Tetrahydroquinolin derivatives, based pharmaceutical composition based on them and their application as fertility modulator

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

 

This invention relates to a compound which has a modulatory activity against FSH receptor, in particular, to a derivative tetrahydroquinoline, pharmaceutical compositions containing these compounds and to the use of the compounds in therapy.

The gonadotropins perform functions important for various processes in the body, including metabolism, temperature regulation and reproductive process. The gonadotropins act on specific cells of the gonadal type, initiating ovarian and testicular differentiation and steroidogeneza. For example, pituitary gonadotropic FSH (follicle stimulating hormone) plays a key role in promoting the development and maturation of the follicle, while the LH (luteinizing hormone) induces ovulation (Sharp, R. Clin Endocrinol. 33:787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35:301-342, 1979). Currently FSH clinically used in combination with LH or hCG for ovarian stimulation, i.e. ovarian hyperstimulation for in vitro fertilization (in vitro fertilization - IVF), and induction of ovulation in women with infertility due to the absence of ovulation (Insler, V., Int. J. Fertility 33:85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Enbryo Transfer 5:3-13, 1988), as well as for the treatment of male hypogonadism and male infertility.

Gonadotropic FSH is released from the anterior pituitary under the influence of th adolapin-releasing hormone and estrogen and from the placenta during pregnancy. In the female body FSH acts on the ovaries, accelerating the development of the follicle, and is the main hormone that regulates the secretion of estrogen. The male body FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis. Purified FSH is used for treating female infertility and for certain types of disorders of spermatogenesis in men. The gonadotropins, intended for therapeutic purposes, can be isolated from human urine and have a low level of 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 for assisted reproduction. (Olijve et al. Mol. Hum. Reprod. 2:371, 1996; Devroey et al. Lancet 339:1170, 1992).

Actions of FSH hormone mediated by specific plasma membrane receptor, which is representative of the large family of receptor associated G-protein. These receptors consist of a single polypeptide with seven transmembrane domains and are able to interact with G-protein, which leads, for example, to the activation of adenylate cyclase.

FSH receptor is highly specific targets in the growth of the ovarian follicle and expressed only in the ovary. Blocking this recipe is RA or inhibition of signal transmission, which usually is induced after activation of the FSH-mediated receptor, will disturb the development of the follicle and, as a consequence, lead to the violation of ovulation and fertility. Therefore, FSH antagonists with low molecular weight formed the basis of new contraceptives. Such FSH antagonists can cause a delay in the development of the follicles (absence of ovulation) with preservation of oestrogen at a level sufficient to prevent adverse effects, for example, on bone mass. On the other hand, compounds that stimulate the activity of FSH receptor can mimic gonadotropic action of the natural ligand.

This invention describes how to obtain low molecular weight analogues of the hormone, which have selective modulatory activity against FSH receptor. The compounds of this invention can be used either as partial agonists or partial antagonists of the FSH receptor.

So, it is now established that below the class of derivatives tetrahydroquinoline formula I or their pharmaceutically acceptable salts possess modulatory activity against FSH.

The formula I

where

R1and R2represent H or Me;

R3represents H, hydroxy, (1-4C)alkoxy, (d the)(1-4C)alkylamino(2-4C)alkoxy or (2-6)heteroseksualci(2-4C)alkoxy;

R4represents H, HE, (1-4C)alkoxy, or R7;

R5represents H, HE, (1-4C)alkoxy, or R7;

provided that if R4represents H, R5different from H, HE, or (1-4C)alkoxy, and where R5represents H, R4different from H, HE, or (1-4C)alkoxy;

R6is a (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloalkyl, (2-6C)heteroseksualci or (1-6C)alkyl;

R7represents amino, (di)(1-4C)alkylamino, (6S)arylcarboxamide, (6S)arylcarboxylic, (2-5C)heteroarylboronic, (2-5C)heteroarylboronic, R8-(2-4C)alkylamino, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy;

R8represents a hydroxy, amino, (1-4C)alkoxy, (di)(1-4C)alkylamino, (2-6C)heteroseksualci, (2-6C)geterotsiklicheskikh, (di)(1-4C)alkylaminocarbonyl or (1-4C)alkoxycarbonyl; and

R9is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl.

R4and R5can be independently selected from each of the groups described above, and should not be the same.

Compounds according to this invention modulate the function of FSH receptor and can be used for the same clinical tasks as natural FSH, if they behave like agonists, with the advantage that they are reavley properties of the modified stability and can be entered otherwise. If they block FSH receptor, can be used, for example, as a method of contraception.

Therefore, modulators of FSH receptor of the present invention can be used for the treatment of infertility, contraception and for the treatment of hormone-dependent disorders such as breast cancer, prostate cancer and endometriosis.

Below the terms used in the description and the formula of the present invention, as is implied, shall have the following meanings.

The term "(1-4C)alkyl", as used herein, means a branched or unbranched alkyl group containing 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

The term "(1-6C)alkyl"as used herein, means a branched or unbranched alkyl group containing 1-6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and hexyl. (1-5C)Alkyl groups are preferred, and most preferred (1-4C)alkyl.

The term "(3-8C)cycloalkyl" means cycloalkyl group containing 3-8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred are (3-6C)cycloalkyl group.

The term "(2-6C)heteroseksualci" means the AET geterotsyklicescoe group, containing 2-6 carbon atoms, preferably 3-5 carbon atoms, and comprising at least one heteroatom selected from the atoms N, O and/or S, which may be joined via a heteroatom, if feasible, or through a carbon atom. Preferred heteroatoms are N or O. Most preferred are piperidyl, piperazinil, morpholinyl and pyrrolidinyl.

The term "(1-4C)alkoxy" means alkoxygroup containing 1-4 carbon atoms, and the alkyl fragment takes the value defined above. (1-2C)Alkoxygroup are preferred.

The term "(2-4C)alkoxy" means alkoxygroup containing 2-4 carbon atoms, and the alkyl fragment takes the value defined above.

The term(di)(1-4C)alkylamino" in this description means an amino group, monosubstituted or disubstituted by alkyl groups, each of which contains 1-4 carbon atoms and has a value defined above.

The term "(6C)aryl" in the present description means a phenyl group which may be optionally substituted by one or more substituents selected from hydroxy, amino, iodine, bromine, chlorine, fluorine, nitro, trifloromethyl, cyano, phenyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)(di)alkylamino, alkyl, alkoxy and (di)alkylamino, the values of which are defined above, for example, phenyl, 3,5-dibromo Anila, 4-biphenyl, 3,5-dichlorophenyl, 3-bromo-6-methylaminophenol, 3-chloro-2,6-acid and 3,5-dimetilfenil.

The term(2-5C)heteroaryl" means substituted or unsubstituted aromatic group containing 2-5 carbon atoms and at least one heteroatom selected from N, O and/or S, for example, imidazolyl, pyridyl, pyrimidyl, thienyl or furyl. The substituents on the heteroaryl group can be selected from the group of substituents defined for (6C)aryl group. Heteroaryl group may be joined through a carbon atom or heteroatom, if possible. Preferred heteroaryl groups are thienyl, furyl and pyridyl.

The term "di(1-4C)alkylamino(2-4C)alkoxy" in the present description means a (di)alkylamino, in which the alkyl portion or the alkyl fragments, each of which contains 1-4 carbon atoms attached(s) via the amino group to the alkyl portion of alkoxygroup containing 2-4 carbon atoms, where (di)alkylamino and alkoxygroup take the values defined above.

The term "(2-6C)heteroseksualci(2-4C)alkoxy" in the present description means geterotsyklicescoe group containing 2-6 carbon atoms and attached to the alkyl portion of alkoxygroup containing 2-4 carbon atoms, where alkoxygroup and heterocytolysine group take the values defined above.

The term "(6S)arylcarboxamide" in this description means a phenyl group, optionally substituted by one or more substituents selected from the group of substituents defined for (6C)aryl group that is attached to the carbonyl fragment carbonylation, where (6C)aryl fragment takes the values defined above.

The term "(6S)arylcarboxylic" in this description means a phenyl group, optionally substituted by one or more substituents selected from the group of substituents defined for (6C)aryl group that is attached to the carbonyl fragment carbonyloxy, where (6C)aryl fragment takes the values defined above.

The term(2-5C)heteroarylboronic" in this description means a heteroaryl group containing 2-5 carbon atoms, optionally substituted by one or more substituents selected from the group of substituents defined for (6C)aryl group attached to carbonyl fragment carbonylation. Heteroaryl fragment in heteroarylboronic takes the values defined above.

The term(2-5C)heteroarylboronic" in this description means a heteroaryl group containing 2-5 carbon atoms, optionally substituted by one or more substituents, selected and from a group of substituents, specified for (6C)aryl group attached to carbonyl fragment carbonyloxy. Heteroaryl fragment in heteroarylboronic takes the values defined above.

The term "(2-6C)geterotsiklicheskikh" in this description means geterotsyklicescoe group containing 2-6 carbon atoms and attached to the carbonyl fragment carbonylation where heterocytolysine the group takes the values defined above.

The term(di)(1-4C)alkylaminocarbonyl" in this description means a (di)alkylamino, in which alkyl(s) group(s) contain(at) 1-4 carbon atoms and which is attached to a carbonyl group through the amino group, where (di)alkylamino takes the values defined above.

The term(di)(1-4C)alkylaminocarbonyl" in this description means a (di)alkylamino, in which alkyl(s) group(s) contain(at) 1-4 carbon atoms and which is attached via the amino group to the carbonyl fragment carbonylation, providing, thus, the functionality of urea, where (di)alkylamino takes the values defined above.

The term "(1-4C)alkoxycarbonyl" in this description means alkoxygroup containing 1-4 carbon atom attached to the carbonyl fragment carbonylation, provide the, thus, the urethane functionality, where alkoxygroup takes the values defined above.

The term "R8-(2-4C)alkylamino" in this description means the group R8attached to the alkyl fragment (2-4C)alkylamino, the meanings of which are defined above.

The term "R8-(2-4C)alkoxy" in the present description means the group R8attached to the alkyl fragment (2-4C)alkoxygroup, the meanings of which are defined above.

The term "R9-methylamino" in this description means the group R9attached to the methyl fragment methylaminopropyl.

The term "R9-methoxy" in this description means the group R9attached to the methyl fragment metoxygroup.

The term "pharmaceutically acceptable salt" refers to salts that are in the field of medical applications suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response and the like and characterized by a reasonable ratio of benefit/risk. Pharmaceutically acceptable salts are well known in the art. They can be obtained during the final isolation and purification of compounds of this invention or separately by the interaction of the functional groups in free base, if it is present, coming up with what her mineral acid, such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acid, such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonate acid and the like Functional group of the acid, if present, may be subjected to interaction with organic or mineral base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

Thus, the invention relates to compounds of formula I, defined above.

In another embodiment of this invention, it relates to compounds of formula I, where R3represents H, hydroxy or (1-4C)alkoxy.

The invention also relates to compounds of formula I, where R4represents H, HE or (1-4C)alkoxy.

In yet another embodiment of the present invention, it provides the compounds of formula I, where R5HE is a, (1-4C)alkoxy, or R7.

In yet another embodiment of the present invention, it provides the compounds of formula I, where R6is a (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloalkyl or (1-6C)alkyl.

In another aspect of this from retina relates to compounds of the formula I, where R6is a (2-5C)heteroaryl or (6C)aryl.

In yet another aspect, the heteroaryl group, R6consists of 4 or 5 carbon atoms.

The invention also relates to compounds of formula I, where R7is a (di)(1-4C)alkylamino, (2-5C)heteroarylboronic, (2-5C)heteroarylboronic, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy.

Another aspect of the present invention are compounds according to formula I, where R7is a (di)(1-4C)alkylamino, (2-5C)heteroarylboronic, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy.

In another aspect this invention relates to compounds of formula I, where R7is a (di)(1-4C)alkylamino, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy.

In another aspect this invention relates to compounds of formula I, where R8-(2-4C)alkoxy group, R7is an R8-ethoxy.

In another aspect this invention relates to compounds of formula I, where R8-(2-4C)alkylamino in the group R7is an R8-ethylamino.

In another aspect, the invention provides compounds of formula I, where R8represents amino, (di)(1-4C)alkylamino, (2-6C)heteroseksualci, (2-6C)geterotsiklicheskikh is on or (1-4C)alkoxycarbonyl.

In yet another exemplary embodiment of the present invention, it provides the compounds of formula I, where R8represents amino, (di)(1-4C)alkylamino, (2-6C)heteroseksualci or (1-4C)alkoxycarbonyl.

In yet another exemplary embodiment of the present invention, it provides the compounds of formula I, where R8represents amino, (di)(1-4C)alkylamino, (2-6C)heteroseksualci or (2-6C)geterotsiklicheskikh.

The invention relates also to compounds according to formula I, where R8represents amino, (di)(1-4C)alkylamino or (2-6C)heteroseksualci.

In another aspect of this invention R8in the compounds of formula I is a (di)(1-4C)alkylamino or (2-6C)heteroseksualci.

In another aspect this invention relates to compounds according to formula I, where heterocytolysine group in R8consists of 4 or 5 atoms C.

According to another embodiment of this invention R9in compounds according to formula I is aminocarbonyl, (2-5C)heteroaryl or (6C)aryl.

According to another exemplary embodiment of the present invention heteroaryl group, R9compounds according to formula I consists of 3, 4 or 5 atoms C.

Another aspect of the present invention refers to compounds in which all of the specific value of g is PP R 1-R9defined in the description above, combined in the compound of formula I.

Following are acceptable methods for obtaining the compounds of the present invention.

The compounds of this invention in which R4and R5represent (1-4C)alkoxy, R1and R2are methyl and R6takes the values defined above, can be obtained from the suitable substituted anilines of General formula II according to reaction Skrupa (Skraup), described in detail in the literature, to obtain the derivatives of 2,2,4-trimethyl-1,2-dihydroquinoline formula IIIa.

Similar reactions cyclocondensation of Skroupa described in the literature: A. Knoevenagel, Chem. Ber. 54:1726, 1921; R.L. Atkins and D.E. Bliss, J. Org. Chem. 43:1975, 1978; J.V. Johnson, B.S. Rauckman, D.P. Baccanari, B. Roth, J.Med. Chem. 32:1942, 1989; W.C. Lin, S.-T. Huang, S.-T. Lin, J. Chin. Chem. Soc. 43:497, 1996; J.P. Edwards, S.J. West, K.B. Marschke, D.E. Mais, M.M. Gottardis and T.K. Jones, J. Med. Chem. 41:303, 1998.

The above reaction is usually carried out at elevated temperature in acetone or mesityloxide in the presence of iodine or a proton acid, such as hydrochloric acid, p-toluensulfonate or aqueous hydrogen iodide. Alternative 1,2-dihydro-2,2,4-trimethylquinoline formula III-a can be obtained by interaction of the corresponding aniline of formula II with acetone in the presence of MgSO4, 4-tert-butylcatechol and yo is a (L.G. Hamann, R.I. Higuchi, L. Zhi, J.P. Edwards and X.-N. Wang, J. Med. Chem., 41:623, 1998). In accordance with another method, the reaction can be carried out in acetone with the use of lanthanide triflates (e.g., scandium triflate) as catalysts. In this case, the reaction may be conducted at room temperature or at elevated temperatures using conventional heating or microwave irradiation (M.E. Theoclitou, L.A. Robinson, Tetrahedron Lett. 43:3907, 2002).

The initial substance can be easily obtained directly from commercial sources or readily synthesized by qualified specialists in this field of technology.

The compounds of formula III-b can be obtained from anilines of General formula II interaction with methyl vinyl ketone are. Similar to the cyclization reaction described in U.S. patent No. 2686182 (Badische Anilin- &Soda-Fabric Aktiengesellschaft).

Subsequent 1-N-acetylation of compounds of formula III-a-b, where R1and R2take the values described above can be carried out using standard conditions. In a typical experiment, the compounds of formula III refluxed in acetic anhydride or subjected to interaction in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine, with the acid chloride of acetic acid in the presence of a base, such as N,N-diisopropylethylamine, triethylamine or sodium hydride, with what rucenim N-acetylated 4-methyl-1,2-dihydroquinoline derivatives of formula IV-a-b.

Similar reactions of N-acylation dihydroquinoline basis described in the literature: G. Reddelien, A. Thurm, Chem. Ber. 65:1511, 1932; Zh. V. Shmyreva, Kh. S. Shikhaliev, E.B. Shpanig, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Teknol. 31:45, 1988; Zh. V. Shmyreva, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko, I.E. Pokrovskaya, Zh. Obshch. Khim. 59:1391, 1989.

Introduction necessary (substituted) phenyl group in position 4 dihydroquinoline bases can be carried out by alkylation of benzene or a suitable substituted benzene compounds of the General structure IV-a-b in accordance with the reaction of the Friedel -. This reaction is usually conducted at elevated temperatures in pure benzene or in an appropriate substituted benzene, or in a suitable inert solvent such as heptane or hexane, benzene, or suitable substituted benzene as a reagent, in the presence of a catalyst of the Lewis acid (e.g., AlCl3,AlBr3,FeCl3or SnCl4). The reaction of alkylation Friedel-with 2,2,4-trimethyl-1,2-dihydroquinoline described in the literature: B.A. Lugovik, L.G. Yudin, A.N. Kost, Dokl. Akad. Nauk SSSR, 170:340, 1966; B.A. Lugovik, L.G. Yudin, S.M. Vinogradova, A.N. Kost, Khim. Geterosikl. Soedin., 7:795, 1971.

Alternative anilines of the General structure II may be subject to interaction with a suitable substituted derivatives of 1-methylstyrene and formaldehyde in acetonitrile at ambient temperature or at an elevated temperature to obtain compounds is s the General formula V-b. Similar to the cyclization reaction described in the literature: J.M. Mellor, G.D. Merriman, Tetrahedron, 51:6115, 1995.

Compounds of General structure V-a-b then may be the regioselective nitration in position 6 tetrahydroquinolines basis to obtain compounds of General structure VI-a-b. This reaction is usually carried out at temperatures in the range from -10°C to room temperature in dichloromethane, using a mixture of nitric acid and acetic anhydride as nitrouse agent. Alternative nitric acid may be added to a solution of compounds of General structure V-a-b in glacial acetic acid or in a mixture of acetic acid and dichloromethane. Similar reactions are regioselective nitration of tetrahydroquinolines described in the literature: B. Golankiewicz, Pol. J. Chem., 54:355, 1980; Zh. V. Shmyreva, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko, I.E. Pokrovskaya, Zh. Obshch. Khim. 59:1391, 1989.

The restoration of the nitro group of compounds of General structure VI-a-b can be performed using various methods, well known in the art for the recovery of aromatic nitro compounds, such as catalytic hydrogenation using catalysts of transition metals processing sulfides, treatment with iron or other metals, and (weak) acid treatment of the dichloride in acidic conditions, etc. In particular, assistance is their nitro compounds of General formula VI-a-b can be carried out by processing of powdered zinc and acetic acid in THF or 1,4-dioxane at a temperature in the range from 0 to 100° C.

Subsequent 6-N-acylation of compounds of formula VII-a-b can be carried out under standard conditions well known to skilled professionals in the art, to obtain compounds of General structure I-a-b. For example, the compounds of formula VII are interacting in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine, with allelochemical (R6-C(O)-Cl) or acid anhydride (R6-C(O)-O-C(O)-R6in the presence of base

such as N,N-diisopropylethylamine, triethylamine, pyridine or sodium hydride, to obtain 6-N-acylated derivatives of 1,2,3,4-tetrahydroquinoline formula I-a-b. Alternative acylation of compounds of General formula VII-a-b to obtain the compounds of General formula I-a-b can be carried out by the interaction with the appropriate carboxylic acid (R6-CO2H) in the presence of coupling reagent such as tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (TBTU), hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU) or hexaphosphate postreproductive (PyBrOP) and a tertiary base, such as N,N-diisopropylethylamine, in a solvent such as N,N-dimethylformamide or dichloromethane, at ambient temperature or at elevated temperature.

The compounds of this invention in which R 3= H, OH or (1-4C)alkoxy, R4= HE, R5= OH or (1-4C)alkoxy and R1, R2and R6take the values defined above, can be obtained by demethylation reactions of compounds of General formula I-c-d. The reaction of demethylation simple aromatic methyl ethers is well known to specialists in this field of technology. Usually demethylation is carried out in the interaction of the compounds of formula I-c-d BBr c3in an inert solvent, such as dichloromethane, at a temperature in the range from low to ambient temperature to obtain demetilirovanny compounds of General formula I-e-i. Alternative demethylation can be carried out by the interaction of compounds of formula I-c-d BF3·Me2's complex at ambient temperature. The degree of demethylation can partly be controlled by careful control of reaction temperature and amount of demetrious reagent. Usually get a mixture of mono-, di - and, if possible, trihydroxy-derivatives of General formula I-e-i, which can be separated chromatographically. The demethylation reaction usually proceeds with a high degree of selectivity with the preferred demethylation at position 5 tetrahydroquinolines basis. The reaction rate demethylation (dealkylation) compounds of General formula I-c-d with testvol the ratio of 5-OMe> 4-(p-Oalk-phenyl)>7-OMe.

The compounds of this invention in which R3represents H or (functionalized) alkoxygroup and R4and/or R5represent (functionalityand) alkoxygroup or alloctype can be obtained by reaction of realtalibkweli or acylation of the hydroxyl groups of compounds of General formula I-e-i (functionalized) alkylhalogenide (for example, charityproviding) or acylhomoserine (for example, 2-forargliga or methylchloroform), respectively, under standard conditions.

The compounds of this invention in which R4= H and R5attached to tetrahydroquinolines basis via a nitrogen atom and R1, R2and R6take the values defined above, can be obtained from N-Boc-1,4-phenylenediamine (VIII). The sequence of reactions (a) Skroupa, (b) acylation and (C) the alkylation of benzene or substituted benzene in accordance with the reaction of the Friedel-as described above, leads to the formation of compounds of General formula h-a. It should be noted that the protective BOC group is cleaved under the reaction conditions of Friedel -.

Alternative N-Boc-1,4-phenylenediamine may be treated with methyl vinyl ketone are followed by acylation and reaction Friedel-as described above, to obtain compounds of General formula is X-b.

In yet another method, the compounds of General formula X-b can be obtained from the partial recovery of 4-methylinosine (XI) with BH3·THF complex and bis(2-methoxyethoxy)alomaliye.com sodium to obtain 4-methyl-1,2-dihydroquinoline and subsequent acetylation, as described above, to obtain compounds XII. Reduction reaction of similar quinoline obtaining 1,2-dihydroquinoline described in the literature: see, for example, D. Roberts, J.A. Joule, J. Org. Chem. 62:568, 1997; R.F. Heier, L.A. Dolak, J.N. Duncan, D.K. Hyslop, M.F. Lipton, I.J. Martin, M.A. Mauragis, M.F. Piercey, N.F. Nichols, P.J.K.D. Schreur, M.W. Smith, M.W. Moon, J. Med. Chem. 40: 639, 1997. The reaction of the Friedel-compound XII with benzene or an appropriate substituted benzene leads to the formation of compounds of General formula XIII, which can be subjected to conversion into compounds of General formula X-b regioselective nitration in position 6 and rehabilitation to the corresponding 6-amino-derived using the above-described conditions. The reaction is regioselective nitration of similar structures have been described in the literature, for example, Zh. V. Shmyreva et al., J. Gen. Chem. USSR (Engl. translation) 59:1234, 1989.

Compounds of General formula X-a-b then may be subjected to reaction injection protective 9-fluorenylmethoxycarbonyl group (Fmoc group), see, for example: T.W. Greene and P.M.Wuts, Protective groups in organic synthesis (3rd ed., John Wiley & Sons, Inc., 1999, see, in particular, page 506). The above protection is normally introduced with the use of FmocCl in THF with pyridine as the base.

Regioselective nitration in position 7 tetrahydroquinolines basics of compounds of General formula XIV-a-b and subsequent reduction of the nitro group (see above) leads to the production of derivatives of 7-amino-1,2,3,4-tetrahydroquinoline General formula XV-a-b. The reaction is regioselective nitration similar frameworks with similar substitution described in the literature; see, for example: S.H. Reich. M.A. Fuhly, D. Nguyen, M.J. Pino et al., J. Med. Chem. 35:847, 1992; A. Ivobe, M. Uchida, K. Kamata, Y. Hotei, H. Kusama, H. Harada, Chem. Pharm. Bull. 49:822, 2001. The nitration conditions similar to the conditions described above.

Reductive alkylation of the amino group in position 7 tetrahydroquinolin-derivatives of the General formula XV-a-b using the appropriate substituted aldehyde and a suitable reducing agent (for example, cyanoborohydride sodium or triacetoxyborohydride sodium) in a suitable solvent, such as methanol or N,N-dimethylformamide, leads to the formation of compounds of General formula XVIa-b. Usually formaldehyde leads to the most prevalent getting 7-dimethylaminomethylene derivative (D = E = Me), while the use of other aldehydes leads to preferential the WMD obtaining monoalkylated compounds of General formula XVIa-b (D = H, E = (functionalized)alkyl). The reaction of reductive alkylation of aromatic amines are well known to the specialists in this field.

Standard cleavage of the protective Fmoc group using piperidine in dichloromethane leads to the production of 6-aminotetrahydrofuran-derivatives of the General formula XVII-a-b, which may be subjected to selective alkylation at position 6, as described above for compounds of the present invention of General formula I-j-k.

In accordance with another method of the amino group in position 7 tetrahydroquinolin-derivatives of the General formula XV-a-b may be subjected to acylation (hetero)arylcarbamoyl acids (G-CO2H) or acylchlorides (G-C(O)-Cl), as described above. The later stages of the strategy of removal protection-acylation (removal of protective 6-N-Fmoc group and acylation of the obtained 6-NH2group), described above, leads to the formation of compounds of the present invention of General formula I-l-m.

The compounds of this invention in which R4= H, R5attached to tetrahydroquinolines basis through an oxygen atom and R1, R2and R6take the values defined above, can be obtained on the basis of 2-methoxy-4-nitroaniline (XVII). The sequence of reactions (a) the introduction of the Fmoc protective group to obtain XIX, (b) vosstanovlenie the nitro-group with obtaining XX, (C) regioselective reaction of Skroupa, (d) acetylation and (e) removing the Fmoc protective group, as described above, leads to the formation of compounds of General formula XXI-a.

Compounds of General formula XXI-b can be obtained by treating compound XX with methyl vinyl ketone are in the conditions described above for the conversion of compounds of formula II to compound III-b with subsequent 1-N-acetylation and removal of the Fmoc protective group, as described above.

Subsequent conversion of compounds of General formula XXI compound XXIII can be carried out by acylation of 6-amino group using a suitable Alliluyeva agent, for example, acylchlorides R6-C(O)-Cl, and the subsequent reaction of the Friedel-with benzene or a suitable derivative of benzene under the conditions described above. If the reaction Friedel-in the presence of Lewis acid is concomitant demethylation of 7-ome functional groups in the compounds of General formula XII. Thus obtained free 7-Oh group in compounds of General formula XXIII may be re-alkylation or acylation (functionalized) alkylhalogenide (for example, charityproviding) or acylhomoserine (for example, 2-forargliga or methylchloroform), respectively, under standard conditions to obtain compounds of General formula I-n-o (E = functionalis the integration of alkyl, acyl or carbamate).

The compounds of this invention in which R4and R5attached to tetrahydroquinolines basis via the nitrogen atom, can be obtained from compounds of General formula XXIV, where PG represents a protective group of a nitrogen atom, for example, BOC, acetyl, methylcarbamate or Fmoc, through the above-described reactions, for example, the reaction of Skroupa or cyclocondensation with methyl vinyl ketone are, 1-N-acetylation, cleavage of protective groups, N-alkylation, reaction of the Friedel -, nitration, nitrogroup reduction and acylation (see above).

The interaction of compounds of General formula XXV with acetone or mesityloxide in accordance with the reaction Skroupa can lead to two different regioisomeric products of General formula XXVI-a and XXVII-a, respectively. The conversion of compounds of General formula XXV using methyl vinyl ketone are in the above-described conditions can lead to regioisomeric products of General formula XXVI-b or XXVII-b, respectively. Typically, these regioisomeric dihydroquinoline may be separated chromatographic methods (silica gel, HPLC or crystallization and may subsequently be subjected to conversion into compounds of the present invention above described methods.

The compounds of this invention in which R5= N, can be obtained recovery 7-deoxygenation compounds of General formula XXVIII or XXXI (L and/or M is a suitable (substituted) alkyl, acyl, allyloxycarbonyl or alkylaminocarbonyl) through selective 7-O-triflation and subsequent recovery group 7-OTf (Tf = trifloromethyl). The target compounds of General formula XXXI available from derivatives of General formula XXVII using the above-described conditions. Reaction (regioselective) deflationary can be carried out under controlled conditions using Tf2N-phenyl and N,N-diisopropylethylamine in DMF at room temperature. Is usually the preferred triflation 7-Oh groups. Subsequent recovery can be carried out using a mixture of tributylphosphine, triethylamine, formic acid and palladium (II)acetate, as described in the literature (see, for example, K.A. Parker, A. Ding, Tetrahedron 56:10249, 2000). The subsequent transformation of the thus obtained compounds of General formula XXX or XXXII using the above conditions leads to the formation of compounds of General formula I-p-q, in which R5= H.

Some compounds of the present invention, which may be in free base form, can stand out from the reaction mixture in the form of headlights is asepticheski acceptable salt. Pharmaceutically acceptable salts can also be obtained by treating the free base of formula I with organic or inorganic acid, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonate acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.

The compounds of this invention possess at least one chiral carbon atom and, therefore, can be obtained in the form of pure enantiomers, a mixture of enantiomers or as a mixture of diastereoisomers. Methods of obtaining pure enantiomers are well known in the art, for example crystallization of salts, which are obtained from optically active acids and racemic mixtures, or chromatography using chiral columns. For the diastereomers can be used in column chromatography with direct or reversed phase.

The compounds of this invention may form a hydrate or a solvate. Specialists in this field it is known that charged compounds to form hydrated compounds during lyophilization from water or form a solvate at the end is Tserovani in a solution of a suitable organic solvent. The compounds of this invention include a hydrate or solvate of such compounds.

For screening active compounds tested at 10-5M should lead to activity that constitutes more than 20% of maximum activity when using FSH as a control. Another criterion may be the value of the EU50that should be <10-5M, preferably <10-7M

The person skilled in the art will understand that the desired value of the EU50depends on which connection to use. For example, the connection with the value of the EU50less than 10-5M is usually considered as a possible candidate to obtain drugs. Preferably this value is less than 10-7M. However, the compound which has a higher value EU50but selectively in relation to a specific receptor, may be even more promising connection.

Methods for determining the receptor binding of gonadotropins in vitro and in vivo to determine the biological activity well known to specialists in this field of technology. Usually downregulation of the receptor is exposed to contact with the compound to be tested and quantified by the binding, stimulation or inhibition of a functional response.

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

How to create recombinant FSH expressing cell lines are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). The expression of the receptor is achieved by expression of DNA that encodes a desired protein. Methods site-directed mutagenesis, ligation of additional sequences, PCR and create a suitable expression systems are now well known in this field. Part of the DNA or the DNA encoding the desired protein can be produced synthetically using standard solid-phase methods, it is preferable to include restriction sites to facilitate ligation. Suitable control elements for transcription and translation included the coding sequence may be provided for the DNA coding sequences. As is well known, expression systems, are currently available that are compatible with a wide range of organisms hosts, including prokaryotic hosts, such as bacteria, t is K and eukaryotic hosts, such as yeast, plant cells, insect cells, mammalian cells, bird cages, etc.

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

Alternative for the quantitative determination of binding substances can be used in isolated cell membranes containing the expressed receptor.

For the quantitative determination of binding can be used in connection with a radioactive or fluorescent label. May also be the definition of competitive binding.

Other experience includes the screening of compounds representing agonist FSH receptor, determining the stimulation of receptor-mediated accumulation of camp. Thus, this method involves the expression of the receptor on the surface of the host cell and the exposure of the cells to the test compound. Then determine the number of camp. The levels of camp may decrease or increase depending on inhibitory or stimulating effect of test compounds on the binding with the receptor.

Screening of antagonists of FSH receptors includes keeping FSH receptor-expressing cells in the tested compound, taken in a certain interval conc the Nations, in the presence of FSH, taken at a fixed close to the maximum effective concentration (i.e. the concentration of FSH, which produces approximately 80% of the maximum stimulation of the accumulation of camp in the absence of test compound). The value of the IC50and the percentage of inhibition of FSH-induced accumulation of camp can be determined for each of the test compounds from the graphs according to the concentration-effect.

In addition to the direct quantitative determination of, for example, levels of camp in the affected cell, can be used cell lines, which in addition to transfection of receptor-coding DNA transliterowany second coding DNA reporter gene, expression of which responds to the levels of camp. Such reporter genes could be the induction of camp or could be created so that they were connected with the new elements sensitive to camp. Typically, the reporter gene expression can be controlled by any sensor that is responsive to changing levels of camp. Suitable reporter genes include, for example, genes encoding β-galactosidase, alkalinisation, Firefly luciferase and green fluorescent protein. The principles of such TRANS-activation experiments well known in the field and described the, for example, in the publication Stratowa, Ch., Himmler, A., Czernilofsky, A.P., (1995) Curr. Opin. Biotechnol. 6:574. The control connection can be used recombinant human FSH. An alternative can be competitive experiments.

This invention relates also to pharmaceutical compositions containing the derivative tetrahydroquinoline General formula I or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable auxiliary additives and, optionally, other therapeutic means. The term "acceptable" in relation to auxiliary additives means that the auxiliary additives must be compatible with other ingredients of the composition and do not adversely impact on the receiving composition recipients.

Compositions include, for example, compositions acceptable for oral, sublingual, subcutaneous, intravenous, intramuscular, local or rectal administration and the like, in a unit dosage forms.

For oral administration the active ingredient may be presented in the form of separate units such as tablets, capsules, powders, granules, solutions, suspensions, etc.

For parenteral administration of the pharmaceutical composition of the present invention may be provided in containers containing a single dose or multiple to the s, for example, in the form of liquids for injection in a pre-defined quantities in sealed vials or ampoules, and may also be stored in dried by sublimation (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water, before use.

The active ingredient, mixed with pharmaceutically acceptable auxiliary additives, for example, as described in the traditionally used reference, Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20thEdition., Lippincott Williams & Wilkins, 2000, see, in particular, Part 5: Pharmaceutical Manufacturing), can pressoffice in solid dosage units such as pills, tablets, or be processed into capsules or suppositories. When using pharmaceutically acceptable liquids the active ingredient can be used in the form of liquid compositions, for example, in the form of a preparation for injection, in the form of solution, suspension, emulsion, or in the form of a spray, for example, a nasal spray.

For solid dosage forms units assumes the use of conventional additives such as fillers, dyes, polymeric binders, etc. can Usually use any pharmaceutically acceptable additive, which does not affect the function of the active ingredients. Suitable carrier materials, which may be the active ingredient of the present invention in the de solid compositions, include lactose, starch, cellulose derivatives, etc. or mixtures thereof, used in the right quantities. For parenteral administration can be used aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmaceutically acceptable dispersants and/or wetting agents, such as propylene glycol or butyleneglycol.

The invention also includes a pharmaceutical composition, described above, in combination with packaging, suitable for the specified composition, and this package is supplied with instructions for use of the composition defined above.

Derivative tetrahydroquinoline of the present invention can also be administered in the form of implantable pharmaceuticals, consisting of a core of active ingredient, coated by a membrane that regulates the rate of release of the active ingredient. Such implants should be applied subcutaneously or topically and will release the active ingredient with approximately constant speed for a relatively long periods of time, comprising, for example, from several weeks to several years. Methods of obtaining implantable pharmaceutical products as such are known in this field and are described, for example, in European patent application 303306 (AKZO Nobel N.V.).

The exact dosage and therefore the and the introduction of the active ingredient or pharmaceutical composition will depend on therapeutic effect, want to achieve (the treatment of infertility; contraception) and can vary depending on the particular compound, the route of administration and the age and condition of the individual subject, which must be entered drug.

Usually for parenteral administration requires smaller dosage than the introduction of other ways that largely depend on absorption. However, the dosage for people preferably contains 0,0001-25 mg per kg of body weight. The desired dose may be administered in a single dose or divided into several smaller doses that are given appropriate intervals during the day, or in the case of a recipient-women in doses that are subject to the introduction of appropriate daily intervals during the menstrual cycle. The dosage and the introduction of men and women can be different.

Thus, the compounds of this invention can be used in therapeutic treatment.

An additional aspect of this invention relates to the use of derivative tetrahydroquinoline General formula I for the manufacture of a medicinal product intended for use in the treatment of disorders sensitive to metabolic pathways, mediated FSH-receptor. Thus, patients who need this can be the appropriate number of compounds according to the but this invention.

In another aspect the invention relates to the use of derivative tetrahydroquinoline General formula I for the manufacture of a medicinal product intended for application to control fertility.

In another aspect the invention relates to the use of derivative tetrahydroquinoline General formula I for the manufacture of a medicinal product intended for use in infertility treatment.

In another aspect this invention relates to the use of derivative tetrahydroquinoline General formula I for the manufacture of a medicinal product intended for use for the prevention of fertility.

The compounds of this invention can also be used for treatment of hormone-dependent disorders such as breast cancer, prostate cancer and endometriosis.

Further, the invention is illustrated by the following examples.

Examples

General notes:

In the examples the following abbreviations are used: DMA = N,N-dimethylaniline, DIPEA = N,N-diisopropylethylamine, TFUK = triperoxonane acid, DtBAD = di-tert-utilisationbased, HATU = hexaphosphate O-(7-asobancaria-1-yl)-N,N,N, N'-tetramethylurea, Fmoc = 9-fluorenylmethoxycarbonyl, Fmoc-Cl = 9-fluorenylmethoxycarbonyl, DMF = N,N-dimethylformamide, DMAP = 4-dimethylaminopyridine, THF = tetrahydrofuran.

If there are no any other condition, all target products of the examples below, liofilizovane from mixtures of water/1,4-dioxane or water/acetonitrile. If the connection is obtained in the form of HCl or TFU-salt corresponding to the acid were added in suitable amounts to the solvent mixture before lyophilization.

Name of target products described in example compiled using Beilstein Autonom program (version: 2.02.119).

To determine the retention time was used the following analytical HPLC methods:

Method 1. Column: 5 μm Luna C-18(2) 150×4.6 mm; flow rate: 1 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: CH3CN/H2About = 1/9 (about./vol.); solvent B: CH3CN; solvent: 0.1m aqueous triperoxonane acid; elution gradient: a/b/C from 65/30/5 to 10/85/5 (about./about./about.) for 30 min, then for an additional 10,00 min elution constant eluent a/b/C = 10/85/5 (about./about./vol.).

Method 2 is identical to method 1 except that elution gradient: eluent a/b/C from 75/20/5 to 15/80/5 (about./about./about.) within 30 minutes, then for an additional 10,00 min elution constant eluent a/b/C 15/80/5 (about./about./vol.).

Method 3 is identical to method 1 except that elution gradient: a/b/C from 35/60/5 to 10/85/5 (about./about./about.) during 30,00 min, then for an additional 10,00 mi the ut elution constant eluent a/b/C = 10/85/5 (about./about./vol.).

Method 4. Column: Luna 3 μm C-18(2) 100×2 mm; flow rate: 0.25 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: H2About; solvent B: CH3CN; elution gradient: a/b from 75/25 to 0/100 (about./about.) within 20 minutes, then for an additional 10,00 min elution constant eluent a/b = 0/100 (about./vol.).

Method 5. Column: Luna 3 μm C-18(2) 100×2 mm; flow rate: 0.25 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: H2About; solvent B: CH3CN; solvent: 50 mm phosphate buffer, pH 2,1; elution gradient: a/b/C from 75/20/10 to 10/80/100 (about./about.) within 20 minutes, then for an additional 10,00 min elution constant eluent a/b/C = 10/80/10 (about./about./vol.).

Method 6 is identical to method 5 except elution gradient: a/b/C from 65/30/5 to 10/85/5 (about./about./about.) over 20,00 min, then within 10,00 min elution constant eluent a/b/C = 10/85/5 (about./about./vol.).

For cleaning products preparative HPLC using the following methods:

Method A. Column: Luna C-18; elution with a gradient of 0.1% triperoxonane acid in N2O/CH3CN (9/1 vol/vol.)/CH3CN from 80/20 to 0/100 (about./about.) within 30-45 minutes, depending on the ease of separation; detection: 210 nm.

Method C. Column: Luna C-18; elution gradient: H2O/CH3CN (9/1 vol/vol.)/CH3CN from 80/20 to 0/100.about.) within 30-45 minutes, depending on the ease of separation; detection: 210 nm.

Example 1

N-[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]-3-chloro-2,6-dimethoxybenzamide

(a) 5,7-Dimethoxy-2,2,4-trimethyl-1,2-dihydroquinoline

A solution of 3,5-dimethoxyaniline (50 g) in acetone (800 ml) was added dropwise to the mixture MgSO4(100 g) and Sc(OTf)3(8.0 g) in 1 l of acetone at room temperature. After 5 hours, add another portion of Sc(OTf)3(3.2 g) and the reaction mixture is stirred until then, until no educt. The solution is filtered, the acetone is partially evaporated in vacuum, causing crystallization specified in the title compound, which is filtered off, getting after drying in a vacuum of 22 g of the product. The remaining mother liquor was concentrated in vacuo and the residue purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.), getting more of 19.4 g specified in the connection header.

Output: 42,

(b)1-Acetyl-5,7-dimethoxy-2,2,4-trimethyl-1,2-dihydroquinoline

A mixture of the compound described in example 1A (42 g), and acetic anhydride (100 ml) was stirred at 100°C for 20 hours. The reaction mixture is poured into 500 ml of ice water with stirring. The resulting solid precipitate is filtered off and dried in vacuum at 40°C for 2 days. The obtained solid brown color is sportsouth in the next stage without additional purification.

Exit 45,

(C)1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin

A mixture of the compound described in example 1b (30 g), and AlCl3(44 g) in anisole (500 ml) was stirred at 50°C for 18 hours. The reaction mixture was cooled (0°C), quenched with water and add ethyl acetate. The mixture is stirred over night. The organic layer is separated, dried over MgSO4, filtered and concentrated in vacuo. The remainder chromatographic on silica gel (elution: heptane/ethyl acetate = 8/2 (about./vol.)).

Output: 15,

(d)1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-6-nitro-1,2,3,4-tetrahydroquinolin

A solution of acetic anhydride (450 μl) in fuming nitric acid (22.5 ml) is added dropwise to a solution of the compound described in example 1C (15 g) in CH2Cl2(500 ml) at 0°C. After complete addition, the reaction mixture was stirred at room temperature for 3 hours. Add water, the organic layer is separated, dried over MgSO4, filtered and concentrated in vacuo. The residue is crystallized from ethanol, getting mentioned in the title compound in the form of a solid crystalline substance.

Output: 10,

(e)1-Acetyl-6-amino-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin

A solution of the compound described in example 1d (11,75 g), and acetic acid (15,5 ml) in THF (600 ml) cooled to 0° C. Powdered zinc (36 g) added in portions and the ice bath removed. The temperature quickly rises to 30°C, after which the reaction mixture is allowed to cool to room temperature. The excess zinc is removed by filtration and to the filtrate add CH2Cl2and a saturated aqueous solution of Na2CO3. The organic layer is separated, dried over MgSO4, filtered and concentrated in vacuo. The product is used in the next stage without additional purification.

Output: 10,9,

(f)N-[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]-3-chloro-2,6-dimethoxybenzamide

General procedure a:To a solution of the compound described in example 1E (100 mg), 3-chloro-2,6-dimethoxybenzoic acid (60 mg) and DIPEA (132 μl) in CH2Cl2(2 ml) is added HATU (143 mg) at room temperature. If the reaction is not complete after 18 hours, add an additional amount of HATU and DIPEA. After completion of the reaction, add saturated aqueous solution of NaHCO3, the organic layer separated, dried (MgSO4) and concentrated in vacuo. Specified in the title compound purified preparative HPLC (method A).

Yield: 87 mg; MS-ESI: [M+H]+= 597,4.

HPLC: Rt=17,98 min (method 1).

Example 2

[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide 4,5-dimethylfuran the h-2-carboxylic acid

General procedure b:To a solution of the compound described in example 1E (800 mg), 4,5-dimethylfuran-2-carboxylic acid (308 mg) and DMA (768 μl) in DMF (10 ml) at room temperature is added HATU (1.1 g). If the reaction is not complete after 18 hours, the reaction mixture is heated to 50°C. After completion of the reaction, water is added and the ethyl acetate, the organic layer separated, dried (MgSO4) and concentrated in vacuo. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Output: 444 mg; MS-ESI: [M+H]+= 521,4.

HPLC: Rt=16,96 min (method 1).

Example 3

[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide 5-bromothiophene-2-carboxylic acid

In accordance with the General method In the connection described in example 1 (800 mg), acelerou 5-bromothiophene-2-carboxylic acid (456 mg), DMA (768 μl) and HATU (1.1 g) in CH2Cl2(10 ml). Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Yield: 1.0 g; MS-ESI: [M+H]+= 589,2; HPLC: Rt=18,90 min (method 2).

Example 4

[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

General method:It races the thief connections described in example 1 (800 mg)and 4-biphenylcarboxylic (475 mg) in CH2Cl2(10 ml) at room temperature add DMA (768 μl). The reaction mixture is stirred until then, until there is the original substance, then add water. The organic layer is separated, dried (MgSO4) and concentrated in vacuo. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Output: 678 mg; MS-ESI: [M+H]+= 579,4; HPLC: Rt=26,19 min (method 2).

Example 5

[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide, furan-2-carboxylic acid

(a)[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide, furan-2-carboxylic acid

In accordance with the General method With the compound described in example 1E (800 mg), acelerou 2-forargliga (217 ml) and DMA (768 μl) in CH2Cl2(10 ml). Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Output: 896 mg

(b)[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide, furan-2-carboxylic acid

General methods D:A solution of the compound described in example 5A (50 mg)in CH2Cl2/sub> (4 ml) cooled to -78°C in an atmosphere of N2. Added dropwise tribromide boron (28 μl) and after complete addition, the reaction mixture is allowed to slowly warm to room temperature. The reaction is quenched with water and add CH2Cl2. The organic layer is separated, dried (MgSO4) and concentrated in vacuo. Specified in the title compound purified preparative HPLC (method A). In the above-described conditions are usually formed of a mixture of compounds with different degree of demethylation, which can be divided preparative HPLC.

Output: 9.1 mg; MS-ESI: [M+H]+= 479,4; HPLC: Rt=23,40 min (method 2).

Example 6

N-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dichlorobenzamide

(a)N-[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dichlorobenzamide

In accordance with the General method With the compound described in example 1E (800 mg), acelerou 3,5-dichlorobenzotrifluoride (460 mg) and DMA (768 μl) in CH2Cl2(10 ml). Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Output: 1,03 g

(b) N-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dichlorobenzamide

In accordance with the General method D from the Association, described in example 6A (50 mg), treated with tribromide boron (24 μl) in CH2Cl2(4 ml). Specified in the title compound purified preparative HPLC (method A).

Output: 9.6 mg; MS-ESI: [M+H]+= 557,2; HPLC: Rt=23,40 min (method 2).

Example 7

[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide 5-chlorothiophene-2-carboxylic acid

(a)[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide 5-chlorothiophene-2-carboxylic acid

In accordance with the General method In the connection described in example 1 (800 mg), acelerou 5-chlorothiophene-2-carboxylic acid (456 mg), DMA (768 μl) and HATU (1.1 g) in CH2Cl2. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Output: 1,0,

(b)[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide 5-chlorothiophene-2-carboxylic acid

In accordance with the General method D, compound described in example 7a (200 mg), treated with tribromide boron (350 μl) in CH2Cl2(25 ml), maintaining the temperature at not higher than -30°C. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.), then drugs the active HPLC (method A).

Yield: 35 mg; MS-ESI: [M+H]+= 529,2; HPLC: Rt=28,24 min (method 2).

Example 8

[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

In accordance with the General method D, compound described in example 4 (50 mg), treated with tribromide boron (100 μl) in CH2Cl2(4 ml), maintaining the temperature at not higher than 0°C. the Reaction mixture also contains the product described in example 10. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./about.))

Yield: 43 mg; MS-ESI: [M+H]+= 565,4; HPLC: Rt=32,53 min (method 2).

Example 9

[1-Acetyl-5,7-dihydroxy-4-(4-hydroxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

In accordance with the General method D, compound described in example 4 (50 mg), treated with tribromide boron (100 μl) in CH2Cl2(4 ml), maintaining the temperature at not higher than 15°C. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Yield: 33 mg; MS-ESI: [M+H]+= 537,4; HPLC: Rt=24,16 min (method 2).

Example 10

[1-Acetyl-5-hydroxy-4-(4-hydroxyphenyl)-7-methoxy-2,2,4-trimethyl-1,2,3,4-tetrahydrothieno the in-6-yl]amide biphenyl-4-carboxylic acid

In accordance with the General method D, compound described in example 4 (400 mg), treated with tribromide boron (800 μl) in CH2Cl2(25 ml), maintaining the temperature at not higher than 0°C. Specified in the header of the connection (a = biproduct as described in example 8) purify by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Yield: 50 mg; MS-ESI: [M+H]+= 551,4; HPLC: Rt=27,58 min (method 2).

Example 11

[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl]amide 4,5-dimethylfuran-2-carboxylic acid

In accordance with the General method D, the compound described in example 2 (200 mg), treated with tribromide boron (336 μl) in CH2Cl2(25 ml), keeping the temperature at a level no higher than -78°C. Specified in the title compound purified preparative HPLC (method A).

Yield: 51 mg; MS-ESI: [M+H]+= 507,4; HPLC: Rt=24,32 min (method 1).

Example 12

N-[1-Acetyl-5-hydroxy-4-(4-hydroxyphenyl)-7-methoxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dichlorobenzamide

In accordance with the General method D, compound described in example 6A (75 mg), treated with tribromide boron (38 μl) in CH2Cl2(5 ml). Specified in the title compound purified preparative HPLC (method A).

Yield: 11 mg; MS-ESI: [M+H]+= 543,4; HPLC: Rsub> t=25,66 min (method 2).

Example 13

N-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dimethylbenzamide

(a)N-[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dimethylbenzamide

In accordance with the General method In the connection described in example 1 (800 mg), acelerou 3,5-dimethylbenzoic acid (330 mg), DMA (768 μl) and HATU (1.1 g) in CH2Cl2(10 ml). Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

The output of 1.18,

(b)N-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dimethylbenzamide

In accordance with the General method D, compound described in example 13A (300 mg), treated with tribromide boron (513 μl) in CH2Cl2(25 ml), keeping the temperature not lower than -40°C. Specified in the title compound purified preparative HPLC (method A).

Yield: 41 mg; MS-ESI: [M+H]+= 517,4; HPLC: Rt=13,89 min (method 3).

Example 14

N-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dibromobenzene

(a)N-[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dibromobenzene

In accordance with the General met the wild In connection described in example 1 (800 mg), acelerou 3,5-dibromobenzoic acid (616 mg), DMA (768 μl) and HATU (1.1 g) in DMF (10 ml). Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Yield: 900 mg

(b)N-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dibromobenzene

In accordance with the General method D, compound described in example 14a (300 mg), treated with tribromide boron (639 mm) in CH2Cl2(25 ml), maintaining the temperature at not higher than -60°C. Specified in the title compound purified preparative HPLC (method B).

Yield: 28 mg; MS-ESI: [M+H]+= 647,2; HPLC: Rt=16,29 min (method 3).

Example 15

[1-Acetyl-2,2,4-trimethyl-7-(2-morpholine-4-ylethoxy)-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

(a)1-Fmoc-2-methoxy-4-nitroaniline

A solution of 2-methoxy-4-nitroaniline (3.0 g) and pyridine (1.6 ml) in THF (30 ml) cooled to 0°C. Small portions add Fmoc (5,07 g), after complete addition, the ice bath removed and the mixture is stirred for 5 hours. THF is removed in vacuo, and the residue is dissolved in CH2Cl2(175 ml). Add methanol (˜100 ml) and CH2Cl2partially removed in vacuum until no residue. The mixture is left for 1 the speakers then the crystals are filtered and dried in vacuum, obtaining specified in the header of the connection.

Output: 6,32 g; MS-ESI: [M+H]+= 391,2.

(b)9-fluorenylmethyl-N-(2-methoxy-4-AMINOPHENYL)carbamate

General method E:A mixture of the compound described in example 15A (6,07 g), acetic acid (8,9 ml) and THF (150 ml) cooled to 0°C. in Several portions add powdered zinc (20.4 g) and the ice bath removed. After the temperature slowly reaches 10°With, she quickly rises to 45°C. the Reaction mixture is allowed to slowly cool to room temperature, the excess zinc is removed by filtration and add CH2Cl2(˜500 ml). The mixture was washed with saturated aqueous NaHCO3(3×200 ml) and saturated salt solution (1×200 ml). The organic layer is separated, dried (MgSO4), filtered and concentrated in vacuo to sediment. The mixture is left overnight at a temperature of 0°C, after which the crystals are filtered and dried in vacuum, obtaining specified in the header of the connection.

Output: 4,45,

(C)N-fluoren-9-ymetray ether (7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl)carbamino acid

A mixture of the compound described in example 15b (4,45 g), I2(157 mg), MgSO4(7,4 g), 4-tert-butylcatechol (61 mg) and acetone (˜350 ml) is refluxed for 5 hours is. MgSO4removed by filtration and the filtrate concentrated in vacuo. Specified in the title compound is obtained by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 9/1 to 7/3 (about./vol.)).

Output: 4,24,

(d)N-fluoren-9-ymetray ether (1-acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl)carbamino acid

To a solution of the compound described in example 15C (4,24 g)in pyridine (25 ml) and CH2Cl2(25 ml) is added a small amount of DMAP (˜20 mg). Then slowly add acetylchloride (2.0 ml) in CH2Cl2(20 ml). After complete addition, the mixture was diluted with CH2Cl2(˜100 ml) and washed with water (3×100 ml), 0.1m HCl (3×100 ml), 0.5m aq. HCl (1×100 ml) and saturated salt solution (1×100 ml). The organic layer is dried (MgSO4) and concentrated in vacuo. Specified in the title compound is obtained by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 9/1 to 7/3 (about./vol.)).

Output: 3,91,

(e)1-Acetyl-6-amino-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline

Piperidine (8.0 ml) are added to a solution of the compound described in example 15d (3,91 g), CH2Cl2(80 ml). After 1.5 hours the reaction mixture was concentrated in vacuo and indicated in the title compound is obtained by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 9/1 is about 7/3 (about./vol.)).

Output: 2,2,

(f) (1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl)amide-biphenyl-4-carboxylic acid

General method F: To a mixture of the compound described in example 15th (2.2 g), toluene (45 ml) and pyridine (5 ml) is added 4-biphenylcarboxylic (of 2.21 g). If the reaction is not complete after 3 hours at room temperature, introducing an additional amount of 4-biphenylcarboxylic (2.0 g). Stirring is continued for 30 minutes, after which the reaction mixture was concentrated in vacuo. The residue is transferred into ethyl acetate (˜100 ml) and washed with saturated aqueous NaHCO3(100 ml), 1M aq. HCl (3×100 ml) and saturated salt solution (100 ml). The organic layer is dried (MgSO4) and concentrated in vacuo. To the residue add CH2Cl2(˜50 ml), the solids removed by filtration and no longer use. The filtrate was concentrated in vacuo and indicated in the title compound is obtained by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 1/1 (vol./vol.)).

Output: 3,1,

(g)(1-Acetyl-7-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

General methods G:To a solution of the compound described in example 15f (3.1 g)in benzene (100 ml) add trichloride aluminum (5.6 g)and the reaction mixture stirred at room temperature for 20 hours. The reaction is quenched with H2On (˜100 ml) and the pH value of the mixture was adjusted to 8 by adding 2M aq. NaOH with vigorous stirring. Add ethyl acetate (˜300 ml) and the organic layer was washed with H2About (2×150 ml) and saturated salt solution (1×150 ml), dried (MgSO4) and concentrated in vacuo, receiving product, which is used in the next stage without additional purification.

Output: 3.5mm,

(h) [1-Acetyl-2,2,4-trimethyl-7-(2-morpholine-4-ylethoxy)-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

General procedure N:A mixture of the compound described in example 15g (70 mg), hydrochloride N-(2-chloroethyl)of the research (31 mg), Cs2CO3and DMF (3 ml) was stirred at 50°until then, until no educt. The reaction mixture was diluted with ethyl acetate (15 ml) and add water (˜15 ml). The organic layer was washed with water (3×15 ml), separated, dried (MgSO4), filtered and concentrated in vacuo. Specified in the title compound obtained as HCl salt by lyophilization from a mixture of 1,4-dioxane and N2Oh, containing HCl.

Yield: 63 mg (HCl salt); MS-ESI: [M+H]+= 618,6; HPLC: Rt=19,49 min (method 4).

Example 16

(1-Acetyl-7-dimethylcarbamoyl-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

In accordance with the General method N. connection, about icanoe in example 15g (79 mg), alkylate 2-chloro-N,N-dimethylacetamide (23 mg) and CsCO3(255 mg) in DMF (2 ml). Specified in the title compound purified by crystallization from CH3CN.

Yield: 15 mg; MS-ESI: [M+H]+= 590,6; HPLC: Rt=23,58 min (method 5).

Example 17

[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(3-piperidine-1-ylpropionic)-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

In accordance with the General method N. the compound described in example 15g (79 mg), alkylate hydrochloride N-(3-chloropropyl)piperidine (or 37.4 mg) and Cs2CO3(255 mg) in DMF (2 ml). Specified in the title compound purified by crystallization from CH3CN.

Yield: 83 mg (HCl salt); MS-ESI: [M+H]+= 630,8; HPLC: Rt=15,49 min (method 5).

Example 18

[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

In accordance with the General method H, the compound described in example 15g (79 mg), alkylate hydrochloride 2-picolylamine (31 mg) and Cs2CO3(255 mg) in DMF (2 ml). Specified in the title compound purified by crystallization from CH3CN.

Yield: 32 mg (HCl salt); MS-ESI: [M+H]+= 596,6; HPLC: Rt=22,41 min (method 6).

Example 19

[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridine-3-ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

In accordance with the General method H is Obedinenie, described in example 15g (79 mg), alkylate hydrochloride 3-picolylamine (31 mg) and Cs2CO3(255 mg) in DMF (2 ml). Specified in the title compound purified by crystallization from CH3CN.

Yield: 36 mg (HCl salt); MS-ESI: [M+H]+= 596,6; HPLC: Rt=19,70 min (method 6).

Example 20

[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridine-4-ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

In accordance with the General method H, the compound described in example 15g (79 mg), alkylate hydrochloride 4-picolylamine (31 mg) and Cs2CO3(255 mg) in DMF (2 ml). Specified in the title compound purified by crystallization from CH3CN.

Yield: 31 mg (HCl salt); MS-ESI: [M+H]+= 596,4; HPLC: Rt=17,09 min (method 6).

Example 21

[1-Acetyl-7-(2-methylethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

In accordance with the General method H, the compound described in example 15g (79 mg), alkylate hydrochloride 2-diethylaminoethylamine (27 mg) and Cs2CO3(255 mg) in DMF (2 ml). Specified in the title compound purified by crystallization from CH3CN.

Yield: 55 mg (HCl salt); MS-ESI: [M+H]+= 576,6; HPLC: Rt=14,94 min (method 5).

Example 22

(1-Acetyl-7-carbamoylphenoxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]amide biphenyl-4-carboxylic acid

In accordance with the General method H connection described in example 15g (79 mg), alkylate 2-chloracetamide (18 mg) and Cs2CO3(255 mg) in DMF (2 ml). Specified in the title compound purified preparative HPLC (method A).

Output: a 60.2 mg; MS-ESI: [M+H]+= 562,4; HPLC: Rt=20,47 min (method 5).

Example 23

(3-{1-Acetyl-6-[(biphenyl-4-carbonyl)amino]-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-7-yloxy}propyl)amide morpholine-4-carboxylic acid

In accordance with the General method H, the compound described in example 15g (79 mg), alkylate morpholine-4-carboxylic acid (40 mg) and Cs2CO3(255 mg) in DMF (2 ml). Specified in the title compound purified preparative HPLC (method A).

Output: 52,4 mg; MS-ESI: [M+H]+= 675,6; HPLC: Rt=22,31 min (method 5).

Example 24

1-Acetyl-6-(3,5-dibromobenzoate)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-7-silt ether furan-2-carboxylic acid

(a)N-(1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl) - for 3,5-dibromobenzene

In accordance with the General method F, the compound described in example 15e (1.0 mg), acelerou 3,5-dibromobenzoate (1,72 g) in toluene (9 ml) and pyridine (1 ml). Specified in the title compound purified by chromatography on silica gel (elution: heptane/ethyl acetate = 8/2 (about./vol.)).

Output: 1,3 mg

(b)N-(1-Acetyl-7-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl) - for 3,5-dibromobenzene

In the accordance with the General method G connection, described in example 24A (1.3 g), stirred with AlCl3(1.0 g) in benzene (50 ml). The resulting product is used in the next stage without additional purification.

Output: 1,39,

(C)1-Acetyl-6-(3,5-dibromobenzoate)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-7-silt ether furan-2-carboxylic acid

A mixture of the compound described in example 24b (100 mg), frailcare (16 μl) and DIPEA (60 μl) in CH2Cl2(5 ml) was stirred at room temperature until, until no starting materials. Add water, the organic layer was separated, washed with a saturated solution of salt, dried (MgSO4) and concentrated in vacuo. Specified in the title compound purified preparative HPLC (method A).

Yield: 47 mg; MS-ESI: [M+H]+= 681,2; HPLC: Rt=31,6 min (method 2).

Example 25

N-[1-Acetyl-7-(2-aminoethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dibromobenzene

General methods I:A mixture of the compound described in example 24b (100 mg), tert-butyl-N-(2-hydroxyethyl)carbamate (29 mg), DtBAD (79 mg), DIPEA (60 μl) and an excess of polymer-bound triphenylphosphine in CH2Cl2(5 ml) was stirred at room temperature until, until no educt. The reaction mixture was filtered and washed with water and saturated salt solution. The organic layer is separated, dried (MgSO4) and conc is t in vacuum. The crude product is transferred in CH3CN (˜1 ml) and add a few drops of TFWC to facilitate removal of tert-BUTYLCARBAMATE. Specified in the title compound purified preparative HPLC (method A).

Yield: 17 mg (TFU salt); MS-ESI: [M+H]+= 630,2; HPLC: Rt=15,6 min (method 2).

Example 26

Tert-Butyl ether {2-[1-acetyl-6-(3,5-dimethylbenzylamine)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-7-yloxy]ethyl}carbamino acid

(a)N-(1-acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl) - for 3,5-dimethylbenzamide

In accordance with the General method F, the compound described in example 15th (1.0 g), acelerou 3,5-dimethylbenzonitrile (0.97 g) in toluene (9 ml) and pyridine (1 ml). Specified in the title compound purified by chromatography on silica gel (elution: heptane/ethyl acetate = 8/2 (about./vol.)).

Output: 1,1,

(b) N-(1-Acetyl-7-hydroxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetragidrokhinolina-6-yl) - for 3,5-dimethylbenzamide

In accordance with the General method G of the compound described in example 26a (1.1 g), stirred with AlCl3(1.0 g) in benzene (50 ml). The resulting product is used in the next stage without additional purification.

Output: 1,3,

(C)Tert-Butyl ether {2-[1-acetyl-6-(3,5-dimethylbenzylamine)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-7-yloxy]ethyl}carbamino acid

In accordance with the General methods of the th I connection, described in example 26b (100 mg), alkylate tert-butyl-N-(2-hidroxietil)carbamate (37 ml), DtBAD (101 mg), DIPEA (77 μl) and the excess of polymer-bound triphenylphosphine in CH2Cl2(5 ml). In this case, the group of tert-BUTYLCARBAMATE not subject to splitting, which leads after purification preparative HPLC (method A) and lifesyle to receive specified in the header of the product.

Yield: 38 mg; MS-ESI: [M+H]+= 600,4; HPLC: Rt=33,1 min (method 2).

Example 27

N-[1-Acetyl-7-(furan-2-ylethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dimethylbenzamide

In accordance with the General method I, compound described in example 26b (100 mg), alkylate 2-(hydroxymethyl)furan (21 μl), DtBAD (101 mg), DIPEA (77 μl) and the excess of polymer-bound triphenylphosphine in CH2Cl2(5 ml). Specified in the title compound purified preparative HPLC (method a) and then lyophilization.

Yield: 16 mg; MS-ESI: [M+H]+= 537,4; HPLC: Rt=33,8 min (method 2).

Example 28

N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridine-4-ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dichlorobenzamide

(a)N-(1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl) - for 3,5-dichlorobenzamide

In accordance with the General method F, the compound described in example 15e (1.0 g), acelerou 3,5-dichlorobenzotrifluoride (1.2 g) in toluene (9 ml) and pyridine (1 ml). Specified in the header is Obedinenie purify by chromatography on silica gel (elution: heptane/ethyl acetate 8/2 (about./vol.)).

Output: 1,47,

(b)N-(1-Acetyl-7-hydroxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) - for 3,5-dichlorobenzamide

In accordance with the General method G of the compound described in example 28a (1.47 g), stirred with AlCl3(1.5 g) in benzene (75 ml). The resulting product is used in the next stage without additional purification.

Output: 1,51,

(C)N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridine-4-ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dichlorobenzamide

In accordance with the General method H, the compound described in example 28b (100 mg), alkylate hydrochloride 4-picolylamine (36 mg) and Cs2CO3(255 mg) in a mixture of DMF (1 ml) and CH2Cl2(4 ml). Specified in the title compound obtained as appropriate TFU salt after preparative HPLC (method a) and subsequent lyophilization.

Yield: 35 mg (TFU salt); MS-ESI: [M+H]+= 588,4; HPLC: Rt=18,0 min (method 2).

Example 29

N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(2-pyrrolidin-1 ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dimethylbenzamide

General methods J:A mixture of the compound described in example 26b (100 mg), hydrochloride 2-chlorethylene (41 mg) and DIPEA (77 μl) in CH2Cl2(5 ml) was stirred at room temperature until, until no educt. Add water, the organic layer is separated, washed with saturated salt solution, dried (gSO 4) and concentrated in vacuo. Purification preparative HPLC followed by lyophilization results specified in the connection header in the form of a corresponding TFU salt.

Yield: 104 mg (TFU salt); MS-ESI: [M+H]+= 554,4; HPLC: Rt=15,2 min (method 2).

Example 30

N-[1-Acetyl-2,2,4-trimethyl-7-(5-methylisoxazol-3-ylethoxy)-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dimethylbenzamide

In accordance with the General method J, the compound described in example 26b (100 mg), alkylate (chloromethyl)-5-methylisoxazole (32 mg) and DIPEA (77 μl) in CH2Cl2(5 ml). Purification preparative HPLC (method A) followed by lyophilization results specified in the connection header.

Yield: 41 mg; MS-ESI: [M+H]+= 552,4; HPLC: Rt=31,3 min (method 2).

Example 31

N-[1-Acetyl-7-(2-diethylaminoethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl] - for 3,5-dimethylbenzamide, TFU salt

In accordance with the General method J, the compound described in example 26b (100 mg), alkylate hydrochloride N,N-diethylaminoethylamine (42 mg) and DIPEA (77 μl) in CH2Cl2(5 ml). Purification preparative HPLC (method A) followed by lyophilization results specified in the connection header in the form of a corresponding TFU salt.

Yield: 43 mg (TFU salt); MS-ESI: [M+H]+= 556,4; HPLC: Rt=15,2 min (method 2).

Example 32

N-[1-is cetyl-2,2,4-trimethyl-4-phenyl-7-(pyridine-4-ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl]-5-bromo-2-methylaminomethyl

(a)N-(1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl)-5-bromo-2-methylaminomethyl

In accordance with the General method F, the compound described in example 15e (1.0 g), acelerou 5-bromo-2-methylaminoethanol (1,43 g) in toluene (9 ml) and pyridine (1 ml). Specified in the title compound is obtained by chromatography on silica gel (elution: heptane/ethyl acetate 8/2 (about./vol.)).

Output: 595 mg

(b)N-(1-Acetyl-7-hydroxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-bromo-2-methylaminomethyl

In accordance with the General method G of the compound described in example 32a (595 mg), stirred with AlCl3(0.75 g) in benzene (50 ml). The resulting product is used in the next stage without additional purification.

Output: 437 mg

(C)N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridine-4-ylethoxy)-1,2,3,4-tetrahydroquinolin-6-yl]-5-bromo-2-methylaminomethyl

In accordance with the General method H, the compound described in example 32b (44 mg), alkylate hydrochloride 4-picolylamine (15 mg) and Cs2CO3(˜100 mg) in a mixture of DMF (1 ml) and CH2Cl2(4 ml). Specified in the title compound obtained as appropriate TFU salt after preparative HPLC (method B).

Yield: 18 mg (TFU salt); MS-ESI: [M+H]+= 629,4; HPLC: Rt=18,1 min (method 2).

Example 33

(1-Acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin the-6-yl)amide, furan-2-carboxylic acid

(a)Tert-Butyl ether (2,2,4-trimethyl-1,2-dihydroquinoline-6-yl)carbamino acid

A mixture of N-BOC-1,4-phenylenediamine (75 g), MgSO4(216 g), 4-tert-butylcatechol (1.8 g) and iodine (4.7 g) in anhydrous acetone (600 ml) is refluxed for 20 hours. MgSO4removed by filtration and the filtrate concentrated in vacuo. The remainder chromatographic on silica gel (elution: heptane/ethyl acetate = 8/2 (about./vol.), receiving the product as a brown oil.

Exit 41,

(b)Tert-butyl methyl ether (1-acetyl-2,2,4-trimethyl-1,2-dihydroquinoline-6-yl)carbamino acid

A solution of the compound described in example 33a (41 g)in pyridine (200 ml) and CH2Cl2(200 ml) cooled to 0°C. added dropwise acetylchloride (21 ml) in CH2Cl2(50 ml). After complete addition, the mixture is stirred for 3 hours at room temperature. Add ethyl acetate (2 l) and H2O (2 l) and the organic layer is separated, dried (MgSO4) and concentrated in vacuo. Specified in the title compound is obtained by crystallization from ethyl acetate.

Output: 23,

(C)1-Acetyl-6-amino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin

In accordance with the General method G of the compound described in example 33b (33,3 g), stirred with AlCl3(40,4 g) in benzene (700 ml). The resulting product was then purified by chromatography on silica gel (blueraven the e: heptane/ethyl acetate = 8/2 (about./vol.)).

Output: 22,4,

(d)9-Fluorenylmethyl ether (1-acetyl-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

To a solution of the compound described in example 33C (22,4 g)in THF (300 ml) is added pyridine (6.4 ml) and the resulting mixture is cooled to 0°C. added dropwise a solution of FmocCl (20.7 g) in THF (100 ml), and after complete addition the mixture is stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and add ethyl acetate (800 ml) and 0,3M aq. HCl (500 ml). The organic layer is separated, washed with 0.3 m HCl (C ml), N2O (500 ml) and saturated salt solution (500 ml), dried (MgSO4) and concentrated in vacuo. The product is used in the next stage without additional purification.

Output: 43,

(e)9-Fluorenylmethyl ether (1-acetyl-2,2,4-trimethyl-7-nitro-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

Fuming nitric acid (3,07 ml) dropwise over 10 minutes, add to the mixture of the compound described in example 33d (43 g), and acetic acid (230 ml) in CH2Cl2(230 ml). The reaction mixture was stirred until complete conversion of the original substance, then add H2O (150 ml). The aqueous layer was separated and extracted with CH2Cl2(150 ml). The combined organic layers washed with saturated aqueous NaHCO3(3×200 ml) and saturated of rest the rum salt (200 ml), then dried over MgSO4and filtered. Add methanol (˜200 ml) and CH2Cl2carefully removed in vacuum, after which the mixture is left overnight at room temperature. Bright yellow crystals are filtered and dried (MgSO4in a vacuum.

Output: 29,3,

(f)9-Fluorenylmethyl ether (1-acetyl-7-amino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

In accordance with the General method E, compound described in example a (20 g), restore using powdered zinc (45 g) and acetic acid (20 ml) in THF (˜600 ml)to give the product, which is used in the next stage without additional purification.

Output: 21,

(g)9-Fluorenylmethyl ether (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

An aqueous solution of formaldehyde (37%, and 3.8 ml) was added to a solution of the compound described in example 33f (12 g), acetic acid (15.7 ml) and cyanoborohydride sodium (2.9 g) in methanol (200 ml), resulting in an exothermic reaction and the formation of a white precipitate. To facilitate stirring, add the additional amount Meon. The mixture is stirred for 15 minutes, the precipitate is filtered and washed with a mixture of Meon/N2About = 1/1 (vol./vol.). The filtrate is partially concentrated to obtain more solid ve is esta, which is also collected. The combined solids recrystallized from CH2Cl2/Meon, getting DIMETHYLPROPANE connection.

Output: 9,7,

(h)1-Acetyl-6-amino-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin

Piperidine (7.7 ml) are added to a solution of the compound described in example 33g (4.5 g)in CH2Cl2(70 ml). After 24 hours the reaction mixture was diluted with CH2Cl2(100 ml) and washed with 0.5 m aq. HCl (2×150 ml), water (100 ml) and saturated salt solution (1 ml). The organic layer is dried (MgSO4) and diluted to a total volume of 200 ml. of the resulting solution was specified in the connection header (˜to 13.8 mg/ml) used in the subsequent synthesis.

(i)(1-Acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide, furan-2-carboxylic acid

The triethylamine (38 μl) and 2-frailcare (27 μl) are added to a solution of the compound described in example 33h (96,6 mg)in CH2Cl2(10 ml) and the resulting mixture is stirred until complete conversion of the original substance. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Output: 5,5 mg; MS-ESI: [M+H]+= 446,2; HPLC: Rt=19,02 min (method 2).

Example 34

(1-Acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide 5-metelli the Hairdryer-2-carboxylic acid

In accordance with the General procedure a, the compound described in example 33h (96,6 mg), acelerou 5-methylthiophene-2-carboxylic acid (39,1 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC (method B).

Output: 35,5 mg; MS-ESI: [M+H]+= 476,2; HPLC: Rt=21,26 min (method 2).

Example 35

(1-Acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

In accordance with the General procedure a, the compound described in example 33h (96,6 mg), acelerou 4-biphenylcarbonic acid (54,4 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC (method B).

Output: 31,5 mg; MS-ESI: [M+H]+= 532,4; HPLC: Rt=24,92 min (method 2).

Example 36

N-(1-Acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) - for 3,5-dibromobenzene

In accordance with the General procedure a, the compound described in example 33h (96,6 mg), acelerou 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified by crystallization from a mixture of CH2Cl2/CH3CN.

Output: 24.3 mg); MS-ESI: [M+H]+= 614,2; HPLC: Rt=27,71 min (method 2).

Example 37

(1-Acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin--yl)amide cyclopentanecarbonyl acid

In accordance with the General procedure a, the compound described in example 33h (137 mg), acelerou cyclopentanecarbonyl acid (128 ml), HATU (224 mg) and DIPEA (400 μl) in CH2Cl2(10 ml). Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Yield: 148 mg; MS-ESI: [M+H]+= 448,4; HPLC: Rt=12,93 min (method 1).

Example 38

N-(1-Acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)isobutyramide

In accordance with the General procedure a, the compound described in example 33h (137 mg), acelerou somaclonal acid (110 μl), HATU (224 mg) and DIPEA (400 μl) in CH2Cl2(10 ml). Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./vol.)).

Yield: 43 mg; MS-ESI: [M+H]+= 422,4; HPLC: Rt=9,99 min (method 1).

Example 39

(1-Acetyl-7-furan-2-ylcarbonyl-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide, furan-2-carboxylic acid

To a solution of the compound described in example 33f (150 mg), and triethylamine (43 μl) in CH2Cl2(1 ml) is added 2-frailcare (30 μl). After full conversion of the initial substance added 1M aqueous HCl, the organic layer is separated, added piperidine (1 ml) and the resulting mixture is stirred over night. actionnow the mixture was washed with 1M aqueous HCl, the organic layer is separated, dried (MgSO4) and concentrated in vacuo. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 1/0 to 0/1 (about./about.)) and then preparative HPLC (method A).

Yield: 18 mg; MS-ESI: [M+H]+= 512,4; HPLC: Rt=19,92 min (method 2).

Example 40

(1-Acetyl-2,2,4-trimethyl-4-phenyl-7-propylamino-1,2,3,4-tetrahydroquinolin-6-yl)amide 5-methylthiophene-2-carboxylic acid

(a)1-Acetyl-6-amino-2,2,4-trimethyl-4-phenyl-7-propylamino-1,2,3,4-tetrahydroquinolin

A General method To:To a mixture of the compound described in example 33f (750 mg), acetic acid (953 μl), cyanoborohydride sodium (135 mg) and Meon (10 ml) add Propionaldehyde (94,2 µl). The mixture is stirred for 18 hours, water is added and the precipitate filtered off. The precipitate is transferred to a CH2Cl2(10 ml), added piperidine (1 ml) and the resulting mixture stirred for 18 hours. The reaction mixture was washed with 1M aqueous HCl, the organic layer was separated and diluted to a total volume of 50 ml of the resulting solution was used in the subsequent stages of the synthesis.

(b)(1-Acetyl-2,2,4-trimethyl-4-phenyl-7-propylamino-1,2,3,4-tetrahydroquinolin-6-yl)amide 5-methylthiophene-2-carboxylic acid

In accordance with the General procedure a, the compound described in example 40A (100 mg), acelerou 5-methylthiophene-2-karbonvansty (39,1 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Output: 18.3 mg); MS-ESI: [M+H]+= 490,4; HPLC: Rt=23,96 min (method 2).

Example 41

(1-Acetyl-7-ethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

(a)1-Acetyl-6-amino-7-ethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin

In accordance with the General method To the compound described in example 33f (750 mg), alkylate by acetaldehyde (73,3 μl) and remove the protective group with piperidine (1 ml), after receiving treatment and dilution of the solution specified in the connection header in CH2Cl2.

(b)(1-Acetyl-7-ethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

In accordance with the General procedure a, the compound described in example 41A (100 mg), acelerou 4-biphenylcarbonic acid (54,4 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Output: 9.8 mg); MS-ESI: [M+H]+= 532,4; HPLC: Rt=25,55 min (method 2).

Example 42

{1-Acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridine-4-ylmethyl)amino]-1,2,3,4-tetrahydroquinolin-6-yl}amide 5-methylthiophene-2-carboxylic acid

(a)1-Acetyl-6-amino-2,2,4-trimethyl-4-phenyl-7-[(pyridine-4-ylmethyl)amino]1,2,3,4-tetrahydroquinolin

In accordance with the General method To the compound described in example 33f (750 mg), alkylate 4-pyridinecarboxamide (125 μl) and remove the protective group with piperidine (1 ml), after receiving treatment and dilution of the solution specified in the connection header in CH2Cl2.

(b) {1-Acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridine-4-ylmethyl)amino]-1,2,3,4-tetrahydroquinolin-6-yl}amide 5-methylthiophene-2-carboxylic acid

In accordance with the General procedure a, the compound described in example 42A (114 mg), acelerou 5-methylthiophene-2-carboxylic acid (39,1 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 51 mg; MS-ESI: [M+H]+= 539,4; HPLC: Rt=13,19 min (method 2).

Example 43

{1-Acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridine-3-ylmethyl)amino]-1,2,3,4-tetrahydroquinolin-6-yl}amide 5-methylthiophene-2-carboxylic acid

(a)1-Acetyl-6-amino-2,2,4-trimethyl-4-phenyl-7-[(pyridine-3-ylmethyl)amino]-1,2,3,4-tetrahydroquinolin

In accordance with the General method To the compound described in example 33f (750 mg), alkylate 3-pyridinecarboxamide (125 μl) and remove the protective group with piperidine (1 ml), after receiving treatment and dilution of the solution specified in the connection header in CH2Cl2.

(b){1-Acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridine-3-ylmethyl)amino]-,2,3,4-tetrahydroquinolin-6-yl}amine 5-methylthiophene-2-carboxylic acid

In accordance with the General procedure a, the compound described in example 43A (114 mg), acelerou 5-methylthiophene-2-carboxylic acid (39,1 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 44 mg; MS-ESI: [M+H]+= 539,4; HPLC: Rt=13,45 min (method 2).

Example 44

N-(1-Acetyl-7-isobutylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) - for 3,5-dibromobenzene

(a)1-Acetyl-6-amino-7-isobutylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin

In accordance with the General method To the compound described in example 33f (750 mg), alkylate Isobutyraldehyde (119 μl) and remove the protective group with piperidine (1 ml), after receiving treatment and dilution of the solution specified in the connection header in CH2Cl2.

(b)N-(1-Acetyl-7-isobutylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) - for 3,5-dibromobenzene

In accordance with the General procedure a, the compound described in example 44a (114 mg), acelerou 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 54 mg; MS-ESI: [M+H]+= 642,4; HPLC: Rt=29,47 min (method 2).

Example 45

(1-Acetyl-7-benzylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide is iphenyl-4-carboxylic acid

(a)1-Acetyl-6-amino-7-benzylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin

In accordance with the General method To the compound described in example 33f (750 mg), alkylate-benzaldehyde (133 ál) and remove the protective group with piperidine (1 ml), after receiving treatment and dilution of the solution specified in the connection header in CH2Cl2.

(b)(1-Acetyl-7-benzylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide-biphenyl-4-carboxylic acid

In accordance with the General procedure a, the compound described in example 45a (113 mg), acelerou 4-biphenylcarbonic acid (54,4 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 114 mg; MS-ESI: [M+H]+= 594,4; HPLC: Rt=26,46 min (method 2).

Example 46

(1-Acetyl-7-benzylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide 5-methylthiophene-2-carboxylic acid

In accordance with the General procedure a, the compound described in example 45A (113 mg), acelerou 5-methylthiophene-2-carboxylic acid (39,1 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 107 mg; MS-ESI: [M+H]+= 538,4; HPLC: Rt=18,59 min (method 2).

Example 47

N-{1-Acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridine-3-ylmethylamino]-1,2,3,4-tetrahydroquinolin-6-yl} - for 3,5-dibromobenzene

In accordance with the General procedure a, the compound described in example 43A (114 mg), acelerou 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 μl) in CH2Cl2(10 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 41 mg; MS-ESI: [M+H]+= 677,2; HPLC: Rt=14,88 min (method 2).

Example 48

N-(1-Acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) - for 3,5-dibromobenzene

(a)4-Methyl-1,2-dihydroquinoline

The solution lepidine (10.0 g) in THF cooled to -78°With, then add a solution BH3·THF in THF (1 M, 70 ml). After 2 hours, add a solution of bis(2-methoxyethoxy)alumothermic sodium in toluene (3,5M, 40 ml) and the reaction mixture stirred for additional 2 hours. Water is added and the mixture is diluted with ethyl acetate. The organic layer is separated, dried (MgSO4) and partially concentrated in vacuo, leading to crystallization specified in the connection header. The crystals are filtered, getting after drying in vacuum, 3.5 g of product. The remaining mother liquor was concentrated in vacuo and the residue purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 0/1 to 1/0 (about./vol.), receiving additional 4.4 g specified in the connection header.

Output: 7,9,

(b)1-Acetyl-4-methyl-1,2-dihydroquinoline

In accordance with the laws the AI with the General method With the connection, described in example 48A (7.9 g), acelerou acetylchloride (11.8 ml) and DMA (34 ml) in CH2Cl2(50 ml) at 0°C. Specified in the title compound purified by chromatography on silica gel (elution: heptane/ethyl acetate = 6/4).

Output: 8,8,

(C)1-Acetyl-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin

In accordance with the General method G of the compound described in example 48b (8.8 g), stirred with AlCl3(18,8 g) in benzene (250 ml). The resulting product is used in the next stage without additional purification.

Output: 12,0,

(d)1-Acetyl-4-methyl-6-nitro-4-phenyl-1,2,3,4-tetrahydroquinolin

To a solution of the compound described in example 48S (5.0 g), and acetic anhydride (189 μl) in CH2Cl2(50 ml) added dropwise fuming HNO3(9.4 ml). After completion of the reaction, water is added, the organic layer was washed with saturated salt solution, is separated and concentrated in vacuo. Specified in the title compound purified by chromatography on silica gel (elution: heptane/ethyl acetate = 6/4 (about./vol.)).

Output: 3,86,

(e)1-Acetyl-6-amino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin

In accordance with the General method E, compound described in example 48d (3,86 g), restore powdered zinc (16 g) and acetic acid (7 ml) in THF (˜250 mg), and receiving the product, which is used in the next stage without additional cleaning is.

Output: 2,2,

(f)9-Fluorenylmethyl ether (1-acetyl-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

To a solution of the compound described in example 48th (1.0 g)in THF (10 ml) is added pyridine (314 μl) and the resulting mixture is cooled to 0°C. Add FmocCl (1.01 g) and the mixture is stirred for 18 hours at room temperature, after which the reaction mixture was concentrated in vacuo. Specified in the title compound purified by chromatography on silica gel (elution: heptane/ethyl acetate = 6/4 (about./vol.)).

Yield: 950 mg

(g)9-Fluorenylmethyl ether (1-acetyl-4-methyl-7-nitro-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

To a solution of the compound described in example 48f (850 mg), and acetic anhydride (17 ml) in CH2Cl2(5 ml) added dropwise fuming HNO3(842 μl). After completion of the reaction, water is added, the organic layer was washed with saturated salt solution, is separated and concentrated in vacuo. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 9/1 to 0/1 (about./vol.)).

Output: 714 mg

(h)9-Fluorenylmethyl ether (1-acetyl-7-amino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

In accordance with the General method E, compound described in example 48g (2.37 g), restore Poroskov the different zinc (5.6 g) and acetic acid (2.4 ml) in THF (˜ 50 mg)to give the product, which is used in the next stage without additional purification.

Output: 2,66,

(i)9-Fluorenylmethyl ether (1-acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamino acid

An aqueous solution of formaldehyde (37%, 650 μl) are added to a solution of the compound described in example 48h (2.66 g), acetic acid (3.1 ml) and cyanoborohydride sodium (232 mg) in methanol (50 ml)and the resulting mixture is stirred for 18 hours. The reaction mixture was concentrated in vacuo, the residue is transferred into ethyl acetate and washed with water and saturated salt solution. The organic layer is separated, dried (MgSO4) and concentrated in vacuo. Specified in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 9/1 to 0/1 (about./vol.)).

Output: 1,0,

(j)1-Acetyl-6-amino-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin

Piperidine (1.8 ml) are added to a solution of the compound described in example 48i (1 g)in CH2Cl2(20 ml) and the mixture is stirred until then, until no educt. The reaction mixture was concentrated in vacuo, and indicated in the title compound purified by chromatography on silica gel (elution with gradient: heptane/ethyl acetate from 9/1 to 0/1 (about./vol.)).

Yield: 370 mg

(k)N-(1-Acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,-tetrahydroquinolin-6-yl) - for 3,5-dibromobenzene

In accordance with the General procedure a, the compound described in example 48j (74 mg), acelerou 3,5-dibromobenzoic acid (70 mg), HATU (131 mg) and DIPEA (120 μl) in CH2Cl2(3 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 82 mg; MS-ESI: [M+H]+= 586,2; HPLC: Rt=22,40 min (method 2).

Example 49

(1-Acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide 5-bromothiophene-2-carboxylic acid

In accordance with the General procedure a, the compound described in example 48j (74 mg), acelerou 5-bromothiophene-2-carboxylic acid (52 mg), HATU (131 mg) and DIPEA (120 μl) in CH2Cl2(3 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 69 mg; MS-ESI: [M+H]+= 514,2; HPLC: Rt=17,01 min (method 2).

Example 50

(1-Acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)amide 5-chlorothiophene-2-carboxylic acid

In accordance with the General procedure a, the compound described in example 48j (74 mg), acelerou 5-chlorothiophene-2-carboxylic acid (52 mg), HATU (131 mg) and DIPEA (120 μl) in CH2Cl2(3 ml). Specified in the title compound purified preparative HPLC and lyophilized.

Yield: 81 mg; MS-ESI: [M+H]+= 468,2; HPLC: Rt=17,49 min (method 2).

Example 51

The biological activity of CHO-FSH in vitro

Activity of compounds in Rel is to FSH experience in the ovary cells of Chinese hamster (Chinese Hamster Ovary - CHO)stably transfected with the receptor FSH person and transfected together with camp-sensitive element (cAMP responsive element CRE)/promoter directing the expression of the reporter gene Firefly luciferase. The binding of ligand to Gs-related FSH receptor will lead to increased levels of camp, which in turn will cause an increased TRANS-activation of reporter construct luciferase. To test the antagonist properties of recombinant FSH is added in a concentration that induces approximately 80% of the maximum incentive to the accumulation of camp in the absence of test compounds (rec-hFSH, 10 mi/ml). The luciferase signal was quantitatively determined using a luminescence counter. For test compounds, the values of the EU50(concentration of test compound that causes premaxillae (50%) stimulation or decrease) is calculated. This is done using the program GraphPad PRISM, version 3.0 (GraphPad software Inc., San Diego).

Connect all of the examples demonstrate the value of the EU50(IC50less than 10-5M in the experiments for the determination of the properties of agonists or antagonists, or both properties. Compounds of examples 5-8, 10-14, 16, 18-20, 33-35, 37, 38, 41, 45-50 demonstrated the importance of the EU50less than 10-7M, at least one of the tests for the determination of biological activity.

1. The production is the same tetrahydroquinoline, corresponding to the formula I

or its pharmaceutically acceptable salt, where

R1and R2represent H or Me;

R3represents H, hydroxy or (1-4C)alkoxy;

R4represents H, HE, (1-4C)alkoxy;

R5HE is a, (1-4C)alkoxy, or R7;

provided that if R4represents H, R5different from IT, or (1-4C)alkoxy;

R6is a (2-5C)heteroaryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, bromine or chlorine;

(6C)aryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, (1-4C)alkoxy, bromine, chlorine, phenyl or (1-4C)(di)alkylamino;

(3-8C)cycloalkyl, (2-6C)heteroseksualci or (1-6C)alkyl;

R7represents amino, (di)(1-4C)alkylamino, (6S)arylcarboxamide, (2-5C)heteroarylboronic, (2-5C)heteroarylboronic, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy;

R8represents amino, (1-4C)alkoxy, (di)(1-4C)alkylamino, (2-6C)heteroseksualci, (2-6C)geterotsiklicheskikh or (1-4C)alkoxycarbonyl; and

R9is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl is, (2-5C)heteroaryl or (6C)aryl.

2. Derived tetrahydroquinoline according to claim 1, where R6is a (2-5C)heteroaryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, bromine or chlorine;

(6C)aryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, (1-4C)alkoxy, bromine, chlorine, phenyl or (1-4C)(di)alkylamino;

(3-8C)cycloalkyl or (1-6C)alkyl.

3. Derived tetrahydroquinoline according to claim 1 or 2, where R7is a (di)(1-4C)alkylamino, (2-5C)heteroarylboronic, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy.

4. Derived tetrahydroquinoline according to claim 1, where R8represents amino, (di)(1-4C)alkylamino, (2-6C)heteroseksualci or (2-6C)-geterotsiklicheskikh.

5. Derived tetrahydroquinoline according to claim 1, where R7is a (di)(1-4C)alkylamino, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy.

6. Derived tetrahydroquinoline according to claim 1, where R8represents amino, (di)(1-4C)alkylamino or (2-6C)heteroseksualci.

7. Derived tetrahydroquinoline according to claim 2, where R8is a (di)(1-4C)alkylamino or (2-6C)heteroseksualci.

8. Derived tetrahydroquinoline according to claim 2, where R7is a (di)(1-4C)alkylamino, R8-(2-4C)alcox is, R9-methylamino or R9-methoxy.

9. Derived tetrahydroquinoline according to claim 1, where R6is a (2-5C)heteroaryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, bromine or chlorine; or

(6C)aryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, (1-4C)alkoxy, bromine, chlorine, phenyl or (1-4C)(di)alkylamino.

10. Derived tetrahydroquinoline according to claim 1, where R6represents (4-5C)heteroaryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, bromine or chlorine; or (6C)aryl, optionally substituted by one or more substituents selected from (1-4C)alkyl, (1-4C)alkoxy, bromine, chlorine, phenyl or (1-4C)(di)alkylamino, and R9is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (3-5C)heteroaryl or (6C)aryl.

11. Derived tetrahydroquinoline according to claim 1, where R7is a (di)(1-4C)alkylamino, R8-ethoxy, R9-methylamino or R9-methoxy, and R9is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (3-5C)heteroaryl or (6C)aryl.

12. Derived tetrahydroquinoline according to claim 1, where R8is a (di)(1-4C)alkylamino, (4-5C)heteroseksualci and R9is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, 3-5C)heteroaryl or (6C)aryl.

13. Pharmaceutical composition having modulating activity against FSH receptor containing derivative tetrahydroquinoline according to any one of claims 1 to 12 and a pharmaceutically acceptable adjuvants.

14. Derived tetrahydroquinoline according to any one of claims 1 to 12 for use for the regulation of fertility.

15. The use of derivative tetrahydroquinoline according to any one of claims 1 to 12 or its pharmaceutically acceptable salt or MES for production of medicines for the regulation of fertility.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 1-sulphonyl-4-aminoalcoxyindole of formula (I) are described, or pharmaceutically acceptable salts thereof, where n is 2 or 3; each of R1 and R2 independently of each other stands for hydrogen, or lower alkyl, or R1 and R2 together with corresponding nitrogen atom may be a part of heterocyclic group, which is selected from morpholino, pyrrolidinyl; R3 stands for hydrogen, or R3 and R1 together with R3 nitrogen atom may be a part of four- or five-membered ring, where R1 and R3 together form an alkylene group; R4 stands for hydrogen; R5 stands for hydrogen; R6 stands for naphthyl, phenyl, not necessarily substituted with one or two substituents, each of which may be a lower alkyl, haloid, lower alcoxy, cyano group, lower alkylsulphonyl, acyl, trifluoromethyl, acetamide, or quinolinyle, thienyl, not necessarily halogen-substituted. The said compounds are selective 5-НТ6 antagonists.

EFFECT: pharmaceutical composition is a receptor modulator.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes cyclic-substituted diphenylazethidinones of the formula (I): wherein each radical among R1, R2, R3, R4, R5 and R6 means independently of one another (C1-C30)-alkylene-(LAG)n wherein n = 1-2; one or two carbon atoms in alkylene residue are replaced with phenyl or piperazinyl residues or (C3-C10)-cycloalkyl residue; one or some carbon atoms in alkylene residue can be replaced with -S(O)n wherein n = 2; -O-, -(C=O)- or -NH-; hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J), O-(C1-C6)-alkyl; (LAG)n means mono- or tricyclic trialkyl ammoniumalkyl residue, -(CH2)0-SO3H, -(CH2)0-COOH, -(CH2)0-C(=NH)(NH2), and pharmaceutically acceptable salts also. Proposed compounds decrease the serum cholesterol content. Also, invention describes using these compounds for preparing a medicinal agent used in treatment of lipid metabolism disorders.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of azethedine of the formula (I): in free form or as a salt wherein Ar means phenyl optionally substituted with one or some substitutes chosen from halogen atom, (C1-C8)-alkyl, cyano-group; R1 means hydrogen atom (H), (C1-C8)-alkyl optionally substituted with hydroxy-, (C1-C8)-alkoxy-, (C1-C8)-alkylcarbonyloxy-group, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl; R2 means H, (C1-C8)-alkyl, (C3-C10)-cycloalkyl; R3 means (C1-C8)-alkyl substituted with phenyl, phenoxy-, (C1-C8)-alkylcarbonyloxy-group, naphthyl; or R2 represents (C3-C10)-cyclalkyl optionally comprising benzo-group, condensed benzo-group, 5-6-membered heterocyclic group comprising 1-3 different heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S), or up to 4 N atoms, or it means 5-6-membered heterocyclic group comprising 1 or 2 ring O or N atoms and optionally substituted with substitutes enumerated in the formula; or R3 means phenyl or naphthyl wherein indicated phenyl, phenoxy- or naphthyl group is substituted optionally with one or some substitutes chosen from halogen atom, cyano-, hydroxy-group, (C1-C8)-alkylcarbonyl, -SO2NH2, (C1-C8)-alkyl, optionally substituted (C1-C8)-alkoxy-, (C1-C8)-alkylthio-group, -SO2-(C1-C8)-alkyl, (C1-C8)-alkoxycarbonyl, (C1-C8)-acylamino-group substituted optionally with (C1-C8)-alkyl by nitrogen atom, (C1-C8)-alkylamino-group, aminocarbonyl, (C1-C8)-alkylaminocarbonyl, di-(C1-C8-alkyl)amino-group, di-(C1-C8-alkyl)aminocarbonyl, di-(C1-C8-alkyl)aminocarbonylmethoxy-group; X means -C(=O)-, -O-, -CH2- or -CH(OH); Y means O, S; m means 1, 2, 3 or 4; each n, p and q means 0 or 1, n + p + q = 1, n + q = 1 and p+ q = 1 and when n means 0 then p means 0. Compounds of the formula (I) inhibit binding eotaxine with CCR-3 receptor that allows their using as component of pharmaceutical composition and for preparing a medicinal agent used in inflammatory or allergic state.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 201 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts. Proposed compounds possess properties of agonists of receptors activated by peroxisome proliferators (PPAR agonists) and can be used in treatment of such diseases as diabetes mellitus, hypertension, atherosclerotic diseases and others. In the general formula (I) R1 means lower alkyl, monocyclic (C3-C6)-cycloalkyl; R2 means hydrogen atom, halogen atom, lower alkyl, lower alkoxy-group wherein at least one of three radicals R3, R4, R5 or R6 is not hydrogen atom; or R3 and R4 are bound together to form a ring with carbon atoms to which they are bound, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-CH=CH-, and R5 and R6 are given above; R7 means lower alkyl, lower alkenyl; R8 means hydrogen atom or lower alkyl; n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition based on the invention compounds and to using compounds of the invention in preparing medicinal agents used in treatment and/or prophylaxis of diseases mediated by agonists PPARα and/or PPARγ.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 13 sch, 71 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel imidazoline-2-yl-aminophenylamides of the formula (I): wherein R1 means phenyl optionally substituted with one, two or three substitutes chosen independently from group comprising alkyl, alkenyl, alkoxy-group, optionally substituted aryl, optionally substituted aryloxy-, aralkyloxy-group, halogen atom, halogenalkyl, halogenalkoxy-, hydroxy-group, hydroxyalkyl, alkylsulfonyl, alkoxyalkyloxy-, hydroxyalkyloxy-, cyano-, hydroxy-group, cycloalkyl, cycloalkyloxy-, cycloalkylalkoxy-, amino-, alkylamino-, dialkylamino-group, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy-group, optionally substituted heterocyclylsulfonyl, optionally substituted heterocyclylalkyloxy-group, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl; R2 means hydrogen atom; A means -C(O)-NRa-(CRbRc)n- or -NRa-C(O)-(CRbRc)n-; n = 1-6; each among Ra, Rb and Rc means independently hydrogen atom or alkyl, or their pharmaceutically acceptable salt or solvates, and to compounds of the formula (II): wherein R1, R2, Rb, Rc and A have above given values; each R3 and R4 means independently hydrogen atom or alkoxycarbonyl; Ra means hydrogen atom, alkyl or cycloalkyl. These compounds are effective modulators of IP receptors and firstly antagonists of IP receptors. Except for, invention involves pharmaceutical compositions containing indicated compounds.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

11 cl, 1 tbl, 10 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of quinoline with general formula Ia or Ib their stereoisomers and pharmaceutical salts, where X represents oxygen or sulphur, Z-CH2, Y-NO2, -C(O)OR5, -NR5SO2R5, -SO2R5 (for Ia) and -NO2 or -C(O)OR5 (for Ib). Description is also given of the method of obtaining Ia and Ib compounds, pharmaceutical compositions based on them, and their use when making medicinal preparations.

EFFECT: compounds can be used for treating lesions, related to inhibition of migration of magrophage, for example, during treatment of septic shock or arthritis.

175 cl, 16 tbl, 22 ex, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA): or the formula (IB): wherein B means hydrogen atom or lower alkyl; A means an unsubstituted or substituted cyclic group chosen from compounds of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) and (k) wherein R1-R4 mean independently of one another hydrogen atom, halogen atom, -CF3, -CHF2, -C(CH3)F2, (C3-C6)-cycloalkyl, lower alkoxy-group, lower alkyl, -OCF3 or phenyl; R5-R10 means independently of one another hydrogen atom, halogen atom, lower alkoxy-group, lower alkyl or -CHF2; R11-R16 mean independently of one another hydrogen atom, halogen atom, alkoxy-group or lower alkyl; R17 means halogen atom or -CHF2; R18-R20 mean independently of one another hydrogen atom, lower alkoxy-group or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicinal agent possessing the selective effect of blockers of NMDA receptors of subtype 2B. Invention provides synthesis of novel biologically active compounds and medicinal agents based on thereof.

EFFECT: valuable medicinal properties of compounds and drugs.

6 cl, 180 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.

SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.

EFFECT: improved method of synthesis, valuable medicinal property of compounds.

2 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) or their pharmaceutically acceptable salts wherein R1 and R2 are similar or different and chosen independently from group comprising aryl and heteroaryl. Each of them as a substitute comprises optionally from one to sic groups chosen from group comprising the following groups: (a) halogen atom; (b) -OCF3 or -OCHF2; (c) -CF3; (d) -CN; (e) alkyl; (f) R18-heteroaljyl; (k) hydroxyl; (l) alkoxyl comprising cyclopropylmethoxyl, and (s) trifluoroalkoxyl; R3 means hydrogen atom (H); R4, R5, R7 and R8 are similar or different and chosen independently from group comprising H, -OH, alkyl, heteroalkyl and

under condition that if Z and/or X means nitrogen atom (N) then all radicals R4, R5, R7 and R8 don't mean -OH; R6 means -C(O)R15; R9 and R10 mean H; R11 is chosen from group comprising H and alkyl; R12 is chosen from group comprising H and alkyl; R13 is chosen from group comprising alkyl and alkoxyl; R14 means H; R15 is chosen from group comprising -NR16R17, -OR16 and alkyl wherein R16 and R17 are similar or different and chosen independently from group comprising H and alkyl; R18 means a substitute chosen from group comprising lower alkyl, halogen alkyl, halogenalkyl, alkoxycarbonyl, dialkylamino-group and piperidinyl; X and Z are similar or different and chosen independently from carbon atom (C) and N. Proposed compounds possess properties of inhibitor of 17β-hydroxysteroid dehydrogenase of type 3. Also, invention describes a pharmaceutical composition based on compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical composition.

16 cl, 23 tbl, 651 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method for treatment.

26 cl, 17 tbl, 221 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 1-sulphonyl-4-aminoalcoxyindole of formula (I) are described, or pharmaceutically acceptable salts thereof, where n is 2 or 3; each of R1 and R2 independently of each other stands for hydrogen, or lower alkyl, or R1 and R2 together with corresponding nitrogen atom may be a part of heterocyclic group, which is selected from morpholino, pyrrolidinyl; R3 stands for hydrogen, or R3 and R1 together with R3 nitrogen atom may be a part of four- or five-membered ring, where R1 and R3 together form an alkylene group; R4 stands for hydrogen; R5 stands for hydrogen; R6 stands for naphthyl, phenyl, not necessarily substituted with one or two substituents, each of which may be a lower alkyl, haloid, lower alcoxy, cyano group, lower alkylsulphonyl, acyl, trifluoromethyl, acetamide, or quinolinyle, thienyl, not necessarily halogen-substituted. The said compounds are selective 5-НТ6 antagonists.

EFFECT: pharmaceutical composition is a receptor modulator.

17 cl, 1 tbl, 6 ex

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