Cyclic aminophenylacetic acid derivatives, process for preparing

Details Cyclic aminophenylacetic acid derivatives, process for preparing Cyclic aminophenylacetic acid derivatives, process for preparing

1992-12-09

1994-10-25

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546 14, 546153, 546166, C07D21524, C07D21548, C07D21516, C07D21506

Patent

active

053590767

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel cyclic aminophenylacetic acid derivatives having immune response-modulating action, their optical isomers and salts, their preparative processes, and therapeutic agents for autoimmune diseases containing them as effective ingredients.


BACKGROUND

For the therapy of chronic diseases (rheumatoid arthritis and autoimmune diseases) with which the immune response is concerned, anti-inflammatory agents, immunomodulators, etc. are used. The formers are for symptomatic therapy, thus cannot become fundamental therapeutic agents. Whereas, the latters, in which gold salt and D-penicillamine, levamisole, lobenzarit, etc. are known, have attracted an attention for the last several years.
The inventors have also studied diligently for the purpose of developing a more effective and safer anti-rheumatic agent and have found previously that the cyclic anthranilic acid derivatives have immunomodulatory action and inducing ability for suppressor T cells, and that they have therapeutic effect against rheumatoid arthritis (Japanese Unexamined Patent Publication No. Hei 1-279867). However in cyclic aminophenylacetic acid derivatives, compounds having such action are not known.
In cyclic aminophenylacetic acid derivatives having different substituent from the compounds in this invention, those having anti-inflammatory, antipyretic and analgesic actions are described in Japanese Unexamined Patent Publication No. Sho 58-116466 and U.S. Pat. No. 3,778,511 (1973), but the immuno-modulating action is not referred at all. These publicly known compounds, with which a possibility to cause gastrointestinal injury is suggested, belong to a category of non-steroidal anti-inflammatory drugs having cyclooxygenase-inhibitory action, and their usefulness is not satisfactory from the points of efficacy and toxicity. Moreover, cyclic aminophenylacetic acid derivatives exhibiting monoamineoxydase-inhibitory action are also known (Chemical Abstract, Vol. 64, 1753c (1966), ibid Vol. 70, 10292f(1969)), but these also differ from the compounds of the invention in the structure and action.


DISCLOSURE OF THE INVENTION

As a result of further extensive studies on relating compounds, the inventors have found that novel cyclic aminophenylacetic acid derivatives represented by a general formula (1) ##STR2## [wherein R and R.sup.1 each independently denotes hydrogen atom or lower alkyl group having 1 to 3 carbon atoms, R.sup.2 denotes a phenyl group (which may be substituted with 1 to 3 groups of halogen atom, methoxy group or their combinations) or trifluoromethyl group, and X denotes a hydrogen atom, lower alkyl group having 1 to 3 carbon atoms, lower alkoxy group, having 1 to 3 carbon atoms, cyano group, thiocyano group, trimethylsilylethinyl group, phenyl group (which may be substituted with halogen atom, methoxy group, methyl group or their combinations), carbamoyl group, carboxyl group, lower alkoxycarbonyl group having 1 to 3 carbon atoms, acetyl group, benzoyl group, nitro group, amino group, lower alkanoylamino group having 1 to 3 carbon atoms, benzoylamino group which may be substituted, phenylsulfonylamino group which may be substituted, lower alkylthio group having 1 to 3 carbon atoms, lower alkylsulfinyl group having 1 to 3 carbon atoms, lower alkylsulfonyl group having 1 to 3 carbon atoms, or halogen atom], their optical isomers and their salts have conspicuous modulating action on immune response, have excellent inhibitory action also against acute inflammation, which cannot be seen with conventional immunomodulatory drugs, and yet do not exhibit cyclooxygenase-inhibitory action.
Further, the inventors have found that they exhibit fast-acting and persistent therapeutic effect against adjuvant arthritis being a typical pathologic model of rheumatoid arthritis. Further, the inventors have come to confirm the safety, too, leading to the completion of the invention.
According to the invention, the compounds represented by the general formula (1) can be prepared through processes,

REFERENCES:
patent: 3778511 (1973-12-01), Bernasconi
patent: 4303590 (1981-12-01), Tanaka et al.
patent: 5124325 (1992-06-01), Kojima
patent: 5281600 (1994-01-01), Kojima

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