WO1996038436A1

WO1996038436A1 - (2-thienyl)alkanoic acid derivatives

Info

Publication number: WO1996038436A1
Application number: PCT/JP1996/001430
Authority: WO
Inventors: Yasuo Ito; Hideo Kato; Shingo Yasuda; Nobuo Ogawa; Shunichiro Sakurai
Original assignee: Hokuriku Seiyaku Co., Ltd.
Priority date: 1995-06-02
Filing date: 1996-05-28
Publication date: 1996-12-05
Also published as: AU5780996A; JPH0948775A

Abstract

Compounds represented by general formula (I) or a salt of the same, wherein R1 represents hydrogen, halogeno, lower alkyl, lower alkoxy or nitro; R2 represents C¿1-10? alkyl, C3-8 cycloalkyl optionally having lower alkyl on its ring or C1-6 alkyl substituted by C3-8 cycloalkyl; R?3¿ represents hydrogen or lower alkyl; and n is an integer of from 2 to 4. The compounds have thromboxane A¿2? and leukotriene D4 antagonisms and are useful in the prevention and/or treatment of diseases selected from the group consisting of ischemic heart diseases, cerebrovascular disorders, thrombosis, asthma and allergic inflammation.

Description

Description (2-Chenyl) alkanoic acid derivative Technical field

The present invention relates to a (2-Chenyl) alkanoic acid derivative or a (2-Chenyl) alkanoic acid derivative which has both a thromboxane A ₂ antagonistic action and a leukotriene antagonistic action and is useful as a platelet aggregation inhibitor, an antithrombotic agent, an antiasthmatic agent, an antiallergic agent and the like. It concerns pharmacologically acceptable salts. Background art

There are few reports on drugs that have both thromboxane A ₂ antagonism and leukotriene antagonism. Examples of such agents include, for example, Japanese Patent Application Laid-Open Nos. 5-2627336, 5-2793336, 6-41051, and the present invention. Japanese Unexamined Patent Publication No. 7-53505 and the like have disclosed.

Thromboxane A ₂ and leuco Toryen acids is ischemic heart disease, cerebrovascular disorders, thrombosis, known as chemical mediators that cause asthma and allergic inflammation, and the like. Then, as antagonists against these chemical mediators, a number of thromboxane A ₂ antagonists or leukotriene antagonists in Until now have been developed, therapeutic effect on the disease have been studied. However, in the Toronboki San A ₂ antagonists or leukotriene antagonists alone at present, no sufficient effect is obtained. Disclosure of the invention

The present inventors have found that drugs having both the thromboxane A ₂ antagonistic action and leukotriene 0 ₄ antagonism, thromboxane A. Assumed to exert a much better therapeutic effect on diseases such as ischemic heart disease, cerebrovascular disorder, thrombosis, and asthma monoallergic inflammation than drugs having either antagonistic action or leukotriene D ₄ antagonistic action Researched hard based on As a result, a novel (2-Chenyl) alkanoic acid derivative according to the present invention Body, found that excellent thromboxane A ₂ has an antagonistic effect and leuco Bok Lien 0 ₄ antagonism, platelet aggregation inhibitors have antithrombotic, useful in extremely as antiasthmatic agents and antiallergic agents Was. The present invention has been completed based on these findings.

That is, the present invention provides the following general formula (I):

(Wherein, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a nitro group; R ² represents -C _{1 Q} (C _1-10 . Similarly an alkyl group notation is), C. may have a lower alkyl group on the ring - C o cycloalkyl group, or c ₃ -C substituted with a cycloalkyl group to c ₈ ₆ R represents a hydrogen atom or a lower alkyl group; n represents an integer of 2 to 4. The present invention provides a novel derivative of a (2-phenyl) alkanoic acid represented by the formula or a salt thereof. is there.

In another aspect of the present invention, there is provided a medicament comprising the above-mentioned (2-phenyl) alkanoic acid derivative or a pharmaceutically acceptable salt thereof. According to a preferred embodiment of the present invention, thromboxane A. The above drug having an antagonistic action and a leukotriene antagonistic action; the above drug used for prevention and Z or treatment of a disease selected from the group consisting of ischemic heart disease, cerebrovascular disease, thrombosis, asthma, and allergic inflammation; A pharmaceutical composition comprising the above-mentioned (2-Chenyl) alkanoic acid derivative or a pharmacologically acceptable salt thereof and a pharmaceutical additive; and ischemic heart disease, cerebrovascular disorder, thrombosis, The above pharmaceutical composition for use in the prevention and / or treatment of a disease selected from the group consisting of asthma and allergic inflammation is provided.

In still another embodiment of the present invention, there is provided an ischemic heart disease, cerebrovascular disorder, thrombosis, asthma, and allergy containing the (2-Chenyl) alkanoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Prevention of diseases selected from the group consisting of inflammation and Or use of the above-mentioned (2-Chenyl) alkanoic acid derivative or a pharmacologically acceptable salt thereof or a method for using the same for the manufacture of the above-mentioned pharmaceutical composition for use in therapy; Administering to a mammal in need of treatment and / or prophylaxis an effective amount of an alkanoic acid derivative or a pharmacologically acceptable salt thereof, preferably in humans, including ischemic heart disease, cerebrovascular disease, thrombosis, A method for preventing and / or treating a disease selected from the group consisting of asthma and allergic inflammation is provided.

The above (2-Chenyl) alkanoic acid derivative is represented by the following formula: 4- [5- (1-1 (4-chlorophenylphenylsulfonylamino) -15-methylhexyl] _2-Chenyl] butyric acid or 4- [ 5- [1- (4-fluorophenylsulfonylamino) -1-5-methylhexyl] —2-phenyl] butyric acid is a preferred embodiment of each of these inventions. Best form

In the formula (I), the lower alkyl group represented by R ¹ and R ³ may be linear or branched. The lower alkyl group, for example, can be used § alkyl group ~ c _4. More specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group are preferable. Examples of the lower alkoxy group represented by R ^1, may be either linear or branched, for example, an alkoxy group to c ₄ can and Mochiiruko. More specifically, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group is preferable. The halogen atom represented by R ^1, a fluorine atom, EnsoHara child, may be either a bromine atom, or iodine atom.

Examples of the alkyl group -C _{1 ()} represented by R ^2, may be either a linear or branched alkyl group. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 3,3-dimethylbutyl group, n-pentyl group, isopentyl Group, neopentyl group, tert-pentyl group, 4,4-dimethylpentyl group, n-hexyl group, isohexyl group, 5-methylhexyl group, 5,5-dimethylhexyl group, n-heptyl Group, n-octyl group, n- A nonyl group, an n-decyl group, or the like can be used.

C ₃ -C represented by R ^2. The cycloalkyl group may have one or more lower alkyl groups on the ring. The lower alkyl group can be straight-chain or branched alkyl group having to c _4. C that may have a lower alkyl group. ~ C. Examples of the cycloalkyl group include: cyclopropyl group, cyclobutyl group, cyclopentyl group, 2-methylcyclopentyl group, 3-methylcyclopentynole group, cyclohexynole group, 4-methynolecyclohexynole group, and 4-ethynolecyclo group. Xyl, 4-propylcyclohexyl, 4-butylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, cycloheptyl, cyclooctyl and the like can be used.

Examples of the -C ₆ alkyl group substituted with a C ₃ -C ₈ cycloalkyl represented by R ² include a cyclopropylmethyl group, a 3-cyclopropylpropyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, —Cyclopentylethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 3-cyclohexylpropyl pyr group, 4-cyclohexylbutyl group, 5-cyclohexylpentyl group, 6-cyclohexylhexyl group , Cycloheptylmethyl group, cyclooctylmethyl group and the like.

Preferred specific examples of the compound of the present invention include the following compounds, but the scope of the present invention is not limited to these examples.

(1) 4- [5-[[1- (1-chlorophenylsulfonylamino) ethyl] 1- 2-Cenyl] methyl butyrate

(2) 4- (5— [1-((4-chlorophenylsulfonylamino) ethyl) —2-phenyl) butyric acid

(3) 4- [1- (1- (4- (phenyl) sulfonylamino) propyl] -1-2-phenyl) butyrate methyl

(4) 4-[5-[1-(4-chlorophenylsulfonylamino) propyl]-2-phenyl] butyric acid

(5) 4- [5- (1-1 (4-chlorophenylsulfonylamino) butyl] 1- 2-phenyl) Butyrate (6) 4-[5-[1-(4-chlorophenylsulfonylamino) butyl] 1-2-phenyl] butyric acid

(7) 4- [5-([1- (4-chlorophenylsulfonylamino) pentyl] -1-2-Chenyl] methyl butyrate

(8) 4- [5- (1- (4-chlorophenylsulfonylamino) pentyl] -1-2-Chenyl] butyric acid

(9) 4- [5- (1- (4-Fluorophenylsulfonylamino) pentyl]-(2-phenyl) methyl butyrate

(1 0) 4-[5-[1-(4-fluorophenylsulfonylamino) pentyl] 1-2-phenyl) Butyric acid

(1 1) 4— [5— [1 (4- (phenyl) sulfonylamino) 1-4-methylpentyl] —2-Chenyl] Methyl butyrate

(1 2) 4-1- [5- (1-1- (4-chlorophenylsulfonylamino) 1-4-methylpentyl] — 2-Chenyl] butyric acid

(1 3) 4-1- [5- [1- (4-fluorophenylsulfonylamino) 1-4-methylpentyl] — 2-Chenyl] methyl butyrate

(1 4) 4-1-5-[1-1-(4-fluorophenylsulfonylamino) 1-4-methylpentyl] 1-2-Chenyl] Butyric acid

(1 5) 4— [5— [1— (4-chlorophenylsulfonylamino) 1,4,4-dimethylpentyl] 1-2-phenyl) Butyrate methyl

(1 6) 4-1 [5-[1-1 (4-chlorophenylsulfonylamino)-1,4-dimethylpentyl]-1-2-phenyl] Butyric acid

(1 7) 4-[5-[1-(4-fluorophenylsulfonylamino) 1, 4-dimethylpentyl] 1-2-phenyl] Butyrate methyl

(1 8) 4— [5— [1— (4-Fluorophenylsulfonylamino) 1,4,4-dimethylpentyl] —2-Chenyl] butyric acid

(1 9) 3- (5- (1- (4- (4-chlorophenylsulfonylamino) hexyl) -1-2-phenyl) methyl propionate

(20) 3-[5-[1-(4-chlorophenylsulfonylamino) hexyl] — 2-Chenyl] propionic acid

(2 1) 4- (5- (1-1- (4-chlorophenylsulfonylamino) hexyl) -1-2-Chenyl) methyl butyrate

(22) 4- [5-([1- (4-chlorophenylsulfonylamino) hexyl] -1-2-phenyl] ethyl ester

(23) 4- [5-[[1- (1-chlorophenylsulfonylamino) hexyl] -2-phenyl] butyric acid

(24) 5- [5- (1- (1- (4-chlorophenylsulfonylamino) hexyl] -1-2-phenyl) methyl valerate

(25) 5-[5-[1-(1-chlorophenylsulfonylamino) hexyl]-1-phenyl) valeric acid

(26) 4- [5- (1- (1-phenylsulfonylaminohexyl) -1-2-phenyl] methyl butyrate

(27) 4- [5- (1-Phenylsulfonylaminohexyl) -1-2-phenyl] butyric acid

(28) Methyl 4- (5— [1— (4-Fluorophenylsulfonylamino) hexyl] -2-phenyl) butyrate

(29) 4- [5- (1- (4-Fluorophenylsulfonylamino) hexyl] -1-2-phenyl) butyric acid

(30) 4- [5-[1- (1-Promophenylsulfonylamino) hexyl] -1-2-Chenyl] methyl butyrate

(3 1) 4-1- [5- (1-1- (4-promophenylsulfonylamino) hexyl] -1-2-phenyl) butyric acid

(3 2) 4-1 [5- [1-1 (4-nitrotrophylsulfonylamino) hexyl] -1-enyl] Methyl butyrate

(3 3) 4— [5— [1— (4-12 trophenylsulfonylamino) hexyl] -1-2-Chenyl] butyric acid

(3.4) 3- [5-([1- (4-chlorophenylsulfonylamino) -1-5-methylhexyl] -12-thenyl] methyl propionate (3 5) 3-[5-[1-1 (4-chlorophenylsulfonylamino)-1-5-methylhexyl]-1-2-phenyl] Propionic acid

(36) 4- (5- (1- (4-chlorophenylsulfonylamino) -1-5-methylhexyl) -12-Chenyl) methyl butyrate

(37) 4- [5-[[1- (4-chlorophenylsulfonylamino) -1-5-methylhexyl] -12-Chenyl] butyric acid

(38) 5— [5— [1— (4-chlorophenylsulfonylamino) -1-5-methylhexyl] 1-2-phenyl) methyl valerate

(3 9) 5-[5-[1-(4-chlorophenylsulfonylamino) 1-5-methylhexyl] 1-2-phenyl] Valeric acid

(40) 4- (5— (1-Phenylsulfonylamino-5-methylhexyl) -12-Chenyl) methyl butyrate

(4 1) 4— [5— (1-Phenylsulfonylamino 5-5-methylhexyl) -1-2-Chenyl] butyric acid

(4 2) 4- [5-[[1- (4-methylphenylsulfonylamino) -1-5-hexylhexyl]-2-Chenyl] methyl butyrate

(43) 4— [5— [1— (4-Methylphenylsulfonylamino) -1-5-methylhexyl] -12-Chenyl] butyric acid

(44) 3- [5-[[1- (4-fluorophenylsulfonylamino) -1-5-methylhexyl] -1-2-phenyl] methyl propionate

(4 5) 3— [5— [1— (4-Fluorophenylsulfonylamino) -1-5-methylhexyl] 1-2-Chenyl] propionic acid

(46) 4- [5-[[1- (4-fluorophenylsulfonylamino) -1-5-methylhexyl] -2-Chenyl] methyl butyrate

(47) 4-[5-[1-(4-fluorophenylsulfonylamino)-1-5-methylhexyl]-1-2-phenyl] Butyric acid

(4 8) 5- (5- (1- (4-Fluorophenylsulfonylamino) -1-5-methylhexyl) -12-Chenyl) methyl valerate

(4 9) 5— [5— [1— (4-fluorophenylsulfonylamino) Tylhexyl] — 2-Chenyl] valeric acid

(50) 4- [5- [1- (1- (4-Bromophenylsulfonylamino) -1-5-methylhexyl] —2-Chenyl] methyl butyrate

(5 1) 4-[5-[1-(1-bromophenylsulfonylamino)-1-5-methylhexyl]-1-2-phenyl] Butyric acid

(52) 4-1 [5-[1-1 (4-12 trophenylsulfonylamino)-1-5-methylhexyl]-1-2-Chenyl] Methyl butyrate

(5 3) 4— [5— [11- (412-trophenylsulfonylamino) -1-5-methylhexyl] -2-Cenyl] butyric acid

(54) 4- [5-([1- (4-chlorophenylsulfonylamino)-1,5,5-dimethylhexyl]-2-phenyl) methyl butyrate

(55) 4— [5— [1— (4-chlorophenylsulfonylamino) -1,5,5-dimethylhexyl] 1-2-Chenyl] butyric acid

(5 6) 4- [5-[[1- (4-fluorophenylsulfonylamino) -1,5-dimethyl-hexyl] -1,2-phenyl] methyl butyrate

(57) 4- [5- [1-1 (4-fluorophenylsulfonylamino) -1,5,5-dimethylhexyl]-2-phenyl] butyric acid

(58) 4- [5-([1- (1-chlorophenylsulfonylamino) heptyl] -12-Chenyl] methyl butyrate

(5 9) 4-1 [5- [1-1 (4-chlorophenylsulfonylamino) heptyl] -1-2-Chenyl] butyric acid

(60) 4-[5-[1-(4-fluorophenylsulfonylamino) heptyl] 1-2- phenyl] methyl butyrate

(6 1) 4— [5— [1— (4-Fluorophenylsulfonylamino) heptyl] -2-Chenyl] butyric acid

(6 2) 4- [5-[1- (4-chlorophenylsulfonylamino) -1-6-methylheptyl] — 2-Chenyl] methyl butyrate

(63) 4- (5- (1- (4-chlorophenylsulfonylamino) -1-6-methylheptyl) -12-Chenyl) butyric acid (64) 4 _ [5-1- (4-Fluorophenylsulfonylamino) -1-6-methylheptyl] — 2-Chenyl] Butyric acid methyl ester

(65) 4- [5-1-1 (4-fluorophenylsulfonylamino) -1-6-methylheptyl] -1-2-Chenyl] butyric acid

(66) 4-1 [5-1-1 (4-chlorophenylsulfonylamino) 1,6,6-dimethylheptyl] 1-2-Cenyl] methyl butyrate

(67) 4- [5-1-1- (4-phenylphenylsulfonylamino) -1,6,6-dimethylheptyl] 1-2-phenyl] butyric acid

(68) 4- [5-1- (4-fluorophenylylsulfonylamino) -1,6,6-dimethylheptyl] 1-2-phenyl] butyrate

(69) 4- [5-1- (4-Fluorophenylsulfonylamino) -1-6-, 6-dimethylheptyl] -12-Chenyl] butyric acid

(70) 4- (5-1- (4-Chlorophenylsulfonylamino) 1-1-cyclohexylmethyl] -2--2-enyl) butyrate methyl

(71) 4-[5-1-1 (4-chlorophenylsulfonylamino) 1-1-cyclohexinolemethinole] 1-2-Chenyl] butyric acid

(72) 4- [5-1- (4-Fluorophenylsulfonylamino) -11-cyclohexynolemethyl] -12-Chenyl] Methyl butyrate

(73) 4- (5-1- (4-Fluorophenylsulfonylamino) -1-cyclohexylmethyl] -2-phenyl) butyric acid

(74) 4- [5-1-1 (4-chlorophenylsulfonylamino) 1-2-cyclohexylethyl] -2-phenyl-butyrate

(75) 4- [5--1-(4-phenylphenylsulfonylamino) -1-2-hexylhexylethyl] -2-thenyl] butyric acid

(76) 4- [5-1-1 (4-fluorophenylsulfonylamino) -12-cyclohexynoleethyl] -2--2-enyl] butyrate methyl

(77) 4- [5-1-1 (4-fluorophenylsulfonylamino) -12-cyclohexinoletyl] -2-phenyl] butyric acid

(78) 4-[5-ί 1-(4-chlorophenylsulfonylamino) 1-3-cycle Methyl pentylpropyl] 1-Chenyl] methyl butyrate

(79) 4-1- [5- (1- (4-chlorophenylphenylsulfonylamino) -1-3-cyclopentylpropyl] —2-phenyl] butyric acid

(80) 4- [5-([1- (4-fluorophenylsulfonylamino) -13-cyclopentylpropyl] -12-Chenyl] methyl butyrate

(8 1) 4-1- [5- (1- (4-Fluorophenylsulfonylamino) -1-cyclopentylpropyl] — 2-Chenyl] butyric acid

(82) 4- (5— [1— (4-chlorophenylsulfonylamino) 1-4-cyclopropylpropyl] —2-phenyl) methyl butyrate

(83) 4- [5- (1- (4-chlorophenylphenylsulfonylamino) -14-cyclopropylpropyl] -12-Chenyl] butyric acid

(84) 4- [5- [1- [1- (4-Fluorophenylsulfonylamino) 1-4-cyclopropylbutyl]-2-Chenyl] methyl butyrate

(85) 4- [5-[[1- (4-fluorophenylsulfonylamino) -14-cyclopropylbutyl] -12-Chenyl] butyric acid

Among the compounds of the present invention, those in which R ³ is a hydrogen atom can be converted, if necessary, to an alkali addition salt, preferably a pharmacologically acceptable salt. It is also possible to convert such salts into free acids. Pharmaceutically acceptable salts include, for example, inorganic alkali salts such as sodium, potassium, calcium, or ammonium; or trimethylamine, triethylamine, pyrrolidine, piperidine, piperazine, or N— Salts of organic bases such as methylmorpholine can be mentioned.

The compound of the present invention represented by the general formula (I) may have an optically active substance or a stereoisomer based on one or more asymmetric carbon atoms. Both isomers of the form and mixtures of two or more isomers in any proportion are encompassed by the present invention. Also, any hydrates and solvates of the compound of the present invention are included in the scope of the present invention.

The (2-Chenyl) alkanoic acid derivative of the present invention represented by the general formula (I) can be produced, for example, by the following method, but the method of producing the compound of the present invention is as follows. However, the present invention is not limited to this method.

That is, the compound of the present invention represented by the general formula (I) has the following general formula (II):

NH ₂

I

R ² — CH — << ^S — (CH2) _n — C0 ₂ R ³

(Wherein, R ² , R ³ and n have the same meanings as described above.)

And an amide derivative represented by the following general formula (I I I):

(Wherein, R ¹ has the same meaning as described above.)

Can be produced by reacting with a sulfonyl chloride derivative represented by the formula in a solvent in the presence of a base, and hydrolyzing the ester if necessary.

The solvent used when reacting the compound of the general formula (II) with the compound of the general formula (III) may be any solvent as long as the reaction is not inhibited. For example, ether solvents such as getyl ether, tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as chloroform, methylene chloride and 1,2-dichloroethane, and aromatic hydrocarbons such as benzene and toluene. Hydrogen solvents, non-protonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide and the like can be used.

As the base used in the above reaction, for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -17-indene, pyridine, or 4-dimethyla An organic base such as minopyridine or an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate can be used. In general, the above reaction may be performed in a range from 0 ° C. to the reflux temperature of the solvent.

In addition, the ester hydrolysis reaction uses a base or an acid in water or a water-containing solvent. It can be done by doing. As the aqueous solvent, for example, a mixed solvent of an organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, tetrahydrofuran, 1,4-dioxane and water, or the like can be used. Wear. As the base, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium chloride, potassium carbonate, etc. can be used. As the acid, for example, hydrochloric acid, hydrobromic acid , Sulfuric acid and the like can be used. Hydrolysis reactions are common

One s

May be performed in a range from 0 ° C. to the reflux temperature of the solvent.

The amide derivative of the formula (II) used as a starting material in this production method can be produced, for example, according to the following method, the details of which are disclosed as reference examples in the working examples of the present specification. ing.

, S, SnC

R ² — C-CI + ^ (CHa) _n — C0 ₂ R ³

OH

SOCI ₂

R ² — CH- ^ (CHjJn one C0 ₂ R ³

NaN ₃

R (CH ₂ ) _n- C0 ₂ R ³

R ² —

(Wherein, R ² , R ³ and n have the same meanings as described above.)

The (2-thenyl) alkanoic acid derivative of the present invention represented by the formula (I) is an excellent thromboxane A. It is characterized by having both an antagonistic action and leukotriene 0 ₄ antagonism. Accordingly, the compounds of the present invention and pharmacologically acceptable salts thereof are useful as medicaments, for example, diseases such as ischemic heart disease, cerebrovascular disease, thrombosis, asthma, and allergic inflammation. It is useful as a medicament for the prevention and treatment of or. above For the prevention and / or treatment of diseases, it is preferable to use a pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient. Such a pharmaceutical composition can be used, for example, as a platelet aggregation inhibitor, an antithrombotic agent, an antiasthmatic agent, and an antiallergy agent.

Such a pharmaceutical composition is, for example, in the form of a composition for oral administration such as capsules, tablets, fine granules, granules, powders, syrups, and the like, or a composition for parenteral administration such as injections. Is administered. These preparations can be manufactured by a conventional method using pharmacologically and pharmaceutically acceptable additives for preparations. For the preparation of a composition for oral administration, for example, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.); disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.); Roxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.); Lubricants (magnesium stearate, talc, etc.); Coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.) Things can be used. For the production of parenteral compositions such as injections, dissolving agents or solubilizers that can constitute aqueous or ready-to-use injections (distilled water for injection, physiological saline, propylene glycol, etc.), pH, etc. Pharmaceutical additives such as regulators (inorganic or organic acids or bases), tonicity agents (salts, glucose, glycerin, etc.) and stabilizers can be used.

The dose of the compound of the present invention to a patient should be appropriately selected depending on the purpose of treatment and / or prevention, the condition of the patient's condition and age, etc., but in general, oral administration per adult per day The dose is about 1 to 100 mg for parenteral administration and about 1 to 500 mg for parenteral administration. Example

Hereinafter, the present invention will be described more specifically with reference examples and examples, but the scope of the present invention is not limited to these examples.

Reference Example 1: Methyl 4- (5-hexanoyl-2-enyl) butyrate

To a solution of 3.0 g of 4- (2-cenyl) methyl butyrate in 1 O ml of benzene was added 8.49 g of anhydrous tin tetrachloride under ice-cooling, and then 2.28 ml of hexanoyl chloride in benzene A 5 ml solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 100 ml of ice water, Extracted with tel. The ether layer was washed successively with water, an aqueous potassium carbonate solution and water, and after dehydration, the solvent was distilled off to obtain 4.44 g of a pale yellow liquid.

IR spectrum (liq) cm — ¹ : 1740, 1658

^{Mass spectrum} m / z: 282 ( ^MΎ )

NMR spectrum δ (CDClg) ppm: 0.90 (3H, t, J = 7Hz), 1.35 (4H, m), 1.73 (2H, qn, J = 7.5Hz), 2.03 (2H, qn, J = 7.5Hz) , 2.38 (2H, t, J = 7.5Hz), 2.83 (2H, t, J = 7.5Hz), 2.89 (2H, t, J = 7.5Hz), 3.68 (3H, s), 6.83 (1H, d, J = 3.5 Hz), 7.54 (1 H, d, J = 3.5 Hz) According to the method of Reference Example 1, the compounds of Reference Examples 2 and 3 were obtained. Reference Example 2: 4- [5- (5-Methylhexanoyl) -1-2-Chenyl] methyl butyrate Properties Light yellow-brown liquid

IR spectrum (liq) cm — ¹ : 1738, 1660

Mass vector m, 'z: 296 (M +)

NMR spectrum δ (CDClg) ppm: 0.89 (6H, d, J = 6.5 Hz), 1.23-1.27 (2H, m), 1.53-1.62 (1H, m), 1.70-1.76 (2H, m), 2.03 ( 2H, qn, J = 7.5Hz), 2.38 (2H, t, J = 7.5Hz), 2.8K2H, t, J = 7.5Hz), 2.89 (2H, t, J = 7.5Hz), 3.68 (3H, s), 6.83 (1H, d, J = 3.5Hz), 7.53 (1H, d, J = 3.5Hz) Reference Example 3: 4- (5-cyclohexylacetyl—2-phenyl) methyl butyrate Properties Light yellow-brown liquid

IR spectrum (lid) cm — ¹ : 1738, 1654

Mass vector m./'z: 308 (M ⁺ )

NMR spectrum δ (CDClg) ppm: 0.97-1.05C2H, m), 1.12-1.19C1H, m), 1.24 -1.32 (2H, m), 1.64-1.77C5H, m), 1.92-1.99 (1H, m) , 2.03 (2H, qn, J = 7.5Hz), 2.38 (2H, t, J = 7.5Hz), 2.69 (2H, d, J = 6.5Hz), 2.89 (2H, t, J = 7.5Hz), 3.68 C3H, s), 6.82C1H, d, J = 3.5Hz), 7.52 (1H, d, J = 3.5Hz) Reference Example 4: 4— [5— (1—hydroxyhexyl) 1-2-Chenyl] butyric acid Methyl To a solution of 5.05 g of methyl 4-(5-hexanoyl-2-cynyl) butyrate in 50 ml of methanol was added 0.51 g of sodium borohydride in portions under ice-cooling, followed by stirring for 1 hour. After evaporating the reaction solution under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water, and after dehydration, the solvent was distilled off to obtain 4.58 g of a light tan liquid.

IR spectrum (liq) cm- ¹ : 3460, 1740

Mass vector m, 'z: 284 (M +)

NMR spectrum δ (CDClg) ppm: 0.88 (3H, t, J = 7Hz), 1.25-1.30 (6H, m), 1.75-1.85 (2H, m), 1.87C1H, d, J = 3.5Hz) , 1.99 (2H, qn, J = 7.5Hz), 2.37 (2H, t, J = 7.5Hz),

2.83 (2H, t, J = 7.5Hz), 3.67 (3H, s), 4.82 (1H, m), 6.63 (1H, d, J = 3.5Hz), 6.77 (1H, d, J =

(3.5 Hz) According to the method of Reference Example 4, the compounds of Reference Examples 5 and 6 were obtained. Reference Example 5: 4- (5- (1-hydroxy-5-methylhexyl) -2-phenyl) methyl butyrate

Property Light yellow liquid

-1

IR spectrum (liq) cm 3452, 1740

Mass spectrum mz 298 (Μ ^Γ )

NMR spectrum _{δ (CDC1 3) ppm: 0.86} (3H, d, J = 7Hz), 0.87 (3H, d, J = 7Hz), 1, 17-1.58 (5H, m), 1.73-1.85C2H, m) , 1.86 (1H, d, J = 4Hz), 1.99 (2H, qn, J = 7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.82 (2H, t, J = 7.5Hz), 3.67 ( 3H, s), 4.80-4.84 (1H, m), 6.63 (1H, d, J = 3.5Hz), 6.77 (1H, d, J = 3.5Hz) Reference example 6: 4— [5— (2-cyclo Hexyl-l-hydroxyl) — 2-phenyl] methyl butyrate

Property Light yellow liquid

-1

I R Sk tonori (liq) cm 3752, 1738

Mass vector m / z: 310 (+)

NMR spectrum δ (CDCl) ppm 0.89-1.02 (2Η, m), 1.11-1.28 (3Η, m), 1.41 -1.49 (1H, m), 1.60-1.80 (7H, m), 1.83 (1H, d, J = 4Hz), 1.99C2H, qn, J = 7.5Hz), 2.37 (2H, t, J = 7.5Hz) , 2.83 (2H, t, J = 7.5Hz), 3.67 (3H, s), 4.92-4.96 (1H, m), 6.63C1H, d, J = 3.5Hz), 6.77 (1H, d, J = 3.5Hz) ) Reference Example 7: 4- (5- (1-chlorohexyl) — 2-Chenyl) methyl butyrate

4- [5- (1-Hydroxyhexyl) -12-thenyl] methyl butyrate 0.95 ml of thionyl chloride was added dropwise to a solution of 3.50 g of methylene chloride in 15 ml of ice and stirred for 50 minutes. The reaction solvent was distilled off under reduced pressure to obtain 3.73 g of a brown liquid.

IR spectrum (liq) cm- ¹ : 1738

Mass vector m, z: 302, 304 (3: 1, M ⁺ )

NMR spectrum _{δ (CDC1 3) ppm: 0.89} (3H, t, J = 7Hz), 1.25-1.45 (6H, m), 2. 00 (2H, qn, J = 7.5Hz), 2.05-2.20 (2H, m), 2.38 (2H, t, J = 7.5Hz), 2.83 (2H, t, J = 7.5Hz), 3.68 (3H, s), 5.10 (1H, t, J = 7.5Hz), 6.6K1H, d , J = 3.5Hz), 6.84 (1H, d, J = 3.5Hz) Reference Example 8: 4- [5- (1-Azidohexyl) -2-Chenyl] Methyl butyrate

4- [5- (1- (hexylhexyl) -1-2-phenyl) methylbutyrate] 3.73 g of N, N-dimethylformamide solution (1 ml), add sodium azide (1.60 g) and add 40 ° The mixture was stirred with C for 1.5 hours. Water was added to the reaction solution, which was extracted with ether. The ether layer was washed with water, and after dehydration, the solvent was distilled off. The residue was purified by silica gel gel chromatography (methylene chloride-n-hexane 3: 2 → 2: 1) to give a colorless liquid 3.

50 g were obtained.

IR spectrum Honoré Les (liq) cm ^_1 2104, 1740

Mass spectrum mz: 309 (M ⁺ )

NMR spectrum δ (CDClg) ppm 0.88 (3H, t, J = 7Hz), 1.25-1.50 (6H, m), 1.

75-1.90C2H, m), 2.00C2H, qn, J = 7.5Hz), 2.38 (2H, t, J = 7.5Hz), 2.84C2H, t, J = 7.5Hz), 3.68 (3H, s), 4.54 C1H, t, J = 7.5Hz), 6.66 (1H, d, J = 3.5Hz), 6.8K1H, d, J = 3.5Hz) Reference Example 9: 4— [5— (1-azide—5-methyl) Xyl)-2-Chenyl], methyl butyrate 4- [5- (1-Hydroxy-5-methylhexyl) -2-phenyl] To a solution of 9.13 g of methyl butyrate in 45 ml of anhydrous ether was added dropwise 2.46 ml of thionyl chloride under ice-cooling. Stirred at room temperature for 40 minutes. To the residue obtained by evaporating the reaction solvent under reduced pressure, N, N-dimethylformamide (27 ml) and sodium azide (3.98 g) were added, and the mixture was stirred at 40 ° C for 1 hour. Water was added to the reaction solution, which was extracted with ether. The ether layer was washed with water, and after dehydration, the solvent was distilled off to obtain 9.19 g of a light reddish brown liquid.

IR spectrum (liq) cm — ¹ : 2104, 1738

Mass spectrum mz: 323 (M ^τ )

NMR spectrum δ (CDClg) ppm: 0.86C3H, d, J = 7Hz, 0.87 (3H, d, J = 7Hz), 1.18-1.61 (5H, m), 1.74-1.88 (2H, m), 2.00 (2H, qn, J = 7.5Hz), 2.38 (2H, t, J = 7.5Hz), 2.84 (2H, t, J = 7.5Hz), 3.68 (3H, s), 4.54 (1H, t, J = 7.5Hz), 6.67C1H, d, J = 3Hz), 6.8K1H, d, J = 3Hz) According to the method of Reference Example 9, the compound of Reference Example 10 was obtained. Reference Example 10: 4- (5- (1-Azido-1-cyclohexylethyl) -12-Chenyl) Methyl butyrate

Description Light reddish brown liquid

IR spectrum (liq) cm ^_i 2104, 1738

Mass spectrum mz: 335 (M ⁺ )

NMR spectrum _{5 (CDC1 9) ppm 0.88-0.99 (} 2H, in), 1.11-1.31 (3H, m), 1.39 -1.44 (1H, m), 1.63-1.80 (7H, m), 2.00 (2H , qn, J = 7.5Hz), 2.38 (2H, t, J = 7.5Hz), 2.84 (2H, t, J = 7.5Hz), 3.68 (3H, s), 4.65 (1H, t, J = 7Hz) , 6.67 (1H, d, J = 3.5Hz), 6.82 (1H, d, J = 3.5Hz) Reference Example 1 1: 4-[5- (1-aminohexyl)-2-Chenyl] Butyric acid Methyl

4- (5- (1-Azidohexyl) -12-Chenyl) methyl butyrate 3.10 g of platinum oxide was added to a solution of 4.47 g of methanol in 35 ml, and hydrogenated at room temperature and pressure for 3 hours. did. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure. Dissolve the residue in dilute hydrochloric acid and add ether Washed. The ether layer was washed with water, and after dehydration, the solvent was distilled off to obtain 2.39 g of a light brown liquid.

IR spectrum (liq) cm — ¹ : 3384, 1738

Mass vector m / z: 283 ( ^τ )

NMR spectrum _{δ (CDC1 0) ppm: 0.87} (3H, t, J = 7Hz), 1.25- 1.40 (6H, m), 1. 65-1.75 (2H, m), 1.98C2H, qn, J = 7.5Hz ), 2.37 (2H, t, J = 7.5Hz), 2.82 (2H, t, J = 7.5Hz),

3.67 (3H, s), 4.07 (1H, t, J = 7Hz), 6.60 (1H, d, J = 3.5Hz), 6.68 (1H, d, J = 3.5Hz) Reference example 1 2: 4— [5 — (1-Amino-5-methylhexyl) -1-2-Chenyl] methyl butyrate

4- [5- (1-azido-5-methylhexyl)-2-phenyl] methyl butyrate

4.To a solution of 56 g of 45 ml of anhydrous tetrahydrofuran in triphenylphosphine 5.

55 g was added, and the mixture was stirred at 40 ° C for 2 hours. To the reaction solution was added water (2.7 ml), and the mixture was stirred at 40 ° C for 22 hours. The solvent was distilled off under reduced pressure, and the residue was acidified by adding dilute hydrochloric acid, and washed with ether. The acidic aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, and after dehydration, the solvent was distilled off to obtain 3.01 g of a pale yellow liquid. IR spectrum (liq) cm ¹ : 3384, 1738

Mass vector mz: 297 (M ^T )

NMR spectrum _{S (CDC1 3) ppm: 0.85} (3H, d, J = 6.5Hz), 0.86 (3H, d, J = 6.5Hz), 1.17-1.42 (4H, m), 1.48-1.72 (3H, m ), 1.98 (2H, qn, J = 7.5Hz), 2.37 (2H, t, J = 7.5Hz), 2.82 (2H, t, J = 7.5Hz), 3.67C3H, s), 4.07 (1H, t, J = 7 Hz), 6.60C1H, d, J = 3.5 Hz), 6.68 (1H, d, J = 3.5 Hz) According to the method of Reference Example 12, the compound of Reference Example 13 was obtained. Reference Example 13 3: 4- [5- (1-Amino-2-cyclohexylethyl) -2-phenyl] methyl butyrate

Property Light yellow liquid

IR spectrum (liq) cm ¹ : 3384, 1738 Mass vector m / z: 309 (M +)

NMR spectrum δ (CDCln) ppm: 0.89-0.98 (2H, m), 1.11-1.25 (3H, m), 1.32 -1.38 (1H, m), 1.56-1.74 (7H, m), 1.98 (2H, qn , J = 7.5Hz), 2.37 (2H, t, J-7.5Hz), 2.81 (2H, t, J = 7.5Hz), 3.67 (3H, s), 4.18 (1H, t, J = 7.5Hz), 6.59 (1H, d, J = 3.5 Hz), 6.68 (1H, d, J = 3.5 Hz) Example 1: 4- [5- [1- (4-chlorophenylsulfonylamino) hexyl] 1 Chenyl] methyl butyrate

4-[5- (1 -aminohexyl) -1-2-phenyl] methyl butyrate 2.35 g and triethylamine 1.2 1 ml of methylene chloride 1 Oml solution under ice-cooling 1.75 g of sulfonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed successively with dilute hydrochloric acid and water, and after dehydration, the solvent was distilled off under reduced pressure. The residue was crystallized from a mixed solution of isopropyl ether and n-hexane, and collected by filtration to obtain 3.08 g of colorless crystals. Recrystallization from a mixed solution of isopropyl ether and n-hexane gave colorless plate crystals having a melting point of 50 to 51 ° C.

Elemental analysis _{_{_{C 21 H 28 C 1 0 4}}} S 9

Theory C 55.07; H, 6.16; N, 3.06

Experimental value C 54.86; H, 6.24; N, 3.05 According to the method of Example 1, the compounds of Examples 2 to 4 were obtained. Example 2:

4- [5— [1— (4-Chlorophenylsulfonylamino) -1-5-methylhexyl] 1-2-Chenyl] Methyl butyrate

Properties Light yellow viscous liquid

IR spectrum (liq) cm — ¹ : 3288, 1738

Mass vector m / z: 471, 473 (3: 1, M +)

NMR spectrum δ (CDClo) ppm: 0.81 (3H, d, J = 6.5Hz), 0.82 (3H, d, J = 6.5Hz), 1.10-1.34 (4H, m), 1.41-1.49C1H, m), 1.68-1.82C2H, m), 1.88C2H, qn, J = 7.5Hz), 2.32 (2H, t, J = 7.5Hz), 2.70 (2H, t, J = 7.5Hz), 3.68C3H, s), 4.54 (1H, q, J = 7.5Hz), 4.86C1H, d, J = 8Hz) , 6.44 (1H, d, J = 6.5Hz), 6.49C1H, d, J = 6.5Hz), 7.33 (2H, d, J = 8.5Hz), 7.63 (2H, d, J = 8.5Hz) : 4- [5-[[1- (4-fluorophenylsulfonylamino)-5-methylhexyl] -12-Chenyl] methyl butyrate

Properties Light yellow viscous liquid

IR spectrum (liq) cm— ¹ : 3284, 1738

Mass spectrum m / z: 455 ( ^MΎ )

NMR spectrum _{S (CDC1 3) ppm: 0.8K3H} , d, J = 6.5Hz), 0.82 (3H, d, J = 6.5Hz), 1.10-1.34 (4H, m), 1.41-1.49 (1H, m) , 1.68-1.82 (2H, m), 1.88 (2H, qn, J = 7.5Hz), 2.31 (2H, t, J = 7.5Hz), 2.70 (2H, t, J = 7.5Hz), 3.68 (3H, s), 4.54 (1H, q, J = 7.5Hz), 4.86C1H, d, J = 7.5Hz), 6.44C1H, d, J = 3.5Hz), 6.48 (1H, d, J = 3.5Hz), 7.04 (2H, t, J = 8.5 Hz), 7.72 (2H, dd, J = 8.5, 5 Hz) Example 4: 4-[5-[1-1 (4-chlorophenylphenylsulfonylamino) 1 2- Cyclohexylethyl] 1-2-Chenyl] Methyl butyrate

Characteristics Colorless plate-like crystals (i_Pr ₂ 0)

87-88 ° C

Elemental analysis value C ₂₃ H _{3 ()} C 1 N0 ₄ S ₉

Theory C 57.07; H, 6.25; N, 2.89

Experimental value C 57.08; H, 6.49; N, 2.80 Example 5: 4- [5- [1- (4-chlorophenylsulfonylamino) hexyl] -1-2-phenyl) butyric acid

4- [5- (1- (4- (phenyl) sulfonylamino) hexyl] -1-2-phenyl) butyrate 2.68 g of methanol in 8 ml of methanol and 5.9 ml of 2N aqueous sodium hydroxide solution The mixture was stirred at 50 ° C for 1 hour. The reaction solvent was distilled off under reduced pressure, water was added to the residue, the mixture was acidified with dilute hydrochloric acid, and extracted with methylene chloride. Methylene chloride layer After washing with water and dehydration, the solvent was distilled off to obtain 2.56 g of colorless crystals. Recrystallization from isopropyl ether gave colorless needles having a melting point of 84.5 to 855.5.

Elemental analysis C. () H _2e C 1 N0 ₄ S ₂

Theory C 54.10; H, 5.90;, 3.15

Experimental value C 53.99; H, 5.97; · Ν, 3.17 According to the method of Example 5, compounds of Examples 6 to 8 were obtained. Example 6: 4- [5- [1- (1-chlorophenylsulfonylamino) -1-5-methylhexyl] -12-phenyl] butyric acid

Colorless plate-like crystals properties (i- Pr ₂ 0)

87.5-89 ° C

Elemental analysis value C ₂₁ H ₂₈ C 1 N0 ₄

Theory C 55.07; H, 6.16; N, 3.06

Experimental value C 54.84; H, 6.37; N, 3.01 Example 7: 4- [5- [1- (4-fluorophenylsulfonylamino) -1-methylhexyl] -2-phenyl] butyric acid

Properties colorless prisms (i-Pr ₉ 0)

Melting point 97.5 ~ 98.5 ° C

Elemental analysis: C ₂₁ H. ₈ FN0 ₄ So

Theory C 57.12; H, 6.39; N, 3.17

Experimental value C 56.92; H, 6.59; N, 3.04 Example 8: 4- [5- (1- (4-chlorophenylsulfonylamino) -12-cyclohexylethyl] -12-phenyl) butyric acid

Properties Colorless plate crystals (AcOEt)

Melting point 1 46 ~ 1 47.5 ° C

Elemental analysis _{_{_{C 22 H 28 C 1 0 4}}} S 2 Theory C 56.22; H, 6.00; N, 2.98

Experimental value C 56.10; H, 6.16; N, 2.90 As an example of the excellent action of the compound of the present invention, thromboxane A was used. Antagonism, airway constriction inhibitory action, and are shown in following each test result of leukotriene 0 ₄ antagonism. As the control drug, it was used daltroban (U.S. Pat. No. 4,443,477) is a thromboxane A ₂ antagonist. Test example 1

Door opening Nbokisan A ₂ antagonism

The trachea of a male Hartley guinea pig was excised according to a conventional method, and a spiral specimen about 2 cm in length was prepared. This was suspended by applying a load of 1.5 g to an extraction test tank filled with Klebs-Henseleit solution at 37 ° C, and the change in isometric tension was recorded. 1 x 1 0- ⁹ ~3 x 10 of Y- 46619 and (Cayman Co., thromboxane A _n prostaglandin H antagonists DOO ₂ receptor) cumulatively applied to experimental bath, concentration-response curve for Control I got Then, after applying the test compounds of a suitable concentration for 5 minutes, by applying a 10 one ⁹ ~ 10- ¾ of U- 46619, to give a concentration response curve. p¾ was calculated from the two concentration-response curves by the method of Schild [Pharmacological Review, Vol. 9, p. 242 (1957)]. In addition, indomethacin (3 × 10 ¹⁶ M: Sigma) was added to the experimental tank in advance, and CJapan J. Pharmacol., In which the effects of thromboxane A ₂ and prostaglandin generated by stimulation of leukotriene D ₄ were removed. 60, 227 (1992)]. Table 1 shows the results. Table 1 Thromboxane A ₂ antagonism

Test compound PKB

Example 5 1 0.0

Example 6 9.6

Example 7 9.3

Example 8 9.0

Control drug 7.6 The present invention compounds showed thromboxane A ₂ antagonistic effect superior compared to the control drug. Test example 2

U-46619 Inhibition of airway stenosis

The airway resistance was evaluated according to the method of Konzett-Roessler [Naunyn-Schmiedberg's Arch. Exp. Path. Pharmak., Vol. 195, p. 71 (1940)]. That is, Hartley male guinea pigs (about 400 g) were anesthetized with urethane (1.5 g / kg, ip) and then ventilated with an artificial respirator (Model 683; Harvard). At this time, the溢気amount exceeding a pressure of about 1 2 cmH ₂ 0 sensor; measured at (Model 7020 Ugo basile Inc.) was used as an index of airway narrowing. A test compound suspended in 5% gum arabic was orally administered to a guinea pig fasted for 24 hours beforehand at 0.3 mg / kg (5 ml / kg), and 2 hours later, U-46619 (4 g / kg; Cayman Was administered to the jugular vein, and the value at the time of the maximum response was measured. Based on the reaction rate assuming 100% complete occlusion, the inhibition rate with respect to the control group was calculated. Table 2 shows the results.

Table 2 Inhibition of U-46619-induced airway stenosis

Test compound inhibition rate (%)

Example 5 9 5

Example 6 8 2

Example 7 6 9

Control Drug 18 The compound of the present invention showed an excellent inhibitory effect on U-46619-induced airway stricture as compared with the control drug. Test example 3

Leuco Trien D ₄ antagonism

The trachea of a male Hartley guinea pig was excised according to a conventional method, and a chain specimen about 2 cm in length was prepared. Transfer 0.5 g of this to an extraction test tank filled with Krebs solution at 37 ° C. And suspended isotonic. Asechirukorin (1 X 10 ^"5 M; Opiso Ichito Injection, first Seiyakusha) was shrunk in a 1 0 one ¹⁰ ~ 1 0- ⁸ M leuco Toryen D ₄ (ULTRA FINE Inc.) experimental bath It applied cumulatively, to obtain a first concentration-response curves. Next, after applying the test compounds of a suitable equivalent concentrations for 30 minutes to obtain a second concentration-response curve similar to the first. pK _B the two concentration-response from the curve Schild method CPharmacological Review is Vol. 9, No. 242, pp calculated in (1957)] in addition, roughening Jimeindometashin the experimental bath (1 x 10 one ⁰ M;. Sigma Was added to remove the effects of thromboxane A and prostaglandin generated by the stimulation of leukotriene [Japan J. Pharmacol., 60, 227 (1992)]. The results are shown in Table 3. Table 3 Leukotriene D ₄ antagonism

Test compound pKB

Example 5 6

Example 6 7.1

Example 7 7.1

Example 8 7.2

Control drug <4 The control drug did not show leukotriene antagonism, but the compound of the present invention showed excellent leukotriene D ₄ antagonism ₍ Test Example 4

Inhibition of Leuco Trien D-induced airway stenosis

The airway resistance was evaluated according to the method of Konzett-Roessler [Naunyn-Schmiedberg's Arch. Exp. Path. Pharmak., Vol. 195, p. 71 (1940)]. That is, male Hartley guinea pigs that had been fasted for 24 hours beforehand were anesthetized with urethane, and the amount of swelling was measured as an index of airway constriction under human respiration. Oral administration of 30 or 10 mg / kg (5 ml / kg) of the test compound suspended in 5% arabic gum, 2 hours later, administration of leukotriene (1 ^ g / kg; ULTRA FINE) into the jugular vein, The value 2 minutes after the maximum reaction was measured. The value indicates that the spill volume at the time of complete occlusion is 100% airway stenosis. Based on the response rates made, the inhibition rate for the control group was calculated. Table 4 shows the results. Incidentally, Roikotoryen D ₄ 1 0 minutes before indomethacin administration (2 mg / kg, iv) , was administered five minutes before propranolol (1 mg / kg, iv) a.

Table 4 Inhibition of leukotriene-induced airway stenosis

Suppression rate (%)

Test compound 1 30 mg / kg 10 mg / kg

Example 5 7 9 7 1

Example 6 1 7 8

Example 7-6 3

Control drug ≤ 0 Control drug did not inhibit leukotriene 0-induced airway stricture, but the compound of the present invention showed excellent inhibitory action against leukotriene D-induced airway stricture. Industrial applicability

The compounds of the present invention are extremely useful as medicaments such as platelet aggregation inhibitors, antithrombotic agents, antiasthmatic agents and antiallergic agents.

Claims

-General formula (I)

Contract

(Wherein, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a nitro group; is represented by C _{1 ()} (C ₁ to C 10. alkyl group, which may have a lower alkyl group on the ring C.～C. cycloalkyl group, or a substituted is enclosed with a cycloalkyl group of c ₃ to c ₈ notation to) the

R ³ represents a hydrogen atom or a lower alkyl group; and n represents an integer of 2 to 4. Or a salt thereof.

2.4— [5— [1— (4-chlorophenylsulfonylamino) -1-5-methylhexyl] —2-phenyl) butyric acid or a salt thereof.

3.4— [5— [1— (4-Fluorophenylsulfonylamino) -1-5-methylhexyl] -12-phenyl) butyric acid or a salt thereof.

4. A medicament comprising the compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof.

5. Thromboxane A ₂ antagonism and leukotriene! ^ The medicament according to claim 4, which has an antagonistic action.

6. The medicament according to claim 4 or 5, which is used for prevention and Z or treatment of a disease selected from the group consisting of ischemic heart disease, cerebrovascular disease, thrombosis, asthma, and allergic inflammation.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof, which is an active ingredient, and a pharmaceutical additive.

8. The medical device according to claim 7, which is used for prevention and / or treatment of a disease selected from the group consisting of ischemic heart disease, cerebrovascular disease, thrombosis, asthma, and allergic inflammation. Medicinal composition.

9. The pharmaceutical composition according to claim 7, which is used as a drug selected from the group consisting of a platelet aggregation inhibitor, an antithrombotic agent, an antiasthmatic agent, and an antiallergic agent.

10. A compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof, which is an active ingredient, and a pharmaceutical additive, and ischemic heart disease, brain 4. The method according to any one of claims 1 to 3, for the manufacture of a pharmaceutical composition used for prevention and / or treatment of a disease selected from the group consisting of vascular disorders, thrombosis, asthma, and allergic inflammation. Or use of the compound according to item 1 or a pharmacologically acceptable salt thereof.

11. A mammal in need of treatment and / or prevention of a therapeutically and / or prophylactically effective amount of the compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof. A method for preventing, treating, or treating a disease selected from the group consisting of ischemic heart disease, cerebrovascular disease, thrombosis, asthma, and allergic inflammation, which comprises administering to a subject.