CN114539111A - 奥当卡替的盐及其制备方法和医药用途 - Google Patents
奥当卡替的盐及其制备方法和医药用途 Download PDFInfo
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- CN114539111A CN114539111A CN202111372621.9A CN202111372621A CN114539111A CN 114539111 A CN114539111 A CN 114539111A CN 202111372621 A CN202111372621 A CN 202111372621A CN 114539111 A CN114539111 A CN 114539111A
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- Prior art keywords
- salt
- hydrochloride
- dsc
- characteristic peaks
- amorphous
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 208000001685 postmenopausal osteoporosis Diseases 0.000 claims abstract description 6
- 102000004171 Cathepsin K Human genes 0.000 claims abstract description 5
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- 239000003112 inhibitor Substances 0.000 claims abstract description 5
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- 239000013078 crystal Substances 0.000 claims description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 18
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Abstract
本发明属于化学药物技术领域,提供了一系列的奥当卡替的盐。本发明还涉及包含这些化合物的盐的药物组合物以及使用该化合物的盐作为组织蛋白酶K抑制剂,用于治疗绝经后骨质疏松和肿瘤骨转移等疾病的药物中的用途。
Description
技术领域
本发明属于化学药物技术领域,提供了一系列的奥当卡替的盐。本发明还涉及包含这些化合物的盐的药物组合物以及使用该化合物的盐作为组织蛋白酶K抑制剂,用于治疗绝经后骨质疏松和肿瘤骨转移等疾病的药物中的用途。
背景技术
奥当卡替(Odanacatib,化合物A,CAS:603139-19-1)是一类组织蛋白酶K抑制剂,用于治疗绝经后骨质疏松和肿瘤骨转移等疾病:
已知的制备方法包括:US2013331597、CN1993314A、CN107001250A、CN108912020A。目前未有奥当卡替的盐报道。
发明内容
本发明为了更好的将该药物应用使用,提供了一系列的奥当卡替的盐。本发明还涉及包含这些化合物的盐的药物组合物以及使用该化合物的盐作为组织蛋白酶K抑制剂,用于治疗绝经后骨质疏松和肿瘤骨转移等疾病的药物中的用途。
具体而言,本发明提供式(I)所示奥当卡替的盐,
如图15所示,其中:
n为0.5-3;
M为酸,与奥当卡替成盐,所成盐选自盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、碳酸盐、碳酸氢盐、亚硫酸盐、亚硫酸氢盐、焦硫酸盐、磷酸一氢盐、磷酸二氢盐、高氯酸盐、过硫酸盐、半硫酸盐、重硫酸盐、硫氰酸盐、磷酸盐、焦磷酸盐、偏磷酸盐、甲酸盐、乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、丙酮酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、柠檬酸盐、4-硝基苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、丙炔酸盐、2-丁炔酸盐、2-羟基-乙烷磺酸盐、乙烯基乙酸盐、酒石酸盐、L-酒石酸盐、富马酸盐、羟乙基磺酸盐、马来酸盐、乳酸盐、乳糖酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚糖酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、草酸盐、三氟乙酸盐、三氟甲磺酸盐、己二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、羟基乙酸盐、藻酸盐、抗坏血酸盐、异抗坏血酸盐、天冬氨酸盐、L-天冬氨酸盐、谷氨酸盐、L-谷氨酸盐、2-苯氧基苯甲酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、乙酰乙酸盐、2-羟基乙磺酸盐、苯磺酸盐、硼酸盐、氯代苯甲酸盐、樟脑酸盐、衣康酸盐、樟脑磺酸盐、左旋樟脑磺酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、氨基磺酸盐、乳糖醛酸盐、半乳糖醛酸盐、环戊基丙酸盐、十二烷基硫酸盐、丙烯酸盐、环戊烷丙酸盐、甘油磷酸盐、甲氧基苯甲酸盐、二葡萄糖酸盐、葡萄糖酸盐、庚酸盐、己酸盐、2-羟基-乙磺酸盐、三甲基乙酸盐、葡糖醛酸盐、月桂酸盐、邻苯二甲酸盐、苯乙酸盐、月桂基硫酸盐、2-乙酰氧基苯甲酸盐、烟酸盐、肉桂酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、苯二甲酸盐、戊二酸盐、羟基马来酸盐、羟基苯甲酸盐、苯乙酸盐、3-羟基-2-萘甲酸盐、3-苯基丙酸盐、异丁酸盐、新戊酸盐、苦味酸盐、硬脂酸盐、2,2-二氯乙酸盐、酰化氨基酸盐、海藻酸盐、4-乙酰氨基苯磺酸盐、葵酸盐、胆酸盐、辛酸盐、壬酸盐、环拉酸盐、酞酸盐、盐酸半胱氨酸盐、山梨酸盐、帕莫酸盐、粘酸盐、盐酸甘氨酸盐、萘二磺酸盐、二甲苯磺酸盐、二盐酸胱氨酸盐、十一酸盐、聚乙烯磺酸盐、磺基水杨酸盐、苯基丁酸盐、4-羟基丁酸盐、聚乙烯硫酸盐、萘-1-磺酸盐、萘-2-磺酸盐或戊酸盐中的至少一种。
作为本发明的一种优选技术方案,n为0.5、1、1.5、2、2.5或3。
作为本发明的一种优选技术方案,所述盐选自盐酸盐和对甲苯磺酸盐。
作为本发明的一种优选技术方案,所述盐选自盐酸盐和对甲苯磺酸盐、n=1。
作为本发明的一种优选技术方案,所述盐为晶型、或者无定型,或其混合物。
作为本发明的一种优选技术方案,所述盐选自盐酸盐、n=1,所述盐为晶型,所述晶型的在9.78、17.67、18.59、19.64、20.06和23.75处有较强特征峰,误差为±0.2°;优选还在11.29、14.65、15.93、20.97和24.72处有特征峰,误差为±0.2°;进一步优选还在13.04、21.91、22.72、、25.57、26.32、27.17、27.95、29.07、31.84、32.45、34.40和37.72处有特征峰,误差为±0.2°;更优选X射线衍射图如图1或图4所示。
作为本发明的一种优选技术方案,所述晶型的DSC图谱所述晶型的DSC在205.2℃±5℃处有最大吸收峰;优选DSC图谱如图2或5所示;
作为本发明的一种优选技术方案,所述晶型的优选所述晶型的TG图谱如图3所示。
作为本发明的一种优选技术方案,所述盐选自对甲苯磺酸盐、n=1,所述盐为晶型,所述晶型的2θ角表示在16.76、17.61、17.93、18.36、19.06、19.76、20.08和21.63处有较强特征峰,误差为±0.2°;优选还在7.70、8.99、9.97、11.19、11.70、11.96、13.83、14.97、15.43、17.28、20.61、21.14、22.35、23.22、23.56、24.56、24.88、25.30、26.58、27.36和29.06处有特征峰,误差为±0.2°;进一步优选还在8.35、9.25、10.75、12.97、23.95、25.89、26.39、27.13、27.93、28.46、29.81、30.13、30.75、31.36、31.83、32.23、32.88、33.32、34.47、34.91、35.67、36.34、37.08、37.86和38.85处有特征峰,误差为±0.2°;更优选X射线衍射图如图6或图9所示。
作为本发明的一种优选技术方案,所述晶型的DSC图谱所述晶型的DSC在95.8℃±5℃处有最大吸收峰;优选DSC图谱如图7或10所示;
作为本发明的一种优选技术方案,所述晶型的优选所述晶型的TG图谱如图8所示。
作为本发明的一种优选技术方案,所述盐选自盐酸盐、n=1,所述盐为无定型,所述无定型的X射线衍射图中,无明显特征峰;优选所述无定型的XRPD如图11所示,DSC如图12所示。
作为本发明的一种优选技术方案,所述盐选自对甲苯磺酸盐盐、n=1,所述盐为无定型,所述无定型的X射线衍射图中,无明显特征峰;优选所述无定型的XRPD如图13所示,DSC如图14所示。
作为本发明的一种优选技术方案,所述化合物的一个以上的氢原子上被同位素氘取代。
本发明进一步提供了一种药物组合物,包括前述盐,和一种以上药学上可接受的载体。
本发明进一步提供了所述盐在制备用于制备作为组织蛋白酶K抑制剂,用于治疗绝经后骨质疏松和肿瘤骨转移等疾病的药物用途。
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
本发明化合物的盐是指“药学上可接受的盐”,由本发明的具有特定取代基的化合物与药学上可接受的酸或碱制备。
本发明的某些化合物的盐可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体,以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明化合物分子的原子是同位素,通过同位素衍生化通常可以延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。并且,包括一个实施方案,其中至少一个原子被具有相同原子数(质子数)和不同质量数(质子和中子和)的原子取代。本发明化合物中包括的同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子、氯原子,其分别包括2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl。特别的是,随其衰退而发射辐射的放射性同位素例如3H或14C可用于药物制剂或者体内化合物的局部解剖学检验。稳定的同位素既不随其量衰减或变化,也不具有放射性,因此其可以安全使用。当构成本发明化合物分子的原子是同位素时,通过用包含相应同位素的试剂替代合成中所用的试剂,可以根据通用方法转化同位素。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(2H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
进一步地,本发明的化合物一个或多个氢原子上被同位素氘(2H)取代,本发明化合物氘代后,具有延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。
所述同位素衍生物的制备方法通常包括:相转移催化方法。例如,优选的氘化方法采用相转移催化剂(例如,四烷基铵盐,NBu4HSO4)。使用相转移催化剂交换二苯基甲烷化合物的亚甲基质子,导致比在酸(例如,甲磺酸)存在下用氘化硅烷(例如三乙基氘化甲硅烷)或用路易斯酸如三氯化铝采用氘化硼酸钠还原而引入较高的氘。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质,代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息,可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005),该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“治疗”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物的盐基于化合物性质的特殊性,其成盐具有相当的难度,本发明的申请人意外地获得奥当卡替盐酸盐和对甲苯磺酸盐,所得的盐酸盐和对甲苯磺酸盐相对于化合物A本身,具有溶解性明显提高和稳定性明显改善的性质,预期可以更好的作为药物使用。
附图说明
图1,实施例1化合物A盐酸盐晶型XRPD谱图;
图2,实施例1化合物A盐酸盐晶型DSC谱图;
图3,实施例1化合物A盐酸盐晶型TG谱图;
图4,实施例2化合物A盐酸盐晶型XRPD谱图;
图5,实施例2化合物A盐酸盐晶型DSC谱图;
图6,实施例3化合物A对甲苯磺酸盐晶型XRPD谱图;
图7,实施例3化合物A对甲苯磺酸盐晶型DSC谱图;
图8,实施例3化合物A对甲苯磺酸盐晶型TG谱图;
图9,实施例4化合物A对甲苯磺酸盐晶型XRPD谱图;
图10,实施例4化合物A对甲苯磺酸盐晶型DSC谱图;
图11,实施例5化合物A盐酸盐无定型XRPD谱图;
图12,实施例5化合物A盐酸盐无定型DSC谱图;
图13,实施例6化合物A对甲苯磺酸盐无定型XRPD谱图;
图14,实施例6化合物A对甲苯磺酸盐无定型DSC谱图;
图15,化合物A的盐的结构示意图。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述,但发明的实施方式不限于此。
本发明所示的X-射线粉末衍射(XRD)谱图采用帕纳科锐影(Empyrean)X-射线衍射仪检测得到,检测条件:Cu-Kα辐射,波长发散狭缝1/4°,X射线光管电压45kV,X射线光管电流40mA,扫描范围3-40°(2θ),步长0.026°,每步扫描时间30.09s。
DSC谱图采用德国耐驰公司的Netzsch DSC-200同步热分析仪检测得到,检测条件:使用氮气气氛,升温速率为10℃/min,从30℃升温至特定温度。
TG谱图采用德国耐驰公司的Netzsch TG-209检测得到,检测条件:使用氮气气氛,升温速率10℃/min,从30℃加热至特定温度。
DVS谱图采用英国SMS(Surface measurement system)公司动态水分吸附仪(Dynamic vapour system)DVS Intrinsic 1测定。控制相对湿度以5%RH的梯度由0%-80%进行测试,当质量变化的速率小于2×10-3%min-1时,仪器系统将进入下一个湿度状态。
实施例A奥当卡替(V)的制备
参照CN107001250A公开的制备方法进行制备,具体地:
步骤1)、制备亚胺羧酸盐中间体(II)
将2,2,2-三氟-1-(4’-(甲基磺酰基)联苯-4-基)乙酮(III)41.8g(128mmol,1eq)、4-氟-L-亮氨酸乙酯(IV)23.7g(134mmol,1.05eq)加入到200mL甲醇中,搅拌溶解,加入44.0g(319mmol,2.5eq)无水碳酸钾。将反应体系加热至50±5℃反应4~5小时。冷却至25~30℃,滤去不溶物。滤液浓缩,残留物中加入乙酸乙酯1000mL打浆1小时。过滤,滤饼用乙酸乙酯200mL洗涤,干燥得到亚胺羧酸盐中间体(黄色固体)。
步骤2)、制备奥当卡替中间体羧酸(IA)
将亚胺羧酸盐中间体(II)65.0g(128mmol,1eq)加入到300mL甲醇中,加入无水氯化锌35.0g(256mmol,2eq)以及水18.4g(1.02mol,8eq),25~30℃搅拌反应30分钟。反应体系降温至-5~0℃,加入硼氢化锂11.3g(512mmol,4eq),控制体系反应温度在-5~5℃之间反应2~3小时。1N盐酸淬灭反应,调节pH至1~2,乙酸乙酯萃取(300mL*2),饱和盐水洗涤(100mL*2),无水硫酸钠干燥。过滤,滤液浓缩得到产物奥当卡替中间体羧酸。
步骤3)、制备奥当卡替中间体羧酸二环己胺盐(IB’)
将奥当卡替中间体羧酸(IA)38.0g(82.4mmol,1eq)溶于200mLMTBE中,加入二环己胺20.9g(115.4mmol,1.4eq),25~30℃搅拌反应2小时,析出白色固体。过滤,滤饼用MTBE洗涤,干燥得到奥当卡替中间体羧酸二环己胺盐。
步骤4)、制备奥当卡替(V)
将奥当卡替中间体羧酸二环己胺盐(IB’)34.0g(53.0mmol,1eq)与1-氨基环丙烷甲腈盐酸盐7.5g(63.6mmol,1.2eq)在150mL DMAc中搅拌溶解,加入HATU 24.2g(63.6mmol,1.2eq)。将体系降温至0~5℃,滴加DIPEA 20.5g(159mmol),维持体系温度在0~10℃。缓慢升温至室温反应3-4小时。反应完毕后将反应液加入到450mL水中,搅拌析出固体,过滤。滤饼用水洗涤,烘干,得到奥当卡替。
实施例1奥当卡替盐酸盐的制备
将526mg的奥当卡替溶解在2ml 1,4-二氧六环溶液中,然后加入约210mg17%的1,4-二氧六环氧盐酸溶液,搅拌1h,40℃浓缩得到奥当卡替盐酸盐固体,35℃真空干燥1d,重量收率98%。
1H NMR(DMSO-d6)δ8.8(1H,s),7.9-8.0(4H,dd),7.8(2H,d),7.5(2H,d),4.4(1H,s),3.0-3.4(6H,m),1.8-1.9(2H,m),1.3-1.4(7H,m),0.8(1H,m),0.6(1H,m)
奥当卡替盐酸盐晶型的Xray数据在9.79、17.68、18.60、19.64、20.06、23.71处有较强特征峰,误差为±0.2°;进一步优选X-Ray数据如下表所示;更优选XRPD如图1所示,DSC如图2所示,TGA如图3所示。
实施例2奥当卡替盐酸盐的制备
将526mg的奥当卡替溶解在2ml 1,4-二氧六环溶液中,加入约210mg17%的1,4-二氧六环氧盐酸溶液,然后加入6ml正己烷,搅拌24h,过滤,得到奥当卡替盐酸盐固体,35℃真空干燥1d,重量收率95%。
1H NMR(DMSO-d6)δ8.8(1H,s),7.9-8.0(4H,dd),7.8(2H,d),7.5(2H,d),4.4(1H,s),3.1-3.3(2H,m),1.8-1.9(2H,m),1.2-1.4(7H,m),0.8(1H,m),0.6(1H,m)
奥当卡替盐酸盐晶型的Xray数据在9.76、17.66、18.59、19.63、20.07和23.80处有较强特征峰,误差为±0.2°;进一步优选X-Ray数据如下表所示;更优选XRPD如图4所示,DSC如图5所示。
综合实施例1和2,按平均值计,盐酸盐晶型的2θ角表示在9.78、17.67、18.59、19.64、20.06和23.75处有较强特征峰,误差为±0.2°;优选还在11.29、14.65、15.93、20.97和24.72处有特征峰,误差为±0.2°;进一步优选还在13.04、21.91、22.72、、25.57、26.32、27.17、27.95、29.07、31.84、32.45、34.40和37.72处有特征峰,误差为±0.2°;更优选X射线衍射图如图1或图4所示。
实施例3奥当卡替对甲苯磺酸盐的制备
将526mg的奥当卡替,190mg对甲苯磺酸一水合物溶解在2ml丙酮或者乙腈溶液中,搅拌1h,40℃浓缩得到油状物,加入4ml异丙醚超声或者搅拌4h,得到奥当卡替对甲苯磺酸盐固体,35℃真空干燥1d,重量收率120%。
1H NMR(DMSO-d6)δ8.8(1H,s),7.8-8.0(4H,dd),7.7(2H,d),7.4(2H,d),4.7(6H,s),4.4(1H,s),3.4(3H,m),2.3(2H,m),1.8-2.0(2H,m),1.2-1.3(8H,m),0.8(1H,m),0.6(1H,m)。
奥当卡替对甲苯磺酸盐晶型的Xray数据在16.76、17.61、17.93、18.36、19.05、19.75、20.08和21.63处有较强特征峰,误差为±0.2°;进一步优选X-Ray数据如下表所示;更优选XRPD如图6所示,DSC如图7所示,TGA如图8所示。
实施例4奥当卡替对甲苯磺酸盐的制备
将526mg的奥当卡替,190mg对甲苯磺酸一水合物溶解在2ml丙酮溶液中,搅拌1h,加入4ml异丙醚或正己烷或甲基叔丁基醚,搅拌4h,得到奥当卡替对甲苯磺酸盐固体,35℃真空干燥1d,重量收率126%。
1H NMR(DMSO-d6)δ8.8(1H,s),7.9-8.0(4H,dd),7.8(2H,d),7.5(2H,d),4.7(6H,s),4.3(1H,s),3.4(3H,m),2.3(2H,m),1.8-1.9(2H,m),1.2-1.4(8H,m),0.8(1H,m),0.6(1H,m)。
奥当卡替对甲苯磺酸盐晶型的Xray数据在16.75、17.61、17.94、18.36、19.07、19.77、20.08和21.63处有较强特征峰,误差为±0.2°;进一步优选X-Ray数据如下表所示;更优选XRPD如图9所示,DSC如图10所示。
综合实施例3和4,按平均值计,对甲苯磺酸盐晶型的2θ角表示在16.76、17.61、17.93、18.36、19.06、19.76、20.08和21.63处有较强特征峰,误差为±0.2°;优选还在7.70、8.99、9.97、11.19、11.70、11.96、13.83、14.97、15.43、17.28、20.61、21.14、22.35、23.22、23.56、24.56、24.88、25.30、26.58、27.36和29.06处有特征峰,误差为±0.2°;进一步优选还在8.35、9.25、10.75、12.97、23.95、25.89、26.39、27.13、27.93、28.46、29.81、30.13、30.75、31.36、31.83、32.23、32.88、33.32、34.47、34.91、35.67、36.34、37.08、37.86和38.85处有特征峰,误差为±0.2°;更优选X射线衍射图如图6或图9所示。
实施例5奥当卡替盐酸盐无定型:
将526mg的奥当卡替溶解在2ml丙酮溶液中,加入约210mg17%的1,4-二氧六环氧酸溶液,搅拌1h,40℃浓缩,得到无定型固体。
其X射线衍射图中,无明显特征峰;优选XRPD如图11所示,DSC如图12所示。
实施例6奥当卡替对甲苯磺酸盐无定型:
将526mg的奥当卡替,190mg对甲苯磺酸一水合物溶解在4ml四氢呋喃溶液中,搅拌1h,40℃浓缩,得到无定型固体。
其X射线衍射图中,无明显特征峰;优选XRPD如图13所示,DSC如图14所示。
实施例7
参照实施例1-4的制备方法,选择其他酸:硫酸/马来酸/琥珀酸/苯甲酸/甲磺酸/草酸/醋酸/柠檬酸/山梨酸/富马酸/酒石酸/苹果酸/种氨基酸(色氨酸、亮氨酸、天门冬氨酸、组氨酸、精氨酸、丙氨酸),均未获得奥当卡替的对应酸盐。
实施例8
按照堆密度的测定方法进行测定,结果如下:
样品 | 堆密度/g/cm<sup>3</sup> |
奥当卡替-实施例A | 0.338 |
对甲苯磺酸盐-实施例3 | 0.443 |
盐酸盐-实施例1 | 0.504 |
实施例9
纯度检测方法如下:
将奥当卡替和对甲苯磺酸盐、盐酸盐放置在50℃和80℃的烘箱环境下,于不同时间点取样,检测纯度,结果如下:
实施例10
将奥当卡替和对甲苯磺酸盐、盐酸盐放置在92.5%RH,25℃的环境下,于不同时间点取样,采用实施例9的纯度检测方法检测纯度,结果如下:
实施例11
将奥当卡替和对甲苯磺酸盐、盐酸盐样品加入到纯水中配置过饱和溶液,超声5min后,过滤测定饱和溶解度,结果如下:
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (16)
1.奥当卡替的盐,其特征在于结构如式Ⅰ所示,
其中:
n为0.5-3;
M为酸,与奥当卡替成盐,所述盐选自盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、碳酸盐、碳酸氢盐、亚硫酸盐、亚硫酸氢盐、焦硫酸盐、磷酸一氢盐、磷酸二氢盐、高氯酸盐、过硫酸盐、半硫酸盐、重硫酸盐、硫氰酸盐、磷酸盐、焦磷酸盐、偏磷酸盐、甲酸盐、乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、丙酮酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、柠檬酸盐、4-硝基苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、丙炔酸盐、2-丁炔酸盐、2-羟基-乙烷磺酸盐、乙烯基乙酸盐、酒石酸盐、L-酒石酸盐、富马酸盐、羟乙基磺酸盐、马来酸盐、乳酸盐、乳糖酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚糖酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、草酸盐、三氟乙酸盐、三氟甲磺酸盐、己二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、羟基乙酸盐、藻酸盐、抗坏血酸盐、异抗坏血酸盐、天冬氨酸盐、L-天冬氨酸盐、谷氨酸盐、L-谷氨酸盐、2-苯氧基苯甲酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、乙酰乙酸盐、2-羟基乙磺酸盐、苯磺酸盐、硼酸盐、氯代苯甲酸盐、樟脑酸盐、衣康酸盐、樟脑磺酸盐、左旋樟脑磺酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、氨基磺酸盐、乳糖醛酸盐、半乳糖醛酸盐、环戊基丙酸盐、十二烷基硫酸盐、丙烯酸盐、环戊烷丙酸盐、甘油磷酸盐、甲氧基苯甲酸盐、二葡萄糖酸盐、葡萄糖酸盐、庚酸盐、己酸盐、2-羟基-乙磺酸盐、三甲基乙酸盐、葡糖醛酸盐、月桂酸盐、邻苯二甲酸盐、苯乙酸盐、月桂基硫酸盐、2-乙酰氧基苯甲酸盐、烟酸盐、肉桂酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、苯二甲酸盐、戊二酸盐、羟基马来酸盐、羟基苯甲酸盐、苯乙酸盐、3-羟基-2-萘甲酸盐、3-苯基丙酸盐、异丁酸盐、新戊酸盐、苦味酸盐、硬脂酸盐、2,2-二氯乙酸盐、酰化氨基酸盐、海藻酸盐、4-乙酰氨基苯磺酸盐、葵酸盐、胆酸盐、辛酸盐、壬酸盐、环拉酸盐、酞酸盐、盐酸半胱氨酸盐、山梨酸盐、帕莫酸盐、粘酸盐、盐酸甘氨酸盐、萘二磺酸盐、二甲苯磺酸盐、二盐酸胱氨酸盐、十一酸盐、聚乙烯磺酸盐、磺基水杨酸盐、苯基丁酸盐、4-羟基丁酸盐、聚乙烯硫酸盐、萘-1-磺酸盐、萘-2-磺酸盐或戊酸盐中的至少一种。
2.根据权利要求1所述奥当卡替的盐,其特征在于,n为0.5、1、1.5、2、2.5或3。
3.根据权利要求1所述奥当卡替的盐,其特征在于,所述盐选自盐酸盐和对甲苯磺酸盐。
4.根据权利要求1所述奥当卡替的盐,其特征在于,所述盐选自盐酸盐和对甲苯磺酸盐,n=1。
5.根据权利要求1-4任一项所述奥当卡替的盐,其特征在于,所述盐为晶型、或者无定型,或其混合物。
6.根据权利要求1所述奥当卡替的盐,其特征在于,所述盐选自盐酸盐、n=1,所述盐为晶型,所述晶型的在9.78、17.67、18.59、19.64、20.06和23.75处有较强特征峰,误差为±0.2°;优选还在11.29、14.65、15.93、20.97和24.72处有特征峰,误差为±0.2°;进一步优选还在13.04、21.91、22.72、、25.57、26.32、27.17、27.95、29.07、31.84、32.45、34.40和37.72处有特征峰,误差为±0.2°;更优选X射线衍射图如图1或图4所示。
7.根据权利要求6所述奥当卡替的盐,其特征在于,所述晶型的DSC图谱所述晶型的DSC在205.2℃±5℃处有最大吸收峰;优选DSC图谱如图2或5所示。
8.根据权利要求6所述奥当卡替的盐,其特征在于,所述晶型的优选所述晶型的TG图谱如图3所示。
9.根据权利要求1所述奥当卡替的盐,其特征在于,所述盐选自对甲苯磺酸盐、n=1,所述盐为晶型,所述晶型的2θ角表示在16.76、17.61、17.93、18.36、19.06、19.76、20.08和21.63处有较强特征峰,误差为±0.2°;优选还在7.70、8.99、9.97、11.19、11.70、11.96、13.83、14.97、15.43、17.28、20.61、21.14、22.35、23.22、23.56、24.56、24.88、25.30、26.58、27.36和29.06处有特征峰,误差为±0.2°;进一步优选还在8.35、9.25、10.75、12.97、23.95、25.89、26.39、27.13、27.93、28.46、29.81、30.13、30.75、31.36、31.83、32.23、32.88、33.32、34.47、34.91、35.67、36.34、37.08、37.86和38.85处有特征峰,误差为±0.2°;更优选X射线衍射图如图6或图9所示。
10.根据权利要求9所述奥当卡替的盐,其特征在于,所述晶型的DSC图谱所述晶型的DSC在95.8℃±5℃处有最大吸收峰;优选DSC图谱如图7或10所示。
11.根据权利要求9所述奥当卡替的盐,其特征在于,所述晶型的优选所述晶型的TG图谱如图8所示。
12.根据权利要求1所述奥当卡替的盐,其特征在于,所述盐选自盐酸盐、n=1,所述盐为无定型,所述无定型的X射线衍射图中,无明显特征峰;优选所述无定型的XRPD如图11所示,DSC如图12所示。
13.根据权利要求1所述奥当卡替的盐,其特征在于,所述盐选自对甲苯磺酸盐盐、n=1,所述盐为无定型,所述无定型的X射线衍射图中,无明显特征峰;优选所述无定型的XRPD如图13所示,DSC如图14所示。
14.根据权利要求1-13任一项所述奥当卡替的盐,其特征在于:所述化合物的一个以上的氢原子上被同位素氘取代。
15.一种药物组合物,其特征在于,包括前述权利要求1-14任一项所述奥当卡替的盐,和一种以上药学上可接受的载体。
16.根据权利要求1-14任一项所述奥当卡替的盐在制备用于制备治疗作为组织蛋白酶K抑制剂相关疾病的药物用途,优选用于治疗绝经后骨质疏松和肿瘤骨转移等疾病的药物用途。
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