WO2014177011A1 - Dimaleate of indolinone derivative, and polymorphs thereof - Google Patents

Dimaleate of indolinone derivative, and polymorphs thereof Download PDF

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Publication number
WO2014177011A1
WO2014177011A1 PCT/CN2014/076124 CN2014076124W WO2014177011A1 WO 2014177011 A1 WO2014177011 A1 WO 2014177011A1 CN 2014076124 W CN2014076124 W CN 2014076124W WO 2014177011 A1 WO2014177011 A1 WO 2014177011A1
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Prior art keywords
compound
dimethyl
fluoro
polymorph
pyrrol
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PCT/CN2014/076124
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French (fr)
Chinese (zh)
Inventor
范传文
张炎峰
林栋�
陈敏华
李书彬
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齐鲁制药有限公司
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Publication of WO2014177011A1 publication Critical patent/WO2014177011A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, specifically relates to N- (5- ((Z) - (5- fluoro-indol-2-carbonyl-3-yl) methyl) - 2,4-dimethyl-1H - pyrrolo -3-yl)-3-( 4 -methylpiperazine small group) propionamide dimaleate (Compound I), polymorph thereof and preparation method thereof, drug containing Compound I and polymorph thereof A composition, and a pharmaceutical use of said Compound I and its polymorph.
  • Background technique N- (5- ((Z) - (5- fluoro-indol-2-carbonyl-3-yl) methyl) - 2,4-dimethyl-1H - pyrrolo -3-yl)-3-( 4 -methylpiperazine small group) propionamide dimaleate
  • Cancer is still the leading cause of human death worldwide. According to statistics, 12 million people worldwide are diagnosed with cancer each year and 9.6 million people die of cancer. It accounts for 13% of all deaths. The number of cancers and deaths worldwide will continue to rise. If no intervention is taken, it is expected that there will be 26 million new cases worldwide in 2030, with a death toll of 17 million. Mortality
  • the top cancers in the world include lung cancer, stomach cancer, liver cancer, and colorectal cancer.
  • Tyrosine kinase is a class of kinases that catalyze the transfer of ⁇ -phosphate on ATP to protein tyrosine residues. It can catalyze the phosphorylation of various substrate protein tyrosine residues and is important in cell growth, proliferation and differentiation. effect. Most of the protein tyrosine kinases discovered so far are oncogene products belonging to oncogenic RNA viruses, and can also be produced by protooncogenes of spinal promoters.
  • a tyrosine kinase inhibitor can act as a competitive inhibitor of adenosine triphosphate ( ⁇ ) binding to tyrosine kinase, or as an analog of tyrosine, blocking tyrosine kinase activity, inhibiting cell proliferation, and developing Become an anti-tumor drug.
  • ⁇ adenosine triphosphate
  • Small molecule tyrosine kinase inhibitors have been widely used as targeted anti-tumor drugs in clinical applications, and can be used in various solid tumors and hematological tumors, and have contributed greatly to the clinical treatment of tumors.
  • WO0160814, WO2008067756, WO2008138184, WO2008138232, WO2007085188, WO2005058309 and WO2006002422, etc. disclose derivatives of the pyrrole-substituted indanone structure type, which have activity to inhibit casein kinase.
  • Sunitinib developed by Pfizer Inc. which is a multi-targeted casein kinase inhibitor, has a strong anti-angiogenic effect and inhibits tumor cell proliferation. From Since its approval by the US FDA in January 2006, the clinical efficacy has been confirmed. It has been marketed in more than 60 countries and is used to treat gastrointestinal basal tumors that have been treated with imatinib and whose disease is still progressing or cannot tolerate the drug. And progressive renal cell carcinoma.
  • WO2011153814A1 discloses N-(5((Z)-(5-fluoro-2-carbonylindole-3-ylidenemethyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)- 3-(4-Methylpiperazin-1-yl)propanamide compound and a process for its preparation, and the compound has the potential to be developed into an antitumor drug, which is hereby incorporated by reference in its entirety.
  • the solubility of this compound is small, and therefore there is a need to find a form with better physical and/or chemical properties to meet the application of drug delivery. Summary of the invention
  • a first aspect of the invention provides a compound of formula I:
  • the compound is named N-(5((Z)-(5-Gaxo- 2 -carbonyl-3-indolyl)methyl)-2,4-dimethyl-1hydro-pyrrole-3-
  • the -3-(4-methylpiperazine small group) propionamide dimaleate salt also referred to as the compound I in the present invention.
  • a compound according to the first aspect of the invention which is a polymorph.
  • a compound according to one aspect of the present invention characterized in that the crystal form uses Cu- ⁇ radiation, X-ray powder diffraction expressed in a 2 ⁇ angle, and has a characteristic absorption peak at a position of about: 0.20. , 8.3 ⁇ 0.20. 13.8 ⁇ 0.20. , 16.6 ⁇ 0.20. 22.2 ⁇ 0.20. , 25.1 ⁇ 0.20. , 26.3 ⁇ 0.20. , 27.9 ⁇ 0.20. ; Preferably, it has a characteristic absorption peak at about the following position: 5.5 ⁇ 0.20. , 6.5 ⁇ 0.20. , 8.3 ⁇ 0.20. , 9.8 ⁇ 0.20. , 11.0 ⁇ 0.20. , 13.0 ⁇ 0.20.
  • the compound according to the first aspect of the present invention is characterized in that differential scanning calorimetry shows that the crystal form has an endothermic peak at 194 to 220 * C, confirming that the compound starts to melt.
  • thermogravimetric analysis of Form A shows that the crystal form loses about 8.5% at 40-170, but does not have a corresponding heat change, is not a solvate or hydrate, and is lost.
  • the weight represents the presence of free solvent; at 200 the weight loss continues and compound I melts.
  • the compound according to the first aspect of the present invention characterized in that the crystal form uses Cu-Ka radiation, X-ray powder diffraction expressed in a 2 ⁇ angle, and has a characteristic absorption peak at a position of about 6.4 ⁇ 0.2. , 9.7 ⁇ 0.20. 12.4 ⁇ 0.20. , 13.0 ⁇ 0.20. , 16.3 ⁇ 0.20. , 22.9 ⁇ 0.20. , 24.3 ⁇ 0.2 °, 25.2 ⁇ 0.2. , 26.2 ⁇ 0.20. ;
  • it has a characteristic absorption peak at about the following position: 6.4 ⁇ 0.20. , 7.5 ⁇ 0.20. , 8.8 ⁇ 0.20. , 9.7 ⁇ 0.20. 12.4 ⁇ 0.20. , 13.0 ⁇ 0.20. , 16.3 ⁇ 0.20. , 17.4 ⁇ 0.20. , 18.0 ⁇ 0.20. 18.8 ⁇ 0.20. 19.6 ⁇ 0.20. 21.8 ⁇ 0.20. 22.9 ⁇ 0.20. 24.3 ⁇ 0.20. , 25.2 ⁇ 0.20. , 26.2 ⁇ 0.20. , 26.9 ⁇ 0.20. , 33.0 ⁇ 0.20. ;
  • the compound according to the first aspect of the invention is characterized in that differential scanning calorimetry shows that the crystal form has an endothermic peak at 188-274, confirming that the compound melts and absorbs heat.
  • thermogravimetric analysis of Form B shows that the crystal form is about 0.56% weight loss and is a solvent free anhydrate.
  • the compound according to the first aspect of the present invention characterized in that the crystal form uses Cu- ⁇ radiation, X-ray powder diffraction expressed in a 2 ⁇ angle, and has a characteristic absorption peak at about the following position: 2.8 ⁇ 0.20. , 5.6 ⁇ 0.20. , 8.4 ⁇ 0.20. , 16.4 ⁇ 0.20. 22.5 ⁇ 0.20. , 25.4 ⁇ 0.20. , 26.6 ⁇ 0.20. , 28.2 ⁇ 0.20. ;
  • it has a characteristic absorption peak at about the following position: 2.8 ⁇ 0.20. , 5.6 ⁇ 0.20. , 8.4 ⁇ 0.20. 11.2 ⁇ 0.20. , 16.4 ⁇ 0.20. 19.5 ⁇ 0.20. 22.5 ⁇ 0.20. 24.0 ⁇ 0.20. , 25.4 ⁇ 0.20. , 26.6 ⁇ 0.20. , 28.2 ⁇ 0.20. ;
  • the compound according to the first aspect of the invention is characterized in that differential scanning calorimetry shows that the crystal form has two endothermic peaks at 150 to 185 C and 209 to 230 t.
  • the first endothermic peak is caused by the loss of DMF in the solvate, and the second endothermic peak indicates that Compound I begins to melt.
  • thermogravimetric analysis of Form C shows that the crystal form has a weight loss of 12.1% and is a N,N-dimercaptocarboxamide (DMF) solvate containing about 1 N,N-dimethylformamide molecule.
  • DMF N,N-dimercaptocarboxamide
  • the compound according to the first aspect of the present invention characterized in that the crystal form uses Cu-Ka radiation, X-ray powder diffraction expressed in a 2 ⁇ angle, and has a characteristic absorption peak at about the following position: 5.6 ⁇ 0.20. , 8.4 ⁇ 0.20. , 14.0 ⁇ 0.20. 22.5 ⁇ 0.20. 23.8 ⁇ 0.20. , 25.4 ⁇ 0.20. , 26.5 ⁇ 0.20. , 28.3 ⁇ 0.20. ;
  • it has a characteristic absorption peak at about the following position: 5.6 ⁇ 0.20. , 8.4 ⁇ 0.20. 9.0 ⁇ 0.20. , 14.0 ⁇ 0.20. , 14.7 ⁇ 0.20. 15.6 ⁇ 0.20. , 16.6 ⁇ 0.20. 18.1 ⁇ 0.20. 22.5 ⁇ 0.20. 23.8 ⁇ 0.20. 24.6 ⁇ 0.20. 25.4 ⁇ 0.20. , 26.5 ⁇ 0.20. 28.3 ⁇ 0.20. 29.5 ⁇ 0.20. ;
  • a compound according to the first aspect of the invention characterized in that the differential scanning calorimetry It is shown that the crystal form has two endothermic peaks at 182 ⁇ 201*C and 202 ⁇ 225.
  • the first endothermic peak is caused by the loss of DMSO in the solvate, and the second endothermic peak indicates that Compound I begins to melt.
  • thermogravimetric analysis of Form D shows that the crystal form has a weight loss of about 11.8% and is a dimethyl sulfoxide (DMSO) solvate containing about one dimethyl sulfone molecule.
  • DMSO dimethyl sulfoxide
  • the reaction is stirred in a solvent of an alcohol, n-butanol or dioxane to obtain a compound of the first aspect of the invention (1); wherein the N-(5-((Z)-(5-fluoro- 2 - Carbonyl hydrazine-3-ylidenemethyl) - 2 , 4 -dimethyl-1 -hydro-
  • the compound of the first aspect (3) or (4) of the present invention is slurried in water and dried by filtration to obtain the compound of the first aspect (2) of the present invention;
  • the compound of the first aspect (3) or (4) of the present invention is dried at 150 to 200 to obtain the compound of the first aspect (2) of the present invention.
  • ⁇ -( 5-(( ⁇ )-(5-fluoro-2-carbonylindole-3-ylidene)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl -3-(4-Methylpiperazin-1-yl)propanamide can be prepared by one of ordinary skill in the art according to the prior art.
  • ⁇ -(5-(( ⁇ )- ( 5 -Fluoro- 2 - ⁇ _ 3 _)methyl) - 2 , 4 -Dimethyl-1 Hydro-pyrrole- 3 -yl)-3-methylpiperazin-1-yl)propanamide It can be prepared by reference to document WO2011153814A1.
  • a third aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any one of the first aspects of the invention, and optionally one or more pharmaceutically acceptable carriers or excipients.
  • a fourth aspect of the invention relates to the use of a compound according to any one of the first aspects of the invention for the manufacture of a medicament for the prophylaxis and/or treatment of a disease or condition associated with a receptor forokinoic acid kinase in a mammal, including a human .
  • the disease or condition associated with the receptor tyrosine kinase refers to proliferation and migration of a tumor mediated by a receptor tyrosine kinase or a tumor cell driven by a receptor tyrosine kinase;
  • the proliferation and migration of the tumor mediated by the receptor tyrosine kinase or the tumor cell driven by the receptor tyrosine kinase means that the erbB receptor tyrosine kinase is sensitive to cancer, such as EGFR or Her2 high-expression and EGF-driven tumors, including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer) , cancers such as neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testes, thyroid, uterus, and vulva, and
  • the invention further relates to a method of preparing a compound according to any one of the first aspects of the invention, which is furthermore related to the prevention or/or treatment of a disease or condition associated with a receptor tyrosine kinase in a mammal, including a human,
  • the method comprises the step of administering to a mammal in need thereof a prophylactically and/or therapeutically effective amount of a compound of any of the first aspects of the invention.
  • the polymorph of Compound I of the present invention has an X-ray powder diffraction characteristic peak expressed by a angle of 2 ,, where " ⁇ 0.2 °" is an allowable measurement error range.
  • the polymorph of the compound I of the present invention can be used in combination with other active ingredients as long as it does not cause other adverse effects such as an allergic reaction.
  • the active compound represented by the polymorph of the compound I of the present invention can be used as the only anticancer The drug is used, or it can be used in combination with one or more other anti-tumor drugs. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
  • composition or “pharmaceutical composition” as used in the present invention is meant to include a product comprising specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from a specified amount of each of the specified ingredients.
  • compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • the pharmaceutical composition may be formulated into a plurality of dosage forms for ease of administration, for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable preparations (e.g., injectable solutions or suspensions, Or an injectable dry powder that can be used immediately after the addition of the drug solvent before injection).
  • oral preparations e.g., tablets, capsules, solutions or suspensions
  • injectable preparations e.g., injectable solutions or suspensions, Or an injectable dry powder that can be used immediately after the addition of the drug solvent before injection.
  • terapéuticaally effective amount is an amount of a drug or pharmaceutical preparation which causes a biological or medical response of a tissue, system, animal or human sought by a researcher, veterinarian, doctor or other person.
  • the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • the polymorph of the compound I of the present invention can be used in mammals, especially humans, at a dose of from 0.001 to 1000 mg/kg body weight per day, for example from 0.01 to 100 mg/kg body weight per day, for example At 0.01 - 10 mg / kg body weight / day.
  • Figure 1 is an X-ray powder diffraction pattern of Compound A Form A of Example 2.
  • Fig. 2 is a diagram showing the differential scanning calorimetry of the compound A crystal form A of Example 2.
  • Fig. 3 is a thermogravimetric analysis chart of the compound A crystal form A of Example 2.
  • Figure 4 is an X-ray powder diffraction pattern of Compound B Form B of Example 8.
  • Figure 5 is a differential scanning calorimetry spectrum of Compound B Form B of Example 8.
  • Fig. 6 is a thermogravimetric analysis diagram of the crystal form B of the compound of Example 8.
  • Figure 7 is an X-ray powder diffraction pattern of Compound C Form C of Example 6.
  • Fig. 8 is a differential scanning calorimetry analysis of the compound C crystal form C of Example 6.
  • Fig. 9 is a thermogravimetric analysis chart of the compound I crystal form C of Example 6.
  • Figure 10 is an X-ray powder diffraction pattern of Compound D Form D of Example 7.
  • Figure 11 is a diagram showing the differential scanning calorimetry of the crystal form D of the compound of Example 7.
  • Figure 12 is a thermogravimetric analysis diagram of the crystal form D of the compound of Example 7. detailed description
  • Instrument model Varian INOVA-400 nuclear magnetic resonance instrument.
  • Test method The sample (100 mg) was placed in a glass plate groove, and the plane was flushed with the glass surface with a glass slide. The sample was placed in a PANalytical Empyrean X-ray powder diffraction analyzer. A 40kV, 40mA copper X-ray source with a scan range of 3 to 45. (2 ⁇ ) , scanning speed 4 minutes, scanning time 6 minutes. The scan error is typically ⁇ 0.2 degrees (2 ⁇ ).
  • Test method A sample weighing 10 mg was placed in a closed aluminum pan with small pinholes at 30. Balance under C, then take 10. The C/min scan rate is heated to 250. ( Dry nitrogen is used as a purge gas.
  • N-( 5-((Z)-(5-fluoro- 2 - ⁇ -3-)) can be prepared according to the method described in WO 2 0111 538 l 4 Al methyl) - 2, 4 - dimethyl-1H - pyrrol-3-yl) -3 - methyl-piperazin-1-yl) propanamide, as shown in Example 1 below.
  • N-( 5-((Z)-(5-fluoro-2-H ⁇ -3-y)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl The stability of various crystal forms of -3-(4-methylpiperazin-1-yl)propanamide dimaleate is better, among which crystal form B is more stable, crystal form A, C, D may degrade or produce crystals under high temperature or high temperature and high humidity conditions.

Abstract

The present invention belongs to the field of medicine and the chemical industry, and in particular relates to N-(5-((Z)-(5-fluoro-2-carbonyl indole-3-yl)methyl)-2,4-dimethyl-1H-pyrrol-3-yl)-3-(4-methyl piperazin-1-yl)propionamide dimaleate (compound I) and polymorphs thereof. The present invention also relates to a method for preparing polymorphs of compound I, a pharmaceutical composition comprising compound I and polymorphs thereof, and the pharmaceutical use of compound I and the polymorphs thereof. The polymorph of compound I of the present invention has a good crystallinity and physical and/or chemical stability.

Description

二氢吲哚酮衍生物的二马来酸盐及其多晶型物 技术领域  Dimaleic acid salt of indanone derivative and polymorph thereof
本发明属于医药化工领域， 具体涉及 N- ( 5- ( ( Z ) -(5-氟 -2-羰基 吲哚 -3-亚)甲基） -2， 4-二甲基 -1 氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪小基） 丙酰胺二马来酸盐（化合物 I ) 、 其多晶型物和制备方法， 含有化合物 I及其多晶型物的药物组合物， 以及所述化合物 I及其多晶型物的制药 用途。 背景技术 The present invention belongs to the field of pharmaceutical chemistry, specifically relates to N- (5- ((Z) - (5- fluoro-indol-2-carbonyl-3-yl) methyl) - 2,4-dimethyl-1H - pyrrolo -3-yl)-3-( 4 -methylpiperazine small group) propionamide dimaleate (Compound I), polymorph thereof and preparation method thereof, drug containing Compound I and polymorph thereof A composition, and a pharmaceutical use of said Compound I and its polymorph. Background technique
癌症目前仍然是全球人类死亡的首要原因。据统计，每年全球 1200 万人被确诊为癌症， 960万人死于癌症。 占所有死亡人数的 13%。 全世 界癌症发病人数和死亡人数将继续上升， 如果不采取干预措施， 预计 2030年全世界将有 2600万新增病例，死亡人数达到 1700万人。死亡率 排在前几位的癌症有肺癌， 胃癌， 肝癌、 结肠直肠癌等。  Cancer is still the leading cause of human death worldwide. According to statistics, 12 million people worldwide are diagnosed with cancer each year and 9.6 million people die of cancer. It accounts for 13% of all deaths. The number of cancers and deaths worldwide will continue to rise. If no intervention is taken, it is expected that there will be 26 million new cases worldwide in 2030, with a death toll of 17 million. Mortality The top cancers in the world include lung cancer, stomach cancer, liver cancer, and colorectal cancer.
酪氛酸激酶是一类催化 ATP上 γ-磷酸转移到蛋白酪氨酸残基上的 激酶， 能催化多种底物蛋白质酪氛酸残基磷酸化， 在细胞生长、 增殖、 分化中具有重要作用。 迄今发现的蛋白酪氨酸激酶中多数是属于致癌 RNA 病毒的癌基因产物， 也可由脊推动物的原癌基因产生。 酪氨酸激 酶抑制剂可作为三磷酸腺苷（ ΑΤΡ )与酪氨酸激酶结合的竟争性抑制剂， 也可作为酪氨酸的类似物， 阻断酪氨酸激酶的活性， 抑制细胞增殖， 可 以开发成为抗肿瘤药物。  Tyrosine kinase is a class of kinases that catalyze the transfer of γ-phosphate on ATP to protein tyrosine residues. It can catalyze the phosphorylation of various substrate protein tyrosine residues and is important in cell growth, proliferation and differentiation. effect. Most of the protein tyrosine kinases discovered so far are oncogene products belonging to oncogenic RNA viruses, and can also be produced by protooncogenes of spinal promoters. A tyrosine kinase inhibitor can act as a competitive inhibitor of adenosine triphosphate ( ΑΤΡ ) binding to tyrosine kinase, or as an analog of tyrosine, blocking tyrosine kinase activity, inhibiting cell proliferation, and developing Become an anti-tumor drug.
小分子酪氨酸激酶抑制剂作为靶向抗肿瘤药物已在临床上广泛应 用， 可以用于各种实体瘤和血液肿瘤， 为肿瘤的临床治疗作出了很大贡 献。 WO0160814, WO2008067756, WO2008138184, WO2008138232, WO2007085188, WO2005058309和 WO2006002422等公开了吡咯取代的 二氢吲哚酮结构类型的衍生物， 具有抑制酪氛酸激酶的活性。 该结构类 型的药物中， 已上市的有辉瑞公司开发的 Sunitinib, 属于多靶点酪氛酸 激酶抑制剂， 有很强的抗血管生成作用， 而且能抑制肿瘤细胞增殖。 自 2006年 1月经美国 FDA批准以来， 临床疗效确切， 目前已在 60多个国家 上市， 用于治疗经伊马替尼治疗而疾病仍在进展或不能耐受该药治疗的 胃肠道基盾瘤和进行性肾细胞癌。 Small molecule tyrosine kinase inhibitors have been widely used as targeted anti-tumor drugs in clinical applications, and can be used in various solid tumors and hematological tumors, and have contributed greatly to the clinical treatment of tumors. WO0160814, WO2008067756, WO2008138184, WO2008138232, WO2007085188, WO2005058309 and WO2006002422, etc. disclose derivatives of the pyrrole-substituted indanone structure type, which have activity to inhibit casein kinase. Among the structural types of drugs, Sunitinib developed by Pfizer Inc., which is a multi-targeted casein kinase inhibitor, has a strong anti-angiogenic effect and inhibits tumor cell proliferation. from Since its approval by the US FDA in January 2006, the clinical efficacy has been confirmed. It has been marketed in more than 60 countries and is used to treat gastrointestinal basal tumors that have been treated with imatinib and whose disease is still progressing or cannot tolerate the drug. And progressive renal cell carcinoma.
WO2011153814A1 公开了 N- ( 5- ( ( Z ) -(5-氟 -2-羰基吲哚 -3-亚) 甲基） -2， 4-二甲基 -1 氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基） 丙酰胺化 合物及其制备方法， 并且该化合物有开发成抗肿瘤药物的潜力， 其全文 引入本发明作为参考。 但该化合物溶解度很小， 因此， 有需求寻找具有 更优的物理和 /或化学性质的形式， 以满足药物输送的应用。 发明内容  WO2011153814A1 discloses N-(5((Z)-(5-fluoro-2-carbonylindole-3-ylidenemethyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)- 3-(4-Methylpiperazin-1-yl)propanamide compound and a process for its preparation, and the compound has the potential to be developed into an antitumor drug, which is hereby incorporated by reference in its entirety. However, the solubility of this compound is small, and therefore there is a need to find a form with better physical and/or chemical properties to meet the application of drug delivery. Summary of the invention
发明人通过大量实验， 成功制备了 N- ( 5- ( ( Z ) -(5-氟 -2-羰基吲 哚 -3_亚)甲基） -2， 4-二甲基 -1氢 -吡咯 _3_基） -3- -甲基哌嗪 -1-基） 丙 酰胺的二马来酸盐形式及其多种结晶型，并证明其在 pH6.8左右的磷酸 盐溶液中溶解度较好， 有利于体内吸收； 并且具有更好的稳定性， 有利 于包装和贮存， 由此完成了本发明。 (5-fluoro-indole-2-carbonyl - - 3 _ alkylene) methyl) - 2,4-dimethyl-1H - pyrrolo inventors by experiment, succeeded N- (5- ((Z) was prepared _ 3 _ group) -3-methylpiperazin-1-yl) propanamide dimaleate form and its various crystal forms, and proved its solubility in phosphate solution of about pH 6.8 It is advantageous for absorption in the body; and has better stability, which is advantageous for packaging and storage, thereby completing the present invention.
本发明第一方面提供了式 I所示的化合物：  A first aspect of the invention provides a compound of formula I:
Figure imgf000003_0001
所述化合物的命名为 N- ( 5- ( ( Z ) -(5-氣 -2-羰基吲哚 -3-亚)甲基） -2, 4-二甲基 -1 氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪小基） 丙酰胺二马来酸 盐， 在本发明中， 亦称为化合物 I 。
Figure imgf000003_0001
The compound is named N-(5((Z)-(5-Gaxo- 2 -carbonyl-3-indolyl)methyl)-2,4-dimethyl-1hydro-pyrrole-3- The -3-(4-methylpiperazine small group) propionamide dimaleate salt, also referred to as the compound I in the present invention.
根据本发明第一方面的化合物， 其为多晶型物。  A compound according to the first aspect of the invention which is a polymorph.
( 1 )根据本发明笫一方面的化合物， 其特征在于， 所述晶型使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处 的特征吸收峰： 5.5士 0.20。、 8.3士 0.20。、 13.8士 0.20。、 16.6士 0.20。、 22.2士 0.20。、 25.1± 0.20。、 26.3± 0.20。、 27.9± 0.20。； 优选地，其具有约为以下位置处的特征吸收峰： 5.5士 0.20。、 6.5士 0.20。、 8.3士 0.20。、 9.8士 0.20。、 11.0士 0.20。、 13.0士 0.20。、 13.8士 0.20。、 16.6士 0.20。、 18.3士 0.20。、 22.2士 0.20。、 22.8士 0.20。、 23.5士 0.20。、 25.1士 0.20。、 26.3士 0.20。、 27.9士 0.2(Γ、 28.7士 0.20"; (1) A compound according to one aspect of the present invention, characterized in that the crystal form uses Cu-Κα radiation, X-ray powder diffraction expressed in a 2 Θ angle, and has a characteristic absorption peak at a position of about: 0.20. , 8.3 ± 0.20. 13.8±0.20. , 16.6 ± 0.20. 22.2 ± 0.20. , 25.1 ± 0.20. , 26.3 ± 0.20. , 27.9 ± 0.20. ; Preferably, it has a characteristic absorption peak at about the following position: 5.5 ± 0.20. , 6.5 ± 0.20. , 8.3 ± 0.20. , 9.8 ± 0.20. , 11.0 ± 0.20. , 13.0 ± 0.20. 13.8±0.20. , 16.6 ± 0.20. , 18.3 ± 0.20. 22.2 ± 0.20. 22.8 ± 0.20. , 23.5 ± 0.20. 25.1 ± 0.20. 26.3 ± 0.20. , 27.9 ± 0.2 (Γ, 28.7 ± 0.20";
在本发明的实施方案中，其具有基本如图 1所示的 X-射线粉末衍射 图谱。  In an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in Figure 1.
根据本发明第一方面的化合物， 其特征在于， 差示扫描量热分析显 示， 该晶型在 194~220*C有吸热峰， 确认化合物开始熔化。  The compound according to the first aspect of the present invention is characterized in that differential scanning calorimetry shows that the crystal form has an endothermic peak at 194 to 220 * C, confirming that the compound starts to melt.
在本发明的具体实施方案中， 其为晶型 。  In a particular embodiment of the invention, it is a crystalline form.
在本发明的具体实施方案中，所述晶型 A的热重分析显示，该晶型 在 40~170 约失重 8.5%， 但并未有相应的热量变化， 不是溶剂化物或 水合物， 其失去的重量代表有游离溶剂存在； 在 200 继续失重， 化合 物 I熔化。  In a particular embodiment of the invention, the thermogravimetric analysis of Form A shows that the crystal form loses about 8.5% at 40-170, but does not have a corresponding heat change, is not a solvate or hydrate, and is lost. The weight represents the presence of free solvent; at 200 the weight loss continues and compound I melts.
( 2 )根据本发明第一方面的化合物， 其特征在于， 所述晶型使用 Cu-Ka辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处 的特征吸收峰： 6.4±0.2。、 9.7士 0.20。、 12.4士 0.20。、 13.0士 0.20。、 16.3士 0.20。、 22.9± 0.20。、 24.3±0.2°, 25.2±0.2。、 26.2± 0.20。； (2) The compound according to the first aspect of the present invention, characterized in that the crystal form uses Cu-Ka radiation, X-ray powder diffraction expressed in a 2 Θ angle, and has a characteristic absorption peak at a position of about 6.4 ± 0.2. , 9.7 ± 0.20. 12.4 ± 0.20. , 13.0 ± 0.20. , 16.3 ± 0.20. , 22.9 ± 0.20. , 24.3 ± 0.2 °, 25.2 ± 0.2. , 26.2 ± 0.20. ;
优选地，其具有约为以下位置处的特征吸收峰： 6.4士 0.20。、 7.5士 0.20。、 8.8士 0.20。、 9.7士 0.20。、 12.4士 0.20。、 13.0士 0.20。、 16.3士 0.20。、 17.4士 0.20。、 18.0士 0.20。、 18.8士 0.20。、 19.6士 0.20。、 21.8士 0.20。、 22.9士 0.20。、 24.3士 0.20。、 25.2± 0.20。、 26.2± 0.20。、 26.9± 0.20。、 33.0± 0.20。；  Preferably, it has a characteristic absorption peak at about the following position: 6.4 ± 0.20. , 7.5 ± 0.20. , 8.8 ± 0.20. , 9.7 ± 0.20. 12.4 ± 0.20. , 13.0 ± 0.20. , 16.3 ± 0.20. , 17.4 ± 0.20. , 18.0 ± 0.20. 18.8 ± 0.20. 19.6 ± 0.20. 21.8 ± 0.20. 22.9 ± 0.20. 24.3 ± 0.20. , 25.2 ± 0.20. , 26.2 ± 0.20. , 26.9 ± 0.20. , 33.0 ± 0.20. ;
在本发明的实施方案中，其具有基本如图 4所示的 X-射线粉末衍射 图讲。  In an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in Figure 4.
根据本发明第一方面的化合物， 其特征在于， 差示扫描量热分析显 示， 该晶型在 188-274Ό有吸热峰， 确认化合物熔化吸热。  The compound according to the first aspect of the invention is characterized in that differential scanning calorimetry shows that the crystal form has an endothermic peak at 188-274, confirming that the compound melts and absorbs heat.
在本发明的具体实施方案中， 其为晶型 8。  In a particular embodiment of the invention, it is Form 8.
在本发明的具体实施方案中，所述晶型 B的热重分析显示，该晶型 约失重 0.56%， 为无溶剂无水物。 ( 3 )根据本发明第一方面的化合物， 其特征在于， 所述晶型使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处 的特征吸收峰： 2.8士 0.20。、 5.6士 0.20。、 8.4士 0.20。、 16.4士 0.20。、 22.5士 0.20。、 25.4± 0.20。、 26.6± 0.20。、 28.2± 0.20。； In a particular embodiment of the invention, the thermogravimetric analysis of Form B shows that the crystal form is about 0.56% weight loss and is a solvent free anhydrate. (3) The compound according to the first aspect of the present invention, characterized in that the crystal form uses Cu-Κα radiation, X-ray powder diffraction expressed in a 2 Θ angle, and has a characteristic absorption peak at about the following position: 2.8 士0.20. , 5.6 ± 0.20. , 8.4 ± 0.20. , 16.4 ± 0.20. 22.5 ± 0.20. , 25.4 ± 0.20. , 26.6 ± 0.20. , 28.2 ± 0.20. ;
优选地，其具有约为以下位置处的特征吸收峰： 2.8士 0.20。、 5.6士 0.20。、 8.4士 0.20。、 11.2士 0.20。、 16.4士 0.20。、 19.5士 0.20。、 22.5士 0.20。、 24.0士 0.20。、 25.4± 0.20。、 26.6± 0.20。、 28.2± 0.20。；  Preferably, it has a characteristic absorption peak at about the following position: 2.8 ± 0.20. , 5.6 ± 0.20. , 8.4 ± 0.20. 11.2 ± 0.20. , 16.4 ± 0.20. 19.5 ± 0.20. 22.5 ± 0.20. 24.0 ± 0.20. , 25.4 ± 0.20. , 26.6 ± 0.20. , 28.2 ± 0.20. ;
在本发明的实施方案中，其具有基本如图 7所示的 X-射线粉末衍射 图谱。  In an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in Figure 7.
根据本发明第一方面的化合物， 其特征在于， 差示扫描量热分析显 示， 该晶型在 150~185 C和 209~230t有两处吸热峰。 第一个吸热峰为 失去溶剂合物中的 DMF所致， 第二个吸热峰表示化合物 I开始熔化。  The compound according to the first aspect of the invention is characterized in that differential scanning calorimetry shows that the crystal form has two endothermic peaks at 150 to 185 C and 209 to 230 t. The first endothermic peak is caused by the loss of DMF in the solvate, and the second endothermic peak indicates that Compound I begins to melt.
在本发明的具体实施方案中， 其为晶型 <。  In a particular embodiment of the invention, it is a crystalline form <.
在本发明的具体实施方案中，所述晶型 C的热重分析分析显示，该 晶型约失重 12.1%, 为 N，N-二曱基甲酰胺（DMF )溶剂合物， 含有约 1 个 N，N-二甲基甲酰胺分子。  In a particular embodiment of the invention, the thermogravimetric analysis of Form C shows that the crystal form has a weight loss of 12.1% and is a N,N-dimercaptocarboxamide (DMF) solvate containing about 1 N,N-dimethylformamide molecule.
( 4 )根据本发明第一方面的化合物， 其特征在于， 所述晶型使用 Cu-Ka辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处 的特征吸收峰： 5.6士 0.20。、 8.4士 0.20。、 14.0士 0.20。、 22.5士 0.20。、 23.8士 0.20。、 25.4± 0.20。、 26.5± 0.20。、 28.3± 0.20。； (4) The compound according to the first aspect of the present invention, characterized in that the crystal form uses Cu-Ka radiation, X-ray powder diffraction expressed in a 2 Θ angle, and has a characteristic absorption peak at about the following position: 5.6 士0.20. , 8.4 ± 0.20. , 14.0 ± 0.20. 22.5 ± 0.20. 23.8 ± 0.20. , 25.4 ± 0.20. , 26.5 ± 0.20. , 28.3 ± 0.20. ;
优选地，其具有约为以下位置处的特征吸收峰： 5.6士 0.20。、 8.4士 0.20。、 9.0士 0.20。、 14.0士 0.20。、 14.7士 0.20。、 15.6士 0.20。、 16.6士 0.20。、 18.1士 0.20。、 22.5士 0.20。、 23.8士 0.20。、 24.6士 0.20。、 25.4士 0.20。、 26.5士 0.20。、 28.3士 0.20。、 29.5士 0.20。；  Preferably, it has a characteristic absorption peak at about the following position: 5.6 ± 0.20. , 8.4 ± 0.20. 9.0 士 0.20. , 14.0 ± 0.20. , 14.7 ± 0.20. 15.6 ± 0.20. , 16.6 ± 0.20. 18.1 ± 0.20. 22.5 ± 0.20. 23.8 ± 0.20. 24.6 ± 0.20. 25.4 ± 0.20. , 26.5 ± 0.20. 28.3 ± 0.20. 29.5 ± 0.20. ;
在本发明的实施方案中， 其具有基本如图 10所示的 X-射线粉末衍 射图谱。  In an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in Figure 10.
根据本发明第一方面的化合物， 其特征在于， 差示扫描量热分析显 示， 该晶型在 182~201*C， 202~225 有两处吸热峰。 第一个吸热峰为失 去溶剂合物中的 DMSO所致， 第二个吸热峰表示化合物 I开始熔化。 A compound according to the first aspect of the invention, characterized in that the differential scanning calorimetry It is shown that the crystal form has two endothermic peaks at 182~201*C and 202~225. The first endothermic peak is caused by the loss of DMSO in the solvate, and the second endothermic peak indicates that Compound I begins to melt.
在本发明的具体实施方案中， 其为晶型 0。  In a particular embodiment of the invention, it is Form 0.
在本发明的具体实施方案中， 晶型 D的热重分析分析显示，该晶型 约失重 11.8%， 为二曱基亚砜 ( DMSO )溶剂合物， 含有约 1个二甲压 砜分子。 本发明的第二方面还涉及本发明第一方面任一项的化合物的制备 方法：  In a particular embodiment of the invention, thermogravimetric analysis of Form D shows that the crystal form has a weight loss of about 11.8% and is a dimethyl sulfoxide (DMSO) solvate containing about one dimethyl sulfone molecule. A second aspect of the invention also relates to a process for the preparation of a compound according to any of the first aspects of the invention:
(1)本发明第一方面第 （3)项的化合物的制备方法：  (1) A method for producing a compound of the first aspect (3) of the present invention:
Ν- ( 5- ( (Ζ) -(5-氟 -2- 吲哚 -3-亚)甲基) -2, 4-二甲基 -1氢-吡 咯 _3 -基） _3- (4-甲基哌嗪小基） 丙酰胺与马来酸在 Ν，Ν-二甲基甲酰胺 (DMF) 中搅拌反应， 得到本发明第一方面第 （3)项的化合物； 其中 所述 Ν- (5- ( (Ζ) -(5-氟 -2-羰基吲哚 -3-亚)甲基) -2, 4-二甲基 -1 氢- 吡咯 -3-基） -3- -曱基哌嗪 -1-基） 丙酰胺与马来酸的摩尔比为 I：2；Ν-( 5-((Ζ)-(5-fluoro-2-indol-3-y)methyl)-2,4-dimethyl-1 hydrogen-pyrrole_ 3 -yl) _3- (4- Methylpiperazine small base) propionamide is stirred with maleic acid in hydrazine, hydrazine-dimethylformamide (DMF) to obtain the compound of the first aspect of the present invention (3); 5-((Ζ)-(5-fluoro-2-carbonylindole-3-ylidene)methyl)-2,4-dimethyl-1 Hydrogen-pyrrol-3-yl)-3--indolyl The molar ratio of pyrazin-1-yl)propanamide to maleic acid is I: 2 ;
(2)本发明第一方面第 （4)项的化合物的制备方法： (2) A method for producing a compound of the first aspect (4) of the present invention:
Ν- ( 5- ( (Ζ) -(5-氟 -2- 吲哚 -3-亚)甲基） -2, 4-二甲基 -1氢-吡 咯 _3_基 )_3-( 4-甲基哌嗪 -1-基）丙酰胺与马来酸在二甲亚砜中搅拌反应， 得到本发明第一方面第（4)项的的化合物； 其中所述 Ν-(5-( ( Ζ ) -(5- 氟 -2- 吲哚 -3-亚)曱基） -2， 4-二甲基 -1氢 -吡咯 -3-基） -3- -甲基派 嗪 -1-基） 丙酰胺与马来酸的摩尔比为 1:2; Ν- (5- ((Ζ) - (5- fluoro-2-indol-3-alkylene) methyl) -2, 4-dimethyl-1H - pyrrolo _ _ 3-yl) _3- (4- Methyl piperazine-1-yl)propanamide is stirred with maleic acid in dimethyl sulfoxide to obtain the compound of the first aspect of the invention (4); wherein the Ν-(5-(( Ζ ) - (5-fluoro - 2 - indol-3-alkylene) Yue-yl) - 2, 4 - dimethyl-1H - pyrrol-3-yl) -3 - methyl-l-yl School) The molar ratio of propionamide to maleic acid is 1:2;
(3)本发明第一方面第 （1)项的化合物的制备方法：  (3) A method for producing a compound of the first aspect (1) of the present invention:
N- ( 5- ( (Z) -(5_氟 -2- 吲哚 _3_亚)甲基） -2， 4-二甲基 -1氢-吡 咯 _3_基 ) -3- ( 4-甲基派嗪 -1-基 )丙酰胺与马来酸在选自四氢呋喃、 四氢 呋喃 /水、 丙酮、 乙酸乙酯、 乙酸异丙酯、 二氯甲垸、 三氯甲垸、 乙醇、 异丙醇、 正丁醇或二氧六环的溶剂中搅拌反应， 得到本发明第一方面第 (1)项的化合物； 其中所述 N- (5- ( (Z) -(5-氟 -2-羰基吲哚 -3-亚)甲 基） -2， 4-二甲基 -1 氢 -吡咯 -3-基） -3- -甲基哌嗪小基） 丙酰胺与马 来酸的摩尔比为 1:2; (4)本发明第一方面第 （2)项的化合物的制备方法： N- ( 5- ( (Z) -(5_氟 -2- 吲哚 _3_亚)甲基） -2， 4-二甲基 -1氢-吡 洛 _3-基） -3- (4-甲基哌嗪 -1-基） 丙酰胺与马来酸在选自水、 DMF/水、 ^ 二甲基乙酰胺（0 ( ） /水、 甲醇、 乙二醇或乙腈的溶剂中搅拌 反应，得到本发明第一方面第（2)项的化合物； 其中所述 N-(5-( (Z) -(5-氟 吲哚 -3-亚)甲基） -2， 4-二甲基 -1 氢 -吡咯 -3-基） -3- (4-甲 基哌嗪 -1-基） 丙酰胺与马来酸的摩尔比为 1:2; 所述 DMF、 DMAC与 水的混合溶剂中只要水的含量不为 0即可， 其中优选 1:0.5-20； N- (5- ((Z) - (5 _ fluoro - 2 - indol _ _ 3 alkylene) methyl) - 2, 4 - dimethyl-1H - pyrrolo _ _ 3-yl) -3- (4 -Methylpyrazin-1-yl)propanamide with maleic acid selected from the group consisting of tetrahydrofuran, tetrahydrofuran/water, acetone, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, ethanol, isopropyl The reaction is stirred in a solvent of an alcohol, n-butanol or dioxane to obtain a compound of the first aspect of the invention (1); wherein the N-(5-((Z)-(5-fluoro- 2 - Carbonyl hydrazine-3-ylidenemethyl) - 2 , 4 -dimethyl-1 -hydro-pyrrol-3-yl)-3-methylpiperazine small base) The molar ratio of propionamide to maleic acid is 1:2; (4) Preparation of a compound of the first aspect of the first item (2) of the present invention is: N- (5- ((Z) - (5 _ fluoro - 2 - indol _ _ 3 alkylene) methyl) - 2, 4 -Dimethyl-1 hydrogen-pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propanamide with maleic acid selected from the group consisting of water, DMF/water, ^dimethyl B The compound of the amide (0 ( ) / water, methanol, ethylene glycol or acetonitrile is stirred to obtain the compound of the first aspect of the invention (2); wherein the N-(5-((Z)-(5) -fluoroindole-3-ylidenemethyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propanamide with Malay The molar ratio of the acid is 1:2; the mixed solvent of DMF, DMAC and water is not required to be 0, wherein preferably 1:0.5-20;
或者，  Or,
将本发明第一方面第 （3)或（4)项的化合物在水中打浆搅拌， 过 滤干燥后得到本发明第一方面第 （2)项的化合物；  The compound of the first aspect (3) or (4) of the present invention is slurried in water and dried by filtration to obtain the compound of the first aspect (2) of the present invention;
或者，  Or,
将本发明第一方面第（ 3 )或（ 4 )项的化合物在 150~200 下烘干， 得到本发明第一方面第 （2)项的化合物。  The compound of the first aspect (3) or (4) of the present invention is dried at 150 to 200 to obtain the compound of the first aspect (2) of the present invention.
在本发明中， Ν- ( 5- ( (Ζ) -(5-氟 -2-羰基吲哚 -3-亚)甲基) -2, 4- 二甲基 -1氢 -吡咯 -3-基） -3- (4-甲基哌嗪 -1-基） 丙酰胺是本领域普通技 术人员根据已有技术可以制备的，在一个示例性的方法中， Ν-(5-((Ζ) -(5-氟 -2- 吲哚 _3_亚)甲基） -2, 4-二甲基 -1 氢 -吡咯 -3-基） -3- -甲 基哌嗪 -1-基） 丙酰胺可以参照文献 WO2011153814A1制备。 本发明的第三方面涉及药物组合物， 其含有本发明第一方面任一项 的化合物， 以及任选地一种或多种药学上可接受的载体或赋形剂。 本发明第四方面涉及本发明第一方面任一项所述的化合物在制备 用于预防和 /或治疗哺乳动物（包括人)与受体酪氛酸激酶相关的疾病或 病症的药物中的用途。 In the present invention, Ν-( 5-((Ζ)-(5-fluoro-2-carbonylindole-3-ylidene)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl -3-(4-Methylpiperazin-1-yl)propanamide can be prepared by one of ordinary skill in the art according to the prior art. In an exemplary method, Ν-(5-((Ζ)- ( 5 -Fluoro- 2 - 吲哚_ 3 _)methyl) - 2 , 4 -Dimethyl-1 Hydro-pyrrole- 3 -yl)-3-methylpiperazin-1-yl)propanamide It can be prepared by reference to document WO2011153814A1. A third aspect of the invention relates to a pharmaceutical composition comprising a compound according to any one of the first aspects of the invention, and optionally one or more pharmaceutically acceptable carriers or excipients. A fourth aspect of the invention relates to the use of a compound according to any one of the first aspects of the invention for the manufacture of a medicament for the prophylaxis and/or treatment of a disease or condition associated with a receptor forokinoic acid kinase in a mammal, including a human .
在本发明中， 所述与受体酪氨酸激酶相关的疾病或病症是指， 由受 体酪氨酸激酶介导的肿瘤或由受体酪氨酸激酶驱动的肿瘤细胞的增殖 和迁移； 在本发明中， 所述由受体酪氨酸激酶介导的肿瘤或由受体酪氨酸激 酶驱动的肿瘤细胞的增殖和迁移是指， erbB受体酪氨酸激酶敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动的肿瘤， 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结直肠、 子宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小细胞肺癌)、神经元、食道、 卵巢、胰腺、前列腺、 腎脏、 皮肤、 睾丸、 甲状腺、 子宫和外阴等的癌症， 和非实体肿瘤如白血病、 多发性骨髓瘤或淋巴瘤等。 本发明还涉及本发明第一方面任一项所述的化合物在制备作为受 本发明还涉及预防 /或治疗哺乳动物 (包括人)与受体酪氨酸激酶 相关的疾病或病症的方法， 所述方法包括给予有需要的哺乳动物施用预 防和 /或治疗有效量的本发明第一方面任一项所述的化合物的步骤。 下面进一步对本发明进行祥细描述： In the present invention, the disease or condition associated with the receptor tyrosine kinase refers to proliferation and migration of a tumor mediated by a receptor tyrosine kinase or a tumor cell driven by a receptor tyrosine kinase; In the present invention, the proliferation and migration of the tumor mediated by the receptor tyrosine kinase or the tumor cell driven by the receptor tyrosine kinase means that the erbB receptor tyrosine kinase is sensitive to cancer, such as EGFR or Her2 high-expression and EGF-driven tumors, including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer) , cancers such as neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testes, thyroid, uterus, and vulva, and non-solid tumors such as leukemia, multiple myeloma, or lymphoma. The invention further relates to a method of preparing a compound according to any one of the first aspects of the invention, which is furthermore related to the prevention or/or treatment of a disease or condition associated with a receptor tyrosine kinase in a mammal, including a human, The method comprises the step of administering to a mammal in need thereof a prophylactically and/or therapeutically effective amount of a compound of any of the first aspects of the invention. The present invention will be further described in detail below:
本发明所引述的所有文献， 它们的全部内容通过引用并入本文， 并且如果这些文献所表达的含义与本发明不一致时， 以本发明的表述 为准。 此外， 本发明使用的各种术语和短语具有本领域技术人员公知 的一般含义， 即便如此， 本发明仍然希望在此对这些术语和短语作更 详尽的说明和解释， 提及的术语和短语如有与公知含义不一致的， 以 本发明所表述的含义为准。  All documents cited in the present invention are hereby incorporated by reference in their entirety, and if the meanings expressed by these documents are inconsistent with the present invention, the expression of the present invention shall prevail. Moreover, the various terms and phrases used in the present invention have the ordinary meanings well known to those skilled in the art, and even though the present invention is intended to provide a more detailed description and explanation of the terms and phrases herein, such terms and phrases are Inconsistent with the well-known meaning, the meaning expressed in the present invention shall prevail.
在本发明中， 所述多晶型物是指物质由于分子或离子按不同方式 排列而形成的晶体； 在本发明的具体实施方案中， 所述化合物 I的多晶 型物是指化合物 I的晶型 A、 晶型 B、 晶型 C、 晶型 D。  In the present invention, the polymorph refers to a crystal formed by the arrangement of molecules or ions in different manners; in a specific embodiment of the invention, the polymorph of the compound I refers to the compound I. Form A, Form B, Form C, Form D.
本发明的化合物 I的多晶型物以 2 Θ角度表示的 X-射线粉末衍射 特征峰， 其中 " ± 0.2° " 为允许的测量误差范围。  The polymorph of Compound I of the present invention has an X-ray powder diffraction characteristic peak expressed by a angle of 2 ,, where "± 0.2 °" is an allowable measurement error range.
本发明的化合物 I的多晶型物可以与其它活性成分组合使用，只要 它不产生其他不利作用， 例如过敏反应。  The polymorph of the compound I of the present invention can be used in combination with other active ingredients as long as it does not cause other adverse effects such as an allergic reaction.
本发明化合物 I的多晶型物所示的活性化合物可作为唯一的抗癌 药物使用， 或者可以与一种或多种其他抗肿瘤药物联合使用。 联合治 疗通过将各个治疗组分同时、 顺序或隔开给药来实现。 The active compound represented by the polymorph of the compound I of the present invention can be used as the only anticancer The drug is used, or it can be used in combination with one or more other anti-tumor drugs. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
本发明所用的术语"组合物 "或 "药物组合物" 意指包括包含指定 量的各指定成分的产品， 以及直接或间接从指定量的各指定成分的组 合产生的任何产品。  The term "composition" or "pharmaceutical composition" as used in the present invention is meant to include a product comprising specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from a specified amount of each of the specified ingredients.
本领域技术人员可以使用已知的药物载体，将本发明的化合物 I， 或化合物 I的多晶型物制备成适合的药物组合物。 所述药物组合物可 特别专门配制成以固体或液体形式供口服给药、 供胃肠外注射或供直 肠给药。  One skilled in the art can prepare a polymorph of Compound I, or Compound I, of the present invention into a suitable pharmaceutical composition using known pharmaceutical carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
所述的药物组合物可配制成许多剂型， 便于给药， 例如， 口服制 剂（如片剂、胶囊剂、 溶液或混悬液）； 可注射的制剂（如可注射的溶液 或混悬液， 或者是可注射的干燥粉末， 在注射前加入药物溶媒后可立 即使用）。  The pharmaceutical composition may be formulated into a plurality of dosage forms for ease of administration, for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable preparations (e.g., injectable solutions or suspensions, Or an injectable dry powder that can be used immediately after the addition of the drug solvent before injection).
本发明所用的术语 "治疗和 /或预防有效量"是引起研究人员、 兽 医、 医生或其他人所寻求的組织、 系统、 动物或人的生物学或医学应 答的药物或药物制剂的量。  The term "therapeutic and/or prophylactically effective amount" as used in the present invention is an amount of a drug or pharmaceutical preparation which causes a biological or medical response of a tissue, system, animal or human sought by a researcher, veterinarian, doctor or other person.
当用于上述治疗和 /或预防时， 本发明化合物 I、 或化合物 I的多晶 型物和药物组合物的总曰用量须由主诊医师在可靠的医学判断范围内 作出决定。 对于任何具体的患者， 具体的治疗有效剂量水平须根据多 种因素而定， 所述因素包括所治疗的障碍和该障碍的严重程度； 所采 用的具体化合物的活性； 所采用的具体组合物； 患者的年龄、 体重、 一般健康状况、 性别和饮食； 所采用的具体化合物的给药时间、 给药 途径和排泄率； 治疗持续时间； 与所采用的具体化合物组合使用或同 时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是， 化合物的剂量从低于为得到所需治疗效果而要求的水平开始， 逐渐增 加剂量， 直到得到所需的效果。 一般说来， 本发明化合物 I的多晶型物 用于哺乳动物特别是人的剂量可以介于 0.001 ~ 1000 mg/kg体重 /天，例 如介于 0.01 ~ 100 mg/kg体重 /天， 例如介于 0.01 - 10 mg/kg体重 /天。 附图说明 When used in the above treatment and/or prophylaxis, the total amount of the sputum of the compound I or the compound I of the present invention and the pharmaceutical composition must be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; Patient's age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drug used in combination with or concurrent with the particular compound employed; Similar factors are known in the medical field. For example, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained. In general, the polymorph of the compound I of the present invention can be used in mammals, especially humans, at a dose of from 0.001 to 1000 mg/kg body weight per day, for example from 0.01 to 100 mg/kg body weight per day, for example At 0.01 - 10 mg / kg body weight / day. DRAWINGS
图 1为实施例 2的化合物 I晶型 A的 X-射线粉末衍射图讲。  BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffraction pattern of Compound A Form A of Example 2.
图 2为实施例 2的化合物 I晶型 A的差示扫描量热分析图讲。 图 3为实施例 2的化合物 I晶型 A的热重分析图谱。  Fig. 2 is a diagram showing the differential scanning calorimetry of the compound A crystal form A of Example 2. Fig. 3 is a thermogravimetric analysis chart of the compound A crystal form A of Example 2.
图 4为实施例 8的化合物 I晶型 B的 X-射线粉末衍射图谱。  Figure 4 is an X-ray powder diffraction pattern of Compound B Form B of Example 8.
图 5为实施例 8的化合物 I晶型 B的差示扫描量热分析图谱。 图 6为实施例 8的化合物 I晶型 B的热重分析图讲。  Figure 5 is a differential scanning calorimetry spectrum of Compound B Form B of Example 8. Fig. 6 is a thermogravimetric analysis diagram of the crystal form B of the compound of Example 8.
图 7为实施例 6的化合物 I晶型 C的 X-射线粉末衍射图谱。  Figure 7 is an X-ray powder diffraction pattern of Compound C Form C of Example 6.
图 8为实施例 6的化合物 I晶型 C的差示扫描量热分析图潘 图 9为实施例 6的化合物 I晶型 C的热重分析图谱。  Fig. 8 is a differential scanning calorimetry analysis of the compound C crystal form C of Example 6. Fig. 9 is a thermogravimetric analysis chart of the compound I crystal form C of Example 6.
图 10为实施例 7的化合物 I晶型 D的 X-射线粉末衍射图谱。 图 11为实施例 7的化合物 I晶型 D的差示扫描量热分析图讲 图 12为实施例 7的化合物 I晶型 D的热重分析图讲。 具体实施方式  Figure 10 is an X-ray powder diffraction pattern of Compound D Form D of Example 7. Figure 11 is a diagram showing the differential scanning calorimetry of the crystal form D of the compound of Example 7. Figure 12 is a thermogravimetric analysis diagram of the crystal form D of the compound of Example 7. detailed description
下面将结合实施例对本发明的实施方案进行详细描述， 但是本领 域技术人员将会理解， 下列实施例仅用于说明本发明， 而不应视为限 定本发明的范围。 实施例中未注明具体条件者， 按照常规条件或制造 商建议的条件进行。 所用试剂或仪器未注明生产厂商者， 均为可以通 过市购获得的常规产品。 本领域技术人员清楚， 在下文中， 如果未特别说明， 本发明所用 材料和操作方法是本领域公知的； 温度以摄氏度 (。C)表示， 操作在室温 或常温（一般为 10~30Ό )环境下进行。 本发明所用的检测仪器：  The embodiments of the present invention are described in detail below with reference to the accompanying drawings. If no specific conditions are specified in the examples, they are carried out according to the general conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained commercially. It will be apparent to those skilled in the art that, hereinafter, the materials and methods of operation of the present invention are well known in the art unless otherwise specified; the temperature is expressed in degrees Celsius (.C) and is operated at room temperature or ambient temperature (typically 10 to 30 Torr). get on. Detection instrument used in the present invention:
( 1 )核磁共振谱  (1) Nuclear Magnetic Resonance Spectroscopy
仪器型号： Varian INOVA-400核磁共振仪。  Instrument model: Varian INOVA-400 nuclear magnetic resonance instrument.
测试条件： 溶剂 DMSO-d6o ( 2 ) X-射线粉末衍射仪 Test conditions: Solvent DMSO-d 6o (2) X-ray powder diffractometer
仪器型号： P ANalytical Empyrean X射线粉末衍射分析仪  Instrument model: P ANalytical Empyrean X-ray powder diffraction analyzer
测试方法： 将研细后的样品 (lOOmg)填在玻璃板凹槽里， 用栽玻片 将其平面与玻璃面挂齐平后， 将样品置于 PANalytical Empyrean X射 线粉末衍射分析仪中， 使用 40kV、 40mA 的铜 X-射线源， 扫描范围 为 3 ~ 45。（2Θ ) ， 扫描速度 4 分钟， 扫描时间 6分钟。 扫描误差通常 为 ±0.2度 (2Θ)。  Test method: The sample (100 mg) was placed in a glass plate groove, and the plane was flushed with the glass surface with a glass slide. The sample was placed in a PANalytical Empyrean X-ray powder diffraction analyzer. A 40kV, 40mA copper X-ray source with a scan range of 3 to 45. (2Θ) , scanning speed 4 minutes, scanning time 6 minutes. The scan error is typically ±0.2 degrees (2 Θ).
( 3 ) TGA/DSC1同步热分析仪  (3) TGA/DSC1 Synchronous Thermal Analyzer
仪器型号： METTLER TGA/DSC1。  Instrument model: METTLER TGA/DSC1.
测试方法：将重 10mg 的样品置于具有小针孔的密闭铝盘中，在 30。C 下保持平衡， 然后以 10。C /min的扫描速率加热至 250。 ( 。 干燥氮气被用 作吹扫气体。 按照 WO20111538l4Al中描述的方法可以制备 N- ( 5- ( ( Z ) -(5- 氟 -2- ^吲哚 -3-亚)甲基） -2， 4-二甲基 -1氢 -吡咯 -3-基） -3- -甲基哌 嗪 -1-基） 丙酰胺， 如下面实施例 1所示。 实施例 1: N- ( 5- ( ( Z ) -(5-氟 吲哚 -3-亚)甲基） -2， 4-二甲 基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基） 丙酰胺的制备： Test method: A sample weighing 10 mg was placed in a closed aluminum pan with small pinholes at 30. Balance under C, then take 10. The C/min scan rate is heated to 250. ( Dry nitrogen is used as a purge gas. N-( 5-((Z)-(5-fluoro- 2 - ^吲哚-3-)) can be prepared according to the method described in WO 2 0111 538 l 4 Al methyl) - 2, 4 - dimethyl-1H - pyrrol-3-yl) -3 - methyl-piperazin-1-yl) propanamide, as shown in Example 1 below. Example 1: N-(5-((Z)-(5-fluoroindol-3-y)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)-3- ( Preparation of 4-methylpiperazin-1-yl)propanamide:
a. Ν-{ 545-氟 -2-氧代 -1,2-二氢 -吲哚 -(3Z)-亚基甲基 1-2,4-二甲基 -1H-  a. Ν-{ 545-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl 1-2,4-dimethyl-lH-
Figure imgf000011_0001
Figure imgf000011_0001
将 3-溴丙酸（ 338 mg, 1.2eq )溶于 5 ml N，N-二曱基曱酰胺 ( DMF ) 中， 室温搅拌至溶解； 加入 4-(4，6-二甲氧基三嗪 -2-基) -4-甲基吗啉盐酸 盐（DMTMM ) ( 618 mg, 1.2eq ) ， 室温搅拌 20 min, 再向其中加入 (3Z)-[(3，5-二甲基 -4-氨基 -1-氢吡咯 -2-基)亚基甲基】 -5-氟吲哚 -2-酮 （501 mg, 1.0 eq), 室温搅拌反应 2 h， TLC检测反应完毕， 将反应¾ 入到 200 ml乙酸乙酯中， 析出固体， 过滤， 乙酸乙酯洗， 干燥， 得目标产物 548 mg (产率 73% ) 。 Dissolve 3-bromopropionic acid (338 mg, 1.2 eq) in 5 ml of N,N-dihydrazinamide (DMF), stir to dissolve at room temperature; add 4-(4,6-dimethoxytriazine) -2-yl)-4-methylmorpholine hydrochloride (DMTMM) (618 mg, 1.2 eq), stirred at room temperature for 20 min, then (3Z)-[(3,5-dimethyl-4) -amino-1-hydropyrrol-2-yl)ylidenemethyl]-5-fluoroindol-2-one (501 Mg, 1.0 eq), the reaction was stirred at room temperature for 2 h, and the reaction was completed by TLC. The reaction was then taken to 200 ml of ethyl acetate. The solid was precipitated, filtered, washed with ethyl acetate and dried to give the desired product 548 mg (yield 73) %).
b. Ν-{ 5-ί5-氟 -2-氧代 -1,2-二氢 -吲哚 -ί3Ζ)-亚基甲基 1-2,4-二甲基 -1H- 吡咯 -3-基} -3-(4-甲基哌嗪 -1-基)丙酰胺的合成：  b. Ν-{ 5-ί5-fluoro-2-oxo-1,2-dihydro-indole-ί3Ζ)-ylidenemethyl 1-2,4-dimethyl-1H-pyrrol-3-yl } Synthesis of -3-(4-methylpiperazin-1-yl)propanamide:
Figure imgf000012_0001
Figure imgf000012_0001
将 Ν-{ 5-[5-氟 -2-氧代 -1,2-二氢 -吲哚 -(3Ζ)-亚基甲基卜2，4-二甲基 -1Η- 吡咯 -3-基} -3-溴-丙酰胺 ( 548 mg, l.Oeq )溶于 4 ml DMF中， 室温搅 拌至溶解， 再向其中加入 4-甲基哌嗪 (850 mg, 4.0eq), 加热至 50。C反 应 4 h, TLC检测反应完毕， 将反应、; 入到 200 ml乙酸乙酯中， 析出 固体， 过滤， 乙酸乙酯洗涤， 干燥， 柱层析得 N- ( 5- ( ( Z ) -(5-H-2- 吲哚 -3-亚)甲基） -2， 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-曱基哌嗪-1- 基） 丙酰胺。  Ν-{ 5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Ζ)-ylidenemethyl b 2,4-dimethyl-1Η-pyrrol-3-yl The -3-bromo-propionamide (548 mg, 1.0 eq) was dissolved in 4 ml of DMF, stirred at room temperature until dissolved, then 4-methylpiperazine (850 mg, 4.0 eq) was added and heated to 50. C reaction 4 h, TLC detection reaction was completed, the reaction, into 200 ml of ethyl acetate, precipitated solid, filtered, washed with ethyl acetate, dried, column chromatography to obtain N- ( 5- ( ( Z ) - ( 5-H-2-indole-3-ylidenemethyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)-3-(4-indolylpiperazin-1-yl)propane Amide.
^ NMR (600MHz, DMSO, 5ppm) : 2.18 2.21(S，6H)， 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t,2H), 6.17(s,4H), 6.86(d,lH),7.63 ( s,lH), 9.16(s,lH), 10.74(s，lH)， 13.56(s,lH)„ 实施例 2: 化合物 I的晶型 A的制备：  ^ NMR (600MHz, DMSO, 5ppm): 2.18 2.21(S,6H), 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t,2H), 6.17(s , 4H), 6.86 (d, lH), 7.63 (s, lH), 9.16 (s, lH), 10.74 (s, lH), 13.56 (s, lH) „ Example 2: Form A of Compound I Preparation:
Ig N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基） -2， 4-二甲基 -1氢- 吡咯 -3-基 ) -3- ( 4-甲基派嗪 -1-基 )丙跣胺与 20ml水混合搅拌 10分钟， 滴加 lg马来酸的四氢呋喃溶液，搅拌 5-10小时，抽滤， 40。C真空干燥， 得到橘黄色的固体 1.39g，收率 90%,经 X-射线粉末衍射检测，其 XRPD 图錯如图 1所示， 经差示扫描量热分析和热重分析， 其 DSC和 DSC图 讲分别如图 2和图 3所示；  Ig N-( 5-((Z)-(5-fluoro-2-indol-3-y)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)-3- ( 4-Methylpyrazine-1-yl)propanamide was mixed with 20 ml of water and stirred for 10 minutes. A solution of lg maleic acid in tetrahydrofuran was added dropwise, stirred for 5-10 hours, and suction filtered, 40. C vacuum drying, to obtain an orange-yellow solid 1.39g, yield 90%, X-ray powder diffraction detection, its XRPD pattern is shown in Figure 1, by differential scanning calorimetry and thermogravimetric analysis, its DSC and The DSC diagrams are shown in Figure 2 and Figure 3, respectively;
^ NMR (600MHz, DMSO, 5ppm) : 2.18 2.21(S，6H)， 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t,2H), 6.17(s,4H), 6.86(d,lH), 6.87 7.66(dd,2H), 7.63 ( s，lH)， 9.16(s,lH), 10.74(s，lH)， 13.56(s,lH)0 实施例 3: 化合物 I的晶型 A的制备： ^ NMR (600MHz, DMSO, 5ppm): 2.18 2.21(S,6H), 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t,2H), 6.17(s,4H), 6.86(d,lH), 6.87 7.66(dd,2H), 7.63 ( s,lH) , 9.16(s,lH), 10.74(s,lH), 13.56(s,lH) 0 Example 3: Preparation of Form A of Compound I:
lOg N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基） -2， 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基） 丙酰胺与 100ml乙酸乙酯混合搅拌 20分钟， 加入 8g马来酸， 搅拌 3~6小时， 抽滤， 50。C真空干燥， 得到 橘黄色的固体 12.4g， 收率 80.2%， 经 X-射线粉末衍射检测， 其 XRPD 图讲基本与图 1一致。 实施例 4: 化合物 I的晶型 A的制备：  lOg N-( 5-((Z)-(5-fluoro-2-indol-3-y)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)-3- ( 4-methylpiperazin-1-yl)propanamide was mixed with 100 ml of ethyl acetate for 20 minutes, 8 g of maleic acid was added, stirred for 3 to 6 hours, and suction filtered, 50. C was vacuum dried to obtain an orange solid 12.4 g, yield 80.2%. The XRPD pattern was substantially consistent with that of Fig. 1 by X-ray powder diffraction. Example 4: Preparation of Form A of Compound I:
2g N- ( 5- ( ( Z ) -(5-氟 吲哚 -3-亚)甲基） -2， 4-二甲基 -1氢- 吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基） 丙酰胺与 20ml正丁醇混合搅拌 10 分钟， 加入 2g马来酸， 搅拌 30~40小时， 抽滤， 40。C真空干燥， 得到 橘黄色的固体 2.0g，收率 64.5%，经 X-射线粉末衍射检测检测 ，其 XRPD 图谱基本与图 1一致。 实施例 5: 化合物 I的晶型 A的制备：  2g N-( 5-((Z)-(5-fluoroindol-3-y)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)-3-(4-A The piperidazine-1-yl)propanamide was mixed with 20 ml of n-butanol for 10 minutes, 2 g of maleic acid was added, stirred for 30 to 40 hours, and suction filtered, 40. C vacuum drying, an orange solid 2.0 g, yield 64.5%, X-ray powder diffraction detection, the XRPD pattern is basically consistent with Figure 1. Example 5: Preparation of Form A of Compound I:
Ig N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基） -2, 4-二甲基 -1氢- 吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基）丙酰胺与 20ml二氧六环混合搅拌 10 分钟， 加入 lg马来酸， 搅拌 5~10小时， 抽滤， 40。C真空干燥， 得到橘 黄色的固体 1.39g， 收率 90%， 经 X-射线粉末衍射检测， 其 XRPD图谱 基本与图 1一致。 实施例 6: 化合物 I的晶型 C的制备：  Ig N-( 5-((Z)-(5-fluoro-2-indol-3-y)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl)-3- ( 4-methylpiperazin-1-yl)propanamide was mixed with 20 ml of dioxane for 10 minutes, lg maleic acid was added, stirred for 5-10 hours, and suction filtered, 40. C was vacuum dried to obtain an orange solid 1.39 g, yield 90%. The XRPD pattern was substantially consistent with that of Fig. 1 by X-ray powder diffraction. Example 6: Preparation of Form C of Compound I:
在室温 ^下， 将 20mlDMF ( N，N-二甲基甲酰胺）和 lg N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基) -2, 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基派嗪 -1-基） 丙酰胺混合， 搅拌， 加入 lg马来酸， 立即溶清， 十分钟后析出固体， 继续搅拌 2小时后， 过滤，真空 60°C干燥 6小时得 到 l.Og (砖红色） 色结晶性粉末， 收率 64.9%, 将得到的产物进行 X- 射线粉末衍射检测，其 XRPD图讲如图 7所示，经差示扫描量热分析和 热重分析， DSC和 TGA图讲分别如图 8、 9所示； At room temperature, 20 ml of DMF (N,N-dimethylformamide) and lg N-(5-((Z)-(5-fluoro-2-indol-3-ylidene)methyl)-2, 4-Dimethyl-1 hydrogen-pyrrol-3-yl)-3-(4-methylpyrazin-1-yl)propanamide mixed, stirred, added lg maleic acid, immediately dissolved, precipitated after ten minutes Solid, stirring for 2 hours, filtering, vacuuming at 60 ° C for 6 hours To l.Og (brick red) color crystalline powder, yield 64.9%, the obtained product was subjected to X-ray powder diffraction detection, and its XRPD pattern is shown in Fig. 7, differential scanning calorimetry and thermogravimetry Analysis, DSC and TGA diagrams are shown in Figures 8 and 9, respectively;
^ NMR (600MHz, DMSO, 5ppm) : 2.18 2.21(S，6H)， 2.54(t,3H), 2.75(s,3H), 2.81 2.90 ( s , 6H ) 3.16(br,8H), 2.86(t,2H), 6.17(s,4H), 6.86(d,lH), 6.87 7.66(dd,2H), 7.63 ( s,lH), 8.02 ( s , 1H ) 9.16(s,lH), 10.74(s,lH), 13.56(s,lH)0 实施例 7: 化合物 I的晶型 D的制备： ^ NMR (600MHz, DMSO, 5ppm): 2.18 2.21(S,6H), 2.54(t,3H), 2.75(s,3H), 2.81 2.90 ( s , 6H ) 3.16(br,8H), 2.86(t, 2H), 6.17(s,4H), 6.86(d,lH), 6.87 7.66(dd,2H), 7.63 ( s,lH), 8.02 ( s , 1H ) 9.16(s,lH), 10.74(s,lH ), 13.56 (s, lH) 0 Example 7: Preparation of Form D of Compound I:
在室温 下， 将 20mlDMSO (二甲基亚砜）和 Ig N- ( 5- ( ( Z ) -(5-氟 吲哚 -3-亚)甲基） -2， 4-二甲基 -1 氢 -吡咯 -3-基） -3- ( 4-甲 基哌嗪 -1-基） 丙酰胺混合， 搅拌， 加入 lg马来酸， 立即溶清， 十分钟 后析出固体， 继续搅拌 2小时后， 过滤，真空 60eC干燥 8小时得到 l.lg 结晶性粉末， 收率 71.4%, 将得到的产物进行 X-射线粉末衍射检测， 其 XRPD图谱如图 10所示，经差示扫描量热分析和热重分析， DSC和 TGA 图谱分别如图 11、 12所示； 20 ml DMSO (dimethyl sulfoxide) and Ig N-( 5-((Z)-(5-fluoroindol-3-y)methyl)-2,4-dimethyl-1 hydrogen at room temperature -pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propanamide, mixed, stirred, added lg maleic acid, immediately dissolved, and after 10 minutes, the solid was precipitated and stirring was continued for 2 hours. filtered and dried in vacuo 60 e C 8 hours to obtain l.lg crystalline powder, yield 71.4%, the obtained product was detected X- ray powder diffraction, XRPD pattern shown in Figure 10, by differential scanning calorimetry And thermogravimetric analysis, DSC and TGA spectra are shown in Figures 11 and 12, respectively;
^ NMR (600MHz, DMSO, 5ppm): 2.18 2.21(S,6H), 2.50 ( S, 6H ) 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t，2H)， 6.17(s,4H), 6.86(d,lH), 6.87 7.66(dd,2H), 7.63 ( s，lH)， 9.16(s,lH), 10.74(s,lH), 13.56(s,lH)e 实施例 8: 化合物 I的晶型 B的制备（晶型 C在水中打浆制备晶型^ NMR (600MHz, DMSO, 5ppm): 2.18 2.21(S,6H), 2.50 (S, 6H) 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t, 2H), 6.17(s,4H), 6.86(d,lH), 6.87 7.66(dd,2H), 7.63 ( s,lH), 9.16(s,lH), 10.74(s,lH), 13.56(s, lH) e Example 8: Preparation of Form B of Compound I (Form C is slurried in water to prepare crystal form
B ) ： B):
在室温 H 下， 将 20mlDMF ( N，N-二甲基甲酰胺）和 lg N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基) -2， 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基派嗪 -1-基） 丙酰胺混合， 搅拌， 加入 lg马来酸， 立即溶清， 十分钟后析出固体， 继续搅拌 2小时后， 过滤， 所得滤饼在 20ml水中 搅拌打浆 2h,得到 1.24g砖红色结晶性粉末，收率 80.0%,纯度 99.3%, 将得到的产物进行 X-射线粉末衍射检测， 其 XRPD图讲如图 4所示， 经差示扫描量热分析和热重分析， DSC和 TGA图傳分别如图 5、 6所 示； At room temperature H, 20 ml of DMF (N,N-dimethylformamide) and lg N-(5-((Z)-(5-fluoro-2-indol-3-y)methyl)-2, 4-Dimethyl-1 hydrogen-pyrrol-3-yl)-3-(4-methylpyrazin-1-yl)propanamide mixed, stirred, added lg maleic acid, immediately dissolved, precipitated after ten minutes The solid was stirred for 2 hours, filtered, and the obtained cake was stirred and beaten in 20 ml of water for 2 hours to obtain 1.24 g of brick red crystalline powder, the yield was 80.0%, the purity was 99.3%, and the obtained product was subjected to X-ray powder diffraction detection. Its XRPD diagram is shown in Figure 4. After differential scanning calorimetry and thermogravimetric analysis, DSC and TGA maps are shown in Figures 5 and 6, respectively;
^ NMR (600MHz, DMSO, 5ppm) : 2.18 2.21(S，6H)， 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t,2H), 6.17(s,4H), 6.86(d,lH), 6.87 7.66(dd,2H), 7.63 ( s，lH)， 9.16(s,lH), 10.74(s，lH)， 13.56(s,lH)e 实施例 9: 化合物 I的晶型 B的制备： ^ NMR (600MHz, DMSO, 5ppm): 2.18 2.21(S,6H), 2.54(t,3H), 2.75(s,3H), 2.81 3.16(br,8H), 2.86(t,2H), 6.17(s , 4H), 6.86 (d, lH), 6.87 7.66 (dd, 2H), 7.63 (s, lH), 9.16 (s, lH), 10.74 (s, lH), 13.56 (s, lH) e Example 9 : Preparation of Form B of Compound I:
在室温条件下， 将 20ml水和 lg N- ( 5- ( ( Z ) -(5-氟 -2-羰基吲哚 -3- 亚)甲基） -2, 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪小基） 丙酰胺 混合， 加入 lg马来酸， 搅拌 5小时后， 抽滤， 40。C真空干燥 15小时， 得到 1.4g砖红色结晶性粉末， 收率 90.9%， 将得到的产物进行 X-射线 粉末衍射检测， 其 XRPD图谱与图 4基本一致。 实施例 10: 化合物 I的晶型 B的制备（晶型 D在水中打浆制备晶 型 B ) ：  20 ml of water and lg N-( 5-((Z)-(5-fluoro-2-carbonylindole-3-y)methyl)-2,4-dimethyl-1 hydrogen- at room temperature Pyrrol-3-yl)-3-(4-methylpiperazine small group) propanamide was mixed, lg maleic acid was added, and after stirring for 5 hours, it was suction filtered, 40. C was vacuum dried for 15 hours to obtain 1.4 g of a brick red crystalline powder in a yield of 90.9%. The obtained product was subjected to X-ray powder diffraction measurement, and its XRPD pattern was substantially identical to that of Fig. 4. Example 10: Preparation of Form B of Compound I (Formation D is slurried in water to prepare Form B):
在室温 ^下， 将 20mlDMSO (二甲基亚砜）和 Ig N- ( 5- ( ( Z ) -(5-氟 -2-^ ^吲哚 -3-亚)甲基） -2， 4-二甲基 -1 氢 -吡咯 -3-基） -3- ( 4-甲 基哌嗪 -1-基） 丙酰胺混合， 搅拌， 加入 lg马来酸， 立即溶清， 降温， 15分钟后析出固体， 继续搅拌 2小时后， 过滤， 所得滤饼在 30ml水中 搅拌打浆 4h， 得到 1.35g砖红色结晶性粉末， 收率 87.0%， 将得到的产 物进行 X-射线粉末衍射检测， 其 XRPD图谱与图 4基本一致。 实施例 11: 化合物 I的晶型 B的制备：  20 ml DMSO (dimethyl sulfoxide) and Ig N-( 5-((Z)-(5-fluoro-2-^^吲哚-3-y)methyl)-2, 4- at room temperature Mix dimethyl-1 Hydrogen-pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propanamide, stir, add lg maleic acid, immediately dissolve, cool down, precipitate after 15 minutes The solid was stirred for 2 hours, filtered, and the obtained cake was stirred and beaten in 30 ml of water for 4 hours to obtain 1.35 g of brick red crystalline powder in a yield of 87.0%. The obtained product was subjected to X-ray powder diffraction detection, and its XRPD pattern and Figure 4 is basically the same. Example 11: Preparation of Form B of Compound I:
在室温条件下， 将 20ml甲醇和 lg N- ( 5- ( ( Z ) -(5-氟 -2-羰基吲哚 -3-亚)甲基） -2, 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基） 丙酰 胺混合，加入 lg马来酸，搅拌 5小时后，抽滤， 40°C真空干燥 15小时， 得到 l.lg砖红色结晶性粉末， 收率 71.5%, 将得到的产物进行 X-射线 粉末衍射检测， 其 XRPD图谱与图 4基本一致。 实施例 12: 化合物 I的晶型 B的制备： 20 ml of methanol and lg N-( 5-((Z)-(5-fluoro-2-carbonylindole-3-ylidene)methyl)-2,4-dimethyl-1 hydrogen- at room temperature Pyrrole-3-yl)-3-(4-methylpiperazin-1-yl)propanamide was mixed, lg maleic acid was added, stirred for 5 hours, suction filtered, and dried under vacuum at 40 ° C for 15 hours to obtain 1. Lg brick red crystalline powder, yield 71.5%, the obtained product was subjected to X-ray powder diffraction detection, and its XRPD pattern was substantially consistent with FIG. Example 12: Preparation of Form B of Compound I:
在室温条件下， 将 20ml水、 lOmlDMF和 lg N- ( 5- ( ( Z ) -(5-氟 -2-羰基吲哚 -3-亚)甲基） -2， 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基） 丙酰胺混合， 加入 0.9g马来酸， 搅拌 5小时后， 抽滤， 40。C真 空干燥 15小时， 得到 1.2g砖红色结晶性粉末， 收率 78.0%, 将得到的 产物进行 X-射线粉末衍射检测， 其 XRPD图谱与图 4基本一致。 实施例 13: 化合物 I的晶型 B的制备：  20 ml water, 10 ml DMF and lg N-( 5-((Z)-(5-fluoro-2-carbonylindole-3-ylidene)methyl)-2,4-dimethyl-1 at room temperature Hydrogen-pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propanamide was mixed, 0.9 g of maleic acid was added, and after stirring for 5 hours, suction filtration was carried out, 40. C was vacuum dried for 15 hours to obtain 1.2 g of a brick red crystalline powder, and the yield was 78.0%. The obtained product was subjected to X-ray powder diffraction measurement, and its XRPD pattern was basically the same as that of Fig. 4. Example 13: Preparation of Form B of Compound I:
将实施例 6制备得到的晶型 C在氮气保护下用烘箱加热至 180。C , 恒温 5min后自然冷却至室温， 所得晶型经粉末 X衍射检测， 其 XRPD 图谱基本与图 4一致。 实施例 14: 溶解度试验  The Form C prepared in Example 6 was heated to 180 in an oven under a nitrogen atmosphere. C, the temperature is naturally cooled to room temperature after 5 minutes, and the obtained crystal form is detected by powder X-ray diffraction, and the XRPD pattern thereof is basically the same as that of Fig. 4. Example 14: Solubility test
配制两种 KH2P04/NaOH緩沖液（ pH值分别为： pH=6.8， pH=2.5 ), 各取 0.2mL緩沖液和 2mg实施例 1得到的 N- ( 5- ( ( Z ) -(5-氟 -2-羰基吲 哚 -3-亚)曱基） -2， 4-二曱基 -1氢 -吡咯 -3-基） -3- -甲基派嗪小基） 丙 酰胺和化合物 I的晶型 A、 B、 C, D (分别为实施例 2、 实施例 8、 实施例 6、 实施例 7制备而得） ， 緩慢搅拌 24 小时以上， 用 0.22 μ ιη 的微孔膜 过滤未完全溶解的固体， 用 HPLC的方法测定溶解度（HPLC可以参照 中国药典 2010版第二部附录 V D的方法） ， 溶解度数据如表 1 所示。 Two kinds of KH 2 P0 4 /NaOH buffers (pH value: 6.8, pH=2.5) were prepared, and 0.2 mL of buffer solution and 2 mg of N-( 5-((Z)-() obtained in Example 1 were respectively taken. 5-fluoro-indole-2-carbonyl-3-yl) Yue-yl) - 2, 4 - two Yue-yl-1H - pyrrol-3-yl) -3 - methyl-l to send a small-yl) propionamide and compound Forms A, B, C, and D of I (prepared in Example 2, Example 8, Example 6, and Example 7, respectively), slowly stirred for more than 24 hours, and filtered through a 0.22 μm η microporous membrane. For the completely dissolved solid, the solubility was determined by HPLC (HPLC can refer to the method of the Chinese Pharmacopoeia 2010 edition, Appendix VD). The solubility data is shown in Table 1.
表 1 实施例 1的化合物、 化合物 I晶型 A、 B、 C、 D Table 1 Compound of Example 1, Compound I Form A, B, C, D
在 pH2.5、 pH6.8磷酸緩冲液中的溶解度试验结果  Solubility test results in pH 2.5, pH 6.8 phosphate buffer
Figure imgf000017_0001
可以看出， Ν- ( 5- ( ( Ζ ) -(5-氟 -2-羰基吲哚 -3-亚）甲基） -2， 4-二 曱基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌 -1-基） 丙酰胺二马来酸盐的各种 晶型的溶解度均高于游离碱的溶解度。 实施例 15: 稳定性试验
Figure imgf000017_0001
It can be seen that Ν-( 5-(( Ζ ) -(5-fluoro-2-carbonylindole-3-ylidene)methyl)-2,4-didecyl-1hydro-pyrrol-3-yl) The solubility of various crystal forms of -3-(4-methylpiperidin-1-yl)propanamide dimaleate is higher than that of the free base. Example 15: Stability test
取化合物 I晶型 A、 B、 C、 D (分别为实施例 2、 实施例 8、 实施 例 6、 实施例 7制备而得） 的样品各两份， 一份用铝箔纸包裹， 室温、 避光放置 48小时， 一份放置在 25° ( 、 45001X光照射线下的光照稳定箱 中 48小时， 考察不同晶型的稳定性， 结果见表 2。  Take two samples of Compound I crystal forms A, B, C, D (prepared in Example 2, Example 8, Example 6, and Example 7 respectively), one portion wrapped with aluminum foil, room temperature, avoid The light was placed for 48 hours, and one was placed in a light-stabilized box at 25° (4,501X) for 48 hours. The stability of the different crystal forms was examined. The results are shown in Table 2.
另取化合物 I晶型 A、 B、 C、 D的样品各两份， 一份放置在 60。C 条件下存放 7天， 一份放置在 40。C〃5%R.H.条件下存放 7天， 考察不 同晶型的稳定性， 结果见表 2。  Another sample of Compound I Form A, B, C, and D was taken in two portions, one at 60. Store under C conditions for 7 days and one at 40. Store under C〃5% R.H. for 7 days, and investigate the stability of different crystal forms. The results are shown in Table 2.
具体的稳定性考察的方法可以参照中国药典 2010 版第二部附录 XIX C的方法； 纯度检测用 HPLC法， 可以参照中国药典 2010版第二 部附录 V D的方法。 晶型的检测同实施例的方法。 表 2化合物 I晶型 A/B/C/D光照、 恒温恒湿条件下的稳定性试验结果 稳定性考察 晶型 A 晶型 B 晶型 C 晶型 D 纯度％ 晶型 纯度％ 晶型 纯度％ 晶型 纯度％ 晶型 For the specific stability investigation method, refer to the method of Appendix XIX C of the second edition of the Chinese Pharmacopoeia 2010 edition; for the HPLC method of purity detection, the method of Appendix V D of the second edition of the Chinese Pharmacopoeia 2010 can be referred to. The detection of the crystal form is the same as the method of the examples. Table 2 Compound I crystal form A/B/C/D illumination, stability test under constant temperature and humidity conditions. Stability investigation crystal form A crystal form B crystal form C crystal form D purity % crystal form purity % crystal form purity % Crystal purity % crystal form
0天 98.94 A 99.34 B 99.49 C 99.20 D 光照 48小时 98.89 A 99.33 B 99.48 C 99.10 D 60 7天 98.84 AB混晶 99.38 B 99.52 C 99.12 D0 days 98.94 A 99.34 B 99.49 C 99.20 D Light 48 hours 98.89 A 99.33 B 99.48 C 99.10 D 60 7 days 98.84 AB mixed crystal 99.38 B 99.52 C 99.12 D
40ORH75%7 BC混 BD混 40ORH75%7 BC mixed BD mixed
97.69 AB混晶 99.29 B 99.45 95.70 天 晶 晶 避光 48小时 98.94 A 99.33 B 99.49 C 99.22 D  97.69 AB mixed crystal 99.29 B 99.45 95.70 day crystal clear light 48 hours 98.94 A 99.33 B 99.49 C 99.22 D
可以看出， N- ( 5- ( ( Z ) -(5-氟 -2- H^吲哚 -3-亚)甲基） -2， 4-二 甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪 -1-基） 丙酰胺二马来酸盐的各种 晶型的稳定性均较好， 其中以晶型 B更为稳定， 晶型 A、 C、 D在高温 或高温高湿条件下有的会降解产生杂质或发生转晶。 It can be seen that N-( 5-((Z)-(5-fluoro-2-H^吲哚-3-y)methyl)-2,4-dimethyl-1hydro-pyrrol-3-yl The stability of various crystal forms of -3-(4-methylpiperazin-1-yl)propanamide dimaleate is better, among which crystal form B is more stable, crystal form A, C, D may degrade or produce crystals under high temperature or high temperature and high humidity conditions.
尽管本发明的具体实施方式已经得到详细的描述， 本领域技术人 员将会理解。 根据已经公开的所有教导， 可以对那些细节进行各种修 改和替换， 这些改变均在本发明的保护范围之内。 本发明的全部范围 由所附权利要求及其任何等同物给出。 Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and alterations may be made to those details in accordance with the teachings of the invention, which are within the scope of the invention. The full scope of the invention is indicated by the appended claims and any equivalents thereof.

Claims

权 利 要 求 Rights request
1、 式 I所示的化合物： 1. Compounds represented by formula I:
Figure imgf000019_0001
Figure imgf000019_0001
2、 权利要求 1的化合物， 其为多晶型物。 2. The compound of claim 1, which is a polymorph.
3、 权利要求 2的化合物， 其特征在于， 所述多晶型物使用 Cu-Ka 辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处的特征 吸收峰： 5.5± 0.20。、 8.3± 0.20。、 13.8± 0.20。、 16.6± 0.20。、 22.2± 0.20。、 25.1± 0.20。、 26.3± 0.20。、 27.9± 0.20。； 3. The compound of claim 2, characterized in that the polymorph uses Cu-Ka radiation and X-ray powder diffraction expressed at an angle of 2Θ, and has a characteristic absorption peak at approximately the following position: 5.5±0.20. , 8.3± 0.20. , 13.8± 0.20. , 16.6± 0.20. , 22.2± 0.20. , 25.1± 0.20. , 26.3± 0.20. , 27.9± 0.20. ;
优选地，其具有约为以下位置处的特征吸收峰： 5.5士 0.20。、 6.5士 0.20。、 8.3士 0.20。、 9.8士 0.20。、 11.0士 0.20。、 13.0士 0.20。、 13.8士 0.20。、 16.6士 0.20。、 18.3士 0.20。、 22.2士 0.20。、 22.8士 0.20。、 23.5士 0.20。、 25.1士 0.20。、 26.3士 0.20。、 27.9士 0.2(Γ、 28.7士 0.20"; Preferably, it has a characteristic absorption peak at approximately: 5.5 ± 0.20. , 6.5±0.20. , 8.3±0.20. , 9.8±0.20. , 11.0±0.20. , 13.0±0.20. , 13.8±0.20. , 16.6±0.20. , 18.3±0.20. , 22.2±0.20. , 22.8±0.20. , 23.5±0.20. , 25.1±0.20. , 26.3±0.20. , 27.9±0.2(Γ, 28.7±0.20";
更优选地， 其具有基本如图 1所示的 X-射线粉末衍射图谱。 More preferably, it has an X-ray powder diffraction pattern substantially as shown in Figure 1.
4、 权利要求 3的化合物， 其特征在于， 差示扫描量热分析显示， 该多晶型物在 194~220 有吸热峰。 4. The compound of claim 3, characterized in that differential scanning calorimetry analysis shows that the polymorph has an endothermic peak at 194~220.
5、 权利要求 2的化合物， 其特征在于， 所述多晶型物使用 Cu-Ka 辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处的特征 吸收峰： 6.4±0.2。、 9.7士 0.20。、 12.4士 0.20。、 13.0士 0.20。、 16.3士 0.20。、 22.9士 0.20。、 24.3±0.2°, 25.2±0.2。、 26.2± 0.20。； 5. The compound of claim 2, characterized in that the polymorph uses Cu-Ka radiation and X-ray powder diffraction expressed at an angle of 2Θ, and has a characteristic absorption peak at approximately the following position: 6.4±0.2. , 9.7±0.20. , 12.4±0.20. , 13.0±0.20. , 16.3±0.20. , 22.9±0.20. , 24.3±0.2°, 25.2±0.2. , 26.2± 0.20. ;
优选地，其具有约为以下位置处的特征吸收峰： 6.4士 0.20。、 7.5士 0.20。、 Preferably, it has a characteristic absorption peak at approximately: 6.4±0.20. , 7.5±0.20. ,
8.8士 0.20。、 9.7士 0.20。、 12.4士 0.20。、 13.0士 0.20。、 16.3士 0.20。、 17.4士 0.20。、 18.0士 0.20。、 18.8士 0.20。、 19.6士 0.20。、 21.8士 0.20。、 22.9士 0.20。、 24.3士 0.20。、 25.2± 0.20。、 26.2± 0.20。、 26.9± 0.20。、 33.0± 0.20。； 8.8±0.20. , 9.7±0.20. , 12.4±0.20. , 13.0±0.20. , 16.3±0.20. , 17.4±0.20. , 18.0±0.20. , 18.8±0.20. , 19.6±0.20. , 21.8±0.20. , 22.9±0.20. , 24.3±0.20. , 25.2± 0.20. , 26.2± 0.20. , 26.9± 0.20. , 33.0±0.20. ;
更优选地， 其具有基本如图 4所示的 X-射线粉末衍射图谱。 More preferably, it has an X-ray powder diffraction pattern substantially as shown in Figure 4.
6、 权利要求 5的化合物， 其特征在于， 差示扫描量热分析显示， 该多晶型物在 188-274 有吸热峰。 6. The compound of claim 5, characterized in that differential scanning calorimetry analysis shows that the polymorph has an endothermic peak at 188-274.
7、 权利要求 2的化合物， 其特征在于， 所述多晶型物使用 Cu-Ka 辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处的特征 吸收峰： 2.8± 0.20。、 5.6± 0.20。、 8.4± 0.20。、 16.4± 0.20。、 22.5± 0.20。、 25.4± 0.20。、 26.6± 0.20。、 28.2± 0.20。； 7. The compound of claim 2, characterized in that the polymorph uses Cu-Ka radiation and X-ray powder diffraction expressed at an angle of 2Θ, and has a characteristic absorption peak at approximately the following position: 2.8±0.20. , 5.6± 0.20. , 8.4± 0.20. , 16.4± 0.20. , 22.5± 0.20. , 25.4± 0.20. , 26.6± 0.20. , 28.2± 0.20. ;
优选地，其具有约为以下位置处的特征吸收峰： 2.8士 0.20。、 5.6士 0.20。、 8.4士 0.20。、 11.2士 0.20。、 16.4士 0.20。、 19.5士 0.20。、 22.5士 0.20。、 24.0士 0.20。、 25.4± 0.20。、 26.6± 0.20。、 28.2± 0.20。； Preferably, it has a characteristic absorption peak at approximately: 2.8 ± 0.20. , 5.6±0.20. , 8.4±0.20. , 11.2±0.20. , 16.4±0.20. , 19.5±0.20. , 22.5±0.20. , 24.0±0.20. , 25.4± 0.20. , 26.6± 0.20. , 28.2± 0.20. ;
更优选地， 其具有基本如图 7所示的 X-射线粉末衍射图谱。 More preferably, it has an X-ray powder diffraction pattern substantially as shown in Figure 7.
8、 权利要求 7的化合物， 其特征在于， 差示扫描量热分析显示， 该多晶型物在 150~185"C和 209~230"C有两处吸热峰。 8. The compound of claim 7, characterized in that differential scanning calorimetry analysis shows that the polymorph has two endothermic peaks at 150~185°C and 209~230°C.
9、 权利要求 2的化合物， 其特征在于， 所述多晶型物使用 Cu-Ka 辐射， 以 2Θ角度表示的 X-射线粉末衍射， 具有约为以下位置处的特征 吸收 5.6± 0.20ο、 8.4± 0.2(Γ、 14.0± 0.2(Γ、 22.5± 0.2(Γ、 23.8± 0.2(Γ、 25.4± 0.20。、 26.5± 0.20。、 28.3± 0.20。； 9. The compound of claim 2, characterized in that the polymorph uses Cu-Ka radiation and X-ray powder diffraction expressed at an angle of 2Θ, and has a characteristic absorption of approximately 5.6±0.20 ° , 8.4 at the following positions ± 0.2(Γ, 14.0± 0.2(Γ, 22.5± 0.2(Γ, 23.8± 0.2(Γ, 25.4± 0.20., 26.5± 0.20., 28.3± 0.20.;
优选地，其具有约为以下位置处的特征吸收峰： 5.6士 0.20。、 8.4士 0.20。、 9.0士 0.20。、 14.0士 0.20。、 14.7士 0.20。、 15.6士 0.20。、 16.6士 0.20。、 18.1士 0.20。、 22.5士 0.20。、 23.8士 0.20。、 24.6士 0.20。、 25.4士 0.20。、 26.5士 0.20。、 28.3士 0.20。、 29.5士 0.20。； Preferably, it has a characteristic absorption peak at approximately: 5.6 ± 0.20. , 8.4±0.20. , 9.0±0.20. , 14.0±0.20. , 14.7±0.20. , 15.6±0.20. , 16.6±0.20. , 18.1±0.20. , 22.5±0.20. , 23.8±0.20. , 24.6±0.20. , 25.4±0.20. , 26.5±0.20. , 28.3±0.20. , 29.5±0.20. ;
更优选地， 其具有基本如图 10所示的 X-射线粉末衍射图谱。 More preferably, it has an X-ray powder diffraction pattern substantially as shown in Figure 10.
10、 权利要求 9的化合物， 其特征在于， 差示扫描量热分析显示， 该多晶型物在 182~201Ό， 202~225Χ有两处吸热峰。 10. The compound of claim 9, characterized in that differential scanning calorimetry analysis shows that the polymorph has two endothermic peaks at 182~201Ό and 202~225Χ.
11、 权利要求 3-10任一项的化合物的制备方法： 11. The preparation method of the compound of any one of claims 3-10:
( 1 )权利要求 7或 8的化合物的制备方法： (1) Preparation method of the compound of claim 7 or 8:
N- ( 5- ( ( Z ) -(5_氟 -2- 吲哚 _3_亚)甲基） -2， 4-二甲基 -1氢-吡 咯 _3 -基） _3- ( 4-甲基哌嗪小基） 丙酰胺与马来酸在 N，N-二甲基甲酰胺 ( DMF )中搅袢反应， 得到权利要求 7或 8的化合物； 其中所述 N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基) -2， 4-二曱基 -1氢 -吡咯 -3-基） -3- ( 4-甲基派嗪 -1-基） 丙酰胺与马来酸的摩尔比为 1:2; N-(5-((Z)-( 5 -fluoro- 2 -indole- 3 -methylene ) -2,4 -dimethyl-1hydro-pyrrol- 3 -yl) _3-(4- Methyl piperazine base) propionamide and maleic acid are reacted in N, N-dimethylformamide (DMF) to obtain the compound of claim 7 or 8; wherein the N-(5-(( Z ) -(5-fluoro-2-indole-3-methylene) -2, 4-dimethyl-1 hydrogen-pyrrol-3-yl) -3- (4-methylpyrazine-1 -base) The molar ratio of propionamide to maleic acid is 1:2;
( 2 )权利要求 9或 10的化合物的制备方法： (2) Preparation method of the compound of claim 9 or 10:
N- ( 5- ( ( Z ) -(5_氟 -2- 吲哚 _3_亚)甲基） -2， 4-二甲基 -1氢-吡 咯 _3 -基 )_3-( 4-甲基哌嗪 -1-基）丙酰胺与马来酸在二甲亚砜中搅袢反应 , 得到权利要求 9或 10的化合物； 其中所述 N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基） -2， 4-二甲基 -1 氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪小基） 丙酰胺与马来酸的摩尔比为 1:2; N-(5-((Z)-( 5 -fluoro- 2 -indole- 3 -methylene ) -2,4 -dimethyl-1hydro-pyrrole- 3 -yl)_3-(4- Methylpiperazine-1-yl) propionamide and maleic acid are reacted in dimethyl sulfoxide to obtain the compound of claim 9 or 10; wherein the N-( 5 -((Z)-( 5- Fluoro- 2 -indole-3-methylene) -2,4 -dimethyl-1-hydro-pyrrol-3-yl)-3-( 4 -methylpiperazine) propionamide and maleic acid The molar ratio of acids is 1:2;
( 3 )权利要求 3或 4的化合物的制备方法： (3) Preparation method of the compound of claim 3 or 4:
N- ( 5- ( ( Z ) -(5-氟 -2- 吲哚 -3-亚)甲基) -2, 4-二甲基 -1氢-吡 咯 -3-基） -3- ( 4-甲基派嗪 -1-基）丙酰胺与马来酸在四氢呋喃、 四氢呋喃 /水、 丙酮、 乙酸乙酯、 乙酸异丙酯、 二氯甲烷、 三氯曱垸、 乙醇、 异丙 醇、 正丁醇、 二氧六环中搅拌反应， 得到权利要求 3或 4的化合物； 其 中所述 N- ( 5- ( ( Z ) -(5-氟 吲哚 -3-亚)甲基) -2, 4-二甲基 -1氢- 吡咯 -3-基） -3- -甲基哌嗪 -1-基） 丙酰胺与马来酸的摩尔比为 I：2； ( 4 )权利要求 5或 6的化合物的制备方法： N-(5-((Z)-(5-fluoro-2-indol-3-methylene)-2, 4-dimethyl-1hydro-pyrrol-3-yl)-3-(4 -Methylpyrazin-1-yl)propionamide with maleic acid in tetrahydrofuran, tetrahydrofuran/water, acetone, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, ethanol, isopropanol, n-propyl alcohol A stirring reaction is carried out in butanol and dioxane to obtain the compound of claim 3 or 4; wherein the N-(5-((Z)-(5-fluoroindole-3-methylene)methyl)-2, The molar ratio of 4-dimethyl-1 hydrogen-pyrrol-3-yl)-3-methylpiperazine-1-yl) propionamide and maleic acid is 1: 2 ; (4) Claim 5 or 6 Preparation method of the compound:
N- ( 5- ( ( Z ) -(5-氟 -2-^ ^吲哚 -3-亚)甲基) -2, 4-二甲基 -1氢-吡 咯 -3-基） -3- ( 4-甲基 嗪 -1-基） 丙酰胺与马来酸在水、 DMF/水、 Ν,Ν- 二甲基乙酰胺（DMAC ) /水、 甲醇、 乙二醇、 乙腈中搅拌反应， 得到 权利要求 5或 6的化合物； 其中所述 Ν- ( 5- ( ( Ζ ) -(5-氟 -2-羰基吲哚 -3- 亚)甲基） -2， 4-二甲基 -1氢 -吡咯 -3-基） -3- ( 4-甲基哌嗪小基） 丙酰胺 与马来酸的摩尔比为 1:2; 所述 DMF、 DMAC与水的混合溶剂中只要 水的含量不为 0即可， 其中优选 1:0.5-20； N-(5-((Z)-(5-fluoro-2-^indol-3-methylene)-2, 4-dimethyl-1hydro-pyrrol-3-yl) -3- (4-Methylazine-1-yl) propionamide and maleic acid are stirred and reacted in water, DMF/water, N,N-dimethylacetamide (DMAC)/water, methanol, ethylene glycol, and acetonitrile, Obtain the compound of claim 5 or 6; wherein said N-(5-((Z))-(5-fluoro-2-carbonylindole-3- (Methylene) -2, 4-dimethyl-1 hydrogen-pyrrol-3-yl) -3- (4-methylpiperazine base) The molar ratio of propionamide to maleic acid is 1:2; As long as the content of water in the mixed solvent of DMF, DMAC and water is not 0, 1:0.5-20 is preferred;
或者， or,
将权利要求 7-10任一项的化合物在水中打浆搅拌，过滤干燥后得到 权利要求 5或 ό的化合物； The compound of any one of claims 7-10 is slurried and stirred in water, filtered and dried to obtain the compound of claim 5 or ό;
或者， or,
将权利要求 7-10任一项的化合物在 150~200 C下烘干，得到权利要 求 5或 6的化合物。 The compound of any one of claims 7-10 is dried at 150~200 C to obtain the compound of claim 5 or 6.
12、 药物组合物， 其含有权利要求 1-10任一项的化合物， 以及任选 地一种或多种药学上可接受的载体或赋形剂。 12. A pharmaceutical composition containing a compound according to any one of claims 1 to 10, and optionally one or more pharmaceutically acceptable carriers or excipients.
13、权利要求 1至 10任一项所述的化合物在制备用于预防和 /或治疗 哺乳动物（包括人)与受体酪氨酸激酶相关的疾病或病症的药物中的用 途； 13. The use of the compound of any one of claims 1 to 10 in the preparation of a medicament for preventing and/or treating diseases or conditions associated with receptor tyrosine kinases in mammals (including humans);
进一步地， 所述与受体酪氛酸激酶相关的疾病或病症是指， 由受体 迁移； 、 ， " Further, the disease or disorder related to receptor tyrosine kinase refers to migration by receptor; , , "
更进一步地， 所述由受体酪氛酸激酶介导的肿瘤或由受体酪氨酸激 酶驱动的肿瘤细胞的增殖和迁移是指， erbB受体酪氣酸激醉敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动的肿瘤， 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结直肠、 子宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小细胞肺癌)、神经元、食道、 卵巢、胰腺、前列腺、 賢脏、 皮肤、 睾丸、 甲状腺、 子宫和外阴等的癌症， 和非实体肿瘤如白血病、 多发性骨髄瘤或淋巴瘤等。 Furthermore, the tumor mediated by receptor tyrosine kinase or the proliferation and migration of tumor cells driven by receptor tyrosine kinase refers to erbB receptor tyrosine acid stimulation-sensitive cancers, such as EGFR or Her2-high expression and EGF-driven tumors include solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectum, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer) , neuronal, esophagus, ovary, pancreas, prostate, viscera, skin, testis, thyroid, uterus and vulva cancers, and non-solid tumors such as leukemia, multiple bone marrow tumors or lymphoma, etc.
14、 预防和 /或治疗哺乳动物（包括人)与受体酪氨酸激酶相关的疾 病或病症的方法， 所述方法包括给有需要的哺乳动物（包括人)施用预防 和 /或治疗有效量的权利要求 1至 10任一项所述的化合物的步骤； 进一步地， 所述与受体酪氨酸激酶相关的疾病或病症是指， 由受体 迁移； 、 ^ " 14. Methods for preventing and/or treating diseases or conditions associated with receptor tyrosine kinases in mammals (including humans), the method comprising administering prophylaxis to mammals (including humans) in need and/or the step of treating an effective amount of the compound of any one of claims 1 to 10; further, the disease or disorder associated with receptor tyrosine kinase refers to migration from the receptor; , ^ "
更进一步地， 所述由受体酪氛酸激酶介导的肿瘤或由受体酪氨酸激 酶驱动的肿瘤细胞的增殖和迁移是指， erbB受体酪氛酸激酶敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动的肿瘤， 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结直肠、 子宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小细胞肺癌)、神经元、食道、 卵巢、胰腺、前列腺、 肾脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴等的癌症， 和非实体肿瘤如白血病、 多发性骨髄瘤或淋巴瘤等。 Furthermore, the tumor mediated by receptor tyrosine kinase or the proliferation and migration of tumor cells driven by receptor tyrosine kinase refers to erbB receptor tyrosine kinase-sensitive cancers, such as EGFR or Her2 High-expression and EGF-driven tumors, including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectum, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), Cancers of neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid gland, uterus and vulva, and non-solid tumors such as leukemia, multiple osteoblastoma or lymphoma.
PCT/CN2014/076124 2013-04-28 2014-04-24 Dimaleate of indolinone derivative, and polymorphs thereof WO2014177011A1 (en)

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