IP Library › Granted Patent US 9,498,470

Granted Patent B2

US 9,498,470 · App. 14/379,028 · Granted Nov 22, 2016

Antiviral drugs for treatment of arenavirus infection

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Quick Facts

Patent No.: US 9,498,470
App. No.: 14/379,028
Granted: Nov 22, 2016
Kind: B2

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Abstract

Compounds, methods and pharmaceutical compositions for treating viral infections, by administering certain compounds in therapeutically effective amounts are disclosed. Methods for preparing the compounds and methods of using the compounds and pharmaceutical compositions thereof are also disclosed. In particular, the treatment and prophylaxis of viral infections such as caused by the Arenavirus family such as Lassa fever, Argentine hemorrhagic fever, Bolivian hemorrhagic fever, and Venezuelan hemorrhagic fever.

Claims (150)

1. A compound of Formula I or a pharmaceutically acceptable salt thereof:

wherein,

E is N,

J is N,

K is C,

G, M, Q, and L are C—R, wherein R is hydrogen,

X is C-D-A-Ar 2 , wherein D-A is R 7 C═CR 8 , wherein R 7 and R 8 are hydrogen,

Ar 1 is phenyl substituted with an alkoxy group, and

Ar 2 is phenyl substituted with a substituent selected from the group consisting of alkyl, substituted alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkoxy, substituted alkoxy, heterocyclic, substituted heterocyclic, carboxyl, carboxylalkyl, and cyano.

2. The compound of claim 1 , wherein R 7 C═CR 8 has a cis configuration.

3. The compound of claim 1 selected from the group consisting of: 5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole and 2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-propan-2-ol.

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. The composition of claim 4 , wherein R 7 C═CR 8 has a cis configuration.

6. The composition of claim 4 , wherein the compound is selected from the group consisting of: 5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole and 2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-propan-2-ol.

7. A method for relieving or causing the regression of a viral infection, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein R 7 C═CR 8 has a cis configuration.

9. The method of claim 7 , wherein said compound is selected from the group consisting of: 5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)-benzimidazole and 2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]-propan-2-ol.

10. The method of claim 7 , wherein the mammal is a human.

11. The method of claim 7 , wherein the viral infection is an Arenavirus infection.

12. The method of claim 11 , wherein the Arenavirus is selected from the group consisting of Lassa, Junín, Machupo, Guanarito, Sabia, Whitewater Arroyo, Chapare, LCMV, and LCMV-like viruses selected from the group consisting of Dandenong, Tacaribe, and Pichinde.

13. The method of claim 7 , which further comprises co-administration of at least one agent selected from the group consisting of antiviral agent, vaccine, and interferon.

14. The compound of claim 1 , wherein R 7 C═CR 8 has a trans configuration.

15. The compound of claim 1 , wherein said compound is selected from the group consisting of:

1-(4-ethoxyphenyl)-5-[(E)-2-(4-ethylphenyl)vinyl]benzimidazole;

1-(4-ethoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)vinyl]benzimidazole;

5-[(E)-2-(4-isopropylphenyl)vinyl]-1-(4-methoxyphenyl)benzimidazole;

5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)-benzimidazole;

5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-ethoxyphenyl)benzimidazole;

5-[(E)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;

5-[(Z)-2-(4-tert-butylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;

5-[(E)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;

5-[(Z)-2-(4-ethylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;

1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimidazole;

1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethoxy)phenyl]vinyl]benzimidazole;

1-(4-ethoxyphenyl)-5-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]benzimidazole;

1-(4-ethoxyphenyl)-5-[(Z)-2-[4-(trifluoromethyl)phenyl]vinyl]benzimidazole;

1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-ethylphenyl)-vinyl]benzimidazole;

1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-ethylphenyl)-vinyl]benzimidazole;

1-(4-tert-butoxyphenyl)-5-[(E)-2-(4-tert-butylphenyl)vinyl]benzimidazole;

1-(4-tert-butoxyphenyl)-5-[(Z)-2-(4-tert-butylphenyl)vinyl]benzimidazole;

methyl 4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoate;

2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol;

5-[(Z)-2-[4-(1-fluoro-1-methyl-ethyl)phenyl]vinyl]-1-(4-isopropoxyphenyl)benzimidazole;

5-[(Z)-2-(4-isopropenylphenyl)vinyl]-1-(4-isopropoxyphenyl)benzimidazole;

5-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]nonan-5-ol;

1-(4-isopropoxyphenyl)-5-[(Z)-2-[4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)phenyl]vinyl]benzimidazole;

3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propanal;

4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzoic acid;

1,1,1-trifluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol;

1,1,1,3,3,3-hexafluoro-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol;

1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopropanol;

4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]benzonitrile;

2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]butan-2-ol;

1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]ethanol;

1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclobutanol;

3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]oxetan-3-ol;

1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopropanamine;

2-hydroxy-2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propanoic acid;

1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclopentanol;

1-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]cyclohexanol;

3-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]azetidin-3-ol;

4-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]tetrahydropyran-4-ol;

2-[4-[(Z)-2-[1-(4-isopropoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-amine; and

2-[4-[(Z)-2-[1-(4-ethoxyphenyl)benzimidazol-5-yl]vinyl]phenyl]propan-2-ol.

16. The composition of claim 4 , wherein R 7 C═CR 8 has a trans configuration.

17. The composition of claim 4 , wherein said compound is selected from the group consisting of: