WO1999038508A1 - Composes, compositions et methodes de traitement ou de prevention d'infections pneumovirales et de maladies associees - Google Patents

Composes, compositions et methodes de traitement ou de prevention d'infections pneumovirales et de maladies associees Download PDF

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WO1999038508A1
WO1999038508A1 PCT/US1999/001985 US9901985W WO9938508A1 WO 1999038508 A1 WO1999038508 A1 WO 1999038508A1 US 9901985 W US9901985 W US 9901985W WO 9938508 A1 WO9938508 A1 WO 9938508A1
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Prior art keywords
compound
methyl
bis
tetrazolyl
imino
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PCT/US1999/001985
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English (en)
Inventor
Theodore J. Nitz
Daniel C. Pevear
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Viropharma Incorporated
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Application filed by Viropharma Incorporated filed Critical Viropharma Incorporated
Priority to JP2000529241A priority Critical patent/JP2002501894A/ja
Priority to BR9908522-4A priority patent/BR9908522A/pt
Priority to EP99905546A priority patent/EP1051169A4/fr
Priority to US09/254,690 priority patent/US6495580B1/en
Priority to NZ505894A priority patent/NZ505894A/xx
Priority to AU25685/99A priority patent/AU759772B2/en
Priority to MXPA00007394A priority patent/MXPA00007394A/es
Priority to CA2319465A priority patent/CA2319465C/fr
Publication of WO1999038508A1 publication Critical patent/WO1999038508A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to compounds, compositions and methods for preventing and treating viral infections, and the diseases associated therewith, particularly those viral infections and associated diseases caused by viruses of the Pneumovirinae subfamily of the Paramyxovi ⁇ dae.
  • the Pneumovirinae subfamily of the Paramyxoviridae family consists of pneumoviruses that cause significant disease in humans and a number of animal species including cattle, goats, sheep, mice and in avian species.
  • Human respiratory syncytial virus (RSV) the prototypic member of the pneumovirus group, is the major pediatric viral respiratory tract pathogen, causing pneumonia and bronchiolitis in infants and young children.
  • RSV disease is seasonal, with outbreaks in the U.S. typically beginning in November and continuing through April. During these yearly epidemics, approximately 250,000 infants contract RSV pneumonia, and up to 35% are hospitalized. Of those hospitalized, mortality rates of up to 5% have been reported.
  • RSV Rematurity, congenital heart disease, bronchopulmonary dysplasia and various congenital or acquired immunodeficiency syndromes are at greatest risk of serious RSV morbidity and mortality.
  • RSV usually causes upper respiratory tract manifestations but can also cause lower respiratory tract disease, especially in the elderly and in immunocompromised persons. Infection in elderly and immunocompromised persons can be associated with high death rates.
  • Natural infection with RSV fails to provide full protective immunity. Consequently, RSV causes repeated symptomatic infections throughout life. 2
  • the pneumoviruses of animals and avian species are similar to the human virus antigenically, in polypeptide composition and in disease causation.
  • ribavirin [l-beta-D-ribofuranosyl-lH-l,2,4-triazole-3- carboxamide], an antiviral nucleoside which is the only pharmaceutical approved by the U.S. Food and Drug Administration (FDA) for treatment of RSV disease, is considered only for certain RSV patients (e.g., those at high risk for severe complications or who are seriously ill with this infection).
  • FDA Food and Drug Administration
  • Recent studies have reported a failure to demonstrate either clinical or economic benefit to patients of ribavirin treatment.
  • ribavirin has certain toxic side-effects and, in order to minimize these, must be administred by inhalation as an aerosol in an enclosed environment.
  • IVIG intravenous immune globulin
  • the invention provides a compound of the formula:
  • Het represents an unsubstituted or substituted five to seven membered heterocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen or sulfur, said heterocyclic ring substituents being at least one selected from those consisting of hydrogen, alkyl, amino, monoalkylamino or. dialkylamino;
  • R x represents a radical selected from the group consisting of hydrogen; halogen; perfluoroalkyl; alkoxyalkyl; amino; alkylamino; dialkylamino; amido; alkylaminoalkyl; an unsubstituted or substituted, saturated or unsaturated, straight- or branched-chain alkyl radical, said alkyl chain substituent being at least one hydroxy group; carboxy; an unsubstituted or substituted phenyl radical (C 6 H 5 ), said phenyl radical substituent being at least one selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl
  • R 2 represents a radical selected from the group consisting of hydrogen, hydroxy, thio, alkoxy, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, carboxamide, carboxamidoalkyl, sulfonamide acetamido;
  • Z represents a substituent selected from the group consisting of hydrogen, formyl, hydroxy or -X-Het, wherein X and Het are as previously defined; the isomeric forms of said compound and the pharmaceutically acceptable salts of said compound.
  • R is a radical selected from the group of hydrogen, hydroxy, alkoxy, alkyl, halogen, nitro or alkoxy monosubstituted with a substituent selected from carboxy, amino, monoalkylamino, dialkylamino or acetamido;
  • R 2 is hydroxy;
  • R 3 is a heterocylic radical selected from the group consisting of 1-pyrazolyl radicals, 1-triazolyl radicals (including the 1,2,3-; 1,2,4-; or 1,3,4- isomers thereof), 4-triazolyl radicals, 1-tetrazolyl radicals or 2-tetrazolyl radicals (including the isomers thereof) and the amino- and alkyl-derivatives of such radicals, including, without limitation, 5-amino-lH-tetrazolyl, 3-amino-4H- 1,2,4 triazolyl
  • the present invention provides a class of novel intermediates that are useful in preparing the anti-viral agents described herein. These intermediates have the general formula:
  • Q represents a reactive group selected from those consisting of 5,5- dimethyl-l,3-dioxan and formyl
  • R 5 is a radical selected from those consisting of hydrogen and hydroxy
  • Rg is a radical selected from those consisting of hydroxy, alkoxy, aryloxy and aralkoxy
  • R 7 is a radical selected from those consisting of hydrogen, hydroxy, alkoxy, alkoxyalkyl, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamide, amidino, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, or alkoxy monosubstituted with
  • the present invention also provides new synthetic methods for preparation of the compounds described herein.
  • One method comprises causing a 3-halogen substituted-4-alkoxy-substituted benzaldehyde, in which the aldehyde moiety is protected with a protecting group, to undergo reaction with an alkylated 6 alkali metal to effect a halogen-alkali metal exchange; adding to the reaction mixture an alkyl ester of an R-substituted benzoic acid under conditions yielding a dialkoxy-R-substituted triphenylcarbinol derivative including said protecting group; deprotecting and reducing the dialkoxy-R-substituted triphenylcarbinol derivative to restore the aldehyde functional groups and convert the triphenylcarbinol moiety to a triphenylmethane moiety; dealkylating any alkoxy substituents to hydroxy substituents; and reacting the aldehyde functional groups with an amine-substituted hetero
  • R substituents on the benzoic acid ester are selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, hydroxy, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamide, amidino, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, or alkoxy monosubstituted with a substituent selected from the group consisting of carboxy, amino, alkylamino or dialkylamino.
  • Another method for preparing compounds of this invention comprises reacting a 4,4'-dihydroxy-3,3'-(4-R-substituted phenyl)methylenebisbenzaldehyde, in which the hydroxy groups are etherified, with the anion of a methyl-substituted heterocyclic reactant to yield a heterocyclic hydroxyalkyl derivative of etherified, R-substituted triphenylmethane as an intermediate product; and subjecting the intermediate product to dehydration and deetherification to produce the desired product.
  • the present invention provides pharmaceutical compositions comprising one or more of the above-described compounds in combination with a pharmaceutically acceptable carrier medium.
  • the present invention provides a method for preventing and treating pneumovirus infection and for preventing and treating diseases associated with pneumovirus infection in living hosts, by administering to a living host susceptible to pneumovirus infection a therapeutically effective amount of a compound of the above structures and/or the isomers and pharmaceutically acceptable salts of said compounds, or pharmaceutical compositions containing same.
  • the compounds of the invention can be conveniently prepared from known starting materials according to one of the synthetic scheme illustrated below, wherein R and Het are as previously defined.
  • Synthetic scheme A involves protection of the aldehyde moiety of a bromobenzaldehyde followed by halogen-metal exchange and reaction of two equivalents of the desired aryl lithium species with an ester group to provide a tri- aryl methanol. Reduction and regeneration of the aldehyde can be achieved with formic acid. Liberation of the phenolic groups with boron tribromide (or pyridine hydrochloride) and condensation of the aldehyde groups with the appropriate heterocyclic amine provides the compounds of the invention.
  • Alk alkyl
  • y ⁇ y Synthetic scheme B involves the reaction of a bis aldehyde, prepared as described in Scheme A, above, with the anion of a methyl heterocycle generated from «-butyl lithium to give a heterocyclic hydroxyalkyl derivative of an etherified, R-substituted triphenylmethane, as an intermediate product.
  • alkyl refers to aliphatic hydrocarbon radicals of one to six carbon atoms in length.
  • alkyl or any variation thereof, used in combination form to name substituents, such as alkoxy (-O- alkyl), alkylthio (-S-alkyl), alkylamino (-NH-alkyl), alkylsulfonyl (-S(O) 2 -alkyl), carboxyalkyl (-alkyl-COOH), or the like, also refers to aliphatic hydrocarbon radicals of one to six carbon atoms in length, and preferably of one to four carbon atoms in length.
  • Het refers to an unsubstituted or substituted 5-7 membered heterocyclic ring substituent on the compounds of the invention, which substituent contains 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, in which the heterocyclic ring substituent is at least one selected from the group of hydrogen, alkyl, amino, alkylamino or dialkylamino.
  • heterocyclic rings include, without limitation, those derived from pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, imidazole, oxazole, thiazole, isoxazole, pyridine, pyrimidine, triazine, morpholine, piperidine, piperazine, 1,2,4-diazepine or the like.
  • sulfonamide refers to a radical or substituent of the formula -SO 2 NR"R'" or -NR"SO 2 R'", wherein R" and R'" are as previously defined. 10
  • anti-pneumovirus compounds within the scope of the invention are exemplified below.
  • In vitro studies have been performed demonstrating the usefulness of compounds described herein as antiviral agents against pneumo viruses.
  • Antiviral activity was measured on the basis of activity against RSV in a cell culture assay.
  • the compounds of the invention can form useful salts with inorganic and organic acids, including, for example, hydrochloric acid, hydrobromic acid, methanesulfonic acid salts, or the like, as well as with inorganic bases, such as sodium or potassium salts.
  • the pharmaceutically acceptable salts of the compounds of the invention are prepared following procedures which are familiar to those skilled in the art.
  • the antiviral pharmaceutical compositions of the present invention comprise one or more of the above-described compounds or precursors thereof, as the primary active ingredient in combination with a pharmaceutically acceptable carrier medium and, optionally one or more supplemental active agents.
  • composition may be prepared in various forms for administration, including tablets, caplets, pills or dragees, or can be filled in suitable containers, such as capsules, or, in the case of suspensions, filled into bottles.
  • pharmaceutically acceptable carrier medium includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • the compounds of the invention are also useful in treating and preventing pneumovirus infections and diseases when used in combination with supplemental active agents, which may be optionally incorporated into the pharmaceutical composition of the invention, or otherwise administered during a course of therapy.
  • supplemental active agents include, without limitation, interferons, ribavirin, and immunomodulators, immunoglobulins, anti-flammatory agents, antibiotics, anti- virals, anti-infectives, and the like, the combination of which with one or more compounds of the invention offers additive or synergistic therapeutic benefit.
  • the active agent may be present in any therapeutically effective amount, which is typically at least 0.1% and generally not more than 90% by weight, based on the total weight of the composition, including carrier medium and/or supplemental active agent(s), if any.
  • the proportion of active agent varies between 1-50% by weight of the composition.
  • compositions suitable for enteral or parenteral administration can be used to make up the composition.
  • Gelatine, lactose, starch, magnesium, stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers or excipients for medicaments may all be suitable as carrier media.
  • Compounds of the invention are useful in treating and preventing pneumovirus infections (and diseases) in humans, as well as in livestock, and may be used to treat cattle, swine and sheep, or to treat avian species such as 12 turkeys, or for other animals susceptible to pneumovirus infection.
  • the term "patient” as used herein includes, without limitation, all of the foregoing.
  • Compounds described herein are also useful in preventing or resolving pneumoviral infections in cell cultures, tissue cultures and organ cultures, as well as other in vitro applications. For example, inclusion of compounds of the invention as a supplement in cell or tissue culture growth media and cell or tissue culture components will prevent pneumoviral infections of cultures not previously infected with pneumoviruses.
  • Compounds described above may also be used to eliminate pneumoviruses from cultures or other materials infected or contaminated with pneumoviruses, after a suitable treatment period, under any number of treatment conditions as determined by the skilled artisan.
  • the compounds of the invention may be administered using any amount and any route of administration effective for attenuating infectivity of the pneumovirus.
  • amount effective to attenuate infectivity of pneumovirus refers to a nontoxic but sufficient amount of the antiviral agent to provide the desired treatment of viral infection. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular antiviral agent and its mode of administration, and the like.
  • the anti- pneumovirus compounds are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to a physically discrete unit of antiviral agent appropriate for the patient to be treated.
  • Each dosage should contain the quantity of active material calculated to produce the desired therapeutic effect either as such, or in association with the selected pharmaceutical carrier medium.
  • the antiviral compounds of the invention will be administered in dosage units containing from about 0.1 ⁇ g to about 50 mg of the antiviral agent, with a range of about 0.001 mg to about 25 mg being preferred.
  • the compounds of the invention may be administered as such, or in the form of a precursor from which the active agent can be derived, such as a prodrug.
  • a 13 prodrug is a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo.
  • Prodrugs of the compounds of the invention may include, but are not limited to mono-, di- or tri-esters of simple or functionalized aliphatic carboxylic acids; esters of carbamic acids (R a -(O-CO-NR b R c ) n ); esters of amino acids (R a -(O-CO-
  • esters of unsubstituted or substituted aromatic acids (R a -(O-CO- aryl) n ), wherein the aryl ring may be substituted with hydroxy, carboxy, lower alkyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phosphoric acid, amino, alkylamido and halogen groups; esters of derivatized phosphoric acids; (acyloxy)methyl or acyloxy(ethyl)ethers (R a -(O-CH 2 -O-CO-R b ) n or R a -(O-
  • R_ is a residue of a compound of the invention
  • Such prodrugs may be prepared according to procedures well known in the field of medicinal chemistry and pharmaceutical formulation science and are within the scope of the present invention.
  • the compounds of the invention may be administered orally, parenterally, such as by intramuscular injection, intraperitoneal injection, intravenous infusion or the like, or by inhalation, such as by aerosol, in the form of a solution or a dry powder, or the like, or by intubation, depending on the nature and severity of the infection being treated.
  • the compounds of the invention may be administered orally, parenterally, or by inhalation or intubation at dosage levels of about 10 "6 mg to about 1000 mg/kg, one or more times a day, to obtain the desired therapeutic effect.
  • the compounds of the invention will typically be administered from 1 to
  • Examples 1-14 illustrate the chemical synthesis of representative compounds of the invention.
  • the ethyl acetate solution was extracted three times with 10% Na 2 CO 3 .
  • the combined aqueous extracts were treated with charcoal, filtered through Celite, 16 and carefully acidified with 6N HC1.
  • the off-white precipitate was isolated, washed with water, dried in vacuo, dissolved in THF (45 mL), diluted with t- butyl methyl ether (45 mL), and filtered through FlorisilTM with THF/t-BME 1:1. Concentration of the filtrate provided 3.85 g (85%) of pure dialdehyde which contained a small amount of residual solvents.
  • compounds of formula II, above may be made with various heterocyclic radicals (R 3 ) by replacing the 1,5-diaminotetrazole with other heterocyclic reactants, as described in Examples 3-6, below.
  • Example 1 The title compound was prepared essentially according to the synthetic procedure set out in Example 1; however, the 1,5-diaminotetrazole in Example 1 was replaced with 2,5-diaminotetrazole.
  • compounds of formula I, above, in which the R, radical is other than hydroxyphenyl may be prepared by substitution of a suitable ester for the methyl 4-methoxybenzoate in step b of the reaction sequence of Example 1, above.
  • substituted esters which may be used to prepare additional compounds having the structure of formula I, above, include alkoxy, halo, perfluoroalkyl, alkoxycarbonyl, alkylaminocarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl, alkoxyalkyl benzoates and esters of pyridine, thiophene, imidazole, furan, pyrole, oxazole, triazole, oxadiazole, thiadiazole, pyrazole, tetrazole, isoxazole, thiazole carboxylates.
  • EXAMPLE 13 5,5'-Bis[l-(2-(4-methyIthiazolyl)ethenyl)]-2,2',4"-methylidynetrisphenol a. 4.4 , -Dibenzyloxy-3.3'-(4-benzyloxyphenyl ' ) methylenebisbenzaldehyde.
  • a solution of 2.0 g (5.74 mmole) of 4,4'-dihydroxy-3,3'-(4- hydroxyphenyl) methylenebisbenzaldehyde in 57 ml of DMF was added 7.95 g (5.76 mmole) of potassium carbonate and 4.09 g (23.9 mmole) of benzylbromide.
  • EXAMPLE 15 Preparation of Prodrugs a) A solution of 255 mg (.5 mmoles) of the compound prepared as described in Example 1, above, in 2.5 ml of anhydrous pyridine and .243 ml of acetic anhydride was left at room temperature overnight. The solvent was removed and to the residue was added 5 ml of water and the mixture was 28 made slightly acidic by the addition of acetic acid. The solid was collected, washed with water followed by hexane and then dried to give 240 mg of the desired triacetate prodrug. b) Following essentially the same procedure, 220 mg of the triacetate derivative was obtained from 200 mg of the compound prepared as described in Example 6, above.
  • Example 16 illustrates the effectiveness of the compounds used in the method of the invention in inhibiting the viral replication of RSV in cell culture.
  • the replication of many viruses may be quantitatively assessed in the laboratory in various cell or tissue culture systems.
  • Such in vitro culture methodologies are available and useable by those skilled in the art for the propagation and quantitative measurement of the replication of pneumoviruses.
  • the following procedure was used for the in vitro quantitative measure of RSV replication.
  • IC 50 Inhibitory Concentration
  • Anti -pneumo virus compounds of the invention were screened for antiviral activity against RSV (strain Long) on cultured HEp2 cells. Standard 96-well culture plates were seeded with 4 x 10 4 HEp2 cells in 200 ⁇ L of Minimal 29
  • EMEM fetal bovine serum
  • FBS fetal bovine serum
  • IC 50 values were then calculated according to the following formula:
  • IC 50 [(Y - B)/(A - B)] x (H - L) + L
  • Y represents the mean OD 570 reading of the cell control wells (CC) divided by 2
  • B represents the mean OD 570 reading of wells of the compound dilution nearest to and below Y
  • A represents the mean OD 570 reading of wells of the compound dilution nearest to and above Y
  • L represents the compound concentration at B
  • H represents the compound concentration at A.
  • a similar assay is useful for various strains of human RSV, including subtype A and subtype B viruses, as well as other pneumoviruses.
  • RSV-A human RSV subtype A
  • human RSV-B RSV subtype B
  • BRSV bovine RSV
  • ORSV ovine RSV
  • test compounds required to achieve 50% inhibition of RSV replication in cell culture indicate that the compounds used in the method of the invention are effective at inhibiting the pneumovirus replication process. It is also demonstrated here that the compounds of the invention are dramatically more potent than Ribavirin at inhibiting viral replication.
  • Example 17 demonstrates that the compounds of the invention are not toxic or detrimental to the health of normal cells at concentrations well above those needed to inhibit pneumovirus replication.
  • compounds of the invention were 31 evaluated in an in vitro cytotoxicity assay.
  • One useful assay for determining the cytotoxic effects of compounds on the growth of cells is a tetrazolium-based colorimetric method (Mossman, T., J. Immun. Methods, 65 (1-2): 55-63 (1983)). This assay measures cell viability, and therefore cytotoxicity, by quantitatively detecting the in situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) by viable cells.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide
  • Cells are seeded in 96-well plates in DMEM containing 5% FBS at a density of 4 x 10 3 cells per well. After incubation for 4 hours at 37°C and 5% CO 2 , 2-fold serial dilutions of compound in 1% DMSO (or solvent alone) are added to quadruplicate wells and the plates are incubated for an additional 68 hours at 37°C and 5% CO 2 , which is equivalent to 3 to 4 cell doublings. The culture medium is removed, and the cells are treated with 1 mg/ml of MTT in phosphate-buffered saline, pH 7.2 for 4 hours at 37°C and 5% CO 2 .
  • the reduced blue formazan crystals produced by the viable cells are solubilized by the addition of 0.04N HC1 in isopropanol.
  • the optical density at 570 nm (OD 570 ) of each well is read using a suitable microplate reader.
  • Cell viability is expressed as the percentage of optical density for compound-treated cells relative to the optical density of solvent alone- treated control wells. The highest compound concentration resulting in an optical density of > 75% of the control is represented as the cellular cytotoxicity value (CC 75 ).
  • the cellular cytotoxicity (CC 75 ) values for the compounds of Examples 1 through 8 are considerably higher than the antiviral (IC 50 ) values for these compounds.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

L'invention concerne des composés, des compositions et des méthodes de prophylaxie et de traitement d'infections causées par les virus de la famille des Paramyxoviridae, et plus précisément de la sous-famille des Pneumovirinae, et de maladies associées à ces infections.
PCT/US1999/001985 1998-01-29 1999-01-29 Composes, compositions et methodes de traitement ou de prevention d'infections pneumovirales et de maladies associees WO1999038508A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP2000529241A JP2002501894A (ja) 1998-01-29 1999-01-29 ニューモウイルス感染および関連疾患の治療または予防のための化合物、組成物および方法
BR9908522-4A BR9908522A (pt) 1998-01-29 1999-01-29 Composto, pró-droga, intermediário para a preparação de um composto, composição farmacêutica, processos para tratar e prevenir infecção por pneumovìrus, para tratar células em cultura, para tratar materiais biológicos, e, para preparar um composto
EP99905546A EP1051169A4 (fr) 1998-01-29 1999-01-29 Composes, compositions et methodes de traitement ou de prevention d'infections pneumovirales et de maladies associees
US09/254,690 US6495580B1 (en) 1998-01-29 1999-01-29 Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
NZ505894A NZ505894A (en) 1998-01-29 1999-01-29 Methylenebisbenzaldehyde derivatives, methylidynetrisphenol derivative and pharmaceuticals thereof; useful for treating or preventing pneumovirus infection and associated diseases
AU25685/99A AU759772B2 (en) 1998-01-29 1999-01-29 Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
MXPA00007394A MXPA00007394A (es) 1998-01-29 1999-01-29 Compuestos, composiciones y metodos para tratar o evitar infeccion de neumovirus y enfermedades asociadas.
CA2319465A CA2319465C (fr) 1998-01-29 1999-01-29 Composes, compositions et methodes de traitement ou de prevention d'infections pneumovirales et de maladies associees

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US7303898P 1998-01-29 1998-01-29
US60/073,038 1998-01-29
US7307898P 1998-01-30 1998-01-30
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US10/280,528 Division US20030092685A1 (en) 1998-01-29 2002-10-25 Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases

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CA (1) CA2319465C (fr)
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489338B2 (en) 2000-06-13 2002-12-03 Bristol-Myers Squibb Company Imidazopyridine and imidazopyrimidine antiviral agents
WO2004014316A2 (fr) * 2002-08-09 2004-02-19 Viropharma Incorporated Composes, compositions et techniques de traitement et de prevention de l'infection par des pneumovirus et de maladies associees
US7323567B2 (en) 2003-10-30 2008-01-29 Boehringer Ingelheim (Canada) Ltd. RSV polymerase inhibitors
WO2010093706A2 (fr) 2009-02-10 2010-08-19 The Scripps Research Institute Vaccination programmée chimiquement
US8119672B2 (en) * 2002-08-09 2012-02-21 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
EP2428226A1 (fr) 2001-10-22 2012-03-14 The Scripps Research Institute Composés de ciblage d'anticorps
US8247576B2 (en) 2003-12-23 2012-08-21 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8343953B2 (en) 2005-06-22 2013-01-01 Astex Therapeutics Limited Pharmaceutical compounds
US8497294B2 (en) 2007-03-14 2013-07-30 Astex Therapeutics Limited Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
WO2015085844A1 (fr) 2013-12-10 2015-06-18 南京明德新药研发股份有限公司 Dérivé d'imidazole utilisé en tant qu'agent antiviral et son utilisation pour la préparation d'un médicament
US9504672B2 (en) 2012-06-29 2016-11-29 Microdose Therapeutx, Inc. Compositions and methods for treating or preventing pneumovirus infection and associated diseases
US10227309B2 (en) 2015-06-08 2019-03-12 Shandong Danhong Pharmaceutical Co., Ltd. Crystal form A of 1-isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo [d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indolin]-2′-one
EP3982994A4 (fr) * 2019-06-13 2023-10-04 Cidara Therapeutics, Inc. Compositions et procédés pour le traitement du virus respiratoire syncytial

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005125A1 (fr) * 1995-07-27 1997-02-13 Warner-Lambert Company Phenols a substitution utilises comme nouveaux antagonistes des canaux calciques lents
US5773646A (en) * 1996-03-29 1998-06-30 G. D. Searle & Co. Meta-substituted phenylene derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1508391A (en) * 1975-01-20 1978-04-26 Sterling Drug Inc Phenylalkylamines
US4324794A (en) * 1980-08-26 1982-04-13 Research Triangle Institute Inhibition of respiratory syncytial virus-induced cell fusion by amidino compounds
US5098920A (en) * 1990-05-04 1992-03-24 G. D. Searle & Co. 1h-substituted-1,2,4-triazole compounds and methods of use thereof for treatment of cardiovascular disorders
WO1995000131A1 (fr) * 1993-06-23 1995-01-05 Cambridge Neuroscience, Incorporated Ligands du recepteur sigma et leur utilisation
CN1163401A (zh) * 1996-02-13 1997-10-29 李占元 全自动血球计数仪试剂及配制方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005125A1 (fr) * 1995-07-27 1997-02-13 Warner-Lambert Company Phenols a substitution utilises comme nouveaux antagonistes des canaux calciques lents
US5773646A (en) * 1996-03-29 1998-06-30 G. D. Searle & Co. Meta-substituted phenylene derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1051169A4 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489338B2 (en) 2000-06-13 2002-12-03 Bristol-Myers Squibb Company Imidazopyridine and imidazopyrimidine antiviral agents
EP2428226A1 (fr) 2001-10-22 2012-03-14 The Scripps Research Institute Composés de ciblage d'anticorps
US20140072532A1 (en) * 2002-08-09 2014-03-13 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
WO2004014316A2 (fr) * 2002-08-09 2004-02-19 Viropharma Incorporated Composes, compositions et techniques de traitement et de prevention de l'infection par des pneumovirus et de maladies associees
WO2004014316A3 (fr) * 2002-08-09 2004-06-17 Viropharma Inc Composes, compositions et techniques de traitement et de prevention de l'infection par des pneumovirus et de maladies associees
US9321739B2 (en) 2002-08-09 2016-04-26 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US8119672B2 (en) * 2002-08-09 2012-02-21 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US8202896B2 (en) 2002-08-09 2012-06-19 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US20120183498A1 (en) * 2002-08-09 2012-07-19 Nitz Theodore J Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US8962667B2 (en) 2002-08-09 2015-02-24 Microdose Therapeutix, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US8846735B2 (en) 2002-08-09 2014-09-30 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US7323567B2 (en) 2003-10-30 2008-01-29 Boehringer Ingelheim (Canada) Ltd. RSV polymerase inhibitors
US9283226B2 (en) 2003-12-23 2016-03-15 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8247576B2 (en) 2003-12-23 2012-08-21 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8691806B2 (en) 2003-12-23 2014-04-08 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8343953B2 (en) 2005-06-22 2013-01-01 Astex Therapeutics Limited Pharmaceutical compounds
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
US8497294B2 (en) 2007-03-14 2013-07-30 Astex Therapeutics Limited Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
WO2010093706A2 (fr) 2009-02-10 2010-08-19 The Scripps Research Institute Vaccination programmée chimiquement
US9504672B2 (en) 2012-06-29 2016-11-29 Microdose Therapeutx, Inc. Compositions and methods for treating or preventing pneumovirus infection and associated diseases
WO2015085844A1 (fr) 2013-12-10 2015-06-18 南京明德新药研发股份有限公司 Dérivé d'imidazole utilisé en tant qu'agent antiviral et son utilisation pour la préparation d'un médicament
US9850251B2 (en) 2013-12-10 2017-12-26 Shandong Danhong Pharmaceutical Co., Ltd. Imidazole derivative used as antiviral agent and use therof in preparation of medicament
US10030029B2 (en) 2013-12-10 2018-07-24 Shandong Danhong Pharmaceutical Co., Ltd. Imidazole derivative used as antiviral agent and use thereof in preparation of medicament
US10227309B2 (en) 2015-06-08 2019-03-12 Shandong Danhong Pharmaceutical Co., Ltd. Crystal form A of 1-isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo [d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indolin]-2′-one
US10633347B2 (en) 2015-06-08 2020-04-28 Shandong Danhong Pharmaceutical Co., Ltd. Crystal form B of 1-isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indolin]-2′-one
US10858322B2 (en) 2015-06-08 2020-12-08 Shandong Danhong Pharmaceutical Co., Ltd. Process for preparing 1-isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo[D]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indolin]-2′-one
EP3982994A4 (fr) * 2019-06-13 2023-10-04 Cidara Therapeutics, Inc. Compositions et procédés pour le traitement du virus respiratoire syncytial

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CA2319465A1 (fr) 1999-08-05
JP2002501894A (ja) 2002-01-22
EP1051169A1 (fr) 2000-11-15
MXPA00007394A (es) 2003-08-01
AU759772B2 (en) 2003-05-01
NZ505894A (en) 2002-12-20
BR9908522A (pt) 2001-10-02
EP1051169A4 (fr) 2002-05-29
CN1289248A (zh) 2001-03-28
CA2319465C (fr) 2013-03-19

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