Substituted dihydropyrimidines, dihydropyrimidones and dihydropyrimidinethiones as calcuim channel blockers

Abstract

The present invention is directed in part towards methods of modulating the function of calcium channels with pyrimidine-based compounds. In addition, the invention describes methods of preventing and treating calcium channel-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to pyrimidine-based compounds and pharmaceutical compositions comprising these compounds.

What is claimed is:  
     
         1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein 
 a) R 1 -R 3  and R 5 -R 8 , are each independently selected from the group consisting of hydrogen, halogen, perhaloalkyl, nitro, amino, a diazo salt, optionally substituted lower alkyl, alkoxy, optionally substituted lower alkylene and optionally substituted five-membered or optionally substituted six-membered heteroaryl ring or optionally substituted six-membered aryl or heteroaryl ring, wherein 
 said lower alkyl and said lower alkylene moieties are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, perhaloalkyl, nitro, amino, hydroxy, alkoxy, sulfhydryl, thioether, cyano, amido, ester, and  
                     
 A is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfone, and —NH;  
 R 12  is selected from the group consisting of hydrogen, hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro, amino, and a diazo salt;  
 n is between 0-4; and  
 said ring moieties are each independently and optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylene,  
 
 b) R 9  is selected from the group consisting of hydrogen, alkyl, alkylene, and a five-membered or six-membered heteroaryl ring or a six-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro, amino, cyano, amido, and ester; and  
 c) R 10  is selected from the group consisting of hydrogen and lower alkyl  
 d) R 11  is selected from the group consisting of: 
 i) hydrogen, alkyl, alkoxy, alkylene, and a five-membered or six-membered heteroaryl ring or a six-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylene, halogen, perhaloalkyl, nitro, amino, cyano, amido, and ester;  
 ii) COY wherein Y is C 1 -C 8  alkyl, C 1 -C 8  alkoxy or NR 13 R 14 , wherein R 13  is hydrogen or C 1 -C 8  alkyl and R 14  is hydrogen, C 1 -C 8  alkyl, or C 1 -C 14  phenalkyl;  
 iii) X or COX wherein X is  
                     
 iv) halogen, CF 3 , cyano, nitro, COONHR 25 , COON(R 25 ) 2 , COOSO 2 R 28 , COONR 25 SO 2 N(R 25 ) 2 , CO 2 R 25 , COON(R 25 ) 2 , COQSO 2 N(R 25 ) 2 , COOSO 2 R 28 .  
 v) CONR 15 R 16 , wherein R 15  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R 16  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, or halosubstituted alkyl, or R 15  and R 16  taken together with the nitrogen atom to which they are attached form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-diarylalkyl-1-piperazinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, alkylthio, halo, trifloromethyl, or hydroxy;  
 vi) Z, COOZ, or C(O)(NH)Z, wherein Z is selected from the group consisting of  
                     
  wherein 
 A) p and q are each independently 0-10;  
 B) R 20  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CF 3 , cyano, nitro, N(R 25 ) 2 , NR 25 CONR 27 , NR 25 CON(R 27 ) 2 , NR 25 SO 2 R 28 , NR 25 SO 2 N(R 27 ) 2 , (CH 2 ) 0-4 CO 2 R 25 , (CH 2 ) 0-4 CON(R 25 ) 2 , (CH 2 ) 0-4 SO 2 N(R 25 ) 2 , (CH 2 ) 0-4 SO 2 R 28 , and C 1-4  alkyl;  
 C) R 21  is selected from the group consisting of hydrogen, cyano, OR 28 , COOR 25 , CON(R 25 ) 2 , and phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CF 3 , cyano, nitro, N(R 25 ) 2 , NR 25 CONR 27 , NR 25 CON(R 27 ) 2 , NR 25 SO 2 R 28 , NR 25 SO 2 N(R 27 ) 2 , (CH 2 ) 0-4 CO 2 R 25 , (CH 2 ) 0-4 CON(R 25 ) 2 , (CH 2 ) 0-4 SO 2 N(R 25 ) 2 , (CH 2 ) 0-4 SO 2 R 28 , and C 1-4  alkyl;  
 D) R 25  and R 27  are each independently selected from hydrogen, C 1-8  alkyl, C 3-8  cycloalkyl, (CH 2 ) 0-4 CF 3 ; and  
 E) R 28  is selected from the group consisting of hydrogen, C 1-8  alkyl, C 3-8  cycloalkyl, and (CH 2 ) 0-4 CF 3 ;  
 
 
 e) X is oxygen or sulfur; and  
 f) Q is oxygen or nitrogen; provided that when Q is oxygen R 3  does not exist.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is hydrogen or optionally substituted lower alkyl.  
     
     
         3 . The compound of  claim 1 , wherein R 1  is optionally substituted lower alkyl.  
     
     
         4 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, and  
       
         
           
           
               
               
           
         
       
       where A is selected from the group consisting of oxygen, sulfur, and —NH and R 12  is selected from the group consisting of hydrogen, hydroxy, alkoxy, haloalkoxy, halogen, haloalkyl, perhaloalkyl, nitro, amino, and a diazo salt, and n is between 0-4.  
     
     
         5 . The compound of  claim 1 , wherein R 2  and R 3  are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and pentyl.  
     
     
         6 . The compound of  claim 1 , wherein R 5  is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and pentyl.  
     
     
         7 . The compound of  claim 1 , wherein R 6 -R 8  are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and pentyl.  
     
     
         8 . The compound of  claim 1 , wherein R 9  is hydrogen or alkyl.  
     
     
         9 . The compound of  claim 1 , wherein R 9  is pentadecyl.  
     
     
         10 . The compound of  claim 1 , wherein R 11  is selected from the group consisting of hydrogen, methoxy, ethoxy, and propoxy.  
     
     
         11 . The compound of  claim 1 , wherein R 11  is COY wherein Y is C 1 -C 8  alkyloxy or NR 13 R 14 , wherein R 13  is hydrogen or C 1 -C 8  alkyl and R 14  is hydrogen, C 1 -C 8  alkyl, or C 1 -C 14  phenalkyl.  
     
     
         12 . The compound of  claim 11 , wherein Y is ethoxy.  
     
     
         13 . The compound of  claim 11 , wherein R 13  and R 14  are each methyl.  
     
     
         14 . The compound of  claim 1 , wherein R 11  is X or COX.  
     
     
         15 . The compound of  claim 14 , wherein p is 0 or 2.  
     
     
         16 . The compound of  claim 1 , wherein R 11  is selected from the group consisting of, COONHR 25 , COON(R 25 ) 2 , COOSO 2 R 28 , COONR 25 SO 2 N(R 25 ) 2 , CO 2 R 25 , COON(R 25 ) 2 , COOSO 2 N(R 25 ) 2 , and COOSO 2 R 28 .  
     
     
         17 . The compound of  claim 1 , wherein R 11  is Z, COOZ, or C(O)(NH)Z.  
     
     
         18 . The compound of  claim 17 , wherein p and q are each independently 0 or 2.  
     
     
         19 . The compound of  claim 1 , wherein R 20  is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CF 3 , cyano, nitro, N(R 25 ) 2 , NR 25 CONR 27 , NR 25 CON(R 27 ) 2 , NR 25 SO 2 R 28 , NR 25 SO 2 N( 27 ) 2 , (CH 2 ) 0-4 CO 2 R 25 , (CH 2 ) 0-4 CON(R 25 ) 2 , (CH 2 ) 0-4 SO 2 N(R 25 ) 2 , (CH 2 ) 0-4 SO 2 R 28 , and C 1-4  alkyl.  
     
     
         20 . The compound of  claim 19 , wherein said halogen is fluorine.  
     
     
         21 . The compound of  claim 19 , wherein said phenyl is substituted with —COOCH 3 .  
     
     
         22 . The compound of  claim 1 , wherein the moiety —C(O)QR 2 R 3  is —C(O)NH 2 .  
     
     
         23 . The compound of  claim 1 , wherein Q is oxygen and R 3  does not exist.  
     
     
         24 . A compound selected from the group consisting of 
 5-ethoxycarbonyl-4-(2-ethoxy-6-pentadecylphenyl)-6-methyl-2′-mercapro-H-benzimidazolyl)methyl-3,4-dihydropyrimidin-2(1H)-one;    5-ethoxycarbonyl-4-(2-methoxy-6-pentadecylphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-ethoxy-6-pentadecylphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-methoxy-6-pentadecylphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-ethoxycarbonyl-4-(2-ethoxy-6-pentadecylphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-methoxy-6-(8′Z, 11′Z, 14′Z)pentadecatrienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-methoxy-6-(8′Z, 11′Z)pentadecadienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-methoxy-6-(8′Z)pentadecenyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-ethoxycarbonyl-4-(2-ethoxy-6-(8′Z, 11′Z, 14′Z)pentadecatrienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-ethoxycarbonyl-4-(2-ethoxy-6-(8′Z, 11′Z)pentadecadienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-ethoxycarbonyl-4-(2-ethoxy-6-(8′Z)pentadecenyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-ethoxy-6-(8′Z, 11′Z, 14′Z)pentadecatrienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-ethoxy-6-(8′Z, 11′Z)pentadecadienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-methoxycarbonyl-4-(2-ethoxy-6-(8′Z)pentadecenyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-isopropoxycarbonyl-4-(2-ethoxy-6-(8′Z, 11′Z, 14′Z)pentadecatrienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-isopropoxycarbonyl-4-(2-ethoxy-6-(8′Z, 11′Z)pentadecadienyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    5-isopropoxycarbonyl-4-(2-ethoxy-6-(8′Z)pentadecenyl phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one;    3,6-dihydro-4-methyl-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1-ethyl 5-methyl diester;    3,6-dihydro-4-methyl-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid bis (ethyl ester);    3,6-dihydro-4-methyl-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1-ethyl 5-isopropyl diester;    3,6-dihydro-4-methyl-6-[2-ethoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1-ethyl 5-methyl diester;    3,6-dihydro-4-methyl-6-[2-ethoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1,5-diethyl diester;    3,6-dihydro-4-methyl-6-[2-ethoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1-ethyl 5-isopropyl diester;    3,6-dihydro-4-methyl-6-[2-isopropoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1-ethyl 5-methyl diester;    3,6-dihydro-4-methyl-6-[2-isopropoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1,5-diethyl diester;    3,6-dihydro-4-methyl-6-[2-isopropoxy-6-pentadecylphenyl]-2-oxo-1,5-(2H)-pyrimidinedicarboxylic acid 1-ethyl, 5-isopropyl diester;    3,6-dihydro-4-methyl-6-(2-methoxy-6-pentadecylphenyl)-2-thioxo-1,5(2H)-pyrimidinedicarboxylic acid bis (ethyl ester);    3,6-dihydro-4-methyl-6-(2-ethoxy-6-pentadecylphenyl)-2-thioxo-1,5(2H)-pyrimidinedicarboxylic acid bis (ethyl ester);    3,6-dihydro-4-methyl-6-(2-isopropoxy-6-pentadecylphenyl)-2-thioxo-1,5(2H)-pyrimidinedicarboxylic acid bis (ethyl ester);    3,6-dihydro-4-methyl-6-(2-methoxy-6-dodecylphenyl)-2-thioxo-1,5(2H)-pyrimidinedicarboxylic acid bis (ethyl ester);    3,6-dihydro-4-methyl-6-(2-ethoxy-6-dodecylphenyl)-2-thioxo-1,5(2H)-pyrimidinedicarboxylic acid bis (ethyl ester);    3,6-dihydro-4-methyl-6-(2-isopropoxy-6-dodecylphenyl)-2-thioxo-1,5(2H)-pyrimidinedicarboxylic acid bis (ethyl ester);    3,6-dihydro-4-methyl-2-thioxo-6-[2-isopropoxy-6-pentadecylphenyl]-1,5(2H)-pyrimidinedicarboxylic acid 5-ethyl]-[1-(phenylmethyl)-4-piperidinyl]ester mono hydrochloride;    3,6-dihydro-4-methyl-2-thioxo-6-[2-ethoxy-6-pentadecylphenyl]-1,5(2H)-pyrimidinedicarboxylic acid 5-ethyl1-[1-(phenylmethyl)-4-piperidinyl]ester mono hydrochloride;    1,2,3,4-tetrahydro-6-methyl-4-[2-methoxy-6-pentadecylphenyl]-3-(1-oxo-propyl)2-thioxo-5-pyrimidinecarboxylic acid ethyl ester;    1,2,3,4-tetrahydro-6-methyl-4-[2-ethoxy-6-pentadecylphenyl]-3-(1-oxo-propyl)2-thioxo-5-pyrimidinecarboxylic acid ethyl ester;    1,2,3,4-tetrahydro-6-methyl-4-[2-isopropoxy-6-pentadecylphenyl]-3-(1-oxo-propyl)-2-tthioxo-5-pyrimidinecarboxylic acid ethyl ester;    1-[(dimethyl amino)carbonyl]-1,2,3,6-tetrahydro-4-methyl-6-[2-methoxy-6-pentadecylphenyl]-2-thioxo-5-pyrimidinecarboxylic acid ethyl ester;    1-[(dimethyl amino)carbonyl]-1,2,3,6-tetrahydro-4-methyl-6-[2-ethoxy-6-pentadecylphenyl]-2-thioxo-5-pyrimidinecarboxylic acid ethyl ester;    1-[(dimethyl amino)carbonyl]-1,2,3,6-tetrahydro-4-methyl-6-[2-isopropoxy-6-pentadecylphenyl]-2-thioxo-5-pyrimidinecarboxylic acid ethyl ester;    3,6-dihydro-4-methyl-2-thioxo-6-[2-methoxy-6-pentadecylphenyl)]-1,5(2H)-pyrimidinedicarboxylic acid, 5-ethyl-1-[1-(phenmethyl)-4-piperidinyl]ester, monohydrochloride;    3,6-dihydro-4-methyl-2-thioxo-6-[2-methoxy-6-pentadecylphenyl)]-1,5(2H)-pyrimidinedicarboxylic acid, 5-(1-methylethyl)1-[1-(phenmethyl)-4-piperidinyl]ester, monohydrochloride;    3,6-dihydro-4-methyl-2-thioxo-6-[2-ethoxy-6-pentadecylphenyl]-1,5(2H)-pyrimidinedicarboxylic acid, 5-(1-methylethyl) 1-[1-(phenylmethyl)-4-piperidinyl]ester, monohydrochloride;    3,6-dihydro-4-methyl-2-thioxo-6-[2-ethoxy-3,5-dinitro-6-pentadecylphenyl]1,5(2H)-pyrimidinedicarboxylic acid, 5-(1-methylethyl) 1-[1-(phenylmethyl)-4-piperidinyl]ester, monohydrochloride;    1,2,3,6-Tetrahydro-4-methyl-1-[3-[methyl(phenylmethyl)amino]propyl]-2-thioxo6-[2-metoxy-6-pentadecylphenyl]-5-pyrimidinedicarboxylic acid, 1-methylethyl ester, monohydrochloride;    1,2,3,6-Tetrahydro-4-methyl-1-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-2-thioxo-6-[2-methoxy-6-pentadecylphenyl]-5-pyrimidinedicarboxylic acid, 1-methylethyl ester, monohydrochloride;    3,6-dihydro-4-methyl-2-thioxo-6-[2-ethoxy-6-pentadecylphenyl]-1,5(2H)-pyrimidinedicarboxylic acid, 1-[1-[(4-florophenyl)methyl]-4-piperidinyl]5-(1-methylethyl)ester, monohydrochloride;    4-ethyl-5-methoxycarbonyl-1-{N-[3-[4-(4-methoxycarbonyl)-4-phenylpiperidin-1-yl]propyl]carboxyamido}-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine;    4-ethyl-5-methoxycarbonyl-1-{N-[3-[4-(4-methoxycarbonyl)-4-phenylpiperidin-1-yl]propyl]carboxyamido}-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine;    5-carboxamido-4-ethyl-1-{N-[-[3-(4-methoxycarbonylphenylpiperidin-1-yl)-propyl]carboxamido}-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine;    4-ethyl-5-(N-methylcarboxamido)-1-{N-[3-(4-methoxycarbonylphenylpiperidin-1-yl)propyl]carboxamido}-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine;    5-methoxycarbonyl-1-{N-[3-[4-(4-methoxycarbonyl)-4-phenylpiperidin-1-yl]propyl]carboxamido}-4-methyl-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine;    5-ethoxycarbonyl-1-{N-[3-[4-(4-methoxycarbonyl)-4-phenylpiperidin-1-yl]propyl]carboxamido}-4-methyl-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine;    5-carboxamido-1-{N-[3-[4-(4-methoxycarbonyl)-4-phenylpiperidin-1-yl]propyl]carboxamido}-4-methyl-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine; and    1-{N-[3-[4-(4-methoxycarbonyl)-4-phenylpiperidin-1-yl]propyl]carboxamido}-4-methyl-5-(N-methylcarboxyamido)-6-[2-methoxy-6-pentadecylphenyl]-2-oxo-1,2,3,6-tetrahydropyrimidine.    
     
     
         25 . A method of modulating the activity of a calcium channel in a cell comprising the step of contacting said cell with a compound of  claim 1 .  
     
     
         26 . A method of treating a disease associated with a cellular calcium channel comprising: 
 a) identifying a subject in need of such treatment;    b) administering to said subject a therapeutically effective amount of a compound of  claim 1 .    
     
     
         27 . The method of  claim 26 , wherein said subject is a human.  
     
     
         28 . The method of  claim 26 , wherein said disease is a cardiovascular disease.  
     
     
         29 . A pharmaceutical composition comprising a compound of  claim 1 , and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.