CN102124010A - 具有血管舒张活性的硝酸异山梨酯 - Google Patents
具有血管舒张活性的硝酸异山梨酯 Download PDFInfo
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- CN102124010A CN102124010A CN2009801321115A CN200980132111A CN102124010A CN 102124010 A CN102124010 A CN 102124010A CN 2009801321115 A CN2009801321115 A CN 2009801321115A CN 200980132111 A CN200980132111 A CN 200980132111A CN 102124010 A CN102124010 A CN 102124010A
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Abstract
本发明涉及在血栓形成和冠状动脉缺血模型中具有优异药理活性的新的3-取代6-硝氧基-六氢呋喃并[3,2-b]呋喃衍生物。
Description
发明领域
本发明涉及具有强力血管舒张活性和延长的作用时间的单硝酸异山梨酯的新衍生物。
背景技术
有机化合物的硝酸酯,通常称为硝化有机化合物,是已知的并且在一段时期内被用作血管舒张剂。其中,单硝化异山梨酯和二硝化异山梨酯的效用是已知的,此外,已经描述了具有血管活性和冠状动脉活性的基于单硝酸异山梨酯的游离羟基的取代反应的化合物。例如专利US-A-4891373描述了用于治疗心绞痛和全身性高血压以及肺动脉高血压的胺丙醇衍生物。
专利US-A-5665766描述了5-单硝酸2-乙酰水杨酸异山梨酯及其抗血小板聚集活性。
上述硝化有机化合物的一个主要问题是其对与称为快速耐受性或耐受性的现象有关的非常敏感的事实,所述事实存在于长期治疗期间对化合物效果减弱的机体反应,接着必须谨慎地并逐渐地增加给药剂量或进行药理洗脱(pharmacological wash-out)中。
还已知降低硝化有机化合物耐受性的一种方法是在分子中引入硫醇基,例如通过使用含氨基酸的硫来引入硫醇基。因此,欧洲专利EP-B-0362575描述了含有半胱氨酸并主要含有甲硫氨酸分子的硝化有机化合物。
专利申请WO-A-92/04337描述了具有血管舒张活性和降低的耐受性的噻唑环的有机硝化衍生物。
专利申请WO-A-93/03037描述了大量具有降低耐受性的高度可变结构的不同的硝化有机血管舒张化合物。
专利申请WO-A-00/20420描述了单硝酸异山梨酯,其中用羧酸或硫代酸来酯化游离羟基,其中所述酯基位于硝基的反式位置。
最后,专利申请WO-A1-2005/037842描述了单硝酸异山梨酯,其中游离羟基被广泛的取代基取代。
然而,本领域所述的化合物由于其有限的作用时间,所以并非完全令人满意。
现在已经惊奇地发现某些化合物,其中一些化合物已经在专利申请WO-A1-2005/037842中要求但未公开,其不仅具有高抗血栓形成活性和高血管舒张活性,而且具有比所述专利申请中描述的其结构同源物更长的作用时间。
发明概述
本发明的目的是提供新的3-取代6-硝氧基-六氢呋喃并[3,2-b]呋喃衍生物,所述衍生物在血栓形成模型和冠状动脉血管舒张模型中具有比本领域所述的其结构类似物更佳的药理活性,并且所述衍生物还表现出更长的作用时间。
本发明的另一目的是提供包含至少一种所述3-取代6-硝氧基-六氢呋喃并[3,2-b]呋喃衍生物的药物组合物。
同样,本发明的另一目的是所述新的3-取代6-硝氧基-六氢呋喃并[3,2-b]呋喃衍生物在制备用于治疗诸如心血管机能障碍和冠状动脉机能障碍的循环系统机能障碍的药物中的用途。
发明详述
本发明涉及式(I)的化合物,其互变异构体、药物可接受的盐、前药或溶剂化物:
其中,G表示-(C=O)-S-基团或-S(O)n-基团,n为选自0、1和2的整数;并且
R表示选自C1-C3烷基和C3烯基的基团;
条件是当R是甲基时,R-G-基团和-ONO2基团在顺式位置。
如下式所示,根据硝酸酯(-ONO2)和R-G-基团的相对方位,式(I)的化合物能够为顺式或反式异构体的形式:
此外,当在式(I)的化合物中,G表示亚砜基-(S=O)-时,作为亚砜基中硫原子手性性质的结果,有四种可能的非对映异构体。
本发明的实施方案涉及式(I)的化合物,其互变异构体、药物可接受的盐、前药或溶剂化物,其中R表示甲基,G表示-(C=O)-S-基团或-S(O)n-基团,n为选自0、1和2的整数,并且其中R-G-基团和-ONO2基团在顺式位置。
本发明的另一实施方案涉及式(I)的化合物,其互变异构体、药物可接受的盐、前药或溶剂化物,其中R表示选自C2-C3烷基和C3烯基的基团,并且G表示-(C=O)-S-基团或-S(O)n-基团,n为选自0、1和2的整数。
本发明的另一实施方案涉及式(II)的化合物,其互变异构体、药物可接受的盐、前药或溶剂化物:
其中n是选自1和2的整数;并且
R表示选自C2-C3烷基和C3烯基的基团。
本发明的另一实施方案涉及式(III)的化合物,其互变异构体、药物可接受的盐、前药或溶剂化物:
其中R表示选自C2-C3烷基和C3烯基的基团,其更优选为乙基、正丙基或烯丙基。
本发明的另一实施方案涉及式(VII)的化合物,其互变异构体、药物可接受的盐、前药或溶剂化物:
其中R表示选自C2-C3烷基和C3烯基的基团,其更优选为乙基、正丙基或烯丙基。
本发明的又一实施方案涉及式(IV)的化合物,其互变异构体、药物可接受的盐、前药或溶剂化物:
具体优选的化合物为:
(3R,3aS,6S,6aS)-6-(乙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((S,R)-乙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((S)-乙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((R)-乙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-(乙磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-(丙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((S,R)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((S)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((R)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-(丙磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-(烯丙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((S,R)-烯丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((S)-烯丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-((R)-烯丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6S,6aS)-6-(烯丙基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-(乙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((S,R)-乙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((S)-乙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((R)-乙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-(乙磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-(丙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((S,R)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((S)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((R)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-(丙磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-(烯丙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((S,R)-烯丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((S)-烯丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-((R)-烯丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
(3R,3aS,6R,6aS)-6-(烯丙基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
S-(3R,3aS,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基硫代乙酸酯
以及它们的互变异构体、药物可接受的盐、前药或溶剂化物。
本发明的化合物可用于预防和/或治疗动脉粥样硬化、心脏移植物血管病(cardiac allograft vasculopathy)、血小板激活、血栓形成、中风和/或氧化应激在其发病机理中起重要作用的病理疾病状态的疗法,所述发病机理例如但不限于变态反应、中风和阿尔茨海默病和/或缺血性心血管病。
可以由不同途径给予所述药物组合物。例如,可以诸如片剂、胶囊剂、糖浆剂和悬浮剂的药物制剂形式口服给予所述药物组合物;同样,可以溶液剂或乳剂等形式肠胃外给予所述药物组合物。
也可以乳膏剂、发膏剂、香膏剂等形式局部给予所述药物组合物,和例如通过使用贴剂或绷带剂经皮给予所述药物组合物。还可以栓剂的形式将所述药物组合物直接应用于直肠。制剂可以包含生理可接受的载体、赋形剂、活化剂、螯合剂、稳定剂等。在注射的情况下,可以添加生理可接受的缓冲剂、加溶剂或等渗液(isotonics)。
本发明的药物组合物可以进一步包含溶栓剂,优选纤溶酶原激活物、尿激酶、链激酶、阿替普酶或阿尼普酶。所述药物组合物还可以包含抗凝剂,优选肝素、双香豆素、醋硝香豆醇、依诺肝素或戊聚糖多硫酸酯。此外,所述药物组合物可以另外包含抗血栓形成剂(antithrombotic agent),优选乙酸水杨酸、潘生丁、噻氯匹定、氯吡格雷、三伏柳、戊聚糖多硫酸酯或阿昔单抗。所述药物组合物还能够包含具有糖蛋白I1b/IIIa特异性的免疫球蛋白或其片段。
或者,本发明的药物组合物还可以包含降血脂剂(hypolipemiant agent),优选辛伐他汀、洛伐他汀、阿托伐他汀、普伐他汀、氟伐他汀、帕伐他汀、利非贝罗、阿昔呋喃、阿昔替酯、葡烟酯或罗苏伐他汀。所述药物组合物还可以包含抗氧化剂/自由基清除剂,优选烟拉文、雷诺嗪、益膜息平(emoxipin)、谷胱甘肽、依达拉奉、累索司特、番茄红素、乙酰半胱氨酸、N-乙酰基-L-半胱氨酸、N-乙酰基-D-半胱氨酸或卡维地洛。
本发明的药物组合物可以用于治疗和/或预防动脉粥样硬化、心脏移植物血管病、血小板激活、血栓形成、中风、由缺血和/或由缺血-再灌注引起的组织损伤,和/或氧化应激在其发病机理(例如但不限于变态反应、中风、阿尔茨海默病、缺血性心血管病)中起重要作用的病理疾病状态;和/或NO(一氧化氮)不足在其发病机理中起重要作用的病理疾病状态。还能够将所述药物组合物用于治疗和/或预防循环系统机能障碍,优选用于心血管机能障碍和冠状动脉机能障碍。
日剂量可以根据患者的具体症状、年龄、体重,给药的具体方式等进行变化,并且成年人的正常日剂量可以在0.1mg至500mg间变化,并且在一天中,能够仅以单一剂量给药或分为多个剂量给药。
本发明的另一方面涉及用于制备式(I)的化合物及其互变异构体、药物可接受的盐、前药或溶剂化物的方法。
如下所示,可以按照与专利申请WO2005/37842所描述的一种方法类似的方法,通过用式R-L的烷基化剂对式(V)的化合物(专利申请WO2005/37842也描述了其制备方法)进行烷基化来制备本发明的其中G表示硫醚基(-S-)的化合物,在式R-L中,R表示选自C1-C3烷基和C3烯基的基团,L表示诸如溴原子的离去基:
如下所示,可以使用取代反应,通过式(VI)的化合物与式R-COSK的化合物反应来制备本发明的其中G表示乙酰硫基(-COS-)的化合物,在式(VI)的化合物中L2表示诸如三氟甲磺酸酯基、对甲苯磺酸酯基或四氢吡喃基的离去基,在式R-COSK的化合物中R表示选自C1-C3烷基和C3烯基的基团:
如下所示,可以按照与专利申请WO2005/037842所描述的一种方法类似的方法,通过用氧化剂氧化式(VI)的化合物来制备本发明的其中G表示亚砜基(-SO-)的化合物:
当期望获得可变比接近50/50(在30/70至70/30的范围内)的非对映异构体混合物时,氧化剂可以为诸如高碘酸钠(NaIO4)的非对映特异性作用剂(non-enantiospecific agent)。然后,通过诸如分级重结晶或色谱分离的常规方法可以进行立体异构体分离。下列溶剂可以用作结晶溶剂:丙酮、二氧杂环己烷、氯仿、甲苯、异丙醇等。这种方法可以为复杂的、缓慢的,并且提供低产量。
为此,当期望获得一种非对映异构体时,优选使用一种文献所述的通用方法来进行对映选择性氧化,所述通用方法例如:
·细胞培养
·酶催化合成
·具有非金属(碘化的化合物)的氧化体系
·使用手性磷酰氯
·使用哑嗪
·手性金属配合物-催化的对映选择性氧化
所有的上述选择中,优选使用手性金属配合物-催化的对映选择性氧化。有大量的关于由金属配合物催化的非对称氧化的文献。大多数体系为使用诸如叔丁基过氧化氢的氧化剂,以异丙氧基钛和酒石酸二乙酯为手性络合催化剂的夏普勒斯环氧化反应的变体。
通过添加诸如(D或L)酒石酸二乙酯的旋光剂,并随后添加可以是或不是旋光性的氧化剂,可以将钛、锰、钒和铁化合物用于形成手性催化剂。
具体优选的是通过钛/L或D酒石酸二乙酯(1-DET或d-DET)配合物和诸如叔丁基过氧化氢或氢过氧化枯烯的氧化剂来催化的对映选择性氧化,其中钛化合物(通常为异丙氧基钛)、酒石酸二乙酯和氧化剂的摩尔比可以变化(1/1/1;1/2/1、2/4/1等)。在存在水(1mol或2mol)的情况下或在无水条件下,这些反应可以进行。
如下所示,可以按照与专利申请WO2005/037842所述的一种方法类似的方法,通过用诸如高碘酸(H5IO6)或高碘酸钠的氧化剂氧化式(III)的化合物来制备本发明的其中G表示砜基(-SO2-)的化合物:
如下所示,最后可以通过式(VIII)化合物的硝化制备本发明的化合物:
例如,通过在0℃,向50体积份的乙酸酐和50体积份的乙酸的混合物中缓慢加入12体积份的HNO3(60%)获得的混合物可以用作硝化剂。
本说明书包括的工作实施例详细地描述了适当的方法以获得通式(I)的数个化合物。按照这些实施例,在本领域技术人员的公知常识内,通过适当修改工作实施例可获得没有明确示例的化合物。这些实施例仅仅用作示例性说明并不应该被认为是限制本发明的范围,这对本领域技术人员也是显而易见的。
实施例
通过质子(1H-NMR)和碳-13(13C-NMR)核磁共振谱法的数据来鉴定下述实施例中获得的化合物。
使用Varian Gemini-200分光计来记录核磁共振谱。
在1H-NMR谱中,标示出工作频率和用于记录谱的溶剂。以δ(ppm)的形式标出信号位置,并且将来自溶剂质子的信号作为参考。氘代氯仿的参考值为7.24ppm,并且六氘代二甲基亚砜的参考值为2.49ppm。偶尔将获得的四甲基硅烷(TMS)质子的信号作为内参,参考值为0ppm。使用下列缩写,在括号内标出与由电子积分测定的每一信号相对应的质子数和信号类型:s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、dd(双峰的双峰)、ddd(双峰双峰的双峰)、s.b.(宽信号)、cs(复杂信号)、s.a.D2O(氘代时简化)、d.a.D2O(氘代时消失)。
13C-NMR谱标示了工作频率和用于运行波谱的溶剂。使用作为参考的溶剂的中央信号,以δ(ppm)的形式指出信号位置。氘代氯仿的参考值为77.00ppm,并且六氘代二甲基亚砜的参考值为39.50ppm。
当进行HPLC分析来测定一些样品的纯度或稳定性时,使用下列条件:
对称C18柱,5mcm,150mm x 3.9mm
温度:30℃
洗脱剂:A:100%水,B:100%乙腈
组成梯度:在30分钟内0%至100%乙腈并在另外的5分钟内用100%乙腈
在实验部分,使用下列缩写:
AcOEt 乙酸乙酯
AcOH 乙酸
DMSO-d6 六氘代二甲基亚砜
EtOH 乙醇
Et2O 二乙醚
HPLC 高效液相色谱
IPA 异丙醇
RT 室温
THF 四氢呋喃
TLC 薄层色谱
实施例
比较例1.(3R,3aS,6S,6aS)-6-(巯基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
在500ml烧瓶中,将根据WO 00/20420获得的10.0g(40.2mmol)S-(3S,3aR,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基硫代乙酸酯溶解于200mL的甲醇中。同时加入100mL氢氧化钠的10%甲醇溶液。快速盖住后在室温(约25℃)下搅拌1分钟,同时加入22.3mL的浓盐酸。将其搅拌并且浓缩至干燥,在低于30℃的温度下,在减压下除去溶剂。
将残留物悬浮于氯仿并过滤溶液,然后在无水硫酸镁上干燥。在过滤之后,在减压条件下除去溶剂,并在减压条件下干燥残留物以获得8.3g相当于标题产物的桔黄色油。产率100%。
1H-NMR(200MHz,CDCl3):5.36-5.26(m,1H,CHONO2),4.95(t,1H,J=5.0Hz,CHCHONO2),4.42(d,1H,J=4.8Hz,CHCHS),4.07(dd,1H,J=4.6Hz,J=4.4Hz,H-CHCHS),3.97(dd,1H,J=5.6Hz,J=2.5HzH-CHCHONO2),3.87-3.76(m,2H,H-CHCHS和H-CHCHONO2),3.45-3.35(m,1H,CHS),1.77(d,1H,J=8.6Hz,SH)。
13C-NMR(50MHz,CDCl3):91.21(CHCHS),81.22(CHONO2),81.07(CHCHONO2),76.15(CH2CHS),69.26(CH2CHONO2),42.82(CHS)。
比较例2.(3R,3aS,6S,6aS)-6-(苄硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
用溴苄代替实施例1(如下所述)中使用的溴乙烷提供标题化合物。
产率:81%HPLC纯度97.0%
1H-NMR(200MHz,DMSO-d6):7.34-7.22(m,5H,Ph),5.50-5.40(m,1H,CHONO2),4.94-4.86(m,1H,CHCHONO2),4.45-4.40(m,1H,CHCHS),4.00-3.74(m,6H,2CH2O+CH2S),3.24(b.s,1H,CHS)。
13C-NMR(50MHz,DMSO-d6):137.90(1C),128.92(2C,CH),128.47(2C,CH),127.01(1C,CH),87.74(CHCHS),82.33(CHCHONO2),81.45(CHONO2),73.33(CH2CHS),68.81(CH2CHONO2),47.90(CHS),34.70(CH2S)。
比较例3.2-((3S,3aS,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基硫基)乙酸乙酯
用溴乙酸乙酯代替实施例1(如下所述)中使用的溴乙烷提供标题化合物。
产率:86.7%HPLC纯度98.9%
1H-NMR(200MHz,DMSO-d6):5.50-5.40(m,1H,CHONO2),4.91(t,1H,J=5.8Hz,CHCHONO2),4.48(d,1H,J=4Hz,CHCHS),4.11(q,2H,OCH 2-CH3),4.02-3.78(m,4H,CH2O),3.51(d,1H,J=4Hz,CHS),3.49(s,2H,CH2S),1.20(t,3H,J=7.8Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):169.84(CO),87.61(CHCHS),82.35(CHCHONO2),81.38(CHONO2),73.26(CH2CHS),68.87(CH2CHONO2),60.91(CH2O),48.76(CHS),32.51(CH2S),13.99(CH3)。
按照类似于实施例4(如下所述)所述的方法,并且从比较例2至3的产物开始获得下列产物:
比较例4.(3R,3aS,6S,6aS)-6-((R,S)-苄基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
作为非对映异构体40/60的混合物,产率:73%,HPLC纯度91.3%。
1H-NMR(200MHz,DMSO-d6):7.34(b.s.,5H,Ph),5.53-5.42(m,1H,CHONO2),4.91(b.s,1H,CHCHONO2),4.89(b.s,0.5H,CHCHSR对映体),4.70-4.60(m,0.5H,CHCHS S对映体),4.30-3.90(m,6H,2HCH2CHONO2+2H CH2CHS+2H CH2S),3.70-3.50(m,1H,CHS)。
13C-NMR(50MHz,DMSO-d6):131.22和131.02(1C),130.41(2C,CH),128.58(2C,CH),127.97(1C,CH),83.24、82.20和82.01相当于CHCHONO2、CHCHS和CHONO2,69.58(来自R对映体的CH2CHS),68.94(来自S对映体的CH2CHS),68.94(来自R对映体的CH2CHONO2),67.11(来自S对映体的CH2CHONO2),64.04(来自S对映体的CHS),63.81(来自R对映体的CHS),56.08(来自R对映体的CH2S)以及55.32(来自S对映体的CH2S)。
比较例5:2-((R,S)-(3S,3aS,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基)亚磺酰基)乙酸乙酯
作为非对映异构体的47/53混合物,产率:84%,HPLC纯度98.0%。
1H-NMR(200MHz,DMSO-d6):5.53-5.46(m,1H,CHONO2),4.90(b.s,1H,CHCHONO2),4.90(b.s,0.5H,CHCHS R对映体),4.71(d,0.5H,CHCHS S对映体),4.30-3.80(m,9H,2H CH2CHONO2+2H CH2CHS+2H CH2S+1H,CHSO+CH2O),1.22(t,3H,CH3)。
13C-NMR(50MHz,DMSO-d6):165.94和165.81(1C,CO),82.88和81.92相当于CHCHONO2、CHCHS和CHONO2,69.41(来自R对映体的CH2CHS),68.94(来自S对映体的CH2CHS),68.83(来自R对映体的CH2CHONO2),67.04(来自S对映体的CH2CHONO2),64.47(来自S对映体的CHS),64.35(来自R对映体的CHS),61.41(CH2O),55.09(来自R对映体的CH2S)以及54.35(来自S对映体的CH2S),13.93(1C,CH3)。
比较例6:(3R,3aS,6S,6aS)-6-((R)-甲基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
方法1
按照类似于实施例4(如下所述)所述的方法,并从7.3g(32.9mmol)的(3R,3aS,6S,6aS)-6-(甲硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯(专利申请WO2005/037842的实施例3所述的产物)开始获得6.6g含有非对映异构体的65/35混合物的反应粗品。
从二氧杂环己烷中,将所得的反应粗品重结晶两次以获得2.9具有95%HPLC纯度的标题产物。
方法2
向12.86g(45.25mmol)异丙氧基钛(IV)与含18.66g(90.5mmol)(+)-L-酒石酸二乙酯(L-DET)的75ml二氯甲烷的混合物中,加入10g(45.25mmol)的(3R,3aS,6S,6aS)-6-(甲硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯(专利申请WO2005/037842的实施例3所述的产物)。将溶液冷却至-40℃并加入8ml(44mmol)叔丁基过氧化氢,并在-40℃下搅拌50h,在室温下搅拌20h。在过滤无机盐之后,在减压条件下浓缩滤液,并用100ml的二乙醚处理所得残留物,并且将其搅拌来获得过滤后的固体以得到6.3g(60%)的标题产物。
1H-NMR(200MHz,DMSO-d6):5.54-5.49(m,1H,CHONO2),4.95-4.85(m,2H,CHCHONO2+CHCHS),4.15-3.89(m,4H,2HCH2CHONO2+2H CH2CHS),3.64-3.59(m,1H,CHSO),2.63(s,3H,CH3S)。
13C-NMR(50MHz,DMSO-d6):82.04和82.00相当于CHCHONO2、CHCHS和CHONO2,69.29(CH2CHS),68.89(CH2CHS),65.66(CHS),36.79(CH3S)。
比较例7.(3R,3aS,6S,6aS)-6-((S)-甲基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
使用来自比较例6的方法1中的第一次重结晶的母液,在减压条件下除去溶剂,并从二氧杂环己烷中重结晶所得残留物以获得1g具有95%HPLC纯度的标题化合物。
1H-NMR(200MHz,DMSO-d6):5.54-5.49(m,1H,CHONO2),4.88(t,1H,CHCHONO2),4.67(d,1H,CHCHS),4.21(dd,1H,H-CHCHS),4.08-3.85(m,3H,2H CH2CHONO2+IH H-CHCHS),3.64-3.59(m,1H,CHSO),2.58(s,3H,CH3S)。
13C-NMR(50MHz,DMSO-d6):82.69和82.04相当于CHCHONO2、CHCHS和CHONO2,68.82(CH2CHS),67.32(CH2CHS),65.84(CHS),35.99(CH3S)。
按照类似于实施例7所述方法中的方法,并从比较例2至5的产物开始获得下列产物:
比较例8:(3R,3aS,6S,6aS)-6-(苄基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
产率:86% HPLC纯度:98.3%
1H-NMR(200MHz,DMSO-d6):7.41(b.s.,5H,Ph),5.54-5.46(m,1H,CHONO2),4.92(b.s.,2H,CHCHONO2+CHCHS),4.64(s,2H,CH2S),4.36(d,1H,J=9.8Hz,CHS),4.08-3.85(m,4H,2H CH2CHONO2+2H CH2CHS)。
13C-NMR(50MHz,DMSO-d6):131.95(2C,CH),129.55(1C,CH),129.03(2C,CH),127.70(1C),82.79(CHCHS),82.33(CHCHONO2),81.75(CHONO2),68.94(CH2CHS),68.22(CH2CHONO2),65.76(CHS),57.18(CH2S)。
比较例9.2-((R,S)-(3S,3aS,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基)磺酰基)乙酸乙酯
产率:54% HPLC纯度:95.5%
1H-NMR(200MHz,DMSO-d6):5.54-5.46(m,1H,CHONO2),5.02(d,1H,J=5Hz CHCHONO2),4.92(t,1H,J=5.6HZ,CHCHS),4.60(d,2H,J=4Hz,CH2S),4.43(d,1H,J=11Hz,CHS),4.30-3.89(m,6H,2HCH2CHONO2+2H CH2CHS+OCH2),1.22(t,3H,J=7.2Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):162.73(1C,CO),82.52(CHCHS),82.34(CHCHONO2),81.73(CHONO2),68.97(CH2CHS),68.08(CH2CHONO2),67.47(CHS),61.87(OCH2),56.60(CH2S),13.77(CH3)。
比较例10:(3R,3aS,6S,6aS)-6-(丁硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
用1-溴丁烷代替实施例1(如下所述)中使用的溴乙烷提供标题化合物。
产率:53% HPLC纯度:92.1%
1H-NMR(200MHz,DMSO-d6):5.50-5.40(m,1H,CHONO2),4.90(t,1H,J=5.8Hz,CHCHONO2),4.42(d,1H,J=4Hz,CHCHS),4.02-3.76(m,4H,CH2O),3.38(d,1H,J=4Hz,CHS),2.59(t,2H,CH2S),1.60-1.45(m,2H,CH2),1.44-1.25(m,2H,CH2),0.87(t,3H,J=7.8Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):88.21(CHCHS),82.36(CHCHONO2),81.42(CHONO2),73.62(CH2CHS),68.79(CH2CHONO2),48.17(CHS),31.03(CH2S),30.30(CH2),21.34(CH2),13.47(CH3)。
比较例11.(3R,3aS,6S,6aS)-6-((R,S)-丁基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
按照类似于实施例4(如下所述)所述的方法,并且从比较例10的产物开始获得产物。
作为非对映异构体的53/47混合物,产率:60%,HPLC纯度:93.1%。
1H-NMR(200MHz,DMSO-d6):5.53-5.46(m,1H,CHONO2),4.87(b.s,1H,CHCHONO2),4.89(b.s,0.5H,CHCHS R对映体),4.63(d,0.5H,CHCHS S对映体),4.25-4.15(dd,0.5H,来自S对映体的H-CHCHS),4.05-3.84(m,3.5H,2H CH2CHONO2+来自R对映体的0.5H H-CHCHS+1H H-CHCHS),3.67-3.55(m,1H,CHSO),2.90-2.60(m,2H,CH2S),1.75-1.55(m,2H,CH2),1.45-1.30(m,2H,CH2),0.91(t,3H,CH3)。
13C-NMR(50MHz,DMSO-d6):83.08和82.00相当于CHCHONO2、CHCHS和CHONO2,69.66(来自R对映体的CH2CHS),68.87(来自S对映体的CH2CHS),68.87(来自R对映体的CH2CHONO2),67.32(来自S对映体的CH2CHONO2),64.51(来自S对映体的CHS),64.15(来自R对映体的CHS),49.80(来自R对映体的CH2S)和49.20(来自S对映体的CH2S),24.57和24.29(1C,CH2),21.35(1C,CH2),13.60(1C,CH3)。
比较例12.(3R,3aS,6S,6aS)-6-(丁基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
按照类似于实施例7(如下所述)所述的方法,从比较例10或11的产物开始获得产物。
HPLC纯度:92.3%。
1H-NMR(200MHz,DMSO-d6):5.54-5.46(m,1H,CHONO2),4.96-4.86(m,2H,CHCHONO2+CHCHS),4.36(d,1H,J=9.8Hz,CHS),4.12-3.85(m,4H,2H CH2CHONO2+2H CH2CHS),3.21(t,2H,J=7.6Hz,CH2S),1.72-1.58(m,2H,CH2),1.48-1.30(m,2H,CH2),0.89(t,3H,J=7.6Hz CH3)。
13C-NMR(50MHz,DMSO-d6):82.86(CHCHS),82.39(CHCHONO2),81.77(CHONO2),68.91(CH2CHS),68.39(CH2CHONO2),66.20(CHS),50.65(CH2S),22.60(CH2),21.03(CH2),13.48(CH3)。
实施例1.(3R,3aS,6S,6aS)-6-(乙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯的合成
在100mL烧瓶中,将4.14g(0.02mol)比较例1的产物与2.99mL(0.04mol)溴乙烷溶解于50mL的二甲基甲酰胺(DMF)中,并加入1.85g(0.022mol)的碳酸氢钠。在40℃将反应混合物搅拌过夜,然后加入500mL的水并用3x100ml的乙酸乙酯萃取。干燥、过滤并浓缩有机相,然后使粗反应产物在硅胶上进行硅胶柱层析,并用己烷/乙酸乙酯的8/2混合物洗脱,在浓缩至干燥后,获得3.06g白色固体形式的标题化合物。
产率:65% HPLC纯度:94.6%
1H-NMR(200MHz,DMSO-d6):5.52-5.40(m,1H,CHONO2),4.89(t,1H,J=5.8Hz,CHCHONO2),4.42(d,1H,J=4Hz,CHCHS),4.02-3.76(m,4H,CH2O),3.41(d,1H,J=4Hz,CHS),2.59(q,2H,J=7.8Hz,CH2S),1.19(t,3H,J=7.8Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):88.18(CHCHS),82.35(CHCHONO2),81.42(CHONO2),73.58(CH2HS),68.78(CH2CHONO2),47.78(CHS),24.60(CH2S),14.55(CH3)。
从(3R,3aS,6S,6aS)-6-巯基六氢呋喃并[3,2-b]呋喃-3-基硝酸酯(比较例1)开始,并用相应的卤代烷代替溴乙烷,并按照类似于实施例1所述的方法,获得下列产物:
实施例2.(3R,3aS,6S,6aS)-6-(丙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
用1-溴丙烷代替实施例1使用的溴乙烷提供标题化合物。
产率:60% HPLC纯度:96.2%
1H-NMR(200MHz,DMSO-d6):5.52-5.40(m,1H,CHONO2),4.90(t,1H,J=5.8Hz,CHCHONO2),4.42(d,1H,J=4Hz,CHCHS),4.02-3.76(m,4H,CH2O),3.38(d,1H,J=4Hz,CHS),2.55(t,2H,CH2S),1.65-1.45(m,2H,CH2),0.93(t,3H,J=7.8Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):88.23(CHCHS),82.36(CHCHONO2),81.43(CHONO2),73.64(CH2CHS),68.80(CH2CHONO2),48.10(CHS),32.64(CH2S),22.32(CH2),13.22(CH3)。
实施例3.(3R,3aS,6S,6aS)-6-(烯丙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
用烯丙基溴代替实施例1使用的溴乙烷获得标题化合物。
产率:87% HPLC纯度:99.3%
1H-NMR(200MHz,DMSO-d6):5.90-5.70(m,1H,CH=CH2),5.46(t,1H,CHONO2),5.20-5.10(m,2H,CH=CH 2),4.90(t,1H,J=5.8Hz,CHCHONO2),4.43(d,1H,J=4Hz,CHCHS),4.02-3.76(m,4H,CH2O),3.30-3.20(m,3H,CHS+CH2S)。
13C-NMR(50MHz,DMSO-d6):134.13(CH=CH2),117.67(CH=CH 2),87.92(CHCHS),82.37(CHCHONO2),81.44(CHONO2),73.43(CH2CHS),68.84(CH2CHONO2),47.41(CHS),33.56(CH2S)。
实施例4.(3R,3aS,6S,6aS)-6-((R,S)-乙基亚磺酰基)六氢呋喃并[3,2-b]-呋喃-3-基硝酸酯
向0.71g(3mmol)实施例1获得的产物的50ml乙腈溶液中加入0.75g(3.3mmol)高碘酸。在室温下搅拌反应48h,然后加入硫代硫酸钠饱和溶液,然后用3x100ml的二氯甲烷萃取反应产物。干燥、过滤并浓缩有机相,然后使粗反应产物进行硅胶柱层析,并用二氯甲烷/甲醇的99/1混合物洗脱,在浓缩至干燥后,获得为白色固体的320mg标题化合物。
作为非对映异构体的51/49混合物,产率:43%,HPLC纯度:99.35%。
1H-NMR(200MHz,DMSO-d6):5.53-5.46(m,1H,CHONO2),4.89(t,1H,J=5.8Hz,CHCHONO2),4.89(d,0.5H,CHCHS R对映体),4.42(d,0.5H,CHCHS S对映体),4.26(dd,0.5H,来自S对映体的H-CHCHS),4.02-3.76(m,3.5H,2H CH2CHONO2+来自R对映体的0.5H H-CHCHS+1H H-CHCHS),3.64-3.57(m,1H,CHSO),2.90-2.55(m,2H,CH2S),1.22(dt,3H,CH3)。
13C-NMR(50MHz,DMSO-d6):83.83、82.82和82.78相当于CHCHONO2、CHCHS和CHONO2,70.35(来自R对映体的CH2CHS),69.61(来自S对映体的CH2CHS),69.56(来自R对映体的CH2CHONO2),68.09(来自S对映体的CH2CHONO2),64.79(来自S对映体的CHS),64.44(来自R对映体的CHS),44.44(来自R对映体的CH2S)以及43.86(来自S对映体的CH2S),7.65和7.36(1C,CH3)。
按照类似于实施例4所述的方法,并从实施例2至3的产物开始获得下列产物:
实施例5.(3R,3aS,6S,6aS)-6-((R,S)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
作为非对映异构体的46/54混合物,产率:81%,HPLC纯度:97.9%。
1H-NMR(200MHz,DMSOd6):5.53-5.46(m,1H,CHONO2),4.87(b.s,1H,CHCHONO2),4.89(b.s,0.5H,CHCHS R对映体),4.65(d,0.5H,CHCHS S对映体),4.30-4.15(d,0.5H,来自S对映体的H-CHCHS),4.05-3.76(m,3.5H,2H CH2CHONO2+来自R对映体的0.5H H-CHCHS+1H H-CHCHS),3.64-3.55(m,1H,CHSO),2.75(t,2H,CH2S),1.75-1.55(m,2H,CH2),1.00(t,3H,CH3)。
13C-NMR(50MHz,DMSO-d6):83.04和82.00相当于CHCHONO2、CHCHS和CHONO2,69.62(来自R对映体的CH2CHS),68.89(来自S对映体的CH2CHS),68.89(来自R对映体的CH2CHONO2),67.33(来自S对映体的CH2CHONO2),64.51(来自S对映体的CHS),64.17(来自R对映体的CHS),51.93(来自R对映体的CH2S)以及51.33(来自S对映体的CH2S),16.21和15.93(1C,CH2),13.04(1C,CH3)。
实施例6.(3R,3aS,6S,6aS)-6-((R,S)-烯丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
作为非对映异构体的44/56混合物,产率:62%,HPLC纯度:95.1%
1H-NMR(200MHz,DMSO-d6):6.00-5.75(m,1H,CH=CH2),5.53-5.30(m,3H,CH=CH 2+CHONO2),4.95-4.83(m,1.5H,CHCHONO2+0.5H CHCHS R对映体),4.65-4.60(m,0.5H,CHCHS S对映体),4.30-4.20(d,0.5H,来自S对映体的H-CHCHS),4.10-3.70(m,3.5H,2H CH2CHONO2+来自R对映体的0.5H H-CHCHS+1HH-CHCHS),3.64-2.90(m,3H,CHS+CH2S)。
13C-NMR(50MHz,DMSO-d6):127.26和127.08(CH=CH2),123.45(CH=CH2),83.17、82.16和82.00相当于CHCHONO2、CHCHS和CHONO2,69.65(来自R对映体的CH2CHS),68.91(来自S对映体的CH2CHS),68.91(来自R对映体的CH2CHONO2),67.21(来自S对映体的CH2CHONO2),63.84(来自S对映体的CHS),63.53(来自R对映体的CHS),54.21(来自R对映体的CH2S)以及53.55(来自S对映体的CH2S)。
实施例7.(3R,3aS,6S,6aS)-6-(乙基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
方法1
向0.71g(3mmol)实施例1获得的产物的50ml乙腈溶液中加入2.05g(9mmol)高碘酸。在室温下搅拌反应48h,然后加入硫代硫酸钠饱和溶液,用3x100ml二氯甲烷萃取反应产物。干燥、过滤并浓缩有机相,并用40ml的2-丙醇搅拌粗反应来获得过滤后的白色固体以得到550mg的标题产物。
产率:68% HPLC纯度:99.5%
方法2
向0.75g(3mmol)实施例4获得的产物的50ml乙腈溶液中加入0.75g(3.3mmol)高碘酸。在室温下搅拌反应48h,然后加入硫代硫酸钠饱和溶液,并用3x100ml二氯甲烷萃取反应产物。干燥、过滤并浓缩有机相,然后使粗反应产物进行硅胶柱层析并用己烷/乙酸二乙酯的1/1混合物洗脱,在浓缩至干燥后,获得为白色固体的620mg标题化合物。
产率:77% HPLC纯度:98.5%
1H-NMR(200MHz,DMSO-d6):5.51-5.46(m,1H,CHONO2),4.95-4.88(m,2H,CHCHONO2+CHCHS),4.36(d,1H,J=9.8Hz,CHS),4.12-3.88(m,4H,2H CH2CHONO2+2H CH2CHS),3.21(q,2H,J=7.4Hz,CH2S),1.22(t,3H,J=7.4Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):82.85(CHCHS),82.30(CHCHONO2),81.67(CHONO2),68.83(CH2CHS),68.35(CH2CHONO2),65.54(CHS),45.61(CH2S),5.44(CH3)。
按照类似于实施例7所述的方法,并从实施例2至3和5至6的产物开始获得下列产物:
实施例8.(3R,3aS,6S,6aS)-6-(丙基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
HPLC纯度:94.2%。
1H-NMR(200MHz,DMSO-d6):5.51-5.46(m,1H,CHONO2),4.93(b.s.,2H,CHCHONO2+CHCHS),4.36(d,1H,J=9.8Hz,CHS),4.12-3.85(m,4H,2H CH2CHONO2+2H CH2CHS),3.19(t,2H,J=7.6Hz,CH2S),1.80-1.60(m,2H,CH2),0.99(t,3H,J=7.6Hz CH3)。
13C-NMR(50MHz,DMSO-d6):82.86(CHCHS),82.37(CHCHONO2),81.74(CHONO2),68.99(CH2CHS),68.38(CH2CHONO2),66.20(CHS),52.53(CH2S),14.56(CH2),12.83(CH3)。
实施例9.(3R,3aS,6S,6aS)-6-(烯丙基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
HPLC纯度:88.4%。
1H-NMR(200MHz,DMSO-d6):5.94-5.72(m,1H,CH=CH2),5.55-5.40(m,3H,CH=CH 2+CHONO2),5.00-4.85(m.,2H,CHCHONO2+CHCHS),4.37(d,1H,J=9.8Hz,CHS),4.12-3.85(m,6H,2H CH2CHONO2+2H CH2CHS+2H SCH2)。
13C-NMR(50MHz,DMSO-d6):125.12(CH=CH2),124.52(CH=CH2),82.78(CHCHS),82.34(CHCHONO2),81.73(CHONO2),68.92(CH2CHS),68.29(CH2CHONO2),65.67(CHS),56.03(CH2S)。
实施例10.S-(3R,3aS,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基硫代乙酸酯的合成
10a.(3S,3aS,6R,6aR)-6-羟基六氢呋喃并[3,2-b]呋喃-3-基4-甲苯磺酸酯的合成
在2L烧瓶中,在0℃下,将100.0g(0.684mol)的(3R,3aR,6S,6aR)-六氢呋喃并[3,2-b]呋喃-3,6-二醇(异山梨醇)溶于600ml的水中,并加入溶于600ml甲苯的130.5g(0.684mol)对甲苯磺酰氯。在0℃,逐滴加入含49.5g(0.751mol)氢氧化钾(86%)的170ml水,添加时间为1/2h,在0℃搅拌反应1h并在室温下搅拌5h。萃取、干燥、过滤并在真空条件下浓缩有机相,然后使粗反应产物进行硅胶柱层析并用二氯甲烷/甲醇的99/1混合物洗脱,在浓缩至干燥后,获得50.0g的标题产物。
1H-NMR(200MHz,DMSO-d6):7.82(d,2H,J=8.4HZ,2o-H),7.48(d,2H,J=8.4HZ,2m-H),4.98(d,1H,OH),4.78(s,1H,CHOTos),4.48-4.35(m,2H,CHCHOH+CHCHOTos),4.15-4.00(m,1H,CHOH),3.81(d,1H,J=2.2Hz,CH2CHOTos),3.69(t,1H,H-CHCHOH),3.28(t,1H,H-CHCHOH),2.42(s,3H,CH3)。
13C-NMR(50MHz,DMSO-d6):145.35(1C,C-SO2-),132.62(1C,C-CH3),130.35(2C,CH),127.62(2C,CH),84.81(CHCHOS2-),84.55(CHOSO2),81.60(CHCHOH),72.28(CH2CHOSO2-),71.57(CH2CHOH),71.48(CHOH),21.11(CH3)。
10b.(3S,3aS,6R,6aR)-6-(四氢-2H-吡喃-2-基氧代)六氢呋喃并[3,2-b]呋喃-3基4-甲基苯磺酸酯的合成
在1L的烧瓶中,在0℃将50.0g(0.166mol)10a中获得的产物溶解于550ml的二氯甲烷中,并逐滴加入45.3mL(0.499mol)的3,4-二氢-2H-吡喃,添加时间为1/2h,然后在0℃加入9.35g(0.037mol)的对甲苯磺酸吡啶盐(PTSP),在0℃搅拌反应1h,并在室温搅拌4h。
用4x400mL的水洗涤有机相,然后干燥、过滤并在真空条件下浓缩有机相,以获得74.3g不用纯化便可用于下一步骤的粗品。
1H-RMN(DMSO-d6,200MHz):7.82(d,2H,J=8.0Hz,o-CHar),7.48(d,2H,J=8.2Hz,m-CHar),4.80(s,1H,CHCHOTHP),4.66-4.43(sc,2H,CHOTos,CHTHP),4.45-4.35(m,1H,CHCHOTos),4.15-4.05(m,1H,CHOTHP),3.85-3.75(sc,4H,CH 2CHOTos,CH 2OTHP),3.50-3.30(sc,2H,CH 2CHOTHP),2.41(s,3H,CH3),1.80-1.27(sc,6H,3CH2THP)。
13C-RMN(DMSO-d6,50MHz):144.3(Car),131.5(Car),129.3(2CHar),126.5(2CHar),96.8和96.5(CHTHP),83.8和83.7,83.2和83.0(CHOTos,CH-CHOTos),80.1和79.2(CHCHOTHP),75.9和74.3(CHOTHP),71.2、69.5和67.6(CH2CHOTos,CH2CHOTHP),60.5和59.9(CH2OTHP),28.9(CH2THP),23.8(CH2THP),20.0(CH3-Car),17.9和17.5(CH2THP)。
10c.S-(3R,3aS,6R,6aR)-6-(四氢-2H-吡喃-2-基氧代)六氢呋喃并[3,2-b]呋喃-3-基硫代乙酸酯的合成
将10b中获得的产物和66.5g(0.582mol)硫代乙酸钾溶解于450ml的二甲基甲酰胺(DMF)中,并且在110℃加热26h。加入2L的乙酸乙酯并且用4x400mL的水洗涤反应混合物,然后干燥、过滤并在真空条件下浓缩有机相。
然后使粗反应产物进行硅胶柱层析并用二氯甲烷/乙酸乙酯的10/1混合物洗脱,在浓缩后获得16.3g标题化合物。
1H-RMN(DMSO-d6,200MHz):4.67(s,1H,CHCHOTHP),4.65-4.50(m,1H,CHCHS),4.60-4.45(m,1H,CHOTHP),4.30-4.10(sc,1H,CHOTHP),3.90-3.70(sc,3H,CH 2OTHP,CHS),3.60-3.50(m,1H,H-CH-CHS),3.50-3.35(sc,2H,CH 2-CHOTHP),2.32(s,3H,CH3-Car),1.80-1.27(sc,6H,3CH 2THP)。
13C-RMN(DMSO-d6,50MHz):194.0(CO),97.0和96.4(CHTHP),81.1和80.9+80.8和80.0(CH-CHS,CH-CHO),76.6和74.9(CHOTHP),71.2和70.9+70.3和68.6(CH2-CHS,CH2-CHOTHP),60.5和59.9(CH2OTHP),45.4和44.7(CHS),29.3(CH2THP),28.9(CH2THP),23.8(CH3CO),17.9和17.6(CH2THP)。
10d.S-(3R,3aS,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基硫代乙酸酯的合成
在5℃下,将10c获得的产物溶解于8mL的乙酸中,并且在5℃下,逐滴加入新制备的乙酸/乙酸酐/硝酸的33.2mL/7.6mL/8.1mL的混合物,添加时间为1h。在5℃搅拌反应混合物1h。加入甲苯(600mL),并用4x400mL盐水、4x400mL碳酸氢钠饱和溶液和400mL水洗涤反应混合物。干燥、过滤并在真空条件下浓缩有机相。然后使粗反应产物进行硅胶柱层析并用甲苯洗脱;在浓缩后,获得1.3g标题化合物。
1H-RMN(CDCl3,200MHz):5.33(ddd,1H,J=8.4Hz,5.4Hz,2.8Hz,CHONO2),4.91(dd,1H,J=4.8Hz,4.8Hz,CHCHONO2),4.55(dd,1H,J=4.8Hz,4.8Hz,CHCHS),4.20-3.80(m,4H,CHS,H-CHCHS,CH 2-CHONO2),3.56(dd,1H,J=8.0Hz,11.2Hz,H-CHCHS),2.34(s,3H,CH3CO)。
13C-RMN(CDCl3,50MHz):194.5(C=O),83.4(CHCHS),82.2(CH-CHONO2),81.6(CHONO2),71.8(CH2-CHS),69.6(CH2-CHONO2),44.7(CHS),30.4(CH3CO)。
从10d中获得的S-(3R,3aS,6R,6aS)-6-(硝氧基)六氢呋喃并[3,2-b]呋喃-3-基硫代乙酸酯开始,并且按照类似于比较例1所述的方法,在第一步中获得(3R,3aS,6R,6aS)-6-巯基六氢呋喃并[3,2-b]呋喃-3-基硝酸酯;由此,按照类似于实施例1至2所述的那些方法可获得下列产物:
实施例11.(3R,3aS,6R,6aS)-6-(乙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
产率:93% HPLC纯度:91.2%
1H-NMR(200MHz,DMSO-d6):5.52-5.40(m,1H,CHONO2),4.86(t,1H,J=5.0Hz,CHCHONO2),4.44(t,1H,J=4.4Hz,CHCHS),4.10-3.10(m,5H,CH 2CHS+CH2CHONO2+CHSEt),2.55(q,2H,J=7.2Hz,CH2S),0.91(t,3H,J=7.2Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):82.76(CHCHS),82.95(CHCHONO2),82.05(CHONO2),73.11(CH2CHONO2),68.97(CH2CHS),46.49(CHS),25.46(CH2),15.51(CH3)。
实施例12.(3R,3aS,6R,6aS)-6-(丙硫基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
产率:40% HPLC纯度:96.5%
1H-NMR(200MHz,DMSO-d6):5.52-5.40(m,1H,CHONO2),4.85(t,1H,J=5.2Hz,CHCHONO2),4.43(t,1H,J=4.4Hz,CHCHS),3.40-3.10(m,2H,CH 2CHS),2.50(b.s.,2H,CH2S),1.60-1.40(m,2H,CH2),0.91(t,3H,J=7.4Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):83.21(CHCHS),82.94(CHCHONO2),82.06(CHONO2),73.09(CH2CHONO2),68.97(CH2CHS),46.77(CHS),33.51(CH2S),23.16(CH2),13.09(CH3)。
按照类似于实施例4所述的方法,并且从实施例11至12中获得的产物开始获得下列产物:
实施例13.(3R,3aS,6R,6aS)-6-((R,S)-乙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
反应粗品在硅胶上进行硅胶柱层析,并用乙酸乙酯洗脱,生成标题化合物的各个非对映异构体。
非对映异构体1
1H-NMR(200MHz,DMSO-d6):5.50-5.42(m,1H,CHONO2),4.91(t,1H,J=5.6Hz,CHCHONO2),4.70(t,1H,J=5.2Hz,CHCHS),4.25-3.80(m,4H,CH 2CHONO2+CH 2CHS),3.63-3.50(m,1H,CHS),3.00-2.70(m,2H,CH2S),1.22(t,3H,J=7.8Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):82.92(CHCHS),82.60(CHCHONO2),81.85(CHONO2),69.34(CH2CHONO2),69.18(CH2CHS),62.24(CHS),44.28(CH2S),6.35(CH3)。
非对映异构体2
1H-NMR(200MHz,DMSO-d6):5.55-5.48(m,1H,CHONO2),4.94(t,1H,J=4.8Hz,CHCHONO2),4.67(t,1H,J=4.0Hz,CHCHS),4.10-3.80(m,3H,CH 2CHONO2+CHS),3.58-3.52(m,2H,CH 2CHS),2.70-2.55(m,2H,CH2S),1.19(t,3H,J=7.6Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):82.89(CHCHS),82.54(CHCHONO2+CHONO2),69.49(CH2CHONO2),66.68(CH2CHS),64.27(CHS),43.89(CH2S),6.08(CH3)。
实施例14.(3R,3aS,6R,6aS)-6-((R,S)-丙基亚磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
对反应粗品进行硅胶柱层析并用乙酸乙酯洗脱生成标题化合物的各个非对映异构体。
非对映异构体1
HPLC纯度:96.0%。
1H-NMR(200MHz,CDCl3):5.36-5.28(m,1H,CHONO2),4.92(t,1H,J=5.6Hz,CHCHONO2),4.72(t,1H,J=5.2Hz,CHCHS),4.45-4.25(m,2H,CH 2CHONO2),4.08-3.86(m,2H,CH 2CHS),3.43-3.32(m,1H,CHS),3.00-2.70(m,2H,CH2S),2.00-1.75(m,2H,CH2),1.09(t,3H,J=7.4Hz,CH3)。
13C-NMR(50MHz,CDCl3):82.91(CHCHS),82.58(CHCHONO2),80.40(CHONO2),70.61(CH2CHONO2),69.52(CH2CHS),64.91(CHS),53.88(CH2S),15.99(CH2),13.14(CH3)。
非对映异构体2
HPLC纯度:95.8%。
1H-NMR(200MHz,CDCl3):5.38-5.31(m,1H,CHONO2),4.93(t,1H,J=5.2Hz,CHCHONO2),4.81(t,1H,J=5.2Hz,CHCHS),4.10(d,1H,J=11.4Hz,CHS),4.07-3.88(m,2H,CH 2CHONO2),3.76-3.39(m,2H,CH 2CHS),2.75-2.40(m,2H,CH2S),1.95-1.70(m,2H,CH2),1.05(t,3H,J=7.4Hz,CH3)。
13C-NMR(50MHz,CDCl3):82.64(CHCHS),82.45(CHCHONO2),81.20(CHONO2),69.82(CH2CHONO2),66.82(CH2CHS),65.82(CHS),53.59(CH2S),15.73(CH2),12.98(CH3)。
按照类似于实施例7所述的方法,并从实施例11-12或13-14获得的产物开始获得下列产物:
实施例15.(3R,3aS,6R,6aS)-6-(乙基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
1H-NMR(200MHz,DMSO-d6):5.58-5.44(m,1H,CHONO2),4.90(t,1H,J=5.2Hz,CHCHONO2),4.75(t,1H,J=4.8Hz,CHCHS),4.27(t,1H,J=7.2Hz,CHS),4.07-3.85(m,4H,CH 2CHONO2+CH 2CHS),3.17(q,2H,J=7.4Hz,CH2S),1.21(t,3H,J=7.4Hz,CH3)。
13C-NMR(50MHz,DMSO-d6):82.81(CHCHS),81.84(CHCHONO2),81.68(CHONO2),69.54(CH2CHONO2),67.51(CH2CHS),63.26(CHS),48.00(CH2S),5.31(CH3)。
实施例16.(3R,3aS,6R,6aS)-6-(丙基磺酰基)六氢呋喃并[3,2-b]呋喃-3-基硝酸酯
HPLC纯度:88.68%。
1H-NMR(200MHz,CDCl3):5.36-5.24(m,1H,CHONO2),5.10-4.70(m,2H,CHCHONO2+CHCHS),4.45-3.90(m,4H,CH 2CHONO2+CH 2CHS),3.68(b.s.,1H,CHS),3.30-2.90(m,2H,CH2S),2.10-1.80(m,2H,CH2),1.10(t,3H,CH3)。
13C-NMR(50MHz,CDCl3):82.94(CHCHS),81.64(CHCHONO2),80.47(CHONO2),70.05(CH2CHONO2),67.99(CH2CHS),66.07(CHS),55.74(CH2S),14.65(H2),13.20(CH3)。
抗血栓形成活性测试
实验步骤
在五天的驯化期之后,使用重量为250g至300g的雄性Wistar大鼠,并且将动物分组,每组8只,用于进行处理。在所有试验中,使用10mL/kg的给药量,通过灌胃用90μmol/kg的各个产物处理大鼠。用于溶解产物的媒介物由含1% Cremophor EL 27963、1%Tween 80以及0.5%Methocel E-15的蒸馏水组成。在自由使用饮用水的8小时禁食期后,在诱导血栓形成前1小时,通过填喂法给予各个产物。
使用应用于颈动脉上的包埋70% FeCl3溶液的贴片,使用与由Feuerstein GZ等人描述的步骤和由Kurz等人后来改进的步骤(Feuerstein GZ,等人Artherioscler.Thromb.Vase.Biol.1999,19:2554-2562,Kurz KD,等人Thromb.Res.1990,60:269-280)相同的步骤诱导血栓形成。在给药之后,在不同的时间评估抗血栓形成效力。在37℃,用戊巴比妥钠麻醉大鼠,然后将其放置在位于手术板上的热毯上的仰卧位置,并且对其加热。切开左侧颈动脉并将电磁血流量探头放置在该动脉上以检测血流量。在进行血栓性刺激后,在接下来的30分钟监测血流量。当流量达到0.0ml/min时,认为血管由于血栓形成而堵塞。
使用Graph Pad Prism程序,通过列联表分析数据。使用费歇尔精确检验计算P值,认为P值<0.05时是统计学显著的。将结果表示为被保护动物的百分数。
表I
异构体2 | ||||
实施例15 | n.d. | 9 | n.d. | 0 |
实施例16 | n.d. | 40 | n.d. | 20 |
抗心绞痛活性测试
在五天的驯化期后,使用重量为250g至300g的雄性Wistar大鼠,并且将动物分组,每组8只,用于进行处理。在所有试验中,除非另作说明,使用10mL/kg的给药量,通过灌胃用90μmol/kg的各个产物处理大鼠。用于溶解产物的媒介物由含1% Cremophor EL 27963、1% Tween 80和0.5% Methocel E-15的蒸馏水组成。在自由使用饮用水的8小时禁食期后,在诱导心绞痛之前1小时,通过填喂法来给予各个产物。
用于测试抗心绞痛活性的步骤是由Hirata Y等人(Hirata Y,等Journal of Cardiovascular Pharmacology 1998,31:322-326)描述的步骤。
在处理之后,用戊巴比妥麻醉动物,并且放置用于标准肢体导联II心电图记录的电极(Grass polygraph模型7,放大器7DA以及前置放大器7P1)。
为了诱导由冠状动脉阻塞引起的冠状动脉心绞痛,将包埋35%氯化铁的袖珍贴片应用于恰好在左心耳下方的冠状动脉左前降枝上。在所有组中,在应用贴片之后,在10分钟内记录ECG。在记录的ECG上检测S波幅的缩短。用与奔腾计算机连接的Biopac系统模型MP100来采集数据。将结果表示为抑制S波减少的百分数对未处理的对照。
表II
从表I和表II可以看出,本发明的化合物具有优异的抗心绞痛和/或抗血栓形成活性,与属于现有技术的那些比较化合物相比,本发明的化合物的持续时间更长。
Claims (10)
2.如权利要求1所述的化合物,其中G表示-S(O)n-基团,n为选自1和2的整数,并且R表示选自C2-C3烷基和C3烯基的基团。
3.如权利要求2所述的化合物,其中G表示-S(O)-基团。
4.如权利要求2所述的化合物,其中G表示-S(O)2-基团。
5.如权利要求2至4中任一权利要求所述的化合物,其中R表示选自乙基、正丙基和烯丙基的基团。
6.如权利要求1所述的化合物,其中所述R-G-基团表示CH3-(C=O)-S-,并且所述基团位于硝酸酯基团的顺式位置。
7.药物组合物,其包含作为活性成分的至少一种权利要求1至6中任一权利要求所述的化合物,任选连同一种或多种药物可接受的赋形剂。
8.如权利要求7所述的药物组合物,其另外包含一种或多种其它的活性成分,所述其它活性成分选自溶栓剂、抗凝剂、抗血栓形成剂、免疫球蛋白类或其片段、降血脂剂以及抗氧化剂/自由基清除剂。
9.用于治疗和/或预防动脉粥样硬化、心脏移植物血管病、血小板激活、血栓症、中风、由于缺血和/或由于缺血-再灌注引起的组织损伤,和/或氧化应激在其发病机理中起重要作用的病理疾病状态,和/或NO不足在其发病机理中起重要作用的病理疾病状态的权利要求7和8中任一权利要求所述的药物组合物。
10.权利要求1至6中任一权利要求所述的至少一种化合物作为活性成分在制备用于治疗和/或预防动脉粥样硬化、心脏移植物血管病、血小板激活、血栓症、中风、由于缺血和/或由于缺血-再灌注引起的组织损伤,和/或其中氧化应激在其发病机理中起重要作用的病理疾病状态的药物中的用途。
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US12/334,986 | 2008-12-15 | ||
US12/334,986 US8211939B2 (en) | 2008-07-22 | 2008-12-15 | Isosorbide nitrates |
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CN105026402A (zh) * | 2013-03-05 | 2015-11-04 | 阿彻丹尼尔斯米德兰德公司 | 异己糖醇单三氟甲磺酸酯及其合成方法 |
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US10691097B2 (en) | 2014-05-09 | 2020-06-23 | The Boeing Company | Path repeatable machining for full sized determinant assembly |
US10501471B1 (en) * | 2018-11-04 | 2019-12-10 | John F. Schmedtje, Jr. | Compounds useful for treating cardiovascular diseases |
US10913748B2 (en) * | 2018-11-04 | 2021-02-09 | Coeurative, Inc. | Compounds useful for treating cardiovascular diseases |
CN113683623B (zh) * | 2021-09-09 | 2022-08-12 | 中国人民解放军空军军医大学 | 一种no供体化合物及其制备方法和用途 |
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DE602008006545D1 (de) | 2011-06-09 |
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WO2010010101A1 (en) | 2010-01-28 |
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