IP Library › Granted Patent US 11,059,792

Granted Patent B2

US 11,059,792 · App. 15/548,909 · Granted Jul 13, 2021

Imidazolyl tricyclic enones as antioxidant inflammation modulators

Inventors: Xin Jiang (Coppell, TX); Bradley William Caprathe (Livonia, MI); Chitase Lee (Ann Arbor, MI); Gary Bolton (Ann Arbor, MI); Christopher F. Bender (Garland, TX); Melean Visnick (Irving, TX)

Assignee: REATA PHARMACEUTICALS, INC.

C07D235/08 A61P29/00 C07C235/02 C07D235/10 C07D235/12 C07D401/04 C07D403/04 C07D403/10 C07D403/14

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Quick Facts

Patent No.: US 11,059,792
App. No.: 15/548,909
Granted: Jul 13, 2021
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed herein are compounds of the formula: (I), wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used as antioxidant inflammation modulators. In some aspects, the present disclosure provides methods wherein the compounds and composition described herein are used for the treatment of diseases and disorders associated with inflammation and cancer.

Claims (122)

1. A compound of the formula:

wherein:

X is —CN or —C(O)R a , wherein R a is —NH 2 ;

R 1 and R 2 are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

R 3 is:

absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:

hydrogen, hydroxy, amino, halo, or cyano; or

alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or

-alkanediyl (C≤6) -Y 1 wherein Y 1 is:

hydroxy, amino, halo, or cyano; or

acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , arylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups;

R 5 is:

absent, hydrogen, or hydroxy; or

-alkanediyl (C≤6) -Y 2 ,

-arenediyl (C≤8) -Y 3 , or

-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,

wherein Y 2 , Y 3 , and Y 4 are each independently:

hydroxy, amino, halo, or cyano; or

alkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups;

provided that R 5 is absent when the atom to which it is bound forms part of a double bond; and

R 6 is alkyl (C≤12) or aryl (C≤12) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , further defined by the formula:

wherein:

X is —CN or —C(O)R a , wherein R a is —NH 2 ;

R 1 and R 2 are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

R 3 is:

absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:

hydrogen, hydroxy, amino, halo, or cyano; or

-alkanediyl (C≤6) -Y 1 , wherein Y 1 is:

hydroxy, amino, halo, or cyano; or

acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; and

R 5 is:

absent, hydrogen, or hydroxy; or

-alkanediyl (C≤6) -Y 2 ,

-arenediyl (C≤8) -Y 3 , or

-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,

wherein Y 2 , Y 3 , and Y 4 are each independently:

hydroxy, amino, halo, or cyano; or

provided that R 5 is absent when the atom to which it is bound forms part of a double bond;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , further defined by the formula:

wherein:

R 1 and R 2 are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

R 3 is:

absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:

hydrogen, hydroxy, amino, halo, or cyano; or

-alkanediyl (C≤6) -Y 1 , wherein Y 1 is:

hydroxy, amino, halo, or cyano; or

R 5 is:

absent, hydrogen, or hydroxy; or

-alkanediyl (C≤6) -Y 2 ,

-arenediyl (C≤8) -Y 3 , or

-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,

wherein Y 2, Y 3, and Y 4 are each independently:

hydroxy, amino, halo, or cyano; or

provided that R 5 is absent when the atom to which it is bound forms part of a double bond;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , further defined by the formula:

wherein:

R 3 is:

absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:

hydrogen, hydroxy, amino, halo, or cyano; or

-alkanediyl (C≤6) -Y 1 , wherein Y 1 is:

hydroxy, amino, halo, or cyano; or

R 5 is:

absent, hydrogen, or hydroxy; or

-alkanediyl (C≤6) -Y 2 ,

-arenediyl (C≤8) -Y 3 , or

-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,

wherein Y 2 , Y 3 , and Y 4 are each independently:

hydroxy, amino, halo, or cyano; or

provided that R 5 is absent when the atom to which it is bound forms part of a double bond;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , further defined by the formula:

wherein:

R 4 is:

hydrogen, hydroxy, amino, halo, or cyano; or

-alkanediyl (C≤6) -Y 1 , wherein Y 1 is:

hydroxy, amino, halo, or cyano; or

R 5 is:

hydrogen or hydroxy; or

-alkanediyl (C≤6) -Y 2 ,

-arenediyl (C≤8) -Y 3 , or

-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,

wherein Y 2 , Y 3 , and Y 4 are each independently:

hydroxy, amino, halo, or cyano; or

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein:

R 4 is:

hydrogen, hydroxy, amino, halo, or cyano; or

R 5 is:

hydrogen or hydroxy; or

7. The compound of claim 2 , further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

8. The compound of claim 1 , wherein the formula is further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

9. A pharmaceutical composition comprising:

a) a compound of claim 1 ; and

b) an excipient.

Assignments (9)

RELEASE OF SECURITY INTEREST Recorded Apr 9, 2025

From: BIOPHARMA CREDIT PLC

To: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

Reel/Frame 070793/0228 →

RELEASE OF SECURITY INTEREST Recorded Apr 9, 2025

From: BIOPHARMA CREDIT PLC

To: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

Reel/Frame 070793/0130 →

AMENDED AND RESTATED PATENT SECURITY AGREEMENT Recorded Jul 12, 2023

From: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

To: BIOPHARMA CREDIT PLC

Reel/Frame 064264/0557 →

PATENT SECURITY AGREEMENT Recorded May 18, 2023

From: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

To: BIOPHARMA CREDIT PLC

Reel/Frame 063697/0461 →

RELEASE OF SECURITY INTEREST Recorded Jun 24, 2020

From: OXFORD FINANCE LLC, AS COLLATERAL AGENT

To: REATA PHARMACEUTICALS, INC.

Reel/Frame 053034/0018 →

SECURITY INTEREST Recorded Jun 14, 2018

From: REATA PHARMACEUTICALS, INC.

To: OXFORD FINANCE LLC, AS COLLATERAL AGENT

Reel/Frame 046357/0605 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 13, 2017

From: CAPRATHE, BRADLEY WILLIAM; LEE, CHITASE; BOLTON, GARY

To: AAPHARMASYN LLC

Reel/Frame 043570/0838 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 13, 2017

From: JIANG, XIN; BENDER, CHRISTOPHER F.; VISNICK, MELEAN

To: REATA PHARMACEUTICALS, INC.

Reel/Frame 043571/0151 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 13, 2017

From: AAPHARMASYN LLC

To: REATA PHARMACEUTICALS, INC.

Reel/Frame 043571/0005 →

Continuity (2)

Provisional Application 62115247 · Feb 12, 2015

Related Publication 20180127380A1 · May 10, 2018

Cited By (1)

US 12,195,443