Anti-fibrotic pyridinones

• US 9,359,379 B2
• Filed: 10/01/2013
• Issued: 06/07/2016
• Est. Priority Date: 10/02/2012
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Buckman, Brad Owen, Nicholas, John Beamond, Ramphal, Johnnie Y., Emayan, Kumaraswamy, Seiwert, Scott D.
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US14/043,121
• Publication Number:
  US 20140107110A1
• Time in Patent Office: 980 Days
• Field of Search: 514/303, 546/119
• US Class Current: 1/1
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• 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 13/12 of the kidneys
• 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 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/86 Oxygen atoms
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 221/04 Ortho- or peri-condensed ring systems
• CPC Class Codes: C07D 223/10 attached in position 2
• CPC Class Codes: C07D 295/125 with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Disclosed are pyridinone compounds, method for preparing these compounds, and methods for treating fibrotic disorders.

Claims

1. A compound having the structure of formula (III):

2. The compound of claim 1, wherein

each R⁹ is independently selected from the group consisting of halogen, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted C_1-6 alkylthio, optionally substituted C_2-8 alkoxyalkyl, optionally substituted C_3-10 carbocyclyl, optionally substituted C_6-10 aryl, —

OR⁵, —

NR¹⁴R¹⁵, —

C(O)R⁸, —

SO₂R¹⁶, and —

NO₂.

3. The compound of claim 1, wherein R¹ is selected from C_6-10 aryl optionally substituted with one or more R⁴, or 5 to 6 membered heteroaryl optionally substituted with one or more R⁴.

4. The compound of claim 3, wherein R¹ is phenyl optionally substituted with one or more R⁴.

5. The compound of claim 3, wherein R¹ is pyridazinyl optionally substituted with one or more R⁴.

6. The compound of claim 3, wherein R¹ is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R⁴.

7. The compound of claim 1, wherein R³ is —

(CH₂)_n—

(C_6-10 aryl) optionally substituted with one or more R⁹.

8. The compound of claim 7, wherein R³ is phenyl, optionally substituted with one or more R⁹.

9. The compound of claim 7, wherein R³ is unsubstituted.

10. The compound of claim 8, wherein R⁹ is selected from cyano, halogen, optionally substituted C_1-6 alkyl, or optionally substituted C_1-6 alkoxy.

11. The compound of claim 10, wherein R⁹ is selected from cyano, fluoro, chloro, methyl, ethyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

12. The compound of claim 1, wherein R⁴ is selected from halogen, optionally substituted C_1-6 alkyl, or C_7-14 aralkyl optionally substituted with one or more R¹¹, or two geminal R⁴ together are oxo.

13. The compound of claim 12, wherein R⁴ is selected from fluoro, methyl, trifluoromethyl, —

(CH₂)₂OH, benzyl, or two geminal R⁴ together are oxo.

14. The compound of claim 1, wherein Z is oxygen.

15. The compound of claim 1, wherein the bonds represented by a solid and dashed line are double bonds.

16. The compound of claim 1, wherein the compound is selected from the group consisting of

17. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

18. A compound of structure

19. A compound of structure

20. A compound of structure

21. A compound of structure