JPH0665222A - Thiazole derivative - Google Patents

Abstract

(57) [Summary] (Modified) [Objective] To provide a thiazole derivative having an excellent active oxygen suppressing action. [Structure] A thiazole derivative represented by the general formula (1). [Wherein R ¹ is a phenyl group substituted with ¹ to 3 lower alkoxy groups; R ² is a pyridylcarbonyl group optionally substituted with a lower alkoxycarbonyl group or a carboxyl group, a carboxyl group or a lower alkoxycarbonyl group A phenyl group substituted with
Represents a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic residue having 3] [Effect] The compound of the formula (1) is associated with ischemia and disorders associated with recanalization of blood. It is useful as a drug for protecting various tissue cells from the above; a therapeutic agent for cardiac ischemic diseases such as myocardial infarction and arrhythmia; and a therapeutic agent for cerebrovascular diseases such as cerebral hemorrhage, cerebral infarction, and transient ischemic attack.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel thiazole derivative.

[0002]

DISCLOSURE OF THE INVENTION The thiazole derivative of the present invention is a novel compound not described in the literature and is represented by the following general formula (1).

[0003]

[Chemical 6]

[In the formula, R ¹ represents a phenyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring. R ² is a pyridylcarbonyl group which may have a lower alkoxycarbonyl group or a carboxy group as a substituent; a 5- to 15-membered monocyclic ring, binary ring or tricyclic ring having 1 to 3 nitrogen, oxygen or sulfur atoms. Heterocyclic residue of a ring; or a group

[0005]

[Chemical 7]

(Wherein R ³ represents a carboxy group, a lower alkoxycarbonyl group, a hydroxyl group-substituted lower alkyl group, a lower alkoxy group, a tri-lower alkyl-substituted silyloxy group, a hydroxyl group or a hydrogen atom. R ⁴ represents a hydrogen atom or a lower alkenyl group. R ⁵ is an amino lower alkoxycarbonyl group which may have a lower alkyl group as a substituent, an amino lower alkoxy substituted lower alkyl group which may have a lower alkyl group as a substituent,
An amino lower alkoxy group which may have a lower alkyl group as a substituent, a lower alkoxy group which has a tetrahydropyranyloxy group or a hydroxyl group, and a phenylsulfonyloxy group-substituted lower which may have a lower alkyl group as a substituent on the phenyl ring Alkoxy group, hydroxysulfonyl group, amino lower alkanoyloxy-substituted lower alkyl group which may have a lower alkyl group as a substituent, lower alkynyloxy group, group-(CO) _l -NHR
⁶ (l represents 0 or 1; R ⁶ represents a hydroxyl group, a phenyl lower alkyl group, a carboxy group-substituted lower alkyl group, an amino group, an aminothiocarbonyl group which may have a benzoyl group, an amidino group, a group

[0007]

[Chemical 8]

(R ⁷ represents a lower alkylthio group or a morpholino lower alkylamino group), a hydrogen atom or a phenyl lower alkoxycarbonyl group-substituted lower alkyl group. ), An amino-substituted lower alkanoyloxy lower alkyl group which may have a lower alkyl group as a substituent, an aminothiocarbonyl group, a group

[0009]

[Chemical 9]

(R ⁸ represents a hydroxyimino group, a lower alkylthio group, a hydrazino group, a lower alkoxy group, a piperazinyl group which may have a lower alkyl group, a morpholino group or a morpholino lower alkylamino group),
A 1,3,4-oxadiazolyl group which may have a 1,2,3,4-tetrazolyl group or an oxo group is shown. ) Is shown. The monocyclic, bicyclic or heterocyclic heterocyclic residue has a lower alkyl group as a substituent, an oxiranyl group,
Hydroxyl-substituted lower alkyl group, lower alkanoyl group, lower alkanoyloxy lower alkyl group, cyano group, oxo group, carboxy-substituted lower alkyl group, lower alkyl group having a lower alkoxycarbonyl group or cyano group as a substituent, lower alkoxycarbonyl group, Lower alkyl group having 1 to 2 groups selected from the group consisting of pyridyl group, furyl group, phenyl group, carboxy group and hydroxyl group as a substituent, carboxy substituted lower alkoxy group, carboxy substituted lower alkylthio group, carboxy group, halogen atom ,
A lower alkoxy group, a hydroxyl group, group ^{_{- (A) l -NR 9 R}} 10
(A represents a lower alkylene group which may have a hydroxyl group as a substituent or a group -CO. L is the same as above. R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a lower alkyl group, a hydroxyl group, A pyrrolidinyl lower alkyl group, a carboxy-substituted lower alkyl group, or an amino-substituted lower alkyl group which may have a lower alkyl group or a phenyl lower alkoxycarbonyl group as a substituent.
⁹ and R ¹⁰ , together with the nitrogen atom to which they are bonded, may be bonded to each other via a nitrogen atom or an oxygen atom or not to form a 5- or 6-membered saturated or unsaturated heterocycle. The heterocycle may be substituted with a lower alkyl group or a carboxy group. ), Amidino groups, aminothiocarbonyl groups and groups

[0011]

[Chemical 10]

(R ^8a represents a hydroxyamino group or a lower alkylthio group), and may have 1 to 3 groups selected from the group consisting of. ] Neutrophils to enemy which enters at the living body, migration reaction, phagocytosis, active oxygen O ₂ ^- production, shows a bactericidal effect by the release of lysosomal enzymes, play an important role in host defense Are believed to be present. However, along with this biological defense reaction, active oxygen released by tissues or neutrophils during ischemia of each tissue and subsequent reperfusion of blood, or during inflammation in the acute phase destroys cells and impairs tissue function. It has been clarified that it causes disability [BRLucchesi, Annual Review of Pharmacology and Toxicology (Ann.Rev.Pharma
col.Toxicol.), 26 , 201 (1986); BAFree
man et al. , Laboratory Investigation, 47 , 412 (198)
2); E. Braunwald., RAKloner, Journal of
Clinical Investigation (J.Clin. Inves
t.), 76 , 1713 (1985); JL Romsonet a.
l. , Circulation, 67 , 10
16 (1983)].

The compound of the present invention represented by the above general formula (1) has an activity of suppressing the release of active oxygen from neutrophils or removing active oxygen species. Therefore, it exerts the action of preventing the production of lipid peroxide in the living body or the action of reducing it. Therefore, the compound of the present invention is useful as a prophylactic and therapeutic agent for various disorders or diseases caused by excessive generation of reactive oxygen species, bioaccumulation of lipid peroxide, or lack of defense mechanism against these. More specifically, the compound of the present invention is a drug that protects various tissue cells from ischemia and damage associated with recanalization of blood, for example, a therapeutic agent for digestive ulcers such as stress ulcers; myocardial infarction Therapeutic agent for cardiac ischemic diseases such as arrhythmia; Therapeutic agent for cerebrovascular diseases such as cerebral hemorrhage, cerebral infarction, transient cerebral ischemic attack; Liver and renal function improving agent for disorders such as transplantation and microcirculatory insufficiency; or , Agents that suppress various cellular disorders that are thought to be due to active oxygen abnormally generated due to causes other than ischemia, such as Behcet's disease, cutaneous vasculitis, ulcerative colitis, malignant rheumatism, arthritis, arteriosclerosis, diabetes It is useful in the pharmaceutical field as a therapeutic agent for the above.

More specifically, each group shown in the present specification is as follows.

As the phenyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring,
For example, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,
4-isopropoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl,
2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3-propoxy-4-methoxyphenyl,
3,5-dimethoxyphenyl, 3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl, 3-
Examples thereof include a phenyl group which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as a substituent on the phenyl ring such as a methoxy-4-ethoxyphenyl group.

Examples of the pyridylcarbonyl group which may have a lower alkoxycarbonyl group or a carboxy group as a substituent include, for example, pyridylcarbonyl, 6-carboxy-2-pyridylcarbonyl and 3-carboxy-2.
-Pyridylcarbonyl, 4-carboxy-2-pyridylcarbonyl, 5-carboxy-3-pyridylcarbonyl, 2-carboxy-4-pyridylcarbonyl, 6-methoxycarbonyl-2-pyridylcarbonyl, 3-ethoxycarbonyl-2-pyridylcarbonyl , 4-propoxycarbonyl-2-pyridylcarbonyl, 5-butoxycarbonyl-3-pyridylcarbonyl, 2-hexyloxycarbonyl-4-pyridylcarbonyl group or the like as a substituent, a straight or branched chain having 1 to 6 carbon atoms The pyridyl carbonyl group which may have an alkoxy carbonyl group or a carboxy group can be illustrated.

1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms
Examples of the 5- to 15-membered monocyclic, dicyclic or tricyclic heterocyclic residue having, for example, pyrrolidinyl, piperidinyl,
Piperazinyl, morpholino, pyridyl, 1,2,5,6
-Tetrahydropyridyl, thienyl, quinolyl, 1,4
-Dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, carbostyril,
3,4-dihydrocarbostyryl, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazolyl, acridinyl, chromanyl. , Isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl, 2,
3-dihydrobenzo [b] furyl, benzothienyl, phenoxathinyl, phenoxazinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thianthrenyl, isoindolinyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, thiazolyl. , Isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-
2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3 -Dithia-2,4-dihydronaphthalenyl,
Phenanthridinyl, 1,4-dithianaphthalenyl, dibenz [b, e] azepinyl, 6,11-dihydro-5
H-dibenz [b, e] azepinyl, 4H-furo [2,2
Examples thereof include a 3-e] -1,2-oxazinyl, 4a, 7a-dihydro-4H-furo [2,3-e] -1,2-oxazinyl group.

The lower alkoxycarbonyl group is, for example, a straight chain having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups. Alternatively, a branched alkoxycarbonyl group can be exemplified.

Examples of the hydroxyl-substituted lower alkyl group include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-
Hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl group, etc. A linear or branched alkyl group having 1 to 6 carbon atoms and having 1 to 3 hydroxyl groups can be exemplified.

Examples of the lower alkoxy group include linear or branched chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

Tri-lower alkyl group-substituted silyloxy groups include trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, tributylsilyloxy, tritert-butylsilyloxy, tripentylsilyloxy, trihexylsilyloxy, dimethyl, tert- Examples thereof include a silyloxy group in which three linear or branched alkyl groups having 1 to 6 carbon atoms such as a butylsilyloxy group are substituted.

Examples of the lower alkenyl group include straight-chain or branched-chain alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl groups. A group can be illustrated.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl groups.

Examples of the amino lower alkoxycarbonyl group which may have a lower alkyl group as a substituent include, for example, aminomethoxycarbonyl, 2-aminoethoxycarbonyl, 1-aminoethoxycarbonyl, 3-aminopropoxycarbonyl, 4-aminobutoxycarbonyl. , 5-aminopentyloxycarbonyl, 6-aminohexyloxycarbonyl, 1,1-dimethyl-2-aminoethoxycarbonyl, 2-methyl-3-aminopropoxycarbonyl, methylaminomethoxycarbonyl,
1-ethylaminoethoxycarbonyl, 2-propylaminoethoxycarbonyl, 3-isopropylaminopropoxycarbonyl, 4-butylaminobutoxycarbonyl, 5-pentylaminopentyloxycarbonyl, 6
-Hexylaminohexyloxycarbonyl, dimethylaminomethoxycarbonyl, 2-dimethylaminoethoxycarbonyl, 3-dimethylaminopropoxycarbonyl, (N-ethyl-N-propylamino) methoxycarbonyl, 2- (N-methyl-N-hexylamino) ) A straight chain or branched chain having 1 to 6 carbon atoms having an amino group which may have 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms as a substituent such as an ethoxycarbonyl group An alkoxycarbonyl group can be illustrated.

Examples of the amino lower alkoxy-substituted lower alkyl group which may have a lower alkyl group as a substituent include aminomethoxymethyl, 2- (2-aminoethoxy) ethyl, 1- (1-aminoethoxy) ethyl,
3- (3-aminopropoxy) propyl, 4- (4-aminobutoxy) butyl, 5- (5-aminopentyloxy) pentyl, 6- (6-aminohexyloxy) hexyl, 1,1-dimethyl-2- (1,1-dimethyl-2
-Aminoethoxy) ethyl, 2-methyl-3- (2-methyl-3-aminopropoxy) propyl, methylaminomethoxymethyl, 2- (1-ethylaminoethoxy) ethyl, 1- (2-propylaminoethoxy) ethyl Three
-(3-isopropylaminopropoxy) propyl, 4
-(4-Butylaminobutoxy) butyl, 5- (5-pentylaminopentyloxy) pentyl, 6- (6-hexylaminohexyloxy) hexyl, dimethylaminomethoxymethyl, 2-dimethylaminoethoxymethyl, 2- (3 -Dimethylaminopropoxy) ethyl, 4
-[(N-ethyl-N-propylamino) methoxy] butyl, 2- [2- (N-methyl-N-hexylamino)
[Ethoxy] ethyl group or the like having 1 to 6 carbon atoms as a substituent, which may have 1 to 2 linear or branched alkyl groups, or a linear or branched chain having 1 to 6 carbon atoms. A linear or branched alkyl group having 1 to 6 carbon atoms having an alkoxy group can be exemplified.

Examples of the amino lower alkoxy group which may have a lower alkyl group as a substituent include, for example, aminomethoxy, 2-aminoethoxy, 1-aminoethoxy,
3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1
-Dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-butylaminobutoxy, 5-pentylaminopentyl Oxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, 2-
Dimethylaminoethoxy, 3-dimethylaminopropoxy, (N-ethyl-N-propylamino) methoxy, 2
1 to 2 carbon atoms having an amino group which may have 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms as a substituent such as a-(N-methyl-N-hexylamino) ethoxy group The linear or branched alkoxy group of 6 can be exemplified.

Examples of the tetrahydropyranyloxy group or the lower alkoxy group having a hydroxyl group include 2- (2-tetrahydropyranyloxy) ethoxy, (3-tetrahydropyranyloxy) methoxy and 1- (4-tetrahydropyranyloxy). Ethoxy, 3- (2-tetrahydropyranyloxy) propoxy, 4- (3-tetrahydropyranyloxy) butoxy, 5- (2-tetrahydropyranyloxy) pentyloxy, 6- (3-tetrahydropyranyloxy) hexyl Oxy, hydroxymethoxy,
2-hydroxyethoxy, 1-hydroxyethoxy, 3
-Hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2
A tetrahydropyranyloxy group such as -hydroxyethoxy, 5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy group, or the like. A straight chain or branched chain alkyl group having 1 to 6 carbon atoms and having 1 to 3 hydroxyl groups can be exemplified.

A phenylsulfonyloxy group-substituted lower alkoxy group which may have a lower alkyl group as a substituent on the phenyl ring is, for example, (2-methylphenylsulfonyloxy) methoxy, 1- (3-methylphenylsulfonyloxy). Ethoxy, 2- (4-methylphenylsulfonyloxy) ethoxy, 3- (2-ethylphenylsulfonyloxy) propoxy, 4- (3-ethylphenylsulfonyloxy) butoxy, 5- (4-
Ethylphenylsulfonyloxy) pentyloxy, 6
-(3-Butylphenylsulfonyloxy) hexyloxy, 1,1-dimethyl-2- (4-isopropylphenylsulfonyloxy) ethoxy, 2-methyl-3-
Such as (4-pentylphenylsulfonyloxy) propoxy, (4-hexylphenylsulfonyloxy) methoxy, 2- (3,4-dimethylphenylsulfonyloxy) ethoxy, (3,4,5-trimethylphenylsulfonyloxy) methoxy group. 1 to 6 linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring
Examples thereof include a phenylsulfonyloxy group-substituted linear or branched alkoxy group having 1 to 6 carbon atoms, which may have three.

Examples of the amino lower alkanoyloxy substituted lower alkyl group which may have a lower alkyl group as a substituent include (2-aminoacetyloxy) methyl, 2- (2-aminoacetyloxy) ethyl, 1-
(2-Aminoacetyloxy) ethyl, 3- (3-aminopropionyloxy) propyl, 4- (4-aminobutyryloxy) butyl, 5- (5-aminopentanoyloxy) pentyl, 6- (6-amino Hexanoyloxy) hexyl, 1,1-dimethyl-2- (2-aminoacetyloxy) ethyl, 2-methyl-3- (3-aminopropionyloxy) propyl, (2-methylaminoacetyloxy) methyl, 1- (2-Ethylaminoacetyloxy) ethyl, 2- (2-propylaminoacetyloxy) ethyl, 3- (3-isopropylaminopropionyloxy) propyl, 4- (4-butylaminobutyryloxy) butyl, 5- ( 5-pentylaminopentanoyloxy) pentyl, 6- (6-hexylaminohexanoyloxy Hexyl, 2-dimethylamino-acetyl) methyl, [2- (N-ethyl--N- propylamino) acetyl] methyl, 2- [2- (N-
A methyl-N-hexylamino) acetyloxy] ethyl group or the like, which may have 1 or 2 straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms as a substituent, such as an amino-substituted straight chain having 2 to 6 carbon atoms. A linear or branched alkyl group having 1 to 6 carbon atoms having a chain or branched alkanoyloxy group can be exemplified.

Examples of the lower alkynyloxy group include ethynyloxy, (2-propynyl) oxy, (2-butynyl) oxy, (3-butynyl) oxy, (1-methyl-2-propynyl) oxy and (2-pentynyl). ) Oxy, (2-hexynyl) oxy group and the like, and straight or branched alkynyloxy groups having 2 to 6 carbon atoms can be exemplified.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
The alkyl moiety such as 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl group has 1 to 6 carbon atoms. And a phenylalkyl group which is a linear or branched alkyl group.

As the carboxy-substituted lower alkyl group,
For example, carboxymethyl, 2-carboxyethyl, 1-
The alkyl moiety such as carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl group has carbon atoms. The carboxyalkyl group which is a linear or branched alkyl group of 1-6 can be mentioned.

Examples of the aminothiocarbonyl group which may have a benzoyl group include aminothiocarbonyl and benzoylaminothiocarbonyl groups.

Examples of the piperazinyl group which may have a lower alkyl group include, for example, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 3-propyl-1-piperazinyl and 2-butyl-. 1
-Piperazinyl, 4-hexyl-2-piperazinyl, 4
-Pentyl-3-piperazinyl, 3,4-dimethyl-1
Examples thereof include a piperazinyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms such as -piperazinyl and 3,4,5-trimethyl-1-piperazinyl group.

Phenyl lower alkoxycarbonyl group As the substituted lower alkyl group, for example, benzyloxycarbonylmethyl, 2- (2-phenylethoxycarbonyl)
Ethyl, 1- (1-phenylethoxycarbonyl) ethyl, 3- (3-phenylpropoxycarbonyl) propyl, 4- (4-phenylbutoxycarbonyl) butyl,
1,1-dimethyl-2- (1,1-dimethyl-2-phenylethoxycarbonyl) ethyl, 5- (5-phenylpentyloxycarbonyl) pentyl, 6- (6-phenylhexyloxycarbonyl) hexyl, 2-methyl 1 to 6 carbon atoms having a phenylalkoxycarbonyl group which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy portion such as 2- (2-methyl-3-phenylpropoxycarbonyl) ethyl group The straight chain or branched chain alkyl group can be exemplified.

Examples of the amino-substituted lower alkanoyloxy lower alkyl group which may have a lower alkyl group as a substituent include (2-aminoacetyloxy) methyl, 1- (2-aminopropionyloxy) ethyl, 2
-(3-Aminopropionyloxy) ethyl, 3- (4
-Aminobutyryloxy) propyl, 4- (5-aminopentanoyloxy) butyl, 5- (6-aminohexanoyloxy) pentyl, 6- (1,1-dimethyl-2)
-Aminoacetyloxy) hexyl, 3- (2-methyl-3-aminopropionyloxy) propyl, methylaminoacetyloxymethyl, dimethylaminoacetyloxymethyl, 2- (2-ethylaminopropionyloxy) ethyl, 3- (3 -Propylaminopropionyloxy) propyl, 4- (4-isopropylaminobutyryloxy) butyl, 5- (5-butylaminopentanoyloxy) pentyl, 6- (6-pentylaminohexanoyloxy) hexyl, (2- Hexylaminoacetyloxy) methyl, [2- (N-ethyl-N-propylamino) acetyloxy] methyl, 2- [3- (N-methyl-N-hexylamino) propionyloxy] ethyl group and the like having 1 carbon atom Having 1 to 2 straight or branched chain alkyl groups of 2 carbon atoms having an amino group with
6 straight-chain or branched-chain alkanoyloxy group-substituted C1-C6 straight-chain or branched-chain alkyl group can be illustrated.

Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio and hexylthio groups. .

Examples of the morpholino lower alkylamino group include morpholinomethylamino, 2-morpholinoethylamino, 1-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino and 5
-(2-morpholino) pentylamino, 6- (3-morpholino) hexylamino, 1,1-dimethyl-2- (4
An alkyl moiety such as -morpholino) ethylamino and 2-methyl-3-morpholinopropylamino group has 1 to 6 carbon atoms.
The morpholinoalkylamino group, which is a linear or branched alkyl group of, can be mentioned.

1,3,4-which may have an oxo group
Examples of the oxadiazolyl group include a 1,3,4-oxadiazolyl group and a 5-oxo-1,3,4-oxazolyl-2-yl group.

Examples of the lower alkanoyl group include straight-chain or branched-chain alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups. it can.

Examples of the lower alkanoyloxy-substituted lower alkyl group include formyloxymethyl, acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl,
2,3-diacetyloxypropyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-
tert-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl, 5,5,4-triacetyloxypentyl, 2-methyl-3-acetyloxypropyl group and the like having 1 to 6 carbon atoms Mention may be made of a linear or branched alkyl group having 1 to 6 carbon atoms and 1 to 3 chain or branched alkanoyloxy groups.

Examples of the carboxy-substituted lower alkoxy group include carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1. -Alkoxy moieties such as dimethyl-2-carboxyethoxy and 2-methyl-3-carboxypropoxy groups have 1 to 6 carbon atoms.
And a carboxyalkoxy group which is a linear or branched alkoxy group.

As the lower alkyl group having a lower alkoxycarbonyl group or a cyano group as a substituent, for example, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl,
3-cyanopropyl, 4-cyanobutyl, 1,1-dimethyl-2-cyanoethyl, 5-cyanopentyl, 6-cyanohexyl, 2-methyl-3-cyanopropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 2
-Propoxycarbonylethyl, 1-butoxycarbonylethyl, 3-methoxycarbonylpropyl, 2,3-
Diethoxycarbonylpropyl, 4-isobutoxycarbonylbutyl, 5-pentyloxycarbonylpentyl, 6-tert-butoxycarbonylhexyl, 1,
1-dimethyl-2-hexyloxycarbonylethyl,
As a substituent such as 5,5,4-trimethoxycarbonylpentyl, 2-methyl-3-ethoxycarbonylpropyl, 1-ethoxycarbonyl-1-cyanomethyl, 2-ethoxycarbonyl-1-cyanoethyl group, the number of carbon atoms is 1 to 1
A straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms having a straight-chain or branched-chain alkoxycarbonyl group of 6 or a cyano group can be exemplified.

Examples of the lower alkyl group having 1 to 2 groups selected from the group consisting of pyridyl group, furyl group, phenyl group, carboxy group and hydroxyl group as a substituent include (2
-Pyridyl) methyl, 1- (3-pyridyl) ethyl, 2
-(4-pyridyl) ethyl, 3- (2-pyridyl) propyl, 4- (3-pyridyl) butyl, 5- (4-pyridyl) pentyl, 6- (2-pyridyl) hexyl, 1,1
-Dimethyl-2- (3-pyridyl) ethyl, 2-methyl-3- (4-pyridyl) propyl, 1- (2-pyridyl) -1-hydroxymethyl, 2- (3-pyridyl)-
1-hydroxyethyl, 3- (4-pyridyl) -1-hydroxypropyl, 5- (2-pyridyl) -4-hydroxypentyl, 6- (2-pyridyl) -6-hydroxyhexyl, (2-furyl) methyl , 1- (3-furyl)
Ethyl, 2- (2-furyl) ethyl, 3- (2-furyl) propyl, 4- (3-furyl) butyl, 5- (2-
Furyl) pentyl, 6- (3-furyl) hexyl, 1,
1-dimethyl-2- (2-furyl) ethyl, 2-methyl-3- (2-furyl) propyl, 1- (2-furyl)-
1-hydroxymethyl, 2- (2-furyl) -1-hydroxyethyl, 1,1-diphenylmethyl, benzyl,
2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-
2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 1
-Phenyl-1-hydroxymethyl, 2-phenyl-1
-Hydroxyethyl, 1-phenyl-2-hydroxyethyl, 3-phenyl-1-hydroxypropyl, 4-phenyl-4-hydroxybutyl, 5-phenyl-5-hydroxypentyl, 6-phenyl-6-hydroxyhexyl, 2 -Methyl-3-phenyl-3-hydroxypropyl, carboxymethyl, 2-carboxyethyl, 1-
Carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, 1-carboxy-1-hydroxy. Methyl, 2-carboxy-1-hydroxyethyl, 3-carboxy-1-hydroxypropyl, 5-carboxy-4-hydroxypentyl, 6-
A straight or branched chain having 1 to 2 carbon atoms having 1 to 2 groups selected from the group consisting of pyridyl group, furyl group, phenyl group, carboxy group and hydroxyl group as a substituent such as carboxy-6-hydroxyhexyl group. The alkyl group can be exemplified.

Examples of the carboxy-substituted lower alkylthio group include carboxymethylthio, 2-carboxyethylthio, 1-carboxyethylthio, 3-carboxypropylthio, 4-carboxybutylthio, 5-carboxypentylthio and 6-carboxyhexylthio groups. , 1,1
-Dimethyl-2-carboxyethylthio, 2-methyl-
A carboxyalkylthio group in which an alkylthio moiety such as a 3-carboxypropylthio group is a linear or branched alkylthio group having 1 to 6 carbon atoms can be mentioned.

As the halogen atom, for example, a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom.

Examples of the pyrrolidinyl lower alkyl group include (1-pyrrolidinyl) methyl, 2- (1-pyrrolidinyl) ethyl, 1- (1-pyrrolidinyl) ethyl and 3-
(1-pyrrolidinyl) propyl, 4- (1-pyrrolidinyl) butyl, 5- (2-pyrrolidinyl) pentyl, 6-
(3-Pyrrolidinyl) hexyl, 1,1-dimethyl-2
-(2-Pyrrolidinyl) ethyl, 2-methyl-3- (1
Examples thereof include a pyrrolidinylalkyl group in which the alkyl moiety such as -pyrrolidinyl) propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

The amino lower alkyl group which may have a lower alkyl group or a phenyl lower alkoxycarbonyl group as a substituent includes aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4
-Aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl,
5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino) methyl, 2- (N-methyl-N-hexylamino) ethyl, 2-dimethylaminoethyl, benzyloxy Carbonylaminomethyl, 2-benzyloxycarbonylaminoethyl, 1- (2-phenylethoxycarbonylamino) ethyl, 2- (3-phenylpropoxycarbonylamino) ethyl, 3- (4-phenylbutoxycarbonylamino) propyl, 4- (5-phenylpentyloxycarbonylamino) butyl, 5- (6-
Phenylhexyloxycarbonylamino) pentyl,
6- (benzyloxycarbonylamino) hexyl, dibenzyloxycarbonylaminomethyl, 2- (N-methyl-N-benzyloxycarbonylamino) ethyl group or the like as a substituent, a straight or branched chain having 1 to 6 carbon atoms A linear alkyl group or a linear or branched alkyl group having 1 to 6 carbon atoms and an amino group which may have 1 to 2 linear or branched phenylalkoxycarbonyl groups having 1 to 6 carbon atoms It can be illustrated.

The saturated or unsaturated heterocyclic ring of 5 or 6-membered ring formed by R ⁹ and R ¹⁰ together with the nitrogen atom to which they are bonded is bonded to each other via a nitrogen atom or an oxygen atom or not. For example, piperazinyl, pyrrolidinyl, morpholinyl, piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, 2-pyrrolinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,4-triazolyl, 1,2,5,6.
-A tetrahydropyridyl group etc. can be illustrated.

Examples of the above-mentioned heterocycle substituted with a carboxy group or a lower alkyl group include 3-carboxypiperazinyl, 3-carboxypyrrolidinyl, 2-carboxypyrrolidinyl, 4-carboxypiperidinyl and 3-carboxy. Piperazinyl, 2-carboxymorpholino, 4-methylpiperazinyl, 4-ethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 3 -Methyl-1,2,4-triazolyl, 2-hexylpiperazinyl, 2-carboxypyrrolidinyl group or other carboxy groups or the above-mentioned hetero groups substituted with a linear or branched alkyl group having 1 to 6 carbon atoms A ring can be illustrated.

Oxo group, lower alkyl group, lower alkanoyl group, lower alkyl group having a lower alkoxycarbonyl group or cyano group as a substituent, lower alkanoyloxy lower alkyl group, hydroxyl group, carboxy group, lower alkoxycarbonyl group, carboxy-substituted lower group An alkyl group,
Group-(A) ₁ -NR ⁹ R ¹⁰ (wherein A and l are the same as above. R ⁹ and R ¹⁰ are the same or different and each is a hydrogen atom, a lower alkyl group, a hydroxyl group, a pyrrolidinyl lower alkyl group, a carboxy-substituted lower group. An alkyl group or an amino-substituted lower alkyl group which may have a lower alkyl group or a phenyl lower alkoxycarbonyl group as a substituent, and R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached,
They may be bonded to each other via a nitrogen atom or an oxygen atom or not to form a 5- or 6-membered saturated or unsaturated heterocycle. A lower alkyl group or a carboxy group may be substituted on the heterocycle. ), A cyano group, a hydroxyl-substituted lower alkyl group, a lower alkyl group having 1 to 2 groups selected from the group consisting of a pyridyl group, a furyl group, a phenyl group, a carboxy group and a hydroxyl group as a substituent, a carboxy-substituted lower alkoxy group, A carboxy-substituted lower alkylthio group, a halogen atom, a lower alkoxy group, an oxiranyl group, an amidino group, an aminothiocarbonyl group and the above chemical formula 1
Examples of the heterocycle having 1 to 3 groups selected from the group represented by 0 (R ^8a is a hydroxyimino group or a lower alkylthio group) include, for example, dibenz [b, e] azepin-3-yl-6. -One, 4-oxo-1,4-dihydroquinolyl, 1-oxopyridyl, 2-oxopyridyl, 1-methyl-3,4-dihydrocarbostyryl, 1
-Ethyl carbostyril, 1-butyl-3,4-dihydrocarbostyril, 1-hexyl carbostyril, 6-
Methoxy-3,4-dihydrocarbostyril, 3-oxo-4-methyl-3,4-dihydro-2H-1,4-benzothiazinyl, 3-oxo-3,4-dihydro-2H
-1,4-benzothiazinyl, 2-carboxy-3-hydroxypyridyl, 2-acetyloxymethylpyridyl, 1-ethoxypyridyl, 2-ethoxycarbonyl-
3-hydroxypyridyl, 3-ethoxycarbonyl-4
a, 7a-dihydro-4H-furo [2,3-e] -1,
2-oxazinyl, 2-chloropyridyl, 4-chloropyridyl, 2- [1- (2-pyridyl) -1-hydroxymethyl] pyridyl, 2- [1- (2-furyl) -1-hydroxymethyl] pyridyl, 2- (1-phenyl-1-
Hydroxymethyl) pyridyl, 4-methyl-1,2,
3,4-tetrahydroquinoxalinyl, 2-carboxymethylpyridyl, 2- (2-carboxyethyl) pyridyl, 2-cyanomethylpyridyl, 2- (4-methyl-1)
-Piperazinyl) pyridyl, 2-morpholinopyridyl,
2- (1,2,4-triazol-1-yl) pyridyl, 2- (2-carboxy-1-pyrrolidinyl) pyridyl, 2- (2-carboxyethyl) aminopyridyl, 2
-(2-Dimethylaminoethyl) aminopyridyl, 2-
(2-carboxyethoxy) pyridyl, 2- (2-carboxyethylthio) pyridyl, 2-carboxypyrazyl, 4-carboxypyrimidyl, 5-carboxyimidazolyl, 1-methyl-1,2,3,4-tetrahydro Quinolyl, 7-hydroxy-3,4-dihydrocarbostyril, 8-hydroxy-3,4-dihydrocarbostyryl, 3-fluoro-2-carboxypyridyl, 4-methoxy-2-carboxypyridyl, 3-oxo-3. , 4-
Dihydro-2H-1,4-benzoxazinyl, 3-hydroxy-2-carboxypyridyl, 2-oxobenzimidazolyl, 4-methyl-3,4-dihydro-2H,
1,4-benzoxazinyl, 4-amino-2-carboxypyridyl, 2-oxobenzothiazolyl, 2-oxobenzoxazolyl, 2-oxo-3-methylbenzothiazolyl, 1,3- Dimethyl-2-oxobenzimidazolyl, 6-hydroxy-3,4-dimethylquinolyl, 4-oxopyridyl, 1-propyl-1,2,3
4-tetrahydroquinolyl, 4-pentyl-1,2,
3,4-tetrahydroquinoxalyl, 3-dimethylamino-2-carboxypyridyl, 2,4-dicarboxypyridyl, 2-carboxypyridyl, 2-carboxypyrrolyl, 2-ethoxycarbonylpyridyl, 2-methoxycarbonylpyrrolyl , 1-methylpyridinium, 1-methyl-1,2,5,6-tetrahydropyridyl, 2-methoxycarbonylfuryl, 2-carboxyfuryl, 2-dimethylaminocarbonylpyridyl, 1-oxo-2-hydroxymethyl-4. -Methylpyridyl, 2-hydroxymethylpyridyl, 2-ethoxycarbonyl-4-methylpyridyl, 2-carboxy-4-methylpyridyl, 2
-(4-Methyl-1-piperazinyl) carbonylpyridyl, 2- (2-dimethylaminoethoxycarbonyl) pyridyl, 2-dimethylaminomethylpyridyl, 2-ethoxycarbonylthienyl, 2-methyl-7-carboxybenzofuryl, 2- Carboxythienyl, 4-ethoxycarbonylthiazolyl, 4-carboxythiazolyl, 4
-Methyl-5-carboxythiazolyl, 3-carboxypyridyl, 2,2-dimethyl-7-carboxy-2,3
-Dihydrobenzo [b] furyl, 4-carboxypyridyl, 2-cyanopyridyl, 4-cyanopyridyl, 2-methyl-4-carbamoylpyridyl, 2,6-dimethyl-
3-carbamoylpyridyl, 2-methyl-3-carboxypyridyl, 2,6-dimethyl-3-carboxypyridyl, 2-formylpyridyl, 3-acetylpyridyl, 2
-{[2- (1-pyrrolidinyl) ethyl] aminocarbonyl} pyridyl, 2-aminothiocarbonylpyridyl,
2- (1-imino-1-methylthiomethyl) pyridyl,
2-amidinopyridyl, 2- (2-dimethylaminoethylamino) pyridyl, 2- (1,2,3,4-tetrazol-5-yl) pyridyl, 2- (2-carboxy-1)
-Pyrrolidinyl) pyridyl, 3-carboxypyrazinyl, 4- (4-methyl-1-piperazinyl) pyridyl,
2- [2- (4-Methyl-1-piperazinyl) -1-hydroxyethyl] pyridyl, 2- (2-dimethylamino-1-hydroxyethyl) pyridyl, 2- (2-hydroxy-1-dimethylaminoethyl) Pyridyl, 2- (1
-Carboxy-1-hydroxymethyl) pyridyl, 2-
[(2-benzyloxycarbonylaminoethyl) aminocarbonyl] pyridyl, 2- (1-hydroxyamino-1-iminomethyl) pyridyl, 4-oxopyrazinyl, 1,4-dioxopyrazinyl, 3-cyanopyrazinyl, 5-cyanopyrazinyl, 2- (1-ethoxycarbonyl-1-cyanomethyl) pyridyl, 2- (1,2-dihydroxyethyl) pyridyl, 6-carboxypyrimidinyl, 2-oxiranylpyridyl, 1-oxopyrimidinyl, 6-cyanopyrimidinyl, 1- Oxopyridyl,
2-cyanopyridyl, 2- (1-methoxycarbonyl-
Oxo group such as 1-cyanomethyl) pyridyl group, carbon number 1
To 6 linear or branched alkyl group, 1 to 6 linear or branched alkanoyl group, and 1 carbon as a substituent
To C6 linear or branched alkoxycarbonyl group or cyano group having a C1 to C6 linear or branched alkyl group, C1 to C6 linear or branched alkanoyloxy group A linear or branched alkyl group having 1 to 3 carbon atoms having 1 to 6 carbon atoms, a hydroxyl group, a carboxy group, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, or the number of carbon atoms in the alkyl portion A carboxyalkyl group which is linear or branched alkyl of 1 to 6 and a group-(A) ₁ NR ⁹ R ¹⁰ (wherein A and l are the same as above. R ⁹ and R ¹⁰ are the same or different; A hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a pyrrolidinylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms, and an alkyl portion is Carboxy which is a linear or branched alkyl group having 1 to 6 carbon atoms An alkyl group, or an amino that may have 1 or 2 linear or branched alkyl group having 1 to 6 carbon atoms or linear or branched phenylalkoxycarbonyl group having 1 to 6 carbon atoms as a substituent Represents a linear or branched alkyl group having 1 to 6 carbon atoms having a group, and R
⁹ and R ¹⁰ , together with the nitrogen atom to which they are bonded, may be bonded to each other via a nitrogen atom or an oxygen atom or not to form a 5- or 6-membered saturated or unsaturated heterocycle. A linear or branched alkyl group having 1 to 6 carbon atoms or a carboxy group may be substituted on the heterocycle. ), A cyano group and a hydroxyl group having 1 to 3 carbon atoms 1 to
A straight chain or branched chain alkyl group having 6 or 1 to 2 carbon atoms having 1 to 2 groups selected from the group consisting of a pyridyl group, a furyl group, a phenyl group, a carboxy group and a hydroxyl group as a substituent, or Branched chain alkyl group, carboxyalkoxy group whose alkoxy part is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, and straight chain or branched chain alkylthio group having 1 to 6 carbon atoms in the alkylthio part A carboxyalkylthio group, a halogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms, an oxiranyl group, an amidino group, an aminothiocarbonyl group, and a group represented by the above Chemical Formula 10 (R
^8a represents a hydroxyimino group or a linear or branched alkylthio group having 1 to 6 carbon atoms. The heterocycle having 1 to 3 groups selected from the group can be exemplified.

As the lower alkylene group which may have a hydroxyl group as a substituent, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene,
Hexamethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, 1-hydroxyethylene,
2-hydroxyethylene, 2-hydroxytrimethylene, 2-hydroxytetramethylene, 3-hydroxypentamethylene, 3-hydroxyhexamethylene and the like, a straight chain having 1 to 6 carbon atoms which may have a hydroxyl group as a substituent. Alternatively, a branched alkylene group can be exemplified.

The compound of the general formula (1) of the present invention is produced, for example, by the method shown below.

[0054]

[Chemical 11]

[In the formula, R ¹ and R ² are the same as defined above. Y represents a halogen atom. The reaction between compound (2) and compound (3) can be carried out by heating in a suitable solvent. Examples of the solvent used here include methanol, ethanol,
Alcohols such as propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, aromatic hydrocarbons such as benzene, toluene, xylene, o-dichlorobenzene, diethyl ether, tetrahydrofuran, dioxane, diglyme, monoglyme. Ethers such as, dichloromethane, chloroform,
Examples thereof include halogenated hydrocarbons such as carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, polar solvents such as acetonitrile, and mixed solvents thereof. The reaction is usually at room temperature to 150
C., preferably at room temperature to about 100.degree. C., and completed in about 1 to 15 hours. The amount of the compound (3) used is at least equimolar, preferably equimolar to the compound (2).
It is preferable that the molar amount is about 1.5 times.

[0056]

[Chemical 12]

[In the formula, R ¹ and R ² are the same as defined above. The reaction between the compound (4) and the compound (5) can be achieved by subjecting it to an ordinary amide bond formation reaction. In this case, an activated compound may be used as the carboxylic acid (5).
As the amide bond formation reaction, usual conditions for the amide bond formation reaction can be applied. For example, (a) a mixed acid anhydride method, that is, a method of reacting a carboxylic acid (5) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with a compound (4), (b) an active ester method or an activity The amide method, that is, the carboxylic acid (5) is used as an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione. A method of reacting the compound (4) with the compound (4), (c) a carbodiimide method, that is, a method of dehydrating the compound (4) to the carboxylic acid (5) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. ) Carboxylic acid halide method, that is, by introducing carboxylic acid (5) into a halide,
As a method of reacting this with compound (4), or (e) as another method, carboxylic acid (5) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and compound (4)
And the method of reacting the compound (4) with an ester of a carboxylic acid (5) and a lower alcohol, for example, under high pressure and high temperature. Further, a method in which the carboxylic acid (5) is activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate and the compound (5) is reacted therewith can also be adopted.

Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate,
Examples include methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound (6) is produced by reacting this with the compound (4) without isolation. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. As the basic compound used, a compound conventionally used in Schotten-Baumann reaction is used, for example, triethylamine,
Trimethylamine, pyridine, dimethylaniline, N-
Methylmorpholine, 4-dimethylaminopyridine, DB
Organic bases such as N, DBU, DABCO, potassium carbonate,
Inorganic bases such as sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate can be mentioned. The reaction is -20 to 100
The reaction is carried out at about 0 ° C, preferably 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the compound (4) is carried out at about -20 ° C to 150 ° C, preferably 10 to 50 ° C for about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. The mixed acid anhydride method does not need to use a solvent, but is generally performed in a solvent. As the solvent to be used, any solvent commonly used in the mixed acid anhydride method can be used, and specifically, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene. Examples thereof include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide. In the method, the carboxylic acid (5), the alkylhalocarboxylic acid and the compound (4) are usually used at least in equimolar proportions. It is preferable to use 1 to 2 moles of each.

In the active ester method or active amide method (b), for example, when benzoxazoline-2-thionamide is used, a suitable solvent which does not influence the reaction, for example, the mixed acid anhydride method is used. 1-methyl-2-pyrrolidone or the like in addition to the same solvent as that used in
0.5 to 150 ° C, preferably 10 to 100 ° C.
It is carried out by reacting for 75 hours. in this case,
The compound (4) and the benzoxazoline-2-thionamide are used in such a ratio that the latter is usually at least equimolar to the former, preferably equimolar to 2-fold. When N-hydroxysuccinimide ester is used, the reaction proceeds advantageously by using a suitable base, for example, the same base as used in the carboxylic acid halide method described below.

In the carboxylic acid halide method (c), the carboxylic acid (5) is reacted with a halogenating agent to obtain a carboxylic acid halide, and the carboxylic acid halide is isolated and purified, or without isolation and purification. , The compound (4) is reacted therewith. The reaction between the carboxylic acid halide and the compound (4) is carried out in a suitable solvent in the presence or absence of a dehydrohalogenating agent. A basic compound is usually used as a dehydrohalogenating agent, and in addition to the basic compound used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride,
Examples thereof include alkali metal alcoholates such as potassium hydride, silver carbonate, sodium methylate and sodium ethylate. The compound (4) may be used in excess as a dehydrohalogenating agent. As the solvent, other than the solvent used in the Schotten-Baumann reaction,
Examples thereof include water, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve, pyridine, acetone, acetonitrile and the like, or a mixed solvent of two or more thereof. The ratio of the compound (4) to the carboxylic acid halide used is not particularly limited and can be selected within a wide range. Usually, the latter is used at least equimolar, preferably equimolar to 5 times the molar amount of the former. The reaction temperature is usually about -30 to 180 ° C, preferably about 0 to 150 ° C,
Generally, the reaction is completed in 5 minutes to 30 hours. The carboxylic acid halide used is produced by reacting the carboxylic acid (5) with a halogenating agent in the absence or presence of a solvent. As the solvent, any solvent which does not adversely influence the reaction can be used, for example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, dioxane and tetrahydrofuran. , Ethers such as diethyl ether, dimethylformamide, dimethylsulfoxide, and the like. As the halogenating agent, an ordinary halogenating agent capable of converting a hydroxyl group of a carboxy group into a halogen can be used, and for example, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, etc. Can be illustrated.
The use ratio of the carboxylic acid (5) and the halogenating agent is not particularly limited and may be appropriately selected. When the reaction is carried out in (1), the latter is usually used in at least an equimolar amount, preferably 2 to 4 times the molar amount of the former. The reaction temperature and reaction time are not particularly limited, but usually room temperature to about 100 ° C, preferably 50 to 80 ° C.
In about 30 minutes to 6 hours.

The method of activating the carboxylic acid (5) with a phosphorus compound such as triphenylphosphine, diethyl chlorophosphate and diethyl cyanophosphate, and reacting this with the compound (4) is carried out in a suitable solvent. Any solvent can be used as long as it does not affect the reaction. Specifically, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene. Examples thereof include ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide. Since the compound (4) itself acts as a basic compound in the reaction, the reaction proceeds well by using it in excess of the theoretical amount. However, if necessary, other basic compounds such as triethylamine and trimethylamine can be used. , Pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DB
It is also possible to use organic bases such as U and DABCO, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The reaction is about 0-150
C., preferably about 0-100.degree. C., for about 1-30 hours. The proportions of the phosphorus compound and the carboxylic acid (5) used with respect to the compound (4) are usually at least equimolar amounts, preferably 1 to 3 times the molar amounts.

The reaction for converting the compound (6) to the compound (1) is 2,4-bis (4-methoxyphenyl) -1,3-
It can be produced by reacting in the presence of a sulfurizing agent such as dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) and phosphorus pentasulfide in the absence of a solvent or in a suitable solvent. Examples of the solvent used here include lower alcohols such as methanol, ethanol and propanol, ethers such as dioxane, tetrahydrofuran, diethyl ether and ethylene glycol monomethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. Kind, benzene,
Aromatic hydrocarbons such as toluene and xylene, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, polar solvents such as acetonitrile, dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide, or a mixture thereof. A solvent etc. can be mentioned. The amount of the sulfurizing agent used is usually 0.5 to 2 times the molar amount of the compound (6), and preferably 0.5 to 2.
It is preferable to use 1.5 times the molar amount. The reaction is usually 50 to
1 to 7 at 300 ° C., preferably around 50 to 250 ° C.
It ends in about time.

The compound (2) as a starting material can be produced, for example, by the method of the following reaction formula-3 or -4.

[0064]

[Chemical 13]

[In the formula, R ² and Y are the same as defined above. The halogenation reaction of compound (7) can be carried out in the presence of a halogenating agent in a suitable solvent. Examples of the halogenating agent used here include halogen molecules such as bromine and chlorine, iodine chloride, sulfuryl chloride, copper compounds such as cuprous bromide, N-bromosuccinimide, N-chlorosuccinimide and the like N. Examples thereof include halogenated succinimide. Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, fatty acids such as acetic acid and propionic acid, and carbon disulfide. The amount of the halogenating agent used is usually equimolar to 1 with respect to the compound (7).
It is preferable to use a 0-fold molar amount, preferably an equimolar to 5-fold molar amount. The reaction is usually completed at 0 to the boiling point of the solvent, preferably at about 0 to 100 ° C. for about 5 minutes to 20 hours.

[0066]

[Chemical 14]

[In the formula, R ² and Y are the same as defined above. Y ₁ is
Indicates a halogen atom. ] The reaction of the compound (8) with the compound (9) or (10) is generally a Friedel-Crafts react.
ion) and can be carried out in the presence of a Lewis acid in a suitable solvent. As the Lewis acid used here, any Lewis acid generally used in the reaction can be used, for example, aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, Examples thereof include concentrated sulfuric acid. Examples of the solvent used include aromatic hydrocarbons such as carbon disulfide, nitrobenzene and chlorobenzene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride and tetrachloroethane. The amount of the compound (9) or (10) used is at least equimolar, preferably equimolar to 5 times the molar amount of the compound (8). The amount of Lewis acid used is usually 2 to 6 times the molar amount of the compound (8). The reaction is usually 0 to 120 ° C,
Preferably, the temperature is 0 to 70 ° C., and the process is completed in 0.5 to 24 hours.

The compound (3) as a starting material can be produced, for example, by the method of the following reaction formula-5 or -6.

[0069]

[Chemical 15]

[Wherein R ¹ is the same as defined above. R ¹¹ represents a lower alkyl group. The reaction of compound (11) with compound (12) can be carried out by reacting in the presence of an acid in a suitable solvent. As the solvent used here, the reaction formula-
Any solvent can be used as long as it is a solvent used in the reaction for converting the compound (6) of 2 into the compound (1). Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid. The amount of the compound (12) used is usually an equimolar to 5-fold molar amount, preferably an equimolar to 3-fold molar amount, relative to the compound (11). The reaction is usually from room temperature to 200 ° C,
Preferably, it is finished at about room temperature to about 150 ° C. for about 1 to 15 hours.

[0071]

[Chemical 16]

[Wherein R ¹ is the same as above. The reaction for converting the compound (13) to the compound (3) can be produced by reacting in a suitable solvent in the presence of a sulfurizing agent. As the solvent used here, any solvent can be used as long as it is a solvent used in the reaction for leading the compound (6) of the reaction formula-2 to the compound (1). Examples of the sulfurizing agent used here include phosphorus pentasulfide,
Lawesson's Reagent etc. can be illustrated. The proportion of the sulfurizing agent used is usually 1 to 10 times the molar amount, preferably 1 to 2 times.
It is better to use a double molar amount. The reaction is usually at room temperature to 15
10 minutes to 5 at 0 ° C., preferably room temperature to around 100 ° C.
It ends in about time.

In the compound (1), R ³ is a nitrogen atom, an oxygen atom or a sulfur atom, each of which has at least one lower alkoxycarbonyl group or R ² has a lower alkoxycarbonyl group.
In the case of a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic residue having ³ to ³ , the corresponding R ³ is at least one carboxy group or R ² is at least one carboxy group. 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms
It can be led to a compound which is a 5- to 15-membered monocyclic, binomial or ternary heterocyclic residue.

In the hydrolysis reaction, any of the usual reaction conditions for hydrolysis can be used. Specifically, for example, basic compounds such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, In the presence of mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, organic acids such as acetic acid and aromatic sulfonic acid, alcohols such as water, methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, dioxane and ethylene glycol dimethyl ether. And the like, a solvent such as acetic acid, or a mixed solvent thereof. The reaction is usually at room temperature to 200
C., preferably at room temperature to around 180.degree. C., and is generally completed in about 10 minutes to 30 hours.

A compound (1) which is a 5- to 15-membered monocyclic, bicyclic or ternary heterocyclic ring having 1 to 3 nitrogen, oxygen or sulfur atoms having at least one formyl group. Is of the general formula (R ¹² ) (R ¹³ ) S ⁺ CH ₃ · X
^- (14) (R ¹² and R ¹³ are lower alkyl groups, and X is a halogen atom) is reacted with a compound represented by the formula (1) to give a nitrogen atom, oxygen atom or sulfur atom having at least one oxiranyl group. It can be led to the compound (1) which is a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 3 rings. The reaction is carried out in the presence of a basic compound in a suitable solvent. As the basic compound used, metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide,
Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium methylate,
Metal alcoholates such as sodium ethylate and potassium t-butoxide, alkyl and aryl lithium or lithium amides such as methyl lithium, n-butyl lithium, phenyl lithium and lithium diisopropylamide, pyridine, piperidine, quinoline, triethylamine, N, N -Examples thereof include organic bases such as dimethylaniline. As the solvent, any solvent can be used as long as it does not affect the reaction, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc., aromatic hydrocarbons such as benzene, toluene, xylene, n. -Aromatic hydrocarbons such as hexane, heptane and cyclohexane, amines such as pyridine and N, N-dimethylaniline, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide, Examples thereof include alcohols such as methanol, ethanol and isopropanol. The reaction temperature is usually -80 to 150 ° C, preferably about -80 to 120 ° C, and generally 0.5 to
The reaction is completed in about 15 hours.

5 to 15 having 1 to 3 nitrogen atom, oxygen atom or sulfur atom having at least one oxiranyl group
The compound (1) which is a monocyclic, bicyclic or tricyclic heterocycle having a member ring is hydrolyzed or represented by the general formula NHR ⁹
By reacting a compound represented by R ¹⁰ (15) (R ⁹ and R ¹⁰ are the same as above), a 1,2-dihydroxyethyl group, a group —CH (OH) —CH ₂ NR ⁹ R ¹⁰ or a group -CH (NR ⁹ R ¹⁰⁾ a nitrogen atom having one at least a -CH ₂ OH, oxygen atoms or a monocyclic 5 to 15-membered ring 1-3 have a sulfur atom, binomial ring or ternary heterocyclic It can be led to the compound (1) which is a ring.

The above hydrolysis can be carried out in a suitable solvent or without solvent in the presence of an acid or a basic compound. As the solvent used, for example, water, methanol, ethanol, lower alcohols such as isopropanol, acetone, ketones such as methyl ethyl ketone, dioxane, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether, acetic acid, fatty acids such as formic acid, dimethyl sulfoxide, Examples thereof include mixed solvents. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid and aromatic sulfonic acid, and examples of the basic compound include sodium carbonate and potassium carbonate. Examples thereof include metal carbonates and metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide. The reaction is usually at room temperature to 2
The reaction proceeds suitably at about 00 ° C, preferably at room temperature to about 150 ° C, and generally ends in about 0.5 to 25 hours.

The reaction of the compound of general formula (1) with the compound of general formula (15) is generally carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of the inert solvent used include benzene, toluene, aromatic hydrocarbons such as xylene, tetrahydrofuran, dioxane, ethers such as diethylene glycol dimethyl ether, lower alcohols such as methanol, ethanol, isopropanol, butanol, acetic acid, ethyl acetate, etc. Acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide and the like can be mentioned. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, Metal alcoholates such as sodium methylate and sodium ethylate, pyridine, ethyl-diisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN),
1,8-diazabicyclo [5.4.0] undecene-7
(DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO), and other organic bases. The use ratio of the compound (1) and the compound (15) is not particularly limited and may be appropriately selected within a wide range, but the latter is at least about equimolar amount to the former, preferably equimolar to large excess amount. It is better to use it to some extent. The reaction is usually performed at about 0 to 200 ° C., preferably about 0 to 170 ° C., and generally the reaction is completed in about 30 minutes to 30 hours.

1 to 3 nitrogen atom, oxygen atom or sulfur atom having an oxo group on at least one of the nitrogen atoms of the heterocycle.
The compound (1), which is a 5- to 15-membered monocyclic, bicyclic or ternary heterocyclic ring, has a nitrogen atom, an oxygen atom or a nitrogen atom in which at least one of the nitrogen atoms of the corresponding heterocycle is unsubstituted. It can be produced by oxidizing the compound (1), which is a 5- to 15-membered monocyclic, binomial or ternary heterocycle having 1 to 3 sulfur atoms. The oxidation reaction is carried out in the presence of an oxidizing agent in a suitable solvent. Examples of the solvent used here include water, formic acid, acetic acid, organic acids such as trifluoroacetic acid, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and dichloromethane, and mixed solvents thereof. it can. Examples of the oxidizing agent used include performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, peroxy acids such as o-carboxyperbenzoic acid, hydrogen peroxide, and metaperiodic acid. Sodium, dichromate, sodium dichromate, dichromate such as potassium dichromate, permanganate, potassium permanganate, permanganate such as sodium permanganate, lead salt such as lead tetraacetate, etc. Is mentioned. The oxidizing agent is usually used in an amount of at least equimolar, preferably equimolar to 2 times the molar amount of the starting material. The above reaction is usually performed at 0 to 40 ° C, preferably 0 ° C to around room temperature, and the reaction is completed in about 1 to 10 hours.

1 to 3 nitrogen atom, oxygen atom or sulfur atom having an oxo group on at least one nitrogen atom of the heterocycle.
The compound (1), which is a 5- to 15-membered monocyclic ring, binary ring or triplet ring, has the general formula R ¹⁴ R ¹⁵ R ¹⁶ Si—CN (1
6) a compound represented by the formula (R ¹⁴ , R ¹⁵ and R ¹⁶ each represent a lower alkyl group) or the general formula R ¹⁷ CH ₂ C
At least a cyano group or a group —CH (R ¹⁷ ) (CN) (R ¹⁷ is the same as above) by reacting with a compound represented by N (17) (R ¹⁷ represents a lower alkoxycarbonyl group). The compound (1) can be a compound having 1 to 5 nitrogen atoms, 1 to 3 oxygen atoms or 1 to 3 sulfur atoms, which is a 5- to 15-membered monocyclic ring, binary ring or triplet ring.

The reaction of compound (1) with compound (17) is carried out in a suitable solvent in the presence or absence of a basic compound. Examples of the basic compound used here include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate and sodium hydride, sodium methylate and sodium ethylate. Examples thereof include alkali metal alcoholates, organic bases such as triethylamine, pyridine, α-picoline, N, N-dimethylaniline, N-methylmorpholine, piperidine and pyrrolidine. Examples of the solvent used include ethers such as dioxane, tetrahydrofuran, monoglyme, diglyme, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, ethanol, lower alcohols such as isopropanol, dimethyl sulfoxide, dimethylformamide, and the like. Examples include polar solvents such as acetonitrile and acetic anhydride. The reaction is usually completed at room temperature to 150 ° C., preferably 60 to 120 ° C. for about 1 to 24 hours. The amount of the compound (17) used is usually an equimolar amount to a large excess amount, preferably an equimolar amount to 5 times the molar amount of the compound (1). The reaction proceeds advantageously when a lower alkanoic acid such as acetic acid, a molecular sieve or the like is added to the reaction system.

The reaction of compound (1) with compound (16) can be carried out in a suitable solvent in the presence of a basic compound. As the solvent and the basic compound used, any of those exemplified for the compound (1) and the compound (17) can be used. The amount of the compound (16) used is usually an equimolar amount to a large excess amount, preferably an equimolar amount to 5 times the molar amount of the compound (1). The reaction is usually at room temperature to
It is carried out at 150 ° C., preferably room temperature to around 100 ° C., and is completed in about 1 to 70 hours.

The compound (1) which is a 5- to 15-membered monocyclic, binary or ternary ring having 1 to 3 nitrogen atom, oxygen atom or sulfur atom having at least one cyano group is suitable. 5- to 15-membered ring having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms having at least one 1,2,3,4-tetrazolyl group by reacting with sodium azide in the presence of ammonium chloride in a solvent To a compound (1) which is a monocyclic ring, a binomial ring or a tricyclic ring. As the solvent used here, any of the solvents exemplified as the compound (1) and the compound (17) can be used.
The amount of sodium azide used is at least equimolar, preferably equimolar to 2 times the molar amount of the compound (1). The reaction is usually at room temperature to 200 ° C., preferably 50
It ends in about 1 to 15 hours at about 150 ° C.

The compound (1) which is a 5- to 15-membered monocyclic ring, binary ring or ternary ring having 1 to 3 nitrogen atom, oxygen atom or sulfur atom having at least one cyano group is (1) and the general formula R ¹¹ C (= S) NH ₂ (12)
(R ¹¹ is the same as above.) Under the same conditions as in the reaction of the compound (11) and the compound (12) in the above Reaction Formula-5 to give at least an aminothiocarbonyl group. The compound (1) can be a compound (1) which is a 5- to 15-membered monocyclic, binary or ternary ring having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms.

The compound (1) which is a 5- to 15-membered monocyclic ring, binary ring or triplet ring having 1 to 3 nitrogen atom, oxygen atom or sulfur atom having at least one aminothiocarbonyl group is an alkyl group. By reacting

[0086]

[Chemical 17]

(R ^{8a '} represents a lower alkylthio group.)
To a compound (1) which is a 5- to 15-membered monocyclic, binomial or ternary ring having 1 to 3 nitrogen atom, oxygen atom or sulfur atom having at least one of The alkylation reaction is carried out by reacting the starting compound with an alkylating agent in the presence or absence of a basic compound in a suitable solvent. Examples of the alkylating agent include the general formula R ¹⁸ Ya (18) (R ¹⁸ represents a lower alkyl group.
a represents a halogen atom. ) And dialkyl sulfates such as dimethyl sulfate.
Examples of the solvent include lower alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and ethylene glycol monomethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, benzene and toluene. , Aromatic hydrocarbons such as xylene, esters such as methyl acetate and ethyl acetate, ketones such as acetone and methyl ethyl ketone, polar solvents such as acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide, or a mixture thereof. A solvent etc. can be illustrated. Examples of the basic compound used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and sodium hydride, and alkali metals such as metallic sodium and metallic potassium. , Alkali metal alcoholates such as sodium ethylate and sodium methylate, triethylamine, pyridine, piperidine,
Examples thereof include organic bases such as N, N-dimethylaniline, N-methylmorpholine, diisopropylethylamine, 4-methylaminopyridine, DBN, DBU and DABCO. When the compound (18) is used as the alkylating agent, copper powder, copper halides such as copper iodide, halogens such as sodium iodide, potassium iodide, etc. may be used, if necessary. Alkali metal compounds may be used. Compound (18) is generally used in an equimolar amount to a large excess amount, preferably about 1 to 3 times the molar amount of the starting compound. The reaction is usually room temperature to 150 ° C., preferably 50 to 1
It finishes in about 1 to 12 hours at around 20 ° C. When dialkyl sulfate is used as the alkylating agent, the amount of the alkylating agent to be used may be at least an equimolar amount, preferably an equimolar to 5-fold molar amount with respect to the raw material compound.
The reaction is generally -30 to 150 ° C, preferably -20 to
It is performed at about 100 ° C. and is completed in about 0.5 to 20 hours.

A 5- to 15-membered monocyclic ring having 1 to 3 nitrogen, oxygen or sulfur atoms having at least one group represented by the above Chemical Formula 17 (R ^{8a '} is the same as defined above), and a term The compound (1) which is a ring or a ternary ring has the general formula R ¹⁹ —N
By reacting with a compound represented by H ₂ (19) (R ¹⁹ represents a hydrogen atom or a hydroxyl group) in a suitable solvent, a group

[0089]

[Chemical 18]

5-1 having 1 to 3 nitrogen atom, oxygen atom or sulfur atom having at least one amidino group
The compound (1) can be a 5-membered monocyclic ring, a binomial ring or a trinomial ring. As the solvent used, any of the solvents used in the alkylation reaction can be used. The amount of the compound (19) used is
At least equimolar, preferably equimolar to large excess. The reaction is usually 0 to 150 ° C., preferably 0 to
It is usually finished in about 1 to 15 hours at around 120 ° C. When using a compound (19) in which R ¹⁹ represents a hydrogen atom, the reaction is preferably carried out in a sealed tube.

The target product thus obtained in each step can be easily isolated and purified by a conventional separation means. Examples of the separating means include solvent extraction method, dilution method,
Examples thereof include recrystallization method, column chromatography, preparative thin layer chromatography and the like.

The compounds of the present invention naturally include stereoisomers and optical isomers.

The thiazole derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. Include. In the above, as the acid, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methane Organic acids such as sulfonic acid and benzoic acid can be mentioned.

Further, among the thiazole derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The compounds of the present invention are usually used in the form of general pharmaceutical preparations. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose,
Typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions,
Suspensions, etc.), ointments and the like. In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride,
Excipients such as glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate , Binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose , White sugar,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oils, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Examples thereof include adsorbents, purified talc, stearates, boric acid powder, and lubricants such as polyethylene glycol. In addition, tablets are tablets with a normal coating, if necessary,
For example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, or a double-layered tablet or a multi-layered tablet can be used. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, excipients such as kaolin and talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, and a disintegrating agent such as laminaranthantene. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood.
When formulating in the form of emulsions and suspensions, all those conventionally used in this field as diluents can be used, such as water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoform. Stearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be mentioned. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation. When formulating in the form of paste, cream and gel, it is possible to widely use those conventionally known in the art as a diluent, for example, white petrolatum, paraffin, glycerin, a cellulose derivative,
Polyethylene glycol, silicone, bentonite, etc. can be used.

The amount of the compound of the general formula (1) of the present invention or a salt thereof to be contained in the pharmaceutical preparation is not particularly limited and may be appropriately selected within a wide range, but it is usually 1 to 70% by weight in the pharmaceutical preparation. Is good.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it may be administered according to various preparation forms, patient's age, sex and other conditions, patient's symptom level and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. Further, in the case of an injection, it is administered alone or mixed with a normal replacement fluid such as glucose or amino acid, and then intravenously administered.
It is administered intradermally, subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, the sex and other conditions, the degree of disease, etc. It is recommended that the daily dose is about 0.2 to 200 mg per kg of body weight.

[0099]

EXAMPLES The present invention will be described in more detail below with reference to reference examples and examples.

Reference Example 1 29 g of 3,4-diethoxybenzonitrile and 23 g of thioacetamide were mixed with 12% of 10% hydrochloric acid-dimethylformamide.
It was dissolved in 0 ml and heated at 90 ° C. for 3 hours. Furthermore, 1
After reacting at 30 ° C. for 5 hours, the solvent was distilled off, and the residue was washed twice with 100 ml of diethyl ether. Water 10
After washing with 0 ml, the crystals were collected by filtration and dried to obtain 21.7 g of 3,4-diethoxythiobenzamide.

NMR spectrum (DMSO-d ₆ ) δp
pm; 1.33 (6H, t, J = 7Hz), 4.04
(2H, q, J = 7Hz), 4.07 (2H, q, J =
7 Hz), 6.95 (1H, d, J = 9.1 Hz),
7.65-7.5 (2H, m), 9.30 (1H, br
s), 9.62 (1H, brs).

Reference Example 2 0.19 ml of bromine was added dropwise to a solution of 0.88 g of 2-ethoxycarbonyl-3-acetyloxy-6-acetylpyridine in 8.8 ml of acetic acid, and the mixture was heated with stirring at 75 ° C. for 5 minutes. 0.77 g of 2-ethoxycarbonyl-3-hydroxy-6- (2-bromoacetyl) pyridine hydrobromide is obtained.

Brown oil ¹ H-NMR (CDCl ₃ ) δ ppm; 1.47 (3
H, t, J = 7.1 Hz), 4.48 (2H, q, J =
7.1 Hz), 4.87 (2H, s), 7.45 (1
H, d, J = 8.8 Hz), 8.21 (1H, d, J =
8.8 Hz), 11.33 (1 H, s).

In the same manner as in Reference Example 2, the compounds shown in Table 1 below are obtained.

[0105]

[Table 1]

¹ H-N of each compound listed in Table 1 above
The MR spectrum data is as follows.

Compound of Reference Example 3 ¹ H-NMR (DMSO-d ₆ ) δ ppm; 3.92
(3H, s), 4.84 (2H, s), 7.15 (1
H, d, J = 8.7 Hz), 8.06 (1H, dd, J
= 2.4 Hz, 8.7 Hz), 8.36 (1H, d, J
= 2.4 Hz).

Compound of Reference Example 4 ¹ H-NMR (DMSO-d ₆ ) δ ppm; 4.91
(2H, s), 7.18 (1H, d, J = 8.7H
z), 8.07 (1H, dd, J = 2.3 Hz, 8.7)
Hz), 8.63 (1H, d, J = 2.3 Hz), 1
2.10 (2H, brs).

Compound of Reference Example 5 ¹ H-NMR (DMSO-d ₆ ) δ ppm; 5.03
(2H, s), 8.83 (1H, brs), 8.97
(1H, d, J = 2.5Hz), 9.20 (1H, d,
J = 1.4 Hz).

Compound of Reference Example 6 ¹ H-NMR (CDCl ₃ ) δ ppm; 4.98 (2
H, s), 7.77 (1H, t, J = 4.9 Hz),
9.05 (2H, d, J = 4.9 Hz).

Example 1 2-Ethoxycarbonyl-3-hydroxy-6- (2-
Bromoacetyl) pyridine 0.77 g, 3,4-diethoxythiobenzamide 0.7 g and ethanol 20 ml
Was added and the mixture was heated under reflux for 3 hours. Ethanol was distilled off, and ethyl acetate-dichloromethane was added to the obtained residue for crystallization to give 0.62 g of 2- (3,4-diethoxyphenyl) -4- (5-hydroxy-6-ethoxycarbonyl-). 2-pyridyl) thiazole is obtained.

Gray powder ¹ H-NMR (DMSO-d ₆ ) δ ppm; 1.35
1.44 (9H, m), 4.07-4.22 (4H,
m), 4.37 (2H, q, J = 7.1Hz), 5.6
7 (1H, brs), 7.08 (1H, d, J = 8.4
Hz), 7.52 to 7.57 (2H, m), 7.55
(1H, d, J = 8.7 Hz), 8.04 (1H,
s), 8.27 (1H, d, J = 8.7 Hz).

Example 2 0.54 g of 2- (3,4-diethoxyphenyl) -4- (5-hydroxy-6-ethoxycarbonyl-2-pyridyl) thiazole was added to 0.34 g of sodium hydroxide and 20 ml of ethanol and water. A 20 ml solution was added, and the mixture was heated under reflux for 2.5 hours. 100 ml of water was added to the reaction solution, which was made acidic with concentrated hydrochloric acid, and then extracted with 70 ml of ethyl acetate four times.
The solvent was concentrated, and the obtained residue was recrystallized from ethyl acetate-diethyl ether to give 0.24 g of 2- (3,4-diethoxyphenyl) -4- (5-hydroxy-6-carboxy-2). -Pyridyl) thiazole is obtained.

Mp: 161.4-162 ° C., light brown powder.

The compounds shown in Table 2 to Table 17 are obtained in the same manner as in Example 1 using appropriate starting materials.

[0116]

[Table 2]

[0117]

[Table 3]

[0118]

[Table 4]

[0119]

[Table 5]

[0120]

[Table 6]

[0121]

[Table 7]

[0122]

[Table 8]

[0123]

[Table 9]

[0124]

[Table 10]

[0125]

[Table 11]

[0126]

[Table 12]

[0127]

[Table 13]

[0128]

[Table 14]

[0129]

[Table 15]

[0130]

[Table 16]

[0131]

[Table 17]

Compound of Example 4 ¹ H-NMR (DMSO-d ₆ ) δ ppm; 1.16-
1.76 (6H, m), 2.49 (1H, s), 3.2
3 (6H, brs), 3.87-4.22 (4H,
m), 4.29 (2H, brs), 4.75 (2H, b)
rs), 7.06 (1H, d, J = 9.0 Hz), 7.
18 (1H, d, J = 8.2 Hz), 7.52 (2H,
brs), 7.88 (1H, s), 7.97-8.06.
(2H, m), 10.95 (1H, brs).

Compound of Example 10 ¹ H-NMR (CDCl ₃ ) δppm; 1.44 (3
H, t, J = 7.0 Hz), 1.46 (3H, t, J =
7.0 Hz), 4.09 (2H, q, J = 7.0H
z), 4.12 (2H, q, J = 7.0Hz), 4.6.
1 (2H, d, J = 5.6Hz), 6.87 (1H,
d, J = 8.2 Hz), 7.03 (1H, brs),
7.05 (1H, d, J = 8.6Hz), 7.26-
7.32 (6H, m), 7.44-7.51 (2H,
m), 7.87 (1H, dd, J = 2.2Hz, 8.6)
Hz), 8.18 (1H, s), 12.55 (1H,
s).

Compound of Example 37 ¹ H-NMR (DMSO-d ₆ ) δ ppm; 1.39
(3H, t, J = 7.0 Hz), 1.41 (3H, t,
J = 7.0 Hz), 3.05-4.08 (12H,
m), 4.13 (2H, q, J = 7.0Hz), 4.1
8 (2H, q, J = 7.0Hz), 7.11 (1H,
d, J = 8.2 Hz), 7.55-7.60 (2H,
m), 8.04 (2H, d, J = 8.5 Hz), 8.2
9 (2H, d, J = 8.5Hz), 8.42 (1H,
s), 9.65 (1H, brs), 9.91 (1H, b
rs), 10.21 (1H, brs), 11.56 (1
H, brs).

Compound of Example 38 ¹ H-NMR (CDCl ₃ ) δppm; 1.45 (3
H, t, J = 7.0 Hz), 1.47 (3H, t, J =
7.0 Hz), 2.63 (3H, s), 4.10-4.
26 (4H, m), 6.88 (1H, d, J = 8.4H
z), 7.35-7.50 (2H, m), 7.89-
8.10 (3H, m), 8.40 (1H, d, J = 6.
7 Hz).

Compound of Example 39 ¹ H-NMR (DMSO-d ₆ ) δ ppm; 1.35
(3H, t, J = 6.9 Hz), 1.37 (3H, t,
J = 6.9 Hz), 4.07-4.21 (4H, m),
7.07 (1H, d, J = 8.3Hz), 7.52 (1
H, dd, J = 2.1 Hz, 8.3 Hz), 7.59
(1H, d, J = 2.1 Hz), 8.03 (2H, d,
J = 7.2 Hz), 8.29 (2H, d, J = 7.2H
z), 8.33 (1H, s).

Compound of Example 40 ¹ H-NMR (CDCl ₃ ) δppm; 1.46 (3
H, t, J = 7.0 Hz), 1.47 (3H, t, J =
7.0 Hz), 2.19 (3H, s), 4.10-4.
25 (4H, m), 5.34 (2H, s), 6.89
(1H, d, J = 8.4 Hz), 7.37 (1H, d
d, J = 2.2 Hz, 8.4 Hz), 7.49 (1H,
d, J = 2.2 Hz), 7.95-8.10 (3H,
m), 8.73 (1H, dd, J = 0.7Hz, 5.2)
Hz).

Compound of Example 41 ¹ H-NMR (CDCl ₃ ) δ ppm; 1.41-1.
86 (6H, m), 1.49 (3H, t, J = 6.5H
z), 1.51 (3H, t, J = 6.5Hz), 3.5
2-3.57 (1H, m), 3.85-3.94 (2
H, m), 3.92 (3H, s), 4.06-4.30.
(7H, m), 4.77 (1H, t, J = 3.2H
z), 6.91 (1H, d, J = 8.4 Hz), 7.0
8 (1H, d, J = 8.7 Hz), 7.35 (1H,
s), 7.52 (1H, dd, J = 1.8 Hz, 8.4)
Hz), 7.61 (1H, d, J = 1.8 Hz), 8.
10 (1H, dd, J = 2.1Hz, 8.7Hz),
8.35 (1H, d, J = 2.1 Hz).

Compound of Example 42 ¹ H-NMR spectrum (DMSO-d ₆ ) δ ppm;
1.36-1.48 (9H, m), 4.13-4.20
(4H, m), 4.69 (2H, q, J = 6.9H
z), 7.12 (1H, d, J = 8.8 Hz), 7.6
1-7.65 (2H, m), 8.75 (2H, d, J =
7.1 Hz), 9.05 (1 H, s), 9.47 (2
H, d, J = 7.1 Hz).

Compound of Example 43 ¹ H-NMR (DMSO-d ₆ ) δ ppm; 1.39
(3H, t, J = 6.9 Hz), 1.41 (3H, t,
J = 6.9 Hz), 4.12-4.27 (4H, m),
7.13 (1H, d, J = 8.2Hz), 7.61-
7.67 (2H, m), 8.38 (1H, dd, J =
1.3 Hz, 5.2 Hz), 8.64 (2H, s),
8.84 (1H, d, J = 5.2 Hz).

Compound of Example 44 ¹ H-NMR (CDCl ₃ ) δppm; 1.49 (3
H, t, J = 7.0 Hz), 1.51 (3H, t, J =
7.0 Hz), 3.72 (1H, brs), 3.94
(5H, s), 4.16 (2H, q, J = 7.0H
z), 4.22 (2H, q, J = 7.0 Hz), 4.2
8 (2H, t, J = 4.1Hz), 6.92 (1H,
d, J = 8.4 Hz), 7.09 (1H, d, J = 8.
7 Hz), 7.37 (1H, s), 7.53 (1H, d)
d, J = 2.1 Hz, 8.3 Hz), 7.61 (1H,
d, J = 2.1 Hz), 8.13 (1H, dd, J =
2.4 Hz, 8.7 Hz), 8.40 (1H, d, J =
2.3 Hz).

Compound of Example 45 ¹ H-NMR (CDCl ₃ ) δppm; 1.49 (3
H, t, J = 7.0 Hz), 1.51 (3H, t, J =
7.0 Hz), 2.42 (3 H, s), 3.90 (3
H, s), 4.15 (2H, q, J = 7.0 Hz),
4.20 (2H, q, J = 7.0Hz), 4.26-
4.31 (2H, m), 4.40-4.44 (2H,
m), 6.92 (1H, d, J = 8.5 Hz), 6.9
6 (1H, d, J = 8.8Hz), 7.33 (2H,
d, J = 8.0 Hz), 7.36 (1H, s), 7.5
2 (1H, dd, J = 2.1 Hz, 8.5 Hz), 7.
61 (1H, d, J = 2.1 Hz), 7.82 (2H,
d, J = 8.0 Hz), 8.07 (1H, dd, J =
2.4 Hz, 8.8 Hz), 8.35 (1H, d, J =
2.4 Hz).

Compound of Example 46 ¹ H-NMR (CDCl ₃ ) δ ppm; 1.49 (3
H, t, J = 7.0 Hz), 1.51 (3H, t, J =
7.0 Hz), 2.44 (6 H, s), 2.89 (2
H, t, J = 5.7 Hz), 3.92 (3H, s),
4.02-4.27 (6H, m), 6.92 (1H,
d, J = 8.4 Hz), 7.05 (1H, d, J = 8.
7 Hz), 7.35 (1 H, s), 7.52 (1 H, d
d, J = 2.0 Hz, 8.3 Hz), 7.61 (1H,
d, J = 2.0 Hz, 8.11 (1H, dd, J =
2.3 Hz, 8.7 Hz), 8.37 (1H, d, J =
2.3 Hz).

Compound of Example 48 ¹ H-NMR (CDCl ₃ ) δ ppm; 0.27 (6
H, s), 1.02 (9H, s), 1.49 (3H,
t, J = 7.0 Hz), 1.51 (3H, t, J = 7.
0 Hz), 2.38 (6H, s), 3.23 (2H,
s), 4.15 (2H, q, J = 7.0Hz), 4.2
2 (2H, q, J = 7.0Hz), 5.23 (2H,
s), 6.90 (1H, d, J = 8.4 Hz), 6.9.
2 (1H, d, J = 8.4 Hz), 7.28 (1H,
s), 7.51 (1H, dd, J = 2.1 Hz, 8.4)
Hz), 7.62 (1H, d, J = 2.1 Hz), 7.
85 (1H, dd, J = 2.3Hz, 8.4Hz),
7.93 (1H, d, J = 2.3 Hz).

Compound of Example 49 ¹ H-NMR (CDCl ₃ ) δppm; 1.47 (3
H, t, J = 7.0 Hz), 1.49 (3H, t, J =
7.0 Hz), 3.90 (3 H, s), 4.12 (2
H, q, J = 7.0 Hz), 4.20 (2H, q, J =
7.0 Hz), 4.50 (2H, d, J = 5.6H
z), 6.71 (1H, d, J = 8.8Hz), 6.9.
0 (1H, d, J = 8.4 Hz), 7.25-7.39
(6H, m), 7.51 (1H, dd, J = 2.1H
z, 8.4 Hz), 7.59 (1H, d, J = 2.1H
z), 7.93 (1H, dd, J = 2.2 Hz, 8.8)
Hz), 8.28 (1H, t, J = 5.6 Hz), 8.
52 (1H, d, J = 2.2 Hz).

Compound of Example 52 ¹ H-NMR (CDCl ₃ ) δppm; 1.49 (3
H, t, J = 7.0 Hz), 1.51 (3H, t, J =
7.0 Hz), 4.18 (2H, q, J = 7.0H
z), 4.42 (2H, q, J = 7.0 Hz), 6.5
7 (1H, dd, J = 1.8Hz, 3.6Hz), 6.
95 (1H, d, J = 8.5 Hz), 7.48 (1H,
s), 7.51 (1H, d, J = 1.3 Hz), 7.7
9 (1H, dd, J = 2.3Hz, 8.5Hz), 8.
26 (1H, d, J = 2.3 Hz), 8.46 (1H,
d, J = 3.6 Hz).

Compound of Example 57 ¹ H-NMR (CDCl ₃ ) δppm; 1.48 (3
H, t, J = 7.0 Hz), 1.50 (6H, t, J =
7.0 Hz), 2.85 (1H, dd, J = 7.3H)
z, 19.2 Hz), 2.95 (1H, dd, J = 1.
9 Hz, 19.2 Hz), 3.50-3.63 (1H,
m), 4.05-4.48 (6H, m), 4.85-
5.02 (1H, m), 6.87 (1H, d, J = 8.
2 Hz), 7.35-7.55 (3H, m).

Compound of Example 60 ¹ H-NMR (CDCl ₃ ) δppm; 1.45 (3
H, t, J = 7.0 Hz), 1.46 (3H, t, J =
7.0 Hz), 4.10-4.24 (5H, m), 4.
85 (2H, s), 6.88 (1H, d, J = 8.4H
z), 7.36 (1H, dd, J = 2.2 Hz, 8.4)
Hz), 7.47 (1H, d, J = 2.2 Hz), 7.
88-7.91 (2H, m), 8.62 (1H, d, J
= 8.3 Hz).

Compound of Example 61 ¹ H-NMR (CDCl ₃ ) δppm; 1.44 (3
H, t, J = 7.0 Hz), 1.47 (3H, t, J =
7.0 Hz), 3.81 (3H, s), 4.10-4.
24 (4H, m), 6.93 (1H, d, J = 8.4H
z), 7.46-7.55 (3H, m), 8.00 (1
H, dd, J = 1.6 Hz, 7.8 Hz), 8.21
(1H, s).

Compound of Example 62 ¹ H-NMR (CDCl ₃ ) δppm; 1.34 (3
H, t, J = 7.1 Hz), 3.88 (3H, s),
3.93 (3H, s), 4.32 (2H, q, J = 7.
1 Hz), 7.47-7.53 (2H, m), 7.78
(1H, s), 7.99 (1H, s), 12.03 (1
H, brs).

Example 70 In the same manner as in Example 1 except that 4 '-(1-morpholino-1-iminomethyl) -2-bromoacetophenone and 3,4-diethoxythiobenzamide were used, 2- (3,4-
Diethoxyphenyl) -4- [4- (1-morpholino-
1-Iminomethyl) phenyl] thiazole is obtained.

Example 71 Example 1 using 3'-amidinoamino-2-bromoacetophenone and 3,4-diethoxythiobenzamide.
In the same manner as in 2- (3,4-diethoxyphenyl)-
4- (3-amidinoaminophenyl) thiazole is obtained.

Example 72 6- [2- (2-hydroxyaminocarbonyl) -2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were prepared in the same manner as in Example 1.
(3,4-Diethoxyphenyl) -4-thiazolyl] pyridine-2-carbohydroxamic acid is obtained.

White powder (recrystallized from ethyl acetate), m
p: 208-210 ° C.

Example 73 6- [1- (2-pyridyl) -1-hydroxymethyl]
Using 2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide, in the same manner as in Example 1, 2- (3,4-diethoxyphenyl) -4- {6-
[1- (2-pyridyl) -1-hydroxymethyl] -2
-Pyridyl} thiazole is obtained.

Example 74 6- [1- (2-furyl) -1-hydroxymethyl]-
2- (α-Bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used in the same manner as in Example 1 to give 2- (3,4-diethoxyphenyl) -4- {6-.
[1- (2-furyl) -1-hydroxymethyl] -2-
Pyridyl} thiazole is obtained.

Example 75 2- (3,4-diethoxyphenyl) was prepared in the same manner as in Example 1 using 6-carboxymethyl-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide. ) -4- (6-Carboxymethyl-2-pyridyl) thiazole is obtained.

Example 76 2- (3,4) was prepared in the same manner as in Example 1 using 6- (2-carboxyethyl) -2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide. -Diethoxyphenyl) -4- [6- (2-carboxyethyl) -2-pyridyl] thiazole is obtained.

Example 77 2- (3,4-diethoxy) was prepared in the same manner as in Example 1 using 6-dimethylaminomethyl-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide. Phenyl) -4- (6-dimethylaminomethyl-2)
-Pyridyl) thiazole dihydrochloride is obtained.

Yellow powder (recrystallized from diethyl ether-ethanol) mp: 195 ° C. (decomposition) Example 78 Using 6-cyanomethyl-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide, In the same manner as in Example 1, 2- (3,4-diethoxyphenyl) -4- (6-cyanomethyl-2-pyridyl) thiazole is obtained.

Example 79 5-Ethoxycarbonyl-2- (α-bromoacetyl)
After using pyrazine and 3,4-diethoxythiobenzamide to react in the same manner as in Example 1, hydrolysis was performed in the same manner as in Example 2 to give 2- (3,4-diethoxyphenyl) -4-. (5-Carboxy-2-pyrazinyl) thiazole is obtained.

White powder (recrystallized from ethyl acetate) ¹ H-NMR spectrum (DMSO-d ₆ ) δ ppm;
1.39 (3H, t, J = 7.0Hz), 1.41 (3
H, t, J = 7.0 Hz), 4.13 (2H, q, J =
7.0 Hz), 4.19 (2H, q, J = 7.0H
z), 7.11 (1H, d, J = 8.5 Hz), 7.5
2-7.72 (2H, m), 8.49 (1H, s),
9.18 (1H, s), 9.60 (1H, s), 13.
83 (1H, brs).

Example 80 4-Ethoxycarbonyl-2- (α-bromoacetyl)
After using pyrimidine and 3,4-diethoxythiobenzamide to react in the same manner as in Example 1, hydrolysis was performed in the same manner as in Example 2 to give 2- (3,4-diethoxyphenyl) -4-. (4-Carboxy-2-pyrimidinyl) thiazole is obtained.

Example 81 5-Ethoxycarbonyl-2- (α-bromoacetyl)
After reacting with imidazole and 3,4-diethoxythiobenzamide in the same manner as in Example 1, Example 2 was performed.
Hydrolysis in the same manner as above gives 2- (3,4-diethoxyphenyl) -4- (5-carboxy-2-imidazolyl) thiazole.

Example 82 4-fluoro-6-ethoxycarbonyl-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used and reacted in the same manner as in Example 1 Hydrolysis as in 2 gives 2- (3,4-diethoxyphenyl) -4- (4-fluoro-6-carboxy-2-pyridyl) thiazole. Example 83 4-methoxy-6-ethoxycarbonyl-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used and reacted in the same manner as in Example 1 and then similar to Example 2. To give 2- (3,4-diethoxyphenyl) -4- (4-methoxy-6-carboxy-2-pyridyl) thiazole. Example 84 4-hydroxy-6-ethoxycarbonyl-2- (α-
After using bromoacetyl) pyridine and 3,4-diethoxythiobenzamide to react in the same manner as in Example 1, 2- (3,4-diethoxyphenyl) was hydrolyzed in the same manner as in Example 2. -4- (4-Hydroxy-6-carboxy-2-pyridyl) thiazole is obtained.

Example 85 4-amino-6-ethoxycarbonyl-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used and reacted in the same manner as in Example 1
Hydrolyzed as in Example 2 to give 2- (3,4-diethoxyphenyl) -4- (4-amino-6-carboxy-
2-pyridyl) thiazole is obtained.

Example 86 4-Dimethylamino-6-ethoxycarbonyl-2-
After using (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide to react in the same manner as in Example 1, hydrolysis was performed in the same manner as in Example 2 to give 2- (3,3).
4-diethoxyphenyl-4- (4-dimethylamino-
6-Carboxy-2-pyridyl) thiazole is obtained.

Example 87 4,6-diethoxycarbonylamino-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were reacted in the same manner as in Example 1 and then Example 2 Hydrolysis in the same manner as above gives 2- (3,4-diethoxyphenyl) -4- (4,6-dicarboxy-2-pyridyl) thiazole.

Light yellow amorphous ¹ H-NMR (DMSO-d ₆ ) δ ppm; 1.39
(3H, t, J = 6.8 Hz), 1.41 (3H, t,
J = 6.8 Hz), 4.10 (2H, q, J = 6.8H)
z), 4.18 (2H, q, J = 6.8Hz), 7.1
2 (1H, d, J = 8.4 Hz), 7.57 (1H,
s), 7.6 (1H, d, J = 8.4 Hz), 8.36
(1H, d, J = 1.4 Hz), 8.73 (1H, d,
J = 1.4 Hz), 13.75 (1H, brs).

Example 88 6- (4-Methyl-1-piperazinyl) -2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were reacted in the same manner as in Example 1 to give 2 −
(3,4-Diethoxyphenyl) -4- [6- (4-methyl-1-piperazinyl) -2-pyridyl] thiazole-3-hydrochloride is obtained.

Yellow needles (recrystallized from ethanol-diethyl ether) mp: 230-234 ° C.

Example 89 6-morpholino-2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were reacted in the same manner as in Example 1 to give 2- (3,4-diethoxy). Phenyl) -4- (6-morpholino-2-pyridyl) thiazole.hydrochloride is obtained.

Yellow needles (recrystallized from ethanol-diethyl ether) mp: 125-128 ° C.

Example 90 6- (1,2,4-triazol-1-yl) -2-
Using (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide, a reaction was performed in the same manner as in Example 1 to give 2- (3,4-diethoxyphenyl) -4- [6-
(1,2,4-triazol-1-yl) -2-pyridyl] thiazole is obtained.

Pale yellow needles (recrystallized from ethanol), m
p: 164-166 ° C.

Example 91 6- (2-Carboxy-1-pyrrolidinyl) -2- (α
-Bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were reacted in the same manner as in Example 1 to give 2
-(3,4-diethoxyphenyl) -4- [6- (2-
Carboxy-1-pyrrolidinyl) -2-pyridyl] thiazole is obtained.

Yellow powder (recrystallized from ethanol-diethyl ether) mp: 170-171 ° C.

Example 92 2- (3,2- (3,2-carboxyethylamino) -2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used in the same manner as in Example 1. Four
-Diethoxyphenyl) -4- [6- (2-carboxyethylamino) -2-pyridyl] thiazole is obtained.

Example 93 4- (2-Dimethylaminoethylamino) -2- (α-
2- (bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used in the same manner as in Example 1 to give 2-
(3,4-Diethoxyphenyl) -4- [4- (2-dimethylaminoethylamino) -2-pyridyl] thiazole.3 hydrochloride is obtained.

Light yellow powder (recrystallized from ethanol-diethyl ether) mp: 240-243 ° C. (decomposition).

Example 94 2- (3,4) was prepared in the same manner as in Example 1 using 6- (2-carboxyethoxy) -2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide. -Diethoxyphenyl) -4- [6- (2-carboxyethoxy) -2-pyridyl] thiazole is obtained.

Example 95 2- (3,2- (3,2-carboxyethylthio) -2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used in the same manner as in Example 1. 4-
Diethoxyphenyl) -4- [6- (2-carboxyethylthio) -2-pyridyl] thiazole is obtained.

Example 96 6- (1-phenyl-1-hydroxymethyl) -2-
Using (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide, in the same manner as in Example 1, 2
-(3,4-diethoxyphenyl) -4- [6- (1-
Phenyl-1-hydroxymethyl) -2-pyridyl] thiazole is obtained.

Example 97 In the same manner as in Example 1 using 6- (1,2-dihydroxyethyl) -2- (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide, 2- (3 , 4
-Diethoxyphenyl) -4- [6- (1,2-dihydroxyethyl) -2-pyridyl] thiazole is obtained.

White needles (recrystallized from ethyl acetate-n-hexane) mp: 112-112.2 ° C.

Example 98 4-Carboxy-6-ethoxycarbonyl-2- (α-
2- (bromoacetyl) pyridine and 3,4-diethoxythiobenzamide were used in the same manner as in Example 1 to give 2-
(3,4-Diethoxyphenyl) -4- (4-carboxy-6-ethoxycarbonyl-2-pyridyl) thiazole is obtained.

White powder (recrystallized from ethanol) mp: 188-189 ° C.

¹ H-NMR (CDCl ₃ ) δ ppm;
1.37-1.66 (9H, m), 4.17 (2H,
q, J = 7.1 Hz), 4.24 (2H, q, J = 7.
1Hz), 4.53 (2H, q, J = 7.4Hz),
6.94 (1H, d, J = 8.7 Hz), 7.57 (1
H, d, J = 8.7 Hz), 7.63 (1 H, s),
8.30 (1H, s), 8.60 (1H, s), 8.9
9 (1H, s).

The compounds shown in Tables 18 to 23 below are obtained in the same manner as in Example 1 using appropriate starting materials.

[0190]

[Table 18]

[0191]

[Table 19]

[0192]

[Table 20]

[0193]

[Table 21]

[0194]

[Table 22]

[0195]

[Table 23]

Compound of Example 99 ¹ H-NMR (CDCl ₃ ) δ ppm; 1.45-1.
54 (6H, m), 2.98-3.01 (1H, m),
3.18-3.22 (1H, m), 4.06-4.09
(1H, m), 4.10 (2H, q, J = 7.0H
z), 4.19 (2H, q, J = 7.0Hz), 6.8
9 (1H, d, J = 8.4 Hz), 7.14 (1H, d
d, J = 0.9 Hz, 7.8 Hz), 7.50 (1H,
dd, J = 2.1 Hz, 8.4 Hz), 7.62 (1
H, d, J = 2.1 Hz), 7.73 (1H, t, J =
7.8 Hz), 8.06 (1 H, s), 8.16 (1
H, dd, J = 0.9 Hz, 7.8 Hz).

Compound of Example 115 ¹ H-NMR (CDCl ₃ ) δppm; 1.50 (3
H, t, J = 6.8 Hz), 1.53 (3H, t, J =
6.8 Hz), 4.17 (2H, q, J = 6.8H)
z), 4.22 (1H, d, J = 6.8 Hz), 6.9.
3 (1H, d, J = 8.4 Hz), 7.48 (1H, d
d, J = 2.1 Hz, 8.4 Hz), 7.62 (1H,
d, J = 2.1 Hz), 8.04 (1H, dd, J =
1.6 Hz, 4.0 Hz), 8.12 (1H, s),
8.44 (1H, d, J = 4.0Hz), 9.06 (1
H, d, J = 1.6 Hz).

Compound of Example 118 ¹ H-NMR (CDCl ₃ ) δppm; 1.51 (3
H, t, J = 7.0 Hz), 1.52 (3H, t, J =
7.0 Hz), 4.18 (2H, q, J = 7.0H
z), 4.24 (2H, q, J = 7.0Hz), 6.9.
5 (1H, d, J = 8.4 Hz), 7.54 (1H,
d, J = 2.1 Hz, 8.4 Hz), 7.62 (1H,
d, J = 2.1 Hz), 8.21 (1H, s), 8.8
3 (1H, s), 9.68 (1H, s).

Compound of Example 119 ¹ H-NMR (CDCl ₃ ) δppm; 1.50 (3
H, t, J = 7.0 Hz), 1.51 (3H, t, J =
7.0 Hz), 4.15 (2H, q, J = 7.0H
z), 4.31 (2H, q, J = 7.0Hz), 6.9.
2 (1H, d, J = 8.4 Hz), 7.57 (1H, d
d, J = 2.1 Hz, 8.4 Hz), 7.64 (1H,
t, J = 5.2 Hz), 7.90 (1H, d, J = 2.
1Hz), 8.53 (1H, s), 9.17 (2H,
d, J = 5.2 Hz).

Compound of Example 120 ¹ H-NMR (CDCl ₃ ) δ ppm; 1.45-1.
52 (6H, m), 4.09-4.27 (4H, m),
6.89 (1H, d, J = 8.4 Hz), 7.23-
7.63 (4H, m), 8.50-8.56 (1H,
m), 9.51 (1H, s).

Example 123 6- (1-carboxy-1-hydroxymethyl) -2-
Using (α-bromoacetyl) pyridine and 3,4-diethoxythiobenzamide, in the same manner as in Example 1, 2
-(3,4-diethoxyphenyl) -4- [6- (1-
Carboxy-1-hydroxymethyl) -2-pyridyl]
Get thiazole.

Example 124 To 15 ml of a suspension of 172 mg of 60% sodium hydride in 15 ml of dimethyl sulfoxide was added 880 mg of trimethylsulfonium iodide, the mixture was reacted at room temperature for 1 hour, and then 2- (3,4-diethoxyphenyl)-. A solution of 1 g of 4- (6-formyl-2-pyridyl) thiazole in 20 ml of dimethyl sulfoxide was added dropwise. After stirring overnight at room temperature, the reaction solution was poured into 150 ml of ice water, and ethyl acetate
Extract 3 times with ml. The extract was washed with water and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 4: 1) to give 760 mg of 2- (3,4-diethoxyphenyl) -4. -(6-Oxiranyl-2-pyridyl) thiazole was obtained.

White solid ¹ H-NMR (CDCl ₃ ) δ ppm; 1.45-1.
54 (6H, m), 2.98-3.01 (1H, m),
3.18-3.22 (1H, m), 4.06-4.09
(1H, m), 4.10 (2H, q, J = 7.0H
z), 4.19 (2H, q, J = 7.0Hz), 6.8
9 (1H, d, J = 8.4 Hz), 7.14 (1H, d
d, J = 0.9 Hz, 7.8 Hz), 7.50 (1H,
dd, J = 2.1 Hz, 8.4 Hz), 7.62 (1
H, d, J = 2.1 Hz), 7.73 (1H, t, J =
7.8 Hz), 8.06 (1 H, s), 8.16 (1
H, dd, J = 0.9 Hz, 7.8 Hz).

Example 125 700 mg of 2- (3,4-diethoxyphenyl) -4- (6-oxiranyl-2-pyridyl) thiazole in 30 ml of dimethyl sulfoxide was added to potassium hydroxide 505.
A solution of 30 mg of water in 30 ml was added, and the mixture was stirred at 100 ° C for 7 hours. After extraction with 50 ml of ethyl acetate three times, the extract was dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 20: 1) and then recrystallized from ethyl acetate-n-hexane to give 350 mg of 2-.
(3,4-diethoxyphenyl) -4- [6- (1,2
-Dihydroxyethyl) -2-pyridyl] thiazole was obtained.

White needle mp: 112-112.2 ° C.

Example 126 2- (3,4-diethoxyphenyl) -4- (2-pyridyl) thiazole 49.6 g methylene chloride 250 ml
To the solution, under ice cooling, metachloroperbenzoic acid (80%) 3
After dropwise adding a solution of 8.5 g of methylene chloride in 400 ml,
Stir at room temperature for 2 hours. Aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the layers are separated. The organic layer is washed with aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was distilled off and the obtained residue was recrystallized from ethyl acetate,
There were obtained 45.2 g of 2- [2- (3,4-diethoxyphenyl) -4-thiazolyl] pyridine 1-oxide.

Light yellow needle mp: 121-123.5 ° C.

In the same manner as in Example 126, but using appropriate starting materials, the above Examples 21, 38, 39, 115, 116 were used.
And 120 compounds were obtained.

Example 127 A mixture of 2- [2- (3,4-diethoxyphenyl) -4-thiazolyl] pyridine 1-oxide (3 g), methyl cyanoacetate (2.6 g) and acetic anhydride (150 ml) at 110 ° C. for 4 hours. After stirring, the mixture was allowed to cool, and the precipitated crystals were collected by filtration, ethanol-
Recrystallized from dimethylformamide to give 2.1 g of 2-
(3,4-Diethoxyphenyl) -4- [6- (1-ethoxycarbonyl-1-cyanomethyl) -2-pyridyl] thiazole was obtained.

Yellow needle mp: 240.5-242.5 ° C.

Example 128 2- [2- (3,4-diethoxyphenyl) -4-thiazolyl] pyridine 1-oxide A suspension of 26.3 g of acetonitrile in 500 ml of acetonitrile was mixed with 21.3 m of triethylamine.
1 and 30.7 ml of cyanotrimethylsilane were added,
Heat to reflux for 2 hours. After distilling off the solvent, an aqueous sodium carbonate solution is added to the obtained residue, and the mixture is extracted with methylene chloride.
After drying over magnesium sulfate, the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography (eluent;
Methylene chloride) and then recrystallized from ethanol to give 22.2 g of 2- (3,4-diethoxyphenyl).
-4- (6-Cyano-2-pyridyl) thiazole was obtained.

White needle mp: 134-136 ° C.

Similar to Example 128, using the appropriate starting materials, Examples 43, 117, 118 and 12 above.
1 compound was obtained.

Example 129 To a solution of 2- (3.4-diethoxyphenyl) -4- (6-cyano-2-pyridyl) thiazole (1.5 g) in dimethylformamide (30 ml) was added ammonium chloride (280 mg) and sodium azide (380 mg). The mixture was stirred at 0 ° C for 9 hours. The reaction solution was acidified by adding dilute hydrochloric acid, and extracted three times with 150 ml of ethyl acetate. After drying over anhydrous sodium sulfate, the solvent is concentrated. Recrystallize from ethanol-ethyl acetate to give 1.19 g of 2- (3,4-diethoxyphenyl) -4- [6- (1,2,3,4-tetrazol-5-yl) -2-pyridyl ) Obtained thiazole.

White powder mp: 243-248 ° C.

The compound of Example 13 was obtained in the same manner as in Example 129, using appropriate starting materials.

Example 130 10.1 g of 2- (3,4-diethoxyphenyl) -4- (6-cyano-2-pyridyl) thiazole, 6.48 g of thioacetamide and 100 ml of a solution of 25% hydrochloric acid-DMF in 100 to 100 ml. Heat and stir at 110 ° C. for 3 hours. The reaction solution is poured into 500 ml of ice water, 1 liter of ethyl acetate is added, and the precipitated insoluble matter is filtered off. After separating the filtrate, it is extracted with 500 ml of ethyl acetate. After washing with water and saturated saline, it is dried over magnesium sulfate. Then, the solvent was distilled off, and the residue was recrystallized from ethanol to give 10.2 g.
2- (3,4-diethoxyphenyl) -4- (6-carbothioamido-2-pyridyl) thiazole was obtained.

Yellow powder mp: 177.5-178 ° C.

Example 131 2- (3,4-diethoxyphenyl) -4- (6-carbothioamido-2-pyridyl) thiazole (1.08 g) in benzene (20 ml) was suspended in dimethyl sulfate (0.34 ml).
Is added and the mixture is heated under reflux for 45 minutes. After cooling, the precipitated crystals were collected by filtration and recrystallized from benzene to give 1.09 g of 2- (3,4
-Diethoxyphenyl) -4- [6- (1-imino-1)
-Methylthiomethyl) -2-pyridyl] thiazole monomethylsulfate was obtained.

Yellow powder mp: 174-177 ° C.

Example 132 2- (3,4-diethoxyphenyl) -4- [6- (1
0.81 g of -imino-1-methylthiomethyl) -2-pyridyl] thiazole monomethylsulfate and a saturated ammonia-methanol solution are heated to reflux in a sealed tube at 100 ° C for 3 hours. After distilling off the solvent, the residue was recrystallized from chloroform-diethyl ether to obtain 0.44 g of 2- (3,4-diethoxyphenyl) -4- (6-amidino-2-pyridyl) thiazole monomethylsulfate. It was

White powder mp: 288-290 ° C.

Example 133 2- (3,4-diethoxyphenyl) -4- [6- (1
To a suspension of 1.55 g of -imino-1-methylthiomethyl) -2-pyridyl] thiazole in 40 ml of methanol, 278 mg of hydroxylamine hydrochloride was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. After distilling off the solvent and adding water, 5
The mixture is made alkaline with an aqueous solution of sodium N-hydroxide and the precipitated crystals are collected by filtration. Recrystallized from ethyl acetate to give 1.03 g of 2- (3,4-diethoxyphenyl) -4- [6-
(N'-hydroxyamidino) -2-pyridyl] thiazole was obtained.

White powder mp: 218-220 ° C.

Example 134 2- (3,4-diethoxyphenyl) -4- (6-oxiranyl-2-pyridyl) thiazole (1 g) in methanol (200 ml) was added with 50% dimethylamine aqueous solution (2.4 g).
Was added and refluxed overnight. The precipitate was filtered, the filtrate was concentrated, purified by silica gel column chromatography (eluent; dichloromethane: methanol = 20: 1) and silica gel thin layer chromatography, and recrystallized from diethyl ether-dichloromethane to give 140 mg. 2-
(3,4-Diethoxyphenyl) -4- [6- (1-hydroxy-2-dimethylaminoethyl) -2-pyridyl] thiazole (A) was obtained. Also, recrystallized from diethyl ether-n-hexane to give 28 mg of 2- (3,3
4-Diethoxyphenyl) -4- [6- (1-dimethylamino-2-hydroxyethyl) -2-pyridyl] thiazole (B) was obtained.

(A); White powder, mp: 106-110 ° C (B); White powder, mp: 107-109.5 ° C.

The compound of Example 110 was obtained in the same manner as in Example 134, using appropriate starting materials.

Pharmacological Tests The pharmacological tests of the compounds of the present invention were carried out by the following methods.

[0229] O from human neutrophils ₂ ^-. Act human neutrophils to generation, M Markert et al method [Method in-
Enzymology Methods in Enzymology, 105 ；
358-365, 1984]. That is, anticoagulated whole blood obtained from a healthy adult was subjected to dextran-hypotonic treatment to obtain white blood cells. The white blood cells were further subjected to a density gradient centrifugation method using Ficoll-Paque to obtain a neutrophil fraction.

[0230] O ₂ ^- For a generation, BN Cronstein
Et al. [J. Exp. Med.], 158 , 1160-117.
7 (1983)], and ferricitochrome C (ferr
icytochrome C) method. That is, in a Hepes-Buffered Hanks' (pH 7.4) solution, 1.3 mg / ml ferricitochrome C
(Ferricytochrome C) and 5 μg / ml cytochalasin B (37 ° C.) at 1 × 10 ⁻⁶ ce
3 × 10 ⁻⁷ M N-formyl-L-methionyl-L-leucyl-L-phenylalanine (N-Form).
yl-L-Methionyl-L- Leucyl-L-Phenylalanine, fML
The amount of ferrocytochrome C (ferrocytochrome C) stimulated by P) and reduced for 4 minutes was measured for absorbance at a wavelength of 550 nm using a spectrophotometer to obtain 25.1 μg / m 2.
l Superoxide dismutase
mutase, SOD) the difference between the absorbance in the presence of O ₂ ^- was produced amount. The test drug was dimethyl sulfoxide (D
MSO) and add to neutrophils before adding fMLP
Preincubation was carried out at 7 ° C for 20 minutes. O ₂ ^- inhibition of generation compared to those with the addition of only a solvent (DMSO), to calculate the% inhibition rate was expressed in 50% inhibitory concentration (IC _50).

Test compound 1. 2- (3,4-diethoxyphenyl) -4- [4-
(2-Hydroxyethoxy) -3-carboxyphenyl] thiazole 2.5- [2- (3,4-diethoxyphenyl) -4-
Thiazol] -2-hydroxybenzenecarbohydroxamic acid 3. 2- (3,4-diethoxyphenyl) -4- (4-
Carbamoylphenyl) thiazole 4. 2- (3,4-diethoxyphenyl) -4- (2-
Carboxy-3-hydroxy-6-pyridyl) thiazole 5. 2- (3,4-diethoxyphenyl) -4- [3-
(1,2,3,4-Tetrazol-5-yl) -4-hydroxyphenyl] thiazole 6. 2- (3,4-diethoxyphenyl) -4- (4-
Carboxymethylaminocarbonylphenyl) thiazole 7.4- [2- (3,4-diethoxyphenyl) -4-
Thiazolyl] benzenecarbohydroxamic acid 8. 2- (3,4-diethoxyphenyl) -4- (3-
Carbazoyl-4-hydroxyphenyl) thiazole 9. 2- (3,4-diethoxyphenyl) -4- (4-
Carbazoylphenyl) thiazole 10.5- [2- (3,4-diethoxyphenyl) -4-
Thiazolyl] -2-hydroxy-3- (2-methyl-2
-Propenyl) benzenehydroxamic acid 11.2- (3,4-diethoxyphenyl) -4- (2-
Hydroxymethyl-4-methyl-6-pyridyl) thiazole 12.2- (3,4-diethoxyphenyl) -4- (1-
Oxo-2-hydroxymethyl-4-methyl-6-pyridyl) thiazole 13. Disodium [2- (3,4-dimethoxyphenyl) -4-thiazolyl] salicylhydroxamate 14. 5- [2- (3,3 4-diethoxyphenyl) -4-
Thiazolyl] -2-hydroxy-3-methylbenzene hydroxamic acid 15. Ethyl [2- (3,4-diethoxyphenyl) -4
-Thiazolyl] benzenehydroxamate 16.1- {3- [2- (3,4-dimethoxyphenyl)
-4-thiazolyl] phenyl} -2-methylisothiourea hydroiodide 17.2- (3,4-diethoxyphenyl) -4- (4-
Carbothioamidophenyl) thiazole 18.2- (3,4-diethoxyphenyl) -4- (N '
-Hydroxyamidinophenyl) thiazole 19. 2- (3,4-diethoxyphenyl) -4- [4-
(1-Imino-1-methylthiomethyl) phenyl] thiazole monomethylsulfate 20.1- {4-[(3,4-diethoxyphenyl) -4
-Thiazolyl] phenyl} thiourea 21. 4- [2- (3,4-diethoxyphenyl) -4-
Thiazolyl] benzohydraside imide / hydrochloride 22.2-methyl-1- {4- [2- (3,4-diethoxyphenyl) -4-thiazolyl]} benzisothiourea / monomethyl sulfate 23.2- ( 3,4-diethoxyphenyl) -4- (2-
Pyrazinyl) thiazole 24.2- (3,4-diethoxyphenyl) -4- (6-
Carbothioamido-2-pyridyl) thiazole 25.2- (3,4-diethoxyphenyl) -4- [6-
(1-Imino-1-methylthiomethyl) -2-pyridyl] thiazole monomethylsulfate 26.2- (3,4-diethoxyphenyl) -4- [6-
(1,2,3,4-Tetrazol-5-yl) -2-pyridyl] thiazole 27.2- (3,4-diethoxyphenyl) -4- [4-
(4-Methyl-1-piperazinyl) -2-pyridyl] thiazole dihydrochloride 28.2- (3,4-diethoxyphenyl) -4- {6-
[2- (4-Methyl-1-piperazinyl) -1-hydroxyethyl] -2-pyridyl} thiazole 29.2- (3,4-diethoxyphenyl) -4- [6-
(N'-hydroxyamidino) -2-pyridyl] thiazole 30.2- [2- (3,4-diethoxyphenyl) -4-
Thiazolyl] -6-pyrimidylcarboxylic acid sodium salt The results are shown in Table 24.

[0232]

[Table 24]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location // A61K 31/425 ACL 9360-4C AED 9360-4C 31/44 ABN 9360-4C 31/495 ABS 9360-4C (C07D 417/04 213: 00 6701-4C 277: 00) 9051-4C (C07D 417/04 241: 00 8615-4C 277: 00) 9051-4C (C07D 417/04 307: 00 7252-4C 277: 00) 9051-4C (C07D 417/10 257: 00 7433-4C 277: 00) 9051-4C (C07D 498/04 265: 00 9283-4C 307: 00) 7252-4C

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents a phenyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring. R
² is a pyridylcarbonyl group which may have a lower alkoxycarbonyl group or a carboxy group as a substituent; 5 to 1 having 1 to 3 nitrogen atom, oxygen atom or sulfur atom
5-membered monocyclic, bicyclic or tricyclic heterocyclic residue; or a group (Wherein R ³ is a carboxy group, a lower alkoxycarbonyl group, a hydroxyl group-substituted lower alkyl group, a lower alkoxy group,
Tri-lower alkyl represents a silyloxy group, a hydroxyl group or a hydrogen atom. R ⁴ represents a hydrogen atom, a lower alkenyl group or a lower alkyl group. R ⁵ may have an amino lower alkoxycarbonyl group which may have a lower alkyl group as a substituent, an amino lower alkoxy substituted lower alkyl group which may have a lower alkyl group as a substituent, and a lower alkyl group as a substituent. Amino lower alkoxy group, a lower alkoxy group having a tetrahydropyranyloxy group or a hydroxyl group, a phenylsulfonyloxy group-substituted lower alkoxy group which may have a lower alkyl group as a substituent on the phenyl ring, a hydroxysulfonyl group,
An amino-lower alkanoyloxy-substituted lower alkyl group which may have a lower alkyl group as a substituent, a lower alkynyloxy group, a group-(CO) _l -NHR ⁶ (l represents 0 or 1, R ⁶ represents a hydroxyl group, phenyl lower group An alkyl group,
Carboxy group-substituted lower alkyl group, amino group, aminothiocarbonyl group which may have benzoyl group, amidino group, group (R ⁷ represents a lower alkylthio group or a morpholino lower alkylamino group.), A hydrogen atom or a phenyl lower alkoxycarbonyl group-substituted lower alkyl group. ), An amino-substituted lower alkanoyloxy lower alkyl group which may have a lower alkyl group as a substituent, an aminothiocarbonyl group, a group (R ⁸ represents a hydroxyimino group, a lower alkylthio group, a hydrazino group, a lower alkoxy group, a piperazinyl group which may have a lower alkyl group, a morpholino group or a morpholino lower alkylamino group), 1, 2, 3, 4
-A 1,3,4-oxadiazolyl group which may have a tetrazolyl group or an oxo group. ) Is shown. The monocyclic, bicyclic or tricyclic heterocyclic residue has a lower alkyl group, an oxiranyl group, a hydroxyl group-substituted lower alkyl group, a lower alkanoyl group, a lower alkanoyloxy lower alkyl group, a cyano group or an oxo group as a substituent. , A carboxy-substituted lower alkyl group, a lower alkyl group having a lower alkoxycarbonyl group or a cyano group as a substituent, a lower alkoxycarbonyl group, a pyridyl group, a furyl group, a phenyl group, a carboxy group and a hydroxyl group as a substituent. A lower alkyl group having 1 to 2 groups, a carboxy-substituted lower alkoxy group, a carboxy-substituted lower alkylthio group, a carboxy group, a halogen atom, a lower alkoxy group, a hydroxyl group, a group-(A) ₁ -NR ⁹ R ¹⁰ (A is a substituted The group represents a lower alkylene group which may have a hydroxyl group or a group -CO. R ⁹ and R ¹⁰ are the same or different and each has a hydrogen atom, a lower alkyl group, a hydroxyl group, a pyrrolidinyl lower alkyl group, a carboxy-substituted lower alkyl group or a lower alkyl group or a phenyl lower alkoxycarbonyl group as a substituent. And R ⁹ and R ¹⁰ are, together with the nitrogen atom to which they are bound, bound to each other through a nitrogen atom or an oxygen atom or with no intervening nitrogen atom or oxygen atom to form a saturated 5- or 6-membered ring. Or an unsaturated heterocycle may be formed, which may be substituted with a lower alkyl group or a carboxy group), an amidino group, an aminothiocarbonyl group and a group (R ^8a represents a hydroxyamino group or a lower alkylthio group.) It may have 1 to 3 groups selected from the group consisting of. ] The thiazole derivative and its salt represented by these.