Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1991-09-06
1993-06-15
Lee, Mary C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544243, 546 22, 546 23, 546 24, 548101, 548111, C07D41302, C07D 928, C07F 906
Patent
active
052200213
DESCRIPTION:
BRIEF SUMMARY
1. Field of the Invention
The invention is geminal phosphonic acids, esters and salts which are useful as anti-arthritic agents.
2. Description of the Related Art
Russian Chemical Reviews 47, 803 (1978) disclose 1,3-dipolar cycloaddition to unsaturated organophosphorus compounds to form five member heterocycles which contain a phosphorus atom in a side-chain such as phosphinyl-.DELTA..sup.2 -pyrazolines, 5-phosphinyl-2-isoxazolines, isoxazolidines.
U.S. Pat. No. 4,746,654 discloses bisphosphonates useful as anti-inflammatory agents.
Australian Patent A-51534/85 discloses bisphosphonates useful in treating abnormal calcium and phosphorus metabolism and useful in treating arthritis.
U.S. Pat. No. 3,683,080 discloses polyphosphonates, in particular diphosphonates useful in inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue.
DE 3,719,513-A (Derwent 89-000580/01) discloses diphosphonic acid derivatives useful in treatment of disorders of calcium metabolism. while the generic formula for these compounds seems similar to those of the claimed invention, by their definition the compounds of the present invention are prohibited.
SUMMARY OF INVENTION
Disclosed is an unsaturated geminal phosphonate of formula (III) where
X.sub.1 is --O--, --NH-- or --N--metal where metal is sodium, potassium, calcium, magnesium, copper, zinc, barium, silver and gold;
R.sub.1 is --H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, -.phi. optionally substituted with 1 through 5 --F, --Cl, --Br, --I, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 cycloalkyl, C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 alkylthio;
R.sub.2-1 is --NO.sub.2, --CN, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, --Cl, --Br, --I, --NO.sub.2, --CN, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, --Br, --I, --NO.sub.2, --CN, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, --O-.phi., C.sub.1 -C.sub.4 alkylthio, --Cl, --Br, --I, --NO.sub.2, --CN, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, --Cl, --Br, --I, --NO.sub.2, --CN, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, --Br, --I, --NO.sub.2, --CN, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, --Br, --I, --NO.sub.2, --CN, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, different and are C.sub.1 -C.sub.4 alkyl, optionally substituted with 1 --CH.sub.3, R.sub.2-6 and R.sub.2-7 are taken together with the attached nitrogen atom to form a 4 through 8 member heterocyclic ring containing a nitrogen, oxygfen or sulfur heteroatom and 0 thru 3 double bonds,
R.sub.3 is --H, C.sub.1 -C.sub.6 alkyl, -.phi. and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The nitrogen containing dipoles (I) are either known to those skilled in the art or can readily be prepared from known compounds by known methods. For a review of the synthesis of dipoles (I) see, 1,3 Dipolar Cycloaddition Chemistry, edited by Albert Padwa, NY, Wiley, 1984. It is preferred that X.sub.1 is --NH--. With regard to R.sub.2 $-$1 it is preferred that R.sub.2-1 is --CO--R.sub.2-5 and --CH(OH)--R.sub.2-5. It is more preferred that R.sub.2-1 is --CO-.phi. optionally substituted with --F, --Cl, --Br, --I, --CN, --CF.sub.3, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkyl, --N(CH.sub.3).sub.2, --N(CH.sub.2 CH.sub.3).sub.2, morpholino, 1-, and 2-naphthalene, 2-thienyl, cyclopropyl and 2-, 3- and 4-pyridyl.
There are two preferred methods of preparing the nitrogen containing dipoles (I) when X.sub.1 is --NH--. One is treating acyl halides or anhydrides with an ethereal solution of diazomethane. Alte
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Khusainova, N. G., and Pudovik, A. N., Russian Chemical Reviews, 47(9):803-813 (1978).
Dunn Colin J.
Nugen Richard A.
Lee Mary C.
McKane Joseph K.
Stein Bruce
The Upjohn Company
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