Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Abstract

The present invention relates to crystalline forms and co-crystals of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, the pharmaceutical formulations, and the therapeutic uses thereof. The present invention also relates to novel crystalline forms of sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate Form I.

1 .- 9 . (canceled) 
     
     
         10 . A crystalline form of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, wherein the crystalline form is Form II, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 6.6°, 10.6°, and 12.5° 2-θ±0.2° 2-θ. 
     
     
         11 . (canceled) 
     
     
         12 . The crystalline form of  claim 10 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 16.2° and 21.4° 2-θ±0.2° 2-θ. 
     
     
         13 . The crystalline form of  claim 12 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 14.3°, 23.5°, and 25.6° 2-θ±0.2° 2-θ. 
     
     
         14 . The crystalline form of  claim 10 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in  FIG. 2 . 
     
     
         15 . A crystalline form of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, wherein the crystalline form is Form III, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 9.6°, 14.0°, and 18.5° 2-θ±0.2° 2-θ. 
     
     
         16 . (canceled) 
     
     
         17 . The crystalline form of  claim 15 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 20.0° and 22.5° 2-θ±0.2° 2-θ. 
     
     
         18 . The crystalline form of  claim 17 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 12.1° and 16.2° 2-θ±0.2° 2-θ. 
     
     
         19 . The crystalline form of  claim 18 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 25.0°, 27.0°, and 29.0° 2-θ±0.2° 2-θ. 
     
     
         20 . The crystalline form of  claim 15 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in  FIG. 3 . 
     
     
         21 . The crystalline form of  claim 15 , characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in  FIG. 8 . 
     
     
         22 . The crystalline form of  claim 15 , characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in  FIG. 14 . 
     
     
         23 . A crystalline form of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, wherein the crystalline form is Form IV, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 6.2°, 16.3°, and 22.3° 2-θ±0.2° 2-θ. 
     
     
         24 . (canceled) 
     
     
         25 . The crystalline form of  claim 23 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 22.7° and 25.8° 2-θ±0.2° 2-θ. 
     
     
         26 . The crystalline form of  claim 25 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 8.6° and 13.2° 2-θ±0.2° 2-θ. 
     
     
         27 . The crystalline form of  claim 26 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 18.7°, 20.0°, and 27.7° 2-θ±0.2° 2-θ. 
     
     
         28 . The crystalline form of  claim 23 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in  FIG. 4 . 
     
     
         29 .- 32 . (canceled) 
     
     
         33 . A crystalline form of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide oxalic acid co-crystal, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 14.5°, 17.1°, and 19.1° 2-θ±0.2° 2-θ. 
     
     
         34 . The crystalline form of  claim 33 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 21.8° and 26.5° 2-θ±0.2° 2-θ. 
     
     
         35 . The crystalline form of  claim 34 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 7.6° and 9.1° 2-θ±0.2° 2-θ. 
     
     
         36 . The crystalline form of  claim 35 , wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 11.6°, 29.7°, and 39.4° 2-θ±0.2° 2-θ. 
     
     
         37 . The crystalline form of  claim 33 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in  FIG. 6 . 
     
     
         38 . A pharmaceutical composition comprising a therapeutically effective amount of the form of  claim 10  and a pharmaceutically acceptable carrier or excipient. 
     
     
         39 . The pharmaceutical composition of  claim 38 , further comprising one to three additional therapeutic agents. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the additional therapeutic agents are each anti-HIV drugs. 
     
     
         41 . The pharmaceutical composition of  claim 39  or  claim 40 , wherein the additional therapeutic agents are each independently selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and other drugs for treating HIV. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein at least two of the additional therapeutic agents are each HIV nucleotide or nucleoside inhibitors of reverse transcriptase. 
     
     
         43 . The pharmaceutical composition of  claim 38 , further comprising tenofovir disoproxil fumarate and emtricitabine. 
     
     
         44 . The pharmaceutical composition of  claim 38 , further comprising tenofovir alafenamide and emtricitabine. 
     
     
         45 . The pharmaceutical composition of  claim 38 , further comprising tenofovir alafenamide hemifumarate and emtricitabine. 
     
     
         46 . The pharmaceutical composition of  claim 38 , wherein the pharmaceutical composition is in a unit dosage form. 
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein the unit dosage form is a tablet. 
     
     
         48 - 51 . (canceled) 
     
     
         52 . A method for treating or prophylactically preventing an HIV infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of a form of  claim 10 .