Title of Invention

4-PHENYL-5-OXO-1,4,5,6,7,8-HEXAHYDROQUINOLINE DERIVATIVES AS MEDICAMENTS FOR THE TREATMENT OF INFERTILITY

Abstract

4-PHENyL-5 0XO-l,4,5,6,7,8HEXAHYDROQUINOLINE DERIVATIVES AS MEDICAMENTS FOR THE TREATMENT OF INFERTILITY The present invention relates to 2-methyl-4-phenyl-5-oxO"l,4,5,6,7,8-hexahydroquinoline derivatives having the general Formula (I) wherein the substituents are defined as in the description, or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said derivatives, as well as to the use of tiiese 2-methyl-4-phenyi-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives in therapy, more specifically for the treatment of fertility disorders.

Full Text

The actions of the FSH honnone are mediated by a specific plasma membrane receptor that is a member of the large family of G-protein co\q)led receptors. These receptors consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading to the activation of adenylate cyclase. The FSH receptor is a highly specific target in the ovarian follicle growth process and is exclusively expressed in the ovary. Blocking of the receptor or inhibiting the signalling which is nomially induced after FSH-mediated receptor activation will disturb follicle development and thus ovulation and fertility. Low molecular weight FSH antagonists could form the basis for new contraceptives, while low molecular weight FSH agonists can be used for the same clinical purposes as native FSH, i.e. for the treatment of infertility and for ovarian hyperstimulation on behalf of in vitro fertilisation. Low molecular weight FSH mimetics with agonistic properties were disclosed in the International Application WO 2000/08015 (Applied Research Systems ARS Holding N.V.) and m WO 2002/09706 (Affymax Research Institute). Certain tetrahydroquinoline derivatives have recently been disclosed in the International Application WO 2003/004028 (AKZO NOBEL N.V.) as FSH modulating substances, either having agonistic or antagonistic properties. There remains a need for low molecular weight hormone mimetics that selectively activate the FSH receptor. To that aim the present invention provides 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives of general formula I R^ is (l-6C)a]kyl, (2.6C)aIkenyl or (2-6C)alkynyl; R^ is halogen; R is SO2NR R or (l-4C)alkoxy5 optionally substituted with one of more fluorine atoms; XisOorNR'^; R^ is R^-(2-8C)alkyl, R^-(3-8C)alkenyl, R^-(3-8C)alkynyl or R^-(2-4C)alkoxy(2-4C)- alkyl; ZisCNorNOa; R^ and R^ are independently H or (l-4C)alkyl; or R^ together with R^ and the N to which they are bonded form a 3-8 membered saturated ring optionally containing a fttrther heteroatom selected from O and S; R^ is OH, (l-4C)alkoxy, NH2; NR^C(0)R^\ NR^SOaR^^ or C(0)NRV°; R^andR^ are independently H or (l-4C)alkyl; R^^ is (l-4C)alkyl, (l-4C)aIkoxy(l-4C)alkyl, orphenyl(l-4C)alkyl or (2-5C)heteroaryl(l-4C)alkyl, both optionally substituted on the (hetero)aromatic ring with one or more substituents selected from OH, NH2, halogen, NO2, CF3, CN, (1-4C)" alkyl, (l-4C)aIkoxy and (di)(l-4C)aIkylamino; R^^ is (l-4C)alkyl, (2-4C)alkenyl, (2-4C)a]kynyl, (l-4C)a]koxy(l"4C)alkyl, (3-6C)- cycloalkyl, (l-4C)aIk:oxy, (di)(l-4C)a]kylamino, or phenyl or (2-5C)heteroaryl, both optionally substituted on the (hetero)aromatic ring with one or more substituents selected from OH, NH2, halogen, NO2, CF3, CN, (l-4C)alkyl, (l-4C)alkoxy and (di)(l- 4C)alkylamino; or a pharmaceutically acceptable salt thereof The 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives according to the present invention are potent FSH receptor activators and can be used for the same clinical purposes as native FSH since they behave like agonists, with the advantage that they may be prepared synthetically, may display altered stability properties and may be administered differently. Thus, the FSH-receptor agonists of the present invention may be used for the treatment of fertility disorders e.g. controlled ovarian hyperstimulation and IVF procedures. The term (l-4C)alkyl as used in the definition means a branched or unbranched alkyl group having 1-4 carbon atoms, being methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. The term (l-6C)aIkyl means a branched or unbranched alkyl groiq) having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. The term (2-4C)alkyl as used in the definition means a branched or unbranched alkyl group having 2-4 carbon atoms. The term (2-8C)a]kyl as used in the definition means a branched or unbranched alkyl groiq) having 2-8 carbon atoms. The term (3-8C)alkenyl means a branched or imbranched alkenyl group having 3-8 carbon atoms, such as 2-propenyl, 2-butenyl, 3-butenyl, pentenyl, hexenyl and octenyl. The term (2-6C)alkenyl means a branched or unbranched alkenyl group having 2-6 carbon atoms, such as ethenyl, n-propenyl, 2-methyl-2-propenyl, 2-butenyl, 3-butenyl, pentenyl and hexenyl. The term (2-4C)aIkenyl likewise means a branched or unbranched alkenyl group having 2-4 carbon atoms, such as ethenyl, 2-propenyl, 2"methyl-2-propenyl, 2-butenyl and 3-butenyL The term (3-8C)alkynyl means a branched or xmbranched alkynyl group having 3-8 carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl and octynyl. The term (2-6C)alkynyl means an alkynyl group having 2-6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl3 pentynyl and hexynyl. The term (2-4C)a]kynyl likewise means an alkynyl group having 2-4 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl and 3-butynyl, The term (l-4C)alkoxy means an alkoxy group having 1-4 carbon atoms, the alkyl moiety having the same meaning as previously defined. (l-2C)Alkoxy groi5)s are preferred. The tenn (3-6C)cycloa]kyl means a cycloalkyl group having 3-6 carbon atoms, being cyclopropy], cyclobutyl, cyclopentyl and cyclohexyl. The term (3-6C)cycloalkyl(l-4C)aIkyl means a cycloalkylaHcyl group, the cycloalkyl group of which has 3-6 carbon atoms with the same meaning as previoxisly defined and the alkyl group having 1-4 carbon atoms with the same meaning as previously defined. The term (2-5C)heteroaryl means a substituted or unsubstituted aromatic group having 2-5 carbon atoms and at least including one heteroatom selected from N, O and S, like imidazolyl, thiadiazolyl, pyridinyl, thienyl or ftiryl. Preferred heteroaiyl groups are thienyl, fuiyl and pyridinyl. The (2-5C)heteroaiyl group may be attached via a carbon atom or a heteroatom, if feasible. The term (2-5C)heteroaryl(l-4C)aIkyl means a heteroarylalkyl group, the heteroaryl group of which contains 2-5 carbon atoms with the same meaning and preferences as previously defined and the alkyl group contains 1-4 carbon atoms with the same meaning as previously defined. The (2-5C)heteroaTyl group may be substituted on the (hetero)aromatic ring with one or more substituents selected from OH, NHa, halogen, NO2, CF3, CN, (l-4C)a]kyl, (l-4C)aIkoxy and (di)(l-4C)alkylamino. The term phenyl(l-4C)alkyl means a phenyl group attached to an alkyl groiq) having 1-4 carbon atoms as defined previously. The phenyl grovsp may be substituted with one or more substituents selected from OH, NH2, halogen, NO2, CF3, CN, (l-4C)alkyl, (1-4C)a]koxy and (di)(l-4C)a]kylamino. The term (di)(l-4C)aIkylamino as used herein means an amino group, monosubstituted or disubstituted with alkyl groups, each of which contains 1-4 carbon atoms and has the same meaning as previously defined. In the definition of Formula IR5 together with R^ and the N to which they are bonded may form a 3-8 membered ring, optionally containing a ftirther heteroatom selected fjxtm O and S, Examples of such ring are pyrrolidin-1-yl, piperidin-1-yl, azepin-1-yl, moipholin-4-yl and thiomoipholin-4-yL The term halogen means fluorine, chlorine, bromine or iodine; chlorine, bromine or iodine being preferred. The term pharmaceutically acceptable salt represents those salts which are, withm the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are weD known in, the art. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the fi"ee base fimction with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfiiric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. In one aspect the invention concems compounds according to formula I wherein X= O. The invention also relates to compounds of formula I, wherein R^ is (l-6C)alkyL In particular, the invention relates to compounds wherein R^ is (l-4C)alkyl. Most particularly, R^ is n-propyl. Another aspect of the invention are compounds according to formula I wherein R^ is CI, Br or I. In yet another aspect, the invention concems compounds of formula I, wherein Z is CN. The invention also relates to compounds according to general Formula I wherein R^ is SOiNR^R^ Still another aspect of the invention concems compounds wherein one or more of the specific definitions of the groups R^ through R^^ and X and Z as defined here above are combined in the definition of the 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives of formula I. Yet another aspect of the invention concems con5)Oimds according to Formula I which have an EC50 in the binding assay of less than 10"^ M (as described in example 33), Suitable methods for the preparation of the 2-methyl"4-phenyl"5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives of the invention are outlined below. The 154,5,6,7,8-hexahydroqimioliae derivatives I of the present invention can be prepared starting fiom cyclohexane-l,3-diones of general formiila II, enanunes of general formula IE and benzaldehydes of general formula IV, wherein R , R , R , R , X and Z are as previously defined, by the well-documented three con[5)onent Hantzsch-type cyclo-condensation reaction. Related Hantzsch-type cyclo-condensation reactions can be found in: Bioorg. Med, Chem. Lett. 12 (2002) 1481-1484, J. Chem. Soc, Perldn Trans. 1 (2002) 114M156, Synlett (2002) 89-92, Drug Dev. Res. 51 (2000) 233-243, J. Med. Chem. 42 (1999) 1422-1427, ibid. 5266-5271, ibid 41 (1998) 2643-2650, WO 9408966, Arzneun.-Forsch./Drug Res. 45 (1995) 1054-1056, J. Med. Chem. 34 (1991) 2248-2260, ibid. 17 (1974) 956-65, Chem. Rev. 72 (1972), 1-42, The above mentioned reaction is typically conducted at elevated teniperature in a protic solvent like for example acetic acid, (iso)prppanol, ethanol, methanol or mixtures thereof Alternatively, compounds of general formula I-a, wherein R , R , R , R and Z are as previously defined and X = O, can be obtained by standard O-alkylation of con5)ounds of general formula V-a. In a typical experiment, compounds V-a are reacted in a solvent, such as dichloromethane, iy^iV-dimethylfonnamide, dimethyl sulfoxide, ethanol, tetrahydrofiiran, 154-dioxane or toluene with appropriately substituted alkyl halides of fonnula VI (Hal = CI, Br, I), in the presence of a base such as triethylamine, iV;A'-diisopropylethylamine (DiPEA), potassium carbonate, cesium carbonate or sodium hydride, optionally in the presence of a catalytic amount of potassium iodide or tetrabutylammonium iodide, to give 0-alkylated derivatives of formula l-a. Alternatively, 0-alkylated compounds of general formula l-a can be obtained by using art known Mitsunobu reactions with alcohols of formula VII, triphenylphosphine (optionally resin bound) and a dialkyl azodicarboxylate (e.g. diethyl azodicarboxylate) in appropriate solvents such as 1,4-dioxane, tetrahydrofiiran or dichloromethane at elevated or ambient temperature. Likewise, compoxmds of general formula I-b, wherein R\ R^, R^, R^ and Z are as previously defined and X = NR', can be obtained by JST-alkylation of compounds of general formula V-b with compounds of general formula VI, using the same methods as described for the conversion of compounds V-a to I-a, Alternatively, con5)Ounds of general formula I-b can be prepared by reductive amination of appropriately substituted aldehydes of formula VIE, wherein E-A is a substituted aBcyl group (e.g. 3-ethoxy-propionaldehyde, (2-methoxy-ethoxy)-acetaldehyde, 7-hydroxy-pentanal) with compounds V-b and a suitable reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, or zinc/acetic acid. Reductive amination reactions are well known in the art. Additionally, compounds of general fomiula V-b can be converted to the corresponding imines of formula V-c upon reaction with aldehydes Vni by methods well known to those skilled in the art, followed by reduction with a reducing agent such as sodium borohydride to give con5)ounds I-b. Additionally, the 134,5,6,7,8-hexahydroquinoline derivatives I of the present invention can be prepared starting from appropriately functionalised 1,4,5,6,7,8-hexahydroquinoline derivatives of general structure DC, wherein R\ R^, R^, X and Z are as previously defined and Y is a substituted alkyl, alkenyl, alkynyl or alkoxyalkyl group and FG is a fimctional group (e.g. halide, protected hydroxyl, protected amino, azido, cyano, carboxylic acid, ester and the like) which can be eventually be converted to groups defined for R^. For example, compounds of general formula I-c can be obtained by removal of a protective group fix)m compounds of general formula IX-a, wherein PG is a suitable protective groiq), such as f-butyldimethylsilyl (TBDMS), tertrahydropyranyl (THP) or benzoate. Protective groiip manipulations are well known in the art: For example, see: Protective groups in Organic Synthesis^ T.W, Greene and P.G.M. Wuts, John Wiley & sons, Inc., New York, 1999 . Compounds of general formula I-d, wherein R\ R^, R^, X and Z are as previously defined, are prepared firom compounds of general formula IX-b in which LG is a leaving group by treatment with aqueous ammonia in a suitable solvent such as 1,4-dioxane, acetonitrile or tetrahydroforan. Alternatively, con:5)ounds of general formula EX-b can be treated with sodium azide in a suitable solvent such as N^N-dimefhylformamide or tetrahydrofiiran, to yield con:5)ounds of general formula DC-c, which can be reduced by the art-known Staudinger reduction using triphenylphosphine (optionally resin bound) in wet THF, optionally in the presence of aqueous HCl to give conipoimds of general formula I-d. In the specific cases of compounds IX-d wherein LG is bromide in an allylic position, the reaction with sodium azide followed by Staudinger reduction can afford Coirpoiands of general formula I-g and I-h, wherein R\ R^, R^, R^\ X and Z are as previously defined, can be prepared by standard j/V-acylation or ^-sulfonylation of con5)ounds of general fonnula IX-:^ which are synthesized fronai derivatives DC-e and (l-4C)alkylatnines of general formula HiN-Alk. In a typical experiment, compounds IX-f are reacted in a solvent, such as dichlorometiiane, ^iV-dimethylfonnamide, ethanol, tetrahydrofiiran, l54-dioxane5 toluene, l-methyl-pyrrolidin-2-one or pyridine with an appropriately substituted acyl halide (e.g. R^^-C(O)-a), acid anhydride (R^^-C(0)-0-C(0)-R^^) or sulfonyl halide (e.g. R^^-SOz-Cl) in the presence of a base such as triethylamine, ^,iV-diisopropylethylamine (DiPEA) or pyridine, to give ^-acylated or ^-sulfonylated derivatives of formula I-g and I-h, respectively. Alternatively, iV-acylated compounds of general formula I-g can be obtained by reaction of derivatives IX-f with a carboxylic acids of general formula R^^-COOH in the presence of a coupling reagent such as diisqprqpyl carbodiimide (DIG), (3-dimethylaniinopropyl)-efhyl-carbodiimide (EDCI), 0-(benzotriazol-l -yl)-iy;jy;JV^iV^Metramethyluronium tetrafluoroborate (TBTU) or 0-(7-azabenzotriazol-l-yl)-JV;JV,iV',iSr'-tetramethyluronium hexafluorophosphate (HATU) and a tertiary amine base (eg. DiPEA) in a solvent such as -NiJV-dimethylformamide or dichloromethane at ambient or elevated temperature. Carboxylic acid derivatives of general formula IX-h, accessible by saponification of corresponding alkyl esters IX-g, can be condensed with amines of general structure R^R^^^NH using a coupling reagent — as described previously for the preparation of derivatives I-g fi:om compounds IX-f—to give compounds of formula I-i, wherein R R% R% R^ R'", X and Z are as previously defined and Y is an alkyl, alkenyl, alkynyl or alkoxyalkyl group. Alternatively, compounds of general formula EX-h can be converted to the corresponding acid chlorides IX-i by art known methods: Treatment of carboxylic acids of general formula IX-h with thionyl chloride or oxalyl chloride and DMF in a suitable solvent such as dichloromethane or toluene gives the corresponding acid chlorides EX-i. Subsequent reaction with amines of general structure R^^*^NH, optionally in tiie presence of a suitable tertiary amine base, yields compounds of general formula I-i. Din Compounds of general formula I-d can be JV-acylated to give compounds of general Y Is an alkyl, alkenyl, alkynyl or alkoxyalkyl group fonnula I-j, wherein R\ R^, R^, R^\ X and Z are as previously defined. These acylations can be achieved using the same synthetic procedures that were described for the prepaxation of derivatives I-g fiom conpounds DC-f Similar to the iV-sulfonylation reactions of derivatives IX-f to give compounds I-h, conpounds I-d can be sulfonylated to give compounds I-k, wherein R\ R^, R^, R", X and Z are as previously defined. Compounds of general fonnula I-l, wherein R\ R^, R^, R^ and Z are as previously defined, can be reductively alkylated with simple aldehydes or ketones (formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, acetone or butan-2-one)3 using the same methodology as described for the preparation of compoimds I-b fix)m V-b, to give coii5)oimds of general fonnula I-m, wherein R\ R^, R^, R"* and Z are as previously defined. The substituted cyclohexane-l,3-diones of general formula n are commercially available or can be prepared by literature procedures. Relevant examples are found in: J. Med Chem. 43 (2000) 4678-4693, Tetrahedron 56 (2000) 4753-4758, J. Med. Chem. 35 (1992) 3429-3447, ibid, 24 (1981) 1026-1034, Org. Synt Coll. Vol. V (1973) 400, Chem. Ber. 88 (1955) 316-327, Justus Liebig Ann. Chem. 570 (1950) 15-31. The compound of formula m-a is commercially available and compoxmd Ul-b has been documented in literature, see for example: Drug Dev. Res. 51 (2000) 225-232. Benzaldehydes of general formula IV-a, wherein R, R and R are as previously defined and X = O, are readily prepared from benzaldehydes of general formula X-a using the same methods as described for the conversion of con:^unds of formula V-a to I-a. Likewise, compounds of general fomiula IV-b, wherein R^, R^ and R^ are as previously defined and X = N-R^, are prepared firom derivatives X-b using the same methods as described for the conversion of connpounds of formula V-b to derivatives I-b. The 1,4,5,6,7,8-hexahydroquinoline derivatives of general formula V can be prepared by the aforementioned Hantzsch-type cyclocondensation reaction between cyclohexanediones 11, enamines IE and aldehydes X. Compounds of general formula V-d-e in which R^ is Br can also be obtained by ortho- broiniiiatioii of phenols or anilines, which are well known to those sHlled in the art. Thus, compounds of formula V-f-g — synthesized from compounds n and HI and aldehydes XI by a Hantzsch-type cyclocondensation reaction — afford corq)ounds of formula V-d-e upon treatment with bromine in a suitable solvent such as acetic acid, ethanol or dichloromethane or mixtures thereof, optionally in the presence of sodium acetate. Alternatively, JV-bromosuccinimide in i^,^-dimethylformamide or acetonitrile can be used to achieve this conversion. For example, see: J. Chem. Soc. Perkin Trans.2 6 (2000) 1113-1118, J. Org. Chem. 44 (1979), 4733-4735. Additionally, conpounds of general formula V-j, wherein R is an amino sulfonyl group and X = O, can be obtained by reacting amines of general formula R^R^NH with corcpoxmds of general formula V-i, optionally in the presence of a tertiary amine base such as triethylamine or DiPEA. Compounds V-i are obtained by chlorosulfonylation of compounds of general formula V-h. For examples in the literature concerning chlorosulfonylation of phenols, see: Tetrahedron 53 (1997) 4145-4158, Bioorg. Med. Chem. Lett 13 (2003) 379-382. The compounds of general formulas VI, Vn and Vin are commercially available, documented in literature or readily prepared by those skilled in the art. The 1,4,5,6,7,8-hexahydroqumolme derivatives of general formula DC can be prepared by the aforementioned Hantzsch-type cyclocondensation reaction between cyclohexanediones n, enamines in and aldehydes XE. Alternatively, alkylation of derivatives of general formula V with reagents Xni-XV — which are documented in literature, commercially available or readily prepared — can also provide derivatives IX by the same methods used for the preparation of compounds I-a-b from V-a-b, as described previously. Benzaldehydes of general formula X and XI are commercially available or can be prepared according to hterature procedures: J. Chem. Soc, Perkia Trans, 2 (2000) 1119-1124, J. Chem. Soc, Chem. Commun, 4 (1993) 419-420, Synlh. Commun. 20 (1990) 2659-2666, Chem. Pharm, Bull. 34 (1986) 121-129, Indian J. Chem. Sect. B 20 (1981) 1010-1013, Monatsh. Chem. 106 (1975) 1191-1201, DE 1070162, J. Org. Chem. 23 (1958) 120, Tetrahedron Lett. 25 (1984), 2901-2904, J. Org. Chem. 25 (1960), 2053-2055, J. Chem, Soc., Perkm Trans. 2 (1992), 2235-2242. Additionally, benzaldehydes of general formula X-c wherein R is bromide and X is N-H can be obtained by bromination of con:5>ounds of general formula XVI using the same procedures described for the conversion of compounds of general formula V-g to V-e. Con5)Ounds of general formula XVI can be obtained by the reduction of the nitro group in compounds of general formula XVn to the corresponding amino group. Typically, conipounds XVn are treated with zinc and acetic acid in a suitable solvent such as THF or dioxane at temperatures between 0 °C and reflux temperature. Alternative methods include treatment with iron, SnCU, or hydrogen in the presence of a transition metal catalyst such paUadiimi or platinum on charcoal, using methods and reagents well known to those skilled in the art. Benzaldehydes of general foimula X-d wherein R^ is as previously defined R^ is an amdnosulfonyl group and X is O can be obtained by chlorosulfonylation of con5)ounds of general formula XI-c followed by reaction with amines of general formula R^R^NH using the same procedures described for the synthesis of compounds of general formula V-j from V-h via V-i. The hydroxyl group of compounds X-d can be triflated by art known methods to give compounds XVIII, which can undergo nucleophilic aromatic substitution with ammonia to yield benzaldehydes X-e. For related aromatic substitution reactions see: J. Med Chem. 6 (1963) 272-275, Indian J. Chem. Sect. B 18 (1979), 88-90. Additionally, derivatives X-d can be converted to conpounds of formula XEX, wherein PG is H or an optional protective group such as 4-nitrobenzyl or 2,5-dimethoxyben2yl, followed by art known Smiles rearrangement to give products of general formula X-e, after deprotection (if necessary). For examples of this type of rearrangement reactions, see: J. Org. Chem. 48 (1983) 5140-5143, Tetrahedron Lett. 30 (1989) 931-934, Tetrahedron 53 (1997) 11919-11928, Synth. Commun. 33 (2003) 2725-2736. Benzaldehydes of general formula XH are prepared from the aforementioned aldehydes of formula X by alkylation with compounds of general formula XHI or XTV, in analogy with the preparation of aldehydes IV-a-b from X-a-b. Alternatively, benzaldehydes of I formula XH, wherein X = NH, can be prepared by the same methods described for the conversion of derivatives X-d to X-e, using appropriately substituted amines of general formula H2N-Y-FG in the reaction sequence. The compounds of the present mvention possess at least two chiral carbon atoms and may therefore be obtained as pure enantiomers, or as a mixture of enantiomers, or as a mixture of diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. For separation of diastereomers, straight phase or reversed phase colxnnns may be used. The compounds of the invention may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an qypropriate organic solvent. The compounds of this invention include the hydrates or solvates of the coii5)Oimds listed. The 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives of the invention were found to be agonists of the FSH receptor. Methods to determine receptor binding, as well as in vitro and in vivo assays to determine biological activity, of gonadotropins are well known. In general, e5q)ressed receptor is contacted with the compound to be tested and binding or stimulation or inhibition of a ftmctional response is measured. To measure a functional response, isolated DNA encoding the FSH receptor gene, preferably the human receptor, is expressed in suitable host cells. Such a cell might be the Chinese Hamster Ovary cell, but other cells are also suitable. Preferably the cells are of mammalian origin (Jia et al, MoLEndocrin., 5:759-776,1991). Methods to construct recombinant FSH expressing cell lines are well known in the art (Sambrook et al.. Molecular Cloning; a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Eqxression of receptor is attained by expression of the DNA encoding the desired protein. Techniques for site directed noiutagenesis, ligation of additional sequences, PCR, and construction of suitable expression systems are all, by now, well known in the art. Portions, or all, of the DNA encoding the desired protein can be constructed synthetically using standard soHd phase techniques, preferably to include restriction sites for ease of ligation. Suitable control elements for transcription and translation of the included coding sequence can be provided to the DNA coding sequences. As is well known, expression systems are now available which are compatible with a wide variety of hosts, including prokaryotic hosts such as bacteria and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, avian cells and the like. Cells e3q)ressing the receptor are then contacted with the test compound to observe binding, or stimulation or inhibition of a functional response. Alternatively, isolated cell membranes containing the e3q)ressed receptor may be used to measure binding of compound. For measurement of binding, radioactive or fluorescent compounds may be used. As reference compound human recombinant FSH can be used. In the alternative also competition binding assays may be perfomied. Another assay involves screening for FSH receptor agonist compounds by determining stimulation of recqrtor mediated cAMP accumulation. Thus, such a method involves expression of the receptor on the cell surface of a host cell and exposing the cell to the test con5)ound. The amount of cAMP is then measured. The level of cAMP will be increased, by tiie stimulating effect of the test compound upon binding to the receptor. In addition to direct measurement of e.g. cAMP levels in the exposed cell, cells lines can be used which in addition to transfection with receptor encoding DNA are also transfected with a second DNA encoding a reporter gene the expression of which responds to the level of cAMP. Such reporter genes might be cAMP inducible or might be constmcted in such a way that they are connected to novel cAMP responsive elements. In general, reporter gene expression might be controlled by any response element reacting to changing levels of cAMP. Suitable reporter genes are e.g. LacZ, alkaline phosphatase, firefly luciferase and green fluorescence protein. The principles of such transactivation assays are well known in the art and are described e.g. in Stratowa, C, Hmunler, A. and CzemiloMy, A., (1995) Curr. Opin. BiotechnoL 6:574. The present invention also relates to a pharmaceutical composition comprising a 2-methyl-4"phenyl-5-oxo-l,455,637,8-hexahydroquinoline derivative or pharmaceutically acceptable salts thereof having the general formula I in admixture with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents. The auxiliaries must be "acceptable" in the sense of being conipatible with the other ingredients of the composition and not deleterioxis to the recipients thereof. Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local, or rectal administration, and the like, all in unit dosage forms for administration. For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like. For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or mufti-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use. Mixed with such pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference, Gennaro, AJL et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & WiUdns, 2000, see especially Part 5: Pharmaceutical Manufecturing), the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray. For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active conipounds can be used. Suitable carriers with which the active agent of the invention can be administered as soUd compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amouBts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. The invention further includes a pharmaceutical coniposition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described The exact dose and regimen of administration of the active ingredient, or a pharmaceutical conposition thereof, may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered. In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, a suitable dosage for humans may be 0.05-25 mg per kg body weight. The desired dose may be presented as one dose or as multiple subdoses administered at appropriate intervals throughout the day, or, in case of female recipients, as doses to be administered at appropriate daily intervals throughout the menstrual cycle. The dosage as weU as the regimen of administration may differ between a female and a male recipient Thus, the con^pounds according to the invention can be used in therapy. A further aspect of the invention resides in the use of a 2-methyl-4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative having the general formula I for the manufacture of a medicament to be used fcff the treatment of disorders responsive to FSH receptor mediated pathways, preferably for the treatment of fertility disorders. Thus, patients in need thereof can be administered with suitable amounts of the conpounds according to the invention. In yet another aspect the invention resides in the use of a 2-methyl-4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative having the general formula I for the manufecture of a medicament to be used for the treatment of infertility. The invention is illustrated by the following examples. General: The following abbreviations are used in the examples: DMA = JVi-A'-dimethylaniline, DiPEA = JST^-diisopropylethylamine, TFA = trifluoroacetic acid, HATU = 0-(7-azabenzotriazole-l-yl)-jy;JV;iV",^'-tetramethyluronium hexafluorophosphate, DMF = jy;iV-dimefhylformamide, THF = tetrahydroftiran, EtOAc = ethyl acetate. Unless stated otherwise, all final products of the examples below were lyophilized from water/1,4-dioxane mixtures, water/^ert-butanol or water/acetonitrile mixtures. If the compound was prepared as TFA salt, TFA was added in an appropriate amount to the solvent mixture before lyophilization. The names of the final products described in the examples were generated using the Beilstein Autonom program (version: 2.02.304). The following analytical HPLC methods were used for determination of retention times: Method 1: Column: 5 pm Luna C-18(2) 150x4.6 mm; flow: 1 ml/min; detection: 210 nm; column ten:5)erature: 40 °C; solvent A: CH3CN/H2O = 1/9 (v/v); solvent B: CH3CN; solvent C: 0.1 M aqueous trifluoroacetic acid; gradient: solvent A/B/C = 75/20/5 to 15/80/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at A/B/C == 15/80/5 (v/v/v). Method 2: Identical to method 1, except for the gradient used: Gradient: solvent A/B/C = 95/0/5 to 15/80/5 (v/v/v) in 20.00 min, then constant for an additional 10.00 min at A/B/C =15/80/5 (v/v/v). The diastereomeric ratio (Diast. ratio) was determined if baseline separation of the individual diastereomers was observed using the appropriate analytical HPLC method. Alternatively, the diastereomeric ratio was determined by ^H NMR analysis when distinct signals corresponding to the diastereomers were identified. The reported diastereomeric ratios relate to the configurations of C-4 and C-7 of the 1,4,5,6,7,8-hexahydroquinoline core. The following methods were used for preparative HPLC-purifications: Method A: Column = Luna C-18. Gradient: 0.1% trifluoroacetic acid in H2O/CH3CN (9/1, v/v)/CH3CN = 80/20 to 0/100 (v/v) in 30-45 min, depending on the ease of separation. Detection: 210 nm. Method B: Colunm = Luna C-18. Gradient: H2O/CH3CN (9/1, v/vyUHsUJN = buuv to 0/100 (v/v) in 30-45 min, depending on the ease of separation. Detection: 210 nm. Example 1 Furan-2-carboxvlic acid l4-r2-bromo-4-f3-cvano-2-methvl-5-oxo-7-propvl-l,4.5,6,7.8-hexahvdro-qiunolin-4-vlV6-ethoxv-T)henoxv1-but-2-envl)-amide (a). 4-f3"Bromo-5-ethoxv-4-hvdroxv-phenvlV2-inethvl-5-oxo-7-propvl-l,4,5,6.7,8-hexahvdro-qidnoline-3 -cafbonitrile A mixture of 3-bromo-5-ethoxy-4-hydroxy-benzaldehyde (6 g), 3-aniinocrotonitrile (2.01 g) and 5-propylcyclohexane-l,3-dione (3.8 g) in ethanol (20 ml) was stirred at 80^C for 4 h_ The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel in heptane/EtOAc =1/1 (v/v) as eluent. Yield: 6.3 g, MS-ESI: [M+H]^ = 445/447 (b). 4-r3-Bromo-4-r4-brQmo-but-2-envloxvV5-ethoxv-phenvn-2-methvl-5-oxo-7- propvl-14,5,6,7,8-hexahvdro-quinoline-3-caibonitrile A mixture of 4-(3-bromo-5-ethoxy-4-hydroxy-phenyl)-2-meihyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (3.04 g), 1,4-dibromobutene (11.68 g) and potassium carbonate (1,887 g) in dioxane (100 ml) was stirred at 80*'C for 5 h. The mixture was poured into water and extracted with dichloromethane. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was dissolved in acetonitrile, washed with petroleimi ether and heptane to remove most of the excess of dibromobutene. The acetonitrile layer was concentrated in vacuo and the residue recrystalHzed fix)m dichloromethane and heptane. Yield: 3.02 g. MS-ESI: [M+H]^ = 579,2 (c). Mixture of 4-r4-f4-Azido-but-2-envloxv)-3-bromo-5-ethQxv-phenvl1-2-methvl-5-oxo-7-prot)vl-14,5,6,7,8-hexahvdro-quinoline-3-carbonitrile and 4-r4-r2-Azido-but-3-envloxvV3-bromo-5-ethoxv-phenvn-2-methvl-5-oxo-7-propvl-l,4.5,6,7,8-hexahvdro-quinoline-3-carbonitrile A mixture of the compound obtained in example lb (1.0 g) and sodium azide (0.34 g) in DMF (50 ml) was stirred for 2 h. The mixture was poured into water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo. Yield: 914 mg: mixture of 2 regio-isomers. MS-ESI: [M+H]^ = 540.2/542.2 (d). Mixture of 4-[4-(4-Amino-but-2-envloxvV3-bromo-5-ethoxv-phenvn-2-methvl-5-oxo-7-propvl-l,4.5,6,7,8-hexahvdro-quinoline-3-carbonitrile and 4-r4-(7.-Amino-but-3- envloxvV3-bromO"5-ethoxv-phenvl1-2-methvl-5-oxo-7-TOOpvl"L4,5,6J,8-hexahvdro-quinoline-3 -carbotdtrile To a solution of the crude mixture of regioisomeric compounds obtained in example Ic (0.914 g) in THF/dichloromethane (2/1 (v/v), 18 ml) was added water (2 ml) and resin bound triphenylphosphine (1.13 g, 3.0 mmol/g loading). The mixture was stirred at 40°C for 8 h. The resin was filtered off and washed with dichloromethane and methanol. The combined organic layers were concentrated in vacuo. Yield: 0.8 g. mixture of 2 regio-isomers. MS-ESI: [M+H]^ = 514.2/516.2 (e). Furan-2-'Carboxylic acid {4-['2"bromo-4-(3-cvano-2-methvl-S-oxo-7-propvl-1,4,5.,6J,8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxv1-but-2-envU -amide A solution of the products obtained in example Id (88.8 mg), DiPEA (151 \x\) and 2-furoyl chloride (34 |il) in dichloromethane (4 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with sat. aq. NaHCOs. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 46.4 mg. MS-ESI: [M+H]'^ = 608.2/610.2; HPLC: Rt = 19,45 min. (diast.l ) Rt = 19.73 min. (diast, 2) (method 1). Diast. ratio: 4:1 Example 2 JV-{4-r2-BronK)-4-f3-cvano-2-methvl-5-oxo-7-propvl"l,4,5,6,7.8-hexahvdro*quinolin-4-vlV6-ethoxv-T)henoxvl-but-2-envU-isobutvramide A solution of the products described in example Id (200 mg), DiPEA (339 ^1) and isobutyryl chloride (81 ^il) in dichloromethane (4 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with sat. aq. NaHCOs. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 82 mg. MS-ESI: [M+H]^ = 584,2/586.2; HPLC: Rt = 19.41 min. (method 1). Diast. ratio: 4:1 Example 3 Cvclopropanecarboxvlic acid l4-r2-bromo-4-(3-cvano-2-methvl-5-oxo-7-propvl-l,4,5,6.7,8-hexahvdro-quinoliD-4-vlV6-etfaoxv-phenoxv1-but-2-envU-amide The title compound was obtained from the mixture of compounds described in example Id (88.8 mg), DiPEA (151 M.1) and cyclopropanecarbonyl chloride (31 \i\) according to the procedure described in example 2, and purified by preparative HPLC (Method B). The regioisomer (example 4) could also be isolated. Yield: 39 mg. MS-ESI: [MH-H]"^ = 582,2/584.2; HPLC: Rt == 18.75 min. (diast, 1) Rt = 18.99 min. (diast. 2) (method 1). Diast. ratio: 4:1 Example 4 Cvclopropanecarboxvlic acid n-r2-broiao-4-f3-cvano-2-ineihvl-5"Oxo-7-propvl-1.4,5,6 J,8-hexahvdro-QumoliD-4-vlV6-etfaoxv-T)henoxvme1favl1-aUvU -amide See example 3. The regioisomer of example 3 was also isolated by preparative HPLC (Method B). Yield: 18 mg. MS-ESI: [M+H]^ = 582.2/584.2; HPLC: Rt = 20.05 min. (diast 1) Rt = 20.37 min, (diast. 2) (method 1). Diast ratio: 4:1 Example 5 JV^(4-r2-BromO"4-f3-cvano-2-methvl-5-oxo-7-propvl-1.4,5,6,7,8-hexahvdro-quinolin-4-vlV6-ethoxv-pheDoxv]-biit-2-eDyl}-2-methoxy-acetamide The title compound was obtained from the mixture of conipounds described in example Id (88,8 mg), DiPEA (151 ^il) and methoxyacetyl chloride (31 |il) according to the procedure described in example 2 and purified by preparative HPLC (Method B). Yield: 44.7 mg. MS-ESI: [M+H]^ = 586,4/588.4; HPLC: R* = 17.26 min. (diast, 1) Rt = 17.56 min. (diast 2) (method 1). Diast. ratio: 4:1 Example 6 l4-r2-Bromo-4-f3-cvano-2-methvl-5-oxo-7-T)ropvl-l,4,5,6,7.8-hexahvdio-quinolin-4-vlV6-ethoxv-phenoxv1-but-2"envll-caTbamic acid ethyl ester The title compound was obtained from the mixture of compounds described in example Id (88.8 mg), DiPEA (151 jil) and ethyl chlorofbrmate (33 \x\) according to the procedure described in example 2 and purified by preparative HPLC (Method B). The regioisomer (example 7) could also be isolated. Yield: 45.4 mg. MS-ESI: [M+H]^ = 586.2/588.2. HPLC: Rt = 21.21 min. (diast. 1) Rt = 21.52 min, (diast. 2) (method 1), Diast. ratio: 4:1 Example 7 11 -r2-Bromo-4-(3-cvano-2-methvl-5"Oxo-7-pTopvl-1,4,5..6,7,8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxvmethvl1-allvll-carbainic acid ethvl ester See exan5)le 6. The regioisomer of example 6 was isolated by preparative HPLC (Method B). Yield: 20 mg. MS-ESI: [M+H]^ = 586.2/588.2; HPLC: Rt = 22.96 min, (diast, 1) Rt = 23.33 min, (diast. 2) (method 1). Diast. ratio: 4:1 Example 8 iV-n-r2-Bromo-4-r3-cvano-2-methvl-5-oxo-7-T)ropvl-1.4,5,6.7.8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxvmethvl1-allvll -benzamide The title compound was obtained from the mixture of conrpounds described in example Id (88.8 mg), DiPEA (151 \i\) and benzoyl chloride (40 |al) according to the procedure described in exanrple 2 and purified by preparative HPLC (Method B). Yield: 14.5 mg. MS-ESI: [M+H]^ = 618.4/620.4; HPLC: Rt = 22.97 min. (diast. 1) Rt = 23.27 min, (diast. 2) (method 1). Diast. ratio: 3:1 Example 9 JV-n-r2-Bromo-4-f3-cvano-2-methvl-5"Oxo-7-propvl-lA5,6J,8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxvmethvn-allvU -acetamide The title compound was from the mixture of confounds described in example Id (88,8 mg), DiPEA (151 ^il) and acetyl chloride (24 ^1) according to the procedure described in example 2 and purified by preparative HPLC (Method B). Yield: 16.7 mg, MS-ESI: [M+m^ = 556.2/568.2; HPLC: Rt = 17.13 min. (diast, 1) Rt = 17,44 min, (diast 2) (method 1), Diast ratio: 3:1 Example 10 4-r2-Bromo-4-f 3-cvano-2-methvl-5-oxo-7-propvl-1,4,5,6J,8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxv1-but-2-enoic acid f2-methoxv-ethvlVamide (a), 4-r2-Bromo-4-f3-cvano-2-methvl-5-oxo-7-pTopvl-L4,5,6,7,8-hexahvdro-qumolin-4-vl)-6-ethoxv-phenoxvl-but-2-enoic acid methyl ester A mixture of the compound described in example la (1.48 g), potassium carbonate (0,919 g) and methyl 4-bromocrotonate (4.759 g) in dioxane (60 ml) was stirred at 80°C under a nitrogen atmosphere for 17 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (firom 1/0 to 0/1) as eluent. Yield: 1.2 g. MS-ESI: pvl+H]^ = 543,2/545.2 (b), 4-r2-Bromo-4-f3-cvano-2-methvl-5-oxo-7-propvl-l,4.5,6,7,8-hexahvdro-quinolin-4-vl)-6-ethoxv-phenoxv1-but-2-enoic acid A solution of 4-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-l54,5,6,7,8-hexahydro-quinolin-4-yl)-6-ethoxy-phenoxy]-but-2-enoic acid methyl ester (1,2 g) in dioxane (100 ml) and 2N sodium hydroxide (2.2 ml) was stirred for 5 days. The mixture was poured into water and the pH was adjusted to 2 using 4N aqueous HCL The resulting mixture was extracted with EtOAc. The organic layer was dried (MgS04)s filtered and concentrated in vacuo. Yield: 1.5 g. MS-ESI: [M+H]"' = 529.2/531.2 (c). 4-r2"BTomo-4-r3-cvano-2-methvl-5-oxo-7-Tjrot?vl-l,4,5.6J,8-hexahvdro-qiunolm^ 4-vlV6-ethoxv-phenoxv1-biit-2-eDoic acid f2-inethoxv-ethvl)-amide A mixture of 4-[2-bromo-4-(3-cyano-2-meihyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-qumolin-4-yl)-6-ethoxy-phenoxy]-but-2-enoic acid (0.1 g), HATU (0,108 g), DiPEA (165 ^il) and 2-methoxyethylamine (25 ^l) in dichloromethane was stirred for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 65.5 mg, MS-ESI: [M+H]^ = 586.4/588.4; HPLC: Rt = 16.39 min. (method 1), Diast. ratio: 5:1 Example 11 4-[2-Bromo-4-(3-cvano-2-methvl-5-oxo-7"propvl-L4,5,6,7,8-hexahydro-quinolin-4-vlV6-efcoxy-i>henoxvl-but-2-enoic acid isopropvl-methvl-amide The title compoimd was obtained from the coir{)ound described in exan5)le 10b (100 mg), DiPEA (165 \i[), HATU (108 mg) and isopropyl-methyl-amine (29 |il) according to the procedure described in exaiaplG 10c. Yield: 65 mg. MS-ESI: [M+H]^ = 584.4/586.4; HPLC: Rt = 19.27 min. (diast. 1) Rt = 19.54 min. (diast. 2) (method 1). Diast ratio: 5:1 Example 12 4-r2-Bromo-4-(3-cvano-2-methvl-5-oxo-7-propvl-L4,5,6J,8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxv1-but-2-enoic acid fpvridin-2-vhnethvlVamide The title compound was obtained fix)m the compoimd described in exanqple 10b (100 mg), DiPEA (165 ^l), HATU (108 mg) and 2-picolylamine (29 ^il) according to the procedure described in example 10c. The residue was purified by preparative HPLC (Method A). Yield: 63 mg (as TFA salt). MS-ESI: [M+H]^ = 619.4/621,4; HPLC: Rt = 9.92 min. (method 1). Diast. ratio: 5:1 Example 13 JV-l4-r2-Bromo-4-r3-cvano-2-methvl-5-oxo-7-propvl-l,4,5,6J,8--hexahvdro-qiiinolin-4-vl)'6-ethoxv-phenoxv1 -butvll -isobutvramide (aV 4-r3-Bromo-4-r4-bromo-butoxvV5-ethoxv-phenvlV2-methvl-5-oxo-7-propvl-l,4.5-,6J,8-hexahydrn-qninoline-3-carbomtrile A mixture of the compound described in example la (2.23 g), l54-dibromobutane (8.65 g) and potassium carbonate (3 g) in DMF (25 ml) was stirred at 60°C for 2 h. The mixture was cooled to room ten5)erature and washed with heptane to remove most of the excess of dibromobutane. The DMF layer was diluted with water and the resulting mixture extracted with EtOAc. The otganic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 4/1 to 1/2) as eluent. Yield: 2.23 g. MS-ESI: [M+H]^ = 581.1 (b). 4-r4-f4-Amino-butoxvV3-broncto-5--ethoxv-phenvl1-2"methvl-5--oxO"7--propvl--l,4," 5,6.7,8-hexahvdro-quinQline-3-carbonitrile To a solution of the product of step a (2 g) in dioxane (60 ml) was added cone. aq. NH4OH (40 ml). The mixture was stirred in an autoclave at 80^C for 17 h, and then concentrated in vacuo. Yield: 2.21 g HBr salt). MS-ESI; [M+HJ^ = 516.4/518,4 fc). JV^M-f2"BromO'4-r3-cyano-2-metfavl-5-oxo-7-propyl-1.4,5,6,7,8-hexahvdro-'quino-lin-4-ylV6-ethoxv-phenoxv1-butvl}-isobutvramide A mixture of the product of step b (117 mg), triethylamine (81 ^l) and isobutyrylchloride (24 ^1) in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 1/0 to 0/1) as eluent Yield: 69 mg. MS-ESI: [M-fH]"' - 610.4/612.4; HPLC: Rt = 19.45 min. (method 1), Diast. ratio: 5:1 Example 14 Etbanesulfonic acid (4-r2-bromo-4-f3-cvano-2-methvl-5-oxo-7-Tyropvl-l,4,5,6,7,8-hexahvdro-quinolin-4-vlV6"ethoxv-phenoxv'|-butvU-amide The title compound was obtained from the compound described in exan5>le 13b (150 mg), triethylamine (104 \il) and ethanesulfonyl chloride (28 \xl) according to the procedure described in example 13c. Yield: 99 mg. MS-ESI: [M+H]^ = 608.2/610.2; HPLC: Rt= 19.32 min. (diast 1) Rt= 19.57 min. (diast. 2) (method 1). Diast. ratio: 4:1 Example 15 Cvclopropanecarboxvlic acid f3-F2-bromo-4-(3-cvanO"2-methvl-5-oxQ-7-prQpvl-1.4.S,6,7,8"hexahydro-quinolin-4-vlV6-ethoxv-phenoxy1-propvU -amide (a). 4-r3"BromO'4-f3-bromo-propoxvV5-ethoxV"T)henvn-2-roethvl-5-oxO"7-propvl-1.4,5,6 J,8-hexahvdrO'quinoIine-3-carbomtrile The title compound was obtained from the compound described in example la (2 g), 1,3-dibromopropane (3.67 ml) and potassium carbonate (2.49 g) according to the procedure described in example 13a. Yield: 2.47 g. MS-ESI: [M+H]"^ = 567.2 (b), 4-r4-r3-Ammo-propoxvV3-brotrK)-5"ethoxv-phenvl1-2-methvl-5-oxo-7-TO 1,4.5,6 J,8-hexahvdro-Qiuiioline-3-cafbonitrile The title compound was obtained from the product of step a (2,37 g) and cone. aq. NH4OH (40 ml) accordiog to the procedure described in example 13b. Yield: 2.45 g (HBr salt). MS-ESI: [M+H]' = 502.3/504.3 (c). Cvclopropanecarboxvhc acid l3-r2-bromo-4-(3-cvano-2-methvl-5-oxo-7-propvl-1,4,5,6 J,8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxv1-propvU -amide A mixture of the product of step b (165 mg), triethylamine (118 ]x\) and cyclopropanecarbonyl chloride (31 ^il) in dichloromethane (2 ml) was stirred for 17 h. The reaction mixture was diluted with EtOAc and washed with 0.5N aqueous HCl. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was chiomatographed on silicagel in heptane/EtOAc (from 3/1 to 0/1) as eluent Yield: 111.2 mg, MS-ESI: [M+H]^ = 570.4/572.4; HPLC: Rt = 18.23 min. (method 1). Diast. ratio: 5:1 Example 16 JV-l5-r2-Bromo-4-f3"Cvano-2-methvl-5-oxo-7-pTopvl-1.4,5,6,7,8-hexahvdrD-quinolin-4"vl)-6-ethoxv-phenoxv1-pentvU -acetamide (a). 4-r3-Bromo-4-f5-chloro-pentvloxvV5-ethoxv-phenvl1-2-methvl-5-oxo-7-propvl-1.4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile The title compound was obtained from the compound described in example la (2 g), 1,5-dichloropentane (4.76 ml) and potassium carbonate (2.49 g) according to the procedure described in example 13a. Yield: 2.1 g. MS-ESI: [M+H]"^ = 549.2/551.2 (b). 4-r4-f5-AminO"pentvloxvV3-bromo-5-ethoxv-phenvll-2-methvl-5-oxo-7-propvl-l,4,5,6.7,8-hexahvdro-quinoline-3-carbonitrile The title compound was obtained from the product of step a (2.0 g) and cone. aq. NH4OH (40 ml) according to the procedure described in example 13b, Yield: 2.1 g (HCl salt). MS-ESI: [M+H]' = 530.3/532.3 (c). N- (5-r2-Bromo-4-r3-cvano-2-methvl-5-oxo-7-propvl-l ,4,5,6,7,8-hexahvdro- quinolin-4"Vl)-6-ethoxv-phenoxv1-pentvU-acetamide I The title compound was obtained from the product of step b (147.5 mg), triethylamine (108 \i[) and acetyl chloride (22 ^1) according to the procedure described in example 15c. Yield: 53.6 mg. MS-ESI: [M+H]^ = 572.4/574.4; HPLC: Rt = 17.44 min. (diast. 1) Rt = 17.75 min. (diast. 2) (method 1). Diast. ratio: 5:1 Example 17 JV-(5-r2-Bromo-4-f3-cvano-2-methvl-5-oxo-7-propvl-L4,5,6J,8-hexahvdto-qumo]^ 4-vlV6-eflioxV"phenoxv1-T>entvll-2-methoxv-acetaniide The title compound was obtained from the con:5)ound described in example 16b (147.5 mg), triethylamine (108 ^il) and methoxyacetyl chloride (28 \xl) according to the procedure described in example 15c, Yield: 88.5 mg. MS-ESI: [M+H]^ = 602.4/604.4; HPLC: Rt= 18,87 min. (diast 1) Rt = 19,20 min, (diast 2) (method 1), Diast ratio: 5:1 Example 18 Furan-2-carboxylic acid l4»['2-bromo-4-r3-cvano-2-methyl-5-oxo-7-propvl-l,4.5,6,7,8-hexahvdrO"quinolin-4-vlV6-ethoxv-phenoxv]-butvll"amide The title compound was obtained from the con:5)ound described in exan:5)le 13b (117 mg), triethylamine (81 ^1) and 2-ftiroyl chloride (23 |il) according to the procedure described in example 13c, Yield: 85.7 mg, MS-ESI: [M+H]^ - 610.4/612.4; HPLC: Rt = 19,66 min. (method 1). Diast. ratio: 5:1 Example 19 JV-(2-[2-Bromo-4"f3-cvano-2-methvl-5-oxo-7-T)ropvl-l,4,5,6,7,8-hexahvdro-quinolin-4-vlV6-ethoxv-phenoxv1-ethvU-methanesulfonamide (a). 4-r3-Bromo-5-ethoxv-4-('2-hvdroxv-ethoxv)-phenvll-2-meihvl-5-oxO"7-propvl-l,4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile A mixture of the compound described in example la (4 g), potassium carbonate (3.73 g) and 2-bromoethanol (1.274 ml) in DMF (30 ml) was stirred at 60°C for 3 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 1/1 to 0/1) as eluent. Yield: 3.1 g. MS-ESI: [M+H]' = 489,4/491.4 (b). Methanesulfonic acid 2-r2-bromo-4-(3-cvano-2-methvl-5-oxo-7-propvl-1,4,5,6,7,8-hexahvdro-quinolin-4-vn-6-ethoxv-phenoxvl-ethvl ester A mixture of the product of step a (2.9 g), triethylamine (2.46 ml) and methanesulfonyl chloride (550 |il) in dichloromethane (50 ml) was stirred for 17 h. The mixture was extracted with 0.5N aqueous HCl. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was chromatographed on silicagel in dichloromethane/methanol from (1/0 to 95/5) as eluent. Yield: 3.38 g. MS-ESI: [M+m^ = 567.2/569.2 (c). 444-f2-Amino-ethoxvV3-bromo-5-el3ioxv-phenvl1-2-methvl-5-oxo-7-propvl- 1.4,5,6,7,8-hexahvdro-qiupolme-3-carboDil3ile A mixture of the product of step b (3.38 g) and cone. aq. NH4OH (60 ml) in dioxane (90 ml) was stirred at 80°C in an autoclave for 17 h. The mixture was concentrated in vacuo. Yield: 3.82 g (MeSOsH salt). MS-ESI: [M+H]' = 488.2/490.2 (d), N- l2-r2-Bromo-4-r3-cvano-2-methvl-5-oxo-7-propvl-l .4.5,6.7.8-hexahvdro- quinolin-4-vlV6-ethoxv-phenoxv1 -etbvl \ -methanesulfonamide A mixture of the product of step c (130.7 mg), triethylamine (93 ^il) and methanesulfonyl chloride 21 pi in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl, The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 57.1 mg. MS-ESI: [M+m"" = 566.0/568.0; HPIX: R^ = 12.49 min. (method 1). Diast. ratio: 4:1 Example 20 ProT)ane-2-sulfonic acid l6-r2-hromo-4-f3-cvano-2-methvl-5-oxo-7-proT)vl-l,4,S,6,7,8-hexahvdro-quinolin-4-vl)-6-ethoxv-phenoxvl -hexvU -amide ra).4-r3-Bromo-4-r6-bromo-hexvloxvV5-ethoxv-phenvn-2-methvl-5-oxo-7-propvl-l,4,5,6,7,8-hexahvdro-quinoline-3-carbaDitrile The title compound was obtained fi-om the conpound described in example la (1 g), 1,6-dibromohexane (2.78 ml) and potassium carbonate (1.24 g) according to the procedure described in example 13a. Yield: 0.93 g. MS-ESI: [M+H]^ = 607.4/609.4 (b), 4-r4-(6-AmiTin-heyy1oxv)-3-bromo-5-ethoxv-phenvll-2-methvl-5-oxo-7-propvl-L4,5,6J,8-hexahvdro-quinoline-3-carbonitrile The title compound was obtained firom the product of step a (0.93 g) and cone. aq. NH4OH (20 ml) according to the procedure described in example 13b. Yield: 1.08 g (HBr salt). MS-ESI: [M+H]" = 544.4/546.4 (c). Propane-2-sulfonic acid l6-r2-bromo-4-f3-cvano-2-methvl-5-oxo-7-propvl-1,4,5,6 J,8-hexahvdro-quinolin-4-vl)-6-ethoxv-phenoxvl-hexvU -amide The title compound was obtained from the con5)ound described in step b (134 mg), triethylamine (89 nl) and isopropylsulfonyl chloride (29 ^1) according to the procedure described in example 13c. Yield: 22.5 mg. MS-ESI: [M+H]^ - 650.4/652.4; HPLC: Rt = 20.20 min. (diast 1) Rt = 20.55 min, (diast. 2) (method 1). Diast. ratio: 5:1 Example 21 4-l4-r2-f2-Ammo-etfaoxvVethoxv1-3-bTomo-5-e1hoxv-phetivl)-2-meth prot>vl-1.4,S,6J,8-hexahvdro-qiHnoliDe-3-carboiiitrile (a). 4- (3-Bromo-5-ethoxv-4-r2-(2-hvdroxv-ethoxvVethoxv1-pheDvU -2-methvl-5-^^ 7-propvl-lA5,6J,8-hexahvdro-quiDo1ii^e-^-nfl.ThnTiitri1e Alkylation of the compound described in example la (5 g) with (2-chloroethoxy)-eihanol (1,42 ml) was performed according to the method described in example 1 Oa. The residue was chromatographed on silica gel in heptane/EtOAc as eluent. Yield: 3.03 g. MS-ESI: [M+H]^ = 533,2/535.2 (b). Methanesulfonic acid 2-{2-f2-bromo-4-(3-cvanO"2-methvl"5-oxo-7-propvl-L4.5,6,7,8-hexahvdro-quinolin-4-vl)-6-ethoxv-phenoxv1-ethoxv) -ethyl ester The title compound was obtained analogously to the method described in example 19b starting from the compound described in example 21a (3.0 g) and methanesulfonyl chloride (522 ^1), Yield: 2.98 g. MS-ESI: [M+H]^ = 611.4/613.4 (c). 4-l4-r2-f2-AmiQO-ethoxv)-ethoxvV3-bromo-5-ethoxv-phenvU-2-methvl-5-oxo-7-propvl-l,4,5.6J,8-hexahvdro-Quinoline-3-carbonitrile The title compound was obtained analogously to the method described in example 19c starting from the compound described in step b (2.98 g) which yielded 3,0 g of the title compound (MeSOsH salt). A small amount (214 mg) was purified by preparative HPLC (Method A). Yield: 221.7 mg (TFA salt). MS-ESI: [M+H]" = 532.2/534,2; HPLC: Rt = 15.39 min (method 2). Diast. ratio: 5:1 Example 22 Cvclopropanecarboxvlic acid r2-l2-r2-bromo-4-(3-cvano-2-methvl-5-oxo-7-propvl-l,4,5.6,7,8-bexahvdro-quinolin-4-vl)-6-ethoxv-phenoxv1-ethoxv)-ethvl)-amide The title compound was obtained analogously to the method described in example 19d starting from the crude compound (MeSOsH salt) described in example 21c (214 mg) and cyclopropanecarbonyl chloride (37 jil), in the presence of triethylamine (141 |il). The residue was purified by preparative HPLC (Method B), Yield: 165 mg. MS-ESI: [M-i-H]^ = 600.4/602.4; HPLC: Rt = 22,40 min (method 2). Diast. ratio: 8:1 Example 23 3-BromQ"5-f3-cvano-2-methvl-5-oxo-7-propvl-L4.5,6,7,8-hexahvdro-quinQlin-4-vl)-2-r2-r2-hvdroxv-ethoxvVethoxv1-iVJV"-dimethvl-ben2ftnfiSTi1fnTiamide (a). 4-r3-Bromo-4-hvdroxv-phenvl)-2-methvl-5-oxo-7-propvl-l,4,5.6,7,8-hexahvdro-aumoline-3-carboDitrile The reaction of 3-broino-4-hydroxy-beiizaldehyde (13.07 g) with 3-animocrotonitril (5.34 g) and 5-propylcyclohexane-l,3-dione (10,02 g) was perfonned according to the method described in example la. Yield: 20.25 g. MS-ESI: [M+H]^ = 401/403 (b), 3-Bromo-5-(3-cvano-2-methvl--5-oxo--7-T)ropvl-L4,5.6J,8-hexahvdro-quinolin-4-vlV2-hvdxoxv-benzenesulfonvl chloride At -10 ^C and under a nitrogen atmosphere, the compound described in example 23a (20.25 g) was added portion wise during 1 h to CISO3H (47 ml). After stirring at -lO'^C for 1 h, the reaction mixture was allowed to warm (room temperature) and stirring was continued for another 17 h. The reaction mixture was poured on crushed ice (800 ml) and extracted several times with EtOAc. The combined organic layers were dried (MgS04), fihered and concentrated in vacuo. The residue was recrystallized from EtOAc, Yield: 23.7 g. MS-ESI; [M+Hj^ = 499.0/501.0 fcV3-Bromo-5"f3-cvano-2-meihvl-S-oxo-7-propvl-L4,S,6.7,8"hexahvdro-quinolin-4- vl)-2-hvdroxv-JV!jy-dimethyl-benzenesulfonamide Dimethylamine was bubbled through a suspension of the compound described in example 23b (4.1 g) in dioxane (85 ml) for 30 min. After stirring for 17 h, the reaction mixture was diluted with EtOAc and washed with water. During extraction the title coinpound crystallized in the water layer. The title conapound was obtained by filtmtioa Yield: 2.19 g. MS-ESI: [M+H]^ = 508.2/510.2 (d). 3-Bromo-5-(3-cvano-2-methvl-5-oxo-7-propvl-1.4,5,6J,8-hexahvdro-cpmolin-4- yl)-2-r2-f2-hvdroxv-etboxvVethoxv]T7^JV'-dimethvl-benzenesulfonamide Alkylation of the con^jound described in example 23 c (740 mg) with 2-(2-chloTo ethoxy)-ethanol (185 ^l) was performed according to the method described in example 10a. Yield: 35.6 mg. MS-ESI: [M+H]^ = 596/598; HPLC: R* - 14.73 min (method 1) Example 24 4- (3-Bromo-4-r2-(2-hvdroxv-ethoxv)-etboxv1-5-isopropoxv-phenvl} -2-methvl-5-oxo-7-propvl-1.4.5.6.7.8-hexahvclro-quinoline-3-caibonitrile CaY 3-Bromo-S-hvdroxy-4-f4-nitro-benzvloxvVbenzaldehyde A mixture of 3-bromo-4,5-dihydroxy-benzaldehyde (2 g), 4-nitrobenzylbromide (2 g), lithium carbonate (680 mg) and a small amount of tetrabutylammonium iodide (ca 50 mg) in DMF (15 ml) was stirred at 60"C for 4 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (MgS04)3 filtered and concentrated in vacuo. Yield: 2.82 g. MS-ESI: [M+H]*^ = 352.0/354.0 fbV 3-Bromo-5-isopropoxv-4-r4-nitro-benzvloxvVbenzaldehvde A mixture of the product of step a (2.82 g), isopropyl iodide (1.6 ml) and potassium carbonate (2.21 g) in DMF (25 ml) was stirred at 60®C for 4 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. Yield: 1.66 g. MS-ESI: [M+m"^ = 394.0/396.0 (c), 4-r3-Bromo-5-isopropoxv-4-f4-nitro-benzvloxv)-phenvn-2-methvl-5-oxo-7-pro-pvl-l,4,5,6.7,8-hexahvdro-quinoline"3-carbonitrile A mixture of the product of step b (1.06 g), 3-aminocrotonitrile (221 mg) and 5-propylcyclohexane-l,3-dione (415 mg) in ethanol (20 ml) was stirred at 80*^C for 17 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel in heptane/EtOAc = 1/1 (v/v) as eluent Yield: 750 mg. MS-ESI: [M+H]"^ = 594,4/596.4 (d). 4-f3-Bromo-4-hvdroxv-5-isopropoxv-phenvlV2-methvl-S-oxo-7-propvl-l,4,S,6,-7,8-hexahvdro-Quinoline-3-carbonitrile To a solution of the product isolated in step c (750 mg) and acetic acid (1.5 ml) in THF (50 ml) was added zinc dust (1.5 g) imder vigorous stirring. The mixture was stirred for 2 h and then filtered. The mixture was diluted with EtOAc and washed with sat. aq. NaHCOs. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. Yield: 720 mg, MS-ESI: [M+H]^ = 457,6/459.6 (e), 4- (3-Bromo-4-r2-f2-hvdroxv-ethoxv)-ethoxv1-5-isopropoxv-phenvU -2-methvl-5-oxo-7-propvl-L4,5.6,7,8-hexahvdro-quinoline-3-carbonitrile A mixture of the crude compound described in step d (100 mg), 2-(2-chloroethoxy)ethanol (27 ^1), potassium carbonate (90 mg) and a catalytic amount of tetrabutylammonium iodide in DMF (3 ml) was stirred for 20 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was chromatographed on sihcagel in heptane/EtOAc (from 1/0 to 0/1) as eluent. Yield: 29 mg. MS-ESI: [M+H]^ = 547.2/549.2; HPLC: Rt= 18.25 min. (method 1). Diast ratio: 3:1 Example 25 4- (3-Bromo-5-ethoxv-4-r2-(2-hvdrQxv-ethoxvVethoxv1-phenvU -2-methvl-3-33itro-7-propvl-4,6J,84etrahvdro-l/?-qiiiaolia-5-ODe (SL\ l-Nitro-propaii-2-one To a cooled solution of nitromethane (1.73 ml) in THF (50 ml) was added sodium hydride (1,28 g). After stirring for 20 min., the mixture is added to a solution of acetylimidazole (2.72 g) in THF (50 ml) and heated at reflux for 17 h. A precipitate formed, which was collected by filtration. The solid was dissolved in water, and the pH was adjusted to 3. The aqueous layer was extracted with EtOAc 3 times. The organic layer was dried (MgS04), filtered and concentrated in vacuo. Yield: 1.84 g. (h\ l-Methyl-2-nitro-vinvlan3ine A mixture of l-nitro-propan-2-one (1.6 g) and ammonium acetate (1.3 g) in toluene (25 ml) was heated at reflux for 17 h. Water was removed fi-om the reaction mixture using a Dean-Stark apparatus. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 1/0 to 0/1) as eluent. Yield: 1.07 g. (c). 4-f3-Bromo-5-ethoxv-4-hvdroxv-phenvlV2-methvl-3-nitro-7-propvl-4,6,7,8-tetra-hvdro-liy-quinolin-5-one A mixture of l-methyl-2-nitro-vinylamine (1 g), S-propylcyclohexane-l^-dione (1,61 g) and 3-bromo-5-ethoxy-4-hydroxy-benzaldehyde (2.57 g) in ethanol (50 ml) was stirred at reflux for 17 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane. A precipitate formed, which was collected by filtration. The solid was chromatographed on silicagel in heptane/EtOAc (fi-om 1/0 to 0/1) as eluent. Yield: 2.8 g. MS-ESI: [M+H]^ = 465.0/467.0 (d). 4-f3-Bromo-5-ethoxv-4-r2-(2-hvdroxv-ethoxvVethoxv1-phenvU-2-methvl-3-nitro-7-propvl-4,6,7,8-tetrahvdro-l.g-quinolin-5-one A mixture of the product described in step c (120 mg), 2-(2-Chloro-ethoxy)-ethanol (39 mg) and potassium carbonate (110 mg) in DMF (1 ml) was stirred at 60° for 17 h. The mixture was diluted with dichloromethane and washed with IN aqueous HCl. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 21.7 mg. MS-ESI: [M+H]^ = 553.0/555.0; HPLC: Rt == 16.12 min. (diast. 1) Rt = 16.46 min. (diast. 2) (method 1). Diast. ratio: 4:1 Example 26 3-Bromo-5-f3-cvano-2-methvl-5-oxo-7-propvl-l,4,5,6J,8-hexahvdro-qx±iolin-4-vlV2-f2-hvdroxv-ethoxvVJVJV"-dimetfavl-benzenesulfonam A mixture of tiie compound described in example 23c (203 mg), 2-bromo ethanol (29.5 \i\), potassium carbonate (187 mg) and potassium iodide (8 mg) in DMF (10 ml) was stirred at 60°C for 17 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B), Yield: 17 mg. MS-ESI: [M+H]"^ = 552.2/554.2; HPLC: Rt = 14.56 min. (method 1) Example 27 4-r3-Bromo-5-ethoxv-4-r2-hydroxy-ethoxvVphenyl1-2-methvl-5-oxo-7-propvl-1,4,5,6,7,8-hexahydro-quinoline-3"Carbanitrile The title con5)ound was obtained fi"om the compoimd described in exaniple la (350 mg), 2-bromo ethanol (111 ^il), potassium carbonate (326 mg) and potassium iodide (8 mg) according to the procedure described in example 26. Yield: 272.3 mg. MS-ESI: [M-fH]' = 489.2/491.2; HPLC: R^ = 21.15 min. (method 2). Diast ratio: 6:1 Example 28 4-r3-Bromo-5-ethoxv-4-(4-hvdroxv-but-2-envloxvVphenvll-2-methvl-5-oxo-7-propvl-l,4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile To a solution of the compound described in example lb (150 mg) in dioxane (2.5 ml) and water (2.5 ml) was added calcium carbonate (130 mg). The mixture was stirred under a nitrogen atmosphere at lOO^C for 4 h. The mixture was diluted with EtOAc and washed with IN aqueous HCl. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 1/0 to 0/1) as eluent. Yield: 95 mg. MS-ESI: [M+H]^ = 515.2/517.2; HPLC: Rt= 16.19 min. (method 1) Example 29 3-Bromo-5-('3-cvano-2-methvl-5-oxo-7-prot)vl-h4,5,6J,8-hexahvdro-quinolin-4-vl)-2-f2-methoxv-ethoxvVJVJV-dimethvl-benzenesulfonamide A mixture of the compound described in example 23c (200 mg), 2-bromoethyl methyl elher (39 |il), potassiimi carbonate (109 mg) and potassium iodide (20 mg) in DMF (5 ml) was stirred at 60*'C for 17 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was chromatographed on aluminum oxide in EtOAc as eluent Yield: 46.8 mg. MS-ESI: [M+H]^ = 566.0/568,0; HPLC: Rt = 19.84 min. (method 1) Example 30 3-Bromo-5-(3-cvano-2-me1hvl-5-oxo-7-OTOPvl-L4,5,6J.8-hexahvdrO"qiunolin-4-vl)-2-r2-f2"me1hoxv-ethoxvVe1hoxv1-MJV"dimethvl-beiizenesidfonatDide A mixture of the compound described in exatrple 23c (202 mg), 2-(2-methoxyethoxy) ethanol (78 ^il), diethyl azodicafboxylate (DEAD) (75 \xl) and resin boxmd triphenyl phosphine (237 mg (1.69 mmol/g loading) in dichloromethane (3 ml) and THF (0.75 ml) was stirred for 17 h. The resin was filtered off and washed with methanol. The combined organic layers were dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 22.5 mg. MS-ESI: [M+H]^ = 610.2/612.2; HPLC: Rt= 19,13 min. (method 1) Example 31 4-r3-Bromo-4-f2-methoxv-ethvlaminoV5-('morpholine-4-sulfonvl)-phenvl')-2-methvl-5-oxo-7-propyl-1.4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile fa). 3-Bromo-5-chlorosulfonvl-4-fluoro-benzoic acid 3-Bromo-4-fluoro-benzoic acid (2.0 g) was dissolved in chlorosulfonic acid (97%, 35 ml) and heated at 170 **C for 72 h. The reaction mixture was cooled to RT and added dropwise to an ice-water mixture. Extraction with EtOAc, drying (MgS04) and concentration in vacuo gave the desired coinpound. Yield: 2.5 g. (h\ 3'Bromo-4-fluoro-5-fmorpholine-4-sulfonvlVbenzoic acid To a solution of 3-BronM)-5-chlorosulfonyl-4-fluoro-benzoic acid (3.0 g) in dioxane/water (9/1 (v/v), 30 ml) was added DiPEA (5 ml) and moipholine (1,65 ml). After stirring for 2 h, the mixture was diluted with EtOAc and washed with 2 M aq. HCl. The organic layer was dried (Na2S04) and concentrated in vacuo. Yield: 2.6 g, (c). 3-Bromo-4-r2-methQxv-ethvlaminoV5-(morpholine-4-sulfonvl)-benzoic acid A solution of 3-Bromo-4-fluoro-5-(morpholine-4-sulfonyl)-benzoic acid (500 mg) in 2-methoxy-ethylamine was heated at 80 °C for 3 h. The mixture was dissolved in 2 M aq, NaOH and washed with EtOAc. The aqueous layer was acidified with 2 M HCl and ) extracted with EtOAc. The organic layer was dried (Na2S04) and concentrated in vacuo. Yield: 575 mg. (d\ 3-Bromo-4-(2-methoxv-ethvlamino)-5-fmorpholine-4-sulfonvlVbenzaldehvde To a solution of the product described in step c (571 mg) in THF was added BHs-THF (4.5 nJ, 1 M in THF). After stirring for 2 h at RT, aqueous work-up, extraction (EtOAc) and concentration in vacuo yielded the crude alcohol, which was dissolved in THF. Mn02 (587 mg) was added and the mixture was stirred overnight. Filtration over decalite and concentration in vacuo gave the desired crude compound, which was purified by crystallization from diethyl ether. Yield: 243 mg. (e). 4-r3-Bromo-4-f2-methoxv-ethvlaminoV5-fmorpholine-4-sulfonvlVphenvn-2-metfavl-5-oxo-7-propvl-l,4,5.6.7,8-hexahvdro-Qumoline-3-carboDitrile A mixture of the product of step d (61 mg), 3-aminocrotonitrile (12.3 mg) and 5-propylcyclohexane-l,3-dione (23.1 mg) in ethanol (5 nil) was stirred at 80 ° C for 17 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method B). Yield: 57 mg. MS-ESI: [M+H]^ - 607.3/609.3; HPLC: Rt = 16.51 min. (diast.l ) Rt = 16.83 min. (diast. 2) (method 1). Diast ratio: 9:1 Example 32 4-r3-Bromo-4-(2-methoxv-ethvlamino)-5-(pVTrolidine-l-sulfonvlVphenvl1-2-metihvl-5-oxO"7-pTopvH.4,5,6J.8-hexahvdro-quinoline-3-carbonitrile faV 3-Bromo-4-fluoro-5-(pvrrolidine-l-sulfonvl)-benzoic acid To a solution of 3-Bromo-5-chlorosulfonyl-4-fluoro-benzoic acid (3.0 g) in dioxane/water (9/1 (v/v), 30 ml) was added DiPEA (5 ml) and pyrrolidine (1.55 ml). After stirring for 2 h, the mixture was diluted with EtOAc and washed with 2 M aq. HCl. The organic layer was dried (Na2S04) and concentrated in vacuo. Yield: 2.3 g. fb). 3-Bromo-4-(2-methoxv-ethvlamino)-5-fpvrrolidine-l-sulfonvl>-benzoic acid A solution of 3-Bromo-4-fluoro-5-(pyrrolidine-l-sulfonyl)-benzoic acid (500 mg) in 2-methoxy-ethylamine was heated at 80 **C for 3 h. The mixture was dissolved in 2 M aq. NaOH and washed with EtOAc. The aqueous layer was acidified with 2 M HCl and extracted with EtOAc. The organic layer was dried (Na2S04) and concentrated in vacuo. Yield: 543 mg. fc). 3-Bromo-4-f2-methoxv-eihvlaminoV5-fpvrrolidine-l-sulfonvD-benzaldehvde To a solution of the product described in step c (542 mg) in THF was added BHs-THF (4.0 ml, 1 M in THF). After stirring for 2 h at RT, aqueous work-up, extraction (EtOAc) and concentration in vacuo yielded the crude alcohol, which was dissolved in THF. Mn02 (578 mg) was added and the nnixture was stirred overnight Filtration over decalite and concentration in vacuo gave the desired crude compound, which was purified by crystallization firom diethyl ether. Yield: 294 mg. (d). 4-r3-Bromo-4-r2-methoxv-e1hvlaminoV5-fpviTolidine-l-sulfonvl)-phe^ meihvl-5-oxo-7-propvl-L4,5,6J.8-hexahvdiD-qumolme-3-carbomtil A mixture of the product of step c (59 mg), S-aminocrotonitrile (12.3 mg) and 5-propylcyclohexane-l,3-dione (23.1 mg) in ethanol (5 ml) was stirred at 80 *^C for 17 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method B). Yield: 57 mg. MS-ESI: [M+H]^ = 591.3/593,3; HPLC: Rt= 18.43 mia. Diast. ratio: 9:1 Example 33 Agonistic activitv of compounds at the human FSH receptor expressed in CHO cells Agonist activity of the compounds at the hxmian FSH receptor was tested in Chinese Hamster Ovary (CHO) cells stably transfected with the human FSH receptor and cotransfected with a cAMP re^onsive element (CRE) / promoter directing the e3q)ression of a firefly luciferase reporter gene. Binding of the compound to the Gs-coupled FSH receptor wiU result in an increase of cAMP, which in turn will induce an increased transactivation of the luciferase reporter construct. The luciferase activity was quantified using a luminescence counter. The compounds were tested in the concentration range of 0.1 nM to 10 |iM. This assay was used to determine the EC50 (concentration of test compound causing half-maximal (50 %) luciferase stimulation) and efficacy of the compounds compared to recombinant human FSH. For this, the software program XL^ (Excel version 2,0, built 30, ID Business Solutions Limited) was used Coirpoxmds of all examples had an activity (EC50) of less than 10"^ M. Some of the coinpounds, such as those of examples 2, 3, 5, 6, 12,13, 17, 20, 22, 23, 24, 26, 28, 29, 30,31 and 32, showed an EC50 of less than 10"^ M. Claims 1. A 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroqumolme derivative according to Formula 1, wherein R^ is (l-6C)alkyl, (2-6C)aIkenyl or (2-6C)aIkynyl; R^ is halogen; R^ is SOaNR^R^ or (l-4C)alkoxy, optionally substituted with one of more fluorine atoms; XisOorNR'; R^ is R^"(2-8C)alkyl, R^.(3.8C)alkenyl, R^-(3-8C)a]kynyl or R^-(2-4C)alkoxy- (2- 4C)alkyl; ZisCNorNOj; R^ and R^ are independently H or (l-4C)alkyl; or R^ together with R^ and the N to which they are bonded form a 3-8 membered saturated ring optionally containing a furth^ heteroatom selected from O and S; R^ is OH, (l-4C)alkoxy, NH^; NR^C(0)R^\ NR^SOaR^^ or C(0)NR^R^^; R and R are independently H or (l-4C)alkyl; R^^ is (l-4C)al]cyl, (l-4C)alkoxy(l-4C)alkyl, or phenyl(l-4C)aIkyl or (2-5C)heteroaryl(l-4C)alkyl, both optionally substituted on the (hetero)aromatic ring with one or more substituents selected ftom OH, NH25 halogen, NO25 CF$, CN, (l"4C)alkyl, (l-4C)aIkoxy and (di)(l-4C)alkylamino; R^^ is (l-4C)alkyl, (2-4C)a]kenyl, (2-4C)aIkynyl, (l-4C)alkoxy(l-4C)alkyl, (3- 6C)cycloaIlcyl, (l-4C)a]koxy, (di)(l-4C)alkylamino, or phenyl or (2-5C)heteroaryl, both optionally substituted on the (hetero)aromatic ring with one or more substituents selected from OH, NH2, halogen, NO2, CF3, CN, (l-4C)a!kyl, (1-4C)aIkoxy and (di)(l-4C)aIkylaniino; or a phannaceutically acceptable salt thereof. 2. The 2-methyl-4-phenyl-5"Oxo-l,4,5,6,7,8-hexahydroqumoline derivative of claim 1, wherein X is O. 3. The 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative of claim 1 of claims 1 or 2, wherein R^ is (l-6C)a]kyl. 4. The 2-methyl-4-phenyl-5-oxo--l,4,5,6,7,8-hexahydroquinoline derivative of any one of claims 1-3, wherein R^ is CI, Br or I. 5. The 2-methyl-4-phenyl-5-oxo-l ,4,5,6,7,8-heMhydroquinoline derivative of any one of claims 1-4, wherein Z is CN. 6. The 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative of any one of claims 1-5, wherein R^ is SOzNR^R^ 7. A 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative of any one of claims 1 -6 for use in therapy. 8. A pharmaceutical coniposition conqirising a 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8- hexahydroquinoline derivative of any one of claims 1-6, and phannaceutically suitable auxiliaries. 9. Use of a 2-methyl-4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative of any one of claims 1-6, or a phannaceutically acceptable salt or solvate thereof, for the manufecture of a medicament for the treatment of fertility disorders.

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4968-CHENP-2007 OTHER DOCUMENT 06-02-2012.pdf

4968-CHENP-2007 POWER OF ATTORNEY 06-02-2012.pdf

4968-CHENP-2007 AMENDED CLAIMS 11-08-2014.pdf

4968-CHENP-2007 AMENDED PAGES OF SPECIFICATION 11-08-2014.pdf

4968-CHENP-2007 ASSIGNMENT 11-08-2014.pdf

4968-CHENP-2007 CORRESPONDENCE OTHERS 03-01-2013.pdf

4968-CHENP-2007 CORRESPONDENCE OTHERS 29-08-2013.pdf

4968-CHENP-2007 ENGLISH TRANSLATION 06-02-2012.pdf

4968-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 11-08-2014.pdf

4968-CHENP-2007 FORM-1 11-08-2014.pdf

4968-CHENP-2007 FORM-3 11-08-2014.pdf

4968-CHENP-2007 FORM-5 11-08-2014.pdf

4968-CHENP-2007 FORM-6 06-02-2012.pdf

4968-CHENP-2007 FORM-6 29-08-2013.pdf

4968-CHENP-2007 FORM-6-1 29-08-2013.pdf

4968-CHENP-2007 OTHERS 29-08-2013.pdf

4968-CHENP-2007 POWER OF ATTORNEY 29-08-2013.pdf

4968-CHENP-2007 AMENDED CLAIMS 11-02-2015.pdf

4968-CHENP-2007 CORRESPONDENCE OTHERS 06-02-2012.pdf

4968-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 11-02-2015.pdf

4968-CHENP-2007 FORM-1 03-01-2013.pdf

4968-CHENP-2007 FORM-13 03-01-2013.pdf

4968-CHENP-2007 POWER OF ATTORNEY 03-01-2013.pdf

4968-chenp-2007-abstract.pdf

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4968-chenp-2007-form 1.pdf

4968-chenp-2007-form 26.pdf

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