WO2011088561A1 - Composés antiviraux et compositions - Google Patents

Composés antiviraux et compositions Download PDF

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Publication number
WO2011088561A1
WO2011088561A1 PCT/CA2011/000070 CA2011000070W WO2011088561A1 WO 2011088561 A1 WO2011088561 A1 WO 2011088561A1 CA 2011000070 W CA2011000070 W CA 2011000070W WO 2011088561 A1 WO2011088561 A1 WO 2011088561A1
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positions
carbon atoms
ring
group containing
independendy
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PCT/CA2011/000070
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English (en)
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Xiaojian Yao
Zhujun Ao
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University Of Manitoba
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Publication of WO2011088561A1 publication Critical patent/WO2011088561A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • the present disclosure provides compounds and compositions having an antiviral effect especially with respect to the HIV-1 virus.
  • AIDS Acquired immune deficiency syndrome
  • This infectious disease has shown the potential to threaten the lives, welfare, and social stability of the world and has been placed as the fourth leading cause of death.
  • Global estimates of the HIV epidemic indicate that there were estimated 31 million people living with HIV-1 and the estimated cumulative total of deaths from AIDS is approximately 12 million. It has been calculated that there are 16,000 new HIV infections per day, one tenth of these in children.
  • Recent studies have clearly shown that about 5-20% of infants born to HIV- positive women acquire the infection through breastfeeding, and this mode may be responsible for 30-42% of HIV infection in infants and young children in Africa.
  • HIV-1 protease (PR), reverse transcriptase (RT) and integrase (IN) are three viral enzymes which are critical for HIV replication. Among them, the reverse transcriptase and integrase seem to be essential for HIV reverse transcription and integration. Soon after infection, HIV-1 reverse transcriptase catalyzes the conversion of viral RNA genome into double-stranded DNA, and the integrase mediates integration of newly synthesized viral DNA into host chromosomes.
  • HIV-1 integrase has also shown to play crucial roles for HIV cDNA nuclear import and host chromatin targeting prior to its integration.
  • HIV-1 protease PR
  • PR HIV-1 protease
  • the rapid emergence of drug resistance as well as issues associated with drug toxicity remain important challenges in the fight against HIV. It is also urgent to develop new anti-HIV agents with novel targets to be used as new HIV prevention and therapy.
  • the present disclosure provides novel compounds as well as uses, methods, and compositions of treating, or reducing the risk of, HIV-infection.
  • the present uses, methods, and compositions utilize the compounds according to the formula:
  • X is a halogen
  • Y may be a hetero atom or a carbon atom
  • each of the 1, 3, 4, 5, and 6 positions on Ring A may be independently selected from H, or a group containing 1-6 carbon atoms;
  • each of the 1, 2, and 4 positions on Ring B may be independently selected from H, or a group containing 1-6 carbon atoms; and each of the 1, 2, 3, and 4 positions on Ring C may be independently selected from H, or a group containing 1-6 carbon atoms.
  • An embodiment of the present disclosure provides uses, methods, and compositions of treating, or reducing the risk of, HIV-infection. The present uses, methods, and compositions utilize the compounds according to the formula:
  • X is a halogen such as CI.
  • HIV refers to human immunodeficiency virus, the lentivirus that causes acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • the HIV virus has two known forms HIV-1 and HIV-2. HIV-1 is the most prevalent accounting for approximately 80% of all HIV infections.
  • treatment refers to the remediation or amelioration of the symptoms and/ or underlying causes of a disease.
  • microbiocide refers to agents that disinfect by destroying, neutralizing, or otherwise inhibiting the growth of disease-carrying microorganisms.
  • Figure 1 shows the structure of various compounds according to the present disclosure including 4-chloro-3- ⁇ [(2,5-dimemylphenyl)amino] sulfonyl ⁇ -N-(2- pyridinylmethyl) benzamide (Compound 1).
  • Figure 2 shows the inhibition of HIV infection by 4-chloro-3- ⁇ [(2,5- dimemylphenyl)aniino]sulfonyl ⁇ -N-(2-pyridinylmethyl) benzamide.
  • C8166 cells were infected with VSV-G pseudotyped HIV-1 (pNL4.3VSV-G/luc+)virus (100 pg of HIV p24) in the presence or absence of the compound. At 48 hrs post-infection equal amounts of cells were harvested and the luciferase activity was measured.
  • Figure 3 shows the effect of 4-cUoro-3- ⁇ [(2,5-dimetJiylphenyl)amino]sulfonyl ⁇ - N-(2-pyridinylmethyl) benzamide on the wild type HIV infection.
  • C8166 cells were infected with a HIV-1 (pNL4.3-GFP virus) (100 pg of HIV p24) in the presence (6) or absence (7) of the compound. Cells were infected with HIV in the presence of the compound which was either removed after two hours or maintained in the culture during viral infection. After 4-days of infection and the levels of HIV-infected (GFP-positive) cells and HlV-induced syncytia formation were counted.
  • HIV-1 pNL4.3-GFP virus
  • Figure 4 shows that 4-chloro-3- ⁇ [(2,5-dimethylphenyl)amino]sulfonyl ⁇ -N-(2- pyridinylmethyl) benzamide blocked HIV-1 infection when it is administered after 2 hours of infection.
  • C8166 cells were infected with HIV-1 virus (pNL4.3-GFP) in the presence or absence of the compound. Cells were infected with HIV for two hours the compound was then added to the culture. HIV infection at different time intervals was monitored by the measurement of HIV p24 production and the presence of HIV infected (GFP-positive) cells.
  • Figure 5 shows an in-vitro HIV-1 reverse transcription assay, a HIV-1 integration assay, and a HIV-1 DNA synthesis analysis. The results indicate Comp. 1 specifically inhibits reverse transcriptase, but not integrase
  • Figure 6 shows different modifications of Comp. 1 to attenuate anti-HlV activity.
  • HIV p24 ELISA (OD 450 ) assays for 3 and 6 days post-infection in the presence of various compounds are shown.
  • Figure 7 shows the effect of changing CI of compound 1 for Br or F.
  • AH0110 (Br replacing CI) achieved a better anti-HIV effect , while F seems to decrease the anti- HIV activity.
  • Figure 8 shows the effect of AH 110 on W nuclear import and replication.
  • A) C8166 T cells were infected with HTV pNL4.3 for 8 hrs and then AH 110 (5 ug/ml) was added. After 24 hrs, compound was maintained or removed from the medium (as indicated). At 48 hrs, HIV Gagp24 was measured in the supernatants.
  • B) C8166 T cells were infected with HIV pNL4.3 for 8 hrs, then the compound was added and the cells were cultured until 20 hours and total HIV DNA (upper panel), 2-LTR cycles (middle panel) and integrated DNA (low panel) were measured by real-time PCR analysis. Results indicate that AH 110 may affect HIV nuclear translocation in addition to affecting reverse transcriptase, since the detected levels of 2-LTR DNA (a marker of nuclear import of viral DNA) was significantly reduced even large amount of reverse transcripted viral DNA present in the cells
  • Figure 9 shows the effect of AH0110 at inhibiting different drug resistant viruses.
  • C8166 T cells were infected with different drug resistant HIV-1 in the presence or absence of AH0110. After 4 days post-infection, HIV infection status was monitored by measurement of the levels of HIVp24 antigen in the supernatant. Results indicate that AH0110 is able to inhibit AZT-, 3TC- and Reltagravir resistant HIV viruses.
  • the present disclosure provides the use of a compound according to Formula I for the treatment of viral infection.
  • the compound according to Formula I may be used for the treatment of HIV infection.
  • the present compounds may be used for treating a variety of retroviruses or other viruses whose replication requires reverse transcription such as Hepadnaviruses (e.g. Hepatitis B).
  • the present disclosure provides the use of a compound according to Formula I for the manufacture of a medicament.
  • the medicament may be for the treatment and prevention of HIV infection.
  • the present disclosure provides a composition comprising a compound according to Formula I and an anti-viral agent.
  • the anti-viral agent may be selected from such nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV integrase inhibitors, and/ or anti-HIV siRNA approaches.
  • the present disclosure provides a method for the treatment of HIV infection, said method comprising to a HIV-infected subject a suitable dose of a compound according to Formula I.
  • the present disclosure provides a composition comprising a compound according to Formula I to constitute an anti-HIV component in a microbiocide which can be used, for example, by females to block the sexual transmission of HIV.
  • the present disclosure provides a prophylactic method for reducing the likelihood of HIV infection, said method comprising administering to a subject at risk of HIV infection a suitable dose of a compound according to Formula I.
  • the present disclosure provides a method of reducing the risk of HIV- transmission from, for example, a nursing mother to her baby.
  • composition comprising a therapeutically effective amount of a compound according to Formula I and a pharmaceutically acceptable carrier.
  • the present disclosure provides a solid composition comprising a therapeutically effective amount of a compound according to Formula I and a pharmaceutically acceptable carrier.
  • the present disclosure provides a liquid composition comprising a therapeutically effective amount of a compound according to Formula I and a pharmaceutically acceptable carrier.
  • X is a halogen
  • Y may be a hetero atom or a carbon atom
  • each of the 1, 3, 4, 5, and 6 positions on Ring A may be independently selected from H, or a group containing 1 -6 carbon atoms;
  • each of the 1, 2, and 4 positions on Ring B may be independently selected from H, or a group containing 1-6 carbon atoms; and each of the 1, 2, 3, and 4 positions on Ring C may be independendy selected from H, or a group containing 1-6 carbon atoms.
  • X may be selected from any suitable halogen such as, for example, CI, F, or Br.
  • X may be CI.
  • Y may be selected from carbon or any suitable heteroatom such as, for example, N, S, O, or P. Y may be selected from carbon or nitrogen.
  • Each of the 1, 3, 4, 5, and 6 positions on Ring A may be independendy selected from H or a group containing 1-6 carbon atoms. It is preferred that at least one of positions 1, 3, 4, 5, and 6 is H. More preferably at least two of positions 1, 3, 4, 5, and 6 are H. More preferably at least three of positions 1, 3, 4, 5, and 6 are H. It is preferred that at least one of positions 1, 3, 4, 5, and 6 is a C1-C4 alkyl group. More preferably at least two of positions 1, 3, 4, 5, and 6 are C1-C4 alkyl group.
  • Positions 1 and 4 on Ring A n ay for example, be selected from groups containing 1-4 carbon atoms such as, methyl, ethyl, methyl alcohol, ethyl alcohol and the like. Positions 3, 5, and 6 on the ring may, for example, be H.
  • Each of the 1, 2, and 4 positions on Ring B may be independently selected from H or a group containing 1-6 carbon atoms. Preferably at least two of positions 1, 2, and 4 are H. More preferably positions 1, 2, and 4 are H.
  • Each of the 1, 2, 3, and 4 positions on Ring C may be independendy selected from H or a group containing 1-6 carbon atoms.
  • Position 4 may, for example, be selected from groups containing 1-4 carbon atoms such as, methyl, ethyl, methyl alcohol, ethyl alcohol, CF 3 , and the like.
  • Two of positions 1, 2, 3 and 4 may be linked through a group containing 3-6 carbon atoms.
  • position 1, 2, 3 and 4 may be linked by propyl, butyl, pentyl, or hexyl group.
  • the groups may contain one or more heteroatoms such as N, S, O, or P.
  • positions 1, 2, 3 and 4 may be linked by a -0-C-0-, - O-C-C-O-, -C-0-C-, or the like.
  • at least two of positions 1, 2, 3, and 4 are H.
  • at least three of positions 1, 2, 3, and 4 are H.
  • the group linking Ring A to Ring B may be altered in various ways.
  • the N and/ or S may be substituted for another heteroatom or for carbon.
  • the group linking Ring B to Ring C may be altered in various ways.
  • the N may be substituted for another heteroatom or for carbon.
  • the present disclosure provides a compound having the formula (I) :
  • X is a halogen
  • Y may be a hetero atom or a carbon atom
  • each of the 1, 3, 4, 5, and 6 positions on Ring A may be independently H, or a group containing 1-6 carbon atoms except that position 1 and 4 cannot both be a CH 3 group;
  • each of the 1, 2, and 4 positions on Ring B may be independently H, or a group containing 1-6 carbon atoms
  • each of the 1, 2, 3, and 4 positions on Ring C may be independently H, or a group containing 1-6 carbon atoms.
  • the present disclosure provides a compound having the formula (I) :
  • X is a halogen
  • Y may be a hetero atom or a carbon atom; each of the 1, 3, 5, and 6 positions on Ring A may be independendy H, or a group containing 1-6 carbon atoms;
  • each of the 1, 2, and 4 positions on Ring B may be independendy H, or a group containing 1-6 carbon atoms;
  • each of the 1, 2, 3, and 4 positions on Ring C may be independendy H, or a group containing 1-6 carbon atoms.
  • the present disclosure provides a compound having the formula (I) :
  • X is a halogen
  • Y may be a hetero atom or a carbon atom
  • each of the 1 and 4 positions on Ring A may be independendy H, or a group containing 1-6 carbon atoms;
  • each of the 3, 5 and 6 positions on Ring A may be independendy H, or a group containing 1-6 carbon atoms provided at least one of positions 3, 5, or 6 is a group containing 1-6 carbon atoms;
  • each of the 1, 2, and 4 positions on Ring B may be independendy H, or a group containing 1-6 carbon atoms; and each of the 1, 2, 3, and 4 positions on Ring C may be independendy H, or a group containing 1-6 carbon atoms.
  • the present compound may be 4-[halo]-3- ⁇ [(2,5- a ⁇ ethylphenyl)amino]sulfonyl ⁇ -N-(2-pyridinylmethyl) benzamide.
  • the present compound may be 4-chloro-3- ⁇ [(2,5-a1 ⁇ 2iemylphenyl)amino]sulfonyl ⁇ -N-(2- pyridinylmethyl) benzamide, 4-bromo-3- ⁇ [(2,5-dimemylphenyl)amino] sulfonyl ⁇ -N-(2- pyridinylmethyl) benzamide, 4-fluro-3- ⁇ [(2,5-dimemylphenyl)amino] sulfonyl ⁇ -N-(2- pyridinylmethyl) benzamide.
  • the present disclosure provides different salts, hydrates, clathrates, solvates, acids etc. of compounds herein.
  • the compounds of the present disclosure may be formulated in a wide variety of oral administration dosage forms and carriers.
  • Oral adrriinistration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups, or suspensions.
  • Compounds of the present disclosure may be efficacious when administered by other routes such as, for example, continuously (e.g. intravenous drip), topically, parenterally, intramuscularly, intravenously, subcutaneously, transdermally (which may include a penetration enhancement agent), buccally, nasally, via inhalation and/ or suppository administration, among other routes of administration.
  • a compound or compounds of the present disclosure, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active ingredients, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended dosage regimen to be employed.
  • compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration (including a microbiocide as a feasible method for women to protect themselves against HIV sexual transmission), or in the form of sterile injectable solutions for parenteral use.
  • a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • excipient includes both one and more than one such excipient.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, and encapsulating materials.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary bmding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions may be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing, and thickening agents.
  • Aqueous suspensions may be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • the compounds of the present disclosure may be formulated for parenteral administration (e. g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the compounds of the present disclosure can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and where patient compliance with a treatment regimen is important.
  • Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington : The Science and Practice of Pharmacy 2005, edited by Philip P. Gerbino, Lippincott Williams & Wilkins, 21st edition. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present disclosure unstable or compromising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
  • terapéuticaally effective amount means an amount required to significantly inhibit viral load in vivo and to reduce related symptoms of the disease in an individual.
  • the dose may be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
  • the active compound or a salt can be administered in combination with other antiviral agents, such as nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV integrase inhibitors, and/or anti-HIV siRNA approach.
  • antiviral agents such as nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV integrase inhibitors, and/or anti-HIV siRNA approach.
  • the active compound or its derivative or salt are administered in combination with another antiviral agent the activity may be increased over the parent compound, and reduced frequency for drug resistance of the virus.
  • the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives.
  • Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or
  • references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions.
  • treatment of a HIV infection also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HIV infection, or the clinical symptoms thereof
  • solvate means a compound of the disclosure or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/ or acceptable for administration to humans in trace amounts.
  • hydrate as used herein means a compound of the disclosure or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clafhrate as used herein means a compound of the disclosure or a salt thereof in the form of a crystal lattice that contains spaces (e. g., channels) that have a guest molecule (e. g. , a solvent or water) trapped within
  • a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
  • a compound refers to one or more compounds or at least one compound.
  • the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • a HIV-1 p24 ELISA Kit was purchased from the AIDS Vaccine Program of the Frederick Cancer Research and Development Center.
  • Luciferase assay system was purchased from Promega Com.
  • the CD4 + C8166 T cell line was maintained in RPMI-1640 medium containing 10% FCS and 1% penicillin and streptomycin.
  • the HIV-1 pNL4.3-GFP proviral plasmid was transfected into 293T cells.
  • the vesicular stomatitis virus G (VSV-G) glycoprotein pseudotyped single cycle replicating virus (pNL4.3VSV-G/Luc+) was produced in 293T by co-transfected HIV-1 provirus pNL4.3ABgl/Luc+ with a VSV-G expresser.
  • viruses 100pg of HIVp24 were incubated with
  • HIV-1 Gag-p24 antigen in each infected culture supernatant by HIV-1 Gag-p24 ELISA.
  • infected cells were fixed with PBS-4% Para formaldehyde and observed under fluorescence microscopy. The HIV syncytia formation was observed under microscopy.
  • luciferase lysis buffer Promega. 10 ⁇ of cell lysate were subjected to the luciferase assay by using a POLARstar OPTIMA (BMG LABTECH, Germany).
  • Compounds 2, 3, 4, and 5 also had an inhibitory effect on HIV infection although the effect was less marked than with Compound 1.

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Abstract

La présente invention concerne de nouveaux composés, ainsi que des utilisations, des procédés et des compositions pour le traitement, ou la réduction du risque, d'une infection par le VIH.
PCT/CA2011/000070 2010-01-20 2011-01-20 Composés antiviraux et compositions WO2011088561A1 (fr)

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US29682710P 2010-01-20 2010-01-20
US29680910P 2010-01-20 2010-01-20
US61/296,827 2010-01-20
US61/296,809 2010-01-20

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WO2013096744A1 (fr) * 2011-12-21 2013-06-27 Novira Therapeutics, Inc. Agents antiviraux de l'hépatite b
WO2014165128A3 (fr) * 2013-03-12 2014-12-11 Novira Therapeutics, Inc. Agents antiviraux contre l'hépatite b
EP2823816A1 (fr) * 2013-07-09 2015-01-14 Tragex Pharma Inhibiteur de la neuropiline et son utilisation pour le traitement des maladies liées à la neuropiline
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
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US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US12011425B2 (en) 2023-01-25 2024-06-18 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009018219A2 (fr) * 2007-07-28 2009-02-05 University Of Chicago Procédés et compositions pour moduler rad51, et recombinaison homologue

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009018219A2 (fr) * 2007-07-28 2009-02-05 University Of Chicago Procédés et compositions pour moduler rad51, et recombinaison homologue

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CA 7 February 2005 (2005-02-07), retrieved from 2224614 accession no. STN Database accession no. 827013-98-9 *

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