Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-12-06
1999-02-02
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
546 22, 546 24, C07F 958, A61K 31675
Patent
active
058665560
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE
This application is a 371 of PCT/FI 95/00315 filed Jun. 2, 1995.
The present invention relates to a specific group of pyridylbisphosphonic acid tetraesters for use as a therapeutical agent, in particular for use in bone diseases.
Bisphosphonates are therapeutic agents for the treatment of pathological bone destruction of various origins, such as osteolytic bone diseases due to malignancy, Paget's disease, and osteoporosis. They are analogues of the physiologically occurring inorganic pyrophosphates. The basic P-C-P structure of the bisphosphonates makes it possible to form a great number of different compounds either by changing the side chains of the carbon atom or by an addition onto the phosphates.
In general, bisphosphonates inhibit osteoclasts, cells, which are responsible for the bone resorption. Known bisphosphonates bound to the bone matrix enter resorbing osteoclasts and reduce the activity of osteoclasts. They inhibit bone resorption both in vitro and in vivo. Limited absorption from the gastrointestinal tract, fast disappearance in bone tissue, and unchanged excretion in urine are all characteristics of known bisphosphonates.
The present innovation is based on the idea of providing bisphosphonate derivatives with high oral bioavailability and with low affinity to bone. This is to avoid side-effect without loosing the antiresorptive activity.
In the patents U.S. Pat. No. 4,447,256, DE 28 31 578 (Suzuld et al.); JP 55089210, JP 55098105, JP 55043054, JP 55043055 (Nissan Chemical industries) a process is disclosed for the preparation of some pyridinylaminomethylenebisphosphonic acid tetraalkylesters. According to the patents the compounds may be used as herbicides.
In the patent EP 337 706 (Isomura et al.) the preparation of cyclyl- or heterocyclyl substituted aminomethylenebisphosphonic acid tetraesters is disclosed, wherein the ring substituent is either partly or fully saturated. The tetraesters were not tested.
In the patent U.S. Pat. No. 4,973,576 (Sakamoto et al.) some isox- azolyl substituted aminomethylenebisphosphonic acid tetraalkylesters are disclosed, but they have basicly been tested in arthritis. Their oral bioavailability is low.
In the patent EP 282 309 azole-aminomethylenebisphosphonic acids and lower alkyl esters are disclosed. The tetraesters were not tested.
In the patent EP 325 482 cycloalkyl-aminomethylenebisphosphonic acids and esters are disclosed. The tetraesters were not tested.
The present invention is directed at a group of pyridinylbisphosphonates with new pharmacological and pharmacokinetic profiles. These new pyridinylbisphosphonates do not inhibit bone resorption in vitro but they inhibit bone resorption in vivo.
Pyridylbisphosphonates do not bind to bone matrix and they seem to need metabolic activation.
The invention thus concerns pyridyl-aminomethylenebisphosphonic acid tetraalkylesters, which are optionally substituted at the pyridine ring, specifically methylenebisphosphonic acid derivatives of the general formula I ##STR1##
in which formula
each of the groups R.sub.1 to R.sub.4 is straight or branched saturated C.sub.1 -C.sub.5 -alkyl group, each of X and Y is independently hydrogen, straight or branched saturated C.sub.1 -C.sub.5 -alkyl group, halogen, hydroxyl, C.sub.1 -C.sub.5 -alkoxy, benzyloxy, acyloxy, nitro, trifluoromethyl group or NR.sub.5 R.sub.6, wherein R.sub.5 and R.sub.6 are the same or different and are hydrogen, C.sub.1 -C.sub.5 -allyl or -acyl, for use as therapeutically active agents.
The groups X and Y, as well as the amino group of the methylenebisphosphonic acid ester frame can substitute any one of the positions 2 to 6 of the pyridyl ring. The groups X and Y are preferably hydrogen or hydroxyl groups, in the latter meaning one or two hydroxyl groups being preferred. The pyridinyl group is preferably a 2-pyridinyl group.
Halogen is fluorine, chlorine, bromine or iodine.
The C.sub.1 -C.sub.5 -alkyl group is straight or branched, such as methyl, ethyl, n-, i-propyl, n-, i- and t-butyl, or -pentyl, preferably methyl or ethyl.
REFERENCES:
patent: 4447256 (1984-05-01), Suzuki et al.
patent: 4973576 (1990-11-01), Sakamoto et al.
Chemical Abstracts, Vol. 101(21),abst.192,195r,Nov. 19,1984.
Chemical Abstracts, vol.105,(26),abst.No.232,453q,Dec. 29,1986.
Chemical Abstracts, vol.106(12),abst.No.90180t,Mar. 23, 1987.
Chemical Abstracts, vol.109(25),abst.No.222,488y,Dec. 19, 1988.
Chemical Abstracts,Vol.117(25),abst.No.251,556-q,Dec. 21, 1992.
Hannuniemi Ritva
Heikkila-Hoikka Marjaana
Kleimola Terttu
Lauren Leena
Liukko-Sipi Sirpa
Leiras Oy
Rotman Alan L.
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