Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-03
1999-07-20
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514406, A61K 31415, C07D23114
Patent
active
059257687
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel pyrazole derivatives and their optional salts, to a process for their preparation and to pharmaceutical compositions in which they are present.
More particularly, the present invention relates to novel pyrazole derivatives which possess a very good affinity for the peripheral cannabinoid receptors, called CB.sub.2 receptors, and are useful in the therapeutic fields in which the CB.sub.2 receptors are involved.
.DELTA..sup.9 -THC is the main active constituent of Cannabis sativa (Tuner, 1985; in Marijuana 1984, Ed. Harvey, DY, IRL Press, Oxford).
The characterization of the cannabinoid receptors has been made possible by the development of synthetic ligands such as the agonists WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) or CP 55940 (J. Pharmacol. Exp. Ther., 1988, 247, 1046-1051).
Numerous articles have described not only psychotropic effects of cannabinoids but also their influence on the immune function (HOLLISTER L. E., J. Psychoact. Drugs, 24, 1992, 159-164). The majority of in vitro studies have shown that cannabinoids have immunosuppressant effects: inhibition of the mitogen induced proliferative responses of T lymphocytes and B lymphocytes (Luo Y. D. et al., Int. J. Immunopharmacol., 1992, 14, 49-56; Schwartz H. et al., J. Neuroimmunol., 1994, 55, 107-115), inhibition of the activity of cytotoxic T cells (Klein et al., J. Toxicol. Environ. Health, 1991, 32, 465-477), inhibition of the microbicidal activity of macrophages and of TNF.alpha. synthesis (Arata S. et al., Life Sci., 1991, 49, 473-479; Fisher-Stenger et al., J. Pharm. Exp. Ther., 1993, 267, 1558-1565), and inhibition of the cytolytic activity and the TNF.alpha. production of certain lymphocytes (Kusher et al., Cell. Immun., 1994, 154, 99-108). In some studies, by contrast, amplification effects have been observed, namely an increase in the bioactivity of interleukin-1 by mouse fixed macrophages or differentiated macrophagic cell lines, due to enhanced levels of TNF.alpha. (Zhu et al., J. Pharm. Exp. Ther., 1994, 270, 1334-1339; Shivers S. C. et al., Life Sci., 1994, 54, 1281-1289).
The effects of cannabinoids are due to an interaction with high-affinity specific receptors present in the central nervous system (Devane et al., Molecular Pharmacology, 1988, 34, 605-613) and peripheral nervous system (Nye et al., The Journal of Pharmacology and Experimental Therapeutics, 1985, 234, 784-791; Kaminski et al., Molecular Pharmacology, 1992, 42, 736-742; Munro et al., Nature, 1993, 365, 61-65).
The central effects are dependent on a first type of cannabinoid receptor (CB.sub.1), which is present in the brain. Furthermore, Munro et al. (Nature, 1993, 365, 61-65) have cloned a second cannabinoid receptor coupled to proteins G, called CB.sub.2, which is present only in the peripheral nervous system and more particularly in the cells of immune origin. The presence of CB.sub.2 cannabinoid receptors in the lymphoid cells may explain the immunomodulation, referred to above, which is exerted by cannabinoid receptor agonists.
Numerous pyrazole derivatives have been described in the literature; more particularly, EP-A-268554 and DE-A-3910248 claim pyrazoles which possess herbicidal properties, EP-A-430186 and JP-A-3031840 claim compounds which are useful in photography and EP-A-418845 claims pyrazoles which possess anti-inflammatory, analgesic and antithrombotic activity.
Pyrazolecarboxamide derivatives have also been described, especially in patent applications EP-A-0289879 and EP-A-0492125; these compounds possess insecticidal properties.
Moreover, patent application EP-A-0477049 describes pyrazole-3-carboxamide derivatives of the formula ##STR2##
in which for example:
R.sub.I is a variously substituted aryl group;
R.sub.II is hydrogen or a (C.sub.1 -C.sub.4)alkyl;
R.sub.III is a hydroxyl group, a (C.sub.1 -C.sub.6)alkoxy or an amino group;
R.sub.IV is hydrogen, a halogen or a (C.sub.1 -C.sub.6)alkyl;
R.sub.V is a variously substituted phenyl group; and
n is 0, 1, 2 or 3.
These compounds are active on
Barth Francis
Casellas Pierre
Millan Joseph
Oustric Didier
Rinaldi Murielle
Alexander Michael D.
Bauman Mary P.
Ramsuer Robert W.
Sanofi
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