MXPA01002753A

MXPA01002753A - 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines as cetp inhibitors

Info

Publication number: MXPA01002753A
Application number: MXPA/A/2001/002753A
Authority: MX
Inventors: Michael Paul Deninno; Roger Benjamin Ruggeri; Ronald Thure Wester; Christian James Mularski
Original assignee: Michael Paul Deninno; Christian James Mularski; Pfizer Products Inc; Roger Benjamin Ruggeri; Ronald Thure Wester
Priority date: 1998-09-17
Filing date: 2001-03-15
Publication date: 2001-11-21

Abstract

Cholesteryl ester transfer protein inhibitors of formula (I), 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

4-CARBOXYAMINO-2-METHYL-1, 2.3.4-TETRAHYDROQUINOLINAS AS INHIBITORS OF THE ESTER TRANSFER PRQTEIN CHOLESTERILIC BACKGROUND OF THE INVENTION This invention relates to inhibitors of cholesteryl ester transfer protein (CETP), to pharmaceutical compositions containing said inhibitors and to the use of said inhibitors to elevate certain levels of lipids in plasma, including high density lipoproteins (HDL) -cholesterol and to decrease certain other lipid levels in the plasma, such as low density lipoprotein (LDL) -cholesterol and triglycerides and therefore to treat diseases that are affected by low HDL-cholesterol levels and / or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (ie, those who have CETP in plasma), including humans. Atherosclerosis and its associated alteration of the coronary artery (CAD) is the main cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and the treatment of dyslipidemia as a modification of diet and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the United States, where cardiovascular diseases account for 44% of deaths, 53% of which are associated with coronary atherosclerotic heart disease. It has been shown that the risk of developing this disease is strongly related to certain levels of lipids in the plasma. Although elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant contributor associated with lipids to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D.J., et al .: "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15). High levels of LDL-cholesterol and triglycerides are positively related, while high levels of HDL-cholesterol are negatively related, with the risk of developing cardiovascular diseases. Thus, dyslipidemia is not a unit risk profile for CHD but may comprise one or more lipid aberrations. Among the many factors that control the plasma levels of these principles on which diseases depend, 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 decrease in HDL- ^ ^? ^ g cholesterol and an increase in LDL-cholesterol. It is believed that this effect on the profile of lipoproteins is pro-atherogenic, especially in subjects whose lipid profile constitutes an increasing risk of CHD. There are no fully satisfactory HDL elevation therapies. Niacin can significantly increase HDL, but it has serious tolerance problems that reduce its acceptance. Fibrates and HMG-CoA reductase inhibitors increase HDL-C only modestly (~ 10-12%). As a result, there is a significant unmet medical need for a well-tolerated agent that can significantly elevate HDL levels in the plasma, reversing or delaying the progression of atherosclerosis. Thus, although there is a variety of anti-atherosclerotic therapies, there is still a continuing need and a continuous search in this field for alternative therapies techniques. EP0818448 (970624) describes the preparation of certain tetrahydroquinolines substituted in, 6, 7, 8 and analogues as inhibitors of cholesteryl ester transfer protein. U.S. Patent No. 5,231,102 discloses a class of 1, 2,3,4-tetrahydroquinolines substituted at 4 which possess an acid group (or group convertible in vivo) at position 2 which are specific antagonists of N-receptors. -methyl-D-aspartate (NMDA) and therefore useful in the treatment and / or prevention of neurodegenerative disorders.

U.S. Patent No. 5,288,725 describes pyrroloquinoline-bradykinin antagonists.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to compounds of formula I Formula I to its prodrugs, and to pharmaceutically acceptable salts of said compounds and said prodrugs; wherein R1 is hydrogen, Y, W-X, W-Y; wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -O-Y, -S-Y, -N (H) -Y or -N- (Y) 2; wherein Y in each case is independently Z or a carbon chain, linear or branched, from one to ten members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, other than the bonding carbon, may be replaced optionally by one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbon is Mrifiltt _____ «_______________________________i optionally mono-, di- or tri-substituted independently with halogen, 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; Z is a ring, of three to twelve members, partially saturated, totally saturated or totally unsaturated, having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings, from three to six members, fused, partially saturated, fully saturated or totally unsaturated, independently considered, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halogen, (C2-C6) alkenyl, (C1-C3) alkyl, hydroxy, alkoxy (Ci-Ce), alkylthio (C1-C4) , amino, nitro, cyano, oxo, carboxy, alkyloxy (Ci-Ceylcarbonyl, mono-N- or di-N, N-alkylamino (CrC6) wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with halogen, hydroxy, (C? -C6) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (C? -C6) alkyloxycarbonyl, mono-N - or di-N, N-alkylamino (Ci-Cß), said alkyl (C? -C6) being optionally substituted with one to nine fluorine atoms; ^ m ^^^ m?? l? ^ l? t R3 is hydrogen or Q; wherein Q is a carbon chain, linear or branched, from one to six members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, other than the binding carbon, can be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halogen, 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; wherein V is a three to twelve member ring partially saturated, fully saturated or totally unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings, three to six members, fused, partially saturated, fully saturated or totally unsaturated, independently considered, having optionally one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V is optionally mono-, di-, tri or tetra-substituted independently with halogen, alkyl (Ci-Cß), alkenyl (C2-C6), hydroxy, alkoxy (Ci-Cß), alkylthio (C? -C4), amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N-alkyl (C? -C6) -carboxamoyl, carboxy, (C? -C6) alkyloxycarbonyl, mono-N- or di-N, N -alkylamino (Ci-Ce), wherein said alkyl (Ci-Ce) or alkenyl (C2-C6) substituent is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (Ci-Cß), alkylthio ( Cr C4), amino, nitro, cyano, oxo, carboxy, alkyloxy (Ci-Cß-carbonyl, mono-N- or di-N, N-alkylamino (C?-C6), said alkyl (Ci-Cß) or (C2-C6) alkenyl optionally substituted with one to nine fluorine atoms; R4 is Q1 or V1; wherein Q1 is a carbon chain, linear or branched, from one to six members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, other than the bonding carbon, can optionally be replaced by a heteroatom selected from oxygen, sulfur or nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halogen, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or disubstituted oxo-cone, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V1; wherein V1 is a ring, from three to six members, partially saturated, fully saturated or completely unsaturated, having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; ^^^ jjjj ^^^ ¡jj te in which said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with halogen, alkyl (d-Cß), alkoxy (Ci-Cß), amino, nitro, cyano, alkyloxy (CrCβJ-carbonyl, mono-N- or di-N, N-alkylamino (Ci-Cβ), wherein said alkyl substituent (CrCβ) is optionally mono-substituted with oxo, optionally having said alkyl substituent (C Ce) of one to nine fluorine atoms, wherein R3 must contain V or R4 must contain V1, and R5, R6, R7, and R8 are each independently hydrogen, a bond, nitro or halo, wherein said link is substituted with T or a linear or branched carbon chain of (C 1 -C 12) partially or completely saturated, or completely unsaturated, said carbon being optionally replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are mono-, di- or tri-substituted independently with halo, said carbon is mono-substituted with hydroxy, said carbon is 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 is mono-substituted with T; wherein T is a partially or fully saturated, or completely unsaturated, ring of three to twelve members, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen; or a bicyclic ring comprising two condensed rings of three to six members partially or completely saturated, or Completely unsaturated, taken independently, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halogen, alkyl (CrCß), alkenyl (C2-Cd), hydroxy, alkoxy (CrCß), alkylthio (C4), amino, nitro, cyano, oxo, carboxy, (C 1 -C 6) alkoxycarbonyl, mono-N- or di-N, N-alkylamino (Ci-Cß) wherein said alkyl substituent (C Cd) is optionally mono-, di- or independently trisubstituted with hydroxy, alkoxy (Ci-Cß), alkylthio (dC), amino, nitro, cyano, oxo, carboxy, alkyloxy (CrC6) -carbonyl, mono-N- or di-N, N-alkylamino (C Ce ), or said alkyl (C Cß) optionally having one to nine fluorine atoms; with the proviso that R5, R6, R7 and R8 is not hydrogen and is not linked to the rest of the quinoline via oxy. A preferred group of compounds, referred to as Group A, contains the compounds having the Formula I as shown above in which the C 2 -methyl is in beta orientation; C4-nitrogen is in beta orientation; 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 Z or (C1-C4) alkyl, said alkyl (C? -C4) being optionally substituted with hydroxy or one to nine fluorine atoms or said alkyl (CrC4) being optionally mono-substituted with Z; wherein Z is a ring, from three to six members, partially saturated, fully saturated or totally unsaturated, having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halogen, alkyl (d-C4), alkoxy (C1-C4), alkylthio (CrC4), nitro, cyano, oxo or alkyloxy (CrC6) -carbonyl, said alkyl substituent (CrC4) being optionally substituted with one to nine fluorine atoms; R3 is Q-V wherein Q is alkyl (CrC4) and V is a five to 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 halogen, alkyl (Ci-Cß), hydroxy, alkoxy (C-pCß), nitro, cyano or oxo, wherein said alkyl (Ci-Cß) optionally has from one to nine fluorine atoms; R4 is alkyl (C4); R6 and R7 is each independently hydrogen, halo, T, (C4) alkyl or (C4) alkoxy, optionally having said (C4) alkyl or rfüfa-írii_ & alkoxy (CrC4) of one to nine fluorine atoms, or optionally said alkyl (C -? - C4) or alkoxy (C? -C4) substituted by T, where T is a five or six membered ring, partially saturated or completely unsaturated, optionally having one to two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halogen, alkyl (C-i-Cß), hydroxy, alkoxy (Ci-Cß), alkylthio (C? -C4), amino, oxo, carboxy, (C? -C6) alkyloxycarbonyl, mono-N- or di-N, N-alkylamino (Ci-C?), Said alkyl substituent (Cr CQ) optionally one to nine fluorine atoms; R5 and R8 are H; or pharmaceutically acceptable salts. A group of compounds that is preferred among Group A compounds, designated Group B, contains the compounds wherein W is carbonyl; X is O-Y, wherein y is alkyl (d-C4), said alkyl (C? -C4) optionally having from one to nine fluorine atoms; Q is alkyl (CrC4) and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or tri-substituted independently with halogen, alkyl (C Cß), hydroxy, alkoxy (C-i-Cß), nitro, cyano or oxo, wherein said alkyl substituent (C-i-Cß) optionally has hydroxy or from one to nine fluorine atoms; R6 and R7 are each independently hydrogen, halogen or (C1-C3) alkyl, said (C1-C3) alkyl optionally having from one to seven fluorine atoms; and pharmaceutically acceptable salts. A group of compounds that is preferred among Group B compounds, termed Group C, contains the compounds wherein Q is methylene and V is phenyl or pyridinyl; wherein said ring V is optionally mono-, di- or trisubstituted independently with halogen, (C1-C2) alkyl or nitro, wherein said (C1-C2) alkyl optionally has one to five fluorine atoms; and pharmaceutically acceptable salts. Especially preferred compounds of Formula I are the following compounds: [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4-ethyl ester -dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-chloro-2-methyl-3,4-dihydro-2H-quinol N-1-carboxylic acid; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2,6,7-trimethyl-3,4-dihydro-2H-qu acid ethyl ester Nolin-1-carboxylic acid; and pharmaceutically acceptable salts of said compounds. Other especially preferred compounds of Formula I are the compounds: rr - mi iin - | > i ^ ^. ^^^^ M ^ i | i ^ M | ^^^^^ Mfct ^^^ ia ^ _______ Ü_ [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) ethyl ester] -methoxycarbonyl-amino] -6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinolin-1 -sidic acid ethyl ester -carboxylic; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; and the pharmaceutically acceptable salts of said compounds. Especially preferred compounds in group C of compounds are compounds in which a. And it is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; and R6 is hydrogen; and R7 is trifluoromethyl; b. And it's ethyl; R 3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is hydrogen, and . _. _____ * ^ fa __- _t,. ^ L 4 R7 is chlorine; C. Y is ethyl; R3 is 3-5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is chlorine; and R7 is hydrogen; d. And it is ethyl; R3 is 3-5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is methyl; and R7 is methyl; and. and is ethyl; R3 is 3-5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is ethyl, and R7 is ethyl; F. Y is ethyl R3 is 3-5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is ethyl; and R7 is hydrogen; g. And it is ethyl; R3 is 3-5-bis-trifluoromethylphenylmethyl; ^^ ¿, Jja3fe. < To tfarfagjjjjt- ^^ < . __ »& R4 is methyl; R6 is trifluoromethyl; and R7 is hydrogen, and h. And it is isopropyl; R3 is 3-5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl, and R7 is hydrogen, and the pharmaceutically acceptable salts of said compounds. A group of compounds, designated Group D, contains the compounds having the formula I as shown below in which methyl C2 is in beta orientation; nitrogen C4 is in beta orientation: 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 is independently (C1-C4) alkyl, said (C1-C4) alkyl optionally having from one to nine fluorine atoms, or said alkyl (CrC) being optionally mono-substituted with Z, wherein Z is a ring, three to six limbs, partially saturated, fully saturated or completely unsaturated, having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di-, or tri-substituted independently with halogen, alkyl (CrC4), alkoxy (CrC4), alkylthio (d-C4), nitro, cyano, oxo or alkyloxy (C? - C6) -carbonyl, said alkyl (C C4) substituent optionally having one to nine fluorine atoms; R3 is Q-V where Q is alkyl (d-d) and V is a five- or six-membered, 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 halogen, alkyl (C Cß), hydroxy, alkoxy (Ci-Cß), nitro, cyano or oxo, said alkyl being (d -Cβ) optionally mono-, di-, or tri-substituted independently with alkoxy (d-Cß) or alkylthio (Ci-Cß) or optionally having said alkyl (Ci-Ce) of one to nine fluorine atoms; R4 is alkyl (d-C); R6 and R7 are each independently H, carbamoyl, oxycarbonyl, oxy or halogen, or halogen, or said carbamoyl, oxycarbonyl or oxy are substituted with (C1-C4) alkyl and said (C1-C4) alkyl being optionally mono-, di- -, or tri-substituted with halogen or hydroxy, or said (C? -C4) alkyl being optionally mono-substituted with (d-C4) alkoxy, carboxy, alkylthio (d-C4), alkyl (d-C4) -carbonyl , amino or mono-N- or di-N, N-alkylamino (C? -C4), or said alkyl (C? -C4) substituent having from one to * - & -. - »* -.-_ 5 nine fluorine atoms; or said alkyl (d-C4), carbamoyl, oxycarbonyl or oxy are optionally mono-substituted with T; wherein T is a ring of three or six members, partially or fully saturated, or completely unsaturated, having optionally one to five two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring T is optionally mono-, di-, tri- or tetra-substituted independently with halogen, (C 1 -C 6) alkyl, hydroxy, alkoxy (CrCβ), nitro, cyano or oxo, said alkyl substituent (Ci) being -Cd), optionally mono-, di- or tri-substituted independently with alkoxy (d-Cß) or alkylamino (d-C6) -thio, or said alkyl substituent (d-Cß) optionally having from one to nine carbon atoms; fluorine; R5 and R8 are H; or a pharmaceutically acceptable salt. A group of compounds that is preferred in Group D of compounds, designated Group E, contains the compounds in which W is carbonyl; X is O-Y, wherein Y is alkyl (d-d), said alkyl (C? -C4) having from one to nine fluorine atoms; Q is alkylene (CrC4) and V is phenyl, pyridinyl or pyrimidyl; wherein said ring V is optionally mono-, di- or trisubstituted independently with halogen, alkyl (d-Cß), hydroxy, alkoxy i int ui r. - ______ ^^^^^^^^ ... ........ . . . . _,. 1 M ^ t ^^^^^^^^^^^^^^^^ (d-Cß), nitro, cyano or oxo, said alkyl substituent (Ci-Ce) optionally having one to nine fluorine atoms; R6 is H, carbamoyl, oxycarbonyl, oxy or halogen, or said carbamoyl, oxycarbonyl or oxy are substituted with (C-1-C2) alkyl and said (C1-C2) alkyl being optionally mono-, di-, or tri-substituted with halogen or hydroxy, or said alkyl substituent (CrC4) having optionally from one to nine fluorine atoms; R7 is H, carbamoyl, oxycarbonyl, oxy or halogen, or said carbamoyl, oxycarbonyl or oxy are optionally substituted with alkyl (d-C4) and said alkyl (CrC4) being optionally mono-, di-, or tri-substituted with halogen or hydroxy, or said alkyl substituent (CrC4) optionally having from one to nine fluorine atoms; and their pharmaceutically acceptable salts. Yet, another aspect of this invention relates to methods for treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, acute stroke, myocardial infarction, injury of reperfusion, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being, both male and female) administering to a mammal in need of such treatment an adequate amount to treat atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, acute stroke, myocardial infarction, reperfusion injury, angioplast restenosis ica, hypertension, vascular complications of diabetes, obesity or endotoxemia of a compound of Formula 1, one of its pro-drugs, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention relates to a method for treating atherosclerosis in a mammal (including a human) by administering to a mammal in need of such treatment, an amount suitable for treating atherosclerosis, of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention relates to a method of treating peripheral vascular disease in a mammal (including a human) by administering to a mammal in need of such treatment an amount suitable for treating peripheral vascular disease, of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method for treating dyslipidemia in a mammal (including a human) by administering to a mammal in need of such treatment an amount _. suitable for treating dyslipidemia, of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention, relates to a method of treating hyperbetalipoproteinemia in a mammal (including a human) by administering to a mammal in need of such treatment an amount suitable for treating hyperbetalipoproteinemia, of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method for treating hypoalphalipoproteinemia in a mammal (including a human) by administering to a mammal in need of such treatment an amount suitable for treating hypoalphalipoproteinemia, of a compound of formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method for treating hypercholesterolemia in a mammal (including a human) by administering to a mammal in need of such treatment, an amount suitable for treating hypercholesterolemia, of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method for treating hypertriglyceridemia in a mammal (including a human) * «- - * -« - - - - - - ^^ «___fe______ administering to a mammal in need of such treatment an amount suitable for treating hypertriglyceridemia, a compound of Formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug. Yet another aspect of this invention relates to a method for treating hypercholesterolemia in a mammal (including a human) by administering to a mammal in need of such treatment an amount suitable for treating hypercholesterolemia, of a compound of Formula I, one of its prodrugs , or a pharmaceutically acceptable salt of said compound or said prodrug. Still another aspect of this invention relates to a method for treating cardiovascular disorders in a mammal (including a human), by administering to a mammal in need of such treatment, an amount suitable for treating cardiovascular disorders, of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method of treating angina in a mammal (including a human) by administering to a mammal in need of such treatment an amount suitable to treat angina, of a compound of formula I, one of its prodrugs , or a pharmaceutically acceptable salt of said compound or said prodrug.

Yet another aspect of this invention relates to a method for treating ischemia in a mammal (including a human) by administering to a mammal in need of such treatment, an amount suitable for treating ischemia, of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method for treating cardiac ischemia in a mammal (including a human) by administering to a mammal in need of such treatment, an amount suitable for treating cardiac ischemia, of a compound of formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention, relates to a method for treating stroke in a mammal (including a human), by administering to a mammal in need of such treatment, an amount suitable for treating stroke of a compound of Formula I, one of its pro-drugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention, relates to a method for treating myocardial infarction in a mammal (including a human) by administering to a mammal in need of such treatment an amount suitable for treating myocardial infarction of a compound of Formula I , one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention, relates to a method of treating reperfusion injury in a mammal (including a human), by administering to a mammal in need of such treatment an amount suitable for treating reperfusion injury of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention, relates to a method for treating angioplastic restenosis in a mammal (including a human), by administering to a mammal in need of such treatment, an amount suitable for treating angioplastic restenosis of a compound of formula I , one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method for treating hypertension in a mammal (including a human) by administering to a mammal in need of such treatment an amount suitable for treating hypertension of a compound of formula I, one of its prodrugs , or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention relates to a method of treating vascular complications of diabetes in a mammal (including a human) by administering to a mammal in need thereof. treatment; an amount suitable for treating the vascular complications of diabetes of a compound of formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of this invention relates to a method of treating obesity in a mammal (including a human) by administering to a mammal in need of such treatment, an amount suitable for treating the obesity of a compound of formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug. Yet another aspect of that invention relates to a method for treating endotoxemia in a mammal in need of such treatment, an amount suitable for treating the endotoxemia of a compound of Fomulal, one of its prodrugs, or an acceptable pharmaceutical salt thereof. compound or of said pro-drug. A preferred dosage is about 0.001 to 100 mg / kg / day of a compound of formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug. An especially preferred dosage is about 0.01 to 10 mg / kg / day of a compound of formula I, one of its prodrugs, 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, one of its prodrugs, or a pharmaceutically acceptable salt thereof. _____f_____i_____ri______ said compound or said pro-drug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, acute 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, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said pro-drug, and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of atherosclerosis in a mammal (including a human) comprising an amount suitable for treating atherosclerosis of a compound of formula I, one of its prodrugs, 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 peripheral vascular disease in a mammal (including a human) comprising a suitable amount for treating peripheral vascular disease, of a compound of formula I, __ * _ »» ..: ._. "__ * _ ** _ * _ *« _ __ j j ^ fett j one of its pro-drugs, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable vehicle. This invention also relates to pharmaceutical compositions for the treatment of dyslipidemia in a mammal (including a human) comprising, an amount suitable for treating the dyslipidemia of a compound of formula I, one of its prodrugs, 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 hyperbetalipoproteinemia in a mammal (including a human) comprising, an amount suitable for treating hyperbetalipoproteinemia of a compound of formula I, one of its prodrugs, or a pharmaceutically salt acceptable of said compound or of said pro-drug, and a pharmaceutically acceptable vehicle. This invention also relates to pharmaceutical compositions for the treatment of hypoalphalipoproteinemia in a mammal (including a human) comprising, an amount suitable for treating hypoalphalipoproteinemia of a compound of formula I, one of its prodrugs, or a pharmaceutically salt acceptable of said compound or said pro-drug, and a pharmaceutically acceptable carrier.

., Z.M ^ ^ ^^. .. - - ~ - ^^? This invention also relates to pharmaceutical compositions for the treatment of N-cholestermidia in a mammal (including a human) comprising an amount suitable for treating hypercholesterolemia of a compound of formula I, one of its components. drugs, 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 hypertriglyceridemia in a mammal (including a human) comprising an amount suitable for treating the hypertriglyceridemia of a compound of formula I, one of its prodrugs, 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 familial hypercholesterolemia in a mammalian (including a human) comprising an amount suitable for treating familial hypercholesterolemia of a compound of formula I, one of its prodrugs, 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 angina in a mammal (including a human), comprising an amount suitable for treating angina of a compound of formula I, one of its prodrugs, or a pharmaceutically acceptable salt ^ j ^^, ^^. ^^^^^^. ^ mvm *. . *******. * * - * 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), comprising an amount suitable for treating the ischemia of a compound of formula I, one of its prodrugs, 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 cardiac ischemia in a mammal (including a human), comprising an amount suitable for treating cardiac ischemia of a compound of formula I, one of its prodrugs, 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 stroke in a mammal (including a human), comprising a suitable amount for treating stroke of a compound of formula I, one of its prodrugs, 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 a suitable amount to treat infarction of * «,« _. »._ ...» .., ... .. - ^ j- ^ ^^^^^^^^^^^ ^^^^^^^^^^^^^ j¡ ^^ ^^^ £ ^ i ^ gH __ myocardium of a compound of formula I, one of its prodrugs, 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 reperfusion injury in a mammal (including a human), comprising an amount suitable for treating reperfusion injury of a compound of formula I, one of its prodrugs, 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 angioplastic restenosis in a mammal (including a human), which comprises an amount suitable for treating angioplastic restenosis of a compound of formula I, one of its prodrugs, 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 hypertension in a mammal (including a human), comprising an amount suitable for treating hypertension of a compound of formula I, one of its prodrugs, 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 vascular complications of diabetes in a _______ MB _______ Í r tx-rf tfüiffr i - - • r ^^^^^ t ^ gHM ^^^^^ i ^^ m ^^? Mammalian M (including a human) comprising a suitable amount to treat the vascular complications of diabetes of a compound of formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically vehicle acceptable. This invention also relates to pharmaceutical compositions for the treatment of obesity in a mammal (including a human) comprising an amount suitable for treating obesity of a compound of Formula I, one of its prodrugs, 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 endotoxemia in a mammal (including a human), which comprises an amount suitable for treating the endotoxemia of a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. This invention also relates to a composition of a pharmaceutical combination comprising: a therapeutically effective amount of a composition comprising: a first compound, said first compound being a compound of Formula I, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said pro-drug; a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of the secretion of the microsomal protein of triglyceride transfer (TP) / Apo B, 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 sequestrant; and / or optionally a pharmaceutical vehicle. Among the second compounds are preferred a HMG-CoA reductase inhibitor and an MTP / Apo B secretion inhibitor. 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 treating atherosclerosis in a mammal comprising administering to a mammal suffering from atherosclerosis; a first compound, said first compound being a compound of Formula I, one of its prodrugs, 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 / Apo B secretion, an inhibitor of cholesterol absorption, an inhibitor of the synthesis of -. .. ^ sS ^. * - ^ - z ^ ± si * ^^ cholesterol, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, in which the amounts of the first and second compounds result in a therapeutic effect. A preferred aspect of the method is one in which the second compound is an HMG-CoA reductase inhibitor or an inhibitor of MTP / Apo B secretion. A particularly preferred aspect of the above method is that in which the HMG inhibitor -CoA reductase is lovastatin, 10 simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. Yet another aspect of this invention is a kit (kit) comprising: a. a first compound, said first compound being a compound of Formula I, one of its prodrugs, or a salt Pharmaceutically acceptable of said compound or of said pro-drug, and a pharmaceutically acceptable carrier in a first unit dosage form; b. a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of MTP / Apo B secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, and a . ? - - < H & ^^ ¿¡¡¡ The present invention relates to a pharmaceutically acceptable vehicle in a second unit dosage form; and c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds, result in a therapeutic effect. A second preferred compound is an HMG-CoA reductase inhibitor or an inhibitor of MTP / Apo B secretion. A particularly preferred HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastin or rivastatin. As used in the present invention, the term "mammals" is understood to refer to all mammals that contain CETP in their plasma, for example, rabbits and primates, such as monkeys and humans. Other certain mammals, for example, dogs, cats, cattle, goats, sheep and horses do not contain CETP in their plasma and are not included in the present invention. The term "suitable to treat", "treat" or "treatment" as used in the present invention includes preventive (eg, prophylactic) and palliative treatment. By "pharmaceutically acceptable" it is understood that the vehicle, The diluent, excipients and / or salts must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. The term "prodrug" refers to compounds that are drug precursors that after administration, they release the drug in vivo by means of some chemical or physiological process (for example, a prodrug to be brought to physiological pH or by enzymatic action becomes the desired drug form). Exemplary prodrugs which by cleavage release the corresponding free acid, and said hydrolyzable ester-forming residues of the compounds of formula I, include, but are not limited to, those having a carboxyl moiety in which the free hydrogen is substituted with (C1-C4) alkyl, (C2-C7) alkanoyloxy-methyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, -crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkylamino (C-1-C2) - (C2-C3) alkyl (such as b-dimethylaminocetyl), carbamoyl-C1-C2alkyl , N, N-dialkyl (C? -C2) -carbamoyl-(C1-C2) alkyl and piperidino-, pyrrolidino- or morpholino- (C2-C3) alkyl. The following paragraphs describe the illustrative ring (s) of the descriptions of the generic rings contained in the present invention. The aromatic ring of five to six illustrative members which optionally have one or two heteroatoms selected ^^^^^^^^^^^^^^^^^^^^^^ - independently of oxygen, nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl , pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl. The rings, from five to eight members, partially saturated, 5 fully saturated or totally unsaturated, illustrative having optionally from one to four heteroatoms independently selected from oxygen, sulfur and nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. More five rings include 2H-members illustrative pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl 10, 2,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H. imidazolyl, 2- midazolinilo, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1, 2-dithiolyl, 1, 3-dithiolyl, 3H-1, 2-oxathiolyl, 1, 2,3-oxadiazolyl, 1 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,4-oxadiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,4-thiadiazolyl, 1,2 , 3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 3H-1, 2,3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazolyl, 1,4-dioxazolyl, 5H-1, 2,5-oxathiazolyl and 1,3-oxathiolyl. For example, additional six membered rings include 2H-pyranyl, 4H- pyranyl, pyridinyl, piperidinyl, piperidinyl, 1, 2-dioxinyl, 1, 3-dioxinyl, 1, 4- dioxanyl 20, morpholinyl, 1, 4- dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, piperazinyl, 1, 3,5-triazinyl, 1, 2,4-triazinyl, 1, 2,3- triazinyl, 1, 3,5-trithianyl, 4H-1, 2-oxazinyl, 1, 2,5-oxathiazinyl, 1,4-oxazinyl, or- ______ ^ .._. - * w ....... ^ afc, ^ ....... Jft,. - > - .. ^^ É ^^ ... _. ", ^ ^ A ^ + * ^ - * _-_________ A .. * isoxazinyl, p-isoxazinyl, 1, 2,5-oxathiazinyl, 1, 2,6-oxathiazinyl, 1, 2,4-oxadiazinyl and 1, 3 , 5,2-oxadiazinyl. By way of example, additional rings of seven members include azepinyl, oxepinyl and thiepinyl. By way of example, additional rings of eight members include cyclooctyl, cyclooctenyl and cyclooctadienyl. Illustrative bicyclic rings comprising two rings, of five or six members, condensed, partially saturated, fully saturated or totally unsaturated, independently considered, which optionally have one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, include indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta (b) pyridinyl, pyran (3,4-b) pyrrolyl, benzofuryl , Sobenzofuryl, benzo (b) thienyl, benzo (b) thienyl, I-indazolyl, indoxazinyl, benzoxazolyl, benzimidazolyl, benzthia-zolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrid (3) , 4-b) - pyridinyl, pyrido (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-20 benzoxazinyl and 4H-1,4-benzoxazinyl. By alkylene is meant a saturated hydrocarbon (straight or branched chain) which lacks one hydrogen atom from each of the terminal carbons. Illustrative of such groups (assuming that the length designated by the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene. By halogen is meant chlorine, bromine, iodine or fluoro. By "alkyl" is meant a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon. Illustrative of said alkyl groups (assuming that the designated length encompasses the particular example) are methyl, ethyl, propyl. Isopropyl, butyl, sec-butyl, butyl, tertiary, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl. By "alkoxy" is meant a saturated straight-chain alkyl or a saturated branched-chain alkyl attached by means of an oxy. Illustrative of said alkoxy groups (assuming the desired length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy. As used herein the term mono-N- or di-N, N-alkyl (C? -Cx) ... refers to the alkyl moiety (CrCx) considered independently when it is di- N, N-alkyl ( d-Cx) ... (x refers to integers). References (e.g. claim 1) to "said carbon" in the phrases "said carbon is optionally mono-, di- or tri-substituted independently with halogen, said carbon is optionally mono-substituted with hydroxy, said carbon being optionally mono- replaced with g ^ fl ^ jg¡ ^ g ^ g ^^ | ^^ jg ^ oxo "refer to each of the carbons in the carbon chain including the binding carbon References to" nitrogen ... di-substituted with "oxo" of the present specification (for example, claim 1) refer to a terminal nitrogen constituting a nitro function It is to be understood that if a carbocyclic or heterocyclic moiety can be bound or otherwise bound to a designated substrate by different atoms of the ring, without indicating a specific binding point, all possible points are included, 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 the like 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 expression 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, meglamine (N-methylglucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

As used herein, the terms "inert solvent in the rean" and "inert solvent" refer to a solvent or a mixture thereof which does not interact with the starting materials, reagents, intermediates or products in such a way that 5 adversely affect the performance of the desired product. The term "cis" refers to the orientation of two substituents relative to one another and to the plane of the ring (either "above" or "below"). Similarly, the term "trans" refers to the orientation of two substituents relative to one another and to the plane of the ring (the substituents being on opposite sides of the ring). The letters alpha and beta refer to the orientation of a substituent with reference to the plane of the ring (ie the page). Beta is above the ring plane (ie the page) and alpha is below the plane of the ring (ie the page). The skilled chemist will recognize that certain compounds of this invention will contain one or more atoms that may be in particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. Said isomers and their mixtures are included in this invention. Also included are the hydrates and solvates of the 20 compounds of this invention. It will be recognized that the compounds of this invention can exist in radiolabelled form, ie, said compounds can contain one or more atoms containing an atomic mass or a mass number - - - * ^ - ^^ *** ^ ^ ^ ^ ^ * - «. * _- -a» é »« a ^ aÉ ______ different from the atomic mass or mass number generally found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine and chlorine include 3H, 14C, 32P, 35S, 18F and 36CI, respeely. The compounds of this invention, one of their prodrugs, a pharmaceutically acceptable salt of said compound or of said prodrug containing the radioisotopes and / or other radioisotopes of other atoms are within the scope of this invention. The radioisotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly preferred for their ease of preparation and detectability. The radiolabelled compounds of the formula of this invention and their prodrugs can be prepared generally by methods well known to those skilled in the art. Conveniently, said radiolabelled compounds can be prepared by performing the procedures described in the schemes and / or the following examples by substituting a non-radiolabeled reagent for an easily available radiolabelled reagent. 15 DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediaminetetraacetic acid. Other features and advantages of this invention will be apparent from this specification and the accompanying claims which describe the invention.

- ^ J *. . . « - "X..'« as. _, -_ _- .. ___ ~.. ... ^. «. ^ | And ff ^^^. ^^ a ^ A ^. ^. ^^ _. .. ..... < _ ^ _, »» ^? jt ..

DETAILED DESCRIPTION OF THE INVENTION In general, the compounds of this invention can be prepared by processes that include processes analogous to those known in the chemical arts, particularly as a consequence of the description contained herein. Certain methods for the manufacture of the compounds of this invention are provided as further aspects of the invention and are illustrated by the following rean schemes. Other procedures are described in the experimental sen. & ^^^^^^ 2 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^ j ^^^^ g ^ SCHEME VI v SCHEME XXII XXIII .... .._., ^ __ ^ _______. "____-_____ _. __a______ ____ i ______ ^ _____________ ^ SCHEME IV SCHEME V SCHEME VI LXIV As an initial note, in the preparation of the compounds of formula I, it is noted that some of the preparation methods useful for the preparation of the compounds described herein, may require protection of a distant function (eg, primary amine, secondary amine, carboxyl in the precursors of formula I). The need for such protection will vary depending on the nature of the distant function and the conditions of the preparation methods. The need for such protection is readily determined by those skilled in the art. The use of said protection / deprotection methods is also deduced from the experience of the technique. For a general description of the protective groups and their use, see T.W. Greene, Protective 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 amines or carboxylic acid functions that can interfere with reactions elsewhere in the molecule if they are unprotected. Accordingly, said functions can be protected by an appropriate protecting group which can be separated in a subsequent step. Protective groups suitable for the protection of amine and carboxylic acid include the protecting groups frequently used in the synthesis of peptides (such as Nt-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethyleneoxycarbonyl for amines and esters of lower alkyl or benzyl for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and which can be typically removed without chemically altering another function in the compound of formula I. According to reaction scheme I, the compounds of formula III, in the that R5, R6, R7 and R8 are as described above and P2 is an appropriate protecting group, can be prepared from the appropriate aromatic amine of formula II wherein R5, R6, R7 and R8 are as described above. The tetrahydroquinoline of formula III is prepared by treating the appropriate aromatic amine of formula II with the required acetaldehyde in a Inert solvent, such as a hydrocarbon (e.g., hexanes, pentanes or cyclohexanes), an aromatic hydrocarbon (e.g., benzene, toluene or xylene), a halocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride or dichloroethane), an ether (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, methyl-15-tert-butyl ether, etc.), a nitrile (eg, acetonitrile or propionitrile), a nitroalkane (eg, 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) during 1-24 hours (preferably 1 hour). The resulting solution is treated with a suitably substituted N-vinyl species (for example, benzyloxycarbonyl, t-butoxycarbonyl, methoxycarbonyl, formyl, acetyl, diallyl or dibenzyl), preferably carboxybenzyloxy, and with a Lewis acid (per example, boron trifluoride, boron trifluoride etherate, zinc chloride, titanium tetrachloride, iron trichloride, aluminum trichloride, alkyl aluminum dichloride, dialkyl aluminum chloride or ytterbium triflate (III); preferably boron trifluoride etherate) or a protic acid, such as a hydrohalic acid (eg, of fluorine, chlorine, bromine or iodine), an alkyl sulfonic acid (eg, p-toluene, methane or trifluoromethane) or carboxylic acid (eg, 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 1 hour). Alternatively, the amine of formula II and acetaldehyde may 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) with titanium tetrachloride in a polar aprotic solvent (preferably in dichloromethane) at a temperature between about -78 ° C to about 40 ° C (preferably 0 ° C) followed by treatment with acetaldehyde at a temperature between about -78 ° C and about 40 ° C (preferably 0 ° C). The The reaction is allowed to proceed for about 0.1 to about 10 hours (preferably 1 hour) at a temperature between about 0 ° C and about 40 ° C (preferably at room temperature).

A ......... > ^ ^ ^ ^ ~ A¡Í. * * - - ~ - - ^ "^ - ^^ - * -" * • -ft * »» »^ '. ^., ^ ^ # At room temperature) providing the imine that is reacted with the N species -vinyl as before. The compounds of formula IV, in which R1, R5, R6, R7 and R8 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding amine of formula III by various reaction routes of amines known to those skilled in the art. Thus, the compounds of formula IV, wherein R1, R5, R6, R7 and R8 are as described above and P1 and P2 are appropriately differentiated protective groups for the amino residues, are prepared from the tetrahydroquinoline of formula III, using the usual method for introducing into the amines the functional groups described for R1 above, see Richard Larock, Comprehensive Organic Transformations. VCH Publishers Inc., New York, 1989 and Jerry March, Advanced Organic Chemistry. John Wiley & Sons, New York, 1985. For example, a compound 15 of formula III is treated with thiocarbonyl chloride, sulfonyl chloride or appropriate sulfinyl chloride, socianate or thioisocyanate in a polar aprotic solvent (preferably dichloromethane) in the presence of a base (preferably pyridine) at a temperature from about -78 ° C to about 100 ° C (preferably starting at 0 ° C and allowing 20 to warm to room temperature) for a period of 1 to 24 hours (preferably 12 hours). The carbamate and urea compounds of formula IV (wherein R 1 is W = C (0), X = 0-Y, S-Y, N (H) -Y, or NY 2) can be prepared from the ^^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^ 5 amines of formula III by means of the corresponding carbamoyl chlorides, treating the amine of formula III with a solution of phosgene in a hydrocarbon solvent (preferably toluene) at a temperature between about 0 ° C and 200 ° C (preferably under reflux). between 0.1 and 24 hours (preferably 2 hours). The corresponding ureas can be prepared by treating a solution of the carbamoyl clurides (prepared as described above) with the appropriate amine in a polar solvent (preferably dichloromethane) at a temperature between about -78 ° C and about 100 ° C (preferably at room temperature) 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 between about 78 ° C and approximately 100 ° C (preferably at room temperature) 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 between 1 and 240 hours (preferably 24 hours). The compound of formula IV, wherein R 1 is Y, can be prepared using methods known to those skilled in the art for Á ^ jg ^^^^^^^^^^^ | ^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The methods include, for example, the formation of the amide from the amine of formula III and an active carboxylic acid followed by reduction of the amide with borane in an ethereal solvent, such as tetrahydrofuran. Alternatively, the alkyl or alkyl-linked substituent may be added by reduction after condensing the amine of formula III with the required carbonyl-containing reactant. Also, the amine of formula III can be reacted with the appropriate alkyl or aryl halide according to methods known to those skilled in the art. Thus, the amine of formula III and an acid (eg, hydrohalic, sulfuric, sulfonic or carboxylic, preferably acetic), are treated with the appropriate carbonyl-containing reactant in a polar solvent (preferably ethanol) at a temperature of about 0. ° C at about 100 ° C (preferably at room temperature) during About 0.1 to 24 hours (preferably 1 hour), followed by treatment with a hydride source (eg, sodium borohydride, sodium cyanoborohydride, preferably sodium triacetoxyborohydride) at a temperature between about 0 ° C and 100 ° C ( preferably at room temperature) for 0.1 to 100 hours (preferably 5 hours). The amine of formula V, wherein R1, R5, R6, R7 and R8 are as described above and P1 is a pcting group, can be prepared from the corresponding compound of formula IV by depction (P2), using methods known to those skilled in the art, including hydrogenolysis, treatment with an acid (for example, trifluoroacetic acid, 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 is used ( for example tetrabutyl ammonium fluoride). For the separation 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 (for example , palladium 5-20% on carbon, palladium hydroxide; preferably, 10% palladium on carbon) in a polar solvent (eg, methanol, ethanol or ethyl acetate, preferably ethanol) at a temperature between about -78 ° C and about 100 ° C, preferably at room temperature, during 0.1 to 24 hours, preferably 1 hour. The compounds of formula VI, wherein R1, R5, R6, R7 and R8 are as described above and P1 is a protecting group as described above, can be prepared from the amine of formula V, corresponding by various Amine reaction pathways known to those skilled in the art. The secondary amine of formula VI, wherein R 3 is as described above, can be prepared using methods known to those skilled in the art to introduce R 3 substituents, such as an alkyl substituent or attached to an alkyl. The methods include, for example, formation of an amide from the amine and an activated carboxylic acid . ^ .. ». ._ * __; - __. . . . '..... .. -. ^ * ¡¡¡¡¡¡¡¡^ ^ ^ ^., .. -. ^ ^ **, ¿.,. ,, *, «.«. ^ A ^ fc ^ .i. followed by reduction of the amide with borane in an ethereal solvent, such as tetrahydrofuran. Alternatively, an alkyl substituent or an alkyl substituent may be added by reduction of the appropriate imine, the imine being formed by condensation of the amine with the reactant containing carbonyl required. Also, the amine 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, hydrohalic, 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 about 0.1 to 24 hours (preferably 1 hour) followed by treatment with a strong hydride (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 5 hours). The compound of formula VII, in which R1, R3, R5, R6, R7 and R8 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding compound of formula IV by methods known to the art. 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 in 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 methods described above for the transformation of the compound of formula IV into the compound of formula V. When R3 is H and R4 is as described above, R4 may be represented by R3 in formulas VI and VII in scheme I, thus providing a synthesis scheme for said compounds. According to scheme II, the compounds of dihydroquinolone of formula XI, in which 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 a species of metalomethyl and a chloroformate followed by hydrolysis. Thus, a mixture of the quinoline of formula X, and an excess (preferably 1.5 equivalents) of a methyl magnesium 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 a Y- or P1-chloroformate at a temperature between about -100 ° C and about 70 ° C (preferably -78 ° C) followed by heating to a temperature between 0 ° C and about 70 ° C (preferably at room temperature) between 0.1 and 24 hours (preferably 1 hour). The resulting mixture is combined with an excess (preferably 2 equivalents) of an acid aqueous (preferably 1 molar hydrochloric acid) and mixed vigorously between 0.1 and 24 hours (preferably 1 hour, or until it is determined that hydrolysis of the intermediate enol ether has been completed). Naturally, the compounds of formula XI are compounds 5 of formula XVI in which R1 is -C (0) OY or P1 is -C (0) OP1 without further transformation. Compounds of formula XV, wherein R5, R6, R7 and R8 are as described above, can be prepared from the corresponding dihydroquinolone of formula XI by appropriate deprotection (including spontaneous decarbonylation), as described for the transformation of the compound of formula IV into the compound of formula V. The compounds of formula XVI, wherein R1, R5, R6, R7 and R8 are as described above and P1 is a protective 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 with the carbonyl oxygen of the 4-position, the substituent may conveniently be separated by treatment with an acid (eg, aqueous HCl) or a base (eg, aqueous sodium hydroxide). Again, for those compounds of formula XVI, wherein R 1 or P is the same as for the compound of formula XI, the transformation described above is not necessary.

A ^^^^^^^^^^^^^^^ (^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^ ¿^ ¿^^^^^^^ ^^^^^^^ ¿^^^^^^ the amino compounds of formula VI, wherein R1, R3, R5 , R6, R7 and R8 are as described above and P1 is a protecting group, they can be prepared from the corresponding dihydroquinolone of formula XVI by a reductive amination sequence, 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) are treated with 0.5 to 1.0 equivalents (preferably 0.55 equivalents) of titanium tetrachloride in the form of of a solution in a (preferably dichloromethane) suitable polar solvent at a temperature between about 0 ° C and about 40 ° C (preferably ambient temperature) for between 1 to 24 hours (preferably 12 hours). the imine of formula XII resulting, it is reduced and by a treatment with a reducing agent (preferably sodium borohydride) in an appropriate polar solvent (preferably ethanol), at a temperature between 0 ° C and about 80 ° C (preferably at room temperature) between 1 and 24 hours (preferably 12 hours) resulting in a mixture of amines of diastereomeric formula VI, in which the trans isomer generally predominates. Alternatively, the reduction can be performed by directly treating the imine of formula XII with an excess (preferably 5 equivalents) of zinc borohydride as a zinc solution as a solution in ether (preferably 0.2 molar) at a temperature between about 0 ° C and about 40 ° C (preferably at room temperature) between 1 and ^^^^^^^^^^^^^^^ and ^^^^^^^^^^^^^^^^^^^^^^^^^^ - 24 hours (preferably 12 hours) resulting in a mixture of amines of diastereomeric formula VI, in which the cis isomer generally predominates. Alternatively, the amine of formula VI, wherein R 1, R 3, R 5, R 6, R 7 and R 8 are as described above and P 1 is a protecting group, can be prepared from the corresponding dihydroquinolone of formula XVI by 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) between 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 2N 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 between about 0 ° C and approximately 100 ° C (preferably at room temperature) between 0.25 and 24 hours (preferably 1 hour). The resulting amine of formula V is obtained as a diastereomeric mixture (in which the cis isomer is predominant). * .-. l,. ^. «fi ^ iS *% ¡it * & r, - ** < ~ "- * A'-" - ^^ * x ^ - '& ^ > ^^ J -' - ~ - l ° 'The secondary amine of formula VI, wherein R1, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group, can be prepared from the appropriate amine of formula V as described in scheme I for the transformation of the compound of formula V compound formula VI. According to scheme III, the compounds of formula I, as described above, can be prepared from the appropriate compounds of formula VI by conversion to the desired carbamate. Thus, the amine of formula VI is treated with the appropriate activated carbonate (e.g., chloroformate, dicarbonate or carbonyldiimidazole followed by alcohol) in a polar solvent (preferably dichloromethane) in the presence of an excess of amine base (preferably pyridine) at a temperature between about -20 ° C and about 40 ° C (preferably at room temperature). environment) between 1 and 24 hours (preferably 12 hours) to Provide the compound of formula I. Alternatively, according to scheme III, when appropriate, if the function in R1 is incompatible with the reaction to form the compound of formula I, then the compound of formula VI protected by P1 can be transformed in the compound of formula I by consequences of protection / deprotection and introduction of the desired substituents. Thus, the amine of formula VI is treated with the appropriate reagent (e.g., precursor of the protecting group, activated carbonate (e.g., 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 between about -20 ° C and about 40 ° C (preferably at room temperature) between 1 and 24 hours (preferably 12 hours) to provide the compound of formula XX. Also, compounds of formula XX, in which it is present P2, can be obtained as shown in scheme I for compounds of formula VII (having P1). The amines of formula XXI, wherein 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 about 100 ° C (preferably at room temperature) for 0.1 to 24 hours (preferably 1 hour). The compounds of formula I or the compounds of formula XXII (wherein R1 is as described above) can be prepared from the corresponding amine of formula XXI (where R4 or P2 is present respectively) by various reaction pathways of amines 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 IV. The amines of formula XXIII can be prepared from the compounds of formula XXII, by suitable deprotection. When P2 is, for * -. v. »-A ^. ^. *. '. * ^ -y. »f¡ i y- - ~. - -. For example, benzyloxycarbonyl, the compound of formula XXII is prepared by treatment with an excess of a hydride source (eg, cyclohexene, hydrogen gas or preferably ammonium formate). in the presence of 0.01 to 2 equivalents (preferably 0.1 equivalent) of a suitable catalyst (preferably 10% palladium on carbon) in a polar solvent (preferably ethanol) at a temperature between about 0 ° C and about 100 ° C (preferably at room temperature) for 0.1 to 24 hours (preferably 1 hour). The compound of formula I in which R 4 is as described above can be prepared using the methods described for the conversion of the compound of formula VI to the compound of formula I in scheme III above. According to scheme IV, the compounds of formula V, wherein R 1, R 5, R 7 and R 8 are as described above, and R 6 is a residue attached to an ether, can be obtained from the quinolones of formula XXX having an OP3 moiety, in which P3 is a protecting group, in the R6 position employing the following methods. In addition, in an analogous manner, said methods can be used to prepare the corresponding compounds, wherein R5, R7 or R8 are a residue attached to an ether, from the corresponding compound of formula XXX having an OP3 moiety in the R5 positions , R7 or R8. Thus, the quinolone of formula XXX is combined with hydroxylamine hydrochloride and a mineral base (preferably sodium acetate) in a ^^^ -___ .. i¡ ^ a¡ ^ _ s_ £ _Ji__ __ * ___. . _ ____ i? = - polar solvent (preferably ethanol) at a temperature between about 0 ° C and about 100 ° C (preferably at reflux) between 1 and 24 hours (preferably 2 hours) to provide the oxime of formula XXXI. The formic oxime * XXXI is treated with an excess (preferably six equivalents) of an aqueous base (preferably 2N potassium hydroxide) and an excess (preferably four equivalents) of a nickel-aluminum alloy (preferably 1: 1 by weight) ), in a polar solvent (preferably ethanol), at a temperature between about 0 ° C and about 100 ° C, (preferably at room temperature) 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 separated using usual methods, if the transformation of the oxime does not result in said cleavage. Alternatively, the compound of formula XXX can be deprotected (separation of P3) by methods known to those skilled in the art, prior to the formation of the oxime of formula XXXI which can then be reduced to form the amine of formula XXXII. The compound of formula V, wherein R6 is a moiety attached to oxy, can be prepared by treating the alcohol of formula XXXII in, for example, Mitsunobu conditions. Thus, the appropriate phenol is treated with a fostin (preferably triphenylphosphine) and an azodicarboxylate (preferably bis- (N-) methylpyrrolidone) azodicarboxamide) and the required ethyl ester in a polar solvent (preferably benzene). Naturally, by means of Schemes I and II, the resulting compound of formula V can be transformed into the precursors of formula VI and for the compounds of formula I of this invention. Alternatively, the compound of formula XX, wherein R6 is a residue attached to an ether and wherein R1, R3 and R4 are as previously decontaminated (secondary amines) and P1 and P2 are protective groups, can be prepared from of the alcohols of formula XXXII as described below. In addition, such processes can be used analogously to prepare the corresponding compounds in which R5, R7 or R8 are a moiety attached to an ether from the corresponding compound of formula XXXII and thus ultimately the compound of formula XXX having a P30- 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 methods of scheme I described above for the conversion of the compound of formula V into the compound of Formula VI Compounds of formula XXXIV, wherein R 4 is as described above, can be prepared from the amines of formula XXXIII by methods analogous to those described in scheme III for the transformation of the compound of formula VI into the compound of formula XX.

The phenol of formula XXXV can be selectively deprotected, for example, when R4? 2CO- is present by treating the carbonate of formula XXXIV with potassium carbonate in a polar solvent (preferably methane), at a temperature between about 0 ° C and about 5 100 °. C (preferably at room temperature) between 1 and 24 hours (preferably 12 hours). The corresponding ethers of formula XX 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 into the compounds of formula V. Naturally, the experts in the will appreciate that phenol can be converted to a variety of functional groups using typical methods, for example, as described by March or Larock, or by conversion to the corresponding triflate for use in a variety of reactions, involving catalysis with a 15 transition metal. Although the following description of scheme V is directed to the modifications of position R6 (the position R6 described in formula I above), those skilled in the art will appreciate that analogous methods can be applied to positions R5, R7 and R8. According to scheme V, the alcohol of formula Ll in which R1, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protective groups and X1 is a linking group in which a carbon atom (eg, methylene) is directly attached to the carbonyl moiety, can___ * _ & _ »-, .. *. . «** ¿&&uku > ~ ¿.f * '*' * - ». . *. ty * • - kv ^^^ & s ^^^^. k: y ^^ yes ^ ^^^^ __ y¿ & ^^ £ ^ ^ prepare from the corresponding ester (in which R12 is a remainder convenient alkyl) by reduction. Thus, the ester of formula L is treated with sodium borohydride / methanol or a boranodimethylsulfide complex in a polar solvent (preferably tetrahydroruran) at a temperature between about 0 ° C and about 100 ° C (preferably at reflux) between 1 and 24 hours (preferably 3 hours). Compounds of formula Lll, wherein R 1, R 3, R 4, R 5, R 7 and R 8 are as described above, P 1 and P 2 are protecting groups and wherein the R 6 position includes an alkyl halide function, can be prepared at starting from the corresponding alcohol of formula Ll by treatment with a trialkylphosphine (preferably triphenylphosphine) and a dihalogen (for example, bromine) in a polar solvent (preferably dichloromethane) at a temperature between about -78 ° C and about 100 ° C (preferably 0 ° C) between 0.1 and 10 hours (preferably 0.5 hours) followed by heating at room temperature between 0.1 and 10 hours (preferably 3 hours). Compounds of the formula Lili, wherein R1, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protective groups, the R6 position includes ether or thioether moieties (ie, Y1 is S u O) and R13 is a substituent attached to a carbon, 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 GH ^ ^ gg ^^^^^ | ^ &g ^^^^^^^^ ___ ^^ between about 0 ° C and about 100 ° C (preferably at room temperature) 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 LIV (ie, Y1 is S or O), wherein X1- is a substituent directly attached through a 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 between about 0 ° C and about 100 ° C (preferably at room temperature) between 1 and 50 hours (preferably 18 hours). Compounds of formula LV, wherein R1, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protective groups, position R6 includes alkyl halides (eg, fluorides) and X1 is a substituent which is a carbon directly attached to the methylene moiety, can be prepared by treating the alcohol of formula L! corresponding with a halogenating agent. For example, the alcohol is treated with a curing agent (preferably diethylaminosulfur trifluoride), in a polar solvent (preferably 1,2-dichloroethane) at a temperature between about 0 ° C and about 100 ° C (preferably 80 ° C) between 0.1 and 10 hours (preferably 0.75 hours). The amide compounds of formula LVII, wherein} R1, R3, R4, R7, and R8 are as described above, P1 and P2 are protecting groups and wherein R6 includes an amide function (such that X is a substituent that is a carbon bonded directly to the cathosteryl moiety and R10 and R11 are substituents selected to provide the desired substituent R6 as defined above), can be prepared from the corresponding carboxylic acid of formula LVI which can itself be prepared from the corresponding carboxylic ester of corresponding L formula. 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) 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 customary methods. The conversion of the carboxylic acid to acid chloride is preferred by dissolving the acid in thionyl chloride and maintaining the solution at a temperature between about ° C and about 80 ° C (preferably at reflux) between 01.1 and 24 hours (preferably 1 hour) before the evaporation of the excess of thionyl chloride. This step is followed by treatment of the resulting acid chloride in a polar solvent (preferably dichloromethane) with the appropriate amine, selected to provide the amide function, and optionally a base Amine (preferably triethylamine) at a temperature between about -78 ° C and about 100 ° C (preferably at room temperature) between 0.1 and 100 hours (preferably 1 hour).

Although the following VI scheme addresses the modifications of the R8 position, those skilled in the art will appreciate that analogous methods can be applied to the positions R5, R7 and R6. According to scheme VI, the compound of formula LXI, wherein R1, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protective groups, can be prepared from the compound of formula LX corresponding by nitration. The compound of formula LX is treated with nitrosyl triflate in a halogenated solvent, such as dichloromethane, at a temperature from about -78 ° C to about 0 ° C for about 0.5 hours to about 3 hours followed by gentle heating to room temperature . The amine of formula LXII, in which R1, R3, R4, R5, R6 and R7 are as described before P1 and P2 are protective 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 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, wherein R1, R3, R4, R5, R6 and R7 are as described above, P1 and P2 are protecting groups and R8 is a function linked to an amine, can be prepared from the compound of ^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^ g ^^^^^^^^^^^^ formula LXII correspondent. The amine of formula LXII is converted into derivatives 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, 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 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 about 1 hour to about 24 hours. Naturally, those skilled in the art will understand that the halide can be transformed into a variety of functional groups using standard methods, for example, as described by Larock or March. The prodrugs of the compounds of formula I can be prepared according to methods known to those skilled in the art. Illustrative procedures are described below. The prodrugs of this invention in which a carboxyl group is a carboxylic acid of formula I, is replaced by an ester, can be prepared by combining the carboxylic acid with the appropriate alkyl halide in the presence of a base, such as potassium carbonate, in a inert solvent, such as dimethylformamide, at a temperature of about 0 to 100 ° C, for about 1 to about 24 hours. Alternatively, the acid is combined with the 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 reflux, for about 1 hour at 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 simultaneous removal of the water that is produced by physical means (e.g. Stark) or chemicals (for example, molecular sieves). The prodrugs of this invention, in which an alcohol function has been converted to 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 ethers can be obtained by reacting the alcohol with a bis- (alkanoylamino) methane in the presence of a catalytic amount of acid in an inert solvent, such as tetrahydrofuran, according to a method described in the U.S.A. 4,997,984. Alternatively, these compounds can be prepared by the methods described by Hoffman et al., In J. Org. Chem. 1994, 59.3530. The glycosides are prepared by reaction of the alcohol and a carbohydrate in an inert solvent, such as toluene, in the presence of acid.

I ^ &k *? a ^ - *. * «/. - • -. ja ___ Mg _ "? aMg___M -j« a > M «» g A. «A.j« a? Aa_ »« «.» _. - »- * & £ _».

Typically, the water formed in the reaction is separated as it is formed as described above. An alternative procedure is the reaction of alcohol, with a halide of a base followed by deprotection. The N- (1-hydroxyalkyl) amides, N- (1-hydroxy-1- (alkoxycarbonyl) methyl) -amides can be prepared by the reaction of the procuring amide with the appropriate aldehyde under neutral or basic conditions (e.g. sodium in ethanol) at temperatures between 25 and 70 ° C. The N-alkoxymethyl or N-1- (alkoxy) alkyl derivatives can be obtained by reacting the N-unsubstituted compound with the necessary alkyl halide in the presence of a base in an inert solvent. The compounds of this invention can also be used in conjunction with other pharmaceutical agents (eg, agents that lower LDL-cholesterol, agents that lower triglycerides) for the treatment of diseases / conditions described herein. For example, they can be used in combination with inhibitors of cholesterol synthesis, inhibitors of cholesterol absorption, inhibitors of MTP / Apo B secretion and other cholesterol-lowering agents, such as fibrates, niacin, ion exchange resins, antioxidants, ACAT inhibitors and bile acid sequestrants. In treatment by combination therapy, both the compounds of this invention and therapies with other drugs are administered to mammals as therapies with other drugs are administered to mammals (eg, humans, males or females) by conventional methods. _ # i ^^^^^^ g ^^^^^ - ^^ a? ^^ _ a¿¿ «_.- __ > Any inhibitor of HMG-CoA reductase can be used as the second compound in the combination aspect of this invention. The term "inhibitor of HMG-CoA reductase" refers to compounds that inhibit the bioconversion of hydroxymethylglutaryl coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily determined by those skilled in the art, according to usual assays (eg, Meth, Enzimol, 1981; 71: 455-509 and references cited therein). A variety of these compounds are described and referenced below, however other HMG-CoA reductase inhibitors will be known to those skilled in the art. The patent of E.U.A. 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, the patent of E.U.A. No. 4,444,784 (the disclosure of which is incorporated herein by reference) discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Also, the patent of E.U.A. No. 4,739,079 (the disclosure of which is incorporated herein by reference) discloses certain substituted characters, such as fluvastatin. Also, the patent of E.U.A. No. 4,346,227 (the disclosure of which is incorporated herein by reference) describes the derivatives of ML-236B, such as pravastatin. Also, EP-491226A (the disclosure of which is incorporated herein by reference), discloses certain pyridyldihydroxyheptenoic acids, such as rivastatin. In addition, the patent of E.U.A.

No. 5,273,995 (the disclosure of which is incorporated herein by reference) discloses certain 6- [2- (pyrrol-1-yl) substituted] alkyl] pyran-2-ones, such as atorvastatin. Any inhibitor of MTP / Apo B secretion (microsomal protein transferring triflicerides and / or apolipoprotein B) 5 can be used as the second compound in the combination aspect of this invention. The expression "inhibitor of MTP / Apo B secretion" refers to compounds that inhibit the secretion of triflicerides, cholesteryl ester and phospholipids. Said inhibition is easily determined by those skilled in the art according to usual tests (for example, Wetterau, J.R. 1992; Science 10 258: 999). In the following, a variety of these compounds are described and taken as reference, however, other inhibitors of MTP / Apo B secretion will be known to those skilled in the art. WO 96/40640 and WO 98/23593 are two illustrative 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-2-carboxylic acid; [2- (2-Acetylamino-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide of 4'- 20-trifluoromethyl-biphenyl-2-carboxylic acid; (2- {6 - [(4'-trifluoromethyl-biphenyl) -carbonyl-amino-S-dihydro-1H-isoquinolin-1-yl-ethyl) -carbamic acid methyl ester; [4-trifluoromethyl-biphenyl-2-carboxylic acid [2- (1 H-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. Any inhibitor of HMG-CoA synthetase can be used as the second compound in the combination aspect of this invention. The term "inhibitor of HMG-CoA synthetase" refers to compounds that inhibit the biosynthesis of hydroxymethylglutaryl coenzyme A from acetyl coenzyme A and acetoacetyl coenzyme A, catalyzed by the enzyme HMG-CoA synthetase. Such inhibition is readily determined by those skilled in the art according to usual tests (Meth Enzymol 1975, 35: 155-160; Meth. Enzymol 1985, 110: 19-26 and references cited therein). A variety of these compounds are described and referenced below, however other HMG-CoA synthetase inhibitors will be known to those skilled in the art. The patent of E.U.A. No. 5,120,729 (the disclosure of which is incorporated herein by reference) discloses certain beta-lactam derivatives. The patent of E.U.A. No. 5,064,856 (the disclosure of which is incorporated herein by reference) discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253). The patent of E.U.A. No. 4,847,271 (the disclosure of which is incorporated herein by reference) describes certain compounds ._ • ______ «* & _- * ... fl. * ¡& j? * S if. - ^^^? & gs ^^^^ of oxetane, such as derivatives of 11- (3-hydroxymethyl-4-oxo-2-oxetail) -3,5,7-trimethyl-2,4-undeca-dienoic acid. 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 HMG-CoA reductase that block transcription of DNA or translational inhibitors that prevent translation of the mRNA encoding HMG-CoA reductase into protein. Such compounds may directly affect transcription or translation, or they may be biotransformed into compounds having the above-mentioned activities, by one or more enzymes in the cholesterol biosynthesis cascade or they may lead to the accumulation of an isoprene metabolite which has the activities mentioned above. Said regulation is easily determined by those skilled in the art according to usual tests (Meth., Enzymol, 1985; 110: 9-19). Next, several compounds are described and referenced, however, other inhibitors of the expression of the HMG-CoA-reductase gene will be known to those skilled in the art. The patent of E.U.A. No. 5,041, 432 (the disclosure of which is incorporated by reference) discloses certain derivatives of 15-substituted lanosterol. Other oxygenated sterols that suppress the synthesis of HMG-CoA reductase have been studied by E.l. Mercer (Prog. Lip. Res. 1993; 32: 357-416): Any squalene synthetase inhibitor can be used as the second compound of this invention. The expression "squalene synthetase inhibitor" refers to compounds that inhibit the condensation of 2 molecules of farnesylpyrrophosphate to form squalene, catalyzed by the enzyme 5-squalene synthetase. Such inhibition is readily determined by those skilled in the art in accordance with usual assays (meth Enzymol, 1969; 15: 393-454 and Meth, Enzymol, 1985; 110: 359-373 and references therein). Next, a variety of these compounds are described and taken as reference, however, other 10 squalene synthetase inhibitors will be known to those skilled in the art. The patent of E.U.A. No. 5,026,554 (the disclosure of which is incorporated by reference) describes fermentation products of microorganism MF5465 (ATCC 740114) including zaragozic acid. A summary of other patented squalene synthetase inhibitors has also 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 expression squalene epoxidase inhibitor is referred to, to compounds that inhibit the bioconservation of squalene and molecular oxygen in squalene-2,3-ophoxide, catalyzed by the enzyme squalene epoxidase. Said inhibition will be readily determined by those skilled in the art according to usual tests (Biochim, Biophys, Act 1984).; 794: 466-471). A variety of these compounds are described and referenced below, however those skilled in the art will know others $ * l & ? & * »» »* - 3 < * «Gí ~ o8 | ggS -_» - & &. + * * 35S_.Aa > '.a-, iyéS? eg- *! *** £ squalene epoxidase inhibitors. The patents of E.U.A. Nos. 5,011, 859 and 5,064,864 (the descriptions of which are incorporated by reference) describe certain fluorine analogues of squalene. EP 395,768 A (the disclosure of which is incorporated by reference) discloses certain substituted allylamin derivatives. PCT publication WO 9312069 A (the disclosure of which is incorporated herein by reference) discloses certain amino alcohol derivatives. The patent of E.U.A. No. 5,051, 534 (the disclosure of which is incorporated herein by reference) discloses certain cyclopropyloxy-squalene derivatives. Any squalene cyclase inhibitor can be used as the second component in the combination aspect of this invention. The expression "squalene cyclase inhibitor" refers to compounds that inhibit the bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalene cyclase. Said inhibition is easily determined by those skilled in the art according to usual tests (FEBS Lett 1989, 244: 347-350). In addition, the compounds described and taken as reference below are cyclase squalene inhibitors, however other squalene cyclase inhibitors will also be known to those skilled in the art. PCT publication WO 9410150 (the disclosure of which is incorporated herein by reference) discloses certain derivatives of 1, 2,3,5,6,7,8,8-octahydro-5,5,8 (beta) -trimethyl-6- isoquinolinamne, such as N-trifluoroacetyl-1, 2,3,5,6,7,8,8-octahydro-2-allyl-5,5,8 (beta) -trimethyl-6 (beta) -isoquinolinamine. French patent publication 2697250 (the description of which is incorporated herein by reference) reference) describes certain derivatives of beta, beta-dimethyl-4-piperidine-ethanol, such as 1- (1, 5,9-trimethyldecyl) -beta, beta-dimethyl-4-pipepdinetanol. Any combined squalene-epoxidase / squalene cyclase inhibitor may be used as the second component in the combination aspect of this invention. Aa expression combined squalene epoxidase / squalene cyclase refers to compounds that inhibit the bioconversion of squalene in lanosterol by means of the intermediate compound squalene-2,3-epoxide. In some tests, it is not possible to distinguish between squalene epoxidase inhibitors and squalene cyclase inhibitors, however, these assays are known to those skilled in the art. Thus, the inhibition by the combined squalene epoxidase / squalene cyclase inhibitors is readily determined by those skilled in the art according to the usual tests cited above, for the squalene cyclase or squalene epoxidase inhibitors. A variety of these compounds are described and referenced below, however other scientists of the art will know of other squalene epoxidase / squalene cyclase inhibitors. The patents of E.U.A. Nos. 5,084,4961 and 5,278,171 (the disclosure of which is incorporated herein by reference) describe certain azadecalin derivatives. EP 468,434 (the disclosure of which is incorporated herein by reference) discloses certain piperidylether and thioether derivatives, such as 2- (1-piperidyl) pentyl-isopentyl sulfoxide and 2- (1-piperidyl) ethyl-ethyl sulphide. PCT publication WO 9401404 (the disclosure of which is incorporated herein by reference) discloses certain acyl - - - - - • - ^ - ^^ 'r nWT TT-- - fñ piperidines, such as 1- (1-oxopentyl-5-phenylthio) -4- (2-hydroxy-1-methyl) ethyl) piperidine . The patent of E.U.A. No. 5,102,915 (the disclosure of which is incorporated herein by reference), discloses certain cyclopropyloxy-squalene derivatives. The starting materials and reagents for the compounds of formula I described above are also readily available and can be easily synthesized by those skilled in the art; using conventional methods of organic synthesis. For example, many of the compounds used herein are related to, or come from, compounds in Those of great scientific interest and commercial necessity, and therefore many of said compounds are commercially available or are listed in the literature or are readily prepared from other substances generally available by methods that are listed in the literature. Some of the compounds of formula I of this invention or intermediates in their synthesis have asymmetric carbon atoms and therefore are individual enantiomers or diastereomers based on their physical-chemical 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 converting the enantiomeric mixture to a diastereomeric mixture, by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereoisomers and converting (e.g.

• ** '- • - A ^^ i ^ .- ^? ¿_ _. «-... -. - • -. . ~ - | - ^ f | f¡ ^^ - -fe ** - 'hydrolyzing) the individual diastereomers in the corresponding pure enantiomers. Also, an enantiomeric mixture of compounds of formula I or an intermediate compound in their synthesis which may contain an acid or basic moiety can be separated into their corresponding pure enantiomers by forming a diastereomeric salt with an optically pure base or chiral acid (e.g. phenyl-ethyl-amine or tartaric acid) and separating the diastereoisomers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers. Said isomers, including the diastereoisomers, enantiomers and their mixtures, are considered part of this invention.

Also, some of the compounds of this invention are atropoisomers (for example, substituted biaryls) and are considered part of this invention. Specifically, the compounds of formula I of this invention can be obtained in enantiomerically enriched form by resolving the racemate of the final compound or an intermediate compound in its synthesis (preferably the final compound) using chromatography (preferably high pressure liquid chromatography [HPLC]) in 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% diethylamine). The concentration of the fractions containing the product provides the desired materials. > XXa_j, »._ 't A.'«? , ~ ^ - ^^. ^ _ ^ £ __ ^ _ and ___. ^ J ^^^^^^^^^^^^^^^^^^ Some of the compounds of formula I of this invention are acids and they 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 salts are within the scope of this invention and can be prepared by conventional methods, such as by combining the acidic and basic entities, generally in a stoichiometric ratio, either 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 dissolution in one (several) suitable solvent (s), 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 said compounds and prodrugs, are all adapted for therapeutic use as agents that inhibit the activity of cholesteryl ester transfer protein in mammals, particularly humans. Thus, the compounds of this invention elevate plasma HDL-cholesterol, its associated components and the functions performed by them in mammals, particularly humans. By virtue of their activity, these agents also reduce plasma levels of'^ ^ * J ^ i ^ 3"A ^ * ¿3SZ * triglycerides, VLDL-cholesterol, LDL-cholesterol and their associated components in mammals, particularly humans.Therefore, these compounds are useful for the treatment and correction of various dyslipidemias observed for being associated with the development and incidence of atherosclerosis and cardiovascular diseases, including hypoalphalipoproteinemia, hyperbetalipoproteinamia, hypertriglyceridemia and familial hypercholesterolemia, and the introduction of a functional CETP gene in an animal that lacks CETP ( mouse) results in reduced levels of HDL (Agellon, LB, et al: J. Biol. Chem. (1991) 266: 10796-10801), increased susceptibility to atherosclerosis (Marotti, KR, et al: Nature (1993 364: 73-75) Also, inhibition of CETP activity with an inhibitory antibody increases HDL-cholesterol in the hamster (Evans, GF, et al: J. of Lipid Research (1994) 35: 1634- 1645) and in the rabbit (Whitlock, M.E., et al: J. Clin. Invest. (1989) 84: 129-137). The increased suppression of plasma CETP by intravenous injection with antisense oligodeoxynucleotides against CETP mRNA reduced atherosclerosis in rabbits fed cholesterol (Sugano, M., et al: J. of Biol. Chem. (1998) 273: 5033 -5036). Importantly, human subjects deficient in plasma CETP due to a genetic mutation have markedly elevated plasma HDL-cholesterol levels and apolipoprotein A-1, the main apoprotein component of HDL. In addition, most demonstrate LDL-cholesterol and apolipoprotein B (the main apolipoprotein component of LDL) in plasma markedly diminished. (Inazu, A., Brown, ML, Hesler, CB, et al .: N. Engl. J. Med. (1990) 323: 1234-1238 Given the negative correlation between HDL-cholesterol levels and associated lipoprothenes to HDL, and the positive correlation between 5 triglycerides, LDL-cholesterol and its associated apolipoproteins in blood with the development of cardiovascular, cerebrovascular and peripheral vascular diseases, the compounds of formula I of this invention, their prodrugs and the salts of said compounds and Prodrugs, by virtue of their pharmacological action, are useful for the prevention, arrest and / or regression of atherosclerosis and its associated morbid conditions These conditions include cardiovascular alterations (eg, angina, cardiac ischemia and myocardial infarction), complications due to therapies of cardiovascular diseases (eg, reperfusion injury and restenosis (eg, reperfusion injury and angioplastic restenosis), hypertension nsión, acute stroke and atherosclerosis associated with organ transplantation. Due to the beneficial effects widely associated with high HDL levels, an agent that inhibits the activity of CETP in humans, by virtue of its ability to increase HDL, also provides valuable avenues for the development of therapies in several other 20 morbid areas. Thus, given the ability of the compounds of formula I of this invention, their prodrugs and the salts of said compounds and prodrugs to alter the lipoprotein composition by means of inhibiting the _H¿ ^^, < «& * a? • < «Gfe * > - "-. &.t; -..- &- * .- ^ s H¡ * ^ j¡ ^^ £ cholesteryl ester transfer, said compounds are useful in the treatment of vascular complications associated with the" diaBetes. Hyperlipidemia occurs 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 cholesteryl ester transfer mediated by CETP abnormally increases in both insulin-dependent diabetes (Bagdade, J.D., Subbaiah, P.V. and Ritter, M.C. 1991. Eur. J. Clin. Invest. 21, 161) as non-insulin dependent (Bagdade, J.D., Ritter, M.C., Lane, J and Subbaiah, 1993. Atherosclerosis 104, 69). It has been suggested that the abnormal increase in cholesterol transfer results in changes in lipoprotein composition, particularly in relation to VLDL and LDL, which are more atherogenic (Bagdade, JD, Wagner, JD, Rudel, LL, Clarkson, TB). 1995 J. Lipid Res. 36, 759). These changes would not necessarily be observed during routine lipid analysis. Thus, the present invention will be useful to reduce the risk of vascular complications as a result of a diabetic state. 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) and nonhuman primates (Quinet, E., Tall, A., Ramakrishnan, R. and Rudel, L., 1991. Journal of Clinical Investigation 87 (5):. 1559-1566) mRNA _ - to _____________ aa «« - j > _- ^ - CETP is expressed at high levels in adipose tissue. The adipose message increases with the feeding of fat (Martin, LJ, Connelly, PW, Nancoo, D., Wood, N., Zhang, ZJ, Maguire, G., Quinet, E., Tall, AR, Marcel, YL Y McPherson, R., 1993. Journal of Lipid Research, 34 (3): 437-46), and is translated into the functional transfer protein and through secretion, contributes significantly to the levels of CETP in plase. In human adipocytes, most of the cholesterol is provided by the LDL and HDL in the plasma (Fong, B. S., and Angel, A., 1989. Biochimica et Biophysica Acta. 1004 (1): 53-60). The uptake of HDL-cholesteryl ester depends greatly part of the CETP (Benoist, F., Lau, P., McDonell, M., Doelle, H., Milne, R. and McPherson, R., 1997. Journal of Biological Chemistry. 271 (38): 235672- 7). This ability of CETP to stimulate HDL-cholesteryl uptake, coupled with enhanced HDL binding to adipocytes in obese subjects (Jiménez, JG, Fong, B., Julien, P., Despres, JP, Rotstein, L ., and Ángel, A., 1989. International Journal of Obesity. 13 (5): 699-709), suggests a role for CETP, not only to generate low HDL phenotype for these subjects, but in the development of obesity proper promoting the accumulation of cholesterol. The inhibitors of CETP activity that block this procedure therefore serve as adjuvants useful for a dietary therapy that causes weight reduction. 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 largely due to the endotoxin, a lipopolysaccharide (LPS) released from the outer surface of bacteria, which causes a broad 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). In vitro studies have shown that the binding of an LPS to HDLs substantially reduces the production and release of mediators of inflammation (Ulevitch, R.J., Johhston, A.R., 1978, J. Clin.Invest., 62, 1313-24). In vitro studies show that transgenic mice expressing apo-AI and high HDL levels of humans are protected from septic shock (Levine, DM, Parker, TS, Donnelly, TM, Walsh, AM and Rubin, AL 1993. Proc. Natl. Acad. Sci. 90, 12040-44). Importantly, the administration of reconstituted HDL to humans treated with endotoxin results 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). Inhibitors of CETP, by virtue of the fact that they increase HDL levels, attenuate the development of inflammation and septic shock. The utility of the compounds of formula I of the invention, their prodrugs and the salts of said compounds and prodrugs as medicinal agents in the treatment of the diseases / conditions described above in mammals (eg, humans, males or females), are demonstrates by the activity of the compounds of this invention in conventional tests and in the in vivo assay described below. The essay in "live" (with modifications appropriate to those skilled in the art) can be used to determine the activity of other lipid or triglyceride controlling agents as well as the compounds of this invention. The combination protocol described below is useful to demonstrate the utility of combinations of the lipid and triglyceride agents (e.g., the compounds of this invention) described herein. Said assays also provide a means by which the activities of the compounds of formula I of this invention can be compared., its prodrugs and the salts of said compounds and prodrugs (or the other agents described herein) with each other and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of said diseases. The following protocols can, of course, 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 cholesterol ester transfer protein by measuring the relative transfer rate of radiolabeled lipids between lipoprotein fractions, essentially as it was previously described by Morton in J. Biol. Chem. 256, 11992, 1981 and by days in Clin. Chem. 34, 2322, 1988. * &«£!. * S .-- * - < ^^ m ^ & "^^ In vitro Cetp Assay The following is a brief description of the cholesteryl ester transfer assay in human plasma (in vitro) and in animal plasma (ex vivo): CETP activity is evaluated in the presence or absence of a drug. by determination of the transfer of 3H (CO) -labelled olester from exogenous HDL-seeking HDL to the non-HDL lipoprotein fraction in human plasma, or from 3H-labeled LDL to the HDL fraction in transgenic mouse plasma. The labeled compounds are prepared in a manner similar to the method described by Morton, in which the activity of endogenous CETP in plasma is used to transfer 3H-CO from the phospholipid liposomes to all lipoprotein fractions in plasma. and HDL by sequential ultracentrifugation at the density cuts of 1019-1.063 and 1.10-1.21 g / ml, respectively, 15. For the activity assay, lipoprotein is added. 3H labeled to plasma at 10-25 nmol CO / ml and the samples incubated at 37 ° C for 2.5-3 hours. The non-HDL lipoproteins are then precipitated by the addition of an equivalent volume of 20% (w / vol) of polyethylene glycol 8000 (days). The samples are centrifuged at 750 g x 20 minutes and the Radioactivity contained in the HDL contained in the supernatant is determined by liquid scintillation. The introduction of variable amounts of the compounds of this invention, such as a solution in dimethylsulfoxide to human plasma, before the addition of radiolabelled cholesteryl oleate, and the comparison of the relative amounts of radiolabels transferred allows to determine the inhibitory activities of the cholesteryl ester transfer.

Cetp in vivo assay The activity of these compounds in vivo can be determined by the amount of agent required for administration, relative to the control, to inhibit the cholesteryl ester transfer activity by 50% at various ex vivo time points or for raise HDL cholesterol by a given percentage in animal species that contain CETP. Transgenic mice expressing both human CETP and human apolipoprotein Al (Charles River, Boston, MA) can be used to evaluate compounds in vivo. The compounds under examination are administered by forced oral feeding in an emulsifying vehicle containing olive oil and sodium taurocholate. Blood is taken retroorbitally from mice before being administered. At different times after administration, varying from 4 hours to 24 hours, animals are sacrificed, blood is obtained by puncture in the heart, and lipid parameters are measured including total cholesterol, HDL and LDL cholesterol and triglycerides . CETP activity is determined by a procedure similar to that described above except that cholesteryl-3H oleate containing LDL is used as the donor source as an opponent to HDL. The values obtained for lipids and activity , ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ they are compared with those obtained before administration and / or those of mice receiving only vehicle.

Plasma lipid assay 5 The activity of these compounds can also be demonstrated, by determining the amount of agent required to alter plasma lipid levels, for example, HDL cholesterol levels, LDL cholesterol levels, of VLDL cholesterol or triglycerides, in the plasma of certain mammals, for example, marmosets that possess a CETP activity and a plasma lipoprotein profile similar to that of humans (Crook et al., Arteriosclerosis 10, 625, 1990). The adult marmosets are assigned to treatment groups, so that each group has a similar mean ± SD for total concentrations of HDL, and / or cholesterol in LDL plasma. After being assigned to a group, marmosets are administered daily a compound mixed in the diet or by intragastric catheter for one to eight days. The marmosets of the control group receive the administration vehicle. The values of total plasma, LDL, VLDL and HDL cholesterol can be determined at any point during the study by obtaining blood from an antecubital and separating the lipoproteins. plasma in their individual subclasses by centrifugation in density gradient, and measurement of cholesterol concentration as previously described (Crook et al., Arteriosclerosis 10, 625, 1990). -, - "- - - - - - - ^ - ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^ - ___ & _ ..

Atherosclerosis in vivo assay The antiatherosclerotic effects of the compounds can be determined by the amount of the compound required to reduce lipid deposition in rabbit aorta. New Zealand White male rabbits were fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (with one meal a day). Rabbits were bled from the marginal vein of the ear and the total plasma cholesterol values of these samples were determined. The rabbits are then assigned to treatment groups, so that each group has a mean ± SD similar to the total concentration of plasma cholesterol, HDL cholesterol concentration, triglyceride concentration and / or cholesterol ester transfer protein activity. After the allocation of groups, the rabbits were given daily compounds given as a mixture with the diet or in a small piece of jam made of gelatin. The rabbits of the control group only receive the dosing vehicle, being the food or the jelly jam. The cholesterol / coconut oil diet is continued, along with the administration of the compound throughout the entire study. The values of plasma cholesterol and cholesterol ester transfer protein activity can be determined at any point during the study by obtaining blood from the marginal vein of the ear. After 3-5 months, the rabbits are sacrificed and the aortas are extracted from the thoracic arch to the branch of the iliac arteries. The aortas are cleaned of the adventitial layer, they are opened longitudinally and stained with Sudan IV as described by Holman et. to the. (Lab. Invest. 1958, 7, 42-47). The percentage of stained surface area is quantified by densitometry using an Optimal Image Analyzing System (Image Processing Systems). Reduced lipid deposition is indicated by a reduction in the percentage of stained surface area, in the compound receiving group compared to rabbits in the control group.

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. Doses of an inhibitor are given, sufficient to result in an increase of > 25% in HDL cholesterol levels. The BMI and the distribution of body fat, defined as waist (C) to hip (C), (RCC), during the course of the 3-6 months of study, and the results of the treatment groups, are controlled. they are compared to those who only receive placebo.

In vivo sepsis assay In vivo studies show that transgenic mice expressing human apo-AI and high HDL levels are protected from septic shock. In this way the ability of CETP inhibitors to protect against septic shock can be demonstrated in transgenic mice, which express both transgenes, apo-AI and human CETP (Levine, D.M., Parker, T.S., Donnelly., T.M., Walsh, A.M. and Rubin, A.L., 1993. Proc. Natl. Acad. Sci. 90, 12040-44). LPS derived from E. coli are administered at 30 mg / kg by injection 1.p. to animals that have been administered a CETP inhibitor in an appropriate dose, to result in an elevation of HDL. The number of surviving mice is determined at times up to 48 hours after the injection of LPS and compared with that of those mice that were only given vehicle only (less CETP inhibitor). The administration of the compounds of this invention, may be through any process that releases a compound of this invention systemically and / or locally. These methods include the oral, parenteral, intraduodenal, etc. routes. Generally, the compounds of this invention are administered orally, but parenteral administration, (e.g., intravenous, intramuscular, subcutaneous or intramedullary), for example, can be used. oral administration is inappropriate for the purpose or when the patient is unable to ingest the medication. 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 dosage 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 combined pharmaceutical agents is used to be used in conjunction with the CETP inhibitors that is effective for the indication in treatment. 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, an effective dose for inhibitors of MTP / Apo B secretion is in the range of 0.01 to 100 mg / kg / day. The compounds of the present invention are generally administered in the form of a pharmaceutical composition, comprising at least one of the compounds of this invention together with a pharmaceutically acceptable carrier, diluent or excipient. 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 different disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and arabic gum.

Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for compressive purposes. Solid compositions of a similar type are also used as fillers in hard and soft gelatin capsules; Preferred materials in this sense also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. A preferred formulation is a solution or suspension in oil, for example, olive oil, Miglyol ™, or Capmul ™, in a soft gelatin capsule. Appropriate antioxidants should be added to avoid 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 similar combinations thereof. For parenteral administration purposes, solutions in sesame or peanut oil or in aqueous propylene glycol can be used, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions can be suly buffered, if necessary, and the liquid diluent with sufficient salt or glucose firstly isotonic. These aqueous solutions are especially sule for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, the sterile aqueous media Employees are readily obtainable by standard techniques well known to those skilled in the art. For the purpose of transdermal administration (for example topical), dilute sterile aqueous or partially aqueous solutions are prepared (usually in a concentration of approximately 0.1% to 5%), on the other hand, similar to the previous parenteral solutions. The methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in the light of this disclosure, to those skilled in the art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 15th Edition (1975). The pharmaceutical compositions according to the invention will contain 0.1% -95% of the compound (s) of the invention, preferably 15-1% -70%. In any case, the composition or formulation to be administered should contain an amount of a compound (s) according to the invention in an amount effective to treat the disease / condition of the subject being treated, e.g., atherosclerosis. As the present invention has an aspect that refers to the treatment of the diseases / conditions described herein with a combination of active ingredients to be administered separately, the invention also relates to combining separate pharmaceutical compositions in the form of "kit". The "kit" comprises two separate pharmaceutical compositions: A compound of formula I, a prodrug thereof or a salt of such a compound or prodrug and a second compound as described below. The "kit" comprises means for containing the separate compositions such as a package, a divided bottle or a package divided by lamellae. Typically, the "kit" comprises instructions for administration of the separate components, the "kit" form is particularly advantageous when the separate components are preferably administered in different dosage forms, (for example oral and parenteral), are administered at different intervals of dosed, or when the prescribing physician wishes to titrate the individual components of the combination. An example of such a "kit" is the so-called "blister pack". The "blister pack" are well known in the packaging industry and are being widely used for the packaging of dosage unit dosage forms (tablets, capsules and the like). The "blister pack" generally consists of a sheet of a relatively rigid material covered with a sheet of a preferably transparent plastic material. During the packaging process, gaps are formed in the plastic sheet. The holes have the size and shape of the tablets or capsules pack. Thereafter, the tablets or capsules are placed in the recesses and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet opposing the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the Gf ^ ^ j¡ '^^^ ^^^^^^ ¿¿^ ^. ^ ^^ "jfrjd gaps between the plastic film and sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the "blister pack" by applying manual pressure on the voids, whereby an opening is formed in the sheet at the location of the pocket. The tablet or capsule can then be extracted through said opening. It would be desirable to provide a reminder in the kit, for example, in the form of numbers next to the tablets or capsules, so that the numbers correspond to the days of the regimen in which the tablets or capsules specified in this way should be ingested . Another example of such a reminder is a calendar printed on the card, for example as follows "First week, Monday, Tuesday, ... etc Second week, Monday, Tuesday" etc. Other variants of reminders will be readily apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules to be ingested on a given day. Also, a daily dose of a compound of formula I can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. This should reflect on the reminder. In another specific embodiment of the invention, a dispenser designed to dispense the daily doses in time and in the order of their intended use is provided. Preferably, the dispenser is equipped with a reminder, so as to facilitate, in addition compliance with the ^^^ * ^^^^^ ¡^ ^ ^ g ^ ^ H ^ * ^ ¡? ^ | regime. An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a reminder in a battery operated microchip memory coupled to a liquid crystal reader, or an audible reminder signal, which, for example, reads the date and the last daily dose that has been taken and / or remembered. When does the next dose have to be taken? The compounds of this invention, either alone or in combination with one another 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 formulation that follows, "active ingredient" means a compound of this invention.

FORMULATION 1 Gelatin capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch, NF 0-650 Fluid powders of starch 0-50 Silicone fluid 350 centistokes 0-15 A tablet formulation is prepared using the ingredients that follow: FORMULATION 2 Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Microcrystalline cellulose 200-650 Silicone dioxide, heartburn 10-650 Stearic acid 5-15 10 The components are mixed and compressed to form tablets Alternatively, the tablets each containing 0.25-15 mg of active ingredient are manufactured as follows: ^^^^^ | g ___ * «_- - + 'j & r ~ * ~, * & eeaK 3fce _» - - .- * - *** * «& • • (a. ^^ ^ - &8 ^^ t = £ ^, - ^ «feg ... ^ ¿, ¿yt * & .. '< a. * AÉ_í > _. . »» FORMULATION 3 Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch 45 Cellulose microcrystalline 35 Polyvinylpyrrolidone (as a 4 10% solution in water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1 The active ingredients, starch and cellulose are passed through a US sieve. UU Mesh No. 45: and mix at the same time. The polyvinylpyrrolidone solution is mixed with the resulting powders which are passed through a US sieve. UU No. 15 14. The granules thus produced are dried at 50 ° -60 ° C and passed through a US sieve. UU No. 18. Mesh, carboxymethyl sodium starch, magnesium stearate and talc, are previously passed through a US sieve. UU No. 60, and is then added to the granulates that, after mixing, are compressed in a compressing machine rendering tablets Suspensions containing 0.25-100 mg each of Active ingredient per 5 ml of doses are manufactured as follows: FORMULATION 4 Suspensions Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml F Aroma is. Colors. Purified water to 5 ml 10 The active ingredient is passed through a US sieve. UU No. 45 and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, the flavor and the color are diluted with a part of the water and added with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared containing the following ingredients: ~ »*. ~. ~ ^ _ ^ W ^^. ^ ___ .J_ ._. ^ - - ^. aa ^. ^^ ^^, ^ ... A ^ .. ^ FORMULATION 5 Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25-100 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, cooling to 30 ° C, and transferred to a filling device. Then, the required amount is fed to a stainless steel container and diluted with the remaining propellant. Then the valves are attached to the container. Suppositories are prepared as follows: FORMULATION 6 Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 Glycerides of fatty acids 2,000 20 Saturated The active ingredient is passed through a US sieve. UU No. 60 mesh and suspended in the glycerides of saturated fatty acids , ___ ^ _ t,, ...? " ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ , - &_ _ _ _. _. previously melted, using the minimum necessary heat. The mixture is then poured into a suppository mold of 2 g nominal capacity and allowed to cool. An intravenous formulation is prepared as follows: FORMULATION 7 Intravenous solution Ingredient Quantity Active ingredient dissolved in 1% ethanol 0.25-100 Intralipid ™ emulsion 1,000 ml The dissolution of the above ingredients is administered intravenously to a patient at a rate of about 1 ml per minute. The soft gelatin capsule is prepared using the following: FORMULATION 8 Soft gelatin capsules with oil formulation Ingredient Quantity (mg / tablet) Active ingredient 10-500 Olive oil or miglyol oil 500-1,000 ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^ ... ^^ l ^^ l ^ j ^^ The active ingredient above can also be a combination of agents.

GENERAL EXPERIMENTAL PROCEDURES The NMR spectra were recorded on a Varian XL-300 (Varian Co., Palo Alto, California), a Bruker AM-300 spectrometer (Bruker Co., Billerica, Massachusetts) or a Varian Unity 400 at approximately 23 ° C to 300 ° C. MHz for protons and 75.4 MHz for carbon nuclei. The chemical conversion is expressed in parts per million derived from tetramethylsilane. The shapes of the peaks are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; sa = wide singlet. The resonances designated as interchangeable do not appear in a separate NMR experiment in which the sample was shaken with several drops of D2O in the same solvent. The chemical ionization at atmospheric pressure (PQPA) and the mass spectrum were obtained in a Fisons Platform II spectrometer. The chemical ionization mass spectra were obtained on a Hewlett-Packard 5989 instrument (Hewlett Packard Co., Palo Alto, California) (ammonia ionization, PBMS). Where the intensity of the ions containing chlorine or bromine is described, the expected intensity ratio (approximately 3: 1 for ions containing 35CI / 37CI) and 1: 1 for ions containing 79Br / 81Br) was observed and only the intensity of the lowest ionic mass is given. ^^^^^^^^^^ & ^^^^^ Column chromatography was performed either with Baker Silica Gel (40 μm) (JT Baker, Phillipsburg, NJ) or with Silica Gel 60 (EM Sciences , Gibbstown, NJ) on glass columns under reduced nitrogen pressure. Radial chromatography was carried out using a Chromatron (model 7924T, Harrison Research). Unless otherwise specified, the reagents were used as obtained from commercial sources. Reactive solvents, dimethylformamide, 2-propanol, tetrahydrofuran and dichloromethane were used, the anhydrous grade was supplied by Aldrich Chemical Company (Milwaukee, Wisconsin). Microanalyses were carried out by Schwarzkopf Microanalytical Laboratory, Woodside, NY. The terms "concentrated" and "evaporated" refer to the removal of the solvent under pressure from a water aspirator in a rotary evaporator with a temperature bath of less than 45 ° C. Reactions carried out at "0-20 ° C" or "0-25 ° C" were performed with initial freezing of the vessel in an isolated ice bath that was allowed to warm to room temperature for several hours. The abbreviation "min" and "h" refers to "minutes" and "hours" respectively.

EXAMPLES EXAMPLE 1 C / S-4-benzyloxycarbonylamino-6-methoxy-2-methyl-5 1.2.3.4-tetrahydro-quinoline-7-carboxylic acid methyl ester To a solution of 4.26 g of methyl 2-methoxy-5-aminobenzoate (23.5 moles) in 65 ml of anhydrous dichloromethane was added 3.34 g of anhydrous sodium sulfate, and the resulting mixture was cooled to -25 ° C. freshly distilled acetaldehyde (1.04 g, 23.5 mmol)) and the mixture was stirred at 25 ° for 2H. The supernatant was cannulated in a solution at -25 ° of N-vinyl-O-benzyl carbamate (1.4 g, 7.8 mmol) in 10 ml of dichloromethane. BF3-Etharate (111 mg, 0.78 mmol) was added over 10 minutes, and the reaction was stirred at -25 ° C for 1.5 h. The reaction extinguished cold with the addition of a 10% aqueous solution of sodium sulfate. The aqueous phase was separated and extracted with dichloromethane (100 ml). The combined organic layers were dried (MgSO4), filtered and concentrated, and the crude material was purified by chromatography on silica gel using dichloromethane to give the title product (0.99 g). 20 1 H NMR (DMSO-d 6) U 1.13 (d, 3 H), 6.58 (s, 1 H). ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ j ^^^^^^^^^^^^^ J ^^^^^^ ^^^^^^^^^ EXAMPLE 2 Ester 1-7-methyl ester of c / s-4-benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 7-methyl ester: To a solution of c-4-benzyloxycarbonylamine-6-methoxy-2-methyl-1, 2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (0.99 g, 2.6 mmol) in anhydrous dichloromethane (30 g. ml) was added pyridine (0.27 ml, 3.35 mmol). The mixture was frozen at 0 ° C and ethyl chloroformate (0.29 ml, 3.1 mmol) was slowly added, the reaction was stirred at 0 ° C for 30 minutes, then at room temperature for 2.5 h. Additional aliquots of pyridine and methyl chloroformate were added leading the reaction to completion. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (75 ml) and water (25 ml). The organic layer was washed with water (25 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by chromatography on silica gel using 25% ethyl acetate / hexane as eluent gave the title product (1.06 g). MS m / z 457 (M ++ i); 1 H NMR (DMSO-d 6) d 1.45 (d, 3 H), 6.68 (s, 1 H).

EXAMPLE 3 Ester 1-7-methyl-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 7-methyl ester: Heated ester 1 - 7-methyl ester of c / s-4-benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid ester (322 mg, 0.71 mmol), palladium on carbon 10% (32 mg) and cyclohexene (9 ml) in 16 ml of ethanol at 80 ° C for 1.25 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by chromatography on silica gel using 1% isopropanol-dichloromethane gave the title product (208 mg, 91%). 1 H NMR (DMSO-d 6) d 1.02 (d, 3 H), 6.68 (s, 1 H).

EXAMPLE 4 Ester 1-Cs-4- (3,5-bis-trifluoromethyl-benzylamino) -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 7-methyl ester: To a solution of cis-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 7-methyl ester (208 mg, 0.64 mmol) in 1, 2-anhydrous dichloroethane (5 ml) was added acetic acid (0.041 ml, 0.71 mmol), followed by 3,5-bis (trifluoromethyl) benzaldehyde (172 mg, 0.71 mmol) and sodium triacetoxyborohydride (0.205 g, 0.97 mmol) ). The reaction was stirred at room temperature for 2 h. The mixture of and the reaction was partitioned between dichloromethane (45 ml) and water (100 ml) and the aqueous phase was adjusted to pH 9. The aqueous phase was extracted with dichloromethane (3 x 10 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 20% acetone / hexane as eluent gave the title product (337 mg, 95%). MS m / z 567 (M ++ NH4); 1 H NMR (CDCl 3) d 1.40 (d, 3 H), 7.14 (s, 1 H).

EXAMPLE 5 Benzyl Ester of 2-methyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. 4-Methoxy-6-trifluoromethylquinoline (5.0 g, 22.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml). The mixture was cooled to -78 ° C, and methyl magnesium chloride (73 ml of a 3.0M solution in tetrahydrofuran, 220 mmol) was added to the resulting suspension. After the addition, benzyl chloroformate (41 ml, 286 mmol) was added to the suspension. After being stirred at room temperature overnight, 75 ml of methanol was added followed by 75 ml of a 1 N aqueous HCl solution. After it was judged by thin layer chromatography that the hydrolysis of the enol ether intermediate was complete, the The volatiles were removed in vacuo, and the remaining aqueous phase was extracted with ethyl acetate (3 x 150 ml). The organic phases were combined and washed with a saturated solution of sodium bicarbonate (82 x 75 ml), brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 47 g of crude product. Purification by chromatography on silica gel, using 10% ethyl acetate / hexane as eluent gave 5.54 g of the title product (69%). 1 H NMR (CDCl 3) d 1.25 (d, 3 H, J = 7 Hz), 2.62 (dd, 1 H, J = 17.2 Hz), 3.05 (dd, 1 H, J = 17, 6 Hz), 5.1-5.2 (m, 1H), 5.28 (d, 1 H, J = 12 Hz), 5.35 (d, 1 H, J = 12 Hz), 7.3-7.5 (m, 5H), 7.71 (dd, 1 H, J = 9.2 Hz), 8.05 (d, 1H, J = 9 Hz), 8.27 (d, 1 H, J = 2 Hz).

EXAMPLE 6 8-Chloro-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. 8-Chloro-4-methoxyquinoline (1.0 g, 5.2 mmol, dissolved in 6 ml of anhydrous tetrahydrofuran) was added dropwise through a cannula to a solution of methyl lithium (18.4 ml of a 1.4 M solution in diethyl ether) cooled in an ice bath. After 45 min, ethyl chloroformate (4.9 ml, 51.7 mmol) was added to the reaction mixture through a syringe. After 1.5 hours, the reaction mixture was quenched with 60 ml of a 1 N aqueous HCl solution, 100 ml of THF and 20 ml of methanol. After 3 days, the tetrahydrofuran was removed in vacuo, and the remaining aqueous phase was extracted with ethyl acetate (3 x 100 ml). The orgaphases were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1.5 g of the crude product. Purification by chromatography on silica gel using 0-20% ethyl acetate / hexane as eluent gave 0.79 g of the title product (57%). 1 H NMR (CDCl 3) d 1.2 (d, 3 H), 1.3 (t, 3 H), 2.6 (d, 1 H), 3.1 (dd, 1 H), 4.2-4.4 (m, 2H), 5.1-5.2 (m, 1 H), 7.2 (d, 1H), 7.6 (d, 1 H), 7.9 (d, 1 H).

EXAMPLE 7 6-Fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline. 6-Fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (3.0 g, 7.9 mmol) was combined with 250 mg of Pd / C at 10% in 50 ml of ethanol and stirred under a hydrogen atmosphere (40 psi) for 1 hour before being filtered through Celite®, rinsing with ethyl acetate, and evaporating the volatiles under reduced pressure yielding 1.34 (69%) of the compound of the title as a colorless oil. 1 H NMR (CDCl 3) d 1.4 (d, 3 H), 2.5 (dd, 1 H), 2.7 (dd, 1 H), 3.7-3.9 (m, 1 H), 4.4 (sa, 1 H), 6.9 (d , 1 H), 7.6 (d, 1H).

EXAMPLE 8 6-Fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester. 6-Fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline (1.01 g, 4.08 mmol) was dissolved in 10 ml of dichloromethane and 5 ml of pyridine, and stirred and stirred. added isopropyl chloroformate (48 ml of a 48 mmol solution in toluene) slowly, through a syringe. After stirring overnight, 100 ml of a 1M aqueous potassium hydroxide solution was added and the aqueous phase was extracted with ethyl acetate (3 x 75 ml), the combined orga were washed with 1 M HCl (2 x 50 ml). ) and 100 ml of each of a saturated solution of sodium bicarbonate and brine, before being dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 1.1 g of an oil, which was purified by chromatography on silica gel eluting with ethyl acetate in 10% hexane to give 940 mg (69%) of the title compound as an oil. 1 H NMR (CDCl 3) d 1.24 (d, 3 H), 1.34 (d, 3 H), 1.38 (d, 3 H), 2.65 (dd, 1 H), 3.05 (dd, 1 H), 5.1-5.3 (m, 2 H) . .-__ .. ^ *. - «~. »- * h iL ^ * ~~ - ~ .- ^. ^ a «a ^, ^^ faith ^ _ EXAMPLE 9 4- (3,5-Bis-trifluoromethylbenzylimino) -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester. 2-Methyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (5.5 g, 15.1 mmol) was combined with triethylamine (15 mL, 106 mmol) and 3, 5-bis-trifluoromethyl-benzylamine (5.5 g, 22.7 mmol) in anhydrous dichloromethane (80 ml). This solution was cooled in a water bath at room temperature while 7.6 ml of a solution of titanium tetrachloride (TiCl4) 1 M in dichloromethane (7.6 mmoles) was added slowly. The reaction was stirred at room temperature overnight before the mixture was poured into a stirred solution of water (125 ml) and potassium carbonate (15 g). After filtration of the resulting emulsion, the filtrate was extracted with ethyl acetate (1 x 200 ml, then 2 x 75 ml), the combined orgaphases were washed with water (100 ml), brine (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give the title product (10.63 g, > theory). 1 H NMR (CDCl 3). d 1.2 (d, 3H), 2.7-2.9 (m, 2H), 4.0-4.1 (m, 1 H), 4.65 (d, 1H), 4.75 (5.1-5.4 (m, 2H), 7.3-7.5 (m , 5H). - - - - - ^^^^^^^^^^^ & EXAMPLE 10 Benzyl ester of cis- and trans-4-_3,5-bis-trifluoromethyl-benzylamino) -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. 5 4- (3,5-Bis-trifluoromethyl-benzylimino) -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (~ 15 mmol) was dissolved in 230 ml of a 0.2 M solution of zinc borohydride in diethyl ether (46 mmoles). After, the reaction was stirred overnight, added methanol to make it react with the excess agent, followed by 400 ml of water. The mixture was treated with potassium carbonate until it became biphasic (pH = 10), followed by extraction with ethyl acetate (1 x 300, then 2 x 100 ml). The organic phases were combined and washed with water (100 ml), brine (75 ml), dried over sodium sulfate, filtered and were concentrated in vacuo giving 10.6 g of a crude mixture of product amines. Purification by chromatography on silica gel using 0-50% ethyl acetate / hexane as eluent gave the cis title product (2.93 g, 33%). 1 H NMR (CDCl 3), d 1.2-1.3 (m, 1 H), 1.25 (d, 1 H, J = 6 Hz), 2.7 (ddd, 1 H), 3.6 (dd, 1 H), 4.1 (d, 1 H), 4.2 (d, 1 H); 4.45 (ddq, 1 H), 5.17 (d, 1 H), 5.27 (d, 1H), 7.35 (sa, 5H), 7.5 (d, 1H), 7.6 (d, 1H), 7.80 (s, 1H) 7.82 (s, 1H), 7.95 (s, 2H). Continuous elutions using increasing concentrations of ethyl acetate provide the trans title product.

EXAMPLE 11 Isopropyl Ester of 6-fluoro-4-hydroxyimino-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid.

A stirred solution of 6-fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester (940 mg, 2.8 mmol), hydroxylamine hydrochloride (215 mg, 3.1 mmol), and sodium acetate (254 mg, 3.1 mmol) in ethanol (20 ml) was heated to reflux for 3 h. Water (25 ml) was added and the volatiles were evaporated in vacuo. Ethyl acetate (100 ml) was added, and the mixture was stirred vigorously for 10 minutes. The aqueous phase was separated and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white foam (937 mg, ca. 100%): 1 H NMR (CDCl 3 ) d 1.1 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 2.73 (dd, 1 H), 3.09 (d, 1 H), 5.0-5.1 (m, 2H), 7.68 (d, 1H), 7.88 (s, 1 H).

EXAMPLE 12 cis and frans-4-amino-6-fluoro-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-auinoline-1-carboxylic acid isopropyl ester.

To a stirred solution of 6-fluoro-4-hydroxyimino-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester (937 mg, 2.82 mmol) in ethanol (40 ml) ) and 2N aqueous KOH (40 mL, 80 mmol) was added aluminum-nickel alloy (1.57 g, 1: 1 by weight, 18 mmol) in portions over 15 minutes (gas evolution). After stirring for 3 h, water (25 ml) was added, then the suspension was filtered through a nylon filter, rinsing with ethyl acetate. The volatiles were removed in vacuo, and the resulting aqueous phase was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 946 mg of an oil containing the title compound as a mixture of about 3: 1 of cis diastereoisomers and trans (94%). 1 H NMR (CDCl 3) d 1.2 (d, 3 H), 1.25 (d, 3 H), 1.3 (d, 3 H), 2.5 (ddd, 1 H), 3.8 (bd, 1 H), 4.4-4.6 (m, 1 H), 5.0 (septet, 1H) 7.3 (d, 1 H), 7.65 (d, 1 H).

EXAMPLE 13 Ester 1-7-methyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline- methyl ester 1.7-dicarboxylic. 7-methyl ester of c / 's-4- (3,5-bis-trifluoromethyl-benzylamino) -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester was dissolved., 7-dicarboxylic acid (335 mg, 0.61 mmol) in anhydrous dichloromethane (5 ml), and pyridine (0.20 ml, 2.5 mmol) was added. Methyl chloroformate (0.057 mL, 0.73 mmol) was slowly added and the reaction was stirred at room temperature for 3 h. Additional aliquots of reagent were added to bring the reaction to term. The reaction mixture was then diluted with 35 ml of dichloromethane, washed with 1 N aqueous HCl solution (2 x 7 ml) and with a saturated solution of sodium bicarbonate (2 x 7 ml) NaHC 3. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 20% acetone / hexane as eluent gave the title product (0.50 g, 90%). MS m / z 607 (M ++ 1), 1 H NMR (CDCl 3) d 1.5-1.75 (br s, 1 H), 6.42 (s, 1 H). Using the appropriate starting materials, examples 14-16, 19-21, 27, 34, 38, 42, 47 and 58 were prepared analogously to the sequence of reactions described for examples 1, 2, 3, 4 and 13; and examples 22, 24-26, 29, 31, 32, 43, 46, 54, 56 and 59 were prepared analogously to the sequence of reactions described for examples 5, 9, 10 and 13; and Examples 17, 18, 23, 28, 30, 35-37, 39-41, 44, 45 and 48 were prepared analogously to the sequence of reactions described for Examples 5, 11, 12, 4 and 13; and Examples 33, 49-52 and 57 were prepared analogously to the sequence of reactions described for Examples 6, 9, 10 and 13; Examples 53 and 55 were prepared analogously to the sequence of reactions described for Examples 5, 7, 8, 11, 12, 4 and 13.

EXAMPLE 14 Ester 1-ethyl 6-methyl ester of cis-4-r (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-3,4-dihydro-2H-auinoline-1.6- ester dicarboxylic MS m / z 607 (M + + 1), 1 H NMR (DMSO-de) d 7.08 (s, 1 H), 1.34-1.6 (br s, 1 H).

EXAMPLE 15 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-ethoxycarbonylmethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 634.5 (M +), 1 H NMR (CDCl 3) d 3.6 (AB, 2H), 3.8 (s, 3H), 6.4 (s, 1 H).

EXAMPLE 16 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1,6,7-tricarboxylic acid ethyl ester-6,6-d-ethyl ester .

MS m / z 652 (M + + NH 4), 1 H NMR (CDCl 3) d 7.22 (s, 1 H), 3.84 (s, 3H).

^ Jt- _ ^? f - "- * ?? rrt J 1 1 ..a._ * & .t¿A :: ._ é- _- -..._ .: .. ._..._.__ ___ . < _-__. ^ - ^ ^ ^ EXAMPLE 17 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-dihydroxyethyl ester 2H-quinoline-1-carboxylic acid MS m / z 587 (M + + 1), 604 (M + + 18); 1 H NMR (CDCI) d 7.82 (C8, s, 1 H), 6.40 (C5, s, 1 H), 1.20 (C2-Me. D, 3H, J = 6.1 Hz).

EXAMPLE 18 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2,6-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 563 (M + +); 1 H NMR (CDCl 3) d 6.39 (s, 1 H), 1.44-1.64 (alif., 6H).

EXAMPLE 19 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -5-methanesulfonylmethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 640.3 (M +); 1 H NMR (CDCl 3) d 1.6 (d, 3 H), 2.6 (s 3 H), 3.5 (s, 3 H), 6.7 (d, 1 H), 7.4 (d, 1 H), 7.6 (d, 1 H).

EXAMPLE 20 Cts-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methanesulfonylmethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 640.3 (M +); 1 H NMR (CDCl 3) d 3.8 (m, 3 H), 6.4 (s, 1 H).

EXAMPLE 21 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methanesulfonylmethyl-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 641 (M + + 1); 1 H NMR (CDCl 3) d 6.88 (s, 1 H), 3.81 (s, 3H).

EXAMPLE 22 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 641 (M + + 1), 618 (M + + 18); H NMR (CDCl 3) d 7.12 (C5, s, 1 H), 1.10 (C2-Me, d, 3H). ^^^^^^ fc ^^^^^ j ^^^^ »^^^^^^^^^^^^^^^^ - ^^^^^^^^^^^^^^ ^^^ X ^^^^^ = g ^^ g | gÍ ^^^ EXAMPLE 23 Ethyl ester of cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6- (methoxycarbonyl- methylamino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 605 (M +), 623 (M + + 18); 1 H NMR (CDCl 3) d 6.83 (s, 1 H), 3.81 (s, 3 H).

EXAMPLE 24 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-chloro-2-ethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 553 (M + + 1), 570 (M + + 18); 1 H NMR (CDCl 3) d 7.81 (s, 1 H), 3.83 (s, 3 H).

EXAMPLE 25 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6-chloro-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 553 (M + + 1), 600 (M + + 18); 1 H NMR (CDCl 3) d 7.79 (s, 1 H), 3.81 (s, 3 H).

EXAMPLE 26 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-fluoro-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 567 (M + + 1), 584 (M + + 18); 1 H NMR (CDCl 3) d 6.65 (d, 1 H, J = 11.1 Hz), 3.87 (s, 3H).

EXAMPLE 27 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-7- (1-methoxycarbonyl-cyclopentyl) -2-methyl-3,4-dihydro-2H- ethyl ester quinoline-1 -carboxylic MS m / z 674.3 (M +); 1 H NMR (CDCl 3) d 1.2 (2, 3 H), 3.6 (s, 3 H), 3.7 (s, 3 H), 3.8 (s, 3 H), 6.4 (s, 1 H), 7.4 (s, 1 H), 7.7 (s, 2H), 7.8 (s, 1H).

EXAMPLE 28 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -isopropoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl esterMS m / z 674.3 (M + + 1), 632 (M + + 18); 1 H NMR (CDCl 3) d 7.75 (s, 1 H), 2.25-2.10 (m, 1 H).

EXAMPLE 29 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-6-chloro-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester MS m / z 621 (M + + 1), 638 (M + + 18); 1 H NMR (CDCl 3) d 7.71 (m, 1 H), 3.84 (s, 3 H).

EXAMPLE 30 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 588 (M + + 2), 605 (M + + 19); 1 H NMR (CDCl 3) d 7.12 (C5, s, 3H), 3.83 (Orne, s, 3H), 1.16 (Me, d, 3H, J = 6.0 Hz).

EXAMPLE 31 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxy-amino-1-6.7-dichloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 587 (M + + 1), 604 (M + + 18); 1 H NMR (CDCl 3) d 7.71-7.65 (m, 2H), 3.83 (s, 3H).

EXAMPLE 32 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxy-benzyl-amino-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 553 (M + + 1), 570 (M + + 18); 1 H NMR (CDCl 3) d 6.88 (C 5, s 1 H), 3.81 (Orne, s, 3 H), 1.16 (Me, d, 3 H, J = 5.6 Hz).

EXAMPLE 33 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxy-amino-amino] -8-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 552 (M +), 569 (M + + 17); 1 H NMR (CDCl 3) d 3.80 (Orne, s, 3H), 1.14 (Me, d, 3H, J = 6.2 Hz).

EXAMPLE 34 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxy-amino-6,7-bis-tert-butoxycarbonylamino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 618 (MA i30); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.4 (s, 1 H). ____? _ £ _i_ii I ¿________I __M _________________? _? EXAMPLE 35 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2,6-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 618 (M +) 533 (M + + 1); 1 H NMR (CDCl 3) d 7.78 (s, 1 H), 3.81 (s, 3 H), 3.87 (s, 6 H).

EXAMPLE 36 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-10-amino] -6-methoxy-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 616.5 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.5 (s, 1 H), 3.87 (s, 6 H). EXAMPLE 37 cis-4-f-3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 547 (M + + 1) 565 (M + + 19); H NMR (CDCl 3) d 7.78 (s, 1 H), 3.81 (s, 3H).

EXAMPLE 38 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6 (2-ethoxycarbonylethyl) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 618.2 (M +); 1 H NMR (CDCl 3) d 2.6 (t, 2 H), 2.9 (t 2 H), 3.8 (s, 3 H), 6.7 (s, 1 H), 7.8 (s, 1 H).

EXAMPLE 39 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2.5.6-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 547 (M + + 1), 565 (M + + 19); 1 H NMR (CDCl 3) d 7.64 (s, 1H), 1-65-1.50 (m, 6H).

EXAMPLE 40 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-6-tert-butyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 575 (M + + 1) 593 (M + + 19); 1 H NMR (CDCl 3) d 6.89 (s, 1 H), 3.80 (s, 3H). ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 537 (M + + i) 1 H NMR (CDCl 3) d 3.80 (Orne, s, 3H), 1.18 (Me, d, 3H, J = 6.0 Hz)., 3.87 (s, 6H).

EXAMPLE 42 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2,8-dimethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 601.6 (M + + 1), 617.5 (M + + 17).

EXAMPLE 43 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-bromo-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 597 (M +), 614 (M + + 17), 616 (M + + 19); 1 H NMR (CDCl 3) d 7.03 (C5, s, 1 H), 3.82 (Orne, s, 3 H) 1.16 (Me, d, 3 H, J = 6.0 Hz).

EXAMPLE 44 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 575 (M + + 1), 592 (M + + 18); 1 H NMR (CDCl 3) d 7.30 (s, 1 H), 3.81 (s, 3H).

EXAMPLE 45 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 565 (M + + 19); 1 H NMR (CDCl 3) d 6.72 (C5, s, 1 H), 3.80 (Orne, s, 3H).

EXAMPLE 46 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-bromo-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 666 (M + + 1); 1 H NMR (CDCl 3) d 7.71 (s, 2 H), 3.84 (s, 3 H). ^^^ e ^ ^^ "" > * 8Sfc? j? is < ^^ EXAMPLE 47 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-8-fluorocarbon ethyl ester 2.6-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 551 (M + + H); 1 H NMR (CDCl 3) d 7.80 (br s, 1 H), 7.7 (br s, 1 H) 7.65 (br s, 1 H), 6.85 (br s, 1 H), 6.5 (br, 1H), 3.8 (s, 3H) , 2.32 (s, 3H) 1.18 (d, 3H, J = 6.0 Hz).

EXAMPLE 48 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-isopropyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1 H NMR (CDCl 3) d 6.73 (C5, s, 1H), 3.80 (Orne, s, 3H) 1.16 (Me, d, 3H, J = 6.0 Hz).

EXAMPLE 49 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-6,8-dichloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 587 (M + + H); 1 H NMR (CDCl 3) d 7.8 (br s, 1 H), 7.7 (br s, 1 H) 7.65 (br, 1H), 7.65 (br, 1H), 7.4 (br, 1 H), 6.85 (br, 1 H), 3.8 (sa, 3H).

EXAMPLE 50 cis-4 - [(3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-amino] -2,6,8-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 547 (M + + H); 1 H NMR (CDCl 3) d 7.8 (br s, 1 H), 7.7 (br s, 1 H) 6.69 (br s, 1 H), 6.65 (br s, 1 H), 3.78 (s, 3 H), 2.3 (s, 3 H), 2.18 (s, 3H).

EXAMPLE 51 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -2,6,8-trimethyl-3,4-d? Hydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 561 (M + + H); H NMR (CDCl 3) d 7.8 (sa, 1H), 7.7 (sa, 2H) 6.95 (sa, 2H), 6.95 (sa, 1 H), 6.6 (sa, 1 H), (2.3 s, 3H), 2.18 (s, 3H).

EXAMPLE 52 cis-4-f (3,5-bis-trifluoromethyl-benzyl-ethoxycarbonyl-amino] -7,8-dichloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 587 (M + + H); 1 H NMR (CDCl 3) d 7.8 (br s, 1 H), 7.7 (br s, 1 H) 7.65 (br s, 1 H), 7.35 (br, 1 H), 6.8 (br, 1 H), 3.8 (br, 3H) . ..._.._ .___.__ .__. . ... -. __ ... _- _ ", ^ __ ife_S ^ ... =. ...... _ »_j | --_ t_ _, .__ ^^^ M. ^^ t EXAMPLE 53 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl- tert -butyl ester aminoj-6-fluoro-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 663 (M + + 1), 650 (M + + 18); 1 H NMR (CDCl 3) d 6.76 (d, 1 H, J = 10.4 Hz), 3.83 (s, 3H).

EXAMPLE 54 Benzyl Ester of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-bromo-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic MS m / z 683 (M + + 1), 700 (M + + 18); 1 H NMR (CDCl 3) d 7.02 (C8, s, 1 H), 3.83 (Orne alif., S, 3H).

EXAMPLE 55 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-fluoro-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 636 (M + + 18); 1 H NMR (CDCl 3) d 6.77 (d, 1 H, J = 9.90 Hz), 3.83 (s, 3H).

EXAMPLE 56 cis-4 - (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester 5 H-NMR (CDCl 3) d 1.2 ( d, 2H), 3.8 (s, 3H), 5.2 (d, 1 H), 5.3 (d, 1 H), 7.1 (s.1 H), 7.4 (s, 5H).

EXAMPLE 57 10 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7,8-dichloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid t-butyl ester MS m / z 615 (M + + H); 1 H NMR (CDCl 3) d 7.8 (br s, 1 H), 7.65 (br s, 2 H), 7.3 (bd, 1 H), 6.8 (bd, 1 H), 3.8 (s, 3 H). ^^ ^: ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ g ^^^^^^ _ "_.___-_ EXAMPLE 58 Isopropyl ester of cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methox? carbonyl-amino] -6-chloro-2- acid methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 567 (M + + H); 1 H NMR (CDCl 3) d 7.8 (br s, 1 H), 7.7 (br s, 1 H), 7.65 (br s, 1 H), 7.45 (br, 1 H), 7.2 (br, 1 H), 6.5 (br, 1 H), 3.8 (s, 3H), 3.82 (s, 3H).

EXAMPLE 59 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester MS m / z 567 (M + + 18); 1 H NMR (CDCl 3) d 1.20 (d, 3 H), 7.04 (d, 1 H), 7.3-7.4 (m, 6 H), 7.6-7.8 (m, 4 H).

EXAMPLE 60 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 1-ethyl ester A mixture of cis-4- [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-3,4-dihydro-2H methyl ester 6-methyl ester. -quinoline-1, 6-dicarboxylic acid (example 14) (500 mg, 0.82 mmol) and 0.41 ml of NaOH 2N in 7.5 ml of THF was heated to 70 ° C. After 1.5 h, the cooled mixture was evaporated to dryness and the sodium salt was isolated by trituration with diisopropyl ether. The salt was suspended in 10 ml of water, acidified with 0.1 N HCl and extracted with 3 x 25 ml of ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to give the title compound (325 mg). MS m / z 593 (M + + 1); 1 H NMR (CDCl 3) d 3.62 (s, 3 H), 6.76 (s, 1 H).

EXAMPLE 61 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester. 7-methyl ester of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydro-2H- ester quinoline-1, 7-dicarboxylic acid (example 13) analogously to Example 60. MS m / z 593 (M +); 1 H-NMR (CDCl 3) d 3.80 (s, 3 H), 6.42 (s, 1 H).

EXAMPLE 62 Ethyl ester of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6- (2-dimethylaminoethylcarbamoyl) -7-methoxy-2-methyl-3,4-dihydro-2H-quinoline- 1 -carboxylic.

A mixture of 1-ethyl ester of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-3,4-dihydro-2H-quinoline- ethyl ester 1,6-dicarboxylic acid (example 60) (75 mg, 1.26 mmol) and 1.5 ml of SOCI2 was refluxed for 1.5 h. The cooled solution was evaporated to dryness and the residue was dried under high vacuum for 30 minutes. The residue was diluted with 0.75 ml of dichloromethane, and sequentially added ^^^^^^^^^^^ ^^^^^^^^^^^^^^^ x ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ethylenediamine (11 mg, 1.26 mmol). After 1.5 h, the reaction mixture was concentrated and the residue was chromatographed (5% MeOH-dichloromethane) to give the desired product (72 mg, 86%). MS m / z 663 (M + + l); 1 H-NMR (CDCl 3) d 3.75 (sd, 3H), 7.22 (s, 1 H). Examples 63-69 were prepared in a manner analogous to Example 62, substituting the appropriate amine either from Example 60 or Example 61. EXAMPLE 63 Cis-4 - [(3,5-bis-trifluoromethyl-benzyl) ethyl ester ) -methoxycarbonyl-amino] -6- [2- (3H-imida-2-l-4-yl) -ethylcarbamoyl] -7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic ester 15 MS m / z 686 (M + +1); 1 H-NMR (CDCl 3) d 3.74 (d, 3H), 7.18 (s, 1H).

EXAMPLE 64 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-carbamoyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 5 EMm / z593 (M ++ l); 1 H-NMR (CDCl 3) d 3.81 (s, 3 H), 6.42 (s, 1 H).

EXAMPLE 65 10 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-7-methylcarbamoyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester EMm / z606 (M ++ 1); 1 H-NMR (CDCl 3) d 3.80 (s, 3 H), 6.39 (s, 1 H).

EXAMPLE 66 cis-4-R3.5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7- [2- (1H-im8dazol-4-yl) -ethylcarbamop-6-methoxy-2 ethyl ester) -methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid EMm / z686 (M ++ 1); 1 H-NMR (CDCl 3) d 3.74 (s, 3 H), 6.38 (s, 1 H).

EXAMPLE 67 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-6-methylcarbamoyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 686 (M + + i); 1 H-NMR (CDCl 3) d 3.90 (s, 3 H), 7.18 (s, 1 H).

EXAMPLE 68 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7 (2-dimethylamino-ethylcarbamoyl) -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline ethyl ester -1-carboxylic MS m / z 663 (M + +1); 1 H-NMR (CDCl 3) d 3.78 (s, 3 H), 6.39 (s, 1 H).

EXAMPLE 69 Cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-7- (2-morpholin-4-yl-ethylcarbamoyl) ethyl ester ) -3.4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 705 (M + + l); 1 H-NMR (CDCl 3) d 3.81 (s, 3 H), 6.39 (s, 1 H).

EXAMPLE 70 cis- (3,5-bis-trif luoromethyl-benzyl) - (2-methyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl) -carbamic acid ethyl ester Cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-benzyl ester was combined carboxylic (example 56) (2.8 g, 4.3 mmol), ethanol (50 ml), and 10% palladium on carbon (280 mg) in a Parr bottle and stirred under 50 psi of hydrogen gas in a Parr shaker for 0.5 h. The mixture was then filtered through a pad of Celite®, eluting with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate / hexane as eluent to give 2.0 g of the title product (90%): MS m / z 516 (M + +2); 1 H-NMR (CDCl 3) d 1.18 (C 2 -Me, d, 3 H, J = 5.8 Hz), 6.50 (C 8, d, 1 H, J = 8.3 Hz), 7.21 (C7, d, 1 H, J = 8.5). Examples 71 and 72 were prepared from the initial compounds indicated analogously to Example 70.

EXAMPLE 71 cis- (3,5-bis-trifluoromethyl-benzyl) - (6-chloro-7-trifluoromethyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl-carbamic acid methyl ester Prepared from cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-7-trifluoromethyl-3,4-dihydro-2H- benzyl ester quinoline-1-carboxylic acid. (Example 54) MS m / z 549 (M + + l); 1H-NMR (CDCl3) d 1.17 (C2-Med, d, 3H, J = 6Hz), 6.79 (s, 1 H), 6.85-6.95 (m, 1 H), 7.55-7.65 (m, 2H), 7.75 (s, 1 H).

EXAMPLE 72 Cis- (3,5-bis-trifluoromethyl-benzyl) - (7-tr.fluoromethyl-2-methyl-1,2,3,4-tetrahydroquinol-4-yl) -carbamic acid methyl ester Prepared from cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. (example 59) MS m / z 515 (M + +1); 1 H-NMR (CDCl 3) d 1.17 (C 2 -Me, d, 3 H), 6.7 (s, 1 H), 7.75 (s, 1 H). 3 ^ Ü ^ ¡* $ £ &% * - - & X tr te * ^ - EXAMPLE 73 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-methyl isopropyl ester -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid To a solution of cis- (3,5-bis-trifluoromethyl-benzyl) - (2-methyl-6-tpfluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid methyl ester ( Example 70) (95 mg, 0.185 mmol) and anhydrous pyridine (0.5 ml) in anhydrous dichloromethane (2 ml) was added isopropyl chloroformate (1.9 ml of a 1M solution in toluene, 1.85 mmol). After stirring at room temperature overnight, water (5 ml) and an aqueous solution of 10% KOH (5 ml) were added, and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic phases were then washed with 1N HCl (3 x 10 ml), then with a saturated solution of sodium bicarbonate, and then with brine (10 ml each). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 117 mg of the crude product. Purification by chromatography on silica gel using 0-10% ethyl acetate / hexane as eluent gave 90 mg of the title compound (81%): MS m / z 602 (M + +2), 619 (M + +19); 1 H-NMR (CDCl 3) d 1.20 (Me, D, 3 H, J = 6.1 Hz), 1.28 (d, 3 H), 1.31 (d, 3 H), 3.83 (Orne, s, 3 H), 5.04 (septet, 1 H) , 7.12 (C5, s, 1H).

Examples 74-84 were prepared analogously to Example 73 from the appropriate amines of Examples 70-72.

EXAMPLE 74 5 cis-4- [3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester MS m / z 602 (M + +2), 6.19 (M + +19); 10 1-NMR (CDCl 3) d 7.10 (C5, s, 1 H), 3.81 (Orne, s, 3H).

EXAMPLE 75 cis-4- [3,5-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester / z 619 (M ++ l9); 1 H-NMR (CDCl 3) d 7.12 (C5, s, 1H), 3.82 (Orne, s, 3H), 1.21 (C2, - Me, d, 3H, J = 6.1 Hz). tíl¡á ^ j ^ ¿^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^ EXAMPLE 76 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-2-methyl- isobutyric acid ester 6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 5 EMm / z633 (M ++ 19); 1 H-NMR (CDCl 3) d7.12 (C8, s, 1H), 3.82 (Orne, s, 3H), 1.21 (C2-Me, d, 3H, J = 5.8 Hz).

EXAMPLE 77 Cyclopentyl ester of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. 1H (CDCl 3) d 7.12 (C5-arom., S, 1H), 3.83 (Orne, s, 3H), 1.24 (C2-Me, d, 3H, J = 15.5 Hz). "___." __.._,. __ .. __ ,, ... _. ».___ ^ ___- ^. __.__., _. __._..___. ... • .J ^ j. ^^, A ^ ", .. ^. ¿_: ^ J.?.j_-__.- .___.____ _..-.__.______» _ ^ EXAMPLE 78 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

MS m / z 601 (M + +1), 618 (M ++ 18); 1 H NMR (CDCl 3) d 7.04 (C 5 arom., D, 1 H, J = 8.0 Hz), 3.82 (Orne, s, 3 H).

EXAMPLE 79 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester.

MS m / z 601 (M + + 1), 618 (M + + 18); 1 H-NMR (CDCl 3) d 7.04 (C5 arom., D, 1 H), 3.82 (Orne, S, 3H).

EXAMPLE 80 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester MS m / z 615 (M + + 1), 632 (M + + 18); 1 H-NMR (CDCl 3) d 7.01 (C5arom., D, 1 H), 3.82 (Orne, alif., S, 3H).

EXAMPLE 81 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-chloro-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 636 (M + + 2), 653 (M + + 19); 1 H-NMR (CDCl 3) d 7.02 (C8 arom., S, 1 H), 3.84 (Orne, alif., S, H).

EXAMPLE 82 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-7-trifluoromethyl-3,4-dihiro-2H-quinoline-1-tert-butyl ester carboxylic 1 H-NMR (CDCl 3) d 1.18 (d, 3 H), 1.50 (s, 9 H), 3.84 (Orne aliph., S, 3 H), 7.0 (s, 1 H).

EXAMPLE 83 cis-4- (3,5-bis-trifluoromethyl-benzyl) - (1-isopropylcarbamoyl) -2-methyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid methyl ester MS m / z 600 (M + + H); 1 H-NMR (CDCl 3) d 7.82 (sa, 1H), 7.8 (sa, 1H), 7.7 (sa, 1H), 7.2 (sa, 1 H), 6.7 (sa, 1 H), 3.8 (s, 3H), 3.75 (sa, 3H).

EXAMPLE 84 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] [2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1] -2-dimethyl-rpopyl ester -carboxylic MS m / z 628 (M +), 646 (M + + 18); 1 H-NMR (CDCl 3) d7.12 (C5, s, 1H), 3.83 (Orne, s, 3K), 1.23 (Me, d, 3H, = J 6.1 Hz).

EXAMPLE 85 Ethyl cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic To a solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -emtoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydroxy-7-methyl ester of 7-methyl ester. 2H-quinoline-1,7-dicarboxylic acid (example 13) (100 mg, 0.16 mmol) in 20 ml of tetrahydrofuran, sodium borohydride (62 mg, 1.6 mmol) was added. The reaction was heated to reflux and methanol (40 ml) was slowly added. After an additional 30 minutes at reflux, the reaction was concentrated and the residue was diluted with 20 ml of H 2 O and extracted with 3 x 50 ml of ethyl acetate. The combined extracts were dried (MgSO4), filtered, concentrated, and the residue was purified by chromatography (30-40% ethyl acetate: hexane) to give 100 mg of the title product. 1 H-NMR (CDCl 3) d 1.1 (d, 3H), 1.3 (t, 3H), 3.75 (s, 3H), 6.4 (s, 1 H), 7.4 (s, 1 H), 7.7 (s, 2H), 7.8 (s, 1H). EXAMPLE 86 Ethyl ester of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-7- (1-hydroxymethyl-cyclopentyl) -6-methoxy-2-methyl-3,4-dihydro-2H- acid quinoline-1-carboxylic acid 10 To a solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-7- (1-ethyl ester) -methoxycarbonyl-cyclopentyl) -2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid (example 27) (700 mg; 1.04 mmoles) in 20 ml of anhydrous tetrahydrofuran, dimethylsulfide-borane complex (1 M THF, 2.28 ml) was added and the reaction was heated to reflux for 3 hours. The reaction was quenched with H2O) and extracted with 50 mL of ethyl acetate. The organic phase was dried (MgSO 4), filtered and concentrated. The residue was chromatographed (25% ethyl acetate / hexane) to give the title product (20 mg). 20 MS m / z 664 (M + + 18); 1 H-NMR (CDCl 3) d 1.1 (d; 3 H), 3.6 (s, 2 H), 3.7 (s, 3 H), 3.8 (s, 3 H), 6.3 (s, 1 H), 7.3 (s, 1 H) , 7.7 (s, 2H), 7.8 (s, 1H). . .. ^ a. - > - - -. . ^ _.____ 5 ^ _ ^ ___ ¡¡£ ^^ _. ^, - .___ j | _ »& u ^ -, __..__. ^ - * ^ »^. __Wlll_______l_? Examples 87-89 were prepared analogously to Example 86 from the indicated initial esters.

EXAMPLE 87 5 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-7- (2-hydroxy-ethyl) -6-methoxy-2-methyl-3,4-dihydro-2H- ethyl ester quinoline-1-carboxylic Prepared from cis-4 - [(3,5-bis-10-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-ethoxycarbonylmethyl-6-methoxy-2-methyl-3,4-dihydro-2H ethyl ester -quinoline-1-carboxylic acid (example 15) MS m / z 592.2 (M +); 1 H-NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 6.4 (s, 1 H), 7.7 (s, 2 H), 7.8 (s, 1 H). EXAMPLE 88 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-hydroxymethyl-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 ethyl ester carboxylic 20 Prepared from cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amyno] -7-methoxy-2-methyl-3-methyl ester 6-methyl ester 4- dihydro-2H-quinoline-1,6-dicarboxylic acid (example 14) MS m / z (M + + 1); 1 H-NMR (CDCl 3) d 6.73 (s; 1 H), 3.8 (s, 3H).

EXAMPLE 89 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-bis-hydroxymethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Prepared from cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4-dihydro-2H-ethyl ester 6,7-dimethyl ester quinoline-1, 6,7-tricarboxylic (example 16) MS m / z 596 (M + + NH 4 +); 1 H-NMR (CDCl 3) d 6.95 (s, 1 H), 3.8 (s, 3 H).

EXAMPLE 90 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-bromoethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of triphenylphosphine (0.457 g, 174 mmol) in anhydrous dichloromethane (15 ml) at 0 ° C is slowly added bromine (84 μl, 1. 6 mmoles). After the reaction was stirred at 0 ° C for 20 minutes, a solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-hydroxymethyl-6-ethyl ester was added. -methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid (example 85) (0.630 g, 1.09 mmol) in dichloromethane (15 ml). The reaction was stirred at 0 ° C for 20 minutes, then at room temperature for 3 h. The reaction mixture was then diluted with chloroform and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using 10-15% ethyl acetate / hexane as eluent gave the title product (0.500 g, 72%): MS m / z 642.1 (M + + 1); 1 H-NMR (CDCl 3) d 15 (d, 3 H), 1.3 (t, 3 H), 3.8 (s, 3 H), 3.85 (s, 3 H), 6.4 (s, 1 H), 7.4 (s, 1 H) ), 7.7 (br, 2), 7.8 (s, 1 H).

EXAMPLE 91 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-bromoethyl-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Prepared as in example 90 from cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-hydroxymethyl-7-methoxy-2-methyl-3,4-ethyl ester -dihydro-2H-quinoline-1-carboxylic acid (example 88). MS m / z 642.1 (M + + 1); 1 H-NMR (CDCl 3) d 6.8 (s, 1 H), 3.8 (s, 3H).

EXAMPLE 92 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-7-methylsulfanylmethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a suspension of sodium thiomethoxide (11 mg, 0.156 mmol) in anhydrous N, N-dimethylformamide (5 ml) was added cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino acid ethyl ester. ] -7-bromoethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid (Example 90) (100 mg, 0.156 mmole), and the reaction was stirred for 6 h . The reaction mixture was poured into water and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess N, N-dimethylformamide was distilled azeotropically with heptane. Purification by chromatography on silica gel using 10-15% ethyl acetate / hexane as eluent gave the title compound (0.040 g, 42%): 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 2.1 (s) , 3H), 3.8 (m, 6H), 6.4 (s, 1 H), 7.3 (s, 1H), 7.7 (s, 2H), 7.8 (s, 1 H). Examples 93-102 were prepared analogously to Example 92 using the required bromide (example 90 or 91) and the appropriate alkoxide or thioalkoxide.

EXAMPLE 93 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-ethylsulfanylmethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 2.55 (q, 2 H), 3.7 (s, 3 H), 6.4 (s, 1 H), 7.3 (s, 1 H), 7.7 (d, 2 H), 7.8 (s, 1 H).

EXAMPLE 94 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7- (5-ethoxycarbonyl-4-methyl-thiazol-2-ylsulfanylmethyl-6-methoxy-2-methyl) ethyl ester - 3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 764.2 (M +); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 H), 2.7 (s, 3 H), 6.4 (s, 1 H), 7. 4 (s, 1H), 7.7 (s, 2H), 7.8 (s, 1H).

EXAMPLE 95 Ethyl ester of cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-7-f2- (3H-imidazol-4-yl) ethoxymethyl-1-6-methoxy-2-methyl-3,4- dihydro-2H-quinoline-1-carboxylic acid MS m / z 673.2 (M + +1); 1 H-NMR (CDCl 3) d 1.15 (d, 3 H), 1.25 (t, 3 H), 2.7 (t, 1 H), 3.8 (s, 3 H), 3.85 (s, 3 H), 6.4 (s, 1 H), 6.8 (s, 1H), 7.2 (s, 1H), 7.58s, 1H), 7.7 (s, 2H), 7.8 (s, 1 H). EXAMPLE 96 Ethyl ester of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7- (5-ethoxycarbonyl-thiazole-2-ylsulfanylmethyl) -6-methoxy-2-methyl-3,4 acid ethyl ester - dihydro-2H-quinoline-1-carboxylic acid Em Em / Z 749.9 (M +); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.4 (t, 3 H), 3.8 (s, 6 H), 4.4 (q, 2 H), 6.4 (s, 1 H), 7.4 (s, 1 H), 7.7 (s, 2H), 7.8 (s, 1H), 8.0 (s, 1 H) M _____ tt_l_É_BI 1T1 tfff? _1 ___ ¥ iryrp ~ - "" - * "EXAMPLE 97 Ethyl ester of cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-ethylsulfanylmethyl-7-methoxy-2- acid methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 623 (M + + i); 1 H NMR (CDCl 3) d 6.68 (s, 1 H), 3.76 (s, 3H).

EXAMPLE 98 10 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-6-methylsulfanylmethyl-3,4-dihydro-2H-quinoline-1 ethyl ester - carboxylic MS m / z 609 (M + + l); 1 H NMR (CDCl 3) d 6.66 (s, 1 H), 3.76 (s, 3 H).

EXAMPLE 99 cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-7-methoxy-6- (2-methoxy-ethoxymethyl) -2-methyl-3,4-dihydro-2H-quinoline ethyl ester - 20 1 -carboxyl MS m / z 637 (M + +1); 1 H NMR (CDCl 3) d 6.82 (s, 1 h), 3.78 (s, 3 H).

EXAMPLE 100 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-6- (1-methoxy-1H-tetrazol-5-ylsulfanylmethyl) ethyl ester - 3.4- dihydro-2H-quinoline-1-carboxylic acid MS m / z 694 (M + + NH 4 +); 1 H NMR (CDCl 3) d 3.76 (s, 3 H), 6.99 (s, 1 H).

EXAMPLE 101 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-7- (2-methoxy-ethoxymethyl) -2-methyl-3,4-dihydro-2H-quinoline, ethyl ester -1- carboxylic MS m / z 561 (M + -75); 1 H NMR (CDCl 3) d 1.1 (d, 3 H), 1.3 (t, 3 h), 3.6 (s, 3 H), 6.2 (s, 1 H), 7. 8 (s, 1H).

EXAMPLE 102 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-propylsulfanylmethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic 1 H NMR (CDCl 3) d 1.0 (t, 3 H), 1.1 (d, 3 H), 1.3 (t, 3 H), 2.5 (t, 2 H), 3.7 (s, 3 H), 6.4 (s, 1 H 9, 7.3 ( s, 1 H), 7.7 (m, 2H), 7.8 (s, 1 H).

EXAMPLE 103 cis-4 - [(3,5-bis-tri-fluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-7-methoxymethyl-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic To a suspension of sodium hydride (4.2 mg, dispersed in a 60% inorganic oil, 0.10 mmol) in N, N-dimethylformamide (2.5 moles) was added cis-4 - [(3,5- bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid (example 85) (50 mg, 0.087 mmol). After the reaction was stirred at room temperature for 30 minutes, iodomethane (60 μl, 0.96 mmol) was added, and the reaction was stirred for 18 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess of N, N-dimethylformamide was azeotroped with heptane. Purification by chromatography on silica gel using 15-25% ethyl acetate / hexane as eluent gave the title product (30mg, 59%): 1 H NMR (CDCl 3) d 1.1 (d, 3H), 1.3 (t, 3H), 3.4 (s, 3H), 3.75 (s, 3H), 3.8 (s, 3H), 6.4 (s, 1 H), 7.4 (s, 1 H), 7.75 (s, 2H), 7.8 (s) , 1 HOUR). Examples 104 and 105 were prepared analogously to Example 103 from the indicated initial alcohol.

EXAMPLE 104 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-6-methoxymethyl-2-methyl-3,4-dihydro-2H-quinoline-1 ethyl ester carboxylic Prepared from cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-hydroxymethyl-7-methoxy-2-methyl-3,4-dihydroxyethyl ester 2H-quinoline-1-carboxylic acid (example 88) MS m / z 610 (M + + NH 4 +); 1 H NMR (CDCl 3) d, 8 (s, 1 H), 3.76 (s, 3 H).

EXAMPLE 105 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-bis-methoxymethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Prepared from cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-bis-hydroxymethyl-2-methyl-3,4-dihydro-2H- ethyl ester quinoline-1-carboxylic acid (example 89) MS m / z 607 (M + + 1); 1 H NMR (CDCl 3) d 6.95 (s, 1 H), 3.82 (s, 3 H).

EXAMPLE 106 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-aminol-6,7-bis-fluoromethyl-2-methyl-3,4-dihydro-2H-quinolin-1-carboxylic acid ethyl ester To a solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-bis-hydroxymethyl-2-methyl-3,4-dihydro-2H- ethyl ester quinoline-1-carboxylic acid (example 89) in 15 ml of 1,2-dichloroethane was added diethylaminosulphuric trifluoride (0.5 ml) and the reaction was heated at 80 ° C for 45 min. The reaction mixture was cooled, adsorbed on SiO2 and chromatographed (20% ethyl acetate / hexane) to give the title product (60 mg). MS m / z 582.3 (M +); ^ Fc 1H NMR (CDCl 3) d 1.1 (d; 3H), 3.8 (s; 3H), 5.35 (s, 2H9, 6.9 (s, 1H), 7.65 (m, 3H), 7.8 (s; 1H) .

EXAMPLE 107 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-8-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A suspension of F3CSO3NO2 (2.6 mmol) was prepared in a flask under a nitrogen atmosphere, 9 ml of dichloromethane [ref. J. Org. Chem. 1973.38 (25), 4243]. The solution was cooled to -78 ° C and a solution of cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3-ethyl ester was added. , 4-dihydro-2H-quinoline-1-carboxylic acid (Example 32) (0.72 g, 1.3 mmol) in anhydrous dichloromethane (5 ml). The reaction was stirred at -78 ° C for 1.5 h, then warmed to 0 ° C and stirred for 1 h and 40 minutes. Water (30 ml) was then added, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title product (0.75 g, 96%). MS m / z 598 (M + + H); 1H-NMR (CDCl3) d7.85 (br s, 1 H), 7.8 (br s, 1H), 7.7 (br s, 1 H), 7.65 (sa, 1H), 7.1 (sa, 1H), 3.80 (s, 3H). -______-,. _ ~ _.... - - ... .- ..... .. ^ .- S ^^., ^^ .. ^^^^^ EXAMPLE 108 Isopropyl ester of cis-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino acid -6-trifluoromethyl-2-methyl-8-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid Prepared analogously to Example 107 from isopropyl ester of cis-4 - [(3,5 bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (Example 73). MS m / z 646 (M + + H); 1 H NMR (CDCl 3) d 8.1 (br s, 1 H), 7.8 (br s, 1 H), 7.7 (br s, 1 H), 7.35 (br s, 1 H), 3.28 (s, 3 H).

EXAMPLE 109 15 Cis-8-amino-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and : cis-8-amino-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-8-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid (Example 107) (0.747 g, 1.25 mmol), ethanol (20 ml), and palladium % on carbon at 10% (0.40 g), and shaken under psi of H2 on a Parr shaker for 2 h and 15 minutes. The mixture was then filtered through a pad of Celite®. The Celite® was washed with ethanol, and the filtrate was concentrated in vacuo. Purification by chromatography on silica gel using 30-100% ethyl acetate / hexane as eluent gave 0.386 g (54%) of cis-8-amino-4 - [(3,5-bs) ethyl ester. -trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1 -carboxylic MS m / z 568 (M + + H); 1 H NMR (CDCl 3) d 7.8 (br s, 1 H), 7.7 (br s, 1 H), 7.65 (br s, 1 H), 6.7 (br, 1 H), 6.38 (br, 1 H), 3.78 (s, 3H), and 0.161 g (24%) of cis-8-amino-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4-ethyl ester -dihydro-2H-quinoline-1 -carboxylic MS m / z 534 (M + + H); 1 H NMR (CDCl 3) d 7.79 (br s, 1 H), 7.7 (br s, 1 H), 7.65 (br s, 1 H), 7.02 (br, 1 H), 6.72 (br, 1 H), 6.4 (bd, 1 H), 3.78 (s, 3H).

EXAMPLE 110 cis-8-amino-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Prepared as in Example 109 from cis-4 - [(3,5-bis-tr? Fluoromethyl-benzyl) -methoxycarbonyl-amino] -6- isopropyl ester ^ g¡ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ J ^^^^^^^^^ ^^^^^^ g ^ ^ ^^^ trifluoromethyl-2-methyl-8-nitro-3,4-dihydro-2H-quinoline-1 -carboxylic acid (Example 108) MS m / z 616 (M + + H ); 1 H NMR (CDCl 3) d 7.8 (br s, 1 H), 7.65 (br s, 2 H), 7.62 (br s, 1 H), 6.8 (br s, 1 H), 3.8 (s, 3 H).

EXAMPLE 111 cis-8-acetylamino-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic Cis-8-amino-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-ethyl ester was added to a preserves phial under a nitrogen atmosphere. methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (Example 109) (30 mg, 0.053 mmol), followed by anhydrous dichloromethane (2 ml), pyridine (0.5 ml), and acetyl chloride (0.015) ml, 0.21 mmol). The reaction was stirred overnight at room temperature before adding ethyl acetate, and the mixture was extracted three times with 1N HCl, followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title product (33 mg, 100%) MS m / z 610 (M + + H); 1 H NMR (CDCl 3) d 7.8 (br br 2 H); 7.7 (sa, 1H), 7.65 (sa, 1H), 3.8 (s, 3H), 2.1 (s, 3H).

EXAMPLE 112 cis-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-8-methoxycarbonylamino-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A cis-8-amino-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3, ethyl ester, was added to a preserver vial. 4-dihydro-2H-quinoline-1 -carboxylic acid (Example 109) (30 mg, 0.053 mmol), followed by anhydrous dichloromethane (2 ml), pyridine (0.5 ml), and methyl chloroformate (0.016 ml, 0.21 mmol) ). The reaction was stirred overnight at room temperature before adding ethyl acetate, and the mixture was extracted three times with 1N HCl, followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product (29 mg, 87%) MS m / z 626 (M + + H); 1 H NMR (CDCl 3) d 7.82 (s, 1 H), 7.8 (ss, 1 H), 7.7 (ss, 1 H), 6.88 (ss, 1 H), 6.7 (ss, 1 H), 3.8 (s, 3H), 3.75 (s, 3H.) The following examples were prepared in optically enriched form by resolution of the corresponding indicated racemates, or an intermediate in their synthesis, using the methods described in the specification.

EXAMPLE 113 [2R.4S] 4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-auinoline-1-carboxylic acid ethyl ester Example 30 EXAMPLE 114 Isopropyl ester of acid [2R. 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Example 73 EXAMPLE 115 Tertiary butyl ester of acid [2R. 4R] 4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Example 74 EXAMPLE 116 Proic acid ester [2R. 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Example 75 _á _________ N_____t_i_a_. ^ ____-__ ^ __ ^ _ B ___ t _ ^ _. "-

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula Formula I one of its prodrugs, a pharmaceutically acceptable salt of said compound or said prodrug; wherein R1 is hydrogen, Y, W-X, W-Y; wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -O- Y, -SY, -N (H) -Y or -N- (Y) 2 i and in each case is independently Z or a carbon chain, linear or branched, from one to ten members, fully saturated , partially unsaturated or totally unsaturated, in which the carbons, other than the bonding carbon, can optionally be replaced by one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri- independently substituted with halogen, said carbon is optionally mono- ? -rfaüÉiTr- * rri _________ a ____ á ________-_-- ___ ß ___ t ^ I ^ ___ i £ l__Í ____ 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 Z; wherein Z is a three to twelve member ring, partially saturated, fully saturated or totally unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings, three six members, fused, partially saturated, fully saturated or totally unsaturated, independently considered, 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 halogen, (C2-C6) alkenyl, (d-CQ) alkyl, hydroxy, alkoxy (C-pCß), alkylthio (d-C4), amino , nitro, cyano, oxo, carboxy, (C -? - C6) -carbonyl, mono-N- or di-N, N-alkylamino (Ci-Cß) alkyloxy wherein said alkyl substituent (Ci-Cß) optionally mono-, di- or tri-substituted independently with halogen, hydroxy, alkoxy (Ci-Cß), alkylthio (CrC4), amino, nitro, cyano, oxo, carboxy, alkyloxy (d-CβJ-carbonyl, mono-N - or di-N, N-alkylamino (Ci-Cß), said alkyl (C Cß) being optionally substituted by one or nine fluorine atoms: R 3 is hydrogen or Q, wherein Q is a carbon chain, linear or branched, from one to six members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, other than the bonding carbon, may be replaced ^^^^^^^^^^^^^ < ^^^^ * ^^^^^^^ _ ^ g ^^^^^^^^^^^^^^^^^^^ * g ^^ optionally by a selected heteroatom of oxygen, sulfur and nitrogen , and said carbon is optionally mono-, di- or tri-substituted independently with halogen, 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; wherein V is a three to twelve member ring partially saturated, fully saturated or totally unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings, three to six members, fused, partially saturated, fully saturated or totally unsaturated, independently considered, having optionally one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V is optionally mono-, di-, tri or tetra-substituted independently with halogen, alkyl (d-Cß), alkenyl (C2-C6), hydroxy, alkoxy (Ci-Ce), alkylthio (CrC4) , amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N-alkyl (C? -C6) -carboxamoyl, carboxy, alkyloxy (C? -C6) -carbonyl, mono-N- or di -N, N-alkylamino (Ci-Cß), wherein said alkyl substituent (C.-Ce) or (C2-C6) alkenyl is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (Ci-). Cß), alkylthio (d-C4), amino, nitro, cyano, oxo, carboxy, alkyloxy (Ci-CβJ-carbonyl, mono-N- or di-NN-alkylamino (CrCβ), said alkyl (C C6) being alkenyl (C -C6) optionally substituted with one to nine fluorine atoms; R4 is Q1 or V1; wherein Q1 is a carbon chain, linear or branched, from one to six members, fully saturated, partially unsaturated or totally unsaturated, in which the carbons, other than the binding carbon, can optionally be replaced by a selected heteroatom of oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri-substituted independently with halogen, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono - Og-10 substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V1; wherein V1 is a ring, from three to six members, partially saturated, fully saturated or totally unsaturated, having one to two heteroatoms independently selected from oxygen, sulfur and 15 nitrogen; wherein said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with halogen, alkyl (d-Cß), alkoxy (d- Cß), amino, nitro, cyano, alkyloxy (CrC6) -carbon It, mono-N- or di-N, N-alkylamino (d-Ce), wherein said alkyl substituent (d-Cß) is optionally mono-substituted with oxo, optionally having said Substituent alkyl (d-C6) of one to nine fluorine atoms; where R3 must contain V or R4 must contain V1; and R5, R6, R7 and R8 are each independently hydrogen, a bond, nitro or halo, wherein said bond is substituted with T or a straight or branched carbon chain of (C.-C12) J, * j * & fc ____. < E_at- ~ ^^ s ^^ s ^ t ^ partial or completely saturated, or completely unsaturated, said carbon being optionally replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are mono- , di- or tri-substituted independently with halo, said carbon is mono-substituted with hydroxy, said carbon is 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 is mono-substituted with T; wherein T is a partially or fully saturated, or completely unsaturated, ring of three to twelve members, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen; or a bicyclic ring comprising two condensed rings of three to six members partially or completely saturated, or completely unsaturated, taken independently, optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halogen, alkyl (d-C6), alkenyl (C2-C6), hydroxy, alkoxy (C6-6), alkylthio (d-C4), amino, nitro, cyano, oxo, carboxy, (C? -C6) alkyloxycarbonyl, mono-N- or di-N, N-alkylamino (d-C?) wherein said alkyl substituent (d-C?) is optionally mono-, di or tri-substituted independently with hydroxy, alkoxy (d-Cß), alkylthio (CrC4), amino, nitro, cyano, oxo, carboxy, alkyloxy (d-C6) -carbonyl, mono-N- or di- N, N-alkylamino (C? -C6), or said alkyl (d-C6) optionally (CrC6), or said alkyl (d-C?) Optionally having one to nine fluorine atoms; with the proviso that R5, R6, R7 and R8 is not hydrogen and is not linked to the rest of the quinoline via oxy.
2. A compound according to claim 1, wherein the C2-methyl is in beta orientation; C4-nitrogen is in beta orientation; 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 Z or alkyl (CrC4), said alkyl (CrC4) being optionally substituted with hydroxy or one to nine fluorine atoms or said alkyl (CrC4) being optionally mono-substituted with Z, wherein Z is a ring, three to six limbs, partially saturated, fully saturated or completely unsaturated, having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halogen, alkyl (d-C4), alkoxy (CrC4), alkylthio (C? -C), nitro, cyano, oxo or alkyloxy (CrCßJ -carbonyl, said alkyl substituent (d-C4) being optionally substituted by one to nine fluorine atoms: R3 is QV wherein Q is alkyl (d-C4) and V is a five or six member ring, partially saturated , fully saturated or totally unsaturated optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halogen, alkyl (d-) Cß), hydroxy, alkoxy (d-Cß), nitro, cyano or oxo, wherein said alkyl (C? -C6) optionally has one to .... _ ^ -__. \ _a ____ J __... ... ... .. * _ .., .._,,. ,,. ... "£ ._.._ ____ nine fluorine atoms; R4 is alkyl (d-C4); R6 and R7 is each independently hydrogen, halo, T, alkyl (d-Ce) or (C? -C6) alkoxy, said alkyl (CrC6) or alkoxy (Ci-Ce) optionally having from one to nine fluorine atoms, or optionally said alkyl (d-Cß) or alkoxy (d-5 Ce) substituted by T, where T is a five or six membered ring, partially saturated or totally unsaturated, optionally having one to two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di- or trisubstituted independently with halogen, alkyl (d-Ce), hydroxy, alkoxy 10 (Ci-Cβ), alkylthio (C Cβ), amino, oxo, carboxy, alkyloxy (CrCβJ-carbonyl, mono-N- or di-N, N-alkylamino (d-Cβ), said alkyl substituent having (d- Cß) optionally one to nine fluorine atoms, and R5 and R8 are H, or a pharmaceutically acceptable salt 3. A compound according to claim 2 wherein W is 15 carbonyl; X is O-Y, wherein Y is alkyl (d-C4), said alkyl (dC4) optionally having from one to nine fluorine atoms; Q is alkyl (CrC4) and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or tri-substituted independently with halogen, alkyl (CrCß), hydroxy, alkoxy (d-Cß), nitro, cyano or oxo, wherein said alkyl substituent 20 (d-Cß) optionally has hydroxy or from one to nine fluorine atoms; and R6 and R7 are each independently hydrogen, halogen or (C1-C3) alkyl, said (C1-C3) alkyl optionally having from one to seven fluorine atoms; or a pharmaceutically acceptable salt. 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 halogen; (C 1 -C 2) alkyl or nitro, wherein said (C 1 -C 2) alkyl optionally has one to five fluorine atoms; or a pharmaceutically acceptable salt. 5. A compound according to claim 1 wherein the compound is [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3, ethyl ester, 4-dihydro-2H-quinolin-1-carboxylic acid; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-chloro-2-methyl-3,4-dihydro-2H-quinolin-1-ethyl ester -carboxylic; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3,4-dihydro-2H-quinolin-1-ethyl ester -carboxylic; [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2,6,7-trimethyl-3,4-dihydro-2H-quinolin-1-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of said compounds. 6. A compound according to claim 1 wherein the compound is [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7- ethyl ester. diethyl-2-methyl-3,4-dihydro-2H-quinolin-1-carboxylic acid; [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-ethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H acid ethyl ester -quinolin-1-carboxylic acid; [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-isopropyl ester ^^^^^^ n ^ ^ trifluoromethyl-3,4-dihydro-2H-quinolin-1-carboxylic acid; or a pharmaceutically acceptable salt of said compounds. 7. A compound according to claim 4 wherein Y is ethyl, R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is hydrogen; and R7 is trifluoromethyl; or a pharmaceutically acceptable salt. 8. A compound according to claim 4 wherein Y is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is hydrogen; and R7 chloro; or a pharmaceutically acceptable salt. 9. A compound according to claim 4 wherein Y is ethyl; 10 R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is chlorine; and R7 hydrogen; or a pharmaceutically acceptable salt. 10. A compound according to claim 4 wherein Y is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is methyl; and R7 methyl; or a pharmaceutically acceptable salt. 11. A compound according to claim 4 wherein Y is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is ethyl; and R7 ethyl; or a pharmaceutically acceptable salt. 12. A compound according to claim 4 wherein Y is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is ethyl; and R7 is hydrogen; or a pharmaceutically acceptable salt. 13. A compound according to claim 4 wherein Y is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is hydrogen; or a pharmaceutically acceptable salt. J ft > J-.a «S * > 14. - A compound according to claim 4 wherein Y is isopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is hydrogen; or a pharmaceutically acceptable salt. 15. A compound according to claim 1 wherein the C2 methyl is in beta orientation; nitrogen C4 is in beta orientation: 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 alkyl (d-C), said alkyl (d-C) optionally having one to nine fluorine atoms, or said alkyl (CrC4) being optionally mono-substituted with Z; wherein Z is a ring, from three to six members, partially saturated, fully saturated or totally unsaturated, having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halogen, alkyl (CrC4), alkoxy (CrC4), alkylthio (d-C4), nitro, cyano, oxo or alkyloxy (d-CßJ- carbonyl, said alkyl substituent (C? -C4) optionally having one to nine fluorine atoms: R3 is QV wherein Q is alkyl (C? -C) and V is a five or six member ring, partially saturated, fully saturated or totally unsaturated optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring V is optionally mono-, di- or tri-substituted independently with halogen, alkyl (d-Cß), hydroxy , alkoxy (d-Cß), nitro, cyano or oxo, said alkyl (d-Cß) being optionally mono-, di- or tri-substituted independently with alkoxy (Cr . ^^^^ "^ a ^ a ^ fe ^ _ ^ C6) or alkylthio (d-C) or optionally having said alkyl (C.-Ce) of one to nine fluorine atoms; R4 is alkyl (d-C4); R6 and R7 are each independently H, carbamoyl, oxycarbonyl, oxy or halogen, or said carbamoiio oxycarbonyl or oxy are substituted with alkyl (dC) and said alkyl (CrC) being optionally mono-, di- or tri-substituted with halogen or hydroxy, or said alkyl (CrC 4) being optionally mono-substituted with (d-C 4) alkoxy, carboxy, alkylthio (C 1 -C 4), alkyl (CrC) -carbonyl, amino or mono-N- or di-N, N -alkylamino (CrC4), or said alkyl substituent (dd) having from one to nine fluorine atoms; or said alkyl (d-d), carbamoyl, oxycarbonyl or oxy are optionally mono-substituted with T; wherein T is a ring of three or six members, partially or fully saturated, or completely unsaturated, having optionally one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring T is optionally mono-, di-, tri- or tetra-substituted independently with halogen, alkyl (d-Cß), hydroxy, alkoxy (C Cß), nitro, cyano or oxo, said alkyl substituent being ( C Cβ) optionally mono-, di- or tri-substituted independently with (d-Cß) alkoxy or alkylthio (d-Cß), or said alkyl (d-Cß) substituent optionally having one to nine fluorine atoms; R5 and R8 are H; or a pharmaceutically acceptable salt. 16. A compound according to claim 15 wherein W is carbonyl; X is O-Y, wherein Y is alkyl (d-C), said alkyl (d-C4) having one to nine fluorine atoms; Q is alkylene (CrC) and V is phenyl, pyridinyl or pyrimidyl; wherein said ring V is optionally mono-, di- or ^^ ^ ¡^ tri-substituted independently with halogen, alkyl (CrC6), hydroxy, alkoxy (d-Cß), nitro, cyano or oxo, said alkyl substituent (CrCe) optionally having one to nine fluorine atoms; R6 is, carbamoyl, oxycarbonyl, oxy or halogen, or said carbamoyl, oxycarbonyl or oxy are substituted with (C1-C2) alkyl and said (d-C2) alkyl being optionally mono-, di- or trisubstituted with halogen or hydroxy, or said substituent (C1-C2) alkyl optionally having from one to nine fluorine atoms; R7 is H, carbamoyl, oxycarbonyl, oxy or halogen, or said carbamoyl, oxycarbonyl or oxy are optionally substituted with alkyl (CrC4) and said (d-C4) alkyl being optionally mono-, di- or tri-substituted with halogen or hydroxy, or said alkyl (d-C4) substituent optionally having from one to nine fluorine atoms; or a pharmaceutically acceptable salt. 17. The use of a compound of claim 1, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug for the manufacture of a medicament, for treating atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular alterations, angina, ischemia, cardiac ischemia, acute stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being, both male and female). ggg ^ ^ g ^^^^^^^ ^ ^^^^^^^^^^^^^^^^^^^^ j ^^ g gg ^^ - - - ^^^ - go - '? : r if 'r 18. - The use as claimed in claim 17, wherein atherosclerosis is treated. 19. The use as claimed in claim 17, wherein peripheral vascular disease is treated. 20. The use as claimed in claim 17, wherein the dyslipidemia is treated. 21. Use as claimed in claim 17, wherein hyperbetalipoproteinemia is treated. 22. The use as claimed in claim 17, wherein hypoalphalipoproteinemia is treated. 23. The use as claimed in claim 17, wherein hypercholesterolemia is treated. 24. The use as claimed in claim 17, wherein hypertriglyceridemia is treated. 15 25.- The use as claimed in claim 17, where cardiovascular changes are treated. 26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, one of its prodrugs, a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. 27.- A pharmaceutical composition for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular alterations, angina, ischemia, cardiac ischemia, acute stroke, myocardial infarction, reperfusion injury, 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 claim 1, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier. 28. A pharmaceutical composition for the treatment of atherosclerosis in a mammal comprising an amount suitable for treating atherosclerosis of a compound of claim 1, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable vehicle. 29. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of claim 1, one of its prodrugs, or a pharmaceutically acceptable salt of said compound or of said prodrug; a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of MTP / Apo B secretion, a PPAR activator, a bile acid reuptake inhibitor, an inhibitor of cholesterol absorption , an inhibitor of cholesterol synthesis, a fibrate, -. -5-. V-Niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor, or a bile acid sequestrant, and a pharmaceutical carrier 30.- A composition in a pharmaceutical combination according to the invention. claim 29, wherein the second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. A composition in pharmaceutical combination according to claim 29, wherein the second compound is lovastatin, simvastatin , pravastatin, fluvastatin, atorvastatin or rivastatin 32. The use of a) a first compound of claim 1, one of its prodrugs, 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 the secretion of MTP / Apo B, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant an ACAT inhibitor or a bile acid sequestrant, for the manufacture of a drug, to treat atherosclerosis in a mammal 33. - The use as claimed in claim 32, wherein the second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. 34.- Use as claimed in Claim 32, wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. 35. - A kit that includes: a. a first compound, said first compound of claim 1 being one of its prodrugs, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier in a first unit dosage form; b. a second compound, said second compound being an HMG-CoA reductase inhibitor, 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 sequestrant, and a pharmaceutically acceptable carrier in a second unit dosage form; and c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect. 36. A kit according to claim 35, wherein said second compound is an inhibitor of the HMG-CoA reductase or an inhibitor of the secretion of MTP / Apo B. 37.- A kit according to claim 35, wherein said second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.