JPH05294930A - Stylyl compound - Google Patents

Abstract

PURPOSE:To obtain a new styryl compound having remarkable and long-active leukotriene(LT) antagonistic action and LT inhibiting action, exhibiting excellent absorption by oral administration and also having 5-lipoxygenase inhibiting action, cyclooxygenase-inhibiting action., etc. CONSTITUTION:The objective compound of formula I [A is H, NR<1>R<2> (R<1> and R<2> are H, alkyl, aralkyl, etc.), cycloalkyl, etc.; Alk<1> and Alk<2> are single bond, alkylene or alkenylene; X<1> and X<2> are single bond, O, SO, SO2, CO, etc.; Y is aryl, heteroring etc.; B is tetrazolyl, phenylsulfonyl, etc.; Z is H, halogen, alkyl, etc.], its pharmaceutically permissible salt or its ester, e.g. (E)-1-(3-(2-(6-(4-(4-ethylphenyl)butoxymethyl)-2-pyridyl)ethenyl)benzoyl) amino-1- cyclopropanecarboxylic acid. This compound can be produced from a compound of formula II or its reactive derivative and the formula H2N-B. Furthermore, the compound is useful as an antiphlogistic agent, an antiallergic agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to leukotriene antagonistic action, leukotriene inhibitory action, 5-lipoxygenase inhibitory action and / or cyclooxygenase inhibitory action, leukotriene B ₄ biosynthesis inhibitory action, human leukocyte migration inhibitory action, chymase inhibitory action, The present invention relates to a novel and pharmaceutically useful styryl compound having a histamine release inhibitory action, an antihistamine action and the like, or a pharmaceutically acceptable salt or ester thereof.

[0002]

BACKGROUND OF THE INVENTION Various leukotrienes produced by the metabolic system of arachidonic acid,
Thromboxane A ₂ , prostaglandin and the like are known as chemical mediators causing allergy, inflammation, asthma and the like. Furthermore, it is considered that the imbalance of these chemical mediators induces various diseases, and in particular, it is practical to develop antagonists and / or biosynthesis inhibitors of these chemical mediators in the arachidonic acid cascade. Is expected from. Among them, leukotriene is synthesized through 5-lipoxygenase and has an important role as a chemical mediator.
₄ , D ₄ and E ₄ are constituents of the slow-reacting substance of anaphylaxis (SRS-A) and are important mediators of allergy and inflammation such as bronchial asthma. Therefore, the compound having a leukotriene antagonistic effect is useful for treating allergy such as bronchial asthma and inflammation. JP-A-62-145
049, 62-142168 and 6
No. 2-53967 discloses certain styryl compounds,
It is disclosed that each of the thiazole compound and the phenylalkenylquinoline compound has a leukotriene antagonistic action and a leukotriene synthesis inhibitory action. Further, JP-A-61-50977 discloses N- [4-oxo-2- (1H-tetrazol-5-yl) -4H-1-benzopyran-8-yl] -4- (4 as a leukotriene antagonist. -Phenylbutoxy) benzamide is disclosed. Further, JP-A-60-142968 discloses certain diazine-ethenylphenyloxamic acid compounds having immune anti-inflammatory and anti-allergic effects, and JP-A-56-145280 discloses 5-
The lipoxygenase inhibitor 6- (12-hydroxy-5,10-dodecadinyl) -2,3,5-trimethyl-1,4-benzoquinone suppresses the biosynthesis and release of SRS-A and is useful as an antiallergic agent. Is disclosed. However, leukotriene and SRS-
Only a few drugs are known to have A antagonism and biosynthesis inhibitory action, and none have been practically used yet. Furthermore, leukotriene B ₄ (LTB ₄ ) is a chemical mediator in various inflammations (gout, etc.), has a strong chemotactic action on human leukocytes, and LTB ₄
Has been reported to be related to inflammation. Furthermore, it is said that myocardial infarction is exacerbated by a large amount of agglutination of leukocytes. Therefore, 5-lipoxygenase inhibitor and leukotriene B ₄ biosynthesis inhibitor can prevent inflammation and deterioration of myocardial infarction. Is expected. As mentioned above,
Although various compounds that specifically act as antagonists of various chemical mediators and inhibitors of enzymes involved in biosynthesis of these chemical mediators have been synthesized, none have been sufficiently applied as pharmaceuticals. On the other hand, it is well known that histamine is also an important causative agent of allergy and inflammation. In recent years, chymase (chymase: chymotrypsin type protease), which is present in mast cell granules and is involved in the release of histamine granules through IgE receptors, has been studied, and by inhibiting this chymase, chemical mediators such as histamine The creation of a new type of antiallergic agent that suppresses the release of is also being investigated. Therefore, development of a single drug capable of controlling multiple chemical mediators and prevention and treatment of allergy, asthma or inflammation are desired.

[0003]

The present invention relates to a styryl compound having a remarkable and long-lasting leukotriene antagonistic action or leukotriene inhibitory action, and further showing excellent absorption by oral administration. Further, the present invention relates to a styryl compound having 5-lipoxygenase inhibitory action and / or cyclooxygenase inhibitory action, LTB ₄ biosynthesis inhibitory action, human leukocyte migration inhibitory action, chymase inhibitory action, histamine release inhibitory action and antihistamine action.

That is, the present invention has the general formula (I)

[Chemical 5] [In the formula, A is hydrogen, formula (a) -N (R ¹ ) (R ² ) (a) (R ¹ and R ² are the same or different and represent hydrogen, alkyl and aralkyl, or R ¹ and R ² Represents a group which is bonded to each other to form a ring with an adjacent nitrogen atom), amino, cycloalkyl, aryl, heterocycle, halogen on the ring, nitro, amino, monoalkylamino,
Dialkylamino, alkanoylamino, hydroxyl group, alkyl, cycloalkyl, alkenyl, alkenyloxy, alkynyl, aralkyl, alkoxy, haloalkyl, cyano, carboxyl, alkoxycarbonyl, tetrazolyl, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, carbamoyl, monoalkylcarbamoyl , Dialkylcarbamoyl, carboxyalkanoylamino, alkoxycarbonylalkanoylamino, phenylsulfonyl, phenylsulfonylamino, formula (b)

[Chemical 6] Formula (c)

[Chemical 7] Formula (d)

[Chemical 8] (R ³ and R ⁴ in the formulas (b), (c) and (d) are the same or different and each represent hydrogen, halogen, haloalkyl, amino, nitro, cyano, hydroxyl group, alkyl or aralkyl). A cycloalkyl, aryl or heterocycle having at least one of the groups (when the aryl or heterocycle is an aromatic ring, the substituent is not formula (d)), phenylsulfonyl, phenylsulfonyl. Halogen, nitro, amino, hydroxyl, alkyl, alkoxy, on the amino or phenyl ring,
Phenylsulfonyl or phenylsulfonylamino having at least one substituent selected from haloalkyl and cyano, Alk ¹ and Alk ² are the same or different, and a single bond, alkylene or alkenylene, X
¹ , X ² is a single bond, oxygen, —S (O) _n — (n is 0,
Indicates an integer of 1 or 2. ), - CO -, - N (R 5) -,
^{-CON (R 6) -, -} N (R 7) CO -, - CH (O
^{R 8) - (R 5,} R 6, R 7 are the same or different and each is hydrogen, alkyl, aralkyl, R ⁸ is hydrogen, alkyl,
Indicates acyl. ), Ring Y is an aryl, heterocycle or an aryl or heterocycle having at least one substituent selected from halogen, nitro, amino, hydroxyl group, alkyl, alkoxy, haloalkyl and cyano on the aromatic ring, B is tetrazolyl, phenylsulfonyl, phenylsulfonyl having at least one substituent selected from halogen, nitro, amino, hydroxyl group, alkyl, alkoxy, haloalkyl and cyano on the ring, or 1 to 2 carboxyl groups. Substituted C1-C8 straight-chain, branched-chain or C3-C7 cyclic-alkyl, Z is hydrogen, halogen, alkyl,
Alkoxy, haloalkyl, alkylthio, alkylsulfinyl and alkylsulfonyl are shown. ] The styryl compound represented by these, its pharmaceutically acceptable salt, or its ester.

Explaining each symbol of the general formula (I) by definition, halogen is chlorine, bromine, fluorine and iodine, and alkyl is a linear or branched alkyl having 1 to 6 carbon atoms. Therefore, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, etc. are straight-chain or branched chain having 1 to 8 carbon atoms. In addition to the above-mentioned straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, heptyl, octyl and the like, and haloalkyl means that the alkyl is substituted with 1 to 5 halogens. And trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3
Alkoxy such as 3,3-pentafluoropropyl is a linear or branched alkoxy having 1 to 6 carbon atoms, and is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary. Butoxy,
Tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like represent the same group as cycloalkyl or cyclic-alkyl having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, monoalkylamino is methylamino, ethylamino, propylamino, butylamino, secondary butylamino, tertiary butylamino, etc., and dialkylamino is dimethylamino, diethylamino, dipropylamino, dibutylamino. And the like, alkylene is a linear or branched alkylene having 1 to 20 carbon atoms, and is methylene, ethylene, trimethylene, propylene, tetramethylene,
Pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, ethylmethylene, dimethylmethylene, diethylmethylene, dimethylethylene,
Diethyl ethylene, dimethyl trimethylene, diethyl trimethylene, dimethyl tetramethylene, diethyl tetramethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, pentadecamethylene, hexadecamethylene,
Heptadecamethylene, octadecamethylene, nonadecamethylene, icosamethylene, and alkenylene are linear or branched alkenylene having 2 to 20 carbon atoms, such as vinylene, propenylene, butenylene, pentenylene, hexenylene, Octenylene, Nonenylene,
Decenylene, undecenylene, dodecenylene, tridecenylene, tetradecenylene, pentadecenylene, hexadecenylene, heptadecenylene, octadecenylene, nonadecenylene, icosenylene, and the like, and alkenyl is an alkenyl having 2 to 8 carbon atoms, vinyl, propenyl, butenyl, pentenyl, pentenyl, pentenyl, and pentenyl. And the like, alkenyloxy has an alkenyl part having 2 to 8 carbon atoms, and includes vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, octenyloxy and the like, and alkynyl has 2 to 8 carbon atoms. Alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, octynyl, and the like, aralkyl is halogen as a substituent, an alkynyl having 1 to 8 carbon atoms. , Benzyl optionally having 1 to 3 alkoxy having 1 to 8 carbons, haloalkyl, amino, nitro, cyano, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl And the like, acyl means acetyl, propionyl, butyryl, valeryl, pivaloyl, benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl, etc., and acyloxy means acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, benzoyloxy, phenylacetyl. Oxy, phenylpropionyloxy, phenylbutyryloxy and the like, alkylthio is methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary butylthio, tertiary butyl Alkylsulfinyl includes thio, pentylthio, isopentylthio, neopentylthio, and hexylthio, and methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, secondary butylsulfinyl, tertiary butylsulfinyl, Pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, hexylsulfinyl and the like, alkylsulfonyl is methylsulfonyl, ethylsulfonyl, propylsulfonyl,
Isopropyl sulfonyl, butyl sulfonyl, isobutyl sulfonyl, secondary butyl sulfonyl, tertiary butyl sulfonyl, pentyl sulfonyl, isopentyl sulfonyl, neopentyl sulfonyl, hexyl sulfonyl, etc., and alkanoyl amino has a branched alkanoyl part. May be, for example, acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino, 3-ethylvalerylamino and the like, and carboxyalkanoylamino may be branched alkanoyl moiety, for example carboxyacetylamino , Carboxypropionylamino, carboxybutyrylamino, carboxyvalerylamino, 3-carboxy-2,2-dimethylpropionylamino, 3-carboxy-3-ethyl Valerylamino, etc., methoxycarbonyl acetylamino the alkoxycarbonylamino alkanoylamino, ethoxycarbonyl acetylamino,
Propoxycarbonylacetylamino, butoxycarbonylacetylamino, ethoxycarbonylacetylamino, methoxycarbonylpropylonylamino, methoxycarbonylbutyrylamino, methoxycarbonylvalerylamino, 3-methoxycarbonyl-2,2-dimethylpropionylamino, 3-methoxy Carbonyl-3-
Ethyl valeryl amino and the like, aryl is phenyl,
1-naphthyl, 2-naphthyl and the like, and monoalkylcarbamoyl means methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, tertiary butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and dialkylcarbamoyl. Is dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, ditertiarycarbamoyl.
Butylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-methyl-N-propylcarbamoyl, N-methyl-N-butylcarbamoyl, N-methyl-N-third
Secondary butylcarbamoyl, N-methyl-N-pentylcarbamoyl, N-methyl-N-hexylcarbamoyl and the like, and the heterocycle is pyrrolidinyl, piperidyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzodioxanyl, benzoxazinyl, benzthiazinyl, quinolyl, and the like are a group which forms a ring with a nitrogen atom adjacent to R ¹ and R ² in addition to the nitrogen atom. , A cyclic amino group which may have a hetero atom such as nitrogen, oxygen and sulfur, and examples thereof include 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1
-Piperazinyl, 1-homopiperazinyl and the like 5- to 7-membered ring saturated cyclic amino compounds are included, and the cyclic amino group may have a substituent at a substitutable position, and such a substituent is halogen. , Nitro, amino, monoalkylamino, dialkylamino, alkanoylamino, hydroxyl group, alkyl, cycloalkyl, alkenyl, alkenyloxy, alkynyl, aralkyl, alkoxy, haloalkyl, cyano, carboxyl, tetrazolyl, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl , Carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, carboxyalkanoylamino, alkoxycarbonylacanoylamino, phenylsulfonyl, phenylsulfonylamino, formula (b)

[Chemical 9] Formula (c)

[Chemical 10] Formula (d)

[Chemical 11] (R ³ and R ⁴ in formulas (b), (c) and (d) are the same or different and represent hydrogen, halogen, haloalkyl, amino, nitro, cyano, hydroxyl group, alkyl and aralkyl). Examples include diphenylmethyl.

The salts of the styryl compound of the present invention include hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, propionate, lactate, oxalate, fumarate and maleic acid. Acid addition with inorganic or organic acids such as salts, mandelate, citrate, tartrate, succinate, glycolate, malate, ascorbate, methanesulfonate, paratoluenesulfonate Alkali metal salts such as salts, sodium salts and potassium salts, salts with alkaline earth metals such as calcium salts and magnesium salts, quaternary ammonium salts, amino acid salts such as lysine salts, triethylamine salts and diethanolamine salts Examples thereof include salts with amines and the like, and pharmaceutically acceptable salts are preferable for achieving the object of the present invention.

The ester of the styryl compound of the present invention is
An alkyl ester, an aralkyl ester, an ester residue which can be hydrolyzed in vivo, and which can be easily decomposed in vivo to give a free carboxylic acid or a salt thereof, such as acetoxymethyl, pivaloyloxymethyl, 1-
Alkanoyloxyalkyl esters such as acetoxyethyl and 1-pivaloyloxyethyl, alkoxycarbonyloxyalkyl esters such as ethoxycarbonyloxymethyl and 1-ethoxycarbonyloxyethyl, esters such as phthalidyl and dimethoxyphthalidyl, carbamoylmethyl and carbamoylethyl. , N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, carbamoylalkyl ester such as N, N-diethylcarbamoylmethyl, alkoxyalkyl ester such as methoxymethyl and methoxyethyl, or 5
-Aminoalkyl esters such as methyl-1,3-dioxolen-2-on-4-ylmethyl ester, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, methylaminopropyl,
Alkylaminoalkyl esters such as ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, morpholinoalkyl esters such as morpholinoethyl, piperidinoethyl, etc. Examples thereof include piperidinoalkyl ester and alkylphenylamino ester such as methylphenylamino.

The present invention further includes the corresponding hydrates and other solvates of the compounds of general formula (I). Geometric isomers exist in the compound of the general formula (I), and for example, any of the (E) -form, the (Z) -form and a mixture thereof are included in the present invention. In the present invention, a particularly preferred geometrical isomer is a (E) -form compound. When an asymmetric carbon atom is present in the compound of general formula (I), all of its racemate, diastereomer and individual optical isomers are included in the present invention.

The compounds of the general formula (I) according to the present invention have the general formula
(II)

[Chemical 12] (Wherein each symbol has the same meaning as defined above) and the carboxylic acid compound or its reactive derivative represented by the general formula (II
I) H ₂ N—B (III) (wherein, B has the same meaning as defined above) is subjected to a usual amide bond-forming reaction with an amine derivative to hydrolyze the ester, if necessary. It can be produced by introducing the obtained carboxylic acid compound into an ester compound that can be hydrolyzed in vivo. When the compound (II) is a free carboxylic acid, the reaction includes tetrahydrofuran, an ether solvent such as dioxane, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, dimethylformamide, and the like. Dimethyl sulfoxide or the like is used, and it is carried out at a temperature from under ice cooling to the boiling point of the solvent used, preferably from room temperature to 60 ° C. Furthermore, if necessary, an organic base such as pyridine, triethylamine, diisopropylethylamine is used as a deoxidizing agent. Further, the compound (II) is a reactive derivative of carboxylic acid (acid halide,
Thiol ester, acid anhydride, mixed acid anhydride, ester, acid azide, acid amide, etc.), the reaction is usually carried out in an inert solvent, organic base such as triethylamine, pyridine, diisopropylethylamine, potassium carbonate, sodium carbonate. , Alkali metal carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate, sodium hydride,
In the presence of an alkali metal base such as n-butyllithium,
It is carried out at a temperature from −10 ° C. to the boiling point of the solvent used. The ester hydrolysis reaction is carried out, for example, in the presence of an acid (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, etc.) or an alkali (sodium hydroxide, potassium hydroxide, potassium carbonate, etc.) in a water-miscible solvent. , It is carried out by a conventional method.

The esterification reaction of a carboxylic acid is carried out by reacting the carboxylic acid compound of the general formula (I) with the general formula (IV) R—X ³ (IV) [wherein R is alkyl, aralkyl, or hydrolyzed in vivo. Among the ester residues that can be used, X ³ represents a halogen (chlorine, bromine, iodine, etc.), an organic sulfonyloxy group (methylsulfonyloxy, benzenesulfonyloxy, paratoluenesulfonyloxy, etc.). ] It can carry out by making the compound represented by these react by a conventional method.

The carboxylic acid compound of the general formula (II), which is a synthetic intermediate of the present invention, has the general formula (V)

[Chemical 13] (In the formula, each symbol has the same meaning as described above.) The compound can be produced by hydrolysis. The hydrolysis reaction is usually carried out in the presence of an acid (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, etc.) or an alkali (sodium hydroxide, potassium hydroxide, potassium carbonate, etc.) in a solvent miscible with water. It is carried out by law.

The above intermediate compound (V) is represented by i) the general formula (VI)

[Chemical 14] (Wherein each symbol has the same meaning as defined above) and a compound represented by the general formula (VII)

[Chemical 15] (Wherein Ph represents phenyl and Z has the same meaning as described above) or is reacted according to the Wittig reaction, or ii) the general formula (VIII)

[Chemical 16] (Wherein each symbol has the same meaning as defined above), and a compound represented by the general formula (IX)

[Chemical 17] (In the formula, Z has the same meaning as described above.) The compound (IX) can be produced by reacting it according to the Wittig reaction.

In the Wittig reaction, as a base for converting a phosphonium salt compound into an ylide compound, alkali metal hydrides, alkali metal hydroxides, alkali metal alcoholates, alkali metal amides, organic lithium, alkali metal carbonates, etc. Examples of the solvent include dimethylformamide, non-protonic polar solvents such as dimethylsulfoxide, alcohol solvents such as methanol, ethanol and isopropyl alcohol, ether solvents such as tetrahydrofuran, hydrocarbon solvents such as benzene and toluene, chloroform, A halogenated hydrocarbon solvent such as dichloromethane, water and a mixed solvent thereof can be used. Moreover, the ylide derived from triphenylphosphine can be used as well, and the phosphonate ylide derived from triphenylphosphite can be used as a modification of the Wittig reaction.

Further, the intermediate compound of the general formula (V) has the general formula (X)

[Chemical 18] (In the formula, L represents a reactive atom or a reactive group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy and the like, and other symbols have the same meanings as described above.) formula ^{(XI) a-X 1 -Alk} 1 -X 2 (XI) ( wherein each symbol has the same meaning as defined above.) can be prepared by reacting a compound represented by the. The reaction is carried out in a suitable solvent (dimethylformamide, dimethylsulfoxide, acetone, methylethylketone, benzene, toluene, xylene, etc.) from room temperature to the boiling temperature of the solvent used. In addition, the reaction may be carried out with an appropriate base (alkali metal hydride, alkali metal alcoholate,
Conveniently, it is carried out in the presence of an alkali metal carbonate, alkali metal amide, etc.).

The compound of the present invention has geometrical isomers, which can also be separated into its (E) form and (Z) form by a conventional method such as fractional crystallization and chromatography.
When the compound of the present invention has an asymmetric carbon, it is usually produced as a racemate or a diastereomer,
This can be optically resolved into optical isomers by a conventional method such as fractional crystallization and chromatography. Further, an optical isomer can be produced using an optically active raw material compound. If desired, the compound of the general formula (I) is an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, lactic acid, oxalic acid, fumaric acid, etc.
Organic acids such as maleic acid, mandelic acid, citric acid, tartaric acid, succinic acid, glycolic acid, malic acid, ascorbic acid, methanesulfonic acid and paratoluenesulfonic acid, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide Treatment with alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, quaternary ammonium salt forming agents such as quaternary ammonium hydroxide, amino acids such as lysine, amines such as triethylamine and diethanolamine. According to the above, the above-mentioned salt can be obtained.

When the compound of the present invention is used as a medicine, it is preferably mixed with a pharmaceutically acceptable excipient, carrier, diluent or other additive for pharmaceutical preparation, to give a tablet,
It can be administered orally or parenterally in the form of granules, powders, capsules, injections, ointments and suppositories. The dose may vary depending on the age, body weight, symptom of the patient, etc., but it is usually 5 to 3 as an oral administration per day for an adult.
It is about 00 mg, which can be administered once or in several divided doses.

[0017]

The styryl compound of the general formula (I) or a pharmaceutically acceptable salt or ester thereof of the present invention has a remarkable and long-lasting leukotriene antagonistic action or leukotriene inhibitory action, and is also orally administered. Shows excellent absorption upon administration. Furthermore, the compound of the present invention is 5
-Has lipoxygenase inhibitory action and / or cyclooxygenase inhibitory action, LTB ₄ biosynthesis inhibitory action, human leukocyte migration inhibitory action, chymase inhibitory action, histamine release inhibitory action and antihistamine action. Therefore, the compounds of the present invention include bronchial asthma, chronic bronchitis, atopic dermatitis, allergic rhinitis, allergic arthritis, allergic conjunctivitis, hay fever, urticaria, food, analgesia, antipyretic, rheumatism, thrombosis, coronary blood vessels. It is useful as a preventive or therapeutic drug for disorders, ischemic heart disease, peptic or duodenal ulcers, etc.

[0018]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 (1) (E) -3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl)
5 g of benzoic acid is dissolved in 20 ml of chloroform, 30 ml of thionyl chloride is added to this solution, and the mixture is refluxed and stirred for 24 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. N for residue
When hexane and isopropyl ether were added and filtered, 4.7 g of (E) -3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoic acid chloride hydrochloride was obtained. Are obtained as ocherous powder crystals. Melting point 150-153 ° C (2) 1.2 g of hydrochloride of acid chloride obtained in (1)
Is dissolved in 10 ml of chloroform. In this solution, 1-
0.28 g of amino-1-cyclopropanecarboxylic acid was added to 10 ml of dimethylformamide and triethylamine 2
Add the suspension in ml and stir at 60-70 ° C for 8 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. 1.6 g of the brown oil obtained are purified using silica gel column chromatography. The developing solvent is chloroform-methanol (2
0: 1 to 10: 1). The target fraction is concentrated under reduced pressure and n-
When collected by filtration with hexane-isopropyl ether, (E)-
1- (3- (2- (6- (4- (4-ethylphenyl)
Butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-1-cyclopropanecarboxylic acid 0.28 g
Are obtained as white powder crystals. Melting point 132-135
℃; corresponding hydrochloride monohydrate, melting point 125-128 ℃
(Disassembly)

Example 2 Hydrochloride of the acid chloride obtained in Example 1 (1) 1.2
g was dissolved in 10 ml of chloroform, and 0.24 g of 5-aminotetrazole dimethylformamide 3 was added to this solution.
ml and triethylamine 2 ml solution are added, and the mixture is stirred under reflux for about 10 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. The obtained residue was thoroughly washed with chloroform and water and dried to give white powdery 3-((E) -2-
(6- (4- (4-ethylphenyl) butoxymethyl)
0.47 g of 2-pyridyl) ethenyl) -N- (1H-5-tetrazolyl) benzamide hemihydrate is obtained. Melting point 247-249 ° C (decomposition)

Example 3 0.12 g of 60% sodium hydride was suspended in 6 ml of dimethyl sulfoxide, and the suspension was stirred under a nitrogen stream at 70 ° C. for about 1 hour. After dissolving sodium hydride, the mixture is cooled to room temperature, 0.52 g of o-toluenesulfonamide is added, and the mixture is further stirred for 1 hour. Tetrahydrofuran 10m in the reaction liquid
1, and ice-cooled, 1.2 g of the hydrochloride of the acid chloride obtained in Example 1 (1) is added with stirring, and the mixture is further reacted for 6 hours. After completion of the reaction, tetrahydrofuran is distilled off under reduced pressure, water and ethyl acetate are added to the residual liquid and the layers are separated. The ethyl acetate layer is dried over magnesium sulfate and then concentrated under reduced pressure. The brown powder obtained is purified by silica gel column chromatography. The developing solvent is chloroform-methanol (50: 1-
25: 1). The target fraction is concentrated, dissolved in acetone, and hydrochloric acid-ethanol is added. The precipitated crystals were collected by filtration, washed with isopropyl ether, and dried to give N- (3-((E) -2- (6- (4- (4
-Ethylphenyl) butoxymethyl) -2-pyridyl)
0.23 g of ethenyl) benzoyl) -2-methylbenzenesulfonamide hydrochloride hemihydrate is obtained. Melting point 11
3 to 115 ° C (decomposition)

Example 4 (E) -3- (2- (6-
(4- (4-ethylphenyl) butoxymethyl) -2-
(E) -2 by reacting pyridyl) ethenyl) benzoic acid chloride with 2-amino-2-ethylbutyric acid.
White crystals of-(3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-2-ethylbutyric acid are obtained. Melting point 9
9-100 ° C (decomposition); Corresponding hydrochloride salt, melting point 137-
140 ° C

Example 5 (E) -3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoic acid (3 g) was added to chloroform (20 ml), tetrahydrofuran (10 ml) and triethylamine (0.3 ml). Dissolved in 73 g,
Ethyl chlorocarbonate 0.7 was added to this solution while stirring under ice cooling.
8 g is added dropwise. After the dropping, the mixture is stirred under ice cooling for about 15 minutes.
Then, to this solution was added 2-amino-2-methylpropionic acid ethyl ester hydrochloride 1.2 g chloroform 5 ml.
And a solution of triethylamine 0.73 g is added. After the addition, the mixture is stirred at the same temperature for 1 hour and then at room temperature for about 15 hours. After completion of the reaction, the solvent is concentrated under reduced pressure. Water and ethyl acetate are added to the obtained residue and the layers are separated. The ethyl acetate layer is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. 4.6 g of the obtained residue is purified by silica gel column chromatography. The developing solvent was benzene-ethyl acetate (10: 1 to 5: 1). The target fraction is collected and concentrated under reduced pressure to obtain 2.2 g of an oily substance. This oily substance was dissolved in acetone, ethanol-hydrochloric acid and isopropyl ether were added, and the precipitated crystals were filtered. As a result, white powdery crystals of (E) -2- (3- (2- (6- (4- ( 2.1 g of 4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-2-methylpropionic acid ethyl ester hydrochloride are obtained. Melting point 66-70 ° C
(Disassembly)

The following compounds are obtained in the same manner as in Example 5. ◎ (E) -1- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-1-cyclopentanecarboxylic acid ethyl ester hydrochloride, Melting point 93 to 95 ° C (decomposition) ◎ (E) -1- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-1-cyclohexane Carboxylic acid ethyl ester hydrochloride, melting point 115-120 ° C (decomposition) ◎ (E) -N- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) Benzoyl) valine ethyl ester hydrochloride, melting point 8
0-85 ° C (decomposition) ◎ (E) -N- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) aspartic acid ethyl ester hydrochloride ◎ (E) -N- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) glutamic acid ethyl ester hydrochloride

Example 6 1.7 g of the ester obtained in Example 5 was added to ethanol 20
0.32 g of sodium hydroxide is dissolved in 5 ml of water and refluxed for about 1 hour. After completion of the reaction, alcohol is distilled off under reduced pressure and water is added. Dilute hydrochloric acid is added to this aqueous solution to add p
Adjust to H 6.0-6.5. Ethyl acetate is added for extraction, the organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, isopropyl ether is added to the residue, and the precipitated crystals are collected by filtration. When this crystal was recrystallized from ethanol-isopropyl ether, white powdery crystal (E) -2- (3- (2- (6- (4
0.63 g of-(4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-2-methylpropionic acid are obtained. Melting point 171-173 ° C (decomposition)

The following compounds are obtained in the same manner as in Example 6. ◎ (E) -1- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-1-cyclopentanecarboxylic acid, melting point 194-195. ° C ◎ (E) -1- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) amino-1-cyclohexanecarboxylic acid, melting point 164-165. ° C ◎ (E) -N- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) valine, melting point 131-132 ° C (decomposition) ◎ ( E) -N- (3- (2- (6- (4- (4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) aspartic acid ◎ (E) -N- (3- (2- (6- (4- 4-ethylphenyl) butoxymethyl) -2-pyridyl) ethenyl) benzoyl) glutamic acid

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI technical display location C07D 213: 00 257: 00) (72) Inventor Michio Terazawa 955, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture Address Yoshitomi Pharmaceutical Co., Ltd. Central Research Laboratory

Claims (1)

[Claims] 1. A compound represented by the general formula (I): [In the formula, A is hydrogen, formula (a) -N (R ¹ ) (R ² ) (a) (R ¹ and R ² are the same or different and represent hydrogen, alkyl and aralkyl, or R ¹ and R ² Represents a group which is bonded to each other to form a ring with an adjacent nitrogen atom), amino, cycloalkyl, aryl, heterocycle, halogen on the ring, nitro, amino, monoalkylamino,
Dialkylamino, alkanoylamino, hydroxyl group, alkyl, cycloalkyl, alkenyl, alkenyloxy, alkynyl, aralkyl, alkoxy, haloalkyl, cyano, carboxyl, alkoxycarbonyl, tetrazolyl, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl, carbamoyl, monoalkylcarbamoyl , Dialkylcarbamoyl, carboxyalkanoylamino, alkoxycarbonylalkanoylamino, phenylsulfonyl, phenylsulfonylamino, formula (b): Formula (c): Formula (d) (R ³ and R ⁴ in the formulas (b), (c) and (d) are the same or different and each represent hydrogen, halogen, haloalkyl, amino, nitro, cyano, hydroxyl group, alkyl or aralkyl). A cycloalkyl, aryl or heterocycle having at least one of the groups (when the aryl or heterocycle is an aromatic ring, the substituent is not the formula (d)), phenylsulfonyl, phenylsulfonyl Halogen, nitro, amino, hydroxyl, alkyl, alkoxy, on the amino or phenyl ring,
Phenylsulfonyl or phenylsulfonylamino having at least one substituent selected from haloalkyl and cyano, Alk ¹ and Alk ² are the same or different, and a single bond, alkylene or alkenylene, X
¹ , X ² is a single bond, oxygen, —S (O) _n — (n is 0,
Indicates an integer of 1 or 2. ), - CO -, - N (R 5) -,
^{-CON (R 6) -, -} N (R 7) CO -, - CH (O
^{R 8) - (R 5,} R 6, R 7 are the same or different and each is hydrogen, alkyl, aralkyl, R ⁸ is hydrogen, alkyl,
Indicates acyl. ), Ring Y is an aryl, heterocycle or an aryl or heterocycle having at least one substituent selected from halogen, nitro, amino, hydroxyl group, alkyl, alkoxy, haloalkyl and cyano on the aromatic ring, B is tetrazolyl, phenylsulfonyl, phenylsulfonyl having at least one substituent selected from halogen, nitro, amino, hydroxyl group, alkyl, alkoxy, haloalkyl and cyano on the ring, or 1 to 2 carboxyl groups. Substituted C1-C8 straight-chain, branched-chain or C3-C7 cyclic-alkyl, Z is hydrogen, halogen, alkyl,
Alkoxy, haloalkyl, alkylthio, alkylsulfinyl and alkylsulfonyl are shown. ] The styryl compound represented by these, its pharmaceutically acceptable salt, or its ester.