[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2018044838A1 - Combinaisons ainsi qu'utilisations de celles-ci et traitements correspondants - Google Patents

Combinaisons ainsi qu'utilisations de celles-ci et traitements correspondants Download PDF

Info

Publication number
WO2018044838A1
WO2018044838A1 PCT/US2017/049021 US2017049021W WO2018044838A1 WO 2018044838 A1 WO2018044838 A1 WO 2018044838A1 US 2017049021 W US2017049021 W US 2017049021W WO 2018044838 A1 WO2018044838 A1 WO 2018044838A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
compound
formula
acceptable salt
bictegravir
Prior art date
Application number
PCT/US2017/049021
Other languages
English (en)
Inventor
Brian Alvin Johns
Original Assignee
Viiv Healthcare Company
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 Company filed Critical Viiv Healthcare Company
Publication of WO2018044838A1 publication Critical patent/WO2018044838A1/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
    • A61K31/535—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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Definitions

  • HIV-1 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.
  • ANTIRETROVIRAL GUIDELINES FOR ADULTS AND ADOLESCENTS GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS IN HIV-1-INFECTED ADULTS AND ADOLESCENTS. Department of Health and Human Services. Available at
  • this invention provides a combination comprising a compound of bictegravir (formula I):
  • this invention provides a pharmaceutical composition comprising the combination of bictegravir, 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 bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • a further embodiment of this invention provides a method for treating human immunodeficiency virus (HIV) in a human, comprising administering to the human a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
  • HAV human immunodeficiency virus
  • bictegravir, 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.
  • bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are co- administered 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 bictegravir (formula I):
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of bictegravir (formula I):
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the combination of bictegravir, 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 bictegravir, 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 bictegravir, 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 bictegravir, 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 bictegravir, 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 bictegravir, 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 bictegravir, or a pharmaceutically acceptable salt thereof; (2) a composition comprising the compound of formula II, or a pharmaceutically acceptable salt thereof;
  • MI HIV maturation inhibitors
  • the compound of formula II is 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4- Chlorobenzyl)(2-(dim- ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamet- hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a- octadecahydro- 2H- of formula II are described in US Patent 9,102,685.
  • Bictegravir 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 (bictegravir):
  • 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 (bictegravir):
  • bictegravir, 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.
  • bictegravir or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are co- administered in a single dosage form.
  • bictegravir, or a pharmaceutically acceptable salt thereof is administered parenterally, and the compound of formula II, or a pharmaceutically acceptable salt thereof, is administered orally.
  • bictegravir, 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.
  • bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are both administered orally.
  • pharmaceutical compositions comprising bictegravir, 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 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.
  • pharmaceutical compositions consisting of TAF, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients are provided.
  • combinations comprising bictegravir, or a
  • a method for treating an HIV infection in a human comprising administering to the human a therapeutically effective amount of bictegravir, , 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 (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 administering to the human a therapeutically effective amount of bictegravir, 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 bictegravir 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 bictegravir, 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 tha t are suitable for treating an HIV infection.
  • pharmaceutical compositions comprising bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, 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
  • bictegravir 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 bictegravir, or a
  • kits comprising bictegravir, 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 bictegravir 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 bictegravir, 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 chosen f rom: 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, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, and B
  • 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.
  • bictegravir, 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
  • TRIZIVIR ® abacavir sulfate+zidovudine+ lamivudine, ABC+AZT+3TC
  • TRUVADA ® tenofovir disoproxil fumarate+emtricitabine
  • HIV protease inhibitors chosen f rom: 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; (3) HIV non-nucleo
  • HIV integrase inhibitors chosen from: raltegravir, elvitegravir, cabotegravir, and dolutegravir (TIVICAY ® ); (6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) chosen from: CX-05168, CX-05045 and CX-14442; (7) HIV gp41 inhibitors chosen from: enfuvirtide, sifuvirtide and albuvirtide; (8) HIV entry inhibitors, such as c o m b in e c t i n ; (9) HIV gp120 inhibitors chosen f rom: Radha-108 (Receptol) and BMS-663068; (10) CCR5 inhibitors chosen from: aplaviroc, vicriviroc, maraviroc, cenicriviroc, PR0- 140, Adaptavir (RAP-101), nifeviroc (TD-0232), TD-
  • Tatlmmune GTU-multi-HIV (FIT-06), AGS-004, gp140[delta]V2.TVI+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PTl, NYVAC-HIV-PT4, DNA-HIV- PT123, VIChREPOL ® , rAAV1-PG9DP, GOVX-Bl l, GOVX-B21, ThV- 01, TUTI- 16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-VlOl, CombiHIVvac, ADVAX, MYM- V201, monomeric gp120 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 HIV gp120 or gp41 are chosen from: bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+ C4E10, 3-BNC- 117, KD-247, PGT145, PGT121, MDXOlO (ipilimumab), A32, 7B2, VRC01
  • latency-reversing agents chosen from: histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; proteasome inhibitors, such as VELCADE ® ; protein kinase C (PKC) activators such as Indolactam, prostratin, ingenol B and DAG-lactones, lonomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQl, amphotericin B, and disulfram; (18) HIV nucleocapsid p7 (NCp7) inhibitors, such as azodicarbonamide; (19) P13K inhibitors chosen from: idelalisib, AZD-8186,
  • bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, a r 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.
  • bictegravir 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 fumarate+emtricitabine), raltegravir+lamivudine, COMPLERA ® (EVIPLERA ® , r
  • bictegravir, 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.
  • bictegravir, 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 bictegravir, 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 bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of bictegravir, 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 bictegravir, 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 bictegravir , 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., 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
  • bictegravir, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof are administered orally.
  • the combination of bictegravir, 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 bictegravir, 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.
  • bictegravir, 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.
  • bictegravir, or a pharmaceutically acceptable salt thereof is administered to the human at about 5 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.
  • bictegravir is administered to the human at about 50 mg, once or twice per day.
  • t h e com pound o f fo rmu la I I or a
  • pharmaceutically acceptable salt thereof is administered to the human at about 1 mg, about 5 mg, about 10mg, 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.
  • the pharmaceutically acceptable salt thereof is administered to the human at about 10mg, once per day.
  • the 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 5 mg, about 10 mg, about 25 mg, about 50 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
  • 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 bictegravir, 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 bictegravir, 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 bictegravir, or a pharmaceutically acceptable salt thereof; and the compound of formula II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV.
  • the term "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.
  • “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.
  • “Bictegravir”, formula I is:
  • Emtricitabine or “FTC” refers to (2R,5S,cis)-4- amino-5-fluoro-l-(2-hydroxymethyl- 1,3-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.
  • salts derived from an appropriate base such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX4 + (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.
  • 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.
  • salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of bictegravir or another compound of the 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., HCl, HBr, H 2 SO 4 , H 3 PO 4 or organic sulfonic acids, to basic centers, typically amines.
  • 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, CHEBI:27369, by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities.
  • 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 + H 3 NCH2COO-.
  • 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.
  • 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. Examples of 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 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 sodium stearyl fumarate
  • salts and acid or base co-formers include fumarate, hemifumarate, sodium, and hydrochloride.
  • the pharmaceutical 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”.
  • Such 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.
  • the amount of 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.
  • both compounds will be combined and administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • the choice of excipient will, to a large extent, depend u p on factors such as the particular mode of
  • 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 bictegravir and the compound of formula II, as compared with the antiviral abilities of each compound alone.
  • Bictegravir (the compound of formula I) and the compound of formula II are synthesized at or on behalf of GlaxoSmithKline ® or ViiV Healthcare Co ® . The structures of each of these compounds are shown above.
  • Example 2 Cells and viruses.
  • HTLV-1 human T-cell leukemia virus type 1
  • MT-4 a human T-cell leukemia virus type 1 (HTLV-1)-transformed human T-cell line
  • HTLV-1 human T-cell leukemia virus type 1
  • 293T cells are maintained in Dulbecco’s modified Eagle medium (DMEM)–F-12 medium containing 10% fetal bovine serum (FBS).
  • DMEM Dulbecco modified Eagle medium
  • FBS fetal bovine serum
  • PBMCs Peripheral blood mononuclear cells
  • PBMCs are separated from whole blood by density gradient centrifugation with Ficoll-Paque Plus ® (GE Healthcare ® , Waukesha, WI) according to the manufacturer’s instructions and are stimulated by the addition of either 20 U/ml of interleukin-2 (IL-2) or 10% natural T-cell growth factor (ZeptoMetrix ® , Buffalo, NY) plus 5 to 10 ⁇ g/ml of phytohemagglutinin (PHA).
  • 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).
  • HIV-1 strain IIIB 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 i s expanded in PHA-activated PBMCs, while HIV-1 NL432 [1] is obtained from A. Adachi (Tokushima University, Tokushima, Japan).
  • 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 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.
  • VSV-G vesicular stomatitis virus glycoprotein G
  • PIV pseudo-HIV
  • Example 3 Antiviral assay in MT-4 cells.
  • the MT-4 cells generated in Example II grow exponentially at a density of 5 X 10 5 or 6 X 10 5 /ml are infected with HIV-1 strain IIIB 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.
  • antiviral activity is determined by a cell viability assay that either measures bioluminescence with a CellTiter-Glo ® luminescent reagent (Promega Corporation ® , Madison, WI) or measured absorbance at 560 and 690 nm using the yellow tetrazolium MTT reagent [3-(4,5- dimethyl-2-thiazolyl)-2,5- diphenyltetrazolium bromide].
  • a cell viability assay that either measures bioluminescence with a CellTiter-Glo ® luminescent reagent (Promega Corporation ® , Madison, WI) or measured absorbance at 560 and 690 nm using the yellow tetrazolium MTT reagent [3-(4,5- dimethyl-2-thiazolyl)-2,5- diphenyltetrazolium bromide].
  • Example 4 Pseudo-HIV assay.
  • the antiviral activities of bictegravir alone, the compound of formula II alone, as well as the combination of bictegravir 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 Corporation ® ).
  • Example 5 Antiviral assay in PBMCs.
  • PBMCs 4 X 10 5 /well
  • PHA- and IL-2-stimulated PBMCs 4 X 10 5 /well
  • PBMC- compound mixture 4 X 10 5 /well
  • An aliquot of the Ba-L–compound mixture i s then transferred to the PBMC- compound mixture and is incubated for 7 days.
  • 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
  • HSA human serum albumin
  • AAG ⁇ 1 -acid glycoprotein
  • HS human serum
  • the protein- adjusted half-maximal effective concentration (PA-EC 50 ) is estimated by multiplying the EC 50 in PBMCs by the fold shift value.
  • PA-EC 50 The protein- adjusted half-maximal effective concentration
  • Example 7 Combination antiviral activity assay in MT-4 cells.
  • the in vitro combination activity relationships of: (1) bictegravir alone; (2) the compound of formula II alone; and (3) bictegravir 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-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 a r e due to the drugs used, and not simply to toxicity.
  • Assays with the MT-4 system format a r e run as described previously [15].
  • 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.
  • anti-hepatitis B virus anti-HBV
  • anti-HCV agents adefovir and ribavirin anti-hepatitis B virus
  • bictegravir alone the compound of formula II alone
  • compound of formula II alone the compound of formula II alone
  • bictegravir 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- CCR5 cells with the Gal Screen reagent (Tropix ® , Bedford, MA) for

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 un être humain au moyen de combinaisons de bictegravir et d'un inhibiteur de maturation, ainsi que des compositions contenant de tels composés.
PCT/US2017/049021 2016-08-31 2017-08-29 Combinaisons ainsi qu'utilisations de celles-ci et traitements correspondants WO2018044838A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662381828P 2016-08-31 2016-08-31
US62/381,828 2016-08-31

Publications (1)

Publication Number Publication Date
WO2018044838A1 true WO2018044838A1 (fr) 2018-03-08

Family

ID=61301604

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/049021 WO2018044838A1 (fr) 2016-08-31 2017-08-29 Combinaisons ainsi qu'utilisations de celles-ci et traitements correspondants

Country Status (1)

Country Link
WO (1) WO2018044838A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130184263A1 (en) * 2011-12-16 2013-07-18 Glaxosmithkline Llc Derivatives of Betulin
US20140243298A1 (en) * 2013-02-25 2014-08-28 Bristol-Myers Squibb Company C-3 alkyl and alkenyl modified betulinic acid derivatives
US20150018298A1 (en) * 2013-07-12 2015-01-15 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130184263A1 (en) * 2011-12-16 2013-07-18 Glaxosmithkline Llc Derivatives of Betulin
US20140243298A1 (en) * 2013-02-25 2014-08-28 Bristol-Myers Squibb Company C-3 alkyl and alkenyl modified betulinic acid derivatives
US20150018298A1 (en) * 2013-07-12 2015-01-15 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

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
WO2017205585A1 (fr) Combinaisons, utilisations et traitements correspondants
WO2018005909A1 (fr) Combinaisons, utilisations et traitements correspondants
US20190151307A1 (en) Methods of treating patients co-infected with a virus and tuberculosis
WO2019016679A1 (fr) Polythérapie
WO2018044853A1 (fr) Combinaisons, utilisations et traitements correspondants
WO2018042332A1 (fr) Combinaisons, utilisations et traitements correspondants
WO2018051250A1 (fr) Combinaison comprenant du ténofovir alafénamide, du bictégravir et du 3tc
US20200171039A1 (en) Combinations and uses and treatments
WO2018044838A1 (fr) Combinaisons ainsi qu'utilisations de celles-ci et traitements correspondants
WO2018044852A1 (fr) Combinaisons, utilisations 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

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: 17847337

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: 17847337

Country of ref document: EP

Kind code of ref document: A1