Substituted pteridines useful for the treatment and prevention of viral infections

• US 10,144,736 B2
• Filed: 07/20/2007
• Issued: 12/04/2018
• Est. Priority Date: 07/20/2006
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Herdewijn, Piet AndreMaurits Maria, De Jonghe, Steven Cesar Alfons, Watkins, William John, Chong, Lee Shun
• Primary Examiner(s): Sznaidman, Marcos L
• Application Number:
  US12/374,457
• Publication Number:
  US 20100305117A1
• Time in Patent Office: 4,155 Days
• Field of Search: 544236
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 475/00 Heterocyclic compounds containing pteridine ring systems
• CPC Class Codes: C07D 475/02 with an oxygen atom directly attached in position 4
• CPC Class Codes: C07D 475/04 with a nitrogen atom directly attached in position 2
• CPC Class Codes: C07D 475/06 with a nitrogen atom directly attached in position 4
• CPC Class Codes: C07D 475/08 with a nitrogen atom directly attached in position 2

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.

Claims

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.