US20030144243A1 - Combination of a crystalline drug form and atiotropium salt - Google Patents

Combination of a crystalline drug form and atiotropium salt Download PDF

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Publication number
US20030144243A1
US20030144243A1 US10/308,829 US30882902A US2003144243A1 US 20030144243 A1 US20030144243 A1 US 20030144243A1 US 30882902 A US30882902 A US 30882902A US 2003144243 A1 US2003144243 A1 US 2003144243A1
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ethyl
diphenylethyl
carboxamide
purine
ribofuranosyluronamide
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Terrence Silk
Julian Smith
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Pfizer Inc
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Pfizer Inc
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Assigned to PFIZER INC. reassignment PFIZER INC. CONSENT Assignors: PFIZER LIMITED
Assigned to PIFZER INC. reassignment PIFZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SILK, TERRENCE VERNON, SMITH, DUNCAN
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    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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    • C07H19/16—Purine radicals

Definitions

  • the present invention relates to a combination of a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide and a tiotropium salt.
  • 6-[(2,2-Diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide also known as 6-[(2,2-diphenylethyl)amino]-9- ⁇ (2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl ⁇ -N- ⁇ 2-[( ⁇ [1-(2-pyridinyl)-4-piperidinyl]amino ⁇ carbonyl)amino]ethyl ⁇ -9H-purine-2-carboxamide) has the structure shown in formula (I) and its preparation is disclosed in International Patent Application number PCT/IB01/00973, published as WO-A-01/
  • 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl] ureido ⁇ ethyl)-9H-purine-2-carboxamide is a selective, functional agonist of the human adenosine A2a receptor and may be used as an anti-inflammatory agent in the treatment of, inter alia, diseases of the respiratory tract. It may therefore be used to treat any disease for which an adenosine A2a receptor agonist is indicated.
  • leukocyte e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • chronic obstructive pulmonary disease cystic fibrosis
  • asthma emphysema
  • bronchiectasis chronic sinusitis and rhinitis.
  • septic shock male erectile dysfunction
  • male factor infertility female factor infertility
  • hypertension stroke
  • epilepsy cerebral ischaemia
  • peripheral vascular disease post-ischaemic reperfusion injury
  • diabetes rheumatoid arthritis
  • multiple sclerosis psoriasis
  • dermatitis allergic dermatitis
  • eczema ulcerative colitis
  • Crohns disease inflammatory bowel disease
  • Heliobacter pylon gastritis non- Heliobacter pylori gastritis
  • non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or a psychotic disorder or for wound healing.
  • Examples 8 and 35 of PCT/IB01/00973 both describe the preparation of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide. These methods provide a solid, amorphous form of the compound (see comparative examples 1 and 2 below).
  • a crystalline form of a drug compound has advantages over an amorphous form in several respects.
  • the compound can be easily purified by crystallisation and recrystallisation.
  • Crystallisation is a much cheaper and more convenient method of purification to perform on a large scale than other known methods of purification such as chromatography.
  • a crystalline form is usually more stable than an amorphous form, both before and during formulation and during subsequent storage.
  • it is generally easier to mill or micronise a crystalline form to a respirable size (generally considered as particles less than 5 microns in diameter) than an amorphous form.
  • the invention provides a combination of a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl] ureido ⁇ ethyl)-9H-purine-2-carboxamide and a tiotropium salt.
  • a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide may be prepared by a process comprising the steps of:
  • the process presented provides a unique and unconventional set of conditions that unexpectedly solve the problem of preparing a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide.
  • the crystalline form provided by the above process has a further unexpected advantage in that it leads to a higher resistivity than the amorphous form at an equivalent concentration in solution.
  • This is of particular benefit in preparing a formulation for use in an atomiser that operates by the principles of electrohydrodynamics (see below) since it is possible to lower the resistivity in such a formulation by the addition of, for example, sodium chloride, but it is currently not possible to raise it.
  • the higher the resistivity of a compound when formulated in solution the more flexibility exists in the choice of a final resistivity for the formulation.
  • Any organic solvent may be used in the process which is capable of dissolving both amorphous 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide and at least 2% w/w water.
  • suitable solvent include 2-butanone, ethyl acetate, acetonitrile, isopropyl acetate, isopropanol, methyl acetate, butan-2-ol and methyl acetate.
  • Preferred organic solvents are 2-butanone, methyl acetate and ethyl acetate. Methyl acetate and ethyl acetate are particularly preferred.
  • the water content of an organic solvent may conveniently be measured using the Karl-Fischer method.
  • a temperature of at least 50° C. is necessary to induce crystallisation at a practicable rate.
  • a temperature of from 50° C. to 80° C. is used.
  • Crystallisation will usually be complete within 24 to 72 hours but longer and shorter periods are possible depending on the choice of organic solvent and temperature.
  • a crystalline form of 6-[(2,2-Diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide and a tiotropium salt can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. They may be administered separately, simultaneously or sequentially.
  • they can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. They may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations may be in coated or uncoated form, as desired.
  • Such solid pharmaceutical compositions may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, stearic acid, glyceryl behenate and talc may be included.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glyco
  • a formulation of the tablet could typically contain from 0.01 mg to 500 mg of active compound whilst tablet fill weights may range from 50 mg to 1000 mg.
  • An example of a formulation for a 10 mg tablet is illustrated below: Ingredient % w/w Compound(s) of the invention 10.000* Lactose 64.125 Starch 21.375 Croscarmellose sodium 3.000 Magnesium Stearate 1.500
  • the tablets can be manufactured by a standard process, for example, direct compression or a wet or dry granulation process.
  • the tablet cores may be coated with appropriate overcoats.
  • compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or a high molecular weight polyethylene glycol.
  • the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol or glycerin, and combinations thereof.
  • the compounds of the invention can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, a co-solvent and/or enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the daily dosage level of the compounds of the invention will usually be from 0.00001 to 100 mg/kg, preferably from 0.0001 to 100 mg/kg (in single or divided doses).
  • tablets or capsules of the compounds of the invention may contain from 0.01 to 500 mg of an active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • the compounds of invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder (either alone or as a mixture, for example a mixture with lactose) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist) or nebuliser, with or without the use of a suitable propellant, e.g.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol (optionally, aqueous ethanol) or a suitable agent for dispersing, solubilising or extending release and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • a lubricant e.g. sorbitan trioleate.
  • Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I-leucine, mannitol or magnesium stearate.
  • the compounds of the invention Prior to use in a dry powder formulation or suspension formulation for inhalation the compounds of the invention will be reduced to a particle size suitable for delivery by inhalation (typically considered as less than 5 microns). Production of particles in a suitable size range could be achieved by the use of a range of destructive methods, for example spiral jet milling or fluid bed jet milling or by use of a range of constructive methods such as supercritical fluid crystallisation or spray drying.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 10 mg of a compound of the invention per actuation and the actuation volume may vary from 1 to 100 ⁇ l.
  • a typical formulation may comprise the compounds of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents may be used in place of propylene glycol, for example glycerol or polyethylene glycol.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or “puff” contains from 1 to 4000 ⁇ g of the compounds of the invention for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 1 ⁇ g to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the compounds of the invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • the compounds of the invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary, vaginal or rectal routes.
  • the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the invention may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
  • the compounds of the invention may be administrated separately, sequentially or simultaneously.
  • a pharmaceutical composition including a combination of a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide and a tiotropium salt together with a pharmaceutically acceptable excipient, diluent or carrier;
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • chronic obstructive pulmonary disease cystic fibrosis
  • asthma emphysema
  • bronchiectasis chronic sinusitis and rhinitis
  • (xii) use as in (xi) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • chronic obstructive pulmonary disease cystic fibrosis
  • asthma emphysema
  • bronchiectasis chronic sinusitis and rhinitis
  • a method of treatment of a mammal, including a human being, with an A2a receptor agonist including treating said mammal with an effective amount of combination of a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide and a tiotropium salt;
  • (xv) a method of treatment of a mammal, including a human being, to treat an inflammatory disease including treating said mammal with an effective amount of a combination of a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide and a tiotropium salt;
  • a method of treatment of a mammal, including a human being, to treat a respiratory disease including treating said mammal with an effective amount of a combination of a crystalline form of 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide and a tiotropium salt;
  • (xvii) a method as in (xvi) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis; and
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • chronic obstructive pulmonary disease cystic fibrosis
  • asthma emphysema
  • bronchiectasis chronic sinusitis and rhinitis
  • Amorphous 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide (5.0 g, 0.0064 moles) was charged to a vessel equipped with a Teflon (Trade Mark)-covered magnetic stirrer bar, a thermometer and a condenser. A solution of 2%v/v water in 2-butanone (50 ml) was then added, and the resultant mixture was heated to 69-71° C.
  • the infrared spectrum was acquired using a Nicolet 360 Avatar FT-IR spectrometer fitted with a d-TGS detector and a single reflection diamond ATR accessory (Golden GateTM).
  • the sample was prepared by placing ca. 0.5 mg of sample on the diamond ATR crystal and ensuring good crystal sample contact by applying pressure through an anvil with a built-in pressure control mechanism.
  • the spectrum was recorded at 4 cm ⁇ 1 resolution using 32 background and 32 sample scans with a Happ Genzel apodisation function.
  • the powder X-ray diffraction pattern was determined using a SIEMENS D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter.
  • the analysis was performed with the goniometer running in step-scan mode set for a 5 second count per 0.02° step over a two theta range of 4° to 45°.
  • the relative intensities of the various peaks within Table 1 may vary due to a number of factors such as for example orientation effects of crystals in the X-ray beam or the purity of the material being analysed or the degree of crystallinity of the sample.
  • the peak positions may also shift for variations in sample height but the peak positions will remain substantially as defined in Table 1.
  • Such further PXRD patterns generated by use of alternative wavelengths are considered to be alternative representations of the PXRD pattern of the crystalline material of the present invention and as such are within the scope of the present invention.
  • Ethyl acetate 25 ml was shaken with deionised water (10 ml) at ambient temperature and the organic phase was collected to give a solution of ethyl acetate that was saturated with water.
  • Amorphous 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide 1.0 g, 0.0013 moles was charged to a vessel equipped with a Teflon®-covered magnetic stirrer bar and a condenser.
  • a 2%v/v solution of water in acetonitrile was prepared by dissolving deionised water (2.0 ml) in acetonitrile and then making the volume up to 100 ml with acetonitrile.
  • Amorphous 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide (1.0 g, 0.0013 moles) was charged to a vessel equipped with a teflon®-covered magnetic stirrer bar and a condenser.
  • a 2%v/v solution of water in acetonitrile as prepared above (10 ml) was then added to the amorphous solid, and the resultant mixture was heated to 55-60° C. under an atmosphere of nitrogen.
  • a seed (approximately 0.005 g) of crystalline 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide was then added and the resultant mixture was stirred at 55-60° C. for 3 days after which time a thick slurry had formed.
  • a 2%v/v solution of water in isopropanol as prepared above (10 ml) was then added to the amorphous solid, and the resultant mixture was heated to 55-60° C. under an atmosphere of nitrogen.
  • a seed (approximately 0.005 g) of crystalline 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide was then added and the resultant mixture was stirred at 55-60° C. for 8 days over which time a slurry formed.
  • Amorphous 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide (1.0 g, 0.0013 moles) was charged to a vessel equipped with a teflon®-covered magnetic stirrer bar and a condenser. To this amorphous solid was then added methyl acetate (10 ml) and deionised water (0.20 ml), and the resultant mixture was heated to 55-60° C. under an atmosphere of nitrogen.
  • a seed (approximately 0.005 g) of crystalline 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide was then added and the resultant mixture was stirred at 55-60° C. for 24 hours over which time a slurry formed. The mixture was then cooled to ambient temperature and the solid was then collected by filtration. The filter cake was then washed with methyl acetate (2 ⁇ 5 ml) and dried at 50° C.
  • a seed (approximately 0.005 g) of crystalline 6-[(2,2-diphenylethyl)amino]-9-(N-ethyl- ⁇ -D-ribofuranosyluronamide)-N-(2- ⁇ N′-[1-(2-pyridyl)-4-piperidyl]ureido ⁇ ethyl)-9H-purine-2-carboxamide was then added and the resultant mixture was stirred at 55-60° C. for approximately 3 weeks over which time a slurry slowly formed. The mixture was then cooled to ambient temperature and the solid was then collected by filtration. The filter cake was then washed with butan-2-ol (2 ⁇ 5 ml) and dried at 50° C.
  • the powder X-ray diffraction pattern was determined using a SIEMENS D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter.
  • the analysis was performed with the goniometer running in step-scan mode set for a 5 second count per 0.020 step over a two theta range of 40 to 55°.
  • the powder X-ray diffraction pattern was determined using a SIEMENS D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter.
  • the analysis was performed with the goniometer running in step-scan mode set for a 5 second count per 0.020 step over a two theta range of 40 to 55°.

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CN115400140A (zh) * 2022-01-27 2022-11-29 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途

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DE10345065A1 (de) * 2003-09-26 2005-04-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aerosolformulierung für die Inhalation enthaltend ein Anticholinergikum
PE20060272A1 (es) 2004-05-24 2006-05-22 Glaxo Group Ltd (2r,3r,4s,5r,2'r,3'r,4's,5's)-2,2'-{trans-1,4-ciclohexanodiilbis-[imino(2-{[2-(1-metil-1h-imidazol-4-il)etil]amino}-9h-purin-6,9-diil)]}bis[5-(2-etil-2h-tetrazol-5-il)tetrahidro-3,4-furanodiol] como agonista a2a
GB0514809D0 (en) 2005-07-19 2005-08-24 Glaxo Group Ltd Compounds
JPWO2021084791A1 (hr) * 2019-10-28 2021-05-06

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KR0166088B1 (ko) 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
IT1254915B (it) * 1992-04-24 1995-10-11 Gloria Cristalli Derivati di adenosina ad attivita' a2 agonista
GB9711643D0 (en) 1997-06-05 1997-07-30 Janssen Pharmaceutica Nv Glass thermoplastic systems
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GB0003960D0 (en) * 2000-02-18 2000-04-12 Pfizer Ltd Purine derivatives
GB0009583D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Respiratory formulations
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TWI227240B (en) * 2000-06-06 2005-02-01 Pfizer 2-aminocarbonyl-9H-purine derivatives
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US20030225089A1 (en) * 2002-04-10 2003-12-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors
CN115400140A (zh) * 2022-01-27 2022-11-29 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途

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