Bis-cyclic guanidines as antibacterial agents

Patent metadata

Field	Value
Publication number	US-11718585-B2
Application number	US-202117516546-A
Country	US
Kind code	B2
Filing date	Nov 1, 2021
Priority date	Jul 24, 2017
Publication date	Aug 8, 2023
Grant date	Aug 8, 2023

Abstract

Provided are novel bis-cyclic guanidine compounds, and the use thereof for treating bacterial infection.

First claim

What is claimed is:

1. A method of preparing a compound of Formula (I)

wherein
R 1 at each occurrence is independently hydrogen, C 1 -C 10 alkyl, alkenyl, alkynyl, aryl, aryl-C 1 -C 6 alkyl, cycloalkyl, or cycloalkyl-C 1 -C 6 alkyl;
R 2 at each occurrence is independently hydrogen, C 1 -C 10 alkyl, alkenyl, alkynyl, aryl, aryl-C 1 -C 6 alkyl, cycloalkyl, or cycloalkyl-C 1 -C 6 alkyl;
X is O or NH
L 1 is —(CR x R y ) n1 ;
L 2 is —(CR x R y ) n2 ;
L is —(CR x R y ) n3 —(CH 2 CH 2 O) m1 -G-(CH 2 CH 2 O) m2 —(CR x R y ) n4 —
R x and R y at each occurrence is independently hydrogen or C 1 -C 4 alkyl;
G is a bond or -(G 1 ) t -, wherein G 1 at each occurrence is independently aryl, cycloakyl, heteroaryl, or heterocycle;
n1 and n2 are each independently 1-4;
m1, m2, n3, and n4 are each independently 0-10;
t is 1, 2, 3, or 4; and
wherein R 1 , R 2 , R x , R y , and G 1 optionally are each independently substituted with one or more substituents selected from the group consisting of halogen, cyano, —OH, C 1 -C 6 alkoxy, —COOH, C 1 -C 6 alkoxycarbonyl, oxo, and amino;
comprising:
reacting an intermediate of Formula (I-i)

 to form the compound of Formula (I).

2. The method of claim 1 , wherein reacting the intermediate of Formula (I-i) to form the compound of Formula (I) comprises reacting the intermediate of Formula (I-i) with cyanogen bromide to form the compound of Formula (I).

3. The method of claim 1 , wherein the intermediate of Formula (I-i) is formed by reacting an intermediate of Formula (I-ii)

and an intermediate of Formula (I-ii′)

with an intermediate of Formula (I-iii)

wherein each occurrence of P 1 is independently selected from allyloxycarbonyl, benzyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl, 3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, and trichloroethyl chloroformate.

4. The method of claim 3 , wherein the intermediate of Formula (I-ii) and the intermediate of Formula (I-ii′) are the same.

5. The method of claim 4 , wherein reacting the intermediate of Formula (I-ii) and the intermediate of Formula (I-ii′) with the intermediate of Formula (I-iii) is performed in the presence of dicyclohexylcarbodiimide.

6. The method of claim 3 , wherein P 1 is tert-butyloxycarbonyl.

7. The method of claim 3 , wherein forming the intermediate of Formula (I-i) further comprises:
forming an intermediate of Formula (I-iv)

 and
reacting the intermediate of Formula (I-iv) to form the intermediate of Formula (I-i).

8. The method of claim 3 , wherein forming the intermediate of Formula (I-ii) comprises:
reacting an intermediate of Formula (I-v)

 with an intermediate of Formula (I-vi)

 wherein P 2 is selected from methyl, ethyl, t-butyl, and benzyl.

9. The method of claim 8 , wherein reacting the intermediate of Formula (I-v) with the intermediate of Formula (I-vi) is performed in the presence of sodium cyanoborohydride under acidic conditions.

10. The method of claim 8 , wherein forming the intermediate of Formula (I-ii) further comprises:
forming an intermediate of Formula (I-vii)

reacting the intermediate of Formula (I-vii) to form an intermediate of Formula (I-viii)

 and
reacting the intermediate of Formula (I-viii) to form the intermediate of Formula (I-ii).

11. The method of claim 8 , wherein P 2 is benzyl.

12. The method of claim 10 , wherein reacting the intermediate of Formula (I-viii) to form the intermediate of Formula (I-ii) is performed in the presence of palladium adsorbed to carbon under a hydrogen atmosphere.

13. The method of claim 8 , wherein the intermediate of Formula (I-v) is formed by reacting an intermediate of Formula (I-ix)

with a reducing agent.

14. The method of claim 13 , wherein the reducing agent is lithium borohydride.

15. The method of claim 13 , wherein the intermediate of Formula (I-ix) is formed by reacting an intermediate of Formula (I-x)

with R 2 —CHO.

16. The method of claim 15 , wherein reacting the intermediate of Formula (I-x) with R 2 —CHO is performed in the presence of sodium cyanoborohydride under acidic conditions.

17. The method of claim 15 , wherein forming the intermediate of Formula (I-ix) further comprises:
forming an intermediate of Formula (I-xi)

 and
reacting the intermediate of Formula (I-xi) to form the intermediate of Formula (I-ix).

Assignees

• Univ South Florida

Inventors

• Cai Jianfeng
• Teng Peng
• Nimmagadda Alekhya

Classifications

• C07D233/46 Primary

  with only hydrogen atoms attached to said nitrogen atoms · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61K45/06

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

• A61P31/04

  Antibacterial agents · CPC title

• C07D403/12

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