Substituted pteridines useful for the treatment and prevention of viral infections

Patent metadata

Field	Value
Publication number	US-10144736-B2
Application number	US-37445707-A
Country	US
Kind code	B2
Filing date	Jul 20, 2007
Priority date	Jul 20, 2006
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

The invention provides 4,6-di- and 2,4,6-tri-substituted pteridine derivatives with a specific substitution pattern which exhibit a significant and selective activity against certain types of viral infections, in particular selectively inhibit replication of Flaviridae such as the hepatitis C virus, and are useful for the prevention and treatment of such viral infections.

First claim

The invention claimed is:

1. A pteridine derivative selected from the group consisting of:
4-ethoxy-6-(4-(trifluoromethoxy)phenyl)pteridin-2-amine,
dimethyl (4-(2-amino-4-ethoxypteridin-yl)phenyl)methylphosphonate,
4-ethoxy-6-(pyridin-3-yl)pteridin-2-amine,
4-ethoxy-6-(1H-pyrazol-5-yl)pteridin-2-amine,
4-ethoxy-6-(pyrimidin-5-yl)pteridin-2-amine,
4-ethoxy-6-(2-fluoropyridin-3-yl)pteridin-2-amine,
4-ethoxy-6-(1H-indol-5-yl)pteridin-2-amine,
4-ethoxy-6-(4-(methylsulfonyl)phenyl)pteridin-2-amine,
4-ethoxy-6-(pyridin-4-yl)pteridin-2-amine,
4-ethoxy-6-(1H-pyrazol-4-yl)pteridin-2-amine,
4-ethoxy-6-(3-(trifluoromethoxy)phenyl)pteridin-2-amine,
4-(2-amino-4-ethoxypteridin-6-yl)-N-cyclopropylbenzamide,
5-(2-amino-4-ethoxypteridin-6-yl)thiophene-2-carbonitrile,
4-ethoxy-6-(2-(trifluoromethoxy)phenyl)pteridin-2-amine,
6-(5-chlorothiophen-2-yl)-4-ethoxypteridin-2-amine,
1-(4-(2-amino-4-ethoxypteridin-6-yl)phenyl)pyrrolidin-2-one,
5-(2-amino-4-ethoxypteridin-6-yl)indolin-2-one,
4-ethoxy-6-(6-methoxypyridin-3-yl)pteridin-2-amine,
4-ethoxy-6-(isoxazol-4-yl)pteridin-2-amine,
methyl 4-(2-amino-4-ethoxypteridin-6-yl)phenylcarbamate,
6-(benzofuran-2-yl)-4-ethoxypteridin-2-amine,
4-ethoxy-6-morpholinopteridin-2-amine,
4-ethoxy-6-(3-methylpyridin-4-yl)pteridin-2-amine,
4-ethoxy-6-(2-methoxypyridin-4-yl)pteridin-2-amine,
4-ethoxy-6-(2-methylpyridin-4-yl)pteridin-2-amine,
4-ethoxy-6-(pyridin-2-yl)pteridin-2-amine,
4-morpholino-6-(3-(trifluoromethoxy)phenyl)pteridin-2-amine,
4-morpholino-6-(4-(trifluoromethoxy)phenyl)pteridin-2-amine,
4-morpholino-6-(4-(morpholinomethyl)phenyl)pteridin-2-amine,
dimethyl (4-(2-amino-4-morpholinopteridin-6-yl)phenyl)methylphosphonate,
6-(4-(methylsulfonyl)phenyl)-4-morpholinopteridin-2-amine,
6-(1H-indol-5-yl)-4-morpholinopteridin-2-amine,
4-morpholino-6-(pyrimidin-5-yl)pteridin-2-amine,
4-morpholino-6-(pyridin-3-yl)pteridin-2-amine,
6-(2-fluoropyridin-3-yl)-4-morpholinopteridin-2-amine,
6-(furan-3-yl)-4-morpholinopteridin-2-amine,
4-morpholino-6-(1H-pyrazol-5-yl)pteridin-2-amine,
4-(2-amino-4-morpholinopteridin-6-yl)-N-cyclopropylbenzamide,
4-morpholino-6-(pyridin-4-yl)pteridin-2-amine,
4-morpholino-6-(1H-pyrazol-4-yl)pteridin-2-amine,
5-(2-amino-4-morpholinopteridin-6-yl)thiophene-2-carbonitrile,
6-(benzo[b]thiophen-2-yl)-4-morpholinopteridin-2-amine,
6-(5-chlorothiophen-2-yl)-morpholinopteridin-2-amine,
1-(4-(2-amino-4-morpholinopteridin-6-yl)phenyl)pyrrolidin-2-one,
methyl 4-(2-amino-4-morpholinopteridin-6-yl)phenylcarbamate,
6-(6-methoxypyridin-3-yl)-4-morpholinopteridin-2-amine,
6-(isoxazol-4-yl)-4-morpholinopteridin-2-amine,
6-(benzofuran-2-yl)-4-morpholinopteridin-2-amine,
5-(2-amino-4-morpholinopteridin-6-yl)indolin-2-one,
N-(4-(2-amino-4-morpholinopteridin-6-yl)phenyl)isobutyramide,
N-(4-(2-amino-4-morpholinopteridin-6-yl)phenyl)pivalamide,
(S)-tert-butyl 1-(4-(2-amino-4-morpholinopteridin-6-yl)phenylamino)-3-hydroxy-1-oxopropan-2-ylcarbamate,
(S)-tert-butyl 1-(4-(2-amino-4-morpholinopteridin-6-yl)phenylamino)-1-oxopropan-2-ylcarbamate,
cyclopropane carboxylic acid [4-(2-amino-4-morpholin-4-yl-pteridin-6-yl)-phenyl]-amide,
6-(2,3-difluorophenyl)-pteridine-2,4-diamine,
(S)-2-amino-N-(4-(2-amino-4-morpholinopteridin-6-yl)phenyl)-3-hydroxypropanamide,
(S)-2-amino-N-(4-(2-amino-4-morpholinopteridin-6-yl)phenyl)propanamide,
4-[2-Amino-6-(4-fluoro-phenyl)-pteridin-4-yloxy]-2-methyl-butan-2-ol,
6-(4-Fluoro-phenyl)-4-(2-morpholin-4-yl-ethoxy)-pteridin-2-ylamine,
6-(4-Fluoro-phenyl)-4-(3-morpholin-4-yl-propoxy)-pteridin-2-ylamine,
4-Cyclopropylmethoxy-6-(4-fluoro-phenyl)-pteridin-2-ylamine,
4-Cyclobutylmethoxy-6-(4-fluoro-phenyl)-pteridin-2-ylamine,
6-(4-Fluoro-phenyl)-4-(tetrahydro-furan-3-yloxy)-pteridin-2-ylamine,
4-Ethylsulfanyl-6-(4-fluoro-phenyl)-pteridin-2-ylamine,
6-(4-fluoro-phenyl)-pteridine-2,4-diamine,
N-4-Cyclopropyl-6-(4-fluoro-phenyl)-pteridine-2,4-diamine,
4-(2,6-Dimethyl-morpholin-4-yl)-6-(4-fluoro-phenyl)-pteridin-2-ylamine,
N-4-Cyclohexyl-6-(4-fluoro-phenyl)-pteridine-2,4-diamine,
N-4-(3-Methyl-benzyl)-6-(4-fluoro-phenyl)-pteridine-2,4-diamine,
N-4-(3-Fluoro-benzyl)-6-(4-fluoro-phenyl)-pteridine-2,4-diamine,
6-(4-Fluoro-phenyl)-4-(4-methyl-piperazin-1-yl)-pteridin-2-ylamine,
6-(4-Fluoro-phenyl)-4-piperazin-1-yl-pteridin-2-ylamine,
N-4-Cyclopropylmethyl-6-(4-fluoro-phenyl)-pteridine-2,4-diamine,
6-(4-Fluoro-phenyl)-4-pyrrolidin-1-yl-pteridin-2-ylamine,
4-Ethoxy-6-(4-fluoro-phenyl)-pteridine,
4-isopropoxy-6-(4-fluoro-phenyl)-pteridine,
4-(2-methoxy-ethoxy)-6-(4-fluoro-phenyl)-pteridine,
[6-(4-Fluoro-phenyl)-pteridin-4-yl]-(4-methyl-cyclohexyl)-amine,
[6-(4-Fluoro-phenyl)-pteridin-4-yl]-(4-methyl-cyclohexyl)-amine, and
4-Ethylsulfanyl-6-(4-fluoro-phenyl)-pteridine
and/or a pharmaceutically acceptable addition salt thereof and/or a stereoisomer thereof and/or a mono- or a di-N-oxide thereof.

2. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to claim 1 , or a pharmaceutically acceptable addition salt thereof, and one or more pharmaceutically acceptable excipients.

3. A pharmaceutical composition according to claim 2 , further comprising one or more other antiviral drugs.

4. A method of treatment of an infection due to a virus, by administering to a patient in need thereof a therapeutically effective amount of a pteridine derivative according to claim 1 , or a pharmaceutically acceptable addition salt thereof, wherein said virus belongs to the Flaviviridae family.

5. A method according to claim 4 , wherein said virus belongs to a genus selected from the group consisting of Genus Flavivirus , Genus Hepacivirus and Genus Pestivirus.

6. A method according to claim 4 , wherein said virus is hepatitis C virus.

7. A method according to claim 4 , wherein said administration is oral administration.

8. A method according to claim 4 , wherein said therapeutically effective amount is from 0.01 mg to 20 mg per day per kg bodyweight of said patient.

9. A method according to claim 4 , wherein said at least one pteridine derivative is administered together with one or more other antiviral drugs.

10. A method according to claim 9 , wherein said other antiviral drug is selected from the group consisting of interferon alpha, ribavirin, NS3 protease inhibitors, and nucleoside- or non-nucleoside-based inhibitors of NS5B polymerase.

11. A pteridine derivative selected from the group consisting of:
4-(2-amino-4-ethoxypteridin-6-yl)-N-methylbenzamide,
6-(benzo[b]thiophen-2-yl)-4-ethoxypteridin-2-amine,
6-(4-Fluoro-phenyl)-4-(2,2,2-trifluoro-ethoxy)-pteridin-2-ylamine,
4-Benzyloxy-6-(4-fluoro-phenyl)-pteridin-2-ylamine,
and/or a pharmaceutically acceptable addition salt thereof and/or a stereoisomer thereof and/or a mono- or a di-N-oxide thereof.

12. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to claim 11 , or a pharmaceutically acceptable addition salt thereof, and one or more pharmaceutically acceptable excipients.

13. A pharmaceutical composition according to claim 12 , further comprising one or more other antiviral drugs.

Assignees

• Herdewijn Piet Andremaurits Maria
• De Jonghe Steven Cesar Alfons
• Watkins William John
• Chong Lee Shun
• Gilead Sciences Inc

Inventors

• Herdewijn Piet Andrémaurits Maria
• De Jonghe Steven Cesar Alfons
• Watkins William John
• Chong Lee Shun

Classifications

• C07D475/02 Primary

  with an oxygen atom directly attached in position 4 · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07D475/04

  with a nitrogen atom directly attached in position 2 · CPC title

• C07D475/06

  with a nitrogen atom directly attached in position 4 · CPC title

• C07D475/00

  Heterocyclic compounds containing pteridine ring systems · CPC title