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

Abstract

The present invention 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. The invention provides compositions, pharmaceutical preparations and methods of correcting the cellular alteration of a mutant CFTR protein wherein the CFTR mutation is a mutation AF508-CFTR, or another mutation of class II.

1 . 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; —CH (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, 
         as a modulator of a mutant CFTR protein for use in the manufacture of a medicament for the treatment of diseases associated with CFTR protein malfunction. 
       
     
     
         2 . A compound according to  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 . A compound according to  claim 1 , said compound being represented by the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound according to  claim 1 , wherein it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II and where a mutation ΔF508-CFTR, or another mutation of class II are involved in CFTR protein malfunction. 
     
     
         5 . A compound according to  claim 4 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         6 . A compound of general formula (II): 
       
         
           
           
               
               
           
         
         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 Q 1  and Q 2  are independently selected from the group consisting of: C, CH, N, NH; 
         wherein A is a fused five-membered ring having 0-3 independently selected heteroatoms wherein the heteroatoms comprise nitrogen, sulfur or oxygen; 
         wherein R 4 , R 5  and R 6  represent optional substituents, which are independently 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 , —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 , which may be optionally preceded by: —C n H (2n−1) R C  which is branched or unbranched wherein n is an integer from 1 to 4; —C n H (2n−3) Rc in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; —C n H (2n−5) R C  which is branched or unbranched wherein n is an integer from 2 to 5; 
         wherein Z 2  is selected from: a single bond, —N(R A ′)—, —S—, —S-alikl-, —O—, —O-alikil-, —C(═O)—, —S(═O)—, —OC(═O)—, —C(═O)N(R A ′)—, —OC(═O)N(R A ′)—, —C(═O))—, —SO 2 —, —SO 2 N(R A ′)—, —N(R A ′)SO 2 —, —N(R A ′)SO 2 N(R A ″)—, —CH 2 O—, —N(R A ′)C(═O)—, —N(R A ′)C(═O)O—, —N(R A ′)C(═O)(R A ″)—, —C(═O)C(═O)—, —N(R A ′)C(═O)O—, —N(R A ′)N(R A ″)—, —N(R A ′)N(R A ″)C(═O)—, —C(═O)N(R A ′)N(R A ″)—, —CH 2 N(R A ′)—, —CH 2 CH 2 O—, —CH 2 CH 2 N(R A ′)—, —CH 2 OCH 2 —, —CH 2 N(R A ′)CH 2 —, —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; 
         wherein R 7  are independently selected from the group consisting of: —H, aromatic ring or heteroaromatic ring; 
         wherein Z 3  is selected from: a single bond, double bond, —N(R A ′)—, —S—, —S-alkyl-, —O—, —O-alkyl-, —C(═O)—, —S(═O)—, —OC(═O)—, —C(═O)N(R A ′)—, —OC(═O)N(R A ′)—, —C(═O))—, —SO 2 —, —SO 2 N(R A ′)—, —N(R A ′)SO 2 —, —N(R A ′)SO 2 N(R A ″) —, —CH 2 O—, —N(R A ′)C(═O)—, —N(R A ′)C(═O)O—, —N(R A ′)C(═O)(R A ″)—, —C(═O)C(═O)—, —N(R A ′)C(═O)O—, —N(R A ′)N(R A ″)—, —N(R A ′)N(R A ″)C(═O)—, —C(═O)N(R A ′)N(R A ″)—, —CH 2 N(R A ′)—, —CH 2 CH 2 O—, —CH 2 CH 2 N(R A ′)—, —CH 2 OCH 2 —, —CH 2 N(R A ′)CH 2 —, —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; 
         wherein R 8  is selected from: H, O, S, aromatic ring or heteroaromatic ring; —C n H (2n+1)  which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n−1)  in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; —C n H (2n−3)  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; 
         wherein the 5-membered ring A is moiety selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         as a modulator of a mutant CFTR protein, for use in the manufacture of a medicament for the treatment of diseases associated with CFTR protein malfunction. 
       
     
     
         7 . A compound according to the  claim 6  having the general formula (IIa) or (IIb): 
       
         
           
           
               
               
           
         
         wherein Q 1 , Q 2 , Q 3 , Q 4 , Q 5  represent optional substituents which are independently selected from the group consisting of: —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, —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) Rc 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) Rc which is branched or unbranched wherein n is an integer from 2 to 5; —PO 3 H 2 , —OPO 3 H 2 . 
       
     
     
         8 . A compound according to  claim 7 , said compound being represented by the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 6 , wherein it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II and where a mutation ΔF508-CFTR, or another mutation of class II. are involved in CFTR protein malfunction. 
     
     
         10 . A compound according to  claim 9 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         11 . A compound of general formula (III): 
       
         
           
           
               
               
           
         
         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 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7  represents optional substituents, which are selected from substituents consisting at least one atom selected from the group consisting of: C, N, S, O, H, P, F, Cl, Br, I; 
         wherein R 4  represents optionally substituted moiety of formula (IIIa): 
       
       
         
           
           
               
               
           
         
         wherein R 5  and R 6  are optional substituents which are independently selected from the group consisting of: OH, NH 2 , COOH, Cl, Br, I, CH 3 , C 2 H 5 ; 
         and having a general formula (IIIb): 
       
       
         
           
           
               
               
           
         
         wherein R 7  is an optional substituent which is independently selected from the group consisting of: —F, —Cl, —Br, —I, —CH 3 , —C 2 H 5 ; 
         wherein R 8  is an optional substituent which is independently selected from the group consisting of: —NH 2 , —NHAr, —OH, —CH 2 Ar, —C(═O)Ar, —OAr; 
         wherein Ar is an aromatic group or heteroaromatic group; 
         wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7  represent optional substituents which are independently selected from the group consisting of: —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, —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 is 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, —PO 3 H 2 , —OPO 3 H 2 ; 
         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, 
         as a modulator of a mutant CFTR protein, for use in the manufacture of a medicament for the treatment of diseases associated with CFTR protein malfunction. 
       
     
     
         12 . A compound according to  claim 11 , said compound being represented by the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound according to  claim 11 , wherein it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II and where a mutation ΔF508-CFTR, or another mutation of class II. are involved in CFTR protein malfunction. 
     
     
         14 . A compound according to  claim 13 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         15 . A compound of general formula (IV): 
       
         
           
           
               
               
           
         
         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 E 1 , E 2  represent substituents which are independently selected from: H, —CH 3 , —C 2 H 5 ; 
         wherein E 3  represents optional substituent selected from: —Cl, —F, —Br, —I, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, —CH 2 I, optionally substituted lower alkyl group; 
         as a modulator of a mutant CFTR protein, for use in the manufacture of a medicament for the treatment of diseases associated with CFTR protein malfunction. 
       
     
     
         16 . A compound according to  claim 15 , said compound being represented by the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound according to  claim 15 , wherein it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II and where a mutation ΔF508-CFTR, or another mutation of class II. are involved in CFTR protein malfunction. 
     
     
         18 . A compound according to  claim 17 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis. 
     
     
         19 . Modulator according to  claim 1 , characterized in that 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. 
     
     
         20 . Modulator according to  claim 1 , characterized in that 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. 
     
     
         21 . Modulator according to  claim 1 , characterized in that it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II. 
     
     
         22 . Modulator according to  claim 6 , characterized in that 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. 
     
     
         23 . Modulator according to  claim 6 , characterized in that 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. 
     
     
         24 . Modulator according to  claim 6 , characterized in that it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II. 
     
     
         25 . Modulator according to  claim 11 , characterized in that 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. 
     
     
         26 . Modulator according to  claim 11 , characterized in that 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. 
     
     
         27 . Modulator according to  claim 11 , characterized in that it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II. 
     
     
         28 . Modulator according to  claim 15 , characterized in that 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. 
     
     
         29 . Modulator according to  claim 15 , characterized in that 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. 
     
     
         30 . Modulator according to  claim 15 , characterized in that it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.