Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-02-21
1995-01-24
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514259, 514312, 514314, 514367, 540480, 540481, 540593, 544283, 544284, 546153, 546155, 546165, 546172, 546175, 548159, C07D21514, C07D40106, A61K 3147
Patent
active
053843185
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to substituted sulfonamides and related compounds of the formula I, depicted below, which by inhibiting 5-lipoxygenase enzyme and/or blocking leukotriene receptors, are useful in the prevention or treatment of asthma, arthritis, psoriasis, ulcers, myocardiaI infarction, stroke, irritable bowel disease and related disease states in mammals. The present invention is also directed to pharmaceutical compositions of, and a method of treatment using said compounds of formula (I).
It is known that leukotrienes are compounds produced in mammals by the metabolism of arachidonic acid. Arachidonic acid is metabolized in mammals by means of two distinct pathways, one leading to prostaglandins and thromboxanes, and the other to several oxidative products known as leukotrienes, which are designated by letter-number combinations such as leukotriene B4 (LTB4), leukotriene C4 (LTC4) and leukotriene D4 (LTD4). The first step in this oxidative pathway is the oxidation of arachidonic acid under the influence of 5-lipoxygenase enzyme, an enzyme which is generally inhibited by the compounds of the present invention, thus blocking the synthesis of all leukotrienes. That in itself provides the mechanism sufficient for the utility of these compounds in the treatment or prevention of asthma (where LTC4 and LTD4 are understood to be mediators), arthritis (where LTB4 is understood to be a mediator), psoriasis (where LTB4 is understood to be a mediator), ulcers (where LTC4 and LTD4 are understood to be mediators), myocardial infarction (where LTB4 is understood to be a mediator), stroke (where LTD4 is understood to be a mediator) and irritable bowel disease (where LTB4 is understood to be a mediator). Supplementing this enzyme inhibitory activity is the general ability of the present compounds to antagonize (i.e., to block receptors of) LTB4, LTC4, LTD4 and LTE4. For a review concerning leukotrienes, see Bailey et al., Ann. Reports Med. Chem. 17, pp. 203-217 (1982).
Eggler et al., in PCT Patent Application PCT/US87/02745, describe racemic or optically active substituted tetralins, chromans and related compounds that inhibit 5-lipoxygenase enzyme and antagonize LTB4 and LTD4, and are therefore useful in the prevention and treatment of asthma, arthritis, psoriasis, ulcers, and myocardial infarction.
Kreft et al., in U.S. Pat. No. 4,661,596, describe disubstituted naphthalenes, dihydronaphthalenes and tetralins that inhibit lipoxygenase enzyme and antagonize LTD4, and are therefore useful in the prevention and treatment of asthma.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein R.sup.1 is quinolyl, substituted quinolyl, benzothiazolyl, substituted benzothiazolyl, benzopyrimidinyl, or substituted benzopyrimidinyl, wherein said substituted quinolyl, substituted benzothiazolyl, and substituted benzopyrimidinyl are substituted with one or more substituents that are independently selected from the group consisting of fluoro, bromo, chloro, phenyl, hydroxy, trifluoromethyl and (C.sub.1 -C.sub.4) alkyl; cycloalkyl, tetrazolyl, or thiazolyl, wherein the foregoing substituted phenyl groups are substituted with one or more substituents independently selected from the group consisting of chloro, fluoro and (C.sub.1 -C.sub.4) alkoxy; thereof.
Preferred compounds of the invention are compounds of the formula I wherein R.sup.1 is 5-fluoro-2-benzothiazolyl, X is O, r.sup.2 is hydrogen, n=1, R.sup.3 is hydroxy, and Z is independently selected from the group consisting of carboxamide, N-methanesulfonyl carboxamide, N-acetyl carboxamide, and N-tetrazoyl caboxamide.
A more preferred compound of the invention is the compound having formula I wherein R.sup.1, R.sup.2, R.sup.3, X and n are as defined in the preceding paragraph, and Z is N-phenylsulfonyl carboxamide.
Specific compounds of the invention are nzohomopyran-4-yl-methyl]-N-(phenylsulfonyl)benzamide, methyl]-N-(phenylsulfonyl)-benzamide, yran-3-ylmethyl]-N-(methanesulfonyl)benzamide,
REFERENCES:
Ann F. Welton, George W. Holland, Douglas W. Morgan, and Margaret O'Donnell, Pulmonary and Antiallergy Agents, 24 Annual Reports in Medicinal Chemistry 61-70 (1989).
Hiroko Masamune and Lawrence S. Melvin, Jr., Novel Applications of Leukotriene Intervention, 24 Annual Reports In Medicinal Chemistry 71-79 (1989).
Stevan W. Djuric, Timothy S. Gaginella, Donald J. Fretland and Peter H. Jones, Recent Advances i the Treatment of Inflammatory Bowel Disease, 24 Annual Reports In Medicinal Chemistry 167-175 (1989).
Ellen L. Smith and John J. Tegeler, Advances in Dermatology, 24 Annual Reports in Medicinal Chemistry 177-186 (1989).
Eggler James F.
Marfat Anthony
Masamune Hiroko
Melvin, Jr. Lawrence S.
Butterfield Garth C.
Gerstl Robert
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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