Method of treatment for decreasing mortality resulting from congestive heart failure

Abstract

A method of treatment using a compound of Formula I: wherein: R 1 is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; R 2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; R 3 is hydrogen or lower alkyl of up to 6 carbon atoms; R 4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4 together with R 5 can represent —CH 2 —0—; X is a valency bond, —CH 2 , oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; R 5 and R 6 are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH 2 — group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or R 5 and R 6 together represent methylenedioxy; or a pharmaceutically acceptable salt thereof, alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of ACE inhibitors, diuretics, and digoxin for decreasing mortality resulting from congestive heart failure (CHF) in mammals, particularly humans.

What is claimed is:  
     
         1 . A method of treatment for decreasing mortality resulting from congestive heart failure in mammals comprising internally administering to a mammal in need thereof an effective amount of a compound which is both a β-adrenoceptor antagonist and a α 1 -adrenoceptor antagonist alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of an angiotensin converting enzyme inhibitor, a diuretic, and digoxin.  
     
     
         2 . A method of treatment according to  claim 1  wherein said mammal is human.  
     
     
         3 . A method of treatment according to  claim 1  wherein said compound is carvedilol.  
     
     
         4 . A method of treatment according to  claim 3  comprising administering said carvedilol in a dosage range of from about 3.125 to about 50 mg given twice daily.  
     
     
         5 . A method of treatment according to  claim 4  comprising administering said carvedilol in a maintenance dose of about 25 mg given twice daily.  
     
     
         6 . A method of treatment according to  claim 4  fcomprising administering said carvedilol in a maintenance dose of between about 25 mg and about 50 mg given twice daily to patients whose weight exceeds about 85 kg.  
     
     
         7 . A method of treatment according to  claim 6  wherein said maintenance dose is about 50 mg given twice daily in patients whose weight exceeds about 85 kg.  
     
     
         8 . A method of treatment according to  claim 3  wherein said ACE inhibitor is captopril, lisinopril, or enalapril, or any pharmaceutically acceptable salt thereof.  
     
     
         9 . A method of treatment according to  claim 3  wherein said diuretic is hydrochlorothiazide or furosemide, or any pharmaceutically acceptable salt thereof.  
     
     
         10 . A method of treatment for decreasing mortality resulting from congestive heart failure in mammals comprising internally administering to a mammal in need thereof an effective amount of a compound of Formula 1:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;  
 R 2  is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;  
 R 3  is hydrogen or lower alkyl of up to 6 carbon atoms;  
 R 4  is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4  together with R 5  can represent —CH 2 —0—;  
 X is a valency bond, —CH 2 , oxygen or sulfur;  
 Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;  
 R 5  and R 6  are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH 2 — group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         11 . A method of treatment according to  claim 10  wherein said mammal is human.  
     
     
         12 . A method of treatment according to  claim 10  wherein said compound is carvedilol.  
     
     
         13 . A method of treatment according to  claim 12  comprising administering said carvedilol in a dosage range of from about 3.125 to about 50 mg given twice daily.  
     
     
         14 . A method of treatment according to  claim 13  comprising administering said carvedilol in a maintenance dose of about 25 mg given twice daily  
     
     
         15 . A method of treatment according to  claim 13  comprising administering said carvedilol in a maintenance dose of between about 25 mg and about 50 mg given twice daily to patients whose weight exceeds about 85 kg.  
     
     
         16 . A method of treatment according to  claim 15  wherein said maintenance dose is about 50 mg given twice daily in patients whose weight exceeds about 85 kg.  
     
     
         17 . A method of treatment for decreasing mortality resulting from congestive heart failure in mammals comprising internally administering to a mammal in need thereof an effective amount of a therapeutic agent selected from the group consisting of an ACE inhibitor, a diuretic, and digoxin in conjunction with a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;  
 R 2  is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;  
 R 3  is hydrogen or lower alkyl of up to 6 carbon atoms;  
 R 4  is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4  together with R 5  can represent —CH 2 —0—;  
 X is a valency bond, —CH 2 , oxygen or sulfur;  
 Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;  
 R 5  and R 6  are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH 2 — group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         18 . A method of treatment according to  claim 17  wherein said mammal is human.  
     
     
         19 . A method of treatment according to  claim 17  wherein said compound is carvedilol.  
     
     
         20 . A method of treatment according to  claim 19  comprising administering said carvedilol in a dosage range of from about 3.125 to about 50 mg given twice daily.  
     
     
         21 . A method of treatment according to  claim 20  comprising administering said carvedilol in a maintenance dose of about 25 mg given twice daily.  
     
     
         22 . A method of treatment according to  claim 20  comprising administering said carvedilol in a maintenance dose of between about 25 mg and about 50 mg given twice daily to patients whose weight exceeds about 85 kg.  
     
     
         23 . A method of treatment according to  claim 22  wherein said maintenance dose is about 50 mg given twice daily in patients whose weight exceeds about 85 kg.  
     
     
         24 . A method of treatment according to  claim 19  wherein said ACE inhibitor is captopril, lisinopril, or enalapril, or any pharmaceutically acceptable salt thereof.  
     
     
         25 . A method of treatment according to  claim 19  wherein said diuretic is hydrochlorothiazide or furosemide, or any pharmaceutically acceptable salt thereof.