CN100588647C - (2s,5z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸的结晶固体形式 - Google Patents
(2s,5z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸的结晶固体形式 Download PDFInfo
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- CN100588647C CN100588647C CN03820017A CN03820017A CN100588647C CN 100588647 C CN100588647 C CN 100588647C CN 03820017 A CN03820017 A CN 03820017A CN 03820017 A CN03820017 A CN 03820017A CN 100588647 C CN100588647 C CN 100588647C
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- acyl amino
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Abstract
本发明将(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸结晶成无水、化学计量的1.5 HCl盐,并公开一种可测量的结晶方法。对所述盐形式进行了表征,并确认手性中心的绝对构型为“S”。(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸是高熔点的,并呈现适用于药物组合物的可接受的非吸湿性。
Description
发明领域
本发明包括一种用于治疗疾病的新化合物,更具体为一种(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐的新盐及其药物组合物,用于治疗涉及由可诱导的一氧化氮合酶同工型不适宜地表达一氧化氮的症状。
在普通转让的2001年9月15日提交的美国申请序列号09/953,049中公开并要求专利保护(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸,该专利要求2000年9月15日提交的美国临时申请60/232,683的优先权,这二篇专利在此均被引用作为参考。(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸也在2002年5月21日公开的国际出版物WO 02/22562中作为描述,该专利是2001年9月15日提交的普通转让的国际专利申请PCT/US0128673的出版物,在此被引入作为参考。
发明背景
一氧化氮(NO)是由多种酶,一氧化氮合酶(NOS)的同工型中的任一种产生的生物活性自由基气体。后来被鉴定为NO的物质的生理活性最初是在20世纪80年代早期发现的,当时人们发现乙酰胆碱导致的血管舒缓依赖血管内皮的存在。由内皮衍生,因而称为内皮衍生的舒缓因子(EDRF)并介导这种血管舒缓的因子已知是通过一种NOS的同工型在血管内皮中产生的NO。NO作为血管扩张剂的活性已知有100多年。此外,NO是由已知的硝基血管舒张药,包括亚硝酸异戊酯和三硝酸甘油衍生的活性物质。一氧化氮还是一种可溶性鸟苷酸环化酶(cGMP)的内源性刺激物,因而刺激cGMP产生。如果NOS受到N-一甲基精氨酸(L-NMMA)抑制,则cGMP形成完全被防止。除了内皮依赖性舒缓之外,还已知NO涉及多种生物作用,包括吞噬性细胞的细胞毒性和中枢神经系统中细胞-细胞通讯。
EDRF鉴定为NO与NO由氨基酸L-精氨酸通过NO合酶合成的生物化学途径的发现一致。存在至少三种如下的NO合酶:
(i)组成型、依赖Ca++/调钙蛋白的酶,位于脑,对受体或生理刺激反应而释放NO;
(ii)不依赖Ca++的酶,一种130kD蛋白,它是由内毒素和细胞因子激活平滑肌、巨噬细胞、内皮细胞和许多其它细胞之后诱导的;和
(iii)组成型、依赖Ca++/调钙蛋白的酶,位于内皮,对受体或生理刺激反应而释放NO。
诱导型一氧化氮合酶(下文″iNOS″)一旦表达就长时间地不断产生NO。临床研究表明NO产生和iNOS表达在许多慢性炎症,例如类风湿性和骨关节炎(例如参见McInnes I.B.等人,J.Exp.Med.184:1519(1996))、炎性肠病(例如参见Lundberg J.O.N.等人,Lancet344:1673,(1994))和哮喘(例如参见Hamid,Q.等人,Lancet 342:1510(1993))中增加,而iNOS被认为是这些慢性炎性疾病中的主要病理因子。
因此,iNOS导致的过度NO产生的抑制作用可能是抗炎作用。但是,由于由eNOS和nNOS产生NO涉及正常生理学,所以优选任何用于治疗炎症的NOS抑制剂对iNOS有选择性,因此通过eNOS产生的NO导致的血压的正常生理调节和由nNOS产生的NO导致的非肾上腺素能、非胆碱能神经传递仍不受影响。
关于所有的药物化合物和组合物,药物化合物的化学和物理稳定性在药物的商业开发中是重要的。这种稳定性包括室温条件,特别是潮湿和储存条件下的稳定性。要预测商品使用期限期间的不同的可能储存条件需要提高不同储存条件下稳定性。稳定的药物可避免使用特定的储存条件和频繁的库存置换。药物化合物还必需在生产过程中稳定,生产过程经常要求研磨药物以获得具有均一粒径和表面积的药物。不稳定的药物通常发生多形态变化。因此,任何提高稳定性特征的药物修饰相对于较不稳定化合物都提供有意义的益处。
已描述了许多iNOS的抑制剂,例如2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸,其在2002年3月21日公开的普通转让的国际公开WO 02/22562中作了描述,所述专利是2001年9月15日提交的国际专利申请PCT/US0128673的出版物。但是,该化合物是无定形固体。因此优选提供一种结晶固体形式的iNOS抑制剂,例如2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸。
发明概述
本发明涉及一种新的结晶盐(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐、药物组合物、用于制备该新盐化合物的方法、药物组合物的制备方法以及使用该新盐化合物和组合物抑制或调节需要这种抑制或调节的受试者的一氧化氮合成的方法,所述方法施用相对于组成型一氧化氮合酶同工型优先抑制或调节可诱导的一氧化氮合酶同工型的化合物的盐。本发明的盐化合物具有有用的一氧化氮合酶抑制活性,并预期用于治疗或预防一氧化氮的合成或过度合成形成作用原因的疾病或症状。
化学计量地,该新盐的晶胞是二个(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸分子和三个盐酸分子。
该新盐表征为某些或所有以下物理度量:元素分析(例如通过燃烧分析)、熔点和熔解热(差示扫描量热法和热重量分析)、折射率(偏光显微术)、X射线粉末衍射图、吸湿(例如DVS湿平衡)和振动特征(拉曼光谱)。
本发明的新盐可以用于治疗包括在某些症状如关节炎下发生的软骨退化。因此,在抑制从L-精氨酸产生NO方面有利的症状包括关节炎症状,例如类风湿性关节炎、骨关节炎、痛风性关节炎、青少年关节炎、脓毒性关节炎、脊关节炎、急性风湿性关节炎、肠病性关节炎、神经性关节炎和化脓性关节炎。此外,NO诱导的软骨细胞呼吸抑制作用可以调节关节炎,特别是骨关节炎中的胞间质损失和继发性软骨矿化。
本发明的盐可以应用的其它症状包括慢性或炎性肠病、心血管局部缺血、糖尿病、充血性心衰、心肌炎、动脉粥样硬化、偏头痛、青光眼、主动脉瘤、反流性食管炎、腹泻、过敏性肠综合征、囊性纤维化、气肿、哮喘、支气管扩张、痛觉过敏、大脑局部缺血、血栓形成性中风、全脑缺血(心搏停止继发)、多发性硬化和其它NO介导的中枢神经系统病症如帕金森氏症和阿耳茨海默氏病。NO抑制可以应用的其它神经变性病症包括病症如缺氧、低血糖、癫痫和外伤(如脊髓和头损伤)、高压性氧惊厥和毒性、痴呆如早老性痴呆和与AIDS相关的痴呆、西德纳姆舞蹈病、杭廷顿氏舞蹈病、肌萎缩性侧索硬化、科尔萨科夫病、与大脑血管病有关的痴愚、睡眠障碍、精神分裂症、抑郁、与经前期综合征(PMS)有关的抑郁或其它症状、焦虑和脓毒性休克中的神经变性和/或神经坏死。
还可以在以下情况下使用本发明的盐:一氧化氮抑制作用还在治疗如疼痛,包括躯体原的(感受伤害的或神经性的)、急性和慢性疼痛中起作用。本发明的化合物可以在任何常规施用普通NSAID或鸦片样镇痛剂的情况下使用。
其中可以用本发明的盐抑制从L-精氨酸产生NO的其它症状包括与多种物质试剂导致的脓毒和/或毒性休克有关的系统性高血压;与细胞因子如TNF、IL-1和IL-2一起治疗;和作为移植治疗中的短期免疫抑制的助剂。
本发明的盐还用于治疗眼病(例如眼高血压视网膜炎葡萄膜炎)、系统性红斑狼疮(SLE)、肾小球性肾炎、再狭窄、病毒感染的炎性后遗症、急性呼吸窘迫综合征(ARDS)、氧化剂诱导的肺损伤、IL2治疗(如癌患者中)、恶病质,免疫抑制(如移植治疗)、胃肠运动疾病、晒斑、湿疹、牛皮癣、龈炎、胰腺炎、感染导致的胃肠道损害、囊性纤维化、对免疫系统功能障碍的治疗(如作为器官移植治疗中的短期免疫抑制的助剂)、引产、腺瘤性息肉、控制肿瘤生长、化学治疗、化学预防和支气管炎。
本发明还涉及用于治疗疼痛,哮喘和其它气道病症、癌症、关节炎、包括视网膜病和青光眼的眼病、包括过敏性肠综合征的炎症相关病症、和其它其中过量产生一氧化氮起作用的病症的药物组合物,所述组合物包含治疗有效量的结晶(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐和药学上可接受的载体、稀释剂或赋形剂。
除了用于人治疗之外,这种形式还用于宠物动物、外来动物和家畜,包括哺乳动物、鸟等的兽医治疗。更优选的动物包括马、狗和猫。
附图简述
图1是本发明的2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl结晶的晶胞图;
图2是本发明2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl的差示扫描量热法研究图;
图3是2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl的粉末X射线图;
图4是与2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5HCl的粉末X射线图重叠的单晶结构的计算的X射线粉末图;
图5是本发明的-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl的热重量分析图;和
图6是本发明的(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸的1.5 HCl盐的拉曼光谱。
发明详述
1.定义
本文所用的术语“治疗”包括预防性、减轻性治疗或恢复健康的治疗。
术语“有效量”意指有益于治疗的剂量。有效量可以单一剂量施用,或者以分开的剂量在一段时间内施用。
术语“球粒状”意指采用大约球粒的形式。
术语“球粒”意指结晶聚集体的普遍形式,其存在于大量不同的物质中,其特征在于导致球对称的径向生长。
缩写
ACN或CH3CN是乙腈
AcOH是乙酸
CH2Cl是氯甲烷
DIBAL是二异丁基氢化铝
DMF是二甲基甲酰胺
Et3N是三乙基胺
EtOAc是乙酸乙酯
KHMDS是六甲基二硅氮化钾
KOH是氢氧化钾
MeI碘甲烷
MS是质谱
MSCl是甲磺酰氯
NaHCO3是碳酸氢钠
Na2SO4是硫酸钠
THF是四氢呋喃
本发明还包括一类包含结晶(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐和一种或多种无毒、药学上可接受的载体和/或稀释剂和/或助剂(本文总称为“载体”物质)以及可能存在的其它活性成分的药物组合物。本发明的结晶形式的(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐可以通过任何适宜的途径,优选以适于这种途径的药物组合物的形式给药,并以有效于目的治疗的剂量给药。例如,活性(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐和组合物可以口、血管内、腹膜内、皮下、肌内或局部给药。
为进行口服,所述药物组合物可以例如为片剂、胶囊、悬浮液或液体的形式。所述药物组合物优选制成包含特定量活性成分的剂量单元。这些剂量单元的实例为片剂或胶囊。活性成分还可以作为组合物注射给药,其中例如可以将盐水、右旋糖或水用作适宜的载体。
治疗活性化合物的给药量和采用本发明化合物和/或组合物进行的病症的剂量方案取决于多个因素,包括受试者的年龄、重量、性别和健康症状,疾病的严重程度,给药途径和频率和所用的特定化合物,因而可以有很大变化。所述药物组合物可以包含范围为大约0.1-2000mg,优选范围为大约0.5-500mg,最优选大约1-100mg的活性成分。大约0.01-100mg/kg体重,优选大约0.5和大约20mg/kg体重,且最优选大约0.1-10mg/kg体重的日剂量可能是合适的。日剂量可以每天施用1-4个剂量。
还可以通过透皮装置施用结晶(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐。优选局部给药使用贮器和多孔膜类型或固体基质种类的贴剂来完成。在任一情况下,通过膜连续地将贮器或微胶囊中的活性剂递送至与受者的皮肤或粘膜接触的活性剂可渗透的粘合剂。如果活性剂通过皮肤吸收,则将受控的和预定的活性剂流施用于受者。在微胶囊的情况下,胶囊化剂还可以起膜的作用。
本发明乳剂的油相可以由已知的成分以已知的方式构成。虽然该相可以仅包含一种乳化剂,但它可以包含至少一种含脂肪或油或者脂肪和油两者的乳化剂。优选亲水性乳化剂与用作稳定剂的亲脂性乳化剂一起包含。它还优选包含油和脂肪两者。含有或不合有稳定剂的乳化剂组成所谓的乳化蜡,而该蜡与油和脂肪一起组成所谓的乳化软膏基质,它形成乳膏制剂的油分散相。适用于本发明制剂的乳化剂和乳化稳定剂包括Tween 60、Span 80、鲸蜡硬脂醇、肉豆蔻醇、一硬脂酸甘油酯和月桂基硫酸钠等。
用于制剂的适宜的油或脂肪的选择基于获得目标化妆品性能,因为可能用于药物乳剂的大部分的油中活性化合物的溶解性是非常低的。因此,乳膏应该优选是不油腻的、不染色的和可洗涤的产品,具有避免从管或其它容器中泄漏的适宜的稠度。可以使用直链或支链、一元或二元烷基酯如二异己二酸酯、硬脂酸异鲸蜡酯、椰子脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、2-乙基己基棕榈酸酯或支链酯的混合物。这些物质可以单独或组合使用,这取决于所需的性能。或者可以使用高熔点脂类如白色软石蜡和/或液体石蜡或其它矿物油。
适于对眼局部给药的制剂还包括眼滴剂,其中活性成分溶解或悬浮在适宜的载体中,特别是活性成分的水性溶剂中。这种制剂中抗炎活性成分优选的存在浓度为0.5-20%,有利地为0.5-10%,特别是大约1.5%w/w。
为治疗目的,通常将结晶(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐与一种或多种适于所指示的给药途径的助剂组合。如果进行口服给药,则可以将化合物与乳糖、蔗糖、淀粉、链烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠和钙盐、明胶、阿拉伯胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合,然后制片剂或胶囊以方便给药。这些胶囊或片剂可以包含控释制剂,它可以在羟丙基甲基纤维素中分散活性化合物而提供。用于肠胃外给药的制剂可以是水性或非水等渗无菌注射液或悬浮液的形式。这些溶液和悬浮液可以由具有一种或多种所述的用于口服制剂的载体或稀释剂无菌粉末或颗粒制备。结晶形式B可以溶于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄基醇、氯化钠和/或不同缓冲剂中。其它给药助剂和方式在药学技术中是公知的。
可以根据以下所示的一般方案制备无定形的(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐:
一般合成方案
a)KOH b)MeI c)TBSCl d)DIBAL e)MsCl F)3-甲基-1,2,4-噁二唑啉-5-酮钾盐g)AcOH h)Tf2O i)KHMDS/(2S,4S)-3-苯甲酰基-2-叔丁基-4-甲基-1,3-噁唑烷-5-酮j)林德乐催化剂k)6N HCl
实施例1-制备(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐:
(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
EX-1A)(Z)-5-叔丁基二甲基甲硅烷氧基-2-戊烯-1-醇(EX-1A)由5,5-二氢-2-吡喃酮(Aldrich)通过Harold,Mohr和TammHelvetica Chimica Acta 66,2,1983744-754的方法制备。
EX-1B)往在CH2Cl2(25mL)中的EX-1A(720mg,3.3mmol)的溶液加入Et3N(525mg,5.3mmol)和甲磺酰氯(561mg,4.90mmol)。将反应混合物于0℃下搅拌15分钟,然后在室温下搅拌16小时。加入附加的CH2Cl2,用NaHCO3、盐水萃取溶液,并干燥得到790mg黄色油。将油溶于DMF(20mL),并加入(513mg,3.7mmol)。将所得的溶液于50℃下搅拌16小时。在真空下除去溶剂,用EtOAc和盐水分配残余物。将有机层干燥(Na2SO4),并浓缩得到一种油,用快速硅胶柱色谱法纯化,用醚∶己烷(1∶1)洗脱得到780mg g(79%)目标受保护的Z-烯丙型环脒产物,为一种澄清的油,通过1HNMR表明它仅包含目标Z-异构体。
EX-1C)将在乙酸(1mL)、THF(3mL)和水(1mL)的混合物中的EX-1B(100mg,0.34mmol)的溶液于室温下搅拌16小时。将所得的溶液真空浓缩至油,将其溶于EtOAc。有机层用饱和的NaHCO3洗涤,干燥(Na2SO4),过滤并蒸发得到80mg(定量)目标醇产物,为一种澄清的无色油。
EX-1D)在0℃下往EX-LC(80mg,0.43mmol)的CH2Cl2(3mL)溶液中加入Et3N(44mg)和三氟甲磺酸酐(triflic anhydride)(146mg,0.52mmol),将混合物搅拌1.5小时。将溶液真空浓缩,并往所得的黄色浆中加入EX-2D(0.15g,0.74mmol)的CH2Cl2(1.5mL)溶液。用快速硅胶柱色谱法纯化粗物质,用EtOAc∶己烷(1∶1)洗脱得到62mg(44%)目标三氟甲磺酸(triflate)产物,为一种澄清的油。
EX-1E)在-78℃下往(2S,4S)-3-苯甲酰基-2-叔丁基-4-甲基-1,3-噁唑烷-5-酮(参照)(532mg,2.04mmol)的THF(10mL)溶液中加入KHMDS(4.48mL,2.2mmol,0.5M,在THF中)。将所得的橙色溶液搅拌15分钟,然后加入EX-ID(580mg,1.8mmol)。将所得的溶液加热至室温,然后加入KHSO4(10%,1.5mL)盐水和EtOAc。将有机层分离,干燥,并真空浓缩得到960mg黄色油。用快速硅胶柱色谱法纯化粗物质,用EtOAc∶己烷(1∶1)洗脱得到138mg(18%)目标烷基化产物,为一种澄色油。
EX-1)往EX-1E(138mg,0.32mmol)的甲醇(10mL)溶液中加入林德乐催化剂(260mg)。将搅拌的浆回流2小时,然后冷却至室温。用硅藻土过滤除去催化剂,并汽提滤液得到目标脱保护的脒产物,为一种浅黄色油。将在HCl(6N,10mL)中的黄色油的溶液回流1.75小时。在真空下除去溶剂,并用反相HPLC法将所得的泡末纯化,用30分钟的0-40%CH3CN/H2O(0.25%乙酸)梯度洗脱。合并包含产物的级分,并浓缩成泡沫。将产物溶于1N HCl,并在真空下除去溶剂(2x)以得到34mg(20%)目标(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐产物。MS计算值C10H19N3O2:m/z=214[M+H]+,实测值:214。(100%)1H NMR(D2O)δ1.40(s,3H),1.5-2.0(m,4H)1.90(s,3H),3.55(m,2H)5.15-5.25(m,乙烯基,1H),5.30-5.45(m,乙烯基,1H)。
表I:分析
实施例2-制备结晶形式的(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸
结晶
含过量盐酸盐的无定形物(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸自由溶于水、甲醇和乙醇,并溶于异丙醇和多种含水溶剂如在THF中的10%水、水饱和的乙酸乙酯、在乙腈中的10%水和含水高级醇。该无定形物在以下受试的无水溶剂中的不溶性达到明显小于1mg/ml:丙酮、MEK、甲基异丁基酮、THF、乙酸乙酯、氯仿、二氯甲烷、己烷、环己烷、二异丙醚、乙腈和甲苯。
将大约460mg(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸溶于10ml HPLC级水中。将已从盐酸盐形式转化成氢氧化物形式的安伯来特IRA400离子交换树脂用于滴定(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸的溶液至pH10.7。氯化物选择性电极表明氯化物减少到200ppm。用Millipore 5μm LS膜将此溶液过滤,并将溶液冻干。对冻干固体进行元素分析,表II,表明氯化物减少到0.25当量,它与200ppm离子选择电极读数一致。
表II
元素分析结果:通过相对于理论值的燃烧分析测定的;重量百分数
元素 | 理论OHCl | 理论0.25HCl | 测定的(双份) |
碳 | 56.3 | 51.96 | 52.47/52.06 |
氢 | 8.98 | 8.72 | 8.89/8.96 |
氮 | 19.7 | 18.18 | 18.16/17.96 |
氯 | 0 | 3.83 | 3.98 |
将盐酸盐,(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸溶于水、各种低级醇、THF-水、乙腈-水和水饱和的乙酸乙酯以得到浓溶液。将上列的反溶剂用于从溶液中得到盐。液-液相离去,在所有情况下获得乳液和玻璃状沉淀。还用少数系统建立蒸汽扩散单元,排它地产生乳液相离去。
旋转蒸发盐酸盐样品,溶解,冻干,并在通风橱中静置4-6周。样品开始自发改变。使用偏振光显微镜检查表明发生结晶。接近一半体积的样品变得无色,并从不结晶,但接近一半的发生结晶。在使用多种溶剂的结晶实验中将某些物质用作种晶,以由(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸盐酸盐得到更多结晶物质。如果有的话,出现非常少的结晶,且然后仅非常慢地结晶。通过偏振光显微镜检查法检测各批的结晶来证明多晶形。结晶习性和光学性能保持与一种形式一致。各批的结晶是双轴的,表现出高双折射面和低双折射面n1-n2<0.006,且光轴出现于低双折射面。
通过用能量分散光谱学SEM/EDS进行扫描电子显微镜检查或进行热载物台偏振光显微镜检查未观察到溶剂化的证据。具有如果不溶解结晶则不能完全除去的变色油相的结晶的低共熔点为大约210℃。
从第一样品中分离许多大结晶以进行结构测定。单位晶胞的化学计量确定为:二个独立的(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸分子和三个HCl。未观察到溶剂化。间隔基为P1(三斜晶系)和晶胞a=8.1623,b=9.0524,c=10.5937,α=71.522,β=73.472,γ=86.086。2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸的绝对构型证明为″S″。
将大约1.5g的(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸,(2.5HCl×2.0 H2O)溶于5.0ml H2O,并加入安伯来特OH树脂以滴定至pH 7,如pH电极和计量器测定。用5μm LS Millipore过滤器将溶液过滤,并冻干得到903mg一盐酸盐。将冻干物质实质上溶于6.0ml含0.38%H2O的异丙醇,然后加入HCl(150μL,12M)以形成倍半盐酸盐。将此混合物搅拌,然后超声处理以在室温下搅拌过夜,以确保饱和和平衡。然后加入种晶(大约0.1mg)并持续搅拌。在数分钟内观察到开始结晶,并在3小时内大量出现。将溶液在室温下搅拌48小时。过滤收集结晶,用少量异丙醇洗涤,并在40℃下真空干燥得到860mg,理论的89%的白色固体。
可以认识到对(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸溶液“种晶”可以在所述条件下开始或增加成核作用。结晶可得自Pharmacia Corporation,4901 Searle Parkway,Skokie,Illinois,US A 60077。
进行二个类似的实验。将数百毫克(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸在异丙醇中溶解至大约与前述实验中的冻干物相同的浓度。不调整盐酸盐浓度。对此系统种晶,并在室温下搅拌。未观察到结晶。在下一步实验中,用浓氢氧化钠将溶液的pH调节至pH 3并种晶。获得一些结晶产物,但产率仅为大约30-40%。加入醚将产率增加至接近90%。
实施例3-表征(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸结晶盐
通过偏振光显微镜检查表明固体2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl是结晶,且微晶尺寸数量级为1微米。聚结的颗粒为球状。通过物理方法对2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl进行元素分析得到与未发生溶剂化的1.5 HCl盐的理论值非常紧密一致的结果,参见表III。库仑KarlFischer水分析发现0.6%水,0.09当量,为二个度量的平均值。
表III
2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl的元素分析结果
通过相对于理论的燃烧分析来测定;重量百分数
元素 | 测定的(双份) | 理论1.5 HCl |
碳 | 44.56/44.57 | 44.82 |
氢 | 7.87/7.93 | 7.71 |
氮 | 15.58/15.60 | 15.68 |
氯 | 19.61/19.68 | 19.85 |
(2S,5Z)-2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5HCl的偏振光显微镜检查发现折射指数nd α1.508,β大约1.59,γ1.608,阴性光学标记和2V接近37度。光轴的强烈分散在干涉图中明显。
差示扫描量热法(DSC)发现在单一熔化点为224℃,而熔解热为147焦耳克-1(参见图2)。
图3显示2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5HCl的粉末X射线图。
参照图4,由与2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl的粉末X射线图重叠的单一结晶结构计算的X射线粉末图与温度差别的公差符合得非常好。在120°K下收集单一结晶数据,并在室温下收集粉末X射线数据。
通过热重量分析(TGA)未观察到质量损失直至熔解开始(见图5)。通过TGA表明熔解期间观察到0.47%损失。
结晶2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl是不吸湿的,处于和低于70%相对湿度。由DVS湿度平衡确定的2-氨基-7-(乙亚胺酰基氨基)-2-甲基庚-5-烯酸1.5 HCl在25℃下的吸湿表明在70%相对湿度(R.H.)下水分增加0.91%,在80%R.H.下增加18.5%,而在90%R.H.下增加76.8%。仪器循环回至低相对湿度,并移出样品,然后通过偏振光显微镜检查进行测定。在从湿平衡中移出之后样品完全结晶,但结晶尺寸增大。通过PLM容易观察到的光学性能表明结晶形式未发生变化,但至少一些样品潮解并在干燥时重结晶。表IV表明由DVS湿平衡确定的详细数据。该盐形式,1.5 HCl没有溶剂化。
表IV
白色结晶固体
MP 253
白色结晶固体
MP 229.33
Claims (3)
1.结晶形式的(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸的1.5盐酸盐,所述结晶形式具有附图3描述的粉末X射线图。
2.一种包含有效量的权利要求1所述的结晶形式的(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸的1.5盐酸盐和药学上可接受的载体的药物组合物。
3.权利要求1所述的结晶形式的(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸的1.5盐酸盐在制备预防或治疗一氧化氮合酶抑制剂适用的临床症状的药物中的应用。
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