Substituted Heterocyclic Compounds

Abstract

Disclosed are novel heterocyclic compounds having the structure which are useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, and myocardial infarction. The compounds are also useful in the treatment of diabetes.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  and R 2  are independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;  
 A is —(CR 9 R 10 ) m —; in which m is 1 or 2; and  
 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 , are independently hydrogen, optionally substituted lower alkyl, or —C(O)R;  
 in which R is —OR 11  or —NR 11 R 12 , where R 11  and R 12  are hydrogen or optionally substituted lower alkyl; or  
 R 3  and R 4 , R 5  and R 6 , R 7  and R 8 , R 9  and R 10 , when taken together with the carbon to which they are attached, represent carbonyl; or  
 R 3  and R 7 , or R 3  and R 9 , or R 3  and R 11 , or R 5  and R 7 , when taken together form a bridging group —(CR 13 R 14 ) n —, in which n is 1, 2 or 3, and R 13  and R 14  are independently hydrogen or optionally substituted lower alkyl;  
 with the proviso that the maximum number of carbonyl groups is 1;  
 the maximum number of —C(O)NR 11 R 12  groups is 1; and  
 the maximum number of bridging groups is 1;  
 T is oxygen or sulfur;  
 X is a covalent bond or —(CR 15 R 16 ) p —, in which R 15  and R 16  are hydrogen, optionally substituted lower alkyl, or —C(O)OR 17  and p is 1, 2 or 3, in which R 17  is hydrogen, optionally substituted lower alkyl, or optionally substituted phenyl;  
 Y 1  and Y 2  are independently —(CR 18 R 19 ) q —, in which q is 1, 2 or 3 and R 18  and R 19  are independently hydrogen, hydroxy, or optionally substituted lower alkyl; with the proviso that R 18  and R 19  are not hydroxy when q is 1; and  
 Z is a covalent bond, —C(O)NR 20 —, or —NR 20 C(O)—, where R 20  is hydrogen or optionally substituted lower alkyl; or  
 Y 2  and Z taken together are a covalent bond;  
 with the proviso, that when R 1  and R 2  are optionally substituted phenyl and X is a covalent bond,  
 Z is not a covalent bond.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is optionally substituted aryl and R 2  is optionally substituted aryl or optionally substituted cycloalkyl.  
     
     
         3 . The compound of  claim 2 , wherein X is a covalent bond and T is oxygen.  
     
     
         4 . The compound of  claim 3 , wherein Y 1  and Y 2  are lower alkylene.  
     
     
         5 . The compound of  claim 4 . wherein Y 1  is methylene or ethylene and Y 2  is methylene.  
     
     
         6 . The compound of  claim 5 , wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are hydrogen and A is methylene.  
     
     
         7 . The compound of  claim 6 , wherein Z is a covalent bond.  
     
     
         8 . The compound of  claim 7 , wherein R 1  is optionally substituted phenyl and R 2  is optionally substituted cyclohexyl.  
     
     
         9 . The compound of  claim 8 , wherein R 1  is 2,6-dimethylphenyl, R 2  is cyclohexyl, and Y 1  is methylene, namely N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]acetamide.  
     
     
         10 . The compound of  claim 7 , wherein R 1  and R 2  are both optionally substituted phenyl.  
     
     
         11 . The compound of  claim 10 , wherein R 1  is 2,6-dimethylphenyl.  
     
     
         12 . The compound of  claim 11 , wherein R 2  is 4-methoxyphenyl and Y 1  is ethylene, namely N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-1-yl}acetamide.  
     
     
         13 . The compound of  claim 11 , wherein R 2  is 2-methoxyphenyl and Y 1  is ethylene, namely N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazinyl}acetamide.  
     
     
         14 . The compound of  claim 6 , wherein Z is —C(O)NR 20 —, in which R 20  is hydrogen.  
     
     
         15 . The compound of  claim 14 , wherein R 1  and R 2  are both optionally substituted phenyl.  
     
     
         16 . The compound of  claim 15 , wherein R 1  is 2,6-dimethylphenyl, R 2  is 2-fluorophenyl, and Y 1  is methylene, namely 4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-fluorophenyl)butanamide.  
     
     
         17 . The compound of  claim 6 , wherein Z is —NR 20 C(O)—, in which R 20  is hydrogen.  
     
     
         18 . The compound of  claim 17 , wherein R 1  and R 2  are both optionally substituted phenyl.  
     
     
         19 . The compound of  claim 18 , wherein R 1  is 2,6-dimethylphenyl, R 2  is 2-fluorophenyl, and Y 1  is methylene, namely N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide.  
     
     
         20 . A method of treating a disease state chosen from diabetes, damage to skeletal muscles resulting from trauma or shock and a cardiovascular disease in a mammal by administration of a therapeutically effective dose of a compound of  claim 1 .  
     
     
         21 . The method of  claim 20 , wherein the cardiovascular disease is atrial arrhythmia, intermittent claudication, ventricular arrhythmia, Prinzmetal's (variant) angina, stable angina, unstable angina, congestive heart disease, or myocardial infarction.  
     
     
         22 . The method of  claim 21 , wherein the disease state is diabetes.  
     
     
         23 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1.