Substituted 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 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 having the following formula:  
       
         
           
           
               
               
           
         
       
       wherein m=1, 2, or 3; 
 R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2  S(O)R 22 , and SO 20 R 22 ;  
 R 6 , R 7  and R 8  each independently selected from the group consisting of hydrogen or C 1-3  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, CO 2 R 20 , CON(R 20 ) 2 , C 1-4  alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , CN, OR 20 , N(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2  or aryl, wherein R 9  and R 10  may together form a carbonyl, or R 11  and R 12  may together form a carbonyl, or R 13  and R 14  may together form a carbonyl, or R 15  and R 16  may together form a carbonyl with the proviso that R 11  and R 13  or R 9  and R 15  or R 9  and R 11  or R 11  and R 15  or R 9  and R 13  may join together to form a ring including from 1 to 3 carbon atoms;  
 R 17  is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C 1-2  alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 , CN, OR 20 , and C 1-6  alkyl;  
 R 20  is selected from the group consisting of H, C 1-15  alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl, CN, —O— C 1-6  alkyl, or CF 3 ; and  
 R 22  is selected from the group consisting of C 1-15  alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O—C 1-6  alkyl, CF 3 , or heteroaryl.  
 
 
     
     
         2 . The compound of  claim 1  wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , SO 2 N(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , C 1-8  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20  SR 20 , N(R 20 ) 2 , S(O)R 22 , or SO 2 R 22 ; 
 R 6 , R 7  and R 8  each independently selected from the group consisting of hydrogen or C 1-3  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, CON(R 20 ) 2 , C 1-4  alkyl, or wherein R 9  and R 10  may together form a carbonyl, or R 11  and R 12  may together form a carbonyl, or R 13  and R 14  may together form a carbonyl, or R 15  and R 16  may together form a carbonyl; and  
 R 20  is selected from the group consisting of H, C 1-15  alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkylcyano, —O—C 1-6  alkyl, or CF 3 .  
 
     
     
         3 . The compound of  claim 1  wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , C 1-5  alkyl, C 2-3  alkenyl, or C 2-3  alkynyl, wherein the alkyl substituent is optionally substituted with CF 3 ; 
 R 6 , R 7  and R 8  are each independently selected from the group consisting of hydrogen or C 1-3  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, CON(R 20 ) 2 , or C 1-4  alkyl wherein R 9  and R 10  may together form a carbonyl, or R 11  and R 12  may together form a carbonyl, or R 13  and R 14  may together form a carbonyl, or R 15  and R 16  may together form a carbonyl;  
 R 17  is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , C 1-2  alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 , CN, OR 20 , and C 1-6  alkyl; and  
 R 20  is selected from the group consisting of H, C 1-8  alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, —O—C 1-3  alkyl, or CF 3 .  
 
     
     
         4 . The compound of  claim 1  wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , C 1-3  alkyl, C 2-3  alkenyl, or C 2-3  alkynyl, wherein the alkyl is optionally substituted with CF 3 ; 
 R 6 , R 7  and R 8  each independently selected from the group consisting of hydrogen or methyl;  
 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 or C 1-2  alkyl, wherein R 9  and R 10  may together form a carbonyl, or R 11  and R 12  may together form a carbonyl, or R 13  and R 14  may together form a carbonyl, or R 15  and R 16  may together form a carbonyl;  
 R 17  is selected from the group consisting of alkyl , cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3 , OR 20 , S(O)R 22 , C 1-2  alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 , CN, OR 20 , and C 1-6  alkyl; and  
 R 20  is selected from the group consisting of H. C 1-5  alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, —OMe, or CF 3   
 
     
     
         5 . The compound of  claim 1  wherein m=1 or 2; 
 R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 22  and C 1-4  alkyl and wherein R 22  is a C 1-3  alkyl;  
 R 6 , R 7  and R 8  each independently selected from the group consisting of hydrogen and C 1-3  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, CON(R 20 ) 2 , C 1-4  alkyl, or aryl wherein the alkyl and aryl substituents are each optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , OR 20 , N(R 20 ) 2 , CON(R 20 ) 2  or aryl wherein R 9  and R 10  may together form a carbonyl, or R 11  and R 12  may together form a carbonyl, or R 13  and R 14  may together form a carbonyl, or R 15  and R 16  may together form a carbonyl with the proviso that R 11  and R 13  or R 9  and R 15  or R 9  and R 11  or R 11  and R 15  or R 9  and R 13  may join together to form a ring;  
 R 17  is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3 , OR 20 , and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 , CN, OR 20 , and C 1-6  alkyl; and  
 R 20  is selected from the group consisting of H, C 1-3  alkyl, or aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent individually selected from the group consisting of halo, —OMe, and CF 3 .  
 
     
     
         6 . The compound of  claim 5  wherein 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  alkyl, or R 9  and R 10  together form a carbonyl, or R 11  and R 12  together form a carbonyl, or R 13  and R 14  together form a carbonyl, or R 15  and R 16  together form a carbonyl, R 10  and R 11  together form —CH 2 CH 2 CH 2 CH 2 —.  
     
     
         7 . The compound of  claim 5  wherein 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, CON(R 20 ) 2 , C 1-3  alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N(R 20 ) 2  and aryl or wherein R 9  and R 10  may together form a carbonyl, or R 11  and R 12  may together form a carbonyl with the proviso that R 11  and R 13  or R 9  and R 15  or R 9  and R 11  or R 11  and R 15  or R 9  and R 13  may join together to form a ring.  
     
     
         8 . The compound of  claim 5  wherein 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, or C 1-2  alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R 20 ) 2,  or aryl or wherein R 9  and R 10  may together form a carbonyl.  
     
     
         9 . The compound of  claim 1  wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , or C 1-3  alkyl wherein the alkyl substituent is optionally substituted with CF 3 .  
     
     
         10 . The compound of  claim 1  wherein R 6 , R 7  and R 8  each independently selected from the group consisting of hydrogen or methyl.  
     
     
         11 . The compound of  claim 1  wherein m=1; 
 R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, CF 3 , OR 20 , or C 1-2  alkyl;  
 R 6 , R 7  and R 8  are each hydrogen;  
 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 or C 1-2  alkyl, or wherein R 9  and R 10  may together form a carbonyl;  
 R 17  is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3 , OR 20 , and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF 3 , OR 20 , and C 1-4  alkyl; and  
 R 20  is selected from the group consisting of H or C 1-3  alkyl.  
 
     
     
         12 . The compound of  claim 11  wherein R 17  is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , OR 20 , and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF 3 , OR 20 , and C 1-4  alkyl.  
     
     
         13  The compound of  claim 1  wherein R 17  is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , OR 20 , and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF 3 , OR 20 , and C 1-4  alkyl.  
     
     
         14 . The compound of  claim 11  wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, halo, CF 3 , OCH 3 , or methyl.  
     
     
         15 . The compound of  claim 11  wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, or methyl.  
     
     
         16 . The compound of  claim 11  wherein R 11  and R 15  are each selected from the group consisting of hydrogen or methyl, R 9 , R 10 , R 12 , R 13 , R 14  and R 16  are each hydrogen and R 9  and R 10  may together form a carbonyl.  
     
     
         17 . A compound of  claim 1  wherein m=1; 
 R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, or methyl;  
 R 6 , R 7  and R 8  are each hydrogen;  
 R 11  and R 15  are each selected from the group consisting of hydrogen or methyl, R 9 , R 10 , R 12 , R 13 , R 14  and R 16  are each hydrogen and R 9  and R 10  may together form a carbonyl;  
 R 17  is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alky, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , OR 20 , and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF 3 , OR 20 , and C 1-4  alkyl; and  
 R 20  is methyl or H.  
 
     
     
         18 . The compound of  claim 17  wherein R 17  is alkyl having from 1 to 6 carbon atoms and cycloalkyl.  
     
     
         19 . The compound of  claim 17  wherein R 17  is a fused phenylcycloalkyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 , OR 20 , C 1-2  alkyl, and aryl.  
     
     
         20 . The compound of  claim 17  wherein R 17  is phenylmethyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 , OR 20 , C 1-4  alkyl, and aryl.  
     
     
         21 . The compound of  claim 17  wherein R 2 , R 3 , and R 4  are each hydrogen and R 1  and R 5  are each methyl.  
     
     
         22 . The compound of  claim 1  wherein m=1; 
 R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen or methyl;  
 R 6 , R 7  and R 8  each hydrogen;  
 R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  and R 16  are each hydrogen; and  
 R 17  is selected from the group consisting of alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 4 to 6 carbon atoms, fused phenylcycloalkyl with a phenyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 , OH, methyl, and aryl, and aryl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 , OH, C 1-2  alkyl, and aryl.  
 
     
     
         23 . The compound of  claim 1  selected from the group consisting of substituted piperazine compound selected from the group consisting of 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmethoxy)propyl]piperazinyl}acetamide, 2-({2-[4(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide, 2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide, 2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, 2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl }piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, 2-(4-{3-[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide, 
 N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, N-(2,6dimethylphenyl)2-{4-[2-hydoxy-3-(2-naphthylmethoxy)propyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide.  
 
     
     
         24 . A method of treatment comprising administering a therapeutically effective amount of a compound of  claim 1  to a mammal in need of a treatment selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases, treating shock conditions, preserving donor tissue and organs used in transplants, or treating cardiovascular diseases.  
     
     
         25 . The method of  claim 24  wherein the cardiovascular disease is selected from the group consisting of atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, or myocardial infarction.  
     
     
         26 . The method of  claim 24  wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.  
     
     
         27 . The method of  claim 24  wherein the mammal is a human.  
     
     
         28 . A pharmaceutical composition of matter comprising the composition of  claim 1  and one or more pharmaceutical excipients.  
     
     
         29 . The pharmaceutical composition of matter of  claim 28  wherein the pharmaceutical composition is in the form of a solution.  
     
     
         30 . The pharmaceutical composition of matter of  claim 28  wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet or a capsule.