AU658310B2 - Rhenium complexes - Google Patents

Description

I I S1 P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT 658 18

S

S

C

Invention Title: Rhenium Complexes The following statement is a full description of this invention, including the best method of performing it known to us: GH&CO REF: P13160-KF:AMP 2 This invention relates to Rhenium complexes and in particular to radiolabelled Rhenium complexes for use in radiotherapy of tumours.

The radioactive isotopes of Rhenium, Rhenium-186 and Rhenium-188 share similar periodic group chemical properties with technetium. Rhenium-186 has a 90.6 hour half-life and decays by beta emission of endpoint energy of 1.07 MeV. It is produced by neutron irradiation of Rhenium-185. Rhenium-188 has a half-life of 17.0h and decays by beta emission of endpoint energy of 2.12MeV.

It can be produced in no-carrier added form by the double 0. neutron capture reaction on Tungsten-186 to form Tungsten-188 with a half-life of 69 days which decays to rhenium-188. 1 88 Re can be obtained by the 188 188 Re generator. 186Re is reactor made from 18sRe metal target.

Both Rhenium-186 and -188 decay by gamma emissions which can be detected with nuclear medicine instruments.

For radioimmunotherapy, however, radiorhenium is demanded in high specific activity because of the nature of S. 20 binding of antibody to tumour cells. Accordingly, 188 Re of high specific activity is preferred for radioimmunotherapy with monoclonal antibodies. On the other hand, 186 Re also has applications for internal radiotherapy where receptor specific interactions do not limit medical applications by delivery of lower specific activity Re-compounds.

Iwai, et al., (1984) has reported radiotherapy of liver cancer using 131 I-labelled Lipiodol. The lipid contrast medium Lipiodol, which is an iodinated poppyseed oil (38% iodine with a specific gravity of 1.3) used as a lymphographic agent, was retained almost selectively in the tumour tissue when injected into the tumour feeding artery. Nakajo et al. (1988) reported the biodistribution and in vivo kinetics of 1 31I]Lipiodol infused into hepatic artery, and estimated the potential of internal radiotherapy of hepatic cancer in five patients treated during 1986 to 1990 (Park et al., 1990).

The authors concluded that: the smaller the vascular S:13160KF/30.06.93 3 tumour, the better the response; large tumours were treated more effectively by a combination of 131I- Lipiodol and intra-arterial chemotherapy, embolization or hyperthermia. Although the mechanism of the selective accumulation of Lipiodol is not fully understood as yet, the combination of Lipiodol with an anticancer agent permits enhanced interatomic drug concentration. SMANCS is an anticancer agent, which has a molecular weight of about 15,000 daltons. A homogeneous suspension of SMANCS in Lipiodol has been used for arterial administration (Konno et al., 1983). The chemotherapy with SMANCS- Lipiodol showed marked anti-tumour effect by survival period and histological observation.

S

13 1 I-Lipiodol or the Lipiodol-anticancer agent 15 combination has shown remarkable effectiveness for liver cancer therapy. The use of 1311 for the labelling of Lipiodol has shown that the 1311 nuclide suffers substantially from several undesirable physical and biological properties, principally the rapid and 20 persistent in vivo dehalogenation. The beta emission of 131I has an endpoint energy of 0.32MeV. Accordingly, we have synthesised 186 Re or 1 88Re labelled complexes for use in combination with Lipiodol as a useful tool for internal radiotherapy of liver cancer. For the purposes, the 186 Re and 188 Re compound must be soluble in Lipiodol and stable.

S:13160KF/30.06.93 4 In one aspect, the present invention provides Rhenium complexes of formula radiolabelled complexes thereof or pharmaceutically acceptable salts thereof:

O

S S NN

R

5 wherein R is straight or branched chain Cl.

1 o alkyl, C 1 i 1 0 alkenyl, C- 1 0 o alkynyl optionally substituted by S* cycloalkyl or aryl; C1- 10 cycloalkyl optionally substituted by straight or branched chain alkyl, alkenyl, alkynyl or aryl; or aryl optionally substituted by 1 0 straight or branched chain alkyl, alkenyl, alkynyl or cycloalkyl.

Preferably, R is -(CH 2 4

CH

3

-(CH

2 6

CH

3 or -(CH 2 8

CH

3 In another aspect, the present invention provides a method of preparing compounds of formula radiolabelled complexes thereof or pharmaceutically acceptable salts thereof, where R is straight or branched chain C1- 10 alkyl, Ci.

10 alkenyl, C1-10 alkynyl optionally substituted by cycloalkyl or aryl; C.o 10 cycloalkyl optionally substituted by straight or branched chain alkyl, alkenyl, alkynyl or aryl; or aryl optionally substituted by straight or branched chain alkyl, alkenyl, alkynyl or cycloalkyl which comprises the steps of treating 1,1,4,4-tetramethylimidazolidino[l, 2-d]dithiaazepine with an acylating agent to provide the acyl derivative; (ii) treating the acyl derivative with a reducing agent to provide of 2,2,9,9-tetramethyl-4,7- (N-CH2-R TMDADT) and (iii) treating the N-CH 2 -R TMDADT derivative with a rhenium agent in the presence of stannous S:13160KF/3.06. S,' 5 chloride to produce compounds of formula or treating 1,1,4,4-tetramethylimidazolidino l, 2-d]dithiaazepine with the desired ubromoalkane followed by (ii) treating the resultant N-alkyl compound with a reducing agent and (iii) treating the resulting N-alkylTMDADT derivative with a rhenium agent in the presence of stannous chloride to produce compounds of formula The synthesis route of Re=0[4-N-CH 2 is shown in scheme 1. Treatment of with an acylating agent such as acylchloride gave N-acyl compounds in good yield.

S 15 The reduction of with a reducing agent such as LiAlH4 afforded N-CH 2 -R compounds in 40-50% yield.

Treatment of compounds with ReO 4 yielding agents such as NH 4 ReO 4 in stannous chloride provides complexes of formula 20 The Re=0 N-n-hexylTMDADT] was crystallized and dissolved in Lipiodol to more than 10mg/lml and the solution showed high chemical stability. The 186 Re=[N-nhexylTMDADT] which is expected as a radiopharmaceutical for liver cancer therapy was also obtained in good yield.

In a further aspect, the present invention provides rhenium complexes of formula radiolabelled complexes thereof or pharmaceutically acceptable salts thereof as radiopharmaceuticals for liver cancer therapy and metastasis of cancer.

Among the Re=0(V) [DADT] complexes made, we have found that 2,2,9,9-tetramethyl-4-N-alkyl-4,7-diaza-l,10decanedithiol (alkyl Me to decanyl) makes stable and Lipiodol soluble Re=0[4-N-alkylTMDADT]. The synthesis route of Re=0[4-N-methyl] is shown in Scheme 2.

1,1,4,4-tetramethylimidazolidino[l,2-d]dithiaazepine was obtained in 94% yield by the reduction of 3,3,10,10-tetramethyl-l,l-dithia-5,8-diazacyclodeca-4,8diene using one molar ratio of sodium borohydride under S:13160KF/30.06.93 6 T s-s

NN

ON

NaBH 4 -0 0

C

0 0*~ 6000 A A. A

A

A. CA s-s N

NH

D LiI 4

R

X C N

N

-j (3) SH HS NH N

R

NH

4 ReO 4 O.1M SnC1 2 (4) SCHEME 1.

7 s-s N N NaBH 4 S -S NHl

(L)

a a a 44ta

CH

3 I LiAIH 4

GH

3 (2) (4) N-H4ReO 4 SCHEME 2.

8 cooling in an ice bath. Iodomethylation of following neutralization with sodium hydroxide gave N-methyl compound Reduction of with LiA1H 4 afforded Nmethyl compound in 40-50% yield. As the HC1 salts obtained were very hygroscopic, rhenium complexes were made using unpurified HC1 salts of according to Mahmood's procedure (1990).

Synthesis of the Rhenium- complexes of formula (I) may be also achieved using a modification of Scheme 2.

In this method an a-Bromo.alkane of the appropriate length can be reacted with the intermediate to form a long chain (C2- 10 N-alkyl compound which is readily reduced to the diaminedithiol ligand using LiAlH 4 This method allows easier and faster reduction step which in turn allows for purer and more stable ligands.

The solubility of the 8 6 Re=0[4-N-n-hexyl TMDADT] in Lipiodol is sufficient to deliver a therapeutic dose within a single standard Lipiodol injection, typically 4- (Konno et al., 1983; Nakajo et al., 1988). It is S 20 anticipated that the higher energy beta emission of 1 86 Re (1.07MeV) and its higher rate of retention in the tumour tissue as compared to 1 3 1 I] Lipiodol (0.32MeV) will improve markedly the efficacy of radionuclide/Lipiodol therapy.

Therefore, in yet another aspect, the present invention provides radiolabelled rhenium complexes of formula or pharmaceutically acceptable salts thereof

O

Re-.

(II)

N

N

S:13160KF/30.06.93 9 where R' is as defined for R in formula in Lipiodol or other lipid soluble oils, long chain fatty acids or esters thereof.

Preferably, the other lipid soluble oils are grape seed oil, mustard seed oil, olive oil and the like.

Esters include glycerides and ethiodol which is the ethyl ester of iodinated fatty acid of poppyseed oil.

In yet another aspect, the present invention provides the use of a radiolabelled rhenium complex of formula (II) to enhance the efficacy of Lipiodol in the treatment of liver cancer.

Formulations of the rhenium complex and oil combination are prepared and administered according to standard techniques. By way of example, about 5-10mg of 15 "6ReO[N-n-hexylTMDADT] of 20-40mCi/mg summing to a dosage of approximately 200mCi dissolved in a single standard Lipiodol injection (4-5ml) ie a concentration of typically not more than 2.5mg/ml is administered. The effective amount of the complex or the combination of the 20 complex and Lipiodol required for use in the above conditions will vary both with the route of administration, the condition under treatment and the host undergoing treatment, and is ultimately at the discretion of the physician.

Complexes of formula or (II) additionally synthesised with linker arms are useful for linking to monoclonal antibodies and radioimmunospecific pharmaceuticals to treat various cancers. As a result of the solubility of complexes of formula (II) in Lipiodol or other lipid soluble oils it has emerged that a combination of a complex of formula (II) with Lipiodol and other anticancer drugs such as SMANCS would be suitable for use in cancer therapy. A preferred use is the administration of the radioactive complex of formula (II) dissolved in Lipiodol via intra-arterial infusion into the liver as practised in the art of medicine.

A further preferred use of compounds of formula (II) is in the treatment of liver cancer, hepatoma and cancer S:13160KF]30.06.93 10 metastasis to the liver resulting from cancer elsewhere in the body such as the colon.

No-carrier added 188 Re is preferred to 186 Re if the chelate is to be attached to a monoclonal antibody and administration in solution in addition to Lipiodol.

In yet another aspect, the present invention provides a pharmaceutical formulation comprising a compound of formula a radio labelled compound thereof or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

A pharmaceutical formulation of the present invention comprises the active compound together with one or more pharmaceutically acceptable carriers and optionally any other therapeutic ingredient. The formulation may conveniently be prepared in unit dosage form and may be prepared according to conventional pharmaceutical techniques. Additionally, the formulations may include one or more accessory ingredients, such as diluents, buffers, flavouring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives and the like.

The present invention also envisages complexes of formula or (II) and their use in cancer therapy wherein the Rhenium is replaced by other radionuclides such as 99 mTc and radiotherapeutic isotopes such as 90 y.

is reactor produced and decays by beta emission of endpoint energy of 2.27MeV and has a half-life of 64 hours.

Specific embodiments of the present invention are illustrated by the following examples. It will be understood, however, that the invention is not confined to specific limitations set forth in the individual examples.

S:13160KF/30.06.93 11

EXAMPLES

2,2-dithio-bis(2-methylpropanal) This compound was prepared originally by Niederhauser et al., (1952). After that, however, several modified procedures were reported (Merz et al., 1963; D'Amico et al, 1975; Corbin et al., 1976; Kung et al., 1984; Liang et al., 1987). We obtained the compound in 40-65% yield according to Liang's method.

3,3,10,1O-tetramethyl-1,2-dithia-5,8-diazacyclodeca-4,8- S 10 diene This cyclic diimine was prepared from 2,2'dithio-bis(2methylpropanal) and ethylenediamine by Kung et al. (1984) and Liang et al. (1987). We synthesized this compound in 50-65% yield according to Liang's procedure.

15 1,1,4,4-tetramethylimidazlidino[,2-d]dithiazepine This compound was synthesized according to a method of Joshua et al. (1987) with modification. A mixture of 4.60g (20mmole) of 3,3,10,10-tetramethyl-l,2-dithia-5,8diazacyclodeca-4,8-diene in 80ml of ethanol was cooled in an ice bath. To this mixture was added 0.756g(20mmole) of NaBH 4 by portions under stirring. The mixture was stirred for 30 min at room temperature, and ethanol was removed by evaporation under reduced pressure. To the residue was added water, and undissolved solid was extracted with ether. The extract was washed with water and dried over sodium sulphate. After removing ether by evaporation under reduced pressure, 4.37g (94.0% yield) of solid was obtained. mp 58-62 0 C. This compound was used without purification for further synthesis.

1,1,4,4-tetramethyl-9-N-methylimidazolidino l,2-d1 dithiazepine (2) To a solution of 4.85g of 1,1,4,4-tetramethylimidazolidino[1,2-d]dithiazepine in 20ml of ethanol was added Ig of methyliodide. The mixture was heated to reflux for 3 hr. After cooling, ether was added and S:13160KF/30.06.93 12 6.15g of crystals was collected by filtration. mp 193- 1940C. The crystals (5.0g) obtained were suspended in of ether and NaOH (0.6g) added in 20ml of H 2 0, and stirred until all of the crystals dissolved in the ether.

The ether layer was separated and washed with water.

After drying the ether layer over sodium sulphate, ether was evaporated under reduced pressure to give 3.20g of oil which crystallized. mp 28-290C, H1NMR(CDC13) Analytical Calcd for C 11

H

22

N

2

S

2 53.61; H, 9.00; N, 11.37. Found: C, 53.53; H, 9.13; N, 11.57.

2,2,9 ,9-pentamethyl-4-N-methyl-4,7-diaza-1 decanedithiol [4(N-Me)] To a solution of N-methyl-bicyclic compound Sin dry THF (100-150ml) was added a large excess of LiAlH 4 (30mmole), and the mixture was refluxed for about 24 hr.

The reaction mixture was quenched with salt. NH 4 C1, and filtered. The contents of the funnel were washed with 100ml of CHC13 twice and the combined filtrate of THF and CHC1 3 was evaporated to dryness under reduced pressure.

20 The residue was dissolved in ether (100ml), and the hydrochloride salt was made by addition of ethanol HC1 and removal of organic solvent under reduced pressure.

The crystallinity of the HC1 salts was poor due to their strong hygroscopic nature.

2,2,9,9-Dentamethyl-4-N-octyl-4,7-diaza-1-1,10decanedithiol [4(N-Me)] To 1 equivalent of was added 1.5 equivalent of 1- Bromooctane in toluene. 2 equivalents of K 2 CO was also added. The reaction was refluxed for 24 hours after which time the toluene was evaporated, water added and the aqueous layer extracted with ether. Purification of the ether layer products was by column chromatography (silica gel dichloromethane eluant) yielded the product in 46.7% yield.

This material was then easily reduced to the S:13160KF/30.06.93 13 diaminedithiol using three equivalents of LiA1H 4 in tetrahydrofuran refluxed for twelve hours General procedure for acylation Preparation of 3 A solution of 1 equivalent of bicyclic compound in ether and 1.2 equivalents sodium hydroxide (1N NaOH

H

2 0) was mixed with stirring in an ice bath, and to that 1 equivalent of acyl chloride was added dropwise. Then the mixture was stirred for 30 min at room temperature.

The ether layer was separated, washed with water and dried over sodium sulphate. After removal of ether, Nacyl diazepine was obtained.

Treatment of 1 (3.85g, 16.56mmole) with n-hexanoyl chloride (2.4g, 17.5mmole) gave an oily compound. After purification by silica gel column chromatography (CHC13), 15 5.0g of the N-n-hexanoyl compound was obtained.

The HC1 salt was colourless silky needles, mp 133-135 0

C.

IR 1656cm-1 NMR (free base).

4* Treatment of 1 (2.32g, 10mmole) with n-octanoyl chloride (1.63g, 10mmole) gave an oily compound. After 20 "purification by silica gel chromatography (CHC1 3 2.86g of the N-n-octanoyl compound was obtained. The HC1 salt was colourless silky needles, mp 127-128 0 C. IR 1653cm 1 Treatment of 1 (2.32g, 10mmole) with decanoyl chloride (1.94g, 10mmole) gave 3.88g of oily compound.

After purification by silica gel chromatography (CHC1 3 3.03g of N-decanoyl compound was obtained as a solid. mp 53-56 0 C. IR 1651cmn 1 Treatment of 1 (2.32g, 10mmole) with myristoyl chloride (2,72g, 10mmole) gave 4.41g of solid compound.

After purification by silica gel chromatography (CHCL 3 of N-myristoyl compound was obtained as a solid. mp 73-74°C. IR 1651cm" 1 S:13160KF/30.06.93 14 General Procedure for the Preparation of N-alkyl-2,2.9,9tetramethyl-4,7-diaza-4-alkyl-1,10-decanedithiol (4) To a solution of N-acyl-bicyclic compound in dry tetrahydrofuran (THF) (100-150ml) was added a large excess of LiAlH 4 (50mmole), and the mixture was refluxed for about 24hr. The reaction mixture was quenched with satd. NH 4 C1, and filtered. The contents of the funnel were washed with 100ml of CHC1 3 twice and the combined filtrate of THF and CHC1 3 was evaporated to dryness under reduced pressure. Water was added (100ml), and the pH was adjusted to 3.0 with concentrated HC1.

The mixture was extracted with diethyl ether (80ml/extraction) to remove ether solublc impurities.

These ether solutions were discarded. The oH was then 15 adjusted to 8.0 and extracted with fresh ether. These ether solutions were dried (Na 2

SO

4 filtered and evaporated under reduced pressure. The residue was dissolved in ether (100ml) and the hydrochloride salt was made by addition of ethanol HC1 and the organic 20 solvent removed under reduced pressure. The crystallinity of the HC1 salts was poor due to their very strong hygroscopic nature.

2,2,9,9-tetramethyl-4,7-diaza-4-n-hexyl-1,10decanedithiol was obtained as oil in 45% yield.

ReO [N-n-Hexyl TM DADTI 1H NMR (CDC1 3 60.9 3H), 1.3-1.4 6H), 1.5 3H), 1.6 3H), 1.8 3H), 1.85-1,90 2H), 1.9.0 3H), 2.2 (d,1H), 2.4 1H), 3.2 1H), 3.25 1H) 3.5 2H) 3.8- 3.9 2H), 4.0 1H), 4.2 1H).

UV Maxima 370, 269nm; IR (Re=O) 942cm- mp 1200C.

Analysis: Found(Calc)C, 37.2(37.0); H, N, 5.2(5.4).

2,2,9,9-tetramethyl-4,7-diaza-4-n-octyl-l,10dedcanedithiol was obtained as oil in 57.6% yield.

SI 3160KF/30.06.93 15 ReOrN-Octyl TM DADTI 1 H NMR (CDC1 3 1 60.9 3H), 1.2-1.4 8H), 1.5 3H), 1.6 3H), 1.8 3H), 1.80-1.90 2H), 1.9 3H), 2.2 1H), 2.3-2.4 1H) 3.1-3.2 1H), 3.2 1H), 3.4-3.55 2H), 3.8-3.9 2H), 3.9-4.0 1H), 4.1-4.2 (m, 1H), IR(Re=O) 941 cm- 1 Preparation of Re=0[4-N-alkyl DADT1 These Rhenium complexes were prepared according to Mahmood's method (1990).

The ligand and NH 4 ReO 4 were mixed in equimolar ratios in 50:50 aqueous ethanol. As the solution stirred, an equivalent amount of the stannous chloride solution [SnCl 2 -2H 2 0(0.1M) was prepared in HCI was added dropwise. Addition of the reducing agent was accompanied by an instantaneous colour change to green-violet. The reaction mixtures were allowed to stir at room temperature for 10 min, after which the ethanol was evaporated under vacuum at room temperature. The reaction mixture was neutralized with K 2

CO

3 and then 20 extracted with chloroform. Following evaporation of the *4*g solvent the crude product was chromatographed on a silica gel column using chloroform as the eluting solvent. Only a deep violet band was eluted, which was collected and concentrated under reduced pressure.

General Procedure for Radiolabelling 1. Reaction of ammonium perrhenate with 2,2,9,9, tetramethyl-4,7-diamino,4-n-hexyl,1-10-decanedithiol (N Hexyl, TM-DADT).

250 mg of N-Hexyl TM DADT (freshly prepared (0.78mmol)) and 209mg of NH 4 ReOA (0.78mmol) (cold) were dissolved in of EtOH and 10ml of To this was added 0.667g (2.96 mmol) of SnCl 2 .2H 2 0 in ml of 0.9M HC1.soln, freshly, prepared and filtered through a 0.22Am filter, over 15 minutes. The reaction was then stirred for two hours under nitrogen. The ethanol was removed in vacuo and the solution neutralised S:13160KF/30.06.93 16 S S 5 *5 with concentrated K 2 C0 3 solution. (pH The aqueous layer was then extracted three times with chloroform (3 x The combined CHC1 3 extracts were then reduced in vacuo and chromatographed with column chromatography on Silica Gel G60 (Merck). The compound was isolated as a purple gum which was induced to crystallise in dichloromethane.

Yield 120mg (0.23mmol) 29.5% 2. Reaction of amnonium perrhenate with 4,7-diamino, 4n-octyl,2,2,9,9-tetramethyl-1,10-decanedithiol: dihydrochloride salt (N-octyl TM DADT). 2HC1.

(1.42mmol) 600mg N-octylTM-DADT-2HC1 and (1.42mmol) 380mg

NH

4 ReO 4 were dissolved in 20ml of EtOH and 20ml of water.

To this was added 90 ml of 0.1M SnCl 2 .2H 2 0 solution in 0.9M HC1 (freshly prepared and filtered). The reaction was allowed to run for 1 hour with stirring under N 2 gas.

The ethanol was then removed in vacuo and the aqueous layer neutralised (pH 8) with solid K 2 C0 3 The compound was then extracted with chloroform (100ml x 3) then the 20 combined CHC1 3 extracts evaporated and the material chromatographed (column chromatography. Silica Gel Merck) CHC1 3 eluant.

The compound was isolated as a purple gum 300mg (39.8% yield).

3. Radiolabelling with 186 Re.

-3mg of Re metal (10mCi) was dissolved and oxidised with

H

2 0 2 (2ml) over 2 hours then 2ml NH 3 27% added to neutralise and form the ammonium perrhenate salt. The solution was then evaporated to dryness, washed with 2ml of H20 into another flask and 2ml of EtOH added with of N-Hexyl TM DADT. 2HC1 (78 Amol) and 3ml of 0.1M SnCl 2 .2H 2 0) (90mmol) in 0.9MHC1 was slowly added. (The solution was filtered through 0.22/m filter and freshly prepared). The reaction was allowed to proceed under N 2 for 2 hours, then removed and the ethanol removed in vacuo. The aqueous layer was neutralised with concentrated K 2 CO solution (-2ml) and extracted with CHC13 (3 x S:13160KF30.06.93 -17 The next day the combined, CHC13 extracts were reduced to dryness in vacuo then redissolved and chromatographed in chloroform on a Merck G40 Silica Column. A faint purple band was collected and registered as The CHC1 3 was removed, then the material dissolved in 2ml EtOH, filtered through millipore 0.22Am filter and chromatographed by rapid t.l.c. (one peak rf=0.9) in CHC1 3

REFERENCES

1. J.L. Corbin and D.E. Work (1976), J. Org. Chem., 41, 489.

2. K. Iwai, H. Maeda and T. Konno (1984), Cancer Res., 44, 2115.

3. J.J. D'Amico and W.E. Dahl (1975), J. Org. Chem., 40, 1224.

4. A.V. Joshua, J.R. Scott, S.M. Sondhi, R.G. Ball and J.W. Lown (1987), J. Org. Chem., 52, 2447.

T. Konno, H, Maeda, K. Iwai, S. Tashiro, S. Maki, T.

Morinaga, M. Mochaninaga, T. Hiraoka and I. Yokoyama 20 1983, Eur. J. Cancer Cli., Oncol., 19, 1053.

6. H.F. Kung, M. Molnar, J. Billings, R. Wicks and M.

Blau (1984), J. Nucl. Med. 25, 326.

7. F.H. Liang, F. Virzi and D.J. Hnatowich (1987), Nucl. Med. Bio., 14, 63.

8. K.W. Merz and M. Specker (1963), Arch. Pharm., 296, 427.

9. A. Mahmood, K.E. Baidoo and S.Z. Lever in Technetium and Rhenium in Chemistry and Nuclear Medicine 3 Edited by M. Nicolini, G. Bandoli and U. Mazzi (1990), pp. 119, Raven Press, New York.

M. Nakajo, H. Kobavashi, K. Shimabukuro, K. Shirono, H. Sakata, M. Taguchi, N. Uchiyama, T. Sonoda and S.

Shinohara (1988), J. Nucl. Med., 29, 1066.

11. W.D. Niederhauser (1952), U.S. Patent 2,580,695.

12. C.H. Park, H.S. Yoo and J.H. Sue (1990), Eur. J.

Nucl. Med., 16, 5143.

S:13160KF/30.06.93

Claims (8)

1. Rhenium complexes of radiolabelled complexes thereof or acceptable salts thereof: C formula pharmaceutically a *aa. I I^ 'Z(I) \I Re.. N N R wherein R is straight or branched chain C 1 10 alkyl, C1- 10 alkenyl, C1- 10 alkynyl optionally substituted by cycloalkyl or aryl; C 1 10 cycloalkyl optionally substituted by straight or branched chain alkyl, alkenyl, 10 alkynyl or aryl; or aryl optionally substituted by straight or branched chain alkyl, alkenyl, alkynyl or cycloalkyl.

2. A method of preparing compounds of formula radiolabelled complexes thereof or pharmaceutically acceptable salts thereof, where R is as defined in claim 1 which comprises the steps of treating 1,1,4,4-tetramethylimidazolidino [1,2-d]diaazepine with an acylating agent to provide the acyl derivative; (ii) treating the acyl derivative with a reducing agent to provide the N-CH 2 R TMDADT derivative and (iii) treating the N-CH 2 R TMDADT derivative with a rhenium agent in the presence of stannous chloride to produce compounds of formula or (i) treating 1,1,4,4-tetramethylimidazolidino[l, 2-d]dithiaazepine with the desired bromoalkane followed by (ii) treating the resultant N-alkyl compound with a S:13160KF/30.06.93 19 reducing agent and (iii) treating the resulting N-alkylTMDADT derivative with a rhenium agent in the presence of stannous chloride to produce compounds of formula

3. Use of rhenium complexes of formula (II) radiolabelled with 18 Re or 18Re or pharmaceutically acceptable salts thereof as radiopharmaceuticals for liver cancer therapy and metastasis of cancer.

4. A pharmaceutical formulation comprising a compound of formula or a compound of formula (I) radiolabelled with 1 86 Re or 188 Re or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

5. A product comprising a radiolabelled rhenium complex of formula (II) radiolabelled with 1 86 Re or 188 Re. Lipiodol or other lipid soluble oil. ormula (II) to enhance the eficacy of Lipiodol (I)n the 25 treatment of liver cancer. Lipiodol or other lipid soluble oil. wherein R' is as defined for R in compounds of formula or a pharmaceutically acceptable salt thereof in Lipiodol or other lipid soluble oil.

6. A product according to claim 5 further comprising one or more other anticancer agents.

7. Use of a radiolabelled rhenium complex of formula (II) to enhance the efficacy of Lipiodol in the 0 25 treatment of liver cancer.

9. Use according to claim 8 in combination with one or more anticancer agents. Is316OKF/S.O. 20 Rhenium complexes of formula MI, radiolabelled complexes thereof or pharmaceutically acceptable salts thereof substantially as herein described with reference to the examples. DATED this 30th day of June 1993 AUSTRALIAN NUCLEAR SCIENCE TECHNOLOGY ORGANISATION By their Patent Attorneys GRIFFITH HACK CO. a. e a. o S S 5 9 S *Sa* *9 55 5 9 'Sn 9W S. S 5* S OS.. a a S. a 95 S S S S:1 31 60KF/30.06.93 0see* 600 ABSTRACT Rhenium complexes of formula radiolabelled complexes thereof or pharmaceutically acceptable salts thereof: Re\ N N R wherein R is straight or branched chain Cl 1 0 alkyl, Cl 1 alkenyl, C 1 10 alkynyl optionally substituted by cycloalkyl or aryl; C1-0 cycloalkyl optionally substituted by straight or branched chain alkyl, alkenyl, 10 alkynyl or aryl; or aryl optionally substituted by straight or branched chain alkyl, alkenyl, alkynyl or cycloalkyl for use in liver cancer therapy and metastasis of cancer. S:1 3160KF/30.06.93