JPH0774218B2 - Benzopyranotriazole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> (In the formula, R is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group,
A cyclononyl group, a cyclodecyl group, a cyclododecyl group or a phenyl group means a cyclohexyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a cyclododecyl group or a phenyl group and a halogen atom. One or more, X means methylene, ethylene, propylene, butylene) and a salt thereof.

The compound of formula (I) has an excellent antiallergic action and is useful as a medicine.

<Prior Art> In recent years, leukotriene D ₄ (hereinafter referred to as LTD ₄ ) has been regarded as important as one of the chemical mediators that are generated by various stimuli such as immune reaction and cause an allergic reaction, and this LTD ₄ It has been considered that the antagonism against glycerin is increasingly important as one of the indicators of the antiallergic effect.

Further, a compound obtained by substituting a lower alkyl group for [1] benzopyrano [2,3-d] -1,2,3-triazol-9 (1H) -one is disclosed in JP-A-55-19292 and Journal of Medicinal Chemistry. E 26, 251-254 (1983). Although this compound has been disclosed to suppress the skin anaphylaxis of allogeneic passively sensitized rats, it does not disclose the aforementioned LTD ₄ antagonism.

<Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of extensive studies to find a compound having an excellent LTD ₄ antagonistic action.

The present invention relates to compounds of formula (I) and salts thereof.

In formula (I), the alkyl group is methyl, ethyl,
Examples thereof include propyl, isopropyl, butyl, tertiary butyl and the like. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. A halogenoalkyl group means one in which one or more of the above halogen atoms are substituted with an alkyl group, examples of which include halogenomethyl,
Halogenoethyl, halogenobutyl, dihalogenomethyl,
Examples thereof include dihalogenobutyl and trihalogenomethyl. Examples of the cycloalkyl group include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclododecyl and the like. Examples of the cycloalkenyl group include cyclobutenyl, cycloheptenyl, cyclohexenyl, cyclooctenyl, cyclodecenyl, cyclododecenyl and the like. The alkylene group means methylene or polymethylene which may be substituted with an alkyl group, and examples thereof include methylene, ethylene, propylene, butylene and the like. As alkenylene, vinylene, propenylene, butenylene, 1-pentenylene, 2-methyl-1-butenylene, 2-methyl-
2-butenylene etc. can be mentioned.

Examples of the salt of the compound of the formula (I) include salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium or ammonia, amines such as tris (hydroxymethyl) aminomethane and N-methylglucamine. It can be illustrated.

Although the compound of formula (I) is represented as a 1H-9-oxo compound for convenience, this compound is represented by the following tautomer (I ′),
It includes (I ″) and (I). These tautomers are also included in the present invention.

Further, for the compound of formula (I), the partial structures R and X
There may be various isomers derived from the above, and these various isomers and mixtures thereof are also included in the present invention.

The compound represented by the formula (I) can be produced according to the following reaction formula.

(In the formula, R and X are the same as above.) That is, the compound of formula (I) can be produced by treating the compound of formula (II) with an acid in the presence or absence of a solvent. The reaction is usually performed under ice cooling to room temperature for 30 minutes to several days. At this time, the reaction can proceed more smoothly by adding anisole. Suitable acids include
Mention may be made of trifluoroacetic acid.

The starting compound (II) used in the above production method is a novel compound and can be produced by the following method.

(In formula, R and X are the same as the above.) The said reaction process is demonstrated.

A compound of formula (V) is produced by reacting a compound of formula (III) with a compound of formula (IV) together with a base such as potassium carbonate or sodium hydride in a solvent such as dimethylformamide or dimethoxyethane which does not participate in the reaction. can do. The reaction is usually carried out at 100 to 200 ° C. for 1 hour to several days.

The compound of formula (VI) can be produced by reacting the compound of formula (V) with sodium hydroxide, potassium hydroxide or the like in a solvent that does not participate in the reaction, for example, hydrous alcohol. The reaction is usually performed at room temperature for 30 minutes to 5 hours.

The compound of formula (VII) can be produced by reacting the compound of formula (VI) with a chlorinating agent in a solvent that does not participate in the reaction such as dichloromethane at room temperature for 30 minutes to 2 hours. A suitable chlorinating agent may be oxalyl chloride.

The compound of formula (II) can be produced by treating the compound of formula (VII) under the conditions of a usual Friedel-Crafts reaction. The reaction is usually carried out in the presence of aluminum chloride in a solvent such as dichloromethane which does not participate in the reaction at -5 ° C to room temperature for 0.5 to 3 hours.

<Effects of the Invention> The compounds of the present invention have excellent LTD ₄ antagonistic activity.

Therefore, the compound of the present invention is applicable to bronchial asthma, allergic gastrointestinal disorders, allergic conjunctivitis, allergic rhinitis, hay fever,
It is effective for treating or preventing urticaria, inflammatory diseases and the like.

The present invention will be described with reference to the following examples, reference examples and test examples.

Example 1 7- [2- (3-chlorophenyl) ethyl]-[1] benzopyrano [2,3-d] -1,2,3-triazole-9 (1
H) -one 7- [2- (3-chlorophenyl) ethyl] -3- (4-methoxybenzyl)-[1] in 30 ml of trifluoroacetic acid.
Benzopyrano [2,3-d] -1,2,3-triazole-9
Add (3H) -one 3.45g and anisole 8.18g, at room temperature
It was stirred for 22.5 hours. The reaction mixture was poured into 200 ml of ice water and extracted with chloroform. The chloroform layer was concentrated, methanol was added, and the insoluble material was collected by filtration. Recrystallization from chloroform-ethanol gave 1.12 g of the title compound as colorless prism crystals with a melting point of 222-223 ° C.

Example 2 represented by the formula (I) in the same manner as in Example 1
Compound 6 was synthesized.

Example 7 7- (2-Cyclohexylethyl)-[1] benzopyrano [2,3-d] -1,2,3-triazol-9 (1H) -one 1) 7- (2-Cyclohexylethyl) -3 -(4-
Methoxybenzyl)-[1] -benzopyrano [2,3-
d] -1,2,3-triazol-9 (3H) -one 5- [4- (2-cyclohexylethyl) phenoxy] -1- (4-methoxybenzyl) -1H-1,2,3 in 250 ml of dichloromethane. -Triazole-4-carboxylic acid 26.0
g, 15.16 g of oxalyl chloride and 1 drop of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour, and then the solvent and low-boiling substances were distilled off under reduced pressure. Dissolve the residue in 250 ml of dichloromethane,
While keeping the temperature below 0 ° C, 24.0 g of aluminum chloride was added over 20 minutes. After stirring at -5 to 0 ° C for 2 hours, the mixture was poured into hydrochloric acid-ice and extracted with dichloromethane. The extract was washed with water and dried, and the solvent was evaporated to give the title compound as a solid.

2) 7- (2-Cyclohexylethyl)-[1] benzopyrano [2,3-d] -1,2,3-triazole-9 (1H)
-One 7- (2-cyclohexylethyl) -3- as above
(4-Methoxybenzyl)-[1] benzopyrano [2,3
-D] -1,2,3-triazol-9 (3H) -one and 65 g of anisole were added to 140 ml of trifluoroacetic acid and left at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel and recrystallized from ethanol to give the title compound (5.61 g).

Melting point 183 to 184 ° C. Elemental analysis values, nuclear magnetic resonance spectra and infrared absorption spectra of the compounds of formula (I) described in the examples are shown in the table below.

Formulas (V), (VI), (VII) and (II) used in the examples
The method of synthesizing the starting material compound will be described below as a reference example.

Reference Example 1 7- [2- (3-chlorophenyl) ethyl] -3- (4
-Methoxybenzyl)-[1] benzopyrano [2,3-
d] -1,2,3-Triazol-9 (3H) -one 1) 5- [4- [2- (3-chlorophenyl) ethyl] phenoxy] -1- (4-methoxybenzyl) -1H
-1,2,3-triazole-4-carboxylic acid 4- [2- (3-chlorophenyl) ethyl] phenol
80 g and 5-chloro-1- (4-methoxybenzyl) -1
100 g of H-1,2,3-triazole-4-carboxylic acid ethyl ester was dissolved in 1000 ml of dimethylformamide, 100 g of potassium carbonate was added, and the mixture was heated and stirred at 120-140 ° C for 3 days. The reaction solution was poured into ice-concentrated hydrochloric acid and extracted with ether. After drying the ether layer, the solvent was distilled off. Residue potassium hydroxide 30
g, 30 ml of water and 1500 ml of ethanol were added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed successively with ethanol and ether, suspended in ethyl acetate-water, and acidified with concentrated hydrochloric acid. The ethyl acetate layer was taken and dried, and then the solvent was distilled off.
The residue was recrystallized from ether-petroleum ether to obtain 105.9 g of the title compound. Melting point 127-130 ° C Elemental analysis Calculated as C ₂₅ H ₂₂ ClN ₃ O ₄ C 64.73 H 4.78 N 9.06 Found C 65.04 H 4.97 N 9.20 2) 7- [2- (3-chlorophenyl) ethyl] -3
-(4-Methoxybenzyl)-[1] benzopyrano [2,
3-d] -1,2,3-triazol-9 (3H) -one 5- [4- [2- (3-chlorophenyl) ethyl] phenoxy] -1- (4-methoxybenzyl) -1H in 500 ml of dichloromethane. 60.0 g of -1,2,3-triazole-4-carboxylic acid was dissolved, and 33 g of oxalyl chloride was added dropwise at room temperature. After the addition, add 1 drop of dimethylformamide and add 1 at room temperature.
Stir for hours. The solvent and low boiling point substances were distilled off under reduced pressure. The residue was dissolved in 1000 ml of dichloromethane, 53 g of aluminum chloride was added while keeping the temperature below 0 ° C, and the mixture was stirred at -5 to 0 ° C for 5.5 hours. The reaction mixture was poured into ice-concentrated hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and dried, and the solvent was distilled off.
The residue was crystallized from chloroform-methanol to obtain the title compound (23.7 g).

Melting point 178-179 ° C Elemental analysis Calculated as C ₂₅ H ₂₀ ClN ₃ O ₃ C 67.34 H 4.52 N 9.42 Measured value C 67.36 H 4.57 N 9.16 Reference example 2 3- (4-methoxybenzyl) -5- (2-phenyl) Ethyl)-[1] benzopyrano [2,3-d] -1,2,3-triazol-9 (3H) -one 2- (2-phenylethyl) phenol and 5-chloro-1- (4-methoxybenzyl) ) -1H-1,2,3-triazole-4-carboxylic acid ethyl ester was reacted in the same manner as in Reference Example 1 to obtain the title compound. Melting point unclear Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ value: 2.90-3.05 (2
H, m), 3.15-3.30 (2H, m), 5.74 (2H, s), 6.87 (2H, d),
7.55 (8H, m), 7.7 (1H, d), 8.1 (1H, d) Reference Example 3 3- (4-methoxybenzyl) -8- (2-phenylethyl)-[1] benzopyrano [2,3- d] -1,2,3-triazol-9 (3H) -one and 3- (4-methoxybenzyl) -6- (2-phenylethyl)-[1] benzopyrano [2,3-d] -1, 2,3-Triazol-9 (3H) -one 3- (2-phenylethyl) phenol and 5-chloro-1- (4-methoxybenzyl) -1H-1,2,3-triazole-4-carboxylate ethyl The ester was reacted in the same manner as in 1) of Reference Example 1 to give 5- [3- (2-phenylethyl) phenoxy] -1- (4-methoxybenzyl) -1H.
-1,2,3-Triazole-4-carboxylic acid was obtained.

Melting point 112-113 ° C (decomposition) 5- [3- (2-phenylethyl) phenoxy] -1- (4-methoxybenzyl) -1H in 150 ml of dichloromethane
1,1,2,3-Triazole-4-carboxylic acid (19.1 g) and oxalyl chloride (11.29 g) were dissolved, dimethylformamide (1 drop) was added, the mixture was stirred at room temperature for 1 hr, and the solvent and low-boiling substances were distilled off under reduced pressure. Dissolve the residue in 80 ml of dichloromethane,
After cooling with ice, 17.80 g of aluminum chloride was added, and the mixture was stirred for 2 hours. The reaction mixture was poured into ice-concentrated hydrochloric acid and extracted with chloroform. After the chloroform layer was dried, the solvent was distilled off. The residue was chromatographed on silica gel to give crude 3- (4
-Methoxybenzyl) -8- (2-phenylethyl)-
[1] Benzopyrano [2,3-d] -1,2,3-triazol-9 (3H) -one (crude I) and 3- (4-methoxybenzyl) -6- (2-phenylethyl)- [1] Benzopyrano [2,3-d] -1,2,3-triazole-9 (3H)
-ON (crude II) was obtained. The crude product I was recrystallized from ethyl acetate to give 3- (4-methoxybenzyl) -8- (2-
Phenylethyl)-[1] benzopyrano [2,3-d]-
1.72 g of 1,2,3-triazol-9 (3H) -one were obtained.

Melting point to 186 ° C (unclear) Elemental analysis Calculated as C ₂₅ H ₂₁ N ₃ O ₂ C 72.98 H 5.14 N 10.12 Found C 73.14 H 5.31 N 9.93 Crude product II was recrystallized from methanol to give 3- (4-methoxy). Benzyl) -6- (2-phenylethyl)-[1] benzopyrano [2,3-d] -1,2,3-triazole-9 (3
H) -one yielded 4.46 g. Melting point 173-174.5 ° C Elemental analysis Calculated value as C ₂₅ H ₂₁ N ₃ O ₂ C 72.98 H 5.14 N 10.12 Measured value C 73.36 H 5.29 N 10.07 Reference example 4 3- (4-methoxybenzyl) -7- (2-phenyl Ethyl)-[1] benzopyrano [2,3-d] -1,2,3-triazol-9 (3H) -one 4- (2-phenylethyl) phenol and 5-chloro-1- (4-methoxybenzyl) ) -1H-1,2,3-triazole-4-carboxylic acid ethyl ester was reacted in the same manner as in Reference Example 1 to obtain the title compound.

Melting point ~ 170 ° C (unclear) Nuclear magnetic resonance spectrum (CDCl ₃ ) δ value: 3.01 (4H, bs), 3.79 (3H, s), 5.61 (2H, s), 6.85-7.45
(11H, m), 8.26 (1H, bs) Reference Example 5 7- (2-Cyclopentylethyl) -3- (4-methoxybenzyl)-[1] benzopyrano [2,3-d] -1,2,3
-Triazol-9 (3H) -one 1) 4- (2-cyclopentylethyl) methoxybenzene 2-ethylene in 150 ml diethylene glycol monoethyl ether
35.9 g of cyclopentyl-1- (4-methoxyphenyl) ethanone and 30 ml of hydrazine hydrate were added and heated to 180 ° C. Next, 30 ml of 40% sodium hydroxide aqueous solution and water 30
ml was added and heated.

About 100 ml of distillate was removed, 2 ml of water was added, and the mixture was heated under reflux for 5 days, poured into water and extracted with petroleum ether. The extract was washed with water and dried, the solvent was distilled off, and some precipitates were filtered off to give the title compound (5.4 g)
Was obtained as a liquid.

2) 4- (2-cyclopentylethyl) phenol 50 ml of dichloromethane is cooled with ice, and aluminum chloride is 7.75 g.
Was added, followed by 7.21 g of dimethyl sulfide.
A solution of 5.4 g of 4- (2-cyclopentylethyl) methoxybenzene in 20 ml of dichloromethane was added dropwise thereto. At room temperature
After stirring for 18 hours, the mixture was poured into hydrochloric acid-ice and extracted with dichloromethane. The extract was washed with water and dried, and the solvent was evaporated to give the title compound 4.41
g was obtained as a colorless liquid.

Nuclear magnetic resonance spectrum (CDCl ₃ ) δ value: 0.9-2.0 (11H, m), 2.46-2.63 (2H, m), 4.60 (1H, bs) 6.
72 (2H, d), 7.03 (2H, d) 3) 7- (2-cyclopentylethyl) -3- (4-
Methoxybenzyl)-[1] benzopyrano [2,3-d]
-1,2,3-triazol-9 (3H) -one 4- (2-cyclopentylethyl) phenol and 5-
Chloro-1- (4-methoxybenzyl) -1H-1,2,3-
The title compound was obtained by reacting triazole-4-carboxylic acid ethyl ester in the same manner as in Reference Example 1.

Melting point 177-178 ° C Elemental analysis Calculated value as C ₂₄ H ₂₅ N ₃ O ₃ C 71.44 H 6.25 N 10.41 Measured value C 71.35 H 6.25 N 10.41 Reference Example 6 5- [4- (2-cyclohexylethyl) phenoxy]
-1- (4-Methoxybenzyl) -1H-1,2,3-triazole-4-carboxylic acid 4- (2-cyclohexylethyl) phenol and 5-
Chloro-1- (4-methoxybenzyl) -1H-1,2,3-
The title compound was obtained by reacting triazole-4-carboxylic acid ethyl ester in the same manner as in 1) of Reference Example 1.

Melting point 135 ° C (decomposition) Elemental analysis Calculated value as C ₂₅ H ₂₉ N ₃ O ₄ C 68.95 H 6.71 N 9.65 Measured value C 68.89 H 6.85 N 9.62 Test example LTD ₄ Antagonism test Male guinea pigs weighing 300 to 600 g were lethal. After letting
The ileum was removed to prepare a specimen with a length of about 2 cm.

This ileum sample was aerated with a mixed gas of 95% O ₂ -5% CO ₂ .
It was suspended in a Magnus tank filled with 5 ml of Tyrode solution (30 ± 1 ° C). Ileal contractions were recorded on a recorder with an isotonic transducer under a load of 0.6 g.

After confirming that a stable contraction reaction occurs, LTD ₄ (3.
0 ng / ml) was added to induce a contraction reaction. The pretreatment time of the drug was set to 1 minute, and the degree of contraction that occurred at that time was compared with the contraction without addition of the test drug.
₅₀ values) were calculated. The following table shows the LTD ₄ antagonism of the compound of the present invention.

Claims (1)

[Claims] 1. A general formula (In the formula, R is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group,
A cyclononyl group, a cyclodecyl group, a cyclododecyl group or a phenyl group means a cyclohexyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a cyclododecyl group or a phenyl group and a halogen atom. One or more, and X represents methylene, ethylene, propylene, butylene) and a salt thereof.