WO2018078149A1 - Nouveaux composés cyclicsulfonimidoylpurinone et dérivés pour le traitement et la prophylaxie d'infection virale - Google Patents

Nouveaux composés cyclicsulfonimidoylpurinone et dérivés pour le traitement et la prophylaxie d'infection virale Download PDF

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WO2018078149A1
WO2018078149A1 PCT/EP2017/077707 EP2017077707W WO2018078149A1 WO 2018078149 A1 WO2018078149 A1 WO 2018078149A1 EP 2017077707 W EP2017077707 W EP 2017077707W WO 2018078149 A1 WO2018078149 A1 WO 2018078149A1
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compound
amino
purin
methyl
benzyl
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PCT/EP2017/077707
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English (en)
Inventor
Chungen Liang
Kun MIAO
Hong Shen
Hongying Yun
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Publication of WO2018078149A1 publication Critical patent/WO2018078149A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Novel cyclicsulfonimidoylpurinone compounds and derivatives for the treatment and prophylaxis of virus infection are novel cyclicsulfonimidoylpurinone compounds and derivatives for the treatment and prophylaxis of virus infection
  • the present invention relates to novel sulfonimidoylpurinones and their derivatives that have Toll-like receptor agonism activity and their prodrugs thereof, as well as their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.
  • the present invention relates to compounds of formula (I),
  • R 1 , R 2 , R 3 and n are described below, or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
  • TLRs Toll-like receptors detect a wide range of conserved pathogen-associated molecular patterns (PAMPs). They play an important role of sensing invading pathogens and subsequent initiation of innate immune responses.
  • PAMPs pathogen-associated molecular patterns
  • TLR3 TLR7 TLR8, and TLR9 are located within endosomes.
  • TLR7 can be activated by binding to a specific small molecule ligand (i.e., TLR7 agonist) or its native ligand (i.e., single-stranded RNA, ssRNA). Following binding of ssRNA to TLR7, the receptor in its dimerized form is believed to undergo a structural change leading to the subsequent recruitment of adapter proteins at its cytoplasmic domain, including the myeloid differentiation primary response gene 88 (MyD88). Following the initiation of the receptor signalling cascade via the MyD88 pathway, cytoplasmic transcription factors such as interferon regulatory factor 7 (IRF-7) and nuclear factor kappa B (NF- ⁇ ) are activated.
  • IRF-7 interferon regulatory factor 7
  • NF- ⁇ nuclear factor kappa B
  • TLR7 is predominately expressed on plasmacytoid cells, and also on B-cells. Altered responsiveness of immune cells might contribute to the reduced innate immune responses during chronic viral infections. Agonist-induced activation of TLR7 might therefore represent a novel approach for the treatment of chronic viral infections.
  • the current therapy of chronic HBV infection is based on two different types of drugs: the traditional antiviral nucleos(t)ide analogues and the more recent Pegylated IFN-a (PEG-IFN-a).
  • the oral nucleos(t)ide analogues act by suppressing the HBV replication. This is a life-long course of treatment during which drug resistance often occurs.
  • PEG-IFN-a Pegylated IFN-a
  • Pegylated IFN-a (PEG-IFN-a) has been used to treat some chronic infected HBV patients within finite therapy duration. Although it has achieved seroconversion in HBeAg at least in a small percentage of HBV patients, the adverse effect makes it poorly tolerable. Notably, functional cure defined as HBsAg seroconversion is very rare with both current therapies. A new generation therapeutic option to treat HBV patients for a functional cure is therefore of urgent need.
  • PEG-IFN-a Pegylated IFN-a
  • PEG-IFN-a is currently used to treat chronic HBV and is an alternative to potentially life-long treatment with antiviral nucleos(t)ide analogues.
  • PEG-IFN- ⁇ therapy can induce sustained immunologic control of the virus following a finite duration of therapy.
  • the percentage of HBV patients that achieve seroconversion with interferon therapy is low (up to 27% for HBeAg-positive patients) and the treatment is typically poorly tolerated.
  • TLR7 agonist As far Imiquimod (ALDARATM) is a U.S. FDA approved TLR7 agonist drug for topical use to treat skin lesions by human papillomavirus.
  • TLR7/8 dual agonist resiquimod (R-848) and the TLR7 agonist 852A have been evaluated for treating human genital herpes and chemotherapy- refractory metastatic melanoma, respectively.
  • ANA773 is an oral pro-drug TLR7 agonist, developed for the treatment of patients with chronic hepatitis C virus (HCV) infection and chronic hepatitis B infection.
  • GS-9620 is an orally available TLR7 agonist.
  • a phase lb study demonstrated that treatment with GS-9620 was safe, well tolerated and resulted in dose- dependent ISG15 mRNA induction in patients with chronic hepatitis B (E. J.
  • the present invention provides a series of novel 6-amino-2-sulfonimidoyl-9-substituted- 7H-purin-8-one compounds that have Toll-like receptor agonism activity and their prodrugs.
  • the invention also provides the bio-activity of such compounds to induce SEAP level increase by activating Toll-like receptors, such as TLR7 receptor, the metabolic conversion of prodrugs to parent compounds in the presence of human hepatocytes, and the therapeutic or prophylactic use of such compounds and their pharmaceutical compositions comprising these compounds and their prodrugs to treat or prevent infectious disease like HBV or HCV.
  • the present invention also provides compounds with superior activity.
  • the compounds of formula (I) also show good solubility, selectivity over TLR8, in vitro and in vivo clearance, Ames, hERG, GSH, PK and safety profiles.
  • the present invention relates to novel compounds of formula (I),
  • R 1 and R 2 are independently selected from H and Ci-6alkyl
  • R 3 is benzyl, said benzyl being unsubstituted or substituted by halogen, cyano, Ci ealkyl or Ci- 6alkoxy;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • the invention also relates to their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I), thereof as TLR7 agonist. Accordingly, the compounds of formula (I) are useful for the treatment or prophylaxis of HBV and/or HCV infection with Toll-like receptors agonism.
  • Ci-6alkyl denotes a saturated, linear or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, w-propyl, isopropyl, w-butyl, isobutyl, iert-butyl and the like.
  • Particular "Ci-6alkyl” groups are methyl, ethyl and w -propyl.
  • Ci-6alkoxy denotes a group of the formula Ci-6alkyl-0-.
  • Examples of Ci- 6 alkoxy group include, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and ie/t-butoxy.
  • Particular "Ci-6alkoxy” groups are methoxy, ethoxy and isopropoxy.
  • a more particular Ci-6alkoxy group is ethoxy.
  • halogen and "halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.
  • enantiomer denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • diastereomer denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.
  • Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
  • pharmaceutically acceptable salts denotes salts which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts include both acid and base addition salts.
  • pharmaceutically acceptable acid addition salt denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, /?-toluen
  • pharmaceutically acceptable base addition salt denotes those pharmaceutically acceptable salts formed with an organic or inorganic base.
  • acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.
  • substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, trieth
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L- tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • an optically active acid such as e.g. D- or L- tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • a pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect.
  • therapeutically effective amount denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • composition denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with
  • pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.
  • the present invention relates to (i) a compound of formula (I),
  • R 1 and R 2 are independently selected from H and Ci-6alkyl
  • R 3 is benzyl, said benzyl being unsubstituted or substituted by halogen, cyano, Ci ealkyl or Ci-
  • n 0, 1, 2, 3, 4, 5 or 6;
  • a further embodiment of present invention is (ii) a compound of formula (I), wherein R 1 and R 2 are simultaneously H or Ci-6alkyl;
  • R 3 is benzyl, said benzyl being unsubstituted or substituted by halogen, Ci-6alkyl or Ci-6alkoxy; n is 1, 2 or 3;
  • a further embodiment of present invention is (iii) a compound of formula (I), wherein R 1 and R 2 are independently selected from H and methyl.
  • a further embodiment of present invention is (iv) a compound of formula (I), wherein R 1 and R 2 are simultaneously H or methyl.
  • a further embodiment of present invention is (v) a compound of formula (I), wherein R 3 is benzyl, methylbenzyl, fluorobenzyl, chlorobenzyl or methoxybenzyl.
  • a further embodiment of present invention is (vi) a compound of formula (I), wherein n is 1 or 2.
  • Another embodiment of present invention is (vii) a compound of formula (I), wherein
  • R 1 and R 2 are simultaneously H or methyl
  • R 3 is benzyl, methylbenzyl, fluorobenzyl, chlorobenzyl or methoxybenzyl;
  • n 1 or 2;
  • compounds of the present invention are selected from:
  • the compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R 1 to R 3 and n are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
  • a compound of formula VII is prepared by cyclization of isocyanate VIII with aminomalononitrile /?-toluenesulfonate.
  • the bicycle compound of formula VI is synthesized by reaction of compound of formula VII with benzoyl isothiocyanate in the presence of inorganic base, such as sodium hydroxide or potassium hydroxide. Alkylation of bicycle compound of formula VI with alkylhalide V in the presence of base, such as K2CO3, NaH or CS2CO3, gives compound of formula IV.
  • Compound of formula III is prepared by oxidation of compound of formula IV with an oxidant, such as meto-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct or HI0 4 .
  • Compound of formula II is obtained by imination of compound of formula III with imination reagent, such as sodium azide in acid, said acid is, for example, Eaton's reagent or PPA.
  • imination reagent such as sodium azide in acid
  • said acid is, for example, Eaton's reagent or PPA.
  • Compound of formula I is obtained by cyclization of compound of formula II in the presence of a base, such as sodium hydride.
  • This invention also relates to a process for the preparation of a compound of formula (I) comprising the following reaction:
  • R 1 , R 2 , R 3 and n are defined above.
  • the base can be for example sodium hydride.
  • a compound of formula (I) when manufactured according to the above process is also an object of the invention.
  • compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula (I) are formulated in an acetate buffer, at pH 5.
  • the compounds of formula (I) are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to activate TLR7 receptor and lead to produce INF-a and other cytokines, which can be used, but not limited, for the treatment or prevention of hepatitis B and/or C viral infected patients.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 50 mg/kg, alternatively about 0.1 to 30 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, preferably contain from about 20 to about 1000 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical
  • composition thereof or aid in the manufacturing of the pharmaceutical product (i.e.,
  • An example of a suitable oral dosage form is a tablet containing about 20 to 1000 mg of the compound of the invention compounded with about 30 to 90 mg anhydrous lactose, about 5 to 40 mg sodium croscarmellose, about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 20 to 1000 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salts or enantiomers or diastereomers thereof.
  • a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salts or enantiomers or diastereomers thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salts or enantiomers or diastereomers thereof for use in the treatment of hepatitis B virus infection.
  • the present invention provides methods for treating or preventing a hepatitis B viral infection and/or hepatitis C viral infection in a patient in need thereof.
  • the present invention further provides methods for introducing a therapeutically effective amount of a compound of formula (I) or other compounds of the invention into the blood stream of a patient for the treatment and/or prevention of hepatitis B and/or C viral infection.
  • the methods of the present invention are particularly well suited for human patients.
  • the methods and doses of the present invention can be useful for, but not limited to, HBV and/or HCV infected patients.
  • the methods and doses of the present invention are also useful for patients undergoing other antiviral treatments.
  • the prevention methods of the present invention are particularly useful for patients at risk of viral infection.
  • These patients include, but are not limited to health care workers, e.g., doctors, nurses, hospice care givers; military personnel; teachers; childcare workers; patients traveling to, or living in, foreign locales, in particular third world locales including social aid workers, missionaries, and foreign diplomats.
  • the methods and compositions include the treatment of refractory patients or patients resistant to treatment such as resistance to reverse transcriptase inhibitors, protease inhibitors, etc.
  • Another embodiment includes a method of treating or preventing hepatitis B viral infection and/or hepatitis C viral infection in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), or enantiomers, diastereomers, prodrugs or pharmaceutically acceptable salts thereof.
  • CDsOD deuterated methanol
  • CDI N,N'-carbonyl diimidazole
  • EC50 the molar concentration of an agonist, which produces 50% of the maximum possible response for that agonist.
  • EtOAc or EA ethyl acetate
  • PE petroleum ether
  • PPA polyphosphoric acid
  • Acidic condition A: 0.1% formic acid and 1% acetonitrile in H 2 O; B: 0.1% formic acid in acetonitrile;
  • Step 1 Preparation of 4-amino-3-benzyl-2-o o-lH-imidazole-5-carbonitrile
  • methanesulphonic acid was added sodium azide (4.5 g, 68.5 mmol) at 50 °C. After being stirred at this temperature for 30 min and cooled to RT. Three parallel reactions were performed using the same reaction conditions and three batches of the resulting mixture were combined. Then the reaction mixture was carefully poured into ammonium hydroxide solution (1.5 L, 1M) at 0 °C.
  • Step 6 Preparation of 6-amino-9-benzyl-2-(l-o o-4,5-dihydro-3H-isothiazol-l-yl)-7H- purin-8-one
  • Example 1-A 1.0 g, faster eluting
  • Example 1-B (1.05 g, slower eluting) as white solids with methanol 5%- 40% (0.05%DEA)/CO 2 on ChiralPak OD-3 column.
  • Example 1-A l H NMR (400 MHz, DMSO-J 6 ) ⁇ ppm: 10.57 (br s, IH), 7.23-7.35 (m, 5H), 6.99 (br s, 2H), 4.94 (s, 2H), 4.01-4.08 (m, IH), 3.74-3.81 (m, IH), 3.31-3.42 (m, IH), 3.09-3.19 (m, IH), 2.23-2.35 (m, IH), 2.12-2.22 (m, IH). MS obsd. (ESI + ) [(M+H) + ] : 345.
  • Example 1-B l H NMR (400 MHz, DMSO-J 6 ) ⁇ ppm: 10.57 (br s, IH), 7.23-7.35 (m, 5H), 7.00 (br s, 2H), 4.95 (s, 2H), 4.01-4.08 (m, IH), 3.74-3.81 (m, IH), 3.31-3.42 (m, IH), 3.10-3.19 (m, IH), 2.22-2.34 (m, IH), 2.12-2.22 (m, IH). MS obsd. (ESI + ) [(M+H) + ] : 345.
  • Step 5 Preparation of 6-amino-2-(3-chloropropylsulfinyl)-9- ⁇ -tolylmethyl)-7H-purin-8- one
  • Step 6 Preparation of 6-amino-2-(3-chloropropylsulfonimidoyl)-9- ⁇ -tolylmethyl)-7H- purin-8-one
  • Compound 2f was prepared in analogy to Step 5 of Example 1 by using 6-amino-2-(3- chloropropylsulfinyl)-9-(p-tolylmethyl)-7H-purin-8-one (compound 2e) instead of 6-amino-9- benzyl-2-(3-chloropropylsulfinyl)-7H-purin-8-one (compound Id). 6-Amino-2-(3- chloropropylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one (11.0 g, compound 2f) was obtained as a yellow solid. MS obsd. (ESI + ) [(M+H) + ]: 395.
  • Step 7 Preparation of 6-amino-2-(l-o o-4,5-dihydro-3H-isothiazol-l-yl)-9-(p-tolylmethyl)- 7H-purin-8-one
  • Example 2 was prepared in analogy to Step 6 of Example 1 by using 6-amino-2-(3- chloropropylsulfonimidoyl)-9-(p-tolylmethyl)-7H-purin-8-one (compound 2f) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (compound le).
  • 6-Amino-2- (l-ojco-4,5-dihydro-3H-isothiazol-l-yl)-9-(' )-tolylmethyl)-7H-purin-8-one (6.0 g, Example 2) was obtained as a white solid.
  • Example 2-B slower eluting, 2.04 g as white solids with methanol 5 -40 (0.05 DEA)/CO 2 on ChiralPak OD-3 column.
  • Step 2 Preparation of 4-amino-3-[(4-chlorophenyl)methyl]-2-o o-lH-imidazole-5- carbonitrile
  • Step 4 Preparation of 6-amino-9-[(4-chlorophenyl)methyl]-2-(3-chloropropylsulfanyl)-7H- purin-8-one
  • Step 5 Preparation of 6-amino-9-[(4-chlorophenyl)methyl]-2-(3-chloropropylsulfinyl)-7H- purin-8-one
  • Compound 3e was prepared in analogy to Step 4 of Example 1 by using 6-amino-9-[(4- chlorophenyl)methyl]-2-(3-chloropropylsulfanyl)-7H-purin-8-one (compound 3d) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfanyl)-7H-purin-8-one (compound lc). 6-Amino-9-[(4- chlorophenyl)methyl]-2-(3-chloropropylsulfinyl)-7H-purin-8-one (10.5 g, compound 3e) was obtained as a brown solid. MS obsd. (ESI + ) [(M+H) + ]: 400.
  • Step 6 Preparation of 6-amino-9-[(4-chlorophenyl)methyl]-2-(3- chloropropylsulfonimidoyl)-7H-purin-8-one
  • Compound 3f was prepared in analogy to Step 5 of Example 1 by using 6-amino-9-[(4- chlorophenyl)methyl]-2-(3-chloropropylsulfinyl)-7H-purin-8-one (compound 3e) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfinyl)-7H-purin-8-one (compound Id). 6-Amino-9-[(4- chlorophenyl)methyl]-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (9.3 g, compound 3f) was obtained as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 415.
  • Step 7 Preparation of 6-amino-9-[(4-chlorophenyl)methyl]-2-(l-o o-4,5-dihydro-3H- isothiazol-l-yl)-7H-purin-8-one
  • Example 3 was prepared in analogy to Step 6 of Example 1 by using 6-amino-9-[(4- chlorophenyl)methyl]-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (compound 3f) instead of 6-amino-9-benzyl-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (compound le).
  • 6- Amino-9-[(4-chlorophenyl)methyl]-2-(l-ojco-4,5-dihydro-3H-isothiazol-l-yl)-7H-purin-8-one (4.7 g, compound 3) was obtained as a white solid.
  • Example 3-B slower eluting, 95 mg as white solids with methanol 5 -40 (0.05 DEA)/CO 2 on ChiralPak OD-3 column.
  • Step 2 Preparation of 4-amino-3-[(4-methoxyphenyl)methyl]-2-o o-lH-imidazole-5- carbonitrile
  • Step 4 Preparation of 6-amino-2-(3-chloropropylsulfanyl)-9-[(4-methoxyphenyl)methyl]- 7H-purin-8-one
  • Compound 4d was prepared in analogy to Step 3 of Example 1 by using 6-amino-9-[(4- methoxyphenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound 4c) instead of 6-amino-9-benzyl- 2-sulfanyl-7H-purin-8-one (compound lb). 6-Amino-2-(3-chloropropylsulfanyl)-9-[(4- methoxyphenyl)methyl]-7H-purin-8-one (18 g, compound 4d) was obtained as a yellow solid. MS obsd. (ESI + ) [(M+H) + ] : 380.
  • Step 5 Preparation of 6-amino-2-(3-chloropropylsulfinyl)-9-[(4-methoxyphenyl)methyl]- 7H-purin-8-one
  • Compound 4e was prepared in analogy to Step 4 of Example 1 by using 6-amino-2-(3- chloropropylsulfanyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one (compound 4d) instead of 6-amino-9-benzyl-2-(3-chloropropylsulfanyl)-7H-purin-8-one (compound lc). 6-Amino-2-(3- chloropropylsulfinyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one (16.0 g, compound 4e) was obtained as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 396.
  • Step 6 Preparation of 6-amino-2-(3-chloropropylsulfonimidoyl)-9-[(4- methoxyphenyl)methyl] -7H-purin-8-one
  • Compound 4f was prepared in analogy to Step 5 of Example 1 by using 6-amino-2-(3- chloropropylsulfinyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one (compound 4e) instead of 6-amino-9-benzyl-2-(3-chloropropylsulfinyl)-7H-purin-8-one (compound Id). 6-Amino-2-(3- chloropropylsulfonimidoyl)-9-[(4-methoxyphenyl)methyl]-7H-purin-8-one (8.5 g, compound 4f) was obtained as a grey solid. MS obsd. (ESI + ) [(M+H) + ]: 411.
  • Step 7 Preparation of 6-amino-9-[(4-methoxyphenyl)methyl]-2-(l-o o-4,5-dihydro-3H- isothiazol-l-yl)-7H-purin-8-one
  • Example 4 was prepared in analogy to Step 6 of Example 1 by using 6-amino-2-(3- chloropropylsulfonimidoyl)-9-[(4-methoxyphenyl)methyl] -7H-purin-8-one (compound 4f) instead of 6-amino-9-benzyl-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (compound le). 6-Amino-9-[(4-methoxyphenyl)methyl]-2-(l-ojco-4,5-dihydro-3H-isothiazol-l-yl)-7H-purin-8- one (5.0 g, Example 4) was obtained as a white solid.
  • Example 4-B slower eluting, 0.7 g as white solids with methanol 5 -40 (0.05 DEA)/CO 2 on ChiralPak OD-3 column.
  • Step 1 Preparation of l-fluoro-4-(isocyanatomethyl)benzene
  • Step 2 Preparation of 4-amino-3-[(4-fluorophenyl)methyl]-2-o o-lH-imidazole-5- carbonitrile
  • Compound 5c was prepared in analogy to Step 2 of Example 1 by using 4-amino-3-[(4- fluorophenyl)methyl]-2-ojco-lH-imidazole-5-carbonitrile (compound 5b) instead of 4-amino-3- benzyl-2-ojco- lH-imidazole-5-carbonitrile (compound la). 6-Amino-9-[(4- fluorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (32.0 g, compound 5c) was obtained as a yellow solid. MS obsd. (ESI + ) [(M+H) + ] : 292.
  • Step 4 Preparation of 6-amino-2-(3-chloropropylsulfanyl)-9-[(4-fluorophenyl)methyl]-7H- purin-8-one
  • Compound 5d was prepared in analogy to Step 3 of Example 1 by using 6-amino-9-[(4- fluorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound 5c) instead of 6-amino-9-benzyl-2- sulfanyl-7H-purin-8-one (compound lb). 6-Amino-2-(3-chloropropylsulfanyl)-9-[(4- fluorophenyl)methyl]-7H-purin-8-one (1.0 g, compound 5d) was obtained as a yellow solid. MS obsd. (ESI + ) [(M+H) + ] : 368.
  • Step 5 Preparation of 6-amino-2-(3-chloropropylsulfinyl)-9-[(4-fluorophenyl)methyl]-7H- purin-8-one
  • Compound 5e was prepared in analogy to Step 4 of Example 1 by using6-amino-2-(3- chloropropylsulfanyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one (compound 5d) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfanyl)-7H-purin-8-one (compound lc). 6-Amino-2-(3- chloropropylsulfinyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one (8.1 g, compound 5e) was obtained as a yellow solid. MS obsd. (ESI + ) [(M+H) + ] : 384.
  • Step 6 Preparation of 6-amino-2-(3-chloropropylsulfonimidoyl)-9-[(4- fluorophenyl)methyl]-7H-purin-8-one
  • Compound 5f was prepared in analogy to Step 5 of Example 1 by using6-amino-2-(3- chloropropylsulfinyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one (compound 5e) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfinyl)-7H-purin-8-one (compound Id). 6-Amino-2-(3- chloropropylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one (2.2 g, compound 5f) was obtained as an off-white solid. MS obsd. (ESI + ) [(M+H) + ] : 399.
  • Step 7 Preparation of 6-amino-9-[(4-fluorophenyl)methyl]-2-(l-o o-4,5-dihydro-3H- isothiazol-l-yl)-7H-purin-8-one
  • Example 5 was prepared in analogy to Step 6 of Example 1 by using 6-amino-2-(3- chloropropylsulfonimidoyl)-9-[(4-fluorophenyl)methyl]-7H-purin-8-one (compound 5f) instead of 6-amino-9-benzyl-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (compound le).
  • 6- Amino-9-[(4-fluorophenyl)methyl]-2-(l-ojcc>-4,5-dihydro-3H-isothiazol-l-yl)-7H-purin-8-one (1.9 g, Compound 5) was obtained as a white solid.
  • Example 5-B slower eluting, 20 mg as white solids with methanol 5 -40 (0.05 DEA)/CO 2 on ChiralPak OD-3 column.
  • Compound 6a was prepared in analogy to Step 3 of Example 1 by using 6-amino-9-[(4- chlorophenyl)methyl]-2-sulfanyl-7H-purin-8-one (compound 3c) and l-bromo-4-chlorobutane instead of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (compound lb) and l-bromo-3- chloropropane.
  • 6-Amino-2-(4-chlorobutylsulfanyl)-9-[(4-chlorophenyl)methyl]-7H-purin-8-one (1.5 g, compound 6a) was obtained as a yellow solid. MS obsd. (ESI + ) [(M+H) + ] : 398.
  • Step 2 Preparation of 6-amino-2-(4-chlorobutylsulfinyl)-9-[(4-chlorophenyl)methyl]-7H- purin-8-one
  • Compound 6b was prepared in analogy to Step 4 of Example 1 by using 6-amino-2-(4- chlorobutylsulfanyl)-9-[(4-chlorophenyl)methyl]-7H-purin-8-one (compound 6a) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfanyl)-7H-purin-8-one (compound lc). 6-Amino-2-(4- chlorobutylsulfinyl)-9-[(4-chlorophenyl)methyl]-7H-purin-8-one (370 mg, compound 6b) was obtained as a brown solid. MS obsd. (ESI + ) [(M+H) + ] : 414.
  • Step 3 Preparation of 6-amino-2-(4-chlorobutylsulfonimidoyl)-9-[(4-chlorophenyl)methyl]- 7H-purin-8-one
  • Compound 6c was prepared in analogy to Step 5 of Example 1 by using 6-amino-2-(4- chlorobutylsulfinyl)-9-[(4-chlorophenyl)methyl]-7H-purin-8-one (compound 6b) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfinyl)-7H-purin-8-one (compound Id). 6-Amino-2-(4- chlorobutylsulfonimidoyl)-9-[(4-chlorophenyl)methyl]-7H-purin-8-one (125 mg, compound 6c) was obtained as a white solid. MS obsd. (ESI + ) [(M+H) + ]: 429.
  • Step 4 Preparation of 6-amino-9-[(4-chlorophenyl)methyl]-2-(l-o o ⁇ 6 -thia-2- azacyclohexen-l-yl)-7H-purin-8-one
  • Example 6 was prepared in analogy to Step 6 of Example 1 by using 6-amino-2-(4- chlorobutylsulfonimidoyl)-9-[(4-chlorophenyl)methyl]-7H-purin-8-one (compound 6c) instead of 6-amino-9-benzyl-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (compound le). 6-amino- 9-[(4-chlorophenyl)methyl]-2-(l-ojco- 6 -thia-2-azacyclohexen-l-yl)-7H-purin-8-one (25 mg, Example 6) was obtained as a white solid.
  • Step 1 Preparation of l-chloro-3-iodo- -dimethyl-propane
  • Compound 7b was prepared in analogy to Step 3 of Example 1 by using l-chloro-3-iodo- 2,2-dimethylpropane (compound 7a) instead of l-bromo-3-chloropropane. 6-Amino-9-benzyl-2- (3-chloro-2,2-dimethyl-propyl)sulfanyl-7H-purin-8-one (1.9 g, compound 7b) was obtained as an off white solid. MS obsd. (ESI + ) [(M+H) + ] : 378.
  • Step 3 Preparation of 6-amino-9-benzyl-2-(3-chloro-2,2-dimethyl-propyl)sulfinyl-7H- purin-8-one
  • Step 4 Preparation of 6-amino-9-benzyl-2-[(3-chloro-2,2-dimethyl-propyl)sulfonimidoyl]- 7H-purin-8-one
  • Step 5 Preparation of 6-amino-9-benzyl-2-(4,4-dimethyl-l-oxo-3,5-dihydroisothiazol-l-yl)- 7H-purin-8-one
  • Example 7 was prepared in analogy to Step 6 of Example 1 by using 6-amino-9-benzyl-2- [(3-chloro-2,2-dimethyl-propyl)sulfonimidoyl]-7H-purin-8-one (compound 7d) instead of 6- amino-9-benzyl-2-(3-chloropropylsulfonimidoyl)-7H-purin-8-one (compound le).
  • 6-Amino-9- benzyl-2-(4,4-dimethyl-l-oxo-3,5-dihydroisothiazol-l-yl)-7H-purin-8-one (73 mg, Example 7) was obtained as a white solid.
  • Example 7-B (slower eluting, 34 mg) as white solids with methanol 5 -40 (0.05 DEA)/CO 2 on ChiralPak OD-3 column.
  • a stable HEK293-Blue-hTLR-7 cell line was purchased from InvivoGen (Cat.#: hkb-htlr7, San Diego, California, USA). These cells were designed for studying the stimulation of human TLR7 by monitoring the activation of NF- ⁇ .
  • a SEAP secreted embryonic alkaline
  • QUANTI-BlueTM kit (Cat.#: rep-qbl, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, a detection medium that turns purple or blue in the presence of alkaline phosphatase.
  • HEK293-Blue-hTLR-7 cells were incubated with addition of 20 ⁇ ⁇ test compound in a serial dilution in the presence of final DMSO at 1% and perform incubation under 37 °C in a C0 2 incubator for 20 hrs. Then 20 ⁇ ⁇ of the supernatant from each well was incubated with 180 ⁇ ⁇ Quanti-blue substrate solution at 37°C for 2 hrs and the absorbance was read at 620-655 nm using a spectrophotometer.
  • the signalling pathway that TLR7 activation leads to downstream NF-KB activation has been widely accepted, and therefore similar reporter assay was also widely used for evaluating TLR7 agonist (Tsuneyasu Kaisho and Takashi Tanaka, Trends in
  • the Compounds and Examples of the present invention were tested in HEK293-hTLR-7 assay for their TLR7 agonism activity as described herein and results are listed in Table 1.
  • the compounds of the invention were found to have EC50 of about 0.1 ⁇ to about 0.9 ⁇

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Abstract

La présente invention concerne des composés de formule (I), dans laquelle R1, R2 et R3 et n sont tels que décrits dans la description, ou un sel, un énantiomère ou un diastéréoisomère pharmaceutiquement acceptables de ceux-ci, et des compositions comprenant ces composés ainsi que des procédés d'utilisation de ces composés.
PCT/EP2017/077707 2016-10-31 2017-10-30 Nouveaux composés cyclicsulfonimidoylpurinone et dérivés pour le traitement et la prophylaxie d'infection virale WO2018078149A1 (fr)

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Publication number Priority date Publication date Assignee Title
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WO2020028097A1 (fr) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique
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WO2020162705A1 (fr) 2019-02-08 2020-08-13 성균관대학교산학협력단 Complexe agoniste du récepteur de type toll 7 ou 8-cholestérol, et son utilisation
WO2020178769A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides cycliques en 2'3' et leurs promédicaments
WO2020178768A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue du dinucléotide 3'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle utilisé en tant que modulateur de sting
WO2020178770A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3'-cycliques et leurs promédicaments
WO2020214663A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020214652A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020237025A1 (fr) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Exo-méthylène-oxindoles substitués qui sont des inhibiteurs de hpk1/map4k1
WO2021034804A1 (fr) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Formulations pharmaceutiques de ténofovir alafénamide
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2021067181A1 (fr) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Vaccins contre le virus de l'hépatite b et méthodes de traitement du vhb
WO2021113765A1 (fr) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
WO2021177679A1 (fr) 2020-03-02 2021-09-10 성균관대학교산학협력단 Nanoparticules mimétiques d'agent pathogène vivant basées sur un squelette de paroi cellulaire d'agent pathogène, et leur procédé de production
WO2021188959A1 (fr) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Promédicaments de nucléosides de 4'-c-substitué-2-halo-2'-désoxyadénosine et leurs procédés de fabrication et d'utilisation
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2022031021A1 (fr) 2020-08-04 2022-02-10 성균관대학교산학협력단 Vaccin à arnm comprenant un adjuvant permettant un contrôle cinétique
WO2022031057A1 (fr) 2020-08-04 2022-02-10 성균관대학교산학협력단 Conjugué d'un médicament fonctionnel et d'un agoniste de récepteur de type toll 7 ou 8, dont le site actif est temporairement inactivé et utilisation associée
WO2022031011A1 (fr) 2020-08-04 2022-02-10 성균관대학교산학협력단 Ensemble adjuvant à action cinétique
WO2022241134A1 (fr) 2021-05-13 2022-11-17 Gilead Sciences, Inc. Combinaison d'un composé de modulation de tlr8 et agent thérapeutique anti-arnsi de vhb
WO2022271684A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271650A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271677A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271659A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2138497A1 (fr) * 2007-03-20 2009-12-30 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé d'adénine
WO2016023511A1 (fr) * 2014-08-15 2016-02-18 正大天晴药业集团股份有限公司 Composés pyrrolopyrimidine utilisés en tant qu'agonistes du tlr7

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2138497A1 (fr) * 2007-03-20 2009-12-30 Dainippon Sumitomo Pharma Co., Ltd. Nouveau composé d'adénine
WO2016023511A1 (fr) * 2014-08-15 2016-02-18 正大天晴药业集团股份有限公司 Composés pyrrolopyrimidine utilisés en tant qu'agonistes du tlr7

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ANSEL, HOWARD C. ET AL.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, LIPPINCOTT, WILLIAMS & WILKINS
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 63231-67-4
D. J CONNOLLY; L. AJ O'NEILL, CURRENT OPINION IN PHARMACOLOGY, vol. 12, 2012, pages 510 - 518
E. J. GANE ET AL., ANNU MEET AM ASSOC STUDY LIVER DIS, 1 November 2013 (2013-11-01)
GENNARO, ALFONSO R. ET AL.: "Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS & WILKINS
HIROAKI HEMMI ET AL., NATURE IMMUNOLOGY, vol. 3, 2002, pages 196 - 200
P. A. ROETHLE ET AL., J. MED. CHEM., vol. 56, 2013, pages 7324 - 7333
ROWE, RAYMOND C.: "Handbook of Pharmaceutical Excipients", 2005, PHARMACEUTICAL PRESS
T. ASSELAH ET AL., CLIN LIVER DIS, vol. 11, 2007, pages 839 - 849
TSUNEYASU KAISHO; TAKASHI TANAKA, TRENDS IN IMMUNOLOGY, vol. 29, no. 7, July 2008 (2008-07-01), pages 329

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US11142750B2 (en) 2018-04-12 2021-10-12 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
US11788077B2 (en) 2018-04-12 2023-10-17 Precision Biosciences, Inc. Polynucleotides encoding optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
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WO2020162705A1 (fr) 2019-02-08 2020-08-13 성균관대학교산학협력단 Complexe agoniste du récepteur de type toll 7 ou 8-cholestérol, et son utilisation
US11766447B2 (en) 2019-03-07 2023-09-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020178770A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3'-cycliques et leurs promédicaments
WO2020178768A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue du dinucléotide 3'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle utilisé en tant que modulateur de sting
WO2020178769A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides cycliques en 2'3' et leurs promédicaments
WO2020214663A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020214652A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020237025A1 (fr) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Exo-méthylène-oxindoles substitués qui sont des inhibiteurs de hpk1/map4k1
WO2021034804A1 (fr) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Formulations pharmaceutiques de ténofovir alafénamide
WO2021067181A1 (fr) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Vaccins contre le virus de l'hépatite b et méthodes de traitement du vhb
WO2021113765A1 (fr) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
WO2021177679A1 (fr) 2020-03-02 2021-09-10 성균관대학교산학협력단 Nanoparticules mimétiques d'agent pathogène vivant basées sur un squelette de paroi cellulaire d'agent pathogène, et leur procédé de production
WO2021188959A1 (fr) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Promédicaments de nucléosides de 4'-c-substitué-2-halo-2'-désoxyadénosine et leurs procédés de fabrication et d'utilisation
WO2022031057A1 (fr) 2020-08-04 2022-02-10 성균관대학교산학협력단 Conjugué d'un médicament fonctionnel et d'un agoniste de récepteur de type toll 7 ou 8, dont le site actif est temporairement inactivé et utilisation associée
WO2022031011A1 (fr) 2020-08-04 2022-02-10 성균관대학교산학협력단 Ensemble adjuvant à action cinétique
WO2022031021A1 (fr) 2020-08-04 2022-02-10 성균관대학교산학협력단 Vaccin à arnm comprenant un adjuvant permettant un contrôle cinétique
WO2022241134A1 (fr) 2021-05-13 2022-11-17 Gilead Sciences, Inc. Combinaison d'un composé de modulation de tlr8 et agent thérapeutique anti-arnsi de vhb
WO2022271684A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271677A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271659A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271650A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase

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