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WO2018042332A1 - Combinaisons, utilisations et traitements correspondants - Google Patents

Combinaisons, utilisations et traitements correspondants Download PDF

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Publication number
WO2018042332A1
WO2018042332A1 PCT/IB2017/055185 IB2017055185W WO2018042332A1 WO 2018042332 A1 WO2018042332 A1 WO 2018042332A1 IB 2017055185 W IB2017055185 W IB 2017055185W WO 2018042332 A1 WO2018042332 A1 WO 2018042332A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
formula
compound
dolutegravir
Prior art date
Application number
PCT/IB2017/055185
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English (en)
Inventor
Brian Alvin Johns
Original Assignee
Glaxosmithkline Intellectual Property (No.2) Limited
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Publication of WO2018042332A1 publication Critical patent/WO2018042332A1/fr

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Classifications

    • 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
    • A61K31/5365—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 ortho- or peri-condensed with heterocyclic 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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 (HIV-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 dolutegravir (formula I):
  • a further embodiment of this invention provides a method for treating human
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof are co- administered in a single dosage form.
  • this invention provides a pharmaceutical composition comprising a therapeutically effective amount of dolutegravir (formula I):
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , 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 dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, wherein said composition further comprises emtricitabine and cobicistat
  • this invention provides a pharmaceutical composition comprising a therapeutically effective amount of the combination of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, wherein said composition further comprises lamivudine and cobicistat.
  • this invention provides a kit comprising:
  • composition comprising dolutegravir, or a pharmaceutically acceptable salt thereof;
  • composition comprising the compound of formula ⁇ , or a
  • dolutegravir which are currently marketed for the treatment and prevention of HIV. Among them is an agent called dolutegravir
  • Dolutegravir has the structure of formula I below:
  • Dolutegravir and/or the compound of formula ⁇ 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 (dolutegravir):
  • 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 (dolutegravir):
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof are coadministered in separate dosage forms.
  • dolutegravir or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof are coadministered in a single dosage form.
  • dolutegravir, or a pharmaceutically acceptable salt thereof is administered parenteraUy , and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, is administered orally.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof are both administered orally.
  • compositions comprising dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • pharmaceutical compositions consisting essentially of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • compositions consisting of TAF, or a
  • combinations consisting essentially of TAF, or a
  • combinations consisting of TAF, or a pharmaceutically acceptable salt thereof; and a compound of formula ⁇ , or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, diluents or excipients are provided.
  • a method for treating an HIV infection in a human comprising administering to the human a therapeutically effective amount of dolutegravir, , or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a
  • pharmaceutically acceptable salt thereof 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.
  • One embodiment of the invention provides a method for treating HIV infection in a human comprising adrninistering to the human a therapeutically effective amount of dolutegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of the compound of formula ⁇ , 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 HTV infection.
  • the present disclosure provides a method for preventing an HTV infection, comprising administering to a human a therapeutically effective amount of dohjtegravir and the compound of formula ⁇ , 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 ctolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , 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 HTV infection.
  • dolutegravir, 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 dolutegravir, or a pharmaceutically acceptable salt thereof, is administered intramuscularly or subcutaneousry, but the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, is administered parenteralry.
  • oral-lead method a pharmaceutically acceptable salt thereof
  • kits comprising dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, in oral and/or parenteral dosage forms are provided.
  • kits comprise dolutegravir in a syringe dosage or tablet dosage form, and the compound of formula ⁇ in a syringe dosage or tablet dosage form.
  • a combination including dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, for the treatment of HTV.
  • 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, MK8591(EFdA); HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., combinectin, CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors)) and CD4 attachment inhibitors, CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, and BRIM inhibitors), compounds that target the HIV capsid ("capsid inhibitors"
  • HIV entry inhibitors
  • peptidylproryl cis-trans isomerase A modulators protein disulfide isomerase inhibitors, complement CSa receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-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, HTV ribonuclease H inhibitors, retrorocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HTV GAG protein inhibitors, HTV POL protein inhibitors, complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase
  • the additional therapeutic is chosen from: HIV protease inhibitors, HTV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HTV nucleoside or nucleotide inhibitors of reverse transcriptase, HTV integrase inhibitors, HTV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, are formulated as a tablet tint may optionally contain one or more other compounds useful for treating HTV.
  • the tablet can contain another active ingredient for treating HTV, such as HTV protease inhibitors, HTV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HTV nucleoside or nucleotide inhibitors of reverse transcriptase, HTV integrase inhibitors, HTV 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: ATRIP-LA* (efavirenz+ienofovir disoproxil fumarate+emtricitabine ), COMPLERA ® (EVIPLERA ® rilpivirine+tenofovir disoproxil fumarate+emtricitabine ), STRJBILD ® (dvrtegravir ⁇ bicistatrHtmofovir disoproxil fumarate+emtricitabine), lamivudine ⁇ iievirapme ⁇ dovu dine, atazanavir sulfate+cobicistat, darunavir+cobicistat, e&viren ⁇ lamivudine-Henofovir disoproxil fumarate, Vacc- 4x+romidepsin, APH-0812, rahegra ⁇ ir+lamivudine, KALETRA ® (ALUVIA* lopinavirf ritonavir), atazanavir
  • HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase chosen from: delavirdine, delavirdine mesylate, nevirapine, (+), etravirine, dapivirine, doravirine, efavirenz, KM023, VM-ISOO, lentinan, AIC-292, EFdA (4'-Ethynyl-2- Fluoro-2'-Deoxy adenosine, or otherwise known as MK-8591), ENDURANT ®
  • 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, ervucitabine, alovudine, phosphazid, fozivudine tidoxil, apricitabine, amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, adefovir, adefovir dipivoxil, festinavir, and MK8591 (EFdA).
  • HIV integrase inhibitors chosen from: raltegravir, elvitegravir, cabotegravir, and bictegravir; (6) HTV non-catalytic site, or allosteric, integrase inhibitors (NCINI) chosen from: CX- 05168, CX-05045 and CX- 14442;
  • HTV gp41 inhibitors chosen from: enfuvirtide, sifuvirtide and albuvirtide; (8) 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);
  • CXCR4 inhibitors chosen from: plerixafor, ALT- 1188, ⁇ 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 poryethyleneimine (PEI), Gepon, VGV- 1, MOR-22, toll-like receptors modulators (tlrl, tlr2, tlr3, tlr4,
  • 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 HIV gpl20 or gp41 are chosen from bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5-K:2G12+ C4E10, 3-BNC-117, KD- 247, PGT145, PGT121, MDXOIO (ipilimumab), A32, 7B2, VRCOl (disclosed in WO 2011/038290), VRCOl-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 ® ;
  • 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 mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, N4L
  • (21) other drugs for treating HIV 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, ⁇ -225, RPI-MN, VSSP, Hlviral, JM0-3100, SB-728-T, RPI-MN, VIR-576, HGTV- 43, MK-1376, rHIV7-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).
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , 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.
  • dolutegravir, or a phannaceuticaUy acceptable sah thereof are combined with one, two, three, four or more additional therapeutic agents selected from rakegravir, TRUVADA* (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirnde, EPZICOM ® (EOVEXA* abacavir sulfete+lamivu- dine, ABC+3TC), TRIZIVIR* (abacavir sulfete+zidovudine+ lamivudine, ABC+AZT+3TC), adefovir, adefovir dipivoxil, STRIBILD* (dvitegravir ⁇ bicistatrKenofovir disoproxil
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and thecomrxxiTKiof formula ⁇ , 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 adrninistration.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and me compouiKl of formula ⁇ , , or a pharmaceutically acceptable salt thereof are administered with one or more additional therapeutic agents.
  • Coadministration of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents generally refers to simultaneous or sequential adrninistration 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.
  • Coadministration includes administration of unit dosages of dolutegravir, or a pharmaceutically acceptable salt thereof, and the con ⁇ xxind of formula ⁇ , ora
  • a unit dose of dolutegravir, or a pharmaceutically acceptable salt thereof; and the ccinrxxind of formula ⁇ , or a pharmaceutically acceptable salt thereof is
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, within seconds or minutes.
  • pharmaceutically acceptable salt thereof 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.
  • 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 dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof are examples of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof, are
  • the combination of dolutegravir, 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 dolutegravir, 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.
  • dolutegravir or a pharmaceutically acceptable salt thereof, is administered to the human at abort about30mg, about
  • dolutegravir, or a pharmaceutically acceptable salt thereof is administered to the human at about S mg, about 10 mg, about 25 mg to 100 mg, at about 25 mg to 75 mg, at about 35 mg to 65 mg or about 45 mg to 55 mg, once or twice per day.
  • dolutegravir, or a pharmaceutically acceptable salt thereof 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 ⁇ , 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.
  • the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof is administered to the human at about 1 Omg, once per day.
  • the pharmaceutically acceptable salt thereof is administered to the human at about 25 mg, once per day.
  • the compound of formula ⁇ , 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 dolutegravir, or a pharmaceutically acceptable salt thereof; and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof.
  • 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 dolutegravir, or a pharmaceutically acceptable salt thereof and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof.
  • this invention relates to pharmaceutical composition
  • a combination comprising dolutegravir, or a pharmaceutically acceptable salt thereof; and the compound of formula ⁇ , or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable carriers therefor.
  • the present invention provides for the use of dolutegravir, or a pharmaceutically acceptable salt thereof; and the compound of formula ⁇ , or a
  • co-administer refers to adrninistration 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 adrninistration 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 IS 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.
  • Dolutegravir TIVICAY ⁇ is currently marketed for the treatment and prevention of HIV.
  • Emtricitabine or “FTC” refers to (2R,5S,cis)-4- amino-5-fluoro-l-(2-hydroxymethyl- 1,3-oxathiolan-S-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 NXi + (wherein X is Ci-CU 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-napmthalenesulfonic, 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 C 1 -C 4 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.
  • 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 dolutegravir 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 inventioa
  • 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.
  • 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 zwittenon, 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, CHEBI:27369, 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) has the formula and it exists in some media (in this case in neutral media) in the form of the zwitterions 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.
  • 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.
  • Retroviruses are RNA viruses and are generally classified into the dpharetrovirus, betaretrovirus, deltaretrovirus, epsilonretrovirus, gammaretrovirus, lenti virus, and spumavirus families.
  • retroviruses include, but are not limited to, human immunodeficiency virus (HIV).
  • 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 ofbeing compatible with the other ingredients and not deleterious to the recipient thereof.
  • carriers or diluents for oral admiiiistration include, but are not limited to: cornstarch, lactose, magnesium stearate, talc, microcrystalline cellulose, stearic acid, povidone,
  • crospovidone dibasic calcium phosphate, sodium starch gh/colate, hydroxy propyl cellulose (e.g., low substituted hydroxypropyl cellulose), hydroxypropylmethyl cellulose (e.g., hydroxypropylmethyl cellulose 2910), sodium lauryl sulfate, mannitol, sodium stearyl fumarate, and talc.
  • salts and acid or base co-formers include fumarate, herrufumarate, 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 al. , Antimicrobial Agents and Chemolkerapy, 55: 814-815 (2011) are followed to test the antiviral abilities of the disclosed and claimed combination of dolutegravir and the compound of formula ⁇ , as compared with the antiviral abilities of each compound alone.
  • Dolutegravir (the compound of formula I) and the compound of formula ⁇ are synthesized at or on behalf of GrlaxoSmi thKline ® or ViiV Healthcare Co ® . 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 (HTL V- 1 )-transformed human T- cell line, are maintained as described previously [12].
  • 293T cells are maintained in Dulbecco's modified Eagle medium (DMEM)-F- 12 medium containing 10% fetal bovine serum (FBS).
  • DMEM Dulbecco's modified Eagle medium
  • FBS fetal bovine serum
  • Peripheral blood mononuclear cells are derived from whole blood samples obtained from HIV-negative donors. PBMCs are separated from whole blood by density gradient centrifugation with FicoU-Paque Plus** (GE)
  • Moh-4 cells persistently infected with HIV-1 ⁇ 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].
  • MAGI-CCRS cells have been described previously [9]).
  • HIV-1 strain WB 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 lucif erase [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-HTV (PHIV) lentiviral vector by cotransfection, along with plasmid pVSV-G (Clontech ® ) into CIP4 cells (a derivative of the 293T human renal epithelial cell line that expresses macrophage scavenger receptor SRA-I to improve adherence to plastic) and harvesting of the cell-free supernatant.
  • Example 3 Antiviral assay in MT-4 cells.
  • the MT-4 cells generated in Example ⁇ grow exponentially at a density of 5 X 10 S or 6X
  • 105/ml are infected with HTV-1 strain ⁇ at a viral multiplicity of infection of 0.001 or a 50% tissue culture infective dose of 4 to 10.
  • the cells are then al .quoted to 96- well plates in the presence of varying concentrations of compounds. After incubation for 4 or S days, antiviral activity is determined by a cell viability assay that either measures
  • the antiviral activities of dolutegravir alone, the compound of formula ⁇ alone, as well as the combination of dolutegravir and the compound of formula n are measured in a single- round assay using a self-inactivating PHTV lenti viral vector.
  • CTP4 cells (2 X loVwell) infected with an amount of PHTV 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 Corporation ® ).
  • 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-3H]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) dolutegravir alone; (2) the compound of formula II alone; and (3) dolutegravir and the compound of formula ⁇ 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 HTV-1 ⁇ -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.S indicate strong synergy; and positive values of 0.1 to 0.2 indicate weak antagonism.
  • anti-HBV anti-hepatitis B virus
  • anti-HCV agents adefovir and ribavirin on: (1) dolutegravir alone; (2) the compound of formula II alone; and (3) dolutegravir and the compound of formula II are examined using linear regression, as described previously [41].
  • the CCR5 inhibitor, maraviroc is evaluated in a checkerboard dilution format using MAGI-CCRS 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 -SO to SO define additivity; ⁇ -S0, antagonism; and >S0, synergy. REFERENCES 1

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Abstract

L'invention concerne des méthodes de traitement du VIH chez un être humain en utilisant des combinaisons de : dolutégravir et d'un inhibiteur de maturation, ainsi que des compositions contenant de tels composés.
PCT/IB2017/055185 2016-08-31 2017-08-29 Combinaisons, utilisations et traitements correspondants WO2018042332A1 (fr)

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WO2020163196A1 (fr) * 2019-02-05 2020-08-13 Viiv Healthcare Company Procédé de traitement du vih au moyen de dolutégravir et de lamivudine

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