WO2019046364A1 - Inhibiteurs de la réplication du virus respiratoire syncytial (vrs) et leurs utilisations - Google Patents

Inhibiteurs de la réplication du virus respiratoire syncytial (vrs) et leurs utilisations Download PDF

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WO2019046364A1
WO2019046364A1 PCT/US2018/048444 US2018048444W WO2019046364A1 WO 2019046364 A1 WO2019046364 A1 WO 2019046364A1 US 2018048444 W US2018048444 W US 2018048444W WO 2019046364 A1 WO2019046364 A1 WO 2019046364A1
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mmol
compound
formula
rsv
mhz
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PCT/US2018/048444
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Thomas Kaiser
Pieter BURGER
Zackery DENTMON
Edgars JECS
Robert Wilson
Stephen PELLY
Nicole PRIBUT
Dennis Liotta
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Emory University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to benzimidazole derivatives having antiviral activity, and in particular having an inhibitory activity on the replication of Respiratory Syncytial Virus (RSV). It further relates to methods for preparing these compounds, pharmaceutical compositions comprising these compounds and uses thereof for the treatment and prevention of RSV.
  • RSV Respiratory Syncytial Virus
  • Respiratory Syncytial Virus is a single stranded, negative sense RNA orthopneumovirus first discovered in 1956. It causes upper and lower respiratory tract infections and infects 60% of infants in their first viral season. It will infect nearly all children by 2-3 years of age. Of those infected by RSV, approximately 3% will develop an infection severe enough to warrant hospitalization. However, RSV infection is not only a problem for the young; severe infections in elderly patients have been increasing in frequency.
  • RSV Symptoms of RSV are similar to the common cold, and spread easily from person to person contact. While RSV may occur in any population segment, infants, the elderly and immunocompromised are especially vulnerable.
  • Virazole® an aerosol form of ribavirin, a nucleoside analogue, which is used for the treatment of serious RSV infection in hospitalized children.
  • Two other drugs, RespiGam® (RSV-IG) and Synagis ® (palivizumab) are polyclonal and monoclonal antibody immunostimulants which are intended as prophylactic agents for prevention of infection.
  • RSV-IG RespiGam®
  • palivizumab Synagis ®
  • palivizumab is not effective in the treatment of established RSV infection.
  • motavizumab designed as a potential replacement of palivizumab, failed to show additional benefits in recent Phase III clinical trials.
  • Yu et al. (Respiratory syncytial virus fusion inhibitors. Part 4: Optimization for oral bioavailability, Bioorganic and Medicinal Chemistry Letters, 17, 2007, 895-901) disclose a series of benzimidazole-based inhibitors of RSV fusion and identified BMS-433771 as a potent inhibitor of RSV in vitro that is orally bioavailable in 4 species and demonstrates antiviral activity in both the BALB/c mouse and cotton rat models of RSV infection following oral administration. The antiviral activity was determined as the reduction of the cytopathic effect induced by the Long (A) strain of virus replicating in HEp-2 human lung epithelial carcinoma cells.
  • PCT application no. WO 2001/095910 discloses imidazopyridine and imidazopyrimidine antiviral agents with antiviral activity showing a wide range of antiviral activity from 0.001 ⁇ to as high as 50 ⁇ , which is not a particularly desired biological activity.
  • Another PCT publication no. WO 2013/068769 discloses pharmaceutical compounds with an isopentyl side chain, having an EC50 of 80 ⁇ or lower, without mentioning any specific values or particularly active compounds.
  • PCT publication no. WO 2012/080446 discloses halogenated derivatives of benzimidazole compounds. Also see PCT publication nos. WO 2014/184163 and WO 2015/022263.
  • R 1 is an optionally substituted alkyl and when X is N then R 2 is a heterocyclyl, and R 3 is absent; and when X is C, then R 2 and R 3 are linked to form a carbocyclyl and R 4 is selected from H, alkyl, alkoxy, halogen, amino, or nitro.
  • R 1 to be an optionally substituted C 3 to C 6 alkyl, preferably an optionally substituted C 4 alkyl, and for the substituents to be selected from ⁇ N, -S0 2 (alkyl) and - OH; and for R 2 to be a C 3 to C 6 heterocyclyl, preferably a C 3 or C 4 heterocyclyl, and for the heteroatoms of the heterocyclyl to be selected from O, N, S or S0 2 or for R 2 and R 3 to be linked to form a C 3 -C 6 carbocyclyl, preferably a C 3 carbocyclyl and for R 4 to be H or halogen.
  • the compounds of Formula A are selected from:
  • a method of treating viral RSV infections in a subject in need thereof comprising administering an effective amount of the compound of Formula A or salts thereof to the subject.
  • the disclosure contemplates derivatives of compounds disclosed herein such as those containing one or more, the same or different, substituents.
  • a pharmaceutical composition comprising a compound of Formula A or salts thereof and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, gel, granules, aerosol, or aqueous buffer, such as a saline or phosphate buffer, or a nanoparticle formulation, emulsion, liposome, etc.
  • the pharmaceutical composition may also include one or more further active antiviral agents, or may be administered in combination with one or more such active agent.
  • methods for preparing the compounds of Formula A or salts thereof comprising mixing one or more starting materials with reagents under conditions such that the products are formed.
  • Figure 1 shows a crystal structure of l '-((l-(4-hydroxybutyl)-lH-benzo[d]imidazol-2- yl)methyl)spiro[cyclopropane-l,3'-pyrrolo[2,3-c]pyridin]-2'( iI)-one (designated herein as ZD-2- 160);
  • Figure 2 shows a crystal structure of 4-(2-((2-oxo-l-(tetrahydro-2H-pyran-4-yl)-l,2- dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)-lH-benzo[d]imidazol-l-yl)butanenitrile
  • Figure 3 shows a crystal structure of l-(l, l-dioxidothietan-3-yl)-3-((l-(4-hydroxybutyl)- lH-benzo[d]imidazol-2-yl)methyl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (designated herein as EJ-2143);
  • Figure 4 is a graph showing CCso data for some exemplary compounds of the disclosure.
  • Figure 5 is a graph showing the ICso data for exemplary compounds of this disclosure against the wild type and RSV-F489 mutant virus.
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
  • Subject refers any animal, preferably a human patient, livestock, mouse model or domestic pet.
  • the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
  • the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
  • the term “combination with” when used to describe administration with an additional treatment means that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof.
  • alkyl means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 20 carbon atoms.
  • a “higher alkyl” refers to unsaturated or saturated hydrocarbon having 6 or more carbon atoms.
  • Cs-Cis refers to an alkyl containing 8 to 18 carbon atoms.
  • a “C6-C22” refers to an alkyl containing 6 to 22 carbon atoms.
  • saturated straight chain alkyls include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, hexadecyl, dodecyl, tetradecyl, izosonyl, octadecyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert- butyl, isopentyl, and the like.
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or “alkynyl", respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2- butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3- methyl- 1-butynyl, and the like.
  • Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or “carbocyclyl” groups.
  • Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.
  • Carbocyclyls include cycloalkyls and cycloalkenyls.
  • Heterocarbocycles or “heterocarbocyclyl” groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, phosphorous, oxygen and sulphur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulphur heteroatoms may be optionally oxidized (e.g. -S(O)-, -SO2-, -N(O)-), and the nitrogen heteroatom may be optionally quaternized.
  • Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • heterocycle or “heterocyclyl” refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom.
  • the mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings.
  • Heterocycle includes heterocarbocycles, heteroaryls, and the like.
  • cycloalkyl and “cycloalkenyl” refer to mono-, bi-, or tri homocyclic ring groups of 3 to 15 carbon atoms which are, respectively, fully saturated and partially unsaturated.
  • Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.
  • the term "derivative" refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue.
  • the derivative may be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration/oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, adding a hydroxyl group, replacing an oxygen atom with a sulfur atom, or replacing an amino group with a hydroxyl group, oxidizing a hydroxyl group to a carbonyl group, reducing a carbonyl group to a hydroxyl group, and reducing a carbon-to-carbon double bond to an alkyl group or oxidizing a carbon-to-carbon single bond to a double bond.
  • a derivative optionally has one or more, the same or different, substitutions.
  • Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry text books, such as those provided in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", Wiley, 6th Edition (2007) Michael B. Smith or “Domino Reactions in Organic Synthesis", Wiley (2006) Lutz F. Tietze, hereby incorporated by reference.
  • the present disclosure relates to com ounds of the general Formula A or salt thereof,
  • R 1 is an optionally substituted alkyl and X may be either N or C.
  • X may be either N or C.
  • R 2 will be a heterocyclyl, and R 3 will be absent; whereas when X is C, then R 2 and R 3 will be linked to form a carbocyclyl.
  • the substituent R 1 can be an optionally substituted C 3 to C 6 alkyl such as a propyl, butyl, pentyl or hexyl chain, which may be straight, branched, saturated or unsaturated.
  • R 1 is an optionally substituted C 4 alkyl, i.e. a butyl chain and is terminally substituted with a nitrile or alcohol group (i.e. ⁇ N or -OH).
  • the substituent R 2 can be a C 3 to C 6 heterocyclyl and in a preferred embodiment is a C 3 or C 4 heterocyclyl and the heteroatoms are selected from O, N, S or SO2.
  • the heterocycles are preferably selected from tetrahydropyran and thietane- 1, 1 -dioxide.
  • the substituents R 2 and R 3 are linked to form a C 3 -C 6 carbocycle.
  • it is a C 3 carbocyclyl (i.e. cyclopropyl).
  • the compound of Formula A may be further exemplified as compounds of Formula Al or Formula A2, or salts thereof,
  • Formula Al Formula A2 wherein n is 1, 2, 3, or 4; Y is selected from N, O, S, or SO2; and R 5 iis OH or N.
  • the compounds of Formula A are selected from:
  • the disclosure relates to methods of treating or preventing a viral infection comprising administering in effective amount of a compound of Formual A or salts thereof disclosed herein to a subject in need thereof.
  • the subject is at risk of, exhibiting symptoms of, suffering from, or diagnosed with a viral infection such as RSV infections.
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with Respiratory syncytial virus (RSV), influenza A virus including subtype H1N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, human adenovirus types (HAdV-1 to 55), human papillomavirus (UPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, parvovirus B 19, molluscum contagiosum virus, JC virus (JCV), BK vims, Merkel cell polyomavirus, coxsackie A vims, norovirus, Rubella vims, lymphocytic choriomeningitis vims (LCMV), yellow fever vims, measles vims, mumps vims, rinderpest vims, California encephalitis vims,
  • RSV
  • methods disclosed herein are contemplated to be administered in combination with other the antiviral agent(s) such as abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, complera, damnavir, delavirdine, didanosine, docosanol, dolutegravir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine,
  • the disclosure contemplates the treatment or prevention of a viral infection using compounds disclosed herein, wherein viral infection is Respiratory syncytial vims (RSV).
  • RSV Respiratory syncytial vims
  • compositions comprising a compound of
  • compositions disclosed herein may be in the form of pharmaceutically acceptable salts, as generally described below.
  • suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).
  • the compounds of the disclosure may also form internal salts, and such compounds are within the scope of the disclosure.
  • a compound contains a hydrogen-donating heteroatom (e.g. H)
  • salts are contemplated to covers isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • Pharmaceutically acceptable salts of the compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/di
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley - VCH, 2002), incorporated herein by reference.
  • compositions for use in the present disclosure typically comprise an effective amount of a compound and a suitable pharmaceutically acceptable carrier.
  • the preparations may be prepared in any manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.
  • the compounds may be formulated as a pharmaceutical preparation comprising at least one compound of the present disclosure and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • the pharmaceutical composition is in the form of a tablet, capsule, pill, gel, granules, aerosol, or aqueous buffer, such as a saline or phosphate buffer, or a nanoparticle formulation, emulsion, liposome, etc.
  • the pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the disclosure, e.g. about 10, 25, 50, 100, 200, 300, 400 or 500 mg per unit dosage.
  • the compounds can be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used.
  • the compound is administered by inhalation through the lungs.
  • the compound will generally be administered in an "effective amount", by which is meant any amount of a compound that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered.
  • an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, lotions, nanoparticles, aerosols and the like.
  • these formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages.
  • Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non- gelatin capsules, and caplets.
  • liquid dosage forms such as solutions, syrups, suspension, shakes, etc.
  • the formulation is administered topically.
  • suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels.
  • the topical formulation is a gel.
  • the formulation is administered intranasally.
  • the pharmaceutical composition comprises a compound disclosed herein and a propellant.
  • an aerosolizing propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFAs), 1,1,1,2,- tetrafluoroethane, 1,1, 1,2,3,3,3-heptafluoropropane or combinations thereof.
  • the disclosure contemplates a pressurized or unpressurized container comprising a compound herein.
  • the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.
  • Formulations containing one or more of the compounds described herein may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • the carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • carrier includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions. Carrier also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants.
  • Delayed release, extended release, and/or pulsatile release dosage formulations may be prepared as described in standard references such as "Pharmaceutical dosage form tablets”, eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington - The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et al., (Media, PA: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment and processes for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.
  • cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate
  • polyvinyl acetate phthalate acrylic acid polymers and copolymers
  • methacrylic resins that are commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), zein,
  • the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
  • Diluents also referred to as "fillers” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture.
  • suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp).
  • starch sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp).
  • Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
  • Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl- ⁇ - alanine, sodium N-lauryl-P-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.
  • the concentration of the compound to carrier and/or other substances may vary from about 0.5 to about 100 wt % (weight percent).
  • the pharmaceutical formulation will generally contain from about 5 to about 100% by weight of the active material.
  • the pharmaceutical formulation will generally have from about 0.5 to about 50 wt. % of the active material.
  • compositions described herein can be formulated for modified or controlled release.
  • controlled release dosage forms include extended release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof.
  • the extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington - The science and practice of pharmacy” (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000).
  • a diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds.
  • Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and carbopol Carbopol® 934, polyethylene oxides and mixtures thereof.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
  • the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl me
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are described in F XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the Tradename tradename Eudragit®.
  • the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames tradenames Eudragit® RL30D and Eudragit ® RS30D, respectively.
  • Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1 :20 in Eudragit® RL30D and 1 :40 in Eudragit® RS30D.
  • the mean molecular weight is about 150,000.
  • Edragit® S-100 and Eudragit® L-100 are also preferred.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the polymers described above such as Eudragit®.RTM. RL/RS may be mixed together in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems may be obtained, for instance, from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL and 90% :Eudragit® 90% RS.
  • Desirable sustained-release multiparticulate systems may be obtained, for instance, from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL and 90% :Eudragit® 90% RS.
  • acrylic polymers may also be used, such as, for example, Eudragit® L.
  • extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form.
  • the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion.
  • the devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and, capsules containing tablets, beads, or granules, etc.
  • An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders.
  • a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method.
  • the congealing method the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed.
  • Delayed release formulations are created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug- containing composition with a selected coating material.
  • the drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers.
  • Enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon.
  • Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methaciylate and/or ethyl methaciylate, and other methacrylic resins that are commercially available under the tradename Eudragit®.
  • cellulosic polymers such as hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose
  • the preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies.
  • the coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
  • a plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
  • plasticizers examples include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt.
  • glidant is talc.
  • Other glidants such as magnesium stearate and glycerol monostearates may also be used.
  • Pigments such as titanium dioxide may also be used.
  • a silicone e.g., simethicone
  • the formulation can provide pulsatile delivery of the one or more compounds.
  • pulse is meant that a plurality of drug doses is released at spaced apart intervals of time.
  • release of the initial dose is substantially immediate, i.e., the first drug release "pulse” occurs within about one hour of ingestion.
  • This initial pulse is followed by a first time interval (lag time) during which very little or no drug is released from the dosage form, after which a second dose is then released.
  • a second nearly drug release- free interval between the second and third drug release pulses may be designed. The duration of the nearly drug release-free time interval will vary depending upon the dosage form design e.g., a twice daily dosing profile, a three times daily dosing profile, etc.
  • the nearly drug release-free interval has a duration of approximately 3 hours to 14 hours between the first and second dose.
  • the nearly drug release-free interval has a duration of approximately 2 hours to 8 hours between each of the three doses.
  • the pulsatile release profile is achieved with dosage forms that are closed and preferably sealed capsules housing at least two drug-containing "dosage units" wherein each dosage unit within the capsule provides a different drug release profile.
  • Control of the delayed release dosage unit(s) is accomplished by a controlled release polymer coating on the dosage unit, or by incorporation of the active agent in a controlled release polymer matrix.
  • Each dosage unit may comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different drug release profile. For dosage forms mimicking a twice a day dosing profile, a first tablet releases drug substantially immediately following ingestion of the dosage form, while a second tablet releases drug approximately 3 hours to less than 14 hours following ingestion of the dosage form.
  • a first tablet releases drug substantially immediately following ingestion of the dosage form
  • a second tablet releases drug approximately 3 hours to less than 10 hours following ingestion of the dosage form
  • the third tablet releases drug at least 5 hours to approximately 18 hours following ingestion of the dosage form. It is possible that the dosage form includes more than three tablets. While the dosage form will not generally include more than a third tablet, dosage forms housing more than three tablets can be utilized.
  • each dosage unit in the capsule may comprise a plurality of drug-containing beads, granules or particles.
  • drug-containing beads refer to beads made with drug and one or more excipients or polymers.
  • Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a "core” comprising both drug and one or more excipients.
  • drug-containing "granules” and “particles” comprise drug particles that may or may not include one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support.
  • Granules generally comprise drug particles and require further processing. Generally, particles are smaller than granules, and are not further processed. Although beads, granules and particles may be formulated to provide immediate release, beads and granules are generally employed to provide delayed release.
  • the compound is formulated for topical administration.
  • suitable topical dosage forms include lotions, creams, ointments, and gels.
  • a "gel” is a semisolid system containing a dispersion of the active agent, i.e., compound, in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle.
  • the liquid may include a lipophilic component, an aqueous component or both.
  • Some emulsions may be gels or otherwise include a gel component.
  • Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components.
  • compositions for preparing lotions, creams, ointments, and gels are well known in the art.
  • the compound described herein can be administered adjunctively with other active compounds.
  • active compounds include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti- narcoleptics.
  • Adjunctive administration means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents.
  • compounds that can be adjunctively administered with the compounds include, but are not limited to, aceclofenac, acetaminophen, adomexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicy
  • the additional active agent(s) can be formulated for immediate release, controlled release, or combinations thereof.
  • MR spectra (3 ⁇ 4, 13 C) were recorded on a 300 MHz Varian VNMRS (75 MHz for 13 C), a 400 MHz Varian INOVA (101 MHz for 13 C), a 400 MHz Varian VNMRS, a 500 MHz Varian INOVA (126 MHz for 13 C) or a 600 MHz Varian INOVA (150 MHz for 13 C).
  • Chemical shifts ( ⁇ ) are reported in ppm and J - values are given in Hz. Multiplicities are reported as a singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) or doublet of doublet (dd). Chemical shifts were recorded using the residual solvent peak or external reference. All spectra were obtained at 25 °C unless otherwise reported. Spectroscopic data were processed using MestReNova v6.0.2. Mass spectrometry was performed by the Emory University Mass Spectroscopy Center.
  • reaction mixture was then concentrated in vacuo to afford a white solid. This was then taken up into DCM and washed with saturated NaHCCb solution. The organic phase was separated and the aqueous phase was extracted three times with DCM. Purification by column chromatography (EtO Ac/Hex) afforded a clear viscous oil (0.917 mg, 2.60 mmol, 51%) which was used directly in the next reaction without further characterization.
  • the reaction was allowed to stir at rt for -3.5 h when monitoring by TLC showed spot-to-spot conversion of starting material to the desired less polar spot.
  • the reaction was diluted with DCM before being quenched with saturated sodium bicarbonate solution, and the product was extracted with DCM (2x50 ml). The organic extract was dried over sodium sulfate, filtered and concentrated to give the desired product as a red oil (0.702 g, 93% yield).
  • reaction stirred at 45 °C for -2.5 h when TLC (95:5 DCM:MeOH) showed complete conversion of the starting chloride to a more polar fluorescent spot with some pyrrolidinone remaining.
  • the reaction mixture was filtered and rinsed with MeOH before the filtrate was adsorbed onto -3 g of Celite to dry load a 12g RediSep CombiFlash silica gel column for purification.
  • Product was eluted with 100% DCM for -4 minutes followed by a slow gradient of 0-10% MeOH in DCM over -35 minutes. The desired product eluted at -26 minutes with -8% MeOH (0.103 g, 39% yield).
  • N4-(tetrahydro-2H-pyran-4-yl)pyridine-3,4-diamine 0.595 g, 3.08 mmol
  • MeCN 20 ml
  • CDI 0.549 g, 3.39 mmol
  • a 100 ml Schlenk tube equipped with a magnetic stirrer bar and cold finger condenser was charged with 400 mg of 3-((3-aminopyridin-4-yl)amino)thietane 1,1-dioxide (1.88 mmol, 1 equiv.) and 18.8 ml of acetonitrile and heated to 80 °C to dissolve the starting material. The heating was removed and 608 mg of CDI (3.75 mmol, 2 equiv.) dissolved in 18.8 ml of acetonitrile was added.
  • a 50 ml Schlenk tube equipped with a magnetic stirrer bar and cold finger condenser was charged with 160 mg of l-(l,l-dioxidothietan-3-yl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.669 mmol, 1 equiv.), 327 mg of CS2CO3 (1.00 mmol, 1.5 equiv.), 11.0 mg of KI (0.067 mmol, 0.1 equiv.), 188 mg of 4-(2-(chloromethyl)-lH-benzo[d]imidazol-l-yl)butanenitrile (0.803 mmol, 1.2 equiv.) and 6.7 ml of DMF.
  • a 100 ml Schlenk tube equipped with a magnetic stirrer bar and cold finger condenser was charged with 150 mg of l-(l,l-dioxidothietan-3-yl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.627 mmol, 1 equiv.), 306 mg of CS2CO3 (0.940 mmol, 1.5 equiv.) and 8.0 ml of acetonitrile and warmed up to 80 °C to dissolve the starting material.
  • NP-RSV-003 was synthesized according to general procedure A as described above. The following quantities were employed: 4-bromo-2-nitroaniline (1.0 g, 4.6 mmol), 60% sodium hydride (277 mg, 6.91 mmol) and 4-bromobutyronitrile (1.02 g, 6.91 mmol) in DCM (20 mL). This procedure yielded NP-RSV-003 (399 mg, 1.40 mmol, 31%) as an orange solid.
  • NP-RSV-012 was synthesized according to general procedure A as described above. The following quantities were employed: 4-bromo-2-nitroaniline (400 mg, 1.84 mmol), 60% sodium hydride (111 mg, 2.77 mmol) and l-bromo-3 -methyl sulfonylpropane (556 mg, 2.77 mmol) in DCM (10 mL). This procedure yielded NP-RSV-012 (316 mg, 0.937 mmol, 51%) as an orange solid.
  • Iron powder (5 eq) was suspended in a solution of the N-alkylated 4-bromo-2-nitroaniline (1 eq) in ethanol, acetic acid and water (2:2: 1) in a single-necked 25 mL round bottomed flask. The flask was subsequently placed in a sonicator and irradiated at room temperature for 1 hour. Once TLC confirmed that all starting material had been consumed the iron powder was filtered off over celite and the resulting filtrate was basified with a 1M solution of NaOH. The crude product was then extracted from the basic solution into DCM three times. The organic phases were combined, dried over MgS0 4 and concentrated in vacuo. The resulting crude material was then purified by column chromatography or taken crude to the subsequent step.
  • NP-RSV-005 was synthesized according to general procedure B as described above. The following quantities were employed: NP-RSV-003 (399 mg, 1.40 mmol) and iron powder (392 mg, 7.02 mmol) in EtOH (3 mL), AcOH (3 mL) and H 2 0 (1.5 mL). This procedure yielded NP- RSV-005 (240 mg, 0.944 mmol, 67%) as a pale orange solid.
  • NP-RSV-013 was synthesized according to general procedure B as described above. The following quantities were employed: NP-RSV-012 (250 mg, 0.741 mmol) and iron powder (207 mg, 3.71 mmol) in EtOH (2 mL), AcOH (2 mL) and H2O (1 mL). This procedure yielded crude NP-RSV-013 (205 mg, 0.667 mmol) as a tan solid.
  • NP-RSV-007 was synthesized according to general procedure C as described above. The following quantities were employed: NP-RSV-5 (200 mg, 0.787 mmol), 2-chl oro- 1, 1,1- trimethoxyethane (0.32 mL, 2.36 mmol) and p-TsOH H 2 0 (15 mg, 0.079 mmol) in DCM (4 mL). This procedure yielded NP-RSV-007 (215 mg, 0.688 mmol, 87%) as a pale-yellow solid.
  • NP-RSV-014 was synthesized according to general procedure C as described above. The following quantities were employed: NP-RSV-013 (150 mg, 0.488 mmol), 2-chl oro- 1, 1,1 - trimethoxyethane (0.20 mL, 1.47 mmol) and p-TsOH H 2 0 (9.0 mg, 0.049 mmol) in DCM (3 mL). This procedure yielded NP-RSV-014 (138 mg, 0.377 mmol, 77%).
  • NP-RSV-010 was synthesized according to general procedure D as described above. The following quantities were employed: RJW-2-010 (100 mg, 0.456 mmol), NP-RSV-007 (171 mg, 0.547 mmol) and K2CO3 (76 mg, 0.55 mmol) in DMF (3 mL). This procedure yielded NP-RSV- 010 (139 mg, 0.281 mmol, 62%) as a yellow solid.
  • NP-RSV-016 was synthesized according to general procedure D as described above. The following quantities were employed: RJW-2-010 (48 mg, 0.22 mmol), NP-RSV-014 (96 mg, 0.26 mmol) and K2CO3 (36 mg, 0.26 mmol) in DMF (1 mL). This procedure yielded NP-RSV-016 (19 mg, 0.035 mmol, 16%) as a white solid.
  • Example 2 Biological Activity for exemplary compounds
  • the assay used for the generation of data was developed by the group of Richard Plemper at Georgia State University. Recombinant RSV strain expressing renilla luciferase were generated as reporter strains for robust automated drug discovery assays, which proposes major advantages over conventional RSV-based assays and a higher propensity to identify early and intermediate stage inhibitors of the viral life cycle (i.e. inhibitors of viral attachment, fusion, and viral polymerase activity) than blockers of viral assembly and egress, because the latter would act downstream of the luciferase reporter expression.
  • early and intermediate stage inhibitors of the viral life cycle i.e. inhibitors of viral attachment, fusion, and viral polymerase activity
  • blockers of viral assembly and egress because the latter would act downstream of the luciferase reporter expression.
  • Table 1 IC 5 o data against Wild Type and RSV-F489 mutant RSV Virus

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Abstract

L'invention concerne un composé selon la formule (A) ou un sel de celui-ci, destiné à être utilisé dans le traitement d'infections par le VRS. L'invention concerne également une méthode de traitement d'infections virales par le VRS à l'aide de composés de formule (A), éventuellement en combinaison avec un ou plusieurs autres agents antiviraux, ainsi que des compositions pharmaceutiques contenant un composé de formule (A) et éventuellement un ou plusieurs autres agents antiviraux.
PCT/US2018/048444 2017-08-29 2018-08-29 Inhibiteurs de la réplication du virus respiratoire syncytial (vrs) et leurs utilisations WO2019046364A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020016309A1 (en) * 2000-06-13 2002-02-07 Kuo-Long Yu Imidazopyridine and imidazopyrimidine antiviral agents
US20070185096A1 (en) * 2004-03-19 2007-08-09 Novartis Pharmaceuticals Corporation Pharmaceutical composition comprising a benzodiazepine derivative and an inhibitor of the rsv fusion protein

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020016309A1 (en) * 2000-06-13 2002-02-07 Kuo-Long Yu Imidazopyridine and imidazopyrimidine antiviral agents
US20070185096A1 (en) * 2004-03-19 2007-08-09 Novartis Pharmaceuticals Corporation Pharmaceutical composition comprising a benzodiazepine derivative and an inhibitor of the rsv fusion protein

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM [o] 20 January 2014 (2014-01-20), "Substance record for SID 172103146", XP055582371, retrieved from NCBI Database accession no. SID 172103146 *

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