Inhibitors of prenyl-protein transferase

• US 20020052363A1
• Filed: 02/16/2001
• Published: 05/02/2002
• Est. Priority Date: 02/18/2000
• Status: Abandoned Application

• Current Assignee: Christopher J. Dinsmore, Jeffrey M. Bergman
• Original Assignee: Christopher J. Dinsmore, Jeffrey M. Bergman
• Inventors: Dinsmore, Christopher J., Bergman, Jeffrey M.
• Application Number:
  US09/784,897
• Publication Number:
  US 20020052363A1
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention comprises piperazine-containing compounds which inhibit prenyl-protein transferases, including farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such therapeutic compounds are useful in the treatment of cancer.

Claims

1. A compound of formula A:

5. The compound of claim 1 selected from the group consisting of:

1-(2-hydroxybenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-methoxybenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1 -(2-butoxybenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-yanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-(2-hydroxybenzoyloxy)benzoyl)-4-[1-(3-((3-(2-hydroxyethoxy)phenyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-methoxy-3-methylbenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5 -imidazolylmethyl]piperazine;

1-(2-butoxy-3-methylbenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(²-methoxy-4-methylbenzoyl)-4-[1 -(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-butoxy-4-methylbenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-butoxy-5 -methylbenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-hydroxybenzoyl)-4-[1 -(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-methoxybenzoyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-butoxybenzoyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-methoxy-3-methylbenzoyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-butoxy-3-methylbenzoyl )-4-[1-(3-((2-methyl -3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-methoxy-4-methylbenzoyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-butoxy-4-methylbenzoyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine;

1-(2-methoxy-5-methylbenzoyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine; and

1-(2-butoxy-5-methylbenzoyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5 -imidazolylmethyl]piperazine.

or a pharmaceutically acceptable salt or optical isomer thereof.

6. The compound of claim 1 that is 1-(2-methoxybenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine, 1-(2-butoxy-3-methylbenzoyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine, or a pharmaceutically acceptable salt or optical isomers thereof.

8. A pharmaceutical composition comprising a pharmaceutical carrier and a compound of claim 1.

9. A method for inhibiting prenyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

10. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

11. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

12. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

13. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

14. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of a compound of claim 1.

15. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

16. A method for treating or preventing a disease selected from cancer, neurofibromin benign proliferative disorder, blindness related to retinal vascularization, infections from hepatitis delta and related viruses, restenosis and polycystic kidney disease, which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

17. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.

18. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A method of conferring radiation sensitivity on a tumor cell which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy.

20. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 in combination with an antineoplastic.

21. A method according to claim 20 wherein the antineoplastic is paclitaxel.

2. A compound of Formula B:

3. A compound of Formula C:

4. A compound of Formula D

7. A compound selected from the group consisting of 1-(tert-butoxycarbonyl)-4-[1-(3-((6-methyl-2-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine, 1-(tert-butoxycarbonyl)-4-[1-(3-((2-methyl-3-pyridyl)oxy)-4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]piperazine, and the pharmaceutically acceptable salts and stereoisomers thereof.