Solid forms of a thiophosphoramidate nucleotide prodrug

Patent metadata

Field	Value
Publication number	US-9856284-B2
Application number	US-201615210509-A
Country	US
Kind code	B2
Filing date	Jul 14, 2016
Priority date	Mar 21, 2012
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

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. A polymorphic form of 2′-C-methyluridine-5′(O-phenyl-N-(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate, wherein the polymorphic form is characterized as Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form K, Form L, Form M, or Form N.

2. Form B of claim 1 , wherein the Form B 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 5.5 to about 5.9 degrees, a peak from about 9.2 to about 9.6 degrees, a peak from about 16.8 to about 17.2 degrees, and a peak from about 26.0 to about 26.4 degrees.

3. Form C of claim 1 , wherein the Form C 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 4.8 to about 5.2 degrees, a peak from about 6.4 to about 6.8 degrees, a peak from about 8.0 to about 8.4 degrees, a peak from about 9.0 to about 9.4 degrees, a peak from about 9.4 to about 9.8 degrees, a peak from about 16.1 to about 16.5 degrees, and a peak from about 22.1 to about 22.5 degrees.

4. Form D of claim 1 , wherein the Form D 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 7.9 to about 8.3 degrees, a peak from about 13.2 to about 13.6 degrees, a peak from about 14.2 to about 14.6 degrees, a peak from about 17.0 to about 17.4 degrees, a peak from about 29.4 to about 29.8 degrees, and a peak from about 34.8 to about 35.2 degrees.

5. Form E of claim 1 , wherein the Form E 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 7.6 to about 8.0 degrees, a peak from about 10.4 to about 10.8 degrees, a peak from about 12.7 to about 13.1 degrees, a peak from about 24.3 to about 24.7 degrees, and a peak from about 24.8 to about 25.2 degrees.

6. Form F of claim 1 , wherein the Form F 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 5.9 to about 6.3 degrees, a peak from about 6.8 to about 7.2 degrees, a peak from about 17.3 to about 17.7 degrees, and a peak from about 17.8 to about 18.2 degrees.

7. Form G of claim 1 , wherein the Form G 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 5.7 to about 6.1 degrees, a peak from about 7.3 to about 7.7 degrees, a peak from about 7.6 to about 8.0 degrees, a peak from about 12.3 to about 12.7 degrees, a peak from about 17.5 to about 17.9 degrees, and a peak from about 18.0 to about 18.4 degrees.

8. Form H of claim 1 , wherein the Form H 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 7.9 to about 8.3 degrees, a peak from about 13.8 to about 14.2 degrees, a peak from about 17.0 to about 7.4 degrees, and a peak from about 19.9 to about 20.3 degrees.

9. Form I of claim 1 , wherein the Form I 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 6.2 to about 6.6 degrees, a peak from about 9.1 to about 9.5 degrees, a peak from about 10.6 to about 11.0 degrees, and a peak from about 11.6 to about 12.0 degrees.

10. Form K of claim 1 , wherein the Form K 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 22.4 to about 22.8 degrees, a peak from about 27.1 to about 27.5 degrees, a peak from about 28.1 to about 28.5 degrees, and a peak from about 31.0 to about 31.4 degrees.

11. Form L of claim 1 wherein the Form L 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 5.5 to about 5.9 degrees, a peak from about 5.8 to about 6.2 degrees, a peak from about 15.0 to about 15.4 degrees, and a peak from about 15.9 to about 16.3 degrees.

12. Form M of claim 1 , wherein the Form M 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 6.1 to about 6.5 degrees, a peak from about 13.0 to about 13.4 degrees, a peak from about 22.0 to about 22.4 degrees, and a peak from about 23.3 to about 23.7 degrees.

13. Form N of claim 1 , wherein the Form N 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 12.2 to about 12.6 degrees, a peak from about 15.1 to about 15.5 degrees, a peak from about 16.9 to about 17.3 degrees, and a peak from about 17.7 to about 18.1 degrees.

14. Amorphous Form O that contains less than about 15% crystallinity of 2′-C-methyluridine-5′-(O-phenyl-N-(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate.

15. Amorphous Form O of claim 14 , wherein the Amorphous Form O contains less than about 1.0% crystallinity.

16. A pharmaceutical composition comprising one or more solid forms of Compound 1 according to claim 1 .

17. A method of ameliorating or treating a viral infection in a patient, said method comprising administering to said patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. A method for inhibiting replication of a hepatitis C virus comprising contacting a cell infected with the hepatitis C virus with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. A method for ameliorating or treating a HCV infection comprising contacting a cell infected with the hepatitis C virus with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. The method of claim 18 , further comprising 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) and a compound of Formula (DD), or a pharmaceutically acceptable salt any of the aforementioned compounds, wherein the compound of Formula (BB), or a pharmaceutically acceptable salt thereof, is

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 B

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

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• C07H19/10 Primary

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · 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

• A61K45/06

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