RU2372337C2 - Dihydropyridine derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to dihydropyridine derivatives with general formula

, or their pharmaceutically acceptable salts, where R¹ is C_1-6alkyl or phenyl, C_1-5heteroaryl, both optionally substituted with one or more substitutes, chosen from hydroxy, amino, halogen, nitro, cyano; R², R³ are independently C_1-4alkyl, C_1-4alkoxy group, C_2-4alkenyloxy group, C_3-4alkynyloxy group, halogen; R⁴ is C_1-6alkyl, C_3-6cycloalkyl, C_3-6cycloalkylC_1-4alkyl, C_6-10aryl, C_6-10arylC_1-4alkyl, C_1-9heteroaryl, where the (hetero)aryl group is optionally substituted with one or more substitutes, chosen from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy group, C_1-4(di)alkylamino group, and, if R⁴ is a phenyl, additionally from C_1-4alkylthio group, C_1-4alkylsulphonyl, R⁵-oxycarbonyl, R⁵-carbonyl or R⁵,R⁶-aminocarbonyl; X is SO₂, CH₂, C(O) or X is absent, where X is CH₂, R⁴ can additionally represent R⁵-oxycarbonyl, or R⁵-carbonyl; R⁵, R⁶ are independently H, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-6cycloakyl, C_3-6cycloalylC_1-4alkyl, C_2-6heterocycloalkyl, C_2-6heterocycloalkylC_1-4alkyl, C_1-4alkoxycarbonylC_1-4alkyl, C_1-4(di)alkylaminocarbonylC_1-4alkyl or C_6-10arylaminocarbonylC_1-4alkyl, C_1-9heteroarylaminocarbonylC_1-4alkyl, C_6-10aryl, C_1-9heteroaryl, C_6-10arylC_1-4alkyl, C_1-9heteroarylC_1-4alkyl, where the (hetero)aryl group is optionally substituted with one or more substitutes, chosen from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy group, C_1-4(di)alkylamino group or R⁵, R⁶ in R⁵, R⁶- aminocarbonyl group can be bonded to a C_2-6heterocycloalkyl ring, as well as to a pharmaceutical composition with antagonistic activity towards FSH receptor and to use of these compounds for making medicinal agents.

EFFECT: compounds which are suitable for treating fertility disorders are obtained and described.

11 cl, 33 ex

Description

The present invention relates to the production of a low molecular weight hormone mimetic that has selective agonistic activity towards the FSH receptor.

Gonadotropins perform important functions in various body functions, including metabolism, thermoregulation and reproductive processes. Gonadotropins act on specific gonadal cells, causing ovarian and testicular differentiation and the formation of steroids. For example, pituitary gonadotropin FSH (follicle-stimulating hormone) plays a major role in stimulating follicular development and maturation, while LH (luteinizing hormone) stimulates ovulation (Sharp, RM Clin. Endocrinol. 33: 787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35: 301-342, 1979). Currently, FSH in combination with LH is used clinically for ovarian stimulation, i.e. for ovarian hyperstimulation for in vitro fertilization (IVF) and ovulation stimulation in anovulatory infertile women (Insler V., Int. J. Fertility 33: 85-97, 1988 ; Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5: 3-13, 1988), as well as with male hypogonadism and male infertility.

Gonadotropin FSH is secreted from the anterior pituitary gland by gonadoliberin and estrogen and from the placenta during pregnancy. In women, FSH acts on the ovaries, stimulating the development of follicles, and is the main hormone that regulates the release of estrogen. In men, FSH is responsible for the preservation of the seminiferous tubules and acts on Sertoli cells, supporting gametogenesis. Purified FSH is clinically used to treat infertility in women and some types of spermatogenesis disorders in men. Gonadotropins intended for therapeutic purposes can be isolated from human urine and are of low purity (Morse et al., Amer. J. Reproduct. Immunol. And Microbiology 17: 143, 1988). Alternatively, they can be obtained in the form of recombinant gonadotropins. Recombinant human FSH is commercially available and is used to maintain reproduction (Olijve et al. Mol. Hum. Reprod. 2: 371, 1996; Devroey et al. Lancet 339: 1170, 1992).

The actions of the hormone FSH are mediated by a specific receptor on the plasma membrane, which is a member of a large family of receptors associated with the G-protein. These receptors consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading to activation of adenylate cyclase.

The FSH receptor is a highly specific target during the growth of the ovarian follicle and is expressed exclusively in the ovary. Blocking the receptor or inhibiting signal transduction, which is usually caused after activation of the FSH-mediated receptor, disrupts the development of the follicle 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, for example, for the treatment of infertility and for ovarian hyperstimulation of in vitro fertilization.

Low molecular weight agonist FSH mimetics have been disclosed in international applications WO 2000/08015 (Applied Research Systems ARS Holding N.V.) and WO 2002/09706 (Affymax Research Institute).

Some derivatives of tetrahydroquinoline are currently disclosed in WO2003 / 004028 (AKZO NOBEL N.V.) as substances that modulate FSH and have agonistic or antagonistic properties.

The present invention relates to the production of low molecular weight hormone mimetics that selectively activate FSH receptors.

Thus, it was found that the following class of dihydropyridine derivatives of formula I or its pharmaceutically acceptable salts has FSH agonistic activity:

Formula I

wherein

R ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl or C _1-5 heteroaryl;

R ² , R ³ independently are C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _2-4 alkenyloxy, C _3-4 alkynyloxy, halogen;

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

R ⁴ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _3-6 cycloalkyl C _1-4 alkyl, C _2-6 heterocycloalkyl, C _2-6 geterotsikloalkilS _1-4 alkyl, C _6-10 aryl, C _6-10 arylC _1-4 alkyl, C _1-9 heteroaryl or C _1-9 geteroarilS _1-4 alkyl.

If X is CH ₂ , then R ⁴ may optionally be R ⁵ -oxyacarbonyl or R ⁵ -carbonyl.

If R ⁴ is phenyl, then in addition to substituents of C _6-10 aryl groups, as mentioned in the definitions, phenyl may optionally be substituted with one or more substituents selected from the following groups:

C _1-4 alkylthio, C _1-4 alkylsulfonyl, R ⁵ -oxyacarbonyl, R ⁵ -carbonyl or R ⁵ , R ⁶ -aminocarbonyl;

R ⁵ , R ⁶ are independently H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl, C _1-4 alkyl, C _2-6 heterocycloalkyl, C _2-6 geterotsikloalkilS _1-4 alkyl, C _1-4 alkoksikarbonilS _1-4 alkyl, C _1-4 (di) alkilaminokarbonilS _1-4 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 arylC _{1 -4} alkyl, C _1-9 heteroaryl C _1-4 alkyl, C _6-10 arylaminocarbonyl C _1-4 alkyl, C _1-9 heteroarylaminocarbonyl C _1-4 alkyl, or R ⁵ , R ⁶ may be bonded to the C _2-6 heterocycloalkyl ring .

The compounds of the present invention modulate the function of the FSH receptor and can be used for the same clinical purposes as the native FSH, since they behave like agonists with the advantage that they can exhibit altered stability properties and can be applied in different ways.

Thus, the FSH receptor agonists of the present invention can be used to treat infertility. Preferably, the compounds of the present invention are used to activate the FSH receptor.

The term “C _1-4 alkyl,” as used herein, means a branched or unbranched alkyl group having 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec -butyl and tert- butyl.

The term “C _1-6 alkyl” means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, n- pentyl and n- hexyl. C _1-5 alkyl groups are preferred, C _1-4 alkyls are most preferred.

The term “C _2-6 alkenyl” means a branched or unbranched alkenyl group having 2-6 carbon atoms, such as ethenyl, 2-butenyl and n- pentenyl.

The term “C _2-4 alkenyl” means a branched or unbranched alkenyl group having 2-4 carbon atoms, such as ethenyl, n- propenyl and 2-butenyl.

The term “C _2-6 alkynyl” means a branched or unbranched alkynyl group having 2-6 carbon atoms, such as ethynyl, propynyl and n- pentynyl.

The term “C _2-4 alkynyl” means a branched or unbranched alkynyl group having 2-4 carbon atoms, such as ethynyl and propynyl.

The term “C _3-6 cycloalkyl” means a cycloalkyl group having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “C _3-6 cycloalkenyl” means a cycloalkenyl group having 3-6 carbon atoms, such as cyclopropenyl, cyclopentenyl and cyclohexenyl.

The term “C _3-6 cycloalkylC _1-4 alkyl” means a cycloalkylalkyl group whose cycloalkyl group has 3-6 atoms with the same meaning as defined above and an alkyl group having 1-4 carbon atoms with the same meaning as defined above.

The term “C _2-6 heterocycloalkyl” means a heterocycloalkyl group having 2-6 carbon atoms, preferably 3-5 carbon atoms, and includes at least one heteroatom selected from N, O and / or S that can be attached if possible through a heteroatom or carbon atom. Preferred are N or O heteroatoms. Most preferred are piperidinyl, morpholinyl, pyrrolidinyl and piperazinyl.

The term “C _2-6 heterocycloalkylC _1-4 alkyl” means a heterocycloalkylalkyl group, the heterocycloalkyl group of which has 2-6 atoms with the same meaning as defined above, and an alkyl group having 1-4 carbon atoms with the same meaning as defined above.

The term “C _1-4 alkoxy” means an alkoxyl group having 1-4 carbon atoms, the alkyl part having the same meaning as defined above. C _1-2 alkoxy groups are preferred.

The term “C _1-4 alkylthio” means an alkylthio group having 1-4 carbon atoms, the alkyl part having the same meaning as defined above.

The term “C _2-4 alkenyloxy” means an alkenyloxy group having 2-4 carbon atoms, the alkenyl moiety having the same meaning as defined above.

The term “C _3-4 alkynyloxy” means an alkynyloxy group having 3-4 carbon atoms, the alkynyl moiety having the same meaning as defined above.

The term “C _6-10 aryl” means an aromatic hydrocarbon group having 6-10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl, which may be optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy groups or C _1-4 (di) alkylamino groups, the alkyl part having the same meaning as defined above. A preferred aromatic hydrocarbon group is phenyl.

The term “C _1-9 heteroaryl” means a substituted or unsubstituted aromatic group having 1-9 carbon atoms, including at least one heteroatom selected from N, O and / or S, such as tetrazolyl, imidazolyl, thiadiazolyl, pyridinyl, (benzo) thienyl, (benzo) furyl, (iso) quinolinyl, tetrahydro (iso) quinolinyl, coumarinyl, quinoxalinyl or indolyl. The substituents in the C _1-9 heteroaryl group may be selected from the group of substituents listed for the C _6-10 aryl group. C _1-5 heteroaryl is preferred. With _{1-9 a} heteroaryl group may be attached, if possible, through a carbon atom or through a heteroatom.

The term “C _1-5 heteroaryl” means a substituted or unsubstituted aromatic group having 1-5 carbon atoms, including at least one heteroatom selected from N, O and / or S, such as tetrazolyl, imidazolyl, thiadiazolyl, pyridinyl, thienyl or furyl, with furyl being most preferred. Preferred heteroaryl groups are thienyl, furyl and pyridinyl. Substituents in the C _1-5 heteroaryl group may be selected from the group of substituents listed for the C _6-10 aryl group.

The term "C _6-10 arylC _1-4 alkyl" means an arylalkyl group, the aryl group of which contains 6-10 carbon atoms with the same meaning as defined above, and an alkyl group having 1-4 carbon atoms with the same meaning as defined above. Most preferred is benzyl.

The term “C _1-9 heteroaryl C _1-4 alkyl” means a heteroarylalkyl group whose heteroaryl group contains 1-9 atoms with the same meaning as defined above, and an alkyl group having 1-4 carbon atoms with the same meaning as defined above.

The term “C _1-4 alkylsulfonyl” means an alkylsulfonyl group, the alkyl group of which contains 1-4 carbon atoms with the same meaning as defined above.

The term “C _1-4 alkoxycarbonyl” means a C _1-4 alkoxycarbonyl group, the alkoxy group of which contains 1-4 carbon atoms with the same meaning as defined above. Preferred are C _1-2 alkoxycarbonyl groups.

The term “C _1-4 alkoxycarbonylC _1-4 alkyl” means an alkoxycarbonylalkyl group, the alkyl group of which contains 1-4 carbon atoms with the same meaning as defined above.

The term “C _1-4 (di) alkylaminocarbonylC _1-4 alkyl” means a (di) alkylaminocarbonylalkyl group, the alkyl group of which contains 1-4 carbon atoms with the same meaning as defined above.

The term “halogen” means fluoro, chloro, bromo and iodo.

The term “pharmaceutically acceptable salts” represents those salts which are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reaction and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be obtained during the final isolation and purification of the compounds of the invention, either separately by reacting the free functional base with a suitable mineral acid, such as hydrochloric acid, phosphoric acid or sulfuric acid, or with an organic acid, such as 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. An acidic functional group may interact with an organic or mineral base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

The invention also relates to compounds of formula I in which R ¹ is C _1-6 alkyl, phenyl or C _1-5 heteroaryl, all optionally substituted with substituents, as mentioned in the definitions. More specifically, the invention relates to compounds in which R ¹ is C _1-6 alkyl, phenyl, C ₄ heteroaryl. The invention also relates to compounds in which R ¹ is n- propyl or furyl.

Another aspect of the invention are compounds of formula I in which R ² , R ³ are halogen and / or C _1-4 alkoxy.

In another aspect, the invention relates to compounds of formula I, in which X is CH ₂ .

Another aspect of the invention is a compound in which R ⁴ is phenyl optionally substituted with substituents as mentioned in the definition.

In another aspect, the invention relates to compounds in which R ⁴ is phenyl, which is substituted in the ortho and / or meta positions. In yet another aspect, the invention relates to compounds of formula I in which R ⁴ is phenyl substituted with R ⁵ , R ⁶ -aminocarbonyl, C _1-4 alkoxy and / or halogen. In another aspect, the invention relates to compounds in which R ⁵ , R ⁶ in R ⁵ , R ⁶ -aminocarbonyl group is a C _1-4 (di) alkylamino group, C _1-4 alkoxycarbonylC _1-4 alkyl, or C _1-9 heteroaryl _1-4 alkyl. In yet another aspect, at least one of R ⁵ , R ⁶ in the R ⁵ , R ⁶ -aminocarbonyl group is H.

In another aspect, the invention relates to compounds wherein C _6-10 aryl, C _6-10 arylC _1-4 alkyl, C _1-9 heteroaryl or C _1-9 geteroarilS _1-4 alkyl in R ⁴ are unsubstituted.

Another aspect of the invention relates to compounds in which X = CH ₂ and in which

R ⁴ is phenyl optionally substituted with substituents as mentioned in the definitions.

Another aspect of the invention relates to compounds in which all of the specific definitions of groups R ¹ to R ⁴ , as hereinbefore defined, are combined in a dihydropyridine compound of formula I.

2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile is excluded from the scope of the invention.

Excluded compound refers to CAS330674-72-1, available from commercial sources like Cembridge Corp., MicroChemistry Ltd, Ambinter, Asinex, Scientific Exchange Inc. and ChemDiv Inc.

Suitable processes for preparing the compounds of the invention are described below.

Derivatives of 1,4-dihydropyridine I of the present invention can be obtained by a well-described Ganch three-component cyclocondensation from cyclohexane-1,3-dione of the general formula II, benzaldehydes of the general formula III and 3-aminocrotonitrile IV, in which R ¹ , R ² , R ³ , R ⁴ and X are as defined above.

Related Ganch cyclocondensation reactions can be found at 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 above reactions are usually carried out at elevated temperatures in a protic solvent, such as, for example, acetic acid, (iso) propanol, ethanol, methanol, or mixtures thereof.

Alternatively, compounds of general formula I can be synthesized by first reacting cyclohexane-1,3-diones of formula II with benzaldehydes of formula III in the presence of a base such as, but not limited to, ammonium acetate, and then reacting the intermediate 2-benzylidenecyclohexane-1,3 a dione of general formula V in which R ¹ , R ² , R ³ , R ⁴ and X have the same meaning as defined above with 3-aminocrotonitrile IV.

Compounds of general formula Ia in which X = a bond and R ⁴ = H can be used to prepare Ibe compounds by O- alkylation, O - (hetero) arylation, O- acylation or O- sulfonylation by conventional methods well known to those skilled in the art .

In a typical experiment, compounds Ia are reacted in a solvent such as dichloromethane, N, N- dimethylformamide, dimethyl sulfoxide, ethanol, tetrahydrofuran, dioxane, toluene, 1-methylpyrrolidin-2-one or pyridine, with an alkyl halide, or an acyl halide, or anhydride sulfonyl halide, or (hetero) aryl halide in the presence of a base such as, but not limited to, triethylamine, N, N-diisopropylethylamine (DiPEA), potassium carbonate, cesium carbonate or sodium hydride, optionally in the presence of a catalytic amount of iodide cal I or tetrabutylammonium iodide, and / or a Cu- or Pd-catalyst to give O -alkylated, O - (hetero) arylated, O or O -acylated -sulfonilirovannogo derivative of formula Ib, Ic, Id and Ie, respectively.

Compounds of the formula If in which X = CH ₂ and R ⁴ = an alkyl acid derivative or a (hetero) aryl acid derivative obtained by alkaline (e.g. NaOH) saponification of the corresponding alkyl ester can be condensed with amines of the general structure R ⁵ , R ⁶ NH or alcohols of the general formula R ⁵ OH using a coupling reagent such as diisopropylcarbodiimide (DIC), (3-dimethylaminopropyl) ethylcarbodiimide (EDCI), O - (benzotriazol-1-yl) - N, N, N ', N' -tetramethyluronium hexafluorophosphate ( TBTU) or O - (7-azabenzotriazole-1-yl) - N, N, N ' , N' -tetrametiluroniygeksaftorfosfat (HATU), a tertiary amine base (DiPEA) in a solvent such as N, N- dimethylformamide or dichloromethane at ambient or elevated temperature to form compounds of formula Ig and Ih.

Substituted cyclohexane-1,3-dione of general formula II are commercially available or can be obtained by methods known from the literature in this field. Suitable 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.

Benzaldehydes of the general formula III are also commercially available or can be prepared according to literature methods: 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 1070162, J. Org. Chem. 23 (1958) 120.

Alternatively, compounds III-a in which X = bond and R ⁴ = H can be used to synthesize III-be compounds by O- alkylation, O - (hetero) arylation, O- acylation or O- sulfonylation using standard conditions, as described above for compounds Ia.

The compounds of the present invention have at least two chiral carbon atoms and therefore can be obtained as pure enantiomers, or as a mixture of enantiomers, or a mixture of diastereomers. Methods for producing pure enantiomers are well known in the art, for example, crystallization of salts that are obtained from optically active acids and racemic mixtures, or chromatography using chiral columns. Columns with a normal phase or a reverse phase can be used to separate the diastereomers.

The compounds of the invention may form hydrates or solvates. Those skilled in the art know that charged compounds form hydrated fragments upon lyophilization with water or form solvates when concentrated in solution with a suitable organic solvent. The compounds of this invention include hydrates or solvates of these compounds.

To select active compounds, testing at 10 ⁻⁵ M should result in an activity of more than 20% of the maximum activity when FSH is used as a comparison. Another criterion may be an EC ₅₀ value, which should be <10 ^-5 M, preferably <10 ^-7 M, even more preferably <10 ^-9 M.

It will be apparent to those skilled in the art that the desired EC ₅₀ values depend on the test compound. For example, a compound with an EC ₅₀ that is less than 10 ⁻⁵ M is a commonly considered drug candidate. Preferably, the value is lower than 10 ⁻⁷ M. However, a compound that has a higher EC ₅₀ but is selective for a particular receptor may even be a better candidate.

Methods for determining gonadotropin receptor binding, as well as in vitro and in vivo assays for determining biological activity, are well known. In general, an expressed receptor is contacted with a test compound, and binding, or stimulation, or inhibition of a functional response is measured.

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

Methods for creating recombinant FSH expressing cell colonies are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Receptor expression is achieved by expression of the DNA encoding the desired protein. Targeted mutagenesis techniques, cross-linking of additional sequences, PCR and the construction of suitable expression systems are currently well known in the art. Fragments or all of the DNA encoding the desired protein can be synthetically engineered using standard solid phase techniques; it is preferable to include restriction sites to reduce crosslinking. Suitable regulatory elements for transcription and translation of the incorporated coding sequence can be incorporated into DNA coding sequences. It is well known that expression systems are currently available that are compatible with a wide range of hosts, including prokaryotic hosts such as bacteria, and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, bird cells and the like.

Cells expressing the receptor are then contacted with a test compound to observe binding, or stimulation, or inhibition of a functional response.

Alternatively, isolated cell membranes containing an expressed receptor can be used to measure the binding of the compound.

Radioactive or fluorescent compounds may be used to measure binding. As a comparison compound, human recombinant FSH can be used.

Alternatively, a competing binding assay can also be performed.

Another assay involves screening for FSH receptor agonist compounds by determining the stimulation of receptor-mediated cAMP accumulation. Thus, a similar method involves expressing the receptor on the cell surface of the host cell and exposing the test compound to the cell. Then the amount of cAMP is measured. The level of cAMP will increase due to the stimulating effect of the test compound on receptor binding.

In addition to directly measuring, for example, the cAMP levels in the affected cell, cell lines can be used that, in addition to transfecting with a DNA encoding receptor, also transfect transfected DNA that encodes a reporter gene whose expression corresponds to the cAMP level. Such reporter genes can be inducible by cAMP or can be obtained in such a way that they are associated with the original elements sensitive to cAMP. In general, reporter gene expression can be controlled by any elements that are sensitive to changes in cAMP levels. Suitable reporter genes are, for example, LacZ, alkaline phosphatase, firefly luciferase and green fluorescent protein. The principles for such transactivation evaluations 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 present invention also relates to a pharmaceutical composition comprising a dihydropyridine derivative or pharmaceutically acceptable salts thereof, having the general formula I in a mixture with pharmaceutically acceptable excipients and optionally other therapeutic agents. Excipients must be “acceptable” in the sense that they are compatible with the other ingredients of the composition and are not harmful to their owners. The pharmaceutical compositions may also contain 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile.

Compositions include, for example, those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local or rectal administration and the like, all in unit dosage units for administration.

For oral administration, the active ingredient may be presented as separate dosage forms, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition can be presented in the form of containers containing one dose or multiple doses of a medicinal product, for example, liquid for injection in predetermined quantities, for example, in sealed vials and ampoules, and can also be stored in a frozen (lyophilized) form, requiring before use, add only a sterile liquid carrier, such as water.

An active agent mixed with similar pharmaceutically acceptable excipients, for example, as described in standard reference Gennaro, AR et al., Remington: The Science and Practice of Pharmacy (20 ^th Edition, Lippincott Williams and Wilkins, 2000, see specifically Part 5 : Pharmaceutical Manufacturing), can be compressed into a solid unit dose, such as pills, tablets, or transferred to capsules or suppositories. Using pharmaceutically acceptable liquids, the active agent can be used in the form of a liquid composition, for example, as a solution for injection, in the form of solutions, suspensions, emulsions or as a spray, for example a nasal spray.

For the preparation of a solid unit dosage form, conventional additives such as fillers, colorants, polymeric binders and the like are used. In general, any pharmaceutically acceptable additives that do not interact with the active compounds may be used. Suitable carriers with which the active agent of the present invention can be used as a solid dosage unit include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions containing pharmaceutically acceptable dispersing agents and / or wetting agents such as propylene glycol or butylene glycol can be used.

The invention further includes a pharmaceutical composition, as described above, in combination with packaging material suitable for said composition, said packaging material including instructions for using the composition.

The exact dosage and mode of administration of the active ingredient or its pharmaceutical composition may vary depending on the particular compound, route of administration and age, and the condition of the individual patient to whom the drug is prescribed.

In general, parenteral administration requires lower doses than other methods of administration that are more dependent on absorption. However, a suitable dosage for humans may be 0.05-25 mg per kg of body weight. The required dosage can be presented as a single dose or multiple sub-doses taken at appropriate intervals throughout the day, or, in the case of female patients, as doses that should be taken daily during the menstrual cycle. Dosage, as well as the regimen, may vary in patients of men and women.

Thus, the compounds in accordance with the invention can be used in therapy.

The invention also relates to the use of a dihydropyridine derivative having the general formula I for the preparation of a medicament for the treatment of metabolic pathway-mediated disorders mediated by the FSH receptor, preferably for the treatment of infertility.

The invention is illustrated by the following examples.

Example 1

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-hexahydroquinoline-3-carbonitrile

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

Yield: 0.95 g.

MS-ESI: [MH] ^- = 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 of N- methylpyrrolidone was stirred for 2 hours at 80 ° C. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phases were concentrated, and after flash column chromatography (silica gel, heptane / ethyl acetate (1/4 v / v), R _f = 0.52), the title compound was obtained.

Yield: 2.2 mg.

MS-ESI: [MH] ^- = 491/493.

Example 2

4- (3-Bromo-4-cyclohexylmethoxy-5-methoxyphenyl) -2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 1b from the product of Example 1a (15 mg) and bromomethylcyclohexane (12 μl).

Yield: 12 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.59.

MS-ESI: [MH] ^- = 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-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 1b from the product of Example 1a (15 mg) and 1-iodo-3-methylbutane (4.7 μl).

Yield: 14 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.56.

MS-ESI: [MH] ^- = 533/535.

Example 4

4- [3-Bromo-4- (5-chlorothiophen-2-ylmethoxy) -5-methoxyphenyl] -2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline- 3-carbonitrile

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

Yield: 4.7 mg.

MS-ESI: [MH] ^- = 593/595/597.

Example 5

[2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6-methoxyphenoxy] acetic methyl ester acid

The title compound was obtained analogously to example 4 from the product of example 1a (0.47 g) and methyl bromoacetic acid (1.0 ml).

Yield: 0.32 g.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.46.

MS-ESI: [MH] ^- = 535/537.

Example 6

2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6-methoxyphenyl ester of 3-methoxybenzoic acid

The title compound was prepared analogously to Example 4 from the product of Example 1a (15 mg) and 3-methoxybenzoyl chloride (5.4 μl).

Yield: 7.4 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.48.

MS-ESI: [MH] ^- = 597/599.

Example 7

4- [3-Bromo-4- (3-cyanobenzyloxy) -5-methoxyphenyl] -2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 4 from the product of Example 1a (15 mg) and 3-bromomethylbenzonitrile (7.6 mg).

Yield: 15 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.51.

MS-ESI: [MH] ^- = 578/580.

Example 8

4- [3-Bromo-5-methoxy-4- (naphthalen-2-ylmethoxy) phenyl] -2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-3 carbonitrile

The title compound was prepared analogously to Example 4 from the product of Example 1a (15 mg) and 2-bromomethylnaphthalene (8.6 mg).

Yield: 11 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.60.

MS-ESI: [MH] ^- = 603/605.

Example 9

2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6-methoxyphenyl ether phenylmethanesulfonic acid

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

Yield: 15 mg.

MS-ESI: [M + H] ⁺ = 619/621.

Example 10

2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6-methoxyphenyl ether thiophen-2- sulfonic acid

The title compound was prepared analogously to Example 9 from the product of Example 1a (15 mg) and thiophene-2-sulfonyl chloride (8.8 mg).

Yield: 20 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.30.

MS-ESI: [MH] ^- = 611/613.

Example 11

4- [3,5-Dibromo-4- (3-methoxybenzyloxy) phenyl] -7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

a) 3,5-Dibromo-4- (3-methoxybenzyloxy) benzaldehyde

A mixture of 3,5-dibromo-4-hydroxybenzaldehyde (0.28 g), 1-bromomethyl-3-methoxybenzene (0.15 ml), potassium carbonate (0.29 g) and potassium iodide (42 mg) in 10 ml of absolute ethanol 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), the title compound was obtained as an off-white solid.

Yield: 0.24 g.

MS-ESI: [MH] ^- = 463/465.

¹ H NMR (CDCl ₃ ): δ = 9.88 (s, 1H), 8.06 (s, 1H), 7.34 (t, 1H), 7.18 (br s, 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-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 1a from 5-ethylcyclohexane-1,3-dione (8.5 mg) and the product of step a (24 mg).

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-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 1a from 3-bromo-5-ethoxy-4-hydroxybenzaldehyl (0.15 g).

Yield: 0.15 g.

R _f (heptane / ethyl acetate (4/6 v / v)) = 0.18.

MS-ESI: [M + H] ⁺ = 479/481.

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

The title compound was prepared analogously to Example 4 from the product of step a (15 mg) 2-bromo-1- (3-nitrophenyl) ethanone (8.4 mg).

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-hexahydroquinolin-4-yl) -6 methyl ester methoxyphenoxymethyl] benzoic acid

The title compound was prepared analogously to Example 4 from the product of Example 1a (0.35 g) and 3-bromomethylbenzoic acid methyl ester (0.18 g).

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-hexahydroquinolin-4-yl) -6-methoxyphenoxymethyl ]benzoic acid

A 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 2M NaOH in water was added. The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was poured into water and acidified with 2M HCl in water to pH 2 and extracted with ethyl acetate several times. The organic phases were washed with water and saturated brine, dried over Na ₂ SO ₄ and evaporated to give 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-hexahydroquinolin-4-yl) -6-methoxyphenoxymethyl ] - N- thiophen-2-ylmethylbenzamide

To a solution of the product of stage b (20 mg) in 2 ml of dichloromethane were added EDCI (7.0 mg), DiPEA (7 μl) and 2-thiophenomethylamine (4.1 μl) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated, and after flash column chromatography (silica gel, heptane / ethyl acetate (1/4 v / v), R _f = 0.78), the title compound was obtained.

Yield: 11 mg.

MS-ESI: [M + H] ⁺ = 694/696.

Example 14

2- Morpholin-4-yl-ethyl ester 3- [2-bromo-4- (3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4- il) -6-methoxyphenoxymethyl] benzoic acid

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

Yield: 11 mg.

MS-ESI: [M + H] ⁺ = 694/696.

Example 15

4- {3-Bromo-5-ethoxy-4- [3- (piperidin-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

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

Yield: 1.08 g.

¹ H NMR (CDCl ₃ ): δ = 9.84 (s, 1H), 8.20 (broad s, 1H), 8.02 (broad d, 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-hexahydroquinolin-4-yl) -6 methyl ester ethoxyphenoxymethyl] benzoic acid

The title compound was prepared analogously to Example 1a from the product of step a (0.26 g).

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-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl ]benzoic acid

The title compound was obtained analogously to example 13b from the product of step b (0.27 g).

Yield: 0.27 g.

MS-ESI: [M + H] ⁺ = 599/601.

d) 4- {3-Bromo-5-ethoxy-4- [3- (piperidin-1-carbonyl) benzyloxy] phenyl} -2-methyl-5-oxo-7-phenyl-1,4,5,6, 7,8-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 13c from the product of step c (20 mg) and piperidine (3.9 μl).

Yield: 15 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.25.

MS-ESI: [M + H] ⁺ = 680/682.

Example 16

N -3- [2-bromo-4- (3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6 methyl ester ethoxyphenoxymethyl] benzoyl glycine

The title compound was prepared analogously to Example 13c from the product of step 15c (20 mg) and glycine methyl ether hydrochloride (4.9 mg).

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 methyl ester ] benzoic acid

The title compound was prepared analogously to Example 1a from 5-ethylcyclohexane-1,3-dione (0.25 g) and the product of step 15a (0.64 g).

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-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl] benzoic acid

The title compound was obtained analogously to example 13b from the product of example 17 (0.43 g).

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- butylbenzamide

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

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-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl] - N- cyclohexylbenzamide

The title compound was prepared analogously to Example 13c from the product of Example 18 (20 mg) and cyclohexylamine (4.9 μl).

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-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl] - N - (2-morpholin-4-yl-ethyl) benzamide

The title compound was prepared analogously to Example 13c from the product of Example 18 (20 mg) and 4- (2-aminoethyl) morpholine (5.5 μl).

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-hexahydroquinoline-3-carbonitrile

a) 3-Iodine-5-methoxy-4- (3-methoxybenzyloxy) benzaldehyde

The title compound was prepared analogously to Example 15a from 4-hydroxy-3-iodo-5-methoxybenzaldehyde (0.70 g) and 1-bromomethyl-3-methoxybenzene (0.39 ml).

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 ( broad s, 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-hexahydroquinolin-3 carbonitrile

The title compound was prepared analogously to Example 1a from the product of step a (24 mg).

Yield: 17 mg.

R _f (heptane / ethyl acetate (1/4 v / v)) = 0.59.

MS-ESI: [MH] ^- = 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

The feedstock was obtained in accordance with the method described by McCarthy et al. (J. Org. Chem. 1986 (29) 1586):

a) 2-Chloro-3-methoxybenzaldehyde

To a solution of N, N, N ' -trimethylethylenediamine (1.27 ml) in 10 ml of tetrahydrofuran at -40 ° C was added n- butyllithium (6.25 ml, 1.6 M solution in hexane). After 15 minutes, the reaction mixture was cooled to -70 ° C and a solution of 3-methoxybenzaldehyde (1.22 ml) in 5 ml of tetrahydrofuran was added. The reaction mixture was allowed to warm to 0 ° C and then cooled again to -70 ° C and n- butyllithium (6.25 ml, 1.6 M solution in hexane) was added. Before a solution of hexachloroethane (7.10 g) in 10 ml of tetrahydrofuran was added to the solution, the reaction mixture was allowed to warm to 10 ° C and then cooled again to -30 ° C. 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. The title compound was obtained after flash column chromatography (silica gel, heptane / ethyl acetate (75/25 v / v), R _f = 0.38), followed by crystallization from heptane.

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-1-chloromethyl-3-methoxybenzene

The product of step a (1.00 g) in 5 ml of tetrahydrofuran at 0 ° C was added to a suspension of lithium aluminum hydride (0.34 g) in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h, and water (0.35 ml) in 5 ml of tetrahydrofuran was added at 0 ° C, followed by a 2M solution of sodium hydroxide in water (0.70 ml) and water (0.70 ml). The resulting white suspension was stirred for 0.5 hour and filtered. The colorless oil obtained after concentrating the filtrate 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. The title compound as a yellow oil, which crystallizes upon standing, was obtained after flash column chromatography (silica gel, heptane / ethyl acetate (75/25 v / v), R _f = 0.43).

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

The title compound was prepared analogously to Example 15a from the product of step b (0.42 g) and 5-bromo-3-ethoxy-4-hydroxybenzaldehyde (0.49 g).

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 (q, 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

The title compound was prepared analogously to Example 1a from 5-propylcyclohexane-1,3-dione (21 mg) and the product of step c (53 mg).

Yield: 60 mg.

R _f (heptane / ethyl acetate (4/6 v / v)) = 0.19.

MS-ESI: [MH] ^- = 597/599/601.

Example 24

N -3- [2-bromo-4- (3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6 methyl ester ethoxyphenoxymethyl] benzoylglycine

a) 3- [2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6 methyl ester ethoxyphenoxymethyl] benzoic acid

The title compound was prepared analogously to Example 1a from 5-propylcyclohexane-1,3-dione (0.95 g) and the product of Example 15a (2.4 g).

Yield: 3.0 g.

R _f (heptane / ethyl acetate (1/1 v / v)) = 0.20.

MS-ESI: [MH] ^- = 591/593.

b) 3- [2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl ]benzoic acid

The title compound was obtained analogously to example 13b from the product of step a (3.0 g).

Yield: 3.0 g.

MS-ESI: [MH] ^- = 577/579.

c) N -3- [2-bromo-4- (3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) methyl ester) -6-ethoxyphenoxymethyl] benzoylglycine

The title compound was prepared analogously to Example 14 from the product of step b (90 mg) and glycine methyl ether hydrochloride (64 mg). Purification was performed by 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

The title compound was prepared analogously to Example 15a from 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.75 g) and 1-bromomethyl-3-methoxybenzene (0.48 ml).

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 ( broad s, 1H), 7.07 (d, 1H), 6.88 (dd, 1H), 5.16 (s, 2H), 4.16 (q, 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

The title compound was prepared analogously to Example 1a from 5- (4-chlorophenyl) cyclohexane-1,3-dione (22 mg) and the product of step a (37 mg).

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

The title compound was prepared analogously to Example 1a from 5-furan-2-ylcyclohexan-1,3-dione (18 mg) and the product of step a (37 mg).

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-hexahydroquinoline-3-carbonitrile

a) 3,5-Dimethoxy-4- (3-methoxybenzyloxy) benzaldehyde

The title compound was prepared analogously to Example 15a from 4-hydroxy-3,5-dimethoxybenzaldehyde (0.91 g) and 1-bromomethyl-3-methoxybenzene (0.75 ml).

Yield: 1.42 g of a light 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 (br s, 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-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 1a from 5-propylcyclohexane-1,3-dione (11 mg) and the product of step a (21 mg).

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-pyridinylmethoxy) phenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile trifluoroacetic acid

a) 3-Bromo-5-ethoxy-4- (3-pyridinylmethoxy) benzaldehyde

The title compound was prepared analogously to example 15a from 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.25 g) and 3-picolyl chloride hydrochloride (0.16 g).

b) 4- [3-Bromo-5-ethoxy-4- (3-pyridinylmethoxy) phenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-3 -carbonitrile trifluoroacetic acid

The title compound was prepared analogously to Example 1a from 5-propylcyclohexane-1,3-dione (0.15 g) and the crude product of step a. The compound was purified by semi-preparative HPLC (Luna C18 [5 μm], flow rate: 20 ml min ^-1 , 10 → 90% CH ₃ CN, 0.1% TFA) and sublimated 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-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl] - N- thiophen-2-ylmethylbenzamide

a) 4- (2-Bromo-6-ethoxy-4-formylphenoxymethyl) benzoic acid methyl ester

The title compound was prepared analogously to example 15a from 4-bromomethylbenzoic acid methyl ester (3.7 g).

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-hexahydroquinolin-4-yl) -6 methyl ester ethoxyphenoxymethyl] benzoic acid

The title compound was prepared analogously to Example 1a from 5-propylcyclohexane-1,3-dione (2.5 g) and the product of step a (6.4 g).

Yield: 6.7 g.

R _f (heptane / ethyl acetate (3/2 v / v)) = 0.20.

MS-ESI: [MH] ^- = 591/593.

c) 4- [2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl ]benzoic acid

The title compound was obtained analogously to example 13b from the product of step b (6.7 g). The reaction mixture was stirred at 50 ° C. overnight.

Yield: 6.4 g.

MS-ESI: [MH] ^- = 577/579.

d) 4- [2-Bromo-4- (3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl) -6-ethoxyphenoxymethyl ] - N- thiophen-2-ylmethylbenzamide

The title compound was obtained analogously to Example 14 from the product of step c (0.10 g) and 2-thiophenomethylamine (52 μl). Purification was performed by 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-hexahydroquinoline-3-carbonitrile

a) 4- [3-Bromo-4-hydroxy-5-ethoxyphenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

The title compound was prepared analogously to Example 1a from 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (2.0 g) 5-propylcyclohexane-1,3-dione (1.3 g).

Yield: 3.6 g.

MS-ESI: [MH] ^- = 443/445.

b) 4- [3-Bromo-4-mesyloxy-5-ethoxyphenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

A mixture of the crude product of step a (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 in within 3 days. Water was added and the reaction mixture was extracted with dichloromethane. The crude title compound was obtained after concentration of the organic phases.

Yield: 1.0 g.

MS-ESI: [MH] ^- = 521/523.

c) 4- [3-Bromo-5-ethoxy-4- (4-nitrophenoxy) phenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-3 carbonitrile

A mixture of the 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 hours. Added dichloromethane and washed the reaction mixture with a 1% solution of hydrochloric acid in water and saturated brine. The organic phase was concentrated and flash column chromatography afforded the title compound (silica gel, heptane / ethyl acetate).

Yield: 0.19 g.

MS-ESI: [MH] ^- = 564/566.

¹ H NMR (CDCl ₃ ): δ = 8.17 (d, 2H), 7.00 (d, 1H), 6.91 (m, 3H), 5.95 (br s, 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, 3H).

Example 31

4- [3-Bromo-5-ethoxy-4- (5-fluoro-2-propylaminobenzyloxy) phenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline -3-carbonitrile

a) (5-Fluoro-2-nitrophenyl) methanol

To a solution of 5-fluoro-2-nitrobenzoic acid (4.58 g) in THF (50 ml), a 1M solution of BH ₃ ∙ THF in THF (62 ml) was added while cooling with an ice bath. The cooling bath was removed and stirring was continued for 1 hour at ambient temperature, followed by refluxing for 4 hours. The reaction mixture was cooled and MeOH was added to break up the 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-nitrobenzyloxy) phenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8 -hexahydroquinoline-3-carbonitrile

A mixture of the 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 hours. The mixture was concentrated in vacuo and the residue was dissolved in DMF (20 ml). To the remaining solution was added the compound described in Example 30a (3.9 g), K ₂ CO ₃ (6.1 g) and a small amount of tetran - butylammonium bromide (about 50 mg). The mixture was stirred for 5 hours at 60 ° C. Water and ethyl acetate were added and the organic 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-fluorobenzyloxy) -3-bromo-5-ethoxyphenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8- hexahydroquinoline-3-carbonitrile

Acetic acid (3.6 ml) and zinc dust (8.2 g) were added to a solution of the product of stage b (3.8 g) in THF (110 ml). The suspension was heated for 1 h at 50 ° C. 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 remaining solid was stirred with a small amount of ethyl acetate to give, after filtration, the title compound as a pale yellow solid.

Yield: 2.8 g.

d) 4- [3-Bromo-5-ethoxy-4- (5-fluoro-2-propylaminobenzyloxy) phenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8 -hexahydroquinoline-3-carbonitrile

A solution of the compound described in step c (200 mg) and propionaldehyde (25 μl) in dichloromethane (5 ml) was stirred for 2 hours. Then, acetic acid (81 μl) and sodium triacetoxyborohydride (300 mg) were added and the reaction mixture was further stirred. within 20 hours. A 2M aqueous NaOH solution was added and stirring was continued for 15 minutes. The organic layer was washed with water and brine, dried and concentrated in vacuo. The title compound was obtained by purification of the residue by preparative HPLC (Luna C18 [5 μm], flow rate: 20 ml min ^-1 , 10 → 90% CH ₃ CN, 0.1% TFA) and lyophilization from a mixture of water and dioxane. Some dialkylated products may also be isolated (see Example 32).

Yield: 109 mg.

MS-ESI: [M + H] ⁺ = 610/612.

Example 32

4- [3-Bromo-4- (2-dipropylamino-5-fluorobenzyloxy) -5-ethoxyphenyl] -2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline- 3-carbonitrile

Obtained from the reaction mixture of Example 31d after preparative HPLC (Luna C18 [5 μm], flow rate: 20 ml min ^-1 , 10 → 90% CH ₃ CN, 0.1% TFA) and lyophilization from a mixture of water and dioxane.

Yield: 12 mg.

MS-ESI: [M + H] ⁺ = 652/654.

Example 33

The bioactivity of CHO-FSH in vitro

The FSH activity of the compounds was tested on Chinese hamster ovary (CHO) cells stably transfected with the human FSH receptor and cotransfected with a cAMP dependent element (CRE) / promoter directing the expression of the firefly luciferase gene. Binding of the ligand to the Gs-linked FSH receptor will lead to an increase in cAMP, which, in turn, will increase the transactivation of the luciferase reporter construct. The luciferase signal was measured with a luminescent counter. For test compounds, EC ₅₀ values (concentration of test compound causing half (50%) of maximum stimulation) were calculated. GraphPad PRISM software version 3.0 (GraphPad software Inc., San Diego) was used for these purposes.

The 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 showed an EC ₅₀ between 10 ⁻⁷ and 10 ⁻⁹ M The compounds of examples 24 and 29 showed an EC ₅₀ at less than 10 ^-9 M.

Claims (11)

1. Derivative of dihydropyridine of the formula 1

or its pharmaceutically acceptable salt, in which
R ¹ is C _1-6 alkyl or phenyl, C _1-5 heteroaryl, both optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, cyano;
R ² , R ³ independently are C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyloxy, C _3-4 alkynyloxy, halogen;
R ⁴ is C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _1-9 heteroaryl, wherein (hetero ) the aryl group is optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C _1-4 alkyl, C _2-4 alkenyl,
C _2-4 alkynyl, C _1-4 alkoxy groups, C _1-4 (di) alkylamino groups, and if R ⁴ is phenyl, additionally from C _1-4 alkylthio groups, C _1-4 alkylsulfonyl, R ⁵ -oxycarbonyl, R ⁵ -carbonyl or R ⁵ , R ⁶ -aminocarbonyl;
X is SO ₂ , CH ₂ , C (O) or X is absent, wherein if X is CH ₂ , R ⁴ may further be R ⁵ -oxyacarbonyl, or R ⁵ -carbonyl;
R ⁵ , R ⁶ are independently H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl, C _1-4 alkyl, C _2-6 heterocycloalkyl, C _2-6 geterotsikloalkilS _1-4 alkyl, C _1-4 alkoksikarbonilS _1-4 alkyl, C _1-4 (di) alkilaminokarbonilS _1-4 alkyl or C _6-10 arilaminokarbonilS _1-4 alkyl, C _1-9 geteroarilaminokarbonilS _1-4 alkyl, C _6-10 aryl, C _1-9 heteroaryl, C _6-10 aryl C _1-4 alkyl, C _1-9 heteroaryl C _1-4 alkyl, wherein the (hetero) aryl group is optionally substituted with one or more substituents selected from hydroxy , amino, halogen, nitro, trifluoro methyl, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 (di) alkylamino or
R ⁵ , R ⁶ in the R ⁵ , R ⁶ -aminocarbonyl group may be bonded to a C _2-6 heterocycloalkyl ring;
with the proviso that the compound is not 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile. 2. The compound according to claim 1, in which R ⁴ is phenyl optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, C _1-4 alkoxy, C _1-4 (di) alkylamino groups, C _1-4 alkylthio groups, C _1-4 alkylsulfonyl, R ⁵ -oxycarbonyl, R ⁵ -carbonyl or R ⁵ , R ⁶ -aminocarbonyl. 3. The compound according to claim 2, in which the substituent in the phenyl group in R ⁴ is R ⁵ , R ^{6 is} aminocarbonyl, C _1-4 alkoxy and / or halogen. 4. The compound according to claim 3, in which R ⁵ in R ⁵ , R ⁶ -aminocarbonyl group is
With _1-4 (di) alkylamino group and R ⁶ is N. 5. The compound according to claim 3, in which R ⁵ in R ⁵ , R ⁶ -aminocarbonyl group is
C _1-9 heteroaryl C _1-4 alkyl, wherein the (hetero) aryl group is optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy groups,
C _1-4 (di) alkylamino groups or C _1-4 alkoxycarbonyl C _1-4 alkyl and R ⁶ is N. 6. The compound according to claims 1-5, in which X is CH ₂ . 7. The compound according to claims 1-6, in which R ¹ is C _1-6 alkyl, phenyl or C _1-5 heteroaryl. 8. The compound according to claims 1 to 7, in which R ² , R ³ are halogen or C _1-4 alkoxygroup. 9. The compound according to claims 1-8 for use in therapy as a medicine for impaired fertility. 10. A pharmaceutical composition having an FSH receptor agonist activity comprising a compound according to any one of claims 1 to 8, including 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1 4,5,6,7,8-hexahydroquinoline-3-carbonitrile and pharmaceutically acceptable excipients. 11. The use of a compound according to any one of claims 1 to 8, including 2-methyl-5-oxo-7-phenyl-4- (3,4,5-trimethoxyphenyl) -1,4,5,6,7,8- hexahydroquinoline-3-carbonitrile, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a medicament for the treatment of impaired fertility.