JP2003327532A - Peptidase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine useful as a medicine for the prevention or treatment of diabetes mellitus and a peptidase inhibitor. <P>SOLUTION: This medicine contains a compound expressed by formula (1) [wherein, A is a heterocyclic ring which is allowed to be substituted, or a hydrocarbon group which is allowed to be substituted; (n) is 0-2 integer; R<SP>1</SP>, R<SP>2</SP>are the same or different, and are each H or a hydrocarbon group which is allowed to be substituted, or form a nitrogen-containing heterocyclic ring together with adjacent nitrogen atom; and R<SP>3</SP>is H, a halogen atom or a hydrocarbon group which is allowed to be substituted] or its salt, or its prodrug. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a drug and a peptidase inhibitor useful as a preventive or therapeutic drug for diabetes and the like.

[0002]

2. Description of the Related Art Peptidases are known to be associated with various diseases. For example, one type of peptidase, dipeptidyl peptidase-IV (hereinafter referred to as DPP-
IV is sometimes abbreviated) is a serine that specifically binds to a peptide containing proline (or alanine) at the second position from the N-terminal and cleaves the C-terminal side of the proline (or alanine) to produce a dipeptide. It is a protease.
DPP-IV has also been shown to be the same molecule as CD26, and has been reported to be related to the immune system. Although the role of DPP-IV in mammals has not been completely clarified, it plays an important role in neuropeptide metabolism, T cell activation, adhesion of cancer cells to endothelial cells, and invasion of HIV into cells. Is believed to be playing. Particularly in terms of glucose metabolism, DPP-IV is an incretin such as GLP-1 (glucagon-like peptide-1) or GIP (Gastric inhibitory peptide / Glucose-depend).
It plays a role in the inactivation of ent insulinotoropic peptide). Speaking of GLP-1, further, the plasma half-life is as short as 1-2 minutes, and the degradation product of DPP-IV, GLP-1 (9-36) amide, acts as an antagonist to the GLP-1 receptor. It is known that its bioactivity is remarkably impaired by being decomposed into DPP-IV such as working. If GLP-1 degradation is suppressed by inhibiting DPP-IV activity, GLP-1 is promoted in a glucose concentration-dependent manner such as promoting insulin secretion.
It is also known that the physiological activity possessed by is enhanced. From these facts, a compound having a DPP-IV inhibitory action is
It is expected to show effects on glucose intolerance, postprandial hyperglycemia, fasting hyperglycemia, and associated obesity / diabetic complications, which are observed in type I and type II diabetes. As therapeutic agents for diabetes currently used, sulfonylurea agents, biguanides, α-glucosidase inhibitors and the like are used. However, although sulfonylureas have a strong hypoglycemic effect, they often cause severe hypoglycemia and require caution in use. As a side effect, biguanides are likely to cause relatively severe lactic acidosis. In addition, α-glucosidase inhibitors suppress digestion and absorption of carbohydrates in the digestive tract and suppress postprandial blood glucose elevation, but side effects such as bloating and diarrhea are a problem (JOSLIN'S DIABETES MELLITUS 13Th.
Edition 521-522).

On the other hand, the following compounds have been reported as carbamoyltriazole derivatives. JP 9-14318
1 is the expression

[Chemical 3] [In the formula, Q is a condensed heterocyclic group having a nitrogen atom at the bridgehead which may have a substituent, W is O or S, R ¹ and
R ² is each a hydrogen atom or an optionally substituted hydrocarbon group, R ¹ and R ² may form an optionally substituted nitrogen-containing heterocyclic group, and R ³ is A hydrogen atom, a halogen atom, or an optionally substituted hydrocarbon group, m is 0 or 1, and n is an integer of 0 to 2] or a salt thereof is a herbicide or an insecticide. , It is described to be useful as an agricultural chemical such as a fungicide. Japanese Patent Laid-Open No. 59-39880 discloses that

[Chemical 4] [Wherein n is 0, 1 or 2, R ¹ and R ² are lower alkyl groups or a lower alkylene group forming a ring of R ¹ and R ² , X is a halogen atom or a lower alkyl group, and R ³ is a hydrogen atom. Alternatively, it represents a lower alkyl group. However, when R ³ is a hydrogen atom, m is
Represents 1, 2, or 3, and when R ³ is a lower alkyl group, m is
Representing 0, 1, 2 or 3] is useful as a herbicide. USP4280831 has
formula

[Chemical 5] It is described that the compound represented by is useful as a herbicide. However, there is no report that these carbamoyltriazole derivatives are useful as a drug or a peptidase inhibitor.

[0004]

[Problems to be Solved by the Invention] It is desired to develop a drug and a peptidase inhibitor which are useful as a preventive or therapeutic drug for diabetes and have excellent properties such as drug efficacy, action time, specificity and low toxicity. It is rare.

[0005]

Means for Solving the Problems The present inventors have found that 1,2,4-triazole having an aminocarbamoyl group at the 1-position is bonded to a sulfur atom at the 3-position and is characterized by its chemical structure. Having an expression

[Chemical 6] [In the formula, A represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, n represents an integer of 0 to 2, R ¹ and R ² are the same or different, and a hydrogen atom Or represents an optionally substituted hydrocarbon group, or R
¹ and R ² together with an adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocycle, R ³ is a hydrogen atom,
A compound represented by a halogen atom or a hydrocarbon group which may be substituted] [hereinafter, sometimes abbreviated as compound (I)] or a salt thereof has an excellent peptidase inhibitory action and prevents diabetes. For the first time, it was found to be useful as a therapeutic drug. Based on this finding, the present inventor has conducted earnest research and completed the present invention. That is, the present invention provides 1) a drug comprising compound (I) or a salt thereof or a prodrug thereof; 2) the drug according to 1) above, which is a preventive or therapeutic drug for diabetes; 3) prevention of diabetic complications. Or 1) which is a therapeutic drug
The pharmaceutical according to 1), which is a preventive or therapeutic drug for impaired glucose tolerance; 5) the pharmaceutical according to 1), which is a preventive or therapeutic drug for obesity; 6) Compound (I) or a salt thereof; A peptidase inhibitor comprising the prodrug thereof; 7) the inhibitor according to 6) above, wherein the peptidase is dipeptidyl peptidase-IV;

The definition of each symbol in the formula (I) will be described in detail below. The "heterocyclic group" in the "optionally substituted heterocyclic group" represented by A is, for example, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than carbon atoms as ring-constituting atoms. Contains 5
To 7-membered monocyclic heterocyclic groups or condensed heterocyclic groups. Examples of the fused heterocyclic group include a 5- to 7-membered monocyclic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom. And the like. Specific examples of the "heterocyclic group" include tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,
Hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, 2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinyl, 2,4-dioxothiazolidinyl, A non-aromatic heterocyclic group such as 1,3-dioxoisoindolyl; and furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, 1-pyrazolyl, 3-pyrazolyl, pyrazolyl,
Isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-
Triazolyl, tetrazolyl, quinolyl, quinazolyl,
Quinoxalyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl, 1H-indazolyl, 1H-pyrrolo [2,3-b] pyrazinyl, 1H-imidazo [4,5-
b] pyridinyl, 1H-imidazo [4,5-c] pyridinyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-b]
Examples include aromatic heterocyclic groups such as pyridazinyl.

The "heterocyclic group" may have 1 to 3 substituents at substitutable positions. Such substituents include, for example, "halogen atom", "nitro group",
"Cyano group", "C _1-3 alkylenedioxy group", "optionally substituted alkyl group having 1 to 10 carbon atoms",
"Alkenyl group having 2 to 10 carbon atoms which may be substituted", "Alkynyl group having 2 to 10 carbon atoms which may be substituted", "Cycloalkyl group having 3 to 10 carbon atoms which may be substituted" , "C3-C which may be substituted"
10 cycloalkenyl group "," optionally substituted cycloalkadienyl group having 4 to 10 carbon atoms "," optionally substituted aryl group having 6 to 14 carbon atoms "," optionally substituted " A good aralkyl group having 7 to 13 carbon atoms ",
"Aryl alkenyl group having 8 to 13 carbon atoms which may be substituted", "non-aromatic heterocyclic group which may be substituted", "aromatic heterocyclic group which may be substituted", "acyl group" , "Optionally substituted amino group", "optionally substituted hydroxy group", "optionally substituted thiol group", "amidino group" and the like.

Here, examples of the "halogen atom" include fluorine, chlorine, bromine, iodine and the like, among which fluorine, chlorine and bromine are preferable. Examples of the “C _1-3 alkylenedioxy group” include methylenedioxy, ethylenedioxy and the like. "C1-C10 alkyl" in the "optionally substituted C1-C10 alkyl group"
As the “10 alkyl group”, for example, 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, heptyl, octyl , Nonyl, decyl and the like.
Examples of the "alkenyl group having 2 to 10 carbon atoms" in the "alkenyl group having 2 to 10 carbon atoms which may be substituted" include, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1 -Butenyl, 2-
Butenyl, 3-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4
-Pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned. Examples of the "alkynyl group having 2 to 10 carbon atoms" in the "optionally substituted C 2 to 10 alkynyl group" include, 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, 1-heptynyl, 1-octynyl and the like can be mentioned.

The above "alkyl group having 1 to 10 carbon atoms",
"C2-C10 alkenyl group" and "C2-C2
10 alkynyl groups "are 1 to 3 at substitutable positions.
May have one substituent. Examples of such a substituent include a cycloalkyl group having 3 to 10 carbon atoms; an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, imidazo [1,2-a] pyridyl, imidazo [1 , 2-a] pyrimidinyl, imidazo [1,2-b] pyridazinyl, etc.); non-aromatic heterocyclic groups (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, etc.);
An amino group which may be mono- or di-substituted by an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, alkoxycarbonyl group, etc.);
An alkylsulfonylamino group having 1 to 8 carbon atoms; an amidino group; an acyl group having 2 to 8 carbon atoms (eg, an alkanoyl group, an alkoxycarbonyl group, etc.); an alkylsulfonyl group having 1 to 8 carbon atoms; Carbamoyl group which may be mono- or di-substituted by an alkyl group; carbon number 1 to
A sulfamoyl group which may be mono- or di-substituted with an alkyl group of 4; a carboxyl group; a hydroxy group; 1
To alkoxy groups having 1 to 6 carbon atoms which may be substituted with 3 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.); 1 to 3 halogen atoms (eg, fluorine, chlorine,
2 to 2 carbon atoms which may be substituted with bromine, iodine, etc.)
An alkenyloxy group having 5 carbon atoms; a cycloalkyloxy group having 3 to 7 carbon atoms; an aralkyloxy group having 7 to 13 carbon atoms; an aryloxy group having 6 to 14 carbon atoms (eg, phenyloxy, naphthyloxy, etc.); An alkylthio group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.);
Aralkylthio group having 7 to 13 carbon atoms; arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio, etc.); sulfo group; cyano group; azido group; nitro group; nitroso group; halogen atom (eg, fluorine, chlorine , Bromine, iodine) and the like.

The "cycloalkyl group having 3 to 10 carbon atoms" in the "optionally substituted cycloalkyl group having 3 to 10 carbon atoms" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. , Bicyclo [2.2.1] heptyl, 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 can be mentioned. Examples of the "cycloalkenyl group having 3 to 10 carbon atoms" in the "optionally substituted cycloalkenyl group having 3 to 10 carbon atoms" include, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2 -Cyclohexen-1-yl, 3-cyclohexen-1-yl and the like can be mentioned. Examples of the "cycloalkadienyl group having 4 to 10 carbon atoms" in the "optionally substituted cycloalkadienyl group having 4 to 10 carbon atoms" include, for example, 2,4-cyclopentadien-1-yl, 2, 4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like can be mentioned. "6 to 6 carbon atoms which may be substituted
Examples of the “aryl group having 6 to 14 carbon atoms” in the “14 aryl group” include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Among them, phenyl, 1-naphthyl,
2-naphthyl and the like are preferable. "C7-C7" in "aralkyl group which may be substituted and has a carbon number of 7-13"
Examples of the “13 aralkyl group” include benzyl, phenethyl, naphthylmethyl and the like. "Arylalkenyl group having 8 to 13 carbon atoms which may be substituted"
Examples of the "arylalkenyl group having 8 to 13 carbon atoms" in include styryl and the like.

The "non-aromatic heterocyclic group" in the "optionally substituted non-aromatic heterocyclic group" is, for example, a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms as ring-constituting atoms. A 5- to 7-membered monocyclic non-aromatic heterocyclic group or condensed non-aromatic heterocyclic group containing 1 to 4 atoms can be mentioned. Examples of the non-aromatic condensed heterocyclic group include a 5-membered to 7-membered monocyclic non-aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or 1 sulfur atom. And a group condensed with a 5-membered ring. Suitable examples of the non-aromatic heterocyclic group include:
Tetrahydrofuryl, 1-pyrrolidinyl, piperidino,
Morpholino, thiomorpholino, 1-piperazinyl, hexamethyleneimine-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4- Dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl, 1,3-dioxoisoindole-2-
And 5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl and the like.

“Aromatic heterocyclic group which may be substituted”
The "aromatic heterocyclic group" in includes, for example, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms as ring members 5
To 7-membered monocyclic aromatic heterocyclic groups or condensed aromatic heterocyclic groups. The fused aromatic heterocyclic group includes, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or 1 sulfur atom. Examples thereof include a group condensed with a 5-membered ring.
Preferred examples of the aromatic heterocyclic group include 2-furyl and 3-
Furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-
Pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-
Imidazolyl, 2-imidazolyl, 4-imidazolyl,
5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl,
4-pyrazolyl, isoxazolyl, isothiazolyl,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2
-Oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,3,4
-Oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-triazol-1-yl,
1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazole- 1-yl, tetrazol-5-yl, 2-quinolyl,
3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl, 2-quinoxalyl, 2-benzofuryl, 3-
Benzofuryl, 2-benzothienyl, 3-benzothienyl, 2-benzoxazolyl, 2-benzothiazolyl,
Benzimidazol-1-yl, benzimidazole-
2-yl, indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,
3-b] Pyridin-6-yl, 1H-imidazo [4,5]
-B] Pyridin-2-yl, 1H-imidazo [4,5-
c] Pyridin-2-yl, 1H-imidazo [4,5-
b] pyrazin-2-yl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-b] pyridazinyl and the like.

The above-mentioned "C3 to C1 which may be substituted"
0 cycloalkyl group "," optionally substituted carbon "
Number 3-10 cycloalkenyl group "," substituted
A cycloalkadienyl group having 4 to 10 carbon atoms,
“Aryl having 6 to 14 carbon atoms which may be substituted
Group "," aralkyl which may be substituted and has 7 to 13 carbon atoms
Kill group "," optionally substituted C8-C13
Lille alkenyl group "," non-aromatic optionally substituted "
Group heterocyclic group ”and“ optionally substituted aromatic heterocycle ”
Examples of the substituent in the “ring group” include 1 to 3 halo.
Place at a gen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
1-3 optionally substituted alkyl groups having 1 to 6 carbon atoms;
Individual halogen atoms (eg fluorine, chlorine, bromine, iodine
C2-6 alkenyl optionally substituted with
Group: C3-C10 cycloalkyl group; C6-C1
4 aryl groups (eg, phenyl, naphthyl, etc.); aromatic
Group heterocyclic groups (eg thienyl, furyl, pyridyl, oxa
Zolyl, thiazolyl, imidazo [1,2-a]) pyridy
Le, imidazo [1,2-a] pyrimidinyl, imidazo
[1,2-b] pyridazinyl etc.); non-aromatic heterocyclic group
(Eg, tetrahydrofuryl, morpholino, thiomorpholin
No, piperidino, pyrrolidinyl, piperazinyl, etc.);
Aralkyl group having 7 to 13 carbon atoms; Alky group having 1 to 4 carbon atoms
Group or 1 to 15 carbon atoms (preferably 2 to 2 carbon atoms)
8) Acyl group (eg, alkanoyl group, etc.) is mono
Or an optionally disubstituted amino group (eg, amino,
No or di-C _2-10Alkanoylamino, C_1-10Al
Coxy-carbonylamino, carbamoylamino, mono
-Or di-C_1-10Alkyl-carbamoylamino, C
_6-14Aryl-carbonylamino, C_3-10Cycloalk
L-carbonylamino, C_7-13Aralkyl Oxy-Cal
Bonylamino, mono- or di-C_1-10Alkyl sulfo
Nylamino, C_6-14Arylsulfonylamino, C_1-6
Alkoxy-carbamoylamino etc.); amidino group;
An acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, etc.);
Mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms
Carbamoyl group which may be present; alkyl group having 1 to 4 carbon atoms
Sulfamoyl optionally mono- or di-substituted with
Group; carboxyl group; alkoxycarbo having 2 to 8 carbon atoms
Nyl group; Hydroxy group; 1-3 halogen atoms (eg,
Even if it is substituted with fluorine, chlorine, bromine, iodine, etc.)
Good alkoxy group having 1 to 6 carbon atoms; 1 to 3 halogens
Substituted with atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
Optionally substituted alkenyloxy group having 2 to 5 carbon atoms; charcoal
Cycloalkyloxy group having a prime number of 3 to 7; carbon number of 7 to 13
Aralkyloxy group; aryloxy having 6 to 14 carbon atoms
Si group (eg, phenyloxy, naphthyloxy, etc.);
All group; 1-3 halogen atoms (eg, fluorine, salt
Number of carbon atoms that may be substituted with hydrogen, bromine, iodine, etc.)
1-6 alkylthio groups; aralkyl having 7-13 carbon atoms
Thio group; arylthio group having 6 to 14 carbon atoms (eg, phenyl group)
Ruthio, naphthylthio, etc.); sulfo group; cyano group;
Zido group; nitro group; nitroso group; halogen atom (eg, fluorine
Fluorine, chlorine, bromine, iodine) and the like. Substituent
Is 1 to 3, for example.

Examples of the "acyl group" include those represented by the formula: -C
OR ⁴ , -CO-OR ⁴ , -SO ₂ R ⁴ , -SOR ⁴ , -P
O ₃ R ⁴ R ⁵ , -CO-NR ^4a R ^5a , -CS-NR ^4a R ^5a
[In the formula, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. R ^4a and R ^5a are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
Or R ^4a and R ^5a , together with the adjacent nitrogen atom,
Forming an optionally substituted nitrogen-containing heterocycle] and the like. The "optionally substituted hydrocarbon group" represented by R ⁴ , R ⁵ , R ^4a or R ^5a is exemplified as the substituent in the "optionally substituted heterocyclic group" represented by A. An optionally substituted alkyl group having 1 to 10 carbon atoms, an "optionally substituted alkenyl group having 2 to 10 carbon atoms", an "optionally substituted alkynyl group having 2 to 10 carbon atoms", "A cycloalkyl group having 3 to 10 carbon atoms which may be substituted", "a cycloalkenyl group having 3 to 10 carbon atoms which may be substituted", "a cycloalkyl group having 4 to 10 carbon atoms which may be substituted""Alkadienylgroup","optionally substituted carbon number 6"
To 14 aryl groups "," optionally substituted C7 to C13 aralkyl groups "," optionally substituted C8 to C13 arylalkenyl groups "and the like.

The "optionally substituted heterocyclic group" represented by R ⁴ , R ⁵ , R ^4a or R ^5a is a substituent in the "optionally substituted heterocyclic group" represented by A. Examples of "optionally substituted non-aromatic heterocyclic group"
And “optionally substituted aromatic heterocyclic group”. Examples of the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R ^4a and R ^5a together with the adjacent nitrogen atom include, for example, at least one nitrogen atom other than carbon atom as a ring-constituting atom. And a 5- to 7-membered nitrogen-containing heterocycle which may further contain 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine,
Hexamethyleneimine, pyrrole, pyrazole, oxazolidine, thiazolidine, imidazole, 1,2,3-triazole, tetrazole, indole and the like can be mentioned. The nitrogen-containing heterocycle may have 1 to 2 substituents at substitutable positions. As such a substituent,
Hydroxy group, 1 to 3 halogen atoms (eg, fluorine,
C optionally substituted with chlorine, bromine, iodine, etc.)
_1-6 alkyl group, C _{7-1 3} aralkyl group (eg, benzyl,
Such as diphenylmethyl).

Preferable examples of "acyl group" include formyl; carboxyl; carbamoyl; C _1-6 alkyl-carbonyl (eg, acetyl, isobutanoyl, isopentanoyl etc.); C _1-6 alkoxy-carbonyl (eg, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.); C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2
-Naphthoyl, etc.); C _6-14 aryloxy-carbonyl (eg, phenyloxycarbonyl, naphthyloxycarbonyl, etc.); C _7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.); mono- or di - (halogen atoms and C _1-6 alkoxy - 1 to 3 substituents substituted C _1-6 alkyl selected from carbonyl) - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, Diethylcarbamoyl,
Ethylmethylcarbamoyl, propylcarbamoyl, trifluoroethylcarbamoyl, etc.); C _6-14 aryl-carbamoyl (eg, phenylcarbamoyl, etc.); C
_3-10 cycloalkyl-carbamoyl (eg cyclopropylcarbamoyl); C _7-13 aralkyl-carbamoyl (eg benzylcarbamoyl); C _1-6 alkylsulfonyl (eg methylsulfonyl); C _6-14 aryl Sulfonyl (eg, phenylsulfonyl, etc.); Nitrogen-containing heterocycle optionally substituted with hydroxy-carbonyl (eg, pyrrolidinylcarbonyl, piperidinocarbonyl, etc.); C _1-6 alkylsulfinyl (eg, methylsulfinyl, etc.) ); C _1-6 alkoxy-carbamoyl
(Eg, methoxycarbamoyl); aminocarbamoyl; hydroxycarbamoyl; thiocarbamoyl and the like.

The "optionally substituted amino group" is, for example, an alkyl group having 1 to 10 carbon atoms or 2-1 to 2 carbon atoms.
0 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-
Examples thereof include an amino group which may be substituted with 1 or 2 substituents selected from 14 aryl groups and acyl groups. Here, "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms", "cycloalkenyl group having 3 to 10 carbon atoms", " Examples of the "aryl group having 6 to 14 carbon atoms" and the "acyl group" include those exemplified as the substituent of the "optionally substituted heterocyclic group" for A. Suitable examples of the substituted amino group include mono- or di-C _1-10 alkylamino (eg, methylamino, dimethylamino, ethylamino, diethylamino,
Propylamino, dibutylamino); mono- or di-
C _2-10 alkenylamino (eg, diallylamino); mono- or di-C _3-10 cycloalkylamino (eg, cyclohexylamino); mono- or di-C _2-10 alkanoylamino (eg, acetylamino, propionyl amino,
Butanoylamino, isobutanoylamino, isopentanoylamino); C _6-14 aryl-carbonylamino (eg, benzoylamino); C _6-14 arylamino (eg, phenylamino); carbamoylamino; mono-
Or di-C _1-10 alkyl-carbamoylamino (eg,
Methylcarbamoylamino, dimethylcarbamoylamino); C _1-10 alkoxy-carbonylamino (eg, methoxycarbonylamino); C _7-13 aralkyloxy-carbonylamino (eg, benzyloxycarbonylamino); C _3-10 cycloalkyl- Carbonylamino (eg,
Cyclopentylcarbonylamino, cyclohexylcarbonylamino); mono- or di-C _1-10 alkylsulfonylamino (eg, methylsulfonylamino, dimethylsulfonylamino); C _6-14 arylsulfonylamino (eg, phenylsulfonylamino); C _{1 -6} alkoxy-carbamoylamino (eg, methoxycarbamoylamino) and the like.

The "optionally substituted hydroxy group" is, for example, an optionally substituted "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms" or "2 carbon atoms". -10 alkynyl group "," C3-10 cycloalkyl group "," C3-10 cycloalkenyl group "," C6-14 aryl group "
Alternatively, a hydroxy group that may be substituted with a "C7-C13 aralkyl group" is exemplified. Here, "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "alkynyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms", "carbon The “cycloalkenyl group having 3 to 10 carbon atoms”, the “aryl group having 6 to 14 carbon atoms” and the “aralkyl group having 7 to 13 carbon atoms” are “an optionally substituted heterocyclic group” represented by the above A. Those exemplified as the substituents in are mentioned. These "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "alkynyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms",
"C3-C10 cycloalkenyl group", "C6
The "to 14 aryl group" and the "C7 to C13 aralkyl group" may each have 1 to 3 substituents at substitutable positions. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an alkoxy group having 1 to 3 carbon atoms, and 2 to 2 carbon atoms.
5 alkoxycarbonyl group, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group, hydroxy group, cycloalkyl group having 3 to 10 carbon atoms, carboxyl group, amino group, alkanoylamino group having 2 to 5 carbon atoms, etc. Is mentioned.

The substituted hydroxy group is preferably
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), alkoxy group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group, hydroxy A group, a carboxyl group, an amino group, an alkanoylamino group having 2 to 5 carbon atoms and a cycloalkyl group having 3 to 10 carbon atoms, each of which may have 1 to 3 substituents. -10 alkoxy group "," 2 to 2 carbon atoms
"10 alkenyloxy group", "C2-C10 alkynyloxy group", "C3-C10 cycloalkyloxy group", "C3-C10 cycloalkenyloxy group", "C6-C6" 14 aryloxy groups "," C7-C13 aralkyloxy groups "and the like. Here, examples of the “alkoxy group having 1 to 10 carbon atoms” include methoxy, ethoxy, propoxy, isopropoxy,
Examples include butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy and the like. Examples of the “alkenyloxy group having 2 to 10 carbon atoms” include allyloxy,
Examples include crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like. Examples of the "alkynyloxy group having 2 to 10 carbon atoms" include ethynyloxy, propynyloxy, pentynyloxy and the like.
Examples of the "cycloalkyloxy group having 3 to 10 carbon atoms" include cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. "C1-C3
“A cycloalkenyloxy group of 0” is, for example, 2-
Examples include cyclopentenyloxy and 2-cyclohexenyloxy. Examples of the "aryloxy group having 6 to 14 carbon atoms" include phenoxy, naphthyloxy and the like. "Aralkyloxy group having 7 to 13 carbon atoms"
As, for example, benzyloxy, phenethyloxy,
Naphthylmethyloxy and the like can be mentioned.

The substituted hydroxy group is more preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, and a carbon number. 1 to 3 substituents selected from 2 to 5 alkanoyl group, cyano group, carbamoyl group, hydroxy group, carboxyl group, amino group, alkanoylamino group having 2 to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms "Alkoxy group having 1 to 10 carbon atoms" which may have a group, "C3 to 3 carbon atoms"
10 cycloalkyloxy groups "or" 7 to 1 carbon atoms
3 aralkyloxy groups ".

The "optionally substituted thiol group" is, for example, optionally substituted "1 carbon atom".
-10 alkyl group "," C2-10 alkenyl group "," C2-10 alkynyl group "," C3 "
-10 cycloalkyl group "," C3-10 cycloalkenyl group "," C6-14 aryl group "or" C7-13 aralkyl group ", which may be substituted with a thiol group. Is mentioned. Here, "1 carbon number
-10 alkyl group "," C2-10 alkenyl group "," C2-10 alkynyl group "," C3 "
"Cycloalkyl group having 10 to 10", "cycloalkenyl group having 3 to 10 carbon atoms", "aryl group having 6 to 14 carbon atoms" and "aralkyl group having 7 to 13 carbon atoms" are represented by A above. What was illustrated in the substituent in "the heterocyclic group which may be substituted" is mentioned. These "C1-C10 alkyl group", "C2-C10 alkenyl group", "C2-C10 alkynyl group",
"C3-C10 cycloalkyl group", "C3-C3
"10 cycloalkenyl group", "aryl group having 6 to 14 carbon atoms" and "aralkyl group having 7 to 13 carbon atoms" include
Each may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, and an alkanoyl group having 2 to 5 carbon atoms. Examples thereof include groups, cyano groups, carbamoyl groups, hydroxy groups, cycloalkyl groups having 3 to 10 carbon atoms, carboxyl groups, amino groups, and alkanoylamino groups having 2 to 5 carbon atoms.

The substituted thiol group is preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.),
Alkoxy group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group, hydroxy group, carboxyl group, amino group, alkanoyl group having 2 to 5 carbon atoms 1 selected from an amino group and a cycloalkyl group having 3 to 10 carbon atoms
To, "alkylthio group having 1 to 10 carbon atoms", "alkenylthio group having 2 to 10 carbon atoms", "alkynylthio group having 2 to 10 carbon atoms", each of which may have 3 to 3 substituents. "A cycloalkylthio group having 3 to 10 carbon atoms",
Examples thereof include a “cycloalkenylthio group having 3 to 10 carbon atoms”, a “arylthio group having 6 to 14 carbon atoms”, and an “aralkylthio group having 7 to 13 carbon atoms”. Examples of the “alkylthio group having 1 to 10 carbon atoms” include methylthio, ethylthio, propylthio, isopropylthio, butylthio,
Isobutylthio, sec.-butylthio, t.-butylthio,
Pentylthio, isopentylthio, neopentylthio,
Hexylthio, heptylthio, nonylthio and the like can be mentioned. As the "alkenylthio group having 2 to 10 carbon atoms",
Examples include allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like.
Examples of the "alkynylthio group having 2 to 10 carbon atoms" include ethynylthio, propynylthio, pentynylthio and the like. Examples of the "cycloalkylthio group having 3 to 10 carbon atoms" include cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Examples of the "cycloalkenylthio group having 3 to 10 carbon atoms" include 2-cyclopentenylthio, 2-cyclohexenylthio and the like. Examples of the “arylthio group having 6 to 14 carbon atoms” include phenylthio, naphthylthio and the like. Examples of the "aralkylthio group having 7 to 13 carbon atoms" include benzylthio, phenethylthio, naphthylmethylthio and the like.

The "optionally substituted heterocyclic group" represented by A has the formula

[Chemical 7] [In the formula, Aa ring is an optionally substituted 5-10 membered aromatic ring, R ^1a is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and L is a divalent group. A hydrocarbon group] is preferred.

The "hydrocarbon group" in the "optionally substituted hydrocarbon group" represented by A is exemplified by the substituents in the "optionally substituted heterocyclic group" represented by A above. "Alkyl group having 1 to 10 carbon atoms", "Alkenyl group having 2 to 10 carbon atoms", "2 carbon atoms"
-10 alkynyl group "," C3-10 cycloalkyl group "," C3-10 cycloalkenyl group "," C4-10 cycloalkadienyl group ",
Examples thereof include "aryl group having 6 to 14 carbon atoms", "aralkyl group having 7 to 13 carbon atoms", "arylalkenyl group having 8 to 13 carbon atoms" and the like. The "hydrocarbon group" may have 1 to 3 substituents at substitutable positions.
Examples of such a substituent include, for example, the "halogen atom", "nitro group", "cyano group", "C _{1- 3} alkylenedioxy group "," optionally substituted non-aromatic heterocyclic group "," optionally substituted aromatic heterocyclic group "," acyl group "," optionally substituted amino group " , "Optionally substituted hydroxy group", "optionally substituted thiol group", "amidino group" and the like.

A is preferably a hydrocarbon group which may be substituted, and more preferably a hydrocarbon group which may be substituted with "an aromatic heterocyclic group which may be substituted". Preferable specific examples of A include, for example, 1) "an aromatic heterocyclic group optionally substituted with 1 to 3 halogen atoms (preferably fluorine, chlorine, bromine, etc.) (preferably imidazo [1,2] -A] pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-
b] pyridazinyl etc.) ", which may be substituted with" alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl etc.) "; 2) alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl etc.) An "aralkyl group having 7 to 13 carbon atoms (preferably benzyl etc.) which may be substituted with 1 to 3 substituents selected from an alkoxy group having 1 to 6 carbon atoms (preferably methoxy, ethoxy etc.)" And so on.

N represents an integer of 0 to 2, preferably 1
Or 2, and more preferably 2.

Examples of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² include the “optionally substituted hydrocarbon group” exemplified as A above. R
^The “optionally substituted hydrocarbon group” represented by ¹ and R ² is preferably selected from a halogen atom, a cyano group, an optionally substituted hydroxy group, an acyl group and an optionally substituted amino group. Is an alkyl group having 1 to 6 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 6 carbon atoms which may be substituted with an amino group (eg, methyl, ethyl, 2- Aminoethyl, propyl, isopropyl). Especially, an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl and isopropyl is preferable. The “optionally substituted nitrogen-containing heterocycle” formed by R ¹ and R ² together with the adjacent nitrogen atom is “an optionally substituted nitrogen-containing heterocycle formed by R ^4a and R ^5a together with the adjacent nitrogen atom. The same thing as a "nitrogen heterocycle" is mentioned. The "optionally substituted nitrogen-containing heterocycle" is preferably a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And an optionally substituted 5- to 7-membered nitrogen-containing heterocycle (eg, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, thiazolidine) and the like. Of these, pyrrolidine, piperidine, morpholine, 4-methylpiperazine, thiazolidine and the like are preferable. "Halogen atom" represented by R ³
Examples thereof include fluorine, chlorine, bromine and iodine. Of these, chlorine is preferred. The “optionally substituted hydrocarbon group” represented by R ³ is the “optionally substituted carbon number 1” exemplified as the substituent of the “optionally substituted heterocyclic group” represented by A. -10 alkyl group "," optionally substituted C2-C10 alkenyl group "," optionally substituted C2-1 "
0 alkynyl group "," optionally substituted 3 carbon atoms "
-10 cycloalkyl group "," optionally substituted C3-10 cycloalkenyl group "," optionally substituted C4-10 cycloalkadienyl group "," substituted " An optionally substituted aryl group having 6 to 14 carbon atoms, an "optionally substituted aralkyl group having 7 to 13 carbon atoms", an "optionally substituted arylalkenyl group having 8 to 13 carbon atoms" and the like. To be The "optionally substituted hydrocarbon group" for R ³ is preferably 1 to 3 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). ~ 1
An alkyl group having 0 to 6 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms, which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). R ³ is preferably a hydrogen atom, a halogen atom, or 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
Is an alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), and more preferably a hydrogen atom.

Preferred examples of the compound (I) include the following compounds. Compound (I-1) A is an aromatic heterocyclic group (preferably imidazo [1,2-a] pyridyl which may be substituted with 1 to 3 halogen atoms (preferably fluorine, chlorine, bromine, etc.). , Imidazo [1,2-a] pyrimidinyl, imidazo [1,2-
b] pyridazinyl etc.) ”, which may be substituted with“ alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl etc.) ”; R ¹ and R ² are the same or different and have 1 to 6 carbon atoms. An alkyl group (eg, methyl, ethyl, propyl, isopropyl); or a 5- to 7-membered nitrogen-containing heterocycle in which R ¹ and R ² together with the adjacent nitrogen atom may be substituted with a C _1-6 alkyl group. (Eg, pyrrolidine, piperidine, morpholine, 4-methylpiperazine,
Thiazolidine, etc.); R ³ is a hydrogen atom, a halogen atom, or 1 to 3 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) An alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.); Compound (I-2) A is 1 to 3 substituents selected from an alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl and the like) and an alkoxy group having 1 to 6 carbon atoms (preferably methoxy, ethoxy and the like). “Aralkyl group having 7 to 13 carbon atoms (preferably benzyl etc.)” which may be substituted with a group; R ¹ and R
² is the same or different, and is an alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl); or R ¹ and R ² together with the adjacent nitrogen atom
Forming a 5- to 7-membered nitrogen-containing heterocyclic ring which may be substituted with a C _1-6 alkyl group (eg, pyrrolidine, piperidine, morpholine, 4-methylpiperazine, thiazolidine, etc.); R ³ is a hydrogen atom; A halogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, methyl, ethyl, propyl, isopropyl, etc.) A compound which is

The salt of compound (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, organic salts, and the like. Examples thereof include salts with acids and salts with basic or acidic amino acids. 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. Suitable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Examples thereof include salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids 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- Examples thereof include salts with toluenesulfonic acid. Preferable examples of salts with basic amino acids 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. Among the above-mentioned salts, sodium salt, potassium salt, hydrochloride and the like are preferable.

The prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which undergoes enzymatic oxidation, reduction or hydrolysis. Compound (I) which changes to (I) and undergoes hydrolysis by gastric acid etc.
It is a compound that changes to. As a prodrug of compound (I), a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds, etc.); The hydroxyl group of compound (I) is acylated, alkylated,
Phosphorylated or borated compounds (eg, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); The carboxyl group of compound (I) is esterified,
Amidated compound (eg, carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds and the like) and the like. These compounds can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) is available from Hirokawa Shoten 1
It may be a compound (I) which is changed under physiological conditions as described in “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pages 163 to 198, 1990. The compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like. Further, the compound (I) is
It may be an anhydride or a hydrate.

The pharmaceutical agent and peptidase inhibitor of the present invention have low toxicity and are mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.).
On the other hand, it can be used as a preventive or therapeutic agent for various diseases described below, or as a diagnostic agent. The pharmaceutical agent and peptidase inhibitor of the present invention may be compound (I) or a salt thereof or a prodrug thereof (hereinafter, may be simply referred to as compound (I)) itself, or compound (I). It may be a composition obtained by mixing the above with a pharmacologically acceptable carrier. Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrant in a solid formulation; a solvent in a liquid formulation , Solubilizing agents, suspending agents, tonicity agents,
It is used as a buffer and soothing agent. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, dextrin, pullulan. , Light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, and the like. 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,
Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose,
Examples thereof include sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Suitable examples of the disintegrant include lactose,
Examples thereof include sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

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 solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. And so on. Suitable examples of the suspending agent, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin,
Surfactants such as benzalkonium chloride, benzethonium chloride and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, Examples include polyoxyethylene hydrogenated castor oil and the like. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include
Examples thereof include benzyl alcohol. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbate and the like. Suitable examples of colorants include water-soluble food tar dyes (eg, food red Nos. 2 and 3, food yellows No. 4 and 5, food blue Nos. 1 and 2, etc.), water-insoluble lake dyes. (Eg, aluminum salts of the water-soluble food tar pigments), natural pigments (eg, β-carotene, chlorophyll, red iron oxide, etc.) and the like. Preferable examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.

Examples of dosage forms of the medicine and peptidase inhibitor of the present invention include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), powders, granules, and troches. , Oral preparations such as syrup; and injections (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip, etc.), external preparations (eg, transdermal preparation, ointment, etc.) ), Suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, nasal agents, pulmonary agents (inhalants), parenteral agents such as eye drops. These preparations may be controlled-release preparations (eg, sustained-release microcapsules, etc.) such as immediate-release preparations or sustained-release preparations. The pharmaceutical agent and peptidase inhibitor of the present invention can be produced by a method conventionally used in the field of formulation technology, such as the method described in the Japanese Pharmacopoeia. Below, the manufacturing method of an oral agent and a parenteral agent is explained in full detail. For example, oral agents include active ingredients such as excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, pregelatinized starch, gum arabic). , Carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, and then, if necessary, taste masking, enteric coating or For the purpose of sustainability, it is produced by coating with a coating base in a manner known per se. Examples of the coating base include sugar coating bases, water-soluble film coating bases, enteric film coating bases, sustained-release film coating bases and the like. As the sugar coating base, sucrose is used, and one or more 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 cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), ROHM Pharma Co.], synthetic polymers such as polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulosic 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., Ltd., methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co.], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co.];
Examples include natural products such as shellac. Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co.], ethyl acrylate / methyl methacrylate copolymer suspension. Suspended liquid [Eudragit NE
(Trade name), ROHM Pharma Co., Ltd., and the like. The coating base described above,
You may mix and use 2 or more types in an appropriate ratio. Further, at the time of coating, a light shielding agent such as titanium oxide, iron sesquioxide, etc. may be used.

For injection, the active ingredient is a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60,
Polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), tonicity agent (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol) , Glucose, etc., along with an aqueous solvent (eg,
Dissolved in distilled water, physiological saline, Ringer's solution, etc.) or oily solvent (eg olive oil, sesame oil, cottonseed oil, vegetable oil such as corn oil, propylene glycol, etc.),
It is produced by suspending or emulsifying. On this occasion,
If desired, additives such as solubilizing agents (eg, sodium salicylate, sodium acetate, etc.), stabilizers (eg, human serum albumin, etc.), soothing agents (eg, benzyl alcohol, etc.) may be used.

The medicament and peptidase inhibitor of the present invention have an excellent peptidase inhibitory action and can suppress the degradation of physiologically active substances such as peptide hormones, cytokines and neurotransmitters by peptidases. Examples of the peptide hormone include glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP).
-2), GIP, growth hormone releasing hormone (GHR
H) and the like. Examples of cytokines include RANTES. Neuropeptide Y (neuropeptide Y) etc. are mentioned as a neurotransmitter.

Examples of peptidases include, for example, E
C 3.4.11.1 (Leucyl aminopeptidase), EC 3.4.11.2 (Mem
brane alanine aminopeptidase), EC 3.4.11.3 (Cystiny
l aminopeptidase), EC 3.4.11.4 (Tripeptide aminopep
tidase), EC 3.4.11.5 (Prolyl aminopeptidase), EC3.
4.11.6 (Aminopeptidase B), EC 3.4.11.7 (Glutamyl ami
nopeptidase), EC 3.4.11.9 (Xaa-Pro aminopeptidase),
EC 3.4.11.10 (Bacterial leucyl aminopeptidase), EC
3.4.11.13 (Clostridial aminopeptidase), EC 3.4.11.
14 (Cytosol alanyl aminopeptidase), EC 3.4.11.15 (Ly
syl aminopeptidase), EC 3.4.11.16 (Xaa-Trp aminopep
tidase), EC 3.4.11.17 (Tryptophanyl aminopeptidas
e), EC 3.4.11.18 (Methionyl aminopeptidase), EC 3.
4.11.19 (D-stereospecific aminopeptidase), EC 3.4.1
1.20 (Aminopeptidase Ey), EC 3.4.11.21 (Aspartyl ami
nopeptidase), EC 3.4.11.22 (Aminopeptidase I), EC
3.4.13.3 (Xaa-His dipeptidase), EC 3.4.13.4 (Xaa-Arg
dipeptidase), EC 3.4.13.5 (Xaa-methyl-His dipeptid
ase), EC 3.4.13.7 (Glu-Glu dipeptidase), EC 3.4.13.
9 (Xaa-Pro dipeptidase), EC 3.4.13.12 (Met-Xaa dipep
tidase), EC 3.4.13.17 (Non-stereospecific dipeptida
se), EC 3.4.13.18 (Cytosol nonspecific dipeptidas
e), EC 3.4.13.19 (Membrane dipeptidase), EC 3.4.13.
20 (Beta-Ala-His dipeptidase), EC 3.4.14.1 (Dipeptid
yl-peptidase I), EC 3.4.14.2 (Dipeptidyl-peptidase
II), EC 3.4.14.4 (Dipeptidyl-peptidase III), EC 3.
4.14.5 (Dipeptidyl-peptidase IV), EC3.4.14.6 (Dipept
idyl-dipeptidase), EC 3.4.14.9 (Tripeptidyl-peptida
se I), EC 3.4.14.10 (Tripeptidyl-peptidase II), EC
3.4.14.11 (Xaa-Pro dipeptidyl-peptidase) and the like. Among these, EC 3.4.14.1, EC 3.4.14.2,
EC 3.4.14.4, EC 3.4.14.5, EC 3.4.14.6, EC 3.4.14.9,
EC 3.4.14.10, EC 3.4.14.11 are preferred, especially EC
3.4.14.5 is preferred.

The drug and peptidase inhibitor of the present invention are prophylactic / therapeutic agents for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.); hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia)・ Low HDL, postprandial hyperlipidemia, etc.) preventive / therapeutic agent; arteriosclerosis preventive / therapeutic agent; impaired glucose tolerance [IGT (Impaired Glucose Tolerance)]
It can be used as a prophylactic / therapeutic agent for insulin, an insulin secretagogue, and an inhibitor of transition from impaired glucose tolerance to diabetes. Regarding the criteria for diabetes, a new criteria was reported by the Japan Diabetes Society in 1999. According to this report, diabetes means a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, 75 g.
Oral glucose tolerance test (75 g OGTT) 2-hour value (glucose concentration in venous plasma) is 200 mg / dl or more, and occasionally blood glucose level (glucose concentration in venous plasma) is 200 mg / dl or more. In addition, it does not correspond to the above-mentioned diabetes mellitus and "the fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or 75 g oral glucose tolerance test (75 g OGT
T) 2 hour value (glucose concentration in venous plasma) is 1
A state that is not “a state showing less than 40 mg / dl” (normal type) is called “boundary type”. Regarding the criteria for diabetes, from ADA (American Diabetes Association) in 1997, 1
WHO reported new criteria in 998. According to these reports, diabetes has a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / d.
1 or more, and 75 g oral glucose tolerance test 2-hour value (glucose concentration in venous plasma) is 200 mg
/ Dl or more.

Further, according to the above report, impaired glucose tolerance means fasting blood glucose level (glucose concentration in venous plasma).
Is less than 126 mg / dl, and the 2-hour 75 g oral glucose tolerance test value (glucose concentration in venous plasma) is 140 mg / dl or more and less than 200 mg / dl. Furthermore, the ADA reported that the fasting blood glucose level (glucose concentration in venous plasma) was 110 m.
The state of g / dl or more and less than 126 mg / dl is IFG (Im
Called paired Fasting Glucose). On the other hand, according to the WHO report, the IFG (Impaired Fasting Glucose)
Among them, the state in which the 75-g oral glucose tolerance test 2-hour value (glucose concentration in venous plasma) is less than 140 mg / dl is called IFG (Impaired Fasting Glycemia). The drug and peptidase inhibitor of the present invention include diabetes, borderline type, which is determined by the above new criteria.
Prevention of glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia)
Also used as a therapeutic drug. Furthermore, the pharmaceutical agent and peptidase inhibitor of the present invention are characterized by borderline type, impaired glucose tolerance, IFG.
(Impaired Fasting Glucose) or IFG (Impaired Fasting Glucose)
It is also possible to prevent the progression from ed fasting glycemia to diabetes.

The drug and peptidase inhibitor of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infectious disease ( Respiratory infections, urinary tract infections, digestive infections, skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, peripheral blood circulation disorders, etc.], obesity , Osteoporosis, cachexia (eg, cancer cachexia, tuberculous cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia or cachexia due to acquired immunodeficiency syndrome) Quality), fatty liver, hypertension, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end stage renal disease, etc.), muscular dystrophy, myocardium Infarction, angina, cerebrovascular disorder (Eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome ,
Acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, inflammation after surgical trauma, swelling remission, neuralgia, pharyngitis, cystitis,
Hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, gastric mucosal damage (including gastric mucosal damage caused by aspirin), etc.),
It can also be used as a prophylactic / therapeutic agent for visceral obesity syndrome and the like. The pharmaceutical agent and peptidase inhibitor of the present invention are
Reduction of visceral fat, suppression of visceral fat accumulation, improvement of glucose metabolism, improvement of lipid metabolism, suppression of oxidized LDL production, improvement of lipoprotein metabolism, improvement of coronary artery metabolism, prevention / treatment of cardiovascular complications, prevention / treatment of heart failure complications, Blood remnant reduction, anovulation prevention / treatment, hirsutism prevention / treatment, hyperandrogenemia prevention / treatment, pancreatic (β cell) function improvement, pancreas (β cell)
It is also used for regeneration and promotion of pancreatic (β cell) regeneration. The medicament and peptidase inhibitor of the present invention are also used for secondary prevention and suppression of progression of the above-mentioned various diseases (eg, cardiovascular events such as myocardial infarction).

The medicine and peptidase inhibitor of the present invention are used for hyperglycemic patients (for example, a fasting blood glucose level is 126 mg).
/ Dl or more or 75g Oral glucose tolerance test (75g
OGTT) A glucose-dependent insulin secretagogue that selectively exerts an insulin secretagogue action in patients with a 2-hour value of 140 mg / dl or more). Therefore, the pharmaceutical agent and peptidase inhibitor of the present invention are useful as a safe preventive or therapeutic drug for diabetes with low risk of vascular complications and hypoglycemia induction, which are harmful effects of insulin.

The doses of the drug of the present invention and the peptidase inhibitor vary depending on the administration subject, administration route, target disease, condition and the like, but when administered orally to an adult diabetic patient, for example, the compound (I ) Is generally used as a single dose of about 0.01 to 100 mg / kg body weight, preferably 0.05 to 30 mg / kg body weight, and more preferably 0.1.
1 to 10 mg / kg body weight, and this amount once to 3 times a day
It is desirable to administer a single dose.

The pharmaceutical agent and peptidase inhibitor of the present invention are used as antidiabetic agents, therapeutic agents for diabetic complications, antihyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-hyperlipidemic agents. It can be used in combination with a drug such as a thrombotic agent, a therapeutic agent for osteoporosis, an anti-dementia agent, an erectile dysfunction improving agent, and a therapeutic agent for urinary incontinence and pollakiuria (hereinafter abbreviated as a concomitant drug). At this time, the administration timing of the drug of the present invention or the peptidase inhibitor and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at a staggered time. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the drug of the present invention or the peptidase inhibitor 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, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound (I) which is an active ingredient of the drug of the present invention and the peptidase inhibitor.

As a therapeutic agent for diabetes, an insulin preparation (eg, animal insulin preparation extracted from bovine or porcine pancreas; human insulin preparation genetically synthesized using Escherichia coli or yeast; insulin zinc; protamine insulin) Zinc; insulin fragment or derivative (eg, INS-1 etc.), insulin sensitizer (eg, pioglitazone hydrochloride, (maleic acid) rosiglitazone, GI-262570, JTT-501, MC
C-555, YM-440, KRP-297, CS-0
11, FK-614, the compound described in WO99 / 58510 (for example, (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid). Etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylureas (eg, tolbutamide, etc.)
Glibenclamide, gliclazide, chlorpropamide,
Trazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate], GLP-1 receptor agonist [eg, GLP-1, NN-2211, AC-3992 (ex
endin-4), BIM-51077, Aib (8,35) hGLP
-1 (7,37) NH ₂ etc.], amylin agonist (eg pramlintide etc.), phosphotyrosine phosphatase inhibitor (eg vanadic acid etc.), dipeptidyl peptidase IV inhibitor (eg NVP-DPP-278, PT-1
00, P32 / 98, LAF-237, etc.), β3 agonist (eg CL-316243, SR-58611-A,
UL-TG-307, SB-226552, AJ-96
77, BMS-196085, AZ40140, etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor,
Glucose-6-phosphatase inhibitor, glucagon antagonist, etc., SGLT (sodium-glucose cotransporte)
r) Inhibitors (eg, T-1095 etc.) and the like can be mentioned.

Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, trrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-1).
12, etc.), neurotrophic factors and their increasing drugs (eg, NG)
F, NT-3, BDNF, the neurotrophin production / secretion promoter described in WO01 / 14372 (for example, 4-
(4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole, etc.), a nerve regeneration promoter (eg,
Y-128), PKC inhibitor (eg, LY-33353)
1), AGE inhibitors (eg, ALT946, pimagegedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (Eg,
Tiapride, mexiletine, etc.). Antihyperlipidemic agents include statin compounds that are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or salts thereof (eg, sodium salt)), squalene Synthetic enzyme inhibitors (eg W
O97 / 10224, for example, N-[[(3
R, 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, etc.) or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), ACAT inhibitor ( Eg, Avasimibe, Eflucimibe, etc.), anion exchange resin (eg, cholestyramine, etc.),
Probucol, nicotinic acid drugs (eg, nicomol (nic
omol), niceritrol, etc.), ethyl icosapentate, phytosterols (eg, soysterols
oysterol), gamma-oryzanol, etc.)
Etc. Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.) or angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (eg Examples include manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), potassium channel openers (eg, levocromakalim, L-27152, AL 0671, NIP-121, etc.), clonidine and the like. Examples of the anti-obesity agent include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampfepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibition Drug (eg, orlistat, etc.), β3 agonist (eg, CL-316243, SR-58611-A, U
L-TG-307, SB-226552, AJ-967
7, BMS-196085, AZ40140, etc.), peptide appetite suppressants (eg, leptin, CNTF (ciliary nerve trophic factor) etc.), cholecystokinin agonists (eg,
Lynchtripto, FPL-15849, etc.) and the like.

Examples of the diuretics include xanthine derivatives (eg, sodium theobromine salicylate, calcium theobromine salicylate, etc.), thiazide type preparations (eg, ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, Penfluthizide, polythiazide, meticlotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), Azosemide, isosorbide,
Ethacrynic acid, piretanide, bumetanide, furosemide and the like can be mentioned. Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), Examples include plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like.
Among them, 5-fluorouracil derivative such as furtulon or neofurtulon is preferable. Immunotherapeutic agents include, for example, microbial or bacterial components (eg, muramyl dipeptide derivative, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( Example,
Interferon, interleukin (IL, etc.), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.) and the like, among which IL-1, IL
-2, IL-12 and the like are preferable.

Examples of antithrombotic agents include heparin (eg,
Heparin sodium, heparin calcium, dalteparin sodium, etc.), warfarin (eg, warfarin potassium, etc.), antithrombin drug (eg, aragatroban, etc.), thrombolytic drug (eg, urokinase, thisokinase) (tiso
kinase), alteplase, nateplase (n
ateplase), monteplase, pamiteplase, etc.), platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) ) Etc.) and the like. Examples of therapeutic agents for osteoporosis include alfacalcidol (alfacalcidol) and calcitriol (calcit).
riol, elcaltonin, salmon calcitonin salmon, estriol
l), ipriflavone, pamidronate disodium, alendronate sodium hydrat
e), disodium incadronate (incadronate diso
dium) and the like. Examples of anti-dementia agents include tacrine, donepezil, rivastigmine, and galantamin.
e) and the like. Examples of the erectile dysfunction improving agent include apomorphine, sildenafil citrate and the like. Examples of therapeutic agents for urinary incontinence and frequent urination include flavoxate hydrochloride (fl
avoxate hydrochloride), oxybutynin hydrochloride (oxyb
utynin hydrochloride), propiverine hydrochloride (propive
rine hydrochloride) and the like.

Furthermore, drugs which have been found to have cachexia-improving effects in animal models and clinical practice, namely, cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, Vol. 49, 5935-5]
939, 1989], progesterone derivatives (eg,
Megesterol Acetate [Journal of Clinical Oncolog
y), Vol. 12, pp. 213-225, 1994], glucosteroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs (both documents are the same as above), fat metabolism improving agents ( (Eg, eicosapentaenoic acid) [British Journal of Cancer, No. 68
Vol., 314-318, 1993], growth hormone,
IGF-1, or TN, a factor that induces cachexia
Antibodies against F-α, LIF, IL-6, oncostatin M and the like can also be used in combination with the pharmaceutical agent or peptidase inhibitor of the present invention.

The concomitant drug is preferably an insulin preparation,
Insulin sensitizer, α-glucosidase inhibitor,
Examples thereof include biguanides, insulin secretagogues (preferably sulfonylureas), and the like. The concomitant drug may be used in combination of two or more kinds at an appropriate ratio. Preferred combinations when using two or more concomitant drugs include, for example, the following. 1) Insulin secretagogue (preferably sulfonylurea agent) and α-glucosidase inhibitor; 2) Insulin secretagogue (preferably sulfonylurea agent) and biguanide agent; 3) Insulin secretagogue (preferably sulfonylurea agent), biguanide agent And α-glucosidase inhibitor; 4) Insulin sensitizer and α-glucosidase inhibitor; 5) Insulin sensitizer and biguanide; 6) Insulin sensitizer, biguanide and α
-Glucosidase inhibitors. When the drug of the present invention and the peptidase inhibitor are used in combination with a concomitant drug, the amount of each drug can be reduced within a safe range in consideration of the opposite effects of the drugs.
In particular, the insulin sensitizer, insulin secretagogue (preferably sulfonylurea drug) and biguanide drug can be reduced in doses lower than usual doses. Therefore, the adverse effects that would be caused by these agents can be safely prevented. In addition, the doses of diabetic complications, antihyperlipidemic agents and antihypertensive agents can be reduced, so that the adverse effects that may be caused by these agents can be effectively prevented.

Compound (I) can be produced according to a method known per se, for example, the method described in JP-A-9-143181, JP-A-59-39880, USP4280831, or the like, or a method analogous thereto.

When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also contained as the compound (I), and the synthetic method and the separation known per se. Each can be obtained as a single item by the method. For example, when the compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I). The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the racemate of the final product according to a conventional method.
As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method or the like is used. 1) Fractional recrystallization method racemate and optically active compound (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-
Tartaric acid, (+)-1-phenethylamine, (-)-1-
Phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) to form a salt, and this is separated by a fractional recrystallization method, and if desired, a free optical isomer is obtained through a neutralization step.

2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separating optical isomers (chiral column) for separation. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series manufactured by Daicel Corporation,
Optical isomers by developing water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as single or mixed solutions To separate. In the case of gas chromatography, for example, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences Inc.). 3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this mixture is subjected to usual separation means (eg, fractional recrystallization, chromatography method, etc.) to obtain a single substance. Then, a method of obtaining an optical isomer by cleaving the optically active reagent site by a chemical treatment such as a hydrolysis reaction. For example, when the compound (I) has hydroxy or 1,2 amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid],
(−)-Menthoxyacetic acid and the like) and the like are subjected to a condensation reaction to obtain an ester or amide diastereomer, respectively. On the other hand, when the compound (I) has a carboxylic acid group, the compound and the optically active amine or alcohol reagent are subjected to a condensation reaction to obtain an amide or ester diastereomer, respectively. The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

[0052]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be explained in more detail by the following Reference Examples, Examples, Experimental Examples and Formulation Examples, but these Examples do not limit the present invention.
It may be changed without departing from the scope of the present invention. The abbreviations in Reference Examples and Examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet doublet, dt: doublet triplet, ddd: doublet doublet, td: triplet doublet, m: multiplet, brs: wide singlet, brt: wide singlet. Triplet, br
q: wide quartet, tt: triplet triplet, J: coupling constant, room temperature: 10-30
℃,%:% by weight

[0053]

Examples Reference Example 1 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyrimidine 2-chloromethylimidazo [1,2-a] pyrimidine ( 1289 mg, 7.7 mmol), 3-mercapto-1,2,4-triazole (778 mg, 7.7 mmol) and potassium carbonate (1063
4 mg of a solution of (mg, 7.7 mmol) in acetonitrile (20 ml) at 70 ° C.
Stir for hours. The reaction solution was returned to room temperature, water (100 ml) was added, and the generated crystals were collected by filtration. It was washed with water (20 ml × 2), acetonitrile (10 ml) and diethyl ether (10 ml) successively and dried to obtain the title compound (893 mg, yield 50%) as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.49 (2H, s), 7.03 (1H, dd,
J = 6.6, 4.4Hz), 7.80 (1H, s), 8.44 (1H, s), 8.50
(1H, dd, J = 4.4, 2.2Hz), 8.91 (1H, dd, J = 6.6, 2.
Reference example 2 6-chloro-2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine 6-chloro-2-chloromethylimidazo [1 , 2-a] pyridazine (2
02 mg, 1 mmol), 3-mercapto-1,2,4-triazole (10
1 mg, 1 mmol) and potassium carbonate (137 mg, 1 mmol) N, N
-The dimethylformamide (2 ml) solution was stirred at room temperature for 1 hour. Water (20 ml) was added to the reaction solution, extraction was performed with methylene chloride (20 ml), the organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (1
86 mg, yield 70%) was obtained as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.50 (2H, s), 7.36 (1H, d,
J = 9.6Hz), 8.16 (1H, d, J = 9.6Hz), 8.18 (1H, s),
8.46 (1H, s).

Reference Example 3 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine 2-chloromethylimidazo [1,2-a] pyridazine (700 mg, 4.
2 mmol), 3-mercapto-1,2,4-triazole (422 mg,
4.2 mmol) and potassium carbonate (577 mg, 4.2 mmol) in N, N-
The dimethylformamide (4 ml) solution was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction solution, and the generated crystals were collected by filtration. It was washed with water (20 ml × 2) and diethyl ether (10 ml) successively and dried to obtain the title compound (381 mg, yield 39%) as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.50 (2H, s), 7.21 (1H, dd,
J = 9.2, 4.4Hz), 8.06 (1H, dd, J = 9.2, 1.4Hz), 8.
13 (1H, s), 8.45 (1H, s), 8.47 (1H, dd, J = 4.4, 1.
Reference Example 4 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyridine 2-chloromethylimidazo [1,2-a] pyrimidine (15.5 g, 93
mmol), 3-mercapto-1,2,4-triazole (9.41 g, 93
mmol) and potassium carbonate (12.9 g, 93 mmol) in acetonitrile (150 ml) were stirred at 70 ° C. for 4 hours. The reaction solution was returned to room temperature, water (500 ml) was added, and the generated crystals were collected by filtration. It was washed with water (200 ml), acetonitrile (100 ml) and diethyl ether (50 ml) successively and dried to obtain the title compound (16.2 g, yield 75%) as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.47 (2H, s), 6.86 (1H, td,
J = 6.6, 1.0Hz), 7.21 (1H, ddd, J = 9.2, 6.6, 1.0H
z), 7.49 (1H, dd, J = 9.2, 1.0Hz), 7.83 (1H, s),
8.44 (1H, s), 8.48 (1H, dt, J = 6.6, 1.0).

Reference Example 5 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyridine (16.2 g, 70 mmol) in methanol (100
ml) -water (170 ml) solution, concentrated sulfuric acid (2.2 ml) and oxone (64.5 g, 105 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 8 with 1N aqueous sodium hydroxide solution under ice cooling, and the precipitated crystals were collected by filtration. It was washed with water (200 ml), acetonitrile (100 ml) and diethyl ether (50 ml) successively and dried to give the title compound (21.4 g, yield 100
%) As white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.91 (2H, s), 6.89 (1H, td,
J = 6.6, 1.0Hz), 7.23 (1H, ddd, J = 9.2, 6.6, 1.
0), 7.47 (1H, dd, J = 9.2, 1.0Hz), 7.87 (1H, s), 8.
54 (1H, dt, 6.6, 1.0Hz), 8.90 (1H, s). Reference Example 6 2-[(1H-1,2,4-triazol-3-ylsulfinyl) methyl] imidazo [1,2-a] ] Pyridine 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyridine (500 mg, 2.2 mmol) in methanol (3
Concentrated sulfuric acid (0.073 ml) and oxone (797 mg, 1.3 mmol) were added to a (ml) -water (5 ml) solution under ice cooling, and the mixture was stirred at room temperature for 5 hours.
To the reaction mixture was added 1N sodium hydroxide aqueous solution under ice cooling to adjust the pH.
Then, the precipitated crystals were collected by filtration. Water (5 ml), ethanol
(5 ml) and diisopropyl ether (5 ml) were washed successively, and dried to obtain the title compound (104 mg, yield 20%) as pale yellow crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.64 (2H, s), 6.88 (1H, td,
J = 6.6, 1.0Hz), 7.23 (1H, ddd, J = 9.2, 6.6, 1.0H
z), 7.51 (1H, dd, J = 9.2, 1.0, Hz), 7.80 (1H, s),
8.50 (1H, dt, J = 6.6, 1.0Hz), 8.87 (1H, s).

Reference Example 7 N, N-diethyl-3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfinyl] -1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylsulfinyl) methyl] imidazo [1,2-a] pyridine (80 mg, 0.324 mmol) and potassium carbonate (54 mg, 0.39 mmol) in dimethyl sulfoxide (1 mol) Diethylcarbamoyl chloride (0.049 m
(1, 3.9 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water (10 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (10 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate: methanol = 10/1, v / v), and diisopropyl ether-
Crystallization from hexane (1 / 1,5 ml) gave the title compound (77 m
g, yield 69%) was obtained as white crystals. Melting point 174.6-175.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.30 (6H, m), 3.40-3.70
(4H, m), 4.74 (2H, s), 6.90 (1H, td, J = 6.7, 1.2H
z), 7.32 (1H, ddd, J = 9.0, 6.7, 1.2Hz), 7.62 (1
H, dt, J = 9.0, 1.2Hz), 7.70 (1H, s), 8.13 (1H, d
t, J = 6.7, 1.2Hz), 8.93 (1H, s). IR (KBr): 1709, 1433, 1275, 1059 cm ^-1 . Elemental analysis C ₁₅ H ₁₈ N ₆ O ₂ S ・ 0.5H ₂ O Calculated as (%): C, 50.69; H, 5.39; N, 23.65. Measured value (%): C, 50.92; H, 5.33; N, 23.88. Reference Example 8 N, N-diethyl-3-[( Imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazol-1-carboxamide 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl ]
Imidazo [1,2-a] pyridine (1420 mg, 4.71 mmol) and potassium carbonate (780 mg, 5.6 mmol) in dimethyl sulfoxide
(10 mol) solution in diethylcarbamoyl chloride (0.659 m
(1, 5.2 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water (30 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (1
(592 mg, yield 93%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.40 (6H, m), 3.50 (4H,
q, J = 7.0Hz), 4.89 (2H, s), 6.81 (1H, td, J = 6.
6, 1.2Hz), 7.17 (1H, ddd, J = 9.0, 6.6, 1.2Hz),
7.48 (1H, dd, J = 9.0, 1.2Hz), 7.78 (1H, s), 8.09
(1H, dt, J = 6.6, 1.2Hz), 8.86 (1H, s).

Reference Example 9 3-{[(3-chloroimidazo [1,2-a] pyridin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-Carboxamide N, N-diethyl-3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide (500 mg, 1.4 mmol) N, N-dimethylformamide
N-chlorosuccinimide (98% content, 314 mg, 2.4 mmol) was added to the (6 ml) solution under ice cooling, and the mixture was stirred at room temperature for 15 hr. Water (20 ml) was added to the reaction mixture, and methylene chloride (20 ml ×
After extraction with 2), the organic layer was washed with saturated saline (20 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 5/1 → ethyl acetate, v / v), and crystallized from diisopropyl ether to give the title compound (180
mg, yield 32%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, br), 3.5 (4H, q, J
= 7.0Hz), 4.89 (2H, s), 6.96 (1H, td, J = 6.8,
1.1Hz), 7.24 (1H, ddd, J = 9.2, 6.8, 1.3Hz), 7.49
(1H, dd, J = 9.2, 1.1Hz), 8.04 (1H, dt, J = 6.8,
1.1Hz), 8.89 (1H, s). Reference Example 10 N, N-diethyl-3-[(mesitylylmethyl) thio] -1H-1,2,4-
Triazole-1-carboxamide 3-[(mesitylmethyl) thio] -1H-1,2,4-triazole (500
mg, 2.14 mmol) and potassium carbonate (355 mg, 2.57 mmol)
Diethyl carbamoyl chloride (0.326 ml, 2.57 mmol) was added to a solution of dimethylsulfoxide (5 ml) in water at room temperature.
It was stirred for a day. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (10 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 1/1, v / v) and crystallized from diisopropyl ether-hexane to give the title compound (514 mg, yield 72%) as white. Obtained as crystals. Melting point 84.0-85.5 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, t, J = 7.0Hz), 2.27
(3H, s), 2.41 (6H, s), 3.62 (4H, brq, J = 7.0Hz),
4.43 (2H, s), 6.87 (2H, s), 8.78 (1H, s) .IR (KB
r): 2970, 1698, 1472, 1429, 1269, 1254 cm ^-1 . Elemental analysis value C ₁₇ H ₂₄ N ₄ Calculated as OS (%): C, 61.41; H, 7.28; N, 16.85. %): C, 61.39; H, 7.17; N, 16.92.

Reference Example 11 N, N-diethyl-3-[(mesitylmethyl) sulfonyl] -1H-1,
2,4-triazole-1-carboxamide N, N-diethyl-3-[(mesitylylmethyl) thio] -1H-1,2,4-
To a solution of triazole-1-carboxamide (333 mg, 1 mmol) in methanol (16 ml) -water (4 ml) was added concentrated sulfuric acid (0.034 ml) and oxone (922 mg, 1.5 mmol), and the mixture was stirred at room temperature for 20 hours. . The reaction solution was adjusted to pH 8 with 1N aqueous sodium hydroxide solution under ice cooling, and extracted with methylene chloride (10 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography (ethyl acetate: hexane = 2/1,
v / v), the first eluate was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (152 mg, yield 42
%) As white crystals. Melting point 132.1-132.4 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, t, J = 7.0Hz), 2.27
(3H, s), 2.41 (6H, s), 3.50-3.70 (4H, m), 4.80 (2
H, s), 6.92 (2H, s), 8.92 (1H, s). IR (KBr): 1717, 1435, 1333, 1429, 1269, 1254 cm ^-1 . Elemental analysis C ₁₇ H ₂₄ N ₄ O ₃ Calculated value for S (%): C, 56.02; H, 6.64; N, 15.37. Measured value (%): C, 56.10; H, 7.51; N, 15.86. Reference Example 12 N, N-diethyl-3- [ (Mesitylmethyl) sulfinyl] -1H-
1,2,4-triazole-1-carboxamide The second eluate in flash silica gel column chromatography performed in Reference Example 11 was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (70 mg, yield 20%). Obtained as white crystals. Melting point 117.3-118.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, brt, J = 6.6Hz), 2.
26 (3H, s), 2.35 (6H, s), 3.55 (4H, brq, J = 6.6H
z), 4.42 (1H, d, J = 13.2Hz), 4.77 (1H, d, J = 13.2)
Hz), 6.89 (2H, s), 8.93 (1H, s). IR (KBr): 1709, 1474, 1431, 1273, 1073 cm ^-1 . Elemental analysis value Calculated as C ₁₇ H ₂₄ N ₄ O ₂ S (%): C, 58.59; H, 6.94; N, 16.08. Actual value (%): C, 58.61; H, 7.24; N, 16.32.

Example 1 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-dimethyl-1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (527 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethyl sulfoxide (5 m
ol) solution in dimethylcarbamoyl chloride (0.295 ml, 3.
(2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20
ml) was added, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (565 mg,
Yield 85%) was obtained as white crystals. Melting point 1991-202.4 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.92 (3H, brs), 3.05 (3H, b
rs), 5.00 (2H, s), 6.90 (1H, td, J = 7.0, 1.0Hz),
7.22 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.41 (1H, dd,
J = 9.2, 1.0Hz), 7.94 (1H, s), 8.54 (1H, td, J
= 7.0, 1.0Hz), 9.35 (1H, s). Elemental analysis value Calculated as C ₁₃ H ₁₄ N ₆ O ₃ S (%): C, 46.70; H, 4.22; N, 25.14. Measured value (%) : C, 46.58; H, 4.08; N, 24.85. Example 2 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-diisopropyl-1H-1,2,4 -Triazole-1-carboxamide 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (526.6 mg, 2 mmol) and potassium carbonate (443 mg, 3.2 mmol) in dimethyl sulfoxide (5
(ml) solution with diisopropylcarbamoyl chloride (589
(mg, 3.6 mmol) was added, and the mixture was stirred at room temperature for 4 days. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (30 ml × 2). The organic layer was washed with water (20 ml) and saturated saline (20 ml),
The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate) and crystallized from diisopropyl ether to give the title compound (348 mg, yield 45%) as white crystals. Melting point 195.0-195.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.60 (12H, m), 3.70-4.20
(2H, m), 4.90 (2H, s), 6.81 (1H, td, J = 7.0, 1.
0Hz), 7.17 (1H, ddd, J = 10.0, 7.0, 1.0Hz), 7.48
(1H, dd, J = 10.0, 1.0Hz), 7.78 (1H, s), 8.09 (1
H, dt, J = 7.0,1.0Hz), 8.75 (1H, s). IR (KBr): 1717, 1360, 1335, 1306 cm ⁻¹ . Elemental analysis value Calculated as C ₁₇ H ₂₂ ClN ₆ O ₃ S (%): C, 52.29; H, 5.68; N, 21.52. Actual value (%): C, 52.34; H, 5.50; N, 21.34.

Example 3 3-{[(3-chloroimidazo [1,2-a] pyridin-2-yl) methyl] sulfonyl} -N, N-dimethyl-1H-1,2,4-triazole-
1-Carboxamide 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-dimethyl-1H-1,2,4-triazole-1-carboxamide (334 mg, 1 mmol) N, N-dimethylformamide (5
N-chlorosuccinimide (98% content, 23%
1 mg, 1.7 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water (20 ml) was added to the reaction solution, extraction was performed with methylene chloride (20 ml × 2), the organic layer was washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (ethyl acetate:
Hexane = 5/1-> ethyl acetate-> ethyl acetate: methanol = 10/1, v / v) and purified by diisopropyl ether to give the title compound (130 mg, yield 35%) as white crystals. . Melting point 174.7-175.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.17 (3H, brs), 3.21 (3H, br
s), 4.90 (2H, s), 6.96 (1H, td, J = 7.0, 1.0Hz),
7.24 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.48 (1H, d
t, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 7.0, 1.0H
z), 8.88 (1H, s). Elemental analysis value Calculated as C ₁₃ H ₁₃ ClN ₆ O ₃ S (%): C, 42.34; H, 3.55; N, 22.36. Measured value (%): C, 42.37 H, 3.53; N, 22.36. Example 4 3-{[(3-chloroimidazo [1,2-a] pyridin-2-yl) methyl] sulfonyl} -N, N-diisopropyl-1H-1,2 , 4-Triazole-1-carboxamide 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-diisopropyl-1H-1,2,4-triazole-1-carboxamide (200 N, N-Dimethylformamide (2.5 ml) solution of (mg, 0.512 mmol) was added with N-chlorosuccinimide (98% content, 105 mg, 0.768 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 hours. Add methylene chloride (20 ml) to the reaction mixture and add water.
(20 ml) and saturated brine (20 ml), and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, methylene chloride was added to the obtained residue, and crystallization was performed to give the title compound (54 mg,
Yield 20%) was obtained as white crystals. The filtrate was subjected to flash silica gel chromatography (ethyl acetate: hexane = 3/2
→ Purified with ethyl acetate, v / v) and crystallized with diisopropyl ether to give the title compound (29 mg, yield 13%). Melting point 231.8-133.9 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.50 (12H, m), 3.80-4.20
(2H, m), 4.90 (2H, s), 6.96 (1H, td, J = 7.0, 1.
0Hz), 7.24 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.50 (1
H, dd, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 7.0,
1.0Hz), 8.78 (1H, s) .IR (KBr): 1717, 1350, 1306, 1148 cm ⁻¹ . Elemental analysis value C ₁₇ H ₂₁ ClN ₆ O ₃ S Calculated value (%): C, 48.05; H, 4.98; N, 19.78. Found (%): C, 48.00; H, 4.94; N, 19.17.

Example 5 3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio]-
N, N-Dimethyl-1H-1,2,4-triazole-1-carboxamide 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyrimidine (465 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethylsulfoxide (5 ml) solution, dimethylcarbamoyl chloride (0.258 ml, 2.8 mm)
ol) was added and the mixture was stirred at room temperature for 2 days. Water (20 ml) in the reaction mixture
Was added and extracted with methylene chloride (10 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (469 mg, yield 77%).
Was obtained as white-yellow crystals. Melting point 149.9-150.3 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.20 (6H, brs), 4.60 (2H, d,
J = 0.8Hz), 6.85 (1H, dd, J = 6.0, 4.0Hz), 7.55 (1
H, s), 8.35 (1H, dd, J = 6.6, 2.2Hz), 8.52 (1H, d
d, J = 4.0, 2.2Hz), 8.73 (1H, s) .IR (KBr): 1701, 1507, 1483, 1402, 1240 cm ⁻¹ . Elemental analysis value Calculated as C ₁₂ H ₁₃ N ₇ OS (% ): C, 47.51; H, 4.32; N, 32.32. Actual value (%): C, 47.13; H, 4.38; N, 31.98. Example 6 3-[(imidazo [1,2-a] pyrimidine-2 -Ylmethyl) sulfonyl] -N, N-dimethyl-1H-1,2,4-triazole-1-carboxamide 3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio]-
N, N-Dimethyl-1H-1,2,4-triazole-1-carboxamide (400 mg, 1.32 mmol) in methanol (5 ml) -water (10 ml)
Concentrated sulfuric acid (0.045 ml) and oxone (1217 mg, 1.98 m) were added to the solution.
mol) was added and the mixture was stirred at room temperature for 12 hours. Water (10 m
l) was added, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography (ethyl acetate: methanol = 10/1 → 2
(1/1, v / v) and crystallized from diisopropyl ether to give the title compound (111 mg, yield 25%) as white crystals. Melting point 215.6-217.1 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.95 (3H, brs), 3.05 (3H, b
rs), 5.06 (2H, s), 7.07 (1H, dd, J = 6.6, 4.0Hz),
7.95 (1H, s), 8.52 (1H, dd, J = 4.0, 2.0Hz), 8.98
(1H, dd, J = 6.6, 2.2Hz), 9.36 (1H, s). Elemental analysis calculated as C ₁₂ H ₁₃ N ₇ O ₃ S (%): C, 42.98; H, 3.91; N, 29.24 Actual value (%): C, 42.81; H, 3.62; N, 19.14.

Example 7 N, N-diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyrimidine (232 mg, 1 mmol) and potassium carbonate (166 mg, 1.2 mmol) in dimethyl sulfoxide (2.5 ml)
Diethylcarbamoyl chloride (0.18 ml, 1.4 m
mol) was added and the mixture was stirred at room temperature for 2 days. Water (20 ml) in the reaction mixture
Was added and extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (268 mg, yield 81
%) As white yellow crystals. Melting point 134.1-134.2 ℃ ¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, t, J = 7.0Hz), 3.40
-3.70 (4H, m), 4.60 (2H, s), 6.85 (1H, dd, J = 6.
6, 4.0Hz), 7.56 (1H, s), 8.35 (1H, dd, J = 6.6, 2.
2Hz), 8.53 (1H, dd, J = 4.0, 2.2Hz), 8.76 (1H, s) .IR (KBr): 1698,1507,1431,1271,1254 cm ^-1 Elemental analysis C ₁₄ H ₁₇ N ₇ Calculated as OS (%): C, 50.74; H, 5.17; N, 29.59. Measured value (%): C, 50.28; H, 5.08; N, 29.26.Example 8 N, N-diethyl-3- [(Imidazo [1,2-a] pyrimidin-2-ylmethyl) sulfinyl] -1H-1,2,4-triazole-1-carboxamide N, N-diethyl-3-[(imidazo [1,2-a] Pyrimidin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide (100 mg, 0.3 mmol) in methylene chloride (10 ml) in m-
Add chloroperbenzoic acid (216 mg, 0.87 mmol) and add 2 at room temperature.
It was stirred for 4 hours. A saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml). The organic layer was saturated brine (20
(ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography (ethyl acetate: methanol = 10/1, v /
Purification by v) gave the title compound (11 mg, yield 10%) as white crystals. Melting point 182.3-182.7 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, t, J = 6.6Hz), 3.40
-3.70 (4H, m), 4.72 (2H, s), 6.89 (1H, dd, J = 6.
6, 4.0Hz), 7.66 (1H, s), 8.39 (1H, dd, J = 6.6, 1.
8Hz), 8.56 (1H, dd, J = 4.0, 1.8Hz), 8.91 (1H, s) .IR (KBr): 1705, 1507, 1435, 1275, 1059cm ^-1 .

Example 9 N, N-Diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide N, N- Diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide (465 mg, 2 mmol) in methanol (10 ml)- Concentrated sulfuric acid (0.068 ml) and oxone (1.844 g, 3 mm) in water (20 ml) under ice cooling.
ol) was added and the mixture was stirred at room temperature for 5 hours. 1N to the reaction mixture under ice cooling
The pH was adjusted to 8 by adding an aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride (30 ml × 2). The organic layer was saturated with brine (30 m
l) Washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (289 mg, yield 40%) as white crystals. Melting point 209.2-210.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (6H, m), 3.40-3.60
(4H, m), 4.93 (2H, s), 6.90 (1H, dd, J = 6.9, 4.2H
z), 7.81 (1H, s), 8.43 (1H, dd, J = 6.9, 1.2Hz),
8.53 (1H, dd, J = 4.2, 1.2Hz), 8.84 (1H, s). IR (KBr): 1707, 1508, 1433, 1325, 1267, 1144 c
m ⁻¹ . Elemental analysis value Calculated as C ₁₄ H ₁₇ N ₇ O ₃ S (%): C, 46.27; H, 4.72; N, 26.98. Measured value (%): C, 46.14; H, 4.59; N , 26.80. Example 10 3-{[(3-chloroimidazo [1,2-a] pyrimidin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-Carboxamide N, N-diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide (100 mg, 0.401 mmol) Solution of N-N-dimethylformamide (1 ml) in N-chlorosuccinimide (98%
Content, 56 mg, 0.413 mmol) were added, and the mixture was stirred at room temperature for 23 hours. Water (10 ml) was added to the reaction mixture, and methylene chloride (10 ml) was added.
It was extracted with. The organic layer was washed with saturated saline (10 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to flash silica gel chromatography.
It was purified by (methylene chloride: methanol = 20/1, v / v) and crystallized from diisopropyl ether-ethyl acetate to give the title compound (74 mg, yield 67%) as white crystals. Melting point 195.6-196.0 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (6H, m), 3.40-3.70
(4H, m), 4.92 (2H, s), 7.04 (1H, dd, J = 6.0, 4.0H
z), 8.37 (1H, dd, J = 6.6, 2.0Hz), 8.58 (1H, dd, J
= 4.0, 2.0Hz), 8.87 (1H, s) .IR (KBr): 1717, 1501, 1437, 1346, 1146 cm ^-1 . Elemental analysis value calculated as C ₁₄ H ₁₆ ClN ₇ O ₃ S (%) : C, 42.27; H, 4.05; N, 24.64. Actual value (%): C, 42.00; H, 3.81; N, 24.62.

Example 11 N, N-diethyl-3-[(imidazo [1,2-b] pyridazin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine (331 mg, 1.43 mmol) and potassium carbonate (237 mg, 1.7 mmol) in dimethyl sulfoxide (2.5 m
l) Diethylcarbamoyl chloride (0.218 ml, 1.
(7 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water (20
ml) was added and the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to flash silica gel chromatography (ethyl acetate: hexane = 10 /
It was subjected to 1 → ethyl acetate, v / v) and crystallized from diisopropyl ether to give the title compound (383 mg, yield 81%) as white-yellow crystals. Melting point 122.5-122.8 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7.2Hz), 3.40
-3.70 (4H, m), 4.59 (2H, s), 7.02 (1H, dd, J = 9.
0, 4.5Hz), 7.44 (1H, dd, J = 4.5, 1.8Hz), 7.97 (1
H, s), 8.27 (1H, dd, J = 4.5, 1.8Hz), 8.77 (1H,
s) .IR (KBr): 1698,1530, 1476, 1431, 1333, 1273, 1236
cm ^-1 . Elemental analysis value C ₁₄ H ₁₇ N ₇ Calculated value as OS (%): C, 50.71, 5.17, 29.59. Measured value (%): C, 50.77, 5.24, 29.62. Example 12 N, N- Diethyl-3-[(imidazo [1,2-b] pyridazin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide N, N-diethyl-3-[(imidazo [1, 2-b] Pyridazin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide (200 mg, 0.604 mmol) in methanol (8 ml) -water (5 ml)
Add concentrated sulfuric acid (0.02 ml) and oxone (557 mg, 0.91 mmo) to the solution.
l) was added and the mixture was stirred at room temperature for 15 hours. 1N to the reaction mixture under ice cooling
The pH was adjusted to 8 by adding an aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was saturated with brine (20 m
l) Washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Flash silica gel chromatography of the residue
It was then subjected to (ethyl acetate → ethyl acetate: methanol = 10/1, v / v) and crystallized from diisopropyl ether to give the title compound (148 mg, yield 67%) as white crystals. Melting point 133.5-134.8 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (6H, m), 3.40-3.60
(4H, m), 4.94 (2H, s), 7.05 (1H, dd, J = 9.0, 4.5H
z), 7.85 (1H, dd, J = 9.0, 1.5Hz), 8.12 (1H, s), 8.
82 (1H, dd, J = 4.5, 1.5Hz), 8.89 (1H, s) .IR (KBr): 1713, 14535, 1337, 1265 cm ^-1 . Elemental analysis value C ₁₄ H ₁₇ N ₇ O ₃ S Calculated (%): C, 46,27; H, 4.72; N, 26.98. Measured (%): C, 46.26; H, 4.68; N, 26.90.

Example 13 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] thio} -N, N-diethyl-1H-1,2,4-triazole-1 -Carboxamide 6-chloro-2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine (500 mg, 1.87 mmol) and potassium carbonate (310 mg, 2.2 Dimethylsulfamoyl chloride (0.3 mmol) in dimethyl sulfoxide (5 mol) solution
(32 ml, 2.62 mmol) was added and the mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (591
mg, yield 86%) was obtained as white yellow crystals. Melting point 104.0-105.0 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7.0Hz), 3.5
7 (4H, q, J = 7.0Hz), 4.56 (2H, s), 7.03 (1H, d, J
= 9.6Hz), 7.84 (1H, d, J = 9.6Hz), 7.92 (1H, s),
8.76 (1H, s) .IR (KBr): 1698, 1520, 1431, 1271, 1254, 1098 cm
^-1 . Elemental analysis value C ₁₄ H ₁₆ ClN ₇ Calculated value as OS (%): C, 45.96; H, 4.41; N, 26.80. Measured value (%): C, 45.88; H, 4.28; N, 26.73. Example 14 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-carboxamide 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] thio} -N, N-diethyl-1H-1,2,4-triazole-1-carboxamide ( 200 mg, 0.55 mmol) in methanol (10 ml)-
Concentrated sulfuric acid (0.018 ml) and oxone (504 mg, in a water (8 ml) solution.
0.82 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 8 with 1N aqueous sodium hydroxide solution under ice cooling, and the precipitated powder was collected by filtration. The obtained powder is subjected to flash silica gel chromatography (ethyl acetate → ethyl acetate:
Methanol = 10/1, v / v), the first eluate was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (111 mg, yield 51%) as white crystals. Melting point 169.0-169.5 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (6H, m), 3.40-3.7
0 (4H, m), 4.92 (2H, s), 7.07 (1H, d, J = 9.4Hz),
8.81 (1H, d, J = 9.4Hz), 8.06 (1H, s), 8.89 (1H,
s) .IR (KBr): 1713, 1522, 1345, 1294, 1265, 1146, 1096
cm ⁻¹ . Elemental analysis value Calculated as C ₁₄ H ₁₆ ClN ₇ O ₃ S (%): C, 42.27; H, 4.05; N, 24.64. Measured value (%): C, 42.29; H, 4.01; N , 24.71. Example 15 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] sulfinyl} -N, N-diethyl-1H-1,2,4-triazole-1 -Carboxamide The second eluate in the flash silica gel column chromatography performed in Example 14 was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (20 mg, yield 10%) as white crystals. Melting point 160.2-164.8 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7.0Hz), 3.4
0-3.70 (4H, m), 4.73 (2H, d, J = 2.2Hz), 7.07 (1H,
d, J = 9.0Hz), 7.83 (1H, d, J = 9.0Hz), 7.94 (1H,
s), 8.94 (1H, s) .IR (KBr): 1707, 1522, 1433, 1292, 1275, 1098 cm ^-1 .

Example 16 3-{[(3-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-Carboxamide N, N-diethyl-3-[(imidazo [1,2-b] pyridazin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide (64 mg, 0.177 mmol) Solution of N-N-dimethylformamide (1 ml) in N-chlorosuccinimide (98%
Content, 58 mg, 0.425 mmol) were added, and the mixture was stirred at room temperature for 30 hours. Water (10 ml) was added to the reaction mixture, and methylene chloride (10 ml) was added.
It was extracted with. The organic layer was washed with saturated saline (10 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to flash silica gel chromatography.
Purification with (ethyl acetate: hexane = 1/1 → ethyl acetate, v / v) gave the title compound (3.8 mg, yield 5%). ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.35 (6H, m), 3.40-3.70
(4H, m), 4.94 (2H, s), 7.12 (1H, dd, J = 9.6, 4.4H
z), 7.89 (1H, dd, J = 9.6, 1.4Hz), 8.46 (1H, dd, J
= 4.4, 1.4Hz), 8.91 (1H, s). IR (KBr): 1715, 1435, 1337, 1265, 1208, 1152 c
m ⁻¹ .Example 17 2-({[1- (1-pyrrolidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (412 mg, 1.57 mmol) and potassium carbonate (260 mg, 1.9 mmol) in dimethyl sulfoxide (5
1-pyrrolidinyl carbonyl chloride (0.277
(ml, 2.5 mmol) was added, and the mixture was stirred at room temperature for 2 days. Water (30 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (25 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (4
85 mg, yield 86%) was obtained as white crystals. Melting point 181.9-184.7 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.82-1.99 (4H, m), 3.62-3.69
(2H, m), 3.74 (2H, m), 4.90 (2H, s), 6.81 (1H, td,
J = 7.0, 1.0Hz), 7.17 (1H, ddd, J = 9.0,7.0, 1.0
Hz), 7.48 (1H, dd, J = 9.0, 1.0Hz), 7.77 (1H, s),
8.09 (1H, dt, J = 7.0, 1.0Hz), 8.95 (1H, s) Elemental analysis C ₁₅ H ₁₆ N ₆ O ₃ Calculated S (%):. C, 49.99; H, 4.47; N, 23.32. Found (%): C, 49.71; H, 4.25; N, 23.14.

Example 18 2-({[1- (1-piperidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2 -[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (526.6 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethyl sulfoxide (5
mol) solution to piperidinyl carbonyl chloride (0.35 m
(1, 3.6 mmol) was added, and the mixture was stirred at room temperature for 2 days. Water (30 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate / hexane = 5/1 → ethyl acetate) and crystallized from diisopropyl ether to give the title compound (426 mg, yield 57%) as white crystals. It was Melting point 154.0-154.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.80 (6H, m), 3.60-3.70
(4H, m), 4.90 (2H, s), 6.80 (1H, td, J = 7.0, 1.0H
z), 7.17 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.47 (1
H, dt, J = 9.2, 1.0Hz), 7.76 (1H, s), 8.08 (1H, d
t, J = 7.0, 1.0Hz), 8.81 (1H, s). IR (KBr): 1717, 1441, 1335, 1250, 1236, 1146 c
m ⁻¹ . Elemental analysis value Calculated value as C ₁₆ H ₁₈ N ₆ O ₃ S (%): C, 51.33; H, 4.85; N, 22.45. Measured value (%): C, 51.34; H, 4.91; N 22.28.Example 19 3-chloro-2- (dichloro {[1- (1-piperidinylcarbonyl))
-1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2-({[1- (1-piperidinylcarbonyl) -1H-1,2, 4-Triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine (200 mg, 0.534 mmol) in N, N-dimethylformamide (2.5 ml) under ice cooling under N-chlorosuccinimide (98%
Content, 306 mg, 2.25 mmol) were added, and the mixture was stirred at room temperature for 48 hours. Water (20 ml) was added to the reaction solution, and methylene chloride (20 ml ×
Extracted in 2). After washing the organic layer with saturated saline (20 ml),
It was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 2/3 → ethyl acetate, v / v) and crystallized from diisopropyl ether to give the title compound (93 mg, yield Rate 37%). Melting point 187.6-190.0 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.50-1.80 (6H, m), 3.60-3.80
(4H, m), 7.05 (1H, td, J = 7.0, 1.0Hz), 7.37 (1H,
ddd, J = 9.2, 7.0, 1.0Hz), 7.59 (1H, dt, J = 9.2,
1.0Hz), 8.16 (1H, dt, J = 7.0, 1.0Hz), 8.77 (1H,
IR (KBr): 1721, 1437, 1366, 1244, 1155 cm ⁻¹ . Elemental analysis value calculated as C ₁₆ H ₁₅ Cl ₃ N ₆ O ₃ S (%): C, 40.22; H, 3.16; N, 17.59. Found (%): C, 40.13; H, 3.14; N, 17.29.

Example 20 2-({[1- (4-morpholinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2 -[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (526.6 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethyl sulfoxide (3
mol) solution with 4-morpholinyl carbonyl chloride (0.327
(ml, 2.8 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (30 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (6
33 mg, yield 84%) was obtained as white crystals. Melting point 204.1-205.0 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.60-3.90 (8H, m), 4.89 (2H,
s), 6.82 (1H, td, J = 6.6, 1.2Hz), 7.18 (1H, ddd,
J = 9.0, 6.6, 1.2Hz), 7.45 (1H, dd, J = 9.0, 1.2
Hz), 7.78 (1H, s), 8.09 (1H, dt, J = 6.6, 1.2Hz),
8.86 (1H, s). Elemental analysis value Calculated as C ₁₅ H ₁₆ N ₆ O ₄ S (%): C, 47.87; H, 4.28; N, 22.33. Actual value (%): C, 47.81; H, 4.72; N, 22.10.Example 21 3-chloro-2-({[1- (1-pyrrolidinylcarbonyl) -1H-1,2,
4-triazol-3-yl] sulfonyl} methyl) imidazo
[1,2-a] Pyridine 2-({[1- (1-pyrrolidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] Pyridine (360 mg, 1 mmol) in N, N-dimethylformamide (5
(ml) solution under ice cooling, N-chlorosuccinimide (98% content,
(204 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Water (20 ml) was added to the reaction solution, extracted with methylene chloride (20 ml × 2), washed with saturated saline solution (20 ml), and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (ethyl acetate: hexane = 5/1 → ethyl acetate → ethyl acetate: methanol = 10/1, v
/ v) and crystallized from diisopropyl ether to give the title compound (78 mg, yield 20%) as white crystals. Melting point 195.9-197.3 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.97 (4H, m), 3.64-3.71
(2H, m), 3.79-3.86 (2H, m), 4.90 (2H, s), 6.96 (1H,
td, J = 6.6, 1.0Hz), 7.25 (1H, ddd, J = 9.2, 6.
6, 1.0Hz), 7.50 (1H, dt, J = 9.2, 1.0Hz), 8.04 (1
. H, dt, J = 6.6,1.0Hz ), 8.98 (1H, s) Elemental analysis C ₁₅ H ₁₅ ClN ₆ O ₃ Calculated S (%): C, 45.63 ; H, 3.83; N, 21.28. Found (%): C, 45.77; H, 3.80; N, 20.73.

Example 22 3-chloro-2-({[1- (4-morpholinylcarbonyl) -1H-1,2,
4-triazol-3-yl] sulfonyl} methyl) imidazo
[1,2-a] Pyridine 2-({[1- (4-morpholinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] N-chlorosuccinimide (98% content, 80 mg, 0.59 mmol) was added to a solution of pyridine (200 mg, 0.53 mmol) in N, N-dimethylformamide (4 ml) under ice cooling, and the mixture was stirred at room temperature for 20 hours. .
Further N-chlorosuccinimide (98% content, 36 mg, 0.27 mm
ol) was added and the mixture was stirred at 55 ° C. for 3 hours. Water (20 ml) in the reaction mixture
Was added, extracted with methylene chloride (20 ml), and saturated saline (20 ml).
(ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (ethyl acetate → ethyl acetate: methanol = 10/1,
The product was purified by v / v) and crystallized from diisopropyl ether to give the title compound (59 mg, yield 27%) as white crystals. Melting point 160.3-161.2 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.60-4.00 (8H, m), 4.90 (2H,
s), 6.97 (1H, td, J = 7.0, 1.0Hz), 7.25 (1H, ddd,
J = 9.0, 7.0, 1.0Hz), 7.46 (1H, dt, J = 9.0, 1.0
Hz), 8.03 (1H, dt, J = 7.0, 1.0Hz), 8.91 (1H, s). Elemental analysis calculated as C ₁₅ H ₁₅ ClN ₆ O ₄ S (%): C, 43.85; H, 3.68 N, 20.46.Actual value (%): C, 43.29; H, 3.58; N, 20.37 Example 23 3-chloro-2-({[1- (1-piperidinylcarbonyl) -1H-1,2 ,
4-triazol-3-yl] sulfonyl} methyl) imidazo
[1,2-a] Pyridine 2-({[1- (1-piperidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] N-chlorosuccinimide (98%) was added to a solution of pyridine (150 mg, 0.401 mmol) in N, N-dimethylformamide (1.5 ml) under ice cooling.
Content, 64 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 20 hours. N-chlorosuccinimide (98% content, 16 mg, 0.12 mm
ol) was further added, and the mixture was stirred at room temperature for 2 hours. Water (2
0 ml) was added, and the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with saturated saline (20 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 10/1, v / v) and crystallized from diisopropyl ether to give the title compound (52 mg, yield 32%) ) Got. Melting point 151.2-151.3 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.80 (6H, m), 3.60-3.80
(4H, m), 4.90 (2H, s), 6.96 (1H, td, J = 6.8, 1.0H
z), 7.13 (1H, ddd, J = 9.2, 6.8, 1.0Hz), 7.49 (1
H, dt, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 6.8,
1.0Hz), 8.84 (1H, s) .IR (KBr): 1717, 1439, 1341, 1250, 1236, 1146 c
m ⁻¹ . Elemental analysis value Calculated as C ₁₆ H ₁₇ ClN ₆ O ₃ S (%): C, 47.00; H, 4.19; N, 20.55. Actual value (%): C, 46.84; H, 4.41; N , 20.19.

Example 24 3-[(2-Methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide 2-methoxybenzyl chloride (0.39 g, 2.5 mmol), 3-mercapto-1,2,4-triazole (0.25 g, 2.5 mmol) and potassium carbonate (0.35 g, 2.5 mmol) in N, The N-dimethylformamide (4 ml) solution was stirred at room temperature for 1 hour. In the reaction solution,
Dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol) was added, and the mixture was further stirred at room temperature for 1 hr. Water (10 mL) was added to the reaction solution, and the mixture was extracted with methylene chloride (2 mL). The organic layer was separated, purified by silica gel chromatography (ethyl acetate: hexane = 3/1 → 1/3, v / v), and crystallized from diisopropyl ether / ethyl acetate to give the title compound (497 mg, yield
68%). Melting point 80.6-81.3 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.22 (6H, s), 3.87 (3H, s),
4.41 (2H, s), 6.80-6.90 (2H, m), 7.20-7.30 (1H, m),
7.35-7.40 (1H, m), 8.73 (1H, s). Elemental analysis calculated as C ₁₃ H ₁₆ N ₄ O ₂ S (%): C, 53.41; H, 5.52; N, 19.16. %): C, 53.42; H, 5.41; N, 19.07. Example 25 3-[(2-Methoxybenzyl) sulfonyl] -N, N-dimethyl-1H
-1,2,4-triazole-1-carboxamide 3-[(2-methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
To a solution of -triazole-1-carboxamide (0.38 g, 1.3 mmol) in methylene chloride (3.5 mL) was added m-chloroperbenzoic acid (0.51 g, 2.1 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. . The reaction solution was washed with saturated aqueous sodium hydrogen carbonate (4 mL) and then subjected to silica gel chromatography (ethyl acetate: hexane = 1/1, v /
(v → ethyl acetate), the first eluate was concentrated under reduced pressure, and crystallized from diisopropyl ether / ethyl acetate to give the title compound (263 mg, yield 63%). Melting point 134.1-135.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.17 (6H, s), 3.68 (3H, s),
4.74 (2H, s), 6.80-6.85 (1H, m), 6.90-7.00 (2H, m),
7.25-7.40 (1H, m), 8.86 (1H, s). Elemental analysis value Calculated as C ₁₃ H ₁₆ N ₄ O ₄ S (%): C, 48.14; H, 4.97; N, 17.27. %): C, 48.18; H, 5.15; N, 16.89. Example 26 3-[(2-methoxybenzyl) sulfinyl] -N, N-dimethyl-
1H-1,2,4-triazole-1-carboxamide The second eluate in the flash silica gel column chromatography performed in Example 25 was concentrated to give the title compound (105 mg, 22%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.17 (3H, brs), 3.19 (3H, br
s), 3.83 (3H, m), 4.52 (1H, d, J = 12.0 Hz), 4.67
(1H, d, J = 12.0 Hz), 6.80-6.90 (2H, m), 7.05 (1H,
dd, J = 1.8, 7.5 Hz), 7.25-7.35 (1H, m), 8.90 (1H,
s).

Example 27 3-[(3-Methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide 3-methoxybenzyl chloride (0.39 g, 2.5 mmol), 3-
Mercapto-1,2,4-triazole (0.25 g, 2.5 mmol),
The title compound (641 mg, yield 88%) was obtained from potassium carbonate (0.35 g, 2.5 mmol) and dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol) in the same manner as in Example 23. Melting point 64.6-66.3 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.16 (6H, s), 3.67 (3H, s),
4.73 (2H, s), 6.81 (1H, dm, J = 8.1 Hz), 6.92 (1H,
dt, J = 1.2, 8.1 Hz), 7.25-7.35 (2H, m), 8.73 (1H,
s). Example 28 3-[(3-Methoxybenzyl) sulfonyl] -N, N-dimethyl-1H
-1,2,4-triazole-1-carboxamide 3-[(3-methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide (0.48 g, 1.6 mmol) and m-chloroperbenzoic acid (0.65 g, 2.6 mmol)
By a method similar to 25, the title compound (241 mg, yield 45%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (6H, s), 3.77 (3H, s),
4.61 (2H, s), 6.80-6.90 (3H, m), 7.15-7.25 (1H, m),
8.87 (1H, s). Elemental analysis calculated as C ₁₃ H ₁₆ N ₄ O ₄ S (%): C, 48.14; H, 4.97; N, 17.27. Actual measurement (%): C, 47.77; H, 4.86; N, 17.07.

Example 29 3-[(3-Methoxybenzyl) sulfinyl] -N, N-dimethyl-
1H-1,2,4-triazole-1-carboxamide The title compound (227 mg, 45%) was obtained as an oil by a method similar to that in Example 26. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (6H, s), 3.76 (3H, s),
4.41 (1H, d, J = 12.9 Hz), 4.52 (1H, d, J = 12.9 H
z), 6.70-6.85 (2H, m), 7.05-7.25 (2H, m), 8.90 (1
H, s). Example 30 3-[(4-Methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide 4-methoxybenzyl chloride (0.39 g, 2.5 mmol), 3-
Mercapto-1,2,4-triazole (0.25 g, 2.5 mmol),
The title compound (622 mg, yield 85%) was obtained from potassium carbonate (0.35 g, 2.5 mmol) and dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol) in the same manner as in Example 23. Melting point 95.0-96.0 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.21 (6H, s), 3.79 (3H, s),
4.33 (2H, s), 6.80-6.90 (2H, m), 7.25-7.35 (2H, m),
8.73 (1H, s). Elemental analysis value Calculated value as C ₁₃ H ₁₆ N ₄ O ₂ S (%): C, 53.41; H, 5.52; N, 19.16. Actual value (%): C, 53.43; H, 5.48; N, 18.88.

Example 31 3-[(4-Methoxybenzyl) sulfonyl] -N, N-dimethyl-1H
-1,2,4-triazole-1-carboxamide 3-[(4-methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide (0.47 g, 1.6 mmol) and m-chloroperbenzoic acid (0.64 g, 2.6 mmol)
The title compound (241 mg, yield 45%) was obtained by a method similar to that of 25. Melting point 121.5-121.6 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.16 (6H, s), 3.78 (3H, s),
4.58 (2H, s), 6.83 (2H, dd, J = 2.1, 6.6 Hz), 7.20
(2H, dd, J = 2.1, 6.6 Hz), 8.87 (1H, s). Elemental analysis calculated as C ₁₃ H ₁₆ N ₄ O ₄ S (%): C, 48.14; H, 4.97; N, 17.27 Actual value (%): C, 48.19; H, 4.96; N, 17.20. Example 32 3-[(4-methoxybenzyl) sulfinyl] -N, N-dimethyl-
1H-1,2,4-triazole-1-carboxamide The title compound (211 mg, 42%) was obtained as an oil by the same method as in Example 26. ¹ H-NMR (CDCl ₃ ) δ: 3.15 (6H, s), 3.77 (3H, s),
4.35-4.55 (2H, m), 6.70-6.90 (2H, m), 7.05-7.25 (2
H, m), 8.89 (1H, s).

Example 33 N, N-Dimethyl-3-[(2-oxo-2-phenylethyl) thio] -1
H-1,2,4-triazole-1-carboxamide 2-bromoacetophenone (0.50 g, 2.5 mmol), 3-mercapto-1,2,4-triazole (0.25 g, 2.5 mmol), potassium carbonate (0.35 g, The title compound (554 mg, yield 76%) was obtained by the same method as in Example 23 from 2.5 mmol) and dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol). Melting point 91.7-92.2 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.14 (6H, s), 4.68 (2H, s),
7.45-7.55 (2H, m), 7.60-7.65 (1H, m), 8.00-8.05 (2
H, m), 8.70 (1H, s). Elemental analysis value Calculated as C ₁₃ H ₁₄ N ₄ O ₂ S (%): C, 53.78; H, 4.86; N, 19.30. Measured value (%): C , 53.94; H, 4.97; N, 19.22. Example 34 N, N-Dimethyl-3-[(2-oxo-2-phenylethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide N , N-Dimethyl-3-[(2-oxo-2-phenylethyl) thio] -1
H-1,2,4-triazole-1-carboxamide (0.41 g, 1.4
mmol) and m-chloroperbenzoic acid (0.55 g, 2.3 mmol) and in the same manner as in Example 25, the title compound (212 mg, yield 47%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.19 (3H, brs), 3.30 (3H, br
s), 5.04 (2H, s), 7.45-7.55 (2H, m), 7.60-7.70 (1
H, m), 7.90-8.00 (2H, m), 8.89 (1H, s). Elemental analysis calculated as C ₁₃ H ₁₄ N ₄ O ₄ S (%): C, 48.44; H, 4.38; N, 17.38. Found (%): C, 48.31; H, 4.41; N, 17.19.

Example 35 N, N-Dimethyl-3-[(2-oxo-2-phenylethyl) sulfinyl] -1H-1,2,4-triazole-1-carboxamide Obtained by a method similar to that in Example 26. The oily product was crystallized from diisopropyl ether / ethyl acetate to give the title compound (211 mg,
42%). Melting point 129.6-132.0 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.18 (3H, brs), 3.31 (3H, br
s), 4.92 (1H, d, J = 15.3 Hz), 5.11 (1H, d, J = 1
5.3 Hz), 7.45-7.55 (2H, m), 7.60-7.70 (1H, m), 7.90
-8.00 (2H, m), 8.87 (1H, s). Elemental analysis value Calculated as C ₁₃ H ₁₄ N ₄ O ₃ S (%): C, 50.97; H, 4.61; N, 18.29. Measured value (% ): C, 51.02; H, 4.61; N, 18.22.

Experimental Example 1 1) Preparation of dipeptidyl peptidase IV crude enzyme solution Regarding the enzymatic activity of dipeptidyl peptidase IV present in the human colon adenocarcinoma cell line Caco-2 cell membrane,
Already reported by Yong S. Chung et al. (Cancer Research
rch), 45, 2976-2982, 1985.
Years). A crude dipeptidyl peptidase IV enzyme solution was prepared from cultured cells of Caco-2 (ATCC HTB-37). Caco-2 cells are 10% FBS
The cells were cultured in a D-MEM medium (manufactured by Nissui) containing (fetal bovine serum, manufactured by Gibco). The cell extract is
The cells collected after removing the medium were treated with 0.5% Triton X-
It was prepared by immersing in 20 mM phosphate buffer (pH 7.5) containing 100, extracting for 30 minutes in an ice bath, and centrifuging at 1500 g for 30 minutes, and separating the supernatant. 20 ml of cell extract 22 ml
Sephadex G-200 (600 ml, Pharmacia) prepared with M Tris-HCl buffer (pH 7.5)
The sample was developed and eluted with the same buffer solution. Fractions of 10 ml each were examined for enzyme activity, and 190 ml to 280 ml fractions (90 ml) were collected. The same buffer solution (260 ml) was added to dilute to give a crude enzyme solution (14 mU / ml, 350 ml). However, 1 U of dipeptidyl peptidase IV enzyme activity
Is the amount of enzyme that produces 1 μmol of p-nitroaniline from glycyl prolyl-p-nitroanilide per minute. 2) Caco-2 derived dipeptidyl peptidase IV
The assay reaction of the inhibitory activity is carried out by the method of Nagatu et al. (Analytical Biochemistry).
try), Vol. 74, 466-467, 1976) using a 96-well flat bottom plate at 37 ° C. 25 μl water, 1M Tris-HCl buffer (pH 7.
5) 10 μl, 1 mM glycyl prolyl-p-nitroanilide (Gly-Pro-p-NA; manufactured by Backchem)
A mixed solution was prepared by adding 5 μl of an N, N-dimethylformamide solution of the test compound to 50 μl of the aqueous solution. Then, 10 μl of the Caco-2-derived dipeptidyl peptidase IV crude enzyme solution obtained in 1) was added to the above mixed solution, and the enzyme reaction was started at 37 ° C. The absorbance after 0 hours and 3 hours was measured at a wavelength of 405 nm using a microplate reader (multiscan bichromatic; manufactured by Lab Systems) to increase the absorbance (ΔOD
s) was calculated. At the same time, an increase in absorbance in the reaction solution containing no test compound (ΔODc) and an increase in absorbance in the reaction solution containing no test compound (ΔOD)
b) is calculated, and the inhibition rate of dipeptidyl peptidase IV enzyme activity is calculated by the formula: {1-[(ΔODs-ΔODb) / (ΔODc-ΔOD
b)]} × 100. The dipeptidyl peptidase IV inhibitory activity of the test compound group was expressed as an IC ₅₀ value (μM) and is shown in [Table 1]. [Table 1] Test compound IC ₅₀ value (Example No.) (μM) 3 1.0 As described above, compound (I) has excellent dipeptidyl peptidase IV enzyme activity, and is therefore useful as a drug for preventing or treating diabetes. .

Experimental Example 2 Measurement of dipeptidyl peptidase IV inhibitory activity in rat plasma was carried out by the method of Raymond et al. (Diabetes, Vol. 47, 1253).
-1258, 1998) using a 96-well flat bottom plate at 30 ° C. 69 μl water, 1 M Tris-HCl buffer (pH 7.5) 10 μl, 1 mM Gly-
A mixed solution was prepared by adding 1 μl of an N, N-dimethylformamide solution of a test compound to 100 μl of a Pro-p-NA aqueous solution. Next, 20 μl of plasma prepared from SD rat blood by a conventional method was added to the above mixed solution, and the enzyme reaction was started at 30 ° C. The absorbance after 0 hour and 1 hour was measured at a wavelength of 405 nm using a microplate reader to determine the increase in absorbance (ΔODs). At the same time, the increase in absorbance in the reaction solution containing no test compound (ΔOD
c), the increase in absorbance (ΔODb) in the reaction solution containing no test compound or enzyme is calculated, and the inhibition rate of dipeptidyl peptidase IV enzyme activity is calculated by the formula: {1-[(ΔODs-ΔODb) / (Δ ODc- △ OD
b)]} × 100. The dipeptidyl peptidase IV inhibitory activity of the test compound group was expressed as an IC ₅₀ value (μM) and is shown in [Table 2]. [Table 2] Test compound IC ₅₀ value (Example No.) (μM) 3 2.4 As described above, since compound (I) has excellent dipeptidyl peptidase IV enzyme activity, it is useful as a drug for preventing or treating diabetes. .

Formulation Example 1 (Production of Capsule) 1) Compound of Example 3 30 mg 2) Finely powdered cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) And 4) are mixed and filled into a gelatin capsule. Formulation Example 2 (Production of tablets) 1) Compound of Example 3 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets Total 140 g 1), The whole amount of 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder, and the mixture is compressed with a tableting machine. Thus, 1 tablet of compound 30 of Example 3
1000 tablets containing mg are obtained.

[0079]

INDUSTRIAL APPLICABILITY The drug and peptidase inhibitor of the present invention are useful as a preventive or therapeutic drug for diabetes,
In addition, it has excellent properties such as drug efficacy, action time, specificity, and low toxicity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 3/04 A61P 3/04 3/10 3/10 43/00 111 43/00 111 C07D 249/12 513 C07D 249/12 513 471/04 108 108 471/04 108A 487/04 144 487/04 144 F Term (reference) 4C050 AA01 BB05 CC08 EE03 FF02 GG01 GG02 HH04 4C065 AA03 BB06 CC01 DD02 EE02 HH01 JJ01 CKK0LL02 PP01 409 CB05 MA01 MA04 NA14 NA15 ZA70 ZC20 ZC35

Claims (7)

[Claims] 1. The formula: [In the formula, A represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, n represents an integer of 0 to 2, R ¹ and R ² are the same or different, and a hydrogen atom Or represents an optionally substituted hydrocarbon group, or R
¹ and R ² together with an adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocycle, R ³ is a hydrogen atom,
Which represents a halogen atom or an optionally substituted hydrocarbon group] or a salt thereof or a prodrug thereof. 2. A preventive or therapeutic drug for diabetes.
The described medicine. 3. The medicine according to claim 1, which is a preventive or therapeutic drug for diabetic complications. 4. The medicine according to claim 1, which is a preventive or therapeutic drug for impaired glucose tolerance. 5. The medicine according to claim 1, which is a preventive or therapeutic drug for obesity. 6. The formula: [In the formula, A represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, n represents an integer of 0 to 2, R ¹ and R ² are the same or different, and a hydrogen atom Or represents an optionally substituted hydrocarbon group, or R
¹ and R ² together with an adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocycle, R ³ is a hydrogen atom,
Which represents a halogen atom or an optionally substituted hydrocarbon group] or a salt thereof or a prodrug thereof, and a peptidase inhibitor. 7. The inhibitor according to claim 6, wherein the peptidase is dipeptidyl peptidase-IV.