Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1993-10-20
1995-08-01
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
556405, 558155, 558158, 558159, 558160, 558161, A61K 3166
Patent
active
054380480
DESCRIPTION:
BRIEF SUMMARY
This application was filed under 35 USC 371 and is based upon PCT International Application PCT/1J 91/00394 which was filed on Dec. 18, 1991.
The invention concerns novel methylenebisphosphonic acid derivatives, in particular novel alkyl or aminoalkyl substituted methylenebisphosphonic ester acids and ester salts, processes for the preparation of these novel compounds, as well as pharmaceutical compositions comprising these novel compounds.
Several publications disclose methylenebisphosphonic acids, their salts and some tetraesters, but there are only a few disclosures of corresponding partial esters, tri-, di- and monoesters.
The preparation of tetraesters of methylenebisphosphonic acids has been described in the publications: EP 0221 611; J. Am. Chem. Soc. 78, (1956) 4450; J. Chem. Soc. (1959) 2266 and 2272; J. Am. Chem. Soc. 84 (1962) 1876; J. Org. Chem. 35, (1970) 3149; J. Org. Chem. 36, (1971) 3843 and Phosphorus, Sulfur and Silicon 42, (1989) 73.
According to the invention it has been discovered that the novel partial esters of substituted methylenebisphosphonic acids and their salts in many cases exhibit more favourable properties than the corresponding bisphosphonic acids and salts due to their better kinetics and availability, their ability to participate as complex formers in the regulation of the metabolism of the organism being maintained.
They are well suited for the treatment of disorders relating to the metabolism of calcium and of other, especially bivalent metals. They may be used both for the treatment of diseases in the skeletal system, especially of bone formation and resorption disorders, such as of osteoporosis and Paget's disease, as well as for the treatment of diseases in the soft tissues, such as of deposition and mineralisation conditions and bone formation disorders.
On the other hand, being pyrophosphate analogs, the new substituted methylenebisphosphonic acid derivatives are also suitable for the treatment of disorders in the (pyro)phosphate functions of the organism, including the functions, wherein an active, but disturbance-prone or wrongly active organic part is attached to (pyro)phosphate or acts as a metal complex or a combination of the last mentioned.
The novel bisphosphonates regulate either directly or over an indirect mechanism the quality and level of cations and/or pyrophosphate compounds freely present in the body fluids as well as of that binding to, active in and liberated from the tissues. Thus they are able to regulate the cellular metabolism, growth and destruction. Consequently they are useful for the treatment of e.g. cancer of the bone and metastases thereof, ectopic calcifications, urolithiasis, rheumatoid arthritis, bone infections and bone degradation.
Typical for the novel substituted methylenebisphosphonates is a selective desired and controlled action, providing for a better therapeutic index.
The invention concerns novel methylenebisphosphonic acid derivatives of the general formula I ##STR2## in which formula R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently are straight or branched, optionally unsaturated C.sub.1 -C.sub.10 -alkyl, optionally unsaturated C.sub.3 -C.sub.10 -cycloalkyl, aryl, aralkyl, silyl SiR.sub.3 or hydrogen, whereby in the formula I at least one of the groups R.sup.1, R.sup.2 , R.sup.3 and R.sup.4 is hydrogen and at least one of the groups R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is different from hydrogen, is C.sub.1 -C.sub.4 -lower alkyl or acyl, -alkyl, -hydroxyalkyl or -aminoalkyl, whereby the oxygen may, as a substituent, contain one group or the nitrogen as a substituent may contain one or two groups, which are C.sub.1 -C.sub.4 -lower alkyl or acyl, or the two substituents of the nitrogen form together with the nitrogen atom a saturated, partly saturated or an aromatic heterocyclic ring, or Q.sup.2 is optionally substituted and optionally partly unsaturated C.sub.3 -C.sub.10 -cycloalkyl, which optionally is bound to the molecule over a straight or branched alkylene group containing 1-4 C-atoms, optically active isomers, of
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Hanhijarvi Hannu
Heikkila-Hoikka Marjaana
Lauren Leena
Nikander Hannu
Pohjala Esko
Ambrose Michael G.
Leiras Oy
Ramsuer Robert W.
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