JPH0812659A - Thiazole derivative and medicinal pharmaceutical preparation containing the same - Google Patents

Abstract

PURPOSE:To obtain a derivative, having antagonistic actions on thromboxane A2 and on leukotrienes and usable as a preventing agent effective against allergic diseases such as thrombosis or asthma. CONSTITUTION:This derivative is expressed by formula I [X is H or a halogen; R1 is carboxyl or a 1-4C alkoxycarbonyl; A is sylfonyl(amide); B is CH2O or CH=CH-R2 (R2 is a lower alkyl, an aryl or H); (n) is 2 or 3; (m) is 1-5], e.g. {4-[3-[(4-chlorophenyl)sulfonyl]propyl]-2-[3-[2-(4-isopropyl-2-thiazolyl) ethenyl]benzoylamino]phenoxy}acetic acid of formula II. The derivative (A is sulfonyl) is obtained by reacting a sulfonic acid derivative of formula III with an acid chloride derivative of formula IV in the presence of a base, then deprotecting the methoxymethyl group with an acid and reacting the produced hydroxyl group with an omega-bromo-fatty acid ester in the presence of a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiazole derivative and a pharmaceutical preparation containing the same.

[0002]

BACKGROUND ART It has been suggested that thromboxane A ₂ and leukotrienes are closely related to allergic inflammation such as bronchial asthma, and thromboxane A ₂ antagonists, leukotriene antagonists and synthase inhibitors have already been developed one after another. However, the involvement of multiple chemical mediators has been clarified in actual pathological conditions, and a sufficient existing therapeutic effect cannot be expected with a single existing enzyme inhibitor or receptor antagonist.

Based on the above, the present inventors examined the development of a drug having a leukotriene antagonistic action in addition to a thromboxane A ₂ antagonistic action. The compound according to the present invention has a structure never disclosed before, and it simultaneously antagonizes both the receptors of thromboxane A ₂ and leukotrienes, and there is no existing drug. Pharmaceutical formulations containing these compounds embody entirely new pharmacological effects.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have synthesized various thiazole derivatives, and as a result of diligent research on their physiological actions, the thiazole derivatives according to the present invention have thromboxane A ₂ antagonism as well as leukotriene antagonism. The present invention has been completed and the present invention has been completed.
Therefore, it is an object of the present invention to provide a novel thiazole derivative and a pharmaceutical preparation containing the same, and thus to provide a pharmaceutical preparation that solves the problems of a single synthase inhibitor or receptor antagonist. To do.

[0005]

Means for Solving the Problems The present invention in accordance with the above objects is achieved by formula (I) (wherein X represents a hydrogen or halogen atom group, and R ₁ represents a carboxyl group or an alkoxycarbonyl group (here, alkoxy group A group has 1 to 4 carbon atoms and is a straight chain or a branched chain), A represents a sulfonyl or sulfonylamide group, and B represents —CH ₂ O— or —CH═.
Represents a CH-group, R ₂ represents a lower alkyl, aryl or hydrogen group, n represents an integer of 2 or 3, and m represents 1
A thiazole derivative or a physiologically acceptable salt thereof.

[0006]

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The present invention is also a thromboxane A ₂ antagonist containing the above thiazole derivative.

The present invention is also a leukotriene antagonist containing the above thiazole derivative.

The present invention is also an antiallergic agent containing the above thiazole derivative.

In the present invention, the thromboxane A ₂ antagonist means a preparation that antagonizes thromboxane A _{2 at the} thromboxane A ₂ receptor, and the leukotriene antagonist means a preparation that antagonizes leukotriene at the leukotriene receptor. To do.

The compound represented by the general formula (I) of the present invention may be a physiologically acceptable salt. As such a salt, an addition salt with an inorganic or organic acid, for example, a hydrochloride salt. , Sulfates, citrates, succinates, methanesulfonates, etc., and salts with organic bases such as ammonium salts, triethylamine salts, pyridine salts, organic amine salts such as tromethamine salts, and various metal salts, for example Alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts and the like are included.

The thiazole derivative represented by the general formula (I) of the present invention has a structure which has never been disclosed. These are represented by the following formula (II) when A is sulfonyl in the general formula (I) (in the formula, X represents hydrogen or a halogen atom, and n
Represents an integer of 2 or 3) and an acid chloride derivative represented by the formula (III) (wherein R ₂ represents a lower alkyl or aryl group) in the presence of a suitable base, It can be obtained by reacting a hydroxyl group formed after deprotection of a methoxymethyl group with an acid with a ω-bromo fatty acid ester in the presence of a base, and optionally subjecting the ester portion formed to alkaline hydrolysis.

[0013]

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[0014]

[Chemical 4]

The sulfone derivative represented by the formula (II) is a known substance and can be prepared by a known method (Japanese Patent Laid-Open No. 4-154766).

When the thiazole derivative of the present invention is produced by this method, 1 mol of the sulfone derivative (II) is
In the presence of 1.0 to 1.5 mol, preferably 1.0 to 1.1 mol of base, 1.0 to 1.0 mol of the acid chloride derivative (III) is present.
1.5 mol, preferably 1.1 mol are reacted. The reaction temperature is generally 0 to 150 ° C., preferably 0 to 50 ° C., and the reaction time is 30 minutes to 15 hours depending on the temperature.

Further, the general formula (I) obtained as the occasion demands
The compound is hydrolyzed by a known method. Suitable bases for this hydrolysis include sodium hydroxide,
Includes potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate and the like.

When A is a sulfonylamide group, the following formula (IV) (wherein X is hydrogen or a halogen atom,
n represents an integer of 2 or 3) is obtained by reacting a sulfonamide derivative represented by the formula (III) with an acid chloride derivative represented by the formula (III) in the presence of a suitable base, and treating the ester moiety with an acid as necessary. To be

[0019]

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The sulfonamide derivative represented by the formula (IV) can be prepared by a known method (Japanese Patent Laid-Open No. 5-262736).

When the thiazole derivative of the present invention is produced by this method, 1 mol of the sulfonamide derivative (IV) is added to 1.0 to 1.5 mol of a base, preferably 1.0 to 1.1.
1. in the presence of a mole of the acid chloride derivative (III).
0 to 1.5 mol, preferably 1.1 mol are reacted. The reaction temperature is generally between 0 and 150 ° C., preferably between 0 and 50.
The reaction time is 30 minutes to 15 minutes depending on the temperature.
Time.

A carboxylic acid derivative is obtained by treating the compound of the general formula (I) obtained as necessary with trifluoroacetic acid.

Examples of the base used in the production of the thiazole derivative of the present invention include triethylamine, potassium carbonate, cesium carbonate, sodium hydride and the like. Examples of the inert solvent include tetrahydrofuran, acetonitrile, ether and N, N-dimethylformamide. , Dimethyl sulfoxide, methylene chloride, methanol, acetone, dioxane and the like.

The thiazole derivative of the present invention is used as a thromboxane A ₂ antagonist and a leukotriene antagonist, and the dose varies depending on the symptom, but in general, the daily dose for adults is 10
-2000 mg, preferably 20-600 mg, and may be administered in 1 to 3 divided doses depending on the symptoms.
The administration method can take any form suitable for administration,
Oral administration is particularly desirable, but intravenous injection or inhalation is also possible.

The compound of the present invention is used as an active ingredient or one of the active ingredients, either alone or mixed with a pharmaceutical carrier or excipient by a conventional method, to obtain tablets, dragees, powders, capsules, granules, suspensions, It can be applied in various forms formulated into emulsions, injection solutions and the like. Examples of carriers or excipients include calcium carbonate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate and the like.

[0026]

EXAMPLES Next, the present invention will be described more specifically by showing examples and test examples, but the present invention is not limited thereto.

Example 1 3- [2- (4-isopropyl-
To 312 mg of 2-thiazolyl) ethenyl] benzoic acid, 0.1 ml of thionyl chloride was added under ice cooling, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the obtained 3- [2-
(4-Isopropyl-2-thiazolyl) ethenyl] benzoyl chloride (yellow crystals) was used in the next reaction without purification.

Under an argon stream, 330 mg of triethylamine was added to a solution of 3- [2- (4-isopropyl-2-thiazolyl) ethenyl] benzoyl chloride in 2 ml of chloroform under ice cooling, and 5- [3-[(4-chlorophenyl) was added.
A solution of 310 mg of sulfonyl] propyl] -2- (methoxymethoxy) aniline in 1 ml of chloroform was added at room temperature for 2 hours.
Stirred for hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.

The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and N- [5- [3-[(4 was obtained from the eluate fraction of hexane-ethyl acetate (2: 1 [v / v])).
5-chlorophenyl) sulfonyl] propyl] -2- (methoxymethoxy) phenyl] -3- [2- (4-isopropyl-2-thiazolyl) ethenyl] benzamide
30 mg was obtained (colorless amorphous, yield 99%).

Under an argon stream, N- [5- [3-
[(4-chlorophenyl) sulfonyl] propyl] -2
-(Methoxymethoxy) phenyl] -3- [2- (4-
Isopropyl-2-thiazolyl) ethenyl] benzamide (530 mg) in methanol (4 ml) -tetrahydrofuran (4 ml)
To the solution was added 0.22 ml of 6N hydrochloric acid, and the mixture was stirred at 50 ° C for 4 hours.

The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 4- [3-[(4-chlorophenyl) sulfonyl] propyl] -2- [3- [2- (4-
520 mg of isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenol were obtained (white crystals, yield 99%).

Under an argon stream, 4- [3-[(4-
Chlorophenyl) sulfonyl] propyl] -2- [3-
[2- (4-Isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenol 520 mg of N, N-
Ethyl bromoacetate 2 in 10 ml dimethylformamide solution
30 mg and potassium carbonate 250 mg were added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.

The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and [4- [3-[(4-chlorophenyl]) was extracted from the hexane-ethyl acetate (1: 1 [v / v]) elution fraction. ) Sulfonyl] propyl] -2- [3-
[2- (4-isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenoxy] ethyl acetate is 52
0 mg was obtained (colorless amorphous, yield 93%).

[4- [3-[(4-chlorophenyl) sulfonyl] propyl] -2- [3- [2- (4-
To a solution of isopropyl 2-thiazolyl) ethenyl] benzoylamino] phenoxy] ethyl acetate (520 mg) in methanol (6 ml) -tetrahydrofuran (6 ml) was added 1N lithium hydroxide (1.23 ml) under ice cooling and the mixture was stirred for 1 hour. The reaction solution was adjusted to pH around 4 with 2N hydrochloric acid, extracted with chloroform, the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to [4- [3-[(4-chlorophenyl) sulfonyl] propyl] -2- [3- [2- (4-isopropyl-2-
420 mg of thiazolyl) ethenyl] benzoylamino] phenoxy] acetic acid was obtained (white crystals, yield 80).
%).

The physical data of this product is the following formula (V)
Support the structure of. mp 208-210 ° C (hexane / methylene chloride) IR (cm ^-1 ): 1670, 1600, 1540, 1140 NMR (CDCl ₃ ) δ (ppm): 1.35 (6H, d, J = 7. 0
Hz), 1.95-2.05 (2H, m), 2.65-2.7
0 (2H, m), 3.05-3.15 (3H, m), 4.7
0 (2H, s), 6.80-8.25 (14H, m), 9.
70 (1H, s)

[0036]

[Chemical 6]

Example 2 4- [2-
(4-Isopropyl-2-thiazolyl) ethenyl] benzoic acid and 5- [3-[(4-chlorophenyl) sulfonyl] propyl] -2- (methoxymethoxy) aniline were used, following the same procedure as in (Example 1). , [4- [3
-[(4-chlorophenyl) sulfonyl] propyl]-
2- [4- [2- (4-Isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenoxy] acetic acid was obtained.

Physical data of this product is represented by the following formula (VI).
Support the structure of. mp 118-121 ° C (hexane / chloroform) IR (cm ^-1 ): 1670, 1600, 1540, 1140 NMR (CDCl ₃ -DMSO-d ₆ ) δ (ppm): 1.35 (6H, d,
J = 6.8 Hz), 1.95-2.05 (2H, m), 2.6
5-2.70 (2H, m), 3.05-3.15 (3H,
m), 4.70 (2H, s), 6.80-8.25 (14
H, m), 9.55 (1H, s)

[0039]

[Chemical 7]

Example 3 3- [2-
(4-Phenyl-2-thiazolyl) ethenyl] benzoic acid and 5- [3-[(4-chlorophenyl) sulfonyl] propyl] -2- (methoxymethoxy) aniline were used, following the same procedure as in (Example 1) below. , [4- [3-
[(4-chlorophenyl) sulfonyl] propyl] -2
-[3- [2- (4-Phenyl-2-thiazolyl) ethenyl] benzoylamino] phenoxy] acetic acid was obtained.

The physical data of this product is represented by the following formula (VI
Support the structure of I). mp-199-200 ° C (methanol / chloroform) IR (cm ^-1 ): 1670, 1600, 1550, 1150 NMR (DMSO-d ₆ ) δ (ppm): 1.85-1.95 (2H,
m), 2.60-2.70 (2H, m), 3.25-3.3
5 (2H, m), 4.75 (2H, s), 6.85-8.0
5 (19H, m), 8.32 (1H, s), 9.75 (1
H, s)

[0042]

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Example 4 3- [2-
(2-thiazolyl) ethenyl] benzoic acid and 5- [3-
[(4-chlorophenyl) sulfonyl] propyl] -2
[4- [3-[(4-Chlorophenyl) sulfonyl] propyl] -2- [3- [2-] using-(methoxymethoxy) aniline and following the same procedure as in (Example 1) below.
(2-thiazolyl) ethenyl] benzoylamino] phenoxy] acetic acid was obtained.

The physical data of this product is represented by the following formula (VII
Support the structure of I). mp 233 ° C (chloroform) IR (cm ^-1 ): 1670, 1600, 1550, 1150 NMR (DMSO-d ₆ ) δ (ppm): 1.85-1.95 (2H,
m), 2.62-2.67 (2H, m), 3.22-3.2
8 (2H, m), 4.75 (2H, s), 6.85-8.30
(14H, m), 8.28 (1H, s), 9.72 (1H,
s)

[0045]

[Chemical 9]

(Embodiment 5) 3- [2-
Using thiazolylmethoxy] benzoic acid and 5- [3-[(4-chlorophenyl) sulfonyl] propyl] -2- (methoxymethoxy) aniline and following the procedure similar to (Example 1) below, [4- [3 -[(4-Chlorophenyl) sulfonyl] propyl] -2- [3- (2-thiazolylmethoxy) benzoylamino] phenoxy] acetic acid was obtained.

Physical data of this product is represented by the following formula (IX).
Support the structure of. mp 169 ° C. (chloroform / methanol) IR (cm ⁻¹ ): 1670, 1600, 1550, 1150 NMR (DMSO-d ₆ ) δ (ppm): 1.90-2.01 (2H,
m), 2.60-2.68 (2H, m), 3.03-3.1
3 (2H, m), 4.58 (2H, s), 5.45 (2H, m)
s), 6.75-7.85 (12H, m), 8.13 (1
H, s), 9.78 (1H, s)

[0048]

[Chemical 10]

Example 6 Under a stream of argon, 3- [2- (4-isopropyl-
To a solution of 2-thiazolyl) ethenyl] benzoyl chloride in 5 ml of chloroform under ice cooling, 0.56 ml of triethylamine.
4- [2-[[(4-chlorophenyl) sulfonyl] amino] ethyl] -2-aminophenoxyacetic acid t-
Add 590 mg of butyl in 5 ml of chloroform and add 1 at room temperature.
Stir for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.

The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and the fraction eluted with hexane-ethyl acetate (2: 1 [v / v]) was [4- [2-[[(4-
Chlorophenyl) sulfonyl] amino] ethyl] -2-
790 mg of t-butyl [3- [2- (4-isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenoxy] acetate was obtained (colorless amorphous, yield 85).
%).

Under an argon stream, [4- [2-
[[(4-Chlorophenyl) sulfonyl] amino] ethyl] -2- [3- [2- (4-isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenoxy] acetate t-butyl 790 mg in methylene chloride 3 ml solution in ice. 2 ml of trifluoroacetic acid was added under cooling and the mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized, extracted with water, and dried over anhydrous sodium sulfate.

Concentrate under reduced pressure to give [4- [2-[[(4-chlorophenyl) sulfonyl] amino] ethyl] -2-
[3- [2- (4-isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenoxy] acetic acid is 320
mg was obtained (white crystals, yield 44%).

The physical data of this product is the following formula (X)
Support the structure of. mp 197-200 ° C (chloroform) IR (cm ^-1 ): 1680, 1600, 1550, 1160 NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 1.33 (6H, d, J
= 6.78 Hz), 2.75-2.78 (2H, m), 3.0
9-3.13 (1H, m), 3.24-3.28 (2H,
m), 4.75 (2H, s), 6.82-8.15 (13
H, m), 8.78 (1H, s)

[0054]

[Chemical 11]

(Embodiment 7) 4- [3-
[(4-chlorophenyl) sulfonyl] propyl] -2
-[3- [2- (4-isopropyl-2-thiazolyl)
Following the procedure similar to the following (Example 1) using ethenyl] benzoylamino] phenol and ethyl 5-bromovalerate, 5- [4- [3-[(4-chlorophenyl) sulfonyl] propyl] -2- [3 -[2- (4-Isopropyl-2-thiazolyl) ethenyl] benzoylamino] phenoxy] valeric acid was obtained.

Physical data of this product is represented by the following formula (XI).
Support the structure of. mp 129-132 ° C. (ethyl acetate) IR (cm ⁻¹ ): 1680, 1590, 1540, 1150 NMR (CDCl ₃ ) δ (ppm): 1.37 (6H, d, J = 7.0)
Hz), 1.88-2.08 (6H, m), 2.44-2.4
7 (2H, m), 2.66-2.70 (2H, m), 3.0
8-3.12 (2H, m), 3.30-3.37 (1H,
m), 4.09-4.12 (2H, m), 6.82-8.0
2 (13H, m), 8.31 (1H, s), 8.67 (1
H, s)

[0057]

[Chemical 12]

Test Example The compound of the present invention showed an antagonistic action against TXA ₂ and LTD _{4 in} an in vitro system (described later) as shown in the following table.

The IC ₅₀ value of the antagonistic effect of the compound of the present invention on TXA ₂ and LTD ₄ in vitro was determined using the following experimental system.

Tracheal sections removed from Hartley male guinea pigs weighing 300-500 g were tyrod at 37 ° C.
In a liquid e, a Magnus tank in which a mixed gas of oxygen (95%)-carbon dioxide (5%) was aerated was loaded with a load of 0.3 g and suspended. Stabilize for about 1 hour and then place TXA _{2 in the} Magnus bath.
Alternatively, LTD ₄ was added at a concentration of 10 ^-7 M and 10 ^-8 M, respectively. The contraction reaction at the time of adding the compound of the present invention to the contraction reaction at this time was measured, and the IC ₅₀ value was calculated. The results are shown in Table 1 below.

[0061]

[Table 1]

(Acute toxicity) An acute toxicity test by oral administration was carried out using male ICR mice (5 weeks old). The LD ₅₀ value of the compound of the present invention was 300 mg / kg or more, and higher safety was confirmed as compared with the effective dose.

[0063]

Industrial Applicability According to the present invention, a novel thiazole derivative and a pharmaceutical preparation containing the same are provided.

Since the thiazole derivative of the present invention is a thromboxane A ₂ antagonist and also a leukotriene antagonist, it is effective against allergic diseases such as thrombosis and asthma, which are diseases involving thromboxane A ₂ and leukotrienes. It can be used as an effective prophylactic.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shingo Koyama 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Terumo Corporation

Claims (4)

[Claims] Claims: The above general formula (I) (in the formula, X represents a hydrogen or halogen atom group, R ₁ represents a carboxyl group or an alkoxycarbonyl group (wherein the alkoxy group has 1 to 4 carbon atoms, and a straight chain or Is a branched chain), A represents a sulfonyl or sulfonylamide group, B represents a —CH ₂ O— or —CH═CH— group, and R ₂ represents a lower alkyl, aryl or hydrogen group. , N is an integer of 2 or 3, and m is an integer of 1 to 5). 2. A thromboxane A ₂ antagonist containing the thiazole derivative according to claim 1. 3. A leukotriene antagonist containing the thiazole derivative according to claim 1. 4. An anti-allergic agent containing the thiazole derivative according to claim 1.