WO2015196116A1 - 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] oxazepin-8-olate - Google Patents

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] oxazepin-8-olate Download PDF

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Publication number
WO2015196116A1
WO2015196116A1 PCT/US2015/036757 US2015036757W WO2015196116A1 WO 2015196116 A1 WO2015196116 A1 WO 2015196116A1 US 2015036757 W US2015036757 W US 2015036757W WO 2015196116 A1 WO2015196116 A1 WO 2015196116A1
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Prior art keywords
compound
hiv
sodium
inhibitors
pharmaceutical composition
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Application number
PCT/US2015/036757
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French (fr)
Inventor
Ernest A. CARRA
Irene Chen
Vahid Zia
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Gilead Sciences, Inc.
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Priority to MA40239A priority Critical patent/MA40239B1/en
Priority to ES15739063.4T priority patent/ES2660862T3/en
Priority to KR1020177001377A priority patent/KR101899803B1/en
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to DK15739063.4T priority patent/DK3157932T3/en
Priority to CR20160589A priority patent/CR20160589A/en
Priority to JP2016574180A priority patent/JP6334007B2/en
Priority to EA201692414A priority patent/EA030967B1/en
Priority to NZ727155A priority patent/NZ727155A/en
Priority to SI201530163T priority patent/SI3157932T1/en
Priority to MX2016016059A priority patent/MX369555B/en
Priority to LTEP15739063.4T priority patent/LT3157932T/en
Priority to AU2015276860A priority patent/AU2015276860B2/en
Priority to BR112016029605-2A priority patent/BR112016029605B1/en
Priority to PL15739063T priority patent/PL3157932T3/en
Priority to RS20180286A priority patent/RS56950B1/en
Priority to SG11201610211QA priority patent/SG11201610211QA/en
Priority to BR122021025861-9A priority patent/BR122021025861B1/en
Priority to US15/320,656 priority patent/US20170197985A1/en
Priority to CU2016000187A priority patent/CU24478B1/en
Priority to MDA20180037A priority patent/MD20180037A2/en
Priority to EP15739063.4A priority patent/EP3157932B1/en
Priority to UAA201613232A priority patent/UA118480C2/en
Priority to MDA20170006A priority patent/MD4584C1/en
Priority to MEP-2018-73A priority patent/ME03037B/en
Priority to MYPI2016704591A priority patent/MY186696A/en
Priority to CA2950307A priority patent/CA2950307C/en
Priority to CN201580033152.4A priority patent/CN106459085B/en
Priority to AP2016009591A priority patent/AP2016009591A0/en
Publication of WO2015196116A1 publication Critical patent/WO2015196116A1/en
Priority to IL249161A priority patent/IL249161B/en
Priority to PH12016502499A priority patent/PH12016502499A1/en
Priority to SV2016005339A priority patent/SV2016005339A/en
Priority to ZA2016/08744A priority patent/ZA201608744B/en
Priority to CY20181100305T priority patent/CY1120025T1/en
Priority to HRP20180455TT priority patent/HRP20180455T1/en
Priority to AU2018203175A priority patent/AU2018203175B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present Invention relates to sodium (2R.5S, 13aR)-7 ; 9»dioxo-10-( ⁇ 2,4,6 ⁇ trifiuoroben2yi ⁇ carbam.oyl) ⁇ 2,3,4,5.7,9,13,13a-octahydro-2,5 ⁇
  • Human immunodeficiency virus infection and related diseases are a major public health problem worldwide.
  • Human immunodeficiency virus type i ( ⁇ -l) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
  • reverse transcriptase a enzyme which are required for viral replication
  • protease a enzyme which are required for viral replication
  • integrase integrase.
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (PaleUa, et ai. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001 ) 410:995-1001).
  • a goal of amtiretrovir a! therapy is to achieve viral suppression in the HIV infected patient.
  • Treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination therapies, he,, several drugs from at least two or more drug classes.
  • decisions regarding the treatment of HIV infected patients are complicated when the patient requires treatment for other medical conditions. Because the standard of care requires the use of multiple different drugs to suppress HIV, as well as to treat other conditions the patient may be experiencing, the potential for drug interaction is a criterion for selection of a drag regimen. As such, there is a need for antiretrovirai therapies having a decreased potential for drug interactions.
  • the present invention is directed to sodium
  • the present invention is directed to crystalline sodium (2R S 5 13aR) ⁇ ?J ⁇ ioxo 0- ⁇ i2A6 ⁇
  • the present invention is directed to sodium
  • the present invention is directed to pharmaceutical formulations comprising sodium (2R.5SJ 3aR)-?,9 ⁇ dioxo-10-((2 ? 4,6 ⁇
  • the present invention is directed to methods of treating or prophylactically preventing an HIV infection by administering sodium
  • the present invention is directed to sodium
  • the present invention is directed to the use of sodium
  • Fi ure 1 XRPD pattern for sodium (2R,5SJ 3a ⁇ -7,9 ⁇ dioxQ ⁇ i0-((2A6 ⁇ tnfluorobenzyl)car bamoy 1 ) ⁇ 2 S 3,4, 5, 7, 9, 13, 13a-octahydro-2, 5 - meibanopyfido[r,2';4,5]p Tazino 2, l-b][l ,3]ox35:epIn-S-o1ats Form ⁇ .
  • F ure 2 DSC for sodium (2R, 5 S, 13 aR)-7 s 9 ⁇ dioxo-.10-((2 ,4,6-
  • Fasied-Staie Simulated Gastric Fluid (FaSSGF).
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 3 ⁇ 4 3 ⁇ 4 C, 3 ⁇ 4, "C, 3 ⁇ 4, t5 N, ts O, 3 ⁇ 4 l8 0, 3 3 ⁇ 4 3 3 ⁇ 4 3S S, ' % 3 ⁇ 4 m l, and % respectively.
  • radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically importan t site of action.
  • Certain isotopieaily- iabeled compounds of Formulas (I) and (II), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, Le, 3 H, and carbon- .14, le. i C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, le. ⁇ , may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.
  • isotopically-kbeled compo nds of Formulas (I) and (II) can generally be prepared by conventional techniques kno n to those skilled in fee art or by processes analogous to those described in the Examples as set out below usin an appropriate isotoplealiy-labeled reagent in place of the non-labeled reagent previously employed.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity .from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Optional or “optionally” means thai the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description Includes both substituted aryl radicals and ary! radicals having no substitution.
  • "Pharmaceutically acceptable carrier, dil uent or exeipient” incS udes without limitation any adjuvant carrier, exeipient, gl ant, sweetening agent, diluent preservative, dye/colorant, .flavor enhancer, surfactant wetting agent, dispersing agent, suspending agent stabilizer, isotonic agent, solvent, or emulsifier which, has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals,
  • a "pharmaceutical composition” refers to a formulation of a. compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor,
  • Effective amount refers to an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and Its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment the type of disease-state or disorder being treated and its severity, drugs used in combination with or eoincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • treatment is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient.
  • treatment also encompasses the administration of a compound or composition according to the present invention post-exposure of the individ al to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the vims in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life, in certain embodiments, the term “treatment” as used herein is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient.
  • the term "treatment” as used herein is further or alternatively intended to mean the administration of a compound or composition according to the present invention to maintain a reduced viral load in a patient.
  • the term “treatment” also encompasses the administration of a compound or composition according to the present in ention postexposure of the individual to the virus but before the appearance of symptoms of the disease; and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
  • treatment is further or alternatively intended to mean, the admin stration of a compound or composition accordin g to the present Invention post-exposure of the individual to the virus as a subsequent or additional therapy to a first-line therapy (e.g., for maintenance of low viral load).
  • prevention means any treatment of a disease or condition thai causes the clinical symptoms of the disease or condition not to develop.
  • prevention also encompasses the administration of a compound or composition according to the present invention pre-exposure of the individual to the virus ⁇ e.g., pre-exposure prophylaxis), to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching deteetible levels in the blood.
  • Subject or “patient” refer to an animal, such as a mammal
  • the subject is a mammal, (or the patient).
  • the subject (or the patient) is human, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), and/or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys).
  • the subject (or the patient) is a human.
  • Human (or patient) in need thereof refers to a human who may have or is suspect to have diseases or conditions that would benefit from certain treatment; for example, being treated with the compounds disclosed herein according to the present application.
  • antiviral agent as used herein is intended to mean an agent
  • inhibitor of HIV replication is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo or in vivo.
  • a "tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present invention includes tauiomers of any said compounds.
  • references to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • description referring to "about X” includes description of "X”.
  • the singular forms "a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to ' he assay” includes reference to one or more assays and equivalents thereof know* to those skilled in the it.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, sate, compositions, dosage forms and other materials which are use in preparing a pharmaceutical composition that is suitable t r veterinary or human
  • Unit dosage forms are physically discrete units suitable as unitary dosages for subjects (e.g., human subjects and other mammals), each unit containing a predetermined quant ity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • S ⁇ methanopyrldo[ 1 T :4, 5]pyrazmo[2 » 1 -b] [ 1 ,3]oxazepm-8- olaie may be an intermediate to the synthesis of sodium (2R.5S, 13aR) ⁇ 7,9-dsoxo ⁇ 10 ⁇ 2,4,6 - irifluorobenzyS)carbamoyl) ⁇ 2,3 ,4,5,7,9, 13, 1 a-octabydro-2,5- meihanopyridof 1 ⁇ 2':4 ]pyra;dr)oi2, ! -bjj j 1 JJoxazepin-S-olate.
  • 2 J 5 ⁇ methanopyrido[i' s 2':4 ! ,53pyra2mo[ > l-b][l 5 3]oxa2:epin-8-oiate may be the final product in the synthesis of sodium (2R ! 5S, 13aR)-7 ; 9-dio3 ⁇ 4o 0-((2,4 5 6-trifluoroberizyl)carbamoy!) ⁇ 2,3AS , 5 13 ? i3aH>ctahydro ⁇ 2 s 5 ⁇ Bet ⁇
  • a polymorphic form or polymorph or eocrystai may have properties such as bioavailability and stability at certain conditions that may be suitable for medical or pharmaceutical uses.
  • a crystallme form of sodium (2R ; 5S,13aR)-7,9-dioxo-I0-((2 ? 4,6 ⁇ irifluorobenzyI)carbamoyl)-2.3 5 4.5 5 7,9, 1.3, 13a ⁇ oetahydro ⁇ 2,5- meChanopyrido[ 1 '.2 ! : 4 ,5 ]pyrazi.no[2, 1 -b] [ 1 ,3 ]oxazepin-8 ⁇ olate may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical compossdon.
  • a crystalline form sodium (2R,5 S, 13aB.)-?,9 ⁇ dioxo ⁇ 10- (( ⁇ ⁇ ifluoro enzy carbamo -a ⁇ ,? ⁇ , ! 3J 3a-ocialtydro ⁇ 2,f5- rnethas3 ⁇ 4op3'rido[! ! 5 2 !
  • crystalline forms may provide desired or suitable hygroscopicky, particle size controls, dissolution rate, solubility, purity, physical and chemical stability manufacturability, yield, and/or process control.
  • crystalline forms of sodium (2R, 5 S, 13a )-7,9-dioxo ⁇ l G ⁇ ((2,4,6 T ifluOTobenz i ⁇ arbamoy -a-S. ⁇ SJ. ⁇ B. iSa- octahydro-2,5-methanopyrido[i f ,2 ! :4,5]pyrazko[2 5 l-h][ l,3]oxazepk ⁇ 8 ⁇ Qlate may provide advantages such as: improving the manu facturing process of an active agent or the stability or storability of a drug product form of the compound or an active ingredient, and/or having suitable bioavailability and/or stability as an active agent.
  • Form I of sodium (2 ,5S,13a )-7,9 ⁇ dioxo ⁇ 10- ((2,4,6 riiluoroben ⁇ I)carbaii3oyl)-2,3 J 4,5 5 9J3 > 13a-octahydro ⁇ 2 > 5- meihanopyrido[r,2 i :4,5Jpyra2ino 2, l ⁇ b][i 5 3]oxazepin-S--olate provides an advantage of improved bioavailability (Table 3) and/or stability (Table 4), The processes for the preparation of the polymorphs described herein and characterization of these polymorphs are described in greater detail below.
  • the compound name provided above is named using ChemBic raw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols.
  • the compound may be named or identified with common names, systematic or non- systematic names, The nomenclature systems and symbols that are eomraonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and international Union of Pure and Applied Chemistry (lUPAC).
  • the compound stracture provided above may be named or identified as sodium (2R,5S 5 13aR)-7,9-dioxo-10- ((2 5 4,6 ⁇ triiluorobenzyl)carbamoyi)-2 5 3 i 4,5,7,9 5 13, 1 :1 ⁇ 2-octahydro-2 ; 5»
  • Polymorphic sodium Form I may exhibit a differential scanning calorirnetry (DSC) thermogram substantially as shown in FIG, 2
  • Polymorphic sodium Form 1 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 3
  • Polymorphic sodium Form I may exhibit dynamic "vapour sorption (DVS) graphs substantially as shown in PIG. 4.
  • XSPD pattern a DSC thermogram, or a TGA graph
  • a pattern, thermogram or graph that is not necessarily identical to those depicted herein, but that fails within the limits of experimental error or deviations when considered by one of ordinary- skill in the ait,
  • polymorphic sodium Form I at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight at least nine, or all of the following (a) ⁇ (j) a ly, (a) polymorphic Form I has an XRPD pattern substantially as shown in FIG 1 and/or FIG. S; (h) polymorphic sodium Form I has a DSC thermogram substantially as shown in FIG 2; (e) polymorphic sodium Form I has a TGA graph substantially as shown in FIG. 3; (d) polymorphic sodium Form ⁇ has DVS graphs substantially as shown in FIG.
  • polymorphic sodium Form I has at least one, at least two, at least three, at least four, or all of the following properties:
  • polymorphic sodium Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree IB-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 1 and/or FIG. 8.
  • polymorphic sodium Form I has an XRPD pattern comprising degree 20 ⁇ refieeiions (+/- 0,2 degrees 2D) at 5.5, 16.1, and 23.3
  • polymorphic sodium Form ⁇ has an XRPD pattern comprising degree 28- rcflections (+/- 0.2 degrees 2 ⁇ ) at 5,5, 16.1, and 23,3 and one or more of the degree 20- refiections (+/- 0,2 degrees 20) at 22.1, 28,5, and 22.5.
  • polymorphic sodium Form 1 has an XRPD pattern comprising degree 28-refleetions ( ⁇ ⁇ ⁇ /- 0.2 degrees 20) at 5.5, 16.
  • polymorphic sodium Form I has an RPD pattern comprising degree 2e ⁇ reflections (+/- 0.2 degrees 28) at 5,5, 16,1, and 23.3 and two of the degree 28- reflections (+/- 0.2 degrees 2 ⁇ ) at 22, 1 , 28.5, and 22.5.
  • polymorphic sodkrai Form I has an XRPD pattern comprising degree 29-reflections ⁇ +/- 0.2 degrees 20) at 5,5, 16.1, and 23,3 and three of the degree 2e ⁇ reikctions (+/- 0.2 degrees 20) at 22.1, 28.5, and 22.5.
  • polymorphic sodium Form I has an XRPD pattern comprising degree 28-refiectioiis (+/- 0,2 degrees 2 ⁇ ) at 5,5, 16.1, 23,3, 22, 1 , 28.5, and 22.5, In one embodiment, polymorphic sodium Form I has an XRPD pattern comprising degree 20- reflections (- ⁇ /- 0.2 degrees 28) at 5,5, 16,1, 23.3, 22,1, 28.5, 22,5, 19.5, and 26.6. In one embodiment, polymorphic sodium Form ⁇ has an XRPD pattern comprising any three degree 20-re flections (+/ ⁇ 0.2 degrees 2 ⁇ ) selected from the group consisting of 5,5, 1 .1, 23.3, 22.1 , 28.5, 22,5, 19.5, 26.6, and 17.9. Pharmaceutical Compositions
  • the compounds described herein are administered as a raw chemical or are formulated as pharmaceutical compositions.
  • Ph rmaceutical compositions of the present invention comprise a compound of Formula (H), including forms and co-crystals thereof, and a pharmaceutically acceptable carrier, diluent or excipien t.
  • the compound of Formula (II) is present in the composition in an amount which is effective to treat a particulaj- disease or condition of interest
  • the activity of compounds of Formula (II) can be determined by one skilled in the art, for example, as described in co-pending application Serial No. 14/133,855, filed December 19, 2013 entitled "POLYCYCLIC-CARBAMOYLPYRIDO E COMPOUNDS AND THEIR
  • PHARMACEUTICAL USE The activity of compounds of Formula (II) can also be determined by one skilled on the art, for example, as described in co-pending FC-T Serial No, US2013/076367, filed December 19, 2013 entitled, "POLYCYCLIC- CARBAMOYLPYRTDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE," Appropriate concentrations and dosages can be readily determined by one skilled in the art, in certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount from about 25 mg to about 500 mg, h certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 100 mg to about 300 mg.
  • a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 5 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 25 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition In an amount of about 50 mg to about 100 mg. in certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 5 mg to about 100 mg, in certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 5 mg, 25 mg, 50 mg, 75, mg, 100 mg, 200 mg, 300 mg, 400 mg or about 500 mg.
  • compositions comprising at least one polymorph (e.g., any one or more of Formula II polymorphic Forms I) as described herein,
  • a composition comprising Formula II polymorphic Form I, described herein is provided.
  • the compositions described here n may comprise substantially pure polymorphic forms, or may be substantially free of other polymorphs and/or impurities.
  • the composition comprises a polymorphic form of sodium (2R,5S, 13aii)-? J 9-dioso 0 (2,4 s 6 rifluoTObenzyl)carbanioyl)-2,3,4,S s ? ; 9 > 13 ; 13a- oetahydro-2,5-methanopyrido[1 ⁇ 2':4,5]pyrazmo[2 s i-h][l s 3]oxazepin-8-olate.
  • compositions comprising a polymorphic form as described herein, wherein the sodium (2R 5 5SJ3aR)-7,9 ⁇ dioxo-10-( ⁇ 2,4,6 ⁇ trifluoroberi2y!carbarrioyl)- 2,3,4,5,7,9, 13, 13a-octahydro-2 s 5-methanop Tldo[r 5 2 i :4,5]pyrazmo[2 !1 1 -b ⁇ [ L ]oxazepin-8- olate within t e composition is substantially pure ⁇ i.e., substantially pure Form ⁇ ).
  • compositions comprising a polymorphic form of sodium
  • ⁇ 2R,SS, 13aR)-7 9-dioxo- 10-((2 5 4,64riiIuorobenz 'I)carbamoyi)-2,3,4,5,7 s 9 13, 13a-octahydsO- 2,S ⁇ methanopyrido 1 ⁇ 2 , :4 5]pyTazmo[2 s l-fo][I,3]oxazepin-8-oiate, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about ⁇ 5%, at least about 90%, at least about 95%, at least about 96%, at least about.
  • composition 97%, at least about 98%, or at least about 99% of sodium (2R,5S, 13aR)-7,9 ⁇ dloxo- 10-((2,4 5 64riiluorobenzyl)carbamoyl)- 2,3,4,5,7,9, .1 , 13a-oc ahydro-2,5-methanopyrido[ 1 ',2':4 s 5]pyrazmo[2 s i-b][l ,3]oxazepiri ⁇ 8 ⁇ olate present in the composition is Formula II, Form L disclosed herein, in certain embodiments, the composition includes at least about 50%, at least about 60%.
  • compositions comprising a polymorphic form disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of sodium (2R,5S s 13a ) » 7 3 9-dioxo-10- ⁇ (2,4,6 ⁇ trifluorobenz 'l)carbamoyi) ⁇ 2,3,4,5,7 s 9J3 s 13a-oetahydro-2,5- methanopwido[r,2 !
  • impurities make up less than about S%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic forms present.
  • Impurities may, for example, include by-products from synthesizing sodium (2R,5S,13aRV7 s 9-dk xo ⁇ 10- ⁇ (2 5 4,6-iritluoroben3 ⁇ 4d)earbamoy!) ⁇ 2.3,4,5,7,9, 13 ,13a ⁇ cctahydro-2,5 ⁇ methanopyrido[] ',2 !
  • impurities include by-products from the process of synthesizing sodium (2 .5S, 13aR)-7,9-dioxo- 10 -((2 4,6 Tifluoroben/,yl)carbamoyi ⁇ - 2,3,4,5,7,9, 3,13a-oetahydro-2,5-methanopyrido[ 1 ',2':4,5]p ⁇ azmo[2, 1 ⁇ b][ ⁇ ,3]oxazepin ⁇ 8- olate.
  • Impurities include contaminants from the process of synthesizing sodium (2R.5S, 13aR) ⁇ 7,9 ⁇ ⁇ ⁇ 10-((2,4,6 ⁇ iritluorobenz !carbarnoyi) - 2,3,4,5,7,9, 13,1.3a-octahydro ⁇ 2 5 5-memanopyrido[ 1 f ,2 i :4,5Jpyra?ino[2 1 ⁇ b][l,3]oxa2epm-8- olate.
  • impurities include degradation products of sodium
  • impurities include other polymorphic forms of sodium ⁇ 2R,5S, i3aR)-7,9-dioxo- i 0-((2,4,6- trifluorobenzy l)carbamoyl)-2, 3,4,5,7,9,13, 13 a-octaiiydro-2, 5- methanop>Tido[r,2';4,5
  • impurities include water or solvent.
  • impurities are selected from the group consisting of byproducts from synthesizing sodium (2R,5S, .! 3aR)-7 5 9-dioxo-10-((2,4,6"
  • the composition comprising Formula II, Form I disclosed herein has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1 % by weight of amorphous or no -crystal line sodium
  • the term "substantially pure” or “substantially free” with respect to a particular polymorphic form of a compound means that the composition comprising the polymorphic form contains less than 95%, less than 90%, less man 80%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other polymorphic forms and/or impuri ties.
  • substantially pure or “substantially fee of refers to a substance .free of other substances, including other polymorphic forms and/or impurities, impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.
  • compositions described herein can be prepared by combining a compound disclosed herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable earner, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as solid dispersions and solid solutions.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdsmiai, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal
  • the pharmaceutical compositions is prepared for oral administration.
  • the pharmaceutical compositions is a tablet.
  • Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition, to a patient.
  • compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention In aerosol form may hold a plurality of dosage units.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this ait; fo example, see Remington: TJie Science and Practice of Pharmacy ⁇ 20th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • the composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention for treatment of a disease or condition of interest in accordance with the teachings of this disclosure.
  • compositions disclosed herein may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection ears be prepared by combining a. compound of the invention with sterile, distilled water so as to fonts a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that rson-covalent!y interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous deliver ⁇ ' system,
  • a solid pharmaceutical composition intended for oral administration can be prepared by mixing a compound of the invention with at least one suitable pharmaceutical excipient to form a solid preformektson composition, which then may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • a pharmaceutical composition is provided, which includes a compound of Formula ( ⁇ ) and a pharmaceutical excipient.
  • the compounds disclosed herein are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drag combination; the severity of the particular disorder or condition; and the subject undergoing therapy, in some embodiments, the compounds of the invention can be administered alone or in combination with other antiviral agents once or twice daily for as long as the patient is infected, latently infected, or to prevent infection (e.g. for multiple years, months, weeks, or days).
  • a method for treating or preventing an HI V infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effecti ve amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • a method for treating as HIV infection m a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two. three, one or two, or one to three) additional therapeutic agents.
  • a method for treating an HIV infectio i a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • the present invention provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection,
  • One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method for treating or preventing an HTV infection in a human having or at risk of having the infection.
  • One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two. three, one or two, or one to three) additional therapeutic agents for use in a method for treating an HIV infection in a human having or at risk of having the infection.
  • One embodiment provides a compound disclosed herein for use in a method for treating or preventing an HTV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • One embodiment provides a compound disclosed herein for use in a method for treating an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • the present invention provides a compound disclosed herein in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection, for use in a method for treating an HIV infection, in certain embodiments, the present invention provides a compound disclosed herein tor use in a. method for treating an HIV infection, wherein the compound is administered in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection.
  • One embodiment provides the use of a compound disclosed herein thereof, in combination with one or more (e.g., one. two, three, one or two, or one to three) additional therapeutic agents in the manufacture of a medicament for treating or preventing an HIV infection in a human having or at risk of having the infection.
  • One embodiment pro vides the use of a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having the infection.
  • One embodiment provides the use of a compound disclosed herein in the manufacture of a medicament for treating or preventing an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination, with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • One embodiment provides the use of a compound disclosed herein thereof in the manufacture of a medicament for treating an HiV Infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • the present invention provides the use of a compound disclosed herein thereof in
  • the present invention provides the use of a compound disclosed herein thereof for treating an Hi V infection, wherein the compound is administered in combination with one or more additional therapeutic- agents which are suitable for treating an HIV infection.
  • a compound as disclosed herein may be combined with one or more additional therapentic agents in any dosage amount of the compound of Formula II (e.g., from 50 mg to 1000 mg of compound).
  • compositions comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • additional therapeutic agents comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
  • kits comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
  • the additional therapeutic agent may be an anti-
  • the additional therapeutic agent is selected from the group consisting of HTV protease inhibitors, HI V non-nuc!eoside inhibitors of reverse transcriptase, HTV ' nucleoside or nucleotide inhibitors of reverse transcriptase, HIV mtegTase inhibitors, HIY non-catalytic site (or allosteric) ituegra.se inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp4i inhibitors (i.e., firsion inhibitors) and CD4 attachment inhibitors), C.XC 4 inhibitors, gp.120 inhibitors, G6PD and NADH-oxidase inhibitors, compounds that target the HIV capsid ("capsid inhibitors"; e.g...
  • capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HiV, and combinations thereof.
  • the additional therapeutic agent may be an anil -HIV agent.
  • the additional therapeutic agent Is selected from the group consisting of HIV protease inhibitors, HiV non-nucleoside or non-nncieotide Inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non ⁇ eatai tie site (or allosteric) integrase inhibitors, HI V entry inhibitors (e.g., CCR5 inhibitors, gp4I inhibitors (I.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 Inhibitors, G6PD and NADH- oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PK)
  • PK protein kinase C
  • NCp7 inhibitors e.g., N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-N-N-phenyl-N-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phen
  • the additional therapeutic is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nncleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV imegrd.se inhibitors, HIY non-catalytic site (or allosteric) integrase inhibitors,
  • a compound of Formula (II) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV.
  • the tablet can contain another active ingredient for treating HIV, such as HI V protease inhibitors, HIV non ⁇ nucleosi.de or non-nucieotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase., i HV integrase inhibitors, HIV non-catalytic site (or allosterie) integrase inhibitors, pharmacokinetic enhancers, arid combinations thereof.
  • the tablet cm contain one or more active ingredients for treating HIV, such as HIV nucleoside or nucleotid inhibitors of reverse transcriptase. In certain embodiments, such tablets are suitable for once daily dosing.
  • the additional therapeutic agent is selected from one or more of:
  • HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir. Indinavir, lopkavir, ritonavir, nelf avir, saquinavir, tipranavir, brecanavir, daronavir, TMC-126, TMC-I 14, mozenavir (DMP-450), JE ⁇ 2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681. DPC-684,
  • HIV non-nucleoside or non-nuckotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, ddav dine, efavirenz, nevtrapine, (+) caianolide A, ctravirke, GW5634, DPC-0S3, DPC-96L DPC-963, MIV-150, TMC 20, rilptvirine, BILR 355 BS, VRX 840773, lersivirine (UK- 453061), RDEA8G6, KM023 and K-1439;
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the grou consisting of zidovudi ne, emtricitabme, didanosine, stavudine, zalcitabine, lamivudme. abacavir, abacavir sulfate, amdoxovir, elviieitabine, iovudine, MTV-210, d-.-FTC. D-d4FG, emtricitabme, phosphatide, fozivudine tidosii, aprieitibine
  • AVX754 KP-1461, GS-91 1 (Gilead Sciences), fosalwdine tidoxH (formerly HDP 99.0003), tenofovir, tenofovir disoproxil firmarate, tenofovir alafenamide, tenofovir ala&namide hemifemarate, tenofovir alafenamide fumarate (Gilead Sciences), GS- 7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 ⁇ Chimerix) and CMX-157 (Chimerix);
  • NICKI allosteric, integrase inhibitors
  • gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-i 144;
  • CCR5 inhibitors selected irons the group consisting of aplaviroc, vicriviroc, raaraviroc, cenicriviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer), and
  • CD4 attachment inhibitors selected from the group consisting of ibaflzumab (TMB-35S) and BMS-G68 (BMS-663068);
  • pharmacokinetic enhancers selected from the group consisting of cohicisiat and SP!-452;
  • the additional therapeutic agent Is selected from one s of:
  • STRIBILD® (elvitegravir+cobieistat+tenofovir disoproxil furaarate +emtricitabine) s doiuiegravir ⁇ - abacavsr sulfate +lamivudme, TRUJMEQ® (doiuiegravir + abacavir + lamivudine) , ianiivudine ⁇ nevirapine + zidovudine, dolutegravir+filpivirine, do ⁇ uiegra vi r t-r Ip ivi vine hydrochloride, atazanavir sulfate + ccbitistat atazanavk + eoblcistat, darutravir + cobieistai, efavirenz ⁇ lamivudine + tenofovir disoproxil fumarate.
  • HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosaraprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopmavir, ritonavir, nelfniavir, neifinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavrr, darunavir, DG-17, TMB-657 (PPL- .100) and TMC-31.091 1 ;
  • HIV non-nucleoside or non-nueleotide inhibitors of reverse transcriptase selected from the group consisting of delavirdine, delavirdme mesylate, nevirapine, ets-avirine, dapivirine, doravirine, rilpivirine, efavirenz, KM-023, VM-150Q, lentinan and AIC- 15 036757
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of VXDEX® and VIDEX® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, eensavudlne, abacavir, abacavir sulfate, amdoxovir, elwcitabine, atovudine, phosphazM, fbzivudine tidoxil, apriciiabme, amdoxovir 5 P-1461, fosatvudme tidoxil, tenofovir, tenofovir
  • HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, c icoric acid, derivatives of c coric acid, 3,5- dicaffeoylqainic acid, derivatives of 3,5 ⁇ dteaffeoylquii_ie acid, aurintricarboxylic acid, derivatives of aurmtriearboxylic acid, caffeic acid phenethyi ester, derivatives of eaffeic acid phenethyi ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raftegravit, dvitegravir, doJutegravir and caboiegravir;
  • NICKI aiiosteric, integrase inhibitors
  • HIV gp41 inhibitors selected from the group consisting of enfuvirtide. sifuvirtide and albuvirtide;
  • HIV entry inhibitors selected from the group consisting of cenicriviroc;
  • HIV gp!20 inhibitors selected from the group consisting of Radha-108 (Receptol) and BMS-663068;
  • CC 5 inhibitors selected from the group consisting of aplaviroe, demoiviroc, maraviroc ; cenicriviroc, PRO- 140, Adaptavir (RAP- 101), nifcviroc (TD-0232), TD- 0680, and vMXP (Hairnipu):
  • CD4 attachment inhibitors selected from, the group consisting of ibalizumab;
  • CXCR4 inhibitors selected from the group consisting of plerixafor. ALT- 1188, vMIP and Haimlpu; (12) Pharmacokinetic enhancers selected from the group consisting of cobiciscat and ritonavir;
  • Immune-based therapies selected, from the group consisting of dermaVir, interleukin-7, piaquem! (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon aita-2b. interferon alfa-n3, pegylated interferon.
  • HIV vaccines selected from the group consisting of peptide vaccines, recombinant s b nit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine), CD4-d.erived peptide vaccines, vaccme combinations, rgpl20 (AIDSVAX), ALVAC fflV (vCP1521)/AIDSVAX B/E
  • gpl 20 (RY144), monomeric gpl 20 HlV-1 subtype C vaccine (Movartis), Rsrnune, ⁇ -l, Centre Vif, Ad5 ⁇ ENYA ⁇ 48, DCVax-001 (CDX-24G1), PEP-6409 s Vaec-4x, Vace-CS, VAC-3S, multic!ade DNA recombinant adenovirus-5 (rAd5), Pemivax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, fflV-LAMP ⁇ vax, Ad3S s Ad35-G 1N, NAcGMB/VSSP 1SA-51, poly-ICLC adjuvanted.
  • vaccines Tatlmmune, GTU-multiHIV (FIT-06), AGS-004, gpI40[d taJV2.TVl+ MF-59, rVSVI ⁇ - ⁇ - ⁇ gag vaccine, SeV-Gag vaccine, AT-20, DN -4, Ad35-GRi /ENV 5 TBC-M4, HIV AX , HIVAX-2, NYVAC-HiV-Fri, YV AC-HIV-PT4, DNA-HIV- PT123, rAAVl-PG9DP f GOVX-BM, GOVX-B21 , ThV-01 , TUTX 6, VGX-3300, TVi-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41 JGR7C, EN41-FPA2, PreV ' axTat, TL-Oi, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, Y
  • HiV antibodies bispeclfic antibodies arx! "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TasdAbs ®, Fab derivatives) including BMS-936559, TMB-360 and those targeting HIV gp!20 or gp4i selected from the group consisting of bavituximab, UB- 21 , C2F5, C2G12, CAEW,
  • latency reversing agents selected from the group consisting of Historic deaeetylase inhibitors such as Romidepsin, vorinostat, panobhiostat; Proteasome inhibitors such as Velcade; protein kka.se C (FKC) activators such as Indoiacfam, Prostraiin, Ingenol B and DAG-lactones, lonomycin, G5K-343, PMA, SAHA, BRI inhibitors, IL- 15, JQ! , disulfram, and amphotericin B;
  • Historic deaeetylase inhibitors such as Romidepsin, vorinostat, panobhiostat
  • Proteasome inhibitors such as Velcade
  • protein kka.se C (FKC) activators such as Indoiacfam, Prostraiin, Ingenol B and DAG-lactones, lonomycin, G5K-343, PMA, SAHA, BRI inhibitors,
  • Np7 HIV nuclcocapsid p7 (NCp7) inhibitors selected from the group consisting of azodicarbonamide;
  • HIY maturation inhibitors selected from the group consisting of BMS-955176 and GSK.-2838232;
  • PI3K inhibitors selected from the group consisting of idelalis b, AZD-8180, bupariisib, CLR-457, pictilisib, neratinib, rigossrtib, rigoserlib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, tasdisib, XL-765, gedatoiisib, VS-SS84, copanlisib, CA1 orotate, perifosine, RG-7666, GSK-263677I, DS-7423, pamilistb, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY- 1082439, puqultimb mesylate, SAR-245409 . , AMG-3 J 9, RP-653G, Z
  • (22) other drugs for treating H!Y selected from the group consisting ofBaBl .ee, MK ⁇ 8507, AG-U05, TR-4S2, MK-8591, REP % CYT 07, alisporivi , NOV-205, TND- 02, metenkcfaiin, PGN-007, Aecmarman, Gammiune, Prolactin, 1 , 5 -dica feoylquinic acid, BIT-225, RPI- N, VSSP, Hlvirai, ⁇ -3 ⁇ 00, SB-728-T.
  • a compound disclosed herein is combined with two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein is combined with four additional therapeutic agents.
  • the two, three four or more additional iherapeuiic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents,
  • a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific
  • a compound disclosed herein is combined with an RTV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein is combined with an HI V nucleoside or nucleotide inhibitor of reverse ⁇ transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a
  • a compound disclosed herein Is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
  • a compound disclosed herein is combined with one, two, three, four or more additional therapeutic agents.
  • a compound disclosed herein is combined with one additional therapeutic agent.
  • a compound disclosed herein Is combined with two additional therapeutic agents, in other embodiments, a compound disclosed herein is combined with three additional therapeutic agents.
  • a compound disclosed herein is combined with four additional therapeutic agents.
  • the one, two, three, four or more additional therapeutic agents cam be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase arid an HIV non-nnckoside inhibitor of reverse transcriptase.
  • a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • & compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
  • a compound disclosed herein is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
  • a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
  • a compound disclosed herein is combined with abacavir, abacavir sulfate, tenofovir, tenofovir disoproxi! fumarate, tenofovir aiafenamide, or tenofovir aiafenamide hemifumarate,
  • a compound disclosed herein is combined with tenofovir, tenofovir disoproxi! fumarate, tenofovir aiafenamide, or tenofovir aiafenamide hemifumarate,
  • a compound disclosed herein is combined with a first additional therapeutic agent selected from tire group consisting of: abacavir, abacavir sulfate, tenofovir, tenofovir disoproxi! fumarate, tenofovir aiafenamide, and tenofovir aiafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and larnivudine,
  • a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil fimrarate, tenofovir aiafenamide., md tenofovir aiafenamide hemifumarate md a second additional therapeutic agent, wherein the second additional therapeutic agent is emiricidbine.
  • a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil fimrarate, tenofovir aiafenamide., md tenofovir aiafenamide hemifumarate md a second additional therapeutic agent, wherein the second additional therapeutic agent is emiricidbine.
  • a compound disclosed herein is combined with one, two, three, four or more additional therapeutic agents selected from Triumeq®
  • TDF+FTC maraviroe
  • enfuvirtide enfuvirtide
  • Epzicom® Livexa®, abacavir sulfate famivudme, AB03TC
  • Tnzivir® abacavir sulfiite+zidovudine+lamivudme
  • a compound disclosed herein is combined with abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ienofovir aiafenamide or tenofovir aiafenamide hemifumarate.
  • a compound disclosed herein is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate.
  • a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fuEwarate, tenofovir afafenam e, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtriciiabine and lamlv dine.
  • a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fuEwarate, tenofovir afafenam e, and tenofovir alafenamide hemifumarate
  • a second additional therapeutic agent selected from the group consisting of emtriciiabine and lamlv dine.
  • a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent wherein the second additional therapeutic agent is emtriciiabine.
  • a compound disciosed herein is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 rag tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein is combined with 10 mg tenofovir alafenamide fumarate. tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate., or tenofovir alafenamide and 200 mg emtricitabine. A compound as disciosed.
  • a compound of formula (II) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a compound disclosed herein is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil, tenofovir disoproxil fumarate, or tenofovir disoproxil hemifumarate and 200 mg emtricitabine.
  • a compound disclosed herein is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine.
  • a compound as disciosed herein e.g., a compound of formula (II)
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered In two or more administrations.
  • a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • a compound disclosed herein is administered with one or more additional therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic- agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient,
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or m inutes, in some
  • a unit dose of a compound disclosed herein Is administered first, followed, after a period of hours (e.g.. 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents, in other embodiments, a unit dose of one or .more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1 -12 hours), by administration of a unit dose of a compound disclosed herein. wms
  • the crystalline forms are characterized by the interiatti.ee plane intervals determ ned by an X-ray powder diffraction pattern (XRPD).
  • XRPD X-ray powder diffraction pattern
  • the di rractogram of XRPD is typically represented by a diagram plotting the intensity of the peaks versus the location of the peaks, i.e., diffraction angie 28 (two-theta) in degrees.
  • the intensities are often given in parenthesis with the following abbreviations; very strong - vst; strong - st; medium ⁇ m; weak ⁇ w; and very weak ⁇ vw.
  • the characteristic peaks of a given XRPD can be selected according to the peak locations and their relative intensity to conveniently distinguish this crystalline structure from others.
  • the measurements of the XRPD peak locations and/or intensity for a given crystal line form of the same compound will vary within a. margin of error.
  • the values of degree 2 ⁇ allow appropriate error margins.
  • the error margins are represented by For example, the degree 2 ⁇ of about "8.7 ⁇ 0.3" denotes a range from about 8.7+03, i.e., about 9,0, to about 8.7-0.3, i.e., about 8,4.
  • the appropriate error of margins for a XRPD can be ⁇ 0.5; 0.4; ⁇ 0.3; ⁇ 0.2; ⁇ 0, 1 ; ⁇ 0.05; or less.
  • the XRPD margin of error is ⁇ 0.2.
  • olaie e.g. a compound of Formula (II)
  • olaie e.g. a compound of Formula (II)
  • a method of producing a composition comprising one or more polymorphs of sodium (2R,5S ! 13a ) ⁇ 7 s 9-dioxo-10-((2,4 s 6- ffifluorobenzyl)carbanioyl) ⁇ 2,3,4 3 5J.9 5 13 s ] 3a-octehydro-2.5- methariopyrido[i , consider2 , :4,5 p ⁇ ' Tazino[2 5 l"b][l,3]oxazepin-8-olate 5 wherein the method comprises combining a compound of Formula (II.) with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the compound of Formula (if).
  • composition comprising one or more polymorphs of sodium (2R,5S,13aR)-7 repeatedly9-dioxo-10-((2,4,6- trifluorobenzyl)earbamoy 1) ⁇ 2, 3,4,5,7,9,13, 13 a ⁇ octahydro ⁇ 2 , 5 - mei aiiopyrido[i ⁇ 2 f :4,5]pyTazino[2J-b][L3]oxazepin-8-o!aie s wherein the method comprises combining sodium (2iL5S J I3aR)-7 s 9-dioxo-10-((2 5 4 s 6-irifSuorobenzyi)carbainoyl)-
  • Solvents suitable for polymorph formation may include, for example., methanol, etharsol water, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl isobufyl ketone, and any mixtures thereof,
  • composition comprising polymorphic Form 1 of sodium (2R,5S J 13aR)-7 3 9 ⁇ dioxo-i0 ⁇ ((2,4,6 ⁇
  • the solvent is selected from the group consisting of ethanol, dimethy!fonnamide, and any mixture thereof.
  • the solvent is a mixture of ethano! and d imet h ! formam ide .
  • methauopyrido[r ⁇ .';4,5]pyra2;mo[24-b][1 ]oxa2 «pio-8 ⁇ olate prepared by combining
  • the solvent is selected from the group consisting of ethanol, dimethyl. formaroide, and any mixture thereof. Irs an embodiment, the solvent is a mixture of ethanol and dimethyl formam ide.
  • polymorphs described herein in the manufacture of a drag product
  • the one or more of the polymorphic forms described herein may be used as an intermediate in the manufacturing process to produce the drug product.
  • compositions comprising one or more of sodium (2 .5S.13aR) ⁇ 7,9 ⁇ dioxo- 10 ⁇ -
  • the article of manufacture is a container comprising a dosage form of sodium (2R 3 5S 5 13aR)-7,9-dIoxo ⁇ i0-ii2 5 4,6 ⁇ irifi
  • the dosage form Is a tablet.
  • Kits also are contemplated.
  • a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition.
  • the instructions for use m the kit may be for treating HI V.
  • the Instructions for use in the kit may be for treating HIV,
  • the polymorphic and solvate forms descrihed herein may potentially exhibit improved properties.
  • the polymorphic and solvate forms described herein may potentially exhibit improved stability.
  • Improved stability could have a potentially beneficial Impact on the manufacture of the Compound of Formula i, such as for example offering the ability to store process
  • the polymorphic and solvate forms descrihed herein may also potentially result in improved yield of the Compound of Formula ⁇ , or potentially result In an Improvement of the quality of the Compound of Formula II.
  • the polymorphic and solvate forms described herein may also exhibit improved pharmacokinetic properties and/or potentially Improved bioavailability.
  • earboxamide (20 g) and ethanol (80 mL) were added to a reaction vessel and warned to about 75 °C.
  • Aqueous sodium hydroxide (22 mL 2 M solution) was added over
  • Figure 8 compares the calculated XRPD pattern of sodium (2R,5S,l3aR)-7 i 9> ⁇ ⁇ 10-( ⁇ 2,4,6- ⁇ 1 ⁇ ! ⁇ ) ⁇ ⁇ ⁇ )-2.3,4,5 ⁇ , ⁇ 3 ⁇ 3 ) ⁇ 3 ⁇ 2 5 5"
  • the space group which was uniquely defined by the systematic absences in the data, was found to be /3 ⁇ 42s2;.
  • the data were integrated using the Bruker SAINT software program and scaled using the SADABS software program.
  • Solution by direct methods produced a complete phasing model compatible with the proposed structure.
  • C is the concentration of the active at time A is the surface area of the tablet (-0.49 cm 2 ) and V is the volume of the media (500 mL).
  • active refers to the parent molecule, whose structure is shared by both Formula I and Formula II.
  • Solubility was determined in the following biorelevant media: 0,1 mM Fasted-State Simulated Gastric Fluid (FaSSGF) pH 1.6 (0,08 mM taurocholate, 0.02 mM lecithin, 34.2 mM NaCl); 18.75 mM Fed-State Simulated Intestinal Fluid (FeSSIF) pH 5 (IS mM taurocholate, 3,75 mM lecithin, 0, 12 M NaCl); and 3.75mM Fasted-State Simulated Intestinal Fluid (FaSSIF) pH 5 (3 mM tauroeholate. 0.75 mM lecithin, 0.10 M NaCl).
  • Each dosing group consisted of 6 male, non-naive purebred beagle dogs. At dosing, the animals weighed, between 10 to 13 kg. The animals were fasted overnight prior to dose administration and up to 4 hr after dosing. Each subject was pre -treated with pentagastrln (6 pg kg) and dosed 30 minutes later with a single 25 ?rsg strength tablet of Formula II Form I or Formula I Form III. Each subject was given .10 mL of water to aid in swallowing.
  • F (%) refers to oral bioavailability
  • AUG refers to area under the curve and Is a measure of total plasma exposure of the Indicated compound
  • C niax refers to the peak plasma concentration of the compound after administration.
  • T bki 30% active, 56% macrocrystalline cellulose, 13% crascarrodkise sodium, 5% magnesium stearate
  • Tahfet 30% active 56% microcrystailitie csllukise, 13% crosearmellose sodium, 1% magnesium stearate

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Abstract

The present Invention relates to 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.

Description

SODIIJM {2 !5S,I3AR)-7;9-DiOX0 t ((2,4s6--TRiFLUOROBENZYIJ)CARB^iOYL)- 2,3,4,5,7,9, 13,13A^CTAHYDRO-2,5-METHANOPYRmOi 1 \2':455]PYRAZINO[2, 1 -
B][] 53]O.XAZEPLN-8-OLATE
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit under 35 U.S.C. 119(e) of
U.S. Provisional Patent Application Serial No. 62/015,245, filed June 20, 2014, the disclosure of which is hereby incorporated by reference in its entirety.
FIELD
[0002] The present Invention relates to sodium (2R.5S, 13aR)-7;9»dioxo-10-({2,4,6~ trifiuoroben2yi}carbam.oyl)~2,3,4,5.7,9,13,13a-octahydro-2,5~
metha.nopyrido[rs2!:4,5]p> azirio[2)l-b][l,3]oxazepk-8-oiate, the crystalline forms, the pharmaceutical formulations, and the therapeutic uses thereof.
BACKGROUND
[0003] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type i (ΗϊΥ-l) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (PaleUa, et ai. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001 ) 410:995-1001).
[0004] A goal of amtiretrovir a! therapy is to achieve viral suppression in the HIV infected patient. Treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination therapies, he,, several drugs from at least two or more drug classes. In addition, decisions regarding the treatment of HIV infected patients are complicated when the patient requires treatment for other medical conditions. Because the standard of care requires the use of multiple different drugs to suppress HIV, as well as to treat other conditions the patient may be experiencing, the potential for drug interaction is a criterion for selection of a drag regimen. As such, there is a need for antiretrovirai therapies having a decreased potential for drug interactions.
[0005] As discussed in co-pending application United States Serial No. 14/133,855, filed December 19, 2013 entitled "POLYCYCLIC-C ARB AMO YLP Y IDONE
COMPOUNDS AND THEIR PHARMACEUTICAL USE", (2R,5S, BaR)~8-hydroxy-7,9- dioxo-N-(2,4,6~ f1uorobenzyl)--2,3,4)557,9,13J3a-octahydro-2J5- nethanopyridoi 1 ',2':4,S fpyrazinof 2, 1 -b] J. ,3'joxazepine- ί 0-earboxamide demonstrates antiviral activity. As discussed in co end g application PCX Serial No. US2G 13/076367, filed December 19, 2013 emitted "POLYCYCLIC-C ARB AMO YLP YRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE", (2R.5S, 13aR)-8-hydfOxy~7,9-dioxo-N-(2A6- iTil¾orobers2yi)-2,3,4,5,7,9, 13, .13 a-octahydro-2, 5 -methanopyrido 1 ',2':4,5]pyrazino[251 - b][l53]oxa¾pine-10-carboxamide demonstrates anti-viral activity.
[0006] (2R,5S, 13aR)-8¾-droxy~759-dioxo-N-(2 A6 r¾^
2,3,4,5,7,9 3 l3a-octehydro-2s5~me anopyr!do[l 2^"4,5]pyrazino[2,l-b][l,3]oxazeplne-10" carboxamide, (Formula I), has the following structure: I)
Figure imgf000003_0001
[0007] it is desired to have physically stable fomis of the compound that are suitable for the therapeutic use and the manufacturing process,
BRIEF SUMMARY
[0008] In certain embodiments, the present invention is directed to sodium
(2R,5S, 13aR)-7,9-<iioxi 10-((2,4,6 fii]«orobenzyl)carbamoyi)-2,3;45S,7,9, 13, 13a-octahydro- 2,5~meihariopyri.do[ ,2,:4,5]pyrazino[2, i-b][ls3]oxazepin-8-okte, having the following structure (Formula II);
Figure imgf000004_0001
[0009] In a still further embodiment, the present invention is directed to crystalline sodium (2R S513aR)~?J~ ioxo 0-{i2A6^
octahydro~2s5-methanopyrido[ 1 ^2';45S] 5¾msro[2 J -fo][l ,3jo.xazepin~8~okie,
[0010] in a still further embodiment, the present invention is directed to sodium
Figure imgf000004_0002
2,5-meftanopyrido[1^2!:4i5]pyrazmo[2,l-b][ls3]oxazepin--8-oiate Form L
[001.1] In a certain em o iment, the present invention is directed to pharmaceutical formulations comprising sodium (2R.5SJ 3aR)-?,9~dioxo-10-((2?4,6~
iTiiluorobenz )carbanioyl)-2 >435;7,9J3J3a-ociahydfo-2,5~
methanopyridoj 1 f 52':4, S ]pyraz;ino[2, Ϊ -b][ 1 ?3joxazepin-8-olate.
[00.12] in another embodiment, the present invention is directed to methods of treating or prophylactically preventing an HIV infection by administering sodium
(2Ry5S/l 3a )~7;9<lioxo 0^(2 A^ ^
255-methanopyrido[1^2':4,5]pyrazino[25l~b][lJ3 |oxazepin-8~ late.
[0013] In another embodiment, the present invention is directed to sodium
(2R,5S, 13aR)-7,9-dioxo- i0-<(2,4,6-trifluorobeozyi)carbamoy!)-2,354,5,7,9, 13, 13a-octahydro- 2,5-memanop ido[1^2!:45S]pyrazino[2,l"b][l,3]oxazepui-S-oiate tor use k methods of treating or prophylactically preventing an HIV infection,
[0014] In another embodiment, the present invention is directed to the use of sodium
(2S,5SS 13aR 7.9~dioxo- 10~({2J4,64Tifiuorobenzyi)carbamoyl)-2,3,4!5,7,9, .13S 13a~octahydro- 2,5"methanopyrido[l\2!:455]p azmo[2sl~b][1 ]oxazepiri--8-oiate in the manufacture of a medicament for treating or prophykcticaliy preventing an HIV infection.
DESCRIPTION OF THE FIGURES
[0015] Fi ure 1: XRPD pattern for sodium (2R,5SJ 3a }-7,9~dioxQ~i0-((2A6~ tnfluorobenzyl)car bamoy 1 )~2S 3,4, 5, 7, 9, 13, 13a-octahydro-2, 5 - meibanopyfido[r,2';4,5]p Tazino 2, l-b][l ,3]ox35:epIn-S-o1ats Form Ϊ.
[0016] F ure 2: DSC for sodium (2R, 5 S, 13 aR)-7s9~dioxo-.10-((2 ,4,6-
Figure imgf000005_0001
methan.opyrido[ii 52':455]pyi-azino[2, 1 -b] [1, joxazepi n-8-olaie Form L
[0017] Figssre 3; TGA for sodium (2 !5SJ3& .}-7i9-dioxo-10-((2,4,6'- trifl oroberizyl)carbamoyl)-2,3,4,5)7,9,13i13a-octahydro~2s5- methanopyrido[ ,2':4,5]ρ Τ ζίηο[2, 1 -b] 1 ,3]oxa7.epin~8-o!ate Form L
[0018] Figure it DVS for sodium (2 S5S, 13aR)-7,9-dioxD-10-((2A6- rriflu roben2yl)c-arbamoyl)~2,3J4,5i7J9, 13, 13a~octahydro-2,5~
Figure imgf000005_0002
[0019] Fi ure 5; Dissolution profiles of Formula I Form I, Formula I Form III. and
Formula II Form I.
[0020] Figure 6: Solubility profiles of Formula I Form E and Formula H Form Ϊ in
Fasied-Staie Simulated Gastric Fluid (FaSSGF).
[0021] Figure I Solubility profiles of Formula I Form Hi and Formula II Form I in
Fed-State Simulated Intestinal Fluid (FeSSIF) and Fasted-S ate Simulated Intestinal Fluid (FaSSIF).
[0022] Fi ure 8; Calculated and Experimental XRPD pattern for sodium
(2R,SS,13a'R)-7,9-diaxo 0-{(2A6~ rito
2s5-metbanopyrido[1^2!:4>5]p ra2ino[2/I-b][l?3]oxazepin~8H¾late FoB¾ I.
DETAILED DESCRIPTION
[0023] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details. The description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to foe construed to limit the claims in any way. Embodiments illustrated under any heading may he combined with embodiments illustrated under any other heading.
Definitions
[0024] Unless the context requires otherwise, throughout the present speci fication and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an opes, inclusive sense, that is as "including, but not limited to".
[0025] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner hi one or more embodiments,
[0026] The invention disclosed herein is also meant to encompass all
pharmaceutically acceptable compounds of Formulas (I) and (II) being isotopicaliy-iabeied by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ¾ ¾ C, ¾, "C, ¾, t5N, tsO, ¾ l80, 3¾ 3¾ 3SS, '% ¾ ml, and % respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically importan t site of action. Certain isotopieaily- iabeled compounds of Formulas (I) and (II), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, Le, 3H, and carbon- .14, le. i C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
[0027] Substitution with heavier isotopes such as deuterium, le. Ή, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances. [0028] Substitution with positron emitting isotopes, such as 11 C, :* 1S0 and J3N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy, isotopically-kbeled compo nds of Formulas (I) and (II) can generally be prepared by conventional techniques kno n to those skilled in fee art or by processes analogous to those described in the Examples as set out below usin an appropriate isotoplealiy-labeled reagent in place of the non-labeled reagent previously employed.
[0029] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity .from a reaction mixture, and formulation into an efficacious therapeutic agent.
[0030] "Optional" or "optionally" means thai the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description Includes both substituted aryl radicals and ary! radicals having no substitution.
[0031 ] "Pharmaceutically acceptable carrier, dil uent or exeipient" incS udes without limitation any adjuvant carrier, exeipient, gl ant, sweetening agent, diluent preservative, dye/colorant, .flavor enhancer, surfactant wetting agent, dispersing agent, suspending agent stabilizer, isotonic agent, solvent, or emulsifier which, has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals,
[0032] A "pharmaceutical composition" refers to a formulation of a. compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor,
[0033] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and Its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment the type of disease-state or disorder being treated and its severity, drugs used in combination with or eoincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
[0034] The term "treatment" as used herein is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the present invention post-exposure of the individ al to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the vims in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life, in certain embodiments, the term "treatment" as used herein is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient. In certain embodiments, the term "treatment" as used herein is further or alternatively intended to mean the administration of a compound or composition according to the present invention to maintain a reduced viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the present in ention postexposure of the individual to the virus but before the appearance of symptoms of the disease; and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. In certain embodiments, the term "treatment" as used herein is further or alternatively intended to mean, the admin stration of a compound or composition accordin g to the present Invention post-exposure of the individual to the virus as a subsequent or additional therapy to a first-line therapy (e.g., for maintenance of low viral load). [0035] "Prevention" or "preventing" means any treatment of a disease or condition thai causes the clinical symptoms of the disease or condition not to develop, The term "prevention" also encompasses the administration of a compound or composition according to the present invention pre-exposure of the individual to the virus {e.g., pre-exposure prophylaxis), to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching deteetible levels in the blood.
[0036] The terms "Subject" or "patient" refer to an animal, such as a mammal
(including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful m human therapy and/or veterinary applications. In some embodiments, the subject is a mammal, (or the patient). In some embodiments the subject (or the patient) is human, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), and/or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In one embodiment, the subject (or the patient) is a human. "Human (or patient) in need thereof refers to a human who may have or is suspect to have diseases or conditions that would benefit from certain treatment; for example, being treated with the compounds disclosed herein according to the present application.
[0037] The term "antiviral agent" as used herein is intended to mean an agent
(compound or biological) that is eifeciive to inhibit the formation and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a human being.
[0038] The term "inhibitor of HIV replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo or in vivo.
[0039] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tauiomers of any said compounds.
[0040] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X". Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to ' he assay" includes reference to one or more assays and equivalents thereof know* to those skilled in the it.
[0041] "Pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, sate, compositions, dosage forms and other materials which are use in preparing a pharmaceutical composition that is suitable t r veterinary or human
pharmaceutical use,
[0042] "Unit dosage forms" are physically discrete units suitable as unitary dosages for subjects (e.g., human subjects and other mammals), each unit containing a predetermined quant ity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
Formula II
[0043] It is desirable to develop a crystalline form of sodium (2R,5S,13aR)-7,9- dioxo- 10-{(2,4s6 rii!uorobes yI)carbamoyl)-2,3s455J;9s 13, 13a--octahydro-2,5~
methanopyrido 1 ',2!:4s5]pyrazino[2, 1 ~b][1 , 3 joxazepin-S-osaie that may be useful in the synthesis of sodium (2R,5S,13aR)"7,9~diox "10-({2J4564rifli5oroben ;yl)carhamoyl)- 2,3,4,5,7,9, 13, 1 a-octahydro-2,S-meihanopyrido[!. '52r:4,S]pyfazIno[2, 1 -b][l,3]oxazepin-§~ olate. A form of sodium (2Ri5S, I3aR)-759-dioxo~10-((2,4s6-irifiuorobenzyi)carbaaioyl)~ 2,3 ,4, 5,7,9, 13, 13 -octahydro-2. S~methanopyrldo[ 1 T :4, 5]pyrazmo[2» 1 -b] [ 1 ,3]oxazepm-8- olaie may be an intermediate to the synthesis of sodium (2R.5S, 13aR)~7,9-dsoxo~10~{{2,4,6 - irifluorobenzyS)carbamoyl)~2,3 ,4,5,7,9, 13, 1 a-octabydro-2,5- meihanopyridof 1 \2':4 ]pyra;dr)oi2, ! -bjj j 1 JJoxazepin-S-olate. A forrn of sodium
{2K,SS,i3aR)-7,9-dk xo~?.G~((2,4^
2J5~methanopyrido[i's2':4!,53pyra2mo[ >l-b][l53]oxa2:epin-8-oiate may be the final product in the synthesis of sodium (2R!5S, 13aR)-7;9-dio¾o 0-((2,456-trifluoroberizyl)carbamoy!)~ 2,3AS , 513?i3aH>ctahydro~2s5^Bet^^
olate, A polymorphic form or polymorph or eocrystai may have properties such as bioavailability and stability at certain conditions that may be suitable for medical or pharmaceutical uses.
[0044] A crystallme form of sodium (2R;5S,13aR)-7,9-dioxo-I0-((2?4,6~ irifluorobenzyI)carbamoyl)-2.354.557,9, 1.3, 13a~oetahydro~2,5- meChanopyrido[ 1 '.2!: 4 ,5 ]pyrazi.no[2, 1 -b] [ 1 ,3 ]oxazepin-8~olate may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical compossdon. In certain embodiments, a crystalline form sodium (2R,5 S, 13aB.)-?,9~dioxo~ 10- (( ^ ^ ifluoro enzy carbamo -a^^^,?^, ! 3J 3a-ocialtydro~2,f5- rnethas¾op3'rido[!! 52!:455]p Ta2;ino[2, i~b][l53]oxa2epm-8-olate provides an advantage of improved bioavailability (Table 3) and/or stability (Table 4), Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to
consistently prepare doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical dmg product or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or deliver}' forms, such as solid oral dosage form including tablets and capsules. Compared to other forms such as non-crystalline or amorphous forms, crystalline forms may provide desired or suitable hygroscopicky, particle size controls, dissolution rate, solubility, purity, physical and chemical stability manufacturability, yield, and/or process control. Thus, crystalline forms of sodium (2R, 5 S, 13a )-7,9-dioxo~l G~((2,4,6 T ifluOTobenz i^arbamoy -a-S.^SJ.^ B. iSa- octahydro-2,5-methanopyrido[i f,2!:4,5]pyrazko[25 l-h][ l,3]oxazepk~8~Qlate may provide advantages such as: improving the manu facturing process of an active agent or the stability or storability of a drug product form of the compound or an active ingredient, and/or having suitable bioavailability and/or stability as an active agent.
[0045] The use of certain solvents has been found to produce different polymorphic forms of sodium (2R .5$. 13a }~?59-dsoxo-1 0-((2,4,6-triflnorobenzyl)carbamoyl)~
23,4,5,7,9, 13, i 3a~octahydrO"255-mete
olate, including polymorphic Form Ϊ, which may exhibit one or more favorable characteristics described above. In certain embodiments, Form I of sodium (2 ,5S,13a )-7,9~dioxo~10- ((2,4,6 riiluoroben^I)carbaii3oyl)-2,3J4,5 59J3>13a-octahydro~2>5- meihanopyrido[r,2i:4,5Jpyra2ino 2, l~b][i53]oxazepin-S--olate provides an advantage of improved bioavailability (Table 3) and/or stability (Table 4), The processes for the preparation of the polymorphs described herein and characterization of these polymorphs are described in greater detail below.
[00 6] The compound name provided above is named using ChemBic raw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols. By way of example, the compound may be named or identified with common names, systematic or non- systematic names, The nomenclature systems and symbols that are eomraonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and international Union of Pure and Applied Chemistry (lUPAC). Accordingly, the compound stracture provided above may be named or identified as sodium (2R,5S513aR)-7,9-dioxo-10- ((254,6~triiluorobenzyl)carbamoyi)-253i4,5,7,9513, 1 :½-octahydro-2;5»
methanopyrido[i^2i:4„5]pyrazi.no[25l»b)[l,3]oxa2;epIsi-S-olate under IUPAC.
[0047] in particular embodiments, crystalline forms of sodium (2R,SS, l3aRV7,9- dloxo 0~((2,4,6 nfiuoroben7yl)^
methanopyrido[ 1. !,2' :4,5 jpyrazino[2.1 -b] [ 1 ,3]oxazepin-8-aiate are disclosed. Formula II Form I
[0048] in a certain embodiment novel forms of sodium (2R,5S, 13aR)-739"dioxo-10-
((2,4,6 rifluorober ;yl)carbamoyl)-2,3,4,5J,9J13J.3a»oc.tahydro-255-- methanopyrido[r,2!:4!5]pyrazmo[2,i-b][13]oxazepin-8-o!ate5 having the following stracture (Formula II) are disclosed:
Figure imgf000012_0001
|0049] In a further embodiment, crystalline forms of sodium (2R,5S, 13aR)-7,9-dioxo-
10-{(2,4!6-trifluorobemyl)cafbamoyl)~2s3,4s5 ,7,9,13 ,13a-octahydro-2,5-
Figure imgf000012_0002
disclosed.
[0050] In a certain embodiment sodium (2R,5S, 13a )-7,9-dioxo~10-{{2,4,6- trifluoroben yl)carbamoyl)~2, 3,4,5,7,9,13, 13 a-octahydro-2, 5 - metha op>Tido[r,2,:4,5]p)'razino[2sl-b] l,3]oxazepin-8-olate Form I is disclosed.
[0051] In one embodiment, provided is polymorphic Form I of sodium (2R,5S,13aR)~
7,9-dioxo- 10-((2,4,6-trifluorobenzyl)carb^oyl)-2}3s4s5,7,9s 13, 13a-octahydro-2,5- ffietlmo rido 1^2^"4,5] >^a^mo 2J -bJ i 3 ¾2¾ jR-S-oiaies wherein, the polymorph exhibits an X-ray powder diffraction (XRPD) pattern, substantially as shown in FIG. 1 and/or FIG. 8. Polymorphic sodium Form I may exhibit a differential scanning calorirnetry (DSC) thermogram substantially as shown in FIG, 2, Polymorphic sodium Form 1 may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 3, Polymorphic sodium Form I may exhibit dynamic "vapour sorption (DVS) graphs substantially as shown in PIG. 4.
[0052] The term "substantially as shown in" when referring, for example, to an
XSPD pattern, a DSC thermogram, or a TGA graph Includes a pattern, thermogram or graph that is not necessarily identical to those depicted herein, but that fails within the limits of experimental error or deviations when considered by one of ordinary- skill in the ait,
[0053] Polymorphic sodium Form I may have a unit cell as determined by crystal X~ ray crystallography of the following dimensions: a = 8.9561 (10) A; b = 13.9202 (14) A; c = 31 , 115 (3) A; a = 90 c; β - 90 c; and γ = 90 °.
[0054] in some embodiments of polymorphic sodium Form I, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight at least nine, or all of the following (a)~(j) a ly, (a) polymorphic Form I has an XRPD pattern substantially as shown in FIG 1 and/or FIG. S; (h) polymorphic sodium Form I has a DSC thermogram substantially as shown in FIG 2; (e) polymorphic sodium Form I has a TGA graph substantially as shown in FIG. 3; (d) polymorphic sodium Form Ϊ has DVS graphs substantially as shown in FIG. 4; (e) polymorphic sodium Form I has a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a = 8.9561 (10) A; b = 13.9202 (1.4) A; c - 31.115 (.3) A; = 90 °; β - 90 °; and γ - 90 °; (f) polymorphic sodium Form I has an orthorhombic crystal system; (g) polymorphic sodium Form I has a P212121 space group; (li) polymorphic sodium Form I has a volume of 3879.2(7) A3; (i) polymorphic Form I has a Z value of 4; and fj) polymorphic Form I has a density of 1.614 Mg mA
[00551 in some embodiments, polymorphic sodium Form I has at least one, at least two, at least three, at least four, or all of the following properties:
XRPD pattern substantially as shown in FIG. ! and/or FIG. b. a DSC thermogram substantially as shown in FIG. 2; c, TGA graphs substantially as sho n in FIG. 3; d. DVS graphs substantially as shown in FIG. 4; arid . a unit cell, as determined by crystal X-ray crystallography, of the following dimensions - 8.9561 (10) A; b = 13.9202 (14) A; c - 31.115 (3) A; a = 90 °; β - 90 c; and γ == 90 °;
[0056] In some embodiments, polymorphic sodium Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree IB-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 1 and/or FIG. 8.
[0057] In certain embodiments, polymorphic sodium Form I has an XRPD pattern comprising degree 20~refieeiions (+/- 0,2 degrees 2D) at 5.5, 16.1, and 23.3, In one embodiment, polymorphic sodium Form Ϊ has an XRPD pattern comprising degree 28- rcflections (+/- 0.2 degrees 2Θ) at 5,5, 16.1, and 23,3 and one or more of the degree 20- refiections (+/- 0,2 degrees 20) at 22.1, 28,5, and 22.5. In one embodiment, polymorphic sodium Form 1 has an XRPD pattern comprising degree 28-refleetions (■÷■/- 0.2 degrees 20) at 5.5, 16. i , and 23,3 and one of th degree 20-refieetions (+/- 0,2 degrees 28) at 22.1, 28.5, and 22,5. in one embodiment, polymorphic sodium Form I has an RPD pattern comprising degree 2e~reflections (+/- 0.2 degrees 28) at 5,5, 16,1, and 23.3 and two of the degree 28- reflections (+/- 0.2 degrees 2Θ) at 22, 1 , 28.5, and 22.5. In one embodiment, polymorphic sodkrai Form I has an XRPD pattern comprising degree 29-reflections {+/- 0.2 degrees 20) at 5,5, 16.1, and 23,3 and three of the degree 2e~reikctions (+/- 0.2 degrees 20) at 22.1, 28.5, and 22.5. In one embodiment, polymorphic sodium Form I has an XRPD pattern comprising degree 28-refiectioiis (+/- 0,2 degrees 2Θ) at 5,5, 16.1, 23,3, 22, 1 , 28.5, and 22.5, In one embodiment, polymorphic sodium Form I has an XRPD pattern comprising degree 20- reflections (-÷·/- 0.2 degrees 28) at 5,5, 16,1, 23.3, 22,1, 28.5, 22,5, 19.5, and 26.6. In one embodiment, polymorphic sodium Form Ϊ has an XRPD pattern comprising any three degree 20-re flections (+/~ 0.2 degrees 2Θ) selected from the group consisting of 5,5, 1 .1, 23.3, 22.1 , 28.5, 22,5, 19.5, 26.6, and 17.9. Pharmaceutical Compositions
[0058] For the purposes of administration, in certain embodiments, the compounds described herein are administered as a raw chemical or are formulated as pharmaceutical compositions. Ph rmaceutical compositions of the present invention comprise a compound of Formula (H), including forms and co-crystals thereof, and a pharmaceutically acceptable carrier, diluent or excipien t. The compound of Formula (II) is present in the composition in an amount which is effective to treat a particulaj- disease or condition of interest The activity of compounds of Formula (II) can be determined by one skilled in the art, for example, as described in co-pending application Serial No. 14/133,855, filed December 19, 2013 entitled "POLYCYCLIC-CARBAMOYLPYRIDO E COMPOUNDS AND THEIR
PHARMACEUTICAL USE", The activity of compounds of Formula (II) can also be determined by one skilled on the art, for example, as described in co-pending FC-T Serial No, US2013/076367, filed December 19, 2013 entitled, "POLYCYCLIC- CARBAMOYLPYRTDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE," Appropriate concentrations and dosages can be readily determined by one skilled in the art, in certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount from about 25 mg to about 500 mg, h certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 100 mg to about 300 mg. In certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 5 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 25 mg to about 100 mg. In certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition In an amount of about 50 mg to about 100 mg. in certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 5 mg to about 100 mg, in certain embodiments, a compound of Formula (II) is present in the pharmaceutical composition in an amount of about 5 mg, 25 mg, 50 mg, 75, mg, 100 mg, 200 mg, 300 mg, 400 mg or about 500 mg.
Formula II
[0059] Provided are also compositions comprising at least one polymorph (e.g., any one or more of Formula II polymorphic Forms I) as described herein, In a particular embodiment, a composition comprising Formula II polymorphic Form I, described herein is provided. In other embodiments, the compositions described here n may comprise substantially pure polymorphic forms, or may be substantially free of other polymorphs and/or impurities.
[0060] In some embodiments, the composition comprises a polymorphic form of sodium (2R,5S, 13aii)-?J9-dioso 0 (2,4s6 rifluoTObenzyl)carbanioyl)-2,3,4,Ss?;9> 13; 13a- oetahydro-2,5-methanopyrido[1^2':4,5]pyrazmo[2si-h][ls3]oxazepin-8-olate. In certain embodiments are provided compositions comprising a polymorphic form as described herein, wherein the sodium (2R55SJ3aR)-7,9~dioxo-10-({2,4,6~trifluoroberi2y!)carbarrioyl)- 2,3,4,5,7,9, 13, 13a-octahydro-2s5-methanop Tldo[r52i:4,5]pyrazmo[2!11 -b}[ L ]oxazepin-8- olate within t e composition is substantially pure {i.e., substantially pure Form Γ). in particular embodiments of compositions comprising a polymorphic form of sodium
<2R,SS, 13aR)-7 9-dioxo- 10-((254,64riiIuorobenz 'I)carbamoyi)-2,3,4,5,7s9 13, 13a-octahydsO- 2,S~methanopyrido 1^2,:455]pyTazmo[2s l-fo][I,3]oxazepin-8-oiate, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about §5%, at least about 90%, at least about 95%, at least about 96%, at least about. 97%, at least about 98%, or at least about 99% of sodium (2R,5S, 13aR)-7,9~dloxo- 10-((2,4564riiluorobenzyl)carbamoyl)- 2,3,4,5,7,9, .1 , 13a-oc ahydro-2,5-methanopyrido[ 1 ',2':4s5]pyrazmo[2s i-b][l ,3]oxazepiri~8~ olate present in the composition is Formula II, Form L disclosed herein, in certain embodiments, the composition includes at least about 50%, at least about 60%. at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of Form I of sodium (2RJS, ί 3aR)-7,9-djoxo- l.0-((2,4;6 rifluorobesi¾'i)carbamoyl)»2J3,4,5?7,9, 13, 13a-ociahydro- 2,5~msthanopyrido[ 1 :4, 5]pyrazino[2, 1 ~b] [ 1 s3]o¾azepm~§~olate,
[0061 ] In other embodiments of compositions comprising a polymorphic form disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of sodium (2R,5Ss13a )»739-dioxo-10-{(2,4,6~ trifluorobenz 'l)carbamoyi)~2,3,4,5,7s9J3s13a-oetahydro-2,5- methanopwido[r,2!:4,5]pyrazino[2,l-b][L3]oxazepin-8--oia.te present in the composition are other polymorphs of sodium (2R,5SJ3a )-7;9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyI)- 2,3,4,5,7,9,13,13a»oetahydro-2,5"methanopyrido[i;2!: 5]p rasino[2;l«bJ[l,3]oxazepin-8- oiate and/or impurities. [0062] In yet other embodiments of compositions comprising the polymorphic forms disclosed herein, impurities make up less than about S%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic forms present. Impurities may, for example, include by-products from synthesizing sodium (2R,5S,13aRV7s9-dk xo~10-{(254,6-iritluoroben¾d)earbamoy!)~ 2.3,4,5,7,9, 13 ,13a~cctahydro-2,5~methanopyrido[] ',2!:4,5]pyrazino[2} 1 -h][l,3]oxazepni-8~ olate, contaminants, degradation products, other polymorphic forms, amorphous form, water, and solvents. In certain embodiments, impurities Include by-products from the process of synthesizing sodium (2 .5S, 13aR)-7,9-dioxo- 10 -((2 4,6 Tifluoroben/,yl)carbamoyi}- 2,3,4,5,7,9, 3,13a-oetahydro-2,5-methanopyrido[ 1 ',2':4,5]p} azmo[2, 1 ~b][ ί ,3]oxazepin~8- olate. In certain embodiments, Impurities include contaminants from the process of synthesizing sodium (2R.5S, 13aR) ·7,9·<ϋοχο~ 10-((2,4,6~iritluorobenz !)carbarnoyi) - 2,3,4,5,7,9, 13,1.3a-octahydro~255-memanopyrido[ 1 f,2i:4,5Jpyra?ino[2 1 ~b][l,3]oxa2epm-8- olate. In certain embodiments, impurities include degradation products of sodium
(2¾5SJ3aR)-7.9^ioxe^lO^
2,5-methanopyrido[ 521:435]pyra2;ino(2, l~b][S;3]oxazepm-8--oIate. in certain embodiments, impurities include other polymorphic forms of sodium {2R,5S, i3aR)-7,9-dioxo- i 0-((2,4,6- trifluorobenzy l)carbamoyl)-2, 3,4,5,7,9,13, 13 a-octaiiydro-2, 5- methanop>Tido[r,2';4,5|pyrazino[2, l-b][i,33oxazepm~8-oSate. In certain embodiments, impurities include water or solvent. In certain embodiments of compositions comprising a polymorphic form disclosed herein, impurities are selected from the group consisting of byproducts from synthesizing sodium (2R,5S, .! 3aR)-759-dioxo-10-((2,4,6"
triiIuorobeazyl)carbamoyl)-2, 3 ,4, 5 , 7,9, 13 , 13 a~octahydro~2, 5 - methanopyrido[r,2":4,5]pyrazmo[2, 1 -b][l ,3]oxazepin-8-olate, contaminants, degradation products, other polymorphic forms, water, solvents and combinations thereof.
[0063] In yet other embodiments, the composition comprising Formula II, Form I disclosed herein has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1 % by weight of amorphous or no -crystal line sodium
(2R,5 S, 3aR)-7,9<Iioxo 0 (2 A6 rffi^
2,5-methanopyrido[i^2,:4,5]pyrazmo[2, l~b][L3]oxa epin-8"Olate,
[0064] In some embodiments, the term "substantially pure" or "substantially free" with respect to a particular polymorphic form of a compound means that the composition comprising the polymorphic form contains less than 95%, less than 90%, less man 80%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other polymorphic forms and/or impuri ties. In certain embodiments, "substantially pure" or "substantially fee of refers to a substance .free of other substances, including other polymorphic forms and/or impurities, impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.
Administration
[0065] Administration of the compounds disclosed herein in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities, The pharmaceutical compositions described herein can be prepared by combining a compound disclosed herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable earner, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as solid dispersions and solid solutions. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdsmiai, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal In one embodiment, the pharmaceutical compositions is prepared for oral administration. In a specific embodiment, the pharmaceutical compositions is a tablet. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition, to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention In aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this ait; fo example, see Remington: TJie Science and Practice of Pharmacy^ 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention for treatment of a disease or condition of interest in accordance with the teachings of this disclosure.
[0066] The pharmaceutical compositions disclosed herein may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection ears be prepared by combining a. compound of the invention with sterile, distilled water so as to fonts a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
Surfactants are compounds that rson-covalent!y interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous deliver}' system,
[0067] For example, a solid pharmaceutical composition intended for oral administration can be prepared by mixing a compound of the invention with at least one suitable pharmaceutical excipient to form a solid preformektson composition, which then may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Accordingly, in one embodiment, a pharmaceutical composition is provided, which includes a compound of Formula (Π) and a pharmaceutical excipient.
[0068] The compounds disclosed herein are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drag combination; the severity of the particular disorder or condition; and the subject undergoing therapy, in some embodiments, the compounds of the invention can be administered alone or in combination with other antiviral agents once or twice daily for as long as the patient is infected, latently infected, or to prevent infection (e.g. for multiple years, months, weeks, or days).
Combination Therapy
[0069] In one embodiment a method for treating or preventing an HI V infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effecti ve amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating as HIV infection m a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two. three, one or two, or one to three) additional therapeutic agents.
[0070] In. one embodiment;, a method for treating an HIV infectio i a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
[0071] In. certain embodiments, the present invention provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection,
[0072] One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method for treating or preventing an HTV infection in a human having or at risk of having the infection. One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two. three, one or two, or one to three) additional therapeutic agents for use in a method for treating an HIV infection in a human having or at risk of having the infection. One embodiment provides a compound disclosed herein for use in a method for treating or preventing an HTV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. One embodiment provides a compound disclosed herein for use in a method for treating an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In certain embodiments, the present invention provides a compound disclosed herein in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection, for use in a method for treating an HIV infection, in certain embodiments, the present invention provides a compound disclosed herein tor use in a. method for treating an HIV infection, wherein the compound is administered in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection.
[0073] One embodiment provides the use of a compound disclosed herein thereof, in combination with one or more (e.g., one. two, three, one or two, or one to three) additional therapeutic agents in the manufacture of a medicament for treating or preventing an HIV infection in a human having or at risk of having the infection. One embodiment pro vides the use of a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having the infection. One embodiment provides the use of a compound disclosed herein in the manufacture of a medicament for treating or preventing an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination, with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. One embodiment provides the use of a compound disclosed herein thereof in the manufacture of a medicament for treating an HiV Infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In certain embodiments, the present invention provides the use of a compound disclosed herein thereof in
combination with one or more additional therapeutic agents which are suitable for heating an HIV infection, in treating an HIV infection, in certain embodiments, the present invention provides the use of a compound disclosed herein thereof for treating an Hi V infection, wherein the compound is administered in combination with one or more additional therapeutic- agents which are suitable for treating an HIV infection.
[0074 ] A compound as disclosed herein (e.g., any compound of Formula (II)) may be combined with one or more additional therapentic agents in any dosage amount of the compound of Formula II (e.g., from 50 mg to 1000 mg of compound).
[0075] In one embodiment, pharmace tical compositions comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided. [0076] In one em odimen s combination pharmaceutical agents comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
[0077] In one embodiment, kits comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
[0078] In the above embodiments, the additional therapeutic agent may be an anti-
HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HTV protease inhibitors, HI V non-nuc!eoside inhibitors of reverse transcriptase, HTV' nucleoside or nucleotide inhibitors of reverse transcriptase, HIV mtegTase inhibitors, HIY non-catalytic site (or allosteric) ituegra.se inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp4i inhibitors (i.e., firsion inhibitors) and CD4 attachment inhibitors), C.XC 4 inhibitors, gp.120 inhibitors, G6PD and NADH-oxidase inhibitors, compounds that target the HIV capsid ("capsid inhibitors"; e.g.. capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HiV, and combinations thereof.
[0079] In other embodiments, the additional therapeutic agent may be an anil -HIV agent. For example, in some embodiments, the additional therapeutic agent Is selected from the group consisting of HIV protease inhibitors, HiV non-nucleoside or non-nncieotide Inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non~eatai tie site (or allosteric) integrase inhibitors, HI V entry inhibitors (e.g., CCR5 inhibitors, gp4I inhibitors (I.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 Inhibitors, G6PD and NADH- oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, and BRD4 inhibitors), compounds that target the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds, HIV nucieocapsld p? (NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-Ll modulators, toil like receptors modulators,, IL-15 agonists, ), HIV antibodies, hispeciflc antibodies and "antibody-like" therapeutic proteins U 2015/036757
(e.g., DARTs®, Duobodies©, Bites®, XmAbs®, TaadAbs ®, Fab derivatives) including those targeting HIV gp! 20 or gp41 , combination drugs for HIV. HIV p i 7 matrix, protein inhibitors, IL-I3 antagonists, Peptidyl-prolyl cis-trans isomerase A modulators. Protein disulfide isomerase inhibitors, Complement C5a receptor antagonists, D A methyitransferase inhibitor, Hi vif gene modulators, Yif dimerization antagonists, HIV- 1 viral infeetivify factor inhibitors, TAT protein inhibitors., HFV-1 Net" modulators, Hck tyrosine k nase modulators, mixed lineage kinase (MLK-3) inhibitors, HiV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, Nuekoprotein inhibitors, Splicing factor modulators, COMM domain containing protein 1 modulators, HIV Rihonudease H inhibitors, Retrocyclin modulators, CD -9 inhibitors, Dendritic ICAM-3 grabbing nonintegr i inhibitors, HIV GAG protei inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, Ubiquitin Hgase inhibitors, Deoxyeytidine kinase inhibitors, Cyc!ln dependent kinase inhibitors Proprotein eonvertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, HIV gene therapy, PI3K inhibitors, compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285 (Boehringer Irrgeiheim), US20140221380 (Japan. Tobacco),
US2014022.1378 (Japan Tobacco), WO 2010/1.30034 (Boehringer Ingelheim), WO
2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Giiead Sciences), WO2014/100323 (Gilead Sciences), W02QI2/145728 (Gilead Sciences), WO20I3/159064 (Giiead Sciences) and WO 2012/003498 (Gilead Sciences) and WO
2013/006792 (Pharma Resources), and. other drugs for treating HIV, arid combinations thereof.
[0080] In certain embodiments, the additional therapeutic is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nncleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV imegrd.se inhibitors, HIY non-catalytic site (or allosteric) integrase inhibitors,
pharmacokinetic enhancers, and combinations thereof.
[0081] la. certain embodiments a compound of Formula (II) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet can contain another active ingredient for treating HIV, such as HI V protease inhibitors, HIV non~nucleosi.de or non-nucieotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase., i HV integrase inhibitors, HIV non-catalytic site (or allosterie) integrase inhibitors, pharmacokinetic enhancers, arid combinations thereof. In certain embodiments, the tablet cm contain one or more active ingredients for treating HIV, such as HIV nucleoside or nucleotid inhibitors of reverse transcriptase. In certain embodiments, such tablets are suitable for once daily dosing.
[0082] In further embodiments, the additional therapeutic agent is selected from one or more of:
(1) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir. Indinavir, lopkavir, ritonavir, nelf avir, saquinavir, tipranavir, brecanavir, daronavir, TMC-126, TMC-I 14, mozenavir (DMP-450), JE~ 2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681. DPC-684,
GW640385X, 1X117, PPL-100, DG35, and AG 1859;
(2) HIV non-nucleoside or non-nuckotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, ddav dine, efavirenz, nevtrapine, (+) caianolide A, ctravirke, GW5634, DPC-0S3, DPC-96L DPC-963, MIV-150, TMC 20, rilptvirine, BILR 355 BS, VRX 840773, lersivirine (UK- 453061), RDEA8G6, KM023 and K-1439;
(3) HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the grou consisting of zidovudi ne, emtricitabme, didanosine, stavudine, zalcitabine, lamivudme. abacavir, abacavir sulfate, amdoxovir, elviieitabine, iovudine, MTV-210, d-.-FTC. D-d4FG, emtricitabme, phosphatide, fozivudine tidosii, aprieitibine
(AVX754), KP-1461, GS-91 1 (Gilead Sciences), fosalwdine tidoxH (formerly HDP 99.0003), tenofovir, tenofovir disoproxil firmarate, tenofovir alafenamide, tenofovir ala&namide hemifemarate, tenofovir alafenamide fumarate (Gilead Sciences), GS- 7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 {Chimerix) and CMX-157 (Chimerix);
(4) HiV integrase inhibitors seiected from the group consisting of curcismm, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5- dicaffeoylquinic acid, derivatives of 3,5-dicaSeoyIquinic acid, aurintricarboxyiic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethy ester, derivatives of caffeic acid phenethyl ester, fyrphosrin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, S 360, Ail- 177, L-870812, and 1.-870810, raltegravir, BMS-538158, GSK364735C, BMS-707G35, K-2048, BA Oi l, eivitegravir, doiutegravif, dolucegravir sodium, and GSK-744;
(6) HIV non-cata!ydc site, or allosteric, integrase inhibitors (NCINI) including, but not limited to, BI-224436, CX0516, CX0S045, CX14442, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim),
WO 2013/159064 (Giiead Sciences), WO 2012/145728 (Oiiead Sciences), WO 2012/003497 (Gslead Sciences), WO 2012/003498 (Giiead Sciences) each of which is incorporated by references in its entirety herein;
(7) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-i 144;
(8) the CXCR4 inhibitor AMD-070;
(9) the entry inhibitor SP01A;
(10) the g l 20 inhibitor BMS 488043;
(11) the G6PD and NADH-oxidase inhibitor immunitin;
(12) CCR5 inhibitors selected irons the group consisting of aplaviroc, vicriviroc, raaraviroc, cenicriviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer), and
CCR5mAb004;
(13) CD4 attachment inhibitors selected from the group consisting of ibaflzumab (TMB-35S) and BMS-G68 (BMS-663068);
(14) pharmacokinetic enhancers selected from the group consisting of cohicisiat and SP!-452; and
(1 5) other drugs for wealing HIV selected from the group consisting of BAS-iOO, SPI- 452, REP 9, SP-OIA, TNX-355, DES6, ODM~93; ODN-1 12, VGV-1. PA-457
(bevkimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99G07A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA- 1050040 (PA-040), and combinations thereof.
In certain embodiments, the additional therapeutic agent Is selected from one s of:
(1) Combination drags selected from the group consisting of ATR1PLA®
(efavirenz-f-t nofbvir disoproxil furaarate +emtricitabine), CO PI..ERA® or EViPLERA® (rilpi virme tenofovir disoproxil fumarate -femtridtabine),
STRIBILD® (elvitegravir+cobieistat+tenofovir disoproxil furaarate +emtricitabine)s doiuiegravir ·÷- abacavsr sulfate +lamivudme, TRUJMEQ® (doiuiegravir + abacavir + lamivudine) , ianiivudine ÷ nevirapine + zidovudine, dolutegravir+filpivirine, do ί uiegra vi r t-r Ip ivi vine hydrochloride, atazanavir sulfate + ccbitistat atazanavk + eoblcistat, darutravir + cobieistai, efavirenz ÷ lamivudine + tenofovir disoproxil fumarate. tenofovir alafenamlde hemifunwate + emtrle tabine + cobieistai ÷ elvitegravir, tenofovir alafenamlde hemifumarate + emtrleitabine, tenofovir alafenamide + emtriciiabine, tenofovir alafenamide hemifumarate ÷ emtricitahine + rilpivirine, tenofovir alafenamide + emtricitabine + rilpivirine s Vaec~4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate+ emtricitabine + eoblcistat, APH-0812, raltegravir + Ianiivudine, KALETRA® (ALUVIA®, lopkavir+ritouavir), atazanavir sulfate + ritonavir, COMBIVIR®
(zidovudine+lamivudine, AZT+3TC), EPZICOM® (Kivexa®, abacavir sulfate +lamivndines ABC+3TC), TRIZIVfR.® (abacavir suifate+zidovudme+lamivudine, ABC+AZT+3TC), TRUVADA® (tenofovir disoproxil fumarate Emtricitabine, TDF+FTC), doravirine + lamivudine + tenofovir disoproxil fumarate, doravirine + iamivudine ÷ tenofovir disoproxil, tenofovir + lamivudine and lamivudine + tenofovir disoproxil fcmarate;
(2) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosaraprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopmavir, ritonavir, nelfniavir, neifinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavrr, darunavir, DG-17, TMB-657 (PPL- .100) and TMC-31.091 1 ;
(3) HIV non-nucleoside or non-nueleotide inhibitors of reverse transcriptase selected from the group consisting of delavirdine, delavirdme mesylate, nevirapine, ets-avirine, dapivirine, doravirine, rilpivirine, efavirenz, KM-023, VM-150Q, lentinan and AIC- 15 036757
292;
(4) HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of VXDEX® and VIDEX® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, eensavudlne, abacavir, abacavir sulfate, amdoxovir, elwcitabine, atovudine, phosphazM, fbzivudine tidoxil, apriciiabme, amdoxovir 5 P-1461, fosatvudme tidoxil, tenofovir, tenofovir
disoproxil, tenofovir disoproxil furnarate, tenofovir disoproxi! hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenaaiide fumarate, adef vir, adefovir dipivoxii, and testinavir;
(5) HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, c icoric acid, derivatives of c coric acid, 3,5- dicaffeoylqainic acid, derivatives of 3,5~dteaffeoylquii_ie acid, aurintricarboxylic acid, derivatives of aurmtriearboxylic acid, caffeic acid phenethyi ester, derivatives of eaffeic acid phenethyi ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raftegravit, dvitegravir, doJutegravir and caboiegravir;
(6) HIV non-catalytic site, or aiiosteric, integrase inhibitors (NCINI) selected from the group consisting of CX-05168, CX-05045 and CX- 14442;
(?) HIV gp41 inhibitors selected from the group consisting of enfuvirtide. sifuvirtide and albuvirtide;
(8) HIV entry inhibitors selected from the group consisting of cenicriviroc;
(9) HIV gp!20 inhibitors selected from the group consisting of Radha-108 (Receptol) and BMS-663068;
(10) CC 5 inhibitors selected from the group consisting of aplaviroe, vieriviroc, maraviroc; cenicriviroc, PRO- 140, Adaptavir (RAP- 101), nifcviroc (TD-0232), TD- 0680, and vMXP (Hairnipu):
(11) CD4 attachment inhibitors selected from, the group consisting of ibalizumab;
(12) CXCR4 inhibitors selected from the group consisting of plerixafor. ALT- 1188, vMIP and Haimlpu; (13) Pharmacokinetic enhancers selected from the group consisting of cobiciscat and ritonavir;
(14) Immune-based therapies selected, from the group consisting of dermaVir, interleukin-7, piaquem! (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon aita-2b. interferon alfa-n3, pegylated interferon. alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MP A) and its ester derivative mycophenoiate mofetil (MMF)S WF-1G, ribavirin, i!.,-2, iL-12, polymer polyethyleneimme (PE ), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptors modulators (tlrl, tlr2, tir/3, tlr4, tir5, tM, tlr7, tlr8, tl?9, tlrlG, tlrl 1, tlr!2 and tlr!3)s rintatolimod and IR-I03;
(15) HIV vaccines selected from the group consisting of peptide vaccines, recombinant s b nit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine), CD4-d.erived peptide vaccines, vaccme combinations, rgpl20 (AIDSVAX), ALVAC fflV (vCP1521)/AIDSVAX B/E
(gpl 20) (RY144), monomeric gpl 20 HlV-1 subtype C vaccine (Movartis), Rsrnune, ίΤν-l, Centre Vif, Ad5~ENYA~48, DCVax-001 (CDX-24G1), PEP-6409sVaec-4x, Vace-CS, VAC-3S, multic!ade DNA recombinant adenovirus-5 (rAd5), Pemivax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, fflV-LAMP~vax, Ad3Ss Ad35-G 1N, NAcGMB/VSSP 1SA-51, poly-ICLC adjuvanted. vaccines, Tatlmmune, GTU-multiHIV (FIT-06), AGS-004, gpI40[d taJV2.TVl+ MF-59, rVSVI ϊ-Πν-ί gag vaccine, SeV-Gag vaccine, AT-20, DN -4, Ad35-GRi /ENV5 TBC-M4, HIV AX , HIVAX-2, NYVAC-HiV-Fri, YV AC-HIV-PT4, DNA-HIV- PT123, rAAVl-PG9DPf GOVX-BM, GOVX-B21 , ThV-01 , TUTX 6, VGX-3300, TVi-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41 JGR7C, EN41-FPA2, PreV'axTat, TL-Oi, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, YM- V201, MVA-CMDR, ETV-01, CDX 401 , rcAd26.MOSl ,HIY-Env and DNA~Ad5 gag/pot/nef/nev (HVTN5G5);
(16) HiV antibodies, bispeclfic antibodies arx! "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TasdAbs ®, Fab derivatives) including BMS-936559, TMB-360 and those targeting HIV gp!20 or gp4i selected from the group consisting of bavituximab, UB- 21 , C2F5, C2G12, CAEW,
C2F5÷C2G12+C4E10, 3-BNC-117 s PGT145, PGT121, MDX010 (ipilimumab). VRC01. Λ32. 7B2, 10E8, VRC-07-523 and VRC07;
(17) latency reversing agents selected from the group consisting of Historic deaeetylase inhibitors such as Romidepsin, vorinostat, panobhiostat; Proteasome inhibitors such as Velcade; protein kka.se C (FKC) activators such as Indoiacfam, Prostraiin, Ingenol B and DAG-lactones, lonomycin, G5K-343, PMA, SAHA, BRI inhibitors, IL- 15, JQ! , disulfram, and amphotericin B;
(18) HIV nuclcocapsid p7 (NCp7) inhibitors selected from the group consisting of azodicarbonamide;
(19) HIY maturation inhibitors selected from the group consisting of BMS-955176 and GSK.-2838232;
(20) PI3K inhibitors selected from the group consisting of idelalis b, AZD-8180, bupariisib, CLR-457, pictilisib, neratinib, rigossrtib, rigoserlib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, tasdisib, XL-765, gedatoiisib, VS-SS84, copanlisib, CA1 orotate, perifosine, RG-7666, GSK-263677I, DS-7423, pamilistb, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY- 1082439, puqultimb mesylate, SAR-245409., AMG-3 J 9, RP-653G, ZSTK.-474, MLN-1 1 17, SF-i .126, RV-1729, sonolisib, LY-3023414, SA -2603 and CLR- 1401 ;
(21) the compounds disclosed in WO 2004/096286 (Gi!ead Sciences), WO
2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO
2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO
2013/006792 (Pharma Resources), WO 2009/062285 (Boehringer Ingslheim), WO 2010/130034 (Boehringer Ingeiheim), WO 2013/0 1096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences),
WO2012/003497 (Gilead Sciences), WG2Q14/100323 (Gilead Sciences),
WO2012/145728 (Gilead Sciences), WO20I3/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and
(22) other drugs for treating H!Y selected from the group consisting ofBaBl .ee, MK~ 8507, AG-U05, TR-4S2, MK-8591, REP % CYT 07, alisporivi , NOV-205, TND- 02, metenkcfaiin, PGN-007, Aecmarman, Gammiune, Prolactin, 1 , 5 -dica feoylquinic acid, BIT-225, RPI- N, VSSP, Hlvirai, ΪΜΟ-3 Ι00, SB-728-T. RPI-MN, ViR-576, HGTV-43, M -1376, rHrV7-shI-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY-635, naltrexone, AAV-eCD4-Ig gene therapy <md PA-1050040 (PA- 040); and combinations thereof,
[0084] In certain embodiments, a compound disclosed herein is combined with two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein is combined with four additional therapeutic agents. The two, three four or more additional iherapeuiic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents, In a specific embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific
embodiment, a compound disclosed herein is combined with an RTV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment a compound disclosed herein is combined with an HI V nucleoside or nucleotide inhibitor of reverse ■transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a
pharmacokinetic enhancer. In another embodiment, a compound disclosed herein Is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
[0085] in certain embodiments, a compound disclosed herein, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein is combined with one additional therapeutic agent. In certain embodiments, a compound disclosed herein Is combined with two additional therapeutic agents, in other embodiments, a compound disclosed herein is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents cam be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents. In a specific embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase arid an HIV non-nnckoside inhibitor of reverse transcriptase. In another specific embodiment a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, & compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment a compound disclosed herein is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
[0086] In certain embodiments, a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
[0087] In a particular embodiment, a compound disclosed herein is combined with abacavir, abacavir sulfate, tenofovir, tenofovir disoproxi! fumarate, tenofovir aiafenamide, or tenofovir aiafenamide hemifumarate,
[0088] in a particular embodiment, a compound disclosed herein is combined with tenofovir, tenofovir disoproxi! fumarate, tenofovir aiafenamide, or tenofovir aiafenamide hemifumarate,
[0089] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from tire group consisting of: abacavir, abacavir sulfate, tenofovir, tenofovir disoproxi! fumarate, tenofovir aiafenamide, and tenofovir aiafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and larnivudine,
[0090] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil fimrarate, tenofovir aiafenamide., md tenofovir aiafenamide hemifumarate md a second additional therapeutic agent, wherein the second additional therapeutic agent is emiricidbine.
[0091] In a particular embodiment a compound disclosed herein is combined with one, two, three, four or more additional therapeutic agents selected from Triumeq®
(dotategravir+abacavir -HamiVudine), dolutegravir + abacavir sulfate + lamivudine, raltegravir, raltegravir + iamlvudine, Truvada® (tenofovir disoproxil fumarate
+emtricitabine, TDF+FTC), maraviroe, enfuvirtide , Epzicom® (Livexa®, abacavir sulfate famivudme, AB03TC), Tnzivir® (abacavir sulfiite+zidovudine+lamivudme,
ABC+AZT+3TC), adefovir, adefovir dipivoxil, Stribiid ® (eivitegravit-f-cobicistatHenofovir disoproxil fumarate +emtricitabine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine+tenofovir disoproxil fumarate +emtricitabhie), Cobicistat, atazanavir sulfate + cobicistat, atazanavir + cobicistat, darunavir ÷ cobicistat, Atripia®
(efavirenz+tenofovir disoproxil fumarate - emtricitebine), atazanavir, atazanavir sulfate, dolutegravk elvitegravir, Aluvia® (Kaleira©, lopinavir+ritonavir), ritonavir , emtrieitabine , atazanavir stdfate + ritonavir, darunavir, lamivudine, Prolastin, fosamprenavir, fosarnprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudsne, A2T+3TC), etravirine, nelfmavir, nelfmavir mesylate, mterferon, didanosme, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, deiavirdme, delavirdine mesylate, Radha~108 (Reeeptol), Hlviral, iamlvudine + tenofovir disoproxil fumarate, efavirenz + lamivudine + tenofovir disoproxil fumarate s phosphaz , lamivudine + nevirapine + zidovudine, abacavir, abacavir sulfate, tenoibvir, tenofovir disoproxil, tenofovir disoproxil fimiarate, darunavir + cobicistat, atazanavir sulfate ÷ cobicistat, atazanavir + cobicistat, tenofovir aiafenamide and tenofovir alafenamlde hemifumarate.
[0092] In a particular embodiment, a compound disclosed herein is combined with abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ienofovir aiafenamide or tenofovir aiafenamide hemifumarate.
[0093] in a particular embodiment, a compound disclosed herein is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate. tenofovir aiafenamide, or tenofovir aiafenamide hemifumarate. [0094] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fuEwarate, tenofovir afafenam e, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtriciiabine and lamlv dine.
[0095] In a particular embodiment, a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent wherein the second additional therapeutic agent is emtriciiabine.
[0096] In certain embodiments, a compound disciosed herein is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 rag tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 10 mg tenofovir alafenamide fumarate. tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate., or tenofovir alafenamide and 200 mg emtricitabine. A compound as disciosed. herein (e.g., a compound of formula (II)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
[0097] In certain embodiments, a compound disclosed herein is combined with 200-
400 mg tenofovir disproxil, tenofovir disoproxil fumarate, or tenofovir disoproxil hemifumarate and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil, tenofovir disoproxil fumarate, or tenofovir disoproxil hemifumarate and 200 mg emtricitabine. in certain embodiments, a compound disclosed herein is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. A compound as disciosed herein (e.g., a compound of formula (II)) may he combmed with the agents provided herein lit any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
[0098] in certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered In two or more administrations.
[0099] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
[0100] In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic- agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient,
[0101] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, i some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or m inutes, in some
embodiments, a unit dose of a compound disclosed herein Is administered first, followed, after a period of hours (e.g.. 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents, in other embodiments, a unit dose of one or .more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1 -12 hours), by administration of a unit dose of a compound disclosed herein. wms
[0102] In certain embodiments, the crystalline forms are characterized by the interiatti.ee plane intervals determ ned by an X-ray powder diffraction pattern (XRPD). The di rractogram of XRPD is typically represented by a diagram plotting the intensity of the peaks versus the location of the peaks, i.e., diffraction angie 28 (two-theta) in degrees. The intensities are often given in parenthesis with the following abbreviations; very strong - vst; strong - st; medium ~ m; weak ~ w; and very weak ~ vw. The characteristic peaks of a given XRPD can be selected according to the peak locations and their relative intensity to conveniently distinguish this crystalline structure from others.
[0103] Those skilled in the art recognize that the measurements of the XRPD peak locations and/or intensity for a given crystal line form of the same compound will vary within a. margin of error. The values of degree 2Θ allow appropriate error margins. Typically, the error margins are represented by For example, the degree 2Θ of about "8.7±0.3" denotes a range from about 8.7+03, i.e., about 9,0, to about 8.7-0.3, i.e., about 8,4. Depending on the sample preparation techniques, the calibration techniques applied to the instruments, human operational variation, and etc, those skilled in the art recognize that the appropriate error of margins for a XRPD can be ±0.5; 0.4; ±0.3; ±0.2; ±0, 1 ; ±0.05; or less. I s certain embodiments of the invention, the XRPD margin of error is ±0.2.
[0104] Additional details of the methods and equipment used for the XRPD analysis are described in the Examples section,
[0105] The XRPD peaks for the crystalline forms of sodium (2R,5S, 13aR)-7,9-dio io~ i0-{(2,456 Tiflnorobenz 4)carbamoyi)-2 ,4,5J?9J3s13a-ocrahydro-2,5-- methanopyridoi 1 \2':4,5]pyrazmo[2, 1 -b]{ i ,3 joxazepin-8-oiate (Formula II) of the present invention can be found below in Table 1
[0106] Table it XRPD peaks for crystalline forms of Formula II Form 1
Figure imgf000036_0001
Preparation of the Polymorphs
[0107] One method of synthesizing (2Rs5S,13a )~8-hydroxy-7i9~diQxo-N-(2J4,6- trifluorobenz>d)-2,3,4,5,759s 13, 13a-octahydro~2,5-met anopyrido[ 1 ',2':4,5 jpyrazmo(2, 1 - b][l,3] xazepine-10~carboxaraide (e.g. a compound of Formula (I)) has been previously described in PCT Publication No. WG2014/100323. This reference is hereby incorporated herein by reference in its entirety, and specifically with respect to the synthesis of
(2 ,5S 3aR 8 iydroxy-7,9~d^
2.5 -methanopyrido[ 1 '.2';4,5]pyrazino[2, 1 -b]( LSjoxazepine- 10-earboxamide. One method of synthesizing sodium (2 .5S, 13aR)-7s9-dioxo-10^(2,4,6~irifluorobe^
2,3?4,5 ,9 3 3a»oetahydrO"255~methanopyrido[1^2':4,S]p Tazino[2s^
olaie (e.g. a compound of Formula (II)) is described herein.
[0108] For example, in one aspect, provided is a method of producing a composition comprising one or more polymorphs of sodium (2R,5S!13a )~7s9-dioxo-10-((2,4s6- ffifluorobenzyl)carbanioyl)~2,3,435J.9513s ] 3a-octehydro-2.5- methariopyrido[i,„2,:4,5 p}'Tazino[25l"b][l,3]oxazepin-8-olate5 wherein the method comprises combining a compound of Formula (II.) with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the compound of Formula (if). In another aspect provided is another method of producing a composition comprising one or more polymorphs of sodium (2R,5S,13aR)-7„9-dioxo-10-((2,4,6- trifluorobenzyl)earbamoy 1)~2, 3,4,5,7,9,13, 13 a~octahydro~2 , 5 - mei aiiopyrido[i^2f:4,5]pyTazino[2J-b][L3]oxazepin-8-o!aies wherein the method comprises combining sodium (2iL5SJ I3aR)-7s9-dioxo-10-((254s6-irifSuorobenzyi)carbainoyl)-
2,3A3,7!9,13 3a-ociahydrQ~2s5-methanopyri^^
oiate with a suitable solvent or a mixture of suitable solvents,
[0109] The choice of a particular solvent or combination of solvents affects the formation favoring one polymorphic fomi of sodium (2R,5SJ3aR)~7.9~dioxo-i0~C{2,4,0~ trifluorobenzyl)carbamoyl)-2,3y4,557.9, 13, 1 '3a~octahydro~2,5- methanopyrido[r,2!:4s5]pyrazino[2sl-b][ l53]oxazepk-8"Olate over another. Solvents suitable for polymorph formation may include, for example., methanol, etharsol water, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl isobufyl ketone, and any mixtures thereof,
[0110] in another aspect, provided s also one or more polymorphs of sodium
(2R,5 S, 13aR.)-7,9-dioxo- 10-{(2s4,6 rifluorobenzyl)oarbamoyi)-2,3 ,4,5,7,9, 13,13a~oetahydro- 2,5-methanopyrido[r,2':4s5]p>Ta¾mof2, l-b][i,3]oxazepin-8-olate produced according to any of the methods described herein.
[01 1 1] It should, be understood that the methods for preparing the polymorphs described herein (including any polymorphic Form !) may yield quantity and quality differences compared to the methods for preparing sodium (2R,5S.13aR)-7,9-dioxo~ 0- ((2,4,6-trifluorobenzyl)carbamoy!)-2,3,4,5,7,¾ 13, 13a-ociahydro-2,5- methanopyrido[ 32':4,S]p>Tazino[2, l--b][].s3]oxazepm-8"Olate produced on laboratory scale,
Formula II, Form I
[0112] in one embodiment, provided is a method of producing a composition comprising polymorphic Form 1 of sodium (2R,5SJ13aR)-739~dioxo-i0~((2,4,6~
trifluorobenzyI)earbamoy f )~2? 3 ,4, 5, 7, , 13, 13 a-ociahydro-2, 5- metha.nopyrido[r,2':4,5]pyrazino[2s i-b][l53]oxa2epin~8~olate, wherein the method comprises combining
Figure imgf000037_0001
octahydro-2, 5 -methan pyr ido [ l :4, SJpyra^in [2, 1 -b] [1 ,3] oxazeplne- 1 -carboxamide with a sodium base {e.g. sodium hydroxide) in a solvent to produce a composition comprising polymorphic Form I of sodium (2R,5S,i 3a )-7,9-dioxo~10-((2,4s6- irif!uorobenzyI)caf bamoyl)-2,3 ,4,5,7, , 13, 13a-o€tahydro~2, 5- metftanopyrido[r,2':4J5]pyra2ino[2, l-b][i,3]oxazepin-8-oiate, wherein the solvent is selected from the group consisting of ethanol, dimethy!fonnamide, and any mixture thereof. In an embodiment, the solvent is a mixture of ethano! and d imet h ! formam ide .
[0113] Provided Is also polymorphic Form I of sodium (2R,5S, 1.3aR)-7,9-dioxo~10-
Figure imgf000038_0001
methauopyrido[r^.';4,5]pyra2;mo[24-b][1 ]oxa2«pio-8~olate prepared by combining
255~meihanopyrido[IV2!:4s5]pyrazino[2J~b][I ]oxazepke~10~earboxaraide with a sodium bass (e.g. sodium hydroxide) in a solvent, wherein the solvent is selected from the group consisting of ethanol, dimethyl. formaroide, and any mixture thereof. Irs an embodiment, the solvent is a mixture of ethanol and dimethyl formam ide.
Uses in Manufacturing of Drag Product
Formula II
[0114] Provided are also a use of the polymorphs described herein in the manufacture of a drag product The one or more of the polymorphic forms described herein (e.g., polymorphic Form Ϊ) may be used as an intermediate in the manufacturing process to produce the drug product.
[0 ! 15] Isi certain embodiments, Form I of sodium (2R,5S, 13aR)~7,9-dioxo- 10-((2s4 ~ irifl uorobenzyl)carhamoy!)-2J 3 ,4, 5, 759, 13 , 13 a-octahydro-2, 5- metlianopyrido[ s2!:4,5]pyra2ino[25l-b][l,3]oxazepiri-§~ola e are used in the manufacture of an active pharmaceutical ingredient.
Articles of Manufacture and Kits
(0116] Compositions comprising one or more of sodium (2 .5S.13aR)~7,9~dioxo- 10·-
{(2,4s6-tri£!uorobenzyi)carbanioyl)-2,3,4,S97,9s 13, 13a-octahydro~2,5- meihanopyrido[r,2,:455]pyfa2ino[2J -b][l,3]osazepta-8-olaie and formulated in one or more pharmaceutically acceptable carriers, excipients or other ingredients can be prepared, placed in m appropriate container, and labeled for treatment of an indicated condition, Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of one or more of sodium (2R.,5Ss13aR)-7s9-dioxo-.10-((254,6"
rifluoroben2y!)carbamoy))--2,:3,4, 5,7,9, ! 3, 13a-odahydro-2,5- ffietMnopyrido{ r>2':455]p Tazi3io[2,l-b][ls3]oxazepiri~8-olaie, and a label containing Instructions for use of the com ound^.
[0117] In some embodiments, the article of manufacture is a container comprising a dosage form of sodium (2R35S513aR)-7,9-dIoxo~i0-ii254,6~irifi
2,3,4,5,7,9, 13 J aH¾iahydro»235-methanopyxido[IV21:455]p Ta ino[2,l-b]|l,3]oxazepm-8~ olate, and one or more pharmaceutically acceptable carriers, exciplmts or other ingredients. In one embodiment of the articles of manufacture described herein, the dosage form. Is a tablet.
[0118] Kits also are contemplated. For example, a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. The instructions for use m the kit may be for treating HI V. In certain embodiments, the Instructions for use in the kit may be for treating HIV,
[01 19] In certain embodiments, the polymorphic and solvate forms descrihed herein may potentially exhibit improved properties. For example, in certain embodiments, the polymorphic and solvate forms described herein may potentially exhibit improved stability. Such Improved stability could have a potentially beneficial Impact on the manufacture of the Compound of Formula i, such as for example offering the ability to store process
intermediate for extended periods of time. Improved stability could also potentially benefit a composition or pharmaceutical composition of the Compound of Formula !L In certain embodiments, the polymorphic and solvate forms descrihed herein may also potentially result in improved yield of the Compound of Formula Π, or potentially result In an Improvement of the quality of the Compound of Formula II. In certain embodiments, the polymorphic and solvate forms described herein may also exhibit improved pharmacokinetic properties and/or potentially Improved bioavailability.
Methods
Synthesis
Sodium (2 5S,13(dy~7t9-dkM>~I0-(@t4t6-tr m
2J >S ,9 3 ~ociakydm^2s5-meth nopyrido[l 2i:4lS]pyr z^
olate (Formula Π) [0120] (2R, 5S,i 3aR)~8- ydroxy-7,9-d50Xo-N»(2,456-irifiuorobeHzyI)^
2,3,4,5,7.9,13, 13a~oeiahydfG«2s5-mefeanopyrMo^^
earboxamide (20 g) and ethanol (80 mL) were added to a reaction vessel and warned to about 75 °C. Aqueous sodium hydroxide (22 mL 2 M solution) was added over
approximately 30 minutes, after which the slurry was cooled to approximately 20 VC over approximately one hour. Sodium (2R,5SJ aR)-7,9-dioxo-I 0-((2,4,6- trifinorobenzyl)earhamoyI)-2.3 ,4, 5 ,7, , 13 , 13 a-octahydro-2, 5- met!ianopyrido[r,2,:4,5]pyfazino[2, l-b][l,33oxii7j pi!i-8-o[ate Form Ϊ was collected by filtration, washed with EtO.H (50 mL) and dried under vacuum.
[0121] 5H NMR (400 MHz, DMSOd6) δ 10.63 (t, J = 5.8 Hz, 1H), 7.88 (s, 1H), 7.29
- 7.07 (m, 2H), 5.20 (dd, J~ 8.6, 3.6 Hz, 1H), 5.09 (t, J::: 4.1 Hz, I H), 4.52 (m, 311), 4.35 (dd, J- 12.8, 3.6 Hz, 1H)9 3.87 (dd, J= 12.7, §.7 Hz, 1H), 2.03 - I.JO (m, 311), 1.76-1.64 (m, 2H), 1.50 - 1.40 (m, 1 H),
Characterization
[0122] Sod urn (2R,SS, 13aR)~7,9~dioxo- 10-{(2 A6- fluorobenzyl)carham
2,3,4,5,7,9, 13, 13a-ociahydro-2s5-methanop> 'ido[ r?2!;4,5]pyrazmo[2,l~b][l53]ox.azepm-8- olate Form I was characterized by various analytical techniques, including X-ray powder diffraction pattern (XPPD), differential scanning caiorimetry (DSC), thermographic asmlysis (TGA), and dynamic vapor sorption (DVS) using the procedures described below.
[0123] X~R y Powder Diffraction: XRPD analysis was conducted on a dif&actometer
(PANartalytical XPERT-PRO, PA analytical B.V., Atmelo, Netherlands) using copper radiation (Cu Κ , λ = 1,5418 A), Samples were prepared for analysis by depositing the powdered sample in the center of an aluminum holder equipped with a zero background plate. The generator was operated at a voltage of 45 kV and amperag of 40 mA. Slits sed were Soile.r 0,02 rad., antiscatter 1,0°, and divergence. The sample rotation speed was 2 sec- Scans were performed from 2 to 40° 2Θ during 5-15 mm with a step size of 0.0167° 2Θ. Data analysis was performed by X'Pert Highscore version 2.2c (PANalytical B.V., Aimelo, Netherlands) and X'Pert data viewer version ! .2d (PANalytical B.V., Aimelo, Netherlands).
[0124] The XRPD pattern for sodium (2¾585133Κ)-759^ίθχο~10-((2,4,β- trifiyorobenzyl)carbamoyl)~2>3,455;7,9513, 13a-oc iydro-2;5- meihanopyrido[r,2p:4,5]pyrazino[2, l~b][l.53]oxazepm-8~olate Form I is represented in Figure L The calculated XRPD pattern for sodium {2R,5S,13aR)~7s9-d!oxo-!0-({2s4,6- trifiuoroben l)carbamoyi)-2,3,4,5s7,9513, 13a-octahydro-2,5~
methanopyrido[ 1 !,2':4S5 jpyrai'.ino[2.1 -b]( 1 ,3]oxazepin-8-o!ate Form I represented in Figure 1 was calculated by using Mercury 3, 1 Development. (Build RCS). Single crystal data for sodium (2R,5S513aR)-7,9-dioxo- l 0-((254!6 rifiuoroben yl)carbamoyi)-2>3,4)5,7,9s 13, 13a- Qetahydro~2,5-rnethanop>Tido 1^2'A Form I was input Into Mercury 3, 1 Development (Build RCS) to calculate the XRPD pattern for sodium
Figure imgf000041_0001
2>5~methanopyrido[1^2i:4,5]pyrazmo[2,l-b][l,3]oxazepiri-B-olats Form L Bulk material, such as stoichiometry arlty between the temperature was obtained on a Rigaku Miniflex II XRD using power settings of 40kV, 15mA, scan speed of 2.0000 degrees per minute, a Miniflex 300/600 goniometer and an ASC-6 attachment, a scan range of 3.000 to 40.000 degrees, an incident slit of 1 .250 degress, a length, limiting slit of 10,0 mm, and SC-70 detector, a receiving slit #ί of 1.250 degrees, continuous scan mode, and a receiving slit #2 of 0,3mm, The sample was prepared by smoothing about. 20 mg of solids on a silicon disk mounted in a metal holder. Acquisition temperature was -21 °C,
[0125] The XRPD pattern for sodium (2R.5S, 13aR)-7,9-dioxo- 1 Q~ii2,4 S~ trifluorohenz}'l)carbamoyl)~2,3,4,S,7,9, 13, 13a~o tahydro-2,5- methariop ido[1^2':4,5]pyrazino[2, l --b][l,3]oxazepi.rs~8~oiate Form I is further represented in Figure 8. The calculated XRPD pattern .for sodium (2R,,55,13aR.)~7,9-dioxo 0-((2A6- Mfluorobenzy!)carbamoy 1 )~2, 3 A 3,7,9,13,13a~octahy dro-2, 5 - methanopyrido[r,2t:4,5]pyrazino[2s l-b][lJ3]oxazepin-8-oIate Form I represented in Figure 8 was calculated by using Mercury 3.1 Development (Build RCS). Single crystal data for sodium
Figure imgf000041_0002
octahydro-2J5~methauop>Tida[1 ^2,:4,5]p3 azmo[2 i-b][l ]oxasepm~8~oiate Form I was Input into Mercury 3.1 Development (Build RCS) to calculate the XRPD pattern for sodium (2R55S513aR)-7}9~dioxo^
2,5-methanopyrido[1^2,:455]pyradno Form I. Bulk material, such as stoic iometry arity between the temperature was obtained on a Rigaku Miniflex II XRD using power settings of 4GkV, ISrnA, scan speed of 2.0000 degrees per minute, a Miniflex 300/600 goniometer and an ASC-6 attachment a scan range of 3.000 to 40,000 degrees, an incident slit of 1.250 degress, a length limiting slit of 10.0 mm, and SC-70 detector, a receiving slit #1 of 1 ,250 degrees, continuous scan mode, artd a receiving slit #2 of 03mm, The sample was prepared by smoothing about 20 mg of solids on a silicon disk mounted in a metal holder. Acquisition temperature was -21 °C,
[0126] Figure 8 compares the calculated XRPD pattern of sodium (2R,5S,l3aR)-7i9> άϊο ο~10-({2,4,6-ίΓΪί1 ο^θί!Ζ^Ι)ο Λ θγί)-2.3,4,5^, ^3^3 )αΐ3ΗγάΓο~255"
methanopyrido[ 1 ',2 A,5 }pyrazmo[2, 1 ~b][ 1,3 joxazepin-8-olate Form Ϊ to the experimental XRPD pattern of sodium (2R55Ss13aR)~7,9~dioxo 0 C2A6~irIi}uorob^
2A4A7,943513a >ciahydre-2,5-methanopy
olate Form I. The comparison shows the degree to which the calculated XRPD and experimental XRPD agree. Strong agreement indicates the solved crystal structure is also the crystal structure of the material analyzed directly by XRPD. This determination can support orthogonal data, about the com position of the bulk material, such as sloichiometry,
[0127] XRPD peaks are found in Table 1 above.
[0128] Differential scanning c lorimeiry: Thermal properties of sodium
(2R SJ3aR)~7s9-dioxo~] ~((2-A64rifl
2,5~methanopyrido[1^2!:4?5]pyra ko[2Jl-b][i>3]oxa epin-8--olate Form I were evaluated using a Differential Scanning Calorimetry (DSC) instrument (TA QiOOO, TA instruments, New Castle, DE, USA). Approximately .1 to 10 mg of solid sample was placed in a standard aluminum pan vented with a pinhole for each experiment and heated at a rate of 10 "C/min under a 50 mL/tnh nitrogen purge. Data analysis was conducted using Universal Analysis 2000 Version 4.7 A (TA Instruments, New Castle, DE, USA). Heat of fusion analysis was conducted by sigmoidal integration of the endotherraic melting peak.
[0129] The DSC for sodium (2R,5S, .13aR)-789-dioxo-10-((2,4,6- trifluorobenzyl)carbamoy 1)~2, 3,4,5,7,9, 13, 13a~octahydro-2,5~
memanopyrido[1 ^2':4,Sjpyr3zino[2,l-b]( L3)oxazepin-8-olaie Form Ϊ is represented in Figure 2.
[0130] Thermo gravimetric analysis: Inermogravimetric analysis (TGA) of sodium
(2R,5S43aR)-7,9 tfoxo~10^(2A6-^
2,5-methanopyrido[i 2!:4,5]pyra ino 2,l--b][l,3]oxazepin-8-olate Form Ϊ was performed on a TGA instrumen (TA Q500, TA Instruments, New Castle, DE, USA). Approximately 1 to 10 mg of solid sample was placed In an open aluminum pan for each experiment and heated at a rate of 10 °C/min under a 60 mL min nitrogen purge using. Data analysis was conducted using Universal Analysis 2000 Version 4,7A (TA instruments, New Castle, DE, USA),
[0131 ] The TGA for sodium (2R,5S}i3aR)-7,9 ?ioxo~10~((2,4,6'~
trIf!uorobenzyl)c.arbamoyi)-2s3}4,5,7i9J.3513a-octahydro-2,5~
methanopyridof 1 ',2!:4,5 jpyrazinGj 2, 1 -b][ 1 ,3]oxazepin-8-olate Form I is represented in. Figure 3.
[0132] Dynamic vapor sorption'. The hygroscopicity of sodium (2R,SS, !3aRV7,9- dioxo-10-({2,4,6-tTifluorob nzyl)carbamoyI)~2 ,455,7,9; 13,13a-octahydro-2;5~
methanopyrido[rs2':4,5]pyrazirjo[25I»bl[l53]oxazepk"8~okte Form. I was evaluated at about 25 "C using a dynamic vapor sorption (DVS) instrument (TGA Q5000 TA Instruments, New Castle, DE). Water adsorption and desorption were studied as a function of relative humidity (RH) over the range of 0 to 90% at room temperature. The humidity in the chamber was increased from the initial level 50% RH to 60% RH and held until the solid and atmosphere reached equilibration. The equilibrium test was continued until passed or expired after 10 hours. At this point, RH was raised 10% higher and the process was repeated until 90% RH was reached and equilibrated. During this period, the water sorption was monitored. For desorption, the relative humidity was decreased in a similar manner to measure a full sorptlon/desorption cycle, The cycle was optionally repeated. All experiments were operated in dm/dt mode (mass variation over time) to determine the equilibratio endpoint
Approximately 3 mg of solid sodium (2R,5 13& )-7,9- ik)xo-l 0-((2,4,6- trifluoroberszy l)carhamoyI)~2, 3,4,5,7,9,13,13 a-octa ydro-2 , 5 - methanopyrido[ i ',2':4,S]pyTazino[X 1 -b][ i ,.3]oxazepin--8-olate was used. Data analysis was conducted using Universal Analysis 2000 Version 4,7.4 (TA Instruments, New Castle, DE, USA).
[0133] The DVS for sodium (2R,5S>13a )-7,9-dioxo-10-((2A6"
trifluorobenzyl)carbamoyl)-2,354,5J7?9, 13, 13a-octahydn 2,5- mefeano yridoi ^^^Sj yra inoPJ-bJi^SJoxazepin-g-olate For ? I is represented in Figure 4. [0134] The indexing data for Formula II Form 1 Is summarized hi Table 2 below.
Table 2% Indexing Data for Formula 11 Form I
Figure imgf000044_0001
[0135] The single crystal X-ray diffraction studies were carried out on a Bruker
APEX II Ultra diffractometer equipped with Mo « radiation (λ = 0.71073 A). Crystals of the subject compound were cut into a 0.22 x 0,18 x 0.04 mm section and mounted on a Cryoloop with Paratone-N oil. Data were collected in a nitrogen gas stream at 100 (2) K. A total of 15725 reflections were collected covering the indices, ~9<=h<~lQ} -! 3<:::£<-'-'- 6, - 37<==/<~36. 7163 reflections were found to be symmetry Independent, with a j¾nt of 0.0682. Indexing and unit-cell refinement indicated an orthorliombic lattice. The space group, which was uniquely defined by the systematic absences in the data, was found to be /¾2s2;. The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SHELXT) produced a complete phasing model compatible with the proposed structure.
[0136] All nonhydrogen atoms were refined amsotropically by full-matrix least- squares (SHF.LXL-2014). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command Ira SHELXL-2014. Crystalfographlc data are summarized in Table 2A. The absolute stereochemistry was set to conform, to previously studied samples of the same compound.
[0137] The single crystal X-ray crystallography data for Formula ii Form I Is summarized in Table 2A below. Table 2A: Single Crystal Data for Formula 11, Form !
Acquisition Space
Z Unit Cell Dimensions
C42 H34 F6 6 Temp, Group
Na2 Oi0
100(2) K P212121 4 Distance (A) Angle O
Form and Solvent in Density
Solvent a b c a
Identification lattice ( g/iti3) β Y
Formula ΪΪ 8.9561 13.9202 31.115
Ethanoi/DMF none 1.614
Form I (10) ( 14) 90 90 90
(3)
Dissolution Profile
[0138] The intrinsic dissolution profile of sodium (2R,5S313a )-759-dioxo-l0-((25436- irifluorobe!izyl)carbamoy 1)~2.3 ,4, 5 , 7,9» 13, 13 a-octafeydro-2, 5- methanopyrido[I',2':4,5]pyra2;mo[2, l-b][L3]oxazepirs-8-oiate (Formula Π) Form I of the present invention and the intrinsic dissolution profiles of Form Ϊ and Form Hi of Formula L the free acid, i2R,5S513aR)-8 iydroxy-?,9<lioxc>- -(2,436 rit]uorobertzy!).
Figure imgf000045_0001
earboxamide (disclosed is the co-pending United States Provisional Application 62/015,238 filed on June 20, 2014 titled CRYSTALLINE FORMS OF (2R,5S, 13 AR)~8~HYDR.OX Y-7,9- D10XO- ~(2,4.6-T iFi/ )ROBENZYL)-2!354!S)7, > 13,13A-OCTAHYDRO-2,5- METFiANOPYRiDO[r,2,:4s5]PYRAZ]NO[2,l-Bl[l33]OXAZEPiNE-i 0- CARBOXAMIDE), were measured by characterizing API dissolution from a constant surface area. Approximately ISO mg of the drug substance was compressed at 1500 psi for approximately 3 seconds using a hydraulic press (Carver Press, Fred Carver, NJ„ USA). The compressed drug substance formed a fl t disk (surface area -0.49 crrT), which was mounted onto a dissolution apparatus (Yars ei industries Inc., Edison, NJ, VK7000, i !20A~02S8). The rotating disk (1 0 rpm) was then lowered into the dissolution medium (500 mL of O.OIN HCl) which was equilibrated to 37il°C. Samples were pulled at pre-determined time points and drug concentrations were measured using an appropriate UPLC-UY method. The intrinsic dissolution rate constant (K) was calculated using the following equation;
[01.391 Where C is the concentration of the active at time A is the surface area of the tablet (-0.49 cm2) and V is the volume of the media (500 mL). Note that the term active as used herein refers to the parent molecule, whose structure is shared by both Formula I and Formula II.
[0140] The dissolution profiles can be found, in Figure 5,
Solubility
[0141] The solubility of the sodium form of the present invention and the free acid,
(2R,5S, 13aR)-g-hydroxy»759-dioxo~N~.(2!4,6-trifIuorobeiizyl)-2,354,5>7,9, 13, 13a-octahydro- 2,5-rnethanopyridoi 1 ',2':4,5 ]pyrazino[2, 1 ~b][ 1 ,3 Joxazepine-! 0~earboxa?nide Form 10 in biorelevant media was determined at room temperature as a function of time. Solubility was determined in the following biorelevant media: 0,1 mM Fasted-State Simulated Gastric Fluid (FaSSGF) pH 1.6 (0,08 mM taurocholate, 0.02 mM lecithin, 34.2 mM NaCl); 18.75 mM Fed-State Simulated Intestinal Fluid (FeSSIF) pH 5 (IS mM taurocholate, 3,75 mM lecithin, 0, 12 M NaCl); and 3.75mM Fasted-State Simulated Intestinal Fluid (FaSSIF) pH 5 (3 mM tauroeholate. 0.75 mM lecithin, 0.10 M NaCl). Approximately 20 mg of die drug substance was mixed on a magnetic stir-plate in 50 mL of biorelevant media, Samples (~-l mL) were pulled every 5-10 min for 2 hours. The samples were immediately filtered/centrifuged for 10 min in a Spirt-X tube equipped with a 0.45 μηι nylon filter. The resulting filtrate was analyzed using an appropriate UPLC-UV method,
[0142] The solubility profiles in FaSSGF can be found m Fignre 6, The solubility profiles in FeSSIF and FaSSIF can be found in Figure 7.
Bioavailability
[0143] The bioavailability of sodium (2Κ,58, 138Κ)~7,9^ϊοχο-10-((2,4,6~ trifluoroberay^car amo ^^J^jS JsBj a-octahydro-l^- methanopyrido[rs2>:4,5]pyTazino[2, l~b][i ,3]oxazepiri-8-olate (Fonnuia 11) Form Ϊ was compared to the bioavailability of (2Rs5Ssi3aR)-S~hydroxy»7,9~dioxo-N-(2,456- iriiiuorobenzyl)~2,3AS,7^^
b3[I,3]ox^epine~10"carboxamide (Formula I) Form III.
[0144] Each dosing group consisted of 6 male, non-naive purebred beagle dogs. At dosing, the animals weighed, between 10 to 13 kg. The animals were fasted overnight prior to dose administration and up to 4 hr after dosing. Each subject was pre -treated with pentagastrln (6 pg kg) and dosed 30 minutes later with a single 25 ?rsg strength tablet of Formula II Form I or Formula I Form III. Each subject was given .10 mL of water to aid in swallowing.
[01 5] Serial venous blood samples (approximately ! ml, each) were taken from each animal at 0, 0.250, 0.483, 0.583, 0.750, LOO, 1.50, 2.00, 4.00, 8.00, 12.0, and 24.0 hours after dosing. The blood samples were collected into Vacuiainer™ tubes containing EDTA- 2 as the and -coagulant and were immediately placed on wet ice pending centri&gation for plasma. An LC/MS/MS method was used to measure the concentration of the test compound in plasma. An aliquot of 100 p.L of each plasma sample was added to a clean 96 weii plate, and 400 pL of cold acetonitrile/internal standard solution (ACN)/(iSTD) was added. After protein precipitation, an aliquot of 110 pL of the supernatant was transferred to a clean 96- well plate and diluted with 300 μL· of water. An aliquot of 25 μL· of the above solution was injected into a TSQ Quantum Ultra LC/MS/MS system utilizing a Hypersil Gold Cl8 BPLC column (50 X 3.0 mm, 5 pm; Ther o-Hyperssi Part # 25105-053030). An Agilent 1200 series binary pump (P/N G1312A Bin Pump) was used for elution and separation, and an HTS Pal autosa.mpl.er (LEAP Technologies, Carrboro, NC) was used for sample injection. A TSQ Quantum Ultra triple quadrupole mass spectrometer was utilized in selective reaction monitoring mode (Thermo Flnnigan, San Jose, CA), Liquid chromatography was performed using two mobile phases: mobile phase A contained 1% acetonitrile In 2.5 inM ammonium formate aqueous solution with pH of 3.0, and mobile phase B contained 90% acetonitrile in 10 mM ammonium formate with pH of 4,6, Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The resulting data are shown In Table 3: F (%) refers to oral bioavailability; AUG refers to area under the curve and Is a measure of total plasma exposure of the Indicated compound; Cniax refers to the peak plasma concentration of the compound after administration.
Table 3i Bioavailability of sodium (2R,5Ss13aR)-7,9-dioxo»10-((2;456- tr ifluorobenzyl)carbamoyI)-2,3 ,4,5,7,9, 13, 13a-oc ahydro-2,5- methanopyrldo[l, J2,:4,51pyrazino[25 i --b][i,3]oKazepIn»8--olate Form I and (2R55S,13aR)-8- bydroxy-7,9-dioxo- ~(2,4.6-trifiuorohenzyl)-2,334,5,7,9,i3s l 3a-octahydro-2,5- methanopyrido[l \2!:4,S]pyrazino[2, 1 -b][ 1 ,3 joxazepine- 1 O-carhoxar de Form III. T bki: 30% active, 56% macrocrystalline cellulose, 13% crascarrodkise sodium, 5% magnesium stearate
Tahfet 30% active, 56% microcrystailitie csllukise, 13% crosearmellose sodium, 1% magnesium stearate
The stability of sodium (2R,5S,13aR)-7;9-dioxo-10~({2,4,6- irS fiuorobenzyl)carbaffioyi)-2,354?5,7,9, 13,13a-octahydfO-2,5- mei¾anopyrido[r,2^i4,5]pyrazrao[2 -b]S_'i!3] xiizepjn-8-olaie Form 1 was tested. As seen in Table 4, below, the compound is stable after four weeks of storage under accelerated conditions. In Table 5, AN refers to area normalization and is the relative peak area of the active with respect to other impurities and components contained in the sample. LS refers to labile strength and is the amount of active present relative to the theoretical amount,
Table 4; Stability of sodium (2R,5S,i3a )»7,9-dioxo-ie^{ ,4,6- trifl!sor besxy^esrb mo ^-SjS^^jTj jiSjl^a- etaliydro^jS- mefhaso yddo l^ '^sSl y ^imi l^-hHl^JoxK in-S-iilate Fo m I
Figure imgf000048_0001
[0147] Each of the references including all patents, patent applications and publications cited in the present application is incorporated herein by reference in its entirety, as if each of them is individually incorporated. Further, it would be appreciated that, in the above teaching of invention, the skilled in the art could make certain changes or
modifications to the invention, and these equivalents would still be within the scope of the invention defined by the appended claim s of the application. Each of the references inc lud ing ail patents, patent applications and publications cited In the present application Is incorporated herein by reference in its entirety, as i f each of them Is individually
incorporated, Further, it would be appreciated that, in the above teaching of Invention, the skilled in the art could make certain changes or modifications to tire invention, and these equivalents would still be within the scope of the Invention defmed by the appended claims of the application.

Claims

What is Claimed:
A compound of Formula II:
Figure imgf000050_0001
2. The compound of claim 1, characterized by being crystalline.
3. The compound of claim 2, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 5.5°, 16.1°, and 233° 2-Θ ± 0,2° 2-0,
4, The compound of claim 3, wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 22. , and 28.5° 2-Θ ± 0.2" 2-0,
5. The compound of claim 4, wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 22.5 and 19,5° 2-0 ± 0,2° 2-Θ.
6, The compound of claim 5, wherein the x-ray powder diffraction (XRPD) pattern has further peaks at about 26.6° and 17,9° 2-8 ± 0.2° 2-Θ.
7, The compound of claim 2, characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in Figure I.
8. The compoimd of claim 2, characterized by differential scanning caiorimetry (DSC) pattern substantially as set forth in Figure 2.
9. The compoimd of daim 2, characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in Figure 4,
10. The compound of any one of claims 1 to 9, characterized in being partially or ly hydrated.
11. The compound of any one of claims 1 to 9, characterized in being anhydrous or essentially anhydrous.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to II, and a pharmaceutically acceptable carrier or excipient,
13. The pharmaceutical composition of claim 12, further comprising one to three additional therapeutic agents.
14. The pharmaceutical composition of claim 13, wherein the additional therapeutic agents are each anti-HIV drugs.
15. The pharmaceutical composition of claim 13 or claim 14, 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
SO of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and other drugs tor treating HIV,
16. The pharmaceutical composition of any one of claims 12 to 14, wherein at least two of the additional therapeutic agents are each HiV nucleoside inhibitors of reverse
transcriptase.
17. T he pharmaceutical composition of claim 12, further comprising tenofovir disoproxi! fu arate and emtricitabine,
18. The pharmaceutical composition of claim 12, further comprising tenofovir alafenamide and emtricitabine.
19. The pharmaceutical composition of claim 12, further comprising tenofovir alafenamide hemifumarate and emtricitabine.
20. The pharmaceutical composition of any one of claims 12 to 18, wherein the pharmaceutical composition is in a unit dosage form.
21. The pharmaceutical composition of claim 20. wherein the unit dosage form is a tablet.
22 Use of a compound of any one of claims 1 to 11 for treating or prophylactic-ally preventing an HIV infection.
SI
23. Use of a compound of any one of claims 1. to 12 for the manufacture of a medicament for treating or pfophylaetically preventing an HIV infection,
24. A compound of arty one of claims 1 to 11 for use in a method for treating or proph lacticaSly preventing an HIV Infection,
25. A meAod for treating or prophylactically preventing an HIV mfection in a human in need thereof, comprising administering to the human a therapeutically effeciive amount of a compound of any one of claims I to 11.
PCT/US2015/036757 2014-06-20 2015-06-19 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] oxazepin-8-olate WO2015196116A1 (en)

Priority Applications (35)

Application Number Priority Date Filing Date Title
MA40239A MA40239B1 (en) 2014-06-20 2015-06-18 (2r, 5s, 13aR) -7,9-dioxo-10 - ((2,4,6-trifluorobenzyl) carbamoyl) -2,3,4,5,7,9,13,13a-octahydro-2,5 sodium methanopyrido [1 ', 2': 4,5] pyrazino [2,1-b] oxazepin-8-olate
AP2016009591A AP2016009591A0 (en) 2014-06-20 2015-06-19 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] oxazepin-8-olate
CU2016000187A CU24478B1 (en) 2014-06-20 2015-06-19 (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] PIRAZINO [2,1-B] [1,3] OXAZEPIN-8-SODIUM OLATE
BR122021025861-9A BR122021025861B1 (en) 2014-06-20 2015-06-19 USE OF (2R, 5S, 13AR)-7,9-DIOXO-10-((2,4,6-TRIFLUOROBENZYL)CARBAMOYL)-2,3,4,5,7,9,13,13A-OCTAHYDRO-2 ,5-METHANOPIRID [1,2:4,5] PYRAZINE [2,1-B][1,3] OXAZEPIN-SODIUM 8-OLATE
KR1020177001377A KR101899803B1 (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
CR20160589A CR20160589A (en) 2014-06-20 2015-06-19 (2R, 5S, 13aR) -7,9-dioxo -10 - ((2,4,6-trifluorobenzyl) carbamoyl) -2,3,4,5,7,9,13,13a-octahydro-2,5 -methanopyrid [1´, 2´: 4,5] pyrazino [2,1-b] [1,3] oxazepin-8-sodium olate
JP2016574180A JP6334007B2 (en) 2014-06-20 2015-06-19 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] oxazepine-8-olate
EA201692414A EA030967B1 (en) 2014-06-20 2015-06-19 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
NZ727155A NZ727155A (en) 2014-06-20 2015-06-19 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
SI201530163T SI3157932T1 (en) 2014-06-20 2015-06-19 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)oxazepin-8-olate
MX2016016059A MX369555B (en) 2014-06-20 2015-06-19 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] oxazepin-8-olate.
LTEP15739063.4T LT3157932T (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
AU2015276860A AU2015276860B2 (en) 2014-06-20 2015-06-19 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
BR112016029605-2A BR112016029605B1 (en) 2014-06-20 2015-06-19 CRYSTALLINE FORM OF (2R, 5S, 13AR) -7,9-DIOXO-10-((2,4,6-TRIFLUOROBENZYL) CARBAMOYL) -2, 3, 4, 5, 7, 9, 13, 13A-OCTAHYDRO- 2, 5-METANOPIRID [1,2: 4,5] PYRAZINE [2,1-B] [1,3] OXAZEPIN-8-OLATE SODIUM, AND PHARMACEUTICAL COMPOSITION
PL15739063T PL3157932T3 (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
RS20180286A RS56950B1 (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
SG11201610211QA SG11201610211QA (en) 2014-06-20 2015-06-19 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] oxazepin-8-olate
ES15739063.4T ES2660862T3 (en) 2014-06-20 2015-06-19 Sodium (2R, 5S, 13aR) -7,9-dioxo-10 - ((2,4,6-trifluorobenzyl) carbamoyl) -2,3,4,5,7,9,13,13a-octahydro-2, 5-methanopyrid [1?, 2?: 4,5] pyrazino [2,1-b] [1,3] oxazepine-8-olate
DK15739063.4T DK3157932T3 (en) 2014-06-20 2015-06-19 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] oxazepine-8-OLAT
US15/320,656 US20170197985A1 (en) 2014-06-20 2015-06-19 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
MDA20180037A MD20180037A2 (en) 2014-06-20 2015-06-19 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
EP15739063.4A EP3157932B1 (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
UAA201613232A UA118480C2 (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
MDA20170006A MD4584C1 (en) 2014-06-20 2015-06-19 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
MEP-2018-73A ME03037B (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
MYPI2016704591A MY186696A (en) 2014-06-20 2015-06-19 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]oxazepin-8-olate
CA2950307A CA2950307C (en) 2014-06-20 2015-06-19 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
CN201580033152.4A CN106459085B (en) 2014-06-20 2015-06-19 Anti-HIV-1 compounds and its crystal form
IL249161A IL249161B (en) 2014-06-20 2016-11-23 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] oxazepin-8-olate
PH12016502499A PH12016502499A1 (en) 2014-06-20 2016-12-14 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
SV2016005339A SV2016005339A (en) 2014-06-20 2016-12-16 (2R, 5S, 13AR) -7,9-DIOXO-10 - ((2,4,6-TRIFLUOROBENCIL) CARBAMOIL) -2,3,4,5,7,9,13,13A-OCTAHIDRO-2,5 -METANOPIRIDO [1 ', 2': 4,5] PIRAZINO [2,1-B] [1,3] OXAZEPIN-8-SODIUM OLATO
ZA2016/08744A ZA201608744B (en) 2014-06-20 2016-12-19 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] oxazepin-8-olate
CY20181100305T CY1120025T1 (en) 2014-06-20 2018-03-13 (2R, 5S, 13AR) -7,9-Dioxo-10 - ((2,4,6-trifluorobenzyl) carbamoyl) -2,3,4,5,7,9,13,13-octahydro-2,5 -Methanol pyride [1 ', 2': 4.5] PYRAZINE [2,1-B] OXAZEPIN-8-OLIVE Sodium
HRP20180455TT HRP20180455T1 (en) 2014-06-20 2018-03-16 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]oxazepin-8-olate
AU2018203175A AU2018203175B2 (en) 2014-06-20 2018-05-08 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

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