Heteroaryl alkyl piperazine derivatives

Abstract

Novel compounds of the general formula: and pharmaceutically acceptable acid addition salts thereof, wherein the compounds are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, in the treatment of diabetes, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

We claim:  
     
         1 . A substituted piperazine compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 m is 1, 2, or 3;  
 q is —NH—, oxygen, or sulfur;  
 R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, CF 3 , OH, and C 1-15  straight or branched alkyl;  
 R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  and R 16  are each independently selected from the group consisting of hydrogen and C 1-4  straight or branched alkyl, and  
 R 17  is heteroaryl that is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, C 1-15  straight or branched alkyl, aryl, cycloalkyl, and CF 3 , wherein the aryl substituents are optionally substituted with 1 substituent selected from the group consisting of methyl, halo and CF 3 .  
 
     
     
         2 . The compound of  claim 1 , wherein m is 1 and q is oxygen;  
     
     
         3 . The compound of  claim 2 , wherein: 
 R 1 , R 3 , R 5 , R 11 , R 12 , R 14  are hydrogen or methyl; and    R 2 , R 4 , R 9 , R 10 , R 13 , R 15  and R 16  are hydrogen.    
     
     
         4 . The compound of  claim 3 , wherein R 1  and R 5  are methyl, R 3 , R 11 , R 12 , and R 14  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         5 . The compound of  claim 3 , wherein the enantiomer is 2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide.  
     
     
         6 . The compound of  claim 3 , wherein the enantiomer is 2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide.  
     
     
         7 . The compound of  claim 3 , wherein R 1  and R 5  are methyl, R 3 , R 11 , R 12 , and R 14  are hydrogen, and R 17  is 2-cyclohexylbenzothiazol-5-yl, namely 2-{4-[3-(2-cyclohexylbenzothiazol-5-yloxy)-2-hydroxypropyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         8 . The compound of  claim 3 , wherein R 1  and R 5  are methyl, R 3 , R 11 , R 12 , and R 14  are hydrogen, and R 17  is 2-(3-trifluoromethylphenyl)-benzoxazol-5-yl, namely (±)-2-[4-(2-hydroxy-3-{2-[3-(trifluoromethyl)phenyl]-benzoxazol-5-yloxy}propyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         9 . The compound of  claim 3 , wherein R 1  and R 5  are methyl, R 3 , R 11 , R 12  and R 14  are hydrogen, and R 17  is 2-(2-chlorophenyl)benzoxazol-5-yl, namely (±)-2-(4-{3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         10 . The compound of  claim 3 , wherein R 1  and R 5  are methyl, R 3 , R 11 , R 12  and R 14  are hydrogen, and R 17  is 2-propylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-propylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         11 . The compound of  claim 3 , wherein R 1  and R 5  are methyl, R 12  and R 14  represent cis dimethyl, R 3  and R 11  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methylbenzothiazole-5-yloxy)propyl]-3,5-cis dimethylpiperazinyl}acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         12 . The compound of  claim 11 , wherein the diastereoisomer is N-(2,6-dimethylphenyl)-2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazole-5-yloxy)propyl]-3,5-cis dimethylpiperazinyl}acetamide.  
     
     
         13 . The compound of  claim 11 , wherein the diastereoisomer is N-(2,6-dimethylphenyl)-2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazole-5-yloxy)propyl]-3,5-cis dimethylpiperazinyl}acetamide.  
     
     
         14 . The compound of  claim 3 , wherein R 1 , R 5  and R 12  are methyl, R 3 , R 11 , and R 14  are hydrogen, and R 17  is 2-(3-fluorophenyl)benzoxazol-5-yl, namely (±)-2-(4-{3-[2-(3-fluorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}-3-methylpiperazinyl)-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         15 . The compound of  claim 14 , wherein the diastereoisomer is 2-((3R)-4-{(2S){3-[2-(3-fluorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}-3-methylpiperazinyl)-N-(2,6-dimethylphenyl)acetamide.  
     
     
         16 . The compound of  claim 14 , wherein the diastereoisomer is 2-((3S)-4-{(2S){3-[2-(3-fluorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}-3-methylpiperazinyl)-N-(2,6-dimethylphenyl)acetamide.  
     
     
         17 . The compound of  claim 14 , wherein the diastereoisomer is 2-((3R)-4-{(2R){3-[2-(3-fluorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}-3-methylpiperazinyl)-N-(2,6-dimethylphenyl)acetamide.  
     
     
         18 . The compound of  claim 14 , wherein the diastereoisomer is 2-((3S)-4-{(2R){3-[2-(3-fluorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}-3-methylpiperazinyl)-N-(2,6-dimethylphenyl)acetamide.  
     
     
         19 . The compound of  claim 3 , wherein R 1 , R 5  and R 12  are methyl, R 3 , R 11 , and R 14  are hydrogen, and R 17  is 2-methylbenzothiazol-6-yl, namely (±)-2-{(3R)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]-3-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         20 . The compound of  claim 3 , wherein R 1 , R 5  and R 12  are methyl, R 3 , R 11 , and R 14  are hydrogen, and R 17  is 2-(2-chlorophenyl)benzoxazol-5-yl, namely (±)-2-(4-{3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}-3-methylpiperazinyl)-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         21 . The compound of  claim 3 , wherein R 1 , R 5  and R 12  are methyl, R 3 , R 11 , and R 14  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         22 . The compound of  claim 3 , wherein R 1 , R 5 , R 11  and, R 12  are methyl, R 3  and R 14  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3,3-dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         23 . The compound of  claim 3 , wherein R 3  and R 12  are methyl, R 1 , R 5 , R 11 , and R 14  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]3-methylpiperazinyl}-N-(4-methylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         24 . The compound of  claim 2 , wherein R 3  is methyl, R 1 , R 5 , R 11 , R 12  and R 14  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-methylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         25 . The compound of  claim 2 , wherein: 
 R 1 , R 2 , R 3 , and R 4  are hydrogen, cyano, trifluoromethyl, or phenyl;    R 5 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15  and R 16  are hydrogen; and    R 12  is hydrogen or methyl.    
     
     
         26 . The compound of  claim 25 , wherein R 1 , R 2  and R 4  are hydrogen, R 3  is trifluoromethyl, R 12  is methyl, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-[4-(trifluoromethyl)phenyl]acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         27 . The compound of  claim 25 , wherein R 1 , R 2 , R 4  and R 12  are hydrogen, R 3  is trifluoromethyl, and R 17  is 2-(4-chlorophenyl)benzoxazol-5-yl, namely, (±)-2-(4-{3-[2-(4-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}piperazinyl)-N-[4-(trifluoromethyl)phenyl]acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         28 . The compound of  claim 25 , wherein R 1 , R 2 , R 4  and R 12  are hydrogen, R 3  is cyano, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-cyanophenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         29 . The compound of  claim 25 , wherein R is phenyl, R 2 , R 3 , R 4  and R 12  are hydrogen, and R 17  is 2-phenylbenzoxazol-5-yl, namely (±)-2-{4-[(2S)-2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]piperazinyl}-N-(2-phenylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         30 . The compound of  claim 25 , wherein R 2  is phenyl, R 1 , R 3 , R 4  and R 12  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazole-5-yloxy)propyl]piperazinyl}-N-(3-phenylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         31 . The compound of  claim 25 , wherein R 2  is phenyl, R 1 , R 2 , R 4  and R 12  are hydrogen, and R 17  is 2-phenylbenzoxazol-5-yl, namely (±)-2-{4-[(2S)-2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]piperazinyl}-N-(3-phenylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         32 . The compound of  claim 25 , wherein R 3  is phenyl, R 1 , R 2 , R 4  and R 12  are hydrogen, and R 17  is 2-phenylbenzoxazol-5-yl, namely (±)-2{4-[2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]piperazinyl}-N-(4-phenylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         33 . The compound of  claim 25 , wherein R 3  is phenyl, R 1 , R 2 , R 4  and R 12  are hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-phenylphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         34 . The compound of  claim 2 , wherein: 
 R 1 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  and R 16  are hydrogen; and    R 2  and R 3  are hydrogen or phenoxy optionally substituted with halo.    
     
     
         35 . The compound of  claim 34 , wherein R 3  is phenoxy, R 2  is hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazol-yloxy)propyl]piperazinyl}-N-(4-phenoxyphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         36 . The compound of  claim 34 , wherein R 3  is phenoxy, R 2  is hydrogen, and R 17  is 2-phenylbenzoxazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]piperazinyl}-N-(4-phenoxyphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         37 . The compound of  claim 34 , wherein R 3  is 4-chlorophenoxy, R 2  is hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[2-hydroxy-3-(2-methylbenzothiazole-5-yloxy)propyl]piperazinyl}-N-[4-(4-chlorophenoxy)phenyl]acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         38 . The compound of  claim 34 , wherein R 2  is phenoxy, R 3  is hydrogen, and R 17  is 2-phenylbenzoxazol-5-yl, namely (±)-2-{4-[(2S)-2-hydroxy-3-(2-phenylbenzoxazol-5-yloxy)propyl]piperazinyl}-N-(3-phenoxyphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         39 . The compound of  claim 34 , wherein R 2  is phenoxy, R 3  is hydrogen, and R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(3-phenoxyphenyl)acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         40 . The compound of  claim 2 , wherein: 
 R 1 , R 3 , R 4 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  and R 16  are hydrogen;    R 2  is hydroxymethyl; and    R 5  is methyl.    
     
     
         41 . The compound of  claim 40 , wherein R 17  is 4-chlorophenylbenzoxazol-5-yl, namely (±)-2-(4-{(2S)-3-[2-(4-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}piperazinyl)-N-[2-(hydroxymethyl)-6-methylphenyl]acetamide, or an enantiomer or diastereoisomer thereof  
     
     
         42 . The compound of  claim 40 , wherein R 17  is 2-methylbenzothiazol-5-yl, namely (±)-2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[2-(hydroxymethyl)-6-methylphenyl]acetamide, or an enantiomer or diastereoisomer thereof.  
     
     
         43 . A method of treating a disease state in a mammal that is alleviable by treatment with a partial fatty acid oxidation inhibitor, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 .  
     
     
         44 . The method of  claim 43 , wherein the disease state is damage to skeletal muscles resulting from trauma or shock, or a cardiovascular disease.  
     
     
         45 . The method of  claim 43 , wherein the cardiovascular disease is atrial arrhythmia, intermittent claudication, ventricular arrhythmia, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, or myocardial infarction.  
     
     
         46 . The method of  claim 43 , wherein the disease state is diabetes.  
     
     
         47 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1.