Oligoamine compounds and derivatives thereof for cancer therapy

• US 20030130356A1
• Filed: 10/16/2002
• Published: 07/10/2003
• Est. Priority Date: 10/16/2001
• Status: Abandoned Application

• Current Assignee: Cellgate, Inc. (Tbg Diagnostics Limited)
• Original Assignee: Slil Biomedical Corp.
• Inventors: Basu, Hirak S., Valasinas, Aldonia L., Blokhin, Andrei V., Frydman, Benjamin, Marton, Laurence J.
• Application Number:
  US10/272,269
• Publication Number:
  US 20030130356A1
• Time in Patent Office: Days
• US Class Current: 514/667
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 211/14 Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
• CPC Class Codes: C07C 215/18 with hydroxy groups and at least two amino groups bound to the carbon skeleton

Abstract

Oligoamine compounds with anti-cancer and anti-proliferative activity are provided, as well as methods for making and using the compounds. The compounds are shown to be active against prostate cancer cell lines and against prostate cancer tumors in mice. The compounds are also useful in treatment of breast cancer and other cancers.

Claims

1. A compound of the formula

2. A compound according to claim 1, where each R₄₀ is independently selected from the group consisting of —

CH₂CH₂CH₂— and

—

CH₂CH₂CH₂CH₂—

.

3. A compound according to claim 2, where each R₄₀ is —

CH₂CH₂CH₂CH₂—

.

4. A compound according to claim 3, where R₃₀ and R₅₀ are —

CH₂CH₂CH₂CH₂—

.

5. A compound according to claim 4, where R₉₀ and each R₈₀ are H.

6. A compound according to claim 5, where R₁₀ is H, R₂₀ is ethyl, R60 is H, and R₇₀ is ethyl.

7. A compound according to claim 6, where y is an integer selected from 5, 7, 9, 11, and 13.

8. A compound according to claim 7, where y is an integer selected from 5, 9, and 11.

9. A compound according to claim 1 of the formula

10. A compound according to claim 1 of the formula

11. A compound according to claim 1 of the formula

12. A compound according to claim 1 of the formula

13. A compound according to claim 1, where R₉₀ and each R₈₀ are independently selected from the group consisting of H, methyl, and ethyl.

14. A compound according to claim 1, where R₉₀ and each R₈₀ are H.

15. A compound according to claim 1, where R₃₀, each R_40, and R₅₀ are independently selected from:

—

CH₂CH₂CH₂CH₂—

—

CHOHCH₂CH₂CH₂—

—

CH₂CHOHCH₂CH₂—

—

CH₂CH₂CHOHCH₂—

, and —

CH₂CH₂CH₂CHOH—

.

16. A compound according to claim 11, where each R₄₀ is —

CH₂CH₂CH₂CH₂— and

R₃₀ and R₅₀ are independently selected from;

—

CH₂CH₂CH₂CH₂—

—

CHOHCH₂CH₂CH₂—

—

CH₂CHOHCH₂CH₂—

—

CH₂CH₂CHOHCH₂—

, and —

CH₂CH₂CH₂CHOH—

.

17. A compound according to claim 16, where R₃₀ and R₅₀ are independently selected from:

—

CHOHCH₂CH₂CH₂—

—

CH₂CHOHCH₂CH₂—

—

CH₂CH₂CHOHCH₂—

, and —

CH₂CH₂CH₂CHOH—

.

18. A compound according to claim 1, where R₁₀, R₂₀, R₆₀, and R₇₀ are independently selected from H, methyl, or ethyl.

19. A compound according to claim 18, where R₁₀ is H and R₆₀ is H.

20. A compound according to claim 19, where R₂₀ and R₇₀ are ethyl.

21. A compound according to claim 1, with the proviso that at least one R₃₀, R_40, or R₅₀ is independently selected from:

—

CHOHCH₂CH₂CH₂—

—

CH₂CHOHCH₂CH₂—

—

CH₂CH₂CHOHCH₂—

—

CH₂CH₂CH₂CHOH—

—

CHOHCH₂CH₂—

—

CH₂CHOHCH₂— and

—

CH₂CH₂CHOH—

.

22. A compound according to claim 21, with the proviso that at least one R₃₀, R_40, or R₅₀ is independently selected from:

—

CHOHCH₂CH₂CH₂—

—

CH₂CHOHCH₂CH₂—

—

CH₂CH₂CHOHCH₂—

; and

—

CH₂CH₂CH₂CHOH—

.

23. A compound according to claim 22, with the proviso that at least one of R₃₀ and R₅₀ is independently selected from:

—

CHOHCH₂CH₂CH₂—

—

CH₂CHOHCH₂CH₂—

—

CH₂CH₂CHOHCH₂—

; and

—

CH₂CH₂CH₂CHOH—

.

24. A method of treating cancer in an individual, comprising the step of administering a therapeutic amount of a compound according to claim 1.

25. A method of treating cancer in an individual, comprising the step of administering a therapeutic amount of a compound according to claim 7.

26. A method of making a compound according to claim 1, comprising the steps of:

a) providing a first compound of the form

H—

N(R₉₀)—

R₅₁—

CON(R₆₀)(R₇₀)

where R₉₀ is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;

R₆₀ and R₇₀ are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;

R₅₁ is selected from the group consisting of

—

CH₂CH₂CH₂—

—

CHO(PG_Hy)CH₂CH₂—

—

CH₂CHO(PG_Hy)CH₂—

—

CH₂CH₂CHO(PG_Hy)—

—

CH₂CH₂—

—

CHO(PG_Hy)CH₂— and

—

C H₂CHO(PG_Hy)—

where PG_Hy is a hydroxy protecting group;

b) providing a second compound of the form

BG_NN(R₈₀)—

R₄₁—

COOH

where blocking group BG_N is selected from the group consisting of an amino protecting group and methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl;

R₄ is selected from the group consisting of

—

CH₂CH₂CH₂—

—

CHO(PG_Hy)CH₂CH₂—

—

CH₂CHO(PG_Hy)CH₂—

—

CH₂CH₂CHO(PG_Hy)—

—

CH₂CH₂—

—

CHO(PG_Hy)CH₂— and

—

CH₂CHO(PG_Hy)—

;

c) activating the carboxyl group of the second compound;

d) coupling the second compound to the first compound to form a compound of the formula

BG_N[N(R₈₀)—

R₄₁—

CO]_g—

N(R₉₀)—

R₅₁—

CON(R₆₀)(R₇₀)

where g is 1;

e) repeating step c) and repeating the coupling step of step d) for (g-1) additional cycles to form a compound of the formula

BG_N[N(R₈₀)—

R₄₁—

CO]_g—

N(R₉₀)—

R₅₁—

CON(R₆₀)(R₇₀)

where g is an integer from 7 to 15;

f) reducing the amide groups to amine groups; and

g) removing any protecting groups BG_N and PG_Hy that may be present in the compound.