Classifications

• • 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
• • 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
  • A61P31/20—Antivirals for DNA viruses
• • 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
  • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
  • C07D473/32—Nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
  • C07D473/36—Sulfur atom

Definitions

• the present invention relates to the use of purine acyclonucleosides as agents in the treatment and/or prophylaxis of hepatitis B, pharmaceutical compositions for use in such therapy and novel purine acyclonucleosides.
• HBV chronic hepatitis B virus infection
• R 1 is hydrogen, halogen, hydroxy, azido, alkoxy, aryloxy, thio, alkylthio, amino, alkylamino, hydrazino, hydroxylamino, benzyloxy, NRR' or NRCOR';
• R 2 is hydrogen, halogen, hydroxy, azido, alkoxy, aryloxy, thio, alkylthio, amino, alkylamino, hydrazino, hydroxylamino, benzyloxy, NRR' or NRCOR';
• R and R' are independently selected from hydrogen, alkyl and aryl
• R 1 is hydroxy or a group capable of being converted in vivo to hydroxy.
• R 2 is amino; or a group which is capable of being converted in vivo to amino.
• the invention further provides a method for the treatment or prophylaxis of hepatitis B viral infection which method includes administering to a patient in need thereof an effective amount of a compound of formula (1), its salts, and pharmaceutically acceptable derivatives.
• the present invention also provides a compound of formula (1), its salts, and pharmaceutically acceptable derivatives for use in treatment or prophylaxis of HBV.
• the compounds of the invention may further be used in the manufacture of a medicament for the treatment or prophylaxis of HBV.
• the present invention provides pharmaceutical compositions for said treatment or prophylaxis which include a compound of formula (1), its salts or pharmaceutically acceptable derivatives in association with a pharmaceutically acceptable carrier or diluent.
• the present invention also provides the use of a compound of formula (1), its salts or pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in the treatment or prophylaxis of HBV.
• the salts of the compounds of formula (1) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutical ly acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
• the pharmaceutically acceptable salts may include conventional non-toxic salts or quaternary ammonium salts of these compounds, which may be formed for example from organic or inorganic acids or bases.
• acid addition salts include, but are not limited to, those formed with pharmaceutically acceptable acids such as acetic, propionic, citric, lactic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, ascorbic, hydrochloric, orthophosphoric, sulphuric and hydrobromic acids.
• Base salts includes, but is not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium magnesium, ammonium and alkylammonium. They may be formed by treating a compound of formula (1) with an appropriate metal hydroxide.
• basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• the compounds of the invention may be in crystalline form or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
• Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable salt, hydrate, prodrug, or any other compound which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula (1) or an antivirally active metabolite or residue thereof.
• compounds where a hydroxy group on the acyclic sidechain has been replaced with a phosphate ester are within the scope of pharmaceutically acceptable derivatives.
• prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where R 1 is a group which is capable of being converted in vivo to hydroxy; or R 2 is a group which is capable of being converted in vivo to amino; or compounds where a free hydroxy group on the acyclic sidechain is converted into a group, for example an ester, a carbonate or a carbamate, which is capable of being converted in vivo back to a hydroxy group.
• a prodrug may include modifications to one or more of the functional groups of a compound of the invention.
• a group which is capable of being converted in vivo used in relation to another functional group includes all those functional groups or derivatives of such groups which upon administration into a mammal may be converted into the stated functional group. Those skilled in the art may readily determine whether a group may be capable of being converted in vivo into the stated functional group using routine enzymatic or animal studies.
• R 1 is hydroxy or a group which is capable of being converted in vivo to hydroxy.
• R 2 is amino, or a group which is capable of being converted in vivo to amino.
• R 1 is hydrogen, halogen, hydroxy, azido, alkoxy, aryloxy, thio, alkylthio, amino, alkylamino, hydrazino, hydroxylamino, benzyloxy, NRR' or NRCOR';
• R 2 is hydrogen, halogen, hydroxy, azido, alkoxy, aryloxy, thio, alkylthio, amino, alkylamino, hydrazino, hydroxylamino, benzyloxy, NRR' or NRCOR';
• R and R' are independently selected from hydrogen, alkyl and aryl
• alkyl used either alone or in compound words such as haloalkyl or alkyl acids is denoted, unless otherwise defined, to mean both the straight chain C ⁇ alkyl or branched chain C 3 . 30 alkyl and the branched or unbranched C 3 . 30 cycloalkyl. Unless otherwise defined, such groups may be saturated or unsaturated.
• the term"aryl refers to any compound which includes or consists of one or more aromatic rings.
• the aromatic rings may be carbocyclic, heterocyclic or pseudoaromatic, and may be mono or polycyclic ring systems and preferably have 2 to 20 carbon atoms.
• the aromatic rings may also have one or more heteroatoms selected from N, S, O and P.
• suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetradyronaphthalene, 1- benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, pyrene.
• pseudoaromatic refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
• pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like.
• alkoxy used either alone or in compound words such as haloalkoxy is denoted, unless otherwise defined, to mean both the straight chain C,. 30 alkoxy or branched chain C 3 . 3u alkoxy and the branched or unbranched C 3 _ 30 cycloalkoxy. Unless otherwise defined, such groups may be saturated or unsaturated.
• esters are denoted to mean those compounds or derivatives which correspond to the ester formed by reaction of an alcohol with an organic acid, preferably a carboxylic acid.
• carboxylic acids from which esters may be formed include amino acids and alkyl acids.
• Preferred amino acids are aliphatic amino acids such as valine and isoleucine, preferably in the L-form.
• Preferred alkyl acids include C 2 -C 4 alkyl acids, and fatty acids from C,,- ⁇ such as lauryl, myristoyl, palmitoyl, stearoyl, eicasanoyl, behenoyl, myristoleic, myristelaidic, palmitoleic, palmitelaidic, n6-octadecenoic, oleic, elaidic, erucic or brassidic acids.
• a preferred group of compounds of formula (1) and formula (la) and pharmaceutically acceptable derivatives of the compounds of formula (1) and formula (la) are those compounds of formula (4)
• X is hydrogen or hydroxy
• R 5 and R 6 are the same or different and together with the oxygen atom to which they are attached form a hydroxy group, an ester, a carbonate, a carbamate, or a thiocarbonate; preferably a hydroxy or an ester;
• the compounds may be prepared by reacting a purine derivative (2) with a compound of formula (3).
• the group R 1 of purine derivative (2) may be any group listed under R 1 for the compound of formula (1) or any group that may be converted by methods known in the art to such groups, such groups include chlorine, bromine or iodine; and R 2 may be any group listed under R 2 for the compound of formula (1) or any group that may be converted by methods known in the art to such groups.
• Z is any suitable leaving group, such as methane sulfonate or bromine, and R 3 and R 4 are hydroxy or a group that may be converted into hydroxy, such groups include ethers and esters. Methods for such conversion are known to those skilled in the art. R 3 and R 4 may be joined together to form an optionally substituted 5 or 6 membered ring system.
• R 3 and R 4 may be joined together to form an optionally substituted 5 or 6 membered ring system.
• a symmetrical triol (5) preferably where n is 1 or 2
• a diester (6) may be converted into a diester (6) by treatment with about one equivalent of a trialkylorthoester, preferably triethylorthoacetate, under appropriate conditions, followed by treatment with about one equivalent of water under appropriate conditions, followed by treatment with water under appropriate conditions.
• the diester may then be isolated by conventional procedures, conveniently this is done via a careful neutralisation of the mixture with a mild base, for example sodium bicarbonate, followed by extraction into an organic solvent.
• a mild base for example sodium bicarbonate
• n 1 are of general formula (3).
• Compounds of formula (6) such as 2-hydroxymethyl-l ,3-propanediol diacetate, and diester compounds including those of general formula (3), such as 3-acetoxy-2- acetoxymethylprop-1-yl methanesulfonate, are novel and form a further aspect of the invention.
• n is 1 in compound (5) and (6).
• the acyclic hydroxyl groups of compounds of formula (1) may be readily converted into esters, ethers or phosphate groups or a mixture of these groups on the acyclic chain.
• Such intermediates may be prepared in accordance with standard procedures and when no longer required the protecting groups removed using standard procedures, such as those described by Greene. Examples of suitable protecting groups are trimethylsilyl and monomethoxytrityl groups.
• acylation and alkylation may be carried out using any conventional procedure such as those generally known in the art or described or referenced in the Third Edition of March's Advanced Organic Chemistry published by Wiley-Interscience.
• acylating agents suitable for the process of acylating the compounds of formula (1) are carboxylic acids, acid halides and acid anhydrides.
• the reaction may be carried out in a conventional manner, for example in a solvent such as pyridine, dimethylformamide, etc. , optionally in the presence of a coupling agent such as N,N'-dicyclohexylcarbodiimide, and optionally in the presence of a catalytic base such as 4-dimethylaminopyridine.
• the product of the reaction may be isolated in a conventional manner.
• alkylating agents suitable for the process of alkylating compounds of formula (1) are alkyl halides, such as methyl, ethyl, propyl, and benzyl chlorides, bromides and iodides; and dialkyl sulfates like dimethyl and diethyl sulfate.
• amino acids or their functional equivalents for example acid halides
• amino protected derivatives of the amino acid or amino acid equivalent for example benzyloxycarbonyl derivatives.
• Such derivatives are commercially available.
• the protecting groups may be removed utilising standard procedures.
• the acylation or alkylation reactions may produce a single derivative of compound (1), incorporating one or more acyl or alkyl groups, or may produce a mixture of compounds incorporating acyl or alkyl groups. The outcome depends on a number of factors, such as the relative amounts and chemical nature of the reactants, the physical conditions of the reaction, and the solvent system. Any mixture produced in this way may be separated using standard techniques, preferably chromatography.
• Protected intermediates of the compounds of formula (1) may also be used to prepare derivatives of compound (1) incorporating phosphate esters.
• the compounds of this invention may also be useful in combination with known antiviral or antiretroviral agents or other pharmaceuticals used in the treatment of viral infections.
• additional pharmaceuticals include immunomodulators, immunostimulants, and antibiotics.
• Exemplative anti-viral agents include AZT, 3TC, acyclovir, famciclovir, ddl, ddC, ganciclovir, saquanivir, loviride, other non-nucleotide reverse transcriptase (RT) inhibitors and protease inhibitors.
• Exemplative immunomodulators and immunostimulants include various interleukins, cytokines, antibody preparations, blood transfusions and cell transfusions.
• Exemplative antibiotics includes antifungal agents, antibacterial agents and anti-Pneumocystis carinii agents.
• such combination products employ the compounds of this invention in the dosage ranges described below and the other pharmaceutically active agent within its approved dosage range.
• the compounds of the invention may be used sequentially with known anti-viral, anti-retroviral or pharmaceutical agents when a combination formulation is inappropriate.
• an effective amount is meant a quantity of active compound which will upon single or multiple dose administration to the patient be effective in controlling the viral infections, such as HBV, or in achieving a blood or tissue level in the patient that corresponds to a concentration of the active compound that has been shown to inhibit a virus, such as HBV, in an assay known to predict for clinical anti-viral activity of chemical compounds.
• an assay known to predict for clinical anti-viral activity of chemical compounds. For example the assay described by Korba and Gerin.
• controlling the viral infections refers to slowing, interrupting, arresting or stopping its growth or replication and does not necessarily indicate a total elimination of the virus.
• Controlling the viral infections will be useful in the treatment and/or prophylaxis of such viral infections.
• a suitable dose of the compound of the invention will be in the range of 0.1 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.5 to 10 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 1 to 1000 mg, preferably 10 to 500 mg of active ingredient per unit dosage form.
• the compounds according to the invention may be administered for therapy by any suitable route, including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) .
• administration will be by the oral route, however it will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the invention and the chosen active ingredient.
• a prodrug of the active compound which is more efficiently absorbed than the unmodified compound is generally preferred.
• compositions of the present invention comprise the compound of formula (1). optionally as a salt or other pharmaceutically acceptable derivative, together with one or more pharmaceutically acceptable carriers, diluents or excipients therefor, and optionally other therapeutic agents.
• Each carrier, diluent or excipient must be pharmaceutically "acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
• Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
• the compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy.
• Such methods include the step of bringing into association the active ingredient with the carrier, diluent or excipient which includes one or more accessory ingredients.
• the compositions 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.
• compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a 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.
• Tablets may be made by compression or moulding, 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. inert diluent, preservative disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
• a binder e.g. inert diluent, preservative disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
• Moulded tablets may be made by moulding 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.
• compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter.
• compositions 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.
• compositions suitable for parenteral administration include aqueous and non- aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the 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 compositions are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• the compounds according to the invention may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art.
• veterinary compositions include those adapted for: (a) oral administration, external application, for example drenches (e.g. , aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
• parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension;
• topical application e.g. as a cream, ointment or spray applied to the skin;
• compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
• 2-Amino-6 ⁇ chloropurine was obtained commercially in 98 % purity from Chugai Boyeki Co. , Ltd. 2-Amino-6-chloropurine was converted to 2-amino-6-iodopurine according to the method of Bisacchi et al. Unreferenced reagents were obtained commercially and used as supplied, unless otherwise specified.
• 5,5-Dicarboxyethyl-2-isopropyl-l ,3-dioxane was prepared according to a modified method of Eliel et al.
• 5,5-Dicarboxylic-2-isopropyl-l ,3-dioxane was synthesised from 5,5- dicarboxyethyl-2-isopropyl-l ,3-dioxane (20.0 g, 72.9 mmol) according to the method of Eliel et al.
• the crude product was re-crystallised from ethyl acetate and petroleum spirit to give 5,5-dicarboxylic-2-isopropyl-l ,3-dioxane (14.1 g, 80%) as a colourless solid.
• 5-Carboxy-2-isopropyl-l ,3-dioxane was synthesised from 5,5-dicarboxylic-2- isopropyl-l ,3-dioxane (15.7 g, 64.8 mmol) according to the method of Eliel et al.
• the crude product was re-crystallised from ethyl acetate and petroleum spirit to give 5- carboxy-2-isopropyl-l ,3-dioxane (9.75 g, 76%) as a colourless solid.
• 2-Amino-6-chloro-9-[(2-isopropyl-l ,3-dioxan-5-yl)methyl]purine was synthesised from 2-isopropyl-5-(methanesulfoxy)methyl-l ,3-dioxane (10. 1 g, 38.5 mmol) according to method used for 9-[3-acetoxy-2-acetoxymethylprop-l-yl]-2-amino-6-iodopurine to give the product as a colourless solid (4.80 g, 40%).
• the product (0.5 g) was dissolved in a little water, centrifuged and made up to 5 ml in volume and HPLC chromatographed in lots of 0.5 ml eluting with water (flow rate of 12 ml/min) The fractions between 13-14 mins and 18-19 mins were collected and were freeze dried to give a pale yellow solid (320 mg).
• the material was dissolved in water (4 ml) and re-chromatographed in 0.5 ml lots. For each fraction the leading and trailing section of the peak containing the triphosphate was cut. This was repeated a further 4 times. Finally the product was dialysed (100 MWCO tubing, 6.5 h, H 2 O) before again purifying by HPLC. This treatment removed a small amount of phosphorus impurity (small 3I P nmr peak at ⁇ +0.93), due, presumably, to some inorganic phosphate.
• the 31 P nmr peaks broadened and moved on HPLC purification so that the purified sample had two broad 31 P peaks at ⁇ - 9.96 (P +P ) and ⁇ -22.07 (P ⁇ ) of intensity ratio 2: 1.
• Palmitoyl chloride (2 07 g, 7 53 mmol) was dissolved in dry dichloromethane and made up to a volume of 10 ml and used as a stock solution
• Tests of antiviral activity in human cells infected with hepatitis B were performed according to the method of Korba and Germ The effective concentration for 50% and 90% inhibition of the replication of the virus was determined from dose response curves. Results for some compounds of the invention are shown in Table 2.
• the oral bioavailability of various compounds of the invention was compared in rats. Briefly, the compounds were administered by oral gavage at 0.2mmol/kg of body weight. The compounds were suspended in 1 mL of an aqueous vehicle containing 1 % carboxymethylcellulose and 0.05% Tween 80. Plasma was sampled over an 8 hour period and the concentration of the parent compound, in this case the compound of example 1 , was determined by hplc.
• the concentration of drug versus time profile was plotted and the area under the curve determined. This was compared with the area under the curve provided by intravenous administration of the sodium salt of the parent compound to provided a measure of total bioavailabilty as a percentage. Results are shown in Table 3.

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