JPH0725754B2 - Novel thiazole compound or salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] [In the formula, R ¹ , R ² and R ³ are the same or different and are a hydrogen atom, a halogen atom, a formyl group, an optionally esterified carboxyl group or an optionally substituted alkyl, alkenyl, alkynyl, aryl or A cycloalkyl group or a formula CH _{2 n} R ⁴ (wherein, R ⁴ represents an imidazolyl group or a 1,2,4-triazolyl group, and the imidazolyl group and the 1,2,4-triazolyl group represent a nitrogen atom in the ring; And n is 0 or 1.).
However, ^one of R ¹ , R ² and R ³ is of the formula CH _{2 n} R ⁴ (wherein R ⁴ and n have the same meanings as described above). ] The novel thiazole compound represented by these, or its salt.

Therefore, an object of the present invention is to provide a novel thiazole compound or a salt thereof which has not only excellent antifungal activity but also antibacterial activity and exhibits an excellent therapeutic effect against human and animal diseases. Especially.

[Prior Art] Currently, amphotericin B is used as a therapeutic agent for deep-seated mycosis.
(U.S. Pat. No. 2,908,611) is mainly used. In addition, as a therapeutic drug for superficial mycosis, 1- [2- (2,4
-Dichlorophenyl) -2- (p-chlorobenzyloxy) ethyl] -1H-imidazole (generic name: econazole, US Pat. No. 3,717,655) and 1-[(2-chlorofinyl) diphenylmethyl] -1H-imidazole (generic name) : Clotrimazole, US Pat. No. 3,655,899) and the like are known.

Recently, cis-1-acetyl-4- [4-[[2 (2,4-
Dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] finyl] piperazine (generic name: ketoconazole,
U.S. Pat. No. 4,358,449) and 2- (2,4-difluorophenyl) -1,3-bis- (1H-1,2,4-triazole-1.
-Yl) propan-2-ol (generic name: fluconazole, U.S. Pat. No. 4,404,216) and the like are reported to be useful as therapeutic agents for fungal diseases.

[Problems to be Solved by the Invention] However, these are still not sufficient in terms of antifungal activity (MIC; μg / ml), pharmacokinetics, toxicity, etc. Was wanted.

[Means for Solving the Problems] Under these circumstances, the present inventors have conducted diligent research and as a result, found that the novel thiazole compound represented by the general formula (I) or a salt thereof is not only fungi but also bacteria. They have found that they are extremely useful as therapeutic agents for infectious diseases, and have completed the present invention.

Hereinafter, the compound of the present invention will be described in detail.

In R ^{1 to} R ³ , a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like; an optionally esterified carboxyl group is a commonly known ester-forming group, for example, methyl. , Ethyl, n-propyl,
n- butyl, C ₁ ~ ₄ alkyl group or a protected or unprotected carboxyl group in aralkyl groups such as benzyl, such as isobutyl; and the alkyl group, e.g., methyl,
Ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, heptyl, a C ₁ ~ ₁₀ alkyl group such as octyl, and alkenyl groups such as vinyl, allyl, the alkynyl group, for example, ethynyl, C ₂ ~ ₆ alkynyl groups such as 2-propynyl; 1-propenyl, isopropenyl, 1-butenyl, the C ₂ ~ ₆ alkenyl groups such as 2-butenyl and the aryl group , for example, Finiru, based on the naphthyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, means C ₃ ~ ₆ cycloalkyl cyclohexyl, alkyl of R ¹ to R ^3, alkenyl, alkynyl, The aryl or cycloalkyl group is a halogen atom, for example, a fluorine atom,
Chlorine atom, bromine atom, iodine atom, etc .; nitro group; cyano group; azido group; amino group; hydroxyl group; carboxyl group; sulfo group; alkyl group, for example, C ₁ mentioned above.
~ ₁₀ alkyl group; alkenyl group, for example, C ₂ described above.
~ ₆ alkenyl group; alkynyl group, for example, C as described above.
_2-6 alkynyl group; an alkyloxy group, for example, methoxy, C ₁ ~ ₄ alkyl group such as ethoxy; cycloalkyl groups such as a C ₃ ~ ₆ cycloalkyl group described above; alkanesulfonyl group, for example, methanesulfonyl , C ₁ ~ ₄ alkanesulfonyl group such as ethanesulfonyl; aryl groups such as phenyl, aryl groups such as naphthyl; a carbamoyl group; a sulfamoyl group; a nitrogen-containing heterocyclic group, for example, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolyl May be substituted with a nitrogen-containing heterocyclic group such as. Further, among the substituents of R ^{1 to} R ³ , the hydroxyl group, the carboxyl group, the amino group and the sulfo group may be protected by a commonly known protecting group.

The salt of the thiazole compound of the general formula [I] is a pharmaceutically acceptable salt, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid; acetic acid, fumaric acid,
Salts with maleic acid, malic acid, tartaric acid, citric acid, aspartic acid and other organic carboxylic acids; methanesulfonic acid,
Examples thereof include salts with sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid; salts with alkaline metals such as sodium and potassium.

The compound of the present invention further includes all isomers (geometrical isomers, optical isomers), hydrates and crystal forms.

The thiazole compound of the general formula [I] or a salt thereof can be produced by a method known per se, for example, the following method.

Manufacturing method 1 [In the formula, R ⁴ has the same meaning as described above, and R ⁵ , R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a halogen atom, an optionally esterified carboxyl group or a substituted group. Is an alkyl, aryl or cycloalkyl group or a formula CH _{2 n} Y (wherein Y is a halogen atom and n has the same meaning as described above). However, one of R ⁵ , R ⁶ and R ⁷ is of the formula CH _{2 n} Y (wherein Y and n have the same meanings as described above). R ⁸ , R ⁹ and R ¹⁰ are the same or different and each is a hydrogen atom, a halogen atom, an optionally esterified carboxyl group or an optionally substituted alkyl, aryl or cycloalkyl group or a formula CH _{2 n} R ⁴ ( In the formula, R ⁴ and n have the same meanings as described above.). However, one of R ⁸ , R ⁹ and R ¹⁰ has the formula − (CH ₂ )
_n −R ⁴ . ] Each group mentioned in R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is represented by R ¹ , R ²
And has the same meaning as described for R ³ . Examples of the halogen atom of Y include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the salt of the compound of the general formula [III] include salts with alkali metals such as sodium, potassium and lithium.

A compound of the general formula [II] in the presence or absence of a solvent,
A compound of the general formula [I] or a salt thereof can be obtained by adding a deoxidizing agent as necessary and reacting with the compound of the general formula [III] or a salt thereof. As the solvent used,
Any substance that does not adversely affect the reaction may be used, and examples thereof include alcohols such as methanol, ethanol, butanol, ethylene glycol and methyl cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; benzene, toluene, Hydrocarbons such as xylene and n-hexane; ethers such as diethyl ether, tetrahydrofuran and dioxane; ethyl acetate,
Examples include esters such as butyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; ketones such as acetone and methylethylketone; nitriles such as acetonitrile and water; You may use it in mixture of 2 or more types.

In this reaction, the amount of the compound of the general formula [III] or a salt thereof to be used is preferably 1 to 10-fold the molar amount of the compound of the general formula [II]. Examples of the deoxidizing agent include bases such as sodium hydroxide, potassium carbonate, sodium hydride, sodium methylate and triethylamine. As the compound of the general formula [III], a compound in which the N-position is acylated with acetyl, benzoyl, ethoxycarbonyl or the like, if necessary, can be used. This reaction may be carried out usually at 0 to 160 ° C. for 30 minutes to 20 hours.

It can also be manufactured by the following method.

Manufacturing method 2 [In the formula, one of R ^1a and R ^2a has the formula CH _{2 n} R ⁴ (in the formula, R ⁴
And n have the same meaning as described above. ), The other is a hydrogen atom or an optionally substituted alkyl, aryl or cycloalkyl group; X is a halogen atom;
Represents an alkali metal; R ¹¹ represents a formyl group or an optionally substituted alkyl or alkenyl group. ] Each group mentioned for R ^1a , R ^2a and R ¹¹ has the same meaning as described for R ¹ , R ² and R ³ . Examples of the halogen atom of X include a fluorine atom, chlorine atom, bromine atom and iodine atom, and examples of the alkali metal of M include lithium.

The compound of the general formula [IV] is reacted with a general organic metal-halogen exchange reaction in the presence or absence of a solvent, for example, an organic metal such as n-butyllithium to give a compound of the general formula [V]
The compound of the formula [Ia] or a salt thereof can be obtained by deriving the compound of the formula (Ia) and then reacting it with an aliphatic halogenated hydrocarbon or a carbonyl compound without isolation. The solvent used may be any solvent that does not adversely influence the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene and n-hexane; ethers such as diethyl ether, tetrahydrofuran and dioxane. These solvents may be used as a mixture of two or more kinds.

Examples of the aliphatic halogenated hydrocarbon or carbonyl compound used in this reaction include aliphatic halogenated hydrocarbons such as methyl iodide, ethyl iodide and allyl bromide; formaldehyde, acetaldehyde, n-butyraldehyde, benzaldehyde, Carbonyl compounds such as N, N-dimethylformamide can be mentioned. Usually, the amount of the aliphatic halogenated hydrocarbon or carbonyl compound used is preferably 1 to 5 times the mol of the compound of the general formula [IV]. This reaction is usually at -100 to 100 ° C for 30 minutes to 24 hours.
It should be carried out on time. In addition, although this reaction described the case where X couple | bonded with 5th-position, when X couple | bonds with 2nd-position or 4th-position, it can carry out similarly.

Manufacturing method 3 [Wherein one of R ^1b and R ^2b is of the formula CH _{2 n} R ⁴ (wherein R ⁴
And n have the same meaning as described above. And the other is a hydrogen atom, a halogen atom, an optionally esterified carboxyl group or an optionally substituted alkyl, alkenyl, alkynyl, aryl or cycloalkyl group; R ^3b is an optionally substituted alkenyl R is a hydrogen atom, an optionally substituted alkyl, alkenyl, alkynyl, aryl or cycloalkyl group; R ¹² , R ¹³ and R ¹⁴ are the same or different and may be substituted alkyl or aryl groups. R ¹⁵ and R ¹⁶ are the same or different and each is a hydrogen atom, a halogen atom, a cyano group, an alkyloxy group, an aryloxy group,
Alkyloxycarbonyl group, alkylcarbonyl group,
An arylcarbonyl group, a carbamoyl group or an optionally substituted alkyl, alkenyl, alkynyl, aryl or cycloalkyl group is shown. ] Each group mentioned for R ^1b , R ^2b , R ^3b , R, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ has the same meaning as described for R ¹ , R ² and R ^3. . The alkyl group of R ¹⁵ and R ^16, for example, methoxy, C ₁ ~ ₄ alkyl group such as ethoxy; aryloxy group, for example, aryloxy groups such as phenoxy; as alkyloxycarbonyl group , for example, C ₁ ~ ₄ alkyloxy group such as methoxy carbonyl; the alkyl group, e.g., C ₁ ~ ₄ alkyl group such as acetyl, the aryl group, for example, arylcarbonyl groups such as benzoyl Is mentioned.

The compound of the general formula [Ib] or a salt thereof can be obtained by reacting the compound of the general formula [VI] with the compound of the general formula [VII] in the presence or absence of a solvent. The solvent used may be any solvent that does not adversely influence the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, and n-hexane; ethers such as diethyl ether, tetrahydrofuran, dioxane; and acetonitrile. Nitriles; halogenated hydrocarbons such as methylene chloride; amides such as N, N-dimethylformamide;
Dimethyl sulfoxide; hexamethylphosphorotriamide, etc. may be mentioned, and these solvents may be used as a mixture of two or more kinds. The compound of the general formula [VII] can be used in the reaction system without being isolated. In this reaction, the amount of the compound of the general formula [VII] used is preferably 1- to 5-fold the molar amount of the compound of the general formula [VI]. This reaction may be carried out usually at -100 to 150 ° C for 10 minutes to 7 days.

This reaction has been described in the case where -COR binds to the 5-position, but it can be similarly performed when -COR binds to the 2-position or 4-position.

Furthermore, as the salt of the compound of the general formulas [Ia] and [Ib], the same salts as those described as the salt of the compound of the general formula [I] can be mentioned.

In addition, the compounds of the general formulas [I], [Ia] and [Ib] or salts thereof include, for example, halogenation, reduction, hydrolysis, acylation, cyclization and the like, which are commonly known methods, alone or in appropriate combination. By doing so, it can be guided to other objects.

The compound of the present invention thus obtained is isolated and collected by a usual method.

Next, the compounds of the general formulas [II], [III], [IV], [VI] and [VII] which are raw materials for producing the compound of the present invention are
tions, Vol. 6, pages 367-409 (1951), Heterocyclic Compounds,
It can be produced by a combination of the methods described in Volume 5, (1957) or methods known per se.

Specifically, for example, it can be indicated by the following route.

[In the formula, X has the same meaning as described above, R ¹⁷ represents a hydrogen atom, an optionally esterified carboxyl group or an optionally substituted alkyl, alkenyl, aryl or cycloalkyl group; ¹⁸ is an optionally esterified carboxyl group or an optionally substituted alkyl, aryl or cycloalkyl group or a formula CH _{2 n} Y (wherein Y and n have the same meanings as described above). R ^18a represents a hydrogen atom or a group and a formula similar to R ¹⁸ ; R ¹⁹ represents a hydrogen atom, an amino group or an optionally substituted alkyl, aryl or cycloalkyl group; and R ²⁰ represents a carbonyl protecting group. . ] Each group mentioned in R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ is represented by R ¹ , R ² and
It has the same meaning as described for R ³ . The carbonyl protecting group for R ²⁰ includes a usual carbonyl protecting group, for example,
Methyl, ethyl, n- propyl, C ₁ ~ ₄ alkyl group such as n- butyl.

Then, the compound of the general formula [XI] is used, for example, for the production of another compound of the present invention by appropriately combining generally known methods such as halogenation, reduction, hydrolysis, acylation and cyclization with each other. It can also be derived to a raw material compound.

[Effect of the Invention] The compound [I] of the present invention and a pharmaceutically acceptable salt thereof are
It is useful as a therapeutic agent for human and animal fungal and bacterial infections.

Next, typical examples of the compound [I] of the present invention are shown to have antifungal activity and antibacterial activity. The symbols used in the test compounds have the following meanings.

n-Pr: n-propyl, iso-Pr: isopropyl, n-Bu: n-butyl (1) Measurement of minimum inhibitory concentration (MIC) of drug against fungus Chemotherapy (Chemotherapy) Vol. 32, No. 9, 568
~ 584 (1984), according to Candida albicans (C
andida albicans), Candida tropicalis (Candida
tropicalis) and Torlopsis glabrata (Tor
ulopsis glabrata), Sabouraud dextrose broth; glucose
20g, peptone 10g / l), shaking culture at 37 ℃ for 24 hours; Aspergillus fumigatu
s), Sporothrix sche
nckii), Fonsecaea pedroso
i), Cladosporium helbarm
rbarum) and Tricophyton rubrum (Tricophy
ton rubrum), which is a matured potato dextrose agar (Potato d
extrose agar medium (manufactured by Nissui Pharmaceutical Co., Ltd.) (however, for Aspergillus fumigatus, Czapek dox agar medium (manufactured by Nissui Pharmaceutical Co., Ltd.) was used. ], The surface of the slope is rubbed after 10 days, and conidia are released into sterile physiological saline containing 0.1% (w / v) Tween 80 (Tween80). The resulting conidial suspension was treated with Sabouraud agar (Sabouraud) containing the drug.
dextroseagar) medium (pH 6) at 30 ° C. for 3 days for Candida albicans, Candida tropicalis and Torulopsis glabrata, 3 days for Aspergillus fumigatus, Sporothrix schenky,
Fonseca pedrosoy, Cladosporium herbalum, and Trichophyton rubrum were cultured for 7 days, and then the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μg / ml). However, the inoculum size was 10 ² cells / plate (10 ⁴ cells / ml).
The results are shown in Table-1.

(2) Measurement of the minimum inhibitory concentration (MIC) of a drug against bacteria The Japanese Society of Chemotherapy Standard Method [Chemotherap (Chemotherap
y) Vol. 29, No. 1, pp. 76-79 (1981)], according to Staphylococcus aureu
s), Staphylococcus epidermides (Staphyloc
occus epidermidis), Streptococcus faecalis, and brain heart
Infusion bros [Brain heart infusion bro
th (manufactured by Eiken Chemical Co., Ltd.)] at 37 ° C. for 24 hours, and the bacterial solution is mixed with a drug containing Mueller Hinton agar (Mueller-Hint
onagar) medium (manufactured by Eiken Chemical Co., Ltd.) and cultured at 37 ° C for 20 hours, and then the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μg / ml). . However, the inoculum size was 10 ⁴ cells / plate (10 ⁶ cells / ml).
The results are shown in Table-2.

EXAMPLES Next, the present invention will be described with reference to Reference Examples and Examples. The symbols used in Reference Examples and Examples have the following meanings. Me: methyl, Et: ethyl, n-Pr: n-
Propyl, iso-Pr: iso-propyl, n-Bu: n-butyl The column chromatography carrier is silica gel [Kieselgel 60, ART.7734 (K
ieselgel60, Art.7734)] was used. Furthermore, the mixing ratio of the mixed solvent depends on the volume ratio.

Reference Example 1 4-chlorobenzthioamide (1.00 g) was dissolved in ethanol (12 ml), and 1,3-dichloroacetone (820 ml) was added to the solution.
Reflux for 1 hour. Then, it is poured into 50 ml of water, 50 ml of diethyl ether is added, and the pH is adjusted to 7 with sodium hydrogen carbonate. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: benzene) to give 4-chloromethyl-2- (4-chlorophenyl) thiazole (840 mg).
(Yield 59.2%) is obtained.

Melting point: 83.0 to 84.5 ° C. (recrystallized from n-hexane) IR (KBr) cm ⁻¹ : 1490,1085,1000,835,825 NMR (CDCl ₃ ) δ value: 4.70 (2H, s), 7.07 to 7.94 (5H, m) In a similar manner, the compounds of Table-3 are obtained.

Example 1 (1) 4-chloromethyl-2- (4-chlorophenyl)
Add 600 mg of thiazole and 900 mg of imidazole to 6 ml of chloroform and reflux for 5 hours. Then, the mixture is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform) to give 2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole 400 mg (yield 5
9.0%).

Melting point: 123.5 to 126.5 ° C. (recrystallized from benzene-n-hexane) IR (KBr) cm ⁻¹ : 1495,1445,1235,1090,1000,830 NMR (CDCl ₃ ) δ value: 5.27 (2H, s), 6.88 to 7.98 (8H, m) Similarly, the compounds in Table 4 are obtained.

(2) 340 mg of 1,2,4-triazole is dissolved in 5 ml of methanol, 950 mg of a solution of sodium methylate in methanol [containing sodium methylate 28% (W / W)] 950 mg is added, and the mixture is reacted at room temperature for 15 minutes. Then, 4-chloromethyl-2- (2,4-difluorophenyl) thiazole 1.00 g
Is added, refluxed for 7 hours, poured into 50 ml of water, and extracted with 50 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is purified by column chromatography (eluting solvent: chloroform) to give 1
-[2- (2,4- (difluorophenyl) thiazole-
680 mg (yield 60.2%) of 4-yl] methyl-1H-1,2,4-triazole are obtained.

Melting point: 132.5 to 133.5 ° C (recrystallized from n-hexane) IR (KBr) cm ^-1 : 1605,1430,1255,1010,870,715 NMR (CDCl ₃ ) δ value: 5.53 (2H, s), 6.62 to 8.48 ( 6H, m) Then, eluting with chloroform: methanol = 20: 1, 4- [2- (2,4-difluorophenyl) thiazol-4-yl] methyl-4H-1,2,4-triazole 110
mg (yield 9.7%) is obtained.

Melting point: 178.5-180.0 ° C (recrystallized from benzene) IR (KBr) cm ^-1 : 1610,1435,1260,1180,1090,850 NMR (CDCl ₃ ) δ value: 5.35 (2H, s), 6.75-8.43 ( 6H, m) Reference Example 2 (1) 1- (4-chlorophenyl) propan-2-one
8.00 g is dissolved in 40 ml of glacial acetic acid, and a solution of 4 ml of glacial acetic acid containing 7.58 g of bromine is added dropwise at 15 to 20 ° C. After reacting for 10 minutes at the same temperature, pour into 200 ml of water and extract with 100 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: benzene: n-hexane = 2: 3) to give oily 1-bromo-1- (4-chlorophenyl).
6.25 g of propan-2-one (yield 53.4%) is obtained.

IR (neat) cm ⁻¹ : 1715,1480,1400,1080,1010, NMR (CDCl ₃ ) δ value: 2.25 (3H, s), 5.37 (1H, s), 7.28 (4H, s) Similarly, The following compound is obtained.

○ 1-Bromo-1- (4-bromophenyl) propan-2-one ○ 1-Bromo-1- (4-nitrophenyl) propan-2-one (2) 1-Bromo-1- (4-nitrophenyl) ) Propan-2-one 1.50 g and 4-chlorobenzthioamide
Dissolve 1.04 g in 15 ml of ethanol and react at room temperature for 30 minutes. Then, it is poured into 100 ml of water, 100 ml of chloroform is added, and the pH is adjusted to 7 with sodium hydrogen carbonate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,5-bis (4-chlorophenyl) -4-methyl. 1.25 g of thiazole (yield 64.4%) is obtained.

Melting point: 177.5 to 178.5 ° C (recrystallized from benzene) IR (KBr) cm ^-1 : 1480,1090,830 NMR (CDCl ₃ ) δ value: 2.50 (3H, s), 7.15 to 7.92 (8H, m) To give the compounds in Table-5.

(3) 2.00 g of 1- (2-methoxycarbonylphenyl) propan-2-one and 1.04 g of calcium carbonate are added to 20 ml of methylene chloride, and 2 ml of methylene chloride solution containing 1.49 g of bromine is added dropwise at 30 to 35 ° C. . After reacting for 30 minutes at the same temperature, it is poured into 20 ml of water and the insoluble matter is filtered off. The organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 2.65 g of an oily substance.

From the NMR spectrum, the oil was found to be 1-bromo-1- (2
-Methoxycarbonylphenyl) propan-2-one and 3-bromo-1- (2-methoxycarbonylphenyl)
It is a 1: 1 mixture with propan-2-one.

2.65 g of this mixture and 1.6 of 4-chlorobenzthioamide
Dissolve 8 g in 14 ml ethanol and leave at room temperature overnight.
Then, the solvent was distilled off under reduced pressure, and the resulting residue was washed with water 20
Add ml and extract with 20 ml of chloroform. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to column chromatography (eluting solvent: benzene: If purified with n-hexane = 1: 1), 1.20 g of 2- (4-chlorophenyl) -4- (2-methoxycarbonylphenyl) methylthiazole (yield 33.
5%).

Melting point: 117.0 to 118.0 ° C. (recrystallized from benzene-n-hexane) IR (KBr) cm ⁻¹ : 1715,1255,1075,830,710 NMR (CDCl ₃ ) δ value: 5.80 (3H, s), 4.52 (2H, s), 6.68 (1H, s), 7.15 ~ 7.95
(8H, m) Then, eluting with benzene: n-hexane = 3: 2, oily 2- (4-chlorophenyl) -5- (2-methoxycarbonylphenyl) -4-methylthiazole 900 mg (yield 25.1 %).

IR (neat) cm ⁻¹ : 1720,1280,1250,1180,750 NMR (CDCl ₃ ) δ value: 2.25 (3H, s), 3.72 (3H, s), 7.00 to 7.70 (8H, m) (4) 3.00 g of 2- (4-chlorophenyl) -4-methylthiazole was dissolved in 30 ml of chloroform, and bromine was added to this.
A 3 ml solution of chloroform containing 2.40 g is added dropwise at 15 to 20 ° C. After reacting for 1 hour at the same temperature, it is poured into 30 ml of ice water and adjusted to pH 7 with sodium hydrogen carbonate. Separate the organic layer,
After washing successively with water and saturated saline and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 5-bromo-2- (4-chlorophenyl) -4-methylthiazole (3.95 g, yield). 95.6%).

Melting point: 121.5 to 122.0 ° C (recrystallized from n-hexane) IR (KBr) cm ^-1 : 1485,1235,1085,1030,830 NMR (CDCl ₃ ) δ value: 2.44 (3H, s), 7.37 (2H, d, J = 9Hz), 7.78 (2H, d, J = 9H
z) (5) 10.65 g of ethyl 2-chloroacetoacetate and 10.00 g of 4-chlorobenzthioamide are added to 100 ml of ethanol and refluxed for 5 hours. Then, the precipitated crystals are collected by filtration,
By washing with isopropyl alcohol, 11.99 g (yield 72.5%) of ethyl 2- (4-chlorophenyl) -4-methylthiazole-5-carboxylate is obtained.

Melting point: 85.0-86.0 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 2980,1715,1370,1265,1095,853 NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7Hz), 2.75 (3H, s), 4.25 (2H, q, J = 7H
z), 7.28 (2H, d, J = 9Hz), 7.77 (2H, d, J = 9Hz) Example 2 (1) 1.25 g of 2,5-bis (4-chlorophenyl) -4-methylthiazole, N- Add 560 mg of bromosuccinimide and 50 mg of α, α′-azobisisobutyronitrile to 50 ml of carbon tetrachloride and reflux for 3 hours. After allowing to cool, 2.13 g of imidazole is added and the mixture is refluxed for 3 hours. Then, the solvent is distilled off under reduced pressure, the obtained residue is dissolved in 50 ml of chloroform, and washed successively with water and saturated saline. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform) to give 2,5-bis (4-chlorophenyl) -4- (1H-imidazole-1).
-Yl) Methyl thiazole 1.00 g (yield 82.6%) is obtained.

Melting point: 169.0 to 171.5 ° C. (recrystallized from methanol) IR (KBr) cm ⁻¹ : 1480,1230,1090,1015,830,750 NMR (CDCl ₃ ) δ value: 5.16 (2H, s), 6.84 to 7.98 (11H, m) In a similar manner, the compounds in Table-6 are obtained.

(2) To 2 ml of dioxane solution containing 100 mg of 2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methyl-5- (2-methoxycarbonylphenyl) thiazole, add 2 ml of concentrated hydrochloric acid and reflux for 4 hours. To do. Then, the solvent was distilled off under reduced pressure to give 5- (2-carboxyphenyl) -2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole hydrochloride (100 mg).
(Yield 94.7%) is obtained.

Melting point: 252.0 to 253.0 ° C. (recrystallized from ethanol) IR (KBr) cm ⁻¹ : 1700,1235,1090,830,770 NMR (d ₆ -DMSO) δ value: 5.35 (2H, s), 7.42 to 7.97 (10H, m), 9.12 (1H, s) (3) 2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methyl-5- (4-nitrophenyl) thiazole 1.50 g suspended in ethanol 30 ml. And stannous chloride dihydrate (3.41 g) and concentrated hydrochloric acid (2.52 ml)
Is added and the mixture is refluxed for 3 hours. Then, it is poured into 30 ml of water, adjusted to pH 13.5 with 2N sodium hydroxide, and extracted with 50 ml of chloroform. The organic layer was washed successively with water and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to give 5- (4-aminophenyl) -2- (4-
1.28 g (yield 92.1%) of chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole are obtained.

Melting point: 194.0-195.0 ° C (recrystallized from ethanol) IR (KBr) cm ⁻¹ : 1595,1485,1305,830,750 NMR (CDCl ₃ ) δ value: 3.70 (2H, bs), 5.16 (2H, s), 6.44 ~ 7.96 (11H, m) (4) 180 mg of 5- (4-aminophenyl) -2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole was dissolved in 3.6 ml of pyridine. While cooling with ice, 0.06 ml of acetic anhydride was added, and the mixture was reacted at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (elution solvent; chloroform:
If purified with methanol = 50: 1), 5- (4-acetylaminophenyl) -2- (4-chlorophenyl) -4-
(1H-imidazol-1-yl) methylthiazole 173m
g (yield 86.1%) is obtained.

Melting point: 233.0 to 253.0 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 1675,1595,1530,1310,1085,830 NMR (d ₆ -DMSO) δ value: 2.11 (3H, s), 5.26 ( 2H, s), 6.76 ~ 8.08 (11H, m), 9.18
(1H, bs) (5) 5- (4-aminophenyl) -2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole 800 mg and bis- (2-bromoethyl)
680 mg of amine hydrobromide is added to 16 ml of methyl ethyl ketone and refluxed for 6 hours. Then, the solvent is distilled off under reduced pressure, 20 ml of water is added to the obtained residue, and the pH is adjusted to 13.5 with 2N sodium hydroxide, followed by extraction with 50 ml of a chloroform: methanol (10: 1) mixture. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; chloroform: methanol = 10: 1) to give 1- [4- [2- (chlorophenyl) -4- (1H-imidazol-1-yl) methyl. Thiazol-5-yl] phenyl] piperazine 200 m
g (yield 21.0%) is obtained.

Melting point: 164.0-166.0 ° C (recrystallized from ethyl acetate) IR (KBr) cm ^-1 : 1600,1480,1440,1235,1085,830 NMR (d ₆ -DMSO) δ value: 2.88-3.69 (9H, m) , 5.27 (2H, s), 6.74 ~ 8.12 (11H,
m) (6) 2- (4-Chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole-5-carboxylate (4.00 g) was dissolved in dry tetrahydrofuran (40 ml) and hydrogenated at -30 ° C. 220 mg of lithium aluminum
Add. Then, after warming to room temperature, it is poured into 100 ml of ice water and adjusted to pH 7 with 2N-hydrochloric acid, and then 200 ml of chloroform.
Extract with. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (eluting solvent: chloroform). , 2- (4
1.00 g (yield 28.6%) of -chlorophenyl) -4- (1H-imidazol-1-yl) methyl-5-thiazolecarbaldevit is obtained.

Melting point: 149.0 to 150.0 ° C. (recrystallized from benzene) IR (KBr) cm ⁻¹ : 1650,1425,1325,1080,830 NMR (CDCl ₃ ) δ value: 5.53 (2H, s), 7.00 to 7.90 (7H, m), 9.92 (1H, s) If the elution with the same solvent is continued, 2- (4-chlorophenyl) -5-hydroxymethyl-4- (1H-imidazol-1-yl) methylthiazole 1.01 g (yield 28.7 %)
To get

Melting point: 184.0-185.0 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 3100,1505,1450,1080,1025,830 NMR (CDCl ₃ ) δ value: 2.22 (1H, bs), 4.80 (2H, s), 5.22 (2H, s), 6.88 ~ 7.92
(7H, m) (7) 2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazol-5-carboxylate (500 mg) was dissolved in a mixed solution of dioxane (10 ml) and concentrated hydrochloric acid (10 ml), Reflux for 8 hours. Then, the precipitated crystals are collected by filtration, suspended in 50 ml of water, and adjusted to pH with sodium hydrogen carbonate.
After adjusting to 7, dissolve by heating. After cooling, the precipitated crystals were collected by filtration to give 2- (4-chlorophenyl) -4- (1H
320 mg (66% yield) of the sodium salt of -imidazol-1-yl) methylthiazol-5-carboxylic acid are obtained.

Melting point: 280.0 or more (recrystallized from water) IR (KBr) cm ^-1 : 1580,1430,1360,1080,830 NMR (d ₆ -DMSO) δ value: 5.68 (2H, s), 6.85 to 7.97 (7H, m) Reference Example 3 (1) 5.00 g of ethyl 2-oxo-n-heptanoate was dissolved in 50 ml of chloroform, and a 5 ml solution of chloroform containing 4.64 g of bromine was added dropwise at 25-30 ° C. After reacting for 30 minutes at the same temperature, pour into 50 ml of ice water and separate the organic layer.
The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 3-bromo-2-oxo-n-heptanoate as a pale yellow oil 7.30. get g.

IR (neat) cm ⁻¹ : 2950,1730,1060 NMR (CDCl ₃ ) δ value: 0.93 (3H, t, J = 6Hz), 1.10 to 2.45 (9H, m), 4.34 (2H, q,
J = 7Hz), 5.00 (1H, t, J = 7Hz) Similarly, the compounds in Table-7 are obtained.

(2) Ethyl 3-bromo-2-oxo-n-heptanoate
Add 2.00 g and 1.37 g of 4-chlorobenzthioamide to 20 ml of ethanol and reflux for 4 hours. Then, pour into 50 ml of water, adjust to pH 7 with sodium hydrogen carbonate, and add chloroform 5
Extract with 0 ml. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is purified by column chromatography (eluting solvent: benzene) to give 5-n-
Butyl-2- (4-chlorophenyl) thiazole-4-
2.00 g of ethyl carboxylate (yield 77.5%) is obtained.

Melting point: 84.0-85.0 ° C (recrystallized from diisopropyl ether) IR (KBr) cm ^-1 : 2950,1705,1460,1260,1210,835 NMR (CDCl ₃ ) δ value: 0.95 (3H, t, J = 6Hz) , 1.13 ~ 1.90 (7H, m), 3.23 (2H, t,
J = 7Hz), 4.43 (2H, q, J = 7Hz), 7.35 (2H, d, J = 9Hz),
7.84 (2H, d, J = 9Hz) Similarly, the compounds in Table-8 are obtained.

(3) 1.00 g of ethyl 5-n-butyl-2- (4-chlorophenyl) thiazole-4-carboxylate is dissolved in 20 ml of dry tetrahydrofuran, and 234 mg of lithium aluminum hydride is added at -50 ° C. Then, after warming to room temperature, the mixture is poured into 50 ml of ice water, adjusted to pH 7 with 2N-hydrochloric acid, and extracted with 50 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is purified by column chromatography (eluting solvent: chloroform) to give 5-n-butyl-2- (4-chlorophenyl) -4.
680 mg of hydroxymethylthiazole are obtained (78.4% yield).

Melting point: 95.0-96.0 ° C (recrystallized from diisopropyl ether) IR (KBr) cm ^-1 : 3200,2920,1445,1085,1030,825 NMR (CDCl ₃ ) δ value: 0.94 (3H, t, J = 6Hz) , 1.07 ~ 1.90 (4H, m), 2.80 (2H, t,
J = 7Hz), 3.12 (1H, bs), 4.69 (2H, s), 7.34 (2H, d, J =
9Hz), 7.79 (2H, d, J = 9Hz) Similarly, the compounds in Table-9 are obtained.

(4) 5-n-butyl-2- (4-chlorophenyl)-
600 mg of 4-hydroxymethylthiazole and 1.11 g of thionyl bromide are added to 12 ml of chloroform and refluxed for 1 hour. Then, it is poured into 30 ml of water, 30 ml of chloroform is added, and the pH is adjusted to 7 with sodium hydrogen carbonate. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
730 mg of 4-bromomethyl-5-n-butyl-2- (4-chlorophenyl) thiazole are obtained.

Melting point: 73.0 to 74.0 ° C (recrystallized from diisopropyl ether) IR (neat) cm ^-1 : 2940,1455,1210,1090,830 NMR (CDCl ₃ ) δ value: 0.96 (3H, t, J = 6Hz), 1.12 ~ 1.95 (4H, m), 2.83 (2H, t,
J = 7Hz), 4.58 (2H, s), 7.35 (2H, d, J = 9Hz), 7.82 (2
H, d, J = 9 Hz) Similarly, the compounds in Table-10 are obtained.

Example 3 (1) 4-Bromomethyl-5-n-butyl-2- (4-
Chlorophenyl) thiazole 630mg and imidazole 5
Add 95 mg to 13 ml of chloroform and reflux for 1 hour. Then, it is poured into 20 ml of water and the organic layer is separated. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform) to give 480 mg of 5-n-butyl-2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole. Rate 78.7%).

Melting point: 65.0-67.0 ° C (recrystallized from diisopropyl ether) IR (KBr) cm ^-1 : 2920,1490,1440,1090,825 NMR (CDCl ₃ ) δ value: 0.92 (3H, t, J = 6Hz), 1.14 ~ 1.90 (4H, m), 2.78 (2H, t,
J = 7Hz), 5.14 (2H, s), 7.04 (2H, bs), 7.32 (2H, d, J,
= 9Hz), 7.60 (1H, bs), 7.77 (2H, d, J = 9Hz) Similarly, the compounds of Table-11 are obtained.

(2) 75 mg of 1,2,4-triazole is dissolved in 10 ml of methanol, 180 mg of a methanol solution of sodium methylate [containing sodium methylate 28% (W / W)] is added thereto, and the mixture is reacted at room temperature for 15 minutes. Then, 250 mg of 4-bromomethyl-5-n-butyl-2- (2,4-difluorophenyl) thiazole is added, refluxed for 2 hours, poured into 50 ml of water and extracted with 50 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to column chromatography (eluting solvent: chloroform).
Purified by 1- [5-n-butyl-2- (2,4-difluorophenyl) thiazol-4-yl] methyl-1H
151 mg of 1,2,4-triazole (yield 62.5%) is obtained.

Melting point: 96.5-98.5 ° C (recrystallized from n-hexane) IR (KBr) cm ^-1 : 2925,1605,1500,1260,1135,850 NMR (CDCl ₃ ) δ value: 0.95 (3H, t, J = 6Hz ), 1.12 to 1.96 (4H, m), 2.94 (2H, t,
J = 7 Hz), 5.44 (2H, s), 6.70-8.40 (5H, m) Reference Example 4 (1) Benzoyloxymethylthioamide 2.0 g and α
Add 3.9 g of -bromo-4,4'-dichlorodeoxybenzoin to 10 ml of ethanol and reflux for 10 minutes. Then, 50 ml of water
After adding 50 ml of diethyl ether, the pH is adjusted to 7 with sodium hydrogen carbonate. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: benzene) to give oily 2-benzoyloxymethyl-4,5-
4.1 g of bis (4-chlorophenyl) thiazole (yield 91
%).

IR (neat) cm ⁻¹ : 1725,1490,1260,1090,825 NMR (CDCl ₃ ) δ value: 5.64 (2H, s), 7.00 to 8.30 (13H, m) (2) 2-benzoyloxymethyl-4 , 5-bis (4-
Chlorophenyl) thiazole 3.5 g and potassium hydride
Add 1.4 g to 35 ml ethanol and reflux for 10 minutes. Then, it is poured into 100 ml of water and extracted with 100 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent;
1.8 g of 4,5-bis (4-chlorophenyl) -2-hydroxymethylthiazole if purified with chloroform)
(Yield 67%) is obtained.

Melting point: 113.5 to 115.0 ° C (recrystallized from benzene-n-hexane) IR (neat) cm ^-1 : 3270,1485,1090,1010,820 NMR (CDCl ₃ ) δ value: 4.52 to 4.95 (3H, m), 6.95 to 7.50 (8H, m) (3) 1.5 g of 4,5-bis (4-chlorophenyl) -2-hydroxymethylthiazole and 1.6 g of thionyl chloride are added to 5 ml of benzene and refluxed for 30 minutes. Then, the solvent is distilled off under reduced pressure, 30 ml of chloroform and 30 ml of water are added to the obtained residue, and the pH is adjusted to 7 with sodium hydrogen carbonate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 4,5-bis (4-chlorophenyl)-
1.2 g (yield 76%) of 2-chloromethylthiazole are obtained.

Melting point: 103.0 to 105.0 ° C (recrystallized from n-hexane) IR (KBr) cm ^-1 : 1480,1080,825 NMR (CDCl ₃ ) δ value: 4.80 (2H, s), 7.00 to 7.60 (8H, m) Example 4 500 mg of 4,5-bis (4-chlorophenyl) -2-chloromethylthiazole and 480 mg of imidazole are added to 10 ml of chloroform and refluxed for 3 hours. Then, the mixture is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform) to give 4,5-bis (4-chlorophenyl) -2- (1
H-imidazol-1-yl) methylthiazole 450 mg
(Yield 82.6%) is obtained.

Melting point: 159.0-160.5 ° C. (recrystallized from benzene-n-hexane) IR (KBr) cm ⁻¹ : 1480,1080,1065,810 NMR (CDCl ₃ ) δ value: 5.44 (2H, s), 7.00 to 7.76 ( 11H, m) Reference Example 5 (1) 4-chlorobenzthioamide (2.0 g) and 2-bromopropionaldehyde diethyl acetal (2.5 g) were dissolved in ethanol (12.5 ml), and water (10 ml) and concentrated hydrochloric acid (0.1 ml) were added thereto.
Add 4 ml of the mixture and reflux for 8 hours. Then, 20 ml of water
And extract with 50 ml of chloroform. The extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is purified by column chromatography (eluting solvent: benzene: n-hexane = 1: 3) to give 1.0 g of 2- (4-chlorophenyl) -5-methylthiazole (yield 40%). .

Melting point: 93.0 ° C. (recrystallized from isopropyl alcohol) IR (KBr) cm ⁻¹ : 1480,1430,1090,965,830 NMR (CDCl ₃ ) δ value: 2.49 (3H, s), 7.20 to 7.50 (3H, m), 7.77 (2H, d, J = 9H
z) (2) 2- (4-chlorophenyl) -5-methylthiazole 690 mg, N-bromosuccinimide 590 mg and α,
α'-Azobisisobutyronitrile 30 mg with carbon tetrachloride 12
Add to ml and reflux for 3 hours. Then, the insoluble matter is filtered off,
The filtrate was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
870 mg (yield 92%) of 5-bromomethyl-2- (4-chlorophenyl) thiazole is obtained.

Melting point: 88.0-89.0 ° C (recrystallized from isopropyl alcohol) IR (KBr) cm ^-1 : 1430,1205,1080,970,820 NMR (CDCl ₃ ) δ value: 4.72 (2H, s), 7.38 (2H, d, J = 9Hz), 7.73 (1H, s), 7.82
(2H, d, J = 9Hz) Example 5 570 mg of 5-bromomethyl-2- (4-chlorophenyl) thiazole and 670 mg of imidazole were added to 5 ml of chloroform.
And dissolve at room temperature overnight. Then, 5 ml of water is added and the organic layer is separated. The organic layer was washed with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform: methanol = 50: 1) to give 2- (4-chlorophenyl) -5- (1H-imidazol-1-yl) methylthiazole 340 mg (yield: Rate 63
%).

Melting point: 128.0 ° C (recrystallized from benzene) IR (KBr) cm ^-1 : 1490,1435,1230,1090,830 NMR (CDCl ₃ ) δ value: 5.32 (2H, s), 6.94 to 7.87 (8H, m) Reference Example 6 (1) 4.1 g of 1-bromo-1- (4-chlorophenyl) propan-2-one and 1.3 g of thiourea were added to 30 ml of ethanol.
And dissolve at room temperature for 8 hours. After standing overnight, 50 ml of chloroform and 30 ml of water are added, and the pH is adjusted to 7.5 with sodium hydrogen carbonate. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is treated with diethyl ether to give 2-amino-5- (4
-Chlorophenyl) -4-methylthiazole 2.7 g (yield
73%).

Melting point: 196.0-197.0 ° C. (recrystallized from isopropyl alcohol) IR (KBr) cm ⁻¹ : 3450,1610,1500,1470,1315,820 NMR (d ₆ -DMSO) δ value: 2.19 (3H, s), 7.39 (4H, s) Similarly, the compounds in Table-12 are obtained.

(2) Dissolve 460 mg of sodium nitrite in 3 ml of concentrated sulfuric acid,
2-amino-5- (4-chlorophenyl) -4-
A 12 ml solution of glacial acetic acid containing 1.0 g of methylthiazole is added dropwise at 10 ° C or lower. Then, 700 mg of bromine was added to 700 mg of 47% hydrobromic acid.
What was dissolved in is added under ice cooling. After reacting at 70-80 ° C for 2 hours, pour into ice and add 1N sodium hydroxide to pH 6
Adjust to 2, and extract with 20 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is purified by column chromatography (eluting solvent: benzene) to give 2-bromo-5- (4-chlorophenyl).
-4-Methylthiazole 500 mg (yield 39%) is obtained.

Melting point: 82.0-83.0 ° C. (recrystallized from n-hexane) IR (KBr) cm ⁻¹ : 1470,1405,1090,1035,825 NMR (CDCl ₃ ) δ value: 2.44 (3H, s), 7.34 (4H, s) In a similar manner, the compounds in Table-13 are obtained.

Example 6 (1) 2-Bromo-5- (4-chlorophenyl) -4-
Methylthiazole 500 mg was added to N, N-dimethylformamide 10
It is dissolved in ml, 590 mg of imidazole is added thereto, and the mixture is refluxed for 5 hours. Then, pour it into 50 ml of water and add 50 ml of chloroform.
Extract with. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is purified by column chromatography (eluting solvent: chloroform) to give 5-
(4-Chlorophenyl) -2- (1H-imidazole-1
-Yl) -4-methylthiazole 230 mg (yield 48.1%)
To get

Melting point: 95.0-97.0 ° C (recrystallized from diisopropyl ether) IR (KBr) cm ^-1 : 1490,1255,1090,1040,990,830 NMR (CDCl ₃ ) δ value: 2.44 (3H, s), 6.50-8.14 (7H , m) Similarly, the compounds in Table-14 are obtained.

(2) 105 mg of 1,2,4-triazole is dissolved in 10 ml of methanol, 75 mg of sodium methylate is added thereto, and the mixture is reacted at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in 5 ml of N, N-dimethylformamide, and 200 mg of 2-bromo-5- (4-chlorophenyl) -4-methylthiazole was added thereto, followed by addition for 1 hour. Bring to reflux. Then, it is poured into 20 ml of water and extracted with 20 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: benzene) to give 1- [5- (4-chlorophenyl) -4-methylthiazol-2-yl] -1H-1,2,4.
-140 mg of triazole (yield 72.9%) are obtained.

Melting point: 174.5 to 175.5 ° C (benzene: recrystallized from n-hexane) IR (KBr) cm ^-1 : 3070,1525,1410,1275,985,820 NMR (CDCl ₃ ) δ value: 2.45 (3H, s), 7.41 ( 4H, s), 8.06 (1H, s), 8.95 (1H,
s) Example 7 (1) 5-bromo-2- (4-chlorophenyl) -4-
(1H-imidazol-1-yl) methylthiazole 300m
g was added to 3 ml of dry tetrahydrofuran, and -60 to-
N-Butyllithium (1.5N-n-hexane solution) at 50 ° C
Add 57 ml dropwise. After reacting for 20 minutes at the same temperature, -60 ℃
Then add 96 mg of methyl iodide. Then, after warming to room temperature, it is poured into 30 ml of ice water and extracted with 30 ml of chloroform.
The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure.
If the obtained residue is purified by column chromatography (eluting solvent; chloroform: methanol = 50: 1),
2- (4-Chlorophenyl) -4- (1H-imidazol-1-yl) methyl-5-methylthiazole (150 mg, yield 61.2%) is obtained.

The melting point, IR, and NMR were consistent with those of the compound obtained in Example 3 (1).

(2) In the same manner as in the method of Example 7 (1), using n-butyraldehyde instead of methyl iodide, 2- (4
-Chlorophenyl) -5- (1-hydroxy-n-butyl) -4- (1H-imidazol-1-yl) methylthiazole is obtained.

Melting point: 148.0-149.0 ° C (recrystallized from isopropyl alcohol) IR (KBr) cm ⁻¹ : 3100,2950,1500,1440,1095,830 NMR (CDCl ₃ ) δ value: 0.70 to 2.08 (7H, m), 4.20 (1H, bs), 4.95 (1H, t, J = 7H
z), 5.16 (2H, s), 6.75 to 7.90 (7H, m) (3) Using N, N-dimethylformamide in place of methyl iodide, in the same manner as in Example 7 (1), Two
-(4-chlorophenyl) -4- (1H-imidazole-
1-iso) methyl-5-thiazole carbaldide is obtained.

The melting point, IR, and NMR were consistent with those of the compound obtained in Example 2 (6).

Example 8 (1) n-Butyllithium (1.5N-n-hexane solution) 2.
19 ml was mixed with 20 ml of dry tetrahydrofuran, to which −
1.33g of methyltriphenylphosphonium iodide at 30 ℃
Add. Then react at room temperature for 4 hours at -40 ° C.
2- (4-Chlorophenyl) -4- (1H-imidazol-1-yl) methyl-5-thiazolecarbaldide 1.
00 g is added, and the mixture is further reacted at room temperature for 1 hour. Then,
After diluting with 100 ml of benzene and filtering off the insoluble matter, 20 ml of water is added to the filtrate and the pH is adjusted to 7 with 2N-hydrochloric acid. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent;
2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methyl-5 by purification with chloroform).
170 mg of vinyl thiazole (yield 17.1%) are obtained.

Melting point: 94.0-96.0 ° C. (recrystallized from ethyl acetate: diisopropyl ether) IR (KBr) cm ⁻¹ : 1495,1440,1170,1085,830 NMR (CDCl ₃ ) δ value: 5.15 (2H, s), 5.32 ( 1H, d, J = 10Hz), 5.51 (1H, d, J = 16
Hz), 6.70 (1H, dd, J = 10Hz, J = 16Hz), 6.90 to 7.87 (7H,
m) (2) 1.00 g of n-propyl-triphenylphosphonium bromide is suspended in 10 ml of dry tetrahydrofuran and 270 mg of potassium tert-butoxide is added at room temperature. After reacting for 30 minutes at room temperature, 2- (4-chlorophenyl)-
400 mg of 4- (1H imidazol-1-yl) methyl-5-thiazole carbaldide are added. After reacting for 1.5 hours at room temperature, it is poured into 50 ml of water, adjusted to pH 7 with 2N-hydrochloric acid, and then extracted with 50 ml of chloroform. The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to column chromatography (eluting solvent: chloroform).
And recrystallized from a mixed solvent of benzene-n-hexane to give 5- (cis-1-butenyl) -2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methylthiazole (270 mg). (Yield 62.2%) is obtained.

Mp: 125.0~127.0 ℃ IR (KBr) cm -1: 1585,1490,1440,1230,1085,830 NMR (CDCl 3) δ value: 1.10 (3H, t, J = 7Hz), 2.00~2.50 (2H, m), 5.20 (2H,
s), 5.82 (1H, dt, J = 2Hz, J = 7Hz), 6.44 (1H, d, J = 12H)
z), 7.00 to 8.00 (7H, m) (3) 1.27 g of carbon tetrabromide is dissolved in 10 ml of methylene chloride, and 2.00 g of triphenylphosphine is added under ice cooling.
After reacting for 10 minutes at the same temperature, 2- (4-chlorophenyl) -4- (1H-imidazol-1-yl) methyl-5-
Add 580 mg of thiazole carbardide. Then, after reacting for 1 hour at the same temperature, it is poured into 50 ml of ice water. The pH is adjusted to 7 with sodium hydrogen carbonate and then extracted with 50 ml of methylene chloride. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform) to give 2- (4-chlorophenyl) -5- (2,2-dibromovinyl) -4- (1H-imidazol-1-yl). Methylthiazole 650 mg (Yield 74
%).

Melting point: 185.0 ° C (recrystallized from benzene) IR (KBr) cm ^-1 : 1455,1345,1275,1085,853,815 NMR (CDCl ₃ ) δ value: 5.20 (2H, s), 7.00 to 8.00 (8H, m) , (4) 2- (4-Chlorophenyl) -5- (2,2-dibromovinyl) -4- (1H-imidazol-1-yl) methylthiazole (460 mg) was suspended in dry tetrahydrofuran (6 ml), and -60 mg was added to the suspension. N-Butyllithium (1.5N-n-
1.8 ml of hexane solution) is added dropwise. After reacting for 30 minutes at the same temperature, pour into 50 ml of ice water. After adjusting the pH to 7 with 2N-hydrochloric acid, extract with 50 ml of chloroform. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent; chloroform: methanol = 10).
2- (4-chlorophenyl) -5 by purification with 0: 1)
150 mg (yield 50%) of ethynyl-4- (1H-imidazol-1-yl) methylthiazole are obtained.

Melting point: 165.0 to 175.0 ° C (decomposition) (recrystallized from benzene) IR (KBr) cm ^-1 : 3070,2080,1585,1495,1230,830 NMR (CDCl ₃ ) δ value: 3.70 (1H, s), 5.21 (2H, s), 7.00 ~ 7.90 (7H, m)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akira Shitsuji 30 Ueno, Kosugi-machi, Imizu-gun, Toyama Prefecture (72) Inventor Hiroshi Sakai 1575 Shimomakino, Takaoka-shi, Toyama Prefecture (72) Inventor Yu Saitogawa Oizumi-naka, Toyama-shi, Toyama Prefecture 7-52 Examiner Seiko Tamura (56) Reference JP-A-57-131787 (JP, A) JP-A-51-133266 (JP, A) JP-A-52-77062 (JP, A) JP-A-56- 25178 (JP, A) West German patent publication 2824690 (DE, A)

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ , R ² and R ³ are the same or different and each is a hydrogen atom, a halogen atom, a formyl group, an optionally esterified carboxyl group or an optionally substituted alkyl, alkenyl, alkynyl, aryl or cycloalkyl group, or a group of the formula ^{_{- (CH 2) n -R 4}} ( wherein, R ⁴ represents an imidazolyl group or a 1,2,4-triazolyl group, the imidazolyl and 1,2,4-triazolyl groups , And is bonded via a nitrogen atom in the ring, and n represents 0 or 1.)
Indicates. However, ^one of R ¹ , R ² and R ³ is represented by the formula − (C
H _{2) n} -R ⁴ (wherein, R ⁴ and n are each,. Which are of the same meaning). ] The thiazole compound or its salt represented by these.