Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1997-10-10
1999-03-23
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514102, A61K 3166
Patent
active
058859730
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/05142 filed 28, Dec. 1994
BACKGROUND OF THE INVENTION
1. Field of the Invention
Bisphosphonates, also known as diphosphonates, are synthetic analogues of pyrophosphate characterized by two carbon-phosphate bonds and a high affinity for mineralized tissues. The substitution of the oxygen atom in the pyrophosphate molecules (P-O-P) by a carbon in the bisphosphonate molecules (P-C-P) made the latter compounds resistant to biological degradation and suitable for clinical use. Bisphosphonates were originally developed as inhibitors of calcium crystal growth and they were found to suppress osteoclast-mediated bone resorption. They were subsequently used for the treatment of acute and chronic conditions characterized by increased bone resorption and/or accelerated bone loss as osteoporosis.
2. Description of the Related Art
However, long term bone resorption inhibition may affect the bone remodeling process, and in consequence bone quality, resulting in bad biomechanical performance and subsequent increased risk of fracture.
It was further found that the presence of a nitrogen molecule in the side chain of the bisphosphonate structure increases its potency and specificity toward bone resorption.
The use of bisphosphonates in the treatment of bone metabolic disorders is known in principle, such as methods to interact with abnormal deposition and dissolution of difficultly soluble calcium salts or as bone resorption inhibition. U.S. Pat. No. 3,962,432 discloses the use of aminoalkane-diphosphonic acids for the treatment of a variety of calcium disorders. U.S. Pat. No. 4,711,880 discloses crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate for oral treatment of disorders of the calcium and phosphate metabolism. U.S. Pat. No. 5,137,880 dicloses bicyclic diphosphonate compounds, pharmaceutical preparations, and methods for treating abnormal calcium and phosphate metabolism. U.S. Pat. No. 5,205,253 discloses diphosphonic acid derivatives, processes for their production and pharmaceutical preparations containing these compounds for the treatment of calcium metabolism. PCT/WO93/11786 discloses a method for the treatment of osteoporosis using bisphosphonates and parathyroid hormone. PCT/WO93/11774 discloses the treatment of periodontal disease with alendronate.
The use of olpadronate and its derivatives as inhibitors of calcium crystal growth is also known in principle. U.S. Pat. No. 4,054,598 discloses a method with sequestering agents, especially for alkaline earth metal ions, having the formula 1-hydroxy-3-amino-alkane-1,1-diphosphonic acids, useful for the treatment of disturbances of the calcium or phosphate metabolism characterized by abnormal deposition of difficultly soluble calcium salts or the abnormal dissolution of hard tissues causing losses of hard bone substance, which cannot be replaced or only by incompletely crystallized tissues, such as Paget's disease, lithiasis, arthritis and others. Spanish Pat. No. P9100885 (Pub. No. ES-A-2034877) discloses pharmaceutical liposome preparations containing bisphosphonates as active compounds.
An effect different from bone resorption inhibition has been searched and anabolic phases has been added to cyclical bisphosphonate treatment (Eur Pat. No. A-162510).
It has now been discovered by the inventors hereof that olpadronate, obtained by a synthesis process herein described (previously known from Argentine Pat. No. 200,473 that discloses a process for the preparation of 1-hydroxyalkyliden-diphosphonic acids and its salts, extended to Argentine Pat. No. 218,558 that discloses a process to prepare 3-amino-1-hydroxy-propylidene-diphosphonic acid and their salts), displays an original anabolic mechanism of action preserving and augmenting bone mass, at non-toxic doses with no irritation of the gastrointestinal tract even in high doses.
SUMMARY OF THE INVENTION
Accordingly, the invention refers to olpadronate compositions and combinations as a new anabolic and non-toxic medicament to prevent or to treat bon
REFERENCES:
patent: 5366965 (1994-11-01), Strein
Ferretti Jose Luis
Labriola Rafael A.
Mondelo Nelida
Papapoulos Socrates
Roldan Emilio J.A.
Criares Theodore J.
Gador S.A.
University of Leiden
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