Concomitant drugs
This invention provides a pharmaceutical agent containing, in combination, a sulfonamide compound and other therapeutic agent, preferably, at least one compound represented by the formula (I): R 1 —SO 2 —NH—CO-A 1 -CH 2 —R 2 [each symbol is as defined in the specification] or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical agent selected from the group consisting of an α-glucosidase inhibitor, an insulin secretagogue, a sulfonylurea and a biguanide, which has a superior therapeutic effect.
1 . A pharmaceutical agent comprising, in combination, at least one compound represented by the formula (I):
R 1 —SO 2 —NH—CO-A 1 -CH 2 —R 2 (I)
wherein
R 1 is a group selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted aryl group and an optionally substituted heterocyclic group, R 2 is an optionally substituted aryl group, or an optionally substituted heterocyclic group, and
A 1 is an optionally substituted divalent group of heterobicycle, or a group represented by —CH═CH-A 2 - wherein A 2 is an optionally substituted divalent group of nitrogen-containing 5- or 6-membered heterocycle,
or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical agent selected from the group consisting of an α-glucosidase inhibitor, an insulin secretagogue, a sulfonylurea and a biguanide.
2 . The pharmaceutical agent of claim 1 , wherein R 1 is a lower alkyl group; a lower alkenyl group optionally substituted by an aryl group; an aryl group optionally substituted by a lower alkyl group or a lower alkenyl group; or a heterocyclic group optionally substituted by a halogen atom, and
R 2 is an aryl group or a heterocyclic group, which group is substituted by at least one group selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower alkoxy group, a lower alkylthio group, an optionally substituted amino group, a morpholino group, an acyl group, a halogen atom, an aryl group, an optionally substituted heterocyclic group, and a nitro group.
3 . The pharmaceutical agent of claim 1 , wherein R 1 is a lower alkyl group, a lower alkenyl group optionally substituted by a phenyl group, a phenyl group optionally substituted by a lower alkyl group or a lower alkenyl group or a halothienyl group,
R 2 is a group selected from the group consisting of a phenyl group, a naphthyl group and pyridyl group, which group is substituted by at least one group selected from the group consisting of a lower alkyl group optionally substituted by a halogen atom, a phenyl group, a phenoxy group or a cyclo(lower)alkyloxy group; a lower alkenyl group; a lower alkynyl group optionally substituted by a phenyl group; a lower alkoxy group optionally substituted by a phenyl group, a cyclo(lower)alkyl group or a thienyl group; a lower alkylthio group; a lower alkylamino group optionally substituted by a lower alkoxycarbonyl group; a lower alkanoylamino group; a lower alkoxycarbonyl group; a halogen atom; a phenyl group; a thienyl group optionally substituted by a halogen atom; a furyl group; a morpholino group; and a nitro group, and
A 1 is a divalent group of heterobicycle selected from the group consisting of benzimidazole, indole, imidazopyridine, benzofuran and indazole, which group is substituted by at least one lower alkyl group; or A 1 is a group represented by —CH═CH-A 2 - wherein A 2 is a divalent group of imidazole, which group is a substituted by at least one group selected from the group consisting of a lower alkyl group and a halogen atom.
4 . The pharmaceutical agent of claim 3 , wherein the heterobicycle for A 1 is imidazopyridine.
5 . The pharmaceutical agent of claim 4 , wherein the compound represented by the formula (I) is
3-[(1-bromo-2-naphthyl)methyl]-N-[(5-chloro-2-thienyl)sulfonyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxamide, or
ethyl {3-chloro-4-[(2-methyl-5-{[(pentylsulfonyl)amino]carbonyl}-3H-imidazo[4,5-b]pyridin-3-yl)methyl]phenyl}methylcarbamate.
6 . The pharmaceutical agent of claim 3 , wherein the heterobicycle for A 1 is benzimidazole.
7 . The pharmaceutical agent of claim 6 , wherein the compound represented by the formula (I) is
1-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-1H-benzimidazole-6-carboxamide,
1-[(3-chloro-4-biphenylyl)methyl]-2-methyl-N-(pentylsulfonyl)-1H-benzimidazole-6-carboxamide, or
1-(4-bromo-2-chlorobenzyl)-2-methyl-N-[(1E)-1-penten-1-ylsulfonyl]-1H-benzimidazole-6-carboxamide.
8 . The pharmaceutical agent of claim 3 , wherein the heterobicycle for A 1 is indole.
9 . The pharmaceutical agent of claim 8 , wherein the compound represented by the formula (I) is
3-[(3-chloro-4-biphenylyl)methyl]-2-methyl-N-(pentylsulfonyl)-1H-indole-5-carboxamide, or
3-[2-chloro-4-(2-thienyl)benzyl]-2-methyl-N-[(4-methylphenyl)sulfonyl]-1H-indole-5-carboxamide.
10 . The pharmaceutical agent of claim 3 , wherein the heterobicycle for A 1 is benzofuran.
11 . The pharmaceutical agent of claim 10 , wherein the compound represented by the formula (I) is
3-[(3-chloro-4-biphenylyl)methyl]-2-methyl-N-[(1E)-1-penten-1-ylsulfonyl]-1-benzofuran-5-carboxamide, or
3-[(3-chloro-4-biphenylyl)methyl]-2-methyl-N-{[(E)-2-phenylvinyl]sulfonyl}-1-benzofuran-5-carboxamide.
12 . The pharmaceutical agent of claim 3 , wherein the heterocycle for A 1 is indazole.
13 . The pharmaceutical agent of claim 12 , wherein the compound represented by the formula (I) is
1-[(3-chloro-4-biphenylyl)methyl]-3-methyl-N-[(1E)-1-penten-1-ylsulfonyl]-1H-indazole-6-carboxamide.
14 . The pharmaceutical agent of claim 3 , wherein A 1 is a group represented by —CH═CH-A 2 - wherein A 2 is a divalent group of imidazole, which is substituted by at least one group selected from the group consisting of a lower alkyl group and a halogen atom.
15 . The pharmaceutical agent of claim 14 , wherein the compound represented by the formula (I) is
(2E)-3-{4-chloro-1-[2-chloro-4-(phenylethynyl)benzyl]-2-methyl-1H-imidazol-5-yl}-N-[(4-methylphenyl)sulfonyl]acrylamide,
(2E)-3-{4-chloro-1-[2-chloro-4-(pentyloxy)benzyl]-2-ethyl-1H-imidazol-5-yl}-N-{[(E)-2-phenylvinyl]sulfonyl}acrylamide,
(2E)-3-{4-chloro-1-[2-chloro-4-(phenylethynyl)benzyl]-2-methyl-1H-imidazol-5-yl}-N-(pentylsulfonyl)acrylamide, or
(2E)-3-{4-chloro-1-[2-chloro-4-(phenylethynyl)benzyl]-2-ethyl-1H-imidazol-5-yl}-N-[(1E)-1-penten-1-ylsulfonyl]acrylamide.
16 . The pharmaceutical agent of claim 3 , wherein the compound represented by the formula (I) is
3-[(1-bromo-2-naphthyl)methyl]-N-[(5-chloro-2-thienyl)sulfonyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxamide,
ethyl {3-chloro-4-[(2-methyl-5-{[(pentylsulfonyl)amino]carbonyl}-3H-imidazo[4,5-b]pyridin-3-yl)methyl]phenyl}methylcarbamate,
1-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-1H-benzimidazole-6-carboxamide,
1-[(3-chloro-4-biphenylyl)methyl]-2-methyl-N-(pentylsulfonyl)-1H-benzimidazole-6-carboxamide,
1-(4-bromo-2-chlorobenzyl)-2-methyl-N-[(1E)-1-penten-1-ylsulfonyl]-1H-benzimidazole-6-carboxamide,
3-[(3-chloro-4-biphenylyl)methyl]-2-methyl-N-(pentylsulfonyl)-1H-indole-5-carboxamide,
3-[(3-chloro-4-biphenylyl)methyl]-2-methyl-N-{[(E)-2-phenylvinyl]sulfonyl}-1-benzofuran-5-carboxamide, or
(2E)-3-{4-chloro-1-[2-chloro-4-(phenylethynyl)benzyl]-2-ethyl-1H-imidazol-5-yl}-N-[(1E)-1-penten-1-ylsulfonyl]acrylamide.
17 . The pharmaceutical agent of claim 1 , which comprises a compound represented by the formula (I) and an α-glucosidase inhibitor in combination.
18 . The pharmaceutical agent of claim 1 , which comprises a compound represented by the formula (I) and an insulin secretagogue in combination.
19 . The pharmaceutical agent of claim 1 , which comprises a compound represented by the formula (I) and a sulfonylurea in combination.
20 . The pharmaceutical agent of claim 1 , which comprises a compound represented by the formula (I) and a biguanide in combination.
21 . A method for preventing and/or treating impaired glucose tolerance disorder, diabetes, gestational diabetes, diabetic complications, insulin resistance syndrome, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases, hyperglycemia, pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases, or skin disorders related to an anomaly of differentiation of epidermic cells in a mammal in need thereof, which comprises administering an effective amount of at least one compound represented by the formula (I):
R 1 —SO 2 —NH—CO-A 1 -CH 2 —R 2 (I)
wherein
R 1 is a group selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted aryl group and an optionally substituted heterocyclic group,
R 2 is an optionally substituted aryl group or an optionally substituted heterocyclic group, and
A 1 is an optionally substituted divalent group of heterobicycle or a substituent represented by —CH═CH-A 2 -, wherein A 2 is an optionally substituted divalent group of nitrogen-containing 5- or 6-membered heterocycle,
or a pharmaceutically acceptable salt thereof, to said mammal, and
administering, to said mammal, an effective amount of at least one pharmaceutical agent selected from the group consisting of an α-glucosidase inhibitor, an insulin secretagogue, a sulfonylurea and a biguanide.
22 . The method of claim 21 , which comprises administering, simultaneously, separately or in a staggered manner to said mammal, an effective amount of at least one compound represented by the formula (I) and an effective amount of at least one pharmaceutical agent selected from the group consisting of an α-glucosidase inhibitor, an insulin secretagogue, a sulfonylurea and a biguanide.
23 . A commercial package comprising a pharmaceutical agent comprising, in combination, at least one compound represented by the formula (I):
R 1 —SO 2 —NH—CO-A 1 -CH 2 —R 2 (I)
wherein
R 1 is a group selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted aryl group and an optionally substituted heterocyclic group,
R 2 is an optionally substituted aryl group or an optionally substituted heterocyclic group, and
A 1 is an optionally substituted divalent group of heterobicycle or a substituent represented by —CH═CH-A 2 -, wherein A 2 is an optionally substituted divalent group of nitrogen-containing 5- or 6-membered heterocycle,
or a pharmaceutically acceptable salt thereof, and
at least one pharmaceutical agent selected from the group consisting of an α-glucosidase inhibitor, an insulin secretagogue, a sulfonylurea and a biguanide, and
a written matter associated with the pharmaceutical agent, the written matter stating that the pharmaceutical agent can or should be used for preventing or treating impaired glucose tolerance disorder, diabetes, gestational diabetes, diabetic complications, insulin resistance syndrome, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases, hyperglycemia, pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases or skin disorders related to an anomaly of differentiation of epidermic cells and that an effective amount of at least one compound represented by the formula (I) and an effective amount of at least one pharmaceutical agent selected from the group consisting of an α-glucosidase inhibitor, an insulin secretagogue, a sulfonylurea and a biguanide, can or should be administered, simultaneously, separately or in a staggered manner to a mammal.