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WO2018042331A1 - Combinaisons, utilisations et traitements correspondants - Google Patents

Combinaisons, utilisations et traitements correspondants Download PDF

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Publication number
WO2018042331A1
WO2018042331A1 PCT/IB2017/055184 IB2017055184W WO2018042331A1 WO 2018042331 A1 WO2018042331 A1 WO 2018042331A1 IB 2017055184 W IB2017055184 W IB 2017055184W WO 2018042331 A1 WO2018042331 A1 WO 2018042331A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
compound
formula
taf
Prior art date
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Ceased
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PCT/IB2017/055184
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English (en)
Inventor
Brian Alvin Johns
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GlaxoSmithKline Intellectual Property No 2 Ltd
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GlaxoSmithKline Intellectual Property No 2 Ltd
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Publication of WO2018042331A1 publication Critical patent/WO2018042331A1/fr
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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

Definitions

  • Human immunodeficiency virus infection and related diseases are a major public health problem worldwide.
  • Human immunodeficiency virus type 1 (HTV-1) encodes three enzymes that are required for viral replication: reverse transcriptase, protease, and integrase.
  • a goal of antiretroviral therapy is to achieve viral suppression in the HIV-infected human.
  • 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, i.e., several drugs from at least two or more drug classes.
  • the present inventors have identified a combination of therapeutic agents, uses thereof, and associated methods of treatment with advantages over previously known agents and combinations.
  • this invention provides a combination comprising a compound of TAF (formula I):
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, in association with one or more therapeutically acceptable carriers therefor.
  • this invention provides a combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, a
  • immunodeficiency virus in a human, comprising administering to the human a therapeutically effective amount of TAF, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
  • TAF or a pharmaceutically acceptable salt thereof
  • the compound of formula II, or a pharmaceutically acceptable salt thereof are coadministered in separate dosage forms.
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are coadministered in a single dosage form.
  • this method further comprises administering an agent chosen from: emtricitabine and lamivudine.
  • this invention provides a method for preventing human immunodeficiency virus (HIV) in a human, comprising administering to the human a therapeutically effective amount of TAF (formula I):
  • this invention provides a pharmaceutical composition comprising a therapeutically effective amount of TAF (formula I):
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, wherein said composition further comprises an agent chosen from: emtricitabine and lamivudine.
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, wherein said composition further comprises emtricitabine and ritonavir
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, wherein said composition further comprises emtricitabine and cobicistat
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, wherein said composition further comprises lamivudine.
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, wherein said composition further comprises lamivudine and ritonavir
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, wherein said composition further comprises lamivudine and cobicistat.
  • this invention provides a kit comprising:
  • composition comprising TAF, or a pharmaceutically acceptable salt thereof
  • composition comprising the compound of formula II, or a
  • Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor that is marketed for the treatment of HIV/ AIDS and has the structure of formula I:
  • TAF isopropyl (2S)-2- [ [ [( li?)-2-(6-aminopurin-9-yl)- 1 -methyl- ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate.
  • TAF is a pro-drug of tenofovir.
  • MI HIV maturation inhibitors
  • the compound of formula II is 4-(((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((R)-2-((4- Chlorobenzyl)(2-(dim- ethylamino)ethyl)amino)- 1 -hydroxyethyl)-l -isopropyl-5a,5b,8,8, 11a- pentamet- hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13,13a-octadecahydro- 2H- of formula II are described in US Patent 9,102,685.
  • TAF and/or the compound of formula II may contain one or more chiral atoms, or may otherwise be capable of existing as enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers, as well as purified enantiomers or
  • One embodiment of the invention provides a method for treating HIV infection in a human comprising administering to the human a therapeutically effective amount of the compound of formula I (TAF):
  • Another embodiment of the invention provides a method for preventing HIV infection in a human comprising administering to the human a therapeutically effective amount of the compound of formula I (TAF):
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are co- administered in separate dosage forms.
  • TAF or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are coadministered in a single dosage form.
  • TAF or a pharmaceutically acceptable salt thereof
  • the compound of formula II, or a pharmaceutically acceptable salt thereof is administered parenterally.
  • TAF is administered in a long-acting parenteral and/or implantable formulation.
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are both administered orally.
  • compositions comprising TAF, or a
  • compositions consisting essentially of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • compositions consisting of TAF, or a
  • combinations consisting of TAF, or a pharmaceutically acceptable salt thereof; and a compound of formula II, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, diluents or excipients are provided.
  • Another embodiment provides further administration of at least one antiretroviral compound.
  • a method for treating an HIV infection in a human comprising administering to the human a therapeutically effective amount of TAF, or a
  • One embodiment of the invention provides a method for treating HIV infection in a human comprising administering to the human a therapeutically effective amount of TAF, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of the compound of formula II, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for treating an HIV infection.
  • the present disclosure provides a method for preventing an HIV infection, comprising administering to a human a therapeutically effective amount of TAF and the compound of formula II, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for preventing an HIV infection.
  • the present disclosure provides a method for preventing an HIV infection, comprising administering to a human a therapeutically effective amount of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for treating an HIV infection.
  • pharmaceutical compositions comprising TAF, or a
  • TAF or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one to two, or one to three) additional therapeutic agents, and a therapeutically acceptable carrier, diluent or excipient are provided.
  • TAF, or a pharmaceutically acceptable salt thereof is administered orally to assess its safety and tolerability, and, if no or low issue in safety and tolerability is found (called "oral-lead method"), then TAF, or a pharmaceutically
  • kits comprising TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, in oral and/or parenteral dosage forms are provided. Certain such kits comprise TAF in a syringe dosage or tablet dosage form, and the compound of formula II in a syringe dosage or tablet dosage form. According to another embodiment, there is provided the use of a combination, including TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, for the treatment of HIV In the above embodiments, the additional therapeutic agent may be an anti-HIV agent.
  • the additional therapeutic agent is chosen from: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, MK-8591 (EFdA), HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, other 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., HIV capsid inhibitor
  • HIV methyltransferase inhibitor HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HTV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrorocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors,
  • the additional therapeutic is chosen from: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are formulated as a tablet that may optionally contain one or more other compounds useful for treating HIV.
  • the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
  • such tablets are suitable for once daily dosing.
  • the additional therapeutic agent may be chosen from one or more of:
  • Combination drugs chosen from: ATRIPLA ® (efavirenz+tenofovir disoproxil fumarate+emtricitabine ), COMPLERA ® (EVIPLERA ® , rilpivirine+tenofovir disoproxil fumarate+emtricitabine ), STRIBILD ® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine), lamivudine+nevirapine+zidovu dine, atazanavir sulfate+cobicistat, darunavir+cobicistat, efavirenz+lamivudine+tenofovir disoproxil fumarate, Vacc- 4x+romidepsin, APH-0812, raltegravir+lamivudine, KALETRA ® (ALUVIA ® , lopinavir ritonavir ), atazanavir sulf
  • HIV protease inhibitors chosen from: amprenavir, atazanavir, fosamprenavir, fosam- prenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB- 657 (PPL-100), TMC-310911, and TMB-657;
  • HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase chosen from: delavirdine, delavirdine mesylate, nevirapine, (+), etravirine, dapivirine, doravirine, efavirenz, KM023, VM-1500, lentinan, AIC-292, EFdA (4'-Ethynyl-2- Fluoro-2'-Deoxyadenosine, or otherwise known as MK-8591), ENDURA T ®
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase chosen from:
  • VIDEX ® and VIDEX ® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, phosphazid, fozivudine tidoxil, apricitabine, amdoxovir, KP-1461, fosalvudinetidoxil, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hernifumarate, adefovir, adefovir dipivoxil, festinavir, and MK-8591 (EFdA).
  • HIV integrase inhibitors chosen from: raltegravir, elitegravir, cabotegravir, dolutegravir (TIVICAY ® ), and bictegravir; (6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) chosen from: CX-05168; CX-05045; CX-14442. (7) HIV gp41 inhibitors chosen from: enfuvirtide, sifuvirtide and albuvirtide;
  • HIV entry inhibitors such as combinectin
  • HIV gpl20 inhibitors chosen from: Radha-108 (Receptol) and BMS-663068;
  • CCR5 inhibitors chosen from: aplaviroc, vicriviroc, maraviroc, cenicriviroc, PR0- 140, Adaptavir (RAP-101), nifeviroc (TD-0232), TD-0680, TBR-220 (TAK-220) and vMIP (Haimipu);
  • CD4 attachment inhibitors such as ibalizumab
  • CXCR4 inhibitors chosen from: plerixafor, ALT-1188, vMIP and Haimipu;
  • Pharmacokinetic enhancers or boosting agents chosen from: cobicistat (TYBOST ® ), ritonavir (NORVIR ® ), and SPI-452;
  • Immune-based therapies chosen from: dermaVir, interleukin-7, lexgenleucel-T (VRX-496), plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferonalfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-2 XL, IL-12, polymer polyethyleneimine
  • HIV vaccines chosen from: peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine), CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDS VAX ® ), ALVAC HIV (vCP1521)/AIDSVAX B/E (gpl20) (RV144), Remune ® , ITV-1, Cantre Vir,Ad5-ENVA-48,DCVax-001 (CDX-2401), PEP-6409, Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAdS), Pennvax-G, YRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, fflV-LAMP-vax, Ad35, Ad35-GRIN,
  • NAcGM3NSSP ISA-51 NAcGM3NSSP ISA-51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multi-HIV
  • HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins such as DARTs ® , Duo-bodies ® , Bites ® , XmAbs®, TandAbs ® , Fab derivatives
  • BMS-936559, TMB-360 and those targeting fflV gpl20 or gp41 are chosen from:
  • bavituximab UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+ C4E10, 3-BNC-l 17, KD- 247, PGT145, PGT121, MDXOIO (ipilimumab), A32, 7B2, VRCOl (disclosed in WO 2011/038290), VRC01-LS (disclosed in WO 2012/106578), VRC-07 (disclosed in WO 2013/086533), and VRC07-523 (disclosed in WO 2015/048770);
  • latency-reversing agents chosen from: histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; proteasome inhibitors, such as VELCADE ® ;
  • PKC protein kinase C activators
  • PLC protein kinase C activators
  • Indolactam, prostratin, ingenol B and DAG- lactones, lonomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQ1, amphotericin B, and disulfram PKC activators
  • NCp7 inhibitors such as azodicarbonamide
  • P13K inhibitors chosen from: idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR- 1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK- 2269557, GSK- 2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mes
  • (21) other drugs for treating fflV chosen from: REP 9, cytolin, CYT-107, alisporivir, BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, SCY-635, prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IM0-3100, SB-728-T, RPI-MN, VIR-576, HGTV- 43, MK-1376, rfflV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY- 635, naltrexone, AAV-eCD4-Ig gene therapy, TEV-90110, TEV-90112, deferiprone, and PA-1050040 (PA-040).
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are combined with one, two, three, four or more additional therapeutic agents.
  • the one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • TAF or a pharmaceutically acceptable salt thereof, are combined with one, two, three, four or more additional therapeutic agents selected from raltegravir, TRUVADA ® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, EPZICOM ® (KIVEXA ® , abacavir sulfate+lamivu- dine, ABC+3TC),
  • TRIZIVIR ® abacavir sulfate+zidovudine+ lamivudine, ABC+AZT+3TC
  • adefovir adefovir dipivoxil
  • STRIBILD ® elvitegravir+cobicista +'tenofovir disoproxil
  • lamivudine+nevirapine+zidovudine abacavir, abacavir sulfate, tenofovir, tenofovir, tenofovir disoproxil and tenofovir disoproxil fumarate.
  • TAP, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are administered with an agent chosen from: emtricitabine and lamivudine.
  • an agent chosen from: emtricitabine and lamivudine in certain embodiments, when TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, are combined with one or more additional therapeutic agents as described above, the components of the composition are
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, thereof are combined with one or more additional therapeutic agents, in a unitary dosage form for simultaneous administration to a human, for example as a solid dosage form for oral administration.
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, , or a pharmaceutically acceptable salt thereof are administered with one or more additional therapeutic agents.
  • Co-administration of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, 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 human.
  • Co-administration includes administration of unit dosages of TAF, or a
  • a unit dose of TAF , or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof 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 TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, within seconds or minutes.
  • a unit dose of TAF , or a pharmaceutically acceptable salt thereof; and the compound of formula II, or a pharmaceutically acceptable salt thereof is administered first, followed, after a period of hours (e.g., l-12hours), 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, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a
  • TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are administered orally.
  • the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof is administered to the human once a day.
  • the combination of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof is administered to the human twice a day.
  • TAF or a pharmaceutically acceptable salt thereof, is administered to the human at about S mg, about 10 mg, about 25 mg, about 30 mg, about 3 S mg, about 40 mg, about 45 mg dose, about SO mg, about SS mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg, once, twice, or three times a day.
  • TAF or a pharmaceutically acceptable salt thereof, is
  • TAF is administered to the human at about 50 mg, once or twice per day.
  • the compound of formula II, or a pharmaceutically acceptable salt thereof is administered to the human at about 1 mg, about 5 mg, about lOmg, about 15mg, about 20 mg, about 25 mg dose, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg once, twice or three times a day.
  • the compound of formula II, or a pharmaceutically acceptable salt thereof is administered to the human at about 1 mg to 50 mg or at about 5 mg to 25 mg once per day.
  • the compound of formula II, or a pharmaceutically acceptable salt thereof is administered to the human at about 5 mg, once per day. In another embodiment, the compound of formula II, or a pharmaceutically acceptable salt thereof, is administered to the human at about 1 Omg, once per day. In another embodiment, the compound of formula II, or a
  • pharmaceutically acceptable salt thereof is administered to the human at about 25 mg, once per day.
  • the compound of formula II, or a pharmaceutically acceptable salt thereof is administered to the human at about S mg, about 10 mg, about 25 mg, about SO mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg, optionally in combination with the boosting agent, NORVIR ® .
  • this invention relates to a combination comprising TAF, or a pharmaceutically acceptable salt thereof; and the compound of formula II, or a
  • this invention relates to the above combination for use in medical therapy.
  • this invention relates to the above combination for use in the treatment of HIV.
  • this invention relates to pharmaceutical composition
  • a combination comprising TAF, or a pharmaceutically acceptable salt thereof and the compound of formula II, or a pharmaceutically acceptable salt thereof.
  • this invention relates to pharmaceutical composition
  • a combination comprising TAF, or a pharmaceutically acceptable salt thereof; and the compound of formula II, or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable carriers therefor.
  • the present invention provides for the use of TAF, or a
  • co-administer refers to administration of two or more agents within a 24-hour period of each other, for example, as part of a clinical treatment regimen. In other embodiments, “co-administer” refers to administration of two or more agents within 2 hours of each other. In other embodiments, “co-administer” refers to administration of two or more agents within 30 minutes of each other. In other embodiments, “co-administer” refers to administration of two or more agents within 15 minutes of each other. In other embodiments, “co-administer” refers to administration at the same time, either as part of a single formulation or as multiple formulations that are administered by the same or different routes.
  • TAF formula I
  • TAF may be associated with fumarate, such as monofumarate and hemifumarate.
  • fumarate such as monofumarate and hemifumarate.
  • Methods for preparing TAF are disclosed in US Patent 7,390,791. TAF is marketed as a hemifumarate for the treatment of HIV and AIDS.
  • Emtricitabine or “FTC” refers to (2R,5S,cis)-4- amino-5-fluoro-l-(2-hydroxymethyl- l,3-oxathiolan-5-yl)- (lH)-pyrimidin-2-one.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound.
  • “pharmaceutically acceptable salts” of the compounds disclosed herein include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C1-C4 alkyl).
  • Pharmaceutically acceptable salts of a nitrogen atom or an amino group include, for example, salts of organic carboxylic acids such as acetic, benzoic, camphorsulfonic, citric, glucoheptonic, gluconic, lactic, fumaric, tartaric, maleic, malonic, malic, mandelic, isethionic, lactobionic, succinic, 2-napththalenesulfonic, oleic, palmitic, propionic, stearic, and trimethylacetic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, camphorsulfonic, citric, glucohepton
  • Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation, such as Na + and NX 4 + (wherein X is independently selected from H or a C1-C4 alkyl group).
  • Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N- methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in Berge, et al, J. Pharma Sci., 66(1), 1-19 (1977), and
  • salts of active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, i.e., they will be salts derived from a
  • physiologically acceptable acid or base may also find use, for example, in the preparation or purification of TAF or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts that are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids, e.g., HC1, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines.
  • compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • a zwitterionic compound is encompassed herein by referring to a compound that is known to form zwitterions, even if it is not explicitly named in its zwitterionic form.
  • Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names.
  • the name zwitterion is assigned the name identification, CHEBL27369, by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. (See, for example, its on-line version at
  • a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign. Sometimes these compounds are referred to by the term “inner salts”. Other sources refer to these compounds as “dipolar ions", although the latter term is regarded by still other sources as a misnomer.
  • aminoethanoic acid the amino acid glycine
  • H2NCH2COOH the amino acid glycine
  • it exists in some media in this case in neutral media in the form of the zwitterions +H3NCH2COO-.
  • Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art.
  • “Therapeutically effective amount” refers to that amount of the compound being administered that will prevent a condition, or will reduce to some extent one or more of the symptoms of the disorder being treated.
  • Pharmaceutical compositions suitable for use herein include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • prevention refers to reducing the risk of infection or exhibiting signs or symptoms of such infection in a human at high risk ho has not been pre-treated.
  • treatment refers to inhibition, reduction, elimination or alleviation of a disease.
  • retrovirus infection or a disease, disorder, or condition associated with a retrovirus infection.
  • Retroviruses are RNA viruses and are generally classified into the alpharetrovirus, betaretrovirus, deltaretrovirus, epsilonretrovirus, gammaretrovirus, lentivirus, and spumavirus families. Examples of retroviruses include, but are not limited to, human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the active agents of the disclosed combination therapy may be administered to a human in any conventional manner. While it is possible for the active agents to be administered as compounds, they are preferably administered as a pharmaceutical composition that can include contact with an acid or base, either in an ionic salt form or in contact with the base or acid (i.e., co-formers) without sharing ions.
  • the salt, acid or base co-former, carrier, or diluent should be acceptable, in the sense of being compatible with the other ingredients and not deleterious to the recipient thereof.
  • carriers or diluents for oral administration include, but are not limited to: cornstarch, lactose, magnesium stearate, talc, microcrystalline cellulose, stearic acid, povidone,
  • crospovidone dibasic calcium phosphate, sodium starch glycolate, hy droxypropy 1 cellulose (e.g., low substituted hy droxypropy 1 cellulose), hy droxypropy lmethyl cellulose (e.g., hy droxypropy lmethyl cellulose 2910), sodium lauryl sulfate, mannitol, sodium stearyl fumarate, and talc.
  • salts and acid or base co-formers include fumarate, hemifurnarate, sodium, and hydrochloride.
  • compositions may be prepared by any suitable method, such as those methods well known in the art of pharmacy, for example, methods such as those described in Gennaro, et al., REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed., Mack Publishing Co., 1990), especially "Part 8: Pharmaceutical Preparations and their Manufacture".
  • suitable methods include the step of bringing into association the compounds with the carrier or diluents and, optionally, one or more accessory ingredients.
  • accessory ingredients include, but are not limited to: fillers, binders, excipients, disintegrants, lubricants, colorants, flavoring agents, sweeteners, preservatives (e.g., antimicrobial preservatives), suspending agents, thickening agents, emulsifying agents, and/or wetting agents.
  • preservatives e.g., antimicrobial preservatives
  • suspending agents thickening agents, emulsifying agents, and/or wetting agents.
  • each compound to be administered ranges from about 0.001 to 100 mg per kg of body weight, such total dose being given at one time or in divided doses.
  • Each compound will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. Alternatively, both compounds will be combined and administered as a formulation in association with one or more
  • compositions and methods for their preparation may be found, for example, in
  • Example 1 HIV Cell Line Assay The HIV cell line experiments taught by Kobayashi, et ah, Antimicrobial Agents and Chemotherapy, 55: 814-815 (2011) are followed to test the antiviral abilities of the disclosed and claimed combination of TAF and the compound of formula II, as compared with the antiviral abilities of each compound alone.
  • TAF the compound of formula I
  • the compound of formula II are synthesized at GlaxoSmithKline ® , Research Triangle Park, NC. The structures of each of these compounds are shown above.
  • Example 2 Cells and viruses.
  • Cells of MT-4, a human T-cell leukemia virus type 1 (HTLV-l)-transformed human T-cell line, are maintained as described previously [12]. 293T cells are maintained in
  • PBMCs Peripheral blood mononuclear cells
  • FBS fetal bovine serum
  • PBMCs Peripheral blood mononuclear cells
  • IL-2 interleukin-2
  • ZeptoMetrix ® 10% natural T-cell growth factor
  • PHA phytohemagglutinin
  • Molt-4 cells persistently infected with HIV-1 IIIB and MT-2 cells [ 16] are obtained from S. Harada (Kumamoto University, Kumamoto, Japan).
  • HeLa-CD4 cells containing an HIV-1 long terminal repeat (LTR)-driven ⁇ -galactosidase reporter gene have been described previously [20].
  • LTR long terminal repeat
  • MAGI-CCR5 cells have been described previously [9]).
  • HIV-1 strain TUB is derived from cell-free supernatants of cultures of the chronically infected cell line, H93B (H9/HTLV-IIIB).
  • HIV-1 strain Ba-L is purchased from Advanced Biotechnologies Inc. ® (Columbia, MD) and is expanded in PHA-activated PBMCs, while HIV-1 NL432 [1] is obtained from A Adachi
  • Plasmid pGJ3-Luci containing a replication-defective HIV lentiviral vector expressing luciferase [21] is licensed from Christian Jassoy (University of Leipzig), and is used to create stocks of a vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped self-inactivating pseudo-HIV (PHIV) lentiviral vector by cotransfection, along with plasmid pVSV-G (Clontech ® ) into CIP4 cells (a derivative of the 293 T human renal epithelial cell line that expresses macrophage scavenger receptor SRA-I to improve adherence to plastic) and harvesting of the cell-free supernatant.
  • VSV-G vesicular stomatitis virus glycoprotein G
  • PIV pseudo-HIV
  • Example 3 Antiviral assay in MT-4 cells.
  • the antiviral activities of TAF alone, the compound of formula II alone, as well as the combination of TAF and the compound of formula II are measured in a single-round assay using a self-inactivating PHIV lentiviral vector.
  • CIP4 cells (2 X 10 4 /well) infected with an amount of PHIV sufficient to produce approximately 50,000 relative light units are added to 96-well black, clear-bottom plates and were incubated for 2 days with all three compounds at varying concentrations. Infected cells are measured as a function of luciferase activity in a luminometer using the Steady-Glo ® reagent (Promega).
  • Example 5 Antiviral assay in PBMCs.
  • PHA- and IL-2-stimulated PBMCs (4 X 10 5 /well) are pre- incubated with each compound alone, and then for the above combination of compounds, for 1 hour, while HTV-1 strain, Ba-L, is mixed with the same compound in a second plate.
  • An aliquot of the Ba-L-compound mixture is then transferred to the PBMC- compound mixture and is incubated for 7 days. After this incubation, supernatants are assayed for reverse transcriptase (RT) activity by incorporation of [methyl- 3 H]dTTP to measure viral replication, as previously described [15].
  • RT reverse transcriptase
  • Example 7 Combination antiviral activity assay in MT-4 cells. The in vitro
  • combination activity relationships of: (1) TAF alone; (2) the compound of formula II alone; and (3) TAF and the compound of formula II are determined as previously described [39]. Multiple concentrations of the compounds are tested in checkerboard dilution fashion in the presence and absence of dilutions of approved anti-HIV drugs, adefovir, or ribavirin.
  • the assay used HIV-l IIIB-infected MT-4 cells, and the interaction of the compound combination is analyzed by dose wise additivity-based calculations to quantify deviation from dose wise additivity at the 50% level.
  • Wells containing the top concentration of compounds by themselves are compared to wells with the top concentration of each of the two compound combinations in order to show that combination effects are due to the drugs used, and not simply to toxicity.
  • Fractional inhibitory concentration (FIC) values in the range of 0.1 to 0.2 indicate weak synergy; values that approach 0.5 indicate strong synergy; and positive values of 0.1 to 0.2 indicate weak antagonism.
  • the effects of the anti-hepatitis B virus (anti-HBV) and anti-HC V agents adefovir and ribavirin on: (1) TAF alone; (2) the compound of formula II alone; and (3) TAF and the compound of formula II are examined using linear regression, as described previously [41].
  • the CCRS inhibitor, maraviroc is evaluated in a checkerboard dilution format using MAGI-CCR5 cells with the Gal Screen reagent (Tropix ® , Bedford, MA) for chemiluminescent endpoints, and data are analyzed as described by Prichard and Shipman [37] by using the MacSynergy II ® program. Synergy volumes in the range of -50 to 50 define additivity; ⁇ -50, antagonism; and >50, synergy. REFERENCES 1

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Abstract

L'invention concerne des méthodes de traitement du VIH chez un être humain au moyen de combinaisons de TAF et d'un inhibiteur de maturation, ainsi que des compositions contenant de tels composés.
PCT/IB2017/055184 2016-08-31 2017-08-29 Combinaisons, utilisations et traitements correspondants Ceased WO2018042331A1 (fr)

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