DNA primase and gyrase inhibitors

Patent metadata

Field	Value
Publication number	US-11339189-B2
Application number	US-201916387870-A
Country	US
Kind code	B2
Filing date	Apr 18, 2019
Priority date	Oct 20, 2016
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

Disclosed herein are compounds that are selective DNA primase and/or gyrase inhibitors. Further disclosed are pharmaceutical compositions comprising these compounds, and the uses of these compounds for treating disorders associated with microbial infections.

First claim

The invention claimed is:

1. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is represented by Formula II:

wherein:
n equals 0 to 10;
A is a covalent bond selected from the group consisting of:

wherein Y is an alkyl group; R 1a comprises a peptide;
each R 5 is independently selected from the group consisting of: hydrogen, a C 1 -C 12 alkyl group, an aryl group, a C 4 -C 20 cycloalkyl group, a mercapto group, an amino, a hydroxy group, a halo group, a cyano group, a nitro group, carboxylate, ester, amide, carbonyl, anhydride, carbonate ester, carbamate, a C 1 -C 10 alkyl group comprising a heteroatom, a haloalkyl group, an alkoxy group, an alkylhydroxy group, a sulfinyl group, a sulfone group, a sulfonate group, and a phosphine group;
R 2 is selected from the group consisting of: an alkyl group, a peptide, —(CH 2 ) 0-5 —C(O)OR b , —(CH 2 ) 0-5 —C(O)SR b , and —(CH 2 ) 0-5 —C(O)NR b , wherein R b is selected from the group consisting of: hydrogen, a C 1 -C 6 alkyl group, an aryl group, and a heteroaryl group;
R4 is selected from the group consisting of hydrogen, an alkylaryl group, an alkyl group, an aryl group, a heteroaryl group, a sulfinyl group, a sulfonate group, a cycloalkyl group, and a heterocyclyl group or a combination thereof,
and R 3 represents up to three substituents, being independently selected from the group consisting of: a trihalomethyl group, a fluorinated alkyl group, a cyano group, a nitro group, a halo group, a sulfonyl group, a sulfonate group, a sulfinyl group, a sulfonamide group, an azo group, a guanidine group, carboxylate, ester, amide, carbonyl, anhydride, carbonate ester, and carbamate.

2. The composition of claim 1 , wherein R 3 represents up to three substituents, being independently selected from the group consisting of: a nitro group, a fluorinated alkyl group, and a halo group.

3. The composition of claim 1 , wherein said compound is selected from the group consisting of:

4. The composition of claim 1 , wherein R 4 comprises a C 1 -C 3 alkyl group, wherein one methylene unit is replaced with a substituent selected from the group consisting of: a C 6 -C 10 aryl, a C 5 -C 10 heteroaryl, a C 5 -C 12 cycloalkyl group, and a C 5 -C 12 heterocyclyl group.

5. The composition of claim 1 , wherein said compound is selected from the group consisting of:

6. The composition of claim 1 , wherein said compound is represented by Formula III:

wherein:
R d is selected from the group consisting of: an ethyl group, a methyl group, a propyl group, and hydrogen; and R 1a comprises a peptide.

7. The composition of claim 1 , wherein R 4 is selected from the group consisting of:

wherein X is a heteroatom.

8. The composition of claim 1 , wherein said compound is selected from Formulae IV and V:

9. The compound of claim 1 , wherein said peptide comprises a cell penetrating peptide.

10. The compound of claim 9 , wherein said cell penetrating peptide comprises a sequence of 3 to 60 amino acids.

11. The compound of claim 9 , wherein said sequence is selected from the group consisting of: SEQ ID NO: 1 (GRKKRRQRRRPQ); and SEQ ID NO: 2 (RRRRRRRR) or any combination thereof.

12. The compound of claim 1 , wherein said compound is represented by Formula IVa:

and wherein R 1 a is SEQ ID NO: 1.

13. The compound of claim 1 , wherein R4 comprises alkylaryl.

14. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1 , and a pharmaceutically acceptable carrier.

15. A method of killing bacteria or inhibiting bacterial reproduction, the method comprises contacting said bacteria with one or more compounds of claim 1 , thereby killing said bacteria or inhibiting said bacteria from reproducing.

16. The method of claim 15 , wherein said inhibiting bacterial reproduction is by inhibiting one or more enzymes selected from the group consisting of: DNA primase, and DNA gyrase.

17. The method of claim 16 , wherein said method is for treating a subject afflicted with microbial infection.

Assignees

• B G Negev Technologies And Applications Ltd At Ben Gurion Univ

Inventors

• Akabayov Barak

Classifications

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D417/04

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

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title