Compounds as modulators of a mutant cftr protein and their use for treating diseases associated with cftr protein malfunction

Abstract

An exemplary embodiment relates to novel protein modulators capable of altering function of the mutant CFTR protein and their use for treating diseases associated with CFTR protein malfunction. An exemplary embodiment provides compositions, pharmaceutical preparations and methods of correcting the cellular alteration of a mutant CFTR protein wherein the CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.

We claim: 
     
         1 . A composition comprising:
 a modulator of a mutant CFTR protein adapted for use in the manufacture of a medication for the treatment of diseases associated with CFTR protein malfunction including:   a compound of general formula (I)   
       
         
           
           
               
               
           
         
       
       its tautomers, E and Z geometrical isomers, optically active forms such as enantiomers, diastereomers and their racemate forms or a mixture of stereoisomeric forms or its pharmaceutically acceptable salts thereof or complexes thereof; 
       wherein Z 1  is independently selected from the group consisting of:
 —C n H (2n) —, which is branched or unbranched wherein n is an integer from 1 to 5; 
 —C n H (2n−2) — in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; 
 —C n H (2n−4) — which is branched or unbranched wherein n is an integer from 2 to 5; —CR′H—, —C 2 H 3 R′—, E or Z—C 2 HR′—, —C 3 H 5 R′—, E or Z—C 3 H 3 R′—, —OCH 2 —, —CH 2 O—, —NR″CH 2 —, —CH 2 NR″—;
 wherein R′ is independently selected from the group consisting of: —H, halogen, —NH 2 , —OH, —CN, CF 3 , —CHF 2 , —CH 2 F, —SH, —SCN, —CH 3 , —C 2 H 5 ; 
 wherein R″ is independently selected from the group consisting of: —H, —CH 3 , —C 2 H 5 ; wherein R 1  and R 2  are independently selected from the group consisting of aromatic ring or heteroaromatic ring. 
 
 
     
     
         2 . The composition of  claim 1 , wherein R 1  and R 2  are independently selected from the group of sub-formula (Ia): 
       
         
           
           
               
               
           
         
       
       wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6  is independently selected N or C atoms wherein ring contain 0-3 nitrogen atoms;
 wherein E 1 , E 2 , E 3 , E 4 , E 5  represents optional substituents, which are selected from: —OR B , —OC(═O)R C , —OC(═O)OR B , —OC(═O)N(R A )R A ′, —C(═O)R C , —C(═O)N(R A )R A ′, —C(═O)N(OR B )R A , —C(═O)OR B , —C(═S)R C , —C(═O)C(═O)R C , —CH 2 OR B , —CH 2 CH 2 OR B , —CH 2 N(R A )R A ′, —CH 2 CH 2 N(R A )R A ′, —CH 2 OCH 2 R C , —CH 2 N(R A )CH 2 R C , —SR D , —S(═O)R D , —SO 2 R D , —SO 2 N(R A )R A ′, —SO 3 R B , —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )C(═O)N(R A ′)R A ″, —N(R A )SO 2 R D , —N(R A )SO 2 N(R A ′)R A ″, —N(R A )R A ′, —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )N(R A ′)R A ″, —N(R A ′)N(R A )C(═O)R C , —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —SCN, —SO 2 CN, —F, Cl, —Br, —I, —PO 3 H 2 , —OPO 3 H 2 , —C n H 2n R C  which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n−2) R C  in E or Z geometrical conformation which branched or unbranched wherein n is an integer from 2 to 5; —C n H (2n−4) R C  which is branched or unbranched wherein n is an integer from 2 to 5;
 wherein R A , R A ′, R A ″ are each independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, —OH; 
 wherein R B  is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, —CH 2 I; 
 wherein R C  is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, —CH 2 I, —F, —Cl, —Br, —I, —NH 2 , 
 wherein R D  is independently selected from the group consisting of: —H, lower alkyl group. 
 
 
     
     
         3 . The composition of  claim 1 , wherein the compound is represented by the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The composition of  claim 2 , wherein the compound is represented by the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 1 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein is a mutation ΔF508-CFTR, or another mutation of class II, and wherein a mutation ΔF508-CFTR, or another mutation of class II are involved in CFTR protein malfunction. 
     
     
         6 . The composition of  claim 2 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein is a mutation ΔF508-CFTR, or another mutation of class II, and wherein a mutation ΔF508-CFTR, or another mutation of class II are involved in CFTR protein malfunction. 
     
     
         7 . The composition of  claim 3 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein is a mutation ΔF508-CFTR, or another mutation of class II, and wherein a mutation ΔF508-CFTR, or another mutation of class II are involved in CFTR protein malfunction. 
     
     
         8 . The composition of  claim 4 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein is a mutation ΔF508-CFTR, or another mutation of class II, and wherein a mutation ΔF508-CFTR, or another mutation of class II are involved in CFTR protein malfunction. 
     
     
         9 . The composition of  claim 5 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         10 . The composition of  claim 6 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         11 . The composition of  claim 7 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         12 . The composition of  claim 8 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         13 . The compound of  claim 1 , wherein said compound is a modulator for use in the treatment of cystic fibrosis wherein it has effect on CFTR-dependent ion transport across cellular membrane and/or it has the ability to increase the number of mutant CFTR proteins that reach the cell surface. 
     
     
         14 . The compound of  claim 1 , wherein said compound is a modulator for use in the treatment of cystic fibrosis wherein it has stabilizing effect on the structure of the mutant CFTR protein and/or blocks the interaction with cellular proteins responsible for the premature degradation of mutant CFTR. 
     
     
         15 . The compound of  claim 1 , wherein said compound is a modulator for use in the treatment of cystic fibrosis wherein it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II. 
     
     
         16 . A method comprising:
 treating cystic fibrosis in a patient including administering a therapeutically effective amount of a compound of a general formula (I), as a modulator of a mutant CFTR protein to the patient having cystic fibrosis:   
       
         
           
           
               
               
           
         
       
       its tautomers, E and Z geometrical isomers, optically active forms such as enantiomers, diastereomers and their racemate forms or a mixture of stereoisomeric forms or its pharmaceutically acceptable salts thereof or complexes thereof;
 wherein Z 1  is independently selected from the group consisting of:
 —C n H (2n) —, which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n−2) — in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; 
 —C n H (2n−4) — which is branched or unbranched wherein n is an integer from 2 to 5; —CR′H—, —C 2 H 3 R′—, E or Z—C 2 HR′—, —C 3 H 5 R′—, E or Z—C 3 H 3 R′—, —OCH 2 —, —CH 2 O—, —NR″CH 2 —, —CH 2 NR″—;
 wherein R′ is independently selected from the group consisting of: —H, halogen, —NH 2 , —OH, —CN, CF 3 , —CHF 2 , —CH 2 F, —SH, —SCN, —CH 3 , —C 2 H 5 ; 
 wherein R″ is independently selected from the group consisting of: —H, —CH 3 , —C 2 H 5 ; wherein R 1  and R 2  are independently selected from the group consisting of aromatic ring or heteroaromatic ring and 
 
 
 
       wherein the compound of effects CFTR-dependent ion transport across a cellular membrane and/or the compound increases the number of mutant CFTR proteins reaching the cell surface. 
     
     
         17 . The method according to  claim 16  wherein the compound has a stabilizing effect on the structure of the mutant CFTR protein and/or blocks the interaction with cellular proteins responsible for the premature degradation of mutant CFTR. 
     
     
         18 . The method according to  claim 16  wherein the compound is effecting a mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.