Fused heterocyclic compounds and analogs thereof, modulators of nuclear hormone receptor function

• US 20030181728A1
• Filed: 12/18/2002
• Published: 09/25/2003
• Est. Priority Date: 12/19/2001
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Zhu, Hong, Salvati, Mark E., Balog, James Aaron, Pickering, Dacia A.
• Granted Patent: US 7,087,636 B2
• Time in Patent Office: Days
• US Class Current: 548/208
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: C07D 209/74 with an oxygen atom in position 1
• CPC Class Codes: C07D 209/76 with oxygen atoms in positions 1 and 3
• CPC Class Codes: C07D 231/54 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 275/06 : with hetero atoms directly attached to the ring sulfur atom

Abstract

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

Claims

1. A compound of the following formula Ia or a salt thereof:

2. A compound of claim 1, selected from the group consisting of:

(3aα

,4α

,7α

,7aα

)-2-(3-Chloro-4-fluorophenyl)-3a,4,7,7a-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (1B);

(3aα

,4α

,7α

,7aα

)-4-(2,3,3a,4,7,7a-Hexahydro-1,1-dioxido-3-oxo-4,7-methano-1,2-benzisothiazol-2-yl)benzoic acid, ethyl ester;

(3aα

,4α

,7α

,7aα

)-2-(3-Chloro-2-fluorophenyl)-3a,4,7,7a-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one, 1,1-dioxide; and

(3aα

,4α

,7α

,7aα

)-3a,4,7,7a-Tetrahydro-2-(2,3,4-trifluorophenyl)-4,7-methano-1,2-benzisothiazol-3(2H)-one, 1,1-dioxide.

3. A compound of the following formula Ib or salt thereof:

4. A compound of claim 3, selected from the group consisting of:

(3aα

,4α

,7α

,7aα

)-Octahydro-3a-hydroxy-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-ethano-3H-indazol-3-one (11G); and

(3aα

,4α

,7α

,7aα

)-Octahydro-3a-hydroxy-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-3H-indazol-3-one.

5. A compound having the following formula Ic, or a salt thereof:

6. A compound having the following formula Id, or a salt thereof:

7. A compound of claim 6, selected from the group consisting of:

(3aα

,4α

,7α

,7aα

)-Octahydro-3-hydroxy-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one (2);

(3aα

,40α

,7α

,7aα

)-Octahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one (3);

(3aα

,4α

,7α

,7aα

)-2,3,3a,4,7,7a-Hexahydro-3-hydroxy-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one (4);

(3aα

,4α

,7α

,7aα

)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-3-methoxy-4,7-methano-1H-isoindol-1-one (5);

(3aα

,4α

,7α

,7aα

)-Octahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-3-(2-propenyl)-4,7-methano-1H-isoindol-1-one (6);

(3aα

,4β

,7β

,7aα

)-Octahydro-3-hydroxy-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindol-1-one (7);

(3aα

,4β

,7β

,7aα

)-Octahydro-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindol-1-one (8);

(3aα

,4α

,7α

,7aα

)-2,3,3a,4,7,7a-Hexahydro-3-hydroxy-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-isoindol-1-one (9);

(3aα

,4α

,7α

,7aα

)-2,3,3a,4,7,7a-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-isoindol-1-one (10);

(1α

,3aα

,4α

,7α

,7aα

)-2,3,3a,4,7,7a-Hexahydro-2-(4-nitro-1-naphthalenyl)-3-oxo-4,7-methano-1H-isoindole-1-carbonitrile (12B);

(3aα

,4β

,7β

,7aα

)-2,3,3a,4,7,7a-Hexahydro-3-hydroxy-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindol-1-one (13B);

(3aα

,4β

,7β

,7aα

)-Octahydro-3-hydroxy-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindol-1-one (14);

(3aα

,4α

,7α

,7aα

)-2-( 1,2-Dihydro-4-methyl-2-oxo-7-quinolinyl)-2,3,3a,4,7,7a-hexahydro-3-methoxy-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-Octahydro-3-methoxy-2-( 1-naphthalenyl)-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-Octahydro-2-(1-naphthalenyl)-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-2-(1,2-Dihydro-4-methyl-2-oxo-7-quinolinyl)-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-2-(3,5-Dichlorophenyl)-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-2-(4-Bromo-1-naphthalenyl)-2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-3-hydroxy-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-2,3,3a,4,7,7a-Hexahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-methano-1H-isoindol-1-one;

(3aα

,4α

,7α

,7aα

)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-2,3,3a,4,7,7a-hexahydro-3-hydroxy-5-methyl-4,7-methano-1H-isoindol-1-one;

(1α

,3aα

,4α

,7α

,7aα

)-2,3,3a,4,7,7a-Hexahydro-2-[4-nitro-3-(trifluoromethyl)phenyl]-3-oxo-4,7-methano-1H-isoindole-1-carbonitrile; and

(3aα

,4α

,7α

,7aα

)-2,3,3a,4,7,7a-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-methano-1H-isoindol-1-one.

8. A pharmaceutical composition capable of treating a NHR—

associated condition, comprising a compound of the following formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

9. A pharmaceutical composition of claim 8 further comprising another anti-cancer agent.

10. 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:

11. The method of claim 10 wherein said nuclear hormone receptor is a steroid binding nuclear hormone receptor.

12. The method of claim 10 wherein said nuclear hormone receptor is the androgen receptor.

13. The method of claim 10 wherein said nuclear hormone receptor is the estrogen receptor.

14. The method of claim 10 wherein said nuclear hormone receptor is the progesterone receptor.

15. The method of claim 10 wherein said nuclear hormone receptor is the glucocorticoid receptor.

16. The method of claim 10 wherein said nuclear hormone receptor is the mineralocorticoid receptor.

17. The method of claim 10 wherein said nuclear hormone receptor is the aldosterone receptor.

18. The method of claim 10 wherein said nuclear hormone receptor is the RORbeta receptor.

19. The method of claim 10 wherein said nuclear hormone receptor is the COUP-TF2 receptor.

20. 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:

21. A process for preparing a compound of the following formula XIV: