JPH0730073B2 - Novel thiazolidin-4-one derivative and acid addition salt thereof - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel 2-pyridyl-thiazolidin-4-one derivative having excellent antagonistic activity against platelet activating factor (hereinafter referred to as PAF).

<Prior Art and Challenges> PAF is a factor that activates rabbit platelets in a trace amount found in the culture supernatant of IgE-sensitized rabbit basophils stimulated with antigen (Benveniste J., et al., JP Med. , 136 , 1356-1377 (1
972)) and acetyl glyceryl ether phosphoryl choline (AGEPC), namely 1-O-hexadecyl / octadecyl-2-O-acetyl-sn-glyceryl-
3-phosphorylcholine (Hanahan.DJ et al., J. Biol. Che
m., 254 , 9355-9385, (1979)).

PAF has various actions other than platelet activating action, such as blood pressure lowering, vascular hyperpermeability, smooth muscle contraction, neutrophil /
It is known to cause physiological effects such as activation of monocytes / macrophages and promotion of hepatic glycogen degradation at extremely low concentrations.

These physiological actions are said to be associated with many diseases such as various kinds of inflammation / allergic diseases, cardiovascular diseases, digestive system diseases and the like. Therefore, for the prevention and / or treatment of these PAF-induced diseases, the search for PAF antagonists has been focused, and in recent years, PAF antagonists have been vigorously searched for.

However, for the prevention or treatment of PAF-induced diseases,
Several compounds have been tried until now, but their effectiveness has not been entirely satisfactory.

On the other hand, many research reports have been made on thiazolidin-4-one derivatives. However, 2 of them
The -pyridyl-thiazolidin-4-one derivatives are limited to the following seven reports. That is, JP-A-54-145670 discloses N- (substituted or unsubstituted phenyl and pyridyl) derivatives having use as agricultural chemicals. Japanese Patent Laid-Open No. 55-55184 discloses compounds centering on N- (substituted or unsubstituted phenyl and benzyl and cycloalkyl) derivatives having use as agricultural chemicals. JP-A-57-85380 and JP-A-57-88170 disclose N- (carboxycyclohexylmethyl) derivative having an anti-complement action and an anti-inflammatory, analgesic and anti-rheumatic action, respectively. N- (carboxymethylphenyl) derivatives are disclosed. JP-A-58-183689 discloses an N- (pyrazinyl) derivative having a use as an agricultural chemical. In addition, U.S. Patent Office No. 4,501,746 states that
N- (substituted phenyl) having use as synthetic intermediate
Derivatives are disclosed, and JP-A-61-103881 discloses N- (substituted carbamoyloxy) derivatives having use as cardiotonic agents.

<Means for Solving the Problem> Under these circumstances, as a result of earnest search for the purpose of searching for a useful PAF antagonist, the present inventors found that the formula [I] [In the formula, R ¹ and R ² may be the same or different and may be represented by the general formula -A-R ⁴ (wherein A is a single bond, C ₁ -C ₈ alkylene, C ₂ -C ₈ alkenylene) or C ₂ -C ₈ alkynylene group, R ⁴ is a hydrogen atom, C ₁ -C ₁₂ alkyl, C ₂ -C ₈ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkyl halogen atom-substituted ,
Represents Or a group represented by the general formula) (CH ₂₎ in _{n -O m (CH 2) n} 'O m' B-R 5 ( wherein, B is a single bond or a C ₁ -C ₆ alkylene radical, R
⁵ is a hydrogen atom, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C
_3- C ₈ cycloalkyl, a substituted silyl group, or a substituted or unsubstituted aryl group, n is an integer of 2 to 4,
m is an integer from 1 to 3, n'is an integer from 2 to 4, m '
Represents 0 or an integer of 1 to 2. ), R ₃ is a hydrogen atom, C ₁ -C ₂ alkyl, allyl, propargyl or the general formula — (CH ₂ ) _l —R ⁶ (wherein R ⁶ represents a halogen atom? Represents an aryl group which may be substituted with one or more hydroxyl groups or a C ₁ -C ₄ alkoxy group, or has the general formula -D-R ⁷ (wherein D represents an oxygen atom or a sulfur atom). , R ⁷ represents a hydrogen atom, a C ₁ -C ₄ alkyl or a C ₁ -C ₄ alkanoyl group), and l represents an integer of 2-4. ] In either a group represented, or the general formula - (CH ₂₎ in _k CO-E-R ⁸ [wherein, E is an oxygen atom, a sulfur atom, an imino or C ₁ -
C ₄ alkylimino group, R ⁸ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or a 5- to 7-membered cyclic amino group which may contain another hetero atom in the ring by E-R ⁸ , and k Represents an integer of 1-3. Or a general formula —F—R ⁹ [wherein F represents a C ₂ -C ₆ alkylene group, R ⁹ is an aromatic heterocyclic group containing a nitrogen atom or a general formula, [In the formula, R ¹⁰ represents a hydrogen atom, C ₁ -C ₄ alkyl or C ₁ -C ₄
Represents an alkanoyl group, R ¹¹ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, or R ¹⁰ and R ¹¹ together,
It represents a cyclic amino group of a 5-7 membered ring which may contain other heteroatoms in the ring. ] It represents the amino group shown by. ] Represents the group represented by. ] The thiazolidin-4-one derivative represented by and its acid addition salt have a selective PAF antagonistic action, and PAF-induced diseases such as various inflammatory / allergic diseases and cardiovascular diseases,
The present invention was found to be extremely useful as a preventive / therapeutic drug for digestive system diseases and the like, leading to the present invention.

Hereinafter, the present invention will be described in detail.

In the present specification, the C ₁ -C ₁₂ alkyl group means, for example, methyl, ethyl, n-propyl, n-butyl, sec.
-Including linear and branched alkyl groups such as butyl, n-pentyl, iso-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl , and C ₂ -C ₈ alkenyl group,
For example, vinyl, 2-propenyl, 2-butenyl, 3
-Methyl-2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
Including linear and branched alkenyl groups such as 2-hexenyl, 4-hexenyl, 5-methyl-4-hexenyl, 2-heptenyl, 6-methyl-5-heptenyl, 2-octenyl, 6-octenyl, C ₃ The —C ₈ cycloalkyl group includes, for example, substituted and unsubstituted cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclohexyl, etc., and is substituted with a halogen atom. C ₁ -C ₆ alkyl includes monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, tridecafluorohexyl groups, and substituted or unsubstituted aryl. The group is, for example, phenyl, naphthyl, p-chlorophenol, o-chlorophenyl, p-
Included substituted and unsubstituted aryl groups such as fluorophenyl, 2,6-dichlorophenyl, P-methoxyphenyl, and 3,4-dimethoxyphenyl, and C ₁ -C ₈ alkylene groups are methylene and ethylene. , Straight-chain and branched alkylene groups such as trimethylene, 1-methyltrimethylene, tetramethylene, pentamethylene, hexamethylene, and heptamethylene, and C ₂ -C ₈ alkenylene groups include vinylene, propenylene, and 2-butenylene. , 2-methyl-2-
Butenylene, 2-pentenylene, 3-pentenylene, 2
-Hexenylene, 3-methyl-2-hexenylene, 3-
It includes linear and branched alkenylene groups such as heptenylene and 4-octenylene. The C ₂ -C ₈ alkynylene group, ethynylene, propynylene, 2-butynylene, 2-
It includes linear and branched alkynylene groups such as methyl-2-butynylene, 2-pentynylene, 3-pentynylene, 2-hexynylene, 3-methyl-2-hexynylene, 3-heptynylene and 4-octynylene. The C ₁ -C ₆ alkylene group means methylene, ethylene, trimethylene, 1-
It includes linear and branched alkylene groups such as methyltrimethylene, tetramethylene, pentamethylene, and hexamethylene, and C ₁ -C ₆ alkylene groups include, for example, methyl, ethyl, n-propyl, n-butyl, sec. -Butyl, n-pentyl, iso-pentyl, n-hexyl and the like linear and branched alkyl groups are included, and the substituted silyl group means trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, trif- Enylmethyldimethylsilyl, t-butyldiphenylsilyl, methyldiisopropylsilyl, methyldi-t-
Includes butylsilyl, tribenzylphenyl, triisopropylsilyl, triphenylsilyl groups. Methyl and C ₁ -C ₂ alkyl group include an ethyl group, and a halogen atom,
Includes fluorine, chlorine and bromine atoms. The C ₁ -C ₄ alkoxy group is, for example, methoxy, ethoxy, n-
It includes linear and branched alkoxy groups such as propoxy, iso-propoxy, and n-butoxy, and the C ₁ -C ₄ alkyl group is, for example, methyl, ethyl, n-propyl, is.
It includes linear and branched alkyl groups such as o-propyl, n-butyl, iso-butyl, etc., and the C ₁ -C ₄ alkanoyl group means, for example, direct formyl, acetyl, propionyl, butyryl, iso-butyryl and the like. A chain- and branched-chain alkanoyl group is included, and C ₁ -C ₄ alkylimino group means methylimino, ethylimino, n-propylimino, is-
An alkylimino group such as butylimino is included, and a 5- to 7-membered ring amino group means pyrrolidinyl, piperidinyl,
Homopiperidinyl, morpholinyl, piperazinyl, N-
Contains a cyclic amino group such as methylpiperazinyl, C ₁ -C ₆
The alkylene group includes a linear and branched alkylene group such as methylene, ethylene, trimethylene, 1-methyltrimethylene, tetramethylene, pentamethylene, hexamethylene, etc., and an aromatic heterocyclic group containing a nitrogen atom. , For example, aromatic heterocyclic groups such as pyrrole, imidazole and pyrazole.

The salt of the thiazolidin-4-one derivative represented by the general formula [I] may be any pharmaceutically acceptable salt,
For example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; formic acid, acetic acid, fumaric acid, maleic acid, citric acid,
Salts with carboxylic acids such as lactic acid, malic acid, tartaric acid and aspartic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid and naphthalenesulfonic acid Examples thereof include salts with inorganic acids and organic acids.

The compounds used in the present invention include optical isomers and geometric isomers, and further include all hydrates and crystal forms.

The thiazolidin-4-one derivative represented by the general formula [I] can be produced, for example, by the following methods.

[Wherein R ¹² and R ¹³ may be the same or different and may be the same as or different from the general formula -A-R ⁴ [wherein A and R ⁴ have the same meanings as described above], ³ has the same meaning as above] The compound [I] of the present invention is a thioglycolic acid derivative [II]
And Schiff base [III] can be prepared by ring closure in an inert solvent. Organic solvents include benzene, toluene, xylene, methylene chloride, 1,
A general inert solvent used in the dehydration reaction of 2-dichloroethane, chloroform, tetrahydrofuran or the like or a mixed solvent thereof with ethanol or the like can be used. The reaction temperature can be carried out at 20 ° C to the reflux temperature, but by carrying out the azeotropic dehydration at the reflux temperature,
It is desirable to accelerate the reaction.

[In the formula, R ³ has the same meaning as described above. Further, the compound [I] includes a primary amine [IV] and a compound [I]
I] and nicotinaldehyde can be produced by ring closure in an inert solvent. As the organic solvent, use a general inert solvent used in the dehydration reaction such as benzene, toluene, xylene, methylene chloride, 1,2-dichloroethane, chloroform and tetrahydrofuran, or a mixed solvent thereof with ethanol or the like. You can The reaction temperature may be 20 ° C. to the reflux temperature, but it is desirable to accelerate the reaction at the reflux temperature and by performing azeotropic dehydration.

[Wherein R ¹⁴ is -A-R ⁴ [wherein A and R ⁴ have the same meanings as described above]]. Group or represented by the general formula] _{(CH 2) n -O m (} CH 2) n 'O m' B-R 5 [wherein ^{B, R 5, n, m} , n ', m' are as defined above Has meaning. ] It represents the group represented by.

R ¹⁵ is, C ₁ -C ₆ alkyl, allyl, propargyl or the general formula - (CH _{2) l} -R ¹⁶ wherein, R ¹⁶ is optionally substituted by one or more C ₁ -C ₄ alkoxy group Represents an optionally substituted aryl group, and l has the same meaning as described above. Group or the general formula -D-R ¹⁷ [wherein represented by], R ¹⁷ represents a C ₁ -C ₄ alkyl radical, D is as defined above. Or a group represented by the general formula] - (CH _{2) k} in -CO-G-R ¹⁸ [wherein, G is a C ₁ -C ₄ alkylimino, R ¹⁸ is C ₁ -C ₄
It represents an alkyl group or G-R ¹⁸ at the amino group of the annular may also be 5-7 membered ring contain other hetero atoms in the ring, k is as defined above. A group represented by or in the general formula -F-R ⁹ [wherein,, F, and R ⁹ are as defined above. ], X represents a leaving group, and R ² has the same meaning as described above. Examples of the leaving group of X include halogen atoms such as chlorine, bromine and iodine, lower alkylsulfonyloxy groups such as methylsulfonyloxy and ethylsulfonyloxy, substituted or unsubstituted such as phenylsulfonyloxy and tolylsulfonyloxy. And aryloxy groups such as acetyloxy and benzoyloxy.

Desirably, halogen atoms such as bromine and iodine are preferable.

Compound [Ib] can be obtained by reacting compound [Ia] with compound [V] in the presence of a base. As the base, an organic alkali metal compound such as butyl lithium, an alkali metal amide such as lithium diisopropylamide, an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as potassium tert-butoxide, 1,5-diazabicyclo (4.3. 0] nonan-5-ene,
1,8-diazabicyclo [5.4.0] undecane-7-ene,
Organic bases such as N-methylmorpholine and 4-dimethylaminopyridine are desirable, and it is desirable to carry out the reaction in an inert solvent such as tetrahydrofuran, dioxane, n-hexane and toluene at −50 ° C. to reflux temperature.

[In the formula, R ¹⁴ and R ¹⁵ have the same meanings as described above. The compound [Id] can be obtained by reacting the compound [V] with the compound [Ic] in the presence of a base. As the base, an organic alkali metal compound such as butyl lithium, an alkali metal amide such as lithium diisopropylamide, an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as potassium tert-butoxide, 1,5-diazabicyclo (4.3. 0] nonan-5-ene,
1,8-diazabicyclo [5.4.0] undecane-7-ene,
Organic bases such as N-methylmorpholine and 4-dimethylaminopyridine are desirable, and it is desirable to carry out the reaction in an inert solvent such as tetrahydrofuran, dioxane, n-hexane and toluene at −50 ° C. to reflux temperature.

[In the formula, X represents a leaving group, and R ¹² , R ¹³ and R ¹⁵ have the same meaning as described above. The compound [If] can be obtained by reacting the compound [VI] with the compound [Ie] in the presence of a base. As the base, an organic alkali metal compound such as butyl lithium, an alkali metal amide such as lithium diisopropylamide, an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as potassium tert-butoxide, 1,5-diazabicyclo (4.3. 0] nonan-5-ene,
1,8-diazabicyclo [5.4.0] undecane-7-ene,
Organic bases such as N-methylmorpholine and 4-dimethylaminopyridine are preferable, and for example, in an inert solvent such as tetrahydrofuran, dioxane, n-hexane and toluene, the reaction temperature may be heating.
It is desirable to react under ice-cooling or room temperature.

[In the formula, R ¹⁹ represents a halogen atom, and R ¹² , R ¹³ and l
Has the same meaning as above. The compound [Ih] is achieved by converting the hydroxyl group of the alcohol derivative [Ig] into a halogen atom. For example, as a halogenating reagent, preferably, phosphorus tribromide, phosphorus pentachloride and thionyl chloride in the presence of an organic base such as pyridine are used, and halogenated carbonization such as methylene chloride, chloroform and 1,2-dichloroethane is performed. hydrogen,
The compound [Ih] is obtained by reacting with an aromatic hydrocarbon such as benzene or toluene as a solvent under ice cooling or heating under reflux. Further, halogenation with a triphenylphosphine-carbon tetrachloride system is also a powerful means.

[In the formula, R ²⁰ represents a C ₁ -C ₄ alkyl or C ₁ -C ₄ alkanoyl group, X represents a leaving group, and R ¹² , R ¹³ and l have the same meanings as described above. The compound [Ii] can be obtained by reacting [Ig] with [VII], preferably in the presence of a base. For example, when R ²⁰ is a C ₁ -C ₄ alkyl group, an inorganic base such as sodium hydride, potassium hydroxide and potassium carbonate or an organic base such as pyridine and triethylamine is used as a base, and dimethylformamide and dimethyl are used as a solvent. The reaction is carried out using sulfoxide, tetrahydrofuran, etc. under ice-cooling or heating under reflux. Also, R ²⁰ is C ₁ -C ₄
In the case of an alkanoyl group, an organic base such as pyridine and triethylamine is used as a base, an aromatic hydrocarbon such as benzene and toluene, an ether solvent such as tetrahydrofuran, or the above organic base is used as a solvent.
Alternatively, it is desirable to use an alkanoylating reagent as a solvent and carry out the reaction under ice-cooling or heating under reflux.

[In the formula, R ²¹ represents a C ₁ -C ₄ alkyl group, and R ¹² , R ¹³ and k have the same meanings as described above. The compound [Ik] is a general ester hydrolysis condition (S. Coffey, “Rodd's Chemist
ry of Carbon Compouds ", 2nd Ed., Vol.1C, Elsevier (19
It can be obtained by hydrolysis under 65), p.92). For example, in the presence of sodium hydroxide and potassium hydroxide,
The reaction is carried out at room temperature or under heating using an alcohol solvent such as methanol or ethanol or an aqueous solvent.

[In the formula, R ²² represents a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkanoyl group, and R ¹² , R ¹³ , D and l have the same meanings as described above. The compound [Il] can be obtained by reacting [Ih] with [VIII], preferably in the presence of a base. For example, in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate or an organic base such as pyridine or triethylamine as a base,
Aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and dichloroethane, ether solvents such as tetrahydrofuran, and dimethylformamide are used as the solvent, and the reaction is carried out under ice-cooling or reflux heating.

[In the formula, X, R ¹ , R ² , R ¹¹ , R ¹⁰ and E have the same meanings as described above. The compound [In] is obtained by reacting the compound [Im] with the compound [IX] in the presence of a base. Examples of the base include organic alkali metal compounds such as butyl lithium, alkali metal amides such as lithium diisopropylamide, alkali metal hydrides such as sodium hydride, and general organic solvents suitable for the base used (for example, In tetrahydrofuran, dioxane, n-hexane, toluene, dimethylformamide, etc.), the reaction temperature may be heating, but is preferably ice-cooling or room temperature.

[Wherein R ¹ , R ² , R ⁹ , R ¹⁹ and F have the same meanings as described above. The compound [Iq] can be obtained by reacting the compound [Ip] with the compound [X] in the presence of a base. Examples of the base include organic alkali metal compounds such as butyllithium, alkali metal amides such as lithium diisopropylamide, alkali metal hydrides such as sodium hydride, and general organic solvents suitable for the base used (for example, In tetrahydrofuran, dioxane, n-hexane, toluene, dimethylformamide, etc.), the reaction temperature may be heating, but is preferably ice-cooling or room temperature.

Incidentally, these starting compounds are known per se or are compounds which can be synthesized by a known synthetic method, for example, the compounds represented by [II] [III] and [XVII] are as described in Reference Examples, It could be obtained by the following method.

[In the formula, R ¹² , R ¹³ and R ³ have the same meanings as described above. ] That is, the raw material compound, E. Schwenk (J. Am. Chem. Soc.,
70 , 3626 (1948)) and the like to perform esterification and halogenation to obtain a bromide [XII]. Furthermore, after this [XII] was converted into a thiol ester compound [XIII] according to the method described in New Experimental Chemistry Course Volume 14, page 1712,
The mercaptan derivative [II] was obtained by hydrolyzing [XIII] with a base such as sodium hydroxide or potassium hydroxide in a water-alcohol mixed solvent.

The Schiff base compound [III] was obtained by dehydration condensation of 3-pyridinecarboxaldehyde and a primary amine [IV] according to the method described in New Experimental Chemistry Course, Vol. 14, page 1410.

The compound [XVII] is methanesulfonylated from the starting compound [XIV] by the method of New Experimental Chemistry Course 14 (III) page 1797,
[XV] was obtained, and this was subjected to the method of WT Olson et al. (J. Am. Chem. So.
c., 69 2451 (1947)) [XVI] obtained, new experimental chemistry course 14
(I) Derived by the method of page 438.

The raw material compounds [Ia], [Ic], [Ie] [Ig], [I
h], [Ij], [Im] and [Ip] are themselves the target compounds of the present invention, and were synthesized, for example, according to the production method (a).

The compound of the present invention represented by the general formula [I] and its acid addition salt can be administered orally or parenterally when used as a medicine. That is, it can be orally administered in the form of commonly used dosage forms, such as tablets, capsules, syrups, suspensions and solutions, or liquid solutions such as solutions, emulsions and suspensions. Molded forms can also be administered parenterally in the form of injections. Furthermore, rectal administration in the form of suppositories, administration of inhalation sprays and administration of transdermal agents are also possible.

In addition, the above-mentioned appropriate dosage form can be produced by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used in an injection form, an acceptable buffering agent, solubilizing agent, isotonic agent, etc. may be added.

The dose and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but usually about 1-per day for an adult.
5000 mg, preferably 10-300 mg, can be administered once or in several divided doses.

<Actions and Effects of the Invention> The compound [I] of the present invention was found to have a desirable pharmacological action as a therapeutic agent for PAF-induced diseases. That is, the compound [I] of the present invention exhibits a strong and selective antagonistic action on PAF and is excellent in in vivo effect. Hereinafter, the pharmacological effects of the compound of the present invention will be described in detail.

[Control effect on platelet aggregation / in vitro test]

(A) Rabbit Platelet Aggregation Control To suppress PAF-induced platelet aggregation, rabbit platelet-rich plasma (PRP) was used to determine the method of Born [GVRBorn,
Modified J. Physiol., London, 162 , 67 (1962)]
d et al. (JF Mustard et al., J.Lab.Clin.Med., 64 , 5
48 (1964)]. That is, in advance,
In a polyethylene container containing 1/10 volume of 3.8% sodium citrate, 80 to 100 ml of blood was collected from each carotid artery of a Japanese white male rabbit without anesthesia. Part of the obtained blood (about 3 ml) was subjected to high-speed centrifugation (11,000 rpm, 60
Second) to obtain a supernatant of platelet poor plasma (PPP), and the remaining blood was subjected to low speed centrifugation (1,000 rpm, 10 minutes) to obtain a supernatant of platelet rich plasma (PRP).

Platelet aggregation was measured by a non-turbid method by stirring PRF at 37 ° C. and 1,000 rpm and measuring with an aggregometer (Hematracer, Nikko Bioscience). Platelet aggregation is% of light transmission
, PRF was 0% and PPP was 10%. 0.2 ml of PRP was placed in a glass cup containing a siliconized iron stir bar and 2 μl of dimethyl sulfoxide was added. Two minutes later PAF dissolved in 0.25% BSA saline was added to the final concentration.
The maximum aggregation was measured by adding 0.005 μg / ml. P
To study the inhibitory activity of compounds on platelet aggregation by AF, 2 μl of the analyte dissolved in dimethylsulfoxide was added instead of dimethylsulfoxide. The PAF inhibition rate of the reagent was determined by the following formula, and the IC ₅₀ value was determined.

The results are shown in Table 1.

(B) Inhibition of human platelet aggregation The inhibition of PAF-induced platelet aggregation was tested using human PRP. The experimental method was carried out in the same manner as in the case of the rabbit described above, and the PAF aggregation inhibition rate of the test drug at the final concentrations of PAF of 0.3 μM and 1 μM was measured to determine the IC ₅₀ value.

The results are shown in Table 2.

In addition, all the test drugs are other aggregating agents, for example,
1 for aggregation induced by ADP, collagen
At 0 μg / ml, there was no effect.

[Inhibitory effect on PAF blood concentration / in vivo test]

Urethane anesthesia for guinea pig (6.25 mg / Kg intraperitoneal administration)
Then, carry out carotid artery and jugular vein cannulation. The carotid cannula is used for blood collection, and the jugular vein cannula is used for intravenous PAF injection.

Compound 27 10% Nitzcol Suspended in liquid at a concentration of 3 mg / ml
Then, administer 1 ml / Kg from the jugular vein kenule. 2 minutes later PA
F0.1 μg / ml was administrated from 1 ml / Kg jugular vein ke
To collect blood. Centrifuge the collected blood at 11,000 rpm for 5 minutes
Then, the hematotrit value is measured and the maximum hematotrit value rises.
Calculate the width (concentration of blood).

As a control, 0.5% methylcellulose solution is administered instead of compound (27).

The blood concentration inhibition rate of compound (27) by PAF was calculated by the following formula.

Results 87% Similarly, the results shown in Table 3 below were obtained.

Mouse PAF lethality test 4-week-old male ICR mouse (purchased from Charles River)
On) to Isomitar Soda (Amobarbital Natri)
Um; Nippon Shinyaku Co., Ltd.) Anesthetized by subcutaneous administration of 100 mg / Kg
To do. 18 minutes later, administer drug or solvent intravenously through the tail vein.
Give. Drug dissolved in 0.2M phosphate buffer at 1mg / ml
However, the dose becomes 10 mg / Kg when the dose is 10 ml / Kg. Drug administration
PAF 10 μg / Kg is administered intravenously through the tail vein 2 minutes later
It PAF is a physiological saline solution containing 0.25% bovine serum albumin
It was dissolved at a concentration of 2 μg / ml and administered at 5 ml / Kg.

After the administration of PAF, the survival of the mouse is observed, and the survival rate after 2 hours is calculated.

Test drug Survival rate control 0% 174 80% 175 60% 182 100% The above results indicate that the action of [I] of the compound of the present invention is potent and highly specific to PAF. This effect was confirmed not only in the in vitro test but also in the in vivo test. Therefore, the compound [I] of the present invention is
It is extremely useful as a preventive or therapeutic agent for PAF-induced diseases such as various inflammations, cardiovascular diseases, allergic diseases, and gastrointestinal ulcers.

The present invention will be described below with reference to Reference Examples and Examples.
The present invention is by no means limited to this.

Reference Example 1 2-mercapto undecanoic acid (i) 2-Bromo-undecanoic acid methyl ester _{n-C 9 H 19 COOH →} n-C 10 H 21 CHBrCOOCH 3 Thionyl chloride (108 ml, 1.48 mol) in undecanoic acid (100
g, 0.54 mol) was added and the mixture was refluxed for 2 hours. Then bromine (29 ml,
0.57 mol) was added dropwise under reflux over 1.5 hours, and the mixture was refluxed for 5 hours.

After cooling to room temperature, methanol (250 ml, 6.1 mol) was added dropwise over 30 minutes and left overnight. Brine was added to the reaction mixture, and the mixture was extracted twice with ether. Soak the extract in water, sodium sulfite water,
It was washed with brine and dried. The solvent was distilled off under reduced pressure to obtain crude 2-bromoundecanoic acid methyl ester (145 g, 97%).

IR (neat) [cm ^-1 ]; 2920, 2850, 1736, 1432, 1144 (ii) 2-acetylthioundecanoic acid methyl ester n-C ₉ H ₁₉ CHBrCOOCH ₃ → nC ₉ H ₁₉ CH (SCOCH ₃ ) COOCH ₃ Dry dimethylformamide (600 ml) was added to 60% sodium hydride (22.5 g, 0.56 mol) under a nitrogen stream. After cooling to 0 ° C, thioacetic acid (51.6g, 0.68mol) was added dropwise at 0-10 ° C. After the dropwise addition, the mixture was kept at 0-10 ° C for 1 hour, and then crude 2-bromoundecanoic acid methyl ester (145g, 0.52mol) was added at 0-1.
The mixture was added dropwise at 0 ° C and kept warm for 2 hours. Brine was added to the reaction mixture, and the mixture was extracted twice with ether. The extract was washed with sodium bicarbonate water, sodium sulfite water, and brine and dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2
-Acetylthioundecanoic acid methyl ester (108 g, 76
%) Was obtained.

IR (neat) [cm ^-1 ]; 2920, 2860, 1738, 1698, 1435, ¹
350,1152,950 (iii) 2- mercaptoundecanoic acid _{n-C 9 H 19 CH (} SCOCH 3) COOCH 3 → n-C 9 H 19 CH (SH) COOH 2- acetylthiazole Own decanoic acid methyl ester (122.2
g, 0.44mol) is dissolved in methanol (527ml) and water (226ml) is added.
ml), sodium hydroxide (67.8 g, 1.67 mol) is added, and the mixture is refluxed for 2 hours. After cooling, water was added and the mixture was extracted twice with hexane. The aqueous layer was adjusted to pH 1-2 with concentrated hydrochloric acid and extracted twice with ether. The extract was washed with brine and dried. The solvent was distilled off under reduced pressure to obtain 2-mercaptoundecanoic acid (95.54 g, 98%).

IR (CHCl ₃ ) cm ⁻¹ ; 2850, 1705 Reference Example 2 N-nicotinylidenemethylamine Nicotinaldehyde (10.7g, 0.1M) in toluene (100m
l) dissolved in 40% methylamine aqueous solution (23.3g, 0.3mo
l) is added and azeotropic dehydration is performed for 3 hours. The reaction mixture was concentrated under reduced pressure and N-nicotinylidenemethylamine (11.7g, 98%)
To get

NMR (CDCl ₃ δ) [ppm]; 3.53 (3H, d, j = 1.7Hz), 7.3-
8.85 (5H, m) Reference Example 3 1-Iodo-2- (2- (1-methylethoxy) ethoxy) ethane (i) Synthesis of 1-chloro-2- (2-methanesulfoxy) ethane 2- (2 -Chloroethoxy) ethanol 20g (0.16mol)
Was dissolved in 200 ml of dichloromethane and triethylamine 16.
2 g (0.16 mol) was added. The reaction solution was ice-cooled, and 18.3 g (0.16 mol) of methanesulfonyl chloride was added dropwise over 1 hour.
After the dropping, the mixture was further stirred with ice cooling for 1 hour. 40 ml of saturated aqueous sodium hydrogen carbonate was added dropwise under ice cooling, and the aqueous layer was extracted with dichloromethane. The extract was washed with 10% aqueous hydrochloric acid, saturated saline, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over magnesium sulfate.
After drying, the solvent was distilled off under reduced pressure to obtain 13.6 g of 1-chloro-2- (2-methanesulfooxyethoxy) ethane (yield 100%).

IR (CHCl ₃ ) cm ^-1 ; 1355, 1300, 1170, 1135, 1115, 96
9,913, ¹ HNMR (CDCl ₃ ) δppm; 4.41-4.38 (2H, m), 3.81-3.76
(4H, m), 3.65 (2H, t, J = 5.9Hz), 3.08 (3H, s) (ii) 1-chloro-2- (2- (1-methylethoxy))
Synthesis of (ethoxy) ethane Dry isopropyl alcohol 1 in a dry four-necked flask
2.2 ml (160 mmol) was added, and 920 mg (40 mmol) of metallic sodium cut into small pieces was added under a nitrogen stream, and the mixture was refluxed for 3 hours. The heating was stopped, and 8.4 g of 1-chloro-2- (2-methanesulfooxyethoxy) ethane was added all at once. After the exotherm subsided, the mixture was cooled to room temperature, diluted hydrochloric acid was added, and the mixture was extracted twice with ether. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After drying, the residue obtained by distilling off the solvent was distilled under reduced pressure, and the residue was dried at 77-83 mmHg and 114-121 ° C.
3.7 g (yield 55%) of -chloro-2- (2- (1-methylethoxy) ethoxy) ethane was obtained.

IR (CHCl ₃ ) cm ^-1 ; 2870, 1460, 1382, 1370, 1335, 130
0, 1120, 1090, 970, 912 ¹ HNMR (CDCl ₃ ) δppm; 3.77 (2H, t, J = 5.9Hz), 3.68-
3.57 (7H, m), 1.17 (6H, d, J = 5.9Hz) Reference Example 4 Synthesis of 1-chloro-2- (2-tert-butyldimethylsilyloxyethoxy) ethane Imidazole 17.8g (261mmol) was added to dimethylformamide.
It was dissolved in 100 ml, 36.3 g (241 mmol) of tert-butyldimethylsilyl chloride was added, and the mixture was stirred. Under ice cooling, 2-
25.0 g (200 mmol) of (2-chloroethoxy) ethanol was added dropwise over 1 hour, the mixture was further stirred for 1 hour, and then left overnight at room temperature. The reaction mixture was poured into 500 ml of saturated saline and extracted twice with ether. The extract was washed twice with saturated saline and dried over magnesium sulfate. After drying, the solvent was distilled off to obtain 47.8 g of 1-chloro-2- (2-tert-butyldimethylsilyloxyethoxy) ethane (yield 100%).

IR (CHCl ₃ ) cm ⁻¹ ; ¹ HNMR (CDCl ₃ ) δppm; Example 1 3,5-Dimethyl-2- (3-pyridine) thiazolidin-4-one (Compound No. 1) N-nicotinylidenemethylamine (12.0g, 0.1mol) was dissolved in toluene (100ml) and thiolactic acid (10.6g, 0.1mo) was added.
A) is added and azeotropic dehydration is performed for 3 hours using a Dean-Stark apparatus. After cooling, wash the reaction with 5% heavy water and
Dry and evaporate the solvent under reduced pressure. Ether was added to the residue for crystallization to obtain 3,5 dimethyl-2- (3-pyridyl) thiazolidin-4-one (15.6 g, 75%).

Melting point 89.5 to 92 ° C IR (nujol) [cm ^-1 ]; 1670, 1582, 1017, 719 Example 2 3-5 dimethyl-2- (3-pyridyl) thiazolidin-4-one obtained in Example 1 (5 g) was recrystallized twice from ethyl acetate: hexane (1: 1) to give cis isomer (compound No.
2) got. The filtrate was purified with a medium-pressure liquid chromatograph (hexane-ethanol) and the trans form (Compound No. 3)
Got

Cis form (Compound No. 2) melting point 98.5 to 99 ° C. Trans form (Compound No. 3) melting point 81 to 82 ° C. Example 3 3,5-dimethyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. .1) Nicotinaldehyde (10.7g, 0.1M) in toluene (100m
l), 40% aqueous methylamine solution (23.3 g, 0.3 mol) and thiolactic acid (10.6 g, 0.1 M) were added, and azeotropic dehydration was carried out for 3 hours using a Dean-Stark apparatus. After cooling, the reaction solution was washed with 5% heavy water and dried, and the solvent was distilled off under reduced pressure. Ether was added to the residue to crystallize 3,5-dimethyl-2
-(3-Pyridyl) thiazolidin-4-one (14.2 g, 6
8%).

Melting point 90-92 ° C. Example 4 3-Methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. 4) Using nicotinaldehyde, a 40% aqueous solution of methylamine and thioglycolic acid, the reaction was carried out according to the method of Example 3 to give 3-methyl-2- (3-pyridyl) thiazolidine-
I got 4-on.

Melting point 96.5-97.5 ° C IR (nujol) [cm ^-1 ]; 1670, 1583, 1236, 1109, 1005,
717 Example 5 5-Methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. 5) The reaction was carried out according to the method of Example 3 using nicotinaldehyde, ammonium carbonate, and thiolactic acid to give 5-methyl-
2- (3-Pyridyl) thiazolidin-4-one was obtained.

Melting point 109.5-110.5 ° C IR (nujol) [cm ^-1 ]; 1680 Example 6 3- (2-hydroxyethyl) -5-methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. 6) Using nicotinaldehyde, ethanolamine, and thiolactic acid, the reaction was carried out according to the method of Example 3, and 3- (2-
Hydroxyethyl) -5-methyl-2- (3-pyridyl) thiazolidin-4-one was obtained.

NMR (δ, CDCl ₃ ) [ppm]; 1.63 (1H, d, J = 6.8Hz), 1.6
6 (2H, d, J = 6.8Hz), 2.8 to 4.2 (6H, m), 5.83 (1H, s) IR (CHCl ₃ ) [cm ^-1 ]; 3400, 2940, 1670, 1593, 1580,
1450, 1360, 1070 Example 7 5-Butyl-3-methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. 7) Dry diisopropylamine (1 ml, 5.7 mmol) is added to dry tetrahydrofuran (3 ml), and butyl lithium hexane solution (3.9 ml, 6.2 mmol) is added dropwise at -40 ° C. After dropping 1
Keep warm at -10 ℃. A solution prepared by dissolving 3-methyl-2 (3-pyridyl) thiazolidin-4-one (1 g, 5.2 mmol) in dry tetrahydrofuran (7 ml) was added to the reaction solution -2.
Add dropwise at 0 to -10 ° C. Incubate at -20 to -10 ℃ for 1 hour,
1-Brombutane (0.78 g, 5.7 mmol) dissolved in tetrahydrofuran (2 ml) and sodium iodide (0.77 g)
g, 5.2 mmol) and hexamethylphosphoric triamide (1 m
l) is added at -10 ° C and kept at room temperature for 2 hours. P in the reaction solution
Add H7.0 phosphate buffer and extract with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (hexane-ethyl acetate) to give 5-butyl-3-methyl-2.
(3-Pyridyl) thiazolidin-4-one (250 g, 20
%) Was obtained.

NMR (CDCl ₃ ) δ [ppm]; 0.93 (3H, t, J = 7.0Hz), 1.2-
2.3 (6H, m), 2.74 (3H, m), 3.9 to 4.3 (1H, m), 5.4 to
5.5 (1H, m) IR (CHCl ₃ ) [cm ^-1 ]; 2925, 2855, 1670, 1590, 1578,
1390, 1303, 1020 Example 8 5,5,3-Trimethyl-2- (3-pyridyl)
Thiazolidin-4-one (Compound No. 8) Dry diisopropylamine (0.95 ml, 5.3 mmol) was added to dry tetrahydrofuran (3 ml), butyllithium hexane solution (3.6 ml, 5.8 mmol) was added dropwise at -40 ° C, and -10 ° C.
Keep it warm for 1 hour. 3,5-dimethyl-2 at -20 to -10 ℃
-(3-Pyridyl) -thiazolidin-4-one (1 g, 4.
A solution of 8 mmol) in dry tetrahydrofuran (7 ml) is added dropwise. Incubate at -20 to -10 ℃ for 1 hour, and add methyl iodide (0.75g, 5.3mmol) to dry tetrahydrofuran (2m
What was melt | dissolved in l) is added at -20 to -10 degreeC. The reaction solution is heated to 0 ° C. over 2 hours and kept warm for 2 hours. In the reaction solution
Add phosphate buffer of pH 7.0 and extract with ethyl acetate. The organic filter is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by medium pressure chromatography (hexane-acetone) and crystallized from ether-hexane (1: 1) to give 5,5,3-trimethyl-2- (3-pyridyl) thiazolidin-4-one. (0.42 g, 39%) was obtained.

NMR (CDCl ₃ ) δ [ppm]; 1.62 (3H, s), 1.68 (3H, s),
2.74 (3H, s), 5.51 (1H, s) IR (nujol) [cm ^-1 ]; 1668, 1590, 1390, 1310, 1135,
1071, 1021 Example 9 5,5-di (cyclohexylmethyl) -3-methyl-2- (3-pyridyl) thiazolidine-4- (Compound No. 8) Diisopropylamine (2.76 ml, 15.8 mmol) was added to dry tetrahydrofuran (9 ml), n-butyllithium hexane solution (10.6 ml, 16.2 mmol) was added dropwise at -20 to -30 ° C, and at -20 to -30 ° C for 1 hour. Kept warm. 3-methyl-2-
(3-Pyridyl) thiazolidin-4-one (3g, 15.4mm
ol) dissolved in dry tetrahydrofuran at -78 ° C
Was added dropwise and kept at the same temperature for 1 hour. Sodium iodide (2.31 g, 15.4 mmol) of bromomethylcyclohexane (3.01 g, 17.0 mmol) was added at -78 ° C and the temperature was raised to room temperature.
I left it overnight. Brine was added to the reaction solution, which was extracted with ethyl acetate, washed with brine and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 5,5-di (cyclohexylmethyl) -3-methyl-2- (3-pyridyl) thiazolidin-4-one (250 mg, 4.2%).

IR (CHCl ₃₎ [cm ^-1]; 2920,1675,1640,1390 Example 10 3-ethoxycarbonyl-5-methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No.9,10 ) 5-methyl-2- (3-pyridyl) thiazolidine-4-
On (10 g, 51.5 mmol) and brom ethyl acetate (6.85 ml, 6
1.8 mmol) is dissolved in dry dimethylformamide (50 ml) and 60% sodium hydride (2.16 g, 54.1 mmol) is added to 0-1.
A small amount was added at 0 ° C. The mixture was kept warm for 1 hour, brine was added to the reaction solution, extracted with ethyl acetate and washed with brine. After drying, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give cis form (5.8 g) (Compound No. 9) and trans form (2.1
g) (Compound No. 10) (yield, 55%) was obtained.

(Compound No. 9) cis-NMR (CDCl ₃ , δ) [ppm]; 1.24 (3H, t, J = 7.2Hz), 1.6
7 (3H, d, J = 7.1Hz), 5.81 (1H, s) IR (CHCl ₃ ) [cm ^-1 ]; 2950, 1740, 1683, 1587, 1575,
1441, 1370, 1014 (Compound No. 10) Trans NMR (CDCl ₃ , δ) [ppm]; 1.25 (3H, t, J = 7.2Hz), 1.6
8 (3H, d, J = 7.1Hz), 5.83 (1H, d, J = 1.7Hz) IR (CHCl ₃ ) [cm ^-1 ]; 2950, 1739, 1685, 1585, 1572,
1370, 1345, 1012 Example 11 3- (2-chloroethyl) -5-methyl-2
-(3-Pyridyl) thiazolidin-4-one (Compound N
o.11, 12) 3- (2-hydroxyethyl) -5-methyl-2- (3
-Pyridyl) thiazolidin-4-one (18.75g, 78.7mm
ol) is dissolved in methylene chloride (200 ml) and pyridine (9.5
5 ml, 118 mmol) was added and thionyl chloride (20 ml,
(274 mmol) was added dropwise at 0 to 5 ° C over 2 hours and kept warm for 5 hours. The reaction solution was washed with sodium bicarbonate water and brine, dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography and crystallized from hexane-ether to give 2,5-cis-3- (2
-Chloroethyl) -5-methyl-2- (3-pyridyl)
Thiazolidin-4-one (7.11g) and 2,5-trans-3
-(Chloroethyl) -5-methyl-2- (3-pyridyl) -thiazolidin-4-one (3.11g) was obtained. (Yield 51%) (Compound No. 12) cis body Melting point 76 to 77 ° C (Compound No. 11) Trans body Melting point 112.5 to 113.5 ° C Example 12 3- (2-methoxyethyl) -5-methyl-
2- (3-pyridyl) thiazolidin-4-one (compound
No.13) 3- (2-hydroxyethyl) -5-methyl-2- (3
-Pyridyl) thiazolidin-4-one (1 g, 4.2 mmol)
Was dissolved in dry dimethylformamide (5 ml), methyl iodide (0.72 g, 5.0 mmol) was added, and 40% sodium hydride (176 mg, 4.4 mmol) was added little by little under ice-cooling, and then kept warm with ice-cooling for 1 hour. To do. The reaction solution is poured into brine and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by medium pressure chromatography (hexane-acetone) to give 3- (2-methoxyethyl) -5-methyl-2- (3-pyridyl) thiazolidin-4-one (0.51 g, 48%).

NMR (CDCl ₃ ) δ [ppm]; 1.62 (0.75H, d, J = 7.1Hz), 1.
66 (2.5H, d, J = 7.1Hz), 3.28 (2.25H, s) 3.3 (0.75H,
s), 5.85 (1H, s) IR (CHCl ₃ ) [cm ^-1 ]; 2935, 1670, 1589, 1576, 1445,
1408, 1300, 1113 Example 13 3- (2-acetoxyethyl) -5-methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. 14) 3- (2-hydroxyethyl) -5-methyl-2- (3
-Pyridyl) thiazolidin-4-one (0.5g, 2.1mmo
l) is dissolved in acetic anhydride (2 ml) and pyridine (0.5 m
l) is added, and the mixture is kept warm for 2 hours under ice cooling. The reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure chromatography (hexane-acetone) to give 3- (2-acetoxyethyl) -5-methyl-2- (3-pyridyl) thiazolidin-4-one (0.45
g, 77%).

NMR (CDCl ₃ ) δ [ppm]; 1.62 (1H, d, J = 7.1Hz), 1.66
(2H, d, J = 7.1Hz), 2.06 (3H, s), 5.74 (1H, s) IR (CHCl ₃ ) [cm ^-1 ]; 2960, 1740, 1693, 1590, 1579,
1350, 1020 Example 14 3-t-Butyloxycarbonylmethyl-5
-Methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. 15, 16) 5-methyl-2- (3-pyridyl) thiazolidine-4-
On, t-butyl bromoacetate and sodium hydride were used to carry out a reaction according to the method of Example 10 to obtain trans-form (Compound No. 15) and cis-form (Compound No. 16) of 3-t-butyloxy. Carbonylmethyl-5-methyl-2- (3-pyridyl) thiazolidin-4-one was obtained.

(Compound No. 15) Trans-body melting point 132-133 ° C IR (nujol) [cm ^-1 ]; 1738, 1690, 1679, 1572, 1260,
1164 (Compound No. 16) cis body Melting point 108 to 108.5 ° C IR (nujol) [cm ^-1 ]; 1738, 1681, 1694, 1591, 1575,
1247, 1170 Example 15 3- (2-Acetylthioethyl) -5-methyl-2- (3-pyridyl) thiazolidin-4-one (Compound No. 17, 18) 2,5-trans-3- (2-chloroethyl) -5-methyl-2- (3-pyridyl) thiazolidin-4-one (1
g, 3.9 mmol) was dissolved in dimethylformamide (5 ml), potassium thioacetate (0.53 g, 4.7 mmol) was added, and the mixture was stirred under ice cooling for 1 hr. After the reaction, sodium bicarbonate water was added, the mixture was extracted with ethyl acetate, washed with brine and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography, 2,5-trans-3- (2-acetylthioethyl). -5-methyl-2-
(3-Pyridyl) thiazolidin-4-one (0.85 g, 78
%) Was obtained.

The cis form was obtained in the same manner.

(Compound No. 17) Trans form Melting point 60 to 62 ° C. (Compound No. 18) Cis form Melting point 55 to 56.5 ° C. Example 16 5- (n-nonyl) -2- (3-pyridyl)
Thiazolidine-4-one (Compound No. 19) 2-Mercaptoundecanoic acid (20 g, 91.6 mmol), nicotinaldehyde (8.64 ml, 9.16 mmol) and ammonium carbonate (3.3 g, 3.43 mmol) were added to benzene (300 ml), azeotropically dehydrated for 2 hours, cooled, and cooled to 30- Ammonium carbonate (3.3 g, 34.3 mmol) was added at 40 ° C. for azeotropic dehydration. The solvent was evaporated under reduced pressure, the residue was purified by silica gel chromatography, and crystallized from ether-hexane to give 5- (n-nonyl) -2-.
(3-Pyridyl) thiazolidin-4-one (16.7g, 59
%) Was obtained.

Melting point 90-95 ° C Example 17 3- (2-hydroxyethyl) -5- (n-
Nonyl) -2- (3-pyridyl) thiazolidin-4-one (Compound No. 20) 2-Mercaptoundecanoic acid (7 g, 32.1 mmol), nicotinaldehyde (3.03 ml, 32.1 mmol) and ethanolamine (1.93 ml, 32.1 mmol) were added to toluene (100 ml) and azeotropically dehydrated for 1 hour. After cooling, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography, and 3- (2-hydroxyethyl) -5- (n-nonyl) -2- (3-pyridyl) thiazolidin-4-one ( 8.17g, 73%) was obtained.

NMR (CDCl ₃ , δ) [ppm]; 0.85-0.9 (3H, m), 2.9-3.
01 (1H, m), 3.65 ~ 3.80 (3H, m), 3.97 ~ 4.01 (0.7 ~
H, m), 4.02 to 4.07 (0.3H, m), 5.78 (0.3H, d, J = 2.0H
z), 5.80 (0.7H, s) Example 18 3- (2-chloroethyl) -5- (n-nonyl) -2- (3-pyridyl) thiazolidin-4-one (Compound No. 21,22) 3- (2-hydroxyethyl) -5- (n-nonyl)-
2- (3-pyridyl) thiazolidin-4-one (3.49
g, 10 mmol) and carbon tetrachloride (20 ml) at room temperature with stirring, triphenylphosphine (3.44 g, 13 mmol) was added, and then the mixture was stirred under reflux for 2.5 hr.

After cooling, the precipitated crystals are separated by filtration, the filtrate is concentrated, and then purified by chromatography to obtain the desired 3- (2-chloroethyl)
-5- (n-nonyl) -2- (3-pyridyl) thiazolidin-4-one cis form (0.55 g), trans form (1.46)
g) and their mixtures (0.94g) (total, 2.95g, 80
%) Was obtained.

Cis form (Compound No. 21): IR (CHCl ₃ ) [cm ^-1 ]; 2915, 28
50, 1675, 1590, 1580, 1350 NMR (δ, CDCl ₃ , ppm); 2.99 (1H, ddd, J = 14.52,7.92and
5.28Hz), 3.49 (1H, dt, J = 1.55and5.28Hz), 3.72 (1
H, ddd, J = 1.55,7.92and5.28Hz), 3.95 (1H, dt, J = 14.
52and5.28Hz), 4.01 (1H, dd, J = 9.90and2.97Hz), 5.8
6 (1H, s) trans form (Compound No. 22): IR (CHCl ₃ ) [cm ⁻¹ ]; 2920, 2850, 1678, 1590, 1580,
1355 NMR (δ, CDCl ₃ , ppm); 2.97 (1H, ddd, J = 14.52,8.24and
4.95Hz), 3.51 (1H, ddd, J = 11.54,5.28and4.95Hz),
3.74 (1H, ddd, 11.54,8.24and4.95Hz), 3.98 (1H, ddd, J
= 9.90,3.63and1.64Hz), 5.85 (1H, d, J = 1.64Hz) Example 19 3- (2-Dimethylaminoethyl) -5-
(N-nonyl) -2- (3-pyridyl) thiazolidine-
4-one (Compound No.23) 2-Mercaptoundecanoic acid (2 g, 9.16 mmol) N-nicotinylidene-N ', N'-dimethylethylenediamine (1.
62 g (9.16 mmol) was dissolved in toluene (50 ml) and azeotropically dehydrated for 2 hours. The solvent was evaporated under reduced pressure, the residue was purified by column chromatography, and 3- (2-dimethylaminoethyl) was used.
-5- (n-nonyl) -2- (3-pyridine) thiazolidin-4-one (3.1 g, 90%) was obtained.

IR (CHCl ₃₎ [cm ^-1]; 2850,1660,1577,1408 Example 20 3- (2-dimethylaminoethyl) -5-
(N-nonyl) -2- (3-pyridyl) thiazolidine-
4-one (Compound No.23) 2-Mercaptoundecanoic acid (5.0 g, 22.9 mmol), pyridine-3-aldehyde (2.16 mmol, 22.9 mmol) and N-dimethylaminoethylamine (2.51 ml, 22.9 mmol) were dissolved in toluene (100 ml) and azeotropically distilled for 2 hours. Dehydrated. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to give 3
-(2-Dimethylaminoethyl) -5- (n-nonyl)
-2- (3-pyridyl) thiazolidin-4-one (7.9
g, 91%).

IR (CHCl ₃₎ [cm ^-1]; 2850,1660,1577,1408 Example 21 5-Ethyl-3- (2-dimethylaminoethyl) -2- (3-pyridyl) thiazolidin-4-one (Compound No .twenty four) Diisopropylamine (1.42 ml, 7.96 mmol) was dissolved in dry tetrahydrofuran, an n-butyllithium hexane solution (5 ml, 8 mmol) was added dropwise at -30 to -40 ° C, and the mixture was kept warm for 1 hour. After cooling to -78 ° C, a solution of 3- (2-dimethylaminoethyl) -2- (3-pyridyl) thiazolidin-4-one (2g, 7.96mmol) in dry tetrahydrofuran (10ml) was added dropwise. I kept it warm for an hour. Post-ethyl iodide (1.24 g, 7.96 mmol) was added, and the temperature was slowly raised to room temperature and the temperature was kept for 30 minutes. Brine was added to the reaction mixture, which was extracted with ethyl acetate, washed with brine and dried. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography to give 5- (ethyl) -3.
-(2-Dimethylaminoethyl) -2- (3-pyridyl) thiazolidin-4-one (1.84 g, 83%) was obtained.

NMR (CDCl, δ) [ppm]; 1.06 (3H, t, J = 7.3Hz), 2.15
(6H, s), 3.75 to 3.85 (1H, m), 4,00 to 4.05 (1H, m),
5.86 (1H, d, J = 2.0Hz) Example 22 5,5-Dimethyl-3- (2-dimethylaminoethyl) -2- (3-pyridyl) thiazolidin-4-one (Compound No. 25) Diisopropylamine (2.84 ml, 15.9 mmol) was dissolved in 6 ml of dry tetrahydrofuran, an n-butyllithium hexane solution (10 ml, 16 mmol) was added dropwise at -20 to -30 ° C, and the mixture was kept warm for 1 hour. Cool to −78 ° C., 3- (2-dimethylaminoethyl) -2- (3-pyridyl) thiazolidine-4-
A solution of ON (2 g, 7.96 mmol) dissolved in 10 ml of dry tetrahydrofuran was added dropwise, and the mixture was kept warm for 1 hour. Methyl iodide (2.26 g, 15.9 mmol) was added, and the mixture was slowly allowed to warm to room temperature and allowed to stand overnight. Brine was added to the reaction mixture, which was extracted with ethyl acetate, washed with brine and dried. The solvent was evaporated under reduced pressure, the residue was purified by column chromatography, and 5,5- (dimethyl) -3- (2-dimethylaminoethyl) -2- (3-
Pyridyl) thiazolidin-4-one (257 mg, 12%) was obtained.

Melting point 67-70 ° C Example 23 3- (2-Dimethylaminoethyl) -5-
(N-nonyl) -2- (3-pyridyl) thiazolidine-
4-one (Compound No.23) 5- (n-Ninor) -2- (3-pyridyl) thiazolidin-4-one (1 g, 3.26 mmol) was dissolved in dry dimethylformamide (10 ml) and potassium carbonate (0.9 g, 6.52 mmo).
l) and 2-dimethylaminoethyl chloride hydrochloride (0.4
7 g, 3.26 mmol) was added and the mixture was kept at 50 ° C. for 10 hours. Brine was added to the reaction solution, which was extracted with ethyl acetate, washed with brine, dried and the solvent was distilled off under reduced pressure. The residue is purified by silica gel chromatography, 3- (2-dirotylaminoethyl) -5-
(N-nonyl) -2- (3-pyridyl) thiazolidine-
4-one (0.41 g, 33%) was obtained.

^{_{IR (CHCl 3) cm -1;}} 2850,1660,1578,1407 Example 24 3- (2-acetylamino-ethyl) -2-
(3-pyridyl) -5- (n-nonyl) thiazolidine-
4-one (Compound No. 26) 3- (2-aminoethyl) -5- (n-nonyl) -2-
(3-Pyridyl) thiazolidin-4-one (0.50 g, 1.4
Acetic anhydride (0.2 g) was added dropwise to a 3 mmol) solution of pyridine (2 ml) under ice-cooling, and the mixture was left overnight at room temperature.

Saturated aqueous sodium hydrogen carbonate (30 ml) was added to the solution, followed by extraction with benzene. The extract was dried and the solvent was evaporated under reduced pressure to give the desired 3- (2-acetylaminoethyl) -5.
-(N-Nonyl) -2- (3-pyridyl) thiazolidin-4-one (0.52g, 92%) was obtained as an oil.

IR (CHCl ₃ ) [cm ^-1 ]; 3430, 2920, 2850, 1665, 1590,
1580, 1365 NMR (δ, CDCl ₃ , ppm); 1.95 (3H, s), 3.93 (0.45H, dd,
990and3.63Hz), 4.03 (0.55H, ddd, 9.24,3.63and1.65H
z), 5.75 (0.55H, d, 1.65Hz), 5.76 (0.45H, s), 6.06
~ 6.11 (1H, m) Example 25 3- (2-Dimethylaminoethyl) -5-
(N-nonyl) -2- (3-pyridyl) thiazolidine-
4-one (trans form) (Compound No. 27) 3- (2-chloroethyl) -5- (n-ninor) -2-
(3-Pyridyl) thiazolidin-4-one trans form (128 mg, 0.35 mmol) in dimethyl sulfoxide (3 ml) solution was added to 50% dimethylamine aqueous solution (1.0 ml, 11 mmol).
After adding, the mixture was heated in a sealed tube at 100 ° C. for 2 hours. After distilling off the solvent under reduced pressure, chloroform (30 ml) was added to the residue, washed twice with saturated aqueous sodium hydrogen carbonate, then dried, and chloroform was distilled off to give the desired 3- (2-dimethylaminoethyl). Trans form of -5- (n-nonyl) -2- (3-pyridyl) thiazolidin-4-one (131 mg, quantitative)
Was obtained as an oil.

IR (CHCl₃)〔cm^-1]; 2930, 2860, 1670, 1580, 1355 NMR (δ, CDCl₃, ppm); 2.15 (6H, s), 2.24 (1H, dt, 12.
87and5.61Hz), 2.46 (1H, ddd, 12.87,7.20and5.94H
z), 2.69 (1H, ddd, 14.19,7.20and5.61Hz), 3.80 (1H,
ddd, 14.19,5.94and5.61Hz), 4.03 (1H, ddd, 8.58,3.96a
nd1.98Hz), 5.86 (1H, d, 1.98Hz) Example 26 Separation and purification of trans isomer and cis isomer 3- (2-dimethylaminoethyl) -5 obtained in Example 2
-(N-nonyl) -2- (3-pyridyl) thiazolidine
-4-g of 7.9 g is converted into medium pressure liquid chromatograph (column size).
40 mm x 500 mm, carrier silica gel-60 Merck developing solvent
Hexane: Ethanol: Ann water = 3000: 300: 50)
Separated, 3- (2-dimethylaminoethyl) -5- (n-
Nonyl) -2- (3-pyridyl) thiazolidine-4-o
Trans form 1.42g and cis form 3.42g and cis, trans
2.77 g of a mixture was obtained.

Trans isomer (Compound No. 27) IR (CHCl ₃ ) [cm ^-1 ]; 2930, 2860, 1670, 1580, 1355 NMR (δ, CDCl ₃ , ppm); 2.15 (6H, s), 40-40.6 (1H , m) 5.86 (1H, d, J = 2.0H
z) cis-form (Compound No. 28) IR (CHCl ₃ ) [cm ⁻¹ ]; 2930, 2860, 1670, 1590, 1360 NMR (δ, CDCl ₃ , ppm); 2.13 (6H, s), 3.97 (1H , dd, J = 3.7and9.8Hz), 5.84
(1H, s) 5% Hydrochloric acid-isopropyl alcohol (5 g, 7 mmol) was added to the obtained trans form (1 g, 2.65 mmol), and the mixture was stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and ethanol: hexane =
It was recrystallized from 1: 3 (5 ml) to give the trans hydrochloride (compound N
o.173) (1.02g, 85%).

Melting point 175.5-178 ° C IR (KBr) cm ^-1 ; 2920, 2850, 2660, 1670, 1460.

Example 27 3-Dimethylaminoethyl-5- (3-hydroxyproth
Pill) -2- (3-pyridyl) thiazolidin-4-one
(Compound No.129)3-dimethylaminoethyl-5- (3-tert-butyldi
Methylsilyloxypropyl) -2- (3-pyridyl)
Thiazolidin-4-one 2.6 g (6.02 mmol) was added to dry tetra
Dissolve in 12 ml of hydrofuran and cool with ice
15 ml of a 1M solution of lumonium in tetrahydrofuran was added dropwise.
It was After the dropping, the temperature was returned to room temperature and the mixture was stirred for 2 hours. After the reaction,
Add 10 ml of saturated aqueous sodium hydrogen carbonate, and extract the sodium hydrogen carbonate with ethyl acetate 6 times.
I put it out. After drying the extract over magnesium sulfate, reduce the solvent.
The crude product thus obtained is removed by pressure distillation, and the resulting crude product is subjected to a row bar column (support medium).
Luk Si-60 Art.9385 Developing solvent Hexane: Ethan
: Ammonia water = 3000: 400: 50)
Cylaminoethyl-5- (3-hydroxypropyl)-
1.7 g of 2- (3-pyridyl) thiazolidin-4-one
88%).

IR (CHCl ₃ ) cm ^-1 ; 3400 (br), 1670, 1595, 1580, 1360 ¹ HNMR (CDCl ₃ ) δppm; 2.16 (6H, s), 4.10-4.15 (1H, m) 5.86 (1H, d, J = 2H
z) Example 28 The following compounds were synthesized according to the methods of Examples 1-26.

However, trans having a steric configuration is a thiazolidin-4-one ring having a trans configuration at the 2- and 5-positions, cis is a compound having the cis-positions at the 2- and 5-positions, and m is a mixture of trans and cis. Represents

Example 29 (+)-cis-3,5-dimethyl-2- (3-pyridyl)-
Thiazolidine-4-one (Compound No. 178) (-)-2-Mercaptopropionic acid (3.86g, 0.036mo
le) in tetrahydrofuran (40 ml) with stirring under ice-cooling under a nitrogen stream, N-nicotinylidenemethylamine (4.37 g, 0.036 mole) in tetrahydrofuran (20 m
l) The solution was added dropwise. The reaction was continued for 12 hours.

Next, ethyl acetate (50 ml) was added to the reaction mixture, and the resulting solution was washed successively with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml) and brine, the organic phase was dried, and the solvent was evaporated under reduced pressure. Thus, a crude product (6.97 g) was obtained as crystals. This product was washed with ether (10 ml) at 0 to 5 ° C and washed with ether (10 ml).
ml) at −10 ° C. to recrystallize (+)-cis
-3,5-Dimethyl-2- (3-pyridyl) -thiazolidin-4-one (3.77 g, yield 50%) was obtained.

mp.66.5 to 68.5 ° C ▲ [α] ²⁶ _D ▼ = + 20.5 ° (C0.44, CHCl ₃ ) Example 30 (-)-cis-3,5-dimethyl-2- (3-pyridyl)-
Thiazolidine-4-one (Compound No. 179) (+)-2-mercaptopropionic acid (3.19g, 0.030mo
le) and N-nicotinylidenemethylamine (3.61 g,
0.030 mole), and in a manner similar to that shown in Example 29, (−)-cis-3,5-dimethyl-2- (3-pyridyl) -thiazolidin-4-one (3.24 g, yield). 52%).

mp.66.0 to 68.5 ° C. [α] ²⁵ _D ▼ = −21.3 ° (C3.28, CHCl ₃ ) Example 31 (−)-trans-3,5-dimethyl-2- (3-pyridyl)
-Thiazolidin-4-one (Compound No. 180) (-)-2-Mercaptopropionic acid (0.53g, 5.0mmo
Titanium tetraisopropoxide (1.42 g, 5.0 mmol) was added to a solution of l) in dichloromethane (5 ml) under a nitrogen stream while stirring at room temperature. Then, while stirring at room temperature, N-nicotinylidenemethylamine (0.60 g,
5.0 mmol) dichloromethane (2 ml) solution was added dropwise. The reaction was continued for 5 hours. Then add water to the reaction mixture,
The mixture was filtered through Celite using dichloromethane (20 ml) as a washing solution, the obtained organic phase was washed with water (10 ml) and brine successively, dried and the solvent was distilled off under reduced pressure to obtain a crude product (0.44).
g) was obtained. This product was purified by silica gel flash column chromatography (hexane-2-propanol = 4:
Purification was carried out in 1), and (-)-trans-3,5-dimethyl-2
-(3-Pyridyl) -thiazolidin-4-one (54 mg)
Was obtained as an oil.

▲ n ²⁷ _D ▼ = 1.6043 ▲ [α] ²⁵ _D ▼ ＝ -132.5 ° (C0.28, CHCl ₃ ) Example 32 (+)-trans-3,5-dimethyl-2- (3-pyridyl)
-Thiazolidin-4-one (Compound No.181) (+)-2-Mercaptopropionic acid (0.53g, 5.0mmo
l), titanium tetraisopropoxide (1.42g, 5.0m
mol) and N-nicotinylidenemethylamine (0.60 g,
5.0 mmol) to give (-)-trans-3,5-dimethyl-2- (3-pyridyl) -thiazolidin-4-one (49 mg) as an oil by a method similar to that shown in Example 31. Got as.

▲ n ²⁶ _D ▼ ＝ 1.6039 ▲ [α] ²⁵ _D ▼ ＝ ＋ 130.8 ° (C0.34, CHCl ₃ ) Example 33 3,5-Dimethyl-2- (3-pyridyl) thiazolidine-
4-one hydrochloride (Compound No. 182) 10 g (0.048 mol) of cis-3,5-dimethyl-2 (3-pyridyl) thiazolidin-4-one obtained in Example 2 was dissolved in 50 ml of ethanol and concentrated. Hydrochloric acid water 4.75 g (0.0456 mol)
Was added dropwise at room temperature and then cooled to 0 ° C., and the precipitated crystals were collected by filtration to give 9.621 g of 3,5-dimethyl-2- (3-pyridyl) thiazolidin-4-one hydrochloride (yield 86.2%). Got with.

Melting point 190-193 ° C Example 34 3,5-Dimethyl-2- (3-pyridyl) thiazolidine-
4-one 1/2 fumarate (Compound No. 183) Obtained in Example 2, cis-3,5-dimethyl-2 (3-
20 g (0.096 mol) of pyridyl) thiazolidin-4-one and 5.58 g (0.048 mol) of fumaric acid are dissolved in 100 ml of ethanol and stirred at room temperature for 1 hour. After that, ethanol was distilled off under reduced pressure, ethyl acetate was added to the residue for crystallization, and 15.88 g (yield 62%) of 3,5-dimethyl-2 (3-pyridyl) thiazolidin-4-one 1/2 fumar The acid salt was obtained.

Melting point 140-143 ℃

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shigeaki Morooka 3-1,98 Kasugade, Konohana-ku, Osaka City, Osaka Prefecture Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Shunji Aono, Kasuga, Konohana-ku, Osaka City, Osaka Prefecture 3-1-198 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Minoru Minoru 4-2-1 Takashi, Takarazuka-shi, Hyogo Prefecture Sumitomo Kagaku Kogyo Co., Ltd. (72) Inventor Rihito Takashi, Takazuka-shi, Hyogo 4-2-1 Sumitomo Kagaku Kogyo Co., Ltd. (72) Inventor Yo Tanabe 2-10-1 Tsukahara, Takatsuki-shi, Osaka Sumitomo Kagaku Kogyo Co., Ltd.

Claims (3)

[Claims] 1. A formula The compound represented by or an acid addition salt thereof. 2. The compound according to claim 1, which is (+)-cis-3,5-dimethyl-2- (3-pyridyl) -thiazolidin-4-one, or an acid addition salt thereof. 3. An anti-PAF (platelet activating factor) agent containing the compound according to claim 1 or 2 or an acid addition salt thereof as an active ingredient.