MXPA99008584A - 4-carboxyamino-2-methyl-1,2,3,4-tetrahidroquinolinas oxi-substitui - Google Patents

Abstract

Cholesteryl ester transfer protein inhibitors, pharmaceutical compositions containing these inhibitors and the use of said inhibitors to elevate certain lipid levels in the plasma including high density lipoprotein cholesterol and to reduce other lipid levels in the plasma, such as lipoprotein low-density cholesterol and triglycerides and, therefore, to treat diseases that are exacerbated by low levels of high-density lipoprotein-cholesterol and / or high levels of low-density lipoprotein-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including human beings

Description

4-CARBOXYAMINO-2-MET1L-1, 2,3,4-TETRAHYDROQUINOLINES OXY- SUBSTITUTE BACKGROUND OF THE INVENTION This invention relates to inhibitors of cholesteryl ester transfer protein (CETP), pharmaceutical compositions containing such inhibitors, and the use of said inhibitors to elevate certain levels of plasma lipids, including lipoprotein. High density lipoprotein (HDL) -cholesterol (Δ), and reduce other levels of plasma lipids, such as low density lipoprotein (LDL) -cholesterol and triglycerides, and, consequently, , treat diseases that are characterized by low levels of HDL-cholesterol and / or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in certain mammalian animals (ie, those that have CETP in their plasma), including humans.

Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify the secondary risk factors (tobacco, obesity and lack of exercise) and the treatment of dyslipidemia with a dietary modification and drug therapy, coronary heart disease (CHD) it is still the most common cause of death in the US, with cardiovascular disease accounting for 44% of all deaths and 53% of these are associated with coronary atherosclerotic heart disease.

It has been shown that the risk of developing this state is strongly correlated with certain levels of plasma lipids. Although a high level of LDL-C may be the most recognized form of dyslipidemia, LDL-C is by no means the only significant lipid that contributes to CHD. A low level of HDL-C is also a known risk factor for CHD [D. J. Gordon et al., "High-Density Lipoprotein Cholesterol and Cardiovascular Disease" (High Density Lipoprotein-Cholesterol and Cardiovascular Disease), Circulation (1989), 79: 8-151.

High levels of LDL-cholesterol and triglycerides correlate positively, while high levels of HDL-cholesterol are negatively correlated, with the risk of developing cardiovascular diseases. Therefore, dyslipidemia is not a unit risk profile for CHD, but may be composed of one or more lipid aberrations.

Among the many factors that control the plasma levels of these principles on which the disease depends, the activity of the cholesteryl ester transfer protein (CETP) affects the other three. The function of this plasma glycoprotein of 70,000 Daltons found in various animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), lipoproteins of very low density (VLDL; ery low density lipoproteins) and chylomicrons. The net result of the CETP activity is a reduction in the HDL-cholesterol level and an increase in the LDL-cholesterol level. It is believed that this effect on the lipoprotein profile is proatherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.

There are no completely satisfactory therapies to raise HDL levels. Niacin can significantly increase HDL levels, but it has serious tolerance problems that reduce its acceptance. Fibrates and inhibitors of hydroxymethylglutaryl. Coenzyme A (HMG-CoA) reductase only moderately elevates (-10-12%) HDL-C levels. As a result, there is a significant unsatisfied medical need for a well-tolerated agent that can significantly elevate plasma HDL levels, thereby reversing or reducing the progress of atherosclerosis.

Therefore, although there is a diversity of antiatherosclerotic therapies, in this field of the technique there is a continuous need and the continuous search for alternative therapies.

In EP0818448 (970624) the preparation of certain 5,6,7,8-substituted tetrahydroquinolines and certain analogous compounds as inhibitors of the cholesteryl ester transfer protein is described.

In the patent of E.U.A. No. 5,231,102 describes a class of 1, 2,3,4-tetrahydroquinolines 4-substituted which possess an acid group) or a group convertible therein in vivo) in position 2, which are specific antagonists of the receptors of N-methyl-D-aspartate (NMDA) and, therefore, are useful in the treatment and / or prevention of neurodegenerative disorders.

In the patent of E.U.A. No. 5,288,725 discloses pyrroloquinolein bradykinin antagonists.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to compounds of formula I Formula Prodrugs thereof, and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein R 1 is hydrogen, Y, W-X or W-Y; Wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -O-Y, -S-Y, -N (H) -Y or -N- (Y) 2; In which Y, in each case, is independently Z or a linear or branched carbon chain of one to ten members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, except the connecting carbon, can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally monosubstituted with oxo, said sulfur is optionally mono- or disubstituted with oxo, said nitrogen is optionally monodi-substituted with oxo, and said carbon chain is optionally monosubstituted with Z; In which Z is a three to eight member ring partially saturated, fully saturated or completely unsaturated, having optionally from one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a nicicyclic ring consisting of two fused rings of three to six members, partially saturated, fully saturated or totally unsaturated, independently considered, having optionally one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; Wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, alkenyl (C2-Ce), alkyl (C-? -6), hydroxyl, alkoxy (Ci-Cß), alkyl (C? C4) thio, amino, nitro, cyano, oxo, carboxyl, alkyl (C? -C6) oxycarbonyl, mono-N or di-N, N-alkyl (CrC6) amino, wherein said alkyl substituent (Ci-C?) is optionally mono-, di- or tri-substituted independently with halo, hydroxyl, alkoxy (CrC6), alkyl (C? -C4) thio, amino, nitro, cyano, oxo, carboxyl, alkyl (C -? - C6) oxycarbonyl, mono-N- or di-N, N-alkyl (C? -C6) amino, said alkyl substituent (Ci-Cß) being optionally substituted with from one to nine fluorine atoms; R3 is hydrogen or Q; In which Q is a linear or branched carbon chain of one to six members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, except the connecting carbon, can be optionally replaced with a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally monosubstituted with oxo, said sulfur is optionally mono- or disubstituted with oxo, said nitrogen being optionally mono-od i-substituted with oxo, and said carbon chain is optionally monosubstituted with V; In which V is a three to eight member ring partially saturated, fully saturated or totally unsaturated, having optionally from one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused rings of three six members, partially saturated, fully saturated or totally unsaturated, independently considered, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; Wherein said substituent V is optionally mono-, di-, tri- or tetra-substituted independently with halo, (C-? - C6) alkyl, (C2-C6) alkenyl, hydroxyl, (C? -C6) alkoxy, alkyl (C? -C) th, amino, nitro, cyano, oxo, carbamoyl, mono-N- or di-N, N-alkyl (C? -C6) carbamoyl, carboxyl, alkyl (C? -C ^ oxycarbonyl) , mono-N- or di-N, N-alkyl (C -? - C6) amine, wherein said alkyl (Ci-Cß) or alkenyl (C2-C6) substituent is optionally mono-, di- -or independently tri-substituted with hydroxyl, (C? -C6) alkoxy, (C? -C4) alkyl, amino, nitro, cyano, oxo, carboxyl, alkyl (CrC6) oxycarbonyl, mono-N or di- N, N-alkyl (C -? - C6) amino or said substituents alkyloCrCß) or alkenyl (C2-C6) are also optionally substituted with from one to nine fluorine atoms; R4 is Q1 or V1; In which Q1 is a linear or branched carbon chain, from one to six members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, except the connecting carbon, can be optionally replaced with a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di- -substituted with oxo, and said carbon chain is optionally monosubstituted with V1: In which V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (C? -C6), alkoxy (Cr C?), Amino, nitro, cyano, alkyl (CrC6) oxycarbonyl, mono -N- or di-N, N-alkyl (C -? - C6) amino, wherein said alkyl substituent (Ci-Cß) is optionally monosubstituted with oxo, said alkyl substituent (Ci-Cß) being optionally substituted with from one to nine fluorine atoms; In which or R3 must contain V or R4 must contain V1; and each of R5, R6, R7, and R8 is independently hydrogen, hydroxyl or oxy, wherein said oxy is substituted with T or a linear or branched carbon chain of one to twelve members, partially saturated, fully saturated or totally unsaturated, wherein the carbons, except the connecting carbon, can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally monosubstituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo. and said carbon chain is optionally monosubstituted with T; In which T is a three to eight member ring partially saturated, fully saturated or completely unsaturated, having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused rings of three to six members, partially saturated, fully saturated or totally unsaturated, independently considered, having optionally one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; Wherein said substituent T is optionally mono-, di-, or tri-substituted independently with halo, alkyl (Ci-Cß), alkenyl (C2-C6), hydroxyl, alkoxy (Ci-Cß), alkyl (CrC4) thio, amino, nitro, cyano, oxo, carboxyl, alkyl (C? -C6) oxycarbonyl, mono-N or di-N, N-alkyl (C? -C6) amino, wherein said alkyl substituent (C-pC?) is optionally mono-, di- or tri-substituted independently with hydroxyl, alkoxy (Ci-Cß), alkyl (C? -C4) thio, amino, nitro, cyano, oxo, carboxyl, alkyl (C? -C6) oxycarbonyl, mono -N- or di-N, N-alkyl (C? -C6) amino, said alkyl substituent (Ci-Cß) being optionally substituted with from one to nine fluorine atoms.

A preferred group of compounds, designated Group A, contains the compounds having the formula I shown above in which Methyl C2 is beta; The nitrogen of C4 is beta; R1 is W-X; W is carbonyl, thiocarbonyl or sulfonyl; X is -O-Y-, -S-Y-, -N (H) -Y- or -N- (Y) 2-; And, in each case, it is independently Z or (C? -C4) alkyl, said (C-? - C4) alkyl optionally having from one to nine fluorine atoms, or said (C1-C4) alkyl being optionally mono-substituted with Z , In which Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, having optionally from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, Wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, alkyl- (C? -C), alkoxy (C1-C4), alkyl (C? -C4) thio, nitro, cyano, oxo or alkyl (C -? - C6) oxycarbonyl, said alkyl substituent (C? -C) being optionally substituted with from one to nine fluorine atoms; R is Q-V, In that Q is (C1-C4) alkylene and V is a partially or fully unsaturated, partially saturated, five or six member ring, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (CrC6), hydroxyl, (C1-C6) alkoxy, hydroxyl, or alkoxy (C? -C6), nitro, cyano or oxo, wherein said (C -? - C6) alkyl substituent is optionally mono-, di- or tri-substituted independently with (C? -C6) alkoxy, or alkyl (C? -C) thio, or said alkyl (Cr Cß) optionally has from one to nine fluorine atoms; R4 is alkyl (CrC4); Each of R6 and R7 is independently hydrogen or (C? -C6) alkoxy, said (C? -C6) alkoxy optionally having from one to nine fluorine atoms or said alkoxy (C? -C6) being optionally mono-substituted with T; In which T is a five to six member ring partially saturated, fully saturated or totally unsaturated, having optionally from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, (C? -C?) Alkoxy, (C? -C4) alkyl, amino, oxo, carboxyl, alkyl (CrC6) oxycarbonyl, mono-N- or di-N, N-alkyl (C? -C6) amino, wherein said alkyl- (C? -C6) substituent optionally has from one to nine atoms of fluorine; Y R5 and R8 are H; And pharmaceutically acceptable salts thereof.

A group of compounds that is preferred among the compounds of Group A, designated Group B, contains the compounds in which W is carbonyl; X is -O-Y wherein Y is alkyl (C -? - C4), said alkyl (C? -C4) optionally having from one to nine fluorine atoms; Q is alkylene ^ -C ^, and V is phenyl, pyridinyl or pyrimidinyl; In which said ring V is optionally mono-, di- or tri-substituted independently with halo, CrCßalkyloxy), hydroxyl, (C-? -Cß) alkoxy, nitro, cyano or oxo, wherein said alkyl substituent (C? C6) optionally has one to nine fluorine atoms; Each of R6 and R7 is independently hydrogen or (C? -C3) alkoxy, said (C-? - C3) alkoxy optionally having from one to seven fluorine atoms; And pharmaceutically acceptable salts thereof.

A group of compounds that is preferred among the Group B compounds, designated Group C, contains the compounds in which Q is methylene, and V is phenyl or pyridinyl; In which said ring V is optionally mono-, di- or tri-substituted independently with halo, nitro or alkyl (C? -C2), wherein said alkyl substituent (C? -C2) optionally has from one to five carbon atoms. fluorine; And pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula I are the compounds: [2R, 4S] -4 - [(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic; Ethyl ester of [2R, 4S] -4 - [(3,5-dinitro-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline 1-carboxylic; [2R, 4S] -4 - [(2,6-Dichloro-pyridin-4-ylmethyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H- ethyl ester quinoline-1 -carboxylic; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline -1-carboxylic; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic; Ethyl ester [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-3,4-dihydro-2H- quinoline-1-carboxylic acid; And pharmaceutically acceptable salts of said compounds.

Other compounds of formula I especially preferred are the compounds: [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-isopropyl ester 1-carboxylic acid; Ethyl esters of pR ^ Sj ^ -KS.d-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic; 2,2-Trifluoro-ethyl ester of [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-d, h, propyl ester. dro-2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydroxy-tert-butyl ester 2H-quinoline-1-carboxylic acid; Ethyl ester [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1- carboxylic; And pharmaceutically acceptable salts of said compounds.

Within Group C of compounds, especially preferred compounds are compounds in which: to. And it's ethyl, R is 3,5-dichlorophenylmethyl, R is methyl, and each of R and D R is methoxy; And it is ethyl, R is 3,5-dinitrophenylmethyl, R is methyl, Each of R and R is methoxy; c. And it's ethyl, R is 2,6-dichloropyridin-4-ylmethyl, R is methyl, and Each of R 6"and D R 7 is methoxy; And it's ethyl, R is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6"and R R7 is methoxy; and. Y is ethyl, R is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, R6 is methoxy, and R7 is hydrogen; And it is ethyl, R .3 is 3,5-bis-trifluoromethylphenylmethyl, R is methyl, R6 is hydrogen, and R7 is methoxy; Y is isopropyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R is methyl, and each of R 6 and R D 7 is methoxy; h. And it is ethyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R is ethyl, and each of R 6"and D R7 is methoxy Y is 2,2,2-trifluoroethyl, R is 3,5-bis-trifluoromethylphenylmethyl, R is methyl, and each of R 6" and R is methoxyl; Y is n-propyl, R is 3,5-bis-trifluoromethylphenylmethyl, R is methyl, and each of R and R is methoxy; k. Y is tert-butyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R is methyl, and each of R6"and D R7 is methoxy; and Y is ethyl, R > 3 is 3,5-bis-trifluoromethylphenylmethyl, R 4 is methyl, R 6 is trifluoromethoxy, and R 7 is hydrogen; And pharmaceutically acceptable salts of said compounds.

A preferred group of compounds, designated Group D, contains the compounds having the formula I shown above in which Methyl C2 is beta; The nitrogen of C4 is beta; R1 is W-Y; W is carbonyl, thiocarbonyl or sulfonyl; Y is alkyl (C? -C6), said alkyl (C? -Ce) optionally having one to nine fluorine atoms, or said alkyl (C -? - C6) being optionally monosubstituted with Z, wherein Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, (C -? - C4) alkyl, (C? -C4) alkoxy, alkyl (C? - C) thio, nitro, cyano , oxo or alkyl (C? -C6) oxycarbonyl, said (C1-C4) alkyl substituent being optionally substituted with one to nine fluorine atoms; R3 is QV, wherein Q is alkyl (C? -C4) and V is a five or six member ring partially saturated, fully saturated or totally unsaturated, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; In which said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, CrCßalkyloxy), hydroxyl, alkoxy (CrC6), nitro, cyano or oxo, wherein said alkyl substituent (C-? -C6) is optionally mono-, di- or tri-substituted independently with (C? -C6) alkoxy or (C? -C4) alkyl, or said alkyl (C? -C6) optionally has from one to nine fluorine atoms; R 4 is (C 1 -C 4) alkyl; Each of R6 and R7 is independently hydrogen or (C -? - C6) alkoxy, said (C? -C6) alkoxy optionally having from one to nine fluorine atoms or said alkoxy (C? -C6) being optionally monosubstituted. with T; In which T is a five to six member ring partially saturated, fully saturated or totally unsaturated, having optionally from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; In which said substituent T is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, alkoxy (Cr Cβ), (C 1 -C 4) alkylthio, amino, oxo, carboxyl, alkyl (CrC 6) oxycarbonyl, mono-N- or D¡-N, N-alkyl (C?-C6) amino, wherein said alkyl- (C? -C6) substituent optionally has from one to nine fluorine atoms; and R5 and R8 are H; And pharmaceutically acceptable salts thereof.

A group of compounds that is preferred among the Group D compounds, designated Group E, contains the compounds in which W is carbonyl; Y is alkyl (C? -C4), said alkyl optionally having (C? -C4) from one to nine fluorine atoms; Q is alkylene (C -? - C4), and V is phenyl, pyridinyl or pyrimidinyl; Wherein said ring V is optionally mono-, di- or tri-substituted independently with halo, (C-? -C6) alkyl, hydroxyl, (C? -C6) alkoxy, nitro, cyano or oxo, wherein said substituent alkyl (C -? - C6) optionally has from one to nine fluorine atoms; Y Each of R6 and R7 is independently hydrogen or (C? -C3) alkoxy, said (C-? - C3) alkoxy optionally having from one to seven fluorine atoms; And pharmaceutically acceptable salts thereof.

An especially preferred compound of formula I is [2R, 4S] - (3,5-bis-trifluoromethyl-benzyl) - (1-butyryl-6,7-dimethoxy-2-methyl-1) methyl ester, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid, or a pharmaceutically acceptable salt of said compound.

Within Group E of compounds, an especially preferred compound is the compound in which: Y is n-propyl, R is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy, or a pharmaceutically acceptable salt thereof. A preferred group of compounds, referred to as Group F, contains the compounds having the Formula I shown above in which the methyl of C2 is beta; the nitrogen of C4 is beta; R1 is Y; Y is alkenyl (C2-Ce) or alkyl (CrC6), said alkenyl (C2-C6) or said alkyl (Ci-Cß) having from one to nine fluorine atoms, or said alkenyl being optionally monosubstituted (C2-C6) or said alkyl (C? -C6) with Z; wherein Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, nitro, cyano, oxo or alkyl (Ci-C-J-oxycarbonyl, said (C1-C4) alkyl optionally substituted with one to nine fluorine atoms: R3 is QV, wherein Q is (C1-C4) alkyl and V is a five or six-membered ring partially saturated, fully saturated or completely unsaturated, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (C? -C6), hydroxyl, alkoxy (CrC6), nitro, cyano or oxo, wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with alkoxy (Ci-Cß) or (C 1 -C 4) alkylthio, or said alkyl (C 1 -C 6) optionally has from one to nine fluorine atoms; R 4 is alkyl (C C4), each of R6 and R7 is independently hydrogen or (C -? - C6) alkoxy, said (C-C) alkoxy optionally having from one to nine fluorine atoms or said alkoxy being optionally monosubstituted (CI-CT) with T; wherein T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, alkoxy (d-C6), alkyl (C-? - C4) thio, amino, oxo, carboxyl, alkyl oxycarbonyl, mono-N- or di-N, N-alkyl (CiC.) amino, wherein said alkyl substituent - (Ci-Cß) optionally has from one to nine fluorine atoms; and R5 and R8 are H; and pharmaceutically acceptable salts thereof. A group of compounds which is preferred among the compounds of Group F, designated Group G, contains the compounds wherein Y is (C 1 -C 4) alkyl, said (C 1 -C 4) alkyl optionally having from one to nine fluorine atoms; Q is (C1-C4) alkylene, and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or tri-substituted independently with halo, alkyl (Ci-Cß), hydroxyl, (C 6 -C 6) alkoxy, nitro, cyano or oxo, wherein said alkyl substituent ( C? -C6) optionally has from one to nine fluorine atoms; and each of R6 and R7 is independently hydrogen or (C-1-C3) alkoxy, said (C1-C3) alkoxy optionally having one of seven fluorine atoms; and pharmaceutically acceptable salts thereof. Especially preferred compounds of Formula I are the compounds: [2R, 4S] - (3,5-bis-trifluoromethyl-benzyl) -1-butyl-6,7-d-methoxy-2-methyl- methyl ester. 1, 2,3,4-tetrahydro-quinol-4-yl) -carbamic acid [2R, 4S] - (3,5-bis-trifluoromethyl-benzyl) methyl ester hydrochloride - [l ^ -ethyl-butyl-J-.beta.-dimethoxy-^ -methyl-1-phenyl-tetrahydroquinoline, and pharmaceutically acceptable salts of said compounds. Within Group G of compounds, especially preferred compounds are compounds in which: a. Y is n-butyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; and b. Y is 2-ethylbutyl, R3 is 3,5-bis-trifluoromethylphenylmethyl ,, R4 is methyl, and each of R6 and R7 is methoxy; and pharmaceutically acceptable salts of said compounds. A preferred group of compounds, designated Group H, contains the compounds having the Formula I shown above in which the C2 methyl is beta; the nitrogen of C4 is beta; R1 is Z; wherein Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, nitro, cyano, oxo or alkyl (Ci-Cβ) oxycarbonyl, said (C 1 -C 4) alkyl optionally having from one to nine fluorine atoms; R3 is Q-V, wherein Q is (C1-C4) alkyl and V is a five or six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (Ci-Cß), nitro, cyano or oxo, wherein said alkyl substituent (Ci-Cß) is optionally mono -, di- or tri-substituted independently with (C? -C6) alkoxy or (C1-C4) alkylthio, or said alkyl (Ct-C6) optionally has from one to nine fluorine atoms; R 4 is (C 1 -C 4) alkyl; each of R6 and R7 is independently hydrogen or alkoxy (C-i-Cß), said alkoxy (Ci-Cß) optionally having one to nine fluorine atoms or said alkoxy (Ci-Cd) with T being optionally monosubstituted; wherein T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent t is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, alkoxy (CQQ), alkyl (C1-C4) thio, amino, oxo, carboxyl , alkyl (Ci-Cß) oxycarbonyl, mono-N- or di-N, N-alkyl (C -? - C6) amino, wherein said alkyl- (C? -C6) substituent optionally has from one to nine atoms of fluorine; and R5 and R8 are H; and pharmaceutically acceptable salts thereof.

A preferred group of compounds, referred to as Group I, contains the compounds having the Formula I shown above in which the methyl of C2 is beta; the nitrogen of C4 is beta; R1 is W-Z; W is carbonyl, thiocarbonyl or sulfonyl; Z is a three to six member ring partially saturated, fully saturated or completely unsaturated, having optionally from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, nitro, cyano, oxo or alkyl (Ci-Cβ) oxycarbonyl, said (C 1 -C 4) alkyl optionally having from one to nine fluorine atoms; R3 is QV, where Q is (C1-C4) alkyl and V is a partially saturated or fully unsaturated five or six member ring, optionally having from one to three heterozotomes independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, (C-? - C6) alkyl, hydroxyl, alkoxy (Ci-Cß), nitro cyano or oxo, wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with alkoxy or alkyl (d-C4) thio, or said alkyl (CI-CT) optionally has one to nine fluorine atoms; R 4 is (C 1 -C 4) alkyl; each of R6 and R7 is independently hydrogen or (C? -C6) alkoxy of one to nine fluorine atoms or said alkoxy (C-i-C?) with T being optionally monosubstituted; wherein T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally nomo-, di- or tri-substituted independently with halo, alkyl- (Ci-Cß), hydroxyl, alkoxy (Ci-Cß), alkyl (C 1 -C 4) thio, amino, oxo, carboxyl , alkyl (CrC6) oxycarbonyl, mono-N- or di-N, N-alkyl (C? -C6) amino, wherein said alkyl substituent (C-? C6) optionally has from one to nine fluorine atoms; and R5 and R8 are H; and pharmaceutically acceptable salts thereof. Yet another aspect of this invention is directed to methods for treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury. , angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammalian animal (including a human being, whether male or female) by administration, to a mammalian animal in need of such treatment, of a quantity, to treat atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis s angioplastic, hypertension, vascular complications of diabetes, obesity or endotoxemia, a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating atherosclerosis in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an at, to treat atherosclerosis, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of that invention is directed to a method of treating peripheral vascular disease in a mammalian animal (including a human) by administration, to a mammalian animal in need of such treatment, of an amount, to treat peripheral vascular disease, of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention is directed to a method of treating dyslipidemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat dyslipidemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating hyperbetalipoproteinemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat hyperbetalipoproteinemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating hypercholesterolemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat hypercholesterolemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating hypertiglyceridemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat hyperticliceridemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating familial hypercholesterolemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat familial hypercholesterolemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention is directed to a method of treating cardiovascular disorders in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat cardiovascular disorders, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating angina in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat angina, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating ischemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat ischemic disease, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating cardiac ischemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat cardiac ischemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method of treating stroke in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat stroke, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating a myocardial infarction in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat myocardial infarction. , of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention is directed to a method of treating reperfusion injury in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat reperfusion injury. , of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention is directed to a method of treating angioplastic restenosis in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat angioplastic restenosis, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention is directed to a method of treating hypertension in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat hypertension, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating vascular complications of diabetes in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat the complications of diabetes, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention is directed to a method of treating obesity in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat obesity, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method of treating endotoxemia in a mammalian animal (including a human) by administering, to a mammalian animal in need of such treatment, an amount, to treat endotoxemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. A preferred dosage is about 0.001 to 100 mg / kg / day of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. An especially preferred dosage is about 0.01 to 10 mg / kg / day of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. This invention is also directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalioproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammalian animal (including a human), comprising a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of atherosclerosis in a mammalian animal (including a human), comprising an amount, for treating atherosclerosis, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of peripheral vascular disease in a mammalian animal (including a human), comprising an amount, to treat peripheral vascular disease, of a compound of Formula I, a prodrug thereof , or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of dyslipidemia in a mammalian animal (including a human), comprising an amount, to treat dyslipidemia, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for the treatment of hyperbetalipoproteinemia in a mammalian animal (including a human), comprising an amount, to treat hyperbetalipoproteinemia, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of hypoalphalipoproteinemia in a mammalian animal (including a human), comprising an amount, for treating hypoalphalipoproteinemia, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of hypercholesterolemia in a mammalian animal (including a human), comprising an amount, for treating hypercholesterolemia, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of hypertriglyceridemia in a mammalian animal (including a human), comprising an amount, for treating hypertriglyceridemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of hypercholesterolemia in a mammalian animal (including a human), comprising an amount, for treating hypercholesterolemia, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of angina in a mammalian animal (including a human), comprising an amount, for treating angina, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of ischemia in a mammalian animal (including a human), comprising an amount, for treating ischemia, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of cardiac ischemia in a mammalian animal (including a human), comprising an amount, for treating cardiac ischemia, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of stroke in a mammalian animal (including a human), comprising an amount, for treating stroke, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of myocardial infarction in a mammalian animal (including a human), comprising an amount, for treating myocardial infarction, of a compound of Formula I, a prodrug thereof , or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of reperfusion injury in a mammalian animal (including a human), comprising an amount, for treating reperfusion injury, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of angioplastic restenosis in a mammalian animal (including a human), comprising an amount, to treat angioplastic restenosis, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of hypertension in a mammalian animal (including a human), comprising an amount, for treating hypertension, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention is also directed to pharmaceutical compositions for the treatment of vascular complications of diabetes in a mammalian animal (including a human), comprising an amount, to treat the vascular complications of diabetes, of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for the treatment of obesity in a mammalian animal (including a human), comprising an amount, for treating obesity, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for the treatment of endotoxemia in a mammalian animal (including a human), comprising an amount, for treating endotoxemia, of a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier.

This invention is also directed to a combination pharmaceutical composition comprising: a therapeutically effective amount of a composition comprising a first compound, which is a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; a second compound, which is an inhibitor of HMG-CoA reductase, an inhibitor of the secretion of the microsomal protein triglyceride transfer (MTP) / apolipoprotein B (Apo B), an activator of PPAR, a bile acid reuptake inhibitor, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a sequestrant bile acids; and / or, optionally, a pharmaceutical vehicle.

Among the second compounds, an inhibitor of HMG-CoA reductase and an inhibitor of MTP / Apo B secretion are preferred.

A particularly preferred inhibitor of HMG-CoA reductase is lovastatin, simvastatin, provastatin, fluvastatin, atorvastatin or rivastatin.

Another aspect of this invention is a method for treating atherosclerosis in a mammalian animal, which comprises administering to a mammalian animal suffering from atherosclerosis; a first compound, which is a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; Y a second compound, which is an inhibitor of HMG-CoA reductase, an inhibitor of MTP / Apo B secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, a resin of ion exchange, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, in which the amounts of the first and second compounds give rise to a therapeutic effect.

A preferred aspect of the above method is that the second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion.

A particularly preferred aspect of the above method is that the HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

Yet another aspect of this invention is a set comprising: to. a first compound, which is a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier, in a first unit dosage form; b. a second compound, which is an inhibitor of HMG-CoA reductase, an inhibitor of MTP / Apo B secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, a resin of ion exchange, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, and a pharmaceutically acceptable carrier, in a second unit dosage form; Y c. means for containing said first and second dosage forms, wherein the amounts of the first and second compounds give rise to a therapeutic effect.

A second preferred compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion.

A particularly preferred inhibitor of HMG-CoA resuctase is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

As used herein, the term "mammalian animals" refers to all mammalian animals that contain CETP in their plasma, such as, for example, rabbits and primates such as hands and humans. Certain different mammalian animals, such as, for example, dogs, cats, cattle, goats, sheep and horses, do not contain CETP in their plasma and, therefore, are not included here.

As used herein, the term "treatment" includes the preventive (eg, prophylactic) and palliative treatments. By "pharmaceutically acceptable" is meant that the carrier, diluent, excipients and / or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "prodrug" refers to compounds that are precursors of drugs that, after their administration, release the drug in vivo by means of some chemical or physiological process (for example, a prodrug becomes the desired drug form upon entry. in contact with physiological pH, or by means of an enzymatic action). Exemplary prodrugs, upon cleavage, release the corresponding free acid, and said moieties of compounds of Formula I that form hydrolysable esters, include, but are not limited to, those having a carboxyl group in which the free hydrogen is substituted by alkyl (C1-C4), (C2-C7) alkanoyl oxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- ( alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- [N- (alkoxycarbonyl) amino] ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyro-lactone-4- ilo, di-N, N-alkyl (Cr C2) (C2-C3) aminoalkyl (such as B-dimethylaminoethyl), carbamoylalkyl (C? -C2), N, N-di-alkyl (C? -C2) carbamoyl-alkyl (C? -C2), and piperidino- , pyrrolidino- or morpholino-alkyl (C2-C3).

The following paragraphs describe exemplary rings for the generic annular descriptions contained herein.

Exemplary aromatic rings of five to six members, optionally having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl. , pyrimidinyl and pyrazinyl.

Exemplary rings of five to eight members, partially saturated, fully saturated or totally unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other exemplary five membered rings include 2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl , 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,4-oxadiazolyl, 1,2 , 5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiazolyl, 1,4-triazolyl, 1,4-thiadiazolyl, 1, 2,3,4-oxatriazolyl, 1, 2 , 3,5-oxatriazolyl, 3H-1, 2,3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazolyl, 1,4-dioxazoliko, 5H-1, 2,5-oxathiazolyl and 1, 3-oxathiolyl.

Other exemplary six-membered rings include 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3-triazinyl, 1,4-triazinyl, 1,2 , 3-triazinyl, 1, 3,5-trityanil, 4H-1, 2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl , 2H-1, 2-oxazinyl, 4H-1,4-oxazinyl, 1, 2,5-oxathiazinyl, 1,4-oxazinyl, 0-isoxazinyl, p-isoxazinyl, 1, 2,5-oxathiazinyl, 1, 2 , 6-oxathiazinyl, 1,4,2-oxadiazinyl and 1, 3,5,2-oxadiazinyl.

Other exemplary seven-membered rings include azepinyl, oxepinyl and thiepinyl.

Other exemplary rings of eight members include cyclooctyl, cyclooctenyl and cyclooctadienyl.

Exemplary bicyclic rings consisting of two fused rings of five or six members, partially saturated, fully saturated or fully unsaturated, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, include indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta (b) pyridinium, pyran (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c) thienyl, H-indazolyl, n-hexazinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolinizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1 -benzopyranyl, pyrido (3,4-b) pyridinyl, pyrido (3,2-b) pyridinyl, pyridine (4,3-b) pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl , 1 H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-ben Zoxazinyl and 4H-1,4-benzoxazinyl.

By "alkylene" is meant a saturated hydrocarbon (straight or branched chain) in which a hydrogen atom has been separated from each of the terminal carbons. Methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene are examples of said groups (assuming that the designated length encompasses the particular example).

By halo, it means chlorine, bromine, iodine or fluorine.

By "alkyl" is meant a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon. Methyl, ethylene, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl are examples of such groups alkyl (assuming that the designated length encompasses the particular example).

By "alkoxy" is meant a straight chain saturated alkyl or a branched chain saturated alkyl, linked through an oxy group. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexyloxy, heptoxy and octoxy are examples of said alkoxy groups (assuming that the designated length encompasses the particular example).

As used herein, the expression mono-N- or di-N, N-alkyl (Cr Cx) .... refers to the alkyl group (C? -Cx) ... (x refers to integers). It is to be understood that if a carbocyclic or heterocyclic group can be bound or bound to a particular substrate through different ring atoms, without a specific fixation point being indicated, then all possible points are considered to be included, either through a carbon atom or, for example, of a trivalent nitrogen atom. For example, the term "pyridyl" means 2,3- or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, etc.

The references (e.g., in claim 1) to "said carbon" in the phrase "said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally monosubstituted with oxo ", they refer to each of the carbons of the carbon chain including the connecting carbon.

References to "nitrogen ... disubstituted with oxo" (for example, in claim 1) refer to a terminal nitrogen that constitutes a nitro functionality.

The term "pharmaceutically acceptable salt" refers to non-toxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene sulfonate. The term also refers to non-toxic cationic salts containing cations such as (but not limited to) sodium, potassium, calcium, magnesium, benzathine (N, N'-dibenzylethylenediamine) ammonium or protonated, choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methylglucamine), benetamine (N-benzylphenethylamine), piperazine and tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

As used herein, the terms "solvent inert to the reaction" and "inert solvent" refer to a solvent or a mixture of solvents that does not interact with the starting materials, reagents, intermediates or products in a way that negatively affects the production of the desired product.

The term "cis" refers to the orientation of two substituents with each other and with respect to the plane of the ring (both "upwards" or both "downwards"). Similarly, the term "trans" refers to the orientation of two substituents with respect to each other and with respect to the plane of the ring (the substituents being on opposite sides of the ring).

Alpha and Beta refer to the orientation of a substituent with respect to the plane of the ring (ie, its face). Beta is above the plane of the ring (that is, its face) and Alpha below the plane of the ring (that is, its face).

The chemist with normal experience will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configuration isomers. All the mentioned isomers and mixtures thereof are included in this invention. Also included are hydrates and solvates of the compounds of this invention.

It will be recognized that the compounds of this invention can exist in radiolabelled form; that is, said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number normally found in nature. The radiosótopos of hydrogen, carbon, phosphorus, sulfur, fluorine and chlorine include 3H, 14C, 32P, 35S, 18F and 36CI, respectively. The compounds of this invention, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug containing those radioisotopes and / or other radioisotopes of other atoms are within the scope of this invention. For ease of preparation and ability to be detected, tritiated hydrogen, i.e., 3H, and carbon-14, i.e., 14C, are particularly preferred. The radiolabelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Such radiolabelled compounds can be conveniently prepared by carrying out the procedures described in the schemes and / or in the following examples and preparations, substituting a non-radiolabeled reagent for an easily available radiolabelled reagent.

DTT means dithiothreitol. DMSO means dimethylsulfoxide. EDTA means ethylenediamine tetraacetic acid. Other features and advantages of this invention will become apparent from this specification and the appended claims with which the invention is described.

DETAILED DESCRIPTION OF THE INVENTION In general, the compounds of this invention can be prepared by methods including procedures analogous to those known in the chemical arts, particularly in light of the description contained herein. Some methods for making the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other procedures can be described in the experimental section.

SCHEME I Vil VI SCHEME II V SCHEME lll XX! SCHEME IV XXXIII XXXIV As an opening note, it is noted that, in the preparation of the compounds of Formula I, some of the preparation methods useful for preparing the compounds described herein may require the protection of a remote functional group (eg, primary amine, amine secondary or carboxyl in the precursors of Formula I). The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation methods. The need for such protection is easily determined by one skilled in the art. The use of said protection / deprotection methods is also within the skill in the art. For a general description of protective groups and their use, see T. W. Greene, Protective Groups in Organic Svnthesis (Protective Groups in Organic Synthesis), John Wiley & amp;; Sons, New York, USA, 1991. For example, in Reaction Schemes I and II, certain compounds of Formula I contain primary amine or carboxylic acid functional groups which, if left unprotected, may interfere with reactions at other sites in the molecule. Accordingly, said functional groups can be protected by an appropriate protecting group which can be eliminated in a subsequent operation. Suitable protecting groups for the protection of amines and carboxylic acids include the protecting groups usually used in the synthesis of peptides (such as, Nt-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethyleneoxycarbonyl for the amines, and lower alkyl or benzyl esters for the acids carboxylic acids), which are not generally chemically reactive under the reaction conditions described and can be typically removed without chemically altering another functional group of the compound of Formula I.

According to Reaction Scheme I, the compounds of Formula III wherein R5, R6, R7 and R8 are as described above and P2 is an appropriate protecting group, can be prepared from the appropriate aromatic amine of Formula II wherein R5, R6, R7 and R8 are as described previously.

The tetrahydroquinoline of Formula III is prepared by treating the appropriate aromatic amine of Formula II with the required acetaldehyde in an inert solvent such as a hydrocarbon (eg, hexanes, pentanes or cyclohexane), an aromatic hydrocarbon (eg, benzene, toluene or xylene) ), a halocarbon (eg, dichloromethane, chloroform, carbon tetrachloride or dichloroethane), an ether (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, methyl tert-butyl ether, etc.) , a nitrile (e.g., acetonitrile or propionitrile), or a nitroalkane (e.g., nitromethane or nitrobenzene), preferably dichloromethane, with a dehydrating agent (e.g., sodium sulfate or magnesium sulfate) at a temperature of about 0 ° C to about 100 ° C (preferably at room temperature), for 1-24 hours (preferably 1 hour). The resulting solution is treated with an appropriately substituted N-vinyl species (for example, benzyloxycarbonyl-, t-butoxycarbonyl-, methoxycarbonyl-, formyl-, acetyl-, diallyl- or dibenzyl-, preferably carboxybenzyloxy-) and with a Lewis acid. [e.g., boron trifluoride, boron trifluoride etherate, zinc chloride, titanium tetrachloride, iron trichloride, aluminum trichloride, alkyl aluminum dichloride, dialkyl aluminum chloride or ytterbium triflate (III); preferably, boron trifluoride etherate] or a protic acid such as a hydrogen halogenide (eg, fluoride, chloride, bromide or iodide), an alkylsulfonic acid (eg, p-toluene-, methane- or trifluoromethane-) or a carboxylic acid (eg, formic, acetic, trifluoroacetic or benzoic), at a temperature from about -78 ° C to about 50 ° C (preferably at room temperature) for a period of 0.1 to 25 hours (preferably 1 hour) .

Alternatively, the amine of Formula II and acetaldehyde can be condensed by treating a solution of the amine and an alkylamine base (preferably triethylamine) in a polar aprotic solvent (preferably dichloromethane), with titanium tetrachloride in a polar aprotic solvent preferably in dichloromethane), at a temperature between about -78 ° C and about 40 ° C (preferably 0 °), followed by a treatment with acetaldehyde at a temperature between about -78 ° C and about 40 ° C (preferably 0 °). The reaction is allowed to develop for a period of from about 0.1 to about 10 hours (preferably 1 hour) at a temperature of between about 0 ° C and about 40 ° C (preferably at room temperature) to obtain an imit which is reacted with the N-vinyl species in the previous way.

The compounds of formula IV in which R1, R5, R6, R7 and R8 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding amine of formula III by various reaction routes for amines, known by those skilled in the art. Thus, the compounds of formula IV in which R1, R5, R6, R7 and R8 are as described above and P1 and P2 are appropriately differentiated protecting groups for the amine groups, are prepared from the corresponding tetrahydroquinoline of formula III using standard methods to derivatize the amines of the functional groups described above for R1; see Richard Larock, Comprehensive Organic Transformations, VCH Publishers Inc., New York, USA, 1989, and Jerry March, Advances Organic Chemistry (Advanced Organic Chemistry), John Wiley & amp; amp;; Sons, New York, USA, 1985. For example, a compound of formula III is treated with the appropriate thiocarbonyl chloride, sulfonyl chloride, sulfonyl chloride, thioisocyanate isocyanate in a polar aprotic solvent (preferably in dichloromethane) in the presence of a base (preferably pyridine), a temperature from about -78 ° C to about 100 ° C (preferably, starting at 0 ° C and leaving a warm-up to room temperature) for a period of 1 to 24 hours (preferably 12 hours).

The carbamate and urea compounds of formula IV (wherein R1 is W = C (O), X = OY, SY, N (H) -Y or NY2) can be prepared from the amines of formula III by the corresponding carbamoyl chlorides, treating the amine of formula III with a solution of phosgene in a hydrocarbon solvent (preferably toluene) at a temperature between about 0 ° C and about 200 ° C (preferably under reflux) for a period of between 0.1 and 24 hours (preferably 2 hours). The corresponding ureas can be prepared by treating a solution of the carbamoyl chlorides (prepared from the above described) with the appropriate amine in a polar solvent (preferably dichloromethane) at a temperature between about -78 ° C and about 100 ° C (preferably at ambient temperature), for a period of between 1 and 24 hours (preferably 12 hours). The corresponding carbamate can be prepared by treating a solution of the carbamoyl chlorides (prepared in the manner described above) with the appropriate alcohol and a suitable base (preferably sodium hydride) in a polar solvent (preferably dioxane) at a temperature between about -78. ° C and approximately 100 ° C (preferably at room temperature), for a period of between 1 and 24 hours (preferably 12 hours). Alternatively, the corresponding carbamate can be prepared by treating a solution of the carbamoyl chlorides in the appropriate alcohol at a temperature between about 0 ° C and about 200 ° C, for a period of between 1 and 240 hours (preferably 24 hours). The compound of formula IV in which R1 is Y can be prepared using methods known to those skilled in the art to introduce substituents and such as an alkyl or alkyl-linked substituent. The methods include, for example, the formation of the amide from the amine of formula III and an activated carboxylic acid, followed by reduction of the amide with borane in an ethereal solvent such as tetrahydrofuran. Alternatively, the alkyl or alkyl-linked substituent may be added by reduction after condensation of the amine of formula III with the required carbonyl-containing reactant. In addition, the amine of formula III can be reacted with the appropriate alkyl or aryl halide according to methods known to those skilled in the art. Therefore, the amine of formula III and an acid (for example, hydrogen, sulfuric, sulphonic or carboxylic acid halide, preferably acetic) with the appropriate carbonyl-containing reactant, in a polar solvent (preferably ethanol), are treated. temperature from about 0 ° C to about 100 ° C (preferably at room temperature) for a period of about 0.1 to 24 hours (preferably 1 hour), followed by the treatment of a hydride source (e.g., sodium borohydride or sodium cyanoborohydride) , preferably sodium triacetoxyborohydride) at a temperature from about 0 ° C to about 100 ° C (preferably at room temperature) for a period of 0.1 to 100 hours (preferably 5 hours). The amine of formula V in which R1, R5, R6, R7 and R8 are as described above and P1 is a protecting group can be prepared from the corresponding compound of formula IV by deprotection (P2) using methods known to those skilled in the art. the technique, including hydrogenolysis, treatment with an acid (for example, triflluoroacetic or hydrobromic acid) or a base (sodium hydroxide), or reaction with a nucleophilic agent (for example, sodium methylthiolate, sodium cyanide, etc.), and, for the trialkylsilylethoxycarbonyl group, a fluoride (e.g., tetrabutylammonium fluoride) is used. For the removal of a benzyloxycarbonyl group, the hydrogenolysis is carried out by treating the compound of the formula IV with a hydride source (for example, hydrogen gas at a pressure of 1 to 10 atmospheres, cyclohexylene or ammonium formate) in the presence of a Suitable catalyzed (eg, 5-20% palladium on carbon, or palladium hydroxide); preferably 10% palladium on carbon) in a polar solvent (for example, methanol, ethanol or ethyl acetate, preferably ethanol), at a temperature between about -78 ° C and about 100 ° C, preferably at room temperature, for a period of 0.1 to 24 hours, preferably 1 hour.

The compounds of formula VI in which R1, R3, R5, R6, R7 and R8 are as described above and P1 is a protective group as described above can be prepared from the corresponding amine of formula V by various reaction routes for amines, known to those skilled in the art. The secondary amine of formula VI in which R3 is as described above can be prepared using methods known to those skilled in the art to introduce R1 substituents such as an alkyl or alkyl-linked substituent. The methods include, for example, the formation of an amide from the amine and an activated carboxylic acid, followed by reduction of the amide with borane in an ethereal solvent such as tetrahydrofuran. Alternatively, an alkyl or alkyl-linked substituent can be added by reduction of the appropriate mine, which has been formed by condensing the amine with the required carbonyl-containing reactant. Further. The amine can be reacted with the appropriate alkyl halide according to methods known to those skilled in the art. Therefore, the amine of formula V and an acid (for example, hydrogen halide, sulfuric, sulphonic or carboxylic, preferably hydrochloric) are treated with the appropriate carbonyl-containing reactant, in a polar solvent (preferably dichloromethane) to a temperature from about 0 ° C to about 100 ° C (preferably at room temperature) for a period of about 0.1 to 24 hours (preferably 1 hour), followed by treatment with a hydride source (eg, sodium borohydride or sodium cyanoborohydride) preferably sodium triacetoxyborohydride) at a temperature from about 0 ° C to about 100 ° C (preferably at room temperature) for a period of 0.1 to 100 hours (preferably 5 hours). The compound of formula VII in which R1, R3, R5, R6, R7 and R8 are as described above and P1 and P2 are protective groups may be appropriate from the corresponding compound of formula IV by methods known to those skilled in the art. , such as, for example, the methods described above, in the transformation of the compound of formula V into the compound of formula VI, for the introduction of the substituent R3. After this, the corresponding compound of formula VI can be prepared from the compound of formula VII by an appropriate deprotection according to methods such as those described above for the transformation of the compound of formula IV into the compound of formula V. When R3 is H and R4 is as described above, R4 may be represented by R3 in formulas VI and VII of scheme I, thus obtaining a synthetic scheme for said compounds. According to scheme II, the dihydroquinolone compounds of formula XI in which R1, R5, R6, R7, R8 and Y are as described above and P1 is a protecting group can be prepared from the corresponding quinoleins of formula X by treatment with a metalomethyl species and a chloroformate, followed by hydrolysis. Thus, a sample of the quinolein of formula X and a methylmagnesium species (Grignard reagent) in excess (preferably 1.5 equivalents), in a polar aprotic solvent (for example, diethyl ether or dichloromethane, preferably tetrahydrofuran), is treated with an excess Y- or P1-chloroformate (preferably 1.5 equivalents) at a temperature of about -100 ° C and about 70 ° C (preferably -78 ° C), followed by heating to a temperature of between about 0 ° C and about 70 ° C (preferably ambient temperature) for a period of between 0.1 and 24 hours (preferably 1 hour). The resulting mixture is combined with an aqueous acid (preferably 1 molar hydrochloric acid) in excess (preferably 2 equivalents) and vigorous mixing is carried out for a period of between 0.1 and 24 hours (preferably 1 hour or until it has been determined that the hydrolysis of the intermediate enolic ether is complete). Of course, the compounds of formula XI are the compounds of formula XVI in which R1 is -C (O) OY or P1 is -C (O) OP1 without further transformation. The compounds of formula XV in which R1, R5, R6, R7 and R8 are as described above can be prepared from the corresponding dihydroquinolone of formula XI by an appropriate deprotection (including a spontaneous decarboxylation) as described to transform the compound of formula IV in the compound of formula V. The compounds of formula XVI in which R1, R5, R6, R7 and R8 are as described above and P1 is a protecting group can be prepared from the corresponding dihydroquinolone of formula XV of described manner for the transformation of the compound of formula III into the compound of formula IV. In certain cases in which the reagent has also reacted by the carbonic oxygen of position 4, the substituent can be conveniently removed by treatment with an acid (for example, aqueous HCl) or a base (for example, aqueous sodium hydroxide). Again, for compounds of formula XVI in which R1 or P1 is the same as in the compound of formula XI, a transformation such as that described above is not necessary. Amine compounds of formula VI in which R1, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group can be prepared from the corresponding dihydroquinolone of formula XVI by a reductive amination sequence. The dihydroquinolone of formula XVI, an excess R3-amine (preferably 1.1 equivalents) and an amine base (preferably triethylamine) are treated in excess (preferably 7 equivalents) in a polar solvent (preferably dichloromethane) with 0.5 to 1.0 equivalents (preferably 0.55 equivalents) of titanium tetrachloride in the form of a solution in a suitable polar solvent (preferably dichloromethane), at a temperature between about 0 ° C and about 40 ° C (preferably ambient temperature) for a period of between 1 and 24 hours (preferably 12 hours). The resulting amine of formula Xll is reduced by treatment with a reducing agent (preferably sodium borohydride) in an appropriate polar solvent (preferably ethanol), at a temperature between about 0 ° C and about 80 ° C (preferably room temperature) during a period of between 1 and 24 hours (preferably 12 hours), to obtain a mixture of amines of diatereomeric formula VI in which the trans isomer is generally favored. Alternatively, the reduction can be carried out by directly treating the imine of formula Xll with excess zinc borohydride (preferably 5 equivalents) in the form of a solution (preferably 0.2 molar) in diethyl ether, at a temperature between about 0 to about 40 ° C (preferably ambient temperature) for a period of between 1 and 24 hours (preferably 12 hours), to obtain a mixture of amines of diastereomeric formula VI in which the cis isomer is generally favored. Alternatively, the amine of formula VI in which R1, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group can be prepared from the corresponding dihydroquinolones of formula XVI by formation of an oxime, reduction and substitution of the amine. Thus, the hydroquinolone of formula XVI, hydroxylamine hydrochloride in excess (preferably 3 equivalents) and a base (preferably sodium acetate) in excess (preferably 2.5 equivalents) in a polar solvent (preferably 2.5 equivalents) in a solvent are reacted polar (preferably ethanol), at a temperature between about 0 ° C and about 100 ° C (preferably at reflux) for a period of between 1 and 24 hours (preferably 2 hours). The resulting oxime of formula Xlll is treated with an aqueous base (preferably 2 N potassium hydroxide) in excess (preferably 6 equivalents) in a polar solvent (preferably ethanol) and with a nickel-aluminum alloy (preferably 1: 1 by weight) in excess (preferably 4 equivalents), at one of between about 0 ° C and about 100 ° C (preferably the ambient temperature) for a period of between 0.25 and 24 hours (preferably 1 hour). The resulting amine of formula C is obtained as a mixture of diastereomers (in which the cis isomer is generally favored). The secondary amine of formula VI in which R1, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group can be prepared from the appropriate amine of formula V in the manner written in scheme I to transform the compound of formula V into the compound of formula VI. According to scheme III, compounds of formula I as those described above can be prepared from the appropriate compounds of formula VI by conversion to the desired carbamate. Thus, the amine of formula VI is treated with the appropriate activated carbonate (for example, chloroformate, dicarbonate or carbonyldimidazole, followed by the appropriate alcohol) in a polar solvent (preferably dichloromethane), in the presence of an amine base (preferably pyridine) in excess, at a temperature between about -20 ° C and about 40 ° C (preferably the ambient temperature) for a period of between 1 and 24 hours (preferably 12 hours), to obtain the compound of formula I. Alternatively, According to scheme III, when appropriate, if the functional group of R1 is incompatible with the reaction to form the compound of formula I, the compound of formula VI protected P1 can then be transformed into the compound of formula I by means of sequences of protection / deprotection and the introduction of the desired substituents. Thus, the amine of formula VI is treated with the appropriate reagent [e.g., a protecting group precursor or an activated carbonate (e.g., chloroformate, dicarbonate or carbonyl imidazole)] in a polar solvent (preferably dichloromethane), in the presence of an amine base (preferably pyridine) in excess, at a temperature between about -20 ° C and about 40 ° C (preferably ambient temperature) for a period of between 1 and 24 hours (preferably 12 hours), for obtain the compound of formula XX. In addition, compounds of formula XX in which P2 is present can be obtained in the manner shown in Scheme I for compounds of formula VII (having P1).

The amines of formula XXI in which R1, R3, R5, R6, R7 and R8 and R4 are as described above and P2 is a protecting group can be prepared from the compound of formula XX by selective protection of P1. When P1 is, for example, t-butoxycarbonyl, the compound of formula XXI is conveniently prepared by treatment with an acid (preferably trifluoroacetic acid) at a temperature between about 0 ° C and about 100 ° C (preferably ambient temperature) during a period of 0.1 to 24 hours (preferably 1 hour). The compounds of formula I or the compounds of formula XXII (wherein R1 is as described above) can be prepared from the corresponding amine of formula XXI (wherein R4 or 2P is present, respectively) by various reaction routes for amines, known to those skilled in the art, such as, for example, those described in scheme I to transform the compound of formula III into the compound of formula IV. The amines of formula XXIII can be prepared from the compounds of formulas XXII by suitable deprotection. When P2 is, for example, benzyloxycarbonyl, the compound of formula XXIII is prepared by treatment with a source of hydrides (eg, cyclohexene, hydrogen gas or, preferably, ammonium formate) is excess, in the presence of 0.01 to 2 equivalents (preferably 0.1 equivalents) of a suitable catalyst (preferably 10% palladium on carbon) in a polar solvent (preferably ethanol), at a temperature between about 0 ° C and about 100 ° C (preferably at room temperature) for a period of 0.1 to 24 hours (preferably 1 hour). The compound of formula I in which R4 is as described above can be prepared using the methods described in scheme III above to convert the compound of formula VI into the compound of formula I. According to scheme IV, the compounds of formula V is that R1, R5, R7 and R8 are as described above and R6 is a group attached to ether can be obtained from the quinolones of formula XXX having an OP3 group at the R6 position, with P3 being a protecting group, using the following methods. In addition, in an analogous manner, said methods can be used to prepare the corresponding compounds wherein R5, R7 and R8 is an ether bound group, starting from the corresponding compound of formula XXX having an OP3 group in any of positions R5, R7 and R8. Thus, the quinolone of formula XXX is combined with hydroxylamine hydrochloride and a base (preferably sodium acetate) in a polar solvent (preferably ethanol) at a temperature between about 0 ° C and about 100 ° C (preferably at reflux) for a period of between 1 and 24 hours (preferably 2 hours), to obtain the oxime of formula XXXI. The oxime of formula XXXI is treated with an aqueous base (preferably 2 N potassium hydroxide) in excess (preferably six equivalents) and with a nickel-aluminum alloy (preferably 1: 1 by weight) in excess (preferably four equivalents) in a polar solvent (preferably ethanol) at a temperature between about 0 ° C and about 100 ° C (preferably ambient temperature), for a period of between 0.25 and 24 hours (preferably 2 hours), to prepare the corresponding amine of formula XXXII . If necessary, the protective group P3 can be eliminated using standard methods if the transformation of the oxime has not led to said cleavage. Alternatively, the compound of formula XXX can be deprotected (removal of P3) by methods known to those skilled in the art, prior to the formation of the oxime of formula XXXI, which can then be reduced to form the amine of formula XXXII. The compound of formula V in which R6 is an oxy-linked group can be prepared by treating the alcohol of formula XXXII under, for example, Mitsunobu conditions. In this way, the appropriate phenol is treated with a phosphine (preferably triphenylosphine), an azodicarboxylate [preferably bis (-N-methylpiperazinyl) azodcarboxamide] and the required alcohol in a polar solvent (preferably benzene).

Of course, through schemes I and II, the resulting compound of formula V can be transformed into the precursors of formula VI for the compounds of formula I of this invention. Alternatively, the compound of formula XX in which R 4 is a group to ether and wherein R 1, R 3, and R 4 are as described above (secondary amines) and P 1 and P 2 are protective groups can be prepared from the alcohols of formula XXXII in the manner described below. In addition, in an analogous manner, said methods can be used to prepare the corresponding compounds wherein R5, R7 or R8 is an ether imido group, starting from the corresponding compound of formula XXXII, and, therefore, finally the compound of formula XXX (ie, the compound of formula XXX having a P3O- at any of positions R5, R7 and R8). The secondary amine of formula XXXII wherein R3 is as described above can be prepared from the corresponding compound of formula XXXII according to methods of scheme I described above to convert the compound of formula V to the compound of formula VI. Compounds of formula XXXIV in which R4 is as described above can be prepared from amines of formula XXXIII by methods analogous to those described in scheme III to transform the compound of formula VI into the compound of formula XX. The phenol of formula XXXV can be selectively deprotected, for example, when R4? 2CO- is present, treating the carbonate of formula XXXIV with potassium carbonate in a polar solvent (preferably methanol) at a temperature between about 0 ° C and about 100 ° C. ° C (preferably the ambient temperature), for a period of between 1 and 24 hours 12 hours). The corresponding XX ethers can be prepared from the phenol of formula XXXV using, for example, the Mitsunobu conditions described above to convert the compounds of formula XXXII into the compounds of formula V. Of course, one skilled in the art will appreciate that the phenol can be derivatized to a variety of functional groups using standard methods, for example those described by March or Larock, or by conversion to the corresponding triflate for use in a variety of reactions involving transition metal catalysis. . The prodrugs of the compounds of formula I can be prepared according to methods known to those skilled in the art. Exemplary procedures are described below. The prodrugs of this invention in which a carboxyl group of a carboxylic acid of formula I is substituted by an ester can be prepared by combining the carboxylic acid with the appropriate alkyl halide in the presence of a base, such as potassium carbonate, in an inert solvent , such as dimethylformamide, at a temperature of about 0 ° C to 100 ° C for a period of about 1 to about 24 hours. Alternatively, the acid is combined with the appropriate alcohol, as a solvent, in the presence of a catalytic amount of an acid such as concentrated sulfuric acid, at a temperature of about 20 ° C to 100 ° C, preferably at reflux, for a period of about 1 hour to about 24 hours. Another method is the reaction of the acid with a stoichiometric amount of the alcohol in the presence of a catalytic amount of acid in an inert solvent, such as toluene or tetrahydrofuran, with concomitant removal, by physical means for example, a Dean-Stark trap) or chemicals (for example, molecular sieves), of the water that is produced. Prodrugs of this invention in which an alcohol function has been derivatized in the ether form can be prepared by combining the alcohol with the appropriate alkyl bromide or iodide in the presence of a base such as potassium carbonate, in an inert solvent such as dimethylformamide., at a temperature of about 0 ° C to 100 ° C for a period of about 1 to about 24 hours. Alkanoylaminomethyl ethers can be obtained by reaction of the alcohol with a bis- (alkanoylamino) methane in the presence of a catalytic amount of acid, in an inert solvent such as tetrahydrofuran, according to a method described in US 4,997,984. Alternatively, these compounds can be prepared by the methods described by Hofman et al. In J. Org. Chem. 1994, 59, 3,530. Glycosides are prepared by the reaction of the alcohol and a carbohydrate in an inert solvent such as toluene, in the presence of acid.

Typically, the water formed in the reaction is removed as it is formed, as described above. An alternative procedure is the reaction of the alcohol with a suitably protected glycosyl halide, in the presence of a base, followed by deprotection. N- (1-hydroxyalkyl) amides and N- [1-hydroxy-1- (alkoxycarbonyl) methyl] amides can be prepared by reaction of the original imide with the appropriate aldehyde under neutral or basic conditions (for example, sodium ethoxide in ethanol ) at a temperature between 25 to 70 ° C. N-Alkoxymethyl or N-1- (alkoxy) alkyl derivatives can be obtained by reaction of the non-N-substituted compound with the necessary alkyl halide in the presence of a base, in an inert solvent. The compounds of this invention can also be used together with other pharmaceutical agents (eg, LDL-cholesterol lowering agents and triglyceride level reducing agents) for the treatment of the diseases / conditions described herein. For example, they can be used in combination with inhibitors of cholesterol synthesis, inhibitors of cholesterol absorption, inhibitors of MTP / Apo B secretion and other cholesterol-lowering agents such as fibrates, niacin, ion exchange resins. , antioxidants, ACAT inhibitors and bile acid sequestrants. In treatment by combination therapy, both the compounds of this invention and the other therapeutic drugs are administered to mammalian animals (e.g., humans, males or females) by conventional methods.

In the combination aspect of this invention, any inhibitor of HMG-CoA reductase can be used as the second compound. The term "HMG-CoA reductase inhibitor" refers to compounds that inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid, catalyzed by the enzyme HMG-CoA reductase. Such inhibition is easily determined by those skilled in the art according to standard assays (eg, Meth, Enzymol, 1981, 71: 455-509 and references cited therein). A variety of these compounds are described and referred to above; however, other inhibitors of HMG-CoA reductase will be known to those skilled in the art. In U.S. Pat. No. 4,231,938 (the disclosure of which is incorporated herein by reference) describes certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. In addition, in U.S. Pat. No. 4,444,784 (the disclosure of which is incorporated herein by reference) describes synthetic derivatives of the aforementioned compounds, such as simvastatin. In addition, in U.S. Pat. No. 4,739,073 (the description of which is incorporated by reference) discloses certain substituted characters, such as fluvastatin. In addition, in U.S. Pat. No. 4,346,227 (the disclosure of which is incorporated by reference) describes ML-236B derivatives, such as pravastatin. Furthermore, in EP-4912263 (the description of which is incorporated by reference) certain pyridyldihydroxyheptenoic acids, such as rivastatin, are described. In addition, in U.S. Pat. No. 5,273,995 (the disclosure of which is incorporated by reference) describes certain 6- [2- (pyrrol-1-yl-substituted) alkyl] pyran-2-ones, such as atorvastatin. In the combination aspect of this invention, any inhibitor of MTP / Apo B secretion (microsomal triglyceride transfer protein, and / or apolipoprotein B) can be used as the second compound.

The term "inhibitor of MTP / Apo B secretion" refers to compounds that inhibit the secretion of triglycerides, cholesteryl ester and phospholipids.

Such inhibition is easily determined by those skilled in the art according to standard assays (eg J.R. Wetterau, 1992. Science, 258: 999). A variety of these compounds are described and referred to below; however, other inhibitors of MTP / Apo B secretion will be known to those skilled in the art. WO 96/40640 and WO 98/23593 are two exemplary publications. Particularly useful, for example, are the following MTP / Apo B secretion inhibitors: [2- (1 H- [1, 2,4] triazol-3-ylmethyl) -1, 2,3,4- 4'-trifluoromethyl-2-biphenyl-2-carboxylic acid tetrahydroisoquinolin-6-yl] -amide; [4-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2-acetylamino-ethyl) -1,2,3,4-tetrahydroisoquinol-6-yl] -amide; (2- {6 - [(4'-trifluoromethyl-biphenyl-2-carbonyl) -amido] -3,4-dihydro-1H-isoquinolin-2-yl} ethyl) -carbamic acid methyl ester; 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (1 H-imidazol-2-ylmethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide; [4-Trifluoromethyl-biphenyl-2-carboxylic acid [2- (2,2-diphenyl-ethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide; and 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2-ethoxy-ethyl) -1,2,3,4-tetrahydroisoquinino-lein-6-yl] -amide. In the combination aspect of this invention, any inhibitor of HMG-CoA synthetase can be used as the second compound. The term "inhibitor of HMG-CoA sistetase" refers to compounds that inhibit the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthetase. Such inhibition is easily determined by those skilled in the art according to standard tests (Meth, Enzymol, 1975, 35: 155-160, Meth, Enzymol, 1985, 110: 19-26 and references cited therein). A variety of these compounds are described and referred to below; however, other inhibitors of HMG-CoA synthetase will be known to those skilled in the art. In U.S. Pat. No. 5,120,729 (the disclosure of which is incorporated herein by reference) describes certain beta-lactam derivatives. In U.S. Pat. No. 5,064,856 (the disclosure of which is incorporated herein by reference) discloses certain spiro-lactonic derivatives prepared by culturing a microorganism (MF5253). In U.S. Pat. No. 4,847,271 (the disclosure of which is incorporated herein by reference) describes certain oxetane compounds, such as 11- (3-hydroxymethyl-4-oxo-2-oxetail) -3,5,7-trimethyl acid derivatives -2,4-undecadienoic. In the combination aspect of this invention, any compound that decreases the expression of the HMG-CoA reductase gene can be used as the second compound. These agents can be transcription inhibitors of HMG-CoA reductase that block transcription of DNA, or inhibitors of translation that prevent translation of the mRNA encoding the HMG-CoA reductase protein. Said compounds may directly affect transcription or translation, or may be biotransformed into compounds having the above activities by one or more enzymes of the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite having the above activities . Said regulation is easily determined by those skilled in the art according to standard tests (Meth, Enzymol, 1985, 110: 9-19). Various compounds are described and referred to below; however, other inhibitors of the expression of the HMG-CoA reductase gene will be known to those skilled in the art. In U.S. Pat. No. 5,041,432 (the disclosure of which is incorporated by reference) discloses certain 15-substituted lanosterol derivatives. Other oxygenated stella that suppress the synthesis of HMG-CoA reductase are discussed by E.l. Mercer (Prog. Lip. Res. 1993, 32: 357-413). Any squalene synthetase inhibitor can be used as the second compound of this invention. The term "centrosyl synthetase inhibitor" refers to compounds that inhibit the condensation of 2 molecules of farnesylpyrrophosphate to squalene form, catalyzed by the enzyme squalene sistetase. Said inhibition is easily determined by those skilled in the art according to standard tests (Meth. Enzymol. 1. 969, 15: 393-454, and Meth. Enzymol. 1985, 110: 359-373 and the references contained therein). A variety of these compounds are described and referred to below; however, other squalene synthetase inhibitors will be known to those skilled in the art. In U.S. Pat. No. 5,026,554 (the disclosure of which is incorporated by reference) fermentation products of microorganism MF5465 (ATCC 74011) including zaragozic acid are described. A summary of other patented squalene sistetase inhibitors has been compiled [Curr. Op. Ther. Patents 81,993), 861-4]. In the combination aspect of this invention, any squalene epoxidase inhibitor can be used as a second compound. The expression "squalene epoxidase inhibitor" refers to compounds that inhibit the bioconversion of squalene and molecular oxygen in squalene-2,3-epoxide, catalyzed by the enzyme squalene epoxidase. Said inhibition is easily determined by those skilled in the art according to standard tests (Biocim Biophys, Acta 1,984, 794: 466-471). A variety of these compounds are described and referred to below; however, other squalene epoxidase inhibitors will be known to those skilled in the art. In U.S. Patents Nos. 5,011,859 and 5,064,864 (the descriptions of which are incorporated by reference) describe certain fluoro-analogous compounds of squalene. In EP 395,768 A (the description of which is incorporated by reference) certain substituted allylamine derivatives are described. In PCT Publication WO 9312069 A (the disclosure of which is incorporated herein by reference) certain amino alcohol derivatives are described. In U.S. Pat. No. 5,051,534 (the disclosure of which is incorporated herein by reference) discloses certain cyclopropyloxy-squalene derivatives. In the combination aspect of this invention, any squalene cyclase inhibitor can be used as a second component. The term "squalene cyclase inhibitor" refers to compounds that inhibit the bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalene cyclase. Said inhibition is easily determined by those skilled in the art according to standard tests (FEBS Lett.989, 244: 347-350). In addition, the compounds described and referred to below are inhibitors of squalene cyclase; however, other squalene cyclase inhibitors will also be known to those skilled in the art. In PCT Publication WO9410150 (the disclosure of which is incorporated herein by reference) certain derivatives of 1, 2, 3, 5, 6, 7, 8, 8a-octahydro-5,8a (beta) -trimethyl-6-isoquinolineamine are described, such as N-trifluoroacetyl-1,2,3,5,6,7,8,8a-octahydro-2-allyl-5, 5, 8a (beta) -trimethyl-6 (beta) -isoquinolineamine. In French Patent Publication 2697250 (the disclosure of which is incorporated herein by reference) there are disclosed certain beta, beta-dimethyl-4-piperidineethanol derivatives, such as 1- (1, 5, 9-trimethyldecyl) -beta, beta-dimethyl -4-piperidineethanol. In the combination aspect of this invention, any combined squalene epoxidase / squalene cyclase inhibitor can be used as a second component. The term "combined squalene epoxidase / squalene cyclase inhibitor" refers to compounds that inhibit the bioconversion of squalene to lanosterol via an intermediate squalene-2,3-epoxide compound. In some trials it is not possible to distinguish between squalene epoxidase inhibitors and squalene cyclase inhibitors; however, these assays are recognized by those skilled in the art. Therefore, inhibition by combined squalene epoxidase / squalene cyclase inhibitors is readily determined by those skilled in the art according to the above standard assays for squalene cyclase or squalene epoxidase inhibitors. A variety of these compounds are described and referred to below; however, other squalene epoxidase / squalene cyclase inhibitors will be known to those skilled in the art. In U.S. Patents Nos. 5,084,461 and 5,278,171 (the descriptions of which are incorporated by reference) describe certain azadecalin derivatives. In EP 468,434 (the disclosure of which is incorporated by reference) certain piperidyl ether and thioether derivatives, such as 2- (1-piperidyl) pentyl-isopentyl sulfoxide, and 2- (1-piperidyl) sulfide are disclosed. ethyl and ethyl. PCT Publication WO 9401404 (the disclosure of which is incorporated herein by reference) discloses certain acyl-piperidines, such as 1- (1-oxopentyl-5-phenyl) -4 - [(2-hydroxy-1-methyl) ) ethyl] piperidine. In U.S. Pat. No. 5,102,915 (the disclosure of which by reference herein) discloses certain cyclopropyloxy-squalene derivatives. The starting materials and reagents for the compounds of formula I described above are also readily available or can be easily synthesized by those skilled in the art using conventional organic synthesis methods. For example, many of the compounds used here are related to, or they come from, compounds on which there is a great scientific interest and a great commercial need, and, consequently, many of such compounds are commercially available or are presented in the bibliography or, by methods that are presented in the bibliography, They easily prepare from other commonly available substances. Some of the compounds of formula I of this invention or of the intermediates of their syntheses have asymmetric carbon atoms and, therefore, are enantiomers or diastereomers. The individual diastereomers of the diastereomer mixtures can be separated, taking into account their physicochemical differences, by methods known per se, such as, for example, chromatography and / or fractional crystallization. The enantiomers can be separated, for example, by high pressure chiral liquid chromatography methods or by converting the mixture of enantiomers into a mixture of diastereomers by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (for example, hydrolyzing) the individual diastereomers in the corresponding pure enantiomers. In addition, the corresponding pure enantiomers of a mixture of enantiomers of the compounds of formula I or of an intermediate product of their synthesis containing an acidic or basic group, can be separated by forming a diastereomeric salt with a chiral base or an optically pure chiral acid. (for example, 1-phenylethylamine or tartaric acid) and separating the diastereomers by fractional crystallization, followed by neutralization to break the salt, thereby obtaining the corresponding pure enentiomers. All the mentioned isomers, including diastereomers, enantiomers and mixtures thereof, are considered part of this invention. In addition, some of the compounds of this invention are atropoisomers (e.g., substituted biaryls) and are considered part of this invention.

More specifically, the compounds of formula I of this invention can be obtained in an enantiomerically enriched form by resolving the racemate of the final compound or of an intermediate product of its synthesis (preferably the final compound) using chromatography [preferably high pressure liquid chromatography (HPLC from English, high p / essure [quid chromatography] on an asymmetric resin [preferably Chiralcel ™ AD or OD (obtained from Chiral Technologies, Exton, Pennsylvania, USA)], with a mobile phase consisting of a hydrocarbon ( preferably heptane or hexane) containing between 0 and 50% isopropanol (preferably between 2 and 20%) and between 0 and 5% of an alkylamine (preferably 0.1% of diethylamine) .The concentration of the fractions containing product provides the materials desired.

Some of the compounds of formula I of this invention are acidic and form a salt with a pharmaceutically acceptable cation. Some of the compounds of formula I of this invention are basic and form a salt with a pharmaceutically acceptable anion. All the salts mentioned are within the scope of this invention and can be prepared by conventional methods such as combining the acidic and basic species, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as appropriate. The compounds can be obtained in crystalline form by dissolving an appropriate solvent (s), such as ethanol, hexanes and water / ethanol mixtures.

In addition, when the compounds of formula I of this invention form hydrates or solvates, these are also within the scope of the invention.

The compounds of formula I of this invention, their prodrugs and the salts of said compounds and prodrugs are all adapted for therapeutic use as agents that inhibit the activity of cholesterol ester transfer protein in mammalian animals, particularly in humans. Therefore, the compounds of this invention raise the plasma levels of HDL-cholesterol and its associated components and the functions performed by them in mammalian animals, particularly in humans. By virtue of their activity, these agents also reduce the plasma levels of triglycerides, LDL-cholesterol, VLDL-cholesterol and their associated components in mammalian animals, particularly in humans.

Therefore, these compounds are useful for the treatment and correction of various dyslipidemias which have been found to be associated with the development and incidence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypertriglyceridemia and familial hypercholesterolemia.

In addition, the introduction of a functional CETP gene into an animal that lacks CETP (mouse) results in reduced levels of HDL [L. B. Agellon et al., J. Biol. Chem. (1991), 266: 10,796-10,801] and an increased susceptibility to atherosclerosis [K. R. Marotti et al., Nature (1993), 364: 73-75]. In addition, the inhibition of CETP activity with an inhibitory antibody raises the level of HDL-cholesterol in the hamster [G. F. Evans et al., J. Of Lipid Research (1994), 35: 1634-1645] and the rabbit [M. E. Whitlock et al, J. Clin. Invest. (1989), 84: 129-137]. The suppression of an increased plasma level of CETP by intravenous injection of antisense oligodeoxynucleotides against CETP mRNA reduced atherosclerosis in rabbits fed cholesterol [M. Sugano et al., J. Of Biol. Chem. (1998), 273. 5,033-5,036]. It is important that human subjects deficient in plasma CETP, due to a genetic mutation, have markedly elevated plasma levels of HDL-cholesterol and apolipoprotein A-I, the main apoproteic component of HDL. In addition, most have markedly reduced plasma levels of LDL-cholesterol and apolipoprotein B, the main apolipoprotein component of LDL [A. Inazu et al., N. Engl. J. Med. (1990), 323: 1234-1.238].

Given the negative correlation between the levels of HDL-cholesterol and those of the lipoproteins associated with HDL, and the positive correlation between triglycerides, LDL-cholesterol and its associated apolipoproteins, in blood, with the development of cardiovascular, cerebrovascular and peripheral vascular diseases , the compounds of formula I of this invention, their prodrugs and the salts of said compounds and prodrugs, by virtue of their pharmacological action, are useful for the prevention, arrest and / or regression of atherosclerosis and its associated morbid states. These include cardiovascular disorders (eg, angina, cardiac ischemia and myocardial infarction), complications due to therapies for cardiovascular diseases (eg, reperfusion injury and angioplastic restenosis), hypertension, stroke and atherosclerosis associated with organ transplantation.

Due to the beneficial effects associated with high levels of HDL, an agent that inhibits CETP activity in humans, by virtue of its ability to increase HDL levels, also provides valuable avenues of therapy for various other disease areas.

Therefore, given the ability of the compounds of formula I of this invention, their prodrugs and their salts of said compounds and prodrugs to alter the lipoprotein composition by means of the inhibition of cholesterol ester transfer, serve to treat vascular complications associated with diabetes. Hyperlipidemia is present in most patients with diabetes mellitus (B.V. Howard, 1987, J. Lipid Res. 28, 613). Even in the presence of normal lipid levels, diabetic patients experience an increased risk of cardiovascular disease (W. B. Kannel and D. L. McGee, .979, Diabetes Care 2, 120). It is known that cholesteryl ester transfer mediated by CETP is abnormally increased in both insulin-dependent diabetes (JD Bagdade, PV Subbaiah and MC Ritter, 1991, Eur. J. Clin. Invest. 21, 161) and insulin-independent (JD Bagdade, MC Ritter, J. Lane and PV Subbaiah, 1993, Atherosclerosis 104, 69). It has been suggested that increased cholesterol transfer results in changes in lipoprotein composition, particularly for VLDL and LDL, which are more atherogenic (JD Bagdade, JD Wagner, LL Rudel and TB Clarkson, 1995, J. Lipid Res. 36 , 759). These changes would not necessarily be observed during a routine lipid scan. Therefore, the present invention will be useful in reducing the risk of vascular complications as a result of the diabetic state.

The described agents are useful in the treatment of obesity. Both in humans (T. Radeau, P. Lau, M. Robb, M. McDonell, G. Ailhaud and R. McPherson, 1995, Journal of Lipid Research 36 (12): 2.552-61) and in non-human primates ( E. Quinet, A. Tall, R. Ramakrishnan and L. Rudel, 1991, Journal of Clinical Investigation 87 (5): 1559-66), mRNA for CETP is expressed at high levels in adipose tissue. The adipose message increases with the ingestion of fats [L. J. Martin, P.W. Connelly, D. Nancoo, N. Wood, Z. J. Zhang, G. Maguire, E. Quinet, A. R. Tall, Y. L. Marcel and R. McPherson, 1993, Journal of Lipid Research 34 83); 437-46), and is translated into a functional transfer protein and, through secretion, contributes significantly to plasma CETP levels. In human adipocytes, most of the cholesterol is provided by plasma LDL and HDL (B. S. Fong and A. Angel, 1989, Biochimica et Biophysica Acta 1.004 (1): 53-60). The absorption of HDL-cholesteryl ester depends largely on CETP (F. Benoist, P. Lau, M. McDonnell, H. Doelle, R. Milne, and R. McPherson, 1997, Journal of Biological Chemistry 272 (38 ): 23.572-7). This ability of CETP to stimulate the absorption of HDL-cholesteryl, together with the enhanced binding of HDL to adipocytes in obese subjects (J. G. Jiménez, B. Fong, P. Julien, JP Despres, L. Rotstein and A. Angel., 1989, International Journal of Obesity, 13 (5): 699-709), suggest a function for CETP, not only in terms of generate the low HDL phenotype in these subjects, but in the development of obesity itself by promoting the accumulation of cholesterol. Therefore, inhibitors of CETP activity that block this process serve as useful adjuvants for dietary therapy by causing a reduction in weight.

Inhibitors of CETP are useful in the treatment of inflammation due to Gram negative sepsis and septic shock. For example, the systemic toxicity of Gram negative sepsis is due in large part to an endotoxin, a lipopolysaccharide (LPS) released from the outer surface of the bacteria, which cause extensive inflammatory response. The lipopolysaccharide can form complexes with lipoproteins (R. J. Ulevitch, A. R. Johhston and D. B. Weinstein, 1981, J. Clin.Invest.667, 827-37). In vitro studies have shown that the binding of LPS to HDL substantially reduces the production and release of mediators of inflammation (R. J. Ulevitch and A. R. Johhston, 1978, J. Clin.Research 62, 1313-24). Live studies show that transgenic mice expressing human apo-AI and high HDL levels are protected against septic shock (DM Levine, TS Parker, TM Donnelly, AM Walsh and AL Rubin, 1993, Proc. Nati. Acad. Sci 90, 12.010-44). It is important to note that the administration of reconstituted HDL to human beings stimulated with endotoxin resulted in a decreased inflammatory response (D. Pajkrt, JE Doran, F. Koster, PG Lerch, B. Arnet, T. van der Poli, JW Ten Cate and SJH Van Deventer, 1996, J. Exp. Med. 184, 1.601-08). Inhibitors of CETP, by virtue of the fact that they raise HDL levels, attenuate the development of inflammation and septic shock.

The utility of the compounds of formula I of the invention, their prodrugs and the salts of said compounds and prodrugs as medical agents in the treatment of the above-described diseases / conditions in mammalian animals (e.g., humans, males and females) is demonstrated by the activity of the compounds of this invention in conventional tests and in the live assay described below. The in vivo assay (with appropriate modifications within the skill of the art) can be used to determine the activity of other lipid or triglyceride controlling agents, as well as the compounds of this invention. The combination protocol described below is useful to demonstrate the utility of the combinations of the lipid and triglyceride controlling agents (e.g., the compounds of this invention) described herein. Said assays further provide a means by which the activities of the compounds of formula I of this invention, their prodrugs and the salts of said compounds and prodrugs (or the other agents described herein) can be compared with each other and with the activities of others. known compounds. The results of these comparisons are useful for determining dosage levels in mammalian animals, including humans, for the treatment of such diseases.

Of course, the following protocols can be varied by those skilled in the art.

The hyperalphacholesterolemic activity of the compounds of formula I can be determined by evaluating the effect of these compounds on the action of the cholesteryl ester transfer protein, by measuring the relative transfer ratio of radiolabelled lipids between lipoprotein fractions, essentially as previously described by Morton in J. Biol. Chem. 256, 11,992, 1981, and by Dias in Clin. Chem. 34, 2.322, 1988.

CETP IN VITRO ESSAY The following is a brief description of the cholesteryl ester transfer assay in human plasma (in vitro) and animal plasma (ex vivo). CETP activity in the presence or absence of drug is analyzed by determining the transfer of cholesteryl oleate (CO), labeled with H, from the exogenous tracer HDL to the non-HDL lipoprotein fraction of human plasma, or the marked LDL with 3H to the HDL fraction of the transgenic mouse plasma. The labeled human lipoprotein substrates are prepared in a manner similar to that of the method described by Morton, in which the endogenous CETP activity in plasma is used to transfer 3H-CO from phospholipid liposomes to all plasma lipoprotein fractions. The LDL and HDL labeled with 3H are subsequently isolated by sequential ultracentrifugation in the density sections of 1.019-1.063 and 1.10-1.21 g / ml., respectively. For the activity assay, 3H-labeled lipoprotein is added to plasma with 10-25 nanomoles of CO / ml and the samples are incubated at 37 ° C for 2.5-3 hours. Non-HDL lipoproteins are then precipitated by the addition of an equal volume of polyethylene glycol 8000 (Dias) at 20% (weight / volume). The samples are centrifuged at 750 g x 20 minutes and, by liquid scintillation, the radioactivity contained in the HDL-containing supernatant is determined. By introducing varying amounts of the compounds of this invention, in the form of a solution in dimethylsulfoxide, in human plasma before the addition of radiolabelled cholesteryl oleate, and comparing the relative amounts of radiolabel transferred, the relative inhibitory activities of the transfer can be determined. of cholesteryl ester.

IN VIVO CETP TEST The activity of these compounds in vivo can be determined by the amount of agent required to be administered, with respect to a control, to inhibit the cholesteryl ester transfer activity by 50% at different time points ex vivo, or to raise the level of HDL-cholesterol in a given percentage in an animal species that contains CETP. To evaluate the compounds in vivo, transgenic mice expressing both human CETP and human apolipoprotein Al (Charles River, Boston, Massachusetts, USA) can be used. The compounds to be examined are administered by oral gastric tube in a vehicle containing olive oil and sodium taurocholate in emulsion. Blood is removed retroorbitally from the mice before dosing. At different times after dosing, ranging from 4 to 24 hours, the animals are sacrificed, blood is obtained by cardiac puncture and the lipid parameters are measured, including total cholesterol, HDL- and LDL-cholesterol, and triglycerides. CETP activity is determined by a method similar to that described above except that, as a donor source, LDL containing 3H-cholesteryl oleate is used in place of HDL. The values obtained for the lipids and the transfer activity are compared with those obtained before dosing and / or with the percents of mice that only received vehicle.

PLASMATIC LIPID ESSAY The activity of these compounds can also be demonstrated by determining the amount of agent required to alter plasma lipid levels, such as, for example, HDL-cholesterol levels, LDL-cholesterol levels, VLDL-cholesterol or triglyceride levels, in the plasma of certain mammalian animals, for example, marmosets, which possess CETP activity and a plasma lipoprotein profile similar to that of humans (Crook et al., Arteriosclerosis 10, 625, 1990) ). Adult marmosets are assigned to treatment groups so that each group has an average value + - similar standard deviation for total plasma cholesterol concentrations, in HDL and / or in LDL. After allocation of the groups, the marmosets are daily administered doses of the compound in the form of a dietary mixture or by intragastric intubation, for a period of one to eight days. The control marmosets only receive the dosing vehicle. The plasma values of total cholesterol, in LDL, in VLDL and in HDL can be determined at any time of the study by obtaining blood from an antecubital vein, separating the plasma lipoproteins in their individual subclasses by means of a gradient density centrifugation, and measuring the concentration of cholesterol in the previously described manner (cook et al., Arteriosclerosis 10, 625, 1990).

IN VIVO ASSAY OF ATHEROSCLEROSIS The antiatherosclerotic effects of the compounds can be determined by the amount of compound required to reduce lipid deposition in the rabbit aorta. New Zealand white male rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (fed once a day). Blood is extracted from the marginal vein of the rabbits ear and the total plasma cholesterol values are determined in these samples. The rabbits are then assigned to treatment groups so that each group has a similar + standard deviation value for the total plasma cholesterol concentration, the HDL-cholesterol concentration, the triglyceride concentration and / or the transfer protein activity. of cholesteryl ester. After allocation of the groups, the rabbits are daily administered doses of the given compound in the form of a dietary mixture or in a small piece of gelatin-based candy. The control rabbits only receive the dosing vehicle, either in the food or in the gelatin candy. Throughout the study the cholesterol / coconut oil diet is continued along with the administration of the compound. Plasma cholesterol values and cholesteryl ester transfer protein activity can be determined at any time during the study by obtaining blood from the marginal vein of the ear. After 3-5 months, the rabbits are sacrificed and the aortas are extracted, from the thoracic arch to the branch of the iliac arteries. The aortas are cleaned of connective tissue, opened longitudinally and then stained with Sudan IV in the manner described by Holman et al. (Lab. Invest. 1958, 7, 42-47). The percentage of stained surface area is quantified by densitometry using an Optimal system for image analysis (Image Processing Systems). A reduced lipid deposit is indicated by a reduction in the percentage of surface area stained in the group that received the compound, with respect to that of the control rabbits.

ANTIOBESITY PROTOCOL The ability of CETP inhibitors to cause weight loss can be evaluated in obese human subjects with a body mass index (BMI). - 30 kg / m2. Sufficient inhibitor doses are administered to result in an increase of > -25% in HDL-cholesterol levels. The BMI and body fat distribution, defined as the waist-to-hip ratio, are examined during the course of the 3-6 month studies and the results of the treatment groups are compared with those of the placebo groups. .

SEPSIS IN VIVO ASSAY In vivo studies show that transgenic mice expressing human apo-AI and high HDL levels are protected against septic shock. Therefore, the ability of CETP inhibitors to protect against septic shock can be demonstrated in transgenic mice expressing transgenes of both human apo-AI and human CETP (DM Levine, TS Parker, TM Donnelly, AM Walsh and AL Rubin , 1993, Proc. Nati, Acad.Sci.90, 12.040-44). LPS from E. Coli is administered in an amount of 30 mg / kg by intraperitoneal injection to animals given a CETP inhibitor at an appropriate dose to raise the HDL level. The number of surviving mice is determined at various times up to 48 hours after the injection of LPS and compared with that of mice to which only vehicle has been administered (minus the CETP inhibitor). The administration of the compounds of this invention can be by means of any method that provides systemically and / or locally a compound of this invention. These methods include the ora, parental, intraduaodenal, etc. pathways. Generally, the compounds of this invention are administered orally, but parenteral administration (eg, intravenous, intramuscular, subcutaneous or intramedullary) can be used when, for example, oral administration is inappropriate for the target or when the patient is incapable of ingest the drug.

In general, an amount of a compound of this invention that is sufficient to achieve the desired therapeutic effect (e.g., elevation of the HDL level) is used. In general, an effective dosage of the compounds of Formula I of this invention, their prodrugs and the salts of said compounds and prodrugs is in the range of 0.01 to 10 mg / kg / day, preferably 0.1 to 5 mg. / kg / day. A dosage of the combination pharmaceutical agents to be used in conjunction with the CETP inhibitors, which is effective for the indication being treated, is used. For example, an effective dosage for inhibitors of HMG-CoA reductase is typically in the range of 0.01 to 100 mg / kg / day. In general, an effective dosage for inhibitors of MTP / Apo B secretion is in the range of 0.01 to 100 mg / kg / day. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable carrier, diluent or excipient. Therefore, the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, the pharmaceutical composition may take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate, are used together with various disintegrating agents such as starch, preferably potato or tapioca starch, and certain complex silicates, and together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also used as fillers in soft and hard gelatin capsules; in this regard, preferred materials also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. A preferred formulation is a solution or suspension in an oil, such as, for example, olive oil, Miglyol * "1 or Capmul611, in a soft gelatin capsule.Antioxidants may be added to prevent long-term degradation, as appropriate When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of this invention may be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as with diluting agents such as water, ethanol. , propylene glycol, glycerol and various combinations thereof For the purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts, may be employed. properly buffered, if necessary, and the liquid diluent can be made first isotonic with enough saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injections. In this regard, the sterile aqueous media employed are all readily obtainable by standard techniques well known to those skilled in the art. For purposes of transdermal administration (eg, topical), dilute, aqueous or partially aqueous solutions are prepared (usually in a concentration of about 0.1% to 5%), otherwise similar to the above parenteral solutions. The methods for preparing various pharmaceutical compositions with a certain amount of active ingredient are known or will be apparent, in light of this description, to those skilled in the art. For examples of methods for preparing pharmaceutical compositions, see Reminqton's Pharmaceutical Siences, Mack Publishing Company, Easter, Pennsylvania, USA, 15th edition (1, 975). The pharmaceutical compositions according to the invention may contain 0.1% -95% of the compound (s) of this invention, preferably 1% -70%. In any case, the composition or formulation to be administered will contain an amount of a compound (s) according to the invention in an amount effective to treat the disease or condition of the subject being treated, such as, for example, Atherosclerosis Since the present invention has an aspect that relates to the treatment of the diseases / conditions described herein with a combination of active ingredients that can be administered separately, the invention also relates to separate pharmaceutical compositions for combination, as a whole. The assembly comprises two separate pharmaceutical compositions: a compound of Formula I, a prodrug thereof or a salt of said compound or of said prodrug, and a second compound as described above. The assembly comprises means for containing the separate compositions, such as a container, a divided jar or a pack of divided sheets. Typically, the assembly comprises instructions for the administration of the separate components. The whole form is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral) or are administered with different dosage ranges, or when the prescribing physician wishes to dose the individual components of the dosage form. the combination. An example of such a set is the so-called "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging unit dosage forms (tablets), capsules, and the like). The blister packs generally consist of a sheet of relatively rigid material covered with a sheet of a plastic material, preferably transparent. During the packaging process cavities are formed in the plastic sheet. The cavities have the size and shape of the tablets or capsules that are going to be packaged. Next, the tablets or capsules are placed in the cavities and the sheet of relatively rigid material is hermetically sealed on the plastic sheet, by the face of the sheet facing the direction in which the cavities were formed. As a result, the tablets or capsules can be removed from the blister pack by manually applying pressure on the cavities, by means of which an opening is formed in the sheet, at the site of the cavity. The tablet or capsule can then be drawn through said opening. It may be desirable to provide a memory aid in the set, such as, for example, in the form of numbers next to the tablets or capsules so that the numbers correspond to the days of the regime in which the tablets or capsules so specified are to be ingested. Another example of such memory aid is a calendar printed on the cardboard, for example, as follows: "First Week, Monday, Tuesday ... Second Week, Monday, Tuesday ...", etc. Other variations of memory aids will be readily apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a given day. In addition, a daily dose of a compound of Formula I may consist of a tablet or capsule while a daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

In another specific embodiment of the invention, there is provided a dispensing device designed to disperse the daily doses, one at a time, in the order of their intended use. Preferably, the dispensing device is provided with a memory aid to further facilitate compliance with the regime. An example of such a memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of said memory aid is a memory microchip, powered by a battery, coupled to a liquid crystal display or an audible recall signal which, for example, indicates the date on which the last daily dose was taken and / or remember when the next dose should be taken. The compounds of this invention, alone or in combination with each other or with other compounds, will generally be administered in a convenient formulation. The following formulation examples are illustrative only, and are not intended to limit the scope of the present invention. In the following formulations, "active ingredient" means a compound of this invention. Hard gelatin capsules are prepared using the following: Formulation 1: gelatin capsules Ingredient Quantity (mg / capsule) Active ingredient 0.25-100 Starch, NF 0-650 Fluid powder of starch 0-50 Fluid silicone, 3.5.10"4 m2 / s 0-15 A formulation for tablets is prepared using the following ingredients: Formulation 2: tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Microcrystalline cellulose 200-650 Silicon dioxide, exposed to vapors 10-650 Stearic acid 5-15 The components are mixed and compressed to form tablets. Alternatively, tablets are prepared, each of which contains 0.25-100 mg of active ingredients, as follows: Formulation 3: tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% solution in water) 4 Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch and cellulose are passed through a No. 45 mesh US sieve. and mix thoroughly. The polyvinylpyrrolidone solution is mixed with the resultant powders and then the mixture is passed through a No. 14 Mali US sieve. The granules thus produced are dried at 50-60 ° C and passed through a No. 18 US mesh screen. Then the sodium carboxymethylcellulose, magnesium stearate and talcum, previously passed through a US 60 mesh screen, are added to the granules, which, after mixing, are compressed in a forming machine. tablets to get tablets. Suspensions are prepared, each of which contains 0.25-100 mg of active ingredient per 5 ml dose, as follows: Formulation 4: suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.25-100 mg Sodium carboxymethylcellulose 50 mg Syrup 1, 25 mg Benzoic acid solution 0.10 ml Flavoring agent desired amount Coloring agent desired amount Purified water up to 5 ml The active ingredient is passed through a US No. 5 mesh screen. and it is mixed with the sodium carboxymethyl cellulose and the syrup to form a paste without lumps. The benzoic acid solution, the flavoring agent and the coloring agent are diluted with some of the water and added, with stirring, to the paste. Then enough water is added until the required volume is obtained. An aerosol is prepared containing the following ingredients: Formulation 5: aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 70.00 The active ingredient and ethanol are mixed, the mixture is added to a portion of the propellant 22, and the whole is cooled to 30 ° C and transferred to a charging device. The required amount is then fed to a stainless steel vessel and diluted with the remaining propellant. Then the valvular units are adjusted to the container. Suppositories are prepared as follows: Formulation 6: suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 Saturated fatty acid glycerides 2,000 The active ingredient is passed through a No. 60 mesh US sieve. and is suspended in the saturated fatty acid glycerides, previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold with a nominal capacity of 2 g, and allowed to cool. An intravenous formulation is prepared as follows: Formulation 7: intravenous solution Ingredient Amount Active ingredient dissolved in al1% ethanol 20 mg Intralipid ™ emulsion 1,000 ml The dissolution of the above ingredients is administered intravenously to a patient at a rate of about 1 ml per minute.

Soft gelatin capsules are prepared using the following: Formulation 8: soft gelatin capsule with oil formulation Ingredient Quantity (mg / capsule) Active ingredient 10-500 Olive oil or Miglyol Oil 500-1,000 The above active ingredient can also be a combination of agents.

GENERAL EXPERIMENTAL PROCEDURES Nuclear magnetic resonance (NMR) spectra were recorded on a Varian XL-300 device (Varian Company, Palo Alto, California, USA), a Bruker AM-300 spectrometer ( Bruker Company, Billerica, Massachusetts, USA) or a Varian Unity 400 device at approximately 23 ° C, at 300 MHz for protons and 75.4 MHz for carbon nuclei. Chemical shifts are expressed in parts per million downfield of tetramethylsilane. The shapes of the peaks are indicated as follows: s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; bs (English, broad singlet, broad singlet) The so-called interchangeable resonances did not appear in a separate NMR experiment in which ours had been agitated with several drops of D2O in the same solvent. Atmospheric pressure (APCl) were obtained on a Fisons Platform II spectrometer, mass spectra by chemical ionization were obtained on a Hewlett-packark 5989 instrument (Hewlett-Packard Company, Palo Alto, California, USA). US) (ammonia ionization, PBMS) When the intensity of ions containing chlorine or bromine is described, the expected ratio of intensities (approximately 3: 1 for ions containing 35CI / 37CI and 1: 1 for ions that contain 79Br / 81Br) and only the intensity of the lower mass ion is given.Column chromatography was carried out with Bake silica gel (40 μm; JT Baker, Phillipsburg, New Jersey, EE .) On glass columns, under a small nitrogen pressure. Radial chromatography was carried out using a Chromatron apparatus (model 7924t, Harrison Research). Unless otherwise specified, the reagents were used as obtained from commercial sources. The dimethylformamide, the 2-propanol, the tetrahydrofuran and the dichloromethane used as reaction solvents, supplied by Aldrich chemical Company (Milwaukee, Wisconsin, USA), were of anhydrous quality. The microanalyses were carried out by Schwarzkopf Microanalytical Laboratory, Woodside, New York, USA): The terms "concentrated" and "evaporated" refer to the removal of the solvent in a rotary evaporator under the pressure of a water tube. , with a bath at a temperature below 45 ° C. The reactions carried out at "0-20 ° C" or "0-25 ° C were carried out with an initial cooling of the vessel in an isolated ice bath, which was allowed to warm to room temperature for several hours. The abbreviations "min" and "h" mean "minutes" and "hours", respectively.

EXAMPLE 1 Benzyl Ester of 6-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid 4,6,7-Trimethoxyquinoline (1.0 g, 4.6 mmol) was dissolved in anhydrous tetrahydrofuran (15 ml). The mixture was cooled to -78 ° C and methylmagnesium chloride (2M) was added., 3 ml of a 3.0 M solution in tetrahydrofuran, 6.9 mmol). The mixture was stirred at -78 ° C for 1 h and then benzyl chloroformate (1.0 mL, 6.9 mmol) was added. The reaction mixture was heated at room temperature for 30 min and then 8 ml of a 1 n aqueous solution of HCL was added. After 30 minutes, tetrahydrofuran was removed in vacuo and the remaining aqueous phase was subjected to extraction with ethyl acetate (3x 30 ml). The organic phases were combined, washed with water (15 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 1.5 g of crude product. Purification by chromatography on silica gel using 0-50% ethyl acetate / hexanes as eluent afforded 0.91 g of the desired product (57%). 1H-NMR (CDL3),: 1.25 (d, 3H), 2.5 (d, 1 H), 3.0 (dd, 1 H), 3.7 (s, 3H), 3.9, (s, 3H), 5.1-5.3 (m, 1H), 5.2 (d, 1H), 5.4 (d, 1H), 7.3-7.5 (m, 7H) .

EXAMPLE 2A 4-Benzylimino-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester The 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (0.83 g, 2.3 mmol) was dissolved in a solution of triethylamine (2.2 ml, 2.3 mmol), in a solution of triethylamine (2.2 ml, 2.3 mmol), benzylamine (0.55 ml, 5.1 mmol) and anhydrous dichloromethane (15 ml). This solution was stirred in a water bath at room temperature while slowly adding 2.5 ml of a 1m solution of titanium tetrachloride (TiCU) in dichloromethane (2.5 mmole). The reaction mixture was allowed to stir at room temperature for 48 h. The reaction mixture was then poured into a stirred solution in water (50 ml) and potassium carbonate (10 g). After filtration, the filtration product was subjected to extraction with ethyl acetate (3 x 100 ml), and the combined organic phases were washed with water (100 ml) and with brine (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the desired mine (1.12 g, near 1005). 1 H-MNR (CDCl 3),: 1, 2 (d, 3 H), 2.7-2.9 (m, 2 H), 3.7 (s, 3 H), 3.9 (s, 3 H), 4, 6 (d, 1 H), 4.7 (d, 1 H), 5.0-5.2 (m, 2H), 5.4 (d, 1 H), 7.2-7.5 (m , 11 H), 7.8 (s, 1 H).

EXAMPLE 2B Benzyl Ester of cis-4-benzylamino-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid The benzyl ester of 4-benzylimino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carbosyl ester (1, 02 g, 2.29 mmol) in ethanol was dissolved (12 ml) and sodium borohydride (96 mg, 2.5 mmol) was added. After the reaction mixture was stirred overnight, more sodium borohydride (43 mg, 1.1 mmol) was added and the reaction mixture was stirred for 20 min. The reaction mixture was concentrated in vacuo to about 8 ml and then neutralized with 1 N HCl. The mixture was extracted with ethyl acetate (3 x 12 ml). The organic phases were combined over sodium sulfate, filtered and concentrated in vacuo to obtain 1.07 g in a crude mixture of amine products. Purification by chromatography on silica gel using 0-20% ethyl acetate / hexanes as eluent provided the cis amine (160 mg, 16%). 1 H-NMR (CDCl 3),: 1, 1-1, 3 (m, 4 H), 2.6 (ddd, 1 H), 3.5 (dd, 1 H), 3.7 (s, 3 H), 3.9 (s, 3H), 3.9 (d, 1 H), 4.1 (d, 1 H), 4.4-4.6 (m, 1H), 5.0 (d, 1 H) ), 5.3 (d, 1 H), 6.9 (s, 1 H), 7.1 (s, 1 H), 7.2-7.5 (m, 10H). Continuous elutions using increasing concentrations of ethyl acetate gave the trans amine.

EXAMPLE 3A 4-Hydroxyimino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A stirred solution of the ethyl ester of acid was heated at reflux for 2 h. 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid (10.0 g, 34.1 mmol), hydroxylamine hydrochloride (7, 1 g, 102 mmol) and sodium acetate (7.0 g, 85 mmol) in ethanol (50 ml). Water (50 ml) was added and volatile compounds were removed in vacuo. Ethyl acetate (175 ml) was added and the mixture was stirred vigorously for 10 min. The aqueous phase was separated and extracted with ethyl acetate (2 x 60 ml). The combined organic layers were washed with brine (25 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the title compound as a white foam (12.28 g, approximately 100%). 1 H-NMR (CDCl 3), d: 1, 1 (d, 3 H), 1.32 (t, 3 H), 2.77 (dd, 1 H), 3.07 (dd, 1 H), 3.89 (s, 6H), 4.2-4.4 (m, 2H), 5.0 (m, 1H), 7.18 (s, 1 H), 7.26 (s, 1 H).

EXAMPLE 3B cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a stirred solution of the 4-hydroxyimino-6-ethyl ester, 7-Dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (11.0 g, 34.1 mmol) in ethanol (100 mL) and a 2 N aqueous solution of KOH (102 mL, 205 millimoles), aluminum-nickel alloy (11.7 g, 136 millimoles) was added in portions over 15 minutes. The reaction mixture was stirred for 35 min and then filtered through a pad of Celite®, rinsing with ethanol. The volatile compounds were removed in vauco and the resulting aqueous phase was subjected to extraction with ethyl acetate (3 x 150 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 16.32 g of crude product. Purification by chromatography on silica gel using 0-4% methanol in dichloromethane as eluent afforded the title compound (6.51 g, 65%). 1 H-NMR (CDCl 3), d: 1, 19 (d, 3 H), J = 6 Hz), 1.25 (m, 1 H 9, 1, 28 (t, 3 H, J = 7 Hz), 2.4 (m, 1 H), 3.76 (m, 1 H), 3.86 (s, 3H), 3.90 (s, 3H), 4.10-4.35 (m, 2H), 4, 5 (m, 1 H), 6.96 (s, 1 H), 7.0 (s, 1 H).

EXAMPLE 3C cis-4-r (3,5-bis-trifluoromethyl-benzyl) -aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of the cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester (527 mg, 1.8 mmol) in dichloroethane (12 ml) was treated successively with acetic acid (0.1 ml, 1.8 mmol) and 3,5-bis-trifluoromethyl-benzaldehyde (0.30 ml, 1.8 mmol). After 35 minutes of stirring at room temperature, sodium triacetoxyborohydride (570 mg, 2.7 mmol) was added to the mixture. After 3 days, 20ml of water was added and the mixture was made alkaline (pH of 10) with potassium carbonate. The mixture was extracted with ethyl acetate (3 x 35 ml), and the combined organic layers were washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, elution being carried out with 0-20% ethyl acetate in hexanes, to obtain the title compound (663 mg). 1 H-NMR (CDCl 3), d: 1, 22 (d, 3 H 9, 1, 3 (t, 3 H), 1.5 (m, 1 H), 2.6 (m, 1 H), 3.55 ( dd, 1 H), 3.87 (s, 3H), 3.89 (s, 3H9, 4.1-4.6 (m, 5H), 7.06 (s, 1 H9, 7.08 (s) , 1h), 7.8 (s, 1 h), 7.95 (s, 2H).

EXAMPLE 4 Cis-4- (benzyl-ethoxycarbonyl-amino) -6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester. Pyridine (0.20 ml, 2.3 mmol) was added. ) and ethyl chloroformate (0.16 ml, 1.7 millimoles) to a solution of the benzyl ester of cis-4-benzyllamino-6,7-dimethoxy-2-methyl-3,4-dihy dro-2H-quinoline-1-carboxylic (Example 2B, 150 mg, 0.34 millimoles) in anhydrous dichloromethane (5 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water (20 ml) and a 2 N aqueous solution of KOH (10 ml) was added. The solution was stirred for 30 min and then the mixture was subjected to extraction with diethyl ether (3 x 25 ml). The organic phases were combined and washed with 1 N HCl (3 x 10 ml) and then with a saturated solution (10 ml) of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain 190 mg of crude product. Purification by chromatography on silica gel using 0-40% ethyl acetate / hexanes as eluent provided the desired final product (146 mg, 83%). Mass spectrometry (MS, mass spectrometry), m / z: 519 (M + + 19), 340 (M + - 178); 1 H-NMR (CDCl 3), d: 6.99 (C8, s, 1 H), 6.42 (C5, s, 1 H). Using the appropriate starting materials, the Examples 5-10, 49, 63 and 65 in a manner analogous to the sequence of reactions described for Examples 1, 2A, 2B and 4, and Examples 11-48 were prepared, 50-62 and 64 in a manner analogous to the sequence of reactions described for Examples 1, 3A, 3B, 3C and 4.

EXAMPLE 5 Benzyl ester of cis-4- (benzyl-isobutoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 484 (M + + 18); 1 H-NMR (CDCl 3), d: 6.45 (C5, s, 1 H), 1.19 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 6 cis-4- (benzyl-methoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z 443 (M + + 1), 460 (M + + 18); 1 H-NMR (CDCl 3), d: 7.10 (C8, s, 1 H), 1.19 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 7 cis-4 ~ .benzyl-isopropoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 470 (M +), 488 (M + + 18); 1 H-NMR (CDCl 3), d: 6.41 (C5, s, 1 H), 1.14 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 8 cis-4-benzyl-hexyloxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 512 (M +); H-NMR (CDCl 3), d: 6.41 (C5, s, 1H), 1, 14 (C2-Me, d, 3H).

EXAMPLE 9 cis-4- (benzyl-butoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 484 (M + ), 502 (M + + 18); 1 H-NMR (CDCl 3), d: 7.04 (C8, s, 1 H), 1.41 (C2-Me, d, 3H, J = 6.20 Hz).

EXAMPLE 10 cis-4- (benzyl-benzyloxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 520 (M + + 2), 537 (M + + 19); 1 H-NMR (CDCl 3), d: 7.28-7.11 (m, 10H), 6.33 (C5, s, 1 H).

EXAMPLE 11 cis-6,7-dimethoxy-4- (methoxycarbonyl-naphthalen-2-methylmethylamino) -2-ylmethyl-amino) -2-methyl-3,4-dihydro-2H-q ethyl ester; inolein-1-carboxylic S, m / z: 493 (M + + 1), 510 (M + + 18); 1 H-NMR (CDCl 3), d: 7.05 (C8, s, 1 H),, 43 (C5, s, 1H), 2.34-2.28 (m, 1H).

EXAMPLE 12 cis-4-r (4-chloro-benzyl) -methoxycarbonyl-amino-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, m / z : 477 (M + + 1), 494 (M + + 17), 1 H-NMR (CDCl 3), d: 6.44 (C5, s, 1 H),, 29-2.18 (m, 1 H).

EXAMPLE 13 cis-6,7-dimethoxy-4 - (4-methoxy-benzyl) -methoxycarbonyl-amino-1-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester S, m / z: 473 (M + + 1), 490 (M + + 18); 1 H-NMR (CDCl 3), d: 6.41 (C5, s, 1H),, 75-3.70 (bs, 12H). EXAMPLE 14 cis-6 J-dimethoxy-4- (methoxycarbonyl-thiophen-2-ylmethyl-amino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, m / z: 449 (M + + 1), 466 (M + + 18); 1 H-NMR (CDCl 3), d: 6.34 (C5, s, 1 H),, 84 (s, 6H).

EXAMPLE 15 Ethyl ester of cis-6-dimethoxy-4-fmethoxycarbonyl- (4-methyl-benzyl) -amino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid S, m / z : 457 (M + + 1), 474 (M + + 18), 1 H-NMR (CDCl 3), d: 6.45 (C5, S, 1 H),, 29 (s, 3H).

EXAMPLE 16 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, m / z: 596 (M + + 18); 1 H-NMR (CDCl 3), d: 7.09 (C8, s, 1H), 6.39 (C5, s, 1 H),, 81 (s, 6H).

EXAMPLE 17 cis-6, 7-dimethoxy-4-rmethoxycarbonyl- (3-trifluoromethyl-benzyl-amino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, m / z 572 (M + + 2), 539 (M + + 18); 1 H-NMR (CDCl 3), d: 7.07 (s, 1 H), 3.78 (s, H).

EXAMPLE 18 cis-6-dimethoxy-4-rmethoxycarbonyl- (2-trifluoromethyl-benzyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid S, m / z: 511 ethyl ester (M + + 1), 528 (M + + 18); 1 H-NMR (CDCl 3), d: 7.06 (C8, s, 1 H),, 46 (C5, s, 1 H).

EXAMPLE 19 Ethyl ester of cis-6,7-dimethoxy-4-r-methoxycarbonyl- (4-trifluoromethyl-benzyl-amino-2-methyl-3,4-dihydro-2H-quinoline.-1-carboxylic acid S, m / z: 511 (M + + 1), 528 (M + + 18); 1 H-NMR (CDCl 3), d: 7.06 (C8, s, 1 H),, 40 (C5, s, 1 H).

EXAMPLE 20 cis-6,7-Dimethoxy-4-rmethoxycarbonyl-3-nitro-5-trifluoromethyl-benzyl) -amino-1-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, m / z: 556 (M + + 1), 573 (M + + 18); 1 H-NMR (CDCl 3), d: 6.39 (s, 1 H), 7.10 (s, 1 H), 7.85 (s, 1 H), 8.32 (s, 1 H), 8 , 40 (s, 1 H).

EXAMPLE 21 Cis-6,7-dimethoxy-4-r-methoxycarbonyl- (3-nitro-benzyl) -amino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester S, m / z: 488 (M + + 1), 505 (M + + 18); 1 H-NMR (CDCl 3), d: 6.42 (s, 1 H), 7.09 (s, 1 H), 7.5-7.7 (m, 2H), 8.2-8.3 ( m, 2H).

EXAMPLE 22 cis-6, 7-dimethoxy-4-fmethoxycarbonyl- (3-phenyl-propyl) -amino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 470 (M +), 488 (M + + 18); 1 H-NMR (CDCl 3), d: 6.36 (C8, s, 1 H), 1.21 (C2-MT, d, 3H).

EXAMPLE 23 cis-6,7-dimethoxy-4- (methoxycarbonyl-phenethylamine.-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 456 (M + ), 474 (M + + 18), 1 H-NMR (CDCl 3), d: 6.36 (C5, s, 1 H).

EXAMPLE 24 cis-6,7-Dimethoxy-4- (methoxycarbonyl-pyridin-2-methylmethylamino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: AAA (M + + 1); 1 H-NMR (CDCl 3), d: 6.51 (C5, s, 1H), 1.13 (C2-Me, d, 3H). EXAMPLE 25 cis-6-dimethoxy-4- (methoxycarbonyl-pyridin-3-ylmethyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: AAA (M + + 1); 1 H-NMR (CDCl 3), d: 7.03 (C8, s, 1 H), 6.39 (C5, s, 1 H).

EXAMPLE 26 cis-4-r (3-cyano-benzyl) -methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 468 (M + + 1), 484 (M + + 17); 1 H-NMR (CDCl 3), d: 7.09 (C8, s, 1 H), 6.39 (C5, s, 1H).

EXAMPLE 27 cis-4-r (3-chloro-benzyl-methoxycarbonyl-amino-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 477 ( M +), 494 (M + + 19); 1 H-NMR (CDCl 3), d: 6.40 (C5, s, 1 H), 1.17 (C2-Me, d, 3H).

EXAMPLE 28 cis-4-r (3,5-difluoro-benzyl) -methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 479 (M + + 1), 496 (M + + 18); 1 H-NMR (CDCl 3), d: 6.39 (C5, s, 1 H), 1.16 (C2-Me, d, 3H).

EXAMPLE 29 cis-6 J-dimethoxy-4- (methoxycarbonyl-pyridin-4-ylmethyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: AAA (M + + 1); 1 H-NMR (CDCl 3), d: 6.40 (C5, s, 1H), 1.17 (C2-Me, d, 3H).

EXAMPLE 30 cis-4-r (3,5-dichloro-benzyl) -methoxycarbonyl-aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 511 ( M +), 528 (M + + 17); 1 H-NMR (CDCl 3), d: 6.39 (C5, s, 1 H), 1.17 (C2-Me, d, 3H).

EXAMPLE 31 cis-4-IY3,5-bis-trifluoromethyl-benzyl-ethoxycarbonyl-amino-2- methyl-6-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z : 625 (M + + 1); 1 H-NMR (CDCl 3), d: 5.26-5.44 (width 1H), 6.56 (s, 1H).

EXAMPLE 32 cis-4-r (3-carboxy-benzyl) -methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 487 (M + + 18), 504 (M + + 18); 1 H-NMR (CDCl 3), d: 6.47 (C5, s, 1H), 1.18 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 33 cis-4-IY2-chloro-5-methanesulfinyl-benzyl) -methoxycarbonyl-amino-1-7.7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester NMR (CDCl 3), d: 6.49 (s, 1 H), 7.1 (s, 1 H).

EXAMPLE 34 cis-6-dimethoxy-4- (methoxycarbonyl-pyridin-4-ylmethyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z : 488 (M + + 1), 505 (M + + 18); 1 H-NMR (CDCl 3), d: 6.47 (s, 1 H), 3.85 (s, 6H).

EXAMPLE 35 cis-4-r (2,4-dinitro-benzyl) -methoxycarbonyl-aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 533 (M + + 1), 550 (M + + 18); 1 H-NMR (CDCl 3), d: 8.95 (s, 1H), 6.43 (C5, s, 1 H), 3.87 (s, 6H).

EXAMPLE 36 cis-4-r (3,5-ditric-benzyl) -methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3-4-dihydro-2H-quinoline-1 ethyl ester -carboxylic MS, m / z 533 (M + + 1), 550 (M + + 18); 1 H-NMR (CDCl 3), d: 8.43 (s, 2H), 6.38 (C5, s, 1 H), 3.84-3.82 (2s, 9H).

EXAMPLE 37 cis-4-r (3-dimethylsulfamoyl-5-trifluoromethyl-benzy-methoxycarbonyl-aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z ethyl ester : 617 (M +), 635 (M + + 18), 1 H-NMR (CDCl 3), d: 6.25 (C5, s, 1 H), 3.84 (s, 3 H), 3.77 (s, 3 H) ), 3.77 (s, 6H), 2.69 (s, 6H).

EXAMPLE 38 cis-4-r (2-chloro-benzyl) -methoxycarbonyl-aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: A77 (M +), 494 (M + + 17); 1 H-NMR (CDCl 3), d: 6.49 (C5, s, 1H), 1, 14 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 39 cis-6,7-dimethoxy-4-rmethoxycarbonyl- (4-nitro-benzyl) -aminol-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 488 (M + + 1), 505 (M + + 18); 1 H-NMR (CDCl 3), d: 6.39 (C5, s, 1H), 3.84 (s, 3H), 3.80-3.77 (2s, 6H).

EXAMPLE 40 Ethyl ester of cis-6,7-dimethoxy-4-rmethoxycarbonyl- (3-sulfamoyl-5-trifluoromethyl-benzyl) -amino-1-methyl-3,4-dihydro-2H-quinoline-1 - MS carboxylic, m / z: 607 (M + + 18); 1 H-NMR (CDCl 3), d: 8.12 (s, 2H), 6.38 (C5, s, 1H), 3.85 (s, 3H), 3.78 (s, 3H).

EXAMPLE 41 cis-4-r2,6-dichloro-pyridin-4-ylmethyl-methoxycarbonyl-amino-1-6.7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z 512 (M +), 278 (M + -233); 1 H-NMR (CDCl 3), d: 6.33 (C5, s, 1 H), 1.19 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 42 cis-6, 7-dimethoxy-4-fmethoxycarbonyl- (3-methoxycarbonyl-benzyl-amino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 501 (M + + 1), 518 (M + + 18); 1H-NMR (CDCl 3), d: 1, 14 (d, 3H, J = 6.2 Hz), 1.29 (t, 3H, J = 7.4 Hz), 3.81 (s, 6H), 3.86 (s, 3H), 3.91 (s, 3H), 6.42 (s, 1 H), 7.06 (s, 1 H), 7.4-7.5 (m, 2H), 7.9-8.0 (m, 2H).

EXAMPLE 43 cis-6,7-Dimethoxy-4-fmethoxycarbonyl-3 (4-methyl-pyridine-1-sulfonyl) -5-trifluoromethyl-benzyl-amino) -2-methyl-3,4-ethyl ester -dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 533 (M + + 1), 550 (M + + 18); H-NMR (CDCl 3), d: 8.95 (s, 1 H), 6.43 (C5, s, 1 H), 3.87 (s, 6H).

EXAMPLE 44 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 593 (M + + 1), 611 (M + + 18); 1 H-NMR (CDCl 3), d: 7.08 (C8, s, 1 H), 1.31-1, 22 (m, 6H).

EXAMPLE 45 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -butoxycarbonyl-aminol-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 621 (M + + 1); 1 H-NMR (CDCl 3), d: 6.38 (C5, s, 1H), 3.84 (s, 3H).

EXAMPLE 46 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -hexyloxycarbonyl-amino-1-7,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline -1- carboxylic S, m / z: 649 (M + + 1), 666 (M + + 18); 1 H-NMR (CDCl 3), d: 6.38 (C5, s, 1 H),, 84 (s, 3H).

EXAMPLE 47 cis-4-r.3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-amino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester , m / z: 549 (M + + 1), 566 (M + + 18); 1 H-NMR (CDCl 3), d: 6.50 (C5, s, 1 H),, 14 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 48 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester S, m / z: 566 (M + + 1); 1 H-NMR (CDCl 3), d: 7.76-7.64 (m, 3H), 3.78 (s, 6H).

EXAMPLE 49 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic S, m / z 641 (M + + 1), 658 (M + + 18); 1 H-NMR (CDCl 3), d: 6.38 (s, 1 H), 7.0 (s, H), 7.7 (s, 2 H), 7.8 (s, 1 H).

EXAMPLE 50 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-5,7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, m / z: 579 (M + + 1), 597 (M + + 18); 1 H-NMR (CDCl 3), d: 7.63 (s, 1 H), 3.78 (s, H).

EXAMPLE 51 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -isopropoxycarbonyl-amino-1-7.7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, m / z: 607 (M + + 1), 624 (M + + 18); 1 H-NMR (CDCl 3), d: 6.41 (s, 1 H), 3.86 (s, H9, 3.79 (s, 3H).

EXAMPLE 52 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -propoxycarbonyl-amino-6,7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 606 (M +), 624 (M + + 18); 1 H-NMR (CDCl 3), d: 6.39 (C5, s, 1 H), 3.86 (s, 3H).

EXAMPLE 53 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -tert-butoxycarbonyl-amino-1-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 ethyl ester - MS carboxylic, m / z: 639 (M + + 19); 1 H-NMR (CDCl 3), d: 6.47 (C5, s, 1 H9, 3.86-3.79 (m, 6H).

EXAMPLE 54 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -sopropoxycarbonyl-aminol-6,7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 ethyl ester - carboxylic MS, m / z: 622 (M + + 1), 639 (M + + 19); 1 H-NMR (CDCl 3), d: 6.40 (C5, s, 1 H), 3.88 (s, 3 H), 3.79 (s, 3 H).

EXAMPLE 55 Propyl Ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -propoxycarbonyl-amino-1-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid S, m / z: 621 (M + + 1), 639 (M + + 19); 1 H-NMR (CDCl 3), d: 7.08 (C8, s, 1 H),, 40 (C5, s, 1 H), 1.18 (C2-Me, d, 3H).

EXAMPLE 56 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester m / z: 593 (M + + 1), 611 (M + + 19); 1 H-NMR (CDCl 3), d: 7.08 (C8, s, 1H),, 38 (C5, s, 1 H), 1.17 (C2-Me, d, 3H).

EXAMPLE 57 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino-1-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester S, m / z: 525 (M +), 542 (M + + 17); 1 H-NMR (CDCl 3), d: 6.34 (s, 1 H), 3.81 (s, H), 3.80 (s, 3H).

EXAMPLE 58 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -propoxycarbonyl-amino-1-7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester S, m / z: 533 (M + + 1), 550 (M + + 18); 1 H-NMR (CDCl 3), d: 6.38 (C5, s, 1 H),, 86 (s, 2H), 3.80 (s, 3H).

EXAMPLE 59 cis-4-r (3,5-chloro-5-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 545 (M + + 1), 562 (M + + 18); 1 H-NMR (CDCl 3), d: 6.26 (s, 1 H), 3.84 (s, 3H).

EXAMPLE 60 Cis-4-retoxycarbonyl- (3-fluoro-5-trifluoromethyl-benzyl-amino-6,7-d-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1) ethyl ester - MS carboxylic, m / z: 543 (M + + 1), 560 (M + + 18); 1 H-NMR (CDCl 3), d: 6.38 (C5, s, 1 H), 1.17 (C2-Me , d, 3H, J = 6.2 Hz).

EXAMPLE 61 cis-4-r (3-fluoro-5-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 529 (M + + 1), 546 (M + + 18); 1 H-NMR (CDCl 3), d: 6.38 (C5, s, 1 H), 1.17 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 62 Cis-4-r (3,5-dimethyl-benzyl-methoxycarbonyl-aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 1H-NMR (CDCl 3) ethyl ester , d: 1, 2 (d, 3H), 2.3 (s, 6H), 3.7 (s, 6H), 3.8 (s, 3H), 6.4 (s, 1H), 6 , 8 (s, 3H), 7.1 (s, 1 H).

EXAMPLE 63 cis-4-f (3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-amino-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, / z: 602 (M +); 1 H-NMR (CDCl 3), d: 3.8 (s, 3 H), 6.75 (s, 1 H).

EXAMPLE 64 cis-4-r (3,5-bis-trifluoromethyl-benzyl) .- (2-dimethylamino-ethoxycarbonyl) -amino-1-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline -1-carboxylic MS, m / z: 636 (M + + 1); 1 H-NMR (CDCl 3), d: 7.07 (C8, s, 1 H), 6.41 (C5, s, 1 H), 3.86 (s, 3H); 3.80 (s, 3H).

EXAMPLE 65 Trans-4-rf3.5-bis-trifluoromethyl-benzyl-methoxycarbonyl-aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 597 (M + + 18); 1 H-NMR (CDCl 3), d: 7.66 (s, 1 H), 3.83 (s, 6H).

EXAMPLE 66 cis-benzyl- (6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid ethyl ester A solution of cis-4-benzyl ester was added (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (Example 4: 1.0 g, 1.9 mmol in ethanol (20 ml) in a Parr bottle, it was loaded with 10% paladin on carbon (10mg), and the mixture was stirred for 2 h under hydrogen gas at a pressure of 344.7 kPa, in a Parr shaker. The mixture was then filtered through a Celite® bed, elution being carried out with ethyl acetate, and the filtration product was concentrated in vacuo, the residue was purified by chromatography on silica gel using 30% ethyl acetate / hexanes as eluent, obtain 660 mg of the desired final product (89%) MS, m / z: 204 (M + - PhCH2NHCO2Et-H2 + 1); 1H-NMR (CDCl3), d: 1.12 (d, 3H), 1.17 (t, 3H), 3.65 (s, 3H), 3.8 (s, 3H), 6, 10 (C5, s, 1 H), 6.44 (C8, s, 1 H), 7.1-7.3 (m, 5H).

EXAMPLE 67 Cs- (3,5-bis-trifluoromethyl-benzyl) - (6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid methyl ester prepared in a manner analogous to that of Example 66 using the cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3 benzyl ester, 4-dihydro-2H-quinoline-1-carboxylic acid (Example 49). MS, m / z: 507 (M + + 1); 1 H-NMR (CDCl 3), d: 6.1 (s, 1 H), 6.3-6.4 (m, 1 H), 7.5-7.6 (m 2 H), 7.7 (s) , 1 HOUR).

EXAMPLE 68 cis-4- (benzyl-ethoxycarbonyl-amino) -6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-na-1-carboxylic acid methyl ester A solution of the cis-benzyl acid ethyl ester (6,7-dimethoxy-2-methyl, 1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid (Example 66, 111 mg, 0.29 mmol) in anhydrous dichloromethane (2 ml) was treated successively with anhydrous pyridine (1 ml) and methyl chloroformate (38 μl, 0.49 mmol). After stirring at room temperature overnight, water (10 ml) and an aqueous solution of 10% KOH (10 ml) were added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic phases were washed with 1 N HCl (2 x 10 ml) and then with a saturated solution (10 ml) of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain 112 mg of crude product. Purification by chromatography on silica gel using 0-50% ethyl acetate / hexanes as eluent provided the desired final product (12.6 mg, 10%). MS, m / z: 443 (M + + 1), 460 (M + + 18); 1 H-NMR (CDCl 3), d: 7.02 (C8, s, 1 H), 6.42 (C5, s, 1 H). Examples 69-106 were prepared from the cis-benzyl- (6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ethyl ester (Example 66) according to analogous procedure to those of Example 68, using the appropriate starting materials.

EXAMPLE 69 cis-4-benzyl-ethoxycarbonyl-amino-6-J-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester EXAMPLE 70 cis- (1-Acetyl-6,7-dimethoxy-2-methyl-1,2,4-tetrahydro-quinoline-4-yl-benzyl-carbamic acid ethyl ester MS, m / z: 428 (M + + 2), 445 (M + + 19), 1 H-NMR (CDCl 3), d: 6.88 (C8, s, 1H), 6.51 (C5, s, 1 H).

EXAMPLE 71 Cis-benzyl- (1-methanesulfonyl-6-J-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl-benzyl-carbamic acid MS, m / z: 463 (M + + 1), 480 (M + + 18); 1 H-NMR (CDCl 3), d: 6.10 (C5, s, 1H),, 73 (N1, s, 3H).

EXAMPLE 72 cis-benzyl- (1-ethylcarbamoyl-6J-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl) -benzyl-carbamic acid ethyl ester MS, m / z: 456 (M + + 1), 473 (M + + 18); 1 H-NMR (CDCl 3), d: 6.81 (C8, s, 1 H), 6.48 (C5, s, 1 H).

EXAMPLE 73 Cis-4- (benzyl-1-ethoxycarbonyl-amine) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS, m / z: 485 (M + + 1), 502 (M + + 18); 1 H-NMR (CDCl 3), d: 7.04 (C8, s, 1 H), 6.43 (C5, s, 1 H). EXAMPLE 74 cis-Benzyl-1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl) -benzyl-carbamic acid ethyl ester MS, m / z 455 (M + + 1), 472 (M + + 18); 1 H-NMR (CDCl 3), d: 6.67 (C8, s, 1 H), 6.48 (C5, s, 1 H).

EXAMPLE 75 cis-4-benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H 2,2,2-trichloro-1,1-dimethyl-ethyl ester -carboxylic-quinoline MS, m / z: 588 (M + + 1), 606 (M + + 19); 1 H-NMR (CDCl 3), d: 7.11 (C8, s, 1 H), 6.43 (C5, s, 1 H).

EXAMPLE 76 cis-4- (benzyl-ethoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carbothioic acid s-methyl ester MS, m / z: 459 (M + + 1), 467 (M + + 18); 280 (M + -178); 1 H-NMR (CDCl 3), d: 7.06 (C8, s, 1 H), 6.48 (C5, s, 1 H), 2.29 (NI, s, 3H).

EXAMPLE 77 Cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid hexyl ester MS, m / z: 512 (M +), 530 (M + + 18); 1 H-NMR (CDCl 3), d: 7.04 (C8, s, 1 H), 6.42 (C5, s, 1H).

EXAMPLE 78 2-Chloro-ethyl ester of cis-4-benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihicro-2H-quinoline-1-carboxylic acid MS, m / z: 490 (M +), 508 (M + 18); 312 (M-178) 1; H-NMR (CDCl 3), d: 7.09 (C8, s, 1 H), 6.44 (C5, s, 1 H).

EXAMPLE 79 Phenyl ester of cis-4- (benzyl-ethoxycarbonyl-amino) -6-J-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 504 (M +), 522 (M + + 18), 1 H-NMR (CDCl 3), d: 6.49 (C5, s, 1 H), 3.85 (C6 / 7, s, 3H), 2.29 (C6 / 7, s, 3H) ..

EXAMPLE 80 Ester of cis-4-benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 471 (M + + 1), 488 (M + + 18); 1 H-NMR (CDCl 3), d: 7.07 (C8, s, 1 H), 6.43 (C5, s, 1 H), 3.86 (C6 / 7, s, 3 H), 3.79 ( C6 / 7, s, 3H).

EXAMPLE 81 cis-4- (benzyl-ethoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isobutyl ester MS, m / z: 485 (M + + 1), 502 (M + + 18); 1 H-NMR (CDCl 3), d: 7.04 (C8, s, 1 H), 6.42 (C5, s, 1 H), 3.86 (C6 / 7, s, 3 H), 3.80 (C6 / 7, s, 3H).

EXAMPLE 82 Cis-benyl (1-isobutyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl-carbamic acid MS, m / z: 471 (M + +) ethyl ester 1), 472 (M + + 18), 1 H-NMR (CDCl 3), d: 6.65 (C8, s, 1 H), 6.48 (C5, s, 1 H), 1.19 (Nl-iPr) .d, 6H).

EXAMPLE 83 Ethyl ester of cis-benzyl- (6,7-dimethoxy-2-methyl-1-methylcarbamoyl-1,2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid MS, m / z: 442 (M + + 1), 459 (M + + 18) 1 H-NMR (CDCl 3) d, d: 6.81 (C8, s, IH), 6, 4 9 (C5, s, 1 H), 2.77 (NI, s, 3H).

EXAMPLE 84 cis-benzyl-r6,7-dimethoxy-2-methyl-1 (3-phenylpropionyl) -1,2,3,4-tetrahydro-quinoline-4-in-carbamic acid ethyl ester MS, m / z: 517 (M + + 1); H-NMR (CDCl 3), d: 3.76 (C6 / 7, s, 3H), 3.75 (C6 / 7, s, 3H). EXAMPLE 85 cis-benzyl- (6,7-dimethoxy-2-methyl-1-propionyl-1,2,3,4-tetrahydro-quinoline-4-yl) carbamic acid ethyl ester MS, m / z. 441 (M1 + 1), 458 (M + + 18); 1 H-NMR (CDCl 3), d: 6.69 (C8, s, IH), 6.50 (C5, s, IH), 3.84 (C6 / 7, s, 3H), 3.79 (C6 / 7, s, 3H).

EXAMPLE 86 cis-benzyl- (6,7-dimethoxy-2-methyl-1-trifluoromethanesulfonyl-1,2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ethyl ester MS, m / z: 518 (M + + 2); H-NMR (CDCl 3, d: 3, 86 (C6 / 7, s, 3H), 3.68 (C6 / 7, s, 3H).

EXAMPLE 87 cis-benzyl-n- (2,2-dimethyl-propionyl) -6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-in-carbamic acid ethyl ester MS , m / z. 469 (M + + 1), 486 (M + + 18), 1 H-NMR (CDCl 3), d: 6, 73 (C8, s, IH), 6, 47 (C5, s, IH), 3, 8 5 ( C6 / 7, s, 3H), 3.79 (C6 / 7, s, 3H), 1, 10 (NI, s, 9H).

EXAMPLE 88 cis-benzyl-1-formyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid ethyl ester. MS, m / z: 413 (M + + 1), 430 (M + + 18); 1 H-NMR (CDCl 3), d: 8, 44 (NI, s, 1 H), 6.62 (C8, s, IH), 6.49 (C5, s, IH), 3.88 (C6 / 7 , s, 3H), 3.67 (C6 / 7, s, 3H).

EXAMPLE 89 cis-benzyl- (6,7-dimethoxy-2-methyl-l-trifluoroacetyl-1,2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ethyl ester MS, m / z: 481 (M + + 1), 499 (M + + 19), 1 H-NMR (CDCl 3), d: 6.81 (C8, s, IH), 6, 49 (C5, s, IH), 3.85 (C6 / 7, s, 3H), 3, 78 (C6 / 7, s, 3H).

EXAMPLE 90 cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester MS, m / z: 471 ( M + + 1), 439 (M + + 19); 1 H-NMR (CDCl 3), d: 7, 06 (C8, s, IH), 6, 42 (C5, s, 1 H), 3.86 (C6 / 7, s, 3H), 3.79 (C6 / 7, s, 3H).

EXAMPLE 91 cis-4- (benzyl-ethoxycarbonyl-amino) -6 acid 2,2,2-trichloro-ethyl ester. 7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z. 576 (M + + 17), 578 (M + + 19); 1 H-NMR (CDCl 3), d: 7, 10 (C8, s, IH), 6.45 (C5, s, IH), 3.88 (C6 / 7, s, 3H), 3.79 (C6 / 7, s, 3H).

EXAMPLE 92 cis-benzyl-6,6-dimethoxy-2-methyl-l-2,2,2-trifluoro-ethanesulfonyl) -1,2,3,4-tetrahydroquinoline-4-ethyl ester iD-carbamic MS, m / z: 531 (M + + 1), 548 (M + + 18); 1 H-NMR (CDCl 3), d: 6.45 (C5, s, IH), 3.87 (C6 or C7, s, 3H), 3.78 (C6 or C7, s, 3H).

EXAMPLE 93 cis-4-benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 2-bromo-ethyl ester MS, m / z . 536 (M + + 1), 554 (M + + 19); 1 H-NMR (CDCl 3), d: 7, 11 (C8, s, 1 H), 6.45 (C5, s, IH).

EXAMPLE 94 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-2,6-dimethoxy-2-methyl-3,4-dihydro-2H-quinole 2,2,2-trichloro-ethyl ester .na-l-carboxylic MS, m / z: 700 (M + + 19); 1 H-NMR (CDCl 3), d: 7, 12 (C8, s, IH) 6.41 (C5, s, IH), 1.23 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 95 Isobutyl ester of cis-4-IY3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 6 0 7 (M + + 1), 625 (M + + 19); 1H-NMR (CDCl 3), d: 7, 09 (C8, s, IH), 6, 39 (C5, s, IH), 1, 18 (C2-Me, d, 3H, J = 6, 1 Hz ), 0.94 (iPr, d, 6H, J = 6, 6 Hz).

EXAMPLE 96 cis-4-r isopropyl ester (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 carboxylic MS, m / z: 593 (M + + 1), 611 (M + + 19); 1H-NMR (CDC 13), d: 7.1 0 (C8, s, IH), 6.3, 8 (C5, s, IH), 1.17 (C2-Me, d, 3H, J = 6, 1 Hz).

EXAMPLE 97 cis-4-3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid butyl ester MS, m / z: 607 (M + + 1), 624 (M + + 18); 1 H-NMR (CDCl 3), d: 7, 08 (C8, s, IH), 6, 39 (C5, s, IH), 1.17 (C2-Me, d, 3H, J = 6, 2 Hz) .

EXAMPLE 98 cis-4- \ (3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2-chloro-ethyl ester) 2 H-auinolein-1-carboxylic MS, m / z: 630 (M + + 17); 1 H-NMR (CDCl 3), d: 7.12 (C8, s, IH), 6.40 (C5, s, IH) , 1, 20 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 99 cis-4-r (3,5-bis-trifluoromethyl-benzD-methoxycarbonyl-amino-1-7,7-dimethoxy-2-methyl-3,4-dihydro) -2H-quinoline-2-bromoethyl ester l-carboxylic MS, m / z: 676 (M + + 19); 1 H-NMR (CDCl 3), d: 7.14 (C8, s, IH), 6.40 (C5, s, IH), 1.20 (C2-Me, d, 3H, J = 6.2 Hz) .

EXAMPLE 100 cis-4- (3,5-bis-trif luoromethyl-benzyl) -methoxycarbonyl-amino] -6-2,2-trichloro-l.l-dimethyl-ethyl ester. 2-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 727 (M + + 18); 1 H-NMR (CDCl 3), d: 7, 14 (C8, s, 1 H), 6.40 (C5, s, IH), 1.20 (C2-Me, d, 3H, J = 6.2 Hz ).

EXAMPLE 101 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline / l-carboxylic acid tert-butyl ester MS, m / z. 6 0 7 (M + + 1), 625 (M + + 19); 1H-NMR (CDCl 3), d: 7, 08 (C 8, s, IH), 6, 39 (C5, s, IH), 1, 15 (C2-Me, d, 3H, J = 6, 1 Hz ).

EXAMPLE 102 Cyclopentyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 637 (M + + 19); 1 H-NMR (CDCl 3), d: 7, 08 (C8, s, IH) 6.38 (C5, s, 1 H), 1.16 (C2-Me, d, 3H, J = 6.2 Hz) .

EXAMPLE 103 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid methyl ester MS, m / z: 565 (M + + 1), 582 (M + + 18); ? -NMR (CDCI3), d: 7, 06 (C8, s, 1 H), 6.39 (C5, s, IH), 1, 17 (C2-Me, d, 3H, J = 6.2 Hz ).

EXAMPLE 104 cis- (3,5-bis-trifluoromethyl-ben-cip-p- (2,2-dimethyl-propionip-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-) methyl ester Incarnate MS, m / z. 592 (M + + 2), 609 (M + + 19); ? -NMR (CDCI3), d: 6, 78 (C8, S, IH), 6.47 (C5, s, 1H), 1.00 (C2-Me, d, 3H, J = 6.5 Hz) .

EXAMPLE 105 Cis- (3,5-bis-trifluoromethyl-benzyl) - (6,7-dimethoxy-2-methyl-tr-fluoroacetyl-1,2,3,4-tetrahydro-quinoline-4-yl) methyl ester ) -carbámico MS, m / z. 602 (M +), 620 (M + + 18); ? -NMR (CDCI3), d: 6.85 (C8, s, IH), 6.48 (C5, s, IH), 1, 14 (C2-Me, d, 3H, J = 6.4 Hz) .

EXAMPLE 106 cis- (3,5-Bis-trifluoromethyl-benzyl) - (1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid methyl ester MS , m / z: 577 (M + + 1); 1 H-NMR (CDCl 3), d: 6, 72 (C8, s, 1 H), 6.47 (C6, s, 1 H), 1.08 (C2-Me, d, 3H, J = 6.3 Hz).

EXAMPLE 107A cis-benzyl-1-chlorocarbonyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ethyl ester. Phosgene (1.0 ml of a solution) was added. 1.93 M in toluene) to a solution of cis-benzyl- (6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ethyl ester (Example 66; 103 mg, 0.268 mmol) in toluene (2.5 ml) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo to obtain the desired carbamoyl chloride (110 mg, 92%).

EXAMPLE 107B cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3 2,2,2-trifluoro-ethyl ester. 4-dihydro-2H-quinoline-1-carboxylic acid A solution of the ethyl ester of benzyl- (1-chloro) -carbonyl-6,7-dimethoxy-2-methyl-1 was stirred at room temperature overnight. 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid (Example 107 A, 24 mg, 0.054 mmol), 2,2,2-trifluoroethanol (0.10 mL, 1.4 mmol) and hydride sodium (56 mg, 60% dispersion in mineral oil, 1.4 millimoles) in anhydrous dioxane (1 ml). The reaction mixture was quenched with 1 ml of water and extracted with ethyl acetate (3 x 15 ml). The combined organic phases were washed with 10 ml of brine, dried over sodium sulphate, filtered and concentrated in vacuo to obtain 43 mg of an oil. Purification by chromatography on silica gel using 0-50% ethyl acetate / hexanes as eluent provided the desired final product (15 mg, 58%). MS, m / z. -510 (M +), 528 (M + + 18); ? -NMR (CDC13), d: 6, 99 (C8, s, IH), 6, 44 (C5, s, 1 H).

EXAMPLES 108A and 108B cis-benzyl-1-dimethylcarbamoyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ethyl ester, and ester Ethyl of cis-benzyl-r6,7-dimethoxy-2-methyl-l- (5-oxo-penta-1,3-dienylcarbamoyl) -1, 2,3,4-tetrahydro-quir? olein-4-in-carbamic acid A solution of the cis-4-benzyl- (1-chlorocarbonyl-6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline) ethyl ester was stirred at room temperature overnight. lein-4-yl) -carbamic acid (Example 107A, 38 mg, 0.085 mmol), pyridine (0.5 ml) and dimethylamine hydrochloride (12 mg, 0.14 mmol) in anhydrous dichloromethane (1 ml). Then 10 ml of water and 10 ml of 2 N KOH were added, which was followed by extraction with ethyl acetate (3 x 10 ml). The combined organic phases were washed with 1N HC1 (2 x 10 ml), 10 ml of a saturated solution of sodium bicarbonate, and 10 ml of brine. The combined washed organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 0-75 L ethyl acetate / hexanes as eluent afforded cis-benzyl- (1-dimethylcarbamoyl-G, 7-dimethoxy-2-methyl-1, 2, ethyl ester, 3,4-tetrahydro-quino-lein-4-yl) -carbamic acid (Example 108A; 10 mg, 24%), MS, m / z: 455 (M +), 277 (M + -178); ? -NMR (CDC13), d: 3.79 (C6 / 7, s, 3H), 3.70 (C6 / 7, s, 3H), 2.79 (NI, s, 6H); and the cis-benzyl- [6,7-dimethoxy-2-methyl-1- (5-oxo-penta-1,3-dylcarbamoyl) -1,2,3,4-ethyl ester. -tetrahydro-quinoline-4-yl] -carbamic acid (Example 108B, 7 mg, 15%), MS, m / z: 508 (M + + 1), 329 (M + -178); ? -NMR (CDCl3), d: 9.46 (aldehyde, d, IH), 3.85 (C6 / 7, s, 3H), 3.79 (C6 / 7, s, 3H).

EXAMPLE 109 cis-benzyl-r6,7-dimethoxy-2-methyl-l-morpholine-4-carbonyl) -1, 2,3,4-tetrahydro-quinoline-4-yl-carbamic acid ethyl ester prepared from the cis-benzyl- (1-chlorocarbonyl-6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid ethyl ester (Example 107A) and morpholine by a procedure analogous to that of Example 108. MS, m / z: 497 (M +), 319 (M + -178); ? -NMR (CDC13), d: 3.82 (C6 / 7, s, 3H), 3.72 (C6 / 7, s, 3H). Examples 110-120 were prepared from the ethyl ester of cis-benzyl- (1-chlorocarbonyl-6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydroquinoline-4-yl). ) -carbamic (Example 107A) and the appropriate alcohol according to procedures analogous to those of Example 107B.

EXAMPLE 110 cis-4- (benzyl-ethoxycarbonyl-amino) -6-2-methoxy-ethyl ester. 7-dimethoxy-2-methyl-3. 4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z. 488 (M + 1 + 2), SOS (M + + 19); ? -NMR (CDCI3), d: 7, 10 (C8, s, IH), 6, 41 (C5, s, 1 H), 3, 8 7 (C6 / 7, s, 3H), 3, 79 ( C6 / 7, s, 3H), 3.37 (N1-OMe, s, 3H).

EXAMPLE 111 Penic acid ester) cis-4- (benzyl-ethoxycarbonyl-amine) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-l-carboxylic acid MS, m / z- 500 (M + + 2), 517 (M + + 19); ? -NMR (CDC13), d: 7.05 (C8, s, IH), 6, 42 (C5, s, IH), 3.85 (C6 / 7, s, 3H), 3.79 (C6 / 7, s, 3H).

EXAMPLE 112 cis-4- (benzyl-ethoxy-carbonyl-amino) -6,7-dimethoxy-2-methyl-3 2,2-dimethyl-propyl ester. 4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 500 (M + +2), 517 (M + + 19), 1H-NMR (CDC13), d: 7, 06 (C8, s, 1 H ), 6.42 (C5, s, 1 H), 0.93 (N1-tBu, s, 9H).

EXAMPLE 113 cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid cyclopentyl ester MS, m / z. 497 (M + + 1) 514 (M + + 18); 1H-NMR (CDC13), d: 7, 06 (C8, s, IH), 6, 41 (C5, s, IH) EXAMPLE 114 cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-l-carboxylic acid but-2-enyl ester MS, m / z : 483 (M + + I), 500 (M + + 18); ? -NMR (CDC1, 3), d: 7.02 (C8, s, IH), 6, 41 (C5, s, IH).

EXAMPLE 115 Cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-l-carboxylic acid allyl ester MS, m / z: 469 ( M + + I), 486 (M + + 18); ? -NMR (CDC13), d: 7.05 (C8, s, IH), 6, 43 (C5, s, IH).

EXAMPLE 116 cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-l-carboxylic acid 2-methylallyl ester MS, m / z: 483 (M + + 1), 500 (M + + 18); 1H-NMR (CDC13), d: 7, 06 (C8, s, IH), 6, 4 3 (C5, s, IH), 1, 7 6 (NI-Me, s, and 3H).

EXAMPLE 117 cis-4-benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid thiophene-2-methyl ester MS, m / z: 525 (M + + 1), 542 (M + + 18); 1 H-NMR (CDC13), d: 6, 42 (C5, s, 1H), 1.15 (C2-Me, d, 3H).

EXAMPLE 118 Thiofen-3-ylmethyl ester of cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 525 (M + + 1), 542 (M + + 18); ? -NMR (CDC13), d: 6, 96 (C8, s, IH), 6.43 (C5, s, IH).

EXAMPLE 119 cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid furan-2-ylmethyl ester MS , m / z. 509 (M + + 1), 526 (M + + 18); ? -NMR (CDC3), d: 6, 98 (C8, s, 1H), 1, 15 (C2-Me, d, 3H).

EXAMPLE 120 cis-4- (benzyl-ethoxycarbonyl-amino) -6,7-dimetho-i-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid furan-3-ylmethyl ester MS, m / z: 509 (M + + 1), 526 (M + + 18); ? -NMR (CDC13), d: 6, 96 (8 s, IH), 6.41 (C5, s, 1H).

Examples 121-124 were prepared from the cis- (3-methyl ester, 5-bis-trifluoromethyl-benzyl) - - (6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid (Example 67) using the appropriate starting materials , according to procedures analogous to those of the sequence of Examples 107A and 107B. EXAMPLE 121 cis-4-r (3,5-bis-tri-fluoromethyl-benzyl) -methoxycarbonyl-amino-1-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-acid ester 2,2-dimethyl-propyl ester quinoline-l-carboxylic MS, m / z: 621 (M + + 1), 639 (M + + 19); 1H-NMR (CDC13), d: 7, 10 (C 8, s, 1 H), 6, 3 9 (C5, s, IH), 1, 1 9 (C2 - Me, d, 3H, J = 6 , 2 Hz).

EXAMPLE 122 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 acid ester 2,2,2-trifluoro-ethyl ester -carboxylic MS, m / z: 632 (M +), 651 (M + + 19); 1 H-NMR (CDC3), d: 7.00 (C8, s, 1 H), 6.40 (C5, s, 1 H), 1.20 (C2-Me, d, 3H, J = 6, 3 Hz).

EXAMPLE 123 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6.7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline ester, l-ethyl-propyl ester -l-carboxylic MS, m / z: 622 (M + + 2), 639 (M '+ 1 9),? - NMR (CDCl 3), d: 7.10 (08, s, IH), 6.39 (C5, s, IH). EXAMPLE 124 cis-4-rf3.5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6.7-dimethoxy-2-methylene-3,4-dihydro-2H3,3-dimethyl-butyl ester -Kinolein-1-carboxylic MS, m / z: 636 (M + + 2), 653 (M + + 19); 1 H-NMR (CDC3), d: 7, 08 (C8, s, IH), 6.37 (C5, s, IH), 1.16 (C2-Me, d, 3H).

EXAMPLE 125 cis- (3,5-bis-trifluoromethyl-benzyl) - (1-butyl-6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) methyl ester - At room temperature, overnight, a solution of cis- (3,5-bis-trifluoromethyl-benzyl) - (6,7-dimethoxy-2-methyl-1, 2,3-methyl ester was stirred at room temperature overnight. , 4-tetrahydroquinoline-4-yl) -carbamic acid (Example 67, 34 mg, 0.067 mmol), acetic acid (4 μl, 0.067 mmol), butyraldehyde (17 μl, 0.34 mmol) and sodium triacetoxybororhydride ( 71 μl, 0.34 mmol) in anhydrous dichloroethane (1 ml). Water (5 ml) was added, the aqueous phase was made alkaline with potassium carbonate and the extraction mixture was subjected to ethyl acetate (3 x 10 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 0-15% ethyl acetate / hexanes as eluent gave 32 mg of the title compound (82%). MS, m / z: 563 (M + + 1) 1 H-NMR (CDCl.), D: 6.31 (08, s, IH), 3.64 (CO2Me, s, 3H), 1.20 (C2-) Me, d, 3H, J = 6.3 Hz). The hydrochloride salt was prepared by treating an ether solution of the free base with an ethereal solution of HC1. Hydrochloride salt: 1 H-NMR (CDC13), d: 3.83 (CO2 Me, s, 3H), 1.20 (C2-Me, d, 3H, J = 6.4 Hz). Examples 126-142 were prepared from cis- (3,5-bis-trifluoromethyl-benzyl) - (6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinolein) methyl ester. -4-yl) -carbamic acid (Example 67) using a procedure analogous to that of Example 125, with the appropriate carboxaldehyde.

EXAMPLE 126 cis- (3,5-bis-trifluoromethyl-benzyl) - (1-ethyl-6,7-d-methoxy-2-methyl-1,2,3,4-tetrahydro-quinolein-4-methyl ester) -l) -carbamic MS, m / z: 535 (M + + 1); H-NMR (CDC3), d: 3, 64 (CO2Me, s, 3H) 1, 21 (C2-Me, d, 3H, J = 6.3 Hz).

EXAMPLE 127 cis- (3,5-bis-trifluoromethyl-benzyl- (6,7-dimethoxy-2-methyl-1-propyl-1,2,3,4-tetrahydro-quinolin-4-yl) methyl ester hydrochloride -carbamic MS, m / z: 549 (M + + 1); 1 H-NMR (CDCl 3), d: 6, 28 (C 8, s, IH) 3, 64 (CO Me, s, 3 H), 1, 20 (C 2 -Me, d, 3 H, J = 6, 3 Hz) .

EXAMPLE 128 cis- (3,5-bis-trifluoromethyl-benzyl- (6,7-dimethoxy-2-methyl-1-dentyl-1,2,3,4-tetrahydro-quinoline-4-) methyl ester hydrochloride il) -carbamic MS, m / z: 577 (M + + 1) 1 H-NMR (CDCl 3), d: 6.30 (08, s, IH) 3, 64 (CO Me, s, 3H), 1, 20 (C2-Me , d, 3H, J = 6, 3 Hz) EXAMPLE 129 cis- (3,5-bis-trifluoromethyl-benzyl-hexyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) methyl ester hydrochloride -carbamic MS, m / z: 591 (M + + 1),? -NMR (CDC3), d: 6.30 (08, s, IH) 3, 64 (CO Me, s, 3H), 1, 20 ( C2 -Me, d, 3H, J = 6, 3 Hz) EXAMPLE 130 cis- (3,5-bis-tri-fluoromethyl-benzyl- (6,7-dimethoxy-2-methyl-1-phenethyl-1,2) 3,4-tetrahydroquinoline hydrochloride. 4-yl) -carbamic MS, m / z: 611 (M + + 1), 1 H-NMR (CDC13), d: 6, 39 (08, s, IH), 3.66 (CO Me, s, 3H) , 1, 27 (C2 -Me, d, 3H, J = 6, 2 Hz) EXAMPLE 131 Metallic hydrochloride of cis- (3,5-bis-trifluoromethyl) -benzyl-F6.7-dimethoxy-2-methyl-1- (3-phenyl-propip-1.2.3.4-tetrahydro- quinoline-4-ill-carbonate MS, m / z: 625 (M + + 1); H-NMR (CDC3), d: 6.06 (08, s, IH), 1.17 (C2-Me, d, 3H, J 6.2 Hz).

EXAMPLE 132 cis- (1-benzyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolein-4-yl) - (3,5-bis) methyl ester hydrochloride -trifluoromethyl-benzyl) -carbamic MS, m / z :. 597 (M + '+ 1), 1 H-NMR (CDC13), d :. 6, 15 (08, s, IH), 1, 18 (02-Me, d, 3H, J 6.3 Hz).

EXAMPLE 133 cis- (3,5-bis-tri-fluoromethyl-benzyl- (l-isobutyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-methyl ester hydrochloride il) -carbamic MS, m / z: 563 (M + + 1);? -NMR (CDC13), d: 6.28 (08, s, 1 H) 3, 8 3 (CO.Me, s, 3H) , 1, 19 (02 -Me, d, 3H, J = 6, 3 Hz) EXAMPLE 134 Cis- (3,5-bis-tri-fluoromethyl-benzyl) -r 6,7-dimethoxy-2-methyl-1- (3-methyl-butyl) -1,2,3,4-tetrahydro acid methyl hydrochloride -quinoline-4-in-carbamic MS, m / z: 577 (M + + 1), 1 H-NMR (CDCl 3), d: 3, 64 (C02Me, s, 3H), 1.20 (C2-Me, d , 3H, J = 6.3 Hz), 0.95 (iPr, d, 6H, J = 6.6 Hz).

EXAMPLE 135 cis- (3,5-bis-tri-fluoromethyl-benzin-ri- (3,3-dimethyl-butyn-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline) methyl ester hydrochloride 4-in-carbamic MS, m / z: 591 (M + + I); 1 H-NMR (CDCl 3), d: 3.63 (CO "Me, s, 3H), 0.98 (tBu, d, 9H ) EXAMPLE 136 cis- (3,5-bis- -trifluoromethyl-benzyl) - (l-but-2-enyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl) methyl ester hydrochloride. ) -carbamic MS, m / z: 561 (M + 1); 1H-NMR (CDCl 3), d: 3, 64 (CO2Me, s, 3H), 1, 18 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 137 Cis- (3,5-bis-trifluoromethyl-benzyl) - (1-cyclopropylmethyl-6,7-dimethoxy-2-methyl-1,2,5,4-tetrahydroquinoline) methyl ester hydrochloride -il) -carbamic MS, m / z: 561 (M + + 1); 1H-NMR (CDC13), d: 6, 50 (08, s, 1 H), 3.64 (CO2 Me, s, 3H) EXAMPLE 138 cis- (3,5-bis-trifluoromethyl-benzyl) -N- (2-ethyl-butyl) -6-J-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline- methyl ester hydrochloride 4-n-carbamic MS, m / z: 591 (M + + 1); 1 H-NMR (CDC13), d: 3.63 (C02Me, s, 3H, 1, 16 (02-Me, d, 3H, J = 6, 2 Hz).

EXAMPLE 139 cis- (3,5-bis-trifluoromethyl-benzyl) - (6,7-dimethoxy-2-methyl-1-thiophen-3-ylmethyl-1,2,3,4-tetrahydro-quinoline-4-methyl ester hydrochloride -il) -carbamic MS, m / z: 603 (M + + 1); 1 H-NMR (CDC13), d: 6.29 (C8, s, 1 H), 1.22 (C2-Me, d, 3H) EXAMPLE 140 cis- (3,5-bis) methyl ester hydrochloride -trifluoromethyl-benzyl) -r6.7-dimethoxy-2-methyl-1- (4,4,4-trifluoro-butyl) -1,2,3,4-tetrahydro-quinoline-4-yl-carbamic MS, m / z: 617 (M + + 1); 1H-NMR (CDC13), d: 3.65 (CO2Me, s, 3H), I, 21 (02-Me, d, 3H, J = 6.0 Hz) EXAMPLE 141 cis- (3,5-bis-trifluoromethyl-benzyl) -6,6,7-dimethoxy-2-methyl-1- (2-methyl-butyl) -1,2,3-methyl ester hydrochloride 4-tetrahydro-quinoline-4-yl -carbamic MS, m / z: 577 (M + + 1); ? -NMR (CDC13), d: 3, 64 (CO2Me, s, 3H), 1, 18 (02-Me, d, 3H, J = 6, 2 Hz).

EXAMPLE 142 cis- (3,5-Bis-trifluoromethyl-benzyl- (l-cyclohexylmethyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4-methyl ester hydrochloride i0-carbamic MS, m / z: 603 (M + + 1); 1 H-NMR (CDC13), d: 3.64 (CO2Me, s, 3H), 1, 1 9 (02 -Me, d, 3H, J = 6, 3 Hz).

EXAMPLE 143A 7-Hydroxy-6-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester A solution of the ethyl ester was heated at 130 ° C for 16 hours. of 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid (10.0 9, 34.1 millimoles) and saddic cyanide (8, 35 9, 170 mmol) in dimethylsulfoxide (35 ml). Water (100 ml) was added, and the mixture was saturated with ammonium chloride and then extracted with ethyl acetate (4 x 100 ml). The combined organic extracts were washed with a saturated solution (50 ml) of sodium bicarbonate and with brine (25 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 0-50% ethyl acetate / hexanes as eluent afforded the title compound (5.1-0.9, 54%).

EXAMPLE 143B 7-Hydroxy-4-hydroxyimino-6-methoxy-2-methyl-3 ethyl ester, 4-dihydro-2H-quinoline-1-carboxylic acid 7-Hydroxy-6-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-ethyl ester was dissolved carboxylic acid (5.10 9, 18.3 mmol) in ethanol (100 ml) and hydroxylamine hydrochloride (3.81 g, 54.8 mmol) followed by satic acetate (3.74 9, 45.7 mmol) was added. . The mixture was heated to reflux for 2 hours and then allowed to stand at room temperature overnight. Water (100 ml) was added, and volatile compounds were removed in vacuo to obtain a yellow suspension. This suspension was filtered and washed with water to obtain the title compound as a fine powder (4.755 g, 89%).

EXAMPLE 143C cis-trans-4-amino-7-hydroxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. Nickel-aluminum alloy (7.6 g) was added. , Not 50%, 65 millimoles), in portions, to a stirred solution of 7-hydroxy-4-hydroxyimino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic acid (4.76 g, 16.2 mmol) in ethanol (100 ml) and a 2N aqueous solution of KOH (50 ml, 97 mmol). After 75 min more nickel-aluminum catalyst (0.95 g, 8.9 mmol) was added and, after 30 min, more (0.95 g, 8.9 mmol). After a further 2 h stirring, the reaction mixture was filtered through a pad of Celite®, rinsing with ethanol and then with water. 6N HCl (15 ml) was added with stirring to the filtration product, which was followed by the dropwise addition of a saturated solution of sodium bicarbonate. Ethyl acetate (50 ml) was added and the solution was stirred vigorously for 20 min. The aqueous layer was separated and subjected to extraction with ethyl acetate (2 x 150 ml). The aqueous layer was then saturated with sodium chloride and subjected to extraction with ethyl acetate (4 x 75 ml). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered as a mixture of stereoisomers (4.49 g, 99%).

EXAMPLE 143D cis-4- (3,5-bis-trifluoromethyl-benzylamino) -7-hydroxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester a stirred suspension of the cis-4-amino-7-hydroxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (4.49 g, 16.0 mmol) in 1 , 2-dichloroethane (100 ml), 3,5-bis (trifluoromethyl) benzaldehyde (2.6 ml, 16.0 mmol) was added, followed by acetic acid (0.9 ml), 16.0 mmol). After 45 min, sodium triacetoxyborohydride (5.1 g, 24.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water (75 ml) and ethyl acetate (75 ml) were added to the mixture, which was then basified to a pH of 10 with sodium potassium carbonate. The mixture was then subjected to extraction of ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 8.17 g of crude product. Purification by chromatography on silica gel using 0.30% ethyl acetate / hexanes as eluent afforded 4.90 g of the title compound (60%).

EXAMPLE 143E cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-methoxy-7-methoxycarbonyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester - carboxylic acid Methyl chloroformate (7.5 ml, 97 mmol) was slowly added to a stirred solution of cis-4- (3,5-bis-trifluoromethyl-benzylamino) -7-hydroxy-6-methoxy-2- ethyl ester. methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (4.9 g, 9.7 mmol) and anhydrous pyridine (30 mL, 371 mmol) in anhydrous dichloromethane (60 mL), cooled to 0 ° C. After stirring at room temperature for 2 days, water (50 ml) and a 2 N aqueous solution (50 ml) of KOH were added to the reaction mixture, which was then subjected to extraction with ethyl acetate (3). x 100 ml). The combined organic phases were washed with a saturated solution of sodium bicarbonate (50 ml) and a brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 5.89 g of crude product. Purification by chromatography on silica gel using 0-25% ethyl acetate / hexanes as eluent afforded 5.05 g of the title compound (84%).

MS, m / z: 623 (M + + 1), 641 (M + + 19); 1 H-NMR (CDCl 3), d 7.32 (08, s, 1H 9, 6.49 (C5, s, 1 H9, 1.15 C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 144 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-7-hydroxy-6-methoxy-2-methyl-3,4-dihydro-2H- quinoline-1-caraboxylic acid A solution of the cis-4 - [(3) ethyl ester was stirred at room temperature., 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-7-methoxycarbonyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (5.0 g, 8.0 mmol) and potassium carbonate (2.2 g, 16 mmol) in methanol (45 ml). After 12 hours, water (100 ml) was added and volatile compounds were removed in vacuo. The mixture was then extracted with ethyl acetate (3 x 100 ml), and the combined organic extracts were washed with a saturated solution (50 ml) of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 4.67. g of raw product. Purification by chromatography on silica gel using 0-25% ethyl acetate / hexanes as eluent afforded 2.27 g of the title compound (50%). MS, m / z: 566 (M + + 2), 583 (M + + 19); 1 H-NMR (CDCl 3), d: 7.07 (08, s, 1 H), 6.36 (05, s, 1 H) EXAMPLE 145 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) acid ) -methoxycarbonyl-amino-1-6-methoxy-2-methyl-7-occytyloxy-3,4-dihydro-2H-quinoline-1-carboxylic acidA solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-hydroxy-6-methoxy-2-methyl- ethyl ester was stirred at room temperature for 2 days. 3,4-dihydro-2H-quinoline-1-carboxylic acid (30 mg, 0.053 mmol), triphenylphosphine (28 mg, 0.11 mmol), 1-octanol (33 μl, 0.21 mmol) and bis- (N-methylpiperazinyl) -azod carboxamide (30 mg, 0.11 mmol) in benzene (1 m) A direct purification of the solution by chromatography on silica gel using 0-20% ethyl acetate / hexanes as eluent afforded the title compound (18 mg, 50 mg). %) MS, m / z: 696 (M + + 19), 376 (M + - 300); 1 H-NMR (CDCl 3), d: 7.08 (C8, s, 1 H), 6.40 (C5, s, 1 H9 1.17 (C2-Me, d, 3H, J = 6.1 Hz) Examples 146-163 were prepared in a manner analogous to that of Example 145 by substituting the appropriate alcohol in the reaction with the cis-4- ethyl ester. [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl] amino] -7-hydroxy-6-methoxy-2-methyl-3,4-d ihdrone-2H-quinoline-1-carboxylic acid.

EXAMPLE 146 Cis-4-r3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7- (2-dimethylamino-ethoxy-9-6-methoxy-2-methyl-3,4-dihydro) ethyl ester -2H- quinoline-1-carboxylic S, m / z: 637 (M + + 2); 1 H-NMR (CDCl 3), d: 7.09 (08, s, 1 H9, 6.39 (05, s, 1 H),. 15 (C2-Me, d, 3H, J = 6.2 Hz) EXAMPLE 147 Ethyl ester of cls-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-7-cyclopentyloxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 - caraboxylic S, m / z: 623 (M + - 300); 1 H-NMR (CDCl 3), d: 7.06 (08, s, 1 H), 6.40 (05, s, 1 H).

EXAMPLE 148 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amnol-7-isopropoxy-6-methoxy-2-methyl-3,4-dihydro-2H ethyl ester -quinoline-1-carboxylic S, m / z: 306 (M + -300); 1 H-NMR (CDCl 3), d: 7.09 (C8, s, 1 H), 6.41 (05, s, 1 H).

EXAMPLE 149 cis-7-benzyloxy-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline -1- carboxylic MS, m / z: 656 (M + +2), 673 (M + +19); 1 H-NMR (CDCl 3), d: 7.12 (08, s, 1 H), 6.43 (06, s, 1 H), 1, 14 (C 2 -Me, d, 3 H, J = 6.2 Hz).

EXAMPLE 150 Ethyl ester of cis-4-r (3,5-b8s-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-methoxy-2-methyl-7- (3-methyl-butoxy) -3,4-dihydro acid ester -2H-quinoline-1-carboxylic MS, m / z: 636 (M + + 2), 653 (M + + 19); 1 H-NMR (CDCl 3), d: 7.09 (C8, s, 1 H), 6.41 (C5, s, 1 H), &39; (C6, s, 1 H), 1.17 (C2-Me, d, 3H, J = 6.2 Hz), 0.96 (07-iPr, d, 6H, J = 6.1 Hz).

EXAMPLE 151 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-butoxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline -1-carboxylic MS, m / z: 622 (M + + 2), 639 (M + + 19); 1H-NMR (CDCl 3), d: 7.08 (c8, s, 1 H), 6.40 (06, s, 1H), 1.17 (C2-Me, d, 3H, J = 6.1 Hz), 0.97 (C7-0- nBu, d, 3H, 7 = 7.4 Hz).

EXAMPLE 152 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6-methoxy-2-methyl-7- (pyridin-2-yl-methoxy) -3 acid ester , 4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 657 (M + + 2); 1 H-NMR (CDCl 3), d: 7.08 (C8, s, 1 H), 6.44 (c6, s, 1H).

EXAMPLE 153 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amnol-6-methoxy-2-methyl-7- (pyridin-3-yl-methoxy) -3 ethyl ester , 4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z 657 (M + + 2); 1 H-NMR (CDCl 3), d: 1.24 (C02Et, t, 3H, J = 7.1 Hz), 1.14 (C2-Me, d, 3H, J = 6.0 Hz).

EXAMPLE 154 cis-4-rf3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6-methoxy-7- (2-methoxy-ethoxy) -2-methyl-3,4-dihydro ethyl ester -2H-quinoline-1-carboxylic MS, m / z: 624 (M + + 2), 641 (M + + 19); 1 H-NMR (CDCl 3), d: 7.10 (C8, s, 1 H), 6.39 (06, s, 1 H), 1.15 (C2-Me, d, 3H, J = 6.0 Hz).

EXAMPLE 155 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-hexyloxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 ethyl ester -carboxylic MS, m / z: 650 (M + + 2), 667 (M + + 19); 1 H-NMR (CDCl 3), d: 7.07 (08, s, 1H9, 6.40 (05, s, 1 H), 1.17 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 156 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-decyloxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 ethyl ester - MS carboxylic, m / z: 723 (M + + 19), 405 (M + -300); 1 H-NMR (CDCl 3), d: 7.09 (C8, s, 1 H), 6.39 (C5, s, 1 H), 1.17 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 157 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-ethoxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline -1-carboxylic 1H-NMR (CDCl 3), d: 7.08 (08, s, 1H), 6.39 (05, s, 1H), 1.46 (C7-Oet, t, 3H, J = 7.0 Hz), 1.29 (CO2Et, t, 3H , J = 7.1 Hz), 1.16 (C2-Me, 3H, J = 6.2 Hz).

EXAMPLE 158 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7- (5-dimethylamino-pentyloxy) -6-methoxy-2-methyl-3,4 acid -dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 678 (M + + 1); 1 H-NMR (CDCl 3), d: 7.06 (C8, s, 1H), 6.39 (C5, s, 1H).

EXAMPLE 159 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-methoxy-2-methyl-7- (pyridin-4-yl-methoxy) -3,4 acid -dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 656 (M + + 1); 1 H-NMR (CDCl 3), d 7.07 (C8, s, 1 H), 6.44 (05, s, 1 H), 1.14 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 160 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-methoxy-2-methyl-7-pentyloxy-3,4-dihydro-2H-quinoline -1- carboxylic MS, m / z: 635 (M + + 1), 652 (M + +18); 1 H-NMR (CDCl 3), d: 7.08 (08, s, 1 H), 6.40 (05, s, 1 H).

EXAMPLE 161 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1- (6-hydroxy-hexyloxy) -6-methoxy-2-methyl-3,4 acid -dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 665 (M + + 1), 682 (M + + 18); 1 H-NMR (CDCl 3), d: 7.10 (08, s, 1 H), 6.39 (05, s, 1 H), 1.16 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 162 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1- (10-hydroxy-decyloxy) -6-methoxy-2-methyl-3,4-dihydro acid -2H-quinoline-1-carboxylic MS, m / z: 721 (M + + 1); 1 H-NMR (CDCl 3), d: 7.08 (C8, s, 1 H), 1.16 (C2-Me, d, 3H, J = 6.0 Hz). EXAMPLE 163 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1- (5-ethoxycarbonyl-pentyloxy) -6-methoxy-2-methyl-2-methyl-3 acid , 4-dihydro-2H-quinoline-1-carboxylic acid MS, m / z: 707 (M + + 1), 725 (M + + 19); 1 H-NMR (CDCl 3), d: 7.08 (C8, s, 1 H), 6.39 (05, s, 1 H), 1.16 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 164 Ethyl ester of cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1- (5- carboxy-pentaloy) -6-methoxy-2-methyl-3,4 acid -dihydro-2H-quinoline-1-carboxylic acid It was prepared by treating a solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxy-carbonyl-amine] -7- ( 5-ethoxycarbonyl-pentyloxy) -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (example 163, 27 mg, 0.04 mmol) in 0.6 ml of THF and 0.2 ml of ethanol, with a 1 M aqueous solution of lithium hydroxide (0.2 ml, 0.2 mmol) at room temperature. After 45 minutes, acidification with 1N HCl and extraction with ethyl acetate, drying of the organic extracts over sodium sulfate and concentration under reduced pressure afforded 25 mg of the title compound. MS, m / z 697 (M + + 19), 378 (M + -300); 1 H-NMR (CDCl 3), d: 6.39 (C5, s, 1H), 3.79 (C6-Ome, s, 3H), 1.16 (Me, d, 3H, J = 6.1 Hz). EXAMPLE 165A 6-Benzyloxy-7-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 6-Benzyloxy-4,7-dimethoxy-quinoline (1.6 g, 5.5 mmol in anhydrous tetrahydrofuran (20 ml) The mixture was cooled to -78 ° C and methylmagnesium chloride (3.8 ml of a 3.0 M solution in tetrahydrofuran, 11.4 mmol) was added. C. for 1 hour and then methyl chloroformate (1.1 ml, 11.4 mmol) was added.The reaction mixture was warmed to room temperature overnight and then 12 ml of a 1 N aqueous solution of HCl was added. minutes, 15 ml of water was added and the tetrahydrofuran was removed in vacuo.After the addition of 40 ml of water, the resulting aqueous phase was subjected to extraction of ethyl acetate (3 x 40 ml) .The organic phases were combined and were washed with 20 ml of each of the following phases: 1 N HCl, saturated aqueous solution of bicarbonate physician, and brine, before being dried over sodium sulfate, filtered and concentrated in vacuo to obtain 1.99 g of the title product (99%).

EXAMPLE 165B 6-Benzyloxy-4-hydroxyimo-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Hydroxylamine hydrochloride (1.1 g, 16 mmol) and sodium acetate (1.1 g, 14 mmol) to a stirred solution of 6-benzyloxy-7-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1.99 g, 5.39 mmol) in 95% ethanol (20 ml), and the mixture was heated to reflux. After 2 hours, water (50 ml) was added and the mixture was subjected to extraction of ethyl acetate (3 x 50 ml). The combined organic phases were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2.05 g of the title compound (99%).

EXAMPLE 165C cis-4-amino-6-hydroxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Aluminum-nickel alloy (1.82 g, Ni 50%, 21.2 mmol), in portions, to a stirred solution of the ethyl ester 6-benzyloxy-4-hydroxyimino-7-methoxy-2-methylene-3,4-dihydro-2H-quinoline-1- carboxylic acid (2.05 g, 5.33 mmol) in ethanol (20 ml) and a 2N aqueous solution of KOH (16 ml, 32 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, and then more aluminum-nickel alloy (1.82 g, 21.2 mmol) was added and the reaction mixture was stirred for 3 hours. Additional 2N aqueous KOH solution (20 ml, 40 mmol) was added and the reaction mixture was stirred for 1 hour. The mixture was then filtered through a pad of Celite®, rinsing with ethyl acetate. The filtration product was concentrated in vacuo and the mixture was subjected to ethyl extraction (3 x 5 ml). The combined organic phases were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 0.65 g of crude product. Purification by chromatography on silica gel using 0.5% methanol / dichloromethane as eluent yielded 387 mg of the title compound (26%).

EXAMPLE 165 D cis-4- (3,5-bis-trifluoromethyl-benzamylamino) -6-hydroxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a stirred suspension of the cis-4-amino-6-hydroxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (387 mg, 1.38 mmol) in dichloromethane (9 ml), 3,5-bis (trifluoromethyl) benzaldehyde (225 μl, 1.38 mmol) was added followed by acetic acid (80 μl, 1.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (440 mg, 2.08 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. Water (5 ml) was added and the mixture was slowly alkalized to a pH of 10 with solid potassium carbonate. The mixture was then extracted with ethyl acetate (3 x 10 ml), and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 680 mg of crude product. Purification by chromatography on silica gel using 0-25% ethyl acetate / hexanes as eluent gave 458 mg of the title compound (65%).

EXAMPLE 165E cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-methoxy-6-methoxycarbonyloxy-2-methyl-3,4-dihydric acid ethyl ester 2H-quinoline-1-carboxylic acid Methyl chloroformate (0.7 ml, 9 mmol) was added slowly to a stirred solution of the ethyl ester of cis-4- (3,5-bis-trifluoromethyl-benzylamine) -6 ethyl ester. -hydroxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (450 mg, 0.89 mmol) and anhydrous pyridine (2.5 ml) in anhydrous dichloromethane (5 ml), at 0 ° C. After stirring overnight at room temperature, water (10 ml) and a 2 N aqueous solution (10 ml) of KOH were added, the mixture was extracted with ethyl acetate (3 x 10 ml), and the Combined organic phases were washed with 1 N HCl (3 x 10 ml), a saturated solution of sodium bicarbonate (10 ml) and then with brine (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain 551 mg of crude product. Purification by chromatography on silica gel using 0-25% ethyl acetate / hexanes as eluent gave 448 mg of the title compound (90%). MS, m / z: 641 (M + + 19); 1 H-NMR (CDCl 3), d: 7.22 (c8, s, 1H), 6.70 (C5, s, 1H), 1.18 (C2-Me, d, 3H, J = 6.1 Hz).

EXAMPLE 166 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-hydroxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 ethyl ester carboxylic acid A solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-6-methoxycarbonyl alcohol ethyl ester was stirred at room temperature overnight. -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (500 mg, 0.80 mmol) and potassium carbonate (222 mg, 1.6 mmol) in methanol (5 ml). A small amount of water was added and the methanol was removed in vacuo. Additional water (20 ml) was added and the aqueous mixture was subjected to extraction with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with a saturated solution of sodium bicarbonate (10 ml) and with brine (10 ml), and then dried over sodium sulfate, filtered and concentrated in vacuo to obtain 412 mg of the crude product. Purification by chromatography on silica gel using 0.20% ethyl acetate / hexanes as eluent gave 378 mg of the title compound (84%). MS, m / z: 565 (M + + 1), 582 (M + + 18); 1 H-NMR (CDCl 3), d: 7.08 (08, s, 1H), 6.52 (C5, s, 1H), 1.15 (C2-Me, d, 3H, J = 6.0 Hz).

EXAMPLE 167 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-amino-1-6-ethoxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 - carboxylic A solution of the cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-hydroxy-7- ethyl ester was stirred at room temperature for 12 hours. methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (30 mg, 0.053 mmol), triphenylphosphine (28 mg, 0.11 mmol), ethanol (16 μl, 0.79 mmol), and bis- (N -methylpiperazinyl) -azodicarboxamine (30 mg, 0.11 mmol) in benzene (1 ml) A direct purification of the solution by chromatography on silica gel using 0-20% vinyl acetate / hexanes as eluent gave 20 mg of the compound of title (67%) MS, m / z: 593 (M +), 610 (M + + 17); 1 H-NMR (CDCl 3), d: 6.39 (C5, s, 1 H), 1.17 (C2-Me, d, 3H, J = 6.2 Hz.) Examples 168-171 were prepared in a manner analogous to that of Example 167 by substituting the appropriate alcohol in the reaction with cis-4 - [(3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-hydroxy-7-methoxy-2-methyl-3,4-ethyl ester -dihydro-2H-quinoline-1-carboxylic acid.

EXAMPLE 168 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6-isopropoxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline 1-carboxylic S, m / z: 624 (M + + 18); 1 H-NMR (CDCl 3), d: 6.42 (C5, s, 1H), 1.18 (C2-Me, d, H, J = 6.1 Hz).

EXAMPLE 169 cis-4-r (3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-amino-1-7-methoxy-2-methyl-6-propyl-3,4-dihydro-2H-quinoline-1-) ethyl ester carboxylic S (Thermospray), MS, m / z: 607 (M + + 1), 624 (M + + 18); 1 H-NMR (CDCl 3), d: .39 (C5, s, 1 H), 1.17 (C2 -Me, d, 3H, J = 6.1 Hz).

EXAMPLE 170 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzopymethoxycarbonyl-amino-6-butoxy-7-methoxy-2-methyl-3,4-dihydro-2H- quinoline-1-carboxylic S, m / z: 621 (M + + 1), 638 (M + + 18); 1 H-NMR (CDCI3), d: 6.39 (C5, s, 1H), 1.17 (C2- Me, d, 3H, J = 6.2 Hz).

EXAMPLE 171 Cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6-cyclopentyloxy-7-methoxy-2-methyl-3,4-dyl ethyl ester hydro-2 H-quinoline-1-carboxylic MS, m / z: 633 (M + + 1), 650 (M + + 18); 1 H-NMR (CDCl 3), d: 6.38 (05, s, 1 H), 1, 18 (C 2 -Me, d, 3 H, J = 6.1 Hz).

EXAMPLE 172 Cis-4-yl (3,5-bis-trifluoromethyl-phenyl) -ethyl-methoxycarbonyl-amino acid ethyl ester} -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl ethyl ester -amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (0.200 g, 0.346 mmol) and tetrahydrofuran (2 ml) in a pre-dried flask, under a nitrogen atmosphere . The solution was cooled to -78 ° C and a 1.83 M solution of n-butyllithium in hexanes (0.degree., 23 g, 0.41 mmol). The reaction mixture was stirred at -78 ° C for 45 minutes, and then methyl iodide (0.026 ml, 0.41 mmol) was added, the reaction mixture was heated to 01 C and stirred for 90 minutes. The reaction was quenched with a saturated solution of ammonium chloride and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to obtain a crude product. Purification by chromatography on silica gel used 20% ethyl acetate / hexanes, followed by 70% diethyl ether / hexanes, as eluent provided the desired methylated product. MS, m / z: 593 (M + + H); 1 H-NMR (CDCl 3), d: 7.85 (bs, 1 H), 7.8 (bs, 2 H), 7.05 (bs, 1 H), 6.5 (bs, 1 H), 3, 9 (s, 3 H), 3.85 (s, 3 H), 1, 65 (d, 1, 5 H, J = 7 Hz), 1, 05 (d, 1, 5 H, J = 7.0 Hz). Examples 173 and 174 were prepared in optically enriched form by resolution of the corresponding indicated racemate, or of an intermediate product of their synthesis, using the methods described in the specification.

EXAMPLE 173 Ethyl ester of f2R, 4S1-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline -1- carboxylic acid. Example 16 EXAMPLE 174 Ethyl ester of T2R, 4S1-4-r (3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydric acid 2H-quinoline-1-carboxylic acid Example 44.

Claims (2)

1. NOVELTY OF THE INVENTION CLAIMS 1. A compound of formula I Formula I A prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R 1 is hydrogen, Y, W-X or W-Y; wherein W is a carbonyl, triocarbonyl, sulfinyl or sulfonyl; X is -O-Y, -S-Y, -N (H) -Y or -N- (Y) 2; in which Y, in each case, is independently Z or a linear or branched carbon chain of one to ten members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, except the connecting carbon, can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally monosubstituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally monosubstituted with Z; wherein Z is a three to eight member ring partially saturated, fully saturated or totally unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused rings of three six members, partially saturated, fully saturated or totally unsaturated, independently considered, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent Z is optionally mono-, or di- or tri-substituted independently with halo, (C2-C6) alkenyl, (C? -C6) alkyl, hydroxyl, alkoxy (Ci-C?), alkyl (CrC) thio , amino, nitro, cyano, oxo, carboxyl, alkyl (Ci-C6) oxycarbonyl, mono-N- or di-N, N-alkyl (CI-CT) amino, wherein said alkyl substituent (CiC.) is optionally mono-, di- or tri-substituted independently with halo, hydroxyl, alkoxy (Ci-Cß), alkyl (CrC 4) thio, amino, nitro, cyano, oxo, carboxyl, alkyl (Ci-Cβ) oxycarbonyl, mono-N- or di-N, N-alkyl (C? -C6) amino, said alkyl substituent (Ci-Cß) being optionally substituted with from one to nine fluorine atoms; R3 is hydrogen or Q; in which Q is a linear or branched carbon chain of one to six members, fully saturated, partially unsaturated or totally unsaturated, in which carbons, except for the connecting carbon, can be optionally replaced with a heteróatome selected from oxygen, sulfur and nitrogen , and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally monosubstituted with oxo, said sulfur is optionally mono- or disubstituted with oxo- said nitrogen is optionally mono- or di-substituted with oxo, and said carabonada chain is optionally monosubstituted with V; wherein V is a three to eight member ring partially saturated, fully saturated or totally unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused rings of three six members, partially saturated, totally saturated or totally unsaturated, independently considered, having optionally one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V is optionally mono-, di-, tri- or tetra-substituted independently with halo, (C -? - C6) alkyl, (C2-C6) alkenyl, hydroxyl, (C? -C6) alkoxy, alkyl (C? -C4) thio, amino, nitro, cyano, oxo, carbamoyl, mono-No di-N, N-alkyl (Ci-Cβ) carbamoyl, carboxyl, alkyl (CrC? Joxycarbonyl, mono-N- or di-N, N-alkyl (C? -C6) amino, wherein said (C-? - C6) alkyl or (C2-C6) alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxyl, alkoxy Cd), alkyl (C? -C4) thio, amino, nitro, cyano, oxo, carboxyl, alkyl (C -? - C6) oxycarbonyl, mono-N- or di-N, N-alkyl (C -? - C6) ) amino, said substituents being optionally substituted (C? -C6) or (C2-C6) alkenyl with one to nine fluorine atoms; R4 is Q1 or V1; in which Q1 is a linear or branched carbon chain, from one to six members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, except the connecting carbon, can optionally be replaced with a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with hydroxyl, said carbon is optionally monosubstituted with oxo, said sulfur is optionally mono- or di-substituted with oxo , said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally monosubstituted with V1; wherein V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with halo, (C? -C6) alkyl, alkoxy (CrC6), amino, nitro, cyano, alkyl (CrC6) oxycarbonyl, mono- N- or di-N, N-alkyl (C? -C6) amino, wherein said (C-? - C6) alkyl substituent is optionally monosubstituted with oxo, said alkyl substituent (C-pCβ) being optionally substituted with from one to nine fluorine atoms; wherein R3, R6, R7 and R8 is independently hydrogen, hydroxyl or oxy, wherein said oxy is substituted with T or a linear or branched carbon chain of one to twelve members, partially saturated, totally saturated or totally unsaturated, wherein the carbons, except the connecting carbon, may optionally be mono-, di- or tri-substituted independently with halo, said carbon is optionally monosubstituted with oxo, said sulfur is optionally mono- or disubstituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo, and said carbon chain is optionally monosubstituted with T; wherein T is a three to eight member ring partially saturated, fully saturated or fully unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused rings of three six members, partially saturated, fully saturated or totally unsaturated, independently considered, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di, or tri-substituted independently with halo, (C -? - C6) alkyl, (C2-C6) alkenyl, hydroxyl, (Ct-C6) alkoxy, (C1-C4) alkyl ) thio, amino, nitro, cyano, oxo, carboxyl, alkyl- (C -? - C6) oxycarbonyl, mono-No di-NN-alkyl (C -? - C6) amino, wherein said alkyl substituent (Ci-) Cß) is optionally mono-, di- or tri-substituted independently with hydroxyl alkoxy (Ci-Cß), alkyl (C 1 -C 4) thio, amino, nitro, cyano, oxo, carboxyl, alkyl (Ci-Cβ) oxycarbonyl, mono -N- or di-N, N-alkyl (C -? - C6) amino, said alkyl substituent (C -? - C6) being optionally substituted with from one to nine fluorine atoms. 2. - A compound according to claim 1, wherein: C2 methyl is beta; the nitrogen of C4 is beta; R1 is W-X; W is carbonyl, thiocarbonyl or sulfonyl; X is -O-Y-, -S-Y-, -N (H) -Y- or -N- (Y) -; And, in each case, it is independently Z or (C 1 -C 4) alkyl, said (C 1 -C 4) alkyl optionally having from one to nine fluorine atoms, or said (C 1 -C 4) alkyl being optionally monosubstituted with Z, wherein Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said Z substituent is optionally mono-, di- or tri- independently substituted with halo, (C? -C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkyl, nitro, cyano, oxo or alkyl (Ci-C?) oxycarbonyl, said alkyl substituent being optionally also substituted (C1-C4) with one to nine fluorine atoms; R3 is Q-V, in which Q is (C1-C4) alkylene and V is a partially saturated, or fully unsaturated, five or six membered partially saturated ring, optionally having one of three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (CrCß), hydroxyl, alkoxy (Ci-Cß), nitro, cyano or oxo, wherein said alkyl substituent ( Ci-Cß) is optionally mono-, di- or tri-substituted independently with (C -? - C6) alkoxy or alkyl (CrC4) thio, or said (C? -C6) alkyl optionally has from one to nine fluorine atoms; R4 is alkyl (C-r C4); each of R6 and R7 is independently hydrogen or alkoxy (Ci-Cß), said alkoxy (C-i-Cß) optionally having from one to nine fluorine atoms or said alkoxy (C? -C6) being optionally monosubstituted with T; wherein T is a five to six member ring partially saturated, fully saturated or fully unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, alkoxy (Cr C6), alkyl (C1-C4) thio, amino, oxo, carboxyl , alkyl (C -? - C6) oxycarbonyl, mono-N- or di-N, N-alkyl (Ci-Cß), wherein said alkyl- (C? -C6) substituent optionally has from one to nine carbon atoms. fluorine; and R5 and R8 are H; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, wherein: W is carbonyl; X is -O-Y wherein Y is (C1-C4) alkyl, said (C-1-C4) alkyl optionally having from one to nine fluorine atoms; Q is alkylene (C-1-C4), and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, (Ci-C?) alkoxy, nitro, cyano or oxo, wherein said alkyl substituent ( C -? - C6) optionally has from one to nine fluorine atoms; each of R6 and R7 is independently hydrogen or (C1-C3) alkoxy, said (C1-C3) alkoxy optionally having from one to seven fluorine atoms; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, wherein: Q is methylene, and V is phenyl or pyridinyl; wherein said ring V is optionally mono-, di- or tri-substituted independently with halo, nitro or (C 1 -C 2) alkyl, wherein said (C 1 -C 2) alkyl substituent optionally has one to five fluorine atoms; or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 1, wherein said compound is: [2R, 4S] -4 - [(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6.7 ethyl ester. -dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-dinitro-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline 1-carboxylic; [2R, 4S] -4 - [(2,6-dichloro-pyridin-4-ylmethyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H- ethyl ester quinoline-1 -carboxylic; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H- ethyl ester quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis-trifluoro-methyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydric acid ethyl ester 2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-3,4-di-hydro-2H- ethyl ester quinoline-1-carboxylic acid; or a pharmaceutically acceptable salt of said compounds. 6. A compound according to claim 1, wherein said compound is: [2R, 4S] -4 - [(3,5-bis-tri-fluoromethyl-benzyl) -methoxycarbonyl-amino] -6 isopropyl ester , 7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis, trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydroxylic acid ethyl ester 2H-quinoline-1-carboxylic acid; 2,2-trifluoro-ethyl ester of [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-acid methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydroxypropyl ester 2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis-tri-fluromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-tert-butyl ester 2H-quinoline-1-carboxylic acid; [2R, 4S] -4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-ethyl ester - carboxylic; or a pharmaceutically acceptable salt of said compounds. 7. A compound according to claim 4, wherein: Y is ethyl, R3 is 3,5-dichlorophenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 4, wherein: Y is ethyl, R3 is 3,5-dinitrophenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 9. - A compound according to claim 4, wherein: Y is ethyl, R3 is 2,6-dichloropyridin-4-ylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 4, wherein: Y is ethyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 4, wherein: Y is ethyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, R6 is methoxy, and R is hydrogen; or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 4, wherein: Y is ethyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, R6 is hydrogen, and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 4, wherein: Y is isopropyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of Rd and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 4, wherein: Y is methyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is ethyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 4, wherein: Y is 2,2,2-trifluoroethyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 16. - A compound according to claim 4, wherein: Y is n-propyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 4, wherein: Y is tert-butyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 4, wherein: Y is ethyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, R6 is trifluoromethoxy, and R is hydrogen; or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 1, wherein: C2 methyl is beta; the nitrogen of C4 is beta; R1 is W-Y; W is carbonyl, thiocarbonyl or sulfonyl; Y is alkyl (C -? - C6), said alkyl (C -? - C6) optionally having from one to nine fluorine atoms, or said alkyl (C? -C6) being Z being optionally monosubstituted, wherein Z is a Three to six member ring partially saturated, fully saturated or completely unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, (C? -C) alkyl, (C-? -C) alkoxy, (C1-C4) alkyl, nitro, cyano, oxo or alkyl (Ci-Cβ) oxycarbonyl, said (C 1 -C 4) alkyl substituent being optionally substituted with one to nine fluorine atoms; R3 is Q-V, wherein Q is (C1-C4) alkyl and V is a five or six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (Ci-Cß), hydroxyl, alkoxy (Ci-Cß), nitro, cyano or oxo, wherein said substituent alkyl (C Cß) is optionally mono-, di- or tri-substituted independently with alkoxy (Ci-Cß) or alkyl (C 1 -C 4) thio, or said alkyl (C 6 -C 6) optionally has from one to nine carbon atoms; fluorine; R 4 is alkyl (Cr C 4); each of R6 and R7 is independently hydrogen or alkoxy (C-i-Cß), said alkoxy (C-i-Cß) optionally having from one to nine fluorine atoms or said alkoxy (C-pCβ) being optionally monosubstituted with T; wherein T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, alkoxy (Cr Ce), alkyl (C -? - C) thio, amino, oxo , carboxyl, alkyl (C -? - C6) oxycarbonyl, mono-N- or di-N, N-alkyl (Ci-Cß) amino, wherein said alkyl- (Ci-Cß) substituent optionally has from one to nine fluorine atoms; and R5 and R8 are H; or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 19, wherein: W is carbonyl; Y is alkyl (C -? - C), said alkyl (C -? - C4) optionally having from one to nine fluorine atoms; Q is (C1-C4) alkylene, and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or tri substituted independently with halo, alkyl (C ^ Cs), hydroxyl, alkoxy (Cr CT), nitro, cyano or oxo, wherein said alkyl substituent (CI-CT) ) optionally has from one to nine fluorine atoms; and each of R6 and R7 is independently hydrogen or (C1-C3) alkoxy, said (C1-C3) alkoxy optionally having one to seven fluorine atoms; or a pharmaceutically acceptable salt thereof. 21. A compound according to claim 1, wherein said compound is the [2R, 4S] - (3,5-bis-trifluoromethyl-benzyl) - (1-butyryl-6,7-) methyl ester. dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid or a pharmaceutically acceptable salt of said compound. 22. A compound according to claim 20, wherein: Y is n-propyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy, or a pharmaceutically salt acceptable of it. 23. A compound according to claim 1, wherein: C2 methyl is beta; the nitrogen of C4 is beta; R1 is Y; Y is alkenyl (C2-Cß) or alkyl (CrCß), said alkenyl (CrC6) or said alkyl (Ci-Cß) having from one to nine fluorine atoms, or said alkenyl (C2-C6) being optionally monosubstituted or said alkyl (C? -C6) with Z; wherein Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl- (C? -C4), alkoxy (C1-C4), alkyl (C1-C4) thio, nitro, cyano, oxo or alkyl (C -? - C6) oxycarbonyl, said (C1-C4) alkyl optionally substituted with from one to nine fluorine atoms; R3 is Q-V, wherein Q is (C1-C4) alkyl and V is a five or six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (Ci-Ce), hydroxyl, alkoxy (Ci-Cß), nitro, cyano or oxo, wherein said substituent alkyl (CrC6) is optionally mono-, di- or tri-substituted independently with (C? -C6) alkoxy or (C1-C4) alkyl thio, or said alkyl (Ci-C?) optionally has one to nine fluorine atoms; R is alkyl (C C4); each of R6 and R7 is independently hydrogen or (C? -C6) alkoxy, said (C? -C6) alkoxy optionally having from one to nine fluorine atoms or said alkoxy (C? -C6) being optionally monosubstituted with T; wherein T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, (C -? - C6) alkyl, hydroxyl, (C6) alkoxy, (C1-C4) alkyl, amino, oxo, carboxyl, alkyl (CI-CT) oxycarbonyl, mono-N- or di-N, N-alkyl (C -? - C6) amino, wherein said alkyl- (C? -C6) substituent optionally has from one to nine fluorine atoms; and R5 and R8 are H; or a pharmaceutically acceptable salt thereof. 24. - A compound according to claim 23, wherein: Y is (C -? - C) alkyl, said alkyl (CrC) optionally having from one to nine fluorine atoms; Q is (C1-C4) alkylene, and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or tri-substituted independently with halo, alkyl (Ci-Cß), hydroxyl, alkoxy (Ci-Cß), nitro, cyano or oxo, wherein said alkyl substituent (C -? - C6) optionally has one to nine fluorine atoms; and each of R6 and R7 is independently hydrogen or (C1-C3) alkoxy, said (C1-C3) alkoxy optionally having one to seven fluorine atoms; or a pharmaceutically acceptable salt thereof. 25. - A compound according to claim 1, wherein said compound is: [2R.4S] - (3,5-bis-trifluoromethyl-benzyl) - (1-butyl-6,7-dimethoxy-) methyl ester. 2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid hydrochloride [2R.4S] - (3,5-bis-trifluoromethyl-benzyl) - [ 1- (2-ethyl-butyl) -6,7-dimethoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline-4-yl] -carbamic acid, or a pharmaceutically acceptable salt of said compounds. 26. A compound according to claim 24, wherein: Y is n-butyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt of said compound. 27. A compound according to claim 24, wherein: Y is 2-ethylbutyl, R3 is 3,5-bis-trifluoromethylphenylmethyl, R4 is methyl, and each of R6 and R7 is methoxy; or a pharmaceutically acceptable salt thereof. 28. - A compound according to claim 1, wherein: C2 methyl is beta; the nitrogen of C4 is beta; R1 is Z; wherein Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, d- or tri-substituted independently with halo, (C? -C) alkyl, (C 1 -C 4) alkyl alkoxy, nitro, cyano, oxo or alkyl (C Cß) oxycarbonyl, said (C1-C4) alkyl optionally having from one to nine fluorine atoms; R3 is Q-V, wherein Q is (C1-C4) alkyl and V is a five or six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, (C? -C6) alkyl, hydroxyl, (C1-C6) alkoxy, nitro, cyano or oxo, wherein said Alkyl substituent (C -? - C6) is optionally mono-, di- or tri-substituted independently with (C C) alkoxy or (C 1 -C 4) alkylthio, or said alkyl (Ci-Cβ) optionally has from one to nine fluorine atoms; R 4 is (C 1 -C 4) alkyl; each of R6 and R7 is independently hydrogen or (C? -C6) alkoxyl, said (C? -C6) alkoxy optionally having from one to nine fluorine atoms or said alkoxy (C? -C6) being optionally monosubstituted with T; wherein T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl- (CrC6), hydroxyl, alkoxy (Ci-Cß), alkyl (C1-C4) thio, amino, oxo, carboxyl, alkyl (Ci-Cβ) oxycarbonyl, mono-N- or di-N, N-alkyl (C -? - C6) amino, wherein said alkyl substituent (C? -C6) optionally has from one to nine fluorine atoms; and R5 and R8 are H; or a pharmaceutically acceptable salt thereof. 29. - A compound according to claim 1, wherein: C2 methyl is beta; the nitrogen of C4 is beta; R1 is W-Z; W is carbonyl, thiocarbonyl or sulfonyl; Z is a three to six member ring partially saturated, fully saturated or totally unsaturated, having optionally from one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, nitro, cyano, oxo or alkyl (Ci-Cβ) oxycarbonyl, said (C 1 -C 4) alkyl optionally having from one to nine fluorine atoms; R3 is Q-V, wherein Q is (C1-C4) alkyl and V is a five or six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, (C? -C6) alkyl, hydroxyl, (C? -C6) alkoxy, nitro, cyano or oxo, wherein said alkyl (Ci-Cß) substituent is optionally mono-, di- or tri-substituted independently with (C -? - C6) alkoxy or alkyl (d-C4) thio, or said alkyl (Ci-C?) optionally has one to nine fluorine atoms; R 4 is (C 1 -C 4) alkyl; each of R6 and R7 is independently hydrogen or (C-i-Cβ) alkoxy, said (C-i-Cβ) alkoxy optionally having from one to nine fluorine atoms or said alkoxy (C6C6) being optionally monosubstituted with T; wherein T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, (C? -C6) alkyl, hydroxyl, alkoxy (C-pC?), alkyl (C1-C4) thio, amino, oxo, carboxyl, alkyl (Ci-Ce) oxycarbonyl, mono-N- or di-N, N-alkyl (Ci-Cß) amino, wherein said alkyl- (Cr? 6) substituent optionally has from one to nine fluorine atoms; and R5 and R8 are H; or a pharmaceutically acceptable salt thereof. The use of a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the manufacture of a medicament for treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity oendotoxemia in a mammalian animal (including a human, be male or female). 31. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. 32.- A pharmaceutical composition for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, restenosis angioplasty, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammalian animal, comprising a therapeutically effective amount of a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. 33.- A combination pharmaceutical composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of MTP / Apo B secretion, a PPAR activator, an inhibitor of bile acid reabsorption, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; and a pharmaceutical vehicle. 34.- A combination pharmaceutical composition according to claim 33, wherein the second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. according to claim 33, wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. 36. The use of a first compound, said first compound being a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; in combination with a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of MTP / ApoB secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin , an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, for the manufacture of a medicament for treating atherosclerosis in a mammalian animal, comprising administering to a mammalian animal. 37. The use according to claim 36, wherein the second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. 38.- The use according to claim 36 , wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. 39.- A set that includes: a. a first compound, said first compound being a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier, in a first unit dosage form; b. a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of MTP / Apo B secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, and a pharmaceutically acceptable carrier, in a second unit dosage form; and c. means for containing said first and second dosage forms, wherein the amounts of the first and second compounds give rise to a therapeutic effect. 40. - An assembly according to claim 39, wherein said second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. 41. An assembly according to claim 39, in wherein said second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.