Intermediates for making 2,4-pyrimidinediamine compounds

• US 7,655,797 B2
• Filed: 08/27/2008
• Issued: 02/02/2010
• Est. Priority Date: 02/01/2002
• Status: Expired due to Term

• Current Assignee: Rigel Pharmaceuticals, Inc.
• Original Assignee: Rigel Pharmaceuticals, Inc.
• Inventors: Keim, Holger, Holland, Sacha J., Molineaux, Susan, Rossi, Alexander B, Payan, Donald G., Clough, Jeffrey, Argade, Ankush, Sylvain, Catherine, Bhamidipati, Somasekhar, Li, Hui, Singh, Rajinder
• Primary Examiner(s): Sullivan; Daniel M
• Assistant Examiner(s): Nwaonicha; Chukwuma O
• Application Number:
  US12/199,705
• Publication Number:
  US 20090082567A1
• Time in Patent Office: 524 Days
• Field of Search: 530/391.1, 530/409, 564/164, 564/167, 560/45, 548/542, 544/358
• US Class Current: 544/323
• 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. Certain disclosed embodiments concern contacting compounds having a formula

or a salt or N-oxide thereof, with 2,4-dichloro-5-fluoropyrimidine under conditions to provide compounds having a formula

Claims

1. A process for preparing a compound of formula (I):

2. The process of claim 1, wherein Y and Z, each independently of the other, is selected from the group consisting of O and NR³⁵.

3. The process of claim 2, wherein one of Y and Z is NH and the other is O.

4. The process of claim 3, wherein Y is O and Z is NH.

5. The process of claim 4, wherein two R³⁵ bonded to the same carbon atom are taken together to form an oxo (═

O) group.

6. The process of claim 5, wherein the other two R³⁵ each independently are hydrogen, methyl or fluoro.

7. The process of claim 2, wherein each of Y and Z is O.

8. The process of claim 7, wherein each R³⁵ is hydrogen.

9. The process of claim 1, wherein two R³⁵ bonded to the same carbon atom are taken together to form an oxo (═

O) group.

10. The process of claim 9, wherein the other two R³⁵ each independently are hydrogen, methyl or fluoro.

11. The process of claim 1, wherein each R³⁵ is hydrogen.

12. The process of claim 1, wherein the compound of formula (II) is selected from the group consisting of:

13. The process of claim 12, wherein the compound of formula (II) is selected from the group consisting of:

14. The process of claim 1, wherein the compound of formula (I) is contacted with from at least 0.8 to about 3.0 equivalents of the compound of formula (II).

15. The process of claim 1, wherein said contacting of the compound of formula (I) with the compound of formula (II) is conducted in an organic solvent, with 0% to about 70% added water by volume, in the presence or absence of a catalytic amount of dilute mineral acid, at a reaction temperature of about 20°

C. to reflux, for about 0.5 hours to about 24 hours.

16. The process of claim 15, wherein the organic solvent is methanol or acetone.

17. The process of claim 16, wherein the reaction temperature is about 60°

C. to about 80°

C.

18. The process of claim 17, wherein the reaction time is about 0.5 hours to about 3 hours.

19. The process of claim 1, which further comprises recovering the compound of formula (I).

20. The process of claim 19, wherein the compound of formula (I) is recovered by filtration, or by isolation from an organic solvent extract and/or by chromatography.

21. The process of claim 20, wherein the compound of formula (I) is recovered by filtration.