Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Patent
1993-10-20
1995-08-15
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
544157, 546 21, 558155, 558157, C07F 944, A61K 3166
Patent
active
054421012
DESCRIPTION:
BRIEF SUMMARY
This is a 35 U.S.C. of PCT/FI91/00396, filed Dec. 18, 1991, now WO92/11268.
This invention concerns novel methylenebisphosphonic acid derivatives, in particular novel halogen substituted methylenebisphosphonic acid amides and ester amides, 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, partial amides and partial ester amides.
The preparation of tetraesters of methylenebisphosphonic acids has been described in the publications: J. Am. Chem. Soc. 78, (1956) 4450; J. Chem. Soc. (1959) 2272; J. 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.
In the EP-patent application 356 866 optionally halogen substituted methylenebisphosphonic acid esters and amide esters are described, which have a cholesterol biosynthesis inhibiting activity.
According to the invention it has been discovered that the novel partial amides and partial ester amides 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 are also 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 W.sup.1, W.sup.2, W.sup.3 and W.sup.4 are independently the group OR.sup.1 or the group NR.sup.2 R.sup.3 wherein R.sup.1, R.sup.2 and R.sup.3 independently are hydrogen or straight or branched, optionally unsaturated C.sub.1 -C.sub.22 -alkyl, optionally substituted, optionally unsaturated C.sub.3 -C.sub.10 -cycloalkyl, aryl, aralkyl or silyl SiR.sub.3, or the groups R.sup.2 and R.sup.3 form together with the adjacent nitrogen atom a 3 to 10-membered saturated, partly saturated or aromatic heterocyclic ring, wherein in addition to the nitrogen atom, there may be one or two heteroatoms from the group N, O and S, provided that in the formula I at least one of the groups W.sup.1, W.sup.2, W.sup.3 and W.sup.4 is hydroxy and at least one of the groups W.sup.1, W.sup.2, W.sup.3 and W.sup.4 is the amino group NR.sup.2 R.sup.3 ,
Q.sup.1 and Q.sup.2 are independently hydrogen, fluorine, chlorine, bromine or iodine, including
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Chem. Abstracts, vol. 92, No. 7, 18 (Feb. 1980) p. 27, abstract 51765k.
Hanhijarvi Hannu
Nupponen Heikki
Pohjala Esko
Vepsalainen Jouko
Dees Jos,e G.
Frazier B.
Leiras Oy
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