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

• US 9,795,603 B2
• Filed: 02/08/2017
• Issued: 10/24/2017
• Est. Priority Date: 05/29/2013
• Status: Active Grant

• Current Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Original Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Inventors: Beauchamps, Marie Georges, Ferretti, Antonio Christian, Gamboa, Juan Antonio, Klopfer, Kevin, Konnecke, William Edward, Kreilein, Matthew Michael, Menon, Anil, Miklos, Amanda Nicole, Traverse, John Fitzgerald
• Primary Examiner(s): LOVE, TREVOR M
• Application Number:
  US15/427,242
• Publication Number:
  US 20170182042A1
• Time in Patent Office: 258 Days
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07B 59/00 Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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.

Claims

1. A method for treating a neuroendocrine tumor, non-small cell lung cancer, glioblastoma multiforme, hepatocellular carcinoma, breast cancer, non-Hodgkin lymphoma, or multiple myeloma, comprising administering to a subject in need thereof 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 or isotopologue thereof, about 40-60% by weight of lactose monohydrate, about 20-40% by weight of low-moisture grade microcrystalline cellulose, about 1-5% by weight of croscarmellose sodium and about 0.5-3% by weight of magnesium stearate.

2. The method of claim 1, wherein the pharmaceutical composition comprises about 49.6% by weight of lactose monohydrate.

3. The method of claim 1, wherein the pharmaceutical composition comprises about 31% by weight of low-moisture grade microcrystalline cellulose.

4. The method of claim 1, wherein the pharmaceutical composition comprises about 10-20% 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.

5. The method of claim 4, 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.

6. The method of claim 5, wherein the pharmaceutical composition comprises 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.

7. The method of claim 1, wherein the pharmaceutical composition comprises about 1% by weight of magnesium stearate.

8. The method of claim 1, wherein the pharmaceutical composition is formulated as a tablet.

9. The method of claim 8, wherein the tablet is film coated.

10. The method of claim 9, wherein the film coating is about 4% by weight of the tablet.

11. The method of claim 1 comprising administering to the subject in need thereof an effective amount of a crystal form of the compound of formula (I), 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(11)-one, or a salt thereof:

12. The method of claim 11, wherein the crystal form has an X-ray powder diffraction pattern further comprising peaks at approximately 8.94, 18.22 and 18.78 °

2θ

.

13. The method of claim 11, wherein the crystal form has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 11.0% of the total mass of the crystal form when heated from about 25°

C. to about 300°

C.

14. The method of claim 11, wherein the crystal form has a single differential thermal analysis thermogram comprising an endotherm between about 90°

C. and about 125°

C. with a maximum at approximately 106-110°

C. when heated from about 25°

C. to about 300°

C.

15. The method of claim 14, wherein the single differential thermal analysis thermogram further comprises an endotherm with a maximum at approximately 193°

C.

16. The method of claim 11, wherein the crystal form is p-xylene solvated.

17. The method of claim 11, wherein the crystal form comprises 0.5 molar equivalents of p-xylene.

18. The method of claim 11, wherein the crystal form is substantially pure.