Therapeutic compounds and methods to treat infection

Patent metadata

Field	Value
Publication number	US-11458121-B2
Application number	US-201816626249-A
Country	US
Kind code	B2
Filing date	Jun 26, 2018
Priority date	Jun 26, 2017
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

Abstract

Disclosed herein are compounds of formula I: or a salt thereof and compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods for treating or preventing a bacterial infection in an animal comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with a bacterial efflux pump inhibitor.

First claim

We claim:

1. A compound of formula I:

or a salt thereof, wherein:
R 1 is hydrogen, halo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, phenyl or heteroaryl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, nitro or cyano;
R 2 is hydrogen, halo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, phenyl or heteroaryl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, nitro or cyano;
R 3 is hydrogen, halo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, phenyl or heteroaryl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, nitro or cyano;
R 4 is hydrogen, halo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 4 ) alkoxy, phenyl or heteroaryl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, nitro or cyano;
R 5 is hydrogen or (C 1 -C 4 )alkyl;
R 6 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, —C(═O)R X , or —C(═O)OR X , wherein the (C 1 -C 6 )alkyl or (C 3 -C 6 )cycloalkyl is optionally substituted with one or more groups selected from halo, OR a or NR a R b ;
R 7a is hydrogen, halo, (C 1 -C 6 )alkyl, —C(═O)OR c , —C(═O)NR d R e , —NR f R g , or phenyl, wherein the (C 1 -C 6 )alkyl or phenyl is optionally substituted with one or more halogen, OR h , (C 1 -C 6 )alkyl, or —NR f R g ;
R 7b is hydrogen, halo, or (C 1 -C 6 )alkyl;
R 8a is hydrogen, halo, (C 1 -C 6 )alkyl, —C(═O)OR c , —C(═O)NR d R e , —NR f R g , or phenyl, wherein the (C 1 -C 6 )alkyl or phenyl is optionally substituted with one or more halogen, OR h , (C 1 -C 6 )alkyl, or —NR f R g ;
R 8b is hydrogen, halo, or (C 1 -C 6 )alkyl;
R 9a is hydrogen, halo, (C 1 -C 6 )alkyl, —C(═O)OR c , —C(═O)NR d R e , —NR f R g , or phenyl, wherein the (C 1 -C 6 )alkyl or phenyl is optionally substituted with one or more halogen, OR h , (C 1 -C 6 )alkyl, or —NR f R g ;
R 9b is hydrogen, halo, or (C 1 -C 6 )alkyl;
each R X is independently (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein the (C 1 -C 6 ) alkyl, or (C 3 -C 6 ) cycloalkyl, is optionally substituted with one or more groups selected from halo, OR a or NR a R b ;
each R a is independently hydrogen or (C 1 -C 4 )alkyl;
each R b is independently hydrogen or (C 1 -C 4 )alkyl; or R a and R b taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
R c is hydrogen or (C 1 -C 4 )alkyl;
R d is hydrogen or (C 1 -C 4 )alkyl;
R e is hydrogen or (C 1 -C 4 )alkyl wherein the (C 1 -C 4 )alkyl is optionally substituted with one or more halo, (C 1 -C 4 )alkoxy, —NH 2 , —NH(C 1 -C 4 ) alkyl or —N((C 1 -C 4 )alkyl) 2 ; or R d and R e taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
R f is hydrogen or (C 1 -C 4 )alkyl;
R g is hydrogen or (C 1 -C 4 )alkyl; or R f and R g taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and
R h is hydrogen or (C 1 -C 4 )alkyl;
provided that the compound of formula I is not

or a salt thereof.

2. The compound of claim 1 that is:

or a salt thereof.

3. A pharmaceutical composition comprising a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

4. The compound of claim 1 , wherein R 1 is hydrogen.

5. The compound of claim 1 , wherein R 2 is hydrogen, bromo, chloro or 4-fluorophenyl.

6. The compound of claim 1 , wherein R 3 is halo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, or phenyl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 4 )alkoxy, or phenyl is optionally substituted with one or more groups selected from halo, (C 1 -C 4 )haloalkyl, or (C 1 -C 4 )alkoxy.

7. The compound of claim 1 , wherein R 3 is fluoro, bromo, chloro, —CF 3 , —OCF 3 , CN, —OCH 3 , 4-fluorophenyl, 4-methoxyphenyl, or 4-trifluoromethylphenyl.

8. The compound of claim 1 , wherein R 4 is hydrogen, bromo, or chloro.

9. The compound of claim 1 , wherein at least one of R 1 , R 2 , R 3 , and R 4 is not hydrogen.

10. The compound of claim 1 , wherein R 6 is hydrogen, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more groups selected from halo, OR 3 or NR 3 R b .

11. A method of treating or preventing a bacterial infection in an animal comprising administering to the animal a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof alone or in the presence of a bacterial efflux pump inhibitor.

12. The method of claim 11 wherein the bacterial efflux pump inhibitor when used in combination with a compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:
R 1A is (C 3 -C 8 )alkyl substituted with two or more groups selected from —NR b1 R c1 , —NHNH 2 , —C(═NR a1 )(NR b1 R c1 ), —NR a1 C(═NR a1 )(R d1 ) and —NR a1 C(═NR a1 )(NR b1 R c1 );
R 2A is hydrogen or (C 1 -C 3 )alkyl;
each R 3A is independently hydrogen, halo or (C 1 -C 4 )alkyl;
R 4A is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and(C 1 -C 4 )haloalkoxy;
R 5A is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy;
R 6A is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C

Assignees

• Univ Rutgers
• Taxis Pharmaceuticals Inc
• Lavoie Edmond J
• Parhi Ajit
• Sagong Hye Yeon

Inventors

• Lavoie Edmond J
• Parhi Ajit
• Sagong Hye Yeon

Classifications

• A61P31/04 Primary

  Antibacterial agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D209/88

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title