EP0631583A1 - Derives acides phosphoniques antiviraux d'analogues de purine - Google Patents

Derives acides phosphoniques antiviraux d'analogues de purine

Info

Publication number
EP0631583A1
EP0631583A1 EP93906699A EP93906699A EP0631583A1 EP 0631583 A1 EP0631583 A1 EP 0631583A1 EP 93906699 A EP93906699 A EP 93906699A EP 93906699 A EP93906699 A EP 93906699A EP 0631583 A1 EP0631583 A1 EP 0631583A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
compound according
compound
formula
amino
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Withdrawn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
EP93906699A
Other languages
German (de)
English (en)
Inventor
Michael Raymond Harnden
Stuart Smithkline Beecham Pharmaceuticals Bailey
Halina T. Smithkline Beecham Pharm. Serafinowska
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 EP0631583A1 publication Critical patent/EP0631583A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • 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 novel compounds which are of potential use as antiviral agents, to processes for their preparation and to their use as pharmaceuticals.
  • EP-A-319228 and EP-A-353955 (Beecham Group p.lc.) disclose a group of purine derivatives containing a 9-[2-(phosphonomethoxy)alkoxy] substituent, which are described as having antiviral activity.
  • EP-A-206459 (Ceskoslovenska akademie ved) discloses a group of
  • Particular compounds of interest are adenine or guanine having a 9-substituent as follows:
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • X is -CH 2 O, -CH 2 or -CH(CH 2 OR 6 )O where R 6 is hydrogen or acyl;
  • R 1 is hydroxy or amino
  • R 2 is amino or hydrogen
  • R 3 is hydrogen or, when X is CH 2 O and Y is O, R 3 may be CH 2 OR 7 where R 7 is hydrogen or acyl;
  • R 4 and R 5 are both phenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- acetoxyphenyl or 2-methylphenyl.
  • the compound of formula (I) is a 2,6-diaminopurine derivative.
  • the compound of formula (I) is a guanine or adenine derivative.
  • R 4 and R 5 are preferably both phenyl.
  • Suitable examples of R 6 /R 7 when acyl include carboxylic acyl, such as C 1-7 alkanoyl and benzoyl optionally substituted in the phenyl ring by one, two or three groups or atoms selected from halogen, such as fluoro, chloro, bromo, and C 1-4 alkyl or C 1-4 alkoxy wherein the alkyl moiety is selected from methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and rert-butyl.
  • Preferred acyl groups include acetyl, propionyl, butyryl, heptanoyl and hexanoyl.
  • X is -CH 2 O and R 3 is hydrogen.
  • X is -CH 2 O and R 3 is CH 2 OR 7 as defined.
  • X is -CH 2 (CH 2 OR 6 )O as defined and R 3 is hydrogen .
  • X is -CH 2 and R 3 is hydrogen.
  • X is -CH 2 and R 3 is CH 2 OR 7 as defined.
  • Y is preferably O.
  • Examples of pharmaceutically acceptable salts of the compound of formula (I) are acid addition salts formed with a pharmaceutically acceptable acid such as hydrochloric acid, orthophosphonc acid and sulphuric acid.
  • Pharmaceutically acceptable salts also include those formed with organic bases, preferably with amines, such as
  • ethanolamines or diamines ethanolamines or diamines
  • alkali metals such as sodium and potassium
  • the compounds of formula (I) including their alkali metal salts may form solvates such as hydrates and these are included wherever a compound of formula (I) or a salt thereof is herein referred to.
  • the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II):
  • R 4 OH and R 5 OH and R 1 , R 2 , and R 3 are as defined in formula (I), and thereafter optionally forming a pharmaceutically acceptable salt thereof.
  • the reaction takes place in a suitable inert solvent such as dichloromethane at temperatures with cooling 0 to 3°C, under an inert atmosphere.
  • a suitable inert solvent such as dichloromethane at temperatures with cooling 0 to 3°C, under an inert atmosphere.
  • R 1 /R 2 /R 3 may be protected. Suitable examples of protecting groups and their removal, are as described in EP-A-242482. A particularly suitable protecting group forR 3 when other than hydrogen is the t-butyldiphenylsilyl group removable by conventional methods.
  • the compounds of formula (ll) may be generated from the corresponding compounds of formula (I), but wherein R 4 /R 5 is replaced by an ethyl group, by treatment with bromotrimethylsilane in dichloromethane followed by chlorination with PCI 5 in dichloromethane: carbon tetrachloride.
  • R 4 /R 5 ethyl compounds of the formula (I) are prepared as described in EP-A-313289 and the aforementioned publications, the subject matter of which are incorporated herein by reference.
  • R 6 /R 7 is hydroxy, appropriate selective protection may be required, eg using acetate.
  • compositions may be prepared in conventional manner, for example, in the case of acid addition salts, by reaction with the appropriate organic or inorganic acid.
  • the invention provides a process for the preparation of a compound of formula (I) wherein R 6 /R 7 is hydrogen which process comprises the deprotection of a corresponding compound of formula (I) wherein R 8 /R 9 . is protected hydroxy.
  • Methods for deprotection, are conventional for the protecting group concerned.
  • the compounds of the invention are of potential use in the treatment of infections caused by viruses, in particular DNA viruses and retroviruses.
  • DN A viruses include herpesviruses such as herpes simplex types 1 and 2, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus.
  • retroviruses include lentiviruses such as visna virus and human immunodeficiency virus (strains 1 and 2).
  • the compounds may also be inhibitors of tumorogenic viruses and/or of potential use in the treatment of neoplastic diseases, i.e. cancer.
  • Compounds of the invention may be formulated for use in a pharmaceutical
  • composition which comprises a compound of formula (I) or
  • a composition which may be administered by the oral route to humans may be compounded in the form of a syrup, tablet 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 composition 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.
  • the compounds may also be presented with a sterile liquid carrier for injection.
  • composition may also be formulated for topical application to the skin or eyes.
  • the composition may be in the form of a cream, lotion or ointment
  • These formulations may be conventional formulations well known in the art, for example, as described in standard books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books and the British Pharmacopaeia.
  • composition for application to the eyes may be a conventional eye-drop
  • composition well known in the art, or an ointment composition.
  • the composition of this invention is in unit dosage form or in some other form that may be administered in a single dose.
  • a suitable dosage unit might contain from 50 mg to 1 g of active ingredient for example 100 to 500 mg.
  • 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 1.0 to 20 mg/kg of body weight per day or more usually 2.0 to 10 mg/kg per day.
  • the invention also provides a method of treating viral infections/diseases in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for the treatment of viral infections/diseases.
  • the compounds of the invention are also believed to exhibit a synergistic antiviral effect in conjunction with interferons; and 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.
  • the following examples illustrate the invention.
  • the resulting phosphonyl dichloridate derivative was suspended in dry dichloromethane (10ml), the appropriate alcohol (3.045mmol) was added and the solution was cooled to 0°-3°C under argon. The reaction mixture was then treated with triethylamine (3;625mmol) followed by 1-methylimidazole (5.8mmol), stirred at 0° -3°C for 10min and then at RT for 1.5h. The precipitate was filtered, washed with dichloromethane and the solvents were

Abstract

On décrit des composés de formule (I) ou un de leurs sels pharmaceutiques acceptables. Dans ladite formule (I) X représente -CH2O, -CH2 ou -CH(CH2OR6)O où R6 représente hydrogène ou acyle; Y représente O ou S; R1 représente hydroxy ou amino; R2 représente amino ou hydrogène; R3 représente hydrogène ou, quand X représente CH2O et Y représente O, R3 peut représenter CH2OR7 où R7 représente hydrogène ou acyle; et R4 et R5 représentent chacun phényle, 4-bromophényle, 4-méthylphényle, 4-méthoxyphényle, 2-acétoxyphényle ou 2-méthylphényle. On décrit aussi leur utilisation pharmaceutique dans le traitement des maladies virales.
EP93906699A 1992-03-18 1993-03-18 Derives acides phosphoniques antiviraux d'analogues de purine Withdrawn EP0631583A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9205917 1992-03-18
GB929205917A GB9205917D0 (en) 1992-03-18 1992-03-18 Pharmaceuticals
PCT/GB1993/000560 WO1993019075A1 (fr) 1992-03-18 1993-03-18 Derives acides phosphoniques antiviraux d'analogues de purine

Publications (1)

Publication Number Publication Date
EP0631583A1 true EP0631583A1 (fr) 1995-01-04

Family

ID=10712396

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93906699A Withdrawn EP0631583A1 (fr) 1992-03-18 1993-03-18 Derives acides phosphoniques antiviraux d'analogues de purine

Country Status (7)

Country Link
EP (1) EP0631583A1 (fr)
JP (1) JPH07504666A (fr)
KR (1) KR950701638A (fr)
AU (1) AU3760793A (fr)
CA (1) CA2132303A1 (fr)
GB (1) GB9205917D0 (fr)
WO (1) WO1993019075A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214668B2 (en) 2002-05-13 2007-05-08 Metabasis Therapeutics, Inc. Phosphonic acid based prodrugs of PMEA and its analogues
WO2003095665A2 (fr) 2002-05-13 2003-11-20 Metabasis Therapeutics, Inc. Procede d'elaboration de promedicaments cycliques de pmea et de pmpa
CA2565966A1 (fr) 2004-06-08 2005-12-29 Metabasis Therapeutics, Inc. Synthese d'esters cycliques induite par l'acide de lewis
ES2401285T3 (es) 2004-12-16 2013-04-18 The Regents Of The University Of California Fármacos con el pulmón como diana
ES2874774T3 (es) 2011-12-22 2021-11-05 Geron Corp Análogos de guanina como sustratos de telomerasa y afectores de la longitud de los telómeros
CN103665043B (zh) 2012-08-30 2017-11-10 江苏豪森药业集团有限公司 一种替诺福韦前药及其在医药上的应用
CN107056838A (zh) 2013-03-15 2017-08-18 加利福尼亚大学董事会 无环核苷膦酸二酯
CN106061984A (zh) 2014-02-13 2016-10-26 配体药物公司 前药化合物及其用途
EP3164136A4 (fr) 2014-07-02 2018-04-04 Ligand Pharmaceuticals, Inc. Composés de promédicaments et leurs utilisations
HRP20220651T1 (hr) 2014-09-15 2022-08-19 The Regents Of The University Of California Nukleotidni analozi
EP3875462A1 (fr) 2015-09-15 2021-09-08 The Regents of The University of California Analogues nucléotidiques

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT89098B (pt) * 1987-11-30 1993-03-31 Beecham Group Plc Processo para a preparacao de derivados de guanina
EP0353955A3 (fr) * 1988-08-02 1991-08-14 Beecham Group Plc Composés chimiques
GB8912043D0 (en) * 1989-05-25 1989-07-12 Beecham Group Plc Novel compounds
DE69129650T2 (de) * 1990-09-14 1999-03-25 Acad Of Science Czech Republic Wirkstoffvorläufer von Phosphonaten

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9319075A1 *

Also Published As

Publication number Publication date
KR950701638A (ko) 1995-04-28
WO1993019075A1 (fr) 1993-09-30
JPH07504666A (ja) 1995-05-25
AU3760793A (en) 1993-10-21
GB9205917D0 (en) 1992-04-29
CA2132303A1 (fr) 1993-09-30

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