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EP2513101A1 - Nouveaux solvates de méthyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate - Google Patents

Nouveaux solvates de méthyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

Info

Publication number
EP2513101A1
EP2513101A1 EP10788081A EP10788081A EP2513101A1 EP 2513101 A1 EP2513101 A1 EP 2513101A1 EP 10788081 A EP10788081 A EP 10788081A EP 10788081 A EP10788081 A EP 10788081A EP 2513101 A1 EP2513101 A1 EP 2513101A1
Authority
EP
European Patent Office
Prior art keywords
solvate
formula
mono
compound
diamino
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10788081A
Other languages
German (de)
English (en)
Inventor
Alfons Grunenberg
Franz-Josef Mais
Winfried Joentgen
Birgit Keil
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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
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Priority to EP10788081A priority Critical patent/EP2513101A1/fr
Publication of EP2513101A1 publication Critical patent/EP2513101A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to novel solvates of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate, in particular the semi-ethanol solvate of the formula (Ia), processes for their preparation, medicaments containing them and their use in the control of diseases
  • the compound of formula (I) for the treatment of, for example, cardiovascular diseases and erectile dysfunction is already known from WO 03/095451.
  • the compound of formula (I) is obtained in the form of a crystal modification, which is referred to below as mesomorphic form.
  • Other polymorphic forms, in particular modification I, and the amorphous form are characterized below.
  • the mesomorphic form has no characteristic melting point, the modification I melts at 244 ° C. Both forms have a characteristic X-ray diffraction pattern, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 13 C solid-state NMR spectrum (Table 1-7, Fig. 1-14).
  • the pseudopolymorphic forms each have a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 13 C solid-state NMR spectrum in comparison to the mesomorphic form or modification I characterized from WO 03/095451 and below (Tab. 1-7, Fig. 1-14).
  • the semi-ethanol solvate contains Vi molecule ethanol, the semihydrate Vi molecule water, the monohydrate one molecule of water, the mono-isopropanol solvate one molecule of isopropanol, the di-DMSO solvate two molecules of dimethylsulfoxide, the sesqui-dioxane solvate 1 , 5 molecules of dioxane, the mono-DMF solvate one molecule of dimethylformamide, the mono-NMP solvate one molecule of N-methyl-pyrrolidone per molecule of the compound of formula (I).
  • the THF-water form contains different amounts of tetrahydrofuran and water in a non-stoichiometric ratio.
  • the pseudopolymorphic forms have in comparison to the WO 03/095451 and characterized below mesomorphic form or modification I of the compound of formula (I) are each a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 13 C Solid-state NMR spectrum (Tables 1-7, Fig. 1-14). X-ray structure elucidation was performed on the semi-ethanol solvate, the mono-isopropanol solvate, the di-DMSO solvate, the sesqui-dioxane solvate and the mono-DMF solvate (Table 8, Fig. 15-19).
  • the present invention relates to the compound of the formula (I) as a semi-ethanol solvate of the formula (Ia)
  • the present invention is the compound of formula (I) as a semi-ethanol solvate of the formula (Ia), characterized in that the X-ray diffractogram of the compound shows a peak maximum of 2 theta angle at 18.8.
  • the preferred subject matter of the present invention is the compound of formula (I) as semi-ethanol solvate of formula (Ia), characterized in that the X-ray diffractogram of the compound peak maxima of the 2-theta angle at 14.0, 18.8 and 24.5 shows.
  • the present invention is the compound of formula (I) as a semi-ethanol solvate of the formula (Ia), characterized in that the NIR spectrum of the compound peak maxima at 6851 cm “ 1.6017 cm “ 1 and 4163 cm “1 shows. .
  • Another object of the present invention is a process for the preparation of the compound of formula (Ia) by suspending the compound of formula (Ia), for example in the mesomorphic form in an ethanol-containing solvent and until the quantitative conversion into the semiautanol solvate is stirred or shaken at a temperature of 10 ° C to the reflux temperature of the solvent.
  • the semi-ethanol solvate of formula (Ia) has better flowability and sievability compared to modification I of the compound of formula (I).
  • the compound of the formula (I) according to the invention as semi-ethanol solvate of the formula (Ia) is used in pharmaceutical formulations in high purity.
  • a pharmaceutical formulation mainly contains the compound of formula (I) as a semi-ethanol solvate of formula (Ia) and no major proportions of any other form of the compound of formula (I).
  • the medicament preferably contains more than 90% by weight, particularly preferably more than 95% by weight, of the compound of the formula (I) as semi-ethanol solvate of the formula (Ia) based on the total amount of the compound of the formula (I).
  • Another object of the present invention is the use of the compound of formula (I) as a semi-ethanol solvate of the formula (Ia) for the manufacture of a medicament for the treatment of diseases, in particular for the treatment of cardiovascular diseases.
  • the compound of formula (I) as a semi-ethanol solvate of the formula (Ia) leads to a vascular relaxation, platelet aggregation inhibition and to a blood pressure reduction and to an increase of the coronary blood flow. These effects are mediated via direct stimulation of soluble guanylate cyclase and intracellular cGMP increase.
  • cardiovascular diseases such as hypertension and cardiac insufficiency, stable and unstable angina pectoris, peripheral and cardiovascular diseases, arrhythmias, for the treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transient and ischemic attacks , peripheral circulatory disorders, prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass and for the treatment of arteriosclerosis, fibrotic diseases such as liver fibrosis or pulmonary fibrosis, asthmatic diseases and diseases of the genitourinary system such as prostatic hypertrophy, erectile Dysfunction, female sexual dysfunction and incontinence, as well as for the treatment of glaucoma.
  • cardiovascular diseases such as hypertension and cardiac insufficiency, stable and unstable angina pectoris, peripheral and cardiovascular diseases, arrhythmias
  • thromboembolic disorders and ischaemias such as myocardi
  • It can also be used to control central nervous system diseases characterized by NO / cGMP system disorders.
  • it is suitable for eliminating cognitive deficits, for improving learning and memory performance and for treating Alzheimer's disease.
  • central nervous system disorders such as states of anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders of food, consumption and addiction absorption.
  • cerebral infarct events Apoplexia cerebri
  • stroke cerebral ischaemias
  • craniocerebral trauma Ceraniocerebral trauma. It can also be used to combat pain.
  • Another object of the present invention is a method for the treatment of diseases, in particular the aforementioned diseases, using an effective amount of the compound of formula (I) as a semi-ethanol solvate of the formula (Ia).
  • the compound of the formula (I) as a semi-ethanol solvate of the formula (Ia) can be suitably applied such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic , vaginal or as an implant or stent.
  • the compound according to the invention can be administered in suitable administration forms.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of suspensions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • pastes scattering powders, implants or stents.
  • the compounds according to the invention can be converted into the stated forms of application. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous for example, antioxidants such ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • compositions containing at least the compound of formula (I) as a semi-ethanol solvate of formula (Ia), usually together with one or more inert, non-toxic, pharmaceutically suitable excipients such as binders, fillers, etc. and their use for the purposes mentioned above.
  • inert, non-toxic, pharmaceutically suitable excipients such as binders, fillers, etc.
  • a single dose contains the active ingredient in amounts of about 1 to about 80, preferably 3 to 30 mg / kg of body weight.
  • Another object of the invention is a process for preparing the compound of formula (I) as a semi-ethanol solvate of the formula (Ia) by suspending the compound of formula (I) in any crystal form or the amorphous form with ethanol and bis to achieve the desired degree of conversion, more preferably to quantitative conversion to the semi-ethanol solvate at a temperature from 10 ° C to the reflux temperature of the solvent, preferably at 15 ° C to 35 ° C, more preferably at 20 to 30 ° C stir or shake.
  • the resulting crystals of the semi-ethanol solvate are separated and dried to constant weight at room temperature or at elevated temperature to remove the solvent present.
  • Suitable solvents are ethanol or ethanol-water mixtures. Preferred is ethanol.
  • the manufacturing processes are carried out under atmospheric pressure. However, it is also possible to work at an elevated or reduced pressure, for example from 0.5 to 5 bar.
  • the DSC thermograms were recorded with differential scanning calorimeters DSC7, Pyris-1 or Diamond from Perkin-Elmer at a heating rate of 20 K min -1 .
  • the measurements were carried out in perforated aluminum crucibles, nitrogen was used as purge gas. ne sample preparation.
  • TGA measurements were carried out with TGA7 TGA7 and Pyris-1 -TGA from Perkin-Elmer at a heating rate of 10 Kmin.sup.- 1
  • the measurements were carried out in open platinum crucibles, nitrogen was used as the purge gas and there was no sample preparation ,
  • the X-ray diffractograms were recorded at room temperature using a STOE STADI-P transmission with a position-sensitive detector (PSD2) (radiation: copper, quay, primary monochromator: Ge [1 1 1], wavelength: 1.5406 ⁇ ).
  • PSD2 position-sensitive detector
  • the Raman spectra were recorded at room temperature using FT-Raman spectrometers RFS 100 and Multi RAM from Bruker. The resolution is 2 cm "1. There was no sample preparation, the measurement was done in glass tubes or on aluminum disc.
  • the IR spectra were recorded at room temperature using FT-IR spectrometers Vertex 80v and IFS 66v from Bruker. The resolution is 2 cm -1 . The measurement was carried out in KBr matrix as a compact.
  • the FIR spectra were recorded at room temperature using FT-IR spectrometers Vertex 80v and IFS 66v from Bruker. The resolution is 2 cm -1 . The measurement was carried out in polyethylene matrix as a compact.
  • the NIR spectra were recorded with a FT-NIR spectrometer IFS 28 / N from Bruker at room temperature. The resolution is 8 cm "1. There was no sample preparation.
  • the solid-state 13 C NMR spectra were recorded at room temperature using a spectrometer DRX 400 from Bruker.
  • the measurement frequency is 100.6 MHz and the rotation frequencies 8500 Hz and 10000 Hz. There was no sample preparation.
  • 0.1 g of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate in the mesomorphic form are suspended in 2 ml of ethanol and stirred at 50 ° C. After one week, the suspension is filtered and the residue is stirred at room temperature and vice versa. dryness dried. The residue is analyzed thermoanalytically and corresponds to the title compound as a semi-ethanol solvate.
  • yl ⁇ carbamate are mixed with 3.5 l of ethanol, dissolved at reflux temperature and filtered off with suction while hot. The filtrate is heated again to reflux temperature, cooled and stirred overnight at room temperature. The residue is isolated, washed with ethanol and dried at 50 ° C in a vacuum. It is investigated thermoanalytically and corresponds to the title compound as a semi-ethanol solvate
  • 0.1 g of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate in the mesomorphic form are suspended in 2 ml of methanol and stirred at 50 ° C. After one week, the suspension is filtered and the residue is dried at room temperature and ambient humidity. The residue is examined by X-ray diffractometry and corresponds to the title compound as a semihydrate.
  • 0.1 g of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate in the mesomorphic form are suspended in 2 ml of ethanol and shaken at 0 ° C. After one week, the suspension is filtered and the residue is stirred at room temperature and vice versa. dryness dried. The residue is analyzed by X-ray diffractometry and corresponds to the title compound as monohydrate.
  • yl ⁇ carbamate in the modification II are suspended in 2 ml of methanol and stirred at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature and ambient humidity. The residue is analyzed by X-ray diffractometry and corresponds to the title compound as monohydrate.
  • yl ⁇ carbamate as isopropanol solvate are dissolved in 59.4 kg of dimethyl sulfoxide and 47.7 kg of ethyl acetate at about 90 ° C hot and filtered.
  • the filtrate is cooled to about 20 ° C, the precipitated solid is filtered off and dried at 45 ° C in vacuum for 24 h.
  • the residue is analyzed by X-ray diffractometry and corresponds to the title compound as the di-DMSO solvate.
  • yl ⁇ carbamate in the modification I are suspended in 7 ml of 1-methyl-2-pyrrolidone and stirred at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature and ambient humidity. The residue is analyzed by X-ray diffractometry and corresponds to the title compound as a mono-NMP solvate.
  • Fig. 1 DSC and TGA thermograms of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidine-5 yl ⁇ carbamate
  • FIG. 3 X-ray diffractograms of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate
  • Fig. 4 Ring opening diagram of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidine -5-yl ⁇ carbamate
  • Fig. 5 IR spectra of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate
  • FIG. 6 IR spectra of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate
  • Fig. 7 Raman spectra of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate
  • Fig. 8 Raman spectra of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate
  • Fig. 10 FIR scene of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl carbamate
  • Fig. 11 NIR peptides of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl carbamate
  • FIG. 15 Calculated X-ray diffractogram and molecular geometry of the semi-ethanol solvate of the Fromel (Ia)
  • FIG. 16 Calculated X-ray diffractogram and molecular geometry of the mono-isopropanol solvate of the formula (Ia)
  • Fig. 17 Calculated X-ray diffractogram and molecular geometry of the di-DMSO solvate
  • Fig. 18 Calculated X-ray diffractogram and molecular geometry of Sesqui-Dioxane solvate
  • Fig. 19 Calculated X-ray diffractogram and molecular geometry of mono-DMF solvate

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux solvates de méthyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate, en particulier le solvate contenant pour moitié de l'éthanol de formule (Ia), leur procédé de fabrication, des médicaments les contenant, et leur utilisation pour lutter contre des maladies.
EP10788081A 2009-12-14 2010-12-13 Nouveaux solvates de méthyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate Withdrawn EP2513101A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10788081A EP2513101A1 (fr) 2009-12-14 2010-12-13 Nouveaux solvates de méthyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP09179028 2009-12-14
EP10788081A EP2513101A1 (fr) 2009-12-14 2010-12-13 Nouveaux solvates de méthyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate
PCT/EP2010/069457 WO2011073118A1 (fr) 2009-12-14 2010-12-13 Nouveaux solvates de méthyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

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EP2513101A1 true EP2513101A1 (fr) 2012-10-24

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US (1) US20120316183A1 (fr)
EP (1) EP2513101A1 (fr)
JP (1) JP2013513640A (fr)
KR (1) KR20120123270A (fr)
CN (1) CN102686588A (fr)
AU (1) AU2010333023A1 (fr)
BR (1) BR112012014320A2 (fr)
CA (1) CA2784010A1 (fr)
IL (1) IL219712A0 (fr)
MX (1) MX2012006719A (fr)
RU (1) RU2012129671A (fr)
WO (1) WO2011073118A1 (fr)

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CN104327107A (zh) 2013-10-17 2015-02-04 广东东阳光药业有限公司 一种氟喹诺酮类抗菌药物的制备方法
EP3389655A2 (fr) 2015-12-14 2018-10-24 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
BR112021000358A2 (pt) 2018-07-11 2021-04-06 Cyclerion Therapeutics, Inc. Uso de estimulantes de sgc para o tratamento de distúrbios mitocondriais

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US20120316183A1 (en) 2012-12-13
BR112012014320A2 (pt) 2016-07-05
RU2012129671A (ru) 2014-01-27
CN102686588A (zh) 2012-09-19
JP2013513640A (ja) 2013-04-22
MX2012006719A (es) 2012-10-15
CA2784010A1 (fr) 2011-06-23
KR20120123270A (ko) 2012-11-08
IL219712A0 (en) 2012-07-31
WO2011073118A1 (fr) 2011-06-23
AU2010333023A1 (en) 2012-06-21

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