Inhibitors of P2X3

• US 20070037974A1
• Filed: 08/11/2006
• Published: 02/15/2007
• Est. Priority Date: 08/15/2005
• Status: Active Grant

• Current Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Original Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Dillon, Michael, Villa, Marzia, Zhai, Yansheng, Schoenfeld, Ryan, Gleason, Shelley, Brotherton-Pleiss, Christine, Jen Lin, Clara
• Granted Patent: US 7,491,821 B2
• Time in Patent Office: Days
• US Class Current: 544/120
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

Compounds of formula 1 are modulators of P2X3 useful for the treatment of pain and genito-urinary, gastrointestinal, and respiratory disorders: wherein

• • R¹ is —C(═S)CH₃, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, furylcarbonyl, acetyl, or carbamoyl; R^2a and R^2b are independently H, methyl, or ethyl; R³ is H or methyl; Y is a bond, —(CR⁴R⁵)_n— or —CR⁴═CR⁵—; wherein R⁴ and R⁵ are each independently H or methyl and n is 1 or 2; X is N or CH; A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl; R⁶, R⁷ and R⁸ are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl (where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy or lower alkylthio) or R⁶ and R⁷ together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl (where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoro-methyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl); and pharmaceutically acceptable salts thereof; wherein when R¹ is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl.

Claims

1. A compound of formula I:

2. The compound according to claim 1 wherein Y is a bond.

3. The compound according to claim 1 wherein A is phenyl, oxazolyl, thiazolyl, furanyl, pyrimidinyl, pyridinyl, pyrazolyl, imidazolyl, pyrrolyl, 1H-[1,2,3]triazolyl or 4,5-dihydro1H-[1,2,4]triazolyl.

4. The compound according to claim 1 wherein A(R⁶)(R⁷)R⁸ is pyrazolo[1,5a]pyrimidinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-indazolyl, 2H-indazolyl, 1H-indolyl, benzofuranyl, 2H-phthalazinyl, imidazo[1,5-a]pyridyl or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl each of which substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl;

where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl.

5. The compound of claim 1, wherein R^2a is methyl, R^2b is H, and R³ is H.

6. The compound of claim 5, wherein X is N.

7. The compound of claim 6, wherein n is 0.

8. The compound of claim 7, wherein A is oxazolyl.

9. The compound of claim 7, wherein R⁶ is 4-fluorophenyl.

10. The compound of claim 7, wherein R⁷ is propyl.

11. The compound of claim 10, wherein R¹ is pyrimidinyl.

12. The compound of claim 10, wherein R¹ is thioacetyl.

13. The compound of claim 10, wherein R¹ is pyridyl.

14. The compound of claim 8, wherein R⁶ is methylthioethyl.

15. The compound of claim 8, wherein R⁶ is phenyl.

16. The compound of claim 8, wherein R⁶ is morpholinomethyl.

17. The compound of claim 7, wherein A is thiazolyl.

18. The compound of claim 17, wherein R⁶ is selected from the group consisting of phenyl, halo-phenyl, alkyl-substituted phenyl, pyridyl, thiophenyl, and trifluoromethyl.

19. A method for modulating the activity of a P2X₃ receptor, comprising contacting a P2X₃ receptor with a compound of formula I

20. The method of claim 19, wherein R^2a is methyl, R^2b is H, and R³ is H.

21. The method of claim 20, wherein X is N.

22. The method of claim 21, wherein n is 0.

23. A method for treating a genitourinary disorder responsive to a P2X₃ modulator, comprising:

administering to a subject in need thereof a compound of formula 1;

 

wherein

R¹ is —

C(═

S)CH₃, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, furylcarbonyl, acetyl, or carbamoyl;

R^2a and R^2b are independently H, methyl, or ethyl;

R³ is H or methyl;

Y is a bond, —

CR⁴R⁵)_n—

or —

CR⁴═

CR⁵—

;

wherein R⁴ and R⁵ are each independently H or methyl and n is 1 or 2;

X is N or CH;

A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl;

R⁶, R⁷ and R⁸ are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl;

where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy or lower alkylthio;

or

R⁶ and R⁷ together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl;

where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl;

and pharmaceutically acceptable salts thereof;

wherein when R¹ is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl.

24. The method of claim 23, wherein R^2a is methyl, R^2b is H, and R³ is H.

25. The method of claim 24, wherein X is N.

26. The method of claim 25, wherein n is 0.

27. A method for treating a genitourinary disorder responsive to a P2X₃ modulator, comprising:

administering to a subject in need thereof a compound of formula 1;

 

wherein

R¹ is —

C(═

S)CH₃, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, furylcarbonyl, acetyl, or carbamoyl;

R^2a and R^2b are independently H, methyl, or ethyl;

R³ is H or methyl;

Y is a bond, —

(CR⁴R⁵)_n—

or —

CR⁴═

CR⁵—

;

wherein R⁴ and R⁵ are each independently H or methyl and n is 1 or 2;

X is N or CH;

A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl;

R⁶, R⁷ and R⁸ are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl;

where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy or lower alkylthio;

or

R⁶ and R⁷ together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl;

where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl;

and pharmaceutically acceptable salts thereof;

wherein when R¹ is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl.

28. A method for treating a respiratory disorder responsive to a P2X₃ modulator, comprising:

administering to a subject in need thereof a compound of formula 1;

 

wherein

R¹ is —

C(═

S)CH₃, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, furylcarbonyl, acetyl, or carbamoyl;

R^2a and R^2b are independently H, methyl, or ethyl;

R³ is H or methyl;

Y is a bond, —

CR⁴R⁵)_n—

or —

CR⁴═

CR⁵—

;

wherein R⁴ and R⁵ are each independently H or methyl and n is 1 or 2;

X is N or CH;

A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl;

R⁶, R⁷ and R⁸ are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl;

where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy or lower alkylthio;

or

R⁶ and R⁷together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl;

where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl;

and pharmaceutically acceptable salts thereof;

wherein when R¹ is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl.

29. A method for treating pain responsive to a P2X₃ modulator, comprising:

administering to a subject in need thereof a compound of formula I;

 

wherein

R¹ is —

C(═

S)CH₃, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, furylcarbonyl, acetyl, or carbamoyl;

R^2a and R^2b are independently H, methyl, or ethyl;

R³ is H or methyl;

Y is a bond, —

CR⁴R⁵)_n—

or —

CR⁴═

CR⁵—

;

wherein R⁴ and R⁵ are each independently H or methyl and n is 1 or 2;

X is N or CH;

A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl;

R⁶, R⁷ and R⁸ are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl;

where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy or lower alkylthio;

or

R⁶ and R⁷ together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl;

where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl;

and pharmaceutically acceptable salts thereof;

wherein when R¹ is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl.