WO1992009611A1 - Produits pharmaceutiques - Google Patents
Produits pharmaceutiques Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound according
- hydrogen
- compound
- formula
- amino
- Prior art date
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 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.
Landscapes
- 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.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9026164.5 | 1990-12-01 | ||
GB909026164A GB9026164D0 (en) | 1990-12-01 | 1990-12-01 | Pharmaceuticals |
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)
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)
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 |
-
1990
- 1990-12-01 GB GB909026164A patent/GB9026164D0/en active Pending
-
1991
- 1991-11-28 AU AU90440/91A patent/AU9044091A/en not_active Abandoned
- 1991-11-28 WO PCT/GB1991/002113 patent/WO1992009611A1/fr active Application Filing
- 1991-11-29 PT PT9964591A patent/PT99645A/pt not_active Application Discontinuation
- 1991-11-29 IE IE417191A patent/IE914171A1/en not_active Application Discontinuation
Patent Citations (2)
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)
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)
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 |
---|---|
AU9044091A (en) | 1992-06-25 |
IE914171A1 (en) | 1992-06-03 |
PT99645A (pt) | 1992-10-30 |
GB9026164D0 (en) | 1991-01-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0182024B1 (fr) | Dérivés de purine et leur utilisation pharmaceutique | |
WO1992009611A1 (fr) | Produits pharmaceutiques | |
JPH0378370B2 (fr) | ||
CZ283182B6 (cs) | Guaninové deriváty, způsob jejich výroby a farmaceutické prostředky s jejich obsahem | |
NL9300058A (nl) | 1,5-anhydrohexitol nucleoside analoga en farmaceutisch gebruik daarvan. | |
JPS63239294A (ja) | 新規アデノシン誘導体及び該化合物を有効成分として含有する医薬組成物 | |
JPS6147839B2 (fr) | ||
CA1276635C (fr) | Les 9-(2-(hydroxymethyl)cyclokylmethyl)guanines | |
KR100232619B1 (ko) | 사이클로프로판 유도체, 이의 제조방법 및 이를 함유하는 약제학적 조성물 | |
CA1288098C (fr) | Les 4-(guanin-9-yl)butanals et leurs derives 3-oxa, 3-thia et 2-ene, a activite antivirale et antitumorale | |
KR940010033B1 (ko) | 항비루스 활성을 갖는 화합물의 제조방법 | |
JPS6087298A (ja) | プリン及びピリミジン非環式ヌクレオシドの環状ピロホスフエート | |
AU3760793A (en) | Antiviral phosphonic acid derivatives of purine analogues | |
JP2001515900A (ja) | 抗ウイルス薬 | |
JPS59501112A (ja) | グアニンの新規誘導体1 | |
US4060616A (en) | Purine derivatives with repeating unit | |
EP0095294A1 (fr) | Dérivés de la déoxyuridine, leurs méthodes de préparation et leur emploi en médecine | |
WO1995009855A1 (fr) | Esters d'amino-acide de penciclovir et de brl 44385 | |
JPS6156171A (ja) | 抗ウイルス性化合物 | |
JP3072600B2 (ja) | 新規化合物、その製法及びそれを含む医薬組成物 | |
NL8400896A (nl) | Werkwijze om farmaceutische preparaten te bereiden met werkzaamheid tegen viri, alsmede werkwijze om purinederivaten te bereiden. | |
US5252575A (en) | Antiviral purine derivatives with improved gastrointestinal absorption | |
EP0095292A1 (fr) | Dérivés de la 5-(2-halovinyl)-2'-déoxyuridine, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur emploi dans le traitement d'infections virales | |
EP0430518A2 (fr) | Dérivés de cyclopentane | |
JPH02264764A (ja) | 抗ウイルス性非環状ヌクレオシド及び非環状ヌクレオチド |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP KR US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |