Pyrane derivatives as both ACE- and NEP-inhibitors

Abstract

Compounds of the formula wherein R, R 1 -R 7 and alk have meaning as defined, pharmaceutical compositions thereof, and use thereof for the treatment and/or prevention of cardiovascular disorders responsive to ACE and NEP inhibition and/or ECE inhibition.

1 - 19 . (canceled)  
   
   
       20 . A method of treating a disorder or a disease in a subject mediated by angiotension converting enzyme and/or neutral endopeptidase in a mammal, wherein the method comprises administering to the mammal in need thereof an effective amount of a compound of formula (I)  
     
       
         
         
             
             
         
       
       wherein  
       R represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl or cycloalkyl-lower alkyl;  
       R 1  represents hydrogen, cycloalkyl, carbocyclic or heterocyclic aryl, or biaryl;  
       alk represents lower alkylene;  
       R 3  represents hydrogen or acyl;  
       R 4  represents oxacycloalkyl, (thia-, oxothia- or diooxothia)-cycloalkyl, azacycloalkyl, or oxacycloalkyl-, (thia-, oxothia- or diooxothia)-cycloalkyl- or azacycloalkyl-lower alkyl;  
       R 5  represents hydrogen or 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;  
       COOR 2  represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;  
       a disulfide derivative derived from a said compound wherein R 3  is hydrogen; or a pharmaceutically acceptable salt thereof.  
     
   
   
       21 . The method of  claim 20 , wherein the disorder or the disease is selected from hypertension, renal failure, pulmonary edema, heart failure, atherosclerosis, pain, depression, certain psychotic conditions, cognitive disorders, angina, premenstrual syndrome, Meniere's disease, hyperaldosteronism, hypercalciurea, ascites, glaucoma, asthma, gastrointestinal disorders such as diarrhea, irritable bowel syndrome and gastric hyperacidity, cerebral ischemia (stroke), subarachnoid hemorraghe, traumatic brain injury, cerebral vasospasm, arterial hypertrophy, restenosis, Raynaud's disease, myocardial infarction, obesity, prostate hyperplasia, migraine, diabetes mellitus, e.g. diabetic nephropathy, pre-eclampsia, transplant rejection such as in aorta or solid organ transplantation and erectile dysfunction.  
   
   
       22 . A method of treating a disorder or a disease in a subject mediated by angiotension converting enzyme and/or neutral endopeptidase in a mammal, wherein the method comprises administering to the mammal in need thereof an effective amount of a compound of formula (Ia)  
     
       
         
         
             
             
         
       
     
     wherein asymmetric carbons carrying the substituents -alk-R 1  and R 4  typically have the S-configuration, or a disulfide derivative derived from a said compound wherein R 3  is hydrogen; or a pharmaceutically acceptable salt thereof.  
   
   
       23 . The method of  claim 22 , wherein the disorder or the disease is selected from hypertension, renal failure, pulmonary edema, heart failure, atherosclerosis, pain, depression, certain psychotic conditions, cognitive disorders, angina, premenstrual syndrome, Meniere's disease, hyperaldosteronism, hypercalciurea, ascites, glaucoma, asthma, gastrointestinal disorders such as diarrhea, irritable bowel syndrome and gastric hyperacidity, cerebral ischemia (stroke), subarachnoid hemorraghe, traumatic brain injury, cerebral vasospasm, arterial hypertrophy, restenosis, Raynaud's disease, myocardial infarction, obesity, prostate hyperplasia, migraine, diabetes mellitus, e.g. diabetic nephropathy, pre-eclampsia, transplant rejection such as in aorta or solid organ transplantation and erectile dysfunction.