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WO1992005176A1 - Xanthines - Google Patents

Xanthines Download PDF

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Publication number
WO1992005176A1
WO1992005176A1 PCT/GB1991/001634 GB9101634W WO9205176A1 WO 1992005176 A1 WO1992005176 A1 WO 1992005176A1 GB 9101634 W GB9101634 W GB 9101634W WO 9205176 A1 WO9205176 A1 WO 9205176A1
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Prior art keywords
formula
substituted
compound
pharmaceutically acceptable
group
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PCT/GB1991/001634
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English (en)
Inventor
Derek Richard Buckle
David Glynn Smith
Ashley Edward Fenwick
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Beecham Group PLC
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Beecham Group PLC
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Priority to KR1019930700918A priority Critical patent/KR930702350A/ko
Priority to JP3517400A priority patent/JPH06501691A/ja
Priority to AU86458/91A priority patent/AU650679B2/en
Publication of WO1992005176A1 publication Critical patent/WO1992005176A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to certain novel compounds having pharmacological activity, to a process for the preparation of such
  • European Patent Application, Publication Number 0369744 also discloses certain 1,3- or 1,3,7- 8-H cycloalkylalkylene xanthines, for use inter alia as bronchodilators in the treatment of asthma.
  • European Patent Application, Publication Number 0389282 also discloses certain 1,3-cycloalkylalkylene 8-substituted xanthines for use inter alia in the treatment or prophylaxis of disorders associated with increased numbers of eosinophils.
  • These compounds are indicated to have bronchodilator activity and thus to be of potential use in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and asthma.
  • the said compounds have a protective effect against the consequences of cerebral metabolic inhibition.
  • the said compounds improve data acquisition or retrieval following transient forebrain ischaemia and are therefore useful in the treatment of cerebral vascular and neuronal degenerative disorders associated with learning, memory and cognitive dysfunctions including cerebral senility, multi-infarct dementia, senile dementia of the Alzheimer type, age associated memory impairment and certain disorders associated with Parkinson's disease.
  • These compounds are also indicated to have neuroprotectant activity. They are therefore useful in the prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events, including cerebral ischaemia due to cardiac arrest, stroke and also after cerebral ischaemic events such as those resulting from surgery and/or during childbirth.
  • treatment with the compound is indicated to be of benefit for the treatment of functional disorders resulting from disturbed brain function following ischaemia.
  • tumour necrosis factor TNF
  • HAV human immunodeficiency virus
  • AIDS acute immune deficiency syndrome
  • rheumatoid arthritis rheumatoid
  • spondylitis spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions
  • sepsis septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, pulmonary inflammatory disease, bone resorption diseases, reperfusion injury, graft vs. host reaction over and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to AIDS, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.
  • R 3 represents substituted or unsubstituted aryl or a substituted alkyl group
  • R 4 represents hydrogen or a group -CO.R 5 wherein R 5 represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl; or R3 together with R 5 represents a substituted or unsubstituted C 2-3 polymethylene chain; and
  • a 1 represents hydrogen or substituted or unsubstituted alkyl.
  • A is unsubstituted.
  • A represents a substituted or unsubstituted C 3-8 cycloalkyl group, especially a C 3-6 cycloalkyl group.
  • A represents a substituted or, preferably, unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
  • A represents a cyclopropyl group or a cyclobutyl group.
  • A represents a cyclopropyl group.
  • R 3 represent a substituted alkyl group. In particular an alkyl group substituted by a carboxy group.
  • R 3 represents a terminally substituted alkyl group, especidly a terminally substituted ethyl or propyl group.
  • a preferred example of R 3 is the substituted alkyl group 2-carboxyethyl.
  • R 3 is the substituted aryl group, o-carboxyphenyl.
  • R 4 represents hydrogen.
  • R 4 represents -CO.R 5 wherein R 5 represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl; or R 3 together with R 5 represents a substituted or unsubstituted C 2-3 polymethylene chain.
  • Suitable optional substituents for the C 2-3 polymethylene chain include up to five, preferably up to three, of the substituents mentioned below in relation to the aryl group and, especially for the C 2 polymethylene chain, substituents of adjacent carbon atoms of the C 2-3 polymethylene chain form a residue of a substituted or unsubstituted phenylene group.
  • R 3 together with R 5 represent a substituted or unsubstituted polymethylene chain it is suitably a substituted or unsubstituted C 2 - polymethylene chain for example -CH 2 CH 2 - or a substituted or
  • a 1 represents a substituted alkyl group it may be substituted as mentioned hereinafter in relation to alkyl groups.
  • Suitable substituted alkyl groups include aralkyl groups wherein the aryl group may be substituted or unsubstituted.
  • a suitable substituted aralkyl group represented by A 1 is a substituted benzyl group, suitably a methoxybenzyl group, for example a 4- methoxybenzyl group.
  • a 1 represents hydrogen.
  • n represents zero or the integer 1.
  • n 1
  • Suitable pharmaceutically acceptable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts.
  • Suitable pharmaceutically acceptable base salts of the compounds of formula (I) include 7-N base salts including metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine.
  • Suitable acid addition salts of the compounds of formula (I) are the acid addition salts including pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and
  • hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, ⁇ -keto glutarate, ⁇ -glycerophosphate and glucose-1- phosphate.
  • the acid addition salt is a hydrochloride salt.
  • solvates include conventional solvates such as hydrates.
  • 'cyclic hydrocarbon radical' includes single ring and fused ring, alicyclic hydrocarbons comprising up to 8 carbon atoms in each ring, suitably up to 6 caroon atoms, for example 3, 4, 5 or 6 carbon atoms.
  • Suitable optional substituents for any cyclic hydrocarbon radical includes a C 1-6 alkyl group or a halogen atom.
  • the term 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, halo alkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl,alkylcarbonyloxy, or alkylcarbonyl groups.
  • Optional substituents for any phenylene group include up to three of the substituents mentioned in relation to the aryl group.
  • alkyl' when used herein the term 'alkyl' whether used alone or when used as part of another group (for example as in an alkylcarbonyl group) includes straight and branched chain alkyl groups, containing from 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, for example methyl, ethyl, propyl or butyl. Suitable optional substituents for any alkyl group include up to five, preferably up to three of the substituents mentioned above in relation to the aryl group.
  • proliferative skin diseases means benign and malignant proliferative skin diseases which are characterized by accelerated cell division in the epidermis, dermis or appendages thereto, associated with incomplete tissue differentiation.
  • diseases include: psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in domesticated animals.
  • the compounds of formula (I) are preferably in pharmaceutically acceptable form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • the invention further provides a process for the preparation of a compound of formula (I) or where appropriate a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, which process comprises: a) for compounds of formula (I) wherein R 3 is substituted or unsubstituted aryl or substituted alkyl and R 4 is hydrogen or -CO.R 5 wherein R 5 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl, by reacting a compound of formula (II):
  • R 1a represents R 1 , as defined in relation to formula (I), or a group convertible to R 1 and R 2a represents R 2 , as defined in relation to formula (I), or a group convertible thereto
  • a 2 represents A 1 as defined in relation to formula (I) or a group convertible thereto
  • R 6 represents hydrogen, a group -CO.R 5a , wherein R 5a represents unsubstituted alkyl, or a group -COR 5b , wherein R 5b is substituted alkyl or substituted or unsubstituted aryl, with a compound of formula (III):
  • R 1a , R 2a and A 2 are as defined in relation to formula (II), Z represents the substituted or unsubstituted C 2-3 polymethylene chain as defined in relation to formula (I) or a protected form thereof, and L 2 represents a leaving group; and thereafter, if required carrying out one or more of the following optional steps:
  • a suitable leaving group L 1 is a halo atom for example a bromine or chlorine atom.
  • L 2 represents a halo atom, for example a bromine or chlorine atom, or a hydroxyl group.
  • L 2 represents a hydroxyl group.
  • a compound of formula (II) wherein R 6 represents -CO.R 5a wherein R 5a is unsubstituted alkyl may be prepared by reacting a compound of formula (II) wherein R 6 is hydrogen with an appropriate compound of
  • reaction between compounds of formulae (II) and ( III) may be carried out using conventional acylation conditions, for example in an aprotic solvent, such as dimethylformamide or tetrahydrofuran, at any
  • the 8-amino group of compound (II) is suitably in an activated form, favorably in an anionic form such as a salted form, for example an alkali metal salted form.
  • the reaction between compounds of formulae (II) and (III) is carried out in an aprotic solvent, such as tetrahydrofuran, at a temperature in the range of 0°C to 100°C, in the presence of a base such as triethylamine.
  • the cyclisation of compound (IV) may be carried out under analogous conditions as appropriate to the reaction between compounds (II) and (III), a favoured aprotic solvent being tetrahydrofuran.
  • a compound of formula (II) wherein R 6 is hydrogen may be prepared by reducing a compound of formula (V):
  • R 1a , R 2a and A 2 are as defined in relation to formula (II); and thereafter if required converting R 1a into R 1 and/or R 2a into R 2 and/or A 2 into A 1 .
  • the reduction of compound (V) may be carried out by using any suitable, conventional reduction method, for example using tin powder and
  • a compound of formula (V) may be prepared by nitrating a compound of the above defined formula (VI):
  • R 1a , R 2a and A 2 are as defined in relation to formula (II), and thereafter, if required, converting R 1a into R 1 and/or R 2a into R 2 and/or A 2 into A 1 .
  • the nitration of compound (VI) may be carried out using any suitable, conventional nitrating agent, for example a nitric acid/acetic acid mixture in an inert solvent, such as dichloromethane, at any temperature providing a convenient rate of formation of the required product, conveniently at ambient temperature.
  • a compound of formula (IV) may be prepared by reacting a compound of formula (II) wherein R 6 is hydrogen, with a compound of formula (VII):
  • L 3 and L 4 each independently represent leaving groups or L 3 together with L 4 represents an oxygen atom; and thereafter, if required, converting R 1a into R 1 and/or R 2a into R 2 and/or A 2 into A 1 .
  • L 3 and L 4 represent leaving groups each may represent the group L 2 as hereinbefore defined.
  • reaction between the compound of formula (II) wherein R 6 is hydrogen and the compound of formula (VII) wherein L 3 together with L 4 is an oxygen atom may be carried out in an aprotic solvent, such as tetrahydrofuran at any temperature providing a suitable rate of formation of the required product, such as in the range of from 20 to 80°C, suitably at 60°C and preferably in the presence of a base such as triethylamine.
  • an aprotic solvent such as tetrahydrofuran at any temperature providing a suitable rate of formation of the required product, such as in the range of from 20 to 80°C, suitably at 60°C and preferably in the presence of a base such as triethylamine.
  • the compound of formula (IV) is not isolated from the reaction between compounds of formulae (II), wherein R 6 is hydrogen, and (VII), but is converted in-situ into a compound of formula (I).
  • a compound of formula (VII), especially when L 3 together with L 4 is an oxygen atom, may also be reacted with a compound of formula (II), wherein R 6 is hydrogen, to provide a compound of formula (I) where in R 1 and R 2 are as defined above, R 4 is hydrogen and R 3 is a substituted or unsubstituted phenyl group having a carboxyl group attached ortho to the carbon atom bonding R 3 to the carbonyl of the N-CO.R 3 group.
  • Conversions of one compound of formula (I) into another compound of formula (I) includes: i) converting a compound of formula (I) wherein A 1 represents hydrogen into a compound of formula (I) wherein A 1 represents
  • R 3 together with R 5 represents a substituted or unsubstituted C 2-3 polymethylene chain, for example when R 3 together with R 5 represents -CH 2 CH 2 - the resulting compoun d of formula (I) is that wherein R 4 is hydrogen and R 3 is -CH 2 CH 2 -CO 2 H, or when R 3 and R 5 together represent a phenylene group then the resulting compound of formula (I) is that wherein R 4 is hydrogen and R 3 is o-carboxyphenyl.
  • Alkylation reaction (i) may be effected by conventional alkylation methods, for example by treatment of the appropriate compound of formula (I) with an alkyl halide of a compound of formula (VII) described below and wherein A 3 is A 1 .
  • hydrolysis of the appropriate compound of formula (I) may be effected by any suitable hydrolysis procedure, for example treatment with lithium hydroxide in aqueous tetrahydrofuran at ambient temperature.
  • Suitable values for R 1a , R 2a and A 2 include R 1 , R 2 and A 1 respectively or nitrogen protecting groups such as benzyl groups.
  • R 1a , R 2a or A 2 represents other than R 1 , R 2 or A 1 repectively, the abovementioned conversions of R 1a into R 1 ,R 2a to R 2 and A 2 into A 1 may be carried out using the appropriate conventional procedure.
  • R 1a , R 2a , or A 2 represents a nitrogen protecting group, such as a benzyl group
  • the protecting group may be removed using the appropriate conventional procedure, such as catalytic hydrogenation, and the resulting product reacted with a compound of formula (VIII):
  • a 3 represents R 1 or R 2 (for converting R 1a into R 1 or R 2a into R 2 ) or A 3 represents A 1 (for converting A 2 into A 1 ) wherein R 1 , R 2 and A 1 are as defined in relation to formula (I) and X represents a leaving group, such as halide, for example bromide or iodide.
  • any reactive group or atom such as the xanthine nitrogen atom may be carried out at any appropriate stage in the aforementioned process.
  • Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected, for example suitable protecting groups for the xanthine nitrogen atoms are benzyl groups.
  • variable A 1 represents a benzyl group or a substituted benzyl group and R 1a and/or R 2a represents a nitrogen protecting group
  • the particular protecting groups chosen will be those which may be prepared and removed without affecting A 1
  • examples of such protecting groups are trialkyl silyl groups such as t-butyl dimethyl silyl or trimethyl silyl groups.
  • R 1a is R 1 and R 2a is R 2 .
  • N-benzyl protecting groups may be prepared by treating the appropriate compound of formula (II) with benzyl chloride in the presence of a base such as triethylamine, bases such as potassium t-butoxide may also be used .
  • the N-benzyl protecting groups may be removed by catalytic hydrogenation over a suitable catalyst, such as palladium on activated charcoal, in a suitable solvent, such as ethanol conveniently at an elevated temperature, or by treatment with anhydrous aluminium chloride in dry benzene at ambient temperature.
  • Trialkylsilyl protected nitrogen groups may be prepared by treating the appropriate compound with a trialkylsilyl halide, for example trimethylsilyl chloride, in the presence of a base such as potassium t-butoxide.
  • the N-trialkylsilyl protecting group may be removed by mild basic hydrolysis or by treatment with a source of fluoride ions such as tetrabutylammoniumfluoride.
  • the present invention accordingly provides a compound of formula (I); or where appropriate a
  • the present invention provides a compound of formula (I); or where appropriate a pharmaceutically acceptable salt thereof; or a
  • the present invention also provides a compound of formula (I); or where appropriate a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, for use as a phosphodiesterase inhibitor.
  • the present invention provides a compound of formula (I) or where appropriate a
  • the present invention provides a compound of formula (I); or where appropriate a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, for use in the treatments mentioned hereinbefore, such as cerebral vascular and neuronal denerative disorders associated with learning, memory and cognitive dysfunctions, peripheral vascular disease or proliferate skin disease or for the prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events or for the inhibition of the production of tumour necrosis factor in for example the treatment of human immunodeficiency virus.
  • a compound of formula (I); or where appropriate a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical
  • composition also comprising a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I); or where appropriate a
  • the active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • compositions are suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
  • the compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where
  • composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or
  • polyvinylpyrrolidone for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch,
  • polyvinylpyrrolidone sodium starch glycollate or microcrystalline cellulose
  • pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
  • corticosteroids such as prednisolone
  • adrenal stimulants such as ACTH
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially tile same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
  • Compounds of formula (I), or if appropriate a pharmaceutically acceptable salt thereof, may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (I) or if appropriate a
  • pharmaceutically acceptable salt thereof are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill B ooks, Remington's Pharmaceutical Sciences, and the
  • pharmaceutically acceptable salt thereof will comprise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
  • suitable unit doses may be 0.1 to 1000mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70kg adult is in the range of about 0.1 to 1000 mg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day; and such therapy may extend for a number of weeks or months.
  • the term 'pharmaceutically acceptable encompasses materials suitable for both human and veterinary use.
  • 1,3-di(cyclopropylmethyl)-8- N-succinimido)xanthine (0.18g, 0.5mmole) and lithium hydroxide monohydrate (0.042g, 1mmole) were stirred together in a water/THF mixture (1:1, 3ml). After 0.5h at ambient temperature the solution was neutralized with dilute hydrochloric acid and filtered to give 1,3-di(cyclopropylmethyl)-8-(3-carboxy- propanoyl)aminoxanthine (0.19g, 100%) m.p.
  • 1,3-Di-cyclopropylmethyl xanthine (20g, 0.076mol) was dissolved in acetic acid (33ml) and then treated with concentratee nitric d (13.2g) at 87°C. After 1 hour, the mixture was cooled to 5°C and the res ulting yellow precipitate filtered off. The yellow crystals were dissolved in
  • 1,3-Di-cylopropylmethyl-8-nitro xanthine (4g, 0,014mol), suspended in 50ml of concentrated hydrochloric acid. was treated with small portions of tin (8g) at room temperature. The mixture was then stirred at room temperature for two hours.
  • Sephadex G200 particle size 40 to 120 micron, was suspended in isotonic saline at 0.5mg/ml, and stored for 48h at 4°C. 1ml of the suspension was given intravenously to rats on days 0,2 and 5. A control group received saline. The test compound was givenbefore the Sephadex on each occasion, with a contact time expected to give maximum activity at the time of the Sephadex administration. Blood was taken from the tail vein of the rats on day 7 for the determination of total and differential leucocyte counts.
  • a control group of at least 6 animals was included each time a compound was evaluated.
  • the control group received Sephadex and the vehicle without test compound.
  • the results in the drug treated animals were compared with the control group.
  • test compound upon Sephadex induced eosinophilia in the rat is set out below.
  • the test compound was given orally 30 minutes before each injection of Sephadex.
  • the Ca 2+ /calmodulin-stimulated PDE (PDE I, see Table 1 and Beavo and Reifsynder (1990) for nomenclature) was prepared from bovine cardiac ventricle. Following chromatography on a Mono Q column, the fractions showing stimulation of PDE activity by Ca 2+ and calmodulin were pooled and further purified on a calmodulin-affinity column.
  • cGMP-stimulated PDE (PDE II), cGMP-inhibited PDE (PDE III) and cAMP-specific PDE (PDE IV) were all isolated from guinea-pig cardiac ventricle.
  • PDEIII The activity of this isoenzyme with cAMP as a substrate was inhibited by cGMP.
  • the isoenzyme could hydrolyse both cAMP and cGMP, the former was the preferred substrate.
  • the activity of this isoenzyme was unaffected by the Ca 2+ calmodulin complex.
  • PDE IV This isoenzyme had high affinity for cAMP, the hydrolysis of which was not inhibited by cGMP.
  • the activity of this isoenzyme was unaffected by the Ca2-calmodulin complex.
  • PDE activity was assayed by the boronate column method as previously described (Reeves et. al., 1987). The enzymes were assayed by incubation at 37°C for 4-30 min. in 50 mM Tris, 5 mM MgCl 2 , pH 7.5 with 3 H- labelled cyclic nucleotide (4 x 10 5 disintegrations min -1 ) and 14 C-labelled nucleotide 5'-monophosphate (3 x 10 3 disintegrations min -1 ). The assay was stopped by boiling and the 3 H-labelled 5'-monophosphate product separated from substrate on boronate columns. The reaction mixture was diluted with 0.5 mL 100 mM HEPES
  • IC 50 values (the concentration of inhibitor required for 50% inhibition of activity) were obtained by incubation of the isoenzyme using 1 mM cGMP as a substrate for PDE I (in the absence of Ca 2+ and calmodulin), PDE II and PDE V and with 1 mM cAMP as a substrate for PDE III and PDE IV.

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  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Composé de formule (I) ou, selon le cas, un de ses sels acceptable pharmaceutiquement; ou un de ses solvates acceptable pharmaceutiquement, dans laquelle R1 et R2 chacun indépendamment représentent une fraction de formule (a): -(CH¿2?)m-A dans laquelle m est zéro ou un entier 1, 2 ou 3 et A représente un radical de carbure d'hydrogène cyclique substitué ou non substitué; R?3¿ représente un groupe aryle substitué ou non substitué ou alkyle substitué; R4 représente hydrogène ou un groupe -CO.R5 dans lequel R5 représente alkyle substitué ou non substitué ou aryle substitué ou non substitué; ou R?3 avec R5¿ représentent une chaîne polyméthylène C¿2-3? substituée ou non substituée; et A?1¿ représente hydrogène ou alkyle substitué ou non substitué; procédé de préparation dudit composé, composition pharmaceutique contenant ledit composé et utilisation dudit composé ou de ladite composition en médecine.
PCT/GB1991/001634 1990-09-26 1991-09-23 Xanthines Ceased WO1992005176A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR1019930700918A KR930702350A (ko) 1990-09-26 1991-09-23 크산틴류
JP3517400A JPH06501691A (ja) 1990-09-26 1991-09-23 キサンチン
AU86458/91A AU650679B2 (en) 1990-09-26 1991-09-23 Xanthines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9020921.4 1990-09-26
GB909020921A GB9020921D0 (en) 1990-09-26 1990-09-26 Novel compounds

Publications (1)

Publication Number Publication Date
WO1992005176A1 true WO1992005176A1 (fr) 1992-04-02

Family

ID=10682765

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/001634 Ceased WO1992005176A1 (fr) 1990-09-26 1991-09-23 Xanthines

Country Status (12)

Country Link
EP (1) EP0550559A1 (fr)
JP (1) JPH06501691A (fr)
KR (1) KR930702350A (fr)
AU (1) AU650679B2 (fr)
CA (1) CA2092429A1 (fr)
GB (1) GB9020921D0 (fr)
IE (1) IE913351A1 (fr)
MX (1) MX9101235A (fr)
NZ (1) NZ239920A (fr)
PT (1) PT99037A (fr)
WO (1) WO1992005176A1 (fr)
ZA (1) ZA917611B (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023401A1 (fr) * 1992-05-21 1993-11-25 Smithkline Beecham Plc Xanthines 8-substituees utilisees en tant qu'inhibiteurs de la phosphodiesterase
WO1996036638A1 (fr) * 1995-05-19 1996-11-21 Chiroscience Limited Xanthines et leur utilisation therapeutique
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism
US5661153A (en) * 1994-07-19 1997-08-26 Japan Energy Corporation 1-arylpyrimidine derivatives and pharmaceutical use thereof
WO1998022464A1 (fr) * 1996-11-15 1998-05-28 Darwin Discovery Limited Xanthines et utilisation therapeutique de ces dernieres
WO1999020625A1 (fr) * 1997-10-23 1999-04-29 Smithkline Beecham Corporation Nouvelles formes polymorphes de cipamfylline
US6090816A (en) * 1994-12-13 2000-07-18 Euro-Celtique S.A. Aryl thioxanthines
WO2002024698A1 (fr) * 2000-09-19 2002-03-28 Schering Corporation Xanthines, inhibiteurs de la phosphodiesterase de type v
US6943171B2 (en) 2001-11-09 2005-09-13 Schering Corporation Polycyclic guanine derivative phosphodiesterase V inhibitors
US6969719B2 (en) 2001-08-28 2005-11-29 Schering Corporation Polycyclic guanine phosphodiesterase V inhibitors
EP1719772A1 (fr) 2002-05-31 2006-11-08 Schering Corporation Procédé de préparation d'inhibiteurs de la phosphodiesterase v de la xanthine et leur précurseurs
US7495004B2 (en) 2002-06-17 2009-02-24 Glaxo Group Limited Purine derivatives as liver X receptor agonists

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9020959D0 (en) * 1990-09-26 1990-11-07 Beecham Group Plc Novel compounds
ES2148170T3 (es) * 1990-12-21 2000-10-16 Beecham Group Plc Derivados de xantina.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0258191A1 (fr) * 1986-08-28 1988-03-02 Sandoz Ag Dérivés de la xanthine
EP0386683A2 (fr) * 1989-03-10 1990-09-12 POLI INDUSTRIA CHIMICA S.p.A. Dérivés de xanthine à activité bronchodilatatoire, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0389282A2 (fr) * 1989-03-23 1990-09-26 BEECHAM - WUELFING GmbH & Co. KG Dérivés de xanthine, procédé pour leur préparation et leur utilisation médicinale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0258191A1 (fr) * 1986-08-28 1988-03-02 Sandoz Ag Dérivés de la xanthine
EP0386683A2 (fr) * 1989-03-10 1990-09-12 POLI INDUSTRIA CHIMICA S.p.A. Dérivés de xanthine à activité bronchodilatatoire, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0389282A2 (fr) * 1989-03-23 1990-09-26 BEECHAM - WUELFING GmbH & Co. KG Dérivés de xanthine, procédé pour leur préparation et leur utilisation médicinale

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023401A1 (fr) * 1992-05-21 1993-11-25 Smithkline Beecham Plc Xanthines 8-substituees utilisees en tant qu'inhibiteurs de la phosphodiesterase
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism
US5661153A (en) * 1994-07-19 1997-08-26 Japan Energy Corporation 1-arylpyrimidine derivatives and pharmaceutical use thereof
US6090816A (en) * 1994-12-13 2000-07-18 Euro-Celtique S.A. Aryl thioxanthines
WO1996036638A1 (fr) * 1995-05-19 1996-11-21 Chiroscience Limited Xanthines et leur utilisation therapeutique
US5821366A (en) * 1995-05-19 1998-10-13 Chiroscience Limited Xanthines and their therapeutic use
US6124288A (en) * 1995-05-19 2000-09-26 Darwin Discovery, Ltd. Xanthines and their therapeutic use
WO1998022464A1 (fr) * 1996-11-15 1998-05-28 Darwin Discovery Limited Xanthines et utilisation therapeutique de ces dernieres
US5919789A (en) * 1996-11-15 1999-07-06 Darwin Discovery Limited Xanthines and their therapeutic use
US6583283B1 (en) 1997-10-23 2003-06-24 Smithkline Beecham Corporation Polymorphic forms of cipamfylline
WO1999020625A1 (fr) * 1997-10-23 1999-04-29 Smithkline Beecham Corporation Nouvelles formes polymorphes de cipamfylline
AU751561B2 (en) * 1997-10-23 2002-08-22 Smithkline Beecham Corporation Novel polymorphic forms of cipamfylline
WO2002024698A1 (fr) * 2000-09-19 2002-03-28 Schering Corporation Xanthines, inhibiteurs de la phosphodiesterase de type v
US6821978B2 (en) 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
RU2302420C2 (ru) * 2000-09-19 2007-07-10 Шеринг Корпорейшн Ингибиторы ксантин-фосфодиэстеразы v, способ их получения, фармацевтическая композиция, применение и способ лечения
US7268141B2 (en) 2000-09-19 2007-09-11 Schering Corporation Xanthine phosphodiesterase V inhibitors
RU2302420C9 (ru) * 2000-09-19 2008-12-10 Шеринг Корпорейшн Ингибиторы ксантин-фосфодиэстеразы v, способ их получения, фармацевтическая композиция, применение и способ лечения
US7531544B2 (en) 2000-09-19 2009-05-12 Schering Corporation Xanthine phosphodiesterase V inhibitors
US6969719B2 (en) 2001-08-28 2005-11-29 Schering Corporation Polycyclic guanine phosphodiesterase V inhibitors
US6943171B2 (en) 2001-11-09 2005-09-13 Schering Corporation Polycyclic guanine derivative phosphodiesterase V inhibitors
EP1719772A1 (fr) 2002-05-31 2006-11-08 Schering Corporation Procédé de préparation d'inhibiteurs de la phosphodiesterase v de la xanthine et leur précurseurs
US7495004B2 (en) 2002-06-17 2009-02-24 Glaxo Group Limited Purine derivatives as liver X receptor agonists

Also Published As

Publication number Publication date
ZA917611B (en) 1992-12-30
AU650679B2 (en) 1994-06-30
EP0550559A1 (fr) 1993-07-14
MX9101235A (es) 1992-05-04
GB9020921D0 (en) 1990-11-07
PT99037A (pt) 1992-08-31
JPH06501691A (ja) 1994-02-24
AU8645891A (en) 1992-04-15
CA2092429A1 (fr) 1992-03-27
IE913351A1 (en) 1992-04-08
NZ239920A (en) 1994-06-27
KR930702350A (ko) 1993-09-08

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