Dipeptide derivatives

Abstract

Compounds of the formula wherein R, R 1 , COOR 2 , R 3 -R 7 , alk, and X have meaning as defined, such being useful as dual inhibitors of angiotensin converting enzyme and neutral endopeptidase, as well as inhibitors of endothelin converting enzyme.

1 . A pharmaceutical composition comprising (a) a compound of the formula (I)  
     
       
         
         
             
             
         
       
       wherein  
       R represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl or cycloalkyl-lower alkyl;  
       R 1  represents lower alkyl, cycloalkyl, carbocyclic or heterocyclic aryl, or biaryl; or R 1  represents (cycloalkyl, carbocyclic aryl, heterocyclic aryl or biaryl)-lower alkyl;  
       alk represents lower alkylene;  
       R 3  represents hydrogen or acyl;  
       R 4  represents hydrogen, optionally substituted lower alkyl, carbocyclic or heterocyclic aryl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl, biaryl-lower alkyl; oxacycloalkyl, thiacycloalkyl, azacycloalkyl, or (oxacycloalkyl, thiacycloalkyl or azacycloalkyl)-lower alkyl;  
       R 5  represents hydrogen or lower alkyl; or  
       R 4  and R 5  together with the carbon atom to which they are attached, represent cycloalkylidene, benzo-fused cycloalkylidene; or 5- or 6-membered (oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene), each optionally substituted by lower alkyl or aryl-lower alkyl;  
       R 6  represents lower alkyl, carbocyclic or heterocyclic aryl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl or biaryl-lower alkyl;  
       R 7  represents lower alkyl, (carbocyclic or heterocyclic aryl)-lower alkyl, cycloalkyl-lower alkyl or biaryl-lower alkyl; or  
       R 6  and R 7 , together with the carbon atom to which they are attached, represent 3- to 10-membered cycloalkylidene which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5- to 7-membered ring; or 5- or 6-membered (oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene), each optionally substituted by lower alkyl or aryl-lower alkyl; or 2,2-norbonylidene;  
       X represents —O—, —S(O) r —, —NHSO 2 —, or —NHCO—;  
       n is zero, one or two; and  
       COOR 2  represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;  
       or a disulfide derivative derived from a said compound wherein R 3  is hydrogen; or a pharmaceutically acceptable salt thereof; and  
       (b) at least one second therapeutic agent selected from angiotensin II receptor antagonists, renin inhibitors, calcium channel blockers, aldosterone synthase inhibitors, diuretics, vasopressin receptor antagonists, cardiotonic drugs, endothelin antagonists and ECE inhibitors, anti-atherosclerotic agents, cholesterol absorption inhibitors, statin HMG CoA reductase inhibitors, nicotinic acid derivatives, thyromimetic agents, and antidiabetic agents.  
     
   
   
       2 . The composition of  claim 1 , wherein the compound has the formula (Ia):  
     
       
         
         
             
             
         
       
     
   
   
       3 . The composition of  claim 1 , wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       4 . The composition of  claim 1 , wherein the angiotensin II receptor antagonists are selected from valsartan, losartan, candesartan, eprosartan, irbesartan and telmisartan.  
   
   
       5 . The composition of  claim 1 , wherein the blockers are selected from bisoprolol, propanolol, atenolol, sotalol and metoprolol.  
   
   
       6 . The composition of  claim 1 , wherein the calcium channel blockers are selected from amlodipine, verapamil, diltiazem, bepridil, felodipine, isradipine, nicardipine, nifedipine, nimodipine and nisoldipine.  
   
   
       7 . The composition of  claim 1 , wherein the aldosterone synthase inhibitors are selected from eplerenone, (+)-fadrozole (WO 01/76574), spironolactone and canrenone.  
   
   
       8 . The composition of  claim 1 , wherein the diuretics are selected from furosemide, hydrochlorothiazide, indapamide, metazolone, amiloride and triamterene  
   
   
       9 . The composition of  claim 1 , wherein the vasopressin receptor antagonists are selected from OPC 21268, SR 49059, SR121463A, SR49059, VPA985, OPC31260 and YM087.  
   
   
       10 . The composition of  claim 1 , wherein the statin HMG CoA reductase inhibitors are selected from atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and pitavastatin.  
   
   
       11 . The composition of  claim 1 , wherein the antidiabetic agents are selected from repaglinide, nateglinide, metformin, rosiglitazone, pioglitazone, glyburide, glipizide, glimepiride, DPP728, LAF237, NH622 and DRF4158.  
   
   
       12 . A method of treating or inhibiting cardiovascular disorders in mammals comprising administering to a mammal in need thereof an effective amount of the pharmaceutical composition of  claim 1 .  
   
   
       13 . The method according to  claim 12  for the treatment of hypertension, edema, salt retention or congestive heart failure.