Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-12-12
1994-05-31
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142305, 514258, 514303, 514333, 514338, 514339, A01N 4340, A61K 3154
Patent
active
053170199
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a method of inhibiting the production of interleukin-1 by monocytes and/or macrophages in a human in need thereof which comprises administering to such human an effective, interleukin-1 production inhibiting amount of a diaryl-substituted imidazole fused to a second heterocyclic ring containing a nitrogen bridgehead atom wherein said second ring may also contain sulfur, oxygen or an additional nitrogen atom, and may contain additional unsaturation.
This invention relates to a method of inhibiting the production of Tumor Necrosis Factor (TNF) by monocytes or macrophages in a mammal in need thereof which comprises administering to such mammal an effective, TNF production inhibiting amount of a compound of Formula (II) as described herein. The compounds of Formula (II) are generally described as diaryl-substituted imidazole fused to a second heterocyclic ring containing a nitrogen bridgehead wherein said ring may also contain sulfur, oxygen, or an additional nitrogen atom, and may contain additional unsaturation.
Lednicer, U.S. Pat. No. 3,455,924, issued Jul. 15, 1969, describes compounds of the formula: ##STR1## wherein Z is a bivalent radical selected from the group consisting of: ##STR2## in which up to two of the parameters R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of hydrogen, lower alkyl and lower alkoxy having 1 to 4 carbon atoms, inclusive, hydroxy and nitro and the remaining parameters are hydrogen.
Adams et al., U.S. patent application Ser. No. 07/255,816, filed Oct. 11, 1988, generically discloses pyridyl substituted pyrrolo-[2,1-a]-imidazoles and pyridines as useful for inhibiting the 5-lipoxygenase pathway of arachadonic acid metabolism in an animal in need thereof. Specifically disclosed are the following compounds: zole; idazole; e; azole; -a]imidazole; [1,2-a]imidazole; and le.
Bender et al., U.S. Pat. No. 4,794,114, issued Dec. 27, 1988, disclose a method of inhibiting the production of IL-1 by monocytes and/or macrophages in a human in need thereof which comprises administering to such human an effective, interleukin-1 production inhibiting amount of a compound of the formula: ##STR3## wherein:
One of R.sup.1 and R.sup.2 must be 4-pyridyl and the other is selected from monosubstituted phenyl wherein said substituent is selected from halo or C.sub.1-4 alkoxy;
X is CH.sub.2, CH.sub.2 CH.sub.2 or S(O)n; and
n is 0, 1 or 2;
Dinarello et al., Int. J. Immunopharmacology, 6(1), 43-50 (1984), suggest that a product of arachidonate lipoxygenase is important in the sequence of events underlying cell activation for the production of human interleukin-1.
Griswold et al., Inflammation, 11(2), 189-199 (1987), discuss the inhibitory effects of 5-(4-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo-(2,1 -b)thiazole and other dual inhibitors of arachidonic acid metabolism (i.e., inhibitors of 5-lipoxygenase and cyclooxygenase mediated arachidonate metabolism) on the edematous and cellular component of arachidonic acid-induced inflammation.
Lee et al., Int. J. Immunopharmac., 10(7), 835-843 (1988), discuss that [5-(4-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo(2,1-b)thiazole], which inhibits both 5-lipoxygenase and cyclooxygenase-mediated arachidonate metabolism, was shown to be a potent inhibitor of IL-1 production by bacterial lipopolysaccharide (LPS)-stimulated human monocytes, and that other cyclooxygenase and/or 5-lipoxygenase inhibitors of arachidonic acid metabolism tested, with the exception of nordihydroguaiaretic acid, were inactive in inhibiting monocyte IL-1 production suggesting that the inhibition of IL-1 production by 5-(4-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo-(2,1-b)thiazole may be dissociated from its inhibition of fatty acid oxygenases.
There remains a need for compounds which are useful in inhibiting the production of interleukin-1 (IL-1) by monocytes and/or macrophages in a human in need of such inhibition.
Studies have indicated that TNF is a glycoprotein and that its activity is associated wit
REFERENCES:
patent: 4794114 (1988-12-01), Bender et al.
Chemical Abstracts, vol. 114, No. 21, Abstract 199,0806, p. 21, May 27, 1991.
Badger Alison M.
Bender Paul E.
Esser Klaus M.
Griswold Don E.
Hanna Nabil
Covington Raymond
Dinner Dara L.
Ivy C. Warren
Lentz Edward T.
SmithKline Beecham Corp.
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