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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • 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

• This invention relates to a method of treatment of HIV-1 infection in humans and animals , and to the use of compounds in the preparation of a medicament for use in the treatment of such infection .
• EP-A-242482 (Beecham Group p . I . e . ) discloses BRL 44385 , the compound of formula (A) :
• Pro-drugs of the compound of formula (A) disclosed EP-A-242482 are of formula (B) :
• HIV-1 human immunodeficiency virus
• This discovery is related to the ability of the triphosphate derivative of BRL 44385 to inhibit the RNA-directed DNA polymerase (reverse transcriptase) activity of human immunodeficiency virus type 1 (HIV-1) .
• the reverse transcriptase of HIV-1 is a virus-encoded enzyme essential for the conversion of genomic RNA into proviral ds-DNA, and is therefore an excellent molecular target for antiviral chemotherapy.
• herpesviruses for example, B-lymphocytes infected with EBV 1 .
• the presence of both herpes and human immunodeficiency viruses in the same cell has particular consequences.
• BRL 44385 would be phosphorylated by herpes virus-encoded thymidine kinase leading to a high level of BRL 44385 triphosphate.
• the triphosphate formed is not only an inhibitor of herpes DNA polymerase, but this work indicates that it also inhibits HIV reverse transcriptase.
• HIV replication may be enhanced by herpesvirus transactivating factors.
• a product of HSV, ICP-4 A product of HSV, ICP-4
• HIV infectious-cell protein
• Double infection of herpesviruses and HIV may result in phenotypic mixing and the production of 'pseudotype' HIV p particles bearing herpesvirus envelope glycoprotems .
• the packaging of HIV genomic RNA with HSV capsid proteins is also believed to occur. Either situation may lead to the infection by HIV of CD4-negative, herpesvirus-permissible cells, previously not susceptible to entry of this virus. This may also result in doubly-infected cells.
• the present invention provides a method of treatment of HIV-1 infections in mammals, including humans, which mammals are infected with herpesviruses, which method comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (A) :
• pro-drugs examples include pro-drugs, pharmaceutically acceptable salts and derivatives.
• pharmaceutically acceptable salts and derivatives are as described in the aforementioned European Patent references, the subject matter of which are incorporated herein by reference.
• pro-drugs of interest are as described in EP-A-413544.
• the compound of formula (A), pro-drugs, salts and derivatives may be prepared as described in the aforementioned European Patent references.
• the compound may be administered by the oral route to humans and may be compounded in the form of syrup, tablets or capsule.
• any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk.
• the compound may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension.
• Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups.
• fluid unit dose forms are prepared containing the compound and a sterile vehicle.
• the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
• Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
• adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
• Preferred parenteral formulations include aqueous formulations using sterile water or normal saline.
• compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
• An amount effective to treat the virus infection depends on the nature and severity of the infection and the weight of the mammal.
• a suitable dosage unit might contain from 50mg to lg of active ingredient, for example 100 to 500mg. Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day.
• the effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of body weight per day or, more usually, 10 to 20 mg/kg per day.
• the present invention also provides the use of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable salt of either of the foregoing, in the preparation of a medicament for use in the treatment of HIV-1 infections in mammals, including humans, which mammals are infected with herpesviruses.
• Such treatment may be carried out in the manner as hereinbefore described.
• the present invention further provides a pharmaceutical composition for use in the treatment of HIV-1 infections in mammals, including humans, infected with herpesviruses, which comprises an effective amount of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable salt of either of the foregoing, and a pharmaceutically acceptable carrier.
• a pharmaceutical composition for use in the treatment of HIV-1 infections in mammals, including humans, infected with herpesviruses which comprises an effective amount of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable salt of either of the foregoing, and a pharmaceutically acceptable carrier.
• Such compositions may be prepared in the manner as hereinafter described.
• the compound of formula (A) and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention.
• herpesvirus infected patients may include prophylaxis of herpesvirus episode attacks (suppressive treatment) .
• suppressive treatment would probably only be given to those patients with frequent recurrences.
• the aforementioned finding in relation to HIV- 1 indicates the need for continuous suppressive treatment with BRL 44385 or a pro-drug to all HIV-1 infected patients with herpesvirus recurrences, particularly HSV-1, HSV-2 and VZV recurrences, even though these recurrences may be infrequent.
• the compound of formula (A) and its prodrugs may also be administered in combination with other antiviral agents, especially anti-HIV agents such as AZT.
• E_;_ coli expressed HIV-1 reverse transcriptase was supplied by the Protein Biochemistry Department of SmithKline Beecham
• the enzyme was stored and diluted in a buffer containing 50mM Tris-HCl (pH 8.0), lOmM Hepes, llOmM NaCl, 5.7mM DTT, 0.3mM EDTA, 0.06% Triton X-100, 50% glycerol.
• the reaction mixture for the HIV-1 RT assay contained in a volume of 120 ⁇ l: 33mM Tris HCl (pH 8.0), lOOmM KCl, 3.3mM MgCl 2 , 3.3mM dithiothreitol, 0.2mM glutathione, 0.33mM EGTA (ethylene glycol-bis- ( ⁇ -aminoethyl ether) N,N-tetra acetic acid), 0.033% Triton X-100, 4.O ⁇ M [ 3 H]dGTP (4.16 Ci/mmol, 16.7 ⁇ Ci/ml) 0-50 ⁇ M BRL 44385-TP, 0.3 A 260 units/ml Poly (rC) .
• P(dG) 12 _ 18 and 167ng/ml RT (equivalent to 1.43nM for an equimolar mixture of p66 and p51 polypeptides) .
• the reaction mixtures without RT were prepared in the microwells of a 96-well plate and preincubated at 37°C before the reactions were started by the addition of 20 ⁇ l of the enzyme solution. The plates were then incubated for 95-100 minutes at 37°C. The reactions were terminated by the addition of 40 ⁇ l of EDTA solution (0.2M, pH6.5) .
• the individual reaction mixtures were transferred to a DEAE filter mat (1205-405, LKB Wallac, Finland), prewetted with 0.3M NaCl/0.03M Na citrate, using a cell harvester (1295-001, LKB Wallac) .
• the filter mat was washed three times in the NaCl/Na citrate buffer and then once in 95% ethanol.
• Scintillation fluid (Beta Plate Scint, LKB Wallac) was added to the dried filter, and the reaction mixtures assayed for incorporation of radioactive dGMP in an LKB 1205 Beta Plate Liquid Scintillation Counter.
• IC 50 BRL 44385-TP 3.7 ⁇ M.
• IC 50 BRL 44385-TP 1.9 ⁇ M.
• Complement Receptor 2 Mediates Enhancement of Human Immunodeficiency virus infection in Epstein-Barr virus-carrying B cells. Tremblay et a_l., J. Exp. Med. 171, 1791 (1990).

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Virology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (2)

Publications (1)

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• 1991
  • 1991-04-13 GB GB919107896A patent/GB9107896D0/en active Pending
• 1992
  • 1992-04-10 JP JP4507714A patent/JPH06506673A/ja active Pending
  • 1992-04-10 EP EP92908131A patent/EP0580657A1/de not_active Withdrawn
  • 1992-04-10 AU AU15412/92A patent/AU1541292A/en not_active Abandoned
  • 1992-04-10 MX MX9201665A patent/MX9201665A/es unknown
  • 1992-04-10 PT PT100367A patent/PT100367A/pt not_active Application Discontinuation
  • 1992-04-10 WO PCT/GB1992/000647 patent/WO1992018130A1/en not_active Application Discontinuation
  • 1992-04-10 IE IE115692A patent/IE921156A1/en not_active Application Discontinuation
  • 1992-04-10 CA CA002108175A patent/CA2108175A1/en not_active Abandoned
  • 1992-04-13 ZA ZA922702A patent/ZA922702B/xx unknown

Non-Patent Citations (1)

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