Cftr corrector for the treatment of genetic disorders affecting striated muscle

Abstract

The present invention relates to the use of CFTR correctors in the treatment of genetic disorders affecting striated muscle selected from sarcoglycanopathies, Brody's disease (BD) and the recessive forms of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT).

1 . A method of treating of genetic disorders affecting striated muscle selected from Brody's disease (BD) and the recessive forms of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT), said method comprising administering an effective amount of a CFTR corrector to a patient in need thereof. 
     
     
         2 . A method according to  claim 1 , wherein the genetic disorder affecting striated muscle is Brody's disease (BD). 
     
     
         3 . A method according to  claim 1 , wherein the genetic disorder affecting striated muscle is the recessive forms of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT). 
     
     
         4 . A method according to  claim 1 , wherein the CFTR corrector is selected from:
 N-(2-(5-chloro-2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)pivalamide (Compound A);   4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (Compound B);   2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-quinazoline (Compound C);   1-(benzo [d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);   N-[2-(5-Chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide (Compound E);   7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline (Compound F);   4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound H);   N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);   2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound L);   N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);   7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline (Compound N);   N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine (Compound P);   N-(2-(3-acetylphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound Q);   N-(2-(2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound R);   N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound S);   2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-one (Compound T);   3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound U);   (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound V); or a pharmaceutically acceptable salt thereof.   
     
     
         5 . A method according to  claim 1 , wherein the CFTR corrector is selected from:
 N-(2-(5-chloro-2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)pivalamide (Compound A);   4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (Compound B);   2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-quinazoline (Compound C);   1-(benzo [d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);   N-[2-(5-Chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide (Compound E);   7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline (Compound F);   4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound H);   N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);   N-(2-(3-acetylphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound Q);   N-(2-(2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound R);   N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound S);   2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-one (Compound T) or a pharmaceutically acceptable salt thereof.   
     
     
         6 . A method of treating of genetic disorders affecting striated muscle selected from Brody's disease (BD) and the recessive forms of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT), said method comprising administering an effective amount of a pharmaceutical composition comprising a CFTR corrector and one or more pharmaceutically acceptable excipients to a patient in need thereof. 
     
     
         7 . A method according to  claim 6 , wherein the genetic disorder affecting striated muscle is Brody's disease (BD). 
     
     
         8 . A method according to  claim 6 , wherein the genetic disorder affecting striated muscle is the recessive forms of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT). 
     
     
         9 . A method according to  claim 6 , wherein the CFTR corrector is selected from:
 N-(2-(5-chloro-2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)pivalamide (Compound A);   4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (Compound B);   2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-quinazoline (Compound C);   1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);   N-[2-(5-Chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide (Compound E);   7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline (Compound F);   4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound H);   N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);   2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (Compound L);   N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);   7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline (Compound N);   N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine (Compound P);   N-(2-(3-acetylphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound Q);   N-(2-(2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound R);   N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound S);   2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-one (Compound T);   3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound U);   (R)-1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound V); or a pharmaceutically acceptable salt thereof.   
     
     
         10 . A method according to  claim 6 , wherein the CFTR corrector is selected from:
 N-(2-(5-chloro-2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)pivalamide (Compound A);   4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (Compound B);   2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-quinazoline (Compound C);   1-(benzo [d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);   N-[2-(5-Chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide (Compound E);   7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline (Compound F);   4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound H);   N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);   N-(2-(3-acetylphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound Q);   N-(2-(2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide (Compound R);   N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound S);   2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-e (Compound T); or a pharmaceutically acceptable salt thereof.