Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-12-22
1989-05-09
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544 49, C07D27902, C07D40112, C07D41712, A61K 3154
Patent
active
048290629
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to new and useful benzothiazine dioxide derivatives. More particularly, it is concerned with certain novel enol oxyalkyl ether derivatives of 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and several other closely-related oxicams, which are of especial value as prodrugs in view of their chemotherapeutic properties.
BACKGROUND ART
In the past, various attempts have been made to obtain new and better anti-inflammatory agents. For the most part, these efforts have involved the synthesis and testing of various steroidal compounds such as the corticosteroids or non-steroidal substances of an acidic nature such as phenylbutazone, indomethacin and the like, including a new agent known as piroxicam. The latter substance is a member of a class of anti-inflammatory/analgesic N-heteroaryl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides (known as oxicams) described and claimed in U.S. Pat. No. 3,591,584 and is specifically, 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide. Other agents of this type are disclosed in U.S. Pat. Nos. 3,787,324, 3,822,258, 4,180,662 and 4,376,768, as well as in German Offenlegungschrift No. 2,756,113 and Published European patent application No. 138,223. In U.S. Pat. No. 4,434,164, there are specifically described and claimed the ethylenediamine, monoethanolamine and diethanolamine salts of 4-hydroxy- 2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, which are particularly valuable in pharmaceutical dosage forms as non-steroidal therapeutic agents for the treatment of painful inflammatory conditions, such as those caused by rheumatoid arthritis, since they are all crystalline, nonhygroscopic, rapidly-dissolving solids with high water solubility. In U.S. Pat. No. 4,309,427, there are disclosed certain novel acyl derivatives (i.e., enol esters) of 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 4-hydroxy-2-methyl-N-(6-methyl-2-pyridinyl)-2H-1,2-benzothiazine-3-carboxa mide 1,1-dioxide, which are useful as nonsteroidal therapeutic agents for alleviating various inflammatory conditions, including those of the skin, especially when given by the topical route of administration. However, in the continuing search for still more improved anti-inflammatory/analgesic agents, there is a need for anti-arthritic agents that are orally administrable and yet at the same time are less ulcerogenic than the parent oxicam compounds of the prior art.
In this connection, it is to be noted that while the prior described enolic oxicam lower alkyl ethers of U.S. Pat. No. 3,892,740 do not possess anti-inflammatory activity to any substantial degree, the more recently described anti-inflammatory oxyalkyl ethers of the enolic oxicams of U.S. Pat. No. 4,551,452 all require that the oxyalkyl moiety be restricted to --CH.sub.2 --O--, --CH(CH.sub.3)--O-- or --CH(C.sub.6 H.sub.5)--O--. As a result, there is little or no information available about the effect of other oxyalkyl ethers in this area and particularly, about compounds like the corresponding enolic oxicam lower oxyalkyl ethers wherein the alkyl moiety is exclusively arranged in a straight chain.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, it has now been found that certain novel enol straight-chain oxyalkyl ether derivatives of 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and several other closely-related known oxicams are useful in therapy as prodrug forms of the known anti-inflammatory and analgesic oxicams. Consequently, the compounds of this invention are useful in therapy as non-steroidal therapeutic agents for alleviating painful inflammatory conditions such as those caused by rheumatoid arthritis, for example. The novel compounds of this invention are of the formula: ##STR1## wherein R.sub.1 is 2-pyridyl, 6-methyl-2-pyridyl, 6-fluoro-2-pyridyl, 6-chloro-2-pyridyl, 5-methyl-3-isoxazolyl, 2-thiazolyl, 5-
REFERENCES:
patent: 3591584 (1971-07-01), Lombardino
patent: 3787324 (1974-01-01), Zinnes et al.
patent: 3822258 (1984-07-01), Zinnes et al.
patent: 3892740 (1975-07-01), Lombardino
patent: 4309427 (1981-01-01), Lombardino
patent: 4551452 (1985-11-01), Marfat
J. G. Lombardino et al., "Potent Antiinflammatory N-Heterocyclic 3-Carboxamides of 4-Hydroxy-2-methyl-2H-1, 2-benzothiazine 1,1-Dioxide", Journal of Medicinal Chemistry, vol. 16, No. 5, p. 493 (1973).
Lombardino Joseph G.
Marfat Anthony
Akers Lawrence C.
Ford John M.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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