EP0580657A1 - Emploi d'un derive de guanine ou ou d'un promedicament de celle-ci dans le traitement d'infections par vih-1 - Google Patents

Emploi d'un derive de guanine ou ou d'un promedicament de celle-ci dans le traitement d'infections par vih-1

Info

Publication number
EP0580657A1
EP0580657A1 EP92908131A EP92908131A EP0580657A1 EP 0580657 A1 EP0580657 A1 EP 0580657A1 EP 92908131 A EP92908131 A EP 92908131A EP 92908131 A EP92908131 A EP 92908131A EP 0580657 A1 EP0580657 A1 EP 0580657A1
Authority
EP
European Patent Office
Prior art keywords
compound
hiv
treatment
formula
mammals
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92908131A
Other languages
German (de)
English (en)
Inventor
Richard Anthony Smithkline Beecham Vere Hodge
Martin David John Smithkline Beecham Kenig
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0580657A1 publication Critical patent/EP0580657A1/fr
Withdrawn legal-status Critical Current

Links

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).

Landscapes

  • 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)

Abstract

Procédé de traitement d'infections par VIH-1 chez des mammifères, lesquels mammifères sont contaminés par l'herpèsvirus, le procédé consiste en l'administration au mammifère nécessitant un tel traitement d'une dose efficace d'un composé de la formule (A) ou d'un promédicament, ou bien un sel, un ester de phosphate et/ou un dérivé d'acyle pharmaceutiquement acceptable de l'un ou l'autre des agents précités.
EP92908131A 1991-04-13 1992-04-10 Emploi d'un derive de guanine ou ou d'un promedicament de celle-ci dans le traitement d'infections par vih-1 Withdrawn EP0580657A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9107896 1991-04-13
GB919107896A GB9107896D0 (en) 1991-04-13 1991-04-13 Pharmaceuticals

Publications (1)

Publication Number Publication Date
EP0580657A1 true EP0580657A1 (fr) 1994-02-02

Family

ID=10693221

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92908131A Withdrawn EP0580657A1 (fr) 1991-04-13 1992-04-10 Emploi d'un derive de guanine ou ou d'un promedicament de celle-ci dans le traitement d'infections par vih-1

Country Status (10)

Country Link
EP (1) EP0580657A1 (fr)
JP (1) JPH06506673A (fr)
AU (1) AU1541292A (fr)
CA (1) CA2108175A1 (fr)
GB (1) GB9107896D0 (fr)
IE (1) IE921156A1 (fr)
MX (1) MX9201665A (fr)
PT (1) PT100367A (fr)
WO (1) WO1992018130A1 (fr)
ZA (1) ZA922702B (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5648211A (en) * 1994-04-18 1997-07-15 Becton, Dickinson And Company Strand displacement amplification using thermophilic enzymes

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY101126A (en) * 1985-12-13 1991-07-31 Beecham Group Plc Novel compounds
GB8713695D0 (en) * 1987-06-11 1987-07-15 Beecham Group Plc Process
EP0353955A3 (fr) * 1988-08-02 1991-08-14 Beecham Group Plc Composés chimiques
GB8918827D0 (en) * 1989-08-17 1989-09-27 Beecham Group Plc Novel compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9218130A1 *

Also Published As

Publication number Publication date
GB9107896D0 (en) 1991-05-29
ZA922702B (en) 1992-12-30
MX9201665A (es) 1992-10-01
WO1992018130A1 (fr) 1992-10-29
JPH06506673A (ja) 1994-07-28
AU1541292A (en) 1992-11-17
PT100367A (pt) 1993-07-30
CA2108175A1 (fr) 1992-10-14
IE921156A1 (en) 1992-10-21

Similar Documents

Publication Publication Date Title
EP0277151B1 (fr) Nouvelle application medicinale de nucleosides
CA2086756C (fr) Penciclovir et famciclovir et derives connexes de la guanine utilises pour le traitement des infections a vih-1
KEATING Antiviral agents
KR940010441B1 (ko) B형감염의 항비루스제
US5039667A (en) Antiviral therapy for hepatitis B with 2',3'-dideoxypurine nucleosides
US10463664B2 (en) Inhibitors of HSV nucleotidyl transferases and uses therefor
AU628137B2 (en) Pharmaceutical treatment
US5674869A (en) Pharmaceutical treatment
EP0580657A1 (fr) Emploi d'un derive de guanine ou ou d'un promedicament de celle-ci dans le traitement d'infections par vih-1
JP2007297412A (ja) ヒト・ヘルペスウイルス−８の治療に対するペンシクロビルの使用
EP0316592A2 (fr) 3'-Fluoro-2',3'-didéoxyuridine, et ses application thérapeutique
EP0728002B1 (fr) Utilisation de derives de 2-aminopurine dans le traitement et la prophylaxie des infections par l'herpesvirus 7 humain
IL87646A (en) Preparation for the treatment of hepatitis virus containing 1 -) 2 '- Deoxy - 2' - Fluoro - Beta - B - D - Arabino - Furanozil (- 5 - Orcil
KR100297568B1 (ko) 아시클로비르유사화합물과2'-비닐치환뉴클레오시드유사체를함유하는바이러스감염치료용조성물

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19930922

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU MC NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19961101