Heterocyclic compounds for cancer chemoprevention

• US 6,166,003 A
• Filed: 02/17/1999
• Issued: 12/26/2000
• Est. Priority Date: 02/17/1999
• Status: Expired due to Term

• Current Assignee: LKT Laboratories Incorporated
• Original Assignee: LKT Laboratories Incorporated
• Inventors: Lam, Luke K. T.
• Primary Examiner(s): POWERS, FIONA
• Application Number:
  US09/251,559
• Time in Patent Office: 678 Days
• Field of Search: 540/1, 549/75, 549/495, 514/183, 514/438, 514/471
• US Class Current: 514/183
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12

Abstract

A compound comprising a heterocyclic moiety, such as a thiophene, covalently attached to an alkylene isothiocyanate moiety. The compound is effective to prevent the occurrence or progression of cancer or a precancerous condition, and can be used for therapeutic or prophylactic purposes. The compound can be provided and administered in the form of a pharmaceutical composition, a cosmetic, a food additive, supplement, or the like. Methods for synthesis and use of the chemopreventive compound of the invention are also provided.

Claims

1. A compound having formula I ##STR13## wherein:

R₁ is H or (alkylene)-NCS;

R₂ is H or (alkylene)-NCS;

R₃ is H, (alkylene)-NCS, or a blocking group; and

Y is Se;

provided that at least one of R₁, R₂ and R₃ is (alkylene)-NCS.

2. The compound of claim 1 wherein R₃ is a blocking group.

3. The compound of claim 2 wherein the blocking group is selected from the group consisting of an alkyl group, an aryl group, an alkoxy group, an alkylenearyl group, an alkylmercapto group, an arylalkyl group, an aryloxy group, CX₃, and X;

wherein X is selected from the group consisting of F, Cl and Br.

4. The compound of claim 3 wherein blocking group is selected from the group consisting of CH₃, OCH₃, SCH₃, CX₃ and X wherein X is selected from the group consisting of F, Cl and Br.

5. The compound of claim 4 wherein the blocking group is selected from the group consisting of CH₃, OCH₃, SCH₃, CF₃ and F.

6. The compound of claim 1 wherein R₁ is H or ((C₁ -C₁₂)alkylene)-NCS;

R₂ is H or ((C₁ -C₁₂)alkylene)-NCS; and

R₃ is H, ((C₁ -C₁₂)alkylene)-NCS, or a blocking group.

7. The compound of claim 1 wherein R₁ is H.

8. The compound of claim 1 wherein R₂ is H.

26. A method for making the compound of claim 1 wherein one of R₁ and R₂ is H;

the other of R₁ and R₂ is (alkylene)-NCS;

R₃ is H or a blocking group; and

Y is Se;

the method comprising;

(a) providing a 5-membered heterocyclic ring having the formula ##STR21## wherein R₃ is H or a blocking group;

one of R₄ and R₅ is H; and

the other of R4 and R₅ is (alkylene) --Br;

(b) substituting the bromide (--Br) with an amine (--NH₂) to yield an alkylene amine intermediate; and

(c) reacting the alkylene amine intermediate with thiophosgene to yield the compound of claim 1 wherein one of R₁ and R₂ is H;

the other of R₁ and R₂ is (alkylene)-NCS;

R₃ is H or a blocking group; and

Y is Se.

27. The method of claim 26 wherein step (b) comprises contacting the 5-membered heterocyclic ring with a phthalimide salt to yield a phthalimidoalkylene intermediate, followed by contacting the phthalimidoalkylene intermediate with hydrazine to yield the alkylene amine intermediate.

28. The method of claim 26 wherein step (b) comprises contacting the 5-membered heterocyclic ring with an azide salt to yield an alkylene azide intermediate, followed by contacting the alkylene azide intermediate with sodium borohydride to yield the alklyene amine intermediate.

29. A method for making the compound of claim 12 wherein R₁ and R₃ are each (alkylene)-NCS;

R₂ is H; and

Y is S, O or Se;

the method comprising;

(a) providing a 5-membered heterocyclic ring having the formula ##STR22## (b) substituting each bromide (--Br) with an amine (--NH₂) to yield a disubstituted alkylene amine intermediate; and

(c) reacting the disubstituted alkylene amine intermediate with thiophosgene to yield the compound of claim 1 wherein R₁ and R₃ are each (alkylene)-NCS;

R₂ is H; and

Y is S, O or Se.

30. The method of claim 29 wherein step (b) comprises contacting the 5-membered heterocyclic ring with a phthalimide salt to yield a disubstituted phthalimidoalkylene intermediate, followed by contacting the disubstituted phthalimidoalkylene intermediate with hydrazine to yield the disubstituted alkylene amine intermediate.

31. The method of claim 29 wherein step (b) comprises contacting the 5-membered heterocyclic ring with an azide salt to yield a disubstituted alkylene azide intermediate, followed by contacting the disubstituted alkylene azide intermediate with sodium borohydride to yield the disubstituted alkylene amine intermediate.

9. A compound having formula I ##STR14## wherein:

R₁ and R₂ are each independently (alkylene)-NCS;

R₃ is H, (alkylene)-NCS, or a blocking group; and

Y is S, O or Se.

10. The compound of claim 9 wherein R₃ is a blocking group selected from the group consisting of an alkyl group, an aryl group, an alkoxy group, an alkylenearyl group, an alkylmercapto group, an arylalkyl group, an aryloxy group, CX₃, and X;

wherein X is selected from the group consisting of F, Cl and Br.

11. The compound of claim 9 wherein Y is S.

12. A compound having formula I ##STR15## wherein:

one of R₁ and R₂ is (alkylene)-NCS;

the other of R₁ and R₂ is H;

R₃ is (alkylene)-NCS; and

Y is S, O or Se.

13. The compound of claim 12 wherein Y is S.

14. A compound having formula I ##STR16## wherein:

R₁ is H or ((C₇ -C₁₂)alkylene)-NCS;

R₂ is H or ((C₇ -C₁₂)alkylene)-NCS;

R₃ is H, ((C₇ -C₁₂)alkylene)-NCS, or a blocking group; and

Y is S, O or Se;

provided that at least one of R₁, R₂ and R₃ is ((C₇ -C₁₂)alkylene)-NCS.

15. A compound having formula I ##STR17## wherein:

R₁ is H or (alkylene)-NCS;

R₂ is H or (alkylene)-NCS;

R₃ is a blocking group selected from the group consisting of OCH₃, SCH₃, CX₃ and F, wherein X is selected from the group consisting of F, Cl and Br; and

Y is S, O or Se;

provided that at least one of R₁ and R₂ is (alkylene)-NCS.

16. The compound of claim 15 wherein Y is S.

17. A pharmaceutical composition formulated for use in a mammal comprising as an active ingredient a compound of formula I ##STR18## wherein:

R₁ is H or (alkylene)-NCS;

R₂ is H or (alkylene)-NCS;

R₃ is H, (alkylene)-NCS, or a blocking group; and

Y is S, O or Se;

provided that at least one of R₁, R₂ and R₃ is (alkylene)-NCS.

18. The pharmaceutical composition of claim 17 further comprising a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 17 formulated for parenteral administration to the mammal.

20. The pharmaceutical composition of claim 17 formulated for topical administration to the mammal.

21. The pharmaceutical composition of claim 17 formulated for oral administration to the mammal.

22. A pharmaceutical composition comprising:

as an active ingredient, a compound of formula I ##STR19## wherein;

R₁ is H or (alkylene)-NCS;

R₂ is H or (alkylene)-NCS;

R₃ is H, (alkylene)-NCS, or a blocking group; and

Y is S, O or Se;

provided that at least one of R₁, R₂ and R₃ is (alkylene)-NCS; and

a pharmaceutically acceptable salt.

23. The pharmaceutical composition of claim 22 formulated for parenteral administration.

24. A method for preventing the occurrence or progression of a cancer or a precancerous condition of the colon, lung, liver, forestomach or bowel in a mammal comprising administering to the mammal a chemopreventive composition comprising a compound of formula I ##STR20## wherein:

R₁ is H or (alkylene)-NCS;

R₂ is H or (alkylene)-NCS;

R₃ is H, (alkylene)-NCS, or a blocking group; and

Y is S, O or Se;

provided that at least one of R₁, R₂ and R₃ is (alkylene)-NCS;

in an amount effective to prevent the occurrence of the cancer or precancerous condition or to slow, halt or reverse the progression of the cancer or precancerous condition.

25. The method of claim 24 wherein the chemopreventive compound is administered prophylactically to prevent the occurrence of the cancer or precancerous condition before, during or after exposure of the mammal to a known or suspected carcinogenic or procarcinogenic compound, agent or event.