Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
  • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
  • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic 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

Definitions

• the present invention relates to a compound D-Glucopyranose 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxybenzoate] and its derivatives. It applies more particularly, but not exclusively, to the preparation and use of these compounds for the preparation of medicaments for the treatment and / or prevention of infections with enveloped viruses, and in particular, in humans, that of herpes, AIDS, influenza, hepatitis B and C, dengue fever, ebola and, in animals, Aujewsky's disease in pigs, for example.
• the action of these derivatives is peculiar. They do not intervene by blocking viral reproduction in the manner of virustatics but by dilating the viral lipid-protein membrane. They are virucides.
• the herpes and AIDS viruses like many others (hepatitis B & C, influenza, SARS, Ebola, etc.) are viruses surrounded by a lipidic envelope, unlike others - such as that of polyomyelitis is devoid - denominated for this, naked virus.
• Wrapped viruses or naked viruses are acellular organisms, totally dependent for their survival on the parasitic cell. Viruses do not have an energy generating system (ATP) or protein synthesis machinery. Although viral nucleic acids encode proteins, their synthesis occurs on the ribosomes of the host cell. Viruses are thus reduced to using the metabolic pathways of the cell and the capacities of synthesis of its chemical synthesis plants that are the ribosomes. Virutatics (triple therapy) by making impossible access to viral metabolic pathways also disturb those of the parasitized molecule that the virus borrows. It is better explained the very poor biological tolerance of these therapies that block viral replication without killing viruses. It greatly limits its effectiveness and its use.
• ATP energy generating system
• the present invention aims at preventing its entry. Two approaches are then possible: - hide the binding site of the host cell,
• virucides of di-tert-butyl structure such as BHT (butylhydroxytoluene) has been demonstrated by double-blind placebo-controlled clinical trials in humans, by the disappearance or abortion of Herpetic attacks by simple application of a topical as soon as the first symptoms appear.
• BHT butylhydroxytoluene
• BHT RNA viruses
• VHS DNA viruses
• BAMFORD will demonstrate that this alteration of the viral envelope results in the removal of a protein (P3) responsible for the adsorption of the virus on the membrane of the host cell.
• ALOIA by electron spin resonance studies on the composition of lipid envelopes, reveals the membrane fluidity of enveloped viruses and HIV in particular under the effect of heat or BHT.
• BHT decreases the membrane rigidity, disorganizing its structure. This disorganization, combined with loss of adsorption power, prevents recognition and fixation of the virus on the host cell membrane.
• ALOIA will experimentally confirm that an incubation for 30 minutes at 37 ° C. in 320 ⁇ g / ml of BHT causes a decrease in the viral infectivity of the H9 lymphocyte cultures by a logarithmic factor of 4.
• AVF1 octaoxyethylene glycol 3,5-di-tert-butyl-4-hydroxybenzoate
• the mode of activity of BHT is complex: o virucidal lysis of the lipido-protein envelope is explained by the hydrophobic properties of BHT.
• BHT lipido-protein envelope
• o fusion inhibitor by inability to locate and melt at the cell attachment site.
• the BHT is non-toxic for the body, it only targets the membrane coded by the virus and not that of the host cell.
• virus and membrane are no longer compatible.
• the virus can not open the door of entry of the host cell to go to reproduce there. He dies phagocyte.
• the invention provides the preparation of a compound D-Glucopyranose 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxybenzoate] defined by the following formula:
• the process for preparing the compound D-Glucopyranose 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxybenzoate] comprises the following steps:
• the compound according to the invention as well as its possible derivatives and addition salts with a pharmaceutically acceptable inorganic or organic acid may be presented in a composition comprising at least one pharmaceutically acceptable excipient.
• composition may be for example in the form of tablets, capsules, dragees, oral solutions or suspensions, emulsions, suppositories.
• compositions thus obtained may also contain preservatives.
• compositions such as 3,5-di-tert-butyl-4-hydroxybenzoic acid (BG4) or 3,5-di-tert-butyl 1-4- octaoxyethylene glycol hydroxybenzoate (AVF1) or a pharmaceutically acceptable derivative thereof.
• BG4 3,5-di-tert-butyl-4-hydroxybenzoic acid
• AVF1 3,5-di-tert-butyl 1-4- octaoxyethylene glycol hydroxybenzoate
• the amount of compound according to the invention and other possible active ingredients in such compositions may vary according to the applications, the age and the weight of the patient.
• BG4 3,5-di-t-butyl-4-hydroxybenzoic acid
• halides in particular bromide and chloride
• This acid has been proposed to prepare antiviral drugs for the treatment of diseases related to an infection of an individual with lipid-enveloped viruses and more particularly herpes viruses, or AIDS.
• the compound of the present invention has several advantages especially with respect to BHT and 3,5-di-t-butyl-4-hydroxybenzoic acid (BG4):
• the process for preparing about one kilogram of D-Glucopyranose 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxybenzoate compound comprises the following steps:
• the first step comprises the synthesis of the acid chloride. 700 g of 3,5-di-tert-butyl-4-hydroxybenzoic acid in 1,400 ml of dioxane are dissolved in a flask with stirring. Then, 450 grams of thionyl chloride (3 equivalents) are introduced and the mixture is heated at 80 ° C. for 3 hours.
• TLC thin layer chromatography
• the second step includes an esterification
• Control of the progress of the reaction is carried out by thin layer chromatography (TLC) using a toluene / formic acid / acetone mixture, para-anisidine phthalate as developer, the frontal ratio or RF being 0.05.
• TLC thin layer chromatography
• the molecular compound RDW031 412.54 g. mol '1 is obtained with a purity of 98% checked by liquid chromatography (HPLC) and then characterized by proton NMR at 400 MHz in deuterated chloroform.
• the compound RDW031 of the present invention has several advantages over BHT and 3,5-di-t-butyl-4-hydroxybenzoic acid (BG4): - Better solubility in water which facilitates the development of more suitable drug preparation for a drug
• - BG 4 from 0.5% to 1%, ie from 0.04 to 0.02 Mol
• - AVF1 from 0.5% to 1%, ie from 0.0083 to 0.166 Mol (8.3 ⁇ 10 3 to
• BHT which has a very low toxicity and remains a reference molecule, only acts on enveloped viruses at concentrations of 8 to 10%. that is, at molar concentrations of 0.3 to 0.4 mol 100 times higher than that of RDW 031.
• D-glucopyranose 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxybenzoate] is a new molecule combining a better solubility, a higher virucidal activity at lower doses than that of BHT and BG4.
• its hydrophilic pole causes disintegration of the viral envelope of the herpes simplex virus (HSV) and has no effect on the polio virus (naked virus).
• virucides can completely eliminate viral colonies and allow the rebirth of the white line, including CD4 lymphocytes and restore the body's immune defenses that HIV paralyzes.

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• 2006
  • 2006-06-23 US US12/306,330 patent/US20100016244A1/en not_active Abandoned
  • 2006-06-23 EP EP06778681A patent/EP2041152A1/de not_active Withdrawn
  • 2006-06-23 WO PCT/FR2006/001486 patent/WO2008000920A1/fr active Application Filing

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