Dihydropyridine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to dihydropyridine derivatives with general formula , or their pharmaceutically acceptable salts, where R1 is C1-6alkyl or phenyl, C1-5heteroaryl, both optionally substituted with one or more substitutes, chosen from hydroxy, amino, halogen, nitro, cyano; R2, R3 are independently C1-4alkyl, C1-4alkoxy group, C2-4alkenyloxy group, C3-4alkynyloxy group, halogen; R4 is C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-4alkyl, C6-10aryl, C6-10arylC1-4alkyl, C1-9heteroaryl, where the (hetero)aryl group is optionally substituted with one or more substitutes, chosen from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy group, C1-4(di)alkylamino group, and, if R4 is a phenyl, additionally from C1-4alkylthio group, C1-4alkylsulphonyl, 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, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloakyl, C3-6cycloalylC1-4alkyl, C2-6heterocycloalkyl, C2-6heterocycloalkylC1-4alkyl, C1-4alkoxycarbonylC1-4alkyl, C1-4(di)alkylaminocarbonylC1-4alkyl or C6-10arylaminocarbonylC1-4alkyl, C1-9heteroarylaminocarbonylC1-4alkyl, C6-10aryl, C1-9heteroaryl, C6-10arylC1-4alkyl, C1-9heteroarylC1-4alkyl, where the (hetero)aryl group is optionally substituted with one or more substitutes, chosen from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy group, C1-4(di)alkylamino group or R5, R6 in R5, R6- aminocarbonyl group can be bonded to a C2-6heterocycloalkyl 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

 

The present invention relates to the production of low molecular weight hormonelike, which has a selective agonistic activity compared to the FSH receptor.

The gonadotropins play a significant role in various body functions, including metabolism, temperature regulation and reproductive processes. The gonadotropins act on specific cells of the gonadal type, causing ovarian and testicular differentiation and the formation of steroids. For example, the pituitary gonadotropin FSH (follicle stimulating hormone) plays a major role in the stimulation of follicle development and maturation, whereas LH (luteinizing hormone), stimulates ovulation (Sharp, R. Clin. Endocrinol. 33: 787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35: 301-342, 1979). At the moment of FSH in combination with LH is used clinically for ovarian stimulation, that is to ovarian hyperstimulation for in vitro fertilization (IVF) and the initiation of ovulation 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 for male hypogonadism and male infertility.

Gonadotropin FSH is secreted from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogen and from the placenta during pregnancy. In women, FSH acts on the ovaries to stimulate the development of follicles, and is the main hormone that regulates the separation of the tion of estrogen. In men, FSH is responsible for the safety of the seminiferous tubules and acts on the Sertoli cells, supporting gametogenesis. Purified FSH clinically used to treat infertility in women and some types of disorders of spermatogenesis in men. The gonadotropins, intended for therapeutic purposes, can be isolated from human urine and are 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 hormone FSH mediated by specific receptor in the cytoplasmic membrane, which is a member of a large family of receptors associated with 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 highly specific for the target in the growth of the ovarian follicle and is expressed exclusively in the ovary. Blocking the receptor or inhibition of signal transmission, which is usually called after activation of the FSH-mediated receptor and disrupt the development of the follicle and, thus, is bulacio and fertility. Low-molecular-weight antagonists of FSH could form the basis for new contraceptives, while low molecular weight agonists FSH can be used for the same clinical purposes as native FSH, for example, for the treatment of infertility and ovarian hyperstimulation in vitro fertilization.

Small molecule mimetics with FSH agonistic properties have been disclosed in the international applications WO 2000/08015 (Applied Research Systems ARS Holding N.V.) and in WO 2002/09706 (Affymax Research Institute).

Some derivative tetrahydroquinoline currently disclosed in the international application WO2003/004028 (AKZO NOBEL N.V.) as substances modulating FSH and having agonistic or antagonistic properties.

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

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

Formula I,

in which

R1is1-6the alkyl, C2-6alkenyl,2-6the quinil, phenyl or1-5heteroaryl;

R2, R3independently are C1-4the alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,2-4alkenyl is the group, With3-4alkyloxy, halogen;

X is SO2CH2C(O) or X is a bond;

R4is1-6the alkyl, C2-6alkenyl,2-6the quinil,3-6cycloalkyl,3-6cycloalkenyl,3-6cycloalkyl1-4the alkyl, C2-6heterocyclization,2-6heterocyclics1-4the alkyl, C6-10the aryl, C6-10arils1-4the alkyl, C1-9heteroaryl or1-9heteroaryl1-4the alkyl.

If X is CH2, R4may optionally be R5-oxycarbonyl or R5-carbonyl.

If R4is phenyl, in addition to alternates With6-10aryl groups as mentioned in the definitions, the phenyl may be optionally substituted by one or more substituents selected from the following groups:

With1-4alkylthio,1-4alkylsulfonyl, R5-oxycarbonyl, R5-carbonyl or R5,R6-aminocarbonyl;

R5, R6independently are H, C1-4the alkyl, C2-4alkenyl,2-4the quinil,3-6cycloalkyl,3-6cycloalkyl1-4the alkyl, C2-6heterocyclization,2-6heterocyclics1-4the alkyl, C1-4alkoxycarbonyl1-4the alkyl, C1-4(di)alkylaminocarbonyl1-4the alkyl, C6-10the aryl, C1-9 heteroaryl,6-10arils1-4the alkyl, C1-9heteroaryl1-4the alkyl, C6-10arylaminoquinolines1-4the alkyl, C1-9heteroarylboronic1-4the alkyl, or R5, R6can be associated with2-6heteroseksualnymi ring.

Compounds in accordance with the present invention modulate the function of FSH receptor and can be used for the same clinical purposes as native FSH, because they behave like agonists, with the advantage that they can be changed properties of stability and can be applied in different ways.

Thus, agonists of the FSH receptor of the present invention can be used to treat infertility. Preferably, the compounds of the present invention were used for activation of the FSH receptor.

The term "C1-4alkyl", as used in the definition means a branched or unbranched alkyl group having 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,Deut-butyl andtert-butyl.

The term "C1-6alkyl" means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl,tert-butyl,npencil andn-hexyl. Preferred are1-5alkyl groups, n is the most preferred are 1-4alkali.

The term "C2-6alkenyl" means a branched or unbranched alkenylphenol group having 2-6 carbon atoms, such as ethynyl, 2-butenyl andn-pentenyl.

The term "C2-4alkenyl" means a branched or unbranched alkenylphenol group having 2-4 carbon atoms, such as ethynyl,n-propenyl and 2-butenyl.

The term "C2-6quinil" means a branched or unbranched alkylamino group having 2-6 carbon atoms, such as ethinyl, PROPYNYL andn-pentenyl.

The term "C2-4quinil" means a branched or unbranched alkylamino group having 2-4 carbon atoms, such as ethinyl and PROPYNYL.

The term "C3-6cycloalkyl" means cycloalkyl group having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "C3-6cycloalkenyl" means cycloalkenyl group having 3-6 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexenyl.

The term "C3-6cycloalkyl1-4alkyl" means cycloalkylcarbonyl group, cycloalkyl group which has 3 to 6 atoms with the same meaning as defined above, and alkyl group having 1-4 carbon atoms with the same meaning as defined above.

The term "C2-6heteroseksualci" means heterocyclyl the second group, having 2-6 carbon atoms, preferably 3-5 carbon atoms, and includes at least one heteroatom selected from N, O and/or S, which may be attached, if possible, through a heteroatom or a carbon atom. Preferred are heteroatoms N or O. Most preferred are piperidinyl, morpholinyl, pyrrolidinyl and piperazinil.

The term "C2-6heterocyclics1-4alkyl" means geterotsiklicheskikh group, heterocytolysine group which has 2 to 6 atoms with the same meaning as defined above, and alkyl group having 1-4 carbon atoms with the same meaning as defined above.

The term "C1-4alkoxy" means the CNS group having 1-4 carbon atoms, with the alkyl part has the same significance as defined above. Preferred are1-2alkoxygroup.

The term "C1-4alkylthio" means allylthiourea having 1-4 carbon atoms, with the alkyl part has the same meaning defined above.

The term "C2-4alkenylacyl" means alkynylamino group having 2-4 carbon atoms, with Alchemilla part has the same meaning defined above.

The term "C3-4alkyloxy" means alkynylamino group having 3-4 carbon atoms, with Alchemilla part has the same value, that is, predelino above.

The term "C6-10aryl" means an aromatic hydrocarbon group having 6-10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indanyl, which may be optionally substituted by one or more substituents selected from hydroxy, amino, halogen, nitro, trifloromethyl, cyano, C1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup or1-4(di)alkylamino, while the alkyl part has the same significance as defined above. The preferred aromatic hydrocarbon group is phenyl.

The term "C1-9heteroaryl" means substituted or unsubstituted aromatic group having 1-9 carbon atoms, comprising at least one heteroatom selected from N, O and/or S, as tetrazolyl, imidazolyl, thiadiazolyl, pyridinyl, (benzo)thienyl, (benzo)furyl, (ISO)chinoline, tetrahydro(ISO)chinoline, coumarinyl, honokalani or indolyl. The substituents in1-9the heteroaryl group may be selected from the group of substituents listed for C6-10aryl group. It is preferable1-5heteroaryl. With1-9heteroaryl group may be attached, if possible, through a carbon atom or through a heteroatom.

The term "C1-5heteroaryl" means substituted or unsubstituted aromatic group, having the Yu 1-5 carbon atoms, comprising at least one heteroatom selected from N, O and/or S, as tetrazolyl, imidazolyl, thiadiazolyl, pyridinyl, thienyl or furyl, and most preferred is furyl. Preferred heteroaryl groups are thienyl, furyl and pyridinyl. The substituents in1-5the heteroaryl group may be selected from the group of substituents listed for C6-10aryl group.

The term "C6-10arils1-4alkyl" means arylalkyl group, aryl group which contains 6 to 10 carbon atoms with the same meaning as defined above, and alkyl group having 1-4 carbon atoms with the same meaning as defined above. Most preferred is benzyl.

The term "C1-9heteroaryl1-4alkyl" means heteroallyl group, a heteroaryl group which contains 1-9 atoms with the same meaning as defined above, and alkyl group having 1-4 carbon atoms with the same meaning as defined above.

The term "C1-4alkylsulfonyl" means alkylsulfonyl group, an alkyl group which contains 1-4 carbon atoms with the same meaning as defined above.

The term "C1-4alkoxycarbonyl" means1-4alkoxycarbonyl group, alkoxygroup which contains 1-4 carbon atoms with the same meaning as defined enter the. Preferred are1-2alkoxycarbonyl group.

The term "C1-4alkoxycarbonyl1-4alkyl" means alkoxycarbonylmethyl group, an alkyl group which contains 1-4 carbon atoms with the same meaning as defined above.

The term "C1-4(di)alkylaminocarbonyl1-4alkyl" means a (di)alkylaminocarbonyl group, an alkyl group which contains 1-4 carbon atoms with the same meaning as defined above.

The term "halogen" means fluorine, chlorine, bromine and iodine.

The term "pharmaceutically acceptable salt" represents those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable ratio of benefit/risk. Pharmaceutically acceptable salts are well known in the prior art. They can be obtained during the final isolation and purification of the compounds of the invention or separately by the interaction of free functional base with a suitable mineral acid, such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acid, such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, Umarova acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonate acid and the like. Acid functional group can interact with organic or mineral base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

The invention also relates to compounds of the formula I, in which R1is1-6the alkyl, phenyl or1-5heteroaryl, all optionally substituted by the substituents as mentioned in the definitions. More specifically, the invention relates to compounds, in which R1is1-6the alkyl, phenyl, C4-heteroaryl. The invention also relates to compounds, in which R1isn-propylene or fullam.

Another aspect of the invention are the compounds of formula I in which R2, R3are halogen and/or C1-4alkoxy.

In another aspect the invention relates to compounds of formula I in which X is CH2.

Another aspect of the invention is a compound in which R4is phenyl, optionally substituted by the substituents as mentioned in the definition.

In another aspect the invention relates to compounds, in which R4is phenyl, which is substituted in theorthoand/ormeta-positions. In another aspect of izopet the tion relates to compounds of the formula I, in which R4is phenyl, substituted R5,R6-aminocarbonyl,1-4alkoxygroup and/or halogen. In another aspect the invention relates to compounds, in which R5,R6in R5,R6-aminocarbonyl group is1-4(di)alkylaminocarbonyl,1-4alkoxycarbonyl1-4the alkyl or C1-9heteroaryl1-4the alkyl. In another aspect, at least one of R5, R6in R5,R6-aminocarbonyl group is N.

In another aspect, the invention relates to compounds, in which6-10aryl, C6-10arils1-4alkyl, C1-9heteroaryl or1-9heteroaryl1-4alkyl in R4are unsubstituted.

Another aspect of the invention relates to compounds, in which X=CH2and

R4is phenyl, optionally substituted by the substituents as mentioned in the definitions.

Another aspect of the invention relates to compounds, in which all distinct definitions of groups of R1to R4as defined here above, the joint in the connection of dihydropyridines of the formula I.

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

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

Suitable methods for obtaining the compounds of the invention are described below.

Derivatives of 1,4-dihydropyridines I of the present invention can be obtained by a well-described three-component cyclocondensation Ganch of cyclohexane-1,3-diones of General formula II, benzaldehyde General formula III and 3-aminocrotononitrile IV, in which R1, R2, R3, R4and X are as defined above.

Related reactions by cyclocondensation Ganch can be found 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 above reaction is typically conducted at elevated temperatures in proton solvent such as, for example, acetic acid, (ISO)propanol, ethanol, methanol or mixtures thereof.

Alternatively, compounds of General formula I can be synthesized by the interaction of the first cyclohexane-1,3-diones of the formula II with benzaldehyde formula III in the presence of a base such as, but not limited to, ammonium acetate, and then the interaction of the intermediate 2-benzylideneamino-1,3-dione of General formula V in which R1, R2, R , R4and X have the same meaning as defined above, with 3-aminocrotononitrile IV.

Compounds of General formula I-a, where X = bond, and R4=H, can be used to obtain compounds I-b-eAbout-alkylation,About-(hetero)AllYouNeed,About-acylation orAbout-sulfonylamine conventional methods, well known specialist in this field.

In the usual experiment of compound I-a interact in such a solvent as dichloromethane,N,N-dimethylformamide, dimethylsulfoxide, ethanol, tetrahydrofuran, dioxane, toluene, 1-methylpyrrolidine-2-he or pyridine, with alkylhalogenide, or allelochemical, or acid anhydride, or sulphonylchloride, or (hetero)helgaleena in the presence of such reasons as, but not limited to, triethylamine,N,N-diisopropylethylamine (DiPEA), potassium carbonate, cesium carbonate or sodium hydride, optionally in the presence of catalytic amounts of potassium iodide or tetrabutylammonium iodide, and/or Cu or Pd-catalyst with the formation of theAbout-alkylated,About-(hetero)ALLROUNDER,About-acylated orAbout-sulfonylamino derivative of the formula I-b, I-c, I-d and I-e, respectively.

Compounds of formula I-f where X=CH2and R4=derivative alkylsilane or proizvodnje (hetero)Kilkelly, the obtained alkali (such as NaOH) by saponification of the corresponding alkyl ether complex, can be condensed with amines of the General structure R5,R6NH or alcohols of General formula R5OH using binding reagent, such as diisopropylcarbodiimide (DIC), (3-dimethylaminopropyl)ethylcarbodiimide (EDCI),About(benzotriazol-1-yl)-N,N,N',N'-tetramethylhexadecane (TBTU) orAbout-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylhexadecane (HATU), and the base of the tertiary amine (DiPEA) in a solvent such asN,N-dimethylformamide or dichloromethane at ambient or elevated temperatures to form compounds of the formula I-g and I-h.

Substituted cyclohexane-1,3-diones of General formula II are commercially available or can be obtained well-known from the literature in this area ways. Suitable examples 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.

Benzaldehyde General formula III are commercially available or can be obtained in accordance with the literary techniques: 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, where X=bond, and R4=H can be used for the synthesis of compounds III-b-eAbout-alkylation,About-(hetero)AllYouNeed,About-acylation orAbout-sulfonylamine using standard conditions as described above for compounds I-a.

Compounds of the present invention have at least two chiral carbon atom and can therefore be obtained in the form of pure enantiomers or as a mixture of enantiomers, or a mixture of diastereomers. Methods of obtaining pure enantiomers are well known in the prior art, for example crystallization of salts, which are obtained from optically active acids and racemic mixtures, or chromatography using chiral columns. For separation of the diastereomers can be used speakers with normal phase or reversed phase.

Compounds of the invention may form a hydrate or a solvate. Specialists in this field it is known that charged compounds form a hydrated fragments in the freeze-drying with water or form a solvate with concentration in solution with a suitable organic solvent. The compounds of this invention include a hydrate or solvate of the listed compounds.

For selection of active compounds is in the testing at 10 -5M should lead to activity more than 20% of maximum activity when FSH is used as a comparison. Another criterion may be the value of EC50that should be <10-5M, preferably <10-7M, even more preferably <10-9M

The specialist will be clear that the desired value of EC50depend on the tested compounds. For example, the connection with EC50that is less than 10-5M is usually considered a candidate for the selection of medicines. Preferably, the value was lower than 10-7M. However, the connection that has higher EC50but is selective for a particular receptor may be an even better candidate.

Methods for determining binding of the receptor of gonadotropins, as well as evaluationin vitroandin vivoto determine biological activity, are well known. In General, the downregulation of the receptor is in contact with the test compound, and measured the binding, or stimulation or inhibition of a functional response.

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

How to create recombinant FSH expressing colonies of cells are well known in the prior art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). The expression of the receptor is achieved by expression of DNA that encodes a desired protein. Methods targeted mutagenesis, binding of additional sequences, PCR and construction of suitable expression systems are now well known in the prior art. Fragments or whole DNA encoding a desired protein can be constructed synthetically by standard solid-phase methods, it is preferable to include restriction sites to loosen the stitching. Suitable regulatory elements for transcription and translation, included the coding sequence may be included in the DNA coding sequences. It is well known that currently available expression systems, which 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 cages and the like.

Cells expressing the receptor is then contacted with a test compound for which lugenia binding, or stimulation or inhibition of a functional response.

Alternatively, the selected cell membrane containing the expressed receptor, can be used to measure binding of the connection.

To measure the binding can be used with radioactive or fluorescent compounds. As compounds of the comparison can be used recombinant human FSH.

Alternatively, can also be performed competitive analysis of the binding.

Other analysis includes the screening of compounds for agonist receptor FSH by defining stimulate receptor-mediated accumulation of cAMP. Thus, this method involves receptor expression on the cell surface of the host cell and the effect on the cell under test compounds. Then measure the amount of cAMP. The cAMP level will increase due to the stimulatory effect of test compounds on the binding with the receptor.

In addition to direct measurement, for example, levels of cAMP in the cell affected, can be used cell lines, which in addition to the transfection of the receptor-encoding DNA, also transfections secondary DNA that encodes a gene-reporter, the expression of which corresponds to the level of cAMP. Such genes reporters m which may be induced by cAMP or can be obtained in this way, that they were associated with the original elements, sensitive to cAMP. In General, the gene expression of the reporter can be controlled by any elements that are sensitive to changes of cAMP levels. Suitable genes reporters are, for example, LacZ, alkaline phosphatase, Svetlanova luciferase and green fluorescent protein. Principles such assessments TRANS-activation are well known in the prior art and described, for example, Stratowa, Ch., Himmler, A. And Czernilofsky, A. P. (1995) Curr. Opin. Biotechnol. 6: 574.

The present invention also relates to pharmaceutical compositions containing a derivative of dihydropyridines or its pharmaceutically acceptable salt having the General formula I in a mixture with pharmaceutically acceptable excipients and optionally other therapeutic agents. The excipient must be "acceptable" in the sense that they are compatible with other ingredients of the composition and is not harmful to their hosts. Pharmaceutical compositions can 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, are suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local or rectal administration and the like, all in units of standard doses for admission.

For peror the form of further introduction of the active ingredient may be presented as separate dosage forms, such as tablets, capsules, powders, granules, solutions, suspensions and the like.

For parentline the introduction of the pharmaceutical composition may be presented in the form of tanks containing a single dose or multiple doses of a medicinal product, for example a liquid for injection in pre-defined quantities, for example, in sealed vials and vials, and may also be stored in chilled (liofilizirovannom), before requiring only the addition of sterile liquid carrier, for example water.

The active agent is mixed with such pharmaceutically acceptable auxiliary substances, for example, as described in the standard reference, Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20thEdition, Lippincott Williams and Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing), may be compressed into solid standard dose, such as pills, tablets, or translated into capsules or suppositories. Using pharmaceutically acceptable liquid, active agent may be used in the form of liquid compositions, for example in the form of solution for injection, in the form of solutions, suspensions, emulsions, or as a spray, for example a nasal spray.

For preparation of standard solid dosage forms using conventional additives such as fillers, dyes, polymeric binders and the like. In General can be and is used any pharmaceutically acceptable additive, which do not interact with the active compounds. Suitable carrier materials, with which an active agent of the present invention can be used as a solid standard drug doses, include lactose, starch, cellulose derivatives and the like or mixtures thereof, used in the right quantities. For parentline injection can be used aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butyleneglycol.

The invention further includes a pharmaceutical composition, as described above, in combinine with packaging material suitable for the specified composition, and specified packaging material includes instructions for using the composition.

The exact dosage and mode of administration of the active ingredient or pharmaceutical composition may vary depending on the particular compound, the route of administration and the age and condition of the individual patient, which prescribe the drug.

In General parentally reception requires lower doses than other methods, which are more dependent on absorption. However, suitable dosage for men can be 0.05 to 25 mg / kg ve the and body. The required dosage can be represented as a single dose or multiple podos taken at appropriate intervals during the day, or, in the case of female patients, the dose that should be taken daily during the menstrual cycle. Dosage, as well as the reception mode may be different in patients men and women.

Thus, the compounds according to the invention can be used in therapy.

The invention relates also to the use of a derivative of dihydropyridines having the General formula I for the preparation of drugs for treatment of disorders sensitive to metabolic pathways, mediated FSH receptor, preferably for the treatment of infertility.

The invention is illustrated in 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-aminocrotononitrile (0,22 g) in 20 ml of absolute ethanol was stirred for 3 h at 75°C. the Reaction mixture was concentrated and after column flash chromatography (silica gel, heptane/ethyl acetate (3/7 vol./vol.), Rf=0,36) received the decree is Noah in the title compound in the form of not-quite-white solid.

Output: 0,95,

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 stage a (15 mg), ethyliodide (6,4 mm), sodium hydride (2.6 mg, 60% in oil) and tetrabutylammonium iodide (1.2 mg) in 0.5 ml ofN-methylpyrrolidone was stirred for 2 h at 80°C. was Added water and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated and after column flash chromatography (silica gel, heptane/ethyl acetate (about 1/4./vol.), Rf=0,52) has been specified in the header of the connection.

Output: 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-hexahydroquinoline-3-carbonitrile

Specified in the title compound was obtained analogously to example 1b from the product of example 1A (15 mg) and bromeilles (12 ál).

Yield: 12 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=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-hexahydroquinoline-3-carbonitrile

Specified in the title compound was obtained analogously to example 1b from the product of example 1A (15 mg) and 1-iodine-3-methylbutane (4,7 mm).

Yield: 14 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=0,56.

MS-ESI: [M-H]-= 533/535.

Example 4

4-[3-Bromo-4-(5-chlorothiophene-2-ylethoxy)-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-chloromethylstyrene (4,3 ml) and cesium carbonate (21 mg) in 1 ml dioxane was stirred at 80°C for 4 h the Reaction mixture was concentrated and after column flash chromatography (silica gel, heptane/ethyl acetate (3/7 vol./vol.), Rf=0,38) has been specified in the header of the connection.

Output: 4,7 mg

MS-ESI: [M-H]-= 593/595/597.

Example 5

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

Specified in the title compound was obtained analogously to example 4 from the product of example 1A (0,47 g) and methyl ester bromoxynil acid (1.0 ml).

Output: 0,32,

Rf(heptane/ethyl acetate (about 1/4./about.))=0,46.

MS-ESI: [M-H]-= 535/537.

Example 6

2-Bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-methoxybenzyloxy ether 3-methoxybenzoic acid

Specified in the title compound was obtained analogously to example 4 from the product of example 1A (15 mg) and 3-methoxybenzylamine (5,4 µl).

Output: 7,4 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=0,48.

MS-ESI: [M-H]-= 597/599.

Example 7

4-[3-Bromo-4-(3-cyanobenzyl)-5-methoxyphenyl]-2-methyl-5-oxo-7-phenyl-1,4,56,7,8-hexahydroquinoline-3-carbonitrile

Specified in the title compound was obtained analogously to example 4 from the product of example 1A (15 mg) and 3-bromomethylbiphenyl (7,6 mg).

Yield: 15 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=0,51.

MS-ESI: [M-H]-= 578/580.

Example 8

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

Specified in the title compound was obtained analogously to example 4 from the product of example 1A (15 mg) and 2-bromoethylamine (8.6 mg).

Yield: 11 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=0,60.

MS-ESI: [M-H]-= 603/605.

Example 9

2-Bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-methoxybenzyloxy ether phenylmethanesulfonyl acid

A mixture of the product from example 1A (15 mg), phenylmethanesulfonyl (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 column flash chromatography (silica gel, heptane/ethyl acetate (about 1/4./vol.), Rf=0,41) has been specified in the header of the connection.

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-hexahydroquinoline-4-yl)-6-methoxybenzyloxy ester thiophene-2-sulfonic acid

Specified in the title compound was obtained analogously PR is a measure of 9 from the product of example 1A (15 mg) and thiophene-2-sulphonylchloride (8,8 mg).

Yield: 20 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=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-hexahydroquinoline-3-carbonitrile

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

A mixture of 3,5-dibromo-4-hydroxybenzaldehyde (0.28 g), 1-methyl bromide-3-methoxybenzoyl (0.15 ml), potassium carbonate (0.29 grams) 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 column flash chromatography (silica gel, heptane/ethyl acetate (3/7 vol./vol.), Rf=0,51) has been specified in the title compound in the form of not-quite-white solid.

Output: 0,24,

MS-ESI: [M-H]-= 463/465.

1H NMR (CDCl3): δ = 9,88 (s, 1H), of 8.06 (s, 1H), 7,34 (t, 1H), 7,18 (users, 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

Specified in the title compound was obtained analogously to example 1 from 5-ethylcyclohexane-1,3-dione (8.5 mg) and the product of stage a (24 mg).

Yield: 26 mg

Rf(heptane/ethyl acetate (3/7 vol./about.))=0,40.

MS-ESI: [M+H]+= 585/587/589.

Example 12

4-{3-Bromo-5-ethoxy-4-[2-(3-nitrophenyl)-2-oksidoksi]phenyl}-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

a)4-(3-Bromo-5-ethoxy-hydroxyphenyl}-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

Specified in the title compound was obtained analogously to example 1A from 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.15 g).

Output: 0,15,

Rf(heptane/ethyl acetate (4/6 about./about.))=0,18.

MS-ESI: [M+H]+= 479/481.

b)4-{3-Bromo-5-ethoxy-4-[2-(3-nitrophenyl)-2-oksidoksi]phenyl}-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

Specified in the title compound was obtained analogously to example 4 of the product of stage a (15 mg), 2-bromo-1-(3-nitrophenyl)ethanone (8,4 mg).

Yield: 14 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=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-hexahydroquinoline-4-yl)-6-methoxyphenoxy]-N-thiophene-2-ylmethylene

a)Methyl ester of 3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-methoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 4 from the product of example 1A (0.35 g) and methyl ester 3-bromomethylphenyl acid (0.18 g).

Output: 0,35,

Rf(heptane/ethyl acetate (3/7 vol./about.))=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-methoxyphenoxy]benzoic acid

A solution of the product of stage a (0.35 g) was dissolved in 20 ml of dioxane/water (7/3.about.) and added 2 ml of 2M NaOH in water. The reaction to the offer was stirred at room temperature for 5 days. The reaction mixture was poured into water and acidified using 2M HCl in water to pH 2 and extracted with ethyl acetate several times. The organic phase was washed with water and saturated brine, dried over Na2SO4and evaporated, having specified in the header of the connection.

Output: 0,35,

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-methoxyphenoxy]-N-thiophene-2-ylmethylene

To a solution of the product of stage b (20 mg) in 2 ml of dichloromethane was added EDCI (7,0 mg), DiPEA (7 μl) and 2-thiophenemethylamine (4,1 μl) and stirred the reaction mixture for 3 h at room temperature. The reaction mixture was concentrated and after column flash chromatography (silica gel, heptane/ethyl acetate (about 1/4./vol.), Rf=0,78) has been specified in the header of the connection.

Yield: 11 mg

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

Example 14

2-Morpholine-4-jatiluwih ester of 3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-methoxyphenoxy]benzoic acid

To a solution of the product of stage 13b (20 mg) in 2 ml of dichloromethane was added TBTU (12 mg), DiPEA (7 μl) and 2-morpholine-4-retinol (4,8 ml) and stirred the reaction mixture for 3 h at room temperature. The reaction mixture was concentrated and after column flash chromatography (silica gel, heptane/ethyl acetate (about 1/4./vol.), Rf=0,48) the floor is or specified in the header of the connection.

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)Methyl ester 3-(2-bromo-6-ethoxy-4-formylphenoxy)benzoic acid

To a solution of 5-bromo-3-ethoxy-4-hydroxybenzaldehyde (0.75 g) in 10 ml DMF was added methyl ether 3-bromomethylphenyl acid (0,77 g), K2CO3(1.0 g) and a catalytic amountn-Bu4NI and the reaction mixture was stirred at 70°C for 1 h was Added a 3% solution of citric acid in water and was extracted the reaction mixture with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4and concentrated. After column flash chromatography (silica gel, heptane/ethyl acetate (about 1/4./vol.), Rf=0,25) has been specified in the header of the connection.

Output: 1,08,

1H NMR (CDCl3): δ = 9,84 (s, 1H), 8,20 (users, 1H), 8,02 (userd, 1H), to 7.77 (d, 1H), 7,65 (d, 1H), 7,47 (t, 1H), 7,39 (d, 1H), total of 5.21 (s, 2H), 4,17 (square, 2N), of 3.94 (s, 3H)and 1.51 (t, 3H).

b)Methyl ester of 3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 1A from the product of stage a (0.26 g).

Output: 0,27,

Rf(heptane/ethyl acetate (3/7 vol./about.))=0,34.

MS-ESI: [M+H]+= 613/615.

) 3-[2-Bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 13b from the product of stage b (0.27 g).

Output: 0,27,

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

Specified in the title compound was obtained analogously to example 13C of the product of stage C (20 mg) and piperidine (3,9 mm).

Yield: 15 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=0,25.

MS-ESI: [M+H]+= 680/682.

Example 16

Methyl etherN-3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoylglycine

Specified in the title compound was obtained analogously to example 13C of the product of stage 15 ° C (20 mg) and hydrochloride licensedialog ether (4.9 mg).

Output: 9,9 mg

Rf(heptane/ethyl acetate (3/7 vol./about.))=0,16.

MS-ESI: [M+H]+= 684/686.

Example 17

Methyl ester of 3-[2-bromo-4-(3-cyano-7-ethyl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 1 from 5-ethylcyclohexane-1,3-dione (0.25 g) and the product stage 15A (0.64 g).

Output: 0,45,

Rf(heptane/ethyl acetate (1/4 vol./is b.))=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-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 13b from the product of example 17 (0,43 g).

Output: 0,38,

Rf(heptane/ethyl acetate (about 1/4./about.))=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-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]-N-tert-butylbenzamide

To a solution of the product of example 18 (0.35 g) in 10 ml dichloromethane was addedtert-butylamine (0,12 ml), DiPEA (0,39 ml) and HATU (0,30 g) and the reaction mixture was stirred for 3 h at 35°C. was Added a 3% solution of citric acid in water and several times were extracted the reaction mixture with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4and concentrated. After column flash chromatography (silica gel, heptane/ethyl acetate (about 1/4./vol.), Rf=0,34) has been specified in the header of the connection.

Output: 0,28,

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-ethoxyphenoxy]-N-cyclohexylbenzene

Specified in the title compound was obtained analogously to example 13C of the product of example 18 (20 mg) and cyclohexylamine (4,9 µl).

Output:7,9 mg

Rf(silica gel, heptane/ethyl acetate (about 1/4./about.))=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-ethoxyphenoxy]-N-(2-morpholine-4-retil)benzamid

Specified in the title compound was obtained analogously to example 13c of the product of example 18 (20 mg) and 4-(2-amino-ethyl)research (5,5 mm).

Yield: 15 mg

Rf(dichloromethane/methanol (95/5 by vol./about.))=0,22.

MS-ESI: [M+H]+= 677/679.

Example 22

4-[3-Iodine-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

Specified in the title compound was obtained analogously to example 15 from 4-hydroxy-3-iodine-5-methoxybenzaldehyde (0,70 g) and 1-methyl bromide-3-methoxybenzene (0,39 ml).

Output: 0,56,

Rf(heptane/ethyl acetate (4/6 about./about.))=0,42.

1H NMR (CDCl3): δ = 9,83 (s, 1H), 7,86 (d, 1H), 7,43 (d, 1H), 7,29 (m, 1H), 7,16 (users, 1H), to 7.09 (d, 1H), to 6.88 (DD, 1H), 5,14 (s, 2H), 3,95 (s, 3H), of 3.84 (s, 3H).

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

Specified in the title compound was obtained analogously to example 1A from the product phase and (24 mg).

Yield: 17 mg

Rf(heptane/ethyl acetate (about 1/4./about.))=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

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

a)2-Chloro-3-methoxybenzaldehyde

To a solution ofN,N,N'-trimethylethylenediamine (1,27 ml) in 10 ml of tetrahydrofuran at -40°C was addedn-utility (6.25 ml, 1.6 m solution in hexane). After 15 min the reaction mixture was cooled to -70°C. and added a solution of 3-methoxybenzaldehyde (1,22 ml) in 5 ml of tetrahydrofuran. The reaction mixture was left to warm to 0°C and then cooled to -70°C. and addedn-utility (6.25 ml, 1.6 m solution in hexane). Before the solution was added a solution of hexachloroethane (7,10 g) in 10 ml of tetrahydrofuran, the reaction mixture was left to warm to 10°C. and then cooled to -30°C. the Reaction mixture was stirred for 2 h at room temperature, poured into 20 ml of 10% HCl in water and was extracted several times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over MgSO4and concentrated. Specified in the title compound was obtained after flash column-chromatography (silica gel, heptane/ethyl acetate (75/25 vol./vol.), Rf=0,38), followed by crystallization from heptane.

Output: 1,06 g

1H NMR (CDCl3): δ = 10,46 (s, 1H), 7,54 (DD, 1H), 7,35 (t, 1 is), 7,17 (d, 1H), 3.96 points (s, 3H).

b)2-Chloro-1-chloromethyl-3-methoxybenzoyl

The product of stage a (1,00 g) in 5 ml of tetrahydrofuran at 0°C was added to a suspension of socialogical (0.34 g) in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h and at 0°C was added water (0.35 ml) in 5 ml of tetrahydrofuran, then 2M sodium hydroxide solution in water (0,70 ml) and water (0,70 ml). The obtained white suspension was stirred for 0.5 hour and was filtered. The colorless oil obtained after concentration of the filtrate was dissolved in 10 ml of 1,2-dichloropropane and added thionyl chloride (1.5 ml). The reaction mixture was heated under reflux overnight and then concentrated. Specified in the title compound as a yellow oil, which crystallizes on standing, was obtained after column flash chromatography (silica gel, heptane/ethyl acetate (75/25 vol./vol.), Rf=0,43).

Output: 0,80,

1H NMR (CDCl3): δ = 7.24 to (t, 1H), to 7.09 (DD, 1H), 6,93 (DD, 1H), 4.72 in (s, 2H), 3,92 (s, 3H).

c)3-Bromo-4-(2-chloro-3-methoxybenzyloxy)-5-ethoxybenzaldehyde

Specified in the title compound was obtained analogously to example 15A of the product of stage b (0,42 g) and 5-bromo-3-ethoxy-4-hydroxybenzaldehyde (0,49 g).

Output: 0,56,

1H NMR (CDCl3): δ = 9,85 (s, 1H), 7,66 (DD, 1H), 7,40 (DD, 1H), 7,39 (d, 1H), 7,29 (m, 1H), 6,94 (DD, 1H), 5,32 (s, 2H), 4,15 (kvar., 2H), 3,93 (s, 3H), 1,4 (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

Specified in the title compound was obtained analogously to example 1 from 5-propylcyclohexane-1,3-dione (21 mg) and the product stage (53 mg).

Yield: 60 mg

Rf(heptane/ethyl acetate (4/6 about./about.))=0,19.

MS-ESI: [M-H]-= 597/599/601.

Example 24

Methyl etherN-3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoylglycine

a)Methyl ester of 3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 1 from 5-propylcyclohexane-1,3-dione (0.95 g) and the product of example 15A (2.4 g).

Output: 3,0,

Rf(heptane/ethyl acetate (1/1 by vol./about.))=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-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 13b from the product of stage a (3.0 g).

Output: 3,0,

MS-ESI: [M-H]-= 577/579.

c)Methyl etherN-3-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoylglycine

Specified in the title compound was obtained as the illogical example 14 of the product of stage b (90 mg) and hydrochloride licensedialog ester (64 mg). Purification was done preparative HPLC (Luna C18 [5 μm], the velocity of flow:

20 ml min-1, 0→90% CH3CN, 1% TFA).

Yield: 59 mg

Rt(CH2Cl2/MeOH (95/5 by vol./about.))=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

Specified in the title compound was obtained analogously to example 15A 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.75 g) and 1-methyl bromide-3-methoxybenzene (0,48 ml).

Output: 0,91 g

Rf(heptane/ethyl acetate (2/1 about./about.))=0,43.

1H NMR (CDCl3): δ = 9,83 (s, 1H), 7,65 (DD, 1H), 7,38 (DD, 1H), 7,29 (m, 1H), 7,13 (users, 1H), 7,07 (d, 1H), to 6.88 (DD, 1H), 5,16 (s, 2H), 4,16 (kvar., 2H), 3,83 (s, 3H), and 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

Specified in the title compound was obtained analogously to example 1 from 5-(4-chlorophenyl)cyclohexane-1,3-dione (22 mg) and the product of stage a (37 mg).

Yield: 32 mg

Rf(heptane/ethyl acetate (3/7 vol./about.))=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

Specified in the title compound was obtained analogion the example 1 from 5-furan-2-illlogical-1,3-dione (18 mg) and the product of stage a (37 mg).

Yield: 37 mg

Rf(heptane/ethyl acetate (3/7 vol./about.))=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

Specified in the title compound was obtained analogously to example 15 from 4-hydroxy-3,5-dimethoxybenzaldehyde (0,91 g) and 1-methyl bromide-3-methoxybenzene (0.75 ml).

Yield: 1.42 g of a light yellow oil.

Rf(heptane/ethyl acetate (1/1 by vol./about.))=0,40.

1H NMR (CDCl3): δ = 9,86 (s, 1H), 7,26 (d, 1H), 7.23 percent (d, 1H), 7,09 (users, 1H),? 7.04 baby mortality (d, 1H), 6,85 (DD, 1H), 5,12 (s, 2H), 3,91 (C, 6N), 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

Specified in the title compound was obtained analogously to example 1 from 5-propylcyclohexane-1,3-dione (11 mg) and the product of stage a (21 mg).

Yield: 22 mg

Rf(heptane/ethyl acetate (3/7 vol./about.))=0,21.

MS-ESI: [M+H]+= 503; [M+Na]+= 525.

Example 28

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

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

Specified in the title compound was obtained analogously to example 15A 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (0.2 g) and 3-picolylamine hydrochloride (0.16 g).

b)4-[3-Bromo-5-ethoxy-4-(3-pyridinylmethyl)phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile triperoxonane acid

Specified in the title compound was obtained analogously to example 1 from 5-propylcyclohexane-1,3-dione (0.15 g) and the crude product stage. The compound was purified prepreparation HPLC (Luna C18 [5 μm], flow rate: 20 ml min-1, 10→90% CH3CN with 0.1% TFA) and lyophilized from a mixture of water and dioxane.

Output: 0,25,

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-ethoxyphenoxy]-N-thiophene-2-ylmethylene

a)Methyl ester of 4-(2-bromo-6-ethoxy-4-formylphenoxy)benzoic acid

Specified in the title compound was obtained analogously to example 15 from methyl ester 4-bromomethylphenyl acid (3.7 g).

Output: 6,4,

1H NMR (CDCl3): δ = 9,84 (s, 1H), of 8.06 (d, 2H), 7,65 (d, 1H), to 7.61 (d, 2H), 7,39 (d, 1H), to 5.03 (s, 2H), 4,16 (square, 2H), 3,93 (s, 3H), of 1.48 (t, 3H).

b)Methyl ester 4-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-4-yl)-6-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 1 from 5-propylcyclohexane-1,3-dione (2.5 g) and the product of stage a (6.4g).

Output: 6,7,

Rf(heptane/ethyl acetate (3/2 about./about.))=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-ethoxyphenoxy]benzoic acid

Specified in the title compound was obtained analogously to example 13b from the product of stage b (6.7 g). The reaction mixture was stirred at 50°C during the night.

Output: 6,4,

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-ethoxyphenoxy]-N-thiophene-2-ylmethylene

Specified in the title compound was obtained analogously to example 14 from the product of stage C (0.10 g) and 2-thiophenemethylamine (52 μl). Purification was performed by preparative HPLC (Luna C18 [5 μm], flow rate: 20 ml min-1, 10→90% CH3CN, 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

Specified in the title compound was obtained analogously to example 1A from 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (2.0 g) 5-propylcyclohexane-1,3-dione (1.3 g).

Output: 3.6V,

MS-ESI: [M-H]-= 443/445.

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

A mixture of the crude product of stage a (0,99 who), methylchloride ones (0.46 ml) and sodium hydroxide (0.32 g) in 4 ml of THF/water (1/1, vol/about.) was stirred at room temperature for 3 days. Added water and was extracted the reaction mixture with dichloromethane. Untreated specified in the title compound was obtained after concentration of the organic phase.

Output: 1,0,

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

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

Output: 0,19,

MS-ESI: [M-H]-= 564/566.

1H NMR (CDCl3): δ = 8.17 and (d, 2H), 7,00 (d, 1H), 6,91 (m, 3H), 5,95 (users, 1H), 4,63 (s, 1H), 4.04 the (DQC., 2H), 2,52 (DD, 1H), 2,42 (d, 2H), 2,25 (m, 1H), measuring 2.20 (s, 3H), of 2.15 (DD, 1H), 1,38 (m, 4H), of 1.20 (t, 3H), of 0.92 (t, 3H).

Example 31

4-[3-Bromo-5-ethoxy-4-(5-fluoro-2-propylaminoethyl)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) wtgf (50 ml) under cooling with ice bath, was added a 1M solution BH 3∙THF in THF (62 ml). The cooling bath was removed and continued stirring for 1 h at ambient temperature, followed by boiling under reflux for 4 hours, the Reaction mixture was cooled and to destroy excess borane was added MeOH. The mixture was concentrated and added to the residue water and ethyl acetate. The organic layer was washed with brine, dried and concentrated.

Output: 4,3,

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 stage a (1.5 g), thionyl chloride (1,94 ml) and few drops of DMF in dichloromethane (30 ml) was stirred for 72 h the Mixture was concentrated under vacuum and the residue was dissolved in DMF (20 ml). To the remaining solution was added the compound described in example 30A (3,9 g), K2CO3(6,1 g) and a small amount of bromide, Tetra-nbutylamine (about 50 mg). The mixture was stirred for 5 h at 60°C. was Added water and was extracted with ethyl acetate and the organic layer with ethyl acetate. The combined organic fractions were washed with brine, dried and concentrated. The residue was recrystallized from toluene.

Output: 3,8,

c)4-[4-(2-Amino-5-forbindelse)-3-bromo-5-ethoxyphenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile

To a solution of the product of stage b (3.8 g) in THF (110 ml) was added acetic acid (3.6 ml) and zinc dust (8,2 g). 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 NaHCO3and brine. Separated organic layer was dried (Na2SO4) and concentrated. The remaining solid was stirred with a small amount of ethyl acetate with education after filtering specified in the title compounds as a pale yellow solid.

Output: 2,8,

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

A solution of the compound described in stage C (200 mg), and Propionaldehyde (25 μl) in dichloromethane (5 ml) was stirred for 2 h Then was added acetic acid (81 ml) and triacetoxyborohydride sodium (300 mg) and additionally stirred the reaction mixture for 20 hours was Added 2M aqueous NaOH solution and continued stirring for 15 minutes the Organic layer was washed with water and brine, dried and concentrated in vacuum. Specified in the title compound was obtained by purification of the residue preparative HPLC (Luna C18 [5 μm], flow rate: 20 ml min-1, 10→90% CH3CN with 0.1% TFA) and lyophilization of the mixture of water and dioxane. Can also be allocated some dialkylamines products (see example 32).

Yield: 109 mg

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

Example 32

4-[3-Bromo-4-(2-dipropylamino-5-forbindelse)-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% CH3CN with 0.1% TFA) and lyophilization of the mixture of water and dioxane.

Yield: 12 mg

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

Example 33

The bioactivity SNO-FSHin vitro

FSH activity of the compounds was tested on cells of the Chinese hamster ovary (Cho), stable transfection human FSH receptor and cotransfection camp dependent element (CRE)/promoter that directs gene expression of Firefly luciferase. The binding of ligand to Gs-related FSH receptor will lead to an increase in camp, which, in turn, will cause an increase in the development of construction of luciferase reporter. The luciferase signal was measured luminescence counter. For test compounds were calculated EU50(concentration of test compound that causes half (50%) of the maximum stimulation). For this purpose, it was used the software GraphPad PRISM, version 3.0 (GraphPad software Inc., San Diego).

Connect all of the examples had activity (EC50less than 10-5M. the Compounds of examples 13, 16, 17, 19-21, 23, 26, 28, 31 and 32 showed the 50when between 10-7and 10-9M. the Compounds of examples 24 and 29 showed EU50when less than 10-9M

1. Derived dihydropyridines of the formula 1

or its pharmaceutically acceptable salt, in which
R1is C1-6the alkyl or phenyl, With1-5heteroaryl, both optionally substituted by one or more substituents selected from hydroxy, amino, halogen, nitro, cyano;
R2, R3independently are C1-4the alkyl, C1-4alkoxygroup,2-4alkenylacyl,3-4alkyloxy, halogen;
R4is C1-6the alkyl, C3-6cycloalkyl,3-6cycloalkyl1-4the alkyl, C6-10the aryl, C6-10arils1-4the alkyl, C1-9heteroaryl, and (hetero)aryl group optionally substituted by one or more substituents selected from hydroxy, amino, halogen, nitro, trifloromethyl, cyano, C1-4of alkyl, C2-4alkenyl,
With2-4the quinil,1-4alkoxygroup,1-4(di)alkylamino, and, if R4is phenyl, optionally from C1-4allylthiourea,1-4alkylsulfonyl, R5-oxycarbonyl, R5-carbonyl or R5,R6-aminocarbonyl;
X is SO2CH2With(O) or X is absent, provided that when X is CH2, R4 may additionally be an R5-oxycarbonyl, or R5-carbonyl;
R5, R6independently are H, C1-4the alkyl, C2-4alkenyl,2-4the quinil,3-6cycloalkyl,3-6cycloalkyl1-4the alkyl, C2-6heterocyclization,2-6heterocyclics1-4the alkyl, C1-4alkoxycarbonyl1-4the alkyl, C1-4(di)alkylaminocarbonyl1-4the alkyl or C6-10arylaminoquinolines1-4the alkyl, C1-9heteroarylboronic1-4the alkyl, C6-10the aryl, C1-9heteroaryl,6-10arils1-4the alkyl, C1-9heteroaryl1-4the alkyl and (hetero)aryl group optionally substituted by one or more substituents selected from hydroxy, amino, halogen, nitro, trifloromethyl, cyano, C1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4(di)alkylamino or
R5, R6in R5, R6-aminocarbonyl group can be associated with C2-6heteroseksualnymi ring;
provided 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 R4is phenyl, optionally substituted by one or more substituents chosen from hydro is si, amino, halogen, nitro, trifloromethyl, cyano, C1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxy, C1-4(di)alkylamino,1-4allylthiourea,1-4alkylsulfonyl, R5-oxycarbonyl, R5-carbonyl or R5,R6-aminocarbonyl.

3. The compound according to claim 2, in which the substituent in the phenyl group, R4is R5,R6-aminocarbonyl,1-4alkoxy and/or halogen.

4. The compound according to claim 3 in which R5in R5,R6-aminocarbonyl group is
With1-4(di)alkylaminocarbonyl and R6is N.

5. The compound according to claim 3 in which R5in R5,R6-aminocarbonyl group is
With1-9heteroaryl1-4the alkyl and (hetero)aryl group optionally substituted by one or more substituents selected from hydroxy, amino, halogen, nitro, trifloromethyl, cyano, C1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,
With1-4(di)alkylamino or1-4alkoxycarbonyl1-4the alkyl and R6is N.

6. The compound according to claims 1 to 5, in which X is CH2.

7. The compound according to claims 1 to 6, in which R1is1-6the alkyl, phenyl or1-5heteroaryl.

8. The compound according to claims 1 to 7, in which R2, R3are halogen or C alkoxygroup.

9. The compound according to claims 1 to 8 for use in therapy as a drug for impairment of fertility.

10. Pharmaceutical composition having agonistic activity against receptor FSH containing 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 compounds 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 its pharmaceutically acceptable salt, or MES for the preparation of drugs for the treatment of infertility.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of making compounds with formula , involving reaction of but-2-enoic acid with chlorotrimethylsilane, bromination of the obtained trimethylsilylcrotonate with N-bromosuccinimide, reaction of the obtained trimethylsilyl-4-bromocrotonate or methyl or ethyl 4-bromocrotonate with dimethylamine so as to obtain 4-dimethylaminocrotonic acid, its separation in form of hydrochloride and chlorination with oxalyl chloride. The method allows for obtaining 4-dimethylamino-2-butenoylchloride, suitable for use as an intermediate compound in the synthesis of pharmaceutically active protein kinase inhibitors.

EFFECT: obtaining the agent, suitable for use as an intermediate compound in the synthesis of pharmaceutically active protein kinase inhibitors.

1 cl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new quinoline derivatives of the general formula (I): , where R1 is 3-(methyloxy)phenyl, R2 is hydrogen, R19 is hydrogen, R20 is methyl, R3 is [(dimethylamino)carbonyl]phenyl, and n is 2; or R1 is 3-cyanophenyl, R2 is hydrogen, R19 is hydrogen, R20 is methyl, R3 is methyl, and n is 2. Invention also concerns prevention or treatment method for clinical states of mammals such as humans, to whom phosphodiesterase 4 (PDE4) inhibitor is prescribed; pharmaceutical composition based on compound of the general formula (I); as well as methods of obtaining compounds of the general formula (I). New compounds with phosphodiesterase (PDE4) inhibition effect were obtained, which can be applied in inflammation and/or allergic disease prevention and/or treatment.

EFFECT: increased efficiency of compounds.

15 cl, 676 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 represents hydrogen atom or linear or branched (C1-C4)-alkyl group; R2 represents hydrogen atom or linear or branched (C1-C4)-alkyl group; R3 represents phenyl, thienyl or furyl group that are substituted optionally with one or more linear or branched (C1-C4)-alkyl group, linear or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 represent independently of one another hydrogen atom, (C3-C6)-cycloalkyl group, linear or branched (C1-C4)-alkyl group comprising optionally amino-group or amino-group substituted with one or two linear or branched (C1-C4)-alkyl groups, hydroxy-group, carboxy-group or alkoxy-group substituted with linear or branched (C1-C4)-alkyl group; or R4 represents hydrogen atom or linear or branched (C1-C4)-alkyl group or benzyl group; R5 represents hydrogen atom, group -SO2OH or formyl group, or R4 and R5 in common with nitrogen atom form group of the general formula (a): wherein R7 and R8 represent independently one another hydrogen atom, linear or branched (C1-C4)-alkyl group; R6 represents phenyl, benzyl, thienyl or furyl group that are substituted optionally with methylenedioxy-group or one or more linear or branched (C1-C4)-alkyl group, linear or branched (C1-C4)-alkoxy-group or halogen atom; X represents group -NH or oxygen atom; Z represents oxygen atom, sulfur atom, group -CH2, group -NH or group -NR11 wherein R11 represents hydrogen atom, linear or branched (C1-C4)-alkyl group, group -SO2OH, linear or branched (C1-C4)-acyl group; n = 0, 1 or 2; m = 1, 2 or 3; o = 1, 2 or 3; p = 0 or 1; r = 0 or 1, and their salts and solvates. Also, invention relates to a method for synthesis of compounds of the general formula (I), to a pharmaceutical composition, its using and to compounds of the general formulas (I''), (II''), (III''), (IV''), (V''), (VI''), (VII''), (VIII'') and (XIII'') given in the invention description. Invention provides synthesis of novel biologically active compounds that are ligands of adenosine A3 receptors but as antagonists preferably.

EFFECT: valuable biological properties of compounds.

20 cl, 1 tbl, 40 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I , wherein Z is -NH-; X is radical; E is phenyl optionally monosubstituted with halogen; T is -O(CH2)m-, -S(CH2)m-; L is phenyl etc.; G1, G2, G3, and G4 are independently hydrogen, C1-C6-alkoxy, R2NH; R7 is -J; M is >NR6; W is direct bond; Het is pyrrolidine optionally monosubstituted at R6, hydroxy; each R6 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl; R2 is ; each R3 is , etc; J are independently hydrogen, chlorine, bromine or iodine; a = 0 or 1; n = 0 or 1; M = 1; p = 2-4; r = 1-4; u = 4 and pharmaceutically acceptable salts thereof. Also disclosed are methods for treatment, growth inhibiting or combating of neoplasm and other disorders and pharmaceutical composition having activity of EGF-R and HER2 kinase inhibitors, as well as method for production of abovementioned compounds.

EFFECT: new compounds with useful biological properties.

31 cl, 3 tbl, 10 ex

FIELD: organic chemistry.

SUBSTANCE: method for production of target compounds of formula IA having high protein kinase inhibitor activity includes interaction of corresponding compound of formula IIA with compound of formula R2XH.

EFFECT: mew compounds with protein kinase inhibitor activity.

14 cl, 6 dwg, 102 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: derivative of quinoline carboxaldehyde i. e. 2-cyclopropyl-4-(4'-fluorophenyl)quinoline 3-carboxaldehyde is prepared by interaction of 3-cyclopropyl-3-oxopropane nitrile with 2-amino-4'-fluorobenzophenone to yield 2-cyclopropyl-4-(4'-fluorophenyl)quinoline 3-carbonitrile followed by its reduction.

EFFECT: enhanced yield of end product, simplified process.

8 cl, 11 ex

The invention relates to pharmaceutical industry and relates to means for obtaining a medicinal product for the treatment of breast cancer and prostate cancer, which represents a quinoline derivative of General formula (I), furthermore, the invention relates to new compounds, pharmaceutical compositions and to methods for producing compounds of formula (I)

The invention relates to substituted 3-cyanohydrins formula (1), where R1, R2, R3, R4, Y and X are such as defined in the claims

-converting enzyme)" target="_blank">

The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

FIELD: chemistry; biochemistry.

SUBSTANCE: present invention pertains to genetic engineering, more specifically to chimeric polypeptides, containing an antagonist of growth hormone receptor. The invention can be used in medicine. The binding domain of the growth hormone is modified by substituting glycine amino acid residue in position 120 and is further modified in site 1, where at least one amino acid residue is substituted, which increases affinity of the growth hormone to its binding domain on the growth hormone receptor. The amino acid residue is then conjugated with the ligand-binding domain of the growth hormone receptor, through a peptide linker.

EFFECT: obtaining a highly effective antagonist of the growth hormone receptor with longer half-life, reduced immunogenesity and nontoxicity, compared to known mutant forms.

35 cl, 16 dwg, 1 tbl

FIELD: medicine; gynecology.

SUBSTANCE: method includes abdominovaginal exposure from 5-7th day of menstrual period. Exposure is carried out with variable pulsating magnetic field generated by apparatus "Polus-2" at maximum intensity, frequency 50 Hz in intermittent duty. Duration of procedure is 20 minutes. Exposure is carried out daily, 3 times a day with interval between procedures not less than 2 hours. Method is noninvasive, improves implantation potential of endometrium due to blood circulation improvement in uterus arteries, and provides multilayer structure in endometrium.

EFFECT: higher incidence of pregnancy in patients with previous failures in extracorporal fertilisation.

3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: releasing peptides of growth hormone are described with formula (I): R112345-R2, where:А1 designates Aib, Apc or Inp; А2 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Тrp; А3 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-2Ser(Bzl) or D-Trp; А4 designates 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); А5 designates Apc, Dab, Dap, Lys, Orn or deleted; R1 designates hydrogen; and R2 designates NH2; and their pharmaceutically acceptable salts.

EFFECT: pharmaceutical compositions and the methods of their application are presented.

25 cl, 1 tbl, 2 ex

Grelin analogs // 2315059

FIELD: chemistry of peptides.

SUBSTANCE: invention relates to peptidyl analogs of grelin showing activity at GHS-receptor. Peptidyl analogs of grelin can be used for identifying a compound able for binding with GHS-receptor and for stimulation of the growth hormone secretion in s subject.

EFFECT: valuable properties of analogs.

10 cl, 1 tbl, 6 ex

The invention relates to medicine

The invention relates to medicine and can be used for the prevention of aging

The invention relates to aqueous pharmaceutical compositions containing human growth hormone, amino acid; histidine, nonionic detergent: poloxamer 188

The invention relates to pharmacology, medicine, and in particular to means analgesic
The invention relates to medicine, in particular to urology and endocrinology

The invention relates to a peptide that includes the analogue of carboxykinase sequence of growth hormone, where carboxykinase sequence contains amino acid residues 177-191 human growth hormone: Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe, or a corresponding sequence of growth hormone, non-human mammal; where in the specified similar amino acids at positions 182 and 189 hGH are connected by a communication in order to facilitate the formation of cyclic conformation, and/or amino acids at positions 183 and 186 hGH are connected by a salt bridge or a covalent bond; or its salts with organic or inorganic acid

FIELD: chemistry.

SUBSTANCE: invention relates to a salt of amine with carbostyril derivative, formed from carbostyril derivative, with formula , R is a halogen atom, substitution position in the side chain is the 3rd or 4th position in the carbostyril skeleton, and the bond between the 3rd and 4th positions on the carbostyril skeleton is a single or double bond, and amine, chosen from: amino acid; C1-6alkyl-substituted amine, which can have a substituted chosen from a group which contains a hydroxy group and an amino group; and amino sugar, which dissolves in water very well. The invention also relates to a pharmaceutical composition which contains a salt of amine with carbostyril derivative of formula (I) as an active ingredient.

EFFECT: new salts are obtained, with useful biological properties.

25 cl, 13 ex

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