Cyclic polyamine compounds for cancer therapy

• US 20030072715A1
• Filed: 08/02/2001
• Published: 04/17/2003
• Est. Priority Date: 08/02/2000
• Status: Abandoned Application

• Current Assignee: Cellgate, Inc. (Tbg Diagnostics Limited), University of Zurich
• Original Assignee: Cellgate, Inc. (Tbg Diagnostics Limited)
• Inventors: Wang, Yu, Basu, Hirak, Frydman, Benjamin, Bhattacharya, Subhra, Popaj, Kasim, Drandarov, Konstantin, Hesse, Manfred, Guggisberg, Armin
• Application Number:
  US09/922,407
• Publication Number:
  US 20030072715A1
• Time in Patent Office: Days
• US Class Current: 424/9.363
• CPC Class Codes: C07D 255/02 not condensed with other rings
• CPC Class Codes: C07D 257/02 not condensed with other rings

Abstract

Novel cyclic polyamine compounds of the form

where A, each A₂ (if present), and A₃ are independently selected from C₁-C₈ alkyl, where each Y is independently selected from H or C₁-C₄ alkyl, where M is selected from C₁-C₄ alkyl, where k is 0, 2, or 3, and where R is selected from C₁-C₃₂ alkyl, as well as all stereoisomers and salts thereof, are disclosed. Additional compounds where k is 1 and A₂ is independently selected from C₁-C₃ alkyl or C₅-C₈ alkyl are also disclosed. Cyclic polyamines, where the amide group is reduced to a secondary amino group, and various derivatives of these compounds, are also described. Synthetic methods for the compounds are described. The compounds are useful for treating diseases caused by uncontrolled proliferation of cells, such as cancer, especially prostate cancer, and for inducing intracellular ATP hydrolysis for treatment of other disorders.

Claims

1. A compound of the formula

2. A compound according to claim 1, wherein each Y group is —

H.

3. A compound according to claim 1, wherein each Y group is —

CH₃.

4. A compound according to claim 1, wherein A, each A₂ (if present), and A₃ are independently selected from C₂-C₄ alkyl.

5. A compound according to claim 1, wherein M is —

CH₂—

.

31. A method of treating cancer or a disease characterized by uncontrolled cell proliferation in an individual in need of such treatment,

comprising the step of administering one or more compounds of claim 1.

34. A method of depleting ATP in a cancerous cell, comprising the step of administering one or more compounds of claim 1 to the cell.

6. A compound of the formula

7. A compound according to claim 6, wherein each Y group is —

H.

8. A compound according to claim 6, wherein each Y group is —

CH₃.

9. A compound according to claim 6, wherein A₁ and A₃ are independently selected from C₂-C₄ alkyl, and A₂ is selected from the group consisting of C₂-C₃ alkyl and C₅ alkyl.

10. A compound according to claim 6, wherein M is —

CH₂—

.

32. A method of treating cancer or a disease characterized by uncontrolled cell proliferation in an individual in need of such treatment,

comprising the step of administering one or more compounds of claim 6.

35. A method of depleting ATP in a cancerous cell, comprising the step of administering one or more compounds of claim 6 to the cell.

11. A compound of the formula

12. A compound according to claim 11, wherein each Y group is —

H.

13. A compound according to claim 11, wherein A₁ and A₃ are independently selected from C₂-C₄ alkyl, and A₂ is selected from the group consisting of C₂-C₅ alkyl.

14. A compound according to claim 11, wherein M is —

CH₂—

.

33. A method of treating cancer or a disease characterized by uncontrolled cell proliferation in an individual in need of such treatment,

comprising the step of administering one or more compounds of claim 11.

36. A method of depleting ATP in a cancerous cell, comprising the step of administering one or more compounds of claim 11 to the cell.

15. A method of synthesizing a compound of the formula

16. The method of claim 15, wherein the ω

-halo alkyl alkanoate is ethyl bromoacetate.

17. The method of claim 16, wherein the aldehyde or ketone-containing compound is an aldehyde-containing compound.

18. The method of claim 16, wherein the step of reacting an ω

-halo alkyl alkanoate with an aldehyde or ketone-containing compound to give an alkene-containing alkanoate compound is performed by reacting the ω

-halo alkyl alkanoate with triphenylphosphine.

19. The method of claim 16, wherein the compound containing two primary amino groups is selected from the group consisting of H₂N—

A₁—

(NH—

A₂)_k—

NH—

A₃—

NH₂

wherein A, each A₂ (if present), and A₃ are independently selected from C₁-C₈ alkyl and k is 0, 1, 2, or 3.

20. The method of claim 19, wherein the compound containing two primary amino groups is selected from the group consisting of spermine, spermidine, and putrescine.

21. The method of claim 16, wherein the step of cyclizing the other amino group with the alkyl alkanoate group to form an amide bond is performed by reacting the compound with antimony (III) ethoxide.

22. The method of claim 16, wherein the step of optionally alkylating any secondary amino groups if present is performed by reacting the compound first with an aliphatic aldehyde to result in a Schiff base, then reducing the Schiff base, resulting in alkylation of the secondary amino groups.

23. The method of claim 22, wherein the step of reducing the Schiff base is performed by using the reagent NaCNBH₃.

24. A method of synthesizing a compound of the formula

25. The method of claim 24, wherein the α

,β

-unsaturated ester is of the formula

(C₁-C₈ alkyl)—

O—

C(═

O)—

CH═

CH—

(C₁-C₃₂ alkyl).

26. The method of claim 24, wherein the compound comprising a primary amino group and a hexahydropyrimidine moiety is of the formula

27. The method of claim 26, wherein j is 0.

28. The method of 27, wherein A₃ is C₄ alkyl.

29. The method of 24, wherein the step of cleaving the methylene bridge of the hexahydropyrimidine moiety is performed with anhydrous HCl in an alcoholic solvent.

30. The method of 24, wherein the step of condensing the newly-generated primary amino group with the ester group to form an amide group is performed with the reagent B(N(CH₃)₂)₃.

37. A compound of the formula

38. The compound of claim 37, wherein A₄ is a nonentity, X is —

Z, —

Z is —

H, and each Y is —

CH₃.

39. The compound of claim 38, wherein M is —

CH₂—

, k is 1, A₁ and A₃ are —

CH₂CH₂CH₂—

, and the single A₂ group is —

CH₂CH₂CH₂CH₂—

.

40. The compound of claim 39, wherein R is —

C₁₃H₂₇.

41. The compound of claim 37, wherein A₄ is C₁-C₈ alkyl, X is —

NHZ, and and Z is selected from one of the 20 genetically encoded amino acids, a peptide of the formula acetyl-SKLQL-, a peptide of the formula acetyl-SKLQ-β

-alanine-, or a peptide of the formula acetyl-SKLQ-.

42. A method of synthesizing a compound of claim 37, wherein A₄ is a nonentity and X is —

H, comprising reducing the carbonyl of the amide group of a compound of the formula

43. A method of synthesizing a compound of claim 37, wherein A₄ is C₂ alkyl, each Y is selected from C₁-C₄ alkyl, and X is —

CN, comprising reacting a compound of the formula

44. A method of synthesizing a compound of claim 37, wherein A₄ is C₃ alkyl and X is —

NH₂, comprising reducing the nitrile group of a compound of the formula