JPH01110683A - N-tetrazolyl thiazole carboxamide derivative and use thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [A represents lower alkyl, (substituted)aryl, 5-6 membered heterocyclic group having a hetero atom selected from O, N and S, or fused heterocyclic group composed of said heterocyclic group fused with benzene ring; R represents H or lower alkyl] or salts thereof. EXAMPLE:2-(2-Methoxyphenyl)-N-(1H-tetrazol-5-yl)-4-thiazole-carboxamide. USE:An antiallergic agent. PREPARATION:A substituted thiazole-carboxylic acid or reactive derivative in the carboxy group thereof expressed by formula II is reacted with an aminotetrazole or reactive derivative in the amino group thereof expressed by formula III in an inert solvent preferably in the presence of a condensing agent such as SOCl2 and, if necessary, in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application 1] This invention relates to an N-tetrazolylthiazole carboxamide derivative having antiallergic activity, a method for producing the same, and a medicament containing the above compound as an active ingredient.

rPrior Art and its Problems, αJ Various compounds are known to have antiallergic activity and are used as medicines, including cromogliquadisodium, chlorpheniramine maleate, tranilast, etc. However, these are not satisfactory in terms of side effects, oral absorption, and efficacy.Therefore, it has been desired to develop an antiallergic agent that does not have the above-mentioned deficiencies and α.

Means for Solving Problem E] As a result of repeated research on anti-allergic agents, the inventors have found that certain N-tetrazolylthiazole carboxylic acid derivatives exhibit excellent anti-allergic activity even when administered orally. They discovered that there were fewer side effects and completed this invention.

[Summary of the Invention 1] The present invention provides a method for treating a compound of the formula [wherein A is a lower alkyl group, has no substituent, or is hydroxy, alkoxy
An aryl group having at least one substituent selected from 7lyl lower alkoxy, lower alkyl carbonyloxy, halo lower furkyl, halogen, nitro and amino, or at least a hetero atom selected from oxygen, nitrogen and sulfur mushroom. A 5- or 6-true heterocyclic group having one true heterocyclic group or a fused heterocyclic group formed by condensing the above heterocyclic group with a benzene ring (
These two heterocyclic groups are unsubstituted or have at least one substituent derived from hydroxy, lower alkyl and halogen), R means hydrogen or a lower alkyl group] or salts thereof It provides:

The above compound comprises (a) a substituted thiazolecarboxylic acid represented by formula 1, or a reactive derivative thereof at the carboxy group, and 7mi/tetrazole or its amino acid represented by the formula The reactive derivatives in group 7 are reacted to obtain compounds of formula (1) or compounds of formula (b) [wherein Al+ means an aryl group having at least one nitro group and R is It is produced by reducing the compound represented by meaning 1 to obtain a compound represented by the formula [wherein Aa means an aryl group having at least one amino group, and R has the above meaning].

The present invention also provides an agent for treating allergic diseases, which contains at least one compound represented by formula (1) or a salt thereof as an active ingredient.

[Detailed Notes 81 (Constant tA) The terms used in this specification are explained in more detail as follows.

The term "lower" includes groups having 1 to 6 carbon atoms, unless otherwise specified.

"Lower alkyl group" or "lower furkyl" in lower furkylcarbonyloxy or halo-lower alkyl
The moiety is a straight-chain or branched saturated hydrocarbon residue having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-
Includes butyl, pentyl and hexyl.

The "lower alkoxy" moiety in aryl lower alkoxy means a group represented by -0-lower furkyl (here, lower alkyl has the above meaning).

The term "alkoxy" means -0-furkyl, where alkyl is a straight or branched saturated hydrocarbon residue.

Preferred alkyls are those containing 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, hexadecyl (cetyl) and octadecyl (stearyl).

"Halo" groups or "halo" moieties in halo-lower alkyl include fluoro, chloro, bromo and iodo.

The term "halo-lower alkyl" means at least one, usually one
Lower alkyl substituted with ~5, preferably 1 to 3 halogens, such as chloromethyl, trifluoromethyl and 2,2,2-trichloroethyl.

The "aryl group" or the "aryl" moiety in 7lyl lower alkoxy refers to monocyclic aryls such as unsubstituted phenyl and lower alkylphenyl (wherein lower alkyl is as defined above), such as tolyl, xylyl, cumenyl. and 2rA-7-aryl such as biphenyl, unsubstituted 7-methyl, lower alkylnaphthyl (wherein lower alkyl is as defined above). These 7-aryl groups may be unsubstituted and at least 1, usually 1 to 5
-1 may have 1 to 3 substituents, preferably 1 to 3 substituents
゜Substituents include hydroxy, alkoxy (e.g. CH30
- or c, , r-rcolo0-), aryl lower alkoxy (e.g. C, H, CI-1,0-), lower alkylcarbonyloxy (e.g. CH, Coo-)
, halo-lower alkyl (eg CF, -), halogen (eg Cl- or Br-), nitro and 7mi/. When the aryl group has two or more substituents,
These may be the same or different.

The term [5-likely 6-membered heterocyclic group having at least one heteroatom selected from oxygen, nitrogen and sulfur] means
Five-shell heterocyclic groups having at least one heteroatom as described above, such as furyl, thienyl, pyrrolyl, imidazolyl,
Included are oxasilyl, thiazolyl, triazolyl, tetrazolyl, and 6-membered heterocyclic groups having at least one of the above heteroatoms, such as bilinol, pyrazinyl, pyridacyl, oxazinyl, thiazinyl, triazinyl, and the like.

The term [a fused heterocyclic group formed by the above-mentioned heterocyclic group and a benzene ring interlocked] refers to a #6 fused heterocyclic group formed from the above-mentioned 5-shell heterocyclic group and a benzene nucleus, such as indolyl, It includes imidazolyl, etc., and fused heterocyclic groups consisting of the above 6-membered heterocyclic group and a benzene nucleus, such as quinolyl, isoquinolyl, quinazolinyl, benzothiazinyl, and the like.

The above two types of heterocyclic groups (non-fused and fused) may be unsubstituted or may have at least 1, usually 1 to 5, preferably 1 to 3 substituents, or substituted The base is
hydroxy, lower alkyl (e.g. CH, - or CI
Hs-) and halogens (e.g. C1- or Br
−). 11 When two or more substituents are present,
These may be the same or different.

The IH-tetrazolyl group represented by the formula 2
It is well known that it has a tautomeric relationship with the +-1-tetrazolyl group.

Therefore, the two groups are substantially identical and isomers containing the groups are considered to be the same compound. Therefore, all isomers containing the above-mentioned groups in the molecule are included in the scope of this invention, but in this book I, r
Only the expression "ltl-tetrazolyl" is used.

The term "salts" includes pharmaceutically acceptable non-toxic salts, including alkali metal salts (e.g. sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.). Non-base salts such as metal salts and ammonium salts, as well as amine salts such as triethylamine salts, triethylamine salts, prochloride salts,
dicyclohexylamine salt, N,N'-dibenzylethylenediamine [, N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethyl 7mino)methane salt, 7enethylbenzylamine salt, etc.] Contains nurturing base salts such as

These salts can be prepared in conventional manner, for example from the corresponding acids and bases or by salt exchange.

(Manufacturing method) The detailed method for manufacturing the compound of formula (+) is as follows.

(a) The compound of formula (1) is a compound of formula (II) or a reactive derivative thereof at the carboxy group which has the formula (I [I)
and its reactive derivative at the amino group.

Reactive derivatives at the carboxy group of compounds of formula (If) include acid halides, acid anhydrides, active esters and active amides. Among these, acid chloride is frequently used as the acid halide.

Examples of the a anhydride include symmetrical anhydrides and mixed acid anhydrides, and the latter include, for example, dialkyl phosphoric acid mixed anhydrides, dialkyl phosphorous acid mixed anhydrides, alkyl carbon a mixed anhydrides,
Active esters include aliphatic carboxylic acids (e.g., piperic acid, trichloroacetic acid) mixed anhydrides, etc., and active esters include methyl ester, ethyl ester, cyanomethyl ester, p-nitrophenyl ester, ester with N-hydroxysuccinimide, etc. is used. As the active amide, amides with imidazole, dimethylimidazole, and triazole are used.

Reaction f) at the amino group of the compound of formula (I[l): y
, conductors include ship bases with aldehydes (e.g. acetaldehyde, impentanal, benzaldehyde), reaction products with silyl compounds (e.g. trimethylsilyl chloride, trimethylsilylacetamide), phosphorus compounds (e.g. phosphorus trichloride, phosphorus oxychloride) and The reaction products of are used.

If the compound of formula (II) is used as the carboxylic acid, it is advantageous to carry out the reaction in the presence of a condensing agent. As a condensing agent, 5OC12, 5O2C1, .

PCI,, Pc1. ,POCl,,P Br,ep(n
Halogenating agent, or N,N'-dicyclohexylcarbodiimide (DCC), N-cyclohexyl-N'-morpholinoethylcarbodiimide, N,N'-diisopropylcarbonimide, CIC○2CI(,,ClC0 ，
C, H,, B r CO-C) E 3, (CILC
O)20. N-ethylbenzisoxazolium salt, 2-chloro-1-methylpyridinium salt, N,N'-
Carbonyl is dioxane, methylene chloride, chloroform, ether, tetrahydro7ran (THF),
7setone, dimethylformamide (DME'), dimethylsulfoxide (DMSO), birinone, benzene, toluene, xylene, etc. are used.

An example of a preferred implementation method is as follows.

First, acid (II) is dissolved in an inert solvent, and a condensing agent is added thereto. When the condensing agent is a halogenating agent, the addition is advantageously carried out under water cooling; in the case of other condensing agents, the addition can be carried out either under water cooling or without cooling (i.e. at room temperature). The mixture is kept at room temperature or under heating, such as boiling point, for 0.5-3 hours.

The active form of the acid thus produced, with or without isolation, is reacted with the amine (III). This reaction is carried out in an inert solvent, if necessary in the presence of a base, to produce the compound (1). The base may be one that captures hydrogen halide, such as Pt5 tertiary amine (
triethylamine, dinotylaniline, etc.)
Amine (I[[) can also be used as a base.

As the inert solvent, the solvent used in the previous step can be used. When the reaction is carried out at room temperature to boiling point for 0.5 to 5 hours, the target substance can be obtained in good yield.

(lJ) The compound of formula (In) can be obtained by reducing the compound of formula (Ill) by a conventional method.

Reduction can be by catalytic or chemical reduction.

In the catalytic reduction, compound (rb) is treated with platinum oxide, palladium on carbon,
Hydrogen is used in the presence of a metal catalyst for catalytic reduction such as rhodium alumina or Raney nickel. Chemical reduction can be carried out with a combination of metal and acid or with a reducing agent.

Compounds of formula (rb) are obtained by method (a).

The raw material compound (■) can be produced by a known method, for example, according to the following reaction formula (A) or (B).

(A) [In the above formula, A'1 is a substituent excluding the free NH2 group (otherwise, it has the same meaning as 8, Ar is an aryl group, A11 (is an alkyl group (preferably a lower alkyl group), Hal is a halogen group ( 1 method (A, preferably C1 or Br)
) is suitable for producing compound (II) in which R is hydrogen. In detail,! In the II's(i) step, the formula (V
) to the compound P2S, or Lawesso
n) Reagent [2,4-bis(4-me)xyphenyl-1,
213,4-dithiaphosphetane-2,4-notion 1
are reacted by a conventional method to obtain a compound of formula (Vl).

Alternatively, in step (io), when A' in formula (V) is an aryl group having an OI-1 group ortho to CON +-12, a compound of formula (V a ) is converted into a haloformate. (e.g. ethyl chlorocarbonate) to give the cyclic intermediate (Vb), which is then treated with P z S s and aqueous alkali to give the compound (■) [7 Pharmazie 21 @161-1665
(,]9966111 Formula Vl)
In the step, it is reacted with a compound of formula (■) (for example, ethyl bromopyruvate) by a conventional method to obtain compound (L).

Compound (I[,) can be hydrolyzed (preferably with an alkali) in step (iii) to lead to compound (■b).

(B) (IX) (X) Method (B)
is particularly suitable for the preparation of compounds of formula (II) in which R is lower alkyl. To be more specific, in step (i),
A compound of formula (IX) is acylated to give a compound of formula (X), which is treated with P2S5 or Lawesson's reagent in step (ii) to give a compound of formula (Ile).
Inc) is hydrolyzed to yield a compound of formula (■). Compounds having flufoxy or lower alkylcarbonyloxy as a substituent may be prepared by replacing the hydroxy of the corresponding compound with hydroxy as a substituent by method A or method B.
obtained by flukoxylation or alkylcarbonyloxylation before or after step (1ii) of the process.

(Applications) The compound of formula <1) has excellent antiallergic activity and is therefore useful as a drug for the treatment (prevention, alleviation, and treatment) of 7-relief diseases.

When used for prevention and/or treatment, the compound (1) of the present invention is used as an active ingredient, and oral administration,
They can be administered in the form of conventional pharmaceutical preparations in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for parenteral or topical administration. Such formulations can be solid, such as capsules, tablets, dragees, ointments, suppositories, or liquid, such as solutions, suspensions, emulsions. If necessary, adjuvants, stabilizers, wetting agents, emulsifiers, and other commonly used additives can be added to the formulation.

In the above applications, the dosage will, of course, vary depending on the age of the patient, the condition, the compound used, the method of administration and the new treatment. However, satisfactory results are generally obtained at doses of about 0.5 to 50 xg/kg, preferably administered in divided doses 2 to 4 times a day or in the form of a sustained release formulation.

[Example] Hereinafter, the present invention will be explained in more detail by referring to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.

Reference example 1) Cf5 i' step) Literature (7 Pbarmazic, 21
, 161-166 (1966)), 10 g of 2-hydroxybenzamide was dissolved in a mixed solvent of dry pyridine 36R1 and dry acetonitrile 2211, and under cooling,
7.8 ml of ethyl chlorocarbonate was added dropwise.

After dropping, the bath temperature was heated to 120°C, the solution was concentrated, the 0 reaction solution was refluxed for 3 hours, poured into water, acidified using concentrated hydrochloric acid, the precipitated solid was collected by filtration, and methanol was added. - Recrystallization from water yielded 10 g of 2,4-dioxodihydro-1,3-benzoxanone.

Obtained oxazine 10. Dry dioxane 300i+
After dissolving in 1', PiS113.6y was added and reacted at 90°C for 4 hours. The 0 reaction mixture was filtered under suction, the solvent was distilled off, water was added, and extraction was performed using ethyl acetate. After drying the extract, the solvent was distilled off and the residue was washed with n-hexane to obtain 12 g of a yellow solid thio compound. Next, 245 ml of IN-potassium hydroxide was added to this thio compound, and the mixture was heated to 80°C.
After reacting for 15 minutes, IN hydrochloric acid was added to the reaction mixture under water cooling to make it acidic, and the precipitated solid was suction filtered. Recrystallization from water yielded 4.77% of 2-hydroxythiobenzamide. Imported pi 19-120℃, (literature value 11
9-120°C, 7 Pharmazie*
2, pp. 161-166 (1966), ) (ftSii process, l @ iii process) Literature (7 Glycartieral and Biological Chemistry (
Agr, B iol, Chew,.

11.780-783 (1970), 3 x 1 of ethyl bromopyruvate was dissolved in 68 x 1 of dry ethanol, and to this was added 2-M dissolved in 40 x 1 of dry ethanol.
Hydroxythiobenz7mid 3.0! I was added dropwise. 1
After refluxing for an hour, the solvent was distilled off from the reaction mixture, water and a 4% aqueous solution of carbonic acid were added to the residue, and the mixture was extracted with ethyl acetate. After drying, the solvent was distilled off, and the resulting residue was purified by column using silica gel to obtain ester form 4,47. I got it. Next, using potassium hydroxide aqueous solution (potassium hydroxide 6.0 g, water 27xl), 9011
Hydrolysis was carried out in methanol at 60°C for 30 minutes, the solvent was distilled off, water was added to the residue to make it acidic, the precipitated solid was collected by filtration, and recrystallization from methanol yielded the target product 2-(
3.3 g of 2-hydroxyphenyl)-4-thiazolecarboxylic acid was obtained. ap, 26B-269°C.

(Literature value 271-272°C, 7Glyceral and Biological Chemistry (Agr.

Biol, Chell, 34, 780-783
(1970), ) Reference Example 2) (Step I, Step II, Step III) 3.5 g of 3-methoxybenz 7amide was suspended in 110 ml of dry dioxane and dissolved by heating to 90°C. Pt555g
The reaction mixture was poured into ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off to obtain 4.0 g of the thio compound as a red oil. 3.4 g of ethyl bromopyruvate
A solution of this thio compound 4.09 dissolved in dry ethanol 50 M1 was added dropwise to a solution of 4 ml of dry ethanol 3611, and after refluxing for 1.5 hours, the solvent was distilled off and water and 4 % aqueous sodium carbonate solution was added and extracted using ethyl acetate. After washing with water and drying, the solvent was distilled off to obtain 6.2 g of ester.

Next, 6.2 g of this ester was dissolved in methanol 8011, and a potassium hydroxide aqueous solution (potassium hydroxide 3.7?
, 12 zf of water) was added, and the mixture was reacted at 60° C. for 30 minutes to perform hydrolysis, and then the supernatant liquid was decanted and the solvent was distilled off. Water was added to the residue, acidified with 2N hydrochloric acid, and then extracted with ethyl acetate.

After washing with water and drying, the solvent was distilled off, and the residue was recrystallized using a mixed solvent of ethyl acetate and petroleum ether in the presence of activated carbon. ) was obtained. Tap, 132-13
3℃.

IR (KBr, cm'): 1700.3200-21
00'H-NMR (DMSO-d, #): 3.83 (
3H,s, -QC Danyu) 6.93~7.47 (41-1, Import wAr-Tsuji) (1,
40 (IH, s, thiazole ring proton) Reference example 3) (Step i, step ii, step iii) Suspend 1 g of 2-7 minnow 3-oxo-butanoic acid ethyl ester hydrochloride in dry methylene chloride 3011 After that, triethylamine 1.69zz! was added and dissolved. After dropping 0.91 ml of 4-nodoxybenzoyl chloride under water cooling, the reaction mixture was returned to room temperature and reacted for 20 minutes. Water was added to the reaction mixture, extracted with methylene chloride, and the growth layer was mixed with water, IN hydrochloric acid, and 4%
After sequentially washing with sodium hydrogen carbonate and saturated saline, and drying (anhydrous sodium sulfate), the solvent was distilled off, the residue was dissolved in a developing solvent (benzene: ethyl acetate = 4:1), and purified with a silica gel column. , the colorless solution after removing the impurities flowing out is collected and the solvent is distilled off, and the white solid 2
-((4-methoxybenzoyl)amino)-3-oxo-butanoic acid ethyl ester 1.28g (yield 83%)
Obtained. mp, 67-69°C.

Next, this 2-((4-methoxybenzoyl)amino)-
After dissolving 1.28 g of 3-oxo-butanoic acid ethyl ester in 40 ml of dry dioxane, Lawesson's reagent 3.
82 was added and reacted at 60°C for 4 hours. Insoluble materials in the reaction mixture were collected by suction filtration, and the solvent was distilled off from the filtrate.
The residue was dissolved in chloroform and purified using a silica sol column (hexane: ethyl acetate = 7:3). The first component flowing out was collected, the solvent was distilled off, and a pale pink solid of 2-(4-
1.1 g of methoxyphenyl-5-methyl-4-thiazolecarboxylic acid ethyl ester (yield: 87%) was obtained.

mp, 65-66°C.

Subsequently, 2-(4-methoxyphenyl)-5-methyl-4-thiazolecarboxylic acid ethyl ester 1.12
was dissolved in 30 zl of methanol, 11.9+1 IN potassium hydroxide was added, and the mixture was reacted at 50°C for 30 minutes.
The solvent was distilled off from the reaction mixture, and water was added to the residue, which was then acidified (pH 2) with 2N hydrochloric acid under water cooling, and the precipitated solid was collected by suction, washed with water, and recrystallized from methanol-water. The target product, 2-(4-methoxy7enyl)-
779 mg of 5-methyl-4-thiazolecarboxylic acid (
Yield: 79%).

9.166-168℃, (white crystal) IR (KBr,
cm'''' words): 3200-2100.1680+1-1
-N! l(DMSO-d,,δ):2.73(3H,s
, -C tanyu) 3.80 (3H, s, -〇C tanyu) 7.00 (2H
, d, benzene ring proton) 7.77 (2H, cl, benzene ring proton) Reference example 4) (Methylation and step iii) 2-(2-hydroxy 7enyl)-4-thiazolecarboxylic acid ethyl ester 1, 58g and Ra potassium 81
5mg in dry acetone 20d', dry DMF 10ml+
0.41 ml of methyl iodide was added dropwise. 5
After reacting at 0 to 60°C for 1 hour, the reaction solution was poured into ice water, extracted using ethyl acetate, the extract was washed with water, and after drying,
The solvent was distilled off to give 1.63 g of methylated product (np, 86~
87°C). The methylated product obtained here was added to a solution in which 1.88 y of potassium hydroxide was dissolved in a mixed solvent of 3011 methanol and 6 ml of water, and hydrolysis was performed at 60° C. for 30 minutes.

After distilling off the methanol, water was added to the residue, acidified with 2N hydrochloric acid, and the precipitated foam solid was recrystallized from methanol/water to yield 1.27. , got the objective. mp.

182-184°C.

I R (KBr, cm-'): 1680.3200'H
-NMR (DMSO-d, δ): 4.00 (3H, s
, -QC Danyu) 6.96-8.33 (4H4, Ar- and) 8.37 (I
H, s, thiazole ring proton) 13.10 (IH,
br-s+-COOH) Reference Example 5) (7cetylation) 2-(2-Hydroxy7enyl)-4-thiazolecarboxylic acid f% 1900xy was dissolved in 15M1 of dry pyridine, and 0.461zffi of acetic anhydride was added dropwise under water cooling. did.

After returning to room temperature and reacting for 1.5 hours, the solvent was distilled off,
Water was added to the residue, acidified using 2N hydrochloric acid, and then extracted with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off to obtain the target product, 2-(2-7cetoxyphenyl).
9921 g of -4-thiazolecarboxylic acid was obtained. 1mp recrystallized from chloroform/n-hexane, 189~
191℃.

'I R (KBr, cz'''): 3200-2100
．． 1760°IH-NMR (DMSO-d, δ): 2
．． 40 (3H mountain-coc wholesale □ 7.07-8.30 (4H, m, Ar-〇) 0.47 (
1)1. s, thiazole ring proton) Reference Example 6) (Step i) ``3-hydroxy-picolinamide 1 under argon flow
pJA and 2 g of Lawson's reagent in 75 d of dry dioxane.
After FIA, the mixture was reacted at 95° C. for 4 hours.

After the reaction, remove the insoluble solids in the reaction mixture by suction filtration,
The solvent was distilled off from the filtrate. The residue was dissolved in methylene chloride and subjected to silica gel column purification g1 (ethyl acetate di-hexane = 1:1), the yellow solution flowing out into 2#r@ was collected, and the solvent was distilled off. The obtained solid was dissolved in chloroform/n
- Recrystallization from hexane gave yellow crystals of 3-hydroxy-thio-picolinamide 546B (yield: 46%). Shizu p, 15'O~151°C.

(Step ii) 500 mg of 3-hydroxy-thio-picolinamide was dissolved in 25M1 of dry ethanol, and then added dropwise to a solution of 42ml of bromopyruvic acid ether 0.5H dissolved in 2011 dry ethanol under a nitrogen stream, followed by heating for 2 hours. After the refluxing reaction, the solvent was distilled off from the reaction mixture,
Water was added to it to make it a 4% Nacinacillium R acid solution, and the mixture was extracted with ethyl acetate.

Yes B! The layer was washed with saturated brine, dried (anhydrous sodium sulfate), the solvent was distilled off, the residue was purified using a silica gel column (ethyl acetate:benzene = 1:9), and the second yellow solution was obtained. were collected and the solvent was distilled off. The obtained solid was recrystallized from methanol and water to give 2-(3-hydroxy-2-pyridyl)·-4-
Thiazole carboxylic acid ethyl ester 260u (yield 3
2%). ap131-134°C.

(Step ii) After dissolving 350IIIg of 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylic acid ethyl ester in ethanol 711 at 80°C, a solution of potassium hydroxide 43619 in water (5,5jj) was added to the solution. was added and reacted for 30 minutes under the same conditions. After the reaction, I added I to the reaction mixture under water cooling.
N-hydrochloric acid was added to neutralize the mixture, and the precipitated solid was collected by suction filtration. This solid was dried and a pale yellow solid of 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylic acid 287
mg (yield 92%). -p300°C or higher.

IR (KBr, ci+-'): 3700-2000.
1600M S (m/z): 289 (M+) Reference Example 7) 2-2-71 Ru 4---Lcarboxylic Material Examination JΔ Shayu (Ith Step) Drying 1.5 g of 2-7 Rancarpoxyamide After dissolving in dioxane 8011, add ptssa, og, 55
After 1.5 hours of reaction at °C, water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. After washing the TA layer with saturated brine and drying (anhydrous sodium sulfate), the solvent was distilled off to give a yellow solid of 2-7-thiocarpoxyamide 1.
63. I got it.

(Step ii) Subsequently, 2-7 lan-thiocarpoxyamide 1°G3t
Dry t with ethanol 65xj! After dissolving with humidification, 1.97z1 of ethyl bromopyruvate was added, and 30
After the reaction was heated to reflux for 1 minute, the solvent was distilled off from the reaction mixture, water was added to the residue, the mixture was made weakly alkaline with a 4% aqueous sodium carbonate solution, and the mixture was diluted with ethyl acetate for 30 minutes.
Extracted twice. The organic layer was washed with saturated brine, dried (anhydrous sulfuric acid) (17 μm), and the solvent was distilled off to give 3.12 g of 2-(2-7lyl)-4-thiazolecarboxylic acid ethyl ester as a pale yellow solid. I got it.

(Step 11) 2-(2-7lyl)-4-thiazolecarboxylic acid ethyl ester 3.12. After dissolving in methanol 50xN, 38.58zi of IN potassium hydroxide aqueous solution was added dropwise,
After 15 minutes of reaction at 55° C., the solvent was distilled off from the reaction mixture, water was added to the residue, acidified with 2N hydrochloric acid under water cooling, and the precipitated solid was collected by suction filtration. This was washed with water and dried to obtain 1.16 g (yield: 46%) of 2-(2-7lyl)-4-thiazolecarboxylic acid as a pale yellowish solid. mp2
57-265℃.

IR(KBrtcx-'): 3700~3200°3
100.1750.1600 H-NMR (DMSO-d, δ): 6.65 (L
H, dd, 7-lyl group 4-position and) 1.15 (lH, d, furyl group 3-position and)? , 82 (f H, d, 7-lyl group 5-position dan-
) 8.12 (IH, s, thiazole TA ratio) Reference example 8) 2-5-Meru 2- Ninyl-5-Meru 4-1
-rucarvone A:B. (Ith step) After suspending 1.74 g of 5-methyl-2-thio7enecarvone M in 50 M1 of dry benzene, 4.5 g of thionyl chloride was added.
41zz! After the reaction, the solvent was distilled off from the reaction mixture, and the residue was further washed and distilled off successively with dry benzene and dry toluene. This residue was dissolved in 10 ml of dry methylene chloride, and this solution was added dropwise under water cooling to a solution of 2 g of 2-amino-3-oquin-butanoic acid ethyl ester and 3,0' txt of triethylamine in dry methylene chloride (50 ml). After returning to room temperature and reacting for 300 minutes, water was added to the reaction mixture and extracted with methylene chloride. After washing the organic layer with water and drying (p! & sodium hydroxide), the solvent was distilled off, and the residue was purified with a silica gel column. ! (benzene: ethyl acetate = 4:1), the pale yellow solution was collected after removing the impurities that were distilled out first, the solvent was removed by ftV, and a pale yellow solid of 2-(5-methyl-2 -thienylcarbonylamino)
-3-oxo-butanoic acid ethyl ester 1.84. I got it.

(Step i) 2-(5-methyl-2-thienylcarbonylamino)-
After dissolving 3-oxo-butanoic acid ethyl ester 1.84 in dry dioxane 80+1, Lawesson's reagent 5.
After 7 g was added and reacted at 80° C. for 2 hours, insoluble solids in the reaction mixture were removed by suction filtration, and the solvent was distilled off from the filtrate. Dissolve the residue in chloroform and purify with a silica gel column! I! (n-hexane: ethyl acetate = 4
: 1), the pale yellow solution after removing the impurities flowing out first was collected and the solvent was distilled off, and the pale yellow solid 2-(5-methyl-2-thienyl)-5-methyl-4- 1.5 g (yield 51%) of thiazole carboxylic acid ethyl ester was obtained.

(Step iii) 2-(5-methyl-2-thienyl)-5-methyl-4-
1°47g of thiazole carboxylic acid ethyl ester to 1?1 methanol? After dissolving in 1Oz/, IN potassium hydroxide aqueous solution 11116.5iN was added and the mixture was reacted at 60°C for 40 minutes.After the reaction, the solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was cooled with water. The solid was acidified with 2N hydrochloric acid and the precipitated solid was collected by suction filtration and washed with water. Add this to methanol
Recrystallized from water to give pale yellow crystals of 2-(5-methyl-2-
thienyl)-5-methyl-4-thiazolecarboxylic acid 1
06 g (yield: 80%) was obtained. mp, 160-161
℃.

IR(KBr, ci+-'): 1670'H-NMR
(DMSO-d,, δ): 2.5043H, 11,
, -C of thienyl group) 2.70 (3H, s, -C of thiazole ring) 6.75 (IH, a, thienyl group 4)
Position H) 7.27 (I H, d, thienyl group in 3rd position Example 1) 2-(2-methoxyphenyl)-4-thiazole carbon fi250u and N,N'-carbonylciimiguzol (CD I) Dry 20'7+y DMF2.5z1
After stirring and reacting at room temperature for 1 hour, 5-7 minotetrazole 109!2 was dissolved in 1.5
A solution of ii' dissolved in dry DMF was added dropwise and reacted at 70°C for 2 hours. The solvent was distilled off, water was added to the residue, and 2N
After acidifying with hydrochloric acid and filtering the precipitated solid and washing with water, the obtained solid was further stirred in ether for a while and filtered, and when dried, the desired product 2-(2-methoxy7enyl) was obtained as a white solid. )-N-(IH-tetrazol-5-yl)
-4-thiazolecarboxamide 255 mg (yield 7
9%).

Example 2) 2-(2-7cetoxyphenyl)-4-thiazolecarbon i'11600zy was suspended in 12111 l of dry benzene, 0.83 i1 of thionyl chloride was added dropwise under water cooling, and the suspension was allowed to flow for 1 hour. After evaporating the solvent, 5 ml of dry benzene was added to the residue and evaporated again.Furthermore, 5 ml of dry toluene was added and the solvent evaporation was repeated to obtain an acid chloride.

Next, 194 mg of 5-7minotetrazole was added to 80xl of dry tetrahydrofuran and 0°3211 of triethylamine.
A solution of the acid chloride obtained earlier dissolved in dry Tetrahydro7ran 5R1 was added dropwise at room temperature. After further reaction for 1.5 hours under the same conditions, the solvent was distilled off, water was added to the residue, acidified with 2N hydrochloric acid under water cooling, and the precipitated solid was collected by filtration, washed with water, and dried with ether again. After washing, the target product 2-(2-7cetoxyphenyl)-
627 zg (yield: 83%) of N-(1!]-tetrazol-5-yl)-4-thiazolecarboxy 7mide was obtained.

Example 3) 2-(2-methoxyphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide 1
91 g was suspended in 30 ml of water, 6.41 ml of 0°IN sodium hydroxide was added, and the mixture was reacted at 85° C. for 1 hour. After distilling off the solvent, dry acetone was added to the residue to crystallize it, and the resulting solid was collected by filtration and dried to give 2-(2-methoxyphenyl)-N-(IH-tetrazol-5-yl)-4-thiazole. Sodium salt of carboxamide 1
99iy (yield 95%) was obtained.

Example 4) 200 mg of 2-(2-hydroxyphenyl)-N-(IH-tetrazol-5-yl)-4-thiazole carboxy 7mide was suspended in 15M1 of dry methanol, and 0.045 zl of 2-7minoethanol was added thereto. was added and dissolved, and the precipitated solid was collected by filtration from the reaction mixture, which was reacted for 30 minutes at room temperature, and washed successively with dry ether and dry acetone. After distilling off the solvent, the filtrate was crystallized by adding dry ether to the residue, which was collected by suction filtration. These crystals were collected and dried to give a white solid, 2-(2-hydroxyphenyl)-N-(IH-tetrazol-5-yl)-4.
- Thiazole carboxy 7mide 2-7mide/ethanol salt 130xt (yield 54%) was obtained.

Example 5) 2-(2-nitrophenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide 20
0mg dried tetrahydro7ran (THF) 30i+e
and dry DMF 13.7zi'no fm mixture W,
After adding palladium-carbon (10%) 200xy, 2
Hydrogenation was carried out for 2 hours. After removing paranoum carbon by suction filtration and concentrating the filtrate under reduced pressure, 200% water was added to the residue.
ij! was added to perform crystallization, and the precipitated solid was collected by filtration and dried to give a colorless solid of 2-(2-7minophenyl)-N-(I
H-tetrazol-5-yl)-4-thiazolecarboxamide 162JIF (yield 89%) was obtained.

Example 6) Under an argon stream, 2-(3-hydroxy-2-pyrinol)-4-thiazole carbon l'1m20011F and N
, N'-carbonyldiimidazole (hereinafter abbreviated as CDI) (291.9 mg) was suspended in dry DMF7zN'(#A), and then reacted at 80° C. for 1.5 hours. To this, 91.9zy of 5-7 minotetrazole in dry DMF (3
d) After the 0 reaction in which the solution was added dropwise and reacted at 85°C for 3.5 hours, the reaction mixture was cooled to room temperature, the precipitated solid was collected by suction filtration, and the obtained solid was washed sequentially with DMF and THF,
Dry to give 2-(3-hydroxy-2-pyridyl)-N-(IH4-tetrazol-5-yl)-4 as a white solid.
-thiazole carboxamide 140+g (yield 54%)
) was obtained.

Ring p, 300℃ or more.

Example 7) Method J 2-(2-7lyl)-4-thiazolecarboxylic acid 300
mg and CD I 373.81 in dry DMF 10ml
1. Next, a solution of 156.9 mg of 5-7 minotetrazole in dry DMF (2z1) was added dropwise. After a further 3 hours of reaction under the same conditions, the solvent was distilled off from the reaction mixture, water was added to the residue,
The mixture was acidified with 2N hydrochloric acid under water cooling, and the precipitated solid was collected by suction filtration. After thorough washing with water, washing with ether and drying, a mushroom-colored solid <F) 2-(2-furyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide 1
7511F (yield 43%) was obtained. mp, 275-27
7°C (methanol/THF/water) Example 8) 2-5-no Ru2- Uniru5-no Ru2-(5
-Methyl-2-thienyl)-5-methyl-4-thiazolecarboxylic acid (300 mg) and CDl (304.911 g) were dissolved in dry DMF8y1 and reacted for 1 hour at room temperature.
MF (2 ml) solution was added dropwise and reacted at 70°C for 3 hours. After the reaction, the solvent was distilled off from the reaction mixture, water was added to the residue, acidified with 2N hydrochloric acid under water cooling, and the precipitated solid was sucked. It was filtered.

After thorough washing with water and drying, a pale yellow solid of 2-(5-methyl-2-thienyl)-5-methyl-N-(IH4-tetrazol-5-yl)-4-thiazolecarboxamide 372.9zy (yield) was obtained. 97%). Theory p, 278
~280°C (methanol/THF/water).

Example 9) 2-3-hi10xy2-py1jiruN-1 ■Eteto--5-yl-24-f'Goot24-carboxyamide monotrium 2-(3-hydroxy- 2-pyridyl)-N-(IH-
After suspending tetrazol-5-yl)-4-thiazolecarboxamide 26'Oi+9 in water, IN
Sodium hydroxide aqueous solution 0.899zz! Add 80
After 30 minutes of reaction at °C, the solvent was distilled off from the reaction mixture, the residue was crystallized from dry acetone, filtered off under suction, and dried to give a yellow solid of 2-(3-hydroxy-2-pyrinol). )-N-(IH-tetrazol-5-yl)-4-
Monosodium salt of thiazole carboxamide 269
u (yield 96%) was obtained. -〇, 300℃ or higher.

Example 10) 2-(2-furyl)-N-(IH-tetrazole-5-
After suspending 100 ml of (Il)-4-thiazolecarboxamide in dry methanol 1011, then adding 0.025 z1 of 2-7minoethanol to dissolve it, and reacting at room temperature for 30 minutes, The solvent was distilled off from the reaction mixture, and dry ether was added to the residue to crystallize it, which was collected by suction filtration. This was dried to give a yellow solid of 2-(2-7lyl).
-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide 2-7 minoethanol salt 100
, 3 mg (yield 81%). mp, 255~2
60℃.

As for other compounds of the present invention (1), the following compounds were synthesized by applying any of the above examples.

2-(2-hydroxyphenyl)-N-(I
H-tetrazol-5-yl)-4-thiazolecarboxamide (1-1).

2-(3-methoxyphenyl)-N-(IH-
Tetrazol-5-yl)-4-thiazolecarboxamide (1-3).

2-(4-methoxyphenyl)-4-thiazolecarboxylic acid to 2-(4-nodoxyphenyl)-N-(IH-
Tetrazol-5-yl)-4-thiazolecarboxy7mide (I-4>).

2-(2-methylphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxy7mide (1-5) from 2-(2-methylphenyl)-4-thiazolecarboxylic acid.

2-(3-methylphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (I-6) from 2-(3-methylphenyl)-4-thiazolecarboxylic acid.

2-(4-Methylphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-7) from 2-(4-methylphenyl)-4-thiazolecarboxylic acid.

2-(4-isopropylphenyl)-N- from 2-(4-isopropyl-7enyl)-4-thiazolecarboxylic acid
(IH-tetrazol-5-yl)-4-thiazolecarboxy7mide (1-8).

2-[4-(t-butyl)phenyl]-4-deazolecarboxylic acid to 2-[+4-(t-butyl)phenyl]
-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-9).

2-(4-chlorophenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-10) from 2-(4-chlorophenyl)-4-thiazolecarboxylic acid.

2-(2-nitrophenyl)-4-thiazolecarboxylic acid to 2-(2-biphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-11).

2-(3,4,5-)dimethoxyphenyl)-4-thiazolecarboxylic acid to 2-(3,4,5-)dimethoxyphenyl)-N-(IH-tetrazol-5-yl)-
4-thiazolecarboxamide (Summer-12).

2-(3,5-dimethoxyphenyl)-4-thiazolecarboxylic acid to 2-(3,5-ditoxy7enyl)-
N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-13).

2-(2,4-dimethoxyphenyl)-4-thiazolecarboxylic acid to 2-(2,4-dimethoxyphenyl)-
N-(IH-tetrazol-5-yl)-4-thiazolecarboxy7mide (1-14).

2-phenyl-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (■-15) from 2-phenyl-4-thiazolecarboxylic acid.

2-(4-hydroxyphenyl)-N-(I
H-tetrazol-°5-yl)-4-thiazolecarboxamide (1-16).

2-(3-)lifluoromethylphenyl)-4-thiazolecarboxylic acid to 2-(3-toIJfluoromethylphenyl)-N-(IH-tetrazol-5-yl)-4
-thiazole carboxami)' (K-17).

2-(3-hydroxy-2-su7tyl)-4-thiazolecarboxylic acid to 2-(3-hydroxy-2-su7tyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxylic acid Amide (I-18).

2-(5-chloro-2-hydroxyphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide ( 1-19).

2-(2-hydroxy-5-methoxyphenyl)-4-
2-(2-hydroxy-5-
methoxyphenyl)-N-(IH-tetrazole-5-
yl)-4-thiazolecarboxy7mide (r-20)
.

2-(2-hydroxy-5-di)6phenyl)-4-thiazolecarboxylic acid to 2-(2-hydroxy-5-nitrophenyl)-N-(iH-tetrazol-5-yl)-4-thiazole Carboxamide (1-21).

2-(2-hydroxy-5-methylphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxy7mide from 2-(2-hydroxy-5-methylphenyl)-4-thiazolecarboxylic acid (1-22).

2-(2-benzyloxyphenyl)-4-thiazolecarboxylic acid to 2-(2-benzyloxyphenyl)-
N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (I-23).

-= 2- (2-ste7lyloxyphenyl)-4-thiazolecarboxylic acid to 2-(2-
Ste7lyloxyphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (I
-25).

2-Methyl-4-thiazolecarboxylic acid to 2-methyl-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-26).

2-(4-methylphenyl)-5-methyl-4-thiazolecarboxylic acid to 2-(4-methyl7enyl)-5-
Methyl-N-(IH-tetrazol-5-yl)-4-
Thiazole carboxamide (■-27).

2-(4-methylpheny)k)-5-inpropyl-4
-thiazolecarboxylic acid to 2-(4-methyl7enylL)-5-isopropyl-N-(IH-tetrazole-
5-yl)-4-thiazolecarboxamide (1-2
8).

2-(4-methoxyphenyl)-5-methyl-4-thiazolecarboxylic acid to 2-(4-methoxy7enyl)-
5-Methyl-N-(11(-tetrazol-5-yl)
-4-thiazolecarboxamide (1-29).

2-(2-pyridyl)-N-(IH-tetrazole-5) from 2-(2-pyrinol)-4-thiazolecarboxylic acid
-yl)-4-thiazolecarboxamide (1-32
).

2-(3-pyridyl)-N-(IH-tetrazole-5) from 2-(3-pyridyl)-4-thiazolecarboxylic acid
-yl)-4-thiazolecarboxamide (1-33
).

2-(4-pyridyl)-N-(IH-tetrazole-5) from 2-(4-pyridyl)-4-thiazolecarboxylic acid
-yl)-4-thiazolecarboxy7mide (1-34
).

2-(6-methyl-2-pyrinol)-4-thiazolecarboxylic acid to 2-(6-methyl-2-pyridyl)-N-
(IH-tetrazol-5-yl)-4-thiazolecarboxy7mide (1-35).

2-(5-promo-3-pyridyl)-4-thiazolecarboxylic acid to 2-(5-promo-3-pyridyl)-N-
(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-36).

2-(2-pyrazinyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-
37).

2-(2-quinolyl)-N-(IH-tetrazole-5) from 2-(2-quinolyl)-4-thiazolecarboxylic acid
-yl)-4-thiazolecarboxamide (1-38
).

2-(2-thienyl)-4-thiazolecarboxylic acid to 2-(2-thienyl)-N-(IH-tetrazole-5
-yl)-4-thiazolecarboxamide (1-40
).

2-(2-ylyl)-5-methyl-4-thiazolecarboxylic acid to 2-(2-7lyl)-5-methyl-N-(I
H-tetrazol-5-yl)-4-thiazolecarboxamide (1-41).

Further, the following salts were produced according to the method of Example 9) Oigari 10).

Sodium salt of 2-(2-hydroxyphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (I-1').

2-7minoethanol salt of 2-(2-hydroxyphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide (1-1”) 2-(4-methoxyphenyl)-N- 2-7minoethanol salt (1-4') of (IH-tetrazol-5-yl)-4-thiazolecarboxamide.

2-(4-methylphenyl)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide 2
-7minoethanol salt (1-7').

2-7minoethanol salt (1-35') of 2-(6-methyl-2-pyrinol)-N-(IH-tetrazol-5-yl)-4-thiazolecarboxamide.

2-(2-pyrazinyl)-N-(IH-tetrazole-
2-7 of 5-yl)-4-thiazolecarboxy7mide
Minoethanol salt (1-37').

2-(2-thienyl)-N-(IH-tetrazole-5
-yl)-4-thiazolecarboxy7mide 2-7minoethanol salt (1-40').

Regarding the raw material compound (II) synthesized according to the above production examples and examples and the compound (1) of the present invention, in Tables 1 and 2, melt and α are ! !
In the case of carboxylic acid release, methanol, methanol/THF/
After recrystallization from water, DMF/water or THF/water, salt values are after recrystallization from ether/ethanol.

Formulation Example 1) (1) Active ingredient 25. OOmg(
2) Lactose 49,00yy Crystalline Cellulose 36.00yy Cornstarch 5. OOxg (3) Hydroxypropyl cellulose 1. OOzg(4)ECG5
05 (carboxymethylcellulose calcium)
2. OOmg (5) Magnesium stearate
1.00+2(6) talc
1.00i + y total 120 mg (1) + (2) are kneaded with a 5% aqueous solution of (3), dried, sized, (4), (5), (6) are added and mixed, 120
Compress with zg (φ7 an) to make tablets.

Formulation example 2) (1) Active ingredient 50.00ry.

(2) Lactose 124.50mg (
3) Cornstarch 20.0OH (4
) Hydroxypropylcellulose 2.00mg (5
) Light silicic anhydride 1,5011F (
6) Magnesium stearate 2.00+wy
A total of 200 mg (1) + (2) + (3) was kneaded with a 5% aqueous solution of (4), dried and sized, then (5) and (6) were added and mixed, and 2001 g was put into a No. 3 hard capsule. Fill it.

In the above Formulation Example 1 and 2, the term "active ingredient" indicates any one of the compounds of general formula (1).

Test Example 1) Experimental Materials and Methods> 1) Animals Male Wistar rats (6 weeks old) were purchased from the Shizuoka Experimental Animal Agricultural Cooperative, and used in the experiment after being preliminarily bred for one week.

2) Antiserum 11vi Journal of Immunology (J, Immunology)
l.

), 106.1002-1011 (1971).

The extract of Ascaris suu was dinitrophenylated (DNP-As) and was administered subcutaneously to the foot of Wistar female rats together with killed pertussis bacteria.
After 5 days, DNP-Asli& was administered to the back muscle for additional sensitization. Three days later, blood was collected, serum was separated, and used as anti-DNP-As serum. The titer of the antiserum was determined by rat 48 hour PCA and was 1:200.

3) 48-hour PCA A 35-fold dilution of anti-DNP-As serum was administered to the 21M site of the right side of the rat's back, which had been shaved in advance, for sensitization. After 48 hours, a 0.5% Evans blue saline solution 111 containing 500 μg of DNP-As was administered into the tail vein to induce a reaction. After 30 minutes, the head was decapitated, the back skin was peeled off, two sensitized areas and 111 control areas were cut out, and microbiological immunology (Micrbiol, I m
munol, ) + 22 + 89~101 (197
According to method B), the amount of Evans blue leached out was determined as an indicator of the reaction. That is, IN potassium hydroxide 1 was added to the scraped skin, and the skin tissue was dissolved by incubation at 37° C. for 16 hours.

0.6N phosphorus Wl-7 setone (5:13) mix X19mN
After adding and mixing, the mixture was centrifuged at 3000 r, p, m for 15 minutes, and the absorbance of the supernatant at 620 n was measured to quantify the leached Evans blue. In addition, compound (1)
was administered intravenously into the tail vein 5 minutes before the induction of the reaction, or suspended in 0.5% tracanth and administered orally 1 hour before the induction of the reaction.

Results> The table below shows the results of tail vein administration and oral administration. From these results, it was found that the compound of this invention clearly suppresses the reaction and has a strong anti-PCA effect.

Mu -F-Shoulder k, (0I-1299 1-1' 0.5 671, 5
98 i-21298 DSCG 5 92 at ROM,)p,! ,, A
Hl Ql-15040 1-1" 50 781-2"
50 601-3' 30
7?1-7' 30
°691-37' 25 55
1-39' 25 75)-40
'25 80I-422573 Tranilast 500 Test Example 2) During the experiment of Test Example 1 above, no signs of toxicity were observed in the animals.

Claims (3)

[Claims] (1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, A is a lower alkyl group, has no substituent, or is hydroxy, alkoxy,
An aryl group having at least one substituent selected from aryl lower alkoxy, lower alkyl carbonyloxy, halo lower alkyl, halogen, nitro and amino, or having at least one hetero atom selected from oxygen, nitrogen and sulfur. or a 6-membered heterocyclic group or a fused heterocyclic group formed by condensing the above heterocyclic group with a benzene ring (
These two heterocyclic groups are unsubstituted or have at least one substituent derived from hydroxy, lower alkyl and halogen), R means hydrogen or a lower alkyl group. Compound or its salts. (2) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, A is a lower alkyl group, has no substituent, or is hydroxy, alkoxy,
aryl group having at least one substituent selected from aryl lower alkoxy, lower alkyl carbonyloxy, halo lower alkyl, halogen, nitro and amino, or having at least one hetero atom selected from oxygen, nitrogen and sulfur 5 or a 6-membered heterocyclic group or a fused heterocyclic group formed by condensing the above heterocyclic group with a benzene ring (
These two heterocyclic groups have no substituents or have at least one substituent derived from hydroxy, lower alkyl and halogen), R means hydrogen or a lower alkyl group. In the method for producing compounds or their salts, (a) Substituted thiazole carboxylic acid or its carboxy group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) [In the formula, A and R have the same meanings as before] A compound of formula (I) is obtained by reacting a reactive derivative of formula (I) with an aminotetrazole represented by the formula ▼ (a mathematical formula, a chemical formula, a table, etc.) (III) or a reactive derivative of its amino group; b) Formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I b) [In the formula, Ab means an aryl group having at least one nitro group, and R means the above meaning] To obtain a compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A method consisting of (3) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, A is a lower alkyl group, has no substituent, or is hydroxy, alkoxy,
An aryl group having at least one substituent selected from aryl lower alkoxy, lower alkyl carbonyloxy, halo lower alkyl, halogen, nitro and amino, or having at least one hetero atom selected from oxygen, nitrogen and sulfur. or a 6-membered heterocyclic group or a fused heterocyclic group formed by condensing the above heterocyclic group with a benzene ring (
These two heterocyclic groups are unsubstituted or have at least one substituent derived from hydroxy, lower alkyl and halogen), R means hydrogen or a lower alkyl group. An allergic disease treatment agent containing at least one compound or a salt thereof as an active ingredient.