JPH04211089A - Condensed thiazole compound - Google Patents

Abstract

PURPOSE:To provide a novel condensed thiazole compound having a lipoperoxide production-inhibiting activity and a lopoxygenase-inhibiting activity and useful as an agent for preventing and treating diseases such as cancers, arterial sclerosis, hepatic diseases, cerebrovascular disorders, inflammation, etc. CONSTITUTION:A compound of formula I (A is a bond, CH2; R<1> is H, aliphatic group, the acyl group of a carboxylic acid, the acyl group of a sulfonic acid; R<2> is H, aromatic group or aliphatic group) [e.g. 3-(2,3-dimethoxycinnamoyl) amino-delta-valerolactam] is reacted with a sulfide compound such as phosphorus pentasulfide, and the reaction product is, if necessary, subjected to the conversion reaction of R<1> to provide the objective condensed thiazole compound of formula II [e.g. 2-(2,3-dimethylstyryl)-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridine].

Description

[Detailed description of the invention]

[00011

[Industrial Field of Application] The present invention relates to a novel condensed thiazole derivative or a salt thereof, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient. More specifically, the present invention relates to novel lipid peroxide production inhibitors and lipoxygenase inhibitors useful as preventive and therapeutic agents for various diseases such as cancer, arteriosclerosis, liver disease, cerebrovascular disorders, and inflammation. [0002] [Prior Art] As it has become clear that the production of lipid peroxide in the body and the accompanying radical reactions have various adverse effects on the living body through membrane damage, enzyme damage, etc., antioxidants and Various attempts have been made to apply lipid peroxide production inhibitors to medicines. Currently, lipid peroxide production inhibitors used in these fields mainly contain vitamin C.
and derivatives of natural antioxidants such as vitamin E, and phenol derivatives. [0003]

[Problems to be Solved by the Invention] However, their basic skeletons are limited and are not necessarily satisfactory from a practical standpoint. In order to widely utilize lipid peroxide production inhibitors in the medical field, there is a need to develop lipid peroxide production inhibitors having a new structure. The main object of the present invention is to provide a novel compound having such an effect of inhibiting lipid peroxide production. [0004]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors synthesized a number of new compounds and investigated the effect of inhibiting lipid peroxide production on each of them. The present inventors first sought to discover that thiazolo[5,4-b]azepine derivatives have these antioxidant effects and lipid peroxide production inhibiting effects, European Patent Publication No. 3518.
56), as a result of intensive studies in search of new compounds having the above-mentioned effects, the general formula [I]

[I] [wherein A is a bond or CH2, R1 is a hydrogen atom or
Each represents an aliphatic group, a carboxylic acid acyl group, or a sulfonic acid acyl group, each of which may have a substituent, and R2 represents a hydrogen atom, or an aromatic ring group or an aliphatic group, each of which may have a substituent. . ] We have succeeded in creating novel condensed thiazole derivatives or salts thereof, and these new compounds have a strong inhibitory effect on lipid peroxide production, 12
We have discovered that it has useful effects as a medicine, such as inhibiting or suppressing hydroxyheptadecatrienoic acid (hereinafter abbreviated as HHT) and lipoxygenase, and leukotriene D4 (LTD4) receptor antagonism, and after further studies, we have developed the present invention. completed. [0005] That is, the present invention provides a novel condensed thiazole compound represented by the general formula [I] (hereinafter simply referred to as compound [I]).
), its salts, methods for producing the same, and pharmaceutical compositions containing the same as an active ingredient. [0006] In the general formula [I], the aliphatic group represented by R1 may be a saturated group or an unsaturated group, such as an alkyl group, an alkenyl group,
Examples include alkynyl groups. The alkyl group may be linear, branched or cyclic. Among these alkyl groups,
Lower alkyl groups having about 1 to 6 carbon atoms are preferred, such as methyl, ethyl, propyl, i-propyl, butyl, i-
Examples include butyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like. The alkenyl group represented by R1 is generally preferably one having 2 to 6 carbon atoms, such as vinyl, allyl, propenyl, i-propenyl, 2-butenyl, 1,3
Examples include butadienyl, 2-pentenyl, 2,4-pentagenyl, and the like. The alkynyl group represented by R1 is generally preferably a group having 2 to 6 carbon atoms, such as ethynyl, 2-propynyl, and the like. The substituent that these aliphatic groups may have may be any group that is commonly used in medicine, and specifically includes hydroxyl, Cl-3 alkoxy, methoxy,
Ethoxy, n-propoxy or 1so-propoxy, such as in methoxymethyl or 1-ethoxyethyl; aryloxy, such as phenoxy; C7-10 aralkoxy, such as benzyloxy; mercapto; C1-3 alkylthio, such as Methylthio or ethylthio; Ce-+o arylthio, such as phenylthio or naphthylthio; C7-10
Aralkylthio, such as benzylthio; amino (
For example, in 2-aminoethyl<); C1-3
Mono- or disubstituted amino substituted with alkyl, such as methylamino, ethylamino or dimethylamino; halogen, such as chloro or bromo (as in 2-bromoethyl etc.); esterified carboxy, such as C2-5 alkoxycarbonyl (methoxy carbonyl or ethoxycarbonyl), or benzyloxycarbonyl, etc.; C2-4 alkoxycarbonyloxy;
Formyl; C2-10 acyl, such as acetyl, propionyl or benzoyl; C2-10 acyloxy, such as acetoxy, propionyloxy or pivaloyloxy; cyano; phthalimide; C2-10 acylamide, such as acetamide or benzamide; C2
-5 alkoxycarbonylamino, such as methoxycarbonylamino or ethoxycarbonylamino; or C7-10 aralkoxycarbonylamino, such as benzyloxycarbonylamino, cyclic amino groups (such as pyrrolidino, morpholino, etc.), carboxyl groups, carbamoyl groups (such as The group consisting of these groups is hereinafter referred to as group A). Among these group A, carboxyl groups, esterified carboxyl groups, carbamoyl groups, mono- or di(CI-3alkyl)amino groups, etc. are particularly preferred. [00071 Examples of the acyl sulfonate group represented by R1 include an alkylsulfonyl group having preferably 1 to 3 carbon atoms, such as methanesulfonyl, ethanesulfonyl, and propanesulfonyl, and a phenylsulfonyl group. Among these, the alkylsulfonyl group may have a substituent selected from Group A above, for example. Especially among these substituents, C such as dimethylamino and diethylamino
Mono- or di-substituted aminos substituted with 1-3 alkyl are preferred. [0008] When the phenylsulfonyl group represented by R1 has a substituent on the phenyl ring, examples of the substituent include halogen (e.g. fluorine, chlorine, bromine, iodine), nitro, amino (CI-3 alkyl, C2 −
It may have 1 or 2 substituents of 4 alkenyl, C3-8 cycloalkyl, or phenyl. ), sulfo, and mercapto. Hydroxy, sulfoxy, sulfamoyl, Cl-
6 alkyl (may have amino, di-C1-3 alkylamino, mono-C1-3 alkylamino, halogen, hydroxy, cyano, or carboxy as a substituent),
CI-e alkoxy (which may have CI-3 alkylthio as a substituent), benzyloxy, Cl-
3 alkylthio, Cl-3 alkyl sulfonamide,
amidino (CI-3 alkyl, optionally substituted with benzyl), CI-3 alkoxyformimidoyl,
Methylenedioxy, Cl-3alkylsulfonyl,
Cl-3 alkylsulfonylamino, esterified carboxy such as C2-4 alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), or benzyloxycarbonyl; C2-4 alkoxycarbonyloxy; formyl; C2-10 acyl such as acetyl, propionyl or benzoyl, etc.; C2-10 acyloxy, such as acetoxy, propionyloxy or pivaloyloxy; cyano; phthalimide; C2-
10 acylamides, such as acetamide or benzamide; C2-4 alkoxycarbonylamino, such as methoxycarbonylamino or ethoxycarbonylamino; or C7-10 aralkoxycarbonylamino, such as benzyloxycarbonylamino; cyclic amino groups, such as pyrrolidino, morpholino, etc. ); and phenyl which may be substituted with a carboxyl group, a carbamoyl group, a halogen, a methoxy group, a C1-3 alkyl group, etc. (the group of these substituents is hereinafter referred to as the P group). Among these, especially hydroxyl group, Cl-6
Alkoxy, CI-s alkyl, halogen, nitro,
amino, mono- or di(CI-s alkyl)amino,
Cl-6 alkylthio, amidino, amino C1-6 alkyl, cyano, CI-e alkoxycarbonyl,
Cl-6 alkoxycarponyloxy, phenyl, phenylamidino, alkoxyformimidoyl are preferred. Furthermore, methyl, methoxy, chlorine, fluorine, amino and the like are particularly preferred. (0009) Furthermore, the carboxylic acid acyl group represented by R1 is generally of the formula R3C0- (wherein R3 is a saturated or unsaturated aliphatic group which may have a substituent or a substituent). [0010] The aromatic ring group represented by R3 includes an aromatic carbocyclic group and an aromatic heterocyclic group. Examples of the former include Examples include phenyl and naphthyl.As the aromatic heterocyclic group, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 4, preferably 1 to 2, heteroatoms such as nitrogen, oxygen, and sulfur is preferred.Aromatic Specific examples of the heterocycle include pyridyl, furyl, thienyl, pyrazinyl, pyrrolyl, imidazolyl, isoxazolyl, and the like.

[0011] Furthermore, such an aromatic ring group may contain the same or another aromatic ring (such as an aromatic heterocycle or an aromatic carbocycle as described above).
A fused group is also preferred. Examples of these fused rings are:
For example, indolyl, benzimidazolyl, quinolyl,
Examples include imidazopyridyl and thiazolopyridyl. [0012] As the substituent that the aromatic carbocyclic group may have, for example, a group selected from the above P group is preferable. Examples of substituents that the aromatic heterocyclic group may have include amino (C2-10 acyl, halogen-substituted C2-
It may have 4-acyl, phenyl, or Cl-3 alkyl as a substituent. ), halogen, nitro, sulfo,
Cyano, hydroxy, carboxy, oxo, CI-t
o alkyl (which may have phenyl, halogen, amino, hydroxy, carboxy, C1-3 alkoxy, CI-s alkylsulfonyl, Cl-3 dialkylamino, etc. as a substituent). C3-6 cycloalkyl, Cl-3 alkoxy, C
2-10 acyl, phenyl (may have halogen, nitro, alkyl, alkoxy, amino, sulfo, hydroxy, cyano as a substituent), oxo, CI
-to alkyl-thio (phenyl, halogen, amino,
Hydroxy, carboxy, CI-s alkoxy, C
It may have 1-3 alkylsulfonyl, di-C1-3 alkylamino, etc. as a substituent. ) (the above group of substituents is hereinafter referred to as group H). Among these H groups, particularly preferred are Cl-10 alkyl, amino, mono- or di(CI-3 alkyl)amino, halogen, amino C1-3 alkyl, and the like. [0013] The aliphatic group represented by R3 may be a saturated group or an unsaturated group, and examples thereof include an alkyl group, an alkenyl group, and an alkynyl group. In addition to the lower alkyl groups mentioned above as the alkyl group represented by R1, the alkyl group also includes higher alkyl groups having 7 or more carbon atoms such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, heptadecyl, and octadecyl. It will be done. The alkyl group represented by R3 is preferably an alkyl group having 1 to 18 carbon atoms,
More preferably, it has 1 to 4 carbon atoms. [00141 The alkenyl group and alkynyl group represented by R3 are preferably the groups described above for R1. As the alkenyl group and the alkynyl group, those having 2 to 4 carbon atoms are particularly preferred. [0015] Examples of the substituent that the saturated or unsaturated aliphatic group represented by R3 may have include those substituted with a substituent selected from the above group A and the above group P. a phenyl group which may be substituted with a phenyl group which may have a substituent selected from the above group P on the ring, a phenethyl amino group or a benzylamino group which may have a substituent selected from the above group P, and a heterocyclic group which may be substituted with a substituent selected from the above group H. etc. Here, examples of the heterocyclic group include the aromatic heterocyclic group mentioned above regarding the aromatic ring group represented by R3, as well as a partially or fully saturated heterocyclic group (e.g., morpholino, piperidinyl, piperidino, piperazinyl, pyrrolidinyl). etc.) are included. [0016] Examples of the aliphatic group represented by R2 include saturated or unsaturated aliphatic groups as described above for R1. Further, as the alkenyl group of the unsaturated aliphatic group represented by R2, in addition to the lower alkenyl group as mentioned as an example of R1, an alkenyl group having 7 to 10 carbon atoms is also preferable. Examples of the substituents that these aliphatic groups represented by R2 may have include the same groups as the substituents of the aliphatic group represented by R3 above, and even if they are further substituted with an oxo group etc. good. [0017] Furthermore, the aromatic ring group represented by R2 is
Examples of R3 include aromatic carbocyclic groups, aromatic heterocyclic groups, and fused ring groups thereof as described above. Further, as substituents that the aromatic carbocyclic group may have, there are groups selected from the above group P, and as substituents that the aromatic heterocyclic group may have, there are groups selected from the above group H. can give. [0018] The number of substituents in the optionally substituted groups represented by R1, R2, and R3 is 1 to 5, preferably 1 to 3. (In formula [I] of 00191, R1 is a hydrogen atom, a C1-6 alkyl which may be substituted with a mono- or di-(CI-3 alkyl) amino group, a C1-3 alkylsulfonyl, or a carboxylic acid acyl group (the acyl group (R) is preferably an acetyl group, a propionyl group, etc., and the methyl group or ethyl group in these groups may further have a substituent as described above.In particular, R
Compounds in which 1 is a hydrogen atom are preferred. R2 is an aromatic ring which may have a substituent (particularly C1-4 alkyl or/and phenyl which may be substituted with nitro) or an aromatic ring which may have a substituent, especially C1-
4 alkyl, Cl-4 alkoxy and/or C6-1
Preferably, the compound is a phenyl or imidazolyl group which may be substituted with aryl, or an alkenyl group having 2 to 4 carbon atoms which may be substituted with indolyl. In particular, the optionally substituted aliphatic group of R2 in formula [I] is represented by the formula R4Y (wherein R4 is an optionally substituted aromatic ring group, and Y is a thiazole ring of a thiazoloazepine ring). Preferably, the compound is a group represented by an unsaturated aliphatic group capable of forming a conjugate bond with. Here, “
As for the "aromatic ring" and "substituent" of the aromatic ring group "' which may have a substituent, the same as described above for R3 applies as is. As Y, for example, -CH
=CH-, -CH=CH-CH=CH-, and the like. Furthermore, R1 is a hydrogen atom, R2 is a phenyl group which may have a substituent, or phenyl, thienyl, furyl,
A compound which is an alkenyl group conjugated with a thiazole ring having 2 to 4 carbon atoms which may be substituted with a pyridyl, pyrazinyl or imidazolyl group is a preferred embodiment from the viewpoint of its function. Particularly preferred examples of the optionally substituted alkenyl group represented by R2 include vinyl substituted with optionally substituted phenyl and butadienyl. [00201 Furthermore, the compound represented by the general formula [I] is R
Stereoisomers may occur depending on the type of substituents of I and R2, but not only these isomers alone,
Mixtures thereof are also included in the invention. [00211 The salt of the compound represented by the general formula [I] is preferably a pharmaceutically acceptable salt, and examples of the pharmaceutically acceptable salt include hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, ), inorganic acids such as phosphoric acid and sulfuric acid, organic acids such as organic carboxylic acids (e.g. oxalic acid, phthalic acid, fumaric acid, maleic acid), and sulfonic acids (e.g. methanesulfonic acid, benzenesulfonic acid). . Also, compound [I]
has an acidic group such as a carboxyl group as a substituent on R1 or R2, inorganic base salts with alkali metals (e.g., sodium, potassium) or alkaline earth metals (e.g., magnesium) and organic bases (e.g., Examples include salts with amines such as dicyclohexylamine, triethylamine, and 2,6-lutidine. [00221 Hereinafter, the compound represented by general formula [I] and its salt will be collectively referred to as compound [I]. [0023] Compound [I] of the present invention can be produced, for example, by the method shown in Scheme (1).

[Formula-■, A, R1 and R2 have the same meanings as above,
R2C0Z represents a reactive derivative of carboxylic acid. ] [0
[024] That is, compound [III] or a salt thereof (salts include the salts described above as the salt of compound [I]) is acylated with a reactive derivative of a carboxylic acid represented by the formula R2C0Z to form compound [II] and then [II
] Compound [I] can be obtained by treating with a sulfurizing agent. More specifically, the reactive derivatives represented by R2C0Z include acid chlorides, acid bromides, imidazolides, acid anhydrides, acid azides, N-phthalimide esters, N-oxysuccinimide esters, and the like. Moreover, instead of using an active ester, the carboxylic acid represented by R2C0OH is directly converted into the compound [III
] may be reacted. [0025] For 1 mol of compound [III], R2C0
The reactive derivative represented by Z is used in an amount of about 1 to 3 moles, preferably about 1 to 1.2 moles. When reacting with a carboxylic acid represented by R2C0OH, usually compound [III] 1
About 1 to 3 moles of carboxylic acid per mole, preferably about 1 to 3 moles of carboxylic acid
1.2 mol to the same compound [III] about 1 to 1.2
react in the presence of molar coupling reagents. [0026] The reaction normally proceeds smoothly under water cooling to room temperature (room temperature in the following description of the production method specifically means 5 to 35°C). The solvent used at this time may be any solvent as long as it is inert to the reaction, and is not particularly limited.
Chloroform, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide, etc. are often used. When using an acid chloride or an acid bromide as an acylating agent, it is desirable to add an amine such as triethylamine or pyridine to the reaction system. The reaction time is usually about 30 minutes to 12 hours, although it depends on the reagent, solvent, and temperature used. [0027] The reaction for converting compound [II] into compound [I] is carried out in the presence of a sulfurizing agent such as phosphorus pentasulfide or Lawesson's reagent. The amount of the sulfurizing agent used at this time is generally about 1 to 3 mol per 1 mol of compound [II], usually about 1 to 3 mol per 1 mol of compound [II].
II] is preferably about equimolar. Pyridine is preferable as a reaction solvent, but there is no particular restriction. The reaction is 50°~1
It is carried out at a temperature of about 20℃, but about 80℃ to 120℃
is desirable. The time required for the reaction varies depending on the reaction temperature, but is usually about 3 to 12 hours, for example about 100 to 1
If the reaction is carried out at 20°C, the reaction will be completed within approximately 5 hours. [0028] In the scheme -■, the substituent represented by R1 may be converted into another substituent represented by R1 at any stage, but usually after obtaining the compound [II, the R1 moiety is It is advantageous to convert. In such a conversion reaction of R1, a compound in which R1 is a hydrogen atom is subjected to a reaction such as alkylation, sulfonylation, or acylation by a conventional method, and each R1
Examples include reactions to obtain the desired compound in which is an optionally substituted alkyl group, sulfonic acid acyl group, or carboxylic acyl group. [0029] These reactions can be carried out according to methods known per se, but can also be carried out, for example, by the following methods. [0030] Compound [Compound in which R1 of II is a hydrogen atom [hereinafter sometimes referred to as compound [I] (R'=H). ] to obtain a compound in which R1 is an acyl group,
Compound [II (R1=H) may be acylated. R1
To obtain a compound in which is a carboxylic acyl group, a reactive derivative of the carboxylic acyl group and a compound [■] (R' = H)
All you have to do is react. The type of reactive derivative of acyl carboxylate, reaction conditions, etc. are determined from compound [III] to compound [I
The reaction described above for the reaction to obtain I] is usually applied as is. Under these conditions, the reaction proceeds smoothly. To lead compound [■] (R' = H) to a compound in which R1 is acyl sulfonate, compound [II (R' =
The method of reacting H) with a sulfonyl halide is advantageous. The reaction is usually carried out in the presence of an amine such as triethylamine or pyridine. The solvent used at this time may be any solvent as long as it is inert to the reaction, but acetone, dioxane, dimethylformamide, tetrahydrofuran, chloroform, methylene chloride and the like are preferably used. Pyridine may be used as a solvent in some cases. The reaction proceeds smoothly at 0° C. to room temperature and is completed in 30 minutes to 5 hours. The amount of amine used at this time is about 1 to 3 moles per 111 moles of the compound, and the amount of the acylating agent is about 1 to 2 moles. (0031) To obtain a compound in which R1 is an alkyl group from a compound in which R1 in compound [II is a hydrogen atom, compound [
II(R]=H) may be subjected to an alkylation reaction. The alkylating agent used at this time is an alkyl halide (
Examples of the halogen include chlorine, bromine, iodine), alkyl esters of sulfonic acids (eg, alkyl esters of p-toluenesulfonic acid, alkyl esters of methanesulfonic acid, etc.). The amount of alkylating agent used is about 1 to 2 mol per mol of compound [■]. The reaction is usually
This is carried out in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine or pyridine. The base is preferably used in an equimolar amount with the alkylating agent. Although there are no particular limitations on the solvent used, for example, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, etc. are preferably used. The reaction is usually
It is carried out under heating, suitably in the range of about 30° to 100°C. [0032] Compound where R1 is an alkyl group [II is R1
can also be obtained by reducing a compound [II] having a carboxylic acid acyl group. Although the reduction can be carried out according to conventional methods, reduction using a reducing agent such as lithium aluminum hydride or diborane is suitable, for example. At this time, ether, tetrahydrofuran, or dioxane is used as the solvent, and the reaction usually proceeds under reflux. [0033] Compound [II can also be produced by other known methods or methods analogous thereto. [0034] Furthermore, among the compounds [III] which are the raw material compounds of the production method of the present invention, the compounds in which R1 is a hydrogen atom are:
A known compound in which R1 is other than a hydrogen atom is, for example, ■. The method of P. 5nyder et al. [J. P. 5nyder
r et al., Journal of Medicinal Chemistry (J, Med, Chem, ). 29.251. (1986)], it can be synthesized by the method of Scheme-II.

[In the formula, A and R1 have the same meanings as above, Et represents an ethyl group, X represents a halogen atom, and BOC represents a tert-butoxycarbonyl group] [0035] Also, the above-mentioned compound [II] Compound [III] can be produced from a compound where R1 is a hydrogen atom according to a reaction that converts the R1 moiety. [0036] Compound [II
can be isolated and purified by conventional separation means such as recrystallization, distillation, and chromatography. When the thus obtained compound [II is obtained in a free form, it can be converted into a salt by neutralization etc. by a method known per se.On the other hand, when it is obtained in a salt form, it can be converted into a free form by a conventional method. It can be turned into something. [0037] Compound [I] of the present invention improves the metabolism of polyunsaturated fatty acids (linoleic acid, γ-lylunic acid, α-lylunic acid, arachidonic acid, dihomo-γ-lylunic acid, eicosapentaenoic acid), particularly Effect of suppressing lipid peroxide production reaction (antioxidant effect), 5-lipoxygenase metabolites [e.g., leukotrienes, 5-hydroperoxyeicosatetraenoic acid (HPETE), 5-hydroxyeicosatetraenoic acid (HETE) ), riboxins, leukotoxins, etc.], inhibition of thromboxane A2 synthase, retention promotion of prostaglandin 12 synthase, LTD4 receptor antagonism, scavenging of reactive oxygen species, etc. It has circulatory system improving effects and anti-allergic effects. [0038] Among the above-mentioned effects, the compound [I] of the present invention tends to significantly exhibit an effect of suppressing the lipid peroxide production reaction (antioxidant effect). [0039] Compound [I] has low toxicity and side effects. [00401] Therefore, the compound [I] of the present invention inhibits thrombosis due to platelet aggregation in mammals (mice, rats, rabbits, dogs, monkeys, humans, etc.), contraction of arterial vascular smooth muscle in the heart, lungs, brain, and kidneys, or Ischemic diseases caused by vasospasm (e.g. myocardial infarction, stroke), neurodegenerative diseases (
Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, muscular dystrophy), head trauma, spinal cord trauma, and other central injury-related functional disorders, memory impairment, and emotional disorders (oxygen deficiency,
Disorders associated with nerve cell necrosis caused by brain damage, stroke, cerebral infarction, cerebral thrombosis, etc.), convulsions and epilepsy that occur after a stroke, cerebral infarction, or brain surgery2 head trauma, nephritis, pulmonary failure, bronchial asthma, and inflammation , arteriosclerosis, atherosclerosis, hepatitis, acute hepatitis, cirrhosis, hypersensitivity pneumonitis, immunodeficiency, caused by damage to enzymes, biological tissues, cells, etc. caused by reactive oxygen species (superoxide, hydroxyl radicals, etc.) It has therapeutic and preventive effects on various diseases such as circulatory system diseases (myocardial infarction, stroke, cerebral edema, nephritis, etc.), tissue fibrosis phenomenon, and carcinogenesis. It is useful as a medicine such as an asthma agent, an anti-allergy agent, an agent for improving the cardiovascular system of the heart and brain, a treatment for nephritis, a treatment for hepatitis, a tissue fibrosis inhibitor, a reactive oxygen species scavenger, and an agent for improving the regulation of arachidonic acid cascade substances. be. [0041] Compound [I] can be administered orally as it is or as a pharmaceutical composition (e.g., tablet, capsule, liquid, injection, halved) mixed with a known pharmaceutically acceptable carrier, excipient, etc. It can be safely administered either intravenously or parenterally. The dosage varies depending on the subject, administration route, symptoms, etc., but for example, when orally administered to adult patients with circulatory system diseases, the single dose is usually about 0.
About 1 mg/kg to 20 mg/kg body weight, preferably about 0.2 mg/kg to 10 mg/kg body weight once a day.
Advantageously, it is administered in about three doses. [0042]

Effects of the Invention: The present invention has excellent lipid peroxide production inhibiting and antioxidant effects, and can be used to treat circulatory system diseases in mammals, etc.
Compounds useful as preventive/therapeutic agents for allergic diseases are provided. [0043]

[Examples] Test examples, working examples, and reference examples are described below, but the present invention is not limited thereto. [0044] Test Example 1 Effect of drug on behavioral changes due to intrathecal administration of ferrous chloride mice. 1 group of 10 male SIc:ICR mice were used. After injecting 5 μm/mouse of physiological saline containing 50 mM ferrous chloride into the subarachnoid space from the 6th lumbar spinal cord to the 1st sacral spinal cord, behavioral observations were made from 15 minutes to 1 hour, and behavioral changes were evaluated. The following criteria were used. Score Behavior change: 0 points: Normal 1 point: Biting the lower limbs and lower abdomen frequently. 2 points: a) Biting the lower body violently, sometimes rolling around b
) Hypersensitivity to external stimuli is observed and the patient becomes aggressive. C) Furirai occurs. Any of the above three reactions is recognized. 3 points 2 Clonic convulsions are observed. 4 points 2 Tonic spasms are observed. Or unilateral or bilateral wave paralysis is observed. 5 points: Death. The suppression rate was expressed based on the scores evaluated using the above criteria. The test compound was orally administered 30 minutes before administration of ferrous chloride. [0045] 100 mg/kg of each compound [I]
Table 1 shows the average score and each inhibition rate when administered orally. The above results demonstrate that the compounds of the present invention have excellent suppressive effects on central nervous system disorders associated with lipid peroxide production caused by ferrous chloride. [0046] The elution in column chromatography in the following Reference Examples and Examples is performed using TLC (ThinLayer
The analysis was carried out under observation using chromatography (thin layer chromatography). For TLC observation, as a TLC plate (Mer
Kieselgel 60F25o (70-230
The solvent used as the elution solvent in column chromatography was used as the developing solvent, and the detection method was U.
A V detector was adopted. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh), also manufactured by Merck, was used. NMR spectra show proton NMR and VARIAN using tetramethylsilane as internal reference.
Measurement was performed using JEMINI 200 (200 MHz spectrometer), and the δ value was expressed in ppm. [0047] The abbreviations used in the examples have the following meanings. S: singlet, br nibroad (wide), d:
doublet, t ni triplet, m: multiplet,
d doublet of doublets, ■Two coupling constants, Hz: Hertz, CDCl3: deuterochloroform, d6
DMSO: heavy dimethyl sulfoxide, %: weight % [0048] Reference example 1 3-(2,3-dimethoxycinnamoyl)amino-δ-
4.28 g of N,N'-carbonyldiimidazole was added to 50 ml of a solution of 5.0 g of valerolactam 2,3-dimethoxycinnamic acid in tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. To this, 3-amino-δ-valerolactam 3.0
2 g was added and stirred at room temperature overnight. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure and purifying the residue by silica gel column chromatography, the title compound was found to have a concentration of 2.91
g (39.8%) was obtained. Melting point 164-166°C (recrystallized from ethanol-hexane) IR(KBr) cnr': 3358.169
5.1661.1622.1579.1538.148
0°1226.1067.797,756. NMR(d
a DMSO) δ: 1.50 to 2°10 (4H, m
), 3.17 (2H, br s), 3.76 (3H, s
), 3.83 (3H, s), 4.29 (LH, m),
6.72 (LH, d, J=15.9Hz), 7.1
2 (3H, m), 7.64 (LH, d, J=15.
9Hz), 7. 66 (IH, m), 8.35 (IH,
d, J=7.9Hz). Elemental analysis value: Calculated value as C16H2o Nz Oa: C, 63, 14; H, 6, 62; N,
9.20°Actual measurement: C, 63,45; H, 6
,72; N, 9.07° [0049] Reference Example 2 3-(3-amino-4-methylbenzoyl)amino-δ
- Valerolactam Reference The title compound was obtained from 3-amino-4-methylbenzoic acid and 3-amino-δ-valerolactam by the same method as Reference 1 (yield 56.3%).
. Melting point 161-164°C (recrystallized from ethyl acetate-hexane) IR(KBr) cnr': 3358.167
5.1645.1575.1539.1495.145
5°1424.1333. NMR(d6DMSO)δ:
1.68-2.10 (4H. m), 3.16 (2H, br s), 4.31
(LH, m), 4.97 (2H, br s), 6.
95-7°15 (3H, m), 7.61 (LH, br
S), 8.22 (LH, d, J = 8.IHz). Elemental analysis value: C□3H□7 N3 o2・0.3H2
Calculated value as 0: C, 61,79; H, 7,0
2; N, 16.63°Actual measurement: C, 61,8
6; H, 7, 11; N, 16.60° [00
501 Reference Example 3 3-(β-3-indolylacryloyl)amino-δ-
Valerolactam Reference By the same method as Reference 1, β-(3
The title compound was obtained from -indolyl)acrylic acid and 3-amino-δ-valerolactam (yield 63.8%)
. Melting point 231-234°C (recrystallized from ethyl acetate-ethanol) IR (KBr) cnr': 3306.3220
．． 1676, 1612.1543, 1526.1491
．． 1459, 1365.1319.1281.809.
752°NMR (d6 DMSOD20) δ: 1.5
4~2.15 (4H, m), 3°18 (2H, m),
4.31 (LH, m), 6.69 (IH, d, J=1
5.8Hz), 7.19 (2H. m), 7.48 (LH, dd, J=2.2, 6.4Hz
), 7.60 (LH, m), 7.64 (LH, d, J=
15.8Hz), 7.75(LH,S), 7.93(I
H, dd, J = 1.8, 6.3Hz), 8.21 (LH
, d, J=8.0Hz). Elemental analysis value: C, H, calculated value as N302-0.3H20: C, 66,56; H, 6,14;
N, 14.55° Actual value: C, 66,52;
H, 6, 25; N, 14.63° [0051
] Reference Example 4 3-(β-(1-methylimidazol-4-yl)acryloyl)amino-δ-valerolactam β-(1-methylimidazol-4-yl)acrylic acid hydrochloride (7g, 37.1 triethylamine (7,5 mmol) in dimethylformamide (60 ml)
1 g, 74.2 mmol) and 1-hydroxybenzotriazole hydrate (6.25 g, 40.8 mmol) were added, cooled with water, and dicyclohexylcarbodiimide (8,
A solution of 42 g, 40.8 mmol) in dimethylformamide (15 ml) was added dropwise. After stirring at 80°C for 30 minutes and then at room temperature for 30 minutes, 3-amino-δ was added to the reaction solution.
- Valerolactam (5.08 g, 44.5 mmol) was added and the mixture was heated and stirred at 50°C for 13 hours. After cooling to room temperature, aqueous sodium bicarbonate was added and extracted with a mixed solvent of chloroform and methanol. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Purification of the residue by flash column chromatography on silica gel and recrystallization from ethanol/chloroform yielded 6.72 g (73.0%) of the title compound.
Obtained. Melting point 280-282°C (recrystallized from ethyl acetate-ethanol) IR(KBr)cnr': 3340.1673
．． 1630.1527.1493.1454.1444
°NMR (de DMSOD20) δ: 1.50~
2.05 (4H, m), 3゜65 (3H, s)
, 4.28 (IH, m), 6.54 (LH, d
, J=15.3Hz), 7.26(LH.d, J~15.3Hz), 7.39(LH,s
), 7.60 (LH, br s), 7.62 (LH
,s). 8, 20 (LH, d, J=8.3Hz). Elemental analysis value: C□2H□6 N4 o2・0. lH2
Calculated value as O: C, 57,63; H, 6,5
3; N, 22.40° value: C, 57,
70; H, 6,77; N, 22.17
゜[0052] Reference Example 5 3-(β-(1-ethyl-2-phenylimidazole-
4-yl)acryloyl)amino-δ-valerolactam β-(1-ethyl-2-phenylimidazol-4-yl)acrylic acid hydrochloride (5.49 g, 20.3 mmol) in thionyl chloride (50 ml) The mixture was heated and stirred for 50 minutes. After completely distilling off excess thionyl chloride under reduced pressure, tetrahydrofuran (50 ml) and triethylamine (4
, 12 g, 40.7 mmol) was added, and after cooling with water, 3-amino-δ-valerolactam (2,79 g, 2
4.4 mmol) was added thereto, and the mixture was stirred at room temperature overnight. Aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with a mixed solvent of chloroform and methanol. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Purification of the residue by flash column chromatography on silica gel yielded 4.29 g of the title compound.
(62.3%) was obtained. Melting point 270-272°C (recrystallized from ethyl acetate-ethanol) IR(KBr) cnr': 3338.168
0.1652.1633.1509.1474.144
6°1361, 796° NMR (de DMSO) δ: 1.32 (3H, t,
J=7.3Hz), 1.50~2.07(4H, m
), 3.15 (2H, brS), 4.05 (2H, Q,
J=7.3H7), 4.27(LH,m), 6.63(
LH, d, J = 15.3Hz), 7.30 (LH, d,
J=15.3Hz), 7.43-7.68 (7H, m)
, 8.20 (LH, d, J=8.1Hz). Elemental analysis value: Calculated value as C engineering, H2°N, 02:
C, 67,44; H, 6,55; N, 16
．． 56° Actual value: C, 69,90; H, 6,5
5; N, 16.42° [0053] Reference Example 6 3-(3-(4-methoxyphenyl))propionylamino-δ-valerolactam 3-(4-methoxyphenyl) was prepared in the same manner as in Reference Example 1. 5.29 g of the title compound was obtained from propionic acid and 3-amino-δ-valerolactam (yield: 86.3
%). Melting point 184-186°C (recrystallized from ethyl acetate-ethanol) IR(KBr) cnr': 3308.166
7, 1640.1540.1514.1496.145
4゜1247, 1035.822゜NMR (de DMSO) δ: 1.43-2.00
(4H, m), 2.34 (2H. m), 2.75 (2H, m), 3.12 (2H, m
), 3.71 (3H, S), 4.14 (LH, m). 6, 81 (LH, d, J=8.7Hz), 7.12
(IH, d, J=8.7Hz), 7.58 (L H
. br s), 8.02 (IH, d, J ~8.1
Hz). Elemental analysis value: Calculated value as C1s H2o N203: C, 65, 20; ■, 7.30; N
, 10.14° value: C, 65, 31;
E[, 7,53; N, 10.03°[00
54] Example 1 2-(2,3-dimethoxystyryl)-4,5,6,7
-tetrahydrothiazolo[5,4-b]pyridine 3-(
2.76 g of 2,3-dimethoxycinnamoyl)amino-δ-valerolactam and 2.02 g of phosphorus pentasulfide were added to 20 ml of pyridine, and the mixture was refluxed for 3 hours. After cooling, the reaction solution was diluted with chloroform-methanol, washed with saturated sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethyl acetate to obtain 260 mg of the title compound.
(10.5%) obtained. Melting point: 122-124°C (recrystallized from ethyl acetate) I
R(KBr) cm-': 3376, 1615.1
577, 1538.1478.1445.1423゜1
365, 1353.1339.1262.1246.1
068.960.782°NMR(de-DMSO)δ
: 1.86 (2H, m), 2.69 (2H, t,
J=5°4Hz), 3.18 (2H, m), 3.
74 (3H, s), 3.81 (3H, s), 6
．． 28 (IH, brS), 6.95 (LH, dd, J
=1.4Hz, 8. IHz), 7.05 (LH, t, J
=7.9Hz). 7, 11 (LH, d, J=16.4Hz), 7
．． 21 (LH, d, J=16.4H7), 7.2
5 (LH. dd, J=1.4Hz, 7.8Hz). Elemental analysis value: C16H]8N2 Calculated value as SO2: C, 63,55; H, 6,00; N,
9.26; S, 10. 60°Actual measurement:
C, 63, 66; H, 6, 11; N,
9.22; S, 10.57° [0055] Example 2 2-(3-amino-4-methylphenyl)-4,5,6
,7tetrahydrothiazolo[5,4-b]pyridine The title compound was obtained from 3-(3-amino-4methylbenzoyl)amino-δ-valerolactam and phosphorus pentasulfide by a method similar to Example 1. (Yield 30.3%). Melting point: 98-101°C (recrystallized from ethyl acetate-hexane: crystal) I R (KBr) cur': 3256.162
1.1568.1544.1513.1471.137
2゜1345, 1309.866, 819. NMR
(CD CI3) δ: 1.99 (2H, m). 2, 17 (3H, S), 2.86 (2H, t, J=
6.4Hz), 3.29(2H,t, J=5.4H
z), 3.67 (3H, br s), 7.00~7
．． 20 (3H, m). Elemental analysis value: Calculated value as C13HI5N3S:
C, 63, 64; H, 6, 16; N, 17
．． 13; S, 13.07° Actual value: C, 63
, 36; H, 6,40; N, 16.78;
S, 13.08° [0056] Example 3 2-(3-amino-4-methylphenyl)-4,5,6
,7-tetrahydrothiazolo[5,4-b]pyridine.
Dihydrochloride 2-(3-amino-4-methylphenyl)-4
, 5,6,7-tetrahydrothiazolo[5,4-b]pyridine was neutralized with hydrochloric acid and recrystallized from ethanol to obtain the title compound (yield 48.1%). Melting point: 186-189℃ (recrystallized from ethanol) ■R
(KBr) cm-': 3438.1602.15
23.1480.1466, 1348.1282°83
6°NMR (d6 DMSOD20) δ: 1.93 (2
H, m), 2.37 (3H.s), 2.77 (2H,t, J=5.2Hz)
, 3.25 (2H, m), 7.39 (LH, d,
J=8. IHz), 7.64 (LH, dd, J=1.
7H2,8,IHz), 7.84(LH,d,J =
1.7H2). Elemental analysis value: Calculated value as C13HI5N3S/2HC1: C, 49,06; H, 5,38; N
, 13.20° Real animal C, 49, 48; H, 5, 7
7: N, 13.23° [0057] Example 4 2- (2-(indol-3-yl)ethynyl) -
4,5゜6.7-tetrahydrothiazolo[5,4-bl
Pyridine hydrochloride 3-(β-3-indolylacryloyl)amino-δ-valerolactam and phosphorus pentasulfide were reacted in the same manner as in Example 1, purified and neutralized with hydrogen chloride to obtain the title compound. (yield 7.4%). Melting point 202-205℃ (recrystallized from ethanol) ■R
(KBr) cm-': 3218.1596.15
72.1528.1455.1404.1355゜13
34, 1284.743°NMR (CDC13) δ: 1.89 (2H, br s
), 2.75 (2H, br s), 3°26 (2H
,br s), 4.19(LH,brs), 7.
21 (2H, m), 7.30 (LH, d, J=16
．． 2Hz), 7.49 (IH, m), 7.70 (LH,
d, J=16.2Hz), 7.8 1~8.00 (2
H, m), 11.88 (LH, s). Elemental analysis value: Calculated value as C16H15N3S-HCl: C, 60,46; H, 5,07; N,
13.22; S, 10.09; C1,11,
15° Actual measurement: C, 60,37; H, 5,05;
N, 13.16; S, 10.19; C
1,11,29° [0058] Example 5 2-(2-(1-methylimidazol-4-yl)ethynyl)-4,5,6,7-tetrahydrothiazolo[5
, 4-bl pyridine dihydrochloride 3-(β-(1-methylimidazol-4-yl)acryloyl)amino-δ-valerolactam and phosphorus pentasulfide were reacted in the same manner as in Example 1, and after purification, chloride was added. Neutralization with hydrogen gave the title compound (yield 14.1%). Melting point 184-187°C (recrystallized from ethanol-chloroform) IR(KBr) cnr': 3410.163
5.1598.1521.1471.1446.135
0°837°NMR (CDC13) δ: 1.89 (2H, m),
2.74 (2H, t, J=5.3H7), 3.24 (
2H, t, J=5.0Hz), 3. 86 (3H, s)
, 4.46 (LH, brs). 7.03 (LH, d, J = 16.5Hz), 7.47 (
IH, d, J = 16.5H7), 7.81 (IH,
s). Elemental analysis value: Cl2H14N4S・2HC1・0.
Calculated value as 5H20: C, 43,91; H, 5
,22; N, 17.07; S, 9.77
: CI, 21.60° Actual value: C, 43,90
; H, 5,34; N, 16.67; S,
10.06; C1,21,63° [0059] Example 6 2-(2-(1-ethyl-2-phenylimidazol4-yl)ethynyl)-4,5,6,7-tetrahydrothiazolo[5 ,4-b]pyridine 3-(β-(1-ethyl 2
The title compound was obtained from -phenylimidazol-4-yl)acryloyl)amino-δ-valerolactam and phosphorus pentasulfide (yield 8.4%). Melting point: 140-142°C (recrystallized from ethyl acetate) I
R(KBr)cnr': 3234.1628.
1552.1538.1446.1371.1344゜1283, 821゜NMR (CDC13) δ: 1.41 (3H, t, J
=7.3Hz), 1.97 (2H. m), 2.82 (2H,t, J=6.4H7), 3.
27 (2H, t, J=5.4Hz), 4.02 (2H,
Q, J=7.3Hz), 7.08(IH, d, J
=16.0Hz), 7.10(IH,S)7, 24
(LH, d, J=16.0Hz), 7.41~7
．． 52 (3H, m), 7.53-7.64 (2H,
m). Elemental analysis value: Calculated value as C19H2ON4S:
C, 67,83; H, 5,99; N, 16.
65; S, 9.53° Actual value: C, 67,59
; H, 5,98; N, 16.26; S,
9.51° [00601 Example 7 2-(2,3-dimethoxystyryl)-4,5,6,7
-Tetrahydrothiazolo[5,4-b]pyridine dihydrochloride 2-(2,3-dimethoxystyryl)-4,5,6
,7-tetrahydrothiazolo[5,4-b]pyridine was neutralized with hydrochloric acid and recrystallized from ethanol-diethyl ether to obtain the title compound (yield 92.7%). Melting point 174-177°C (recrystallized from ethanol-diethylnithenyl) IR(KBr) cnr': 2546.162
6.1609.1592.1574.1478.144
3゜1431, 1345.1272.1066, 795
°NMR (d6 DMSOD20) δ: 1.93 (2
H, t, J = 4.9H2), 2.79 (2H, t, J
=6. IH7), 3. 30(2H,t,,T=4.8
Hz), 3.79 (3H, S), 3.84 (3H, S
), 7.08 (LH,br d, J=8.8Hz)
, 7.16 (LH, d, J=8.1Hz), 7.
28 (IH, br d, J=7.4Hz), 7.3
6 (IH, d, J=16.5H7), 7.48 (IH
, d, J = 16.5Hz). Elemental analysis value: Cl6HI8N2 SO2・2HC1
Calculated values as: C, 51,20; H, 5,37;
N, 7.46; S, 8.54; C1
, 18, 89° Actual measurement: C, 52, 11; H, 5
,41; N, 7.46; S, 8.97;
C1,18,41°[00611 Example 8 2-(2-(1-ethyl-2-phenylimidazol4-yl)ethynyl)-4,5,6,7-tetrahydrothiazolo[5,4-b] Pyridine dihydrochloride 2- (
Neutralize 2-(1-ethyl-2-phenylimidazol4-yl)ethynyl)-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridine with hydrochloric acid and recrystallize from ethanol diethyl ether. The title compound was obtained. (Yield 94.2%). Melting point: 181-184°C (recrystallized from ethanol-diethyl ether) IR(KBr)car': 3420.1586
．． 1532.1480.1464.1340°NMR (
d6 DMSO) δ: 1.41 (3H, t, J=7
．． 3Hz), 1.89 (2H, m), 2.74 (2H
, t, J=6.2Hz), 3.24(2H, t, J=5
．． 0Hz), 4.17 (2H, Q, J=7.3Hz)
, 5.22(LH,br S) , 7.01(L
H, d, J=16.4Hz), 7.55(LH, d
, J=16.4Hz), 7.62~7°75 (3
H, m), 7.78-7.88 (2H, m), 8.0
9 (LH, S). Elemental analysis value: C19H2oN4S・2HC1・0.5
Calculated value as H20: C, 54, 54; H, 5,
54; N, 13.39; S, 7.66;
C1, 16, 95° Actual value: C, 54, 70;
H, 5,60; N, 13.37; S, 7.
80; C1,16,83° [0062] Example 9 4-acetyl-2-(2,3-dimethoxystyryl)-
4゜5,6.7-tetrahydrothiazolo[5,4-bl
Pyridine 2-(2,3-dimethoxystyryl)-4,5
,6,7-tetrahydrothiazolo[5,4-b]pyridine (1,0 g, 3.3 mmol) of pyridine (10
ml) While cooling the solution with water, add acetic anhydride (0.68 g,
6.6 mmol) was added dropwise. After the reaction solution was heated and stirred at 80° C. for 3 hours, aqueous sodium bicarbonate was added and extracted with a chloroform-methanol mixed solvent. The extract was dried over magnesium sulfate and then concentrated, and the residue was purified by Fouch's column chromatography to obtain crystals, which were further recrystallized from hexane-ethyl acetate to give the title compound, 867.
(yield 76.0%). Melting point 185-187°C (recrystallized from hexane-ethyl acetate) IR(KBr) cur': 1651.159
3.1575.1536.1478.1446.127
3°1065, 962.785.762° NMR (CDC13) δ: 2.16 (2H, m),
2.34 (3H, s), 2.95 (2H. t, J=6.3Hz), 3.87 (8H, m), 6.8
6 (IH, dd, J=1.4Hz, 8.0Hz). 7, 06 (LH, t, J=8.1Hz), 7.
16-7.33 (2H, m), 7.61 (LH, d,
J=16,5Hz). Elemental analysis value: Calculated value as Cl8H2ON2 SO3: C, 62,77; H, 5,85; N,
8.13; S, 9.31° Actual value: C, 62,
67; H, 5, 79; N, 8.12; S
, 9.45° [0063] Example 10 2-(2,3-dimethoxystyryl)-4-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,
4-bl pyridine 2-(2,3-dimethoxystyryl)-4,5,6,7
-tetrahydrothiazolo[5,4-bl pyridine (1,
A solution of 0 g, 3.3 mmol) in pyridine (10 ml) was mixed with methanesulfonyl chloride (0, 3.3 mmol) while cooling with water.
45 g, 3.97 mmol) was added dropwise. After the reaction solution was heated and stirred at room temperature for 3 hours, aqueous sodium bicarbonate was added and extracted with a chloroform-methanol mixed solvent. The extract was dried over magnesium sulfate and then concentrated, and the residue was purified by Fouch's column chromatography. The obtained crystals were further recrystallized from hexane-ethyl acetate to obtain the title compound 1.
09g was obtained (yield 86.8%). Melting point 134-136°C (recrystallized from hexane-ethyl acetate) IR(KBr) cnr': 1623.157
7, 1535.1472.1445.1348.133
8°1261, 1155.1085.970.808.
760°NMR (CDC1a) δ: 2.09 (2H,
m), 2.91 (2H, t, J=6.5H7),
2.98 (3H, S), 3.83 (2H, m), 3
．． 87 (3H, S), 3.88 (3H, S), 6.
88 (LH, dd, J=1.6Hz, 8.0Hz)
, 7.06 (IH, t, J=7.9Hz) ,
7.17 (LH, dd, J = 1.6Hz, 7.
9Hz), 7.21(IH, d, J=16.5H
z), 7.56 (IH. d, J=16.5Hz). Elemental analysis value: Calculated value as C17H2ON25204: C, 53,66; H, 5,30; N,
7.36; S, 16.86° Actual value: C, 53
,71; H,5,42; N, 7.58;
S, 16.85° [0064] Example 11 2-(2,3-dimethoxystyryl)-4-(2-dimethylaminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-b ]Pyridine dihydrochloride 2-(2,3-dimethoxystyryl)-4,5,6,7
-tetrahydrothiazolo[5,4-b]pyridine (1,
0 g, 3.3 mmol) and powdered potassium carbonate (
N,N-dimethylaminoethyl chloride hydrochloride (0.57 g, 3
．． After adding 97 mmol) and heating and stirring at 90° C. for 4 hours, water was added and organic matter was extracted with a chloroform-methanol mixed solvent. The extract was dried over magnesium sulfate and then concentrated. The residue was purified by Fouch's ram chromatography to obtain an oily compound, which was neutralized with hydrochloric acid and recrystallized from diethyl ether-ethanol to yield 870 mg of the title compound. (yield 54.4%). Melting point 118-121°C (recrystallized from diethyl ether-ethanol) IR(KBr) cm-': 2694.1692.
1602.1576, 1505.1480.1344.
1271, 1190.1064.790.750. N
M R (d6D M SO ) δ: 2.02 (2H,
m), 2.79 (2H, m), 2.81 (3H, s
), 2.83 (3H, s), 3.47 (2H. m), 3.78 (3H, S), 3.83 (3H, S),
3.92 (2H, m), 4.54 (2H, m), 7.0
2 (LH, dd, J=1.8Hz, s, IHz)
, 7.09 (LH, t, J=7.8H2) ,
7.33 (LH, dd, J = 1.8Hz, 7.
6Hz), 7.34(LH, d, J=16.4H
z), 7.54 (IH. d, , T = 16.4Hz). Elemental analysis value: C2oH27N3SO2・2HC1・2
Calculated value as H20: C, 49,79; H, 6,
89; N, 8.71; S, 6.65;
C1, 14, 70° Actual measurement: C, 49, 33; H
, 6, 41; N, 8.21; S, 6.62
; C1,14,37° [0065] Example 12 2-(2-(4-methoxyphenyl)ethyl) -4,
5°6.7-Tetrahydrothiaso[5,4-bl pyridine] 3-(2-(4-
The title compound was obtained from methoxyphenyl)) propionylamino-δ-valerolactam and phosphorus pentasulfide (yield 21.5%). Melting point: 89-91°C (recrystallized from petroleum ether-diethyl ether) IR(KBr) cnr': 2952.161
0.1558.1513.1490.1443.135
0°1303, 1282.1242.1034.815
°NMR (CDC1a) δ: 1.94 (2H, m),
2.78 (2H, t, J=6.4H7), 2.9
5 (2H, m), 3.10 (2H, nx), 3.2
4 (2H, t, J=5.4Hz), 3.79 (3H
,s), 6.83(LH,d, J=8.6Hz)
, 7.14 (LH, d, J = 8.6 Hz). Elemental analysis value: Calculated value as C15HI8N2SO:
C, 65, 66; H, 6, 61; N, 10
．． 21; S, 11.65° Actual value: C, 65
, 42; H, 6, 60; N, 1
0.03; S, 11.73° JP-A-4 211089

Claims (5)

[Claims] Claim 1: Formula [I] [I] [In the formula, A is a bond or CH2, and R1 is a hydrogen atom or an aliphatic group, each of which may have a substituent, or an acyl carboxylate group. R2 represents a hydrogen atom, or an aromatic ring group or an aliphatic group each of which may have a substituent. ] or its salt. 2. R1 is a hydrogen atom, and R2 is an aromatic ring group which may have a substituent or an alkenyl group having 2 to 4 carbon atoms substituted with an aromatic ring group which may have a substituent. The compound according to claim 1. [Claim 3] Reacting a compound represented by formula [II] [II] [wherein A, R1 and R2 are as defined in claim 1] with a sulfurizing agent, and optionally converting R1. A method for producing the compound according to claim 1, which comprises subjecting the compound to a reaction. 4. A lipid peroxide production inhibitor comprising the compound according to claim 1. 5. A boxygenase inhibitor comprising the compound according to claim 1.