CETP inhibitors in combination with antihypertensive agents and uses thereof

Abstract

This invention relates to pharmaceutical combinations of a cholesteryl ester transfer protein (CETP) inhibitor or a pharmaceutically acceptable salt thereof; and an antihypertensive agent or a pharmaceutically acceptable salt thereof, optionally in combination with an HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, kits containing such combinations and methods of using such combinations to treat subjects suffering from atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetaliproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being either male or female).

1 . A method of treating a disorder or condition selected from atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetaliproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal, including a human, comprising administering to said mammal a cholesteryl ester transfer protein (CETP) inhibitor or a pharmaceutically acceptable salt thereof; and an antihypertensive agent or a pharmaceutically acceptable salt thereof, optionally in combination with an HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, in amounts that render the active agents effective in the treatment of said disorder or condition.  
   
   
       2 - 4 . (canceled)  
   
   
       5 . A method according to  claim 1 , wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluindostatin, velostatin, dihydrocompactin, compactin, fluvastatin, atorvastatin, glenvastatin, dalvastatin, carvastatin, crilvastatin, bervastatin, cerivastatin, rosuvastatin, pitavastatin, mevastatin, or rivastatin.  
   
   
       6 . A method according to  claim 1 , wherein said antihypertensive agent is a calcium channel blocker, an ACE inhibitor, an A-II antagonist, a diuretic, a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker.  
   
   
       7 . A method according to  claim 6 , comprising the hemicalcium salt of atorvastatin.  
   
   
       8 . A method according to  claim 7 , wherein said antihypertensive agent is a calcium channel blocker, said calcium channel blocker being verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, avanidpine, amlodipine, amlodipine besylate, manidipine, cilinidipine, lercanidipine or felodipine or a pharmaceutically acceptable salt of said calcium channel blocker.  
   
   
       9 . A method according to  claim 8 , wherein said calcium channel blocker is felodipine, nifedipine or amlodipine or a pharmaceutically acceptable salt thereof.  
   
   
       10 . A method according to  claim 7 , wherein said antihypertensive agent is an A-II antagonist, said A-II antagonist being losartan, irbesartan, telmisartan or valsartan or a pharmaceutically acceptable salt of said A-II antagonist.  
   
   
       11 . A method according to  claim 7 , wherein said antihypertensive agent is a diuretic, said diuretic being amiloride, bendroflumethiazide or a pharmaceutically acceptable salt thereof.  
   
   
       12 . A method according to  claim 7 , wherein said antihypertensive agent is a beta-adrenergic receptor blocker, said beta-adrenergic receptor blocker being carvedilol or a pharmaceutically acceptable salt thereof.  
   
   
       13 . A method according to  claim 7 , wherein said antihypertensive agent is an ACE inhibitor, said ACE inhibitor being benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, trandolapri, ramipril, zestril, zofenopril, cilaapril, temocapril, spirapril, moexipril, delapril, imidapril, ramipril, terazosin, urapidin, indoramin, amolsulalol, alfuzosin or a pharmaceutically acceptable salt thereof.  
   
   
       14 . A method according to  claim 7 , wherein said antihypertensive agent is an alpha-adrenergic receptor blocker, said alpha-adrenergic receptor blocker being doxazosin, prazosin, trimazosin or a pharmaceutically acceptable salt thereof.  
   
   
       15 . A method according to  claim 1  wherein the CETP inhibitor is a compound of Formula I,  
     
       
         
         
             
             
         
       
     
     a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug;  
     wherein R 1  is 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 ; 
 wherein 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 eight 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, (C 2 -C 6 )alkenyl, (C 1 -C 6 ) alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino, said (C 1 -C 6 )alkyl substituent is also optionally substituted with from one to nine fluorines;  
 R 2  is a partially saturated, fully saturated 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 or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R 2  is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said R 2  ring is optionally attached through (C 1 -C 4 )alkyl;  
 wherein said R 2  ring is optionally mono-, di- or tri-substituted independently with halo, (C 2 -C 6 )alkenyl, (C 1 -C 6 ) alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, oxo or (C 1 -C 6 )alkyloxycarbonyl; R 3  is hydrogen or Q;  
 wherein Q 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 eight 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, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C 1 -C 6 ) alkylcarboxamoyl, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino, said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl substituents are also optionally substituted with from one to nine fluorines;  
 R 4  is cyano, formyll, W 1 Q 1 , W 1 V 1 , (C 1 -C 4 )alkyleneV 1  or V 2 ;  
 wherein W 1  is carbonyl, thiocarbonyl, SO or SO 2 ,  
 wherein Q 1  is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons 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 1 ;  
 wherein V 1  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, 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 1  substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, oxo, amino, nitro, cyano, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-substituted with oxo, said (C 1 -C 6 )alkyl substituent is also optionally substituted with from one to nine fluorines;  
 wherein V 2  is a partially saturated, fully saturated or fully unsaturated five to seven membered ring containing one to four heteroatoms selected independently from oxygen, sulfur and nitrogen;  
 wherein said V 2  substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 2 )alkyl, (C 1 -C 2 )alkoxy, hydroxy, or oxo wherein said (C 1 -C 2 )alkyl optionally has from one to five fluorines; and  
 wherein either R 3  must contain V or R 4  must contain V 1 ;  
 R 5 , R 6 , R 7 and R 8  are independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T or a partially saturated, fully saturated or fully unsaturated (C 1 -C 12 ) straight or branched carbon chain wherein carbon may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with T;  
 wherein T 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 T substituent is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino, said (C 1 -C 6 )alkyl substituent also optionally has from one to nine fluorines;  
 wherein R 5  and R 6 , or R 6  and R 7 , and/or R 7  and R 8  may also be taken together and can form at least one ring that is a partially saturated or fully unsaturated four to eight membered ring optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;  
 wherein said rings formed by R 5  and R 6 , or R 6  and R 7 , and/or R 7  and R 8  are optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkylsulfonyl, (C 2 -C 6 )alkenyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C 6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino wherein said (C 1 -C 6 )alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkylthio, amino, nitro, cyano, oxo, carboxy, (C 1 -C C   6 )alkyloxycarbonyl, mono-N- or di-N,N-(C 1 -C 6 )alkylamino, said (C 1 -C 6 )alkyl substituent also optionally has from one to nine fluorines;  
 and an antihypertensive agent or a pharmaceutically acceptable salt thereof; optionally in combination with an HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, in amounts that render the active agents effective in the treatment of said disorder or condition.  
 
   
   
       16 . A method according to  claim 15 , wherein the CETP inhibitor of formula I is  
     
       
         
         
             
             
         
       
     
     a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug;  
     wherein R 1  is Y, W—X or W—Y;  
     wherein W is carbonyl;  
     X is —O—Y; 
 wherein 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 and said nitrogen is optionally mono-, or di-substituted with oxo;  
 R 2  is a partially saturated, fully saturated 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 independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo; or said R 2  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;  
 R 3  is a fully saturated, one or two membered carbon chain wherein said carbon is optionally mono-substituted with oxo, and said carbon chain is mono-substituted with V;  
 wherein V is a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen;  
 wherein said V substituent is optionally mono-, di-, or tri-, substituted independently with halo, (C 1 -C 2 )alkyl, wherein said (C 1 -C 2 )alkyl substituents are also optionally substituted with from one to five fluorines;  
 R 4  is acetyl, formyll or (C 1 -C 6 )alkoxy;  
 R 5  and R 8  are hydrogen;  
 R 6  and R 7  are independently hydrogen, halo, (C 1 -C 2 )alkoxy or a saturated (C 1 -C 2 )alkyl chain wherein said (C 1 -C 2 )alkyl chain is optionally mono-, di- or tri-substituted independently with fluorines.  
 
   
   
       17 . A method according to  claim 1 , wherein said CETP inhibitor is [2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt of said compound.  
   
   
       18 . A method according to  claim 17 , wherein said antihypertensive agent is amlodipine besylate or a pharmaceutically acceptable salt thereof.  
   
   
       19 . A method of treating a disorder or condition selected from atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetaliproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal, including a human, comprising administering to said mammal: 
 a) [2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof; in combination with b) atorvastatin or a pharmaceutically acceptable salt thereof; and    c) amlodipine besylate or a pharmaceutically acceptable salt thereof, in amounts that render the active agents effective in the treatment of said disorder or condition.