Methylenebisphosphonic acid derivatives

Details Methylenebisphosphonic acid derivatives Methylenebisphosphonic acid derivatives

1993-10-20

1995-02-28

Tsang, Cecilia

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514 86, 514107, 544243, 546 21, 558162, A61K 31675, A61K 31665, C07F 902, C07F 906

Patent

active

053937481

DESCRIPTION:

BRIEF SUMMARY
The invention concerns novel methylenebisphosphonic acid derivatives substituted at the methylene carbon, in particular novel bisphosphonic ester acids and ester salts substituted at the methylene carbon, as well as processes for the preparation of these novel compounds, and pharmaceutical formulations comprising these novel compounds.
Several publications disclose methylenebisphosphonic acids, their salts or some tetraesters, but there are only a few disclosures of corresponding partial esters, tri-, di- and monoesters.
In the patents U.S. Pat. No. 4,447,256 and DE 28 31 578 (Suzuki et al.) a process is disclosed for the preparation of some pyridyl aminomethylenebisphosphonic acid tetraethyl esters. According to the patents the compounds may be used as herbicides, however, no disclosure is found of a pharmaceutical effect of the compounds.
In the patent EP 337 706 (Isomura et al.) the preparation of such cyclyl- or heterocyclyl substituted aminomethylenebisphosphonic acid tetraesters is disclosed, wherein the ring substituent is either partly or fully saturated.
In the patent EP 282 320 (Sakamoto et el.) the preparation of some isoxazolyl substituted aminomethylenebisphosphonic acid tetraalkyl esters as well as the preparation of two partial esters is disclosed.
In the patent EP 298 553 (F. H. Ebetino) the preparation of methylenephosphonoalkyl phosphinates, substituted at the methylene carbon, is disclosed.
The preparation of tetraesters of methylenebisphosphonic acids has been described also in the publications: J. Am. Chem. Soc. 78, (1956) 4450; J. Chem. Soc. (1959) 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, EP patent application 221 611.
According to the invention it has been discovered that the novel substituted partial esters of 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 also are suitable for the treatment of disorders in the (pyro)phosphate functions of the organism, including those functions, wherein an active, but disturbance-prone or wrongly functioning organic part is coupled 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 ##STR1## in which formula R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently are a 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

REFERENCES:
patent: 3303139 (1967-02-01), Blaser et al.
patent: 3957858 (1976-05-01), Kerst
patent: 3962318 (1976-06-01), Kerst
patent: 4447256 (1984-05-01), Suzuki et al.
patent: 4870063 (1989-09-01), Binderup et al.
patent: 4973576 (1990-11-01), Sakamoto et al.
Chem. Abstracts, vol. 111, No. 19, 6 (Nov. 1989), p. 748, abstract 174388h and JP,A,63295595 (Yamanouchi Pharmaceutical Co. Dec. 1, 1988).
Chem. Abstracts, vol. 92, No. 7, 18 (Feb. 1980) p. 27, abstract 51765k and Probl. Gematol. Perelir. Kvori, 1979, 24(8), 14-17 (Russ).

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