Farnesyltransferase inhibitors

• US 20030216441A1
• Filed: 05/10/2002
• Published: 11/20/2003
• Est. Priority Date: 05/10/2002
• Status: Abandoned Application

• Current Assignee: Steven F. Weinstock
• Original Assignee: Steven F. Weinstock
• Inventors: Sham, Hing L., Wang, Weibo, Gwaltney, Stephen L. II, Sullivan, Gerard M., Nelson, Lissa T.J., OʼConnor, Stephen J.
• Application Number:
  US10/144,225
• Publication Number:
  US 20030216441A1
• Time in Patent Office: Days
• US Class Current: 514/341
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds having the formula

are farnesyltransferase inhibitors. Also disclosed are methods of making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.

Claims

1. A compound of formula (I)

2. The compound of claim 1 wherein A is heteroaryl.

3. The compound of claim 2 wherein L is absent.

4. The compound of claim 3 wherein R¹ and R² are hydrogen.

5. The compound of claim 4 selected from the group consisting of

1-[(1-methyl-1H-imidazol-5-yl)methyl]-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile;

1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl}-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile;

4-(3-chlorophenyl)-1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carbonitrile;

methyl 1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl}-4-(1-naphthyl)-1,2,5,6-tetrahydropyridine-3-carboxylate; and

4-[(5-{[5-(morpholin-4-ylcarbonyl)-4-(1-naphthyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-1H-imidazol-1-yl)methyl]benzonitrile.

6. The compound of claim 3 wherein one of R¹ and R² is other than hydrogen.

7. The compound of claim 6 selected from the group consisting of

1-[(4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile;

and

1-[1-(1-methyl-1H-imidazol-5-yl)-3-phenylprop-2-ynyl]-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile.

8. The compound of claim 2 wherein L is (CH₂)_nC(O).

9. The compound of claim 8 selected from the group consisting of

1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl}-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile;

1-({1-[4-cyano-3-(1-naphthyl)benzyl]-1H-imidazol-5-yl }acetyl)-5-methoxy-1,2,3,6-tetrahydropyridine-4-carbonitrile;

1-{3-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]propanoyl}-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile; and

4-(3-chlorophenyl)-1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl}-1,2,5,6-tetrahydropyridine-3-carbonitrile.

10. The compound of claim 2 wherein L is selected from the group consisting of N(R⁵)(CH₂)_nC(O) and CH(NR⁵R⁶)C(O).

11. The compound of claim 10 selected from the group consisting of

4-cyano-N-(4-cyanobenzyl)-N-[(1-methyl-1H-imidazol-5-yl)methyl]-5-(1-naphthyl)-3,6-dihydropyridine-1(2H)-carboxamide;

1-({(4-cyanobenzyl)[(1-methyl-1H-imidazol-5-yl)methyl]amino}acetyl)-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile;

1-[(2R)-2-[(4-cyanobenzyl)amino]-3-(1-methyl-1H-imidazol-5-yl)propanoyl]-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile; and

1-[(2R)-2-[(4-cyanobenzyl)(methyl)amino]-3-(1-methyl-1H-imidazol-5-yl)propanoyl]-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile.

12. The compound of claim 2 wherein L is selected from the group consisting of alkylene and N(R⁵).

13. The compound of claim 12 selected from the group consisting of

1-[2-(4-cyanophenyl)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)ethyl]-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile;

1-[2-(4-cyanophenyl)-2-fluoro-2-(1-methyl-1H-imidazol-5-yl)ethyl]-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile; and

1-{[(4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methyl]amino}-5-(1-naphthyl)-1,2,3,6-tetrahydropyridine-4-carbonitrile.

14. A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.

15. A method for inhibiting farnesyltransferase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of claim 1, or a therapeutically acceptable salt thereof.

16. A method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of claim 1, or a therapeutically acceptable salt thereof.