JPH09255678A - Thiazole derivative-metal complex - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject metal complex having excellent active oxygen inhibitory activity, thus useful for treating diseases due to excessive production of active oxygen species such as myocardial infarction and cerebral infarction, by reaction of a specific thiazole derivative with a metal or metal salt. SOLUTION: This new complex is composed of a thiazole derivative (anionic form thereof) of formula I [R<1> is (substituted) phenyl; R<2> is a 5-15-membered mono- or poly-(substituted)heterocyclic residue bearing 1-3 N, O, S, etc.; R<3> and R<4> are each H, a lower alkyl, hydroxyl, pyrrolidinyl lower alkyl, carboxyl- substituted lower alkyl, (substituted) amino-substituted lower alkyl, etc.] and a metal or metal salt, having excellent active oxygen inhibitory activity, thus being useful as a therapeutic agent for diseases due to excessive production of active oxygen. This complex is obtained by reaction of the compound of formula I such as 2-(3,4-diethoxyphenyl)-4-(2-carboxy-6-pyridyl)thiazole with a metal salt such as cupric sulfate to form a compound having structure expressed by formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiazole derivative-metal complex.

[0002]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel thiazole derivative-metal complex useful as a drug.

[0003]

The thiazole derivative-metal complex of the present invention is a novel compound not described in the literature and is a complex of the following thiazole derivative or an anion thereof with a metal or a metal salt.

The thiazole derivative has the general formula

[0005]

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[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 nitrogen atom, oxygen atom or sulfur atom
It shows a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic residue having 3 to 3. The monocyclic, bicyclic or tricyclic heterocyclic residue may have a lower alkyl group, a benzoyl group, a lower alkylthio group, a phenylaminothiocarbonyl group as a substituent, or an amino group which may have a lower alkyl group as a substituent. Lower alkoxycarbonyl group, 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 ³ R
⁴ (A represents a lower alkylene group which may have a hydroxyl group as a substituent or a group -CO. L represents 0 or 1.
R ³ and R ⁴ are the same or different and are amino-substituted, which may have 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. A lower alkyl group is shown. Further, R ³ and R ⁴ together with the nitrogen atom to which they are bonded are 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. Good. The heterocycle may be substituted with a lower alkyl group or a carboxy group. ), Amidino groups, aminothiocarbonyl groups and groups

[0007]

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(R ⁵ represents a hydroxyamino group or a lower alkylthio group), and may have 1 to 3 groups selected from the group consisting of. ] Is represented.

[0009] 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, an important role in host defense It is believed to be responsible. 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.Ph.
armacol.Toxicol.), 26 , 201 (1986); BA
Freeman et al. , Laboratory Investigation, 47 , 412 (1
982); E. Braunwald., RAKloner, Journal of Clinical Investigation (J. Clin. In
vest.), 76 , 1713 (1985); JL Romson e.
t al. , Circulation, 67 , 1
016 (1983)].

A complex of a thiazole derivative represented by the above general formula (1) or an anion thereof with a metal or a metal salt (hereinafter referred to as "the compound of the present invention") suppresses the release of active oxygen from neutrophils. In addition to having the activity of removing (scavenging) active oxygen species (radicals). Therefore, it exerts the action of preventing the in vivo production of lipid peroxide and 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 ulcer such as stress ulcer; 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 due to transplantation, microcirculatory failure, etc. , 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, Adult Respiratory Distress Syndrome (Adult Respinatory Dist
It is useful in the pharmaceutical field as a therapeutic agent for ress Syndrom, ARDS, etc.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION More specifically, each group shown in the present specification is as follows.

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

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.

1 to 3 nitrogen atom, oxygen atom or sulfur atom
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.

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 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. .

The amino lower alkoxycarbonyl group which may have a lower alkyl group as a substituent includes, 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 group having 1 to 6 carbon atoms as a substituent such as ethoxycarbonyl group An alkoxycarbonyl group can be illustrated.

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

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.

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.

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 alkoxycarbonyl group include linear groups having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. Alternatively, a branched alkoxycarbonyl group can be exemplified.

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 is, for example, (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 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.

Examples of the carboxy-substituted lower alkylthio group include carboxymethylthio, 2-carboxyethylthio, 1-carboxyethylthio, 3-carboxypropylthio, 4-carboxybutylthio, 5-carboxypentylthio, 6-carboxyhexylthio. , 1,1
-Dimethyl-2-carboxyethylthio, 2-methyl-
Examples thereof include 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.

Examples of the halogen atom include a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

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.

As the pyrrolidinyl lower alkyl group, for example, (1-pyrrolidinyl) methyl, 2- (1-pyrrolidinyl) ethyl, 1- (1-pyrrolidinyl) ethyl, 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.

Examples of the phenyl lower alkoxycarbonyl group include benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl and 6-phenyl. Hexyloxycarbonyl, 1,
1-dimethyl-2-phenylethoxycarbonyl, 2-
Examples thereof include a phenylalkoxycarbonyl group in which an alkoxycarbonyl moiety such as a methyl-3-phenylpropoxycarbonyl group is a linear or branched alkoxycarbonyl 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 5- or 6-membered heterocyclic ring formed by R ³ and R ⁴ 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 lower alkyl group or a carboxy 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 straight chain or branched alkyl group having 1 to 6 carbon atoms or the above-mentioned hetero group substituted with carboxy group A ring can be illustrated.

Lower alkyl group, benzoyl group, lower alkylthio group, phenylaminothiocarbonyl group, amino lower alkoxycarbonyl group which may have a lower alkyl group as a substituent, oxiranyl group, hydroxyl group-substituted lower alkyl group, lower alkanoyl group, Lower alkanoyloxy lower alkyl group, cyano group, oxo group, carboxy-substituted lower alkyl group, lower alkoxycarbonyl group as a substituent or lower alkyl group having a cyano group, lower alkoxycarbonyl group, pyridyl group as a substituent, furyl group, phenyl Lower alkyl group having 1 to 2 groups selected from the group consisting of group, carboxy group and hydroxyl group, carboxy substituted lower alkoxy group, carboxy substituted lower alkylthio group, carboxy group, halogen atom, lower alkoxy group, hydroxyl group, group ^{(A) l-NR 3 R} 4 ( wherein A represents an optionally substituted lower alkylene group or a group -CO have a hydroxyl group as a substituent .l represents 0 or 1 .R ³ and R
⁴ is the same or different, 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. Show. Also R ³ and R
⁴ may be bonded to each other with a nitrogen atom to which they are bonded, through 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. ), An amidino group, an aminothiocarbonyl group and 1 to 3 groups selected from the group represented by the above Chemical formula 4 (R ⁵ is a hydroxyamino group or a lower alkylthio group), for example, dibenz [B, e] azepin-3-yl-6-one, 4-oxo-1,4-dihydroquinolyl, 1-oxopyridyl, 2
-Oxopyridyl, 1-methyl-3,4-dihydrocarbostyril, 1-ethylcarbostyryl, 1-butyl-
3,4-dihydrocarbostyril, 1-hexylcarbostyryl, 6-methoxy-3,4-dihydrocarbostyryl, 3-oxo-4-methyl-3,4-dihydro-2
H-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-4a, 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-tetrahydroquinolyl, 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-benzoxazinini Le, 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-carboxy Pyridyl, 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- (1,2,2
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- 1-cyanomethyl) pyridyl, 1-benzoyl-1,2,3,4-tetrahydroquinolyl, 1-benzoylcarbostyryl, 4-benzoyl-3,4-dihydro-2H-1,4-benzothiazolyl, 4-benzoyl- 1,2,3,4-tetrahydroquinoxalinyl,
4-benzoyl-3,4-dihydro-2H-1,4-benzoxazinyl, 2-ethylthiobenzoxazolyl, 2-propylthiobenzimidazolyl, 2-butylthiobenzothiazolyl, 6-pentylthiocarboyl Straight or branched chain alkyl having 1 to 6 carbon atoms such as styryl, 7-hexylthio-3,4-dihydrocarbostyryl, 2- (2-dimethylaminoethoxycarbonyl) pyridyl, 2-phenylaminothiocarbonylpyridyl group Group, benzoyl group, linear or branched alkylthio group having 1 to 6 carbon atoms, phenylaminothiocarbonyl group, 1 to 2 linear or branched alkyl group having 1 to 6 carbon atoms as a substituent 1 to 3 linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms, an oxiranyl group, and a hydroxyl group having an amino group that may have A linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkanoyl group having 1 to 6 carbon atoms, or a linear or branched alkanoyloxy group having 1 to 6 carbon atoms. A straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, a cyano group, an oxo group, and a carboxyalkyl group which is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety. , A linear or branched alkyl group having 1 to 6 carbon atoms as a substituent, which has a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms or a cyano group,
A linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a pyridyl group as a substituent, a furyl group, a phenyl group,
1 to 2 groups selected from the group consisting of carboxy group and hydroxyl group
A linear or branched alkyl group having 1 to 6 carbon atoms,
A carboxyalkoxy group in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, a carboxyalkylthio group in which the alkylthio moiety is a straight chain or branched chain alkylthio group having 1 to 6 carbon atoms, carboxy group, a halogen atom, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, group ^{- (a) l NR 3 R} 4 ( wherein a represents which may have a hydroxyl group as a substituent carbon Represents a straight-chain or branched alkylene group of the formulas 1 to 6 or a group -CO. L represents 0 or 1. R ³ and R ⁴ are the same or different and each is a hydrogen atom, a straight chain of 1 to 6 carbon atoms. A chain or branched alkyl group, 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 a linear or branched alkyl group having 1 to 6 carbon atoms Carboxyalkyl, a branched alkyl group , Or 1 to a straight-chain or branched alkyl group or a linear or branched phenyl alkoxycarbonyl group having 1 to 6 carbon atoms having 1 to 6 carbon atoms as a substituent
A linear or branched alkyl group having 1 to 6 carbon atoms having an amino group which may be 2 is shown. Also R ³ and R
^{4 and} , 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 saturated or unsaturated heterocyclic ring of 5 to 6 membered ring. A linear or branched alkyl group having 1 to 6 carbon atoms or a carboxy group may be substituted on the heterocycle. ),
An amidino group, an aminothiocarbonyl group and a group represented by the above chemical formula 4 (R ⁵ is a hydroxyamino group or a carbon number of 1 to 6)
Is a linear or branched alkylthio group. The heterocycle having 1 to 3 groups selected from the group can be exemplified.

Of the heterocycles constituting the heterocyclic group represented by R ² , pyridine, pyrrole, thiophene, pyrimidine, pyrazine, thiazole, furan and the like are particularly preferable,
Further, it is preferable that at least one carboxyl group is substituted on the heterocycle.

The anion form of the thiazole derivative represented by the general formula (1) is, as a substituent on the heterocycle represented by R ² in the derivative, a hydroxyl-substituted lower alkyl group; a carboxy-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 group; a carboxy-substituted lower alkoxy group; a carboxy-substituted lower alkylthio group; a carboxy group; a hydroxyl group; ^{- (A) l-R 3} R 4 '
(A, l and R ³ represent the same .R 4 ^'is hydroxyl group or a carboxy-substituted lower alkyl group as defined above. Also this R ³ and R
^{4 'are} coupled to each other without these or via a nitrogen atom or oxygen atom together with the nitrogen atom bonded 5
A 6-membered saturated or unsaturated heterocycle may be formed.
At least one carboxy group as a substituent is substituted on the heterocycle. ) And the group

[0037]

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An example is a compound in which at least one hydroxyl group or carboxy group of (R ^{5 ′} represents a hydroxyamino group) is converted to an anion (—O ⁻ or —COO ⁻ ).

Examples of the metal constituting the compound (complex) of the present invention include, for example, Group IA, Group IIA, Group IIB, Group
IIIB genus, IVB and VB genus typical metal and periodic table IIIA group, IVA group, VA group, VIA group, VIIA group, VIIA group,
Examples include so-called d-block transition metals of Group VIII and Group IB. Among these, transition metals such as iron, copper, platinum, vanadium, nickel, cobalt and manganese, and typical metals such as barium and zinc are particularly preferable.

The thiazole derivative of the general formula (1) of the present invention can be obtained, for example, from JP-A-5-51318 and JP-A-6-6.
It is disclosed in Japanese Patent No. 5222, and the manufacturing method thereof is also described in these publications.

The thiazole derivative-metal complex of the present invention is
It can be produced by various methods, and a representative production example thereof is a method of reacting the thiazole derivative represented by the general formula (1) with a metal salt in a suitable solvent.

Examples of the solvent used in this method include halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, cyclohexane, and the like.
Aliphatic hydrocarbons such as n-hexane, n-heptane, and n-pentane, diethyl ether, dioxane, diisopropyl ether, tetrahydrofuran, tetrahydropyran, dimethoxyethane, dibutyl ether, ethers such as ethylene glycol dimethyl ether, methanol, ethanol, Lower alcohols such as propanol,
Water, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, nitriles such as acetonitrile and propionitrile, carbon disulfide, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane, Examples thereof include polar solvents such as 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, tetramethylurea and hexamethylphosphoric triamide, and mixed solvents thereof.

The metal salt used in this method is a salt of the above metal, for example, the general formula MnXm (where M is the same as the above metal. X is a halogen atom, hydroxyl group, nitrate ion, sulfuric acid). Ion, carbonate ion, PY ₆ ion (Y
Halogen atom) is a lower alkyl group R ⁶ SO ₃ ion (R ⁶ is with a halogen atom), YO ₄ ions (Y is the same), BY ₄ ions (Y is the same) or R ⁷ O-
Group (R ⁷ is a lower alkanoyl group). n and m each represent an integer of 1 to 8. ) Metal salts and H ₂
Mention may be made of metal salts such as PtCl ₆ . In the definition represented by X in the above general formula, the halogen atom and the lower alkanoyl group are as described above. As the lower alkyl group having a halogen atom, for example, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 2-fluoroethyl, 2,2
-Difluoroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 4-chlorobutyl, 3,4-
Dichlorobutyl, 3-fluoropentyl, 2,3,4-
Trifluoropentyl, 2,3-dichlorohexyl,
1 to 3 halogen atoms such as 6,6-dibromohexyl group
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms.

Specific examples of the metal salt represented by the above general formula MnXm include, for example, FeCl ₂ , FeBr ₂ , Fe.
I ₂ , FeSO ₄ , FeCO ₃ , Fe (OH) ₂ , FeCl
₃ , FeBr ₃ , FeI ₃ , Fe ₂ (CO ₃ ) ₂ , Fe (O
H) ₃ , Fe ₃ (SO ₄ ) ₂ , Fe (NO ₃ ) ₂ , Fe (NO
₃ ) ₃ , Fe (ClO ₄ ) ₃ , Fe (ClO ₄ ) ₂ , Cu
₂ I ₂ , Cu ₂ Cl ₂ , CuCl ₂ , CuBr ₂ , CuF ₂ ,
Cu (OH) ₂ , Cu (OCOCH ₃ ) ₂ , Cu (NO ₃ )
₂ , CuSO ₄ , Cu ₂ Br ₂ , Cu ₂ SO ₄ , Cu ₂ (O
H) ₂ , ZnCl ₂ , ZnI ₂ , ZnBr ₂ , ZnF ₂ , Z
n (NO ₃ ) ₂ , Zn (OH) ₂ , Zn (OCOC
_{H 3) 2, ZnSO 4,} BaBr 2, BaCO 3, BaC
l ₂ , BaF ₂ , BaI ₂ , Ba (OH) ₂ , Ba (OCO
CH ₃ ) ₂ , Ba (ClO ₄ ) ₂ , Ba (NO ₃ ) ₂ , BaS
O ₄ , PtBr ₂ , PtCl ₂ , Pt (OH) ₂ , Pt
I ₂ , PtF ₅ , VBr ₃ , VCl ₂ , VCl ₄ , VF ₂ , V
F ₃ , VF ₄ , V (OH) ₂ , V (OH) ₃ , MnCl ₃ ,
MnCl ₂ , MnBr ₂ , MnF ₂ , MnI ₂ , Mn (O
H) ₃ , Mn (OH) ₂ , Mn (OCOCH ₃ ) ₂ , MnC
O ₃ , Mn ₂ (SO ₄ ) ₃ , MnSO ₄ , Mn (NO ₃ ) ₂ ,
NiBr ₂ , NiCl ₂ , NiI ₂ , Ni (OCOCH ₃ )
₂ , Ni (NO ₃ ) ₂ , NiCO ₃ , NiSO ₄ , Ni (O
H) ₂ , CoBr ₂ , CoI ₂ , CoCl ₂ , Co (OCO
CH ₃ ) ₂ , Co (OH) ₂ , CoCO ₃ , Co (N
O ₃₎ may be mentioned _2, CoSO _4, and the like.

The ratio of the thiazole derivative of the general formula (1) to the metal salt to be used is not particularly limited and may be appropriately selected from a wide range.
It is preferable to use a 5-fold molar amount, preferably 0.5 to 2-fold molar amount.

In the reaction of the thiazole derivative of the general formula (1) with a metal salt, a basic compound such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium hydrogen carbonate is added to the reaction system. May be.

The reaction of the thiazole derivative of the general formula (1) with a metal salt is usually 0 to 150 ° C., preferably 0 to 100.
The reaction proceeds suitably at around 0 ° C., and the reaction is generally completed within a few minutes to a week.

The compound of the present invention thus obtained can be easily isolated and purified by a conventional separation means. Examples of the separating means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography and the like.

The compounds of the present invention may be provided as solvates. When the compound of the present invention has a cationic complex structure, it can form a salt with the metal salt X represented by the general formula MnXm (M, X, n and m are the same as above). Further, when adopting a cationic complex structure, it can bind to an anion such as OH ⁻ in addition to the thiazole derivative of the general formula (1).

The compounds of the present invention are usually used in the form of general pharmaceutical preparations. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. As this pharmaceutical preparation, various forms can be selected according to the purpose of treatment,
Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions,
Suspensions and the like), ointments and the like. In molding into tablets, those conventionally known in the art can be widely used as carriers, for example, lactose, sucrose, sodium chloride,
Glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate , Polyvinylpyrrolidone and other binders, disintegrators such as dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose , White sugar,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oil, etc., absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. And a lubricant such as purified talc, stearate, boric acid powder, polyethylene glycol and the like. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multi-layer tablet. In molding into the form of pills, carriers conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, and a disintegrant such as laminaran agar. For shaping 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 semi-synthetic 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 the art as diluents can be used, for example, water, lactic acid aqueous 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 to prepare an isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the pharmaceutical preparation as required. 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 present invention to be contained in the pharmaceutical preparation is not particularly limited and may be appropriately selected within a wide range.
Usually, it should be 1 to 70% by weight in the pharmaceutical preparation.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it is administered according to various preparation forms, age, sex and other conditions of the patient, degree of symptoms of the patient 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, they are administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age of the patient, sex and other conditions, degree of disease and the like, but the amount of the compound of the present invention which is an active ingredient is usually 1
It is recommended that the daily dose is about 0.2 to 200 mg per kg of body weight.

[0054]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1 500 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole was dissolved in 70 ml of ethanol, and cupric sulfate pentahydrate 1 was added to the solution.
69 mg of 10 ml aqueous solution was added, and the mixture was allowed to stand at room temperature for 14 hours to obtain a green prism crystal. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried to give 517 mg of 2- (3,4-diethoxyphenyl) -4.
A-(2-carboxy-6-pyridyl) thiazole / copper (II) complex was obtained.

Green powder mp: 284-285 ° C. (decomposition) Elemental analysis value (as C ₃₈ H ₃₄ N ₄ O ₈ S ₂ Cu.3H ₂ O) UV spectrum λ (max) (methanol): 261 nm, 308 nm The obtained metal complex had a ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to copper of 2 It was confirmed by the X-ray crystal structure analysis method that the complex was 1: 1. The crystals belonged to the triclinic form and the space group was P-1. The crystal lattice constants are as shown in Table 1 below, and the determined structures are shown below.

[0057]

[Chemical 6]

Example 2 500 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole was dissolved by heating in 80 ml of ethanol and left to cool. A 20 ml aqueous solution of 375 mg of ferrous sulfate heptahydrate was added to this,
A red prism crystal was obtained by standing at room temperature for 1 week. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried to give 340 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl).
A thiazole / iron (II) complex was obtained.

Red powder mp: 291-293 ° C. (decomposition) Elemental analysis value (as C ₃₈ H ₃₄ N ₄ O ₈ S ₂ Fe.H ₂ O) UV spectrum λ (max) (methanol): 262 nm, 296 nm The obtained metal complex had a ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to iron of 2 It was confirmed by the X-ray crystal structure analysis method that the complex was 1: 1. The crystals belonged to the triclinic form and the space group was P-1. The crystal lattice constants are as shown in Table 1 below, and the determined structures are shown below.

[0060]

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Example 3 500 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole was dissolved by heating in 60 ml of ethanol, and ferric nitrate nonahydrate was added thereto. A brown prism crystal was obtained by adding 545 mg of 10 ml aqueous solution and leaving it at room temperature for 48 hours. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried to give 400 mg of 2- (3,4-diethoxyphenyl).
-4- (2-carboxy-6-pyridyl) thiazole
An iron (III) complex was obtained.

Brown prismatic crystal mp: 300 ° C. or higher Elemental analysis value (C ₃₈ H ₃₄ N ₄ O ₈ S ₂ Fe ₂ (NO ₃ ) ₂ (O
H) as ₂ ) UV spectrum λ (max) (methanol): 312 nm In the obtained metal complex, the ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to iron was 1: 1. It was confirmed by the X-ray crystal structure analysis method that it was a complex of. Crystals belong to monoclinic, space group was P2 ₁ / a. The crystal lattice constants are as shown in Table 1 below, and the determined structures are shown below.

[0063]

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Example 4 500 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole was dissolved by heating in 100 ml of methanol, and 148 mg of zinc acetate dihydrate was added thereto. A solution of 10 ml of methanol was added, and the mixture was allowed to stand at room temperature for 48 hours, and then the solvent was distilled off. 80 ml of acetonitrile was added to the obtained residue and dissolved by heating. By leaving it at room temperature for 48 hours, colorless prism crystals were obtained. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried to give 485 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole. A zinc (II) complex was obtained.

White powder mp: 300 ° C. or higher Elemental analysis value (as C ₃₈ H ₃₄ N ₄ O ₈ S ₂ Zn.1 / 2H ₂ O) UV spectrum λ (max) (methanol): 262 nm, 305 nm The obtained metal complex had a ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to zinc of 2 It was confirmed by the X-ray crystal structure analysis method that the complex was 1: 1. The crystals belonged to the triclinic form and the space group was P-1. The crystal lattice constants are as shown in Table 1 below, and the determined structures are shown below.

[0066]

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Example 5 500 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole was dissolved by heating in 80 ml of ethanol, and 185 mg of zinc chloride was added thereto.
20 ml of ethanol solution was added and the mixture was allowed to stand at room temperature for 14 hours to obtain colorless prism crystals. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried to give 558 mg of 2- (3,4-diethoxyphenyl) -4.
-(2-carboxy-6-pyridyl) thiazole / Zn
A Cl ₂ complex was obtained.

White powder mp: 300 ° C. or higher Elemental analysis value (as C ₁₉ H ₁₈ N ₂ O ₄ SZnCl ₂ ) UV spectrum λ (max) (methanol): 262 nm, 308 nm The obtained metal complex had a ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to zinc of 1. It was confirmed by the X-ray crystal structure analysis method that the complex was 1: 1. Crystals belong to monoclinic, space group was P2 ₁ / n. The crystal lattice constants are shown in Table 1 below.
And the determined structure is shown below.

[0069]

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Example 6 500 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole was dissolved by heating in 80 ml of ethanol, and 331 mg of manganese acetate tetrahydrate was added thereto. A 20 ml solution of ethanol was added, and the mixture was allowed to stand at room temperature for 24 hours to obtain yellow prism crystals. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried to obtain 320 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl).
A thiazole / manganese (II) complex was obtained.

Yellow powder mp: 300 ° C. or higher Elemental analysis value (as C ₃₈ H ₃₄ N ₄ O ₈ S ₂ Mn.1 / 2H ₂ O) UV spectrum λ (max) (methanol): 261 nm, 303 nm The obtained metal complex had a ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to manganese of 2 It was confirmed by the X-ray crystal structure analysis method that the complex was 1: 1. The crystals belonged to the triclinic form and the space group was P-1. The crystal lattice constants are as shown in Table 1 below, and the determined structures are shown below.

[0072]

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Example 7 200 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole and 22 mg of sodium hydroxide were dissolved by heating in 54 ml of water, and nickel sulfate-6 was added thereto. 36 ml of an aqueous solution containing 71 mg of the hydrate was added, heated at 80 ° C. for 10 minutes, and allowed to stand at room temperature for 14 hours to obtain blue prism crystals. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried to 1
61 mg 2- (3,4-diethoxyphenyl) -4-
A (2-carboxy-6-pyridyl) thiazole.nickel (II) complex was obtained.

Blue powder mp: 300 ° C. or higher Elemental analysis value (as C ₃₈ H ₃₄ N ₄ O ₈ S ₂ Ni.H ₂ O) UV spectrum λ (max) (methanol): 257 nm, 294 nm The obtained metal complex had a ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to nickel of 2 It was confirmed by the X-ray crystal structure analysis method that the complex was 1: 1. The crystals belonged to the monoclinic form and the space group was C2 / c. The crystal lattice constants are as shown in Table 1 below, and the determined structures are shown below.

[0075]

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Example 8 148 mg of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole and 16 mg of sodium hydroxide were dissolved by heating in 40 ml of water, and cobalt chloride-6 20 ml of an aqueous solution containing 48 mg of the hydrate was added, the mixture was heated at 80 ° C. for 10 minutes, and left at room temperature for 14 hours to obtain red prism crystals. A part of this crystal was subjected to X-ray structural analysis, and the remaining crystal was collected by filtration and dried.
0 mg of 2- (3,4-diethoxyphenyl) -4-
A (2-carboxy-6-pyridyl) thiazole / cobalt (II) complex was obtained.

Red powder mp: 300 ° C. or higher Elemental analysis value (as C ₃₈ H ₃₄ N ₄ O ₈ S ₂ Co.H ₂ O) UV spectrum λ (max) (methanol): 260 nm, 292 nm In the obtained metal complex, the ratio of 2- (3,4-diethoxyphenyl) -4- (2-carboxy-6-pyridyl) thiazole to cobalt was 2 It was confirmed by the X-ray crystal structure analysis method that the complex was 1: 1. The crystals belonged to the monoclinic form and the space group was C2 / c. The crystal lattice constants are as shown in Table 1 below, and the determined structures are shown below.

[0078]

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[0079]

[Table 1]

Pharmacological test (1) Preparation of neutrophils from human peripheral venous blood The method of Markert et al. [M. Markert, PC Andrews and BM]
Babior; in "Methods in Enzymology", vol.105,358-365
(1984)]. That is, blood was collected from a healthy adult volunteer who had no breakfast using a JMS blood bag (manufactured by Japan Medical Supply Co., containing CPD) by brachial puncture. To this venous blood, an ACD solution (containing sodium citrate 0.2M, citric acid 0.14M and glucose 0.22M) and 6% dextran T-70 (manufactured by Pharmacia) were respectively added to 0.2 volume of blood, 0 volume. 0.5 volume was added, and the mixture was stirred and allowed to stand for 1 hour to precipitate red blood cells. The supernatant was placed in a centrifuge tube and centrifuged at 1000 rpm for 15 minutes to precipitate blood cell components. Discard the supernatant and add 0.1 to the remaining precipitate.
Distilled water containing mM EDTA was added to puncture the red blood cells and then made isotonic with hypertonic sodium chloride. 1000
The precipitate obtained by centrifugation at rpm × 15 minutes was subjected to hypotonic treatment again to return to isotonicity, and then overlaid with a Ficoll-Pack (Pharmacia) solution at 1200 rpm × 25 at 25 ° C.
Minute centrifugation was performed. Only the neutrophil fraction precipitated on the bottom of the centrifuge tube was suspended in phosphate buffered saline (PBS) containing 0.1 mM EDTA, washed with PBS, the number of cells was counted, and the experiment was performed.

[0081] (2) O ₂ from neutrophils ^- with neutrophils prepared in assay above method production, O ₂ ^- is using the absorbance at 460nm is changed when reduced cytochrome C O ₂ ⁻ was quantified. That is, human neutrophils 10 ⁶ cells / tube, 15 mM Hepes-Hanks buffer (Hanks (for tissue culture, phenol red-free) manufactured by Nissui Pharmaceutical Co., Ltd. was added with hepes to a concentration of 15 mM, and sodium hydrate was added thereto. (pH adjusted to 7.4)
And a reaction mixture containing the test compound was pre-incubated at 37 ° C. for 20 minutes. Cytochalasin B (dissolved in dimethylformamide, manufactured by Sigma) 10 minutes before the addition of the stimulant
To 1 μg / ml, and 5 minutes before the start of the reaction, cytochrome C (manufactured by Sigma, dissolved in 15 mM Hepes-Hanks buffer) was added to 1.31 mg / ml.
N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and 4β are used as stimulants.
Forbol 12β myristate acetate (PM
A) was used. The concentration of these stimulants was 3 × 10
^-7 M, and the latter is 1 × 10 ^-8 M. The reaction was initiated by the addition of a stimulant, and after a time to give the previously investigated linearity (about 4 minutes for fMLP, about 10 minutes for PMA).
Minutes), N-ethylmaleimide (manufactured by Sigma, dissolved in distilled water) was added to the reaction mixture so as to have a concentration of 45 μg / ml. Neutrophils were submerged by centrifugation at 3000 rpm for 10 minutes, and the absorbance at 460 nm of the supernatant was measured with a spectrophotometer (JASCO, UVIDEC-340).

[0082] O ₂ ^- purpose to see the reduction of the specific cytochrome C to, superoxide dismutase (S
OD, Sigma, 15 mM Hepes - taking the difference between the absorbance in the presence and absence of lysis in Hanks buffer), producing absorbance after stimulation additive O ₂ ^- and the amount. The assay was performed in duplicate in the absence of SOD, and in a single assay in the presence of SOD, and the average value of the difference was shown as% of the absorbance in the presence of the solvent (in the absence of the test compound).

The results are shown in Table 2 below.

[0084]

[Table 2]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location (C07D 417/04 213: 78 277: 22)

Claims (1)

[Claims] 1. A compound of the 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 represents a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic residue having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms. The monocyclic, bicyclic or tricyclic heterocyclic residue may have a lower alkyl group, a benzoyl group, a lower alkylthio group, a phenylaminothiocarbonyl group as a substituent, or an amino group which may have a lower alkyl group as a substituent. Lower alkoxycarbonyl group, 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 having alkoxy alkoxy group or cyano group as a substituent Alkyl group, 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, Androgenic atom, a lower alkoxy group, a hydroxyl group, group ^{- (A) l -NR 3 R} 4 (A which may have a hydroxyl group as a substituent a lower alkylene group or a group -
Indicates CO. l represents 0 or 1. R ³ and R ⁴ are the same or different and are amino-substituted, which may have 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. A lower alkyl group is shown. Further, R ³ and R ⁴ together with the nitrogen atom to which they are bonded are 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. Good. The heterocycle may be substituted with a lower alkyl group or a carboxy group. ), An amidino group, an aminothiocarbonyl group and a group (R ⁵ represents a hydroxyamino group or a lower alkylthio group.) 1 to 3 groups may be selected. ] The complex of the thiazole derivative or its anion body represented by these, and a metal or a metal salt.