WO2005091804A2 - Inhibiteurs de la famille des paramyxovirus et leurs methodes d'utilisation - Google Patents

Inhibiteurs de la famille des paramyxovirus et leurs methodes d'utilisation Download PDF

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Publication number
WO2005091804A2
WO2005091804A2 PCT/US2005/004565 US2005004565W WO2005091804A2 WO 2005091804 A2 WO2005091804 A2 WO 2005091804A2 US 2005004565 W US2005004565 W US 2005004565W WO 2005091804 A2 WO2005091804 A2 WO 2005091804A2
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Prior art keywords
paramyxovirus
alkyl
inhibitor composition
aryl
separately
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PCT/US2005/004565
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English (en)
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WO2005091804A3 (fr
Inventor
Richard K. Plemper
Richard W. Compans
James P. Snyder
Aiming Sun
Dennis C. Liotta
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Emory University
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Publication of WO2005091804A3 publication Critical patent/WO2005091804A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds

Definitions

  • the present disclosure is generally related to compositions and compounds and methods for administration to hosts and, more particularly, is related to compositions and compounds for treatment of conditions and/or diseases related to paramyxovirus.
  • MV measles virus
  • RSV respiratory syncytial virus
  • hPIV human parainfluenza viruses
  • embodiments of the present disclosure include methods of treating paramyxovirus, vaccines for protecting against paramyxovirus, and pharmaceutical composition including a paramyxovirus inhibitor compound or composition.
  • the vaccine for protecting against paramyxovirus includes: structure 1 as described herein.
  • the pharmaceutical composition includes: a paramyxovirus inhibitor composition in combination with a pharmaceutically acceptable carrier, wherein the paramyxovirus inhibitor composition is present in a dosage level effective to treat paramyxovirus, and structure 1 as described herein.
  • the method of treating paramyxovirus includes: administering to a host in need of treatment an effective amount of at least one paramyxovirus inhibitor composition, wherein the paramyxovirus inhibitor composition includes structure 9 described herein.
  • the vaccine for protecting against paramyxovirus includes: structure 9 as described herein.
  • the pharmaceutical composition includes: a paramyxovirus inhibitor composition in combination with a pharmaceutically acceptable carrier, wherein the paramyxovirus inhibitor composition is present in a dosage level effective to treat paramyxovirus, and structure 9 as described herein.
  • a paramyxovirus inhibitor composition in combination with a pharmaceutically acceptable carrier, wherein the paramyxovirus inhibitor composition is present in a dosage level effective to treat paramyxovirus, and structure 9 as described herein.
  • FIG. 1 illustrates an embodiment of a compound that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 2 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 3 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 4 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 5 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 6 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 7 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIGS. 8 A through 8D illustrate embodiments of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 9 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 10 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 11 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 12 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 13 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 14 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 15 illustrates an embodiment of compounds that can be used in an embodiment of a paramyxovirus inhibitor composition.
  • FIG. 16 is a graph illustrating AS-48 activity against primary MV isolates.
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of synthetic organic chemistry, biochemistry, molecular biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the compositions and compounds disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C, and pressure is at or near atmospheric. Standard temperature and pressure are defined as 20 °C and 1 atmosphere.
  • the term "host” or "organism” includes both humans, mammals (e.g., cats, dogs, horses, etc.), and other living species that are in need of treatment for conditions/diseases caused directly or indirectly by paramyxovirus family.
  • a living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal.
  • compositions of the present disclosure can be used prophylactically as preventative agents for these conditions/diseases caused directly or indirectly by paramyxovirus family.
  • a “composition” can include one or more chemical compounds, as described below.
  • paramyxovirus inhibitor compound means a compound, pharmaceutically acceptable salt, prodrug, or derivative thereof that inhibits or otherwise interferes with the biological activity of the paramyxovirus.
  • derivative means a modification to the disclosed compounds including, but not limited to, hydrolysis, reduction, or oxidation products, of the disclosed compounds. Hydrolysis, reduction, and oxidation reactions are known in the art.
  • therapeutically effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms caused directly or indirectly by paramyxovirus family being treated.
  • a therapeutically effective amount refers to that amount which has the effect of preventing the condition/disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the condition/disease (prophylactic treatment), alleviation of symptoms of the condition/disease, diminishment of extent of condition/disease, stabilization (i.e., not worsening) of condition/disease, preventing spread of condition/disease, delaying or slowing of condition/disease progression, amelioration or palliation of the condition/disease state, and combinations thereof.
  • “Pharmaceutically acceptable salt” refers to those salts that retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic or organic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and the like.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients.
  • a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • “treat”, “treating”, and “treatment” are an approach for obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, preventing the condition/disease from occurring in an animal that may be predisposed to the condition/disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), alleviation of symptoms of the condition/disease, diminishment of extent of condition/disease, stabilization (i.e., not worsening) of condition/disease, preventing spread of condition/disease, delaying or slowing of condition/disease progression, amelioration or palliation of the condition/disease state, and combinations thereof.
  • “treat”, “treating”, and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • prodrug refers to an agent that is converted into a biologically active form in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Harper, NJ. (1962). Drug Latentiation in Jucker, ed. Progress in Drug Research, 4:221-294; Morozowich et al. (1977). Application of Physical Organic Principles to Prodrug Design in E. B. Roche ed.
  • topically active agents refers to compositions of the present disclosure that elicit pharmacological responses at the site of application (contact) to a host.
  • topically refers to application of the compositions of the present disclosure to the surface of the skin and mucosal cells and tissues.
  • alk refers to straight or branched chain hydrocarbon groups, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, and the like.
  • substituted alkyl refers to alkyl groups substituted with one or more groups, preferably selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), and the like.
  • alkoxy means an alkyl group linked to oxygen thus: R-O-.
  • R represents the alkyl group.
  • An example would be the methoxy group CH 3 O-.
  • aromatic or aryl refer to aromatic homocyclic (i.e., hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferably having 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl is a preferred aryl group.
  • substituted aryl refers to aryl groups substituted with one or more groups, preferably selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), and the like.
  • halogen and halo refer to fluorine, chlorine, bromine, and iodine.
  • heterocycle refers to fully saturated or partially or completely unsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring.
  • aromatic for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
  • the rings of multi-ring heterocycles may be either fused, bridged and/or joined through one or more spiro unions.
  • substituted heterocycle refers to heterocycle, heterocyclic and heterocyclo groups substituted with one or more groups preferably selected from alkyl, substituted alkyl, alkenyl, oxo, aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), cyano, nitro, amido, amino, substituted
  • salts denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • zwitterions inner salts
  • Salts of the compounds having a certain formula may be formed, for example, by reacting of a first compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the disclosed compounds that contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2- hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesul
  • the disclosed compounds that contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D- glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • organic bases e.g., organic amines
  • organic amines such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Solvates of the compounds of the disclosure are also contemplated herein.
  • lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, dieth
  • Solvates of the compounds are preferably hydrates. To the extent that the disclosed compounds, and salts thereof, may exist in their tautomeric form, all such tautomeric forms are contemplated herein as part of the present disclosure. All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated within the scope of this disclosure. Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected stereoisomers.
  • the chiral centers of the compounds of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the terms "including”, “such as”, “for example” and the like are intended to refer to exemplary embodiments and not to limit the scope of the present disclosure.
  • Paramyxovirus The paramyxovirus family of negative stranded enveloped RNA viruses contains highly contagious, airborne pathogens such as measles virus (MV), respiratory syncytial virus (RSV), human parainfluenza viruses (hPIV), and mumps viruses.
  • Paramyxovirus infection is initiated by attachment of viral particles to target cell receptors through the viral surface glycoprotein hemagglutinin, hemagglutinin-neuraminidase, or glycoprotein, depending on the genus of virus. After receptor binding, in most cases these proteins provide fusion support for the fusion (F) glycoprotein, which is responsible for mediating pH-independent fusion of the viral envelope with the target cell plasma membrane. Structural studies on a number of viral fusion proteins have suggested that prior to interaction with the host cell, fusion proteins exist in a metastable state.
  • Aa microdomain in the MV fusion (F) protein was identified that is structurally conserved in the paramyxovirus family (e.g., MV, RSV, and hPIV) and constitutes a target site for paramyxovirus inhibitor compounds and compositions.
  • the microdomain is conserved in the paramyxovirus family, the following discussion specifically describes the microdomain as it pertains to MV, but the disclosure, paramyxovirus inhibitor compounds and compositions, and the methods of use thereof, are not limited to only MV, but pertain to the entire paramyxovirus family that includes this microdomain.
  • the F cavity resembles a rough cylinder with a diameter and a height of approximately 10 angstroms in the neck-domain of the MV fusion protein that is essential for fusion protein functionality resulting in viral entry. This is a target for development of antiviral agents that would prevent entry of MV and other members of the paramyxovirus family.
  • Embodiments of the paramyxovirus inhibitor composition designed to fit into this cavity, exhibit high activity against both live MV and measles enveloped glycoprotein-induced cell-to-cell fusion.
  • a contoured, cylindrical cavity with a width and depth of approximately 10 angstroms was identified, which is located on an internal surface at the top of the short neck between the helical stem and the globular head of the F trimer.
  • the floor and walls of the cavity show a high degree of hydrophobicity that partially decreases towards its top.
  • the hydrophobic lle269 residue located at the cavity's base is essential for fusion activity of the molecule.
  • the polar R268 residue located at the rim of the cavity is essential for fusion activity.
  • the top of the cavity is open to solvent, although during fusion with the accompanying conformational modifications it might be partially occluded.
  • the paramyxovirus inhibitor compound according to modeling studies would seal the floor of the cylinder with a hydrophobic plug, but simultaneously reach to the bottom of the cylinder to engage in polar interactions with water.
  • double substitutions of MV F residues 94 and 270, or 257 and 270 to histidine prevent fusion at pH 7.0, consistent with the polar center of a potential inhibitor being charged. Both positive and negative variations were introduced below.
  • the paramyxovirus inhibitor compounds included in the paramyxovirus inhibitor composition discussed below substantially satisfy this characteristic.
  • Embodiments of paramyxovirus inhibitor compounds in the paramyxovirus inhibitor composition specifically inhibit fusion and spread of live MV and MV glycoprotein-induced membrane fusion.
  • the paramyxovirus inhibitor compositions induce negligible cytotoxicity and do not interfere with receptor binding, F protein biosynthesis or transport.
  • the paramyxovirus inhibitor compounds in the paramyxovirus inhibitor composition do prevent F-induced lipid mixing. Mutations in the postulated target site alter viral sensitivity to inhibition.
  • MV infection results from fusion of either the viral envelope or an infected cell with the plasma membrane of an uninfected cell. This is initiated by insertion of a hydrophobic stretch of the F ectodomain, the fusion peptide, into the target cell membrane.
  • Inhibition of enveloped viruses at the stage of viral entry provides a novel route for therapeutic intervention, as evidenced by the peptidic H1N entry inhibitor T-20, for example.
  • Other inhibitory peptides have demonstrated considerable in vitro potency against retroviruses and paramyxoviruses.
  • Virus-derived peptides may be immunnogenic in vivo; larger peptides are often highly cost intensive to manufacture; and peptides frequently possess poor absorption within the GI tract, necessitating intravenous delivery.
  • Embodiments of the paramyxovirus inhibitor composition provide a non-peptidic small molecule to inhibit MV entry. Additional details regarding paramyxovirus are described in Example 1 below.
  • paramyxovirus inhibitor compositions can be used to treat and/or prevent conditions/diseases directly or indirectly caused by the paramyxovirus, and/or interfere and/or inhibit biological processes related to the paramyxovirus. Additional uses and/or applications of the paramyxovirus inhibitor compositions are described below.
  • An embodiment of the paramyxovirus inhibitor compositions can include, but is not limited to, one or more arylamide compounds or arylamide derivative.
  • the paramyxovirus inhibitor compositions can include, but is not limited to, one or more compounds having structure 1, 2, 2', 2", 3, 3', 4, 4', 5, 5', 6, 6', 7, and 7', as shown in FIGS.
  • the paramyxovirus inhibitor compositions can include, but is not limited to, one or more compounds (structures 8A-8KKK, as shown in FIGS. 8A through 8D.
  • the paramyxovirus inhibitor compositions can include, but is not limited to, one or more compounds having structure 9, 10, 10', 10", 11, 11', 12, 12', 13, 13', 14, 14', 15, and 15', shown in FIGS. 9 through 15.
  • the paramyxovirus inhibitor compound can include analogues, homologues, isomers, or derivatives of the compounds described in FIGS. 1-8D, that can function in a similar biological manner as the compounds described in FIGS.
  • FIG. 1 illustrates an embodiment of a paramyxovirus inhibitor compound, structure 1.
  • Wl and W2 can each independently be chains, rings, and/or heterorings (that in some embodiments connect Wl and W2).
  • YI and Y2 can include groups such as, but not limited to, alkyl, aryl, F, Cl, Br, I, NH 2 , NR 2 , NHR (R-alkyl), CONHR, COOH, OH, OR, or SR.
  • H could be substituted with a halogen, for example, H can be substituted with a halogen on hydrocarbons (alkyl and aryl) and heterocyclic rings.
  • Wl and W2 are NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • A is NH, NR, and O;
  • Zl is CH 2 , CHR, CR 2 , O, and NR;
  • Z2 is a phenyl, an aryl, and a 5 or 6-membered heterocyclic ring;
  • YI is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • Y2 is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • X is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2
  • FIG. 2 illustrates embodiments of a paramyxovirus inhibitor compound, structures 2, 2', and 2".
  • A, B, Zl, Wl, W2, YI, Y2, and X are the same as groups those described in reference to FIG. 1, structure 1.
  • Wl and W2 are NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • A is NH, NR, and O;
  • Zl is CH 2 , CHR, CR 2 , O, and NR;
  • YI is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • Y2 is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • X is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 .
  • FIG. 3 illustrates embodiments of a paramyxovirus inhibitor compound, structures 3 and 3'.
  • A, B, Wl, W2, YI, Y2, X, and R1-R5 are the same as those groups described in reference to FIG. 1 , structure 1 , and FIG. 2, structures 2, 2', and 2".
  • Wl and W2 are NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • A is NH, NR, and O;
  • YI is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • Y2 is NH 2 , OH, CN, NO , CONHOH, and CONH 2 ;
  • X is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 .
  • FIG. 4 illustrates embodiments of a paramyxovirus inhibitor compound, structures 4 and .4'.
  • Wl and W2 are NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • A is NH, NR, and O;
  • YI is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • Y2 is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • X is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 .
  • FIG. 5 illustrates embodiments of a paramyxovirus inhibitor compound, structures 5 and 5'.
  • Wl, W2, YI, Y2, X, and R1-R5 are the same as those groups described in reference to FIG. 1, structure 1, and FIG. 2, structures 2, 2', and 2".
  • Wl and W2 are NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • YI is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • Y2 is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 ;
  • X is NH 2 , OH, CN, NO 2 , CONHOH, and CONH 2 .
  • FIG. 6 illustrates embodiments of a paramyxovirus inhibitor compound, structures 6 and 6'.
  • Wl, W2, YI, Y2, and R1-R5 are the same as those groups described in reference to FIG. 1, structure 1, and FIG. 2, structures 2, 2', and 2".
  • Wl and W2 are NH 2 , OH, CN, NO 2 , CONHOH, and
  • FIG. 7 illustrates embodiments of a paramyxovirus inhibitor compound, structures 7 and 7'.
  • Wl, YI, Y2, and R1-R5 are the same as those groups described in reference to FIG. 1, structure 1, and FIG. 2, structures 2, 2', and 2".
  • FIG. 8 A through 8D illustrates embodiments of the paramyxovirus inhibitor compound, structures 8 A through 8KKK. Table 1 in Example 1, elaborates on the activity of these structures depicted in FIGS. 8A through 8D.
  • the paramyxovirus inhibitor compositions can include, but is not limited to, one or more compounds having structure 9, 10, 10', 10", 11, 1 1 ', 12, 12', 13, 13', 14, 14', 15, and 15', shown in FIGS. 9 through 15.
  • A, B, Zl, Z2, Wl, W2, YI, Y2, X, and R1-R5 are the same as the groups described in reference to FIGS. 1 and 2 described above.
  • Ql through Q5 can include carbon (C) atoms (3 to 5) and/or nitrogen (N) atoms (0, 1, or 2).
  • the associated functional group e.g., Y2, X, YI, Wl, and W2 for Ql, Q2, Q3, Q4, and Q5, respectively
  • the associated functional group e.g., Y2, X, YI, Wl, and W2 for Ql, Q2, Q3, Q4, and Q5, respectively
  • Y2 is not included in the compound.
  • the two N atoms are not adjacent to one another in the ring and a C atom is positioned between the two N atoms.
  • Ql and Q3 are N atoms
  • Q2, Q4, and Q5 are C atoms.
  • Some embodiments of the present disclosure are directed to interfering and/or inhibiting MV proliferation and/or MV glycoprotein-induced syncytial formation. Such inhibition can be accomplished by binding the paramyxovirus inhibitor composition (e.g., the paramyxovirus inhibitor compound their derivatives, pharmaceutically acceptable salts, prodrugs, etc., and combinations thereof (hereinafter "paramyxovirus inhibitor composition” or "paramyxovirus inhibitor compound”)) to render MV inactive.
  • paramyxovirus inhibitor composition e.g., the paramyxovirus inhibitor compound their derivatives, pharmaceutically acceptable salts, prodrugs, etc., and combinations thereof (hereinafter "paramyxovirus inhibitor composition” or "paramyxovirus inhibitor compound”)
  • paramyxovirus inhibitor composition e.g., the paramyxovirus inhibitor compound their derivatives, pharmaceutically acceptable salts, prodrugs, etc., and combinations thereof
  • paramyxovirus inhibitor composition e.g., the paramyxovirus inhibitor compound their derivatives, pharmaceutical
  • compositions and dosage forms include a pharmaceutically acceptable salt of disclosed or a pharmaceutically acceptable polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
  • Pharmaceutical compositions and unit dosage forms typically also include one or more pharmaceutically acceptable excipients or diluents.
  • Advantages provided by the paramyxovirus inhibitor composition such as, but not limited to, increased solubility and/or enhanced flow, purity, or stability (e.g., hygroscopicity) characteristics can make them better suited for pharmaceutical formulation and/or administration to patients than the prior art.
  • compositions are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, intravenous, intraarterial, or bolus injection), topical, or transdermal administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., intramuscular, subcutaneous, intravenous, intraarterial, or bolus injection
  • topical e.g., topical, or transdermal administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as hard gelatin capsules and soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in- water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g.,
  • compositions, shape, and type of dosage forms of the paramyxovirus inhibitor composition can vary depending on their use.
  • a dosage form used in the acute treatment of a disease or disorder may contain larger amounts of the active ingredient (e.g., the paramyxovirus inhibitor composition) than a dosage form used in the chronic treatment of the same disease or disorder.
  • a parenteral dosage form may contain smaller amounts of the active ingredient than an oral dosage form used to treat the same disease or disorder.
  • Typical pharmaceutical compositions and dosage forms can include one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy or pharmaceutics, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • oral dosage forms such as tablets or capsules may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
  • compositions and dosage forms that include one or more compounds that reduce the rate by which an active ingredient will decompose.
  • Such compounds which are referred to herein as "stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • pharmaceutical compositions or dosage forms of the disclosure may contain one or more solubility modulators, such as sodium chloride, sodium sulfate, sodium or potassium phosphate, or organic acids. A specific solubility modulator is tartaric acid.
  • Typical dosage forms of the compounds of the disclosure include a pharmaceutically acceptable salt, or a pharmaceutically acceptable polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, in an amount of from about 10 mg to about 1000 mg (e.g., about is used interchangeably with approximately), preferably in an amount of from about 25 mg to about 750 mg, and more preferably in an amount of from about 50 mg to about 500 mg.
  • the paramyxovirus inhibitor composition can be delivered using lipid- or polymer-based nanoparticles.
  • the nanoparticles can be designed to improve the pharmacological and therapeutic properties of drugs administered parenterally (Allen, T.M., Cullis, P.R. Drug delivery systems: entering the mainstream. Science. 303(5665): 1818-22 (2004)).
  • compositions of the disclosure that are suitable for oral administration can be presented as discrete dosage forms, such as, but not limited to, tablets (including without limitation scored or coated tablets), pills, caplets, capsules, chewable tablets, powder packets, cachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion.
  • Such compositions contain a predetermined amount of the pharmaceutically acceptable salt of the paramyxovirus inhibitor composition, and may be prepared by methods of pharmacy well known to those skilled in the art.
  • Typical oral dosage forms of the paramyxovirus inhibitor composition are prepared by combining the pharmaceutically acceptable salt of the paramyxovirus inhibitor composition in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of the paramyxovirus inhibitor composition desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, microcrystalline cellulose, kaolin, diluents, granulating agents, lubricants, binders, and disintegrating agents. Due to their ease of administration, tablets and capsules represent the most advantageous solid oral dosage unit forms, in which case solid pharmaceutical excipients are used. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. These dosage forms can be prepared by any of the methods of pharmacy.
  • compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form, such as a powder or granules, optionally mixed with one or more excipients. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms of the disclosure include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, and AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa., U.S.A.), and mixtures thereof.
  • An exemplary suitable binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the disclosure is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the paramyxovirus inhibitor composition to provide tablets that disintegrate when exposed to an aqueous environment.
  • Tablets that contain too much disintegrant may swell, crack, or disintegrate in storage, while those that contain too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) should be used to form solid oral dosage forms of the disclosure.
  • the amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions include from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • calcium stearate stearate
  • magnesium stearate mineral oil
  • light mineral oil glycerin
  • sorbitol sorbitol
  • mannitol polyethylene glycol
  • other glycols stearic acid
  • sodium lauryl sulfate talc
  • hydrogenated vegetable oil e.g., peanut
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. This disclosure further encompasses lactose-free pharmaceutical compositions and dosage forms, wherein such compositions preferably contain little, if any, lactose or other mono- or di-saccharides.
  • AEROSIL 200 manufactured by W. R. Grace Co. of Baltimore, Md.
  • CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions of the disclosure can include excipients that are well known in the art and are listed in the USP (XXI)/NF (XVI), which is incorporated herein by reference.
  • lactose-free compositions include a pharmaceutically acceptable salt of the paramyxovirus inhibitor composition, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Preferred lactose-free dosage forms include a pharmaceutically acceptable salt of the disclosed compounds, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • This disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms comprising the disclosed compounds as active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that include lactose and at least one active ingredient that includes a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials) with or without desiccants, blister packs, and strip packs.
  • Controlled and Delayed Release Dosage Forms Pharmaceutically acceptable salts of the disclosed compounds can be administered by controlled- or delayed-release means.
  • Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions, (e.g., Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000)).
  • Conventional dosage forms generally provide rapid or immediate drug release from the formulation.
  • controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels.
  • controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from underdosing a drug (e.g., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug.
  • Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.
  • a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the compositions of the disclosure. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
  • dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • OROS® Alza Corporation, Mountain View, Calif. USA
  • OROS® that can be used to administer compounds and compositions of the disclosure
  • OROS® Push- PullTM Delayed Push-PullTM
  • Multi-Layer Push-PullTM Multi-Layer Push-PullTM
  • Push-StickTM Systems all of which are well known. See, e.g., worldwide website alza.com.
  • Additional OROS® systems that can be used for the controlled oral delivery of compounds and compositions of the disclosure include OROS®-CT and L-OROS® ; see, Delivery Times, vol. 11, issue II (Alza Corporation).
  • OROS® oral dosage forms are made by compressing a drug powder (e.g., a paramyxovirus inhibitor composition) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser), (e.g., Kim, Cherng-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, Pa.: 2000)).
  • a drug powder e.g., a paramyxovirus inhibitor composition
  • a specific dosage form of the paramyxovirus inhibitor composition includes: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer interposed between the inner surface of the wall and at least the external surface of the drug layer located within the cavity, wherein the drug layer includes a salt of an paramyxovirus inhibitor composition, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, (e.g., U.S.
  • Another specific dosage form of the disclosure includes: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation includes a salt of a paramyxovirus inhibitor composition, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form
  • Parenteral dosage forms can be administered to patients by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • controlled-release parenteral dosage forms can be prepared for administration of a patient, including, but not limited to, administration DUROS®-type dosage forms, and dose-dumping.
  • Suitable vehicles that can be used to provide parenteral dosage forms of the disclosure are well known to those skilled in the art.
  • Examples include, without limitation: sterile water; Water for Injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, Sodium Chloride Injection, Ringer's injection, Dextrose Injection, Dextrose and Sodium Chloride injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Compounds that alter or modify the solubility of a pharmaceutically acceptable salt of a paramyxovirus inhibitor composition disclosed herein can also be incorporated into the parenteral dosage forms of the disclosure, including conventional and controlled-release parenteral dosage forms.
  • Topical dosage forms of the disclosure include, but are not limited to, creams, lotions, ointments, gels, shampoos, sprays, aerosols, solutions, emulsions, and other forms know to one of skill in the art. (e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton, Pa. (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia, Pa. (1985)).
  • viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed.
  • suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.
  • suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g., a gaseous propellant, such as freon), or in a squeeze bottle.
  • a pressurized volatile e.g., a gaseous propellant, such as freon
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. (e.g., Remington's Pharmaceutical Sciences, 18.sup.th Ed., Mack
  • Transdermal and mucosal dosage forms of the paramyxovirus inhibitor composition include, but are not limited to, ophthalmic solutions, patches, sprays, aerosols, creams, lotions, suppositories, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. (e.g., Remington's
  • transdermal dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes, as oral gels, or as buccal patches.
  • Additional transdermal dosage forms include "reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient.
  • Examples of transdermal dosage forms and methods of administration that can be used to administer the active ingredient(s) of the disclosure include, but are not limited to, those disclosed in U.S. Pat. Nos.: 4,624,665; 4,655,767; 4,687,481;
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal and mucosal dosage forms encompassed by this disclosure are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue or organ to which a given pharmaceutical composition or dosage form will be applied.
  • excipients include, but are not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, to form dosage forms that are non-toxic and pharmaceutically acceptable.
  • additional components may be used prior to, in conjunction with, or subsequent to treatment with pharmaceutically acceptable salts of an the paramyxovirus inhibitor composition.
  • penetration enhancers can be used to assist in delivering the active ingredients to or across the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, an tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as TWEEN 80 (polysorbate 80) and SPAN 60 (sorbitan monostearate).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of the active ingredient(s).
  • a solvent carrier its ionic strength, or tonicity
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of the active ingredient(s) so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery- enhancing or penetration-enhancing agent.
  • Different hydrates, dehydrates, co- crystals, solvates, polymorphs, anhydrous, or amorphous forms of the pharmaceutically acceptable salt of an paramyxovirus inhibitor composition can be used to further adjust the properties of the resulting composition.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
  • a typical kit includes a unit dosage form of a pharmaceutically acceptable salt of a paramyxovirus inhibitor composition and optionally, a unit dosage form of a second pharmacologically active compound, such as anti-proliferative agent.
  • the pharmaceutically acceptable salt of a paramyxovirus inhibitor composition is the sodium, lithium, or potassium salt, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
  • kits may further include a device that can be used to administer the active ingredient.
  • devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
  • Kits of the disclosure can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients (e.g, a paramyxovirus inhibitor composition).
  • active ingredients e.g, a paramyxovirus inhibitor composition
  • the kit can include a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non- aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Other embodiments are directed to the use of the paramyxovirus inhibitor composition in the preparation of a medicament for the treatment conditions/diseases caused by the paramyxovirus.
  • Example 1 describes the effects of various paramyxovirus inhibitor compounds.
  • IC 50 inhibitory concentrations
  • IC 50 tissue culture infective dose
  • TCID 50 tissue culture infective dose

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Abstract

L'invention concerne des méthodes pour traiter des paramyxovirus, des vaccins pour une protection contre les paramyxovirus, et une composition pharmaceutique comprenant un composé inhibiteur ou une composition inhibitrice de paramyxovirus.
PCT/US2005/004565 2004-02-11 2005-02-11 Inhibiteurs de la famille des paramyxovirus et leurs methodes d'utilisation WO2005091804A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098239A3 (fr) * 2007-02-09 2008-09-25 Univ Emory Inhibiteurs de la famille des paramyxovirus et procédés d'utilisation de ceux-ci
WO2021198413A1 (fr) * 2020-04-02 2021-10-07 Janssen Vaccines & Prevention B.V. Compositions de vaccin stabilisées

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4835168A (en) * 1985-12-16 1989-05-30 Eli Lilly And Company Thiadiazole antiviral agents
US6043276A (en) * 1998-06-25 2000-03-28 Georgetown University School Of Medicine Compounds obtained from salvia species having antiviral activity
US20030187063A1 (en) * 2001-03-08 2003-10-02 Pooran Chand Compounds useful for inhibiting paramyxovirus neuraminidase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4835168A (en) * 1985-12-16 1989-05-30 Eli Lilly And Company Thiadiazole antiviral agents
US6043276A (en) * 1998-06-25 2000-03-28 Georgetown University School Of Medicine Compounds obtained from salvia species having antiviral activity
US20030187063A1 (en) * 2001-03-08 2003-10-02 Pooran Chand Compounds useful for inhibiting paramyxovirus neuraminidase

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098239A3 (fr) * 2007-02-09 2008-09-25 Univ Emory Inhibiteurs de la famille des paramyxovirus et procédés d'utilisation de ceux-ci
WO2021198413A1 (fr) * 2020-04-02 2021-10-07 Janssen Vaccines & Prevention B.V. Compositions de vaccin stabilisées

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