Compounds for treating cystic fibrosis

A compound of general Formula Ib-1:

• or a pharmaceutically acceptable enantiomer, salt, solvate or prodrug thereof, wherein:
• X represent CR9 or N;
• wherein R9 represents H;
• OH;
• halo;
• C1-C4-alkyl;
• SOmR10 wherein m is 0, 1, 2 or 3 and wherein R10 represents H, NH2 or C1-C4-alkyl;
• or NR11R12 wherein R11 and R12 represent each independently H or C1-C4-alkyl;
• R4 represents H;
• halo;
• NH2;
• OH;
• alkyloxy;
• aryloxy;
• heteroaryloxy;
• —O—CO—NH—CHPh2;
• NR13R14 wherein R13 and R14 represent each independently an alkyl group;
• —NH-Ph-CONH2;
• —NH—CH2—R15 wherein R15 represents COOH, —COOalkyl, alkyloxyaryl, arylalkyl or heteroarylalkyl;
• —NH—CHR16R17 wherein R16 represents hydroxymethyl or methyl and R17 represents hydroxymethyl, COOH or COOalkyl;
• or —NHCO—R18 wherein R18 represents H, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• R5 represents H;
• halo;
• alkyl;
• OH;
• alkyloxy;
• aryloxy;
• arylalkyloxy;
• heteroarylalkyloxy;
• SOpR19 wherein p is 0, 1, 2 or 3 and wherein R19 represents H, NH2, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• or NR20R21 wherein R20 and R21 represents each independently a group selected from H, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylalkylcarbonyl, heteroarylalkylcarbonyl and alkyloxyarylcarbonyl;
• R6 represents H;
• arylalkyl wherein the aryl group is optionally substituted by one or more group selected from halo and carboxyl;
• heteroarylalkyl;
• heteroarylaminoalkyl wherein the heteroaryl group is optionally substituted by one or more group selected from halo and NH2;
• aminoalkyl;
• aryl substituted by one or more group selected from halo, alkyloxy, hydroxymethyl, CONH2, COOH, COOalkyl, SO3H and SO2NH2;
• provided that:
• R4 and R5 are not both H;
• R5 and R6 are not both H;
• R5 and R4 are not both Cl;
• and provided that compound of Formula I″ is not
• 4-(2-amino-6-hydroxy-9H-purin-9-yl)benzamide;
• N-2-phenethyl-9H-purine-2,6-diamine;
• 9-benzyl-9H-purin-6-amine;
• 9-(3-phenylpropyl)-9H-purin-6-amine;
• 4-(2-amino-6-hydroxy-9H-purin-9-yl)benzoic acid;
• 9-benzyl-2-chloro-N-(4-methoxybenzyl)-9H-purin-6-amine;
• 2-chloro-9H-purin-6-amine;
• 2-amino-9H-purin-6-ol;
• 3-(2-amino-6-hydroxy-9H-purin-9-yl)benzoic acid.

A pharmaceutical composition comprising a compound of general Formula Ib-1

• or a pharmaceutically acceptable enantiomer, salt, solvate or prodrug thereof, wherein:
• X represent CR9 or N, wherein R9 represents H;
• OH;
• halo;
• C1-C4-alkyl;
• SOmR10 wherein m is 0, 1, 2 or 3 and wherein R10 represents H, NH2 or C1-C4-alkyl;
• or NR11R12 wherein R11 and R12 represent each independently H or C1-C4-alkyl;
• R4 represents H;
• halo;
• NH2;
• OH;
• alkyloxy;
• aryloxy;
• heteroaryloxy;
• —O—CO—NH—CHPh2;
• NR13R14 wherein R13 and R14 represent each independently an alkyl group;
• —NH-Ph-CONH2;
• —NH—CH2—R15 wherein R15 represents COOH, —COOalkyl, alkyloxyaryl, arylalkyl or heteroarylalkyl;
• —NH—CHR16R17 wherein R16 represents hydroxymethyl or methyl and R17 represents hydroxymethyl, COOH or COOalkyl;
• or —NHCO—R18 wherein R18 represents H, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• R5 represents H;
• halo;
• alkyl;
• OH;
• alkyloxy;
• aryloxy;
• arylalkyloxy;
• heteroarylalkyloxy;
• SOpR19 wherein p is 0, 1, 2 or 3 and wherein R19 represents H, NH2, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• or NR20R21 wherein R20 and R21 represents each independently a group selected from H, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylalkylcarbonyl, heteroarylalkylcarbonyl and alkyloxyarylcarbonyl;
• R6 represents H;
• arylalkyl wherein the aryl group is optionally substituted by one or more group selected from halo and carboxyl;
• heteroarylalkyl;
• heteroarylaminoalkyl wherein the heteroaryl group is optionally substituted by one or more group selected from halo and NH2;
• aminoalkyl;
• aryl substituted by one or more group selected from halo, alkyloxy, hydroxymethyl, CONH2, COOH, COOalkyl, SO3H and SO2NH2;
• provided that:
• R4 and R5 are not both H;
• R5 and R6 are not both H;
• R5 and R4 are not both Cl;
• and provided that compound of Formula Ib-1 is not
• 4-(2-amino-6-hydroxy-9H-purin-9-yl)benzamide;
• N2-2-phenethyl-9H-purine-2,6-diamine;
• 9-benzyl-2-chloro-N-(4-methoxybenzyl)-9H-purin-6-amine;
• and at least one pharmaceutically acceptable carrier.

A medicament comprising a compound of general Formula Ib-1

• or a pharmaceutically acceptable enantiomer, salt, solvate or prodrug thereof, wherein:
• X represent CR9 or N, wherein R9 represents H;
• OH;
• halo;
• C1-C4-alkyl;
• SOmR10 wherein m is 0, 1, 2 or 3 and wherein R10 represents H, NH2 or C1-C4-alkyl;
• or N11R12 wherein R11 and R12 represent each independently H or C1-C4-alkyl;
• R4 represents H;
• halo;
• NH2;
• OH;
• alkyloxy;
• aryloxy;
• heteroaryloxy;
• —O—CO—NH—CHPh2;
• NR13R14 wherein R13 and R14 represent each independently an alkyl group;
• —NH-Ph-CONH2;
• —NH—CH2—R15 wherein R15 represents COOH, —COOalkyl, alkyloxyaryl, arylalkyl or heteroarylalkyl;
• —NH—CHR16R17 wherein R16 represents hydroxymethyl or methyl and R17 represents hydroxymethyl, COOH or COOalkyl;
• or —NHCO—R18 wherein R18 represents H, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• R5 represents H;
• halo;
• alkyl;
• OH;
• alkyloxy;
• aryloxy;
• arylalkyloxy;
• heteroarylalkyloxy;
• SOpR19 wherein p is 0, 1, 2 or 3 and wherein R19 represents H, NH2, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• or NR20R21 wherein R20 and R21 represents each independently a group selected from H, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylalkylcarbonyl, heteroarylalkylcarbonyl and alkyloxyarylcarbonyl;
• R6 represents H;
• arylalkyl wherein the aryl group is optionally substituted by one or more group selected from halo and carboxyl;
• heteroarylalkyl;
• heteroarylaminoalkyl wherein the heteroaryl group is optionally substituted by one or more group selected from halo and NH2;
• aminoalkyl;
• aryl substituted by one or more group selected from halo, alkyloxy, hydroxymethyl, CONH2, COOH, COOalkyl, SO3H and SO2NH2;
• provided that:
• R4 and R5 are not both H;
• R5 and R6 are not both H;
• R5 and R4 are not both Cl;
• and provided that compound of Formula I′ is not
• 4-(2-amino-6-hydroxy-9H-purin-9-yl)benzamide;
• N2-2-phenethyl-9H-purine-2,6-diamine;
• 9-benzyl-2-chloro-N-(4-methoxybenzyl)-9H-purin-6-amine.

A method of treatment of a disease or disorder associated with chloride channels comprising the administration to a patient in need thereof of a compound of general Formula Ib-1:

• or a pharmaceutically acceptable enantiomer, salt, solvate or prodrug thereof, wherein:
• X represent CR9 or N, wherein R9 represents H;
• OH;
• halo;
• C1-C4-alkyl;
• SOmR10 wherein m is 0, 1, 2 or 3 and wherein R10 represents H, NH2 or C1-C4-alkyl;
• or NR11R12 wherein R11 and R12 represent each independently H or C1-C4-alkyl;
• R4 represents H;
• halo;
• NH2;
• OH;
• alkyloxy;
• aryloxy;
• heteroaryloxy;
• —O—CO—NH—CHPh2;
• NR13R14 wherein R13 and R14 represent each independently an alkyl group;
• —NH-Ph-CONH2;
• —NH—CH2—R15 wherein R15 represents COOH, —COOalkyl, alkyloxyaryl, arylalkyl or heteroarylalkyl;
• —NH—CHR16R17 wherein R16 represents hydroxymethyl or methyl and R17 represents hydroxymethyl, COOH or COOalkyl;
• or —NHCO—R18 wherein R18 represents H, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• R5 represents H;
• halo;
• alkyl;
• OH;
• alkyloxy;
• aryloxy;
• arylalkyloxy;
• heteroarylalkyloxy;
• SOpR19 wherein p is 0, 1, 2 or 3 and wherein R19 represents H, NH2, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or alkyloxyaryl;
• or NR20R21 wherein R20 and R21 represents each independently a group selected from H, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, alkyloxyaryl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylalkylcarbonyl, heteroarylalkylcarbonyl and alkyloxyarylcarbonyl;
• R6 represents H;
• arylalkyl wherein the aryl group is optionally substituted by one or more group selected from halo and carboxyl;
• heteroarylalkyl;
• heteroarylaminoalkyl wherein the heteroaryl group is optionally substituted by one or more group selected from halo and NH2;
• aminoalkyl;
• aryl substituted by one or more group selected from halo, alkyloxy, hydroxymethyl, CONH2, COOH, COOalkyl, SO3H and SO2NH2;
• provided that:
• R4 and R5 are not both H;
• R5 and R6 are not both H;
• R5 and R4 are not both Cl.