WO1997021691A1 - Thiazole derivatives - Google Patents

Abstract

Thiazole derivatives of general formula (I) and salts thereof, exhibiting both leukotriene D4 and thromboxane A2 receptor antagonisms. In formula (I), X is carbonyl or sulfonyl; Y is carboxyl, C1-C5 alkoxycarbonyl or 1H-tetrazol-5-yl; Z is C1-C5 alkyl, C3-C6 cycloalkyl or phenyl; W is C2-C5 alkylene or 1,4-cyclohexylene, and R is optionally subsituted phenylsulfonylamino, phenylsulfonyl, N'-phenylthioureido or C1-C5 alkylsulfonylamino.

Description

 Description Thiazole derivatives Branch surgery

The present invention relates to a novel thiazol derivative having leukotriene D (hereinafter abbreviated as LTD) receptor antagonism and thromboxane A ₂ (hereinafter abbreviated as TXA ₂ ) receptor antagonism, and a synthetic intermediate thereof. The present invention relates to a body and salts thereof, and a wipe allergic agent containing them. Background art

 For the treatment of allergic diseases such as bronchial asthma, an anti-allergic agent such as a histamine receptor antagonist or a mediator release inhibitor from mast cells, or steroids, is used. Bronchodilators such as tin derivatives and tri-exchanger receptor stimulants have been used.

 In recent years, allergic diseases have been recognized as allergic inflammation based on their pathological state, and the involvement of various inflammatory cell mediators has been clarified. Taking bronchial asthma as an example, bronchial asthma is characterized by increased airway responsiveness to various stimuli, with reversible airway narrowing, airway mucosal edema, increased mucus secretion, and infiltration of inflammatory cells into the airway wall. It is recognized as a disease.

In addition, regarding the mediators involved, LTD has a strong bronchoconstrictive effect, has an increased airway vascular permeability and mucus secretion effect, and TXA ₂ supports not only a strong bronchoconstrictive effect but also airway hyperreactivity. It is suggested that With the trend of therapeutic research for allergic diseases such as bronchial asthma, LTD receptor antagonists and TXA ₂ synthesis inhibitors have been launched on the market, and TXA ₂ receptor antagonists have been clinically applied. Higher efficacy has been confirmed compared to conventional antiallergic agents.

However, as described above, allergic diseases such as bronchial asthma are caused by the simultaneous involvement of various mediators, resulting in their pathology. Its efficacy is limited, and by simultaneously suppressing both the mediators, LT Da and TXA ₂ , which are the major mediators in allergic conditions, a new anti-allergic agent that can be expected to have superior therapeutic effects Development is desired.

LTD., And as a compound having both a receptor antagonism for both mediators TXA _2, JP-3 258 759, JP-A No. 4 one 1 54757, JP-A No. 4-1 54766, JP-A No. 5 26 2736 And Japanese Patent Application Laid-Open Nos. 5-279336 and 6-41 051, which are structurally different from the compounds of the present invention. Receptor antagonism of LTD, which is considered to be a major mediator, is considered to have insufficient potency to expect a sufficient therapeutic effect as an antiallergic agent.

The present invention has been made in view of the current state of treatment and therapeutic research for such allergic diseases, and it is an object of the present invention to provide LTD ₄ and TXA which play a major role in the development of allergic diseases. _An object of the present invention is to provide a novel compound which has a potent therapeutic effect on both of the two mediators and which can be expected to have a more excellent therapeutic effect, and an antiallergic agent comprising these as active ingredients. Disclosure of the invention

The present inventors have conducted intensive studies in order to achieve the above-mentioned object in the treatment of allergic diseases and the above-mentioned research trends. As a result, the thiazole derivative of the present invention is mainly used for the development of allergic diseases. With superior antagonistic activity against both mediators, LTD ₄ and TXA ₂ , which play an important role, and are superior to single mediator-receptor antagonists or synthetic inhibitors mentioned above. The inventors have found that the present invention has an effect, and have completed the present invention.

 That is, the present invention provides a compound represented by the general formula (I):

(Wherein, X is the force Ruponiru group or a sulfonyl group,丫is a carboxyl groups, C ₅ alkoxycarbonyl group, or 1 H- Te Torazoru 5 I le group, Z is C, - ₅ alkyl groups, C ₃ - 6 cycloalkyl or phenyl group, W is C ₂ - a ₅ alkylene group or a 1, 4 xylene group to Shikuro, R represents an optionally substituted phenylpropyl sulfonyl amino group, Fuweniru sulfonyl group, N '- off We two Ruchiourei de group or C, -. ₅ alkylsulfonyl is alkylsulfonyl § Mi amino group) represented by thiazole derivative or a salt thereof and the general formula (I) thiazole derivative or a pharmacologically in An antiallergic agent containing an acceptable salt as an active ingredient and a general formula (II) which is a synthetic intermediate of a thiazole derivative of the general formula (I)

(式中、 Zは C ,- 5 アルキル基、 C 3- 6 シクロアルキル基またはフエ二 ル基であり、 Wは C₂- ₅ アルキレン基または 1， 4ーシクロへキシレン 基であり、 Rは置換されていてもよいフ Iニルスルホニルァミ ノ基、 フ ヱニルスルホニル基、 N' —フヱ二ルチオゥレイ ド基または C，- ₅ アル キルスルホニルァミ ノ基である。 ） で示されるベンジルァミン誘導体ま たはその塩に関する。

(Wherein, Z is C, - 5 alkyl group, a C 3- 6 cycloalkyl group or a phenylene Le group, W is C ₂ - a ₅ alkylene group or a 1, 4-xylene group to Shikuro, R represents a substituted which may be full I sulfonyl sulfonyl § Mi amino group, full Wenirusuruhoniru group, N '- off We two Ruchiourei de group or C, -. ₅ is Al kill sulfonyl § Mi amino group) Benjiruamin derivative represented by Or its salt.

 In the above general formulas (I) and (II), the C, -5 alkoxycarbonyl group represented by 丫 is a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group. , N-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, n-pentoxycarbonyl group and the like. Preferably, it is a methoxycarbonyl group.

Examples of the C ₅ alkyl group represented by Z include straight groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, and n-pentyl group. Or a branched alkyl group. Particularly preferred are an isopropyl group and a tert-butyl group. C ₃ - The ₆ cycloalkyl group, cyclopropyl group, Shikuropuchi group, cyclopentyl group, cyclohexyl group cyclohexylene. Particularly preferred are a cyclopropyl group and a cyclobutyl group.

C ₂ represented by W - The ₅ alkylene group, an ethylene group, trimethylene down group, Te Toramechiren group, pentamethylene group. Particularly preferred is a tetramethylene group.

R which may be substituted represented by R: r-nylsulfonylamino group, r-inylsulfonyl group, N'-f: L-dithiothioureido group includes a fluorine atom, a chlorine atom, a bromine atom Halogen atoms such as iodine atoms, alkyl groups such as methyl and ethyl groups, and ethoxy groups and ethoxy groups. And a lucoxy group. Particularly preferred are a fluorine atom, a chlorine atom, a bromine atom, a methyl group and a methoxy group. C, - ₅ alkylsulfonyl amino group, methyl, Echiru, n- propyl, i an isopropyl, n-butyl, i Sobuchiru, tert- heptyl, alkylsulfonyl straight銷or is branched, such as n- pentyl Ami Group.

 When 化合物 or more asymmetric carbon atoms are present in the compounds of the present invention represented by the general formulas (I) and (II), any of the racemic forms, diastereoisomers and individual optical isomers may be used. It is included in the present invention, and when a geometric isomer is present, the (E) -form, the (Z) -form and a mixture thereof are all included in the present invention.

 Salts of the compounds of the present invention represented by the general formulas (I) and (II) are also included in the compounds of the present invention. These salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates, phosphates, carbonates, etc. Inorganic acid salts, lower alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, and arylsulfonates such as P-toluenesulfonate Organic salts such as fumarate, succinate, citrate, tartrate, oxalate, and maleate; amino acids such as glycine, alanine, glutamate, and aspartate; and sodium And alkali metal salts such as salts and potassium salts. Preference is given to sodium salts or hydrochlorides.

The thiazole derivative of the general formula (I) can be produced by the following method. Manufacturing a method Λ

Κ method Β method C

 (I c)

Formula D

 I d)

(Wherein, X, Z, W and R are as defined above, Y 'is C, - representing the _s Arco Kishikarubo two Le group.) [Preparation method a] Preparation of the compound of the present invention represented by the general formula (II)

 -The compound represented by the general formula (III) (which can be produced by the production method described in JP-A-6-80654) and the compound represented by the general formula (IV) are subjected to a dehydration reaction in an inert solvent. The compound represented by the general formula (II) can be produced by a reduction reaction with a reducing agent. The compound represented by the general formula (II) is a useful synthetic intermediate of the compound represented by the general formula (I).

 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, and for example, ethanol, methanol, and the like are preferable.

 The reducing agent to be used is not particularly limited as long as it is a normal reducing agent for reducing an imino group to an amino group, but for example, sodium borohydride, lithium aluminum hydride and the like are preferable.

 This reaction uses 1 to 1.3 equivalents of the compound represented by the general formula (IV) and 1 to 3 equivalents of the reducing agent with respect to the compound represented by the general formula (III). In this reaction, a molecular sieve may be present in the reaction solution in order to promote the dehydration reaction. In this case, the amount of the molecular sieve is usually 20 Omg for the compound〗 mm 0 I represented by the general formula (I I I).

 The reaction temperature may be appropriately selected from the range of room temperature to the boiling point of the solvent, and the reaction time may be appropriately selected from the range of 4 to 12 hours.

 — The compound represented by the general formula (III) can also be produced by the following production method.

■ S ", CH ₃

(VII) (In the formula, Z is the same as described above.)

 That is, the compound represented by the general formula (III) can be produced by dehydrating and condensing the compound represented by the general formula (VIII) with isophthaldialdehyde in acetic anhydride.

 In this reaction, 1 to 20 equivalents of isophthaldialdehyde and an excess amount, preferably 2 to 3 equivalents of acetic anhydride are used based on the compound represented by the general formula (VII).

 The reaction temperature may be appropriately selected from the range of 50 to 180 ° C, and the reaction time may be appropriately selected from the range of 5 to 36 hours.

[Process A] in the general formula (I) Y is C, - ₅ alkoxy process of the present invention compound represented by the general formula is a carbonyl group (I a)

 By reacting the compound represented by the general formula (II) with the compound represented by the general formula (V) in an inert solvent in the presence of a base or in the coexistence of a base and 4-dimethylaminoviridine, the desired general compound is obtained. The compound represented by the formula (Ia) can be produced. The compound represented by the general formula (Ia) is a useful synthetic intermediate for the compound represented by the general formula (Ib). The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction. For example, dichloromethane, 1,2-dichloroethane and the like are preferable.

 The base to be used is not particularly limited as long as it usually acts as a base, but a tertiary ammine organic base such as triethylamine or pyridine is preferable.

 In this reaction, the compound represented by the general formula (V) is used in an amount of up to 3 equivalents and the base is used in an amount of 2 to 8 equivalents based on the compound represented by the general formula (II).

 When 4-dimethylaminopyridine coexists, the amount is determined by the general formula (I

It is usually used in an amount of 0.5 equivalent to the compound represented by I). The reaction temperature ranges from 0 to 80 ° C, and the reaction time is! 1 to 1 ◦ Time may be selected as appropriate.

 [Production method B] Production method of the compound of the present invention represented by the general formula (Ib), wherein 丫 in the general formula (I) is a carboxyl group.

 — The desired compound represented by the general formula (Ib) can be produced by subjecting the compound represented by the general formula (la) to a hydrolysis reaction with a base in an inert solvent.

 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction. For example, methanol and ethanol are preferred.

 The base to be used is not particularly limited as long as it is usually used for a hydrolysis reaction of an ester group. For example, a 1 N aqueous sodium hydroxide solution, a 1 N aqueous potassium hydroxide solution and the like are preferable.

 The amount of the base is 1 to 50 equivalents to the compound represented by the general formula (la).

 The reaction temperature may be appropriately selected from the range of 0 ° C. to the boiling point of the solvent, and the reaction time may be appropriately selected from the range of 1 to 8 hours.

 [Production Method C] A method for producing the compound of the present invention represented by the general formula (Ic), wherein X is a carbonyl group and Y is a carboxy group in the general formula (I).

 — The desired compound represented by the general formula (1c) can be produced by reacting the compound represented by the general formula (II) with phthalic anhydride in an inert solvent. This reaction may be carried out in the presence of a base in the reaction solution in advance.

The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction. For example, toluene and 1,2-dimethoxetane are preferable. The base to be used is not particularly limited as long as it usually acts as a base, and for example, sodium acetate, potassium acetate and the like are preferable.

 In this reaction, a compound represented by the general formula (II) is converted to phthalic anhydride! Use up to 2 ◦ equivalents and 1.3 equivalents of base.

 The reaction temperature may be appropriately selected from the range of room temperature to the boiling point of the solvent, and the reaction time may be appropriately selected from the range of 2 to 48 hours.

 [Production method D] Production method of the compound of the present invention represented by the general formula (Id), wherein X is a carbonyl group and Y is a 1 H-tetrazol-5-yl group in the general formula (I)

 The compound represented by the general formula (II) and the compound represented by the general formula (VI) are condensed alone or in a solvent such as condensing agent or hydroxy 1H-benzotriazole monohydrate (hereinafter, abbreviated as HOBt). By performing a condensation reaction in combination with the above, the desired compound represented by the general formula (Id) can be produced.

 The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction. For example, N, N-dimethylformamide and the like are preferable.

 The condensing agent to be used is not particularly limited as long as it usually acts as a dehydrating condensing agent. For example, 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (hereinafter abbreviated as ws C), Dicyclohexylcarbodiimide is preferred.

 This reaction generally uses 1 equivalent of the compound represented by the general formula (VI), 1.1 equivalent of the condensing agent, and 1.1 equivalent of H 0 Bt with respect to the compound represented by the general formula (II). .

The reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time is 2-30. What is necessary is just to select suitably from the range of time.

 All of the target compounds produced by the above-mentioned production methods a and A to D can be isolated and purified by a conventional method.

The thiazole derivative of the general formula (I) thus obtained has an excellent anti-allergic effect because it has both LT DA receptor antagonism and TXA ₂ receptor antagonism, and has an allergic bronchial effect. It is highly effective in preventing and treating various allergic diseases such as asthma, rhinitis and conjunctivitis, atopic dermatitis, gastroenteritis, colitis, spring catarrh, and nephritis.

 The thiazole derivative of the present invention can be used alone or in various dosage forms using a known preparation method. For example, it can be used for oral preparations such as tablets, capsules, granules, powders and syrups, and parenteral preparations such as injections, nasal drops, eye drops, ointments, suppositories and inhalants. The dosage varies depending on the patient's symptoms, age, body weight, therapeutic effect, administration method, and administration period.For oral administration, it is preferable that the dose be in the range of 0.1 mg to 1 g per adult per day. is there. BEST MODE FOR CARRYING OUT THE INVENTION

 〔Example〕

 Hereinafter, the compounds and the production method of the present invention will be described in more detail with reference to Examples, but the present invention is not limited to only these Examples. In addition,

The 'H-NMR spectrum was measured with a J NM-EX270 type spectrometer (270 MHz, manufactured by JEOL Ltd.) using tetramethylsilane (TMS) as an internal standard. Indicated by The mass spectrum was measured with a QP1 OOOEX type spectrum meter (manufactured by Shimadzu Corporation).

(Reference Example 1) (E) — 3— (2- (4-cyclobutyl thiazol-2-yl) ethenyl) Production of benzaldehyde

 A mixture of 4.2 g of 4-cyclobutyl-2-methylthiazole, 18.4 g of isophthaldialdehyde and 4 ml of acetic anhydride was heated to reflux for 12 hours while stirring. Acetic anhydride was distilled off under reduced pressure, ethyl ether was added, and insolubles were filtered off. Then, 2.8 ml of concentrated hydrochloric acid was added and the mixture was dried under reduced pressure. The residue was washed with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, extracted with getyl ether, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 5.2 g of compound were obtained.

Ή-NMR (DMS O-d6) (5: 1.86 to 2.15 (2H, m), 2.22 to 2.45 (4H, m), 3.69 (1H, quint), 6.88 (lH, s), 7.40 (2H, d) , 7.54 (1H, t), 7.78 (lH, dd), 7.81 (1H, dd), 8.02 (1H, s), 10.04 (1H, s)

MS On): 269 (M ⁺ ), 240, 212

 (Example 1)

 (E) 1 N— (2—benzenesulfonamidoethyl) 1 3— (2-

Preparation of (4-cyclobutylthiazol-1-yl) ethenyl) benzylamine (Preparation method a)

(E) — 3- (2- (4-cyclobutylthiazo-1-yl-2-ethyl) ethenyl) benzaldehyde 404 mg, a mixture of 320 mg of 2-benzenesulfonamidoethylamine and 1 OmI of ethanol was added to 70 After stirring at 6 ° C for 6 hours, sodium borohydride (64 mg) was added, and the mixture was further stirred for 1 hour. After distilling off the solvent under reduced pressure, water was added for extraction with chloroform.The organic layer was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The residue was purified by (form: methanol: 98: 2) to obtain 347 mg of the title compound. The physical properties are shown in Table 1. Hereinafter, Examples 2 to 52 were produced in the same manner as in Example 1. Table 1 shows the physical property values of the compounds of the obtained Examples.

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(Example 53)

 (E) -2- (N— (2-benzenesulfonamidoethyl) -1-N— (3- (2- (4-cyclobutylthiazol-12-yl) ethenyl) benzyl)) Sulfamoylbenzoic acid Of methyl acid salt (Process A)

 (E) —N— (2-benzenesulfonamidoethyl) -13- (2- (4-cyclobutylthiazol-1-yl) ethenyl) obtained in Example 1 91 mg of benzylamine, 78 mg of methyl 2-chlorosulfonyl benzoate was added to a mixture of 0.2 ml of lyethylamine, 12 mg of 4-dimethylaminopyridine, and 1 OmI of 1,2-dichloroethane, and the mixture was stirred at 40 ° C. for 5 hours. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Ether = 9: Purification by〗) to give 94 mg of the title compound. Table 2 shows the physical property values.

Thereafter, Examples 54 to 106 were produced in the same manner as in Example 53. Table 2 shows the physical property values of the obtained compound.

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(Example 107)

 (E) -2- (N— (2-benzenesulfonamidoethyl) -1-N— (3- (2- (4-cyclobutylthioazol-1-yl) ethenyl) benzyl)) Sulfamoylbenzoic acid Production (Method B)

 (E) -2- (N- (2-benzenesulfonamidoethyl) -N- (3- (2- (4-cyclobutylthioazo-1-yl) ethenyl) obtained in Example 53 Benzyl)) 8 Omg of methyl sulfamoylbenzoate was dissolved in 4 ml of methanol, 3 ml of a 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred at 40 C for 3 hours. Ice water was added to the reaction solution, the mixture was neutralized with a 1N aqueous hydrochloric acid solution, and the deposited precipitate was collected by filtration to obtain 65 mg of the title compound. Table 3 shows the physical property values.

Thereafter, Examples # 08 to 160 were produced in the same manner as in Example 107. Table 3 shows the physical property values of the obtained compound.

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〔実施例 1 61〕

(Example 1 61)

 (E) — N— (2-benzenesulfonamidoethyl) -N- (3- (2- (4-cyclobutylthiazo-1-yl-2-yl) ethenyl) benzyl) Production of phthalamide acid (Process C)

 (E) -N- (2-benzenesulfonamidoethyl) 1-3- (2- (4-cyclobutylthiazol-2-yl) ethenyl) obtained in Example 1 Benzoamine 1 0 mg and phthalic acid A mixture of 327 mg of anhydride and 10 ml of toluene was stirred at 120 ° C. for 24 hours. After distilling off the toluene under reduced pressure, the residue was purified by silica gel gel column chromatography (chloroform: methanol 2 9: 1) to obtain 13 mg of the title compound. Table 4 shows the physical property values.

Thereafter, Examples 162 to 192 were produced in the same manner as in Example 161. Table 4 shows the physical property values of the obtained compound.

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 (E) 1-5— (2-(N— (2— (4-chlorobenzenebenzenesulfonamide) ethyl) 1 N— (3— (2-(4-cyclobutyl thiazol-1--2-yl) ) Ethenyl) benzyl) carpamoyl) phenyl) Production of 1H-tetrazole (Preparation D)

 (E) -N- (2- (4-cyclobenzenebenzenesulfonamide) ethyl) obtained in Example 9-13- (2- (4-cyclobutyltylazol-2-yl) ethenyl) benzylamine Mixture of 1 75 mg, 3— (1H—Tetrazol-5-yl) Benzoic acid 68 mg, WSC 76 mg, H0Bt6 1 mg and N, N—dimethylformamide 5 ml Was stirred at room temperature for 17 hours. After evaporating N, N-dimethylformamide under reduced pressure, add water, acidify with 2N aqueous hydrochloric acid, extract with ethyl acetate, wash the organic layer with water, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give 50 mg of the title compound. Table 5 shows the physical property values.

Thereafter, Examples 194 to 200 were produced in the same manner as in Example 193. Table 5 shows the physical property values of the obtained compound.

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 (E) — 2— (N- (4— (4-chlorobenzenebenzenesulfonamide) butyl) -1-N— (3- (2- (4-cyclobutylthiazol-1-yl) ethenyl) benzyl )) Production of sodium salt of sulfamoylbenzoic acid (E) -2- (N— (4- (4- (4-chlorobenzenebenzenesulfonamide) butyl) -N— (3) obtained in Example 117 — (2- (4-cyclobutylthiazol-1-yl) ethenyl) benzyl)) Dissolve 1 O Omg of sulfamoylbenzoic acid in 1 OmI of methanol, then add 2 N aqueous sodium hydroxide solution 0.07 m After I was added, the residue was dried under reduced pressure to give 92 mg of the title compound.

 'Η- NMR (DMS 0-d6) 5: 1.22 (4H, brs), 1.80-2.10 (2H, m) 2.20-2.40 (4H, m), 2.58 (2H, m), 3.13 (2H, m) , 3 64 (1 H, quint), 4.52 (2H, s) 7.20 ~ 7.35 (7H, m), 7.40 ~ 7.48 (2H, m), 7.61 (2H, d), 7.69 ~ 7.80 (3H, m) , 7.97 (lH, br s)

 (Example 202)

 (E)-2-(N-(4-(4-cyclobenzenebenzenesulfonamide) butyl) 1 N-(3-(2- (4-cyclobutylthiazole 1-2-yl) ethenyl) benzyl )) Production of Ninatridium Sulfamoylbenzoate Salt (E) —2— (N— (4— (4-chlorobenzenebenzenesulfonamide) butyl) obtained in Example 11-17—N— ( 3- (2- (4-Cyclobutylthiazol-2-yl) ethenyl) benzyl)) Dissolve 1 O Omg of sulfamoylbenzoic acid in 1 OmI of methanol and then add 2N aqueous sodium hydroxide solution 0.1 After adding 4 ml, the mixture was evaporated to dryness under reduced pressure to obtain 91 mg of the title compound.

'Η-NMR (DMS O- d6) δ: 1.12 (2H, m), 1,26 (2H, m)' 1.80-2.10 (2H, m), 2.20-2.40 (4H, m), 2.49 ( 2H, m), 3.11 (2H, t), 3.64 (1 H, quint), 4. 53 (2H, s), 7.20~7.35 (5H, m), 7.40~7.60 (4H, m), 7.64 (2H, d), 7.71 (1H P d) 8.32 (3H, s)

 (Test example)

Then thiazole Ichiru derivatives of the present invention will be described by way of Test Examples will be have a good receptor antagonism and anti-allergic effects on both Medellin Ieta of LT D <and TXA _2.

The compounds of the present invention were tested for钪LTD action, anti-TXA ₂ activity and枋喘breath action. The test method and test results are shown below.

 [Test Example 1] (TDA action)

After guinea pigs were exsanguinated and killed, the ileum was removed to prepare an ileum specimen. The specimen 95% 0 ₂ - aerated with 5% C 0 ₂ mixed gas, at 37 ° C for data kept in Irodo (T yr 0 de) Magnus bath filled with liquid 2m I, load 1 g of the sample And the contraction reaction caused by the addition of LTD ₄ was recorded isotonic.

After the specimens were stabilized, LTD 0.05-3.5 ngZml was treated cumulatively and the contractile response was observed. Once a stable contractile response is obtained, the test substance was pretreated five minutes prior to LTD ₄ addition, and then give again cumulatively added contractile response to LTD. p A ₂ values were calculated according to the method of Van mouth Tsu Sa厶(V an R oss um). The results are shown in Table 6 below.

[Test Example 2] (Anti-TXA ₂ action)

After guinea pigs were exsanguinated and killed, the trachea was removed and strip-shaped tracheal muscle specimens were prepared according to the method of Takagi et al. The specimen 95% 〇 ₂ - 5% C 0 ₂ mixed gas was vented, in a Magnus bath filled with Tyrode (T yrode) solution 2m I kept at 37 ° C, multiplied by the load 1 g of the sample The contraction response caused by the suspension and the addition of U-46619 was recorded isotonic. After stabilizing the samples, it was observed cumulatively treated contractile response of U- 466 1 9, 1 0- ' ° ~ 1 0- 7 M. When a stable contractile response was obtained, the test substance was pretreated 5 minutes before the addition of U-46619, and then U-46619 was again cumulatively added to obtain a contractile response. The PA ₂ value was calculated according to the method of Van Rossum. The results are shown in Table 6 below.

The compounds of the present invention from those results, LT Da and TXA binocular Die evening _c Table 6 Test Example 1 was confirmed to have excellent receptor antagonistic action against one _2, 2 Results

- Example Anti LTDA effect (p A ₂₎ Anti-TX A ₂ activity (p A ₂₎

1 07 9.23 6.67

 1 08 1 0 .53 6.67

 1 09 1 0 .08 7 .05

 1 1 0 1 0 .38 6.36

 1] 1 9.30 6.38

 1 1 2 9 .89 6.84

 1 1 3 9 .89 7.59

 1 1 4 9 .83 7 .1 2

 1 1 5 8. 97 6 • 99

 1 1 6 9 .67 6 .23

 1 1 7 9 .93 7 .8 1

 1 1 8 9. 1 7 6 • 52

1 1 9 9 .22 6.47 Example Anti-LTD action (Α ₂ ) Anti-ΤΧ Α ₂ action (Ρ Α ₂ )

1 2 1 9.65 7.1 9

 1 22 9.76 6.82

 1 23 1 0.04 7 .06

 1 24 1 0.42 6.78

 1 26 9.62 6 • 88

 1 27 9.65 6.92

 1 28 9. 1 8 6.29

 1 30 9.23 7.84

 1 3 1 9. 1 2 7. 1 5

 1 32 8.55 7-2 1

 1 33 9.69 7.62

 1 34 9.23 7.69

 1 35 9.23 6.1.5

 1 36 9.76 7 .08

 1 37 8. 21 7 ■ 03

 1 38 9.53 6 ■ 60

 1 40 9.79 6 • 97

 1 4 1 9. 05 6.88

 1 42 1 0.1 9 7.26

 1 43 9.42 6.43

 1 44 9.80 7 • 59

1 45 9. 7 1 6. 09 Example Anti LTDA effect (p A ₂₎ Anti-TX A ₂ activity (p A

1 47 9 .30 6.64

 1 49 9 .03 6 .0 1

 1 54 1 0 .3 1 7.33

 1 56 1 0 • 1 7 7 • 03

 1 57 9 .94 7 • 74

 1 58 9.99 6.64

 1 59 1 0 .0 1 7.38

 1 60 1 0 •〗 2 6 • 78

 1 63 8. 34 7 • 66

 1 65 8 • 69 7 • 1 9

 1 69 9 • 05 6 • 29

 1 76 8, 72 7. 3 1

 1 82 8 06 8 ■ 05

 1 86 8 95 7 7 1

 1 87 9 1 0 8 .05

 1 88 8.5. 5 1 7 89

 1 93 8 88 6 35

 1 94 8 8 1 7 • 1 4

[Test Example 3] (Anti-asthmatic effect)

The anti-asthmatic effect was examined by passive sensitization guinea pig immediate asthmatic response. That is, on the day before the experiment, guinea pigs were treated with anti-DN PZo V aI bumin guinea pig serum (guinea pig PCA titer; X102) 4) was administered through the ear vein for sensitization. On the day of the experiment, after pretreatment with pyrilamine (10 mg / kg i.p.), normal airway resistance was measured by the double flow plethysmograph method according to the method of Pennock et al. The test substance (3mgZkg) was dissolved in DMS〇, then dissolved in 50% normal guinea pig serum monophysiological saline solution, and administered to the ear vein 5 minutes before inhalation of the antigen. Immediate asthmatic response was induced by inhalation exposure to a 1% ovalbumin saline solution as an antigen using an ultrasonic nebulizer for 3 minutes, and airway resistance was measured 5 minutes (4 to 6 minutes) after the end of inhalation. The data was represented by the inhibition rate calculated by the following equation.

Suppression rate (%) = (1-1 (A-B) / (C-D)) X I 00

 A: Airway resistance value after inhalation of antigen in the test substance group

 B: Airway resistance before inhalation of antigen in the test substance group

 C: Airway resistance after inhalation of antigen in control group

 D: Airway resistance before inhalation of antigen in control group

Table 7 shows the results. From the results, it was confirmed that the compound of the present invention had an excellent anti-asthmatic effect.

Table 7 Results of Test Example 3

 (Formulation example)

 Next, Formulation Examples of the compound of the present invention are shown, but the formulation is not limited thereto.

 (Formulation Example 1)

 According to the following formulation, a tablet containing 100 mg of the active ingredient per tablet was prepared.

 (Component) (mg)

Compound of Example 11

Lactose 3 0

Corn starch 4 0

Microcrystalline cellulose 1 5 Methyl cellulose 3 Magnesium stearate 2

 (Formulation Example 2)

 According to the following formulation, 190 mg of the mixed ingredient containing 100 mg of the active ingredient was filled in a capsule to prepare a capsule.

 (Component) (mg)

Compound of Example 1 17 100

Lactose 5 0

Corn starch 3 0

Microcrystalline cellulose 8

Magnesium stearate 2 Industrial applicability

 The novel thiazol derivative represented by the general formula (I) of the present invention has both LTD4 receptor antagonism and TxAz receptor antagonism, and exhibits excellent antiasthmatic activity. Therefore, the compounds of the present invention are useful as antiallergic agents for treating and preventing various allergic diseases such as allergic bronchial asthma.

Claims

1. General formula (I)

 Oki (In the formula, X is a carbonyl group or a sulfonyl group, 丫 is a carboxy group, a C ₅ alkoxyl group or a 1 H-tetrazol-5-yl group, Z is a 5 alkyl group, C 3 - 6 cycloalkyl or phenyl group, W is C ₂ - ₅ alkylene group or a 1, 4 key circumference to Shikuro R is a phenylsulfonylamino group, a phenylsulfonylamino group, a N'-phenylthioureido group or a C 5 alkylsulfonylamino group which may be substituted. ) A thiazole derivative represented by or a salt thereof.  2. The thiazole derivative or a salt thereof according to claim 1, wherein Y in the general formula (I) is a carboxyl group or a 1 H-tetrazoruyl 5-yl group. 3. General formula (I) Y at the C, - ₅ alkoxy thiazole Ichiru derivative or a salt thereof billed ranging claim 1 wherein a carbonyl group. 4. The thiazole derivative or the thiazole derivative according to claim 2, wherein Z in the general formula (I) is a cyclobutyl group, and R is a phenylsulfonylamino group or a phenylsulfonyl group which may be substituted. salt. 5. The method according to claim 4, wherein in the general formula (I), X is a sulfonyl group, 丫 is a 2-hydroxyloxyl group, W is a tetramethylene group, and R is a 4-chloro-phenylsulfonylamino group. Thiazole derivatives or salts thereof. 6. An antiallergic agent comprising the thiazole derivative or a salt thereof according to any one of claims 1 to 5 as an active ingredient.  7. A method for treating an allergic disease using the thiazole derivative or a salt thereof according to any one of claims 1 to 5.  8. General formula (II)

(Wherein, Z is C, - ₅ alkyl group, a: _Cs-6 cycloalkyl group or a phenylene Le group, W is C ₂ - a ₅ alkylene group or a 1, cyclohexylene group 4-cyclopropyl, R represents a substituted A benzylsulfonylamino group, a phenylsulfonyl group, or N'-phenyl: an L-dithiothioperido group or a C, -5 alkylsulfonylamino group which may be optionally substituted.) Or its salt.