WO1993019075A1 - Antiviral phosphonic acid derivatives of purine analogues - Google Patents
Antiviral phosphonic acid derivatives of purine analogues Download PDFInfo
- Publication number
- WO1993019075A1 WO1993019075A1 PCT/GB1993/000560 GB9300560W WO9319075A1 WO 1993019075 A1 WO1993019075 A1 WO 1993019075A1 GB 9300560 W GB9300560 W GB 9300560W WO 9319075 A1 WO9319075 A1 WO 9319075A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrogen
- compound according
- 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 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
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5516084A JPH07504666A (en) | 1992-03-18 | 1993-03-18 | Antiviral phosphonic acid derivatives of purine analogs |
KR1019940703269A KR950701638A (en) | 1992-03-18 | 1993-03-18 | Antiviral phosphonic acid derivatives of purine analogues |
EP93906699A EP0631583A1 (en) | 1992-03-18 | 1993-03-18 | Antiviral phosphonic acid derivatives of purine analogues |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929205917A GB9205917D0 (en) | 1992-03-18 | 1992-03-18 | Pharmaceuticals |
GB9205917.9 | 1992-03-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993019075A1 true WO1993019075A1 (en) | 1993-09-30 |
Family
ID=10712396
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1993/000560 WO1993019075A1 (en) | 1992-03-18 | 1993-03-18 | Antiviral phosphonic acid derivatives of purine analogues |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0631583A1 (en) |
JP (1) | JPH07504666A (en) |
KR (1) | KR950701638A (en) |
AU (1) | AU3760793A (en) |
CA (1) | CA2132303A1 (en) |
GB (1) | GB9205917D0 (en) |
WO (1) | WO1993019075A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7193081B2 (en) | 2002-05-13 | 2007-03-20 | Metabasis Therapeutics, Inc. | Process for preparation of cyclic prodrugs of PMEA and PMPA |
US7214668B2 (en) | 2002-05-13 | 2007-05-08 | Metabasis Therapeutics, Inc. | Phosphonic acid based prodrugs of PMEA and its analogues |
US7582758B2 (en) | 2004-06-08 | 2009-09-01 | Metabasis Therapeutics, Inc. | Lewis acid mediated synthesis of cyclic esters |
US8101745B2 (en) | 2004-12-16 | 2012-01-24 | The Regents Of The University Of California | Lung-targeted drugs |
US9593137B2 (en) | 2011-12-22 | 2017-03-14 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US9775852B2 (en) | 2013-03-15 | 2017-10-03 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
US9801884B2 (en) | 2014-09-15 | 2017-10-31 | The Regents Of The University Of California | Nucleotide analogs |
US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
US9994600B2 (en) | 2014-07-02 | 2018-06-12 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
US10377782B2 (en) | 2015-09-15 | 2019-08-13 | The Regents Of The University Of California | Nucleotide analogs |
US10449210B2 (en) | 2014-02-13 | 2019-10-22 | Ligand Pharmaceuticals Inc. | Prodrug compounds and their uses |
US11970482B2 (en) | 2019-01-08 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0319228A2 (en) * | 1987-11-30 | 1989-06-07 | Beecham Group Plc | Novel compounds |
EP0353955A2 (en) * | 1988-08-02 | 1990-02-07 | Beecham Group Plc | Novel compounds |
EP0399743A1 (en) * | 1989-05-25 | 1990-11-28 | Beecham Group Plc | Phosphonomethylthio-alkoseypureine derivatives, intermediate products for their preparation and pharmaceutical compositions containing them |
CA2051239A1 (en) * | 1990-09-14 | 1992-03-15 | John Edward Starrett Jr. | Prodrugs of phosphonates |
-
1992
- 1992-03-18 GB GB929205917A patent/GB9205917D0/en active Pending
-
1993
- 1993-03-18 CA CA002132303A patent/CA2132303A1/en not_active Abandoned
- 1993-03-18 WO PCT/GB1993/000560 patent/WO1993019075A1/en not_active Application Discontinuation
- 1993-03-18 JP JP5516084A patent/JPH07504666A/en active Pending
- 1993-03-18 KR KR1019940703269A patent/KR950701638A/en not_active Application Discontinuation
- 1993-03-18 AU AU37607/93A patent/AU3760793A/en not_active Abandoned
- 1993-03-18 EP EP93906699A patent/EP0631583A1/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0319228A2 (en) * | 1987-11-30 | 1989-06-07 | Beecham Group Plc | Novel compounds |
EP0353955A2 (en) * | 1988-08-02 | 1990-02-07 | Beecham Group Plc | Novel compounds |
EP0399743A1 (en) * | 1989-05-25 | 1990-11-28 | Beecham Group Plc | Phosphonomethylthio-alkoseypureine derivatives, intermediate products for their preparation and pharmaceutical compositions containing them |
CA2051239A1 (en) * | 1990-09-14 | 1992-03-15 | John Edward Starrett Jr. | Prodrugs of phosphonates |
Cited By (27)
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 |
US7193081B2 (en) | 2002-05-13 | 2007-03-20 | Metabasis Therapeutics, Inc. | Process for preparation of cyclic prodrugs of PMEA and PMPA |
US7582758B2 (en) | 2004-06-08 | 2009-09-01 | Metabasis Therapeutics, Inc. | Lewis acid mediated synthesis of cyclic esters |
US8101745B2 (en) | 2004-12-16 | 2012-01-24 | The Regents Of The University Of California | Lung-targeted drugs |
US8318700B2 (en) | 2004-12-16 | 2012-11-27 | The Regents Of The University Of California | Lung-targeted drugs |
US10035814B2 (en) | 2011-12-22 | 2018-07-31 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
US9593137B2 (en) | 2011-12-22 | 2017-03-14 | 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 |
US10562926B2 (en) | 2011-12-22 | 2020-02-18 | 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 |
US10076533B2 (en) | 2013-03-15 | 2018-09-18 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
US9775852B2 (en) | 2013-03-15 | 2017-10-03 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
US10195222B2 (en) | 2013-03-15 | 2019-02-05 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
US10076532B2 (en) | 2013-03-15 | 2018-09-18 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
US10449207B2 (en) | 2013-03-15 | 2019-10-22 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
US11278559B2 (en) | 2014-02-13 | 2022-03-22 | Ligand Pharmaceuticals Incorporated | Prodrug compounds and their uses |
US10449210B2 (en) | 2014-02-13 | 2019-10-22 | Ligand Pharmaceuticals Inc. | Prodrug compounds and their uses |
US9994600B2 (en) | 2014-07-02 | 2018-06-12 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
US10150788B2 (en) | 2014-07-02 | 2018-12-11 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses thereof |
US10213430B2 (en) | 2014-09-15 | 2019-02-26 | The Regents Of The University Of California | Nucleotide analogs |
US10702532B2 (en) | 2014-09-15 | 2020-07-07 | The Regents Of The University Of California | Nucleotide analogs |
US9801884B2 (en) | 2014-09-15 | 2017-10-31 | The Regents Of The University Of California | Nucleotide analogs |
US11344555B2 (en) | 2014-09-15 | 2022-05-31 | The Regents Of The University Of California | Nucleotide analogs |
US11014950B2 (en) | 2015-09-15 | 2021-05-25 | The Regents Of The University Of California | Nucleotide analogs |
US10377782B2 (en) | 2015-09-15 | 2019-08-13 | The Regents Of The University Of California | Nucleotide analogs |
US11572377B2 (en) | 2015-09-15 | 2023-02-07 | The Regents Of The University Of California | Nucleotide analogs |
US11970482B2 (en) | 2019-01-08 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
Also Published As
Publication number | Publication date |
---|---|
GB9205917D0 (en) | 1992-04-29 |
JPH07504666A (en) | 1995-05-25 |
KR950701638A (en) | 1995-04-28 |
CA2132303A1 (en) | 1993-09-30 |
EP0631583A1 (en) | 1995-01-04 |
AU3760793A (en) | 1993-10-21 |
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