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WO1992005175A1 - Derives de xanthine - Google Patents

Derives de xanthine Download PDF

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Publication number
WO1992005175A1
WO1992005175A1 PCT/GB1991/001633 GB9101633W WO9205175A1 WO 1992005175 A1 WO1992005175 A1 WO 1992005175A1 GB 9101633 W GB9101633 W GB 9101633W WO 9205175 A1 WO9205175 A1 WO 9205175A1
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WO
WIPO (PCT)
Prior art keywords
group
formula
pharmaceutically acceptable
compound
xanthine
Prior art date
Application number
PCT/GB1991/001633
Other languages
English (en)
Inventor
Derek Richard Buckle
David Glynn Smith
Ashley Edward Fenwick
Original Assignee
Beecham Group Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group Plc filed Critical Beecham Group Plc
Priority to AU85413/91A priority Critical patent/AU653364B2/en
Priority to KR1019930700919A priority patent/KR930702351A/ko
Publication of WO1992005175A1 publication Critical patent/WO1992005175A1/fr

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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
    • C07D473/04—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 compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
  • Werner et al, pages 2044-2048 discloses certain l,3-dimethyl-8-substituted xanthines. No pharmacological activity is disclosed for these compounds.
  • 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 8-substituted 1,3- dicycloalkylalkylene 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. In addition treatment with these compounds is indicated to be of benefit for the treatment of functional disorders resulting from disturbed brain function following ischaemia.
  • these compounds may also have potential as inhibitors of the production of tumour necrosis factor (TNF) and hence have potential for the treatment of human immunodeficiency virus (HIV), acute immune deficiency syndrome (AIDS), rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endo toxic 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, fever 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.
  • HCV human immunodeficiency virus
  • AIDS acute immune deficiency syndrome
  • rheumatoid arthritis rheumato
  • Rl and ⁇ x- each independently represent a moiety of formula (a):
  • m represents zero or an integer 1, 2 or 3 and A represents a substituted or unsubstituted cyclic hydrocarbon radical;
  • R3 represents NO2, a halogen atom, a hydroxy group.an alkoxy group or a methyl group substituted with 1 or 2 groups of formula CO2R wherein R in each group is independently hydrogen or alkyl or a group of formula O-L-A* wherein L is a bond or a linking group and A* is a saturated or unsaturated heterocyclic group, or B? represents a group of formula
  • R s and R ⁇ each independently represent hydrogen, alkyl, aralkyl, an unsaturated heterocyclic group or R s and R* together with the nitrogen to which they are attached form an unsaturated heterocyclic group; and R represents an alkyl, aralkyl or an (unsaturated heterocyclyDalkyl group.
  • A represents a substituted or unsubstituted alicyclic hydrocarbon radical.
  • A is unsubstituted.
  • A represents a substituted or unsubstituted C3.8 cycloalkyl group, especially a C3.6 cycloalkyl group.
  • A represents a substituted or, preferably, unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
  • A represents a cyclopropyl group or a cyclobutyl group.
  • Particular aralkyl groups are benzyl and naphthylmethyl groups.
  • Particular substituents for the aryl moiety of any aralkyl group include NO2 and alkoxy, especially NO2 and methoxy.
  • R s and/or R* represents aralkyl
  • examples include benzyl and nitrobenzyl, especially 2-nitrobenzyl.
  • R4 represents aralkyl examples include methoxybenzyl, such as 4-methoxybenzyl; trimethoxybenzyl, such as 3,4,5-trimethoxybenzyl; nitrobenzyl, such as 2- or 4-nitrobenzyl; and naphthylmethyl.
  • the saturated or unsaturated heterocyclic group represented by A* is attached by a ring carbon atom to the 0 atom of the group O-L-A 1 .
  • preferred carbon linked heterocyclic groups represented by A ⁇ are single ring heterocyclic groups having 6 ring atoms, which ring atoms comprise 1 or 2, especially 1, heteroatoms, selected from O or N, preferably N; particular examples include piperidinyl groups.
  • a suitable linking group is a CI ⁇ Q alkylene chain, optionally interrupted by an oxygen atom.
  • An Example of a linking group L is -(CH2)2-0-(CH2)2--
  • suitable heterocyclic groups represented by A ⁇ are single ring heterocyclic groups having 5- or 6- ring atoms which ring atoms comprise 1 or 2, especially 1, heteroatoms selected from 0 or N, preferably N; particular examples include piperazinyl groups, especially N-piperazinyl groups.
  • Particular substituents for the heterocyclic groups represented by A ⁇ include aralkyl, especially benzyl, and alkyl carbonyl wherein the alkyl group may be substituted or unsubstituted, a particular substituent for the said alkyl group being a carboxy group or an alkyl ester thereof.
  • substituents for the heterocyclic group represented by A are benzyl and or an ester thereof.
  • R s or R* represent an unsaturated heterocyclic group
  • particular groups are single ring, 6-membered heterocyclic groups which ring atoms comprise 1 or 2, preferably 1, heteroatoms selected from 0 or N, preferably N;suitable examples are heteroaryl groups such as pyridyl.
  • suitable heterocyclic groups are single ring, 5- or 6- membered heterocyclic groups optionally comprising 1 or 2, preferably 1, additional heteroatoms in the ring; particular examples include imidazolyl groups.
  • R represents an (unsaturated heterocyclyDalkyl group
  • suitable examples are heteroarylalkyl groups such as heteroarylmethyl groups, the unsaturated heterocyclyl group suitably being a single ring, 6-membered heterocyclyl group which ring atoms comprise 1 or 2, preferably 1, heteroatoms selected from O or N, preferably N; particular examples include pyridylmethyl groups.
  • R ⁇ represents nitro, a halogen atom, an alkoxy group, such as an ethoxy group, or a group NR S R* wherein R s and R- each independently represent hydrogen or alkyl, especially hydrogen.
  • R3 represents R S R*
  • R s represents hydrogen and R ⁇ represents alkyl, aralkyl or an unsubstituted heterocyclic group.
  • R is alkyl
  • suitable examples include C1.4 alkyl such as methyl.
  • A represents a cyclopropyl group.
  • R ⁇ represents NH2.
  • R 4 represents an alkyl or aralkyl group.
  • R 4 represents an aralkyl group, especially a benzyl group.
  • Favourably, m represents 1.
  • Suitable pharmaceutically acceptable solvates are those used conventionally such as hydrates.
  • 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 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.
  • cyclic hydrocarbon radical includes single ring and fused ring, alicyclic hydrocarbons comprising up to 8 carbon atoms in each ring, suitably up to 6 carbon atoms, for example 3, 4, 5 or 6 carbon atoms.
  • Suitable optional substituents for any cyclic hydrocarbon radical includes a C ⁇ _g alkyl group or a halogen atom.
  • alkyl' when used herein 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.
  • Optional substituents for alkyl groups include those mentioned herein for aryl groups.
  • 'aryl' (whether used alone or when used as part of other groups for example as in an aralkyl group) 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.
  • 'heterocyclic' or 'heterocyclyl' when used herein refers to groups comprising single or fused rings which rings each comprise 4 to 7, suitably 5 or 6 ring atoms, which ring atoms comprise up to 4 hetero atoms selected from 0, N or S.
  • Optional substituents for any 'heterocyclic' or 'heterocyclyl' group include alkyl, alkoxy, halo, carboxy or an alkyl ester thereof, aralkyl or alkyl carbonyl wherein the alkyl group may be substituted or unsubstituted.
  • 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), which process comprises reacting a compound of formula (II):
  • R ⁇ a represents TO-, as defined in relation to formula (I), or a group convertible to R* and R ⁇ a represents R ⁇ , as defined in relation to formula (I), or a group convertible thereto and R ⁇ a represents R ⁇ as defined in relation to formula (I), or a group convertible thereto, with a compound of formula (III):
  • R 4 is as defined in relation to formula (I) and i ⁇ represents a leaving group; and thereafter, if required carrying out one or more of the following optional steps:
  • a suitable leaving group i is a halo atom, for example a bromine or chlorine atom.
  • reaction between compounds of formulae (II) and (III) may be carried out using conventional alkylation conditions, for example in an aprotic solvent, such as dimethylformamide, tetrahydrofuran or dimethylsulphoxide, at any temperature providing a suitable rate of formation of the required product, for example in the range of from 0°C to 100°C, conveniently at ambient temperature.
  • an aprotic solvent such as dimethylformamide, tetrahydrofuran or dimethylsulphoxide
  • the compound of formula (II) is in an activated form, suitably in an anionic form such as a salted form, for example an alkali metal salted form.
  • the activated form of the compound of formula (II) is conveniently prepared by treating a compound of formula (II) with a base, suitably an alkali metal alkoxide, for example potassium t-butoxide, or an alkali metal hydride, for example sodium hydride.
  • a base suitably an alkali metal alkoxide, for example potassium t-butoxide, or an alkali metal hydride, for example sodium hydride.
  • a compound of formula (II) may be prepared by reacting a compound of formula (IV):
  • R ⁇ a represents l, as defined in relation to formula (I), or a group convertible to Rl and R ⁇ represents R ⁇ , as defined in relation to formula (I), or a group convertible thereto, with a reagent capable of substituting the C-8 hydrogen of the compound of formula (IV) with a group R3 O wherein R ⁇ b represents R ⁇ , as defined above in relation to formula (II), or a group convertible thereto; and thereafter, if required carrying out one or more of the following optional steps:
  • R ⁇ a represents nitro
  • R ⁇ b preferably represents R ⁇ i.e. nitro
  • R3b preferably represents a group convertible to R ⁇ a .
  • R ⁇ b is a nitro group which may then if required be converted to groups R ⁇ a other than nitro.
  • Suitable reagents for substituting the C-8 hydrogen of the compound of formula (IV) with a group R ⁇ b are the appropriate conventional reagents.
  • One particularly suitable reagent is a nitrating agent.
  • the nitration of compound (II) 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 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.
  • the compound of formula (IV) is reacted with a suitable nitrating agent to provide a compound of formula (II) wherein R ⁇ a represents a nitro group and then converting the nitro group into a halogen atom or a group of the abovedefined formula -NR s Rt, suitably via the halogen atom.
  • R ⁇ represents a nitro group
  • suitable conversions of the nitro group into another group ⁇ a include the following:
  • a nitro group may be converted into a halogen atom by using any convenient halogenating agent.
  • One suitable halogenating agent is a hydrogen halide, suitably reacted in aqueous conditions for example by using concentration hydrochloric acid at an elevated temperature, for example in the range of from 50 to 150°C.
  • a further suitable halogenating agent is a phosphorous oxyhalide, such as phosphorous oxychloride or phosphorous oxybromide, which may be reacted in any suitable solvent, such as dimethylformamide, suitably at an elevated temperature for example in the range of from 50°C to 150°C.
  • a nitro group may conveniently be converted into an amino group by conventional reduction methods for example by using tin powder and concentrated hydrochloric acid at ambient temperature or by using sodium dithionite in aqueous methanol at ambient temperature.
  • R ⁇ a represents a halogen atom
  • it may be converted into a methyl group substituted with 1 or 2 groups of formula CO2R wherein R is as defined above, by reacting the required compound of formula (II) wherein R ⁇ a is halogen, with the appropriate mono or bis malonate wherein the esterifying moiety is a group R as defined above, in the presence of a base such as sodium hydride in an aprotic solvent at any temperature providing a suitable rate of formation of the required product, conveniently at an elevated temperature such as in the range of 40°C to 120°C, for example 80°C.
  • a base such as sodium hydride
  • an aprotic solvent at any temperature providing a suitable rate of formation of the required product, conveniently at an elevated temperature such as in the range of 40°C to 120°C, for example 80°C.
  • R ⁇ in the compound of formula (II) represents a halogen atom it may be converted into a group -O-L-Al, wherein L and A ⁇ are as defined in relation to formula (I), by reaction with a reagent of formula (V) or, preferably, an activated form thereof:
  • reaction between the compound of formula (II) when R ⁇ a is halogen and the compound of formula (V) may be carried out under analogous conditions to the above described reaction between compounds of formulae (II) and (III).
  • Suitable activated forms of the compound of formula (V) are salted forms such as alkali metal salted forms.
  • the activated form of compounds of formula (V) are prepared by treating the compound of formula (III) with a base, suitably an alkali metal base such as those referred to above.
  • R ⁇ in the compound of formula (II) represents a halogen atom it may be converted into a group -NR s Rt by reacting with a reagent of formula (VI):
  • R s and * are as defined above.
  • reaction between the compound of formula (II) and the compound of formula (VI) may be carried out in any suitable solvent, such as toluene, at any temperature providing a convenient rate of formation of the product, but suitably at an elevated temperature, such as in the range of from 50° to 180°C, at atmospheric or an elevated pressure.
  • suitable solvent such as toluene
  • Suitable alkylation methods for use in the abovementioned conversions include those used conventionally in the art, for example methods using halides, preferably iodides, in the presence of a base such as potassium carbonate in any convenient solvent for example acetonitrile or toluene.
  • the nitro group may be converted into the halogen atom as described above.
  • the conversion of the halogen atom into an alkoxy group may be effected by any conventional alkoxylation procedure, for example treating the halogen with a source of alkoxy ions, such as a sodium alkoxide.
  • Suitable conversions of a compound of formula (I) into another compound of formula (I) generally include converting one group B ⁇ into another group RS.
  • NR S R* represents a piperidinyloxy group, which may thereafter be converted into an (N-4-oxo-butanoic acid) piperidinyloxy group, by treatment with succinic hydride in dry dimethylformamide, or into an (N-benzyl) piperidinyloxy group, by conventional benzylation procedures.
  • a compound of formula (IV) may be prepared according to methods disclosed in EP 0369744.
  • Suitable values for ⁇ a and R-- ⁇ - include R* and ⁇ respectively or nitrogen protecting groups such as silyl groups.
  • Rla or R ⁇ a represents other than Rl or B-- repectively
  • the abovementioned conversions of R ⁇ a into R ⁇ and ⁇ a to Bs- may be carried out using the appropriate conventional procedure.
  • 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 silyl groups, especially trialkyl silyl groups such as t-butyl dimethyl silyl or trimethyl silyl groups.
  • 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 pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
  • 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 treatment of and/or prophylaxis of disorders associated with increased numbers of eosinophils, such as asthma, and allergic disorders associated with atopy, such as urticaria, eczema and rhinitis.
  • 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 pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, for use in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and asthma.
  • 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 ⁇ £ ⁇ 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 pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
  • 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.
  • the composition is 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.
  • 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 appropriate.
  • 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; fillers, 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; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example star
  • 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.
  • 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 the 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.
  • 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 Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
  • the compound of formula (I), or if appropriate a 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 lOOOmg, such a ⁇ .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.
  • Potassium t-butoxide (1.3 ) was added to a solution of 8-amino-l,3-di(cyclopropylmethyl)xanthine (2.7g, lOmmole) in DMF (25ml) and the resulting mixture was stirred for 0.5hr at ambient temperature. Methyl iodide (1.78g,0.78ml, 12.5mmole) was added to the red solution, an exothermic reaction resulted and a precipitate formed. After stirring for 10 minutes the mixture was added to ethyl acetate (200ml), washed with dilute hydrochloric acid (50ml), water(50ml) and dried (MgS04).
  • 2-Hydroxyethylpyridine (0.32g, 1.1 equiv) was added dropwise to a suspension of 8-chloro-l,3-di(cyclopropylmethyl)-7-(4- methoxybenzyDxanthine (lg, 2.41 mmol) and sodium hydride (O.l ⁇ g of a 60% dispersion in oil, 1.5 equivs) in dry DMSO (20ml) and was heated at 80°C for 16h. The reaction mixture was poured into water, neutralized and extracted into ethyl acetate (x3). The combined organic solutions were dried, filtered and concentrated.
  • This compound was prepared according to the procedure of Example 9 but with 4-aminopyridine replacing imidazole. Purification by column chromatography afforded l,3-di(cyclopropylmethyl)-7-(4-methoxybenzyl)- 8-(4-pyridylamino)xanthine (35%); mp 207-208°C (decomp, ethylacetate/hexane).
  • 8-Chloro-l,3-di(cyclopropylmethyl)-7-(3 pyridylmethyDxanthine was prepared from 3-chloromethylpyridine and 8-chloro-l,3- di(cyclopropylmethyl)xanthine according to the procedure of Example 14, except that the reaction mixture was heated at 80°C for 16h. The free base was dissolved in dry ether and the solution was saturated with hydrogen chloride gas. 8-Chloro-l,3-di(cyclopropylmethyl)-7-(3- pyridylmethyDxanthine hydrochloride, m.p.
  • This compound was prepared according to the procedure of Example 6 using 2-(2-(N-piperizinyl)ethoxy)ethanol and 8-chloro-l,3- di(cyclopropylmethyl)-7-(4-methoxybenzyl]xanthine. Purification by column chromatography over silica gel using 4% methanol/dichloromethane afforded l,3-di(cyclopropylmethyl)-7-(4- methoxybenzyl)-8-[2-(2-[iV-piperizinyl]ethoxy)ethoxy]xanthine (44%) as an oil.
  • l,3-Di(cyclopropylmethyl)-7-(4-methoxybenzyl)-8-(4- piperidinyloxy)xanthine maleate was prepared according to the procedure of Example 6 but with 4-hydroxypiperidine replacing 2- hydroxyethylpyridine. Purification by column chromatography over silica gel afforded l,3-di(cyclopropylmethyl)-7-(4-methoxybenzyl)-8-(4- piperidinyloxy)xanthine (50%) as an oil.
  • Succinic anhydride (0.23g, 1.2 equivs) was added to a solution of 1,3- di(cyclopropylmethyl)-7-(4-methoxybenzyl)-8-(4-piperidinyloxy)xanthine (0.92g, 1.92 mmoles) in dry THF (20ml).
  • Benzyl bromide (0.17g, 1.2 equivs), triethylamine (0.21g, 2.5 equivs), and l,3-di(cyclopropylmethyl)-7-(4-methoxybenzyl)-8-(4- piperidinyloxy)xanthine (0.40g, 8.4 x 10" ⁇ mmole) were stirred in dry tetrahydrofuran (10ml) for 16h. The reaction mixture was poured into aqueous sodium bicarbonate solution and extracted into dichloromethane.
  • the maleate salt was prepared and recrystallised from methanol/diisopropyl ether to afford the pure material as a white solid mp 160-161°C.
  • 1,3-Di-cyclopropylmethyl xanthine (20g, 0.076mol) was dissolved in acetic acid (33ml) and then treated with concentrated nitric acid (13.2g) at 87°C. After 1 hour, the mixture was cooled to 5°C and the resulting yellow precipitate filtered off. The yellow crystals were dissolved in dichloromethane and washed with water. The separated organic layer was then dried over anhydrous sodium sulphate and concentrated in vacuo. The product crystallized from the concentrate to yield a yellow crystalline product yield 12.2g, (56.5%), m.p. 207°C (with decomposition). 1 ⁇ L NMR (COCl3):
  • 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 given before 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 compoimd 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 + and calmodulin were pooled and further purified on a calmodulin-affinity column. cGMP-stimulated PDE (PDE H), cGMP-inhibited PDE (PDE HI) and cAMP-specific PDE (PDE IV) were all isolated from guinea-pig cardiac ventricle. Initial chromatography on a 20 ml Mono Q column resolved PDE III from a peak that contained both PDE II and PDE IV.
  • PDE V cGMP-selective PDE
  • 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 MgCl2, pH 7.5 with 3 H- labelled cyclic nucleotide (4 x 10 ⁇ disintegrations min _ ) and ⁇ C-labelled nucleotide 5'-monophosphate (3 x 10 ⁇ disintegrations min" 1 ). The assay was stopped by boiling and the ⁇ H-labelled 5'-monophosphate product separated from substrate on boronate columns.
  • the reaction mixture was diluted with 0.5 mL 100 mM HEPES [N-(2-hydroxyethyl)piperazine-N 1 -2-ethanesulfonic acid], 100 mM NaCl, pH 8.5, and applied to the colu ⁇ m.
  • the column was extensively washed with the same buffer, and the 5'-nucleotide eluted with 6 mL of 0.25 M acetic acid.
  • the recovery of product as judged by 14 C-recovery was approximately 80%. All assays were linear with time of incubation and concentration of enzyme over the range used in these experiments.
  • IC50 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 Ca2+ and calmodulin), PDE II and PDE V and with 1 mM cAMP as a substrate for PDE III and PDE IV.
  • a range of inhibitor concentrations from 0.1 x IC50 to 100 x IC50 was used.

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Abstract

Un 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 représentent chacun indépendamment 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 NO¿2?, un atome halogène, un groupe hydroxy, un groupe alkoxy ou un groupe méthyle substitué par 1 ou 2 groupes de formule CO2R, dans laquelle R dans chaque groupe représente indépendamment hydrogène ou alkyle ou un groupe de formule O-L-A?1¿, dans laquelle L représente une liaison ou un groupe de liaison et A1 représente un groupe hétérocyclique saturé ou insaturé, ou R3 représente un groupe de formule NRsRt dans laquelle Rs et Rt chacun indépendamment représentent hydrogène, alkyle, aralkyle, un groupe hétérocyclique insaturé, ou Rs et Rt, avec l'azote auquel ils sont combinés, forment un groupe hétérocyclique insaturé; et R4 représente un groupe alkyle, aralkyle ou alkyle(hétérocyclyle insaturé); procédé de préparation dudit composé, composition pharmaceutique contenant ledit composé et utilisation dudit composé ou de ladite composition en médecine.
PCT/GB1991/001633 1990-09-26 1991-09-23 Derives de xanthine WO1992005175A1 (fr)

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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
US5817662A (en) * 1992-11-09 1998-10-06 Cell Therapeutics, Inc. Substituted amino alkyl compounds
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
WO2002002560A3 (en) * 2000-07-04 2002-04-25 Novo Nordisk As Purine-2,6-diones which are inhibitors of the enzyme dipeptidyl peptidase iv (dpp-iv)
WO2005012303A1 (fr) * 2003-07-31 2005-02-10 Schering Corporation Metabolite de l'inhibiteur de xanthine phosphodiesterase 5 et derives de ce metabolite, utiles dans le traitement de la dyserection
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WO2005058898A3 (fr) * 2003-12-16 2005-08-11 Ranbaxy Lab Ltd Inhibiteurs de la phosphodiesterase
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WO2006018117A1 (fr) * 2004-08-14 2006-02-23 Sanofi-Aventis Deutschland Gmbh 8-aminoalcoxi-xanthines substituees, leur procede de production, et leur utilisation en tant que medicaments
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US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
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EP0369744A2 (fr) * 1988-11-14 1990-05-23 SMITHKLINE BEECHAM PHARMA GmbH Dérivés de Xanthine, procédé pour leur 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

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US5817662A (en) * 1992-11-09 1998-10-06 Cell Therapeutics, Inc. Substituted amino alkyl compounds
US5889011A (en) * 1992-11-09 1999-03-30 Cell Therapeutics, Inc. Substituted amino alkyl compounds
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism
US6090816A (en) * 1994-12-13 2000-07-18 Euro-Celtique S.A. Aryl thioxanthines
US6124288A (en) * 1995-05-19 2000-09-26 Darwin Discovery, Ltd. Xanthines and their therapeutic use
WO1996036638A1 (fr) * 1995-05-19 1996-11-21 Chiroscience Limited Xanthines et leur utilisation therapeutique
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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
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US6821978B2 (en) 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
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GB9020959D0 (en) 1990-11-07
IE913350A1 (en) 1992-04-08
MX9101237A (es) 1992-05-04
JPH06501251A (ja) 1994-02-10
PT99062A (pt) 1992-08-31
EP0550570A1 (fr) 1993-07-14
AU653364B2 (en) 1994-09-29
ZA917610B (en) 1992-09-30
AU8541391A (en) 1992-04-15
KR930702351A (ko) 1993-09-08
CA2092430A1 (fr) 1992-03-27
NZ239921A (en) 1993-12-23

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