Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1990-10-09
1992-07-14
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
548413, A61K 31675, C07F 9572
Patent
active
051303043
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutically acceptable salts, to method for producing said new compounds, to pharmaceutical compositions containing the new compounds, to dosage units of the compositions, and to methods of treating patients using said compositions and dosage units.
The present compounds have the formula I ##STR1## in which R.sub.1 -R.sub.8 can be the same or different and stand for hydrogen or a straight or branched aliphatic C.sub.1 -C.sub.10 hydrocarbon radical.
In addition, R.sub.3 when taken together with either R.sub.1 or R.sub.5 can form a saturated aliphatic 5-, 6- or 7-membered ring, which may be substituted with one or more C.sub.1 -C.sub.4 -alkyl radicals.
In particular, R.sub.1 -R.sub.8 stand for hydrogen or C.sub.1 -C.sub.4 -alkyl.
The invention comprises all possible stereoisomeric forms of compounds of formula I as well as mixtures thereof.
As stated above, the invention also relates to salts of the compounds of formula I which are tetrabasic acids and thus form mono-, di-, tri-, and tetrabasic salts with bases. As examples of salts formed with pharmaceutically acceptable, non-toxic bases, mention may be made of alkali metal salts and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, and calcium salts, as well as salts with ammonia and suitable non-toxic amines, such as lower alkylamines, e.g. triethylamine, lower alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cyclo-alkylamines, e.g. dicyclohexylamine, benzylamines, e.g. N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-.beta.-phenethylamine, N,N'-dibenzylethylenediamine or dibenzylamine, and heterocyclic amines, e.g. morpholine, N-ethylpiperidine and the like.
In addition to the above, in vivo easily hydrolyzable esters are also envisaged. Being tetrabasic acids, the compounds of formula I can form mono-, di-, tri-, or tetraesters.
Examples of such ester forming residues are alkanoyl-oxymethyl of three to six carbon atoms, 1-(alkanoyloxy)ethyl of four to seven carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl of five to eight carbon atoms, alkoxycarbonyloxy)ethyl of four to six carbon atoms, 1-(alkoxycarbonyloxymethyl of four to seven carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl of five to eight carbon atoms, 3-phthalidyl, 4-crotono-lactonyl, .gamma.-butyrolacton-4-yl, (2-oxo-1,3dioxolen-4-yl)-methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and (5-phenyl-2-oxo-1,3dioxolen-4-yl)methyl as well as dialkylaminoalkyl, acetonyl, and methoxymethyl.
A number of bisphosphonic acid derivatives are known for use within the present field. SU 1002300 describes the preparation of 1-hydroxy-3-(4'-morpholinyl)-propylidene-1,1-bisphosphonic acid and 1-hydroxy-3-(1'-piperidyl)-propylidene-1,1-bisphosphonic acid and mentions the possible use of these compounds as complex forming agents and in the preparation of drugs influencing calcium metabolism.
The normal bones are living tissues undergoing constant resorption and redeposition of calcium, with the net effect of maintenance of a constant mineral balance. The dual process is commonly called "bone turnover". In normal growing bones, the mineral deposition exceeds the mineral resorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition resulting in osteoporosis or in hypercalcemia, for instance due to malignancy or primary hyperparathyroidism. In other pathological conditions the calcium deposition may take place in undesirable amounts and areas leading to e.g. osteoarthritis, rheumatoid arthritis, kidney or bladder stones, atherosclerosis, and Paget's disease which is a combination of an abnormal high bone resorption followed by an abnormal calcium deposition.
The compounds of the present invention are able to increase bone mass by reducing bone resorption. The increase in bone mass is measured by the increase in tibia metaphyseal weight.
Experiments in rats have shown that the compounds of the present invention are surprisingly potent i
REFERENCES:
patent: 4871720 (1989-10-01), Jaeggi
March, J. Advanced Organic Chemistry Third Edition John Wiley and Sons, Inc., 1985, p. 689, 664-665.
Binderup Ernst T.
Liisberg Sven
Ambrose Michael G.
Lee Mary C.
Leo Pharmaceutical Products Ltd.
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