Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-06-07
1999-11-23
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546 1, 546332, 546334, 546335, 546336, 546337, 546339, 546340, 546343, 546344, 546346, A61K 31435, A61K 3144, C07D21172, C07D40100
Patent
active
059903147
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C.sub.4, D.sub.4 and E.sub.4) and the dihydroxyleukotrienes aeukotriene B.sub.4). This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.
The peptidoleukotrienes are implicated in the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response is expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses. The pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and increased mucous production.
By comparison, LTB.sub.4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs).
Leukotrienes are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.
Leukotriene B.sub.4 (LTB.sub.4) was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy-(Z,E,E,Z)-6,8,10,14-eicosatetraenoic acid. ##STR2## It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA.sub.4. It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB.sub.4 has been shown to be a potent stimulus in vivo for PMN leukocytes, causing increased chemotactic and chemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB.sub.4 are mediated through distinct receptor sites on the leukocyte cell surface that exhibit a high degree of stereospecifiity. Pharmacological studies on human blood PMN leukocytes indicate the presence of two classes of LTB.sub.4 -specific receptors that are separate from receptors specific for the peptide chemotactic factors. Each of the sets of receptors appear to be coupled to a separate set of PMN leukocyte functions. Calcium mobilization is involved in both mechanisms.
LTB.sub.4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper-responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction.
By antagonizing the effects of LTB.sub.4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of this invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a factor.
SUMMARY OF THE INVENTION
In a first aspect, this invention covers a compound of formula I ##STR3## or an N-oxide, or a pharmaceutically acceptable salt, where A is CH.sub.2 and Z is S(O).sub.q where q is 0, 1 or 2, CH.sub.2, CHOH, C.dbd.O, or NRx, or O; or five-membered heteroaryl-C.sub.1 to C.sub.10 -aliphatic-O--, unsubstituted or substituted phenyl-C.sub.1 to C.sub.10 -aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C.sub.1 to C.sub.20 -aliphatic-O--, or R is unsubstituted or substituted phenyl-C.sub.1 to C.sub.10 -aliphatic-O--where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; C.sub.5 aliphatic)CHO, --(C.sub.1 to C.sub.5 aliphatic)CH.sub.2 OR.sub.5 ; lower alkyl; phenyl(CH.sub.2).sub.0-3 CO.
In a further aspect, this inven
REFERENCES:
patent: 5643914 (1997-07-01), Daines
Enantiomeric specificity at the deacylation process of tryptic catalysis, Tanizawa et al., Mar. 16, 1987, vol. 916 pp. 205-212.
Chemical Abstracts, vol. 108. Issued 1988, 16395, Antibodies to 4-hydroxyandrostenedione.
Tanizawa et al, Chemical Abstracts, vol. 108, #163953a (1988).
Higel Floyd D.
Kanagy James M
Kinzig Charles M.
SmithKline Beecham Corporation
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