WO1992009611A1 - Produits pharmaceutiques - Google Patents

Produits pharmaceutiques Download PDF

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Publication number
WO1992009611A1
WO1992009611A1 PCT/GB1991/002113 GB9102113W WO9209611A1 WO 1992009611 A1 WO1992009611 A1 WO 1992009611A1 GB 9102113 W GB9102113 W GB 9102113W WO 9209611 A1 WO9209611 A1 WO 9209611A1
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WO
WIPO (PCT)
Prior art keywords
compound according
hydrogen
compound
formula
amino
Prior art date
Application number
PCT/GB1991/002113
Other languages
English (en)
Inventor
Michael Raymond Harnden
Stuart Bailey
Halina Teresa Serafinowska
Original Assignee
Beecham Group Plc
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 Beecham Group Plc filed Critical Beecham Group Plc
Publication of WO1992009611A1 publication Critical patent/WO1992009611A1/fr

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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 Table
    • 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

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.l.c.) 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 9-(phosphonomethoxyalkyl)adenines, which are described as having antiviral activity.
  • 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:
  • R is hydroxy or amino; R 2 is amino or hydrogen;
  • R3 is hydrogen or, when X is CH 2 0 and Y is 0, R3 may be CH2O 9 where R9 is hydrogen or acyl; R4 and R5 are both hydrogen or the same C ⁇ _ alkyl group; and Rg and R7 are independently C 2 _7 alkanoyloxy or benzoyloxy wherein the phenyl moiety is optionally substituted.
  • the compound of formula (I) is a 2,6-c aminopurine derivative.
  • the compound of formula (I) is a guanine or adenine derivative.
  • R4 and R5 include hydrogen, methyl, ethyl, n- and iso-propvl. preferably hydrogen or methyl.
  • Rg and R7 when alkanoyloxy include acetoxy, propionyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy, straight chain or branched; in particular pivaloyloxy.
  • Rg and R7 when benzoyloxy may be optionally substituted as defined below for RQ/RC, benzoyl.
  • acyl examples include carboxylic acyl, such as C ⁇ _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 ⁇ _4 alkyl or C1.4 alkoxy wherein the alkyl moiety is selected from methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butvl.
  • Preferred acyl groups include acetyl, propionyl, butyryl, heptanoyl and hexanoyl.
  • X is -CH 2 0 and R3 is hydrogen.
  • X is -CH 2 0 and R3 is CH2OR9 as defined.
  • X is -CH 2 (CH 2 ORg)0 as defined and R3 is hydrogen.
  • X is -CH 2 and R3 is hydrogen.
  • X is -CH 2 and R3 is CH2OR9 as defined.
  • Y is preferably 0.
  • 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, orthophosphoric acid and sulphuric acid.
  • Pharmaceutically acceptable salts also include those formed with organic bases, preferably with amines, such as ethanolamines or diamines; and 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):
  • the compound of formula (II) is preferably in the form of a suitable salt, such as the tetrabutylammonium salt, the tetramethylammomum salt and those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine.
  • a suitable salt such as the tetrabutylammonium salt, the tetramethylammomum salt and those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine.
  • a suitable salt such as the tetrabutylammonium salt, the tetramethylammomum salt and those with lower alkylamines such as triethy
  • Suitable values for Q include halo, such as chloro.
  • reaction takes place in a suitable inert solvent such as N,N-dimethyl- formamide (DMF) OR l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone (DMPU), at elevated temperatures 20-100°C, preferably 30-80°C.
  • suitable inert solvent such as N,N-dimethyl- formamide (DMF) OR l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone (DMPU)
  • Suitable examples of protecting groups and their removal are as described in EP-A-242482.
  • a particularly suitable protecting group is the t-butyldiphenylsilyl group removable by conventional methods.
  • Rg/Rg 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 Rg/Rg is hydrogen which process comprises the deprotection of a corresponding compound of formula (I) wherein Rg/Rg is protected hydroxy.
  • Preferred methods for deprotection include removal of the acetyl group.
  • the compounds of the invention are of potential use in the treatment of infections caused by viruses, in particular DNA viruses and retroviruses.
  • DNA 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.
  • compositions which comprises a compound of formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient.
  • 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 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé répondant à la formule (I), ou un sel pharmaceutiquement acceptable de celui-ci. Dans ladite formule, X représente -CH2O, -CH2 ou -CH(CH2OR8)O où R8 représente hydrogène ou acyle; Y représente O ou S; R1 représente hydroxy ou amino; R2 représente amino ou hydrogène; R3 représente hydrogène ou, lorsque X représente CH2O et que Y représente O, R3 peut représenter CH2OR9 où R9 représente hydrogène ou acyle; R4 et R5 représentent tous les deux hydrogène ou le même groupe alkyle C1-4; et R6 et R7 représentent indépendamment l'un de l'autre alcanoyloxy C2-7 ou benzoyloxy où la fraction phényle est éventuellement substituée.
PCT/GB1991/002113 1990-12-01 1991-11-28 Produits pharmaceutiques WO1992009611A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909026164A GB9026164D0 (en) 1990-12-01 1990-12-01 Pharmaceuticals
GB9026164.5 1990-12-01

Publications (1)

Publication Number Publication Date
WO1992009611A1 true WO1992009611A1 (fr) 1992-06-11

Family

ID=10686328

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/002113 WO1992009611A1 (fr) 1990-12-01 1991-11-28 Produits pharmaceutiques

Country Status (5)

Country Link
AU (1) AU9044091A (fr)
GB (1) GB9026164D0 (fr)
IE (1) IE914171A1 (fr)
PT (1) PT99645A (fr)
WO (1) WO1992009611A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0632048A1 (fr) * 1993-06-29 1995-01-04 Mitsubishi Chemical Corporation Dérivés esters phosphoniques de nucléotides
US5656745A (en) * 1993-09-17 1997-08-12 Gilead Sciences, Inc. Nucleotide analogs
US5663159A (en) * 1990-09-14 1997-09-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
WO1998004569A1 (fr) * 1996-07-26 1998-02-05 Gilead Sciences, Inc. Analogues de nucleotides
US5756486A (en) * 1993-09-17 1998-05-26 Gilead Sciences, Inc. Method for dosing therapeutic compounds
US5798340A (en) * 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
US5817647A (en) * 1993-04-01 1998-10-06 Merrell Pharmaceuticals Inc. Unsaturated acetylene phosphonate derivatives of purines
US5922695A (en) * 1996-07-26 1999-07-13 Gilead Sciences, Inc. Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
US5935946A (en) * 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method
US6451340B1 (en) 1997-07-25 2002-09-17 Gilead Sciences, Inc. Nucleotide analog compositions
US8592397B2 (en) 2003-01-14 2013-11-26 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8598185B2 (en) 2005-06-13 2013-12-03 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US8871271B2 (en) 2005-06-13 2014-10-28 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0270885A1 (fr) * 1986-11-18 1988-06-15 Bristol-Myers Squibb Company Synthèse d'acides purine-9-ylalkylèneoxyméthyl phosphoniques
EP0353955A2 (fr) * 1988-08-02 1990-02-07 Beecham Group Plc Composés chimiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0270885A1 (fr) * 1986-11-18 1988-06-15 Bristol-Myers Squibb Company Synthèse d'acides purine-9-ylalkylèneoxyméthyl phosphoniques
EP0353955A2 (fr) * 1988-08-02 1990-02-07 Beecham Group Plc Composés chimiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Biochemical Pharmacology, vol. 38, no. 19, October 1989, Pergamon Press, (Oxford, GB), J.J. FREED et al.: "Evidence for acyloxymethyl esters of pyrimidine 5'-deoxyribonucleotides as extracellular sources of active 5'-deoxyribonucleotides in cultured cells", pages 3193-3198, see abstract; figures 1,2 *
Nucleosides & Nucleotides, vol. 9, no. 4, 1990, Marcel Dekker, Inc., C.U. KIM et al.: "Synthesis of 9-Ä(phosphonomethoxy)methylÜguanine and 9-[2-hydroxy-1-(phosphonomethoxy)ethylÜguanine", pages 579-585, see the whole publication *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663159A (en) * 1990-09-14 1997-09-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
US5817647A (en) * 1993-04-01 1998-10-06 Merrell Pharmaceuticals Inc. Unsaturated acetylene phosphonate derivatives of purines
US5922696A (en) * 1993-04-01 1999-07-13 Merrell Pharmaceuticals Inc. Ethylenic and allenic phosphonate derivatives of purines
US6037335A (en) * 1993-06-29 2000-03-14 Mitsubishi Chemical Corporation Phosphonate-nucleotide ester derivatives
CN1040761C (zh) * 1993-06-29 1998-11-18 三菱化学株式会社 含乙基膦酸酯侧链的稠合含氮杂环衍生物含有它们的药物组合物及其应用
EP0632048A1 (fr) * 1993-06-29 1995-01-04 Mitsubishi Chemical Corporation Dérivés esters phosphoniques de nucléotides
US5656745A (en) * 1993-09-17 1997-08-12 Gilead Sciences, Inc. Nucleotide analogs
US6225460B1 (en) 1993-09-17 2001-05-01 Gilead Sciences, Inc. Nucleotide analogs
US5756486A (en) * 1993-09-17 1998-05-26 Gilead Sciences, Inc. Method for dosing therapeutic compounds
US5798340A (en) * 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
US5886179A (en) * 1993-09-17 1999-03-23 Gilead Sciences, Inc. Nucleotide analogs
US6069249A (en) * 1996-07-26 2000-05-30 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
US5977089A (en) * 1996-07-26 1999-11-02 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
US5922695A (en) * 1996-07-26 1999-07-13 Gilead Sciences, Inc. Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
WO1998004569A1 (fr) * 1996-07-26 1998-02-05 Gilead Sciences, Inc. Analogues de nucleotides
USRE38333E1 (en) 1996-07-26 2003-11-25 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
US5935946A (en) * 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method
US6451340B1 (en) 1997-07-25 2002-09-17 Gilead Sciences, Inc. Nucleotide analog compositions
US8716264B2 (en) 2003-01-14 2014-05-06 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8592397B2 (en) 2003-01-14 2013-11-26 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US9457036B2 (en) 2003-01-14 2016-10-04 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US9744181B2 (en) 2003-01-14 2017-08-29 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8598185B2 (en) 2005-06-13 2013-12-03 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US8871271B2 (en) 2005-06-13 2014-10-28 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US9018192B2 (en) 2005-06-13 2015-04-28 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US9545414B2 (en) 2005-06-13 2017-01-17 Bristol-Myers Squibb & Gilead Sciences, Llc Unitary pharmaceutical dosage form
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof

Also Published As

Publication number Publication date
PT99645A (pt) 1992-10-30
IE914171A1 (en) 1992-06-03
AU9044091A (en) 1992-06-25
GB9026164D0 (en) 1991-01-16

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