Novel benzothiazepine and benzothiepine compounds

Abstract

A pharmaceutical useful as a therapeutic agent and a preventive agent for hyperlipemia, and a pharmaceutical useful as a therapeutic agent and a preventive agent for hepatic disorders associated with cholestasis, particularly, primary biliary cirrhosis and primary sclerosing cholangitis, and a pharmaceutical useful as a therapeutic agent and a preventive agent for obesity, fatty liver and steatohepatitis are provided. A benzothiazepine or benzothiepine compound represented by the following formula (1A) having a thioamide bond and a quaternary ammonium substituent:

1 . A composition comprising:
 a pharmaceutically acceptable carrier;   a therapeutic agent or preventive agent for coronary artery diseases; and   a compound represented by the following formula (1A):   
       
         
           
           
               
               
           
         
         wherein, 
         R 1a  and R 2a  may be the same as or different from each other and each represents alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms; 
         m a  is an integer of 0 to 4; 
         R x  represents halogen atom, nitro group, amino group, cyano group, hydroxy group, carboxy group, —NR 3 R 4  where R 3  and R 4  may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms, —CONH 2 , —SO 3 H, alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms, where the alkyl group, the alkenyl group and the alkynyl group may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidyl, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; one or more methylenes which constitute the alkyl group, the alkenyl group and the alkynyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO 2 —, —NHCO—, —NR 8a —, and —N + W a− R 9a R 10a —, 
         R 8a  represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms; the alkyl group and the alkenyl group in R 8a  may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxyl, 
         R 9a  and R 10a  may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms, and may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxyl, and 
         W a−  represents counteranion; 
         the combination of (A 1 , A 2 , A 3 ) represents (CH 2 , NH, CH), (CH 2 , CH(OH), CH), (NH, CH(OH), CH) or (CH 2 , CH 2 , N); 
         Y represents any of —NHCS—, —NHCSNH— or —NHCSO—, wherein —NH of —NHCS— represents a bond which binds to the adjacent benzene ring and CS— represents a bond which binds to the adjacent Z a , and —NH of —NHCSO— represents a bond which binds to the adjacent benzene ring and CSO— represents a bond which binds to the adjacent Z a ; 
         Z a —(N + R 5a R 6a R 7a ) n  represents an alkyl group or alkenyl group having 2 to 10 carbon atoms which is substituted with—N + R 5a R 6a R 7a , the number of the substituents being n; wherein one or more methylenes which constitute Z a  may be replaced with any of phenylene which may have a substituent or —O—; wherein the substituent(s) in the phenylene which may have the substituent are 1 to 4 substituents selected from the group consisting of alkyl groups having 1 to 5 carbon atoms, alkoxy groups having 1 to 5 carbon atoms, nitro group, halogen atoms, trifluoromethyl group and —CH 2 N +R   5a R 6a R 7a ; wherein the substituents may be the same as or different from each other; and wherein n is an integer of 1 or 2; and 
         each of N + R 5a R 6a R 7a  is independently any of the following I), II) or III): 
         I) R 5a , R 6a  and R 7a  may be the same as or different from one another, and each represents alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms; wherein the alkyl group, the alkenyl group and the alkynyl group may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidyl, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and wherein one or more methylenes which constitute the alkyl group, the alkenyl group and the alkynyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO 2 —, —NHCO—, —NR 8 —, and —N + W − R 9 R 10 —, 
         R 8  represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms, the alkyl group and the alkenyl group in R 8  may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxyl, 
         R 9  and R 10  may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms, and may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxyl, and 
         W −  represents a counteranion; 
         II) N +R   5a R 6a R 7a  represents a monocyclo or bicyclo ring formed of 4 to 9 carbon atoms in addition to the ammonium nitrogen atom, with a proviso that a position of binding to Z a  is the ammonium nitrogen atom; wherein, in the monocyclo and bicyclo rings, one of the carbon atoms which constitutes the ring may be replaced with any of oxygen, nitrogen or sulfur atom; and the monocyclo and bicyclo rings may be substituted with one or more groups of hydroxy, oxo, thioxo, cyano, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, carboxy, —CONH 2 , —SO 3 H and —R 11 , 
         R 11  represents alkyl group having 1 to 8 carbon atoms or alkenyl group having 2 to 8 carbon atoms, the alkyl group and the alkenyl group in R 11  may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidyl, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO 2 —, —NHCO—, —NR 8 —, and —N + W − R 9 R 10 ; R 8 , R 9 , R 10  and W −  are the same as the above; and the group which is not involved in the formation of the monocyclo ring and the bicyclo ring in R 5a , R 6a  and R 7a  is the same as the above I); and 
         III) N + R 5a R 6a R 7a  represents a pyridinium ring, a quinolinium ring or an isoquinolinium ring with a proviso that a position of binding to Z a  is the ammonium nitrogen atom; wherein the pyridinium ring, the quinolinium ring and the isoquinolinium ring may be substituted with one or more groups of cyano, nitro, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 5 carbon atoms, carboxy, —CONH 2 , —SO 3 H, halogen, hydroxy, tetrahydropyranyl and —R 12a , 
         R 12a  represents alkyl group having 1 to 9 carbon atoms or alkenyl group having 2 to 9 carbon atoms, the alkyl group and the alkenyl group in R 12a  may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —S—, —O—, —CO 2 —, —NHCO—, —NR 8 —, and —N + W − R 9 R 10 —; 
         R 8 , R 9 , R 10  and W −  are the same as the above; and 
         X −  represents a counteranion. 
       
     
     
         2 . The composition according to  claim 1 , wherein the therapeutic agent or preventive agent for coronary artery diseases is a cholesterol lowering agent. 
     
     
         3 . The composition according to  claim 2  wherein the cholesterol lowering agent is one or more selected from a 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a fibrate drug, a cholesterol absorption inhibitor, a bile acid absorber, probucol, AGI-1067, nicotinic acid and a derivative thereof, a microsomal transfer protein (MTP) inhibitor, an acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitor, a cholesterol ester transfer protein (CETP) inhibitor, a squalene synthase inhibitor, a peroxisome proliferator-activated receptor (PPAR) agent and phytosterol. 
     
     
         4 . The composition according to  claim 3  wherein the cholesterol lowering agent is the HMG-CoA reductase inhibitor. 
     
     
         5 . The composition according to  claim 4  wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin, fluvastatin, lovastatin, atorvastatin, rosuvastatin and pitavastatin. 
     
     
         6 . The composition according to  claim 3  wherein the cholesterol lower agent is both the HMG-CoA reductase inhibitor and the cholesterol absorption inhibitor. 
     
     
         7 . The composition according to  claim 6  wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin, fluvastatin, lovastatin, atorvastatin, rosuvastatin and pitavastatin, and the cholesterol absorption inhibitor is ezetimibe. 
     
     
         8 . A composition comprising:
 a pharmaceutically acceptable carrier;   a therapeutic agent or preventive agent for coronary artery diseases; and   a compound represented by the following formula (1B):   
       
         
           
           
               
               
           
         
         wherein, 
         R 1  and R 2  may be the same as or different from each other, and each represents alkyl group having 1 to 10 carbon atoms; 
         m is an integer of 1 or 2; 
         R 3  and R 4  may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms; 
         the combination of (A 1 , A 2 , A 3 ) represents (CH 2 , NH, CH), (CH 2 , CH(OH), CH), (NH, CH(OH), CH) or (CH 2 , CH 2 , N); 
         Y represents any of —NHCS—, —NHCSNH— or —NHCSO—, wherein —NH of —NHCS— represents a bond which binds to the adjacent benzene ring and CS— represents a bond which binds to the adjacent Z a , and —NH of —NHCSO— represents a bond which binds to the adjacent benzene ring and CSO— represents a bond which binds to the adjacent Z a ; 
         Z a —(N + R 5a R 6a R 7a ) n  represents an alkyl group or alkenyl group having 2 to 10 carbon atoms which is substituted with —N + R 5a R 6a R 7a , the number of the substituents being n; wherein one or more methylenes which constitute Z a  may be replaced with any of phenylene which may have a substituent or —O—; wherein the substituent(s) in the phenylene which may have the substituent are 1 to 4 substituents selected from the group consisting of alkyl groups having 1 to 5 carbon atoms, alkoxy groups having 1 to 5 carbon atoms, nitro group, halogen atoms, trifluoromethyl group and —CH 2 N + R 5a R 6a R 7a ; wherein the substituents may be the same as or different from each other; and wherein n is an integer of 1 or 2; and 
         each of N + R 5a R 6a R 7a  is independently any of the following I), II) or III): 
         I) R 5a , R 6a  and R 7a  may be the same as or different from one another, and each represents alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms; wherein the alkyl group, the alkenyl group and the alkynyl group may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidyl, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and wherein one or more methylenes which constitute the alkyl group, the alkenyl group and the alkynyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO 2 —, —NHCO—, —NR 8 —, and —N + W − R 9 R 10 —, 
         R 8  represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms, the alkyl group and the alkenyl group in R 8  may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxyl, 
         R 9  and R 10  may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms, and may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxyl, and 
         W −  represents a counteranion; 
         II) N + R 5a R 6a R 7a  represents a monocyclo or bicyclo ring formed of 4 to 9 carbon atoms in addition to the ammonium nitrogen atom, with a proviso that a position of binding to Z a  is the ammonium nitrogen atom; wherein, in the monocyclo and bicyclo rings, one of the carbon atoms which constitutes the ring may be replaced with any of oxygen, nitrogen or sulfur atom; and the monocyclo and bicyclo rings may be substituted with one or more groups of hydroxy, oxo, thioxo, cyano, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, carboxy, —CONH 2 , —SO 3 H and —R 11 , 
         R 11  represents alkyl group having 1 to 8 carbon atoms or alkenyl group having 2 to 8 carbon atoms, the alkyl group and the alkenyl group in R 11  may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidyl, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO 2 —, —NHCO—, —NR 8 —, and —N + W − R 9 R 10 ; R 8 ; R 9 , R 10  and W −  are the same as the above; and the group which is not involved in the formation of the monocyclo ring and the bicyclo ring in R 5a , R 6a  and R 7a  is the same as the above I); and 
         III) N + R 5a R 6a R 7a  represents a pyridinium ring, a quinolinium ring or an isoquinolinium ring with a proviso that a position of binding to Z a  is the ammonium nitrogen atom; wherein the pyridinium ring, the quinolinium ring and the isoquinolinium ring may be substituted with one or more groups of cyano, nitro, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 5 carbon atoms, carboxy, —CONH 2 , —SO 3 H, halogen, hydroxy, tetrahydropyranyl and —R 12a , 
         R 12a  represents alkyl group having 1 to 9 carbon atoms or alkenyl group having 2 to 9 carbon atoms, the alkyl group and the alkenyl group in R 12a  may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —S—, —O—, —CO 2 —, —NHCO—, —NR 8 —, and —N + W − R 9 R 10 —; 
         R 8 , R 9 , R 10  and W −  are the same as the above; and 
         X −  represents a counteranion. 
       
     
     
         9 . The composition according to  claim 8 , wherein the therapeutic agent or preventive agent for coronary artery diseases is a cholesterol lowering agent. 
     
     
         10 . The composition according to  claim 9  wherein the cholesterol lowering agent is one or more selected from a 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a fibrate drug, a cholesterol absorption inhibitor, a bile acid absorber, probucol, AGI-1067, nicotinic acid and a derivative thereof, a microsomal transfer protein (MTP) inhibitor, an acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitor, a cholesterol ester transfer protein (CETP) inhibitor, a squalene synthase inhibitor, a peroxisome proliferator-activated receptor (PPAR) agent and phytosterol. 
     
     
         11 . The composition according to  claim 10  wherein the cholesterol lowering agent is the HMG-CoA reductase inhibitor. 
     
     
         12 . The composition according to  claim 11  wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin, fluvastatin, lovastatin, atorvastatin, rosuvastatin and pitavastatin. 
     
     
         13 . The composition according to  claim 10  wherein the cholesterol lowering agent is both the HMG-CoA reductase inhibitor and the cholesterol absorption inhibitor. 
     
     
         14 . The composition according to  claim 13  wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin, fluvastatin, lovastatin, atorvastatin, rosuvastatin and pitavastatin, and the cholesterol absorption inhibitor is ezetimibe. 
     
     
         15 . A composition comprising:
 a pharmaceutically acceptable carrier;   a therapeutic agent or preventive agent for coronary artery diseases; and   a compound represented by the following formula (1):   
       
         
           
           
               
               
           
         
         wherein, 
         R 1  and R 2  may be the same as or different from each other, and each represents alkyl group having 1 to 10 carbon atoms; 
         m is an integer of 1 or 2; 
         R 3  and R 4  may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms; 
         Y represents any of —NHCS—, —NHCSNH— or —NHCSO—, wherein —NH of —NHCS— represents a bond of binding to the adjacent benzene ring and CS— represents a bond of binding to the adjacent Z, and —NH of —NHCSO— represents a bond of binding to the adjacent benzene ring and CSO— represents a bond of binding to the adjacent Z; 
         Z—(N + R 5 R 6 R 7 ) n  represents alkyl or alkenyl having 2 to 10 carbon atoms which is substituted with —N + R 5 R 6 R 7 , the number of the substituent being n, and one or more methylenes which constitute Z may be replaced with any of phenylene or —O—; and wherein n is an integer of 1 or 2; and 
         each of N + R 5 R 6 R 7  is independently any of the following I), II) or III): 
         I) R 5 , R 6  and R 7  may be the same as or different from one another, and each represents alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms; wherein the alkyl group, the alkenyl group and the alkynyl group may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidyl, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and wherein one or more methylenes which constitute the alkyl group, the alkenyl group and the alkynyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO 2 —, —NHCO—, —NR 8 —, and —N + W − R 9 R 10 —; and 
         R 8 , R 9 , R 10  and W −  are the same as the above; 
         II) N + R 5 R 6 R 7  represents a monocyclo or bicyclo ring formed of 4 to 9 carbon atoms in addition to the ammonium nitrogen atom, with a proviso that a position of binding to Z is the ammonium nitrogen atom; wherein, in the monocyclo and bicyclo rings, one of the carbon atoms which constitutes the ring may be replaced with any of oxygen, nitrogen or sulfur atom; and the monocyclo and bicyclo rings may be substituted with one or more groups of hydroxy, oxo, thioxo, cyano, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, carboxy, —CONH 2 , —SO 3 H and —R 11 , 
         R 11  is the same as the above); and 
         the group which is not involved in the formation of the monocyclo ring and the bicyclo ring in R 5 , R 6  and R 7  is the same as the above I); and 
         III) N + R 5 R 6 R 7  represents a pyridinium ring, a quinolinium ring or an isoquinolinium ring, with a proviso that a position of binding to Z is the ammonium nitrogen atom; wherein the pyridinium ring, the quinolinium ring and the isoquinolinium ring may be substituted with one or more groups of cyano, nitro, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 5 carbon atoms, carboxy, —CONH 2 , —SO 3 H, and —R 12 , 
         R 12  represents alkyl group having 1 to 9 carbon atoms or alkenyl group having 2 to 9 carbon atoms, the alkyl group and the alkenyl group in R 12  may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH 2  and —SO 3 H; and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —S—, —CO 2 —, —NHCO—, —NR—, and —N + W − R 9 R 10 —; and R 8 , R 9 , R 10  and W −  are the same as the above; and 
         X −  represents a counteranion. 
       
     
     
         16 . The composition according to  claim 15  wherein the therapeutic agent or preventive agent for coronary artery diseases is a cholesterol lowering agent. 
     
     
         17 . The composition according to  claim 16  wherein the cholesterol lowering agent is one or more selected from a 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a fibrate drug, a cholesterol absorption inhibitor, a bile acid absorber, probucol, AGI-1067, nicotinic acid and a derivative thereof, a microsomal transfer protein (MTP) inhibitor, an acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitor, a cholesterol ester transfer protein (CETP) inhibitor, a squalene synthase inhibitor, a peroxisome proliferator-activated receptor (PPAR) agent and phytosterol. 
     
     
         18 . The composition according to  claim 17  wherein the cholesterol lowering agent is the HMG-CoA reductase inhibitor. 
     
     
         19 . The composition according to  claim 18  wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin, fluvastatin, lovastatin, atorvastatin, rosuvastatin and pitavastatin. 
     
     
         20 . The composition according to  claim 17  wherein the cholesterol lowering agent is both the HMG-CoA reductase inhibitor and the cholesterol absorption inhibitor. 
     
     
         21 . The composition according to  claim 20  wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin, fluvastatin, lovastatin, atorvastatin, rosuvastatin and pitavastatin, and the cholesterol absorption inhibitor is ezetimibe. 
     
     
         22 . A composition comprising:
 a pharmaceutically acceptable carrier; and   a compound represented by the following formula (III):   
       
         
           
           
               
               
           
         
         wherein (sp) is the following formula (sp-14) 
       
       
         
           
           
               
               
           
         
         wherein *a binds to —NHCSNH— and *b binds to (an); and 
         (an) is the following formula (an-288); 
       
       
         
           
           
               
               
           
         
       
       with the HMG-CoA reductase 
     
     
         23 . The composition according to  claim 22  wherein the HMG-CoA reductase inhibitor is pravastatin. 
     
     
         24 . A composition comprising:
 a pharmaceutically acceptable carrier; and   a compound represented by the following formula (1):   
       
         
           
           
               
               
           
         
         wherein (sp) is the following formula (sp-14) 
       
       
         
           
           
               
               
           
         
         wherein *a binds to —NHCSNH— and *b binds to (an); and 
         (an) is the following formula (an-288); 
       
       
         
           
           
               
               
           
         
       
       with the HMG-CoA reductase inhibitor. 
     
     
         25 . The composition according to  claim 24  wherein the HMG-CoA reductase inhibitor is pravastatin.