Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1991-05-06
1992-10-06
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514107, 558155, 558161, 562 21, A61K 31685, A61K 3166, C07F 940, C07F 938
Patent
active
051531836
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a methylenediphosphonic acid compound which is useful as a drug for anti-inflammation and anti-rheumatism.
BACKGROUND ART
Japanese patent application laid-open (kokai) No. SHO 59-42395 discloses a compound similar to the compound of formula (1) according to the present invention, provided X is S and R.sup.2 is a non-substituted phenyl group or phenyl group having one or more halogens, nitro group, lower alkyl group, lower alkoxy group, trifluoromethyl, amino group, carboxyl group or alkoxycarbonyl group. However, such compound is not considered to be satisfactory in the effect of anti-inflammation. Also, other compounds of the diphosphonic acid structure are known for anti-inflammation and anti-arthritis by, for example, Japanese Patent Application laid-open (kokai) Nos. SHO 58-174395 and 58-174394. Further, Japanese Patent Application laid-open (kokai) No. SHO 60-174792 reports that 1-substituted amino-1-substituted thioalkyl methylenediphosphonic acid is effective as a anti- rheumatic drug. Still further, clinical demonstrations have been made with disodium (1-hydroxyethylidene)bis-phosphonate as an agent for treatment of osteoporosis. Thus, the compounds of the methylenediphosphonic acid structure have been examined variously as a drug for anti-inflammation or for the treatment of disturbances in calcium metabolism, but further improvement is desired.
On the other hand, inhibitors of cycloxygenase and/or lipoxygenase have been extensively investigated as a new non-steroidal anti-inflammatory drug. In particular, special attention is given to the 2,6-di-tert-butylphenol structure as a dual inhibitor or 5-lipoxygenase inhibitor. For example, there are disclosed 3-(3,5-di-(tert-butyl)-4-hydroxybenzylidene-1-methoxypyrolidine-2-one, etc. in Japanese patent application laid-open Nos. SHO 61-257967, 63-115859 and 63-115960; 3,5-di-tertiary butyl-4-hydroxycinnamamides in Japanese patent application laid-open No. SHO 63-130570; 3,5-di-tert-butyl-4-hydroxystyrene derivatives in Japanese patent application laid-open (kokai) No. SHO 63-24498; 3,5-di-tert-butyl-4-hydroxyphenyl thioether as a substituted phenolic thioether in Japanese patent application laid-open (kokai) No. SHO 63-310821; and 3-(3,5-bis(tert-butyl)-4-hydroxyphenylthio-propanylpyrrolidine in Japanese patent Application laid-open (kokai) No. SHO 63-310820. But, they are weak in anti-inflammatory effect or have no effect in vivo and are thus scarcely in the level of practical application.
The inventors noted the inhibitors of 5-lipoxygenase in the arachidonate cascade for developing a non-steroidal anti-inflammatory drug and, at the same time, investigated diphosphonic acid as an agent for treatment of disturbances in bone metabolism, and thus found that with an anti-oxidation structure attached to diphosphonic acid, there was produced an effect not found in the conventional drugs for inflammation accompanying disturbances in bone metabolism.
The object of the present invention is to provide a novel compound which is useful as a drug having an excellent anti-inflammatory effect.
Disclosure of the Invention
This invention relates to a methylenediphosphonic acid compound expressed by the formula ##STR2## (in the formula, R.sup.1 representing a pharmacologically allowable cation, hydrogen or a straight or branched alkyl group comprising from 1 to 4 carbon atoms, R.sup.1' s in the formula being the same or different; X representing CH.sub.2 or S(CH.sub.2).sub.n (n being 0-4); and R.sup.2 representing ##STR3## (R.sup.3 representing a straight or branched alkyl group comprising from 1 to 6 carbon atoms; and R.sup.4 representing a straight or branched alkyl group of comprising of 1 to 4 carbon atoms (R.sup.3 and R.sup.4 may be the same or different))), manufacturing method of said compound and an anti-inflammatory agent containing said compound as an effective component.
Best Mode for Carring Out the Invention
Where R.sup.1 is a pharmacologically allowable cation, it may be a metallic cation, ammonium, amin
REFERENCES:
patent: 5043330 (1991-08-01), Nguyen et al.
Kawabe Norio
Matsumoto Shu
Takanishi Keijiro
Ambrose Michael G.
Lee Mary C.
Miller Austin R.
Toray Industries Inc.
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