Bis-phosphonate compounds

Details Bis-phosphonate compounds Bis-phosphonate compounds

2001-07-09

2003-04-15

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C534S010000, C534S014000, C514S102000

Reexamination Certificate

active

06548042

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not Applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pharmaceutical compound and composition for use in medicine.
2. Description of the Related Art
It is well known in the art that phosphonate compounds, for example bisphosphonates, have a high affinity for hydroxyapatite crystals and thus tend to localise in vivo in regions of bone metabolism. Moreover, it has also been established that phosphonate compounds are generally low in toxicity.
U.S. Pat. No. 4,880,007 (Amersham International PLC) discloses complexes formed between (a) an amino di- or polyphosphonate; and (b) a paramagnetic metal ion, such as gadolinium (III). Such complexes exhibit calcified tissue seeking properties which render them useful as contrast agents for investigating bone metabolism by NMR scanning.
Similarly, U.S. Pat. No. 5,236,695 (Concat Ltd.) discloses polyphosphonate ligands containing three or more phosphonate groups, combined with paramagnetic metal cations which are administered in the form of pharmacologically acceptable salts. Such compounds are useful as MRI contrast agents which tend to localise in bone tissue without being conjugated to bone-specific biomolecules.
Bisphosphonates have also been used in combination with technetium-99 (Tc-99m). Indeed, Tc-99m is routinely used with carriers such as methylene bisphosphonate, for imaging in hospitals. Furthermore, U.S. Pat. No. 4,830,847 discloses diphosphonate-derivatised macromolecules, such as proteins, suitable for use as technecium-99m based scanning agents and anticalcification agents. Typically, the scanning agents are prepared by combining Tc-99m in a 3+, 4+ and/or 5+ oxidation state with the disphosphonate-derivatised macromolecule. Also disclosed are pharmaceutical compositions containing such diphosphonate-derivatised macromolecules.
The therapeutic applications of bisphosphonate compounds are also well documented in the art. For example, WO 96/39150 (Merck & Co., Inc.) discloses the use of bisphosphonates, such as alendronate, in the prevention or treatment of bone loss associated with rheumatoid arthritis. Similarly, GB 2,331,459 (SPA) discloses an injectable composition for treating skeletal and bone disorders which comprises a bisphosphonate in combination with a benzyl alcohol. Eisenhut et al. (Appln. Radiat. Isot., Vol 38, No.7, ps35-540) disclose the use of
131
I-labelled benzylidinediphosphonates for the palliative treatment of bone metastases. Finally, WO 95/11029 (Merck & Co., Inc.) discloses compositions comprising bisphosphonate and growth hormone secretagogues, which are useful for reducing the deleterious effects of osteoporosis in elderly patients.
The present invention seeks to provide improved phosphonate compounds for use in medicine. In particular, the invention seeks to provide pharmaceutical compounds which exhibit improved activity in the palliative and curative treatment of bone disorders, and/or which may also be suitable for use in medical imaging techniques.
SUMMARY OF THE INVENTION
Aspects of the invention are presented in the accompanying claims and in the following description.
In the broadest aspect, the present invention relates to a pharmaceutical compound for use in medicine. The pharmaceutical may be for a therapeutic use and/or a diagnostic use.
More specifically, the present invention provides a pharmaceutical compound, or pharmaceutically acceptable salt thereof, for use in medicine, wherein said compound is of formula I
R—Ar—X—Y
wherein
R is a pharmaceutically active moiety;
Ar is an aromatic moiety;
X is a linker group; and
Y is a moiety comprising two phosphonate groups.
In a preferred aspect of the invention, Y comprises a geminal bisphosphonate group.
In a further preferred aspect, the invention provides a pharmaceutical compound, or pharmaceutically acceptable salt thereof, of formula II
wherein Z is H, NH
2
or an oxy substituent. Preferably, Z is H or OH.
The pharmaceutical compound of the present invention comprises a linker group, X.
In a preferred aspect, the linker group of the invention is a substituted or unsubstituted C
1-4
alkylene group.
In an alternative preferred aspect of the invention, X is a C
1-4
amine group, C
1-4
ether group or a C
1-4
thioether group, each of which may be substituted or unsubstituted.
In another preferred aspect of the invention, X is S═O or SO
2
.
Where X is substituted, suitable substituents include one or more groups which do not interfere with the pharmaceutical activity of the compound in question. Exemplary non-interfering substituents include hydroxy, amino, halo, alkoxy, and alkyl.
The pharmaceutical compound of the present invention also comprises an aromatic moiety, Ar.
Preferably, the aromatic moiety of the compound is electron deficient.
In a more preferred aspect, the aromatic moiety of the invention is a single aromatic ring. However, other aromatic moieties are also suitable for use in the invention, for example, aromatic moieties comprising more than one aromatic ring, where the aromatic rings may be fused together or joined via one or more suitable spacer groups
Examples of aromatic moieties suitable for the present invention include substituted or unsubstituted phenyl, naphthyl, thiophenyl, furyl, pyridyl and pyrrole groups.
Where the aromatic moiety is substituted, suitable substituents include one or more groups which do not interfere with the pharmaceutical activity of the compound in question. Exemplary non-interfering substituents include hydroxy, amino, halo, alkoxy, and alkyl.
The pharmaceutical compound of the present invention also comprises a pharmaceutically active moiety, R.
In a preferred aspect, R comprises a radiolabel. Examples of radiolabels suitable for use in the present invention include
124
I,
125
I,
131
I,
211
At (an &agr;-emitter),
186
Re, Tc-99m, and &bgr;-emitting bromine nuclei.
In an alternative preferred aspect, the pharmaceutically active moiety of the invention may comprise a functional group (or ligand) to which a metal ion can be chelated, or is chelated thereto. Species of the former type, i.e. those comprising a functional group to which a metal ion can be chelated, could be potentially useful for complexing any excess radiolabel close to the bone, thereby preventing radiolabel poisoning.
By way of definition, the term “chelate” refers to a complex in which a ligand is coordinated to a metal ion at two or more points, so that there is a ring of atoms including the metal, and where the term “ligand” refers to an ion or molecule that can donate a pair of electrons to said metal ion.
Suitable functional groups or ligands to which a metal ion may be chelated include amine, hydroxy, or carboxylic acid moieties.
In a particularly preferred aspect, the metal ion chelated to the functional group is paramagnetic. In the present context, the term “paramagnetic” refers to metal ions having net orbital or spin magnetic moments that are capable of being aligned in the direction of an applied magnetic field. Such atoms have a positive (but small) susceptibility and a relative permeability slightly in excess of one. Paramagnetism occurs in all atoms with unpaired electrons, e.g. transition metal ions with unpaired electron shells.
Examples of suitable paramagnetic metals include those of the lanthanide elements with atomic numbers 58 to 70, and those of the transition metals with atomic numbers 21 to 29, 42 and 44. Typical examples include chromium (III), manganese (II), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praesodymium (III), neodymium (III), samarium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III) and ytterbium (III).
The pharmaceutically active moiety, R, may also comprise a paramagnetic component other than a paramagnetic ion, for example, a moiety comprising the group NO.
Compounds of the invention containing paramagnetic moieties or radiolabels may have applications in the field of medical imaging, especially calcified t

Affiliated with

Also associated with

Rating

Bis-phosphonate compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Bis-phosphonate compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bis-phosphonate compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3042560