Substituted thiazole-benzoisothiazole dioxide derivatives, process for their preparation and their use

1. A compound of the formula I

wherein

R1, R2 are each, independently of one another, H, aryl, COOH, (C 1 –C 6 )-alkylene-COOH, —COO(C 1 –C 6 )-akyl, (C 1 –C 6 -alkylene-COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 1 –C 6 )-alkylene-aryl, heterocycle, (C 1 –C 6 )-alkylene-heterocycle, CF 3 , OCF 3 , CN, (CH 2 ) 1-6 —OH, O—(C 1 –C 6 )-alkyl, CO—(C 1 –C 6 )-alkyl, —C(O)O-alkyl, COOH or CON(R9)(R10),

wherein said aryl, (C 1 –C 6 )-alkylene-aryl, heterocycle and (C 1 –C 6 )-alkylene-heterocycle radicals are optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, CF 3 , OCF 3 , N(R9)(R10), piperidinone, piperazine, piperazinone, N—(C 1 –C 6 -alkylene)piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine, NO 2 , CN, O—(C 1 –C 6 )-alkyl, S(O) 0-2 —(C 1 –C 6 )-alkyl, SO 2 —N(R9)(R10), CO—(C 1 –C 6 )-alkyl, —COOH, (C 1 –C 6 )-alkylene-COOH, COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COO(C 1 –C 6 )-alkyl, (C 3 –C 10 )-cycloalkyl or phenyl,

wherein said piperidinone, pirazine, piperazinone, N—(C 1 –C 6 )-alkylene)piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine and phenyl are optionally substituted one or more times by F, Cl, Br (CH 2 ) 0-2 OH, COOH, CN, NO 2 , —O—(C 1 –C 6 )-alkyl, —NH—O—(C 1 –C 6 )-alkyl, —(CO)—NH—O—(C 1 –C 6 )-alkylene-N(R9)(R10), —(CO)—(C 1 –C 6 )-alkyl, —(C 1 –C 6 )-alkyl, CF 3 , OCF 3 or N(R9)(R10);

R3 is H, (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene aryl, —C(O)-aryl, (C 1 –C 6 )-alkylene-heterocycle or CO—(C 1 –C 6 )-alkyl,

wherein said (C 1 –C 6 )-alkylene aryl, —C(O)-aryl and (C 1 –C 6 )-alkylene-heterocycle radicals are optionally substituted one or more times by F, Cl, Br, (C 1 –C 6 )-alkyl, COOH, COO—(C 1 –C 6 )-alkyl, CF 3 or OCF 3 ;

R4, R5 are each, independently of one another, H, F, Cl, Br, (C 1 –C 6 )-alkyl, CF 3 , OCF 3 , NO 2 , N(R9)(R10), CN, O—(C 1 –C 6 )-alkyl, CO—(C 1 –C 6 )-alkyl, COOH, (C 1 –C 6 )-alkylene-COOH, CON(R9)(R10), (C 1 –C 6 )-alkylene-CON(R9)(R10), COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COO(C 1 –C 6 )-alkyl, S(O) 0-2 —(C 1 –C 6 )-alkyl, S(O) 2 —N(R9)(R10) or CH 2 OH, CH 2 OCH 3 ;

R6, R7 are each, independently of one another, H, F, Cl, Br, (C 1 –C 6 )-alkyl, cyclopropyl, tetrafluorocyclopropyl, or difluorocyclopropyl; or

R6 and R7 together form the group ═CH 2 ;

R8 is H, CH 3 , CF 3 or CH 2 OH;

R9 is H or (C 1 –C 4 )-alkyl;

R10 is H or (C 1 –C 4 )-alkyl; or

R9 and R10 form together, with the N atom to which they are bonded, a 3–9 membered ring system;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein:

R1 is aryl, (C 1 –C 6 )-alkyl, (C 2 –C 2 )-alkenyl, (C 1 –C 6 )-alkylene-aryl, heterocyclic, (C 1 –C 6 )-alkylene-heterocycle, CF 3 , OCF 3 , CN, (CH 2 ) 1-6 —OH, O—(C 1 –C 6 )-alkyl, CO—(C 1 –C 6 )-alkyl, C(O)O-alkyl, COOH or CON(R9)(R10),

wherein said aryl, (C 1 –C 6 )-alkylene-aryl, heterocycle and (C 1 –C 6 )-alkylene-heterocycle radicals are optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, CF 3 , OCF 3 , N(R9)(R10), piperidinone, piperazine, piperazinone, N—(C 1 –C 6 -alkylene)-piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine, NO 2 , CN, O—(C 1 –C 6 )-alkyl, S(O) 0-2 —(C 1 –C 6 )-alkyl, SO 2 —N(R9)(R10), CO—(C 1 –C 6 )-alkyl, —COOH, (C 1 –C 6 )-alkylene-COOH, —COO(C 1 –C 6 )-alkyl, (C 0 –C 6 )-alkylene —COO(C 1 –C 6 )-alkyl, C 3 –C 10 -cycloalkyl or phenyl,

wherein said piperidinone, piperazine, piperazinone, N—(C 1 –C 6 )-alkylene)-piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine and phenyl are optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, COOH, CN, NO 2 , —O—(C 1 –C 6 )-alkyl, —NH—O—(C 1 –C 6 )-alkyl, —(CO)—NH—O—(C 1 –C 6 )-alkylene-N(R9)(R10), —(CO)—(C 1 –C 6 )-alkyl, —(C 1 –C 6 )-alkyl, CF 3 , OCF 3 or N(R9)(R10);

R2 is H, aryl, COOH, (C 1 –C 6 )-alkylene-COOH, —COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COO(C 1 –C 6 )-alkyl; (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 1 –C 6 )-alkylene-aryl, heterocycle, (C 1 –C 6 )-alkylene-heterocycle, CF 3 , OCF 3 , CN, —(CH 2 ) 1-6 —OH, O—(C 1 –C 6 )-alkyl, CO—(C 1 –C 6 )-alkyl, C(O)O-alkyl, COOH or CON(R9)(R10),

wherein said aryl, (C 1 –C 6 )-alkylene-aryl, heterocycle and (C 1 –C 6 )-alkylene-heterocycle radicals are optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, (C 1 –C 6 )-alkyl (C 1 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, CF 3 , OCF 3 , N(R9)(R10), piperidinome, piperazine, piperazinone, N—(C 1 –C 6 -alkylene)piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine, NO 2 , CN, O—(C 1 –C 6 )-alkyl, S(O) 0-2 —(C 1 –C 6 )-alkyl, SO 2 —N(R9)(R10), CO—(C 1 –C 6 )-alkyl, —COON, (C 1 –C 6 )-alkylene-COOH, —COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COO(C 1 –C 6 )-alkyl, C 3 –C 10 -cycloalkyl or phenyl;

R3 is H, (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-aryl, —C(O)-aryl, (C 1 –C 6 )-alkylene-hererocycle or CO—(C 1 –C 6 )-alkyl;

R 4 , R5 are each, independendy of one another, N, F, Cl, Br, (C 1 –C 6 )-alkyl, CF 3 , OCF 3 , NO 2 , N(R9)(R10), CN, O—(C 1 –C 6 )-alkyl, CO—(C 1 –C 6 )-alkyl, COOH, (C 1 –C 6 )-alkylene-COOH, —CON(R9)(R10), (C 1 –C 6 )-alkylene-CON(R9)(R10), COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COO(C 1 –C 6 )-alkyl, S(O) 0-2 —(C 1 –C 6 )-alkyl, S(O) 2 —N(R9)(R10), CH 2 OH or CH 2 OCH 3 ;

R6, R7 are each, independently of one another, H, F, Cl, Br, (C 1 –C 6 )-alkyl, cyclopropyl, tetrafluorocyclopropyl, difluorocyclopropyl; or

R6 and R7 together form the group ═CH 2 ;

R8 is H, CH 3 , CF 3 or CH 2 OH;

R9 is H or (C 1 –C 4 )-alkyl;

R10 is H or (C 1 –C 4 )-alkyl; or

R9 and R10 form together, with the N atom to which they are bonded, a 3–9 membered ring system;

and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 wherein:

R1 is phenyl, naphthyl, thionaphthyl or pyridyl,

wherein said phenyl, naphthyl, thionaphthyl and pyridyl are optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, CF 3 , OCF 3 , N(R9)(R10), piperidinone, piperazine, piperazinone, N—(C 1 –C 6 -alkylene)piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine, NO 2 , CN, O—(C 1 –C 6 )-alkyl, S(O) 0-2 —(C 1 –C 6 )-alkyl, SO 2 —N(R9)(R10), CO—(C 1 –C 6 )-alkyl, COOH, (C 1 –C 6 )-alkylene-COOH, COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COO(C 1 –C 6 )-alkyl, C 3 –C 10 -cycloalkyl or phenyl,

wherein said piperidinone, piperazine, piperazinone, N—(C 1 –C 6 )-alkylene)-piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine and phenyl are optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, COOH, CN, NO 2 —O—(C 1 –C 6 )-alkyl, —NH—O—(C 1 –C 6 )-alkyl, —(CO)—NH—O—(C 1 –C 6 )-alkylene-N(R9)(R10), —(CO)—(C 1 –C 6 )-alkyl, —(C 1 –C 6 )-alkyl, CF 3 , OCF 3 or N(R9)(R10);

R2 is H, (C 1 –C 6 )-alkyl, COOH, (C 1 –C 6 )-alkylene-COOH, —COO(C 1 –C 6 )-alkyl or (C 1 –C 4 )-alkylene-COO(C 1 –C 6 )-alkyl;

R 3 is H, (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-aryl, C(O)-aryl, (C 1 –C 6 )-alkylene-heterocycle or CO—(C 1 –C 6 )-alkyl;

R4, R5 are H;

R6, R7 are H;

R8 is H;

R9 is H or (C 1 –C 4 )-alkyl;

R10 is H or (C 1 –C 4 )-alkyl;

and pharmaceutically acceptable salts thereof.

4. The compound of claim 3 wherein:

R1 is phenyl,

wherein said phenyl is optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 1 –C 6 )-alkynyl, CF 3 , OCF 3 , N(R9)(R10), piperidinone, piperazine, piperazinone, N—(C 1 –C 6 -alkylene)piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine, NO 2 , CN, O—(C 1 –C 6 )-alkyl, S(O) 0-2 —(C 1 –C 6 )-alkyl, SO 2 —N(R9)(R10), CO—(C 1 –C 6 )-alkyl, COOH, (C 1 –C 6 )-alkylene-COOH, COO(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COO(C 1 –C 6 )-alkyl, C 3 –C 10 -cycloalkyl or phenyl,

wherein said piperidinone, piperazine, piperazinone, N—(C 1 –C 6 )-alkylene)piperazine, N—(C 1 –C 6 -alkylene)piperazinone, morpholine, thiomorpholine and phenyl are optionally substituted one or more times by F, Cl, Br, (CH 2 ) 0-2 OH, COOH, CN, NO 2 , —O—(C 1 –C 6 )-alkyl, —NH—O—(C 1 –C 6 )-alkyl, —(CO)—NH—O—(C 1 –C 6 )-alkylene-N(R9)(R10), —(CO)—(C 1 –C 6 )-alkyl, —(C 1 –C 6 )-alkyl, CF 3 , OCF 3 or N(R9)(R10);

R2 is H, (C 1 –C 6 )-alkyl, —(O)O—(C 1 –C 6 )-alkyl, —(C 1 –C 6 )-alkylene-C(O)O—(C 1 –C 6 )-alkyl, —COOH or —(C 1 –C 6 )-alkylene-COOH;

R3 is H, (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-aryl, —C(O)-aryl, (C 1 –C 6 )-alkylene-heterocycle or CO—(C 1 –C 6 )-alkyl;

R4, R5 are H;

R6, R7 are H;

R8 is H;

R9 is H;

R10 is H;

and pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5 further comprising at least one other active ingredient.

7. The pharmaceutical composition of claim 6 , wherein said other active ingredient comprises one or more antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylreas, biguanides, meglitinides, thiazoildinediones, α-glucosidase inhibitors, active ingredients which act on The ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, cannabinoid 1 receptor antagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, Jeptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors PPAR modulators, cannabinoid 1 receptor antagonists, RXR modulators or TR-β agonists or amphetamines.

8. A method of reducing blood sugar comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

9. A method of treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compouna of claim 1 .

10. A method of treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .