Arylsulfonamide derivatives as C-Jun-N-Terminal Kinases (JNK's) inhibitors

1. A sulfonamide according to formula I

a geometrical isomer thereof, an optically active form thereof, an enantiomer thereof, a diastereomer thereof, a mixture thereof, or a salt thereof

wherein:

Ar 1 is a substituted or unsubstituted aryl group;

X is O or S;

Ar 2 is a substituted or unsubstituted thienylene group;

R 1 and R 2 are independently selected from the group consisting of hydrogen and a C 1 -C 6 -alkyl group;

R a , R a′ , R b , R b′ are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl;

or R a′ and R a or R b′ together with the carbon atoms they are linked, form a substituted or unsubstituted 5-8-membered saturated, partially unsaturated or aromatic ring containing optionally one or more heteroatoms selected from O, N, S;

R 3 is selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl;

or R 3 and R a or R a′ form, together with the N atom linked to R 3 , a 5-8-membered saturated ring, containing optionally at least one further heteroatom selected from O, N, S;

R 4 is selected from the group consisting of H and —C(H)R 5 R 6 ;

R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl;

m is an integer from 1 to 5;

n is an integer from 0 to 2; and

p is an integer from 1 to 10;

wherein the compound according to formula I is

selected from the group consisting of

4-Chloro-N-{5-[1-(4-trifluoromethyl-benzyl)-piperidin-3-ylsulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-{5-[2,2-dimethyl-3-(4-trifluoromethyl-benzylamino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-(5-{3-[methyl-(4-trifluoromethyl-benzyl)-amino]-propylsulfamoyl}-thiophen-2-ylmethyl)-benzamide;

4-Chloro-N-{5-[3-(hexyl-methyl-amino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-{5-[2-(4-trifluoromethyl-benzylamino)-cyclohexylsulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-[5-(2 hexylamino-ethylsulfamoyl)-thiophen-2-ylmethyl]-benzamide;

4-Chloro-N-{5-[1-(4-trifluoromethyl-benzyl)-piperidin-4-ylsulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-[5-(3-hexylamino-2,2-dimethyl-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-{5-[3-(4-trifluoromethyl-benzylamino)-benzylsulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-{5-[3-(4-trifluoromethyl-benzylamino)-propylsulfamoyl]thiophen-2-ylmethyl)benzamide;

4-Chloro-N (5-{[1-(4-trifluoromethyl-benzyl)-piperidin 3-ylmethyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide;

4-Chloro-N (5-{methyl-[3-(4-trifluoromethyl-benzylamino)-propyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide;

4-Chloro-N-{5-[(3-hexylamino-propyl)-methyl sulfamoyl]-thiophen-2-ylmethyl}-benzamide;

4-Chloro-N-(5-{[1-(4-trifluoromethyl-benzyl)-pyrrolidin-2-ylmethyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide; and

4-Chloro-N-{5-[2,2-dimethyl-3-(3-trifluoromethanesulfonyl-phenylamino]-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide.

2. A medicament comprising the sulfonamide according to claim 1 and one or more pharmaceutically acceptable diluents or excipients.

3. A pharmaceutical composition comprising at least one sulfonamide according to claim 1 and one or more of a pharmaceutically acceptable carrier, diluent or excipient.

4. A process for the preparation of the sulfonamide according to claim 1 wherein R 4 is not H, comprising

reductively aminating a carbonyl group of formula VII with a compound of formula VI

5. A process for the preparation of the sulfonamide, according to claim 1 , wherein R 4 is H, comprising

deprotecting a compound of formula IV

6. The process according to claim 4 wherein the compound of formula VI is obtained by deprotecting a compound of formula IV

7. The process according to claim 5 wherein the compound of formula IV is obtained by reacting a compound of formula II with a compound of formula III

8. A process for the preparation of the sulfonamide according to claim 1 , comprising

N-sulfonylating a compound of formula X with a sulfonylchloride of formula III

9. The process according to claim 8 wherein the compound of formula X is obtained by deprotecting a compound of formula IX

wherein P is a protecting group.

10. The process according to claim 9 wherein the compound of formula IX is obtained by reductively aminating a compound of formula VII with a compound of formula VIII

wherein P is a protecting group.

11. A process for the preparation of a compound of formula I, according to claim 1 , comprising

reductively aminating a carbonyl group of formula XIII with an amine of formula XIV

12. The process according to claim 11 wherein the compound of formula XIII is obtained by oxidizing a compound of formula XII

13. The process according to claim 12 wherein the compound of formula XII is obtained by sulfonylating a compound of formula XI