JPH01190679A - Optically active novel thiazolidine-4-one derivative and acid-addition salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [Ar is aryl (substituted by halogen or lower alkoxy); X is straight-chain or branched chain lower alkylene or single bond; R is H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, acyloxy, OH, aryl, etc.; Py is pyridyl] and acid-addition salt thereof. EXAMPLE:(+)-cis-5-(4-Chlorophenyl)-3-methyl-2-(3-pyridyl)-thiazolidine -4-one. USE:A medicine and active ingredient for anti-platelet-activating factor agent. Useful as a medicine for preventing and treating an induced disease such as allergic disease, circulatory disease or alimentary disease. PREPARATION:For example, an optically active compound expressed by formula II is reacted with a compound expressed by formula III in an organic solvent to close a ring and the resultant mixture of cis isomer and trans isomer is readily separated to cis isomer and trans isomer by conventional separation means to provide the compound expressed by formula I.

Description

[Detailed Description of the Invention] <Industrial Application Field> The present invention provides an excellent platelet activating factor (hereinafter referred to as PAF) <Prior Art and Problems> P) J? is a factor that activates rabbit platelets in trace amounts (Nenvenlste J, et al.
J.E.: (p, Med,, 136. 1556-1
377 (1972)), acetylglyceryl ether phosphorylcholine (A()EPC), i.e.
1-0-hexadecyl/octadecyl-2-〇-acetyl-8n-glyceryl-3-phosphorylcholine (Han
ahan D, J.

et al., J. Biol, Chem, 254*
9355-2385* (1979)) is a trace active substance in vivo whose structure has been determined.

In addition to activating the platelets, PAF also has various physiological effects such as lowering blood pressure, increasing vascular permeability, smooth muscle contraction, activating neutrophils, monocytes, and phages, and promoting hepatic glycodenolysis. It is known to cause effects at very low concentrations.

These physiological effects are said to be related to many diseases, such as various inflammatory and allergic diseases, circulatory system diseases, and digestive system diseases.

Therefore, in order to prevent and/or treat the onset of PAF N, the search for PAF antagonists has been focused, and in recent years,
Searches for PAP antagonists have been actively conducted.

However, although several compounds have been tried to date for the prevention or treatment of PAF-induced diseases, their efficacy has not been fully satisfactory.

On the other hand, research on 4-thiazolidinone derivatives is limited to the following seven reports. That is,
JP-A-54-745670 discloses N-(substituted or unsubstituted phenyl and pyridyl) derivatives which have uses as agricultural chemicals. Japanese Unexamined Patent Publication No. 55-55
Publication No. 184 discloses compounds centered on N- (substituted or unsubstituted phenyl, pencil, and cycloalkyl) derivatives that have uses as drugs.
, JP-A-57-85380 and JP-A-57-
Publication No. 88170 describes N-(carboxycyclohexylmethyl) derivatives having anti-complement effects and N-(carboxycyclohexylmethyl) derivatives having anti-inflammatory, analgesic and anti-rheumatic effects, respectively.
-(carboxymethylphenyl) derivatives are disclosed.

JP-A-58-186689 discloses N-(pyrazinyl) derivatives that have uses as agricultural chemicals.

Further, U.S. Pat. No. 4,501,746 discloses N-(substituted phenyl) derivatives that have uses as synthetic intermediates, and furthermore, JP-A No. 6,1-103881 discloses
There are many N-(substituted carbamoyloxy) derivatives used as cardiotonic agents in the publications, but there are no reports that they have the same usefulness as the present invention, that is, anti-PAF action. Not yet.

<Means for solving the problem> Under these circumstances, the present inventors have developed a useful PA
As a result of intensive searches for the purpose of searching for F antagonists, we found - Formula (1) [wherein Ar represents an aryl group or an aryl group substituted with a halogen atom or a lower alkyloxy group, and lower alkylene at! ' or a single bond, R represents a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, acyloxy, di-lower alkylamino, hydroxyl group, or aryl group, or is substituted with /I'i lower alkyloxy group. represents an aryl group, and Py represents a pyridyl group. ] The optically active 2-pyridylthiazolidin-4-one derivative and its acid addition salt are selective PAs.
The present invention was based on the discovery that it has an F antagonistic effect and is extremely useful as a preventive treatment for PAF-induced diseases, such as various inflammatory and allergic diseases, circulatory system diseases, and digestive system diseases. reached.

The present invention will be explained in detail below.

In this BAa, lower alkyl groups include 12 methyl, ethyl, n-700 vir, inpropyl,
n-butyl, isobutyl, 5ec-butyl, tert-
cl-4 alkyl groups such as butyl; examples of lower alkoxy groups include methoxy, ethoxy, n-zoloboxy, incytoxy, n-butoxy, incytoxy, 8
C1-4 flukoxy groups such as eC-butoxy and tert-detoxy; Aryl groups include, for example, phenyl and naphthyl; Lower alkylene groups include, for example, methylene, ethylene, 7'o-hylene, trimethylene, and tetramethylene. , 1-methyltrimethylene, etc.
l-4 alkylene group; As a lower alkenyl group, for example, C,~4 alkenyl group such as allyl, butenyl; As a lower alkynyl group, and 03-4 alkynyl group such as If zolopargyl; As a cycloalkyl group For example, C3-? A cycloalkyl group; As an acyloxy group, for example, a 01-4 flucatsuyloxy group such as acetyloxy or a 7-7 cycloalkyl group such as a benzoyl group.
0yloxy group; Examples of the di-lower alkylamino group include dimethylamino group, diethylamino group, etc.
l-4 fulkylamino group; Examples of the halo atom include a fluorine atom, a chlorine atom, a bromine atom, and the like.

Furthermore, the term "substituted aryl group" refers to an aryl group substituted with one or more t substituents, and the substituents are as described above.

In addition, the pyridyl group represented by Py is thiazolidine-4
- It may be bonded to the 2-position of the pyridine ring and any of the 2-position, 3-position, or 4-position of the pyridine ring.

- The salt of the thiazolidine-4-one d-conductor represented by formula (1) may be any pharmaceutically acceptable salt, such as salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Salts: Salts with organic carboxylic acids such as formic acid, acetic acid, fumaric acid, maleic acid, phosphoric acid, tartaric acid, aspartic acid: methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid , salts with inorganic acids such as salts with sulfonic acids such as naphthalenesulfonic acid, and salts with organic acids.

Optically active thiazolidine-4 represented by general formula [1]
-On crocodile conductors can be manufactured, for example, by the following method.

(a) R (II) CI:l (1') [
In the formula, Ar, Py, X and R have the same meanings as above. ] It can be produced by ring-closing an optically active compound [...] with (1) in an organic solvent. As the organic solvent, common inert solvents such as benzene, toluene, xylene, methylene chloride, 1,2-OR ethane, tetraroform, and tetrahydrofene can be used. The reaction temperature can be from 20° C. to reflux temperature, but it is preferable to accelerate the reaction by performing azeotropic dehydration at reflux temperature.

Product [I'] is usually 2-pyridylthiazolidine-4-
cis body and tra between the substituents at the 2nd and 5th positions of the on skeleton
Although it is a mixture with the ns form, it can be easily isolated by conventional separation means such as silica delta ram chromatography.
The optically active form [I] can be obtained by separating the s-form and the t-rang form.

(4OH Ar-C0-C0OH+Py-CHO+H2N-X-R
-+ CI']★ CM) CRT) (V) [In the formula, Ar, Py, V
It can also be obtained by reacting :l in an organic solvent.

Examples of M solvents include benzene, toluene, and xylene.
Common inert solvents such as tJE-modified methylene, 1,2-dichloroethane, chloroform, and tetrahydrofuran can be used. The reaction temperature can be from 20° C. to reflux temperature, but it is preferable to accelerate the reaction by carrying out azeotropic dehydration at reflux temperature. In addition, the product [1'] was similarly produced by the above-mentioned method, and the cia body and t
Optically active form CI] can be obtained by separating the rans form.

Note that these raw material compounds are either known compounds per se or compounds that can be synthesized by known synthesis methods, such as optically active compounds ([] and [1]
The compound represented by can be obtained by the following method as described in the reference side.

r ArCH2C0OH-+ ArCH, COOMe -h
ArCHCOOMe〔■〕〔Tsu〕〔■〕 COCH3! Py-CHO+ H2 to -X-R → [1] (IVI
EV) [wherein Ar, Py, X and R have the same meanings as above. ] In other words, the raw material compound (ff) is esterified into ester [■] according to the method described in New Experimental Chemistry Course, Vol. 14, page 1002, and this is converted into ester [■] according to the method described in New Experimental Chemistry Course, Vol. Then, halogenation is performed to obtain the bromine compound [■].Furthermore, [■] is converted into a thiol ester compound [YI], [■] according to the method described in "Shin Jikken Kagaku Koza Vol. ] is hydrolyzed with a base such as sodium hydroxide or potassium hydroxide in a water-alcohol mixed solvent to obtain a di-semi-mercaptan visiting conductor [...']. Furthermore, [u′] is replaced with an optically active amine derivative, such as herring, synfunin, ephedrine, etc., using Bonner's method (W,
A.

Bonner, J, Org, Chem, e 3i
3*, 1831 (1958)), an active mercaptan conductor (U) is obtained.

In addition, the ship base compound (1) is an aldehyde [■] and a part of an amine [v].
It was obtained by dehydration condensation according to the method described on page 0.

The compound of the present invention represented by formula CI and its acid addition salt can be administered orally or parenterally when used as a medicine. That is, it can be administered orally in commonly used dosage forms, such as tablets, capsules, syrups, suspensions, solutions, etc., or in liquid forms such as solutions, emulsions, suspensions, etc. The molded product can also be administered parenterally in the form of an injection. Furthermore, rectal administration in the form of a layered preparation, administration in the form of an inhalation spray or transdermal preparation is also possible.

Also, suitable dosage layers as described above can be developed by incorporating the active compound into acceptable conventional carriers, excipients, binders, stabilizers, etc. Furthermore, when used in the form of an injection, acceptable buffers, solubilizing agents, isotonic agents, and the like may be added.

The dosage and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but the usual dosage for adults is approximately 1.
Preferably 10-300 drops can be administered once or in divided doses.

Effects of the Invention> It has been revealed that the compound (1) of the present invention has desirable pharmacological effects as a therapeutic agent for PAF'-induced diseases. That is, the compound (1) of the present invention exhibits a strong and selective PAF antagonistic effect. The pharmacological effects of the compounds of the present invention will be explained in detail below.

[Inhibitory effect on platelet aggregation/in vitro test] Inhibition of platelet aggregation in captive rabbits PAF-induced platelet a collection was inhibited by the Born method (G
, V., R., Born, J., Physiol,, L.
The method of Mustard et al. (J, F, Mustard
d et al., J. Lab., C11n, Med.
, 64°548 (1964)). That is, in advance, 5.8% sodium citrate 1/
From the carotid artery of a Japanese white male sex in a polyethylene cleft container containing 1 o volume - 80 to 1 o per animal.

-'s blood was collected without anesthesia. A portion of the obtained blood (approximately 3-) was centrifuged at high speed (11,00 Orpm).

60 seconds) Platelet-poor blood in the supernatant! (ppν) and remainder)
The blood was centrifuged at low speed (1,000 rpm, 10 minutes) to obtain a supernatant, platelet-rich plasma (PRP).

Platelet aggregation was determined by turbidimetry at 37°C 1. o o o.

The PRP was stirred at rpm and measured with an Agrimeter (Hematotracer, Bingen Bioscience).

Platelet performance is shown as a spectrum of light transmittance, and PRP is 0s1p.
pp was set as 100chi. 0.21 of PRP was placed in a siliconized glass cuvette containing a Yutetsu stir bar and 2 μj'ft of dimethyl sulfoxide was added. 2
Minutes later, PAP dissolved in 0.25% BSA saline was added to a final concentration of 0.005 μg and maximum aggregation was measured. To study the inhibitory activity of compounds against platelet aggregation by PAF K, 2 μl of the test reagent dissolved in dimethyl sulfoxide instead of dimethyl sulfoxide
added. Using the formula below, calculate the PAF inhibition rate of the test drug and calculate the IC5° value.

The results are shown in Table 1.

Table 1: Inhibitory effect of bovine platelet aggregation by PAP In addition, all of the test drugs were inhibited by other aggregating agents, such as AD.
P, for aggregates spun by collagen, 1
At 0 μg or more, there was no effect at all.

As a result, the effect of the compound CI) of the present invention q PAF V
This effect was confirmed not only in vitro tests but also in vivo tests. Therefore, the compound of the present invention CI
) is associated with the onset of PAFis, various inflammations such as rheumatism, circulatory system diseases such as DIC and cardiac anaphylaxis, allergic diseases such as acne, gastric ulcers, duodactyly mmm, gastrointestinal diseases such as intestinal diseases, etc. It is extremely useful as a preventive and therapeutic agent for ulcers, etc.

The present invention will be explained below using reference examples and examples.
The present invention is not limited thereto.

Reference Example 1 Methyl-(4-chlorophenyl)-acetate m (2.4%k) K dissolved in concentrated sulfuric acid 2.75 de
Add and reflux for 6 hours. Cool, add heavy sodium water, and stir. The organic layer was separated and dried over anhydrous sodium sulfate;
Filter and concentrate to dryness to obtain methyl-(4-chlorophenyl)-
Acetate) 102gt-4. ([$94chi) NMJR (CDCJ,) δppm z 54 0
(2He a ) * 5.70 (5H, 8)e
7.15-7.55 (4H,8) Reference Example 2 Methyl-(4-chlorogastric phenyl)-bromoacetate lr Methyl-(4-chlorogastric phenyl)-7cetate 1102
g (0.55 mol) was dissolved in 1001 carbon tetrachloride and
Bromosuccinimide 97.9, F C0.55? +
1 Methyl-(4-lyqrophenyl)bromoacetate) 15
We get 0.9. (Yield 103rs).

NMR (CDCJ3) δppm s 5-7 9
(5a-s)-5,31(I H-s)=
7-3~7-7 (4He s) Reference fftJ
5 Methyl-α-(4-chlorophenylcouα-acetylthioacetate 60% oily sodium hydride 22.0 # (0,55
Dry dimethylformamide V600 under nitrogen atmosphere (mol)
T! Add Lt.

Thioacetic acid, 46.0 g (0.61 M) at 0-10 °C
After dropping, keep warm at 0 to 10°C for 1 hour.

Is this methyl (4-ri00 phenyl) de 4 moase? -1
150# (0-55 mol) dissolved in dry dimethylformamide 2001a/ is added dropwise at 0-10°C and kept warm for 1 hour after dropping.

Add 1 ots of brine to the reaction solution and extract twice with benzene. The organic layer was washed with 5-dihydrous aqueous solution and diluted with 10-dilute saline solution.
Wash twice, dry over anhydrous sodium sulfate, filter and concentrate. The residue was purified by silica gel chromatography (5% ethyl acetate-hexane) using fi L, methyl-α-(4-
12
8. Get O1.

(Yield 95cm) NMR (CDCl2) 299m; 2.3
5 (5H, a ), 3.74 (5H, a
L 5.28 (I H, B), 7.25-7.4
0 (4H, m) Reference N 4 α-(4-/lorophenyl)α-mercaptoacetate methyl α-(4-chlorophenyl)-α-acetylthioacetate) 100 g (0.39 mol) was degassed. A solution of 62.4 g (1,56 mol) of sodium hydroxide dissolved in 550 Td of methanol and 150 mm of degassed water is added and refluxed for 5 hours. After cooling, add 10% saline and wash with hexane twice.

The aqueous layer was adjusted to 1 to 2 with concentrated hydrochloric acid, extracted twice with benzene, the organic layer was washed with io*on water, dried over anhydrous sodium sulfate, concentrated to dryness, and α-(4-chlorophenyl) α
- 68 g of mercapto vinegar fR (5 semi-isomers) was obtained. (Yield 86.8%) NMR (CDC) 3) 299m;
2.62 (1H9d, J ~7.6Hz)t
4-67 (I H, d, J = 7.6 Hz).

7.3-7.45 (4H, B) According to the method of Reference Examples 1-4, the following racemic compounds were obtained.

(Transformation) α-(2,(5-di/a-lophenyl)-α-mercaptoacetic acid Nagigo spectrum (CDCl2 e δe ppm ) 2-82
(IH,d-J=8-2 Hz) 5-65
(I Hed, J'8-2 Hz) 7-0~,7
-5 (3H,m) (b) α-(3,4-dimethoxyphenyl)-α-mercaptoacetic acid 2-61 (I H= d-J'7-3Hz) *
3-87 (5H-1!1) 3.90 (3H, 8), 4
-69CIHt Mark J=7-3 Hz) 6-
7 ~7-1 (3He m) (c) α
-(6,4,5-trimethoxyphenyl)-α-mercaptoacetic acid 2.62 (I H, d, J-7-34z), 3-
84 (5H.

s), 5.88C6H, s)e 4.66 (IH.

d, J□7-5 Hz)-6-5 to 6-8 (2H
*m)(d) α-(4-methoxyphenyl)
-α-Mercaptoacetic acid 2.59 (I H, a, J-7,4Hz) * 3.
80 (5H*s), 4.67 (I H, dt
J-7,4H2)s 6.8-7.5 (4H, m) (e) α-(α-naphthyl)-α-mercaptoacetic acid 2.68 (I H, d, J=7-6Hz) 5 .5
0 (I H, d, J = 7-6 Hz) 7.5~
8.4 (7H, m) (f) α-(4-fluoro)-α-mercaptoacetic acid 2-62 (I H, d, J=7-4Hz) 4-
70 (1H9d, J=7.4H2)6.9~7.7(4
H, m) Reference Example 5 Optical resolution of α-phenyl-α-mercazotoacetic acid derivative (~ (→-α-mercazoto α-(4-chlorophenyl)cinchonidine acetate (43,911,0-150 mol) was degassed and /-le (900117)KJil!Turn it cloudy and stir at 60°C to prepare (e)-α-mercapto-α-(4
-ion)x=ru)acetic acid (30.2g, 0.150 m
A degassed ethanol (5Qmj) solution of ol) was added.

Then, stirring was stopped and the mixture was allowed to stand at room temperature for 2 hours. The precipitated crystals were filtered and dried to give crude salt - (42,6yl 58
%) was obtained.

Ethanol (20
00ml) at 80°C with stirring. At that point, stirring was stopped, the mixture was allowed to cool to room temperature, and left to stand for 48 hours. The precipitated crystals were filtered and dried to give crude salt -■ (22.9g, 31%
) was obtained. Crude salt - (22.5g) was degassed and then dissolved in ethanol (1000ml) at 80°C with stirring. Then, stirring was stopped, the mixture was allowed to cool to room temperature, and left standing for 20 hours. The precipitated crystals were filtered and dried to give (t)-α-mercapto-α-(4-chlorophenyl)acetic acid ciconison ag.
m.

Crystals (15.8 g, 21%) were obtained.

Next, aqueous 10-thiosulfuric acid (100 m) and methanol (2011!j) were added to the purified salt for decomposition, followed by extraction twice with ether. The organic phase was dried and the solvent was distilled off under reduced pressure to obtain (→-α-mercazoto α-(4-chlorophenyl)acetic acid (5,95,!ii′,20).

mp-123~125°C [α)'; = +84.8° (CO, 748, Et, o
n)(b) (→-α-Mercapto α-(4-chlorophenyl)cin*nin acetate (54-7110-186 mol) was added to a degassed ethanol (2701M) solution at room temperature under stirring.
(e)-α-merkanot α-(p-xen phenyl)
A solution of acetic acid (57.6 g, 0-186 mol) in degassed ethanol (19017) was added. Then, stirring was stopped and the mixture was allowed to stand at room temperature for 10 hours. The precipitated crystals were filtered and dried to obtain crude salt-■ (33.0 g, 36%). Degassed ethanol (55 g) of crude salt - (32.8 g)
C1m/) at 80°C with stirring. At that point, stirring was stopped, the mixture was allowed to cool to room temperature, and left to stand for 24 hours. Further, gentle stirring was performed at room temperature for 2 hours, and the precipitated crystals were filtered and dried.
8#, 12ch) was obtained.Next, 1cio*sulfur water (501m) and methanol (1017) were added to the above purified salt to decompose it, and 2
Extraction was performed twice. The organic phase was dried and the solvent was distilled off under reduced pressure.
(→-α-Mercazot-α-(4-chlorophenyl)acetic acid (4.45 g, 12%)'1 m.

mp-123-125°C [α) = -84,1° (CD', 503.1!!toa
) (Q) (→-α-Merker r to α-(4-/
lorophenyl) l-ephedrine acetate (4,08,9,0,025moA'
) and α-mercazotyl α-(4-chlorophenyl)acetic acid (5,00L D, 025W11) were dissolved in ethanol at 10 dK, allowed to stand at room temperature for 10 hours, and the precipitated crystals were filtered off, and a small amount of ethyl It was washed with ether and dried to obtain crude salt -■ (2,74,?).

Crude salt-■ was dissolved in ethanol (81 u) under heating at K, allowed to cool to room temperature, and allowed to stand for 15 hours. The precipitated crystals were filtered and dried to obtain a crude salt (1,07N). Coarse salt
(2) was dissolved under heating with ethanol (3i1/)K, allowed to cool to room temperature, and allowed to stand for 24 hours. The precipitated crystals were filtered and dried to give (→-crystals of j-27 nidoline salt of a-mercazoto α-(4-chlorophenyl)acetic acid (0,61,
9)! Obtained.

Next, it was added to 1M hydrochloric acid (10 MI) for decomposition, and extracted twice with ether. The organic phase was dried and the solvent was removed under reduced pressure to give (-)-α-(4-chloro7enyl)acetic acid (
0.33 g) t-obtained.

mp-120-122℃ (:a)fi'--75,8°(c O,425,g
toa) Reference Example 6 N-nicotinylidenemethylamine ■ Nicotinaldehyde 10.7 # (0.1 mol) t-
Dissolved in toluene 1001111, added 40% methylamine aqueous solution 23.39 (0.3 mol) and azeotropically dehydrated for 3 hours. The reaction solution was completely condensed under reduced pressure, and N-nicotinylidene methylamine 11.7. ft4ru.

NMR (CDCj3) appm; 3.53 (3H
, a, , y = L7 Hz L 7-3 to 8-85
(5H,m) Reference Example 7 5-(4-chlorophenyl)-3-methyl-2-(3-
Synthesis of pyridyl)thiazolidin-4-one.

8H Racemic α-(4-chlorophenyl)-α-mercapto-acetic acid io,oy (0,049 mol) synthesized in Reference Example 4 and N-ecotinylidenemethylamine synthesized in Reference Example 6 5.88. 9 (0,049 mol) to toluene 10
0117? and azeotropically dehydrated for 2 hours. After cooling, the reaction solution was washed with 5 seconds of heavy sour water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crystallization yields 5-(4-phenyl)-3-methyl-2-(3-pyridyl)-thiazolidin-4-one IS, 5#. (Yield 90. Old 1° Melting point 100-101.5°C Reference Example 8 5-(4-chlorophenyl)-6 obtained in Reference Example 7
-Methyl-2-(3-pyridyl)thiazolidin-4-one (3 g) using a liquid chromatograph (Lichroprep@
5i-5Q (4Q ~ 153 μm) was purified using mobile phase ethanol:hexane = 1:9) and trans-isomer I and ci
Form a H was obtained.

Melting point (trans form 1): 140-140.5°
Cz (cis form ff): 120-120.5°C Reference Example 9 5-(4-chloro-n-phenyl)-3-methyl-2-(3-
pyridyl)thiazolidin-4-one Racemic α-(4-chlorophenyl)-α-mercha synthesized in Reference Example 4,
'Toluene 5Qd was added with 5.0II (0,025 mol) of to-acetic acid, 2.64 # (0,025 mol) of nicotinaldehyde, and 5.75.9 (0,074 mol) of a 40% aqueous methylamine solution to 5Qd of toluene for 3 hours. Perform boiling dehydration. Cool, concentrate under reduced pressure, and chromatograph the residue on silica sol (5% acetone-
Purified with chloroform), slightly recrystallized with ether,
5-(4-ri44phenyl)-3-methyl-2-(3-
6.59 g of pyridyl)-thiazolidin-4-one are obtained. (Yield 87.6+%) Melting point 100-101.5°C Similar to Reference Example 7 or 9, inter alia listed in Table 3,
Reference Examples 10 to 47 were obtained.

Example 1. (+) -cis -5-(4-rioo
7z=ru)-3-methyl-2-(31'lysyl)-thiazolidin-4-one (+)-α-mercaftho α-(4-chlorophenyl)
Acetic acid (10-72,!i', 0.053mo/)
Tonico≠idenemethylamine (" 6.371
1-0.053 mol) of tetrahydro7 run (
20II! /) The solution was added dropwise. The reaction was continued for 10 hours, and then toluene (50 m) was added to the reaction mixture.
The solvent was removed under reduced pressure. The obtained crude product is 0-5'OK
It was cooled and crystallized to obtain crude crystals (17,15F). The obtained crude crystals were recrystallized from ether at 0 to 5°C to give (+)-C1s-5-(4-chlorophenyl)-3-methyl-2-(3-pyridyl)-thiazolidine. -4-one (9,369.

A yield of 58% was obtained.

! lip, 77.5-79.0°C [α1 formula 7 = +26.7° (c O,60,
cHci3) Example 2. (-) -cis -5-(
4-rioo7z=ru)-3-methyl-2-(3-pyridyl)V゛1 -thiazuridin-4-one 1(-)-α-
Mercateto α-(4-chlorophenyl)acetic acid (6,1
11,0-030mcy/) and N-=ko”?”rf
"Nj? Lua On (3,631!, 0.030
mol) in the same manner as in Example 1, (-)-cis-5-(4-chlorophenyl)-3-methyl-2-(3-)'lysyl )
-thiazolidin-4-one (5,52 L yield, 60 liters) was obtained.

mp, 75.0-77.5℃ [α] name' = -25,5° (GO, 601CHC
l3) Example 3. (-) -trans-5-(4
-chlorophenyl)-3-methyl-2-(3-pyridyl)-thiazolidin-4-one and.

Its (+) -cis form (+)-α-mercazoto α-(4-chlorophenyl)
Acetic acid (,0-83,!9, 4.1 mmoA!)
and N-nico♂4denmethylami7 (0,4911
Add Molecular Seeds 4A (1.0 g) to a toluene solution (10d) of 4.1 mmol) and heat at 50°C.
The reaction was carried out for 3 hours while stirring. Next, 1 Molecular Seeds was filtered off, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane dichloromethane-ethanol = 5:1:1) to elute quickly. Compound (-) -trans -5-(
4-chlorophenyl)-3-methyl-2-(3-pyridyl)-thiazolidin-4-one (0.19 g, yield 15
Compound (+)-c1θ-5-(4-
chlorophenyl)-3-methyl-2-(3-gyridyl)
-thiazolidin-4-one (0,6OL yield 48%) was obtained.

(-)-trans body mp-137~138℃ [α] Back=-54.8° (c 1.17.cHcz3)
(+) -C1e body mp, 77~79°C [α] Trade = +26.6° (co, 70tc'b Rono 3)
Example 4゜(+) -trans -5-(4+chlorophenyl)
-6-Methyl-2-(3-gylydyl)-thiazolidin-4-one(-)-α-mercapto-α-(4-chloro7enyl)
Acetic acid (0,651, 3,2 mmoJ) and N-=coliΩ)'denmethylamine (0,38 fi, 3,2
mmol) in the same manner as in Example 3,
(+)-trans-5-(4-chlorophenyl)-
3-methymp, 135-137°C

Claims (5)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Ar represents an aryl group or an aryl group substituted with a halogen atom or a lower alkoxy group,
represents a linear or branched lower alkylene group or a single bond, R is a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, acyloxy,
It represents di-lower alkylamino, a hydroxyl group or an aryl group, or an aryl group substituted with a lower alkoxy group, and Py represents a pyridyl group. ] Optically active 2-pyridylthiazolidine-4 represented by
-one derivatives and acid addition salts thereof. (2) The compound according to claim 1, wherein the pyridine ring is bonded to the 2-position of the thiazolidine ring skeleton at the 2- or 3-position. (3) The compound according to claim 1, which has a (+)-trans steric structure. (4) An anti-PAF agent containing the optically active 2-pyridylthiazolidin-4-one derivative and its acid addition salt as set forth in claim 1 as an active ingredient. (5) The anti-PAF agent according to claim 4, which has a (+)-trans steric structure.