Sulfonamide derivatives of 3-substituted imidazol[1,2-d]-1,2,4-thiadiazoles and 3-substituted-[1,2,4] thiadiazolo[4,5-a] benzimidazole as inhibitors of fibrin cross-linking and transglutaminases

Sulfonamide compounds and its pharmaceutically acceptable salts, having the general formula (I):

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• wherein B is a 3-substituted imidazo[1,2-d]-1,2,4-thiadiazoles having the formula:
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• wherein X3 and X4 are independently hydrogen, lower alkyl, halo, nitro, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, amino, lower alkylamino, lower dialkylamino, lower alkylcarbamoyl;
• or B is a group having the formula:
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• wherein X3 and X4 has the same definition as defined above;
• X1 is hydrogen, lower alkyl, aryl-[lower alkyl]-, heterocyclyl-[lower alkyl]-, a group of formula —(CH2)n—CO—W wherein n and W is hydroxy, lower alkoxy, amino, lower alkylamino, n=1 to 6;
• A is a spacer selected from the group consisting of (1) C2-10 alkylene, (2) C4-10 alkylene, wherein the C4-10 alkylene is optionally substituted with one or two hydroxy groups at the non-terminal carbon atom of the carbon chain;
• Y is a spacer selected from the group consisting of:
• (1)
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• X5 is lower alkyl, aryl-[lower alkyl]-, heterocyclyl-[lower alkyl]-, a group of formula —(CH2)n—CO—W wherein W is as defined above or X5 is the following group:
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• wherein W is as defined above;
• X2 is:
• (1) heterocyclyl, heterocyclyl-[lower alkyl]-, the heterocyclic ring being attached at any heteroatom or carbon atom which results in the creation of a stable structure, and the heterocyclic ring being optionally substituted with 1-3 substituents selected from lower alkyl, halo, hydroxy, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkoxy, lower acyl, lower alkoxycarbonyl, lower alkyl-sulfonyl, amido, allyl, benzyl, trifluoroacetyl, trifluoromethyl, carboxy;
• the [lower alkyl] portion of heterocyclyl-[lower alkyl]-group is optionally substituted with 1-3 substituents selected from hydroxy, lower alkylcarbamoyl, phenyl, heterocyclyl, carboxy and lower alkoxycarbonyl;
• (2) aryl, aryl-[lower alkyl]-, or lower cycloalkyl, with the aryl group being optionally substituted with 1 to 3 substituents selected from lower alkyl, halo, nitro, amino, hydroxy, lower alkoxy, lower alkylamino, lower dialkylamino, trifluoromethyl, trifluoromethoxy, carboxy, 2-carboxyethyl, 2-methoxycarboxyethyl, piperazinylmethyl, 3-amino-3-oxopropyl, amidino, NR′R″, OC(O)R′, OC(O)OR′, OC(O)NR′R″, NR′(COR′), NHC(O)NR′R″, NHC(O)OR′, with R′ and R″ being independently hydrogen, lower alkyl, aryl, aryl-[lower alkyl]-, or lower alkyl substituted with hydroxy, amino, lower alkylamino, carboxy or lower alkoxycarbonyl, or R′ and R″ in NR′R″ when taken together forming a five or six membered heterocyclic ring selected from piperidinyl, pyrrolidinyl, morpholinyl and prolyl, the heterocyclic ring being optionally substituted with lower alkyl, carboxy, amino, phenyl, lower alkoxycarbonyl or lower dialkylamino;
• the [lower alkyl] portion of aryl-[lower alkyl]-group is optionally substituted with 1-3 substituents selected from hydroxy, lower alkylcarbamoyl, phenyl, heterocyclyl, carboxy and lower alkoxycarbonyl;
• (3) monosubstituted alkyl with substituent selected from halo, nitro, amino, hydroxy, lower alkoxy, lower alkylamino, lower dialkylamino. NR′R″, OC(O)R′, NR′(COR′), NHC(O)NR′R″, NHC(O)OR′, with R′ and R″ being as defined above.
• or
• the group Y—SO2—X2 when taken together form a cyclic radical:
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