WO2004056840A1

WO2004056840A1 - Novel compounds useful in boron neutron capture therapy

Info

Publication number: WO2004056840A1
Application number: PCT/SE2003/002007
Authority: WO
Inventors: Arne Eek; Jonas Malmquist; Lars-Inge Olsson
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2002-12-20
Filing date: 2003-12-18
Publication date: 2004-07-08
Anticipated expiration: 2005-06-20
Also published as: AU2003288855A1; SE0203823D0

Abstract

The present invention relates to novel compounds useful in boron neutron capture therapy. A further aspect of the invention is the use of the compounds in tumour therapy and in the manufacture of a medicament for use in tumour therapy. Yet another aspect of the invention is a method for preparing the novel compounds. A further aspect of the invention is a pharmaceutical preparation comprising said compounds.

Description

NOVEL COMPOUNDS USEFUL IN BORON NEUTRON CAPTURE THERAPY

Field of the invention

The present invention relates to novel compounds useful in boron neutron capture therapy, the use of these compounds in tumour therapy, as well as pharmaceutical preparations comprising said compounds. Yet another aspect of the invention is a method for preparing the novel compounds.

Background of the invention

Boron neutron capture therapy (BNCT) is a form of radiation therapy requiring two components: ¹⁰B and low energy thermal neutrons. The ¹⁰B is administered to the subject to be treated in the form of a boron-containing compound that accumulates in the tumour. The subject to be treated is then irradiated with low energy thermal neutrons from a nuclear reactor or cyclotron.

When low energy thermal neutrons hit ¹⁰B they generate an α-particle and ⁷Li. The thermal neutrons have a relatively low energy. However, upon generation of ⁷Li and an α-particle, sufficient energy to destroy a cell is generated. Since the α-particle and ⁷Li are relatively large they are only transported about 5-10 μm in the tissue, i.e. a distance corresponding to the diameter of a tumour cell. Thus, BNCT can be used to selectively irradiate tumours while minimizing the radiation damage to non-malignant tissue.

A major challenge in BNCT is to find a non-toxic carrier molecule for the boron atom that will concentrate in the cells of the tumour to ensure sufficient selectivity (Sweet W.H., Journal of Neuro-Oncology (1997), 33, 19-26). One approach has been to use boron- containing nucleosides, nucleotides or oligonucleotides (EP 1 113 020 A2). Another approach has been the use of nucleosides and oligonucleotides comprising a boronated phosphoramidate (WO 94/01440 Al). Further, carboranyl pyrimidines have been prepared for use in BNCT. Purine and pyrimidine nucleosides containing a carboranyl group attached to the purine or pyrimidine base have also been reported. The synthesis of nido- carborane-cobalamin conjugates that could be useful in neutron capture therapy has also been performed (H.P.C. Hogenkamp et al. Nuclear Medicine and Biology (2000), 27, 89- 92).

Outline of the invention

The novel compounds according to the present invention are defined by the general formula (I):

wherein R is selected from -CN, -OH, -H₂O and -NO₂ and L is selected from O O O O O O

II II II II II II P-OH *— P-O-P-OH -P-O-P-O-P-OH

I I I I I o O o O O O

X

X X X X X

Y

Y Y Y Y Y

Y in each of formula above is each and independently selected from a borane or a carborane, which can be selected from

X in each formula above is each and independently selected from

wherein n=l, 2, 3 or 4

or X is

wherein n=l or 2;

Z in each formula above is each and independently selected from hydrogen or a hydrophilizing substituent, such as aminomethyl, 2-aminoethyl, 3-amino-propyl, l,3-propandiol-2-yl-methoxyl, ethyleneglycoxyl or diethyleneglycoxyl; and

M=cobalt, cobalt-57, iron; and wherein the symbol * indicates the location of the binding.

In formula I above, M indicates a metal atom that co-ordinates the complex.

When one or more stereocenter is present in the molecule, the compounds according to formula (I) can be in the form of a stereoisomeric mixture, e.g. a mixture of diastereomers and/or a mixture of enantiomers. Diastereomers are stereoisomers whose molecules are not mirror images of each other. Enantiomers are stereoisomers whose molecules are mirror images of each other. Further, the compounds according to formula (I) can be in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer. The compounds according to formula (I) can also be in the form of a racemic mixture, i.e. an equimolar mixture of enantiomers. The compounds can also be in the form of solvates, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the above-mentioned activity. The compounds according to formula (I) can also be in the form of pharmaceutically acceptable salts. Such salts are for example salts formed with mineral acids such as hydrochloric acid; alkali metal salts such as sodium or potassium salts; or alkaline earth metal salts such as calcium or magnesium salts.

Examples of compounds according to formula (I) are 3-(l,12-dicarba-cZαso- dodecaborane(12)-l-yl)propyl-cyanocobinamide phosphoric acid and O, O'-di[3, 3'-(l,12- dicarba-c/ojo-dodecaborane( 12)- 1 -yl)propyl] -cyanocobinamide pyrophosphoric acid.

Borane is defined herein as a polyhedral borane, see Gmelin Handbook of Inorganic and Organometallic Chemistry (8 ed. 1991). Carborane is defined herein as a compound wherein at least one carbon atom is incorporated into a polyhedral borane. Carboranes can be synthesised according to descriptions in Carboranes (R. Grimes ed. 1970), Gmelin Handbook of Inorganic and Organometallic Chemistry (8^l ed. 1991) and Science 1972, 78, 462.

The wording boron neutron capture therapy (BNCT) as used herein is defined as a method for tumour therapy comprising the steps of administering a boron-containing compound to a subject to be subjected to therapy and irradiating said subject with thermal neutrons.

The wording tumour as used herein is defined in accordance with Dorland's Illustrated Medical Dictionary, 26^th edition, 1985, Sounders, i.e. as a growth of tissue in which the multiplication of cells is uncontrolled and progressive. Uncontrolled multiplication is defined as a state differing from the normal multiplication of cells, e.g. a state in which the rate of multiplication of cells is significantly increased. The wording progressive in this context is defined as advancing or increasing in severity. A tumour cell is defined as a cell in said tissue.

As used herein, the term therapy is defined in accordance with Dorland's Illustrated Medical Dictionary, 26^th edition, 1985, Saunders, i.e. as the treatment of disease. The terms "therapeutic" and "therapeutically" should be construed accordingly. The wording tumour therapy as used herein is thus defined as treatment of disease caused by or associated with a tumour.

The compounds according to formula (I) above are useful in BNCT. The compounds according to formula (I) comprise a Factor B moiety, i.e. a significant part of the vitamin B₁₂ molecule. Said compounds further comprise a linker and a boron-containing moiety. The linker is defined as a moiety located between the Factor B moiety and the boron- containing moiety. The boron-containing moiety is defined as a group containing boron, and can be a borane or a carborane (see Y in formula I above). Fast-growing cells such as tumour cells show an increased uptake of vitamin B₁₂ related structures.

One aspect of the present invention is the use of a compound according to formula (I) for the manufacture of a medicament for tumour therapy.

BNCT can be used for the therapy of a wide range of tumours. Tumours can be classified histologically according to principles defined by the World Health Organization (World Health Organization, International Histological Classification of Tumours, 1967-1978). Tumour types that can be treated using BNCT with the compounds according to formula (I) above include glioblastoma, anaplastic astrocytoma, lowgrade astrocytoma, brain stem glioma, meningioma, peripheral neuroepithelioma, lymphomas, metastatic brain tumour and arterio venous malformations. The compounds according to formula (I) may also be used in BNCT for therapy of inter alia melanomas and breast cancer.

A further aspect of the invention is the use of a compound according to formula (I) for the manufacture of a medicament for therapy of glioblastoma, anaplastic astrocytoma, lowgrade astrocytoma, brain stem glioma, meningioma, peripheral neuroepithelioma, metastatic brain tumour or arteriovenous malformations. Another aspect of the invention is the use of a compound according to formula (I) for the manufacture of a medicament for therapy of melanomas, prostate cancer, lung cancer and breast cancer.

Yet another aspect of the invention is a method of tumour therapy wherein a pharmaceutically and pharmacologically effective amount of a compound according to formula (I) is administered to a subject in need of such therapy, in conjunction with BNCT.

A further aspect of the invention is a method of tumour therapy of glioblastoma, anaplastic astrocytoma, lowgrade astrocytoma, brain stem glioma, meningioma, peripheral neuroepithelioma, metastatic brain tumour or arteriovenous malformations wherein a pharmaceutically and pharmacologically effective amount of a compound according to formula (I) is administered to a subject in need of such treatment in conjunction with BNCT.

A further aspect of the invention is a method of tumour therapy of melanoma or breast cancer wherein a pharmaceutically and pharmacologically effective amount of a compound according to formula (I) is administered to a subject in need of such treatment in conjunction with BNCT.

The therapy defined hereinbefore may be applied as a sole therapy or may involve, in addition to boron neutron capture therapy, conventional surgery or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) Agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab) , farnesyl transf erase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib) and 6-acrylamido-N-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and WO02/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

Preparation of the compounds according to formula (I)

The compounds according to formula (I) of the present invention may be prepared by the following method.

A compound of the formula (II)

wherein R is selected from -CN, -OH, -H₂O and -NO₂, is reacted with a compound of the formula III

O

II

HO- - ^■pP-- O — F— Y ( III )

I I OH or formula TV

O

II HO-P— O Y— G ( IV )

OH wherein Y is a borane or a carborane, F is ribose, and G is 5,6-dimethylbenzimidazole or hydrogen. II is coupled with HI or IV using a coupling reagent like DCC (dicyclohexylcarbidiimide) or a similar reagent such as EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride) or DIC (1,3-diisopropylcarbodiimide) and using pyridine or a similar base such as collidine in a polar aprotic solvent like DMF (dimethylformamide) or a similar solvent such as NMP (N-methylpyrrolidone) or DMA (dimethylacetamide) until the reaction is completed.

The compounds HI and IV were prepared from the corresponding hydroxyl-derivative: O II

HO-F — Y HO-P — O — F — Y

OH or or

O II HO— Y— G HO-P— O Y— G

OH wherein Y is a borane or a carborane, F is a ribose-group or hydrogen, and G is a 5,6- dimethylbenzimidazole group. The phosphoric acid function was introduced by reacting a hydroxyl-containing compound with phosphoroxychloride in trimethylphosphate at room temperature.

Pharmaceutical formulations

For clinical use, the boron-containing compounds according to formula (I) are in accordance with the present invention suitably formulated into pharmaceutical formulations for parenteral administration. Also rectal, oral or any other route of administration may be contemplated by the skilled man in the art of formulations. Thus, the boron-containing compounds according to formula (I) are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of a solid, semi-solid or liquid diluent.

Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

In the preparation of oral pharmaceutical formulations in accordance with the invention, the boron-containing compound(s) according to formula (I) to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain the active compound in combination with- solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

In one aspect of the present invention, the boron-containing compound according to formula (I) may be administered within 24 hours prior to the neutron irradiation of the subject to be treated, typically 30-60 minutes prior to neutron irradiation. In a further aspect of the invention the dosage of the boron-containing compound may be in pulses. A typical dose of the boron-containing compound according to formula (I) is within the range of from 0.01 - 100 mg per kg body weight.

Biological evaluation

Boron compound

To dissolve the boron compound distilled water is added. After dissolution the solution is sterile filtrated (0,2 γm PES, Polyetersulfon).

Cell cultures

Cells are maintained in humidified air 0,5% CO₂ at 37 °C in D-MEM (Dulbecco 's Modified Eagle's Medium) supplemented with 10% fetal bovine serum (inactivated), streptomycin (100 mg/mL) and penicillin (100 U/mL).

To study the accumulation of the boron, the cells are incubated in vented TC flasks for 18 h with the boron compound and harvested by trypsinization, re-suspended in serum-free medium (no boron), and counted in Bϋrker chamber. Subsequently, the cells are concentrated by centrifugation (1600 g 5 min).

Boron analysis

Boron concentrations are quantified by means of inductively coupled plasma atomic emission spectrometry (ICP-AES) using a Spectro-Ciros CCD (SpectroNordic AB). ICP- AES can measure total boron (¹⁰B and ^πB) with a detection limit of 0,01 ppm in the applications used for these analyses.

For boron analysis, cell pellets are digested at 60°C for 1 h in 0,5 mL of a 1+1 mixture of concentrated sulfuric and nitric acids. The samples are then diluted 1+9 with working solution to a final concentration of 10% acid, 0,1% Triton-X and 0,1 ppm yttrium. Yttrium is used as an inner standard for control of the instrument. To avoid any matrix effects, the standard curve is prepared using the same solution. Boron ICP Standard (from Merck, traceable to NIST 3107) is added to prepare the standards. Five points are used for standard curve, including 0 ppm standard. Standardization of the instrument is performed each day. A control sample with a boron concentration close to that in the test sample is measured before the samples.

Samples of cell culture medium containing the tested boron compounds are analyzed the same way, but without acid added to the standards, control and samples.

Results

Human malign glioma cells (U343MgaC12:6) were incubated with compound 2 (see below) over night. The accumulation ratio (cell-associated boron concentration/boron concentration in the incubation medium) was 12.5.

Human breast carcinoma cells (ZR75) were incubated with compound 2 (see below) over night. The accumulation ratio (cell-associated boron concentration/boron concentration in the incubation medium) was 41-48.

Examples

EXAMPLE 1

3-fl.l2-dicarba-c/o₁yo-dodecaborane(12)-l-yl)propyl-cyanocobinamide phosphoric acid (2) and O. O'-di|^"3, 3^,-(l,12-dicarba-c/o5ⁱo-dodecaborane(12)-l-yl)propyn-cyanocobinamide pyrophosphoric acid (3).

STEP A. 3-(l,12-dicarba-c/o 0-dodecaborane(12 -l-yl)propyl phosphoric acid (1). l-(3- hydroxypropyl)-/?-carborane (Malmquist et al. Tetrahedron, 52, 1996, 9207-9218) (68 mg) was suspended in dry trimethyl phosphate (2 mL). Under N₂-atmosphere phosphorus oxychloride (0.5 mL) was added and the mixture was stirred at room temperature for 2 h. The product was separated through the addition of H₂O (20 mL). The precipitate was extracted with CHC1 (3x2 mL). The combined organic phases were dried with Na₂SO₄, filtered and concentrated in vacuo to give the title compound (89 mg) in 93 % yield.

1H-NMR (CD₃OD) 3.83 (dt, 2H, CH₂-O-P), 2.63 (s, 1Η, H-C), 1.70 ( m, 2Η, C-CH₂-), 1.52 (m, 2Η, CH₂-CH₂-CH₂).

Mass spectrometry in electrospray mode [MS(ES+)] m/z calculated for [M+H]⁺: 283, observed: 283.

STEP B. 3-(l,12-dicarba-c/o^O-dodecaborane(12)-l-yl)propyl-cvanocobinamide phosphoric acid (2) and O. O'-di[^"3, 3'-(l 2-dicarba- o,so-dodecaborane(12)-l-yl)propyπ- cyanocobinamide pyrophosphoric acid (3). A solution of 3 -( 1 , 12-dicarba-c/σ.ϊo- dodecaborane(12)-l-yl)propyl phosphoric acid (30 mg) and cobinamide dicyanide (50 mg, purchased from SIGMA) dissolved in of pyridine (2 mL) was concentrated to dryness in vacuo. This process was repeated twice more, followed by addition of of dry N,N- dimethylformamide (2 mL), dry pyridine (3 mL), and dicyclohexylcarbodiimide (0.37 g) thereto. The mixture was stirred at room temperature for 19 days, and the reaction was concentrated under reduced pressure. H₂O and acetonitrile was then added and the precipitate filtered off. The product was purified on a reverse phase column using a gradient of ammonium acetate (10 mM) and acetonitrile as eluent to give 3-(l,12-dicarba- c/øsø-dodecaborane(12)-l-yl)propyl-cyanocobinamide phosphoric acid (30 mg) in 49 % yield, (mass spectrometry in electrospray mode [MS(ES+)] m/z calculated for [M+H]⁺: 1280, observed: cluster of peaks centered around 1280) and O. O'-dir3. 3'-( 12-dicarba- c/oiO-dodecaborane(12)-l-yl)propyll-cyanocobinamide yrophosphoric acid in 15 % yield (mass spectrometry in electrospray mode [MS(ES+)] m/z calculated for [M+H]⁺: 1545, observed: cluster of peaks centered around 1545).

EXAMPLE 2

3-ri2'-(3"-(5^,",6'"-dimethylbensimidazol-2"'-ylVpropyl)-l'.12^,-dicarba- θ θ- dodecaborane(12)- -yllpropyl-cyanocobinamide phosphoric acid.

STEP A. 3-ri2'-(3"bromo-propyll-l'.12'-dicarba-c/o^o-dodecaboranefl2Vl'-yllpropan- l-ol (4). To an ice-cold solution of bis-(3-hydroxypropyl)- -carborane (81 mg) ((3,3'- [ 1 ", 12"-dicarba-c/o_?o-dodecaborane( 12)- 1 ", 12"-diyl]bis-propan- 1,1' -diol)) and carbontetrabromide (110 mg) in dry dichloromethane (2.5 mL) was added triphenylphosphine (105 mg). The resulting solution was stirred for 25 minutes and concentrated. The residue was stirred with dry diethyl ether (5 mL). After filtration and concentration of the filtrate, the crude product was purified by flash column chromatography on silica gel, with hexane-diethyl ether-ethyl acetate-gradient as the eluent (R/=0.35 hexane/diethyl ether 1:1) to give the title compound (12 mg) in 12 % yield.

Mass spectrometry in electron impact mode [MS(EI)] m/z calculated for M^": 323, observed: 323 within the expected boron cluster envelope.

STEP B. 3-ri2'-(3"-(5'".6'"-dimethylbensimidazol-2'"-ylVpropyn-l'J2^,-dicarba-c/o^- dodecaborane(12)-l '-yllpropan-1-ol (5). To an ice-cold mixture of 5,6- dimethylbenzimidazole (7 mg) and sodium hydride (10 mg) in dry N,N- dimethylformamide (0.5 mL) was added the title compound of STEP A (12 mg) in dry N,N-dimethylformamide (0.5 mL). The mixture was stirred for 2 hours at room temperature, whereafter H₂O was added. The crude product was concentrated to dryness in a stream of Ν₂. H₂O was added and the product was extracted with dichloromethane (3x2 mL). The combined organic phases were dried with Na₂SO₄, filtered and concentrated in vacuo to give the title compound (8.4 mg) in 58 % yield.

Mass spectrometry in electrospray mode [MS(ES+)] m/z calculated for [M+H]⁺: 389, observed: 389.

STEP C. 3-ri2'-(3"-r5'",6"'-dimethylbensimidazol-2'"-yl)-propyl}-lM2'-dicarba- Q^- dodecaborane(12 - -yllpropyl phosphoric acid (6). The compound from STEP B (8 mg) was esterified to the title compound (9 mg) in 91% yield following the same procedure as described in EXAMPLE 1 STEP A.

Mass spectrometry in electrospray mode [MS(ES+)J m/z calculated for [M+H]⁺: 469, observed: 469.

STEP D. 3-ri2'-{3"-(5"^,,6'"-dimethylbensimidazol-2'"-yl)-ρropyll-l'.12'-dicarba-cZo.yo- dodecaborane(12)- -vnpropyl-cyanocobinamide phosphoric acid (7). The compound from STEP C (9 mg) was esterified to the title compound in too low yield to isolate following the same procedure as described in EXAMPLE 1, STEP B.

Mass spectrometry in electrospray mode [MS(ES+)] m/z calculated for [(M+2H/2]⁺: 734, observed: 734.

Claims

1. A compound according to formula I,

wherein R is selected from -CN, -OH, -H₂O and -NO₂ and L is selected from

OH

Y in each formula above is each and independently selected from a borane or a carborane;

X in each formula above is each and independently selected from H_n ^C^ wherein n=l, 2, 3 or 4

or X is

wherein n=l or 2;

Z in each formula above is each and independently selected from hydrogen, aminomethyl, 2-aminoethyl, 3-amino-propyl, l,3-propandiol-2-yl-methoxyl, ethyleneglycoxyl or diethyleneglycoxyl; and pharmaceutically acceptable salts, solvates and the stereoisomers thereof.

2. A compound according to claim 1 , wherein Y is selected from

wherein M is cobalt, cobalt-57 or iron.; and pharmaceutically acceptable salts, solvates and the stereoisomers thereof.

3. A compound according to claim 2, which is 3-(l,12-dicarba-cZoiO- dodecaborane(12)-l-yl)propyl-cyanocobinamide phosphoric acid or O, O'-di[3, 3'- (1,12-dicarba-cZo6O-dodecaborane( 12)- 1 -yl)propyl] -cyanocobinamide pyrophosphoric acid.

4. A compound according to any one of claims 1-3 for use as in therapy.

5. A pharmaceutical composition comprising a compound according to any one of claims 1-4 together with a pharmaceutically acceptable carrier or diluent.

6. A process for the preparation of a compound of formula (I) according to any one of claims 1-3 comprising the steps of reacting a compound of the formula (II)

wherein R is selected from -CN, -OH, -H₂O and -NO₂, with a compound of the formula III

O HO-P— o — F — Y ( I" ) OH or with a compound of formula IV

O

II HO-P — O- Y— G ( IV )

OH wherein Y in formula HI and IV is each and independently a borane or a carborane, F is ribose, and G is 5,6-dimethylbenzimidazole or hydrogen.

7. A compound selected from the group consisting of

O O O

O o O II II II II II

*— P-O-P-O-P-OH *— P-OH *— P-O-P-OH

I o o O O O O

I I I

X

X X X X X

Y

Y Y Y

OH wherein Y in each formula above is each and independently selected from

Xis

wherein n=l, 2, 3 or 4;

or X is

and wherein n=l or 2;

Z is hydrogen; aminomethyl; 2-aminoethyl; 3-amino-propyl; l,3-propandiol-2-yl- methoxyl; ethyleneglycoxyl or diethyleneglycoxyl;

and M is cobalt, cobalt-57 or iron.

8. Use of a compound according to any one of claims 1-3 for the manufacture of a medicament for use in tumour therapy.

9. Use according to claim 8, wherein said use is in boron neutron capture therapy of a tumour.

10. Use according to claim 8 or 9 wherein the tumour is glioblastoma, anaplastic astrocytoma, lowgrade astrocytoma, brain stem glioma, meningioma, peripheral neuroepithelioma, metastatic brain tumour or arteriovenous malformations.

11. Use according to claim 8 or 9 wherein the tumour is melanoma, prostate cancer, lung cancer or breast cancer.

12. A method of tumour therapy wherein a pharmaceutically and pharmacologically effective amount of a compound according to any one of claims 1-3 is administered to a subject in need of such treatment in conjunction with boron neutron capture therapy.