Phenothiazin derivatives, method for the production thereof and use thereof as pharmaceuticals
View Patent ↗The invention relates to compounds of the formula I, wherein R1, R2, R3, R4, R5, R6, R7, A and B are as defined herein, the pharmaceutical compositions and the uses as pharmaceuticals.
1. A compound of formula I
wherein:
R1 is H, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-aryl, CO—(C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, or (C 2 -C 6 )-alkylene-O—(C 1 -C 6 )-alkyl;
R2 and R3 independently of one another are H, F, Cl, Br, CN, NO 2 , (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CO—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-phenyl, SCF 3 , SF 5 , or SCH 3 ;
R4 and R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , ═O, (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, —CO—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CO—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CONH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-NH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-NH—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl]-O—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N[(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-aryl, SF 5 , (C 0 -C 6 )-alkyl-S(O) x (C 1 -C 6 )-alkyl, S(O) x (C 1 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, S(O) x (C 2 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, —SO 2 —NH—(C 0 -C 6 )-alkyl, —SO 2 —N—[(C 0 -C 6 )-alkyl] 2 , S(O) x (C 0 -C 6 )-alkylene-heterocycle, S(O) x (C 1 -C 6 )-alkylene-CO-heterocycle, —NH—SO 2 —(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-cycloalkyl, (C 0 -C 6 )-alkylene-heterocycle, or (C 0 -C 6 )-alkylene-aryl;
x is 0, 1, or 2;
R6 and R7 independently of one another are H, F, Cl, Br, CN, NO 2 , ═O, ═S, ═N—O—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—CO—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CO—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-aryl, SF 5 , or S(O) x —(C 1 -C 6 )-alkyl;
A is a 5- to 10-membered heterocycle, which may be fused to a further 5- to 10-membered ring; and
B is a 4- to 8-membered cycloalkyl ring, a 4- to 10-membered heterocycle or a 6- to 10-membered aryl ring;
or a physiologically acceptable salt thereof.
2. The compound according to claim 1 , wherein
R4 and R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, —CO—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CO—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CONH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-NH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-NH—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl]-O—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N [(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-aryl, SF 5 , (C 0 -C 6 )-alkyl-S(O) x (C 1 -C 6 )-alkyl, S(O) x (C 1 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, S(O) x (C 2 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, —SO 2 —NH—(C 0 -C 6 )-alkyl, —SO 2 —N—[(C 0 -C 6 )-alkyl] 2 , S(O) x (C 0 -C 6 )-alkylene-heterocycle, S(O) x (C 1 -C 6 )-alkylene-CO-heterocycle, —NH—SO 2 —(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-cycloalkyl, (C 0 -C 6 )-alkylene-heterocycle, or (C 0 -C 6 )-alkylene-aryl;
or a physiologically acceptable salt thereof.
3. The compound according to claim 1 , wherein
R4 and R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, —CO—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CO—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CONH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-NH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-NH—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl]-O—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N [(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-aryl, SF 5 , (C 0 -C 6 )-alkyl-S(O) x (C 1 -C 6 )-alkyl, S(O) x (C 1 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, S(O) x (C 2 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, —SO 2 —NH—(C 0 -C 6 )-alkyl, —SO 2 —N—[(C 0 -C 6 )-alkyl] 2 , S(O) x (C 0 -C 6 )-alkylene-heterocycle, S(O) x (C 1 -C 6 )-alkylene-CO-heterocycle, —NH—SO 2 —(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-cycloalkyl, (C 0 -C 6 )-alkylene-heterocycle, or (C 0 -C 6 )-alkylene-aryl; and
A is a 5- to 10-membered heterocycle which contains a —C═N— bond in the alpha position, wherein the heterocycle may be fused to a further 5- to 10-membered ring;
or a physiologically acceptable salt thereof.
4. The compound according to claim 1 , wherein
R2 and R3 are H;
R4 and R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, —CO—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CO—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CONH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-NH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-NH—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl]-O—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N[(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-aryl, SF 5 , (C 0 -C 6 )-alkyl-S(O) x (C 1 -C 6 )-alkyl, S(O) x (C 1 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, S(O) x (C 2 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, —SO 2 —NH—(C 0 -C 6 )-alkyl, —SO 2 —N—[(C 0 -C 6 )-alkyl] 2 , S(O) x (C 0 -C 6 )-alkylene-heterocycle, S(O) x (C 1 -C 6 )-alkylene-CO-heterocycle, —NH—SO 2 —(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-cycloalkyl, (C 0 -C 6 )-alkylene-heterocycle, or (C 0 -C 6 )-alkylene-aryl; and
A is a 5-membered heterocycle which contains a —C═N— bond in the alpha position, wherein the heterocycle may be fused to a further 5- to 10-membered ring;
or a physiologically acceptable salt thereof.
5. The compound according to claim 1 , wherein
R2 and R3 are H;
R4 and R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, —CO—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CO—(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CONH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-NH(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-NH—COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-CON[(C 0 -C 6 )-alkyl]-O—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N [(C 0 -C 6 )-alkyl] 2 , (C 0 -C 6 )-alkylene-aryl, SF 5 , (C 0 -C 6 )-alkyl-S(O) x (C 1 -C 6 )-alkyl, S(O) x (C 1 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, S(O) x (C 2 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, —SO 2 —NH—(C 0 -C 6 )-alkyl, —SO 2 —N—[(C 0 -C 6 )-alkyl] 2 , S(O) x (C 0 -C 6 )-alkylene-heterocycle, S(O) x (C 1 -C 6 )-alkylene-CO-heterocycle, —NH—SO 2 —(C 1 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-cycloalkyl, (C 0 -C 6 )-alkylene-heterocycle, or (C 0 -C 6 )-alkylene-aryl;
A is thiazol-2-yl, pyrazol-3-yl, pyridin-2-yl, oxazol-2-yl, isoxazol-3-yl, imidazol-2-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, [1,3,4]thiadiazol-3-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-2-yl, [1,2,4]triazin-3-yl, [1,2,4]triazin-6-yl, thiazolo[4,5-b]pyridin-2-yl, thieno[2,3-d]thiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, benzimidazol-2-yl, quinolin-2-yl, isoquinolin-3-yl, 4,5,6,7-tetrahydro-benzothiazol-2-yl, 4,5,6,7-tetrahydrobenzoxazol-2-yl, 4,5,6,7-tetrahydro-benzimidazol-2-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl, 5,6-dihydro-4H-cyclopentathiazol-2-yl, or 4,5-dihydrothiazol-2-yl; and
B is cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, phenyl, pyridyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyrazolyl, or isoxazolyl;
or a physiologically acceptable salt thereof.
6. The compound according to claim 1 , wherein
R1 is H or (C 1 -C 6 )-alkyl;
R2 and R3 are H;
R4 is H, F, Cl, Br, (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, ═O, (C 1 -C 6 )-alkyl, or (C 0 -C 6 )-alkylene-aryl;
R5 is H;
R6 is H;
R7 is H, F, Cl, Br, ═O, ═N—O—(C 0 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;
A is thiazol-2-yl, pyrazol-3-yl, isoxazol-3-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, [1,3,4]thiadiazol-3-yl, pyridazin-2-yl, thiazolo[4,5-b]pyridin-2-yl, or thieno[2,3-d]thiazol-2-yl; and
B is cyclopentyl, cyclohexyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, oxetanyl, piperidinyl, or indanyl;
or a physiologically acceptable salt thereof.
7. The compound according to claim 1 , wherein
R1 is (C 1 -C 6 )-alkyl;
R2 and R3 are H;
R4 is H, F, Cl, Br, (C 0 -C 6 )-alkylene-COO—(C 0 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-O—(C 0 -C 6 )-alkyl, ═O, (C 1 -C 6 )-alkyl, or (C 0 -C 6 )-alkylene-aryl;
R5 is H;
R6 is H;
R7 is H, F, Cl, Br, ═O, ═N—O—(C 0 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;
A is thiazol-2-yl, pyrazol-3-yl, isoxazol-3-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, [1,3,4]thiadiazol-3-yl, pyridazin-2-yl, thiazolo[4,5-b]pyridin-2-yl, or thieno[2,3-d]thiazol-2-yl; and
B is cyclopentyl, cyclohexyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, oxetanyl, piperidinyl, or indanyl;
or a physiologically acceptable salt thereof.
8. A pharmaceutical composition comprising at least one compound according to claim 1 or a physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
9. A pharmaceutical composition comprising at least one compound according to claim 2 or a physiologically acceptable salt thereof, in combination with a pharmacologically acceptable carrier or excipient.
10. A pharmaceutical composition comprising at least one compound according to claim 3 or a physiologically acceptable salt thereof, in combination with a pharmacologically acceptable carrier or excipient.
11. A pharmaceutical composition comprising at least one compound according to claim 4 or a physiologically acceptable salt thereof, in combination with a pharmacologically acceptable carrier or excipient.
12. A pharmaceutical composition comprising at least one compound according to claim 5 or a physiologically acceptable salt thereof, in combination with a pharmacologically acceptable carrier or excipient.
13. A pharmaceutical composition comprising at least one compound according to claim 6 or a physiologically acceptable salt thereof, in combination with a pharmacologically acceptable carrier or excipient.
14. A pharmaceutical composition comprising at least one compound according to claim 7 or a physiologically acceptable salt thereof, in combination with a pharmacologically acceptable carrier or excipient.
15. The pharmaceutical composition according to claim 8 , comprising at least one further active ingredient.
16. The pharmaceutical composition according to claim 9 , wherein the further active ingredient is selected from antidiabetics, hypoglycemic active ingredients, HMGCOA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, PPAR delta 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, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose-1,6-biphosphatase, modulators of glucose transporter 4, inhibitors of glutamine-fructose-6-phosphate amidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, modulators of the sodium-dependent glucose transporter 1, modulators of the sodium-dependent glucose transporter 2, GPR40 modulators, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaB kinase, modulators of glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, human growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 modulators, uncoupling protein 3 modulators, leptin agonists, DA agonists, bromocriptine, Doprexin, lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR-β agonists, and amphetamines.
17. A method for treating type-2 diabetes, schizophrenia, or for lowering blood glucose level lowering blood glucose level, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 , or a physiologically acceptable salt thereof.
18. A method for manufacturing a pharmaceutical composition comprising at least one compound according to claim 1 or a physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient, comprising mixing the compound according to claim 1 or the physiologically acceptable salt thereof with the pharmaceutically acceptable carrier or excipient, and converting this mixture into a form suitable for administration.