Androgen receptor modulators and methods of treating disease using the same

• US 20070004679A1
• Filed: 02/06/2006
• Published: 01/04/2007
• Est. Priority Date: 05/17/2004
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Schlienger, Nathalie, Badalassi, Fabrizio, Thygesen, Mikkel, Fejzic, Alma, Pawlas, Jan, Lund, Birgitte, Bonhaus, Douglas, Lewinsky, Rasmus
• Application Number:
  US11/348,949
• Publication Number:
  US 20070004679A1
• Time in Patent Office: Days
• US Class Current: 514/79
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/504 forming part of bridged ring systems
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/32 by oxygen atoms
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/38 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/48 : having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/62 : attached in position 4
• CPC Class Codes: C07D 215/20 : Oxygen atoms
• CPC Class Codes: C07D 215/40 : attached in position 8
• CPC Class Codes: C07D 215/48 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 217/02 : with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 217/22 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 221/20 : Spiro-condensed ring systems
• CPC Class Codes: C07D 221/22 : Bridged ring systems
• CPC Class Codes: C07D 237/34 : with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
• CPC Class Codes: C07D 241/42 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 285/14 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 295/06 : substituted by halogen atoms or nitro radicals
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• 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 451/04 : with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 451/06 : Oxygen atoms
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems

Abstract

Disclosed herein are bicycloaryl compounds of Formula (I) that selectively modulate nuclear receptors, preferably the androgen receptor, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and methods of treating disease comprising administering a compound of Formula (I) to a patient in need thereof.

Claims

1. A method of treating an inflammatory condition comprising identifying a patient in need thereof and administering to said patient a therapeutically effective amount of a non-steroidal androgen receptor agonist of Formula (I):

wherein

R₁ and R₂ are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR₄, CONR₄R₅, NHCOR₄, NHSO₂R₄, OCOR₄, COR₄, SR₄, S(O)_nR₈, SO₂NR₈R₉;

R₃ is selected from the group consisting of cyano, nitro, S(O)_nR₈, SO₂NR₈R₉, OSO₂R₄, P(O)(OR₄)(OR₅), P(O)(OH)(NR₄R₅), PO(NR₄R₅)₂, COOR₄;

ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

Y₁ and Y₂ are CR₆R₇;

R₄ and R₅ are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;

R₆ and R₇ are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR₄, NR₄R₅, SR₄, COR₄, COOR₄, CONR₄R₅, NHCOR₄, OCOR₄, CSR₄, CSOR₄, CSNR₄R₅, NHCSR₄, OCSR₄, S(O)_nR₄, SO₂NR₄R₅, OSO₂R₄, NHSO₂R₄;

R₈ and R₉ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and

n is an integer from 1 to 3;

or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.

2. The method of claim 1, wherein the inflammatory disorder is selected from the group consisting of rheumatoid arthritis, asthma, allergic rhinitis, alopecia, lupus, inflammatory bowel disease and multiple sclerosis.

3. The method of claim 1, wherein the patient is a mammal.

4. The method of claim 3, wherein the mammal is a human.

5. A method of reducing fertility in a male subject comprising identifying a male subject in need thereof and administering to the male subject a therapeutically effective amount a non-steroidal androgen receptor agonist of Formula (I):

wherein

R₁ and R₂ are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR₄, CONR₄R₅, NHCOR₄, NHSO₂R₄, OCOR₄, COR₄, SR₄, S(O)_nR₈, SO₂NR₈R₉;

R₃ is selected from the group consisting of cyano, nitro, S(O)_nR₈, SO₂NR₈R₉, OSO₂R₄, P(O)(OR₄)(OR₅), P(O)(OH)(NR₄R₅), PO(NR₄R₅)₂, COOR₄;

ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

Y₁ and Y₂ are CR₆R₇;

R₄ and R₅ are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;

R₆ and R₇ are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR₄, NR₄R₅, SR₄, COR₄, COOR₄, CONR₄R₅, NHCOR₄, OCOR₄, CSR₄, CSOR₄, CSNR₄R₅, NHCSR₄, OCSR₄, S(O)_nR₄, SO₂NR₄R₅, OSO₂R₄, NHSO₂R₄;

R₈ and R₉ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and

n is an integer from 1 to 3;

or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.

6. The method of claim 5, wherein the male subject is a mammal.

7. The method of claim 6, wherein the mammal is a human.

8. A method of treating a burn subject comprising identifying a subject in need thereof and administering to said subject a therapeutically effective amount of a non-steroidal androgen receptor agonist of Formula (I):

wherein

R₁ and R₂ are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR₄, CONR₄R₅, NHCOR₄, NHSO₂R₄, OCOR₄, COR₄, SR₄, S(O)_nR₈, SO₂NR₈R₉;

R₃ is selected from the group consisting of cyano, nitro, S(O)_nR₈, SO₂NR₈R₉, OSO₂R₄, P(O)(OR₄)(OR₅), P(O)(OH)(NR₄R₅), PO(NR₄R₅)₂, COOR₄;

ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

Y₁ and Y₂ are CR₆R₇;

R₄ and R₅ are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;

R₆ and R₇ are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR₄, NR₄R₅, SR₄, COR₄, COOR₄, CONR₄R₅, NHCOR₄, OCOR₄, CSR₄, CSOR₄, CSNR₄R₅, NHCSR₄, OCSR₄, S(O)_nR₄, SO₂NR₄R₅, OSO₂R₄, NHSO₂R₄;

R₈ and R₉ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and

n is an integer from 1 to 3;

or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.

9. The method of claim 8, wherein the non-steroidal androgen agonist reduces catabolism, reduces infection rate, and increase muscle strength.

10. The method of claim 8, wherein the subject is a mammal.

11. The method of claim 10, wherein the mammal is a human.

12. A method of treating dry eye syndrome comprising identifying a patient in need thereof and administering to said patient a therapeutically effective amount of a non-steroidal androgen receptor agonist of Formula (I):

wherein

R₁ and R₂ are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR₄, CONR₄R₅, NHCOR₄, NHSO₂R₄, OCOR₄, COR₄, SR₄, S(O)_nR₈, SO₂NR₈R₉;

R₃ is selected from the group consisting of cyano, nitro, S(O)_nR₈, SO₂NR₈R₉, OSO₂R₄, P(O)(OR₄)(OR₅), P(O)(OH)(NR₄R₅), PO(NR₄R₅)₂, COOR₄;

ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

Y₁ and Y₂ are CR₆R₇;

R₄ and R₅ are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;

R₆ and R₇ are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR₄, NR₄R₅, SR₄, COR₄, COOR₄, CONR₄R₅, NHCOR₄, OCOR₄, CSR₄, CSOR₄, CSNR₄R₅, NHCSR₄, OCSR₄, S(O)_nR₄, SO₂NR₄R₅, OSO₂R₄, NHSO₂R₄;

R₈ and R₉ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and

n is an integer from 1 to 3;

or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.

13. The method of claim 12, wherein the non-steroidal androgen receptor affects the functioning of the lacrimal and meibomian glands.

14. The method of claim 13, wherein non-steroidal androgen receptor increases the functioning of the lacrimal and meibomian glands.

15. The method of claim 12, wherein the patient is a mammal.

16. The method of claim 14, wherein the mammal is a human.

17. A method for treating or ameliorating the symptoms of an autoimmune disease comprising identifying a patient in need thereof and administering to said patient a therapeutically effective amount of a non-steroidal androgen receptor agonist of Formula (I):

wherein

R₁ and R₂ are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR₄, CONR₄R₅, NHCOR₄, NHSO₂R₄, OCOR₄, COR₄, SR₄, S(O)_nR₈, SO₂NR₈R₉;

R₃ is selected from the group consisting of cyano, nitro, S(O)_nR₈, SO₂NR₈R₉, OSO₂R₄, P(O)(OR₄)(OR₅), P(O)(OH)(NR₄R₅), PO(NR₄R₅)₂, COOR₄;

ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

Y₁ and Y₂ are CR₆R₇;

R₄ and R₅ are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;

R₆ and R₇ are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR₄, NR₄R₅, SR₄, COR₄, COOR₄, CONR₄R₅, NHCOR₄, OCOR₄, CSR₄, CSOR₄, CSNR₄R₅, NHCSR₄, OCSR₄, S(O)_nR₄, SO₂NR₄R₅, OSO₂R₄, NHSO₂R₄;

R₈ and R₉ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and

n is an integer from 1 to 3;

or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.

18. The method of claim 17, wherein the autoimmune disease is multiple sclerosis.

19. The method of claim 17, wherein the non-steroidal androgen receptor agonist increases muscle mass and decreases the number of relapses.

20. The method of claim 17, wherein the patient is a mammal.

21. The method of claim 20, wherein the mammal is a human.

22. A method for treating a neurodegenerative disorder comprising identifying a patient in need thereof and administering to said patient a therapeutically effective amount of a non-steroidal androgen receptor agonist of Formula (I):

wherein

R₁ and R₂ are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR₄, CONR₄R₅, NHCOR₄, NHSO₂R₄, OCOR₄, COR₄, SR₄, S(O)_nR₈, SO₂NR₈R₉;

R₃ is selected from the group consisting of cyano, nitro, S(O)_nR₈, SO₂NR₈R₉, OSO₂R₄, P(O)(OR₄)(OR₅), P(O)(OH)(NR₄R₅), PO(NR₄R₅)₂, COOR₄;

ring A is a 5- or 6-membered, optionally aromatic, partially saturated or completely saturated carbocycle or heterocycle, containing up to two heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

ring B is an optionally substituted monocyclic or bicyclic heterocycle, containing up to three heteroatoms, selected from the group consisting of NR₆R₇, O, SO₂, S, C═

O and C═

S;

Y₁ and Y₂ are CR₆R₇;

R₄ and R₅ are each independently selected from the group consisting of hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl;

R₆ and R₇ are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, OR₄, NR₄R₅, SR₄, COR₄, COOR₄, CONR₄R₅, NHCOR₄, OCOR₄, CSR₄, CSOR₄, CSNR₄R₅, NHCSR₄, OCSR₄, S(O)_nR₄, SO₂NR₄R₅, OSO₂R₄, NHSO₂R₄;

R₈ and R₉ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and

n is an integer from 1 to 3;

or pharmaceutically acceptable salts, esters, amides, prodrugs, or stereoisomers thereof.

23. The method of claim 22, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson'"'"'s disease and Kennedy'"'"'s disease.

24. The method of claim 22, wherein the patient is a mammal.

25. The method of claim 24, wherein the mammal is a human.