8-Substituted Benzoazepines as Toll-Like Receptor Modulators

• US 20080234251A1
• Filed: 08/17/2006
• Published: 09/25/2008
• Est. Priority Date: 08/19/2005
• Status: Active Grant

• Current Assignee: Array Biopharma Incorporated (Pfizer Inc.)
• Original Assignee: Array Biopharma Incorporated (Pfizer Inc.)
• Inventors: Eary, C. Todd, Doherty, George A., Groneberg, Robert D., Jones, Zachary
• Granted Patent: US 8,153,622 B2
• Time in Patent Office: Days
• US Class Current: 514/213.01
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• 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: C07D 223/16 Benzazepines; Hydrogenated benzazepines

Abstract

Provided are compositions and methods useful for modulation of signaling through the Toll-like receptors TLR7 and/or TLR8. The compositions and methods have use in the treatment of autoimmunity, inflammation allergy, asthma, graft rejection, graft versus host disease, infection, sepsis, cancer and immunodeficiency.

Claims

1. A compound of the Formula

2. The compound of claim 1, wherein R² is OR⁶.

3. The compound of claim 2, wherein R⁶ is alkyl.

4. The compound of claim 3, wherein R⁶ is ethyl.

5. The compound of claim 1, wherein R² is NR⁶R⁷.

6. The compound of claim 5, wherein R⁶ and R⁷ are independently H, alkyl or heteroalkyl.

7. The compound of claim 6, wherein R⁶ and R⁷ are independently H, ethyl, propyl, or CH₂CH₂OCH₃.

8. The compound of claim 1, wherein Y is aryl.

9. The compound of claim 8, wherein said aryl is substituted with C(═

O)R⁸.

10. The compound of claim 9, wherein R⁸ is OR⁶, NR⁶R⁷ or heterocycloalkyl.

11. The compound of claim 10, wherein R⁶ and R⁷ are independently selected from H and alkyl.

12. The compound of claim 10, wherein Y is

13. The compound of claim 1, wherein Y is CF₂CF₃.

14. The compound of claim 1, wherein R¹, R³, R⁴, R^5a, R^5b and R^5c are each hydrogen.

15. The compound of claim 1, selected from:

(1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate;

(1E,4E)-2-amino-N,N-bis(2-methoxyethyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E,4E)-2-amino-N,N-diethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E,4E)-2-amino-8-(perfluoroethyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide;

(1E,4E)-2-amino-N-ethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide;

(1E,4E)-2-amino-8-(perfluoroethyl)-N-propyl-3H-benzo[b]azepine-4-carboxamide;

(1E,4E)-ethyl 2-amino-8-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepine-4-carboxylate;

(1E,4E)-ethyl 2-amino-8-(4-(methoxycarbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E,4E)-ethyl 2-amino-8-(4-(methylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate;

(1E,4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide; and

pharmaceutically acceptable salts thereof.

16. A kit for treating a TLR7- and/or TLR8-mediated condition, comprising:

a) a first pharmaceutical composition comprising a compound of claim 1; and

b) optionally instructions for use.

17. The kit of claim 16 further comprising (c) a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a second compound for treating a TLR7- and/or TLR8-mediated condition.

18. The kit of claim 17, further comprising instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof.

19. A pharmaceutical composition, which comprises a compound as claimed in claim 1 together with a pharmaceutically acceptable diluent or carrier.

22. A method of treating a TLR7- and/or TLR8-mediated condition, comprising administering to a patient in need thereof an effective amount of a compound of claim 1.

23. A method of modulating a patient'"'"'s immune system, comprising administering to a patient in need thereof an effective amount of a compound of claim 1.

20-21. -21. (canceled)