JP2005126430A - Diabetes drug - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a diabetes drug for sulfonylurea secondary failure expressing excellent insulin secretion effect and hypoglycemic effect even for patients who can not obtain insulin secretion effect by using a sulfonylurea compound, a quick-acting insulin secretion promoter or the like, thererfore, can not obtain sufficient hypoglycemic effect. <P>SOLUTION: The diabetes drug for sulfonylurea secondary failure contains a dipeptidyl peptidase IV inhibitor. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a therapeutic agent for sulfonylurea secondary ineffective diabetes comprising an inhibitor of dipeptidyl peptidase-IV (sometimes abbreviated as DPP-IV in the present specification).

A sulfonylurea compound (hereinafter sometimes abbreviated as SU agent) is widely used as a first-line drug for an oral hypoglycemic agent. However, when a SU agent is continuously administered to a diabetic patient, a state in which a sufficient blood glucose lowering effect cannot be obtained, that is, a sulfonylurea secondary failure is caused.
In patients with sulfonylurea secondary ineffective diabetes, the therapeutic effect by administration of the SU agent cannot be expected, and therefore treatment with an insulin preparation is performed.
On the other hand, DPP-IV inhibitors are known to be useful as antidiabetic agents (see, for example, Patent Document 1).

International Publication No. WO02 / 066274 Pamphlet

  The object of the present invention is to provide an excellent insulin secretion effect and blood glucose lowering effect even in diabetic patients who cannot obtain an insulin secretion effect with a sulfonylurea compound or a fast-acting insulin secretagogue and therefore cannot obtain a sufficient blood glucose lowering effect. The present invention provides a therapeutic agent for sulfonylurea secondary ineffective diabetes.

  A further object of the present invention is that there are no side effects such as vascular complications or hypoglycemia induced when administering an insulin preparation (especially long-term administration) to a sulfonylurea secondary ineffective diabetic patient, and an excellent therapeutic effect is obtained. It is to provide a therapeutic agent for sulfonylurea secondary ineffective diabetes.

As a result of intensive studies, the present inventors found for the first time that a DPP-IV inhibitor is useful as a therapeutic agent for sulfonylurea secondary ineffective diabetes, and completed the present invention.
That is, the present invention relates to 1) a therapeutic agent for sulfonylurea secondary ineffective diabetes comprising a DPP-IV inhibitor;
2) The agent according to 1) above, wherein the secondary failure of the sulfonylurea is caused by the sulfonylurea compound;
3) The agent according to 1) above, wherein the secondary failure of sulfonylurea results from a fast-acting insulin secretagogue;
4) Use of a dipeptidyl peptidase-IV inhibitor for the manufacture of a therapeutic agent for sulfonylurea secondary ineffective diabetes;
5) A method for treating sulfonylurea secondary ineffective diabetes in a mammal, which comprises administering an effective amount of a dipeptidyl peptidase-IV inhibitor to the mammal;
6) An insulin secretion promoter for sulfonylurea secondary ineffective diabetic patients, comprising a dipeptidyl peptidase-IV inhibitor;
7) Use of a dipeptidyl peptidase-IV inhibitor to produce an insulin secretagogue for patients with sulfonylurea secondary ineffective diabetes;
8) A method for promoting insulin secretion in a patient, which comprises administering an effective amount of a dipeptidyl peptidase-IV inhibitor to a sulfonylurea secondary ineffective diabetic patient.

The therapeutic agent for sulfonylurea secondary ineffective diabetes of the present invention is an excellent insulin, even in a diabetic patient who cannot obtain an insulin secreting effect with a sulfonylurea compound or a fast-acting insulin secretagogue and therefore cannot obtain a sufficient hypoglycemic effect. Has secretory effect and blood glucose lowering effect.
Further, the therapeutic agent for sulfonylurea secondary ineffective diabetes of the present invention is a side effect (eg, vascular complication, hypoglycemia) induced by administration of an insulin preparation (especially long-term administration) or glucagon-like peptide (GLP) -1. There are no side effects (eg, hypoglycemia, vomiting) induced when administered, and it is used safely.

In the present specification, a DPP-IV inhibitor means a compound that inhibits the enzyme activity of DPP-IV [Classification by International Commission on Biochemistry (IUBMB): EC 3.4.14.5]. The compound may be either peptidic or non-peptidic, but is preferably non-peptidic.
Moreover, as long as DPP-IV inhibitor retains DPP-IV inhibitory activity, the form thereof may be different before and after administration in vivo. In other words, the DPP-IV inhibitor may be an “active metabolite” having DPP-IV inhibitory activity after it has undergone in vivo metabolism to become a structural change body. Furthermore, the DPP-IV inhibitor may be a “prodrug” that is converted into an active form by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo.
The DPP-IV inhibitory activity can be confirmed, for example, by a method using “Method of Raymond et al. (Diabetes, 47, 1253-1258, 1998)”.

［式中、Ａ環は置換されていてもよい５−１０員芳香環を、
Ｒ^１およびＲ^２は同一または異なって、置換されていてもよい炭化水素基または置換されていてもよい複素環基を、
Ｘは結合手、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−または−ＮＲ^３−（Ｒ^３は水素原子または置換されていてもよい炭化水素基を示す）を；
Ｌは２価の炭化水素基を示す］で表される化合物またはその塩。 Examples of the DPP-IV inhibitor include nitrogen-containing heterocyclic compounds, specifically the following compounds (1) to (13).
(1) Formula described in WO02 / 066274:

[Wherein the A ring represents an optionally substituted 5-10 membered aromatic ring,
R ¹ and R ² are the same or different and each represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
X represents a bond, —O—, —S—, —SO—, —SO ₂ — or —NR ³ — (R ³ represents a hydrogen atom or an optionally substituted hydrocarbon group);
L represents a divalent hydrocarbon group] or a salt thereof.

The salt of the compound represented by formula (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid. And salts with organic acids, salts with basic or acidic amino acids, and the like.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
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.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of the salt with organic acid include 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- And salts with toluenesulfonic acid.
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
The compound represented by the formula (I) may be an anhydrate, a hydrate, or a prodrug.

Preferable examples of the compound represented by the formula (I) include the following compounds.
(Compound Ia)
Ring A is
1) a cyano group;
2) a C _1-10 alkyl group (preferably ethyl) or a C _2-10 alkenyl group (preferably ethenyl) which may be substituted with a carbamoyl group or a carboxyl group, respectively;
3) An optionally substituted hydroxy group [preferably having 1 to 3 substituents selected from a carbamoyl group, a carboxyl group, and an alkoxycarbonyl group having 2 to 5 carbon atoms (preferably methoxycarbonyl). An alkoxy group having 1 to 10 carbon atoms (preferably methoxy, isopropoxy); a hydroxy group; an aralkyloxy group having 7 to 13 carbon atoms (preferably benzyloxy)] [more preferably, carbamoylmethoxy];
4) Acyl group [preferably having 1 to 3 substituents selected from C _1-6 alkyl-carbonyl (preferably acetyl), carbamoyl, mono- or di- (halogen atom and C _1-6 alkoxy-carbonyl) C _1-6 alkyl) -carbamoyl (preferably methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, trifluoroethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, etc.), C _3-10 cycloalkyl-carbamoyl (preferably Is cyclopropylcarbamoyl), C _7-13 aralkyl-carbamoyl (preferably benzylcarbamoyl), nitrogen-containing heterocyclic-carbonyl optionally substituted with hydroxy-carbonyl (preferably pyrrolidinylcarbonyl, piperidinocarbonyl), C _{1 -6} alkyl Sulfonyl (preferably methylsulfonyl), C _1-6 alkylsulfinyl (preferably methylsulfinyl), carboxyl, C _1-6 alkoxy-carbonyl (preferably methoxycarbonyl), thiocarbamoyl];
5) an optionally substituted amino group (preferably carbamoylamino);
6) An optionally substituted thiol group [preferably an alkylthio group having 1 to 10 carbon atoms which may be substituted with a carbamoyl group (preferably methylthio)];
7) An optionally substituted heterocyclic group [preferably a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms (preferably methyl, trifluoromethyl), a carboxyl group, a carbon number 2 to 8 alkoxycarbonyl groups (preferably ethoxycarbonyl), cyano group, carbamoyl group, amino group, mono- or di-C _2-10 alkanoylamino group (eg acetylamino, isopentanoylamino), C _{1- 10} alkoxy-carbonylamino group (eg, methoxycarbonylamino), carbamoylamino group, mono- or di-C _1-10 alkyl-carbamoylamino group (eg, methylcarbamoylamino, dimethylcarbamoylamino), C _6-14 aryl- carbonylamino group (e.g., benzoylamino), C _3-10 cycloalkyl - carbonyl amino group C _7-13 aralkyloxy - carbonylamino group, mono- - or di -C _1-10 alkylsulfonylamino group (e.g., methylsulfonyl, dimethylamino sulfonylamino), C _6-14 arylsulfonylamino group and a C _1-6 alkoxy An aromatic heterocyclic group (preferably furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, each optionally having 1 to 2 substituents selected from carbamoylamino groups (eg, methoxycarbamoylamino), Pyridyl, pyrrolyl, triazolyl) or a non-aromatic heterocyclic group (preferably dioxoisoindole, 5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl)];
8) an amidino group;
A benzene ring optionally having 1 to 2 substituents selected from:
R ¹ is an alkyl group having 4 to 10 carbon atoms (preferably isobutyl or neopentyl) or a cycloalkylalkyl group having 4 to 10 carbon atoms (preferably cyclopropylmethyl);
R ² is an aryl group having 6 to 14 carbon atoms (preferably having 1 to 2 substituents selected from a halogen atom (preferably fluorine and chlorine) and C _1-6 alkyl (preferably methyl). Is phenyl);
X is a bond;
A compound wherein L is C _1-10 alkylene (preferably —CH ₂ —);

(Compound Ib)
Ring A is
1) a C _1-10 alkyl group (preferably ethyl) or a C _2-10 alkenyl group (preferably ethenyl) which may be substituted with an alkoxycarbonyl group having 2 to 8 carbon atoms (preferably ethoxycarbonyl) or a carbamoyl group. );
2) An optionally substituted hydroxy group [preferably an alkoxy group having 1 to 10 carbon atoms (preferably methoxy) optionally substituted with a carbamoyl group; more preferably carbamoylmethoxy];
3) an acyl group (preferably carbamoyl, thiocarbamoyl, carboxyl);
4) An optionally substituted heterocyclic group [preferably a C _1-6 alkyl group (preferably methyl), a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms (preferably ethoxycarbonyl), a cyano group, carbamoyl Group, amino group, mono- or di-C _2-10 alkanoylamino group (eg, acetylamino, isopentanoylamino), C _1-10 alkoxy-carbonylamino group (eg, methoxycarbonylamino), carbamoylamino group, Mono- or di-C _1-10 alkyl-carbamoylamino group (eg, methylcarbamoylamino, dimethylcarbamoylamino), C _6-14 aryl-carbonylamino group (eg, benzoylamino), C _3-10 cycloalkyl-carbonyl amino group, C _7-13 aralkyloxy - carbonylamino group, mono- - or di -C _1-10 A Kill sulfonylamino group (e.g., methylsulfonyl, dimethylamino sulfonylamino), C _6-14 arylsulfonylamino group and a C _1-6 alkoxy - carbamoylamino group (e.g., methoxy carbamoylamino) substituted 1 to 2 atoms selected from An aromatic heterocyclic group which may have a group (preferably furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) or a non-aromatic heterocyclic group (preferably 5-oxooxaxyl Diazol-3-yl)];
A benzene ring optionally having 1 to 2 substituents selected from:
R ¹ is an alkyl group having 4 to 10 carbon atoms (preferably isobutyl or neopentyl) or a cycloalkylalkyl group having 4 to 10 carbon atoms (preferably cyclopropylmethyl);
R ² is an alkyl group having 1 to 10 carbon atoms (preferably butyl) optionally substituted by 1 to 3 halogen atoms;
X is -O-;
A compound wherein L is C _1-10 alkylene (preferably —CH ₂ —);

Among the compounds of the formula (I), in particular 2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1,3 -Thiazole-4-carbonitrile;
2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1,3-thiazole-4-carboxylic acid;
2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1,3-thiazole-4-carboxamide;
Ethyl 2- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -1,3-thiazole-4-carboxylate;
(E) -3- [3- (aminomethyl) -4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolyl] -2-propenamide;
(E) -3- [3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] -2-propenamide;
3- (aminomethyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide;
2-{[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxy} acetamide and the like are preferable.

［式中、ｆは１または２を；ｇは０，１または２を；Ｘｂは−ＣＨ_２−、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−または−ＮＲ^３−（Ｒ^３は水素原子またはC₁₋₆アルキル基を示す）を；Ｒは水素原子、シアノ基、−ＣＨＯ、−Ｂ(ＯＨ)_２、−Ｐ(Ｏ)(ＯＲ^３)、−ＣＣＲ^４または−ＣＨ＝ＮＲ^５ （Ｒ^４は水素原子、フッ素原子、C₁₋₆アルキル基、シアノ基、ニトロ基、−ＯＲ^３、−ＣＯ_２Ｒ^３または−ＣＯＲ^３を（Ｒ^３は前記と同意義を示す）；Ｒ^５はフェニル基、水酸基、−ＯＲ^３、−ＯＣＯＲ^３またはベンジルオキシ基を（Ｒ^３は前記と同意義を示す）を示す）を；Ａｂは置換されていてもよいアミノ酸残基を示す］で表される化合物またはその塩。
式中、Ｒ^３で示されるC₁₋₆アルキル基としては、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec.-ブチル、t.-ブチル、ペンチル、イソペンチル、ネオペンチル、1−エチルプロピル、ヘキシル、イソヘキシル、1,1−ジメチルブチル、2,2−ジメチルブチル、3,3−ジメチルブチル、2−エチルブチルなどが挙げられる。 (2) Formulas described in WO95 / 15309 etc .:

Wherein f is 1 or 2, g is 0, 1 or 2; Xb is —CH ₂ —, —O—, —S—, —SO—, —SO ₂ — or —NR ³ — (R ³ represents a hydrogen atom or a C _1-6 alkyl group); R represents a hydrogen atom, a cyano group, —CHO, —B (OH) ₂ , —P (O) (OR ³ ), —CCR ⁴ or —CH ═NR ⁵ (R ⁴ is a hydrogen atom, a fluorine atom, a C _1-6 alkyl group, a cyano group, a nitro group, —OR ³ , —CO ₂ R ³ or —COR ³ (R ³ is as defined above) R ⁵ represents a phenyl group, a hydroxyl group, —OR ³ , —OCOR ³ or a benzyloxy group (R ³ is as defined above); Ab represents an amino acid residue which may be substituted; Or a salt thereof.
In the formula, examples of the C _1-6 alkyl group represented by R ³ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl. Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

Examples of the amino acid residue in the “optionally substituted amino acid residue” represented by Ab include a group obtained by removing OH of a carboxyl group constituting these amino acids from α-amino acids or β-amino acids.
Here, as the α-amino acid, for example, alanine, arginine, asparagine, aspartic acid, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline. Ornithine, homocysteine and the like.
Examples of β-amino acids include β-alanine, β-aminocyclopropanoic acid, β-aminocyclobutanoic acid, β-aminocyclopentanoic acid, β-aminocyclohexanoic acid, β-aminocycloheptanoic acid, β-aminocyclooctanoic acid Is mentioned. The β-amino acid may have an unsaturated bond in the carbon chain constituting the amino acid.
The α-amino acid and β-amino acid described above may be any of D-form, L-form, and DL-form, but natural L-form is preferred.

The amino acid residue may have 1 to 2 substituents on the amino group or amino acid side chain constituting the amino acid.
As the above-mentioned “substituent on the amino group”, an optionally substituted hydrocarbon group, an optionally substituted piperidinyl group and the like are preferable.
Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” include a C _1-6 alkyl group, a C _3-12 cycloalkyl group, a C _2-6 alkenyl group, a C _3-12 cycloalkenyl group, C _2-6 alkynyl group, C _4-12 cycloalkadienyl group, C _6-14 aryl group (preferably phenyl group), C _7-15 aralkyl group (preferably benzyl group, phenethyl group), adamantyl group, bicyclo [2.2.1] heptyl group, bicyclo [3.1.1] heptyl group and the like.
The hydrocarbon group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include a halogen atom (preferably fluorine and chlorine); a cyano group; an acyl group. A hydroxymethyl group; a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (preferably fluorine); an optionally substituted C _6-14 aryl group Or the amino group which may be mono- or di-substituted by the heterocyclic group which may be substituted is mentioned.
Examples of the acyl group in the “hydroxyl group that may be substituted with an acyl group” include, for example, the acyl groups exemplified as the substituent of the A ring in the compound Ia described above.
Examples of the C _6-14 aryl group in the “ _optionally substituted C _6-14 aryl group” include a phenyl group and a naphthyl group.
Examples of the heterocyclic group in the “optionally substituted heterocyclic group” include a pyridyl group, a pyrimidyl group, a pyrazyl group, a quinolyl group, an isoquinolyl group, a quinoxalyl group, and the like.
The C _6-14 aryl group and heterocyclic group may have 1 to 3 substituents at substitutable positions. Examples of such substituents include a halogen atom (preferably fluorine, chlorine). , Bromine); cyano group; nitro group; C _1-6 alkyl group; C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (preferably fluorine); carboxyl group; carbamoyl group; C _{1 A -6} alkylsulfonyl group (preferably a methanesulfonyl group); an aminosulfonyl group (preferably a dimethylaminosulfonyl group) which may be mono- or di-substituted with a C _1-6 alkyl group.
The substituent in the “optionally substituted hydrocarbon group” is particularly preferably a 5-nitro-2-pyridylamino group, a 5-cyano-2-pyridylamino group, a 2-pyrimidylamino group, a 2-pyrazylamino group, or the like. is there.
Examples of the substituent in the “optionally substituted piperidinyl group” include a C _1-6 alkyl group; a hydroxymethyl group; the “optionally substituted C _6-14 aryl group” or an optionally substituted group. Examples thereof include the “optionally substituted C _6-14 aryl group” and the “optionally substituted heterocyclic group” exemplified in the “amino group optionally mono- or di-substituted with a heterocyclic group”. The number of substituents is, for example, 1 to 3.

Examples of the “substituent on the amino acid side chain” include, for example, an optionally substituted hydrocarbon group, a hydroxyl group, and C _1-10 alkoxy optionally substituted with 1 to 3 halogen atoms (preferably fluorine). Group, an acyl group, an optionally substituted amino group, and the like.
Here, examples of the hydrocarbon in the “optionally substituted hydrocarbon group” include a C _1-10 alkyl group, a C _3-12 cycloalkyl group, a C _2-10 alkenyl group, and a C _3-12 cycloalkenyl group. Is mentioned.
The hydrocarbon group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include an amino group and a C _1-6 alkyl-carbonylamino group (preferably Acetylamino group), hydroxy group, C _1-6 alkoxy group, heterocyclic group (preferably pyridyl) and the like.
The “acyl group” is preferably a nitrogen-containing heterocyclic-carbonyl group which may be substituted. Examples of the “optionally substituted nitrogen-containing heterocycle” include a halogen atom (preferably fluorine, chlorine, bromine), a cyano group, a nitro group, and 1 to 3 halogen atoms (preferably fluorine). An optionally substituted C _1-6 alkyl group (eg, trifluoromethyl group), a C _1-6 alkoxy group, an amino group optionally mono- or di-substituted with a C _1-6 alkyl group, a hydroxy group, A nitrogen-containing heterocycle optionally having 1 to 3 substituents selected from a carboxyl group and a C _1-6 alkyl-oxycarbonyl group (preferably pyridine, pyridazine, pyrimidine, pyrazine, imidazole, pyrazole, thiazole, Thiazole, oxazole, isoxazole and the like).
Examples of the substituent in the “optionally substituted amino group” include a substituent selected from a carboxyl group, a carbamoyl group, a C _1-6 alkyl-oxycarbonyl group, and a nitrogen-containing heterocyclic group (preferably pyridyl). _{Or a} C _1-6 alkyl group which may have 3 or the like. These substituents may be bonded to a hydroxy group, a carboxyl group, an amino group or the like on the amino acid side chain.

Examples of the salt of the compound represented by the formula (II) include the same salts as the salt of the compound represented by the formula (I).
The compound represented by the formula (II) may be an anhydride, a hydrate, or a prodrug.

で表される(2S)-1-{{{2-[(5-シアノピリジン-2-イル)アミノ]エチル}アミノ}アセチル}-2-シアノ-ピロリジン (DPP-728)（WO98／19998に記載）、
式

で表される(2S)-1-{[(3-ヒドロキシ-1-アダマンチル)アミノ]アセチル}-2-シアノ-ピロリジン(LAF237) （WO00／34241に記載）、
(2S)-1-{{{2-[(1-ピリミジン-2-イルピペリジン-4-イル}アミノ}アセチル}-2-シアノ-ピロリジン（WO02/30890に記載）、
(2S)-1-{{{2-[(ピラジン-2-イル)アミノ]エチル}アミノ}アセチル}-2-シアノ-ピロリジン、(S)-1-{1-[5-(N,N-ジメチルアミノスルホニル)-2-ピリジルアミノ]-2-メチル-2-プロピルアミノ}アセチル-2-ピロリジンカルボニトリル （K-361）（WO02/51836に記載）、
などのN-(N'-置換グリシル)-2-シアノ-ピロリジン誘導体；
式

で表されるL-threo-イソロイシル チアゾリジン （P32/98）、L-allo-イソロイシル チアゾリジン、L-threo-イソロイシル ピロリジン、L-allo-イソロイシル ピロリジン、L-バリル ピロリジンなどのチアゾリジンあるいはピロリジン誘導体（WO01／72290などに記載）；
式

で表される化合物（PT−100）；
式

で表される化合物（P93/01）；などが挙げられる。 Preferable examples of the compound represented by the formula (II) include the formula

(2S) -1-{{{2-[(5-cyanopyridin-2-yl) amino] ethyl} amino} acetyl} -2-cyano-pyrrolidine (DPP-728) (in WO98 / 19998 Description),
formula

(2S) -1-{[(3-hydroxy-1-adamantyl) amino] acetyl} -2-cyano-pyrrolidine (LAF237) (described in WO00 / 34241),
(2S) -1-{{{2-[(1-pyrimidin-2-ylpiperidin-4-yl} amino} acetyl} -2-cyano-pyrrolidine (described in WO02 / 30890),
(2S) -1-{{{2-[(pyrazin-2-yl) amino] ethyl} amino} acetyl} -2-cyano-pyrrolidine, (S) -1- {1- [5- (N, N -Dimethylaminosulfonyl) -2-pyridylamino] -2-methyl-2-propylamino} acetyl-2-pyrrolidinecarbonitrile (K-361) (described in WO02 / 51836),
N- (N′-substituted glycyl) -2-cyano-pyrrolidine derivatives such as;
formula

Thiazolidine or pyrrolidine derivatives such as L-threo-isoleucil thiazolidine (P32 / 98), L-allo-isoleucil thiazolidine, L-threo-isoleucil pyrrolidine, L-allo-isoleucil pyrrolidine, L-valyl pyrrolidine represented by the formula (WO01 / 72290 etc.);
formula

A compound represented by (PT-100);
formula

And the like (P93 / 01);

(3) N-substituted 2-cyanopyrrole and 2-cyanopyrroline derivatives described in WO01 / 55105. Preferably, (S, S) -1- (2-amino-3,3-dimethylbutyryl) -2,5-dihydro-1H-pyrrole-2-carbonitrile.
(4) The heterocyclic compound described in WO02 / 02560. Preferably, 7-benzyl-8- [6- (hydroxymethyl) -1,4-diazepan-1-yl] -1,3-dimethyl-3,7-dihydropurine-2,6-dione.
(5) A pyrrolidine derivative fused with cyclopropane described in WO01 / 68603. Preferably, (1S, 3S, 5S) -2-[(2S) -2-amino-3,3-dimethylbutyryl] -3-cyano-2-azabicyclo [3.1.0] hexane.
(6) A proline derivative described in WO02 / 14271. Preferably, (2S) -1-[(2S, 4S) -4- (3-chloro-4-cyanophenyl) amino-2-pyrrolidinylcarbonyl] -2-cyanopyrrolidine.
(7) Cyanopyrrolidine derivatives described in WO02 / 38541. Preferably, (2S, 4S) -1-[(2S, 3S) -2-amino-3-methyl-pentanoyl] -2-cyano-4-fluoropyrrolidine, (2S, 4S) -2-cyano-4- Fluoro-1-[(1-hydroxymethyl) cyclopentylamino] acetylpyrrolidine, (2S, 4S) -2-cyano-4-fluoro-1- (1-hydroxy-3-adamantylamino) acetylpyrrolidine.
(8) WO02 / 02560, WO 03/055881, WO 03/040174, WO 03/037327, WO 03/035057, WO 03/035067, WO 03/024942, WO 03/024965, WO 03/004498, WO 03 / 004496, WO 03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO 03/000180, WO 03/000181, EP 1258476, WO 0251836, WO 02/68420, US 6432969, etc. Compound; P93 / 01 and the like.

で表される化合物およびその塩（例、塩酸塩、リン酸塩）（MK-0431）。
（１０）式：

で表される化合物（BMS−477118）。
（１１）WO2004／014860に記載された式：

［式中、Ａａ環は置換されていてもよい５−１０員芳香環を、
Ｒ⁶およびＲ⁷は同一または異なって、置換されていてもよい炭化水素基または置換されていてもよい複素環基を、
ＸａおよびＹａは同一または異なって、結合手、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ₂−または−ＮＲ⁸−（Ｒ⁸は水素原子または置換されていてもよい炭化水素基を示す）を；
Ｌａは２価の炭化水素基を示す。］で表される化合物またはその塩。
式（III）で表される化合物の塩としては、式（Ｉ）で表される化合物の塩と同様のものが挙げられる。
式（III）で表される化合物は、無水和物であっても、水和物であってもよく、さらにプロドラッグであってもよい。 (9) Formula:

And a salt thereof (eg, hydrochloride, phosphate) (MK-0431).
(10) Formula:

A compound represented by (BMS-477118).
(11) Formula described in WO2004 / 014860:

[Wherein the Aa ring represents an optionally substituted 5- to 10-membered aromatic ring,
R ⁶ and R ⁷ are the same or different and each represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
Xa and Ya are the same or different and represent a bond, —O—, —S—, —SO—, —SO ₂ — or —NR ⁸ — (R ⁸ represents a hydrogen atom or an optionally substituted hydrocarbon group. Show);
La represents a divalent hydrocarbon group. Or a salt thereof.
Examples of the salt of the compound represented by the formula (III) include the same salts as those of the compound represented by the formula (I).
The compound represented by the formula (III) may be an hydrate, a hydrate, or a prodrug.

Preferable examples of the compound represented by the formula (III) include the following compounds.
(Compound III-a)
Aa ring is 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.);
2) a nitro group;
3) a cyano group;
4) an alkylenedioxy group having 1 to 3 carbon atoms (eg, methylenedioxy);
5) Halogen atom, hydroxy group, carboxyl group, C2-C8 alkoxycarbonyl group (e.g., ethoxycarbonyl), carbamoyl group, cyano group, amino group, C2-C8 alkylcarbonylamino group (e.g., acetyl) Amino, isobutanoylamino), C2-C8 alkoxycarbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino), C1-C8 alkylsulfonylamino group (e.g., methylsulfonylamino), carbon number 2-8 alkylcarbamoylamino groups (eg, methylcarbamoylamino), carboxyl-C _1-6 alkylthio groups (eg, carboxylmethylthio), C2-C8 alkoxycarbonyl-C _1-6 alkylthio groups (eg, ethoxy) carbonyl methyl thio) and carbamoyl -C _1-6 A An alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, butyl, pentyl) or 2 carbon atoms each optionally having 1 to 3 substituents selected from a quilthio group (eg, carbamoylmethylthio) -10 alkenyl groups (eg, ethenyl, 3-butenyl);
6) An optionally substituted hydroxy group [eg, halogen atom; substituted with 1 or 2 substituents selected from a carboxyl group and an alkoxycarbonyl group having 2 to 5 carbon atoms (eg, tert-butoxycarbonyl) C1-C3 alkoxy group (e.g., methoxy, carboxylmethoxy, tert-butoxycarbonylmethoxy); C2-C5 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl); C2-C5 1 or 2 selected from alkylcarbonyl group (eg, pivaloyl); cyano group; C _1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl) and C _1-10 alkylsulfonyl group (eg, methylsulfonyl) Carbamoyl group optionally substituted by one substituent; hydroxy group; carboxyl group; amino ; Alkylcarbonylamino group having 2 to 5 carbon atoms (e.g., acetylamino); selected from C _1-6 alkyl group (e.g., methyl, ethyl) and C _2-8 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) An aromatic heterocyclic group optionally substituted by 1 to 3 substituents (eg, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl); and a cycloalkyl group having 3 to 10 carbon atoms Each having 1 to 3 substituents selected from (eg, cyclopropyl, cyclohexyl),
An alkoxy group having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy), a cycloalkyloxy group having 3 to 10 carbon atoms (eg, cyclopentyloxy) or 7 to 13 carbon atoms An aralkyloxy group (eg, benzyloxy); a hydroxy group];
7) Acyl group [eg, formyl, carboxyl, C _1-6 alkyl-carbonyl (eg, acetyl), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl), carbamoyl, aminocarbamoyl, hydroxycarbamoyl, mono- or di - (halogen atoms and C _1-6 alkoxy - carbonyl (e.g., 1 to 3 substituents substituted C _1-6 alkyl selected from ethoxycarbonyl)) - carbamoyl (e.g., methylcarbamoyl, ethyl Carbamoyl, propylcarbamoyl, dimethylcarbamoyl, trifluoroethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, etc.), C _3-10 cycloalkyl-carbamoyl (eg, cyclopropylcarbamoyl), C _7-13 aralkyl-carbamoyl (eg, benzylcarbamoyl), Hydro Sheet which may be nitrogen-containing heterocycle substituted with - carbonyl (e.g., pyrrolidinylcarbonyl, piperidinocarbonyl), C _1-6 alkylsulfonyl (e.g., methylsulfonyl), C _1-6 alkylsulfinyl (e.g., Methylsulfinyl), thiocarbamoyl];
8) An optionally substituted amino group [eg, amino, mono- or di-C _2-10 alkylcarbonylamino (eg, acetylamino, propionylamino, isobutanoylamino, isopentanoylamino), C _{1- 10} alkoxy-carbonylamino (eg, methoxycarbonylamino), carbamoylamino, mono- or di-C _1-10 alkyl-carbamoylamino (eg, methylcarbamoylamino, dimethylcarbamoylamino), C _6-14 aryl-carbonylamino ( Examples, benzoylamino), C _3-10 cycloalkyl-carbonylamino (eg, cyclopentylcarbonylamino), C _7-13 aralkyloxy-carbonylamino (eg, benzyloxycarbonylamino), mono- or di-C _1-10 Alkylsulfonylamino (eg, methylsulfonylamino) , Dimethyl sulfonylamino), C _6-14 arylsulfonylamino (e.g., phenylsulfonylamino), C _1-6 alkoxy - carbamoylamino (e.g., methoxy carbamoylamino), a carbamoyl -C _1-10 alkylamino (e.g., carbamoylmethyl Amino), C _2-5 alkoxycarbonyl-C _1-10 alkylamino (eg, methoxycarbonylmethylamino, tert-butoxycarbonylmethylamino)];
9) an optionally substituted cycloalkyl group having 3 to 10 carbon atoms [eg, a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms (eg, methyl, trifluoromethyl), Carboxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), cyano group, carbamoyl group, amino group, mono- or di-C _2-10 alkylcarbonylamino group (eg, Acetylamino, isopentanoylamino), C _1-10 alkoxy-carbonylamino group (eg, methoxycarbonylamino), carbamoylamino group, mono- or di-C _1-10 alkyl-carbamoylamino group (eg, methylcarbamoyl) Amino, dimethylcarbamoylamino), C _6-14 aryl-carbonylamino group (eg, benzo Ylamino), C _3-10 cycloalkyl-carbonylamino group, C _7-13 aralkyloxy-carbonylamino group, mono- or di-C _1-10 alkylsulfonylamino group (eg, methylsulfonylamino, dimethylsulfonylamino), C _3-10 cycloalkyl optionally having 1 to 3 substituents selected from a C _6-14 arylsulfonylamino group and a C _1-6 alkoxy-carbamoylamino group (eg, methoxycarbamoylamino) Group (eg, cyclopropyl, cyclobutyl)];
10) an aryl group having 6 to 14 carbon atoms (eg, phenyl);
11) An optionally substituted thiol group [eg, an alkylthio group having 1 to 10 carbon atoms that may be substituted with a carbamoyl group (eg, methylthio)];
12) An optionally substituted heterocyclic group [eg, C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms (eg, methyl, trifluoromethyl), carboxyl group, carbon number 2 To 8 alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl), cyano group, carbamoyl group, amino group, mono- or di-C _2-10 alkylcarbonylamino group (eg, Acetylamino, isopentanoylamino), C _1-10 alkoxy-carbonylamino group (eg, methoxycarbonylamino), carbamoylamino group, mono- or di-C _1-10 alkyl-carbamoylamino group (eg, methylcarbamoylamino) Dimethylcarbamoylamino), C _6-14 aryl-carbonylamino group (eg, Nzoylamino), C _3-10 cycloalkyl-carbonylamino group, C _7-13 aralkyloxy-carbonylamino group, mono- or di-C _1-10 alkylsulfonylamino group (eg, methylsulfonylamino, dimethylsulfonylamino), A C _6-14 arylsulfonylamino group, a C _1-6 alkoxy-carbamoylamino group (eg, methoxycarbamoylamino), an alkylcarbonyl group having 2 to 5 carbon atoms (eg, acetyl) and a carbamoyl-C _1-6 alkyl group ( An aromatic heterocyclic group optionally having 1 or 2 substituents selected from (eg, carbamoylmethyl) (preferably furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrrolyl, triazolyl) Or a non-aromatic heterocyclic group (preferably dioxoyl 5-oxooxadiazol-3-yl; 5-oxothiadiazol-3-yl; 3-oxopiperazin-1-yl; 2,3-dioxopiperazin-1-yl; 5-dioxopiperazin-1-yl)]];
13) an amidino group;
A benzene ring optionally having 1 or 2 substituents selected from:
R ⁶ is an alkyl group having 3 to 10 carbon atoms (preferably isobutyl) or a cycloalkylalkyl group having 4 to 10 carbon atoms (preferably cyclopropylmethyl);
R ⁷ is a halogen atom (eg, fluorine, chlorine, etc.), a hydroxy group, a nitro group, an amino group, an optionally halogenated alkyl group having 1 to 6 carbon atoms (eg, trifluoromethyl, methyl, etc.), carbon 1 to 3 selected from an alkoxy group of 1 to 6 (eg, methoxy, etc.), an aromatic heterocyclic group (eg, quinolyl, thienyl, etc.) and a cycloalkyl group of 3 to 10 carbon atoms (eg, cyclopentyl, etc.) (Preferably 1 or 2) each may have a substituent,
An alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like), an aryl group having 6 to 14 carbon atoms (eg, phenyl and the like) or An aralkyl group having 7 to 13 carbon atoms (eg, benzyl, phenethyl, naphthylmethyl, etc.);
Xa is a bond;
A compound in which Ya is a bond; and La is C _1-10 alkylene.

Among the compounds of the formula (III), among others (2E) -3- [3- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) quinolin-6-yl] acrylamide;
5-[[3- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) quinolin-6-yl] oxy] pentanoic acid;
4- [3- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) quinolin-6-yl] piperazin-2-one;
1- [3- (aminomethyl) -2-isobutyl-4- (4-methylphenyl) quinolin-6-yl] piperazine-2,5-dione and the like are preferable.

［式中、R⁹は水素原子または低級（C₁₋₆）アルキルを；
R¹⁰は低級（C₁₋₆）アルキル、低級（C₁₋₆）アルコキシ、パーフルオロ低級（C₁₋₆）アルキル、アミノおよびハロゲンから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよいヘテロシクリル；またはハロゲン、低級（C₁₋₆）アルキル、低級（C₁₋₆）アルコキシ、アミノおよびパーフルオロ低級（C₁₋₆）アルキルから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよいアリールを示し；
R¹¹およびR¹²は、これらが結合する炭素原子と共に、フェニル環（該フェニル環は、ハロゲン、低級（C₁₋₆）アルキル、パーフルオロ低級（C₁₋₆）アルキルおよび低級（C₁₋₆）アルコキシから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよい）、または5,6または7員飽和環（該飽和環はＯ，ＮおよびＳから選ばれるヘテロ原子を含んでいてよく；ハロゲン、低級（C₁₋₆）アルキル、パーフルオロ低級（C₁₋₆）アルキルおよび低級（C₁₋₆）アルコキシから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよく；5または6員芳香環（該芳香環はＯ，ＮおよびＳから選ばれるヘテロ原子を含んでいてよく；ハロゲン、低級（C₁₋₆）アルキル、パーフルオロ低級（C₁₋₆）アルキルおよび低級（C₁₋₆）アルコキシから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよい）とオルト縮合していてもよい）を形成する。］で表される化合物またはその塩。
式（IV）で表される化合物の塩としては、式（Ｉ）で表される化合物の塩と同様のものが挙げられる。
式（IV）で表される化合物は、無水和物であっても、水和物であってもよく、さらにプロドラッグであってもよい。 (12) Formula described in WO03 / 068748:

[Wherein R ⁹ represents a hydrogen atom or lower (C _1-6 ) alkyl;
R ¹⁰ is a mono-, di- or tri-substituted substituent selected from lower (C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, perfluorolower (C _1-6 ) alkyl, amino and halogen. Optionally substituted heterocyclyl; or mono-, di-, di-, di- or di- (substituents) selected from halogen, lower (C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, amino and perfluoro lower (C _1-6 ) alkyl; Represents-or tri-substituted aryl;
R ¹¹ and R ¹² together with the carbon atom to which they are attached are phenyl rings (the phenyl ring is halogen, lower (C _1-6 ) alkyl, perfluorolower (C _1-6 ) alkyl and lower (C _{1- 6} ) may be mono-, di- or tri-substituted with a substituent selected from alkoxy, or a 5, 6 or 7 membered saturated ring (wherein the saturated ring represents a heteroatom selected from O, N and S) Mono-, di- or tri-substituted with substituents selected from halogen, lower (C _1-6 ) alkyl, perfluoro lower (C _1-6 ) alkyl and lower (C _1-6 ) alkoxy A 5- or 6-membered aromatic ring (the aromatic ring may contain a heteroatom selected from O, N and S; halogen, lower (C _1-6 ) alkyl, perfluoro lower (C _{1 -6)} alkyl and lower (C _1-6) alkoxy Mono with a substituent selected from -, di - or tri - may be substituted) to form an ortho-fused or may be). Or a salt thereof.
Examples of the salt of the compound represented by formula (IV) include the same salts as the salt of the compound represented by formula (I).
The compound represented by the formula (IV) may be an anhydride, a hydrate, or a prodrug.

［式中、XcはNまたはC−R¹⁷を；
R¹³およびR¹⁴は独立して水素原子または低級（C₁₋₆）アルキルを；
R¹⁵は低級（C₁₋₆）アルキル、パーフルオロ低級（C₁₋₆）アルキル、アミノ、低級（C₁₋₆）アルコキシおよびハロゲンから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよいヘテロシクリル；またはハロゲン、低級（C₁₋₆）アルキル、アミノ、低級（C₁₋₆）アルコキシおよびパーフルオロ低級（C₁₋₆）アルキルから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよいアリールを；
R¹⁶は低級（C₁₋₆）アルキル；低級（C₁₋₆）アルコキシ；低級（C₁₋₆）アルキルチオ；低級（C₁₋₆）アルキル、低級（C₁₋₆）アルコキシ、パーフルオロ低級（C₁₋₆）アルキル、アミノおよびハロゲンから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよいヘテロシクリル；低級（C₁₋₆）アルキル、低級（C₁₋₆）アルコキシ、ハロゲン、アミノおよびパーフルオロ低級（C₁₋₆）アルキルから選ばれる置換基でモノ−、ジ−またはトリ−置換されていてもよいアリール；アリールオキシ−低級（C₁₋₆）アルキルまたはシクロアルキルを；
R¹⁷は水素原子または低級（C₁₋₆）アルキルを示す。］で表される化合物またはその塩。
式（Ｖ）で表される化合物の塩としては、式（Ｉ）で表される化合物の塩と同様のものが挙げられる。
式（Ｖ）で表される化合物は、無水和物であっても、水和物であってもよく、さらにプロドラッグであってもよい。 (13) Formula described in WO03 / 068757:

[Wherein Xc represents N or C—R ¹⁷ ;
R ¹³ and R ¹⁴ independently represent a hydrogen atom or lower (C _1-6 ) alkyl;
R ¹⁵ is a mono-, di- or tri-substituted substituent selected from lower (C _1-6 ) alkyl, perfluoro lower (C _1-6 ) alkyl, amino, lower (C _1-6 ) alkoxy and halogen. Or optionally substituted with a substituent selected from halogen, lower (C _1-6 ) alkyl, amino, lower (C _1-6 ) alkoxy and perfluoro lower (C _1-6 ) alkyl. -Or tri-optionally substituted aryl;
R ¹⁶ is lower (C _1-6 ) alkyl; lower (C _1-6 ) alkoxy; lower (C _1-6 ) alkylthio; lower (C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, perfluoro Heterocyclyl optionally substituted mono-, di- or tri- with a substituent selected from lower (C _1-6 ) alkyl, amino and halogen; lower (C _1-6 ) alkyl, lower (C _1-6 ) Aryl optionally mono-, di- or tri-substituted with a substituent selected from alkoxy, halogen, amino and perfluoro lower (C _1-6 ) alkyl; aryloxy-lower (C _1-6 ) alkyl or Cycloalkyl;
R ¹⁷ represents a hydrogen atom or lower (C _1-6 ) alkyl. Or a salt thereof.
Examples of the salt of the compound represented by the formula (V) include the same salts as those of the compound represented by the formula (I).
The compound represented by the formula (V) may be an anhydride, a hydrate, or a prodrug.

The therapeutic agent for sulfonylurea secondary ineffective diabetes of the present invention (hereinafter sometimes abbreviated as the agent of the present invention) is a pharmaceutical product obtained by mixing a DPP-IV inhibitor as it is or with a pharmacologically acceptable carrier. After preparing the composition, it can be administered to a mammal (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey).
The content of the DPP-IV inhibitor in the agent of the present invention varies depending on the type of DPP-IV inhibitor, the size of the preparation, etc., but is, for example, 1 to 90% by weight, preferably 5 to 80% by weight.
As the pharmacologically acceptable carrier described above, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, It is blended as a solubilizer, suspending agent, isotonic agent, buffer, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like can be mentioned.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.

Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, polyvinyl Examples include hydrophilic polymers such as pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.

Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
Preferable examples of the soothing agent include benzyl alcohol.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Suitable examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos. 1 and 2), water-insoluble lake dyes (E.g., an aluminum salt of the water-soluble edible tar dye), natural dyes (e.g., [beta] -carotene, chlorophyll, bengara, yellow ferric oxide) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

Examples of the dosage form of the agent of the present invention include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, suspensions. Oral preparations such as turbid agents; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments) Etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, drops, eye drops, transpulmonary agents (inhalants) and the like, and these are orally or parenterally, respectively. Safe administration. These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).
The agent of the present invention can be produced by a method commonly used in the field of pharmaceutical technology, such as the method described in the Japanese Pharmacopoeia. Below, the specific manufacturing method of a formulation is explained in full detail.

For example, oral preparations contain active ingredients such as excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, pregelatinized starch, Arabic Rubber, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc., and compression molded, and if necessary, taste masking, enteric Alternatively, for the purpose of durability, it is produced by coating with a coating base by a method known per se.
Examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base and the like.
As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma Co., Ltd.], synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.

Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic polymers such as Rohm Pharma Co.], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], and methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]; Examples include natural products such as shellac.
Examples of sustained-release film coating bases include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymers such as turbid liquid [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] can be used.
Two or more kinds of the above-described coating bases may be mixed and used at an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.

For injections, the active ingredient is a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, Phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), etc. and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) or oily solvents (eg, , Olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, propylene glycol, etc.) and the like. At this time, additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used as desired.
Among the various preparations described above, an oral preparation excellent in convenience or compliance is preferable.

In the present specification, “sulfonylurea secondary ineffectiveness” in “sulfonylurea secondary ineffective diabetes” constitutes “ATP-sensitive K ⁺ channel of pancreatic β cell (hereinafter sometimes abbreviated as K _ATP channel)” An agent that promotes insulin secretion from pancreatic β cells by binding to sulfonylurea receptor 1 (SUR1), closing the _KATP channel, and causing depolarization of the cell membrane (eg, sulfonylurea compound (sulfonylurea anti-antigen)) It means a state in which a sufficient blood glucose lowering effect cannot be obtained when a “diabetic drug)” or a rapid-acting insulin secretagogue) is administered continuously or for a long time (for example, 2 weeks or more, preferably 4 weeks or more).
Examples of the sulfonylurea compound include a compound having a sulfonylurea skeleton or a derivative thereof such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, and glybazole.
In addition, as a fast-acting insulin secretagogue, a compound that does not have a sulfonylurea skeleton, but promotes insulin secretion from pancreatic β cells as well as a sulfonylurea compound, such as repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt water Examples thereof include glinide compounds such as Japanese products.
The sulfonylurea secondary ineffectiveness may be caused by either a sulfonylurea compound or a fast-acting insulin secretagogue.

Examples of diabetes in “sulfonylurea secondary ineffective diabetes” include, for example, type 1 diabetes, type 2 diabetes, gestational diabetes, impaired glucose tolerance (IGT (Impaired Glucose Tolerance)), IFG (Impaired Fasting Glucose), IFG (Impaired Fasting). Glycemia), diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataracts, macrovascular disorders, osteopenia, diabetic hyperosmotic coma, infections (eg, respiratory infections, urinary tract infections) Digestive organ infection, skin soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder] and the like. Of these, type 2 diabetes is preferred.
The therapeutic agent for sulfonylurea secondary ineffective diabetes of the present invention is an excellent insulin, even in a diabetic patient who cannot obtain an insulin secreting effect with a sulfonylurea compound or a fast-acting insulin secretagogue and therefore cannot obtain a sufficient hypoglycemic effect. Has secretory effect and blood glucose lowering effect.

  The dose of the agent of the present invention varies depending on the administration subject, administration route, target disease, and the like. For example, when orally administered to an adult diabetic patient, the active ingredient DPP-IV inhibitor is usually about 1 dose. 0.01 to 100 mg / kg body weight, preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight. It is desirable to administer this amount once or twice a day.

The agent of the present invention is for the purpose of enhancing the effect of the agent, reducing the dosage, etc., for treating diabetes, treating diabetic complications, antihyperlipidemic agent, antihypertensive agent, antiobesity agent, diuretic agent, It can be used in combination with a drug such as an antithrombotic agent (hereinafter abbreviated as a concomitant drug). At this time, the administration timing of the agent of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference. Furthermore, the agent of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the agent of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the DPP-IV inhibitor that is the active ingredient of the agent of the present invention.

Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli or yeast; insulin zinc; protamine insulin zinc; insulin Fragments or derivatives (eg, INS-1 etc.), insulin sensitizers (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), GI-262570, Reglixane (JTT-501), Netoglitazone (MCC-555), KRP-297, Riboglitazone (CS-011), FK-614, Ragaglitazar (NN-622), Tesaglitazar (AZ-242), Muraglitaza The compounds described in (Muraglitazar) (BMS-298585), EML-16336, WO99 / 58510 (eg (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy Imino] -4-phenylbutyric acid), compounds described in WO01 / 38325, BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY-510929, Balaglitazone (NN -2344), T-131 or a salt thereof, THR-0921), PPARγ agonist, PPARγ antagonist, PPARγ / α dual agonist, α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate), biguanide agent (eg, Phenformin, metformin, buformin or a salt thereof (eg, hydrochloride, fumarate, succinate)), GLP-1 receptor agonist [eg, GLP-1, NN-2211, AC-2993 (exe ndin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ ], amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), β3 Agonists (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6) -Phosphatase inhibitor, glucagon antagonist, somatostatin receptor agonist), SGLT (sodium-glucose cotransporter) inhibitor (eg, T-1095), 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498 etc.), adiponectin or Its agonist, IKK inhibitor (eg AS-2868, etc.), leptin resistance Good drugs, somatostatin receptor agonists (WO01 / 25228, WO03 / 42204, WO98 / 44921, WO98 / 45285, WO99 / 22735, etc.), glucokinase activators (eg, Ro-28-1675), etc. Is mentioned.

Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minarerestat, fidarestat (SNK-860), CT-112), neurotrophic factor and its increase drug (For example, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [ 3- (2-methylphenoxy) propyl] oxazole)), nerve regeneration-promoting drugs (eg, Y-128), PKC inhibitors (eg, ruboxistaurin mesylate (LY-333531)), AGE inhibition Agents (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazoliu) Mubromide (ALT766), EXO-226), active oxygen scavenger (eg, thioctic acid), cerebral vasodilator (eg, thiaprid, mexiletine), somatostatin receptor agonist (BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitors and the like.
Antihyperlipidemic agents include statins that are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, or salts thereof (eg, sodium salt, calcium salt) ), Squalene synthase inhibitors (eg, compounds described in WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds ( Eg, bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, Avasimibe, Eflucimibe) , Anion exchange resins (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol), ethyl icosapentate, plant sterols (eg, soysterol, gamma oryzanol) (γ-oryzanol)) and the like.
Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan medoxomil, 1-[[ 2 '-(2,5-Dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7- Carboxylic acid), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, lebucromakalim, L-27152, AL 0671, NIP-121), clonidine and the like.
Anti-obesity agents include, for example, central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Example: SB-568849; SNAP-7941; compounds described in WO01 / 82925 and WO01 / 87834, etc.); neuropeptide Y antagonist (eg, CP-422935, etc.); cannabinoid receptor antagonist (eg, SR-141716) , SR-147778, etc.); Ghrelin antagonists; 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498 etc.), pancreatic lipase inhibitors (eg, orlistat, ATL-962), β3 agonists (eg, CL- 316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, A 40140), peptidic anorectics (e.g., leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (e.g., lintitript, FPL-15849), and the like.

  Examples of diuretics include xanthine derivatives (e.g., sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (e.g., etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, (Methiclotiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide , Bumetanide, furosemide and the like.

Examples of the antithrombotic agent include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), thrombolytic drug ( Examples, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase, platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol) ), Ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.
The concomitant drug is preferably an insulin preparation, an insulin resistance improving agent, an α-glucosidase inhibitor, a biguanide agent or the like.

The present invention further relates to an “insulin secretion promoter for sulfonylurea secondary ineffective diabetic patients, comprising a DPP-IV inhibitor”.
Here, examples of the DPP-IV inhibitor and sulfonylurea secondary ineffective diabetes include those described above.
The aforementioned insulin secretagogue can be produced and used in the same manner as the sulfonylurea secondary ineffective diabetes therapeutic agent using a DPP-IV inhibitor. The insulin secretagogue is useful as a therapeutic agent for sulfonylurea secondary ineffective diabetes, and a sulfonylurea compound or a fast-acting insulin secretagogue cannot provide an insulin secretion effect, and therefore a sufficient blood glucose lowering effect cannot be obtained. The patient also has excellent insulin secretion effect and blood glucose lowering effect.
The present invention further relates to “ATP sensitivity that cannot be closed by stimulation with a sulfonylurea receptor 1-binding compound containing a DPP-IV inhibitor (eg, sulfonylurea compound, fast-acting insulin secretagogue). Concerning “K ⁺ channel closure agents”.
Here, examples of the DPP-IV inhibitor, the sulfonylurea compound, and the fast-acting insulin secretagogue include those described above.
The aforementioned occlusive agent can be produced and used in the same manner as the sulfonylurea secondary ineffective diabetes treatment agent using a DPP-IV inhibitor. Specifically, the occlusive agent is useful as a therapeutic agent for sulfonylurea secondary ineffective diabetes.

The present invention will be described in more detail with reference to the following examples and experimental examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
In the following examples and experimental examples, 2-{[3- (aminomethyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolinyl] oxy} acetamide monohydrate is Abbreviated as compound A.

  Compound A (150 mg), lactose (1184 mg), corn starch (360 mg), HPC-L (trade name, manufactured by Nippon Soda Co., Ltd.) (60 mg), carboxymethylcellulose calcium (trade name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) (60 mg), crystalline cellulose (trade name: Avicel, manufactured by Asahi Kasei Kogyo Co., Ltd.) (172 mg) and magnesium stearate (14 mg) were mixed in a mortar. 200 mg of the resulting mixture was tableted using a hydraulic pump press (manufactured by Riken Seiki) to obtain tablets with a diameter of 8 mm.

Experimental example 1

Streptozocin (STZ) (120 mg / kg body weight) was administered to 1.5-day-old male WKY rats to prepare N-STZ-1.5 rats, which are type 2 diabetes models.
After glibenclamide (10 mg / kg body weight / day) was orally administered to N-STZ-1.5 rats (male, 24 rats) for 4 weeks to form a sulfonylurea secondary ineffective type 2 diabetes model, the rats were classified into groups A to D. Divided into 4 groups (6 animals each), 0.5% methylcellulose suspension for group A (control group), glibenclamide (10 mg / kg body weight) for group B and nateglinide (50 mg / kg body weight) for group C Compound D (3 mg / kg body weight) was orally administered to group D (hereinafter, methylcellulose suspension, glibenclamide, nateglinide and compound A administered to groups A to D may be collectively referred to as test compounds). is there).
Subsequently, each rat was orally administered with a 1 g / kg body weight glucose solution, and blood was collected from the rat tail vein before and after administration of the glucose solution (before and after administration of the test compound), and the plasma glucose level and plasma insulin were collected. The value was measured.
Plasma glucose levels were measured by enzymatic method using L-type Wako Glu2 (trade name, Wako Pure Chemical Industries, Ltd.). Plasma insulin levels were measured using Shionoria Insulin Kit (trade name, Shionogi Pharmaceutical Co., Ltd.). And measured by radioimmunoassay.
Plasma glucose rise 60 minutes after glucose solution administration (glucose load 0-60 minutes); plasma insulin increase value 10 minutes after glucose solution administration (before test compound administration—10 minutes after glucose load); and glucose solution administration 10 The plasma insulin elevation values after minutes (after sugar load 0-60 minutes) are shown in [Table 1], [Table 2] and [Table 3], respectively. The values in the table are average values (n = 6).


[Table 1]

Group Plasma glucose elevation (mg / dl)
Group A (control) 172.72
Group B (Glibenclamide) 180.65
Group C (nateglinide) 185.95
Group D (Compound A) 134.83

[Table 2]

Group Plasma insulin elevation (μU / ml)
Group A (control) 19.37
Group B (Glibenclamide) 18.03
Group C (nateglinide) 18.76
Group D (Compound A) 44.06

[Table 3]

Group Plasma insulin elevation (μU / ml)
Group A (control) 24.88
Group B (Glibenclamide) 22.76
Group C (nateglinide) 16.78
Group D (Compound A) 46.69

As shown in [Table 1], administration of glibenclamide (a sulfonylurea compound) or nateglinide (a fast-acting insulin secretagogue) to sulfonylurea secondary ineffective type 2 diabetic rats does not produce a plasma glucose lowering effect. However, when Compound A (DPP-IV inhibitor) was administered, an excellent plasma glucose lowering effect was obtained.
In addition, as shown in [Table 2] and [Table 3], even when glibenclamide (a sulfonylurea compound) or nateglinide (a fast-acting insulin secretagogue) is administered to sulfonylurea secondary ineffective type 2 diabetic rats, plasma Although an insulin-increasing effect was hardly obtained, an excellent plasma insulin-increasing effect was obtained when Compound A (DPP-IV inhibitor) was administered.

Experimental example 2

N-STZ-1.5 rats (male, 24 animals) prepared in Experimental Example 1 were divided into 4 groups (6 animals each), of which 2 groups (hereinafter sometimes abbreviated as M group) had 0.5% methylcellulose suspension. Glybenclamide (10 mg / kg body weight) was orally administered to the remaining 2 groups (hereinafter sometimes abbreviated as Group G) for 4 weeks. After continuous administration for 4 weeks, 0.5% methylcellulose suspension was orally administered to each of the M group and G group (control group) and glibenclamide (10 mg / kg body weight) to each of the remaining 1 group.
Subsequently, a 1 g / kg body weight glucose solution was orally administered to each rat, and blood was collected from the rat tail vein before and 10 and 60 minutes after administration of the glucose solution, and plasma glucose level and plasma insulin level were measured.
The plasma glucose level and plasma insulin level were measured in the same manner as in Experimental Example 1.
The plasma glucose rise value 60 minutes after glucose solution administration (glucose load 0 to 60 minutes) and the plasma insulin rise value 10 minutes after glucose solution administration (glucose load 0 to 60 minutes) are shown in [Table 4] and [Table 4], respectively. Table 5]. The values in the table are average values (n = 6).


[Table 4]

Group Plasma glucose elevation (mg / dl)
Group M (control) 100.05
Group M (Glibenclamide) 51.72
Group G (control) 172.72
Group G (Glibenclamide) 180.65

[Table 5]

Group Plasma insulin elevation (μU / ml)
Group M (control) 29.25
Group M (Glibenclamide) 49.70
Group G (control) 24.88
Group G (Glibenclamide) 22.76

As shown in [Table 4], glycenclamide (sulfonylurea compound) administration showed a plasma glucose lowering effect in the M group, whereas this effect was not observed in the G group. Moreover, as shown in [Table 5], in group M, glycenclamide (a sulfonylurea compound) administration showed an effect of increasing plasma insulin, whereas in group G, the effect was not observed.
That is, it was confirmed that N-STZ-1.5 rats orally administered with glibenclamide (10 mg / kg body weight) for 4 weeks are sulfonylurea secondary ineffective type 2 diabetic rats.

The therapeutic agent for sulfonylurea secondary ineffective diabetes of the present invention is an excellent insulin, even in a diabetic patient who cannot obtain an insulin secreting effect with a sulfonylurea compound or a fast-acting insulin secretagogue and therefore cannot obtain a sufficient hypoglycemic effect. Has secretory effect and blood glucose lowering effect.

Claims (8)

  A therapeutic agent for sulfonylurea secondary ineffective diabetes comprising a dipeptidyl peptidase-IV inhibitor.   The agent according to claim 1, wherein the secondary failure of the sulfonylurea is caused by the sulfonylurea compound.   The agent according to claim 1, wherein the secondary failure of sulfonylurea results from a fast-acting insulin secretagogue.   Use of a dipeptidyl peptidase-IV inhibitor for the manufacture of a therapeutic agent for sulfonylurea secondary ineffective diabetes.   A method for treating sulfonylurea secondary ineffective diabetes in a mammal, comprising administering an effective amount of a dipeptidyl peptidase-IV inhibitor to the mammal.   An insulin secretagogue for sulfonylurea secondary ineffective diabetic patients, comprising a dipeptidyl peptidase-IV inhibitor.   Use of a dipeptidyl peptidase-IV inhibitor for producing an insulin secretagogue for sulfonylurea secondary ineffective diabetic patients. A method for promoting insulin secretion in a sulfonylurea secondary ineffective diabetic patient, comprising administering an effective amount of a dipeptidyl peptidase-IV inhibitor.