 0.76 g of 4-benzyl-4-(W'A/'-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.

To a solution of 4-ben2yl-4-(W,A/'-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tort-butyl ester (0.76 g, 2.02 mmoi) in methylene chloride (2 ml) at 0°C was added trifluoroacetic acid (5 ml) and the mixture was stirred for 60 min. The mixture was quenched with ethanol {20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 4-benzylpiperidine-4-carboxylic acid A/'A/'-dimethylhydrazide in quantitative yield.

To a solution of 2-torf-butoxycarbonylaminc-3-(1 H-indole-3-yl)propionic acid (0.37 g, 1.2 mmol) in methylene chloride (15 ml) and dimethylformamid (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.16 mg, 1.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.20 mmol) and the mixture was stirred for 30 min. Then 4-benzylpiperidine-4-carboxylic acid N'/V'-dimethylhydrazide (0.26g, 1.0 mmol) and diisopro-pylethylamine (0.69 ml, 4.0 mmol) was added and the mixture was stirred overnight. Methyl¬ene chloride (100 mi) was added and the mixture was washed with saturated aqueous so¬dium hydrogencarbonate (20 ml), water (20 ml), dried (MgS04), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chloride/(10% ammonia in methanol) (9:1) to give 0.43 g of (2-(4-benzyl-4-(A/',JV-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indole-3-ylmethyl)-2-oxoethyl)carbamic acid tert-butyl ester as a colorless oil.

To a solution of (2-{4-benzyM-(A/',A/'-dimethylhydrazinocarbonyf)piperidine-1-yl}-1-(1/-/-indole-3-ylmethyl)-2-oxoethyt)carbamic acid tert-butyl ester (0.40 g, 0.73 mmol) in methylene chloride (3 ml) at 0°C was added triftuoroacetic acid (3 ml) and the mixture was stirred for 30 min. The mixture was quenched with ethanol {20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 0.63 g of 1- HPLC: R, = 7.52min (H8)
LC-MS: R, = 7.61 min, m/z = 448.4 (m+1)
(122-(4-Benzyl2(W'N'Kiimetnylhydra2inocarbonyf)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyl)carbamic acid tert-butyl ester

To a solution of 2-ferf-butoxycarbonylamino-2-methytpropionic acid (0.18 g, 0.88 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazoIe (0.12 mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropy[)carbodiimide hydrochloride (0.12 g, 0.88 mmol) and the mixture was stirred for 30 min. Then 1-(2-amino-3-(1H-indol-3-yl)propionyi)-4-benzylpiperidine-4-carboxylic acid W'A/'-dimethylhydrazide (0.46 g, 0.73 mmol) and diisopro-pylethytamine (0.50 ml, 2.92 mmol) was added and the mixture was stirred overnight. Meth¬ylene chloride (100 ml) was added and the mixture was washed with saturated aqueous so¬dium hydrogencarbonate (20 mi), water (20 ml), dried (MgS04), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chioride/(10% ammonia in methanol) (9:1) to give 0.31 g of (1-(2-(4-benzyl-4-(A/',W-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyfjcarbamic acid terf-butyl ester as a colorless oil.
HPLC:R, = 10.25 min (H8)
LC-MS: R, = 9.66 min, m/z = 633.2 (m+1)
2-Amino-/V-[(1R)-2-[4-benzyl-4-(W',W-dimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethyl]-2-methyfpropionamide

To a solution of (1-{2-(4-benzyM-(W;/V'-dimethylhydra2inocarbonyl)piperidine-1-yl)-l-{iH-indol-3-ylmethy[)-2-oxoethylcarbamoyl)-1-methylethyi)carbamic acid tert-butyi ester {0.29 g, 0.46 mmol) in methylene chloride (3 ml) at 0°C was added trifiuoroacetic acid (3 ml) and the mixture was stirred for 30 min. The mixture was quenched with ethanol {20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 0.25 g of 2-amino-A/-[(1 R)-2-[42enzyl2{N;W'Hdimethylhydrazinocarbonyl)piperidin-1-yl]-1-{(1H-indoI-3-yl)methyl)-2-oxoethyl]-2-methytpropionamide as a white amorph powder.
HPLC: R, = 24.56 min (A1), R, = 24.95 min (B1), R, = 7.73 min (H8) LC-MS: R, = 7.74 min, m/z = 533.4 (m+1)
Example 7
2-Amino-W2(1R)-2-[(3R)-3-benzyl-3-(W',W'-dimethyl-hydrazinocarbonyl)-piperidin-1-yl]-1-benzyloxymethyl-2-oxo-ethyl}-2-methyl-propionamide

2-Amino-W-[(1R)-2-[(3R)-3-benzyl-3-(WV2imemylhydrazinocarbonyl)-piperidin-1-yl]-1-((iH-indol-3-yl)methyl)-2-oxoethyn-2-methylpropionamide

Example 9
1-{(2R)-2-£N-((2E)-S-Amino-5-methyJhex-2-enoyO-N-methylamino)-3-(biphenyM-yOpropionylH-benzytpiperidine-4-carboxyfic acid ethyl ester

LC-MS: Rt = 12.36 min, m/z: 624.4 (M+H) HPLC:Rt = 42.785 min (A1) HPLCrRt = 45.148 min (B1)

LC-MS: Rt = 11.92 min, m/z: 584.4 (M+H) HPLC:Rt = 39.893 min (A1) HPI_C:Rt = 42.046 min (B1)
Example 12
H(2R)-2-[N-((2E)-5-Amino-3,5-dimethylhex-2-enoyl)-N-methylamino]-3-(2-naphthyl)propionyl}-4-benzylpipejidine-4-cai,boxylic acid ethyl ester

LC-MS: Rt = 12.21 min, m/z: 598.2 (M+H) HPLC:Rt= 40.541 min (A1) HPLC: Rt = 42.780 min (B1)

Example 14
(3S)-1-E(2R)-2-((2E)-5-Amino-3,5-dimethylhex-2-enoylamino)-3-(1H-indol-3-yl)propiony!]-3-benzylpiperidine-3-carboxylic acid ethyl ester

LC-MS: Rt = 10.42 min, m/z: 573.2 (M+H) HPLC:Rt = 36.680 min (A1) HPLC:Rt = 38.563 min (B1)
Example 15
(3S)-1-[(2R)-2-{3-{Aminomethyl)ben2oyiamino)-3-{1H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid ethyl ester

LC-MS: Rt = 10.24 min, m/z: 567.4 (M+H) HPLC:Rt = 36.118 min(A1) HPLC:Rt = 38.052 min (B1)
Example 16

HPLC: Rt = 31.198 min(B1)
Example 17
(2E)-5-Amino-5-methylhex-2-enoic acid N-[(1 R)-2-[3-benzyl-3-(N',N'-dimethylhydra2inocarbonyl)-piperidtn-1-yl]-1-((1H-indol-3-yl)methyl)-2-oxoethylJamide

Example 19
(2E)-5-Amino-5-methylhex-2-enoicacid{(1R)-2-[3-benzyl-3-(N',N'-dimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-{benzyloxymethyl)-2-oxoethyl}amide

HPLC: Rt = 33.297 / 33.640 min (B1)
Example 22
2-Amino-N-{(1R)-2-t3-benzyl-3-(N',N'-dimethylhydra2inocarbonyl)piperidin-1-yl]-l.((iH-indol-3-yl)methyl)-2-oxoethyl}-2-methylproptonamide

WE CLAIM:
I. A compound selected from the group consisting of:
l-{(2R)-2-[N-((2F)-5-Amino-5-methylhex-2-enoyl)-N-methylamino]-3-(2-naphthy])propiony){-4-benzylpipcridinc-4-carboxylic acid methylamide

l-{(2R)-2-|N--((2E)-5-Amino-5-melhy!hex-2-cnoyl)-N-mcthylaminoJ-3-(biphenyl-4-yl)propion;lI-4-benzylpiperidine-4-carboxylic acid metliylamide

l-{(2R)-2-[N-((2H)-5-Amino-3,5-dimethylhex-2-enoyl)-N-melhylamino|-3-(biphenyI-4-yl)propionyl j -4-benzylpiperidinc-4-carboxylic acid methylamide

l-((2R}-2-!N-|(2E)-4-(l-Aminocyclobut\'l)but-2-enoylJ-N-methy!aminoj-3-(biphenyl-4-yl)propionyl)-4-beiizylpiperidine-4-carboxylic acid methylamide

2-Amino-N-f(lR)-2-[4-benzyI-4-(N'.N'-dimelhylhydra7inocarbon\[)piperidin-l-yl]-l-((lH-indo!-3-yl)melliyl)-2-oxocthyl|-2-methylpropionamidc

2-AminowV" {(] R)-2-[(3R)-3-bcn/yl-3-(.V', ,V'-dimethyl--hydrazinocarbonyI)-piperidin-1 -yl]-1 -benzy!oxymelhyI-2-oxo-clh> i! -2-methyl-propionamidc

2-Amino-A'-|(lR)-2-[{3R)-3-bt;nzyl-3-(,'VW--dimethylhydrazinocarbonyl)-piperidin-l-yl]-l-((l//-indol-3-yl)methyl)-2-Gxocthyl]-2-mcthylpropionamide

l-{(2R)-2-|N-((2E)o-Amino-5-mcthylhex-2-enoyi)-N-methylaminoJ-3-(biphenyl-4-yl)propionyl|-4-bcn/ylpiperidine-4-carboxylic acid ethyl ester

l-{(2R)-2-fN-((2E)-5-Amino-3.5-dimelhylhex-2-enoyl)-N-methylaminol-3-{biphenyl-4-yl)propionyij-4-bt;nzylpiperidine-4-carboxylic acid ethyl ester

l-{{2R)-2-[N-((2E)-5-Amino-5-methylhex-2-cnoyl)-N-methylamino]-3-{2-naphthyl)propionyl!-4-benzylpipcridine-4-earboxylic acid ethyl ester

l-{(2R)-2-[N-((2H)-5-Amino-3.5-dimcthylhex-2-enoyl)-N-methylammo]-3-(2-naphthyl)propionyl)-4-benzyipipcridine-4-carboxylic acid elhyl eslcr

(3S)-l-[(2R)-2-{(2E)-5-Amino-5-melhylhex-2-enoylamino)-3-(lH-indol-3-yl)propionyl|-3-benzylpiperidine-3~carboxylic acid ethyl ester

(3S)-l-[(2R)-2-((2r-)-5-Amino-3.5-dimethyllicx-2-enoylamino)-3-{lH-indol-3-yI)propionyl]-3-benzylpiperidinc-3-carboxyiic acid ethyl ester

(3S)-l-[(2R)-2-(3-(Aminomelhyl)bcn7oylamino)-3-(lH-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid ethyl ester

{2E)-5-Amino-5-mcthy!hex-2-cnoic acid N-|(lR)-2-|4-bcn/.yl-4-(N^N'-dimethylhydra/inocarbon^■l)pipcridin-■]-yl]-l-((2-naphthyl)mcthyl)-2-oxoethyl}-N-methylamide

(2E) 5-Amino-5-mcthylhcx-2-cnoicacidN-[(lRV2-[3-bcn7yl-3-(N',N'-dimethylhydrazinocarbonyl)-pipt;ridin-1 -yl]-1 -({1 H-indol-3-yl)methyi)-2-oxoethyljamide

(2E)-5-Amino-5-melhylhex-2-enoic acid N-({lR)-2-[3-benzyl-3-(N^N'-dimethylhydl'azinocarbonyl)-pipcridin- 1 -yl |-1 -((2-naphthyl)methyl)-2-oxoethyl}-N-methyl-amide

(2E)-5-Amino-5-mcthylhex-2-t;noic acid {(1 K)-2-l3-benzyl-3-{N'.N■-dinlethyl-hydrazinocarbonyl)pipc^idin- I -y 11-1 -(bt;nzyloxymelhyl)-2-oxoethyl i amide

2-Amino-N-|2-|3-bcn7yl-3-(N\N'-dimcthylhydrazinocarbonyl)piperidin-l-yl]-l-((2-naphthyl)melhyl)-2-oxo-ethyl ] -2-methyl-prapionamide

2-Amino-N-{{lR)-2-[3-benzyl-3-(N'.N'-dimL;diylhydra/.inocarbonyl)pipcridin-l-yl]-l-((biphenyl-4-yl)mcthyl)-2-oxocthyl]-2-mcthylpropionamide

2-Amino-N'|( lR)-2-[3-benyl 1-3-1 N'.N-dimcthylhydrazinocarbonyOpipcridin-1-yl]-l-((lH-indol'3-yl)melhyl)-2-oxoclhyll-2-methylpropionamidt;

2-Amino-N-{2-|3-benzyl-3-(N'-methylhydrazinocarbonyl)piperidin-l-yl]-l-(benzyIoxymcthyl)-2-oxoethy!i-2-mcthylpropionamide

2-Amino-N-{(lR)-2-[3-ben2yl-3-(N'-methylhydra2inocarbonyl)piperidin-l-yl]-l-{(lH-indol-3-yl)nicthyl)-2-oxoelhyl}-2-melhylpropionamidc

l-[(2R)-2-(2-Amino-2-methylpropionylamino)-3-(l-H-indol-3-yl)propionyl]-3-benzylpiperidine-3-carboxylic acid {pyrrolidin-l-yl)amide

2-Amino-N-{(lR)-2-[3-benzyl-3-(N,N,,N,-trimethylhydrazinocarbonyl)piperidin-l-yl]-l-({lH-indol-3-yl)methyl)-2-oxoethyl)-2-methylpropionamide

and pharmaceutically acceptable salts thereof.

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Patent Number

225599

Indian Patent Application Number

IN/PCT/2000/621/CHE

PG Journal Number

52/2008

Publication Date

26-Dec-2008

Grant Date

19-Nov-2008

Date of Filing

08-Nov-2000

Name of Patentee

NOVO NORDISK A/S

Applicant Address

NOVO ALLE, DK-2880 BAGSVAERD,

Inventors:

#	Inventor's Name	Inventor's Address
1	HANSEN, THOMAN, KRUSE	78 TIBBEVANGEN, DK-2730 HERLEV,
2	ANKERSEN, MICHAEL	34,1TH DALGAS HAVE, DK-2000 FREDERIKSBERG,

PCT International Classification Number

C07D 211/62

PCT International Application Number

PCT/DK99/00260

PCT International Filing date

1999-05-10

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	PA 1998 00875	1998-07-01	Denmark
2	DK 0636/98	1998-05-11	Denmark