Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Reexamination Certificate
2000-04-03
2002-06-25
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
C562S008000, C562S023000, C562S025000
Reexamination Certificate
active
06410782
ABSTRACT:
OBJECT OF THE PRESENT INVENTION
Object of the present invention are salts of diphosphonic acids or diphosphonates and a procedure for their preparation.
Object of the present invention is also the use of mentioned salts of diphosphonic acids or diphosphonates for treatment of osteoporosis.
Object of the present invention are again pharmaceutical compositions which contain, as active principle, the mentioned salts of diphosphonic acids or diphosphonates and the use of these compositions in the treatment of osteoporosis.
STATUS OF THE TECHNIQUE
As well known osteoporosis is a disease of the skeleton that is characterised by the disarrangement and by the loss of bone tissue, with increase of skeleton fragility and predisposition to fractures.
As an example, is reported that in US this disease afflicts more than 25 millions of persons and it causes 1.300.000 fractures every year.
The social cost is consequently very high accounting for more than 10 billions of US dollars per year. The same figures are reported in Europe and in Japan.
The elderly is the population with the highest risk. Unfortunately the problem is becoming progressively more serious in the view of the progressive grow old of population. A forecast of the fracture incidence in the future sixty years assumes an increase of at least three times. Women are more exposed that men, particularly during the first 5 years after the menopausal period.
At present, from a therapeutic viewpoint, either a mono-therapy with fluorides, as reported by Melmon & Morrelli, Clinical Pharmacology: Basic Principles in Therapeutics, 497 (1992), N. Engl. J. Med. 306,446 (1982) is used, or addition use of combined therapies with calcium, fluoride and oestrogens are reported to retain some advantages as compared to the mono-therapy.
Alternatively, another class of compounds prescribed for the treatment of osteoporosis includes disphosphonates; these agents are mostly administered by oral route, but besides having the unsolved inconvenient of a poor absorption (from 1 to 5% of dose), they also develop, as primary adverse events, oesophagitis and gastro-intestinal disorders of moderate-severe intensity.
To overcame this inconvenient, several clinical studies have been carried out, in the search of new compounds that combine a high pharmacological activity together with a better tolerability an increased bioavailability as compared to known available compounds.
For example, in the treatment of uro-litiasis and for inhibition of bone resorption, diphosphonic acids and their salts are described in the U.S. Pat. No. 4,621,077; namely, the biological activities of mentioned phosphonic acids or their corresponding sodium salts are reported. The degree of absorption, i.e. the bioavailability, of those compounds resulted however very low and for this reason, in order to achieve in the body active concentrations of the active principle, high doses had to be administered with consequent occurrence of gastro-intestinal adverse reactions which worse tolerability.
OBJECTIVES OF THE INVENTION
objective of the present invention is to make available diphosphonates that have an increased bioavailability when administered by oral route.
Objective of the present invention is also to make available diphosphonates that are more effective in the treatment of osteoporosis while retaining a lower incidence of oesophagus and gastro-intestinal adverse events as compared to those known compounds already available.
Again, objective of the present invention is to make available diphosphonates which can be administered both by oral or intravenous route.
Again, objective of the present invention is to make available diphosphonates that display an improved therapeutic index in treatment of osteoporosis as compared to the known drugs at present used in the medical practice.
Objective of the present intention is also to make available a procedure for the preparation of diphosphonates.
Objective of the present invention is also to make available pharmaceutical formulations, containing at least one diphosphonate as active principle, easy to be administered, well tolerated and able to allow a high therapeutic index.
DESCRIPTION OF THE INVENTION
These and other objectives with further advantages which are clarified in the description below, are obtained by diphosphonates or salts of diphosphonic acids and linear, branched, substituted and non-substituted, cyclic, hetero-cyclic, aromatic amino-alcohol derivatives, said diphosphonates having the following general formula:
where R=R
1
or R≠R
1
and R and R
1
are chosen among H, OH, Cl, linear or branched, substituted or not substituted alkyl groups, linear or branched, substituted or not substituted alkylidenic chain, or they are chosen among:
More particularly, according to the present invention, mentioned amino-alcohols are chosen among linear and branched amino-alcohols, and specifically they are chosen among:
H
2
N—CH
2
CH
2
OH (XVI)
(CH
3
)
3
N
+
—CH
2
CH
2
OH (XX)
Always according to the present invention, mentioned amino-alcohols are cyclic and hetero cyclic amino-alcohols and are chosen among
Again, according to the present invention, mentioned substituted alkylidenic chain, defined in formula (I), is chosen equal to:
with n within 1 and 6, where R
2
=R
3
or R
2
≠R
3
and R
2
and R
3
are chosen among H, linear or branched, cyclic, substituted or non-substituted alkyl groups, or R
2
and R
3
represent, together with the nitrogen atom N, an aliphatic or aromatic hetero-cycle.
Always according to the present invention, the substituted alkylidenic chain, defined in formula (I), is also chosen equal to
where n is within 1 and 6 and R
4
is chosen among:
According to the present invention, of particular interest appeared the salt obtained between a diphosphonic acid of general formula (I), where R≠R
1
, R is chosen equal to OH and R
1
is chosen as substituted linear alkylidenic chain of formula (X) , where n=3, R
2
and R
3
are equal to H according to the following formula:
or 4-amino-1-hydroxybutane-1,1-biphosphonic acid (alendronic acid) and one branched amino-alcohol of formula
or 2-amino-2-hydroxymethyl-1,3-propanediol (trometamine). Mentioned salts, always according to the present invention, depending upon the preparation procedure, are formed by the residues corresponding to the diphosphonic acid and the amino-alcohol in a variable molar ratio, while they can be advantageously used in the treatment of osteoporosis. Mentioned molar ratios can vary between 1:1 and 1:2 (diphosphonic acid : amino-alcohol).
Diphosphonates according to the prior art, retain a non satisfactory pharmacokinetic profile, characterised by a very poor absorption from the gastro-intestinal tract, with a systemic bioavailability ranging between 1 to 5% of the oral dose. About 50% of the absorbed dose is then eliminated with the urine in 24 hours, while the dose left is retained by bone tissue and afterwards eliminated very slowly. The unabsorbed diphosphonate is instead eliminated with the faeces.
This behaviour has to be attributed to the physico-chemical properties of the products, which being highly hydro-soluble hardly penetrate the lipid membranes. Oral doses much higher than those bioavailable are then necessary to achieve and maintain a therapeutic effective concentration at the target site (bone), with consequent increase of the local gastro-intestinal adverse events like nausea and diarrhoea.
Diphosphonates according to the present invention, due to the lower dissociation degree of the salt and to the physico-chemical properties of the amino-alcohol, are characterised by a lower water solubility and an increased lipid solubility as compared to the known diphosphonates (sodium salts).
These characteristics confer remarkable advantages in the absorption process trough the biological membranes, thus improving bioavailability.
In addition, diphosphonates of the present invention, did show a promising pharmaco-toxicological profile in relation to the expected use in t
Parente Antonio
VanGulik Fred
Geange Ltd.
Vollano Jean F.
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