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WO1994004145A1 - Traitement d'infections virales chez l'homme - Google Patents

Traitement d'infections virales chez l'homme Download PDF

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Publication number
WO1994004145A1
WO1994004145A1 PCT/US1993/007878 US9307878W WO9404145A1 WO 1994004145 A1 WO1994004145 A1 WO 1994004145A1 US 9307878 W US9307878 W US 9307878W WO 9404145 A1 WO9404145 A1 WO 9404145A1
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WO
WIPO (PCT)
Prior art keywords
substituted
hiv
virus
cells
unsubstituted
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Application number
PCT/US1993/007878
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English (en)
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WO1994004145A9 (fr
Inventor
Arthur P. Pardee
Jia-Qiang Li
Clyde Crumpacker
Lin Zhang
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Dana Farber Cancer Institute
Beth Israel Hospital
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Publication date
Application filed by Dana Farber Cancer Institute, Beth Israel Hospital filed Critical Dana Farber Cancer Institute
Publication of WO1994004145A1 publication Critical patent/WO1994004145A1/fr
Publication of WO1994004145A9 publication Critical patent/WO1994004145A9/fr

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Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom

Definitions

  • human immunodeficiency virus type 1 (HIV-1, also referred to as HTLV-III LAV or HTLV-III/LAV) and, to a lesser extent, human immunodeficiency virus type 2 (HIV-2) is the etiological agent of the acquired immune deficiency syndrome
  • AIDS While AIDS, itself, does not necessarily cause death, in many individuals the immune system is so severely depressed that various other diseases (secondary infections or unusual tumors) Epstein-Barr virus related lymphomas among others occur, which ultimately results in death. These secondary infections may be treated using other medications. However, such treatment can be adversely affected by the weakened immune system.
  • Some humans infected with the AIDS virus seem to live many years with little or no symptoms, but appear to have persistent infections.
  • Another group of humans suffers mild immune system depression with various symptoms such as weight loss, malaise, fever and swollen lymph nodes. These syndromes have been called persistent generalized lymphadenopathy syndrome (PGL) and AIDS related complex (ARC) and may or may not develop into AIDS. In all cases, those infected with the HIV are believed to be persistently infective to others.
  • PDL persistent generalized lymphadenopathy syndrome
  • ARC AIDS related complex
  • LTR long terminal repeat
  • TNF ⁇ tumor necrosis factor ⁇
  • TNF ⁇ tumor necrosis factor ⁇
  • Most known methods for treating individuals infected by HIV have focused on preventing integration of the virus into the host cell's chromosome or on stages other than provirus. Thus, one area of interest has been drugs that affect reverse transcriptase. Many of the proposed therapeutic methods, however, have not proven clinically effective.
  • R and R-. are each independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted aryl, and substituted and unsubstituted alkoxy.
  • Preferred compounds of formula I include those in which at least one of the substituents R and R-, is hydrogen and/or at least one of said substituents is allyl.
  • Specifically preferred compounds include 3-lapachone (i.e., R and R-, both being hydrogen), and allyl-3-lapachone, particularly 0 3-allyl-3-lapachone (i.e., R being allyl and R, being hydrogen) .
  • the compounds of formula I can reduce or inhibit expression of genes operably linked to the HIV LTR. 5
  • the compounds of formula I can treat cells including human cells infected acutely and chronically by immunodeficiency viruses, for example HIV, preferably HIV-1, and thus can be used to treat humans infected by HIV.
  • immunodeficiency viruses for example HIV, preferably HIV-1
  • HIV immunodeficiency virus
  • These compounds can be used against a different target than the conventional drugs being used to treat humans infected by 5 HIV, e.g., reverse transcriptase inhibitors such as zidovudine (AZT), 2' ,3'-dideoxyinosine (ddl) and 2' ,3' -dideoxycytidine (ddC) .
  • reverse transcriptase inhibitors such as zidovudine (AZT), 2' ,3'-dideoxyinosine (ddl) and 2' ,3' -dideoxycytidine (ddC) .
  • AZT zidovudine
  • ddl 2' ,3'-dideoxyinosine
  • ddC 2' ,3' -dideoxycytidine
  • the present compounds should be effective in cells Q that are resistant to such compounds.
  • compounds of the present invention can be used to block HIV-1 LTR directed expression in AZT resistant cell lines.
  • compositions comprising a compound of formula I and a suitable carrier therefor for use in the conditions referred to above.
  • Figure 1 shows the inhibitory effects of 3-lapachone (varying concentrations) on TNF ⁇ and PMA induced HIV LTR directed gene expression.
  • Figure 2 shows kinetics of inhibition on HIV LTR directed cytokine stimulated gene expression by /3-lapachone.
  • Figure 3 shows inhibitory effects of 3-allyl-/3-lapachone on HIV LTR directed gene expression.
  • Figure 4 shows inhibition of HIV-1 replication by y3-lapachone in acutely infected human peripheral blood mononuclear cells.
  • I can be used to treat cells infected by an immunodeficiency virus, preferably human cells infected with HIV, and thus can be used for treatment in HIV infected individuals:
  • R and R-i are each independently selected from the group consisting of hydrogen, substituted and unsubstituted aryl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkyl and substituted and unsubstituted alkoxy.
  • the alkyl groups preferably have from 1 to about 15 carbon atoms , more preferably from 1 to about 10 carbon atoms , still more preferably from 1 to about 6 carbon atoms.
  • the term alkyl unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members. Straight or branched chain noncyclic alkyl groups are generally more preferred than cyclic groups.
  • the alkenyl groups preferably have from 2 to about 15 carbon atoms, more preferably from 2 to about 10 carbon atoms, still more preferably from 2 to about 6 carbon atoms. Especially preferred alkenyl groups have 3 carbon atoms (i.e., 1-propenyl or 2-propenyl) , with the allyl moiety being particularly preferred. Phenyl and napthyl are generally preferred aryl groups.
  • Alkoxy groups include those alkoxy groups having one or more oxygen linkage and preferably have from 1 to 15 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • Said substituted R and R-, groups may be substituted at one or more available positions by one or more suitable groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, aryl groups having from six to ten carbon atoms, halogen such as fluoro, chloro and bromo, and N, 0 and S, including heteroalkyl, e.g., heteroalkyl having one or more of said hetero atom linkages (and thus including alkoxy, aminolakyl and thioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • suitable groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon
  • the compounds of formula I provide effective therapy of chronically infected cells (i.e. cells infected by a virus which is an immunodeficiency virus such as FIV, SIV, HIV, etc.) as evidenced by a reduction in, preferably a complete repression of, HIV LTR directed gene expression.
  • a gene operably linked to the HIV LTR i.e. cells infected by a virus which is an immunodeficiency virus such as FIV, SIV, HIV, etc.
  • an effective amount of a compound of formula I will reduce the expression of a gene operably linked to the HIV LTR.
  • the gene is operably linked to an HIV-1 LTR.
  • the term operably linked means that the gene is under the control of the HIV LTR and positioned in a nucleotide sequence to accomplish this.
  • the gene is downstream of the LTR, which acts as a promoter.
  • the gene corresponds to a viral gene such as the HIV env gene, HIV tat gene, HIV rev gene, etc.
  • the present invention can be used in treating those diagnosed as having AIDS as well as those having ARC, PGL and those seropositive but asymptomatic patients.
  • a preventative it can also be used prophylactically as a preventative for high risk individuals.
  • Compounds of formula I can be used to treat cells, especially mammalian cells and in particular human cells, infected by an immunodeficiency virus such as HIV infected cells. As a result of treatment with compounds of formula I viral expression is significantly reduced. 3-lapachone and allyl-?-lapachone are preferred compounds of formula I.
  • HIV viral expression can be studied by a number of methods such as looking at the expression of a marker gene, e.g. CAT, Lac Z, etc., operably linked to the HIV LTR, which acts as the promoter.
  • a marker gene e.g. CAT, Lac Z, etc.
  • Use of the present compounds such as 3-lapachone can significantly reduce expression of such a marker.
  • HIV viral expression is turned on and enhanced by HIV LTR stimulators such as tumor necrosis factor- ⁇ (TNF ⁇ .) or phorbol 12-myristate-13-acetate (PMA) .
  • TNF ⁇ tumor necrosis factor- ⁇
  • PMA phorbol 12-myristate-13-acetate
  • One product of this expression, i.e., tat can further augment such viral expression.
  • a marker gene such as Lac Z operably-linked to the HIV LTR in HIV infected cells
  • the addition of an effective amount of compounds of formula I significantly inhibits expression of this gene product, thereby indicating that HIV expression under the control of the HIV LTR such as HIV envelope glycoprotein expression has been inhibited if not completely stopped.
  • P 24 a major structural protein (product of gag), has been widely used for monitoring HIV-1 replication in cells and vireamia in individuals .
  • the effective amount used to obtain such a result is at or below micromolar concentrations. Furthermore, the administration of the compounds of the present invention at effective concentrations, which inhibit HIV expression, has not been found to adversely affect cells.
  • T ne compounds of the present invention can be administered to HIV infected individuals or to individuals at high risk for HIV infection. For exam le, those having sexual relations with an HIV infected partner, intravenous drug users, etc. Because of its inhibitory effect, the compounds of the present invention, or pharmaceutical compositions comprising one ore more compounds of formula I can be used prophylactically as a method of prevention for such individuals to minimize their risk. One would administer the compound at an effective amount as set forth below by methodology such as described herein.
  • the absence of cytotoxicity of the compounds of formula I indicates that these compounds affect positive or negative regulators of HIV LTRs, preferably HIV-1 LTR, that are more critical to the retrovirus than the host cell.
  • one or more compounds of the invention is administered in an amount sufficient to reduce of the amount of protein expressed by the gene by at least about • j _5 25 percent relative to an untreated cell, more preferably an amount sufficient to reduce the amount of protein by at least about 50 percent and still more preferably a reduction of the amount of protein expressed by least about 75 percent relative to an untreated cell.
  • a suitable effective dose of one or more compounds of formula I will be preferably in the range 1 to 5,000 ⁇ g per kilogram body weight of
  • the desired dose is suitably administered once or several more sub-doses administered at appropriate intervals throughout the day, or other appropriate schedule. These sub-doses may be administered 0 as unit dosage forms, for example, containing 1 to 2,000 ⁇ g, preferably 10 to 1,000 ⁇ g per unit dosage form.
  • Administration of the compounds of the invention may be by any suitable route including oral, rectal, nasal, topical 3 5 (including buccal and sublingual) , vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intrader al) with oral or parenteral being preferred. It will be appreciated that the preferred route may vary with, for example, the condition and age of the recipient.
  • the administered ingredients may be used in therapy in conjunction with other medicaments such as reverse transcriptase inhibitors such as dideoxynucleosides, e.g. zidovudine (AZT),
  • reverse transcriptase inhibitors such as dideoxynucleosides, e.g. zidovudine (AZT)
  • TAT antagonists such as Ro 3-3335, Ro 24-7429, protease inhibitors and other agents such as 9-(2-hydroxyethoxymethyl)guanine (acyclovir) , interferon, e.g., alpha-interferon, interleukin II, and phosphonoformate (Foscarnet) or in conjunction with other immune modulation agents including bone marrow or lymphocyte transplants or other medications such as levamisol or thymosin which would increase lymphocyte numbers and/or function as is appropriate. Because many of these drugs are directed to different targets, e.g., viral integration, it is anticipated that a synergistic result will be obtained by this combination.
  • the present compounds may be effective when the above-described drugs are not or are no longer effective.
  • compounds of the present invention can be used in cells that are resistant to reverse transcriptase inhibitors such as AZT, ddl, and ddC.
  • the compounds of formula (I) can be used to block HIV-1 LTR directed LTR expression in such resistant cell lines and for treatment of such resistant strains.
  • the present compounds can block HIV-1 LTR directed expression in an AZT resistant strain of HIV-1.
  • the present invention can be used therapeutically in an individual as that individual develops resistance to drugs that act on different, targets such as AZT, ddl, ddC, R03-3335, etc. It is expected that the present invention can be used for treatment of HIV-1 infected individuals who develop resistance to any drug that targets a different state in the viral life cycle than the present compounds.
  • compositions of the invention comprise at least one compound of formula I together with one or more acceptable carriers thereof and optionally other therapeutic ingredients, including those therapeutic agents discussed supra.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compositions may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes and may be prepared by an methods well known in the art of pharmacy.
  • compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion or packed in liposomes and as a bolus, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • compositions suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising one or more compounds of formula I and a pharmaceutically acceptable carrier.
  • a suitable topical delivery system is a transdermal patch containing the ingredient to be administered.
  • compositions suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • compositions suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations 5 wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions suitable for vaginal administration may be 0 presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which 0 may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water
  • injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • HIV-1 was obtained from the culture supernatant of HTLV-III B -producing H9 (H9/HTLV-III ⁇ ) cells. During the exponential phase of growth, cell free supernatant was harvested, standardized for reverse transcriptase (RT) activity, and frozen in aliquots at -70°C. Clinical isolates of HIV-1 were prepared from patients testing positive for the human immunodeficiency virus, and standardized for RT activity.
  • PNAZ Dulbecco's modified Eagle's medium
  • PNAZ is an expression construct of lacZ gene driven by HIV-1 LTR. Expression of /3-galactosidase can be greatly increased by administration of PMA or TNF ⁇ .
  • PBMC Human peripheral blood mononuclear cells
  • RPMI 1640 supplemented with 20% FCS (Sigma) , penicillin, streptomycin, and L-glutamine in the presence of PHA (3 ⁇ g/ml) .
  • FCS Sigma
  • RPMI 8402 cell line received from Tushino Ando (Aichi Cancer Research Institute, Nagoya, Japan), is a human T lymphatic cell line. It was grown in RPMI 1640 medium supplemented with 15% FCS and L-glutamine.
  • a stock solution was prepared of /3-lapachone in dimethylsulfoxide (DMSO) at a 20 mM concentration. Aliquots of the stock solution were stored frozen at -20°C.
  • DMSO dimethylsulfoxide
  • PBMC Peripheral blood mononuclear cells
  • RTU reverse transcriptase unit
  • RNA of HIV-1 reverse transcriptase was assayed with HIV-1 RNA Detection Kit (GeneTrak, Framingham, MA) according to manufacturer's instructions. Briefly, the total cellular RNA was prepared, dot blotted onto a nitrocellulose membrane, and hybridized with 32 P labeled probe for RT RNA.
  • / 3-lapachone exhibited strong inhibition of expression of HIV LTR in the absence of a decrease in cell survival.
  • / 3-lapachone provided inhibition against stimulation by PMA at an IC ⁇ Q of 0.3 ⁇ M, and inhibition against stimulation by TNF ⁇ at 0.7 ⁇ M.
  • /3-lapachone can reduce HIV LTR activity to near zero, indicating its inhibition of basal activity.
  • EXAMPLE 6 o
  • a chronically infected T-lymphocyte line and the promyelocytic cell line OM10.1 inhibition of expression of P 24 antigen was seen at IC ⁇ Q - 0.057 ⁇ M following treatment with /3-lapachone whereas AZT and ddl had little effect.
  • the cell line OM10.1 contains one copy of HIV-1 cell 5 integrated into its genome and continually produces a low level of HIV-1 proteins. This cell line was kindly supplied by NIH-AIDS Research and Reference Reagent Program.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

Traitement de cellules infectées ou d'êtres humains porteurs d'un virus provoquant une maladie immunodéficitaire, à l'aide de composés de lapachone spécifiques et de compositions contenant ces substances.
PCT/US1993/007878 1992-08-21 1993-08-23 Traitement d'infections virales chez l'homme WO1994004145A1 (fr)

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US93347992A 1992-08-21 1992-08-21
US07/933,479 1992-08-21

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033988A1 (fr) * 1995-04-25 1996-10-31 Wisconsin Alumni Research Foundation Synthese nouvelle et utilisation d'analogues de beta-lapachone
WO1997008162A1 (fr) * 1995-08-24 1997-03-06 Dana-Farber Cancer Institute Agents anti-tumoraux derives de beta-lapachones
WO1997007797A1 (fr) * 1995-08-25 1997-03-06 Dana-Farber Cancer Institute Traitement de l'affection de la prostate chez l'homme au moyen de derives beta-lapachone
WO1997032587A1 (fr) * 1996-03-04 1997-09-12 Dana-Farber Cancer Institute Methodes de traitement d'infections virales
US5824700A (en) * 1996-02-20 1998-10-20 Wisconsin Alumni Research Foundation Ortho-quinone derivatives novel synthesis therefor and their use in the inhibition of neoplastic cell growth
US6245807B1 (en) 1995-08-24 2001-06-12 Dana-Farber Cancer Institute Treatment of human prostate disease
WO2002058694A2 (fr) * 2000-11-07 2002-08-01 Dana-Farber Cancer Institute, Inc. Procede de traitement de tumeurs et de cancers hematologiques
WO2003090710A1 (fr) * 2002-04-23 2003-11-06 Case Western Reserve University Systemes d'administration de lapachone, compositions de lapachone et utilisations associees
US6962944B2 (en) 2001-07-31 2005-11-08 Arqule, Inc. Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same
US7070797B2 (en) 2000-11-07 2006-07-04 Dana Farber Cancer Institute, Inc. Method of treating hematologic tumors and cancers
US7074824B2 (en) 2001-07-31 2006-07-11 Arqule, Inc. Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same
WO2006078503A2 (fr) 2005-01-07 2006-07-27 Arqule, Inc. Compositions pour moduler une parp et procedes pour la cribler
US7361691B2 (en) 2002-12-02 2008-04-22 Arqule, Inc. Method of treating cancers using β-lapachone or analogs or derivatives thereof
EP2033638A2 (fr) 2004-02-20 2009-03-11 Arqule, Inc. Béta-lapachone pour le traitement du cancer pancréatique
EP2033640A2 (fr) 2004-02-20 2009-03-11 Arqule, Inc. Béta-lapachone pour le traitement du cancer des poumons
EP2033639A2 (fr) 2004-02-20 2009-03-11 Arqule, Inc. Béta-lapachone pour le traitement du cancer du colon
US7649013B2 (en) 2003-11-26 2010-01-19 Arqule, Inc. Methods of protecting against radiation injury
US7790765B2 (en) 2007-04-30 2010-09-07 Arqule, Inc. Hydroxy sulfonate of quinone compounds and their uses
US7812051B2 (en) 2004-08-11 2010-10-12 Arqule, Inc. Pharmaceutical compositions of β-lapachone and β-lapachone analogs with improved tumor targeting potential
US7902354B2 (en) 2006-08-21 2011-03-08 Arqule, Inc. Lapachone compounds and methods of use thereof
US8067459B2 (en) 2007-10-16 2011-11-29 Arqule, Inc. Lapachone compounds and methods of use thereof
WO2013059896A1 (fr) * 2011-10-25 2013-05-02 Universidade Federal Do Rio De Janeiro-Ufrj Utilisation de pyranonaphtoquinones comme antiviral, composition pharmaceutique contenant des pyranonaphtoquinones, et médicament contenant des pyranonaphtoquinones pour le traitement d'infections causées par le virus de la dengue
US8614228B2 (en) 2004-08-11 2013-12-24 Arqule, Inc. Quinone prodrug compositions and methods of use

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CHEMICAL ABSTRACTS, Volume 88, No. 20, issued 13 November 1978, (Columbus, Ohio, USA), 165933, SCHURECH et al., "Beta-Lapachone, an Inhibitor for Oncornavirus Reverse Transcriptase and Eukaryotic DNA Polymerase-Alpha. Inhibitory Effect, Thiol Dependency and Specificity"; & (Pharm. Div., Ciba-Geigy Ltd., Basel, Switz.), EUR. J. BIOCHEM., 1978, Vol. 84, No. 1, pp. 197-205. *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5763625A (en) * 1995-04-25 1998-06-09 Wisconsin Alumni Research Foundation Synthesis and use of β-lapachone analogs
WO1996033988A1 (fr) * 1995-04-25 1996-10-31 Wisconsin Alumni Research Foundation Synthese nouvelle et utilisation d'analogues de beta-lapachone
WO1997008162A1 (fr) * 1995-08-24 1997-03-06 Dana-Farber Cancer Institute Agents anti-tumoraux derives de beta-lapachones
US6245807B1 (en) 1995-08-24 2001-06-12 Dana-Farber Cancer Institute Treatment of human prostate disease
WO1997007797A1 (fr) * 1995-08-25 1997-03-06 Dana-Farber Cancer Institute Traitement de l'affection de la prostate chez l'homme au moyen de derives beta-lapachone
US5824700A (en) * 1996-02-20 1998-10-20 Wisconsin Alumni Research Foundation Ortho-quinone derivatives novel synthesis therefor and their use in the inhibition of neoplastic cell growth
US5969163A (en) * 1996-02-20 1999-10-19 Wisconsin Alumni Research Foundation Ortho-quinone derivatives, novel synthesis therefor, and their use in the inhibition of neoplastic cell growth
WO1997032587A1 (fr) * 1996-03-04 1997-09-12 Dana-Farber Cancer Institute Methodes de traitement d'infections virales
US7070797B2 (en) 2000-11-07 2006-07-04 Dana Farber Cancer Institute, Inc. Method of treating hematologic tumors and cancers
WO2002058694A2 (fr) * 2000-11-07 2002-08-01 Dana-Farber Cancer Institute, Inc. Procede de traitement de tumeurs et de cancers hematologiques
WO2002058694A3 (fr) * 2000-11-07 2003-12-04 Dana Farber Cancer Inst Inc Procede de traitement de tumeurs et de cancers hematologiques
US7074824B2 (en) 2001-07-31 2006-07-11 Arqule, Inc. Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same
US6962944B2 (en) 2001-07-31 2005-11-08 Arqule, Inc. Pharmaceutical compositions containing beta-lapachone, or derivatives or analogs thereof, and methods of using same
KR100734341B1 (ko) * 2001-07-31 2007-07-03 아르퀼 인코포레이티드 β-라파콘, 또는 이의 유도체 또는 유사체를 함유하는약학 조성물 및 이의 사용 방법
US6890950B2 (en) 2002-04-23 2005-05-10 Case Western Reserve University Lapachone delivery systems, compositions and uses related thereto
WO2003090710A1 (fr) * 2002-04-23 2003-11-06 Case Western Reserve University Systemes d'administration de lapachone, compositions de lapachone et utilisations associees
US7361691B2 (en) 2002-12-02 2008-04-22 Arqule, Inc. Method of treating cancers using β-lapachone or analogs or derivatives thereof
US7649013B2 (en) 2003-11-26 2010-01-19 Arqule, Inc. Methods of protecting against radiation injury
EP2033639A2 (fr) 2004-02-20 2009-03-11 Arqule, Inc. Béta-lapachone pour le traitement du cancer du colon
EP2033640A2 (fr) 2004-02-20 2009-03-11 Arqule, Inc. Béta-lapachone pour le traitement du cancer des poumons
EP2033638A2 (fr) 2004-02-20 2009-03-11 Arqule, Inc. Béta-lapachone pour le traitement du cancer pancréatique
US7812051B2 (en) 2004-08-11 2010-10-12 Arqule, Inc. Pharmaceutical compositions of β-lapachone and β-lapachone analogs with improved tumor targeting potential
US8614228B2 (en) 2004-08-11 2013-12-24 Arqule, Inc. Quinone prodrug compositions and methods of use
WO2006078503A2 (fr) 2005-01-07 2006-07-27 Arqule, Inc. Compositions pour moduler une parp et procedes pour la cribler
US7902354B2 (en) 2006-08-21 2011-03-08 Arqule, Inc. Lapachone compounds and methods of use thereof
US8039503B2 (en) 2006-08-21 2011-10-18 Arqule, Inc. Lapachone compounds and methods of use thereof
US7790765B2 (en) 2007-04-30 2010-09-07 Arqule, Inc. Hydroxy sulfonate of quinone compounds and their uses
US8067459B2 (en) 2007-10-16 2011-11-29 Arqule, Inc. Lapachone compounds and methods of use thereof
WO2013059896A1 (fr) * 2011-10-25 2013-05-02 Universidade Federal Do Rio De Janeiro-Ufrj Utilisation de pyranonaphtoquinones comme antiviral, composition pharmaceutique contenant des pyranonaphtoquinones, et médicament contenant des pyranonaphtoquinones pour le traitement d'infections causées par le virus de la dengue

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