HRP20050577A2 - Tetrahydroquinoline derivatives - Google Patents

Description

This invention relates to a compound that has FSH receptor modulating activity, in particular to a tetrahydroquinoline derivative, to a pharmaceutical preparation containing the same, as well as to the use of said compound in medical therapy.

Gonadotropins serve important functions in a variety of bodily functions including metabolism, temperature regulation, and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The pituitary gonadotropin FSH (follicle stimulating hormone) for example plays a leading 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). Currently, FSH is used clinically, in combination with LH or hCG, for ovarian stimulation or ovarian hyperstimulation for in vitro fertilization (IVF) and induction of ovulation 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.

FSH gonadotropin is released from the anterior lobe of the pituitary under the influence of gonadotropin-releasing hormone and estrogen, and from the placenta during pregnancy. In women, FSH acts on the ovaries promoting the development of follicles and is the main hormone that regulates the secretion of estrogen. In men, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis. Purified, it is used clinically for the treatment of infertility in women and for some forms of absence of spermatogenesis in men. Gonadotropins intended for therapeutic purposes can be isolated from human urine and are of poor purity (Morse et al, Amer. J. Reproduct. Immunol. and Microbiology 17:143, 1988). Alternatively, they can be obtained as recombinant gonadotropins. Recombinant human FSH is commercially available and is used in assisted reproduction (Olijve et al. Mol. Hum. Reprod. 2:371, 1996; Devroey et al. Lancet 339:1170, 1992).

The actions of the FSH hormone are mediated by a specific plasma membrane receptor that is a member of a large family of G-protein coupled receptors. These receptors consist of one polypeptide with seven transmembrane domains and are capable of interacting with G proteins, leading to, for example, the activation of adenylate cyclase.

The FSH receptor is a highly specific target in the process of follicle growth in the ovary and is exclusively expressed in the ovary. Blocking this receptor or inhibiting the signaling that is normally induced after FSH-mediated receptor activation will interfere with follicular development and thus ovulation and fertility. Low molecular weight FSH antagonists could therefore form the basis for new contraceptives. Such FSH antagonists could lead to weakened follicular development (no ovulation) with still sufficient residual estrogen production to avoid adverse effects on eg 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 selectively have modulatory activity on the FSH receptor. The compounds of the present invention can either be used as (partial) agonists or (partial) antagonists of the FSH-receptor.

Accordingly, it has now been discovered that the following class of tetrahydroquinoline compounds of formula I or their pharmaceutically acceptable salts have FSH-modulating activity:

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where

R 1 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, (2-6C)heterocycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl;

R4 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)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 compounds according to the present invention modulate the function of the FSH receptor and can be used for the same clinical purposes as natural FSH if they behave as agonists, with the advantage that they show changed stability properties and can be applied differently. If they block the FSH receptor, they can be used, for example, as a contraceptive.

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

The following terms are intended to have the meanings indicated hereinafter as used in the specifications and requirements.

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

The term (2-4C)alkyl as used herein means a branched or unbranched alkyl group having 2-4 carbon atoms, and is 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, with (1-4C)alkyl most preferred.

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 having the same meaning as defined above.

The term (di)(1-4C)alkenylamino as used herein means an amino group, monosubstituted or disubstituted with alkenyl groups, each containing 2-4 carbon atoms such as allyl and 2-butenyl, and has the same meaning as is determined in the previous text.

The term (3-8C)cycloalkyl as used herein refers to a cycloalkyl group having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. (3-6C)cycloalkyl groups are preferred.

The term (2-6C)heterocycloalkyl as used herein refers to a heterocycloalkyl group having 2-6 carbon atoms, preferably 3-5 carbon atoms, and includes at least one heteroatom selected from N, O and/or S, which may be attached via heteroatoms if possible, or via carbon atoms. Preferred heteroatoms are N or O. The heterocycloalkyl group may be substituted with a methyl or ethyl group on the carbon atom, or heteroatom if feasible. The most preferred heterocycloalkyl groups are piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and 1-methyl-2-piperidinyl.

The term (1-4C)Alkoxy as used herein refers to an alkoxy group having 1-4 carbon atoms, wherein the alkyl moiety has the same meaning as defined above. (1-2C) alkoxy groups are preferred.

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 or (1-4C)(di)alkylamino, wherein the alkyl alkoxy and (di)alkylamino moieties have the same meaning as defined above, for example phenyl, 3,5- dibroimophenyl, 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 refers to a substituted or unsubstituted aromatic group having 2-5 carbon atoms, including at least one heteroatom selected from N, O and/or S, such as 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. The heteroaryl group can be attached through a carbon atom or a heteroatom, if this is feasible. Preferred heteroaryl groups are thienyl, furyl and pyridyl.

The term (2-6C)heterocycloalkyl(1-4C)alkyl as used herein means a heterocycloalkyl group having 2-6 carbon atoms attached to an alkyl group having 1-4 carbon atoms, wherein the heterocycloalkyl group and the alkyl group have the same meaning as defined above.

The term (2-6C)heterocycloalkylcarbonylamino as used herein means a heterocycloalkyl group having 2-6 carbon atoms attached to the carbonyl half of the carbonylamino group, wherein the heterocycloalkyl group has the same meaning as defined above.

The term (2-6C)heterocycloalkylcarbonylamino(2-4C)alkyl as used herein means a heterocycloalkylcarbonylamino group in which the heterocycloalkyl moiety contains 2-6 carbon atoms, linked via an amino group to an alkyl group having 2-4 carbon atoms, wherein the heterocycloalkylcarbonylamino group and alkyl group have the same meaning as defined above.

The term (di)(1-4C)alkylaminocarbonyl as used herein refers to a (di)alkylamino group, in which the alkyl group(s) have 1-4 carbon atoms, attached via an amino group to a carbonyl group, wherein (di)alkylamino group has the same meaning as defined above.

The term (3-8C)cycloalkylaminocarbonyl as used herein means a cycloalkyl group having 3-8 carbon atoms attached to the amino half of the aminocarbonyl group, wherein the cycloalkyl group has the same meaning as defined above.

The term (di)(1-4C)alkylaminocarbonylamino as used herein refers to a (di)alkylamino group, in which the alkyl group(s) have 1-4 carbon atoms, attached via an amino group to the carbonyl moiety of the carbonylamino group, thereby allowing urea functionality, wherein the (di)alkylamino group has the same meaning as defined in the previous text.

The term (di)(1-4C)alkylaminocarbonylamino(2-4C)alkyl as used herein means a (di)alkylaminocarbonylamino group, in which the alkyl group(s) have 1-4 carbon atoms, attached via an amino group to an alkyl group which has 2-4 carbon atoms, wherein the (di)alkylaminocarbonylamino group and the alkyl group have the same meaning as defined in the previous text.

The term (2-5C)heteroaryl(1-4C)alkyl as used herein means a heteroaryl group having 2-5 carbon atoms attached to an alkyl group having 1-4 carbon atoms, wherein the heteroaryl group and the alkyl group have the same meaning as defined in the previous text.

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

The term (6C)arylamino as used herein means a phenyl group, optionally substituted with one or more substituents selected from the group specified for the (6C)aryl group, attached to an amino group, wherein the aryl group has the same meaning as defined in previous text.

The term (6C)aryl(1-4C)alkylamino as used herein means a phenyl group, optionally substituted with one or more substituents selected from the group specified for the (6C)aryl group, attached to the alkyl moiety of an alkylamino group having 1-4 carbon atom, wherein the aryl group and the alkylamino group have the same meaning as defined in the previous text.

The term (2-5C)heteroaryl(1-4C)alkylamino as used herein means a heteroaryl group having 2-5 carbon atoms, optionally substituted with one or more substituents selected from the group of substituents specified for the (6C)aryl group, attached to the alkyl moiety of an alkylamino group having 1-4 carbon atoms, wherein the heteroaryl group and the alkylamino group have the same meaning as defined above.

The term (1-4C)Alkoxy(2-4C)alkyl as used herein means an alkoxy group having 1-4 carbon atoms attached to an alkyl group having 2-4 carbon atoms, wherein the alkoxy group and the alkyl group have the same meaning as defined above.

The term (di)[(1-4C)alkoxy(2-4C)alkyl]amino as used herein refers to an amino group, monosubstituted or disubstituted with (1-4C)alkoxy(2-4C)alkyl groups. (1-4C)Alkoxy(2-4C)alkyl group is an alkoxy group having 1-4 carbon atoms, attached to an alkyl group having 2-4 carbon atoms and has the same meaning as defined in the previous text.

The term (1-4C)alkylamino(-4C)alkyl as used herein means an alkylamino group having 1-4 carbon atoms, attached via an amino group to an alkyl group having 2-4 carbon atoms, wherein the alkyl moieties have the same meaning as defined in the previous text.

The term (di)[(1-4C)alkylamino(2-4C)alkyl]amino as used herein refers to an amino group, monosubstituted or disubstituted with (1-4C)alkylamino(2-4C)alkyl groups. (1-4C)alkylamino(2-4C)alkyl group is an alkylamino group that has 1-4 carbon atoms, linked through an amino group to an alkyl group that has 2-4 carbon atoms and has the same meaning as defined in the previous text.

The term amino(2-4C)alkyl as used herein means an aminoalkyl group having 2-4 carbon atoms, wherein the alkyl moiety has the same meaning as defined above.

The term (di)[amino(2-4C)alkyl]amino as used herein means an amino group, monosubstituted or disubstituted with aminoalkyl groups having 2-4 carbon atoms and having the same meaning as defined above.

The term hydroxy(2-4C)alkyl as used herein means a hydroxyalkyl group having 2-4 carbon atoms, wherein the alkyl moiety has the same meaning as defined above.

The term (di)[hydroxy(2-4C)alkyl]amino as used herein means an amino group, monosubstituted or disubstituted with hydroxyalkyl groups, having 2-4 carbon atoms and has the same meaning as defined above.

The term R 5 -(2-4C)alkyl as used herein means an R 5 group attached to an alkyl moiety having 2-4 carbon atoms and having the same meaning as defined above.

The term R5-carbonyl-(1-4C)alkyl as used herein denotes the R5 group attached to the carbonyl half of the carbonylalkyl group, wherein the alkyl half has 1-4 carbon atoms and has the same meaning as defined above.

The term pharmaceutically acceptable salt represents those salts which, within the scope of medical judgment, are suitable for contact use on human tissues and tissues of lower animals without excessive toxic, irritant, allergic response and the like, and are proportionate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be obtained during the final isolation and purification of the compounds of this invention, either separately by reacting the free base functional group, if present, with a suitable inorganic acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. If present, the acid functional group can react with an organic or inorganic base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

Accordingly, the present invention relates to compounds of formula I as defined hereinabove.

In yet another aspect, the present invention provides compounds of formula I wherein R 1 and R 2 are Me.

This invention also relates to compounds of formula I, characterized in that R3 is (2-6C)heterocycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (2-6C)heterocycloalkylcarbonylamino(2 -4C)alkyl, R5-(2-4C)alkyl, R5-carbonyl(1-4C)alkyl.

In another aspect, this invention relates to compounds according to formula I characterized in that R3 is (2-6C)heterocycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, R5-(2- 4C)alkyl, R5-carbonyl(1-4C)alkyl.

In yet another further aspect, this invention relates to compounds according to formula I characterized in that R3 is (2-6C)heterocycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl or R5-(2 -4C)alkyl.

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

According to another subsequent achievement of this invention, the heterocycloalkyl group in heterocycloalkyl(1-4C)alkyl in R3 according to formula I consists of 4, 5 or 6 C atoms, and the heteroaryl group in heteroaryl(1-4C)alkyl in R3 consists of 3, 4 or 5 C atoms.

In another embodiment, the present invention relates to compounds according to formula I, characterized in that R4 is (6C)aryl.

In yet another further development, this invention provides compounds of formula I wherein R5 is (di)(1-4C)alkylamino, amino, (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, (di)[hydroxy(2-4C)alkyl]amino.

In another aspect, this invention relates to compounds according to formula I characterized in that R5 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, this invention relates to compounds according to formula I characterized in that R5 is (di)(1-4C)alkylamino, amino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1- 4C)alkylamino, (6C)aryl(1-4C)alkylamino.

Another aspect of this invention are compounds of formula I wherein R5 is (di)(1-4C)alkylamino or amino.

In yet another aspect of this invention, compounds of formula I are provided wherein R 5 is (di)(1-4C)alkylamino.

Another aspect of the present invention relates to compounds characterized in that all the specific definitions of the groups R1 to R5 as defined above are combined in the compound of formula I.

In the following text, the procedures for obtaining the compounds of this invention are generally presented.

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The compounds of the present invention of formula I can be prepared starting with the well-described Skraup reaction. Carrying out this reaction on N-tert-butoxycarbonyl (N-Boc) protected 1,4-phenylenediamine (II) gives the 1,2-dihydroquinoline derivative III.

Related Skraup cyclocondensation reactions are 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. Joned, J. Med. Chem. 41:303, 1998.

The above-mentioned reaction is typically carried out at elevated temperature in acetone or mesityl oxide in the presence of iodine or a protogenic acid such as hydrochloric acid, p-toluenesulfonic acid or aqueous hydrogen iodide. Alternatively, the compound of formula III can be obtained by reacting compound II with acetone in 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 yet another process, the reaction can be carried out in acetone using a lanthanide triflate (eg scandium triflate) as a catalyst. In this case, the reaction can proceed at room temperature or at an elevated temperature using conventional thermal or microwave radiation (M.E. Theoclitou and L.A. Robinson, Tetrahedron Lett. 43:3907, 2002).

The compound of formula III-b can be obtained from N-Boc-1,4-phenylenediamine II by reaction with methyl vinyl ketone. Related cyclizations are described in US Patent 2,686,182 (Badische Anilin- & Soda-Fabrik Aktiengesellschaft).

The following 1-N-acetylation of compounds of formula III-a-b can be carried out using standard conditions. In a typical experiment, compounds of formula III-a-b are heated under reflux in acid 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 give produced 1-N-acetyl-4-methyl-1,2-dihydroquinoline derivatives of formula IV-a-b.

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

The following 6-N-acylation of compounds of formula V-a-b can be carried out using standard conditions to give compounds of general formula VI-a-b, wherein R4 is as previously defined. For example, compounds of formula V-a-b are reacted in a solvent such as dichloromethane, tetrahydrofuran or toluene with an acyl halide (R4-C(O)-Cl) or an acid anhydride (R4-C(O)-O-C(O)-R4) in the presence of a base such as N,N-diisopropylethylamine, triethylamine, pyridine or sodium hydride to give 6-N-acylated 4-methyl-1,2-dihydroquinoline derivatives of formula VI-a-b. Alternatively, acylation of compounds of general formula V-a-b to give compounds of general formula VI-a-b can also be achieved by reaction with the appropriate carboxylic acid (R4-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 room or elevated temperature.

Introduction of the necessary substituted phenyl group at position 4 of the dihydroquinoline skeleton can be achieved via Friedel-Crafts alkylation of anisole with compounds of general structure VI-a-b to give compounds of general formula VII-a-b. This reaction is usually carried out at elevated temperature either in anisole or in a suitable inert solvent such as heptane or hexane with anisole as a reagent, catalyzed by a Lewis acid (eg AlCl3, AlBr3, FeCl3 or SnCl4). Friedel-Crafts alkylation with 2,2,4-trimethyl-1,2-dihydroquinolines is described in the literature by B.A. Lugovik, L.G. Yudin and A.N. bone, Dokl. Acad. Nauk SSSR, 170:340, 1966; B.A. Lugovik, L.G. Yudin, S.M.: Vinogradova and A.N. Bone, Khim. Heterocycle. Soedin, 7:795, 1971.

Alternatively, N-Boc-1,4-phenylenediamine II can be reacted with 2-(4-methoxyphenyl)-propene and formaldehyde in acetonitrile at room or elevated temperature, followed by 1-N-acetylation as described in the previous text, to obtain the compound VII-b in which R4 = O-tert-Bu. Related cyclizations are described in the literature: J.M. Mellor and G.D. Merriman, Tetrahedron, 51:6115, 1995. Removal of the Boc protecting group and subsequent acylation of the 6-amino functional group with an acyl halide (R4-C(O)-Cl) as described above affords compounds of general structure VII-b in wherein R4 is as previously described.

Separation of the aromatic methyl ether in the compounds of the general formula VII-a-b gives 4-(4-hydroxyphenyl) substituted tetrahydroquinoline derivatives of the general formula VIII-a-b, setting the conditions for the functionalization of the free OH group.

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Demethylation reactions of aromatic methyl ethers are well known to those skilled in the art. In a typical experiment, demethylation is accomplished by reacting a compound of formula VII-a-b with BBr 3 in an inert solvent such as dichloromethane at low to room temperature to give demethylated compounds of general formula VIII-a-b. Alternatively, demethylation can be achieved after reaction of the compounds of formula VII-a-b with the BF3Me2S complex at room temperature.

Selective O-alkylation of compounds of the general formula VIII-a-b with functionalized alkyl halides of the general formula IX-a leads to the formation of compounds with the general formula I-a-b. Alkylation reactions of aromatic hydroxyl groups are well known in the art. Typically, a solution of a compound of general formula VIII-a-b in a suitable solvent such as 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile, acetone or N,N-dimethylformamide is treated with a base (e.g. N,N-diisopropylamine, triethylamine, K2CO3, Cs2CO3 or NaOH) and a suitable alkylating reagent of general formula IX, for example benzyl bromide, 3-(dimethylamino)-propyl chloride, 4-(2-chloroethyl)-morpholine, 2-picolyl chloride or 2-chloroacetamide. Alternatively, the alkylation can be achieved via the known Mitsunobu-type alkylation. In this case, a solution of the compound of the general formula VIII-a-b in a suitable solvent such as 1,4-dioxane, tetrahydrofuran, or dichloromethane is treated with (bonded resin) triphenyl phosphine, diethyl- or di-tert-butyl azodicarboxylate and a functionalized alcohol of the general formula IX-b. As a rule, both alkylation procedures can be used for all R3 groups, but a suitable protecting group strategy may be required if R3 contains a nucleophilic group such as a secondary amine or hydroxyl group. The choice of protecting group and conditions for deprotection are trivial for the skilled person.

Another process for obtaining compounds of this invention begins with the alkylation of compounds of general formula VIII-a-b with esters of general 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 or elevated temperature. The ester functional group in the resulting compounds of general formula XI-a-b where A = Me or Et can then be selectively reduced under controlled conditions to give compounds of general formula XII-a-b using an appropriate reducing agent such as lithium aluminum hydride at lower temperatures or sodium borohydride in an inert solvent such as tetrahydrofuran. The free hydroxyl group in compounds of general formula XIII-a-b can then be reacted with 4-toluenesulfonyl chloride (Ts-Cl) or methanesulfonyl chloride (Ms-Cl) in an inert solvent such as 1,4-dixane, N,N-dimethylformamide or THF in the presence of an appropriate base such as triethylamine or pyridine to form the appropriate leaving group (compounds of general formula XIV-a-b; LG = Ts or Ms). Nucleophilic substitution with an appropriate nucleophile (amine or alkoxide) under conditions known to the skilled person then gives access to compounds of general formula I-a-b wherein R 3 = R 5 -(2-4C)alkyl and R 5 is as previously defined.

Conversion of compounds of the general formula XI-a-b in which A = tert-Bu into carboxylic acids of the general formula XII-a-b can be carried out by deprotection of the tert-butyl ester functional group. In a typical experiment, a tert-butyl ester of the general formula XI-a-b (A = tert-Bu) is dissolved in dichloromethane and treated with a strong acid such as trifluoroacetic acid. The resulting carboxylic acids of general formula XII-a-b can then be condensed in the appropriate alcohol or amine in the presence of a coupling agent 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 bases, e.g. N,N-diisopropylethylamine, in a solvent as which are N,N-dimethylformamide or dichloromethane at room or elevated temperature to give compounds of general formula I-a-b wherein R 3 = R 5 -carbonyl(1-4C)alkyl and R 5 is as previously defined.

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Some of the compounds of this invention, which may be in the form of a free base, 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, hydrobromic, hydroiodic, 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 therefore can be obtained as pure enantiomers, or as mixtures of enantiomers, or as mixtures of diastereomers. Procedures for obtaining pure enantiomers are well known in the art, for example, crystallization of salts obtained from optically active acids and racemic mixtures, or chromatography using chiral columns. For diastereomers, straight-phase or reversed-phase columns can be used.

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

For the selection of active compounds, testing at 10-5 M must result in an activity higher than 20% of the maximum activity when FSH is used as a reference. Another criterion could be the EC50 value which must be < 10-5 M, preferably < 10-7 M.

A skilled artisan will recognize that desired EC50 values are dependent on the compound being tested. For example, a compound with an EC50 of less than 10-5 M is generally considered a drug candidate of choice. It is preferred that this value is lower than 10-7 M. However, a compound that has a higher EC50 but is selective for a particular receptor may even be a better candidate.

Methods for determining receptor binding, as well as in vitro and in vivo assays for determining biological activity, of gonadotropins are well known. Generally, the receptor that is expressed is brought into contact with the test compound and binding or stimulation or inhibition of a functional response is measured.

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

Procedures for constructing cell lines expressing recombinant FSH are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, last edition). The expression of the receptor is achieved by the expression of DNA that codes for the desired protein. Techniques for site-directed mutagenesis, ligations or additional sequences, PCR, and the assembly of an appropriate expression system are all, by now, well known in the art. Portions, or all, of the DNA encoding the desired protein can be assembled synthetically using standard solid phase techniques, preferably including restriction sites for ease of ligation. Suitable control elements for transcription and translation of the coding sequences involved may be provided for the DNA coding sequences. As is well known, expression systems are now available that are compatible with a wide variety of hosts, including prokaryotic hosts 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 the test compound to observe binding, or stimulation or inhibition of a functional response.

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

To measure binding, radioactively labeled or fluorescently labeled compounds can be used. Competitive binding assays can also be performed.

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

Screening for FSH receptor antagonists involves incubating FSH receptor-expressing cells with a concentration range of test compound in the presence of a fixed, submaximal effective, FSH concentration (ie, an FSH concentration that induces approximately 80% of the maximal stimulation of cAMP accumulation in the absence of test compound). From the concentration-effect curves, the IC50 value and percent inhibition of FSH-induced cAMP accumulation can be determined for each of the tested compounds. Human recombinant FSH can be used as a reference. Alternatively, competitive tests can also be conducted.

In addition to direct measurement of, for example, cAMP levels in exposed cells, cell lines can be used which, in addition to transfection with DNA coding for the receptor, are also transfected with another DNA coding for a reporter gene whose expression corresponds to the cAMP level. Such reporter genes may be cAMP inducible or may be assembled in such a way that they are linked to new cAMP appropriate elements. In general, reporter gene expression could be controlled by any response element that responds to altered cAMP levels. Suitable reporter genes are, for example, genes encoding β-galactosidase, alkaline phosphatase, firefly luciferase and green fluorescence protein. The basics of such transactivation assays are well known in the art and are described, for example, in Stratowa, Ch., Himmler, A. and Czernilofsky, A.P., (1995) Curr.Opin.Biotechnol. 6:574.

The present invention also relates to a pharmaceutical composition comprising a tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof having the general formula I in admixture with pharmaceutically acceptable excipients and optionally other therapeutic agents. Auxiliary substances must be "acceptable" in the sense that they are compatible with the other ingredients of the preparation and that they are not harmful to their recipient.

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

For oral administration, the active substance can be taken as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of the present invention may be taken in single-dose or multi-dose containers, e.g., injectable liquids in predetermined quantities, for example in sealed containers and ampoules, and may also be stored in dry frozen (lyophilized ) conditions requiring only the addition of a sterile liquid carrier, eg water, before use.

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

For the production of rigid dosing units, the use of traditional additives such as fillers, dyes, polymer binders and the like is expected. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the active substance of the present invention can be administered as a solid preparation include lactose, starch, cellulose derivatives and the like, or a mixture thereof, used in appropriate amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injectable solutions containing pharmaceutically acceptable dispersants and/or wetting agents such as propylene glycol or butylene glycol may be used.

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

The tetrahydroquinoline derivatives of this invention can also be applied in the form of a pharmaceutical preparation for implantation, which consists of a core of active substance, coated with a membrane that regulates the release rate. Such inserts are to be administered subcutaneously or topically, and will release the active ingredient at an approximately constant rate over relatively long periods of time, for example weeks to years. Processes for obtaining pharmaceutical preparations for implantation as such are known in the art, for example as 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, will necessarily depend on the therapeutic effect that is to be achieved (infertility treatment; contraception), and may vary with the specific compound, route of administration, and with the age and condition of the individual patient the medicine is applied.

In general, parenteral administration requires lower doses than other administration methods that are more dependent on absorption. However, it is preferred that the dose for humans contains 0.0001-25 mg per kg of body weight. humans contain 0.0001-25 mg per kg of body weight. The desired dose may consist of a single dose or multiple sub-doses administered at appropriate intervals throughout the day, or, in the case of female recipients, as doses administered at appropriate daily intervals during the menstrual cycle. The dosage as well as the administration regimen may differ between male and female recipients.

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

A further aspect of the present invention is the use of a tetrahydroquinoline derivative compound having the general formula I for the manufacture of a medicament for use in the treatment of disorders responsive to FSH receptor mediated pathways. Accordingly, patients in need may receive appropriate amounts of the compounds of the present invention.

In another aspect, this invention is in the use of a tetrahydroquinoline derivative compound having the general formula I for the production of a drug to be used for fertility control.

In yet another aspect, this invention is in the use of a tetrahydroquinoline derivative compound having the general formula I for the production of a drug to be used for the treatment of infertility.

In yet another aspect, this invention is in the use of a tetrahydroquinoline derivative compound having the general formula I for the production of a drug to be used to prevent fertility.

The compounds of this 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; TBTU = O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate; HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Fmoc = 9-fluorenylmethoxycarbonyl; Fmoc-Cl = 9-fluorenylmethoxycarbonyl chloride; DMF = N,N-dimethylformamide; Boc = tert-butoxycarbonyl; THF = tetrahydrofuran.

The names of the final products described in the examples were generated using the Beilstein Autonom program (version: 2.02.119).

Unless otherwise stated, all final products of the examples in the following text were lyophilized from water/1,4-dioxane or water/acetonitrile mixtures. If the compound was obtained as an HCl or TFA salt, the corresponding acids were added in appropriate amounts to the solvent mixture before lyophilization.

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

Procedure 1: Column: 5μm Luna C-18(2) 150x4.6 mm; flow rate: 1ml/min; detection: 210 nm; column temperature: 40 °C; solvent A: CH3CN/H2O = 1/9 (v/v); solvent B: CH3CN; solvent C: 0.1 M aqueous solution of trifluoroacetic acid; gradient: solvent A/B/C = 63/30/5 to 10/85/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at A/B/C = 10/ 85/5 (v/v/v).

Procedure 2: Identical to procedure 1, except for the gradient used: Gradient: solvent A/B/C = 75/20/5 to 15/80/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at A7B7C = 15/80/5 (v/v/v).

Procedure 3: 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 mM phosphate buffer, pH 2.1; gradient: solvent A/B/C = 70/20/10 to 10/80/10 (v/v/v) in 20.00 min, then constant for an additional 10.00 min at A/B/C = 10/ 80/10 (v/v/v).

Procedure 4: Identical to procedure 3, except for the gradient used: Gradient: solvent A/B/C = 65/30/5 to 10/85/5 (v/v/v) in 20.00 min, then constant for an additional 10.00 min at A/B/C = 10/85/5 (v/v/v).

Procedure 5: Identical to procedure 3, except for the gradient used: Gradient: solvent A/B = 75/25 to 0/100 (v/v) in 20.00 min, then constant for an additional 10.00 min at A/B/C = 0/100 (v/v).

Procedure 6: Identical to procedure 1, except for the gradient used: Gradient: solvent A/B/C = 35/60/5 to 10/85/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at A/B/C = 10/85/5 (v/v/v).

The following procedures are used for preliminary HPLC purifications:

Procedure A: Column = Luna C-18. Gradient: 0.1% trifluoroacetic acid in H2O/CH3CN (9/1, v/v)/CH3CN = 100/0 to 0/100 (v/v) in 30-45 min, depending on ease of separation. Detection: 210 nm. Appropriate fractions were collected and concentrated (partially) in vacuo.

Procedure B: Column = Luna C-18. Gradient: H2O/CH3CN (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

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

(And). (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 heated under by reflux for 20 h. MgSO4 was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed in a short column of silica gel using heptane/ethyl acetate = 8/2 (v/v) 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 1a (41 g) in pyridine (200 ml) and CH 2 Cl 2 (200 ml) was cooled to 0°C. Acetyl chloride (21 mL) in CH2Cl2 (50 mL) was added dropwise. After complete intake, 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 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

The compound described in example 1b (15 g) was stirred in a mixture of CH2Cl2 and TFA (9/1 (v/v), 300 ml) for 2 h. The reaction mixture was cooled to 0°C, and the pH was adjusted to pH 7 using 2 M aqueous NaOH solution. The organic layer was separated, washed with saturated brine, dried and concentrated in vacuo to give a solid product which was used without further purification in the next step.

Yield: 10.4 g

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

To a solution of the compound described in section 1c (10 g) and DIPEA (40 ml) in CH2Cl2 (100 ml), 4-biphenylcarbonyl chloride (9.8 g) was added and the resulting mixture was stirred for 18 hours at room temperature. Water was added, the organic layer was removed, dried and concentrated in vacuo. The product was crystallized from ethyl acetate.

Yield: 15 g

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

During stirring, aluminum trichloride (9.7 g) was added to a mixture of the compound described in Example 1d (10.0 g) and anhydrous methoxybenzene (anisole) (50 ml) and the resulting mixture was stirred at 35°C for 18 hours. After this time, 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 h. The resulting precipitate was collected by filtration and dried in vacuo to give the title compound.

Yield: 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]-amide

To a solution of the compound described in example 1e (7.9 g) in CH2Cl2 (200 ml) at 0°C, a solution of boron tribromide (5 ml) in CH2Cl2 (50 ml) was added and the mixture was kept for 4 h at 0°C. Water (ca. 500 ml) was carefully added and the resulting mixture was vigorously stirred. The organic layer was separated, dried and concentrated in vacuo. The title compound was obtained by crystallization from ethyl acetate.

Yield: 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-quinoline- 6-yl}-amide

General Procedure A: To a solution of the compound described in Example 1f (70 mg) in DMF (2 ml) was added Cs 2 CO 3 (200 mg) and 2-dimethylaminoethyl chloride (17 mg). The resulting mixture was stirred overnight, after which water and ethyl acetate were added. The organic layer was separated, dried and concentrated in vacuo. The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 18 mg (TFA salt); MS-ESI: [M+H]+ = 576.6; HPLC: Rt = 14.96 min (Procedure 3).

Example 2

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

According to general procedure A, the compound described in example 1f (70 mg) was alkylated with 3-dimethylaminopropyl chloride (19 mg) and Cs 2 CO 3 (200 mg) in DMF (2 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 58 mg (TFA salt); MS-ESI: [M+H]+ = 590.4; HPLC: Rt = 15.36 min (Procedure 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-tetrahydro-quinoline -6-yl}-amide

According to general procedure A, the compound described in example 1f (70 mg) was alkylated with 3-morpholinepropyl chloride (26 mg) and Cs 2 CO 3 (200 mg) in DMF (2 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 56 mg (TFA salt); MS-ESI: [M+H]+ = 631.6; HPLC: Rt = 15.40 min (Procedure 3).

Example 4

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

According to general procedure A, the compound described in example 1f (100 mg) was alkylated with 2-picolyl chloride hydrochloride (33 mg) and Cs 2 CO 3 (325 mg) in DMF (5 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 60 mg (TFA salt); MS-ESI: [M+H]+ = 596.4; HPLC: Rt = 19.75 min (Procedure 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-quinoline -6-yl}-amide

According to general procedure A, the compound described in example 1f (100 mg) was alkylated with 3-chloromethyl-1-methylpiperidine hydrochloride (33 mg) and Cs 2 CO 3 (325 mg) in DMF (5 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 60 mg (TFA salt); MS-ESI: [M+H]+ = 615.4; HPLC: Rt = 16.70 min (Procedure 2).

Example 6

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

According to general procedure A, the compound described in example 1f (100 mg) was alkylated with 2-diethylamino-ethyl chloride hydrochloride (35 mg) and Cs 2 CO 3 (325 mg) in DMF (5 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 67 mg (TFA salt); MS-ESI: [M+H]+ = 604.4; HPLC: Rt = 16.38 min (Procedure 2).

Example 7

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

According to general procedure A, the compound described in example 1f (100 mg) was alkylated with 4-picolyl chloride hydrochloride (33 mg) and Cs 2 CO 3 (325 mg) in DMF (5 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 61 mg (TFA salt); MS-ESI: [M+H]+ = 596.4; HPLC: Rt = 16.64 min (Procedure 2).

Example 8

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

According to General Procedure A, the compound described in Example 1f (100 mg) was alkylated with morpholine-4-carboxylic acid (3-chloropropyl)amide (53 mg) and Cs 2 CO 3 (325 mg) in DMF (5 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water.

Yield: 95 mg; MS-ESI: [M+H]+ = 675.6; HPLC: Rt = 18.24 min (Procedure 3).

Example 9

Biphenyl-4-carboxylic acid {1-acetyl-4-[4-(2-azepan-1-yl-ethoxy)-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 (100 mg) was alkylated with 2-(hexamethyleneimino)ethyl chloride hydrochloride (42 mg) and Cs 2 CO 3 (325 mg) in DMF (5 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 60 mg (TFA salt); MS-ESI: [M+H]+ = 630.6; HPLC: Rt = 17.25 min (Procedure 2).

Example 10

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

According to General Procedure A, the compound described in Example 1f (1.0 g) was alkylated with 3-picolyl chloride hydrochloride (488 mg) and Cs 2 CO 3 (3.2 mg) in DMF (10 ml). The product was purified by preparative HPLC (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 884 mg (TFA salt); MS-ESI: [M+H]+ = 596.4; HPLC: Rt = 16.55 min (Procedure 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]-amide

According to general procedure A, the compound described in example 1f (100 mg) 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 (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 40 mg; MS-ESI: [M+H]+ = 562.6; HPLC: Rt = 21.63 min (Procedure 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]-amide

(And). (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 the compound described in example 1f (2.58 g), tert-butyl bromoacetate (826 μl), K2CO3 (2.8 g) and acetone (100 ml) was stirred for 18 h at 50°C. The solids were removed by filtration and the filtrate was concentrated in vacuo to obtain the product which was used in the next step without further purification.

Yield: 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 described in example 12a (3.2 g) was stirred in a mixture of CH 2 Cl 2 and TFA (9/1 (v/v), 100 ml) for 3 h. Toluene (100 ml) was added and the mixture was concentrated in vacuo to give a solid 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-quinolin-6-yl]-amide

General Procedure B: 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) was added TBTU (84 mg) at room temperature. If the reaction did not come to an end after 18 h, more TBTU and DIPEA were added. After completion of the reaction, water was added, the organic layer was separated, washed with saturated brine, dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Procedure A).

Yield: 48 mg; MS-ESI: [M+H]+ = 602.4; HPLC: Rt = 18.19 min (Procedure 4).

Example 13

Biphenyl-4-carboxylic acid {1-acetyl-4-[4-(isopropylcarbamoyl-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 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 (Procedure A).

Yield: 45 mg; MS-ESI: [M+H] + = 604.6; HPLC: Rt = 18.63 min (Procedure 4).

Example 14

Biphenyl-4-carboxylic acid [1-acetyl-4-(4-diethylcarbamoylmethoxy-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 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 (Procedure A).

Yield: 51 mg; MS-ESI: [M+H]+ = 618.4; HPLC: Rt = 19.09 min (Procedure 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-picolylamine (70 mg), DIPEA (226 μl) and TBTU (84 mg) in CH 2 Cl 2 (5 ml). The title compound was purified by preparative HPLC (Procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 52 mg (TFA salt); MS-ESI: [M+H] + = 653.6; HPLC: Rt = 11.31 min (Procedure 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 (Procedure A).

Yield: 50 mg; MS-ESI: [M+H]+ = 642.6; HPLC: Rt = 21.31 min (Procedure 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-quinoline -6-yl)-amide

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

Yield: 34 mg; MS-ESI: [M+H]+ = 620.4; HPLC: Rt = 19.70 min (Procedure 3).

Example 18

Biphenyl-4-carboxylic acid {1-acetyl-4-[4-(benzylcarbamoyl-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 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 (Procedure A).

Yield: 53 mg; MS-ESI: [M+H]+ = 652.6; HPLC: Rt = 22.26 min (Procedure 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-quinoline -6-yl)-amide

According to general procedure B, the compound described in example 12b (82 mg) was treated with N,N-dimethylethylenediamine (49 mg), DIPEA (226 μl) and TBTU (84 mg) in CH 2 Cl 2 (5 ml). The title compound was purified by preparative HPLC (Procedure A). Lyophilization from a mixture of aqueous HCl and 1,4-dioxane gave the title compound as the HCl salt.

Yield: 11 mg (HCl-salt); MS-ESI: [M+H] + = 633.4; HPLC: Rt = 13.74 min (Procedure 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]-amide

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

Yield: 35 mg; MS-ESI: [M+H]+ = 576.4; HPLC: Rt = 19.25 min (Procedure 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 (Procedure A).

Yield: 85 mg; MS-ESI: [M+H]+ = 632.4; HPLC: Rt = 12.48 min (Procedure 3).

Example 22

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

(And). (1-Acetyl-2,2,4-trimethyl-1,2-dihydro-quinolin-6-yl)-carbamic acid 9-fluoren-ylmethyl ester

FmocCl (25 g) was added to a solution of the compound described in example 1c (17 g) and DIPEA (40 ml) in CH2Cl2 (100 ml) and the resulting mixture was stirred for 18 h at room temperature. Ethyl acetate (200 ml) and water (150 ml) were added, the organic layer was separated, dried and concentrated in vacuo. The title compound was purified by silica gel chromatography using CH2Cl2 as eluent.

Yield: 16.6 g

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

During stirring, aluminum trichloride (24.2 g) was added to a 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 h. After this time, 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 resulting precipitate was collected by filtration and dried in vacuo to afford the title compound.

Yield: 10.1 g.

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

Boron tribromide (5.05 ml) was added dropwise to a mixture of the compound described in example 22b (10.1 g) in anhydrous CH2Cl2 (500 ml) and the resulting mixture was stirred for 2.5 h at room temperature. The reaction was quenched with ice water at 0°C and CH2Cl2 was added. The organic layer was separated, dried and stored at 4°C for 20 h. The formed solids were collected by filtration and dried in vacuo to give a solid product that was used without further purification.

Yield: 12.5 g.

(d). 1-Acetyl-6-amino-2,2,4-trimethyl-4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-1,2,3,4-tetrahydroquinoline

A mixture of the compound described in Example 22c (1.0 g), Cs 2 CO 3 (1.8 g), 4-(3-chloropropyl)morpholine (330 mg) and DMF (5 ml) was stirred at 60 °C for 18 h. Water was added and the mixture was extracted with CH2Cl2. The organic layer was dried and concentrated in vacuo. The title compound was purified by silica gel chromatography using CH2Cl2/2% concentrated ammonia in MeOH = 1/0 ⇒ 9/1 (v/v) as eluent.

Yield: 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: To a solution of the compound described in Example 22d (132 mg), 5-bromo-2-methylamino benzoic acid (101 mg) and DIPEA (225 μl) in CH 2 Cl 2 (3 ml) was added HATU (166 mg) at room temperature . The reaction mixture was stirred for 18 h at room temperature. Ethyl acetate (15 ml) and 2 M aqueous NaOH (15 ml) were added. The organic layer was separated and washed with 2 M aqueous NaOH (10 ml) and water (15 ml), dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Procedure A).

Yield: 69.8 mg; MS-ESI: [M+H]+ = 663.4; HPLC: Rt = 14.65 min (Procedure 3).

Example 23

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

According to general procedure C, the compound described in Example 22d (132 mg) was acylated with 3,5-dichloro-2,6-dimethoxybenzoic acid (110 mg), DIPEA (225 μl) and HATU (166 mg) in CH2Cl2 (3 ml ). The title compound was purified by preparative HPLC (Procedure A).

Yield: 68.3 mg; MS-ESI: [M+H]+ = 684.3; HPLC: Rt = 13.45 min (Procedure 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

(And). (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 the compound described in example 1f (1 g), ethyl bromoacetate (220 μl), K2CO3 (850 mg) and acetone (25 ml) was stirred for 6 h at 50°C. The solids were removed by filtration and the filtrate was concentrated in vacuo to give the product which was used without further purification in the next step.

Yield: 1.2 g.

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

LiAlH4 (78 mg) was carefully added to a solution of the compound described in example 24a in THF (10 ml) at 0°C, and the resulting mixture was stirred for 3 h at room temperature. 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 which was used without further purification in the next step.

Yield: 1 g

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

To a solution of the compound described in Example 24b (1 g) and DIPEA (1.7 ml) 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 h, water was added, 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.

Yield: 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 the compound described in example 24c (87 mg) in CH3CN (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 (procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to obtain the corresponding TFA salt.

Yield: 47 mg (TFA salt); MS-ESI: [M+H] + = 628.6; HPLC: Rt = 11.53 min (Procedure 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 described in example 24c (87 mg) 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 (Procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 21 mg (TFA salt); MS-ESI: [M+H]+ = 619.8; HPLC: Rt = 10.95 min (Procedure 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 described in example 24c (87 mg) was treated with 3-aminomethylpyridine (119 mg) in CH 3 CN (5 ml). The title compound was purified by preparative HPLC (Procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 40 mg (TFA salt); MS-ESI: [M+H] + = 639.4; HPLC: Rt = 10.15 min (Procedure 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 described in example 24c (100 mg) was treated with ethanolamine (100 mg) in CH 3 CN (5 ml). The title compound was purified by preparative HPLC (Procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 50 mg (TFA salt); MS-ESI: [M+H]+ = 592.6; HPLC: Rt = 10.32 min (Procedure 1).

Example 28

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

According to general procedure D, the compound described in example 24c (100 mg) was treated with ethylenediamine (110 mg) in CH 3 CN (5 ml). The title compound was purified by preparative HPLC (Procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 45 mg (TFA salt); MS-ESI: [M+H]+ = 591.4; HPLC: Rt = 7.04 min (Procedure 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-tetrahydro-quinoline -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 (Procedure A) and lyophilized from a mixture of CH3CN and water containing TFA to give the corresponding TFA salt.

Yield: 95 mg (TFA salt); MS-ESI: [M+H] + = 617.6; HPLC: Rt = 9.54 min (Procedure 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

(And). 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 alkylated (with concomitant removal of the Fmoc protecting group) with morpholine-4-carboxylic acid (3-chloropropyl)amide (448 mg) using Cs2CO3 (1.8 g) in DMF (5 ml). The title compound was purified by chromatography on silica gel using CH2Cl2/2% concentrated ammonia in MeOH = 1/0 ⇒ 9/1 (v/v) as eluent.

Yield: 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 acylated with 3,5-dichloro-2,6-dimethoxybenzoic acid (230 mg), DIPEA (558 μl) and HATU (609 mg) in CH2Cl2 (5 ml ). The title compound was purified by preparative HPLC (Procedure A).

Yield: 102 mg; MS-ESI: [M+H]+ = 727.4; HPLC: Rt = 22.37 min (Procedure 2).

Example 31

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

(And). 1-Acetyl-6-amino-2,2,4-trimethyl-4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydroquinoline

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) was stirred at 60 °C for 18 h. The reaction did not reach the end and additional amounts of Cs2CO3 and N-(2-chloroethyl)-morpholine hydrochloride were added. After the reaction was complete, water was added and the mixture was extracted with CH2Cl2. The organic layer was dried and concentrated in vacuo. The title compound was purified by chromatography on silica gel using CH2Cl2/2% concentrated ammonia in MeOH = 1/0 ⇒ 9/1 (v/v) as eluent.

Yield: 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 described in Example 31a (157 mg) was acylated with 3,5-dibromobenzoic acid (150 mg), DIPEA (313 μl) and HATU (204 mg) in CH 2 Cl 2 (5 ml). The title compound was purified by preparative HPLC (Procedure A).

Yield: 71 mg (TFA salt); MS-ESI: [M+H]+ = 700.2; HPLC: Rt = 16.12 min (Procedure 2).

Example 32

N-{1-Acetyl-2,2,4-trimethyl-4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-quinolin-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 (Procedure A).

Yield: 162 mg (TFA salt); MS-ESI: [M+H]+ = 576.4; HPLC: Rt = 9.37 min (Procedure 2).

Example 33

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-dimethyl-benzamide

According to general procedure C, the compound described in Example 31a (200 mg) was acylated with 3,5-dimethylbenzoic acid (103 mg), DIPEA (399 μl) and HATU (260 mg) in CH 2 Cl 2 (7.5 ml). The title compound was purified by preparative HPLC (Procedure A).

Yield: 57.5 mg (TFA salt); MS-ESI: [M+H]+ = 570.4; HPLC: Rt = 12.62 min (Procedure 2).

Example 34

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

According to general procedure C, the compound described in Example 31a (200 mg) was acylated with 2,5-dichlorobenzoic acid (131 mg), DIPEA (399 μl) and HATU (260 mg) in CH 2 Cl 2 (7.5 ml). The title compound was purified by preparative HPLC (Procedure A).

Yield: 130 mg (TFA salt); MS-ESI: [M+H] + = 610.2; HPLC: Rt = 11.70 min (Procedure 2).

Example 35

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

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

Yield: 80 mg (TFA salt); MS-ESI: [M+H] + = 601.4; HPLC: Rt = 9.95 min (Procedure 2).

Example 36

N-{1-Acetyl-2,2,4-trimethyl-4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-quinolin-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 (Procedure A).

Yield: 59 mg (TFA salt); MS-ESI: [M+H]+ = 542.4; HPLC: Rt = 9.99 min (Procedure 2).

Example 37

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

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

Yield: 80 mg (TFA salt); MS-ESI: [M+H]+ = 598.2; HPLC: Rt = 15.39 min (Procedure 2).

Example 38

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

According to general procedure C, the compound described in Example 31a (161 mg) was acylated with 2,3-dichlorobenzoic acid (106 mg), DIPEA (322 μl) and HATU (210 mg) in CH 2 Cl 2 (5 ml). The title compound was purified by preparative HPLC (Procedure A).

Yield: 113 mg (TFA salt); MS-ESI: [M+H] + = 610.2; HPLC: Rt = 11.42 min (Procedure 2).

Example 39

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

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

Yield: 127 mg (TFA salt); MS-ESI: [M+H]+ = 620.2; HPLC: Rt = 12.24 min (Procedure 2).

Example 40

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

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

Yield: 158 mg (TFA salt); MS-ESI: [M+H]+ = 586.2; HPLC: Rt = 11.49 min (Procedure 2).

Example 41

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

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

Yield: 95 mg (TFA salt); MS-ESI: [M+H]+ = 585.2; HPLC: Rt = 9.53 min (Procedure 2).

Example 42

N-{1-Acetyl-2,2,4-trimethyl-4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-quinolin-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 and washed with water (15 ml), dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Procedure A).

Yield: 200 mg (TFA salt); MS-ESI: [M+H] + = 610.2; HPLC: Rt = 13.23 min (Procedure 2).

Example 43

N-{1-Acetyl-2,2,4-trimethyl-4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-quinolin-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 and washed with water (15 ml), dried and concentrated in vacuo. The title compound was purified by preparative HPLC (Procedure A).

Yield: 167 mg (TFA salt); MS-ESI: [M+H]+ = 587.4; HPLC: Rt = 10.28 min (Procedure 2).

Example 44

CHO-FSH in vitro bioactivity

The FSH activity of the compounds was tested in Chinese Hamster Ovary (CHO) cells stably transfected with the human FSH receptor and cotransfected with a cAMP response element (CRE)/promoter that directs expression of the firefly luciferase reporter gene. Ligand binding to the Gs-coupled FSH receptor will result in an increase in cAMP, which in turn will trigger increased transactivation of the luciferase reporter construct. To test the antagonistic properties, recombinant FSH was 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 was quantified using a luminescence counter. For test compounds, EC50 values (concentration of test compound causing half-maximal (50%) stimulation or reduction) were calculated. For this purpose, the computer program GraphPad PRISM, version 3.0 (GraphPad software Inc., San Diego) was used.

The compounds of all examples showed an EC 50 (IC 50 ) value of less than 10-5 M in either an agonistic or antagonistic assay or both. Compounds of Examples 3, 4, 7, 10-13, 16, 36, 37, 39, 41 and 42 showed an EC50 (IC50) of less than 10-7 M in at least one of the tests.

Claims (10)

1. Tetrahydroquinoline derivative according to formula 1, [image] or a pharmaceutically acceptable salt thereof, characterized in that R 1 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, (2-6C)heterocycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 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)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. 2. Derivative according to claim 1, characterized in that R3 is (2-6C)heterocycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (2-6C)heterocycloalkylcarbonylamino(2-4C) alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl. 3. Derivative according to claims 1 or 2, characterized in that R5 is (di)(1-4C)alkylamino, amino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino or (6C)aryl(1-4C)alkylamino. 4. Derivative according to claims 1-3, characterized in that R5 is (di)(1-4C)alkylamino or amino. 5. Derivative according to claims 1-4, characterized in that R5 is (di)(1-4C)alkylamino. 6. Derivative according to claims 1-5, characterized in that R4 is (6C)aryl. 7. Derivative according to claims 1-6, characterized in that R3 is (2-6C)heterocycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl or R5-(2-4C)alkyl. 8. Pharmaceutical preparation, characterized in that it contains a tetrahydroquinoline derivative of any one of claims 1-7 and pharmaceutically suitable excipients. 9. The tetrahydroquinoline derivative of claims 1-7, characterized in that it is used for treatment. 10. The use of a tetrahydroquinoline derivative of any of claims 1-7 or its pharmaceutically acceptable salt or solvate, indicated by the fact that it is used for the production of a drug for fertility regulation.