JP2000355550A - Ketosis improver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a ketosis improver having excellent actions and a low toxicity and useful for prophylaxis and treatment of hepatic type glycogenosis, endocrine diseases, congenital glucide or organic acid dysbolism, etc., by including an insulin resistance improving agent of specific hormones. SOLUTION: This improver is obtained by including an insulin resistance improving agent. The improving agent is preferably a compound represented by the formula R is a (substituted) hydrocarbon or a (substituted) heterocyclic ring; Y is CO, CH(OH) or NR3 [R3 is a (substituted) alkyl]; m is 0 or 1; n is 0-2; X is CH or N; A is a direct bond or a 1-7C bivalent aliphatic hydrocarbon; Q is O or S; R1 is H or an alkyl; ring E may further have 1-4 substituent groups which may be bound to R1 to form a ring; L and M are each H or together may be bound to form a direct bond} (e.g. pioglitazone hydrochloride) or its salt. The content of the improving agent in the improver is 0.1-100 wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a ketosis improving (or treating) agent comprising an insulin sensitizer. The present invention also relates to an acidosis improving (or treating) agent comprising an insulin sensitizer. Further, the present invention relates to a non-ketonic hyperosmolar coma, an infectious disease, diabetic osteopenia, diabetic gangrene, xerostomia, deafness, angina pectoris, cerebrovascular disease comprising an insulin sensitizer. The present invention relates to an agent for preventing or treating a disorder or peripheral blood circulation disorder.

[0002]

2. Description of the Related Art Ketosis is a state in which a large amount of ketone bodies accumulates in tissues and body fluids mainly due to enhanced production of ketone bodies and exceeding their availability. It is known that the concentration of hydrogen ions released from the ketone body increases, causing acidosis. In addition, acidosis is a state in which the acid-base balance of a body fluid, particularly blood, is tilted toward the acid side, and it is known that consciousness disorder or coma occurs in severe acidosis.

[0003] The insulin sensitizer is also called an insulin sensitivity enhancer, and is used as a therapeutic agent for diabetes, if necessary, in combination with another therapeutic agent for diabetes. For example, JP-A-9-67271 (EP-A749751) discloses that “insulin sensitivity enhancer, α-glucosidase inhibitor, aldose reductase inhibitor, biguanide agent, statin compound, squalene synthesis inhibitor, fibrate compound, LDL, Pharmaceuticals comprising a combination of a catabolic promoter and at least one angiotensin converting enzyme inhibitor "are described. WO 98/57634 also states that “effective and non-toxic pharmaceutically acceptable amounts of insulin sensitizers (insu
lin sensitizer) and a biguanide hypoglycemic agent are administered to mammals to obtain diabetes and conditions associated with diabetes mell.
Itus) is described. On the other hand, it is known that insulin sensitizers are also useful as agents for preventing and treating cachexia (WO 97/37656). However, it is not known that an insulin sensitizer is useful as a ketosis improving agent or an acidosis improving agent.

[0004]

There is a need for the development of a ketosis ameliorating agent which has excellent action and low toxicity. In addition, there is a need for the development of an acidosis improving agent having an excellent action and low toxicity.

[0005]

The present invention provides: (1) a ketosis improving agent comprising an insulin sensitizer; (2) an insulin sensitizer having a general formula:

Embedded image [Wherein, R represents an optionally substituted hydrocarbon or heterocyclic group; Y represents —CO—, —CH (OH) — or —NR ³ — (R ³ represents an optionally substituted alkyl group; M is 0 or 1; n is 0, 1 or 2; X is CH or N; A is a bond or a group having 1 to 1 carbon atoms.
7 is a divalent aliphatic hydrocarbon group; Q is an oxygen atom or a sulfur atom; R ¹ is a hydrogen atom or an alkyl group, respectively. Ring E may further have 1 to 4 substituents, and the substituents may combine with R ¹ to form a ring. L and M each represent a hydrogen atom or may be bonded to each other to form a bond. (3) the insulin sensitizer is pioglitazone hydrochloride, wherein the compound is a compound represented by the formula: or a salt thereof;
Troglitazone, rosiglitazone, 4- [4- [2-
(5-methyl-2-phenyloxazol-4-yl)
The improving agent according to the above (1), which is ethoxy] benzyl] isoxazolidin-3,5-dione or 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione. (4) the ameliorating agent according to the above (1), wherein the ketosis is diabetic ketosis; (5) the ameliorating agent according to the above (1), wherein the ketosis is a ketosis induced by a biguanide; The ameliorating agent according to the above (1), which is an agent for preventing / treating diseases, endocrine diseases, congenital carbohydrate or organic acid metabolism disorders, acetone bloody vomiting or gastrointestinal diseases; (7) containing an insulin sensitizer (8) an insulin sensitizer having a general formula

Embedded image [Wherein, R represents an optionally substituted hydrocarbon or heterocyclic group; Y represents —CO—, —CH (OH) — or —NR ³ — (R ³ represents an optionally substituted alkyl group; M is 0 or 1; n is 0, 1 or 2; X is CH or N; A is a bond or a group having 1 to 1 carbon atoms.
7 is a divalent aliphatic hydrocarbon group; Q is an oxygen atom or a sulfur atom; R ¹ is a hydrogen atom or an alkyl group, respectively. Ring E may further have 1 to 4 substituents, and the substituents may combine with R ¹ to form a ring. L and M each represent a hydrogen atom or may be bonded to each other to form a bond. (9) the insulin sensitizer is pioglitazone hydrochloride, which is a compound represented by the formula:
Troglitazone, rosiglitazone, 4- [4- [2-
(5-methyl-2-phenyloxazol-4-yl)
The improving agent according to the above (7), which is ethoxy] benzyl] isoxazolidin-3,5-dione or 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione. (10) the ameliorating agent according to the above (7), wherein the acidosis is diabetic acidosis; (11) the ameliorating agent according to the above (7), wherein the acidosis is an acidosis caused by a biguanide; Or the ameliorating agent according to the above (7), which is a prophylactic / therapeutic agent for a respiratory disease; A prophylactic / therapeutic agent for diabetic gangrene, xerostomia, deafness, angina pectoris, cerebrovascular disorder or peripheral blood circulation disorder; (14) an insulin sensitizer is piog hydrochloride Tazon, troglitazone, rosiglitazone, 4- [4- [2
-(5-Methyl-2-phenyloxazol-4-yl) ethoxy] benzyl] isoxazolidine-3,5
(15) an improving agent according to the above (13), which is -dione or 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione; And (16) an acidosis improving agent comprising a combination of an insulin sensitizer and insulin.

[0006] The insulin sensitizer used in the present invention is a drug that restores the function of the insulin receptor that has been damaged and improves insulin resistance. Examples include the compound represented by the general formula (I) or a salt thereof.

In the general formula (I), the hydrocarbon group in the optionally substituted hydrocarbon group represented by R includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an alicyclic-aliphatic hydrocarbon group. Examples include a hydrogen group, an araliphatic hydrocarbon group, and an aromatic hydrocarbon group. The number of carbon atoms in these hydrocarbon groups is preferably 1 to 14. As the aliphatic hydrocarbon group,
An aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferred. Examples of the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl, isohexyl, heptyl, and octyl. A saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, an alkyl group, etc.); for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3
-Butenyl, 2-methyl-1-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, 2,4-hexadiynyl, 5- Hexynyl, 1-heptynyl, 1-octynyl and other unsaturated aliphatic hydrocarbon groups having 2 to 8 carbon atoms (eg, alkenyl group,
Alkadienyl group, alkynyl group, alkadiynyl group, etc.). As the alicyclic hydrocarbon group, an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable. Examples of the alicyclic hydrocarbon group include cyclopropyl, cyclobutyl,
A saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cyclopentyl, cyclohexyl and cycloheptyl (eg, cycloalkyl group) and 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2 -Cyclohexenyl, 3-cyclohexenyl, 1
-Unsaturated alicyclic hydrocarbon groups having 5 to 7 carbon atoms such as -cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, and 2,4-cycloheptadienyl (eg, cycloalkenyl group, cycloalkadienyl group, etc.). Can be

As the alicyclic-aliphatic hydrocarbon group, those in which the alicyclic hydrocarbon group and the aliphatic hydrocarbon group are bonded (eg, cycloalkyl-alkyl group, cycloalkenyl-alkyl group, etc.) are exemplified. Among them, an alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms is preferable. As the alicyclic-aliphatic hydrocarbon group, for example, cyclopropylmethyl,
Cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptyl Ethyl and the like. As the araliphatic hydrocarbon group, an araliphatic hydrocarbon group having 7 to 13 carbon atoms (eg, an aralkyl group or the like) is preferable. Examples of the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl, α-naphthylmethyl, α -Naphthylethyl, β-naphthylmethyl, β-
And naphthylalkyl having 11 to 13 carbon atoms such as naphthylethyl. As the aromatic hydrocarbon group, an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, an aryl group or the like) is preferable. Examples of the aromatic hydrocarbon group include phenyl and naphthyl (α-naphthyl, β-naphthyl).

In the general formula (I), the heterocyclic group in the optionally substituted heterocyclic group represented by R is a heterocyclic group selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include a 5- to 7-membered heterocyclic group or a condensed ring group having 1 to 4 atoms. As the fused ring, for example, such a 5- to 7-membered heterocyclic ring,
And a condensed ring with a 6-membered ring containing two or more nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom.
Specific examples of the heterocyclic group include 2-pyridyl and 3-pyridyl.
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
Yl, tetrazol-5-yl, benzimidazole-
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 And 1H-imidazo [4,5-b] pyrazin-2-yl, benzopyranyl, dihydrobenzopyranyl and the like. The heterocyclic group is preferably a pyridyl, oxazolyl or thiazolyl group.

In the general formula (I), the hydrocarbon group represented by R and the heterocyclic group are each substituted at an arbitrary substitutable position.
It may have up to 5, preferably 1 to 3 substituents. Examples of the substituent include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and an optionally substituted amino group. An optionally substituted acyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, an amidino group, a carbamoyl group, a sulfamoyl group,
Examples include a sulfo group, a cyano group, an azide group, and a nitroso group. Examples of the aliphatic hydrocarbon group include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, and an alkynyl group. Preferable examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, for example, 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, decyl and the like can be mentioned. Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl,
2-butenyl, 3-butenyl, 2-ethyl-1-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, 5-hexenyl and the like. Preferred examples of the alkynyl group include:
An alkynyl group having 2 to 10 carbon atoms, for example, ethynyl, 1-
Propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.

The alicyclic hydrocarbon group may have 3 to 1 carbon atoms.
And two saturated or unsaturated alicyclic hydrocarbon groups, for example, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like. Preferred examples of the cycloalkyl group include cycloalkyl groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2. 2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.
2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and the like. Preferable examples of the cycloalkenyl group include a cycloalkenyl group having 3 to 10 carbon atoms, for example, 2-cycloalkenyl group.
Cyclopenten-1-yl, 3-cyclopenten-1-
Yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Preferable examples of the cycloalkadienyl group include a cycloalkadienyl group having 4 to 10 carbon atoms, for example, 2,4-cyclopentadiene-1.
-Yl, 2,4-cyclohexadien-1-yl, 2,5
-Cyclohexadien-1-yl and the like. Preferable examples of the aryl group include aryl groups having 6 to 14 carbon atoms, for example, phenyl, naphthyl (1-naphthyl, 2-
Naphthyl), anthryl, phenanthryl, acenaphthylenyl and the like.

Preferred examples of the aromatic heterocyclic group include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
Aromatic monocyclic heterocyclic groups such as triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; for example, 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, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxadinil, Phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatridinyl, phenatrolinyl, 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, 1,2,4-
And aromatic condensed heterocyclic groups such as triazolo [4,3-b] pyridazinyl.

Preferred examples of the non-aromatic heterocyclic group include, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, morpholino, Thiomorpholino and the like. Examples of halogen atoms include fluorine, chlorine, bromine and iodine. In the amino group which may be substituted, the substituted amino group includes an N-monosubstituted amino group and an N, N-disubstituted amino group.
Examples of the substituted amino group include a C _1-10 alkyl group,
An amino group having one or two substituents of a _2-10 alkenyl group, a C _2-10 alkynyl group, an aromatic group, a heterocyclic group or a C _1-10 acyl group (eg, methylamino, dimethylamino, ethyl Amino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino and the like.

The acyl group in the optionally substituted acyl group includes, for example, an acyl group having 1 to 13 carbon atoms, for example, an alkanoyl group having 1 to 10 carbon atoms, and an acyl group having 3 to 10 carbon atoms.
And a cycloalkanoyl group having 4 to 10 carbon atoms, a cycloalkenoyl group having 4 to 10 carbon atoms, and an aromatic carbonyl group having 6 to 12 carbon atoms. Preferred examples of the alkanoyl group having 1 to 10 carbon atoms include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like. Preferable examples of the alkenoyl group having 3 to 10 carbon atoms include acryloyl, methacryloyl, crotonoyl, isocrotonyl and the like. Carbon number 4-10
Preferable examples of the cycloalkanoyl group include, for example, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl and the like. Preferable examples of the cycloalkenoyl group having 4 to 10 carbon atoms include 2-cyclohexenecarbonyl. Preferable examples of the aromatic carbonyl group having 6 to 12 carbon atoms include benzoyl, naphthoyl, nicotinoyl and the like. Examples of the substituent in the substituted acyl group include an alkyl group having 1 to 3 carbon atoms, for example, an alkoxy group having 1 to 3 carbon atoms, a halogen atom (eg, chlorine, fluorine, bromine, etc.), a nitro group, a hydroxyl group, And an amino group.

In the optionally substituted hydroxyl group, examples of the substituted hydroxyl group include an alkoxy group, a cycloalkyloxy group, an alkenyloxy group, a cycloalkenyloxy group, an aralkyloxy group,
Examples include an acyloxy group and an aryloxy group. Preferable examples of the alkoxy group include an alkoxy group having 1 to 10 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy and neopentyl. Pentyloxy, hexyloxy, heptyloxy, nonyloxy and the like can be mentioned. Preferable examples of the cycloalkyloxy group include a cycloalkyloxy group having 3 to 10 carbon atoms, for example, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Preferable examples of the alkenyloxy group include an alkenyloxy group having 2 to 10 carbon atoms, for example, allyloxy,
Crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like. Preferable examples of the cycloalkenyloxy group include a cycloalkenyloxy group having 3 to 10 carbon atoms, such as 2-cyclopentenyloxy and 2-cyclohexenyloxy. Preferable examples of the aralkyloxy group include an aralkyloxy group having 7 to 10 carbon atoms, such as phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, and more preferably an acyloxy group having 2 to 13 carbon atoms.
And alkanoyloxy groups (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) and the like. Preferable examples of the aryloxy group include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy. The aryloxy group may have one or two substituents, and examples of such a substituent include a halogen atom (eg, chlorine, fluorine, bromine and the like). Examples of the substituted aryloxy group include 4-chlorophenoxy and the like.

In the optionally substituted thiol group, examples of the substituted thiol group include an alkylthio group, a cycloalkylthio group, an alkenylthio group, a cycloalkenylthio group, an aralkylthio group, an acylthio group and an arylthio group. Can be Preferable examples of the alkylthio group include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-
Butylthio, t.-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like. Preferable examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Preferred examples of the alkenylthio group include alkenylthio groups having 2 to 10 carbon atoms, such as allylthio, crotylthio,
2-pentenylthio, 3-hexenylthio and the like. Preferable examples of the cycloalkenylthio group include a cycloalkenylthio group having 3 to 10 carbon atoms, such as 2-cyclopentenylthio and 2-cyclohexenylthio. Preferred examples of the aralkylthio group include an aralkylthio group having 7 to 10 carbon atoms, for example, phenyl-C _1-4.
Alkylthio (eg, benzylthio, phenethylthio, etc.) and the like. Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanoylthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.). Preferable examples of the arylthio group include an arylthio group having 6 to 14 carbon atoms, such as phenylthio and naphthylthio. The arylthio group may have one or two substituents, and examples of such a substituent include a halogen atom (eg, chlorine, fluorine, bromine, etc.). Examples of the substituted arylthio group include 4-chlorophenylthio.

Examples of the carboxyl group which may be esterified include, for example, an alkoxycarbonyl group, an aralkyloxycarbonyl group and an aryloxycarbonyl group. Preferable examples of the alkoxycarbonyl group include an alkoxycarbonyl group having 2 to 5 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Preferable examples of the aralkyloxycarbonyl group include an aralkyloxycarbonyl group having 8 to 10 carbon atoms, such as benzyloxycarbonyl. Preferable examples of the aryloxycarbonyl group include an aryloxycarbonyl group having 7 to 15 carbon atoms, such as phenoxycarbonyl and p-tolyloxycarbonyl. The substituent in the hydrocarbon group and the heterocyclic group represented by R is
Preferred are an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group and an aryl group having 6 to 14 carbon atoms, and more preferred are _C1-3 alkyl, furyl, thienyl, phenyl and naphthyl.

In the general formula (I), the substituent on the hydrocarbon group and the heterocyclic group represented by R may be an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group. When it is a group, it may further have one or more suitable substituents, preferably one to three, and examples of such a substituent include an alkyl group having 1 to 6 carbon atoms and a carbon number of 2 Alkenyl group having 6 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, 6 to 14 carbon atoms
Aryl groups, aromatic heterocyclic groups (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic groups (eg, tetrahydrofuryl, morpholino,
Thiomorpholino, piperidino, pyrrolidino, piperazino, etc.), an aralkyl group having 7 to 9 carbon atoms, an amino group, N-
Mono-C _1-4 alkylamino group, N, N-di-C _1-4 alkylamino group, acylamino group having 2 to 8 carbon atoms (eg, acetylamino, propionylamino, benzoylamino, etc.), amidino group, carbon An acyl group having 2 to 8 carbon atoms (eg, an alkanoyl group having 2 to 8 carbon atoms), a carbamoyl group,
N-mono-C _1-4 alkylcarbamoyl group, N, N-di-C _1-4 alkylcarbamoyl group, sulfamoyl group,
N-mono-C _1-4 alkylsulfamoyl group, N, N-
Di-C _1-4 alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms, hydroxyl group, alkoxy group having 1 to 4 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms, 3 carbon atoms To 7 cycloalkyloxy groups, 7 to 9 aralkyloxy groups, 6 carbon atoms
To 14 aryloxy groups, mercapto groups, 1 to 1 carbon atoms
4, an alkylthio group having 4 to 7 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6 to 14 carbon atoms, a sulfo group, a cyano group, an azido group, a nitro group, a nitroso group, and a halogen atom. In the general formula (I), R is preferably an optionally substituted heterocyclic group. R is more preferably a pyridyl, oxazolyl or thiazolyl group optionally having 1 to 3 substituents selected from C _1-3 alkyl, furyl, thienyl, phenyl and naphthyl.

In the general formula (I), Y represents —CO—, —CH
(OH) - or -NR ³ - (. R ³ is showing an alkyl group which may be substituted) shows a but, -CH (OH) - or -NR ³ - is preferable. Here, as the alkyl group in the optionally substituted alkyl group represented by R ³ , an alkyl group having 1 to 4 carbon atoms, for example, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like. Examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine) and an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy,
Isobutoxy, sec.-butoxy, t.-butoxy, etc.),
Examples thereof include a hydroxyl group, a nitro group, and an acyl group having 1 to 4 carbon atoms (eg, formyl, acetyl, propionyl, etc.). m represents 0 or 1, but preferably 0
It is. n represents 0, 1 or 2;
Or 1. X represents CH or N, preferably CH.

In the general formula (I), A represents a bond or a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms. The aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated. Specific examples thereof include _{-CH 2 -, - CH (CH} 3) -, - (CH
₂ ) _2- , -CH (C ₂ H ₅ )-,-(CH ₂ ) ₃ -,-(C
_{H 2) 4 -, - (} CH 2) 5 -, - (CH 2) 6 -, - (CH
_{2) 7} - saturated ones, such as, for example, -CH = CH -, - C
_{(CH 3) = CH -,} - CH = CH-CH 2 -, - C (C
_{2 H 5) = CH -,} - CH 2 -CH = CH-CH 2 -, - C
_{H 2 -CH 2 -CH = CH-} CH 2 -, - CH = CH-C
_{H = CH-CH 2 -,} - CH = CH-CH = CH-CH
And unsaturated compounds such as な ど CH—CH ₂ —. A
Is preferably a bond or a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, and the aliphatic hydrocarbon group is preferably further saturated. A is more preferably a bond or — (CH ₂ ) ₂ —. As the alkyl group represented by R ¹ , the same alkyl groups as those described above for R ³ can be used. R ¹ is preferably a hydrogen atom.

In the general formula (I), a partial structural formula

Embedded image Wherein each symbol is as defined above. ]. Ring E may further have 1 to 4 substituents at any substitutable position. Examples of such a substituent include an alkyl group, an optionally substituted hydroxyl group, a halogen atom, an optionally substituted acyl group,
Examples include a nitro group and an optionally substituted amino group. These are all the same as those described above as the substituent for the hydrocarbon group and the heterocyclic group represented by R.

Ring E, ie a partial structural formula

Embedded image [In the formula, R ² represents a hydrogen atom, an alkyl group, an optionally substituted hydroxyl group, a halogen atom, an optionally substituted acyl group, a nitro group or an optionally substituted amino group. ]. Alkyl group represented by R ² carbonization, optionally substituted hydroxyl group, a halogen atom, an optionally substituted acyl group and optionally substituted amino group, both represented by the foregoing R The same substituents as those described for the hydrogen group and the heterocyclic group can be used. R ² is preferably a hydrogen atom, an optionally substituted hydroxyl group or a halogen atom. R ² is more preferably a hydrogen atom or an optionally substituted hydroxyl group, particularly preferably a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms.

In the general formula (I), L and M represent a hydrogen atom or a bond bonded to each other, and are preferably a hydrogen atom. Here, the compound in which L and M are bonded to each other to form a bond includes (E) -form and (Z) -form with respect to the double bond at the 5-position of the azolidinedione ring. Compounds in which L and M each represent a hydrogen atom include:
There are (R) -form and (S) -form optical isomers due to the asymmetric carbon at the 5-position of the azolidinedione ring.
These include optically active and racemic forms of the (R) -form and the (S) -form.

Preferred examples of the compound represented by the general formula (I) include, for example, a compound wherein R has 1 to 3 substituents selected from C _1-3 alkyl, furyl, thienyl, phenyl and naphthyl. A pyridyl, oxazolyl or thiazolyl group; m is 0; n is 0 or 1; X is CH; A is a bond or-(CH ₂ ) _2- ; R ¹ is a hydrogen atom;

Embedded image And R ² is a hydrogen atom or a C _1-4 alkoxy group; and compounds in which L and M are hydrogen atoms.

Preferred examples of the compound represented by formula (I) include, for example, 5- [4- [2- (5-ethyl-2-
Pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione (generic name: pioglitazone / AD-4833); 5
-[[4-[(3,4-dihydro-6-hydroxy-2,
5,7,8-tetramethyl-2H-1-benzopyran-2
-Yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (generic name: troglitazone / CS-04
5); 5-[[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (generic name: rosiglitazone / BRL-4965
3); 5- [3- [4- (5-methyl-2-phenyl-
4-thiazolylmethoxy) phenyl] propyl] -2,
4-oxazolidinedione and the like. The compound represented by the general formula (I) is particularly preferably pioglitazone.

As the salt of the compound represented by the general formula (I), a pharmacologically acceptable salt, for example, a salt with an inorganic base,
Examples thereof include salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of salts with inorganic bases include salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with aluminum and ammonium. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be

The compound represented by the general formula (I) or a salt thereof is preferably pioglitazone hydrochloride, troglitazone or rosiglitazone (or a maleate thereof), and particularly preferably pioglitazone hydrochloride.

The compound represented by the general formula (I) or a salt thereof is described, for example, in JP-A-55-22636 (EP-A82).
03), JP-A-60-208980 (EP-A 155)
845), JP-A-61-286376 (EP-A20)
8420) and JP-A-61-85372 (EP-A 17
7353), JP-A-61-267580 (EP-A19)
3256), JP-A-5-86057 (WO 92/18)
501), JP-A-7-82269 (EP-A 6052)
28), JP-A-7-101945 (EP-A61274)
3), EP-A-643050, EP-A-71065
9 and the like, or a method analogous thereto.

The insulin sensitizer used in the present invention may further include, for example, 4- [4-
[2- (5-methyl-2-phenyloxazole-4-
Yl) ethoxy] benzyl] isoxazolidine-3,
5-dione (JTT-501); 5-[[3,4-dihydro-2- (phenylmethyl) -2H-1-benzopyran-6-yl] methyl] -2,4-thiazolidinedione (generic name: ene Glitazone); 5-[[4- [3-
(5-methyl-2-phenyl-4-oxazolyl) -1
-Oxopropyl] phenyl] methyl] -2,4-thiazolidinedione (generic name: dalglitazone / CP-8
6325); 5- [2- (5-methyl-2-phenyl-
4-oxazolylmethyl) benzofuran-5-ylmethyl] -2,4-oxazolidinedione (CP-927
68); 5- (2-naphthalenylsulfonyl) -2,
4-thiazolidinedione (AY-31637); 4-
[(2-Naphthalenyl) methyl] -3H-1,2,3,5
-Oxathiadiazole-2-oxide (AY-30
711); 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione (MCC-555); [5-[(2,4-dioxothiazolidine-5) -Yl) methyl] -2-methoxy-N-[[4- (trifluoromethyl) phenyl] methyl] benzamide (AHG-255);
(3,5,5,8,8-pentamethyl-5,6,7,8
-Tetrahydronaphthalen-2-yl) ethenyl] benzoic acid (LGD1069); 6- [1- (3,5,5)
8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropyl] nicotinic acid
(LG100268); 1,4-bis [4-[(3,5
-Dioxo-1,2,4-oxadiazolidine-2-yl) methyl] phenoxy] -2-butene (YM-44
0); bexarotene; GI-26257
0; DRF-2593; HQL-975; DN-10
8; CS-011; dexlipotam;
INS-1; AR-H-0329242; CLX-09
01; FK-614; KRP-297; CRE-163
36; NN-2344; BM-13-1258; S-1
5261; KB-R-7785; DRF-2725; G
W-2570; GW-2433; MXC-3255; L
-746449; L-767827; L-78328
1; GW-409544 and the like. The compounds described above may be used as salts. As such a salt, those similar to the salt of the compound represented by formula (I) described above are used.

The insulin sensitizer used in the present invention further includes, for example, a compound represented by the general formula described in WO 99/58510.

Embedded image [Wherein, R ⁴ represents an optionally substituted hydrocarbon group or a heterocyclic group; Xa represents a bond, -CO-, -CH
(OH) - or -NR ⁹ - (R ⁹ is a hydrogen atom or optionally which may be substituted alkyl group) a group represented by;
k is an integer of 1 to 3; Ya is an oxygen atom, a sulfur atom,
Have a ring Ea further 1 to 3 _{substituents; -SO -, - SO 2 -} - or -NR ¹⁰ (R ¹⁰ is a hydrogen atom or an unsubstituted or represents an alkyl group optionally) a represented by the group P is an integer of 1 to 8; R ⁵ is a hydrogen atom, a hydrocarbon group or a heterocyclic group which may be substituted; q is an integer of 0 to 6;
r represents 0 or 1; R ⁸ represents a hydroxy group, —OR ¹¹ (R
¹¹ represents an optionally substituted hydrocarbon group) or-
NR ¹² R ¹³ (R ¹² and R ¹³ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group; And R ¹² and R ¹³ may combine to form a ring); R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or an optionally substituted hydrocarbon group;
R ⁶ may combine with R ⁵ to form a ring. Or a salt thereof.

[0031] In the general formula (II), the "each optionally substituted hydrocarbon group or heterocyclic group" represented by R ^4, for example those exemplified for R in the general formula (I) is used . R ⁴ is preferably an optionally substituted heterocyclic group, and more preferably an optionally substituted pyridyl, oxazolyl, thiazolyl or triazolyl. R ⁴ is particularly preferably alkyl having 1 to 3 carbons, cycloalkyl having 3 to 7 carbons,
Pyridyl, oxazolyl, thiazolyl or triazolyl which may have one or two substituents selected from furyl, thienyl, phenyl and naphthyl. Here, furyl, thienyl, phenyl and naphthyl are obtained from alkyl having 1 to 3 carbons, alkoxy having 1 to 3 carbons, halogen (eg, fluorine, chlorine, bromine, iodine, etc.) and haloalkyl having 1 to 3 carbons. It may have one or two selected substituents.

In the general formula (II), as the “optionally substituted alkyl group” represented by R ⁹ in Xa, those exemplified as R ³ in Y in the general formula (I) are used. In the general formula (II), k represents an integer of 1 to 3, and is preferably 1 or 2. In the general formula (II),
Ya is -O -, - S -, - SO -, - SO 2 - or -
NR ¹⁰ — (R ¹⁰ represents a hydrogen atom or an optionally substituted alkyl group) is preferred, with —O—, —S— or —NR ¹⁰ — being preferred. Here, as the “optionally substituted alkyl group” represented by R ¹⁰ , those exemplified as R ³ in Y in the general formula (I) are used.

In the general formula (II), the substituent in the “benzene ring optionally having 1 to 3 substituents” represented by the ring Ea includes the ring Ea in the general formula (I) What was illustrated as a substituent is used. The substituent is preferably an alkyl group having 1 to 4 carbon atoms,
To 4 alkoxy groups or halogen atoms. In the general formula (II), p is preferably an integer of 1 to 3.
In the general formula (II), the "each optionally substituted hydrocarbon group or heterocyclic group" represented by R ^5, those exemplified is used as R in the example formula (I). R ⁵ is preferably an optionally substituted hydrocarbon group. R ⁵ is more preferably an alkyl group having 1 to 4 carbon atoms, each of which may be substituted;
A phenylalkenyl group of 10 and an aryl group having 6 to 14 carbon atoms. The substituent which these hydrocarbon groups may have is preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 14 carbon atoms and an aromatic heterocyclic group (eg, furyl, thienyl). ).

In the general formula (II), q is preferably an integer of 0 to 4. In the general formula (II), for R ⁸ , R ¹¹
As the “optionally substituted hydrocarbon group” represented by, for example, those exemplified as R in the general formula (I) are used. R ¹¹ is preferably “an alkyl group having 1 to 4 carbon atoms” and “an alkyl group having 1 to 4 carbon atoms (preferably methyl or ethyl) or a carbon number optionally substituted with a halogen atom (preferably chlorine)”. 6 to 10 aryl groups (preferably phenyl) ". In the general formula (II),
Regarding R ⁸ , the “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” represented by R ¹² and R ¹³ include, for example, those exemplified as R in formula [I]. Is used. As the “optionally substituted acyl group” represented by R ¹² and R ¹³ , for example, those exemplified as the substituent for R in formula (I) can be used. Examples of the ring formed by combining R ¹² and R ¹³ include a 5- to 7-membered cyclic amino group. Among them, 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 4-morpholino, 4-thiomorpholino and the like are preferable.

In the general formula (II), examples of the “optionally substituted hydrocarbon group” represented by R ⁶ and R ⁷ include those exemplified as R in the general formula (I).
In particular, those similar to the “optionally substituted alkyl group” exemplified as R ³ in Y in the general formula (I) are preferable. Examples of the ring and R ⁶ and R ⁵ is formed by combining 5 to cycloalkanes and the carbon number of 5 to 11 carbon atoms
11 cycloalkenes and the like, specifically, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, cyclononane, cyclononene, cyclodecane, cyclodecene, cycloundecane and cycloundecene, etc. Can be

The compound represented by the general formula (II) has an (E) -form and a (Z) -form with respect to an imino bond. The compounds include the (E) -form and the (Z) -form alone and a mixture thereof.

Preferable examples of the compound represented by the general formula (II) include the following compounds (1) to (10). (1) Z-2- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -2
-Phenylacetic acid; (2) Z-4- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -4
-Phenylbutyric acid; (3) Z-2- (4-bromophenyl) -2- [4-
(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] acetic acid; (4) Z-2- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -2
-(4-phenoxyphenyl) acetic acid; (5) Z-4- (4-fluorophenyl) -4- [4-
(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid; (6) Z-3-methyl-2- [4- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid; (7) E-4- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -4
-Phenylbutyric acid; (8) E-4- (4-fluorophenyl) -4- [4-
(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] butyric acid; (9) E-4- [4- (5-methyl-2-phenyl-4)
-Oxazolylmethoxy) benzyloxyimino] -4
-Phenylbutyramide; (10) E-8- [4- (5-methyl-2-phenyl-
4-oxazolylmethoxy) benzyloxyimino]-
8-Phenyloctanoic acid; These compounds may be simply abbreviated as compound (1) or compound (2) below. As the salt of the compound represented by the general formula (II), those similar to the salts of the compound represented by the general formula (I) are used. Particularly, a sodium salt, a potassium salt, a hydrochloride and the like are preferable.

The insulin sensitizer is preferably pioglitazone hydrochloride, troglitazone, rosiglitazone (preferably maleate thereof), 4- [4- [2-
(5-methyl-2-phenyloxazol-4-yl)
[Ethoxy] benzyl] isoxazolidin-3,5-dione or 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione, particularly preferably pioglitazone hydrochloride .

The insulin sensitizer contained in the ketosis ameliorating agent or the acidosis ameliorating agent of the present invention comprises 2
There may be more than one species. For example, as a specific combination when two insulin sensitizers are used, pioglitazone hydrochloride, troglitazone, rosiglitazone (preferably maleate thereof), 4- [4- [2-
(5-methyl-2-phenyloxazol-4-yl)
[Ethoxy] benzyl] isoxazolidin-3,5-dione, 5-[[6- (2-fluorobenzyloxy)-
2-naphthyl] methyl] -2,4-thiazolidinedione, 1,4-bis [4-[(3,5-dioxo-1,
2,4-oxadiazolidine-2-yl) methyl] phenoxy] -2-butene, bexarotene,
GI-262570, DRF-2593, HQL-97
5 and one selected from DN-108.

The ketosis ameliorating effect is evaluated, for example, by adding a test compound to a "system that causes ketosis" and measuring a change in the ketone body concentration in this system. For example, Wistar fatt rat, a model animal of non-insulin dependent (type 2) diabetes,
y rat), since diabetic ketosis is observed, the plasma total ketone body concentration was measured between the Wistar Fatty rat group (experimental group) to which the test compound was administered and the Wistar Fatty rat group (subject group) to which the test compound was not administered. Can be evaluated to evaluate the ketosis improving effect of the test compound. Here, the plasma total ketone body concentration is the concentration of a ketone body (eg, acetoacetic acid, 3-hydroxybutyric acid, etc.) in plasma, and is measured, for example, as follows. [Measurement Method of Plasma Total Ketone Body Concentration] 3-Hydroxybutyric acid (3-HB) in a sample was converted to 3-hydroxybutyric acid (3-HB) in the presence of β-thionicotinamide adenine dinucleotide oxidized form (thio-NAD).
-Hydroxybutyrate dehydrogenase (3-HBDH) is specifically oxidized, and acetoacetic acid (AcAc) and β-thionicotinamide adenine dinucleotide reduced form (thioNA
DH). On the other hand, AcAc is specifically reduced by 3-HBDH in the presence of β-nicotinamide adenine dinucleotide reduced form (NADH), and 3-HB and β-nicotinamide adenine dinucleotide oxidized form (N
AD). Thio NAD thus produced
By measuring the generation rate of H, 3-HB in the sample can be determined.
And the total ketone body concentration which is the sum of AcAc. As described above, the ketosis in the present invention includes diabetic ketosis. Here, diabetic ketosis means ketosis observed in diabetic (type 1 diabetes, type 2 diabetes, etc.) patients. Further, as shown in the experimental examples described later, ketosis may be caused by the biguanide, but the ketosis in the present invention includes ketosis caused by the biguanide.

The action of improving acidosis is evaluated, for example, by adding a test compound to a "system causing acidosis" and measuring the change in plasma pH in this system. Because of the change, they are also evaluated by measuring the change in these concentrations. For example, as described above, the Wistar Fatty rat group to which the test compound was administered (experimental group)
By comparing the plasma total ketone body concentration between the test compound and the Wistar Fatty rat group (subject group) to which the test compound is not administered, the effect of the test compound for improving acidosis can be estimated and evaluated. As described above, the acidosis in the present invention includes diabetic acidosis. Here, diabetic acidosis means acidosis observed in diabetic (type 1 diabetes, type 2 diabetes, etc.) patients. In addition, acidosis may be caused by a biguanide, and the acidosis in the present invention includes acidosis caused by a biguanide.

The ketosis ameliorating agent or acidosis ameliorating agent of the present invention may be the insulin sensitizer itself, which is the active ingredient, but usually, the active ingredient and a pharmacologically acceptable carrier are known per se. [Methods commonly used in the technical field of pharmaceutical preparations, for example, Japanese Pharmacopoeia (for example,
And the like described in Amendment). Examples of the dosage form of the ketosis improving agent or the acidosis improving agent of the present invention include oral preparations such as tablets, capsules (including soft capsules and microcapsules), powders, granules, syrups and the like; and injections (eg, subcutaneous injection) Preparations, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, transnasal preparations, transdermal preparations,
Ointments), suppositories (eg, rectal suppositories, vaginal suppositories, etc.), parenteral preparations such as pellets and drops.

Hereinafter, a method for producing an oral preparation and a parenteral preparation will be specifically described. Oral preparations include, as active ingredients, excipients (eg, lactose, sucrose, starch, D-mannitol, xylitol, sorbitol, erythritol, crystalline cellulose, light anhydrous silicic acid, etc.), disintegrants (eg, calcium carbonate, starch) Carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethylstarch, light anhydrous silicic acid, etc., binders (eg, pregelatinized starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose) , Hydroxypropylmethylcellulose, polyvinylpyrrolidone, crystalline cellulose, methylcellulose, sucrose, D-mannitol, trehalose, dextrin, etc.) or lubricants (eg, talc, Magnesium stearic acid, calcium stearate, colloidal silica, is produced by compression molding by adding polyethylene glycol 6000, etc.). In addition, in oral preparations, hydrochloric acid, phosphoric acid, malonic acid, succinic acid, DL-malic acid, tartaric acid,
Acids such as maleic acid, fumaric acid, citric acid or sodium carbonate, sodium hydrogen carbonate, sodium citrate,
A base such as sodium tartrate may be added.

Further, the oral preparation may be coated by a method known per se for the purpose of masking taste, enteric coating or sustained release. Examples of the coating agent include enteric polymers (eg, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose) ), Gastric-soluble polymers (eg, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E)
Water-soluble polymer (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), water-insoluble polymer (eg, ethylcellulose, aminoalkyl methacrylate copolymer RS, ethyl acrylate.
For example, methyl methacrylate copolymer), wax and the like are used. When coating is performed, a plasticizer such as polyethylene glycol and a light-shielding agent such as titanium oxide and iron sesquioxide may be used together with the coating agent.

Injectables are prepared by dispersing the active ingredient in a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HC
O60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc., preservatives (eg, methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, phenol, etc.), tonicity agents (eg, sodium chloride, glycerin) , D-sorbitol, D-mannitol, xylitol, glucose, fructose, etc. together with an aqueous solvent (eg, distilled water, physiological saline, Ringer's solution, etc.) or an oily solvent (eg, olive oil, sesame oil, cottonseed oil, corn oil, etc.) Vegetable oils; propylene glycol, macrogol, tricaprylin, etc.). At this time, if desired, a solubilizing agent (eg,
Sodium salicylate, sodium acetate, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc., suspending agents (eg, Surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxy Hydrophilic polymers such as ethylcellulose and hydroxypropylcellulose), buffering agents (eg, phosphoric acid) , Acetates, carbonates, buffers such as citrate), stabilizers (eg, human serum albumin), soothing agents (eg, propylene glycol, lidocaine hydrochloride, benzyl alcohol, etc.), preservatives (eg, Additives such as paraoxybenzoates, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like may be used.

An external preparation is produced by preparing the active ingredient into a solid, semi-solid or liquid composition. For example, the solid composition contains the active ingredient as it is or as an excipient (eg, lactose, D-mannitol, starch, crystalline cellulose, sucrose, etc.), a thickener (eg, natural gums, cellulose derivatives, (Acrylic acid polymer etc.) is added and mixed to form a powder. The liquid composition is produced almost in the same manner as in the case of injection.
The semi-solid composition is preferably an aqueous or oily gel or an ointment. In addition, these compositions each include a pH regulator (eg, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), a preservative (eg, paraoxybenzoates, chlorobutanol, benzalkonium chloride, benzyl) Alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.).

Suppositories are prepared by making the active ingredient an oily or aqueous solid, semi-solid or liquid composition. Examples of the oily base used in the production of the composition include glycerides of higher fatty acids (eg, cocoa butter,
Witepsols (Hulls Actiengesellschaft, Germany), etc., medium fatty acid triglycerides (eg, Migrols (Huls Actiengesellschaft, Germany), etc.), vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). No. Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.

The content of the insulin sensitizer in the ketosis ameliorating agent or acidosis ameliorating agent of the present invention is, for example, 0.1 to 100% by weight, preferably 5 to 80% by weight.
% By weight.

The ketosis ameliorating agent or acidosis ameliorating agent of the present invention has low toxicity, and is effective in mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig,
It is safely used orally or parenterally for monkeys. The dose of the ketosis ameliorating agent and the acidosis ameliorating agent of the present invention may be in accordance with the dose of the insulin sensitizer which is the active ingredient, and is the subject to be administered, the age and weight of the subject to be administered, symptoms, administration time, dosage form. It can be appropriately selected depending on the administration method and the like. Here, the dose of the insulin sensitizer can be appropriately selected based on the clinically used dose. For example, a ketosis ameliorating agent or an acidosis ameliorating agent is administered to an adult (body weight 50k).
When administered to g), the daily dose is usually from 0.01 to 0.01 as the active ingredient insulin sensitizer.
The dose is 1000 mg, preferably 0.1 to 600 mg, which can be administered once or several times a day.
In particular, when a ketosis ameliorating agent or an acidosis ameliorating agent containing pioglitazone hydrochloride as an insulin sensitizer is orally administered to an adult (body weight 50 kg), the daily dose of the ameliorating agent is usually 7 as pioglitazone hydrochloride. 0.5-60 mg, preferably 15-45 m
g, this amount can be administered once or twice a day. When a ketosis improving agent or an acidosis improving agent containing troglitazone as an insulin sensitizer is orally administered to an adult (body weight 50 kg), the daily dose of the ameliorating agent is usually 100 to 100 mg as troglitazone. 1000 mg, preferably 20
0 to 600 mg, and this amount can be administered once or twice a day. When a ketosis improving agent or an acidosis improving agent containing rosiglitazone (or a maleate thereof) as an insulin sensitizer is orally administered to an adult (body weight 50 kg), one of the improving agents is used.
The daily dose is usually 1 to 12 mg as rosiglitazone (or its maleate), preferably 2 to 12 mg.
12 mg, which can be administered once or twice a day.

The ketosis ameliorating agent of the present invention may be a disease exhibiting ketosis, for example, hepatic glycogenosis, endocrine disease (eg, hyperthyroidism, acromegaly, pheochromocytoma, glucagonoma, etc.), congenital carbohydrate or Abnormal organic acid metabolism (eg, fructose bisphosphatase deficiency, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, β-ketothiolase deficiency, hyperlactic acidemia, etc.), acetonemic vomiting, gastrointestinal tract It can improve (treat) ketosis observed in diseases (eg, diarrhea, etc.) and is used as a prophylactic / therapeutic agent for these diseases.

The acidosis ameliorating agent of the present invention can improve (treat) acidosis observed in diseases exhibiting acidosis such as impaired consciousness, coma, and respiratory diseases (eg, pulmonary tuberculosis). It is used as a prophylactic / therapeutic agent.

In the ketosis ameliorating agent and the acidosis ameliorating agent of the present invention, for the purpose of “reducing the amount of the insulin sensitizer used”, “reducing the side effects of the insulin sensitizer”, etc. A concomitant drug that does not adversely affect the ketosis improving effect or acidosis improving effect can be used. Such concomitant drugs include, for example, "drugs for treating diabetes other than insulin sensitizers", "drugs for treating diabetic complications",
Examples include "antiobesity drugs", "hypertensive drugs", "hyperlipidemic drugs", "diuretics" and the like. Further, when using the ketosis improving agent and the acidosis improving agent of the present invention, a diet therapy (a treatment method by nutrition or calorie restriction) or an exercise therapy may be performed.

Examples of the above "agents for treating diabetes other than insulin sensitizers" include insulin secretagogues, biguanides, insulin, α-glucosidase inhibitors, β3 agonists and the like. Examples of the insulin secretagogue include a sulfonylurea agent. Specific examples of the sulfonylurea agent include, for example, tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide and its ammonium salt, glibenclamide, gliclazide, 1-butyl-3
-Methanylyl urea, carbutamide, glibornuride,
Glipizide, gliquidone, glisoxepide, glybuthiazole, glybuzole, glyhexamide, glymidine,
Glypinamide, fenbutamide, tolcyclamide, glimepiride and the like. In addition to the above, examples of the insulin secretagogue include N-[[4- (1-methylethyl) cyclohexyl] carbonyl] -D-phenylalanine [Nateglinide, AY-416]
6], (2S) -2-benzyl-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionate calcium dihydrate [Mitiglinid
e), KAD-1229], Repaglinide, GL
P (Glucagon-like peptide) -1, GLP-1 (7
-36) -amide, V8-GLP-1 (LY-30716)
1), Exendin-4 (AC-2993), D
PP-728-A, V-411, JT-608 and the like.

Examples of biguanides include phenformin, metformin, buformin and the like.
Examples of the insulin include animal insulin extracted from bovine and porcine pancreas; semi-synthetic human insulin enzymatically synthesized from insulin extracted from porcine pancreas;
Examples include human insulin synthesized by genetic engineering using Escherichia coli and yeast. As insulin, 0.1.
Insulin zinc containing 45 to 0.9 (w / w)% zinc; zinc chloride, protamine zinc produced from protamine sulfate and insulin, and the like are also used.
Further, the insulin may be a fragment or derivative thereof (eg, INS-1, etc.). Insulin includes various types such as super fast-acting type, fast-acting type, two-phase type, intermediate type and continuous type, and these can be appropriately selected depending on the condition of the patient. As α-glucosidase inhibitors,
Examples include acarbose, voglibose, miglitol, emiglitate, and the like. As a β3 agonist (β3 adrenergic receptor agonist),
For example, SR-58611-A, SB-226552, AZ40140 and the like can be mentioned. In addition to the above, “diabetics other than insulin sensitizers” include, for example, ergoset (ergoset)
set), pramlintide, leptin,
BAY-27-9955, T-1095 and the like.

Examples of the "agent for treating diabetic complications" include aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors and the like. Examples of aldose reductase inhibitors include tolrestat; epalrestat; 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid; imirestat; zenarestat; 6-fluoro- 2,3-dihydro-2 ', 5'-dioxo-spiro [4H-1-benzopyran-4,4'-imidazolidin] -2-carboxamide (SNK-860);
Zopolrestat; sorbinyl; 1-[(3-bromo-
2-benzofuranyl) sulfonyl] -2,4-imidazolidinedione (M-16209); CT-112; NZ-314; ARI-5
09 and the like. As glycation inhibitors,
For example, pimagedine and the like can be mentioned. Examples of protein kinase C inhibitors include NGF, LY-33
3531 and the like. In addition to the above, examples of the "agent for treating diabetic complications" include alprostadil, tiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl icosapentate, memantine, and pimagedline (pimagedline; ALT-711).

The "anti-obesity agent" includes, for example, lipase inhibitors, appetite suppressants and the like. Examples of the lipase inhibitor include orlistat.
Appetite suppressants include, for example, dexfenfuramine, fluoxetine, sibutramine, biamine and the like.

Examples of the above-mentioned "agent for treating hypertension" include angiotensin converting enzyme inhibitors, calcium antagonists, potassium channel openers, angiotensin II antagonists and the like. Examples of the angiotensin converting enzyme inhibitors include, for example, captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, selonapril, cilazapril, enalaprilate, fosinopril, mobertopril, perindopril, quinapril, spirapril, spirapril, spirapril, spirapril, spirapril, spirapril, spirapril, spirapril No.
Examples of the calcium antagonist include nifedipine, amlodipine, efonidipine, nicardipine and the like. Examples of potassium channel openers include Levcromakalim, L-27152, AL0671, NIP-121 and the like. Examples of angiotensin II antagonists include losartan, candesartan cilexetil, valsartan, irbesartan, (5-methyl-2-oxo-1,3-dioxolene-
4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-
Propyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-
4-ylmethyl] imidazole-5-carboxylate (CS-8
66) and E4177.

Examples of the "agent for treating hyperlipidemia" include HMG-CoA reductase inhibitors, fibrate compounds and the like. HMG-CoA reductase inhibitors include, for example, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, ripantile, cerivastatin, itavastatin, ZD-4522
Or salts thereof (eg, sodium salts and the like). Examples of the fibrate compounds include, for example, bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyrifibrate, ronifibrate, simfibrate,
Theofibrate and the like.

Examples of the above-mentioned "diuretic" include xanthine derivative preparations, thiazide preparations, anti-aldosterone preparations, carbonic anhydrase inhibitors, chlorobenzenesulfonamide preparations and the like. Examples of the xanthine derivative preparation include sodium theobromine salicylate and calcium theobromine salicylate. Examples of the thiazide-based preparation include ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, penflutide, polythiazide, methyclothiazide and the like. As anti-aldosterone preparations,
Examples include spironolactone and triamterene. Examples of the carbonic anhydrase inhibitor include acetazolamide and the like. Chlorbenzenesulfonamide-based preparations include, for example, chlorthalidone, mefluside,
And indapamide. In addition to the above, examples of the "diuretic" include azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

The above concomitant drugs may be used in combination of any two or more kinds. Specific combinations when using two concomitant drugs in combination include, for example, “combination of insulin secretagogue and biguanide agent”, “combination of insulin secretagogue and α-glucosidase inhibitor”, “ Combinations of insulin and biguanides "," combinations of insulin and α-glucosidase inhibitors "and the like.

When the ketosis ameliorating agent of the present invention is used for the improvement (treatment) of diabetic ketosis, particularly the ketosis observed in patients with type 1 diabetes, it is possible to use a combination of an insulin sensitizer and insulin. preferable. When the acidosis improving agent of the present invention is used for improving (treating) acidosis observed in diabetic acidosis, particularly in patients with type 1 diabetes, it is preferable to use a combination of an insulin sensitizer and insulin. .

The timing of administration of the insulin sensitizer and the concomitant drug is not limited.
They may be administered at the same time or at different times. The dose of the concomitant drug may be in accordance with the dose clinically used, and may be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, dosage form, administration method, combination, and the like. Can be. The administration form of the concomitant drug is not particularly limited as long as the insulin sensitizer and the concomitant drug are combined at the time of administration. Such administration forms include, for example, 1) administration of a single preparation obtained by simultaneously preparing an insulin sensitizer and a concomitant drug, and 2) separate administration of the insulin sensitizer and the concomitant drug. Administration of the two preparations prepared in the same manner by the same administration route, and 3) the time difference of the two preparations obtained by separately preparing the insulin sensitizer and the concomitant drug in the same administration route. Obtained by separately formulating an insulin sensitizer and a concomitant drug 2)
5) Simultaneous administration of different preparations by different administration routes; 5) Administration of two preparations obtained by separately formulating an insulin sensitizer and a concomitant drug with different administration routes at different times (for example, Administration in the order of insulin sensitizers, concomitant drugs, or administration in the reverse order).

For example, when an “antidiabetic agent other than an insulin sensitizer” is administered to an adult (body weight 50 kg), the daily dose is usually 0.1 to 2500 mg.
It is preferably 0.5 to 1000 mg, and this amount is
It can be administered in several divided doses. When an insulin secretagogue is administered to an adult (body weight 50 kg),
The daily dose is usually 0.1 to 1000 mg, preferably 1 to 100 mg, and this amount can be administered once or several times a day. When the biguanide is administered to an adult (body weight 50 kg), the daily dose is usually 10 to 2500 mg, preferably 100 to 10 mg.
It can be administered once or several times a day. Insulin for adults (weight 50k)
g) (usually as an injection), the daily dose is usually 10 to 100 U (unit), preferably 10 to 80 U (unit), and this amount is 1 to 10 U / day. It can be administered in several divided doses. When an α-glucosidase inhibitor is administered to an adult (body weight 50 kg), the daily dose is usually 0.1 to 400 mg,
The dose is preferably 0.6 to 300 mg, which can be administered in one or several divided doses a day. When a β3 agonist is administered to an adult (body weight 50 kg), the daily dose is usually 10 to 2000 mg, preferably 100 to 2000 mg.
This amount can be administered once or several times a day.

For example, when the "drug for treating diabetic complications" is administered to an adult (body weight 50 kg), the daily dose is usually 0.1 to 2000 mg, and this amount is administered once to several times a day. Can be divided and administered. When an aldose reductase inhibitor is to be administered to an adult (body weight 50 kg), the daily dose is usually 1 to 1000 mg, which can be administered once or several times a day. . Glycation inhibitor is administered to adults (weight 50k)
g), the daily dose is usually 1 to
2000 mg, which can be administered once or several times a day. When the protein kinase C inhibitor is administered to an adult (body weight 50 kg), the daily dose is usually 0.1 to 100 mg, and
It can be administered once or several times a day.

For example, an “anti-obesity drug” is administered to an adult (body weight 50 k
When administered to g), the daily dose is usually 0.1 mg.
The dose may be in the range of 01 to 1000 mg, preferably 0.1 to 1000 mg, which may be administered once or several times a day. When the lipase inhibitor is administered to an adult (body weight 50 kg), the daily dose is usually 0.1 to 10
It can be administered once or several times a day. For appetite suppressants, adults (weight 50k)
g), the daily dose is usually 0.1 mg.
It can be administered in an amount of from 01 to 1000 mg, preferably from 0.1 to 500 mg, once or several times a day.

For example, an “antihypertensive drug” is administered to an adult (body weight 5
0 kg), the daily dose is usually 0.01 to 1000 mg, which can be administered once or several times a day. When an angiotensin converting enzyme inhibitor is administered to an adult (body weight 50 kg), the daily dose is usually 0.01 to 500 mg,
Preferably, the dose is 0.1 to 100 mg, which can be administered once or several times a day. When the calcium antagonist is administered to an adult (body weight 50 kg), the daily dose is usually 0.1 to 500 mg, preferably 1 to 500 mg.
This amount can be administered once or several times a day. Potassium channel opener,
When administered to an adult (body weight 50 kg), the daily dose is usually 0.01 to 1000 mg.
It can be administered once or several times a day. When an angiotensin II antagonist is administered to an adult (body weight 50 kg), the daily dose is usually 0.1 to 500 m
g, preferably 1 to 100 mg, which can be administered once or several times a day.

For example, when the "hyperlipidemic agent" is administered to an adult (body weight 50 kg), the daily dose is usually 0.01 to 3000 mg, preferably 1 to 2000 mg. Can be administered once or several times a day. When the HMG-CoA reductase inhibitor is administered to an adult (body weight 50 kg), the daily dose is as follows:
Usually, the dose is 0.01 to 100 mg, preferably 0.5 to 50 mg, which can be administered once or several times a day. Fibrates are administered to adults (weight 50k)
g), the daily dose is usually 1 to
The dose is 2000 mg, preferably 10 to 1500 mg, which can be administered once or several times a day.

For example, a “diuretic” is administered to an adult (body weight 50 k
When administered to g), the daily dose is usually 0.1 mg.
It can be administered in an amount of from 01 mg to 100 g, preferably from 0.05 mg to 10 g, once or several times a day. A xanthine derivative preparation is administered to an adult (body weight 50k).
When administered to g), the daily dose is usually 0.1 mg.
It is 1 to 100 g, preferably 0.5 to 10 g, and this amount can be administered once or several times a day. When the thiazide preparation is administered to an adult (body weight 50 kg), the daily dose is usually 0.01 to 2000 m
g, preferably 0.05 to 500 mg.
It can be administered once or several times a day. When the anti-aldosterone preparation is administered to an adult (body weight 50 kg), the daily dose is usually 1 to 2000 mg, preferably 10 to 1000 mg, and the dose is administered once or several times a day. can do. When the carbonic anhydrase inhibitor is administered to an adult (body weight 50 kg), the daily dose is usually 10 to 5000 mg, preferably 50 to 50 mg.
２０００2000 mg, which can be administered once or several times a day. When a chlorobenzenesulfonamide preparation is administered to an adult (body weight 50 kg), 1
The daily dose is usually 1 to 2000 mg, preferably 10 to 1000 mg, and this dose can be administered once or several times a day.

The compounding ratio of the insulin sensitizer and the concomitant drug can be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, dosage form, administration method and the like. For example, 0.0001 to 10000 parts by weight of the concomitant drug may be used for 1 part by weight of the insulin sensitizer.

The present invention provides "a non-ketonic hyperosmolar coma containing an insulin sensitizer, an infection (eg, respiratory tract infection, urinary tract infection, digestive tract infection, skin and soft tissue infection). , Lower limb infections), diabetic osteopenia, diabetic gangrene, xerostomia, deafness, angina, cerebrovascular disorder or peripheral blood circulation disorder " , Human, mouse, rat, rabbit, dog, cat,
It is safely used orally or parenterally for cattle, horses, pigs, monkeys, etc. The production method, dosage form, dosage, combination method, and the like of the prophylactic / therapeutic agent are the same as those of the above-described ketosis improving agent or acidosis improving agent. Further, in the prophylactic / therapeutic agent, for the purpose of "reducing the amount of the insulin sensitizer used", "reducing the side effects of the insulin sensitizer", etc. Similar concomitant drugs can be used.

[0071]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to Examples and Experimental Examples, but these do not limit the present invention.

EXAMPLES Example 1 2479.5 g of pioglitazone hydrochloride (2% as pioglitazone)
250g), l3930.5g of lactose and 540g of carboxymethylcellulose calcium (carmellose calcium) were placed in a fluidized-granulation dryer (manufactured by Powrex), preheated and mixed, and an aqueous solution in which 450g of hydroxypropylcellulose was dissolved was added.
By spraying 00 g, a granulated powder was obtained. Granulated powder obtained 16
820g is passed through a cutter mill (manufactured by Showa Chemical Machinery Co., Ltd.)
The powder was sized. 16530g of sized powder obtained, 513g of carmellose calcium and 57g of magnesium stearate
Is mixed using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho), and 16800 g of the mixed powder is tableted using a tableting machine (manufactured by Kikusui Seisakusho), and 15 mg of pioglitazone per tablet is obtained.
140,000 tablets having the following composition were obtained.

Example 2 In the same manner as in Example 1, 3 tablets of pioglitazone were used per tablet.
140,000 tablets containing 0 mg and having the following composition were obtained.

Example 3 In the same manner as in Example 2, 4 tablets of pioglitazone were used per tablet.
140,000 tablets having the following composition and containing 5 mg were obtained.

Experimental Example 1 The effect of an insulin sensitizer (pioglitazone hydrochloride) on diabetic ketosis in Wistar fatty rats, a non-insulin dependent diabetes mellitus (NIDDM) model, was examined. First, Wistar Fatty rats (31 weeks old, male) were divided into two groups (six in each), and one group contained pioglitazone hydrochloride (1 mg / kg body weight / day) suspended in a 0.5 (w / v)% aqueous methylcellulose solution.
The other group was orally administered a 0.5 (w / v)% aqueous solution of methylcellulose for 14 days. After administration, blood was collected from the tail vein of Wistar Fatty rats, and the total ketone body concentration in the plasma was determined by Auto Wako total ketone body (trade name) (Wako Pure Chemical Industries, Ltd.)
And the enzymatic method using a Hitachi 7070 automatic analyzer. In addition, 0.5 (w / v) was added to Wistar leanrat (6 rats), a non-diabetic (normal) model.
% Methylcellulose aqueous solution was orally administered for 14 days, and the total ketone body concentration in plasma was measured in the same manner as described above.

The results are shown in [Table 1]. In the table, W. lean,
W. fatty acid and Pio indicate Wistar lean rat, Wistar faty rat and pioglitazone hydrochloride, respectively. Numerical values in the table indicate average value ± standard deviation (number of subjects = 6). *: P <0.01 (Dannet test for Wistar fatty rat) As shown in [Table 1], the total ketone body concentration in the normal model Wistar lean rat was 97.67 ± 23.
18 μM. On the other hand, the total ketone body concentration in the NIDDM model Wistar Fatty rat (pioglitazone hydrochloride non-administration group) was 170.23 ± 22.33 μM,
The concentration was increased by 72.56 μM as compared with the total ketone body concentration of the Wistar lean rat, a normal model. Also, NI
The total ketone body concentration in Wistar Fatty rat (pioglitazone hydrochloride administration group), which is a DDM model, was 125.
72 ± 12.49 μM, which was 44.51 μM lower than the total ketone body concentration in the pioglitazone hydrochloride non-administration group. The above results revealed that an insulin sensitizer (pioglitazone hydrochloride) improved diabetic ketosis.

Experimental Example 2 An insulin sensitizer (pioglitazone hydrochloride) was used in Wistar Fatty rat, a NIDDM model.
Of the drug on ketosis induced by a biguanide (metformin) was investigated. First, Wistar Fatty rats (31 weeks old, male) were divided into three groups (six in each) of groups A, B, and C. Metformin (300 mg / kg body weight) suspended in (w / v)% methylcellulose aqueous solution
/ Day) for group C, metformin (300 mg / kg body weight / day) suspended in 0.5 (w / v)% aqueous methylcellulose solution and
Pioglitazone hydrochloride (1 mg / kg body weight / day) suspended in a 0.5 (w / v)% aqueous methylcellulose solution was orally administered for 14 days. After administration, blood was collected from the tail vein of Wistar Fatty rats, and the total ketone body concentration in plasma was measured in the same manner as in Experimental Example 1.

The results are shown in [Table 2]. In the table, W. fatty,
Met and Pio stand for Wistar Fatyrat, metformin and pioglitazone hydrochloride, respectively.
The numerical values in the table are the average value ± standard deviation (number of subjects =
6) is shown. As shown in [Table 2], the total ketone body concentration in the group not administered with metformin and pioglitazone hydrochloride (Group A) was 170.23 ± 22.33 μM. On the other hand, the total ketone body concentration in the metformin-administered group (group B) was 182.00.
The concentration was ± 22.50 μM, which was 11.77 μM higher than the total ketone body concentration in the group not administered with metformin and pioglitazone hydrochloride (group A). The total ketone body concentration in the group administered metformin and pioglitazone hydrochloride (group C) was 155.25 ± 42.12 μM, which was 26.75 compared to the total ketone body concentration in the group administered metformin (group B).
μM was reduced.

Experimental Example 3 The total ketone body concentration in Wistar Fatty rat plasma was measured in the same manner as in Experimental Example 2 except that the administration period was changed from 14 days to 7 days. The results are shown in [Table 3]. In the table,
W. fatty, Met and Pio indicate Wistar Faty rat, metformin and pioglitazone hydrochloride, respectively. Numerical values in the table indicate average value ± standard deviation (number of subjects = 6). As shown in [Table 3], the total ketone body concentration in the group not administered with metformin and pioglitazone hydrochloride (Group A) was 160.37 ± 14.00 μM. On the other hand, the total ketone body concentration in the metformin-administered group (Group B) was 199.923.
The concentration was ± 55.69 μM, which was 38.86 μM higher than the total ketone body concentration in the group not administered with metformin and pioglitazone hydrochloride (group A). The total ketone body concentration in the group administered metformin and pioglitazone hydrochloride (group C) was 153.50 ± 26.14 μM, which was 45.73 compared to the total ketone body concentration in the group administered metformin (group B).
μM was reduced. From the results of Experimental Examples 2 and 3, it was revealed that the insulin sensitizer (pioglitazone hydrochloride) improves ketosis caused by a biguanide (metformin). Furthermore, the results of Experimental Examples 2 and 3 reveal that the insulin sensitizer (pioglitazone hydrochloride) improves not only ketosis caused by the biguanide (metformin) but also ketosis caused by diabetes. Became.

[0079]

The ketosis ameliorating agent of the present invention has low toxicity and exhibits ketosis, for example, hepatic glycogenosis, endocrine diseases (eg, hyperthyroidism, acromegaly, pheochromocytoma, glucagonoma, etc.). , Congenital carbohydrate or organic acid metabolism disorders (eg, fructose bisphosphatase deficiency,
As a preventive or therapeutic agent for methylmalonic acidemia, propionic acidemia, isovaleric acidemia, β-ketothiolase deficiency, hyperlactic acidemia, etc., acetonemic vomiting, gastrointestinal diseases (eg, diarrhea, etc.) Useful. Further, the acidosis ameliorating agent of the present invention has a low toxicity, a disease exhibiting acidosis,
For example, disturbance of consciousness, coma, respiratory disease (eg, pulmonary tuberculosis)
It is useful as a prophylactic / therapeutic agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/426 A61K 31/426 31/427 31/427 31/4439 31/4439 31/455 31/455 38 / 28 45/06 45/06 A61P 3/00 A61P 3/00 3/10 3/10 9/14 9/14 11/00 11/00 25/00 25/00 27/16 27/16 33/00 33 / 00 C07D 213/80 // C07D 213/80 263/44 263/44 277/34 277/34 291/04 291/04 413/12 413/12 417/12 417/12 A61K 37/26

Claims (16)

[Claims] (1) A ketosis ameliorating agent comprising an insulin sensitizer. (2) an insulin sensitizer having a general formula: [Wherein, R represents an optionally substituted hydrocarbon or heterocyclic group; Y represents —CO—, —CH (OH) — or —NR ³ — (R ³ represents an optionally substituted alkyl group; M is 0 or 1; n is 0, 1 or 2; X is CH or N; A is a bond or a group having 1 to 1 carbon atoms.
7 is a divalent aliphatic hydrocarbon group; Q is an oxygen atom or a sulfur atom; R ¹ is a hydrogen atom or an alkyl group, respectively. Ring E may further have 1 to 4 substituents, and the substituents may combine with R ¹ to form a ring. L and M each represent a hydrogen atom or may be bonded to each other to form a bond. The compound according to claim 1, which is a compound represented by the formula: (3) the insulin sensitizer is pioglitazone hydrochloride, troglitazone, rosiglitazone, 4- [4-
[2- (5-methyl-2-phenyloxazole-4-
Yl) ethoxy] benzyl] isoxazolidine-3,
The improver according to claim 1, which is 5-dione or 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione. 4. The ameliorating agent according to claim 1, wherein the ketosis is diabetic ketosis. 5. The method according to claim 1, wherein the ketosis is ketosis caused by a biguanide. 6. The ameliorating agent according to claim 1, which is a preventive or therapeutic agent for hepatic glycogenosis, endocrine disease, congenital carbohydrate or organic acid metabolism disorder, acetonemic vomiting or gastrointestinal disease. 7. An acidosis improving agent comprising an insulin sensitizer. 8. An insulin sensitizer having a general formula: [Wherein, R represents an optionally substituted hydrocarbon or heterocyclic group; Y represents —CO—, —CH (OH) — or —NR ³ — (R ³ represents an optionally substituted alkyl group; M is 0 or 1; n is 0, 1 or 2; X is CH or N; A is a bond or a group having 1 to 1 carbon atoms.
7 is a divalent aliphatic hydrocarbon group; Q is an oxygen atom or a sulfur atom; R ¹ is a hydrogen atom or an alkyl group, respectively. Ring E may further have 1 to 4 substituents, and the substituents may combine with R ¹ to form a ring. L and M each represent a hydrogen atom or may be bonded to each other to form a bond. Or a salt thereof. (9) the insulin sensitizer is pioglitazone hydrochloride, troglitazone, rosiglitazone, 4- [4-
[2- (5-methyl-2-phenyloxazole-4-
Yl) ethoxy] benzyl] isoxazolidine-3,
The improving agent according to claim 7, which is 5-dione or 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione. 10. The method according to claim 7, wherein the acidosis is diabetic acidosis. 11. The ameliorating agent according to claim 7, wherein the acidosis is acidosis caused by a biguanide. 12. The ameliorating agent according to claim 7, which is an agent for preventing or treating consciousness disorder, coma or respiratory disease. 13. A non-ketonic hyperosmotic coma containing an insulin sensitizer, infectious disease, diabetic osteopenia, diabetic gangrene, xerostomia, deafness, angina, cerebrovascular disorder. Or a prophylactic / therapeutic agent for peripheral blood circulation disorders. 14. An insulin sensitizer, wherein pioglitazone hydrochloride, troglitazone, rosiglitazone, 4- [4-
[2- (5-methyl-2-phenyloxazole-4-
Yl) ethoxy] benzyl] isoxazolidine-3,
The improving agent according to claim 13, which is 5-dione or 5-[[6- (2-fluorobenzyloxy) -2-naphthyl] methyl] -2,4-thiazolidinedione. 15. A ketosis improving agent comprising a combination of an insulin sensitizer and insulin. 16. An acidosis improving agent comprising a combination of an insulin sensitizer and insulin.