WO2022171138A1 - Forme cristalline d'un composé hétérocyclique contenant de l'azote, procédé de préparation associé et utilisation correspondante - Google Patents

Forme cristalline d'un composé hétérocyclique contenant de l'azote, procédé de préparation associé et utilisation correspondante Download PDF

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WO2022171138A1
WO2022171138A1 PCT/CN2022/075711 CN2022075711W WO2022171138A1 WO 2022171138 A1 WO2022171138 A1 WO 2022171138A1 CN 2022075711 W CN2022075711 W CN 2022075711W WO 2022171138 A1 WO2022171138 A1 WO 2022171138A1
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crystal form
formula
compound
ray powder
compound shown
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PCT/CN2022/075711
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Chinese (zh)
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李迪
段灵峻
夏广新
毕光庆
柯樱
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上海医药集团股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a crystal form of a nitrogen-containing heterocyclic compound, a preparation method and application thereof.
  • the epidermal growth factor receptor (EGFR, also known as ErbB or HER) family includes four receptor tyrosine kinases, namely EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4).
  • EGFR epidermal growth factor receptor
  • HER2 ErbB2
  • HER3 ErbB3
  • ErbB4 ErbB4
  • ErbB2 overexpression occurs in 30% of all breast cancers and is also associated with other human cancers such as colon, ovary, bladder, stomach, esophagus, lung, uterine and prostate cancers. ErbB2 overexpression is also associated with poor prognosis in other cancers, including metastasis and early recurrence.
  • Chinese patent CN107141293A discloses a nitrogen-containing heterocyclic compound whose chemical name is N 4 -(4-([1,2,4]-triazolo[4,3-c]pyrimidin-7-yloxy)- 3-methylphenyl)-N 6 -(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, its molecular formula is C 25 H 23 N 9 O 2 , whose structural formula is shown in formula I:
  • Chinese patent CN107141293A discloses that the compound of formula I is an amorphous compound.
  • an amorphous pharmaceutical product has no regular crystal structure and often has defects, such as poor thermodynamic stability. Therefore, it is necessary to improve various properties of the above-mentioned compounds.
  • the technical problem to be solved by the present invention is that the stability of the amorphous form of the existing formula I compound is poor, and for this reason, the present invention provides a crystal form of a nitrogen-containing heterocyclic compound, its preparation method and application.
  • the crystal form of the present invention has better stability.
  • the present invention provides a crystalline form A of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 5.20 ⁇ 0.2°, 7.30 ⁇ 0.2°, 10.36 ⁇ 0.2°, 14.60 ⁇ 0.2°, 15.54° There are diffraction peaks at ⁇ 0.2°, 15.93 ⁇ 0.2°, 17.76 ⁇ 0.2°, 18.66 ⁇ 0.2°, 19.90 ⁇ 0.2°, 21.68 ⁇ 0.2° and 22.64 ⁇ 0.2°;
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form A is further 16.37 ⁇ 0.2°, 16.95 ⁇ 0.2°, 18.30 ⁇ 0.2°, 19.16 ⁇ 0.2° , 19.73 ⁇ 0.2°, 20.76 ⁇ 0.2°, 22.04 ⁇ 0.2°, 22.81 ⁇ 0.2°, 23.97 ⁇ 0.2°, 24.54 ⁇ 0.2°, 24.91 ⁇ 0.2° and 26.38 ⁇ 0.2° have diffraction peaks at one or more places .
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form A is 11.56 ⁇ 0.2°, 12.12 ⁇ 0.2°, 13.18 ⁇ 0.2°, 15.27 ⁇ 0.2° , 20.54 ⁇ 0.2°, 21.27 ⁇ 0.2°, 23.02 ⁇ 0.2°, 23.22 ⁇ 0.2°, 23.64 ⁇ 0.2°, 25.69 ⁇ 0.2°, 26.01 ⁇ 0.2°, 27.53 ⁇ 0.2°, 28.13 ⁇ 0.2°, 28.64 ⁇ 0.2° , 28.97 ⁇ 0.2°, 30.37 ⁇ 0.2°, 32.31 ⁇ 0.2°, 33.69 ⁇ 0.2°, 34.60 ⁇ 0.2°, 35.36 ⁇ 0.2°, 35.94 ⁇ 0.2° and 37.96 ⁇ 0.2° have diffraction peaks at one or more places .
  • the X-ray powder diffraction pattern of the crystal form A represented by the 2 ⁇ angle also has diffraction peaks at the diffraction angles as shown in Table 1:
  • the diffraction peak, d value and peak height percentage can be shown in Table 2:
  • the XRPD pattern of the crystal form A is substantially as shown in FIG. 1 .
  • the crystal form A has a weight loss of ⁇ 0.40% at a temperature range of 35°C to 150°C; preferably, the crystal form A has a weight loss of about 0.40% at 150°C.
  • thermogravimetric analysis curve of the crystal form A is substantially as shown in FIG. 4 .
  • thermogravimetric analysis curve of the crystal form A has an endothermic peak at 272.9 ⁇ 5°C.
  • the differential scanning calorimetry of the crystal form A is substantially as shown in FIG. 7 .
  • the hygroscopic weight gain of the crystal form A at 80% RH is 0.27%; preferably, the dynamic moisture adsorption pattern of the crystal form A is basically as shown in FIG. 10 .
  • the X-ray powder diffraction pattern is measured using Cu-K ⁇ radiation lines.
  • the present invention provides a crystal form B of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 9.92 ⁇ 0.2°, 10.45 ⁇ 0.2°, 10.81 ⁇ 0.2°, 15.71 ⁇ 0.2°, 16.32° There are diffraction peaks at ⁇ 0.2°, 17.01 ⁇ 0.2°, 20.93 ⁇ 0.2° and 22.31 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form B at 2 ⁇ angle is further 5.36 ⁇ 0.2°, 13.29 ⁇ 0.2°, 18.25 ⁇ 0.2°, 18.71 ⁇ 0.2° and One or more diffraction peaks at 25.01 ⁇ 0.2°.
  • the XRPD pattern of the crystal form B is substantially as shown in FIG. 2 .
  • the weight loss of the crystal form B is ⁇ 4.0% in the temperature range of 36.4°C to 160°C; preferably, the weight loss of the crystal form B is about 3.98% at 160°C.
  • thermogravimetric analysis curve of the crystal form B is substantially as shown in FIG. 5 .
  • thermogravimetric analysis curve of the crystal form B has endothermic peaks at 66.3 ⁇ 5°C and 278.0 ⁇ 5°C, and an exothermic peak at 180.3°C ⁇ 5°C.
  • the differential scanning calorimetry of the crystal form B is substantially as shown in FIG. 8 .
  • the X-ray powder diffraction pattern is measured using Cu-K ⁇ radiation lines.
  • the present invention provides a crystal form C of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2 ⁇ angle is at 7.61 ⁇ 0.2°, 11.28 ⁇ 0.2°, 13.82 ⁇ 0.2°, 16.71 ⁇ 0.2°, 20.12° There are diffraction peaks at ⁇ 0.2° and 22.30 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form C expressed at 2 ⁇ angle is further 15.25 ⁇ 0.2°, 23.54 ⁇ 0.2°, 25.01 ⁇ 0.2° and 25.89 ⁇ 0.2° There are diffraction peaks at one or more of them.
  • the present invention provides a crystalline form C of the compound represented by formula I, which is represented by X-ray powder diffraction at 2 ⁇ angle
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form C is further 9.38 ⁇ 0.2°, 10.65 ⁇ 0.2°, 12.87 ⁇ 0.2°, 15.71 ⁇ 0.2° , 17.98 ⁇ 0.2°, 18.79 ⁇ 0.2°, 21.47 ⁇ 0.2°, 27.25 ⁇ 0.2°, 28.10 ⁇ 0.2°, 30.83 ⁇ 0.2°, 32.31 ⁇ 0.2° and 33.93 ⁇ 0.2° have diffraction peaks at one or more places .
  • the X-ray powder diffraction pattern of the crystal form C represented by the 2 ⁇ angle is at the diffraction angle as shown in Table 4. There are diffraction peaks at:
  • the XRPD pattern of the crystal form C is substantially as shown in FIG. 3 .
  • the weight loss of the crystal form C in the temperature range of 29.0°C to 150°C is less than or equal to 0.90%; preferably, the weight loss of the crystal form C at 150°C is about 0.90%.
  • thermogravimetric analysis curve of the crystal form C is substantially as shown in FIG. 6 .
  • thermogravimetric analysis curve of the crystal form C has an endothermic peak at 289.2 ⁇ 5°C and an exothermic peak at 244.5 ⁇ 5°C.
  • the differential scanning calorimetry of the crystal form C is substantially as shown in FIG. 9 .
  • the X-ray powder diffraction pattern is measured using Cu-K ⁇ radiation lines.
  • the present invention also provides a method for preparing the aforementioned crystal form A of the compound represented by formula I, which includes Scheme 1 or Scheme 2;
  • the described scheme 1 comprises the following steps: the described compound shown in formula I is slurried and crystallized in methanol, and the solid is collected to obtain the described crystal form A of the compound shown in formula I, the described methanol and the described
  • the volume-to-mass ratio of the compound shown in formula I is 10-50 mL/g;
  • Described scheme 2 comprises the steps: the solution of described compound shown in formula I separates out solid by cooling down and/or the natural volatilization of solvent, collects solid and obtains described crystal form A of compound shown in formula I, described
  • the solvent of the solution is a mixed solvent of dichloromethane and methanol; the volume ratio of the dichloromethane and methanol is 1:(1 ⁇ 4); the mixed solvent and the compound shown in the formula I
  • the volume-to-mass ratio is 20-200 mL/g.
  • the scheme 1 and scheme 2 further include drying.
  • the drying temperature may be 45 ⁇ 5°C.
  • the beating method is a conventional beating method in the field, such as stirring.
  • the solution of the compound represented by formula I is obtained by stirring at room temperature or heating under reflux.
  • the volume-to-mass ratio of the mixed solvent to the compound represented by formula I is 20-30 mL/g; for example, 20 mL/g.
  • the volume-to-mass ratio of the mixed solvent to the compound represented by formula I may be 105 mL/g.
  • the present invention also provides a method for preparing the aforementioned crystal form B of the compound shown in formula I, which comprises the following steps: the solution of the compound shown in formula I is volatilized to separate out a solid, and the solid is collected to obtain the described
  • the solvent in the solution is a mixed solvent of dichloromethane and methanol.
  • the volume ratio of the dichloromethane and methanol may be 83:1.
  • the volume-to-mass ratio of the mixed solvent to the compound represented by formula I is 0.7 mL/mg.
  • the present invention also provides a method for preparing the aforementioned crystal form C of the compound shown in formula I, which comprises the following steps: the compound shown in formula I is slurried and crystallized in tetrahydrofuran, and the solid is collected to obtain the The crystal form C of the compound represented by formula I; the volume-to-mass ratio of the tetrahydrofuran to the compound represented by formula I is 10-50 mL/g.
  • the preparation method further comprises vacuum drying.
  • the vacuum drying temperature may be 45 ⁇ 5°C.
  • the volume-to-mass ratio of the tetrahydrofuran to the compound represented by formula I is 10-30 mL/g, for example, 16 mL/g.
  • the beating method is a conventional beating method in the field, such as stirring.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising substance X and at least one pharmaceutical excipient; the substance X is the aforementioned crystalline form A or C of the compound represented by formula I.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising substance Y and at least one pharmaceutical excipient, the aforementioned crystal form B of the compound represented by formula I.
  • the selection of the pharmaceutical excipients varies due to the route of administration and the characteristics of the action, and can usually be the conventional fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending agents in the field. agent, etc.
  • compositions can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingually, buccally, rectally, urethraally, vaginally, nasally, by inhalation or topically, the preferred route is oral.
  • the present invention provides the use of the aforementioned crystalline form A or C of the compound represented by formula I in the preparation of a medicine or an "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor", the medicine is used for inhibiting the EGFR and/or ErbB2 receptor tyrosine kinase-treated disease or ErbB2 (HER2)-positive advanced malignancy.
  • EGFR and/or ErbB2 receptor tyrosine kinase inhibitor the medicine is used for inhibiting the EGFR and/or ErbB2 receptor tyrosine kinase-treated disease or ErbB2 (HER2)-positive advanced malignancy.
  • the "disease treated by inhibition of EGFR and/or ErbB2 receptor tyrosine kinase" is a disease treated by selective inhibition of ErbB2 receptor tyrosine kinase.
  • the "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor” is a selective ErbB2 receptor tyrosine kinase inhibitor.
  • the disease to be treated by selectively inhibiting ErbB2 receptor tyrosine kinase is breast cancer or gastric cancer.
  • the disease of the ErbB2 (HER2) positive advanced malignant tumor is breast cancer.
  • the present invention provides a use of the aforementioned crystalline form B of the compound represented by formula I in the preparation of a drug or an "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor" for inhibiting EGFR and/or ErbB2 receptor tyrosine kinase inhibitors. and/or ErbB2 receptor tyrosine kinase-treated disease or ErbB2 (HER2)-positive advanced malignancy.
  • the "disease treated by inhibition of EGFR and/or ErbB2 receptor tyrosine kinase" is a disease treated by selective inhibition of ErbB2 receptor tyrosine kinase.
  • the "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor” is a selective ErbB2 receptor tyrosine kinase inhibitor.
  • the disease to be treated by selectively inhibiting ErbB2 receptor tyrosine kinase is breast cancer or gastric cancer.
  • the disease of the ErbB2 (HER2) positive advanced malignant tumor is breast cancer.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention provides a crystal form A, B or C of the compound represented by formula I. Compared with the amorphous form described in Example 4 of CN107141293A, the crystal form of the present invention has more stable thermal stability properties. The pharmacokinetic properties of Form A and Form C are better than those of the amorphous form.
  • Fig. 1 is the X-ray powder diffraction pattern of the crystal form A obtained in Example 1;
  • Fig. 2 is the X-ray powder diffractogram of obtained crystal form B in embodiment 2;
  • Fig. 3 is the X-ray powder diffractogram of the obtained crystal form C in embodiment 3;
  • Fig. 4 is the thermogravimetric analysis diagram of obtained crystal form A in embodiment 1;
  • Fig. 5 is the thermogravimetric analysis diagram of obtained crystal form B in embodiment 2;
  • Fig. 6 is the thermogravimetric analysis diagram of obtained crystal form C in embodiment 3;
  • Fig. 7 is the differential scanning calorimetry of the crystal form A obtained in Example 1;
  • Fig. 8 is the differential scanning calorimeter of the crystal form B obtained in Example 2;
  • Fig. 9 is the differential scanning calorimetry of the crystal form C obtained in Example 3.
  • Fig. 10 is the hygroscopicity test (DVS) diagram of the obtained crystal form A in Example 1;
  • Fig. 11 is the X-ray powder diffraction comparison diagram before and after the obtained crystal form A moisture attracting property test in Example 1;
  • Fig. 12 is the change diagram of crystal form B heating X-ray powder diffraction pattern in Effect Example 1;
  • Fig. 13 is the change diagram of crystal form C heating X-ray powder diffractogram in Effect Example 1;
  • Figure 14 is the X-ray powder diffraction pattern of the amorphous compound I prepared according to the method described in Example 4 of Chinese Patent CN107141293A.
  • the X-ray powder diffraction patterns described in this application were collected on a PANalytical Empyrean X-ray powder diffractometer and a PANalytical X'Pert3 X-ray powder diffractometer.
  • Step size 0.0167 degrees
  • the differential scanning calorimetry (DSC) data described in this application were collected from TA Instruments Q200 and TA Instruments Q2000 differential scanning calorimeters, the instrument control software was Q Series, and the analysis software was Universal Analysis. Usually 1-10 mg of the sample is placed in an aluminum crucible with a lid (unless otherwise specified), and the sample is raised from room temperature to 300 °C at a heating rate of 10 °C/min under the protection of 50 mL/min of dry N2 , At the same time, the TA software recorded the heat change of the sample during the heating process. In this application, melting points are reported as onset temperatures.
  • thermogravimetric analysis (TGA) data described in this application are collected from TA Instruments Q500 and TA Instruments Q5000 thermogravimetric analyzers, the instrument control software is Q Series, and the analysis software is Universal Analysis. Usually 2-15mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 400°C at a heating rate of 10°C/min under the protection of 50mL/min dry N2 by means of segmented high-resolution detection. At the same time, the TA software recorded the weight change of the sample during the heating process.
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • the amorphous sample of Compound I described in the following examples was prepared by the method described in Example 4 of CN107141293A, and its XRPD pattern is shown in FIG. 14 .
  • Example 6 After testing, the X-ray powder diffraction data of the solids obtained in Example 1 and Example 2 are shown in Table 6, the XRPD diagram is shown in Figure 1, the TGA diagram is shown in Figure 4, and the DSC diagram is shown in Figure 7 , the results show that the obtained solid product is the crystal form A described in the application. TGA data shows that the crystal sample loses about 0.40% weight when heated to 150°C, and there is a single melting endothermic peak at 272.9°C (peak temperature) in DSC.
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 2% but not less than 0.2%
  • hygroscopic weight gain is less than 0.2%.
  • Example 3 After testing, the X-ray powder diffraction data of the solid obtained in Example 3 is shown in Table 8, its XRPD diagram is shown in Figure 2, its TGA diagram is shown in Figure 5, and its DSC diagram is shown in Figure 8, the results show that the obtained The solid product is the crystal form B described in this application. TGA data shows that the sample of this crystal form loses about 3.98% in weight when heated to 160°C, and there are endothermic peaks at 66.3°C (peak temperature) and 278.0°C (peak temperature) in DSC, There is an exothermic peak at 180.3°C (peak temperature).
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 9, its XRPD diagram is shown in Figure 3, its TGA diagram is shown in Figure 6, and its DSC diagram is shown in Figure 9, the results show that the obtained
  • the solid product is the crystal form C described in this application.
  • TGA data shows that the sample of this crystal form loses about 0.90% when heated to 150°C, and there is an exothermic peak at 244.5°C (peak temperature) in DSC, and an exothermic peak at 289.2°C (peak temperature) There is an endothermic peak.
  • the crystal form B was heated to 210 °C and transformed into the crystal form A (the crystal form B was heated to 210 °C by conventional methods, and then the crystal form changes were detected). B is stable.
  • the crystal form C is transformed into the crystal form A after heating to 260 °C. According to the Burger-Ramberger Rules, it shows that the crystal form A is more stable than C.
  • Form A is more thermodynamically stable than forms B and C.
  • SD rats (provided by Shanghai Sipple Bikai Laboratory Animal Co., Ltd., certificate number: 2008001669476) were divided into groups of 5, and were given different crystal forms and amorphous forms (see Table 10) by gavage respectively. Before and 5, 15, 30, 60, 90, 120, 240, 360, 480, 600, and 1440 min after administration, 0.4 mL of blood was collected from the fundus venous plexus of rats.
  • the blood samples were centrifuged at 8000 rpm for 5 min, the upper plasma was separated, 50 ⁇ L of plasma sample was added, 300 ⁇ L of acetonitrile (Propranolol, 25 ng/ml) containing internal standard was added to precipitate the protein, vortexed for 10 min, 6000 g, 4 °C for 20 min, 20 ⁇ L of supernatant was taken and 80 ⁇ L of ultrapure water was added After dilution, 80 ⁇ L of supernatant was taken by centrifugation and injected into 96-well plate, and the plasma drug concentration was obtained by LC/MS/MS detection, and then the corresponding pharmacokinetic parameters were calculated, (CMC-Na is sodium carboxymethyl cellulose, HPMC is hydroxypropyl methylcellulose) shown in Table 12.
  • CMC-Na is sodium carboxymethyl cellulose
  • HPMC hydroxypropyl methylcellulose

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Abstract

L'invention concerne une forme cristalline d'un composé hétérocyclique contenant de l'azote, un procédé de préparation associé et une application correspondante. Une forme cristalline A d'un composé représenté par la formule I présente un pic de diffraction à 5,20 ± 0,2°, 7,30 ± 0,2°, 10,36 ± 0,2°, 14,60 ± 0,2°, 15,54 ± 0,2°, 15,93 ± 0,2°, 17,76 ± 0,2°, 18,66 ± 0,2°, 19,90 ± 0,2°, 21,68 ± 0,2°, et 22,64 ± 0,2° dans un spectre de diffraction de rayons X sur poudre représenté par un angle de 2θ. La forme cristalline a une meilleure stabilité. La propriété pharmacocinétique de la forme cristalline A du composé représenté par la formule I et une forme cristalline C est meilleure que celle d'une forme amorphe.
PCT/CN2022/075711 2021-02-10 2022-02-09 Forme cristalline d'un composé hétérocyclique contenant de l'azote, procédé de préparation associé et utilisation correspondante WO2022171138A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107141293A (zh) * 2016-03-01 2017-09-08 上海医药集团股份有限公司 一种含氮杂环化合物、制备方法、中间体、组合物和应用
CN109422755A (zh) * 2017-09-01 2019-03-05 上海医药集团股份有限公司 一种含氮杂环化合物、制备方法、中间体、组合物和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107141293A (zh) * 2016-03-01 2017-09-08 上海医药集团股份有限公司 一种含氮杂环化合物、制备方法、中间体、组合物和应用
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