Solid forms of a thiophosphoramidate nucleotide prodrug

Patent metadata

Field	Value
Publication number	US-9394330-B2
Application number	US-201414578883-A
Country	US
Kind code	B2
Filing date	Dec 22, 2014
Priority date	Mar 21, 2012
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

The present application relates to solid state forms, for example, crystalline forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate, pharmaceutical compositions that can include one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate, and methods of treating or ameliorating diseases and/or conditions with one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate. Also disclosed herein are methods of treating diseases and/or conditions with one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate in combination with one or more other agents.

First claim

What is claimed is:

1. 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form A.

2. Form A of claim 1 , wherein the Form A is characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak from about 6.8 to about 7.2 degrees, a peak from about 8.3 to about 8.7 degrees, a peak from about 15.6 to about 16.0 degrees, a peak from about 21.2 to about 21.6 degrees, a peak from about 21.8 to about 22.2 degrees, a peak from about 22.4 to about 22.8 degrees, and a peak from about 23.1 to about 23.5 degrees.

3. Form A of claim 1 , wherein the Form A is characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6 degrees, and a peak at about 23.3 degrees.

4. Form A of claim 1 , wherein the Form A is characterized by a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, and a peak at about 21.4 degrees in an X-ray powder diffraction pattern.

5. Form A of claim 1 , wherein the Form A is characterized by a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6 degrees, and a peak at about 23.3 degrees in an X-ray powder diffraction pattern.

6. Form A of claim 1 , wherein the Form A is characterized by an X-ray powder diffraction pattern of FIG. 1 .

7. Form A of claim 1 , wherein the Form A is characterized by a melting point of about 138° C.

8. Form A of claim 1 , wherein the Form A is characterized by a DSC thermogram of FIG. 2 .

9. Form A of claim 1 , wherein the Form A is characterized by one or more peaks in a 13 C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 172.0 ppm, a peak at about 146.6 ppm, a peak at about 130.4 ppm, a peak at about 104.1 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm.

10. Form A of claim 1 , wherein the Form A is characterized by a peak at about 130.4 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm in a 13 C NMR solid state spectrum.

11. Form A of claim 1 , wherein the Form A is characterized by a peak at about 172.0 ppm, a peak at about 146.6 ppm, a peak at about 130.4 ppm, a peak at about 104.1 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm in a 13 C NMR solid state spectrum.

12. Form A of claim 1 , wherein the Form A is characterized by a 13 C NMR solid state spectrum of FIG. 3 .

13. 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Amorphous Form O.

14. Amorphous Form O of claim 13 , wherein the Amorphous Form O contains less than about 30% crystallinity.

15. Amorphous Form O of claim 13 , wherein the Amorphous Form O contains less than about 15% crystallinity.

16. Amorphous Form O of claim 13 , wherein the Amorphous Form O contains less than about 1.0% crystallinity.

17. A process for producing the compound of claim 1 , comprising:
a) contacting Compound 1, having the structure

with first amount of ethyl acetate to form a mixture;
b) heating the mixture until the solids are dissolved;
c) cooling the mixture to allow precipitation of a solid;
d) optionally adding a second amount of ethyl acetate and repeating steps a, b and c; and
e) isolating the solid Form A from said mixture.

18. The process of claim 17 , wherein the temperature in step b) is about 60° C.

19. The process of claim 17 , wherein the second amount of ethyl acetate in step d) is approximately equal to the first amount of ethyl acetate used in step a).

20. A pharmaceutical composition comprising the compound of claim 1 .

21. A method of ameliorating or treating a HCV infection comprising administering to a subject suffering from the HCV infection an amount of the compound of claim 1 .

22. A method for inhibiting replication of a hepatitis C virus comprising contacting a cell infected with the hepatitis C virus with the compound of claim 1 .

23. A method for ameliorating or treating a HCV infection comprising contacting a cell infected with the hepatitis C virus with the compound of claim 1 .

24. The method of claim 21 , further comprising administering one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB)

or a pharmaceutically acceptable salt thereof, wherein B BB1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; X BB can be O (oxygen) or S (sulfur); R BB1 can be selected from —Z BB —R BB9 , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; Z BB can be selected from O (oxygen), S (sulfur) and N(R BB10 ); R BB2 and R BB3 can be independently selected from hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl, an optionally substituted C 1-6 haloalkyl and an optionally substituted aryl(C 1-6 alkyl); or R BB2 and R BB3 can be taken together to form a group selected from an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl, an optionally substituted C 3-6 aryl and an optionally substituted C 3-6 heteroaryl; R BB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl and an optionally substituted allenyl; R BB5 can be hydrogen or an optionally substituted C 1-6 alkyl; R BB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C 1-6 alkyl, —OR BB11 and —OC(═O)R BB12 ; R BB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C 1-6 alkyl, —OR BB13 and —OC(═O)R BB14 ; R BB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C 1-6 alkyl, —OR BB15 and —OC(═O)R BB16 ; R BB9 can be selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl); R BB10 can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heter

Assignees

• Alios Biopharma Inc

Inventors

• Kuldipkumar Anuj K
• Medek Ales
• Ferris Lori Ann
• Mudunuri Praveen
• Jung Young Chun
• Willcox David Richard
• Waldo Michael
• Nugent William Aloysius

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• C07H19/06

  Pyrimidine radicals · CPC title

• C07H19/10 Primary

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title