Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use

Patent metadata

Field	Value
Publication number	US-9403829-B2
Application number	US-201213689972-A
Country	US
Kind code	B2
Filing date	Nov 30, 2012
Priority date	Dec 2, 2011
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

Provided herein are compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, solid forms, isotopologues and metabolites thereof, and methods of their use for the treatment of a disease, disorder, or condition.

First claim

What is claimed is:

1. A pharmaceutical composition comprising an effective amount of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, or a pharmaceutically acceptable salt, isotopologue, metabolite or solid form thereof, stearic acid and lactose monohydrate.

2. The pharmaceutical composition of claim 1 , comprising about 0.1-5% by weight of stearic acid.

3. The pharmaceutical composition of claim 2 , comprising about 0.4% by weight of stearic acid.

4. The pharmaceutical composition of claim 1 , comprising about 40-60% by weight of lactose monohydrate.

5. The pharmaceutical composition of claim 4 , comprising about 49.2% by weight of lactose monohydrate.

6. The pharmaceutical composition of claim 1 , further comprising microcrystalline cellulose.

7. The pharmaceutical composition of claim 6 , comprising about 20-40% by weight microcrystalline cellulose.

8. The pharmaceutical composition of claim 7 , comprising about 31% by weight of microcrystalline cellulose.

9. The pharmaceutical composition of claim 1 , further comprising a disintegrant.

10. The pharmaceutical composition of claim 9 , wherein the disintegrant is croscarmellose sodium.

11. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition comprises from about 1-5% by weight of croscarmellose sodium.

12. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises about 40-60% by weight of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, or a pharmaceutically acceptable salt, isotopologue, or solid form thereof.

13. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition comprises about 15% by weight of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, isotopologue, or solid form thereof.

14. A pharmaceutical composition comprising Form A of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, stearic acid and lactose monohydrate, wherein the Form A has an X-ray powder diffraction pattern with one or more peaks expressed in twp-theta at approximately 8.3, 18.2 or 21.7degrees.

15. The pharmaceutical composition of claim 1 , further comprising magnesium stearate.

16. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises from about 0.5-3% by weight of magnesium stearate.

17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition comprises from about 1% by weight of magnesium stearate.

18. The pharmaceutical composition of any claim 1 , wherein the pharmaceutical composition is formulated as a tablet.

19. The pharmaceutical composition of claim 18 , wherein the tablet is film coated.

20. The pharmaceutical composition of claim 19 , wherein the film coating is about 4% by weight of the tablet.

21. A method for treating or preventing cancer, an inflammatory condition, an immunological condition, a neurodegenerative disease, diabete, obesity, a neurological disorder, an age-related disease, a cardiovascular condition, or a conditions treatable or preventable by inhibition of a kinase pathway, comprising administering an effective amount of a pharmaceutical composition of claim 1 to a subject in need thereof.

22. The method of claim 21 , wherein the kinase pathway is the TOR kinase pathway.

23. A method for achieving a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of complete response, partial response or stable disease in a subject comprising administering an effective amount of a pharmaceutical composition of claim 1 to a subject having a solid tumor.

24. A method for improving International Workshop Criteria (IWC) for NHL, International Uniform Response Criteria for Multiple Myeloma (IURC), Eastern Cooperative Oncology Group Performance Status (ECOG) or Response Assessment for Neuro-Oncology (RANO) Working Group for GBM, comprising administering an effective amount of a pharmaceutical composition of claim 1 to a subject in need thereof.

25. Crystal Form A of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, having an X-ray powder diffraction pattern with one or more peaks expressed in two-theta at approximately 8.3, 13.2, 18.2 or 21.7 degrees.

26. The solid Form A of claim 25 , having a DSC thermogram with an endotherm at a peak temperature of about 199° C.

27. The crystal Form A of claim 26 , having less than about 0.1% weight loss between about 25° C. to about 100° C. in a thermogravimetric thermogram.

28. The crystal Form A of claim 27 , wherein Form A is anhydrous.

29. The crystal Form A of claim 28 , wherein Form A is substantially pure.

Assignees

• Signal Pharm Llc

Inventors

• Connolly Terrence Joseph
• Klopfer Kevin Joseph
• Leong William Wei-Hwa
• Menon Anil
• Miklos Amanda Nicole
• Boersen Nathan
• Cohen Benjamin
• Gamboa Juan Antonio
• Hui Ho-Wah
• Kreilein Matthew Michael
• Lee Thomas
• Li Ying
• Xu Jean

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title