Indoline derivatives for treatment and/or prevention of fibrosis diseases

Abstract

The invention relates to the use of Indoline derivatives, and their effective dose in the prevention and/or treatment of fibrosis diseases. The compound can effectively prevent and/or treat a fibrosis disease without cytotoxicity or genotoxicity.

What is claimed is: 
     
         1 . A method for prevention and/or treatment of a fibrosis disease in a subject, comprising administering a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of a compound having a comprising about a daily dose of the compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, or 2; 
         R 1  is SO 2 R a , in which R a  is alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; 
         R 2  is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, cyano, nitro, OR b , SR b , S(O)R b , NHC(O)—CH═CH—C(O)R b , NHC(O)—CH═CH—C(O)NR c R d , SO 2 NR c R d , OC(O)R b , C(O)NR c R d , NR c R d , NHC(O)R b , NHC(O)NR c R d , or NHC(S)R c , in which each of R b , R c , and R d , independently, is H, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and 
         each of R 3 , R 4 , R 5 , and R 6 , independently is, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, cyano, nitro, OR b , SR b , S(O)R b , CH═CH—C(O)NR c R d , NHC(O)—CH═CH—C(O)R b , NHC(O)—CH═CH—C(O)NR c R d , SO 2 NR c R d , OC(O)R b , C(O)NR c R d , NR c R d , NHC(O)R b , NHC(O)NR c R d , or NHC(S)R c , in which each of R b , R c , and R d , independently, is H, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl. 
         or a pharmaceutically acceptable salt, solvate or prodrug as an active ingredient in a range from about 100 mg to about 1,400 mg in one or more unit dosage forms. 
       
     
     
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         20 . The method of  claim 1 , wherein the pharmaceutical composition is in one or more capsule forms or tablet forms. 
     
     
         21 . The method of  claim 1 , wherein the pharmaceutical composition comprises the active ingredient in a daily dose ranging from about 140 mg to about 1,050 mg in one or more unit dosage forms. 
     
     
         22 . The method of  claim 1 , wherein the pharmaceutical composition comprises about 100 mg to about 300 mg of the active ingredient in a single tablet. 
     
     
         24 . The method of  claim 1 , wherein the pharmaceutical composition comprises about 100 mg to about 500 mg of the active ingredient in a single capsule. 
     
     
         25 . The method of  claim 1 , wherein pharmaceutical composition of is for use in combination with a second anti-fibrosis agent. 
     
     
         26 . The method of  claim 6 , wherein wherein the second anti-fibrosis agent is pirfenidone, nintedanib, LOXL2 antibody, simtuzumab, IL-13 antibody, lebrikizumab, αVβ6 antibody, STX-100, CTGF antibody, FG-3019, tipelukast, MN-001, aerosol pirfenidone or GP-101. 
     
     
         27 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
       
     
     
         28 . The method of  claim 1 , wherein the compound of formula (I) is 3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide having the following structure: