Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-06
1998-05-19
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514399, 5462741, 5483111, 5483154, C07D23360, C07D40512, C07D40514, A61K 31415
Patent
active
057536821
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This application is a 371 of PCT/JP94/00836 filed on May 25, 1994.
This invention relates to novel imidazole compounds. The compounds of the present invention inhibit the action of the lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals, especially human subjects. This invention also relates to pharmaceutical compositions comprising such compounds.
BACKGROUND ART
Arachidonic acid is known to be the biological precursor of several groups of biologically active endogenous metabolites. The first step in the metabolism of arachidonic acid is its release from membrane phospholipids, via the action of phospholipase A2. Arachidonic acid is then metabolized either by cyclooxygenase to produce prostaglandins including prostacyclin, and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes.
The leukotrienes are extremely potent substances which elicit a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The peptide leukotrienes (LTC.sub.4, LTD.sub.4, LTE.sub.4) are important bronchoconstrictors and vasoconstrictors, and also cause plasma extravasation by increasing capillary permeability. LTB.sub.4 is a potent chemotactic agent, enhancing the influx of leukocytes and inducing their subsequent degranulation at the site of inflammation. A pathophysiological role for leukotrienes has been implicated in a number of human disease states including asthma, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome (ARDS), inflammatory bowel diseases (e.g. Crohn's disease), endotoxin shock, and ischemia-induced myocardial injury. Any agent that inhibits the action of lipoxygenases is expected to be of considerable therapeutic value for the treatment of acute and chronic inflammatory conditions.
Several review articles on lipoxygenase inhibitors have been published. See J. A. Salmon and L. G. Garland: Progress in Drug Research, 1991, 37, pp9-90 (Birkhauser Verlag), H. Masamune and L. S. Melvin, Sr.: Annual Reports in Medicinal Chemistry, 1989, 24, pp71-80 (Academic Press), and B. J. Fitzsimmons and J. Rokach: Leukotrienes and Lipoxygenases, 1989, pp 427-502 (Elsevier).
Compounds of similar structure to the compounds of the present invention are disclosed in EP 0 488 602 Al, EP 0 409 413 A2 and EP 0 375 404 A2.
The present inventors have worked to prepare compounds capable of inhibiting the action of lipoxygenase and after extensive research they have succeeded in synthesizing a series of compounds as disclosed in detail herein.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides novel imidazole compounds of the following chemical formula I ##STR1## and the pharmaceutically-acceptable salts thereof, wherein
Y is hydrogen, C.sub.1 -C.sub.8 alkyl, halosubstituted C.sub.1 -C.sub.4 alkyl, phenyl, substituted phenyl, C.sub.7 -C.sub.4 phenylalkyl, C.sub.7 -C.sub.4 (substituted phenyl)alkyl, pyridyl, substituted pyridyl, C.sub.6 -C.sub.13 pyridylalkyl or C.sub.6 -C.sub.13 (substituted pyridyl)alkyl, wherein each substituent is independently halo, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halosubstituted C.sub.1 -C.sub.4 alkyl, halosubstituted C.sub.1 -C.sub.4 alkoxy, NR.sup.4 R.sup.5, CO.sub.2 R.sup.4 or CONR.sup.4 R.sup.5, wherein R.sup.4 and R.sup.5 are each, independently, hydrogen or C.sub.1 -C.sub.6 alkyl;
Ar.sup.1 and Ar.sup.2 are each, independently, phenylene, mono-substituted phenylene or di-substituted phenylene, wherein the substituents are, independently, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo-substituted C.sub.1 -C.sub.4 alkyl or halo-substituted C.sub.1 -C.sub.4 alkoxy;
X and X.sup.1 are each, independently, O, S, SO or SO.sub.2 ;
R.sup.1 is hydrogen or C.sub.1 -C.sub.4 alkyl; and
R.sup.2 and R.sup.3 are each, independently, methylene, ethylene or propylene.
A preferred group of compounds of this invention consists of compounds of t
REFERENCES:
patent: 5223525 (1993-06-01), Wu et al.
patent: 5246957 (1993-09-01), Cozzi et al.
patent: 5276037 (1994-01-01), Dowell et al.
patent: 5403859 (1995-04-01), Edwards et al.
Ando Kazuo
Mano Takashi
Stevens Rodney W.
Butterfield Garth
Ginsburg Paul H.
Pfizer Inc.
Rao Deepak R.
Richardson Peter C.
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