WO2018199798A1 - Dérivés peptidiques d'une préparation antivirale zanamivir - Google Patents

Dérivés peptidiques d'une préparation antivirale zanamivir Download PDF

Info

Publication number
WO2018199798A1
WO2018199798A1 PCT/RU2017/000278 RU2017000278W WO2018199798A1 WO 2018199798 A1 WO2018199798 A1 WO 2018199798A1 RU 2017000278 W RU2017000278 W RU 2017000278W WO 2018199798 A1 WO2018199798 A1 WO 2018199798A1
Authority
WO
WIPO (PCT)
Prior art keywords
influenza virus
zanamivir
general formula
associate
type
Prior art date
Application number
PCT/RU2017/000278
Other languages
English (en)
Russian (ru)
Inventor
Николай Владимирович БОВИН
Александр Александрович ЧИНАРЁВ
Original Assignee
Общество с ограниченной ответственностью "Синтавр"
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 Общество с ограниченной ответственностью "Синтавр" filed Critical Общество с ограниченной ответственностью "Синтавр"
Priority to PCT/RU2017/000278 priority Critical patent/WO2018199798A1/fr
Publication of WO2018199798A1 publication Critical patent/WO2018199798A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to the chemistry of organic compounds, pharmacology and medicine, and relates to the development and preparation of co-associates consisting of various types of oligoglycine molecules that are highly effective in inhibiting the influenza virus.
  • Viral diseases are responsible for both global pandemics and annual seasonal epidemics such as influenza. Outbreaks of disease can be characterized by increased virulence and can occur suddenly, leading to high mortality. Importantly, viral diseases are not limited to diseases in humans. For example, flu also affects livestock and birds.
  • influenza virus drugs are used whose action is aimed at suppressing the replication of the influenza virus.
  • the main target for drug intervention is viral neuraminidase, an enzyme necessary for the normal budding of viral particles and the manifestation of the infectious properties of the influenza virus.
  • Zanamivir is the first derivative of guanidino-neuraminic acid that acts on the neuraminidase of the influenza virus, which has become used as a medicine against the influenza virus. Subsequent developments [11] were aimed at obtaining analogues, with increased activity and bioavailability, as well as prolonged action. Dimerization of the zanamivir molecule by combining two monomers at hydroxyl 07 resulted in the production of an analog of approximately the same activity as the monomer, but with a prolonged action. However, this is not enough for effective treatment of influenza, since zanamivir and similar neuraminidase inhibitors only reduce the duration of the disease by 1 to 2 days, but do not lead to a radical rapid cure, and are also unable to act preventively.
  • antenna peptides - [H-Gly n -NH] 2 -4X representing from 2 to 4 oligoglycine chains (antennas) associated with a branching center (X), which is used as ⁇ , ⁇ -diaminoalkane oligoethyleneglycol with terminal amino groups, as well as di, are tri- and tetraamino derivatives of pentaerythritol.
  • the antennas reach a critical size, 4 - 7 Gly residues, the peptide molecules are capable of spontaneous self-assembly of supramers.
  • supramers they are polyglycine-I structures, where oligoglycine chains are located at the sites of the hexagonal lattice, spiral, and multiple hydrogen bonds arise between them.
  • oligoglycine chains are located at the sites of the hexagonal lattice, spiral, and multiple hydrogen bonds arise between them.
  • transmission electron and scanning probe microscopy methods it was shown that morphologically the supramers are extended planar formations (20 crystals); their height approximately corresponds to the length of the peptide molecule (40-70 A), and planar sizes vary in the range from 50 to 5000 nm.
  • Substituents of various nature can be covalently attached to the ends of the antennas of the branched molecules (directly or via a spacer / linker insert, sp); modified [R-sp-Gly n- NH] 2-4 X molecules are also capable of self-assembly as polyglycine-ll.
  • the surface of the formed supramers is covered with R groups, which ensure the solubility of the supramers in water, their resistance to sedimentation, as well as biological activity.
  • the indicated effect is caused by the specific recognition of neuraminic acid (Neu5Aca) residues by the viral lectin hemagglutinin (HA); this interaction is weak (K D ⁇ 1 ⁇ mol) at the monovalent level, but its affinity increases by 2–3 orders of magnitude with multipoint binding of the virus to glycopeptide supramers.
  • glycopeptide supramers adsorbed on viral particles sterically hinder the interaction of the latter with target cells.
  • the principle of the suppression of infectivity described above was proposed to be used for the construction of new generation antiviral drugs [1, 3-6].
  • supramers of mixed composition consisting of glycopeptide molecules and a diluent peptide [Suc-Gly 6 -NH (CH 2 ) 2] 2, the antennas of which are terminated with small hydrophilic groups (for example, ⁇ ( ⁇ 2 ) 2 C (0) -), which do not significantly affect the self-assembly of supramers (Fig. 1).
  • Mixed supramers suppress the interaction of fetuin with the influenza virus even in micromolar concentrations (1C 50 ⁇ 0.1 - 10 ⁇ mol), being 2–3 orders of magnitude more powerful blockers than monomeric 6'SLN.
  • the present invention is the creation of new effective inhibitors of influenza viruses of humans and animals based on zanamivir, promising for use in clinical practice.
  • the technical result of the invention is the development and preparation of new effective inhibitors of human and animal influenza viruses based on zanamivir, as well as the development and preparation of new multimeric derivatives (co-associates), which possess not only a prolonged action, but also an increased inhibitory activity against neuraminidase, and as a result, they are characterized by an increased ability to suppress the reproduction of the influenza virus.
  • X represents a spacer group
  • p is an integer from 6 to 10.
  • the spacer group X is —OC (0) NH (CH 2 ) 6 NHCO (CH 2 ) 4 CO—.
  • n 9.
  • X represents a spacer group
  • p is an integer from 6 to 10;
  • n is an integer from 6 to 10;
  • R represents ⁇ -, NOOSSN 2 CH 2 CO— or HOSN 2 CO—;
  • the molar ratio of compounds (I) and (II) in the co-associate is from 1: 10 to
  • the spacer group X is —OC (0) NH (CH 2 ) 6 NHCO (CH 2 ) 4 CO—.
  • n 9.
  • m is 9.
  • Y is a linker for linking the activated carboxyl group —COOW to a spacer
  • W represents an activating residue
  • W is a 4-paranitrophenyl moiety.
  • the present invention also relates to the use of compounds of the general formula (I) as well as co-associates of the invention as inhibitors of human influenza viruses.
  • the types of virus for which the co-associates of the invention can be used are A or B.
  • the subtype of type A human influenza virus is H1 or NC.
  • the invention relates to the use of compounds of general formula (I), as well as co-associates of the invention, for the manufacture of a medicament for the treatment and / or prophylaxis of diseases associated with the human influenza virus.
  • the invention also includes pharmaceutical compositions for treating and / or preventing diseases associated with human influenza viruses, comprising a therapeutically effective amount of compounds of the general formula (I) or co-associates of the invention.
  • the invention also includes the preparation of compounds of general formula (I) as well as co-associates of the invention.
  • a chaotropic agent is a substance capable of breaking hydrogen bonds, for example, a thiocyanate anion or urea.
  • An associate is physically stable (that is, one that can be reliably detected by physical methods) at the considered temperature, a complex of identical (associate) or different (co-associate) small molecules that are not interconnected by covalent bonds.
  • Supramer is a general term that includes both homogeneous associates (see above) and co-associates.
  • Influenza virus - as used herein means any strain of human influenza viruses. That is, any type of human influenza virus selected from types A or B. In particular, any type of human influenza virus type A that has a subtype of H1 or NS, determined by the antigenicity of the surface hemagglutinin protein; however, the virus subtype determined by the surface protein neuraminidase can be any. Human influenza C viruses and avian influenza viruses are not included in this document.
  • a linker is a molecular fragment connecting two functional fragments of a bioconjugate, in this case, a fragment responsible for binding to a virus and a fragment responsible for association.
  • the linker does not significantly affect the properties of the bioconjugate, therefore, they strive to make it as simple as possible. Since the properties of the linker can be performed by an infinite variety of molecular fragments, it is difficult to define it in the form of a chemical formula, and therefore it is advisable to use the term “linker” as a substitute for the chemical formula.
  • Activating residue is a molecular group used to increase the reactivity of a carboxyl group in amidation reactions.
  • any activating residues including, for example, such as 4-nitrophenyl, pentachlorophenyl, 4.000 Congresspellorophenyl and others.
  • Zanamivir (Zanamivir, Zn) - (2R, 3R, 4S) - 4 - [(diaminomelidene) amino] - 3-acetamido-2 - [(1 R, 2R) - 1, 2,3-trihydroxypropyl] - 3.4 -dihydro-2H-pyran-6-carboxylic acid.
  • compositions are those which, within the framework of a medical report, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, etc., and correspond to a reasonable ratio of benefit and risk.
  • pharmaceutically acceptable non-toxic salts include those formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic, citric or malonic acids. Description of drawings
  • Figure 2 Scheme for the synthesis of a zanamivir derivative with an activated carboxyl group in the spacer of the general formula - zanamivir-XY-COOW.
  • Reagents and conditions i. MeONa, MeON, 4 h, room t-pa, silica gel chromatography; ii. p- N0 2 C 6 H 4 OCOCI, DMAP, Ru, 12 h, room. t-pa, silica gel chromatography; iii. BocNH (CH 2 ) NH 2 , DMAP, Ru, 12 h, br. t-pa, silica gel chromatography; iv. Ph 3 P, THF, 12 h, br t-ra; v.
  • the second way to obtain multimers is to create star-like molecules and similar ones, when a limited number of ligands (3 - 8) are usually attached to a symmetric matrix, which, unlike polymers, has a certain structure; their main disadvantage is the relatively short distance between the ligands, which does not allow true multi-point binding to the target.
  • the distance between the sial-binding proteins of the influenza virus exceeds the distance of 10 nm [6], which is difficult to achieve within the framework of the concept of this type of multimeric molecules.
  • the first problem (associated with polymers) is solved by the use of supramers instead of true polymers [10]
  • the second problem is solved by the optimal (usually significant, as in the above example of the sial-binding proteins of the influenza virus) distance between ligands - the development and use of a co-associate that uses “diluent” molecules [10].
  • the drug zanamivir (Zn) is a 4-guanidino derivative of the neuraminic acid glycol, which is an analogue of the transition state of the sialic substrate in the catalytic site of neuraminidase (NA) [1 1, 12], it acts on neuraminidase and not on influenza hemagglutinin.
  • NA neuraminidase
  • the number of copies of neuraminidase (target of action of zanamivir) on the virion is approximately three times lower than
  • Branched associating peptides including molecules with four oligoglycine antennas, were previously prepared using the activated ester method in the classical solution version of its implementation [1].
  • the synthesis scheme for self-associated tetrant oligoglycines includes several cycles of lengthening of peptide antennas; the antennas are sequentially expanded onto one or two glycine residues, starting with tetraaminomethylmethane [NH 2 CH 2 ] 4C, which serves as a branching center.
  • the first step within each cycle is the acylation of tetraamine with the tert-butyloxycarbonylglycine / glycylgicin L / -oxysuccinimide ester (Boc-Gly-OSu / Boc-Gly 2 -OSu); a complete reaction is achieved through the use of an excess of activated ether (10 - 20 mol.% based on NH 2 -rpynny).
  • ninhydrin reagent 2.5 g of ninhydrin in a mixture of Me 2 CO / H 2 0 / AcOH, 96: 4: 1
  • Mass spectra were obtained on a Vision-2000 time-of-flight spectrometer (Thermo Bioanalysis Corp., Great Britain) with laser ionization of the sample from the matrix surface (MALDI), which was used as dihydroxybenzoic acid.
  • MALDI matrix surface
  • SUBSTITUTE SHEET (RULE 26) A solution of 100 ⁇ mol [Suc-Gly 9- NHCH 2 ] 4C in 1 ml of distilled water (pH about 6) or in PBS buffer (sodium phosphate buffer) (pH about 7) is heated to 60-80 for 1-2 minutes ° C. To the resulting heated solution was added a solution of 10 ⁇ mol [Zanamivir-X-C1u 9- MCHS 2 ] 4 C in distilled water (0.5 ml) at a temperature of 60-80 ° C, after which the resulting solution was cooled to room temperature over 10-20 minutes ; the resulting co-associate is stored at 4 ° C and used without further manipulation, except for dilution.
  • the subject of the invention also includes the administration to a subject in need of appropriate treatment or prophylaxis of a therapeutically effective amount of zanamivir inhibitors of the general formula (I) or a co-associate of the invention.
  • a therapeutically effective amount is meant such an amount of a zanamivir inhibitor of general formula (I) or a co-associate of the invention, administered or delivered to a patient, in which the patient is most likely to exhibit the desired response to treatment (prophylaxis).
  • the exact amount required can vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.
  • An inhibitor of general formula (I) or a co-associate of the invention or a pharmaceutical composition containing a compound of general formula (I) or co-associate can be administered to the patient in any amount and by any route of administration effective for treating or preventing a disease.
  • compositions comprising the essence of the invention can be administered orally, parenterally, topically, and the like to the human or other animals.
  • a compound of general formula (I) or a co-associate can be administered daily to a patient for a certain period of days (e.g. 2-10 days), and then a period follows without taking a compound of general formula (I) or co-associate ( e.g. 1-30 days).
  • a dose of each of the components of the combination therapy is administered during the desired treatment period.
  • Compounds of combination therapy may be administered the patient both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.
  • the invention also relates to pharmaceutical compositions that contain the compounds of the invention (or a prodrug or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such as can be administered to the patient in conjunction with -associates constituting the essence of the present invention, and which do not destroy the pharmacological activity of this co-associate, and are also non-toxic when administered in doses sufficient for accurate delivery of a therapeutic amount of the compound.
  • compositions of this invention comprise a compound of general formula (I) or co-associates in conjunction with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers , preservatives, binders, lubricants, etc., suitable for a particular dosage form.
  • pharmaceutically acceptable carriers may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers , preservatives, binders, lubricants, etc.
  • Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers.
  • excipients such as cocoa butter and suppository wax
  • oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil
  • glycols such as propylene glycol
  • esters such as ethyl oleate and ethyl laur
  • composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate
  • dyes such as sodium lauryl sulfate and magnesium stearate
  • release fluids such as sodium lauryl sulfate and magnesium stearate
  • film-forming agents such as sodium lauryl sulfate and magnesium stearate
  • sweeteners such as sodium lauryl sulfate and magnesium stearate
  • flavors and fragrances such as sodium lauryl sulfate and magnesium stearate
  • preservatives and antioxidants such as sodium lauryl sulfate and magnesium stearate
  • the subject of this invention is also dosage forms — a class of pharmaceutical compositions whose composition is optimized for a particular route of administration into the body in a therapeutically effective dose, for example, for administration to the body orally, topically, pulmonally, for example, as an inhalation spray, or intravascularly, intranasally , subcutaneously, intramuscularly, as well as by the infusion method, in recommended dosages.
  • a therapeutically effective dose for example, for administration to the body orally, topically, pulmonally, for example, as an inhalation spray, or intravascularly, intranasally , subcutaneously, intramuscularly, as well as by the infusion method, in recommended dosages.
  • Dosage forms of the present invention may contain formulations prepared using liposome methods, microencapsulation methods, methods of preparing nanoforms of the drug, or other methods known in the pharmaceutical industry.
  • the active principle is mixed with one or more pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
  • pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
  • Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.
  • a pharmaceutical composition in the form of a gelatin capsule can be prepared by mixing the active principle with a solvent and filling the mixture with soft or hard capsules.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used that contain pharmacologically compatible agents, for example propylene glycol or butylene glycol.
  • zanamivir derivatives of general formula (I), as well as co-associates of the invention are able to inhibit infection of cells with influenza viruses much more effectively than monomeric zanamivir.
  • suprameric molecules of the invention in addition to high antiviral activities are also characterized by low toxicity, and they are also free from the drawback that characterizes the polymer derivatives of zanamivir - the uncertainties of their structure.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne la chimie des composés organiques, de la pharmacie et de la médecine humaine et notamment la mise au point et l'obtention d'un nouveau médicament pour traiter des maladies provoquées par le virus de la grippe. A cet effet on utilise des dérivés de Zanamavir ayant la formule générale (I) [Zanamivir-Х-Glyn-NHCH2]4С, ainsi que des co-associés constitués de molécules oligoglycéniques de types différents, et notamment le dérivé de Zanamavir ayant la formule générale (I): [Zanamivir-Х-Glyn-NHCH2]4С, et d'un peptide sélectionné parmi les peptides de formule générale (II): [R-GlynGlym-NHCH2]4C, dans lesquels, n, R et Х ont des valeurs indiquées dans le descriptif. Le rapport molaire d'un dérivé de Zanamivir (I) et d'un peptide (II) dans un co-associé est compris entre 1:10 et 1:100. Ces co-associés ont une efficacité élevée en termes d'inhibition des virus de la grippe et offrent de bonnes perspectives en termes de leur utilisation dans la pratique clinique. La présente invention concerne également des compositions pharmaceutiques contenant une quantité thérapeutiquement efficace de co-associés de l'invention.
PCT/RU2017/000278 2017-04-28 2017-04-28 Dérivés peptidiques d'une préparation antivirale zanamivir WO2018199798A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/RU2017/000278 WO2018199798A1 (fr) 2017-04-28 2017-04-28 Dérivés peptidiques d'une préparation antivirale zanamivir

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2017/000278 WO2018199798A1 (fr) 2017-04-28 2017-04-28 Dérivés peptidiques d'une préparation antivirale zanamivir

Publications (1)

Publication Number Publication Date
WO2018199798A1 true WO2018199798A1 (fr) 2018-11-01

Family

ID=63919943

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2017/000278 WO2018199798A1 (fr) 2017-04-28 2017-04-28 Dérivés peptidiques d'une préparation antivirale zanamivir

Country Status (1)

Country Link
WO (1) WO2018199798A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055149A1 (fr) * 1999-03-12 2000-09-21 Biota Scientific Management Pty. Ltd. Composes dimeres en tant qu'inhibiteurs de la neuraminidase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055149A1 (fr) * 1999-03-12 2000-09-21 Biota Scientific Management Pty. Ltd. Composes dimeres en tant qu'inhibiteurs de la neuraminidase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WATSON, KEITH G. ET AL.: "Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 6, 2004, pages 1589 - 1592, XP055383072 *

Similar Documents

Publication Publication Date Title
NZ747501A (en) Amino acid derivatives functionalized on the n-terminal capable of forming drug encapsulating microspheres
US6444706B2 (en) Guanidine derivatives, processes for preparing them and their use as pharmaceutical compositions
JP2014111628A (ja) ウイルス融合のインヒビターのコレステロール誘導体
RU2676713C2 (ru) Терапевтические пептиды
WO2005116036A1 (fr) Derives de curcumol, composition en comprenant, et leur utilisation pour la fabrication de medicaments
CN111718395B (zh) 一种前药激活化合物、前药体系及其制备方法和应用
WO2021164677A1 (fr) Inhibiteur capable de résister à la fusion du virus respiratoire syncytial
WO2017152756A1 (fr) Conjugué crgd-erlotinib et son procédé de préparation
EP0374888A3 (fr) Tannins sulfatés et leurs sels
JPH07505371A (ja) 免疫調節活性を有する新規親油性オリゴペプチド
US7268162B2 (en) Aloe-emodin derivatives and their use in the treatment of neoplasias
US9828333B2 (en) Compounds for the treatment of influenza
EP2599783B1 (fr) N6 -(ferrocenylmethyl)quinazoline-2,4,6-triamine (h2), ses dérivés et promédicaments, utilisés en tant qu'agents anti-microbiens, anti-parasitaires, anti-protozoaires et anti-leishmanias
JP5583017B2 (ja) インフルエンザウイルス感染症の予防ないし治療剤
WO2020057422A1 (fr) Dérivé du sulfonium de vancomycine et procédé de préparation de celui-ci, composition pharmaceutique et utilisations
WO2018199798A1 (fr) Dérivés peptidiques d'une préparation antivirale zanamivir
JP6910043B2 (ja) ヘマグルチニン結合ペプチド、および、これを含むインフルエンザウイルス感染症の予防・治療薬
US6440946B1 (en) Multiple-agents-binding compound, production and use thereof
US10059743B2 (en) Peptide derivative for regulating thymic stromal lymphoid protein-mediated signaling and pharmaceutical composition for preventing and treating allergy and asthma diseases comprising same
BG63208B1 (bg) Бициклични тахикининови антагонисти, тяхното приготовляване и използуване в фармацевтични състави
CN116262132A (zh) 抗胰腺癌多肽药物偶联物及其无载体自组装纳米药物和制备方法及应用
CN110922450B (zh) Psma激活式抗肿瘤前药cpt-x及其制备方法和应用
WO2015096725A1 (fr) Lipopeptide linéaire pourvu d'un groupe terminal présentant une structure lipophile, son procédé de préparation et son utilisation
RU2612221C1 (ru) Блокаторы вируса гриппа
WO2019223644A1 (fr) Polypeptide, composition pharmaceutique et utilisation associées

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: 17906956

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: 17906956

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 19/12/2019)