Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-12
2000-03-07
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514575, 546146, 546147, 558233, 560132, 560133, C07C25908, C07C25910, C07D21700, A61K 3147
Patent
active
060340967
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP97/02407 filed May 12, 1997.
The present invention relates to novel compounds and the use thereof as anti-inflammatory and immunosuppressive agents.
The role of cytokines (such as IL-1.beta. and .alpha., TNF.alpha. and IL-6) in the development of inflammatory reactions is well known (Dinarello C. A. and Wolff S. M., New Eng. J. Med. 328(2): 106113, 1993; Tracey K. J. and Cerami A., Crit. Care Med. 21: S415, 1993; Melli M. and Parente L., Cytokines and lipocortins in inflammation and differentiation. Wiley-Liss. New York 1990; Dawson M. M. Lymphokines and Interleukins. CRC Press. Boca Raton, Fla. 1991). A great number of searches have been carried out in order to find compounds, named cytokine suppressive anti-inflammatory drugs (CSAID), exerting an inhibitory effect on the production of pro-inflammatory cytokines, particularly IL-1.beta. and TNF.alpha. (Lee J. C. et al., Nature 372: 739, 1994; Davidsen S. K. and Summers J. B., Exp. Opin. Ther. Patents. 5(10): 1087, 1995), and recently wide-spectrum agents named non-traditional non-sterodial anti-inflammatory drugs have been disclosed (Chiou G. C. Y. and Liu S. X. L., Exp. Opin. Ther. Patents. 6(1): 41,1996).
Tanaka et al., Chem. Pharm. Bull., 31(8), 2810-2819 (1983) report the importance of the hydroxamic group for the antiinflammatory activity: it is said to have such a paramount role as to overshadow the other parts of the molecule, wherein groups such as the methoxy one can increase the inflammatory potency, whereas other groups, such as the acetamido one, cause a decrease in the activity.
Now it has surprisingly been found that hydroxamic acid derivatives containing an amidobenzoic moiety exert, contrary to what reported in the prior art, a remarkable antiinflammatory action, together with an immunosuppressive activity.
Therefore the present invention relates to compounds of formula (I): ##STR1## wherein R' is hydrogen or (C.sub.1-4)alkyl; A is adamantyl or a mono-, bi- or tricyclic residue optionally partially or totally unsaturated, which can contain one or more heteroatoms selected from the group consisting of N, S or O and optionally substituted by hydroxy, alkanoyloxy, primary, secundary or tertiary amino, amino(C.sub.1-4)alkyl, mono- or di(C.sub.1-4)alkyl-amino(C.sub.1-4)alkyl, halogen, (C.sub.1-4)alkyl, tri(C.sub.1-4)alkylammonium(C.sub.1-4) alkyl; NR' group wherein R' is as defined above; absent; oxygen atom; when at the same time X is different from 0 and Y is different from hydroxy, unless said fluorenyl is substituted by a tri(C.sub.1-4)alkylammonium(C.sub.1-4) alkyl group.
As hereinbelow meant, an alkyl group as defined above is, for example, methyl, ethyl, 2-methylethyl, 1,3-propyl, 1,4-butyl, 2-ethylethyl, 3-methylpropyl, 1,5-pentyl, 2-ethylpropyl, 2-methylbutyl and analogues, whereas a mono-, bi or tricyclic group as defined above can be phenyl, cyclohexyl, pyridyl, piperidyl, pyrimidyl, pyridazyl, naphthyl, indenyl, anthranyl, phenanthryl, fluorenyl, furanyl, pyranyl, benzofuranyl, chromenyl, xanthyl, isothiazolyl, isoxazolyl, phenothiazyl, phenoxazyl, morpholyl, thiophenyl, benzothiophenyl and the like. A halogen atom can be chlorine, bromine or fluorine. Finally, by alkanoyloxy group, acetyloxy, propionyloxy, ipropionyloxy, butanoyloxy and similar are meant.
A first group of preferred compounds of formula I are those wherein R' is hydrogen; A is selected from phenyl, 1- or 2- naphthyl, cyclohexyl, 1- or 2- 1,2,3,4-tetrahydronaphthyl, adamantyl, quinolinyl, isoquinolinyl, 1- or 2- indenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl optionally substituted as mentioned above; methylene, ethylene, propylene or propenyl group;
A second group of preferred compounds are those wherein R' is hydrogen; A is optionally substituted phenyl or 1- or 2- naphthyl, more preferably 1- or 2- naphthyl; R is phenyl when A is phenyl, or is hydrogen when A is 1- or 2- naphthyl; R, B, m and r are as defined above; Y is OH and the C.sub.1 -C.sub.3 alkylene chain is as defined above for the first group of preferred compoun
REFERENCES:
patent: 2800498 (1957-07-01), Chabrier et al.
patent: 4314936 (1982-02-01), Yaron et al.
patent: 4711900 (1987-12-01), Varma et al.
patent: 5280015 (1994-01-01), Jacobson et al.
Patent Abstracts of Japan, vol. 5, No. 132 (C-68) [804], Aug. 22, 1981 & JP 56 068650 A, Otsuka Seiyaku K.K., Jun. 9, 1981.
Fuji et al., Chemical Abstracts, vol. 87, No. 5, Abstract No. 39,013, col. 2, Aug. 1, 1977.
Bertolini Giorgio
Biffi Mauro
Leoni Flavio
Mascagni Paolo
Mizrahi Jacques
Davis Zinna Northington
Italfarmaco S.p.A.
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