2,4-Pyrimidinediamine compounds and their uses

• US 20040029902A1
• Filed: 01/31/2003
• Published: 02/12/2004
• Est. Priority Date: 02/01/2002
• Status: Active Grant

• Current Assignee: Rigel Pharmaceuticals, Inc.
• Original Assignee: Rigel Pharmaceuticals, Inc.
• Inventors: Holland, Sasha J., Clough, Jeffrey, Keim, Holger, Argade, Ankush, Sylvain, Catherine, Bhamidipati, Somasekhar, Li, Hui, Singh, Rajinder, Payan, Donald, Molineaux, Susan, Rossi, Alexander B.
• Granted Patent: US 7,557,210 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5395 having two or more nitrogen atoms in the same ring, e.g. oxadiazines
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 27/16 Otologicals
• 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 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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: C07D 239/48 : Two nitrogen atoms
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 407/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : 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 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/14 : Ortho-condensed systems
• CPC Class Codes: C07F 5/027 : Organoboranes and organoborohydrides

Abstract

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

Claims

1. A compound according to structural formula (I):

2. The compound of claim 1 in which L¹ and L² are each, independently of one another, selected from the group consisting of a direct bond, (C1-C3) alkyldiyl optionally substituted with one or more of the same or different R⁹ groups and 1-3 membered heteroalkyldiyl optionally substituted with one or more of the same or different R⁹ groups, wherein:

R⁹ is selected from the group consisting of (C1-C3) alkyl, —

OR^a, —

C(O)OR^a, (C5-C10) aryl optionally substituted with one or more of the same or different halogens, phenyl optionally substituted with one or more of the same or different halogens, 5-10 membered heteroaryl optionally substituted with one or more of the same or different halogens and 6 membered heteroaryl optionally substituted with one or more of the same or different halogens; and

R^a is as defined in claim 1.

3. The compound of claim 2 in which L¹ and L² are each, independently of one another, selected from the group consisting of methano, ethano and propano, each of which may be optionally monosubstituted with an R⁹ group.

4. The compound of claim 3 in which the R⁹ group is selected from the group consisting of —

OR^a, —

C(O)OR^a, halophenyl and 4-halophenyl, wherein R^a is as defined in claim 1.

5. The compound of claim 1 in which R⁶ is hydrogen.

6. The compound of claim 1 or 5 in which R⁵ is selected from the group consisting of an electronegative group, halo, —

F, —

CN, —

NO₂, —

C(O)R^a, —

C(O)OR^a, —

C(O)CF₃, —

C(O)OCF₃, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, —

OCF₃ and —

CF₃.

7. The compound of claim 1 in which at least one of L1 or L2 is a direct bond.

8. The compound of claim 1 according to the structure (Ia):

9. The compound of claim 8 in which R² is selected from the group consisting of phenyl, naphthyl, 5-10 membered heteroaryl, benzodioxanyl, 1,4-benzodioxan-(5 or 6)-yl, benzodioxolyl, 1,3-benzodioxol-(4 or 5)-yl, benzoxazinyl, 1,4-benzoxazin-(5,6,7 or 8)-yl, benzoxazolyl, 1,3-benzoxazol-(4,5,6 or 7)-yl, benzopyranyl, benzopyran-(5,6,7 or 8)-yl, benzotriazolyl, benzotrazol-(4,5, 6 or 7)-yl, 1,4-benzoxazinyl-2-one, 1,4-benzoxazin-(5,6,7 or 8)-yl-2-one, 2H-1,4-benzoxazinyl-3(4H)-one, 2H-1,4-benzoxazin-(5,6,7 or 8)-yl-3(4H)-one, 2H-1,3-benzoxazinyl-2,4(3H)-dione, 2H-1,3-benzoxazin-(5,6,7 or 8)-yl-2,4(3H)-dione, benzoxazolyl-2-one, benzoxazol-(4,5, 6 or 7)-yl-2-one, dihydrocoumarinyl, dihydrocoumarin-(5,6,7 or 8)-yl, 1,2-benzopyronyl, 1,2-benzopyron-(5,6,7 or 8)-yl, benzofuranyl, benzofuran-(4,5,6 or 7)-yl, benzo[b]furanyl, benzo[b]furan-(4,5,6, or -7)-yl, indolyl, indol-(4,5,6 or 7)-yl, pyrrolyl and pyrrol-(1 or 2)-yl, each of which maybe optionally substituted with one or more of the same or different R⁸ groups, where R⁸ is as defined in claim 1.

10. The compound of claim 8 in which R² and/or R⁴ are each, independently of one another, a heteroaryl selected from the group consisting of:

11. The compound of claim 10 in which R² and R⁴ are the same.

12. The compound of claim 10 or 11 in which each R³⁵ is independently selected from the group consisting of hydrogen, R^d, —

NR^cR^c, —

(CH₂)_m—

NR^cR^c, —

C(O)NR^cR^c, —

(CH₂)_m—

C(O)NR^cR^c, —

C(O)OR^d, —

(CH₂)_m—

C(O)OR^d and —

(CH₂), —

OR^d, where m, R^c and R^d are as defined in claim 1.

13. The compound of claim 12 in which each m is one.

14. The compound of claim 8 in which R² is an optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom.

15. The compound of claim 8 in which R⁴ is an optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom.

16. The compound of claim 8 in which R² and/or R⁴ are each, independently of one another, a phenyl optinally substituted with one, two or three R⁸ groups, where R⁸ is as defined in claim 1.

17. The compound of claim 16 in which R² and R⁴ are each the same or different optionally substituted phenyl.

18. The compound of claim 16 or 17 in which the optionally substituted phenyl is mono substituted.

19. The compound of claim 18 in which the R⁸ substituent is at the ortho, meta or para position.

20. The compound of claim 19 in which R⁸ is selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, —

OR^d, —

O—

(CH₂)_m—

NR^cR^c, —

O—

C(O)NR^cR^c, —

O—

(CH₂)_m—

C(O)NR^cR^c, —

O—

C(O)OR^a, —

O—

(CH₂)_m—

C(O)OR^a, —

O—

C(NH)NR^cR^c, —

O—

(CH₂)_m—

C(NH)NR^cR^c, —

NH—

(CH₂)_m—

NR^cR^c, —

NH—

C(O)NR^cR^c and —

NH—

(CH₂)_m—

C(O)NR^cR^c, where m, R^a, R^c and R^d are as defined in claim 1.

21. The compound of claim 16 or 17 in which the optionally substituted phenyl is a disubstituted phenyl.

22. The compound of claim 21 in which the R⁸ substituents are positioned 2,3-;

2,4-;

2,5-;

2,6-;

3,4-;

or 3,5-.

23. The compound of claim 21 in which each R⁸ is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, —

OR^a optionally substituted with one or more of the same or different R^a or R^b groups, —

O—

(CH₂)_m—

NR^cR^c, —

O—

C(O)NR^cR^c, —

O—

(CH₂)_m—

C(O)NR^cR^c, —

O—

C(O)OR^a, —

O—

(CH₂)_m—

C(O)OR^a, —

O—

C(NH)NR^cR^c, —

O—

(CH₂), —

C(NH)NR^cR^c, —

NH—

(CH₂)_m—

NR^cR^c, —

NH—

C(O)NR^cR^c and —

NH—

(CH₂)_m—

C(O)NR^cR^c, where m, R^a, R^b and R^c are as defined in claim 1.

24. The compound of claim 16 or 17 in which the optionally substituted phenyl is trisubstituted.

25. The compound of claim 24 in which the R⁸ substituents are positioned 2,3,4;

2,3,5;

2,3,6;

2,4,5;

2,4,6;

2,5,6;

or 3,4,5.

26. The compound of claim 25 which each R⁸ is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, —

OR^a optionally substituted with one or more of the same or different R^a or R^b groups, —

O—

(CH₂)_m—

NR^cR^c, —

O—

C(O)NR^cR^c, —

O—

(CH₂)_m—

C(O)NR^cR^c, —

O—

C(O)OR^a, —

O—

C(NH)NR^cR^c, —

O—

(CH₂)_m—

C(O)OR^a, —

O—

(CH₂)_m—

C(NH)NR^cR^c, —

NH—

(CH₂)_m—

NR^cR^c, —

NH—

C(O)NR^c and —

NH—

(CH₂), —

C(O)NR^cR^c, where m, R^a, R^b and R^c are as defined in claim 1.

27. The compound of claim 24 in which the trisubstituted phenyl has the formula:

28. The compound of claim 17 in which R² and R⁴ are the same.

29. The compound of claim 8 according to structural formula (Ib):

30. The compound of claim 29 in which R¹¹, R¹², R¹³ and R¹⁴ are each hydrogen.

31. The compound of claim 29 in which R¹² and R¹³ are each hydrogen.

32. The compound of claim 8 according to structural formula (Ic):

33. The compound of claim 32 in which R⁴ is an optionally substituted heteroaryl.

34. The compound of claim 32 in which R¹⁸ is —

O—

CH₂—

C(O)—

NHCH₃.

35. The compound of claim 1 which inhibits mast cell or basophil cell degranulation as measured in an in vitro assay.

36. The compound of claim 35 which has an IC50 of about 20 μ

M or less.

37. A compound according to structural formula (Id):

38. The compound of claim 37 in which when R¹⁵ is halogen or nitro, then R² is not 3,4,5-tri (C1-C6) alkoxyphenyl.

39. The compound of claim 38 in which R¹⁵ is selected from the group consisting of —

CN, —

NC, —

NO₂, halogen, —

F, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, —

CF₃, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy and —

OCF₃.

40. The compound of claim 39 in which R¹⁵ is selected from the group consisting of halo, Br, F, —

CF₃ and —

NO₂.

41. The compound of claim 37 which inhibits mast cell or basophil cell degranulation as measured in an in vitro assay.

42. The compound of claim 41 which has an IC₅₀ of about 20 μ

M or less.

46. A pharmaceutical composition comprising a pyrimidinediamine compound and a pharmaceutically acceptable carrier, diluent or excipient, said pyrimidinediamine compound being a compound according to structural formula (Id):

47. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

49. The composition of any one of claims 46-48 in which the compound is in the form of a pharmaceutically acceptable salt.

50. The composition of claim 49 in which the salt is a hydrochloride salt, a hydrogen sulfate salt, a sulfate salt, a phosphate salt, an alkane sulfonate salt, a methane sulfonate salt, an ethane sulfonate salt or a p-tolune sulfonate salt.

51. A method of inhibiting cell degranulation, comprising contacting a cell with an amount of a compound according to any one of claims 1, 37 or 43 effect to inhibit degranulation.

52. The method of claim 51 in which the cell is a human mast, basophil cell, neutrophil or eosinophil cell.

53. A method of inhibiting cell degranulation, comprising contacting a mast or basophil cell with an amount of a composition according to any one of claims 46-48 effective to inhibit degranulation.

54. The method of claim 53 in which the cell is a human mast, basophil cell, neutrophil or eosinophil cell.

55. A method of treating a disease characterized by, caused by or associated with mast or basophil cell degranulation, comprising administering to an animal suffering from such a disease an effective amount of a composition according to any one of claims 46-48.

56. The method of claim 55 in which the animal is a human.

57. The method of claim 55 in which the disease is selected from the group consisting of allergic diseases, low grade scarring, diseases associated with tissue destruction, diseases associated with tissue inflammation, inflammation, and scarring.

58. The method of claim 57 in which the allergic disease is selected from the group consisting of conjunctivitis, rhinitis, asthma, atopic dermatitis and food allergies.

59. The method of claim 57 in which the low grade scarring is selected from the group consisting of scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction.

60. The method of claim 57 in which the disease associated with tissue destruction is selected form the group consisting of COPD, cardiobronchitis and post myocardial infarction.

61. The method of claim 57 in which the disease associated with tissue inflammation is selected from the group consisting of irritable bowel, spastic colon and inflammatory colon disease.

62. A method of inhibiting a Syk kinase, comprising the step of contacting the Syk kinase or an active fragment thereof with an effective amount of a 2,4-pyrimidinediamine compound according to claim 1.

63. The method of claim 62 which is practiced in vitro with an isolated or recombinant Syk kinase.

64. The method of claim 62 in which the Syk kinase is practiced in vitro with a cell or cell population that expresses an endogenous or recombinant Syk kinase.

65. The method of claim 62 which is practiced in vivo.

66. A method of inhibiting a Syk kinase in an animal, comprising the step of administering to the animal an amount of a 2,4-pyrimidinediamine compound according to claim 1 effective to inhibit the Syk kinase.

67. A method of treating or preventing a disease mediated at least in part by Syk kinase activity, comprising the step of administering to an animal in need thereof an amount of a 2,4-pyrimidinediamine compound according to claim 1 effective to inhibit the Syk kinase activity, thereby treating or preventing the disease.

68. A method of treating or preventing a disease mediated at least in part by Syk kinase activity, comprising the step of administering to an animal in need thereof an amount-of a composition according to claim 46 effective to inhibit the Syk kinase activity, thereby treating or preventing the disease.

70. A method of inhibiting an Fc receptor signal transduction cascade, contacting a cell comprising an Fc receptor having a gamma homodimer with an amount of a 2,4-pyrimidinediamine compound according to claim 1 effective to inhibit its signal transduction cascade.

71. The method of claim 70 in which the Fc receptor is selected from the group consisting of Fcα

RI, FCγ

RI, FCγ

RIII and Fcε

RI.

43. A compound selected from any compound in TABLE 1 which inhibits mast cell or basophil cell degranulation as measured in an in vitro assay, with the proviso that the compound is not

N2,N4-bis(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R070790);

N2,N4-bis(2-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R081166);

N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R088814);

N2,N4-bis(2-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R088815);

N2,N4-bisphenyl-5-fluoro-2,4-pyrimidinediamine (R091880);

N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R092788);

N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R067962);

N2,N4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067963);

N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067964);

N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R070153);

N2,N4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R070791);

or

N2,N4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine (R008958).

44. The compound of claim 43 which has an IC₅₀ of about 20 μ

M or less.

45. A pharmaceutical composition comprising a pyrimidinediamine compound and a pharmaceutically acceptable excipient, carrier or dilutent, said pyrimidinediamine compound being a compound according to structural formula (I):

48. A pharmaceutical composition comprising a compound selected from any compound in TABLE 1 which inhibits mast cell or basophil cell degranulation as measured in an in vitro assay and a pharmaceutically acceptable carrier, diluent or excipient.

69. The method of claim 72 or 74 in which the animal is a human.