JPH02169583A - Vinylthiazole derivative and drug containing same derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H, 1-5C alkyl; R<2> and R<3> are H, (substituted) phenylalkyl, 1-5C alkyl or R<2> joins with R<3> to form cyclopentane, etc.; R<4> and R<5> are H, 1-5C alkyl or (substituted) phenyl, etc.; m is 0-5; n is 0-2] or salt of said compound. USE:Antagonizing agent against leukotriene or drug for prevention and curing of allergic disease. PREPARATION:For instance, 2-(aminostyryl) thiazoles expressed by formula II are reacted with sodium nitrite and diazotated, then reacted with cuprous thiocyanate to obtain 2-(thiocyanatestyryl) thiazole compound, thus resultant compound is hydrolyzed to prepare 2-(mercaptostyryl) thiazole and said compound is reacted with halocarboxylic acid derivative expressed by formula III (X is halogen) to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel vinylthiazole derivative having leukotriene antagonism F@cold and a drug containing the same as an active ingredient.

[Problems to be solved by conventional technology and invention]

In order to prevent or treat allergic diseases, there are methods of suppressing the release of anaphylaxis mediators and methods of using antagonists to act on the released mediators. Jindayrum Fisted Lomo Gricate [The Merck Index (T
he MerckIndex) 2nd edition 2jl# (/ri7
t)], Tranilast C Day Pharmacology Journal, 7i, J Tata (/
7r)] are typical drugs belonging to the former category, and drugs that antagonize histamine, which is one of the mediators of allergic reactions, include drugs that antagonize histamine, such as diphenhydramine, chlorpheniramine, astemizole, terfenazine, and flemastine. etc. are well known. However, from the lungs of bronchial asthma patients, there is a substance that cannot be antagonized by antihistamines, namely SR8 (Slow Reacting 5ub).
stance) is released [problem of allergy (progr, allerg.
y), each other! 39 (/9t2)], and recently, this 5R8 (leukoto IJ-C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) is collectively called SR3 (procedure). Dingop National Academy of Sciences Nynisny (Proc.
Natl, Acad, Sci, U, S, A-).

76,≠27yo (/ri72) and 77, 20/Hiroshi (luri♂0); Neichi-y-(Nature),
It's J♂.

1041 (/910))) is considered to be an important factor involved in human asthma attacks (proceeding).
Of National Academy of Op Science:
L −x Sx −(Proc, Natl, Ac
ad.

Sci U, S, A,), 10. /7i2 (
/f#3) :l.

Several leukotriene antagonists are known in patents or literature. For example, FP represented by the following formula: CH, CH, CH, CH, CH, CHI
L-j! r712 [AgentSand Actions.

ri, /33 (/ri7ri)], the following formula: KC-≠0hiro [Japanese Journal
Of 7 Armory (Jap, J, Pharm
,).

33, 267 (l♂3)], ○No-107g [Organic Synthetic Chemistry, Guyo (2)
), t J A (tri♂7)] Following formula: LY-/7/♂r3 [Journal of Pharmacology and Experimental Therapeutics (J, Pharmacol, Exp.

Ther, ), JJj (1) /III (/91j
)], etc., but no practical example has been reported to date.

The present inventors have already found the following formula: [wherein R1 is a hydrogen atom or the number of carbon atoms /~! R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 1 carbon atoms, a lower alkoxycarbonyl group, or a phenyl group which may have a substituent, and R2 and R3 represent - Together, the 2-methylene group and R7 each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group, or a straight-chain or branched lower alkyl group having 3 to 3 carbon atoms. ) may form a butadienylene group. Further, A represents a linking group with chain member l-≠. ] It has been discovered that the thiazole derivative represented by
/ '41 Publication). However, although these compounds had leukotriene antagonistic effects when administered intravenously,
It was not observed after oral administration (in vivo).

[Means for solving problems]

The present inventors further searched for compounds that have a strong leukotriene antagonistic effect even when administered orally and are effective as therapeutic agents for various diseases caused by leukotrienes. As a result, the novel vinylthiazole derivatives having a thioether bond according to the present invention are
They discovered that it has excellent leukotriene antagonism even when administered orally, leading to the completion of the present invention.

That is, the gist of the present invention is the following general formula (1) (in the above formula, R1 represents a hydrogen atom or a linear or branched alkyl group having carbon number/-1, and R2 and R3 each independently represent It represents a hydrogen atom, a phenylalkyl group which may have a substituent on the benzene ring, or a linear or branched alkyl group having 1 carbon atoms, but when R2 and R3 are taken together, it is a cyclopentane ring or cyclohexane. It may form a ring.

R4 and R5 each independently represent a hydrogen atom, carbon number/
~j straight chain or branched alkyl group or phenyl group which may have a substituent, each independently a hydrogen atom,
Halogen atom, straight chain or branched alkyl group with carbon number/-1, carbon number/~! Alkoxy group, carboxyl group, alkoxycarbonyl group with a total carbon number of 2 to O, carbon number λ
It represents an acyl group, an amino group, an acylamino group having a carbon number of λ to j, or a nitro group. ) It is difficult to form a butadienylene group represented by Further, m represents an integer of O-, and represents an integer of ntiO~2. ) and pharmaceutically acceptable salts thereof, as well as leukotriene antagonists containing the compounds as active ingredients.

The present invention will be explained in more detail below.

The range of compounds included in the above general formula (I) is as follows:
The invention is not limited to the following specific examples.

R', R2, R3, R', R', R6, R? ,R
Examples of straight chain or branched alkyl groups having carbon number/-j that can be included in 11 and R9 include methyl group, ethyl group, n-
Examples include propyl group, i-furoyl group, ropetyl group, -butyl group, 5ec-butyl group, -butyl group% n-pentyl group, 1-pentyl group, and t-pentyl group.

Further, examples of the phenylalkyl group which may have a substituent on the benzene ring that may be included in R2 and R3 include phenyl group, benzyl group, phenylethyl group, phenylpropyl group, and phenylbutyl group. Examples of substituents on the benzene ring include lower alkyl groups such as methyl, ethyl and n-propyl; halogen atoms such as chlorine, bromine and fluorine; methoxy, ethoxy and n-propoxy groups; Examples include lower alkoxy groups; lower alkoxycarbonyl groups such as methoxycarbonyl groups and ethoxycarbonyl groups; carboxyl groups; hydroxyl groups; nitro groups; amino groups; cyano groups; lower acylamino groups such as acetylamino groups and propionylamino groups.

Examples of the alkoxy group having 1 carbon atoms that can be included in R6, R7, R8 and R9 include methoxy group, ethoxy group, low propoxy group, ■-propoxy group, low propoxy group,
Examples include t-butoxy group and n-pentyloxy group, and examples of the alkoxycarbonyl group having a total carbon number of 2 to 2 include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, etc. group, n-butoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group, l-pentyloxycarbonyl group, etc., and the number of carbon atoms is d~! Examples of the noacyl group include an acetyl group, propionyl group, n-butyryl group, i-butyryl group, n-pentanoyl group, and 1-pentanoyl group, and examples of the acylamino group having 2 to j carbon atoms include an acetylamino group. , propionylamino group, n-butyrylamino group, ■
Examples include -butyrylamino group and lowpentanoylamino group.

Further, as substituents of the substituted phenyl group that can be included in R4 and R5, halogen atoms such as chlorine atom, real atom, and fluorine atom; hydroxyfur group: methoxy group, ethoxy group, n
-Lower alkoxy groups such as propoxy groups; methyl groups, ethyl groups; lower alkyl groups such as n-propyl groups, 1-propyl groups, and ropetyl groups; lower alkoxycarbonyl groups such as methoxycarbonyl groups and ethoxycarbonyl groups; carboxyl groups; Amino group: nitro group; cyano group; acylamino group such as acetylamino group and propionylamino group.

Among the compounds represented by the above general formula (1), preferable ones have the λ substituents on the benzene ring at the meta position, and the positional relationship between the substituents at both ends of the ethylene double bond is Entgegen (E ) is the l compound.

The vinylthiazole derivative of the present invention is not limited to specific isomers, but includes all geometric isomers, optical isomers, and mixtures thereof, such as racemates.

The vinylthiazole derivative of the present invention can be synthesized by various methods. For example, it can be synthesized by the synthetic route shown in Reaction Formula-7 below.

R2, R3, R4, R5 and m in the above reaction formula represent elementary atoms.

First, in the CA-/] step, the aniline derivative ([) was prepared by Bruce O. West et al. in the Journal of the Chemical Society Dalton Transactions (J.

CHEH, SOC, DALTON TRAS,) No. 14
It is converted into a thiocyanate derivative (In) using the method via diazonium salt described in t3~/yo/page (Iriza 3rd year).

This thiocyanate derivative (III) is I:A--2)
As shown in the steps, it is easily hydrolyzed by a conventional method to form a thiol derivative (IV). This hydrolysis easily occurs using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in a water-containing organic solvent such as water-containing ethanol at a temperature ranging from 0'C to the boiling point of the solvent. The thiol derivative produced here can be isolated, but if isolation is not necessary, the reaction mixture after the completion of step CA--2) may be used as it is in the next step. Especially (A-3] and [A-
When synthesizing vinylthiazole derivatives (Ta) as in step [μ], the reaction mixture after hydrolysis is
・Add the locarboxylic acid derivative (V) or the acrylic acid derivative (■) and add /-2 in the temperature range from 0°C to the boiling point of the solvent.
It can be easily synthesized by stirring for 0 hours.

When synthesizing vinylthiazole derivative (rb),
Since hydrolysis of the ester may occur when the reaction is carried out in a water-containing solvent system, the thiol derivative ((1/) is isolated and treated as shown in steps (A--t) and CA-6).
It may be reacted with a raw ester derivative (VIT) or an acrylic ester derivative (VIil). In this reaction, sodium hydride, sodium carbonate,
Alkali metal inorganic bases such as potassium carbonate, sodium hydroxide, and potassium hydroxide or organic bases such as triethylamine and N-methylmorpholine are used;
:] In the case of Michael addition type reactions such as the process, organic basic catalysts such as benzyltrimethylammonium hydroxide can also be used. As the reaction solvent, an organic solvent such as tetrahydrofuran, N,N-dimethylformamide, acetone, methyl ethyl ketone, alcohol, etc. is used, and the reaction temperature may be within the temperature range of 0° C. to the boiling point of the solvent.

[A-! ] and [A-6] The vinylthiazole derivative (Ib) obtained in steps [A-6] can be easily converted into the vinylthiazole derivative (Ia) by hydrolyzing its ester group by a conventional method. The hydrolysis step of I:A-7) is easily carried out using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in a water-containing organic solvent such as water-containing ethanol at a temperature within the temperature range of θ°C to the solvent boiling point. can be done.

The vinylthiazole derivative thus obtained (Ia
) and (Ib) are each converted into a sulfoxide derivative (tc; n=/) by oxidizing the sulfur atom in a conventional manner.
and (Id:n=/) or sulfone derivative (Ic
;n=-2) and (Idzn=2). These oxidation steps (A-1 and CA y
Suitable oxidizing agents used in step 3 are commonly used oxidizing agents such as peroxychloride salts such as periodate; hydrogen peroxide; and organic peracids such as peracetic acid; is alcohol such as methanol and ethanol;
Acetic acid; Organic solvents such as ethers and ethers such as tetrahydrofuran, or water-containing solvent systems in which water is added to these organic solvents can be used.

The sulfoxide derivative (Id; n = /) oyohi, < sulfone derivative (Id; n - = j) is hydrolyzed under the same conditions as in the [:A-73 step] as shown in step (A-10). By doing this, the corresponding sulfoxide derivatives (Ic; n=/) and sulfone derivatives (Ic; n
=-2).

Furthermore, the vinylthiazole derivative (Ib) can also be synthesized, for example, by the synthetic route shown in Reaction Formula-2 below.

Reaction formula-2 In the above reaction formula, R2, R3, R', R5 and m are as defined in general formula (11), and R represents a lower alkyl group.

That is, for the benzaldehyde derivative (IX), 2-
Methylthiazole derivative (X) is mixed with ~2 equivalents of O6 and 0.2 equivalents of lower fatty acid anhydride. The vinylthiazole derivative (I
b) obtain. As the lower fatty acid anhydride, acetic anhydride, propionic anhydride, rhobutyric anhydride, etc. are used, and as the reaction solvent, a high boiling point solvent such as xylene, dimethyl sulfoxide, dimethyl formamide, etc. is used.However, the reaction can be carried out without a solvent. You can. The reaction temperature ranges from room temperature to λj O'(:
, preferably 110 to iro"c.

The compound (1) of the present invention has significant leukotriene antagonistic activity. That is, the antagonistic effect of the compound of the present invention on SR8 was determined in v using isolated guinea pig ileum.
When tested in vitro, it was found that it had a selective antagonistic effect on SR8 even at low concentrations. Therefore, the compounds of the present invention can be used to treat various diseases caused by leukotrienes.
For example, it is effective for the prevention and/or treatment of allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, cerebral vascular lining, or angina pectoris caused by decreased coronary flow.

The leukotriene antagonist of the present invention includes, as an active ingredient,
The compound represented by the above general formula (1) or a pharmaceutically acceptable salt thereof is contained together with a solid or liquid pharmaceutical carrier or diluent, that is, additives such as excipients and stabilizers. When the above compound has a carboxyl group, preferred salts are pharmaceutically acceptable non-toxic salts such as alkali metal salts and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts, calcium salts. , aluminum salts and the like. Ammonium salts, lower alkyl amines [e.g. triethylamine]
salts, hydroxy lower alkyl amines [e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)
amine, tris(hydroxymethyl)aminometa/or N-methyl-[)-J)'/I/camine] salt, cycloalkylamine [e.g. dicyclohexylamine] salt, benzylamine (N-eva, N,N'-di Suitable non-toxic amine salts, such as benzylethylenediamine salt and dibenzylamine salt, are likewise preferred.

When focusing on the basicity of the thiazole ring of the compound of the present invention, preferred salts include hydrochloride, methanesulfonate,
Hydrobromide, sulfate, phosphate, fumarate, cono-
Examples include non-toxic salts such as phosphates. Since these salts are water-soluble, they are most suitable for use as injections.

In the leukotropin antagonist, the proportion of therapeutically active ingredient to carrier ingredient can vary between 0% by weight and 0% by weight. Leukotriene antagonists are available in granules,
It may be administered orally in the form of fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids, or intravenously or intramuscularly as an injection. It may also be administered intradermally or subcutaneously. It can also be used in the form of suppositories, nasal drops, eye drops, or inhalants for local administration to the rectum, nose, eyes, and lungs. Alternatively, it may be prepared as a powder for injection before use. Pharmaceutical organic or inorganic, suitable for oral, enteral, parenteral or topical administration.
Solid or liquid carriers or diluents can be used to prepare the leukotriene antagonists of the invention. Examples of excipients used in producing solid preparations include lactose, sucrose, starch, Merck, cellulose, texturin, kaolin, calcium carbonate, and the like.

Liquid preparations for oral administration, i.e. emulsions, syrups,
Suspensions, solutions, etc. - contain an inert diluent used for concentration, such as water or vegetable oil.

In addition to inert diluents, the formulations may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents, or preservatives. Liquid preparations may be enclosed in capsules of absorbable material such as gelatin. Preparations for parenteral administration, i.e. injections, suppositories, nasal drops, eye drops,
Examples of solvents or suspending agents used in the production of inhalants include water, propylene glycol, polyethylene glycol, benzyl aral, ethyl oleate, lecithin, and the like.

Examples of bases used in suppositories include cacao butter, emulsified cacao butter, lauric butter, and lytepsol. The preparation method may be any conventional method.

Clinical dosages for a compound of the invention for adults when used by oral administration are generally 7 daily doses of 0.0/
-100ρ■, preferably 0.0/~100m
9, but it is more preferable to increase or decrease the amount as appropriate depending on age, pathological condition, symptoms, presence or absence of simultaneous treatment, etc. The daily dose of the leukotrione antagonist may be administered 7 times a day, or divided into 2 or 3 doses every 7 days at appropriate intervals;
Intermittent administration may also be performed.

When used as an injection, the compound of the present invention is preferably administered continuously or intermittently to adults in an equivalent amount of 0,007 to 100 m9.

〔Effect of the invention〕

According to the present invention, a novel vinylthiazole derivative having significant leukotriene antagonism is provided. The same vinylthiazole derivative is used as a leukotriene antagonist.
It is useful for the prevention and treatment of various diseases involving leukotrienes, such as allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, angina pectoris caused by cerebral vasoconstriction or decreased coronary flow.

〔Example〕

The present invention will be explained in more detail below based on synthesis examples, examples, and test examples of reaction intermediates, but these are not intended to limit the scope of the present invention in any way. [IRJ, 1'-TLCJ and l'-NMRj in Synthesis Examples and Examples
represent "infrared absorption spectrum,""thin layer chromatography," and "nuclear magnetic resonance spectrum," respectively, and the proportion of solvent described in the section of separation by chromatography indicates the volume ratio; The solvent in parentheses indicates the developing solvent.1 rIRJ is measured by the KBr tablet method unless otherwise specified, and the unit is Crn-1.
The solvent in parentheses of "NMR" indicates the measurement solvent, and the unit is δppm.

Further, the compound boils described in Examples correspond to the boils described in Table 7, Table 2, Table 3, and Table ≠.

In addition, in Tables 1 and 2, Me and Et represent a methyl group and an ethyl group, respectively.

Synthesis example/2-(3-thiocyanate styryl)-μ-i! −(3
-aminostyryl)-μm ingrovir thiazole z,
oy, sodium nitrite 8 μ72 and water t, 2! me
To the mixture, under water-cooled stirring,! While maintaining the temperature below °C, a solution of 3.4 trnl of concentrated sulfuric acid in 10 g of water was added dropwise. After the dropwise addition was completed, the mixture was stirred at the same temperature for 75 minutes to prepare a diazonium salt.

This diazonium salt solution was added to an ice-cooled thiocyanate solution.
M-2,3J-P, potassium thiocyanate 2 hiro, sy
and water/3rrtl mixture.

Stir for 30 minutes under water cooling, then raise the temperature to room temperature t3
After stirring for an hour, the precipitated solid was extracted with ethyl acetate. After drying, the solvent was distilled off and the resulting crude product was subjected to silica gel column chromatography (hexane/ethyl acetate = 4/l).
The title compound was purified with 2.79 ? (Yield θ%)
I got it.

m, p, ("C); J, 2-33 ■R (cr/I-']; I/:, 2/l/L
O,/jI O.

Riyo O 7 Hiroyoshi Synthesis Example 2 In the same manner as Synthesis Example//, λ-(3-thiocyanatostyryl)-μmt-butylthiazo-1-2-(3-thiocyanatostyryl)-cuphenylthiazole, u-(
J-thiocyanate styryl)-+-(4t-tolyl)thiazole, 2-[3-thiocyanate styryl)benzothiazole, and λ-(3-thiocyanate))-j-methylbenzothiazole were obtained.

Synthesis Example 3 j-(3-thiocyanate styryl)- obtained in Synthesis Example 1
Hiro-Isopropylthiazole/, 2j? , sodium hydroxide 3.3? , 20 me of ethanol and 20.1 of ice is stirred at room temperature for 1 hour. After 1 hour, the product was extracted with a mixed solvent of ethyl acetate and toluene. /hexane=///0→t/r) to obtain the oily title compound (yield 4t3%).

■ R(CWI-'); C, :/! 10. /
≠9ta, 10rij, HataTLCRf =0. t/ (x
Synthesis Example G Perform the same operation as in Synthesis Example 3 to obtain 2-(3-mercaptosteryl)-pt-butylthiazole, λ(3-mercaptostyryl)- Cuphenylthiazole, λ-(3-
Mercaptostyryl)-gu(4t-1ruyl)thiazole, 2-(3-mercaptostyryl)benzothiazole, and 2-(3-mercaptostyryl)-termethylbenzothiazole were obtained.

Example 1 @ ``'rQIfflL*(t, 0 object - 2J' Q
my) N,N-dimethylformamide λ,j punishment solution,
While stirring under water cooling, 60% sodium hydride≠j■ was added. After the addition, the temperature was raised to room temperature while stirring, and after 75 minutes, Copecomo-2-methylpropionate ethyl/yojμ was added to the reaction mixture. After stirring at room temperature for 10 minutes, further +
Stir for 30 minutes at o'c. After cooling the reaction mixture with water, /
The product was extracted with a mixed solvent of ethyl acetate and toluene. After drying, the solvent was distilled off and the obtained crude product was subjected to silica gel column chromatography (ether/low hexane=/ /1) Purify by
The oily title compound 2/Oyny (yield to) was obtained.

IR[crr+-1]; v=tyts, taej,
12 Otsu 011130, II/,! ;TLCRf=0. 'l 7 (!-Til:n-hexane=/:J) Example 2 In the same manner as in Example 1, the title compounds shown as compound numbers /, /r and 20 in Table 1 were obtained.

Example 3 Compound 2701q obtained in Synthesis Example 3, ethyl acrylate ♂μ! and tetrahydrofuran2. One drop of benzyltrimethylammonium hydroxide was added to the mixture of A' and the mixture was stirred at room temperature overnight.

The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ether/low hexane l/J') to obtain the title compound/2θη (yield: j7) as an oil.

IRI:crn-”]; v=t72t,/r♂o,
iti tao.

/23ta, //70. the law of nature! 0 TLCR, f=0. lI/(!-thyl:n-hexane=/:J) Example Hiro, z-diethyl-≠-(3-formylphenylthio)
Ethyl butyrate OO~, no methyl-Hiro-isopropylthiazole? T, 7r? and acetic anhydride 4topμ! The mixture was heated and stirred on a 770°C oil bath for 4tt hours. After the reaction was completed, the reaction mixture was extracted with toluene, washed with water, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (toluene/ether = 20//→/!//)
The oily title compound j60 (yield μ4L%) was purified by
) was obtained.

TLCFLf=0. t♂(ether:n-hexane:=
l:/) NMR (CD01m) 0. J' A (1=H,
t)/, 2-2. /(/OH,m), 2.
2-j,,2(yoH,m),j,4j(jH,s).

6.64 (/H,S), 7.0-7.7(t
H, m) Example! Compound 2♂O■ synthesized in Synthesis Example 1 was mixed with ethanol j t
ttl, then 3N aqueous sodium hydroxide solution/'711 was added, and the mixture was refluxed with stirring on an IOO°C oil bath for 1 hour. The reaction mixture was cooled to room temperature, whereupon 3
-Chloro-λ, 2-dimethylpropionic acid o, r4ty
was added and stirred at room temperature for 2 days. After the reaction was completed, the pH was adjusted to 2 with /N-hydrochloric acid, and the product was extracted with ethyl acetate. After drying, the crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (n-hebutane/ethyl acetate = J
' / /→2/l) to obtain the title compound 7.
(Yield 2/%) was obtained.

m, p, [°C); 107~//θ rR(crn-':); v=tyoo, tt4to
,tt! 7j.

ri60 Example 6 The compound was obtained.

Example 7 Compound 2007n9 obtained in Example 1, 200 μl of sodium hydroxide, ethanol J rttl and 1.2 tt of water
l mixture! The mixture was stirred at 0° C. for 1 hour. After cooling the reaction mixture, the pH was adjusted to j with /N-hydrochloric acid, the product was extracted with toluene, the toluene layer was dried, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ether/low hexane = / / / → Purify with ether (alone),
The title compound/J-0■ (yield: ♂l) was obtained.

m, p, ['c]; //7-t/7. rIR(
m']; ν=/6ri0. /2!0. //j!
.

the law of nature! ! Example! In the same manner as in Example 7, compound numbers 2, ri, /
The title compounds shown as J, /2 and 2/ were obtained.

EXAMPLE The compound 100 obtained in Example 1 was dissolved in methanol/100g and ether 200g, and a 2ml solution of sodium periodate 100g in 2ml of water was added dropwise while stirring under water cooling. After completion of the dropwise addition, the reaction mixture was heated to room temperature; 7. Stir for 5 hours, then stir for 5 more hours.
Stirred at 0°C for 30 minutes. From the reaction mixture, toluene-
The product was extracted with ethyl acetate, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ether/n-hexane=///-+2//) to obtain 120 ml of the title compound as an oil (yield: 6 h).

[R[crn-']; v=/71j, /II! !
, /230,1/2! .

lO Hiromu! TLCrcf=o, ro (ether: n-hexa7
=/ : / ) Example i.

Compound l♂0~ obtained in Example≠ was dissolved in tetrahydrofuran/
To this solution was added a solution of sodium tungstate/■ in water/rtrl containing a trace amount of acetic acid, and then after continued stirring at 6°C for an hour, the reaction mixture was dissolved. Water was added to the solution, and the product was extracted with ethyl acetate. After drying, the solvent was distilled off and the obtained crude product was subjected to silica gel chromatography (ether/n-hexane=l//
) to obtain the oily title compound/73~ (yield 0%)
I got it.

IR(crn), v=/720. /II! j, /j
Purification at θ0° (ethyl acetate alone) yields the title compound l (
A yield of 10% was obtained.

m, p, ('C:); /J/,,t-/3! IR [
:cTn'); v=I710. //70. l0I1
0゜ri, it! 223. //Hiro0 TLCRf = 0.34 (ether 20-hexane =
/:/) Example// The compound obtained in Synthesis Example t of 23 and the compound 100~ were added to methanol 2. ! , 1, and a water/rttl solution of sodium periodate was added thereto under stirring at room temperature. 3. At room temperature.
After stirring for 3 hours, the temperature was further raised to 60°C, and stirring was continued for 1 hour. After the reaction was completed, water was added to the reaction mixture, the pH was adjusted to J with /N-hydrochloric acid, and the product was extracted with ethyl acetate-toluene. After drying the extract, the solvent was distilled off and the resulting crude product was subjected to silica gel column chromatography.Compounds 2j to Otode shown in Table 2 below can be synthesized according to the method of the above-mentioned Examples.

Table 2 Example 12 Well-pulverized vinylthiazole derivative (Compound Haruhiro) 1
000? , lactose j+9009, crystalline cellulose 2000
ff, low substituted hydroxypropylcellulose 1000
? , and 1ooy of magnesium stearate were mixed well, and the compound ioom in the tablets was prepared by direct compression.
Uncoated tablets containing y were prepared. Sugar-coated tablets and film-coated tablets were produced by sugar-coating or film-coating these uncoated tablets.

Example/3 Production of capsules Well-pulverized vinylthiazole derivative (compound A4)
t 000? , corn starch 30002, lactose 6200? , Crystalline cellulose/000? , and 1 ooy of magnesium stearate to prepare capsules containing io of the above compound in 1 capsule/20 .

Example/4L Production of inhalant Well-pulverized vinylthiazole derivative (Compound shop≠)
JP, medium-chain saturated fatty acid triglyceride 702, and sorbitan monooleate O8λ2 are thoroughly mixed, and the mixture is mixed with each /! , 2■! Weigh it into a ml aerosol aluminum container, and add 1 Freon per container.
/Mixture)♂Hiroshi, after cold filling of r■,! injection 100
A metered dose inhaler containing the compound j was prepared in a 1 container jd by attaching a μnuma quantitative adapter.

Example/j SR8 antagonism in vitro.

Male Hartley () (artl) weighing 200~HirojO2
After extracting the terminal ileum of a guinea pig and washing the lumen, the ileum was placed in a tissue bath of ml containing Tyrode's solution consisting of the following components. Its components are sodium chloride/, 36mM, potassium chloride 2.7mM,
Sodium hydrogen carbonate/, RImM, magnesium chloride/, OJ'mM, calcium chloride 1. ? mm
, sodium dihydrogen phosphate 0.4 tmMs and glucose 3.6mM. Keep the temperature of the liquid in the bath at 37°C, and then! Aerated with oxygen/3% carbon dioxide. To eliminate contractions caused by histamine and acetylcholine, the buffer contains io? /ml Mevilamine Toyo x 10
9/me of atropin was added. Isometric measurements were performed with an isotonic transducer (T[)-//2S, Nihon Kohden) tension displacement transducer, and changes in the number of grams of tension were measured using a recticorder (RTG-'112≠, Nihon Kohden).
It was recorded in A tension of O0!2 was passively applied to the ileum to obtain an ileal contraction response to SR8 extracted from guinea pig lungs.

The sustained contraction height due to l unit of SR3 (equivalent to histamine jn?) was used as a control. Add various concentrations of the test drug into the tissue bath and observe control contractions! Concentration of test drug attenuated by Q% (IC
s. ) was taken as the minimum effective concentration and the results are shown in Table 3.

Table 3 Example/Male Hartle with weight 350-5002
y) Anesthetize a guinea pig with urethane and use a Barbard type respirator to test the Conzzetto wrestler (K).
Airway resistance was measured by a modified version of the Onzett-Roessler method. TD40. /~/, 0μg/
The suppression rate (%) by oral administration of the test drug against the increase in airway resistance caused by intravenous administration of # was calculated and the results are shown in Table μ.

The following 2 publicly known methods were used for comparison in the same manner as in Table 1 Reference Examples Example/J.
The suppression rate of increase in airway resistance due to intravenous administration and oral administration of the compound was calculated and the results are shown in Table 5.

Table 5 Test Examples Acute Toxicity Test SD male rats! Weekly μ~! The compound of the present invention was suspended in a 7% tragacanth solution and orally administered to one group of animals,
Observations were made in the evening to determine the number of deaths, and the results are shown in Table 5.

Table 5

Claims (4)

[Claims] (1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above formula, R^1 represents a hydrogen atom or a straight chain or branched alkyl group having 1 to 5 carbon atoms. , R^2 and R
^3 is each independently a hydrogen atom, a phenylalkyl group which may have a substituent on the benzene ring, or a carbon number of 1
~5 represents a straight chain or branched alkyl group, but R^
2 and R^3 may be combined to form a cyclopentane ring or a cyclohexane ring. R^4 and R^5 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or a phenyl group which may have a substituent, and R^4 and R^5
Together, there are ▲mathematical formulas, chemical formulas, tables, etc.▼(
In the formula, R^6, R^7, R^8 and R^9 each independently represent a hydrogen atom, a halogen atom,
Straight chain or branched alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, carboxyl group, total carbon number 2 to 5
6 alkoxycarbonyl group, an acyl group having 2 to 5 carbon atoms, an amino group, an acylamino group having 2 to 5 carbon atoms, or a nitro group. ) may form a butadienylene group. Also, m represents an integer from 0 to 5, and n represents 0-2.
represents an integer. ) and pharmaceutically acceptable salts thereof. (2) The compound according to claim 1, wherein in the general formula (I), the substituent on the benzene ring is located at the meta position. (3) The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above formula, R^1 is a hydrogen atom or a straight chain or branched alkyl group having 1 to 5 carbon atoms. , R^2 and R^3 each independently represent a hydrogen atom, a phenylalkyl group which may have a substituent on the benzene ring, or a linear or branched alkyl group having 1 to 5 carbon atoms. It represents R
^2 and R^3 may be combined to form a cyclopentane ring or a cyclohexane ring. R^4 and R^5 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or a phenyl group which may have a substituent, and R^4 and R^
Together with 5, there are ▲mathematical formulas, chemical formulas, tables, etc.▼
(In the formula, R^6, R^7, R^8 and R^9 each independently represent a hydrogen atom, a halogen atom,
Straight chain or branched alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, carboxyl group, total carbon number 2 to 5
6 alkoxycarbonyl group, an acyl group having 2 to 5 carbon atoms, an amino group, an acylamino group having 2 to 5 carbon atoms, or a nitro group. ) may form a butadienylene group. Also, m represents an integer from 0 to 5, and n represents an integer from 0 to 2.
represents an integer. 1. A leukotriene antagonist comprising a vinylthiazole derivative represented by () and a pharmaceutically acceptable salt thereof as an active ingredient. (4) The leukotriene antagonist according to claim 3, characterized in that in the general formula (I), the active ingredient is a vinylthiazole derivative in which the substituent on the benzene ring is at the meta position or a pharmaceutically acceptable salt thereof. agent.