Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1986-03-31
1988-03-22
Sutto, Anton H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
2605024P, C07F 938, C07F 940
Patent
active
047329980
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 is a straight or branched, saturated or unsaturated aliphatic or alicyclic C.sub.1 -C.sub.10 hydrocarbon radical, an aryl or an aryl-C.sub.1 -C.sub.4 -alkyl radical, R.sub.1 if desired being unsubstituted or substituted with straight or branched C.sub.1 -C.sub.4 -alkyl, amino, C.sub.1 -C.sub.4 -alkylamino, di-(C.sub.1 -C.sub.4 -alkyl)-amino, carboxy, C.sub.1 -C.sub.4 -alkyoxycarbonyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, phenoxy, mercapto, C.sub.1 -C.sub.4 -alkylthio, phenylthio, halogen, trifluoromethyl; R.sub.2 stands for hydrogen, C.sub.1 -C.sub.8 -alkyl, aryl-C.sub.1 -C.sub.4 -alkyl or halogen; X is O or S, and n is an integer from 0 to 2; with the proviso that R.sub.2 cannot be hydrogen or methyl if n=0 and R.sub.1 is methyl.
In particular, R.sub.1 stands for straight or branched C.sub.3 -C.sub.6 -alkyl, phenyl or benzyl optionally substituted with amino, hydroxy, methyl or halogen, and R.sub.2 for hydrogen, straight or branched C.sub.1 -C.sub.4 -alkyl, benzyl or halogen; preferably R.sub.1 is propyl, butyl, aminopropyl, aminobutyl, 2,2,2-trifluoroethyl, phenyl or tolyl, and R.sub.2 is hydrogen, methyl, ethyl or chlorine.
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, 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.
Being tetrabasic acids, the compounds of formula I can form mono-, di-, tri- or tetraesters. The esters of the present invention are in vitro easily hydrolyzable esters, the ester forming residue being selected from the group consisting of alkanoyloxymethyl 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, 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.
Especially preferred are alkanoyloxyalkyl and alkoxycarbonyloxy alkyl esters, such as pivaloyloxymethyl and ethoxycarbonyloxyethyl esters.
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. The calcium deposition may also take place in undesirable amounts and areas leading to other pathological conditions, e.g. osteoarthritis, rheumatoid arthritis, atherosclerosis, and Paget's
Leo Pharmaceutical Products Ltd.
Sutto Anton H.
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