Bisphosphonic acid derivatives, their production and use

Details Bisphosphonic acid derivatives, their production and use Bisphosphonic acid derivatives, their production and use

1987-08-10

1989-09-26

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

544 57, 540467, 540544, C07D27912, C07F 965, A61K 3167, A61K 3154

Patent

active

048700630

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutically acceptable salts and easily hydrolyzable esters thereof, to methods 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 ##STR2## in which R.sub.1 -R.sub.11 can be the same or different and stand for hydrogen, a straight or branched aliphatic or alicyclic C.sub.1 -C.sub.10 hydrocarbon radical, an aryl or an aryl-C.sub.1 -C.sub.4 -alkyl radical; n is zero or one, and m is zero, one or two.
In addition R.sub.2 and R.sub.4 when taken together 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.11 stand for hydrogen, C.sub.1 -C.sub.5 -alkyl, or phenyl.
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 acids and thus form 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, 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, cycloalkylamines, 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.
The esters of the present compounds are in vivo easily hydrolyzable. Examples of such ester forming residues are alkanoyloxymethyl of three to six carbon atoms, 1-(alkanoyloxy)ethyl of four to severn carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl of five to eight carbon atoms, alkoxycarbonyloxymethyl of three to six carbon atoms, 1-(alkoxycarbonyloxy)ethyl of four to seven carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl of five to eight carbon atoms, 3-phthalidyl, 4-crotonolactonyl, .gamma.-butyrolacton-4-yl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl as well as dialkylaminoalkyl, acetonyl, and methoxymethyl.
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 e.g. hypercalcemia, for instance due to malignancy or primary hyperparathyroidism, or in osteoporosis. 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.
Most of the currently available therapeutic agents for the treatment of osteoporosis, e.g. estrogens and calcitonin, act by reducing bone resorption in the osteoporotic patient. Since bone fracture is a severe problem in osteoporosis, the ideal therapeutic agent should be able to increase bone mass to a level which exceeds the fracture threshold.
Experiments in rats have shown that the compounds of the present invention like known bisphosphonates (e.g. 1-hydroxyethylidene-1,1-bisphosphonic acid (etidronate) and 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (APD)) reduce bone resorption as shown by their inhibition of the urinary excretion of hydroxyproline, but in contrast

REFERENCES:
patent: 4264768 (1981-04-01), Quinlan
patent: 4311663 (1982-01-01), Quinlan

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