SUBSTITUTED BENZOAZEPINES AS TOLL-LIKE RECEPTOR MODULATORS

• US 20110092485A1
• Filed: 08/18/2010
• Published: 04/21/2011
• Est. Priority Date: 08/18/2009
• Status: Active Grant

• Current Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company), Array Biopharma Incorporated (Pfizer Inc.)
• Original Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company), Array Biopharma Incorporated (Pfizer Inc.)
• Inventors: Yang, Hong Woon, Lyssikatos, Joseph P., Dietsch, Gregory, Burgess, Laurence E., Howbert, James Jeffry, Newhouse, Brad, Hershberg, Robert
• Granted Patent: US 8,691,809 B2
• Time in Patent Office: Days
• US Class Current: 514/213.01
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• 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 31/04 Antibacterial agents
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 223/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• 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 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/10 linked by a carbon chain containing aromatic rings

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 treating or preventing disease, including cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft-verses-host disease.

Claims

1. A compound having the formula I:

2. The compound according to claim 1, having the formula II:

3. The compound according to claim 2, having the formula IIa:

4. The compound according to claim 2, having the formula IIb:

5. The compound according to claim 1, having the formula III:

6. The compound according to claim 1, having the formula IV:

7. The compound according to claim 1, having the formula V:

8. The compound according to claim 1, having the formula VI:

9. The compound according to claim 8, wherein:

R¹¹ is selected from aryl and saturated or partially saturated heterocycle, wherein said aryl is substituted with T;

T is selected from heterocycle and —

(O)_u(CH₂)_sC(O)R⁸;

R⁸ is selected from —

OR¹⁰ and alkyl;

R¹⁰ is selected from alkyl, —

(CH₂)R¹², and hydrogen, wherein said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine;

R¹² is selected from cycloalkyl and aryl;

u is selected from 0 and 1;

s is selected from 1 and 2; and

R³ and R⁴ are independently alkyl;

wherein said alkyl is optionally substituted with one or more —

OH.

10. The compound according to claim 8, wherein:

R¹¹ is aryl substituted with T;

T is selected from —

(O)_u(CH₂)_sC(O)R⁸, and —

CH(OH)CH₂OH;

R⁸ is selected from —

OR¹⁰ and alkyl;

R¹⁰ is selected from alkyl, —

(CH₂)R¹², and hydrogen, wherein said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine;

R¹² is selected from cycloalkyl and aryl;

u is selected from 0 and 1;

s is selected from 1 and 2; and

R³ and R⁴ are independently alkyl;

wherein said alkyl is optionally substituted with one or more —

OH.

11. The compound according to claim 1, selected from the group consisting of:

12. The compound according to claim 11, selected from the group consisting of:

13. The compound according to claim 11, selected from the group consisting of:

14. The compound according to claim 11, selected from the group consisting of:

15. The compound according to claim 1, wherein the salt is a pharmaceutically acceptable salt.

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

a) a pharmaceutical composition comprising a compound of claim 1 or a tautomer, enantiomer or salt thereof; and

b) optionally instructions for use.

17. A pharmaceutical composition, which comprises a compound of claim 1 or a tautomer, enantiomer or salt thereof together with a pharmaceutically acceptable diluent or carrier.

18. 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 or a tautomer, enantiomer or salt thereof.

19. 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 or a tautomer, enantiomer or salt thereof.