Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1997-04-07
1998-12-15
Henley, III, Raymond
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 17, 514532, 514533, 514534, 514539, C07C 6976
Patent
active
058499431
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a U.S. National Phase application based upon PCT Application No. CA95/00601 filed on Oct. 24, 1995, copending therewith, which was based upon U.S. Application No. 08/330,172 filed Oct. 27, 1994, copending therewith, abandoned on Oct. 27, 1994, priority of which is claimed hereunder.
BACKGROUND OF THE INVENTION
This invention relates to compounds and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases and methods of treatment thereof.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
A number of stilbene derivatives are known in the chemical literature. Toda et al., in Chem. Commun. 1234-5 (1984) describe the dialdehydes A and the diol B is described by Tsuji et al, J. Am. Chem. Soc. 88, 1289-92 (1966), and diol C was prepared by Dhawau et al., J. Org. Chem., 45, 922-4 (1980). No utility is disclosed for these compounds, nor do they carry the R.sup.1 substituent of the present invention. ##STR2##
Structure D is disclosed as having usefulness for treating hyperlipidemia by Hashimoto et al, European Patent Application 424,541 (May 2, 1991). ##STR3##
These compounds (D) lack the second carbon substituent X of the present invention and have an unrelated utility.
SUMMARY OF THE INVENTION
The invention encompasses novel compounds of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases. ##STR4##
The invention also encompasses certain pharmaceutical compositions and methods for treatment of cyclooxygenase-2 mediated diseases comprising the use of compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases ##STR5## or pharmaceutically acceptable salts thereof wherein X is consisting of
A preferred genus of compounds of Formula I is that wher
REFERENCES:
patent: 5082974 (1992-01-01), Hashimoto et al.
patent: 5344991 (1994-09-01), Reitz et al.
patent: 5393790 (1995-02-01), Reitz et al.
patent: 5474995 (1995-12-01), Ducharme et al.
Toda et al., "A New Preparative Method for (E)-2, 3-Diarylbut-2-enedials", Journal of the Chemical Society, Chemical Communications, No. 18, Sep. 1984, pp. 1234-1235.
Tsuji et al., "Organic Synthesis by means of noble metal compounds. XXI. Palladium-catalyzed carbonylation of diphenylacetylene", Journal of the American Chemical Society, vol. 88, No. 6, Mar. 20, 1966, pp. 1289-1292.
Dhawan et al., "Preparation of Benzocyclobutenols from o-halostyrene oxides", vol. 45, No. 5, 29 Feb. 1980, pp. 922-924.
Atkinson Joseph
Wang Zhaoyin
Billups Richard C.
Henley III Raymond
Jones Dwayne C.
Merck Frosst Canada Inc.
Panzer Curtis C.
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