JPS61271265A - Novel oxanylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [A is group of formula IV - formula VI (R<1> is H, lower alkyl or acyl; R<2> is H or lower alkyl; R<3> is H, lower alkyl, benzyl, etc.; X is halogen); R' is H or lower alkyl]. EXAMPLE:trans-4-(Ethyloxamoyl)aminomethylcyclohexanecarboxylic acid. USE:Useful as various pharmaceuticals such as remedy for arthrorheumatism, nephritis, autoimmune diseases, asthma, uriticaria, and allergic rhinitis, immuno- promotor, carcinostatic agent, etc. PREPARATION:The compound of formula I can be produced by reacting the aromatic amine of formula II with the oxanyl derivative of formula III (Z is halogen) having active halogen atom, in an inert solvent (e.g. pyridine, THF, dioxane, etc.) in the presence or absence of a basic catalyst (e.g. triethylamine) under cooling, at room temperature or under heating (at <=300 deg.C).

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to oxanilic acid derivatives having immunomodulatory and antiallergic effects.

(b) Prior Art Conventionally, there are many oxanilic acid derivatives that have remarkable anti-allergic effects, and they are still being actively researched.

In particular, JP-A-53-63342, JP-A-53-6332
Publication No. 5, Publication No. 53-62835, Publication No. 53-103
No. 435 or Journal of Medicin
al Chemistry) VoL 2L No 9
930-935 (1978) and the like describe that oxamic acid derivatives have remarkable anti-allergic effects.

However, there are very few reports on immunomodulatory effects in these known documents, and there are only a few reports in JP-A-57-64652.
No. 4, No. 57-165354, etc., describe that oxanilic acid derivatives have an immune function regulating effect.

(c) Problems to be Solved by the Invention The present inventors paid attention to the immunomodulating effect of oxanilic acid derivatives and conducted intensive research to synthesize a novel oxanilic acid derivative that has not been described in the literature.

An object of the present invention is to provide a new oxanilic acid derivative, and another object is to find an oxanilic acid derivative having immunomodulatory and antiallergic effects.

8-NH-COCOOR (In the formula, R represents a hydrogen atom or a lower alkyl group. (However, in the formula, R1 represents a hydrogen atom, a lower alkyl group, or an acyl group, and R2 represents a hydrogen atom or a lower alkyl group. group, R3
represents a hydrogen atom, a lower alkyl group, an alkenyl group, a benzyl group, or a benzyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and X represents a halogen atom. )].

To explain R and A in the above general formula (I) in detail, R is a hydrogen atom, methyl, ethyl, propyl,
A straight chain or branched lower alkyl group such as butyl is a hydrogen atom, or methyl, ethyl, propyl, butyl is a hydrogen atom, a straight chain or branched lower alkyl group such as methyl, ethyl, propyl, butyl, or allyl.

3. Alkenyl groups such as 3-dimethylallyl, benzyl groups, or halogen atoms such as fluorine, chlorine, bromine, and iodine, lower alkyl groups such as methyl, ethyl 910 biru, and butyl, methoxy, ethoxy, and propoxy.

A benzyl group substituted with 1 to 3 lower alkoxy groups such as butoxy at arbitrary positions, and X is fluorine or chlorine.

It means that one or two halogen atoms such as bromine or iodine are substituted at any position.

It means a lower alkyl group such as thyl, ethyl, propyl, butyl.

Next, the manufacturing method of the present invention will be explained, but these are merely examples, and of course it can be manufactured by other chemically similar methods.

Manufacturing method A-NH2+ ZCOCOOR-A-NflCOCO
OR(II) (I[[) (
I) (wherein, Z is a halogen atom, and A and R have the same meanings as above) Aromatic amines of general formula (■) and ・ of general formula (III)
Oxanyl derivatives having active halogen atoms are combined with pyridine, tetrahydrofuran, dioxane, chloroform,
Methylene chloride, benzene, toluene.

A basic catalyst (e.g. triethylamine, pyridine, dimethylaniline) in an inert solvent such as xylene.

By reacting for about 1 to 20 hours in the presence or absence of sodium carbonate, sodium hydroxide, etc., under cooling, at room temperature, or under heating (300°C or less), a compound represented by general formula (1) is produced. The desired product can be obtained in good yield.

In addition, the product can be made into a highly pure target product by using purification means such as recrystallization with an appropriate organic solvent or column chromatography using a packing material such as silica gel or alumina.

Further, the compound of the present invention can be formed into a salt if necessary. In other words, it includes pharmacologically acceptable salts, including salts with alkali metals such as sodium and potassium, alkaline earth metal salts such as calcium, and salts with inorganic bases such as aluminum salts. , or ammonium salts.

trimethylamine, triethylamine 5 arginine,
Examples include organic bases such as lysine.

(e) Effect The compound of the present invention showed a remarkable inhibitory effect on adjuvant arthritis in rats.

In addition, in Arthus reaction experiments using rats, antigens and
It showed an inhibitory effect on hyperpermeability caused by antibody reaction.

In addition, in an antibody production enhancement effect experiment using mice, a tendency to significantly enhance antibody production was observed.

It also showed a significant inhibitory effect on homologous passive skin reactions (PCA reactions) in rats.

It also showed a remarkable inhibitory effect on histamine release test from guinea pig lung sections.

As described above, the compound of the present invention exhibited excellent pharmacological effects in various animal experiments, suggesting its usefulness as a pharmaceutical.

(f) Example The present invention will be explained in more detail below with reference to Examples.

Example 1 Trans-4-aminocyclohexanecarboxylic acid 3.2
g into 100 ml of dry tetrahydrofuran to which was added 2.1 g of triethylamine. Next, 2.7 g of ethyloxanyl chloride was dried in 20 m of tetrahydrofuran! Gradually add the diluted mixed solution dropwise to room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and water was directly added to the residue for extraction. After dehydrating the extract, it was concentrated, adsorbed on a column chromatograph packed with silica gel, and separated and purified using ethyl acetate as a developing solvent, producing colorless needle crystals of trans-4 (
3.8 g of ethyloxamoyl)aminomethylcyclohexanecarboxylic acid was obtained.

Chemical structure % Formula % 3.1 g of 4-aminosalicylic acid are added to 100 ml of dry tetrahydrofuran, followed by 2.1 g of triethylamine. Dry tetrahydrofuran 20% while cooling in a water bath.
2.7 g of ethyloxanyl chloride diluted with 11 is gradually added dropwise with stirring.

After completion of the dropwise addition, the mixture was returned to room temperature and stirred for 10 hours. After the reaction, the reaction solution was distilled off under reduced pressure, water was added to the residue, the precipitated crystals were collected by filtration, dried, and recrystallized from ethanol to give 4-(ethyloxamoyl) having the following structural formula as colorless prism crystals. ) 3.9 g of amino-salicylic acid were obtained.

Chemical Structural Formula % Formula % A compound having the following structural formula was synthesized according to the method of Examples 1 and 2.

Chemical structural formula % Formula % Shape Colorless prismatic crystal Recrystallization solvent Methanol Example 4 A compound having the following structural formula was synthesized according to the method of Examples 1 to 3.

Chemical Structural Formula % Formula % Shape Pale yellow prismatic crystal recrystallization solvent
Methanol-Isoflobil Ether Example 5 A compound having the following structural formula was synthesized according to the method of Examples 1 to 4.

Chemical Structural Formula % Formula % Shape Colorless prismatic crystals Recrystallization Solvent Methanol (T) Effects of the Invention The compounds of the present invention have adjuvant arthritis suppressing effects, Arthus reaction suppressing effects, and antibody production. Pharmaceuticals that have an enhancing effect, a PCA reaction suppressing effect, and an anti-5RBC antibody production suppressing effect, and are therapeutic agents for rheumatoid arthritis, nephritis, autoimmune diseases, asthma, hives, allergic rhinitis, or immune promoters, anticancer agents, etc. It is a compound useful as

Patent applicant: Hisamitsu Pharmaceutical Co., Ltd. Representative Hirotaka Nakatomi

Claims (1)

[Claims] 1. General formula A-NHCOCOOR [In the formula, R is a hydrogen atom or a lower alkyl group, and A is ▲a numerical formula, a chemical formula, a table, etc.▼or ▲a mathematical formula, a chemical formula, a table, etc.▼ Or ▲There are mathematical formulas, chemical formulas, tables, etc.▼
(wherein, R^1 represents a hydrogen atom, a lower alkyl group, or an acyl group, R^2 represents a hydrogen atom or a lower alkyl group, and R represents a hydrogen atom, a lower alkyl group, an alkenyl group, or a benzyl group. or a benzyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, X means a halogen atom)].