Heterocyclic compounds as antibiotic potentiators

Patent metadata

Field	Value
Publication number	US-2016168140-A1
Application number	US-201514965759-A
Country	US
Kind code	A1
Filing date	Dec 10, 2015
Priority date	Dec 12, 2014
Publication date	Jun 16, 2016
Grant date	—

Abstract

The invention relates to heterocyclic compounds and their use as antibiotics and/or as antibiotic potentiators. The compounds may act as colistin potentiators and SOS inhibitors.

First claim

What is claimed is:

1 . A compound of formula Ia, formula IIa, or formula IIIa:

wherein
each L is independently selected from the group consisting of C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —(C 1 -C 6 alkylene)-O—, —(C 1 -C 6 alkylene)-NR 7 —, —NR 7 —(C 1 -C 6 alkylene)-, —O—(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene), —(C 1 -C 6 alkylene)-NR 7 —(C 1 -C 6 alkylene), —NR 7 C(O)—, —C(O)—, —C(O)C(O)NR 7 —, —C(O)NR 7 —, —C(O)NR 7 -(alkylene)-, —C(O)—(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-C(O)—, and —(C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-,
n is 0 or 1,
Ar is aryl, optionally substituted with one to five R 5 groups; or heteroaryl, optionally substituted with one to four R 5 groups,
B is an alkylene group, optionally interrupted by an oxygen, a carbonyl (C═O), or sulfonyl group (SO 2 ), and optionally substituted by one to four groups, which are independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy,
D is CR 7 or N,
each R 1 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, (R 7 ) 2 N—(C 1 -C 6 alkylene)-, nitro, cyano, SO 2 R 8 , SO 2 N(R 7 ) 2 , C(O)OR 7 , C(O)N(R 7 ) 2 , C(O)R 7 , N(R 7 ) 2 , NR 7 C(O)R 8 , NR 7 C(O)N(R 7 ) 2 , NR 7 C(O)OR 8 , NR 7 SO 2 R 8 , optionally substituted aryl, or optionally substituted heteroaryl; or two R 1 groups are linked together to form an optionally substituted 5- or 6-membered aromatic moiety or an optionally substituted 4- to 7-membered non-aromatic cyclic moiety,
R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, C(O)R 7 , or C 1 -C 6 -alkyloxycarbonyl,
R 3 and R 4 are independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, C(O)R 7 , or C 1 -C 6 -alkyloxycarbonyl; or R 3 and R 4 , together with the nitrogen to which they are attached, form a 4- to 6-membered heterocycle, optionally substituted with one or more groups independently selected from oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, SO 2 R 8 , C(O)OR 7 , C(O)N(R 7 ) 2 , C(O)R 7 , NR 7 SO 2 R 8 , NR 7 C(O)OR 7 , NR 7 C(O)N(R 7 ) 2 , and NR 7 C(O)R 7 ,
each R 5 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, nitro, cyano, SO 2 R 8 , SO 2 N(R 7 ) 2 , C(O)OR 7 , C(O)N(R 7 ) 2 , C(O)R 7 , N(R 7 ) 2 , NR 7 C(O)R 8 , NR 7 C(O)N(R 7 ) 2 , NR 7 C(O)OR 8 , NR 7 SO 2 R 8 , optionally substituted aryl-(C 1 -C 6 alkylene), optionally substituted aryl, optionally substituted heterocyclyl-(C 1 -C 6 alkylene), optionally substituted heterocyclyl, optionally substituted C 3 -C 7 cycloalkyl, or optionally substituted heteroaryl; and/or two R 5 groups are linked together to form an optionally substituted 5- or 6-membered aromatic moiety or an optionally substituted 4- to 7-membered non-aromatic cyclic moiety,
R 6 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl-(C 1 -C 6 alkylene), optionally substituted C 1 -C 6 -alkylcarbonyl, or C 1 -C 6 -alkyloxycarbonyl,
each R 7 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, and
each R 8 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
Z is CH or N,
x is 0, 1, 2, 3, or 4, and
if x is 0, Ar is not unsubstituted;

or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.

2 . The compound of formula Ia as claimed in claim 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.

3 . The compound of formula Ia as claimed in claim 1 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein n is 1.

4 . The compound of formula Ia as claimed in claim 1 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein n is 0.

5 . The compound of formula Ia as claimed in claim 1 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z is N.

6 . The compound of formula Ia as claimed in claim 1 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z is CH.

7 . The compound of formula IIa as claimed in claim 1 or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.

8 . The compound of formula IIa as claimed in claim 7 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein D is CR 7 .

9 . The compound of formula IIa as claimed in claim 7 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein D is N.

10 . The compound of formula IIIa as claimed in claim 1 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.

11 . The compound of formula IIIa as claimed in claim 10 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein D is CR 7 .

12 . The compound of formula IIIa as claimed in claim 10 , or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof, wherein D is N.

13 . The compound of claim 1 selected from the group consisting of the compounds in Tables 1-15.

14 . A method of treating a microbial infection in a subject in need thereof, the method comprising administering a compound of claim 1 .

15 . The method of claim 14 , further comprising administering an antimicrobial agent.

16 . A method of increasing the activity of an antimicrobial agent, the method comprising administering the antimicrobial agent in combination with at least one compound that potentiates the activity of the antimicrobial agent.

17 . The method of claim 16 , wherein the at least one compound that potentiates the activity of the antimicrobial agent inhibits the SOS response in bacteria.

18 . The method of claim 16 , wherein the at least one compound that potentiates the activity of the antimicrobial agent is a compound of claim 1 .

19 . A composition comprising a compound of claim 1 .

20 . The composition of claim 19 , further comprising an antimicrobial agent.

Assignees

• Univ North Carolina
• Synereca Pharmaceuticals

Inventors

• Jones Michael L
• Lilly John C
• Ankala Sudha
• Singleton Scott

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D239/95

  with hetero atoms directly attached in positions 2 and 4 · CPC title

• A61K45/06

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

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title