Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-09-13
1993-06-08
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544 95, 544 96, C07D41300, A61K 31535
Patent
active
052179680
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to pro-drugs of certain 3-hydroxybenzothiophenes which have a 2-enamido side chain. More particularly it relates to cyclic pro-drugs of N-alkenyl-3-hydroxybenzo[b]thiophene-3-carboxamides which exhibit cyclooxygenase and 5-lipoxygenase inhibitory action, pharmaceutical compositions thereof, and the use thereof to treat various mammalian diseases.
U.S. Pat. No. 4,760,086, issued Jul. 26, 1988, describes a large number of N-alkenyl-3-hydroxybenzo[b]-thiophene-3-carboxamides of formula (I) ##STR1## wherein each of X.sub.1 -X.sub.4, R and R.sup.1 -R.sup.4 are broadly defined as lower alkyl, aryl, heteroaryl, lower cycloalkyl, benzyl, lower alkenyl or lower alkynyl any of which may be substituted by a variety of substituents.
Said compounds are disclosed to be effective inhibitors of cyclooxygenase and 5-lipoxygenase and, therefore, of value in the treatment of inflammation, pain, fever and other prostaglandin and/or leukatriene mediated diseases.
U.S. Pat. No. 4,656,265, issued Apr. 7, 1987, describes cyclic pro-drugs of non-steroidal anti-inflammatory oxicams. In said pro-drugs, the parent oxicams are chemically modified to form a fused 1,3-oxazine ring system, which, in vivo, is cleaved to restore the parent compound.
SUMMARY OF THE INVENTION
This invention provides compounds of formula (II) below ##STR2## wherein X is hydrogen, trifluoromethyl, fluoro, chloro, lower alkyl, lower alkoxy, lower alkylthio, phenyl or 2,4-difluorophenyl;
each of R.sup.1 and R.sup.2 is hydrogen, phenyl, substituted phenyl wherein the substituent is chloro, fluoro, lower alkyl, lower alkoxy, lower alkylthio or hydroxy; furyl, thienyl, substituted thienyl wherein the substituent is lower alkyl, chloro or fluoro; lower alkyl, chloro, lower alkoxycarbonyl; furyl or pyrryl, which compounds are cyclic pro-drugs of compounds of formula (I) above wherein each of R, R.sup.1 and R.sup.4 is hydrogen.
The substituents (R.sup.1 and R.sup.2) on the double bond can be syn, anti or a mixture of both. Thus, in formula (II), substituents R.sup.1 and R.sup.2 are indicated as being attached to the double bond by wavy lines. This representation is intended to depict all forms of the isomers of formula (II) compounds. The individual isomers of formula (II) compounds can be prepared by starting with the appropriate isomer of the requisite formula (I) reactant. Alternatively, the isomers can be separated from a mixture thereof by known methods such as chromatography.
Formula (II) compounds, unlike the parent compounds of formula (I), are not enolic acids and, therefore, show less gastric irritation than do the parent compounds. Following their administration to a mammal, including a human, formula (II) compounds release the parent compound by some metabolic process.
Also included in this invention are pharmaceutical compositions suitable for administration to a mammal, including a human, said compositions comprising a pharmaceutically acceptable carrier and a cyclooxygenase and/or 5-lipoxygenase inhibiting amount of a compound of formula (II); and a method of treating diseases arising from biological mediators formed by cyclooxygenase and/or 5-lipoxygenase catalyzed reactions in a mammalian body which comprises administering to a mammal in need of such treatment a cyclooxygenase and/or 5-lipoxygenase inhibiting amount of a compound of formula (II).
DETAILED DESCRIPTION OF THE INVENTION
Compounds of formula (II) are prepared by reacting a compound of formula (I) wherein each of R, R.sup.1 and R.sup.4 is hydrogen with phosgene as cyclizing agent in a reaction-inert solvent in the presence of an acid binding agent at a temperature of -70.degree. C. to +50.degree. C.
Suitable reaction-inert solvents, i.e., solvents which do not react with reactants or products in such a manner as to reduce yield of the desired product, are halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers such as ethyl or isopropyl ether, dioxane and tetrahydrofuran;
REFERENCES:
patent: 3925386 (1975-12-01), Jager et al.
patent: 4656265 (1987-04-01), Lombardino et al.
patent: 4760086 (1988-07-01), Tischler et al.
Chem. Abst. vol. 106 No. 13 p. 42 95809q (1987).
Fedowich Valerie M.
Ginsburg Paul H.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
LandOfFree
N-alkylbenzo(b)thieno [3,2-b]oxazin-2,4-diones does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N-alkylbenzo(b)thieno [3,2-b]oxazin-2,4-diones, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-alkylbenzo(b)thieno [3,2-b]oxazin-2,4-diones will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1934204