WO2001014368A1 - Traitement de la grippe, composes et compositions a cet effet - Google Patents

Traitement de la grippe, composes et compositions a cet effet Download PDF

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Publication number
WO2001014368A1
WO2001014368A1 PCT/US2000/023062 US0023062W WO0114368A1 WO 2001014368 A1 WO2001014368 A1 WO 2001014368A1 US 0023062 W US0023062 W US 0023062W WO 0114368 A1 WO0114368 A1 WO 0114368A1
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WO
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Prior art keywords
compound
administered
radical
alkyl
precursor
Prior art date
Application number
PCT/US2000/023062
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English (en)
Inventor
Guy D. Diana
Original Assignee
Viropharma Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Viropharma Incorporated filed Critical Viropharma Incorporated
Priority to AU67980/00A priority Critical patent/AU6798000A/en
Publication of WO2001014368A1 publication Critical patent/WO2001014368A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to compounds, compositions and methods for the treatment and prevention of influenza infection.
  • the present invention relates to novel pyrazol[3,4-f]indazole-3,7-dione derivatives, pharmaceutical compositions containing such derivatives and their use in treating and preventing influenza infection and other viral diseases.
  • influenza viruses There are three known types of influenza viruses which affect human beings: Influenza A, B and C.
  • Influenza A viruses have been isolated from many animal species in addition to humans, while the influenza B and C viruses infect mainly humans.
  • the influenza viruses are enveloped viruses containing negative single-stranded RNA's which are segmented and encapsidated.
  • the influenza virus envelope is characterized by the presence of two surface glycoproteins: hemagglutinin and neuraminidase.
  • the influenza A and B virions are pleomorphic and are usually 80-120 nm in diameter.
  • the influenza C virion has many distinctive properties and is thus distinguished from the closely related A and B virions. Infection with influenza A or B often can cause a highly contagious, acute respiratory illness.
  • Influenza viruses have a major impact on morbidity leading to increases in hospitalization and visits to health care providers. High rates of hospitalization are observed for patients over 65 years of age and also for children less than 5 years of age. Influenza virus is also unique among respiratory viruses in being a cause of excess mortality. Furthermore, the spread of influenza virus through a population can result in epidemics which have considerable economic impact. For example, high rates of mortality were observed due to influenza infection during the influenza epidemics of 1957, 1968 and 1977. Fields Virology. Second Edition, Volume 1, pp. 1075-1152 (1990). There are relatively few known compounds that have significant antiviral activity against influenza viruses. Two of these, amantadme and ⁇ mantadine, are approved in the United States for the treatment of influenza virus disease.
  • the present invention provides compounds, including lsome ⁇ c forms, of the following structure:
  • R represents an alkyl (C,-C 6 ) radical which may be straight or branched;
  • V represents a substituent selected from the group consisting of COOR,, CONR 2 R 3 SO 2 NR 4 R 5 and
  • W, X, Y and Z represent the same or different substituents selected from the group consisting of hydrogen, alkyl (C r C 6 ), halogen, monohaloalkyl, dihaloalkyl, perhaloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, COOR' and CONR"R'";
  • R, and R' are the same or different and represent hydrogen or an alkyl (C r C 6 ) radical;
  • R 2 , R , R 4 , R 5 , R" and R'" are the same or different and represent hydrogen or an alkyl, aryl, aralkyl, heterocyclic, heterocyclicalkyl, acyl or carboxyalkyl radical, said aryl radical and the aryl moiety of said aralkyl radical having the formula:
  • R 6 , R 7 , R 8 , and R 9 are the same or different and represent hydrogen, alkyl (C r C 6 ), halogen, monohaloalkyl, dihaloalkyl, perhaloalkyl, thio, alkoxy, alkylthio, alkylamino, dialkylamino, COOH, CONH 2 and SO 2 and H 2 and the pharmaceutically acceptable salts of said compound.
  • the present invention provides pharmaceutical compositions comp ⁇ sing one or more of the above-desc ⁇ bed pyrazolo[3,4 f] ⁇ ndazole-3,7-d ⁇ one de ⁇ vatives in combination with a pharmaceutically acceptable earner medium.
  • the present invention provides methods for treating and preventing viral influenza infections in living hosts by administe ⁇ ng an effective amount of the compounds of the invention to a host susceptible to influenza infection or suffe ⁇ ng from such an infection.
  • the compounds of the invention can be conveniently prepared from known starting mate ⁇ als and specific embodiments of anti-mfluenza compounds within the scope of the invention are exemplified below In vitro studies demonstrating the usefulness of the compounds of the invention as antiviral agents against the influenza virus have been performed Antiviral activity was measured on the basis of inhibition of influenza virus transc ⁇ ptase The method for determining the antiviral activity of the compounds of the invention is desc ⁇ bed in the examples that follow Among the particularly prefe ⁇ ed embodiments of the invention are compounds, including isome ⁇ c forms, having formula I, above, wherein R represents methyl, V represents -SO 2 NHR 4 ,W, X, Y and Z are selected from the group consisting of hydrogen, alkyl, alkoxy, t ⁇ fluoromethyl and difluoromethyl and R 4 represents a heterocy c group having the formula I, above, wherein R represents methyl, V represents -SO 2 NHR 4 ,W, X, Y and Z are selected from
  • R 6 , R 7 , R 8 and R 9 are the same or different and represent hydrogen, alkyl, alkoxy, t ⁇ fluoromethyl or difluoromethyl, and the pharmaceutically acceptable salts of such compound
  • the compounds of the present invention do not include those of formula I, above, in which V represents para-S0 2 NR 4 R 5 , and R 4 and R 5 both represent hydrogen, or in which V represents COOH and one of W, X, Y or Z also represents COOH
  • V represents para-S0 2 NR 4 R 5
  • R 4 and R 5 both represent hydrogen
  • V represents COOH and one of W, X, Y or Z also represents COOH
  • Such compounds are the subject of expired U S Patent 2,739,153.
  • the use of such compounds for the treatment or prevention of influenza virus infection is within the scope of this invention.
  • alkyl refers to straight or branched 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.
  • acyl is used herein in accordance with its ordinary meaning to refer to an organic radical derived from a carboxylic acid by the removal of the hydroxyl group, such as acetyl, benzoyl or the like.
  • the compounds of formula I, above, including their pharmaceutically acceptable salts exhibit antiviral activity against influenza virus and are useful in treating and/or preventing infections or diseases associated with these viruses in living hosts.
  • the compounds of the invention or precursors (e.g., prodrugs) thereof and their pharmaceutically acceptable salts are also useful in treating and preventing viral infections and diseases in living hosts when used in combination with other active agents, including but not limited to interferons, ribavirin, amantadine, rimantadine, neuraminidase inhibitors, protease inhibitors, immunoglobulins, immunomodulators, anti-inflammatory agents, antibiotics, antivirals, anti-infectious agents, and the like.
  • Compounds described herein are also useful in preventing or resolving viral infections in cell, tissue or organ cultures and 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 viral infections or contaminations of cultures not previously infected with viruses. Compounds described above may also be used to eliminate viruses from cultures or other biological materials infected or contaminated with viruses (e.g., blood), after a suitable treatment period, under any number of treatment conditions as determined by the skilled artisan.
  • the compounds of the invention can form salts with inorganic and organic bases, including, for example, alkali metal salts, such as Na or K salts, alkaline earth metal salts, such as Ca or Mg salts, ammonium, substituted ammonium and other amine salts such as morpholine, piperidine or pyridine salts.
  • Acid salts of the compounds described above also have antiviral activity.
  • Suitable salt forming acids include both inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, methyl sulfonic acid or. the like.
  • compositions of the present invention comprise one or more of the compounds of formula I above, as the active ingredient in combination with a pharmaceutically acceptable carrier medium or auxiliary agent.
  • 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 active agent may be present in an amount of at least 0.5% and not more than 90% by weight based on the total weight of the composition, including carrier medium and/or auxiliary agent(s).
  • the proportion of active agent various between 5 to 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 medicament components may all be suitable as carrier media or excipients.
  • the compounds of the invention may be administered using any amount and any route of administration effective for attenuating infectivity of the influenza virus.
  • amount effective to attenuate infectivity of influenza virus 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, its mode of administration, and the like.
  • the anti-influenza compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form 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 and/or the supplemental active agent(s), if any.
  • the antiviral compounds of the invention will be administered in dosage units containing from about 0.1 mg to about 500 mg of the antiviral agent, with a range of about 1 mg to about 100 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 prodrug is a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabohc processes in vivo to the active compound
  • Prodrugs include, without limitation, esters of the compounds of Formula I, above, having a carboxyl functionality Such esters may be prepared from simple or functionahzed aliphatic alcohols Such prodrugs may be prepared according to procedures well known in the field of medicinal chemistry and pharmaceutical formulation science
  • the compounds may be administered orally, rectally, parenterally, such as by intramuscular injection, subcutaneous injection, intravenous infusion or the like, mtracisternally, mtravagmally, intrape ⁇ toneally, locally, such as by powders, ointments, drops or the like, or by inhalation, such as by aerosol or the like, depending on the nature and seventy of the infection being treated
  • the compounds of the invention may be administered at dosage levels of about 10 3 to about 120 mg/kg of subject body weight per day and preferably from about 10 2 to about 30 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect
  • a suitable dose for oral administration would be on the order of 30 mg/kg of body weight per day, whereas a typical dose for inhalation would be on the order of 10 2 mg/kg of body weight per day
  • pyrazolo[3,4-f]mdazole-3,7-d ⁇ one derivatives desc ⁇ bed herein can be administered to any host which is susceptible to influenza infection, the compounds are intended for the treatment of mammalian hosts, and especially humans
  • the compounds of the invention will typically be administered from 1 to 4 times a day so as to deliver the above-mentioned daily dosage
  • the exact regimen for administration of the compounds and compositions desc ⁇ bed herein will necessa ⁇ ly be dependent on the needs of the individual host being treated, the type of treatment administered and the judgment of the attending medical specialist
  • influenza virus transc ⁇ ptase produced by the compounds of the invention, it is anticipated that these compounds will be useful not only for therapeutic treatment of infection, but for influenza viral prophylaxis, as well
  • the above-noted dosages will be essentially the same whether for treatment or prophylaxis of influenza infection.
  • Example 1 illustrates the chemical synthesis of a compound which is considered to be a representative embodiment of the invention. Any reference to acidification in the example indicates that the intermediate or the compound of the invention was acidified to pH 3.0.
  • An assay for influenza A/WSN virus transcription was performed with detergent-treated purified influenza virions and rabbit globin messenger RNA according to the following procedure.
  • Duplicate reactions (50 ⁇ l in 96 well polypropylene U-bottom plates) contained 50 mM Hepes, pH 8, 5 mM dithiothreitol (DTT), 5 mM magnesium chloride, 0.02% Triton X-100, 30 ⁇ M ATP, 0.3 ⁇ M CTP, 0.5 ⁇ M GTP, 2 ⁇ Ci 35S-UTP (Amersham SJ1303), 0.75 ⁇ g (15 ⁇ g/ml) purified virions, and 50 ng of rabbit globin messenger RNA.
  • Test compounds were solubilized with 100% dimethylsulfoxide (DMSO) and were present in the reactions at 1% DMSO. Incubation was for 45 minutes at 31°C.
  • DMSO dimethylsulfoxide
  • TCA ice-cold 7% trichloracetic acid
  • the TCA precipitates were filtered onto Millipore HATF plates pre-wetted with 200 ⁇ l of 7% TCA + 2% sodium pyrophosphate without yeast tRNA. Plates were washed four times with 5% TCA + 2% sodium pyrophosphate and filters were dried and punched onto pressure sensitive film, and quantitated using a Molecular Dynamics Storm System.
  • IC 50 values represent the concentration of the compound required to achieve a 50% inhibition of influenza A/WSN virus transcriptase activity.
  • the results of the assay for inhibition of viral transcriptase activity of the compounds tested revealed IC 50 values ranging from 0.3 to about 25 ⁇ M.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

La présente invention concerne des dérivés de pyrazolo[3,4-f]indazole-3,7-diones convenant au traitement préventif et curatif de l'infection par un virus de la grippe.
PCT/US2000/023062 1999-08-26 2000-08-23 Traitement de la grippe, composes et compositions a cet effet WO2001014368A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67980/00A AU6798000A (en) 1999-08-26 2000-08-23 Compounds, compositions and methods for treating influenza

Applications Claiming Priority (2)

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US15076399P 1999-08-26 1999-08-26
US60/150,763 1999-08-26

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WO2001014368A1 true WO2001014368A1 (fr) 2001-03-01

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7459432B2 (en) 2001-09-24 2008-12-02 Imperial College Innovations Ltd. Modification of feeding behavior
US20090304630A1 (en) * 2003-05-16 2009-12-10 Hemispherx Biopharma Treating severe and acute viral infections
EP2329839A1 (fr) 2002-01-10 2011-06-08 Imperial Innovations Limited Modification du comportement d'alimentation par GLP-1 et PYY
EP2371378A1 (fr) 2003-01-10 2011-10-05 Imperial Innovations Limited Modification des habitudes alimentaires
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684024A (en) * 1996-01-25 1997-11-04 Viropharma Incorporated Pyrazole dimers compositions and methods for treating influenza
US5821243A (en) * 1996-07-22 1998-10-13 Viropharma Incorporated Compounds compositions and methods for treating influenza

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684024A (en) * 1996-01-25 1997-11-04 Viropharma Incorporated Pyrazole dimers compositions and methods for treating influenza
US5821243A (en) * 1996-07-22 1998-10-13 Viropharma Incorporated Compounds compositions and methods for treating influenza

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 116, no. 8, 24 February 1992, Columbus, Ohio, US; abstract no. 61551R, NAEF R.: "Synthesis, porton-NMR and electronic absorption spectra of 2,6-disubstituted derivatives of 2,6-dihydrobenz(1,2-c:4,5-c')dipyrazol-3,7-dione, a new cross-conjugated chromophore" page 108; column 1; XP002933099 *
DYES PIGM., vol. 17, no. 2, 1991, (ENG), pages 113 - 121 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7459432B2 (en) 2001-09-24 2008-12-02 Imperial College Innovations Ltd. Modification of feeding behavior
US8217001B2 (en) 2001-09-24 2012-07-10 Imperial Innovations Limited Modification of feeding behavior
EP2329839A1 (fr) 2002-01-10 2011-06-08 Imperial Innovations Limited Modification du comportement d'alimentation par GLP-1 et PYY
EP2371378A1 (fr) 2003-01-10 2011-10-05 Imperial Innovations Limited Modification des habitudes alimentaires
US20090304630A1 (en) * 2003-05-16 2009-12-10 Hemispherx Biopharma Treating severe and acute viral infections
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour

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Publication number Publication date
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