WO2023061437A1 - 抗肿瘤药物的盐及其晶型 - Google Patents

抗肿瘤药物的盐及其晶型 Download PDF

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WO2023061437A1
WO2023061437A1 PCT/CN2022/125069 CN2022125069W WO2023061437A1 WO 2023061437 A1 WO2023061437 A1 WO 2023061437A1 CN 2022125069 W CN2022125069 W CN 2022125069W WO 2023061437 A1 WO2023061437 A1 WO 2023061437A1
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phenyl
amino
piperazinyl
oxo
methoxy
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French (fr)
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李文华
田松川
朱明辉
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上海汇伦医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • the invention relates to an antitumor drug, in particular to N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo Substitute-6-phenyl-8(7H)-pteridinyl) phenyl) acrylamide salt and its crystal form.
  • epidermal growth factor receptor tyrosine kinase plays an important role.
  • the expression rate of EGFR reaches 40-80%. Therefore, selectively inhibiting EGFR can achieve the purpose of treating lung cancer.
  • the first aspect of the present invention provides a compound N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo A pharmaceutically acceptable salt of 6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide.
  • the pharmaceutically acceptable salts include maleate, benzenesulfonate, methanesulfonate, potassium hydrogensulfate, potassium dihydrogenphosphate, L-tartrate, fumarate, citrate, L- - Malate, hippurate and succinate.
  • Pharmaceutically acceptable salts of 8(7H)-pteridinyl)phenyl)acrylamide include sulfate, mesylate, maleate and fumarate.
  • the pharmaceutically acceptable salt of 8(7H)-pteridinyl)phenyl)acrylamide is methanesulfonate.
  • the pharmaceutically acceptable salt of 8(7H)-pteridinyl)phenyl)acrylamide is fumarate.
  • the pharmaceutically acceptable salt of 8(7H)-pteridinyl)phenyl)acrylamide is maleate.
  • N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl of the present invention -8(7H)-pteridyl)phenyl)acrylamide pharmaceutically acceptable salts can be anhydrous, hydrate or solvate
  • hydrates can be monohydrates, dihydrates or polyhydrates; the salts can be amorphous or crystalline.
  • the compound N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl- 8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate is anhydrous.
  • the second aspect of the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo - 6-phenyl-8(7H)-pteridinyl) phenyl) acrylamide methanesulfonate crystals, said crystals including type I, type II, type III, type IV, and type V crystals.
  • Type I crystals of phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate the type I crystals are hydrate crystals, and the crystals have at least one of the following characteristics:
  • Type I crystal has a thermogram (DSC) as shown in Figure 1, with absorption peaks at about 102.63°C and 199.38°C; and an exothermic peak at about 227.17°C, at which temperature Type I crystallization occurs Crystalline transformation.
  • DSC thermogram
  • Type I crystal has a thermogravimetric analysis (TGA) as shown in FIG. 2 , the type I crystal is in the range of 30-120° C., and the percentage of mass loss is about 5.35%.
  • TGA thermogravimetric analysis
  • N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6- Form II crystals of phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate, which is anhydrous.
  • the type II crystal form has at least one of the following characteristics:
  • Type II crystal has a DSC diagram and a TGA diagram as shown in Figure 3, and the DSC has an absorption peak at about 300.96°C;
  • Type III crystals of phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate the type III crystals are hydrate crystals, and the type III crystals have at least one of the following characteristics:
  • the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7- Oxo-6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type IV crystal form, said IV crystal form has at least one of the following characteristics:
  • TGA is in the range of 30-100°C, the percentage of mass loss is about 1.69%; in the range of 100-200°C, the percentage of mass loss is about 3.71%;
  • the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7- Oxo-6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate V crystal form.
  • the V-type crystal has at least one or more of the following characteristics:
  • 2 ⁇ (o) In its X-ray powder color spectrum, 2 ⁇ (o) has characteristic peaks at least at about 7.7, 14.4, 16.6, 18.6, and 20.4;
  • 2 ⁇ (o) In its X-ray powder color spectrum, 2 ⁇ (o) has characteristic peaks at least at about 7.7, 11.7, 14.4, 16.6, 17.6, 18.2, 18.6, 20.4, 22.3, 23.6, 22.8, 24.4;
  • the third aspect of the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo -
  • the method is obtained by compounding N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl) phenyl) amino)-7-oxo-6-benzene Base-8(7H)-pteridinyl)phenyl)acrylamide with corresponding acids such as maleic acid, benzenesulfonic acid, methanesulfonic acid, potassium hydrogensulfate, potassium dihydrogenphosphate, L-tartaric acid, fumaric acid , anhydrous citric acid, L-malic acid, hippuric acid, succinic acid, added to a solvent for recrystallization to prepare.
  • the solvent is a protic solvent or an aprotic solvent.
  • the solvent is selected from: acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, water or a mixed solvent of two or more solvents.
  • the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7- Oxo-6-phenyl-8 (7H)-pteridinyl) phenyl) acrylamide mesylate crystallization preparation method, described method comprises at least one or more steps in the following steps:
  • the non-limiting organic solvent includes: acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, toluene; in step 3, the non-limiting anti-solvent Including: acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, toluene, water; in step 3, if no anti-solvent is added, the corresponding crystals can be prepared by volatilizing the solvent, heating and then cooling.
  • the type II or III crystal can be prepared by the following method: heating and dissolving the mesylate salt of compound I in an organic solvent, and then volatilizing the solvent.
  • the solvent is dichloromethane
  • type II crystals are obtained; when the solvent is methanol or ethanol, type III crystals are obtained.
  • the type IV crystal can be prepared by dissolving the compound mesylate in an organic solvent under heating, and then cooling and crystallizing, and the organic solvent is such as toluene;
  • the type V crystal can be prepared by dissolving the compound mesylate or the compound Alkali and methanesulfonic acid are dissolved in an organic solvent or a water-containing mixed solvent, and then cooled and crystallized or added with an anti-solvent;
  • the solvent for preparing V-type crystals is preferably water, acetone or a mixed solvent of the two.
  • the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7- Oxo-6-phenyl-8 (7H)-pteridinyl) phenyl) acrylamide methanesulfonate V-type crystal preparation method, the method comprises the following steps:
  • the fourth aspect of the present invention provides a pharmaceutical composition containing N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl) Phenyl)amino)-7-oxo-6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide pharmaceutically acceptable salts, especially mesylate, and pharmaceutically acceptable excipients, solvent or thinner.
  • the pharmaceutical composition can be in the form of tablets, capsules, granules, liquid preparations or injections and the like.
  • the auxiliary materials can be excipients, dispersants, lubricants, binders and the like.
  • Excipients include lactose, sucrose, mannitol and similar substances.
  • Dispersants include starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like.
  • Binders include polyvinyl alcohol, hydroxypropyl cellulose, and the like.
  • Lubricants such as magnesium stearate, talc and the like.
  • the pharmaceutical composition contains N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo- 6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate V crystal, and pharmaceutically acceptable auxiliary materials.
  • the pharmaceutical composition contains N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo- 6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate monohydrate, and pharmaceutically acceptable auxiliary materials.
  • the fifth aspect of the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo -Use of 6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate or its pharmaceutical composition in the preparation of medicines for treating EGFR-mediated diseases.
  • the disease contains any one or more EGFR 20insX mutations, EGFR G719X mutations, and ERBB2 mutations.
  • the EGFR 20insX mutation is EGFR V774-C775insX mutation, EGFR H773-V774insX mutation, EGFR P772-H773insX mutation, EGFR N771-P772insX mutation, EGFR D770-N771insX mutation, EGFR V769-D770insX mutation, EGFR S768-V769ins7 mutation, 67EGFRA -S768insX mutation, EGFR V765-M766insX mutation, EGFR Y764-V765 insX mutation, EGFR A763-Y764 insX mutation, EGFR D761-E762 insX mutation.
  • the EGFR 20insX mutation is preferably EGFR V774-C775insX mutation, EGFR H773-V774insX mutation, EGFR P772-H773insX mutation, EGFR N771-P772insX mutation, EGFR D770-N771insX mutation, EGFR V769-D770insX mutation; more preferably EGFR H773-V774insX mutation, EGFR D770-N771insX mutation, EGFR V769-D770insX mutation.
  • X represents amino acid, amino acid is G, A, V, L, I, P, F, Y, W, S, T, C, M, N, Q, D, E, K, R, H; as the present invention
  • X is any one of amino acids, or any combination of two or more, or any combination of three or more, or any combination of four or more.
  • X represents an amino acid
  • the amino acid X is A, S, D, C, specifically including but not limited to: at least one of EGFR G719A mutation, EGFR G719S mutation, EGFR G719D mutation, and EGFR G719C mutation.
  • ERBB2 mutations include: at least one of ERBB2D769Y mutation, ERBB2V777_G778insCG mutation, ERBB2V777L mutation, ERBB2A775_G776insYVMA mutation; preferably ERBB2A775_G776insYVMA mutation.
  • the sixth aspect of the present invention provides a kind of N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo -A use of 6-phenyl-8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease, the disease being cancer.
  • the cancers include, but are not limited to, lung cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, and the like.
  • Figure 1 shows the N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type I crystal DSC chart.
  • Figure 2 shows the N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type I crystallization TGA diagram.
  • Figure 3 shows the N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type II crystal DSC chart and TGA chart.
  • Figure 4 shows the N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type II crystal XRD pattern.
  • Figure 5 shows that N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type III crystal TGA diagram.
  • Figure 6 shows N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type IV crystal DSC chart and TGA chart.
  • Figure 7 shows N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -DSC chart of type V crystal of 8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate.
  • Figure 8 shows N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate V-type crystallization TGA diagram.
  • Figure 9 shows that N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxo-6-phenyl -8(7H)-pteridinyl)phenyl)acrylamide methanesulfonate type V crystal XRD pattern.
  • the present invention is further illustrated by the examples below, and the examples are only used to more specifically illustrate preferred embodiments of the present invention, and are not intended to limit the technical solution of the present invention.
  • the above-mentioned solutions of the present invention are all technical solutions that can realize the object of the present invention.
  • the temperature and reagents used in the following examples can be replaced by the above-mentioned corresponding temperatures and reagents to achieve the purpose of the present invention.
  • Embodiment 1 the preparation of compound
  • Embodiment 2 the preparation of salt
  • Recrystallization was performed as follows according to the method described below.
  • Embodiment 3 Bioavailability experiment of different salts
  • Embodiment 4 the preparation of mesylate salt type I crystal
  • Embodiment 5 the preparation of type II crystal of methanesulfonate
  • Embodiment 6 the preparation of type III mesylate crystal
  • Embodiment: 7 the preparation of type IV crystallization of mesylate
  • Form IV About 50 mg of the compound mesylate salt was placed in a 2 mL glass vial plus 1.0 mL of toluene. After being suspended at 50° C. for 2 weeks, the slurry sample was transferred to a 1.5 mL centrifuge tube, the solid sample was collected after centrifugation at 14000 rpm for 5 min, and then dried in a vacuum oven to obtain Form IV. It has DSC and TGA as shown in Figure 6, DSC shows an absorption peak at 303.79°C; TGA data shows that in the range of about 30-100°C, the mass loss percentage of Form IV is about 1.69%.
  • Embodiment: 8 the preparation of mesylate V-type crystal
  • Embodiment 9 Solubility experiments in different media
  • N/A means hardly soluble.
  • the experimental results show that the compound mesylate salt type II crystals and type V crystals have excellent solubility properties in water and various dissolution media.
  • Embodiment 10 Stability experiment

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Abstract

本发明涉及抗肿瘤药物的盐及其晶型，具体地，涉及化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐及其晶体。本发明的药用盐及其晶体具有优异的溶解性和稳定性，可用于治疗EGFR介导的相关疾病。

Description

抗肿瘤药物的盐及其晶型 技术领域
本发明涉及一种抗肿瘤药物，具体涉及N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的盐及其晶型。
背景技术
在众多的酪氨酸激酶中，表皮生长因子受体酪氨酸激酶(EGFR)具有重要作用，在肺癌中，EGFR的表达率达到40-80％。因此，选择性地抑制EGFR可以达到治疗肺癌的目的。
名称为N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的化合物，公开于专利文献1(CN106279173 A)以及专利文献3(CN106279173 A)中，为EGFR抑制剂，具有良好的抗肿瘤活性，且对T790M突变型具有高的选择抑制作用。
专利文献2(WO2013170671A1)中公开的化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺(本发明在此描述为化合物I)为游离形式，在pH6.8时的溶解度仅为9.7μg/mL，化合物在甲醇中微溶，在丙酮，或在水中几乎不溶解，化合物的溶解性较差，导致体内吸收差，生物利用度低等缺陷。
为了解决现有技术中的问题，亟需开发一种能提高该化合物溶解度并增加化合物在体内溶出度的方法。尽管将化合物开发成盐是提高溶解度的有效方法，但本发明化合物并非与所有的有机酸或者无机酸都能成盐，其成盐性具有不可预知性，不同的盐的溶解性、稳定性以及结晶性等理化性能更无法预测。
发明内容
本发明的第一方面，提供一种化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐。
具体地，所述药用盐包括马来酸盐、苯磺酸盐、甲磺酸盐、硫酸氢钾盐、磷酸二氢钾盐、L-酒石酸盐、富马酸盐、柠檬酸盐、L-苹果酸盐、马尿酸盐和琥珀酸盐。
优选地，化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐包括硫酸盐、甲磺酸盐、马来酸盐和富马酸盐。
任选地，化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐为甲磺酸盐。
任选地，化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基 -8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐为富马酸盐。
任选地，化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐为马来酸盐。
本发明的N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐，特别是甲磺酸盐、富马酸盐、马来酸盐，具有优异的结晶性能何优异的生物利用度。
本发明所述的N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺药用盐，特别是甲磺酸盐、富马酸盐、马来酸盐，可以是无水物，也可以是水合物或溶剂合物，例如，水合物可以为一水合物、二水合物或多水合物；所述盐可以是无定型，也可以是晶体结构。
优选地，化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐为一水合物。
优选地，化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐为无水物。
优选地，化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐为二水合物。
本发明的第二方面，提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐晶体，所述晶体包括I型、II型、III型、IV型、和V型结晶。
作为本发明的优选方案，N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐的I型结晶，所述I型结晶为水合物结晶，所述结晶至少具有一种以下特征：
(1)I型结晶具有如图1所示的热谱图(DSC)，在约102.63℃、199.38℃处有吸收峰；在约227.17℃处有放热峰，在该温度下I型结晶发生晶型转变。
(2)I型结晶具有如图2所示的热重分析(TGA)，I型晶型在30-120℃范围内，质量减失百分比约5.35％。
作为本发明的优选方案，N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐的II型结晶，所述II型结晶为无水物。所述II型晶型至少具有一种以下特征：
(1)II型结晶具有如图3所示的DSC图及TGA图，DSC在约300.96℃处有吸收峰；
(2)其TGA在30-120℃范围内，质量减失百分比约0.59％。
(3)具有如图4的X-射线粉末衍射图谱。
作为本发明的优选方案，N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐的III型结晶，所述III型结晶为水合物结晶，所述III型结晶至少具有一种以下特征：
(1)其DSC在约306.8℃处有吸收峰；
(2)其TGA在30-120℃范围内，质量减失百分比约5.0％。
作为本发明的优选方案，本发明提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐IV型晶型，所述IV晶型至少具有一种以下特征：
(1)其DSC在303.79℃有吸收峰；
(2)其TGA在30-100℃范围内，质量减失百分比约1.69％；在100-200℃范围内，质量减失百分比约3.71％；
作为本发明的优选方案，本发明提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐V晶型。所述V型结晶具有至少一种或以上以下特征：
①其X-射线粉末颜色图谱中，2θ(o)至少在约7.7、14.4、16.6、18.6、20.4处有特征峰；
②其X-射线粉末颜色图谱中，2θ(o)至少在约7.7、11.7、14.4、16.6、17.6、18.2、18.6、20.4、22.3、23.6、22.8、24.4处有特征峰；
③其具有如图7的DSC图，DSC在295.08℃有吸收峰；
④其具有如图9的X-射线粉末衍射图谱；
⑤具有如图8的TGA图，其TGA在30-120℃范围内，质量减失百分比约2.47％；
⑥其X-射线粉末衍射图中，具有如下表1所示的2θ(o)、d值以及I％数值：
2θ(°) d-value I％
7.712 11.454 100.0
10.200 8.665 7.1
10.422 8.482 9.0
2θ(°) d-value I％
11.719 7.545 11.9
12.667 6.983 4.9
13.486 6.560 6.6
13.761 6.430 7.4
14.365 6.161 35.1
16.601 5.336 24.9
17.379 5.099 8.7
17.587 5.039 11.4
17.878 4.957 8.8
18.213 4.867 15.3
18.654 4.753 19.1
19.241 4.609 10.1
20.450 4.339 23.9
21.145 4.198 11.9
22.286 3.986 16.1
22.777 3.901 15.6
23.579 3.770 15.6
24.358 3.651 15.8
25.692 3.465 4.4
26.360 3.378 8.7
27.193 3.277 10.7
27.748 3.212 7.1
28.849 3.092 5.7
29.331 3.043 4.4
2θ(°) d-value I％
30.152 2.962 6.8
31.170 2.867 6.9
33.095 2.705 2.8
34.725 2.581 2.9
39.292 2.291 2.8
表1
应当理解，本发明的X-射线粉末衍射图中，2θ在±0.2o范围内均为正常误差，d值在±0.1范围内均为正常误差。
本发明的第三方面，提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺盐的制备方法。所述方法通过将化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺与相应的酸，如马来酸、苯磺酸、甲磺酸、硫酸氢钾、磷酸二氢钾、L-酒石酸、富马酸、无水柠檬酸、L-苹果酸、马尿酸、琥珀酸，加入到溶剂中进行重结晶制备得到。所述溶剂为质子性溶剂或非质子性溶剂，优选地溶剂任选自：丙酮、甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、水中的一种或两种及以上溶剂的混合溶剂。
作为本发明的优选方案，本发明提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐结晶的制备方法，所述方法包括下述步骤中至少一个或多个步骤：
①将化合物游离碱、甲磺酸于水或至少一种有机溶剂或含水混合溶剂中混合；
②将化合物甲磺酸盐溶于水或至少一种有机溶剂或含水混合溶剂中；
③在加入或不加入反溶剂的条件下结晶，并过滤所述结晶；和/或
④将任意一种结晶在加热条件下制备另一种结晶。
具体而言，步骤①或步骤②中，所述有机溶剂非限制性包括：丙酮、甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、甲苯；步骤③中，所述的反溶剂非限制性包括：丙酮、甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、甲苯、水；步骤③中，若不加入反溶剂，结晶可以通过挥发溶剂、加热再冷却等过程，制备相应的结晶。
作为本发明的优选方案，所述II或III型结晶可以通过以下方法制备：将化合物I甲磺酸盐加热溶解于有机溶剂，然后使溶剂挥发后制备得到。当溶剂为二氯甲烷时，得到II型 结晶；当溶剂为甲醇或乙醇时，得到III型结晶。所述IV型结晶可将化合物甲磺酸盐在加热下溶解于有机溶剂中，然后冷却结晶制备得到，所述有机溶剂如甲苯；所述V型结晶可通过将化合物甲磺酸盐或化合物游离碱与甲磺酸溶于有机溶剂或含水混合溶剂中，然后冷却析晶或加入反溶剂制备得到；制备V型结晶的溶剂优选水、丙酮或两者的混合溶剂。
作为本发明的优选方案，本发明提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐V型结晶的制备方法，所述方法包含以下步骤：
①将化合物游离碱与甲磺酸在水或至少一种有机溶剂或含水混合溶剂中混合；优选地有机溶剂为丙酮；
②加热搅拌后冷却析晶。
本发明的第四方面，提供一种药物组合物，所述药物组合物含有N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐，特别是甲磺酸盐，以及药学上可接受的辅料、溶剂或稀释剂。所述药物组合物可以是以片剂、胶囊剂、颗粒剂、液体制剂或注射剂等。
所述的辅料可以是赋形剂、分散剂、润滑剂、粘合剂等。赋形剂包括乳糖、蔗糖、甘露醇及类似的物质。分散剂包括淀粉、微晶纤维素、低取代羟丙基纤维素等。粘合剂包括聚乙烯醇、羟丙基纤维素等类似物质。润滑剂如硬脂酸镁、滑石等。
优选地，所述药物组合物含有N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐V型结晶，以及药学上可接受的辅料。
优选地，所述药物组合物含有N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐一水合物，以及药学上可接受的辅料。
本发明的第五方面，提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐或其药物组合物在制备治疗EGFR介导的疾病的药物中的用途。所述疾病含有任意一种及以上的EGFR 20insX突变、EGFR G719X突变、ERBB2突变。
所述EGFR 20insX突变为EGFR V774-C775insX突变、EGFR H773-V774insX突变、EGFR P772-H773insX突变、EGFR N771-P772insX突变、EGFR D770-N771insX突变、EGFR V769-D770insX突变、EGFR S768-V769insX突变、EGFR A767-S768insX突变、EGFR V765-M766insX突变、EGFR Y764-V765 insX突变、EGFR A763-Y764 insX突变、EGFR D761-E762 insX突变。所述EGFR 20insX突变优选为EGFR V774-C775insX突变、EGFR  H773-V774insX突变、EGFR P772-H773insX突变、EGFR N771-P772insX突变、EGFR D770-N771insX突变、EGFR V769-D770insX突变；更优选为EGFR H773-V774insX突变、EGFR D770-N771insX突变、EGFR V769-D770insX突变。X表示氨基酸、氨基酸为G,A,V,L,I,P,F,Y,W,S,T,C,M,N,Q,D,E,K,R,H；作为本发明的优选方案、X为氨基酸中的任意一种、或任意两种及以上的组合、或任意三种及以上的组合、或任意四种及以上的组合。
优选地，所述EGFR 20insX突变任选自：EGFR V769_D770insASV突变、EGFR V769_D770insDNP突变、EGFR D770_N771insNPG突变、EGFR D770_N771insG突变、EGFR D770_N771insNPH突变、EGFR D770_N771insSVD突变、EGFR H773_V774insPH突变、EGFR H773_V774insH突变中的至少一种。
EGFR G719X突变中，X表示氨基酸，氨基酸X为A,S,D,C、具体包括但不限于：EGFR G719A突变、EGFR G719S突变、EGFR G719D突变、EGFR G719C突变中的至少一种。
ERBB2突变包括：ERBB2D769Y突变、ERBB2V777_G778insCG突变、ERBB2V777L突变、ERBB2A775_G776insYVMA突变中的至少一种；优选ERBB2A775_G776insYVMA突变。
本发明的第六方案，提供一种N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐或其药物组合物在制备治疗疾病的药物中的用途、所述疾病为癌症。所述癌症包括但不限于肺癌、乳腺癌、胰腺癌、前列腺癌、卵巢癌、宫颈癌等。
附图说明
图1示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐I型结晶DSC图。
图2示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐I型结晶TGA图。
图3示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐II型结晶DSC图和TGA图。
图4示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐II型结晶XRD图。
图5示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐III型结晶TGA图。
图6示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐IV型结晶DSC图和TGA图。
图7示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐V型结晶的DSC图。
图8示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐V型结晶TGA图。
图9示出了N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐V型结晶XRD图。
具体实施方式
以下通过实施例进一步说明本发明，实施例仅用于更具体的说明本发明优选地实施方案，不用于对本发明的技术方案进行限定。上述本发明的方案均为可实现本发明目的之技术方案。以下实施例所采用温度和试剂，均可以用上述相应温度和试剂替代以实现本发明之目的。
实施例1：化合物的制备
参考中国专利公开CN106279173A或WO2016192609A1记载的方法制备化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺。
实施例2：盐的制备
将50mg的化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺、分别加入到不同的2mL实验小瓶中、随后分别加入苯磺酸、甲磺酸、硫酸氢钾、L-酒石酸、柠檬酸、L-苹果酸、马尿酸、硫酸、富马酸等(式I化合物与所加入的酸的摩尔比为1:1.1)。每一种酸均用1mL的以下6种溶剂分别进行重结晶操作：丙酮/水混合溶剂(1:1、v/v)、甲醇、乙醇、异丙醇、丙酮、乙酸乙酯。
重结晶按照下述方法如下进行。
将上述所有样品置于磁力搅拌器上(50℃)进行搅拌(500rpm)反应15小时。然后将温度调至25℃、继续搅拌2小时。随后将悬浊的样品离心(8000rpm,5min)、沉淀放置于真空干燥箱中干燥以除去残留溶剂。干燥后得到的产物通过PLM观察其结晶情况。若为晶体，则用XRPD测定。
酸 成盐性 盐的结晶性 *
苯磺酸 成盐 结晶度低
甲磺酸 成盐 结晶度高
硫酸氢钾 成盐 结晶度低
L-酒石酸 在部分溶剂中成盐 结晶度低
柠檬酸 成盐 结晶度低
L-苹果酸 成盐 结晶度低
马尿酸 未形成盐 --
表2.盐的筛选结果
实施例3：不同盐的生物利用度实验
在2％DMSO+1％Tween 80+97％(0.5％CMC-Na水溶液)中以约10mg/mL的浓度制备化合物不同盐的给药溶液，采用SD小鼠,体重180-194g的雄性小鼠进行实验，通过口服给药。在指定的时间点手动约束动物，通过尾静脉或心脏穿刺收集约150μL的血样，用于终末出血到EDTA-K2管中。采样后15分钟内离心获得血浆。通过LC-MS进行检测。AUC及生物利用度(F％)列于下表3。
  AUC last(hr*ng/mL) F(％)
游离碱 735.2 14.15
硫酸盐 1446.7 37.98
富马酸盐 1625.7 31.51
甲磺酸盐 1641.6 31.86
表3
实验结果表明，化合物甲磺酸盐的AUC、生物利用度与游离碱相比具有显著性的提高。
实施例4：甲磺酸盐I型结晶的制备
将4.7g化合物游离碱(7.8mmol)，14.1mL丙酮和5.73mL水加入250mL圆底烧瓶搅拌分散、称取1.097g甲磺酸(11.15mmol)滴加入烧瓶、N2保护。加热至60℃，得到深红色溶液，搅拌1h。缓慢降温至约30℃，开始缓慢析晶。保持25℃搅拌1h，再滴入14.1mL丙酮、搅拌过夜。过滤、滤饼用14.1mL丙酮淋洗、得到6.26g橘红色固体，50℃减压干燥1h后得到5.3g橘红色固体，为化合物甲磺酸盐水合物I型晶型。滴定法测得水分含量5.048％；TGA数据显示30-120℃范围内有约5.3％的失重；DSC显示在约102.6℃、约199.38℃有峰，并在后续的升温过程中出现的放热峰(227.17℃)，发生晶型转变。
实施例5：甲磺酸盐II型结晶的制备
将约25mg化合物甲磺酸盐溶解在二氯甲烷中、在40mL样品瓶中50℃搅拌得到澄清溶液。将40mL样品瓶在室温下敞口放置、使溶剂彻底蒸发并收集固体，得到II型晶型。II型晶型的DSC以及TGA如图3所示。DSC显示在约306.96℃处有吸收峰；TGA数据显示在30-120℃范围内，质量减失百分比约0.15％，表明化合物甲磺酸盐II型结晶为无水物。图3的DSC以及TGA图表明化合物甲磺酸盐II型结晶具有很高的热稳定性。II型结晶具有如图4的X-射线粉末衍射图谱。
实施例6：甲磺酸盐III型结晶的制备
将约25mg化合物甲磺酸盐溶解在甲醇中、在40mL样品瓶中50℃搅拌得到澄清溶液。将40mL样品瓶在室温下敞口放置、使溶剂彻底蒸发并收集固体。得到III型晶型。III型晶型的DSC以及TGA如图5所示，TGA数据显示在约30-120℃范围内，III型晶型的质量减失百分比约5.0％。
实施例:7：甲磺酸盐IV型结晶的制备
将约50mg的化合物甲磺酸盐置于2mL玻璃小瓶中加1.0mL甲苯。在50℃下混悬2周后、将浆液样品转移到1.5mL离心管中、在14000rpm离心5min后收集固体样品，然后在真空干燥箱中干燥，得到IV型晶型。其具有如图6所示的DSC及TGA，DSC显示在303.79℃有吸收峰；TGA数据显示在约30-100℃范围内，IV型晶型的质量减失百分比约1.69％。
实施例:8：甲磺酸盐V型结晶的制备
称取化合物游离碱0.6g，将其置于8mL的小瓶中，先加入0.19g甲磺酸，然后加入1.8mL丙酮溶液和0.75mL纯水，并用氮气保护，置于恒温磁力搅拌器上(60℃/700rpm)搅拌1h、之后将其悬浮液冷却至室温，加入1.8mL丙酮，搅拌过夜。得到的固体产物，为V型结晶。具有如图6所示的XRPD衍射图谱，以及具有如图7所示的DSC和图8所示的TGA。DSC显示在295.08℃有吸收峰；TGA数据显示在30-120℃范围内，V型结晶有2.4％的质量失重，为一水合物结晶。图7表明，化合物甲磺酸盐V型结晶同样具有极高的热稳定性
实施例9：不同介质的溶解度实验
测定化合物甲磺酸盐不同结晶在水溶液、SGF(模拟人类饥饿状态下空胃时的胃液)、FaSSIF(模拟人类餐前饥饿状态下小肠内的肠液)、FeSSIF(模拟人类餐后饱食状态下小肠内的肠液)中的溶解度，如下表4所示(单位mg/mL)。
Figure PCTCN2022125069-appb-000001
表4
N/A表示几乎不溶解。实验结果表明化合物甲磺酸盐II型结晶、V型结晶在水及多种溶解介质中均具有优异的溶解性能。
实施例10：稳定性实验
在温度25±2℃；湿度50％±5％条件下，测定化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐及V型结晶的稳定性，如下表5所示。
  0月 3月 6月
外观 橙黄色粉末 橙黄色粉末 橙黄色粉末
总杂质含量％ 0.42 0.45 0.41
水分含量％ 2.8 2.7 2.7
晶型 V型晶型 V型晶型 V型晶型
表5
化合物N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐及V型结晶显示出优异的稳定性，在长期存放中，据观察，在长达6个月存放期限内，并未出现晶型转变现象，杂质或水分含量也没有显著差异。
应理解，在阅读了本发明的上述公开内容之后，在不脱离本发明申请的方面构思和精神的情况下，本领域普通技术人员可以对本发明的技术方案作各种改动、调整或组合等，这些等价形式同样落于本申请要求保护的范围内。

Claims (13)

  1. N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的药用盐，其特征在于，所述药用盐包括马来酸盐、苯磺酸盐、甲磺酸盐、硫酸氢钾盐、磷酸二氢钾盐、L-酒石酸盐、富马酸盐、柠檬酸盐、L-苹果酸盐、马尿酸盐和琥珀酸盐。
  2. 根据权利要求1所述的药用盐，其特征在于，所述药用盐为N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺的硫酸盐、甲磺酸盐、马来酸盐和富马酸盐中的任一种。
  3. 根据权利要求1所述的药用盐，其特征在于，所述药用盐为N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐晶体。
  4. 根据权利要求1所述的药用盐，其特征在于，所述药用盐为N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐水合物。
  5. 根据权利要求4所述的药用盐，其特征在于，所述药用盐为N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐一水合物。
  6. 根据权利要求3所述的药用盐，其特征在于，所述N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐晶体至少具有一种以下特征：
    其X-射线粉末衍射图谱中，2θ(o)至少在约7.7、14.4、16.6、18.6、20.4处有特征峰；
    其X-射线粉末衍射图谱中，2θ(o)至少在约7.7、11.7、14.4、16.6、17.6、18.2、18.6、20.4、22.3、23.6、22.8、24.4处有特征峰；
    其DSC在约295.08℃有吸收峰；
    其具有图9的X-射线粉末衍射图谱；
    其TGA在约30-120℃范围内，质量减失百分比约2.47％。
  7. 根据权利要求3所述的药用盐，其特征在于，所述的N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐结晶是通过以下步骤中一个或多个步骤制备得到：
    将化合物游离碱、甲磺酸盐，在加热或不加热下，溶于水或至少一种有机溶剂或含水混合溶剂中；
    将化合物甲磺酸盐，在加热或不加热下，溶于水或至少一种有机溶剂或含水混合溶剂中；
    在加入或不加入反溶剂的条件下结晶，并过滤所述结晶；和/或
    将任意一种结晶在加热条件下制备另一种结晶。
  8. 根据权利要求5所述的药用盐，其特征在于，所述的N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐结晶，其通过以下步骤制备得到：
    将化合物游离碱、甲磺酸盐加热溶于水或至少一种有机溶剂或含水混合溶剂中，然后冷却结晶。
  9. 根据权利要求8所述的药用盐，其特征在于，在所述的N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐结晶过程中，所述有机溶剂为丙酮。
  10. 药物组合物，其特征在于，所述组合物包含N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐以及药学上可接受的辅料。
  11. N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺甲磺酸盐及其晶体在制备治疗EGFR介导的疾病的药物中的用途。
  12. 根据权利要求11所述的用途，其特征在于，所述EGFR介导的疾病包含EGFR20insX突变、EGFR G719X突变、ERBB2突变中的任一种。
  13. 根据权利要求11所述的用途，其特征在于，EGFR介导的疾病为癌症。
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Publication number Priority date Publication date Assignee Title
CN106279173A (zh) * 2015-05-29 2017-01-04 华东理工大学 蝶啶酮衍生物作为egfr抑制剂的应用
CN108721298A (zh) * 2017-04-19 2018-11-02 华东理工大学 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用
WO2022042755A1 (zh) * 2020-08-28 2022-03-03 华东理工大学 抑制突变型egfr的化合物及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279173A (zh) * 2015-05-29 2017-01-04 华东理工大学 蝶啶酮衍生物作为egfr抑制剂的应用
CN108721298A (zh) * 2017-04-19 2018-11-02 华东理工大学 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用
WO2022042755A1 (zh) * 2020-08-28 2022-03-03 华东理工大学 抑制突变型egfr的化合物及其应用

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