Pyrimidine derivatives for prevention and treatment of gram-negative bacterial infection, contamination and fouling

Patent metadata

Field	Value
Publication number	US-12318388-B2
Application number	US-202117327551-A
Country	US
Kind code	B2
Filing date	May 21, 2021
Priority date	Apr 18, 2019
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

Abstract

New pyrimidine derivatives together with a membrane penetrating agent, optionally with a detectable isotope and pharmaceutical composition for use in treatment or prevention of Gram-negative bacterial infection in a host mammal in need of such treatment or prevention and use as inhibitors of Gram-negative biofilm formation on a surface of biomaterial or medical device, particularly of cardiovascular device such as prosthetic heart valve or pacemakers. New pyrimidine derivatives together with a membrane penetrating agent; for use as radiotracer in diagnosing or prognosing Gram-negative bacterial infection in a host mammal.

First claim

What is claimed is:

1. A method of treating or reducing the risk of a Gram-negative bacterial infection in a host mammal in need of such treatment or reduction of the risk of a Gram-negative bacterial infection, comprising administering to the host mammal:
(a) a pharmaceutical composition comprising a pyrimidine derivative represented by formula (I):

or an optical isomer, a racemic mixture of optical isomers, a pharmaceutically acceptable acid addition salt, a pharmaceutically acceptable metal salt, or an alkylated ammonium salt thereof; and

(b) a membrane penetrating agent;

wherein:
X 1 and X 2 are independently N, CH, or CR 8 , wherein R 8 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; with the exception that if one of X 1 or X 2 is equal to N, then the remaining of X 1 or X 2 is selected from CH and CR 8 ,
—Y— is —O— or —S—;

R 1 and R 2 are independently C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, or aryl-C 1-6 -alkyl wherein the alkyl or cycloalkyl moiety is optionally mono or polysubstituted with OH or an halogen and the aryl moiety is optionally mono or polysubstituted with an halogen, —C 1-6 alkyl, —C 1-6 alkoxy, —OH, —NO 2 , —CN, —NH 2 , —NHR 8 , —N(R 8 ) 2 —COOH, —COOR 8 , —CONH 2 , —CONHR 8 , —CON(R 8 ) 2 , —SO 2 NH 2 , —SO 2 NHR 8 , or —SO 2 N(R 8 ) 2 ; and
R 3 , R 4 , R 5 , R 6 and R 7 are independently H, an halogen, a C 1-6 alkyl, C 1-6 alkoxy, —OH, —NO 2 , —CN, —NH 2 , —NHR 8 , —N(R 8 ) 2 —COOH, —COOR 8 , —CONH 2 , —CONHR 8 , —CON(R 8 ) 2 , —SO 2 NH 2 , —SO 2 NHR 8 , or —SO 2 N(R 8 ) 2 .

2. The method according to claim 1 , wherein R 3 and R 7 are hydrogen and R 4 and R 5 are independently a halogen.

3. The method according to claim 1 , wherein X 1 is CH or CR 8 and X 2 is N.

4. The method according to claim 3 , wherein the pyrimidine derivative is selected from the group consisting of:
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c);
9-methyl-N-((1R,2S)-2-phenylcyclopropyl)-2-(propylthio)-9H-purin-6-amine (2c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(propylthio)-9H-purin-6-amine (3c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-propyl-2-(propylthio)-9H-purin-6-amine (4c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-isopropyl-2-(propylthio)-9H-purin-6-amine (5c);
9-cyclopropyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (6c);
9-butyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (7c);
9-(sec-butyl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (8c);
9-(tert-butyl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (9c);
9-cyclobutyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (10c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-pentyl-2-(propylthio)-9H-purin-6-amine (11c);
9-cyclopentyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (12c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-hexyl-2-(propylthio)-9H-purin-6-amine (13c);
9-cyclohexyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (14c);
9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c);
2-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-2-(propylthio)-9H-purin-9-yl) ethanol (16c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (17c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9-(2,2,2-trifluoroethyl)-9H-purin-6-amine (18c);
(1S,2R,3S,4R)-4-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-2-(propylthio)-9H-purin-9-yl) cyclopentane-1,2,3-triol (19d);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(ethylthio)-9-methyl-9H-purin-6-amine (20c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(ethylthio)-9//-purin-6-amine (21c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(methylthio)-9H-purin-6-amine (22c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-propoxy-9H-purin-6-amine hydrochloride (23t·HCl);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (24c);
2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (25c);
and
2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-9H-purin-6-amine (26c);
or an optical isomer, a racemic mixture of optical isomers, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts thereof.

5. The method according to claim 3 , wherein the pyrimidine derivative is selected from the group consisting of:
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(propylthio)-9H-purin-6-amine (3c);
9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (17c);
(1S,2R,3S,4R)-4-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-2-(propylthio)-9H-purin-9-yl) cyclopentane-1,2,3-triol (19d);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(methylthio)-9H-purin-6-amine (22c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(methylthio)-9H-purin-6-amine (24c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(ethylthio)-9-methyl-9H-purin-6-amine (20c);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-ethyl-2-(ethylthio)-9H-purin-6-amine (21c);
and
2-(butylthio)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-9H-purin-6-amine (25c);
or an optical isomer, a racemic mixture of optical isomers, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts thereof.

6. The method according to claim 3 , wherein the pyrimidine derivative is selected from the group consisting of:
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c);
9-allyl-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)-9H-purin-6-amine (15c); and
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-(prop-2-yn-1-yl)-2-(propylthio)-9H-purin-6-amine (17c)
(1S,2R,3S,4R)-4-(6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-2-(propylthio)-9H-purin-9-yl) cyclopentane-1,2,3-triol (19d).

7. The method according to claim 1 , wherein X 1 is N and X 2 is CH or CR 8 .

8. The method according to claim 7 , wherein the pyrimidine derivative is selected from the group consisting of:
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-methyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (27k);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (28x·HCl);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(propylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (29x·HCl);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30k);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(ethylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (31x·HCl);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-ethyl-6-(propylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (32x·HCl);
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-1-isopropyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (33k·HCl);
and
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(methylt

Assignees

• Univ Liege

Inventors

• Lancellotti Patrizio
• Oury Cécile
• Pirotte Bernard
• Musumeci Lucia
• Jacques Nicolas
• Goffin Eric

Classifications

• A61K51/0459

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A01N43/90

  having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system · CPC title

• A01N43/713

  having rings with four or more nitrogen atoms as the only ring hetero atoms · CPC title

• A61P31/04

  Antibacterial agents · CPC title