JPS6058981A - 5-pyridyl-1,3-thiazole derivative, production thereof and medicinal composition containing the same - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is cycloalkyl, cyclic amino or amino which may have lower alkyl, phenyl, etc. as a substituent group; R<2> is pyridyl which may have lower alkyl as a substituent group; R<3> is phenyl which may have lower alkoxyl or hydroxyl, etc. as a substituent group) or a salt thereof. EXAMPLE:4-(4-Methoxyphenyl)-2-methylamino-5-(3-pyridyl)-1,3-thiazole. USE:Useful for treating pains, inflammatory diseases, ulcerative diseases in digestive organs, etc., having improved antipyretic, analgesic, anti-inflammatory and antiulcer action, etc. and high safety region with very low toxicity. PREPARATION:A compound of formula II (R<2>' is pyridyl which may have lower alkyl as a substituent group; X is halogen) is reacted with a compound of formula III in a solvent, e.g. tetrahydrofuran (THF), in the presence of a basic substance to afford the aimed compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 5-viridi1v-1,3 which has analgesic, antipyretic, antiinflammatory, antiulcer, thromboxane A2 (TXA2) synthase inhibition, platelet aggregation inhibition, etc. -Thiazo-yv rust conductor, its fit! ! ? The present invention relates to a td method and a pharmaceutical composition comprising the same.

Hitherto, 5-pyridyl-1,3-thiazo-/L/@ conductors are hardly known. The present inventors synthesized various new 5-pyridi/L'-1,3-thiazole/I/@ conductors,
As a result of a bioassay system search, these compounds showed excellent analgesic, antipyretic, antiinflammatory, antiulcer, and thromboxane A2 (TX
A2) It was found that it has physiological effects such as inhibition of synthetic enzymes and inhibition of platelet aggregation.

That is, the present invention has the following features: (1) General formula [wherein R1 has a cycloalkyl μ group, a cyclic amino group, and one or two lower alkyl, phenyl, acety/l/ or lower alkoxycarbonylaceti μ as a substituent; Good amino group, substituent toshi hydroxy μ,
pboxy/L/or a μ group which may have lower alkoxycarbonyl or carboxy A/, 2-pboxy/L/L'6 or 2-
R2 is a pyridine group which may have a 1-brohenyl group; Indicates a phenyl group that may be used. ] 1,3-thiazo-/I/ derivative or its salt, (2) general formula % formula % ( ) [wherein R3 is mandatory as defined above, R2' is lower alkyl as a substituent A pyridiμ group which may have
indicates a halogen atom. ] and the compound represented by the general formula [wherein R1 has the same meaning as above. ] and (3) a method for producing a compound represented by the general formula (%) and a salt thereof, which is characterized by reacting the compound represented by the general formula (I) or a salt thereof with the compound represented by the general formula (I) as an active ingredient. A pharmaceutical composition comprising:

In the general formulas (1) and (TI), examples of the cycloalkyl(V) group represented by R1 include those with 3 to 7 carbon atoms, such as cycloproyl, cyclobuty/I/, cyclobenzi μ, and V chlorohexyl, and as a cyclic amino group. is, for example, piperidino, pyrrolidino, mophorino, piperazino, 4
-Methylpiperazino.

Examples include 4-acetyp-pibewodino. Examples of the lower alkyl substituent of the amino group represented by R1 include methi μ, ethyl μ, n-propyl, 1-propy μ, n
-Butyl and other carbon atoms having 1 to 4 carbon atoms, lower alkoxycarbonyl acetate groups include those having 4 to 6 carbon atoms, such as methoxycarbonyl carbonyl acetate, ethoxycarbonyl carbonyl acetate, and n-derboxycarbonyl carbonyl acetyl group. Examples of the alkyl μ group represented by R1 include methyl, ethyl/lz, n-propyl, 1-propyl, n-
Butyl, 1-buty/L', n-bench/L/, H-
Examples include those having 1 to 9 carbon atoms such as hexyl/l/, n-octyl/l/, yl-noni/l/, and n-decylρ, and this aρkiμ group has hydroxyVA/,
The lower alkoxycarbonyl may be substituted with ρ-boxyl or lower alkoxycarbonyl, and examples of the lower alkoxycarbonyl include those having 2 to 5 carbon atoms, such as methoxycarbonyl, methoxycarbonyl, and n-propoxycarbonyl. can give. The phenyl group represented by R1 has carboxyl, 2-capoxyethenyl/I/
Alternatively, it may have 2-pboxy-1-7''CI henyl as a substituent.

The pyridyl group represented by R2 may be 2-pyridyl, 3-pyridi/L', or 4-pyridiμ, and these may be substituted with carbon atoms such as methyl, ethylμ, n-f-propyl, etc. at any position on the ring. It may have 1 to 4 lower alkyl groups as substituents. The pheni/L/ group represented by R3 may have 1 to 3 substituents of lower a-lower alkylalkyl) hydroxy μ or halogen at any apparent position, and the lower alkoxy is, for example, methoxy Examples of lower alkyl include those having 1 to 4 carbon atoms, such as , etkyne, and n-propoxy;
Examples of the halogen include those having 1 to 4 carbon atoms, such as V and n-propyμ, and fluorine, chlorine, odorant, and iodine. Furthermore, the phenyl group represented by R3 may be substituted with methylenedioxy at any adjacent position on the ring.

The compound represented by general formula (I) may be a salt of a pharmacologically acceptable organic acid or antic acid, and examples of such a salt include hydrochloric acid.

Examples include salts of hydrobromic acid, phosphoric acid, sulfuric acid, ceric acid, methanesulfonic acid, etc.

The compound represented by the general formula (I) can be produced by reacting the compound represented by the general formula (II) and the compound represented by the general formula (m) in the presence of a basic substance. This reaction is usually carried out using, for example, water, Apco, acetonitrile, tetofhydrofufuran, dimethylformamide.

It is carried out in a solvent such as 1,2-dimethoxyethane.

The contact ratio between compound (n) and compound (T[) is
)l-! Compound (FJ) 1-1.2 for :/I/
7μ is preferred. Examples of basic substances include triethyl amine, sodium hydroxide, sodium carbonate, and potassium salt. The amount of the basic substance added is usually 2.0 to 3.0 mol, preferably 20 to 2.5 mol, per 1 mol of compound (■). The reaction temperature is usually carried out within the range of θ°C to the 011 point of the solvent. In this reaction, compound (U) and compound (II) first react to form a compound of the general formula [wherein R1, R2' and R3 have the same meanings as above.

] is produced, which is then ring-closed to produce compound (I-a). In order to carry out these reactions more advantageously, the compound (■) and the compound (IN
) is preferably brought into contact at a temperature below room temperature, and then warmed or heated to above room temperature.

Compound (1) thus obtained can be purified in a fraction by a known fractional 1M purification means such as chromatography, solvent extraction, crystallization, recrystallization, etc.

The compound (I) of the present invention and its salts exhibit excellent antipyretic, analgesic, anti-inflammatory, anti-ulcer, platelet aggregation-inhibiting, and thromboxane A2 synthesis inhibiting effects on mammals including humans, and have no toxicity. Extremely weak and has a high margin of safety. Therefore, the compounds of the present invention can be used for the treatment of pain, inflammatory diseases, chronic rheumatic diseases, gastrointestinal ulcer diseases, ischemic circulatory disorders based on platelet thrombosis, etc. in mammals. The administration method is, for example, I! which is used orally in the form of tablets, capsules, powders, granules, etc. 1 or parenterally as an injection or pellet. The dosage for each adult is usually 50 to 500 mg per day orally and 50 to 200 mg parenterally in 1 to 3 divided doses.

Among the compounds represented by general formula (I), 4-[4-
Phenyl-5-(3-viridi/l/)-t.

3-Thiazo-μ]butyric acid, 4-(4-(4-methquinphenyl)-5-(3-viridi/1/)-1,3-thiazo-
μ] Butyric acid has a particularly excellent thromboxane synthetase inhibitory effect, and 2-phenyl-4-(4-methquinpheni/L
')-5-(3-pyridi/')7-1,3-thiazole, 2-cyclohexy/L'-4-(4-methoxyphene A/)-5-(3-pyridiμ)-1,3- Thiazo/
L', 2-cyclohex! //L/-4-Feniyv-s
-(3-pyridi/l/)-1,3-thiazole is especially f
! 2-amino-4-(
4-methquinphenyA/)-5-(3-pyridiμ)-1
,3-thiazo-p.

2-Mef/L'amino-4-(4-methoxyphenyrho)
-5-(3-viridi/l/)-1,3-thiazole, 2
-ethyl/I/-4-(4-methoxyphenyl)-5-(
3-pyridi)v)-1,3-thiazole has particularly excellent analgesic, antipyretic, and anti-inflammatory effects.

The compound represented by the general formula (II) can be prepared, for example, by the following method.

[In the formula, R2, R3 and X have the same meanings as above, R
4 is a lower 1 having 1 to 4 carbon atoms, such as methyl or ethyl p.
Indicates a p-kyl group. ] The reaction of leading compound (V) to compound (Vl) is carried out by reacting compound (V) with lithium diisopropylamine. This reaction is usually carried out in a solvent such as anhydrous tetrahydrofuran or anhydrous diethyl/ether at -70' to 10°C.

The reaction that leads compound (VI) to compound (■) is the reaction that leads to compound (■).
It is carried out by reacting VI) with compound (■). This reaction is usually carried out in a solvent such as anhydrous tetrahydrofuran or anhydrous diethyl ether as described above. It will be held in

Compound (If) can be obtained by reacting compound (w!1) with a halogen. This reaction is carried out, for example, by reacting compound (■) with a halogen such as chlorine or bromine in a solvent such as acetic acid. The reaction temperature is usually 10 to 100°C and the reaction time is usually 1 to 10 hours. The product is made into an anticonvulsant salt by adding ether μ, isopropyl μ ether p, etc. to the reaction solution, and after removing the solvent, the residue is diluted with ethyl acetate and ethyl acetate. It can be purified by crystallization from methanol etc.

Further, the compound represented by the general formula (TE) can be produced, for example, as follows.

[In the formula, R1 has the same meaning as above, R5 is a methoxy or ethoxy group, or a phenylene/l/ group, R6 is a cyclic amino group, a disubstituted lower acylamino group, or a diphenylamino group, R7 is a cycloalkyl μ group, Alkyl which may have hydroxyl, carboxy/l/ or lower aμkoxycarboniμ as a substituent, phenyl group which may have 2-carboxyethenyl/I/ or 2-carboxy-1-propenyl shows. ] To lead the compound (IK) to the compound (X[), the compound (
This is carried out by reacting IX) with compound (X). This reaction is carried out in an organic solvent, and examples of the solvent include menalene chloride and chloroform. The contact ratio of compound (IX) and compound (X) is usually such that compound (X) t. O~
1.5 mol. The reaction temperature is usually 0~50°C, and the reaction time is usually 1~5 hours.

In order to convert compound (XI) into compound (■), a well-known alkaline or acidic hydrolysis reaction is carried out. Sodium hydroxide and potassium hydroxide are used for alkaline hydrolysis, and hydrochloric acid is used for acidic hydrolysis. Bromic acid is used.

As the solvent, water or a water-containing organic solvent (ethanol, methanol, dioxane, etc.) is used.

Compound (Xi[) is introduced into compound (XIv) by reacting compound (Xll) with hydrogen sulfide under basic conditions). Triethylamine as base,
Pyridine is preferred, and methylene chloride, chloroform, triethylamine, pyridine, etc. are used as reaction solvents. The reaction is usually carried out at -10C to 30T under normal pressure or increased pressure.

In order to lead compound (XI[) to compound (III), compound (XIII) may be reacted with P4S1o.

This reaction is carried out in an aqueous solvent such as ether, tetrahydrofuran, methylene blackide, or chloroform within a temperature range from room temperature to the boiling point of the solvent. ) is used in an amount of 0.57 p to 1.2 mol.

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

Example 1 Acetonitrile lvi8 of N-methylthiourea 242
g/solution of 2-bromo-i-(4.-itoxyphenylene/L/)-2-(3-pyridyl)-ethanone hydropromide. Suspend 0.4 trtl of triethylamine slowly while stirring.

After completion of the dropwise addition, the mixture was stirred at reflux temperature for 3 hours and the solvent was distilled off. Saturated sodium hydrogen oxide solution is added to the residue, extracted with ethyl acetate, dried, and the solvent is distilled off. Recrystallization of the product from ethyl acetate-isopropyl ether yields 4-(
4-Methoxyphenymu)-2-methylamino-5-(3
-pyridi/I/) -1,3-thiazole 650q (8
5%) is obtained. Melting point 158-159°C.

Example λ 2-bromo-1-(4-methoxyphenylene)V)-2 in acetonitrile/I/401R1 solution of thiourea 516q
-(3-pyridiA/)-ethanone hydropromide 2.
Suspend 5 g of triethylamine and add 0.0 g of triethylamine while stirring.
Slowly drip 95 yit. After finishing dropping, remove. The crystals are washed with saturated sodium bicarbonate solution, water, ethanol, and ethyl ether in this order, and dried. Recrystallized from THF' to give 2-amino-4-(4-methoxypheni/
1.59 (90%) of l/)-5-(3-viridi/L/)-1,3-thiazole are obtained.

Melting point 265-266°C.

Example 3 Acetonitrile IV4 of thiopropionic acid amide 493#
2-bromo-1-(4-methoxyphenyleneμ) in 0al solution
)-2-(3-pydinoV)-ethanone 2,159 was suspended, and while stirring triethylamine 0. 7 8
Gently drip yl. After completion of the dropwise addition, the mixture was stirred at reflux temperature for 3 hours and the solvent was distilled off. Add saturated aqueous sodium hydrogen acetate solution, extract with ethyl acetate, dry, and evaporate the solvent. Ethyl acetate-isopropylether-4-(4-methoxyphenyl/L/)-5-(3-viridi/L/)-1.3-thiazole 1.389 (91%)
is obtained. Melting point 59-60°C.

2-bromo-1-(4-methoxypheny)V)-2-(
2.269 g of 3-pyridyl)ethanone hydropromide is suspended in 40 d of acetonitrile, 1.0 g of 4-methoxycarbonylbutanethioamide is added, and 0.8 tyl of triethylamine is added dropwise while stirring. Stir at reflux temperature for 3 hours, distill off the solvent, and add saturated aqueous sodium bicarbonate. The product was extracted with ethyl acetate, washed with water,
After drying, it was concentrated and purified by silica gel column chromatography (acetic acid, ethyl-isopropyl ether (1:1)) to obtain 2-(3-methoxycarponylpropylene/L/L/
)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole 15C (yield 72.6%) is obtained. oily substance.

Example S 2-(3-methoxycarbonyl!repropylene)-4-(4-methoxycarponyx=/l/) obtained in Example S
-5-(3-pyridi/I/)-1,3-thiazo-pl,
Dissolve 5 sulfur in 5* methanol and 1 ml of sodium hydroxide.
．． Add 5g of 5til solution of water and stir at 80o for 2 hours. Add water and adjust the pl (6,0) with N-Hananic acid,
Extract the product with ethyl acetate. (Wash with special soup, dry)
After cooling, the crystals were recrystallized from ethyl acetate to give 2-(
3-poxypropyl)v)-4-(4-methoxyphenyl7+z)-5(3-pyridiμ)-1,3-thiazo-/
l'1.29 (yield 83%) is obtained. Melting point 163-
164℃.

Example 2 2-(3-Methoxycarboniμglohy Iv)-4-(,i-methoxyphenyl)-5-(3
-pyridi1v)-1,3-thiazole 770 mV T
Dissolve in HF'1Off and cool on ice. After adding 100 g of lithium aluminum hydride little by little and stirring for 1 hour, water was added and the mixture was extracted with ethyl acetate. After washing the organic layer with water and drying, the organic layer was washed with water and purified by phosphor gel column chromatography (chloroform-methano/l/(9:1)) to yield 2-(4-hydroxybutylene/l/)- 4-(
4-methoxypheny)v)-s-(3-pyridi/l')
-1,3-Thiazo-Iv576q (yield 81%) is obtained. oily substance.

Example Z 2-amino-4-(4-methquinphenyl)-5-(3
-pyridi/L/)-1,3-thiazole IL! DM me
Dissolve in FS, add 580 μl of ethoxycarbonylacetyl chloride under water cooling, and stir.

After 30 minutes, saturated aqueous sodium bicarbonate is added and the product is extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated, and recrystallized from tetrahydrofuran to give 2-ethoxyca! Bonylacetylamino-4-(4-methoxypheni)
L/) -5(3-pyridyl)-1,3-thiazo-/L
/850ffq (yield 6196) is obtained. Melting point 202-
203℃.

Examples and 2-bromo-1=(4-methquinpheni)V)-2-(
Add 1.0 g of 3-pyridyl)-ethanone hydropromide and 387 g of 1-pipefuzine carpotioamide to acetonitrile/I/15 water, and slowly add 0.4 tsl of triethylamine while stirring.

After completion of the dropwise addition, the mixture was stirred at reflux temperature for 2 hours and the solvent was distilled off. Add saturated sodium chloride solution to the residue and add ethyl acetate.
After extraction and drying, the solvent is distilled off.

Dissolve the residue in 2 portions of pyridine, cool on ice, add 0.3 ml of acetic chloride, and leave at room temperature for several hours.

The reaction solution was poured into ice water and extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated. Silica gel column chromatography (ethyl acetate-methanol/L/(9:1)
) and purified with 2-(4-acetyl/l'-1-
piperazini/l/)-4-(4-metogishifeni/l/
)-5-(3-pyridi/l/)-1,3-thiazole 3
oovy (yield 2896) is obtained.

Example Z 2-amino-4-(4-methquinphenyl)-5-(3
-pyridi/L/)-1,3-thiazo-)V2O3
Dissolve in % hydrochloric acid methanol/l/3.2g and evaporate the solvent. The residue was recrystallized from methanol-ethyl acid to give 2-amino-4-(4-methoxyphenyl/L/)-5
-(3-pyridi/L/)-1,3-thiazo-)lz18
0fff (80% yield) is obtained. One piece 145-150t
E0 Table 1 shows examples of compounds produced according to the above Examples. Note that the melting point is uncorrected.

Reference Example 1 A solution of 33.2 txt of diisogropi amine in 300 tst of anhydrous tetrahydrofuran was cooled to -78°, and while stirring, a solution of n-butyllithium hexane (1.6M) was added.
Drop 148 ayt. After the addition is completed, the mixture is stirred at the same temperature for 10 minutes, and then 20 t of β-picoline is added dropwise. After raising the temperature to -10°LO' and stirring for 20 minutes, 1v19.41F of p-7 ethyl dichloride was added to 40N of anhydrous tetophhydrofone! Dissolve and drip. After dropping, stir at room temperature for 1 hour and add 100s4 of honcho. The organic solvent was distilled off under reduced pressure, and the concentrated solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, concentrated, and the product was crystallized from ethyl acetate-isoglobyl ether to give 1-(4-methoxyphenylene/I/)-2
-(3-viridiIv)-xthanone 20.89 (yield 85
%) is obtained. Melting point 71-72° Based on the above reference example,
p-ethyl anisate), ethyl benzoate #3.
4-dimethoxybenzoethyl/L/, ≠-methoxymethyneethylbenzoate ρ.

The following compounds can be synthesized by using methyμ 4-fluorobenzoic acid.

1-Pheny/L/-2-(3-pyridi)v)-ethanone Melting point 44.5-45.5°1-(3,4-dimethoxy7x'=)v)-2-(3-
pyridi)v) xthanone melting point 114-115゜1-(
3,4,5-)rimethoxypheni)V)-2-(3-pyridyl)ethanone Melting point 1041105°1-(4-methoxymethoxypheni/l/)-2-(3
-Pyridyl)ethanone Melting point 43-44° 1-(4-fluorophenyl)v)-2-(3-pyridi/L/)ethanone Same as oil, but also a-picoline, r-picoline instead of β-picoline. , 3.5-tLttidine can be used to synthesize the following compounds.

1-phenyl-2-(2-pyridi/L/)-ethanone
Melting point 59-60° 1-(4-methquinpheni/Iz)-2-(2-pyridi/I/)ethanone Melting point 77-78°' 1-Phenyl-2-(4-pyridyl)ethanone Melting point 109-110
゜1-(4-Methoquinphenyl/l/)-2-(4-pyridi/L/)ethanone Melting point 103-104゜1-Phenyl-2-(5-methyμm3-pyridyl)ethanone Melting point 5
3-54゜1-(4-ethylphenyl)-2-(3-pyridyl)ethanone Upper point 80-81゜1-(3,4-methylenedioxyphenylene/I/)-2-
(3-pyridi/L/) ethanone Melting point 98-99° 1-(4-methoxyphenylene/L/) obtained from Reference Example
Dissolve 6.85 g of -2-(3-pyridi/L/)ethanone in 36111 acetic acid, add 1.7 l of bromine, and stir at 80° for 3 hours. The reaction solution is cooled with ice water, and the precipitated crystals are filtered. When the crystals were washed with ethanol and ethyl ether and dried, 10.49% of the hydrobromide of 2-bromo-1-(4-methoxyphenylene/L')-2-(3-pyridi/I/)ethanone (yield) was obtained. 89%) is obtained. Melting point: 188-195° The hydrobromide salt of the following compound can be obtained in the same manner as in Reference Example.

2-bromo-1-phenyl-2-(3-pyridi/I/)
Ethanone Melting point 208-215° ゛2-Glomu 1
-(3,4-dimethoxyphenylene IL/)-2-(3-pyridyl)ethanone Melting point*1191-193°2-bromo-F-(3,4,5-)rimethoxyphenylene A
/)-2-(3-pyridi/I/)ethanone melting point"118
4-186゜2-bromo-1-(4-hydroxyphenylene/L/)-2
-(3-pyridi/I/)ethanone *22-brome-1
-(4-fluorophene)v)-2-(3-pyridi/I
/) Ethanone Melting point 189-191゜2-bromo-1-phenylene/l/-2-(2-pyridi/I
/) Ethanone Melting point 180-181°? l,
v /J-methoxyphenyl)-2-(2-pyridyl)ethanone 1 point 170-171゜2-brom-1-phenylv-Z-(4-pyridip)ethanone Melting point 230-23292-brom-1-(4
-methoxyphenyl)-2-(4-pyridifi/)ethanone 1゛j (point 207209゜2-bromo-1-phenyl-2-(5-methyl-3-pyridi)v)ethanone Melting point 189-93 2- 10mu-1-(4-ethylphenyl-(3-pyridiμ)ethanone Melting point 1 4 5-14662-bromo-
1-(3.4-methylenedioxyphenyl)-2-(3
-4'Rishi/L/) Ethanone Melting point 174-175.

*1 Melting point indicates hydrobromide.

*2 Wood bromate was used directly for Fe thiazole 17 formation reaction without purification.

Experimental example A. Anti-inflammatory effect by Carr F Genin edema method (C.E method) JCl: SD flat male 1 weight 180-2209
) using 6 animals per group, Winter et al.
al ) method CProc, Sac, exp, B
iol, Med, 111 +544 (1962))
I investigated according to the following. One hour after the oral administration of the specimen, 0.05 ml of a 1% carrageenan saline solution was subcutaneously injected into the heel. Three hours after carrageenan injection, the hind paw volume and the injection volume were measured, and the edema volume was determined from the difference. The edema volume was compared between the sample-administered group and the non-specimen-administered control group to determine the edema suppression rate.

B. Analgesic effect test CP by phenylquinone rising syndrome method, (+ method) Using 10 Slc:ICR male mice (4 weeks old, 9 body weight, 20 ± 29) per group, Siegmund
) et al. (J, PharmacoloHyan
dExperim Ontal Therapautic
A, 18.412 (1959)].

Thirty minutes after the oral administration of the specimen, 0.02% phenymuquinone 0.1 tyl/10 gk was administered intraperitoneally, and the writhing exhibited by the mouse was observed for 20 minutes.
) or stretching
I counted the number of times. The suppression rate was determined by comparing the average number of tests between the sample administration group and the non-specimen administration control group.

C8 water immersion restraint stress ulcer test (W, L method) SD male and female rats (7j1, total instar weight 190-240 g) using a group of 6 rats, according to the method of Takagi and Manbe (Jpn).

J, Pharmacol, 18.9 (19(38),
1], after fasting for 24 hours (however, water was taken ad libitum),
I experimented. Place the rat in a stainless steel cage.
5 hours in a water tank adjusted to 23C up to the xiphoid bone of the thorax)
I got it. The diameter (mm) of each ulcer was measured under the head of the glandular gastric mucosa, and the sum was used as the ulcer index. The specimen was orally administered 30 minutes before water immersion. The ulcer index was compared between the sample-administered group and the non-specimen-administered control group to determine the inhibition rate.

D. Acute toxicity test in mice (acute toxicity) IC at 5 weeks of age
R-strain male Maunus, 5 animals per group, 500 ay/each sample
kq was orally administered, and mortality was measured for 7 days.

Representative examples of the above test results are shown in Table 2.

Continuing from page 1■Int, CI,' Identification symbol Internal serial number procedure
Amendment (spontaneous) 1. Indication of the case, Application No. 167042 of 1982 and the pharmaceutical composition containing the same 3. Person making the amendment f! Relationship with I Patent applicant location 2-27 Doshomachi, Higashi-ku, Osaka Name (29)
3) Takeda Pharmaceutical Co., Ltd. Representative: Iku Kurabayashi Department 4, Agent address: 2-17-85 Jusanhonmachi, Yodoyo-ku, Osaka, Tokyo Contact information (T, V Permits and Regulations Division) Telephone: 278-2219221
q6. Insert "hydrochloride" after "Contents of amendment (1)".

"Melting point" on page 38, lines 14-15 of LtJ Dokan is corrected to "melting point" 1.

that's all

Claims (3)

[Claims] (1) General formula [wherein R1 is a cycloapkyl/L' group, a cyclic amino group,
Substituents include lower apkiμ, pheniμ, acetyl/L/,
Rirui is an amino group which may have 1 or 2 lower alkoxycarbonyl acetyl, or a substituent hydroxy! , Carboxy A/,! Riri is an alkyl p group which may have a lower alkoxycarbonyl or a phenyl group which may have a carboxyl, 2-carboxyethenyl/L/W or 2-carboxy-1-propenyl as a substituent. R2 represents a pyridyl group which may have lower alkyl as a substituent, and R3 represents a phenyl group which may have lower alkoxy, lower alkyl, hydroxyl, halogen or methylenedioxy as a substituent. ] A 1,3-thiazo-iv derivative or a salt thereof. (2) General formula % Formula % [In the formula, R2' is a pyridyl group which may have a lower alkyl as a substituent, and R3 is a substituent of lower alkoxy, lower alkyl, and doxy, halogen or methylenedioxy. X represents a halogen atom. ] and the general formula % formula % [wherein R1 is a cycloalkylv group, a cyclic amino group, a
An amino group which may have 1 or 2 lower alkyl, phenyl, acetyl, or lower a[mu]koxycarbonyl acetyl as a substituent; an amino group which may have hydroxyl, phenyl, acetyl, or lower a[rho]koxycarbonyl as a substituent; The formula represents an optionally-carboxylic acid p group or a carboxyl, 2-poxyethene/L', or 2-poxy-1-probenip group as a substituent. [In the formula, R1, R2' and R3 are Q as defined above. ] A method for producing a 1,3-thiazo-/I/M conductor or a salt thereof. (3) General formula [wherein R1 is cycloalkyl] V group, cyclic amino group, lower alkyl as a substituent, feni μ, acetyl/L/, 1
) or an amino group which may have 1 or 2 lower a[mu]koxycarbonyl acetyl, @substituent, hydroxycarbo[mu]boxy/l/or an alkyl[mu] group which may have a lower alkoxycarbonyl or as a substituent - boxyl, 2-carpoxyethene/L' or 2
R2 is a pyridyl group which may have lower argyl as an R substituent, and R3 is a substituent of lower alkoxy, lower alkyl, hydroxyl. , the halogen atom represents a phenyl group which may have methylenedioxy. ] A pharmaceutical composition comprising a 1,3-thiazo-)V derivative or a salt thereof as an active ingredient.