Annulated 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines

A method for treating atherosclerosis in a mammal comprising administering to a mammal in need of treatment thereof;

• a first compound, said first compound being a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug
• wherein R1 is hydrogen, Y, W—X, or W—Y;
• wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
• X is —O—Y, —S—Y, —N(H)—Y or —N—(Y)2;
• Y for each occurrence is independently Z or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z;
• wherein Z is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C2-C6)alkenyl, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino, said (C1-C6)alkyl optionally substituted with from one to nine fluorines;
• R3 is hydrogen or O;
• wherein O is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V;
• wherein V is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said V substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy, (C1-C6)alkoxy, (C1-C6)alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N— or di-N,N-(C1-C6)alkylcarboxamoyl, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl or (C2-C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino or said (C1-C6)alkyl or (C2-C6)alkenyl are optionally substituted with from one to nine fluorines;
• R4 is O1 or V1;
• wherein O1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V1;
• wherein V1 is is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
• wherein said V1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, nitro, cyano, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-substituted with oxo, said (C1-C6)alkyl substituent optionally having from one to nine fluorines;
• wherein either R3 must contain V or R4 must contain V1;
• and
• R5 and R6, or R6 and R7, and/or R7 and R8 are taken together and form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
• wherein said ring or rings formed by R5 and R6, or R6 and R7, and/or R7 and R8 are optionally mono-, di- or tri-substituted independently with halo, (C1-C6)alkyl, (C1-C4)alkylsulfonyl, (C2-C6)alkenyl, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino, said (C1-C6)alkyl substituent optionally having from one to nine fluorines;
• provided that the R5, R6, R7 and/or R8, as the case may be, that do not form at least one ring are each independently hydrogen, halo, (C1-C6)alkoxy or (C1-C6)alkyl, said (C1-C6)alkyl optionally having from one to nine fluorines;
• and
• a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant
• wherein the amounts of first and second compounds result in a therapeutic effect.

A kit comprising:

• a. a first compound, said first compound being a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of
• said prodrug
• wherein R1 is hydrogen, Y, W—X, or W—Y;
• wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
• X is —O—Y, —S—Y, —N(H)—Y or —N—(Y)2;
• Y for each occurrence is independently Z or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z;
• wherein Z is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said Z substituent is optionally mono-, di- or tri-substituted independently with halo, (C2-C6)alkenyl, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino, said (C1-C6)alkyl optionally substituted with from one to nine fluorines;
• R3 is hydrogen or O;
• wherein O is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V;
• wherein V is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said V substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N— or di-N,N-(C1-C6)alkylcarboxamoyl, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl or (C2-C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino or said (C1-C6)alkyl or (C2-C6)alkenyl are optionally substituted with from one to nine fluorines;
• R4 is O1 or V1;
• wherein O1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V1;
• wherein V1 is is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
• wherein said V1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, nitro, cyano, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-substituted with oxo, said (C1-C6)alkyl substituent optionally having from one to nine fluorines;
• wherein either R3 must contain V or R4 must contain V1;
• and
• R5 and R6, or R6 and R7, and/or R7 and R8 are taken together and form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;
• wherein said ring or rings formed by R5 and R6, or R6 and R7, and/or R7 and R8 are optionally mono-, di- or or tri-substituted independently with halo, (C1-C6)alkyl, (C1-C4)alkylsulfonyl, (C2-C6)alkenyl, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N— or di-N,N-(C1-C6)alkylamino, said (C1-C6)alkyl substituent optionally having from one to nine fluorines;
• provided that the R5, R6, R7 and/or R8, as the case may be, that do not form at least one ring are each independently hydrogen, halo, (C1-C6)alkoxy or (C1-C6)alkyl, said (C1-C6)alkyl optionally having from one to nine fluorines 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 MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier in a second unit dosage form;
• and
• c. means for containing said first and second dosage forms
• wherein the amounts of first and second compounds result in a therapeutic effect.