Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1993-11-29
2001-07-03
Kelly, C. H. (Department: 1774)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C562S013000
Reexamination Certificate
active
06255288
ABSTRACT:
Methanebisphosphonic acid derivatives, in particular bisphosphonate compounds, are used clinically to inhibit excessive bone resorption in a variety of diseases such as tumour-induced osteolysis, Paget's disease and osteoporosis. Radiolabelled bisphosphonates are also used diagnostically to identify sites of high bone turnover.
As the compounds bind to bone mineral and inhibit bone resorption, there has been general concern that bisphosphonates could have a deleterious effect on callus formation and remodelling, which is an essential part of the fracture repair process. Kanis, for example, teaches in Lancet 1984, 27-33 that bisphosphonates, as inhibitors of bone resorption, may indeed halt skeletal losses but on the other hand delay the repair of microfractures by reducing the rate of remodelling of damaged bone and inhibiting callus formation. As another example, Reid et al. in Lancet 1988, 143-146 found Lhat bisphosphonate treatment, in this particular case done with disodium pamidronate (=APD), caused a reduction in bone formation and a very low rate of bone turnover which raised the possibility of impaired microfracture repair. Furthermore, Alpar, in J. Clin. Hosp. Pharmacy 9 (1984) 341-344, expressed the view that the natural process of bone healing cannot be influenced by any drug.
Furthermore, one commercially available bisphosphonate, disodiumn etidronate, is even known to inhibit bone mineralization and to delay callus formation and fracture healing in man and animals at doses within the therapeutic range [see G. A. M. Finelllan et al., Clin. Orthopaed. Rol. Res. 120 (1976) 115-124; L. Flora et al., Metabol. Bone Dis. Rel. Res. 4/5 (1981) 289-300].
Very surprisingly, it has now been found that certain methanebisphosphonic acid derivatives have a highly beneficial effect on fracture repair. In vivo experiments show that in the treated animals, e.g. sheep, there is a more prolific callus and the ultimate torsional strength of the healing osteotomy is significantly greater, whereas fracture stiffness remains unaffected. These results show that it is possible to use said methanebisphosphonic acid derivatives to promote a more rapid and stronger fracture healing.
The invention therefore relates to the use of a methanebisphosphonic acid derivative of formula I
wherein
(a) R
1
and R
2
are each independently of the other halogen or
(b) R
1
is hydrogen and R
2
is a group Ar—S—, Het
1
—NH—, Cyc—NH—, Ar—S—A—N(R′)—, Het
3
—S—A—N(R′)— or is N-phenylthiocarbamoyl, wherein Ar is unsubstituted or substituted phenyl, Het
1
and Het
3
are each unsubstituted or substituted monocyclic 5- or 6-membered monoaza-, diaza- or thiaza-aryl which is bound through a ring carbon atom, Cyc is cycloalkyl, A is alkylene and R′ is hydrogen or lower alkyl, or
(c) R
1
is hydrogen or hydroxy and R
2
is —A—R
3
, wherein A is alkylene, and
R
3
is either Ar as defined above or is Het
2
, which has the meaning of Het
1
but can be bound through a ring carbon atom or a ring nitrogen atom, or
R
3
is unsubstituted or substituted bicyclic monoaza-, diaza- or triaza-aryl which is bound through a ring carbon atom or a ring nitrogen atom, or
R
3
is unsubstituted amino or amino which is mono- or disubstituted by alkyl, cycloalkyl, Ar-alkyl, Ar—O-alkyl, Ar—S-alkyl or Het
1
-alkyl each independently of one another, and Ar and Het
1
are as defined above, or
R
3
is unsubstituted or Ar-substituted alkyleneamino, wherein two alkylene carbon atoms may be additionally linked to each other through alkylene, and Ar is as defined above,
or of the methanebisphosphonic acid esters 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester or 1-(4-phenylthiobutylamino)methane-1,1-diphosphonic acid tetraethyl ester,
or a pharmaceutically acceptable salt thereof, or any hydrate thereof, (for the manufacture of a pharmaceutical composition) for the treatment of fractures.
Administration of said methanebisphosphonic acid derivatives will benefit all mammals including man with fractures of any bone, especially vertebra, femur or radius.
The present invention is expected to have far reaching clinical and financial implications for the management of fractures. Treatment with said methanebisphosphonic acid derivatives promotes callus formation and fracture union, reducing the time required for mechanical fixation, thus allowing earlier mobilization and weight-bearing. This shorter immobilization time will result in considerable reductions in secondary complications (e.g. reflex sympathetic algodystrophy, tibial non-union, reduced risk of pulmonary embolism, muscle wasting and further bone loss secondary to immobilization) to produce enormous medical and economical benefit.
Thus, “treatment of fractures” means, in particular, promoting fracture healing, and, furthermore, improving the mechanical stability of the healing fracture.
Such fractures may be, for example, (a) the common, traumatic (disabiling and non-osteoporotic) fractures, (b) the osteoporotic fractures (which are due to osteoporosis or osteopenia of any etiology), (c) fractures due to Paget's disease or (d) iatrogenic fractures.
“Iatrogenic fractures” means fractures due to bone loss as a consequence of side effects of other drugs, e.g. in asthma patients receiving high doses of corticosteroids.
In a particular embodiment of the invention, said methanebisphosphonic acid derivatives can be used to treat the common, traumatic fractures, the osteoporotic fractures or the iatrogenic fractures.
The osteoporotic fractures have—with increased ageing of the population—become a major health-care problem. More than 40% of women will suffer fracture of the spine, hip or wrist by the age of 70. Each year in the USA there are 1.2 billion osteoporotic fractures costing an estimated $10 billion per year, of which $6 billion alone is due to hip fractures (250,000 cases per year). In the elderly these fractures are often slow to heal and cause prolonged functional disability. Half the patients are unable to walk unaided and one quarter require long-term nursing care. Towards the end of their lives, ⅓ of women and ⅙ of men will have suffered a hip fracture, leading to death in 12-20% of cases. In view of this immense problem of morbidity and mortality associated with osteoporotic fractures, pharmaceutical agents which serve to improve fracture healing will be a major therapeutic advance.
In another embodiment of the invention, said methanebisphosphonic acid derivatives can be used to treat the common, traumatic fractures.
In a further embodiment of the invention, said methanebisphosphonic acid derivatives can be used to treat all fractures in mammals which are not suffering from Paget's disease.
In just another embodiment of the invention, said methanebisphosphonic acid derivatives can be used to treat all fractures in mammals which are not suffering from Paget's disease or osteoporosis.
The beneficial properties of the methanebisphosphonic acid derivatives according to the invention can be demonstrated, for example, in a fracture model where the effect of the active substance on the healing of a 3 mm osteotomy gap in the mid-diaphysis of the ovine tibia is evaluated using the model of fracture repair under rigid unilateral fixation of Goodship and Kenwright [J. Bone Joint Surgery 67B (1985) 650-655]. In this model, twelve skeletally mature adult female Welsh Mule sheep of body mass 60-70 kg are divided randomly into two groups of six. The animals are housed in large indoor pens under a fixed day length of 18 hours light to suppress the oestrus cycle. The experimental group is given, for example, 0.5 mg/ks of active substance in 250 ml saline as a slow intravenous infusion over a period of one hour once a week for four weeks prior to osteotomy and twelve weeks post-operatively. The control group is oiven a similar infusion of saline alone at identical intervals.
At weekly intervals throughout the twelve week healing period the repair process is evaluated by standard view radiographs, dual
Chambers Timothy J.
Goodship Allen E.
Green Jonathan
McNally Donal S.
Walker Peter
Kelly C. H.
Loeschron Carol A.
Novartis Corporation
LandOfFree
Certain methanebisphosphonic acid derivatives in fracture... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Certain methanebisphosphonic acid derivatives in fracture..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Certain methanebisphosphonic acid derivatives in fracture... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2566251