Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-07-27
2003-08-12
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S102000, C514S114000, C514S740000
Reexamination Certificate
active
06605603
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATION
This application is a national stage of PCT/EP99/08269 filed Oct. 29, 1999, and based upon Argentina Application No. P980105446 filed Oct. 30, 1998, under the International Convention.
BACKGROUND OF THE INVENTION
The present invention relates to novel uses of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid or any of its soluble salts or any of its hydrates.
1. Field of the Invention
The compound 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid, or any of its soluble salts or any of its hydrates, belongs to the group of bisphosphonates which are compounds containing two phosphonate groups bound to a carbon and two additional groups R
1
and R
2
, respectively, which bind strongly to calcium crystals, inhibit their growth, suppress bone resorption and are being used in the treatment of a variety of disorders of bone metabolism.
2. Summary of the Invention
1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid is the amino-substituted form of olpadronate (OPD) and is hereafter sometimes referred to as NH
2
-OPD.
Bisphosphonates are recognized potent inhibitors of bone resorption and are successfully used in the treatment of common bone disorders such as osteoporosis and tumoral bone diseases, amongst others. Structurally, bisphosphonates are derivatives of methylene bisphosphonate in which the two hydrogens on the geminal carbon atom are replaced by two groups, namely R
1
and R
2
, which usually are not identical. In many cases the R
1
moiety is a hydroxyl group, because of its ability to form a tridentate structure together with the two phosphonate groups to bind bone material.
Extensive studies have been carried out on the effects of bisphosphonates on bone cells, in particular those related to their anti-resorptive potency. The molecular mechanisms involved in such actions, however, are not clear. The anti-resorptive activity and its utility in the treatment of osteoporoses and related bone diseases have, for example, been reported and described in the following patents: WO 94/00129 to Frances M. et al., WO 93/11786 to Gueddes A. et al., WO 92/14474 to McOskar et al., U.S. Pat. No. 4,942,157 to Gall R. et al., and in U.S. Pat. No. 3,962,432 to Schmidt-Dunker M.
Although it appears that the nature of the R
2
moiety of bisphosphonates determines their anti-resorptive activity, replacement of the hydroxyl group in R
1
by an NH
2
group in some bisphosphonates (e.g. olpadronate and pamidronate) markedly reduces their anti-resorptive activity. This decrease in anti-resorptive efficacy of the amino derivatives is thought to be due to substitution-dependent changes in the cellular effects of the compounds, since their affinity for bone mineral is not significantly affected. This lack of anti-resorptive activity is, for example, disclosed in vanBeek et al., 1996, Journal of Bone and Mineral Research, vol. 11, no. 10, pp. 1492-1497, and international patent application PCT/EP96/02981, the latter disclosing the use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the treatment of osteoporoses, arthritis and periodontal diseases.
The structure and stability of skeletal bones is—to a high degree—influenced and determined by an equilibrium between the activities of osteoblasts and osteoclasts, i.e. the cells responsible for mineralization and resorption of bone structure, respectively. Therefore, bones are subject to a continuous restructuring process involving anabolic and catabolic reactions. In human beings, as of the age of 30, the catabolic processes prevail such that there will be a net loss in total bone substance naturally. Consequently, the rate at which the renewal of the bone tissue takes place will be lowered with increasing age.
Object of the present invention is to provide means for prevention of the onset of clinically pathological bone-conditions.
Another object of the present invention is to avoid a predisposition to bone disfunctions or bone diseases.
Yet a further object of the present invention is to optimize the physiological bone functions in patients.
The present invention in its various aspects and embodiments disclosed hereafter solves all these objectives and provides further advantages.
SUMMARY OF THE INVENTION
The present invention is related to novel uses of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid and/or any of its soluble salts and/or any of its hydrates. For the purposes of the following specification, it is intended that the term 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid also encompasses any of its soluble salts and/or any of its hydrates.
Briefly stated, the present invention provides novel uses of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid, medicaments comprising 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid and screening methods involving 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid.
Within one aspect of the present invention, there is provided the use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for selective modulation of osteoblasts. Furthermore, there is provided the use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for the maintenance of a healthy bone structure.
There is also provided the use of b
1
-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for the prevention of osteopathies in healthy patients.
The invention also provides for the use of 1-amino-3-(N,N-diethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for the treatment of patients who have recently undergone treatment with corticosteroids.
Additionally there is provided the use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for post-treatment of osteopathies wherein an anti-resorptive activity is not desired.
The invention also provides for the use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for the treatment of children having an osteopathy.
In another aspect of the invention, there is provided the use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for the stimulation of both signalling cascades and reaction mechanisms mediating the action of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid which can be blocked by Ca
2+
-channel blockers.
In yet another aspect of the present invention, there is provided the use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid for the manufacture of a medicament for the mobilization of Ca
2+
-ions from IP
3
sensitive stores.
In yet another aspect of the invention, there is provided a method for screening for Ca
2+
-channel blockers comprising the steps:
treatment of cells having Ca
2+
-channels with a putative Ca
2+
-channel blocker;
contacting the cells with 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid;
measuring a response as a result of the contacting step.
It is envisioned that the treatment-step and the contacting-step occur sequentially with the treatment-step preceding the contacting-step or vice versa, or that they occur simultaneously.
In another aspect, the invention also provides a method for screening for functional analogues of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid, comprising the steps:
treatment of cells having Ca
2+
-channels with Ca
2+
-channel blockers;
contacting the cells with the putative functional analogue which, in the absence of any Ca
2+
-channel blockers, is known to cause a Ca
2+
-ion influx into the cells;
measuring a response as a result of the contacting step.
It is envisioned that the treatment-step and the contacting-step occur sequentially with the treatment-step preceding the contacting-step or vice versa, or that
Boland Ricardo
Papapoulos Sokrates E.
Perez-Lloret Anibal
Roldan Emilio J. A.
Vazquez Guillermo
Gador S.A.
Jiang S.
Padmanabhan Sreeni
Pendorf & Cutliff
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