Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-11-13
1995-04-04
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544 32, 544 14, C07D27916, C07D51304, A61K 3154
Patent
active
054038391
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to pyrroloquinoline and pyrrolophenothiazine carboxamides and related compounds, methods of preparing such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in treating inflammation (e.g., arthritis) or other prostaglandin or leukotriene mediated diseases.
Oxindole-carboxamides useful as antiinflammatory agents and analgesics are referred to in U.S. Pat. Nos. 4,556,672, 4,569,942, 4,644,005, 4,678,802, and 4,686,224, and in U.S. Ser. No. 670,697, filed Nov. 13, 1984, and U.S. Ser. No. 821,296, filed Jan. 22, 1986.
U.S. Pat. No. 4,695,571 refers to tricyclic oxindoles as antiinflammatory agents.
United States Patent 4,690,943 refers to 1,3-diacyl-2-oxindoles as antiinflammatory agents and analgesics.
U.S. Pat. No. 4,658,037 and U.S. Ser. No. 670,697, filed Nov. 13, 1984, refer to intermediates for preparing oxindole carboxamides.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein the broken line represents an optional double bond; X is O, S, CH.sub.2 or CH.sub.2 CH.sub.2 ; R is selected from the group consisting of hydrogen, halogen (e.g., fluorine, chlorine, bromine and iodine), C.sub.1 -C.sub.6 alkoxy (e.g., OCH.sub.3) , C.sub.1 -C.sub.6 alkanoyl, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl; R.sup.2 is selected from the group consisting of phenyl, substituted phenyl, heterocyclic groups, and substituted heterocyclic groups, said substituted phenyl and substituted heterocyclic groups being substituted with 1 or 2 substituents independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl, trifluoromethyl, and halogen (e.g. fluorine, chlorine, bromine and iodine); hydrogen, halogen (e.g., fluorine, chlorine, bromine and iodine), C.sub.1 -C.sub.6 alkyl, and trifluoromethyl, or R.sup.3 and R.sup.4, taken together with the carbon atoms to which they are attached, form a six-membered carbocyclic aromatic ring, said aromatic ring being optionally substituted with one or two substituents selected from the group consisting of halogen (e.g., fluorine, chlorine, bromine or iodine), C.sub.1 -C.sub.6 alkyl, and trifluoromethyl; and the pharmaceutically acceptable salts thereof. The "floating bond" in formula I is intended to indicate that R.sup.1 may be connected to any one of positions a, b and c of the aromatic ring. Position b is preferred. When R.sup.2 is a heterocyclic group, R.sup.2 is preferably selected from benzothiazole, isoxazole, isothiazole, oxazole, pyridine, thiazole and thiadiazole. The foregoing heterocyclic groups may be substituted as described above.
The present invention also relates to a pharmaceutical composition useful in the treatment of inflammation or other prostaglandin or leukotriene mediated diseases comprising an amount of a compound of the formula I effective to treat inflammation or another prostaglandin or leukotriene mediated disease and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a prostaglandin or leukotriene mediated disease comprising administering to a patient in need of such treatment a compound of formula I in an amount effective to treat such disease.
The present invention also relates to intermediates useful in preparing the foregoing compounds and to methods of preparing the foregoing compounds.
A preferred embodiment of the present invention relates to compounds of the formula ##STR3## wherein R.sup.1, R.sup.2 and X are as defined above and R.sup.5 is selected from the group consisting-of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl, and the pharmaceutically acceptable salts thereof. More preferably R.sup.1 is hydrogen or fluorine; R.sup.2 is phenyl, 2,4-difluorophenyl, pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl, or isoxazolyl, and R.sup.5 is hydrogen or fluorine.
Another preferred embodiment of the present invention relates to compounds of the formula ##STR4## wherein R.sup.1, R.sup.2, R.sup.3 and X are as defined above, and the
REFERENCES:
Hamada et al Tetrahedron Letters, No. 18, Apr. 1977, pp. 1519-1522.
Cattanach et al Jour. Chem. Soc. No. 10, 1973, 1041-1047.
Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 265 (14), Oct. 1967, pp. 758-761.
Wiseman et al Jour. Med. Chem., 16 (1), Jan. 1973, pp. 131-134.
Lombardino Joseph G.
McManus James M.
Mylari Banavara L.
Ford John M.
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc
Richardson Peter C.
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