WO1999032490A1 - Prodrugs of lobucavir and methods of use - Google Patents

Prodrugs of lobucavir and methods of use 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
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Prior art keywords
γçö
hydrogen
lobucavir
compound
cγçö
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Application number
PCT/US1998/025815
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French (fr)
Inventor
Robert Zahler
Natesan Murugesan
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Bristol-Myers Squibb Company
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Priority to AU17115/99A priority Critical patent/AU1711599A/en
Publication of WO1999032490A1 publication Critical patent/WO1999032490A1/en

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    • 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:

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  • 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

Compounds of formula (I) wherein R1 and R2 are both (II) or wherein one of R1 and R2 is hydrogen and the other is (III); and a pharmaceutically acceptable salt thereof are useful antiviral agents. These compounds are prodrugs of lobucavir and produce antivirally effective amounts of lobucavir following administration.

Description

Prodrugs Of Lobucavir And Methods Of Use
This application claims priority from provisional application Serial No. 60/068,341 filed December 19, 1997.
Background Of The Invention
Lobucavir, [lR-(lα,2β,3α)]-2-amino-9-[2,3-bis(hydroxy- methyl)cyclobutyl]-l,9-dihydro-6H-purin-6-one,
Figure imgf000003_0001
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.
Slusarchyk et al. in U.S. Patent 5,126,345 disclose that the compounds of the formula
Figure imgf000003_0002
wherein Rx includes
Figure imgf000003_0003
and O II
R7 and R8 include hydrogen and C- R6 wherein R6 is hydrogen, alkyl, substituted alkyl, or aryl possess antiviral activity.
Norbeck et al. in U.S. Patent 5,153,352 disclose cyclobutyl antiviral agents of the formula
D
E wherein A includes
Figure imgf000004_0001
J can be hydroxy, L can be amino, E can be hydrogen, and G and D are independently selected from -CH2OH, -CH2OC(O)R21 wherein R21 is alkyl, and -CH2OC(O) CH(R22)(NHR23) wherein R22 is the sidechain of any of the naturally occurring amino acids and R23 is hydrogen or -C(O)CH(R24)(NH2) wherein R24 is the sidechain of any of the naturally occurring amino acids.
Ichikawa et al. in European Patent 358,154 disclose antiviral agents of the formula
Figure imgf000004_0002
wherein B includes
Figure imgf000004_0003
R4 includes hydrogen and protecting groups such as acyl.
Processes for preparing lobucavir are disclosed by Bisacchi et al. in U.S. Patent 5,064,961, by Ahmad in U.S. Patent 5,233,076, by Godfrey et al. in U.S. Patent 5,185,463, by Singh et al. in U.S. Patents 5,412,134 and 5,608,064, by Pariza et al. in U.S. Patent 5,235,052 and by Godfrey et al. in European Patent Application 736,533.
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.
Brief Summary Of The Invention
The lobucavir prodrugs of this invention are the compounds of the formula
(I)
Figure imgf000005_0001
wherein Rj. and R2 are both -C | H-™ 2
CH ( CH3 ) 2 or wherein one of Rj and R2 is hydrogen and the other is j? (L,
— C— CH — ΝH2 , and pharmaceutically acceptable salts thereof.
CH (CH3 ) 2
The configuration of the compounds of formula I as drawn above is absolute. Detailed Description Of The Invention
This invention is directed to compounds which are useful as prodrugs of lobucavir. The term 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 Rj and R2 are
and the two monoesters, i.e. one of
Figure imgf000006_0001
Rj and R2 is hydrogen and the other is
This mixture can be separated by
Figure imgf000006_0002
silica gel chromatography to give the Ν-[(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.
Hydrogenation of the N-[(phenylmethoxy)carbonyl]-L-valinyl diester removes the N-protecting groups and gives the L-valinyl diester prodrug of formula I. Similarly, hydrogenation of the mixture of N- [(phenylmethoxy)carbonyl] -L-valinyl monoesters removes the N- protecting groups and gives a mixture of the two monoester L-valinyl prodrugs of formula I. The compound of formula I wherein Rx is O
II (L)
— C— CH-NH2
I and R2 is hydrogen can be separated by fractional
CH ( CH3 ) 2 crystallization.
The compound of formula I wherein Rj is hydrogen and R2 is
0
II (L)
— C — CH— NH2
I can be obtained from the corresponding compound of
CH ( CH3 ) 2 formula I wherein Rλ is hydrogen and R2 is
by hydrogenation. The compound of
Figure imgf000007_0001
formula I wherein Rj is hydrogen and R2 is o Oo
( L )
C— - CH -- NH— C- 0— CH2— <θ) . is separated from a mixture of
CH ( CH3 ) 2 the two N-[(phenylmethoxy)carbonyl]-L-valine monoesters by reverse phase preparative high pressure liquid chromatography.
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. In addition to hydrohalide salts, i.e. hydrochloride, hydrobromide, and hydroiodate salts, 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-naphthalenesulfonate, nicotinate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate salts. These 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 Rj and
0
II (L)
— C — CH— NH2 R2 is hydrogen and the other is I
CH- (CH3 ) 2 The lobucavir prodrugs of this invention are useful in treating the same viral conditions as lobucavir. Thus, 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. Typically, 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.
The following examples are illustrative of the invention.
Example 1 (lS.2R.3R)-3-r(2-Amino-1.6-dihvdro-6-oxo-purm-9-yl)-2- (hydroxymethyl)cyclobutyll methyl L-valinate hydrochloride
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. Ethyl acetate (1200 ml) was added and the organic layer was washed with water (2 x 500 ml) and brine (500 ml), dried, and concentrated. The residue was chromatrographed on silica gel using 100:5 methylene chloride/methanol to afford the diester as a light yellow solid (Rf = 0.68, silica gel 5:1 methylene chloride/methanol). Further elution using 100:7 methylene chloride/methanol afforded a mixture 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%). The A:B (52:48) mixture of the two monoesters (8.0 g, 16.04 mmol), concentrated HC1 (1.4 ml) and 800 mg of 10% palladium on carbon catalyst in methanol (200 ml) was hydrogenated at 50 psi for 3 hours, filtered and concentrated to afford a white solid (6.0 g, crude weight). This material was dissolved in about 6 ml of water with heating (60°C). Isopropanol (about 15 ml) was added to the above mixture with slight warming until a cloudy solution was obtained (about 15 ml). The solution was kept overnight at room temperature to give a crystalline solid. Recrystallization (2x) of this solid afforded 1.2 g of title product as white crystals; m.p. 226 - 228°C.
Anal, calc'd for C16H24N6O4 • 1.0 HC1 • 1.0 H2O:
C,47.05; H, 6.38; N, 20.58; Cl, 8.68 Found: C,47.05; H, 6.43; N, 20.56; Cl, 8.84. MS mlz 363 (M-H)" (100), 246, 203, 123, 116.
Example 2
(lR.2R.4S)-2-r(2-Amino-1.6-dihvdro-6-oxo- purin-9-yl)-4-(hvdroxymethyl)cvclobutyll methyl L-valinate hydrochloride
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) and 1,3- dicyclohexylcarbodiimide (2.0 g, 9.73 mmol) were added and the reaction was stirred for another 20 hours. The reaction mixture was filtered and the filtrate was evaporated under vacuum to remove most of the solvent. Ethyl acetate (1500 ml) was added and the organic layer was washed with water (2 x 500 ml) and brine (500 ml), dried, and concentrated. The residue was chromatographed on silica gel using 100:5 methylene chloride/methanol to afford 2.94 of the N-protected L-valinyl diester as a light yellow solid, Rf = 0.68, silica gel 5:1 methylene chloride/methanol. Further elution using 100:10 methylene chloride/methanol afforded a mixture of the two N-protected L-valinyl monoesters. The mixture of two monoesters was separated by preparative HPLC on a 50 x 50 mm. ODS S 10 column using 62% solvent A (10% methanol, 90% water, 0.1% trifluroacetic acid) and 38% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid) to provide 1.3 g of (lR,2R,4S)-2-[(2-amino-l,6-dihydro- 6-oxo-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methyl-N- [(phenylmethoxy)carbonyl]-L-valinate as a white solid; Rf = 0.5, silica gel 5:1 methylene chloride/methanol.
A mixture of this N-protected L-valinyl monoester (1.1 g, 2.21 mmol), 0.19 ml of concentrated hydrochloric acid and 100 mg of 10% palladium on carbon catalyst in methanol (40 ml) was hydrogenated at 50 psi for 3.5 hours, filtered, and concentrated. The residue was dissolved in water (10 ml) and the solvent was freeze dried to afford 780 mg of title product as an amorphous white solid; m.p. 170 - 175°C. MS mlz 365 (M+H)+(100), 224, 209, 151.
Example 3 riS.2R.3R)-[3-(2-Amino-1.6-dihvdro-6-oxo-purin-9-yl)-1.2- cyclobutanediyll methyl bis(L-valine) dihydrochloride
The N-[(phenylmethoxy)carbonyl] -L-valinyl diester prepared in
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 C21H33N7O5 • 2.1 HC1 • H2O:
C,45.19; H, 6.70; N, 17.57; Cl, 13.34 Found: C,45.54; H, 6.78; N, 17.10; Cl, 13.53. MS mlz 464 (M+H)+(100), 431, 365, 306, 225, 144.
Example 4
Two groups of three rats were fasted overnight and then administered single oral doses of lobucavir (100 mg/kg, 377 μmol/kg) or (lS,2R,3R)-3-[(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-2-(hydroxymethyl)- cyclobutyl] methyl L-valinate hydrochloride (monoester of Example 1, 158 mg/kg, 377 μmol/kg) as a suspension in 1.5% carboxymethylcellulose
(Avicel®) by gavage. Serial blood samples were collected from the jugular vein immediately prior to dosing (0 min.) and at 0.25, 0.5, 1.0, 2, 4, 6, 8, 12 and 24 hours after dosing. Plasma was prepared from each blood sample and analyzed for lobucavir by a liquid chromatography/mass spectroscopy (LC/MS) method. The plasma concentration versus time profile was analyzed by standard pharmacokinetic methods to determine the maximal plasma concentration (C max) and the area under the curve (AUC) for lobucavir after dosing either lobucavir or the monoester of Example 1. The data obtained are shown in the following table.
Compound Administered C max (μM) AUC (mM
Lobucavir 21 93
Monoester of Example 1 85 440

Claims

What is claimed is:
1. A compound of the formula:
Figure imgf000013_0001
wherein:
┬░ <L, Ri and R2 are both ΓÇö cΓÇö CH ΓÇö NH2
CH (CH3 ) 2 or wherein one of R: and R2 is hydrogen and the other is
ΓÇö CΓÇö CH ΓÇö NH2 ; and a pharmaceutically acceptable salt thereof.
CH (CH3 ) 2
2. A compound of claim 1 wherein: f (L, one of Rx and R2 is hydrogen and the other is ΓÇö cΓÇö CH ΓÇö NH2 ; and a
CH (CH3 ) 2 pharmaceutically acceptable salt thereof.
3. The compound of Claim 2, (lS,2R,3R)-3-[(2-amino-l,6-dihydro-6- oxo-purin-9-yl)-2-(hydroxymethyl)cyclobutyl] methyl L-valinate hydrochloride.
4. A method of achieving increased blood levels of the antiviral agent lobucavir which comprises administering to man an antivirally effective amount of a compound of the formula:
Figure imgf000014_0001
wherein Rj and R2 are both ΓÇö cΓÇö CH ΓÇö NH2
CH (CH3 ) 2 or wherein one of Rj and R2 is hydrogen and the other is ff <L, — C— CH — ΝH2 ; and a pharmaceutically acceptable salt thereof.
CH (CH3 ) 2
5. A method of claim 4 wherein: one of Rj and R2 is hydrogen and the other is
0 I T \
II ( L ) ΓÇö CΓÇö CH ΓÇö NH2 ; and a pharmaceutically acceptable salt thereof.
CH (CH3 ) 2
6. The method of Claim 5 wherein the compound administered is (lS,2R,3R)-3-[(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-2- (hydroxymethyl)cyclobutyl] methyl L-valinate hydrochloride.
7. The method of treating a human patient having a viral infection selected from one or more of cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, and hepatitis B which comprises administering an antivirally effective amount of a compound of the formula:
Figure imgf000015_0001
wherein:
┬░ <L, Rx and R2 are both ΓÇö CΓÇö CH ΓÇö NH2
CH(CH3)2 or wherein one of Rj and R2 is hydrogen and the other is f ╬▒,
ΓÇö CΓÇö CH ΓÇö NH2 ; and a pharmaceutically acceptable salt thereof.
CH(CH3)2
8. The method of Claim 7 wherein: one of Rx and R2 is hydrogen and the other is
0 IT \
II ( ) ΓÇö CΓÇö CH ΓÇö H2 ; and a pharmaceutically acceptable salt thereof. CH(CH3 ) 2
9. The method of Claim 8 wherein the compound administered is (lS,2R,3R)-3-[(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-2- (hydroxymethyl)cyclobutyl] methyl L-valinate hydrochloride.
10. The method of Claim 7 wherein the compound is administered orally.
PCT/US1998/025815 1997-12-19 1998-12-04 Prodrugs of lobucavir and methods of use WO1999032490A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016754A2 (en) * 1998-09-18 2000-03-30 Glaxo Group Limited Antiviral combinations comprising lamivudine and lobucavir
CN113939504A (en) * 2018-12-12 2022-01-14 詹森生物制药有限公司 Cyclobutyl nucleoside analogues as antiviral agents

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016754A2 (en) * 1998-09-18 2000-03-30 Glaxo Group Limited Antiviral combinations comprising lamivudine and lobucavir
WO2000016754A3 (en) * 1998-09-18 2000-08-03 Glaxo Group Ltd Antiviral combinations comprising lamivudine and lobucavir
CN113939504A (en) * 2018-12-12 2022-01-14 詹森生物制药有限公司 Cyclobutyl nucleoside analogues as antiviral agents

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AR014135A1 (en) 2001-02-07

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