Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-12-10
1993-01-26
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514300, 546 15, 546113, 544236, 544280, 544350, 548153, 548207, 548453, 5483031, 5483605, 5483011, 5483575, A61K 31435, C07D47104
Patent
active
051822890
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to certain heterobicyclic compounds having antiinflammatory activity and antiallergic conditions and to pharmaceutical compositions and methods employing such compounds.
U.S. Pat. No. 4,569,942 discloses certain 2-oxindole-1-carboxamide compounds having an acyl substituent at the 3-position as having analgesic and antiinflammatory activities.
European published patent Application No. 0 175 551 discloses 1,3-diacyl-2-oxindole compounds, while European published patent Application Nos. 0 181 136 and 0 173 520 disclose substituted 2-oxindole-3-carboxamides and tricyclic and quadracyclic compounds including the 2-oxindole-3-carboxamide unit as antiinflammatory agents.
The art also includes numerous disclosures of 3,3-disubstituted 2-oxindoles, as pharmaceutically active compounds, e.g. British Patent No. 1,132,318, Dutch Patent Application No. 6604752 (anti-inflammatory), and South African Patent 68-01099 (antidepressants).
1,3-dihydro-3,3-dimethyl-2H-[2,3-b]-pyridin-2-one is disclosed by Ficken et al. in J. Chem. Soc., 747-89 (1961). No pharmaceutical utility is mentioned for the compound.
Pyrrolidinopyridine derivatives having geminal substitution are disclosed in Chem. Abstracts, Vol. 77, No. 19, Abst. No. 12637e (1972). No pharmaceutical activity is disclosed.
Japanese Patent Application 51068571 discloses compounds of the formula ##STR1## wherein R is substituted phenyl, and are useful for inflammatory conditions.
SUMMARY OF THE INVENTION
It has now surprisingly been found that compounds of formulas (I) and (II) below have particularly advantageous properties useful in the treatment of inflammation or allergies by inhibiting the formation of lipoxygenase and cyclooxygenase derived products of arachidonic acid metabolism. The compounds of formulas (I) and (II) are represented by the structural formulas: ##STR2## or a pharmaceutically acceptable salt or solvate thereof, wherein
A represents a fused 5- or 6-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms in the ring, each heteroatom independently represents O, S, N or NR.sup.6 wherein R.sup.6 in the group NR.sup.6 is hydrogen or C.sub.1 to C.sub.4 alkyl;
the dotted lines represent optional double bonds, such that
when the bond to X is a double bond, X is O or S; and
when the bond to X is a single bond, X is --OR.sup.10 wherein R.sup.10 is alkyl or aralkyl;
T.sup.2 and T.sup.3 independently represent S, SO or SO.sub.2 ;
m and n independently represent 0 or 1;
R.sup.1 represents hydrogen, alkyl, aryl, aralkyl, or a 5- or 6-membered heterocyclic aromatic ring having from 1 to 3 heteroatoms in the ring, each heteroatom independently selected from NR.sup.6, O, S or N atoms;
R.sup.2 and R.sup.3 independently represent hydrogen; SO.sub.2 that R.sup.2 or R.sup.3 is not hydrogen or halogen;
--D--OCO--R.sup.4 wherein D represents an alkylene group having from 1 to 4 carbon atoms and R.sup.4 is alkyl, aryl or aralkyl;
a C.sub.3 to C.sub.7 spirocarbocyclic ring whereby R.sup.2 and R.sup.3 are joined together;
the rings represented by A, R.sup.1, aryl or aralkyl may each be optionally substituted by up to three Y substituents;
wherein each Y substituent independently represents --OH, hydroxyalkyl, alkyl, halogen, --NO.sub.2, alkoxy, alkoxyalkyl, alkylthio, --CF.sub.3, --CN, cycloalkyl, alkynyloxy, alkenyloxy, --S(O).sub.p --R.sup.4 (wherein R.sup.4 is defined above and p is an integer from 0 to 2), --CO--R.sup.5 (wherein R.sup.5 represents --OH, --NH.sub.2, --NHR.sup.4, N(R.sup.4).sub.2 or --OR.sup.4 in which R.sup.4 is as defined above), --O--D--COR.sup.5 (wherein D is defined above and R.sup.5 is as defined above), --NH.sub.2, --NHR.sup.4, --N(R.sup.4).sub.2 (wherein R.sup.4 is as defined above) or --NHC(O)H.
As used herein, the terms below have the following meaning, unless otherwise indicated:
halogen--represents fluoro, chloro, bromo or iodo;
alkyl (including the alkyl portions of alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl)--represents straight and branched hydrocarbon chains and
REFERENCES:
Ficken et al., J. Chem. Soc., pp. 747-748 (1961).
Adler et al., J. Med. Chem. 6(5) pp. 480-483 (1963).
Tetrahedron Letters vol. 28, No. 35, pp. 4027-4030 (1987).
Journal of the American Chemical Society vol. 81, No. 1, pp. 740-743 (1959).
Arzneimittel Wirkungen pp. 46, 54, 55 (1981).
Advanced Organic Chemistry Second Edition McGraw Hill pp. 146-150 (1977).
Kaminski James J.
Sherlock Margaret H.
Ting Pauline C.
Tom Wing C.
Dentz Bernard
Mazer Edward H.
Nelson James R.
Schering Corporation
Thompson Paul A.
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