Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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 the use of a 1-(2-(hydroxymethyl)- l,3-oxathiolan-5-yl)-cytosine derivative and physiologically functional derivatives thereof for the treatment of hepatitis B viral infections.
• Hepatitis B virus is a viral pathogen of major worldwide importance. HBV is most common in Asian countries, and prevalent in sub-Saharan Africa. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer. In the United States more than ten thousand people are hospitalized for HBV illness each year, an average of 250 die with fulminant disease. The United States currently contains an estimated pool of 500,000 - 1 million infectious carriers. Chronic active hepatitis will develop in over 25% of carriers and often progresses to cirrhosis. It is estimated that 5000 people die from HBV-related cirrhosis each year in the U.S.A. and that perhaps 1000 die from HBV-related liver cancer.
• European Patent Specification 0 382 526 discloses certain 1,3-oxathio- lane nucleoside analogues which are effective in inhibiting the replication of human immunodeficiency virus (HIV) .
• R is a hydrogen atom or a C. , alkyl group
• a preferred compound of formula (I) is that in which R is a hydrogen atom, namely: 1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine.
• the compound of formula (I) contains two chiral centers and therefore exists in the form of two pairs of optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures.
• the compound of formula (I) may be either a cis- or a trans- isomer or mixtures thereof. Each cis- and trans- isomer can exist as one of two enantiomers or mixtures thereof including racemic mixtures. All such isomers and mixtures thereof including racemic mixtures are within the scope of the invention.
• the cis- isomers of the compound of formula (I) are preferred.
• the invention includes the optical and geometric isomers and all tautomeric forms of the compound of formula (I); of the cis isomers, the (-) isomer, ie. (-)-cis-l-(2-(2-hydroxymethyl)-1.3-oxathiolan-5- yl)-5-fluorocytosine, is especially preferred.
• a compound of formula (I) or a physiologically functional derivative thereof for use in the treatment or prophylaxis of a hepatitis B virus infection.
• a method for the treatment or prophylaxis of a hepatitis B virus infection in a host for example, a mammal such as a human which comprises treating the host with a therapeutically effective amount of a compound of formula (I) or a physiologically functional derivative thereof.
• physiologically functional derivative is meant a pharmaceutically acceptable salt, ester or salt of an ester of a compound of formula (I) or any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) the said compound of formula (I) or an active metabolite or residue thereof.
• Preferred esters in accordance with the invention include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl e.g. n-propyl, t-butyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl) , arylalkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxyme hyl) , and aryl (e.g. phenyl) ; sulfonate esters such as alkyl- or arylalkylsulfonyl (e.g.
• phosphate esters may be further esterified by, for example, a C- -_ aallccoohhooll oo:r reactive derivative thereof, or by a 2,3-di(C, mecanic,)acyl glycerol.
• Any alkyl moiety present in such esters advantageously contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms.
• Any aryl moiety present in such esters advantageously comprises a phenyl group optionally substituted e.g. by halogen, C alkyl, C. alkoxy or nitro.
• the cytosine amino group may be present In the form of an amide, e.g. -NHCOR where R is C- - alkyl or aryl (e.g. phenyl optionally substituted by halogen, C. , alkyl, C. , alkoxy, nitro or hydroxyl) .
• R is C- - alkyl or aryl (e.g. phenyl optionally substituted by halogen, C. , alkyl, C. , alkoxy, nitro or hydroxyl) .
• Examples of pharmaceutically acceptable salts according to the invention include base salts, e.g. derived from an appropriate base, such as alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) salts, ammonium and NX (wherein X is C. , alkyl).
• alkali metal e.g. sodium
• alkaline earth metal e.g. magnesium
• ammonium e.g. ammonium
• NX wherein X is C. , alkyl
• Pharmaceutically acceptable acid addition salts include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
• organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids
• organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
• inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
• the amount of the compound of formula (I) (hereinafter also referred to as the "active ingredient”) or physiologically functional derivative thereof which Is required in a medication to achieve the desired effect will depend on a number of factors, in particular the specific application, the nature of the particular compound used, the mode of administration and the condition of the patient.
• a suitable dose will be in the range of 3.0 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg per kilogram body weight per day and most preferably in the range 15 to 60 mg per kilogram body weight per day.
• the desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form.
• the active ingredient should be administered to achieve peak plasma concentrations of the active ingredient of from about 1 to about 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 a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 100 mg/kg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
• the compound of formula (I) or a physiologically functional derivative thereof herein as “active ingredient” is typically admixed with, inter alia, one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
• the formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
• Formulations of the present invention suitable for oral administration may 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 or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
• Formulations suitable for oral use as described above may also include buffering agents designed to neutralize stomach acidity.
• buffers may be chosen from a variety of organic or inorganic agents such as weak acids or bases admixed with their conjugated salts.
• Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• Formulations for rectal administration may be presented as a suppository with a suitable base comprising for-example cocoa butter or a salicylate.
• Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injections solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, as liposomes or other microparticulate systems which are designed to target the compounds to blood components or one or more organs.
• the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• sterile liquid carrier for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
• the compound of formula (I) may be prepared for example in accordance with the processes described in European Patent Specification 0 382 526 or by processes analogous thereto.
• R- is hydrogen or a hydroxy protecting group and L is a leaving group
• SUBSTITUTE SHEET (wherein R and R are as defined above) with an agent serving to convert the oxo group in the 4-position of the uracil ring to an amino group; any remaining protecting groups being removed for example by acid or base hydrolysis to produce the desired product.
• the hydroxy protecting group includes protecting groups such as acyl (e.g. acetyl) , arylacyl (e.g. benzoyl or substituted benzoyl), trityl or monomethoxytrityl, benzyl or substituted benzyl, trialkylsilyl (e.g. dimethyl-£-butylsilyl) or diphenylmethylsilyl.
• the 5-R-cytosine compound may be optionally protected with silyl, e.g. trimethyl silyl groups. Such groups may be removed in conventional manner.
• the leaving group L is a leaving group typical of those known in the art of nucleoside chemistry e.g. halogen such as chlorine or bromine, alkoxy such as methoxy or ethoxy or acyl such as acetyl or benzoyl.
• the reaction in process a) may be effected in an organic solvent (e.g. 1,2-dichloroethane or acetonitrile) in the presence of a Lewis acid such as stannic chloride or trimethylsilyl triflate.
• organic solvent e.g. 1,2-dichloroethane or acetonitrile
• Lewis acid such as stannic chloride or trimethylsilyl triflate.
• R- is defined above, as described in Can. J. Research, 8, 129 (1933) and European Patent Specification 0 382 526.
• Reaction of compounds of formula III with a mercaptoacetal HSCH-CH(OR)- , wherein R is C- , alkoxy such as HSCH repeatCH(OC conducH_)- , known in the art (Che . Ber. 85:924-932, 1952) yields compounds of formula IIA wherein L is OR (alkoxy) e.g. methoxy or ethoxy.
• compounds of formula IIA, wherein L is alkoxy may be converted to compounds of formula IIA wherein L is halogen or acyl by methods known in the art of carbohydrate chemistry.
• Compounds of formula III may be prepared from 1,2-0-isopropylidene glycerol by introduction of R. (e.g. trisubstituted silyl, benzyl or trityl) and removal of the isopropylidene group with mild acid (e.g. aqueous formic or acetic acid) or zinc bromide in acetonitrile, followed by oxidation of the alcohol group with aqueous periodate.
• R. e.g. trisubstituted silyl, benzyl or trityl
• mild acid e.g. aqueous formic or acetic acid
• zinc bromide e.g. aqueous formic or acetic acid
• the compound _ of formula IIB is advantageously treated with 1,2,4-triazole, advantageously together with 4-chlorophenyl dichlorophosphate, to form the corresponding 4-(l,2,4-triazoylyl) compound which is then converted to the desired 4-amino (cytidine) compound by reaction with for example methanol.
• the starting materials of formula IIB be prepared for example by reaction of an appropriate (optionally protected) base with a compound of formula IIA in an analogous manner to that described in process a) .
• Separation of the ( ⁇ )-cis and ( ⁇ )-trans isomers for example in a protected form may be accomplished by chromatography on silica gel with mixtures of organic solvents such as ethyl acetate/methanol, ethylacetate/hexane or dichloromethane/methanol. Any protecting group may then be removed using the appropriate reagent for each group.
• Resolution of the ( ⁇ )-enantiomers may be accomplished enzymatically with an esterase such as pig liver esterase (Sigma Chemical Co., St. Louis, MO 63178) wherein one enantiomer of a 5'-acyl derivative of the compound of formula I is de-esterified. After separation, the remaining esterified compound of formula I may be reacted under basic conditions (e.g. NH project in methanol or NaOMe in methanol) to give the individual (+)- and (-)-enantiomers.
• an esterase such as pig liver esterase (Sigma Chemical Co., St. Louis, MO 63178) wherein one enantiomer of a 5'-acyl derivative of the compound of formula I is de-esterified. After separation, the remaining esterified compound of formula I may be reacted under basic conditions (e.g. NH stamp in methanol or NaOMe in methanol) to give the individual (+)- and (-)-enantiomers.
• the ( ⁇ * )-cis or ( ⁇ )-trans isomers of the compound of formula I may be reacted with a phosphorylating agent (e.g. phosphorous oxychloride) in an inert solvent such as triethylphos- phate, acetonitrile or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimi- dinone to yield the 5'-monophosphate derivative or a salt thereof.
• a phosphorylating agent e.g. phosphorous oxychloride
• an inert solvent such as triethylphos- phate, acetonitrile or l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimi- dinone
• an enzyme such as snake venom 5' -nucleotidase preferentially hydrolyzes one of the enantiomers. Separation and subsequent dephosphorylation
• the compound of formula (I) may be converted into a pharmaceutically acceptable ester by reaction with an appropriate esterifying agent, for example, an acid halide or anhydride.
• the compound of formula (I) may be converted into a pharmaceutically acceptable salt thereof in a conventional manner, for example, by treatment with an appropriate base.
• An ester or salt of a compound of formula (I) may be converted into the parent compound, for example, by hydrolysis.
• (+)-Cis and (+)-trans-2-benzoyloxymethyl-5-(N -acetyl-cyto- sin-l-yl)-1,3-oxathiolane are prepared and separated to the (+)-cis and (+)trans isomers as described in European Patent (EP) Specification 0 382 526.
• the N, -acetyl and 2-benzoyl groups are removed with dimethylamine in ethanol, and the product, ( ⁇ )-cis-l-(2- (hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine, is isolated.
• (+)-Cis and (+)-trans-2-benzoyloxymethyl-5-(uracil-1-yl)- 1,3-oxathiolane are prepared as described in EP 0 382 526.
• the isomers are separated on silica gel using EtOAc/MeOH as eluant (EP 0 382 526).
• the ( ⁇ )-cis isomer is reacted with acetic anhydride in pyridine at room temperature to give the 2-acetate.
• Solvent is removed in vacuo at ⁇ 30 C C.
• the 2-acetate is then dissolved in CHC1, and washed with aqueous sodium bicarbonate.
• (+)-Cis and ( ⁇ )-trans 2-benzoyloxymethyl-5-(thymin-N-yl)-1,3-oxathio- lane are prepared and separated to the (+)-cis and (+)-trans isomers as described in European Patent Specification 0 382 526.
• the (+)-cis isomer is reacted with acetic anhydride in pyridine at room temperature to give the 2-acetate.
• Solvent is removed in vacuo at ⁇ 30 ⁇ C.
• the 2-acetate is then dissolved in CHC1_ washed with aqueous sodium bicarbonate.
• the separated organic layer is dried, and CHC1_ is evaporated .in vacuo.
• Conversion of the thymine base to the 5-methyleytosine base is carried out by preparation of the 4-(1,2,4-triazol-l-yl) derivative according to the methods of C.B. Reese, J.Chem.Soc, Perkins 1, 1171, 1984 and W.L. Sung, Nucleic Acids Res. 9:6139, 1981, using 1,2,4-triazole and 2 equivalents of 4-chlorophenyldichlorophosphate in dry pyridine at ambient temperature.
• the "Active Ingredient” is 1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine.
• formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
• formulations D and E are prepared by direct compression of the admixed ingredients.
• the lactose in formulation E is of the direct compression type (Dairy Crest - "Zeparox").
• Active ingredient 250 Pregelatinized Starch NF15 150 400
• the formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression. mg/tablet
• Drug release takes place over a period of about 6-8 hours and is complete after 12 hours.
• a capsule formulation is prepared by admixing the ingredients of Formulation D in Example 3 above and filling into a two-part hard gelatin capsule.
• Formulation B (infra) is prepared in a similar manner.
• Capsules of formulation D are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
• controlled release capsule formulation is prepared by extruding ingredients a, b and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with controlled-release membrane (d) and filled into a two-piece, hard gelatin capsule.
• the active ingredient is dissolved in most of the water (35°C-40 C C) and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate.
• the batch is then made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 mL amber glass vial (type 1) and sealed with sterile closures and overseals.
• the active ingredient is dissolved in a mixture of the glycerol and most of the purified water.
• An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavor.
• the volume is made up with purified water and mixed well.
• Witepsol H15 is melted in a steam-jacketed pan at 45 " -C maximum.
• the active ingredient is sifted through a 200 M sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix.
• the entire suspension is passed through a 250 M stainless steel screen and, with continuous stirring, is allowed to cool to 40°C. At a temperature of 38 ⁇ > C to 40°C, 2.02 g of the mixture is filled into suitable, 2 mL plastic molds. The suppositories are allowed to cool to room temperature.
• Example 9 Pessaries mg/pessary
• HBV Hepatitis B Virus
• Intracellular HBV DNA* (pg/up cell DNA)

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• 1991
  • 1991-05-02 GB GB919109506A patent/GB9109506D0/en active Pending
• 1992
  • 1992-04-30 PT PT100435A patent/PT100435B/pt not_active IP Right Cessation
  • 1992-04-30 ZA ZA923185A patent/ZA923185B/xx unknown
  • 1992-04-30 MY MYPI92000749A patent/MY137298A/en unknown
  • 1992-05-01 UA UA93004171A patent/UA37251C2/uk unknown
  • 1992-05-01 EP EP92908933A patent/EP0583274A1/en not_active Withdrawn
  • 1992-05-01 RU RU93058325A patent/RU2104700C1/ru active
  • 1992-05-01 WO PCT/GB1992/000803 patent/WO1992019246A1/en not_active Application Discontinuation
  • 1992-05-01 AU AU16620/92A patent/AU1662092A/en not_active Abandoned
  • 1992-05-01 IL IL101757A patent/IL101757A0/xx unknown
  • 1992-05-01 JP JP4508657A patent/JPH06506929A/ja active Pending
  • 1992-05-01 CA CA002102120A patent/CA2102120A1/en not_active Abandoned
  • 1992-06-24 MX MX9203214A patent/MX9203214A/es unknown
  • 1992-07-01 IE IE136392A patent/IE921363A1/en not_active Application Discontinuation

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