Use of neutrophil elastase inhibitors in liver disease

Abstract

The invention relates to methods for treating chronic liver disease, in particular nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), with neutrophil elastase inhibitors. The invention further relates to pharmaceutical compositions comprising neutrophil elastase inhibitors.

What is claimed is: 
     
         1 . A method of treating chronic liver disease, comprising administering a therapeutically effective amount of (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile or a pharmaceutically acceptable salt, polymorph, solvate, or solvates of the salts thereof to a patient in need of treatment. 
     
     
         2 . The method of  claim 1 , wherein the chronic liver disease is nonalcoholic fatty liver disease (NAFLD). 
     
     
         3 . The method of  claim 1 , wherein the chronic liver disease is nonalcoholic steatohepatitis (NASH). 
     
     
         4 . The method of  claim 1 , wherein the therapeutically effective amount comprises a dosage of 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg once a day. 
     
     
         5 . The method of  claim 1 , further comprising administering one or more additional therapeutic agents. 
     
     
         6 . The method of  claim 5 , wherein the additional therapeutic agent is a neutrophil elastase inhibitor. 
     
     
         7 . The method of  claim 6 , wherein the neutrophil elastase inhibitor is silevestat or avelestat. 
     
     
         8 . The method of  claim 5 , wherein the additional therapeutic agent treats or ameliorates NAFLD or NASH via a mechanism other than inhibition of neutrophil elastase. 
     
     
         9 . The method of  claim 8 , wherein the additional therapeutic agent is GFT505, seladelpar, cenecriviroc, GS-0976, GS-9674, selonsertib, or obeticholic acid. 
     
     
         10 . The method of  claim 5 , wherein the additional therapeutic agent is an anti-diabetes agent. 
     
     
         11 . The method of  claim 10 , wherein the anti-diabetes agent is pioglitazone, rosiglitazone, liraglutide, dulaglutide, semaglutide, canagliflozin, empagliflozin, luseogliflozin, or ipragliflozin. 
     
     
         12 . A pharmaceutical composition for the treatment of chronic liver disease comprising (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile or a pharmaceutically acceptable salt, polymorph, solvate, or solvates of the salts thereof and a pharmaceutically acceptable carrier. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the pharmaceutical composition is formulated as a tablet. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the tablet comprises (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile or a pharmaceutically acceptable salt, polymorph, solvate, or solvates of the salts thereof and one or more diluents, disintegrants, surfactants or lubricants. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutical composition comprises 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg of (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile or a pharmaceutically acceptable salt, polymorph, solvate, or solvates of the salts thereof. 
     
     
         16 . A method of treating chronic liver disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a composition according to  claim 12 . 
     
     
         17 . The method of  claim 16 , wherein the chronic liver disease is NAFLD. 
     
     
         18 . The method of  claim 16 , wherein the chronic liver disease is NASH. 
     
     
         19 . The method of  claim 16 , wherein the pharmaceutical composition comprises 1 mg, 2 mg, 5 mg, 10 mg, or 20 mg of (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile or a pharmaceutically acceptable salt, polymorph, solvate, or solvates of the salts thereof.