Boronic acid adducts of rhenium dioxime and technetium-99m dioxime complexes containing a biochemically active group

• US 5,387,409 A
• Filed: 01/07/1992
• Issued: 02/07/1995
• Est. Priority Date: 01/18/1990
• Status: Expired due to Term

• Current Assignee: Bracco Suisse SA
• Original Assignee: Bracco International B.V. (Bracco SPA)
• Inventors: Eckelman, William C., Jurisson, Silvia, Linder, Karen E., Nunn, Adrian D.
• Primary Examiner(s): Stoll, Robert L.
• Assistant Examiner(s): COVERT, JOHN
• Application Number:
  US07/818,705
• Time in Patent Office: 1,127 Days
• Field of Search: 424/1.1, 424/1.45, 424/1.53, 424/1.65, 424/1.69, 424/1.73, 534/10, 534/14
• US Class Current: 424/1.45
• CPC Class Codes: A61K 2123/00 Preparations for testing in vivo
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Abstract

Boronic acid adducts of technetium-99m and radioactive rhenium dioxime complexes, each of which include biochemically active groups, are useful as diagnostic and therapeutic agents, respectively.

Claims

1. A boronic acid adduct of technetium dioxime or rhenium dioxime complexes having the formula

View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 43, 44, 45, 46, 47, 48, 49, 50, 51)

2. The boronic acid adduct of claim 1 wherein said biochemically active group at R₃ is a metabolic substrate or inhibitor, or a molecule with an affinity for a specific receptor.

3. The boronic acid adduct of claim 1 containing the spacer (A₁)_p wherein p is an integer greater than zero, and the various A₁ units (which form a straight or branched chain) are independently selected from --CH₂ --, --CHR₄ --, --CR₄ R₅ --, --CH═

CH═

, --CH═

CR₅ --, --CR.tbd.C--, cycloalkyl, cycloalkenyl, aryl, heterocyclo, oxygen, sulfur, ##STR30## --NH--, --HC═

N--, --CR₄ ═

N--, --NR₄ --, --CS--;

wherein R₄ and R₅ are independently selected from alkyl, alkenyl, alkoxy, aryl, 5- or 6-membered nitrogen or oxygen containing heterocycle, halogen, hydroxy or hydroxyalkyl.

4. The boronic acid adduct of claim 1 wherein (A₁)_p is absent or is selected from alkyl, oxa-alkyl, hydroxyalkyl, hydroxyalkoxy, alkenyl arylalkyl, alkenyl, arylalkylamide, alkylamide, alkylamine and (alkylamine)alkyl.

5. The boronic acid adduct of claim 1 wherein (A₁)_p is absent or is selected from --(CH₂)_2-3 --, --CH₂ --CH═

CH--CH₂ --, ##STR31## --(A₃ --O--A₃ '"'"')_1-3 --, --(A₃ --NH--A₃ '"'"')_1-3 -- or --CH₂ CH═

CH--;

wherein A₃ and A₃ '"'"' are the same or different alkyl.

6. A boronic acid adduct in accordance with claim 1 wherein X is a halide.

7. A boronic acid adduct in accordance with claim 6 wherein X is chloride or bromide.

8. A boronic acid adduct in accordance with claim 7 wherein X is chloride.

9. A boronic acid adduct in accordance with claim 1 wherein X is hydroxy.

10. A boronic acid adduct in accordance with claim 1 wherein Y is dimethylglyoxime, 1,2-cyclohexanedione dioxime, 1,2-cyclopentanedione dioxime, or 3-methyl-l,2-cyclopentanedione dioxime.

11. A boronic acid adduct in accordance with claim 1 wherein R₃ is asteroid.

12. A boronic acid adduct in accordance with claim 11 wherein R₃ is estradiol, [17α

(E)-3,17-dihydroxy-1,3,5(10)-estratrien-17-yl]ethenyl.

13. A boronic acid adduct in accordance with claim 12 wherein R₃ is MIVE, [[11-β

, 17-α

(E)]-3,17-dihydroxy-11-methoxy-1,3,5(10)-estratrien-17-yl]ethenyl.

14. A boronic acid adduct in accordance with claim 1 wherein R₃ is a substrate for a muscarinic receptor.

15. A boronic acid adduct of claim 14 wherein R₃ is 3-quinuclidinyl benzilate.

16. A boronic acid adduct in accordance with claim 1 wherein R₃ is a hypoxia-mediated nitro-heterocyclic group.

17. A boronic acid adduct in accordance with claim 16 wherein R₃ is a hypoxia-mediated nitro-heterocyclic group and the spacer-R₃ portion of the complex are selected from ##STR32## the ring portion being a 5- or 6-membered cyclic or aromatic ring, wherein;

n is the total number of substitution positions available on the 5- or 6-membered ring;

said one or more R groups are independently hydrogen, halogen, alkyl, aryl, alkoxy, oxa-alkyl, hydroxyalkoxy, alkenyl, arylalkyl, arylalkylamide, alkylamide, alkylamine and (alkylamine)alkyl;

X₁ is nitrogen, sulfur, oxygen, --CR═

or --CRR--; and

(A₁)_p can be absent in which case the R₃ group is linked to the rest of the adduct of claim 1 via a nitrogen or carbon atom, or (A₁)_p comprises the link between R₃ and said rest of the adduct of claim 1.

18. The boronic acid adduct of claim 17 wherein said hypoxia-mediated nitro-heterocyclic group is selected from 2-, 4- or 5-nitroimidazoles, nitrofurans, nitrothiazoles and derivatives thereof.

19. A compound according to claim 1 having the name Tc(chloride)(dimethylglyoxime)₃ (estradiol boron).

20. A compound according to claim 1 having the name TcCl(cyclohexanedionedioxime)₃ (estradiol boron).

21. A compound according to claim 1 having the name [TcCl(dimethylglyoxime)₃ [3-quinuclidinyl(4-boronobenzilate)]].

22. A compound according to claim 1 having the name Tc(chlorine)(1,2-cyclohexanedionedioxime)₃ 1-(2-nitroimidazoyl)benzylboron.

23. A compound according to claim 1 having the name Tc(chlorine)(dimethylglyoxime)₃ 1-(2-nitroimidazoyl)benzylboron.

24. A compound according to claim 1 having the name Tc(chlorine)(dimethylglyoxime)₃ -4-(2-nitroimidazole ethyl)phenyl boron.

25. A compound according to claim 1 having the name Tc(chlorine)(dimethylglyoxime)₃ -1-(n-propyl-2-nitroimidazolyl)boron.

26. A compound according to claim 1 having the name Tc(chlorine)(dimethylglyoxime)₃ -1-(propene-2-nitroimidazolyl)boron.

27. A compound according to claim 1 having the name Tc(chlorine)(dimethylglyoxime)₃ -1-(4-nitroimidazolyl) benzylboron.

28. A compound according to claim 1 having the name Tc(chlorine)(1,2-cyclohexane-dionedioxime)₃ -1-(4-nitroimidazolyl)benzylboron.

29. A compound according to claim 1 having the name Tc(hydroxy)dimethylglyoxime)₃ -1-(2nitroimidazolyl)benzylboron.

30. A compound according to claim 1 having the name Tc(chlorine)(1,2-cyclohexane-dionedioxime)₃ -1-(propane-nitroimidazolyl)boron.

31. A compound according to claim 1 having the name Tc(chlorine)(1,2-cyclohexane-dionedioxime)₃ -1-(propene-nitroimidazolyl)boron.

43. A method for the diagnostic imaging of hypoxic tissue in a mammalian species comprising the administration of a complex of formula I in claim 1 wherein M is technetium-99m and R₃ is or contains a hypoxia-mediated nitro-heterocyclic group.

44. A method for providing radiotherapy to a mammalian species in need thereof comprising the administration of a complex of formula I in claim 1 wherein M is a radionuclide of rhenium and wherein R₃ is or contains a hypoxia-mediated nitro-heterocyclic group or is selected from estrogen, estradiols and derivatives thereof.

45. A method for the diagnostic imaging of the heart in a mammalian species comprising the administration of a complex of formula I in claim 1 wherein M is technetium-99m and R₃ is or contains a biochemically active group selected from sugars and substrates for muscarinic receptors.

46. A method for the diagnostic imaging of the brain in a mammalian species comprising the administration of a complex of formula I in claim 1 wherein M is technetium-99m and R₃ is or contains a biochemically active group selected from substrates for muscarinic receptors and sugars and amphetamines.

47. A method for the diagnostic imaging of carcinoma in a mammalian species comprising the administration of a complex of formula I in claim 1 wherein M is technetium-99m and R₃ is or contains a hypoxia-mediated nitro-heterocyclic group, a sugar, or asteroid or molecule with an affinity for asteroid receptor site.

48. A method for the diagnostic imaging of estrogen receptor sites in a mammalian species in need thereof comprising the administration of a complex of formula I in claim 1 wherein M is technetium-99m and R₃ is selected from estrogen, estradiols and estradiol derivatives.

49. The method of claim 48 wherein the estrogen receptor site is selected from breast and uterine carcinoma.

50. A compound according to claim 1 having the name ^99m TcCl(DMG)₃ [(RR or RS)QNB boron].

51. A compound according to claim 1 having the name ^99m TcCl(CDO)₃ (QNB-boron).

32. A kit suitable for labelling with a radionuclide of technetium or rhenium, said kit comprising:

(i) a source of anion;

(ii) a boronic acid derivative, (or compounds which can react in situ to form a boronic acid derivative) having the formula ##STR33## or a pharmaceutically acceptable salt thereof, wherein R₇ and R₇ '"'"' are each independently hydrogen, alkyl, or aryl, or where R₇ and R₇ '"'"' taken together are --(CR₈ R₉)_2-6 -- and R₈ and R₉ are independently hydrogen or alkyl; and

wherein R₃ is or contains a biochemically active group selected from the group consisting of hypoxia-mediated nitro-heterocyclic groups, steroids, sugars, barbiturates, monoamine oxidase substrates and inhibitors, antihypertensives, substrates for muscarinic receptors and substrates for dopamine receptors;

and wherein (A₁)_p is absent or is a spacer group, wherein, when p is an integer greater than zero, the various A₁ units (which form a straight or branched chain) are independently selected from --CH₂ --, --CHR₄ --, --CR₄ R₅ --, --H═

CH═

, --CH═

CR₄ --, --CR₄ ═

CR₅ --, --C.tbd.C--, cycloalkyl, cycloalkeny, aryl, heterocyclo, oxygen, sulfur, ##STR34## --NH--, --HC═

N--, --CR₄ ═

N--, --NR₄ --, or --CS--, in which R₄ and R₅ are independently selected from alkyl, alkenyl, alkoxy, aryl, 5- or 6-membered nitrogen or oxygen containing heterocycle, halogen, hydroxy or hydroxyalkyl;

(iii) a dioxime having the formula ##STR35## or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂ are each independently hydrogen, halogen, alkyl, aryl, amino or a 5- or 6-membered nitrogen or oxygen containing heterocycle, or together R₁ and R₂ are --(CR₈ R₉)_n -- wherein n is 3, 4, 5 or 6 and R₈ and R₉ are each independently hydrogen or alkyl; and

,

(iv) a reducing agent.

33. A kit in accordance with claim 32 wherein the source of anion is a source of halide.

34. A kit in accordance with claim 32 wherein the source of anion is chloride or bromide.

35. A kit in accordance with claim 32 wherein the dioxime is dimethylglyoxime, 1,2-cyclohexanedione dioxime, 1,2-cyclopentanedione dioxime, or 3-methyl-1,2-cyclopentanedione dioxime.

36. A kit in accordance with claim 32 wherein the reducing agent is a stannous salt.

37. A kit in accordance with claim 32 wherein said biochemically active group is a metabolic substrate or inhibitor, or a molecule with an affinity for a receptor site.

38. A kit in accordance with claim 32 wherein R₃ is asteroid.

39. A kit in accordance with claim 32 wherein R₃ is estradiol, [17α

(E)-3,17-dihydroxy-1,3,5(10)-estratrien-17-yl]ethenyl.

40. A kit in accordance with claim 32 wherein R₃ is MIVE, [[11-β

, 17-α

(E)]-3,17-dihydroxy-11-methoxy-1,3,5(10)-estratrien-17-yl]ethenyl.

41. A kit in accordance with claim 32 wherein R₃ is a substrate for a muscarinic receptor.

42. A kit in accordance with claim 32 wherein R₃ is 3-quinuclidinyl benzilate.