IP Library › Granted Patent US 11,541,034
Granted Patent B2
US 11,541,034 · App. 17/554,091 · Granted Jan 3, 2023

Nitrile-containing antiviral compounds

Inventors: Dafydd Rhys Owen (Concord, MA); Martin Youngjin Pettersson (Littleton, MA); Matthew Richard Reese (Mystic, CT); Matthew Forrest Sammons (Quincy, MA); Jamison Bryce Tuttle (Marblehead, MA); Patrick Robert Verhoest (Newton, MA); Liuqing Wei (Ledyard, CT); Qingyi Yang (Lexington, MA); Xiaojing Yang (Waterford, CT)
Assignee: Pfizer Inc.
A61K31/403A61K31/401A61K31/427A61P31/14C07D403/12C07B2200/13
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Quick Facts
Patent No.
US 11,541,034
App. No.
17/554,091
Granted
Jan 3, 2023
Kind
B2
Abstract

The invention relates to compounds of Formula I″ wherein R, R 1 , R 2 , R 3 , p, q and q′ are as defined herein, pharmaceutical compositions comprising the compounds, methods of treating coronavirus infection such as COVID-19 in a patient by administering therapeutically effective amounts of the compounds, and methods of inhibiting or preventing replication of coronaviruses such as SARS-CoV-2 with the compounds.

Claims (31)

1. A method of treating a coronavirus infection in a patient, the method comprising co-administering a therapeutically effective amount of the compound (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide having the structure

or a solvate or hydrate thereof, and ritonavir to the patient.

2. The method of claim 1 wherein the compound (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a solvate or hydrate thereof and ritonavir are co-administered to the patient orally.

3. The method of claim 2 wherein about 10 mg to about 1500 mg per day of the compound (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a solvate or hydrate thereof and about 10 mg to about 1000 mg per day of ritonavir are co-administered.

4. The method of claim 3 wherein about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg or 750 mg of the compound (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a solvate or hydrate thereof is co-administered orally to the patient twice a day.

5. The method of claim 4 wherein ritonavir is co-administered orally to the patient twice a day.

6. The method of claim 5 wherein about 300 mg of the compound (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a solvate or hydrate thereof and about 100 mg of ritonavir are co-administered to the patient twice a day.

7. The method of claim 1 wherein crystalline (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide is co-administered.

8. The method of claim 1 wherein (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, Solid Form 1, which is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 3 and comprising diffraction peaks 7.6, 9.8, 11.4, 11.9, 12.7, 15.7, 15.8, 17.3, 17.8, 18.3, 18.9, 19.7, 19.9, 20.5, 21.0, 21.7, 22.2, 22.5, 23.1, 23.6, 24.7, 25.3, 27.0, 27.2, 27.9, 28.1, 29.5, 32.6, 35.7 and 37.0 degrees two theta, wherein each peak is ±0.2 degrees two theta, is co-administered.

9. The method of claim 7 wherein crystalline (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide which is characterized by a solid-state 19 F NMR peak with a chemical shift at −73.3±0.1 ppm and solid-state 13 C NMR peaks with chemical shifts at 31.0±0.1 ppm, 27.9±0.1 ppm and 178.9±0.2 ppm is co-administered.

10. The method of claim 7 wherein (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, Solid Form 4, which is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 6 and comprising diffraction peaks 7.6, 9.8, 10.8, 11.2, 11.4, 11.7, 12.0, 12.3, 12.7, 13.7, 14.9, 15.1, 15.9, 17.5, 18.0, 18.2, 18.5, 18.8, 20.0, 20.4, 20.7, 21.1, 21.6, 21.8, 22.3, 23.1, 23.4, 24.2, 24.9, 25.2, 26.1, 27.0, 27.2, 28.1, 28.9, 29.4, 29.5, 29.8, 30.0, 30.6, 30.8, 31.3, 31.8, 32.5, 32.8, 33.2, 33.4, 35.5, 35.6, 36.0, 36.4, 37.1, 38.7, 39.4, 39.5 and 39.8 degrees two theta, wherein each peak is ±0.2 degrees two theta, is co-administered.

11. The method of claim 7 wherein crystalline (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide which is characterized by one or more peaks selected from the group consisting of a solid-state 19 F NMR peak with chemical shift at −73.6±0.1 ppm and solid-state 13 C NMR peaks at 26.9±0.1 ppm, 21.6±0.1 ppm and 41.5±0.1 ppm is co-administered.

12. The method of claim 1 wherein amorphous (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide is co-administered.

13. The method of claim 1 wherein (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, methyl tert-butyl ether solvate is co-administered.

14. The method of claim 13 wherein crystalline (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, methyl tert-butyl ether solvate is co-administered.

15. The method of claim 14 wherein (1R,2S,5S)—N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, methyl tert-butyl ether solvate, Solid Form 2, which is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 1 and comprising diffraction peaks 7.1, 10.5, 11.3, 11.8, 12.5, 12.9, 14.2, 15.7, 16.0, 16.8, 17.0, 18.5, 18.8, 19.1, 19.9, 20.2, 20.8, 21.1, 21.4, 21.7, 22.2, 23.1, 23.4, 23.7, 25.3, 27.3, 27.9, 28.3, 28.5, 29.1, 29.4, 30.2, 30.8, 32.0, 33.3, 33.8, 35.4, 36.4 and 36.1 degrees two-theta, wherein each peak is ±0.2 degrees two theta, is co-administered.

16. The method of claim 1 wherein the coronavirus infection is a SARS-CoV-2 infection and (1R,2S,5S)-N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl{-6,6-dimethyl-313-methyl-N- (trifluoroacetyl)-L-valyl]-3azabicyclo[3.1.0]hexane-2-carboxamide is co-administered.

17. The method of claim 2 wherein the coronavirus infection is a SARS-CoV-2 infection and (1R,2S,5S)-N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl{-6,6-dimethyl-313-methyl-N- (trifluoroacetyl)-L-valyl]-3azabicyclo[3.1.0]hexane-2-carboxamide is co-administered.

18. The method of claim 3 wherein the coronavirus infection is a SARS-CoV-2 infection.

19. The method of claim 4 wherein the coronavirus infection is a SARS-CoV-2 infection.

20. The method of claim 5 wherein the coronavirus infection is a SARS-CoV-2 infection.

21. The method of claim 6 wherein the coronavirus infection is a SARS-CoV-2 infection and (1R,2S,5S)-N-{(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl{-6,6-dimethyl-313-methyl-N- (trifluoroacetyl)-L-valyl]-3azabicyclo[3.1.0]hexane-2-carboxamide is co-administered.

22. The method of claim 7 wherein the coronavirus infection is a SARS-CoV-2 infection.

23. The method of claim 8 wherein the coronavirus infection is a SARS-CoV-2 infection.

24. The method of claim 9 wherein the coronavirus infection is a SARS-CoV-2 infection.

25. The method of claim 10 wherein the coronavirus infection is a SARS-CoV-2 infection.

26. The method of claim 11 wherein the coronavirus infection is a SARS-CoV-2 infection.

27. The method of claim 12 wherein the coronavirus infection is a SARS-CoV-2 infection.

28. The method of claim 13 wherein the coronavirus infection is a SARS-CoV-2 infection.

29. The method of claim 14 wherein the coronavirus infection is a SARS-CoV-2 infection.

30. The method of claim 15 wherein the coronavirus infection is a SARS-CoV-2 infection.

Assignments (1)
ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023
From: PFIZER INC.
To: PFIZER INC.
Reel/Frame 063119/0087 →
Cited By (1)
US 12,577,240