Diamide antimicrobial agents

Patent metadata

Field	Value
Publication number	US-11555010-B2
Application number	US-202016937933-A
Country	US
Kind code	B2
Filing date	Jul 24, 2020
Priority date	Jul 25, 2019
Publication date	Jan 17, 2023
Grant date	Jan 17, 2023

Abstract

This invention is directed to compounds of Formula (I)pharmaceutically acceptable salts, esters, and prodrugs thereof, to their preparation, to pharmaceutical compositions comprising compounds of Formula I, and to their uses as antimicrobial agents.

First claim

The invention claimed is:

1. A compound of Formula I

wherein:
R 1 represents aryl, wherein aryl is substituted with 1 to 3 substituents selected from a group consisting of H, —X, S(C 1-6 alkyl), O(C 1-6 alkyl), and CX 3 ;
R 2 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 hetero cycloalkyl, and polyethyleneglycol, wherein each of said R 2 groups are independently substituted with 1-3 substituents selected from a group consisting of C 1 -C 6 alkyl, H, C 1 -C 6 alkenyl, (CH 2 —O—(CH 2 ) 1-4 ) 6 —OH, C 1 -C 6 alkynyl, OH, O(C 1 -C 6 alkyl), F, Cl, Br, I, NO 2 , —C(═O)H, —C(═O)OH, —C(═O)O(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), and —C(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 3 is selected from a group consisting of C 1-6 alkyl-NH 2 , CH(CH 3 )—NH 2 , CH(CH 2 CH 2 CH 3 )—NH 2 , CH(CH 2 CH 2 CH 2 CH 3 )—NH 2 , (CH 2 ) 0-3 — C 3 -C 8 hetero cycloalkyl wherein each R 3 group is independently substituted with 1-3 substituents independently selected from a group consisting of H, C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), F, Cl, Br, I, NO 2 , —C(═O)H, —C(═O)OH, —C(═O)O(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), and —C(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, arylalkyl, and heteroaryl-alkyl, wherein each of the R 4 groups is independently substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 6 alkyl, H, OH, O(C 1 -C 6 alkyl), F, Cl, Br, I, NO 2 , —C(═O)H, —C(═O)OH, —C(═O)O(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), and —C(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 5 is H or methyl; and
X is selected from Cl, I, Br, and F.

2. The compound of claim 1 , wherein in R 1 has at least one substituent ortho to the carbonyl group, wherein the at least one substituent is selected from the group consisting of X, O(C 1-6 alkyl), and CX 3 ; and
X is selected from I and Br.

3. The compound of claim 1 , wherein R 2 is represents C 1 -C 6 alkyl, substituted with 1-3 substituents independently selected from the group consisting of (CH 2 —O—(CH 2 ) 2 ) 6 —OH, C 1 -C 6 alkyl, H, OH, and O(C 1 -C 6 alkyl).

4. The compound of claim 1 , wherein R 3 is selected from the group consisting of C 1 -C 4 alkyl-NH 2 , CH(CH 3 )—NH 2 , CH(CH 2 CH 3 )—NH 2 , CH(CH 2 CH 2 CH 3 )—NH 2 , CH(CH 2 CH 2 CH 2 CH 3 )—NH 2 , (CH 2 ) 0-1 —C 4 -C 6 -heterocycloalkyl, wherein each R 3 group is independently substituted with 1-2 substituents selected from the group consisting of C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), F, Cl, Br, I, H, NO 2 , —C(═O)H, —C(═O)OH, —C(═O)O(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), and —C(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).

5. The compound of claim 1 , wherein R 4 is selected from the group consisting of C 1 -C 6 alkyl, cyclo-hexyl, benzyl, wherein each of the alkyl, cyclo-hexyl, and benzyl group is substituted with 1-2 substituents independently selected from the group consisting of C 1 -C 3 alkyl, H, OH, O(C 1 -C 3 alkyl), F, Cl, Br, and I.

6. The compound of claim 1 , wherein
R 1 represents an aryl group, said aryl group substituted with X;
R 2 represents C 4 -C 8 cycloalkyl;
R 3 is selected from a group consisting of C 1-6 alkyl-NH 2 , CH(CH 3 )—NH 2 , CH(CH 2 CH 3 )—NH 2 , CH(CH 2 CH 2 CH 3 )—NH 2 , CH(CH 2 CH 2 CH 2 CH 3 )—NH 2 , and (CH 2 ) 0-1 -heterocyclyl;
R 4 represents cyclo-hexyl;
R 5 represents H; and
X represents I, Cl, or Br.

7. A compound of Formula I of claim 1 selected from:

8. The compound of claim 1 , wherein the salt of compound I is an acid addition salt and is selected from the group consisting of sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, phosphoric, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid, and any combinations thereof.

9. The compound of claim 1 , wherein the salt is a base addition salt and is selected from the group consisting of calcium, magnesium, potassium, sodium, ammonium, zinc, a basic amine salt, and any combinations thereof, wherein the basic amine is selected from the group consisting of triethylamine, diisopropylethylamine, trimethylamine, N,N′-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine and any combinations thereof.

10. A method of inhibiting a N-acetylglucosaminidase in a cell, the method comprising contacting the cell with a compound of claim 1 .

11. The method of claim 10 , comprising inhibiting a N-acetylglucosaminidase in the cytosol of a cell.

12. The method of claim 11 , wherein the N-acetylglucosaminidase comprises an autolysin.

13. A method of treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , thereby treating or preventing a bacterial infection in a subject.

14. The method of claim 13 , wherein the bacterium is Gram-positive.

15. The method of claim 14 , wherein the Gram-positive bacterium is selected from the group consisting of Streptococcus sp., Staphylococcus sp., Enterococcus sp., Corynebacterium sp., Listeria sp., Clostridium sp. and Bacillus sp.

16. The method of claim 13 , wherein the bacterium is Gram-negative.

17. The method of claim 16 , wherein the Gram-negative bacterium is selected from the group consisting of Salmonella sp., Escherichia sp., Klebsiella sp., Acinetobacter sp., Pseudomonas sp., Vibrio sp. and Enterobacter sp.

18. The method of claim 13 , wherein the subject is further administered at least one additional antibacterial agent.

19. The method of claim 13 , wherein the subject is a mammal.

Assignees

• Univ Brown
• Bryant Univ

Inventors

• Basu Amit
• Reid Christopher W
• Iwasaki Nola Camille
• Prete Joseph

Classifications

• A61P31/04 Primary

  Antibacterial agents · CPC title

• A61K45/06

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

• A61K31/4465

  only substituted in position 4 · CPC title

• C07C237/22

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title