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

1. A pharmaceutical composition comprising:

a modulator of a mutant CFTR protein used for the manufacture of a medication for the treatment of disease associated with CFTR protein malfunction, wherein the modulator comprises a compound of formula (I)

its tautomers, E and Z geometrical isomers, optically active forms or its pharmaceutically acceptable salts thereof or complexes thereof;

wherein R 1 and R 2 are each the sub-formula (Ia):

wherein E 1 , E 2 , E 3 , E 4 , E 5 represents one or more substituents, which are selected from:

OR B , —OC(═O)R C , —OC(═O)OR B , —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 , —CH 2 OR B , —CH 2 CH 2 OR B , —CH 2 N(R A )R A ′, —CH 2 N(R A )CH 2 R C , —SR D , —S(═O)R D , —SO 2 R D , —SO 3 R B , —N(R A )C(═O)R C , —N(R A )SO 2 R D , —N(R A )R A ′, —NO 2 , —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 is branched or unbranched wherein n is an integer from 2 to 5; and —C n H (2n−4) R C which is branched or unbranched wherein n is an integer from 2 to 5;

wherein R A and R A ′ are each independently selected from the group consisting of: —H, lower alkyl group, —CF 3 , —CHF 2 , —CH 2 F, and —OH;

wherein R B is independently selected from the group consisting of: —H, lower alkyl group, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, and —CH 2 I;

wherein R C is independently selected from the group consisting of: —H, lower alkyl group, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, —CH 2 I, —F, —Cl, —Br, —I, and —NH 2 ; and

wherein R D is independently selected from the group consisting of: —H and lower alkyl group;

wherein the compound of formula (I) is present in a pharmaceutical composition.

2. The pharmaceutical composition of claim 1 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR 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.

3. The pharmaceutical composition of claim 1 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis.

4. The pharmaceutical composition of claim 2 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis.

5. The pharmaceutical composition 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.

6. The pharmaceutical composition of claim 1 , wherein said compound is a modulator for use in the treatment of cystic fibrosis, wherein it 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.

7. The pharmaceutical composition 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.

8. A pharmaceutical composition comprising:

a modulator of a mutant CFTR protein used for the manufacture of a medication for the treatment of disease associated with CFTR protein malfunction, wherein the modulator comprises a compound represented by the following structure:

its tautomers, E and Z geometrical isomers, optically active forms or its pharmaceutically acceptable salts thereof or complexes thereof;

wherein the compound is present in a pharmaceutical composition, and wherein the pharmaceutical composition further comprises 2-[(3-nitrophenyl)methylsulfanyl]-3,7-dihydropurin-6-one.