Nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino)

Details Nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino) Nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino)

1994-03-31

1997-01-28

Geist, Gary

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

558482, 558483, A61K 3121, C07C20304

Patent

active

055978479

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP93/01906, filed Jul. 20, 1993.


TECHNICAL FIELD

Object of the present invention are nitric esters of derivatives of 2-(2,6-di-halo-phenylamino)phenylacetic acid, their pharmaceutical utilization and process for their preparation.


PRIOR ART

The sodium salt of the 2-(2,6-di-chlorophenylamino)phenylacetic acid has been used for a long time in the pharmaceutical field for its anti-inflammatory activity and has been sold throughout the world for many years. The process for its preparation has been described in the Dutch Patent application No. 6.604.752 and in the U.S. Pat. No. 3,558,690.
The pharmacological profile and the effectiveness of the sodium salt of the 2-(2,6-di-chlorophenylamino)phenylacetic acid are described in Am.J.Med.80, Suppl. 4B, 1-87 (1986), while other data concerning its pharmacological activity as anti-inflammatory agent are reported, for instance, in C.A.74, 86215 m (1971); Krupp et al. Experimentia 29,450 (1973).
The utilization of the 2-(2,6-di-chlorophenylamino)phenylacetic acid as an anti-inflammatory preparation causes, as known, very severe adverse reactions, for instance in the gastro-intestinal apparatus, as well as damages to the liver and the kidneys. There exist numerous experimental evidences [S.MONCADA, R. M. J.PALMER, E. A.HIGGS, Pharmacological Reviews, 43(2), 109-142 (1991); T. F.LUSHER, C. M.BOULANGER, Y.DOHI, Z.YANG, Hypertension, 19, 117-130 (1992)], on whose basis the integrity of the vasal endothelium is assumed to act as a basically important protective barrier to prevent the onset of pathologic reactions in various organs and apparatuses.
Such protective barrier, and therefore the integrity of the vasal endothelium, is ensured, on the physiological plane, by the presence of nitric oxide and prostacyclin.
The treatment with drugs having an anti-inflammatory activity, such as, for instance, the sodium salt of the 2-(2,6-di-chloro-phenylamino)phenylacetic acid, causes the inhibition of the cyclo-oxygenase, an enzyme which governs the synthesis of the prostacyclin precursor. As a consequence, the production of prostacyclin being in this way inhibited, the tissular reserve of same is markedly depauperated, with ensuing compromission of the vasal endothelium.
As said, because of this endothelial damage due to the reduction of prostacyclin, diffuse pathologic reactions break out which affect the gastrointestinal apparatus, the kidneys and the liver.


OBJECTS OF THE INVENTION

Object of the present invention is to provide a product which, while ensuring the maintenance of the pharmacological activity characteristic of the known anti-inflammatory preparations, can also eliminate the adverse reactions caused by the treatment with said drugs.
Another object of the present invention is the realization of a process for the preparation of derivatives of the 2-(2,6-di-halo-phenylamino)phenylacetic acid having an anti-inflammatory activity and that are exempt from those adverse reactions that are typical of the anti-inflammatory drugs.


DESCRIPTION OF THE INVENTION

These and still other objects and advantages which shall appear from the following description are obtained by derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid, which derivatives, according to the present invention, have the following general formula: ##STR2## wherein:
A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, X is a halogen selected among chloride and bromine, Y is selected among oxygen, NH, NR.sub.1, wherein R.sub.1 is a linear or branched alkyl group and n is comprised between 1 and 10.
In fact, it has been observed that the introduction of a group such as a terminal nitric ester in the derivatives of the 2-(2,6-di-halo-phenylamino)phenylacetic acid as in (I) permits to preserving the pharmacological activity of anti-inflammatory drugs, while eliminating the adverse reactions caused by the treatment with said drugs. The present invention also includes a pharmaceutical composition comprising an effective

REFERENCES:
patent: 3558690 (1971-01-01), Sallmann et al.

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