ZA200504775B - Tetrahydroquinoline derivatives - Google Patents

Description

. Tetrahy droquinoline derivatives

The invention relates to a compound having FSH receptor modulatory activity, in particular a tetrahydroquinoline Clerivative, to a pharmaceutical composition containing the same, as well as 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 hypophyseal gonadotropin FSH (follicle stimulating hormone) for example plays a pivotal role in “the stimulation of follicle development and maturation whereas 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 applied clinically, in combination with LH or hCG, for ovarian stimulation i.e. ovariam hyperstimulation for in vitro fertilisation (IVF) and induction of ovulation in infertille anovulatory women (Insler, V., Int. J. Fertility 33:85- 97, 1988, Navot and Rosenwakss, J. Vitro Fert. Embryo Transfer 5:3-13, 1988), as well as for male hypogonadism and mmale infertility.

The gonadotropin FSH is released from the anterior pituitary under the influence of gonadotropin-releasing hormome and oestrogens, and from the placenta during pregnancy. In the female, FSH. acts on the ovaries promoting development of follicles and is the major hormone regoulating secretion of oestrogens. In the male, FSH is responsible for the integrity o-f the seminiferous tubules and acts on Sertoli cells to support gametogenesis. Purified FSH is used clinically to treat infertility in females and for some types of failure of spermatogenesis in males. Gonadotropins destined for therapeutic purposes can be is.olated from human urine sources and are 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 available commercially and is being used in assisted reproduction (Olijve etal. Mol. Hum. Reprowd. 2:371, 1996; Devroey et al. Lancet 339:1 170, 1992).

Ww 0 2004/0567°80 PCT/EP2003/051025

The actions of the FSH hormone are mediated by a specific plasma membmane receptor . that is a member of the large family of G-protein coupled receptors. These receptors consist of a single polypeptide with seven transmembrane domains ancl are able to interact with the Gs protein, leading e.g. to the activation of adenylate cycl ase.

The FSH receptor is a highly specific target in the ovarian follicle growth process and is exclusivesly expressed in the ovary. Blocking this receptor or inhibiting the signaling which is nOmally induced after FSH-mediated receptor activation will d-isturb follicle developmemt and thus ovulation and fertility. Low molecular weight FSH antagonists could therefore form the basis for new contraceptives. Such FSH antagonists could give rise tow diminished follicle development (no ovulation) with still suffi<cient estrogen production left to avoid adverse effects on e.g. bone mass. On thes other hand, compounds that stimulate FSH receptor activity may serve to mimic the= gonadotropic effect of the natural ligand.

The preset invention describes the preparation of low molecular weight hormone analogs thaat selectively have modulatory activity on the FSH receptor. T he compounds of the inveention can either be used as (partial) agonists or (partial) antagonists of the

FSH-recepotor.

Thus, it has now been found, that the following class of tetralhydroquinoline compounds of formula I or pharmaceutically acceptable salts thereof, have FSH- modulatory activity:

<3 - . R3 re N 7

TC Le

RS N” "Ri

ON

Formula I wherein

R! and R? are H Or Me;

R® is H, hydroxy, (1-4C)alkoxy, (di)(1-4C)alkylamino(2-4C)alko=xy or (2- 6)heterocycloalkyyl(2-4C)alkoxy;

R® is H, OH, (1-aC)alkoxy or R”

R’® is H, OH, (1-AC)alkoxy or R” with the proviso that if R* is H, R® is not H, OH or (1-4C)alkoxy and that &fR%isH,R* is not H, OH or (1-4C)alkoxy;

R® is (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloalkyl, (2-6C)heterocyclo-alkyl or Q- 6C)alkyl;

R’ is amino, (dii)(1-4C)alkylamino, (6C)arylcarbonylamino, (6C)arylcarbonyloxy, (2- 5C)heteroarylcamrbonylamino, (2-5C)heteroarylcarbonyloxy, R8-(2-4C)alk=ylamino, R®- (2-4C)alkoxy, R -methylamino or R*-methoxy;

R® is hydroxy, azmino, (1-4C)alkoxy, (di)(1-4C)alkylamino, (2-6C)heteroc-yeloalkyl, (2- 6C)heterocycloalkylcarbonylamino, (di)(1-4C)alkylaminocarbonylamirio or (1- 4C)alkoxycarbonylamino and

R® is aminocarb onyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or C6C)aryl.

R* and R® can independently be selected form each of the groups menticoned and need not be the same.

The compoundss according to the present invention modulate the FSH rec eptor function i and can be used for the same clinical purposes as mative FSH if thesy behave like agonists, with ®the advantage that they display altered stability properties and may be administered differently. If they block the FSH receptor they can be used e.g. as a

Y contraceptive agent.

Thus, the FSH-receptor modulators of the present inventicsn may be used for treating infertility, for contraception and for treatment of hormone-edependent disorders such as breast cancer, prostate cancer, and endometriosis.

The following terms are intended to have the indicated mmeanings denoted below as used in the specification and claims.

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

The term (3-8C)cycloalkyl means a cycloalkyl group hav-ing 3-8 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. (3- 6C)cycloalkyl groups are preferred.

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

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

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

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

The term (6C)aryl as used herein means a phenyl ggroup, which may optionally be substituted with one or more substituents selected frosm hydroxy, amino, iodo, bromo, chloro, fluoro, nitro, trifluoromethyl, cyano, phenyl, (1-4C)alkyl, (1 -4C)alkoxy, (1- 4C)(di)alkylamino, the alkyl, alkoxy and (di)alkyla-mino moieties having the same - meaning as previously defined, for example phenyl. 3,5-dibromophenyl, 4-biphenyl, ’ 3,5-dichlorophenyl, 3-bromo-6-methylamino-phenyl , 3-chloro-2,6-dimethoxyphenyl and 3,5-dimethylphenyl.

The term (2-5C)heteroaryl means a substituted or unssubstituted aromatic group having 2-5 carbon atoms, at least including one heteroatom selected from N, O and/or S, like imidazolyl, pyridyl, pyrimidyl, thienyl or furyl. Thee substituents on the heteroaryl group may be selected from the group of substituents listed for the (6C)aryl group. The heteroaryl group may be attached via a carbon atom or a heteroatom, if feasible.

Preferred heteroaryl groups are thienyl, furyl and pyridyl.

The term di(1-4C)alkylamino(2-4C)alkoxy as used herein means a (di)alkylamino group, the alkyl moeity or alkyl moieties of which each contains 1-4 carbon atoms, connected via the amino group to the alkyl moiety> of an alkoxy group having 2-4 carbon atoms, in which the (di)alkylamino group anc the alkoxy group have the same meaning as previously defined.

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

The term (6C)arylcarbonylamino as used herein mv eans a phenyl group, optionally substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, connected to the carbonyl mo ety of a carbonylamino group, the ’ (6C)aryl moiety having the same meaning as previously defined.

The term (6C)arylcarbonyloxy as used herein meeans a phenyl group, optionally substituted with one or more substituents selected from the group of substituents listed for the (6C)aryl group, connected to the carbonsyl moiety of a carbonyloxy group, the - (6C)aryl moiety having the same meaning as prewiously defined.

The term (2-5C)heteroarylcarbonylamino as ussed herein means a heteroaryl group containing 2-5 carbon atoms, optionally substituted with one or more substituents selected from the group of substituents listed fo-r the (6C)aryl group, connected to the carbonyl moiety of a carbonylamino grovap. The heteroaryl moiety in the . heteroarylcarbonylamino group has the same me-aning as previously defined.

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

The term (2-6C)heterocycloalkylcarbonylarmino as used herein means a heterocycloalky! group having 2-6 carbon atoms, connected to the carbonyl moiety of a carbonylamino group, the beterocycloalkyl group having the same meaning as previously defined.

The term (di)(1-4C)alkylaminocarbonyl as use=d herein means a (di)alkylaminogroup, the alkyl group(s) of which having 1-4 carbon atoms, connected via the amino group to a carbonyl group, the (di)alkylamino group h.aving the same meaning as previously defined.

The term (di)(1-4C)alkylaminocarbonylamnino as used herein means a (di)alkylaminogroup, the alkyl group(s) of which having 1-4 carbon atoms, connected via the amino group to the carbonyl moiety of & carbonylamino group, thus providing a urea functionality, the (di)alkylamino group khaving the same meaning as previously defined.

The term (1-4C)alkoxycarbonylamino as used herein means an alkoxy group having 1- 4 carbon atoms, attached to the carboyl nmoiety of a carbonylamino group, thus } providing a carbamate functionality, the alkoxy group having the same meaning as previously defined

The term R®-(2-4C)alkylamino as used herein means a R® group attached to the alkyl c moiety of a (2-4C)alkylamino group, Thaving the same meaning as previously defined.

The term RS-(2-4C)alkoxy as used herein means a R® group attached to the alkyl moiety of a (2-4C) alkoxy group, having the same meaning as previously defined.

The term R%-methylamino as used herein means a R’ group attached to the methyl moiety of a methylamino group.

The term R’-methoxy as used herein means a R® group attached to the methyl moiety of a methoxy group.

The term pharmaceutically acceptable salt represents those salts which are, within the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable bemefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. They mmay be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting a free base function, if present, with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. If present, an acid function can be reacted wvith an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.

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

In another embodiment the invention relates to compounds according to Formula I, wherein R? is H, hydroxy or (1-4C)alkoxy.

The invention also relates to compounds of formula I, wherein R* is H, OH or (1- 4C)alkoxy.

In another embodiment the invention provides compounds of Formula I wherein Riis

OH, (1-4C)alkoxy or R’.

In another embodiment the invention prosvides compounds of Formula I wherein Ris ) (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloal kyl or (1-6C)alkyl.

In another aspect the invention relates toe compounds according to Formula I wherein

RS is (2-5C)heteroaryl or (6C)aryl.

In still another aspect the heteroaryl group in R® consists of 4 or 5 C atoms.

The invention also relates to compounds according to Formula I wherein Ris (di)(1- 4C)alkylamino, (2-5C)heteroarylcarbonyg/lamino, (2-5C)heteroarylcarbonyloxy, RE-(2- 4C)alkoxy, R>-methylamino or R>-methoexy.

Another aspect of the invention are compounds according to Formula I wherein R is (di)(1-4C)alkylamino, (2-5C)heteroarylcarbonyloxy, R:.-(2-4C)alkoxy, R’- methylamino or R’-methoxy.

In still another aspect the invention relates to compounds according to Formula I wherein R” is (di)(1-4C)alkylamino, R®~q2-4C)alkoxy, R*-methylamino or R®-methoxy.

In another aspect the invention relates #o compounds according to Formula I wherein

R%(2-4C)alkoxy in R is R®-ethoxy.

In still another aspect the invention relates to compounds according to Formula I wherein R3-(2-4C)alkylamino in R is R_®-ethylamino.

In another embodiment the invention provides compounds of Formula I wherein Ris amino, (di)(1-4C)alkylamino, . (2-6C)heterocycloalkyl, 2- 6C)heterocycloalkylcarbonylamino or ( 1-4C)alkoxycarbonylamino.

In another embodiment the invention perovides compounds of Formula I wherein R® is amino, (di)(1-4C)alkylamino, (2-6C)he terocycloalkyl or (1-4C)alkoxycarbonylamino.

In yet another embodiment the invention provides compounds of Formula I wherein R® is amino, (di)(1-4C)alkylamimo, (2-6C)heterocycloalkyl or @- 6C)heterocycloalkylcarbonylamino.

The invention also relates to compoun.ds according to Formula I wherein R? is amino, ’ (di)(1-4C)alkylamino or (2-6C)heteroc=ycloalkyl.

In yet another aspect of the inventiom R3 in the compounds of Formula I is (di)(1- 4C)alkylamino or (2-6C)heterocycloallikyl.

In another aspect the invention relates to compounds according to Formula I wherein : the heterocycloalkyl group in RS consists of 4 or 5 C atoms.

According to another embodiment of the invention R’ according to Formula 1 is aminocarbonyl, (2-5C)heteroaryl or (6C)aryl

According to yet another embodiment of the invention the heteroaryl group in rR’ according to Formula I consists of 3,4 or 5 C atoms.

Yet another aspect of the invention concerns compounds wherein all specific definitions of the groups R' through R” as defined here above are combined in the compound of Formula I.

Suitable methods for the preparation of the compounds of the invention are outlined below.

A

OAK OAK AIK OAK )

QO — OC

AO NH, aio N a AKO NZ ao NLC

N R1 R1 oP oP

I OI-aR!'R?>=Me IV-aR!R?2=Me V-aR1,R2=Me mM-bR'R2=H VLR R2=H V-bRLR2=H

A A A

. [& OC np? he

ON : HN ) HN :

AlkO N R2 AKO N rR AKO N rR

Ri R1 R1

Pr. PN PS

VI-aR!,R?=Me VII-aR!,R?=Me aR, R2=Me

VI-bRIRZ=H VIL-bR!RZ2=H I-bRIL,R?2=H : A=H, 0A

Alk = (1-4C)alkyl

The compounds of the present invention in which R* and R® are (1-4C)alkoxy, R' and : R® are methyl and R® is as previously defined can be prepared starting from appropriately substituted anilines of general formula II, by means of the well- ’ documented Skraup reaction, which yields 2,2,4-trimethyl-1,2-dihydroquinoline derivatives of formula ITI-a.

Related Skraup cyclocon densations are found in 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 amd S.-T. Lin, J. Chin. Chem. Soc. 43:497, 1996; J.P. Edwards,

S.J. West, K.B. Marschke, D.E. Mais, MM. Gottardis and T.K. Jones, J. Med. Chem. 41:303, 1998.

The abovementioned reaction is typically conducted at elevated temperature in acetone or mesityl oxide in the paresence of iodine or protic acid such as hydrochloric acid, p- toluenesulfonic acid or aqueous hydrogen iodide. Alternatively, 1,2-dihydro-2,2,4- trimethylquinolines of formula IlI-a can be prepared by reacting the corresponding aniline of formula II with acetone in the presence of MgSO, 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). Im yet another procedure, the reaction can be performed in acetone using lanthanide triflates (e.g. scandium triflate) as catalysts. In this case, the reaction can be run at room temperature or at elevated temperatures using conventional heating or microwave irradiation (M. E. Theoclitou and L. A. Robinson, Tetrahedron

Lett. 43:3907, 2002).

Starting materials can be either obtained directly from commercial sources or easily prepared by those skilled in the art.

Compounds of formula II-b can be prepared from anilines of general formula IT by reaction with methyl vinyl ketone. Related cyclizations are described in Untited States

Patent 2,686,182 (Badiscche Anilin- & Soda-Fabrik Aktiengesellschaft).

Subsequent 1-N-acetylation of compounds of formula Il-a-b wherein R!, and R? are as previously defined, cama be carried out using standard conditions. In a typical experiment, compounds of formula III are heated under reflux in acetic anhydride or reacted in a solvent sucha as dichloromethane, tetrahydrofuran, toluene or pyridine with acetyl chloride in the presence of a base such as N,N-diisopmopylethylamine, ’ triethylamirme or sodium hydride to give N-acetylated 4-methyl-1,2-clihydroquinoline derivatives of formula IV-a-b.

Related N-.acylations of a dihydroquinoline scaffold are found #n literature: G.

Reddelien smrd A. Thurm, Chem. Ber. 65:1511, 1932; Zh. V. Shmyreva, Kh. S.

Shikhaliev and E.B. Shpanig, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol. 31:45, 1988; Zh. V. Shmyreva, Kh, S. Shikhaliev, LP. Zalukaev, Y™.A. Ivanov, Y.S.

Ryabokoby-1ko and LE. Pokrovskaya, Zh. Obshch. Khim. 59:1391, 19889.

TIntroductiom of the requisite (substituted) phenyl group at position 4 of the dihydroquimoline scaffold can be accomplished via Friedel-Crafts alkylation of benzene ow an appropriately substituted benzene with the compounds of general structure TW-a-b. This reaction is typically conducted at elevated temperatures either in neat benzeme or the appropriately substituted benzene or in an approperiate inert solvent such as hesptane or hexane with benzene or the appropriately substituted benzene as reagent, under catalysis of a Lewis acid (e.g. AlCl, AlIBr; FeCl; o-r SnCly). Friedel-

Crafts alkylations with 2,2 4-trimethyl-1,2-dihydroquinolines are described in literature by B.A. Luagovik, L.G. Yudin and AN. Kost, Dokl. Akad. Nauk SSSR, 170:340, 1966;

B.A. Lugovik, L.G. Yudin, S.M. Vinogradova and A.N. Kost, Khim. Geterosikl.

Soedin, 7:795, 1971.

Alternatively, anilines of general structure II can be reacted withm an appropriately substituted 1-methylstyrene derivative and formaldehyde in acetonitrile at ambient or elevated temperature to give compounds of general structure V-b. R.elated cyclizations are described in literature: JM. Mellor and G.D. Merriman, Tetrahedron, 51:6115, 2s 1995.

Compoun-ds of general structure V-a-b can then be nitrated regioselectively at position 6 of the tetrahydroquinoline scaffold to give compounds of general structure VI-a-b.

This reaction is typically conducted at temperatures in the range of —10 °C to room ] 30 temperature in dichloromethane using a mixture of nitric acid and acsetic anhydride as a nitrating reagent, Alteratively, nitric acid can be added to a solutiors of the compounds of gene-ral structure V-a-b in glacial acetic acid or in a mixture of acetic acid and ’ dichloromethane. Related regioselective nitrations of tetrahwydroquinolines are describeed in literature: B. Golankiewicz, Pol. J. Chem., 54:355, 1980; Zh. V. ' Shmyre=va, Kh. S. Shikhaliev, L.P. Zalukaev, Y.A. Ivanov, Y.S. Ryabokobylko and LE.

Pokrovskaya, Zh. Obshch. Khim. 59:1391, 1989.

Reduction of the nitro group of the compounds of general structure VI-a-b can be accompolished by a large variety of methods well known in the art for the reduction of aromatic nitro compounds such as transition metal catalyzed hydreogenation, treatment with sulfides, treatment with iron or other metals and (mild) acid, treatment with tin dichloride under acidic conditions and the like. More specifically, the reduction of the nitro group of the compounds of general formula VI-a-b can be accomplished by treatment with zinc dust and acetic acid in THF or 1,4-dioxane in the temperature range of 0°C to 100 °C.

Subseqguent 6-N-acylation of compounds of formula VII-a-b can be carried out using standaxd conditions, well known to those skilled in the art to give compounds of general structure I-a-b. For example, compounds of formula JI are reacted in a solvenat such as dichloromethane, tetrahydrofuran, toluene or pyridine with an acyl halide (RS-C(O)-Cl) or acid anhydride (R®-C(0)-O-C(0)-R®) in thie presence of a base

A A ha ne © OH )

HN —i HN

CL BoG™

MeO NTL 4] NA,

IPN PN

I<R1R2=Me, A=0Alk,H I.eB=Me, A=0Alk, IR'R>=H, Me

I-dR,R? =H, A=0Alk, H I-fB=Me, A=0H,R! R>=H, Me } I.gB=H,A=0H,R!R?>=H, Me

I-h B=Me, A=H,R,IR?=H, Me

IiB=H,A=H,R.R?2 =H, Me : Alk = (1-4C)alkyl such as N,N-diisopropylethylamine, triethylamine, pyridine or sodium hydride to give 6-N-acylated-1,2,3,4-tetrahydroquinoline derivatives of formula I-a-b. Altematively, acylation of compounds of general formula VII-a-b to give compounds of general formula I-a-b can also be accomplished by reaction vith an appropriate carboxylic acid (R-CO:H) in the presence of a coupling reagemt such as O-(benzotriazol-1-yl)-

N,N,N’, N’-tetramethyluronium tetrafluoroborate (TBBTU), O-(7-azabenzotriazol-1-yl)-

N,N,N’, N’-tetramethyluronium bexafluorophOsphate (HATU) or bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOF) and a tertiary base, e.g. NN -diisopropylethylamine, in a solvent such as N,N-dimethylformamide or dichloromethane at ambient or elevated temperature.

Compounds of the present invention wherein R3 = HE, OH or (1-4C)alkoxy, R*=OH,

R® = OH or (1-4C)alkoxy and R', R* and R® arc as previously described can be prepared by demethylation reactions of compommnds of general formula I-c-d.

Demethylation reactions of aromatic methyl ethers are well known to those skilled in the art. In a typical experiment, demethylation is achieved upon reaction of a compound of formula I-c-d with BBr; in an inert s«olvent such as dichloromethane at low to ambient temperature to give demethylated compounds of general formula I-e-i.

Alternatively, demethylation can be accomplished upon reaction of compounds of formula I-c-d with BFyMe;S complex at ambient temperature. The degree of demethylation can be controlled to some extent by” carefully controlling the reaction temperature and amount of the demethylating reagent. Generally, mixtures of mono-, di- and, if relevant, trihydroxy compounds of general formula I-e-i are obtained, which can be separated by chromatography, The demethylation reaction generally proceeds with a moderate degree of selectivity, with preferemtial demethylation at position 5 of the tetrahydroquinoline scaffold. The reaction rate €or demethylation (dealkylation) of compounds of general formula I-c-d is 5-OMe > 4-(p-OAlk-phenyl) > 7-OMe. ; Compounds of the present invention wherein R3 is HX or a (functionalised) alkoxy group and R* and/or R® are (functionalised) alkoxy groups or acyloxy groups can be prepared by realkylation or acylation reactions of the hydroxyl groups of compounds of general formula I-e-i with (functionalised) alkyl halides (e-g. chloroethylpyrrolidine) or acyl ’ halides (e.g. 2-furoyl chloride or methyl chloroformmate), respectively, under standard conditions.

The compounds of the present invention in which R* =H and R® is connected to the tetrahydroquinoline scaffold via a nitrogen atom amd R!, R? and R® are as previously defined can be prepared starting from N-Boc-1,4-phenylene diamine (VIID). The reaction sequence (a) Skraup reaction, (b) acetylation and (c) Friedel-Crafts alkylation of benzene or a substituted benzene as described before leads to the formation of compounds of general formula X-a. It should be noted that the Boc-protective group is cleaved off under the reaction conditions of the Frieclel-Crafts reaction.

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

A

Boc Boc ®

HN — , HN Ne + HN

NH. N @® r2 } 2 N RY oP IPN vit xX X-aR!,R2=Me

X-bRLR2=H

A J se cr p.

NZ N N oP PN

XI XI Xm . 15

In yet another procedure, compounds of general foxmula X-b can be obtained starting : with the partial reduction of 4-methylquinoline «XI) with BH; THF complex and

~15- ’ sodium bis(2-methoxy-ethoxy)alumimum dihydride to give 4-methyl-1,2- ’ dihydroquinoline, followed by acctylaticon as described before to give compound XII.

Reductions of related quinolines to 1,2 -dibydroquinolines are described in literature: see, for example: D. Roberts and J. A. ¥oule, J. Org. Chem. 62:568, 1997; R. F. Heier,

L.A. Dolak, J. N. Duncan, D. K. Hyslop, M. F. Lipton, L J. Martin, M. A. Mauragis,

M. F. Piercey, N. F. Nichols, P. J. K. ID. Schreur, M. W. Smith and M. W. Moon, J.

Med. Chem. 40; 639, 1997. Friedel—Crafis reaction of XII with benzene or an appropriately substituted benzene gives compounds of general formula XIII, which can be converted to compounds of general formula X-b by the regioselective 6-nitration and reduction to the corresponding 6 -amino derivative using previously described conditions. Regioselective nitration reactions on similar scaffolds have been reported in literature, see for example: Zh. V. Shmysreva et al, J. Gen. Chem. USSR (Engl. Transl.) 59: 1234, 1989.

Compounds of general formula X-a-b- can then be protected with the art known 9- fluorenylmethyloxycarbonyl group (Fnnoc-group), see for example: T. W. Greene and

P. M. Wats, Protective groups in orgamic synthesis (3* ed., John Wiley & Sons, Inc, 1999, see especially p. 506.). The abovementioned protection is conveniently carried out using FmocCl in THF with pyridine as a base.

A A A

LO 0 LC

Xeab — HN ® HN ® . HN ®

Cy HN b& ~ ™y A N 0 0 o

XIV-a:R!,R2=Me XV-a:R!,R?*=Me XVI-a:R!, RZ =Me

XIV-b:RLR2=H XV-b:R,R2=H XVIb:R!, R2=H

Regioselective nitration at position 7 of the tetrahydrogquinotine scaffold of compounds of general formula XIV-a-b, followed by reduction of the nitro group (vide supra),

gives 7-amino-1,2,3,4-tetrahydroquinoliine derivatives of general formula XV-a-b. ' Regioselective nitrations on related scaffolds with a similar substitution pattern can be found in literature; see, for example: S. H. Reich, M. A. M. Fulry, D. Nguyen, M. L

Pino et. al, J. Med. Chem. 35: 847, 1992; A. Ivobe, M. Uchida, K. Kamata, Y. Hotei,

H. Kusama, H, Harada, Chem. Pharm. Bull. 49: 822, 2001. The nitration conditions are similar to those described previously.

A A

(J ~r° ®

XVlI-a-b _ @® —_— oN ® ™y CH y Q 0 4)

XVI-aR!,R2=Me IjR!,R2=Me

XVI-bRI, R2=H I-kR!,RZ=H

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

Standard cleavage of the Fmoc protective group using piperidine in dichloromethane leads to 6-amino tetrahydroquinoline derivatives of general formula XV1I-a-b which can be acylated selectively at position 6 as described before to give compounds of the present invention of general formula I- j-k. } In another procedure, the amino group at position 7 of tetrahydroquinoline derivatives of general formula XV-a-b can be acylated with (hetero)aryl carboxylic acids (G-

004/056780 PCT/EP2003/051025

CO-H) or acyl chlorides (G-C(O)-Cl) as was described previously. In the subsequent steps, the same deprotection-aacylation strategy (deprotection of 6-N-Fmoc and acylation of the resulting 6-NJH,) that was described previously then leads to compounds of the present invention of general formula I-}-m.

A o~p® ®

LC war —= J AL Aw

H Ri 5 AL

IIR! R2=Me

I-mR,R?2=H

G = aryl, heteroaryl

The compounds of the present -invention in which R* =H and R® is connected to the tetrahydroquinoline scaffold via an oxygen atom and R', R? and R6 are as previously defined can be prepared startin g from 2-methoxy-4-nitroaniline (XVII). The reaction sequence (a) Fmoc-protection to give XIX, (b) reduction of the nitro-group to give XX, followed by (c) regioselective Skraup reaction, (d) acetylation and (¢) Fmoc- deprotection as described before leads to the formation of compounds of general formula XXI-a.

Compounds of general formula XXI-b may be obtained by treating compound XX with methyl vinyl ketone using the conditions described previously for the conversion of compounds of formula II to II-b, followed by 1-N-acetylation and Fmoc deprotection as described before.

Subsequent conversion of cormpounds of general formula XXI to XXIII may be effected by acylation of the 6—~amino group using an appropriate acylating agent, for 2 example acyl chloride R®-C(O)~Cl, followed by Friedel-Crafts reaction with benzene or an appropriate benzene derivative using conditions described previously. Under the

Lewis-acidic conditions of thes Friedel-Crafts reaction concomitant demethylation of the 7-OMe function in comporands of general formula XXII occurs, The thus obtained free 7-OH grovap in compounds of general formula XXIII may be realkylated or : acylated with (feanctionalised) alkyl halides (e.g. chloroethylpyrrolidine) or acyl halides (e.g. 2-furoyl chloride or methyl chloroformate), respectively, undeer standard : conditions to provide compounds of general formula I-n-o (E = functionalized alkyl, acyl or carbamate). fmoc fmos

HN HN HN HN EN

OL 0 OL

So ~O, No NO, So NH, So NTR

PN

Xvi XIX XX XXI-aR!, R?=Me

XXI-b RL, IR?=H

A A

R8 o + oo OJ we I uN Y Y x HN HN — Ce — 0 ee" en © a Ri HO NT RE 0 N" RI ° EN E PN

XX-aR!, R?=Me XXI-aR1,R2=Me I-nR!_ R2=Me

XXI-bR!, R2=H XXII-bR1,R2=H loR'SR2=H

A =H, (1-4C)alkoxy

Compounds of the present invention in which R* and R® are connected wwia a nitrogen atom to the tetrahydroquinoline scaffold can be prepared from compounds of general formula XXIV, wherein PG is a nitrogen protective group, e.g. Boc, acetyl, methylcarbamaste or Fmoc, via the previously described reactions e.g.: Skeraup reaction or cyclocondemsation with methyl vinyl ketone, 1-N-acetylation, clesavage of the protective group, N-alkylation, Friedel-Crafts reaction, nitration, nitro-reduction and acylation (vide supra).

an-6 OAK oO ane : EN a. JO fo”

HN N HN N

" NH, i H, le H ALO ;

XxXav XXV XXVI-aRL,R?=Me XXVII-aR!,R?= Me

XXVI-bR'\R2=H XXVIL-bR! R?=H

Skraup reactions with acetone or mesityl oxide on compounds of general for-mula XXV may lead to two different regioisomeric products of general formula X_XVI-a and

XXVII-a, respectively. Conversion of compounds of general formula XXXV using methyl winyl ketone under previously described conditions may afford regioisomeric products with general formula XXVI-b en XXVII-b, respectively. Genemally, these regioisomneric dihydroquinolines can be separated using chromatographical techniques (silicage=1, HPLC) or crystallization and can subsequently be converted to compounds =3 ra R3 ® R60 ® RC on (J) “Cr rr TX

HN —_ IN rep @ rR

OL k= CLs

Ho gi 0 N7 Ri H EY Ri

A oA 0

XXX-aR!,R==M

XXV1l-aR!,R?=Me XXIX-aR!, R2=Me SR Rl. R= hg

XXVII-bR!,R2=H XXIX-bR!,R2=H ’ r3 i

R60 | ® )

L @ N. R6.__O

Rog” Me ¥ M hd Re

HIN M _— ) pp —>= MW ® R2 THO I R1 ® y R2

HO N~ RI H R1 o

A PN

XX "XI-aR!,R2=Me XXX1-aR!, R?=Me IpR!,R==Me

XX XI-bR,R2=H XXXI-bR!,R?=H IqRL,R2=H of the current invention via the previously described routes.

Compounds of the present invention wherein R® = H may be prepared by reductive 7- deoxygenation of compounds of general formula XX VIII or XXXI (L and/or M is 5s appropriate (substituted) alkyl, acyl alkyloxycarbonsyl or alkylaminocarbonyl) via selective 7-O-triflation and subsequent reduction of the 7-OTf (Tf = trifluoromethylsulfonyl) group. The requisite compounds of general formula XXXT are accessible from derivatives of general formula XXWII using previously described conditions. The (regioselective) triflation reaction may be effected under controlled conditions using TfN-phenyl and N,N-diisopropylesthyl amine in DMF at room temperature. Generally, preferential triflation of the 7-OH group occurs. The subsequent reduction can be accomplished using a mmixture of triphenyl phosphine, trietyl amine, formic acid and pailadium(ll) acetate as described in the literature. See for example K.A. Parker, Q. Ding, Tetrahedron 56:10249, 2000. Conversion of the thus obtained compounds with general formula XXX or XXXII using previously described conditions then leads to compounds of genemal formula I-p-g, in which R=

H.

Some of the compounds of the invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.

The pharmaceutically acceptable salts may also be obtained by treating the free base of formula IT with 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, methanesulph_onic acid, famaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbiec acid.

The compounds of the present invention possess at least one chiral carbon atom and may therefore be obtained as pure enantiomers, or as a mixture of enantiomers, or as a mixture of diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g crystallization of salts which are obtaine«d from optically active acids and the racemic mixture, or chromatography using chiral columns. For diastereomers, ) straight phase or reversed phase columns may be used.

The compounds of the invention may form hydrates or solvates. It is known to those of ’ skill in the art that charged compounds form hydrated spescies when lyophilized with water, or form solvated species when concentrated in a solution with an appropriate ) organic solvent. The compounds of this invention include the hydrates or solvates of the compounds listed.

For selecting active compounds testing at 10° M must resu=lt in an activity of more than 20% of the maximal activity when FSH is used as a reference. Another criterion might be the ECso value which must be < 10° M, preferably < 10~" M.

The skilled artisan will recognize that desirable ECso v-alues are dependent on the compound tested. For example, a compound with an ECso which is less than 10° M is generally considered a candidate for drug selection. Preferably this value is lower than 107M. However, a compound which has a higher ECs, but is selective for the particular receptor, may be even a better candidate.

Methods to determine receptor binding, as well as in vitroand in vivo assays to determine biological activity, of gonadotropins are w-ell known. In general, the expressed receptor is contacted with the compound tO be tested and binding or stimulation or inhibition of a functional response is measumred.

To measure a functional response, isolated DNA encodlling the FSH receptor gene, 2 preferably the human receptor, is expressed in suitable hosst cells. Such a cell might be the Chinese Hamster Ovary cell, but other cells are also suitable. Preferably the cells are of mammalian origin (Jia et al, Mol. Endocrin., 5:759-776, 1991).

Methods to construct recombinant FSH expressing cell limes are well known in the art (Sambrook et al, Molecular Cloning: a Laboratory MJanual, Cold Spring Harbor 2s Laboratory Press, Cold Spring Harbor, latest edition). Experession of receptor is attained by expression of the DNA encoding the desired protein. Techniques for site directed mutagenesis, ligation of additional sequences, PCR, @and construction of suitable . expression systems are all, by now, well known in the art. Portions, or all, of the DNA encoding the desired protein can be constructed synth-etically using standard solid 0 phase techniques, preferably to include restriction sites for ease of ligation. Suitable control elements for transcription and translation of the included coding sequence can be provided to the DNA coding sequemces. As is well known, expression systems are ‘ now available which 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 lik-e.

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

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

For measurement of binding, radioactiwely labeled or fluorescently labeled compounds may be used. Also competition binding assays can be performed.

Another assay involves screening for FF'SH receptor agonist compounds by determining stimulation of receptor mediated cAMIP accumulation. Thus, such a method involves expression of the receptor on the cell surface of a host cell and exposing the cell to the test compound. The amount of CAME is then measured. The level of cAMP can be is reduced or increased, depending on the inhibitory or stimulating effect of the test compound upon binding to the receptox.

Screening for FSH receptor antagonists involves incubation of FSH receptor- expressing cells with a concentration wange of the test compound in the presence of a fixed, submaximally effective, FSH concentration (i.e, a FSH concentration that induces approximately 80% of the maximal stimulation of cAMP accumulation in the absence of test compound). From thes concentration-effect curves, the ICso value and the percentage of inhibition of FSH-anduced cAMP accumulation can be determined for each of the test compounds. 45 In addition to direct measurement of e.g. CAMP levels in the exposed cell, cells lines can be used which in addition to transfection with receptor encoding DNA are also transfected with a second DNA encoding a reporter gene the expression of which . responds to the level of cAMP. Such weporter genes might be cAMP inducible or might be constructed in such a way that they are connected to novel cAMP responsive : 30 elements. In general, reporter gene expression might be controlled by any response element reacting to changing levels of cAMP. Suitable reporter genes are e.g. the genes - encoding PB-galactosidase, alkaline phosphatase, firefly luciferase and green fluorescence protein. The principles of stch transactivation assays are well known in . the art and are described e.g. in Stratow~a, Ch., Himmler, A. and Czernilofsky, A.P., (1995) Curr.Opin.Biotechnol. 6:574. As reference compound human recombinant FSH can be used. In the alternative also competition assays can be performed

The present invention also relates to & pharmaceutical composition comprising a tertrahydroquinoline derivative or pharmaceutically acceptable salts thereof having the general formula I in admixture with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents. The auxiliaries must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

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

For oral administration, the active ingredlient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.

For parenteral administration, the pharmanceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring osnly the addition of sterile liquid carrier, e.g. water, prior to use.

Mixed with such pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference, Gennaro, A.R. et all, Remington: The Science and Practice of

Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, see especially Part 5:

Pharmaceutical Manufacturing), the activ-e agent may be compressed into solid dosage units, such as pills, tablets, or be processe=d into capsules or suppositories. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.

For making solid dos age units, the use of conventional additives such as fillers, : colorants, polymeric beinders and the like is contemplated. In general any pharmma- ceutically acceptable additive which does not interfere with the function of the active . compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be usesd, containing pharmaceutically acceptable dispersing agents and/or wetting agents, ssuch as propylene glycol or butylene glycol.

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

The tetrahydroquinolirae derivatives of the invention can also be administered in the form of implantable pharmaceutical devices, consisting of a core of active material, encased by a release rate-regulating membrane. Such implants are to be applied subcutaneously or locally, and will release the active ingredient at an approximately constant rate over relatively large periods of time, for instance from weeks to years.

Methods for the prepamration of implantable pharmaceutical devices 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 regimen of administration of the active ingredient, or a pharmaceutical composition thereof, will necessarily be dependent upon the therapeutic effect to be achieved gtreatment of infertility; contraception), and may vary with the particular compound, “the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered.

In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, a dosage for humans preferably comtains 0.0001-25 mg per kg body weight. The desired dose may be presented as one dowse or as multiple subdoses administered at appropriate intervals throughout the day, -or, in case of female recipients, as doses to be adminisstered at appropriate daily intervals throughout the menstrual cycle. The dosage as well as the regimen of administration may differ between a female and a male recipient.

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

A further aspect of thie invention resides in the use of a tetrahydroquinoline de-xivative compound having the general formula I for the manufacture of a medicament to be used for the treatmemt of disorders responsive to FSH receptor mediated pa-thways.

Thus, patients in need thereof can be administered with suitable amounts of the compounds according to the invention.

In another aspect the: invention resides in the use of a tetrahydroquinoline derivative compound having the general formula I for the manufacture of a medicament to be used for the control of fertility.

In yet another aspect the invention resides in the use of a tetrahydroquinoline derivative compound having the general formula I for the manufacture of a medicamerat to be used for the treatment of infertility.

In still another aspect the invention resides in the use of a tetrahydroquuinoline derivative compouncl having the general formula I for the manufacture of a medicament to be use=d to prevent fertility.

The compounds according to the invention can also be used for the treatrment of hormone-dependent dlisorders such as breast cancer, prostate cancer and endome=triosis.

The invention is illustrated by the following examples.

Examples

General Comments: . The following abbreviations are used in the examples: DMA = N,N-dimethyl:aniline,

DIPEA = N,N-diisop-ropylethylamine, TFA = trifluoroacetic acid, DtBAD = di-tert- ] butyl azodicarboxyylate, HATU = O-(7-azabenzotriazole-1-yl)-N,N,N’,N’-

tetrameth-yluronium hexafluorophosphate, Fmoc = 9-fluorenylmethoxycarbonyl, Fmoc- . Cl = 9-flmiorenylmethoxycarbonylchloride, DMF = N,N-dimethylformamide, DMAP = 4-dimeth=ylaminopyridine, THF = tetrahydrofuran. : Unless stzated otherwise, all final products of the examples below are lyophilize=d from water/1,4~dioxane mixtures or water/acetonitrile mixtures. If the compourad was prepared as a HCI- or TFA salt, the respective acids were added in appropriate ammounts to the solvent mixture before lyophilization.

The names of the final products described in the examples are generated usZing the

Beilstein Autonom program (version: 2.02.119).

The following analytical HPLC methods are used for determination of retention —times:

Method A: Column: § pm Luna C-18(2) 150x4.6 mm; flow: 1ml/min; detection: 210 nm; colmmn temperature: 40 °C; solvent A: CH;CN/H20 = 1/9 (v/v); solwent B:

CH3CN; solvent C: 0.1 M aqueous trifluoroacetic acid; gradient: solvent A/B/C = 65/30/5 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 (VIVIv).

Method 2: Identical to method 1, except for the gradient used: Gradient: solven® A/B/C = 75/20/55 to 15/80/5 (v/v/v) in 30.00 min, then constant for an additional 10.009 min at

A/B/C= 15/80/5 (vIVIV).

Method 3: Identical to method 1, except for the gradient used: Gradient: solvent A/B/C = 35/60/55 to 10/85/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at

A/BIC= 10/85/5 (vivIv).

Method <4: Column: 3 pm Luna C-18(2) 100x2 mm; flow: 0.25m)/min; detectieon: 210 nm; column temperature: 40 °C; solvent A: HzO; solvent B: CH;CN; gradient: solvent

A/B = 755/25 to 0/100 (v/v) in 20.00 min, then constant for an additional 10.008 min at A/B=0/ 100 (v/v).

Method =5: Column: 3 pm Luna C-18(2) 100x2 mm; flow: 0.25ml/min; detectieon: 210 nm; column temperature: 40 °C; solvent A: H,0; solvent B: CH;CN; 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 mim, then constant for an additional 10.00 min at A/B/C = 10/80/10 (v/v/v).

Method &: Identical to method 5, except for the gradient used: Gradient: solvenst 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/vIv).

The following methods are used for preparative HPLC-purifications:

Method A: Column = Luna C-18. Gradient: 0.1% trifluoroacetic acid in H;O/CH3;CN } (9/1, v/v)/CH3CN = 80/20 to 0/100 (v/v) in 30-45 min, depending on the ease of sepaxation. Detection; 210 nm.

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

Exammple 1

N-[1 -Acetyl-5,7-dimethoxy-4-(4-methoxy-phenyl)-2,2.4-trimethys} 1.2.3 4-tetrahydro- quin olin-6-y1}-3-chloro-2.6-dimethoxy-benzamide (a). S,7-Dimethoxy-2,2 4-trimethyl-1,2-dihydroquinoline

A solution of 3,5-dimethoxyaniline (50 g) in acetone (800 ml) was added dropwise to a mixture of MgSO04 (100 g) and Sc(OTf)3 (8.0 g) in 1 1 of acetone at room temperature.

After 5 h another portion of Sc(OTf); (3.2 g) was added and the reaction mixture was stirred until no starting material remained. After filtration, the acetone was partially evapeorated in vacuo causing crystallization of the title compound which was collected by filtration to yield 22 g after drying in vacuo. The remaining mother liquor was concentrated in vacuo and the residue was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent to gi~ve an additional 19.4 g of the title compound.

Yield: 42g. f (b). 1-Acetyl-5,7-dimethoxy-2,2.4-trimethyl-1,2-dihydsoquinolin €

A muixture of the compound described in example 1a (42 g) and. acetic anhydride (100 ml) ~was stirred at 100 °C for 20h. The reaction mixture was poured in 500 ml of ice- water while stirring. The precipitated solids were collected by filtration and dried in vaciao at 40 °C for 2 days. The remaining brown solid could be used crude for further synthetic transformations.

Yield: 45g. .

(c). 1-Acetyl-5.7-dimethoxy-4-(4-methoxyphenyl)-2,2 4-trimmethyl-1,2.3.4-tetrahydro- . quinoline

A mixture of the compound described in example 1b (30 g) aand AICI; (44 g) in anisole . (500 ml) was stirred at 50°C for 18 h. The reaction mixtuare was cooled (0°C) and 5s quenched with water and ethyl acetate was added. The mixt-ure was stirred overnight.

The organic layer was separated, dried over MgSO, filtered zand concentrated in vacuo.

The residue was chromatographed on silicagel using heptanee/ethyl acetate = 8/2 (v/v) as the eluent.

Yield: 15 g. (d). 1-Acetyl-5.7-dimethoxy-4-(4-methoxyphenyl)-2,2,4--trimethyl-6-nitro-1.2.3.4- tetrahydroquinoline

A solution of acetic anhydride (450 pl) in fuming nitric amcid (22.5 ml) was added dropwise to a solution of the compound described in example lc (15 g) in CHCl (500 ml) at 0 °C. After complete addition the reaction mixture was stirred at room temperature for 3 h, Water was added and the organic layer was separated, dried over

MgSO, filtered and concentrated in vacuo. The residue wass crystallized from ethanol to give the title compound as a crystalline solid.

Yield: 10 g. (e). 1-Acetyl-6-amino-5,7-dimethoxy-4-(4-methoxypheny])-2.2 4-trimethyl-1.2.3.4- tetrahydroquinoline

A solution of the compound described in example 1d (11.75 g) and acetic acid (15.5 ml) in THF (600 ml) was cooled to 0 °C. Zinc dust (36 g) was added in portions and the ice-bath removed. The temperature rose rapidly to 30 °C, after which the reaction mixture was allowed to cool down to room temperature. The excess of zinc was removed by filtration and to the filtrate was added CH,Cl» and a saturated aqueous solution of Na,CO;. The organic layer was separated, dried over MgSO, filtered and concentrated in vacuo. The product was used crude in the next step.

Yield: 10.9 g.

®. N-[1-Acetyl-5,7-dimethoxy-4-( 4-nmethoxy-phenyl)-2,2 4-trimethyl-1,2.3.4- . tetrahydro-quinolin-6-y1]-3-chloro-2,6-dimethoxy-benzamide

General procedure A: To a solution of the compound described in example 1e (100 . mg), 3-chloro-2,6-dimethoxybenzoic acid (60 mg) and DIPEA (132 pl) in CH.CL (2 ml) was added HATU (143 mg) at room temperature. If the reaction did not reach completion after 18 h, more HATU and ¥DIPEA were added. After completion of the reaction a saturated aqueous solution of NaHCO; was added, the organic layer was separated, dried (MgSOs) and concentrated in vacuo. The title compound was purified by preparative HPLC (method A).

Yield: 87 mg. MS-ESI: [M+H]" = 597.4

HPLC: R, = 17.98 min (method 1).

Example 2 4 5-Dimethyl-furan-2-carboxylic_acid [1—acetyl-5.7-dimethoxy-4-(4-methoxy-phenyl)- 2,2.4-trimethyl-1,2,3 4-tetrahydro-quinolin-6-yl]-amide

General procedure B: To a solution of she compound described in example le (800 mg), 4,5-dimethylfuran-2-carboxylic acid (308 mg) and DMA (768 pl) in DMF (10 mi) was added HATU (1.1 g) at room temperature, If the reaction did not reach completion after 18 h, the reaction mixture was heated to 50 °C. After completion of the reaction, water and ethyl acetate were added, the organic layer was separated, dried (MgSO,) and concentrated in vacuo. The title cormpound was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 444 mg. MS-ESI: [M+H]" = 521.4

HPLC: R; = 16.96 min (method 1).

Example 3 5-Bromo-thiophene-2-carboxylic acid [1—acetyl-5.7-dimethoxy-4-(4-methoxy-phenyl)- 2,2 4-trimethyl-1,2.3 4-tetrahydro-quinolim-6-yl ]-amide

According to general procedure B, the compound described in example 1e (800 mg), was acylated with 5-bromothiophene-2-c.arboxylic acid (456 mg), DMA (768 pl) and

HATU (1.1 g) in CH>Cl; (10 ml). The title compound was purified by chromatography . 30 on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 1.0 g. MS-ESL: [M+H]" = 589.2; HXPLC: R, = 18.90 min (method 2).

Example 4 . Biphenyl-4-carboxylic acid [1-acetyl-5.7~- dimethoxy-4-(4-methoxy-phenyl)-2.2.4- trimethyl-1.2 3 4-tetrahydro-guinolin-6-yl}-am#de

General procedure C: To a solution of the compound described in example le (800 mg) and 4-biphenylcarbonyl chloride (475 mg) in CH2Clz (10 ml) was added DMA (768 pi) at room temperature. The reaction mixture was stirred until no starting material remained at which point water was added. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 678 mg. MS-ESIL: [M+H]" = 579.4; HPL_C: R,= 26.19 min (method 2).

Example §

Furan-2-carboxylic acid [1-acetyl-5-hydroxy—7-methoxy-4-(4-methoxy-phenyl)-2.2.4- trimethyl-1,2.3 4-tetrahydro-quinolin-6-yl}-amuide (a). Furan-2-carboxylic acid [l-acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2.2.4- trimethyl-1,2 3 4-tetrahydroquinolin-6-yl]-amicle

According to general procedure C, the compound described in example le (800 mg) was acylated with 2-furoyl chloride (217 pl) amd DMA (768 pul) in CHCl, (10 ml). The title compound was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 896 mg (b). Furan-2-carboxylic acid [1-acetyl-5-hyciroxy-7-methoxy-4-(4-methoxy-phenyl)- 2.2 4-trimethyl-1,2.3 4-tetrahydro-quinolin-6-y~1]-amide

General procedure D: A solution of the compound described in example Sa (50 mg) in CH.Cl; (4 ml) was cooled to —78 °C, under~ an atmosphere of N2. Boron tribromide (28 pl) was added dropwise and after complete addition, the reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched with water and CHoCl, was added. The organic layer was separated, dried (MgSOs) and concentrated in vacuo. The title compound wa s purified by preparative HPLC (method

A). Under the above described conditions, generally mixtures of compounds with a - varying degree of demethylation are formed, which may be separated by preparative

HPLC methods. _ Yield: 9.1 mg; MS-ESI: [M+H]" = 479.4; HPL.C: R, = 23.40 min (method 2).

Example 6 : N-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2.2.4-trimethyl-1,2,3 4- tetrahydro-quinolin-6-yl]-3,5-adichloro-benzamide : (a). N-[1-Acetyl-5,7-dimethoxy-4-(4-methoxyphenyl)-2.2.4-trimethyl-1,2 3 4-tetra- hydroquinolin-6-yl]-3,5-dichlorobenzamide

According to general procedure C, the compound described in example le (800 mg) was acylated with 3,5-dichlorobenzoyl chloride (460 mg) and DMA (768 pl) in CHCl, (10 ml). The title compouna was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 1.03 g (b). MN-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2.2.4-trimethyl-1.2,3.4- tetrahydro-quinolin-6-yl}-3,5-«dichloro-benzamide

According to general procedume D, the compound described in example 6a (50 mg) was treated with boron tribromide (24 pl) in CHCl, (4 mi). The title compound was purified by preparative HPLC. (method A).

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

Example 7 5-Chloro-thiophene-2-carboxylic acid [1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy- phenyl)-2,2 4-trimethyl-1.2.3 ,4-tetrahydro-quinolin-6-yl]-amide (a). S5-Chlorothiophene-2-carboxylic acid [1-acetyl-5,7-dimethoxy-4-(4-methoxy- phenyl)-2.2.4-trimethyl-1.2.3 ,4-tetrahydroquinolin-6-yl]-amide

According to general procedure B, the compound described in example le (800 meg) was acylated with 5-chlorothiiophene-2-carboxylic acid (456 mg), DMA (768 pl) and

HATU (1.1 g) in CHCl, (10 mnl). The title compound was purified by chromatography on silicagel using heptane/ethwsyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 1.0 g (b). 5-Chiloro-thiophene-2-carboxylic acid _[1-acetyl-5-hydroxy-7-methoxy-4-(4- methoxy-phenyl)-2,2,4-trimethhyl-1.2,3 4-tetrahydro-quinolin-6-yl]-amide

According to general procedure D, the compound described in example 7a (200 mg) was treated with boron tribromide (350 pl) in CHCl, (25 ml) but in this case the temperature was not allowed to exceed -30 °C. The title compound was purified by chromatography on silicagel wising heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the . eluent , followed by preparativee HPLC (method A).

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

Example 8

Biphenyl-4-carboxylic acid _ [1-acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)- 2.2 4-trimethyl-1.2 3 4-tetrahyciro-quinolin-6-yl}-amide

According to general procedure D, the compound described in example 4 (50 mg) was treated with boron tribromide (100 pl) in CH2Cl, (4 ml) but in this case the temperature was not allowed to exceed O °C. The reaction mixture also contains the product described in example 10. The title compound was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 43 mg; MS-ESL: [M+HJ" = 565.4; HPLC: R;= 32.53 min (method 2).

Example 9

Biphenyl-4-carboxylic acid [1-acetyl-5,7-dihydroxy-4-(4-hydroxy-phenyl)-2.2.4- trimethyl-1,2.3 4-tetrahydro-quuinolin-6-ylf]-amide

According to general procedure D, the compound described in example 4 (50 mg) was treated with boron tribromide (100 pl) in CHxCl> (4 ml) but in this case the temperature was allowed to reach 15 °C. The title compound was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

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

Example 10

Biphenyl-4-carboxylic acid _ [1-acetyl-5-hydroxy-4-( 4-hydroxy-phenyl)-7-methoxy- 2.2 4-trimethyl-1,2,3 4-tetrahy «ro-guinolin-6-yl}-amide

According to general procedure D, the compound described in example 4 (400 mg) was treated with boron tribromidle (800 pul) in CH,Ch (25 ml) but in this case the temperature was not allowed to exceed 0 °C. The title compound (= a byproduct as described in example 8) vwwas purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => (0/1 (v/v) as the eluent. . Yield: 50 mg; MS-ESL [M+HY" = 551.4; HPLC: R,= 27.58 min (method 2).

Example 11 . 4,5-Dimethhyl-furan-2-carboxylic acid [1-acetyl-5-hydroxy-7-methoxy-4-(4-me=thoxy- phenyl)-2.2 4-trimethyl-1.2.3 4-tetrahydro-quinolin-6-yl]-amide : According: to general procedure D, the compound described in example 2 (200 ng) was treated with boron tribromide (336 pl) in CHChL (25 ml) but in this case the temperatumre was kept at —78 °C. The title compound was purified by preparatives HPLC (method A).

Yield: 51 mug; MS-ESI: [M+H]" = 507.4; HPLC: R, = 24.32 min (method 1).

Example 12

N-[1-Acetoyt5-hydroxy-4-(4-hydroxy-phenyl)-7-methoxy-2.2.4-trimethyl-1.2.3.=4- tetrahydrow-quinolin-6-y1]-3.5-dichloro-benzamide

According to general procedure D, the compound described in example 6a (75 rmg) was treated with boron tribromide (38 pl) in CHCl, (5 ml). The title compound was purified by preparative HPLC (method A).

Yield: 11 mg; MS-ESL: [M+H]" = 543.4; HPLC: R,=25.66 min (method 2).

Example 13

Ne 1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2.2 4-trimethyl-1,2.3 4 tetrahydroy-quinolin-6-yl }-3.5-dimethyl-benzamide (a). IN| 1-Acetyl-5.7-dimethoxy-4-(4-methoxyphenyl)-2.2.4-trimethyl-1 2,3 4-tetra- hydroguimolin-6-yI]-3.5-dimethyl-benzamide

Accordin g to general procedure B, the compound described in example le (8200 mg), was acylated with 3,5-dimethylbenzoic acid (330 mg), DMA (768 pl) and HA TU (1.1 g) in CHCl; (10 ml). The title compound was purified by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 1.18 ¢g (). N- 1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyl)-2.2.4-trimethyl -1.2,3.4- tetrahydr o-quinolin-6-y1]-3.5-dimethyl-benzamide : Accordimg to general procedure D, the compound described in example 13a (C300 mg) was treased with boron tribromide (513 pt) in CH.Ch (25 ml), but in this case the . temperate was not allowed to exceed —40 °C. The title compound was pucrified by preparati-ve HPLC (method A).

Yield: 41 mg; MS-ESE [M+H]" = 517.4; HPLC: R,= 13.89 min (method 3).

Exampple 14 i N-[1- cetyl-5-hydroxy-7-methoxy-4-(4-methoxy-phenyD-2.2 =4-trimethyl-1,2,3.4- tetrahy2dro-quinolin-6-yl]-3.5-dibromo-benzamide (a). N-[1-Acetyl-5.7-dimethoxy-4-(4-methoxyphenyl)-2.2 ad-trimethyl-1.2.3.4-tetra- hydrocuinolin-6-yl]-3,5-dibromobenzamide

According to general procedure B, the compound described in example le (800 mg), was acylated with 3,5-dibromobenzoic acid (616 mg), DMA (768 pl) and HATU (1.1 g) in DMF (10 ml). The title compound was purified by chromatography on silicagel using Theptane/ethyl acetate = 1/0 => 0/1 (v/v) as the eluent.

Yield: 900 mg (b). ZV-[1-Acetyl-5-hydroxy-7-methoxy-4-(4-methoxy-pheny®)-2.2.4-trimethyl-1.2.3.4- tetrah=ydro-quinolin-6-yl]-3.5-dibromo-benzamide

According to general procedure D, the compound described in example 14a (300 mg) was tweated with boron tribromide (639 ul) in CHzClz (25 ml), but in this case the temperature was not allowed to exceed —60 °C. The title compound was purified by prepamative HPLC (method B).

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

Examaple 15

Biphesnyl-4-carboxylic acid [1-acetyl-2,2 4-trimethyl-7-( 2-mmorpholin-4-yl-ethoxy)-4- phenysl-1 2.3 .4-tetrahydro-quinolin-6-yl]-amide (a). 1=Fmoc-2-methoxy-4-nitroaniline

A solution of 2-methoxy-4-nitroaniline (3.0 g) and pyridine (1.6 ml) in THF (30 ml) was cooled to 0 °C. FmocCl (5.07 g) was added in portions amd after complete addition the ic e-bath was removed and the mixture was stirred for 5 h_ The THF was removed in vacuo and the residue dissolved in CHzClz (175 ml). Metharol (ca 100 ml) was added and the CH,Cl, was partly removed ir vacuo until a precip~itate formed. The mixture was allowed to stand for 1 h, after which time the crystals vwere collected by filtration and disied in vacuo to give the title compound. } Yield: 6.32 g; MS-ESL: [M+H]"=391.2

: (b). 9-Fluorenylmethyl N-(2-methoxy-4-aminophenyl)carlbamate

General procedure E: A mixture of the compound described in example 15a (6.07 g), acetic acid (8.9 ml) and THF (150 ml) was cooled to 0 °C Zinc dust (20.4 g) was added in portions and the ice bath was removed. After the temperature slowly reached 10 °C it rapidly rose to 45 °C. After the reaction mixture was allowed to cool down to room temperature, the excess of zinc was removed by filtration and a large amount of

CHCl; (ca 500 ml) was added. The mixture was warshed with saturated aqueous

NaHCO; (3x200 ml) and brine (1x200 ml). The organ ic layer was separated, dried (MgSOs) , filtered and concentrated in vacuo until a precipitate formed. The mixture was allowed to stand overnight at 0 °C, after which time -the crystals were collected by filtration and dried in vacuo to give the title compound.

Yield: 4.45 g. (c). (I-Methoxy-2.2 4-trimethyl-12-dihydroguinolin-6-y1)-carbamic acid 9H-fluoren- 9-ylmethyl ester

A mixture of the compound described in example 15b 4.45 g), I> (157 mg), MgSO, (7.4 g), 4-tert-butylcatechol (61 mg) and acetone (ca 350 ml) was heated at reflux for 5 h. The MgSO, was removed by filtration and the filtrate was concentrated in vacuo.

The title compound was obtained by chromatography on silicagel using heptane/ethyl acetate = 9/1 => 7/3 (V/V) as the eluent.

Yield: 424 g. (d). (1-Acetyl-7-methoxy-2,2 4-trimethyl-1,2-dihydroquimolin-6-yl)-carbamic acid 9H- fluoren-9-ylmethyl ester

To a solution of the compound described in example 15 ¢ (4.24 g) in pyridine (25 ml) and CHCl; (25 ml) was added a small amount of DMA P (ca 20 mg). Acetyl chloride (2.0 ml) in CHCl, (20 ml) was slowly added. After complete addition the mixture was diluted with CH,Cl, (ca 100 ml) and washed with water (3x100 ml), 0.1 M aq HCl (3x100 ml), 0.5 M aq HCI (1x100 ml) and brine (1x10 ml). The organic layer was . dried (MgSO,) and concentrated in vacuo. The title compound was obtained by chromatography on silicagel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as the eluent.

Yield: 3.91 g. (e). 1-Acetyl-6-amino-7-methoxy-2.2 4-trime#hyl-1,2-dihydroguinoline ) Piperidine (8.0 ml) was added to a solution of the compound described in example 15d (3.91 g) in CH,CL (80 ml). After 1.5 h, the resaction mixture was concentrated in vacuo and the title compound was obtained by chromatography on silicagel using heptane/ethyl acetate = 9/1 => 7/3 (v/v) as the eluent.

Yield: 22 g (f). Biphenyl-4-carboxylic acid (1-acetyl-7-methoxy-2.2 4-trimethyl-1.2- dihydroquinolin-6-yl)-amide

General procedure F: To a mixture of the «<ompound described in example 15¢ (2.2 g), toluene (45 ml) and pyridine (5 ml) was added 4-biphenylcarbonyl chloride (2.21 g). If the reaction did not reach completion after 3 h at room temperature, an’additional portion of 4-biphenylcarbonyl chloride (2.0 g) was added. Stirring was continued for 30 min, after which the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (ca 100 ml) and wasshed with saturated aq NaHCO; (100 ml), 1 M aq HCI (3x100 ml) and brine (100 ml). “The organic layer was dried (MgSO4) and concentrated in vacuo. To the residue was ad«led CH,Cl, (ca 50 ml) and the solids were removed by filtration and discarded. The filtrate was concentrated in vacuo and the title compound was obtained by chromatography on silicagel using heptane/ethyl acetate = 1/0 => 1/1 (v/v) as the eluent,

Yield: 3.1¢. (g). Biphenyl4-carboxylic acid (1-acetyl-7-hydroxy-2,2 4-trimethyl-4-phenyl-1,2.3.4- tetrahydroquinolin-6-yI)-amide

General procedure G: To a solution of the compound described in example 15 (3.1 g) in benzene (100 ml) was added alumirmum trichloride (5.6 g) and the reaction mixture was stirred for 20 h at room temperature. The reaction was quenched with H,O (ca 100 ml) and the pH of the mixture was adjusted to pH 8 with 2 M aq NaOH while . stirring vigorously. Ethyl acetate (ca 300 mol) was added and the organic layer was washed with HO (2x150 ml) and brine (1x 150 ml), dried (MgSOs) and concentrated in vacuo to yield the product that was used without further purification,

Yield: 3.5 g. (h). Biphenyl-4-carboxylic acid [1-acetyl-2,2 4-trimethyl-7-(2-morpholin-4-yl-ethoxy)- ’ 4-phenyl-1,2,3 4-tetrahydro-quinolin-6-yl}-arnide

General procedure H: A mixture of the compound described in example 15g (70 mg),

N-(2-chloroethyl)-morpholine hydrochlorides (31 mg), Cs2CO; and DMF (3 ml) was stirred at 50 °C, until no starting material remained. The reaction mixture was diluted with ethyl acetate (15 ml) and water was added (ca 15 ml). The organic layer was washed with water (3x15 ml), separated, dried (MgSO.) , filtered and concentrated in vacuo. The title compound was obtained as the corresponding HCl salt by lyophilization from a mixture of 1,4-dioxane and H>O containing HCI.

Yield: 63 mg (HCI salt); MS-ESI: [M-+H]" = 618.6; HPLC: R; = 19.49 min (method 4).

Example 16

Biphenyl-4-carboxylic acid (1-acetyl-7-dim ethylcarbamoylmethoxy-2.2 4-trimethyl-4- phenyl-1.2.3 4-tetrahydro-quinolin-6-yl)-amiide

According to general procedure H, the compound described in example 15g (79 mg) was alkylated with 2-chloro-N,N-dimethylacetamide (23 mg) and Cs2CO3 (255 mg) in

DMF (2 ml). The title compound was purifiesd by crystallization from CH;CN.

Yield: 15 mg; MS-ESI: [M+H]" = 590.6; HPPLC: R, = 23.58 min (method 5).

Example 17

Biphenyl-4-carboxylic acid [1-acetyl-2,2 4-trimethyl-4-phenyl-7-(3-piperidin-1-yl- propoxy)-1,2.3 4-tetrahydro-quinolin-6-yl]-aamide

According to general procedure H, the conpound described in example 15g (79 mg) was alkylated with N-(3-chloropropyl)piperiidine hydrochloride (37.4 mg) and Cs>CO3 (255 mg) in DMF (2 ml). The title compound was purified by crystallization from

CH;CN.

Yield: 83 mg (HCI salt); MS-ESI: [M+H]" = 630.8; HPLC: R; = 15.49 min (method 5).

Example 18 . Biphenyl-4-carboxylic acid [1-acetyl-2,2 4-trimethyl-4-phenyl-7-(pyridin-2- ylmethoxy)-1.2.3 4-tetra’hydro-quinolin-6-yI]-amide - According to general procedure H, the compound described in example 15g (79 mg) was alkylated with 2-picolyl chloride hydrochloride (31 mg) and Cs,CO3 (255 mg) in

DMF (2 ml). The title compound was purified by crystallization from CH;CN.

Yield: 32 mg (HCI salt); MS-ESI: [M+H]" = 596.6; HPLC: R; = 22.41 min (method 6).

Example 19

Biphenyl-4-carboxylic acid [1-acetyl-2 2 4-trimethyl-4-phenyl-7-(pyridin-3- ylmethoxy)-1,2,3.4-tetra hydro-quinolin-6-yl]-amide

According to general procedure H, the compound described in example 15g (79 mg) was alkylated with 3-picolyl chloride hydrochloride (31 mg) and Cs>COj3 (255 mg) in

DMF (2 ml). The title compound was purified by crystallization from CH;CN.

Yield: 36 mg (HCI salt); MS-ESI: [M+H]" = 596.6; HPLC: R,= 19.70 min (method 6).

Example 20

Biphenyl-4-carboxylic acid [1-acetyl-2,2 4-trimethyl-4-phenyl-7-(pyridin-4- ylmethoxy)-1,2.3.4-tetra hvdro-quinolin-6-yi}-amide

According to general procedure H, the compound described in example 15g (79 mg) was alkylated with 4-picolyl chloride hydrochloride (31 mg) and Cs2CO;3 (255 mg) in

DMF (2 ml). The title compound was purified by crystallization from CH;CN . Yield: 31 mg (HCI salt); MS-ESI: [M+H]" = 596.4; HPLC: R= 17.09 min (method 6).

Example 21

Biphenyl-4-carboxylic acid [1-acetyl-7-(2-dimethylamino-ethoxy)-2.2 4-trimethyl-4- phenyl-1.2 3 4-tetrahydro-quinolin-6-yl]-amide

According to general procedure H, the compound described in example 15g (79 mg) was alkylated with 2-dimmethylaminoethylchloride hydrochloride (27 mg) and Cs2CO3 (255 mg) in DMF (2 mal). The title compound was purified by crystallization from

CH;CN. ) Yield: 55 mg (HCI salt); MS-ESI: [M+H]" = 576.6; HPLC: R, = 14.94 min (method 5).

Example 22 . Biphenyl-4-carboxylic cid (1-acetyl-7-carbamoylmethoxy-2.2 4-trimethyl-4-phen-vl- 1.2.3 4-tetrahydro-quinoRin-6-yl)-amide : According to general procedure H, the compound described in example 15g (79 ng) was alkylated with 2-chToroacetamide (18 mg) and Cs;CO; (255 mg) in DMF (2 ml).

The title compound was purified by preparative HPLC (method A).

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

Example 23

Morpholine-4-carboxylic acid (3-{1-acetyl-6-[(biphenyl-4-carbonyl)-amino]-2,2= ,4- trimethyl-4-phenyl-1.2,3 4-tetrahydro-quinolin-7-yloxy}-propyl)-amide

According to general procedure H, the compound described in example 15g (79 mng) was alkylated with morgpholine-4-carboxylic acid (3-chloropropyl)amide (40 mg) end

Cs,COs (255 mg) in DMF (2 ml). The title compound was purified by preparative

HPLC (method A).

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

Example 24

Furan-2-cathoxylic acid 1-acetyl-6-(3,5-dibromo-benzoylamino)-2.2.4-trimethyM-4- phenyl-1,2.3.4-tetrahydro-quinolin-7-yl ester (8). N-(1-Acetyl-7-mmethoxy-2.2 4-trimethyl-1,2-dihydroquinolin-6-yl)-3,5-dibrormo- benzamide

According to general procedure F, the compound described in example 15¢ (1.0 g) wvas acylated with 3,5-dibroxmobenzoyl chloride (1.72 g) in toluene (9 ml) and pyridines (1 ml). The title compownd was obtained by chromatography on silicagel us-ing heptane/ethyl acetate = 8/2 (v/v) as the eluent.

Yield:13g (b). N-(1-Acetyl-7-hydwoxy-2.2.4-trimethyl-4-phenyl-1,2.3.4-tetrahydroquinolin-6-=yi)- 3.5-dibromo-benzamide . According to general preocedure G, the compound described in example 24a (1.3 g) wwas stirred with AICL (1.0 g) in benzene (50 ml). The product obtained was used without further purification.

Yield: 1.39 ¢g (c). Furan-2-carboxylic acid 1-acetyl-6-(3,5-dibromo-benzoylsamino)-2.2 4-trimethyl-4- phenyl-1,2.3 4-tetrahydro-quinolin-7-yl ester

A mixture of the compound described in example 24b (100 mgg), furoyl chloride (16 pl) and DIPEA (60 pl) and CHCl, (5 ml) was stirred at room temperature until no starting material remained. Water was added and the organic layer waas separated, washed with brine, dried (MgSO) and concentrated in vacuo. The title cammpound was purified by preparative HPLC (method A).

Yield: 47 mg; MS-ESL [M+H]" = 681.2; HPLC: R, = 31.6 mim (method 2).

Example 25

N-[1-Acetyl-7-(2-amino-ethoxy)-2.2 4-trimethyl-4-phenyl-1,2_.3 4-tetrahydro-quinolin- 6-v1]-3,5-dibromo-benzamide

General procedure I: A mixture of the compound described in example 24b (100 mg), tert-butyl N-(2-hydroxyethyl)carbamate (29 mg), DtBAD (79 mg), DIPEA (60 pl) and an excess of polymer bound triphenylphosphine in CH,Cl (5 ml) was stirred at room temperature until no starting material remained. The reaction mixture was filtered and washed with water and brine. The organic layer was separamted, dried (MgSO4) and concentrated in vacuo. The crude product was taken up in CHE3CN (ca 1 ml) and a few drops of TFA were added facilitating cleavage of the terr-butylcarbamate. The title compound was purified by preparative HPLC (method A).

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

Example 26 {2-[1-Acetyl-6-(3.5-dimethyl-benzoylamino)-2.2 4-trimethyl-43-phenyi-1,2,3.4- tetrahydro-quinolin-7-yloxy]-ethyl}-carbamic acid zert-butyl esster (3). N-(1-Acetyl-7-methoxy-2.2 4-trimethyl-1,2-dihydroquimolin-6-yl)-3.5-dimethyl- benzamide

According to general procedure F, the compound described in example 15¢ (1.0 g) was acylated with 3,5-dimethylbenzoyl chloride (0.97 g) in toluen_e (9 ml) and pyridine (1 . 30 ml). The title compound was obtained by chromatogragphy on silicagel using heptane/ethyl acetate = 8/2 (v/v) as the eluent. } Yield: 1.1g

Claims (22)

1. Claims

   ) 1. A tetrahydroquinol#ne derivative according to Formula 1, ] R3 C ro HK Crs C N Rt EN Formula I or a pharmaceutically acceptable salt thereof, wherein ) R' and R? are H or Me . R’ is H, hydroxy, (1 -4C)alkoxy, (di)(1-4C)alkylamino(2-4C)alkoxy or (2- 6)heterocycloalkyl(2-4C)alkoxy R* is H, OH, (1-4C)alkoxy or R’ R’ is H, OH, (1-4C) alkoxy or R’ with the proviso that if R* is H, R® is not H, OH or (1-4C)alkoxy and that if R® is H, R* is not H, OH or (1-4C)alkoxy R®is (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1- 6C)alkyl R is amino, (di)(1-@C)alkylamino, (6C)arylcarbonylamino, (6C)arylcarbonyloxyy, (2-5C)heteroarylcarbonylamino, (2- 5C)heteroarylcarborayloxy, R®-(2-4C)alkylamino, R3-(2-4C)alkoxy, R’- methylamino or R’-mmethoxy R? is hydroxy, amino, (1-4C)alkoxy, (di)(1-4C)alkylamino, (2- 6C)heterocycloalkyl , (2-6C)heterocycloalkylcarbonylamino, (di)(1- 4C)alkylaminocarbosnylamino, (1-4C)alkoxycarbonylamino and R’ is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl.
2. 2. The tetrahydroquinoline derivative of clamim 1 wherein R® is (2-5C)heteroaryl, (6C)aryl, (3-8C)cycloalkyl or (1-6C)alkyel.
3. 3. The tetrahydroquinoline derivative of clamims 1 or 2 wherein R is (di)(1- . 4C)alkylamino, (2-5C)heteroarylcarbonyloxy, R®-(2-4C)alkoxy, R*-methylamino or R’-methoxy.
4. 4. The tetrahydroquinoline derivative of clasims 1-3 wherein R® is amino, (di)(1- 4C)alkylamino, (2-6C)heterocycloalkyl or (2- 6C)heterocycloalkylcarbonylamino.
5. 5. The tetrahydroquinoline derivative of cla-ims 1-4 wherein R” is (di)(1- 4C)alkylamino, R®-(2-4C)alkoxy, R®-metthylamino or R*-methoxy
6. 6. The tetrahydroquinoline derivative of clazims 1-5 wherein R? is amino, (di)(1- 4C)alkylamino or (2-6C)heterocycloalky ll. .
7. 7. The tetrahydroquinoline derivative of clazims 1-6 wherein R® is (di)(1- 4C)alkylamino or (2-6C)heterocycloalkyll. :
8. 8. The tetrahydroquinoline derivative of claims 1-7 wherein R” is (di)(1- 4C)alkylamino, R®-(2-4C)alkoxy, R*-met-hylamino or R*-methoxy.
9. 9. The tetrahydroquinoline derivative of claims 1-8 wherein R® is (2-5C)heteroaryl or (6C)aryl.
10. 10. The tetrahydroquinoline derivative of claims 1-9 wherein R® is (4-5C)heteroaryl or (6C)aryl and R9 is aminocarbonyl, (di®(1-4C)alkylaminocarbonyl, (3- 5C)heteroaryl or (6C)aryl.
11. 11. The tetrahydroquinoline derivative of claEms 1-10 wherein R” is (di)(1- 4C)alkylamino, R3-ethoxy, R’-methylami no or R*-methoxy and R’ is aminocarbonyl, (di)(1-4C)alkylaminocart>onyl, (3-5C)heteroaryl or (6C)aryl
12. 12. The tetrahydroguinoline derivative of claims 1-11 wherein R® is, (di)(1- 4C)alkylamino, (4-5C)heterocycloalkyl amd R® is aminocarbonyl, (di)(1- 4C)alkylaminocarbonyl, (3-5C)heteroaryl or (6C)aryl,
13. 13. A pharmaceutical composition comprising the tetrahydroquinoline derivative of any one of claims 1-12 and pharmaceutically suitable auxiliaries.
14. 14. The tetrahydroquinoline derivative of claimms 1-12 for use in therapy.

    PCT/EP2003/051025
15. 15. Use of the tetrahydroquinoline derivative of any one of claims 1-12 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for fertility regulation.
16. 16. Use of the tetrahydroquinoline derivativ-e of claims 1-12 in the manufacture of a medicament for treating a disease, illn ess, disorder or condition.
17. 17. A substance or composition for use in a- method of fertility regulation, said substance or composition comprising the tetrahydroquinoline derivate of any one of claims 1-12 or a pharmaceutically acceptable salt or solvate thereof, and said method comprising administering said substance or composition.
18. 18. A derivative according to any one of cl aims 1 to 12 or 14, substantially as herein described and illustrated.
19. 19. A composition according to claim 13, substantially as herein described and illustrated.
20. 20. Use according to claim 15 or claim 16 , substantially as herein described and illustrated.
21. 21. A substance or composition for use in a method of treatment according to claim 17, substantially as herein described and illustrated.
22. 22. A new derivative, a new composition, a new use of a derivative as claimed in any one of claims 1 to 12, or a substarce or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET