|Abstract:||Pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with other antidiabetics differing from the enhancer in the mechanism of action, which shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes.|
|Inventor(s):||Ikeda; Hitoshi (Higashiosaka, JP), Sohda; Takashi (Takatsuki, JP), Odaka; Hiroyuki (Kobe, JP)|
|Assignee:||Takeda Chemical Industries, Ltd. (Osaka, JP)|
1. A method for reducing the side effects of respective active components administered to a diabetic patient, which comprises administering to said patient a therapeutically
effective amount of a compound represented by the formula: ##STR8##
wherein R' represents an optionally substituted hydrocarbon or heterocyclic group; Y represents a group represented by --CO--, --CH(OH)-- or --NR.sup.3 -- wherein R.sup.3 represents an optionally substituted alkyl group; m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or a C.sub.1-7 divalent aliphatic hydrocarbon group; Q represents an oxygen atom or sulfur atom; R.sup.1 represents hydrogen atom or an alkyl group; ring E may optionally have 1 to 4 further substituents, and the substituents may optionally be combined with R.sup.1 to form a ring; L and M respectively represent a hydrogen atom, or L and M may optionally be combined with each other to form a bond; with a proviso that R' does not represent benzopyranyl group when m and n are 0, X represents CH, A represents a bond, Q represents sulfur atom, R.sup.1, L and M represent hydrogen atoms and ring E does not have further substituents; or a pharmacologically acceptable salt thereof, in combination with an insulin secretion enhancer.
2. The method according to claim 1, wherein the compound represented by the formula (II) is the compound represented by the formula: ##STR9##
3. The method according to claim 1, wherein the compound represented by the formula (II) is pioglitazone or its pharmacologically acceptable salts.
4. The method according to claim 1, wherein the insulin secretion enhancer is glibenclamide.
5. The method according to claim 1, wherein the compound represented by the formula (Il) is pioglitazone and the insulin secretion enhancer is glibenclamide.
6. The method according to claim 1, wherein the compound represented by the formula (II) is 5-[[4-[2(-methyl-2-pyridylamino)ethoxy]phenyl]methyl-2,4-thiazolidinedione or its pharmacologically acceptable salts.
7. The method according to claim 1, wherein the compound represented by the formula (II) is troglitazone or its pharmacologically acceptable salts.
8. The method according to claim 1, wherein the insulin secretion enhancer is a sulfonylurea.
9. The method according to claim 8, wherein the sulfonylurea is selected from tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4chloro-N-[(1-pyrolidinylamino)carbonyl]-benzenesulfonamide or its ammonium salt, glibenclamide, gliclazide, 1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide and tolcyclamide.
10. The method according to claim 1, wherein R' is an optionally substituted heterocyclic group.
11. The method according to claim 10, wherein R' is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4thiazolyI, 5-thiazolyl, 2-oxazolyl, 4oxazolyl, 5-oxazolyl, 1,2,4oxadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridin-6yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl and benzopyranyl; each of which may have 1 to 5 substituents selected from the group consisting of C.sub.1-15 aliphatic hydrocarbon group; C.sub.3-12 alicyclic hydrocarbon group; C.sub.6-14 aryl group; aromatic heterocyclic group selected form the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4,-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4thiadiazolyl, 1,3,4thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, .alpha.-carbolinyl, .beta.carbolinyl, y-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1, 2,4triazolo[4, 3-a]pyridyl and 1,2,4triazolo[4,3-b]pyridazinyl; non-aromatic heterocyclic group selected from the group consisting of oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, morpholino and thiomorpholino; halogen atom; nitro group; amino groups which may have one or two substituents selected from C.sub.1-10 alkyl group, C.sub.2-10 alkenyl group, C.sub.2-10 alkynyl group, aromatic group, heterocyclic group or C.sub.1-10 acyl group; C.sub.1-13 acyl group which may be substituted by C.sub.1-3 alkyl group, C.sub.1-3 alkoxy group, halogen atom, nitro group, hydroxyl group or amino group; hydroxyl group; C.sub.1-10 alkoxy group; C.sub.3-10 cycloalkyloxy group; C.sub.2-10 alkenyloxy group; C.sub.3-10 cycloalkenyloxy group; C.sub.7-10 aralkyloxy group; C.sub.2-13 acyloxy group; C.sub.6-14 aryloxy group which may be substituted with one or two halogen atoms; thiol group; C.sub.1-10 alkylthio group; C.sub.3-10 cycloalkylthio group; C.sub.2-10 alkenylthio group; C.sub.3-10 cycloalkenylthio group, C.sub.7-10 aralkylthio group, C.sub.2-13 acylthio group; C.sub.6-14 arylthio group which may be substituted with one or two halogen atoms; carboxyl group; C.sub.2-5 alkoxycarbonyl group; C.sub.8-10 aralkyloxycarbonyl group; C.sub.7-15 aryloxycarbonyl group; amidino group; carbamoyl group; sulfamoyl group; sulfo group; cyano group; azido group and nitroso group.
12. The method according to claim 1, wherein the insulin secretion enhancer is selected from the group consisting of N-[[4-(1-methylethyl)cyclohexyl)carbonyl]-D-phenylalanine; calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate dihydrate and glimepiride.
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