HRP20050576A2 - Tetrahydroquinoline derivatives - Google Patents

Description

The invention relates to a compound that has FSH receptor modulator properties, especially a tetrahydroquinolone derivative, to a pharmaceutical preparation containing the same, as well as to the use of said compound in medical treatment.

Gonadotropins play a significant role in a variety of bodily functions including metabolism, temperature regulation, and the reproductive process. Gonadotropins act on specific cell types in the gonads to induce ovarian and testicular differentiation and steroidogenesis. The pituitary gonadotropin FSH (follicle-stimulating hormone), for example, plays a central role in stimulating follicle development and maturation, while LH (luteinizing hormone) induces ovulation (Sharp, R. M. Clin. Endocrinol. 33:787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35:301-342, 1979). Nowadays, FSH is used clinically in combination with LH and hCG, to stimulate the ovaries, i.e. ovarian hyperstimulation in in vitro fertilization (IVF) and ovulation induction in infertile anovulatory women (Insler, V., Int. J. Fertility 33:85-97, 1988; Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5:3- 13, 1988), as well as for male hypogonadism and male infertility.

The gonadotropin FSH is released from the anterior adrenal gland under the influence of gonadotropin-releasing hormone and estrogen, and forms the placenta during pregnancy. In women, FSH works by stimulating the development of follicles and is the main hormone that regulates the secretion of estrogen. In males, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to enable gametogenesis. Purified FSH is used clinically to treat infertility in women and in some types of absence of spermatogenesis in men. Gonadotropins intended for therapeutic purposes can be isolated from human urine and are of low purity (Morse et al., Amer. J. Reprod. 2 :371, 1996; Devorey et al. Lancet 339:1170, 1992).

The action of the FSH hormone is realized through specific receptors in the plasma membrane that belong to a large group of receptors that are connected to the G protein. These receptors consist of a single polypeptide with seven transmembrane domains and can interact with the Gs protein, which leads, for example, to the activation of adenylate cyclase.

The FSH receptor is a highly specific target in the ovarian follicle growth process and is exclusively expressed in the ovary. Blocking these receptors, or inhibiting the signals that are normally induced after FSH-mediated receptor activation, will interfere with follicular development and therefore ovulation and fertility. Low molecular weight FSH antagonists can therefore form the basis for new contraceptives. Such FSH antagonists can lead to incomplete follicle development (no ovulation) with estrogen production still sufficient to avoid harmful effects on, for example, bone mass. On the other hand, compounds that stimulate FSH receptor activity may serve to mimic the gonadotropic effect of the natural ligand.

This invention describes the preparation of low molecular weight hormone analogs that have selective modulatory activity at the FSH receptor. The compounds of the present invention can be used as (partial) agonists or (partial) antagonists of the FSH receptor.

Therefore, it has now been found that the following categories of tetrahydroquinoline compounds of formula I or their pharmaceutically acceptable salts have FSH modulatory activity:

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where

are R1 and R2 equal to H or Me,

R 3 is H, hydroxy, (1-4C) alkoxy; (di)(1-4C) alkylamino(2-4C) alkoxy or (2-6) heterocycloalkyl(2-4C) alkoxy,

R 4 is H, OH, (1-4C) alkoxy or R 7 ;

R 5 is H, OH, (1-4C) alkoxy or R 7 ;

with the proviso that R 4 is H, R 5 is not H, OH or (1-4C) alkoxy and that if R 5 is H, R 4 is not H, OH or (1-4C) alkoxy;

R 6 is (2-5C)heteroaryl, (6C)aryl, (3-8)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)alkyl;

R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (6C)arylcarbonyloxy; R 8 -(2-4C)alkylamino, R 8 -(2-4C)alkoxy, R 9 -methylamino or R 9 -methoxy;

R8 is hydroxy, amino, (1-4C) alkoxy, (di)(1-4C) alkylamino, (2-6C) heterocycloalkyl, (2-6C) heterocycloalkylcarbonylamino, (di)(1-4C) alkylaminocaronylamino or (1- 4C)Alkoxycarbonylamino and

R 9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl.

R 4 and R 5 may be independently selected from each of the aforementioned groups and need not be identical.

The compounds of this invention modulate FSH receptor function and can be used for the same clinical purposes as native FSH if they act as agonists, with the advantage that they have altered stability properties and can be administered in a different way. If they block the FSH receptor, they can be used, for example, as a contraceptive agent.

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

The following terms have the meanings indicated below when used in the specification and claims.

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

The term (3-8C)cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, namely cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred groups are (3-6C)cycloalkyl.

The term (2-6C)heterocycloalkyl means a heterocycloalkyl group having 2-6 carbon atoms, preferably 3-5 carbon atoms, and including at least one heteroatom selected from N, O and/or S, which can be attached via heteroatoms as possible, or carbon atom. Preferred heteroatoms are N or O. Most preferred are piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl.

The term (1-4C)Alkoxy means an alkoxy group having 1-4 carbon atoms, an alkyl radical having the same meaning as previously defined. (1-2C) alkoxy groups are preferred.

The term (2-4C) alkoxy means an alkoxy group having 2-4 carbon atoms, and the alkyl residue has the same meaning as previously defined.

The term (di)(1-4C)alkylamino as used herein means an amino group, monosubstituted or disubstituted with alkyl groups, each containing 1-4 carbon atoms and has the same meaning as previously defined.

The term (6C)aryl, as used herein, refers to a phenyl group, which may optionally be substituted with one or more substituents selected from hydroxy, amino, iodo, bromo, chloro, fluoro, nitro, trifluoromethyl, cyano, phenyl, ( 1-4C)alkyl, (1-4C)alkoxy, (1-4C)(di)alkylamino, and an alkyl, alkoxy and (di)alkylamino residue has the same meaning as previously defined, for example phenyl; 3,5-dibromophenyl, 4-biphenyl; 3,5-dichlorophenyl, 3-bromo-6-methylamino-phenyl, 3-chloro-2,6-dimethoxyphenyl and 3,5-dimethylphenyl.

The term (2-5C)heteroaryl denotes a substituted or unsubstituted aromatic group having 2-5 carbon atoms selected from N, O and/or S, such as imidazole, pyridyl, pyrimidyl, thienyl or furyl. Substituents on the heteroaryl group can be selected from the group of substituents listed for the (6C)aryl group. A heteroaryl group can be attached via a carbon atom or a heteroatom, if possible. Preferred heteroaryl groups are thienyl, furyl and pyridyl.

The term di(1-4C)alkylamino(2-4C)alkoxy, as used herein, means a (di)alkylamino group, an alkyl radical or alkyl radicals, each of which contains 1-4 carbon atoms, linked via an amino group to an alkyl radical of an alkoxy group which has 2-4 carbon atoms, where the (di)alkylamino group and the alkoxy group have the same meaning as previously defined.

The term (2-6C)heterocycloalkyl(2-4C)alkoxy, as used herein, means a heterocycloalkyl group having 2-6 carbon atoms, linked to an alkyl radical or an alkoxy group having 2-4 carbon atoms in which the alkoxy group and heterocycloalkyl group have the same meaning as previously defined.

The term (6C)arylcarbonyloxy, as used herein, means a phenyl group, preferably substituted with one or more substituents with one or more substituents selected from the group of substituents listed for the (6C)aryl group, attached to the carbonyl moiety of the carbonyloxy group, and (6C) )aryl residue has the same meaning as previously defined.

The term (2-5C)heteroarylcarbonylamino, as used herein, refers to a heteroaryl group containing 2-5 carbon atoms, optionally substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, linked to the carbonyl residue of the carbonylamino groups. The heteroaryl residue in the heteroarylcarbonylamino group has the same meaning as previously defined.

The term (2-5C)heteroarylcarbonyloxy, as used herein, means a heteroaryl group containing 2-5 carbon atoms, preferably substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, attached to the carbonyl moiety of the carbonyloxy group . The heteroaryl residue in the heterocarbonyloxy group has the same meaning as previously defined.

The term (di)(1-4C)alkylaminocarbonyl, as used herein, means a (di)alkylamino group, an alkyl group(s) having 1-4 carbon atoms, linked from an amino group to a carbonyl group, and a (di)alkylamino group has meaning the same as previously defined.

The term (di)(1-4C)alkylaminocarbonylamino, as used herein, denotes a (di)alkylamino group, an alkyl group(s) having 1-4 carbon atoms, linked by an amino group to the carbonyl group of the carbonylamino group, thereby providing urea as a functional group, and the (di)alkylamino group has the same meaning as previously defined.

The term (1-4C)Alkoxycarbonylamino, as used herein, means an alkoxy group having 1-4 carbon atoms, attached to the carbonyl residue of the carbonylamino group, thereby providing a carbonylamino group, thereby providing a carbamate functional group, and the alkoxy group has the same meaning as previously defined.

The term R 8 -(2-4C)alkylamino, as used herein, means the group R 8 attached to the alkyl residue of the (2-4C)alkylamino group, and has the same meaning as previously defined.

The term R 8 -(2-4C)alkoxy, as used herein, means the group R 8 which is attached to the alkyl residue of the (2-4C)alkoxy group, and has the same meaning as previously defined.

The term R9-methylamino, as used herein, means the R9 group attached to the methyl residue of the methylamino group.

The term R9-methoxy, as used herein, means an R9 group attached to the methyl residue of a methoxy group.

The term pharmaceutically acceptable salt means those salts which, within the framework of medical evaluation, are suitable for contact application in the tissues of humans and lower animals without inappropriate toxicity, irritation, allergic response or the like, and are in accordance with a reasonable ratio of usefulness and risk. Pharmaceutically acceptable salts are well known in the art. They can be obtained during the final isolation and purification of the strain of the invention, or separately by reacting the free base, if present, with a suitable mineral salt such as hydrochloric acid, phosphoric acid, sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. If present, the acid may react with an organic or mineral alkali, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide.

The invention thus relates to compounds of Formula I as defined above.

In another way of application, the invention relates to compounds according to Formula I, where R 3 is equal to H, hydroxy or (1-4C) alkoxy.

The invention also relates to compounds of Formula I, where R 4 is equal to H, OH or (1-4C) alkoxy.

In another mode of application, the invention describes compounds of Formula I where R 5 is equal to OH, (1-4C) alkoxy or R 7 .

In another mode of application, the invention describes compounds of Formula I where R 6 is equal to (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloaryl or (1-6C)alkyl.

In another application, the invention relates to compounds according to Formula I where R 6 is equal to (2-5C)heteroaryl or (6C)aryl.

In another embodiment, the heteroaryl group in R6 consists of 4 to 5 carbon atoms.

The invention also relates to compounds according to Formula I where R7 is (di)(1-4C)alkylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroarylcarbonyloxy, R8-(2-4C) alkoxy, R9-methylamino or R9-methoxy.

In another field of application, the invention relates to compounds according to Formula I where R 7 is (di)(1-4C)alkylamino, R 8 -(2-4C)alkoxy, R 9 -methylamino or R 9 -methoxy.

In another field of application, the invention relates to compounds according to Formula I where R 8 -(2-4C) alkoxy in R 7 is equal to R 8 -ethoxy.

In another field of application, the invention relates to compounds according to Formula I where R8-(2-4C)alkylamino in R7 equals R8-ethylamino.

In another field of application, the invention relates to compounds according to Formula I where R8 is equal to amino, (di)(1-4C)alkylamino, (2-6C)heterocycloalkyl, (1-4C)alkoxycarbonylamino.

In another field of application, the invention relates to compounds according to Formula I where R8 is equal to amino, (di)(1-4C)alkylamino, (2-6C)heterocycloalkyl, (1-4C)heterocycloalkylcarbonylamino.

The invention also relates to compounds according to Formula I where R8 is amino, (di)(1-4C)alkylamino or (2-6C)heterocycloalkyl.

In yet another field of application of the invention, R 8 in the compounds of Formula I is (di)(1-4C)alkylamino or (2-6C)heterocycloalkyl.

Another way of applying the invention relates to compounds according to Formula I where the heterocycloalkyl group in R8 consists of 4 to 5 carbon atoms.

According to another way of applying the invention, R 9 according to Formula I is aminocarbonyl, (2-5C)heteroaryl or (6C)aryl.

According to another method of application, the heteroaryl group in R9 according to Formula I consists of 3, 4 or 5 C-atoms.

Another field of the invention relates to compounds where all the specific definitions of the groups R 1 to R 9 , as defined above, are combined in a compound of Formula I.

Suitable procedures for the preparation of the compounds of the invention are described below.

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Compounds of the present invention in which R4 and R5 are (1-4C)alkoxy, R1 and R2 are methyl and R6 are as previously defined may be prepared starting from suitably substituted anilines of the general formula II by the well-described Skraup reaction, which affords 2, 2,4-trimethyl-1,2-dihydroquinoline derivatives of formula III.

Related Skraup cyclic condensations can be found 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 and B. Roth, J. Med. Chem. 32:1942, 1989; TOILET. Lin; S.-T. Huang and 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-mentioned reaction is typically carried out at elevated temperature in acetone or mesityl oxide with iodine or a protic acid such as hydrochloric acid, p-toluenesulfitic acid or aqueous hydrogen iodide. Alternatively, 1,2-dihydro-2,2,4-trimethylquinolines of formula III can be prepared by reacting the corresponding aniline of formula II with acetone in the presence of MgSO4, 4-tert-butylcatechol and iodine (L.G. Hamann, R.I. Higuchi, L. Zhi; J. P. Edwards and X-N Wang, J. Med. Chem, 41:623, 1998). In another procedure, the reaction can be carried out in acetone using lanthanide triflates (eg scandium triflate) as catalysts. In this case, the reaction can be carried out at room temperature or at elevated temperatures using conventional heating or microwave irradiation (M.E. Theoclitou and L.A. Robinson, Tetrahedron Lett. 43.3907, 2002).

The starting material can be obtained either directly from commercial inventions or it can simply be prepared by experts in the field.

Compounds of formula III-b can be prepared from aniline by the general formula II by reaction with methyl vinyl ketone. Related cyclizations are described in United States Patent 2,686,182 (Badische Anilin- & Soda-Fabrik Aktiengesellschaft).

1-N-acetylation of compounds of formula III-a-b where R1 and R2 are as defined above follows and can be carried out using standard conditions. In a typical experiment, compounds of formula III are heated at reflux in acetic anhydride or reacted in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine with acetyl chloride in the presence of a base such as N,N-diisopropylethylamine, triethylamine or sodium hydride to form N-acetylated 4-methyl-1,2-dihydroquinoline derivative of formula IV-a-b.

Related N-acylations of the dihydroquinoline backbone can be found in the literature: G. Reddelien and A. Thurm, chem. Ber. 65:1511, 1932; Zh. V. Shmyrev; Kh. S. Shikhaliev and E.B. Shpanig Assoc. Vyssh. Uchebn. Dept., Chem. Chem. Technol. 31:45, 1988; Zh. V. Shmyreva, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko and I.E. Pokrovskaya, Zh. Obshch. Chem. 59:1391, 1989.

Introduction of the necessary (substituted) group at position 4 of the dihydroquinoline backbone can be achieved by Friedel-Crafts alkylation of benzene or with compounds of the general structure IV-a-b. This reaction is typically carried out at elevated temperatures either in benzene itself or suitably substituted benzene or in a suitable inert solvent such as heptane or hexane with benzene or suitably substituted benzene as a reagent, catalyzed by a Lewis acid (e.g. AlCl3, AlBr3, FeCl3 or SnCl4). Friedel-Crafts alkylation with 2,2,4-trimethyl-1,2-dihydroquinolines is described in the literature in B.A. Lugovik, L.G. Yudin, S.M. Vinogradova and A.N. Bone, Khim. Heterocycle. Soedin, 7:795, 1971.

Alternatively, anilines of general structure II can be reacted with an appropriately substituted 1-methylstyrene derivative and formaldehyde in acetonitrile at ambient or elevated temperature to give compounds of general structure V-b. The related cyclizations are described in the literature: J.M. Mellor and G.D. Merriman, Tetrahedron, 51:6115,1995.

Compounds of general structure V-a-b can then be nitrated site-selectively at the 6-position of the tetrahydroquinolone backbone to give compounds of general structure VI-a-b. This reaction is typically carried out at temperatures ranging from -10°C to room temperature in dichloromethane using a mixture of nitric acid and acetic anhydride as the nitration reagent. Alternatively, nitric acid can be added to a solution of compounds of general structure V-a-b in glacial acetic acid or to a mixture of acetic acid and dichloromethane. In this connection, according to the place of selective nitration of tetrahydroquinolones, the following are 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 and I.E. Pokrovskaya, Zh. Obshch. Chem. 59:1391, 1989.

Introduction of the necessary (substituted) phenyl group at position 4 of the dihydroquinoline backbone can be achieved by Friedel-Crafts alkylation of benzene or suitably substituted benzene with compounds of general structure IV-a-b. This reaction is typically carried out at elevated temperatures either in pure benzene or suitably substituted benzene or in a suitably inert solvent such as heptane or hexane with benzene or suitably substituted benzene as the reagent, catalyzed by a Lewis acid (e.g. AlCl3, AlBr3, FeCl3 or SnCl4 ). Friedel-Crafts alkylations with 2,2,4-trimethyl-1,2-dihydroquinoline are described in the literature in B.A. Lugovik, L.G. Yudin, S.M. Vinogradova and A.N. Bone, Khim. Heterocycle. Soedin, 7:795, 1971.

Alternatively, anilines of general structure can be reacted with an appropriately substituted 1-methylstyrene derivative and formaldehyde in acetonitrile at ambient or elevated temperature to form compounds of general structure V-b. The respective cyclizations described are described in the literature: J.M. Mellor and G.D. Merriman, Tetrahedron, 51:6115, 1995.

Compounds of general structure V-a-b can then be nitrated site-specifically at the 6-position of the tetrahydroquinoline backbone to give compounds of general structure VI-a-b. This reaction is typically carried out at temperatures ranging from -10°C to room temperature in dihydrochloromethane using a mixture of nitric acid and of acetic anhydride as a nitrating reagent. Alternatively, nitric acid can be added to a solution of compounds of general structure V-a-b in glacial acetic acid and dichloromethane. The respective site-specific nitrations of tetrahydroquinolines are 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 and I.E. Pokrovskaya, Zh. Obshch. Chem. 59:1391, 1989.

Reduction of the nitro group of compounds of the general structure VI-a-b can be achieved by a large number of procedures well known in the art as reduction of aromatic nitro compounds, such as transition metal-catalyzed hydrogenation, treatment with sulfides, treatment with iron or other metals or a mild acid, treatment with tin dichloride in acidic conditions and the like. Specifically, reduction of the nitro group of compounds of general formula VI-a-b can be achieved by treatment with zinc dust and acetic acid in THF or 1,4-dioxane in the temperature range from 0°C to 100°C.

The following 6-N-acylation of compounds of formula VII-a-b can be carried out using standard conditions well known to those skilled in the art to give compounds of general structure I-a-b. For example, compounds of formula VII are reacted in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine with an acyl halide (R 6 -C(O)-Cl) or an acid anhydride (R 6 -C(O)-Cl-(O)-R 6 ) in the presence of a base such as N,N-diisopropylethylamine, triethylamine, pyridine or sodium hydride to give the 6-N-acylated-1,2,3,4-tetrahydroquinoline derivative of formula I-a-b. Alternatively, acylation of compounds of general formula VII-a-b, to give compounds of general formula I-a-b, can be achieved by reaction with a suitable carboxylic acid (R6-CO2H) in the presence of a coupling reagent such as O-(benzotriazol-1-yl)-N ,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or bromotripyrrolidinephosphonium hexafluorophosphate (PyBrOP) and tertiary base, eg N,N-diisopropylethylamine, in a solvent such as N,N-dimethylformamide or dichloromethane at ambient or elevated temperature.

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The compounds of this invention where R3 = H, OH or (1-4C) alkoxy, R4 = OH, R5 = OH or (1-4C) alkoxy and R1, R2 and R6 are as previously described can be prepared by demethylation reactions compounds of the general formula I-c-d. Demethylation reactions of aromatic methyl ethers are well known to those skilled in the art. In a typical experiment, demethylation is carried out when a compound of formula I-c-d is reacted with BBr3 in an inert solvent such as dichloromethane at reduced to ambient temperature to give demethylated compounds of general formula I-e-i. Alternatively, demethylation can be achieved after reaction of compounds of formula I-c-d with a BF3·Me2S complex at ambient temperature. The degree of demethylation can be controlled to some extent by carefully monitoring the reaction temperature and the amount of demethylation reagent. In general, mixtures of mono-, di- and, if relevant, trihydroxy compounds of the general formula I-e-i, which are chromatographically separated. Demethylation reactions generally proceed with a moderate degree of selectivity, with preferential demethylation at position 5 of the tetrahydroquinoline backbone. The reaction rate for demethylation (dealkylation) of compounds of the general formula I-c-d is 5-OMe > 4-(p-OAlk-phenyl) >7-OMe.

The compounds of this invention, where R3 is equal to H or a (functionalized) alkoxy group and R4 and/or R5 are functionalized alkoxy groups or acyloxy groups, can be prepared by realkylation or, respectively, acylation reactions of hydroxyl groups of compounds of the general formula I-e-i with (functionalized) alkyl halides (eg chloroethylpyrrolidine) or acyl halides (eg 2-furoyl chloride or methyl chloroformate) under standard conditions.

The compounds of this invention, wherein R4 = H and R5 is linked to the tetrahydroquinoline backbone via a nitrogen atom and R1, R2 and R6 are as previously defined, can be prepared starting from N-Boc-1,4-phenylene diamine (VIII ). The sequence of reactions (a) Skraup reaction, (b) acetylation, and (c) Friedell-Crafts alkylation of benzene or substituted benzene, as previously described, produces compounds of general formula X-b. It should be noted that the Boc protecting group is cleaved under the reaction conditions of the Friedel-Crafts reaction.

Alternatively, N-Boc-1,4-phenylene diamine can be treated with methyl vinyl ketone, followed by acetylation and the Friedel-Crafts reaction, as previously described, to give compounds of general formula X-b.

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Compounds of general formula X-b can be prepared by a different procedure, starting with partial reduction of 4-methylquinoline (XI) with BH3·THF complex and sodium bis(2-methoxyethoxy)aluminum dihydride to give compound XII. The reduction of related quinolines is described in the literature: see, for example, d. Roberts and 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, and M. W. Moon, J. Med. Chem. 40: 639, 1997. Friedel-Crafts reaction between XII and benzene or suitably substituted benzene gives compounds of general formula XIII, which can be converted to compounds of general formula X-b by site-specific 6-nitration and reduction of the corresponding 6-amino derivative using the conditions described above. Locally specific nitration reactions on similar backbones have been published in the literature, see for example: Zh. V. Shmyreva et al., J. Gen. Chem. USSR (English translation) 59:1234, 1989.

Compounds of general formula X-a-b can then be protected, known in the art with a 9-fluorenylmethyloxycarbonyl group (Fmoc group), see for example: T. W. Greene and P. M. Wuts, Protecting Groups in Organic Synthesis (3rd ed., John Wiley & Sons, Inc., 1999 , see especially p. 506). The above-mentioned protection is conveniently carried out using FmocCl in THF with pyridine as base.

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Site-specific nitration at position 7 of the tetrahydroquinoline backbone of compounds of general formula XVI-a-b, followed by reduction of the nitro group (vide supra), gives the 7-amino-1,2,3,4-tetrahydroquinoline derivative of general formula XV-a-b. Site-specific nitrations on related backbones with similar substitution patterns can be found in the literature; see, for example: S. H. Reich, M. A. M. Fuhry, D. Nguyen, M. J. Pino et al., J. Med. Chem. 35:875, 1992; A. Ivobe, M. Uchida, K. Kamata, Y. Hotei, H. Kusama, H. Harada, Chem. Pharm. Bull. 49:822, 2001. Nitration conditions are similar to those described previously.

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Reductive alkylation of the amino group at position 7 of tetrahydroquinoline derivatives of general formula XV-a-b using suitably substituted aldehydes and a suitable reducing agent (e.g. sodium cyanoborohydride or sodium triacetoxy borohydride) in a suitable solvent such as methanol or N,N-dimethylformamide gives compounds of general formula XVIa -b. In general, formaldehyde leads to the formation of predominantly 7-dimethylamino tetrahydroquinoline derivatives (D = E = Me), while other aldehydes predominantly give monoalkylated compounds of the general formula XVIa-b (D = H, E = (functionalized) alkyl). Reductive alkylations of aromatic amines are well known to those skilled in the art.

Standard cleavage of the Fmoc protecting group using piperidine in dichloromethane yields 6-amino tetrahydroquinoline derivatives of general formula XVII-a-b which can be selectively acylated at the 6-position, as previously described, to form compounds of the present invention of general formula I-j-k.

In another procedure, the amino group at position 7 of tetrahydroquinoline derivatives of general formula XV-a-b can be alylated with (hetero)aryl carboxylic acids (G-CO2H) or acyl chlorides (G-C(O)-cl) as previously described. In subsequent steps, the deprotection-acylation strategy (deprotection with 6-N-Fmoc and acylation to give 6-NH2), previously described, which then leads to the compounds of the present invention of general formula I-l-m.

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Compounds of this invention where R4 = H and R5 is connected to the tetrahydroquinoline backbone via an oxygen atom and R1, R2 and R6 are as defined above can be prepared from 2-methoxy-4-nitroaniline (XVII). The reaction sequence is (a) protection with Fmoc to give XIX, (b) reduction of the nitro group to give XX followed by (c) site-specific Skraup reaction, (d) acetylation, and (e) deprotection of Fmoc, as previously defined, compounds of the general formula XXI are formed.

Compounds of general formula XXI-b can be prepared by treating compound XX with methyl vinyl ketone using the conditions described above for the conversion of compounds of formula II and III-b, followed by 1-N-acetylation and deprotection of Fmoc, as described above.

The subsequent conversion of compounds of general formula XXI to XXIII can be effected by acylation of the 6-amino group using a suitable acylating agent, for example acyl chloride R6-C(O)-Cl, followed by a Fiedel-Crafts reaction with benzene or a suitable benzene derivative using conditions described previously. Under the Lewis acid conditions of the Friedel-Crafts reaction, accompanying demethylation of the 7-OMe group occurs in the compounds of formula XXII. The thus formed free 7-OH in the compounds of general formula XXIII can be realkylated or acylated with (functionalized) alkyl halides (e.g. chloroethylpyridine) or acyl halides (e.g. 2-furoyl chloride or methyl chloroformate), respectively, under standard conditions in order to obtained compounds of the general formula I-n-o (E = functionalized alkyl, acyl or carbamate).

[image]

The compounds of this invention in which R4 and R5 are joined to a nitrogen atom on the tetrahydroquinoline backbone can be prepared from compounds of the general formula XXIV, where PG is a nitrogen protecting group, eg Boc, acetyl, methylcarbamate or Fmoc, via the previously described reactions eg: Skraup reaction or cyclic condensation with methyl vinyl ketone, 1-N-acetylation, cleavage of the protecting group, N-alkylation, Friedel-Crafts reaction, nitration, nitrate reduction and acylation (vide supra).

[image]

Two different regioisomeric products of the general formula XXVI-a and XXVII-a can be formed by the Skraup reaction with acetone or mesityl oxide on the compounds of the general formula XXV. The conversion of the compounds of the general formula XXV using methyl vinyl ketone under the previously described conditions gives the regioisomeric compounds XXVI-b and XXVII -b. In general, these regioisomeric dihydroquinolones can be separated using chromatographic techniques (silica gel, HPLC) or crystallization and can be further converted to the compounds of this invention by the methods previously described.

[image]

The compounds of this invention where R 5 = H can be prepared by reductive 7-deoxygenation of compounds of general formula XXVIII or XXXI (L and/or M is a suitable (substituted) alkyl, acyl alkyloxycarbonyl or alkylaminocarbonyl) via selective 7-O-triflation followed by reduction of 7-OTf (Tf = trifluoromethylsulfonyl) group. The required compounds of general formula XXXI can be obtained from derivatives of general formula XXVII using the previously described conditions. The (site-specific) triflation reaction can be effected under controlled conditions using Tf2N-phenyl and N,N-diisopropylethyl amine in DMF at room temperature. In general, triflation of the 7-OH group occurs preferentially. The reduction, which follows, can be achieved using a mixture of triphenyl phosphine, triethyl amine, formic acid and palladium (II) acetate, as described in the literature. See, e.g., K. A. Parker, Q. Ding, Tetrahedron 56:10249, 2000. Conversion of the thus obtained compounds of general formula XXX or XXXII using the conditions described above which then results in compounds of general formula I-p-q wherein R5 = H.

Some of the compounds of the invention, which may be in free base form, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. A pharmaceutically acceptable salt can also be obtained by treating the free base of formula I with an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.

The compounds of this invention have at least one chiral carbon atom and can therefore be obtained as pure enantiomers, or as a mixture of enantiomers, or as a mixture of diastereomers. Procedures for obtaining pure enantiomers are well known in the art, eg crystallization of salts obtained from optically active acids and racemic mixtures, or chromatography using chiral columns. Direct phase or reverse phase columns can be used for diastereoisomers.

The compounds of this invention may form hydrates or solvates. Those skilled in the art are aware that charged compounds form hydrated forms when lyophilized with water, or form solvated forms when concentrated in solution with a suitable organic solvent. The compounds of this invention also include hydrates or solvates of said compounds.

In order to select active compounds, testing at 10-5 M should show activity greater than 20% of maximal activity when FSH is used as reference. Another criterion can be the EC50 value, which must be < 10-5 M, preferably < 10-7 M.

One skilled in the art will recognize that the preferred EC50 value depends on the compound being tested. For example, a compound with an EC50 value of less than 10-5 M is generally considered a drug candidate. Preferably, this value is lower than 10-7 M. However, a compound that has a higher EC50 but is selective for a particular receptor may be an even better candidate.

Methods for determining receptor binding, both in vitro and in vivo assays to determine biological activity, for gonadotropins are well known. Generally, the expressed receptor is contacted with a test compound and binding or stimulation or inhibition of a functional response is measured.

In order to measure the functional response, the isolated DNA encoding the gene for the FSH receptor, preferably the human receptor, is expressed in suitable host cells. Such a cell can be a Chinese hamster ovary cell, but other cells are also suitable. Cells of mammalian origin are preferred (Jia et al. Mol. Endocrin., 5:759-776, 1991).

Procedures for the construction of recombinant FSH-expressing cells 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 the expression of DNA that codes for the desired protein. Techniques for site-specific mutagenesis, ligation of additional sequences, PCR, or construction of suitable systems are, by now, all well known in the art. Portions, or all, of the DNA encoding the desired protein can be constructed synthetically using standard solid phase techniques, preferably containing restriction sites to facilitate ligation.

For DNA coding sequences, suitable control elements for transcription and translation of the embedded coding sequence can be provided. As is well known, there are no expression systems that are compatible with the vast majority of hosts, including prokaryotic cells such as bacteria and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, avian cells and the like.

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

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

Radiolabeled or fluorescently labeled compounds can be used to measure binding. Competition binding assays can also be performed.

Another test involves screening for FSH receptor agonist compounds by determining receptor-mediated stimulation of cAMP accumulation. Therefore, this method involves expressing the receptor on the surface of a host cell and exposing the cell to the compound being tested. Then the amount of cAMP is measured. The level of cAMP can be decreased or increased depending on the inhibitory or stimulatory effect of the tested compound after binding to the receptor.

Screening for FSH receptor antagonists involves incubating cells expressing the FSH receptor with a range of concentrations of test compound in the presence of FSH at a fixed, submaximal effective concentration (ie, the concentration of FSH that induces approximately 80% of the maximal stimulation of cAMP accumulation in the absence of test compound). For each of the tested compounds, IC50 values and percent inhibition of FSH-induced cAMP accumulation can be determined from the concentration-effect curves.

In addition to direct measurement of, for example, the level of cAMP in exposed cells, cell lines can also be used in which, along with the transfection of the DNA that codes for the receptor, transfection with another DNA, which codes for the gene reporter for the expression corresponding to the level of cAMP, was also carried out. Such reporter genes may be inducible with cAMP or may be engineered in such a way that they are linked to novel cAMP-responsive elements. In general, reporter gene expression can be controlled by the response of any element that responds to changes in cAMP levels. Suitable reporter genes are, for example, genes encoding ß-galactosidase, alkaline phosphatase, firefly luciferase and green fluorescent protein. The principles of such transactivation assays are well known in the art and are described in, e.g., Stratowa, Ch., Himmler, A. and Czernilofsky A. P., (1995) Curr. Opin. Biotechnol. 6:574. Human recombinant FSH can be used as a reference compound. Alternatively, a competition test can be conducted.

This invention also relates to pharmaceutical preparations containing tetrahydroquinoline derivatives or their pharmaceutically acceptable salts of the general formula I in admixture with pharmaceutically acceptable excipients and possibly other therapeutic agents. Excipients must be "acceptable" in the sense that they are compatible with other ingredients of the preparation and that they are not harmful to their recipients.

Formulations include, for example, those suitable for oral sublingual, subcutaneous, intravenous, intramuscular, topical or rectal administration, and the like, all in unit dosage form for administration.

For oral administration, the active ingredient can be in separate units, such as tablets, capsules, powders, granules, solutions, suspensions or the like.

For parenteral administration, the pharmaceutical composition of the invention can be in a unit-dose or multiple-dose container, e.g. liquid for injection in a predetermined amount, e.g. sealed vials or ampoules, and can also be stored in a freeze-dried (lyophilized) form. which only requires the addition of a sterile liquid vehicle, eg water, before use.

Mixing with such pharmaceutically acceptable excipients, for example, is described in the standard reference, Genaro, A.R. et al. Remington: The Science and Practice of Pharmacy (20th ed., Lippincott Williams & Williams, 2000, see especially Part 5: Pharmaceutical Manufacturing), the active ingredient can be compressed into solid dosage units, such as pills, tablets, or can be processed in capsules or suppositories. Using pharmaceutically acceptable liquids, the active ingredient can be administered as a liquid preparation, eg as an injectable preparation, in the form of a solution, suspension or emulsion, or as a spray, eg as a nasal spray.

For the preparation of solid unit dosages, the use of conventional additives such as fillers, dyes, polymer binders and the like is foreseen. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compound can be used. Suitable carriers, with which the active agent of the invention can be administered as a solid preparation, include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injectable solutions are used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.

The invention further includes pharmaceutical compositions, as previously described herein, in combination with packaging material suitable for said compositions, said packaging material including instructions for use of the composition for the purpose as previously described herein.

The tetrahydroquinoline derivatives of the invention can also be applied in the form of pharmaceutical devices for implantation, which consist of an active material in the core, surrounded by a membrane for regulating the release. Such implants are for subcutaneous or topical administration and release the active ingredient at an approximately constant rate over a relatively long period of time, for example weeks to years. Processes for the preparation of pharmaceutical devices for implantation as such are known in the art, as for example described in European Patent 0,303,306 (AKZO Nobel N.V.).

The exact dose and administration regimen of the active ingredient, or its pharmaceutical preparation, necessarily depends on the therapeutic effect to be achieved (infertility treatment; contraception) and may vary in relation to the individual compound, method of administration, age and condition of the individual subject to whom the medication is administered.

In general, parenteral administration requires lower doses compared to other routes of administration that depend more on absorption. However, dosing in humans is preferably 0.0001-25 mg per kg of body weight. The desired dose may be formulated as a single dose or as multiple doses administered at convenient intervals throughout the day, or in the case of female recipients, as doses to be administered at convenient daily intervals during the menstrual cycle. The dosage as well as the administration regimen may differ between female and male recipients.

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

A further aspect of the invention resides in the use of a compound, a tetrahydroquinolone derivative of general formula I for the manufacture of a medicament for use in the treatment of disorders responsive to FSH receptor mediated pathways. Therefore, suitable amounts of the compounds of the invention can be administered to patients in need thereof.

Another aspect of the invention consists in the use of a compound, a tetrahydroquinolone derivative of the general formula I for the production of a medicament to be used for fertility control.

Another aspect of the invention consists in the use of the compound, a tetrahydroquinolone derivative of the general formula I for the production of a medicament to be used for the treatment of infertility.

Another different aspect of the invention consists in the use of the compound, a tetrahydroquinolone derivative of the general formula I for the manufacture of a medicament to be used for the prevention of conception.

The compounds of the invention can also be used to treat hormone-dependent disorders such as breast cancer, prostate cancer and endometriosis.

The invention is illustrated by the following examples.

EXAMPLES:

General remarks:

The following abbreviations are used in the examples: DMA = N,N-dimethylaniline, DIPEA = N,N-diisopropylethylamine, TFA = trifluoroacetic acid, DtBAD = di-tert-butyl azodicarboxylate, HATU = O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate, Fmoc = 9-fluorenylmethoxycarbonyl, Fmoc-Cl = 9-fluorenylmethoxycarbonylchloride, DMF = N,N-dimethylformamide, DMAP = 4-dimethylaminopyridine, THF = tetrahydrofuran.

Unless otherwise indicated, all final products of the following examples are lyophilized with water/1,4-dioxane or water/acetonitrile mixtures. If the compound is prepared as an HCl or TFA salt, the appropriate amino acids are added in appropriate amounts to the solvent mixtures prior to lyophilization.

The names of the final products described in the examples are generated by the Beilstein Autonom program (version 2.02.119).

The following analytical HPLC methods are used to determine retention times:

Method 1: Column: 5 µm Luna C-18(2) 150 x 4.6 mm; flow rate: 1 ml/min; detection 210 nm; column temperature: 40°C; solvent A: CH3CN/H2O = 1/9 (volume/volume); solvent B: CH3CN; solvent C: 0.1 M aqueous trifluoroacetic acid; gradient: solvent A/B/C = 65/30/5 to 10/85/5 (volume/volume/volume) in 30.00 min, then constant for an additional 10.00 min at A/B/C = 10/ 85/5 (volume/volume/volume).

Method 2: Identical to Method 1, except using a gradient: Gradient: Solvent A/B/C = 75/20/5 to 15/80/5 (vol/vol/vol) in 30.00 min, then constant additional 10 .00 min at A/B/C = 15/80/5 (volume/volume/volume).

Method 3: Identical to Method 1, except using a gradient: Gradient: solvent A/B/C = 35/60/5 to 10/85/5 (vol/vol/vol) in 30.00 min, then constant additional 10 .00 min at A/B/C = 10/85/5 (volume/volume/volume).

Method 4: Column: 3 µm Luna C-18(2) 100x2 mm; flow rate: 0.25 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: H2O; solvent B: CH3CN; gradient: solvent A/B = 75/25 to 0/100 (volume/volume) in 20.00 min, then constant additional 10.00 min at A/B/C 10/80/10 (volume/volume/volume) .

Method 5: Column: 3 µm Luna C-18(2) 100x2 mm; flow rate: 0.25 ml/min; detection: 210 nm; column temperature: 40°C; solvent A: H2O; solvent B: CH3CN; solvent C: 50 nm phosphate buffer, pH 2.1; gradient: solvent A/B/C = 70/20/10 to 10/80/10 (volume/volume/volume) in 20.00 min, then constant additional 10.00 min at A/B/C 10/80/ 10 (volume/volume/volume).

Method 6: Identical to Method 5, except using a gradient: Gradient: Solvent A/B/C = 65/30/5 to 10/85/5 (vol/vol/vol) in 20.00 min, then constant additional 10 .00 min at A/B/C 10/85/5 (volume/volume/volume).

The following methods are used for preparative HPLC purifications:

Method A: Column = Luna C-18. Gradient: 0.1% trifluoroacetic acid H2O/CN3CN (9/1, vol/vol)/CH3CN = 80/20 to 0/100 (vol/vol) in 30-45 min, depending on ease of separation. Detection: 210 nm.

Method B: Column = Luna C-18. Gradient: H2O/CN3CN (9/1, v/v)/CH3CN = 80/20 to 0/100 (v/v) in 30-45 min, depending on ease of separation. Detection: 210 nm.

Example 1

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

(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 a mixture of MgSO4 (100 g) and Sc(OTf)3 (8.0 g) in 1 L of acetone at room temperature. After 5 hours, a second portion of Sc(OTf)3 (3.2 g) is added and the reaction mixture is stirred until starting material is present. After filtration, the acetone is partially evaporated in vacuo causing crystallization of the title compound which is collected by filtration in a yield of 22 g after drying in vacuo. The remaining mother liquor was concentrated in vacuo and the residue purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent to give an additional 19.4 g of the title compound.

Yield: 42 g.

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

A mixture of the compounds 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 while stirring. The precipitated solid is collected by filtration and dried in vacuo for 2 days. The remaining brown solid can be used as raw material for further synthetic transformations.

Yield: 45 g.

(c) 1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline

A mixture of the compounds described in example 1b (30 g9 and AlCl3 (44 g) in anisole (500 ml) was stirred at 50°C for 18 hours. The reaction mixture was cooled (0°C) and quenched with water and ethyl acetate was added. The mixture was stirred overnight. The organic layer was separated, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed on silica gel using heptane/ethyl acetate = 8/2 (v/v) as eluent.

Yield: 15 g.

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

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

Yield: 10 g.

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

A solution of the compound described in Example 1d (11.75 g) and acetic acid (15.5 ml) in THF (600 ml) was cooled to 0 °C. Zinc dust (36 g) is added in portions and the ice bath is removed. The temperature is rapidly raised to 30°C, after which the reaction mixture is allowed to cool to room temperature. Excess zinc is removed by filtration and CH2Cl2 and saturated Na2CO3 solution are added to the filtrate. The organic layer is separated, dried over MgSO4, filtered and concentrated in vacuo. The product is used as raw material in the next step.

Yield: 10.9 g

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

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) was added HATU (143 mg) at room temperature. If the reaction is not complete after 18 hours, more HATU and DIPEA are added. After completion of the reaction, saturated aqueous NaHCO3 solution is added, the organic layer is separated, dried (MgSO4) and concentrated in vacuo. The title compound is purified by preparative HPLC (method A).

Yield: 87 mg. MS-ESI: [M + H] + = 597.4; HPLC: Rt = 17.98 min (method 1)

Example 2

4,5-Dimethyl-furan-2-carboxylic acid [1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro -quinolin-6-yl]-amide

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) was added HATU (1.1 g ) at room temperature. If the reaction is not complete after 18 hours, the reaction mixture is heated to 50 °C. After completion of the reaction, water and ethyl acetate are added, the organic strain is separated, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (volume/volume) as eluent.

Yield: 444 mg. MS-ESI: [M + H] + = 521.4; HPLC: Rt = 16.96 min (method 1)

Example 3

5-Bromo-thiophene-2-carboxylic acid [1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline -6-yl]-amide

According to general procedure B, the compound described in Example 1e (800 mg) is acylated with 5-bromothiophene-2-carboxylic acid (456 mg), DMA (768 µl) and HATU (1.1 g) in CH 2 Cl 2 (10 ml). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 1.0 g MS-ESI: [M + H] + = 589.2; HPLC: Rt = 18.90 min (method 2)

Example 4

Biphenyl-4-carboxylic acid [1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl ]-amide

General Procedure C: To a solution of the compound described in Example 1e (800 mg) and 4-biphenylcarbonyl chloride (475 mg) in CH 2 Cl 2 (10 ml) was added DMA (768 µl) at room temperature. The reaction mixture is stirred until the starting material is present and then water is added. The organic layer is separated, dried (MgSO4) and concentrated in vacuo. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 678 mg. MS-ESI: [M + H] + = 579.4; HPLC: Rt = 26.19 min (method 2)

Example 5

Furan-2-carboxylic acid [1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6 -yl]-amide

(a) Furan-2-carboxylic acid [1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline- 6-yl]-amide

According to general procedure C, the compound described in Example 1e (800 mg) is acylated with 2-furoyl chloride (217 µl) and DMA (768 µl) in CH 2 Cl 2 (10 ml). The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 896 mg

(b) Furan-2-carboxylic acid [1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline- 6-yl]-amide

General Procedure D: A solution of the compound described in Example 5a (50 mg) in CH 2 Cl 2 (4 ml) was cooled to -78 °C under a nitrogen atmosphere. Boron tribromide (28 µl) was added dropwise and after completion of the reaction, the reaction mixture was slowly warmed to room temperature. The reaction is then cooled with water and CH2Cl2 is added. The organic layer is separated, dried (MgSO4) and concentrated in vacuo. The title compound is purified by preparative HPLC (method A). Under the conditions described above, mixtures of compounds with different degrees of demethylation are generally formed, which can be separated by preparative HPLC methods.

Yield: 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-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]- 3,5-dichloro-benzamide

(a) N-[1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl] -3,5-dichloro-benzamide

According to general procedure C, the compound described in example 1e (800 mg) is acylated with 3,5-dichlorobenzoyl chloride (460 mg) and DMA (768 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 1.03 g

(b) N-[1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6- yl]-3,5-dichloro-benzamide

According to general procedure D, the compound described in Example 6a (50 mg) is treated with boron tribromide (24 µl) in CH 2 Cl 2 (4 ml). The title compound is purified by preparative HPLC (method A).

Yield: 9.6 mg. MS-ESI: [M + H] + = 557.2; HPLC: Rt = 23.40 min (method 2)

Example 7

5-chloro-thiophene-2-carboxylic acid [1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro -quinolin-6-yl]-amide

(a) 5-chloro-thiophene-2-carboxylic acid [1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4- tetrahydro-quinolin-6-yl]-amide

According to general procedure B, the compound described in Example 1e (800 mg) is acylated with 5-chlorothiopene-2-carboxylic acid (456 mg), DMA (768 µl) and HATU (1.1 g) in CH 2 Cl 2 (10 ml). The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield. 1.0 g

(b) 5-chloro-thiophene-2-carboxylic acid [1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3, 4-tetrahydro-quinolin-6-yl]-amide

According to general procedure D, the compound described in example 7a (200 mg) is treated with boron tribromide (350 µl) in CH 2 Cl 2 (25 ml) but without allowing the temperature to exceed -30 °C. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent, followed by preparative HPLC (method A).

Yield: 35 mg. MS-ESI: [M + H] + = 529.2; HPLC: Rt = 28.24 min (method 2)

Example 8

Biphenyl-4-carboxylic acid [1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6 -yl]-amide

According to general procedure D, the compound described in Example 4 (50 mg) is treated with boron tribromide (100 µl) in CH 2 Cl 2 (4 ml), but in this case the temperature is not allowed to exceed 0 °C. The reaction mixture also contains the products described in Example 10. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 43 mg. MS-ESI: [M + H] + = 565.4; HPLC: Rt = 32.53 min (method 2)

Example 9

Biphenyl-4-carboxylic acid [1-acetyl-5,7-dihydroxy-4-(4-hydroxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl ]-amide

According to general procedure D, the compound described in Example 4 (50 mg) is treated with boron tribromide (100 µl) in CH 2 Cl 2 (4 ml), but in this case the temperature is allowed to exceed 15 °C. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 33 mg. MS-ESI: [M + H] + = 537.4; HPLC: Rt = 24.16 min (method 2)

Example 10

Biphenyl-4-carboxylic acid [1-acetyl-5-hydroxy-4-(4-hydroxy-phenyl)-7-methoxy-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6 -yl]-amide

According to general procedure D, the compound described in Example 4 (50 mg) is treated with boron tribromide (800 µl) in CH 2 Cl 2 (25 ml), but in this case the temperature is not allowed to exceed 0 °C. The title compound (= by-product described in example 8) is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 50 mg. MS-ESI: [M + H] + = 551.4; HPLC: Rt = 27.58 min (method 2)

Example 11

4,5-Dimethyl-furan-2-carboxylic acid [1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4 -tetrahydro-quinolin-6-yl]-amide

According to general procedure D, the compound described in example 2 (200 mg) is treated with boron tribromide (336 µl) in CH 2 Cl 2 (25 ml) but in this case the temperature is kept at -78 °C. The title compound is purified by 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-hydroxy-phenyl)-7-methoxy-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]- 3,5-dichloro-benzamide

According to general procedure D, the compound described in example 6a (75 mg) is treated with boron tribromide (38 µl) in CH 2 Cl 2 (5 ml). The title compound is purified by preparative HPLC (method A).

Yield: 11 mg. MS-ESI: [M + H] + = 543.4; HPLC: Rt = 25.66 min (method 2)

Example 13

N-[1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]- 3,5-dimethyl-benzamide

(a) N-[1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl] -3,5-dimethyl-benzamide

According to general procedure B, the compound described in example 1e (800 mg) is acylated with 3,5-dimethylbenzoic acid (330 mg), DMA (768 µl) and HATU (1.1 g) in CH 2 Cl 2 (10 ml). The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield 1.18 g

(b) N-[1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6- yl]-3,5-dimethyl-benzamide

According to general procedure D, the compound described in Example 13a (300 mg) is treated with boron tribromide (513 µl) in CH 2 Cl 2 (25 ml) but in this case the temperature is not allowed to exceed -40 °C. The title compound is purified by 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-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]- 3,5-dimethyl-benzamide

(a) N-[1-acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl] -3,5-dimethyl-benzamide

According to general procedure B, the compound described in example 1e (800 mg) is acylated with 3,5-dimethylbenzoic acid (616 mg), DMA (768 µl) and HATU (1.1 g) in DMF (10 ml). The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 900 mg

(b) N-[1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6- yl]-3,5-dimethyl-benzamide

According to general procedure D, the compound described in Example 14a (300 mg) is treated with boron tribromide (639 µl) in CH 2 Cl 2 (25 ml) but in this case the temperature is not allowed to exceed -60 °C. The title compound is purified by preparative HPLC (method A).

Yield: 28 mg. MS-ESI: [M + H] + = 647.2; HPLC: Rt = 16.29 min (method 3)

Example 15

Biphenyl-4-carboxylic acid [1-acetyl-2,2,4-trimethyl-(2-morpholin-4-yl-ethoxy)-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl ]-amide

(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) was cooled to 0 °C. FmocCl (5.07 g) was added in portions and after the addition was complete, the ice bath was removed and the mixture was stirred for 5 hours. The THF was removed in vacuo and the residue was dissolved in CH2Cl2 (175 mL). Methanol (ca. 100 mL) was added and the CH 2 Cl 2 was partially removed in vacuo until a precipitate formed. The mixture was allowed to stand for one hour, after which the crystals were collected by filtration and dried in vacuo to give the title compound.

Yield: 6.32 g MS-ESI: [M + H] + = 391.2

(b) 9-Fluoroenylmethyl N-(2-methoxy-4-aminophenyl)carbamate

General Procedure E: A mixture of the compound described in Example 15a (6.07 g), acetic acid (8.9 ml) and THF (150 ml) was cooled to 0°C. Zinc dust (20.4 g) was added in portions and the water bath was removed. After the temperature slowly reaches 10 °C, it quickly reaches 45 °C. After the reaction mixture is allowed to cool to room temperature, excess zinc is removed by filtration and a large amount of CH 2 Cl 2 (approximately 500 ml) is added. The mixture was washed with saturated aqueous NaHCO3 (3 x 200 ml) and brine (1 x 200 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo until a precipitate formed. The mixture was left overnight at 0 °C, after which the crystals were collected by filtration and dried in vacuo to give the title compound.

Yield: 4.45 g

(c) (7-Methoxy-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-carbamic acid 9H-fluoren-9-yl methyl ester

A mixture of the compounds described in example 15b (4.45 g); I 2 (157 mg), MgSO 4 (7.4 g), 4-tert-butylcatechol (61 mg) and acetone (approx. 350 ml) were heated at reflux for 5 hours. MgSO4 is removed by filtration and the filtrate is concentrated in vacuo. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as eluent.

Yield: 4.24 g

(d) (1-Acetyl7-methoxy-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester

To a solution of the compound described in Example 15c (4.24 g) in pyridine (25 ml) and CH 2 Cl 2 (25 ml) was added a small amount of DMAP (approximately 20 mg). Acetyl chloride is slowly added to CH2Cl2 (20 ml). After complete addition, the mixture was diluted with CH2Cl2 (100 ml) and washed with water (3 x 100 ml), 0.1 M aqueous HCl (3 x 100 ml), 0.5 M aqueous HCl (1 x 100 ml) and sat. saline solution (1 x 100 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as eluent.

Yield: 3.91 g

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

To a solution of the compound described in Example 15 d (3.91 g) in CH 2 Cl 2 (80 ml), piperidine (8.0 ml) was added. After 1.5 hours; the reaction mixture is concentrated in vacuo and the title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as eluent.

Yield: 2.2 g

(f) Biphenyl-4-carboxylic acid (1-acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydro-quinolin-6-yl)-amide

General procedure F: To a mixture of the compound described in example 15 e (2.2 g); 4-biphenylcarbonyl chloride (2.21 g) was added to toluene (45 ml) and pyridine (5 ml). If the reaction is not complete after 3 hours at room temperature, additional 4-biphenylcarbonyl chloride (2.0 g) is added. Stirring was continued for 30 minutes, after which the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (ca 100 ml) and washed with saturated NaHCO 3 (100 ml), 1M aqueous HCl (3 x 100 ml) and saturated brine (100 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. CH2Cl2 (about 50 ml) is added to the residue and the solid is removed by filtration and discarded. The filtrate was concentrated in vacuo and the title compound was obtained by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 3.1 g

(g) Biphenyl-4-carboxylic acid (1-acetyl-7-hydroxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

General procedure G: To a solution of the compound described in Example 15f (3.1 g) in benzene (100 ml) was added aluminum trichloride (5.6 g) and the reaction mixture was stirred for 20 hours at room temperature. The reaction was quenched with H 2 O (ca 100 ml) and the pH of the mixture was adjusted to pH 8 with 2M aqueous NaOH, with vigorous stirring. Ethyl acetate (ca. 300 ml) was added and the organic layer was washed with H 2 O (2 x 150 ml) and brine (1 x 150 ml), dried (MgSO 4 ) and concentrated in vacuo without further purification.

Yield: 3.5 g

(h) Biphenyl-4-carboxylic acid [1-acetyl-2,2,4-trimethyl-(2-morpholin-4-yl-ethoxy)-4-phenyl-1,2,3,4-tetrahydro-quinoline- 6-yl]-amide

General Procedure H: A mixture of the compound described in Example 15 g (70 mg), N-(2-chloroethyl)-morpholine hydrochloride (31 mg), Cs2CO3 and DMF (3 ml) is stirred at 50°C until an initial material. The reaction mixture was diluted with ethyl acetate (15 ml) and water (ca. 15 ml) was added. The organic layer was washed with water (3 x 15 ml), separated, dried (MgSO4), filtered and concentrated in vacuo. The title compound is obtained as the corresponding HCl salt by lyophilization from a mixture of 1,4-dioxane and H2O containing HCl.

Yield: 63 mg (HCl salt); MS-ESI: [M + H] + = 618.6; HPLC: Rt = 19.49 min (method 4)

Example 16

Biphenyl-4-carboxylic acid (1-acetyl-7-dimethylcarbamoylmethoxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to general procedure H, the compound described in example 15 g (79 mg) is alkylated with 2-chloro-N,N-dimethylacetamide (23 mg) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound was purified by crystallization from CH3CN.

Yield: 15 mg. MS-ESI: [M + H] + = 590.6; HPLC: Rt = 23.58 min (method 5)

Example 17

Biphenyl-4-carboxylic acid [1-acetyl-2,2,4-trimethyl-4-phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-quinoline-6 -yl]-amide

According to general procedure H, the compound described in example 15 g (79 mg) is acylated with N-(3-chloropropyl)piperidine hydrochloride (37.4 mg) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound was 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

Biphenyl-4-carboxylic acid [1-acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridin-2-yl-methoxy)-1,2,3,4-tetrahydro-quinolin-6-yl ]-amide

According to general procedure H, the compound described in example 15 g (79 mg) is alkylated with 2-picolyl chloride hydrochloride (31 mg) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound was 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

Biphenyl-4-carboxylic acid [1-acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridin-3-yl-methoxy)-1,2,3,4-tetrahydro-quinolin-6-yl ]-amide

According to general procedure H, the compound described in example 15 g (79 mg) is alkylated with 2-picolyl chloride hydrochloride (31 mg) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound was 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

Biphenyl-4-carboxylic acid [1-acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridin-4-yl-methoxy)-1,2,3,4-tetrahydro-quinolin-6-yl ]-amide

According to general procedure H, the compound described in example 15 g (79 mg) is alkylated with 2-picolyl chloride hydrochloride (31 mg) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound was 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

Biphenyl-4-carboxylic acid [1-acetyl-7-(2-dimethylamino-ethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl]- amide

According to general procedure H, the compound described in example 15 g (79 mg) is alkylated with 2-picolyl chloride hydrochloride (31 mg) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound was purified by crystallization from CH3CN.

Yield: 55 mg. MS-ESI: [M + H] + = 576.6; HPLC: Rt = 14.95 min (method 5)

Example 22

Biphenyl-4-carboxylic acid (1-acetyl-7-carbamoylmethoxy-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to general procedure H, the compound described in example 15 g (79 mg) is alkylated with 2-chloroacetamide (18 mg) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound is purified by preparative HPLC (method A).

Yield: 60.2 mg. MS-ESI: [M + H] + = 562.4; HPLC: Rt = 20.47 min (method 5)

Example 23

Morpholine-4-carboxylic acid (3-{1-acetyl-6-[(biphenyl-4-carbonyl)amino]-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinoline -7-yloxy}-propyl)-amide

According to general procedure H, the compound described in example 15 g (79 mg) is alkylated with morpholine-4-carboxylic acid (3-chloropropyl)amide (40 g) and Cs 2 CO 3 (225 mg) in DMF (2 ml). The title compound is purified by preparative HPLC (method A).

Yield: 52.4 mg. MS-ESI: [M + H] + = 675.6; HPLC: Rt = 22.31 min (method 5)

Example 24

Furan-2-carboxylic acid 1-acetyl-6-(3,5-dibromo-benzoylamino)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl ester

(a) N-(1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-3,5-dibromo-benzamide

According to general procedure F, the compound described in Example 15e (1.0 g) is acylated with 3,5-dibromobenzoyl chloride (1.72 g) in toluene (9 ml) and pyridine (1 ml). The title compound is obtained by chromatography on silica gel using heptane/ethyl acetate = 8/2 (v/v) as eluent.

Yield 1.3 g

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

According to general procedure G, the compound described in Example 24a (1.3 g) was mixed with AlCl 3 (1.0 g) in benzene (50 ml). The resulting compound is used without further purification.

Yield 1.39 g

(c) Furan-2-carboxylic acid 1-acetyl-6-(3,5-dibromo-benzoylamino)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinoline-7 -yl ester

A mixture of the compounds described in Example 24b (100 mg), furoyl chloride (16 µl) and DIPEA (60 µl) and CH2Cl2 (5 ml) was stirred at room temperature while the starting material was present. Water was added and the organic layer was separated, washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The title compound is purified by 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-amino-ethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]-3,5-dibromo- benzamide

General Procedure I: A mixture of the compounds described in Example 24b (100 mg), tert-butyl N-(2-hydroxyethyl)carbamate (29 mg), DtBAD (79 mg), DIPEA (60 µl) and an excess of triphenylphosphine-linked polymer in CH2Cl2 (5 ml) is stirred at room temperature as long as the starting material is present. The reaction mixture is filtered and washed with water and saturated brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The crude product was taken up in CH3CN (ca. 1 ml) and a few drops of TFA were added to facilitate cleavage of the tert-butylcarbamate. The title compound is purified by preparative HPLC (method A).

Yield: 17 mg (TFA salt). MS-ESI: [M + H] + = 630.2; HPLC: Rt = 15.6 min (method 2)

Example 26

{2-[1-Acetyl-6-(3,5-dimethyl-benzoylamino)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-7-yloxy]-ethyl}- carbamic acid tert-butyl ester

(a) N-(1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-3,5-dimethyl-benzamide

According to general procedure F, the compound described in Example 15e (1.0 g) is acylated with 3,5-dibromobenzoyl chloride (0.97 g) in toluene (9 ml) and pyridine (1 ml). The title compound is obtained by chromatography on silica gel using heptane/ethyl acetate = 8/2 (v/v) as eluent.

Yield 1.1 g

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

According to general procedure G, the compound described in Example 26a (1.1 g) was mixed with AlCl 3 (1.0 g) in benzene (50 ml). The resulting compound is used without further purification.

Yield 1.3 g

(c) {2-[1-Acetyl-6-(3,5-dimethyl-benzoylamino)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-7-yloxy]- ethyl}-carbamic acid tert-butyl ester

According to general procedure I, the compound described in Example 26b (100 mg) is alkylated with 2-(hydroxymethyl)furan (21 µl), DtBAD (101 mg), DIPEA (77 µl) and an excess of triphenylphosphine-linked polymer in CH2Cl2 (5 ml ). In this case, tert-butylcarbamate is not cleaved, giving the title product after preparative HPLC (method A) and lyophilization.

Yield: 38 mg. MS-ESI: [M + H] + = 600.4; HPLC: Rt = 33.1 min (method 2)

Example 27

N-[1-Acetyl-7-(furan-2-ylmethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]-3,5-dimethyl- benzamide

According to general procedure I, the compound described in Example 26b (100 mg) is alkylated with 2-(hydroxymethyl)furan (21 µl), DtBAD (101 mg), DIPEA (77 µl) and an excess of triphenylphosphine-linked polymer in CH2Cl2 (5 ml ). The title product is purified by preparative HPLC (method A), followed by lyophilization.

Yield: 16 mg. MS-ESI: [M + H] + = 537.4; HPLC: Rt = 32.8 min (method 2)

Example 28

N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridin-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-6-yl]-3,5-dichloro- benzamide

(a) N-(1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-3,5-dichloro-benzamide

According to general procedure F, the compound described in Example 15e (1.0 g) is acylated with 3,5-dichlorobenzoyl chloride (1.2 g) in toluene (9 ml) and pyridine (1 ml). The title compound is obtained by chromatography on silica gel using heptane/ethyl acetate = (/2 (v/v) as eluent.

Yield 1.47 g

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

According to general procedure G, the compound described in Example 28a (1.47 g) was mixed with AlCl 3 (1.5 g) in benzene (75 ml). The resulting compound is used without further purification.

Yield 1.51 g

(c) N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridin-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-6-yl]-3,5 -dichloro-benzamide

According to general procedure H, the compound described in example 28b (100 mg) is alkylated with 4-picolyl chloride hydrochloride (36 mg) and Cs 2 CO 3 (225 mg) in a mixture of DMF (1 ml) and CH 2 Cl 2 (4 ml). The title compound is obtained as the corresponding TFA salt after preparative HPLC (method A), followed by lyophilization.

Yield: 35 mg (TFA 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-yl-ethoxy)-1,2,3,4-tetrahydroquinolin-6-yl]-3, 5-dimethyl-benzamide

General Procedure: A mixture of the compounds described in Example 26b (100 mg), 2-chloroethylpyrrolidine hydrochloride (41 mg) and DIPEA (77 µl) in CH2Cl2 (5 ml) is stirred at room temperature while the starting material is present. Water was added and the organic strain was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by preparative HPLC followed by lyophilization gives the title compound as the corresponding TFA salt.

Yield: 104 mg (TFA salt). MS-ESI: [M + H] + = 554.4; HPLC: Rt = 15.2 min (method 2)

Example 30

N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(5-methyl-isoxazol-3-ylmethoxy)-4-phenyl-1,2,3,4-tetrahydro-quinoline-6 -yl]-3,5-dimethyl-benzamide

According to general procedure J, the compound described in example 26b (100 mg) is alkylated with (chloromethyl)-5-methylisoxazole (32 mg), and DIPEA (77 µl) in CH 2 Cl 2 (5 ml). Purification by preparative HPLC (Method A) followed by lyophilization gives the title compound.

Yield: 41 mg. MS-ESI: [M + H] + = 552.4; HPLC: Rt = 31.3 min (method 2)

Example 31

N-[1-Acetyl-7-(2-diethylamino-ethoxy)-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl]-3,5-dimethyl- benzamide; compound with trifluoroacetic acid

According to general procedure J, the compound described in example 26b (100 mg) is alkylated with N,N-diethylaminoethyl chloride hydrochloride (42 mg), and DIPEA (77 µl) in CH 2 Cl 2 (5 ml). Purification by preparative HPLC (Method A), followed by lyophilization affords the title compound as the corresponding TFA salt.

Yield: 43 mg (TFA salt). MS-ESI: [M + H] + = 556.4; HPLC: Rt = 15.2 min (method 2)

Example 32

N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridin-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-6-yl]-5-bromo-2- methylamino-benzamide

(a) N-(1-Acetyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-5-bromo-2-methylamino-benzamide

According to general procedure F, the compound described in Example 15e (1.0 g) is acylated with 5-bromo-2-methylamino-bezoyl chloride (1.43 g) in toluene (9 ml) and pyridine (1 ml). The title compound is obtained by chromatography on silica gel using heptane/ethyl acetate = 8/2 (v/v) as eluent.

Yield: 595 mg

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

According to general procedure G, the compound described in Example 32a (597 mg) was mixed with AlCl 3 (0.75 g) in benzene (50 ml). The resulting compound is used without further purification.

Yield: 437 mg

(c) N-[1-Acetyl-2,2,4-trimethyl-4-phenyl-7-(pyridin-4-ylmethoxy)-1,2,3,4-tetrahydroquinolin-6-yl]-5-bromo -2-methylamino-benzamide

According to general procedure H, the compound described in example 32b (44 mg) is alkylated with 4-picolyl chloride hydrochloride (15 mg) and Cs 2 CO 3 (ca 100 mg) in a mixture of DMF (1 ml) and CH 2 Cl 2 (4 ml). The title compound is obtained as the corresponding TFA salt after preparative HPLC (method B).

Yield: 18 mg (TFA salt). MS-ESI: [M + H] + = 629.4; HPLC: Rt = 18.1 min (method 2)

Example 33

Furan-2-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

(a) (2,2,4-trimethyl-1,2-dihydroquinolin-6-yl) carbamic acid tert-butyl ester

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) was refluxed during 20 hours. MgSO4 is removed by filtration and the filtrate is concentrated in vacuo. The residue was chromatographed on a short plug of silica gel using heptane/ethyl acetate = 8/2 as eluent to give the product as a brown oil.

Yield 41 g.

(b) (1-Acetyl-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl) carbamic acid tert-butyl ester

A solution of the compound described in Example 33a (41 g) in pyridine (200 ml) and CH 2 Cl 2 (200 ml) was cooled to 0°C. Acetyl chloride (21 ml) and CH2Cl2 (50 ml) were added dropwise. After the addition was complete, the mixture was stirred for 3 hours at room temperature. Ethyl acetate (2 L) and H2O (2 L) were added and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound was obtained by crystallization from ethyl acetate.

Yield: 23 g

(c) 1-acetyl-6-amino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinoline

According to general procedure G, the compound described in Example 33b (33.3 g) was mixed with AlCl 3 (40.4 g) in benzene (700 ml). The product is purified by chromatography on silica gel using heptane/ethyl acetate = 8/2 (v/v) as eluent.

Yield: 22.4 g

(d) (1-acetyl-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

To a solution of the compound described in Example 33c (22.4 g) in THF (300 ml) and the resulting mixture was cooled to 0°C. A solution of FmocCl (20.7 g) in THF (100 mL) was added dropwise and after the addition was complete, the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and ethyl acetate (800 mL) and 0.3 M aqueous HCl (2 x 500 mL), H 2 O (500 mL) and saturated brine (500 mL) were added, followed by drying (MgSO 4 ) and concentration in vacuo. The product is used in the next step without further purification.

Yield: 43 g

(e) (1-acetyl-2,2,4-trimethyl-7-nitro-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

Fuming nitric acid (3.07 ml) was added dropwise over a period of 10 min to a mixture of the compound described in Example 33d (43 g) and acetic acid (230 ml) in CH 2 Cl 2 (230 ml). The reaction mixture was stirred until complete conversion of the starting material, after which H2O (150 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (150 ml). The combined organic layers were washed with saturated aqueous NaHCO3 (3 x 200 ml) and saturated brine (200 ml), followed by drying over MgSO4 and filtration. Methanol (ca. 200 ml) was added and the CH2Cl2 was carefully removed in vacuo, after which the mixture was left to stand at room temperature overnight. Clear yellow crystals were collected by filtration and dried (MgSO4) in vacuo.

Yield: 29.3 g

(f) (1-acetyl-7-amino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

According to general procedure E, the compound described in example 33e (20 g) is reduced using zinc dust (45 g) and acetic acid (20 ml) in THF (ca. 600 ml) to give the product which is used as crude in the next step .

Yield: 21 g

(g) (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

An aqueous solution of formaldehyde (37%; 3.8 ml) was added to a solution of the compound described in Example 33f (12 g), acetic acid (15.7 ml) and sodium cyanoborohydride (2.9 g) in methanol (200 ml), which leads to an exothermic reaction and the formation of a white precipitate. An additional amount of MeOH is added to facilitate mixing. After stirring for 15 min, the precipitate was collected by filtration and washed with MeOH/H 2 O = 1/1 (v/v). The filtrate is partially concentrated to form more solid material, which is also collected. The combined solids are recrystallized from CH2Cl2/MeOH to give the dimethylated compound.

Yield: 9.7 g

(h) 1-acetyl-6-amino-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinoline

Piperidine (7.7 ml) was added to a solution of the compound described in Example 33g (4.5 g) in CH 2 Cl 2 (70 ml). After 24 hours, the reaction mixture was diluted with CH 2 Cl 2 (100 mL) and 0.5 M aqueous HCl (2 x 150 mL), water (100 mL) and saturated brine (1 mL). The organic layer is dried (MgSO4) and diluted to a total volume of 200 ml. This stock solution of the title compound (ca. 13.8 mg/ml) is used for further reactions.

(i) Furan-2-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

Triethylamine (38 µl) and 2-furoyl chloride (27 µl) were added to a solution of the compound described in Example 33h (99.6 mg) in CH 2 Cl 2 (10 ml) and the resulting mixture was stirred until complete conversion of the starting material. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 5.5 mg. MS-ESI: [M + H] + = 446.2; HPLC: Rt = 19.02 min (method 2)

Example 34

5-Methyl-thiophene-2-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to General Procedure A, the compound described in Example 33h (96.6 mg) is acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH2Cl2 (10 ml ). The title compound is purified by preparative HPLC (Procedure B).

Yield: 35.5 mg. MS-ESI: [M + H] + = 476.2; HPLC: Rt = 21.26 min (method 2)

Example 35

Biphenyl-4-carboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to General Procedure A, the compound described in Example 33h (96.6 mg) is acylated with 5-4-biphenylcarboxylic acid (54.4 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by preparative HPLC (Procedure B).

Yield: 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-tetrahydro-quinolin-6-yl)-3,5-dibromobenzamide

According to General Procedure A, the compound described in Example 33h (96.6 mg) is acylated with 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound was purified by crystallization from CH2Cl2/CH3CN.

Yield: 24.3 mg. MS-ESI: [M + H] + = 614.2; HPLC: Rt = 27.71 min (method 2)

Example 37

Cyclopentanecarboxylic acid (1-acetyl-7-dimethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to General Procedure A, the compound described in Example 33h (175 mg) is acylated with cyclopentanecarboxylic acid (128 µl), HATU (224 mg) and DIPEA (400 µl) in CH2Cl2 (10 ml). The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

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-tetrahydro-quinolin-6-yl)-isobutyramide

According to general procedure A, the compound described in example 33h (137 mg) is acylated with isobutanoic acid (110 µl), HATU (224 mg) and DIPEA (400 µl) in CH2Cl2 (10 ml). The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent.

Yield: 43 mg. MS-ESI: [M + H] + = 422.4; HPLC: Rt = 9.99 min (method 1)

Example 39

Furan-2-carboxylic acid (1-acetyl-7-furan-2-ylcarbonylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

To a solution of the compound described in example 33f (150 mg) and triethylamine (43 µl) in CH2Cl2 (1 ml) was added 2-furoyl chloride (30 µl). After complete consumption of the starting material, 1 M aqueous HCl was added, the organic layer was separated followed by the addition of piperidine (1 ml) and the resulting mixture was stirred overnight. The reaction mixture was washed with 1M aqueous HCl, the organic layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent, followed by preparative HPLC (method A).

Yield: 18 mg. MS-ESI: [M + H] + = 512.4; HPLC: Rt = 19.92 min (method 2)

Example 40

5-Methyl-thiophene-2-carboxylic acid (1-acetyl-2,2,4-trimethyl-4-phenyl-7-propylamino-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

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

General Procedure K: To a mixture of the compounds described in Example 33f (750 mg), acetic acid (935 µl), sodium cyanoborohydride (135 mg) and MeOH (10 ml) was added propionaldehyde (94.2 µl). The mixture is stirred for 18 hours, water is added and the precipitate is collected by filtration. The precipitate was taken up in CH 2 Cl 2 (10 ml), piperidine (1 ml) was added and the resulting mixture was stirred for 18 h. The reaction mixture was washed with 1 M aqueous HCl, the organic layer was separated and diluted to a total volume of 50 ml. This solution is used for the following reactions.

(b) 5-Methyl-thiophene-2-carboxylic acid (1-acetyl-2,2,4-trimethyl-4-phenyl-7-propylamino-1,2,3,4-tetrahydro-quinolin-6-yl) -amide

According to General Procedure A, the compound described in Example 40a (100 mg) is acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 18.3 mg. MS-ESI: [M + H] + = 490.4; HPLC: Rt = 23.96 min (method 2)

Example 41

Biphenyl-4-carboxylic acid (1-acetyl-7-ethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

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

According to general procedure K, the compound described in Example 33f (750 mg) was alkylated using acetaldehyde (73.3 µl) and deprotected with piperidine (1 ml) to give a solution of the title compound in CH 2 Cl 2 after workup and dilution.

(b) Biphenyl-4-carboxylic acid (1-acetyl-7-ethylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to General Procedure A, the compound described in Example 41a (100 mg) is acylated with 4-biphenylcarboxylic acid (54.4 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 9.8 mg. MS-ESI: [M + H] + = 532.4; HPLC: Rt = 25.55 min (method 2)

Example 42

5-Methyl-thiophene-2-carboxylic acid {1-acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridin-4-ylmethyl)-amino]-1,2,3,4-tetrahydro -quinolin-6-yl}-amide

(a) 1-Acetyl-6-amino-2,2,4-trimethyl-4-phenyl-7-[(pyridin-4-ylmethyl)-amino]-1,2,3,4-tetrahydro-quinoline

According to general procedure K, the compound described in Example 33f (750 mg) was alkylated using 4-pyridinecarboxaldehyde (125 µl) and deprotected with piperidine (1 ml) to give a solution of the title compound in CH2Cl2 after workup and dilution.

(b) 5-Methyl-thiophene-2-carboxylic acid {1-acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridin-4-ylmethyl)-amino]-1,2,3, 4-tetrahydro-quinolin-6-yl}-amide

According to General Procedure A, the compound described in Example 42a (114 mg) is acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 51 mg. MS-ESI: [M + H] + = 539.4; HPLC: Rt = 13.19 min (method 2)

Example 43

5-Methyl-thiophene-2-carboxylic acid {1-acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridin-3-ylmethyl)-amino]-1,2,3,4-tetrahydro -quinolin-6-yl}-amide

(a) 1-Acetyl-6-amino-2,2,4-trimethyl-4-phenyl-7-[(pyridin-4-ylmethyl)-amino]-1,2,3,4-tetrahydro-quinoline

According to general procedure K, the compound described in Example 33f (750 mg) was alkylated using 3-pyridinecarboxaldehyde (125 µl) and deprotected with piperidine (1 ml) to give a solution of the title compound in CH2Cl2 after workup and dilution.

(b) 5-Methyl-thiophene-2-carboxylic acid {1-acetyl-2,2,4-trimethyl-4-phenyl-7-[(pyridin-3-ylmethyl)-amino]-1,2,3, 4-tetrahydro-quinolin-6-yl}-amide

According to General Procedure A, the compound described in Example 43a (114 mg) is acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by 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-tetrahydro-quinolin-6-yl)-3,5-dibromo-benzamide

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

According to general procedure K, the compound described in Example 33f (750 mg) was alkylated using isobutyraldehyde (119 µl) and deprotected with piperidine (1 ml) to give a solution of the title compound in CH 2 Cl 2 after workup and dilution.

(b) N-(1-Acetyl-7-isobutylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3,5-dibromo-benzamide

According to General Procedure A, the compound described in Example 44a (114 mg) is acylated with 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 54 mg. MS-ESI: [M + H] + = 642.4; HPLC: Rt = 29.47 min (method 2)

Example 45

Biphenyl-4-carboxylic acid (1-acetyl-7-benzylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

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

According to general procedure K, the compound described in example 33f (750 mg) was alkylated using benzaldehyde (133 µl) and deprotected with piperidine (1 ml) to give a solution of the title compound in CH 2 Cl 2 after workup and dilution.

(b) Biphenyl-4-carboxylic acid (1-acetyl-7-benzylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to General Procedure A, the compound described in Example 45a (113 mg) is acylated with 4-biphenylcarboxylic acid (54.4 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 114 mg. MS-ESI: [M + H] + = 594.4; HPLC: Rt = 26.46 min (method 2)

Example 46

5-Methyl-thiophenl-2-carboxylic acid (1-acetyl-7-benzylamino-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to General Procedure A, the compound described in Example 45a (113 mg) is acylated with 5-methylthiophene-2-carboxylic acid (39.1 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by 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-[(pyridin-4-ylmethyl)-amino]-1,2,3,4-tetrahydro-quinolin-6-yl}- 3,5-dibromo-benzamide

According to general procedure A, the compound described in Example 43a (114 mg) is acylated with 3,5-dibromobenzoic acid (77 mg), HATU (157 mg) and DIPEA (239 µl) in CH 2 Cl 2 (10 ml). The title compound is purified by 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-tetrahydro-quinolin-6-yl)-3,5-dibromo-benzamide

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

A solution of lepidin (10.0 g) in THF was cooled to -78°C, after which a solution of BH3·THF in THF (1M, 70 ml) was added. After 2 hours, a solution of sodium bis(2-methoxy-ethoxy)aluminum dihydride in toluene (3.5 M; 40 ml) was added and the reaction mixture was stirred for an additional 2 hours. Add water and dilute the mixture with ethyl acetate. The organic layer was separated, dried (MgSO4) and partially concentrated in vacuo leading to crystallization of the compound. The crystals were collected by filtration to give 3.5 g after drying in vacuo. The rest of the mother liquor was concentrated in vacuo and the residue was purified by chromatography on silica gel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as eluent to give an additional 4.4 g of the title compound.

Yield 7.9 g

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

According to general procedure C, the compound described in Example 48a (7.9 g) is acylated with acetyl chloride (11.8 ml) and DMA (34 ml) in CH 2 Cl 2 (50 ml) at 0 °C. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 6/4 as eluent.

Yield 8.8 g

(c) 1-Acetyl-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline

According to general procedure G, the compound described in Example 48b (8.8 g) was mixed with AlCl 3 (18.8 g) in benzene (250 ml). The obtained product is used without further purification.

Yield 12.0 g

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

To a solution of the compound described in Example 48c (5.0 g) and acetic anhydride (189 µl) in CH 2 Cl 2 (50 ml) was added dropwise fuming HNO 3 (9.4 ml). After the reaction is complete, water is added and the organic layer is washed with saturated brine, separated and concentrated in vacuo. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 6/4 as eluent.

Yield 3.86 g

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

According to general procedure E, the compound described in example 48d (3.86 g) is reduced using zinc dust (16 g) and acetic acid (7 ml) in THF (ca 250 ml) to give the product which is used as crude in the next step.

Yield 2.2 g

(f) (1-Acetyl-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

To a solution of the compound described in Example 48e (1.0 g) in THF (10 ml) and the resulting mixture was cooled to 0 °C. FmocCl (1.01 g) was added and the mixture was stirred for 18 h at room temperature, after which time it was concentrated in vacuo. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 6/4 as eluent.

Yield: 950 mg

(g) (1-Acetyl-4-methyl-7-nitro-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

To a solution of the compound described in Example 48f (850 mg) and acetic anhydride (17 µl) in CH2Cl2 (5 ml) was added dropwise fuming HNO3 (9.4 ml). After the reaction is complete, water is added and the organic layer is washed with saturated brine, separated and concentrated in vacuo. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 0/1 (v/v) as eluent.

Yield: 714 mg

(h) (1-Acetyl-7-amino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

Using general procedure E, the compound described in Example 48g (2.37 g) is reduced using zinc dust (5.6 g) and acetic acid (2.4 ml) in THF (ca 50 ml) to give the product which is used as raw material in the next step.

Yield 2.66 g

(i) (1-Acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-carbamic acid 9-fluorenylmethyl ester

An aqueous solution of formaldehyde (37%, 650 µl) was added to a solution of the compound described in example 48h (2.66 g), acetic acid (3.1 ml) and sodium cyanoborohydride (232 mg) in methanol (50 ml). The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with water and brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 0/1 (v/v) as eluent.

Yield 1.0 g

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

To a solution of the compound described in Example 48i (1 g) in CH 2 Cl 2 (20 ml) was added piperidine (1.8 ml) and the mixture was stirred until starting material was present. The title compound is purified by chromatography on silica gel using heptane/ethyl acetate = 9/1 => 0/1 (v/v) as eluent.

Yield 370 mg

(k) N-(1-Acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3,5-dibromo-benzamide

According to General Procedure A, the compound described in Example 48j (74 mg) is acylated with 3,5-dibromobenzoic acid (70 mg), HATU (131 mg) and DIPEA (120 µl) in CH 2 Cl 2 (3 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 82 mg. MS-ESI: [M + H] + = 586.2; HPLC: Rt = 22.40 min (method 2)

Example 49

5-Bromo-thiophene-2-carboxylic acid (1-acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to general procedure A, the compound described in example 48j (74 mg) is acylated with 5-bromothiophene-2-carboxylic acid (52 mg), HATU (131 mg) and DIPEA (120 µl) in CH 2 Cl 2 (3 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 69 mg. MS-ESI: [M + H] + = 514.2; HPLC: Rt = 17.01 min (method 2)

Example 50

5-Chloro-thiophene-2-carboxylic acid (1-acetyl-7-dimethylamino-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-6-yl)-amide

According to General Procedure A, the compound described in Example 48j (74 mg) is acylated with 5-chlorothiophene-2-carboxylic acid (52 mg), HATU (131 mg) and DIPEA (120 µl) in CH 2 Cl 2 (3 ml). The title compound is purified by preparative HPLC and lyophilized.

Yield: 81 mg. MS-ESI: [M + H] + = 468.2; HPLC: Rt = 17.49 min (method 2)

Example 51

Biological activity of CHO-FSH in vitro

The activity of FSH compounds was tested in Chinese Hamster Ovary (CHO) cells, in which transfection with the human FSH receptor is stable and counter-transfection with cAMP responsive element (CRE) was performed. )/promoter that expresses the firefly luciferase reporter gene. Ligand binding to the GS-coupled FSH receptor will lead to an increase in cAMP, which in turn will induce transactivation of the luciferase reporter construct. To test for antagonistic properties, recombinant FSH is added at a concentration that induces approximately 80% of the maximal stimulation of cAMP accumulation in the absence of the test compound (rec-hFSH, 10 mU/ml). The luciferase signal is quantified using a bioluminescence counter. EC50 values (concentration of the tested compound that causes half the maximal effect (50 %) of stimulation or reduction) are calculated for the tested compounds. For this purpose, the software program GraphPadPrism, version 3.0 (GraphPad software Inc., San Diego) is used.

The compounds of all examples have an EC 50 (IC 50 ) value of less than 10-5 M in either the agonist or antagonist assay set-up or both. The compounds of Examples 5-8, 10-14, 16, 18-20, 33-35, 37, 38, 41 and 45-50 have an EC50 of less than 10-7 M in at least one of the tests.

Claims (15)

1. Tetrahydroquinoline derivative according to Formula I, or its pharmaceutically acceptable salt, characterized in that: R1 and R2 equal to H or Me, R 3 is H, hydroxy, (1-4C) alkoxy; (di)(1-4C) alkylamino(2-4C) alkoxy or (2-6) heterocycloalkyl(2-4C) alkoxy, R 4 is H, OH, (1-4C) alkoxy or R 7 ; R 5 is H, OH, (1-4C) alkoxy or R 7 ; with the proviso that R 4 is H, R 5 is not H, OH or (1-4C) alkoxy and that if R 5 is H, R 4 is not H, OH or (1-4C) alkoxy; R 6 is (2-5C)heteroaryl, (6C)aryl, (3-8)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (6C)arylcarbonyloxy; R 8 -(2-4C)alkylamino, R 8 -(2-4C)alkoxy, R 9 -methylamino or R 9 -methoxy; R8 is hydroxy, amino, (1-4C)alkoxy, (di)(1-4C)alkylamino, (2-6C)heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino, (di)(1-4C)alkylaminocaronylamino or (1- 4C)Alkoxycarbonylamino and R 9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. 2. Tetrahydroquinoline derivative from claim 1, characterized in that R6 is (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloaryl or (1-6C)alkyl. 3. Tetrahydroquinoline derivative according to claims 1 and 2, characterized in that R7 is (di)(1-4C)alkylamino, (2-5C)heteroarylcarbonyloxy, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy. 4. Tetrahydroquinoline derivative from claims 1-3, characterized in that R8 is equal to amino, (di)(1-4C)alkylamino, (2-6C)heterocycloalkyl or (2-6C)heterocycloalkylcarbonylamino. 5. Tetrahydroquinoline derivative from claims 1-4, characterized in that R7 is (di)(1-4C)alkylamino, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy. 6. Tetrahydroquinoline derivative from claims 1-5, characterized in that R8 is equal to amino, (di)(1-4C)alkylamino, (2-6C)heterocycloalkyl. 7. Tetrahydroquinoline derivative from claims 1-6, characterized in that R8 is equal to (di)(1-4C)alkylamino, (2-6C)heterocycloalkyl. 8. Tetrahydroquinoline derivative from claims 1-7, characterized in that R7 is (di)(1-4C)alkylamino, R8-(2-4C)alkoxy, R9-methylamino or R9-methoxy. 9. Tetrahydroquinoline derivative from claims 1-8, characterized in that R6 is equal to (2-5C)heteroaryl or (6C)aryl. 10. Tetrahydroquinoline derivative from claims 1-9, characterized in that R6 is equal to (4-5C)heteroaryl or (6C)aryl and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (3-5C)heteroaryl or ( 6C)aryl. 11. Tetrahydroquinoline derivative from claim 1-10, characterized in that R7 is (di)(1-4C)alkylamino, R8-ethoxy, R9-methylamino or R9-methoxy and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl , (3-5C)heteroaryl or (6C)aryl. 12. Tetrahydroquinoline derivative from claim 1-11, characterized in that R8 is equal to (di)(1-4C)alkylamino, (4-6C)heterocycloalkyl and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (3- 5C)heteroaryl or (6C)aryl. 13. Pharmaceutical preparation characterized in that it contains a tetrahydroquinoline derivative from claims 1-12 and pharmaceutically suitable excipients. 14. Tetrahydroquinoline derivative from claims 1-12, characterized in that it is used in treatment. 15. Use of a tetrahydroquinoline derivative from any of claims 1-12 or its pharmaceutically acceptable salt or solvate, indicated by the fact that it is used in the production of medication for fertility regulation.