KR20080011402A - Dihydropyridine derivatives - Google Patents

Abstract

The present invention relates to dihydropyridine derivatives having general formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, (1-5C) heteroaryl R2, R3 are independently (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C) alkynyloxy, halogen X is SO2, CH2, C(O) or X is absent R4 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C) cycloalkyl, (3-6C)cycloalkenyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C) heterocycloalkyl, (2-6C)heterocycloalkyl(1-4C)alkyl, (6-10C)aryl, (6-10C) aryl(1-4C)alkyl, (1-9C)heteroaryl or (1-9C)heteroaryl(1-4C)alkyl. The compounds are useful for the treatment of fertility disorders.

Description

Dihydropyridine Derivatives {DIHYDROPYRIDINE DERIVATIVES}

The present invention describes the preparation of low molecular weight hormone analogs with selectively acting activity on the FSH receptor.

Gonadotropin plays an important role in a variety of body functions, including metabolism, temperature control and reproductive processes. Gonadotropin acts on specific gonad cell types to initiate ovarian and testicular differentiation and steroid production. For example, the pituitary gonadotropin (SHF) plays a central role in stimulating follicle development and maturation, whereas LH (luteinizing hormone) induces ovulation (Sharp, RM Clin Endocrinol. 33: 787-807, 1990; Dorrington and Armstrong, Recent Prog.Horm. Res. 35: 301-342,1979). Recently, for ovarian stimulation, i.e. for in vitro fertilization (IVF) and ovarian hyperstimulation responses for ovulation induction in ovulatory women without fertility [Insler, V., Int. J. Fertility 33: 85-97 , 1988, Navot and Rosenwaks, J. Vitro Fert.Embryo Transfer 5: 3-13, 1988), as well as FSH in combination with LH for male hypogonadism and male infertility.

Gonadotropin FSH is released from the anterior pituitary gland and under the placenta during pregnancy under the influence of gonadotropin-releasing hormone and estrogen. In women, FSH acts on the ovary, which promotes follicle development, and is a major hormone that regulates the release of estrogens. In men, FSH is responsible for the maintenance of the tubules and acts on the support cells responsible for spouse formation. Pure FSH is used clinically to treat infertility in women and clinically for the failure of some types of sperm development in men. Gonadal stimulating hormones for therapeutic purposes can be isolated from human urine sources and are of low purity (Morse et al, Amer. J. Reproduct. Immunol. And Microbiology 17: 143, 1988). Alternatively, it can be prepared as a recombinant gonadotropin. Recombinant human FSH is commercially available and used for assisted reproduction (Olijve et al. Mol. Hum. Reprod. 2: 371, 1996; Devroey et al. Lancet 339: 1170, 1992).

The action of the FSH hormone is mediated by certain plasma membrane receptors that are members of a large family of G-protein coupled receptors. This receptor consists of a single polypeptide with seven transmembrane domains and can interact with the Gs protein, which induces the activity of adenylate cyclase. FSH receptors are very specific targets in ovarian follicle growth and are expressed exclusively in the ovary. Normally, inhibition of signaling or blocking of receptors induced after activation of FSH-mediated receptors can interfere with follicle development, which can interfere with ovulation and reproduction. Low molecular weight FSH antagonists can form the basis for new contraceptives, while low molecular weight FSH agonists can be used for the same clinical purposes as the original FSH. In other words, it can be used to treat ovarian hyperstimulation and infertility instead of in vitro fertilization.

Low molecular weight FSH analogs with antagonistic properties are disclosed in international applications WO 2000/08015 (Applied Research Systems ALS Holding N. V.) and WO 2002/09706 (Affimax Research Institute).

Certain tetrahydroquinoline derivatives have recently been disclosed in international application WO 2003/004028 (Akzo Nobel V.) as FSH modulators with functional or antagonistic properties.

The present invention describes the preparation of low molecular weight hormone analogs that selectively activate the FSH receptor.

Thus, dihydropyridine compounds of formula (I) or their pharmaceutically acceptable salts of the following classes with FSH receptor action activity are now found:

In the above formula,

R ¹ is (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, phenyl or (1-5C) heteroaryl;

R ² , R ³ are independently (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (2-4C) alkenyloxy, (3- 4C) alkynyloxy or halogen;

X is SO ₂ , CH ₂ , C (O), or X is a bond;

R ⁴ is (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl, (2-6C) heterocycloalkyl (1-4C) alkyl, (6-10C) aryl, (6-10C) aryl (1-4C) alkyl , (1-9C) heteroaryl or (1-9C) heteroaryl (1-4C) alkyl.

When X is CH ₂ , R ⁴ may also be R ⁵ -oxycarbonyl or R ⁵ -carbonyl.

When R ⁴ is phenyl, phenyl may also be optionally substituted with one or more substituents selected from the following group in addition to the substituents for the (6-10C) aryl group as mentioned in the definition:

(1-4C) alkylthio, (1-4C) alkylsulfonyl, R ⁵ -oxycarbonyl, R ⁵ -carbonyl or R ⁵ , R ⁶ -aminocarbonyl.

R ⁵ , R ⁶ are independently H, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1 -4C) alkyl, (2-6C) heterocycloalkyl, (2-6C) heterocycloalkyl (1-4C) alkyl, (1-4C) alkoxycarbonyl (1-4C) alkyl, (1-4C) ( Di) alkylaminocarbonyl (1-4C) alkyl, (6-10C) aryl, (1-9C) heteroaryl, (6-10C) aryl (1-4C) alkyl, (1-9C) heteroaryl (1 -4C) alkyl, (6-10C) arylaminocarbonyl (1-4C) alkyl or (1-9C) heteroarylaminocarbonyl (1-4C) alkyl, or R ⁵ , R ⁶ are (2-6C) Can be bonded to a heterocycloalkyl ring.

The compound according to the present invention modulates FSH receptor function, which acts as an agonist and thus can be used for the same clinical purposes as the original FSH, exhibit altered stable properties and be administered separately.

Thus, the FSH-receptor agonist of the present invention can be used for the treatment of infertility. Preferably, the compounds of the present invention are used for the activation of FSH-receptors.

The term (1-4C) alkyl as used in the definition means a branched or unbranched alkyl group of 1 to 4 carbon atoms and is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl .

The term (1-6C) alkyl refers to branched or unbranched alkyl groups of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. (1-5C) alkyl groups are preferred, and (1-4C) alkyl is most preferred.

The term (2-6C) alkenyl refers to a branched or unbranched alkenyl group having 2 to 6 carbon atoms such as ethenyl, 2-butenyl and n-pentenyl.

The term (2-4C) alkenyl means branched or unbranched alkenyl having 2 to 4 carbon atoms, such as ethenyl, n-propenyl and 2-butenyl.

The term (2-6C) alkynyl means branched or unbranched alkenyl groups having 2 to 6 carbon atoms, such as ethynyl, propynyl and n-pentynyl.

The term (2-4C) alkynyl means an alkynyl group having 2 to 4 carbon atoms, such as ethynyl and propynyl.

The term (3-6C) cycloalkyl means a cycloalkyl group having 3 to 6 carbon atoms and is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term (3-6C) cycloalkenyl refers to cycloalkenyl groups having 3 to 6 carbon atoms, such as cyclopropenyl, cyclopentenyl and cyclohexenyl.

The term (3-6C) cycloalkyl (1-4C) alkyl is a cycloalkyl group having from 3 to 6 carbon atoms in which the cycloalkyl group has the same meaning as defined above, and from 1 to 1 carbon atoms in which the alkyl group has the same meaning as defined above. It means a cycloalkylalkyl group which is four alkyl groups.

The term (2-6C) heterocycloalkyl has from 2 to 6 carbon atoms, preferably from 3 to 5 carbon atoms, and comprises at least one hetero atom selected from N, O and / or S, and via or By heterocycloalkyl group it is possible, if possible, to be attached via a carbon atom. Preferred hetero atoms are N or O. Most preferred are piperidinyl, morpholinyl, pyrrolidinyl and piperazinyl.

The term (2-6C) heterocycloalkyl (1-4C) alkyl is a heterocycloalkyl group having 2 to 6 carbon atoms in which the heterocycloalkyl group has the same meaning as defined above, and wherein the alkyl group has the same meaning as defined above. Heterocycloalkylalkyl group which is an alkyl group of 1 to 4 atoms.

The term (1-4C) alkoxy means an alkoxy group having 1 to 4 carbon atoms in which the alkoxy moiety has the same meaning as defined above. The (1-2C) alkoxy group is preferable.

The term (1-4C) alkylthio means an alkylthio group having from 1 to 4 carbon atoms in which the alkyl moiety has the same meaning as defined above.

The term (2-4C) alkenyloxy means an alkenyloxy group having from 2 to 4 carbon atoms in which the alkenyl moiety has the same meaning as defined above.

The term (3-4C) alkynyloxy means an alkynyloxy group having 3 to 4 carbon atoms in which the alkynyl moiety has the same meaning as defined above.

The term (6-10C) aryl is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1 -4C) alkoxy or 6-10 aromatic hydrocarbon groups which may be optionally substituted with one or more substituents selected from (1-4C) (di) alkylamino, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl Wherein the alkyl moiety has the same meaning as defined above. Preferred aromatic hydrocarbon groups are phenyl.

The term (1-9C) heteroaryl refers to substituted or unsubstituted aromatic groups of 1 to 9 carbon atoms comprising at least one hetero atom selected from N, O and / or S, such as tetrazolyl, imidazolyl, thiadizolyl , Pyridinyl, (benzo) thienyl, (benzo) furyl, (iso) quinolinyl, tetrahydro (iso) quinolinyl, coumarinyl, quinoxalinyl or indolyl. Substituents on the (1-9C) heteroaryl group may be selected from the group of substituents described for the (6-10C) aryl group. (1-5C) heteroaryl is preferred. The (1-9C) heteroaryl group may be attached via a carbon atom or a hetero atom if possible.

The term (1-5C) heteroaryl refers to substituted or unsubstituted aromatic groups of 1 to 5 carbon atoms comprising at least one hetero atom selected from N, O and / or S, such as tetrazolyl, imidazolyl, thiadizolyl , Pyridinyl, thienyl or furyl, with furyl being most preferred. Preferred heteroaryl groups are thienyl, furyl and pyridinyl. Substituents on the (1-5C) heteroaryl group may be selected from the group of substituents described for the (6-10C) aryl group.

The term (6-10C) aryl (1-4C) alkyl is an aryl group having 6 to 10 carbon atoms in which the aryl group has the same meaning as defined above, and having 1 to 4 carbon atoms in which the alkyl group has the same meaning as defined above. It means an arylalkyl group which is an alkyl group. Most preferred is benzyl.

The term (1-9C) heteroaryl (1-4C) alkyl is a heteroaryl group having from 1 to 9 carbon atoms having the same meaning as defined above, and the alkyl group having the same meaning as defined above with carbon atom 1 Heteroarylalkyl group which is from 4 to 4 alkyl groups.

The term (1-4C) alkylsulfonyl means an alkylsulfonyl group wherein the alkyl group is an alkyl group of 1 to 4 carbon atoms having the same meaning as defined above.

The term (1-4C) alkoxycarbonyl refers to a (1-4C) alkoxycarbonyl group wherein the alkoxy group is an alkoxy group having 1 to 4 carbon atoms having the same meaning as defined above. (1-2C) alkoxycarbonyl group is preferable.

The term (1-4C) alkoxycarbonyl (1-4C) alkyl refers to an alkoxycarbonylalkyl group wherein the alkali group is an alkyl group of 1 to 4 carbon atoms having the same meaning as defined above.

The term (1-4C) (di) alkylaminocarbonyl (1-4C) alkyl refers to a (di) alkylaminocarbonylalkyl group wherein the alkyl group is an alkyl group of 1 to 4 carbon atoms having the same meaning as defined above.

The term halogen means fluorine, chlorine, bromine or iodine.

The term pharmaceutically acceptable salts refers to salts that are within the scope of pharmaceutical judgment and are of suitable benefit / risk ratio, suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, and the like. Pharmaceutically acceptable salts are well known in the art. This may be obtained during the final isolation and purification of the compounds of the invention, or the free base functional groups may be selected from suitable inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid or ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid. Can be obtained individually by reacting with organic acids such as succinic acid, propionic acid, acetic acid, methanesulfonic acid and the like. Acid functional groups can be reacted with inorganic bases or organic bases such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

The invention also relates to compounds of formula (I), wherein R ¹ is (1-6C) alkyl, phenyl or (1-5C) heteroaryl, all optionally substituted with substituents as mentioned in the definitions above. More particularly, the present invention relates to compounds wherein R ¹ is (1-4C) alkyl, phenyl or 4C-heteroaryl. The invention also relates to compounds wherein R ¹ is n-propyl or furyl.

Another aspect of the invention is a compound of formula I, wherein R ² , R ³ are halogen and / or (1-4C) alkoxy.

In another aspect, the invention relates to compounds of formula (I), wherein X is CH ₂ .

Another aspect of the invention is a compound wherein R ⁴ is phenyl optionally substituted with substituents as mentioned in the definition. In another aspect, the invention relates to compounds wherein R ⁴ is phenyl substituted at the ortho and / or meta position. In another aspect, the invention relates to compounds of formula (I), wherein R ⁴ is phenyl substituted with R ⁵ , R ⁶ -aminocarbonyl, (1-4C) alkoxy and / or halogen. In another aspect, the present invention R ^5, R ⁶ - aminocarbonyl in R ^5, R ⁶ are (1-4C) (di) alkylamino, (1-4C) alkoxycarbonyl (1-4C) alkyl or (1-9C) heteroaryl (1-4C) alkyl. In another aspect, R ^5, R ⁶ - is aminocarbonyl in R ^5, R ⁶ 1 or more of the H.

In another aspect, the invention provides (6-10C) aryl, (6-10C) aryl (1-4C) alkyl, (1-9C) heteroaryl or (1-9C) heteroaryl (1-4C) at R ⁴ Alkyl is unsubstituted.

Another aspect of the invention relates to compounds wherein X is CH ₂ and R ⁴ is phenyl optionally substituted with substituents as mentioned in the definition.

Another aspect of the invention relates to compounds in which all specific definitions of the groups R ¹ to R ⁴ and X as defined herein above are combined in the dihydropyridine compound of formula (I).

Compound 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile is seen Excluded from the invention.

The unclaimed compounds relate to CAS330674-72-1, which is available from commercial sources such as Cambridge Corporation, Microchemistry Limited, Ambinter, Acinex, Scientific Exchange Incorporated and Chemdev Incorporated.

Suitable methods for the preparation of the compounds of the present invention are outlined below.

The 1,4-dihydropyridine derivatives of the general formula (I) of the present invention are prepared by the three component Hantzsch-type cyclo-condensation reaction, Can be prepared starting from 1,3-dione, benzaldehyde of formula III and 3-aminocrotonitrile of formula IV, wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined above have.

Related arch condensation reactions are described in Bioorg. Med. Chem. Lett. 12 (2002) 1481-1484, J. Chem. Soc., Perkin Trans. 1 (2002) 1141-1156, 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, Arzneim.-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 abovementioned reaction is usually carried out at high temperature in a protic solvent such as, for example, acetic acid, (iso) propanol, ethanol, methanol or mixtures thereof.

Alternatively, the compound of formula (I) may be reacted with a benzaldehyde of formula (III) following the reaction of cyclohexane-1,3-dione of formula (II) in the presence of a base such as, but not limited to, ammonium acetate, 2-benzylidene-cyclohexane-1,3-dione of Formula V, wherein R ¹ , R ² , R ³ , R ⁴ and X have the same meaning as defined above, is substituted with 3-amino It can be synthesized by reacting with tonitrile.

O-alkylation, O- (hetero) arylation, O-acylation or O-sulfonylation using standard conditions well known to those skilled in the art using compounds of formula (Ia) wherein X = a bond and R ⁴ = H Compound Ibe can be prepared by

In a typical experiment, compound Ia is optionally a catalytic amount of potassium iodide in the presence of a base such as but not limited to triethylamine, N, N-diisopropylethylamine (DiPEA), potassium carbonate, cesium carbonate or sodium hydride Or tetrabutylammonium iodide, and / or Cu- or Pd-catalyst in the presence of a solvent such as dichloromethane, N, N-dimethylformamide, dimethyl sulfoxide, ethanol, tetrahydrofuran, dioxane, toluene, 1-methyl O-alkylation of the formulas Ib, Ic, Id and Ie by reaction with alkyl halides or acyl halides or acid anhydrides or sulfonyl halides or (hetero) aryl halides in pyrrolidin-2-one or pyridine, respectively, O- (hetero) arylated, O-acylated or O-sulfonylated derivatives are obtained.

Solvent compounds of formula If, wherein X = CH ₂ and R ⁴ = alkyl acid derivative or (hetero) aryl acid derivative obtained by base mediated (e.g., NaOH) saponification of the corresponding alkyl ester, are solvents at ambient or elevated temperature Coupling agents such as diisopropyl carbodiimide (DIC), (3-dimethylaminopropyl) -ethyl-carbodiimide (EDCI), O- (benzotriazole, for example in N, N-dimethylformamide or dichloromethane -1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (TBTU) or O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) and a tertiary amine base (e.g. DiPEA) are condensed with an amine of formula R ⁵ , R ⁶ NH or an alcohol of formula R ⁵ OH to formula Ig and Ih The compound of can be obtained.

Substituted cyclohexane-1,3-dione of formula (II) is commercially available or can be prepared by literature procedures known in the art. Related examples are described 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.

Benzaldehyde of formula III is also commercially available, or literature procedure [J. Chem. Soc., Perkin Trans. 2 (2000) 1119-1124, J. Chem. Soc., Chem. Commun. 4 (1993) 419-420, Synth. 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 1070 162, J. Org. Chem. 23 (1958) 120].

Alternatively, O-alkylation, O-arylation, O-A using compound III-a, wherein X = a bond and R ⁴ = H, using the same standard conditions as described above for compound Ia Compound III-be can be synthesized by silylation or O-sulfonylation.

Since the compounds of the present invention have two or more chiral carbon atoms, they can be obtained as pure enantiomers, as mixtures of enantiomers, or as mixtures of diastereomers. Methods of obtaining pure enantiomers are known in the art, for example crystallization of salts obtained from optically active acids and racemic mixtures, or by chromatography using chiral columns. For the separation of diastereomers, straight phase or reverse phase columns can be used.

The compounds of the present invention may form hydrates or solvates. It is known to those skilled in the art to form hydrated species when the charged compound is lyophilized with water, or when concentrated in solution with a suitable organic solvent. Compounds of the present invention include hydrates or solvates of the compounds described.

In the selection of the active compound, a maximum activity of at least 20% should be obtained when testing at 10 ⁻⁵ M than when using FSH as reference material. Another criterion is EC ₅₀ , which should be <10 ^-5 M, preferably <10 ^-7 M, even more preferably <10 ^-9 M.

One skilled in the art will recognize that the preferred EC ₅₀ value depends on the compound being tested. For example, compounds having an EC ₅₀ of less than 10 ⁻⁵ M are generally considered as candidates for drug selection. Preferably this value is less than 10 ⁻⁷ M. However, compounds that are higher at EC ₅₀ but selective for specific receptors may be even better candidates.

Methods of measuring receptor binding as well as in vitro and in vivo assays for determining the biological activity of gonadotropins are well known. In general, the expressed receptor is contacted with the compound to be tested and the binding or stimulation or inhibition of the functional response is measured.

To measure the functional response, isolated DNA encoding the FSH receptor gene, preferably the human receptor, is expressed in an appropriate host cell. Such cells may be Chinese hamster ovary cells, but other cells are also suitable. Preferably, the cells are cells of mammalian origin (Jia et al, Mol. Endocrin., 5: 759-776, 1991).

Methods of constructing 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). Expression of the receptor is achieved by expression of DNA encoding a given protein. Sites involved in mutagenesis, ligation of additional sequences, PCR and techniques for constructing an appropriate expression system are all well known in the art. Preferably, some or all of the DNA encoding a given protein can be constructed synthetically using standard solid phase techniques to include restriction sites to facilitate ligation. Suitable control elements for transcription and translation of the included coding sequence can be provided in the DNA coding sequence. As is well known, expression systems are currently available that 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 expressing the receptor are then contacted with the test compound to observe binding or stimulation or inhibition of the functional response.

Alternatively, isolated cell membranes containing expressed receptors can be used to measure binding of the compounds.

For the measurement of binding, radioactive or fluorescent compounds can be used. As reference compound, human recombinant FSH can be used.

Alternatively, a competitive binding assay can also be performed.

Another assay involves screening for FSH receptor agonist compounds by measuring the stimulation of receptor mediated cAMP accumulation. Thus, this method involves expressing a receptor on the cell surface of a host cell and exposing the cell to a test compound. Then measure the amount of cAMP. The level of cAMP can be increased by stimulating the effect of the test compound upon binding to the receptor.

For example, in addition to directly measuring cAMP levels in exposed cells, cell lines transformed with a second DNA encoding informational gene expression in addition to transformation with receptor encoding DNA and also in response to the level of cAMP can be used. Such informative genes may be cAMP inducible or may be constructed in such a way that they bind to novel cAMP reactive elements. In general, informational gene expression can be controlled by any response element that reacts to change cAMP levels. Suitable informational genes are, for example, LacZ, alkali phosphates, firefly luciferases and green fluorescent proteins. The principles of such transcriptional activity assays are well known in the art and are described, for example, in Stratowa, Ch., Himmler, A. and Czernilofsky, A.P., (1995) Curr. Opin. Biotechnol. 6: 574.

The invention also relates to a pharmaceutical composition comprising a dihydropyridine derivative of formula (I) or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant and optionally with other therapeutic agents. The adjuvant should be "acceptable" in terms of compatibility with other components of the composition and should not be harmful to its recipients. The pharmaceutical composition also contains 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3- Carbonitrile.

The compositions include those suitable for oral, sublingual, transdermal, intravenous, intramuscular, nasal, topical or rectal administration, etc., in all unit dosage forms for administration.

For oral administration, the active ingredient may be present as discrete units such as tablets, capsules, powders, granules, solutions, suspensions and the like.

For parenteral administration, the compositions of the present invention may be present in unit doses or in multi-dose containers, such as sealed vials or ampoules, for example in a predetermined amount of infusion liquid, and freezing only by adding a sterile liquid carrier such as water before use. It can also be stored in a dry state.

Active agents are described, for example, in Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, in particular Part 5: Pharmaceutical Manufacturing), and the active agent is mixed with the active agent. For example, it may be compressed into a solid dosage form such as pills, tablets, or processed into capsules or suppositories. Using pharmaceutically acceptable liquids, the active agents can be applied as fluid compositions, such as infusion preparations, in the form of solutions, suspensions, emulsions or as sprays such as, for example, nasal sprays.

To prepare solid formulations, the use of conventional additives such as fillers, colorants, polymer binders and the like is contemplated. In general, any pharmaceutically acceptable additive may be used that does not interfere with the function of the active compound. Suitable carriers to which the active agents of the present invention can be administered as solid compositions include lactose, starch, cellulose derivatives, and the like, or mixtures thereof, used in appropriate amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions containing pharmaceutically acceptable dispersing and / or wetting agents such as propylene glycol or butylene glycol can be used.

The invention further includes a pharmaceutical composition as described herein above in combination with a packaging material suitable for the composition, wherein the packaging material is used herein to provide instructions for use in a composition for use as described above. Include.

The exact dose and regimen of administration of the active ingredient or pharmaceutical composition thereof may vary depending upon the particular compound, route of administration, and age and condition of the individual to whom the agent will be administered.

In general, parenteral administration requires a lower dose than other administration methods, which are more dependent on absorption. However, a suitable dose for humans may be 0.05 to 25 mg per kg body weight. A given dose may be present as one dose or as multiple sub doses administered at appropriate intervals throughout the day, or in the case of female recipients, as a dose for administration at appropriate daily intervals during the menstrual cycle. The dosage regimen as well as the dosage regimen may differ between female and male recipients.

Thus, the compounds according to the invention can be used for treatment.

Another aspect of the invention is the use of a dihydropyridine derivative compound of formula (I) for the manufacture of a medicament for use in the treatment of disorders reactive to FSH receptor mediated pathways, preferably in the treatment of infertility.

The invention is illustrated by the following examples.

Example  One

4- (3- Bromo -4- Ethoxy -5- Methoxyphenyl )-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

a) 4- (3- Bromo -4-hydroxy-5- Methoxyphenyl )-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-heck four Hydroquinoline-3- Carbonitrile

5-phenylcyclohexane-1,3-dione (0.51 g), 3-bromo-5-methoxy-4-hydroxybenzaldehyde (0.62 g) and 3-aminocrotonitrile (0.22 in 20 mL of absolute ethanol) g) was stirred at 75 ° C. for 3 hours. The reaction mixture was concentrated and after flash column chromatography (silica gel, heptane / ethyl acetate (3/7, v / v), R _f = 0.36) gave the title compound as off white solid.

Yield: 0.95 g. MS-ESI: [M−H] ⁻ = 463/465.

b) 4- (3- Bromo -4- Ethoxy -5- Methoxyphenyl )-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-hexahydroquinoline-3- Carbonitrile

A mixture of the product of step a (15 mg), ethyl iodide (6.4 μl), sodium hydride (2.6 mg, 60% in oil) and tetrabutylammonium iodide (1.2 mg) in 0.5 mL NMP at 80 ° C. for 2 hours. Stirred. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated and the title compound was obtained after flash column chromatography (silica gel, heptane / ethyl acetate (1/4, v / v), R _f = 0.52).

Yield: 2.2 mg. MS-ESI: [M−H] ⁻ = 491/493.

Example  2

4- (3- Bromo -4- Cyclohexylmethoxy -5- Methoxyphenyl )-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-heck four Hydroquinoline-3- Carbonitrile

Starting with the product of Example 1a (15 mg) and bromomethylcyclohexane (12 μl), the title compound was obtained in a similar manner to Example 1b.

Yield: 12 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.59. MS-ESI: [M−H] ⁻ = 559/561.

Example  3

4- [3- Bromo -5- Methoxy -4- (3- Methylbutoxy )- Phenyl ]-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-heck four Hydroquinoline-3- Carbonitrile

Starting with the product of Example 1a (15 mg) and 1-iodo-3-methylbutane (4.7 μl), the title compound was obtained in a similar manner to Example 1b.

Yield: 14 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.66. MS-ESI: [M−H] ⁻ = 533/535.

Example  4

4- [3- Bromo -4- (5- Chlorothiophene -2- Ilmethoxy ) -5- Methoxyphenyl ]-2- methyl -5-oxo-7-phenyl-1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

A mixture of the product of Example 1a (15 mg), 2-chloro-5-chloromethylthiophene (4.3 μl) and cesium carbonate (21 mg) in 1 ml dioxane was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated and after flash column chromatography (silica gel, heptane / ethyl acetate (3/7, v / v), R _f = 0.38) to give the title compound.

Yield: 4.7 mg. MS-ESI: [M−H] ⁻ = 593/595/597.

Example  5

[2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Methoxyphenoxy ] -Acetic acid Methyl ester

Starting with the product of Example 1a (15 mg) and bromoacetic acid methyl ester (1.0 mL), the title compound was obtained in a similar manner to Example 4.

Yield: 0.32 g. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.44. MS-ESI: [M-H] ⁻ = 535/537.

Example  6

3- Methoxybenzoic acid  2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-heck four Hydroquinolin-4-yl) -6- Methoxyphenyl  ester

Starting with the product of Example 1a (15 mg) and 3-methoxy-benzoyl chloride (5.4 μl), the title compound was obtained in a similar manner to Example 4.

Yield: 7.4 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.48. MS-ESI: [M−H] ⁻ = 597/599.

Example  7

4- [3- Bromo -4- (3- Cyanobenzyloxy ) -5- Methoxyphenyl ]-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-heck four Hydroquinoline-3- Carbonitrile

Starting with the product of Example 1a (15 mg) and 3-bromomethylbenzonitrile (7.6 mg), the title compound was obtained in a similar manner to Example 4.

Yield: 15 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.51. MS-ESI: [M−H] ⁻ = 578/580.

Example  8

4- [3- Bromo -5- Methoxy -4- (naphthalene-2- Ilmethoxy )- Phenyl ]-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-hexahydroquinoline-3- Carbonitrile

Starting with the product of Example 1a (15 mg) and 2-bromomethylnaphthalene (8.6 mg), the title compound was obtained in a similar manner to Example 4.

Yield: 11 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.60. MS-ESI: [M−H] ⁻ = 603/605.

Example  9

Phenylmethanesulfonic acid  2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Heck Sahydroquinolin-4-yl) -6- Methoxyphenyl  ester

A mixture of the product of Example 1a (15 mg), phenylmethanesulfonyl chloride (9.2 mg) and triethylamine (9.4 μl) in 1 ml dichloromethane was stirred at room temperature for 2 hours. The reaction mixture was concentrated and after flash column chromatography (silica gel, heptane / ethyl acetate (1/4, v / v), R _f = 0.41) to afford the title compound.

Yield: 15 mg. MS-ESI: [M + H] ⁺ = 619/621.

Example  10

Thiophene-2- Sulfonic acid  2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-hexahydroquinolin-4-yl) -6- Methoxyphenyl  ester

Starting with the product of Example 1a (15 mg) and thiophene-2-sulfonyl chloride (8.8 mg), the title compound was obtained in analogy to Example 9.

Yield: 20 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.30. MS-ESI: [M-H] ⁻ = 611/613.

Example  11

4- [3,5- Dibromo -4- (3- Methoxybenzyloxy )- Phenyl ] -7-ethyl-2- methyl -5-oxo-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile

a) 3,5- Dibromo -4- (3- Methoxybenzyloxy )- Benzaldehyde

3,5-dibromo-4-hydroxybenzaldehyde (0.28 g), 1-bromomethyl-3-methoxybenzene (0.15 mL), potassium carbonate (0.29 g) and potassium iodide in 10 mL of absolute ethanol ( 42 mg) was stirred at 80 ° C. for 2 days. The reaction mixture was concentrated and after flash column chromatography (silica gel, heptane / ethyl acetate (3/7, v / v)) R _f = 0.51) gave the title compound as off-white solid.

Yield: 0.24 g. MS-ESI: [M−H] ⁻ = 463/465. ¹ H NMR (CDCl ₃ ): δ = 9.88 (s, 1H), 8.06 (s, 1H), 7.34 (t, 1H), 7.18 (bs, 1H), 7.15 (d, 1H), 6.93 (dd, 1H ), 5.10 (s, 2H), 3.85 (s, 3H).

b) 4- [3,5- Dibromo -4- (3- Methoxybenzyloxy )- Phenyl ] -7-ethyl-2- methyl -5-oxo-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile

Starting from 5-ethylcyclohexane-1,3-dione (8.5 mg) and the product of step a (24 mg), the title compound was obtained in a similar manner to Example 1a.

Yield: 26 mg. R _f (heptane / ethyl acetate (3/7, v / v)) = 0.40. MS-ESI: [M + H] ⁺ = 585/587/589.

Example  12

4- {3- Bromo -5- Ethoxy -4- [2- (3- Nitrophenyl )-2- Oxoethoxy ]- Phenyl }-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

a) 4- (3- Bromo -5- Ethoxy -4- Hydroxyphenyl )-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-heck four Hydroquinoline-3- Carbonitrile

Starting from 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.15 g), the title compound was obtained in analogy to Example 1a.

b) 4- {3- Bromo -5- Ethoxy -4- [2- (3- Nitrophenyl )-2- Oxoethoxy ]- Phenyl }-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

Starting with the product of step a (15 mg) and 2-bromo-1- (3-nitrophenyl) -ethanone (8.4 mg), the title compound was obtained in analogy to Example 4.

Yield: 14 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.58. MS-ESI: [M + H] ⁺ = 642/644.

Example  13

3- [2-bromo-4- (3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6 -Methoxyphenoxymethyl] -N-thiophen-2-ylmethylbenzamide

a) 3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydro Quinolin-4-yl) -6- Methoxyphenoxymethyl ] -Benzoic acid methyl  ester

Starting with the product of Example 1a (0.35 g) and 3-bromomethylbenzoic acid methyl ester (0.18 g), the title compound was obtained in a similar manner to Example 4.

Yield: 0.35 g. R _f (heptane / ethyl acetate (3/7, v / v)) = 0.34. MS-ESI: [M + H] ⁺ = 613/615.

b) 3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Methoxyphenoxymethyl ] -Benzoic acid

The solution of the product of step a (0.35 g) was dissolved in 20 mL of dioxane / water (7/3, v / v) and 2 mL of 2 M NaOH in water was added. The reaction mixture was stirred for 5 days at room temperature. The reaction mixture was poured into water, acidified to pH 2 with 2 M HCl in water and then extracted several times with ethyl acetate. The organic phase was washed with water and saturated brine, dried over Na ₂ SO ₄ and evaporated to afford the title compound.

Yield: 0.35 g. MS-ESI: [M + H] ⁺ = 599/601.

c) 3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Methoxyphenoxymethyl ] -N-thiophene-2- Monomethylbenzamide

To a solution of the product of step b (20 mg) in 2 mL of dichloromethane is added EDCI (7.0 mg), DiPEA (7 μl) and 2-thiophenmethylamine (4.1 μl) and the reaction mixture is allowed to stand for 3 hours at room temperature. Stirred at. The reaction mixture was concentrated and after flash column chromatography (silica gel, heptane / ethyl acetate (1/4, v / v), R _f = 0.78) to afford the title compound.

Yield: 11 mg. MS-ESI: [M + H] ⁺ = 694/696.

Example  14

3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinol Lin-4-yl) -6- Methoxyphenoxymethyl ] -Benzoic acid 2-morpholine-4- Ethyl  ester

To a solution of the product of Example 13b (20 mg) in 2 mL dichloromethane were added TBTU (12 mg), DiPEA (7 μl) and 2-morpholin-4-ylethanol (4.8 μl) and the reaction mixture was Stir at room temperature for 3 hours. The reaction mixture was concentrated and the title compound was obtained after flash column chromatography (silica gel, heptane / ethyl acetate (1/4, v / v), R _f = 0.48).

Yield: 11 mg. MS-ESI: [M + H] ⁺ = 694/696.

Example  15

4- {3- Bromo -5- Ethoxy -4- [3- (piperidine-1-carbonyl)- Benzyloxy ]- Phenyl }-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

a) 3- (2- Bromo -6- Ethoxy -4- Formylphenoxymethyl ) -Benzoic acid methyl  ester

3-bromomethylbenzoic acid methyl ester (0.77 g), K ₂ CO ₃ (1.0 g) and catalytic amount of n-Bu ₄ NI were converted to 5-bromo-3-ethoxy-4-hydroxybenzaldehyde in 10 mL of DMF. (0.75 g) was added to the solution and the reaction mixture was stirred at 70 ° C for 1 hour. A solution of 3% citric acid in water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO ₄ and concentrated. The title compound was obtained after flash column chromatography (silica gel, heptane / ethyl acetate (1/4, v / v), R _f = 0.25).

Yield: 1.08 g. ¹ H NMR (CDCl ₃ ): δ = 9.84 (s, 1H), 8.20 (bs, 1H), 8.02 (bd, 1H), 7.77 (d, 1H), 7.65 (d, 1H), 7.47 (t, 1H ), 7.39 (d, 1H), 5.21 (s, 2H), 4.17 (q, 2H), 3.94 (s, 3H), 1.51 (t, 3H).

b) 3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -Benzoic acid methyl  ester

Starting from the product of step a (0.26 g), the title compound was obtained in a similar manner to Example 1a.

Yield: 0.27 g. R _f (heptane / ethyl acetate (3/7, v / v)) = 0.34. MS-ESI: [M + H] ⁺ = 613/615.

c) 3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -Benzoic acid

Starting from the product of Example b (0.27 g), the title compound was obtained in a similar manner to Example 13b.

Yield: 0.27 g. MS-ESI: [M + H] ⁺ = 599/601.

d) 4- {3- Bromo -5- Ethoxy -4- [3- (piperidine-1-carbonyl)- Benzyloxy ]- Phenyl } -2-methyl-5-oxo-7- Phenyl -1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

Starting from the product of step c (20 mg) and piperidine (3.9 μl), the title compound was obtained in analogy to Example 13c.

Yield: 15 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.25. MS-ESI: [M + H] ⁺ = 680/682.

Example  16

Glycine, N-3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8- Hexa Hydroquinolin-4-yl) -6- Ethoxyphenoxymethyl ] Benzoyl , methyl  ester

Starting from the product of step 15c (20 mg) and glycine methyl ester hydrochloride (4.9 mg), the title compound was obtained in analogy to Example 13c.

Yield: 9.9 mg. R _f (heptane / ethyl acetate (3/7, v / v)) = 0.16. MS-ESI: [M + H] ⁺ = 684/686.

Example  17

3- [2-bromo-4- (3-cyano-7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6 - Ethoxyphenoxymethyl ] -Benzoic acid methyl  ester

Starting with 5-ethylcyclohexane-1,3-dione (0.25 g) and the product of Example 15a (0.64 g), the title compound was obtained in a similar manner to Example 1a.

Yield: 0.45 g. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.25. MS-ESI: [M + H] ⁺ = 579/581.

Example  18

3- [2- Bromo -4- (3- Cyano -7-ethyl-2- methyl -5-oxo-1,4,5,6,7,8- Hexahydro -Quinolin-4-yl) -6- Ethoxyphenoxymethyl ] -Benzoic acid

Starting from the product of Example 17 (0.43 g), the title compound was obtained in a similar manner to Example 13b.

Yield: 0.38 g. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.17. MS-ESI: [M + H] ⁺ = 563/565.

Example  19

3- [2-bromo-4- (3-cyano-7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6 - Ethoxyphenoxymethyl ]-N- tert - Butyl Benzamide

To a solution of the product of Example 18 (0.35 g) in 10 mL of dichloromethane, tert-butylamine (0.12 mL), DiPEA (0.39 mL) and HATU (0.30 g) were added and the reaction mixture was stirred at 35 ° C. for 3 hours. Stirred at. A solution of 3% citric acid in water was added and the resulting mixture was extracted several times with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO ₄ and concentrated. The title compound was obtained after flash column chromatography (silica gel, heptane / ethyl acetate (1/4, v / v), R _f = 0.34).

Yield: 0.28 g. MS-ESI: [M + H] ⁺ = 620/622.

Example  20

3- [2- Bromo -4- (3- Cyano -7-ethyl-2- methyl -5-oxo-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -N- Cyclohexylbenzamide

Starting from the product of Example 18 (20 mg) and cyclohexylamine (4.9 μl), the title compound was obtained in a similar manner to Example 13c.

Yield: 7.9 mg. R _f (silica gel, heptane / ethyl acetate (1/4, v / v)) = 0.43. MS-ESI: [M + H] ⁺ = 646/648.

Example  21

3- [2- Bromo -4- (3- Cyano -7-ethyl-2- methyl -5-oxo-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -N- (2-morpholin-4-yl-ethyl)- Benzamide

Starting with the product of Example 18 (20 mg) and 4- (2-aminoethyl) -morpholine (5.5 μl), the title compound was obtained in a similar manner to Example 13c.

Yield: 15 mg. R _f (dichloromethane / methanol (95/5, v / v)) = 0.22. MS-ESI: [M + H] ⁺ = 677/679.

Example  22

4- [3- Iodo -5- Methoxy -4- (3- Methoxybenzyloxy )- Phenyl ]-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-heck four Hydroquinoline-3- Carbonitrile

a) 3- Iodo -5- Methoxy -4- (3- Methoxybenzyloxy )- Benzaldehyde

Starting with 4-hydroxy-3-iodo-5-methoxybenzaldehyde (0.70 g) and 1-bromomethyl-3-methoxybenzene (0.39 mL), the title compound was obtained in the same manner as in Example 15a. .

Yield: 0.56 g. R _f (heptane / ethyl acetate (4/6, v / v)) = 0.42. ¹ H NMR (CDCl ₃ ): δ = 9.83 (s, 1H), 7.86 (d, 1H), 7.43 (d, 1H), 7.29 (t, 1H), 7.16 (bs, 1H), 7.09 (d, 1H ), 6.88 (dd, 1H), 5.14 (s, 2H), 3.95 (s, 3H), 3.84 (s, 3H).

b) 4- [3- Iodo -5- Methoxy -4- (3- Methoxybenzyloxy )- Phenyl ]-2- methyl -5-oxo-7- Phenyl -1,4,5,6,7,8-hexahydroquinoline-3- Carbonitrile

Starting from the product of step a (24 mg), the title compound was obtained in a similar manner to Example 1a.

Yield: 17 mg. R _f (heptane / ethyl acetate (1/4, v / v)) = 0.59. MS-ESI: [M−H] ⁻ = 631.

Example  23

4- [3- Bromo -4- (2- Chloro -3- Methoxybenzyloxy ) -5- Ethoxyphenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

Starting materials are described in McCarthy et al., J. Org. Chem. 1986 (29) 1586, according to the method described in:

a) 2- Chloro -3- Methoxybenzaldehyde

At −40 ° C. n-butyl lithium (6.25 mL, 1.6 M in hexane) was added to a solution of N, N, N′-trimethylethylenediamine (1.27 mL) in 10 mL of tetrahydrofuran. After 15 minutes, the reaction mixture was cooled to -70 ° C and a solution of 3-methoxybenzaldehyde (1.22 mL) in 5 mL tetrahydrofuran was added. The reaction mixture was warmed to 0 ° C. and cooled again to −70 ° C. before n-butyl lithium (6.25 mL, 1.6 M in hexane) was added. The reaction mixture was warmed to 10 ° C. and cooled again to −30 ° C. and then added to a solution of hexachloroethane (7.10 g) in 10 mL tetrahydrofuran. The reaction mixture was stirred for 2 hours at room temperature, poured into 20 mL of 10% HCl in water and extracted several times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over MgSO ₄ and concentrated. After flash column chromatography (silica gel, heptane / ethyl acetate (75/25, v / v), R _f = 0.38) crystallized from heptane to afford the title product.

Yield: 1.06 g. ¹ H NMR (CDCl ₃ ): δ = 10.46 (s, 1H), 7.54 (dd, 1H), 7.35 (t, 1H), 7.17 (d, 1H), 3.96 (s, 3H).

b) 2- Chloro -One- Chloromethyl -3- Methoxybenzene

A solution of the product of step a (1.00 g) in 5 ml tetrahydrofuran at 0 ° C. was added a suspension of lithium aluminum hydride (0.34 g) in 5 ml tetrahydrofuran. The reaction mixture was stirred for 1 hour at room temperature, 5 mL of tetrahydrofuran in water (0.35 mL) was added at 0 ° C., then 2M sodium hydroxide (0.70 mL) and water (0.70 mL) in water were added. . The white suspension obtained was stirred for 0.5 h and then filtered. After concentrating the filtrate, the resulting colorless oil was dissolved in 10 ml of 1,2-dichloropropane and thionyl chloride (1.5 ml) was added. The reaction mixture was refluxed overnight and concentrated. After flash column chromatography (silica gel, heptane / ethyl acetate (75/25, v / v), R _f = 0.43) the title compound was obtained as a yellow oil which crystallized upon standing.

Yield: 0.80 g. ¹ H NMR (CDCl ₃ ): δ = 7.24 (t, 1H), 7.09 (dd, 1H), 6.93 (dd, 1H), 4.72 (s, 2H), 3.92 (s, 3H).

c) 3- Bromo -4- (2- Chloro -3- Methoxybenzyloxy ) -5- Ethoxybenzaldehyde

Starting from the product of step b (0.42 g) and 5-bromo-3-ethoxy-4-hydroxybenzaldehyde (0.49 g), the title compound was obtained in analogy to Example 15a.

Yield: 0.56 g. ¹ H NMR (CDCl ₃ ): δ = 9.85 (s, 1H), 7.66 (dd, 1H), 7.40 (dd, 1H), 7.39 (d, 1H), 7.29 (t, 1H), 6.94 (dd, 1H ), 5.32 (s, 2H), 4.15 (quar., 2H), 3.93 (s, 3H), 1.44 (t, 3H).

d) 4- [3- Bromo -4- (2- Chloro -3- Methoxybenzyloxy ) -5- Ethoxyphenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

Starting from 5-propylcyclohexane-1,3-dione (21 mg) and the product of step c (53 mg), the title compound was obtained in analogy to Example 1a.

Yield: 60 mg. R _f (heptane / ethyl acetate (4/6, v / v)) = 0.19. MS-ESI: [M-H] ⁻ = 597/599/601.

Example  24

Glycine, N-3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] Benzoyl , methyl  ester

a) 3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydrate Loquinolin-4-yl) -6- Ethoxyphenoxymethyl ] -Benzoic acid methyl  ester

Starting with 5-propylcyclohexane-1,3-dione (0.95 g) and the product of Example 15a (2.4 g), the title compound was obtained in a similar manner to Example 1a.

Yield: 3.0 g. R _f (heptane / ethyl acetate (1/1, v / v)) = 0.20. MS-ESI: [M−H] ⁻ = 591/593.

b) 3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -Benzoic acid

Starting from the product of step a (3.0 g), the title compound was obtained in a similar manner to Example 13b.

Yield: 3.0 g. MS-ESI: [M−H] ⁻ = 577/579.

c) glycine, N-3- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hex four Hydroquinolin-4-yl) -6- Ethoxyphenoxymethyl ] Benzoyl , methyl  ester

Starting from the product of step b (90 mg) and glycine methyl ester hydrochloride (64 mg), the title compound was obtained in a similar manner to Example 14. Purification was achieved via preparative HPLC (Luna C18 [5 μm], flow rate: 20 mL min ⁻¹ , 0 → 90% CH ₃ CN, 1% TFA).

Yield: 59 mg. R _t (CH ₂ Cl ₂ / MeOH (95/5, v / v)) = 0.54. MS-ESI: [M + H] ⁺ = 650/652.

Example  25

4- [3- Bromo -5- Ethoxy -4- (3- Methoxybenzyloxy )- Phenyl ] -7- (4- Chlorophenyl )-2- methyl -5-oxo-1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

a) 3- Bromo -5- Ethoxy -4- (3- Methoxybenzyloxy )- Benzaldehyde

Starting with 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.75 g) and 1-bromomethyl-3-methoxybenzene (0.48 mL), the title compound was obtained in a similar manner to Example 15a. .

Yield: 0.91 g. R _f (heptane / ethyl acetate (2/1, v / v)) = 0.43. ¹ H NMR (CDCl ₃ ): δ = 9.83 (s, 1H), 7.65 (dd, 1H), 7.38 (dd, 1H), 7.29 (t, 1H), 7.13 (bs, 1H), 7.07 (d, 1H ), 6.88 (dd, 1H), 5.16 (s, 2H), 4.16 (quar., 2H), 3.83 (s, 3H), 1.56 (t, 3H).

b) 4- [3- Bromo -5- Ethoxy -4- (3- Methoxybenzyloxy )- Phenyl ] -7- (4- Chlorophenyl ) -2-methyl-5-oxo-1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

Starting with 5- (4-chlorophenyl) -cyclohexane-1,3-dione (22 mg) and the product of step a (37 mg), the title compound was obtained in a similar manner to Example 1a.

Yield: 32 mg. R _f (heptane / ethyl acetate (3/7, v / v)) = 0.19. MS-ESI: [M + H] ⁺ = 633/635/637.

Example  26

4- [3- Bromo -5- Ethoxy -4- (3- Methoxybenzyloxy )- Phenyl ] -7-furan-2-yl-2- methyl -5-oxo-1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile

Starting with 5-furan-2-ylcyclohexane-1,3-dione (18 mg) and the product of Example 25a (37 mg), the title compound was obtained in a similar manner to Example 1a.

Yield: 37 mg. R _f (heptane / ethyl acetate (3/7, v / v)) = 0.24. MS-ESI: [M + H] ⁺ = 589/591.

Example  27

4- [3,5- Dimethoxy -4- (3- Methoxybenzyloxy )- Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile

a) 3,5- Dimethoxy -4- (3- Methoxybenzyloxy )- Benzaldehyde

Starting with 4-hydroxy-3,5-dimethoxybenzaldehyde (0.91 g) and 1-bromomethyl-3-methoxybenzene (0.75 mL), the title compound was obtained in the same manner as in Example 15a.

Yield: 1.42 g pale yellow oil. R _f (heptane / ethyl acetate (1/1, v / v)) = 0.40. ¹ H NMR (CDCl ₃ ): δ = 9.86 (s, 1H), 7.26 (d, 1H), 7.23 (d, 1H), 7.09 (bs, 1H), 7.04 (d, 1H), 6.85 (dd, 1H ), 5.12 (s, 2H), 3.91 (s, 6H), 3.82 (s, 3H).

b) 4- [3,5- Dimethoxy -4- (3- Methoxybenzyloxy )- Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile

Starting from 5-propylcyclohexane-1,3-dione (11 mg) and the product of step a (21 mg), the title product was obtained in analogy to Example 1a.

Yield: 22 mg. R _f (heptane / ethyl acetate (3/7, v / v)) = 0.21. MS-ESI: [M + H] ⁺ = 503; [M + Na] ⁺ = 525.

Example  28

4- [3- Bromo -5- Ethoxy -4- (3-pyridinyl Methoxy ) Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile Trifluoroacetic acid

a) 3- Bromo -5- Ethoxy -4- (3- Pyridinylmethoxy )- Benzaldehyde

Starting with 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.25 g) and 3-picolyl chloride hydrochloride (0.16 g), the title compound was obtained in analogy to Example 15a.

b) 4- [3- Bromo -5- Ethoxy -4- (3- Pyridinylmethoxy ) Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -3- Carbonitrile Trifluoroacetic acid

Derived from 5-propylcyclohexane-1,3-dione (0.15 g) and the crude product of step a, similar to Example 1a to afford the title compound. The compound was purified by semipreparative HPLC (Luna C18 [5 μm], flow rate: 20 mL min ⁻¹ , 10 → 90% CH ₃ CN, 0.1% TFA) and lyophilized from a mixture of water and dioxane.

Yield: 0.25 g. MS-ESI: [M + H] ⁺ = 536/538.

Example  29

4- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -N-thiophene-2- Monomethylbenzamide

a) 4- (2- Bromo -6- Ethoxy -4- Formylphenoxymethyl ) -Benzoic acid methyl  ester

Starting from 4-bromomethylbenzoic acid methyl ester (3.7 g), the title compound was obtained in a similar manner to Example 15a.

Yield: 6.4 g. ¹ H NMR (CDCl ₃ ): δ = 9.84 (s, 1H), 8.06 (d, 2H), 7.65 (d, 1H), 7.61 (d, 2H), 7.39 (d, 1H), 5.03 (s, 2H ), 4.16 (q, 2H), 3.93 (s, 3H), 1.48 (t, 3H).

b) 4- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -Benzoic acid methyl  ester

Starting from 5-propylcyclohexane-1,3-dione (2.5 g) and the product of step a (6.4 g), the title compound was obtained in a similar manner to Example 1a.

Yield: 6.7 g. R _f (heptane / ethyl acetate (3/2, v / v)) = 0.20. MS-ESI: [M-H] ⁻ = 591/593.

c) 4- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -Benzoic acid

Starting from the product of step b (6.7 g), the title compound was obtained in a similar manner to Example 13b. The reaction mixture was stirred overnight at 50 ° C.

Yield: 6.4 g. MS-ESI: [M−H] ⁻ = 577/579.

d) 4- [2- Bromo -4- (3- Cyano -2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydroquinoline -4-yl) -6- Ethoxyphenoxymethyl ] -N-thiophene-2- Monomethylbenzamide

Starting from the product of step c (0.10 g) and 2-thiophenmethylamine (52 μl), the title compound was obtained in a similar manner to Example 14. Purification was achieved via preparative HPLC (Luna C18 [5 μm], flow rate: 20 mL min ⁻¹ , 10 → 90% CH ₃ CN, 1% TFA).

Yield: 54 mg. MS-ESI: [M + H] ⁺ = 674/676.

Example  30

4- [3- Bromo -5- Ethoxy -4- (4- Nitrophenoxy )- Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile

a) 4- (3- Bromo -4-hydroxy-5- Ethoxyphenyl )-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile

Starting with 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (2.0 g) and 5-propylcyclohexane-1,3-dione (1.3 g), the title compound was obtained in a similar manner to Example 1a. .

Yield: 3.6 g. MS-ESI: [M−H] ⁻ = 443/445.

b) 4- (3- Bromo -4- Mesyloxy -5- Ethoxyphenyl )-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hex four Hydroquinoline-3- Carbonitrile

A mixture of crude product (0.99 g), mesyl chloride (0.46 mL) and sodium hydroxide (0.32 g) in 4 mL of THF / water (1/1, v / v) was stirred at room temperature for 3 days. . Water was added and the reaction mixture was extracted with dichloromethane. The crude title compound was obtained after concentration of the organic phase.

Yield: 1.0 g. MS-ESI: [M−H] ⁻ = 521/523.

c) 4- [3- Bromo -5- Ethoxy -4- (4- Nitrophenoxy )- Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3- Carbonitrile

The mixture of product of step b (0.20 g), 1-fluoro-4-nitrobenzene (53 μl) and cesium carbonate (0.22 g) was dissolved in dimethyl sulfoxide (1 mL) and stirred at 80 ° C. for 16 h. It was. Dichloromethane was added and the reaction mixture was washed with a solution of 1% hydrochloric acid in water and saturated brine. The organic phase was concentrated and after flash column chromatography (silica gel, heptane / ethyl acetate) to afford the title compound.

Yield: 0.19 g. MS-ESI: [M−H] ⁻ = 564/566. ¹ H NMR (CDCl ₃ ): δ = 8.17 (d, 2H), 7.00 (d, 1H), 6.91 (m, 3H), 5.95 (bs, 1H), 4.63 (s, 1H), 4.04 (dq, 2H ), 2.52 (dd, 1H), 2.42 (d, 2H), 2.25 (m, 1H), 2.20 (s, 3H), 2.15 (dd, 1H), 1.38 (m, 4H), 1.20 (t, 3H) , 0.92 (t, 3 H).

Example  31

4- [3- Bromo -5- Ethoxy -4- (5- Fluoro -2- Propylamino - Benzyloxy )- Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydro -Quinoline-3- Carbonitrile

a) (5- Fluoro 2-nitro- Phenyl ) -Methanol

To a solution of 5-fluoro-2-nitrobenzoic acid (4.58 g) in THF (50 mL) while cooling with an ice bath was added a 1 M solution of BH ₃ .THF in THF (62 mL). The cooling bath was removed and stirring continued at ambient temperature for 1 hour and then refluxed for 4 hours. The reaction mixture was cooled down and methanol was added to break up excess borane. The mixture was concentrated and water and ethyl acetate were added to the residue. The organic layer was washed with brine, dried and concentrated.

Yield: 4.3 g.

b) 4- [3- Bromo -5- Ethoxy -4- (5- Fluoro 2-nitro- Benzyloxy )- Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydro -Quinoline-3- Carbonitrile

The mixture of crude product of step a (1.5 g), thionyl chloride (1.94 mL) and a few drops of DMF in dichloromethane (30 mL) was stirred for 72 h. The mixture was concentrated in vacuo and the residue was dissolved in DMF (20 mL). To the remaining solution was added compound (3.9 g), K ₂ CO ₃ (6.1 g) and a small amount of tetra-n-butylammonium bromide (about 50 mg) described in Example 30a. The mixture was stirred at 60 ° C. for 5 hours. Water and ethyl acetate were added and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried and concentrated. The residue was recrystallized from toluene.

Yield: 3.8 g

c) 4- [4- (2-amino-5- Fluoro - Benzyloxy ) -3- Bromo -5- Ethoxy - Phenyl ]-2- methyl -5-oxo-7-propyl-1,4,5,6,7,8- Hexahydro -Quinoline-3- Carbonitrile

To a solution of the product of step b (3.8 g) in THF (110 mL) was added acetic acid (3.6 mL) and zinc powder (8.2 g). The suspension was heated at 50 ° C. for 1 hour. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO ₃ and brine. The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated. The residual solid was stirred with a small amount of ethyl acetate and after filtration the title compound was obtained as a pale yellow solid.

Yield: 2.8 g

d) 4- [3- Bromo -5- Ethoxy -4- (5- Fluoro -2- Propylamino - Benzyloxy )- Phenyl ] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8- Hexahydro -Quinoline-3- Carbonitrile

The solution of compound (200 mg) and propionaldehyde (25 μl) described in step c in dichloromethane (5 mL) was stirred for 2 hours. Acetic acid (81 μl) and sodium triacetoxyborohydride (300 mg) were then added and the mixture was stirred for an additional 20 hours. 2 M aqueous NaOH solution was added and stirring continued for 15 minutes. The organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (Luna C18 [5 μm], flow rate: 20 mL min ⁻¹ , 10 → 90% CH ₃ CN, 0.1% TFA), lyophilized from a mixture of water and dioxane and titled The compound was obtained. Some dialkylated products could also be isolated (see Example 32).

Yield: 109 mg. MS-ESI: [M + H] ⁺ = 610/612.

Example  32

4- [3-bromo-4- (2-dipropylamino-5-fluoro-benzyloxy) -5-ethoxy-phenyl] -2-methyl-5-oxo-7-propyl-1,4, 5,6,7,8-hexahydro-quinoline-3-carbonitrile

The reaction mixture of Example 31d was purified by preparative HPLC (Luna C18 [5 μm], flow rate: 20 mL min ⁻¹ , 10 → 90% CH ₃ CN, 0.1% TFA) from the mixture of water and dioxane After lyophilization, the title compound was obtained.

Yield: 12 mg. MS-ESI: [M + H] ⁺ = 652/654.

Example  33

CHO - FSH In vitro  Biological activity

The FSH activity of the compounds was tested in Chinese hamster ovary (CHO) cells stably transformed with human FSH receptors and co-transformed with cAMP reactive element (CRE) / promoter to direct the expression of firefly luciferase information genes. Binding of ligands to the FSH receptor coupled to Gs resulted in an increase in cAMP, leading to an increase in the metastatic activity of the luciferase information construct. Luciferase signal was quantified using an luminescence counter. For the test compound, the EC ₅₀ value (the concentration of the test compound resulting in stimulation of 1/2 (50%) of the maximum value) was calculated. For this purpose, a software program GraphPad PRISM, version 3.0 (GraphPad Software Inc., San Diego, USA) was used.

Compounds of all examples had an activity (EC ₅₀ ) of less than 10 ⁻⁵ M. The compounds of Examples 13, 16, 17, 19-21, 23, 26, 28, 31 and 32 exhibited an EC ₅₀ of 10 ⁻⁷ to 10 ⁻⁹ M. The compounds of Examples 24 and 29 exhibited an EC ₅₀ of less than 10 ⁻⁹ M.

Claims (12)

Except for 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile, Dihydropyridine derivative compounds of formula (I) or a pharmaceutically acceptable salt thereof: Formula I

In the above formula, R ¹ is (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl or phenyl, (1-5C) heteroaryl [both hydroxy, amino, halogen, nitro, trifluoro One or more selected from methyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) (di) alkylamino Optionally substituted with a substituent; R ² , R ³ are independently (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (2-4C) alkenyloxy, (3- 4C) alkynyloxy or halogen; R ⁴ is (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl, (2-6C) heterocycloalkyl (1-4C) alkyl, (6-10C) aryl, (6-10C) aryl (1-4C) alkyl , (1-9C) heteroaryl or (1-9C) heteroaryl (1-4C) alkyl, wherein the (hetero) aryl group is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C Optionally substituted with one or more substituents selected from alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) (di) alkylamino], and R ^{In case of tetravalent} phenyl, in addition to the above substituents, (1-4C) alkylthio, (1-4C) alkylsulfonyl, R ⁵ -oxycarbonyl, R ⁵ -carbonyl or R ⁵ , R ⁶ -aminocarbonyl Substituted; X is SO ₂ , CH ₂ , C (O) or X is absent, wherein when X is CH ₂ , R ⁴ can also be R ⁵ -oxycarbonyl or R ⁵ -carbonyl; R ⁵ , R ⁶ are independently H, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1 -4C) alkyl, (2-6C) heterocycloalkyl, (2-6C) heterocycloalkyl (1-4C) alkyl, (1-4C) alkoxycarbonyl (1-4C) alkyl, (1-4C) ( Di) alkylaminocarbonyl (1-4C) alkyl, (6-10C) arylaminocarbonyl (1-4C) alkyl, (1-9C) heteroarylaminocarbonyl (1-4C) alkyl, (6-10C ) Aryl, (1-9C) heteroaryl, (6-10C) aryl (1-4C) alkyl or (1-9C) heteroaryl (1-4C) alkyl [wherein the (hetero) aryl group is hydroxy, amino, halogen , Nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy or (1-4C) (di) alkyl Optionally substituted with one or more substituents selected from amino], or R ^5, R ⁶ - aminocarbonyl in R ^5, R ⁶ is (2-6C) may be bonded to the heterocycloalkyl ring. The compound of claim 1, wherein R ⁴ is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, ( 1-4C) alkoxy, (1-4C) (di) alkylamino, (1-4C) alkylthio, (1-4C) alkylsulfonyl, R ⁵ -oxycarbonyl, R ⁵ -carbonyl or R ⁵ , And phenyl optionally substituted with one or more substituents selected from R ⁶ -aminocarbonyl. The compound of claim 2, wherein the substituent of phenyl at R ⁴ is R ⁵ , R ⁶ -aminocarbonyl, (1-4C) alkoxy and / or halogen. A compound aminocarbonyl in R ^5, R ⁶ are (1-4C) (di) alkylamino in that - according to claim 3, R ^5, R ^6. 4. The method of claim 3, R ^5, R ⁶ - amino-carbonyl in R ⁵ is (1-4C) alkoxycarbonyl (1-4C) alkyl, R ⁶ is H in the compound. 4. The method of claim 3, R ^5, R ⁶ - aminocarbonyl in R ⁵ is (1-9C) heteroaryl (1-4C) alkyl [wherein (hetero) aryl groups are hydroxy, amino, halogen, nitro, trifluoromethyl Romethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) (di) alkylamino or (1- Optionally substituted with one or more substituents selected from alkoxycarbonyl (1-4C) alkyl, and R ⁶ is H. ⁴ . The compound of any one of claims 1 to 6, wherein X is CH ₂ . 8. The compound of claim 1, wherein R ¹ is (1-6C) alkyl, phenyl or (1-5C) heteroaryl. The compound of any one of claims 1-8, wherein R ² , R ³ are halogen and / or (1-4C) alkoxy. The compound of any one of claims 1-9 for use in therapy. Comprising 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically suitable adjuvant. 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile, or its Use of the compound of any one of claims 1 to 9, including a pharmaceutically acceptable salt or solvate, for the manufacture of a medicament for the treatment of fertility disorder.