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WO1999032490A1 - Promedicaments du lobucavir et leur mode d'utilisation - Google Patents

Promedicaments du lobucavir et leur mode d'utilisation Download PDF

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Publication number
WO1999032490A1
WO1999032490A1 PCT/US1998/025815 US9825815W WO9932490A1 WO 1999032490 A1 WO1999032490 A1 WO 1999032490A1 US 9825815 W US9825815 W US 9825815W WO 9932490 A1 WO9932490 A1 WO 9932490A1
Authority
WO
WIPO (PCT)
Prior art keywords
γçö
hydrogen
lobucavir
compound
cγçö
Prior art date
Application number
PCT/US1998/025815
Other languages
English (en)
Inventor
Robert Zahler
Natesan Murugesan
Original Assignee
Bristol-Myers Squibb Company
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 Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU17115/99A priority Critical patent/AU1711599A/en
Publication of WO1999032490A1 publication Critical patent/WO1999032490A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine

Definitions

  • cytomegalovirus is an antiviral agent with activity reported against human cytomegalovirus, herpes simplex virus type 1 and 2, varicella zoster virus, and hepatitis B.
  • Lobucavir and related compounds are disclosed by Slusarchyk et al. in U.S. Patent 5,126,345, by Norbeck et al. in U.S. Patent 5,153,352, and by Ichikawa et al. in European Patent 358,154.
  • R x includes
  • R 7 and R 8 include hydrogen and C- R6 wherein R 6 is hydrogen, alkyl, substituted alkyl, or aryl possess antiviral activity.
  • J can be hydroxy
  • L can be amino
  • E can be hydrogen
  • G and D are independently selected from -CH 2 OH, -CH 2 OC(O)R 21 wherein R 21 is alkyl, and -CH 2 OC(O) CH(R 22 )(NHR 23 ) wherein R 22 is the sidechain of any of the naturally occurring amino acids and R 23 is hydrogen or -C(O)CH(R 24 )(NH 2 ) wherein R 24 is the sidechain of any of the naturally occurring amino acids.
  • R 4 includes hydrogen and protecting groups such as acyl.
  • Nalacyclovir hydrochloride which is the valine ester of the antiviral agent acyclovir is disclosed in U.S. Patent 4,957,924.
  • Prodrugs of the antiviral agent ganciclovir are disclosed in PCT Patent Application 97/27195.
  • lobucavir prodrugs of this invention are the compounds of the formula
  • prodrug includes compounds that following administration are converted in situ to lobucavir or to an antivirally active metabolite of lobucavir.
  • the prodrugs of this invention are useful as antiviral agents as they are converted to lobucavir following oral or parenteral administration and may provide improved bioavailability as compared to lobucavir following oral administration.
  • the lobucavir prodrugs of formula I are prepared by reacting lobucavir with N-[(phenylmethoxy)carbonyl]-L-valine. This reaction gives a mixture of the diester, i.e. both R j and R 2 are
  • R j and R 2 is hydrogen and the other is
  • This mixture can be separated by silica gel chromatography to give the ⁇ -[(phenylmethoxy)carbonyl]-L- valinyl diester and a mixture of the two N-[(phenylmethoxy)carbonyl]-L- valinyl monoesters.
  • the above reaction is preferably performed in the presence of a coupling reagent such as dicyclohexycarbodiimide, 1-ethyl- 3-(3-dimethlaminopropyl)carbodiimide, benzotriazol-1- yloxytris(dimethyl-amino)phosphonium hexafluorophosphate, or carbonyldiimidazole.
  • the L-valinyl prodrugs of formula I can be obtained in the form of a pharmaceutically acceptable salt such as a hydrohalide salt by including the hydrohalide acid within the hydrogenation reaction mixture.
  • a pharmaceutically acceptable salt such as a hydrohalide salt by including the hydrohalide acid within the hydrogenation reaction mixture.
  • other pharmaceutically useful salts of the prodrug compounds of formula I include acetate, adipate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, furmarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthal
  • salts can be prepared by hydrogenating the N- [(phenylmethoxy)carbonyl] protected prodrug in the presence of an appropriate amount of the corresponding acid, by reacting the prodrug (as a free base) with an appropriate amount of the corresponding acid, or by exchanging one counterion for another by using ion exchange chromatography.
  • the preferred lobucavir prodrugs of this invention are the monoesters, i.e. the compounds of the formula I wherein one of R j and
  • the lobucavir prodrugs of this invention are useful in treating the same viral conditions as lobucavir.
  • the lobucavir prodrugs are useful in treating cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, and hepatitis B virus infections. They are also believed to be useful in the treatment of other viral infections including the human immunodeficiency virus and other herpes virus infections, such as Epstein-Barr virus, human herpes virus type 6, human herpes virus type 8, and the like.
  • the prodrugs can be administered orally or parenterally with oral administration being preferred. The amount of prodrug administered can vary according to the type and severity of the infection being treated.
  • the prodrug will be administered orally in an amount of from about 1 mg/kg to about 10 mg/kg in from one to as many as four doses over 24 hours to provide a total amount of from about 1 mg/kg to about 40 mg/kg of prodrug per day, preferably from about 1 mg/kg to about 20 mg/kg per day.
  • the lobucavir prodrug compounds of this invention can also be employed in combination with other known antiviral agents including acyclovir, famciclovir, ganciclovir, valacyclovir, adefovir, foscarnet sodium, cidofovir, alpha interferon, hepatitis B immune globulin, lamivudine, indinavir, saquinavir, ritonavir, zalcitibine, zidovudine, didanosine, stavudine, etc.. If employed in such combination, the amount of prodrug utilized can be less than that described above.
  • the lobucavir prodrug compounds of this invention can be formulated according to conventional and well known practices. Suitable oral formulations include tablets and capsules. Various conventional pharmaceutical excipients such as stabilizers, preservatives, extenders, flavoring agents, etc. can be included.
  • Lobucavir (9.0 g, 33.96 mmol) was dissolved in warm 60°C dimethylformamide (300 ml), and then cooled to room temperature.
  • 4- Dimethylaminopyridine (830 mg, 6.79 mmol), N-[(phenylmethoxy)- carbonyl]-L-valine (12.37 g, 49.3 mmol) and l-ethyl-3-(3-dimethyl- aminopropyDcarbodiimide, hydrochloride (11.4 g, 59.43 mmol) were added. After stirring at room temperature for 20 hours, the reaction mixture was filtered and the filtrate was vacuum distilled to remove most of the solvent.
  • A:B (52:48) of the two monoesters [A is (lS,2R,3R)-3-[(2-amino-l,6-dihydro-6- oxo-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methyl-N- [(phenylmethoxy)carbonyl] -L-valinate and B is (lR,2R,4S)-2-[(2-amino- l,6-dihydro-6-oxo-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl-N- [(phenylmethoxy)carbonyl]-L-valinate] as an oil (7.0 g, 45%).
  • Lobucavir (12.9 g, 48.63 mmol) was dissolved in warm (60°C) dimethylformamide (800 ml), and then cooled to room temperature.
  • 4- Dimethylaminopyridine (1.19 g, 9.73 mmol)
  • N-[(phenylmethoxy)- carbonyl]-L-valine (15.28 g, 60.79 mmol)
  • 1,3- dicyclohexylcarbodiimide 2.0 g, 9.73 mmol
  • Example 2 (1.5 g, 2.05 mmol), concentrated HC1 (0.36 ml), and 150 mg of 10% palladium on carbon catalyst in methanol (60 ml) was hydrogenated at 50 psi for 3 hours, filtered, and concentrated. The solid was dissolved in water (50 ml) and the solvent was evaporated in vacuo to afford 980 mg of title product as a white solid; m.p. greater than 190°C (dec). Anal, calc'd for C 21 H 33 N 7 O 5 • 2.1 HC1 • H 2 O:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés de formule (I), dans laquelle R1 et R2 sont (II) ou bien R1 ou R2 est hydrogène et l'autre est (III), ainsi qu'un sel pharmaceutiquement acceptable desdits composés, qui sont des agents antiviraux utiles. Ces composés sont des promédicaments du lobucavir et produisent, après administration, du lobucavir en des quantités efficaces contre les virus.
PCT/US1998/025815 1997-12-19 1998-12-04 Promedicaments du lobucavir et leur mode d'utilisation WO1999032490A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17115/99A AU1711599A (en) 1997-12-19 1998-12-04 Prodrugs of lobucavir and methods of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6834197P 1997-12-19 1997-12-19
US60/068,341 1997-12-19

Publications (1)

Publication Number Publication Date
WO1999032490A1 true WO1999032490A1 (fr) 1999-07-01

Family

ID=22081942

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/025815 WO1999032490A1 (fr) 1997-12-19 1998-12-04 Promedicaments du lobucavir et leur mode d'utilisation

Country Status (5)

Country Link
AR (1) AR014135A1 (fr)
AU (1) AU1711599A (fr)
PE (1) PE20000051A1 (fr)
UY (1) UY25311A1 (fr)
WO (1) WO1999032490A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016754A2 (fr) * 1998-09-18 2000-03-30 Glaxo Group Limited Combinaisons antivirales
CN113939504A (zh) * 2018-12-12 2022-01-14 詹森生物制药有限公司 作为抗病毒药的环丁基核苷类似物

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126345A (en) * 1988-03-30 1992-06-30 E. R. Squibb & Sons, Inc. Bis (hydroxymethyl) cyclobutyl triazolopyrimidines
US5153352A (en) * 1988-10-25 1992-10-06 Bristol-Myers Squibb Company Process for preparation of intermediates of carbocyclic nucleoside analogs
WO1994024134A1 (fr) * 1993-04-09 1994-10-27 Hoechst Aktiengesellschaft Nouveaux esters carboxyliques de 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine, leur fabrication et leur utilisation
WO1995009855A1 (fr) * 1993-10-01 1995-04-13 Smithkline Beecham P.L.C. Esters d'amino-acide de penciclovir et de brl 44385
EP0654473A1 (fr) * 1993-11-18 1995-05-24 Ajinomoto Co., Inc. Dérivés de cyclopropane et agents antiviraux les contenant
EP0694547A2 (fr) * 1994-07-28 1996-01-31 F. Hoffmann-La Roche AG Dérivés 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)-méthoxy-1,3-propanediol
WO1997030051A1 (fr) * 1996-02-16 1997-08-21 Medivir Ab Derives de nucleosides acycliques

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126345A (en) * 1988-03-30 1992-06-30 E. R. Squibb & Sons, Inc. Bis (hydroxymethyl) cyclobutyl triazolopyrimidines
US5153352A (en) * 1988-10-25 1992-10-06 Bristol-Myers Squibb Company Process for preparation of intermediates of carbocyclic nucleoside analogs
WO1994024134A1 (fr) * 1993-04-09 1994-10-27 Hoechst Aktiengesellschaft Nouveaux esters carboxyliques de 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine, leur fabrication et leur utilisation
WO1995009855A1 (fr) * 1993-10-01 1995-04-13 Smithkline Beecham P.L.C. Esters d'amino-acide de penciclovir et de brl 44385
EP0654473A1 (fr) * 1993-11-18 1995-05-24 Ajinomoto Co., Inc. Dérivés de cyclopropane et agents antiviraux les contenant
EP0694547A2 (fr) * 1994-07-28 1996-01-31 F. Hoffmann-La Roche AG Dérivés 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)-méthoxy-1,3-propanediol
WO1997030051A1 (fr) * 1996-02-16 1997-08-21 Medivir Ab Derives de nucleosides acycliques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BEAUCHAMP et al., "Amino Acid Ester Prodrugs of Acyclovir", ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, March 1992, Volume 3, No. 3, pages 157-164. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016754A2 (fr) * 1998-09-18 2000-03-30 Glaxo Group Limited Combinaisons antivirales
WO2000016754A3 (fr) * 1998-09-18 2000-08-03 Glaxo Group Ltd Combinaisons antivirales
CN113939504A (zh) * 2018-12-12 2022-01-14 詹森生物制药有限公司 作为抗病毒药的环丁基核苷类似物

Also Published As

Publication number Publication date
AR014135A1 (es) 2001-02-07
PE20000051A1 (es) 2000-04-23
UY25311A1 (es) 2000-12-29
AU1711599A (en) 1999-07-12

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