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WO2019011337A1 - Forme cristalline de qaw-039, son procédé de préparation et son utilisation - Google Patents

Forme cristalline de qaw-039, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2019011337A1
WO2019011337A1 PCT/CN2018/095694 CN2018095694W WO2019011337A1 WO 2019011337 A1 WO2019011337 A1 WO 2019011337A1 CN 2018095694 W CN2018095694 W CN 2018095694W WO 2019011337 A1 WO2019011337 A1 WO 2019011337A1
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Prior art keywords
crystalline form
preparation
crystal form
compound
present
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English (en)
Chinese (zh)
Inventor
陈敏华
张炎锋
王金秋
钱佳乐
张晓宇
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Crystal Pharmaceutical Suzhou Co Ltd
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Crystal Pharmaceutical Suzhou Co Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of QAW-039 and a preparation method and use thereof.
  • QAW-039 (Fevipiprant) is a potential prostaglandin D2 receptor 2 (DP2/CRTh2) antagonist for the treatment of asthma, atopic dermatitis and allergic rhinitis, developed by Novartis.
  • DP2/CRTh2 prostaglandin D2 receptor 2
  • QAW-039 has achieved positive results in clinical trials, reducing eosinophils that play a role in airway inflammation, safely and effectively reducing eosinophilic airway inflammation in patients with moderate or severe asthma, and improving patients.
  • the lung function and quality of life are expected to be innovative asthma drugs in recent decades.
  • the present inventors have found crystalline forms CS5 and CS6 of the compound (I) excellent in properties.
  • the crystal form of the present invention is at least one of stability, melting point, solubility, in vitro and in vivo dissolution, wettability, bioavailability, adhesion, compressibility, fluidity, and processability, purification, formulation production, and the like. There are advantages, especially low wetting, good stability, high dissolution, and strong developability of the preparation, which provides a new and better choice for the development of drugs containing QAW-039, which is of great significance.
  • the main object of the present invention is to provide a novel crystalline form of the compound (I), a process for its preparation and use.
  • the present invention also provides the crystal form CS5 of the compound (I) (hereinafter referred to as "crystal form CS5").
  • the X-ray powder diffraction of the crystal form CS5 has a characteristic peak at a diffraction angle 2 ⁇ value of 13.6 ° ⁇ 0.2 °, 19.6 ° ⁇ 0.2 °, 21.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 20.2° ⁇ 0.2°, and 22.7° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 20.2° ⁇ 0.2°, and 22.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS5 has one, or two, or three places in the diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 24.6° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 8.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 24.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has a diffraction angle 2 ⁇ of 13.6° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.5° ⁇ 0.2°, 4.7° ⁇ 0.2°, and 20.2° ⁇ 0.2°. Any of 22.7° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, 24.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 26.2° ⁇ 0.2°, 27.5° ⁇ 0.2° There are three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve, or 13 characteristic peaks.
  • the X-ray powder diffraction pattern of Form CS5 is as shown in FIG.
  • the present invention further provides a method for preparing a crystalline form CS5, which comprises: dissolving a raw material of the compound (I) in an alcohol solvent system, stirring and crystallization, separating and drying to obtain .
  • the alcohol solvent is preferably methanol, or ethanol, or propanol, or any mixture thereof, and the crystallization time is preferably from 1 to 15 days;
  • the alcohol solvent is preferably a mixed solvent of methanol and ethanol, and the crystallization time is preferably 5 days;
  • volume ratio of methanol to ethanol is preferably from 1:3 to 3:1, more preferably from 1:1.
  • the crystal form CS5 provided by the invention has the following beneficial effects:
  • the crystalline form CS5 provided by the invention has high solubility in simulated biological medium and pure water, and provides a good solution for the good dissolution of the crystalline form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the preparation, and achieves an ideal Drug bioavailability and efficacy.
  • the crystalline form CS5 of the present invention has a uniform particle size distribution. Its uniform particle size helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal, saving cost, reducing the crystallinity change and the risk of crystal transformation in the grinding, and improving the quality control.
  • the present invention also provides the crystal form CS6 of the compound (I) (hereinafter referred to as "crystal form CS6").
  • the X-ray powder diffraction of the crystal form CS6 has a characteristic peak at a diffraction angle 2 ⁇ value of 10.1 ⁇ 0.2°, 15.5° ⁇ 0.2°, and 20.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 12.2° ⁇ 0.2°, 27.3° ⁇ 0.2°, and 30.3° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystalline form CS6 has characteristic peaks at diffraction angle 2 ⁇ values of 12.2 ° ⁇ 0.2 °, 27.3 ° ⁇ 0.2 °, and 30.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS6 has a diffraction angle 2 ⁇ value of 10.1 ⁇ 0.2°, 15.5° ⁇ 0.2°, 20.1° ⁇ 0.2°, 12.2° ⁇ 0.2°, 27.3° ⁇ 0.2°, There are characteristic peaks at any 3, or 4, or 5, or 6 of 30.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form CS6 is as shown in FIG.
  • the present invention also provides a method for preparing a crystal form CS6, which comprises: dissolving a compound (I) as a raw material in a mixed system of a ketone and an alcohol solvent, and adding a high polymer. After evaporation, it is obtained.
  • the ketone solvent is preferably acetone, or methyl ethyl ketone, or a mixture thereof, and the alcohol solvent is preferably methanol, or ethanol, or isopropanol, or any mixture thereof, the ketone
  • the volume ratio of the solvent-like solvent to the alcohol solvent (v:v) is preferably from 1:15 to 15:1, the crystallization time is preferably from 1 to 15 days, and the high polymer is composed of equal-mass polycaprolactone, Polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose and sodium alginate;
  • the ketone solvent is preferably acetone
  • the alcohol solvent is preferably ethanol
  • the volume ratio (v:v) of the ketone solvent to the alcohol solvent is preferably 1:3, and the crystallization time is It is preferably 5 days.
  • the crystal form CS6 provided by the invention has the following beneficial effects:
  • the crystal form CS6 provided by the present invention has good stability.
  • the crystalline bulk drug provided by the invention has good physical and chemical stability.
  • the crystalline form CS6 did not change at 25 ° C / 60% relative humidity for at least 3 months, its chemical purity was above 99%, and the chemical purity remained basically unchanged during the placement process.
  • the crystalline form provided by the present invention has good physical and chemical stability in the formulation.
  • the crystalline form CS6 of the present invention is mixed with an adjuvant to form a pharmaceutical preparation, and is allowed to stand at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for at least 3 months, and the crystal form of the present invention remains unchanged in the preparation.
  • the crystalline bulk drug and preparation have good physical and chemical stability. During the storage and formulation process, the crystalline form CS6 will not be converted into other crystal forms, and the chemical purity of the crystalline form CS6 remains basically unchanged during storage. In order to ensure the quality of the drug substance and preparation is consistent and controllable.
  • the crystalline form CS6 provided by the present invention has low wettability, and after weight equilibration at 80% relative humidity, the weight gain is about 1.17%, which is slightly wettability.
  • Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity also affects the preparation, storage and post-treatment of the drug.
  • the low moisture absorbing crystal form has strict requirements on storage conditions, reduces material storage and quality control costs, and has strong economic value.
  • the crystalline form CS6 provided by the invention has good solubility in simulated biological medium and pure water, and provides a good solution for the good dissolution of the crystalline form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the human body, and achieves an ideal medicine. Bioavailability and efficacy.
  • the crystalline form CS6 of the present invention also has good dissolution and dissolution rates.
  • Dissolution is a prerequisite for absorption.
  • Good in vitro dissolution makes the absorption of the drug higher, and the in vivo exposure characteristics are better, thereby improving the bioavailability and improving the efficacy of the drug; a good in vitro dissolution rate allows the drug to be administered after the drug is administered. The highest concentration can be reached quickly in the plasma, thus ensuring rapid drug action.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS5, CS6 of the present invention or any mixture thereof, and at least one pharmaceutically acceptable carrier , diluent or excipient.
  • crystalline form CS5, CS6 or any combination thereof provided by the present invention for the preparation of a pharmaceutical preparation of a prostaglandin D2 receptor 2 antagonist.
  • the present invention provides the use of the crystalline forms CS5 and CS6 or any combination thereof in the preparation of a pharmaceutical preparation for the treatment of asthma and/or atopic dermatitis and/or allergic rhinitis.
  • the compound (I) as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of formula (I) as a starting material is in the form of a solid powder.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline forms CS5 and CS6 of the present invention are pure, unitary, and are substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Figure 1 is an XRPD pattern of a crystal form CS5 obtained according to Example 1 of the present invention.
  • Example 2 is a DSC chart of a crystal form CS5 obtained according to Example 1 of the present invention.
  • Figure 3 is a TGA diagram of a crystalline form CS5 obtained in accordance with Example 1 of the present invention.
  • Example 4 is an XRPD pattern of a crystal form CS5 obtained according to Example 2 of the present invention.
  • Figure 5 is a PSD diagram of a crystalline form CS5 of the present invention.
  • Figure 6 is an XRPD pattern of a crystalline form CS6 obtained according to Example 3 of the present invention.
  • Figure 7 is a 1 H NMR chart of the crystalline form CS6 obtained according to Example 3 of the present invention.
  • Figure 8 is a DSC chart of a crystalline form CS6 obtained according to Example 3 of the present invention.
  • Figure 9 is a TGA diagram of a crystalline form CS6 obtained in accordance with Example 3 of the present invention.
  • Figure 10 is a DVS diagram of the crystalline form CS6 of the present invention.
  • Figure 11 is an XRPD pattern of the crystalline form CS6 of the present invention placed at 25 ° C / 60% relative humidity for 6 months (the top view is before placement and the lower figure is after placement).
  • Figure 12 is an in vitro dissolution profile of a crystalline form CS6 tablet of the present invention.
  • the invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention.
  • PSD particle size distribution
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • HPLC high performance liquid chromatography
  • HPLC high performance liquid chromatography
  • the particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system. This test uses a wet method and the dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • the QAW-039 used in the following examples was prepared according to the prior art, for example according to the preparation method disclosed in WO2005123731A1.
  • the DSC of the crystalline form CS5 obtained in this example showed an endothermic peak near the temperature of 95 ° C, and the endothermic peak was the dehydration endothermic peak of the crystalline form CS5.
  • the TGA of the form CS5 obtained in this example is as shown in Fig. 3, and has a weight loss of about 10.2% when heated to around 140 °C.
  • Gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated feeding intestinal fluid
  • the crystalline form CS5 of the present invention was dissolved in a saturated solution of SGF, FaSSIF, FeSSIF and water, respectively, and after 1 hour of equilibrium, the content of the sample in the saturated solution (microgram/ml) was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • the nuclear magnetic resonance spectrum is shown in Fig. 7.
  • the DSC of the crystalline form CS6 obtained in this example showed an endothermic peak near the temperature of 46 ° C, and the endothermic peak was the dehydration endothermic peak of the crystalline form CS6.
  • the TGA of the crystalline form CS6 obtained in this example is as shown in Fig. 9, and has a weight loss of about 5.5% when heated to around 140 °C.
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystalline form CS6 of the present invention has no change in crystal form and the chemical purity remains substantially unchanged after being left for 3 months under the condition of 25 ° C / 60% relative humidity, indicating that the crystalline form CS2 of the present invention has good physical and chemical stability.
  • Example 8 Dynamic solubility of crystalline form CS6
  • Gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated feeding intestinal fluid
  • the crystalline form CS6 of the present invention was dissolved in a saturated solution of SGF, FaSSIF, FeSSIF and water, respectively, and after 1 hour of equilibrium, the content of the sample in the saturated solution (microgram/ml) was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the crystalline form CS6 of the invention has good solubility in SGF, FeSSIF, FaSSIF and pure water, which provides a good solution for the good dissolution of the crystal form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the preparation, which is ideal. Drug bioavailability and efficacy.
  • the crystalline form CS6, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate (the contents of the respective components shown in Table 9 below) of the compound (I) were weighed and mixed for 2 minutes. It was pressed into a piece by a manual tableting machine, and a circular die of 6 mm in diameter was pressed at a pressure of 5 KN ⁇ 1 KN, and the tablet weight was 75 mg ⁇ 1 mg. Packed in 35cc HDPE bottles (one per bottle), each bottle contains 1g desiccant and sealed with a sealing machine. The crystal form of the active ingredient was not changed before and after preparation of the preparation.
  • the tablets prepared above were allowed to stand under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 3 months, and the crystal form did not change in the tablets containing the crystalline form CS6.
  • the results are shown in Table 10 below, indicating that the crystalline form CS6 has good stability in the formulation.
  • Example 10 In vitro dissolution and in vitro dissolution rate of crystalline CS6
  • the tablets containing the crystalline form CS6 obtained in Example 9 were tested for dissolution in vitro, and the dissolution was measured according to the Chinese Pharmacopoeia 2015 edition 0931 dissolution and release assay conditions, as follows:
  • Dissolution method paddle method
  • the in vitro dissolution of the crystalline form CS6 is shown in Table 11 below, and it is shown in Fig. 12 that the tablet having the crystalline form of the present invention as an active ingredient has a good dissolution rate and a dissolution rate.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne la forme cristalline d'un composé (I), son procédé de préparation, son utilisation, sa composition pharmaceutique et son application dans la préparation d'un antagoniste 2 du récepteur de la prostaglandine D2 ainsi que la préparation d'un médicament pour le traitement de l'asthme, de l'eczéma de contact allergique ou de la rhinite allergique. La forme cristalline selon la présente invention est faiblement hygroscopique, stable et à forte de dissolution. Elle présente une morphologie se prêtant mieux à une application pharmaceutique, fournissant ainsi de nouvelles voies pour l'élaboration de préparations pharmaceutiques.
PCT/CN2018/095694 2017-07-14 2018-07-13 Forme cristalline de qaw-039, son procédé de préparation et son utilisation Ceased WO2019011337A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100210610A1 (en) * 2004-06-17 2010-08-19 Kamlesh Jagdis Bala Organic compounds
CN106188040A (zh) * 2016-06-28 2016-12-07 浙江宏鑫染化材料有限公司 一种Fevipiprant及其中间体的制备方法
WO2017056001A1 (fr) * 2015-09-29 2017-04-06 Novartis Ag Procédé de préparation d'acide 1- (4-méthanesulfonyl-2-trifluorométhyl-benzyl)-2-méthyl -1h-pyrrolo[2,3-b]pyridin-3-yl-acétique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100210610A1 (en) * 2004-06-17 2010-08-19 Kamlesh Jagdis Bala Organic compounds
WO2017056001A1 (fr) * 2015-09-29 2017-04-06 Novartis Ag Procédé de préparation d'acide 1- (4-méthanesulfonyl-2-trifluorométhyl-benzyl)-2-méthyl -1h-pyrrolo[2,3-b]pyridin-3-yl-acétique
CN106188040A (zh) * 2016-06-28 2016-12-07 浙江宏鑫染化材料有限公司 一种Fevipiprant及其中间体的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANDHAM, D.A. ET AL.: "Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma", ACS MEDICINAL CHEMISTRY LETTERS, vol. 8, 25 April 2017 (2017-04-25), pages 582 - 586, XP002781657 *

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