WO2021208055A1 - 一种噻吩并哒嗪类化合物的晶型及其制备方法和应用 - Google Patents
一种噻吩并哒嗪类化合物的晶型及其制备方法和应用 Download PDFInfo
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- WO2021208055A1 WO2021208055A1 PCT/CN2020/085268 CN2020085268W WO2021208055A1 WO 2021208055 A1 WO2021208055 A1 WO 2021208055A1 CN 2020085268 W CN2020085268 W CN 2020085268W WO 2021208055 A1 WO2021208055 A1 WO 2021208055A1
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- pyridazine
- thieno
- aminomethyl
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- 239000013078 crystal Substances 0.000 title claims abstract description 28
- -1 thiofuran pyridazine compound Chemical class 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 title abstract 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- FWXGWFHVNWTRJO-UHFFFAOYSA-N thieno[2,3-d]pyridazine-7-carboxamide Chemical compound S1C=CC=2C1=C(N=NC=2)C(=O)N FWXGWFHVNWTRJO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 4
- 238000001228 spectrum Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000005855 radiation Effects 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
- BECCJFVVNMJZMR-UHFFFAOYSA-N thieno[2,3-d]pyridazine Chemical compound N1=NC=C2SC=CC2=C1 BECCJFVVNMJZMR-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 230000020172 G2/M transition checkpoint Effects 0.000 description 1
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to the crystal of (S)-2-(4-fluorophenyl)-4-(piperidine-3-aminomethyl)thieno[2,3-d]pyridazine-7-carboxamide hydrochloride Type and its preparation method and application.
- (S)-2-(4-Fluorophenyl)-4-(piperidine-3-aminomethyl)thieno[2,3-d]pyridazine-7-carboxamide is a potent inhibitor of kinase CHK1 Therefore, it has the ability to prevent cell cycle stop in G2/M checkpoint in response to DNA damage.
- These compounds thus have anti-cell proliferation (for example, anti-cancer) activity, and can also be used in combination with other anti-tumor drugs to enhance the efficacy of other anti-tumor drugs. Therefore, it can be used to treat humans or animals.
- the technical problem to be solved by the present invention is to provide a crystal form of a thienopyridazine compound with higher stability under high humidity storage conditions, which is suitable for preparing stable pharmaceutical preparations.
- a crystal form of a thienopyridazine compound specifically related to (S)-2-(4-fluorophenyl)-4-(piperidine-3-aminomethyl) )
- Thieno[2,3-d]pyridazine-7-carboxamide hydrochloride its structural formula (I) is as follows:
- the purpose of the present invention is to provide a method for preparing the above new crystal form, the steps are as follows: (S)-2-(4-fluorophenyl)-4-(piperidine-3-aminomethyl)thieno[2,3 -d] Pyridazine-7-carboxamide is salted with hydrochloric acid at a temperature of 10-100°C in an aqueous medium, and the obtained crystals are separated and dried to a constant weight to remove the adsorbed water and solvent.
- the amount of water and the amount of hydrochloric acid are sufficient to form a stoichiometric hydrochloric acid salt hydrate, and is sufficient to thoroughly mix the raw materials used with water and hydrochloric acid. Any amount of water can be used, because the crystal water that occurs in the process of raw material salt formation Absorption leads to the formation of hydrates, and no further hydrates are obtained. The appropriate amount of water should be limited to both complete mixing and low solubility loss.
- the separated compound crystals can be dried at room temperature or higher temperature (less than 70°C), normal pressure or reduced pressure.
- the isolation of the compound of the present invention can be carried out at 0 to 60°C, preferably at 10 to 30°C.
- the water-containing medium can be (C 1 ⁇ C 3 )alkanol, such as methanol, ethanol, n-propanol, isopropanol, etc., or a water-soluble solvent, such as acetone, methyl ethyl ketone, acetonitrile, 1, 4-Dioxane, etc. or mixed solvents compatible with water.
- the invention has the following beneficial effects: the crystal form has higher stability, especially when stored under high humidity conditions; it is suitable for preparing various forms of medicines.
- Figure 1 is an X-ray powder diffraction pattern of the compound of the present invention.
- Figure 2 is the TGA profile of the compound of the present invention.
- Figure 3 is a DSC chart of the compound of the present invention.
- Figure 4 is the infrared spectrum of the compound of the present invention.
- the instrument model is Brucker D8Advance X-ray powder diffractometer for X-ray powder diffraction, test conditions: 3.000°-40.005°, Step 0.020°, Step time 0.4s, Anode: Cu, 25°C.
- Figure 1 is an X-ray powder diffraction pattern of the compound of the present invention.
- the sample is at 4.11 ⁇ 0.20°, 5.82 ⁇ 0.20°, 6.85 ⁇ 0.20°, 7.41 ⁇ 0.20°, 8.22 ⁇ 0.20°, 9.67 ⁇ 0.20°, 13.73 ⁇ 0.20° , 14.10 ⁇ 0.20°, 14.85 ⁇ 0.20° shows the strongest and second strongest characteristic diffraction peaks.
- FIG. 2 is the TGA profile of the compound of the present invention
- Figure 3 is the DSC profile of the compound of the present invention.
- TGA analysis shows that this sample is a hydrate.
- TGA analysis shows that when the temperature reaches about 120°C, the sample loses 2 molecules of crystal water; when the temperature reaches At about 260°C, the sample loses about 1 molecule of hydrogen chloride, and the temperature continues to rise and the sample decomposes.
- Figure 4 is an infrared spectrum of the compound of the present invention. According to the infrared spectrum data of Figure 4, it is shown that the sample is at 3374.62cm-1, 3049.15cm-1, 2792.21cm-1, 1624.53cm-1, 1474.85cm-1, 1403.67cm-1, 200.50cm-1, 1160.94cm- 1. 822.48cm-1 and 779.30cm-1 show characteristic absorption peaks.
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明提供了一种噻吩并哒嗪类化合物的晶型及其制备方法和应用,所述噻吩并哒嗪类化合物的晶型如式(I)所述的(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺盐酸盐。本发明的噻吩并哒嗪类化合物的晶型具有较高的稳定性,特别是在湿度高的条件下储存,适合于制备各种形式的药物。
Description
本发明涉及(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺盐酸盐的晶型及其制备方法和应用。
(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺是激酶CHK1的强效抑制剂,因而具有防止应答DNA损伤的G2/M关卡细胞周期停止的能力。这些化合物从而具有抗细胞增殖(例如抗癌)的活性,且还可以与其它抗肿瘤药物联合使用,增强其它抗肿瘤药物的疗效。因此可用于治疗人体或动物。
发明内容
本发明所要解决的技术问题是提供一种在湿度高的储藏条件下有较高稳定性的一种噻吩并哒嗪类化合物的晶型,以适合制备稳定的药物制剂。
为此,本发明采用如下的技术方案:一种噻吩并哒嗪类化合物的晶型,具体涉及(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺盐酸盐,其结构式(I)如下:
以2θ衍射角表示的X射线粉末衍射(仪器型号:Brucker D8 Advance X-射线粉末衍射仪,测试条件:3.000°-40.005°,Step0.020°,Step time 0.4s,Anode:Cu,25℃)图谱在4.11±0.20°,5.82±0.20°,6.85±0.20°,7.41±0.20°,8.22±0.20°,9.67±0.20°,13.73±0.20°,14.10±0.20°,14.85±0.20°处显示出最强和次强的特征衍射峰。
本发明的目的在于提供上述新晶型的制备方法,其步骤如下:(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺在含水介质中,在10~100℃的温度下与盐酸成盐,所得晶体分离并干燥到恒定重量,以除去被吸附的水和溶剂。
水的量和盐酸的量足以形成化学计量的盐酸盐水合物,并且足以使所用的原料与水和盐酸彻底混合,可以采用任意量的水,这是因为原料成盐过程中发生的结晶水的吸收导致水合物的形成,并且不会得到进一步的水合物,合适的水量应限制在既能发生完全混合,又只有低的溶解度损失。
分离出来的化合物晶体可以在室温下或者较高温度下(小于70℃)下、常压或者减压进行干燥。
本发明的化合物的分离可以在0~60℃进行,优选在10~30℃进行。 含水的介质可以是(C
1~C
3)链烷醇,如甲醇、乙醇、正丙醇、异丙醇等,也可以是与水相溶的溶剂,如丙酮、丁酮、乙腈、1,4-二氧六环等或者与水相溶的混合溶剂。
本发明具有以下有益效果:本晶型有较高的稳定性,特别是在湿度高的条件下储存;适合制备各种形式的药物。
图1为本发明化合物的X-射线粉末衍射图谱。
图2为本发明化合物的TGA图谱。
图3为本发明化合物的DSC图谱。
图4为本发明化合物的红外图谱。
具体实施例方式
下面结合说明书附图和具体实施例方式对本发明作进一步的说明,但并不因此将本发明限制在所述的实施例范围之中。下面实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照说明书选择。除非特殊说明,所有的百分比和份数按照重量计算。
实施例1:
将1克(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺溶于10ml水:甲醇(1:1)的溶剂中,加入盐酸0.2ml,升温至回流,溶解澄清,冷却析出晶体,过滤,减压干燥得产品0.96g,纯度99.12%。
实施例2:
将1克(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺溶于10ml水:乙醇(3:7)的溶剂中,加入盐酸0.2ml,升温至回流,溶解澄清,冷却析出晶体,过滤,减压干燥得产品0.90g,纯度99.30%。
实施例3:
将1克(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺溶于10ml水:异丙醇(2:8)的溶剂中,加入盐酸0.2ml,升温至回流,溶解澄清,冷却析出晶体,过滤,减压干燥得产品0.92g,纯度99.21%。
实施例4:
将1克(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺溶于10ml水:丙酮(3:7)的溶剂中,加入盐酸0.2ml,升温至回流,溶解澄清,冷却析出晶体,过滤,减压干燥得产品0.88g,纯度99.68%。
实施例5:
将1克(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺溶于10ml水:乙腈(3:7)的溶剂中,加入盐酸0.2ml,升温至回流,溶解澄清,冷却析出晶体,过滤,减压干燥得产品0.89g,纯度99.74%。
实施例6:性能测试实验
以上实施例所得产品的进行XRD、TGA、DSC实验。经实验可以看出,以上实施例所得产品的进行X-射线粉末衍射图谱(XRD)、TGA、DSC的图谱与说明书附图的图1、图2、图3和图4一致。
其中,采用仪器型号为Brucker D8Advance X-射线粉末衍射仪进行X-射线粉末衍射,测试条件:3.000°-40.005°,Step0.020°,Step time 0.4s,Anode:Cu,25℃。TGA仪器型号:TA Q500,DSC仪器型号:TA Q2000。10℃/分钟程序升温。红外仪器型号:Nicolet iS10FI-IR,KBr压片。
如图1所示,图1为本发明化合物的X-射线粉末衍射图谱。根据图1的X-射线粉末衍射图谱数据表明:本样品在4.11±0.20°,5.82±0.20°,6.85±0.20°,7.41±0.20°,8.22±0.20°,9.67±0.20°,13.73±0.20°,14.10±0.20°,14.85±0.20°处显示出最强和次强的特征衍射峰。
如图2和图3所示,图2为本发明化合物的TGA图谱,图3为本发明化合物的DSC图谱。根据图2和图3的TGA图谱和DSC图谱数据表明:(1)TGA分析表明:本样品为水合物,TGA分析表明,当温度达到120℃左右时,样品失去2分子结晶水;当温度达到260℃左右时,样品失去约1分子氯化氢,继续升高温度,样品分解。(2)DSC分析显示,本样品在84℃、132℃各有一个吸热峰,分别对应样品失去两分子结晶水的吸热峰;255℃左右有一个吸热峰,为样品融化分解所致。
如图4所示,图4为本发明化合物的红外图谱。根据图4的红外图谱数据表明:本样品在3374.62cm-1、3049.15cm-1、2790.21cm-1、1624.53cm-1、1474.85cm-1、1403.67cm-1、200.50cm-1、1160.94cm-1、 822.48cm-1、779.30cm-1显示特征吸收峰。
实施例7:稳定性试验
将实施例1、2、3、4和5样品进行稳定性试验。加速试验(40℃±2℃、相对湿度75%±5%)、长期试验的数据表明:(温度25℃±2℃;相对湿度60%±5%)储存条件下,36个月,样品的晶型稳定,水分、有关物质、光学异构体及含量无明显变化。进行加速试验的数据表明::(温度40℃±2℃;相对湿度75%±5%)储存条件下,6个月,样品的晶型稳定性水分、有关物质、光学异构体及含量无明显变化。请参见表1为加速试验(40℃±2℃、相对湿度75%±5%)结果;表2为长期稳定性试验(25℃±2℃、相对湿度60%±10%)结果。
表1
表2
需要声明的是,上述发明内容及具体实施方式意在证明本发明所提供技术方案的实际应用,不应解释为对本发明保护范围的限定。本领域技术人员在本发明的精神和原理内,当可作各种修改、等同替换、或改进。
Claims (9)
- 根据权利要求1所述的噻吩并哒嗪类化合物的晶型,其特征在于,(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺与盐酸的化学当量为1:2。
- 根据权利要求2所述的噻吩并哒嗪类化合物的晶型,其特征在于,还含2分子水。
- 根据权利要求1-3任一所述的噻吩并哒嗪类化合物的晶型,其特征在于,用CuKα辐射、以2θ角度表示的X射线粉末衍射光谱至少在4.11±0.20°,5.82±0.20°,6.85±0.20°,7.41±0.20°,8.22±0.20°,9.67±0.20°,13.73±0.20°,14.10±0.20°,14.85±0.20°处存在衍射峰。
- 一种如权利要求1~4任一所述的噻吩并哒嗪类化合物的晶型的制备方法,包括下列步骤:将(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺与 盐酸溶于含水的极性溶剂中反应,以得到如式I所述的(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺盐酸盐。
- 根据权利要求5所述的制备方法,其特征在于,(S)-2-(4-氟苯基)-4-(哌啶-3-氨甲基)噻吩并[2,3-d]哒嗪-7-甲酰胺与盐酸的摩尔比为1:2。
- 根据权利要求5所述的制备方法,其特征在于,所述极性溶剂至少选自为C1-C4的一元醇、乙腈、丙酮的一种。
- 根据权利要求5所述的制备方法,其特征在于,所述极性溶剂与水的体积比为1~5:1。
- 一种如权利要求1~4任一所述的噻吩并哒嗪类化合物的晶型在制备用于治疗或预防肿瘤的药物中的应用。
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CN101481380A (zh) * | 2008-01-08 | 2009-07-15 | 浙江医药股份有限公司新昌制药厂 | 噻吩并哒嗪类化合物及其制备方法、药物组合物及其用途 |
CN104628741A (zh) * | 2009-09-18 | 2015-05-20 | 吴章桂 | 新颖化合物及其用于抑制蛋白激酶的治疗用途 |
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CN101481380A (zh) * | 2008-01-08 | 2009-07-15 | 浙江医药股份有限公司新昌制药厂 | 噻吩并哒嗪类化合物及其制备方法、药物组合物及其用途 |
CN104628741A (zh) * | 2009-09-18 | 2015-05-20 | 吴章桂 | 新颖化合物及其用于抑制蛋白激酶的治疗用途 |
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