JPS6058904B2 - Novel cyclohexanecarboxylic acid amide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (I) R1, CONHA [ζ] (I) , , -H, in which a halogen atom, hydroxyl group, carboxyl group or lower alkoxycarbonyl group is present at any position from 1 to The present invention relates to a novel cyclohexanecarboxylic acid amide derivative represented by a phenyl group or a pyridyl group substituted with three members, R representing a lower alkyl group, and R′ representing a hydrogen atom or a methyl group.

To explain A and R in the general formula (1) more specifically, A represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-
The lower alkyl group of R is methyl, ethyl,
Represents a lower alkyl group such as n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

Disodium cromoglycate (trade name: Ifuntal) has been known as an anti-allergic agent that suppresses the release of chemical mediators caused by antigen-antibody reactions, but this drug has no medicinal effect when administered orally. There were various restrictions on its use.

Therefore, there is a strong demand for the development of antiallergic agents that have sufficient therapeutic effects even when administered orally. Therefore, the present inventors synthesized a series of novel cyclohexanecarboxylic acid amide derivatives with the aim of developing an antiallergic agent that is effective when administered orally. The novel cyclohexanecarboxylic acid amide derivative obtained by the present invention has an excellent antiallergic effect and also has remarkable medicinal efficacy even when administered orally, making it a useful compound as a pharmaceutical.

The antiallergic effect of the present invention will be shown below through pharmacological experiments. Experimental method Homologous passive skin reaction in rats Tada. ．． Tetal(Tada,.T.&0kum
ura. ．． J. ImmurK)1. ．． Shokyu 1002, 1
Homologous passive cutaneous anaphylaxis reaction (HOmOlOg..PCA) according to the method of 971)
Tested in 190f Wistar male rats.

That is, dinitrophenol (DNP) is reacted with the extracted protein of Ascarissuum to form DNP-A.
s(Dlnitr'0pheny1c0np1edAs
carissuuTnextract) and used it as an antigen. Anti-DNP-As rat serum was prepared using this antigen and used as an antibody. Apply this antibody with sufficient titer to the hairless back skin of a rat at 0.1 mt/sit in 3 locations on one side.
Inject 0.1 mt of physiological saline in 3 places on the other side.
One site was injected intradermally to check for experimental errors. After the invitation time, 1.0 ml of an antigen solution (2.0 ml of protein) containing 0.25% Evans Blue was intravenously injected. The rats were then exsanguinated and skinned, and the product of the major axis and minor axis of the dye leakage area was determined as the percolation coefficient (PI).
Also Harada. ．． M. etal (HaradalM.
, Takeuchi. ．． M. , FukaOlT. &Ka
tagiri. ．． K. ;J. pharm. pharma
cOl. ,? 218.1971) method. The amount of leaked dye was measured. The drug was administered at 2000 m9 2 hours before antigen administration.
1k9 was administered orally.

The results of the above pharmacological experiments revealed that the compound of the present invention has an excellent antiallergic effect and is effective when administered orally.

Next, the method for producing the compound of the present invention will be explained, but these are only examples, and the compound can also be produced by other chemically similar methods.

The starting materials, cis and trans cyclohexanecarboxylic acid derivatives, can be obtained in good yields by the method disclosed in Japanese Patent Application No. 52-7263λ and Japanese Patent Application No. 53-4608.

Production method A method in which a compound represented by the general formula (■) is reacted with a reactive derivative of a cyclohexanecarboxylic acid derivative represented by the general formula (■).

To explain the manufacturing method in more detail, the general formula (■
) to the amines represented by general formula (■) (e.g., acid halides, ester derivatives, acid anhydrides), organic compounds such as tetrahydrofuran, acetone, chloroform, pyridine, benzene, toluene, etc. The reaction may be carried out in a solvent.

Further, when using an acid halide, the reaction proceeds quickly by using a deoxidizing agent (for example, trimethylamine, triethylamine, N-dimethylaniline, pyridine, sodium carbonate, potassium carbonate, etc.). Further, among the cyclohexanecarboxylic acid amide derivatives obtained by this method, the ester form can be further hydrolyzed if desired. Hydrolysis is carried out using an acid (e.g. hydrochloric acid,
The reaction may be carried out at room temperature or under heating in the presence of an alkali (eg, potassium hydroxide, sodium hydroxide, etc.) or an alkali (eg, potassium hydroxide, sodium hydroxide, etc.). The reaction conditions are appropriately selected depending on the solvent used, the amount of acid or alkali, and the temperature. EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 A mixture of cis-1-methyl-4-isohexylcyclohexanecarboxylic acid 4.5y1 thionyl chloride 5mt1 benzene 30mt was reacted under reflux for 3 hours, and then the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain an acid. The chloride was added dropwise to a mixed solution of 4.5 fl ml of methyl anthranilate, 30 ml of tetrahydrofuran, 11 ml of triethylamine, and 4 ml of triethylamine (7 L) under ice cooling.

Thereafter, 3 powders were added at room temperature, and the mixture was further reacted at 50°C for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water, dehydrated, and then the ether was distilled off. The obtained oil was distilled under reduced pressure to obtain 5.7y of a colorless and transparent oil N-(2-methoxycarbonylphenyl)cis-1-methyl 4-isohexylcyclohexanecarboxylic acid amide. The boiling point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Boiling point 155-1600C/0.3 order Hg infrared absorption spectrum νc=0 (film) 169cm 1670cm-1
Mass spectrum M+359 Elemental analysis value C22H33NO3 Theoretical value C: 73.50H: 9.25N: 3.90 Actual value C: 73.47H: 9.12N: 3.96 Example 2 cis 1-methyl-4-isohexylcyclohexane A mixture of 4.5y of carboxylic acid, 5 mt of thionyl chloride, 30 ml of benzene was reacted under reflux for 3 hours, and then the solvent and excess thionyl chloride were distilled off under reduced pressure. It was added dropwise into the mixed solution under ice cooling.

Thereafter, the mixture was allowed to react at room temperature for 7 hours. After the reaction, the solvent was distilled off under reduced pressure and water and diluted hydrochloric acid were added to the residue to make it weakly acidic.
Extracted with extractor. The ether layer was washed with water, dehydrated, and then evaporated under reduced pressure. The resulting residue was adsorbed onto a column packed with silica gel and expanded with chloroform, and the eluate was evaporated under reduced pressure to form white crystals of N-(2-carboxyphenyl)cis. 1
-Methyl-4-isohexylcyclohexanecarboxylic acid amide 3.8y was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point 111-113 analysis c infrared absorption spectrum νc=O
(KBr) 1705, 16 house d-1 mass spectrum M+
345 Elemental analysis value C2lH3lNO3 Theoretical amount C: 73.01H: 9.04N: 4.05 Actual value C: 73.06H: 9.01N: 4.09 Example 3 Trans 1-methyl-4-isohexylcyclohexanecarboxylic acid 4 .5y1 thionyl chloride 5ml, benzene 30m
The mixture of 1 was reacted under reflux for 3 hours, then the solvent and excess thionyl chloride were distilled off under reduced pressure, and the acid chloride obtained was added dropwise at room temperature to a mixed solution of anthranilic acid 4.1y1, 30 ml of tetrahydrofuran, and 4 ml of triethylamine. did.

Thereafter, the mixture was allowed to react at room temperature for 7 hours. After the reaction, the solvent was distilled off under reduced pressure, water and dilute hydrochloric acid were added to the residue to make it weakly acidic, and the precipitated crystals were collected and recrystallized from methanol to form colorless prism crystals of N-(2-carboxyphenyl ) 4.9y of trans-1-methyl-4-isohexylcyclohexanecarboxylic acid amide was obtained. The melting point, infrared absorption spectrum, mass vector, and elemental analysis values of this substance were as follows.

Melting point 139-1400C Infrared absorption spectrum νc=0
(KBr) 1702, 1655 cm-1 Mass spectrum M+345 Elemental analysis value C2lH3lNO3 Theoretical value C: 73.01H: 9.04N: 4.05 Actual value C: 72.95H: 9.08N: 4.01 Example 4 Trans 1-Methyl-4-isohexylcyclohexanecarboxylic acid 4.5y1 thionyl chloride 5ml, benzene 30ml
The mixture of t was reacted under reflux for 3 hours, and then the solvent and excess thionyl chloride were distilled off under reduced pressure.
1. It was dropped into a mixed solution of 4 ml of triethylamine at room temperature.

Thereafter, the mixture was allowed to react at room temperature for 7 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water, dehydrated, and then evaporated under reduced pressure. The resulting residue was adsorbed onto a column packed with silica gel and expanded with chloroform. The eluate was evaporated under reduced pressure to form colorless prism crystals of N-(
5.2y of 2-methoxycarbonylphenyl)trans-1-methyl-4-isohexylcyclohexanecarboxylic acid amide was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point 73-76°C Infrared absorption spectrum νc=0(K
Br) 1696, 1660 cm-1 mass spectrum M+
359 Elemental analysis value C2.

H33NO3 theoretical value C:73.50H:9.25N:3
．． 90 Actual value C: 73.56H: 9.32N: 3.87
Example 5 A mixture of 4.5 y of cis-1-methyl-4-isohexylcyclohexanecarboxylic acid, 5 ml of thionyl chloride, and 30 ml of benzene was reacted under reflux for 3 hours, and then the solvent and excess thionyl chloride were distilled off under reduced pressure. The acid chloride was added dropwise to a mixed solution of 3.4y of 5-chloroanthranilic acid, 30ml of tetrahydrofuran, and 4ml of triethylamine under ice cooling.

Thereafter, the mixture was allowed to react at room temperature for 7 hours. After the reaction, the solvent was distilled off under reduced pressure and water and diluted hydrochloric acid were added to the residue to make it weakly acidic.
Extracted with ether. The ether layer was washed with water, dehydrated, and then evaporated under reduced pressure. The resulting residue was adsorbed onto a column packed with silica gel, expanded with ether, and the eluate was evaporated under reduced pressure to form colorless prism crystals of N-(2-carboxy-4-chlorophenyl). ) 3.7q of cis-1-methyl-4-isohexylcyclo\xanecarboxylic acid amide was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point 112-113℃ Infrared absorption spectrum νc=0(
KBr) 1700. ．． 11680cm-1 Mass spectrum M+379 Elemental analysis value C2lH3OClNO3 Theoretical value C: 66.39H: 7.96N: 3.69 Actual value C: 66.43H: 7.92N: 3.65 Example 6 cis 1-methyl-4-iso A mixture of 4.5y of hexylcyclohexanecarboxylic acid, 5ml of thionyl chloride, and 30ml of benzene was reacted under reflux for 3 hours, and then the solvent and excess thionyl chloride were distilled off under reduced pressure. 76f1 was added dropwise to a mixture of 60 ml of acetone and 4 mt of triethylamine at room temperature.

Thereafter, the reaction was allowed to proceed at room temperature for 7 hours. After the reaction, the solvent is distilled off under reduced pressure, water and dilute hydrochloric acid are added to the residue to make it weakly acidic, and the precipitated crystals are filtered out and recrystallized from a mixed solvent of methanol-isopropyl ether to form colorless prism crystals. N-(3-carboxy2-pyridyl)cisny 1
-Methyl-4-iso xylcyclohexanecarboxylic acid amide 4.3y was obtained. The melting point, infrared absorption spectrum, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point 175-177℃ Infrared absorption spectrum νc=0(
KBr) 1670, 1650cfn-1 Mass spectrum M+346 Elemental analysis value C2OF[30N203 Theoretical value C: 69.33H: 8.73N: 8.09 Actual value C: 69.26H: 8.71N: 8.12 Below Example 6
The following compound was synthesized according to the method of .

N-(2-carboxy4-methylphenyl)cis-1
-Methyl-4-isohexylcyclohexanecarboxylic acid amide Melting point 92-94°C N-(3,5-dichloro-4-hydroxyphenyl)
Cis-1-methyl-4-isohexylcyclohexanecarboxylic acid amide Melting point 155-156°C N-(3-carboxy-4-hydroxyphenyl)cis-1-methyl-4-isoxylcyclohexanecarboxylic acid amide Melting point 197-198°C N-(3- Carboxy-5-chlorophenyl)cis-1
-Methyl-4-isohexylcyclohexanecarboxylic acid amide melting point 149-1500C N-(3-methoxycarbonyl-2-pyridyl)cis-1-methyl-4-isohexylcyclohexanecarboxylic acid amide melting point 95-96°C N-(2-carboxy phenyl)trans-4-ethylcyclohexanecarboxylic acid amide melting point 190-191
°C N-(2-carboxyphenyl)trans-4-n-butylcyclohexanecarboxylic acid amide melting point 192-19
4℃ N-(2-carboxyphenyl)trans-4-isobutylcyclohexanecarboxylic acid amide melting point 170-1
7? CN-(2-carboxyphenyl)trans-4-Ter
t-butylcyclohexanecarboxylic acid amide melting point 186~
188°C N-(2-carboxyphenyl)trans-4-n-pentylcyclohexanecarboxylic acid amide Melting point 176-17
7°C N-(2-carboxyphenyl)trans-4-isohexylcyclohexanecarboxylic acid amide melting point 180-1
87C

Claims (1)

[Scope of Claims] 1 General Formula ▲ Numerical formula, chemical formula, table, etc. ▼ A novel cyclohexanecarboxylic acid amide derivative represented by a phenyl group or pyridyl group substituted at 1 to 3 positions, R is a lower alkyl group, and R^1 is a hydrogen atom or a methyl group.