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|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)|
|Filing Date:||Jul 18, 2000|
|Claims:||1. A method for treating diabetic complications in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of an insulin sensitivity enhancer in combination with a squalene synthesis inhibitor. |
2. The method according to claim 1, wherein the insulin sensitivity enhancer is 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 oxygen atom or sulfur atom; R.sup.1 represents hydrogen atom or an alkyl group; ring E may optionally have further 1 to 4 substituents, and the substituents may optionally be combined with R.sup.1 to form a ring; L and M respectively represents hydrogen atom, or L and M may optionally be combined with each other to form a bond; or a pharmacologically acceptable salt thereof.
3. The method according to claim 2, wherein R is an optionally substituted heterocyclic group.
4. The method according to claim 3, 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, 4-pyradizinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-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-6-yl, 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, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 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, 1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[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.
5. The method according to claim 2 wherein m is 0.
6. The method according to claim 2, wherein X is CH.
7. The method according to claim 2, wherein R.sup.1 is hydrogen atom.
8. The method according to claim 2, wherein the partial formula: ##STR9##
wherein R.sup.2 represents hydrogen atom, an alkyl group, an optionally substituted hydroxyl group, a halogen atom, an optionally substituted acyl group, nitro group or an optionally substituted amino group.
9. The method according to claim 2, wherein L and M are hydrogen atom.
10. The method according to claim 2, wherein R is pyridyl, oxazolyl or thiazolyl group optionally having 1 to 3 substituents selected from C.sub.1-3 alkyl, furyl, thienyl, phenyl and naphthyl; m is 0; n is 0 or 1; X is CH; A is a bond or --(CH.sub.2).sub.2 --; R.sup.1 is hydrogen atom; the partial formula: ##STR10##
and R.sup.2 is hydrogen atom or C.sub.1-4 alkoxy group; and L and M are both hydrogen atom.
11. The method according to claim 1, wherein the insulin sensitivity enhancer is pioglitazone or its hydrochloride.
12. The method according to claim 1, wherein the insulin sensitivity enhancer is troglitazone.
13. The method according to claim 1, wherein the insulin sensitivity enhancer is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl-2,4-thiazolidinedione or its pharmacologically acceptable salts.
14. The method according to claim 1, wherein the insulin sensitivity enhancer and squalene synthesis inhibitor are mixed together to form an admixture and the admixture is administered to the mammal.
15. The method according to claim 1, wherein the insulin sensitivity enhancer and squalene synthesis inhibitor are not mixed together but are administered independently to the mammal.