Inhibitors of bruton's tyrosine kinase

• US 8,563,563 B2
• Filed: 01/30/2012
• Issued: 10/22/2013
• Est. Priority Date: 09/22/2006
• Status: Active Grant

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated)
• Inventors: Honigberg, Lee, Verner, Erik, Pan, Zhengying
• Primary Examiner(s): MURRAY, JEFFREY H
• Application Number:
  US13/361,730
• Publication Number:
  US 20120129821A1
• Time in Patent Office: 631 Days
• Field of Search: None
• US Class Current: 514/262.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/4825 Proteins, e.g. gelatin gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 13/12 of the kidneys
• 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 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• 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 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• 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 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

Disclosed herein are compounds that form covalent bonds with Bruton'"'"'s tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Claims

1. A method for treating a B-cell proliferative disorder in a subject in need thereof comprising administering to the subject two or more agents, wherein the first agent is an irreversible inhibitor of Bruton'"'"'s tyrosine kinase (Btk) and the second agent is an anti-cancer drug, wherein the irreversible inhibitor is a compound having the structure of Formula (A):

2. The method of claim 1, wherein the B-cell proliferative disorder is a lymphoma.

3. The method of claim 1, wherein the B-cell proliferative disorder is selected from nodal marginal zone B cell lymphoma, extranodal marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma, diffuse large B cell lymphoma, follicular lymphoma, Waldenstrom macroglobulinemia, mantle cell lymphoma, and burkitt lymphoma.

4. The method of claim 1, wherein the B-cell proliferative disorder is plasma cell myeloma.

5. The method of claim 1, wherein the B-cell proliferative disorder is a leukemia.

6. The method of claim 1, wherein the B-cell proliferative disorder is selected from B-cell prolymphocytic leukemia and Burkitt leukemia.

7. The method of claim 1, wherein the anti-cancer drug is a proapoptotic agent, angiogenesis inhibitor, dexamethasone, or a combination thereof.

8. The method of claim 1, wherein the anti-cancer drug is a proapoptotic agent.

9. The method of claim 1, wherein the anti-cancer drug is an angiogenesis inhibitor.

10. The method of claim 1, wherein the anti-cancer drug is dexamethasone.

11. The method of claim 1, wherein the irreversible inhibitor of Btk and the anti-cancer drug are administered simultaneously.

12. The method of claim 1, wherein the irreversible inhibitor of Btk and the anti-cancer drug are administered sequentially.

13. The method of claim 1, wherein the irreversible inhibitor of Btk is administered orally.

15. The method of claim 1 wherein L₃, X and L₄ taken together form a nitrogen containing heterocyclic ring.

16. The method of claim 1 wherein G is

17. The method of claim 1 wherein R₆, R₇, and R₈ are each independently H.

18. The method of claim 1 wherein the compound has the structure

14. A method for treating a plasma cell myeloma in a subject in need thereof comprising administering to the subject two or more agents, wherein the first agent is an irreversible inhibitor of Bruton'"'"'s tyrosine kinase (Btk) and the second agent is an agent for treating plasma cell myeloma, wherein the irreversible inhibitor is a compound having the structure of Formula (A):

20. The method of claim 14 wherein the compound has the structure

19. A method for treating a B-cell proliferative disorder in a subject in need thereof comprising administering to the subject two or more agents, wherein the first agent is an irreversible inhibitor of Bruton'"'"'s tyrosine kinase (Btk) and the second agent is an anti-cancer drug, wherein the selective, covalent inhibitor is a compound having the structure of