Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-06-28
1995-05-23
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544 34, C07D51304, A61K 3154
Patent
active
054182310
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US 91/09161, filed Dec. 16, 1991.
TECHNICAL FIELD
This invention relates to novel pyrimido-benzothiazine derivative compounds. The compounds of the present invention inhibit the action of the lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds.
BACKGROUND ART
Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids via the action of phospholipase. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Compounds that inhibit lipoxygenase are expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Recently, several review articles on lipoxygenase inhibitors have been reported. See H. Masamune and L. S. Melvin, Sr., in: Annual Reports in Medicinal Chemistry 24 (1989) pp. 71-80 (Academic); and B. J. Fitzsimmons and J. Rokach in: Leukotrienes and Lipoxygenases (1989) pp. 427-502 (Elsevier).
Offenlegungsschrift 1695595 discloses certain pyrimido-benzothiazines which are useful for blocking phosphodiesterases. Sakamuki, M. et al. and Sako, M. et al. both in 12th Symposium on Progress in Organic Reactions and Syntheses, Symposium Papers, Nov. 8-9, 1985, Nagoya, pp. 186-189 and p. 190; and Sako, M. et al., Chem. Pharm. Bull., 32, pp. 2474-2476 (1984), disclose the syntheses of certain pyrimido-benzothiazines.
Certain derivatives of phenothiazine of the general formula ##STR2## wherein X is, inter alia, S, SO or SO.sub.2 ; R.sup.1 is, inter alia, H or (C.sub.1 -C.sub.6)alkyl; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are inter alia, independently H, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl or --(CH.sub.2).sub.n M where n is 0-6 and M is halogen or various groups and T is H or OR.sup.15 where R.sup.15 is H or various groups are disclosed in EP 138481, published Apr. 24, 1985 and corresponding to JP 60155165, as leukotriene biosynthesis inhibitors useful in treating allergic conditions, asthma, cardiovascular disorders, inflammation and certain skin diseases.
DISCLOSURE OF THE INVENTION
The present invention provides pyrimido-benzothiazine derivative compounds of the following formulae: ##STR3## and the pharmaceutically-acceptable salts thereof, wherein R.sup.1 is hydrogen or (C.sub.1 -C.sub.6)alkyl; R.sup.2 is hydrogen, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or (C.sub.1 -C.sub.6)halosubstituted alkyl; R.sup.3 is hydrogen or (C.sub.1 -C.sub.6)alkyl; R.sup.4 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.1 -C.sub.6)alkoxy-(C.sub.1 -C.sub.6)alkyl or aryl-(C.sub.1 -C.sub.6)alkyl; provided that in formula (I), R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are not simultaneously hydrogen, R.sup.2, R.sup.3 and R.sup.4 are not simultaneously hydrogen when R.sup.1 and R.sup.4 are respectively methyl; provided further that in formula (II), R.sup.1, R.sup.2 and R.sup.3 are not simultaneously hydrogen and R.sup.2 and R.sup.3 are not simultaneously hydrogen when R.sup.1 is methyl; and provided further still that the groups R.sup.2 and R.sup.3 may be attached to any available position on the ring in formula (I) or (II).
A preferred group of compounds comprises compounds of formula (I) wherein R.sup.1 is (C.sub.1 -C.sub.6)alkyl. Also preferred are compounds of formula (I) wherein R.sup.1 is methyl and R.sup.2 is halogen, (C.s
REFERENCES:
patent: 3483198 (1969-12-01), Goldman
patent: 4845083 (1989-04-01), Fortin et al.
Shimada et al., Chemical Abstracts, vol. 117, entry 234028b (1992).
M. Sako et. al., 12th Symposium on Progress in Organic Reactions and Syntheses, 1985.
M. Sako et. al., Chem. Pharm. Bull., 32(6) 2474-2476 (1984).
T. Hiramatsu et. al., J. C. S. Chem. Comm., 1977, 557-558.
Shimada Kaoru
Shishido Yuji
Benson Gregg C.
Brokke Mervin E.
Ford John M.
Pfizer Inc.
Richardson Peter C.
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