Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1992-02-03
1994-12-27
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
558155, 558161, A61K 3166, C07F 940
Patent
active
053766490
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention concerns novel methylenebisphosphonic acid derivatives, in particular novel halogen substituted methylenebisphosphonic ester acids and ester salts, as well as processes for the preparation of these novel compounds and pharmaceutical compositions comprising such novel compounds.
Several publications disclose methylenebisphosphonic acids, their salts or some tetraesters, but there are only a few disclosures of corresponding halogen substituted tri-, di- and monoesters (partial esters). The U.S. Pat. No. 4,478,763 (1984) discloses a new process for the preparation of unsymmetrical isopropyl esters of (mono- and difluoromethylene)bisphosphonic acids. As further publications disclosing fluorine substituted compounds, the following may be mentioned: J. Org. Chem., 51, (1986), 4788, J. Am. Chem. Soc., (1987) 5542, and Bioorg. Chem., (1988) 111. Thus neither the properties of the novel partial esters of (halogenmethylene)bisphosphonic acids and their salts according to the invention, nor their use as medicaments, have been investigated.
SUMMARY OF THE INVENTION
According to the invention it has now been discovered that the novel partial esters of methylenebisphosphonic acids and their salts in many cases exhibit more favourable properties than the corresponding bisphosphonic acids and their salts due to their better kinetics and availability and, their ability to participate as complex formers in the regulation of the metabolism of the organism being maintained.
In addition 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 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 mineralization conditions and bone formation disorders.
DETAILED DESCRIPTION
The novel bisphosphonates regulate either directly or by an indirect mechanism the level of cations freely present in the body fluids, as well as the level of cations 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.
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 C.sub.1 -C.sub.22 -alkyl, C.sub.2 -C.sub.22 -alkenyl, C.sub.2 -C.sub.22 -alkynyl, C.sub.3 -C.sub.10 -cycloalkyl, C.sub.3 -C.sub.10 -cycloalkenyl, aryl, aralkyl, silyl 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, Q.sup.1 is hydrogen, fluorine, chlorine, bromine or iodine, and Q.sup.2 is chlorine, bromine or iodine, including the stereoisomers, such as the geometrical isomers and the optically active isomers, of the compounds, as well as the pharmaceutically acceptable salts of the compounds.
C.sub.1 -C.sub.22 -alkyl is straight or branched, preferably lower alkyl with 1 to 7 C-atoms, preferably 1 to 4 C-atoms, such as methyl, ethyl, propyl, isopropyl, or butyl, i-butyl, s-butyl or t-butyl, or pentyl, hexyl or heptyl, whereby preferably at least two, but more preferably three of the groups R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen or it is C.sub.8 -C.sub.22 -alkyl, whereby preferably at least two, but more preferably three of the groups R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen. Long chain is preferably a straight or branched C.sub.14 -C.sub.18 -alkyl group.
C.sub.2 -C.sub.22 -alkenyl may also be straight or branched, and is preferably lower alkenyl with 2 to 7 C-atoms, preferably 2 to 4 C-atoms, a
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Organic Phosphorus Compounds; Kosolapoff, G. M. et al. Eds.; vol. 7; Wiley-Interscience: New York, 1976; pp. 9-10.
Chem. Abstracts, vol. 111, No. 19, 6 (Nov. 1989), p. 748, abstract 174388h and JP,A,63295595 (Yamanouchi Pharmaceutical Co., Dec. 1, 1988).
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Nupponen Keikki
Pohjala Esko
Vepsalainen Jouko
Ambrose Michael G.
Lee Mary C.
Leiras Oy
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