WO1992018517A1 - Procede de traitement ou de prevention du virus de l'hepatite b - Google Patents

Procede de traitement ou de prevention du virus de l'hepatite b Download PDF

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Publication number
WO1992018517A1
WO1992018517A1 PCT/US1992/003144 US9203144W WO9218517A1 WO 1992018517 A1 WO1992018517 A1 WO 1992018517A1 US 9203144 W US9203144 W US 9203144W WO 9218517 A1 WO9218517 A1 WO 9218517A1
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WIPO (PCT)
Prior art keywords
dideoxycytidine
thia
active compound
formula
administered
Prior art date
Application number
PCT/US1992/003144
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English (en)
Inventor
Yung-Chi Cheng
Chung K. Chu
Hea O. Kim
Kirupathevy Shanmuganathan
Original Assignee
Yale University
The University Of Georgia Research Foundation, Inc.
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Filing date
Publication date
Application filed by Yale University, The University Of Georgia Research Foundation, Inc. filed Critical Yale University
Publication of WO1992018517A1 publication Critical patent/WO1992018517A1/fr
Priority to US08/301,298 priority Critical patent/US5817667A/en
Priority to US10/646,980 priority patent/US7262213B2/en
Priority to US10/656,889 priority patent/US20050192299A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Definitions

  • the present invention concerns (-)3'-thia-2'3'-dideoxycytidine and (-)5-fluoro-3'-thia-2',3'-dideoxycytidine, a method for preparing the same and the use of the same or ( ⁇ )3'-thia-2',3'-dideoxycytidine or ( ⁇ )5-fluoro-3'-thia-2',3'-dideoxycytidine in a method for
  • the present invention also relates to dioxolanecytosine and particularly (-)-L-ß-dioxolane-cytosine and its use in a method for treating patients having hepatitis B virus or to prevent hepatitis B virus infection.
  • HBV Hepatitis B virus
  • RNA ribonucleic acid
  • the rationale for a chemotherapeutic treatment for hepatitis B is the inhibition of the viral DNA polymerase.
  • HBV DNA polymerase has a common evolutionary origin with the reverse transcriptase from retroviruses (Miller, R.H., and Robinson, W.S., "Common Evolutionary Origin of Hepatitis B Virus and Retroviruses,” Proc. Natl. Acad. Sci. USA. 83: 2531-2535, 1986).
  • Inhibitors for reverse transcriptase of oncogenic RNA viruses suppress the polymerase from HBV (Matthes, E.,
  • ddC 2'3-Dideoxycytidine
  • ddC 2'3-Dideoxycytidine
  • ddC was also shown to have potent antiviral activity against duck hepatitis B virus both in vitro (Lee, B., Luo, W. , Suzuk, S., Robins, M.
  • HIV human immunodeficiency virus
  • ARC AIDS-related complex
  • PDL lymphadenopathy
  • AIDS-related neurological conditions such as dementia
  • Kaposi's sarcoma thrombocytopenia purpurea
  • BCH-189 ( ⁇ )-2',3'-dideoxy-3'-thiacytidine
  • dioxolane-T as anti HIV agents are discussed in Chu et al, J. Org. Chem., 56, 6503-6505, (1991); Jeong et al.
  • BCH-189 was reported as a racemic mixture in J.A.
  • (+) OddC (+)-D-ß-dioxolane-cytosine or (+)D-ß- dioxolane-C
  • An object of the present invention is to provide (-)3'- thia-2',3'-dideoxycytidine and (-)5-fluoro-3'-thia-2',3'- dideoxycytidine and a method of preparing the same.
  • a further object of the present invention is to provide ß-dioxolane cytosine and particularly (-)-L-ß-dioxolanecytosine.
  • It is another object of the present invention is to treat patients suffering with the hepatitis B virus or to prevent hepatitis B virus infection in a patient.
  • the present invention concerns (-)3'-thia-2',3'-dideoxycytidine of the following formula:
  • the present invention also relates to (-)5-fluoro-3'-thia-2',3'-dideoxycytidine of the following formula:
  • the instant invention is also directed to a method of separating (-)3'-thia-2',3'-dideoxycytidine from ( ⁇ )3'-thia- 2',3'-dideoxycytidine.
  • the method comprises contacting ( ⁇ )3'-thia-2',3'-dideoxycytidine with deoxycytidine
  • the present invention also concerns a method of
  • hepatitis B virus infection or preventing hepatitis B virus infection in a patient, e.g., a mammal, e.g., a human comprising administering to the patient an effective amount of a substituted-1,3-oxathiolane compound selected from the group consisting of (-)3'-thia- 2',3'-dideoxycytidine, ( ⁇ )3'-thia-2',3'-dideoxycytidine, (-)5-fluoro-3'-thia-2',3'-dideoxycytidine and ( ⁇ )5-fluoro-3'-thia-2',3'-dideoxycytidine, preferably (-)3'-thia-2',3'-dideoxycytidine or (-) 5-fluoro-3'-thia-2',3'-dideoxycytidine, or a salt or ester thereof, either alone or in admixture with a pharmaceutically acceptable carrier.
  • the present invention also concerns ß-dioxolanecytosine and particularly (-)-L-ß-dioxolane-cytosine of the formula
  • the present invention also concerns a method of treating hepatitis B virus infection or preventing hepatitis B virus infection in a patient, e.g., a mammal, e.g., a human comprising administering to the patient an effective amount of a ß-dioxolane-cytosine, particularly (-)-L-ß- dioxolane cytosine, or a salt or ester thereof, either alone or in admixture with a pharmaceutically acceptable carrier.
  • a patient e.g., a mammal, e.g., a human
  • a ß-dioxolane-cytosine particularly (-)-L-ß- dioxolane cytosine
  • a salt or ester thereof either alone or in admixture with a pharmaceutically acceptable carrier.
  • Fig. 1 depicts a Southern blot analysis of the
  • Fig. 2 is a Southern analysis of intracellular HBV
  • Lanes 10, 11, 12 DNAs from cells untreated (lane 10) or treated with 2 ⁇ m 5-fluoro-3'-thia-2',3-dideoxycytidine (lane 11) and 3'-thia 2',3'-dideoxycytidine (lane 12) for 12 days and further incubation in the absence of drugs for 12 more days.
  • RC Relaxed circular episomal HBV DNAs; I: Integrated HBV DNAs.
  • Fig. 3 is a Southern blot depicting the reversibility of 5-fluoro-3'-thia-2',3-dideoxycytidine and 3'-thia-2',3'-dideoxycytidine.
  • 2.2.15 cells untreated or treated with 2 ⁇ M of 5-fluoro-3'-thia-2',3-dideoxycytidine and 3'-thia-2',3'-dideoxycytidine for 12 days were incubated with drug-free medium for 6 or 12 more days.
  • HBV specific DNAs in the medium were analyzed as described in Fig. 1.
  • RC
  • Fig. 4 is a Northern blot analysis of RNAs.
  • Total RNAs were extracted from 2.2.15 cells untreated (lane 1) or treated with 2.0 ⁇ m 5-fluoro-3'-thia-2',3'-dideoxycytidine (lane 2) and 3'-thia-2',3'-dideoxycytidine (lane 3) for 12 days.
  • Each lane represents 20 ⁇ g total RNAs.
  • Fig. 5 is a Southern blot depicting the comparative potency of various analogs of 3'-thia-2',3'-dideoxycytidine as inhibitors of HBV replication.
  • 2.2.15 cells were treated with various analogues at 1.0 ⁇ M for 12 days. Media were analyzed for the presence of HBV DNAs as described in Fig.l.
  • Fig. 6A depicts a HPLC profile of a mixture of ( ⁇ )3'-thia-2',3'-dideoxycytidine before a deamination.
  • Fig. 6B depicts a HPLC profile 16 hours after
  • Fig. 7A depicts a HPLC profile of a control having only (+)3'-thia-2',3'-dideoxycytidine before deamination.
  • Fig. 7B depicts a HPLC profile of a UV spectrum 16 hours after deamination of (+)3'-thia-2',3'-dideoxycytidine.
  • Fig. 8A depicts a HPLC profile of (-)3'-thia-2',3'- dideoxycytidine before a deamination.
  • Fig. 8B depicts a HPLC profile of (-)3'-thia-2',3'- dideoxycytidine 16 hours after a deamination.
  • Fig. 9A depicts a HPLC profile of ⁇ -SddC before a deamination.
  • Fig. 9B depicts a HPLC profile of ⁇ -SddC 16 hours after a deamination.
  • Fig. 10 is a UV spectrum for 3'-thia-2',3'-dideoxycytidine.
  • Fig. 11 is a UV spectrum for 3'-thia-2',3'-dideoxyuridine.
  • Figs. 12A and Fig. 12B each depict a Southern analysis of intracellular HBV DNA wherein 2.215 cells are untreated (control) or treated.
  • Fig. 13 is a Southern blot analysis of the comparative potency of several compounds as inhibitors of intracellular HBV DNA after a one week incubation with HBV 2.2.15 cells. DETAILED DESCRIPTION OF THE INVENTION
  • the rationale for a chemotherapeutic treatment for hepatitis B virus is the inhibition of the viral DNA
  • HBV specific transcripts were not affected by drug treatment.
  • interruption of drug treatment resulted in a return of HBV virus to both intra- and extracellular populations.
  • 3'-Thia-2',3'-dideoxyuridine analogs were found not to be active against HBV replication. There was concern that cytidine analogs can be deaminated intracellularly to
  • cyd/dcyd deaminase inhibitor suggests that catabolic inactivation by deaminase may not be important.
  • the present invention concerns a method involving the administration of one or more of (-) 3'-thia-2',3'- dideoxycytidine, ( ⁇ )3'-thia-2',3'-dideoxycytidine, (-)5- fluoro-3'-thia-2',3-dideoxycytidine or ( ⁇ )5-fluoro-3'-thia- 2',3'-dideoxycytidine (referred to herein as "the compounds of formula (I)”) or a salt or ester thereof, alone or in
  • admixture with a pharmaceutically acceptable carrier in order to treat patients suffering from hepatitis B virus or to prevent hepatitis B virus infection.
  • Formula (I) includes the following:
  • R is selected from the group consisting of H and F.
  • formula (I) refers to (-)3'-thia-2',3'-dideoxycytidine, ( ⁇ )3'-thia-2',3'-dideoxycytidine, (-)5-fluoro-3'-thia-2',3'-dideoxycytidine or ( ⁇ ) 5-fluoro-3'-thia-2',3'-dideoxycytidine or combinations thereof.
  • the present invention also concerns a method involving the administration of ß-dioxolane-cytosine and particularly (-)-L-ß-dioxolane-cytosine of the formula
  • ß-dioxolane- ⁇ ytosine or (-)-L- ß-dioxolane-cytosine are hereinafter referred to as the compounds of formula (I').
  • Preferred esters of the compounds for use in the invention of formula (I) include the compounds in which H of
  • R HOCH 2 is replaced by R - C in which the non-carbonyl moiety R of the ester grouping is selected from hydrogen, straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, t- butyl, n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl optionally substituted by halogen, C 1-4 alkyl or C 1-4 alkoxy); substituted dihydro pyridinyl (e.g., N- methyldihydro pyridinyl); sulphonate esters such as alkyl or arakylsulphonyl (e.g., methanesulphonyl); sulphate esters; amino acid esters (e.g., L-
  • esters derived from polyfunctional acids such as carboxylic acids containing more than one carboxyl group, for example, dicarboxylic acids HO 2 C(CH 2 ) n CO 2 H where n is an integer of 1 to 10 (for example, succinic acid) or phosphoric acids.
  • esters are derived from such acids, each acidic group is preferable esterified by a compound for use in the invention or other nucleosides or analogues and derivatives thereof to provide esters of the formula (II)
  • R is H or F
  • W is and n is an integer of 1 to 10 or - J is any nucleoside
  • nucleosides and nucleoside analogues are 3'-azido-2'-3'-dideoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine, 2',3'-dideoxythymidine, 2',3'-dideoxy-2',3'-didehydro-thymidine, and 2',3'-dideoxy-2',3'-didehydroxytidine and ribavirin.
  • any alkyl-moiety present advantageously contains 1 to 16 carbon atoms, preferably 1 to 4 carbon atoms and could contain one or more double bonds.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • the esters may be a C 1-16 alkyl ester, an unsubstituted benzoyl ester or a benzoyl ester substituted by at least one halogen (bromine, chlorine, fluorine or iodine), saturated or unsaturated C 1-6 alkyl, saturated or unsaturated C 1-6 alkoxy, nitro or trifluoromethyl groups.
  • Pharmaceutically acceptable salts of the compounds of formula (I) or formula (I') include those derived from pharmaceutically acceptable inorganic acids and bases.
  • Suitable acids include hydrochloric,
  • benzenesulfonic acids Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of formula (I) or formula (I') and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium, calcium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium
  • the amount of the compound of formula (I) or formula (I') for use in the present invention will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately determined by the discretion of the attendant physician or veterinarian.
  • a suitable dose will be in the range from about 1 to about 100 mg/kg of body weight per day, such as 2 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 2 to 10 mg/kg/day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, at two, three, four or more sub- doses per day.
  • unit dosage conveniently administered in unit dosage; for example, containing 0.5 to 50 mg, conveniently 20 to 1000 mg most conveniently 50 to 700 mg, of active ingredient (compound of formula (I) or formula (I')) per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to 75 ⁇ M, preferably about 2 to 50 ⁇ M, most preferably about 3 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus containing about 0.1 to 50 mg/kg of the active ingredient.
  • the compound of formula (I) or formula (I') may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides for the use of a pharmaceutical formulation comprising a compound of formula (I) or formula (I') or a pharmaceutically acceptable
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub- lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration are provided.
  • administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution; as a suspension; or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
  • the compounds of formula (I) or formula (I') may also be formulated for parental administration (e.g., by
  • injection for example, bolus injection or continuous infusion
  • unit dose form in
  • compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the compounds according to formula (I) or formula (I') may be formulated as ointments, creams or lotions, or as a
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents,
  • stabilizing agents suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising an active ingredient in a flavored base, usually sucrose and acacia or tragacanth;
  • pastilles comprising the active ingredient in a suitable liquid carrier.
  • Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the compounds of formula (I) may be used as a liquid spray or dispersible powder or in the form of drops.
  • Drops may be formulated with an aqueous or non-aqueous base comprising one or more dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs.
  • the compounds of formula (I) or formula (I') are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other
  • Pressurized packs may comprise a suitable propellant such as
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds of formula (I) or formula (I') may take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be
  • unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • compositions for use according to the invention may also contain other active ingredients such as antimicrobial agents or preservatives.
  • the compounds of formula (I) of formula (I') may also be used in combination with other therapeutic agents, for example, other anti-infective agents.
  • the compounds of formula (I) or formula (I') may be employed together with well known antiviral agents, e.g., adenine arabinoside or ulcererferon ⁇ .
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or formula (I') or a physiologically acceptable derivative thereof together with another therapeutically active agent, in particular, an anti-HBV agent.
  • each compound may be either the same or different from that when the compound of formula (I) or formula (I') is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • the compounds of formula (I) or formula (I') and their pharmaceutically acceptable derivations may be prepared by any method known in the art for the preparation of compounds of analogous structure.
  • R 1 is hydrogen or a hydroxyl protecting group as defined herein and the anomeric group L is a displaceable atom or group and is reacted with an appropriate base.
  • Suitable groups L include alkoxy carbonyl groups such as ethoxy carbonyl or halogens, for example, iodine, bromine or chlorine or -OR' where R' is a substituted or unsubstituted, saturated or unsaturated alkyl group, e.g., a C 1-4 -alkyl group such as methyl, or R' is a substituted or
  • unsubstituted aliphatic or aromatic acyl group e.g., a C 1-6 - aliphatic acyl group such as acetyl and an aromatic acyl group such as benzoyl.
  • hexamethyldisilazine in a compatible solvent such as methylene chloride using a Lewis acid (such as titanium tetrachloride or stannic chloride) or trimethylsilytriflate.
  • a compatible solvent such as methylene chloride using a Lewis acid (such as titanium tetrachloride or stannic chloride) or trimethylsilytriflate.
  • the 1,3-oxathiolanes of formula (III) may be prepared, for example, by reaction of an aldehyde of formula (IV) with a mercaptoacetal of formula (V) in a compatible organic solvent, such as toluene, in the presence of an acid
  • catalyst as a para-toluene sulfonic acid or a Lewis acid, e.g., zinc chloride.
  • the mercaptoacetals of formula (IV) may be prepared by methods known in the art, for example, G. Hesse and I.
  • the aldehydes of formula (V) may be prepared by methods known in the art, for example, E.G. Halloquist and H.
  • one compound of formula (I) is converted to another compound of formula (I) by base interconversion.
  • base interconversion may be effected either by simple chemical transformation (e.g., the
  • the compounds of formula (I) may be prepared by the reaction of a compound of formula (VI)
  • P is a protecting group, followed by removal of the protecting group.
  • the compounds of formula (VI) may be prepared for reaction by a suitable epoxide (IX)
  • hydroxyl protecting groups include groups selected from alkyl (e.g., methyl, t- butyl or methoxymethyl), aralkyl (e.g., benzyl,
  • heterocyclic groups such as tetrahydropyranyl, acyl, (e.g., acetyl or penzoyl) and silyl groups such as trialkylsilyl (e.g., t- butyldimethylsilyl).
  • acyl e.g., acetyl or penzoyl
  • silyl groups such as trialkylsilyl (e.g., t- butyldimethylsilyl).
  • alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions.
  • Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF 3 etherate and acetic anhydride followed by removal of acetate groups so formed at an appropriate stage in the synthesis.
  • Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
  • the compounds of formula (I) are generally obtained as a mixture of the cis and trans isomers.
  • 1,6-Anhydro-L-gulose was prepared in one step from L- gulose by the treatment of L-gulose with an acid, e.g., 0.5N HCl in 60% yield (Evans, M.E., Earish, F. W., Carbohydr. Res. (1973), 28., 359). Without selective protection as was done before (Jeong, L. S.; Alves, A. J.; Carrigan, S. W.; Kim, H. O.; Beach, J. W.; Chu, C. K. Tetrahedron Lett.
  • pyrimidines e.g., silylated thymine and N-acetylcytosine
  • Inorganic basis salts may be prepared by reacting the free base with a suitable base such as an alkoxide (e.g., sodium methoxide) optionally in the presence of a solvent such as an alcohol (e.g., methanol).
  • a suitable base such as an alkoxide (e.g., sodium methoxide) optionally in the presence of a solvent such as an alcohol (e.g., methanol).
  • Pharmaceutically acceptable salts may also be prepared from other salts, including other
  • a compound of formula (I) may be converted into a pharmaceutically acceptable phosphate or other ester by reaction with a phosphorylating agent, such as POCl 3 or a suitable esterifying agent, such as an acid halide or anhydride, as appropriate.
  • a phosphorylating agent such as POCl 3
  • a suitable esterifying agent such as an acid halide or anhydride, as appropriate.
  • An ester or salt of a compound of formula (I) may be converted to the parent compound, for example, by hydrolysis.
  • Resolution of the final product or an intermediate or starting material therefore may be effected by any suitable method known in the art: see, for example. Stereochemistry of Carbon Compounds, by E.L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents, by S.H. Wilen.
  • the present invention is also directed to a novel methodology to prepare (-)3'-thia-2',3'-dideoxycytidine or (-)5-fluoro-3'-thia-2',3'-dideoxycytidine from ( ⁇ )-3'-thia-2',3'-dideoxycytidine or ( ⁇ )5-fluoro-3'-thia-2',3'-dideoxycytidine, respectively.
  • the method takes advantage of the stereospecificity of the action of deoxycytidine deaminase (from either mammalian or bacteria sources) which converts deoxycytidine to deoxyuridine, and the separation of 3'-thia-2',3'-dideoxycytidine and SddU.
  • the deamination is carried out at 37°C for 16 hours.
  • the ID 50 of (+)3'-thia-2',3'-dideoxycytidine, ( ⁇ )3'-thia-2',3'-dideoxycytidine and (-)3'-thia-2',3'-dideoxycytidine against HBV were found to be approximately > 0.5 ⁇ m, 0.1 ⁇ m and 0.02 ⁇ m respectively, which indicates that (-)3'-thia-2',3'-dideoxycytidine is the primary form responsible for the anti HBV effect.
  • virus DNA polymerase is able to interact with the unnatural (-)- configuration. It can be expected that the therapeutic index of (-)3'-thia- 2',3'-dideoxycytidine should be better than the (+)- or ( ⁇ )-form of 3 '-thia-2',3'-dideoxycytidine or its analogues.
  • a 10L, 3-neck flask was flame dried under vacuum and filled with argon. A positive flow of argon was maintained while the flask was fitted with a dried mechanical stirrer and charged with 100 g (0.15 eq) of DMAP, 3200 ml (39.7 moles, 7 eq) of anhydrous pyridine, and 500 g (5.67 moles, 1.00 eq) of cis-2-butene-1,4-diol. The flask was fitted with a septum. The contents were stirred at 0oC under continuous flow of argon.
  • the solution was decanted from the solids and the pyridine was evaporated in vacuo.
  • the remaining material was dissolved in ether and washed once with saturated CuSO 4 solution, twice with saturated NaHCO 3 solution and twice with water.
  • the ethereal solution was dried over MgSO 4 , filtered, evaporated, and placed on a vacuum pump overnight.
  • the solid residue was dissolved in water and the resulting solution was extracted twice with ether.
  • the ether solution was washed, dried over MgSO 4 , filtered, evaporated, and further dried in vacuo.
  • the reaction can be performed using two different methods:
  • the acetate In order to obtain reasonable results, the acetate must be at least 80% pure by GC. An amount of 92.1g of an oil containing 85.3% of acetate by GC, and 64.62g of
  • the quenched mixture was then filtered through 1-2 inches of silica gel (using a 3000 ml fritted funnel).
  • Silylated glycolaldehyde (141.41 g, 0.474 mol) is dissolved in toluene (2200 ml) in a three neck, 3000 ml round bottom flask.
  • the flask was equipped with a stir bar, glass stopper, rubber septa, and a Dean-Stark trap to remove water during the reflux.
  • Thioglycolic acid (33.93 ml, 0.488 mol) was added to the solution, and then heat was applied. The reaction usually takes approximately two hours to go to completion, and can be monitored by TLC (3:1 hexane:ether).
  • ⁇ 310oC is performed.
  • the ratio of ⁇ :ß-isomers present may be more accurately determined by HPLC analysis of the product on a Rainin
  • a dry appropriate size flask was charged with 8.20 ml diol (0.996 mols, 1 eq), 2.44g DMAP (0.020 mols, 0.2 eq), and 500 ml methylene chloride (0.2 molar solution; can be done at elevated concentrations up to 0.5 molar). This solution was reduced in temperature to 0oC then 41.8 ml triethyl amine (0.300 mols, 3 eq) was added via addition funnel. The mixture needed to be shaken by hand
  • 2.2.15 cells were inoculated at a density of 3 X 10 5 cells/ 5ml in 25 cm 2 flask. Drugs were added to the medium 3 days after the inoculation. Cells were grown in the presence of drugs for 12 days With changes of medium every 3 other days. At end of the incubation, the medium was centrifuged (10 minutes, 2,000 X g) and the supernatant was subjected to a final concentration of 10% (wt/vol) PEG 8,000. The virus was pelleted (10 minutes 10,000 X g). The pellet was
  • TNE buffer (10 mM Tris pH 7.5, 100 mM NaCl, 1 mM EDTA).
  • the suspension was adjusted to 1 % SDS and 0.5 mg/ml proteinase K and incubated for 2 hours at 55°C.
  • the digest was extracted with phenol, chloroform and the DNA was precipitated with ethanol.
  • the DNA pellet was dissolved in TE 80 (10 mM Tris pH 8.0, 1 mM EDTA) and electrophoresed in a 0.8% agarose gel, followed by blotting onto Hybond-N membrane (Amersham).
  • the filter was hybridized with 32 P-labeled HBV DNA probe, washed with 2 X SSC containing 0.2 % SDS at room temperature for 1 hour, 0.1 X SSC containing 0.2 % SDS at 55oC for 1/2 hour and
  • Drug-treated cells were lysed with a buffer containing 10 mM Tris pH 7.5, 5 mM EDTA, 150 mM NaCl and 1% SDS.
  • the cell lysate was digested with 100 ⁇ g/ml proteinase K at 55oC for at least 2 hours and deproteinized by extraction with phenol.
  • Nucleic acids were precipitated with 2 volumes of ethanol.
  • the pellet of nucleic acid was redissolved in 10 mM Tris pH 8.0, 1 mM EDTA followed by 100 ⁇ g per ml RNase treatment at 37°C for 1 hour. Concentrated ammonium acetate was added to the aqueous phase to yield a final 0.4 M ammonium acetate solution.
  • the nucleic acids were
  • RNA (20 ⁇ g per lane) was electrophoresed through 1% agarose gel containing 1.1 M formaldehyde and transferred to Hybond-N membrane. The immobilized RNA was hybridized with 32 P-labeled HBV DNA probe and the membrane was autoradiographed as described above.
  • CEM T lymphoblastoid cells
  • RPMI 1640 supplemented with 5% fetal bovine serum at a concentration of 2 X 10 3 cells per ml.
  • the cells were incubated with different concentrations of compounds for 4 days. At day 4, the cell number was determined by a coulter counter or a hemocytometer.
  • the CEM cells (5 X 10 4 ) cells were collected and freeze-thawed three times.
  • the cell lysate was incubated with RNase (10 ⁇ g/ml) at 37°C for 30 minutes.
  • the sample was treated with proteinase K (100 ⁇ g/ml) at 55°C for 1 hour.
  • a 0.8 volume of supersaturated Nal (2.5 gNal in 1 ml hot water) was added to the sample and heated at 90°C for 10 minutes.
  • the DNA was immobilized on nitrocellulose paper by using a slot blot apparatus (Schleicher & Schuell, Keene, NH).
  • the mtDNA on the nitrocellulose paper was detected with a mtDNA specific probe as described previously (Chen, C.H., Cheng, Y.C., "Delayed Cytotoxicity and Selective Loss of Mitochondria DNA in Cells Treated with the Anti-Human Immunodeficiency Virus Compound 2',3'-Dideoxycytidine," J. Biol. Chem. 264: 11934-11937, 1989).
  • the antiviral effects were measured by analysis of extracellular HBV DNA (Fig.1). The experiment revealed that the amount of extracellular HBV DNA decreased in a dose dependent manner.
  • the inhibitory concentration for a 50% decrease in viral replication (HBID 50 ) of these compounds are presented in Table 1. At concentration of 2 ⁇ M, both 5- fluoro-3'-thia-2',3-dideoxycytidine and 3'-thia 2',3'- dideoxycytidine completely inhibited the replication of HBV, approximately 50% inhibition by 3'-FddC, whereas neither ddC nor D4C had any impact effect.
  • Episomal HBV DNAs in 2.2.15 cells treated with different concentrations of 5-fluoro-3'- thia-2',3'-dideoxycytidine and 3'-thia-2',3'-dideoxycytidine were also traced.
  • Cellular DNAs were digested with Hind III that does not cleave within HBV genome, and subjected to Southern analysis using P 32 -labeled HBV DNA as a probe.
  • the chromosomally integrated HBV DNA genome and the episomal DNA can be separated in the gel and can be differentially quantified. While episomal DNA decreased in a dose dependent manner as extracellular HBV DNAs, both the amount and the restriction enzyme pattern of the chromosomally integrated HBV genome were unaltered (Fig.2).
  • Mitochondria DNA content was measured by slot blot
  • MtID50s concentration of compounds which caused a 50% reduction in mitochondria DNA content
  • Table 1 Both 5-fluoro-3'-thia-2',3-dideoxycytidine and 3'-thia 2',3'-dideoxycytidine inhibited HBV replication at concentrations hundreds or thousands fold lower than concentrations which induced cytotoxicity in CEM cells.
  • ddC a potent polymerase gamma inhibitor
  • D4C had a lower value of MtID 50 (2.0 ⁇ M) than HBID 50 (2.4 ⁇ M).
  • HBID 50 2.4 ⁇ M.
  • D4C would be expected to have a mitochondria effect before the anti-HBV effect was achieved as the same phenomenon observed in treatment with ddC.
  • 3'-FddC had a greater selective index than both ddC and D4C.
  • the ED 50 versus the MTID 50 ratio is about the same as ddC, suggesting 3'-FddC is not the drug of choice either.
  • HBV RNA transcripts Three major transcripts of approximately 3.5, 2.5, and 2.1 Kb were detected in the total cellular RNA extract. The HBV specific transcripts were not affected at all by 2.0 ⁇ M 5-fluoro-3'-thia-2',3'-dideoxycytidine and 3'-thia-2',3'-dideoxycytidine treatment (Fig. 4).
  • ( ⁇ )3'-Thia-2',3'-dideoxycytidine can be deaminated only up to approximately 50%; no further deamination has been observed. After HPLC separation, (-)3'-Thia-2',3'-dideoxycytidine was resubjected to deaminase and showed no sign of deamination at all (Figs. 8A and 8B).
  • ⁇ -3'-Thia-2',3'-dideoxycytidine has a different retention time from (+)3'-thia-2',3'-dideoxycytidine on HPLC ( ⁇ -3'-thia-2',3'-dideoxycytidine has a retention time of approximately 6.9 minutes compared with (+)3'-thia-2',3'-dideoxycytidine which has a retention time of approximately 8.3 minutes using no salt solvent system under the same condition as the one used in the case of (+)3'-thia-2',3'-dideoxycytidine and (-)3'- thia-2',3'-dideoxycytidine). However, no deamination occurred (Fig. 9A and Fig. 7B) under the same condition that
  • (+) 3 ' -thia-2',3'-dideoxycytidine was completely deaminated.
  • (+)5-fluoro-3'-thia-2',3'-dideoxyuridine and (-)5-fluoro-3'- thia-2',3'-dideoxycytidine was confirmed using the chemically synthesized 5-fluoro-3'-thia-2',3'-dideoxyuridine as a
  • Example 18 Assay Condition .HPLC Analysis.
  • the 2.2.15 cells (clonal cells derived from Hep G2 cells that were transfected with a plasmid containing HBV DNA) that secrete hepatitis B virions were used.
  • the 2.2.15 cells were maintained in minimal essential medium (MEM) supplemented with 10% fetal bovine seirum. Cells were incubated at 37°C in a moist atmosphere containing 5% CO 2 in air.
  • the 2.2.15 cells were inoculated at a density of 3 X 10 5 cells/ 5 ml in 25 cm 2 flask. The compounds studied were added to the medium three days after inoculation. Cells were grown in the presence of drugs for 12 days with changes of medium every three days.
  • the medium was centrifuged (10 minutes, 2,000 X g) and polyethylene glycol (M r 8,000) was added to the supernatant to a final concentration of 10% (wt/vol.)
  • the virus was pelleted (10 minutes 10,000 X g).
  • the pellet was resuspended at 1/100th the original volume in TNE buffer (10 mM Tris pH 7.5, 100 mM NaCl, 1 mM EDTA).
  • the suspension was adjusted to 1% SDS and 0.5 mg/ml proteinase K and incubated for 2 hours at 55°C.
  • the digest was extracted with phenolchloroform and the DNA was precipitated with ethanol.
  • the DNA pellet was dissolved in TE 80 (10 mM Tris HCl pH 8.0, 1 mM EDTA) and then electrophorsed in a 0.8% agarose gel followed by blotting onto Hybond-N membrane (Amersham, Arlington,
  • the filter was hybridized with
  • HBV DNA 32 P-labeled HBV DNA (Bam HI insert from plasmid Pam6 (American Type Culture Collection, Rockville, Maryland) probe, washed with 2 X SSC containing 0.2% SDS at room temperature for 1 hour, 0.1 X SSC containing 0.2% SDS at 55°C for 1/2 hour and then autoradiographed. The intensity of the autoradiographic bands was quantitated by a scanning densitometer. The amount of HBV-specific DNAs was similar in separate experiments performed in duplicate. HBID 50 was defined as the drug
  • the 2.2.15 cell line was used to evaluate the antiviral activities of (+)3'-thia-2',3'-dideoxycytidine, (-)3'-thia- 2',3'-dideoxycytidine and ( ⁇ )3'-thia-2',3'-dideoxycytidine.
  • the antiviral effects were measured by analysis of
  • the anti-HBV effect of each of the two racemic 3'-thia- 2',3'-dideoxycytidine was examined as described above.
  • the ID 50 of (+)3'-thia-2',3'-dideoxycytidine, ( ⁇ )3'-thia-2',3'-dideoxycytidine and (-)3'-thia-2',3'-dideoxycytidine are approximately > 0.5 ⁇ m, 0.1 ⁇ m and 0.02 ⁇ m, respectively, which indicates that (-)3'-thia-2',3'-dideoxycytidine is the primary form responsible for the anti-HBV effect observed for ( ⁇ )3'-thia-2',3'-dideoxycytidine.
  • (+) -form may even interfere with the (-)- form based on the observation that the (-)- form is approximately 5 fold more active than the ( ⁇ ) form of 3'-thia-2',3'-dideoxycytidine at the same dose (if there is no interference, it should be only 2-fold). A similar observation was also made for 5-fluoro-3'-thia-2',3'-dideoxycytidine.
  • Example 21 CEM Growth in 3'-thia-2',3'-dideoxycytidine
  • CEM were seeded at 3.5 ⁇ 10 4 cells per ml onto Corning 6-well dishes at 5 ml per well in RPMI 1640 + 5% dialized FBS + kanamycin at 100 mg/ml.
  • Cell number was determined on days 2, 4 and 6 after seeding. The cells were pipetted to break clumps, and then 1 ml was removed from each well and diluted into 9 ml saline. The saline + cells were pipetted well to break clumps and counted via a coutler counter.
  • (+)3'-thia-2',3'-dideoxycytidine was seen to be very toxic to the cells with an ID 50 of 1.26 ⁇ m.
  • ( ⁇ )3'-thia-2',3'-dideoxycytidine was less toxic with an ID 50 of 7.2 ⁇ m.
  • the therapeutic index for -OddC should be equal or better than -SddC, in fact, from an economical point of view, -OddC may be even more valuable than -SddC due to its low ID 50 (anti HBV).

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Abstract

Composés agissant contre le virus de l'hépatite B, notamment (-)3'-thia-2',3'-didésoxycytidine, (-)5-fluoro-3'-thia-2', 3'-didésoxycytidine, (U) beta-dioxolane cytosine et (-)-L-beta-dioxolane cytosine. On décrit un procédé de traitement d'un patient atteint du virus de l'hépatite B ou de prévention d'une infection par le virus de l'hépatite B, lequel procédé consiste à administrer au patient une quantité efficace d'un composé actif choisi à partir du groupe composé de (a) (-)3'-thia-2', 3'-didésoxycytidine, (b) (U)3'-thia-2',3'-didésoxycytine, (c)(-)5-fluoro-3'-thia-2',3'-didésoxycytidine, (d) (U)5-fluoro-3'-thia-2' 3'-didésoxycytidine, (e) (U) beta-dioxolane-cytosine et (f) (-)-L-beta-dioxolane cytosine, ou un sel ou un ester de ce composé, utilisé seul ou mélangé à un diluant.
PCT/US1992/003144 1991-04-17 1992-04-16 Procede de traitement ou de prevention du virus de l'hepatite b WO1992018517A1 (fr)

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