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WO1998039287A1 - Composes de benzothrone et ses utilisations antivirales - Google Patents

Composes de benzothrone et ses utilisations antivirales Download PDF

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Publication number
WO1998039287A1
WO1998039287A1 PCT/US1998/004140 US9804140W WO9839287A1 WO 1998039287 A1 WO1998039287 A1 WO 1998039287A1 US 9804140 W US9804140 W US 9804140W WO 9839287 A1 WO9839287 A1 WO 9839287A1
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Prior art keywords
group
benz
benzanthrone
alkyl
anthracene
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PCT/US1998/004140
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English (en)
Inventor
Michael R. Johnson
Myung-Chol Kang
Alexei G. Nemazany
Kenner C. Rice
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Trimeris, Inc.
THE UNITED STATES OF AMERICA as represented by the SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES;
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Priority to AU66809/98A priority Critical patent/AU6680998A/en
Priority to EP98908887A priority patent/EP1021397A4/fr
Publication of WO1998039287A1 publication Critical patent/WO1998039287A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/20—Polycyclic condensed hydrocarbons
    • C07C15/38—Polycyclic condensed hydrocarbons containing four rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
    • C07C17/354—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction by hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/18—Polycyclic aromatic halogenated hydrocarbons
    • C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/44—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
    • C07C49/665—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings

Definitions

  • the present invention relates to benzanthrones and derivatives thereof having antiviral activity, and to the use of benzanthrones and benzanthrone derivatives as inhibitors of membrane fusion associated events, such as viral transmission.
  • a typical treatment for an RSV infection involves the administration of ribavirin
  • ribavirin As an aerosol, which can reduce the severity of lower respiratory infections.
  • ribavirin has a low level of efficacy, as well as a variety of undesirable side effects.
  • the treatment of RSV infections with ribavirin is described by C.B. Hall et al., Journal of the American Medical Association, 1983, 249, 2666-2670.
  • the present invention provides such a treatment.
  • the present invention is directed to benzanthrone and benzanthrone derivative compositions having antiviral activity and to pharmaceutical compositions for the treatment of a viral infection, which comprise a therapeutically effective amount of at least one benzanthrone or benzanthrone derivative.
  • Preferred benzanthrones and benzanthrone derivatives include 7H-benz [de]anthracen-7-ones and salts thereof of formula,
  • R lf R 2 , and R 3 are the same or different, and are individually selected from the group consisting of hydrogen, halide, alkyl, nitrile, nitro, alkanoly, benzyl, benzoly, hydroxyl, methylenedioxy, ethylenedioxy, dialkyamino, and cyclic amino;
  • R 4 is selected from the group consisting of hydrogen, alkyl, benzyl, benzoly;
  • R 5 and R 6 are hydrogen or alkyl having one to four carbon atoms, or form a 5- or 6-membered heterocyclic ring with the nitrogen to which they are attached, where the 5- or 6-membered heterocyclic ring is selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; and
  • X and Y are selected from the group consisting of carbon, nitrogen and oxygen.
  • Preferred antiviral compositions include those containing a 3-substituted benzanthrone or salt thereof of formula
  • Ri is selected from the group consisting of alkyl and aryl sulfonamide, such as CONHS0 2 CH 3 , tetrazole, natural and synthetic carbonyl amino acids, such as CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-leucine, and CO-proline, carbonyl-N-methylpiperazine, amide, halide, hydroxymethyl, methoxymethyl, and carboxylic acids, and those compositions that contain a 3 , 9-disubstituted benzanthrone or salt thereof of formula
  • R x and R 2 are the same or different, and are individually selected from the group consisting of alkyl and aryl sulfonamide, such as CONHS0 2 CH 3 , tetrazole, natural and synthetic carbonyl amino acids, such as CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-N-methylpiperazine, CO-leucine, and CO-proline, carbonyl-N-methylpiperazine, amide, halide, hydroxymethyl, and carboxylic acid, including CONH2 , CN, Br, C0 2 H, and C0 2 Na.
  • alkyl and aryl sulfonamide such as CONHS0 2 CH 3 , tetrazole
  • natural and synthetic carbonyl amino acids such as CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-N-methylpiperazine, CO-leucine, and CO-proline, carbon
  • the most prefered 3-substituted benzanthrones and salts are of formula
  • the invention also relates to a method for the treatment of a viral infection, which comprises administering to a patient having a viral infection a therapeutically effective amount of an antiviral composition comprising at least one of benzanthrone or benzanthrone derivative, where the benzanthrone or benzanthrone is preferably a 7H-benz[de]anthracen-7-one, an azabenzanthrone, a 7H-benz[de] anthracene, or a derivative thereof, as described above.
  • the method of the invention typically comprises mixing the benzanthrone or benzanthrone derivative with a pharmaceutically suitable carrier to facilitate the administration of the antiviral composition.
  • the benzanthrone and benzanthrone derivative compositions are used to treat RSV infections.
  • the present invention is directed to compositions comprising benzanthrones and benzanthrone derivatives having antiviral activity, and to a method of treating viral infections, in particular, RSV infections, with compositions comprising benzanthrones and benzanthrone derivatives.
  • Benzanthrones having antiviral activity include 7H-benz [de] anthracene-7-ones of formula I,
  • R lf located at one of positions C 8 to C llf R 2 , located at one of positions C x to C 3 , and R 3 , located at one of positions C 4 to C 6 are the same or different, and are individually selected from the group consisting of hydrogen, halide, alkyl, nitrile, nitro, alkanoly, benzyl, benzoly, hydroxy1, methylenedioxy, ethylenedioxy, dialkyamino, and cyclic amino;
  • R 4 is selected from the group consisting of hydrogen, alkyl, benzyl, benzoly;
  • R 5 and R 6 when taken individually are selected from the group consisting of hydrogen and alkyl having one to four carbon atoms, or may form a 5- or 6-membered heterocyclic ring with the nitrogen to which they are attached, where the 5- or 6-membered heterocyclic ring is selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; and
  • X and Y are selected from the group consisting of carbon, nitrogen and oxygen.
  • a composition comprising at least one benzanthrone or benzanthrone derivative having antiviral activity may be administered to the patient by any means known in the art.
  • the benzanthrone composition may be mixed with a suitable pharmaceutical carrier.
  • Benzanthrones and benzanthrone derivatives may be tested for anti-RSV activity by a variety of methods known in the art.
  • benzanthrones and benzanthrone derivatives may be tested for the ability to disrupt the ability of HEp2 cells acutely infected with RSV (i.e.
  • Uninfected confluent monolayers of Hep-2 cells are grown in microtiter wells in 3% EMEM (Eagle Minimum Essential Medium w/o L-glutamine [Bio hittaker Cat. No. 12-125F] , with fetal bovine serum [FBS; which had been heat inactivated for 30 minutes at 56°C; Bio Whittaker Cat. No. 14-501F) supplemented at 3%, antibiotics (penicillin/streptomycin; Bio Whittaker Cat. No. 17-602E) added at 1%, and glutamine added at 1%.
  • EMEM Eagle Minimum Essential Medium w/o L-glutamine [Bio hittaker Cat. No. 12-125F]
  • FBS fetal bovine serum
  • antibiotics penicillin/streptomycin
  • Bio Whittaker Cat. No. 17-602E glutamine added at 1%.
  • Hep2 cells for addition to uninfected cells, cultures of acutely infected Hep2 cells are washed with DPBS (Dulbecco's Phosphate Buffered Saline w/o calcium or magnesium; Bio Whittaker Cat. No. 17-512F) , and cell monolayers are removed with Versene (1:5000; Gibco Life Technologies Cat. No. 15040-017) . The cells are spun 10 minutes, and resuspended in 3% FBS. Cell counts are performed using a hemacytometer. Persistent cells are added to the uninfected Hep-2 cells.
  • DPBS Dynabecco's Phosphate Buffered Saline w/o calcium or magnesium
  • Versene (1:5000; Gibco Life Technologies Cat. No. 15040-017
  • the cells are spun 10 minutes, and resuspended in 3% FBS. Cell counts are performed using a hemacytometer. Persistent cells are added to the uninfected Hep-2 cells
  • the antiviral assay may be conducted by, first, removing all media from the wells containing uninfected Hep-2 cells, then adding a benzanthrone or benzanthrone derivative and 100 acutely RSV-infected Hep2 cells per well. Wells are then incubated at 37°C for 48 hours.
  • Crystal Violet stain approximately 50 ⁇ l 0.25% Crystal Violet stain in methanol are added to each well. The wells are rinsed immediately, to remove excess stain, and allowed to dry. The number of syncytia per well are then counted, using a dissecting microscope.
  • XTT 3-bis[2-Methoxy-4-nitro-5- sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt
  • 50 ⁇ l XTT (lmg/ml in RPMI buffered with lOO M HEPES, pH 7.2-7.4, plus 5% DMSO) are added to each well.
  • the OD 450/690 is measured (after blanking against growth medium without cells or reagents, and against reagents) according to standard procedures.
  • Anti-RSV activity c ⁇ _n also be assayed in vivo via well known mouse models.
  • RSV can be administered intranasally to mice of various inbred strains. Virus replicates in lungs of all strains, but the highest titers are obtained in P/N, C57L/N and DBA/2N mice. Infection of BALB/c mice produces an asymptomatic bronchiolitis characterized by lymphocytic infiltrates and pulmonary virus titers of 10 4 to 10 5 pfu/g of lung tissue (Taylor, G. et al. , 1984, Infect. Immun. 43:649-655) .
  • Cotton rat models of RSV are also well known. Virus replicates to high titer in the nose and lungs of the cotton rat but produces few if any signs of inflammation.
  • Benzanthrones and benzanthrone derivatives may be prepared from readily available starting materials.
  • 3-bromobenzanthrone is treated with CuCN to provide 3-cyanobenzanthrone.
  • the 3-cyanobenzanthrone is then hydrolyzed with sodium hydroxide to yield 3-carboxylic benzanthrone.
  • the 3-substituted amides of benzanthrones are prepared by reacting 3-carboxylic benzanthrones with thionyl chloride to yield the acid chloride followed by substitution with corresponding amines.
  • amino acid derivatives of 3-carbonybenzanthrones a mixture of the acyl chloride of benzanthrone-3-carboxylic acid (1 mmol) , a suitable amino derivative (1.1 mmol), such as , e.g., aspartic acid or DL-leucine, and potassium carbonate (3 mmol) (freshly tempered at 200°C for 36 hours at reduce pressure, and ground before use) in 50 ml of anhydrous 1,4-dioxane is stirred at reflux temperature, i.e., 102 to 105°C, for 4 hours. After cooling, the solvent is removed under reduced pressure in a rotary evaporator, and 25 ml of water is added.
  • a suitable amino derivative such as , e.g., aspartic acid or DL-leucine
  • potassium carbonate 3 mmol
  • reaction mixture is then neutralized to a pH of 6 to 7 by the addition of acetic acid.
  • acetic acid is then added to the reaction mixture.
  • the resulting precipitate is then collected by filtration, washed with 5 ml of cold water, dried, and recrystaUized from nitromethane. Yields range from about 36 to about 47 percent.
  • the 3-tetrazole and methane sulfonamide derivatives of benzanthrones are prepared from a mixture of the acyl chloride of benzanthrone-3-carboxylic acid (1 mmol) and a suitable amino derivative (1.1 mmol), such as , e.g., lH-tetrazole or methane sulfonamide, in 40 ml of anhydrous pyridine, which is stirred at reflux temperature, i.e., 115 to 117 °C for 3 hours. After cooling, the is pyridine removed under reduced pressure in a rotary evaporator, and 40 ml of water is added. The resulting precipitate is then collected by filtration, washed with 10 ml of cold water, dried, and recrystaUized from nitromethane. Yields range from about 57 to about 61 percent.
  • the 3,9-substituted benzanthrones are prepared from a mixture of the acyl chloride of benzanthrone-3 ,9-dicarboxylic acid (1 mmol), a suitable amine, such as, e.g., 0.1 mol ammonium hydroxide or 2.4 mmol N-methyl piperazine, and potassium carbonate (freshly tempered at 200°C for 36 hours at reduce pressure, and ground before use) in 50 ml of anhydrous 1,4-dioxane, which is stirred at reflux temperature, i.e., 102 to 105°C, for 3.5 hours. After cooling, the solvent is removed under reduced pressure in a rotary evaporator, and 25 ml of water is added.
  • a suitable amine such as, e.g., 0.1 mol ammonium hydroxide or 2.4 mmol N-methyl piperazine
  • potassium carbonate freshly tempered at 200°C for 36 hours at reduce pressure, and ground before use
  • the antiviral properties of a number of benzanthrone compositions were determined by tests using 0 ELISA (Enzyme-linked Immunosorbent Assay) , RSV plaque reduction assay, and RSV infectious center assay.
  • 9-Dibromo-benz (de) anthracene-7-one was synthesized from the bromination reaction of 3-bromo-benz (de) anthracene-7-one for 30 18 hours using the same procedure used for Example 20.
  • the product was recrystaUized from nitrobenzene in the form of yellow needles.
  • the 9-Bromo-7-oxo-benz (de) anthracene-3-carboxamide was prepared from 7-oxo-benz (de)anthracene-3-carboxamide using the bromination reaction procedure of Example 20 for 48 hours with recrystallization from nitrobenzene.
  • N-[ (Methylsulfonyl) -9- (methylsulfonyl) carbamoyl-7-oxobenz (de) anthracen-3-yl] formamide was prepared from 3 , 9-di- [benz (de) anthracene-7-one] carbonyl chloride with the procedure of Example 12 with recrystallization from nitromethane.
  • N-(9, 10-Dioxoanthryl) -2-N-chloroethanamide was produced by adding chloroacetyl chloride (5 g, 4.46 mmol) to 1-aminoantraquinone (5 g, 2.25 mmol) in dry benzene (100 ml), and heating the reaction mixture at 90°C for 1.5 hours.
  • l-Amino-6-bromo-4-methyl-3H-naphtho(l,2 , 3-de) quinolin-2 , 7- dione was similarly prepared from l-[6-bromo-5-methyl-2 ,7- dioxo-2 , 7-dihydro-3H-naphtho (1,2, 3-de) pyridinium chloride, and recrystaUized from N,N-dimethyIformamide with charcoal.

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Abstract

L'invention porte sur des benzothrones et de leurs dérivés aux propriétés antivirales et sur des compositions antivirales contenant au moins un benzothrone ou un de ses dérivés. Les benzothrones et leurs dérivés contiennent des 7H-benz[de]anthracène-7-ones, des azabenzothrones, et des 7H-benz[de]anthracènes. L'invention porte également sur un procédé de traitement des infections virales par des préparations pharmaceutiques antivirales comportant au moins un benzothrone ou un de ses dérivés.
PCT/US1998/004140 1997-03-05 1998-03-04 Composes de benzothrone et ses utilisations antivirales WO1998039287A1 (fr)

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AU66809/98A AU6680998A (en) 1997-03-05 1998-03-04 Benzanthrone compounds and antiviral uses thereof
EP98908887A EP1021397A4 (fr) 1997-03-05 1998-03-04 Composes de benzothrone et ses utilisations antivirales

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US3859797P 1997-03-05 1997-03-05
US60/038,597 1997-03-05
US3373898A 1998-03-03 1998-03-03
US09/033,738 1998-03-03

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006019955A3 (fr) * 2004-07-14 2006-08-24 Harvard College Methodes et compositions antivirales
JP2007154174A (ja) * 2005-11-11 2007-06-21 Sumitomo Chemical Co Ltd 共役高分子化合物およびそれを用いた高分子発光素子
WO2008006454A1 (fr) * 2006-07-11 2008-01-17 Merck Patent Gmbh Polymères électroluminescents et leur utilisation
WO2009124184A3 (fr) * 2008-04-04 2010-01-21 The Cleveland Clinic Foundation Procédés d’activation de la rnase l
US7838537B2 (en) 2003-01-22 2010-11-23 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7888363B2 (en) 2003-01-22 2011-02-15 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
JP2011511837A (ja) * 2008-02-13 2011-04-14 ブリストル−マイヤーズ スクイブ カンパニー Ｃ型肝炎ウイルス阻害剤
CN103805166A (zh) * 2012-11-14 2014-05-21 吉林奥来德光电材料股份有限公司 苯并蒽类有机发光材料及其制备方法和应用
CN103805167A (zh) * 2012-11-14 2014-05-21 吉林奥来德光电材料股份有限公司 有机蓝色发光材料及其制备方法和应用

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7838537B2 (en) 2003-01-22 2010-11-23 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7888363B2 (en) 2003-01-22 2011-02-15 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7893108B2 (en) 2004-07-14 2011-02-22 President And Fellows Of Harvard College Antiviral methods and compositions
WO2006019955A3 (fr) * 2004-07-14 2006-08-24 Harvard College Methodes et compositions antivirales
JP2007154174A (ja) * 2005-11-11 2007-06-21 Sumitomo Chemical Co Ltd 共役高分子化合物およびそれを用いた高分子発光素子
CN101489961A (zh) * 2006-07-11 2009-07-22 默克专利有限公司 电致发光聚合物及其用途
US7790057B2 (en) 2006-07-11 2010-09-07 Merck Patent Gmbh Electroluminescent polymers and use thereof
JP2009542868A (ja) * 2006-07-11 2009-12-03 メルク パテント ゲーエムベーハー エレクトロルミネセンスポリマー及びその使用
WO2008006454A1 (fr) * 2006-07-11 2008-01-17 Merck Patent Gmbh Polymères électroluminescents et leur utilisation
JP2011511837A (ja) * 2008-02-13 2011-04-14 ブリストル−マイヤーズ スクイブ カンパニー Ｃ型肝炎ウイルス阻害剤
WO2009124184A3 (fr) * 2008-04-04 2010-01-21 The Cleveland Clinic Foundation Procédés d’activation de la rnase l
CN103805166A (zh) * 2012-11-14 2014-05-21 吉林奥来德光电材料股份有限公司 苯并蒽类有机发光材料及其制备方法和应用
CN103805167A (zh) * 2012-11-14 2014-05-21 吉林奥来德光电材料股份有限公司 有机蓝色发光材料及其制备方法和应用
CN103805166B (zh) * 2012-11-14 2015-12-02 吉林奥来德光电材料股份有限公司 苯并蒽类有机发光材料及其制备方法和应用
CN103805167B (zh) * 2012-11-14 2015-12-02 吉林奥来德光电材料股份有限公司 有机蓝色发光材料及其制备方法和应用

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EP1021397A4 (fr) 2000-10-04
AU6680998A (en) 1998-09-22
EP1021397A1 (fr) 2000-07-26

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