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WO1996002543A1 - Derives 2,3-dihydroxycyclopentane de purines - Google Patents

Derives 2,3-dihydroxycyclopentane de purines Download PDF

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Publication number
WO1996002543A1
WO1996002543A1 PCT/EP1995/002705 EP9502705W WO9602543A1 WO 1996002543 A1 WO1996002543 A1 WO 1996002543A1 EP 9502705 W EP9502705 W EP 9502705W WO 9602543 A1 WO9602543 A1 WO 9602543A1
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Prior art keywords
formula
compound
group
groups
compounds
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PCT/EP1995/002705
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English (en)
Inventor
Michael Gregson
George Blanch Ewan
Malcolm Chandler
Barry Edward Ayres
Original Assignee
Glaxo Group Limited
AYRES, Diana, Sally
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Application filed by Glaxo Group Limited, AYRES, Diana, Sally filed Critical Glaxo Group Limited
Priority to AU29829/95A priority Critical patent/AU2982995A/en
Publication of WO1996002543A1 publication Critical patent/WO1996002543A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • the present invention relates to therapeutically active substituted 2,3- dihydroxy cyclopentane derivatives, processes for the manufacture of said compounds, pharmaceutical formulations containing said compounds and the use of said compounds in chemotherapy.
  • novel compounds which are effective in treating inflammatory diseases.
  • Inflammation is a primary response to tissue injury or microbial invasion and is
  • Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes.
  • Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by gene expression in vascular endothelium in response to a variety
  • leukocytes The primary function of leukocytes is to defend the host from invading organisms such as bacteria and parasites. Once a tissue is injured or infected
  • R 1 represents a hydrogen atom or a C3_8cycloalkyl or C ⁇ al yl group
  • R2 represents a group selected from
  • C3_8cycloalkyl substituted by one or more groups e.g. 1 , 2 or 3 groups
  • groups e.g. 1 , 2 or 3 groups
  • 1, 2 or 3 ring carbon atoms is substituted by the same or different groups selected from C2-7acylamino, guanidino, oxo and (CH2)p 3 (where p and R 3 are as defined previously)
  • _6alkyl (vi) C3_8cycloalkylC* ⁇ ⁇ alkyl in which one or more of the ring carbon atoms
  • Z is a hydrogen atom or an optionally substituted aromatic ring selected from phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl and benzimidazolyl where the ring is optionally substituted by one or more groups (e.g. 1, 2 or 3 groups) which may be the same or different and are selected from C-j- ⁇ alkyl, C2-7acylamino, guanidino, carboxyC ⁇ alkyl, hydroxy,
  • groups e.g. 1, 2 or 3 groups
  • Q represents an oxygen or sulphur atom
  • Ph represents phenyl
  • Suitable salts of the compounds of formula (I) include physiologically acceptable salts such as acid addition salts derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates and maleates, and, if appropriate, inorganic base salts such as alkali metal salts, for example sodium salts.
  • physiologically acceptable salts such as acid addition salts derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates and maleates, and, if appropriate, inorganic base salts such as alkali metal salts, for example sodium salts.
  • Other salts of the compounds of formula (I) include salts which are not physiologically acceptable but may be useful in the preparation of compounds of formula
  • Suitable solvates of the compounds of formula (I) include hydrates.
  • R 2 in compounds of formula (I) contains one or more asymmetric carbon atoms the invention includes all diastereoisomers of compounds of formula (I) and mixtures thereof. Otherwise, the stereochemical configuration of compounds of the invention is as depicted in formula (I) above. It is to be understood that all tautomeric forms of the compounds of formula (I) are included within the scope of this invention.
  • the cycloalkyl group within R1 or R2 may be a monocydic or bridged cyclic ring.
  • suitable cycloalkyl ring systems include C3.8 monocydic cycloalkyl groups such as cyclopropyl, cyclopentyl and cyclohexyl.
  • the C3_s cycloalkyl group may particularly represent cyclopentyl or cyclohexyl.
  • 'aryl' as part of an group may represent, for example, a phenyl group optionally substituted by one or more substituents (e.g. 1 , 2 or 3 substituents) which may be the same or different and are selected from halogen, hydroxyl, C*i-3alkoxy and C ⁇ _3alkyl.
  • substituents e.g. 1 , 2 or 3 substituents
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group.
  • suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.
  • alkylene' as part of a group means a straight or branched alkylene chain.
  • suitable alkylene chains include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CHCH3CH2- and -CH 2 C(CH3) 2 CH 2 -.
  • the C2-6alkylene group may particularly represent -CH2CH2-, -CH2CH2CH2- or -CH 2 C(CH3) 2 CH2-.
  • R 2 represents a group -(CHR 5 ) m (Alk2) n Z
  • the chain -(CHR 5 ) m (Alk2) n - may particularly represent a bond, -CH2-, -CH2CH2-, -CHR 5 CHCH3CH2- or -CHR 5 CH2- (where R 5 is a group CH2R 6 and R 6 is as defined previously).
  • 'C2-7acylamino' within R 2 means a C2-7alkanoylamino group wherein the C-i- ⁇ alkyl portion thereof is a straight or branched alkyl group as previously defined and may be optionally substituted by one or more halogen atoms such as fluorine.
  • suitable C2-7alkanoylamino groups within R 2 include acetamido and trifluoroacetamido.
  • the term 'pyridyl' means a 2-, 3- or 4-pyridyl group;
  • the term 'pyrimidinyl' means a 2-, 4- or 5-pyrimidinyl group;
  • the term 'imidazolyl * means a 1-.2- 4- or 5-imidazolyl group;
  • the term 'triazolyl' means a 1 , 2, 4-triazolyl group (e.g. 1, 2, 4-thazol-l-yl or 1 , 2, 4-triazol-3-yl).
  • R " - preferably represents a C*]_3alkyl group, especially ethyl.
  • a preferred group of compounds of the invention are compounds of formula (I) in which R 2 represents a substituted cyclopentyl or cyclohexyl group wherein the ring is substituted by one or two groups, especially one or two groups selected from hydroxy, Nh , methylamino, dimethylamino, acetamido or trifluoroacetamido.
  • Preferred substituents include hydroxy, NH 2 and dimethylamino.
  • a further preferred group of compounds of the invention are compounds of formula (I) in which R 2 represents a pyrrolidin-3-yl or piperidin-3-yl group in which the ring nitrogen atom is substituted by hydrogen, C ⁇ _3alkyl (e.g. ethyl) or benzyl.
  • R 2 represents (CHR 5 ) m (Alk2) n Z where R 5 , m and n are as defined previously and Z is an optionally substituted imidazolyl group.
  • Particularly preferred are those compounds in which -(CH2R ⁇ ) (Alk2)n- represents -CH2CH2-.
  • Specific compounds of the present invention include: (1 S,2R,3S,4R)-4-[trans-2-(4-Amino-cyclohexylamino)-6-(2,2-diphenyl- ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentanecarboxylic acid ethylamide;
  • compounds of formula (I) to inhibit leukocyte function may be demonstrated, for example, by their ability to inhibit superoxide (O2") generation from neutrophils stimulated with chemoattractants such as N- formylmethionyl-leucyl-phenylalanine (fMLP). Accordingly, compounds of formula (I) are of potential therapeutic benefit in providing protection from leukocyte-induced tissue damage in diseases where leukocytes are implicated at the site of inflammation.
  • OF2 superoxide
  • fMLP N- formylmethionyl-leucyl-phenylalanine
  • Examples of disease states in which the compounds of the invention have potentially beneficial anti-inflammatory effects include diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis (including chronic bronchitis), cystic fibrosis, asthma (including allergen-induced asthmatic reactions), emphysema, rhinitis and septic shock.
  • Other relevant disease states include diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), Helicobacter-pylori induced gastritis and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure, and non-steroidal anti-inflammatory drug-induced gastropathy.
  • compounds of the invention may be used to treat skin diseases such as psoriasis, allergic dermatitis and hypersensitivity reactions.
  • cardiac conditions such as peripheral vascular disease, post-ischaemic reperfusion injury and idiopathic hypereosinophilic syndrome.
  • Compounds of the invention which inhibit lymphocyte function also have use in the treatment of auto-immune diseases such as rheumatoid arthritis and diabetes.
  • Compounds of the invention may also be useful in inhibiting metastasis.
  • compounds of formula (I) are useful in human or veterinary medicine, in particular as anti-inflammatory agents.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory conditions who are susceptible to leukocyte-induced tissue damage.
  • a method for the treatment of a human or animal subjed with an inflammatory condition who is susceptible to leukocyte-induced tissue damage comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • compositions for use in anti-inflammatory therapy comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together, if desirable, with one or more physiologically acceptable carriers or excipients.
  • the compounds according to the invention may, for example, be formulated for oral, buccal, parenteral, topical or rectal administration, preferably for parenteral or topical (e.g. by aerosol) administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution 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, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non- aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl ⁇ - hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweeten
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • topical administration as used herein, we include administration by insufflation and inhalation.
  • preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator, solutions for nebulisation or drops (e.g. eye or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol.
  • Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.
  • Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1,1,1,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1,1,1,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Capsules and cartridges of for example gelatin, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
  • the pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example anti-inflammatory agents such as corticosteroids or NSAIDs.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example an anti- inflammatory agent such as a corticosteroid or NSAID.
  • another therapeutically active agent for example an anti- inflammatory agent such as a corticosteroid or NSAID.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further aspect of the invention.
  • Compounds of the invention may conveniently be administered in amounts of, for example, 0.01 to 500mg/kg body weight, preferably 0.01 to 100mg/kg body weight, 1 to 4 times daily.
  • the precise dose will of course depend on the age and condition of the patient and the particular route of administration chosen.
  • a compound of formula (I) may be prepared by treating a compound of formula (II)
  • R a and R* 3 each represent a hydrogen atom or together form an alkylidene group such as isopropylidene
  • siH2 wherein R2a is a group R or is a protected derivative thereof
  • the displacement reaction to introduce the amine moiety may be carried out by heating the reagents at a temperature in the range of 50 u to 150 ⁇ 0 optionally in the presence of a solvent such as dimethylsulphoxide.
  • a compound of formula (II) in which Q represents a sulphur atom may be prepared from a compound of formula (II) in which Q represents an oxygen atom and R a and R D together form an alkylidene group such as isopropylidene by thianation followed, if appropriate, by the removal of the alkylidene group.
  • the thianation readion may be conveniently effected using known thianation agents such as hydrogen sulphide, phosphorus pentasulphide or Lawesson's reagent (p-methoxyphenylthiophosphine sulphide dimer).
  • the readion may be carried out in a known manner.
  • an acid such as hydrochloric acid may conveniently be added in catalytic amounts and the reaction carried out in a polar solvent such as acetic acid or ethanol.
  • Lawesson's reagent the readion may conveniently be carried out in a dry solvent such as toluene or methylene chloride.
  • a compound of formula (II) in which Q represents an oxygen atom may be prepared by treating a compound of formula (III)
  • R a and R D are as defined previously
  • 2,2-diphenylethylamine preferably in the presence of a base such as an amine base (e.g. diisopropylethylamine) and in a solvent such as an alcohol (e.g. isopropanol) at an elevated temperature (e.g. reflux), followed if desired by removing any protecting groups present.
  • a base such as an amine base (e.g. diisopropylethylamine)
  • a solvent such as an alcohol (e.g. isopropanol) at an elevated temperature (e.g. reflux)
  • R 1 , R a and R b are as previously defined
  • compounds of formula (II) may be prepared from compounds of formula (IV) by reaction with a compound of formula (R c O) 2 CH0 2 CR d (where R c and R d each independently represents C 1 _ alkyl) followed by readion with 2,2-diphenylethylamine, preferably in the presence of a base as previously described followed if desired by removing any protecting groups present.
  • Suitable bases for use in the reaction include tertiary amines such as, for example, triethylamine.
  • the reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, butanol, preferably at elevated temperature, such as the reflux temperature of the chosen solvent.
  • Compounds of formula (V) may be prepared by any of the methods known in the art for the preparation of compounds of analogous structure. For example, according to one method, compounds of formula (V) may be prepared from intermediates of formula (VI)
  • OR 1 OR by reaction with an amine of formula R 1 NH 2 at elevated temperature and pressure.
  • a compound of formula (II) in which Q represents an oxygen atom may also be prepared by treating a compound of formula (VIII)
  • R a and R* 3 are as defined previously
  • an active derivative thereof such as a corresponding mixed anhydride with an amine R 1 NH2, followed if desired by removing any protecting groups present.
  • the amination reaction may be effeded in known manner, for example by adding the amine in a solvent s ⁇ ch as a halogenated hydrocarbon (e.g. methylene chloride) or in dimethylformamide, in the presence of an amine such as triethylamine at about 0° to 20°C to the compound (VIII) or, more particularly, a corresponding mixed anhydride.
  • a solvent s ⁇ ch as a halogenated hydrocarbon (e.g. methylene chloride) or in dimethylformamide
  • an amine such as triethylamine at about 0° to 20°C
  • the mixed anhydride may be prepared, for example, by treating compound (VIII) with pivaloyl chloride, conveniently at about 0°C.
  • a compound of formula (VIII) may be prepared by oxidising a compound of formula (IX)
  • OR * OR or a salt thereof (wherein R a and R D together form an alkylidene group such as isopropylidene), followed if desired by removing the alkylidene group.
  • the oxidation reaction may be effected in known manner using an oxidising agent such as potassium permanganate or pyridinium dichromate, or, preferably, ruthenium trichloride in the presence of sodium periodate .
  • a compound of formula (IX) wherein R a and R b each represents H may be prepared by treating a compound of formula (X)
  • R p is a suitable hydroxyl protecting group, such as an acyl group
  • R p is a suitable hydroxyl protecting group, such as an acyl group
  • a suitable chlorinating agent such as pyridine hydrochloride in the presence of copper (I) chloride and t-butyl nitrite.
  • the amines R2aNH2 are either known in the art or may be prepared by the methods described in the Examples Section hereinafter or by methods analogous to such methods hereinafter.
  • Compounds of formulae (II), (VIII), (IX) and (X) are novel intermediates and represent further aspeds of the present invention.
  • Compounds of formula (II) in which R a and R D represent hydrogen atoms are also adive compounds in their own right and constitute a further particular aspect of the present invention.
  • a compound of formula (I) may be prepared by subjecting a protected derivative of a compound of formula (I) to readion to remove the proteding group or groups.
  • Protedion and deprotection of functional groups may be effeded using conventional means.
  • amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) or sulphonyl (e.g.
  • Hydroxyl groups may be proteded using any conventional hydroxyl protecting group, for example, as described in "Protedive Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press,
  • hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • alkyl e.g. methyl, t-butyl or methoxymethyl
  • aralkyl e.g. benzyl, diphenylmethyl or triphenylmethyl
  • heterocyclic groups such as tetrahydropyranyl
  • acyl e.g. acetyl or benzoyl
  • silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • the hydroxyl protecting groups
  • alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic conditions.
  • Aralkyl groups such as triphenylmethyl may similarly be removed by solvolysis, e.g. by hydrolysis under acidic conditions.
  • Aralkyl groups such as benzyl may be cleaved by hydrogenolysis in the presence of a Noble metal catalyst such as palladium-on-charcoal.
  • Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
  • Carboxyl protecting groups may conveniently be represented by appropriate hydroxyl protecting groups above with deprotection effected according to the methods described above.
  • An example of such a group is an alkyl (e.g. methyl or t- butyl) group which can be removed by acid hydrolysis (e.g. using t fluoroacetic or hydrochloric acid) or an aralkyl (e.g. benzyl) group which can be removed by catalytic hydrogenolysis.
  • Particularly suitable hydroxyl proteding groups represented by R* 3 include acyl groups such as acetyl or benzoyl.
  • An alkylidene protecting group may conveniently be removed by acid-catalysed hydrolysis, for example using thfluoroacetic, sulphuric or hydrochloric acid.
  • Compounds of formula (I) may also be prepared from other compounds of formula (I) or protected derivatives thereof using conventional interconversion procedures, including N-acylation, N-debenzylation and oxidation of a hydroxyl group to a ketone, followed, if necessary, by the removal of any protecting groups present.
  • Individual isomers of formula (I) may either be prepared from starting materials having the desired stereochemistry or by epimerisation, resolution or chromatography (e.g. HPLC separation) at an appropriate stage in the synthesis of the required compounds of formula (I) as appropriate using conventional means.
  • the product of the above procedure may be converted into a salt by treatment of the resulting free base with a suitable acid using conventional methods.
  • Physiologically acceptable acid addition salts of the compounds of formula (I) may be prepared by reacting a compound of formula (I) in the form of a free base with an appropriate acid optionally in the presence of a suitable solvent such as an ester (e.g. ethyl acetate) or an alcohol (e.g. methanol, ethanol or isopropanol).
  • a suitable solvent such as an ester (e.g. ethyl acetate) or an alcohol (e.g. methanol, ethanol or isopropanol).
  • Inorganic basic salts may be prepared by reacting a compound of formula (I) using conventional methods.
  • Solvates e.g. hydrates
  • a compound of formula (I) may be formed during the work-up procedure of one of the aforementioned process steps.
  • 'silica' refers to silica gel for chromatography, 0.063 to 0.20mm mesh (e.g. Merck Art 7735); 'flash silica' refers to silica gel for chromatography, 0.040 to 0.063mm mesh (e.g. Merck Art 9385).
  • column elution was accelerated by an applied pressure of nitrogen at up to 10 p.s.i
  • N,N-dimethyl formamide 400ml was stirred at room temperature for 24h. (It became a clear solution by 2h and again a suspension by 24h). The precipitate was collected by filtration, washed with a small quantity of ethyl acetate to give the title compound (7.95g) as a white solid. The filtrate was evaporated to dryness and the residue was triturated with ethyl acetate to give more of the title compound (47.52o) as a white solid.
  • H22 CI2 N5 O3 requires 390.109970, 1 H nmr ⁇ (CDCI3) 1.18 (t, 3H), 1.28 (s, 1H). 1.46 (s, 1 H), 1.85-2.67 (m,2H) 2.85 (d, 1 H), 3.32 (m,2 H), 3.66 (s, 2H), 4.52 (d, 1H), 4.75 (t, 2H), 5.94 (s, 1 H), 8.06 (d 1 H).
  • Triethylorthoformate (8ml) and concentrated hydrochloric acid (0.1ml) was added to (3aR,4S,6R,6aS)--6-(5-Amino-2 I 6-dichloro-pyrimidin-4-ylamino)-2,2- dimethyl-tetrahydro-cyclopenta [1 ,3] dioxole-4-carboxylic acid ethylamide (500 mg).
  • the reaction mixture was stirred at room temperature for 24h and then the solvent was evaporated under reduced pressure to give a gum.
  • This gum was treated with butan-l-ol (15ml) and heated under reflux under nitrogen for 4 days. It was allowed to cool and the solvent was evaporated under reduced pressure to give a brown foam (576mg). This was purified by column chromatography on flash silica eluted with methanol-chloroform mixtures (0%
  • (CHBr3) v includes 3420.6, 1616.5cm "1 ' > 1 H nmr ⁇ (CDCI3) includes 1.18 (t, 3H), 1.31 (s, 3H), 1.56 (s, 3H), 2.45-2.71 (m, 2H), 2.74-2.87 (m, 1 H), 3.24-3.41 (m, 2H), 4.25 (bs, fine coupling, 2H), 4.36 (t, 1H), 4.78-5.0 (m, 3H), 5.78 (s, fine coupling, 1 H), 5.94 (s, 1H), 7.08-7.41 (m, 10H), 7.77 (s, 1H).
  • the readion mixture was stirred at room temperature for 4.5h and then the solvent was removed under reduced pressure to give a brown foam.
  • the foam was treated with butan-1-ol (15ml) and heated under reflux under nitrogen for 18h.
  • the readion mixture was allowed to cool and the solvent was evaporated under reduced pressure to give a gum.
  • a solution of the gum in acetonitrile (25ml) was treated with 2M hydrochloric acid (40ml) and stirred at room temperature for 3h.
  • the solvent was removed under reduced pressure by azeotroping with toluene several times to give a gum (489 mg).
  • Carbocyclic Guanosine 2 (38g) was dissolved in acetonitrile (760 ml). Dimethylaminopyridine (200 mg) was then added and the solution maintained at 20 °C in a water bath. Acetic anhydride (47.5 ml) was then added dropwise over 35 min. with stirring. After 1 h the dark solution was treated with methanol (40 ml) and stirred for a further 20 min. Evaporation of the solvent under reduced pressure gave the crude product as an oil. Trituration of this oil with water (200 ml) gave the title compound as a brown solid (41 g). MH + measured at 408.151909 C17H22N5O7 requires 408.151923.
  • - H nmr ⁇ (DMSO-d6) includes 7.86 (s, 1H), 6.46 (s, 2H), 5.57 (m, 1 H), 5.21 (m, 1 H), 4.85 (m, 1 H), 4.20 (m, 2H), 3.4 (m, 1 H), 2.35 (m, 1 H), 1.85 (m, 1 H), 2.1 (s, 3H), 2.08 (s, 3H),
  • nmr ⁇ (DMSO-d6) includes 8.18 (s, 1H), 7.4-7.16 (m, 10H), 4.63 (m, 1 H), 4.57 (m, 1 H), 4.25 (m, 1 H), 4.04 (m, 1 H), 3.83 (m, 1 H), 3.52 - 3.4 (m, 2H), 2.23 (m, 1 H), 2.03 (m, 1 H), 1.61 (m, 1 H).
  • 1 H nmr ⁇ (CD3OD) includes 8.03 (s, 1 H), 7.36 - 7.12 (m, 10H), 5.10 (m, 2H), 4.95 - 4.70 (m. 1 H), 4.47 (t, J 7.5Hz, 1 H), 4.20 (m, 2H), 3.05 (m, 1H), 2.60 (m, 2H), 1.56 (s, 3H). 1.32 (s, 3H).
  • 1 H nmr ⁇ (CDCI3) includes 7.43 (s, 1H), 7.36 (m, 10H), 4.55 - 4.1 (m, 6H), 3.55 - 3.25 (m, 4H), 2.85 (m, 1 H), 2.77 - 2.32 (m, 8H), 1.66 - 1.36 (m, 6H), 1.18 (t, 7 Hz, 3H).

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  • Organic Chemistry (AREA)
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Abstract

Des dérivés de 2,3-dihydroxycyclopentane ont la formule générale (I), dans laquelle R1 représente hydrogène, cycloalcoyle C¿3-8? ou alcoyle C1-6; R?2¿ représente cycloalcoyle C¿3-8?, alcoyle C1-6 de cycloalcoyle C3-8; Alk1Y, -(CHR?5)¿m(Alk2)nZ ou cycloalcoyle C3-8, alcoyle C1-6 de cycloalcoyle C3-8, pyrrolidin-3-yle, 2-oxopyrrolidin-4-yle, 2-oxopyrrolidin-5-yle, pipéridin-3-yle ou pipéridin-4-yle substitués de manière appropriée, et Q représente oxygène ou soufre. Les composés ayant la formule (I), ainsi que leurs sels et solvates, sont utiles en médecine comme agents anti-inflammatoires, notamment pour traiter des patients souffrant d'états inflammatoires et susceptibles de présenter des lésions tissulaires induites par des leucocytes.
PCT/EP1995/002705 1994-07-14 1995-07-12 Derives 2,3-dihydroxycyclopentane de purines WO1996002543A1 (fr)

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AU29829/95A AU2982995A (en) 1994-07-14 1995-07-12 2,3-dihydroxy cyclopentane derivatives of purines

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WO1999043676A3 (fr) * 1998-02-26 1999-10-21 Hoechst Marion Roussel Inc 2-[trans-(4- aminocyclohexyl) amino]purines 6,9-disubstituees
US6413974B1 (en) 1998-02-26 2002-07-02 Aventis Pharmaceuticals Inc. 6,9,-disubstituted 2-[trans-(4-aminocyclohexyl) amino] purines
JP2002193967A (ja) * 2000-07-10 2002-07-10 Sumika Fine Chemicals Co Ltd ２，６−ジクロロプリンの製造方法
US6426337B1 (en) 1996-12-24 2002-07-30 Smithkline Beecham Corporation 2-(Purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6479487B1 (en) 1998-02-26 2002-11-12 Aventis Pharmaceuticals Inc. 6, 9-disubstituted 2-[trans-(4-aminocyclohexyl)amino] purines
US6495528B1 (en) 1998-06-23 2002-12-17 Smithkline Beecham Corporation 2-(Purin -9-yl)-tetrahydrofuran-3,4-diol derivatives
US6762170B1 (en) 1998-01-31 2004-07-13 Smithklinebeecham Corporation 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6861524B2 (en) 2000-10-31 2005-03-01 Aventis Pharmaceuticals Inc. Acyl and sulfonyl derivatives of 6,9-disubstituted 2-(trans-1,4-diaminocyclohexyl)-purines and their use as antiproliferative agents
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WO2008037477A1 (fr) 2006-09-29 2008-04-03 Novartis Ag PYRAZOLOPYRIMIDINES UTILISÉES COMME INHIBITEURS DES LIPIDES KINASES Pl3K
WO2008052734A1 (fr) 2006-10-30 2008-05-08 Novartis Ag Composés hétérocycliques en tant qu'agents anti-inflammatoires
WO2009087224A1 (fr) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
EP2157091A1 (fr) 2003-05-02 2010-02-24 Novartis AG Inhibiteurs de phosphatidylinositol 3-kinase
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
EP2206499A1 (fr) 2004-11-02 2010-07-14 Novartis AG Derives de quinuclidine et leur utilisation en tant qu'antagonistes des recépteurs muscariniques m3
WO2010088335A1 (fr) 2009-01-29 2010-08-05 Novartis Ag Benzimidazoles substitués destinés au traitement d'astrocytomes
EP2270008A1 (fr) 2005-05-20 2011-01-05 Novartis AG 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones comme inhibiteurs de kinases lipidiques et/ou de la pi3 kinase
EP2281819A1 (fr) 2004-01-21 2011-02-09 Novartis AG Dérivés du benzimidazole ou du benzoxazole
WO2011015652A1 (fr) 2009-08-07 2011-02-10 Novartis Ag Dérivés 3-hétéroarylméthyl-imidazo[1,2-b]pyridazin-6-yliques comme modulateurs de la tyrosine kinase c-met
WO2011018454A1 (fr) 2009-08-12 2011-02-17 Novartis Ag Composés hydrazone hétérocycliques et leurs utilisations pour traiter le cancer et l'inflammation
EP2286813A2 (fr) 2006-01-31 2011-02-23 Novartis AG Utilisation de dérivés de naphthyridine comme medicaments
WO2011020861A1 (fr) 2009-08-20 2011-02-24 Novartis Ag Composés d'oximes hétérocycliques
WO2011022439A1 (fr) 2009-08-17 2011-02-24 Intellikine, Inc. Composés hétérocycliques et leurs utilisations
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
WO2012034095A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions comme inhibiteurs de trk
WO2012034091A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions à titre d'inhibiteurs de trk
WO2012107500A1 (fr) 2011-02-10 2012-08-16 Novartis Ag Composés de [1, 2, 4] triazolo [4, 3 -b] pyridazine en tant qu'inhibiteurs de la tyrosine kinase c-met
WO2012116217A1 (fr) 2011-02-25 2012-08-30 Irm Llc Composés et compositions en tant qu'inhibiteurs de trk
WO2012116237A2 (fr) 2011-02-23 2012-08-30 Intellikine, Llc Composés hétérocycliques et leurs utilisations
EP2532679A1 (fr) 2005-10-21 2012-12-12 Novartis AG Anticorps humains dirigés contre l'IL -13 et utilisations thérapeutiques
WO2013038362A1 (fr) 2011-09-15 2013-03-21 Novartis Ag 3-(quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyradines substituées en position 6 à activité tyrosine kinase
WO2013149581A1 (fr) 2012-04-03 2013-10-10 Novartis Ag Produits combinés comprenant des inhibiteurs de tyrosine kinase et leur utilisation
WO2014151147A1 (fr) 2013-03-15 2014-09-25 Intellikine, Llc Combinaison d'inhibiteurs de kinase et ses utilisations
WO2015084804A1 (fr) 2013-12-03 2015-06-11 Novartis Ag Combinaison d'un inhibiteur de mdm2 et d'un inhibiteur de braf, et leur utilisation
US9174994B2 (en) 2011-11-23 2015-11-03 Intellikine, Llc Enhanced treatment regimens using mTor inhibitors
WO2016011956A1 (fr) 2014-07-25 2016-01-28 Novartis Ag Polythérapie
WO2016016822A1 (fr) 2014-07-31 2016-02-04 Novartis Ag Polythérapie
EP3603634A1 (fr) 2004-05-18 2020-02-05 Novartis AG Composition pharmaceutique comprenant du glycopyrrolate et un agoniste du récepteur beta2 adrénergique
WO2021152488A1 (fr) 2020-01-29 2021-08-05 Novartis Ag Méthodes de traitement d'une maladie inflammatoire ou obstructive des voies respiratoires à l'aide d'un anticorps anti-tslp
US11666888B2 (en) 2018-02-05 2023-06-06 Bio-Rad Laboratories, Inc. Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand

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US6528494B2 (en) 1996-12-24 2003-03-04 Brian Cox 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6762170B1 (en) 1998-01-31 2004-07-13 Smithklinebeecham Corporation 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1999043676A3 (fr) * 1998-02-26 1999-10-21 Hoechst Marion Roussel Inc 2-[trans-(4- aminocyclohexyl) amino]purines 6,9-disubstituees
US6413974B1 (en) 1998-02-26 2002-07-02 Aventis Pharmaceuticals Inc. 6,9,-disubstituted 2-[trans-(4-aminocyclohexyl) amino] purines
US6479487B1 (en) 1998-02-26 2002-11-12 Aventis Pharmaceuticals Inc. 6, 9-disubstituted 2-[trans-(4-aminocyclohexyl)amino] purines
CN1128149C (zh) * 1998-02-26 2003-11-19 阿旺蒂斯制药公司 6,9－二取代的2－[反－(4－氨基环己基)氨基]嘌呤
US6495528B1 (en) 1998-06-23 2002-12-17 Smithkline Beecham Corporation 2-(Purin -9-yl)-tetrahydrofuran-3,4-diol derivatives
JP2002193967A (ja) * 2000-07-10 2002-07-10 Sumika Fine Chemicals Co Ltd ２，６−ジクロロプリンの製造方法
US6861524B2 (en) 2000-10-31 2005-03-01 Aventis Pharmaceuticals Inc. Acyl and sulfonyl derivatives of 6,9-disubstituted 2-(trans-1,4-diaminocyclohexyl)-purines and their use as antiproliferative agents
US7429595B2 (en) 2000-10-31 2008-09-30 Aventis Pharmaceuticals Inc. Acyl and sulfonyl derivatives of 6,9-disubstituted 2-(trans-1,4-diaminocyclohexyl)-purines and their use as antiproliferative agents
EP2157091A1 (fr) 2003-05-02 2010-02-24 Novartis AG Inhibiteurs de phosphatidylinositol 3-kinase
EP2281819A1 (fr) 2004-01-21 2011-02-09 Novartis AG Dérivés du benzimidazole ou du benzoxazole
EP3603634A1 (fr) 2004-05-18 2020-02-05 Novartis AG Composition pharmaceutique comprenant du glycopyrrolate et un agoniste du récepteur beta2 adrénergique
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
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WO2006056471A1 (fr) 2004-11-29 2006-06-01 Novartis Ag Derives de 5-hydroxy-benzothiazole presentant une activite agoniste de l'adrenorecepteur beta-2
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EP2292617A1 (fr) 2005-05-20 2011-03-09 Novartis AG Dérivés de 1,3-dihydro-imidazo[4,5-c]quinolin-2-one comme inhibiteurs de kinase lipidique et/ou de kinase pi3
EP2270008A1 (fr) 2005-05-20 2011-01-05 Novartis AG 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones comme inhibiteurs de kinases lipidiques et/ou de la pi3 kinase
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
EP2532677A1 (fr) 2005-10-21 2012-12-12 Novartis AG Anticorps humains dirigés contre l'IL -13 et utilisations thérapeutiques
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WO2008052734A1 (fr) 2006-10-30 2008-05-08 Novartis Ag Composés hétérocycliques en tant qu'agents anti-inflammatoires
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