MXPA01002880A - 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors - Google Patents

Abstract

Cholesteryl ester transfer protein inhibitors, of the Formula (I), prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

Description

1. 2,3,4-TETRAHIDRQQUiNOLLNAS 2-SUSTlTU.PAS W-.M1NO SUBSTITUTED AS TRANSFER PROTEIN INHIBITORS OF ESTER COLESTERILiCO BACKGROUND OF THE INVENTION This invention relates to cholesteryl ester transfer protein (CETP) inhibitors, to pharmaceutical compositions containing such inhibitors and to the use of such inhibitors to elevate certain plasma lipid levels, including cholesterol associated with high density lipoproteins ( HDL), and to reduce other plasma lipid levels, such as cholesterol associated with low density lipoproteins and triglycerides and, therefore, to treat diseases that are affected by low levels of HDL cholesterol and / or high cholesterol levels LDL and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (ie, those that have CETP in their plasma), including humans. Atherosclerosis, and coronary artery disease (CAD) associated with it, is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity and lack of exercise) and the treatment of dyslipidemia with diet modification and drug therapy, coronary heart disease (CHD) continues being the most common cause of death in the United States, where cardiovascular diseases account for 44% of all deaths, 53% of which are associated with atherosclerotic coronary heart disease. It has been shown that the risk of developing this condition is closely related to certain levels of plasma lipids. Although elevated levels of LDL-C may be the most recognized form of dyslipidemia, it 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 (Gordon, DJ, et al., "High-density Lipoprotein Cholestero and Cardiovascular Disease", Circulation, (1989), 79: 8-15). . High levels of LDL cholesterol and triglycerides are positively correlated, while high levels of HDL cholesterol are negatively correlated with the risk of developing cardiovascular diseases. Thus, dyslipidemia is not a unitary 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 disease-dependent principles, the activity of the cholesteryl ester transfer protein (CETP) affects all three. The role of this plasma glycoprotein of 70,000 daltons found in several animal species, including humans, is to transfer cholesteryl ester and triglycerides between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL) ), very low density lipoproteins (VLDL) and chylomicrons. The net result of CETP activity is a reduction in HDL cholesterol and an increase in LDL cholesterol. It is believed that this effect on the lipoprotein profile is pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk of CHD. There is no totally satisfactory therapy to raise HDL. Niacin can significantly increase HDL, but has severe tolerance problems that reduce acceptance. Fibrates and inhibitors of HMG CoA reductase only modestly increase HDL-C (-10-12%). As a result, there is a significant unmet medical need for an agent that is well tolerated and that can significantly raise plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis. Thus, although there is a diversity of anti-atherosclerotic therapies, the need still exists and alternative therapy is still sought in this field of the art. EP0818448 (970624) describes the preparation of certain tetrahydroquinolines 5, 6,7,8 substituted and analogues thereof, as inhibitors of the cholesteryl ester transfer protein. U.S. Patent No. 5,231,102 discloses a class of 4-substituted 1, 2,3,4-tetrahydroquinolines possessing an acid group (or a group convertible thereto in vivo) at position 2, which are antagonists specific for N-methyl-D-aspartate (NMDA) receptors and, therefore, are useful in the treatment and / or prevention of neurodegenerative disorders. U.S. Patent No. 5,288,725 discloses pyrroloquinoline bradykinin antagonists.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to compounds of formula I prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs; wherein R1 is Y, W-X or W-Y; where W is carbonyl, thiocarbonyl, sulfinyl or sulfonyl X is -O-Y, -S-Y, -N (H) -Y or -N- (Y) 2; where Y, for each case, is independently Z or a linear or branched carbon chain, from one to ten members, fully saturated, partially unsaturated or totally unsaturated, where the carbons other than the connecting carbon can be optionally replaced with one or two selected heteroatoms independently between oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono or di-substituted with oxo, said nitrogen is optionally mono or disubstituted with oxo, and said carbon chain is optionally mono-substituted with Z; where Z 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 that costs two condensed rings of three to six members partially saturated, fully saturated or totally unsaturated, taken independently, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, (C2-C6) alkenyl, (C-? -C6) alkyl, hydroxy, alkoxy (Ci-Cß), alkylthio (C4), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C -? - C6), mono-N- or di-N, N-alkylammon (Ci-Cß), wherein said alkyl substituent (C Cß) is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C? -C6) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ct-C6), mono-N- or di -N, N-alkylamino (Ci-Ce), and said alkyl substituent (CrC6) is also optionally substituted with one to nine fluorine atoms; R2 is a linear or branched carbon chain, from one to six members, partially saturated, fully saturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen , wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di- substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to seven member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring R2 is optionally linked through an alkyl group (C1 -C4); wherein said ring R2 is optionally mono-, di- or trisubstituted independently with halo, (C2-C3) alkenyl, (Ci-Cß) alkyl, hydroxy, alkoxy (Ci-Cß), alkylthio (C 1 -C 4), amino, nitro , cyano, oxo, carboxy, alkoxycarbonyl (Ci-Cß), mono-N- or di-N, N-alkylamino (C -? - C6) wherein said alkyl substituent (Ci-Ce) is optionally mono-, di- or tri- substituted independently with halo, hydroxy, (C? -C6) alkoxy, (C1-C4) alkylthio, oxo or alkyloxycarbonyl (d-C6); R3 is hydrogen or Q; where Q is a linear or branched carbon chain of one to six members fully saturated, partially unsaturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or trisubstituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted 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 mono-substituted with V; where V is a three to eight member ring partially saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members partially saturated, totally saturated or totally unsaturated, taken independently, which optionally have one to three heteroatoms , independently selected from nitrogen, sulfur and oxygen; wherein said substituent V is optionally mono-, di-, tri-, or tetra-substituted independently with halo, alkyl (CrC6), alkenyl (C2- C6), hydroxy, alkoxy (C -? - C6), alkylthio (C-) ? -C), amino, nitro, cyano, oxo, carboxamoyl, mono-N or di-N, N-alkylcarboxamoyl (C? -C6), carboxy, alkoxycarbonyl (Ci-Cß), mono-N- or di-N , N-alkylamino (Ci-Cß) where said (C -? - C6) alkyl or (C2-C6) alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (Ci-Cß), alkylthio (Cr C4), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C? -C6), mono-N- or di-N, N-alkylamino (C?), And said alkyl substituents (Ct-C?) Or (C2-C6) alkenyl are also optionally substituted with one to nine fluorine atoms; R4 is cyano, formyl, W1Q1, WV, alkylene (CrC4) V1 or V2; where W1 is carbonyl, thiocarbonyl, SO or S02, where Q1 is a carbon chain of one to six members, linear or branched, fully saturated, partially unsaturated or totally unsaturated, in which the carbons 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 mono-substituted with hydroxy, said carbon is optionally mono-substituted 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 mono-substituted with V1; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six partially saturated members , fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with halo, (C? -C6) alkyl, alkoxy, (Ci-Ce), hydroxy, oxo, amino, nitro, cyano, alkoxycarbonyl ( C? -C6), mono-N- or di-N, N-alkylamino wherein said alkyl substituent (C C6) is optionally mono-substituted with oxo, and said alkyl substituent (C-? - C6) is also optionally substituted with one to nine fluorine atoms; where V2 is a five to seven member ring partially saturated, fully saturated or totally unsaturated containing one to four heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V2 is optionally mono-, di- or trisubstituted independently with halo, (C1-C2) alkyl, (C2) alkoxy or oxo, wherein said (C-? - C2) alkyl optionally has from one to five carbon atoms. fluorine; where R4 does not include oxycarbonyl directly attached to the nitrogen of C? where R3 must contain V or R4 must contain V1; and R5, R6, R7 and R8 are independently hydrogen, a bond, nitro or halo, wherein said bond is substituted with T or a straight or branched carbon chain (C -? - C? 2), partially saturated, totally saturated or totally unsaturated, wherein the carbon can be optionally replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted 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 mono-substituted with T; where T is a three to eight member ring partially saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halo, (C? -C6) alkyl, (C2-C6) alkenyl, hydroxy, (Ct-C?) alkoxy, alkylthio (dC), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C? -C6), mono-N- or di-N, N-alkylamino (C -? - C6) where said alkyl substituent (C? -C6) is optionally mono-, di- or independently tri-substituted with hydroxy, (C-? - C6) alkoxy, (C-? - C4) alkylthio, amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ci-Cß), mono-N- or di- N, N-alkylamino (C-α-Ce) and said alkyl substituent (C - ε-C6) also optionally has from one to nine fluorine atoms; where R5 and R6, or R6 and R7, and / or R7 and R8 can also be taken together and can form at least one ring which is a partially saturated or fully unsaturated four to eight member ring optionally having from one to three selected heteroatoms independently between hydrogen, sulfur and oxygen; wherein said rings formed by R5 and R6, or R6 and R7, and / or R7 and R8 are, optionally mono-, di- or tri- substituted independently with halo, alkyl (C? -C6), alkylsulfonyl (C1-C4) , (C2-C2) alkenyl, hydroxy, (C -? - C6) alkoxy, alkylthio (dC), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ct-C6), mono-N- or di-N, N-alkylamino (C C6) wherein said (C? -C6) alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (CrC6), alkylthio (C1-C4), amino. nitro, cyano, oxo, carboxy, alkoxycarbonyl (C -? - C6), mono-N- or di-N, N-alkylamino (C C6) and said alkyl substituent (Ci-Cß) optionally also has from one to nine atoms of fluorine.

A preferred group of compounds, referred to as group A, contains the compounds having the formula I shown above, wherein the C2 substituent is beta; nitrogen 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, for each case, it is independently (C 1 -C 4) alkyl, said (C 1 -C 4) alkyl optionally having hydroxy or from one to nine fluorine atoms, or said (C 1 -C 4) alkyl being optionally mono-substituted with Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrC), alkoxy (C1-C4), alkylthio (C1-C4), nitro, cyano, oxo or alkyloxycarbonyl (CrC6), said alkyl being (C1-C4) optionally substituted with one to nine fluorine atoms; R2 is a straight or branched partially saturated, fully saturated or fully unsaturated carbon chain (C1-C4) in which the carbons other than the connecting atom can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said atoms carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di- replaced with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (CrC6), amino, nitro, alkyloxycarbonyl (CrC4) or carboxy; R3 is Q-V where Q is alkyl (CrC4) and V is a partially saturated, fully saturated or fully unsaturated five to 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), hydroxy, alkoxy (CrC), alkyloxycarbonyl (d-Cß), nitro, cyano or oxo and wherein said substituent alkyl (CrC6) optionally has from one to nine fluorine atoms; R4 is carbonyl or carbamoyl wherein said carbonyl radical is optionally mono-substituted with V1 or alkyl (CrC2) and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or alkyl (CrC2), in any case, optionally having said alkyl (CrC2) optionally mono-substituted with V1 or said alkyl (CrC2) of one to nine fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, nitro or alkyl (CrC2), said alkyl (CrC2) optionally having from one to five fluorine atoms; each of R6 and R7 independently hydrogen, halo, T, (C? -C6) alkoxy or alkyl (CrC?), said substituent optionally (C? -C6) or alkyl (CrC6) having from one to nine fluorine atoms or said substituent being (C6) alkoxy or alkyl (CrCβ) optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five or six member ring having optionally one or 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), hydroxy, alkoxy (CrCe), alkylthio (C1-C4), amino, oxo, carboxy, alkyloxycarbonyl (CrCe), mono- / V- or di-? /,? -alkylamino (CrCβ), wherein said alkyl substituent (CrCβ) optionally has from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring that is a partially or fully unsaturated five or six membered ring optionally having one or two heteroatoms independently selected from hydrogen, sulfur and oxygen; R5 and R8 are H; and pharmaceutically acceptable salts thereof. A group of compounds that is preferred among group A of compounds, designated group B, contains the compounds wherein W is carbonyl; X is O-Y where Y is alkyl (CrC), wherein said alkyl substituent (CrC4) optionally has hydroxy or from one to nine fluorine atoms; R2 is (C1-C4) alkyl, alkyloxymethylene (CrC2) or cycloalkyl (Cs-Cs); Q is (C 1 -C 4) alkyl and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrCβ), hydroxy, alkoxy (CrCβ), nitro, cyano or oxo, wherein said alkyl substituent (CrCβ) optionally has from one to nine carbon atoms. fluorine; R 4 is carbonyl or carbamoyl, wherein said carbonyl or carbamoyl is optionally mono-substituted with hydrogen or (C 1 -C 2) alkyl; each of R6 and R7 are independently hydrogen, (d-C3) alkoxy or alkyl (CrCß), said alkoxy (CrC3) optionally having one to seven fluorine atoms and optionally having said alkyl (CrCe) of one to nine carbon atoms. fluorine; and the pharmaceutically acceptable salts thereof. A group of compounds that is preferred among group B of compounds, designated group C, contains the compounds wherein Q is methyl and V is phenyl or pyridinyl; wherein said ring V is optionally mono-, di- or trisubstituted independently with halo, nitro or alkyl (CrC2), wherein said alkyl (CrC2) optionally has one to five fluorine atoms; and the pharmaceutically acceptable salts thereof. Especially preferred compounds of formula I are the compounds: [2S, 4S 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3 isopropyl ester, 4-dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-propyl ester -carboxylic; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-tert-butyl ester -quinoline-1-carboxylic acid; [2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester -carboxylic; and the pharmaceutically acceptable salts of said compounds. Other especially preferred compounds of formula I are the compounds; [2S, 4S] 4- [1- (3,5-bis-trifluoromethyl-benzyl) -ureido-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- isopropyl ester 1-carboxylic acid; [2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-propyl ester -carboxylic; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester -carboxylic; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; and the pharmaceutical salts of said compounds. Other especially preferred compounds of formula I are the compounds: [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formylamine] -2-methyl-6-ethyl ester trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quininoic acid isopropyl ester -1-carboxylic; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester -carboxylic; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline isopropyl ester -1-carboxylic; [2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 isopropyl ester -carboxylic; and pharmaceutically acceptable salts of said compounds.

Especially preferred compounds within group C of compounds are the compounds in which a. And it is isopropyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H; b. And it is n-propyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H; c. And it's tert-butyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H; d. And it is isopropyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; Rβ is trifluoromethyl; and R7 is H; and. And it is ethyl; R2 is methyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H; 10 f. And it is isopropyl; R2 is cyclopropiio; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is carbamoyl; R6 is trifluoromethyl; and 15 R7 is H; g. And it is ethyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H; h. And it is isopropyl; R2 is methoxymethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H; i. And it is n-propyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H; j. And it is ethyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethio; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H; k. And it is sopropilo; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is formyl; R6 is trifluoromethyl; R7 is H; I. And it is ethyl; R2 is methyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H; m. And it is isopropyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H; n. And it is ethyl; R2 is ethyl; R is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H; or. And it is ethyl; R2 is cyclopropyl; R 3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H; p. And it is sopropilo; R2 is methyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H; and q. And it is sopropilo; R2 is methyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; Rd is trifluoromethyl; and R7 is H; and pharmaceutically acceptable salts of said compounds. A preferred group of compounds, called group D, contains the compounds having the formula I as shown above, wherein the C2 substituent is beta; the nitrogen of C4 is beta; R is W-Y; W is carbonyl, thiocarbonyl or sulfonyl; Y is alkyl (CrC6), optionally having said alkyl (C Ce) of one to nine fluorine atoms or said alkyl (CrCe) being optionally mono-substituted with Z, where Z is a three to six member ring partially saturated, totally saturated or totally unsaturated having one or 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, alkoxy (CrC 4), alkylthio (C 1 -C 4), nitro, cyano, oxo or alkoxycarbonyl (d-Ce) , said substituent being (C1-C4) alkyl optionally substituted with one to nine fluorine atoms; R2 is a straight or branched, partially saturated, fully saturated or totally unsaturated carbon chain (CrC4), where the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is Q-V, where Q is (C1-C4) alkyl and V is a five or six member partially saturated, fully saturated or fully unsaturated 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 (d-Cß), hydroxy, alkoxy (d-Cß), nitro, cyano or oxo, wherein said alkyl substituent (d) -Cß) optionally has one to nine fluorine atoms; R4 is carbonyl or carbamoyl, wherein said carbonyl radical is optionally mono-substituted with V1 or alkyl (CrC2) and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or alkyl (CrC2), in any case, said alkyl being (CrC2) optionally mono-substituted with V1 or said alkyl (CrC2) optionally having from one to five fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V is optionally mono-, di-, or trisubstituted independently with halo, nitro or alkyl (CrC2), said alkyl (CrC2) having optionally from one to five fluorine atoms; each of R6 and R7 is independently hydrogen, halo, T, alkoxy (CrCe) or alkyl (CrC6), said substituent optionally having alkoxy (CrCß) or alkyl (d-Cß) of one to nine fluorine atoms or said substituent being alkoxy (d-C6) or alkyl (d-Cß) optionally mono-substituted with T; where T is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono, di-, or trisubstituted independently with halo, alkyl (CrCß), hydroxy, alkoxy (d-Cß), alkylthio (d-C4), amino, oxo, carboxy, alkoxycarbonyl mono-N- or di- / V,? / - alkylamino (CI-CQ), wherein said alkyl substituent (CrC6) optionally has from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring that is a five to six member ring partially saturated or fully unsaturated having optionally one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H; and the pharmaceutically acceptable salts thereof. A preferred group of compounds, called group E, contains the compounds having the formula I shown above, wherein the C2 substituent 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 one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (d-Ce), said alkyl substituent ( dd) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or fully unsaturated carbon chain (dd) where the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono -, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or fully unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member partially saturated, fully saturated or fully unsaturated 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 (d-Cß), hydroxy, alkoxy (d-Cß), nitro, cyano or oxo, said alkyl substituent (d- Cß) optionally has from one to nine fluorine atoms; R4 is carbonyl or carbamoyl, wherein said carbonyl radical is optionally mono-substituted with V1 or alkyl (CrC2) and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or alkyl (CrC2), in any case, said alkyl being (CrC2) optionally mono-substituted with V1 or optionally having said alkyl (d-C2) of one to five fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or tri-substituted independently with halo, (d-C2) alkyl or nitro, said alkyl substituent (CrC2) having one to five fluorine atoms; each of R6 and R7 is independently hydrogen, halo, T, alkoxy (d-Cß) or alkyl (d-Cß), said substituent having alkoxy (d-Cß) or alkyl (d-Cß) optionally having from one to nine atoms of fluorine or said substituent being alkoxy (d-Cß) or alkyl (d-Cß) optionally mono-substituted with T, where T is a five or six member ring partially saturated, fully saturated or fully unsaturated optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halo, alkyl (d-Cß), hydroxy, alkoxy (d-Cß), alkylthio (dd), amino, oxo, carboxy, alkyloxycarbonyl (CrC6), mono -N- od-N, N-alkylammon (d-C6), wherein said alkyl substituent (d-C6) optionally has from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring which is a five or six member ring partially saturated or fully unsaturated having optionally one to two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R6 are H, and pharmaceutically acceptable salts thereof. A preferred group of compounds, called group F, contains the compounds having the formula I as shown above, wherein the C2 substituent is beta; the nitrogen of C4 is beta; R1 is Y, where Y is alkyl (CrCe), said alkyl (d-Cß) optionally having from one to nine fluorine atoms or said alkyl (CrCs) being optionally mono-substituted with Z 'where Z is a three-to-three ring six members partially saturated, fully saturated or totally unsaturated having one or 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, alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (CrC 6), said substituent being alkyl (dd) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated saturated, fully saturated or totally unsaturated carbon chain (dd) in which the carbons, other than the connecting carbon, can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di- replaced with oxo; or said R is a three to five member ring partially saturated, fully saturated or completely unsaturated having optionally a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member partially saturated, fully saturated or fully unsaturated 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), hydroxy, alkoxy (d-Cß), nitro, cyano or oxo, wherein said alkyl substituent (d-Cß) ) optionally has from one to nine fluorine atoms; R4 is carbonyl or carbamoyl wherein said carbonyl radical is optionally mono-substituted with V1 or alkyl (d-C2) and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or alkyl (CrC2), in any case, said alkyl (CrC2) optionally mono-substituted with V1 or optionally having said alkyl (CrC2) of one to five fluorine atoms; where V is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrC2) or nitro, said alkyl substituent (CrC2) having from one to five fluorine atoms; each of R6 and R7 is independently halo, T, alkoxy (d-C6) or alkyl (d-Cß), said substituent optionally having alkoxy (CrCe) or alkyl (CrC6) of one to nine fluorine atoms or said substituent being (C? -C6) alkoxy or (dd) alkyl optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five or six member ring having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halo, alkyl (dd), hydroxy, alkoxy (d-Cß), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (dd), mono-N - or di »N, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine of fluorine; or wherein R6 and R7 are taken together and form a ring which is a partially or fully unsaturated five or six membered ring optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H; and the pharmaceutically acceptable salts thereof.

A preferred group of compound, called group G, contains the compounds having the formula I as shown hereinbefore, wherein the C2 substituent is beta; the nitrogen of C4 is beta; R1 is Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (dd), said substituent being alkyl (dd) optionally substituted with one to nine fluorine atoms; R2 is a straight or branched partially saturated, fully saturated or totally unsaturated carbon chain (d-d), in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen; sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R is a three to five member ring partially saturated, fully saturated or fully unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member partially saturated, fully saturated or fully unsaturated 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 (dd), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) is optionally mono -, di- or tri-substituted independently with alkoxy (dd) or alkylthio (dd) or said alkyl (dd) optionally has from one to nine fluorine atoms; R 4 is carbonyl or carbamoyl wherein said carbonyl radical is optionally monosubstituted with V 1 or alkyl (dd) and said carbamoyl radical is optionally mono- or di-substituted independently with V 1 or alkyl (d-C 2), in any case, said alkyl being ( -d) optionally monosubstituted with V1 or optionally having said (C1-C2) alkyl of one to five fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, alkyl (d-d) or nitro, said alkyl substituent optionally having (d-d) from one to five fluorine atoms; each of R6 and R7 are independently hydrogen; halo, T, alkoxy (dd) or alkyl (dd), said alkoxy (dd) or alkyl (dd) substituent optionally having from one to nine fluorine atoms or said substituent being alkoxy (dd) or alkyl (dd) optionally mono- replaced with T; where T is a partially saturated, saturated or fully unsaturated five or six member ring optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (dd), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (dd), mono-N- od -N, N-akylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; or where R6 and R7 are taken together and form a ring which is a partially or fully unsaturated five or six membered ring having optionally one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H; and the pharmaceutically acceptable salts thereof. A preferred group of compounds, referred to as group H, contains the compounds having the formula I shown above, wherein W is carbonyl; X is O-Y-, where Y is alkyl (d-d), wherein said alkyl substituent (d-d) is optionally substituted with one to nine fluorine atoms; R2 is alkyl (d-d) or cycloalkyl (C3-d); R3 is hydrogen; R 4 is alkylene (Crd) V 1; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, nitro or alkyl (d-d), said alkyl substituent (d-d) optionally having from one to five fluorine atoms; each of R6 and R7 is independently hydrogen, halo, T, alkoxy (dd) or alkyl (dd), said substituent optionally having alkoxy (CrCe) or alkyl (CrCe) of one to nine fluorine atoms or alkoxy substituent (CrCe) ) or alkyl (dd) optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five or six member ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (d-d), alkylthio (d-d), amino; oxo, carboxy, alkoxycarbonyl (d-d), mono-N- or di-N, N-alkylamino (C? -C6), wherein said alkyl substituent (CrC6) optionally has one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring which is a partially or fully unsaturated five or six membered ring having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono- or di-substituted independently with halo, alkyl (d-Cß), alkoxy (d-C6) or oxo, wherein said alkyl substituent (dd) optionally has from one to nine atoms of fluorine; R5 and R8 are H; and pharmaceutically acceptable salts thereof. A group of compounds which is preferred among the group H of compounds, designated group I, confers the compounds wherein X is OY, where Y is alkyl (d-C3), wherein said alkyl substituent (dd) optionally has one to seven fluorine atoms; R2 is alkyl (d-d) or cycloalkyl (C3-C5); R4 is methyleneV1. where V1 is a fully unsaturated six-membered ring optionally having one or two nitrogens; wherein said substituent V1 is mono-, di- or tri-substituted independently with halo, nitro or (C1-C2) alkyl, said alkyl (d-d) optionally having from one to five fluorine atoms; each of Rd and R7 are independently hydrogen, halo, alkoxy (d-d) or alkyl (d-C3), said substituents optionally having (C1-C3) alkoxy or alkyl (d-d) of one to seven fluorine atoms; or wherein R6 and R7 are taken together and form a ring that is a five or six member ring that is partially saturated or totally unsaturated and optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H, and pharmaceutically acceptable salts of the mimes. Other especially preferred compounds of formula I are the compounds: [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-methyl-6-trifluoromethyl-3,4-dihydro-2H- ethyl ester quinoline-1-carboxylic acid; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-methy1-6-trifluoromethyl-3,4-dihydro-2H-quinanoin-1-propyl ester -carboxylic; [2R, 4S] 4- (3,5-bis-trifluoromethy1-benzylamino) -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R.4S] 4- (3,5-bis-trifluoromethyl-benzyl-amino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; and pharmaceutically acceptable salts of said compounds. The compounds are also claimed: [2R.4S] 4-amino-2-methyl-6-trifiuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-amino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R.4S] 4-amino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R.4S] 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S.4S] 4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; and the pharmaceutically acceptable salts of said compounds. Another aspect of this invention relates to methods for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalfaliproteinemia, hypercholesterolemia, hypertrigiiceridemia, hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, injury of reperfusion, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being, both men and women) by administering to a mammal in need of such treatment a quantity for the treatment of the atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalfaliproteinemia, hypercholesterolemin, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke. Myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of atherosclerosis in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat atherosclerosis of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of a peripheral vascular disorder in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat the peripheral vascular disorder of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of dyslipidemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat the dyslipidemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hyperbetaiipoproteinemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat hyperbetalipoproteinemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hypoalphalipoproteinemia in a mammal (including humans) by administering to a mammal in need of such treatment an amount for treating hypoalphalipoproteinemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hypercholesterolemia in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat hypercholesterolemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hypertriglyceridemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat the hypertriglyceridemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of familial hypercholesterolemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat familial hypercholesterolemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of cardiovascular disorders in a mammal (including humans) by administering to a mammal in need of such treatment an amount for treating cardiovascular disorders of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said prodrug. Another aspect of this invention relates to a method for the treatment of angina in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat angina of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of ischemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat ischemic disease of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of cardiac ischemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat cardiac ischemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention pertains to a method for the treatment of stroke in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat stroke of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug.

Another aspect of this invention relates to a method for the treatment of myocardial infarction in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat myocardial infarction of a compound of Formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of reperfusion injury in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat the reperfusion injury of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of angioplastic restenosis in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat angioplastic restenosis of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of hypertension in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat hypertension of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of vascular complications of diabetes in a mammal (including humans) by administering to a mammal in need of such treatment an amount to treat vascular complications of the diabetes of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of obesity in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat obesity of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of endotoxemia in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat endotoxemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. A preferred dose is from 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 dose is from 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 also relates 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 also relates to pharmaceutical compositions for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalfaliproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (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 said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of atherosclerosis in a mammal (including a human), which comprises an amount for treating atherosclerosis 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 also relates to pharmaceutical compositions for the treatment of peripheral vascular disease in a mammal (including a human), which comprises an amount for treating 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 also relates to pharmaceutical compositions for the treatment of dyslipidemia in a mammal (including a human), comprising an amount to treat the dyslipidemia 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 also relates to pharmaceutical compositions for the treatment of hyperbetalipoproteinemia in a mammal (including a human), which comprises an amount for treating hyperbetalipoproteinemia 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 also relates to pharmaceutical compositions for the treatment of hypoalphalipoproteinemia in a mammal (including a human), which comprises an amount for treating hypoalphalipoproteinemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt thereof. said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of hypercholesterolemia in a mammal (including in a human), comprising an amount for treating hypercholesterolemia of a compound of formula I, a prodrug thereof, or a pharmaceutically salt acceptable of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of hypertriglyceridemia in a mammal (including in 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 also relates to pharmaceutical compositions for the treatment of familial hypercholesterolemia in a mammal (including a human), comprising an amount for treating familial hypercholesterolemia 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 also relates to pharmaceutical compositions for the treatment of angina in a mammal (including a human), which comprises 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 and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of ischemia in a mammal (including a human), which comprises a condition for treating the ischemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt thereof. said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of cardiac ischemia in a mammal (including a human), comprising an amount for treating cardiac ischemia of a compound of formula I, a prodrug thereof, or a pharmaceutically salt acceptable of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of stroke in a mammal (including a human), comprising an amount for treating stroke 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 also relates to pharmaceutical compositions for the treatment of myocardial infarction in a mammal (including a human), comprising an amount for treating myocardial infarction 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 also relates to pharmaceutical compositions for the treatment of reperfusion injury in a mammal (including a • human), comprising an amount for treating the 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 also relates to pharmaceutical compositions for the treatment of angioplastic restenosis in a mammal (including a human), which comprises an amount for treating 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 also relates to pharmaceutical compositions for the treatment of hypertension in a mammal (including a human), comprising an amount for treating hypertension 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 also relates to pharmaceutical compositions for the treatment of vascular complications of diabetes in a mammal (including a human), which comprises an amount to treat the vascular complications of diabetes of a compound of formula I, a prodrug of the same, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of obesity in a mammal (including a human), comprising an amount for treating obesity 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 also relates to pharmaceutical compositions for the treatment of endotoxemia in a mammal (including a human), comprising an amount for treating the endotoxemia 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 also relates to a combination pharmaceutical composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; a first compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of the secretion of the triglyceride transfer protein microsomal (MTP) / ApoB, a PPAR activator, 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 bile acid complexing agent; and / or, optionally, a pharmaceutical carrier. Among the second compounds, an inhibitor of the HMG-CoA reductase and an inhibitor of MTP / Apo B secretion. A particularly preferred inhibitor of HMG-CoA reductase is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. Another aspect of this invention is a method for the treatment of atherosclerosis in a mammal comprising administering to a mammal suffering from atherosclerosis; a first compound, said first compound being a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and 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, a ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid complexer, where the amounts of the first and second compounds produce a therapeutic effect. A preferred aspect of the above process is that in which the second compound is an HMG-CoA reductase inhibitor or an inhibitor of MTP / ApoB secretion. A particularly preferred aspect of the above process is that in which the HMG inhibitor is used. -CoA reductase is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. Yet another aspect of this invention is a team comprising: a. a first compound, said first compound being 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, 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, a resin ion exchange, an antioxidant, an ACAT inhibitor or a bile acid complexing agent and an acceptable vehicle in a second unit dosage form; and c. means for containing said first and second dosage unit forms, wherein the amounts of the first and second compounds produce a therapeutic effect. A second preferred compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / ApoB secretion. A particularly preferred HMG-CoA reductase inhibitor rivastatin. As used herein, it is understood that the term mammals refers to all mammals that contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans.

Certain other mammals, for example, dogs, cats, cows, goats, sheep and horses do not contain CETP in their plasma and, therefore, are not included here. The term "treatment" as used herein includes preventive (e.g., prophylactic) and palliative treatment. By "pharmaceutically acceptable salts" is meant the vehicle, diluent, excipients and / or salts that have to be compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The term "prodrug" refers to compounds that are drug precursors, which after administration, release the drug in vivo by some chemical or physiological processes (e.g., a prodrug which when carried to physiological pH by an enzymatic action becomes in the desired drug form). Exemplary prodrugs, upon cleavage, release the corresponding free acid, and such hydrolyzable ester-forming moieties of the compounds of formula I include, but are not limited to, those having a carboxyl radical in which the free hydrogen has been replaced by alkyl (C1-C4), (C2-C) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1-alkoxycarbonyloxymethyl having ae to oa? a? iuuß us miuunu, .- (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) having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonium, gamma-butyrolacton-4-yl, di-N, N -alkylamino (CrC2) -alkyl (C2-C3), (such as b-dimethylaminoethyl), carbamoyl-alkyl (dd), N, N-di-alkylcarbamoyl (Crd) -alkyl (dd) and piperidino-, pyrrolidino- or morpholino ((C2-C3) alkyl.

The following paragraphs describe exemplary rings for the descriptions of generic rings contained in this document. Exemplary five- or six-membered aromatic rings 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, pyridazinyl, pyrimidinyl. and pyrazinyl. Rings of five to eight partially saturated, fully saturated or fully unsaturated members, 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, -pyrazzolinyl, 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-oxadiazolium, 1,2,3-triazolyl, 1,4-triazolyl, 1,4-thiadiazolyl, 1, 2,3,4-oxatrlazolyl, 1, 2 , 3,5-oxatriazolyl, 3H-1, 2,3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazoyl, 1,4-dioxazolyl, 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, 3,5-triazinyl, 1,4-triazinyl, 1, 2,3-triazinyl, 1, 3,5-trityanyl, 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, , 4-oxazinyl, or 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, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen include indolizinyl, indolyl, isoindolyl , 3H-indolyl, 1 H-isoindolyl, indolinyl, cyclopenta (b) pyridinyl, pyran (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl benzo (b) thienyl, benzo (c) thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, benzoimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido (3,4-b) -pyridinyl, pyrido (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl , 1 H-2,3-benzoxazinyl, 4H-3.1-benzoxazinyl, 2H-1.2 -benzoxazinyl and 4H-1,4-benzoxazinyl.

Alkylen means a saturated hydrocarbon (straight or branched chain) in which a hydrogen atom has been removed from each of the terminal carbons. Examples of such groups (assuming that the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene). Halo means chlorine, bromine, and iodine or fluorine. By "alkyl" is meant a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon. Examples of such alkyl groups (assuming that the designated length encompasses the particular example) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl. By "alkoxy" is meant straight chain saturated alkyl or branched chain saturated alkyl attached through an oxy group. Examples of such alkoxy groups (assuming that the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy. As used herein, the term mono-N- or di-N, N-alkyl (dd) ... refers to the alkyl radical (dd) taken independently when it is di-N, N-alkyl (Cid). .. (x refers to integers).

The references (e.g., in claim 1) to "said carbon" in the phrase "said carbon is optionally mono-, di- or trisubstituted independently with halo, said carbon is optionally mono-substituted hydroxy, said carbon is optionally mono- substituted with oxo "refers to the carbons of the carbon chain including the carbon connection. References to a "nitrogen ... di-substituted with oxo" in this document (e.g., in claim 1) refer to a terminal nitrogen that constitutes a nitro functionality. It will be understood that if a carbocyclic or heterocyclic radical can be linked or otherwise bound to a designated substrate through different ring atoms without indicating a specific point of attachment, reference is made to all possible points, either through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2, 3- or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, and so on. 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 such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N.N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglumine (N -methylglucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol). As used herein, the terms "reaction inert solvent" and "inert solvent" refer to a solvent or a mixture thereof that does not interact with the starting materials, reagents, intermediates or prodrugs in a manner that adversely affects the performance 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 "up" or both "down").

Analogously, 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, the page). Beta is above the plane of the ring (that is, the page) and alpha is below the plane of the ring (ie, the page). Chemists of ordinary experience will recognize that certain compounds of this invention will contain one or more atoms that may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such 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 forms, that is, said compounds can contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The radioisotopes of hydrogen, carbon, phosphorus, fluorine and chlorine include 3H, 14C, 32P, 35S, 18F and 36CI, respectively. The compounds of this invention, or prodrugs thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug containing these radioisotopes and / or other radioisotopes of other atoms, are within the scope of this invention. Particularly preferred are tritiated radioisotopes, i.e., 3 H and carbon-14, i.e., 14C, for their easy preparation and detectability. The radiolabeled compounds of formula I of this invention and the prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabelled compounds can be prepared by performing the procedures described in the schemes and / or in the examples and preparations shown below, by replacing a non-radiolabelled reagent with a readily available radiolabelled reagent. DTT means dithiothreitol, DMSO means dimethyl sulfoxide, EDTA means ethylenediamine tetraacetic acid.

Other features and advantages of this invention will be apparent from this specification and the appended claims describing the invention.

DETAILED DESCRIPTION OF THE INVENTION In general, the compounds of this invention can be obtained by processes that include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. In the experimental section, other procedures can be described.

SCHEME I Vil VI SCHEME II VI V SCHEME SCHEME IV SCHEME V LV! LVIIi LV SCHEME VI LXGV SCHEME Vil LXX LXXI LXXII SCHEME VIII LXXXI LXXXII As an initial note, it should be noted that in the preparation of the compounds of formula I some of the preparation methods suitable for the preparation of the compounds described herein require protection of a remote functionality (eg, primary amine, secondary amine or carboxyl in the precursors of formula I). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation procedures. The need for such protection is easily determined by one skilled in the art. The use of such protection / deprotection procedures is also within the skill in the art. As a general description of the protective groups and their use, see T.W. Greene, Protecfive Groups in Organic Svnthesis, John Wiley & Sons, New York, 1991. For example, in reaction schemes I and II certain compounds of formula I contain primary amine or carboxylic acid functionalities that can interfere with reactions and other sites of the molecule if left unprotected. Accordingly, such functionalities can be protected by an appropriate protective group that can be removed at a later stage. Suitable protecting groups for the protection of the amine and the carboxylic acid include the protecting groups commonly used in the synthesis of peptides (such as Nt-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethyleneoxycarbonyl for amines, and lower alkyl or benzyl esters for acids carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionalities of the compound of formula I. According to reaction scheme I, the compounds of formula III in which R2, R5, R6, R7 and R8 are as described above and P2 is a suitable protecting group, they can be prepared from the appropriate aromatic amine of formula II wherein R5, R6, R7 and R8 are as described above. The tetrahydroquinoline of formula III is prepared by treating the appropriate aromatic amine of formula II with the required carboxaldehyde, in an inert solvent such as a hydrocarbon (eg, hexanes, pentanes or cyclohexane), an aromatic hydrocarbon (eg, benzene) , toluene or xylene), a halocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride or dichloroethane), an ether (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, methyl tert-butyl ether, etc. .), a nitrile (e.g., acetonitrile or propionitrile), a nitroalkane (e.g., nitromethane or nitrobenzene), preferably dichloromethane, with a dehydrating agent (e.g., sodium sulfate or magnesium sulfate), at a temperature from about 0 ° C to about 100 ° C (preferably at room temperature) for 1-24 hours (preferably 1 hour) The resulting solution is treated with a conveniently substituted N-vinyl species (eg, benzyloxycarbonyl, t-butoxycarbonyl, methoxycarbonyl, formyl-, acetyl-, diallyl- or dibenzyl-N-vinyl), preferably carboxybenzyloxy-N-vinyl and with a Lewis acid ( for example, boron trifluoride, boron trifluoride etherate, zinc chloride, titanium tetrachloride, iron trichloride, aluminum trichloride, aluminum alkyl dichloride, dialkyl aluminum triflate of ytterbium (II); preferably boron trifluoride etherate) or a protic acid such as hydrohalogenic acid (eg, fluorine, chlorine, bromine or iodine), an alkyl sulfonic acid (eg, p-toluene, methane or trifluoromethane) or carboxylic acid (e.g. formic, acetic, trifluoroacetic or benzoic), at a temperature from about -78 ° C to about 50 ° C (preferably at room temperature), for 0.1 to 24 hours (preferably for 1 hour). Alternatively, the amine of formula II and the appropriate carboxaldehyde can be condensed by treating a solution of the amine and an alkyl amine 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 ° C), followed by treatment with carboxaldehyde at a temperature between about -78 ° C and about 40 ° C (preferably 0 ° C.) The reaction is allowed to proceed for about 0.1 to about 10 hours (preferably for 1 hour), at a temperature between about 0 ° C and about 40 ° C (preferably at room temperature), yielding the amine , which is reacted with the N-vinyl species as described above. IV wherein R1, R2, 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 of amines known per se. those skilled in the art.

Thus, the compounds of formula IV in which R1, R2, R5, R6, R7 and R8 are as described above and P1 and P2 are protective groups appropriately differentiated for the amine radicals, are prepared from the corresponding tetrahydroquinoline of formula III using standard procedures for transforming amines into the functional groups described for R1 above, see Richard Larock, Comprehensive Orqanic Transformations, VCH Publishers Inc., New York, 1989 and Jerry March, Advanced Orqanic Chemistry, John Wiley & Sons, New York, 1985. For example, a compound of formula III is treated with the appropriate carbonyl chloride, sulfonyl chloride or sulfinyl chloride, isocyanate or thiocyanate, in a polar aprotic solvent (preferably dichloromethane), in the presence of a base (preferably pyridine), at a temperature of about -78 ° C to about 100 ° C (preferably starting at 0 ° C and allowing to warm to room temperature) for a period of 1 to 24 hours (preferably 12 hours). The carbamate of formula IV and the urea compounds (wherein R1 is W = C (O), X = OY, SY, N (H) -Y or NY2) can be prepared from the amines of formula III by means of the corresponding carbamoyl chlorides, by treating the amine of formula III with a solution of phosgene in a hydrocarbon solvent (preferably toluene) at a temperature comprised between about 0 ° C and about 200 ° C (preferably under reflux) for a period comprised between 0.1 and 24 hours (preferably 2 hours).

The corresponding ureas can be prepared by treating a solution of the carbamoyl chlorides (prepared as described above) with the appropriate mine in a polar solvent (preferably dichloromethane), at a temperature between about -78 ° C and about 100 ° C. ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 12 hours). The corresponding carbamate can be prepared by treating a solution of the carbamoyl chlorides (prepared as described above) with the appropriate alcohol and a suitable base (preferably sodium hydride) in a polar solvent (preferably dioxane), at a temperature comprised between about -78 ° C and about 100 ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 12 hours). Alternatively, the corresponding carbamate can be prepared by treating a solution of the carbamoyl chlorides at a temperature between about 0 ° C and about 200 ° C in the appropriate alcohol, for a period of between 1 and 240 hours (preferably 24 hours). 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 their Y-substituents such as an alkyl substituent or attached to alkyl. 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 substituents can be attached by reduction after condensation of the amine of formula III with the required carbonyl-containing reagent. In addition, the amine of formula III can be reacted with the appropriate alkyl or aryl halide according to procedures known to those skilled in the art. Thus, the amine formula III and an acid (eg, halogenic, sulfuric, sulfonic or carboxylic, preferably acetic) are treated with the appropriate carbonyl-reagent reagent, in a polar solvent (preferably ethanol), at a temperature of about 0. ° C at approximately 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, sodium cyanoborohydride or preferably sodium triacetoxyborohydride), at a temperature of 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, R2, 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 known procedures by those skilled in the art, including hydrogenolysis, treatment with an acid (for example, trifluoroacetic or hydrobromic acid), a base (sodium hydroxide), or reaction with a nucleophile (for example, sodium methylthiolate, sodium cyanide, etc.) and for the trialkylsilylethoxycarbonyl group a fluoride (for example, tetrabutyl ammonium fluoride) is used. For the removal of a benzyloxycarbonyl group, the hydrogenolysis is carried out by treating the compound of formula IV with a hydride source (for example, 1 to 10 atmospheres of hydrogen gas, cyclohexene or ammonium formate) in the presence of a suitable catalyst ( example, palladium of 5-20% on carbon, 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 IV wherein R 1, R 2, R 3, R 5, R 6, R 7 and R8 are as described above and P1 is a protecting group as described above, can be prepared from the corresponding amine of formula V by various amine reaction routes known to those skilled in the art. Compounds of formula VI in which R3 is as described above, can be prepared using methods known to those skilled in the art to introduce R3 substituents; including for example, the procedures described for the introduction of the substituent R1 in the transformation of the compounds of formula III into the compounds of formula IV. The methods include, for example, the formation of an amide from the amine of formula V and an activated carboxylic acid, followed by reduction of the amide with borane in an ether solvent such as tetrahydrofuran. Alternatively, an alkyl substituent may be added or bound to alkyl by reduction of the appropriate imine, the imine being formed by condensation of the amine of formula V with the required carbonyl-containing reagent. In addition, the amine of formula V can be reacted with the appropriate alkyl halide according to methods known to those skilled in the art. Thus, the amine of formula V and an acid (eg, halogenic, sulfuric, sulfonic or carboxylic, preferably hydrochloric) are treated with the appropriate carbonyl-containing reagent in a polar solvent (preferably dichloromethane), at a temperature of about 0. ° C at 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 0.1 to 100 hours (preferably for 5 hours). The compound of formula VII in the R, R2, R3, R5, R6, R7 and R8 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding compound of formula IV by procedures known to the experts in the art; for example, the methods described for the introduction of the above substituent R3 in the transformation of the compound of formula V into the compound of formula VI. After this, the corresponding compound of formula VI can be prepared from the compound of formula VII by appropriate deprotection, such as the procedures described above for the transformation of the compound of formula IV into the compound of formula V. When R3 is H and R4 s as described above, R4 can be represented by R3 in formulas VI and VII of scheme I, thus providing a synthetic scheme for such compounds. According to scheme II, the dihydroquinolone compounds of formula XI wherein R2, R5, R6, R7, R8 and Y are as described above and P1 is a protecting group, can be prepared from the corresponding quinolines of formula X by treatment with organometallic species and a chloroformate, followed by hydrolysis. Thus, a mixture of the quinoline of formula X and an excess (preferably 1.5 equivalents) of an organomagnesium species (Grignard reagent) in a polar aprotic solvent (for example, diethyl ether or dichloromethane, preferably tetrahydrofuran) is treated with an excess (preferably 1.5 equivalents) of Y- or P1-chloroformate, at a temperature comprised between about -100 ° C and about 70 ° C (preferably -78 ° C), followed by heating at a temperature comprised between about 0 ° C and about 70 ° C (preferably room temperature) for a period between 0.1 and 24 hours (preferably 1 hour). The resulting mixture is combined with an excess (preferably 2 equivalents) of an aqueous acid (preferably 1 molar hydrochloric acid) and mixed vigorously for a period between 0.1 and 24 hours (preferably 1 hour), or until it is determined that hydrolysis of the intermediate enol ether has been completed). Of course, the compounds of formula XI are the compounds of formula XVI wherein R1 is -C (O) OY or P1 is C (O) OP1 without further transformation. Compounds of formula XV wherein R2, R5, R6, R7 and R8 are as described above, can be prepared from the corresponding dihydroquinolone of formula XI (wherein the compound of formula XI contains P1) by appropriate deprotection ( including spontaneous decarboxylation) as described for the transformation of the compound of formula VI into the compound of formula V. Compounds of formula XVI wherein R1, R2, 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 as described 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 on the carbonyl oxygen in position 4, the substituent can be conveniently removed by treatment with an acid (for example HCl) or a base (for example, aqueous sodium hydroxide). Again, for compounds of formula XVI wherein R1 or P1 is the same as for the compound of formula XI, such a transformation as described above is not necessary. The amine compounds of formula VI in which R1, R2, 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 sequence of reductive amination. The dihydroquinolone of formula XVI, an excess (preferably 1.1 equivalents) of an R3-amine and an excess (preferably 7 equivalents) of an amine base (preferably triethylamine) in a polar solvent (preferably dichloromethane), is treated with a 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 at room temperature), over a period of time comprised between 1 and 24 hours (preferably 12 hours). The resulting imine of formula XII is reduced by treatment with a reducing agent (preferably sodium borohydride) in an appropriate polar solvent (preferably ethanoi), at a temperature between about 0 ° C and about 80 ° C (preferably at room temperature) , for a period comprised between 1 and 24 hours (preferably 12 hours), resulting in a mixture of diastereomeric amines of formula VI, generally with a higher quality of the trans isomer. Alternatively, the reduction can be carried out by treating the imine of formula XII directly with an excess (preferably 5 equivalents) of zinc borohydride as a solution in ether (preferably 0.2 molar), at a temperature comprised between about 0 ° C and about 40 ° C (preferably room temperature), for a period of between 1 and 24 hours (preferably 12 hours), resulting in a mixture of diastereomeric amines of formula VI, generally with a greater proportion of the cis isomer. Alternatively, the amine of formula VI wherein R1, R2, R3, R5, Rd, R7, and R8 are as described above and P1 is a protecting group, can be prepared from the corresponding dihydroquinolines of formula XVI by the formation of an oxime, reduction and substitution of the amine. Thus, the dihydroquinolone of formula XVI, an excess (preferably 3 equivalents) of hydroxylamine hydrochloride and an excess (preferably 2.5 equivalents) of a base (preferably sodium acetate) are reacted at a temperature between about 0 ° C and about 100 ° C (preferably at reflux) for a period between about 1 and 24 hours (preferably 2 hours), in a polar solvent (preferably ethanol). The resulting oxime of formula XIII is treated with an excess (preferably 6 equivalents) of aqueous base (preferably 2 N potassium hydroxide), in a polar solvent (preferably ethanol) and an excess (preferably 4 equivalents) of a nickel-aluminum alloy (preferably 1: 1 by weight), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature), for a period between 0.25 and 24 hours (preferably 1 hour). The resulting amine of formula V is obtained in the form of a diastereomeric mixture (the cis isomers generally predominating). The secondary amine of formula VI in which R1, R2, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group, can be prepared from the amine of appropriate formula V as described in scheme I for the transformation of the compound of formula V into the compound of formula VI. According to scheme III, the compounds of formula I as described above, can be prepared from the appropriate compounds of formula VI using procedures known to those skilled in the art.; including, for example, the methods described for the introduction of the substituent R1 in the transformation of the compounds of formula III into the compounds of formula V. Alternatively, according to scheme III, when appropriate, if the functionality in R1 is incompatible with the reaction to form the compound of formula I, then the compound of formula VI with protected P1 can be transformed into the compound of formula I by the protection / deprotection sequences and the introduction of the desired substituents. Thus, the amine of formula VI is treated with the appropriate reagent (for example, precursor of the protecting group, activated carbonate (for example chloroformate, dicarbonate or carbonyl imidazole)) in a polar solvent (preferably dichloromethane), in the presence of an excess of amine base (preferably pyridine), at a temperature comprised between about -20 ° C and about 40 ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 12 hours), to produce the compound of formula XX. In addition, compounds of formula XX, in which P2 is present, can be obtained as shown in scheme I for compounds of formula VII (having P1). The amines of formula XXI wherein R2, R3, R5, R6, R7, R8 and R4 are as described above and P2 is a protecting group, can be prepared from the compound of formula XX by selective deprotection 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 100 ° C (preferably at room temperature) , for a period of 0.1 to 24 hours (preferably 1 hour). The compounds of the formula I or the compounds of the formula XXII (wherein R1 is as described above), can be prepared from the corresponding amine of formula XXI (wherein R4 or P is respectively present) by various routes of amine reaction known to those skilled in the art, for example, those described in scheme I for the transformation of the compound of formula III into the compound of formula V. The amines of formula XXIII can be prepared from the compounds of formula XXII through adequate deprotection. When P2 is, for example, benzyloxycarbonyl, the compound of formula XXIII is prepared by treatment with an excess of a hydride source (eg, cyclohexane, hydrogen gas or preferably ammonium formate) 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 ethanoi), at a temperature between about 0 ° C and about 100 ° C (preferably at room temperature), over 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 for the conversion of the compound of formula VI into the compound of formula I of scheme III above. According to scheme IV, the compounds of formula V in which R1, R2, R5, R7 and R8 are as described above, and R6 is an ether-linked radical, can be obtained from the quinolones of formula XXX having a radical OP3, where P3 is a protecting group, in the Re position, employing the following procedures. Furthermore, in an analogous manner, such methods can be used to prepare the corresponding compounds wherein R5, R7 or R8 are an ether-linked radical starting from the corresponding compound of formula XXX having an OP3 radical at positions R5, R7 or R8 . • Thus, the quinolone of formula XXX is combined with hydroxylamine hydrochloride and a mineral base (preferably sodium acetate) in a polar solvent (preferably ethanol), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at reflux), for a period comprised between 1 and 24 hours (preferably 2 hours), to produce the oxime of formula XXXI. The oxime of formula XXXI is treated with an excess (preferably six equivalents) of an aqueous base (preferably 2 N potassium hydroxide) and an excess (preferably four equivalents) of a nickel-potassium alloy (preferably 1: 1 by weight) in a polar solvent (preferably ethanol), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature), for a period between 0.25 and 24 hours (preferably 2 hours), to prepare the corresponding amine of formula XXXII. If necessary, the protecting group P3 can be removed using conventional procedures if the transformation of the oxime does not produce such 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 wherein P3 is H, which can then be reduced to form the amine of formula XXXII. The compound of formula V in which R6 is an oxy-linked radical, can be prepared by treating the alcohol of formula XXXII under, for example, Mitsunobu conditions. Thus, the phenol of formula XXXIII is treated with a phosphine (preferably triphenylphosphine) and an azodicarboxylate (preferably bis- (N-methylpiperazinyl) -azodicarboxamide) and the required alcohol in a polar solvent (preferably benzene). Of course, by means of Schemes I and II, the resulting compound of formula V can be transformed into the precursors of formula VI or formula VIII for the compounds of formula I of this invention. Alternatively, the compound of formula XX in which R6 is an ether-linked radical, wherein R1, R2, R3 and R4 are as described above and P1 and P2 are protecting groups, can be prepared from the alcohols of formula XXXII as described later. Furthermore, in an analogous manner, such methods can be used to prepare the corresponding compounds wherein R5, R7 or R8 are an ether bound radical starting from the corresponding compound of formula XXXII and, therefore, finally, the compound of formula XXX (that is, the compound of formula XXX that has a P3O- in positions R5, R7 or R8). The secondary amine of formula XXXIII wherein R3 is as described above, can be prepared from the corresponding compound of formula XXXII according to the procedures of Scheme I described above for the conversion of the compound of formula V to the compound of formula SAW. Compounds of formula XXXIV wherein R4 is as described above, can be prepared from the amines of formula XXXIII by procedures analogous to those described in scheme III for the transformation of the compound of formula VI into the compounds of formula XX or of formula I. The phenol of formula XXXV can be selectively deprotected, for example, when certain carbonyl-linked groups R4 are present, by treatment of the carbonate of formula XXXIV with potassium carbonate in a polar solvent (preferably methanol), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature) for a period between 1 and 24 hours (preferably 12 hours). The corresponding XX ethers can be prepared from the phenol of formula XXXV using, for example, the Mitsunobu conditions described above for the conversion of the compounds of formula XXXII in the compounds of formula V.

Of course, one skilled in the art will appreciate that phenol can be transformed into a variety of functional groups using conventional methods, for example, as described in March or Larock, or by conversion into the corresponding triflate for use in a variety of reactions including transition metal catalysis. Although the following description of scheme V refers to the modifications of position R6 (position R6 described in formula I above), those skilled in the art will appreciate that analogous procedures can be applied to positions R5, R7 and R8. According to scheme V, the alcohol of formula Ll in which R1, R2, R3, R4, R ^ R7 and R8 are as described above, P1 and P2 are protecting groups and X1 is a linking group in which a carbon (eg, methylene) is directly attached to the carbonyl radical , can be prepared from the corresponding ester (where R12 is a convenient alkyl radical) by reduction. Thus, the ester of formula L is treated with sodium borohydride / methanol or a complex of borane-dimethyl sulphide in a polar solvent (preferably tetrahydrofuran), at a temperature comprised between approximately 0 ° C and approximately 100 ° C (preferably at reflux), for a period comprised between 1 and 24 hours (preferably 3 hours). Compounds of formula Lll wherein R1, R2, R3, R4, R5, R7 and R8, are as described above, P1 and P2 are protecting groups and wherein the R6 position includes an alkyl halide functionality, can be prepared from the corresponding alcohol of formula Ll by treatment with trialkylphosphine (preferably triphenylphosphine) and a dihalogen (for example, bromine), in polar solvent (preferably dichloromethane), at a temperature between about 0 ° C and about 100 ° C (preferably at 0 ° C), for a period comprised between 0.1 to 10 hours (preferably 0.5 hours), followed by heating to room temperature for a period between 0.1 and 10 hours (preferably 3 hours). Compounds of the formula Lili wherein R1, R2, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protecting groups, the Rd position includes ether and thioether radicals (ie, Y1 is S or O) and R13 is a carbon-bonded substituent, can be prepared by treating the alkyl halide of formula Lll in a polar solvent (preferably N, N-dimethylformamide) with the required alkoxide or thioalkoxide, at a temperature comprised between about 0 ° C and approximately 100 ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 6 hours). Alternatively, ethers and thioethers of formula Lili can be prepared by treating the corresponding alcohols and thiols of formula LV (ie, Y1 is S or O), wherein X1 is a substituent directly attached through carbon to the methylene moiety , with a base preferably sodium hydride) and the required alkylating agent in a polar solvent (preferably N, N-dimethylformamide), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature), over a period of time between 1 and 50 hours (preferably 18 hours). The compounds of formula LV in which R1, R2, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protective groups, position R6 includes alkyl halides (for example fluorides) and X1 is a substituent which is carbon directly attached to the methylene radical, can be prepared by treating the corresponding alcohol of formula Ll with a halogenating agent. For example, the alcohol is treated with a fluorinating agent (preferably diethylaminosulfur trifluoride) in a polar solvent (preferably 1,2-dichloroethane), at a temperature between about 0 ° C and about 100 ° C (preferably at 80 ° C). C), for a period comprised between 1 and 10 hours (preferably 0J5 hours). The amine compounds of formula LVII wherein R1, R2, R3, R4.

R5, R7 and R8 are as described above, P1 and P2 are protecting groups and wherein R6 includes an amide functionality (such that X is a substituent that is carbon directly attached to the carbonyl radical and R10 and R11 are substituents selected for producing the desired R6 substituent defined above), can be prepared from the corresponding carboxylic acid of formula LVI which, in turn, can be prepared from the corresponding carboxylic ester of formula L.

Thus, the ester of formula L is treated with an aqueous hydroxide (preferably lithium, sodium or potassium) in a polar solvent (preferably tetrahydrofuran and / or methanol), at a temperature between about 0 ° C and about 100 ° C ( preferably at room temperature), for a period comprised between 0.1 and 100 hours (preferably 1 hour). The amide of formula LVII can be prepared from the corresponding acid of formula LVI by conventional procedures. The conversion of the carboxylic acid to the acid chloride is preferred by dissolving the acid in thionyl chloride and maintaining the solution at a temperature between about 0 ° C and about 80 ° C (preferably under reflux), for a period of time between 0.1 and 24 hours (preferably 1 hour), before the evaporation of the excess of thionyl chloride. This step is continued by treatment of the resulting acid chloride residue in a polar solvent (preferably dichloromethane) with the appropriate amine, selected to produce the amide functionality, and optionally an amine base (preferably triethylamine) at a temperature comprised between about -78 ° C and approximately 100 ° C (preferably at room temperature), for a period comprised between 0.1 and 100 hours (preferably 1 hour).

Although the following description of Scheme VI refers to the modifications of position R8, those skilled in the art will appreciate that analogous procedures can be applied for positions R5, R6, R7. According to scheme VI, the compound of formula LXI wherein R1, R2, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding compound of LX formula by nitration. The compound of formula LX is treated with nitrosyltriflate in a halogenated solvent, such as dichloromethane, at a temperature from about -78 ° C to about 0 ° C, for a period of from about 0.5 hours to about 3 hours, followed by heating to temperature ambient. The amine of formula LXII wherein R1, R2, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protecting groups, can be prepared from the corresponding compound of formula LXI by reduction. The compound of formula LXI is hydrogenated by treatment with hydrogen gas in the presence of a noble metal catalyst (eg, palladium on carbon) in a polar solvent such as ethanol, at a temperature of from about 0 ° C to about 100 ° C. for about 1 to 24 hours at elevated pressure (eg, 1 to 3 atmospheres). The compound of formula LXIII in which R1, R2, R3, R4, R5, Rd and R7 are as described above and P1 and P2 are protective groups and R8 is an amine-linked functionality, can be prepared from the corresponding formula LXII. The amine of formula LXII is transformed following procedures analogous to those described in scheme I for the conversion of the compound of formula III into the compound of formula IV. The compound of formula LXIV wherein R1, R2, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding compound of formula LXII. The amine of formula LXII is treated with t-butyl nitrate and anhydrous cupric halide in a polar solvent, at a temperature of about 30 ° C to about 100 ° C, for a period of about 1 hour to about 24 hours. Of course, one skilled in the art will understand that the halide can be transformed into a variety of functional groups using conventional methods, for example, as described in Larock or March. According to scheme VII, heterocycles of formula LXXI wherein R1, R2, R3, R4, R5 and R8 are as described above, P1 and P2 are protecting groups and R20 is a nitrogen-containing heterocycle condensed with the Quinoline ring structure, can be prepared from the compound of formula LXX, wherein P3 is a protecting group, by selective deprotection. When P3 is, for example, benzyloxycarbonyl, the compound of formula LXX is conveniently cleaved to produce the compound of formula LXXI by treatment with a source of hydrogen (preferably 3 atmospheres of hydrogen gas), in the presence of a suitable catalyst (preferably paired at 10% 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 compounds of formula LXXII, wherein R1, R2, R3, R4, R5 and R8 are as described above, P1 and P2 are protective groups, R20 is and nitrogen containing a heterocycle fused to the quinoline ring structure , and the "Substituent" is selected to produce the desired compounds described above, can be prepared from the corresponding amine of formula LXXI by various amine reaction routes known to those skilled in the art, for example, those described in the scheme I for the transformation of the compounds of formula III in the compounds of formula IV. The compounds of formula LXX can be prepared according to the procedures described in Schemes I, II and III. For example, in Scheme II, quinolines of formula X are formed by procedures known to those skilled in the art from the arylamines of formula II wherein R5 and R6, R6 and R7 or R7 and R8 comprise a ring as described above. These bicyclic arylamines are also synthesized by a variety of methods known to those skilled in the art. Such bicyclic arylamines are used in the sequence of transformations as illustrated in Schemes I and III to prepare the desired compounds. The compounds of formula LXX can also be obtained from the compounds of formula I, wherein R5 and R6, R6 and R7 or R7 and R8 contain a functionality susceptible to cyclization, for example Scheme VIII, thus forming the desired ring , employing procedures known to those skilled in the art to cyclize such substituents. For example, the compound of formula LXXXI1 of scheme VIII is reacted with P3NH2 to give the protected P3 isoindoline. According to scheme VIII, the diesters of formula LXXX are reduced by producing the corresponding dialcohols of formula LXXXI according to procedures analogous to those described in scheme V for the transformation of the compounds of formula L into the compounds of formula Ll. The activation of these alcohols by electrophilic attack can be performed by several conventional methods, such as conversion to a halide or sulfonate (preferably conversion to the bis-bromide of formula LXXXII by treatment with two equivalents of dibromotriphenylphosphorane). The formation of the cyclohexane of formula LXXXIII can be achieved by treating the bis-bromide with a sulfide (preferably sodium sulphide) in an immiscible aqueous / organic solvent system (preferably a mixture of water and toluene) containing a suitable phase transfer catalyst. (preferably triethylhexylammonium bromide), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature) for a period of 1 to 100 hours (preferably 12 hours). Oxygen heterocycles of formula LXXXIV can be formed using conventional etherification methods including a nucleophilic displacement reaction with an appropriate bis-electrophile from the corresponding compound of formula LXXXIi. For example, oxaciclo formation can be achieved by treating a bis-bromide in an immiscible aqueous solvent (preferably benzene) with an aqueous solution of hydroxide (preferably 30% sodium hydroxide) containing a suitable phase transfer catalyst ( preferably benzyl tri-n-butylammonium chloride) at a temperature comprised between about 0 ° C and about 100 ° C (preferably at 80 ° C), for a period comprised between 1 and 100 hours (preferably 4 hours). The lactones of formula LXXXV and LXXXVI, wherein R1, R2, R3, R4, R5 and R8 are as described above and P1 and P2 are protecting groups, they can be formed using conventional lactonization methods including an oxidative cyclization of the corresponding dialcohol of the formula LXXXI. Thus, a suitable bis-alcohol is treated with an oxidizing agent (preferably pyridine chloroformate) in a polar aprotic solvent (preferably dichloromethane), at a temperature between about 0 ° C and about 100 ° C (conveniently at room temperature) , for a period comprised between 1 and 100 hours (preferably 24 hours) to prepare a mixture of the lactones of formula LXXXV and of formula LXXXVI that can be separated by conventional methods. The prodrugs of the compounds of the formula I can be prepared according to procedures known to those skilled in the art. Exemplary procedures are described below. Prodrugs of this invention in which a carboxyl group of a carboxylic acid of formula I is replaced by an ester, can be prepared by combining the carboxylic acid with appropriate alkyl halide, in the presence of a base such as potassium carbonate in a solvent inert such as dimethylformamide, at a temperature of about 0 to 100 ° C for a period of about 1 to about 24 hours. Alternatively the acid is combined with appropriate alcohol as solvent in the presence of a catalytic amount of acid such as concentrated sulfuric acid, at a temperature of about 20 to 100 ° C, preferably at the reflux temperature for a period of about 1 hour to approximately 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 the joint removal of water produced by physical means (eg, Dean-Stark trap) or chemicals (for example, molecular sieves).

The prodrugs of this invention in which an alcohol function has been transformed as an ether, 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 to 100 ° C, for about 1 to about 24 hours. The alkanoylaminomethyl esters 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 procedure described in E.U.A. No. 4,997,984.

Alternatively, these compounds can be prepared by the procedures described by Hoffman et al., In J. Org. Chem. 1994, 59, 3530. The 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 being formed, as described above. An alternative procedure is the reaction of the alcohol with a suitable protected glycosyl halide in the presence of base followed by deprotection. The N- (1-hydroxyalkyl) amides, N- (1-hydroxy-1- (alkoxycarbonyl) methyl) amides can be prepared by reaction of the parent amine with the appropriate aldehyde under neutral or basic conditions (for example, ethoxide sodium in ethanol ), at temperatures between 25 and 70 ° C. The N-alkoxymethyl or N-1 - (alkoxy) alkyl derivatives can be obtained by the reaction of the N-unsubstituted compound with the necessary alkyl halide in the presence of a base in an inert solvent. The compounds of this invention may also be used in conjunction with other pharmaceutical agents (eg, LDL-cholesterol reducing agents or triglyceride reducing agents) for the treatment of the diseases / conditions described herein. For example, they can be used in combination with cholesterol synthesis inhibitors, cholesterol absorption inhibitors, inhibitors of MTP / Apo B secretion and other cholesterol lowering agents such as fibrates, niacin, ion exchange resins, antioxidants, inhibitors of ACAT and bile acid complexers. In treatment with combination therapies, the two compounds of this invention and the other drug therapies are administered to mammals (e.g., humans and females) by conventional procedures. In the combination aspect of this invention, any HMG-CoA reductase inhibitor 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 conventional tests (eg, Meth. Enzymol, 1981).; 71: 455-509 and references cited here). A variety of these compounds are described and mentioned below, however, other HMG-CoA reductase inhibitors will be known to those skilled in the art. U.S. Patent No. 4,231,938 (the disclosure of which is incorporated herein by reference) discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Patent No. 4,444,784 (the disclosure of which is incorporated herein by reference) discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. In addition, U.S. Patent No. 4,739,073 (the disclosure of which is incorporated herein by reference) discloses certain substituted Intents, such as fluvastatin. In addition, U.S. Patent No. 4,346,227 (the disclosure of which is incorporated herein by reference) discloses ML-236B derivatives, such as pravastatin. In addition, EP-491226A (the disclosure of which is incorporated herein by reference) discloses certain pyridihydroxyheptenoic acids, such as rivastatin. In addition, U.S. Patent No. 5,237,995 (the disclosure of which is incorporated herein by reference) discloses certain 6- [2- (substituted-pyrrol-1-yl) 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 will be readily determined by those skilled in the art in accordance with conventional assays (eg, J.R. 1992; Science 258: 999). A variety of these compounds are described and mentioned below, however, other inhibitors of MTP / Apo A secretion will be known to those skilled in the art. WO 96/40640 and WO / 98/23593 are two exemplary publications. For example, the following inhibitors of MTP / Apo B secretion are particularly useful: [2- (1 H- [1, 2,4] triazol-3-ylmethyl) -1, 2,3,4-tetrahydro-isoquinolin -6-yl] -amide of 4-trifluoromethyl-biphenyl-carboxylic acid; 4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2- (2-acetylaminyl-ethyl) -1,2,3,4-tetrahydro-isoquinolyl-6-yl] -amide; (2- {6 - [(4, -trifluoromethyl-biphenyl-2-carbonyl) -amino] -3,4-dihydro-1H-isoquinolyl-2-yl} .- methyl ester. etl) -carbamic; 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (1H-imidazol-2-ylmethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] amide; 4-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2,2-diphenyl-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide; and 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2-ethoxy-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide. In the combinatorial aspect of this invention, any inhibitor of HMG-CoA synthase can be used as the second compound. The term "HMG-CoA synthase inhibitor" 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 synthase. Such inhibition is readily determined by those skilled in the art in accordance with conventional assays (Meth, Enzymol, 1975; 35: 155-160: Meth Enzymol, 1985; 110: 19-26 and references cited herein). A variety of these compounds are described and mentioned below, however, other HMG-CoA synthase inhibitors will be known to those skilled in the art. U.S. Patent No. 5,120,729 (the disclosure of which is incorporated herein by reference) discloses certain beta-lactam derivatives. U.S. Patent No. 5,064,856 (the disclosure of which is incorporated herein by reference) discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253). U.S. Patent No. 4,847,271 (the disclosure of which is incorporated herein by reference) discloses certain oxetane compounds such as 11- (3-hydroxymethyl-4-oxo-2-oxetail) -3,5,7-trimethyl acid derivatives -2,4-undeca-dienoic. Any compound that decreases the expression of the HMG-CoA reductase gene can be used as the second compound in the combination aspect of this invention. These agents can be transcription inhibitors of HGM-CoA reductase that block transcription of DNA or translational inhibitors that prevent the translation of the mRNA coding for HMG-CoA into proteins. Such compounds may affect transcription and / or translation directly, or may be biotransformed into compounds having the above-mentioned activities by one or more enzymes of the cholesterol biosynthetic cascade, or may lead to the accumulation of an isoprene metabolite having the mentioned above. Such regulation will be readily determined by those skilled in the art according to conventional tests (Meth, Enzymol, 1985; 110: 9-19). Next, several compounds are described and referenced, however, other inhibitors of the expression of the HGM-CoA reductase gene will be known to those of skill in the art. U.S. Patent No. 5,041, 432 (the disclosure of which is incorporated by reference) discloses certain 15-substituted lanosterol derivatives. He. Mercer (Prog. Lip Res. 1993; 32: 357-416) describes other oxygenated sterols that repress the synthesis of HGM-CoA reductase. Any squalene synthetase inhibitor can be used as the second compound of this invention. The term "squalene synthetase" refers to compounds that inhibit the condensation of 2 molecules of farnesylpyrrophosphate to form squalene, catalyzed by the enzyme squalene synthetase. Such inhibition is easily determined by those skilled in the art according to conventional tests (Meth. Enzymol.; 15: 393-454 and Meth. Enzymol. 1985; 110: 359-373 and references contained herein). A variety of these compounds are described and mentioned below, however, other inhibitors of squalene synthetase will be known to those skilled in the art. U.S. Patent No. 5,026,554 (the disclosure of which is incorporated herein by reference) discloses fermentation products of microorganism MF5465 (ATCC 74011) including zaragozic acid. A summary of other patented squalene synthetase inhibitors has been compiled (Curr Op. Ther.Patents (1993) 861-4).

Any squalene epoxidase inhibitor can be used as the second compound in the combination aspect of this invention. The term "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. Such inhibition is readily determined by those skilled in the art in accordance with conventional assays (Biochim, Biophys, Acta 1984; 794: 466-471). Next, several of these compounds are described and mentioned, however, other squalene epoxidase inhibitors will be known to those skilled in the art. U.S. Patent Nos. 5,011,859 and 5,064,864 (the descriptions of which are incorporated by reference) describe certain fluoro analogues of squalene. EP 395,768 A (the disclosure of which is incorporated by reference) discloses certain substituted allylamine derivatives. PCT publication WO 9312069 (the disclosure of which is incorporated herein by reference) discloses certain amino alcohol derivatives. U.S. Patent No. 5,051, 534 (the disclosure of which is incorporated herein by reference) discloses certain cyclopropyl-squalene derivatives. Any squalene cyclase inhibitor can be used as a second component in the combination aspect of this invention. The term "squalene cyclase inhibitor" refers to compounds that inhibit the bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by the squalene cyclase enzyme. Such inhibition is easily determined by those skilled in the art according to conventional tests (FEBS Lett. 1989; 244: 347-350). In addition, the compounds described and cited below are squalene cyclase inhibitors, however, other squalene cyclase inhibitors will also be known to those skilled in the art. PCT publication 9410150 (the disclosure of which is incorporated herein by reference) discloses certain derivatives of 1, 2,3,5,6,7,8,8a-octahydro-5,5,8a- (beta) -trimethyl-6-isoquinolinamine , such as N-trifluoroacetyl-1, 2,3,5,6J, 8,8a-octahydro-2-allyl-5,5,8a (beta) -trimethyl-6-isoquinolinamine. French patent publication 2697250 (the disclosure of which is incorporated herein by reference) discloses certain beta, beta-dimethyl-4-piperidine ethanol derivatives such as 1- (1, 5,9-trimethyldecyl) -beta, beta-dimethyl-4- piperidineethanol. Any combination inhibitor of squalene epoxidase / squalene cyclase can be used as the second component in the combination aspect of this invention. The term "combined squalene epoxidase / squalene cyclase inhibitor" refers to compounds that inhibit the bioconversion of squalene to lanosterol by an intermediate squalene-2,3-epoxide. In some assays 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. Thus, the inhibition by squalene epoxidase combined inhibitors of squalene cyclase is readily determined by those skilled in the art according to conventional assays mentioned above for the squalene epoxidase or squalene cyclase inhibitors. A variety of these compounds are described and mentioned, however, other inhibitors of squalene epoxidase and squalene cyclase will be known to those skilled in the art. U.S. Patent Nos. 5,084,461 and 5,278,171 (the disclosures of which are incorporated by reference) disclose certain azadecalin derivatives. EP 468,434 (the disclosure of which is incorporated by reference) discloses certain piperidinyl ether and thio ether derivatives such as 2- (1-piperidinyl) pentyl isopentyl sulfoxide and 2- (1-piperdyl) ethyl sulfide. PCT publication WO 9401404 (the disclosure of which is incorporated herein by reference) discloses certain acyl-piperidines such as 1- (1-oxopentyl-5-phenylthio) -4- (2-hydroxy-1-methyl) -ethyl) piperid Na U.S. Patent No. 5, 102,915 (the disclosure of which is incorporated herein by reference) discloses derivatives of cyclopropyloxy-squalene. Starting materials and reagents from the above-described compounds of formula I can also be easily purchased or easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related or come from compounds in which there is a broad scientific interest and commercial need and, consequently, many such compounds are commercially available, are presented in the literature or are readily available. obtainable from others - substances commonly acquired by procedures presented in the bibliography.

Some compounds of formula I of this invention or intermediates in their synthesis have asymmetric carbon atoms and, therefore, are enantiomers or diastereomers. The diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known per se, for example, by chromatography and / or fractional crystallization. The enantiomers can be separated, for example, by chiral HPLC methods or by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, alcohol), separating the diastereomers and converting (eg, hydrolyzing) the individual diastereomers in the corresponding pure enantiomers. In addition, an enantiomeric mixture of the compounds of formula I or an intermediate in their synthesis containing an acidic or basic radical can be separated into their corresponding pure enantiomers by the formation of a diastereomic salt with an optically pure base or chiral acid (e.g. 1-phenylethylamine or tartaric acid) and the separation of the diastereomers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered part of this invention. In addition, some of the compounds of this invention are atropisomers (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 resolution of the racemate of the final compound or an intermediate of its synthesis (preferably the final compound), using chromatography (preferably high pressure liquid chromatography [HPLC] ]) or an asymmetric resin (preferably Chiralcel ™ AD or OD [obtained from Chiral Technologies, Exton, Pennsylvania]) 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 alkyl amine (preferably 0.1% of diethylamine). The concentration of the product containing the fractions produces the desired materials. Some 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 such salts are within the scope of this invention and can be prepared by conventional procedures such as the combination of the acidic and basic entities, 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 in an appropriate solvent such as ethanol, hexanes or water / ethanol mixtures. In addition, when the compounds of formula I of this invention form hydrates or solvates, they are also within the scope of the invention. The compounds of formula I of this invention, their prodrugs and the salts of such compounds and prodrugs are adapted for therapeutic use as agents that inhibit the activity of cholesterol ester transfer protein in mammals, particularly in humans. Thus, the compounds of this invention elevate plasma HDL cholesterol, its associated components and the functions performed by them in mammals, particularly in humans. By virtue of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and its associated components in mammals, particularly in humans. Therefore, these compounds are useful in the treatment and correction of the various dyslipidemias observed that are associated with the development and incidence of atherosclerosis and cardiovascular diseases, 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 the reduction of HDL levels (Angellon, LB, et al: J. Biol. Chem. (1991) 266: 10796-10801) and increases the susceptibility to atherosclerosis. (Marotti, K. R. et al: Nature (1993) 364: 73-75). In addition, inhibition of CETP activity with an inhibitory antibody increases HDL cholesterol in hamsters (Evans, GF et al: J of Lipid Research (1994) 35: 1634-1645) and rabbits (Whitlock, ME, et al: J. Clin. Invest. (1989) 84: 129-137). Suppression of plasma CETP increase by intravenous injection with antisense oligodeoxynucleotides against CETP mRNA reduced atherosclerosis in rabbits fed cholesterol (Sugano, M. et al: J. of Biol. Chem. (1988) 273: 5033- 5026). Importantly, humans with plasma CETP deficiency due to a genetic mutation have markedly elevated levels of HDL cholesterol and apolipoprotein A-1 in plasma, the main component of HDL apoprotein. In addition, most demonstrate a marked reduction in LDL cholesterol and apolipoprotein B in plasma (the main component of LDL apolipoprotein). (Inazu, A., Brown, M.L., Hesler, C.B., et al: N. Engl. J. Med. (1990) 323: 1234-1238). Given the negative correlation between levels of HDL cholesterol and HDL-associated lipoproteins 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 such compounds and prodrugs, by virtue of their pharmacological action, are useful for the prevention, arrest and / or regression of atherosclerosis and its associated disease states. These include cardiovascular disorders (eg, angina, cardiac ischemia and myocardial infarction), complications due to therapies of cardiovascular diseases (eg, reperfusion injury and angioplastic restenosis), hypertension, stroke and atherosclerosis associated with organ transplantation. Because of the beneficial effects widely associated with elevated HDL levels, an agent that inhibits CETP activity in humans, by virtue of its ability to increase HDL, also provides valuable avenues for therapy in several distinct disease areas. . Thus, given the ability of the compounds of formula I of this invention, their prodrugs and the salts of such compounds and prodrugs to alter the lipoprotein composition by inhibition of cholesterol ester transfer, are useful in the treatment of complications vascular diseases associated with diabetes. Hyperlipidemia is present in the majority of subjects with diabetes mellitus (Howard, B.V. 1987, J. Lipid, Res. 28, 613). Even in the presence of normal lipid levels, diabetic subjects experience an increased risk of cardiovascular diseases (Kannel, W.B. and McGee, D.L. 1979. Diabetes Care 2, 120). It is known that the transfer of the cholesteryl ester mediated by CETP is abnormally increased in both insulin dependent diabetes (Bagdade, JD Subbaiah, PV and Ritter, MC, 1991. Eur. J. Clin. Invest. 21, 161) and in the non-insulin-dependent diabetes (Bagdade JD, Ritter, MC, Lane, J. and Subbaiah, 1993. Atherosclerosis 104, 69). It has been suggested that the abnormal increase in cholesterol transfer produces changes in the composition of lipoproteins, particularly for VLDL and LDL, which are more atherogenic (Bagdade, J.D., Wagner, J.D., Rudel, L.L., and Clarkson, T.B. 1995 J. Lipid, Res., 36, 759). These changes are not necessarily observed during routine lipid analysis. Thus, the present invention will be useful to produce the risk of vascular complications as a result of diabetes. The described agents are useful in the treatment of obesity. Both in humans (Radeau, T., Lau, P., Robb, M., McDonnell, M., Ailhaud, G. and McPherson, R., 1995. Journal of Lipid Research, 36 (12): 2552-61) as in non-human primates (Quinet, E. Tall, A., Ramakrishnan, R. and Rudel, L., 1991. Journal of Clinical Investigation, 87 (5): 1559-66), the mRNA for CETP is expressed at high levels in the adipose tissue. The adipose messenger increases with the ingestion of fats (Martin, LJ, Connelly, PW, Nancoo, D., Wood, N., Zhang, ZJ Maguire, G., Quinet, E., Tall, AR, Marcel, YL and McPherson, R., 1993. Journal of Lipid Research 34 (3): 437-46) and translates into functional transfer proteins and, by secretion, contributes significantly to plasma CETP levels. In human adipocytes, the majority of cholesterol is provided by plasma LDL and HDL (Fong B. S., and Angel, A., 1989. Biochimica et Biophysica Acta. 1004 (1): 53-60). The uptake of HDL cholesteryl ester depends to a large extent on CETP (Benoist, F., Lau, P., McDonnell, M., Doelle, H., Milne, R. and McPherson, R., 1997. Journal of Biological Chemistry 272 (38): 2357-7).

This ability of CETP to stimulate the uptake of HDL cholesteril together with the increased binding of HDL to adipocytes in obese subjects (Jiménez, JG, Fong., B., Julien, P., Despres, JP, Rotstein, L. , and Angel, A., 1989. International Journal of Obesity 13 (5): 699-709), suggests a role for CETP not only in the generation of the phenotype of low HDL levels for these subjects, but also in the development of obesity, promoting the accumulation of cholesterol. The inhibitors of CETP activity that block this process, therefore, serve as useful adjuvants for diet therapy for the purpose of reducing weight. CETP inhibitors 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 causes an extensive inflammatory response. The lipopolysaccharides can form complexes with lipoproteins (Ulevitch, R.J., Johhston, A.R., and Weinstein, D.B., 1981. J. Clin.Invest.667, 827-37). Certain in vitro studies have shown that the binding of LPS to HDL substantially reduces the production and release of mediators of inflammation (Ulevitch, R.J., Johhston, A.R., 1978, J. Clin.Research 62, 1313-24). Certain in vitro studies demonstrate that transgenic mice expressing human apo-Al and elevated HDL levels are protected from septic shock (Levine, DM, Parker, TS, Donnelly, TM, Walsh, AM and Rubin, AL 1993. Proc. Nati Acad. Sci. 90, 12040-44). Importantly, the administration of reconstituted HDL to human beings exposed to endotoxins, resulted in a lower inflammatory response (Pajkrt, D., Doran, JE, Koster, F., Lerch, PG, Arnet, B., Van Der Poli , T., ten Cate, JW, and van Deventer, SJH 1996. J. Exp. Med. 184, 1601-08). CETP inhibitors, 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 such compounds and prodrugs as medical agents in the treatment of the diseases / conditions described above in mammals (e.g., humans, men or women) are demonstrated by the activity of the compounds of this invention in conventional tests and in the in vivo 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 and triglyceride control agents as well as the compounds of this invention. The combination protocol described below is useful to demonstrate the utility of combinations of lipids and triglycerides (e.g., the compounds of this invention) described herein. Such assays also provide a means by which the activities of the compounds of formula I of this invention, their prodrugs and the salts of such compounds and prodrugs (or the other agents described herein) can be compared with each other and with the activities of other compounds known. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases. Of course, the following protocols may 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 radiolabeled lipids between lipoprotein fractions, essentially as previously described by Morton. in J. Biol. Chem. 256, 11992, 1981 and by Dias in Clin. Chem. 34, 2322, 1988.

In vitro CETP assay The following is a brief description of the cholesteryl ester transfer assay in human plasma (in vitro) and the animal plasma (ex vivo): the CETP activity in the presence or absence of the drug is assayed determined the transfer of oleate of cholesteryl labeled with 3H (CO) from an exogenous HDL indicator to the non-HDL lipoprotein fraction in human plasma, or from LDL labeled with 3H to the HDL fraction is transgenic mouse plasma. The labeled human lipoprotein substrates will be prepared analogously to the method described by Morton in which the endogenous plasma CETP activity is employed to transfer 3H-CO from the phospholipid liposomes to all lipoprotein fractions in plasma. Subsequently, LDL and HDL labeled with 3H are isolated by sequential ultracentrifugation with density cuts of 1.019-1.063 and 1.10-1.21 g / ml, respectively. For the activity assay, 3 H-labeled lipoprotein is added to the plasma at concentrations of 10-25 nmoles CO / ml and the samples are incubated at 37 ° C for 2.5-3 hours. Then, the non-HDL proteins are precipitated by the addition of an equal volume of polyethylene glycol 80000 (Dias) at 20% (w / v). The samples are centrifuged at 750 g X 20 minutes and the radioactivity contained in the HDL-containing supernatant is determined by liquid scintillation. The introduction of variable amounts of the compounds of this invention as a solution of dimethisulfoxide to human plasma, before the addition of the radiolabelled cholesteryl oleate, and the comparison of the relative amounts of radiolabel transferred, allow the determination of the inhibitory activities of the transfer of cholesteryl ester.

In vivo CETP Assay The activity of these compounds in vivo can be determined by the amount of agent required to be administered, with respect to the control, to inhibit the cholesteryl ester transfer activity by 50% at various ex vivo time points, or to raise HDL cholesterol by a given percentage in an animal species that contains CETP. Transgenic mice expressing both human CETP and human apolipoprotein Al (Charles River, Boston, MA) can be used to evaluate the compounds in vivo. The compounds to be examined are administered by an oral probe in an emulsion vehicle containing olive oil and sodium taurocholate. Blood is drawn from the mice retroorbitally before the dose is administered. At different times after dosing, which vary between 4 hours and 24 hours, the animals are sacrificed, blood is drawn through cardiac puncture and the lipid parameters are measured, including total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides. . The CETP activity is determined by a procedure similar to that described above with the exception that LDL containing cholesteryl oleate labeled with 3H is used as a donor source instead of HDL. The values obtained for the lipids and the transfer activity are compared with those obtained before dosing and / or with those from mice that only received vehicle.

Plasma lipid assay The activity of these compounds can also be demonstrated by determining the amount of agent needed to alter plasma lipid levels, for example, HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain mammals, 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 a similar SD mean for total cholesterol, HDL and / or plasma LDL concentrations. After group assignment, the marmosets receive daily doses of compound as a mixture with the diet or by intragastric intubation from days 1 to 8. Control marmosets receive only the dosing vehicle. The values of total cholesterol, LDL, VLDL and HDL can be determined at any time during the study by obtaining blood from an antecubital vein, separating the plasma lipoproteins in their individual subclasses by centrifugation with density gradient, and measuring the concentration of cholesterol as it has been previously described (Crook et al., Arteriosclerosis 10, 625, 1990).

Atherosclerosis test in vivo The anti-atherosclerotic effects of the compounds can be determined by the amount of the compound necessary to reduce the deposition of lipids in the aorta of rabbits. A diet containing 0.2% cholesterol and 10% coconut oil is supplied for 4 days (once a day) to New Zealand white rabbits. Blood is drawn from the rabbits from the marginal vein of the ear and the plasma cholesterol levels are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar SD mean for the total plasma cholesterol concentration, the HDL cholesterol concentration, the triglyceride concentration and / or the transfer protein activity. of cholesterii ester. After group allocation, the rabbits receive daily the dose of the compound administered as a mixture with the diet or on a small piece of gelatin-based confection. Control rabbits only receive the dosing vehicle, either food or gelatin manufacture. The cholesterol / coconut oil diet is continued, along with the administration of the compound throughout the entire study. The plasma cholesterol values and the activity of the cholesteryl ester transfer protein can be determined at any time during the study by drawing blood from the marginal vein of the ear. After 3-5 months, the rabbits are sacrificed and the aortas are removed from the tcic arch in the branch of the iliac arteries. The aortas are cleared of adventitia, open longitudinally and then stained with Sudan IV as described by Holman et al. (Lab. Invest. 1958, 7, 42-47). The percentage of the stained surface area is quantified by densitometry using an Optimal Image Analyzing System (Image Processing Systems). The reduction in lipid deposition is indicated by a reduction in the percentage of the specific surface stained in the group receiving the compound compared to the control rabbits.

Anti-obesity Protocol The ability of CETP inhibitors to cause weight loss can be evaluated in obese humans with a body mass index (BMI) > 30 kg / m2. The doses of inhibitor are administered in an amount sufficient to produce an increase of > 25% of HDL cholesterol levels. The BMI and body fat distribution, defined as a ratio between waist (W) and hip (H) (WHR), are controlled during the course of the 3-6 month studies, and the results for the groups of treatment are compared with those obtained with subjects receiving placebo.

In vivo sepsis assay Certain in vivo studies demonstrate that transgenic mice expressing human apo-Ai and elevated HDL levels are protected from septic shock. Thus, the ability of CETP inhibitors to protect septic shock can be demonstrated in transgenic mice expressing both human apo-AI and human transgenes of CETP (Levine, DM, Parker, TS, Donnelly, TM Walsh, AM and Rubin, AL, 1993. Proc. Nati, Acad. Sci. 90, 12040-44). LPS derived from E. Coli, at a concentration of 30 mg / kg, is administered by i.p. injection to animals that have received a CETP inhibitor at an appropriate dose to result in the elevation of HDL. The number of surviving mice is determined at times up to 48 hours after injection of LPS and compared to mice that received only vehicle (less CETP inhibitor). The administration of the compounds of this invention can be carried out by any method that releases a compound of this invention systemically and / or locally. These procedures include oral, parenteral, intraduodenal, etc. routes. Generally, the compounds of this invention are administered orally, but parenteral administration (eg, intravenous, intramuscular, subcutaneous or intramedullary) can be used, for example, when oral administration is inappropriate for the recipient or when the patient is not You can 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 HDL) is used. In general, an effective dose for the compounds of formula I of this invention, their prodrugs and the salts of such compounds and prodrugs is in the range of 0.01 to 10 mg / kg / day, preferably 0.1 to 5 mg / kg / day. . A dose of the combination pharmaceutical agents to be used in conjunction with the CETP inhibitors is used which is effective for the indication to be treated. For example, typically, an effective dose for the HMG-CoA reductase inhibitors is in the range of 0.01 to 100 mg / kg / day. In general, a dose of effect for inhibitors of MTP / ApoB 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. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, a pharmaceutical composition can 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 disintegrants such as starch and preferably potato starch or tapioca, and certain complex silicates, 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 forming tablets. Solid compositions of a similar type are also employed as fillers in soft and hard gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. A preferred formulation is a solution or suspension is an oil, for example, olive oil, Miglyol ™ or Capmul ™, in a soft gelatin capsule. When appropriate, antioxidants can be added to prevent long-term degradation. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For the purposes of parenteral administration, solutions of sesame or peanut oil or aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts may be employed. Such aqueous solutions may conveniently be buffered, if necessary, and the liquid diluent may first be made saline with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, all of the sterile aqueous media employed can be readily obtained by conventional techniques well known to those skilled in the art. For the 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 for those skilled in the art. As examples of processes for preparing pharmaceutical compositions, see Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975). The pharmaceutical compositions according to this invention may contain from 0.1% to 95% of the compound (s) of this invention, preferably from 1% to 70%. In any case, the composition or formulation to be administered will contain an amount of compound (s) according to the invention effective to treat the disease / condition of the subject being treated, for example, atherosclerosis. As 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 a combination of the separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: a compound of the formula I or a prodrug thereof, or a salt of such a compound or prodrug, and a second compound as described above. The equipment comprises means for containing the separate compositions, such as a container, a divided bottle or a divided container with a sheet. Typically, the equipment includes instructions for the administration of the separate components. The form of the kit is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), administered at different dosage intervals, or when the corresponding physician wishes to concentrate the individual components of the combination. An example of such equipment is the so-called blister. Blisters are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules and the like). The bister usually consist of a sheet of relatively rigid material covered with a sheet of preferably transparent plastic material. During the packaging process, cavities are formed in the plastic sheet. The cavities have the size and shape of the tablets or capsules to be packaged. The tablets or capsules are then placed in the cavities and the sheet of relatively rigid material is sealed with the plastic sheet on the side of the sheet opposite the direction in which the cavities were formed. As a result, the tablets or capsules are sealed in the cavities between the plastic sheet and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister by manually pressing on the cavity, whereby an opening is formed in the sheet at the cavity site. The tablet or capsule can then be removed through said opening. It may be desirable to provide a reminder in the set, for example, in the form of numbers close to the tablets or to the capsules, the numbers corresponding to the days of the regime in which the tablets or capsules thus specified must be ingested. Another example of such a reminder is a calendar printed on the card, for example, as indicated below: "first week, Monday, Tuesday, ... etc ... second week Monday, Tuesday ..." etc. Other variations of reminders will be evident. A "daily dose" may be a single tablet or capsule or several tablets or capsules to be taken on a given day. In addition, a daily dose of the compound of formula I can consist of a tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The reminder should reflect this. In another specific embodiment of this invention, a dispenser designed to deliver the daily doses, one at a time, in the desired order of use is provided. Preferably, the dispenser has a reminder, so that it further facilitates compliance with the regime. An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been delivered. Another example of such a reminder is a battery operated microchip memory, coupled to a liquid crystal display, or a reminder auditory signal that, for example, shows the data of the last daily dose taken and / or remembers when it should Take the next dose. The compounds of this invention, either 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 formulations shown below, "active ingredient" means a compound of this invention.

FORMULATION 1 Gelatin capsules Hard gelatin capsules are prepared using the following: Canfidad Ingredient (mg / capsule) Active ingredient 0.25-100 Starch, NF 0-650 Fluid starch powder 0-50 Silicone fluid 350 centistokes 0-15 A tablet formulation is prepared using the following ingredients: FORMULATION 2 Compressed Ingredient Quantity (mg / com primido) Active ingredient 0.25-100 Cellulose, microcrystalline 200-650 Silicon dioxide, pyrolyzed 10-650 Stearic acid 5-15 The components are mixed and pressed to form tablets. Alternatively, tablets are made that each contain 0.25-100 mg of active ingredients, as indicated below: FORMULATION 3 Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone (in the form of a 10% solution in water) 4 Carboxymethylcellulose sodium 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch and cellulose are passed through a U.S. No. 45 and they mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders and mixed then passed through an E.U.A. mesh screen. No. 14. The granules thus produced are dried at 50 ° C-60 ° C and passed through a U.S. mesh screen. No. 18. Next, the sodium carboxymethyl starch, the magnesium stearate and the talc, previously passed through a U.S. mesh screen. No. 60, are added to granules which, after mixing, are pressed into a tablet machine to produce tablets. The suspensions they contain, each 0.25-100 mg of active ingredient per 5 ml dose, are manufactured as indicated below: FORMULATION 4: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.25-100 mg Carboxymethromellose sodium 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Flavoring agent c.v. Colorant . c.v. Purified water, up to 5 ml The active ingredient is passed through a No. 45 mesh screen and mixed with the sodium carboxymethylcellulose and the syrup to form a uniform paste. The benzoic acid, flavoring and coloring solution is diluted with some water and added, with stirring. Then enough water is added to produce the necessary volume. An aerosol solution is prepared containing the following ingredients: FORMULATION 5: Aerosol Ingredient Amount (% by weight) active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C and transferred to a cooling device. filled in. The necessary amount is then introduced into a stainless steel container and diluted with the rest of the propellant. Then the valve units in the container are adjusted. Suppositories are prepared as follows: FORMULATION 6: Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 Glycerides of saturated fatty acids 2,000 The active ingredient is passed through a U.S. mesh screen. No. 60 and is suspended in the glycerides of saturated fatty acids, 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 Quantity Active ingredient 20 mg Intralipid ™ Emulsion 1,000 ml The solution 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 capsules with oil formulation.

Ingredient Size (mg / capsule) Active ingredient 10-500 Olive Oil or Miglyol ™ 500-1000 The above active ingredient can also be a combination of agents.

General experimental procedures The NMR spectra were recorded on a Varian XL-300 spectrometer (Varian Co., Palo Alto, California, a Bruker AM-300 spectrometer (Bruker Co., Billerica, Massachusetts) or a Varian Unity spectrometer, at approximately 23 ° C, at 300 MHz for protons and at 75.4 mHz for carbon nuclei Chemical shifts are expressed in parts per million downfield of tetramethylsilane The shapes of the peaks are referred to as follows: s, singlet; , doublet, t, triplet, q, quadruplet, m, multiplet, sa = broad singlet The interchangeable designated resonances did not appear in a different experiment in which the samples were shaken with several drops of D2O in the same solvent. Chemical ionization masses at atmospheric pressure (APCl) were obtained on a Fisons Platform II Spectrometer Chemical mass spectra were obtained on a Hewlett-Packa instrument rd 5989 (Hewlett-Packard Co., Palo Alto, California) (ammonia ionization, PBMS). When the intensity of the ions containing chlorine or bromine is described, the intensity ratio expected in the observed (approximately 3: 1 for ions containing 35CI / 37CI and 1: 1 for ions containing 79Br / 81Br) and only the intensity of the lower mass ion is provided. Column chromatography was performed with Baker silica gel (40 μm) (J.T. Baker, Phillipsburg, N.J.) or silica gel 60 (EM Sciences, Gibbstown, N.J.) on glass columns under low nitrogen pressure. Radial chromatography was performed using a Chromatron (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 the reaction solvent were of the anhydrous quality supplied by Aldrich Chemical Company (Milwaukee, Wisconsin). Microanalyses were performed by Schwarzkopf Microanalytical Laboratory, Woodside, NY. The terms "concentrated" and "evaporated" refer to the removal of the solvent at the pressure of a water aspirator in a rotary evaporator with a bath temperature of less than 45 ° C. Reactions performed at "0-20 ° C" or "0-25 ° C" were performed with initial cooling of the vessel in an asylee bath that was allowed to warm to room temperature for several hours. The abbreviation "min" and "h" mean "minutes" and "hours" respectively.

EXAMPLES EXAMPLE 1A EXAMPLE 1B Benzyl ester of c / s- (2-methyl-2,3,4,6,7,8-hexahydro-1H-cyclopentarglolinolin-4-iQ-carbamic acid ester and cs- (2-methyl) benzyl ester - methyl-2,3A6.7.8-hexahydro-1 H-cyclopenta f] quinolin-4-yl) -carbamic Indan-5-ylamine (1.5 g, 11.3 mmol) was dissolved in anhydrous dichloromethane (50 ml). Sodium sulfate (1.0 g) was added and the mixture was cooled to -25 ° C. Acetaldehyde (0.63 ml, 11.3 mmol) was added and the reaction was stirred at -25 ° C for 1 hour. The solid sodium sulfate was then filtered off and the filtrate was added at -25 ° C to O-benzyl-N-vinyl carbamate (2.0 g, 11.3 mmol), followed by boron trifluoride diethyl etherate (0.14 ml, 1.13 mmoles). The reaction was stirred at -25 ° C for 1 hour and allowed to warm to room temperature for 30 minutes. The reaction mixture was concentrated and the crude product was purified by chromatography on silica gel using ethyl acetate / hexanes as eluent to yield 800 mg of c / s- (2-methyl-2, 3.4, benzyl) ester. 6,7, 8-hexahydro-1 H-cyclopenta [g] quinoIin-4-yl) -carbamic acid. 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.5 (q, 1 H), 2.3 (m, 1 H), 3.5 (m, 1 H), 5.1 (s, 2 H), 6.4 (s, 1 H) , 7.0 (s, 1 H), 7.4 (m, 5H); and 260 mg of c / s- (2-methyl-2,3,4,6,7,8-hexahydro-1 H-cyclopenta [f] quinolin-4-yl) -carbamic acid benzyl ester. 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.5 (q, 1 H), 2.3 (m, 1 H), 3.5 (m, 1 H), 5.1 (s, 2 H), 6.4 (s, 1 H) , 7.0 (s, 1 H), 7.4 (m, 5H).

EXAMPLE 1C c / s-4-benzloxycarbonylamino-2-methyl-2,3,4,6-7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ethyl ester To a solution of the benzyl ester of c / s- (2-methyl-2,3,4,6,7,8-hexahydro-1 H -cyclopenta [g] quinolin-4-yl) -carbamic acid (example 1A) (2.0 g, 4.9 mmol) in anhydrous dichloromethane (50 ml) was added pyridine (1.0 ml). The mixture was cooled to 0 ° C and ethyl chloroformate (1.0 ml) was slowly added. The reaction was stirred at 0 ° C for 30 minutes and then at room temperature for 4 hours. The reaction mixture was washed twice with 25 ml of 2N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 15% ethyl acetate / hexanes as eluent afforded the title product (500 mg). 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.2 (t, 3 H), 4.2 (m, 2 H), 5.2 (s, 2H), 7.0 (s, 1 H), 7.3 (s, 1 H), 7.4 (m, 5H).

EXAMPLE 1D C / 's-4-amino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta fgl quinoline-1-carboxylic acid ethyl ester C / s-4-benzyloxycarbonylamino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ethyl ester (Example 1C) was refluxed for 2 hours. (500 mg), 10% palladium on carbon (150 mg) and a mixture of ethanol-cyclohexene (1: 1, 50 ml). The reaction mixture was cooled to room temperature, filtered through Celite® and concentrated in vacuo. Purification by chromatography on silica gel using 5% methanol / ethyl acetate afforded the title compound (350 mg). EM / 258 (M + -16); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 2.1 (m, 2 H), 2.4 (m, 1H), 4.2 (m, 2H), 4.5 (m, 1 H), 3.8 (dd, 1H), 7.2 (s, 2H).

EXAMPLE 1 E C / s-4- (3,5-bis-trifluoromethyl-benzylamino) -2-methyl-2,3,4,6,7,8-hexahydro-cyclopentatr quinoline-1-carboxylic acid ethyl ester To a solution of c / s-4-amino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ethyl ester (Example 1 D) (0.35) g, 1.28 mmol) in anhydrous 1,2-dichloroethane (50 ml), acetic acid (0.073 ml, 1.28 mmol) was added, followed by 3,5-bis (trifluoromethyl) benzaidehyde (0.21 ml, 1.28 mmol) and sodium triacetoxyborohydride. (0.406 g, 1.92 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with chloroform and washed with 1 N NaOH. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel using 10% ethyl acetate / hexanes as eluent afforded the title compound (approximately 300 mg). 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 2.6 (m, 1 H), 3.6 (dd, 1 H), 4.5 (m, 1 H), 7.30 (s, 1 H) , 7.35 (s, 1 H), 7.8 (s, 1 H), 8.0 (s, 2H).

EXAMPLE 2 4-Facetyl- (3,5-bis-trifluoromethyl-benzyl) -amino-T-2- metip-2,3,4,6,8,8-hexahydro-cyclopenta fa 1 quinoline-1-carboxylic acid ethyl ester A solution of c / s-4- (3,5-bis-trifluoromethyl-benzylamino) -2-methyl-2,3,4,6J, 8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ethyl ester (example 1 E) (50 mg, 0.1 mmol) and pyridine (0.15 ml, 1.85 mmol) in dichloromethane (2.5 ml), cooled in an ice water bath as added acetyl chloride (0.2 ml, 2.8 mmol) ) by means of a syringe. After stirring overnight at room temperature, the mixture was washed with 2N HCl, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 25% ethyl acetate / hexanes to yield 20 mg of the title compound. MS m / z 542.5 (M +); 1 H NMR d 1.1 (d, 3 H), 2.3 (s, 3 H), 6.8 (s, 1 H), 7.3 (s, 1 H).

EXAMPLE 3A Propylidene- (4-trifluoromethyl-phenyl) -amine To a solution of 4-trifluoromethylaniline (3.3 g, 20.5 mmol) and triethylamine (8.3 g, 83 mmol) in 100 mL of dichloromethane, cooled in a water / ice bath, titanium tetrachloride (11.4 m of an 1.0 M solution in dichloromethane, 11.4 mmol). After 25 minutes, propionaldehyde (1.8 g, 25.6 mmol) was slowly added as a solution in dichloromethane. After one more hour of stirring in the water / ice bath, an aqueous potassium carbonate solution (-100 ml of a 1 M solution) was added. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude title product which was used without further purification. 1 H NMR (CDCl 3) d 1.2 (t, 3 H), 2.5 (dq, 2 H), 7.05 (d, 2 H), 7.56 (d, 2 H), 7.84 (t, 1 H, J = 4.4 Hz).

EXAMPLE 3B Benzyl ester of c / s- (2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid The crude propylidene- (4-trifluoromethyl-phenyl) -amine of Example 3A and O-benzyl-N-vinyl carbamate (3.1 g, 17.4 mmol) in 200 ml of dichloromethane were combined and the mixture was cooled in a water bath. / ice as added boron trifluoride diethyl etherate (0.25 g, 1.7 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated to ~50 ml and purified directly by chromatography on silica gel using 50% dichloromethane / hexanes as eluent, to yield 2.5 g of the title product. 1 H NMR (CDCl 3) d 0.96 (t, 3 H), 1.42 (q, 1 H), 1.53 (m, 2 H), 2.29 (m, 1 H), 3.37 (m, 1 H), 4.05 (s, 1 H ), 4.88 (d, 1 H), 5.00 (m, 1 H), 5.16 (s, 2H), 6.44 (d, 1H), 7.20 (dd, 1 H), 7.38 (m, 6H).

EXAMPLE 3C C s-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of the benzyl ester of c / s- (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolyl-4-yl) -carbamic acid (example 3B) (37.0 g, 97. 9 mmol) and pyridine (23.2 g, 293.7 mmol) in dichloromethane (1 L) was cooled in a water / ice bath as slowly added ethyl chloroformate (37.2 g, 342.6 mmol). After stirring at room temperature overnight, the mixture was cooled with an ice / water bath as 1 M potassium hydroxide solution was added to stop the reaction. The organic phase was washed twice with a 2M hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude product which was purified by chromatography on silica gel using 10% ethyl acetate. 15% / hexanes as eluent to produce 40 g of the title product. 1 H NMR (CDCl 3) d 0.83 (t, 3 H), 1.28 (t, 3 H), 1.4-1.6 (m, 3 H), 2.53 (m, 1 H), 4.23 (m, 2 H), 4.47 (m, 1 H) , 4.80 (m, 1H), 4.94 (m, 1H), 5.18 (s, 2H), 7.3-7.6 (m, 8H).

EXAMPLE 3D C / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of c / 's-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (example 3C) (18.0 g, mmoles) in 150 ml of each of cyclohexane and ethanol, treated with 10% palladium on carbon (10.0 g, 50% water by weight). After heating to reflux for 1 hour, the cooled mixture was filtered through Celite® and concentrated in vacuo to yield the crude product, which was purified by silica gel chromatography using 25-50% ethyl acetate / hexanes as eluent to produce 8.8 g of the title product. 1 H NMR (CDCl 3) d 0.83 (t, 3 H), 1.25 (m, 4 H), 1.45 (m, 1 H), 1.6 (m, 1 H), 2.49 (m, 1 H), 3.81 (m, 1 H ), 4.2 (m, 2H), 4.4 (m, 1 H), 7.47 (m, 2H), 7.69 (s, 1 H).

EXAMPLE 3E c / s-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of c / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (3D example) (8.8 g, 27.8 mmol) was treated sequentially with acetic acid (5.0 g, 83.5 mmol), 3,5-bis-trifluoromethyl-benzaldehyde (6J4 g, 27.8 mmol), followed by sodium triacetoxyborohydride (29.5 g, 139.2 mmol). After stirring for 24 hours at room temperature, the mixture was combined with 500 ml of 1 M potassium hydroxide and the aqueous layer was extracted with dichloromethane (2 x 200 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude product, which was purified by chromatography on silica gel using 5-10% ethyl acetate / hexanes as eluent to yield 13.8 g. of the product of the title. 1 H NMR (CDCl 3) d 0.85 (t, 3 H), 1.27 (m, 4 H), 1.45 (m, 2 H), 1.67 (m, 1 H), 2.66 (m, 1 H), 3.56 (m, 1 H), 4.1-4.3 (m, 4H), 4.42 (m, 1 H), 7.49 (d, 1 H, J = 8.5 Hz), 7.52 (d, 1 H, J = 8.5 Hz), 7.76 (s, 1 H) 7.79 (s, 1 H), 7.91 (s, 2H).

EXAMPLE 3F c / s-4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 acid ethyl ester -carboxylic A solution of the ethyl ester of c / 's-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-qui Nol-1-carboxylic acid (example 3E) (2.0 g, 3.65 mmol) in 20 ml of formic acid was treated with acetic anhydride (11.29 g, 111 mmol) and sodium formate (1.25 g, 18.5 mmol). After stirring for 24 hours at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel using 10-15% ethyl acetate / hexanes as eluent to yield 1.8. g of the product of the title. EM / 77 / 571.2 (M ++ 1); 1 H NMR (mixture-5: 1 of formamide rotamers, CDCl 3) d 0J 5 (t, 3 H), 1.28 (t, 3 H), 1.42 (m, 1 H), 1.6-1.75 (m, 2 H), 2.3 (m) , 1 H), 4.15-4.3 (m, 2H), 4.3-4.4 (m, 1 H), 4.5-4.7 (ma, 1 H), 4.8-5.8 (ma, 2H), 7.14 and 7.08 (s, 1 H), 7.5-7.6 (m, 2H), 7.74 (s, 2H), 7.80 and 7.86 (s, 1 H), 8.47 and 8.62 (s, 1 H). Examples 4-49D were prepared in a manner analogous to the sequence of reactions described for Examples 1A-2 or 3A-3F, as appropriate, using the appropriate starting materials.

EXAMPLE 4 Cs-4- (benzyl-formyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 413 (M + + 1), 430 (M + + 18); 1 H NMR (CDCl 3) d 8.40 (formyl-H, s, 1 H), 1.18 (C2-Me, d, 3H, J = 6.2 Hz).

EXAMPLE 5 C / S-4- (Benzyl-trifluoromethanesulfonyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS / 77 / z 518 (M + + 2); 1 H NMR (CDCl 3) d 6.81 (C5, s, 1 H), 4.61 (m, 1 H).

EXAMPLE 6 cis-4- (1-benzyl-3-methyl-thioureido) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 458 (M + + 1), 475 (M + + 18); 1 H NMR (CDCl 3) d 7.08 (C8, s, 1 H), 6.35 (C5, s, 1 H), 2.43-2.34 (m, 1H).

EXAMPLE 7 Ethyl ester of cis-4-fbenzyl-r.4-chloro-phenyl) -acetyl-amino acid} -6.7- dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 555 (M + + 18); 1 H NMR (CDCl 3) d 6.33 (C5, s, 1 H), 5.32, (d, 1 H, J = 15.7 Hz), 3. 42 (s, 2H).

EXAMPLE 8 Ethyl ester of cis-4- acid. { benzyl-r (3-chloro-phenyl) -acetin-amine > -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS / tt / z 555 (M + + 18); 1 H NMR (CDCl 3) d 6.39 (C5, s, 1 H), 5.35, (d, 1 H, J = 15.7 Hz).

EXAMPLE 9 Ethyl ester of cis-4- acid. { benzyl-r (3-chloro-phenyl) -acetin-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 581 (M + + 1); 1 H NMR (CDCl 3) d 6.32 (C5, s, 1 H), 5.35, (d, 1 H, J = 15.8 Hz), .43 (s, 2H).

EXAMPLE 10 Ethyl ester of cis-4-f-benzyl-r (3-trifluoromethyl-phenyl) -acet-p-amine > - 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 571 (M + + 1), 588 (M + + 18); 1 H NMR (CDCl 3) d 6.33 (C5, s, 1 H), 5.35, (d, 1 H, J = 15.8 Hz), .42 (s, 2H).

EXAMPLE 11 Ethyl ester of cis-4 acid. { benzyl-r.3-nitro-phenH) -acetyl-amino} -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 548 (M + + 1), 565 (M + + 18); 1 H NMR (CDCl 3) d 6.35 (C5, s, 1 H), 5.32, (d, 1 H, J = 15.7 Hz).

EXAMPLE 12 Ethyl ester of cis-4-benzyl-r (3,5-bis-trifluoromethyl-pheno-acetyl-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid) MS m / z 657 (M + + 19); 1 H NMR (CDCl 3) d 6.35 (C5, s, 1 H), 5.35, (d, 1 H, J = 15.7 Hz), .42 (s, 2H).

EXAMPLE 13 Ethyl ester of cis-4-fbenzyl-r (2-trifluoromethyl-phenyl) -acetyl-amino acid} - 6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 571 (M + + 1), 588 (M + + 18); 1 H NMR (CDCl 3) d 6.48 (C5, s, 1 H), 5.35, (d, 1 H, J = 15.7 Hz).

EXAMPLE 14 Ethyl ester cis-4- (benzyl-r (2-chloro-phenyl) -acetin-amino> -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 - carboxylic MS m / z 537 (M + + 1), 554 (M + + 18); 1 H NMR (CDCl 3) d 6.43 (C5, s, 1 H), 3.65, (s, 2H).

EXAMPLE 15 Ethyl ester of cis-4-benzyl-r (4-trifluoromethyl-phenyl) -acetyl-amino acid > - 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 571 (M + + 1) 588 (M + + 18); 1 H NMR (CDCl 3) d 6.30 (C5, s, 1H), 5.33, (d, 1H, J = 15.6 Hz), .30 (s, 2H).

EXAMPLE 16 Ethyl ester of cis-4- acid. { benzyl (4-nitro-phenyl) -acetyl-amino) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 548 (M + + 1), 565 (M + + 18); 1 H NMR (CDCl 3) d 6.34 (C5, s, 1 H), 5.34, (d, 1 H, J = 15.5 Hz).

EXAMPLE 17 Ethyl ester of cis-4- acid. { r.3,5-bis-trifluoromethyl-phenyl) -acetyl-1-methyl-amino} -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS / 77 / z 563 (M + + 1); 1 H NMR (CDCl 3) d 2.84 (s, 3 H), 7.0 (s, 1 H).

EXAMPLE 18 Ethyl ester of cis-4- acid. { benzyl-r.2.3,6-trichloro-phenyl) -acetyl-amino} - 6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 605 (M +), 624 (M + + 19); 1 H NMR (CDCl 3) d 7.46-7.21 (m, 10H), 5.39 (d, 1 H, J = 15.7 Hz).

EXAMPLE 19 Ethyl ester of cis-4-fr (3-5-bis-trifluoromethyl-benzyl) -methanesulfonic-amino-6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 617 (M + + 18); 1 H NMR (CDCl 3) d 7.07 (C8, s, 1H), 6.16 (C5, s, 1H), 3.02 (s, H).

EXAMPLE 20 Ethyl ester of cis-4- acid. { (3,5-bis-trifluoromethyl-benzyl) -f (3,5-bis-trifluoromethyl-phenyl) -acetin-amino-1-7,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic MS m / z 793 (M + + 18); 1 H NMR (CDCl 3) d 6.23 (C5, s, 1 H), 2.25-2.18 (m, 1 H). EXAMPLE 21 cis-4 - ((3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-6-dimethoxy-2-methyl-3,4-d-hydroxy-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 549 (M + + 1), 566 (M + + 18); 1 H NMR (CDCl 3) d 8.42 (formyl, s, 1 H), 6.38 (C5, s, 1 H), 3.83 (s, H), 3.79 (s, 3H).

EXAMPLE 22 cis-4-phenylthio- (3,5-bis-trifluoromethyl-benzyl) -amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 610 (M +), 628 (M + + 18); 1 H NMR (CDCl 3) d 7.15 (s, 1 H), 5.52 (d, 1 H, J = 16.3 Hz).

EXAMPLE 23 isopropyl ester of cis-4- 3,5-bis-trifluoromethyl-benzyl) -trifluoroacetyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 666 (M + + 2), 683 (M + + 19); 1 H NMR (CDCl 3) d 7.13 (s, 1 H), 5.36 (d, 1 H, J = 15.9 Hz). EXAMPLE 24 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonylacetyl-amino-1-7,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 620 (M +), 638 (M + + 18); 1 H NMR (CDCl 3) d 6.41 (C5, s, 1 H), 5.44 (d, 1 H, J = 16.5 Hz).

EXAMPLE 25 Ethyl ester of cis-4-α (3,5-bis-trifluoromethyl-benzyl) -trifluoroacetyl-aminol-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 617 (M + + 1), 634 (M + + 18); 1 H NMR (CDC! 3) d 7.13 (C8, s, 3H), 6.34 (C6, d, 1 H).

EXAMPLE 26 Ethyl ester of cis-4-iacetyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-7,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid EMm / z563 (M ++ 1), 580 (M ++ 18); 1 H NMR (CDCl 3) d 7.12 (C8, s, 3H), 6.38 (C6, d, 1H), 230 (C4-acetyl, s, 3H).

EXAMPLE 27 Ethyl ester of cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino1-2-rnetl-2,3,4,6,7,8-hexahydro-cyclopentag-quinoline-1 - carboxylic MS m / z 560 (M + + NH 4); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 2.2 (s, 3 H), 6.8 (s, 1 H), 7.4 (s, 1 H), 7.7 (s, 2 H), 7.8 (s, 1 H).

EXAMPLE 28 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -cyano-amino-1-7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid EMm / z563 (M + + 18); 1 H NMR (CDCl 3) d 7.08 (C8, s, 1H), 6.78 (C5, d, 1H).

EXAMPLE 29 cis-4-r.3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 597 (M + + 1), 614 (M + '18); 1 H NMR (CDCl 3) d 8.51 (s, 1 H), 2.45-2.39 (m, 1 H), 1.35-1.30 (m, H). EXAMPLE 30 cis-4-r isopropyl ester (3,5-bis-trifluoromethyl-benzyl-methanesulfonyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid) MS m / z 648 (M + + 2), 665 (M + + 19); 1 H NMR (CDCl 3) d 3.01 (s, 3 H), 4.43 (d, 1 H, J = 16.8 Hz).

EXAMPLE 31 cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester EM / 77 / z 610.9 (M +); 1 H NMR (CDCl 3) d 2.24-2.32 (m, 4 H), 3.99 (d, 1 H, J = 16.0 Hz), 5.52 (d, 1 H, J = 16.0 Hz).

EXAMPLE 32 cis-4-phanediyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester 1 H NMR (CDCl 3) d 2.3 (s, 3 H), 3.2 (s, 3 H), 7.7 (s, 1 H).

EXAMPLE 33 Ethyl ester of cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino1-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic 1 H NMR (CDCl 3) d 2.3 (s, 3 H), 3.2 (s, 3 H), 7.7 (s, 2 H).

EXAMPLE 34 Cis-4-facetyl- (3,5-bis-trifluoromethyl-benzyl) -aminol-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-propyl ester carboxylic MS m / z 624.9 (M +); 1 H NMR (CDCl 3) d 0.9 (t, 3 H), 2.2 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 35 cis-4-acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 624.9 (M +); 1 H NMR (CDCl 3) d 1.2 (dd, 6 H), 2.2. (s, 3H), 4.4 (q, 1 H), 7.1 (s, H).

EXAMPLE 36 Cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester 1 H NMR (CDCl 3) d 0.9 (t, 3 H), 2.2. (s, 3H), 3.2 (s, 3H), 7.1 (s, H), 7.7 (s, 2H).

EXAMPLE 37 Cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-2- cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 611.2 (M + + 1); 1 H NMR (CDCl 3) d 2.2 (s, 3 H), 4.2. (m, 2H), 7.1 (s, 1 H).

EXAMPLE 38 Ethyl ester of cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino1-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 585.3 (M + + 1); 1 H NMR (CDCl 3) d 0.6 (m, 3 H), 2.2 (s, 3 H), 7.1 (s, 1 H), 7.7 (s, 2H).

EXAMPLE 39 Cis-4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-2-m-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 558 (M + + 2), 575 (M + + 19); 1 H NMR (CDCl 3) a 4: 1 mixture of amide rotamers A and B. Rotamer A d 7.14 (s, 1 H), 8.46. (s, 1 H). Rotamer B d 7.08 (s, 1 H), 8.60 (s, 1H).

EXAMPLE 40 cis-4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester MS m / z 598 (M + + 2), 615 (M + + 19); H NMR (CDCl 3) a 5: 1 mixture of amide rotamers A and B. Rotamer A d 8.46 (s, 1H). Rotamer B d 8.61 (s, 1H).

EXAMPLE 41 Cis-4-racethyl- (3, 5-bis-trifluoromethyl-benzyl-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-propyl ester. - carboxylic MS m / z 612 (M + + 2), 629 (M + + 19); 1 H NMR (CDCl 3) d 3.98 (d, 1 H, J = 16.1 Hz), 5.51 (d, 1 H, J = 16.1 Hz), 7.14 (s, 1 H).

EXAMPLE 42 cis-4- (benzyl-methanesulfonyl-amino) -6-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 462 (M +), 480 (M + + 18); 1 H NMR (CDCl 3) d 6.70 (C5, s, 1 H), 2.87 (sulfonyl-Me, s, 3H).

EXAMPLE 43 cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester MS m / z 569.1 (M + -t-Bu); 1 H NMR (CDCl 3) d 1.3 (s, 9 H), 2.3 (s, 3 H), 7.1 (s, 1 H). EXAMPLE 44 cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -aminol-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 598 (M + + 2), 614 (M + + 18); 1 H NMR (CDCl 3) d 4.00 (d, 1 H, J = 16.0 Hz), 5.52 (d, 1 H, J = 16.0 Hz), 7.14 (s, 1 H).

EXAMPLE 45 Ethyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinolin -1-carboxylic MS m / z 583 (M + + 1); 1 H NMR (CDCl 3) a 5.5: 1 mixture of amide rotamers A and B. Rotamer A d (s, 1 H). R rotamer B 8.61 (s, 1 H).

EXAMPLE 46 cis-4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-ethyl-6-trifluoromethyl-N 3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 599.1 (M + + 1); 1 H NMR (CDCl 3) d 0.7 (t, 3 H), 1.3 (dd, 6 H), 2.3 (s, 3 H), 7.1 (s, 1 H), 7.7 (s, 2 H). EXAMPLE 47 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS / z 585.1 (M + + 1); 1 H NMR (CDCl 3) d 0.7 (t, 3 H), 1.3 (dd, 6 H), 7.1 (s, 1 H), 8.5 (s, 1 HOUR).

EXAMPLE 48 cis-4-r.3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester E m / z 571.1 (M + + 1); 1 H NMR (CDCl 3) d 1.3 (m, 9 H), 5.0 (m, 2 H), 7.1 (s, 1 H), 8.5 (s, 1 HOUR).

EXAMPLE 49A cis-4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amine-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester MS m / z 511 (M + - CO2t-Bu); 1 H NMR (CDCl 3) d 1.5 (m, 9 H), 1.8 (m, 1 H), 8.5 (s, 1 H).

EXAMPLE 49B cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -aminol-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 571 (M + 1+); 1 H NMR (CDCl 3) a mixture about 1: 3 of rotamers d 2,22 and 2.26 (s, 3H), 6.99 and 7.10 (s, 1 H).

EXAMPLE 49C cis-4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 557 (M + 1+); H NMR (CDCl 3) a mixture approximately 1: 6 of rotamers d 1, 17 and 1.22 (d, 3H), 7.05 and 7.14 (s, 1 H), 8.61 and 8.47 (s, 1 H).

EXAMPLE 49D cis-4-racethyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 585 (M + 1+); 1 H NMR (CDCl 3) a mixture about 1: 4 of rotamers d 1.16 and 1.20 (d, 3H), 2.24 and 2.30 (s, 3H), 7.05 and 7.12 (s, 1 H).

EXAMPLE 50A cis-4-r (3,5-bis-trifluoromethyl-benzyl) -chlorocarbonyl-amino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dithy-2H- ethyl ester was dissolved. quinoline-1-carboxylic acid (prepared in a manner analogous to that of the procedures described in examples 3A-3E) (146 mg, 0.28 mmol), in 2 ml of a 1.93 M phosgene solution in toluene (3.9 mmol). After heating to reflux for 1.5 h, the sample was concentrated in vacuo to yield the title product (125 mg, 76%). 1 H NMR (CDCl 3) d 1.2-1.6 (m, 7 H), 2.2-2.4 (m, 1 H), 4.2-4.6 (m, 4 H), 5.2-5.6 (m, 2 H), 7.1 (s, 1 H), 7.5-7.9 (m 5H).

EXAMPLE 50B cis-4-RI-3,5-bis-trifluoromethyl-benzyl-ureido-1-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -chlorocarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- ethyl ester was dissolved. 1-carboxylic acid (example 50A) (25 mg) in dichloromethane (4 ml) and cooled in an ice-water bath as gaseous ammonia condensed in the solution. After stirring overnight at room temperature, the reaction mixture was quenched with 10 ml of 1 N HCl and extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with 10 ml of saturated sodium bicarbonate, 10 ml of brine, 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 product (0.091 g, 76%). MS m z 563 (M + + 1); 1 H NMR (CDCl 3) d 1.18 (Me, d, 3 H, J = 5.9 Hz), 1.2-1.4 (m, 4 H), 2.1-2.2 (m, 1 H), 4.1-4.3 (m, 3 H), 4.3- 4.5 (m, 1 H), 4.9 (sa, 2H), 5.0-5.3 (m, 3H), 7.20 (C5, s, 1 H), 7.5 (d, 1 H), 7.6 (d, 1 H), 7.75 (s, 2H), 7.8 (2, 1 H). Examples 51-76 were obtained from the appropriate starting material in a manner analogous to the sequence of reactions employed in Examples 50A and 50B.

EXAMPLE 51 C / 's-4- (1-Benzyl-3,3-dimethyl-ureido) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 456 (M + + 1), 473 (M + + 18); H NMR (CDCl 3) d 7.05 (C8, s, 1 H), 2.81 (urea-Me, s, 6H).

EXAMPLE 52 C / S-4- (Benzyl-methylsulfanylcarboml-amine) -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 459 (M + + 1), 476 (M + + 18); 1 H NMR (CDCl 3) d 7.05 (C8, s, 1 H), 2.41 (Me-sulfonyl carbonyl s, 3H).

EXAMPLE 53 C / s-4-ri- (3,5-bis-trifluoromethyl-benzyl) -ureido-1-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline- ethyl ester ethyl ester 1 -carboxylic MS m / z 564 (M + + 1), 581 (M + + 18); 1 H NMR (CDCl 3) d 6.46 (C5, s, 1 H), 5.18 (d, 1 H, J = 16.9 Hz), .86 (s, 3 H), 3.92 (s, 3 H).

EXAMPLE 54 C / 's-4-ri- (3,5-bis-trifluoromethyl-benzyl) -ureido1-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 572 (M + + 1), 589 (M + + 18); H NMR (CDCl 3) d 7.75 (s, 2H), 1.31-1.27 (m, 3H).

EXAMPLE 55 C / 's-4-r (3,5-bis-trifluoromethyl-benzyl) -methylsulfanylcarbonyl-amino-2-methyl-2, 3,4,6,7,8-hexahydro-cyclopenta.qlquinoline-1-ethyl ester carboxylic MS m / z 574 (M +); 1 H NMR (CDCl 3) d 1.2 (d, 3 H), 1.4 (t, 3 H), 2.4 (s, 3 H), 6.8 (a, 1 H), 3 (s, 1 H), 7.7 (s, 2 H).

EXAMPLE 56 C / s ^ -rO.S-bis-trifluoromethyl-benzD-ureidol ^ -methyl-2,3,4,6,7,8-hexahydro-cyclopentaryl-1-carboxylic acid ethyl ester MS m / z 543 (M +); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.4 (t, 3 H), 6.9 (s, 1 H), 7.4 (s, H).

EXAMPLE 57 C / s-4-r (3,5-bis-trifluoromethyl-benzyl) - (2-oxo-pyrrolidine-1-carbonyl) -aminol-2-methyl-2,3,4 ethyl ester 6,7,8-hexahydro-cyclopentaglucoline-1-carboxylic acid MS / z 629 (M + + NH 4); 1 H NMR (CDCl 3) d 1.3 (t, 3 H), 2.1 (m, 1 H), 6.9 (a, 1 H), 7.3 (s, H), 7.9 (a, 2 H).

EXAMPLE 58 C / 's-4-r (3,5-bis-trifluoromethyl-benzyl) -3-methyl-ureidol-2-methyl-2,3,4,6,7,8-hexahydroxyethyl ester c8clopentarg1guinolina-1 -carboxílico MS m / z 557.1 (M +); 1 H NMR (CDCl) d 1.1 (d, 3 H), 1.3 (t, 3 H), 6.85 (s, 1 H), 7.8 (s, 3 H).

EXAMPLE 59 Ethyl ester of cis-4-ri- (3,5-bis-trifluoromethyl-benzyl) -3,3-dimethyl-ureido-1-2-methyl-2-3, 4,6,7,8-hexahydro-cyclopentacid gujnoline-1 - carboxylic 1 H NMR (CDCl 3) d 1.2 (d, 2 H), 1.3 (t, 3 H), 2.4 (m, 1 H), 7.1 (s, 1 H), 7.3 (s, 1 H), 7.8 (d, 3 H).

EXAMPLE 60 Ethyl ester of cis-4-f1- (3,5-bis-trifluoromethyl-benzyl) -3- (4,5-dihydro-thiazol-2-yl) -ureido1-2- acid ethyl ester methyl-2,3,4,6,7,8-hexahydro-cyclopentatr quinoline-1-carboxylic H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 2.7 (m, 1 H), 7.8 (s, H), 8.0 (s, 2 H).

EXAMPLE 61 Ethyl ester of cis-4-ri- (3,5-bis-trifluoromethyl-benzyl) -3-thiazol-2-yl-uredodo-2-methyl-2,3,4,6,7,8-hexahydro- cyclopenta fgl guinoline-1-carboxylic 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 6.8 (s, 1 H), 6.9 (d, 1 H), .3 (s, 1 H).

EXAMPLE 62 Cis-4-ri- (3,5-bis-trifluoromethyl-benzyl) -ureido-1-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 537 (M +), 554 (M + + 17); 1 H NMR (CDCl 3) d 6.96 (C5, s, 1 H), 1.13 (Me, d, 3H, J = 6.0 Hz).

EXAMPLE 63 Ethyl ester of cis-9-ri- (3,5-bis-trifluoromethyl-benzyl) -ureido-1-7-methyl-1,2,3,7,8,9-hexahydro-6-aza-c clopentara1naphthalene-carboxylic MS m / z 543.2 (M +); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 2.2 (m, 1 H), 7.15 (q, H), 7.7 (s, 2 H), 7.8 (s, 1 H).

EXAMPLE 64 Ethyl ester of cis-9-ri- (3,5-bis-trifluoromethyl-benzyl) -3-methyl-ureidol-7-methyl-1, 2,3,7,8,9-hexahydro-6- aza-cyclopentafa1naphthalenecarboxylic MS m / z 557.3 (M +); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 2.0 (m, 2 H), 7.2 (q, H), 7.7 (s, 2 H), 7.8 (s, 1 H).

EXAMPLE 65 Ethyl ester of cis-9-f (3,5-bis-trifluoromethyl-benzyl) -methylsulfanylcarbonyl-amino-1-7-methyl-1, 2,3,7-8,9-hexahydro-6-aza - cyclopentane naphthalene carboxylic MS m / z 592 (M + + NH 4); 1 H NMR (CDCl 3) d 1.2 (t, 3 H), 2.4 (s, 3 H), 4.2 (q, 2 H), 7.1 (d, 1 H), 7.2 (d, 1 H), 7.5 (s, 2 H).

EXAMPLE 66 Ethyl ester of cis-4-f1- (3,5-bis-trifluoromethyl-benzyl) -ureido-2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopentarquinquinol na-1-carboxylic H NMR (CDCl 3) d 0.4 (m, 3 H), 2.1 (m, 2 H), 2.9 (m, 4 H), 6.9 (s, 1 H), 7.35 (s, 2 H), 7.8 (s, 3 H).

EXAMPLE 67 Ethyl ester of cis-4-ri- (3,5-bis-trifluoromethyl-benzyl) -3-methyl-ureido-1-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopentanthizoquinoline- 1- carboxylic 1 H NMR (CDCl 3) d 0.4 (m, 3 H), 2.8 (d, 3 H), 6.9 (s, 1 H), 7.4 (s, 1 H), 7.8 (s, 3 H).

EXAMPLE 68 Ethyl ester of cis-6-n- (3,5-bis-trifluoromethyl-benzyl) -ureido-8-methyl-1,2,3,6J, 8-hexahydro-9-aza-cyclopenta [α-naphthalene-] 9-carboxylic 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 2.2 (m, 1 H), 2.9 (m, 1 H), 6.8 (m, 1H), 7.1 (d, 1 H), 7.75 (s, 2H), 7.8 (s, 1 H).

EXAMPLE 69 Ethyl ester of cis-4-ri- (3,5-bis-trifluoromethyl-benzyl) -ureido-2- (cyclopropyl-6-trifluoromethoxy-3,4-dihydro-2H-guinoline-1-carboxylic acid) MS m / z 614.3 (M ++ 1); 1 H NMR (CDCl 3) d 6.85 (s, 1 H).

EXAMPLE 70 cis-4-H- (3,5-bis-trifluoromethyl-benzyl) -ureido-1-cyclopropyl-6-trifluoromethoxy-3,4-dihydro-2H-gulnoline-1-carboxylic acid isopropyl ester MS m / z 612 (M ++ 1); 629 (M + + 18); 1 H NMR (CDCl 3) d 1.41-1.33 (m, 6H), 4.18 (d, 1 H, J = 15.0 Hz), .55-4.65 (sa, 2H, -CONH2), 5.18 (d, 1 H, J = 15.0 Hz), 7.85 (s, 3H).

EXAMPLE 71 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methylsulfanylcaronyl-amino-1-cyclopropyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 642 (M +); 659 (M + + 17); 1 H NMR (CDCl 3) d 2.43 (s, 3 H), 7.12 (s, 1 H).

EXAMPLE 72 Iso-propyl ester of cis-4-α (3,5-bis-trifluoromethyl-benzyl) - (O-methyl) -hydroxamylcarbonyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H - quinoline-1 -carboxylic MS m / z 643 (M ++ 2); 660 (M + + 19); 1 H NMR (CDCl 3) d 3.68 (s, 3 H), 7.17 (s, 1 H).

EXAMPLE 73 cis-4-f-3, 5-bis-trifluoromethyl-benzyl) -ureidol-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester 1 H NMR (CDCl 3) d 1.1 (dd, 6 H), 3.1 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 74 cis-4-ri- (3,5-bis-trifluoromethyl-benzyl) -ureido-2- methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 602.2 (M +); 1 H NMR (CDCl 3) d 3.2 (s, 3 H), 3.4 (s, 2 H), 4.8 (s, 2 H), 7.2 (s, H), 7.8 (s, 3 H).

EXAMPLE 75 Cis-4-RI -3,5-bis-trifluoromethyl-benzyl) -ureido-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-propyl ester. carboxylic E m / z 616.2 (M ++ 1); 1 H NMR (CDCl 3) d 3.2 (s, 3 H), 3.4 (s, 2 H), 4.8 (s, 2 H), 7.2 (s, H), 7.8 (s, 3 H).

EXAMPLE 76 Cis-4-f1- (3,5-bis-trifluoromethyl-benzyl) -ureido1-2- c.c.-propyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester.

MS m / z 626.1 (M ++ 1); 1 H NMR (CDCl 3) d 0.9 (m, 3 H), 4.1 (m, 4 H), 7.5 (s, 2 H), 7.8 (s, 3H). EXAMPLE 77 Ethyl ester of cis-4-r2- (3,5-bis-trifluoromethyl-phenyl) -acetylamino-1-7,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 - carboxylic To a solution of cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (150 mg, 0.50 mmol) and 3,5-acid bis-trifluoromethylphenylacetic acid (138 mg, 0.51 mmol) in 1.5 ml of anhydrous dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (192 mg, 0.66 mmol) was added and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with 0.1 N HCl (2 x 10 ml), 0.1 N NaOH (2 x 10 ml) and brine (1 x 10 ml). The organic phase was dried (MgSO4), filtered and concentrated, and the residue was chromatographed using 20: 1 hexanes: ethyl acetate. The title compound crystallized from the pooled fractions (129 mg, 46%). pf. 157-9 ° C; MS m / z 549 (M ++ 1); 1 H NMR (CDCl 3) d 1.07 (d, 3 H), 7.70-7.78 (m, 3 H) EXAMPLE 78 AND EXAMPLE 79 Ethyl ester of cis-4-ri- (3,5-bis-trifluoromethyl-benzyl) -3- (2-chloroethyl) -ureido-1-6-dimethoxy-2-methyl-3,4 acid -dihydro-2H-quinoline-1-carboxylic acid ester and cis-4-r (3,5-bis-trifluoromethyl-benzyl) - (4,5-dihydro- or? azol-2-yl) -aminol- ethyl ester 6.7-dimethoxy-2-methyl-3,4-dihydro-2H-quinol-1-carboxylic acid A solution of cis - [(3,5-bis-trifluoromethyl-benzyl) -amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester (105 mg , 0.20 mmoles) in tetrahydrofuran (1 ml) was cooled in an ice water bath as 2-chloroethyl socianate was added. After stirring overnight at room temperature, the solvent was evaporated under a stream of nitrogen. The residue was combined with water (4 ml) and heated to reflux, the mixture was cooled to room temperature, made basic with a concentrated aqueous solution of ammonium hydroxide, extracted with ethyl acetate (3 x 10 ml), dried over sodium sulfate, filtered and concentrated in vacuo.

The resulting material was purified by chromatography on silica gel eluting with 0-30% ethyl acetate in hexanes to yield 37 mg of the title product of Example 78. 1 H NMR (CDCl 3) d 1.2 (d, 3H), 1.3 (t, 3H), 1.35 (m, 1 H), 2.2 (m, 1 H), 3.5-3.8 (m, 5H), 3.8 (s, 3H), 3.9 (s, 3H), 4.1-4.3 (m , 2H), 4.4 (m, 1H), 4.8-5.2 (m, 3H), 6.45 (C5, s, 1 H), 7.13 (C8, s, 1 H), 7.7-7.78 (m, 3H). Elutions were continued with 30-70% ethyl acetate in hexanes yielding 7 mg of the title compound of Example 79. E m / z 591 (M + +1); 1 H NMR (CDCl 3) d 1.2 (d, 3 H), 1.3 (t, 3 H), 1.35 (m, 1 H), 2.2 (m, 1 H), 3.8 (s, 3 H), 3.8-3.9 (m, 2 H) , 3.9 (s, 3H), 4.1-4.5 (m, 6H), 4.8-5.3 (m, 2H), 6.5 (C5, s, 1 H), 7.1 (C8, s, 1 H), 7J-7.8 ( m, 3H). Examples 80-95 were prepared in an optically enriched form by resolution of the corresponding indicated racemate, or an intermediate of their synthesis, using the procedures described in the specification.

EXAMPLE 80 Isopropyl ester of f2S acid, 4S1 4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- carboxylic Example 29 EXAMPLE 81 Isopropyl ester of 2S, 4S1 4-ri- (3,5-bis-trifluoromethyl-benzyl) -ureido1-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester Example 70 EXAMPLE 82 [2S, 4S] 4- [Acetyl (3,5-bis-trifluoromethyl-benzylamino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinol-na-1 ') isopropyl ester carboxylic Example 31 EXAMPLE 83 Ethyl ester of T2R acid, 4S1 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic Example 38 EXAMPLE 84 Propyl ester of acid [2S. 4S1 4 - [(3,5-bis-trifluoromethyl-benyl) -formyl-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Example 40 EXAMPLE 85 [2S, 4S1 4-Racethyl- (3,5-bis-trifluoromethyl-benzyl) -aminol-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester.

Example 41 EXAMPLE 86 Ethyl ester of acid [2R. 4S1 4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-amino-1-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Example 42 EXAMPLE 87 [2S, 4S1 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-tert -butyl ester. - carboxylic Example 43 EXAMPLE 88 Ethyl ester of [2S. 4S1 4-racethyl- (3-5-bis-trifluoromethyl-benzyl) -amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Example 44 EXAMPLE 89 [2S, 4S1 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-aminol-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.

Example 45 EXAMPLE 90 [2R, 4S1 4-Racethyl- (3,5-bis-trifluoromethyl-benzopylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid) isopropyl ester.

Example 46 EXAMPLE 91 Isopropyl ester of [2R. 4S1 4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-aminol-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Example 47 EXAMPLE 92 [2R, 4S1 4-f (3,5-bis-trifluoromethyl-benzyl) -formyl-aminol-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Example 48 EXAMPLE 93 Ethyl ester of T2R acid, 4S1 4-racethyl- (3,5-bis-trifluoromethyl-bencip-aminol-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid) Example 49 EXAMPLE 94 Ethyl ester of [2R, 4S1 4-r (3,5-bis-trifluoromethyl-benzyl) -formyl-aminol-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester Example 49C EXAMPLE 95 [2R, 4S14-Racethyl- (3,5-bis-trifluoromethyl-benzyl-amino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Example 49D

Claims (53)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; wherein R1 is Y, W-X or W-Y; where W is carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -O-Y, -S-Y, -N (H) -Y or -N- (Y) 2; where Y, for each case, is independently Z or a linear or branched carbon chain, from one to ten members, fully saturated, partially unsaturated or totally unsaturated, where the carbons other than the connecting carbon can be optionally replaced with one or two selected heteroatoms independently between oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted 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 mono-substituted with Z; where Z is a three to eight member ring partially saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members , partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent Z is optionally mono-, di or trisubstituted independently with halo, (C2-C6) alkenyl, (C-? -C6) alkyl, hydroxy, (C6) alkoxy, alkylthio (CrC), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C? -C6), mono-N- or di-N, N-alkylamino (Ci-Cß), wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C? -C6) alkoxy, alkylthio (C?? C), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ci-Ce), mono-N- or di -N, N-alkylamino (Ci-Cß), and said alkyl substituent (Ci-Cß), is also optionally substituted with one to nine fluorine atoms; R2 is a linear or branched carbon chain, from one to six members, partially saturated, fully saturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di- -substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to seven member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring R2 is optionally attached through an alkyl group (C -? - C); wherein said ring R2 is optionally mono-, di- or trisubstituted independently with halo, alkenyl (C2-Ce), alkyl (C6-6), hydroxy, alkoxy (CsC), alkylthio (C-? -C4) , amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C Cβ), mono-N- or di-N, N-alkylamino (C-C6), wherein said alkyl substituent (CrC6) is optionally mono-, di- or tri- substituted independently with halo, hydroxy, (C? -C6) alkoxy, (C1-C4) alkylthio, oxo or alkyloxycarbonyl (C -? - C6); R3 is hydrogen or Q; where Q is a fully saturated, partially unsaturated or fully unsaturated linear or branched carbon-based amount of one to six members, in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom selected from oxygen, sulfur, and nitrogen and said carbon is optionally mono-, di- or trisubstituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V; where V is a three to eight member ring partially saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V is optionally mono-di-, tri- or tetra-substituted independently with halo, alkyl (Ci-Cß), alkenyl (C2-C6), hydroxy, alkoxy (C? -6), alkylthio (C-? -C4), amino, nitro, cyano, oxo, carboxamoyl, mono-N or di-N, N-alkylcarboxamoyl (C-pCß), carboxy, alkoxycarbonyl (C? -C6), mono-N- or di-N, N-alkylamino (C -? - C6) where said (C? -C6) alkyl or (C2-C?) Alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C-? - C6) alkoxy ), alkylthio (d ~ C), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (CrC6), mono-N- or di-N, N-alkylamino (Ci-Cß), and said alkyl substituents (C-? -C6) or (C2-C6) alkenyl are also optionally substituted with one to nine fluorine atoms; R4 is cyano, formyl, W1Q1 'W1V1, alkylene (C4) V1 or V2; where W1 is carbonyl, thiocarbonyl, SO or SO2, where Q is a carbon chain of one to six members, linear or branched, fully saturated, partially unsaturated or totally unsaturated, in which the carbons can be optionally replaced with a heteroatom selected from oxygen , sulfur and nitrogen and said carbon is optionally mono-, di- or trisubstituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted 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 mono-substituted with V1; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six partially saturated members , fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with haloalkyl (Ci-Cß), alkoxy (Ci-Cß), hydroxy, oxo, amino, nitro, cyano, alkoxycarbonyl (Ci-Cβ) ), mono-N- or di-N, N-alkylamino wherein said (C-? - C6) alkyl substituent is optionally mono-substituted with oxo, and said alkyl substituent (C? -C6) is also optionally substituted with each other. nine fluorine atoms; where V2 is a five to seven member ring partially saturated, fully saturated or totally unsaturated containing one to four heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V2 is optionally mono-, di- or trisubstituted independently with halo, alkyl (C? -C2), alkoxy (C? -C2) or oxo, wherein said alkyl (C? -C2) optionally has from one to five fluorine atoms; where R4 does not include oxycarbonyl directly attached to the C4 nitrogen; where R3 must contain V or R4 must contain V1; and R5, R6, R7 and R8 are independently hydrogen, a bond, nitro, or halo, wherein said bond is substituted with T or a straight or branched, partially saturated, saturated or fully carbon chain (C? -C-? 2) or fully unsaturated, where the carbon can be optionally replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon being optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or disubstituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with T,; where T is a three to twelve member ring partially saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members partially saturated, fully saturated or totally unsaturated, taken independently, 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, hydroxy, alkoxy (CC?), alkyl (C? -C), amino , nitro, cyano, oxo, carboxy, alkoxycarbonyl (C-rCß), mono-N- or di-N, N-alkylamino (Ci-Ce) wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with hydroxy, (C? -C6) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (CrC?), mono-N- or di-N, N-alkylamino ( Cr Ce) and said alkyl substituents (Ct-Cd) also optionally have from one to nine fluorine atoms; where R5 and R6, or R6 and R7, and / or R7 and R8 may also be taken together and may form at least one ring which is a four to eight member ring partially saturated or fully unsaturated having optionally from one to three heteroatoms independently selected from hydrogen, sulfur and oxygen; wherein said rings formed by R5 and R6, or R6 and R7, and / or R7 and R8 are optionally mono-, di- or tri-substituted independently with halo, alkyl (Ci-Ce), alkylsulfonyl (Cr C4), alkenyl ( C2-C6), hydroxy, alkoxy (Ci-Cß), alkylthio (C? -C), amino nitro, cyano, oxo, carboxy, alkoxycarbonyl (d-Ce), mono-N- or di-N, N-alkylamino (Cr Cß) wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with hydroxy, (C? -C6) alkoxy, (C1-C4) alkyl, amino nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ci-Cß), mono-N- or di-N, N-alkylamino (Ci-Ce) and said alkyl substituent (C? -C6) optionally also has from one to nine fluorine atoms.

2. A compound according to claim 1, wherein the substituent C2 is beta; nitrogen 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, for each case, it is independently (C1-C4) alkyl, optionally said alkyl (C-t-C4) hydroxy or from one to nine fluorine atoms, or said (C1-C4) alkyl being optionally mono-substituted with Z; where Z is a three to six member ring partially saturated, totally or totally unsaturated having optionally one or 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 alkyloxycarbonyl (Ci- Cß), said alkyl (C -? - C4) being optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or fully unsaturated carbon chain (C? -C) in which carbons other than the connecting atom can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or disubstituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C-? - C6) alkoxy, amino, nitro, alkyloxycarbonyl (C1-C4) or carboxy; R3 is Q-V where Q is alkyl (C-r C4) and V is a five or six member partially saturated, fully saturated or fully unsaturated 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 (Ci-Cß), hydroxy, (C 1 -C 4) alkoxy, alkyloxycarbonyl (Ci-Cß), nitro, cyano, or oxo, wherein said alkyl substituent (C Ce) optionally has one to nine fluorine atoms; R 4 is carbonyl or carbamoyl wherein said carbonyl radical is optionally mono-substituted with V 1 or (C 1 -C 2) alkyl and said carbamoyl radical is optionally mono- or di-substituted independently with V 1 or alkyl (CrC 2), in any case, optionally having said alkyl (C? -C2) optionally mono-substituted with V1 or said alkyl (C? -C2) of one to nine fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, nitro or alkyl (CrC2), said alkyl (C-t-C2) optionally having from one to five fluorine atoms; each of R6 and R7 is independently hydrogen, halo, T, (C6-C6) alkoxy or (C-C3) alkyl, said substituent optionally (C6) alkoxy or (C6-6) alkyl having from one to nine fluorine atoms or said substituent being alkoxy (CrC6) or alkyl (C-? - C6) optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five or six member ring having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (d-Cß), hydroxy, alkoxy (C? -C6), alkylthio (C1-C4), amino, oxo, carboxy, alkyloxycarbonyl (Ci-Ce), mono-N- or di-N, N-alkylamino (d-Cß), wherein said alkyl substituents (d-C6) optionally have from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring that is a partially or fully unsaturated five or six membered ring optionally having one or two heteroatoms independently selected from hydrogen, sulfur and oxygen; 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 where Y is (C 1 -C 4) alkyl, wherein said (C 1 -C 4) alkyl substituent optionally has hydroxy or from one to nine fluorine atoms; R2 is alkyl (d-C), alkyloxymethylene (d-C2) or cycloalkyl (C3-C); Q is (C 1 -C 4) alkyl and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or trisubstituted independently with halo, (C? -C6) alkyl, hydroxy, (C? -C6) alkoxy, nitro, cyano or oxo, wherein said alkyl substituent (CrC6) it optionally has from one to nine fluorine atoms; R4 is carbonyl or carbamoyl, wherein said carbonyl or carbamoyl is optionally mono-substituted with hydrogen or alkyl (C? -C2); each of R6 and R7 are independently hydrogen, (C? -C3) alkoxy or (Ci-C3) alkyl, said (C3) alkoxy optionally having from one to seven fluorine atoms and optionally having said alkyl (d-Ce) from one to nine fluorine atoms; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3, wherein Q is methyl and V is phenyl or pyridinyl; wherein said ring V is optionally mono-, di- or tri- substituted independently with halo, nitro, or alkyl (d-C2), wherein said alkyl (d-C2) optionally has from one to five fluorine atoms; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, wherein said compound is [2S, 4S] 4 - [(3,5-bis-trifluoro-methyl-benzyl) -formyl-amino] -2-c isopropyl ester. Clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-tert-butyl ether carboxylic; [2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolone isopropyl ester -1-carboxylic; or ethyl ester of [2R, 4S] 4- [acetyl- (3,5-bis-trif! uomethyl-benzyl) -amino-2-methyl-6-trifluoromethyl-3,4-dihicro-2H-quinoline] -1-carboxylic acid, or a pharmaceutically acceptable salt of said compounds.

6. A compound according to claim 1, wherein said compound is [2S, 4S] 4- [1- (3,5-bis-trifluoromethyl-benzyl) -ureido] -2-cyclopropyl isopropyl ester. -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester -carboxylic; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-qu acid isopropyl ester Noline-1-carboxylic acid; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 isopropyl ester. -carboxylic acid, or a pharmaceutically acceptable salt of said compounds.

7. A compound according to claim 1, wherein said compound is [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amine] ethyl ester] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; ethyl ester of [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-etl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 isopropyl ester -carboxylic; [2R, 4S] 4- [Acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; or a pharmaceutically acceptable salt of said compounds.

8. A compound according to claim 4, wherein Y is isopropyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenimethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 4, wherein Y is n-propyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 4, wherein And it's tere-butyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmefyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 4, wherein; And it is sopropilo; R2 is ethyl; R 3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

12. - A compound according to claim 4, wherein And it is ethyl; R2 is methyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 4, wherein; And it is sopropilo; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is carbamoyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 4, wherein Y is ethyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 4, wherein And it is isopropyl; R2 is methoxymethyl; R3 is 3,5-bis-trifluoromethylphenylmefyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 4, wherein And it is n-propyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmefyl; R 4 is acetyl; Rd is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 4, wherein And it is ethyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

18. - A compound according to claim 4, wherein And it is isopropyl; R2 is ethyl; R3 is 3,5-bis-trifiuoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; R7 is H, or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 4, wherein And it is ethyl; R2 is methyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 4, wherein Y is isopropyl; R2 is cyclopropyl; R 3 is 3,5-bis-trifiuoromethylphenylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

21. A compound according to claim 4, wherein And it is ethyl; R2 is ethyl; R3 is 3-5-bis-trifluoromethylphenylmethyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 4, wherein And it is ethyl; R2 is cyclopropyl; R 3 is 3-5-bis-trifluoromethylphenylmefyl; R 4 is formyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

23. A compound according to claim 4, wherein And it is isopropyl; R2 is methyl; R3 is 3,5-b.s-trifluoromethylphenylmethyl; R4 is 9 formyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

24. A compound according to claim 4, wherein Y is isopropyl; R2 is methyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R 4 is acetyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.

25. A compound according to claim 1, wherein the substituent C2 is beta; the nitrogen of C4 is beta; R1 is W-Y; W is alkyl, thiocarbonyl or sulfonyl; Y is alkyl (d-Ce), optionally having said alkyl (CrC6) of one to nine fluorine atoms or said alkyl (Ci-Ce) being optionally mono-substituted with Z, wherein Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrC4), alkoxy (C1-C4), alkylthio (C1-C4), nitro, cyano, oxo or alkoxycarbonyl (d-Cß) , said alkyl substituent (d-C4) being optionally substituted with one to nine fluorine atoms; R2 is a linear or branched, partially saturated, fully saturated or fully unsaturated carbon chain (C1-C4), where the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di- replaced with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or fully unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is QV, where Q is (C1-C4) alkyl and V is a partially saturated, fully saturated or fully unsaturated five to 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 (C Ce), hydroxy, (C? -C6) alkoxy, nitro, cyano or oxo, wherein said alkyl substituent (C C?) it optionally has from one to nine fluorine atoms; R4 is carbonyl or carbamoyl, where said carbonyl radical is optionally mono-substituted with V1 or alkyl (C? -C2) and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or alkyl (C? -C2), any case, said alkyl (C? -C2) being optionally mono-substituted with V1 or having alkyl (C? -C) optionally of one to five fluorine atoms; where 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- or tri-substituted independently with halo, nitro or (C1-C2) alkyl, said (C? -C2) alkyl optionally having from one to five fluorine atoms; each of R6 and R7 is independently hydrogen, halo, T, alkoxy (d-Ce) or alkyl (Ci-Cß), said substituent optionally having (C6-alkoxy) or alkyl (CrC6) having from one to nine fluorine atoms or said substituent being (C? -C6) or alkyl (CrC6) optionally mono-substituted with T; where T is a five to six member ring partially saturated, fully saturated or completely unsaturated, optionally having one or 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, hydroxy, (C? -C6) alkoxy, alkyl (dd), amino, oxo, carboxy, alkoxycarbonyl (d) -C6), mono-N- or di-N, N-alkylamino (d-Cß), wherein said alkyl substituent (d-Cß) optionally has from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring which is a five or six member ring partially saturated or fully unsaturated optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H; or a pharmaceutically acceptable salt thereof.

26. A compound according to claim 1, wherein the substituent 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 totally unsaturated having optionally one or two independently selected heteroatoms. between oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 4) alkyl, alkoxy (dC), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (C 6 -C 6), said substituent being (C1-C4) alkyl optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or fully unsaturated carbon chain (C1-C4) where the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono-di-substituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or fully unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is Q-V, where Q is (C1-C4) alkyl and V is a five or six member partially saturated, fully saturated or fully unsaturated 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, (Ct-C6) alkyl, hydroxy, (C? -C6) alkoxy, nitro cyano or oxo, wherein said alkyl substituent (d) -Cß) optionally has one to nine fluorine atoms; R4 is carbonyl or carbamoyl, wherein said carbonyl radical is optionally mono-substituted with V1 or alkyl (C? -C2) and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or alkyl (d-C2), in any wherein said alkyl (C? -C2) is optionally mono-substituted with V1 or optionally having said alkyl (d-C2) of one to five fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, (C1-C2) alkyl or nitro, said (C2) alkyl substituent optionally having from one to five fluorine atoms; each of R6 and R7 is independently hydrogen, halo, T, alkoxy (C Ce) or alkyl (dO), said substituent having alkoxy (CrCe) or alkyl (d-Cß) optionally having from one to nine fluorine atoms or being said alkoxy (d-Cß) or alkyl (CrCe) substituent optionally mono-substituted with T, where T is a partially saturated, fully saturated or fully unsaturated five to six member ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrC6), hydroxy, alkoxy (CrC6), alkylthio (C1-C4), amino, oxo, carboxy, alkyloxycarbonyl (CrC6), mono-N - od-N, N-alkylamino (d-Cß), wherein said (C C6) alkyl substituent optionally has from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring which is a five or six member ring partially saturated or fully unsaturated having optionally one to two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H, or a pharmaceutically acceptable salt thereof.

27. A compound according to claim 1, wherein the substituent C2 is beta; the nitrogen of C4 is beta; R1 is Y, wherein Y is (d-C8) alkyl, said alkyl (d-Cs) optionally having one to nine fluorine atoms or said (d-C8) alkyl being optionally mono-substituted with Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or trisubstituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (CrC4), nitro, cyano, oxo or alkoxycarbonyl (d-Cß), said alkyl substituent ( C1-C4) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated saturated, fully saturated or totally unsaturated carbon chain (dd) in which the carbons, other than the connecting carbon, can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di- replaced with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member partially saturated, fully saturated or fully unsaturated 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 (d-Cß), hydroxy, alkoxy (d-C6), nitro, cyano, or oxo, wherein said alkyl substituent is optionally one or nine fluorine atoms; R4 is carbonyl or carbamoyl wherein said carbonyl radical is optionally mono-substituted with V1 or alkyl (CrC2) and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or (C1-C2) alkyl, in any case, said alkyl (CrC2) optionally mono-substituted with V1 or optionally having said alkyl (d-C2) of one to five fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or tri-substituted independently with halo, alkyl (CrC2) or nitro, said substituent optionally having (C1-C2) alkyl of one to five fluorine atoms; each of R6 and R7 is independently halo, T, alkoxy (d-Cß) or alkyl (d-Cß), said substituent optionally having alkoxy (d-Cß) ° alkyl (d-C6) of one to nine fluorine atoms or said alkoxy (d-Cß) or alkyl (d-Cß) substituent being optionally mono-substituted with T; where T is a partially saturated, fully saturated or fully unsaturated five or six member ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (d-Cß), hydroxy, alkoxy (d-Cß), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl mono-N - or di-N, N-alkylamino (CrCe), wherein said alkyl substituent (d-Ce) optionally has one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring that is a five or six member ring partially saturated or fully unsaturated having optionally one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H, or a pharmaceutically acceptable salt thereof.

28. A compound according to claim 1, wherein the C2 substituent is beta; the nitrogen of C4 is beta; R1 is Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), alkoxy (dd) alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (d-Ce), said alkyl substituent being (C1-C4) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or totally unsaturated carbon chain (dd), in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo or hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member ring partially saturated, fully saturated or totally unsaturated having optionally 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 (d-Cß), hydroxy, alkoxy (CrCe), nitro, cyano or oxo, wherein said alkyl substituent (d-Cß) ) is optionally mono-, di-, or trisubstituted independently with alkoxy (d-Cß) or alkylthio (dd) or said alkyl (d- C6) optionally has one or nine fluorine atoms; R4 is carbonyl or carbamoyl wherein said carbonyl radical is optionally monosubstituted with V1 or (C1-C2) alkyl and said carbamoyl radical is optionally mono- or di-substituted independently with V1 or alkyl (d-C2), in any case, said (C 1 -C 2) alkyl optionally monosubstituted with V 1 or optionally having said alkyl (C C 2) of one to five fluorine atoms; where V1 is a three to six member ring partially saturated, fully saturated or fully unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrC2) or nitro, said substituent optionally having (C1-C2) alkyl of one to five fluorine atoms; each of R6 and R7 are independently hydrogen, halo, T, alkoxy (Ci-Cß) or alkyl (d-Ce), said substituent optionally having alkoxy (CrC6) or alkyl (d-Cß) of one to nine fluorine atoms or said substituent being alkoxy (d-Cß) or alkyl (d-Cß) optionally mono-substituted with T; where T is a partially saturated, saturated or fully unsaturated five or six member ring optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halo, alkyl (CrC6), hydroxy, alkoxy (d-C6), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (CrC6), mono -N- or di-N, N-alkylamino (d-C6), wherein said alkyl substituent (CrC6) optionally has from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring which is a partially or fully unsaturated five or six membered ring optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H; or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1, wherein W is carbonyl; X is O-Y-, where Y is (C1-C5) alkyl, wherein said alkyl substituent (d-C5) is optionally substituted with one to nine fluorine atoms; R2 is (C1-C4) alkyl or (C3-C5) cycloalkyl; R3 is hydrogen; R 4 is (C 1 -C 4) alkylene V 1; where V1 is a five or six member ring partially saturated, fully saturated or completely unsaturated having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di- or trisubstituted independently with halo, nitro or alkyl (CrC2), said substituent optionally having (C1-C2) alkyl of one to five fluorine atoms; each of R6 and R7 is independently hydrogen, halo, T, alkoxy (d-Cß) or alkyl (dd), said substituent optionally having alkoxy (d-Cß) or alkyl (d-Cß) of one to nine fluorine atoms or said substituent being alkoxy (d-Cß) or alkyl (d-Cß) optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five or six member ring having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri- 2 independently substituted with halo, alkyl (dd), hydroxy, alkoxy (CrCe), alkylthio (C 1 -C 4), amino, oxo, carboxy, alkoxycarbonyl (d-Cß), mono-N- or di- N, N-alkyl lamino (CrC6), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; or wherein R6 and R7 are taken together and form a ring which is a partially or fully unsaturated five or six membered ring having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono- or di-substituted independently with halo, alkyl (dd), alkoxy (d-C6) or oxo, wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; cR5 and R8 are H, or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 29, wherein X is O-Y, where Y is (d-C3) alkyl, wherein said alkyl substituent (d-C3) optionally has one to seven fluorine atoms; R2 is alkyl (d-C3), or cycloalkyl (C3-d), R4 is methylene V1; where V1 is a fully unsaturated six-membered ring optionally having one or two nitrogens; wherein said substituent V1 is mono-, di-, or tri-substituted independently with halo, nitro, or alkyl (CrC2), said alkyl (CrC2) optionally having from one to five fluorine atoms; each of Rd and R7 are independently hydrogen, halo, alkoxy (d-d) or (C1-C3) alkyl, said substituents optionally having alkoxy (d-d) or alkyl (d-d) of one to seven fluorine members; or wherein R6 and R7 are taken together and form a ring that is a five to six member ring that is partially saturated or completely unsaturated and optionally has one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; R5 and R8 are H, or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 1, wherein said compound is [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-methyl-6-trifluoromethyl-3-ethyl ester. 4-dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-etl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S, 4S] 4- (3,5-bis-trifluoromethyl-benzylamino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; or a pharmaceutically acceptable salt of said compounds.

32. The compound selected from the group consisting of [2R, 4S] 4-amino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-amino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4-amino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4-amino-2-etiI-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S, 4S] 4-amino-2'-Cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; and the pharmaceutically acceptable salts of said compounds.

33. The use of a compound as claimed in claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the manufacture of a medicament for the treatment of atherosclerosis, vascular disease peripheral, dyslipidemia, hyperbetalipoproteinemia, hypoalfaliproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic resteinosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being, both men and women).

34. The use as claimed in claim 33, in which atherosclerosis is treated.

35.- The use as claimed in claim 33, in which peripheral vascular disease is treated.

36.- The use as claimed in claim 33, in which the dyslipidemia is treated.

37.- The use as claimed in claim 33, in which hyperbetalipoproteinemia is treated.

38.- The use as claimed in claim 33, in which hypoalphalipoproteinemia is treated.

39.- The use as claimed in claim 33, in which hypercholesterolemia is treated.

40.- The use as claimed in claim 33, in which hypertriglyceridemia is treated.

41.- The use as claimed in claim 33, in which cardiovascular disorders are treated.

42. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier, diluent or excipient.

43.- The pharmaceutical composition for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalfaliproteinemia, 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 mammal, comprising a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, diluent or excipient.

44.- The pharmaceutical composition for the treatment of atherosclerosis in a mammal, comprising an amount for treating atherosclerosis of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier, diluent or excipient.

45.- The combination pharmaceutical composition comprising: a therapeutically effective substance of a composition comprising a first compound, said first compound being a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug; a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of MTP / ApoB secretion, a PPAR activator, a bile acid reuptake inhibitor, an inhibitor of cholesterol absorption, a inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid complexing agent; and a pharmaceutical carrier, diluent or excipient.

46.- The combination pharmaceutical composition according to claim 45, wherein the second compound is an inhibitor of the HMG-CoA reductase and an inhibitor of the secretion of MTP / Apo B.

47.- The combination pharmaceutical composition according to claim 45, wherein the second compound is lovastatin, simvastatin, pravastatin, fiuvastatin, atorvastatin or rivastatin.

48. The use of a) a first compound, said first compound being a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; in combination with b) 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 complexer for the manufacture of a medicament for the treatment of atherosclerosis in a mammal.

49. The use as claimed in claim 48, wherein a second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion.

50. Use as the one It is claimed in claim 48, wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

51.- A team that includes: a. a first compound, said first compound being a compound according to claim 1, a prodrug of! same, or a pharmaceutically acceptable salt of said compound or of 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 / ApoB secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, a resin of ion exchange, an antioxidant, an inhibitor of ACAT or a bile acid complex and an acceptable vehicle in second unit dosage form; and c. means for containing said first and second dosage unit forms, wherein the amounts of the first and second compounds produce a therapeutic effect.

52. - The kit according to claim 51, wherein said second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. The equipment according to claim 51, in wherein said second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.