IP Library › Granted Patent US 9,592,221

Granted Patent B2

US 9,592,221 · App. 15/064,452 · Granted Mar 14, 2017

Antibacterial agents: aryl myxopyronin derivatives

Inventors: Richard H. Ebright (New Brunswick, NJ); Yon W. Ebright (New Brunswick, NJ); Juan Shen (New Brunswick, NJ); James Bacci (Monmouth Junction, NJ); Anne-Cecile Hiebel (Monmouth Junction, NJ); William Solvibile (Monmouth Junction, NJ); Christopher Self (Monmouth Junction, NJ); Gary Olson (Monmouth Junction, NJ)

Assignees: Rutgers, The State University of New Jersey; Provid Pharmaceuticals Inc.

A61K31/366 A61K31/381 A61K31/404 A61K31/4025 A61K31/4178 A61K31/427 A61K31/4433 C07D309/36 C07D309/38 C07D405/06 C07D405/12 C07D407/06 C07D407/12 C07D409/06 C07D417/06

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,592,221
App. No.: 15/064,452
Granted: Mar 14, 2017
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention provides compounds of formula Ia, Ib and Ic: and salts thereof, wherein variables are as described in the specification, as well as compositions comprising a compound of formula Ia-Ic, methods of making such compounds, and methods of using such compounds, e.g., as inhibitors of bacterial RNA polymerase and as antibacterial agents.

Claims (105)

1. A method of inhibiting a bacterial RNA polymerase, comprising contacting a bacterial RNA polymerase with a compound of formula Ia, Ib or Ic:

or a salt thereof, wherein:

W is sulfur, oxygen, or nitrogen;

X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;

one of R 1 and R 2 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy, wherein any C 1 -C 5 alkyl and C 1 -C 5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; or

one of R 1 and R 2 is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1 and R 2 is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

V′, W′, X′, Y′, and Z′ are individually carbon or nitrogen; wherein at least three of V′, W′, X′, Y′, and Z′ are carbon;

one of R 1′ and R 2′ is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy, wherein any C 1 -C 5 alkyl and C 1 -C 5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; or

one of R 1′ and R 2′ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1′ and R 2′ is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3′ , R 4′ , and R 5′ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

W″ is sulfur, oxygen, or nitrogen;

U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;

one of R 1″ and R 2″ is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy, wherein any C 1 -C 5 alkyl and C 1 -C 5 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; or

one of R 1″ and R 2″ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1″ and R 2″ is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3″ is absent or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4″ , R 5″ , and R 6″ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 5 and R 6 are individually H or methyl;

G is one of —CH═CH—NHC(O)—R 7 , —CH═CH—NHC(S)—R 7 , —CH 2 CH 2 NHC(O)—R 7 , —CH 2 CH 2 NHC(S)—R 7 , —CH 2 NHNHC(O)—R 7 , or —CH 2 NHNHC(S)—R 7 ;

R 7 is one of C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 8 ) 2 ;

each R 8 is independently one of hydrogen or —C 1 -C 6 alkyl;

R 9 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, wherein any C 1 -C 10 alkyl or C 2 -C 10 alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NR a R b ;

each R a is C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; and

each R b is H or C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy.

2. The method of claim 1 , comprising contacting the bacterial RNA polymerase with a compound of formula Ia′, Ib′ or Ic′:

or a salt thereof, wherein:

W is sulfur, oxygen, or nitrogen;

X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;

one of R 1 and R 2 is C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, alkoxy, or furanyl; and the other of R 1 and R 2 is absent or is one of H, halogen, or C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;

R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

V′, W′, X′, Y′, and Z′ are individually carbon or nitrogen; wherein at least four of V′, W′, X′, Y′, and Z′ are carbon;

one of R 1′ and R 2′ is C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy, or furanyl; and the other of R 1′ and R 2′ is absent, or is one of H, halogen, or C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;

R 3′ , R 4′ , and R 5′ each is absent, or each of R 3′ , R 4′ , and R 5′ is one of is H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

W″ is sulfur, oxygen, or nitrogen;

U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;

one of R 1″ and R 2″ is C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy, or furanyl; and the other of R 1″ and R 2″ is absent, or is one of H, halogen, or C 1 -C 8 alkyl or C 1 -C 8 alkoxy optionally substituted by at least one of halogen, hydroxy, or alkoxy;

R 3″ is absent or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4″ , R 5″ , and R 6″ each is absent, or each of R 4″ , R 5″ , and R 6″ is H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl; and

R 5 and R 6 are individually H or methyl;

G is one of —CH═CH—NHC(O)—R 7 , —CH═CH—NHC(S)—R 7 , —CH 2 CH 2 NHC(O)—R 7 , —CH 2 CH 2 NHC(S)—R 7 , —CH 2 NHNHC(O)—R 7 , or —CH 2 NHNHC(S)—R 7 ;

R 7 is one of C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 8 ) 2 ; and

each R 8 is independently one of hydrogen or —C 1 -C 6 alkyl.

3. The method of claim 1 , comprising contacting the bacterial RNA polymerase with a compound of formula Ia, or a salt thereof.

4. The method of claim 1 , comprising contacting the bacterial RNA polymerase with a compound of formula Ib, or a salt thereof.

5. The method of claim 1 , comprising contacting the bacterial RNA polymerase with a compound of formula Ic, or a salt thereof.

6. The method of claim 1 , wherein R 6 is H.

7. The method of claim 1 , wherein R 6 is methyl.

8. The method of claim 1 , wherein the salt is a pharmaceutically acceptable salt.

9. The method of claim 1 , comprising contacting the bacterial RNA polymerase with a composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method of inhibiting a bacterial RNA polymerase, comprising contacting a bacterial RNA polymerase with a compound selected from:

and salts thereof.

11. A method of treating a bacterial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula Ia, Ib or Ic:

or a pharmaceutically acceptable salt thereof, wherein:

W is sulfur, oxygen, or nitrogen;

X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;

R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

V′, W′, X′, Y′, and Z′ are individually carbon or nitrogen; wherein at least three of V′, W′, X′, Y′, and Z′ are carbon;

R 3′ , R 4′ , and R 5′ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

W″ is sulfur, oxygen, or nitrogen;

U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;

one of R 1″ and R 2″ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of and R 2″ is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3″ is absent or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4″ , R 5″ , and R 6″ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 5 and R 6 are individually H or methyl;

G is one of —CH═CH—NHC(O)—R 7 , —CH═CH—NHC(S)—R 7 , —CH 2 CH 2 NHC(O)—R 7 , —CH 2 CH 2 NHC(S)—R 7 , —CH 2 NHNHC(O)—R 7 , or —CH 2 NHNHC(S)—R 7 ;

R 7 is one of C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 8 ) 2 ;

each R 8 is independently one of hydrogen or —C 1 -C 6 alkyl;

R 9 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, wherein any C 1 -C 10 alkyl or C 2 -C 10 alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NR a R b ;

each R a is C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; and

each R b is H or C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy.

12. The method of claim 11 , comprising administering to the mammal a therapeutically effective amount of a compound of formula Ia′, Ib′ or Ic′:

or a pharmaceutically acceptable salt thereof, wherein:

W is sulfur, oxygen, or nitrogen;

X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;

R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

V′, W′, X′, Y′, and Z′ are individually carbon or nitrogen; wherein at least four of V′, W′, X′, Y′, and Z′ are carbon;

R 3′ , R 4′ , and R 5′ each is absent, or each of R 3′ , R 4′ , and R 5′ is one of is H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

W″ is sulfur, oxygen, or nitrogen;

U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;

R 3″ is absent or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4″ , R 5″ , and R 6″ each is absent, or each of R 4″ , R 5″ , and R 6″ is H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl; and

R 5 and R 6 are individually H or methyl;

G is one of —CH═CH—NHC(O)—R 7 , —CH═CH—NHC(S)—R 7 , —CH 2 CH 2 NHC(O)—R 7 , —CH 2 CH 2 NHC(S)—R 7 , —CH 2 NHNHC(O)—R 7 , or —CH 2 NHNHC(S)—R 7 ;

R 7 is one of C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 8 ) 2 ; and

each R 8 is independently one of hydrogen or —C 1 -C 6 alkyl.

13. The method of claim 11 , comprising administering to the mammal a therapeutically effective amount of a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

14. The method of claim 11 , comprising administering to the mammal a therapeutically effective amount of a compound of formula Ib, or a pharmaceutically acceptable salt thereof.

15. The method of claim 11 , comprising administering to the mammal a therapeutically effective amount of a compound of formula Ic, or a pharmaceutically acceptable salt thereof.

16. The method of claim 11 , wherein R 6 is H.

17. The method of claim 11 , wherein R 6 is methyl.

18. The method of claim 11 , comprising administering to the mammal a composition comprising a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method of treating a bacterial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound selected from:

and pharmaceutically acceptable salts thereof.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 3, 2023

From: EBRIGHT, RICHARD H.

To: HOWARD HUGHES MEDICAL INSTITUTE

Reel/Frame 064480/0239 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 3, 2023

From: EBRIGHT, RICHARD H.; EBRIGHT, YON W.; SHEN, JUAN

To: RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

Reel/Frame 064480/0316 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 3, 2023

From: BACCI, JAMES; HIEBEL, ANNE-CECILE; SOLVIBLE, WILLILAM; OLSON, GARY; SELF, CHRISTOPHER

To: PROVID PHARMACEUTICALS INC.

Reel/Frame 064480/0490 →

Continuity (3)

Division 14409407

Provisional Application 61661670 · Jun 19, 2012

Related Publication 20160263083A1 · Sep 15, 2016