Radiolabelled bisphosphonates and method

Details Radiolabelled bisphosphonates and method Radiolabelled bisphosphonates and method

2002-05-08

2003-03-18

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C562S013000

Reexamination Certificate

active

06534488

ABSTRACT:

This application is a 371 of PCT/EP00/07490 filed Aug. 2, 2000.
FIELD OF THE INVENTION
The present invention relates to
32
P- or
33
P-labelled bisphosphonates as radiotherapeutic radiopharmaceuticals. The
32
P or
33
P-labelled bisphosphonates, which are chemically identical to the unlabelled agent, are expected to target the lesion site in an identical manner, but also deliver a significant radiocytotoxic effect to the surrounding cells. This should result, given the favourable energetics of the &bgr; particle emission from the
32
P nuclide, in a loss of proliferative capacity of cells associated with the tumour lesion. The relative stability and in vivo localisation of bisphosphonates makes them good candidates as
32
P/
33
P delivery vehicles.
BACKGROUND OF THE INVENTION
Bisphosphonates are known as palliatives to treat osteosarcoma or bone metastases associated with carcinoma such as breast or prostate. These agents, such as Pamidronate and Clodronate, exert a negative effect upon osteoclasts at the site of the lesion resulting in decreased bone resorption at this site. Bisphosphonates, however, appear to lose activity with time necessitating repeat administration.
There have been extensive examples of bisphosphonate syntheses in the literature over the last 25 years. Synthesis of the &agr;-hydroxyl-methylene bisphosphonates, those most commonly studied with respect to bone disorders, have largely been performed under harsh conditions of elevated temperatures, often resulting in low-yielding reactions. The common route of synthesis to such compounds involves heating a source of phosphorus, usually phosphorous acid, with the appropriate carboxylic acid and PCI
3
. This synthesis is not ideal for the incorporation of
32/33
P into a bisphosphonate, due to the safety and radiological hazards associated with volatile
32/33
PCI
3
, and the fact that the primary role of the PCI
3
is to generate an activated carbonyl compound rather than as a source of the phosphonate groups. The poor yields often obtained from the traditional syntheses are not appropriate for radiolabelling with an expensive radionuclide.
Tris(trimethylsilyl) phosphite, P(OTms)
3
, has been isynthesised from PCI
3
and, alternatively, from phosphorous acid and, subsequently, used to introduce phosphorus into compounds.
U.S. Pat. No. 3,965,254 describes the use of
32/33
P in bisphosphonates for the treatment of bone cancer. It was shown that the
32
P or
33
P radionuclide could be targeted to the tumour site. The patent describes the incorporation of
32
P into EHDP (disodium ethane-1-hydroxy-1,1-diphosphonate) and its subsequent use in in vivo studies. The synthesis used to generate the radiolabelled bisphosphonates followed the conventional synthesis using
32/33
PCI
3
. Within the synthetic route the reaction is, at times heated to 145° C. for up to 6 hours and a reflux of 40 hours duration. The final yield was approximately 65%. This route of preparation for these compounds is seen as inappropriate for the reasons outlined above.
Accordingly, it is one object of this invention to supply a convenient and improved route of synthesis for radiolabelled bisphosphonates, for the use in therapeutic treatment of bone metastatic disease.
SUMMARY OF THE INVENTION
In one aspect the invention provides a method of making a bisphosphonate, which method comprises reacting a tris(silyl)phosphite with an activated carbonyl compound and hydrolysing the resulting intermediate according to the reaction scheme:
 P(OX)
3
+RCO.Y→Intermediate→RC(OH)(PO.[OH]
2
)
2
where
each X is the same or different and is tri-(C
1
-C
12
hydrocarbyl)silyl,
R is C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, C
2
-C
12
aryl (including heteroaryl) or substituted variants of these where functionalised groups, if present, are appropriately masked (ie. protected) during the synthesis,
and Y is an activating moiety.
The functional group(s) of the ‘substituted variants’ can be amino (primary, secondary or tertiary), hydroxy, alkoxy or fluorine. R is preferably C
1
-C
12
alkyl, C
1
-C
12
fluoroalkyl or C
1
-C
12
primary, secondary or tertiary aminoalkyl or a derivative of these, or a substituted alkyl group containing nitrogen as part of a heterocyclic ring system. R is most preferably C
1
-C
6
alkyl or C
2
-C
9
primary, secondary or tertiary aminoalkyl. Preferred C
2
-C
9
aminoalkyl groups are —(CH
2
)
p
NQ
2
where p is 2 or 3 and Q is H or C
1
-C
5
alkyl, with —(CH
2
)
2
NH
2
, —(CH
2
)
3
NH
2
and (CH
2
)
3
NMe(pentyl) being especially preferred.
In the starting tris(silyl)phosphite P(OX)
3
, X is tri-(C
1
-C
12
hydrocarbyl)silyl, e.g. trialkylsilyl or triarylsilyl, conveniently trimethylsilyl since derivatised trimethylsilanes are readily commercially available. Mixed phosphites are possible and may be preferred.
The starting activated carbonyl compound of formula RCO.Y is preferably an acid halide, particularly an acid chloride or acid bromide; an acid anhydride; an &agr;-ketophosphonate; or an active ester such as that derived from N-hydroxysuccinimide. Hence the activating moiety Y can be: a leaving group such as halogen (especially Cl or Br), or an acid anhydride linkage (RCO)
2
O, or an active ester, examples of which are well known to those skilled in the art. Alternatively, Y can be a phosphonate —PO(OR′″)
2
, ie. RCOY may be an &agr;-ketophosphonate. Preparation of bisphosphonates has also been achieved using an active ester derived from 2-hydroxypyridine and also acid anhydrides. Active esters derived from pentafluorophenol and hydroxybenztriazole are also possible. These reactions show how the increased nucleophilicity of the silylated phosphites (compared with trialkyl phosphites) permits the use of much less activated carbonyl compounds in the formation of the desired products.
When Y is a leaving group, the Intermediate generally has the formula RC(OZ)(PO.[OX]
2
)
2
where Z is H or X. When RCOY is an &agr;-ketophosphonate, an addition reaction rather than a substitution reaction may take place, e.g.:
P(OX)
3
+RCO.PO(OR′″)
2
→RC(OZ)(PO)[OX]
2
)(PO[OR′″]
2
)→RC(OH)(PO[OH]
2
)
2
where R′″ is C
1-12
alkyl or X (by treatment of the —O-alkyl system with TmsBr or Tmsl).
The R group is chosen to provide a desired substituent on the hydroxymethane-bisphosphonate unit.
Various bisphosphonate drugs R
1
CR
2
(PO[OH]
2
)
2
have been commercialised as follows:
Name
R
1
R
2
Etidronate
OH
—CH
3
Ibandronate
OH
—CH
2
CH
2
NMe(pentyl)
Alendronate
OH
—(CH
2
)
3
NH
2
Pamidronate
OH
—(CH
2
)
2
NH
2
Clodronate
Cl
Cl
Preferably the tris(silyl)phosphite contains
32
P or
33
P, either at 100% abundance or at least at an artificially high isotopic abundance of e.g. at least 1%. Preferably 2 molar equivalents of the tris(silyl)phosphite are reacted with 1 molar equivalent of the activated carbonyl compound. Although use of elevated temperatures is possible, the reaction is found to go in high yield at ambient temperature, thus providing a convenient route for introducing
32
P or
33
P into a bisphosphonate molecule of choice.
Dry aprotic solvents such as diethyl ether or tetrahydrofuran can be used to help facilitate handling of the reactants. Reaction times depend on the leaving group and on the quantity of solvent used. With modest quantities of solvent, reaction times are typically 10 to 15 min with an acid chloride or anhydride but it can require heating for several hours with less activated carbonyl compounds.
There results an intermediate having the formula RC(OZ)(PO.[OX]
2
)
2
or RC(OZ)(PO)[OX]
2
)(PO[OR′″]). In general these intermediates are believed novel and form further aspects of this invention. They may readily be hydrolysed to the desired bisphosphonates by the addition of excess methanol or water at elevated or preferably ambient temperature. Some of the resulting bisphosphonates are new compounds.
Thus the invention also provides rad

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