EP2504337A1 - Novel polymorphic shapes of methyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-5-yl)carbamate - Google Patents

Novel polymorphic shapes of methyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-5-yl)carbamate

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Publication number
EP2504337A1
EP2504337A1 EP10784755A EP10784755A EP2504337A1 EP 2504337 A1 EP2504337 A1 EP 2504337A1 EP 10784755 A EP10784755 A EP 10784755A EP 10784755 A EP10784755 A EP 10784755A EP 2504337 A1 EP2504337 A1 EP 2504337A1
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Prior art keywords
compound
formula
modification
tion
compound according
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EP10784755A
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German (de)
French (fr)
Inventor
Alfons Grunenberg
Franz-Josef Mais
Winfried Joentgen
Birgit Keil
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Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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Priority to EP10784755A priority Critical patent/EP2504337A1/en
Publication of EP2504337A1 publication Critical patent/EP2504337A1/en
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    • 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
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to novel polymorphic forms of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -LH-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate of Formula (I), in particular the modification I, 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.
  • the mesomorphic form does not have a characteristic melting point. It has a characteristic X-ray diffraction pattern, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 1 C solid-state R spectrum (Table 1-7, Fig. 1-7).
  • the mesomorphic form is metastable and therefore not suitable for use in pharmaceutical formulations such as solid and semi-solid preparations.
  • four more polymorphic forms and the amorphous form were found.
  • the polymorphic forms have distinctly different melting points of 244 ° C. (modification I), 201 ° C. (modification II), 165 ° C. (modifi- tion III) and 141 ° C (modification IV) and each have a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, MR spectrum and 1 C-Fes1otro ⁇ er NMR spectrum (Tab. 1-7, Fig 1-7).
  • the present invention is the compound of formula (I) in the modification I.
  • the invention relates to the compound of formula (I) in the modification I, which in the X-ray diffractogram essentially the following preferred peak maximum of 2 theta angle at 6.1 having.
  • a preferred subject of the invention is the compound of formula (I) in the modification I, which has in the X-ray diffractogram substantially the following preferred peak maxima of the 2-theta angle at 6.1, 14.7 and 22.2.
  • the invention relates to the compound of formula (I) in the modification I, which has in the IR spectrum substantially the following preferred peak maximum at 3451 cm "1 .
  • the invention relates to the compound of the formula (I) in the modification I which has in the NIR spectrum essentially the following preferred peak maximum at 6834 cm -1 :
  • General aspects in connection with the present invention are pharmacological properties, the processability, the Preparation process, the side-effect profile, the stability and the pharmacological activity of the modification I of the compound of formula (I).
  • the modification I of the compound of formula (I) is thermodynamically stable and stable even after processing via suspensions. It is therefore particularly suitable for use in pharmaceutical formulations, such. As suspensions or creams, but also in other preparations that are produced via suspended drug, such as in aqueous granulation or wet grinding.
  • the use according to the invention of the stable modification I ensures that no changed solubility due to a transformation can occur. This increases the safety for preparations containing the compound of formula (I) and reduces the risk to the patient.
  • a pharmaceutical formulation mainly contains the compound of the formula (I) in the modification I and no major proportions of any other form of the compound of the formula (I).
  • the medicament preferably contains more than 90% by weight of Percent, particularly preferably more than 95 percent by weight of the compound of the formula (I) in the modification I 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) in the modification I for the manufacture of a medicament for the treatment of diseases, in particular for the treatment of cardiovascular diseases.
  • the compound of the formula (I) in the modification I leads to a vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an 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 may also be used to control central nervous system diseases characterized by disturbances of the NO / cGMP system.
  • central nervous system diseases characterized by disturbances of the NO / cGMP system.
  • 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 the consumption of food, pleasure and addictive substances.
  • cerebral infarct events Apoplexia cerebri
  • stroke cerebral infarct events
  • cerebral ischaemias cerebral ischaemias and craniocerebral trauma.
  • It can also be used to control pain.
  • it has anti-inflammatory action and can therefore be used as anti-inflammatory agents.
  • 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) in the modification I.
  • the compound of the formula (I) in the modification I can be suitably applied, e.g. 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.
  • the prior art is capable of rapidly and / or modifying the compound of formula (I) in the modification I-releasing forms of administration, e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, suspensions or aerosols.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • capsules for example hard or soft gelatin capsules
  • 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 to be applied, films / wafers or capsules, suppositories, ear or eye 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 include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example Albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents eg liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example Albumin
  • compositions containing at least the compound of formula (I) in the modification I usually together with one or more inert, non-toxic, pharmaceutically suitable excipients such as binders, fillers, etc., as well as their use in the previously mentioned purposes.
  • a single dose contains the active ingredient in amounts of about 1 to about 80, preferably 3 to 30 mg kg body weight.
  • the invention further provides a process for the preparation of the compound of the formula (I) in the modification I by, for example, suspending the compound of the formula (I) in the mesomorphic form in an inert solvent and obtaining it to the desired degree of conversion, more preferably until the quantitative conversion to the modification I at a temperature of 10 ° C to the reflux temperature of the solvent, preferably at 15 ° C to 35 ° C, more preferably stirred or shaken at 20 to 30 ° C.
  • the resulting crystals of modification I are separated and dried to constant weight at room temperature or at elevated temperature to remove the solvent present.
  • Suitable inert solvents are lower alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, 1-pentanol or ketones, such as acetone, or alkanes, such as n-pentane, cyclobutane lopentane, n-hexane, cyclohexane, or tetrahydrofuran, acetonitrile, toluene, ethyl acetate, 1,4-dioxane or mixtures of said solvents. Preference is given to acetonitrile and acetone or mixtures of the solvents mentioned.
  • 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.
  • elevated or reduced pressure for example from 0.5 to 5 bar.
  • the percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight.
  • Solvent ratios, dilution ratios and concentration data of liquid-liquid solutions refer in each case to the volume.
  • the DSC thermograms were by differential scanning Calorimetern DSC7, Pyris-1 or dia- mond of Fa. Perkin-Elmer at a heating rate of 20 K min "1 was added. The measurements were carried out in perforated aluminum pans, as the purge gas was used nitrogen There was. no sample preparation.
  • thermo scales TGA7 and Pyris-1 -TGA from Perkin-Elmer were carried out with thermo scales 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, using nitrogen as purge gas and 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.
  • Example 1.1 Approx. 100 mg of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate of the formula (I) in of the mesomorphic form are suspended in 3 ml of acetonitrile and stirred at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound in modification I.
  • Example 1.2 Approx. 100 mg of methyl ⁇ 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl ⁇ carbamate of the formula (I) in of the mesomorphic form are suspended in 3 ml of acetonitrile and stirred
  • Fig. 1 DSC and TGA thermograms of the modifications I-IV, the mesomorphic and the amorphous form
  • Fig. 2 X-ray diffractograms of the modifications I-IV, the mesomorphic and the amorphous form
  • Fig. 3 IR spectra of the modifications I-IV, the mesomorphic and the amorphous form
  • Fig. 4 Raman spectra of the modifications I-IV, the mesomorphic and the amorphous form
  • Fig. 5 FIR spectra of the modifications I-IV, the mesomorphic and the amorphous form
  • Fig. 6 MR spectra of the modifications I-IV, the mesomorphic and the amorphous form

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Abstract

The invention relates to novel shapes of methyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-B]pyridine-3-yl]pyrimidin-5-yl)carbamate of the formula (I), in particular the modification I, to a method for the production thereof, to medications comprising same, and to the use thereof for treating illnesses.

Description

Neue polymorphe Formen von Methyl{4,6-diaimno-2 1-(2-fluorobenzyl)-lH-pyrazolo[3.,4- bl pyridin-3-vH pyrimidin-5-yll carbamat  New polymorphic forms of methyl {4,6-diaimno-2 1- (2-fluorobenzyl) -1H-pyrazolo [3, 4-bl pyridine-3-vH pyrimidin-5-yl carbamate
Die Erfindung betrifft neue polymorphe Formen von Methyl {4,6-diamino-2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl} carbamat der Formel (I), insbesondere die Modifikation I, Verfahren zu deren Herstellung, diese enthaltende Arzneimittel sowie deren Verwendung bei der Bekämpfung von Krankheiten. The invention relates to novel polymorphic forms of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -LH-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} carbamate of Formula (I), in particular the modification I, processes for their preparation, medicaments containing them and their use in the control of diseases.
Methyl {4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl} carbamat wird in WO 03/095451 beschrieben und entspricht der Verbindung der Formel (I): Methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate is described in WO 03/095451 and corresponds to the compound of formula (I):
(I) (I)
Die Herstellung und Verwendung der Verbindung der Formel (I) zur Behandlung von beispielsweise kardiovaskulären Erkrankungen und erektiler Dysfunktion ist bereits aus WO 03/095451 bekannt. Auf die dort beschriebene Weise wird die Verbindung der Formel (I) in Form einer Kristallmodifikation erhalten, die im Folgenden als mesomorphe Form bezeichnet wird. Die mesomorphe Form hat keinen cha- rakteristischen Schmelzpunkt. Sie hat ein charakteristisches Röntgendiffraktogramm, IR-Spektrum, Ra- man-Spektrum, FIR-Spektrum, NIR-Spektrum und 1 C-Festkö^er-> R-Spektrum (Tab. 1-7, Abb. 1- 7). The preparation and use of the compound of the formula (I) for the treatment of, for example, cardiovascular diseases and erectile dysfunction is already known from WO 03/095451. In the manner described therein, the compound of formula (I) is obtained in the form of a crystal modification, which is referred to below as mesomorphic form. The mesomorphic form does not have a characteristic melting point. It has a characteristic X-ray diffraction pattern, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and 1 C solid-state R spectrum (Table 1-7, Fig. 1-7).
Es wurde nun gefunden, dass die mesomorphe Form metastabil und deshalb nicht für die Verwendung in pharmazeutischen Formulierungen, wie beispielsweise festen und halbfesten Zubereitungen, geeignet ist. Überraschenderweise wurden vier weitere polymorphe Formen und die amorphe Form gefunden. Die polymorphen Formen haben im Vergleich zur aus WO 03/095451 bekannten mesomorphen Form deutlich unterschiedliche Schmelzpunkte von 244°C (Modifikation I), 201°C (Modifikation II), 165°C (Modifika- tion III) und 141°C (Modifikation IV) und besitzen jeweils ein charakteristisches Röntgendiffraktogramm, IR-Spektrum, Raman-Spektrum, FIR-Spektrum, MR-Spektrum und 1 C-Fes1köφer-NMR-Spektrum (Tab. 1-7, Abb. 1-7). It has now been found that the mesomorphic form is metastable and therefore not suitable for use in pharmaceutical formulations such as solid and semi-solid preparations. Surprisingly, four more polymorphic forms and the amorphous form were found. The polymorphic forms have distinctly different melting points of 244 ° C. (modification I), 201 ° C. (modification II), 165 ° C. (modifi- tion III) and 141 ° C (modification IV) and each have a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, MR spectrum and 1 C-Fes1köφer NMR spectrum (Tab. 1-7, Fig 1-7).
Gegenstand der vorliegenden Erfindung ist die Verbindung der Formel (I) in der Modifikation I. Gegenstand der Erfindung ist die Verbindung der Formel (I) in der Modifikation I, die im Röntgendiffraktogramm im wesentlichen das folgende bevorzugte Peakmaximum des 2 Theta Winkels bei 6,1 aufweist. The present invention is the compound of formula (I) in the modification I. The invention relates to the compound of formula (I) in the modification I, which in the X-ray diffractogram essentially the following preferred peak maximum of 2 theta angle at 6.1 having.
Ein bevorzugter Gegenstand der Erfindung ist die Verbindung der Formel (I) in der Modifikation I, die im Röntgendiffraktogramm im wesentlichen die folgenden bevorzugten Peakmaxima des 2 Theta Winkels bei 6,1, 14,7 und 22,2 aufweist. A preferred subject of the invention is the compound of formula (I) in the modification I, which has in the X-ray diffractogram substantially the following preferred peak maxima of the 2-theta angle at 6.1, 14.7 and 22.2.
Gegenstand der Erfindung ist die Verbindung der Formel (I) in der Modifikation I, die im IR- Spektrum im wesentlichen das folgende bevorzugte Peakmaximum bei 3451 cm"1 aufweist. The invention relates to the compound of formula (I) in the modification I, which has in the IR spectrum substantially the following preferred peak maximum at 3451 cm "1 .
Gegenstand der Erfindung ist die Verbindung der Formel (I) in der Modifikation I, die im NIR- Spektrum im wesentlichen das folgende bevorzugte Peakmaximum bei 6834 cm"1 aufweist. Generelle Aspekte im Zusammenhang mit der vorliegenden Erfindung sind pharmakologische Eigenschaften, die Prozessierbarkeit, das Herstellungsverfahren, das Nebenwirkungsprofil, die Stabilität und die pharmakologische Wirksamkeit der Modifikation I der Verbindung der Formel (I). The invention relates to the compound of the formula (I) in the modification I which has in the NIR spectrum essentially the following preferred peak maximum at 6834 cm -1 : General aspects in connection with the present invention are pharmacological properties, the processability, the Preparation process, the side-effect profile, the stability and the pharmacological activity of the modification I of the compound of formula (I).
Überraschenderweise ist die Modifikation I der Verbindung der Formel (I) thermodynamisch stabil und auch nach Verarbeitung über Suspensionen lagerstabil. Sie eignet sich deshalb besonders für den Einsatz in pharmazeutischen Formulierungen, wie z. B. Suspensionen oder Cremes, aber auch in anderen Zubereitungen, die über suspendierten Wirkstoff hergestellt werden, wie beispielsweise bei der wässrigen Granulation oder Nassmahlung. Durch den erfindungsgemäßen Einsatz der stabilen Modifikation I wird sichergestellt, dass keine geänderte Löslichkeit aufgrund einer Umwandlung vorkommen kann. Dies erhöht die Sicherheit für Zubereitungen enthaltend die Verbindung der Formel (I), und das Risiko für den Patienten wird verringert. Surprisingly, the modification I of the compound of formula (I) is thermodynamically stable and stable even after processing via suspensions. It is therefore particularly suitable for use in pharmaceutical formulations, such. As suspensions or creams, but also in other preparations that are produced via suspended drug, such as in aqueous granulation or wet grinding. The use according to the invention of the stable modification I ensures that no changed solubility due to a transformation can occur. This increases the safety for preparations containing the compound of formula (I) and reduces the risk to the patient.
Die erfindungsgemäße Verbindung der Formel (I) in der Modifikation I wird in pharmazeutischen Formulierungen in hoher Reinheit eingesetzt. Aus Stabilitätsgründen enthält eine pharmazeutische Formulierung hauptsächlich die Verbindung der Formel (I) in der Modifikation I und keine größeren Anteile einer anderen Form der Verbindung der Formel (I). Bevorzugt enthält das Arzneimittel mehr als 90 Gewichts- Prozente, besonders bevorzugt mehr als 95 Gewichtsprozente der Verbindung der Formel (I) in der Modifikation I bezogen auf die Gesamtmenge der enthaltenen Verbindung der Formel (I). The compound of the formula (I) according to the invention in the modification I is used in high purity in pharmaceutical formulations. For stability reasons, a pharmaceutical formulation mainly contains the compound of the formula (I) in the modification I and no major proportions of any other form of the compound of the formula (I). The medicament preferably contains more than 90% by weight of Percent, particularly preferably more than 95 percent by weight of the compound of the formula (I) in the modification I based on the total amount of the compound of the formula (I).
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung der Verbindung der Formel (I) in der Modifikation I zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, insbesondere zur Behandlung von Herz-Kreislauferkrankungen. Another object of the present invention is the use of the compound of formula (I) in the modification I for the manufacture of a medicament for the treatment of diseases, in particular for the treatment of cardiovascular diseases.
Die Verbindung der Formel (I) in der Modifikation I führt zu einer Gefäßrelaxation, Thrombozyten- aggregationshemmung und zu einer Blutdrucksenkung sowie zu einer Steigerung des koronaren Blutflusses. Diese Wirkungen sind über eine direkte Stimulation der löslichen Guanylatcyclase und einem intrazellulären cGMP -Anstieg vermittelt. Sie kann daher in Arzneimitteln zur Behandlung von kardiovaskulären Erkrankungen wie beispielsweise zur Behandlung des Bluthochdrucks und der Herzinsuffizienz, stabiler und instabiler Angina pectoris, peripheren und kardialen Gefäßerkrankungen, von Arrhythmien, zur Behandlung von thromboembolischen Erkrankungen und Ischämien wie Myokardinfarkt, Hirnschlag, transistorisch und ischämische Attacken, periphere Durchblutungsstörungen, Verhinderung von Restenosen wie nach Thrombolysetherapien, percutan transluminalen Angioplastien (PTA), percutan transluminalen Koronarangioplastien (PTCA), Bypass sowie zur Behandlung von Arteriosklerose, fibrotischen Erkrankungen wie Leberfibrose oder Lungenfibrose, asthmatischen Erkrankungen und Krankheiten des Urogenitalsystems wie beispielsweise Prostatahypertrophie, erektile Dysfünktion, weibliche sexuelle Dysfünktion und Inkontinenz sowie zur Behandlung von Glaucoma eingesetzt werden. Sie kann auch zur Bekämpfüng von Krankheiten im Zentralnervensystem eingesetzt werden, die durch Störungen des NO/cGMP-Systems gekennzeichnet sind. Insbesondere ist sie geeignet zur Beseitigung kognitiver Defizite, zur Verbesserung von Lern- und Gedächtnisleistungen und zur Behandlung der Alzheimer'schen Krankheit. Sie eignet sich auch zur Behandlung von Erkrankungen des Zentralnervensystems wie Angst-, Spannungs- und Depressionszuständen, zentralnervös bedingten Sexualdysfünktionen und Schlafstörungen, sowie zur Regulierung krankhafter Störungen der Nahrungs-, Genuss- und Suchtaittelaufhahme. The compound of the formula (I) in the modification I leads to a vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular cGMP increase. It can therefore be used in medicaments for the treatment of 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. It may also be used to control central nervous system diseases characterized by disturbances of the NO / cGMP system. In particular, it is suitable for eliminating cognitive deficits, for improving learning and memory performance and for treating Alzheimer's disease. It is also suitable for the treatment of 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 the consumption of food, pleasure and addictive substances.
Weiterhin eignet sie sich auch zur Regulation der cerebralen Durchblutung und stellt somit ein wirkungsvolles Mittel zur Bekämpfung von Migräne dar. Furthermore, it is also suitable for the regulation of cerebral blood flow and thus represents an effective means of combating migraine.
Auch eignet sie sich zur Prophylaxe und Bekämpfüng der Folgen cerebraler Infarktgeschehen (Apoplexia cerebri) wie Schlaganfall, cerebraler Ischämien und des Schädel-Hirn-Traumas. Ebenso kann sie zur Bekämpfüng von Schmerzzuständen eingesetzt werden. Zudem besitzt sie antiinflammatorische Wirkung und kann daher als entzündungshemmende Mittel eingesetzt werden. It is also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma. It can also be used to control pain. In addition, it has anti-inflammatory action and can therefore be used as anti-inflammatory agents.
Außerdem eignet sie sich zur Behandlung der pulmonalen arteriellen Hypertonie, Störungen der Mikrozirkulation, Atemwegsinfektionen, Reperfusionsschäden, Atemwegserkrankungen, Lungenerkrankungen und dem Raynauds Syndrom. It is also useful in the treatment of pulmonary arterial hypertension, microcirculation disorders, respiratory tract infections, reperfusion injury, respiratory disease, lung disease and Raynaud's syndrome.
Weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Behandlung von Erkrankungen, insbesondere der zuvor genannten Erkrankungen, unter Verwendung einer wirksamen Menge der Verbindung der Formel (I) in der Modifikation I. 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) in the modification I.
Die Verbindung der Formel (I) in der Modifikation I kann auf geeignete Weise appliziert werden, wie z.B. oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otisch, vaginal oder als Implantat bzw. Stent. The compound of the formula (I) in the modification I can be suitably applied, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic, vaginal or as an implant or stent.
Für diese Applikationswege kann die erfindungsgemäße Verbindung in geeigneten Applikationsformen verabreicht werden. For these administration routes, the compound according to the invention can be administered in suitable administration forms.
Für die orale Applikation eignen sich nach dem Stand der Technik funktionierende schnell und/oder modifiziert die Verbindung der Formel (I) in der Modifikation I abgebende Applikationsformen, wie z.B. Tabletten (nichtüberzogene oder überzogene Tabletten, beispielsweise mit magensaftresistenten oder sich verzögert auflösenden oder unlöslichen Überzügen, die die Freisetzung der erfindungsgemäßen Verbindung kontrollieren), in der Mundhöhle schnell zerfallende Tabletten oder Filme/Oblaten, Filme/Lyophylisate, Kapseln (beispielsweise Hart- oder Weichgelatinekapseln), Dragees, Granulate, Pellets, Pulver, Suspensionen oder Aerosole. For oral administration, the prior art is capable of rapidly and / or modifying the compound of formula (I) in the modification I-releasing forms of administration, e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, suspensions or aerosols.
Die parenterale Applikation kann unter Umgehung eines Resorptionsschrittes geschehen (z.B. intravenös, intraarteriell, intrakardial, intraspinal oder intralumbal) oder unter Einschaltung einer Resorption (z.B. intramuskulär, subcutan, intracutan, percutan oder intraperitoneal). Für die parenterale Applikation eignen sich als Applikationsformen u.a. Injektions- und Infusionszubereitungen in Form von Suspensionen, Ly- ophilisaten oder sterilen Pulver. 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). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of suspensions, lyophilisates or sterile powders.
Für die sonstigen Applikationswege eignen sich z.B. Inhalationsarzneiformen (u.a. Pulverinhalatoren, Nebulizer), lingual, sublingual oder buccal zu applizierende Tabletten, Filme/Oblaten oder Kapseln, Sup- positorien, Ohren- oder Augenpräparationen, Vaginalkapseln, wässrige Suspensionen (Lotionen, Schüttelmixturen), lipophile Suspensionen, Salben, Cremes, transdermale therapeutische Systeme (wie bei- spielsweise Pflaster), Pasten, Streupuder, Implantate oder Stents. Die erfindungsgemäße Verbindung können in die angeführten Applikationsformen überführt werden. Dies kann in an sich bekannter Weise durch Mischen mit inerten, nichttoxischen, pharmazeutisch geeigneten Hilfsstoffen geschehen. Zu diesen Hilfsstoffen zählen u.a. Trägerstoffe (beispielsweise mikrokristalline Cellulose, Laktose, Mannitol), Lösungsmittel (z.B. flüssige Polyethylenglycole), Emulgatoren und Disper- gier- oder Netzmittel (beispielsweise Natriumdodecylsulfat, Polyoxysorbitanoleat), Bindemittel (beispielsweise Polyvinylpyrrolidon), synthetische und natürliche Polymere (beispielsweise Albumin), Stabilisatoren (z.B. Antioxidantien wie beispielsweise Ascorbinsäure), Farbstoffe (z.B. anorganische Pigmente wie beispielsweise Eisenoxide) und Geschmacks- und / oder Geruchskorrigentien. For other routes of administration are, for example, inhalation medicines (including powder inhalers, nebulizers), lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye 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. These excipients include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example Albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.
Weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel, die mindestens die Verbindung der Formel (I) in der Modifikation I, üblicherweise zusammen mit einem oder mehreren inerten, nichttoxischen, pharmazeutisch geeigneten Hilfsstoffen wie beispielsweise Binder, Füllstoffe, etc. enthalten, sowie deren Verwendung zu den zuvor genannten Zwecken. Another object of the present invention are pharmaceutical compositions containing at least the compound of formula (I) in the modification I, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients such as binders, fillers, etc., as well as their use in the previously mentioned purposes.
Im allgemeinen hat es sich als vorteilhaft erwiesen, die erfindungsgemäße Verbindung in Gesamtmengen von etwa 0,5 bis etwa 500, vorzugsweise 5 bis 100 mg/kg Körpergewicht pro Tag, gegebenenfalls in Form mehrerer Einzelgaben, zur Erreichung der gewünschten Ergebnisse zu verabreichen. Eine Einzelgabe enthält den Wirkstoff in Mengen von etwa 1 bis etwa 80, vorzugsweise 3 bis 30 mg kg Körpergewicht. In general, it has proved to be advantageous to administer the compound of the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per day, optionally in the form of several single doses to achieve the desired results. A single dose contains the active ingredient in amounts of about 1 to about 80, preferably 3 to 30 mg kg body weight.
Weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der Verbindung der Formel (I) in der Modifikation I, indem man die Verbindung der Formel (I) beispielsweise in der mesomorphen Form in einem inerten Lösungsmittel suspendiert und bis zum Erreichen des gewünschten Umwandlungsgrads, besonders bevorzugt bis zur quantitativen Umwandlung in die Modifikation I bei einer Temperatur von 10°C bis zur Rückflusstemperatur des Lösungsmittels, bevorzugt bei 15°C bis 35°C, besonders bevorzugt bei 20 bis 30°C rührt oder schüttelt. Die erhaltenen Kristalle der Modifikation I werden abgetrennt und zur Entfernung des vorhandenen Lösungsmittels bei Raumtemperatur oder bei erhöhter Temperatur bis zur Gewichtskonstanz getrocknet. Als inerte Lösungsmittel eignen sich niedere Alkohole, wie Methanol, Ethanol, n-Propanol, iso-Propanol, n-Butanol, sec-Butanol, iso-Butanol, 1-Pentanol oder Ketone wie Aceton, oder Alkane wie n-Pentan, Cyc- lopentan, n-Hexan, Cyclohexan, oder Tetrahydrofuran, Acetonitril, Toluol, Ethylacetat, 1,4-Dioxan oder Gemische der genannten Lösungsmittel. Bevorzugt sind Acetonitril und Aceton oder Gemische der genannten Lösungsmittel. Generell werden die Herstellungsprozesse unter Atmosphärendruck ausgeführt. Jedoch ist es auch möglich bei einem erhöhtem oder erniedrigtem Druck, beispielsweise von 0.5 bis 5 bar, zu arbeiten. Die Prozentangaben in den folgenden Tests und Beispielen sind, sofern nicht anders angegeben, Gewichtsprozente; Teile sind Gewichtsteile. Lösungsmittelverhältnisse, Verdünnungsverhältnisse und Konzentrationsangaben von flüssig flüssig-Lösungen beziehen sich jeweils auf das Volumen. The invention further provides a process for the preparation of the compound of the formula (I) in the modification I by, for example, suspending the compound of the formula (I) in the mesomorphic form in an inert solvent and obtaining it to the desired degree of conversion, more preferably until the quantitative conversion to the modification I at a temperature of 10 ° C to the reflux temperature of the solvent, preferably at 15 ° C to 35 ° C, more preferably stirred or shaken at 20 to 30 ° C. The resulting crystals of modification I are separated and dried to constant weight at room temperature or at elevated temperature to remove the solvent present. Suitable inert solvents are lower alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, 1-pentanol or ketones, such as acetone, or alkanes, such as n-pentane, cyclobutane lopentane, n-hexane, cyclohexane, or tetrahydrofuran, acetonitrile, toluene, ethyl acetate, 1,4-dioxane or mixtures of said solvents. Preference is given to acetonitrile and acetone or mixtures of the solvents mentioned. Generally, 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 percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid-liquid solutions refer in each case to the volume.
Experimenteller Teil Experimental part
Ausführungsbeispiele: EXAMPLES
Die DSC-Thermogramme wurden mit Differential Scanning Calorimetern DSC7, Pyris-1 oder Dia- mond der Fa. Perkin-Elmer mit einer Heizrate von 20 Kmin"1 aufgenommen. Die Messungen wurden in perforierten Aluminiumtiegeln durchgeführt, als Spülgas wurde Stickstoff verwendet. Es gab keine Probenvorbereitung. The DSC thermograms were by differential scanning Calorimetern DSC7, Pyris-1 or dia- mond of Fa. Perkin-Elmer at a heating rate of 20 K min "1 was added. The measurements were carried out in perforated aluminum pans, as the purge gas was used nitrogen There was. no sample preparation.
Die TGA-Messungen wurden mit Thermowaagen TGA7 und Pyris-1 -TGA der Fa. Perkin-Elmer mit einer Heizrate von 10 Kmin"1 durchgeführt. Die Messungen erfolgten in offenen Platin-Tiegeln, als Spülgas wurde Stickstoff verwendet. Es gab keine Probenvorbereitung. The TGA measurements were carried out with thermo scales 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, using nitrogen as purge gas and no sample preparation.
Die Röntgendiffraktogramme wurden mit einem STOE STADI-P Transmissions-Diffraktometer mit ortsempfindlichem Detektor (PSD2) bei Raumtemperatur aufgenommen (Strahlung: Kupfer, Kai, Primär-Monochromator: Ge [1 1 1], Wellenlänge: 1,5406 Ä).  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 Å).
Die Raman-Spektren wurden mit FT-Raman-Spektrometern RFS 100 und Multi RAM der Fa. Bru- ker bei Raumtemperatur aufgenommen. Die Auflösung beträgt 2 cm"1. Es gab keine Probenvorbereitung. Die Messung erfolgte in Glasröhrchen oder auf Alu-Disc. 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.
Die IR-Spektren wurden mit FT-IR-Spektrometern Vertex 80v und IFS 66v der Fa. Bruker bei Raumtemperatur aufgenommen. Die Auflösung beträgt 2 cm"1. Die Messung erfolgte in KBr-Matrix als Pressling. 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.
Die FIR-Spektren wurden mit FT-IR-Spektrometern Vertex 80v und IFS 66v der Fa. Bruker bei Raumtemperatur aufgenommen. Die Auflösung beträgt 2 cm"1. Die Messung erfolgte in Polyethylen- Matrix als Pressling. 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.
Die NIR-Spektren wurden mit einem FT-NIR-Spektrometer IFS 28/N der Fa. Bruker bei Raumtemperatur aufgenommen. Die Auflösung beträgt 8 cm"1. Es gab keine Probenvorbereitung. 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.
Die Festkörper- 1 C-NMR-Spektren wurden mit einem Spektrometer DRX 400 der Fa. Bruker bei Raumtemperatur aufgenommen. Die Messfrequenz beträgt 100,6 MHz und die Rotationsfrequenzen 8500 Hz und 10000 Hz. Es gab keine Probenvorbereitung. Beispiel 1 The solid-state 1 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. example 1
Herstellung von Methyl{4,6-diamino-2-ri-(2-iluorobenzyl)-lH-pyrazolor3,4-blpyridin-3- yllpyrimidin-5-v carbamat der Formel (I) in der Modifikation I Preparation of methyl {4,6-diamino-2-ri- (2-iluorobenzyl) -1H-pyrazolor3,4-blpyridin-3-yl-pyrimidine-5-v carbamate of the formula (I) in the modification I
Beispiel 1.1 Ca. 100 mg Methyl{4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5- yl}carbamat der Formel (I) in der mesomorphen Form werden in 3 ml Acetonitril suspendiert und bei Raumtemperatur gerührt. Nach einer Woche wird die Suspension filtriert und der Rückstand bei Raumtemperatur bei Umgebungsfeuchte getrocknet. Er wird röntgendiffraktometrisch untersucht und entspricht der Titel Verbindung in der Modifikation I. Beispiel 1.2 Example 1.1 Approx. 100 mg of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate of the formula (I) in of the mesomorphic form are suspended in 3 ml of acetonitrile and stirred at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound in modification I. Example 1.2
Ca. 100 mg Methyl{4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5- yl}carbamat der Formel (I) in der mesomorphen Form werden in 2 ml Aceton suspendiert und bei 50°C am Rückfluss gerührt. Nach einer Woche wird die Suspension filtriert und der Rückstand bei Raumtemperatur bei Umgebungsfeuchte getrocknet. Er wird röntgendiffraktometrisch untersucht und entspricht der Titelverbindung in der Modifikation I. Approximately 100 mg of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate of the formula (I) in the mesomorphic form are suspended in 2 ml of acetone and stirred at 50 ° C at reflux. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound in the modification I.
Beispiel 1.3 Example 1.3
7, 1 kg Methyl{4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5- yl}carbamat der Formel (I) als Di-DMSO-Solvat werden in 171,6 kg Ethylacetat und 42 kg Ethanol suspendiert und 20 h bei ca. 73 °C am Rückfluss gerührt. Die Suspension wird auf RT abgekühlt, abgesaugt und mit Ethylacetat und Wasser gewaschen. Das feuchte Produkt wird bei 50°C im Vakuum getrocknet. Es wird röntgendiffraktometrisch untersucht und entspricht der Titelverbindung in der Modifikation I. 7. 1 kg of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate of the formula (I ) as the di-DMSO solvate are suspended in 171.6 kg of ethyl acetate and 42 kg of ethanol and stirred at about 73 ° C for 20 h at reflux. The suspension is cooled to RT, filtered off with suction and washed with ethyl acetate and water. The moist product is dried at 50 ° C in a vacuum. It is examined by X-ray diffractometry and corresponds to the title compound in the modification I.
Beispiel 2 Example 2
Herstellung von Methyl{4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-blpyridin-3- vHpyrimidin-5-yll carbamat der Formel (I) in der Modifikation II Preparation of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-blipyridine-3-vH-pyrimidin-5-ylcarbamate of the formula (I) in the modification II
Beispiel 2.1 Example 2.1
110,5 g von Methyl{4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5- yl}carbamat der Formel (I) als HCl-Salz werden in 1960 ml Ethanol bei Raumtemperatur suspen- diert. Es werden 140 ml Triethylamin zudosiert und 3 h bei RT nachgerührt. Der Festoff wird abgesaugt und mit Ethanol gewaschen. Das feuchte Produkt wird über Nacht bei 50°C im Vakuum getrocknet. Es wird röntgendiffraktometrisch untersucht und entspricht der Titelverbindung in der Modifikation II. Beispiel 3 110.5 g of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate of the formula ( I) as HCl salt are suspended in 1960 ml of ethanol at room temperature. diert. There are metered in 140 ml of triethylamine and stirred for 3 h at RT. The Festoff is filtered off with suction and washed with ethanol. The moist product is dried overnight at 50 ° C in a vacuum. It is examined by X-ray diffractometry and corresponds to the title compound in the modification II. Example 3
Herstellung von Methyl{4,6-diamino-2-ri-(2-fluorobenzyl)-lH-pyrazolor3,4-blpyridin-3- yllpyrimidin-5-yll carbamat der Formel (I) in der Modifikation III Preparation of methyl {4,6-diamino-2-ri- (2-fluorobenzyl) -1H-pyrazolor3,4-blipyridine-3-yl-pyrimidin-5-ylcarbamate of the formula (I) in the modification III
Beispiel 3.1 Example 3.1
3 , 1 g Methyl{4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5- yl} carbamat der Formel (I) in der Modifikation II werden in 60 ml Methanol suspendiert und bei RT gerührt. Nach einer Woche wird die Suspension filtriert und der Rückstand bei Raumtemperatur bei Umgebungsfeuchte getrocknet. Anschließend wird der Wirkstoff 20 min bei 125°C getempert. Der Wirkstoff wird röntgendiffraktometrisch untersucht und entspricht der Titelverbindung in der Modifikation III. Beispiel 4 3.1 g of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate of the formula (I ) in the modification II are suspended in 60 ml of methanol and stirred at RT. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. Subsequently, the active ingredient is annealed at 125 ° C for 20 min. The active ingredient is examined by X-ray diffractometry and corresponds to the title compound in the modification III. Example 4
Herstellung von Methyl{4,6-diamino-2-n-(2-fluorobenzyl)-lH-pyrazolor3,4-blpyridin-3- vHpyrimidin-5-yl| carbamat der Formel (I) in der Modifikation IV Preparation of methyl {4,6-diamino-2-n- (2-fluorobenzyl) -1H-pyrazolor3,4-blipyridine-3-vH-pyrimidin-5-yl carbamate of the formula (I) in the modification IV
Beispiel 4.1 Example 4.1
3 g Methyl {4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl]pyrimidin-5- yl} carbamat der Formel (I) in der Modifikation II werden in 60 ml Aceton suspendiert und bei 3 g of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate of the formula (I) in the modification II are suspended in 60 ml of acetone and at
-20°C gerührt. Nach zwei Wochen wird die Suspension filtriert und der Rückstand bei Raumtemperatur bei Umgebungsfeuchte getrocknet. Anschließend wird der Wirkstoff 30 min bei 125°C getempert. Der Wirkstoff wird röntgendiffraktometrisch untersucht und entspricht der Titelverbindung in der Modifikation IV. Beispiel 5 -20 ° C stirred. After two weeks, the suspension is filtered and the residue is dried at room temperature at ambient humidity. Subsequently, the active ingredient is annealed at 125 ° C for 30 min. The active ingredient is examined by X-ray diffractometry and corresponds to the title compound in the modification IV. Example 5
Herstellung der amorphen Form von Methyl{4,6-diamino-2-n-(2-fluorobenzyl)-lH-pyrazolor3,4- blpyridin-3-yl1pyrimidin-5-yl| carbamat der Formel (I) Beispiel 5.1 Preparation of the amorphous form of methyl {4,6-diamino-2-n- (2-fluorobenzyl) -1H-pyrazolor3,4-blipyridin-3-yl1-pyrimidin-5-yl carbamate of the formula (I) Example 5.1
3 g Methyl {4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl]pyrimidin-5- yl}carbamat der Formel (I) in der Modifikation I werden in 1,1 1 Tetrahydrofuran heiß gelöst, filt- riert und bei Raumtemperatur bei Umgebungs feuchte stehengelassen, bis das Lösungsmittel verdunstet ist. Der Rückstand wird röntgendiffraktometrisch untersucht und entspricht der Titelverbindung in der amorphen Form. 3 g of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate of the formula (I) in the modification I are dissolved in 1,1 1 tetrahydrofuran hot, filtered and allowed to stand at room temperature in ambient humidity until the solvent has evaporated. The residue is analyzed by X-ray diffractometry and corresponds to the title compound in the amorphous form.
Tab. 1 : Differential Scanning Calorimetry und Thermogravimetrie Tab. 1: Differential scanning calorimetry and thermogravimetry
Schmelzpunkt melting point
Masseverlust (Zersetzung)  Loss of mass (decomposition)
[Gewichts-%] [Wt%]
[°C] [° C]
Modifikation I 244 < 0,5 Modification I 244 <0.5
Modifikation II 201 < 0,5 Modification II 201 <0.5
Modifikation III 165 < 0,5 Modification III 165 <0.5
Modifikation IV 141 < 1 mesomorph - ca. 8 amorph - ca. 10 Modification IV 141 <1 mesomorphic - ca. 8 amorphous - ca. 10
Tab. 2: Röntgendiffraktometrie Tab. 2: X-ray diffractometry
Peakmaximum [2 Theta] Peak maximum [2 theta]
ModifikaModifikaModifikaModifikameso- tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationation II tion III tion IV morph
3,6 8,3 6,6 10,6 4,0 3.6 8.6 6.6 10.6 4.0
4,9 11,3 7,7 11,6 5,2 4.9 11.3 7.7 11.6 5.2
6,1 11,5 13,9 12,8 6,1 6.1 11.5 13.9 12.8 6.1
7,0 12,1 15,1 13,4 9,1 7.0 12.1 15.1 13.4 9.1
7,3 13,6 15,6 13,8 13,0 7.3 13.6 15.6 13.8 13.0
8,8 14,1 16,8 14,1 15,2 8,8 14,1 16,8 14,1 15,2
9,9 14,8 17,4 16,1 16,9 9.9 14.8 17.4 16.1 16.9
10,9 16,3 17,5 16,5 17,5 10.9 16.3 17.5 16.5 17.5
12,0 17,0 17,8 17,6 21,0 12.0 17.0 17.8 17.6 21.0
12,3 17,5 18,2 17,8 23,7 12.3 17.5 18.2 17.8 23.7
14,7 18,2 19,5 18,0 25,6 14.7 18.2 19.5 18.0 25.6
15,3 19,0 19,8 18,6 15.3 19.0 19.8 18.6
16,5 21,1 20,5 19,0 16.5 21.1 20.5 19.0
17,6 22,1 22,7 19,6 17.6 22.1 22.7 19.6
18,2 22,9 23,0 20,1 18.2 22.9 23.0 20.1
18,4 23,3 23,3 21,0 18.4 23.3 23.3 21.0
19,8 24,0 23,7 21,4 19.8 24.0 23.7 21.4
20,8 25,1 24,1 21,9 Peakmaximum [2 Theta] 20.8 25.1 24.1 21.9 Peak maximum [2 theta]
ModifikaModifikaModifikaModifikameso- tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationation II tion III tion IV morph
21,1 25,4 24,4 22,8 21.1 25.4 24.4 22.8
21,3 26,1 25,4 24,5 21.3 26.1 25.4 24.5
21,8 26,7 26,3 25,3 21.8 26.7 26.3 25.3
22,2 28,6 26,8 25,4 22.2 28.6 26.8 25.4
22,9 29,3 28,1 26,2 22.9 29.3 28.1 26.2
24,1 30,4 28,7 26,5 24.1 30.4 28.7 26.5
24,4 34,0 30,4 27,5 24.4 34.0 30.4 27.5
24,7 35,6 31,2 28,1 24.7 35.6 31.2 28.1
25,6 36,9 32,8 28,3 25.6 36.9 32.8 28.3
26,0 37,7 33,8 28,6 26.0 37.7 33.8 28.6
26,8 35,1 30,5 26.8 35.1 30.5
27,4 37,6 32,5 27.4 37.6 32.5
27,8 33,5 27.8 33.5
28,1 33,8 28.1 33.8
28,3 35,6 28.3 35.6
29,3 36,2 29.3 36.2
29,7 29.7
30,1 Peakmaximum [2 Theta] 30.1 Peak maximum [2 theta]
ModifikaModifikaModifikaModifikameso- tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationation II tion III tion IV morph
30,9 30.9
31,7 31.7
32,0 32.0
32,7 32.7
33,0 33.0
33,5 33.5
34,2 34.2
35,3 35.3
35,6 35.6
36,0 36.0
Tab. 3 : IR-Spektroskopie Tab. 3: IR spectroscopy
Wellenzahl [cm-1] Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
3483 3507 3503 3489 3633 3451 3483 3507 3503 3489 3633 3451
3470 3484 3409 3287 3443 3331 3470 3484 3409 3287 3443 3331
3451 3397 3365 3157 3330 3217 3451 3397 3365 3157 3330 3217
3387 3291 3268 2954 3222 3150 3387 3291 3268 2954 3222 3150
3330 3158 3092 1710 2952 2953 3330 3158 3092 1710 2952 2953
3276 3024 3022 1628 1705 1707 3276 3024 3022 1628 1705 1707
3214 2955 2987 1561 1630 1628 3214 2955 2987 1561 1630 1628
3133 1724 2949 1515 1566 1566 3133 1724 2949 1515 1566 1566
2952 1632 2843 1492 1511 1510 2952 1632 2843 1492 1511 1510
1712 1608 1733 1480 1492 1492 1712 1608 1733 1480 1492 1492
1636 1562 1627 1439 1477 1478 1636 1562 1627 1439 1477 1478
1567 1491 1609 1363 1437 1438 1567 1491 1609 1363 1437 1438
1509 1477 1563 1342 1390 1390 1509 1477 1563 1342 1390 1390
1478 1437 1511 1324 1351 1351 1478 1437 1511 1324 1351 1351
1441 1386 1492 1302 1323 1323 1441 1386 1492 1302 1323 1323
1387 1345 1477 1288 1288 1289 1387 1345 1477 1288 1288 1289
1350 1322 1454 1247 1277 1276 1350 1322 1454 1247 1277 1276
1323 1287 1438 1187 1247 1248 Wellenzahl [cm-1] 1323 1287 1438 1187 1247 1248 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
1289 1275 1388 1169 1232 1233 1289 1275 1388 1169 1232 1233
1276 1235 1356 1144 1174 1175 1276 1235 1356 1144 1174 1175
1249 1170 1322 1112 1140 1141 1249 1170 1322 1112 1140 1141
1232 1141 1288 1090 1112 1112 1232 1141 1288 1090 1112 1112
1174 1112 1274 1075 1061 1061 1174 1112 1274 1075 1061 1061
1139 1087 1250 1059 1030 1031 1139 1087 1250 1059 1030 1031
1111 1071 1230 1031 940 940 1111 1071 1230 1031 940 940
1086 1030 1185 939 911 911 1086 1030 1185 939 911 911
1075 995 1173 910 863 864 1075 995 1173 910 863 864
1062 937 1140 871 846 847 1062 937 1140 871 846 847
1031 907 1109 857 820 820 1031 907 1109 857 820 820
1004 874 1095 849 808 808 1004 874 1095 849 808 808
941 849 1068 822 797 796 941 849 1068 822 797 796
911 812 1034 807 774 774 911 812 1034 807 774 774
867 799 974 799 757 758 867 799 974 799 757 758
849 781 940 777 712 713 849 781 940 777 712 713
820 665 911 765 643 621 820 665 911 765 643 621
808 671 865 753 621 591 808 671 865 753 621 591
795 644 839 708 590 576 Wellenzahl [cm-1] 795 644 839 708 590 576 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
774 627 820 683 568 534 774 627 820 683 568 534
760 587 806 642 534 519 760 587 806 642 534 519
715 570 795 593 519 715 570 795 593 519
631 536 777 571 631 536 777 571
594 762 531 594 762 531
576 704 576 704
535 641 535 641
87 87
572 572
533 533
513 513
Tab. 4: Raman-Spektroskopie Tab. 4: Raman spectroscopy
Wellenzahl [cm-1] Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
3452 3397 3081 3068 3067 3332 3452 3397 3081 3068 3067 3332
3387 3143 3023 3028 3024 3067 3387 3143 3023 3028 3024 3067
3331 3095 2985 2942 2956 3030 Wellenzahl [cm-1] 3331 3095 2985 2942 2956 3030 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
3086 3079 2947 2850 2608 2955 3086 3079 2947 2850 2608 2955
3054 3056 2929 1704 1704 2843 3054 3056 2929 1704 1704 2843
3022 3025 2844 1621 1618 2592 3022 3025 2844 1621 1618 2592
2990 3006 2589 1599 1578 2329 2990 3006 2589 1599 1578 2329
2953 2956 1730 1576 1508 1703 2953 2956 1730 1576 1508 1703
2834 2843 1633 1507 1479 1617 2834 2843 1633 1507 1479 1617
2604 1728 1616 1486 1448 1577 2604 1728 1616 1486 1448 1577
1702 1641 1597 1444 1423 1508 1702 1641 1597 1444 1423 1508
1633 1619 1565 1421 1380 1479 1633 1619 1565 1421 1380 1479
1618 1567 1504 1389 1323 1447 1618 1567 1504 1389 1323 1447
1598 1503 1483 1373 1309 1423 1598 1503 1483 1373 1309 1423
1577 1478 1440 1343 1278 1380 1577 1478 1440 1343 1278 1380
1508 1442 1421 1323 1252 1354 1508 1442 1421 1323 1252 1354
1477 1434 1385 1303 1233 1323 1477 1434 1385 1303 1233 1323
1447 1417 1367 1251 1177 1309 1447 1417 1367 1251 1177 1309
1420 1385 1329 1232 1157 1250 1420 1385 1329 1232 1157 1250
1380 1372 1289 1170 1142 1232 1380 1372 1289 1170 1142 1232
1351 1344 1250 1156 1114 1176 1351 1344 1250 1156 1114 1176
1322 1322 1229 1145 1063 1157 Wellenzahl [cm-1] 1322 1322 1229 1145 1063 1157 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
1307 1308 1186 1115 1036 1142 1307 1308 1186 1115 1036 1142
1289 1288 1174 1062 964 1113 1289 1288 1174 1062 964 1113
1277 1277 1143 1035 823 1062 1277 1277 1143 1035 823 1062
1249 1244 1109 1006 798 1035 1249 1244 1109 1006 798 1035
1225 1232 1061 964 777 963 1225 1232 1061 964 777 963
1175 1172 1031 824 742 911 1175 1172 1031 824 742 911
1157 1144 996 807 717 823 1157 1144 996 807 717 823
1140 1115 958 799 645 797 1140 1115 958 799 645 797
1112 1059 912 773 591 776 1112 1059 912 773 591 776
1064 1032 820 739 560 742 1064 1032 820 739 560 742
1034 964 805 719 536 716 1034 964 805 719 536 716
961 906 796 647 521 645 961 906 796 647 521 645
910 820 784 598 472 591 910 820 784 598 472 591
823 800 776 564 447 566 823 800 776 564 447 566
808 772 744 535 408 536 808 772 744 535 408 536
796 740 706 446 368 521 796 740 706 446 368 521
777 719 558 403 331 471 777 719 558 403 331 471
773 646 540 350 265 447 773 646 540 350 265 447
768 629 599 320 221 410 Wellenzahl [cm-1] 768 629 599 320 221 410 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
741 588 589 264 190 368 741 588 589 264 190 368
717 556 566 247 158 332 717 556 566 247 158 332
644 538 534 231 264 644 538 534 231 264
632 526 514 220 220 632 526 514 220 220
592 467 479 194 190 592 467 479 194 190
559 436 439 140 157 559 436 439 140 157
534 349 403 117 534 349 403 117
465 316 364 465 316 364
447 268 327 447 268 327
265 287 265 287
233 257 233 257
296 231 296 231
266 219 266 219
246 188 246 188
215 156 215 156
189 189
160 Tab. 5: FIR- Spektroskopie 160 Tab. 5: FIR spectroscopy
Wellenzahl [cm-1] Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
487 461 478 454 495 496 487 461 478 454 495 496
466 447 437 425 485 489 466 447 437 425 485 489
451 435 402 393 469 484 451 435 402 393 469 484
430 426 363 379 447 481 430 426 363 379 447 481
407 405 334 368 430 471 407 405 334 368 430 471
365 362 310 340 406 463 365 362 310 340 406 463
343 346 284 322 368 447 343 346 284 322 368 447
325 324 231 246 331 436 325 324 231 246 331 436
318 304 189 238 289 430 318 304 189 238 289 430
291 246 168 216 262 407 291 246 168 216 262 407
262 240 105 196 236 329 262 240 105 196 236 329
237 212 156 188 289 237 212 156 188 289
218 194 113 160 263 218 194 113 160 263
188 167 108 237 188 167 108 237
160 146 92 189 160 146 92 189
96 104 158 96 104 158
96 96 Wellenzahl [cm-1] 96 96 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
92 92
84 84
Tab. 6: NIR- Spektroskopie Tab. 6: NIR spectroscopy
Wellenzahl [cm-1] Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
9793 9786 9905 8809 8789 8797 9793 9786 9905 8809 8789 8797
8779 8798 8845 8462 8408 8420 8779 8798 8845 8462 8408 8420
7828 8534 8687 7851 7107 7109 7828 8534 8687 7851 7107 7109
6834 8450 8472 6857 6846 6850 6834 8450 8472 6857 6846 6850
6724 8152 7852 6667 6636 6637 6724 8152 7852 6667 6636 6637
6631 7866 7305 6011 5977 5976 6631 7866 7305 6011 5977 5976
6328 6949 5966 5106 5244 5236 6328 6949 5966 5106 5244 5236
6059 6842 5875 5064 5057 5057 6059 6842 5875 5064 5057 5057
5984 6784 5782 4971 4984 4984 5984 6784 5782 4971 4984 4984
5846 6666 5722 4795 4802 4798 5846 6666 5722 4795 4802 4798
5593 6357 5430 4741 4660 4660 5593 6357 5430 4741 4660 4660
5095 6044 5028 4659 4432 4432 Wellenzahl [cm-1] 5095 6044 5028 4659 4432 4432 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
5058 5971 5920 4538 4149 4148 5058 5971 5920 4538 4149 4148
4965 5874 5846 4486 4056 4053 4965 5874 5846 4486 4056 4053
4916 5811 5755 4439 4916 5811 5755 4439
4865 5625 5720 4216 4865 5625 5720 4216
4808 5429 5627 4155 4808 5429 5627 4155
4646 5231 5244 4092 4646 5231 5244 4092
4595 5107 5116 4595 5107 5116
4531 5067 5071 4531 5067 5071
4485 5004 4010 4485 5004 4010
4419 4965 4974 4419 4965 4974
4348 4891 4899 4348 4891 4899
4268 4836 4763 4268 4836 4763
4199 4805 4665 4199 4805 4665
4062 4732 4546 4062 4732 4546
4659 4491 4659 4491
4553 4433 4553 4433
4503 4386 4503 4386
4481 4338 4481 4338
4443 4224 Wellenzahl [cm-1] 4443 4224 Wave number [cm -1 ]
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
4402 4175 4402 4175
4367 4049 4367 4049
4329 4329
4262 4262
4164 4164
4120 4120
4057 4057
4037 4037
C-Festkörper-NMR-Spektroskopie ppm C solid-state NMR spectroscopy ppm
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
52 53 31 51 22 32 52 53 31 51 22 32
95 94 44 94 26 35 95 94 44 94 26 35
116 116 52 117 31 42 116 116 52 117 31 42
123 122 95 125 35 53 123 122 95 125 35 53
126 124 116 128 41 96 126 124 116 128 41 96
128 130 123 134 52 115 ppm 128 130 123 134 52 115 ppm
ModifikaModifikaModifikaModifikameso- amorph tion I tion II tion III tion IV morph ModifikaModifikaModifikaModificationamorphosis tion II tion III tion IV morph
130 131 133 141 96 125 130 131 133 141 96 125
133 135 142 144 115 133 133 135 142 144 115 133
138 142 150 147 124 142 138 142 150 147 124 142
141 147 158 150 128 150 141 147 158 150 128 150
149 149 161 158 132 159 149 149 161 158 132 159
150 150 161 141 162 150 150 161 141 162
158 154 149 158 154 149
161 158 158 161 158 158
161 161 161 161
Abb. 1: DSC- und TGA-Thermogramme der Modifikationen I-IV, der mesomorphen und der amorphen Form Fig. 1: DSC and TGA thermograms of the modifications I-IV, the mesomorphic and the amorphous form
Abb. 2: Röntgendiffraktogramme der Modifikationen I-IV, der mesomorphen und der amorphen Form  Fig. 2: X-ray diffractograms of the modifications I-IV, the mesomorphic and the amorphous form
Abb. 3: IR-Spektren der Modifikationen I-IV, der mesomorphen und der amorphen Form Fig. 3: IR spectra of the modifications I-IV, the mesomorphic and the amorphous form
Abb. 4: Raman -Spektren der Modifikationen I-IV, der mesomorphen und der amorphen Form  Fig. 4: Raman spectra of the modifications I-IV, the mesomorphic and the amorphous form
Abb. 5: FIR-Spektren der Modifikationen I-IV, der mesomorphen und der amorphen Form  Fig. 5: FIR spectra of the modifications I-IV, the mesomorphic and the amorphous form
Abb. 6: MR-Spektren der Modifikationen I-IV, der mesomorphen und der amorphen Form  Fig. 6: MR spectra of the modifications I-IV, the mesomorphic and the amorphous form
Abb. 7: 1 C-Festkörper-NMR-Spektren der Modifikationen I-IV, der mesomorphen und der amor- phen Form Fig. 7: 1 C solid-state NMR spectra of modifications I-IV, mesomorphic and amorphous forms

Claims

Patentansprüche : Claims:
1. Methyl{4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazoloP^ 1. Methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -lH-pyrazoloP ^
yl} carbamat der Formel  yl} carbamate of the formula
in der Modifikation I. in modification I.
2. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass das Röntgendiffraktogramm der Verbindung ein Peakmaximum des 2 Theta Winkels bei 6,1 zeigt. 2. A compound according to claim 1, characterized in that the X-ray diffractogram of the compound shows a peak maximum of 2 theta angle at 6.1.
3. Verbindung nach Ansprüchen 1 und 2, dadurch gekennzeichnet, dass das Röntgendirfraktogramm der Verbindung Peakmaxima des 2 Theta Winkels bei 6, 1 , 14,7 und 22,2 zeigt. 3. A compound according to claims 1 and 2, characterized in that the Röntgendirfraktogramm the compound shows peak maxima of the 2 theta angle at 6, 1, 14.7 and 22.2.
4. Verbindung nach Ansprüchen 1 bis 3, dadurch gekennzeichnet, dass das IR-Spektrum der4. A compound according to claims 1 to 3, characterized in that the IR spectrum of
Verbindung ein Peakmaximum bei 3451 cm"1 zeigt. Claim streichen? Compound shows a peak maximum at 3451 cm "1 .
5. Verbindung nach Ansprüchen 1 bis 4, dadurch gekennzeichnet, dass das NIR-Spektrum der Verbindung ein Peakmaximum bei 6834 cm"1 zeigt. 5. A compound according to claims 1 to 4, characterized in that the NIR spectrum of the compound shows a peak maximum at 6834 cm -1 .
6. Verbindung nach Ansprüchen 1 bis 5, dadurch gekennzeichnet, dass das NIR-Spektrum der Verbindung Peakmaxima bei 6834, 6631 und 4419 cm"1 aufweist. 6. A compound according to claims 1 to 5, characterized in that the NIR spectrum of the compound has peak maxima at 6834, 6631 and 4419 cm -1 .
7. Verbindung nach einem der Ansprüche 1 bis 6 zur Behandlung von Krankheiten. 7. A compound according to any one of claims 1 to 6 for the treatment of diseases.
8. Arzneimittel enthaltend eine Verbindung gemäß einem der Ansprüche 1 bis 6 und keine größeren Anteile einer anderen Form der Verbindung der Formel (I). 8. A medicament comprising a compound according to any one of claims 1 to 6 and no major proportions of another form of the compound of formula (I).
9. Arzneimittel enthaltend eine Verbindung gemäß einem der Ansprüche 1 bis 6 in mehr als 90 Gewichtsprozente bezogen auf die Gesamtmenge der enthaltenen Verbindung der Formel (I). 9. A medicament comprising a compound according to any one of claims 1 to 6 in more than 90 percent by weight based on the total amount of the compound of formula (I).
10. Verfahren zur Herstellung der Verbindung gemäß einem der Ansprüche 1 bis 6, indem die Verbindung der Formel (I) beispielsweise in der mesomorphen Form in einem inerten Lösungsmittel suspendiert und bis zur quantitativen Umwandlung in die Modifikation I bei einer Temperatur von 10°C bis zur Rückflusstemperatur des Lösungsmittels gerührt oder geschüttelt wird. 10. A process for the preparation of the compound according to any one of claims 1 to 6, by suspending the compound of formula (I), for example in the mesomorphic form in an inert solvent and until the quantitative conversion to the modification I at a temperature of 10 ° C to stirred or shaken to the reflux temperature of the solvent.
11. Verwendung der Verbindung gemäß einem der Ansprüche 1 bis 6 zur Herstellung eines Arzneimittels zur Behandlung von Herz-Kreislauf erkrankungen. 11. Use of the compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of cardiovascular diseases.
12. Methode zur Behandlung von Herz-Kreislauferkrankungen durch Verabreichung einer wirksamen Menge einer Verbindung gemäß einem der Ansprüche 1 bis 6. 12. A method for the treatment of cardiovascular diseases by administering an effective amount of a compound according to any one of claims 1 to 6.
EP10784755A 2009-11-27 2010-11-23 Novel polymorphic shapes of methyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-5-yl)carbamate Withdrawn EP2504337A1 (en)

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PCT/EP2010/067985 WO2011064189A1 (en) 2009-11-27 2010-11-23 Novel polymorphic shapes of methyl{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-5-yl)carbamate

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