WO2022171138A1 - 一种含氮杂环化合物的晶型、其制备方法及应用 - Google Patents

一种含氮杂环化合物的晶型、其制备方法及应用 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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French (fr)
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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

Abstract

一种含氮杂环化合物的晶型、其制备方法及应用。一种如式I所示的化合物的晶型A，其以2θ角表示的X射线粉末衍射图在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°和22.64±0.2°处有衍射峰，该晶型有较好的稳定性。式I所示化合物的晶型A和晶型C的药代性质优于无定型。

Description

一种含氮杂环化合物的晶型、其制备方法及应用
本申请要求申请日为2021年2月10日的中国专利申请2021101854466的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种含氮杂环化合物的晶型、其制备方法及应用。
背景技术
表皮生长因子受体(EGFR,也称ErbB或HER)家族包括4种受体酪氨酸激酶，分别是EGFR(ErbB1或HER1)、ErbB2(HER2)、ErbB3(HER3)和ErbB4(HER4)。一些研究者已经证明EGFR和ErbB2在癌症进展中的作用，在头、颈和肺的鳞癌也表达高水平的EGFR。在全部乳腺癌中，发生ErbB2过量表达的占30％，其还与其它人类癌症还有如：结肠、卵巢、膀胱、胃、食管、肺、子宫和***癌症有关。ErbB2过表达也与其它癌症的预后不良有关，包括转移和早期复发。
中国专利CN107141293A公开一种含氮杂环化合物，其化学名称为N 4-(4-([1,2,4]-***并[4,3-c]嘧啶-7-基氧基)-3-甲基苯基)-N 6-(4,4-二甲基-4,5-二氢噁唑-2-基)喹唑啉-4,6-二胺，其分子式为C 25H 23N 9O 2，其结构式如式I所示：
Figure PCTCN2022075711-appb-000001
上述化合物可通过选择性抑制ErbB2受体酪氨酸激酶治疗疾病。中国专利CN107141293A公开式I化合物是无定型化合物，一般来说，无定型的药物产品没有规则的晶体结构，往往具有缺陷，比如热力学稳定性较差等。因此，改善上述化合物的各方面性质是很有必要的。
发明内容
本发明所要解决的技术问题为现有的式I化合物的无定型的稳定性较差，为此，本 发明提供一种含氮杂环化合物的晶型、其制备方法及应用。本发明的晶型具有较佳的稳定性。
本发明提供一种如式I所示的化合物的晶型A，其以2θ角表示的X射线粉末衍射图在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°和22.64±0.2°处有衍射峰；
Figure PCTCN2022075711-appb-000002
在本发明一些实施方案中，较佳地，所述的晶型A的以2θ角表示的X射线粉末衍射图还在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°和26.38±0.2°中的一处或多处有衍射峰。
在本发明一些实施方案中，更佳地，所述的晶型A的以2θ角表示的X射线粉末衍射图还在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°和37.96±0.2°中的一处或多处有衍射峰。
所述的晶型A以2θ角表示的X射线粉末衍射图，其以2θ角表示的X射线粉末衍射图还在如表1所示的衍射角处有衍射峰：
表1
编号 衍射角2θ(±0.2°)
1 5.20
2 7.30
3 10.36
4 11.56
5 12.12
6 13.18
7 14.60
8 15.27
9 15.54
10 15.93
11 16.37
12 16.95
13 17.76
14 18.30
15 18.66
16 19.16
17 19.73
18 19.90
19 20.54
20 20.76
21 21.27
22 21.68
23 22.04
24 22.64
25 22.81
26 23.02
27 23.22
28 23.64
29 23.97
30 24.54
31 24.91
32 25.69
33 26.01
34 26.38
35 27.53
36 28.13
37 28.64
38 28.97
39 30.37
40 32.31
41 33.69
42 34.60
43 35.36
44 35.94
45 37.96
。
在本发明一些实施方案中，所述的晶型A以2θ角表示的X射线粉末衍射图中，其衍射峰、d值和峰高百分比可如表2所示：
表2
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.20 17.01 48.01
2 7.30 12.11 29.62
3 10.36 8.54 35.04
4 11.56 7.66 11.33
5 12.12 7.30 14.34
6 13.18 6.72 5.19
7 14.60 6.07 36.28
8 15.27 5.80 11.98
9 15.54 5.70 100.00
10 15.93 5.56 33.59
11 16.37 5.42 20.56
12 16.95 5.23 21.76
13 17.76 4.99 37.81
14 18.30 4.85 21.22
15 18.66 4.76 41.19
16 19.16 4.63 24.83
17 19.73 4.50 17.98
18 19.90 4.46 30.97
19 20.54 4.32 6.97
20 20.76 4.28 17.10
21 21.27 4.18 10.59
22 21.68 4.10 26.45
23 22.04 4.03 17.56
24 22.64 3.93 26.29
25 22.81 3.90 20.81
26 23.02 3.86 9.84
27 23.22 3.83 6.82
28 23.64 3.76 3.52
29 23.97 3.71 16.14
30 24.54 3.63 13.27
31 24.91 3.57 19.49
32 25.69 3.47 2.82
33 26.01 3.42 9.75
34 26.38 3.38 14.09
35 27.53 3.24 7.63
36 28.13 3.17 2.14
37 28.64 3.12 2.76
38 28.97 3.08 4.29
39 30.37 2.94 1.59
40 32.31 2.77 1.68
41 33.69 2.66 7.30
42 34.60 2.59 1.83
43 35.36 2.54 2.67
44 35.94 2.50 0.65
45 37.96 2.37 2.40
。
在本发明一些实施方案中，所述的晶型A的XRPD图谱基本如图1所示。
在本发明一些实施方案中，所述的晶型A在35℃至150℃温度范围失重≤0.40％；较佳地，所述的晶型A在150℃失重约0.40％。
在本发明一些实施方案中，所述的晶型A的热重分析曲线图谱基本如图4所示。
在本发明一些实施方案中，所述的晶型A的热重分析曲线在272.9±5℃处具有吸热峰。
在本发明一些实施方案中，所述的晶型A的差示扫描量热图谱基本如图7所示。
在本发明一些实施方案中，所述的晶型A在80％RH下的吸湿增重为0.27％；较佳地，所述的晶型A的动态水分吸附图谱基本如图10所示。
在本发明一些实施方案中，所述的X射线粉末衍射图使用Cu-Kα辐射谱线测得。
本发明提供一种如式I所示的化合物的晶型B，其以2θ角表示的X射线粉末衍射图在9.92±0.2°、10.45±0.2°、10.81±0.2°、15.71±0.2°、16.32±0.2°、17.01±0.2°、20.93±0.2°和22.31±0.2°处有衍射峰；
Figure PCTCN2022075711-appb-000003
在本发明一些实施方案中，较佳地，所述的晶型B以2θ角表示的X射线粉末衍射图还在5.36±0.2°、13.29±0.2°、18.25±0.2°、18.71±0.2°和25.01±0.2°中的一处或多处有衍射峰。
在本发明一些实施方案中，较佳地，所述的晶型B以2θ角表示的X射线粉末衍射图中，其衍射峰、d值和峰高百分比还可如表3所示：
表3
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.36 16.47 10.12
2 9.92 8.92 46.98
3 10.45 8.47 43.41
4 10.81 8.19 100.00
5 13.29 6.66 5.05
6 15.71 5.64 19.38
7 16.32 5.43 27.02
8 17.01 5.21 14.06
9 18.25 4.86 3.25
10 18.71 4.74 9.91
11 20.93 4.24 12.61
12 22.31 3.99 15.32
13 25.01 3.56 6.87
。
在本发明一些实施方案中，所述的晶型B的XRPD图谱基本如图2所示。
在本发明一些实施方案中，所述的晶型B在36.4℃至160℃温度范围失重≤4.0％；较佳地，所述的晶型B在160℃失重约3.98％。
在本发明一些实施方案中，所述的晶型B的热重分析曲线图谱基本如图5所示。
在本发明一些实施方案中，所述的晶型B的热重分析曲线在66.3±5℃和278.0±5℃处存在吸热峰，在180.3℃±5℃处存在放热峰。
在本发明一些实施方案中，所述的晶型B的差示扫描量热图谱基本如图8所示。
在本发明一些实施方案中，所述的X射线粉末衍射图使用Cu-Kα辐射谱线测得。
本发明提供一种如式I所示的化合物的晶型C，其以2θ角表示的X射线粉末衍射图在7.61±0.2°、11.28±0.2°、13.82±0.2°、16.71±0.2°、20.12±0.2°和22.30±0.2°处有衍射峰；
Figure PCTCN2022075711-appb-000004
在本发明一些实施方案中，较佳地，所述的晶型C的以2θ角表示的X射线粉末衍射图还在15.25±0.2°、23.54±0.2°、25.01±0.2°和25.89±0.2°中的一处或多处有衍射峰。
本发明提供一种如式I所示的化合物的晶型C，其以2θ角表示的X射线粉末衍射
图在7.61±0.2°、11.28±0.2°、13.82±0.2°、15.25±0.2°、16.71±0.2°、20.12±0.2°、
22.30±0.2°、23.54±0.2°、25.01±0.2°和25.89±0.2°处有衍射峰；
Figure PCTCN2022075711-appb-000005
在本发明一些实施方案中，较佳地，所述的晶型C的以2θ角表示的X射线粉末衍射图还在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°和33.93±0.2°中的一处或多处有衍射峰。
在本发明一些实施方案中，更佳地，所述的晶型C以2θ角表示的X射线粉末衍射图，其以2θ角表示的X射线粉末衍射图还在如表4所示的衍射角处有衍射峰：
表4
编号 衍射角2θ(±0.2°)
1 7.61
2 9.38
3 10.65
4 11.28
5 12.87
6 13.82
7 15.25
8 15.71
9 16.71
10 17.98
11 18.79
12 20.12
13 21.47
14 22.30
15 23.54
16 25.01
17 25.89
18 27.25
19 28.10
20 30.83
21 32.31
22 33.93
。
在本发明一些实施方案中，较佳地，所述的晶型C以2θ角表示的X射线粉末衍射图中，其衍射峰、d值和峰高百分比可如表5所示：
表5
编号 衍射角2θ(±0.2°) d值 相对强度％
1 7.61 11.62 15.84
2 9.38 9.43 3.49
3 10.65 8.31 5.64
4 11.28 7.84 100.00
5 12.87 6.88 4.88
6 13.82 6.41 12.61
7 15.25 5.81 8.25
8 15.71 5.64 4.42
9 16.71 5.31 15.21
10 17.98 4.93 3.19
11 18.79 4.72 1.54
12 20.12 4.41 35.66
13 21.47 4.14 3.38
14 22.30 3.99 34.73
15 23.54 3.78 9.00
16 25.01 3.56 8.39
17 25.89 3.44 7.35
18 27.25 3.27 3.49
19 28.10 3.18 5.98
20 30.83 2.90 2.21
21 32.31 2.77 0.99
22 33.93 2.64 0.82
在本发明一些实施方案中，所述的晶型C的XRPD图谱基本如图3所示。
在本发明一些实施方案中，所述的晶型C在29.0℃至150℃温度范围失重≤0.90％；较佳地，所述的晶型C在150℃失重约0.90％。
在本发明一些实施方案中，所述的晶型C的热重分析曲线图谱基本如图6所示。
在本发明一些实施方案中，所述的晶型C的热重分析曲线在289.2±5℃处具有吸热峰，在244.5±5℃处存在放热峰。
在本发明一些实施方案中，所述的晶型C的差示扫描量热图谱基本如图9所示。
在本发明一些实施方案中，所述的X射线粉末衍射图使用Cu-Kα辐射谱线测得。
本发明还提供了一种前述的如式I所示化合物的晶型A的制备方法，其包括方案1或方案2；
所述的方案1包括如下步骤：所述的如式I所示化合物在甲醇中打浆析晶，收集固体得所述的如式I所示化合物的晶型A，所述的甲醇与所述的如式I所示化合物的体积质 量比为10～50mL/g；
所述的方案2包括如下步骤：所述的如式I所示化合物的溶液通过降温和/或溶剂自然挥发析出固体，收集固体得所述的如式I所示化合物的晶型A，所述的溶液的溶剂为二氯甲烷和甲醇的混合溶剂；所述的二氯甲烷和甲醇的体积比为1:(1～4)；所述的混合溶剂与所述的如式I所示化合物的体积质量比为20～200mL/g。
在本发明一些实施方案中，所述的方案1和方案2还包括干燥。
在本发明一些实施方案中，所述的干燥的温度可为45±5℃。
在本发明一些实施方案中，所述的打浆方式为本领域常规的打浆方式，例如搅拌。
在本发明一些实施方案中，所述的如式I所示化合物的溶液通过常温搅拌或加热回流溶清得到。
在本发明一些实施方案中，较佳地，所述的方案1中，所述的混合溶剂与所述的如式I所示化合物的体积质量比为20～30mL/g；例如20mL/g。
在本发明一些实施方案中，较佳地，所述的方案2中，所述的混合溶剂与所述的如式I所示化合物的体积质量比可为105mL/g。
本发明还提供了一种前述的如式I所示化合物的晶型B的制备方法，其包括如下步骤：所述的如式I所示化合物的溶液通过挥发析出固体，收集固体得所述的如式I所示化合物的晶型B，所述的溶液中的溶剂为二氯甲烷和甲醇的混合溶剂。
在本发明一些实施方案中，所述的二氯甲烷和甲醇的体积比可为83:1。
在本发明一些实施方案中，所述的混合溶剂与所述的如式I所示化合物的体积质量比为0.7mL/mg。
本发明还提供了一种前述的如式I所示化合物的晶型C的制备方法，其包括如下步骤：所述的如式I所示化合物在四氢呋喃中打浆析晶，收集固体得所述的如式I所示化合物的晶型C；所述的四氢呋喃与所述的如式I所示化合物的体积质量比为10～50mL/g。
在本发明一些实施方案中，所述的制备方法还包括真空干燥。
在本发明一些实施方案中，所述的真空干燥温度可为45±5℃。
在本发明一些实施方案中，较佳地，所述的四氢呋喃与所述的如式I所示化合物的体积质量比为10～30mL/g，例如16mL/g。
在本发明一些实施方案中，所述的打浆方式为本领域常规的打浆方式，例如搅拌。
本发明还提供了一种药物组合物，其包括物质X和至少一种药用辅料；所述的物质X为前述的如式I所示化合物的晶型A或C。
本发明还提供了一种药物组合物，其包括物质Y和至少一种药用辅料，前述的如式 I所示化合物的晶型B。
所述的药用辅料的选择因施用途径和作用特点而异，通常可为本领域常规的填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂、助悬剂等。
所述的药物组合物可以通过口服、注射(静脉、肌肉、皮下和冠状动脉内)、舌下、经颊、经直肠、经尿道、经***、经鼻、吸入或局部途径施用，优选途径是口服。
本发明提供了一种前述如式I所示化合物的晶型A或C在制备药物或“EGFR和/或ErbB2受体酪氨酸激酶抑制剂”中的应用，所述的药物用于通过抑制EGFR和/或ErbB2受体酪氨酸激酶治疗的疾病或治疗ErbB2(HER2)阳性的晚期恶性肿瘤的疾病。
在本发明一些实施方案中，所述的“通过抑制EGFR和/或ErbB2受体酪氨酸激酶治疗的疾病”为通过选择性抑制ErbB2受体酪氨酸激酶治疗的疾病。
在本发明一些实施方案中，所述的"EGFR和/或ErbB2受体酪氨酸激酶抑制剂”为选择性ErbB2受体酪氨酸激酶抑制剂。
在本发明一些实施方案中，所述的通过选择性抑制ErbB2受体酪氨酸激酶治疗的疾病为乳腺癌或胃癌。
在本发明一些实施方案中，所述的ErbB2(HER2)阳性的晚期恶性肿瘤的疾病为乳腺癌。
本发明提供了一种前述如式I所示化合物的晶型B在制备药物或“EGFR和/或ErbB2受体酪氨酸激酶抑制剂”中的应用，所述的药物用于通过抑制EGFR和/或ErbB2受体酪氨酸激酶治疗的疾病或治疗ErbB2(HER2)阳性的晚期恶性肿瘤的疾病。
在本发明一些实施方案中，所述的“通过抑制EGFR和/或ErbB2受体酪氨酸激酶治疗的疾病”为通过选择性抑制ErbB2受体酪氨酸激酶治疗的疾病。
在本发明一些实施方案中，所述的"EGFR和/或ErbB2受体酪氨酸激酶抑制剂”为选择性ErbB2受体酪氨酸激酶抑制剂。
在本发明一些实施方案中，所述的通过选择性抑制ErbB2受体酪氨酸激酶治疗的疾病为乳腺癌或胃癌。
在本发明一些实施方案中，所述的ErbB2(HER2)阳性的晚期恶性肿瘤的疾病为乳腺癌。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明提供了一种如式I所示化合物的晶型A、B或C。本发明的晶型相对于CN107141293A实施例4记载的无定型具有更稳定的热稳定性质。晶型A和晶型C的药代性质优于无定型。
附图说明
图1为实施例1中所得晶型A的X射线粉末衍射图；
图2为实施例2中所得晶型B的X射线粉末衍射图；
图3为实施例3中所得晶型C的X射线粉末衍射图；
图4为实施例1中所得晶型A的热重分析图；
图5为实施例2中所得晶型B的热重分析图；
图6为实施例3中所得晶型C的热重分析图；
图7为实施例1中所得晶型A的差式扫描量热图；
图8为实施例2中所得晶型B的差式扫描量热图；
图9为实施例3中所得晶型C的差式扫描量热图；
图10为实施例1中所得晶型A的引湿性测试(DVS)图；
图11为实施例1中所得晶型A引湿性测试前后的X射线粉末衍射对比图；
图12为效果实施例1中晶型B加热X射线粉末衍射图变化图；
图13为效果实施例1中晶型C加热X射线粉末衍射图变化图；
图14为据中国专利CN107141293A实施例4记载的方法制备得到的合物I无定型的X射线粉末衍射图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
采集数据所用的仪器及方法：
本申请所述的X射线粉末衍射图在PANalytical Empyrean型X射线粉末衍射仪及PANalytical X'Pert3型X射线粉末衍射仪上采集。
Empyrean型X射线粉末衍射的方法参数如下：
X射线类型：Cu,Kα
Figure PCTCN2022075711-appb-000006
1.540598；
Figure PCTCN2022075711-appb-000007
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
发散狭缝：自动
扫描模式：连续
扫描范围：自3.0至40.0度
每步扫描时间：17.780秒
步长：0.0167度
PANalytical X'Pert3型X射线粉末衍射的方法参数如下：
X射线类型：Cu,Kα
Figure PCTCN2022075711-appb-000008
1.540598；
Figure PCTCN2022075711-appb-000009
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
发散狭缝：1/16度
扫描模式：连续
扫描范围：自3.0至40.0度
每步扫描时间：46.665秒
步长：0.0263度
本申请所述的差示扫描量热分析(DSC)数据采自于TA Instruments Q200型及TA Instruments Q2000型差示扫描量热仪，仪器控制软件是Q Series，分析软件是Universal Analysis。通常取1～10毫克的样品放置于加盖(除非特别说明)的铝坩埚内，以10℃/min的升温速度在50mL/min干燥N 2的保护下将样品从室温升至300℃，同时TA软件记录样品在升温过程中的热量变化。在本申请中，熔点是按起始温度来报告的。
本申请所述的热重分析(TGA)数据采自于TA Instruments Q500型及TA Instruments Q5000型热重分析仪，仪器控制软件是Q Series，分析软件是Universal Analysis。通常取2～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在50mL/min干燥N 2的保护下将样品从室温升至400℃，同时TA软件记录样品在升温过程中的重量变化。
本申请所述的动态水分吸附图在SMS公司的Intrinsic型及Intrinsic Plus型动态水分 吸附仪上采集。本发明所述的动态水分吸附测试的方法参数如下：
温度：25℃
保护气体及流量：N 2，200毫升/分钟
dm/dt：0.002％/分钟
最小dm/dt平衡时间：10分钟
最大平衡时间：180分钟
相对湿度范围：0％RH-95％RH-0％RH
相对湿度梯度：10％(0％RH-90％RH-0％RH)、5％(90％RH-95％RH和95％RH-90％RH)
以下实施例中所述的化合物I的无定型样品是通过CN107141293A实施例4记载的方法制备得到，其XRPD图如图14所示。
实施例1化合物I晶型A的制备
无定型样品5g，甲醇100mL，25℃搅拌18h析晶，抽滤，45±5℃真空干燥烘干，得固体样品，即为化合物I晶型A，纯度99.8％。
实施例2化合物I晶型A的制备
取样0.4g无定型样品，二氯甲烷/甲醇(1:4,v/v)42ml，回流溶清，敞口静置挥发，得到固体，抽滤，45±5℃真空干燥烘干，即为化合物I晶型A，纯度99.57％。
经检测，实施例1和实施例2所得固体的X射线粉末衍射数据如表6所示，其XRPD图如图1所示，其TGA图如图4所示，其DSC图如图7所示，结果表明所得固体产物为本申请所述的晶型A，TGA数据显示该晶型样品加热至150℃失重约0.40％，且DSC中在272.9℃(峰值温度)存在单一熔化吸热峰。
取晶型A约20mg，采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表7所示。引湿性实验的DVS图如图10所示，样品测试前后的XRPD对比图如图11所示。
表6
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.20 17.01 48.01
2 7.30 12.11 29.62
3 10.36 8.54 35.04
4 11.56 7.66 11.33
5 12.12 7.30 14.34
6 13.18 6.72 5.19
7 14.60 6.07 36.28
8 15.27 5.80 11.98
9 15.54 5.70 100.00
10 15.93 5.56 33.59
11 16.37 5.42 20.56
12 16.95 5.23 21.76
13 17.76 4.99 37.81
14 18.30 4.85 21.22
15 18.66 4.76 41.19
16 19.16 4.63 24.83
17 19.73 4.50 17.98
18 19.90 4.46 30.97
19 20.54 4.32 6.97
20 20.76 4.28 17.10
21 21.27 4.18 10.59
22 21.68 4.10 26.45
23 22.04 4.03 17.56
24 22.64 3.93 26.29
25 22.81 3.90 20.81
26 23.02 3.86 9.84
27 23.22 3.83 6.82
28 23.64 3.76 3.52
29 23.97 3.71 16.14
30 24.54 3.63 13.27
31 24.91 3.57 19.49
32 25.69 3.47 2.82
33 26.01 3.42 9.75
34 26.38 3.38 14.09
35 27.53 3.24 7.63
36 28.13 3.17 2.14
37 28.64 3.12 2.76
38 28.97 3.08 4.29
39 30.37 2.94 1.59
40 32.31 2.77 1.68
41 33.69 2.66 7.30
42 34.60 2.59 1.83
43 35.36 2.54 2.67
44 35.94 2.50 0.65
45 37.96 2.37 2.40
表7晶型A的引湿性实验
Figure PCTCN2022075711-appb-000010
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％。
实施例3化合物I晶型B的制备
称取约15mg无定型样品至20mL玻璃小瓶中，加入0.5mL二氯甲烷/甲醇(3:1,v/v)溶解样品，将所得溶液过滤至另一20mL玻璃小瓶中，向所得澄清溶液中加入10mL二氯甲烷，将所得样品转移至室温敞口挥发，得到固体，即为化合物I晶型B。
经检测，实施例3所得固体的X射线粉末衍射数据如表8所示，其XRPD图如图2所示，其TGA图如图5所示，其DSC图如图8所示，结果表明所得固体产物为本申请所述的晶型B，TGA数据显示该晶型样品加热至160℃失重约3.98％，且DSC中在66.3℃(峰值温度)和278.0℃(峰值温度)存在吸热峰，在180.3℃(峰值温度)存在放热峰。
表8
编号 衍射角2θ(±0.2°) d值 相对强度％
1 5.36 16.47 10.12
2 9.92 8.92 46.98
3 10.45 8.47 43.41
4 10.81 8.19 100.00
5 13.29 6.66 5.05
6 15.71 5.64 19.38
7 16.32 5.43 27.02
8 17.01 5.21 14.06
9 18.25 4.86 3.25
10 18.71 4.74 9.91
11 20.93 4.24 12.61
12 22.31 3.99 15.32
13 25.01 3.56 6.87
实施例4化合物I晶型C的制备
取无定型样品2.5g，加四氢呋喃40ml，室温搅拌3h，得到固体，抽滤，45±5℃真空干燥得固体，即为化合物I晶型C，纯度99.78％。
经检测，本实施例所得固体的X射线粉末衍射数据如表9所示，其XRPD图如图3所示，其TGA图如图6所示，其DSC图如图9所示，结果表明所得固体产物为本申请所述的晶型C，TGA数据显示该晶型样品加热至150℃失重约0.90％，且DSC中在244.5℃(峰值温度)存在放热峰，在289.2℃(峰值温度)存在吸热峰。
表9
编号 衍射角2θ(±0.2°) d值 相对强度％
1 7.61 11.62 15.84
2 9.38 9.43 3.49
3 10.65 8.31 5.64
4 11.28 7.84 100.00
5 12.87 6.88 4.88
6 13.82 6.41 12.61
7 15.25 5.81 8.25
8 15.71 5.64 4.42
9 16.71 5.31 15.21
10 17.98 4.93 3.19
11 18.79 4.72 1.54
12 20.12 4.41 35.66
13 21.47 4.14 3.38
14 22.30 3.99 34.73
15 23.54 3.78 9.00
16 25.01 3.56 8.39
17 25.89 3.44 7.35
18 27.25 3.27 3.49
19 28.10 3.18 5.98
20 30.83 2.90 2.21
21 32.31 2.77 0.99
22 33.93 2.64 0.82
。
效果实施例1：晶型转换关系
如图12所示，晶型B加热至210℃转变为晶型A(将晶型B通过常规加热到210℃，然后检测其晶型变化情况)，根据Burger-Ramberger Rules，表明晶型A比B稳定。
如图13所示，晶型C加热至260℃后转变为晶型A，根据Burger-Ramberger Rules，表明晶型A比C稳定。
结论：晶型A较晶型B和C热力学上更稳定。
效果实施例2：固态稳定性测试结果如表10所示。
表10
Figure PCTCN2022075711-appb-000011
结论：无定型和晶型A通过在25℃/60％RH和25℃/60％RH条件下敞口放置一周， 以及晶型A在80℃条件下密封放置24小时进行评估，结果表明：无定型在测试条件下纯度下降，晶型A在上述测试条件下具有较好的物理和化学稳定性。
效果实施例3：不同晶型和无定型给药后大鼠体内吸收比较
SD大鼠(由上海西普尔必凯实验动物有限公司提供，合格证编号：2008001669476)，每5只分为一组，分别灌胃给予不同晶型和无定型(见表10)，分别于给药前和给药后5、15、30、60、90、120、240、360、480、600、1440min于大鼠眼底静脉丛取血0.4mL。血样于8000rpm离心5min，分离上层血浆，血浆样品50μL，加入300μL含内标的乙腈(Propranolol，25ng/ml)沉淀蛋白，涡旋10min，6000g，4℃离心20min，取上清20μL加入超纯水80μL稀释后，离心取上清80μL于96孔板进样，在LC/MS/MS中进行检测得到血浆药物浓度，再计算相应的药代参数，(CMC-Na为羧甲基纤维素钠，HPMC为羟丙基甲基纤维素)见表12所示。
表11动物分组及给药情况
Figure PCTCN2022075711-appb-000012
表12不同晶型样品灌胃给药后药代参数
Figure PCTCN2022075711-appb-000013
Figure PCTCN2022075711-appb-000014
结论：本次实验分别将A晶型和C晶型样品用0.5％HPMC和0.5％CMC-Na混悬及无定型用0.5％CMC-Na混悬，以15mg/kg的剂量大鼠灌胃给药，比较药代参数，结果显示，晶型A和晶型C的药代性质优于无定型。

Claims (13)

  1. 一种如式I所示的化合物的晶型A，其特征在于，其以2θ角表示的X射线粉末衍射图在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°和22.64±0.2°处有衍射峰；
    Figure PCTCN2022075711-appb-100001
  2. 如权利要求1所述的如式I所示的化合物的晶型A，其特征在于，所述的晶型A的以2θ角表示的X射线粉末衍射图还在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°和26.38±0.2°中的一处或多处有衍射峰；
    和/或，所述的晶型A在35℃至150℃温度范围失重≤0.40％；
    和/或，所述的晶型A的热重分析曲线在272.9±5℃处具有吸热峰；
    和/或，所述的晶型A在80％RH下的吸湿增重为0.27％；
    和/或，所述的X射线粉末衍射图使用Cu-Kα辐射谱线测得。
  3. 如权利要求2所述的如式I所示的化合物的晶型A，其特征在于，所述的晶型A的以2θ角表示的X射线粉末衍射图还在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°和37.96±0.2°中的一处或多处有衍射峰；较佳地，所述的晶型A的XRPD图谱基本如图1所示；
    和/或，所述的晶型A在150℃失重0.40％；较佳地，所述的晶型A的热重分析曲线图谱基本如图4所示；
    和/或，所述的晶型A的差示扫描量热图谱基本如图7所示；
    和/或，所述的晶型A的动态水分吸附图谱基本如图10所示。
  4. 一种如权利要求1-3中任一项所述的如式I所示的化合物的晶型A的制备方法，其特征在于，其为方案1或方案2，
    所述的方案1包括如下步骤：所述的如式I所示化合物在甲醇中打浆析晶，收集固体得所述的如式I所示化合物的晶型A，所述的甲醇与所述的如式I所示化合物的体积质量比为10～50mL/g；
    所述的方案2包括如下步骤：所述的如式I所示化合物的溶液通过降温和/或溶剂自然挥发析出固体，收集固体得所述的如式I所示化合物的晶型A，所述的溶液的溶剂为二氯甲烷和甲醇的混合溶剂；所述的二氯甲烷和甲醇的体积比为1:(1～4)；所述的混合溶剂与所述的如式I所示化合物的体积质量比为20～200mL/g。
  5. 如权利要求4所述的如式I所示的化合物的晶型A的制备方法，其特征在于，所述的方案1和方案2还包括干燥；较佳地，所述的干燥的温度为45±5℃；
    和/或，所述的方案2中，所述的混合溶剂与所述的如式I所示化合物的积比质量体为105mL/g；
    和/或，所述的打浆的方式为搅拌；
    和/或，所述的如式I所示化合物的溶液通过常温搅拌或加热回流溶清得到；
    和/或，所述的方案1中，所述的混合溶剂与所述的如式I所示化合物的体积质量比为20～30mL/g；例如20mL/g。
  6. 一种如式I所示的化合物的晶型C，其以2θ角表示的X射线粉末衍射图在7.61±0.2°、11.28±0.2°、13.82±0.2°、16.71±0.2°、20.12±0.2°和22.30±0.2°处有衍射峰；
    Figure PCTCN2022075711-appb-100002
  7. 如权利要求6所述的如式I所示的化合物的晶型C，其特征在于，所述的晶型C的以2θ角表示的X射线粉末衍射图还在15.25±0.2°、23.54±0.2°、25.01±0.2°和25.89±0.2°中的一处或多处有衍射峰。
  8. 一种如式I所示的化合物的晶型C，其特征在于，其以2θ角表示的X射线粉末衍射图在7.61±0.2°、11.28±0.2°、13.82±0.2°、15.25±0.2°、16.71±0.2°、20.12±0.2°、
    22.30±0.2°、23.54±0.2°、25.01±0.2°和25.89±0.2°处有衍射峰；
    Figure PCTCN2022075711-appb-100003
  9. 如权利要求8所述的如式I所示的化合物的晶型C，其特征在于，所述的晶型C的以2θ角表示的X射线粉末衍射图还在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°和 33.93±0.2°中的一处或多处有衍射峰；
    和/或，所述的晶型C在29.0℃至150℃温度范围失重≤0.90％；较佳地，所述的晶型C在150℃失重约0.90％；
    和/或，所述的晶型C的热重分析曲线在289.2±5℃处具有吸热峰，在244.5±5℃处存在放热峰；
    和/或，所述的X射线粉末衍射图使用Cu-Kα辐射谱线测得。
  10. 如权利要求9所述的如式I所示的化合物的晶型C，其特征在于，所述的晶型C的XRPD图谱基本如图3所示；
    和/或，所述的晶型C的热重分析曲线图谱基本如图6所示；
    和/或，所述的晶型C的差示扫描量热图谱基本如图9所示。
  11. 一种如权利要求6-10中任一项所述的如式I所示的化合物的晶型C的制备方法，其特征在于，其包括如下步骤：所述的如式I所示化合物在四氢呋喃中打浆析晶，收集固体得所述的如式I所示化合物的晶型C；所述的四氢呋喃与所述的如式I所示化合物的体积质量比为10～50mL/g；
    较佳地，所述的制备方法还包括真空干燥；更佳地，所述的真空干燥温度为45±5℃；
    和/或，所述的四氢呋喃与所述的如式I所示化合物的体积质量比为10～30mL/g，例如16mL/g；
    和/或，所述的打浆的方式为搅拌。
  12. 一种药物组合物，其特征在于，其包括物质X和至少一种药用辅料；所述的物质X为如权利要求1-3中任一项所述的如式I所示化合物的晶型A或如权利要求6-10中任一项所述的如式I所示化合物的晶型C。
  13. 一种如权利要求1-3中任一项所述的如式I所示化合物的晶型A或如权利要求6-10中任一项所述的如式I所示化合物的晶型C在制备药物、“EGFR和/或ErbB2受体酪氨酸激酶抑制剂”中的应用，所述的药物用于通过抑制EGFR和/或ErbB2受体酪氨酸激酶治疗的疾病或治疗ErbB2阳性的晚期恶性肿瘤的疾病；
    较佳地，所述的“通过抑制EGFR和/或ErbB2受体酪氨酸激酶治疗的疾病”为通过选择性抑制ErbB2受体酪氨酸激酶治疗的疾病；
    和/或，所述的"EGFR和/或ErbB2受体酪氨酸激酶抑制剂”为选择性ErbB2受体酪氨酸激酶抑制剂；
    更佳地，所述的通过选择性抑制ErbB2受体酪氨酸激酶治疗的疾病为乳腺癌或胃癌；
    和/或，所述的ErbB2阳性的晚期恶性肿瘤的疾病为乳腺癌。
PCT/CN2022/075711 2021-02-10 2022-02-09 一种含氮杂环化合物的晶型、其制备方法及应用 WO2022171138A1 (zh)

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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

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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

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