MXPA00010582A - Pharmaceutical composition for the treatment of diabetes - Google Patents

Abstract

A pharmaceutical composition which comprises aninsulin sensitizer in combination with an anorectic, which is useful as an agent for preventing or treating diabetes.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF DIABETES TECHNICAL FIELD The present invention concerns a pharmaceutical composition comprising an insulin sensitizer (agent that improves insulin resistance) in combination with an anorectic. The pharmaceutical composition of the present invention can be used as an agent to prevent or treat diabetes, etc.

BACKGROUND OF THE INVENTION Examples of prior references in the art concerning an insulin sensitizer or an anorectic are mentioned below. 1) JP-A H9 (1997) -67271 describes "a pharmaceutical composition, an enhancer of insulin sensitivity in combination with at least one member selected from the group consisting of the α-glucosidase inhibitor, an aldose reductase inhibitor, an biguanidine, a statin compound, an inhibitor of squalene synthesis, a fibrate compound, an LDL catabolism enhancer and a REF 123745 inhibitor of angiotensin converting enzyme. 2) JP-A H5 (1993) - 148196 discloses that "a pharmaceutical composition comprising 4- [2-μ2-hydroxy-2-phenylethylamino) ethoxyphyphenyl acetic acid, or its precursors or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier "may contain an anorectic wun, a vitamin, a blood pressure lowering agent and a blood glucose lowering agent, for example, sulfonylureas, biguanidines and thiazolidindicetones. 3) Diabetes Frontier, Vol. 8, p. 499 (1977) discloses that "CL316243 completely inhibited the weight gained in dark adipose tissues caused by troglitazone" when CL315243 (β 3 adrenergic receptor antagonist) and troglitazone were administered to obese rats. 4) W093 / 3724 discloses that 3-guanidinopropionic acid (3-GPA) antagonizes in a dose-dependent manner the gained weight that occurs in obese, KKAr diabetic mice that were treated with pioglitazone hydrochloride, a sensitizing agent to the insulin.

) Egypt. J. Pharm. Sci.-, vol. 29, No. 1-4, pp, 355-356 (1988) describes "interactions of some anorexigenic drugs with tolbutamide in normal and diabetic rats". 6) 097/27847 discloses that "acetaminophenols which are useful as antiobesity and antidiabetic compounds can be used together with" fenfluramines, dexfenfluramines, fentanyl, ß3'A adrenergic receptor agonists.

These prior references in the art do not specifically describe or suggest combining an insulin sensitizer with an anorectic, and effects of such combination.

The origin of non-insulin-dependent diabetes mellitus (NIDDM) includes insufficient action of insulin in the liver and peripheral tissues (insulin resistance) as well as deficiency in the secretion of insulin in the pancreas. The onset of insulin resistance is highly affected by the present environmental satiety such as fatigue and obesity, and food therapy is used primarily for the reduction of insulin resistance. However, the observance and continuation of the food-therapy is accompanied by mental pains of the patients, and in many cases it does not give the desired results. Therefore, an insulin sensitizer is used as a subsidiary drug for food therapy, and an anti-obesity drug is used in patients accompanied by a high degree of obesity.

The insulin sensitizer strengthens the action of insulin in diabetic patients with lower blood sugar.

In obesity, the number of insulin receptors in fat cells themselves is reduced because of the hypertrophy of fatty tissues, additionally, insulin resistance is reinforced by accelerated secretion of cytokines that cause insulin resistance such as TNF-a . The increase in the amount of insulin required accelerates the secretion of insulin in the pancreas. As a result, in the majority of cases, obesity is accompanied by hyper-insulinenia or hyper-lipidemia.

On the other hand, an anorectic does not result in lowering blood glucose in many cases, although they reduce body fat. The anorexic is known to have collateral effects such as dependence, hydrodipsia, constipation, nausea, emesis, gastric discomfort, stomach flatulence, vertigo, palpitation, rash, increase in GTO or GPT, sleep disorders, etc.

It is convenient, the development of excellent drugs that are sufficiently improved, as a medicine that has an effect on diabetic treatment without apparent detection of side effects.

DESCRIPTION OF THE INVENTION As a result of several studies of medical properties such as an effect on diabetic treatment, a side effect, etc., the inventors here combined an insulin sensitizer with an anorectic for the first time, and found, for the first time, that such combination unexpectedly provides truly excellent properties as a medicine such as, an excellent blood sugar lowering effect, with no apparent detection of side effects, etc. Based on this finding, the inventors hereby concluded the present invention.

It means that, the present invention concerns (1) a pharmaceutical composition comprising an insulin sensitizer in combination with an anorectic; (2) a pharmaceutical composition according to the above (1), wherein the insulin sensitizer is a compound of the invention. formula: wherein R represents a hydrocarbon group or a heterocyclic group, each of which may be substituted; Y, represents a group of the formula: -CO-, -CH (OH) - or -NR3- wherein R3 represents an alkyl group that can be substituted; ra, is 0 or 1; n, is 0, 1 or 2; X, represents CH or N; A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q, represents oxygen or sulfur; R1 represents hydrogen or an alkyl group; the ring E can additionally have 1 to 4 substituents, which can form a ring in combination with R1; L and M, respectively, represent hydrogen or can be combined with each other to form a chemical ligation; or a salt thereof: (3) a pharmaceutical composition according to the above (1), wherein the insulin sensitizer is pioglitazone hydrochloride, troglitazone, rosiglitazone or 4- [4- [2- (6-methyl -2-phenyloxazol-4-yl) ethoxy] benzyl] isoxazolidin-3, 5-diketone; (4) a pharmaceutical composition according to the above (2), wherein the compound of the formula (I) or salt thereof is pioglitazone hydrochloride; (5) a pharmaceutical composition according to the above (1), wherein the anorectic is a central anorectic; (6) a pharmaceutical composition according to the above (5), in which the central anorectic is mazindol; (7) a pharmaceutical composition according to the above (1), wherein the insulin sensitizer is hydrochloride d epioglitazone and the anorectic is mazindol; (8) a pharmaceutical composition according to the foregoing (1) which is for preventing or treating diabetes; (9) a pharmaceutical composition according to the above (8), wherein the diabetes mellitus is not insulin-dependent; (10) a pharmaceutical composition according to the above (2) _, wherein the compound of formula (I) or salt thereof is trooglitazone; (11) a pharmaceutical composition according to the above (2), wherein the compound of the formula (I) or salt thereof is rosiglitazone or its maleate; (12) a pharmaceutical composition according to the above (1), which is to prevent or treat diabetic complications; (13) a pharmaceutical composition according to the above (1), which is to prevent or treat the alteration in glucose tolerance; (14) a pharmaceutical composition which comprises an insulin sensitizer and is used in combination with an anorectic; (15) a method for preventing or treating diabetes in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic; (16) a method for preventing or treating diabetic complications in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic; (17) a method for preventing or treating impaired glucose tolerance in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic; (18) use of an insulin sensitizer to treat diabetes which is used in combination with an anorectic; (19) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating diabetic complications which is used in combination with an anorectic; (20) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance which is used in combination with an anorectic; Y (21) a method for reducing the amount of an insulin sensitizer or / and an anorectic administered to a diabetic mammal, which comprises administering to said mammal an effective amount thereof.

The insulin sensitizer used in the present invention means any and all drugs that restore the altered insulin receptor function and improve insulin resistance.

Specific examples of insulin sensitizer include the above-mentioned compound represented by formula (I) or a salt thereof.

As regards formula (I), examples of the hydrocarbon group in the hydrocarbon group which can be substituted by R include aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, alicyclic-aliphatic hydrocarbon groups, aromatic-aliphatic hydrocarbon groups, and hydrocarbon groups aromatics The number of carbon atoms constituting such hydrocarbon groups is preferably 1 to 14.

The aliphatic hydrocarbon group is preferably an aliphatic C? _8 hydrocarbon group. Examples of the aliphatic hydrocarbon group include saturated aliphatic C?-8 hydrocarbon groups (eg alkyl groups, etc.) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl , neopentyl, t-pentyl, hexyl, isohexyl, heptyl, and octyl; and unsaturated aliphatic C2-8 hydrocarbon groups (eg, alkenyl groups, alkadienyl groups, alkynyl groups, alkyldinyl groups, etc.) such as vinyl, 1- propenyl, 2-propenyl, 1-butenyl, 3-butenyl, 2-methyl- l- propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2, -hexadinyl, 5-hexynyl, 1-heptinyl, and 1-octynyl.

The alicyclic hydrocarbon group is preferably an alicyclic C3_7 hydrocarbon group. Examples of the alicyclic hydrocarbon group include saturated C3-7 alicyclic hydrocarbon groups (e.g., cycloalkyl groups, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and unsaturated alicyclic C5-7 hydrocarbon groups (e.g. cycloalkenyl, cycloalkadienyl groups, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, and 2, 4 -cycloheptadienyl.

The alicyclic-aliphatic hydrocarbon group is a group consisting of the above-described alicyclic hydrocarbon and aliphatic hydrocarbon group (e.g., cycloalkyl-alkyl groups, cycloalkenyl-alkyl groups, etc.) and is preferably an alicyclic-aliphatic C4-9 hydrocarbon group.

Examples of the alicyclic-aliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc.

The aromatic-aliphatic hydrocarbon group is preferably an aromatic-aliphatic C7-13 hydrocarbon group (for example, aralkyl groups, etc.). examples of the aliphatic aromatic hydrocarbon group include C7-9 phenylalkyl such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; Cp-13 naphthylalkyl such as α-naphthylmethyl, α-nephthylethyl, β-naphthylmethyl, and β-naphthylethyl.

The aromatic hydrocarbon group is preferably a C6 hydrocarbon group? aromatic (for example aryl groups, etc.).

Examples of the aromatic hydrocarbon group include phenyl and naphthyl (α-naphthyl and β-naphthyl).

As regards the formula (I), examples of the heterocyclic group in a hetrocyclic group which can be substituted by R is a 5- to 7-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen in addition to carbon as members of the ring or a condensed cyclic group. Examples of the fused ring include one consisting of such a 5- to 7-membered heterocyclic group with a ring containing 1 or 2 nitrogen atoms, a benzene ring, or a five-membered ring containing a sulfur atom.

Examples of the heterocyclic group include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,, 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, lH-indazol-3-yl, lH-pyrrolo [2, 3-b] pyrazin-2-yl, lH-pyrrolo [2, 3-b] pyridin-6-yl, lH-imidazole [ 4, 5-b] pyridin-2-yl, lH-imidazol [4, 5-c] pyridin-2-yl, 1H-imidazol [4, 5-b] pyrazin-2-yl, benzopyranyl and dihydrobenzopyranyl. The preferred heterocyclic group is the pyridyl, oxasolyl or thiazolyl group.

As regards formula (I), the hydrocarbon group and the heterocyclic group for R may respectively have 1 to 5, preferably 1 to 3 substituents in substitutable positions.

Such substituents include, for example, aliphatic hydrocarbon groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, halogen group, nitro, amino that can be substituted, acyl group that can be substituted, hydroxy group that can be substituted, thiol group that can be substituted , carboxyl group that can be esterified, amidino, carbamoyl, sulfamoyl, sulfo, cyano, azido, and nitroso.

Examples of the aliphatic hydrocarbon group include straight chain or branched aliphatic hydrocarbon groups having 1 to 5 carbon atoms, such as aryl groups, alkenyl groups, and alkynyl groups.

The preferred alkyl group is a C? -? Or alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-ethylpropyl , hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, and decyl.

The preferred alkenyl group is a C2_? 0 alkenyl group, such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l- butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and -hexenyl.

The preferred alkynyl group is a C2-? 0 alkynyl group, such as ethynyl, -1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentynyl, 3-pentynyl, 4-Pentynyl, 1-Hexynyl, 2-Hexynyl, 3-Hexynyl, 4-Hexynyl, and 5-Hexynyl.

Examples of the alicyclic hydrocarbon group include saturated and unsaturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms, such as cycloalkyl groups, cycloalkenyl groups, and cycloalkcadienyl groups.

The preferred cycloalkyl group is a C3-10 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2. Ljheptyl, bicyclo [2.2.2.] octyl, bicyclo [3.2.1.Joctyl, bicyclo [3.2.2] nonyl, bicyclo [3.3. ljnonilo, bicycle [4.2. IJnonilo, ybiciclo [4.3. l] decilo.

The preferred cycloalkenyl group is a C3-10 cycloalkenyl group, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl.

The preferred cycloalkadienyl group is a C 4 -α or cycloalkadienyl, such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and 2,5-cyclohexadien-1-yl.

The preferred aryl group is a C6-? aryl, such as phenyl, naphthyl (1-naphthyl, 2-naphthyl), anthryl, phenanthryl, and acenaphthylenyl.

The preferred aromatic group includes monocyclic aromatic heterocyclic groups, such as 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, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and fused aromatic heterocyclic groups, such as benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, IH-benzotriazolyl, quinolyl, isoquinolyl, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, α-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxyntinyl, thiantrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [ 1, 2-b] pyridazinyl, pyrazolo [l, 5-a] pyridyl, imidazofl, 2-ajpyridyl, imidazo [l, 5-a] pyridyl, imidazo [l, 2-b] pyridazinyl, imidazo [l, 2] a] pyrimidinyl, 1,2,4-triazolo [4, 3-a] pyridyl, and 1,2,4-triazolo [4, 3-b] pyridazinyl.

The preferred non-aromatic heterocyclic group includes oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, morpholino, and thiomorpholino.

Examples of halogen include fluorine, chlorine, bromine, and iodine.

As far as the amino group which can be substituted is concerned, examples of the substituted amino group include N-monosubstituted groups and N, N-di-substituted amino groups. Examples of the substituted amino group include amino groups having one or two substituents selected from the group consisting of C? -? 0 alkyl groups, C2-? Or alkenyl groups, C2_? 0 alkynyl groups, aromatic groups, heterocyclic groups, or C groups ? -? or acyl (for example methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino,? icotinoylamino, etc.).

Examples of the acyl group in the acyl groups which can be substituted include C1-13 acyl groups, for example, C1-10 alkanoyl groups, C3-10 alkenoyl groups, C4-10 cycloalkanoyl groups, C4-10 cycloalkenoyl groups, Ce-ia groups aromatic carbonyl.

Preferred examples of the C 1-10 alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, hepatnoyl, and octanoyl.

Preferred examples of the alkenoyl C3-10 groups include acryloyl, methacryloyl, crotonoyl, and isocrotonoyl.

Preferred examples of the C4-10 cycloalkanoyl groups include cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, and cycloheptanecarbonyl.

Preferred examples of the C-? Or cycloalkenoyl groups include 2-cyclohexencarbonyl.

Preferred examples of the C6-? 2-aromatic carbonyl groups include benzoyl, naphthoyl, and nicotinoyl.

Examples of the substituents on the substituted acyl groups include C? _ Alkyl groups, C? _ Alkoxy groups, halogen (e.g., chlorine, fluorine, bromine, etc.), nitro, hydroxy and amino As to the hydroxy group which may be substituted, examples of the substituted hydroxy include alkoxy groups, cycloalkyloxy groups, alkenyloxy groups, cycloalkenyloxy groups, aralkyloxy groups, acyloxy groups, and aryloxy groups.

The preferred alkoxy group includes C? -? 0 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, and nonyloxy.

The preferred cycloalkyloxy group includes C3-10 cycloalkyloxy groups, such as cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.

The preferred alkenyloxy group includes C2-? Or alkenyloxy groups, such as allyloxy, crotyloxy, 2-pentenyloxy, and 3-hexenyloxy.

The preferred cycloalkenyloxy group includes C3-10 cycloalkenyloxy groups, such as 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy.

A preferred arallyoxyloxy group includes C 7-10 aralkyloxy groups, such as phenyl C 4 alkyloxy (for example benzyloxy, phenethyloxy, etc.).

The preferred acyloxy group includes C2_3 acyloxy groups, more preferably C2-4 alkanoyloxy groups (for example acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.).

The preferred aryloxy group includes C6-i4 aryloxy groups, such as phenoxy, and naphthyloxy- These aryloxy groups may have 1 or 2 substituents. Examples of the substituents include halogen (for example, chlorine, fluorine, bromine, etc.). examples of the substituted aryloxy group include 4-chlorophenoxy.

As to the thiol group which can be substituted, examples of the substituted thiol group include alkylthio groups, cycloalkylthio groups, alkenylthio groups, cycloalkenylthio groups, aralkylthio groups, acylthio groups, and arylthio groups.

The preferred alkylthio group includes C 1 -C alkylthio groups, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, and pentthylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, and nonylthio.

The preferred cycloalkylthio group includes C2-10 cycloalkylthio groups such as cyclobutylthio, cyclopentylthio, and cyclohexylthio.

The preferred alkenylthio group includes C2-? Or alkenylthio groups, such as allylthio, crotylthio, 2-phenethylthio, and 3-hexenylthio.

The preferred cycloalkenylthio group includes C3-10 cycloalkenylthio groups such as 2-cyclopentylthio, and 2-cyclohexenylthio.

The preferred aralkylthio group includes C7-10 aralkylthio groups, such as phenyl-C4-4 alkylthio (for example benzylthio, phenethylthio, etc.).

The acylthio group is preferably a C2_3 acylthio group, more preferably a C2-4 alkanoylthio group (for example acetylthio, propionylthiol, butyrylthio, isobutyrylthio, etc.).

The preferred arylthio group includes C6-i4 arylthio groups, such as phenylthio, and naphthylthio. This arylthio group can have 1 6 2 substituents. Examples of the substituents include halogen (for example, chlorine, fluorine, bromine, etc.). Examples of the substituted arylthio group include 4-chlorophenylthio.

The carboxyl group that can be esterified includes alkoxycarbonyl groups, aralkyloxycarbonyl groups, and aryloxycarbonyl groups.

The preferred alkoxycarbonyl group includes C2_5 alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl.

The preferred aralkyloxycarbonyl group includes Cs-io-aralkyloxycarbonyl groups, such as benzyloxycarbonyl.

The preferred aryloxycarbonyl group includes C7-15 aryloxycarbonyl groups, such as phenoxycarbonyl, and p-tolyloxycarbonyl.

The preferred substituent on the hydrocarbon or heterocyclic group for R includes C1-10 alkyl groups, aromatic heterocyclic groups, and Cβ-? 4 aryl groups. Particularly preferred is C? _3 alkyl, furyl, thienyl, phenyl, or naphthyl-.

As regards formula (I), when the bitumen on the hydrocarbon or heterocyclic group for R is an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group, this substituent You can additionally have one or more, preferably 1 to 3 suitable substituents. Examples of such substituents include C? -6 alkyl groups, C2-e alkenyl groups, C2-alkynyl groups, C3-7 cycloalkyl groups, C6-? 4 aryl groups, aromatic heterocyclic groups (for example thienyl, furyl, pyridyl, oxazolyl) , thiazolyl, etc.), non-aromatic heterocyclic groups (for example tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperazino, etc.), C7-9 aralkyl groups, amino groups, N-mono-C? -4 alkylamino groups , N, N-di-C? -4 alkylamino groups, C2-8 acylamino groups (for example acetylamino, propionylamino, benzoylamino, etc.), amidino, C2_8 acyl groups (for example C2_8 alkanoyl groups, etc.), carbamoyl, N-mono-C? -4 alkylcarbamoyl groups, N, N-di-C? _ alkylcarbamoyl, sulfamoyl groups, N-mono-C? _4 alkylsulfamoyl groups, N, N- "di-C? _4 alkylsulfamoyl, -carboxyl groups , C2-8 alkoxycarbonyl groups, hydroxy, C? -alkoxy groups, C2-5 alkenyloxy groups, C3-7 cycloalkyloxy groups, C7-9 aralkyloxy groups, C6-? 4 aryloxy groups, m ercapto, C1-4 alkylthio groups, C7-9 groups. aralkylthio, Cß-? arylthio, sulfo, cyano, azido, nitro, nitroso, and halogen.

In the formula (I), R is preferably a heterocyclic group that can be substituted. More preferably, R is pyridyl, oxazolyl, or thiazolyl group, which may have 1 to 3 substituents selected from the group consisting of C1-3 alkyl, furyl, thienyl, phenyl, and naphthyl.

As regards the formula (I), Y, represents -CO-, -CH (OH) -, or -NR3-, wherein R3 represents an alkyl group that can be substituted. Preferred is -CH (OH) - or -NR3-.

Examples of an alkyl group in the alkyl group which can be substituted for R3 include C? -alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl. Examples of the substituent include halogen (for example, fluorine, chlorine, bromine, iodine), C 4 -alkoxy groups, (for example methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, etc.) , hydroxy, nitro, and C? _ acyl groups (for example formyl, acetyl, propionyl, etc.).

The symbol m represents 0 or 1, and is preferably 0.

The symbol n represents 0, 1 or 2, and is preferably 0 or 1.

X represents CH or N, and CH is preferable.

As regards formula (I), A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms. This aliphatic hydrocarbon group can be straight or branched chain and can additionally be saturated or unsaturated. Thus, for example, -CH2-, -CH (CH3) -, - (CH2) 2-, -CH (C2H5) -, - (CH2) 3-, - (CHA 4-, "(CH2) 5-, - (CH2) 6-, - (CH2) 7-, etc. can be mentioned for the saturated bivalent aliphatic hydrocarbon group, while -CH = CH-, -C (CH3) = CH-, CH = CH-CH2- , -C (C2H5) = CH-, -CH2-CH = CH-CH2-, -CH2-CH2-CH = CH-CH2-, -CH = CH-CH = CH-CH2-, -CH = CH-CH = CH-CH = CH-CH2-, etc. They may be mentioned for the unsaturated bivalent aliphatic hydrocarbon group A, preferably it represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, which is preferably a saturated group More preferably, A represents a chemical ligation or - (CH2) 2-.

The alkyl group for R1 includes one similar to the alkyl group for the R3 described above, R1 is preferably hydrogen ^ With regard to formula (I), the partial structural formula: it is preferably & the formula: Where each symbol has the same meaning as described above.

In addition, ring E optionally has 1 to 4 substituents in substitutable positions. Examples of such substituents include an alkyl group, a hydroxy group, which can be substituted, halogen, an acyl group that can be substituted, nitro, and an amino group that can be substituted. These substituents can be the same as the mentioned substituents for the hydrocarbon or heterocyclic group for R.

The E ring, that is the partial structural formula: Jy is preferably the formula: "X wherein R represents hydrogen, an alkyl group, a hydroxy group that can be substituted, halogen, an acyl group that can be substituted, nitro, or an amino group that can be substituted.

The alkyl group, hydroxy group, which can be substituted, halogen, acyl group which can be substituted, and the amino group which can be substituted, for R2, can each be the same as the mentioned substituents for the hydrocarbon or heterocyclic group for R. R2 is preferably hydrogen, hydroxy group that can be substituted, or halogen. R2 is more preferably hydrogen, or hydroxy group that can be substituted. R 2 is especially preferably hydrogen, or a C 4 -4 alkoxy group.

In regard to formula (I), L and M respectively represent hydrogen or can be combined to each other to form a chemical bond, and preferably are hydrogen.

The compound in which L and M are combined to form a chemical bond can exist as isomers (E) - and (Z) - due to the double bond in position 5 of the azolidindicetone ring.

The compound is that L and M respectively represent hydrogen, can exist as optical isomer, for example forms (R) - and (S) -, with respect to the asymmetric carbon in position 5 of the azolidindicetone ring. This compound includes these optically active compounds, for example (R) - and (S) - forms, as well as the racemic form.

The preferred compound represented by the formula (I) includes the compound in which R represents the pyridyl, oxazolyl, or thiazolyl group, optionally having 1 to 3 substituents selected from the group consisting of C? -3 alkyl, furyl, thienyl, - phenyl, and naphthyl; m is 0; n is 0 or 1; X represents CH; A represents a chemical bond or - (CH2) 2-; R1 represents hydrogen; the E ring, that is to say the partial structural formula: J & - is the formula: 53- wherein R2 is hydrogen or a C? -alkoxy group; and L and M represent hydrogen.

Examples of the preferred compound represented by the formula (I) include: - [4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidindicetone (generic name: pioglitazone); - [[4- [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinediketone (generic name: troglitazone / CS-045); - [[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidindicetone (generic name: rosiglitazone / BRL-49653); Y - [3- [4- (5-methyl-2-phenyl-4-thiazolylmethoxy) phenyl] propyl] -2,4-oxazolidindicetone.

A compound represented by formula (I) is especially preferably pioglitazone.

A salt of a compound represented by formula (I) is preferably a pharmacologically acceptable salt, which includes salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

The preferred salt with an inorganic base includes alkali metal salts such as sodium, potassium, etc. Or alkaline earth metal such as calcium, magnesium, etc .; aluminum salts, and ammonium salts.

The preferred salt with an organic base includes salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, etc.

The preferred salt with an inorganic acid includes salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

The preferred salt with an organic acid includes salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

The preferred salt with a basic amino acid includes salts with arginine, lysine, ornithine, etc. The preferred salt with an acidic amino acid includes salts with aspartic acid, glutamic acid, etc.

A compound represented by the formula (I) or salt thereof is preferably pioglitazone hydrochloride, troglitazone or rosiglitazone (or its maleate), especially preferably pioglitazone hydrochloride.

A compound represented by the formula (I) or salt thereof can be produced according to methods described in JP-A S55 (1980) -22636 (EP-A-8203). JP-A S60 (1985) -2089980 (EP-A-155845), JP-A S61 (1986) -286376 (EP-A-208420), JP-A S61 (1986) -85372, (EP-A-177353 ), JP-A S61 (1986) -267580 (EP-A-193256), JP-A H5 (1993) -86057 (WO-A-92/18501), JP-A H7 (1995) -82269 (EP- A-605228), JP-A H7 (1991) -101945 (EP-A-612743), EP-A-643050, EP-A-710659, etc., or analogous methods thereto.

Examples of the insulin sensitizer employed in the present invention include, in addition to the compounds described above, (±) -4- [4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] benzyl] isoxazolidin-3,5-diketone (JTT-501) or its salts; - [[3,4-dihydro-2- (phenylmethyl) -2H-1-benzopyran-6-yl] methyl] -2,4-thiazolidindicetone (generic name: englitazone) or its salts (preferably sodium salt); - [[4- [3- (5-methyl-2-phenyl-4-oxazolyl) -1-oxopeopyl] phenyl] methyl] -2,4-thiazolidindicetone (generic name: darglitazone / CP-86325) or its salts (preferably sodium salt); - [2- (5-methyl-2-phenyl-4-oxazolylmethyl) benzofuran-5-ylmethyl] -2,4-oxazolidindicetone (CP-92768) or its salts; - (2-naphthalenylsulfonyl) -2, -thiazolidindicetone (AY-31637) or its salts; 4 - [(2-Naphthalenyl) methyl] -3H-l, 2, 3, 5-oxathiadiazol-2 (AY-30711) oxide or its salts; - [[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidindicetone (MCC-555) or its salts; (±) - [5- [(2,4-dioxothiazolidin-5-yl) methyl] -2-methoxy-N - [[4- (trifluoromethyl) phenyl] methyl] benzamido (AHG-255) or its salts; 4- [1 - (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydranaphthalen-2-yl) ethenylbenzoic acid (LGD1069) or its salts; 6- [l- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl) cyclopropyl] nicotinic acid (LGD100268) or its salts; 1, -bis [4- [(3,5-dioxo-1,2,4-oxazolidin-2-yl) methyl] denoxy] -2-butene (YM-440) or its salts, etc.

Salts of these compounds include those similar to the salt of a compound represented by the formula (I) mentioned above.

An insulin sensitizer is preferably pioglitazone hydrochloride, troglitazone, rosiglitazone (or its maleate), or (±) -4- [4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] benzyl] isoxazolidin-3, 5-diketone, especially preferably pioglitazone hydrochloride.

An anorectic means any and all drugs that suppress appetite by acting directly or indirectly on an appetite center. Specific examples of anorexic include central anorectics and substances related to physiologically active peptides. Central anorexics mean drugs that act on adrenoreceptors-α, β-adrenoreceptors, dopamine receptors, or serotonin receptors to suppress appetite.

Preferred examples of central anorexics include adrenoreceptors-a antagonists (eg, yohimbine, etc.), adrenoreceptors-β agonists (eg, mazindol, amphetamine, dextroamphetamine, phentermine, benzfetamine, methamphetamine, phendimetrazine, phenmetrazine, diethylpropion, sibutramine, phenylpropanolamine , clonbenzorex, etc.), dopamine agonist receptors (eg ER-230, doprexin, etc.), serotonin agonist receptors (eg, dexfenfluramine, fenfluramine, etc.), 5-HT agonists (eg (+) norfenfluramine, sertraline, etc.) / cimetidine, ergoset, etc.

The substances related to physiologically active peptides means physiologically active peptides which act directly or indirectly on an appetite central to suppress the appetite, its analogues; agonists or antagonists of such physiologically active peptides.

Preferred examples of the substances related to physiologically active peptides include leptin and its analogs, leptin agonist receptors, leptin resistance enhancing agents, neuropeptide Y (NPY) (eg, NGD-95-1, SR-120819-A, PD-160170, 1229-U-91, etc.), cholecystokinin agonists (CCK) (e.g., FPL-15849, GW-5823 , GW-7178, GI-248573, AR-R-19021, etc.), glucagon-like peptide 1 (GLP-1) or its analogues or its agonists (eg, AZM-134, etc.), galanin antagonist , glucagon agonist, melanin concentrating hormone (MCH) agonist, melanocortin agonists (especially, melanocortin 4 agonist receptors (MC4R), mixed MC4R / MC3R agonists), enterostate LNA agonists, tripeptidylpeptidase II inhibitors (e.g. , UCL-1397, etc.), corticotropin-releasing hormone or its analogs or its agonists (for example urocortin, etc.), etc.

An anorectic is preferably central anorectic, more preferably adrenoreceptor-β agonists, especially preferably mazindol.

In the pharmaceutical composition of the present invention, a pharmaceutical composition is particularly preferably employed in which an insulin sensitizer is pioglitazone hydrochloride and an anorectic is mazindol.

A pharmaceutical composition of the present invention can be used as an agent to prevent or treat diabetes. Examples of diabetes include insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus and etc. A pharmaceutical composition of the present invention is especially and preferably used for non-insulin dependent diabetes mellitus.

Additionally, a pharmaceutical composition of the present invention can be used as an agent to prevent or treat diabetic complications (eg, neuropathy, nephropathy, retinopathy, macroangiopathy, coronary artery disease, osteopenia, etc.).

Additionally, a pharmaceutical composition of the present invention can be used as an agent to treat impaired glucose tolerance. With regard to the definition of impaired glucose tolerance, WHO (World Health Organization) suggests a criterion in a glucose tolerance test with 75 g, oral (75g OGTT). According to this criterion, the alteration in glucose tolerance means a condition in which a fasting glucose level (glucose concentration in venous plasma) is lower than 140 mg / dl, and a glucose level 2 hours later ( glucose concentration in venous plasma) when a glucose tolerance test with 75 g, oral is conducted after fasting overnight, variations of 140 to 199 mg / del.

Diabetes means a condition in which a fasting glucose level (glucose concentration in venous plasma) is 140 mg / dl or more, and a glucose nicel two hours later (glucose concentration in venous plasma), when driving A glucose tolerance test with 75 g orally after fasting overnight is 200 mg / dl or more.

With respect to the diabetes criterion, new criteria have • been reported since ADA (American Diabetic Association) in 1997 and from WHO in 1998.

According to these reports, diabetes means a condition in which a fasting glucose level (glucose concentration in venous plasma) is 126 mg / dl or more, and a glucose sample two hours later (glucose concentration in venous plasma), when a glucose tolerance test with oral 75 g is conducted after fasting overnight, is 200 mg / dl or more.

According to previous reports, alteration in glucose tolerance means a condition in which a fasting glucose level (glucose concentration in venous plasma) is lower than 126 mg / dl, and a glucose level two hours later ( glucose concentration in venous plasma), when a glucose tolerance test is conducted with 75 g orally, after fasting overnight, it is 140 mg / dl or more and less than 200 mg / dl.

According to the ADA reports, a condition in which a fasting glucose level (venous plasma glucose concentration) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Alteration in Fasting Glucose). According to the report of the WHO, a condition, between this IFG (Alteration in Fasting Glucose), where a glucose level two hours later (glucose concentration in venous plasma), when driving a glucose tolerance test with 75 g, oral, after fasting all night, it is less than 140 mg / dl, it is called IFG (Alteration in Glucose in Fasting). The pharmaceutical composition of the present invention can also be used as an agent to prevent or treat diabetes, impaired glucose tolerance, IFG (Fasting Glucose Alteration), IFG (Alteration in Glucose in Fasting), all of which are defined by the new criteria above. The pharmaceutical composition of the present invention can also prevent the progression of diabetes from the alteration in tolerance to. glucose, IFG (Alteration in Fasting Glucose) or IFG (Fasting Glicemia).

Additionally, a pharmaceutical composition of the present invention can also be used as an agent to prevent or treat diseases such as hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases (eg, arteriosclerosis, etc.), polycystic ovarian syndrome, diabetes in pregnancy, pancreatitis, glomerulonephritis, glomerular scletosis, hypertensive nephrosclerosis, and etc., or syndromes (for example, syndrome X, obesity syndrome with visceral fat, etc.) considering some of these diseases in combination.

A pharmaceutical composition of the present invention can be obtained by a combination of active ingredients, an insulin sensitizer and an anorectic. These active ingredients can be »subjected to pharmaceutical manufacturing processes by separate or concomitantly mixing with acceptable pharmaceutical carriers in accordance with means known per se [conventional means in the field of pharmaceutical manufacturing techniques, for example, means described in the Pharmacopoeia of Japan (for example, 13th Edition, etc.) ß.

Examples of dosage forms of a pharmaceutical composition of the present invention or their respective active ingredients include oral dosage forms such as tablets capsules (including soft capsules and microcapsules), powders, granules, syrups, and the like; and non-oral dosage forms such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intra-peritoneal injections, etc.), forms of external application (e.g., nasal spray preparations, transdermal preparations, ointments, etc.), suppositories, etc.), tablets, infusions for drops, and, etc.

Methods for producing oral dosage forms and non-oral dosage forms are specifically explained below.

Oral dosage forms are produced by addition to the active ingredients, for example, of an excipient (eg, lactose, sucrose, starch, D-mannitol, xylitol, sorbitol, erythritol, crystalline cellulose, light salicylic anhydride, etc.) , a disintegrator (eg, calcium carbonate, starch, carboxymethylcellulose, calcium carboxymethylcellulose, light substituted hydroxypropylcellulose, sodium croscarmellose, sodium carboxymethylstarch, light salicylic anhydride, etc.), a binder (eg α-starch, gum arabic, carboxymethylcellulose) , hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crystalline cellulose, methylcellulose, sucrose, D-mannitol, trehalose, dextrin, etc. ') or a lubricant (eg, talc, magnesium stearate, calcium stearate, talc, colloidal silica, polyethylene glycol 6000 , etc.), and then the resulting mixture is compressed and molded. For oral dosage forms, acids, such as hydrochloric acid, phosphoric acid, acid. succinic, DL-malic acid, tartaric acid, malic acid, fumaric acid, citric acid, and etc .; or bases such as sodium carbonate, sodium bicarbonate, sodium citrate, sodium tartrate, and etc. They can be added for the purpose of promoting the dissolution of the active ingredients.

Oral dosage forms can be coated, by the method known per se, to disguise the flavor either for enteric dissolution or constant release. Examples of a coating material that can be used include enteric coating polymers such as cellulose acetate phthalate, methacrylic acid L copolymet, methacrylic acid LD copolymer, methacrylic acid S copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, etc .; polymers for gastric coating such as polyvinylacetal diethylaminoacetate, E-copolymer of aminoalkyl methacrylate, etc .; water soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, etc .; water-insoluble polymers such as ethylcellulose, RS-copolymers of aminoalkyl methacrylate, ethylacrylate-methylmethacrylate copolymer, etc .; waxes, and etc., when the coating is carried out, plasticizers, such as polyethylene glycol, and etc .; and sunscreens such as titanium oxide, iron sesquioxide, and etc. They can be used together with the previous coating material.

The injections can be produced by dissolving, suspending or emulsifying the active ingredients in an aqueous vehicle (eg distilled water, physiological saline solution, Ringer's solution, etc.) or an oily vehicle (eg vegetable oils such as olive oil, Sesame oil, cottonseed oil, corn oil, etc.; or propylene glycol, macrogol, tricaprilin, etc.) together with a dispersant (for example, Tween 80 (produced by Atlas Powder, USA), HCO 60 (produced by Niko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), an isotizing agent (e.g., sodium chloride, glycerol, D-sorbitol, D-mannitol, xylitol, glucose, fructose, etc.) and etc.

If desired, additives such as a solubilizer (eg sodium salicylate, sodium acetate, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tisaminomethane, cholesterol, triethanolamine, carbonate) are also employed. sodium, sodium citrate, etc.), a suspending agent (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, becetonium chloride, glyceryl monostearate, and etc .; and hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and the like), a regulating agent (eg buffer solutions such as phosphate, acetate, carbonate, citrate, and etc.), a stabilizer (eg, example, human serum albumin, etc.), a calming agent (for example propylene glycol, lidocaine hydrochloride, benzyl alcohol, etc.), an antiseptic (eg the esters of p-hydroxybenzoic acid, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.) and etc.

Forms for external application can be produced by processing the active ingredients in a solid, i-solid or liquid composition. For example, a solid composition is produced by processing the active ingredients, either as such or in mixtures with an excipient (eg, lactose, D-mannitol, starch, microcrystalline cellulose, sucrose, etc.), a thickener (for example, natural gums, cellulose derivatives, acrylic acid, polymers, etc., in powders) The above liquid composition is produced substantially in the same manner as in the case of injections.The semi-solid composition is preferably provided in form of an aqueous or oily gel or an ointment form These compositions may optionally contain an agent for pH control (for example, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), an antiseptic (e.g. , esters of p-hydroxybenzoic acid, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), and etc.

The suppositories can be produced by processing the active ingredients in an aqueous or oily composition, whether solid, semi-solid or liquid. Examples of oleaginous bases that can be used to produce the composition include higher fatty acid glycerides [e.g., cocoa butter, Witepsols ("huels Aktiengesellschaft", Germany), etc.], triglycerides of medium chain fatty acids [e.g. Migriols ("huels Aktiengesellschaft, Germany), etc.], vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.), etc. Examples of water-soluble bases include polyethylene glycols, propylene glycol, etc. Additionally, examples of the hydrophilic bases include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers, etc.

The method for administering a pharmaceutical composition of the present invention is not limited, provided that an insulin sensitizer and an anorectic are combined at the time of administration. Examples of such methods include 1) administration of a single preparation prepared from an insulin sensitizer and an anorectic at the same time; 2) concomitant administration of two classes of preparations prepared from an insulin sensitizer and an anorectic separately by the same route of administration; 3) separate administration of two classes of preparations prepared from an insulin sensitizer and an anorectic separately by the same route of administration; 4) concomitant administration of two classes of preparations prepared from an insulin sensitizer and an anorectic separately by different routes of administration; 5) separate administration of two classes of preparations prepared from an insulin sensitizer and an anorectic separately by different routes of administration (eg, administration of an insulin sensitizer and an anorectic in that order, or in reverse order); and etc. Among all the above 2) and 3) are preferred.

Preferred embodiments include processing an insulin sensitizer and an anorectic separately in oral dosage forms such as tablets, and administering the oral dosage forms concomitantly or separately.

A pharmaceutical composition of the present invention is low in toxicity potential, and can be safely used in mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, equine, porcine, monkey, etc.) either orally or non-orally.

The dose of a pharmaceutical composition of the present invention can be appropriately determined with reference to the recommended dose for the corresponding drugs, and can be appropriately selected according to the subject, the age and body weight of the subject, clinical status, time of administration, dosage form, method of administration, combination of drugs, and etc.

The dosage of an insulin sensitizer and an anorectic can be appropriately selected based on clinically used dosages.

For administration of an insulin sensitizer to a diabetic adult patient (body weight: 50 Kgs.), For example, the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose can be administered once up to several times per day. Especially, when pioglitazone hydrochloride is used as the insulin sensitizer, the dose of pioglitazone hydrochloride per day is usually 7.5 to 60 mg, preferably 15 to 45 mg. When troglitazone is used as the insulin sensitizer, the dose of troglitazone per day is usually 100 to 1000 mg, preferably 200 to 600 mg. When rosiglitazone (or its maleate) is used as the insulin sensitizer, the dose of rosiglitazone per day is usually 1 to 12 mg, preferably 2 to 12 mg.

For administration of an anorexic to a diabetic adult patient (body weight: 50 Kgs.), For example, the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. Especially, when mazindol is used as the anorectic, the dose of mazindol per day is usually 0.1 to 5 mg, preferably 1 to 3 mg.

The ratio of an insulin sensitizer and an anorectic in a pharmaceutical composition of the present invention can be appropriately selected according to the subject, the age and body weight of the subject, clinical status, time of administration, dosage form, method of administration, combination of drugs, and etc.

For example, an anorectic is used in a proportion of usually about 0.0001 to 0.2 parts by weight and preferably about 0.001 to 0.02 parts by weight relative to one part by weight of an insulin sensitizer.

When the pharmaceutical composition of the present invention is administered to a diabetic patient, it provides excellent medicinal properties compared to the administration of the insulin sensitizer or an anorectic alone, for example, a tendency to decrease the patient's body weight is observed.

The pharmaceutical composition of the present invention is free of apparent detection of side effects such as dependence, hydrodipsia, constipation, nausea, emesis, gastric discomfort, stomach flatulence, vertigo, palpitation, rash, increase of GTO or GTP, sleep disorders, etc. .

A pharmaceutical composition of the present invention possesses an action of reducing the increased blood sugar in comparison with the administration of an insulin sensitizer or an anorectic alone.

Additionally, a pharmaceutical composition of the present invention possesses an action of decreasing the increased blood lipid or action of knocking down the insulin in the blood as compared to the administration of an insulin sensitizer or an anorectic alone.

Additionally, a pharmaceutical composition of the present invention has an excellent action of knocking down the sugar in the blood, and consequently, the amount of drugs used can be reduced compared to the administration of an insulin sensitizer or an anorectic alone.

The use of a pharmaceutical composition of the present invention in combination with insulin provides an excellent blood sugar lowering effect.

Insulin means any and all substances that have an insulin action, and exemplified, for example, animal insulin extracted from bovine or porcine pancreas; Semi-synthesized human insulin which is enzymatically synthesized from insulin extracted from porcine pancreas; and human insulin synthesized by genetic engineering techniques that typically use Escherichia coli or yeast; and etc. Among these, human insulin synthesized by genetic engineering techniques that typically use Escherichia coli or yeast is preferred.

Additionally, insulin used is insulin-zinc containing 0.45 to 0.9 (w / w)% zinc; protamine-zinc-insulin produced from zinc chloride, protamine sulfate and insulin; and etc.

While insulin is available in a variety of types such as super immediate action, immediate action, bi-modal action, intermediate action, long-acting, and so on, these types can be appropriately selected -according to the conditions of the patient.

For administration (usually administration in the form of injections) of insulin to an adult patient (body weight: 50 Kgs.), For example, the dose per day is usually 10 to 100 U (Units), preferably 10 to 80 U.

(Units).

The use of a pharmaceutical composition of the present invention in combination with insulin facilitates the reduction of the amount of insulin used when compared to the amount used at the same time of administration of an insulin alone. Therefore, the risk of blood vessel complications and induction of hypoglycemia, both of which are maladies due to the administration of a large amount of insulin, is low. Since a pharmaceutical composition of the present invention possesses an excellent action of lowering blood sugar, a satisfactory effect of preventing or treating diabetes can be obtained equally if the amount of insulin used is reduced when compared to the administration of insulin alone. .

Additionally, the use of a pharmaceutical composition of the present invention in combination with insulin secretion enhancers, -biguanides, α-glucosidase inhibitors, and the like. It contributes a more excellent effect of lowering of the sugar in the blood.

Examples of insulin secretion enhancers include sulfonylureas. Specific examples of the sulfonylureas include tolbutamide, glycopyramide or its ammonium salts, glibenclamide, gliclazide, l-butyl-3-gliquidone, glisoxepide, glibutiazole, glibuzole, glihexamide, glimidine, glipinamide, fenbutamide, tolciclamide, gli epiride, etc.

In addition to the above, examples of insulin secretion enhancers include N - [[4- (l-methylethyl) cyclohexyl] carbonyl] -D-phenylalanine (nateglinide, AY-4166), (2S) -2-benzyl- 3- (calcium cis-hexahydro-2-isoindolinylcarbonyl) propionate dihydrate (KAD-1229), rapaglinide, etc.

For administration of the insulin secretion enhancers to an adult patient (body weight: 50 Kgs.), For example, the dose per day is usually 0.1 to 1000 mg, preferably 1 to 100 mg.

Examples of the biguanidines include phenformin, metformin, buformin, etc.

For the administration of the biguanidines to an adult patient (body weight: 50 Kgs.), For example, the dose per day is usually 10 to 2500 mg, preferably 100 to 1000 mg.

Examples of α-glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate, etc.

For administration of a-glucosidase inhibitors to an adult patient (body weight: 50 Kgs.), For example, the dose per day is usually 0.1 to 400 mg, preferably 0.6 to 300 mg.

Various classes of the drugs mentioned above can be used in combination with two or more of them optionally selected. Specific examples of combination when two classes of drugs are used in combination include "combination of an insulin secretion enhancer and an α-glucosidase inhibitor", "combination of insulin and a biguanidine", "combination of insulin and an inhibitor a- glucosidase, etc.

The action of lowering the blood sugar of a pharmaceutical composition in the present invention can be evaluated by determining the concentration of glucose or Hb (hemoglobin) Aic in venous plasma, and then the concentration obtained is compared between before the administration and after the administration. HbAlc means glycosylated hemoglobin, and is gradually produced in response to the concentration of glucose in the blood. Therefore, HbA? C is nonetheless important as a control blood sugar index which is not easily influenced by rapid changes in blood sugar in diabetic patients.

BEST MODALITY TO CARRY OUT THE INVENTION The following Reference Examples and Examples are intended to describe the present invention in further detail and does not mean that they were constructed as a definition of the scope of the invention.

Reference Example 1 A fluidized bed granulator and dryer (produced by Powerex) was loaded with 2479.5 g of pioglitazone hydrochloride (2250 g in terms of pioglitazone), 13930. 5 g of lactose and 540 g of calcium carboxymethylcellulose (carmellose calcica) was then mixed at the preheating temperature and 7500 g of an aqueous solution containing 450 g of hydroxypropylcellulose was sprayed to produce granules. 16820 g of granules were processed in a blade mill (produced by Showa Kagaku Kikai Kousakusho) to produce ground granules. 16530 g of ground granules, 513 g of calcium carmellose and 57 g of magnesium stearate were mixed to produce powder mixture by using a polishing mixer (produced by Showa Kagaku Kikai Kousakusho). 16800 g of the powder mixture was tabletted using a tablet press (produced by Kikusui Seisakusho) to produce 140000 tablets having the following composition and each containing 15 mg of pioglitazone.

Composition per tablet (Unit: mg) 1) Pioglitazone hydrochloride 16. 53 2) Lactose 92.87 3) Carmellose Calcium 7.2 4) Hydroxypropylcellulose 3.0 ) Magnesium stearate - 0.4 Total 120. 0 Reference Example 2 In a manner similar to Reference Example 1, 140,000 tablets were obtained having the following composition and each containing 30 mg of pioglitazone.

Composition per tablet (Unit: mg) 1) Pioglitazone hydrochloride 33. 06 2) Lactose 76.34 3) Carmellose Calcium 7.2 4) Hydroxypropylcellulose 3.0 ) Magnesium stearate 0.4 Total 120.0 Reference Example 3 Similar to Reference Example 2, 140,000 tablets having the following composition and each containing 45 mg of pioglitazone were obtained.

Composition per tablet (Unit: mg): 1) Pioglitazone hydrochloride 49.59 2) Lactose 114.51 3) Carmellose calcica 10.8 4) Hydroxypropylcellulose 4.5 ) Magnesium stearate 0.6 Total: 180.0 Example 1 The effects of concomitant administration of pioglitazone hydrochloride and mazindol in non-insulin dependent diabetic patients (NIDDM) were studied.

When pioglitazone hydrochloride (45 mg / day, oral administration) was administered concomitantly to a NIDDM patient. [a sample (man); 44 years old; body weight 99.0 Kgs; the fasting blood sugar was 242.0 mg / dl; HbAic was 11.0%] under treatment with mazindol (1.0 mg / day, oral administration) during the 8 week period, the fasting blood sugar was 70.0 mg / dl, the HbA? c decreased by 2.00 %, and the body weight decreased 1.00 Kgs.

When a placebo (oral administration) was administered to NIDDM patients [55 samples (20 men and 35 women); from 37 to 73 years of age (57.9 + 8.7 (mean ± standard deviation), body weight was 59.8 ± 12.1 (mean ± standard deviation of 54 samples) Kgs. Fasting blood sugar was 180.1 ± 23.0 (mean ± standard deviation) mg / dl; HbA? C 8.8 ± 1.3 (mean ± standard deviation%) during the period of 12 ± 2 weeks, fasting blood sugar increased by 3.4 ± 27.3 mg / dl (average ± standard deviation of 55 samples), HbA? C increased by 0.45 ± 0.86% (mean ± standard deviation of 54 samples), and body weight decreased by 0.19 ± 1.21 Kgs. (Mean ± standard deviation of 55 samples).

When pioglitazone hydrochloride (45 mg / day, oral administration) was administered only to NIDDM patients [50 samples 824 man and 24 women); from 23 to 78 years of age (55.8 ± 10.7 (mean ± standard deviation), body weight 62.7 ± 10.5 (mean ± standard deviation) Kgs, fasting blood sugar was 190.5 ± 31.1 (mean ± standard deviation) ) mg / dl; HbAic was 9.3 ± 1.6 (mean ± standard deviation) of 49 samples)] during the period of 12 ± 2 weeks, body weight increased by 0.72 ± 2.06 kg (mean ± standard deviation of 50 samples) .

When placebo (oral administration) was administered concomitantly to a NIDDM patient [One sample (female); 51 years old; body weight 60.0 Kgs; Fasting blood sugar 200.0 mg / dl; HbAic 9.3%] under treatment with mazindol (0.5 mg / day, oral administration) during the 12-week period, body weight changed 0.00 Kgs.

Thus, the administration of pioglitazone hydrochloride in combination with mazindol provided excellent sugar-lowering action, and a tendency to decrease body weight compared to the administration of pioglitazone hydrochloride or mazindol alone, which confirmed that The pharmaceutical composition of the present invention possesses excellent medicinal properties.

Industrial Application A pharmaceutical composition of the present invention is useful as an agent for preventing or treating diabetes, an agent for preventing or treating diabetic complications, and an agent for treating alterations in glucose tolerance, without apparent detection of side effects.

Additionally, a pharmaceutical composition of the present invention possesses an action of abatement of increased sugar in the blood, action to abate the lipids in the blood or action to abate the insulin in the blood in comparison with the administration of a sensitizer to insulin or an anorexic alone.

Additionally, a pharmaceutical composition of the present invention has an excellent blood sugar lowering action, and consequently, the amount of drug used may be reduced compared to the administration of an insulin sensitizer or an anorectic alone.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following:

Claims (21)

1. A pharmaceutical composition which is characterized in that it comprises an insulin sensitizer in combination with an anorectic or compound that generates anorexia.

Q 2. A pharmaceutical composition according to claim 1, characterized in that the insulin sensitizer is a compound of the formula: wherein R represents a hydrocarbon group or a heterocyclic group, each of which may be substituted; Y represents a group of the formula: -CO-, -CH (OH) - or -NR3-wherein R3 represents an alkyl group that can be substituted; m is 0 or 1; n is 0, 1 or 2; x represents CH or N; a represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q represents oxygen or sulfur; R1 represents hydrogen or an alkyl group; ring E can additionally have 1 to 4 substituents, which can form a ring in combination with R1; L and M respectively represent hydrogen or can be combined with one another to form a chemical ligation; or a salt of it.

3. A pharmaceutical composition according to claim 1, characterized in that the insulin sensitizer is pioglitazone hydrochloride, troglitazone, rosiglitazone or 4- [4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] benzisoxaolidin-3, 5-diketone.

4. A pharmaceutical composition according to claim 2, characterized in that the compound of formula (I) or salt thereof is pioglitazone hydrochloride.

5. A pharmaceutical composition according to claim 1, characterized in that the anorectic is a central anorectic.

6. A pharmaceutical composition according to claim 5, characterized in that the central anorectic is mazindol.

7. A pharmaceutical composition according to claim 1, characterized in that the insulin sensitizer is pioglitazone hydrochloride and the anorectic is mazindol.

8. A pharmaceutical composition according to claim 1, which is characterized in that it is to prevent or treat diabetes.

9. A pharmaceutical composition according to claim 8, characterized in that diabetes is non-insulin dependent diabetes mellitus.

10. A pharmaceutical composition according to claim 2, characterized in that the compound of the formula (I) or salt thereof is troglitazone.

11. A pharmaceutical composition according to claim 2, characterized in that the compound of the formula (I) or salt thereof is rosiglitazone or its maleate.

12. A pharmaceutical composition according to claim 1, characterized in that it is to prevent or treat diabetic complications.

13. A pharmaceutical composition according to claim 1, characterized in that it is able to prevent or treat alterations in glucose tolerance.

14. A pharmaceutical composition which is characterized in that it comprises an insulin sensitizer and is used in combination with an anorectic.

15. A method for preventing or treating diabetes in a mammal in need thereof, which is characterized in that it comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic.

16. A method for preventing or treating diabetic complications in a mammal in need thereof, which is characterized in that it comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic.

17. A method for preventing or treating alterations in glucose tolerance in a mammal in need thereof, which is characterized in that it comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic.

18. Use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating diabetes which is used in combination with an anorectic.

19. ^ Use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating diabetic complications which is used in combination with an anorectic.

20. Use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating alterations in glucose tolerance which is used in combination with an anorectic.

21. A method for reducing side effects of an insulin sensitizer or / and an anorectic administered to a diabetic mammal, which is characterized in that it comprises administering to said mammal an effective amount thereof.