Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-09-30
1996-08-27
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549399, 549400, 549401, 549403, A61K 3135, C07D31122
Patent
active
055501524
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel benzopyran and other benzo-fused leukotriene B.sub.4 (LTB.sub.4) antagonists, to pharmaceutical compositions containing such compounds, and to a method of using such compounds as LTB.sub.4 antagonists.
The compounds of this invention inhibit the action of LTB.sub.4 and are therefore useful in the treatment of LTB.sub.4 induced illnesses such as inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis and other skin disorders such as eczema, erythma, pruritis and ache, stroke and other forms of reperfusion injury, graft rejection, autoimmune diseases, asthma, and other conditions where marked neutrophil infiltration occurs.
Leukotriene B.sub.4 antagonists are disclosed in European patent publications 276 064 and 292 977 which refer to diphenylethers, benzophenones, and other compounds containing two phenyl groups, and 7-(3-alkoxy-4-alkanoylphenoxy)alkoxy benzopyran derivatives, respectively.
SUMMARY OF THE INVENTION
According to the invention, it was found that the following compounds of formula I have LTB.sub.4 antagonistic properties: ##STR1## wherein A is O, CH.sub.2, S, NH, or N(C.sub.1 -C.sub.6 alkyl); n is 0, 1 or 2; R.sup.1 is a substituent at position b or c as follows: carboxy; cis or trans --(CH.sub.2).sub.m --CR.sup.4 .dbd.CR.sup.5 --CO.sub.2 H; ##STR2## wherein m is 0, 1 or 2, R' is carboxy, tetrazolyl or CH.sub.2 OH, and X is O, CH.sub.2, S, NH or N(C.sub.1 -C.sub.6 alkyl); --(CH.sub.2).sub.m CR.sup.4 R.sup.5 R.sup.6 wherein m is as defined above; R.sup.4 and R.sup.5 are hydrogen or each independently are C.sub.1 -C.sub.6 alkyl, or are taken together with the carbons to which they are attached to form C.sub.3 -C.sub.7 cycloalkyl, R.sup.6 is hydroxyl, carboxy, or tetrazolyl; or --CONR.sup.7 R.sup.8 wherein R.sup.7 and R.sup.8 are hydrogen or each independently are C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 perfluoroalkyl, C.sub.1 -C.sub.6 alkylsulfinyl, phenylsulfinyl, C.sub.1 -C.sub.6 alkylsulfonyl, phenylsulfonyl, R.sup.9 -substituted phenyl or hydroxy, except that R.sup.7 and R.sup.8 cannot be both hydroxy; R.sup.2, R.sup.9, R.sup.15, and R.sup.16 are hydrogen or each independently are one or any two of the following: fluoro, chloro, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.4 perfluoroalkyl, C.sub.1 -C.sub.4 perfluoroalkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl or C.sub.1 -C.sub.6 alkylsulfonyl; R.sup.3 is --(CH.sub.2).sub.q CHR.sup.11 R.sup.12, --O(CH.sub.2).sub.q R.sup.12, --O(CH.sub.2).sub.p CHR.sup.11 R.sup.12, or --O(CH.sub.2).sub.p R.sup.12, wherein p is 0, 1 or 2 and q is 0, 1, 2, or 3; R.sup.11 is hydrogen, C.sub.1 -C.sub.6 alkyl or R.sup.16 -substituted phenyl wherein R.sup.16 is as defined above; R.sup.12 is C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.8 cycloalkyl; or phenyl, thienyl, pyridyl, furyl, naphthyl, quinolyl, isoquinolyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted by phenyl, R.sup.5, or R.sup.15 -substituted phenyl wherein R.sup.15 is as defined above; and the salts and esters of those compounds of formula I containing a carboxy group, wherein the esters contain an ester group R.sup.13 selected from the group consisting of C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6) alkyl, C.sub.3 -C.sub.7 cycloalkyl, and benzyl substituted by fluoro, chloro, C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkoxy.
Preferred compounds of the invention are those of formula I wherein A is oxygen, those wherein n is 1, those wherein R.sup.1 is at position c and is 1-carboxyethyl, 2-carboxy -2-propyl, 1-carboxypropyl, 3 -carboxy-3-pentyl, 1-carboxycyclopentyl, 1-carboxycyclohexyl or 1- (5-tetrazoyl)cyclopentyl, those wherein R.sup.2 is hydrogen or monofluoro, and those wherein R.sup.3 is benzyl, 4-fluorobenzyl, 4-phenylbenzyl or 4-(4-fluorophenyl)benzyl. Specific compounds of the formula I are those wherein A is oxygen, n is 1, R.sup.1 is a substituent at position c and is 1-carboxyethyl, 2-carboxy-2-propyl, 1-carbox
REFERENCES:
patent: 4565882 (1986-01-01), Miyano et al.
patent: 5059609 (1991-10-01), Eggler et al.
Djurio et al. Journal of Medicinal Chemistry, vol. 32, pp. 1146-1147 (1989).
M. Uemura et al., in Tetrahedron Letters, vol. 21, No. 21, pp. 2069-2072 (1980).
Koch Kevin
Melvin, Jr. Lawrence S.
Reiter Lawrence A.
Ruggeri Sally G.
Ginsburg Paul H.
Holtrust Gezina
Peabody John
Pfizer Inc.
Richardson Peter C.
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