Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-11-25
1993-04-27
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514364, 514365, 514370, 514372, 514374, 514377, 514378, 514380, 514383, 514381, 514398, 514399, 548112, A61K 3141, A61K 3142, A61K 31415, C07F 906
Patent
active
052062538
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns novel diphosphonic acid derivatives, processes for their production as well as pharmaceutical preparations which contain these substances.
Diphosphonic acid derivatives are described in DE-PS 18 13 659 of which 1-hydroxyethane-1,1-diphosphonic acid has gained importance as an agent for the treatment of Paget's disease.
1,1-diphosphonates are described in EP 274 158 whose alkyl chain is substituted by a piperidine ring and interrupted by a heteroatom.
In addition 1,1-diphosphonic acids are described in EP 186 405 whose alkyl chain is substituted by 6-membered heterocyclic rings and interrupted by a heteroatom.
It was found that alkane-1,1-diphosphonic acids substituted by 5-membered heterocyclic rings in which the alkyl chain is interrupted by oxygen show a substantially more pronounced effect on calcium metabolism than the previously known compounds. These substances are therefore particularly suitable for treating a wide range of disturbances in calcium metabolism. In particular they can be applied particularly effectively in cases where the build-up and break-down of bone is disturbed, i.e. they are suitable for the treatment of diseases of the skeletal system such as e.g. osteoporosis, Paget's disease, Bechterew's disease among others. On the basis of these properties they can, however, also be used in the treatment of bone metastases, urolithiasis and for the prevention of heterotopic ossifications. Since they influence calcium metabolism they in addition form a basis for the treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.
The present invention thus provides diphosphonates having the general formula I ##STR2## in which Het is selected from the group consisting of a pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, dithiazolyl and tetrazolyl ring as well as their dihydro and tetrahydro derivatives, which ring can be partially hydrogenated and is unsubstituted or substituted at least once by C.sub.1 -C.sub.6 alkyl, halogen, amino or CF.sub.3, C.sub.1 -C.sub.5 alkyl, and R.sub.9 should each be, independently of each other, hydrogen or C.sub.1 -C.sub.5 alkyl,
In this connection Het is understood as a ring such as the pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiazole, 1,2,4-triazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-dithiazole, 1,3,4-dithiazole, 1,2,4-dithiazole and tetrazole ring as well as their hydrogenated or partially hydrogenated derivatives such as for example dihydro and tetrahydro derivatives.
In this connection the pyrazole, imidazole, thiazole and 1,2,5-thiadiazole ring and in particular the imidazole and 4,5-dihydroimidazole ring are preferred.
The heterocylic rings can, if desired, be substituted once or twice by C.sub.1 -C.sub.6 alkyl groups, preferably a methyl, ethyl or isopropyl group, as well as by halogen, the amino or CF.sub.3 group.
Halogen is understood as fluorine, chlorine or bromine.
C.sub.1 -C.sub.5 alkyl should preferably represent a methyl, ethyl or isopropyl group. The group --NR.sub.8 R.sub.9 is preferably an amino, dimethylamino or diethylamino group.
X preferably represents hydrogen or hydroxy, the value of n is preferably 0.
Asymmetric carbon atoms can be in the R or S configuration and the compounds can be present in an optically active form or as a racemic mixture. They are also provided by the present invention. The enantiomeric derivatives can be obtained by using optically pure precursors.
Compounds having the general formula I are prepared by well-known methods, preferably by
a) a carboxylic acid having the general formula II ##STR3## in which Het, R.sub.1 -R.sub.6, m and n have the meanings set forth above, is reacted with a mixture of phosphorous acid or phosphoric acid and a phosphorus halide or phosphoroxyhalide and subsequently saponified to form the free diphosphonic acid, or
b) a carboxylic acid ch
REFERENCES:
CA 99(25)212705c Antiinflammatory and antiarthritic pyrazolylethane phosphonates, Biere et al., p. 662, 1983.
CA 114(25)164505s Preparation of . . . regulators, Bosies et al. p. 806, 1991.
Bauss Frieder
Bosies Elmar
Boehringer Mannheim GmbH
Lee Mary C.
McKane Joseph K.
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