WO2022199699A1 - Forme cristalline de sel de composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation - Google Patents

Forme cristalline de sel de composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation Download PDF

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WO2022199699A1
WO2022199699A1 PCT/CN2022/083147 CN2022083147W WO2022199699A1 WO 2022199699 A1 WO2022199699 A1 WO 2022199699A1 CN 2022083147 W CN2022083147 W CN 2022083147W WO 2022199699 A1 WO2022199699 A1 WO 2022199699A1
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nitrogen
heterocyclic compound
fused heterocyclic
containing fused
formula
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PCT/CN2022/083147
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Chinese (zh)
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夏广新
楼江松
翟雄
葛辉
王倩
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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • 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 salt of a nitrogen-containing fused heterocyclic compound, a preparation method and application thereof.
  • a nitrogen-containing fused heterocyclic compound I the structure of which is shown in the following formula, the compound I has been disclosed in patent CN2016112650832.
  • the compound I has high selectivity to CDK4 and CDK6 at the molecular level, and high inhibitory activity.
  • the compound I has better inhibitory activity on breast cancer cells at the cellular level, and also has a significant inhibitory effect on tumor cells related to cyclin-dependent kinase activity at the animal level.
  • the invention provides a new crystal form of a nitrogen-containing fused heterocyclic compound salt, a preparation method and application thereof.
  • the crystalline form of the salt of the nitrogen-containing fused heterocyclic compound of the present invention has less hygroscopicity and better stability and pharmacokinetic properties than the free base.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a crystalline form of a salt of a nitrogen-containing fused heterocyclic compound, which is the crystalline form A of the maleate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-a, and represented by formula II-b.
  • the crystalline form A of the maleate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-a the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 5.818° ⁇ 0.2°, 8.458° ⁇ 0.2° , 11.183° ⁇ 0.2°, 11.562° ⁇ 0.2°, 12.063° ⁇ 0.2°, 13.357° ⁇ 0.2°, 17.701° ⁇ 0.2°, 21.604° ⁇ 0.2°, 23.203° ⁇ 0.2°, 24.423° ⁇ 0.2° and 26.986 There are diffraction peaks at ° ⁇ 0.2°;
  • the crystal form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by the formula II-b, the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 5.886° ⁇ 0.2°, 8.513° ⁇ 0.2° , 11.715° ⁇ 0.2°, 13.417° ⁇ 0.2°, 17.993° ⁇ 0.2°, 18.844° ⁇ 0.2°, 23.393° ⁇ 0.2°, 24.678° ⁇ 0.2° and 29.458° ⁇ 0.2° have diffraction peaks.
  • the target type is Cu target;
  • the crystal form B of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by the formula II-b, its X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 4.139° ⁇ 0.2°, 5.182° ⁇ 0.2° , 9.201° ⁇ 0.2°, 10.822° ⁇ 0.2°, 11.379° ⁇ 0.2°, 14.098° ⁇ 0.2°, 14.723° ⁇ 0.2°, 20.244° ⁇ 0.2° and 25.802° ⁇ 0.2°, the target type used is Cu target;
  • the crystal form A of the succinate of the nitrogen-containing fused heterocyclic compound represented by formula II-c its X-ray powder diffraction pattern represented by 2 ⁇ angle is at 5.918° ⁇ 0.2°, 8.460° ⁇ 0.2°, Diffraction at 11.759° ⁇ 0.2°, 13.364° ⁇ 0.2°, 18.123° ⁇ 0.2°, 18.90° ⁇ 0.2°, 23.523° ⁇ 0.2°, 24.743° ⁇ 0.2°, 25.085° ⁇ 0.2° and 29.684° ⁇ 0.2° peak, the target type used is Cu target;
  • the crystal form A of the hydrochloride of the nitrogen-containing fused heterocyclic compound represented by the formula II-d the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 6.657° ⁇ 0.2°, 11.219° ⁇ 0.2°, Diffraction at 11.742° ⁇ 0.2°, 18.220° ⁇ 0.2°, 21.820° ⁇ 0.2°, 22.542° ⁇ 0.2°, 24.183° ⁇ 0.2°, 24.760° ⁇ 0.2°, 25.946° ⁇ 0.2° and 26.841° ⁇ 0.2° Peak, the target type used is Cu target.
  • the crystalline form A of the maleate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-a is also as follows Diffraction peaks at one or more 2 ⁇ angles: 16.903 ⁇ 0.2°, 18.782 ⁇ 0.2°, 22.222 ⁇ 0.2°, or 24.781 ⁇ 0.2°.
  • the crystalline form A of the maleate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-a has the characteristics in the X-ray powder diffraction pattern represented by 2 ⁇ The peaks and relative intensities are shown in Table 1 below:
  • the crystalline form A of the maleate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-a has the X-ray powder diffraction substantially as shown in FIG. 1 . picture.
  • the crystalline form A of the maleate of the nitrogen-containing fused heterocyclic compound represented by formula II-a has a hygroscopic weight gain of 1.1 in the range of 0% RH to 80% RH %; wherein, the weight gain percentage is the percentage of the weight gain of the sample after moisture absorption to the weight of the sample before this moisture absorption.
  • the crystalline form A of the maleate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-a has an adsorption isotherm curve (DVS )picture.
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b, the X-ray powder diffraction pattern represented by the 2 ⁇ angle is still 12.376 There are diffraction peaks at ° ⁇ 0.2° and/or 17.108° ⁇ 0.2°.
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has the characteristics in the X-ray powder diffraction pattern represented by 2 ⁇ The peaks and relative intensities are shown in Table 2 below:
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has the X-ray powder diffraction substantially as shown in FIG. 9 . picture.
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has a differential scanning calorimetry (DSC) pattern at 261 ⁇ 5°C There is an endothermic peak at , and the heat of fusion is 159.47 J/g.
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has the differential scanning calorimetry substantially as shown in FIG. 31 . picture.
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has a thermogravimetric analysis (TGA) chart at 100 ⁇ 5°C
  • TGA thermogravimetric analysis
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has a thermogravimetric analysis diagram substantially as shown in FIG. 32 .
  • the hygroscopic weight gain of the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b is 2.0 in the range of 0% RH to 80% RH %, wherein the weight gain percentage is the percentage of the weight gain of the sample after moisture absorption to the weight of the sample before this moisture absorption.
  • the crystalline form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has the adsorption isotherm curve (DVS )picture.
  • the crystalline form B of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b, the X-ray powder diffraction pattern represented by the 2 ⁇ angle is also as follows Diffraction peaks at one or more 2 ⁇ angles: 7.900° ⁇ 0.2°, 10.269° ⁇ 0.2°, 16.161° ⁇ 0.2°, 16.935° ⁇ 0.2°, 21.738° ⁇ 0.2°, 24.401° ⁇ 0.2°, 25.407° ⁇ 0.2°, 26.571° ⁇ 0.2° or 27.600° ⁇ 0.2°.
  • the crystal form B of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has the characteristic peaks of the X-ray powder diffraction pattern represented by 2 ⁇ and relative intensities are shown in Table 3 below:
  • the crystalline form B of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b has an X-ray powder diffraction substantially as shown in FIG. 10 . picture.
  • the crystalline form A of the succinate of the nitrogen-containing fused heterocyclic compound represented by formula II-c, the X-ray powder diffraction pattern represented by the 2 ⁇ angle is further one of the following Diffraction peaks at or at multiple 2 ⁇ angles: 12.421° ⁇ 0.2°, 17.039° ⁇ 0.2°, 21.622° ⁇ 0.2° or 26.920° ⁇ 0.2°.
  • the crystal form A of the succinate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-c has the characteristic peaks of the X-ray powder diffraction pattern represented by 2 ⁇ and The relative intensities are shown in Table 4 below:
  • the crystal form A of the succinate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-c has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .
  • the crystalline form A of the succinate of the nitrogen-containing fused heterocyclic compound represented by formula II-c has a hygroscopic weight gain of 1.6% in the range of 0% RH to 80% RH , wherein the weight gain percentage is the percentage of the weight gain of the sample after moisture absorption to the weight of the sample before this moisture absorption.
  • the crystalline form A of the succinate of the nitrogen-containing fused heterocyclic compound represented by formula II-c has the adsorption isotherm (DVS) curve as shown in FIG. 29 . picture.
  • the crystalline form A of the hydrochloride salt of the nitrogen-containing fused heterocyclic compound represented by formula II-d is one of the following Diffraction peaks at or at multiple 2 ⁇ angles: 8.921° ⁇ 0.2°, 13.164° ⁇ 0.2°, 14.978° ⁇ 0.2°, 17.584° ⁇ 0.2°, 19.140° ⁇ 0.2°, 20.126° ⁇ 0.2°, 20.583° ⁇ 0.2 ° or 28.023° ⁇ 0.2°.
  • the crystalline form A of the hydrochloride salt of the nitrogen-containing fused heterocyclic compound represented by formula II-d has the characteristic peaks of the X-ray powder diffraction pattern represented by 2 ⁇ and The relative intensities are shown in Table 5 below:
  • the crystalline form A of the hydrochloride salt of the nitrogen-containing fused heterocyclic compound represented by formula II-d has an X-ray powder diffraction pattern substantially as shown in FIG. 24 .
  • the hygroscopic weight gain of the crystalline form A of the hydrochloride of the nitrogen-containing fused heterocyclic compound represented by formula II-d is 3.0% in the range of 0%RH to 40%RH , the weight gain is 1.5% in the range from 40%RH to 80%RH, and the weight loss is 4.5% in the range from 80%RH to 0%RH; wherein, the percentage of weight gain is the difference between the weight gain of the sample after moisture absorption The percentage of the weight of the sample before this moisture absorption, the weight loss percentage is the percentage of the weight of the sample after dehumidification and the weight of the sample before this dehumidification.
  • the crystalline form A of the hydrochloride salt of the nitrogen-containing fused heterocyclic compound represented by formula II-d has the adsorption isotherm (DVS) curve as shown in FIG. 30 . picture.
  • the present invention also provides a method for preparing a crystal form of a salt of a nitrogen-containing fused heterocyclic compound, which is method 1, method 2 or method 3:
  • Method 1 it comprises the following steps: crystallizing the maleate of the nitrogen-containing fused heterocyclic compound represented by formula II-a in a solvent to obtain the nitrogen-containing fused heterocyclic compound represented by formula II-a
  • the crystal form A of the maleate salt of the cyclic compound is one or more of ethanol, ether solvent and water-ketone solvent whose volume ratio is 1:28-1:22;
  • Method 2 it comprises the steps of: mixing the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by the formula II-b, the succinate salt of the nitrogen-containing fused heterocyclic compound represented by the formula II-c, or the formula
  • the hydrochloride of the nitrogen-containing fused heterocyclic compound represented by II-d is crystallized in a C 1-3 alcohol solvent to obtain the fumaric acid of the nitrogen-containing fused heterocyclic compound represented by the formula II-b Salt crystal form A, the crystal form A of the succinate of the nitrogen-containing fused heterocyclic compound represented by formula II-c or the salt of the nitrogen-containing fused heterocyclic compound represented by formula II-d Form A of the acid salt;
  • Method 3 it comprises the following steps: crystallizing the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b in a water-ether solvent with a volume ratio of 1:8-1:3 to obtain The fumarate crystal form B of the nitrogen-containing fused heterocyclic compound shown in formula II-b;
  • the molar concentration of the maleate of the nitrogen-containing fused heterocyclic compound represented by formula II-a is preferably 0.009-0.032 mol/L, such as 0.025 mol/L, and another example 0.026 mol/L .
  • the crystallization method is preferably a natural cooling method, a slow volatilization method or a stirring crystallization method.
  • the temperature at which the maleate of the nitrogen-containing fused heterocyclic compound represented by formula II-a is dissolved in the solvent is preferably 30-80° C. ( For example 50-70°C, another example 60°C).
  • volatilization is preferably carried out at 0-6°C (for example, 4°C).
  • the ether solvent is preferably methyl tert-butyl ether.
  • the ketone-based solvent-ketone-based solvent in water is preferably acetone.
  • the volume ratio of the water-ketone solvent is preferably 1:26-1:24, such as 1:25.
  • the molar concentration of the hydrochloride of the nitrogen-containing fused heterocyclic compound represented by formula II-d is preferably 0.010-0.032 mol/L, for example, 0.025 mol/L.
  • the crystallization method is preferably a natural cooling method.
  • the fumarate of the nitrogen-containing fused heterocyclic compound shown in the formula II-b, the succinate of the nitrogen-containing fused heterocyclic compound shown in the formula II-c The temperature at which the acid salt or the hydrochloride of the nitrogen-containing fused heterocyclic compound represented by formula II-d is dissolved in the C 1-3 alcohol solvent is preferably 30-80 °C, for example, 50- 70°C, another example is 60°C.
  • the C 1-3 alcohol solvent is preferably ethanol.
  • the molar concentration of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b is preferably 0.010-0.032 mol/L, for example, 0.025 mol/L.
  • the crystallization method is preferably a stirring crystallization method.
  • the stirring time is preferably 8-12 hours.
  • the stirring temperature is preferably 0-8°C, eg 4°C.
  • the ether solvent in the water-ether solvent is preferably tetrahydrofuran.
  • the volume ratio of the water-ether solvent is preferably 1:7-1:5, such as 1:6.
  • the maleate of the nitrogen-containing fused heterocyclic compound represented by the formula II-a the maleate of the nitrogen-containing fused heterocyclic compound represented by the formula II-b, the The fumarate of the nitrogen-containing fused heterocyclic compound shown, the succinate of the nitrogen-containing fused heterocyclic compound shown in the formula II-c, or the nitrogen-containing fused heterocyclic compound shown in the formula II-d.
  • the hydrochloride of nitrogen-fused heterocyclic compound is prepared according to the following steps: preferably according to the following steps:
  • the nitrogen-containing fused heterocyclic compound I is subjected to a salt-forming reaction with an acid to obtain the salt of the nitrogen-containing fused heterocyclic compound;
  • Described acid is maleic acid, fumaric acid, succinic acid or hydrochloric acid (for example 36% hydrochloric acid);
  • the conditions and operations of the described salt-forming reaction can be the conventional conditions and operations of this type of reaction in this area, and the present invention is particularly preferably the following conditions and operations:
  • the solvent is preferably a C 1-3 alcohol solvent (such as ethanol), an ether solvent (such as methyl tertiary butyl ether), and a volume ratio of 1:28-1:22.
  • Water-ketone solvent volume ratio of 1:25 water-acetone
  • water-ether solvent volume ratio of 1:6 water-tetrahydrofuran in a volume ratio of 1:8-1:3.
  • the amount of the solvent may not be specifically limited, as long as it does not affect the progress of the reaction.
  • the mass-to-volume ratio of the nitrogen-containing fused heterocyclic compound I to the solvent is preferably 5-40 g/ml, for example, 10-20 g/ml, and also for example, 14.0 g/ml.
  • the molar ratio of the nitrogen-containing fused heterocyclic compound I to the acid may be 1:1.0-1:1.5, for example, 1:1.1.
  • the acid is added to the solution containing the nitrogen-containing fused heterocyclic compound I to carry out the salt-forming reaction;
  • the solution containing the acid is added to the solution containing the nitrogen-containing fused heterocyclic compound I to carry out the salt-forming reaction.
  • the temperature of the salt-forming reaction may be 30-80°C, such as 50-70°C, or 60°C.
  • the salt of the nitrogen-containing fused heterocyclic compound can be directly crystallized in a solvent without post-treatment.
  • the progress of the salt-forming reaction can be monitored by a conventional monitoring method in the art (eg TLC), and the end point of the reaction is that the nitrogen-containing fused heterocyclic compound I no longer reacts or disappears.
  • the time of the salt-forming reaction is 8-32h, for example, 16h.
  • the method for preparing the crystal form of the salt of the nitrogen-containing fused heterocyclic compound is method a, method b or method c:
  • Method a it comprises the following steps: crystallizing the nitrogen-containing fused heterocyclic compound I and maleic acid in the above-mentioned solvent to obtain the maleic acid of the nitrogen-containing fused heterocyclic compound represented by formula II-a
  • the crystal form A of the salt the molar ratio of the nitrogen-containing fused heterocyclic compound I to maleic acid is 1:1.0-1:1.5;
  • Method b it comprises the following steps: crystallizing the nitrogen-containing fused heterocyclic compound I and "fumaric acid, succinic acid or hydrochloric acid" in the above-mentioned C 1-3 alcohol solvent to obtain the described formula II-b
  • Method c it comprises the following steps: crystallizing the nitrogen-containing fused heterocyclic compound I and fumaric acid in the above-mentioned water-ether solvent with a volume ratio of 1:8-1:3 to obtain the described formula II-
  • the post-processing after crystallization includes the following steps: centrifugation, solid collection and drying.
  • the present invention also provides a crystalline form of a salt of a nitrogen-containing fused heterocyclic compound prepared according to the above-mentioned method for preparing a crystalline form of a salt of a nitrogen-containing fused heterocyclic compound.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the above-mentioned crystalline form of the salt of a nitrogen-containing fused heterocyclic compound or a crystalline form of the above-mentioned salt of a nitrogen-containing fused heterocyclic compound prepared by the above-mentioned method for preparing the crystalline form of the salt of a nitrogen-containing fused heterocyclic compound. Crystal forms of salts of nitrogen-fused heterocyclic compounds, and pharmaceutically acceptable excipients.
  • the pharmaceutical excipients are conventional pharmaceutical excipients in the field, and their selection varies depending on the route of administration and function characteristics, preferably including fillers, diluents, adhesives, wetting agents, disintegrating agents, etc. Dissolving agent, lubricant, emulsifier, suspending agent.
  • the auxiliary materials in the pharmaceutical composition include sugars, cellulose and its derivatives, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium hydrogen phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, semi-solid such as lipids or paraffins, binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, glidants such as colloidal silica, Light anhydrous silicic acid, crystalline cellulose, talc or magnesium stearate, disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dry corn Starch, lubricants such as stearic acid, magnesium stearate, sodium stearoyl fumarate, polyethylene glycol.
  • solid inorganic substances such as calcium phosphate, dicalcium hydrogen phosphate, hydroxyapatite, calcium
  • the pharmaceutical composition can be solid or liquid, such as solid oral dosage forms, including tablets, granules, powders, pills and capsules; liquid oral dosage forms, including solutions, syrups, suspensions, dispersions and emulsions; Injectable preparations, including solutions, dispersions and lyophilisates.
  • the formulations can be adapted for rapid, delayed or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolving or fast-melting formulation.
  • Administration routes include oral administration, intravenous subcutaneous injection, injection into tissue administration, transdermal administration, rectal administration, intranasal administration, etc. The preferred route is oral administration.
  • the present invention provides the use of a substance A in the preparation of a cyclin-dependent kinase inhibitor, wherein the substance A is the crystalline form of the salt of the above-mentioned nitrogen-containing fused heterocyclic compound, and the The preparation method of the salt crystal form is the crystal form of the salt of the nitrogen-containing fused heterocyclic compound or the above-mentioned pharmaceutical composition.
  • the present invention provides an application of a substance A in the preparation of a medicine; the substance A is the crystal form of the above-mentioned nitrogen-containing fused heterocyclic compound salt, and the preparation of the above-mentioned crystalline form of the nitrogen-containing fused heterocyclic compound salt
  • the crystalline form of the salt of the nitrogen-containing fused heterocyclic compound prepared by the method or the above pharmaceutical composition is used for preventing or treating diseases related to abnormal cell cycle regulation.
  • the medicament is used to inhibit tumor.
  • the present invention provides an application of a substance A in the preparation of a medicine;
  • the substance A is the crystal form of the above-mentioned nitrogen-containing fused heterocyclic compound salt, and the preparation of the above-mentioned crystalline form of the nitrogen-containing fused heterocyclic compound salt
  • the crystalline form of the salt of the nitrogen-containing fused heterocyclic compound prepared by the method or the above-mentioned pharmaceutical composition, the medicine is used for the prevention or treatment of tumors (such as breast cancer, pancreatic cancer, colorectal cancer, lung cancer, non-small cell cancer) , brain astrocytoma, chronic myelogenous leukemia, acute monocytic leukemia, liver cancer (including hepatocellular carcinoma, hepatic adenocarcinoma), gastric cancer, non-small cell lung cancer, glioblastoma, and prostate adenocarcinoma one or more).
  • tumors such as breast cancer, pancreatic cancer, colorectal cancer, lung cancer
  • the tumor is preferably an advanced solid tumor, more preferably one or more of breast cancer, pancreatic cancer, colorectal cancer and lung cancer.
  • An article eg, a reaction mixture
  • room temperature often abbreviated as "RT.” This means that the temperature of the item is close to, or the same as, the temperature of the space, such as the room or fume hood in which the item is located.
  • the room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • a method or step may be referred to herein as "overnight.” This refers to, for example, a time interval of a method or step that spans the hours of night when the method or step may not be actively observed.
  • the time interval is about 8 to about 20 hours, or about 10 to 18 hours, typically about 16 hours.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that: the crystalline form of the salt of the nitrogen-containing fused heterocyclic compound of the present invention has less hygroscopicity, better stability and higher bioavailability than free bases, and has a relatively low hygroscopicity. High druggability.
  • Fig. 1 is an X-ray powder diffraction pattern of the maleate salt form A of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Figure 2 is an X-ray powder diffraction pattern of the maleate salt form B of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Figure 3 is an X-ray powder diffraction pattern of the maleate salt form C of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Figure 4 is an X-ray powder diffraction pattern of the maleate salt form D of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Fig. 5 is the X-ray powder diffraction pattern of the maleate salt form E of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Fig. 6 is the X-ray powder diffraction pattern of the maleate salt form F of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Fig. 7 is an X-ray powder diffraction pattern of the maleate salt form G of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Figure 8 is an X-ray powder diffraction pattern of the maleate salt form H of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Figure 9 is an X-ray powder diffraction pattern of the fumarate salt form A of the nitrogen-containing fused heterocyclic compound represented by formula II-b.
  • Fig. 10 is an X-ray powder diffraction pattern of the fumarate salt form B of the nitrogen-containing fused heterocyclic compound represented by formula II-b.
  • Figure 11 is an X-ray powder diffraction pattern of the fumarate salt form C of the nitrogen-containing fused heterocyclic compound represented by formula II-b.
  • Figure 12 is an X-ray powder diffraction pattern of the fumarate salt form D of the nitrogen-containing fused heterocyclic compound represented by formula II-b.
  • Figure 14 is an X-ray powder diffraction pattern of the succinate form A of the nitrogen-containing fused heterocyclic compound represented by formula II-c.
  • Figure 15 is an X-ray powder diffraction pattern of the dimaleate salt form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 16 is the X-ray powder diffraction pattern of the mono-L-tartrate salt form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 17 is an X-ray powder diffraction pattern of the mono-citrate crystal form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 18 is an X-ray powder diffraction pattern of the dicitrate crystal form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 19 is the X-ray powder diffraction pattern of the mono-L-malate salt form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 20 is the X-ray powder diffraction pattern of the monophosphate crystal form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 21 is the X-ray powder diffraction pattern of the diphosphate crystal form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 22 is the X-ray powder diffraction pattern of the dimethanesulfonate salt form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 23 is an X-ray powder diffraction pattern of the dimethanesulfonate salt form B of the nitrogen-containing fused heterocyclic compound.
  • Figure 24 is an X-ray powder diffraction pattern of the hydrochloride salt form A of the nitrogen-containing fused heterocyclic compound represented by formula II-d.
  • Figure 25 is the X-ray powder diffraction pattern of the dihydrochloride salt form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 26 is the X-ray powder diffraction pattern of the sulfate crystal form A of the nitrogen-containing fused heterocyclic compound.
  • Figure 27 is the isotherm adsorption curve of the maleate salt form A of the nitrogen-containing fused heterocyclic compound represented by formula II-a.
  • Figure 28 is the isotherm adsorption curve of the fumarate salt form A of the nitrogen-containing fused heterocyclic compound represented by formula II-b.
  • Figure 29 is the isotherm adsorption curve of the succinate form A of the nitrogen-containing fused heterocyclic compound represented by formula II-c.
  • Figure 30 is the isotherm adsorption curve of the hydrochloride salt form A of the nitrogen-containing fused heterocyclic compound represented by formula II-d.
  • Figure 31 is a differential scanning thermogram of crystal form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b.
  • Figure 32 is a thermogravimetric analysis diagram of the crystal form A of the fumarate salt of the nitrogen-containing fused heterocyclic compound represented by formula II-b.
  • Figure 33 shows the nitrogen-containing fused heterocyclic compound I maleate crystal form A as shown in formula II-a, the nitrogen-containing fused heterocyclic compound I fumarate crystal form A as shown in formula II-b, such as Nitrogen-containing fused heterocyclic compound I succinate crystal form A represented by formula II-c, nitrogen-containing fused heterocyclic compound I hydrochloride crystal form A represented by formula II-d and free base were injected into rat plasma.
  • the meaning of the unit M is mol/L
  • the meaning of nM is nmol/L
  • the meaning of mM is mmol/L.
  • the nitrogen-containing fused heterocyclic compound I was prepared according to the method of Example 63 of Patent CN106928219A.
  • maleate crystal form A Take 120 mg of nitrogen-containing fused heterocyclic compound I, add 8.6 ml of ethanol, and stir to dissolve at 60°C. Get 30mg (mol ratio is 1:1.1) maleic acid, add 0.6ml ethanol to dissolve, add dropwise to above-mentioned nitrogen-containing fused heterocyclic compound I solution under stirring, the solid is slowly separated out, naturally cooled to room temperature, centrifuged, and the solid is vacuumed at room temperature After drying overnight (16 h, the same below), 127 mg of the maleate crystal form A of the nitrogen-containing fused heterocyclic compound (referred to as "maleate crystal form A”) was obtained.
  • the X-ray powder diffraction pattern is shown in Figure 1.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 5.818° ⁇ 0.2°, 8.458° ⁇ 0.2°, 11.183° ⁇ 0.2°, 11.562° ⁇ 0.2°, 12.063° ⁇ 0.2°, 13.357° ⁇ 0.2°, 17.701° ⁇ 0.2°, 21.604° ⁇ 0.2°, 23.203° ⁇ 0.2°, 24.423° ⁇ 0.2°, 26.986° ⁇ 0.2°, 16.903 ⁇ 0.2°, 18.782 ⁇ 0.2°, 22.222
  • the weight change of maleate crystal form A from 0% RH to 80% RH is 1.1%, and the isotherm adsorption curve is shown in FIG. 27 .
  • maleate salt form B Take 30 mg of maleate salt form B and put it in a centrifuge tube, and place it in a chloroform solvent atmosphere at room temperature for 3 days to obtain maleate salt form A of a nitrogen-containing fused heterocyclic compound.
  • the 1 H-NMR data and X-ray powder diffraction pattern are basically the same as those of Example 1-1.
  • the 1 H-NMR data and X-ray powder diffraction pattern are basically the same as those of Example 1-1.
  • maleate salt crystal form B Take about 20 mg of maleate salt crystal form B, add 0.2 ml of water, dissolve it, filter, and add 5 ml of acetone dropwise to the filtrate with stirring to precipitate a solid, continue stirring for about 30 minutes, and centrifuge to obtain a nitrogen-containing fused heterocyclic compound of maleic acid. salt form A.
  • the 1 H-NMR data and X-ray powder diffraction pattern are basically the same as those of Example 1-1.
  • the 1H-NMR data are basically the same as those of Example 1-1.
  • the X-ray powder diffraction pattern is shown in Figure 9.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 5.886° ⁇ 0.2°, 8.513° ⁇ 0.2°, 11.715° ⁇ 0.2°, 13.417° ⁇ 0.2°, 17.993° ⁇
  • the differential scanning thermogram is shown in Figure 31, which has an endothermic peak at 261 ⁇ 5°C and a heat of fusion of 159.47 J/g.
  • thermogravimetric analysis chart is shown in Figure 32, and its thermogravimetric analysis (TGA) chart is 0.0395 ⁇ 0.0002% weight loss at 100 ⁇ 5°C, 2.246 ⁇ 0.002% at 210 ⁇ 5°C, and 293 ⁇ 5°C Weight loss was 43.92 ⁇ 0.02%.
  • the fumarate crystal form A has a weight change of 2.0% in the range from 0% RH to 80% RH, and the isotherm adsorption curve is shown in FIG. 28 .
  • fumarate crystal form B Take 100 mg of the mixture containing fumarate crystal form A, add 1.0 ml of water and 1.0 ml of tetrahydrofuran to dissolve the clear solution, add the clear solution dropwise to 5 ml of tetrahydrofuran under stirring, and precipitate immediately, followed by oil, and continue stirring at 4 °C overnight. The solid was precipitated, centrifuged, and vacuum-dried at room temperature overnight to obtain the fumarate crystal form B of the nitrogen-containing fused heterocyclic compound represented by formula II-b (referred to as "fumarate crystal form B").
  • the X-ray powder diffraction pattern is shown in Figure 10.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 4.139° ⁇ 0.2°, 5.182° ⁇ 0.2°, 9.201° ⁇ 0.2°, 10.822° ⁇ 0.2°, 11.379° ⁇ 0.2°, 14.098° ⁇ 0.2°, 14.723° ⁇ 0.2°, 20.244° ⁇ 0.2°, 25.802° ⁇ 0.2°, 7.900° ⁇ 0.2°, 10.269° ⁇ 0.2°, 16.161° ⁇ 0.2°, 16.935° ⁇ 0.2°
  • the 1 H-NMR data are basically the same as those of Example 2-1.
  • the 1 H-NMR data are basically the same as those of Example 2-1.
  • Form C Properties The sample is partially dissociated or degraded according to HPLC and 1 H-NMR.
  • the 1 H-NMR data are basically the same as those of Example 2-1.
  • Form D Properties The sample is partially dissociated or degraded according to HPLC and 1 H-NMR.
  • the 1 H-NMR data are basically the same as those of Example 2-1.
  • the X-ray powder diffraction pattern is shown in FIG. 13 .
  • Form E Properties According to 1 H-NMR, the sample is partially dissociated or degraded.
  • succinate crystal form A Take 120 mg of nitrogen-containing fused heterocyclic compound I, add 8.6 ml of ethanol, and heat and stir at 60° C. to dissolve. Get 31mg (molar ratio of 1:1.1) succinic acid, add 0.6ml ethanol to dissolve, add dropwise to the above nitrogen-containing fused heterocyclic compound I solution under stirring, slowly separate out, naturally cool to room temperature, centrifuge, and dry the solid under vacuum at room temperature overnight , to obtain 128 mg of the succinate crystal form A of the nitrogen-containing fused heterocyclic compound (referred to as "succinate crystal form A").
  • the X-ray powder diffraction pattern is shown in Figure 14, and the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 5.918° ⁇ 0.2°, 8.460° ⁇ 0.2°, 11.759° ⁇ 0.2°, 13.364° ⁇ 0.2°, 18.123° ⁇ and There is a diffraction peak at 26.920° ⁇ 0.2°.
  • the weight change of succinate form A from 0% RH to 80% RH is 1.6%, and the isotherm adsorption curve is shown in FIG. 29 .
  • the weight change of the dimaleate salt form A0%RH to 80%RH was 5.3%.
  • Mono L-tartrate Form A has a weight change of 10.1% from 0% RH to 80% RH.
  • Mono-citrate Form A has a weight change of 7.6% from 0% RH to 80% RH.
  • the weight change of dicitrate Form A from 0% RH to 80% RH was 19.2%.
  • the weight change of mono L-malate Form A from 0% RH to 80% RH is about 6.0%.
  • Monophosphate Form A has a weight change of 12.0% from 0% RH to 80% RH.
  • the X-ray powder diffraction pattern is shown in Figure 22.
  • the crystalline monomethanesulfonate salt form A has a weight change of 7.10% from 0% RH to 80% RH.
  • the X-ray powder diffraction pattern is shown in Figure 24.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle is at 6.657° ⁇ 0.2°, 11.219° ⁇ 0.2°, 11.742° ⁇ 0.2°, 18.220° ⁇ 0.2°, 21.820° ⁇ 0.2 °, 22.542° ⁇ 0.2°, 24.183° ⁇ 0.2°, 24.760° ⁇ 0.2°, 25.946° ⁇ 0.2°, 26.841° ⁇ 0.2°, 8.921° ⁇ 0.2°, 13.164° ⁇ 0.2°, 14.978° ⁇ 0.2°,
  • the hydrochloride salt form A has a weight change of 1.5% from 40%RH to 80%RH, a weight change of 4.5% from 80%RH to 0%RH, and a weight change of 3.0 from 0%RH to 40%RH. %, the isotherm adsorption curve is shown in Figure 30.
  • the X-ray powder diffraction pattern is shown in Figure 25.
  • the sulfate crystal form A has a weight change of 18.7% from 0% RH to 80% RH.
  • the maleate crystal form A-H of the nitrogen-containing fused heterocyclic compound shown in formula II-a obtained from 1-10 in Example 1 was subjected to hygroscopicity test and stability, and the test results are shown in Table 7:
  • Acetonitrile was an HPLC-pure reagent (Merck), and formic acid (HCOOH) was an HPLC-pure reagent produced by CMW Company.
  • Ammonium formate was HPLC 99.0% reagent (Sigma) CAS: 540-69-2; Lot: BCBF05932.
  • Internal standard reference substance Propranolol hydrochloride (China Institute for Food and Drug Control) CAS: 525-66-6; Lot: 100783-200401.
  • the liquid phase-mass spectrometry analysis system was composed of Waters AcQuity UPLC series AB-API 4000Q-trap mass spectrometer detector.
  • the experimental rat SD was provided by Shanghai Sipple Bikai Laboratory Animal Co., Ltd.
  • the nitrogen-containing fused heterocyclic compound I succinate crystal form A represented by formula II-c and the nitrogen-containing fused heterocyclic compound I hydrochloride crystal form A represented by formula II-d are respectively according to the above embodiment 1-1.
  • 2, 3, and 12-1 were obtained by the preparation method;
  • the nitrogen-containing fused heterocyclic compound I (abbreviated as "free base") was prepared according to the method of Example 63 of Patent CN106928219A.
  • Nitrogen-containing fused heterocyclic compound I maleate crystal form A as shown in formula II-a accurately weigh 9.26 mg of maleate crystal form A, add 0.9% normal saline to 10.05 ml and grind into a uniform solution State, concentration: 0.75mg/ml (calculated as free base), as a solution for gavage administration.
  • Nitrogen-containing fused heterocyclic compound I (free base): Accurately weigh 14.77 mg of the free base solid, add 0.5% CMC-Na to 19.7 ml and grind into a uniform solution state, the concentration is: 0.75 mg/ml as a gavage administration solution.
  • Gavage group 15 SD rats, 180 ⁇ 20 g, were divided into three groups, and respectively were given compound I maleate crystal form A, succinate crystal form A, fumarate crystal form A, free
  • the blood samples were centrifuged at 8000 rpm for 5 min, and the plasma was collected and stored in a centrifuge tube at -20°C for later use.
  • Plasma sample 50 ⁇ L add 300 ⁇ L acetonitrile containing internal standard (Propranolol, 25ng/ml) to precipitate protein, vortex for 10 min, 6000g, 4 °C, centrifuge 10 min, again 6000g, 4 °C, centrifuge for 10 min, take the supernatant in 96-well plate, Plasma drug concentrations were determined using a liquid phase-mass spectrometry system (LC/MS/MS).
  • LC/MS/MS liquid phase-mass spectrometry system
  • Figure 33 shows the curves of maleate crystal form A, succinate crystal form A, fumarate salt form A, free base and hydrochloride crystal form A after intragastric administration of rat plasma.
  • the crystalline form A of the nitrogen-containing fused heterocyclic compound I maleate represented by formula II-a and the nitrogen-containing fused heterocyclic compound I fumarate represented by formula II-b are obtained.
  • Crystal form A, nitrogen-containing fused heterocyclic compound I succinate crystal form A as shown in formula II-c, and nitrogen-containing fused heterocyclic compound I hydrochloride crystal form A as shown in formula II-d were administered by gavage respectively After administration to rats, the rate and extent of in vivo absorption and elimination of maleate form A, succinate form A, and fumarate form A are very similar.
  • the absorption of the hydrochloride form A is close to that of the free base, but the AUC and Cmax of the hydrochloride form A are slightly larger than those of the free base. Therefore, the absorption of maleate crystal form A, fumarate crystal form A, succinate crystal form A, and hydrochloride crystal form A in rats is better than that of free base.
  • Stake out amount weigh about 1.5g of the test sample, put it in a weighing bottle, and place it open (9 weighing bottles in total);
  • Lighting light box (VIS: 4.6klux, UVA: 1.0W/m2);
  • Test items appearance, moisture, related substances, content
  • Test equipment Waters HPLC, Agilent HPLC, moisture meter.

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Abstract

L'invention concerne une forme cristalline d'un sel d'un composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation. La forme cristalline est une forme cristalline A de fumarate d'un composé hétérocyclique condensé contenant de l'azote représenté par la formule II-b, une forme cristalline B de fumarate du composé hétérocyclique condensé contenant de l'azote représenté par la formule II-b, une forme cristalline A de maléate d'un composé hétérocyclique condensé contenant de l'azote représenté par la formule II-a, une forme cristalline A de succinate d'un composé hétérocyclique fusionné contenant de l'azote représenté par la formule II-c, ou une forme cristalline A de sel chlorhydrate d'un composé hétérocyclique condensé contenant de l'azote représenté par la formule II-d. Les formes cristallines sont moins hygroscopiques, et ont une stabilité et des propriétés pharmacocinétiques améliorées par rapport à une base libre.
PCT/CN2022/083147 2021-03-26 2022-03-25 Forme cristalline de sel de composé hétérocyclique condensé contenant de l'azote, son procédé de préparation et son utilisation WO2022199699A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105481858A (zh) * 2014-10-11 2016-04-13 上海医药集团股份有限公司 一种含氮稠杂环化合物、其制备方法、组合物及应用
CN106928219A (zh) * 2015-12-31 2017-07-07 上海医药集团股份有限公司 含氮稠杂环化合物、制备方法、中间体、组合物和应用
CN108264512A (zh) * 2016-12-30 2018-07-10 上海医药集团股份有限公司 含氮稠杂环化合物、其制备方法、中间体、组合物和应用

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CN105481858A (zh) * 2014-10-11 2016-04-13 上海医药集团股份有限公司 一种含氮稠杂环化合物、其制备方法、组合物及应用
CN106928219A (zh) * 2015-12-31 2017-07-07 上海医药集团股份有限公司 含氮稠杂环化合物、制备方法、中间体、组合物和应用
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