Bacterial efflux pump inhibitors

Patent metadata

Field	Value
Publication number	US-10836706-B2
Application number	US-201716078572-A
Country	US
Kind code	B2
Filing date	Feb 23, 2017
Priority date	Feb 24, 2016
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

Disclosed herein are compounds of formula I: and salts thereof. Also disclosed are compositions comprising compounds of formula I and methods using compounds of formula I.

First claim

The invention claimed is:

1. A compound of formula I:

wherein:
X is —O—, Y is —C(H)(NR b1 R c1 ) and n is 1;
R 1 is (C 2 -C 8 )alkyl substituted with two or more groups independently selected from —NR b2 R c2 ;
each R 2 is independently hydrogen, halo or (C 1 -C 4 )alkyl;
each R 3 is independently hydrogen, halo or (C 1 -C 4 )alkyl;
R 4 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 5 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 6 is hydrogen;
R 7 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 8 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 b1 and R c1 are each independently hydrogen or (C 1 -C 4 )alkyl; and
each R b2 and R c2 is independently hydrogen or (C 1 -C 4 )alkyl;
or a salt thereof.

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

3. The compound of claim 1 , wherein R 8 is hydrogen.

4. A compound of formula I:

wherein:
X is —O—, Y is —C(H)(NR b1 R c1 )— and n is 1;
R 1 is (C 1 -C 8 )alkyl substituted with one or more groups selected from —NR b2 R c2 , —NHNH 2 , —C(—NR a2 )(NR b2 R c2 ), —NR a2 C(—NR a2 )(R d2 ) and —NR a2 C(—NR a2 )(NR b2 R c2 );
each R 2 is independently hydrogen, halo or (C 1 -C 4 )alkyl;
each R 3 is independently hydrogen, halo or (C 1 -C 4 )alkyl;
R 4 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 5 is (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, or phenyl wherein phenyl 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 6 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 7 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 8 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 b1 and R c1 are each independently hydrogen or (C 1 -C 4 )alkyl;
each R a2 is independently hydrogen or (C 1 -C 4 )alkyl;
each R b2 and R c2 is independently hydrogen or (C 1 -C 4 )alkyl; and
R d2 is (C 1 -C 3 )alkyl;
or a salt thereof.

5. The compound of claim 1 , wherein R 5 is tert-butyl, —CF 3 , phenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-fluorophenyl, or 3,4-difluorophenyl.

6. A compound of formula I:

wherein:
X is —O—, Y is —C(H)(NR b1 R c1 ) and n is 1;
R 1 is (C 1 -C 8 )alkyl substituted with one or more groups selected from —NR b2 R c2 , —NHNH 2 , —C(—NR a2 )(NR b2 R c2 ), —NR a2 C(—NR a2 )(R d2 ) and —NR a2 C(—NR a2 )(NR b2 R c2 );
each R 2 is independently hydrogen, halo or (C 1 -C 4 )alkyl;
each R 3 is independently hydrogen, halo or (C 1 -C 4 )alkyl;
R 4 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 5 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 6 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 7 is (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, or phenyl wherein phenyl 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 8 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 b1 and R c1 are each independently hydrogen or (C 1 -C 4 )alkyl;
each R a2 is independently hydrogen or (C 1 -C 4 )alkyl;
each R b2 and R c2 is independently hydrogen or (C 1 -C 4 )alkyl; and
R d2 is (C 1 -C 3 )alkyl;
or a salt thereof.

7. The compound of claim 1 , wherein R 7 is tert-butyl, —CF 3 , phenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-fluorophenyl, or 3,4-difluorophenyl.

8. The compound of claim 1 , wherein the moiety:

of the compound of formula I is:

9. The compound of claim 1 , wherein the moiety:

Assignees

• Univ Rutgers

Inventors

• Lavoie Edmond J
• Parhi Ajit
• Blankson Gifty A
• Wang Liping
• Chen Xiao
• Zhang Yongzheng
• Kaul Malvika
• Pilch Daniel S

Classifications

• A61K45/06 Primary

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

• A61K31/138

  Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377) · CPC title

• C07C217/42

  having etherified hydroxy groups and at least two amino groups bound to the carbon skeleton · CPC title

• A61K31/14

  Quaternary ammonium compounds, e.g. edrophonium, choline (betaines A61K31/205) · CPC title

• A61K31/137

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title