Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate

Patent metadata

Field	Value
Publication number	US-12030906-B2
Application number	US-202318099477-A
Country	US
Kind code	B2
Filing date	Jan 20, 2023
Priority date	May 1, 2017
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

The present invention relates to novel salts and crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate for use in treating viral infections. In some embodiments, the viral infection is caused by a virus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and Paramyxoviridae.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a crystalline form of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 22.3°, 16.9°, and 16.2°±0.2° 2−θ and one to three additional therapeutic agents.

2. The pharmaceutical composition of claim 1 , wherein the additional therapeutic agents are each active against a virus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and Paramyxoviridae.

3. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against Lassa virus.

4. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against Junin virus.

5. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against MERS virus.

6. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against SARS virus.

7. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against ebolavirus.

8. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against Marburg virus.

9. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against Zika virus.

10. The pharmaceutical composition of claim 2 , wherein the additional therapeutic agents are each active against respiratory syncytial virus.

11. A pharmaceutical composition comprising a crystalline form of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 22.3°, 16.9°, and 16.2°±0.2° 2−θ and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a unit dosage form.

12. A pharmaceutical composition comprising a crystalline form of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 22.3°, 16.9°, and 16.2°±0.2° 2−θ, prepared by combining a therapeutically effective amount of the crystalline form with a pharmaceutically acceptable excipient.

13. A method for treating a viral infection in a human, the method comprising administering to a human in need thereof a therapeutically effective amount of a crystalline form of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 22.3°, 16.9°, and 16.2°±0.2° 2−θ.

14. The method for treating a virus infection in a human of claim 13 wherein the viral infection is caused by a virus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and Paramyxoviridae.

15. The method of claim 14 , wherein the viral infection is caused by the Arenaviridae virus.

16. The method of claim 15 , wherein the Arenaviridae virus is Lassa virus or Junin virus.

17. The method of claim 14 , wherein the viral infection is caused by the Coronaviridae virus.

18. The method of claim 17 , wherein the Coronaviridae virus is MERS virus or SARS virus.

19. The method of claim 14 , wherein the viral infection is cause by the Filoviridae virus.

20. The method of claim 19 , wherein the Filoviridae virus is ebolavirus or Marburg virus.

21. The method of claim 14 , wherein the viral infection is cause by the Flaviviridae virus.

22. The method of claim 21 , wherein the Flaviviridae virus is Zika virus.

Assignees

• Gilead Sciences Inc

Inventors

• Brak Katrien
• Carra Ernest A
• Heumann Lars V
• Larson Nate

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07F9/6561 Primary

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title