WO2018044853A1 - Combinaisons, utilisations et traitements correspondants - Google Patents

Combinaisons, utilisations et traitements correspondants Download PDF

Info

Publication number
WO2018044853A1
WO2018044853A1 PCT/US2017/049051 US2017049051W WO2018044853A1 WO 2018044853 A1 WO2018044853 A1 WO 2018044853A1 US 2017049051 W US2017049051 W US 2017049051W WO 2018044853 A1 WO2018044853 A1 WO 2018044853A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
compound
formula
dolutegravir
Prior art date
Application number
PCT/US2017/049051
Other languages
English (en)
Inventor
Brian Alvin Johns
Original Assignee
Viiv Healthcare Conpany
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Viiv Healthcare Conpany filed Critical Viiv Healthcare Conpany
Publication of WO2018044853A1 publication Critical patent/WO2018044853A1/fr

Links

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
    • A61K31/495—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame

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):
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprisin; the combination of dolutegravir, 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 dolutegravir, 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 dolutegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, are coadministered in separate dosage forms.
  • dolutegravir, 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 dolutegravir (formula I):
  • 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 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 dolutegravir, 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 dolutegravir, 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 dolutegravir, 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 dolutegravir, 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 dolutegravir, 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 dolutegravir, or a pharmaceutically acceptable salt thereof;
  • composition comprising the compound of formula II, or a
  • US Patent 8,129,385 describes a class of HIV integrase inhibitors of (4R,12aS)-N-(2,4- difluorobenzyl) ⁇ 7-hydroxy ⁇ 4-methyj -6,8-di oxo-3,4,6,8, 12, 12a-hexahydro ⁇ 2H- pyrido[r,2 ! :4,5]pyrazino[2, l -b][l,3]oxazine-9-carboxamide, which are currently marketed for the treatment and prevention of HIV.
  • Dolutegravir has the structure of formula I below:
  • MI HIV maturation inhibitors
  • the compound of formula II is (lR)-4-[(lR,3a ⁇ ,5aR,5bR,7aR,l la ⁇ , l lbR, 13aR,13bR)-3a- ⁇ [2- (l,l-dioxido-4-thiomorpholinyl)ethyl]amino ⁇ -5a,5b, 8,8, 1 la-pentamethyl-l-(l-propen-2 -yl)- 2,3, 3a,4,5,5a,5b,6,7,7a,8, 11, 1 la,l lb, 12,13, 13a, 13b-octadecahydro-lH-cyclopenta[a]chrysen- 9-yl]-l-(fluoromethyl)-3-cyclohexene-l-carboxylic acid.
  • 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 II, or a pharmaceutically acceptable salt thereof are coadministered in separate dosage forms.
  • dolutegravir 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.
  • dolutegravir, or a pharmaceutically acceptable salt thereof is administered parenterally, and the compound of formula II, or a pharmaceutically acceptable salt thereof, is administered orally.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof both administered parenterally in a long-acting intravenous formulation, either together or separately.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are both administered orally.
  • compositions comprising dolutegravir, 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.
  • pharmaceutical 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.
  • combinations comprising dolutegravir, or a
  • combinations consisting essentially of TAF, or a
  • 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 dolutegravir, , or a pharmaceutically acceptable salt thereof, and the compound of formula II, 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 dolutegravir, 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 atherapeutically 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 dolutegravir and the compound of formula II, or a pharmaceutically acceptable salt thereof, in combination with atherapeutically 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 dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeutic agents th at are suitable for treating an HIV infection.
  • compositions comprising dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a
  • 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 subcutaneously, but the compound of formula II, or a pharmaceutically acceptable salt thereof, is administered parenterally.
  • kits comprising dolutegravir, 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 dolutegravir in a syringe dosage or tablet dosage form, and the compound of formula II in a syringe dosage or tablet dosage form.
  • a combination including dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, for the treatment of HIV.
  • the additional therapeutic agent may be an anti-HIV agent.
  • the additional therapeutic agent is cho s en fro m : 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 (PK)
  • PK protein kinase
  • peptidylprolyl cis-trans isomerase A modulators protein disulfide isomerase inhibitors, complement C5a 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, 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
  • 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.
  • dolutegravir, 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: (1) 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 ® , lopina
  • 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), ENDURANT ®
  • 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, 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) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) chosen from: CX- 05168, CX-05045 and CX- 14442;
  • HIV gp41 inhibitors chosen from: enfuvirtide, sifuvirtide and albuvirtide;
  • HIV entry inhibitors such as c o m b i n e cti n ;
  • HIV gpl20 inhibitors cho sen from : Radha-108 (Receptol) and BMS-663068;
  • CCR5 inhibitors chosen from: aplaviroc, vicriviroc, maraviroc, cenicriviroc, PROMO, 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; (13) Pharmacokinetic enhancers or boo sting agents cho sen from : cobicistat (TYBOST ® ), ritonavir (NORVIR ® ), and SPI-452;
  • Immune-based therapies cho sen 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 (MP A) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-2 XL, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV- 1, MOR-22, toll-like receptors modulators (tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrl
  • HIV vaccines chosen from: peptide vaccines, recombinant subunit protein vac- cines, 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, HIV-LAMP-vax, Ad35, Ad35-GRIN,
  • bavituximab UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+ C4E10, 3-BNC-l 17, KD- 247, PGT145, PGT121, MDXO1O (ipilimumab), A32, 7B2, VRCOl (disclosed in WO 201 1/038290), 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
  • amphotericin B and disulfram
  • Np7 HIV nucleocapsid p7 (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 mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, ML
  • W02013/159064 (Gilead Sciences ® ) and WO 2012/003498 (Gilead Sciences ® ); and (21) other drugs for treating HIV chosen from: REP 9, cytolin, CYT-107, alisporivir, BanLec, MK-8507, AG-1 105, 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, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY- 635, naltrexone, AAV-eCD4-Ig gene
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, ar e 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 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+cobicistat+tenofovir disoproxil
  • lamivudine+nevirapine+zidovudine abacavir, abacavir sulfate, tenofovir, tenofovir, tenofovir disoproxil and tenofovir disoproxil fumarate.
  • dolutegravir, 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 dolutegravir, 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 administered as a simultaneous or sequential regimen. When administered sequentially, either combination may be administered in two or more administrations.
  • Co-administration of dolutegravir, 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
  • Co-administration includes administration of unit dosages of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a
  • a unit dose of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, 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 II, or a pharmaceutically acceptable salt thereof, within seconds or minutes.
  • a pharmaceutically acceptable salt thereof is administered first, followed, after a period of hours (e.g., l - 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 ofhours (e.g., l -12 hours), by administration of a unit dose of dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof.
  • dolutegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are administered first, followed, after a period of hours (e.g., l - 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 ofhours (e.g., l -12 hours), by administration of a unit dose of dolutegravir, or a pharmaceutically acceptable salt thereof,
  • 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 about 5 mg, about 10 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg dose, about 50 mg, about 55 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.
  • dolutegravir, or a pharmaceutically acceptable salt thereof is administered to the human at about 5 mg, about 10 mg, about 25 mg to lOO 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 c om p o und of form ul a I I 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 lOmg, once per day. In another embodiment, the compound of formula II, or a
  • this invention relates to a combination comprising dolutegravir, or a pharmaceutically acceptable salt thereof; and the compound of formula II, or a pharmaceutically acceptable salt thereof.
  • this invention relates to the above combination for use in medical therapy. In another embodiment, this invention relates to the above combination for use in the treatment of HIV.
  • this invention relates to pharmaceutical composition comprising a combination comprising dolutegravir, or a pharmaceutically acceptable salt thereof and the compound of formula II, or a pharmaceutically acceptable salt thereof.
  • this invention relates to pharmaceutical composition comprising a combination comprising dolutegravir, 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 dolutegravir, or a pharmaceutically acceptable salt thereof; and the compound of formula II, 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.
  • Dolutegravir TIVICAY ®
  • FTC 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 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 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.
  • 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.
  • zwitterion zwitterions
  • 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
  • H3NCH2COO 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.
  • a method for the treatment or prophylaxis of diseases, disorders, and conditions is provided herein.
  • An example of a disease, disorder, or condition includes, but is not limited to, a 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.
  • 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.
  • the active agents 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, hydroxypropyl 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, hemifumarate, 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 Chemotherapy, 55: 814-815 (2011) are followed to test the antiviral abilities of the disclosed and claimed combination of dolutegravir and the compound of formula II, as compared with the antiviral abilities of each compound alone.
  • Dolutegravir (the compound of formula I) and the compound of formula II are synthesized at or on behalf of GlaxoSmithK!ine* or ViiV Healthcare Co*. The structures of each of these compounds are shown above.
  • Exasnple 2 Cells and viruses.
  • HTLV-l Vtransformed human T- ceil line a human T-cell leukemia virus type 1 (HTLV-l Vtransformed human T- ceil line, are maintained as described previously [ 12]. 293 T cells are maintained in Dulbecco's modified Eagle medium (DMEM)--F- 12 m edium 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 DCitrif ligation with Ficoll-Paque Pius ® (GE
  • HIV-1 strain ⁇ i s derived from cell -free supematants 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 i s expanded in PHA-activated PBMCs, while HIV-1 NL432 [1] is obtained from A.
  • Plasmid pGJ3-Luci containing a replication-defective HIV lentivirai 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) lenti viral vector by cotransfection, along with plasmid pVSV-G (Clontech*) into CIP4 ceils (a derivative of the 293T human renal epithelial ceil line that expresses macrophage scavenger receptor SRA-l to improve adherence to plastic) and harvesting of the cell-free supernatant.
  • VSV-G vesicular stomatitis virus glycoprotein G
  • PIV pseudo-HIV
  • the MT-4 cells generated in Example II grow exponentially at a density of 5 X 10 ' or 6 X 10 5 /ml are infected with HIV-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 aliquoted to 96-well plates in the presence of varying concentrations of compounds. After incubation for 4 or 5 days, antiviral activity is determined by a cell viability assay that either measures
  • Example 4 Pseudo-HIV assay.
  • the antiviral activities of dolutegravir alone, the compound of formula II alone, as well as the combination of dolutegravir and the compound of formula II are measured in a single- round assay using a self-inactivating PHIV lentiviral vector.
  • CIP4 cells (2 X IQ Ywell) 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 kimmometer using the Steady-Glo ® reagent (Promega Corporation ® ).
  • Example 5 Antiviral assay in PBMCs.
  • PHA- and IL-2-stimuiated PBMCs (4 X l OVwell) are pre- incubated with each compound alone, and then for the above combination of compounds, for I hour, while HIV- 1 strain, Ba-L, i s mixed with the same compound in a second plate.
  • An aliquot of the Ba-L-compound mixture i s 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 6 Effects of human serum and serum proteins.
  • HSA human serum albumin
  • AAG 3 -aeid glycoprotein
  • HS human serum
  • PA-EC 50 protein-adjusted half-maximal effective concentration
  • combination activity relationships of: (1) dolutegravir alone: (2) the compound of formula II alone; and (3) dolutegravir 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 drags, adefovir, or ribavirin. The assay used HIV-1 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 inhibitor ⁇ ' 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.
  • anti-HBV anti-hepatitis B virus
  • anti-HCV agents adefovir and ribavirin on: (1) dolutegravir alone; (2) the compound of formula II alotie; and (3) dolutegravir and the compound of formula.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement du VIH chez l'homme au moyen de combinaisons de: dolutégravir et d'un inhibiteur de maturation, ainsi que des compositions contenant de tels composés.
PCT/US2017/049051 2016-08-31 2017-08-29 Combinaisons, utilisations et traitements correspondants WO2018044853A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662381807P 2016-08-31 2016-08-31
US62/381,807 2016-08-31

Publications (1)

Publication Number Publication Date
WO2018044853A1 true WO2018044853A1 (fr) 2018-03-08

Family

ID=61309468

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/049051 WO2018044853A1 (fr) 2016-08-31 2017-08-29 Combinaisons, utilisations et traitements correspondants

Country Status (1)

Country Link
WO (1) WO2018044853A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020163196A1 (fr) * 2019-02-05 2020-08-13 Viiv Healthcare Company Procédé de traitement du vih au moyen de dolutégravir et de lamivudine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110015196A1 (en) * 2009-07-14 2011-01-20 Hetero Research Foundation Lupeol-type triterpene derivatives as antivirals
US20130184263A1 (en) * 2011-12-16 2013-07-18 Glaxosmithkline Llc Derivatives of Betulin
US20140221361A1 (en) * 2013-02-06 2014-08-07 Bristol-Myers Squibb Company C-19 modified triterpenoids with hiv maturation inhibitory activity
US20160067255A1 (en) * 2014-09-04 2016-03-10 Gilead Sciences, Inc. Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110015196A1 (en) * 2009-07-14 2011-01-20 Hetero Research Foundation Lupeol-type triterpene derivatives as antivirals
US20130184263A1 (en) * 2011-12-16 2013-07-18 Glaxosmithkline Llc Derivatives of Betulin
US20140221361A1 (en) * 2013-02-06 2014-08-07 Bristol-Myers Squibb Company C-19 modified triterpenoids with hiv maturation inhibitory activity
US20160067255A1 (en) * 2014-09-04 2016-03-10 Gilead Sciences, Inc. Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020163196A1 (fr) * 2019-02-05 2020-08-13 Viiv Healthcare Company Procédé de traitement du vih au moyen de dolutégravir et de lamivudine

Similar Documents

Publication Publication Date Title
US11234985B2 (en) Antiviral therapy
US20160067255A1 (en) Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir
EP3356355B1 (fr) Composés et combinaisons pour le traitement du vih
WO2018005909A1 (fr) Combinaisons, utilisations et traitements correspondants
WO2017205585A1 (fr) Combinaisons, utilisations et traitements correspondants
US20190151307A1 (en) Methods of treating patients co-infected with a virus and tuberculosis
EP3655106A1 (fr) Polythérapie
US11191763B2 (en) HIV post-exposure prophylaxis
WO2018044853A1 (fr) Combinaisons, utilisations et traitements correspondants
WO2018051250A1 (fr) Combinaison comprenant du ténofovir alafénamide, du bictégravir et du 3tc
WO2018042332A1 (fr) Combinaisons, utilisations et traitements correspondants
US20200171039A1 (en) Combinations and uses and treatments
WO2018044852A1 (fr) Combinaisons, utilisations et traitements correspondants
WO2018044838A1 (fr) Combinaisons ainsi qu'utilisations de celles-ci et traitements correspondants
WO2018042331A1 (fr) Combinaisons, utilisations et traitements correspondants
WO2018044822A1 (fr) Combinaisons, utilisations et traitements correspondants
AU2017268621B2 (en) Antiviral therapy
US20200246351A1 (en) Combinations and uses and treatments thereof
US20220265689A1 (en) Hiv pre-exposure prophylaxis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17847344

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17847344

Country of ref document: EP

Kind code of ref document: A1