Short acting phenylalkylamine calcium channel blockers and uses thereof

Abstract

The present invention relates to the use of a pharmaceutically effective amount of an short-acting calcium channel blocking compound to treat ischemic heart conditions, cardiac arrhythmias, hypertensive crisis in an emergency room setting, hypertension before, during, or after surgery, no-reflow phenomenon following reperfusion, and diseases associated with decreased skeletal muscle blood flow. The invention also relates to pharmaceutical compositions formulated for use in such methods and to kits for such methods.

1 . A pharmaceutical composition comprising a compound having the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, wherein
 each a, b, c, d, e, f, and g is, independently, —CH 2 —, —O—, —S—, or a single bond; 
 each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 20  is, independently: H, lower alkyl, lower alkyl substituted with —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkyl substituted with fluorine or chlorine, lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO 2 (lower alkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or chlorine, or CO 2 R 10 ; 
 each R 10  is, independently, lower alkyl or lower alkoxyalkyl; 
 R 18  is H, CN, or CO 2 R 10 ; and 
 R 19  is CH 3  or H; and 
 
       wherein the compound is not verapamil, gallopamil, emopamil, mepamil, or devapamil. 
     
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 20  is CO 2 R 10 , lower alkyl substituted by —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkyl), or lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl). 
   
   
       3 . The pharmaceutical composition of  claim 2 , wherein R 19  is H, g is a single bond, and R 20  is H. 
   
   
       4 . The pharmaceutical composition of  claim 2 , wherein R 19  is H, g is a single bond, R 20  is CO 2 R 10 , and -d-R 14  and -e-R 15  are not both —O-(lower alkyl) or —O-(lower alkoxyalkyl). 
   
   
       5 . The pharmaceutical composition of  claim 1 , wherein
 (a) R 17  is lower alkyl;   (b) R 18  is CN or CO 2 R 10 ;   (c) at least one of -a-R 11 , -b-R 12 , or -c-R 13  is, independently:
 (i) —O-(lower alkyl); 
 (ii) —O-(lower alkyl substituted with —CO 2 (lower alkyl)); 
 (iii) —O-(lower alkyl substituted with —CO 2 (lower alkoxyalkyl)); 
 (iv) —O-(lower alkyl substituted with fluorine or chlorine); 
 (v) —O-(lower alkoxyalkyl); 
 (vi) —O-(lower alkoxyalkyl substituted with —CO 2 (lower alkyl)); 
 (vii) —O-(lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl)); 
 (viii) —O-(lower alkyl substituted with fluorine or chlorine); or 
 (ix) -(single bond)-CO 2 R 10 ; and 
   (d) at least one of -d-R 14 , -e-R 15 , -f-R 16 , or -g-R 20  is, independently,
 (i) —O-(lower alkyl); 
 (ii) —O-(lower alkyl substituted with —CO 2 (lower alkyl)); 
 (iii) —O-(lower alkyl substituted with —CO 2 (lower alkoxyalkyl)); 
 (iv) —O-(lower alkyl substituted with fluorine or chlorine); 
 (v) —O-(lower alkoxyalkyl); 
 (vi) —O-(lower alkoxyalkyl substituted with —CO 2 (lower alkyl)); 
 (vii) —O-(lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl)); 
 (viii) —O-(lower alkyl substituted with fluorine or chlorine); or 
 (ix) -(single bond)-CO 2 R 10 . 
   
   
   
       6 . The pharmaceutical composition of  claim 5 , wherein at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , or R 20  is CO 2 R 10 , lower alkyl substituted by —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkyl), or lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl). 
   
   
       7 . The pharmaceutical composition of  claim 6 , wherein R 19  is H, g is a single bond, and R 20  is H. 
   
   
       8 . The pharmaceutical composition of  claim 6 , wherein
 g is a single bond;   R 20  is CO 2 R 10 ; and   -d-R 14  and -e-R 15  are not both —O-(lower alkyl) or —O-(lower alkoxyalkyl).   
   
   
       9 . The pharmaceutical composition of  claim 1 , wherein said compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       10 . The pharmaceutical composition of  claim 1 , wherein said compound is 
     
       
         
         
             
             
         
       
     
   
   
       11 . The pharmaceutical composition of  claim 1 , wherein said pharmaceutical composition is formulated for treating a condition selected from the group consisting of:
 ischemic heart conditions;   cardiac arrhythmia;   hypertensive crisis in an emergency room setting;   hypertension before, during, or after surgery;   no-reflow phenomenon following reperfusion; and   a disease associated with decreased skeletal muscle flow.   
   
   
       12 . A kit comprising
 (a) a pharmaceutical composition comprising a compound having the following structure:   
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, wherein
 each a, b, c, d, e, f, and g is, independently, —CH 2 —, —O—, —S—, or a single bond; 
 each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 20  is, independently: H, lower alkyl, lower alkyl substituted with —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkyl substituted with fluorine or chlorine, lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO 2 (lower alkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or chlorine, or CO 2 R 10 ; 
 each R 10  is, independently, lower alkyl or lower alkoxyalkyl; 
 R 18  is H, CN, or CO 2 R 10 ; and 
 R 19  is CH 3  or H; and 
 
       (b) instructions for using the pharmaceutical composition of (a) for the treatment of a condition selected from the group consisting of:
 ischemic heart conditions; 
 cardiac arrhythmia; 
 hypertensive crisis in an emergency room setting; 
 hypertension before, during, or after surgery; 
 no-reflow phenomenon following reperfusion; and 
 a disease associated with decreased skeletal muscle flow; 
 
       wherein the compound is not verapamil, gallopamil, emopamil, mepamil, or devapamil. 
     
   
   
       13 - 21 . (canceled) 
   
   
       22 . A method of treating an ischemic heart condition or cardiac arrhythmia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, wherein
 each a, b, c, d, e, f, and g is, independently, —CH 2 —, —O—, —S—, or a single bond; 
 each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 20  is, independently: H, lower alkyl, lower alkyl substituted with —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkyl substituted with fluorine or chlorine, lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO 2 (lower alkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or chlorine, or CO 2 R 10 ; 
 each R 10  is, independently, lower alkyl or lower alkoxyalkyl; 
 R 18  is H, CN, or CO 2 R 10 ; and 
 R 19  is CH 3  or H; 
 
       wherein the compound is not verapamil, gallopamil, emopamil, mepamil, or devapamil. 
     
   
   
       23 - 29 . (canceled) 
   
   
       30 . The method of  claim 22 , wherein said ischemic heart condition is selected from the group consisting of stable angina, unstable angina and vasospastic angina 
   
   
       31 . The method of  claim 22 , wherein said cardiac arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), premature atrial, nodal, or ventricular depolarizations, atrial tachycardia, ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes. 
   
   
       32 . (canceled) 
   
   
       33 . A method of treating a hypertensive crisis in an emergency room setting, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, wherein
 each a, b, c, d, e, f, and g is, independently, —CH 2 —, —O—, —S—, or a single bond; 
 each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 20  is, independently: H, lower alkyl, lower alkyl substituted with —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkyl substituted with fluorine or chlorine, lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO 2 (lower alkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or chlorine, or CO 2 R 10 ; 
 each R 10  is, independently, lower alkyl or lower alkoxyalkyl; 
 R 18  is H, CN, or CO 2 R 10 ; and 
 R 19  is CH 3  or H; 
 
       wherein the compound is not verapamil, gallopamil, emopamil, mepamil, or devapamil. 
     
   
   
       34 - 40 . (canceled) 
   
   
       41 . The method of  claim 33 , wherein said administering comprises sublingual, buccal, intranasal, inhalation, or parenteral administration 
   
   
       42 . (canceled) 
   
   
       43 . A method of treating hypertension before, during, or after surgery, or no-reflow phenomenon following reperfusion, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, wherein
 each a, b, c, d, e, f, and g is, independently, —CH 2 —, —O—, —S—, or a single bond; 
 each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 20  is, independently: H, lower alkyl, lower alkyl substituted with —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkyl substituted with fluorine or chlorine, lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO 2 (lower alkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or chlorine, or CO 2 R 10 ; 
 each R 10  is, independently, lower alkyl or lower alkoxyalkyl; 
 R 18  is H, CN, or CO 2 R 10 ; and 
 R 19  is CH 3  or H; 
 
       wherein the compound is not verapamil, gallopamil, emopamil, mepamil, or devapamil. 
     
   
   
       44 - 50 . (canceled) 
   
   
       51 . The method of  claim 43 , wherein said administering comprises parenteral administration. 
   
   
       52 . (canceled) 
   
   
       53 . A method of treating a disease associated with decreased skeletal muscle blood flow, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, wherein
 each a, b, c, d, e, f, and g is, independently, —CH 2 —, —O—, —S—, or a single bond; 
 each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 20  is, independently: H, lower alkyl, lower alkyl substituted with —CO 2 (lower alkyl), lower alkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkyl substituted with fluorine or chlorine, lower alkoxyalkyl, lower alkoxyalkyl substituted with —CO 2 (lower alkyl), lower alkoxyalkyl substituted with —CO 2 (lower alkoxyalkyl), lower alkoxyalkyl substituted with fluorine or chlorine, or CO 2 R 10 ; 
 each R 10  is, independently, lower alkyl or lower alkoxyalkyl; 
 R 18  is H, CN, or CO 2 R 10 ; and 
 R 19  is CH 3  or H; 
 
       wherein the compound is not verapamil, gallopamil, emopamil, mepamil, or devapamil. 
     
   
   
       54 - 60 . (canceled) 
   
   
       61 . The method of  claim 53 , wherein said disease associated with decreased skeletal muscle blood flow is Raynaud's phenomenon or intermittent claudication. 
   
   
       62 . The method of  claim 53 , wherein said administering comprises sublingual, buccal, transdermal, intranasal, inhalation or topical administration. 
   
   
       63 - 64 . (canceled)