CN117015535A - (4s)-24-氯-4-乙基-73-氟-35-甲氧基-32,5-二氧代-14-(三氟甲基)-32h-6-氮杂-3(4,1)-吡啶-1(1)-[1,2,3]三唑-2(1,2),7(1)-5二苯庚烷-74-甲酰胺的结晶形式 - Google Patents
(4s)-24-氯-4-乙基-73-氟-35-甲氧基-32,5-二氧代-14-(三氟甲基)-32h-6-氮杂-3(4,1)-吡啶-1(1)-[1,2,3]三唑-2(1,2),7(1)-5二苯庚烷-74-甲酰胺的结晶形式 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
本发明涉及(4S)‑24‑氯‑4‑乙基‑73‑氟‑35‑甲氧基‑32,5‑二氧代‑14‑(三氟甲基)‑32H‑6‑氮杂‑3(4,1)‑吡啶‑1(1)‑[1,2,3]三唑‑2(1,2),7(1)‑5二苯庚烷‑74‑甲酰胺的结晶形式(即晶体变型I和晶体变型II)、其制备方法、包含其的药物组合物及其在防治疾病中的用途。
Description
本发明涉及(4S)-24-氯-4-乙基-73-氟-35-甲氧基-32,5-二氧代-14-(三氟甲基)-32H-6-氮杂-3(4,1)-吡啶-1(1)-[1,2,3]三唑-2(1,2),7(1)-二苯庚烷(dibenzenaheptaphane)-74-甲酰胺的结晶形式(即晶体变型I和晶体变型II)、其制备方法、包含其的药物组合物及其在防治疾病中的用途。
式(I)的化合物,(4S)-24-氯-4-乙基-73-氟-35-甲氧基-32,5-二氧代-14-(三氟甲基)-32H-6-氮杂-3(4,1)-吡啶-1(1)-[1,2,3]三唑-2(1,2),7(1)-二苯庚烷-74-甲酰胺,又名为4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}氨基)-2-氟苯甲酰胺,从WO2017/005725中获知并具有下式结构:
的化合物。
式(I)的化合物用作XIa因子抑制剂,并且由于其特殊的作用机制,在口服给药后可用于治疗和/或预防疾病,优选血栓形成性或血栓栓塞性疾病和/或血栓形成性或血栓栓塞性并发症,特别是心血管疾病(包括冠状动脉疾病、心绞痛、心肌梗死或支架血栓形成)以及脑血管动脉疾病和导致短暂性缺血发作(TIA)、缺血性卒中(包括心源性和非心源性卒中)的其他疾病,和/或导致外周动脉疾病的外周动脉的病症,包括外周动脉闭塞、急性肢体缺血、截肢、介入治疗(如血管成形术、支架植入术或手术和搭桥)后的再闭塞和再狭窄,和/或支架血栓形成。
式(I)的化合物可如WO2017/005725中的实施例234和实施例235所述制备。使用所述方法获得无定形形式的式(I)的化合物。获得的无定形形式的式(I)的化合物即使经过大量实验仍无法转变为无溶剂的结晶形式,所述实验例如为1)将式(I)的化合物溶于溶剂中并进行常规的结晶实验(包括例如蒸发溶剂和冷却溶液),或2)使无定形形式的式(I)的化合物的饱和溶液浆化。不同类型的溶剂以及溶剂的混合物已经过尝试。
WO2019/175043中记载了式(I)的化合物无法以无溶剂的结晶形式分离,但外消旋混合物中包含的式(I)的化合物能够结晶。外消旋混合物中包含的式(I)的化合物的这种结晶行为用于以简易且可量化的方式制备无定形固态形式的式(I)的化合物(对映体纯的形式)。包含式(I)的化合物的外消旋物质作为晶体在有机溶剂中的溶解度低得多。基于所需的无定形形式的式(I)的化合物(对映体纯的形式)和结晶形式的包含式(I)的化合物的外消旋物质具有不同的动力学溶解度这一原理,能够以高对映体过量值(ee-value)获得式(I)的化合物(对映体纯的形式)。
因此,研发的目的是提供无溶剂的结晶形式的式(I)的化合物。
出人意料地,已发现,无定形形式的式(I)的化合物可溶于溶剂中,并且在用晶体变型A的式(II)的化合物接种后,式(I)的化合物以晶体变型I的形式结晶。
无定形形式可通过未显示特征反射的X射线粉末衍射图以及未显示熔化行为的DSC热谱图(图17和16)来表征。目前已发现无定形形式相较于晶体变型I具有吸湿性和更低的稳定性。
式(I)的化合物的下列结晶形式已被鉴定为晶体变型I和晶体变型II。在本发明变型的上下文中,多晶型形式(polymorphic form)和多晶型物(polymorph)含义相同。除了无定形形式以外还存在这些结晶形式。所有这些——结晶形式和无定形形式——都是式(I)的化合物的不同固体形式。
相较于式(I)的化合物的无定形形式,式(I)的化合物的晶体变型I在吸湿性和热稳定性方面具有有利的特性。无定形形式、晶体变型I和晶体变型II的动态蒸汽吸附等温线表明在80%相对湿度下样品分别获得3.2%、0.04%和2.13%质量的水。热稳定性通过以下方式进行研究:将样品在90℃下于密闭容器中储存1周,然后用HPLC测量所有有机杂质的总量(方法3)。在储存后,无定形形式测量的有机杂质为4.4%,而晶体变型I未检测到有机杂质。
式(I)的化合物的晶体变型I为熔点以下的热力学稳定形式。
因此,式(I)的化合物的晶体变型I适用于制药领域,特别适用于药物组合物。
本发明的药物组合物包含式(I)的化合物的晶体变型I和任选地其他药学上可接受的赋形剂。
式(I)的化合物的不同形式可通过X射线粉末衍射、差示扫描量热法(DSC)、红外光谱和拉曼光谱来区分。
式(I)的化合物的晶体变型I可通过红外光谱表征,所述红外光谱显示出至少以下最大吸收波数(value of the band maxima)(cm-1):1705、1641、1429,优选至少以下最大吸收波数(cm-1):1705、1641、1503、1429、791,更优选至少以下最大吸收波数(cm-1):1705、1641、1503、1429、1383、1039、791,最优选至少以下最大吸收波数(cm-1):3401、1705、1613、1641、1503、1429、1383、1205、1039和791。晶体变型I的式(I)化合物还可通过如图7所示的红外光谱表征。
式(I)的化合物的晶体变型II可通过红外光谱表征,所述红外光谱显示出至少以下最大吸收波数(cm-1):1664、1571、1134,优选至少以下最大吸收波数(cm-1):1664、1571、1525、1373、1134,更优选至少以下最大吸收波数(cm-1):1664、1571、1525、1417、1373、1134、1032,最优选至少以下最大吸收波数(cm-1):1664、1571、1525、1417、1373、1134、1032、870、825和775。晶体变型II的式(I)的化合物还可通过如图8所示的红外光谱表征。
式(I)的化合物的晶体变型I可通过拉曼光谱表征,所述拉曼光谱显示出至少以下最大吸收波数(cm-1):1625、1239、991,优选至少以下最大吸收波数(cm-1):1625、1572、1528、1239、991,更优选至少以下最大吸收波数(cm-1):1625、1572、1528、1359、1329、1239、991,最优选至少以下最大吸收波数(cm-1):3059、1694、1625、1572、1528、1431、1359、1329、1239和991。晶体变型I的式(I)的化合物还可通过如图9所示的拉曼光谱表征。
式(I)的化合物的晶体变型II可通过拉曼光谱表征,所述拉曼光谱显示出至少以下最大吸收波数(cm-1):1623、1604、1336,优选至少以下最大吸收波数(cm-1):1623、1604、1527、1336、981,更优选至少以下最大吸收波数(cm-1):1663、1623、1604、1527、1247、1336、981,最优选至少以下最大吸收波数(cm-1):1710、1663、1623、1604、1527、1374、1247、1336、981和709。晶体变型II的式(I)的化合物还可通过如图10所示的拉曼光谱表征。
式(I)的化合物的晶体变型I可通过X射线粉末衍射图(在20±5℃下并以Cu-Kα1作为辐射源)表征,所述X射线粉末衍射图显示出至少以下反射:17.8、19.1、25.5,优选至少以下反射:10.6、17.8、19.1、19.4、25.5,更优选至少以下反射:10.6、13.9、17.8、19.1、19.4、23.4、25.5,最优选至少以下反射:10.6、13.9、17.8、19.1、19.4、20.8、22.0、22.6、23.4和25.5,分别以2θ值±0.2°表示。晶体变型I的式(I)的化合物还可通过如图11所示的X射线粉末衍射图(在20±5℃下并以Cu-Kα1作为辐射源)表征。
式(I)的化合物的晶体变型II可通过X射线粉末衍射图(在20±5℃下并以Cu-Kα1作为辐射源)表征,所述X射线粉末衍射图显示出至少以下反射:11.0、16.8、23.6,优选至少以下反射:8.9、11.0、16.8、20.2、23.6,更优选至少以下反射:7.9、8.9、11.0、16.8、18.3、20.2、23.6,最优选至少以下反射:7.9、8.9、11.0、16.8、17.3、18.3、20.2、21.9、23.6和26.5,分别以2θ值±0.2°表示。晶体变型II的式(I)的化合物还可通过如图12所示的X射线粉末衍射图(在20±5℃下并以Cu-Kα1作为辐射源)表征。
制备方法
本发明还涉及一种通过将无定形形式的式(I)的化合物溶于惰性溶剂中并以晶体变型A的式(II)的化合物为晶种使晶体变型I的式(I)的化合物结晶来制备晶体变型I的式(I)的化合物的方法。
本发明的惰性溶剂为乙腈、四氢呋喃、丙酮、乙酸乙酯、乙酸异丙酯、乙酸丁酯、丁-2-酮、1,4-二氧杂环己烷、2-甲基吡啶、4-甲基戊-2-酮、正庚烷、环己烷、甲基环己烷、2-(丙-2-基氧基)丙烷或2-甲氧基-2-甲基丙烷,或醇类如丁-1-醇、丁-2-醇、丙-2-醇、丙-1-醇、2-甲基丙-1-醇、乙醇或甲醇,和/或它们的混合物,以及所述溶剂与水的混合物。优选的溶剂为乙醇和水的混合物。
本发明还涉及一种通过将无定形形式的式(I)的化合物溶于乙醇中并添加水,然后以晶体变型A的式(II)的化合物为晶种使晶体变型I的式(I)的化合物结晶来制备晶体变型I的式(I)的化合物的方法。
式(II)的化合物,4-({(2S)-2-[4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丙酰基}氨基)-2-氟苯甲酰胺,具有下式结构:
的化合物。
本发明还涉及一种通过将式(III)的化合物在烘箱中在减压下干燥,优选在50℃和10毫巴下干燥一天来制备晶体变型II的式(I)的化合物的方法。其他温度和压力的组合还可引起丙酮的去溶剂化,其中去溶剂化方法的进程和/或结果可通过TGA和XRPD测量验证。
式(III)的化合物,4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}-氨基)-2-氟苯甲酰胺丙酮,具有下式结构:
的化合物。
治疗方法
本发明还涉及晶体变型I和/或晶体变型II的式(I)的化合物用于治疗和/或预防疾病,优选血栓形成性或血栓栓塞性疾病和/或血栓形成性或血栓栓塞性并发症的用途。
本发明还涉及晶体变型I和/或晶体变型II的式(I)的化合物用于治疗和/或预防以下疾病的用途:心血管疾病(包括冠状动脉疾病、心绞痛、心肌梗死或支架血栓形成)以及脑血管动脉疾病和导致短暂性缺血发作(TIA)、缺血性卒中(包括心源性和非心源性卒中)的其他疾病,和/或导致外周动脉疾病的外周动脉的病症,包括外周动脉闭塞、急性肢体缺血、截肢、介入治疗(如血管成形术、支架植入术或手术和搭桥)后的再闭塞和再狭窄,和/或支架血栓形成。
药物组合物
本发明的式(I)的化合物的晶体变型I和晶体变型II可具有全身和/或局部活性。为此,其能够以合适的方式给药,例如通过口服、肠胃外、肺部、经鼻、舌下、经舌(lingual)、口腔、直肠、阴道、皮肤、透皮(transdermal)、结膜、经耳途径给药或作为植入物或支架。
对于这些给药途径,本发明的式(I)的化合物的晶体变型I和晶体变型II可以合适的给药形式给药。
为了口服给药,可将本发明的式(I)的化合物的晶体变型I和晶体变型II配制成本领域已知的剂型,其快速和/或以缓和方式递送本发明的化合物,所述剂型为例如片剂(未包衣或包衣的片剂,例如具有延迟溶解或不溶的肠溶包衣或控释包衣)、口服-崩解片剂、薄膜/薄片(wafer)、薄膜/冻干剂(lyophilisate)、胶囊(例如硬明胶胶囊或软明胶胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、悬浮剂、气溶胶或溶液剂。可将本发明的化合物以结晶形式和/或无定形形式和/或溶解形式掺入所述剂型中。
肠胃外给药可通过避免吸收步骤(例如静脉内、动脉内、心脏内、脊柱内或腰椎内)或包括吸收步骤(例如肌肉内、皮下、皮内、经皮或腹膜内)而进行。适用于肠胃外给药的给药形式尤其为溶液剂、悬浮剂、乳剂、冻干剂或无菌粉剂形式的注射和输液用制剂。
适用于其他给药途径的实例为用于吸入的药物剂型(尤其是粉末吸入剂、喷雾剂)、滴鼻剂、鼻用溶液剂、喷鼻剂;用于经舌、舌下或口腔给药的片剂/薄膜/薄片/胶囊;栓剂;滴眼剂、眼膏剂(eye ointment)、洗眼杯(eye bath)、眼部插入剂(ocular insert)、滴耳剂、喷耳剂(ear spray)、耳用粉剂、洗耳剂(ear-rinse)、耳填塞剂(ear tampon);阴道胶囊、水性悬浮剂(洗剂、振荡合剂(mixturae agitandae))、亲脂性悬浮剂、乳剂、软膏剂、乳膏剂(cream)、经皮治疗系统(例如贴剂)、乳液剂(milk)、糊剂、泡沫剂、扑粉、植入物或支架。
式(I)的化合物的晶体变型I和晶体变型II可掺入所述给药形式中。这可以本身已知的方式通过与药学上合适的赋形剂混合而实现。药学上合适的赋形剂尤其包括
·填料和载体(例如纤维素、微晶纤维素(例如)、乳糖、甘露糖醇、淀粉、磷酸钙(例如/>)),
·软膏剂基质(例如凡士林、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水软膏、聚乙二醇),
·栓剂基质(例如聚乙二醇、可可脂、硬脂),
·溶剂(例如水、乙醇、异丙醇、丙三醇、丙二醇、中等链长甘油三酯脂肪油、液体聚乙二醇、链烷烃),
·表面活性剂、乳化剂、分散剂或湿润剂(例如十二烷基硫酸钠)、卵磷脂、磷脂、脂肪醇(例如)、失水山梨糖醇脂肪酸酯(例如/>)、聚氧乙烯失水山梨糖醇脂肪酸酯(例如/>)、聚氧乙烯脂肪酸甘油酯(例如/>)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、脂肪酸甘油酯、泊洛沙姆(poloxamer)(例如/>),
·缓冲液、酸和碱(例如磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨基丁三醇(trometamol)、三乙醇胺),
·等渗剂(例如葡萄糖、氯化钠),
·吸附剂(例如高度分散二氧化硅),
·增粘剂、凝胶形成剂、增稠剂和/或粘合剂(例如聚乙烯吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、淀粉、卡波姆、聚丙烯酸(例如);海藻酸盐、明胶),
·崩解剂(例如改性淀粉、羧甲基纤维素钠、羟基乙酸淀粉钠(例如)、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠(例如/>)),
·流量调节剂、润滑剂、助流剂和脱模剂(例如硬脂酸镁、硬脂酸、滑石、高度分散二氧化硅(例如)),
·包衣材料(例如糖、虫胶)和用于快速溶解或以缓和方式溶解的薄膜或扩散膜的成膜剂(例如聚乙烯吡咯烷酮(例如)、聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、乙酸纤维素、乙酸纤维素邻苯二甲酸酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如/>)),
·胶囊材料(例如明胶、羟丙基甲基纤维素),
·合成聚合物(例如聚乳酸、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如)、聚乙烯吡咯烷酮(例如/>)、聚乙烯醇、聚乙酸乙烯酯、聚环氧乙烷、聚乙二醇及其共聚物和嵌段共聚物),
·增塑剂(例如聚乙二醇、丙二醇、丙三醇、三乙酸甘油酯、三乙酰基柠檬酸酯、邻苯二甲酸二丁酯),
·渗透促进剂,
·稳定剂(例如抗氧化剂,例如抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基茴香醚、丁基羟基甲苯、没食子酸丙酯),
·防腐剂(例如对羟基苯甲酸酯(paraben)、山梨酸、硫柳汞(thiomersal)、苯扎氯铵、乙酸氯己定、苯甲酸钠),
·着色剂(例如无机颜料,例如氧化铁、二氧化钛),
·调味剂、甜味剂、遮味剂和/或气味掩蔽剂。
此外,本发明还涉及一种包含至少本发明的式(I)的化合物的晶体变型I和/或晶体变型II和通常一种或多种药学上合适的赋形剂的药物组合物,及其根据本发明的用途。
本发明的药物组合物的剂量
基于已知的评估可用于治疗疾病的化合物的实验室技术,通过用于确定对哺乳动物上述症状的治疗的药理学测定,并通过将这些结果与用于治疗这些症状的已知药物的结果进行比较,可以容易地确定用于治疗各种所需适应症的本发明化合物的有效剂量。在治疗这些症状之一时待给药的活性成分的量可根据这样的考虑而广泛变化:如所使用的具体化合物和剂量单位、给药方式、治疗周期、所治疗患者的年龄和性别以及所治疗症状的性质和程度。
待给药的活性成分的总量通常为肠胃外给药约5至250mg/24小时以获得有效结果和口服给药约5至500mg/24小时以获得有效结果。
尽管如此,若合适,仍可能有必要偏离指定的用量,具体取决于体重、给药途径、个体对活性成分的反应、制剂类型和给药的时间或间隔。
除非另有说明,以下试验和实施例中的重量数据为重量百分比;份数为重量份数。除非另有说明,溶剂比、稀释比和液/液溶液剂的浓度数据基于每种情况下的体积计。
工作实施例
缩写:
br s 宽单峰(NMR中)
br d 宽双重峰(NMR中)
br t 宽三重峰(NMR中)
d 天数、双重峰(NMR中)
DCI 直接化学电离(MS中)
dd 双重双峰(NMR中)
DMSO 二甲基亚砜
eq. 当量
ESI 电喷雾电离(MS中)
h 小时
HPLC 高压高效液相色谱
LC/MS 液相色谱-质谱联用
m 多重峰(NMR中)
min 分钟
MS 质谱
NMR 核磁共振谱
q 四重峰(quartet,quadruplet)(NMR中)
RP 反相(HPLC中)
RT 室温
Rt 保留时间(HPLC中)
s 单峰(NMR中)
t 三重峰(NMR中)
T3P 2,4,6-三丙基-1,3,5,2,4,6-三氧杂三膦烷-2,4,6-三氧化物
HPLC、LC-MS和GC方法:
方法1:仪器:Waters ACQUITY SQD UPLC系统;柱:Waters Acquity UPLC HSS T3C18 1.8μm,50mm×1.0mm;洗脱液A:水+0.025%甲酸,洗脱液B:乙腈+0.025%甲酸;梯度:0.0min 10%B→1.2min 95%B→2.0min 95%B;柱温箱:50℃;流速:0.40mL/min;UV检测:210-400nm。
方法2:仪器:Thermo Scientific FT-MS;UHPLC:Thermo Scientific UltiMate3000;柱:Waters HSS T3 C18 1.8μm,75mm×2.1mm;洗脱液A:水+0.01%甲酸;洗脱剂B:乙腈+0.01%甲酸;梯度:0.0min 10%B→2.5min 95%B→3.5min 95%B;柱温箱:50℃;流速:0.90mL/min;UV检测:210-400nm。
方法3:Agilent 1290系统;柱:YMC Triart C18ExRS1.9μm,50mm×2mm;洗脱液A:乙酸铵水溶液(0.77g/L)/氨缓冲溶液pH 9;洗脱液B:乙腈;梯度:0.0min 5%B→10min65%B→10.01min 5%B→11min 5%B;柱温箱:40℃;流速:1mL/min;UV检测:220nm。
1H-NMR方法: 1H-NMR谱图在Bruker光谱仪上(如所示的在400MHz、500MHz或600MHz下)于室温下在氘代溶剂(d6-DMSO)中获得。给出了相对于辐照频率以ppm计的有关化学位移δ的信息。使用氘代溶剂的信号作为内标。
实施例1:(4S)-24-氯-4-乙基-73-氟-35-甲氧基-32,5-二氧代-14-(三氟甲基)-
32H-6-氮杂-3(4,1)-吡啶-1(1)-[1,2,3]三唑-2(1,2),7(1)-二苯庚烷-74-甲酰胺(又名为
4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代
吡啶-1(2H)-基]丁酰基}氨基)-2-氟苯甲酰胺)(式(I)的化合物)的制备
式(I)的化合物可如WO2017/005725中的实施例234和实施例235所述制备。使用所述方法获得无定形形式的式(I)的化合物。
WO2017/005725中的实施例234示出了外消旋体形式的式(I)的化合物的1H-NMR:
1H-NMR(400MHz,DMSO-d6):δ[ppm]=10.76(br s,1H),9.13(s,1H),7.86-7.80(m,2H),7.79-7.77(m,1H),7.69(t,1H),7.66-7.61(m,1H),7.56-7.49(m,2H),7.37(dd,1H),7.13(s,1H),6.53(s,1H),5.55-5.49(m,1H),3.26(s,3H),2.14-2.02(m,2H),0.79(t,3H)。
实施例2:4-({(2S)-2-[4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]
苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丙酰基}氨基)-2-氟-苯甲酰胺(式(II)的化合物)
的制备
实施例2.1:1-(2-溴-4-氯-3-氟苯基)-4-(三氟甲基)-1H-1,2,3-三唑
以2-溴-4-氯-3-氟苯胺(WO 2016/168098,第59-60页)为起始原料通过以下方式合成1-(2-溴-4-氯-3-氟苯基)-4-(三氟甲基)-1H-1,2,3-三唑:首先生成叠氮衍生物(在亚硝酸叔丁酯和叠氮基三甲基硅烷的存在下,类似于WO 2017/005725的第92-93页中实施例2.18A的合成),然后进行叠氮衍生物与三氟丙炔的环加成反应(在氧化亚铜(I)的存在下,类似于WO 2017/005725的第102页中实施例2.26A的合成)。
实施例2.2:4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-2,5-
二甲氧基吡啶
将1-(2-溴-4-氯-3-氟苯基)-4-(三氟甲基)-1H-1,2,3-三唑(982mg,2.85mmol)、(2,5-二甲氧基吡啶-4-基)硼酸(WO 2019/175043,第23-24页)(626mg,3.42mmol,1.2当量)和碳酸钾(1.18g,8.55mmol,3.0当量)的混合物溶于1,4-二氧杂环己烷(50mL)中,并用氩气吹扫10min后加入[1,1-双(二苯基膦基)二茂铁]二氯化钯(II)单二氯甲烷加合物(233mg,0.29mmol,0.1当量)。将反应混合物在100℃下(已预热至100℃的油浴)搅拌过夜。加入另外的(2,5-二甲氧基吡啶-4-基)硼酸(209mg,1.14mmol,0.4当量)和[1,1-双(二苯基膦基)二茂铁]二氯化钯(II)单二氯甲烷加合物(116mg,0.14mmol,0.05当量)。将反应混合物在100℃下再搅拌5h,在室温下放置过周末并通过(其用1,4-二氧杂环己烷洗涤)过滤。合并的滤液在减压下浓缩。将残留物通过色谱法(硅胶,洗脱液:环己烷/乙酸乙酯梯度)纯化。收率:432mg(理论值的38%)。
LC-MS(方法2):Rt=2.13min;MS(ESIpos):m/z=403[M+H]+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=9.17/9.16(2x s,1H),8.03/8.01(2x d,1H),7.86(s,1H),7.75/7.75(2x d,1H),6.82(s,1H),3.79(s,3H),3.54(s,3H)。
实施例2.3:4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲 氧基吡啶-2(1H)-酮
将吡啶氢溴酸盐(429mg,2.68mmol,2.5当量)加入到4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-2,5-二甲氧基吡啶(432mg,1.07mmol)于N,N-二甲基甲酰胺(10mL)中的溶液中。将混合物在100℃下搅拌过夜并在减压下浓缩。将残留物溶于水。加入乙酸乙酯并进行相分离后,将水相用乙酸乙酯萃取两次。将合并的有机相经无水硫酸钠干燥,过滤,并在减压下浓缩。将残留物通过色谱法(硅胶,洗脱液:二氯甲烷/甲醇梯度)纯化。收率:285mg(理论值的68%)。
LC-MS(方法2):Rt=1.46min;MS(ESIpos):m/z=389[M+H]+
1H-NMR(600MHz,DMSO-d6):δ[ppm]=11.3(br s,1H),9.23(s,1H),8.10-7.99(m,1H),7.77(m,1H),7.15(s,1H),6.41(s,1H),3.45(s,3H)。
实施例2.4:4-({(2S)-2-[4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1- 基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丙酰基}氨基)-2-氟苯甲酰胺(式(II)的化合物)
在室温下在氩气气氛下将1,1,3,3-四甲基胍(420μL,3.35mmol,3.0当量)加入到4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基吡啶-2(1H)-酮(438mg,1.12mmol)于2-丙醇/丙酮(4:1,7.5mL)中的溶液中。将混合物在室温下搅拌15min,然后加入4-{[(2R)-2-溴丙酰基]氨基}-2-氟苯甲酰胺(WO 2020/127504,实施例1.19A,第76页)(355mg,1.23mmol,1.1当量)和另外的2-丙醇/丙酮(4:1,7.5mL)。将反应混合物在室温下搅拌过夜并在减压下浓缩。将残留物通过色谱法(硅胶,洗脱液:二氯甲烷/甲醇梯度)和制备型HPLC(反相,洗脱液:乙腈/水梯度)纯化。收率:539mg(理论值的81%)。
LC-MS(方法2):Rt=1.65min;MS(ESIpos):m/z=597[M+H]+
1H-NMR(500MHz,DMSO-d6):δ[ppm]=10.72/10.63(2x s,1H),9.24/9.13(2x s,1H),8.06-7.99(m,1H),7.79-7.74(m,1H),7.72-7.60(m,2H),7.56-7.48(m,2H),7.38-7.32(m,1H),7.27/7.25(2x s,1H),6.48/6.47(2x s,1H),5.51-5.44(m,1H),3.47/3.45(2x s,3H),1.65/1.64(2x s,3H)。
实施例3:4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-
5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}-氨基)-2-氟苯甲酰胺丙酮(式(III)的化合物)
的制备
式(III)的化合物可如WO2019/175043中所述的式(IIc)的化合物进行制备。使用所述方法获得结晶形式的式(III)的化合物。
实施例4:晶体变型A的式(II)的化合物的制备
将306mg无定形形式的式(II)的化合物在室温下溶于20mL 50体积%乙醇和50体积%水的混合物中。将溶液在室温下搅拌24小时,从而析出白色固体。将溶剂在旋转蒸发仪中蒸发。获得的固体在40℃的真空烘箱中干燥16小时。获得273mg晶体变型A的式(II)的化合物。1H-NMR谱图(于DMSO-d6中)如图19所示。
实施例5:制备晶体变型的式(I)的化合物的尝试
将约10mg无定形形式的式(I)的化合物溶于1mL热乙醇中。冷却至室温后,将溶液在敞口小瓶中搅拌直至溶剂完全蒸发。获得的固体为无定形的。
实施例6:制备晶体变型的式(I)的化合物的尝试
将100mg无定形形式的式(I)的化合物在室温下悬浮于2.5mL 50体积%乙醇和50体积%水的混合物中。将悬浮液搅拌4周,然后过滤并干燥。获得的固体为无定形的。
实施例7:晶体变型I的式(I)的化合物的制备
将30mg无定形形式的式(I)的化合物在室温下溶于2mL乙醇中。将660μL水逐滴加入到溶液中直至观察到溶液浑浊。然后用1mg式(II)的化合物的晶体变型A接种溶液。接种后不久,观察到析出更多小颗粒,但颗粒在搅拌后迅速消失,从而产生看似澄清的溶液。在室温下搅拌48小时后,获得悬浮液。将固体真空过滤并在环境条件下干燥过夜。获得的固体的XRPD图对应于式(I)的化合物的晶体变型I。所得的固体的1H-NMR分析表明该固体含有约5重量%的式(II)的化合物。式(I)的化合物的峰位于δ[ppm]=6.53(s,1H)、3.26(s,3H)和0.79(t,3H)处,以及式(II)的化合物的峰位于δ[ppm]=6.48/6.47(2x s,1H)、3.47/3.45(2x s,3H)和1.65/1.64(2x s,3H)处。这些峰用于积分以测定5重量%的式(II)的化合物。1H-NMR谱图如图1所示。
实施例8:纯的式(I)化合物形式的晶体变型I的式(I)的化合物的制备
将300mg无定形形式的式(I)的化合物在室温下溶于3.8mL乙醇中。将3.5mL水逐滴加入到溶液中直至观察到溶液浑浊。加入2滴乙醇以获得澄清溶液。用1.5mg实施例7中获得的固体接种澄清溶液,然后在室温下搅拌2天。将所得的悬浮液过滤并在环境条件下干燥过夜。获得146mg式(I)的化合物的晶体变型I。所得的固体的1H-NMR分析表明式(II)的化合物的量低于检测限。1H-NMR谱图如图2所示。
实施例9:纯的式(I)化合物形式的晶体变型I的式(I)的化合物的制备
将20.0g无定形形式的式(I)的化合物在室温下溶于40.0g丙-2-醇和10.0g丙酮的混合物中。将混合物加热至60℃,并在60分钟内将126.0g水加入到所得溶液中。用100.0mg式(I)的化合物的晶体变型I接种所得混合物,并在60℃下搅拌3小时。然后再加入4.8g无定形形式的式(I)的化合物,并将混合物在60℃下搅拌过夜。将所得的悬浮液在60分钟内冷却至20℃,并在20℃下搅拌90分钟。将由此获得的悬浮液真空过滤,用42.5g质量比为4:1:12的丙-2-醇:丙酮:水的混合物洗涤两次,并在40℃下真空干燥。收率:22.4g(理论收率的90.3%)晶体变型I的灰白色(pale-white)固体。
实施例10:晶体变型II的式(I)的化合物的制备
将40mg式(III)的化合物在50℃下在减压下干燥以获得晶体变型II的固体。
实施例11:式(I)的化合物的无定形形式、晶体变型I和晶体变型II的物理表征
实施例11.1:热重分析(TGA)
使用Perkin Elmer Pyris 6或Mettler Toledo TGA/DSC1进行热重分析(TGA)。用氮气以20-50mL·min-1的流速吹扫仪器。将约5-15mg每个样品置于铝或氧化铝坩埚中。所有测量的加热速率均为10℃·min-1,其中变型I和II的温度范围为25-300℃,无定形形式的温度范围为25-280℃。未进行样品制备。TGA热谱图如图3以及图4和图15所示。
实施例11.2:差示扫描量热分析(DSC)
图16:式(I)的化合物(无定形形式)的DSC曲线
使用Mettler Toledo DSC822e进行差示扫描量热分析(DSC)。用氮气以50mL·min-1的流速吹扫量热仪。将约3-10mg样品置于铝坩埚中,而无需进行样品制备。在20℃·min-1的加热速率下,温度范围为-10-280℃。DSC热谱图如图16所示。
图5:式(I)的化合物(晶体变型I)的DSC曲线
使用Mettler Toledo DSC3进行差示扫描量热分析(DSC)。用氮气以50mL·min-1的流速吹扫量热仪。将约3-10mg样品置于铝坩埚中,而无需进行样品制备。在20℃·min-1的加热速率下,温度范围为-10-300℃。DSC热谱图如图5所示。
图6:式(I)的化合物(晶体变型II)的DSC曲线
使用Netzsch Phoenix DSC 204F1进行差示扫描量热分析(DSC)。用氮气以20mL·min-1的流速吹扫量热仪。将约3-10mg样品置于铝坩埚中,而无需进行样品制备。在10℃·min-1的加热速率下,温度范围为25-300℃。DSC热谱图如图6所示。
表1:差示扫描量热分析
实施例11.3:红外光谱
使用Thermo Scientific Nicolet iS10光谱仪和Bruker alpha光谱仪在衰减全反射(ATR)几何结构中进行红外光谱测量。未进行样品制备,并且每个单独的测量由32次或64次扫描组成。红外光谱如图7和图8所示。
表2:式(I)的化合物(晶体变型I和晶体变型II)的红外光谱
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实施例11.4:式(I)的化合物的拉曼光谱
使用Bruker MultiRAM进行拉曼光谱测量。未进行样品制备,并且每个单独的测量由64次或128次扫描组成,使用的激光功率为300或600mW。拉曼光谱如图9和图10所示。
表3:式(I)的化合物(晶体变型I和晶体变型II)的拉曼光谱
实施例11.5:式(I)的化合物的X射线粉末衍射(XRPD)
在STOE STADIP或D8Bruker Advance衍射仪上记录X射线粉末衍射(XRPD)数据,使用单色化的Cu-Kα1辐射源和位敏探测器,发生器设置为40kV和40mA。样品以过渡模式收集,要么装入标准玻璃毛细管,要么制备成两个箔之间的薄层。扫描范围在2°和40°2θ之间,其中对于STOE STADIP,在15秒/步下,步长为0.5°,对于D8 Bruker Advance,在1.28秒/步下,步长为0.009194171°。X射线粉末衍射图如图11、图12和图17所示。
表4:式(I)的化合物(晶体变型I和晶体变型II)的X射线粉末衍射(XRPD)
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实施例11.6:式(I)的化合物(无定形形式、晶体变型I和晶体变型II)的动态蒸汽
吸附
使用DVS Resolution重量吸附分析仪(伦敦,英国)测定晶体变型I和晶体变型II的水分吸附等温线。使用DVS Intrinsic仪器(Surface Measurement Systems SMS)测定无定形形式的水分吸附等温线。将样品在0%相对湿度(rH)下干燥1000分钟(无定形形式为1340分钟)。之后记录干重。湿度从10%逐步增加至90%rH(无定形形式为95%rH)然后再降至0%rH。各相对湿度设定点的平衡判据为每分钟0.002%相对质量变化(作为时间的函数)。动态蒸汽吸附等温线如图13、图14和图20所示。
表5:式(I)的化合物(无定形形式、晶体变型I和晶体变型II)的动态蒸汽吸附
实施例12:式(II)的化合物(晶体变型A)的X射线粉末衍射(XRPD)
在PANalytical X’Pert PRO衍射仪上记录X射线粉末衍射(XRPD)数据,使用Cu-Kα辐射源和位敏探测器,发生器设置为40kV和40mA。样品以过渡模式收集,制备成两个箔之间的薄层。扫描范围在2°和40°2θ之间,其中在25秒/步下,步长为0.013°。X射线粉末衍射图如图18所示。
表6:式(II)的化合物(晶体变型A)的X射线粉末衍射(XRPD)
实施例13:式(II)的化合物(实施例2.4)的生理功效评估
本发明的化合物用于治疗血栓栓塞性疾病的适用性可在以下测定系统中得以证明:
a)试验说明(体外)
a.1)FXIa抑制作用的测量
本发明的物质的XIa因子抑制作用使用生化试验系统测定,该系统利用肽XIa因子底物的反应来测定人XIa因子的酶活性。本文中,XIa因子从肽XIa因子底物中切割C端氨基甲基香豆素(AMC),测量其荧光性。在微孔板中进行测定。
将测试物质溶于二甲基亚砜中并在二甲基亚砜中连续稀释(3000μM至0.0078μM;试验中得到的最终浓度:50μM至0.00013μM)。在每种情况下,将1μL稀释的物质溶液置于购自Greiner的白色微孔板(384孔)的孔中。然后依次加入20μL测定缓冲液(50mM Tris/HClpH 7.4;100mM氯化钠;5mM氯化钙;0.1%牛血清白蛋白)和20μL购自Kordia的XIa因子(测定缓冲液中为0.45nM)。在孵育15min后,通过添加20μL购自Bachem的溶于测定缓冲液中的XIa因子底物Boc-Glu(OBzl)-Ala-Arg-AMC(测定缓冲液中为10μM)开始酶反应,将混合物在室温(22℃)下孵育30min,然后测量荧光性(激发:360nm,发射:460nm)。将含测试物质的测试批料和不含测试物质的对照批料(仅用二甲基亚砜替代二甲基亚砜中的测试物质)测得的发射强度进行比较,并根据浓度/活性关系计算IC50值。该试验的活性数据如下表A所示(部分为多次独立的单个测定的平均值)。
表A:
实施例编号 | IC50[nM] |
2.4 | 1.2 |
a.2)选择性的测定
为了证明物质对于FXIa抑制作用的选择性,检测测试物质抑制其他人丝氨酸蛋白酶(例如Xa因子、胰蛋白酶和纤溶酶)的潜力。为了测定Xa因子(购自Kordia,1.3nmol/L)、胰蛋白酶(购自Sigma,83mU/mL)和纤溶酶(购自Kordia,0.1μg/mL)的酶活性,将这些酶溶解(50mmol/L Tris缓冲液[C,C,C-三(羟甲基)氨基甲烷]、100mmol/L NaCl、0.1%BSA[牛血清白蛋白]、5mmol/L氯化钙,pH 7.4)并与于二甲基亚砜中的不同浓度的测试物质以及不含测试物质的二甲基亚砜一起孵育15min。然后通过添加合适的底物(Xa因子和胰蛋白酶的底物为5μmol/L购自Bachem的Boc-Ile-Glu-Gly-Arg-AMC,纤溶酶的底物为50μmol/L购自Bachem的MeOSuc-Ala-Phe-Lys-AMC)开始酶反应。在22℃下孵育30min后,测量荧光性(激发:360nm,发射:460nm)。将含测试物质的测试混合物和不含测试物质的对照混合物(仅用二甲基亚砜替代二甲基亚砜中的测试物质)测得的发射强度进行比较,并根据浓度/活性关系计算IC50值。
a.3)凝血酶生成测定(凝血酶生成图)
在根据Hemker的凝血酶生成测定中,在体外人血浆(购自Octapharma的)中测定测试物质的效果。
在根据Hemker的凝血酶生成测定中,凝血酶血浆的活性通过测量底物I-1140(Z-Gly-Gly-Arg-AMC,Bachem)的荧光切割产物而测定。反应在不同浓度的测试物质或相应溶剂的存在下进行。为了开始反应,使用购自Thrombinoscope的试剂(30pM至0.1pM重组组织因子、24μM于HEPES中的磷脂)。此外,还使用购自Thrombinoscope的凝血酶校准品,其酰胺水解活性用于计算含未知量的凝血酶的样品的凝血酶活性。根据制造商的说明书(Thrombinoscope BV)进行试验:将4μL测试物质或溶剂、76μL血浆和20μL PPP试剂或凝血酶校准品在37℃下孵育5min。在加入20μL于20mM Hepes中的2.5mM凝血酶底物、60mg/mLBSA、102mM氯化钙后,在120min内每20s测量一次凝血酶生成。使用购自Thermo Electron的配备有390/460nm滤光片对和分配器的荧光分析仪(Fluoroskan Ascent)进行测量。
使用Thrombinoscope软件计算并绘制凝血酶生成图。计算以下参数:滞后时间、达峰时间、峰值、ETP(内源性凝血酶潜能)和拖尾开始。
a.4)抗凝活性的测定
在体外人血浆和大鼠血浆中测定测试物质的抗凝活性。使用0.11摩尔柠檬酸钠溶液作为接收液直接抽取新鲜全血至柠檬酸钠/血的混合比为1:9。抽血后立刻彻底混合并以约4000g离心15分钟。上清液收集为(乏血小板)血浆。
凝血酶原时间(PT,别名:凝血活酶时间,快速检测)使用市售检测试剂盒(购自Boehringer Mannheim的或购自Instrumentation Laboratory的RecombiPlastin)在不同浓度的测试物质或相应溶剂的存在下测定。将测试化合物与血浆一起在37℃下孵育3分钟。然后通过添加凝血活酶开始凝血,并测定样品出现凝血的时间点。测定引起凝血酶原时间翻倍的测试物质的浓度。
活化部分凝血活酶时间(APTT)使用市售检测试剂盒(购自Roche的PTT试剂)在不同浓度的测试物质或相应溶剂的存在下测定。将测试化合物与血浆和PTT试剂(脑磷脂、高岭土)一起在37℃下孵育3分钟。然后通过添加25mM氯化钙开始凝血,并测定出现凝血的时间。测定引起APTT延长50%或翻倍的测试物质的浓度。
a.5)血浆激肽释放酶活性的测定
为了测定本发明的物质的血浆激肽释放酶抑制作用,使用生化试验系统,该系统利用肽血浆激肽释放酶底物的反应来测定人血浆激肽释放酶的酶活性。本文中,血浆激肽释放酶从肽血浆激肽释放酶底物中切割C端氨基甲基香豆素(AMC),测量其荧光性。在微孔板中进行测定。
将测试物质溶于二甲基亚砜中并在二甲基亚砜中连续稀释(3000μM至0.0078μM;试验中得到的最终浓度:50μM至0.00013μM)。在每种情况下,将1μL稀释的物质溶液置于购自Greiner的白色微孔板(384孔)的孔中。然后依次加入20μL测定缓冲液(50mM Tris/HClpH 7.4;100mM氯化钠溶液;5mM氯化钙溶液;0.1%牛血清白蛋白)和20μL购自Kordia的血浆激肽释放酶(测定缓冲液中为0.6nM)。在孵育15min后,通过添加20μL购自Bachem的溶于测定缓冲液中的底物H-Pro-Phe-Arg-AMC(测定缓冲液中为10μM)开始酶反应,将混合物在室温(22℃)下孵育30min,然后测量荧光性(激发:360nm,发射:460nm)。将含测试物质的测试批料和不含测试物质的对照批料(仅用二甲基亚砜替代二甲基亚砜中的测试物质)测得的发射强度进行比较,并根据浓度/活性关系计算IC50值。该试验的活性数据如下表B所示(部分为多次独立的单个测定的平均值)。
表B:
实施例编号 | IC50[nM] |
2.4 | 3.4 |
附图说明:
图1:实施例7中获得的固体的1H NMR
图2:实施例8中获得的固体的1H NMR
图3:式(I)的化合物(晶体变型I)的TGA曲线
图4:式(I)的化合物(晶体变型II)的TGA曲线
图5:式(I)的化合物(晶体变型I)的DSC曲线
图6:式(I)的化合物(晶体变型II)的DSC曲线
图7:式(I)的化合物(晶体变型I)的红外光谱
图8:式(I)的化合物(晶体变型II)的红外光谱
图9:式(I)的化合物(晶体变型I)的拉曼光谱
图10:式(I)的化合物(晶体变型II)的拉曼光谱
图11:式(I)的化合物(晶体变型I)的X射线粉末衍射(XRPD)
图12:式(I)的化合物(晶体变型II)的X射线粉末衍射(XRPD)
图13:式(I)的化合物(晶体变型I)的动态蒸汽吸附
图14:式(I)的化合物(晶体变型II)的动态蒸汽吸附
图15:式(I)的化合物(无定形形式)的TGA曲线
图16:式(I)的化合物(无定形形式)的DSC曲线
图17:式(I)的化合物(无定形形式)的X射线粉末衍射(XRPD)
图18:式(II)的化合物(晶体变型A)的X射线粉末衍射(XRPD)
图19:式(II)的化合物(晶体变型A)的1H NMR
图20:式(I)的化合物(无定形形式)的动态蒸汽吸附。
Claims (12)
1.具有下式(I)的(4S)-24-氯-4-乙基-73-氟-35-甲氧基-32,5-二氧代-14-(三氟甲基)-32H-6-氮杂-3(4,1)-吡啶-1(1)-[1,2,3]三唑-2(1,2),7(1)-二苯庚烷-74-甲酰胺的结晶形式
其为晶体变型I或晶体变型II。
2.根据权利要求1所述的式(I)的化合物的晶体变型I,其通过在20±5℃下并以Cu-Kα1作为辐射源测量的X射线粉末衍射图表征,所述X射线粉末衍射图显示出以2θ值±0.2°表示的至少以下反射:17.8、19.1、25.5。
3.根据权利要求1所述的式(I)的化合物的晶体变型II,其通过在20±5℃下并以Cu-Kα1作为辐射源测量的X射线粉末衍射图表征,所述X射线粉末衍射图显示出以2θ值±0.2°表示的至少以下反射:11.0、16.8、23.6。
4.根据权利要求1所述的式(I)的化合物的晶体变型I,其通过拉曼光谱表征,所述拉曼光谱显示出至少以下最大吸收波数(cm-1):1625、1239、991。
5.根据权利要求1所述的式(I)的化合物的晶体变型II,其通过拉曼光谱表征,所述拉曼光谱显示出至少以下最大吸收波数(cm-1):1623、1604、1336。
6.根据权利要求1所述的式(I)的化合物的晶体变型I,用于治疗和/或预防血栓形成性或血栓栓塞性疾病和/或血栓形成性或血栓栓塞性并发症。
7.根据权利要求1所述的式(I)的化合物的晶体变型II,用于治疗和/或预防血栓形成性或血栓栓塞性疾病和/或血栓形成性或血栓栓塞性并发症。
8.制备权利要求1所述的式(I)的化合物的晶体变型I的方法,其特征在于,将无定形形式的式(I)的化合物溶于惰性溶剂中,并以具有下式(II)的4-({(2S)-2-[4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丙酰基}氨基)-2-氟苯甲酰胺的晶体变型A为晶种使式(I)的化合物的晶体变型I结晶
9.根据权利要求8所述的方法,其特征在于,所述惰性溶剂选自乙腈、四氢呋喃、丙酮、乙酸乙酯、乙酸异丙酯、乙酸丁酯、丁-2-酮、1,4-二氧杂环己烷、2-甲基吡啶、4-甲基戊-2-酮、正庚烷、环己烷、甲基环己烷、2-(丙-2-基氧基)丙烷和2-甲氧基-2-甲基丙烷,和醇类如丁-1-醇、丁-2-醇、丙-2-醇、丙-1-醇、2-甲基丙-1-醇、乙醇和甲醇,和它们的混合物,以及所述溶剂与水的混合物。
10.根据权利要求8所述的方法,其特征在于,所述惰性溶剂为乙醇和水的混合物。
11.制备权利要求1所述的式(I)的化合物的晶体变型II的方法,其特征在于,将具有下式(III)的4-({(2S)-2-[4-{5-氯-2-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丁酰基}-氨基)-2-氟苯甲酰胺丙酮在烘箱中在减压下干燥,优选在50℃和10毫巴下干燥一天
12.具有式(II)的4-({(2S)-2-[4-{3-氯-2-氟-6-[4-(三氟甲基)-1H-1,2,3-三唑-1-基]苯基}-5-甲氧基-2-氧代吡啶-1(2H)-基]丙酰基}氨基)-2-氟苯甲酰胺
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