Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
  • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• • 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
• • 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
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/56—One oxygen atom and one sulfur atom

Definitions

• the present invention relates to certain enzyme inhibitors which are especially useful for co-administration with other therapeutic compounds such as antiviral compounds in order to provide an improved therapeutic effect including reduction in toxic side-effects.
• a therapeutic nucleoside that has been found to have a particularly beneficial clinical effect against a spectrum of conditions associated with Human Immunodeficiency Virus (HIV) infections such as Acquired Immune Deficiency Syndrome (AIDS), ATDS-related complex (ARC) and asymptomatic infections, is the compound 3'-azido-3'-deoxythymidine(AZT) having the approved name zidovudine.
• HBV Human Immunodeficiency Virus
• AIDS Acquired Immune Deficiency Syndrome
• ARC ATDS-related complex
• asymptomatic infections is the compound 3'-azido-3'-deoxythymidine(AZT) having the approved name zidovudine.
• This compound at low doses is generally very well tolerated by patients and is now widely used in the treatment of HIV infections.
• zidovudine some haematological suppression including anaemia and neutropenia may be observed, presumably arising from a certain limited level of toxicity of zidovudine observed towards
• uridine and cytidine could reverse the toxic effect of zidovudine in yitro(Sommadosi, et al., Antimicrobial Agents Chemo., 1987, 31 :453- 454).
• uridine is toxic to humans when given via continuous infusion in vivo.
• uridine is administered to a patient in an intermittent schedule, it is rapidly eliminated from the plasma(van Groeniger, et al., 1986, Cancer Treatment Rept. 70:745-750).
• 5-benzyl barbituate compounds have been described as uridine phosphorylase inhibitors which are useful for reducing the toxicity and anemia induced by antiviral drugs, such as AZT, as well as for potentiating anticancer drugs and combatting their host-toxicity(PCT Publication No. WO 91/16315). Furthermore, benzyloxy derivatives of BAU have been reported to decrease the bone marrow toxicity of pyrimidine nucleoside analogs, such as AZT(published under WO 89/09603, October 19, 1989, PCT US89/01528).
• US Patent 5,077,280 discloses a treatment for AJDS-type diseases in which a pyrimidine nucleoside compound, such as AZT, and a uridine phosphorylase inhibitor are co-administered either simultaneously or sequentially to treat the viral infection and protect or rescue uninfected cells in the afflicted subject.
• a pyrimidine nucleoside compound such as AZT
• a uridine phosphorylase inhibitor are co-administered either simultaneously or sequentially to treat the viral infection and protect or rescue uninfected cells in the afflicted subject.
• R- is H, Cj.g straight or branched-chain alkyl, C2-6 alkenyl, or (C 3 al yl- C3-6 cycloalkyl-C ⁇ _3 alkyl) optionally substituted by 1 or 2 substituents selected from -OR 8 or -NR 8 R9(wherein R 8 and R ⁇ are the same or different and are selected from H, C ⁇ _6 straight or branched-chain alkyl, and aralkyl); or a -CH2ZR 10 , -ZCH2R 10 , or CH2ZRlO a ZRlO group(wherein R ⁇ a i s selected from C ⁇ .
• R ⁇ is selected from Cj_6 straight or branched chain alkylene and R ⁇ is selected from Cj_6 straight or branched chain alkyl) each of RlOa and RIO being optionally substituted by 1 or 2 substituents independently selected from -OR-* and -NR R9(wherein R 8 and R-- are as defined above) and Z is selected from O, S, -CH2O-, or -CH2S-); R 2 is selected from O or S; R 3 is selected from O, S, -SO, -SO2.
• Preferred compounds of formula (I) are those of formula (IA) and esters and prodrugs thereof
• R- -TM is a C2.3 straight or branched chain alkyl group substituted by one or two hydroxyl groups
• R a is H or -OR --- wherein R ⁇ a is a C3.5 straight or branched chain alkyl group optionally substituted by fluoro
• R ⁇ - ⁇ - is H or -O-Ar-R 7a wherein Ar is phenyl and R 7a is fluoro, chloro or cyano; provided that one but not both of R 4a and R 6a is H.
• amino acid esters of the compounds of the present invention can be in the D, L, or DL configuration with the L configuration preferred.
• the compounds of formula (I) or (IA), or prodrugs thereof may be in the form of their pharmaceutically acceptable addition salts, which are preferably non-toxic base salts and include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, salts with organic bases such as dicyclohexylamine and N-methyl-D-glutamine, and salts with amino acids such as arginine and lysine.
• pharmaceutically acceptable addition salts are preferably non-toxic base salts and include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, salts with organic bases such as dicyclohexylamine and N-methyl-D-glutamine, and salts with amino acids such as arginine and lysine.
• the compounds of the present invention are in the non-salt form.
• R 9a is selected from C ⁇ . ⁇ straight or branched-chain alkyl, and aralkyl)may also act as prodrugs, -COR 8 , -CSR 8 , -COCR 8 R 8 NR 8 R 8 , -CSCR 8 R 8 NR 8 R 8 , -CR 8 R 8 OCOR 8 , - SO2OR 8 , -PO(OR 8 )2 or -PS(OR 8 )2(wherein R 8 is as defined hereinbefore).
• Particularly preferred compounds of formula I in accordance with the invention are: l-((2-hydroxyethoxy)methyl)-5-(3-propoxybenzyl)uracil, l-((2-hydroxyethoxy)methyl)-5-(3-sec-butoxybenzyl)uracil,
• the most preferred compounds of formula I in accordance with the invention are- l-((2-hydroxy-l-(hydroxymethyl)ethoxy)methyl)-5-(3-phenoxybenzyl)uracil, l-((2-hydroxy-l-(hydroxymethyl)ethoxy)methyl)-5-(3-(3-fluorophenoxy)benzyl)uracil,
• the compounds of the present invention are useful for the inhibition of the enzyme uridine phosphorylase in mammals(e.g., humans) in need of such enzyme inhibition which comprises administering to a mammal in need thereof an effective amount of a compound of the invention or a pharmaceutical composition comprising a said compound in combination with one or more pharmaceutically acceptable carriers.
• the present invention is thus based on the use of compounds of formula I in combination with pyrimidine nucleosides such as zidovudine and reducing the cellular toxicity of the pyrimidine nucleoside, such as the stem cell and haematological toxicity.
• a uridine phosphorylase inhibitor of formula (I) or a prodrug thereof, for use in medicine especially in combination with pyrimidine nucleosides such as zidovudine for the reduction of pyrimidine nucleoside(e.g.,zidovudine) induced toxicity in mammals(e.g., humans).
• a treatment for AIDS-type diseases in which a pyrimidine nucleoside analogue, such as zidovudine, and a uridine phosphorylase inhibitor of the invention are co-administered either simultaneously or sequentially to protect or rescue uninfected cells from the toxic effects of the pyrimidine nucleoside in a mammal(e.g., a human) requiring such treatment.
• a pyrimidine nucleoside analogue such as zidovudine
• a uridine phosphorylase inhibitor of the invention are co-administered either simultaneously or sequentially to protect or rescue uninfected cells from the toxic effects of the pyrimidine nucleoside in a mammal(e.g., a human) requiring such treatment.
• AIDS-type diseases are defined herein as Acquired Immune Deficiency Disease(AIDS), AIDS-related complex(ARC), asymptomatic HIV infections, as well as any disease which causes a deficiency in the immune system.
• Pyrimidine nucleoside analogues which are useful according to the present invention include, for example, 3 , -azido-3'-deoxythymidine(AZT); 3'-azido-2',3'- dideoxyuridine( AZddU) ;
• the compounds of the present invention are not restricted to use for the reduction of zidovudine toxicity. Accordingly, the compounds of the present invention can be utilized to inhibit the enzyme uridine phosphorylase in a mammal(e.g., a human) when such enzyme inhibition is desired. Therefore, other uses of the compounds of the invention which rely on the inhibition of uridine phosphorylase are also encompassed by the present invention.
• Such uses include: enhancing the antitumor activity of halogenated pyrimidines(e.g., 5-fluoro-2'-deoxyuridine, 5-fluorouridine and 5- fluorouracil) and antineoplastic pyrimidine nucleosides(e.g., 5-fluoro-2'- deoxyuridine(FdUrd), 5-trifluoromethyldeoxyuridine(TFT), and 5- bromovinyldeoxyuridine(BVdU)) which are subject to degradation by uridine phosphorylase.
• the uridine phosphorylase inhibitors of the present invention are useful for reducing the toxicity of antineoplastic pyrimidine nucleosides as well as for potentiating the efficacy of antineoplastic drugs.
• the compounds of the invention can be administered to a mammal either prior to, during or subsequent to administration of the antineoplastic agent.
• antineoplastic agent are preferably administered prior to administration of the antineoplastic agent to inhibit the uridine phosphorylase enzyme and thereby prevent the degradation of the antineoplastic agent.
• the compounds of the present invention can also be used in the treatment of nervous disorders(e.g., schizophrenia and Parkinson's disease) and in the treatment of diseases in which increased levels of uridine are beneficial.
• nervous disorders e.g., schizophrenia and Parkinson's disease
• diseases in which increased levels of uridine are beneficial e.g., schizophrenia and Parkinson's disease
• the present invention provides a uracil derivative as hereinbefore defined for use in the manufacture of a medicament for use in reducing zidovudine induced toxicity or potentiating the antitumor effects of antineoplastic pyrimidine nucleosides, or in the treatment of nervous disorders and diseases in which increased levels of uridine are beneficial.
• the present invention further provides :
• a method for the treatment or prophylaxis of an HIV infection in a mammal including a human, which comprises administering to the said mammal an effective anti-HTV amount of zidovudine or a pharmaceutically acceptable salt or ester thereof in combination with an effective uridine phosphorylase inhibiting amount of a compound of figure I as defined hereinbefore.
• a method for the treatment or prophylaxis of tumors in a mammal including a human, which comprises administering to the said mammal an effective anti ⁇ tumor amount of 5-fluorouracil in combination with an effective uridine phosphorylase inhibiting amount of a compound of figure I as defined hereinbefore.
• Zidovudine(or a pharmaceutically acceptable salt or ester thereof) or an antineoplastic pyrimidine nucleoside, and the said uridine phosphorylase inhibitor may be employed in combination in accordance with the invention by administration of the components of the combination to an appropriate subject either concomitantly, for example in a unitary pharmaceutical formulation, or, more preferably, separately, or sequentially within a sufficient time period whereby the desired therapeutic effect of the combination is achieved.
• Zidovudine may be administered per se or in the form of a pharmaceutically acceptable salt, e.g., an alkali metal salt such as sodium or potassium, an alkaline earth salt or ammonium salt.
• a pharmaceutically acceptable salt e.g., an alkali metal salt such as sodium or potassium, an alkaline earth salt or ammonium salt.
• the mono-, di- or triphosphates of zidovudine or their pharmaceutically acceptable base salts(i.e., alkali metal, alkaline earth or ammonium salt) can also be substituted for zidovudine in the combination described by this invention.
• Zidovudine or a pharmaceutically acceptable salt or ester thereof and the uridine phosphorylase inhibitor of formula I may be administered respectively for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and other clinical factors.
• a suitable dose of zidovudine or a pharmaceutically acceptable salt or ester thereof is in the range of 5 to 250 mg per kilogram body weight of the recipient per day, preferably in the range of 5 to 40 mg per kilogram body weight per day and most preferably in the range of 5 to 10 mg per kilogram body weight per day in combination with each of the aforementioned uridine phosphorylase inhibitors of formula I.
• the desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throught 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.
• a dose should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 uM(the abbreviation uM is used herein as micromolar), preferably about 2 to 50 uM, most preferably about 3 to about 30 uM.
• 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(the abbreviation "mg/kg” is well understood by one of ordinary skill in the art).
• 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 antineoplastic pyrimidine nucleosides of the present invention are those which are known in the art and are administered according to procedures known by one skilled in the art of treating antineoplastic disease.
• Particularly preferred antineoplastic pyrimidine nucleosides used in accordance with the present invention include but are not limited to: 5-fluoro-2'-deoxyuridine, 5-fluorouridine, 5-fluorouracil, 5-fluoro-2'- deoxyuridine(FdUrd), 5-trifluoromethyldeoxyuridine(TFT), and 5- bromovinyldeoxyuridine(BVdU)).
• the antineoplastic pyrimidine nucleosides of the present invention are readily available to the skilled practicioner in the art.
• the uridine phosphorylase inhibitor of formula I may be administered in a dosage in the range of 1 to 300 mg per kilogram body weight of the recipient per day, preferably in the range of 3 to 100 mg per kilogram body weight per day, most preferably in the range of 5 to 30 mg per kilogram body weight per day in combination with zidovudine or the antiviral pyrimidine nucleoside analogs or antineoplastic pyrimidine nucleosides described hereinbefore. Unless otherwise indicated, all weights of active ingredients are calculated as the parent free base compound of formula I; for salts thereof the figures would be increased proportionally.
• the desired dose is preferably presented as one, two 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 200 mg, preferably 10 to 200 mg, most preferably 10 to 100 mg of a compound of formula I.
• Zidovudine and the uridine phosphorylase inhibitor are employed in an appropriate ratio whereby the above-mentioned toxic effects of zidovudine are reduced or obviated without significant reduction of the therapeutic effect of zidovudine or the antiviral pyrimidine nucleosides.
• antiviral pyrimidine nucleosides hereinbefore described are used in combination with the uridine phosphorylase inhibitor to reduce the toxic effects of the antiviral pyrimidine nucleosides without significant reduction of the therapeutic effect of the antiviral pyrimidine nucleosides.
• antineoplastic pyrimidine nucleosides described hereinbefore and the uridine phosphorylase inhibitor are employed in an appropriate ratio whereby the above-mentioned antitumor effects of the antineoplastic pyrimidine nucleoside are enhanced or increased.
• Zidovudine and the uridine phosphorylase inhibitor are preferably administered in a pharmaceutical formulation, either in a single pharmaceutical formulation containing both components or in separate pharmaceutical formulation, each containing one of the components of the combinations.
• the present invention thus includes as a further feature a pharmaceutical formulation comprising a uridine phosphorylase inhibitor of formula I optionally in combination with zidovudine together with at least one pharmaceutically acceptable carrier or excipient.
• Each carrier must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• Formulations include those adapted for oral, rectal, nasal, topical (including buccal and sublingual), vaginal and 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 adapted 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 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.
• 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, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) 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 controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
• Formulations 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.
• compositions for transdermal administration may be delivered by passive diffusion or by electrically-assisted transport, for example, iontophoresis (see, for example, Pharmaceutical Research 3(6), 318, (1986)) and may take the form of an optionally buffered aqueous solution of a compound of formula I.
• Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
• Formulation 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 for parenteral administration include aqueous and non-aqueous isotonic sterile injection 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.
• the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules 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.
• 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.
• Zidovudine is 3'-azido-3'-deoxythymidine(AZT) and is commercially available under the tradename RETRO VIR® from Burroughs Wellcome Co., Research Triangle Park, North Carolina, USA. It is an antiviral compound active against human immunodeficiency virus(HTV) and is approved for the treatment of HTV infection in both children and adults.
• the preparation of zidovudine has been disclosed(Horowitz J.P. et al., J. Org. Chem. 29: 2076(1964) and Glinski R.P. et al., ibid. 38: 4299(1973)) and its synthesis and use in the treatment of AIDS and AIDS-related complex has been disclosed in U.S. Patent No. 4,724,232(1988) which is incorporated in its entirety herein by reference.
• Zidovudine is well known in the art.
• Compounds of formula (I) may be prepared by hydrolysis of the corresponding compound of formula (II)
• R 2 to R-- are as hereinbefore defined and Q is NH2, OR* 3 or SR ⁇ 3 wherein R-* 3 is C j_6 straight or branched chain alkyl group to give a compound of formula (I) where R 1 is H, and thereafter optionally converted to a compound of formula (I) wherein R- is other than H.
• the compound of formula (II) may exist in tautomeric form.
• the hydrolysis of a compound of formula (II) may suitably be carried out with inorganic or organic acids (for example glacial acetic acid/aqueous chloroacetic acid, 20% hydrochloric acid/aqueous sodium nitrite or sulphuric acid), with an aqueous alkali (for example 20% sodium hydroxide), or when Q is SH and the compound is in the tautomeric form, with an organic peroxide and an organic alcohol (for example hydrogen peroxide/tert-butanol), and at a temperature of 0-250°C and preferably 20-150°C (for example the reflux temperature).
• inorganic or organic acids for example glacial acetic acid/aqueous chloroacetic acid, 20% hydrochloric acid/aqueous sodium nitrite or sulphuric acid
• an aqueous alkali for example 20% sodium hydroxide
• Q is SH and the compound is in the tautomeric form
• an organic peroxide and an organic alcohol for example hydrogen peroxide/
• the conversion to a compound of formula (I) wherein R- is other than H may be carried out by the reaction of a compound of formula (I) where R- is H with a silylating agent, for example, trimethylsilyl chloride, bis(trimethylsilyl)acetamide or hexamethyldisilazane either neat or in a suitable inert solvent, for example, 1,2- dichloroethane or dichloromethane at a temperature of between 0-150° C (preferably the reflux temperature) and then further reacting the intermediate generated with XR- (wherein X is a leaving group, for example, halogen(preferably chloro or bromo) or acyloxy, and R- is as defined hereinbefore other than H) at a temperature of between 0-150° C (preferably at ambient temperature).
• a glycosidic bond forming catalyst e.g., trifluoromethane sulfonic acid, 4-toluenesulfonic acid, stannic chloride or trie
• the conversion can be effected by reacting an excess of the compound of formula (I) where R- is H with XR* (wherein X is a leaving group, for example, halogen(preferably chloro or bromo) or acyloxy, and R- is as defined hereinbefore other than H) in an inert organic solvent(e.g., DMF, DMSO) in the presence of a base(e.g., K2CO3, NaHCO3 or NaH) at a temperature of between 0-150° C.
• XR* wherein X is a leaving group, for example, halogen(preferably chloro or bromo) or acyloxy, and R- is as defined hereinbefore other than H
• an inert organic solvent e.g., DMF, DMSO
• a base e.g., K2CO3, NaHCO3 or NaH
• R 2 , R 3 , R 4 , R , and R ⁇ are as hereinbefore defined
• B is that portion of R- other than -OH or -NH2
• Y is O or NH
• R ⁇ 2 is Cl-6 straight or branched-chain alkyl, C H ⁇ or substituted aryl, with ammonia gas or an organic amine(for example, methylamine, dimethylamine).
• the reaction will generally be carried out with stirring in an organic solvent such as an organic alcohol, e.g., methanol or ethanol, at a temperature between 0-150° C, preferably ambient temperature; or by treatment with a metal alkoxide(e.g., sodium ethoxide) in water or alcohol; or by treatment with an inorganic base(e.g., a metal hydroxide such as NaOH or KOH) in H2O or alkanol solvent(e.g., methanol); or by treatment with alcohol(e.g., ethanol) in the presence of potassium carbonate; or by hydrolysis with aqueous acid(e.g., IN hydrochloric acid) optionally with an organic cosolvent such as tetrahydrofuran.
• an organic solvent such as an organic alcohol, e.g., methanol or ethanol
• the reaction temperature may conveniently be between 0-150° C. and preferably at ambient temperature.
• the target hydroxy compounds may be formed from the intermediate O- benzyl ethers by treatment with hydrogen in an organic alcohol solvent(e.g., ethanol) in the presence of a catalyst(e.g., palladium).
• the target hydroxy compounds may be formed from the O-trimethylsilyl ether intermediate by hydrolysis with neat or aqueous organic alcohol(e.g., ethanol) under acidic or neutral conditions.
• neat or aqueous organic alcohol(e.g., ethanol) under acidic or neutral conditions.
• Compounds of formula III can be prepared by reacting a compound of formula (I) where R- is H with XBYCOR 12 (wherein X, B, Y and R 12 are as previously defined) by the methods described herein for the preparation of compounds of formula I by replacing XR 1 with XBYCOR 12 .
• esters depicted in formula III are prodrugs as defined hereinbefore and thereby constitute a further aspect of this invention.
• the compounds of formula III are also hydrolysed by any of the standard methods of hydrolysis of carboxylic acid esters such as those described in, e.g., J. March, Advanced Organic Chemistry, 2nd edit., 349-353, McGraw-Hill, N.Y., 1977.
• R 4 , R-- and R ⁇ are as defined hereinbefore and R-* 4 is C ⁇ .
• a suitable inert solvent such as tetrahydrofuran with a non-nucleophilic base(e.g., lithium diisopropylamide, sodium, sodium hydride or potassium tert-butoxide) at a temperature of -100-25° C. (preferably -78° C).
• a non-nucleophilic base e.g., lithium diisopropylamide, sodium, sodium hydride or potassium tert-butoxide
• the resulting anionic intermediate is then reacted with an alkyl formate(preferably ethyl formate) at a temperature of -78-25° C(preferably -30° C).
• the resulting anionic salt of the alpha-formyl ester is then reacted with a urea derivative, such as thiourea, guanidine, O-alkylisourea or S-alkylisothiourea at a temperature of -78-25° C.
• a urea derivative such as thiourea, guanidine, O-alkylisourea or S-alkylisothiourea
• the intermediate anionic salts may be O-alkylated using an alkylating agent(e.g., methyl iodide or dimethyl sulfate) to generate an enol ether which is reacted with thiourea, guanidine, O-alkylisourea or S-alkylisothiourea.
• an alkylating agent e.g., methyl iodide or dimethyl sulfate
• This compound was prepared in an analogous manner to that of Example IG with the replacement of 0.30 g of l-((2-acetoxyethoxy)methyl)-5- (3-propoxybenzyl) uracil with 0.73 g of 2-((l,2,3,4-tetrahydro-2,4-dioxo-5-(3-propoxybenzyl)-l-pyrimidinyl) methoxy)-l,3-propanediyl diacetate.
• Bis(trimethylsilyl)acetamide (8.24 ml, 32.5 mmoles) was added to a stirred suspension of 5-(3-phenoxybenzyl)uracil (5.435 g, 18.5 mmoles) in 1,2-dichloroethane (95 ml) under nitrogen. The mixture was refluxed with stirring for 3 hours, the heat removed and the solution that formed cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (3.15 g, 16.0 mmoles) in acetonitrile (15 ml) was added to the cooled solution, the resulting solution allowed to warm to ambient temperature and stirred under nitrogen for 18 hours.
• This compound was prepared in an analogous manner to that of Example 3F with 9.10 g of 2-(bromomethoxy)-l,3-propanediyl dibenzoate (see below for preparation).
• the chromatography fractions were spin evaporated in vacuo to give 10.09 g of 2-((l,2,3,4-tetrahydro-2,4-dioxo-5-(3-phenoxybenzyl)-l- pyrimidinyl)methoxy)-l,3-propanediyl dibenzoate as a white solid, which was used without further purification.
• 2-(Bromomethoxy -l .3-propanediyl dibenzoate A mixture of 15 g (0.04 mol) of 2-(acetoxymethoxy)-l,3-propanediyl dibenzoate, 70 mL of dry dichloromethane, and 17 mL of bromotrimethylsilane was gently refluxed for 18 h. The solution was evaporated in vacuo to give the target compound, 2-(Bromomethoxy)-l,3-propanediyl dibenzoate, as a light amber oil in quantitative yield.
• This compound was prepared in an analogous manner to that of Example 3G with the replacement of 8.40 g of l-((2-acetoxyethoxy)methyl)-5- (3-phenoxybenzyl)uracil and 300 mL of methanol saturated with ammonia gas in Example 3G with 9.25 g of 2-((l,2,3,4-tetrahydro-2,4-dioxo-5-(3-phenoxy- benzyl)-l-pyrimidinyl)methoxy) -1, 3-propanediyl dibenzoate and 200 mL of 40% aqueous methyl amine, respectively. The mixture was sealed in a bomb and heated at 80°C for 5 days. Since the reaction was incomplete, the solvent was removed in vacuo.
• Bis(trimethylsilyl)acetamide (2.05 ml, 8.4 mmoles) was added to a stirred suspension of 5-(3-(3-fluoropropoxy)benzyl)uracil (1.30 g, 4.7 mmoles) in dichloroethane (45 ml) under nitrogen. The mixture was refluxed with stirring for 35 minutes, the heat removed, and the solution which formed cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (0.81 g, 4.1 mmoles) in acetonitrile (5 ml) was added to the cooled solution and the resulting solution allowed to warm to ambient temperature and stirred under nitrogen for 18 hours.
• Bis(trimethylsilyl)acetamide (1.4 ml, 5.6 mmoles) was added to a stirred suspension of 5-(3-sec-butoxybenzyl)uracil (0.875 g, 3.2 mmoles) in dichloroethane (35 ml) under nitrogen. The mixture was refluxed with stirring for 35 minutes, the heat removed, and the solution which formed cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (0.55 g, 2.8 mmoles) in acetonitrile (5 ml) was added to the cooled solution and the resulting solution allowed to warm to ambient temperature and stirred under nitrogen for 18 hours.
• Bis(trimethylsilyl)acetamide (1.30 mL, 5.3 mmoles) was added to a stirred suspension of 5-(3-(3-fluorophenoxy)benzyl)uracil (0.937 g, 3.0 mmoles) in dichloroethane (35 mL) under nitrogen. The mixture was refluxed with stirring for 35 minutes, and the resultant solution cooled in an ice bath. A solution of 2-(bromomethoxy)-l,3-propanediyl dibenzoate (0.76 g, 2.0 mmoles) in acetonitrile (4 mL) was added to the cooled solution, and the resultant solution was allowed to warm to ambient temperature and stirred under nitrogen for 18 hours.
• Bis(trimethylsilyl)acetamide (1.30 mL, 5.3 mmoles) was added to a stirred suspension of 5-(3-(4-fluorophenoxy)benzyl)uracil (0.937 g, 3.0 mmoles) in dichloroethane (35 mL) under nitrogen. The mixture was refluxed with stirring for 45 minutes, and the resultant solution cooled in an ice bath. A solution of 2-(bromomethoxy)-l,3-propanediyl dibenzoate (0.76 g, 2.0 mmoles) in acetonitrile (4 mL) was added to the cooled solution, and the resultant solution was allowed to warm to ambient temperature and stirred under nitrogen for 18 hours.
• This compound was prepared from 2-fluorophenol (Aldrich) in an analogous manner to that of Examples 7A to 7C with the replacement of ethyl 3-(3-(3-fluorophenoxy)phenyl)acrylate with ethyl 3-(3-(2-fluorophenoxy) phenyl) acrylate (3.20g, 11.2mmol).
• the filtrate was concentrated in vacuo and chromatographed on Silica Gel 60 using 5% EtOAc/hexanes. The fractions containing only ethyl 3-(3-(2-fluorophenoxy) phenyl)propionate were combined and concentrated to give 1.16g (36%) of a clear, colorless oil.
• This compound was prepared in an analogous manner to that of Example 7A and 7B with the replacement of 3-fluorophenol with 3-chlorophenol (Aldrich) (lO.Og, 77.8mmd).
• the chromatography fractions that contained only ethyl 3-(3-(3-chlorophenoxy)phenyl)acrylate were combined and concentrated in vacuo to give 14.40g (79%) of a clear, colorless oil.
• 3-Cyanophenol (Aldrich) (19.06 g, 160 mmoles) was added to a solution of sodium (3.90 g, 170 mmoles) in methanol (140 ml). The solution was stirred for 18 hours at ambient temperature, and the methanol was removed in vacuo . The phenoxide was dissolved in N-methyl-2-pyrrolidinone (Aldrich) (100 ml) and heated in a 175°C oil bath. l-Bromo-3-fluorobenzene (Aldrich) (28.0 g, 160 mmoles) was added, and the solution was stirred for 3 days at 170-180°C.
• This compound was prepared in an analogous manner to that of Example 12F with the replacement of 0.95 g of (2-acetoxyethoxy)methyl bromide in Example 19F with 1.89 g of 2-(bromomethoxy)-l,3-propanediyl dibenzoate.
• the chromatography fractions were spin evaporated in vacuo to give 2.42 g of a clear oil.
• This compound was prepared in an analogous manner to that of Example 12G with the replacement of 1.60 g of l-((2-acetoxyethoxy)methyl)-5-(3-(3- chlorophenoxy)benzyl)uracil in Example 19G with 1.82 g of 2-((l,2,3,4- tetrahydro-2,4-dioxo-5-(3-(3-chlorophenoxy)benzyl)-l-pyrimidinyl)methoxy)- 1,3 -propanediyl dibenzoate.
• the methanol was removed m vacuo. and the residue was dissolved in ethyl acetate (100 ml) and extracted with 0.3 N NaOH (5 x 50 ml).
• aqueous extracts were cooled in an ice bath, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (3 x 100 ml). The organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo.
• Enzvme inhibition studies Assays were conducted in 20 mM potassium phosphate buffer, pH 8, 1 mM EDTA, 1 mM dithiothreitol containing 170 mM [2-l 4 C] uridine (7 mCi/mmole), various amounts of inhibitor or buffer and 20 mL of enzyme in a final volume of 60 mL. The reaction was carried out for 30 minutes 37°C then terminated by boiling for 1 minute. Precipated proteins were removed by centrifugation, and 5mL of the supernatant were spotted on silica gel thin layer chromatography sheets (with fluorescence indicator) that were prespotted with 5 mL of a mixture of 10 mM each uracil and uridine.
• the plates were developed in chloroform:methanol:acetic acid (90:5:5), and uridine and uracil were detected by UV quenching.
• the pyrimidines areas were cut out and counted by liquid scintillation in 5ml of Ready Safe (Beckman).
• the cpm (velocity) of the inhibitor containing samples were compared to those of the control, and percent inhibition values were calculated. Plots of percentage of inhibition versus the logarithm of inhibitor concentration were used to calculate the IC50 values (the concentration of inhibitor needed to give a 50%) reduction of the enzyme reaction rate) shown below.
• formulations 29 A 29B and 29C are prepared by wet granulation of the ingredients (except the magnesium stearate) with a solution of the povidone followed by drying of the granules, addition of the magnesium stearate and compression.
• formulation 29D is prepared by direct compression of the admixed ingredients.
• the lactose used is of the direct compression type.
• the following formulation 29E is a controlled release tablet and is prepared by wet granulation of the ingredients (except magnesium stearate) with a solution of the povidone, followed by drying of the granules, addition of the magnesium stearate and compression.
• Active ingredient 100 Hydroxypropylmethylcellulose 100 (Methocel K4M Premium)
• formulations 30A and 30B are prepared by admixing the uncompressed ingredients and filling into a two-part hard gelatin capsule.
• the Macrogol 4000, B.P. is melted and the active ingredient dispersed therein.
• the thoroughly mixed melt is then filled into a two-part hard gelatin capsule.
• Active ingredient lOOmg Sterile, pyrogen free phosphate buffer (pH 7.0), q.s. to 10ml
• the active ingredient is dissolved in most of the phosphate buffer (35-40°C), then made up to volume and filtered through a sterile micropore filter into a 10 ml amber glass vial (type 1) and sealed with a sterile closure and oversea!.
• Exam le 32 is dissolved in most of the phosphate buffer (35-40°C), then made up to volume and filtered through a sterile micropore filter into a 10 ml amber glass vial (type 1) and sealed with a sterile closure and oversea!.
• the active ingredient is used as a powder wherein at least 90% of the particles are of 63 m or less.
• the symbol "m” as used herein means micron.
• Witepsol HI 5 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 a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol HI 5 is added to the suspension and stirred to ensure a homogeneous mix.
• the entire suspension is passed through a 250 m stainless steel screen and, with continuous stirring, is allowed to cool to about 40°C. At a temperature of 38°C to 40°C, 1.80 g of the mixture is filled into suitable plastic moulds. The suppositories are allowed to cool to room temperature.

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• 1992
  • 1992-07-10 GB GB929214720A patent/GB9214720D0/en active Pending
• 1993
  • 1993-07-09 MX MX9304152A patent/MX9304152A/es unknown
  • 1993-07-09 AU AU45116/93A patent/AU4511693A/en not_active Abandoned
  • 1993-07-09 CA CA002139836A patent/CA2139836A1/en not_active Abandoned
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  • 1993-07-09 WO PCT/GB1993/001443 patent/WO1994001414A1/en not_active Application Discontinuation
  • 1993-07-09 ZA ZA934970A patent/ZA934970B/xx unknown
  • 1993-07-09 JP JP6503128A patent/JPH07508983A/ja active Pending
  • 1993-07-09 EP EP93914912A patent/EP0649413A1/en not_active Withdrawn

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