Pyrimidine derivatives for prevention and treatment of bacterial infections

Patent metadata

Field	Value
Publication number	US-11434241-B2
Application number	US-201916958023-A
Country	US
Kind code	B2
Filing date	Feb 14, 2019
Priority date	Feb 14, 2018
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

Abstract

Pyrimidine derivatives of formula (I):optionally with a detectable isotope, pharmaceutical composition and method of preparation thereof. Pyrimidine derivatives for use in treatment or prevention of bacterial infection in a host mammal in need of such treatment or prevention and use as inhibitors of biofilm formation on a surface of biomaterial or medical device, particularly of cardiovascular device such as prosthetic heart valve or pacemakers. Pyrimidine derivatives for use as radiotracer in diagnosing or prognosing bacterial infection in a host mammal.

First claim

The invention claimed is:

1. A pyrimidine derivative represented by formula (I)

or optical isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts thereof;
wherein:
X 1 and X 2 are independently N, CH, 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 are selected from CH, 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, 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 ;
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 pyrimidine derivative according to claim 1 comprising at least one detectable isotope.

3. The pyrimidine derivative according to claim 2 wherein the detectable isotope is selected from 3H, 18 F, 19 F, 11 C, 13 C, 14 C, 75 Br, 76 Br, 120 I, 123 I, 125 I, 131 I, 15 O, and 13 N.

4. The pyrimidine derivative according to anyone of claim 1 wherein R 3 and R 7 are hydrogen and R 4 and R 5 are independently an halogen.

5. The pyrimidine derivative according to claim 1 , wherein X 1 is CH or CR 8 and X 2 is N.

6. The pyrimidine derivative according to claim 5 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)-9H-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 optical isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts thereof.

7. The pyrimidine derivative according to claim 5 which is N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine (1c).

8. The pyrimidine derivative according to claim 1 wherein X 1 is N and X 2 is CH or CR 8 .

9. The pyrimidine derivative according to claim 8 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-(methylthio)-1-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (34k.HCl);
or optical isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts thereof.

10. The pyrimidine derivative according to claim 1 wherein X 1 and X 2 are CH or CR 8 .

11. The pyrimidine derivative according to claim 10 which is:
N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-7-ethyl-2-(methylthio)-7H-pyrrolo [2,3-d]pyrimidin-4-amine hydrochloride (35p.HCl);
or optical isomers, racemic mixtures thereof, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, or alkylated ammonium salts thereof.

12. The pyrimidine derivative according to claim 1 wherein R 3 and R 7 are H and R 4 , R 5 is a fluorine.

13. A method of treating a bacterial infection in mammal in need of such treatment comprising administering to the mammal the pyrimidine derivative according to claim 1 .

14. A pharmaceutical composition comprising a pyrimidine derivative according to claim 1 in combination with pharmaceutically acceptable diluent, adjuvant and/or carrier.

15. A method of reducing bacterial infection in a host mammal, wherein said method comprises applying said pyrimidine derivative according to claim 1 on the surface of a biomaterial implant prior to implantation of said implant in said host mammal.

16. A method for reducing bacterial growth in biofilm formation comprising applying on a surface of a medical device, an effective amount of a pyrimidine derivative according to anyone of claim 1 .

Assignees

• Univ Liege

Inventors

• Lancellotti Patrizio
• Oury Cécile
• Pirotte Bernard

Classifications

• C07D473/18

  one oxygen and one nitrogen atom, e.g. guanine · CPC title

• C07D473/40 Primary

  with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6 · CPC title

• A61F2/24

  Heart valves {; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body} · CPC title

• A61L2300/404

  Biocides, antimicrobial agents, antiseptic agents · CPC title

• A61F2/0077

  Special surfaces of prostheses, e.g. for improving ingrowth (A61F2/30767 takes precedence) · CPC title