Crowned dithiocarbamate metal complexes and methods for their use

• US 20070166227A1
• Filed: 02/10/2005
• Published: 07/19/2007
• Est. Priority Date: 02/10/2004
• Status: Abandoned Application

• Current Assignee: Purdue Research Foundation (Purdue University)
• Original Assignee: Purdue Research Foundation (Purdue University)
• Inventors: Liu, Shuang, He, Zhengjie
• Application Number:
  US10/588,343
• Publication Number:
  US 20070166227A1
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: A61K 51/0423 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 51/044 having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins rifampin A61K51/0459
• CPC Class Codes: A61K 51/0476 complexes from monodendate ligands, e.g. sestamibi
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage

Abstract

Compositions containing crowned dithiocarbamate metal complexes and methods of using these compositions; neutral and cationic radioactive metal-nitrido complexes of crowned dithiocarbamates (DTCs) and methods of using these complexes as radiopharmaceuticals for diagnosis and treatment of cardiovascular disorders, infectious diseases, and cancer; tripodal chelatormetal complexes of crowned DTCs and methods of using these complexes for treating diseases such as those characterized by nitric oxide overproduction; and methods of using crowned DTCs for heavy metal detoxification are described.

Claims

1. A composition comprising a compound comprising a formula (M≡

N)L¹ and pharmaceutically acceptable salts thereof;

wherein N is nitrogen;

M is a transition metal; and

L¹ is a first crowned dithiocarbamate, wherein the first crowned dithiocarbamate comprises a first crown ether-containing group of formula [(CH₂)_a—

O]_b—

(CH₂)_c, wherein a is at least 2, b is at least 3, and c is at least 2.

2. The composition of claim 1, wherein the first crowned dithiocarbamate comprises a formula:

and pharmaceutically acceptable salt thereof;

wherein R¹ or R² comprises the first crown ether-containing group, or R¹ and R² together comprise the first crown ether-containing group.

3. The composition of claim 1, wherein the transition metal is a radioactive metal.

4. The composition of claim 1, wherein the transition metal is ^99mTc or ^94mTc.

5. The composition of claim 1, wherein the transition metal is ¹⁸⁶Re or ¹⁸⁸Re.

6. The composition of claim 1, wherein subscript a in the formula of the first crown ether-containing group is 2, 3, 4, or 5.

7. The composition of claim 1, wherein subscript a in the formula of the first crown ether-containing group is 2 or 3.

8. The composition of claim 1, wherein subscript a in the formula of the first crown ether-containing group is 2.

9. The composition of claim 1, wherein subscript b in the formula of the first crown ether-containing group is 3, 4, 5, 6, 7, or 8.

10. The composition of claim 1, wherein subscript b in the formula of the first crown ether-containing group is 3, 4, 5 or 6.

11. The composition of claim 1, wherein subscript c in the formula of the first crown ether-containing group is 2, 3, 4, or 5.

12. The composition of claim 1, wherein subscript c in the formula of the first crown ether-containing group is 2 or 3.

13. The composition of claim 1, wherein subscript c in the formula of the first crown ether-containing group is 2.

14. The composition of claim 1, wherein the first crowned dithiocarbamate comprises

15. The composition of claim 1, wherein the first crowned dithiocarbamate comprises

16. The composition of claim 1, wherein the first crowned dithiocarbamate comprises

17. The composition of claim 1, wherein the first crowned dithiocarbamate comprises

18. The composition of claim 1, wherein the first crowned dithiocarbamate comprises

19. The composition of claim 1, wherein the first crowned dithiocarbamate comprises

20. The composition of claim 1, wherein the first crowned dithiocarbamate is selected from the group consisting of

21. The composition of claim 1, wherein the compound is selected from the group consisting of:

22. The composition of claim 1, wherein the compound further comprises L² and comprises a formula (M≡

N)L¹L² and pharmaceutically acceptable salts thereof;

wherein L² is a second crowned dithiocarbamate, wherein the second crowned dithiocarbamate comprises a second crown ether-containing group of formula [(CH₂)_a—

O]_b—

(CH₂)_c, wherein a is at least 2, b is at least 3, and c is at least 2.

23. The composition of claim 22, wherein the second crowned dithiocarbamate comprises a formula:

and pharmaceutically acceptable salt thereof;

wherein R¹ or R² comprise the second crown ether-containing group, or R¹ and R² together comprise the second crown ether-containing group.

24. The composition of claim 22, wherein subscript a in the formula of the second crown ether-containing group is 2, 3, 4, or 5.

25. The composition of claim 22, wherein subscript a in the formula of the second crown ether-containing group is 2 or 3.

26. The composition of claim 22, wherein subscript a in the formula of the second crown ether-containing group is 2.

27. The composition of claim 22, wherein subscript b in the formula of the second crown ether-containing group is 3, 4, 5, 6, 7, or 8.

28. The composition of claim 22, wherein subscript b in the formula of the second crown ether-containing group is 3, 4, 5 or 6.

29. The composition of claim 22, wherein subscript c in the formula of the second crown ether-containing group is 2, 3, 4, or 5.

30. The composition of claim 22, wherein subscript c in the formula of the second crown ether-containing group is 2 or 3.

31. The composition of claim 22, wherein subscript c in the formula of the second crown ether-containing group is 2.

32. The composition of claim 22, wherein the second crowned dithiocarbamate comprises

33. The composition of claim 22, wherein the second crowned dithiocarbamate comprises

34. The composition of claim 22, wherein the second crowned dithiocarbamate comprises

35. The composition of claim 22, wherein the second crowned dithiocarbamate comprises

36. The composition of claim 22, wherein the second crowned dithiocarbamate comprises

37. The composition of claim 22, wherein the second crowned dithiocarbamate comprises

38. The composition of claim 22, wherein the second crowned dithiocarbamate is selected from the group consisting of

39. The composition of claim 1, wherein the compound is selected from the group consisting of:

40. The composition of claim 1, wherein the compound further comprises L³, L⁴ and L⁵ and comprises a formula:

and pharmaceutically acceptable salts thereof;

wherein L³, L⁴, and L⁵ each comprises an isonitrile of formula;

wherein q is 0-3;

Z is carbon or silicon;

R³, R⁴ and R⁵ are the same or different, and are selected from the group consisting of H, C₁-C₁₀ alkyl substituted with 0-5 R⁶, aryl substituted with 0-5 R⁶, heteroaryl substituted with 0-5 R⁶, and macrocyclic crown ether containing 2-8 ether-oxygen atoms;

wherein R⁶ is selected from the group consisting of H, OH, OR⁷, C(═

O)OR⁷, C(═

O)NR⁸R⁹, PO(OR⁸)₂, PO(NR⁸R⁹)₂ and SO₂R⁷; and

R⁷, R⁸ and R⁹ are the same or different, and are selected from the group consisting of H, alkyl, aryl, and heteroaryl, or R⁸ and R⁹ together form a macrocyclic crown ether containing 2-8 ether-oxygen atoms.

41. The composition of claim 1, wherein the compound further comprises L³, L⁴, and L⁵ and comprises a formula:

and pharmaceutically acceptable salts thereof;

wherein L³, L⁴, and L⁵ together form a tripodal chelator of formula;

wherein U is selected from the group consisting of R¹³B, CR¹³ and P(═

O);

A¹, A² and A³ are imine-N containing heterocycles;

A⁴, A⁵ and A⁶ are selected from the group consisting of NR¹⁴, PR¹⁴, S, and O;

R¹⁰, R¹¹ and R¹² are selected from a group of formula —

(CH₂)_g—

, wherein g is 2-5;

R¹³ is selected from the group consisting of H, alkyl and aryl; and

R¹⁴ is selected from the group consisting of H, alkyl, aryl, and alkoxyalkyl.

42. The composition of claim 41, wherein the tripodal chelator is selected from the group consisting of

43. A composition comprising a compound comprising a formula:

and pharmaceutically acceptable salt thereof;

wherein M is a transition metal selected from the group consisting of Fe(II), Fe(III), Mn(II), Mn(III), Co(II), Co(III), Ni(II), Cu(II), Zn(II), Ru(II), Ru(III), Pd(II), and Pt(II);

p and p′

are integers and are independently selected from 0-2;

R¹ and R² comprise a crown ether-containing group of formula [(CH₂)_a—

O]_b—

(CH₂)_c, wherein a is at least 2, b is at least 3, and c is at least 2, or wherein R¹ and R² together comprise the crown ether-containing group;

L⁶ is a tripodal chelator with a formula selected from the group consisting of

wherein U is selected from the group consisting of R¹³B, CR¹³, and P(═

O);

A¹, A² and A³ are imine-N containing heterocycles;

A⁴, A⁵ and A⁶ are selected from the group consisting of NR¹⁰, PR¹⁰, and S;

R¹⁰, R¹¹ and R¹² are selected from a group of formula —

(CH₂)_g—

, wherein g is 2-5;

R¹³ is selected from the group consisting of H, alkyl and aryl; and

R¹⁴ is selected from the group consisting of H, alkyl, aryl, and alkoxyalkyl.

44. A method for radioimaging a subject comprising:

a) providing

i) a subject; and

ii) a composition comprising a compound comprising a formula (M≡

N)L¹ and pharmaceutically acceptable salts thereof;

b) administering the composition to the subject; and

c) scanning at least a portion of the subject using a radioimaging device;

wherein N is nitrogen;

M is a radioactive transition metal; and

L¹ is a first crowned dithiocarbamate, wherein the first crowned dithiocarbamate comprises a first crown ether-containing group of formula [(CH₂)_a—

O]_b—

(CH₂)_c, wherein a is at least 2, b is at least 3, and c is at least 2.

45. The method of claim 44, wherein at least a portion of the subject is tissue suspected of being diseased.

46. The method of claim 44, wherein the at least a portion of the subject is myocardial tissue.

47. The method of claim 44, wherein the subject is a mammal.

48. A method of treating a disease resulting from overproduction of nitric oxide or reactive oxygen species, comprising:

a) providing;

i) a subject with a disease; and

ii) a composition comprising a compound comprising a formula;

and pharmaceutically acceptable salt thereof; and

b) administering the composition to the subject;

wherein M is a transition metal selected from the group consisting of Fe(II), Fe(III), Mn(II), Mn(III), Co(II), Co(III), Ni(II), Cu(II), Zn(II), Ru(II), Ru(III), Pd(II), and Pt(II);

p and p′

are integers and are independently selected from 0-2;

R¹ and R² comprises a crown ether-containing group of formula [(CH₂)_a—

O]_b—

(CH₂)_c, wherein a is at least 2, b is at least 3, and c is at least 2, or wherein R¹ and R² together comprise the crown ether-containing group;

L⁶ is a tripodal chelator with a formula selected from the group consisting of;

wherein U is selected from the group consisting of R¹³B, CR¹³, and P(═

O);

A¹, A² and A³ are imine-N containing heterocycles;

A⁴, A⁵ and A⁶ are selected from the group consisting of NR¹⁰, PR¹⁰, and S;

R¹⁰, R¹¹ and R¹² are selected from a group of formula (CH₂)_g—

, wherein g is 2-5;

R¹³ is selected from the group consisting of H, alkyl and aryl; and

R¹⁴ is selected from the group consisting of H, alkyl, aryl, and alkoxyalkyl.

49. A method of treating metal poisoning, comprising:

a) providing;

i) a subject with metal poisoning, and

ii) a composition comprising a crowned dithiocarbamate; and

b) administering the composition to the subject;

wherein the crowned dithiocarbamate comprises a crown ether-containing group of formula [(CH₂)_a—

O]_b—

(CH₂)_c, wherein a is at least 2, b is at least 3, and c is at least 2.