KR20050085694A - Tetrahydroquinoline derivatives and their use as fsh receptor modulators - Google Patents

Abstract

The present invention relates to tetrahydroquinoline derivatives having general formula (I) or a pharmaceutically acceptable salt thereof, wherein Rl and R 2 are H, Me; R3 is (2-6C)heterocycloalkyl(1-4C)alkyl, (2-5C) heteroaryl(1-4C)alkyl, (6C)aryl (1-4C)alkyl, (1-4C)(di) alkylaminocarbonylamino(2-4C)alkyl, (2-C) heterocycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R 5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl, (6C)aryl, (3- 8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C) alkyl and R5 is (di)(1-4C)alkylamino, (1-4C)alkoxy, amino, hydroxy, (6C)arylamino, (di)(3- 4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C) alkylamino, (di)[(1-4C)alkoxy(2-4C)alkyl]amino, (di)[(1-4C)alkylamino(2-4C) alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl] amino. The present invention also relates to pharmaceutical compositions comprising said derivatives and the use of these derivatives to regulate fertility.

Description

TETRAHYDROQUINOLINE DERIVATIVES AND THEIR USE AS FSH RECEPTOR MODULATORS

The present invention relates to compounds having FSH receptor modulating activity, in particular tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and the use of such compounds in medical treatment.

Gonadotropin plays an important role in various body functions, including metabolism, thermoregulation and reproductive processes. Gonadotropin acts on specific gonadal cell types that initiate differentiation and steroidgenesis of the ovaries and testes. Pituitary gonadotropin FSH (follicular stimulating hormone) plays a central role in stimulating follicle development and maturation, for example, and LH (luteinizing hormone) induces ovulation (Sharp, RM Clin Endocrinol. 33: 787- 807, 1990; Dorrington and Armstrong, Recent Prog.Horm. Res. 35: 301-342, 1979). Recently, for ovarian stimulation, ie in vitro fertilization (IVF) and ovarian hyperstimulation for ovulation induction in infertile women (Insler, V., Int. J. Fertility 33: 85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5: 3-13, 1988), and for male sexual dysfunction and male infertility, FSH is clinically applied with LH or hCG.

Gonadotropin FSH is released from the anterior pituitary gland and from the placenta during pregnancy under the influence of gonadotropin-releasing hormone and estrogen. In women, FSH is a major hormone that acts on the ovary to promote the development of follicles and regulate the secretion of estrogens. In men, FSH participates in the integrity of the lavage canal and acts on Sertoli cells supporting sporulation. Purified FSH is used clinically for the treatment of infertility in women and for some types of male spermatogenesis insufficiency. Gonadotropin, intended for therapeutic purposes, can be isolated from human urine sources and is of low purity (Morse et al, Amer. J. Reproduct. Immunol. And Microbiology 17: 143, 1988). Alternatively, they can be prepared as recombinant gonadotropins. Recombinant human FSH is commercially available and used to aid reproduction (Olijve et al. Mol. Hum. Reprod. 2: 371, 1996; Devroey et al. Lancet 339: 1170, 1992).

The action of the FSH hormone is mediated by certain plasma membrane receptors that are members of a large family of G-protein coupled receptors. These receptors consist of a single polypeptide with seven transmembrane domains and can interact with the Gs protein to induce the activity of, for example, adenylate cyclase.

FSH receptors are fairly specific targets in ovarian follicle growth and are expressed only in the ovaries. Blocking this receptor or inhibiting signal transduction normally induced after FSH-mediated receptor activation impedes follicle development and subsequent ovulation and pregnancy. Thus, low molecular weight FSH antagonists can form the basis of new contraceptives. Such FSH antagonists can produce sufficient estrogen to induce follicle incidence (no ovulation) while avoiding side effects such as bone mass. On the other hand, compounds that stimulate FSH receptor activity may act to mimic the gonadotropin effect of natural ligands.

The present invention describes a method for the preparation of low molecular weight hormone analogs with selective regulatory activity on FSH receptors. The compounds of the present invention can be used as (partial) agonists or (partial) antagonists of FSH-receptors.

Thus, it was found that the tetrahydroquinoline compounds of formula (I) or their pharmaceutically acceptable salts of the following classes have FSH-modulating activity:

Where

R ¹ and R ² are H, Me;

R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl, (2-5C) heteroaryl (1-4C) alkyl, (6C) aryl (1-4C) alkyl, (1-4C) (di ) Alkylaminocarbonylamino (2-4C) alkyl, (2-6C) heterocycloalkylcarbonylamino (2-4C) alkyl, R ^5- (2-4C) alkyl or R ⁵ -carbonyl (1-4C Alkyl;

R ⁴ is (2-5C) heteroaryl, (6C) aryl, (3-8C) cycloalkyl, (2-6C) heterocycloalkyl or (1-6C) alkyl;

R ⁵ is (di) (1-4C) alkylamino, (1-4C) alkoxy, amino, hydroxy, (6C) arylamino, (di) (3-4C) alkenylamino, (2-5C) hetero Aryl (1-4C) alkylamino, (6C) aryl (1-4C) alkylamino, (di) [(1-4C) alkoxy (2-4C) alkyl] amino, (di) [(1-4C) alkyl Amino (2-4C) alkyl] amino, (di) [amino (2-4C) alkyl] amino or (di) [hydroxy (2-4C) alkyl] amino.

The compounds of the present invention modulate FSH receptor function and can be used for the same clinical purposes as natural FSH when they act like agonist, with the advantage that they exhibit varying stability properties and can be administered differently. If the compound blocks the FSH receptor, it can be used, for example, as a contraceptive.

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

The following terms have the meanings described below as used in the specification and claims.

As used herein, the term (1-4C) alkyl refers to branched or unbranched alkyl groups having 1 to 4 carbon atoms, namely methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

As used herein, the term (2-4C) alkyl refers to branched or unbranched alkyl groups having 2 to 4 carbon atoms, ie ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

As used herein, the term (1-6C) alkyl refers to branched or unbranched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and hexyl . (1-5C) alkyl groups are preferred, with (1-4C) alkyl being most preferred.

As used herein, the term (di) (1-4C) alkylamino refers to an amino group mono- or disubstituted with an alkyl group each containing 1 to 4 carbon atoms and having the meanings described above.

As used herein, the term (di) (1-4C) alkenylamino is an amino group which contains 2 to 4 carbon atoms each and is monosubstituted or bisubstituted with an alkenyl group as described above, such as allyl and 2-butenyl. Means.

As used herein, the term (3-8C) cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms, ie cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. (3-6C) cycloalkyl group is preferred.

The term (2-6C) heterocycloalkyl, as used herein, has from 2 to 6, preferably from 3 to 5 carbon atoms, and possibly N, O and / or which may be linked via heteroatoms or carbon atoms. It means a heterocycloalkyl group containing at least one heteroatom selected from S. Preferred heteroatoms are N or O. Heterocycloalkyl groups may be substituted with methyl or ethyl groups at carbon atoms or possibly heteroatoms. Most preferred heterocycloalkyls are piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and 1-methyl-2-piperidinyl.

As used herein, the term (1-4C) alkoxy refers to an alkoxy group having 1 to 4 carbon atoms and the alkyl moiety has the same meaning as described above. The (1-2C) alkoxy group is preferable.

As used herein, the term (6C) aryl is hydroxy, amino, iodo, bromo, chloro, fluoro, nitro, trifluoromethyl, cyano, phenyl, (1-4C) alkyl, (1-4C) ) Alkoxy, a phenyl group which may be optionally substituted with one or more substituents selected from (1-4C) (di) alkylamino, wherein the alkyl, alkoxy and (di) alkylamino moieties have the same meaning as described above, Such as 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, as used herein, means a substituted or unsubstituted aromatic group having at least one heteroatom selected from N, O and / or S and having 2 to 5 carbon atoms, for example Imidazolyl, pyridyl, pyrimidyl, thienyl or furyl. Substituents on the heteroaryl group may be selected from the group of substituents listed for the (6C) aryl group. Heteroaryl groups may be linked via heteroatoms or carbon atoms, if possible. Preferred heteroaryl groups are thienyl, furyl and pyridyl.

As used herein, the term (2-6C) heterocycloalkyl (1-4C) alkyl refers to a heterocycloalkyl group having 2 to 6 carbon atoms, linked to an alkyl group having 1 to 4 carbon atoms, wherein the heterocycloalkyl group And alkyl groups have the same meanings as described above.

As used herein, the term (2-6C) heterocycloalkylcarbonylamino means a heterocycloalkyl group having 2 to 6 carbon atoms linked to the carbonyl portion of the carbonylamino group, wherein the heterocycloalkyl group is the same as described above. Has meaning.

As used herein, the term (2-6C) heterocycloalkylcarbonylamino (2-4C) alkyl refers to a heterocycloalkylcarbonylamino group [heterocycloalkyl moiety connected via an amino group to an alkyl group having 2 to 4 carbon atoms Containing 2 to 6 carbon atoms, wherein the heterocycloalkylcarbonylamino group and alkyl group have the same meaning as described above.

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

As used herein, the term (3-8C) cycloalkylaminocarbonyl group refers to a cycloalkyl group having 3 to 8 carbon atoms linked to the amino portion of an aminocarbonyl group, wherein the cycloalkyl group has the same meaning as described above.

As used herein, the term (di) (1-4C) alkylaminocarbonylamino has from 1 to 4 carbon atoms in the alkyl group (s), linked through an amino group to the carbonyl portion of the carbonylamino group to provide urea functionality. Means a (di) alkylamino group, said (di) alkylamino group has the same meaning as mentioned above.

 As used herein, the term (di) (1-4C) alkylaminocarbonylamino (2-4C) alkyl is one to four carbon atoms of the alkyl group (s) linked via an amino group to an alkyl group having two to four carbon atoms. An individual (di) alkylaminocarbonylamino group, and the (di) alkylaminocarbonylamino group and the alkyl group have the same meaning as described above.

As used herein, the term (2-5C) heteroaryl (1-4C) alkyl refers to a heteroaryl group having 2 to 5 carbon atoms linked to an alkyl group having 1 to 4 carbon atoms, wherein the heteroaryl group and alkyl group are described above. It has the same meaning as one.

As used herein, the term (6C) aryl (1-4C) alkyl is a phenyl group linked to an alkyl group having 1 to 4 carbon atoms and optionally substituted with one or more substituents selected from the group of substituents listed for the (6C) aryl group above. The aryl group and the alkyl group have the same meaning as described above.

The term (6C) arylamino, as used herein, refers to a phenyl group linked to an amino group and optionally substituted with one or more substituents selected from the group of substituents listed for the (6C) aryl group, wherein the aryl group is the same as described above. Has meaning.

As used herein, the term (6C) aryl (1-4C) alkylamino is linked to the alkyl moiety of an alkylamino group having 1 to 4 carbon atoms and is selected from the group of substituents listed for the above (6C) aryl group. An optionally substituted phenyl group, wherein the aryl group and alkylamino group have the same meaning as described above.

As used herein, the term (2-5C) heteroaryl (1-4C) alkylamino is linked to the alkyl moiety of an alkylamino group having 1 to 4 carbon atoms and is selected from the group of substituents listed for the (6C) aryl group above. It means a heteroaryl group having 2 to 5 carbon atoms, optionally substituted with the above substituents, the heteroaryl group and alkylamino group has the same meaning as described above.

As used herein, the term (1-4C) alkoxy (2-4C) alkyl refers to an alkoxy group having 1 to 4 carbon atoms, linked to an alkyl group having 2 to 4 carbon atoms, wherein the alkoxy group and alkyl group are as described above. Has the same meaning.

As used herein, the term (di) [(1-4C) alkoxy (2-4C) alkyl] amino refers to an amino group mono- or disubstituted with a (1-4C) alkoxy (2-4C) alkyl group. The (1-4C) alkoxy (2-4C) alkyl group is an alkoxy group having 1 to 4 carbon atoms, which is linked to an alkyl group having 2 to 4 carbon atoms and has the same meaning as described above.

As used herein, the term (1-4C) alkylamino (2-4C) alkyl refers to an alkylamino group having 1 to 4 carbon atoms linked through an amino group to an alkyl group having 2 to 4 carbon atoms, the alkyl moiety being described above Has the same meaning as

As used herein, the term (di) [(1-4C) alkylamino (2-4C) alkyl] amino refers to an amino group mono- or disubstituted with a (1-4C) alkylamino (2-4C) alkyl group. A (1-4C) alkylamino (2-4C) alkyl group is an alkylamino group having 1 to 4 carbon atoms which is linked via an amino group to an alkyl group having 2 to 4 carbon atoms and has the same meaning as described above.

As used herein, the term amino (2-4C) alkyl refers to an aminoalkyl group having 2 to 4 carbon atoms, with the alkyl moiety having the same meaning as described above.

As used herein, the term (di) [amino (2-4C) alkyl] amino refers to an amino group mono- or disubstituted with an aminoalkyl group, having from 2 to 4 carbon atoms and having the same meaning as described above.

As used herein, the term hydroxy (2-4C) alkyl refers to a hydroxyalkyl group having 2 to 4 carbon atoms, wherein the alkyl moiety has the same meaning as described above.

As used herein, the term (di) [hydroxy (2-4C) alkyl] amino refers to an amino group mono- or disubstituted with a hydroxyalkyl group having 2 to 4 carbon atoms and the same meaning as described above.

As used herein, the term R ^5- (2-4C) alkyl means an R ⁵ group bonded to an alkyl moiety having from 2 to 4 carbon atoms having the same meaning as described above.

The term R ⁵ -carbonyl- (1-4C) alkyl, as used herein, refers to an R ⁵ group bonded to a carbonyl moiety of a carbonylalkyl group having 1 to 4 carbon atoms and having an alkyl moiety having the same meaning as described above. it means.

The term pharmaceutically acceptable salts is those salts which are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., within the scope of medical judgment, and balanced at an appropriate benefit / risk ratio. Means. Pharmaceutically acceptable salts are known in the art. These salts, in the course of the final separation and purification of the compounds of the present invention, or, if present, provide free base functional groups with appropriate inorganic acids (e.g. hydrochloride, phosphoric acid, or sulfuric acid), or organic acids (e.g. ascorbic acid, citric acid, tartaric acid, Lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like). If present, acid functionalities can be reacted with organic or inorganic bases such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

The present invention therefore relates to compounds of formula (I) as defined above.

Another embodiment of the invention provides compounds of formula I, wherein R ¹ and R ² are Me.

In addition, the present invention R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl, (2-5C) heteroaryl (1-4C) alkyl, (2-6C) heterocycloalkylcarbonylamino (2 -4C) alkyl, R ^5- (2-4C) alkyl, R ⁵ -carbonyl (1-4C) alkyl.

In another aspect, the invention provides that R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl, (2-5C) heteroaryl (1-4C) alkyl, R ^5- (2-4C) alkyl, R ⁵ -carbonyl (1-4C) alkyl.

In another aspect, the invention provides that R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl, (2-5C) heteroaryl (1-4C) alkyl or R ^5- (2-4C) alkyl It relates to a compound of formula (I).

In another aspect, the invention relates to compounds of formula (I), wherein R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl.

In another embodiment of the invention, the heterocycloalkyl group of the heterocycloalkyl (1-4C) alkyl in R ³ of Formula I is composed of 4, 5 or 6 C atoms and heteroaryl (1-4C) alkyl in R ³ The heteroaryl group of is composed of 3, 4 or 5 C atoms.

In another embodiment, this invention relates to compounds of Formula (I), wherein R ⁴ is (6C) aryl.

In another embodiment, the invention relates to compounds of formula (I), wherein R ⁵ is (di) (1-4C) alkylamino, amino, (di) (3-4C) alkenylamino, (2-5C) heteroaryl (1-4C) alkyl Amino, (6C) aryl (1-4C) alkylamino, (di) [(1-4C) alkoxy (2-4C) alkyl] amino, (di) [(1-4C) alkylamino (2-4C) alkyl ] Amino, (di) [amino (2-4C) alkyl] amino, (di) [hydroxy (2-4C) alkyl] amino.

In another aspect, the invention provides that R ⁵ is (di) (1-4C) alkylamino, (2-5C) heteroaryl (1-4C) alkylamino, (di) [(1-4C) alkoxy (2- 4C) alkyl] amino, (di) [(1-4C) alkylamino (2-4C) alkyl] amino, (di) [amino (2-4C) alkyl] amino or (di) [hydroxy (2-4C ) Alkyl] amino.

In another aspect, the invention provides that R ⁵ is (di) (1-4C) alkylamino, amino, (di) (3-4C) alkenylamino, (2-5C) heteroaryl (1-4C) alkylamino , (6C) aryl (1-4C) alkylamino.

Another aspect of the invention is a compound of formula I, wherein R ⁵ is (di) (1-4C) alkylamino or amino.

In another aspect of the invention, there is provided a compound of Formula I, wherein R ⁵ is (di) (1-4C) alkylamino.

Another aspect of the invention relates to compounds in which all specific definitions of the R ¹ to R ⁵ groups as defined above are combined in the compound of formula (I).

Suitable methods for preparing the compounds of the present invention are summarized below.

The compounds of the present invention represented by the formula (I-a) can be prepared starting from the well-known Skraup reaction. This reaction is carried out in N-tert-butoxycarbonyl (N-Boc) protected 1,4-phenylenediamine (I1) to give 1,2-dihydroquinoline derivative III-a.

Associated scrabb ring condensation reactions are found in the following 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; W.C. 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 reactions are usually carried out at high temperature in the presence of iodine or amphoterics such as hydrochloric acid, p- toluenesulfonic acid or aqueous hydrogen iodide, in acetone or methyl oxide. Alternatively, compounds of formula III-a may be prepared by reacting compounds of formula II with acetone in the presence of MgSO ₄ , 4-tert-butylcatechol and iodine (LG Hamann, RI Higuchi, L. Zhi). JP Edwards and X.-N. Wang, J. Med. Chem, 41: 623, 1998). In another procedure, this reaction can be carried out in acetone using lanthanide triflate (eg scandium triflate) as catalyst. In this case, the reaction can be carried out using conventional heating or microwave irradiation at room temperature or at high temperature (ME Theoclitou and LA Robinson, Tetrahedron Lett. 43: 3907, 2002).

Compounds of formula III-b can be prepared from N-Boc-1,4-phenylenediamine II by reaction with methyl vinyl ketone. Related cyclization reactions are described in US Pat. No. 2,686,182 (Badische Anilin- & Soda-Fabrik Aktiengesellschaft).

Subsequent 1-N-acetylation of the compound of formula III-a-b can be carried out using standard conditions. In a typical experiment, the compound of formula III-ab is heated under reflux in acetic anhydride or in the presence of a base such as N, N-diisopropylethylamine, triethylamine or sodium hydride or dichloromethane, tetrahydrofuran, toluene or React with acetyl chloride in a solvent such as pyridine to form the 1-N-acetyl-4-methyl-1,2-dihydroquinoline derivative of Formula IV-ab.

Standard digestion of Boc protecting groups under conditions known to those skilled in the art affords 6-amino-1,2-dihydroquinoline derivatives of the formula V-a-b. This reaction is usually carried out in dichloromethane in the presence of trifluoroacetic acid.

Subsequent 6-N-acylation of the compound of formula Vab is carried out using standard conditions in which R ⁴ produces a compound of formula VI-ab as described above. For example, a compound of formula Vab may be prepared in an solvent such as dichloromethane, tetrahydrofuran or toluene, in the presence of a base such as N, N-diisopropylethylamine, triethylamine, pyridine or sodium hydride (R ^4- C (O) -Cl) or acid anhydride (R ⁴ -C (O) -OC (O) -R ⁴ ) to react 6-N-acylated 4-methyl-1 of formula VI-ab, To produce a 2-dihydroquinoline derivative. Alternatively, acylation of compounds of formula Vab to provide a compound of formula VI-ab will, O - (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium-tetra borate (TBTU) fluoroalkyl, O - (7- aza-benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate in (HATU) or bromo Mott repeater Raleigh Dino Force Phonium hexafluorophosphate (PyBrOP) and tertiary bases such as N, N - di in the presence of coupling reagents such as diisopropylethylamine, N, N - dimethylformamide or dichloromethane in a solvent such as methane suitable at room temperature or high temperature-carboxylic acid (R ⁴ -CO ₂ H) and reaction It can carry out by making it carry out.

Introduction of the essentially substituted phenyl group at position 4 of the dihydroquinoline backbone is carried out to alkylate the anisole with Friedel-Crafts using the compound of formula VI-ab to produce the compound of formula VII-ab. can do. This reaction is usually carried out in Lewis acid (eg AlCl ₃ , AlBr _3, FeCl ₃ or in anisole or in a suitable inert solvent such as heptane or hexane together with anisole as reagent). SnCl ₄ ) is carried out at high temperature under a catalyst. Friedel-Craft alkylation with 2,2,4-trimethyl-1,2-dihydroquinoline is described by BA Lugovik, LG Yudin and AN Kost, Dokl. Akad. Nauk SSSR, 170: 340, 1966; BA Lugovik, LG Yudin, SM Vinogradova and AN Kost, Khim. Geterosikl. Soedin, 7: 795, 1971.

Alternatively, N-Boc-1,4-phenylenediamine II is reacted with 2- (4-methoxyphenyl) -propane and formaldehyde in acetonitrile at room temperature or elevated temperature, followed by 1- as described above. N-acetylation can yield the compound of Formula VII-b, wherein R ⁴ = O-tert-Bu. Related cyclization reactions are described in JM Mellor and GD Merriman, Tetrahedron, 51: 6115, 1995. Degradation of Boc protecting groups as described above and acyl halides of 6-amino functional groups (R ⁴ -C (O). Subsequent acylation with) -Cl) allows R ⁴ to obtain a compound of formula VII-b as described above.

Decomposition of the aromatic methyl ether in the compound of formula VII-ab provides a 4- (4-hydroxyphenyl) substituted tetrahydroquinoline derivative of formula VIII-ab, providing a step for the functionalization of the free OH group .

Demethylation reactions of aromatic methyl ethers are known in the art. In a typical experiment, a demethylation reaction is achieved in which a compound of formula VII-ab is reacted with BBr _{3 in an} inert solvent such as dichloromethane at low to room temperature to obtain a demethylated compound of formula VIII-ab. Alternatively, the compound of formula VII-ab may be demethylated by reaction with a BF ₃ .Me ₂ S complex at room temperature.

Selective O-alkylation of a compound of Formula VIII-ab with a functionalized alkyl halide of Formula IX-a forms a compound of Formula Iab. Alkylation reactions of aromatic hydroxyl groups are known in the art. Typically, a solution of the compound of formula VIII-ab is prepared in a suitable solvent such as 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile, acetone or N, N-dimethylformamide in a base (e.g., N, N- Diisopropylamine, triethylamine, K ₂ CO ₃ , Cs ₂ CO ₃ or NaOH) and suitable alkylating reagents of formula IX-a such as benzyl bromide, 3- (dimethylamino) -propyl chloride, 4- (2- Treated with chloroethyl) -morpholine, 2-picolylchloride or 2-chloroacetamide. Alternatively, it can be alkylated by known Mitsnov type alkylation methods. In this case, the solution of the compound of formula VIII-ab (resin-bonded) triphenyl phosphine, diethyl- or di-tert-butyl azodica in a suitable solvent such as 1,4-dioxane, tetrahydrofuran or dichloromethane Treatment with carboxylate and functionalized alcohol of formula (IX-b). In principle, both alkylation methods can be used for all R ³ groups, but an appropriate protecting group strategy may be required if R ³ comprises nucleophilic groups such as secondary amines or hydroxyl groups. Protective group selection and deprotection conditions are apparent to those skilled in the art.

Another procedure for obtaining a compound of the present invention begins with alkylating a compound of formula VIII-a-b with an ester of formula X.

The alkylation reaction is usually carried out in the presence of a base such as N, N-diisopropylethylamine or sodium hydride in a suitable solvent such as N, N-dimethylformamide or tetrahydrofuran at room temperature or high temperature. Ester functional groups in the resulting compounds of Formula XI-ab wherein A = Me or Et are selectively reduced under controlled conditions at low temperatures using controlled reducing agents such as lithium aluminum hydride or sodium hydride in an inert solvent such as tetrahydrofuran Obtain the compound of XIII-ab. The free hydroxyl group of the compound of formula XIII-ab is then subjected to 4- in an inert solvent such as 1,4-dioxane, N, N-dimethylformamide or THF in the presence of a suitable base such as triethylamine or pyridine. React with toluenesulfonyl chloride (Ts-Cl) or methanesulfonyl chloride (Ms-Cl) to form appropriate leaving groups (compounds of formula XIV-ab; LG = Ts or Ms, respectively). Under the conditions known to those skilled in the art, nucleophilic substitution with an appropriate nucleophile (amine or alkoxide) may be such that R ³ = R ^5- (2-4C) alkyl and R ⁵ is a compound of formula Iab as described above.

The conversion of the compound of formula (XI-ab), wherein A = tert-Bu, to the carboxylic acid of formula (XII-ab) can be carried out by deprotection of tert-butyl ester functionality. In a typical experiment, the tert-butyl ester of formula XI-ab (A = tert-Bu) is dissolved in dichloromethane and treated with a strong acid such as trifluoroacetic acid. A carboxylic acid of formula XII-ab, at room temperature or high temperature O - (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium borate as tetrafluoroborate (TBTU), O - (7- aza-benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate as a phosphate (HATU) or bromo Mott repeater Raleigh Dino force hexafluorophosphate (PyBrOP ) And tertiary bases such as N, N - in the presence of a coupling agent such as diisopropylethylamine, N, N - dimethylformamide or dichloro methane and the solvent by condensation reaction with the appropriate alcohol or amine in the same R ³ = R ⁵ - carbonyl (1- 4C) alkyl and R ⁵ can yield a compound of formula Iab as described above.

Some of the compounds of the present invention, which may be in the form of a free base, may be separated from the reaction mixture in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts may also be formulated with a free base of formula (I) as an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, It can be obtained by treating with tartaric acid, citric acid, benzoic acid, and ascorbic acid.

The compounds of the present invention bear one or more chiral carbon atoms and thus can be obtained as pure enantiomers, as a mixture of enantiomers, or as mixtures of diastereomers. Methods for obtaining pure enantiomers, such as crystallization of salts from optically active acids and racemic mixtures, or chromatography using chiral columns are known in the art. In the case of diastereomers, linear or reversed phase columns can be used.

The compounds of the present invention may form hydrates or solvates. It is known to those skilled in the art that charged compounds form species that are hydrated with water upon lyophilization or solvated species with an appropriate organic solvent when concentrated in solution. Compounds of the invention include hydrates or solvates of the compounds listed.

The activity of the results tested at 10 ⁻⁵ M to select the active compound should be at least 20% of the maximum activity when using FSH as reference. Another criterion is the EC ₅₀ value, which must be <10 ^-5 M, preferably <10 ^-7 M.

Those skilled in the art will appreciate that the preferred EC ₅₀ value depends on the compound being tested. For example, compounds having an EC ₅₀ of less than 10 ⁻⁵ M are generally considered as candidates for drug selection. Preferably this value is 10 ⁻⁷ M or less. However, even if the EC ₅₀ is higher, compounds selective for a particular receptor may be better candidates.

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

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

Methods of constructing cell lines expressing recombinant FSH are well known to those skilled in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Expression of the receptor is achieved by expression of DNA encoding the protein of interest. Techniques for positional mutagenesis, ligation of additional sequences, PCR, and construction of appropriate expression systems are well known in the art to date. Standard solid phase techniques can be used to synthesize part or all of the DNA encoding the protein of interest, preferably to include restriction sites for easy ligation. Suitable regulatory components for the transcription and translation of the coding sequence included can be provided in the DNA coding sequence. As is well known, expression systems are currently available that are compatible with a wide variety of hosts including prokaryotic hosts such as bacterial and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, avian cells and the like. .

The cells expressing the receptor are then contacted with the test compound to observe the binding or stimulation or inhibition of the functional response.

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

For binding measurements, radiolabeled or fluorescently labeled compounds can be used. Competitive binding analysis can also be performed.

Another analysis involves screening for FSH receptor agonist compounds by measuring stimulation of receptor mediated cAMP accumulation. Thus, such methods include expression of the receptor on the cell surface of the host cell and exposure of the cell to the test compound. The amount of cAMP is then measured. The level of cAMP can be reduced or increased depending on the inhibitory or stimulatory effect of the test compound upon binding to the receptor.

Screening for FSH receptor antagonists involves FSH receptors with a range of test compounds at fixed FSH concentrations that exhibit a non-maximal effect (i.e., FSH concentrations that induce approximately 80% of the maximum stimulation of cAMP accumulation in the absence of test compounds). -Culturing the expressing cells. From the concentration-effect curves,% inhibition of FSH-induced cAMP accumulation and IC ₅₀ values can be determined for each test compound. As reference compound, human recombinant FSH can be used. Alternatively, competitive analysis can be conducted.

In addition to direct measurement of cAMP levels, eg, in exposed cells, cell lines may also be used that have been transfected with receptor coding DNA and also transfected with a second DNA encoding a reporter gene that expresses in response to the level of cAMP. Such reporter genes may be cAMP inducible or may be constructed in a way that is linked to novel cAMP response components. In general, reporter gene expression can be regulated with any response component that responds to changes in the level of cAMP. Suitable reporter genes are, for example, genes encoding β-galactosidase, alkaline phosphatase, firefly luciferase and green fluorescent protein. The principles of such transactivation assays are well known in the art, such as Stratowa, Ch., Himmler, A. and Czernilofsky, A.P., (1995) Curr. Opin. Biotechnol. 6: 574.

The present invention also relates to pharmaceutical compositions comprising a tetrahydroquinoline derivative of formula (I) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant and optionally other therapeutic agents. Adjuvants should be "acceptable" in the sense of being compatible with the other ingredients of the composition and harmless to the recipient.

The composition includes all unit dosage forms for administration, such as those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, topical, rectal administration, and the like.

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

For parenteral administration, the pharmaceutical compositions of the present invention may be provided in unit-dose or multi-dose containers, such as sealed vials and ampoules, such as a predetermined amount of injectable liquid, and may also be dispensed with a sterile liquid carrier such as water prior to use. It can be stored in a freeze dried or lyophilized state just added.

Such pharmaceutically acceptable adjuvants, such as those described in standard references, Gennaro, AR et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, especially Part 5: Pharmaceutical Manufacturing). The active agent mixed with the adjuvant is compressed into a solid formulation, such as a pill, tablet, or processed into a capsule or suppository. Pharmaceutically acceptable liquids may be used to apply the active agent as a fluid composition, such as an injection formulation, in the form of a solution, suspension, emulsion, or spray, such as a nasal spray.

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

The present invention further includes a pharmaceutical composition in combination with a packaging material suitable for the composition, as described above, wherein the packaging material includes instructions for use of the composition for use as described above.

In addition, the tetrahydroquinoline derivatives of the present invention may be administered in the form of implantable pharmaceutical devices consisting of a core of active substance wrapped by a release rate-controlling membrane. Such implants are applied subcutaneously or topically, releasing the active agent at approximately constant rates over a relatively long time period, such as weeks to years. Methods of making implantable pharmaceutical devices are known in the art, for example as described in European Patent 0,303,306 (Akzo Nobel V.).

The exact dosage and regimen of the active ingredient, or pharmaceutical composition thereof, depends essentially on the therapeutic effect to be realized (treatment of infertility; contraception), depending on the particular compound, route of administration, and the age and symptoms of the individual subject to which the medicament is administered. It can vary.

Parenteral administration generally requires lower dosages than other methods of administration, which are more dependent on absorption. However, dosages for humans preferably comprise 0.0001 to 25 mg / kg body weight. Preferred doses may be given as single doses or as multiple doses administered at appropriate intervals on the same day, or, in the case of female recipients, doses administered at appropriate daily intervals throughout the menstrual cycle. Dosage and usage may vary between male and female recipients.

Thus, the compounds of the present invention can be used for treatment.

Another aspect of the present invention is the use of a tetrahydroquinoline derivative compound of formula (I) for the manufacture of a medicament for use in the treatment of diseases that respond to FSH receptor mediated pathways. Thus, a patient in need thereof may be administered in an appropriate amount of a compound of the present invention.

In another aspect the invention relates to the use of a tetrahydroquinoline derivative compound of formula I for the manufacture of a medicament for use in pregnancy control.

In another aspect the invention relates to the use of a tetrahydroquinoline derivative compound of formula I for the manufacture of a medicament for use in the treatment of infertility.

In another aspect the present invention relates to the use of a tetrahydroquinoline derivative compound of formula (I) for the manufacture of a medicament for use in the prevention of pregnancy.

The compounds according to the invention can also be used for the treatment of hormone-dependent diseases such as breast cancer, prostate cancer and endometriosis.

The invention is illustrated by the following examples.

General description

The following abbreviations are used in the examples: DMA = N, N-dimethylaniline, DIPEA = N, N-diisopropylethylamine; TFA = trifluoroacetic acid, DtBAD = di-tert-butyl azodicarboxylate; TBTU = O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate; HATU = 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; Fmoc = 9-fluorenylmethoxycarbonyl; Fmoc-Cl = 9-fluorenylmethoxycarbonylchloride; DMF = N, N-dimethylformamide; Boc = tert-butoxycarbonyl; THF = tetrahydrofuran.

The final product names described in the examples are made using the Beilstein Autonom program (version: 2.02.119).

Unless stated otherwise, all final products of the following examples are lyophilized from water / 1,4-dioxane mixtures or water / acetonitrile mixtures. If the compound is prepared with HCl- or TFA salt, an appropriate amount of each acid is added to the solvent mixture prior to lyophilization.

The following analytical HPLC method is used to determine residence time:

Method 1: Column: 5 μm Luna C-18 (2) 150 × 4.6 mm; Flow rate: 1 ml / min; Detection: 210 nm; Column temperature: 40 ° C .; Solvent A: CH ₃ CN / H ₂ O = 1/9 (v / v); Solvent B: CH ₃ CN; Solvent C: 0.1 M aqueous trifluoroacetic acid; Gradient: at 30.00 min solvent A / B / C = 65/30/5 to 10/85/5 (v / v / v), then A / B / C = 10/85/5 (v / v / v) Constant for an additional 10.00 minutes.

Method 2: Same as Method 1 except for the gradient used: Gradient: Solvent A / B / C = 75/20/5 to 15/80/5 (v / v / v) followed by A / B for 30.00 minutes Constant for an additional 10.00 minutes at / C = 15/80/5 (v / v / v).

Method 3: Column: 3 μm Luna C-18 (2) 100 × 2 mm; Flow rate: 0.25 ml / min; Detection: 210 nm; Column temperature: 40 ° C .; Solvent A: H ₂ 0; Solvent B: CH ₃ CN; Solvent C: 50 mM phosphate buffer, pH 2.1; Gradient: at 20.00 min solvent A / B / C = 70/20/10 to 10/80/10 (v / v / v), then A / B / C = 10/80/10 (v / v / v) Constant for an additional 10.00 minutes.

Method 4: Same as Method 3, except for the gradient used: Gradient: Solvent A / B / C = 65/30/5 to 10/85/5 (v / v / v) followed by A / B for 20.00 minutes Constant for an additional 10.00 minutes at / C = 10/85/5 (v / v / v).

Method 5: Same as Method 3, except for the gradient used: Gradient: Solvent A / B = 75 / 25-0 / 100 (v / v) followed by A / B / C = 0/100 (v) for 20.00 minutes / v) constant for an additional 10.00 minutes.

Method 6: Same as Method 1, except for the gradient used: Gradient: Solvent A / B / C = 35/60/5 to 10/85/5 (v / v / v) followed by A / B for 30.00 minutes Constant for an additional 10.00 minutes at / C = 10/85/5 (v / v / v).

The following method is used for preparative HPLC-purification:

Method A: Column = Luna C-18. Gradient: 0.1% trifluoro in H ₂ 0 / CH ₃ CN (9/1, v / v) / CH ₃ CN = 100/0 to 0/100 (v / v), depending on the ease of separation, for 30 to 45 minutes. Roacetic acid. Detection: 210 nm. Appropriate fractions were collected and concentrated (partially) in vacuo.

Method B: Column = Luna C-18. Gradient: H ₂ O / CH ₃ CN (9/1, v / v) / CH ₃ CN = 80/20 to 0/100 (v / v), depending on the ease of separation. Detection: 210 nm.

Example 1

Biphenyl-4-carboxylic acid {1-acetyl-4- [4-[(2-dimethylamino-ethoxy) -phenyl] -2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline -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), MgSO ₄ (216 g), 4-tert-butylcatechol (1.8 g) and iodine (4.7 g) in anhydrous acetone (600 mL) Heated to reflux for 20 hours. MgSO ₄ was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on short plugs of silica gel with heptane / ethyl acetate = 8/2 (v / v) as eluent to afford the product as a brown oil.

Production volume: 41 g.

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

The solution of compound (41 g) described in Example 1a in pyridine (200 mL) and CH ₂ Cl ₂ (200 mL) was cooled to 0 ° C. Acetyl chloride (21 mL) was added dropwise in CH ₂ Cl ₂ (50 mL). After the addition was complete, the mixture was stirred at room temperature for 3 hours. Ethyl acetate (2 L) and H ₂ 0 (2 L) were added and the organic layer was separated, dried 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-1,2-dihydroquinoline

Compound (15 g) described in Example 1b was stirred in a mixture of CH ₂ Cl ₂ and TFA (9/1 (v / v), 300 mL) for 2 hours. The reaction mixture was cooled to 0 ° C. and the pH was adjusted to pH 7 using 2 M NaOH aqueous solution. The organic layer was separated, washed with brine, dried and concentrated in vacuo to afford the crude product used in the next step without further purification.

Production volume: 10.4 g.

(d) biphenyl-4-carboxylic acid (1-acetyl-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl) -amide

To a solution of compound (10 g) and DIPEA (40 mL) described in Example 1c in CH ₂ Cl ₂ (100 mL) was added 4-biphenylcarbonyl chloride (9.8 g) and the resulting mixture was 18 at room temperature. Stir for hours. Water was added and the organic layer was separated, dried and concentrated in vacuo. The product was crystallized from ethyl acetate.

Production amount: 15 g.

(e) biphenyl-4-carboxylic acid [1-acetyl-4- (4-methoxyphenyl) -2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] -amide

While stirring, aluminum trichloride (9.7 g) was added to the mixture of the compound described in Example 1d (10.0 g) and anhydrous anisole (50 mL), and the resulting mixture was stirred at 35 ° C. for 18 hours. Then water was added at 0 ° C. and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried and partially concentrated in vacuo, and the mixture was stored at 0 ° C. for 18 hours. The precipitate formed was collected by filtration and dried in vacuo to afford the title compound.

Production volume: 7.9 g.

(f) biphenyl-4-carboxylic acid [1-acetyl-4- (4-hydroxyphenyl) -2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]- amides

To a solution of the compound described in Example 1e (7.9 g) in CH ₂ Cl ₂ (200 mL) at 0 ° C. is added a solution of boron tribromide (5 mL) in CH ₂ Cl ₂ (50 mL) and the mixture is Leave at 0 ° C. for 4 hours. Water (about 500 mL) was added carefully and the resulting mixture was vigorously stirred. The organic layer was separated, dried and concentrated in vacuo. Crystallization from ethyl acetate gave the title compound.

Production volume: 6.1 g.

(g) biphenyl-4-carboxylic acid {1-acetyl-4- [4- (2-dimethylamino-ethoxy) -phenyl] -2,2,4-trimethyl-1,2,3,4-tetrahydro -Quinolin-6-yl} -amide

General Procedure A: Cs ₂ CO ₃ (200 mg) and 2-dimethylamino-ethylchloride hydrochloride (17 mg) were added to a solution of compound (70 mg) described in Example 1f in DMF (2 mL). After addition of water and ethyl acetate, the resulting mixture was stirred overnight. The organic layer was separated, dried and concentrated in vacuo. The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 18 mg (TFA salt); MS-ESI: [M + H] ⁺ = 576.6; HPLC: R _t = 14.96 min (Method 3).

Example 2

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

According to General Procedure A, the compound described in Example 1f (70 mg) was alkylated with 3-dimethylamino-propylchloride hydrochloride (19 mg) and Cs ₂ CO ₃ (200 mg) in DMF (2 mL). The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 58 mg (TFA salt); MS-ESI: [M + H] ⁺ = 590.4; HPLC: R _t = 15.36 min (Method 3).

Example 3

Biphenyl-4-carboxylic acid {1-acetyl-2,2,4-trimethyl-4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -1,2,3,4-tetra Hydro-quinolin-6-yl} -amide

According to General Procedure A, the compound described in Example 1f (70 mg) was alkylated with 3-morpholinopropylchloride (26 mg) and Cs ₂ CO ₃ (200 mg) in DMF (2 mL). The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 56 mg (TFA salt); MS-ESI: [M + H] ⁺ = 631.6; HPLC: R _t = 15.40 min (Method 3).

Example 4

Biphenyl-4-carboxylic acid {1-acetyl-2,2,4-trimethyl-4- [4- (pyridin-2-ylmethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline-6 -Yl} -amide

According to General Procedure A, the compound described in Example 1f (100 mg) was alkylated with 2-picolinyl chloride hydrochloride (33 mg) and Cs ₂ CO ₃ (325 mg) in DMF (5 mL). The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 60 mg (TFA salt); MS-ESI: [M + H] ⁺ = 596.4; HPLC: R _t = 19.75 min (Method 2).

Example 5

Biphenyl-4-carboxylic acid {1-acetyl-2,2,4-trimethyl-4- [4- (1-methyl-piperidin-3-ylmethoxy) -phenyl] -1,2,3,4- Tetrahydro-quinolin-6-yl} -amide

According to General Procedure A, the compound (100 mg) described in Example 1f was converted to 3-chloromethyl-1-methylpiperidine hydrochloride (33 mg) and Cs ₂ CO ₃ (325 mg) in DMF (5 mL). Alkylated. The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 60 mg (TFA salt); MS-ESI: [M + H] ⁺ = 615.4; HPLC: R _t = 16.70 min (Method 2).

Example 6

Biphenyl-4-carboxylic acid {1-acetyl-4- [4-[(2-diethylamino-ethoxy) -phenyl] -2,2,4-trimethyl-1,2,3,4-tetrahydro- Quinolin-6-yl} -amide

According to General Procedure A, the compound (100 mg) described in Example 1f was alkylated with 2-diethylamino-ethyl chloride (35 mg) and Cs ₂ CO ₃ (325 mg) in DMF (5 mL). The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 67 mg (TFA salt); MS-ESI: [M + H] ⁺ = 604.4; HPLC: R _t = 16.38 min (Method 2).

Example 7

Biphenyl-4-carboxylic acid {1-acetyl-2,2,4-trimethyl-4- [4- (pyridin-4-ylmethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline-6 -Yl} -amide

According to General Procedure A, the compound (100 mg) described in Example 1f was alkylated with 4-picolylchloride hydrochloride (33 mg) and Cs ₂ CO ₃ (325 mg) in DMF (5 mL). The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 61 mg (TFA salt); MS-ESI: [M + H] ⁺ = 596.4; HPLC: R _t = 16.64 min (Method 2).

Example 8

Morpholine-4-carboxylic acid [3- (4- {1-acetyl-6-[(biphenyl-4-carbonyl) -amino] -2,2,4-trimethyl-1,2,3,4-tetra Hydro-quinolin-4-yl} -phenoxy) -propyl] -amide

According to General Procedure A, the compound (100 mg) described in Example 1f was converted to morpholine-4-carboxylic acid (3-chloropropyl) amide (53 mg) and Cs ₂ CO ₃ (325 mg) in DMF (5 mL). Alkylated. The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of CH ₃ CN and water.

Production amount: 95 mg; MS-ESI: [M + H] ⁺ = 675.6; HPLC: R _t = 18.24 min (Method 3).

Example 9

Biphenyl-4-carboxylic acid {1-acetyl-4- [4- (2-azpan-1-yl-ethoxy) -phenyl] -2,2,4-trimethyl-1,2,3,4-tetra Hydro-quinolin-6-yl} -amide

According to General Procedure A, the compound (100 mg) described in Example 1f was alkylated with 2- (hexamethyleneimino) ethyl hydrochloride (42 mg) and Cs ₂ CO ₃ (325 mg) in DMF (5 mL). It was. The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 60 mg (TFA salt); MS-ESI: [M + H] ⁺ = 630.6; HPLC: R _t = 17.25 min (Method 2).

Example 10

Biphenyl-4-carboxylic acid {1-acetyl-2,2,4-trimethyl-4- [4- (pyridin-3-ylmethoxy) -phenyl-1,2,3,4-tetrahydro-quinoline-6- Il} -amide

According to General Procedure A, the compound (1.0 g) described in Example 1f was alkylated with 3-piccoloylchloride hydrochloride (488 mg) and Cs ₂ CO ₃ (3.2 mg) in DMF (10 mL). The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 884 mg (TFA salt); MS-ESI: [M + H] ⁺ = 596.4; HPLC: R _t = 16.55 min (Method 3).

Example 11

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

According to General Procedure A, the compound (100 mg) described in Example 1f was alkylated with 2-chloroacetamide (24 mg) and Cs ₂ CO ₃ (325 mg) in DMF (5 mL). The product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 40 mg; MS-ESI: [M + H] ⁺ = 562.6; HPLC: R _t = 21.63 min (Method 2).

Example 12

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

(a) (4- {1-acetyl-6-[(biphenyl-4-carbonyl) amino] -2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-4-yl } Phenoxy) acetic acid tert-butyl ester

A mixture of compound (2.58 g), tert-butyl bromoacetate (826 μl), K ₂ CO ₃ (2.8 g) and acetone (100 mL) described in Example 1f was stirred at 50 ° C. for 18 hours. The solid was removed by filtration and the filtrate was concentrated in vacuo to give the product used for the next step without further purification.

Production volume: 3.2 g.

(b) (4- {1-acetyl-6-[(biphenyl-4-carbonyl) amino] -2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-4-yl Phenoxy) acetic acid

The compound (3.2 g) described in Example 12a was stirred in a mixture of CH ₂ Cl ₂ and TFA (9/1 (v / v), 100 mL) for 3 hours. Toluene (100 mL) was added and the mixture was concentrated in vacuo to afford the crude product which was used without further purification.

Yield: 3.3 g.

(c) biphenyl-4-carboxylic acid [1-acetyl-4- (4-allylcarbamoylmethoxy-phenyl) -2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline- 6-yl] -amide

General Procedure B: TBTU (84 mg) was added to a solution of the compound described in Example 12b (82 mg), allylamine (37 mg) and DIPEA (226 μl) in CH ₂ Cl ₂ (5 mL) at room temperature. If the reaction did not end after 18 hours, further TBTU and DIPEA were added. After the reaction was completed, water was added, the organic layer was separated, washed with brine, dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Method A).

Production amount: 48 mg; MS-ESI: [M + H] ⁺ = 602.4; HPLC: R _t = 18.19 min (Method 4).

Example 13

Biphenyl-4-carboxylic acid {1-acetyl-4- [4- (isopropylcarbamoyl-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 12b (82 mg) was treated with isopropylamine (38 mg), DIPEA (226 μl) and TBTU (84 mg) in CH ₂ Cl ₂ (5 mL). The title compound was purified by preparative HPLC (Method A).

Production amount: 45 mg; MS-ESI: [M + H] ⁺ = 604.6; HPLC: R _t = 18.63 min (Method 4).

Example 14

Biphenyl-4-carboxylic acid [1-acetyl-4- (4-diethylcarbamoylmethoxy-phenyl) -2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6- General] -amide

According to General Procedure B, the compound described in Example 12b (82 mg) was treated with diethylamine hydrochloride (47 mg), DIPEA (226 μl) and TBTU (84 mg) in CH ₂ Cl ₂ (5 mL). . The title compound was purified by preparative HPLC (Method A).

Production amount: 51 mg; MS-ESI: [M + H] ⁺ = 618.4; HPLC: R _t = 19.09 min (Method 4).

Example 15

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

According to General Procedure B, the compound described in Example 12b (82 mg) was treated with 4-picolinylamine (70 mg), DIPEA (226 μl) and TBTU (84 mg) in CH ₂ Cl ₂ (5 mL). . The title compound was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 52 mg (TFA salt); MS-ESI: [M + H] ⁺ = 653.6; HPLC: R _t = 11.31 min (Method 4).

Example 16

Biphenyl-4-carboxylic acid [1-acetyl-4- (4-{[(furan-2-ylmethyl) -carbamoyl] -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 12b (82 mg) was treated with 2-furfurylamine (63 mg), DIPEA (226 μl) and TBTU (84 mg) in CH ₂ Cl ₂ (5 mL). . The title compound was purified by preparative HPLC (Method A).

Production: 50 mg; MS-ESI: [M + H] ⁺ = 642.6; HPLC: R _t = 21.31 min (Method 3).

Example 17

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

According to General Procedure B, the compound (82 mg) described in Example 12b was treated with 2-methoxyethylamine (49 mg), DIPEA (226 μl) and TBTU (84 mg) in CH ₂ Cl ₂ (5 mL). It was. The title compound was purified by preparative HPLC (Method A).

Production amount: 34 mg; MS-ESI: [M + H] ⁺ = 620.4; HPLC: R _t = 19.70 min (Method 3).

Example 18

Biphenyl-4-carboxylic acid {1-acetyl-4- [4- (benzylcarbamoyl-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 12b (82 mg) was treated with benzylamine (49 mg), DIPEA (226 μl) and TBTU (84 mg) in CH ₂ Cl ₂ (5 mL). The title compound was purified by preparative HPLC (Method A).

Production amount: 53 mg; MS-ESI: [M + H] ⁺ = 652.6; HPLC: R _t = 22.26 min (Method 3).

Example 19

Biphenyl-4-carboxylic acid (1-acetyl-4- {4-[(2-dimethylamino-ethylcarbamoyl) -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 12b (82 mg) was diluted with N, N-dimethylethylenediamine (49 mg), DIPEA (226 μl) and TBTU (84 mg) in CH ₂ Cl ₂ (5 mL). Treated. The title compound was purified by preparative HPLC (Method A). Lyophilization from a mixture of aqueous HCl and 1,4-dioxane gave the title compound as an HCl-salt.

Production amount: 11 mg (HCl-salt); MS-ESI: [M + H] ⁺ = 633.4; HPLC: R _t = 13.74 min (Method 3).

Example 20

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

According to General Procedure B, the compound described in Example 12b (82 mg) was treated with CH ₂ Cl ₂ (5 mL) in methylamine hydrochloride (20 mg), DIPEA (226 μl) and TBTU (84 mg). The title compound was purified by preparative HPLC (Method A).

Production amount: 35 mg; MS-ESI: [M + H] ⁺ = 576.4; HPLC: R _t = 19.25 min (Method 3).

Example 21

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

According to General Procedure B, the compound described in Example 12b (110 mg) was treated with morpholine (74 mg), DIPEA (296 μl) and TBTU (109 mg) in CH ₂ Cl ₂ (5 mL). The title compound was purified by preparative HPLC (Method A).

Production amount: 85 mg; MS-ESI: [M + H] ⁺ = 632.4; HPLC: R _t = 12.48 min (Method 3).

Example 22

N- {1-acetyl-2,2,4-trimethyl-4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -5-bromo-2-methylamino-benzamide

(a) (1-acetyl-2,2,4-trimethyl-1,2-dihydro-quinolin-6-yl) -carbamic acid 9-fluorenylmethyl ester

To a solution of compound (17 g) and DIPEA (40 mL) described in Example 1c in CH ₂ Cl ₂ (100 mL) was added FmocCl (25 g) and the resulting mixture was stirred at rt for 18 h. Ethyl acetate (about 200 mL) and water (150 mL) were added and the organic layer was separated, dried and concentrated in vacuo. The title compound was purified by chromatography on silica gel using CH ₂ Cl ₂ as eluent.

Production volume: 16.6 g.

(b) [1-acetyl-4- (4-methoxyphenyl) -2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] -carbamic acid 9-fluorenyl Methyl ester

While stirring, aluminum trichloride (24.2 g) was added to the mixture of the compound described in Example 22a (16.5 g) and anhydrous anisole (150 mL), and the resulting mixture was stirred at 35 ° C. for 18 hours. Then water was added at 0 ° C. and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried, partially concentrated in vacuo, and the mixture was stored at 0 ° C. for 18 hours. The precipitate formed was collected by filtration and dried in vacuo to afford the title compound.

Production volume: 10.1 g.

(c) [1-acetyl-4- (4-hydroxyphenyl) -2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl] -carbamic acid 9-fluorenyl Methyl ester

Boron tribromide (5.05 mL) was added dropwise to the mixture of compound (10.1 g) described in Example 22b in anhydrous CH ₂ Cl ₂ (500 mL), and the resulting mixture was stirred at room temperature for 2.5 hours. The reaction was quenched with ice water at 0 ° C. and CH ₂ Cl ₂ was added. The organic layer was separated, dried and stored at 4 ° C. for 20 hours. The solid formed was collected by filtration and dried in vacuo to yield the crude product which was used without further purification.

Production volume: 12.5 g.

(d) 1-acetyl-6-amino-2,2,4-trimethyl-4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -1,2,3,4-tetra Hydroquinoline

A mixture of the compound (1.0 g), Cs ₂ CO ₃ (1.8 g), 4- (3-chloropropyl) morpholine (330 mg) and DMF (5 mL) described in Example 22c was stirred at 60 ° C. for 18 hours. It was. Water was added and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried and concentrated in vacuo. The title compound was purified by chromatography on silica gel using CH ₂ Cl ₂ /2% ammonia in MeOH = 1/0 => 9/1 (v / v) as eluent.

Production amount: 527 mg.

(e) N- {1-acetyl-2,2,4-trimethyl-4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -1,2,3,4-tetrahydro -Quinolin-6-yl} -5-bromo-2-methylamino-benzamide

General Procedure C: HATU (166) in a solution of the compound described in Example 22d (132 mg), 5-bromo-2-methylamino benzoic acid (101 mg) and DIPEA (255 μl) in CH ₂ Cl ₂ (3 mL). Mg) was added at room temperature. The reaction mixture was stirred at rt for 18 h. Ethyl acetate (15 mL) and 2 M aqueous NaOH (15 mL) were added. The organic layer was separated, washed with 2M aqueous NaOH (10 mL) and water (15 mL), dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Method A).

Production amount: 69.8 mg; MS-ESI: [M + H] ⁺ = 663.4; HPLC: R _t = 14.65 min (Method 3).

Example 23

N- {1-acetyl-2,2,4-trimethyl-4- [4- (3-morpholin-4-yl-propoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -3,5-dichloro-2,6-dimethoxy-benzamide

According to General Procedure C, the compound described in Example 22d (132 mg) was diluted with 3,5-dichloro-2,6-dimethoxybenzoic acid (110 mg), DIPEA (255 μl) in CH ₂ Cl ₂ (3 mL) and Acylated with HATU (166 mg). The title compound was purified by preparative HPLC (Method A).

Production amount: 68.3 mg; MS-ESI: [M + H] ⁺ = 684.3; HPLC: R _t = 13.45 min (Method 3).

Example 24

Biphenyl-4-carboxylic acid [1-acetyl-4- (4- {2-[(furan-2-ylmethyl) -amino] -ethoxy} -phenyl) -2,2,4-trimethyl-1,2 , 3,4-tetrahydro-quinolin-6-yl] -amide

(a) (4- {1-acetyl-6-[(biphenyl-4-carbonyl) amino] -2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-4-yl } -Phenoxy) acetic acid ethyl ester

A mixture of compound (1 g), ethyl bromoacetate (220 μl), K ₂ CO ₃ (850 mg) and acetone (25 mL) described in Example 1f was stirred at 50 ° C. for 6 hours. The solid was removed by filtration and the filtrate was concentrated in vacuo to give the product used for the next step without further purification.

Production volume: 1.2 g.

(b) biphenyl-4-carboxylic acid {1-acetyl-4- [4- (2-hydroxyethoxy) phenyl] -2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline- 6-yl} -amide

LiALH ₄ (78 mg) was carefully added to a solution of compound (1.2 g) described in Example 24a in THF (10 mL) at 0 ° C. and the resulting mixture was stirred at rt for 3 h. Ethyl acetate (50 mL) was added dropwise, followed by water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL) and the combined organic fractions were washed with brine. The organic layer was dried and concentrated in vacuo to give the product used for the next step without further purification.

Production amount: 1 g.

(c) methanesulfonic acid 2- (4- {1-acetyl-6-[(biphenyl-4-carbonyl) amino] -2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline- 4-yl} phenoxy) ethyl ester

To a solution of compound (1 g) and DIPEA (1.7 mL) described in Example 24b in CH ₂ Cl ₂ (15 mL) was added dropwise a solution of methanesulfonyl chloride (310 μL) in CH ₂ Cl ₂ (5 mL). After 2 hours, water was added and the organic layer was separated, dried and concentrated in vacuo. The title compound was purified by chromatography on silica gel using heptane / ethyl acetate = 9/1 => 1/1 (v / v) as eluent.

Production amount: 870 mg.

(d) biphenyl-4-carboxylic acid [1-acetyl-4- (4- {2-[(furan-2-ylmethyl) -amino] -ethoxy} -phenyl) -2,2,4-trimethyl- 1,2,3,4-tetrahydro-quinolin-6-yl] -amide

General Procedure D: 2-furfurylamine (107 mg) was added to a solution of compound (87 mg) described in Example 24c in CH ₃ CN (5 mL) and the resulting mixture was stirred at 70 ° C. for 18 h. . The mixture was concentrated in vacuo and the product was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 47 mg (TFA salt); MS-ESI: [M + H] ⁺ = 628.6; HPLC: R _t = 11.53 min (Method 4).

Example 25

Biphenyl-4-carboxylic acid (1-acetyl-4- {4- [2- (2-hydroxy-1,1-dimethyl-ethylamino) -ethoxy] -phenyl} -2,2,4-trimethyl- 1,2,3,4-tetrahydro-quinolin-6-yl) -amide

According to General Procedure D, the compound (87 mg) described in Example 24c was treated with 2-amino-2-methyl-propan-1-ol (100 mg) in CH ₃ CN (5 mL). The title compound was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 21 mg (TFA salt); MS-ESI: [M + H] ⁺ = 619.8; HPLC: R _t = 10.95 min (Method 4).

Example 26

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

According to General Procedure D, the compound (87 mg) described in Example 24c was treated with 3-aminomethylpyridine (119 mg) in CH ₃ CN (5 mL). The title compound was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 40 mg (TFA salt); MS-ESI: [M + H] ⁺ = 639.4; HPLC: R _t = 10.15 min (Method 4).

Example 27

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

According to General Procedure D, the compound (100 mg) described in Example 24c was treated with ethanolamine (100 mg) in CH ₃ CN (5 mL). The title compound was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 50 mg (TFA salt); MS-ESI: [M + H] ⁺ = 592.6; HPLC: R _t = 10.32 min (Method 1).

Example 28

Biphenyl-4-carboxylic acid (1-acetyl-4- {4- [2- (amino-ethylamino) -ethoxy] -phenyl} -2,2,4-trimethyl-1,2,3,4-tetra Hydro-quinolin-6-yl) -amide

According to General Procedure D, the compound (100 mg) described in Example 24c was treated with ethylenediamine (110 mg) in CH ₃ CN (5 mL). The title compound was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 45 mg (TFA salt); MS-ESI: [M + H] ⁺ = 591.4; HPLC: R _t = 7.04 min (Method 1).

Example 29

Biphenyl-4-carboxylic acid {1-acetyl-2,2,4-trimethyl-4- [4- (2-piperazin-1-yl-ethoxy) -phenyl] -1,2,3,4-tetra Hydro-quinolin-6-yl} -amide

According to General Procedure D, the compound described in Example 24c (100 mg) was treated with piperazine (140 mg) in CH ₃ CN (5 mL). The title compound was purified by preparative HPLC (Method A) and lyophilized from a mixture of water containing CH ₃ CN and TFA to afford the corresponding TFA salt.

Production amount: 95 mg (TFA salt); MS-ESI: [M + H] ⁺ = 617.6; HPLC: R _t = 9.54 min (Method 1).

Example 30

Morpholine-4-carboxylic acid (3- {4- [1-acetyl-6- (3,5-dichloro-2,6-dimethoxy-benzoylamino) -2,2,4-trimethyl-1,2,3 , 4-tetrahydro-quinolin-4-yl] -phenoxy} -propyl) -amide

(a) morpholine-4-carboxylic acid (3- {4- [1-acetyl-6-amino-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinolin-4-yl]- Phenoxy} -propyl) -amide

Following the same procedure as described in Example 22d, the compound described in Example 22c (1.0 g) was converted to morpholine-4-carboxylic acid (3-chloropropyl) using Cs ₂ CO ₃ (1.8 g) in DMF (5 mL). Alkylated with amide (448 mg) (with simultaneous removal of Fmoc protecting groups). The title compound was purified by chromatography on silica gel using CH ₂ Cl ₂ /2% ammonia in MeOH = 1/0 => 9/1 (v / v) as eluent.

Produced amount: 894 mg.

(b) morpholine-4-carboxylic acid (3- {4- [1-acetyl-6- (3,5-dichloro-2,6-dimethoxy-benzoylamino) -2,2,4-trimethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -phenoxy} -propyl) -amide

According to General Procedure C, the compound described in Example 30a (228 mg) was diluted with 3,5-dichloro-2,6-dimethoxybenzoic acid (230 mg), DIPEA (558 μl) in CH ₂ Cl ₂ (5 mL) and Acylated with HATU (609 mg). The title compound was purified by preparative HPLC (Method A).

Production amount: 102 mg; MS-ESI: [M + H] ⁺ = 727.4; HPLC: R _t = 22.37 min (Method 2).

Example 31

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -3,5-dibromo-benzamide

(a) 1-acetyl-6-amino-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetra Hydroquinoline

A mixture of the compound described in Example 22c (1.0 g), Cs ₂ CO ₃ (1.8 g), N- (2-chloroethyl) -morpholine hydrochloride (375 mg), and DMF (5 mL) at 60 ° C Stir for 18 hours. The reaction did not end, so additional amounts of Cs ₂ CO ₃ and N- (2-chloroethyl) -morpholine hydrochloride were added. After the reaction was completed, water was added, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried and concentrated in vacuo. The title compound was purified by chromatography on silica gel using CH ₂ Cl ₂ /2% ammonia in MeOH = 1/0 => 9/1 (v / v) as eluent.

Produced amount: 905 mg.

(b) N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro -Quinolin-6-yl} -3,5-dibromo-benzamide

According to General Procedure C, the compound (157 mg) described in Example 31a was converted to 3,5-dibrobenzobenzoic acid (150 mg), DIPEA (313 μl) and HATU (204 mg) in CH ₂ Cl ₂ (5 mL). Acylated. The title compound was purified by preparative HPLC (Method A).

Production amount: 71 mg (TFA salt); MS-ESI: [M + H] ⁺ = 700.2; HPLC: R _t = 16.12 min (Method 2).

Example 32

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -2-chloro-benzamide

According to General Procedure C, the compound described in Example 31a (150 mg) was acylated with 2-chlorobenzoic acid (81 mg), DIPEA (299 μl) and HATU (195 mg) in CH ₂ Cl ₂ (6 mL). . The title compound was purified by preparative HPLC (Method A).

Production amount: 162 mg (TFA salt); MS-ESI: [M + H] ⁺ = 576.4; HPLC: R _t = 9.37 min (Method 2).

Example 33

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -3,5-dimethyl-benzamide

According to General Procedure C, the compound described in Example 31a (200 mg) was converted into 3,5-dimethylbenzoic acid (103 mg), DIPEA (399 μl) and HATU (260 mg) in CH ₂ Cl ₂ (7.5 mL). It was a true story. The title compound was purified by preparative HPLC (Method A).

Production amount: 57.5 mg (TFA salt); MS-ESI: [M + H] ⁺ = 570.4; HPLC: R _t = 12.62 min (Method 2).

Example 34

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -2,5-dichloro-benzamide

According to General Procedure C, the compound described in Example 31a (200 mg) was converted into 2,5-dichlorobenzoic acid (131 mg), DIPEA (399 μl) and HATU (260 mg) in CH ₂ Cl ₂ (7.5 mL). It was a true story. The title compound was purified by preparative HPLC (Method A).

Production amount: 130 mg (TFA salt); MS-ESI: [M + H] ⁺ = 610.2; HPLC: R _t = 11.70 min (Method 2).

Example 35

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -5-methyl-2-nitro-benzamide

According to General Procedure C, the compound described in Example 31a (157 mg) was prepared with 5-methyl-2-nitrobenzoic acid (97.3 mg), DIPEA (313 μl) and HATU (204 mg) in CH ₂ Cl ₂ (5 mL). Acylated. The title compound was purified by preparative HPLC (Method A).

Production amount: 80 mg (TFA salt); MS-ESI: [M + H] ⁺ = 601.4; HPLC: R _t = 9.95 min (Method 2).

Example 36

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -benzamide

According to General Procedure C, the compound described in Example 31a (157 mg) was acylated with benzoic acid (65.6 mg), DIPEA (313 μl) and HATU (204 mg) in CH ₂ Cl ₂ (5 mL). The title compound was purified by preparative HPLC (Method A).

Production amount: 59 mg (TFA salt); MS-ESI: [M + H] ⁺ = 542.4; HPLC: R _t = 9.99 min (Method 2).

Example 37

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -4-tert-butyl-benzamide

According to General Procedure C, the compound (161 mg) described in Example 31a was purified with 4-tert-butylbenzoic acid (99 mg), DIPEA (322 μl) and HATU (210 mg) in CH ₂ Cl ₂ (5 mL). It was a true story. The title compound was purified by preparative HPLC (Method A).

Production amount: 80 mg (TFA salt); MS-ESI: [M + H] ⁺ = 598.2; HPLC: R _t = 15.39 min (Method 2).

Example 38

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -2,3-dichloro-benzamide

According to General Procedure C, the compound (161 mg) described in Example 31a was diluted with 2,3-dichlorobenzoic acid (106 mg), DIPEA (322 μl) and HATU (210 mg) in CH ₂ Cl ₂ (5 mL). It was a true story. The title compound was purified by preparative HPLC (Method A).

Production amount: 113 mg (TFA salt); MS-ESI: [M + H] ⁺ = 610.2; HPLC: R _t = 11.42 min (Method 2).

Example 39

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -4-bromo-benzamide

According to General Procedure C, the compound (260 mg) described in Example 31a was acylated with 4-bromobenzoic acid (179 mg), DIPEA (517 μl) and HATU (338 mg) in CH ₂ Cl ₂ (5 mL). It was. The title compound was purified by preparative HPLC (Method A).

Production amount: 127 mg (TFA salt); MS-ESI: [M + H] ⁺ = 620.2; HPLC: R _t = 12.24 min (Method 2).

Example 40

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -4-methoxy-3-methyl-benzamide

According to General Procedure C, the compound described in Example 31a (260 mg) was prepared with 4-methoxy-3-methylbenzoic acid (148 mg), DIPEA (517 μl) and HATU (338 mg) in CH ₂ Cl ₂ (5 mL). Acylated). The title compound was purified by preparative HPLC (Method A).

Production amount: 158 mg (TFA salt); MS-ESI: [M + H] ⁺ = 586.2; HPLC: R _t = 11.49 min (Method 2).

Example 41

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -4-dimethylamino-benzamide

According to General Procedure C, the compound (260 mg) described in Example 31a was acylated with 4-dimethylaminobenzoic acid (147 mg), DIPEA (517 μl) and HATU (338 mg) in CH ₂ Cl ₂ (5 mL). It was. The title compound was purified by preparative HPLC (Method A).

Production amount: 95 mg (TFA salt); MS-ESI: [M + H] ⁺ = 585.2; HPLC: R _t = 9.53 min (Method 2).

Example 42

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -3-trifluoromethyl-benzamide

To a solution of the compound described in Example 31a (260 mg) and pyridine (500 μl) in toluene (4.5 mL) was added 3- (trifluoromethyl) benzoyl chloride (185 mg). Ethyl acetate (15 mL) and water (15 mL) were added. The organic layer was separated, washed with water (15 mL), dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Method A).

Production amount: 200 mg (TFA salt); MS-ESI: [M + H] ⁺ = 610.2; HPLC: R _t = 13.23 min (Method 2).

Example 43

N- {1-acetyl-2,2,4-trimethyl-4- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -3-nitro-benzamide

To a solution of the compound described in Example 31a (260 mg) and pyridine (500 μl) in toluene (4.5 mL) was added 3-nitrobenzoyl chloride (165 mg). Ethyl acetate (15 mL) and water (15 mL) were added. The organic layer was separated, washed with water (15 mL), dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Method A).

Production amount: 167 mg (TFA salt); MS-ESI: [M + H] ⁺ = 587.4; HPLC: R _t = 10.28 min (Method 2).

Example 44

CHO-FSH In Vitro Life

The FSH activity of the compounds was tested in Chinese hamster ovary (CHO) cells stably transfected with human FSH receptor and transfected together with cAMP response element (CRE) / promoter to direct expression of the firefly luciferase reporter gene. Binding of the ligand to the Gs-coupled FSH receptor will result in an increase in cAMP, which in turn will lead to increased transactivation of the luciferase reporter construct. To test the antagonistic properties, recombinant FSH was added (rec-hFSH; 10 mU / ml) at a concentration that induced about 80% of the maximum stimulation of cAMP accumulation in the absence of test compound. Luciferase signal was quantified using an luminescence counter. For test compounds, EC ₅₀ values (concentrations of test compound causing stimulation or reduction of half maximum (50%)) were calculated. For this purpose, a software program GraphPad PRISM, version 3.0 (GraphPad software Inc., San Diego) was used.

Compounds of all examples exhibited EC ₅₀ (IC ₅₀ ) values of less than 10 ⁻⁵ M in either or both agonist or antagonist assay devices. The compounds of Examples 3, 4, 7, 10-13, 16, 36, 37, 39, 41 and 42 showed an EC ₅₀ (IC ₅₀ ) of less than 10 ⁻⁷ M in one or more of the above assays.

Claims (10)

Tetrahydroquinoline derivative of Formula 1, or a pharmaceutically acceptable salt thereof. Formula 1 (Wherein R ¹ and R ² are H, Me; R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl, (2-5C) heteroaryl (1-4C) alkyl, (6C) aryl (1-4C) alkyl, (1-4C) (di ) Alkylaminocarbonylamino (2-4C) alkyl, (2-6C) heterocycloalkylcarbonylamino (2-4C) alkyl, R ^5- (2-4C) alkyl or R ⁵ -carbonyl (1-4C Alkyl; R ⁴ is (2-5C) heteroaryl, (6C) aryl, (3-8C) cycloalkyl, (2-6C) heterocycloalkyl or (1-6C) alkyl; R ⁵ is (di) (1-4C) alkylamino, (1-4C) alkoxy, amino, hydroxy, (6C) arylamino, (di) (3-4C) alkenylamino, (2-5C) hetero Aryl (1-4C) alkylamino, (6C) aryl (1-4C) alkylamino, (di) [(1-4C) alkoxy (2-4C) alkyl] amino, (di) [(1-4C) alkyl Amino (2-4C) alkyl] amino, (di) [amino (2-4C) alkyl] amino or (di) [hydroxy (2-4C) alkyl] amino) The compound of claim 1, wherein R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl, (2-5C) heteroaryl (1-4C) alkyl, (2-6C) heterocycloalkylcarbonylamino ( 2-4C) alkyl, R ^5- (2-4C) alkyl or R ⁵ -carbonyl (1-4C) alkyl. The compound of claim 1, wherein R ⁵ is (di) (1-4C) alkylamino, amino, (di) (3-4C) alkenylamino, (2-5C) heteroaryl (1-4C) Derivatives which are alkylamino or (6C) aryl (1-4C) alkylamino. The derivative of any of claims 1-3, wherein R ⁵ is (di) (1-4C) alkylamino or amino. The derivative of claim 1, wherein R ⁵ is (di) (1-4C) alkylamino. The derivative according to any one of claims 1 to 5, wherein R ⁴ is (6C) aryl. The compound of claim 1, wherein R ³ is (2-6C) heterocycloalkyl (1-4C) alkyl, (2-5C) heteroaryl (1-4C) alkyl or R ^5- ( 2-4C) alkyl derivatives. A pharmaceutical composition comprising the tetrahydroquinoline derivative of any one of claims 1 to 7 and a pharmaceutically suitable adjuvant. The tetrahydroquinoline derivative according to any one of claims 1 to 7 for use in therapy. Use of the tetrahydroquinoline derivative of any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for controlling pregnancy.