JPS6388168A - 3-benzoylpropionic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [X is H, halogen, lower alkyl, cycloalkyl, lower alkoxy, benzyl, phenylthio or phenyl which may have a substituent group (halogen or CH3); Y is lower alkyl or acyl; R is H or lower alkyl; n is 1 or 2]. EXAMPLE:3-Acetylthiomethyl-3-benzoylpropionic acid. USE:A remedy for autoimmune diseases, e.g. chronic rheumarthritis, systemic lupus erythematosus, etc., and diseases caused by immunological function insufficiency, e.g. cancer, microbism, asthma, etc. PREPARATION:A compound expressed by formula I is reacted with formaldehyde in pyridine in the presence of a secondary amine to give a compound expressed by formula III, which is then reacted with a compound expressed by the formula YSH in an organic solvent to afford the compound expressed by formula I (R is H). Furthermore, the resultant compound, as desired, is reacted with a normally used alkylating agent in an organic solvent in the presence of a base to provide the compound expressed by formula I (R is lower alkyl).

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a novel 3-benzoylpropionic acid derivative, and more particularly to 3-benzoyl-3-mercapto which is effective in the treatment of autoimmune diseases such as rheumatoid arthritis. This invention relates to methylpropionic acid derivatives.

[Prior Art] There are several therapeutic agents for rheumatoid arthritis, which is one of the autoimmune diseases, and these include anti-inflammatory agents and immunotherapeutic agents.

Immunotherapy agents include gold preparations, D-penicillamine, levamisole, and lobenzarit (commonly known as 0CA).

[Problems to be Solved by the Invention] However, anti-inflammatory agents are symptomatic therapeutic agents and cannot be used as fundamental therapeutic agents. Although immunotherapeutic agents have recently been attracting attention as agents for treating the cause, these agents are not necessarily satisfactory in terms of their effects, side effects, toxicity, and the like.

[Means for resolving the problem] As a result of intensive research, the present inventors discovered that 3-benzoyl-3-
We discovered that mercaptomethylpropionic acid has a strong effect on the immune system and also has an excellent effect on adjuvant arthritis (a pathological model of rheumatoid arthritis, a typical autoimmune disease), and completed the present invention. .

The present invention will be explained in detail below.

The object of the present invention has the general formula (wherein X is a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a Hensyl group
represents a phenylthio group, a phenyl group or a substituted phenyl group, Y represents a lower alkyl group or an acyl group, R represents a hydrogen atom or a lower alkyl group, and n represents 1 or 2. ) is a 3-benzoylpropionic acid derivative represented by

In the present invention, halogen atoms are fluorine, chlorine, bromine, and iodine, and lower alkyl groups have 1 to 4 return atoms such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl groups. It is an alkyl group, and cycloalkyl groups include a cyclopentyl group and a cyclohexyl group. In addition, lower alkoxy groups include methoxy and ethoxy groups, and substituted phenyl groups include phenyl groups substituted with halogen atoms or methyl groups, such as p-methylphenyl, p-chlorophenyl, o-bromphenyl, etc. and p-bromphenyl group.

The acyl group is a lower aliphatic acyl group such as an acetyl group or a propionyl group, or an aromatic acyl group such as a benzoyl group or a toluoyl group.

The compound represented by Formula 1 can be produced, for example, by the following methods (1) to (3).

That is, (1) General formula (wherein, X and n have the same meanings as above). ) to the carboxylic acid compound represented by 0.1 to 1.
1 molar equivalent of a secondary amine (for example, dimethylamine, diethylamine, piperidine, a compound represented by the general formula morpholin (wherein X and n are as defined above)).

(2) Next, the compound represented by the formula
chloroform, carbon tetrachloride, carbon disulfide, acetone, ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc.), where Y is as defined above. ) and 0.01 to 1.5 molar equivalents of a base catalyst (e.g., sodium carbonate, potassium carbonate, lithium oxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, diisopropyl). ethylamine, pyridine, etc.) for 0.5 to 24 hours at -20 to 50°C. certain compounds) can be produced.

(3) Also, bases (such as sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen blown acid, sodium hydroxide, , potassium hydroxide, sodium hydride, sodium alkoxide, etc.), a commonly used alkylating agent (for example, alkyl halide, dialkyl sulfate, etc.) is added to the compound obtained in (2) above.
A compound of formula (3) in which R is a lower alkyl group can be produced by reacting with the following.

[Effects of the Invention] The compound represented by formula 1, which is the object of the present invention, has an excellent effect on adjuvant arthritis and also has a strong inhibitory effect on the blastogenesis of lymphocytes. In addition to autoimmune diseases such as rheumatism and systemic erythematous lupus, cancer,
It is useful for treating diseases based on immune dysfunction such as bacterial infections and asthma.

[Example] Hereinafter, the present invention will be specifically explained with reference to Reference Examples and Examples.

(Reference Example 1) 19.2 g of 3-(2-methylbenzoyl)propionic acid
37 ml of pyridine, 4.7 g of paraformaldehyde and 4 mQ of piperidine were added to the mixture, and the mixture was heated at 55 to 60° C. for 5 hours with stirring. Ice water was added to the reaction mixture, the mixture was made weakly acidic by adding concentrated hydrochloric acid, and extracted with ether. After washing the organic layer with water and drying with magnesium sulfate, the ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using hexane-ether as a developing solvent to obtain an oily 3-(2-methyl 14.7 g of benzoyl)-3-methylenepropionic acid were obtained.

(Reference Examples 2 to 13) Using the compound represented by Formula I, the corresponding compound represented by Formula (1) was obtained according to Reference Example 1.

The physical properties of the compounds obtained in Reference Examples 1 to 13 above are as follows.
Shown in the table.

Table 1 (Note) Ph: Phenyl group (Example 1) 3-benzoyl-3-methylenepropionic acid 19.0 g
was dissolved in 300 ml of ether, and while stirring at room temperature, 15 ml of an ether solution containing 8.5 ml of thioacetic acid was added dropwise over 20 minutes, followed by further stirring at room temperature for 5 hours. Ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using hexane-ether as a developing solvent, and then recrystallized from hexane-ether to obtain 20.2 g of 3-acetylthiomethyl-3-benzoylpropionic acid. I got it.

(Example 2) 3-benzoyl-3-methylenepropion M19. Og
ether at 300 mA), 11 ml of ethyl mercaptan and 40 ml of hexamethyl phosphoric triamide.
was added, and an aqueous solution 3 of 14 g of potassium blown acid was added under stirring at room temperature.
0 ml was added dropwise over 10 minutes, and the mixture was further stirred at room temperature for 9 hours. 60 ml of 2N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ether. After washing the organic layer with water, drying with magnesium sulfate,
The ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using hexane-ether as a developing solvent to obtain oily 3-benzoyl-3-ethylthiomethylpropionic acid 19. 9g was obtained.

(Examples 3 to 24) Example 1 or Example 2 using a compound represented by formula (■)
The corresponding compound represented by formula (1) was obtained according to the following procedure.

Physical properties of the compounds obtained in Examples 1 to 24 above (Example 25) 26.6 g of 3-acetylthiomethyl-3-benzoylpropionic acid was dissolved in 200 ml of dimethylformamide, 14.4 ml of diethyl sulfate and 7 ml of potassium carbonate.
．． 60 g was added and stirred at room temperature for 4 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic residue was washed with water, dried over magnesium sulfate, and then ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane-ether as a developing solvent to obtain an oily ethyl 3-acetylthiomethyl-3-benzoylpropionate.
I got sg.

(Examples 26 to 30) Corresponding compounds represented by formula I were obtained according to Example 25 using the compounds represented by formula (1).

The physical properties of the compounds obtained in Examples 25 to 30 are shown in Table 3.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, X is a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a benzyl group,
Represents a phenylthio group, a phenyl group, or a phenyl group substituted with a halogen atom or a methyl group, Y represents a lower alkyl group or an acyl group, R represents a hydrogen atom or a lower alkyl group, and n represents 1 or 2. . ) A 3-benzoylpropionic acid derivative represented by: