Spirocyclic compounds useful as modulators of nuclear hormone receptor function

• US 20060019978A1
• Filed: 06/20/2005
• Published: 01/26/2006
• Est. Priority Date: 06/21/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Balog, James Aaron
• Granted Patent: US 7,235,563 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: C07D 221/20 Spiro-condensed ring systems
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

Spirocyclic compounds, methods of using such spirocyclic compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds are disclosed.

Claims

1. A compound having formula (I):

2. The spirocyclic compound according to claim 1 wherein:

X and Y are independently selected from H, CH, NO₂, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, and/or CF₂CF₃; and

Z is H, CH, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, or CF₂CF₃.

3. The spirocyclic compound according to claim 1 having formula (II):

4. The spirocyclic compound according to claim 1 having formula (III):

5. The spirocyclic compound according to claim 1 selected from:

5-(7,9-Dioxo-8-aza-spiro[4.5]dec-8-yl)-quinoline-8-carbonitrile;

4-(7,9-Dioxo-8-aza-spiro[4.5]dec-8-yl)-2-trifluoromethyl-benzonitrile;

5-(7,9-Dioxo-8-aza-spiro[4.5]dec-8-yl)-3-trifluoromethyl-pyridine-2-carbonitrile;

8-(4-Nitro-naphthalen-1-yl)-8-aza-spiro[4.5]decane-7,9-dione;

or 8-(3-Methyl-4-nitro-phenyl)-8-aza-spiro[4.5]decane-7,9-dione.

6. A pharmaceutical composition capable of treating a NHR-associated condition, comprising a compound of formula (I):

7. The pharmaceutical composition according to claim 6, wherein:

X and Y are independently selected from H, CH, NO₂, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, and/or CF₂CF₃; and

Z is H, CH, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, or CF₂CF₃.

8. The pharmaceutical composition according to claim 6, wherein the spirocyclic compound has formula (II):

9. The spirocyclic compound according to claim 6 having formula (III):

10. The pharmaceutical composition according to claim 6, wherein the spirocyclic compound has formula (III):

11. A method of modulating the function of a nuclear hormone receptor which comprises administering to a mammalian species in need thereof an effective nuclear hormone receptor modulating amount of a compound of the following formula (I):

12. The method according to claim 11, wherein:

X and Y are independently selected from H, CH, NO₂, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, and/or CF₂CF₃; and

Z is H, CH, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, or CF₂CF₃.

13. The method according to claim 11, wherein the spirocyclic compound has formula (II):

14. The method according to claim 11, wherein the spirocyclic compound has formula (III):

15. The method of claim 11 wherein the nuclear hormone receptor is selected from estrogen receptor, progesterone receptor, glucocorticoid receptor, mineralocorticoid receptor, aldosterone receptor, or steroid and xenobiotic receptor.

16. The method of claim 11 wherein said nuclear hormone receptor is androgen receptor or mutated androgen receptor.

17. A method for treating a condition or disorder comprising administering to a mammalian species in need thereof a therapeutically effective amount of a compound of the following formula (I):

18. The method according to claim 17, wherein:

X and Y are independently selected from H, CH, NO₂, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, and/or CF₂CF₃; and

Z is H, CH, F, Cl, Br, I, CH₃, CH₂CH₃, CF₃, or CF₂CF₃.

19. The method according to claim 17, wherein the spirocyclic compound has formula (II):

20. The method according to claim 17, wherein the spirocyclic compound has formula (III):