Aminophenyl derivatives as selective androgen receptor modulators

• US 7,585,877 B2
• Filed: 01/09/2006
• Issued: 09/08/2009
• Est. Priority Date: 01/10/2005
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Thygesen, Mikkel Boas, Lund, Birgitte Winther, Badalassi, Fabrizio, Lewinsky, Rasmus, Schlienger, Nathalie, Pawlas, Jan
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US11/329,267
• Publication Number:
  US 20060160845A1
• Time in Patent Office: 1,338 Days
• Field of Search: 546/124, 514/304
• US Class Current: 514/304
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• 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 5/24 of the sex hormones
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/06 : Oxygen atoms

Abstract

Disclosed herein is a novel class of aminophenyl compounds having the structure:

wherein R₁ is cyano or nitro and ring A is a bi- or tricyclic bridged heterocycle and to their use as modulators of androgen receptor for the treatment or prevention of conditions relating thereto.

Claims

1. A compound represented by formula (I):

2. The compound of claim 1, wherein:

Z₁ and Z₂ are independently selected from the group consisting of unsubstituted —

(C₁-C₄alkyl, —

(C₁-C₄alkylOH, —

(C₁-C₄alkyl(halo), halo, cyano, —

OR₄, —

OC(O)R₄, —

CF₃, —

CHO and —

CH═

NOR₄;

R₆ and R₇ are independently selected from the group consisting of hydrogen, unsubstituted —

(C₁-C₄alkyl, —

(C₁-C₄)alkylOH, —

(C₁-C₄)alkyl(halo), halo, cyano, —

OR₄, —

OC(O)R₄ and —

CF₃; and

, R₄ is selected from the group consisting of hydrogen, unsubstituted (C₁-C₄)alkyl, unsubstituted (C₃-C₆)cycloalkyl and unsubstituted aryl.

3. The compound of claim 1, wherein optionally substituted 8-azabicyclo[3.2.1]oct-8-yl has the structure:

4. The compound of claim 3, wherein R₆ is hydroxy.

5. The compound of claim 4, wherein R₇ is —

(C₁-C₄alkyl.

6. The compound of claim 5, wherein R₇ is bonded to the same carbon atom to which R₆ is bonded.

7. The compound of claim 1, wherein Z₁ is alkyl, halogen, haloalkyl or hydroxyalkyl.

8. The compound of claim 1, wherein Z₂ is alkyl, halogen, haloalkyl or hydroxyalkyl.

9. The compound of claim 1, wherein Z₁ is methyl or ethyl and Z₂ is halogen.

10. The compound of claim 1, wherein Z₁ is methyl or ethyl and Z₂ is chloro.

11. The compound of claim 1, wherein Z₁ is methyl, and Z₂ is chloro.

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

endo-8-(3-chloro-2-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbenzonitrile;

6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenzoic acid;

3-Bromo-2-chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile;

endo-8-(2,3-Dimethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-iodobenzonitrile;

endo-8-[2-(hydroxymethyl)-3-methyl-4-nitrophenyl]-8-azabicyclo[3.2.1]octan-3-ol;

endo-8-(2-Chloro-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitrobenzaldehyde;

endo-8-(3-Chloro-2-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitrobenzaldehyde oxime;

endo-8-(2-Chloro-3-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenzoic acid;

endo-8-(2-Hydroxymethyl-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile;

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile hydrochloride; and

,

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile mesylate.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

14. A compound represented by formula (I):

15. The compound of claim 14, wherein:

Z₁ is selected from the group consisting of hydrogen, unsubstituted —

(C₁-C₄alkyl, —

(C₁-C₄)alkylOH, —

(C₁-C_C4)alkyl(halo), chloro, bromo, iodo, cyano, —

OR₄, —

OC(O)R₄, —

CF₃, —

CHO and —

CH═

NOR₄;

Z₂ is selected from the group consisting of hydrogen, unsubstituted —

(C₁-C₄)alkyl, —

(C₁-C₄)alkylOH, —

(C₁-C₄)alkyl(halo), halo, cyano, —

OR₄, —

OC(O)R₄, —

CF₃, —

CHO and —

CH═

NOR₄;

R₆ and R₇ are independently selected from the group consisting of hydrogen, unsubstituted —

(C₁-C₄)alkyl, —

(C₁-C₄alkylOH, —

(C₁-C₄alkyl(halo), halo, cyano, —

OR₄, —

OC(O)R₄ and —

CF_3;

and,

R₄ is selected from the group consisting of hydrogen, unsubstituted (C₁-C₄)alkyl, unsubstituted (C₃-C₆)cycloalkyl and unsubstituted aryl.

16. The compound of claim 15, wherein the optionally substituted 8-azabicyclo[3.2.1]oct-8-yl group has the structure:

17. The compound of claim 16, wherein R₆ is hydroxy.

18. The compound of claim 17, wherein R₇ is —

(C₁-C₄)alkyl.

19. The compound of claim 18, wherein R₇ is bonded to the same carbon atom to which R₆ is bonded.

20. The compound of claim 14, wherein Z₁ is alkyl, chloro, bromo, iodo, haloalkyl or hydroxyalkyl.

21. The compound of claim 14, wherein Z₂ is alkyl, halogen, haloalkyl or hydroxyalkyl.

22. The compound of claim 14, selected from the group consisting of:

4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-trifluoromethylbenzonitrile;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile; and

2-(trifluoromethyl)-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl) benzonitrile.