Combination containing sgc activators and mineralocorticoid receptor antagonists

Abstract

The present invention relates to the combination of activators of soluble guanylate cyclase (sGC activators) with mineralocorticoid receptor antagonists (MR antagonists) and to the use of the combination for the treatment and/or prophylaxis of cardiac and cardiovascular disorders, of renal and cardiorenal disorders, of pulmonary and cardiopulmonary disorders and also for the treatment and/or prophylaxis of fibrotic disorders.

1 .- 11 . (canceled) 
     
     
         12 . A method for the treatment of diabetes, diabetic retinopathy, and/or non-diabetic retinopathy, comprising administering a therapeutically effective amount of a combination comprising an sGC activator and a non-steroidal MR antagonist to a human or animal in need thereof, wherein the sGC activator is (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of the formula (X) 
       
         
           
           
               
               
           
         
       
       or a salt, solvate or solvate of a salt thereof and the non-steroidal MR antagonist is (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 
       
         
           
           
               
               
           
         
       
       of the formula (IV). 
     
     
         13 . The method of  claim 12 , wherein the sGC activator and the non-steroidal MR antagonist are administered in a combined unit dosage form. 
     
     
         14 . The method of  claim 12 , wherein the sGC activator and the non-steroidal MR antagonist are administered in two separate unit dosage forms. 
     
     
         15 . The method of  claim 12 , wherein the sGC activator and the non-steroidal MR antagonist are administered sequentially. 
     
     
         16 . The method of  claim 12 , wherein the sGC activator and the non-steroidal MR antagonist are administered orally. 
     
     
         17 . The method of  claim 12 , wherein the non-steroidal MR antagonist of the formula (IV) is administered at a dosage from about 1 to 100 mg od. 
     
     
         18 . The method of  claim 12 , wherein the non-steroidal MR antagonist of the formula (IV) is administered at a dosage from about 2.5 to 50 mg od. 
     
     
         19 . The method of  claim 12 , wherein the non-steroidal MR antagonist of the formula (IV) is administered at a dosage from 10 to 40 mg od. 
     
     
         20 . The method of  claim 12 , wherein the human or animal is treated for diabetes. 
     
     
         21 . The method of  claim 12 , wherein the human or animal is treated for diabetic retinopathy. 
     
     
         22 . The method of  claim 12 , wherein the human or animal is treated for non-diabetic retinopathy. 
     
     
         23 . The method of  claim 12 , wherein the sGC activator and the non-steroidal MR antagonist are administered in different dose intervals. 
     
     
         24 . A pharmaceutical composition comprising an sGC activator that is (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino phenyl)-3-cyclopropylpropanoic acid of the formula (X) 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, or solvate of a salt thereof and a non-steroidal MR antagonist that is (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (IV) 
       
         
           
           
               
               
           
         
       
       and an inert, non-toxic, pharmaceutically suitable excipient,
 wherein the non-steroidal MR antagonist of the formula (IV) has a dosage from about 1 to 100 mg od. 
 
     
     
         25 . The medicament of  claim 24 , wherein the non-steroidal MR antagonist of the formula (IV) has a dosage from about 2.5 to 50 mg od. 
     
     
         26 . The medicament of  claim 24 , wherein the non-steroidal MR antagonist of the formula (IV) has a dosage from 10 to 40 mg od. 
     
     
         27 . A kit comprising an sGC activator that is (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of the formula (X) 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, or solvate of a salt thereof and a non-steroidal MR antagonist that is (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (IV) 
       
         
           
           
               
               
           
         
       
       wherein the sGC activator and the non-steroidal MR antagonist are in different dose forms. 
     
     
         28 . The kit of  claim 27 , wherein the non-steroidal MR antagonist of the formula (IV) has a dosage from about 1 to 100 mg od. 
     
     
         29 . The kit of  claim 27 , wherein the non-steroidal MR antagonist of the formula (IV) has a dosage from about 2.5 to 50 mg od. 
     
     
         30 . The kit of  claim 27 , wherein the non-steroidal MR antagonist of the formula (IV) has a dosage from 10 to 40 mg od.