CN1382140A - 具有神经营养活性的吡咯烷和哌啶、以及含有它们的相关组合物 - Google Patents
具有神经营养活性的吡咯烷和哌啶、以及含有它们的相关组合物 Download PDFInfo
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- CN1382140A CN1382140A CN00812744A CN00812744A CN1382140A CN 1382140 A CN1382140 A CN 1382140A CN 00812744 A CN00812744 A CN 00812744A CN 00812744 A CN00812744 A CN 00812744A CN 1382140 A CN1382140 A CN 1382140A
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Abstract
本发明提供了具有通式结构(I)、(II)、(III)的化合物。本发明还提供了包含所述化合物的药物组合物,以及使用这些组合物来治疗和预防其特征是神经元损伤的病症的方法。
Description
发明领域
本发明涉及具有神经营养活性的新的吡咯烷和哌啶。这些化合物以及相关组合物和方法可用于治疗和预防神经疾病例如帕金森氏病、阿尔茨海默氏病、中风、多发性硬化、肌萎缩性侧索硬化、糖尿病性神经病和贝尔麻痹。
发明背景
神经变性疾病
神经变性疾病在全球范围内给公众健康带来了严重威胁。最严重的这类疾病之一是阿尔茨海默氏病(“AD”),这是造成老年人痴呆的主要原因,并且在美国是排名第四的常见死亡病因。在美国,据估计总共有两百万-三百万人患有AD,并且对于65岁以上的人群,有5%以上的人患有AD。虽然AD的精确病因尚有待确定,但是该疾病的特征是存在大量淀粉样蛋白斑,在涉及认知功能的脑区域有神经原纤维结,以及从基底前脑到皮层和海马区域发生的胆碱能神经元变性。目前对于AD没有任何有效治疗。Brinton,R.D.和Yamazaki,R.S.,Pharm.Res.,1998,15,386-398。
与AD相似,帕金森氏病(“PD”)是中枢神经系统(″CNS″)的进行性变性疾病。在一般人群中,该疾病的一生发生率大约为2%。在PD中,塞梅林神经节的多巴胺能神经元的变性导致在控制自发性运动的脑区域—纹状体中多巴胺水平下降。因此,标准治疗已把目标集中在施用能补充脑患病区域多巴胺水平的活性剂(例如L-多巴和溴隐亭)上。然而,由于神经细胞持续死亡和该疾病的进展,这种多巴胺能治疗方案失去了治疗效力。同时,在PD早期中观察到的无意识震颤发展成动作困难期,并最终不能运动。因此,人们正在积极地寻求替代治疗。Pahwa,R.和Koller,W.C.,Drugs Today,1998,34,95-105。
躯体感觉神经系统的神经变性疾病也构成了一类衰弱其可能地致死的病症。肌萎缩性侧索硬化(“ALS”)是致命的疾病,其特征是上和下运动神经元的进行性变性。虽然ALS的精确病因尚是未知的,但是普遍的理论提出,兴奋毒性和/或氧化应激反应是致病因素。利鲁唑是第一个被批准市售的用于ALS的药物。其具有抗兴奋毒性的作用,并且已表明能提高ALS患者的存活比例。然而,该药物不能治愈ALS,目前正在进行替代活性剂的临床试验。Louvel,E.,Hugon,J.和Doble,A.,Trends Pharmacol.Sci.,1997,18,196-203。
外周神经病是多种代谢和血管疾病的继发症。特别是约有30%的糖尿病患者患有某些类型的外周神经病,这些神经病可影响小的有髓神经纤维,引起疼痛和温度感觉丧失,或影响大的神经纤维,引起运动或躯体感觉缺陷。药物治疗是针对症状的,最佳的治疗和预防方法仍然是通过饮食和施用胰岛素来维持正常血糖水平。Bissels,G.J.和Van Dam,P.S.,Neurosci.Res.Commun.,1997,20,1-10。
现在有大量证据表明,一些蛋白生长因子或神经营养因子的不足可能在外周和中枢神经变性疾病中起着重要的病因作用。Tomlinson,D.R.,Fernyhough,P.和Diemel,L.T.,Diabetes,1997,46(suppl.2)S43-S-49;Hamilton,G.S.,Chem.Ind.,(London)1998,4,127-132;Louvel,E.,Hugon,J.和Doble,A.,TrendsPharmacol.Sci.,1997,18,196-203;Ebadi,M.,等人,Neurochem.Int.,1997,30,347-374。
这些神经营养因子可根据结构分为两类:1)神经营养素(neutrophins),包括神经生长因子(“NGF”);神经胶质细胞衍生神经营养生长因子(“GDNF”);脑衍生神经营养因子(“BDNF”);神经营养素3(“NT-3”);神经营养素4/5(“NT-4/5”);神经营养素2(“NT-2”);和与细胞因子分子家族有关的纤毛状神经营养因子(“CNTF”)。所有神经营养因子都促进轴突分枝,诱导分化,并抑制特定外周和中枢神经元亚群中的编程性细胞死亡或细胞程序死亡。例如,NGF对脊神经节的交感神经和感觉神经元以及CNS中内隔膜的胆碱能神经元具有营养作用,这表明其有可能用于治疗AD。CNTF对神经元,包括副交感神经、感觉、交感神经、运动、小脑、海马、和中隔神经元的宽阔横断面具有营养作用。特别值得关注的是这样的事实,CNTF部分防止神经损害后骨骼肌的萎缩,但是对于受神经支配的肌肉则没有影响,这表明CNTF主要在病理状态下起作用。因此,目前正在评价CNTF对于肌与骨骼疾病例如ALS的影响。
蛋白神经营养剂的临床应用受到了其有限生物利用度的严重阻碍,尤其是在CNS中更是如此。需要将这些活性剂直接施用到脑中以实现治疗效果—这是比较危险和麻烦的给药途径。
化学活性剂
Lyons,W.E.,等人(Proc.Natl.Acad.Sci.,1994,91(8),3191-5)描述了免疫抑制药物FK506的神经营养作用,该药物在PC12细胞和感觉神经节培养物中表现出神经营养活性:
Vertex Pharmaceuticals,Inc.(“Vertex”)在南非申请964852中公开了一些化合物,这些化合物可用于抑制FKBP12亲免疫因子的旋转异构酶(rotamase)活性,并刺激轴突在细胞培养物中生长。下述结构是这些化合物的典型代表:
共同属于Guilford Pharmaceuticals,Inc.,GPI NIL Holdings,Inc.和Johns Hopkins University School of Medicine(统称为“Guilford”)的专利公开了一些化合物,这些化合物可用于抑制FKBP型亲免疫因子的活性,刺激神经元生长和再生,以及治疗神经疾病。
特别是,Guilford的U.S.专利5,696,135和PCT申请WO96/40140公开了使用涉及FK506和雷怕霉素的2-哌啶酸衍生物来治疗动物中神经疾病的的方法。据述其中的化合物可用于抑制FKBP型亲免疫因子的旋转异构酶活性,在体外刺激小鸡脊神经节中的神经元生长,并促进大鼠中受损的坐骨神经的恢复。
Guilford的U.S.专利5,798,355公开了使用大环和无环2-哌啶酸衍生物的方法,据述这些衍生物能抑制FKBP型亲免疫因子的酶活性,和刺激神经元生长和再生。
Guilford的U.S.专利5,614,547和5,795,908、以及PCT申请WO 96/40633公开了一系列N-乙醛酰基-脯氨酰基酯化合物,据述这些化合物可用于抑制FKBP-12亲免疫因子旋转异构酶活性,促进神经元生长和再生,和治疗神经疾病。下述结构是这些化合物的典型代表:
Guilford的U.S.专利5,801,197和PCT申请WO 97/16190公开了一系列非免疫抑制性2-哌啶酸衍生物,据述这些化合物可用于治疗动物中受损害的神经。下述结构是这系列类似物的代表性结构:
Guilford的U.S.专利5,721,256公开了一些化合物,据述这些化合物可用于抑制FKBP旋转异构酶活性,促进神经元生长和再生,以及影响动物中神经元的活动。下述结构是这系列氨磺酰化合物的典型代表:
Guilford的U.S.专利5,801,187和PCT申请WO 98/13355公开了一系列杂环酯和酰胺化合物,据述这些化合物可用于抑制FKBP旋转异构酶活性,促进神经元生长和再生,以及影响动物中神经元的活动。下述结构是这些化合物的典型代表:
Guilford的PCT申请WO 98/13343公开了一系列杂环硫酯和酮化合物,据述这些化合物可用于抑制FKBP旋转异构酶活性,促进神经元生长和再生,以及影响动物中神经元的活动。下述结构是这些化合物的典型代表:
Guilford的PCT申请WO 98/29116公开了一系列杂环硫酯的N-连接的氨磺酰化合物,据述这些化合物可用于抑制FKBP旋转异构酶活性,促进神经元生长和再生,以及影响动物中神经元的活动。下述结构是这些化合物的典型代表:
Guilford的PCT申请WO 98/29117公开了一系列杂环硫酯的N-连接的脲和氨基甲酸酯化合物,据述这些化合物可用于抑制FKBP旋转异构酶活性,促进神经元生长和再生,以及影响动物中神经元的活动。下述结构是这些化合物的典型代表:
Guilford的PCT申请WO 98/37882公开了使用小分子氨基甲酸酯和脲化合物的方法,据述这些化合物可用于抑制FKBP型亲免疫因子的旋转异构酶活性,刺激神经元生长和再生。下述结构是这些化合物的典型代表:
Guilford的PCT申请WO 98/37885公开了一系列杂环酯、酰胺、硫酯和酮的N-氧化物化合物,据述这些化合物可用于抑制FKBP的旋转异构酶活性,促进神经元生长和再生,以及治疗动物中神经疾病。下述结构是这些化合物的典型代表:
Guilford的PCT申请WO 98/25950公开了一系列含有至少2个脯氨酸残基的四肽和五肽化合物,据述这些化合物可用于抑制FKBP的旋转异构酶活性,促进神经元生长和再生,以及影响动物中神经元的活动。
都属于Ariad Gene Therapeutics,Inc.(“Ariad”)的专利和出版物公开了一些活性剂,据述这些活性剂可用于将亲免疫因子多聚化、基因治疗应用、激活基因转录、激动细胞程序死亡、或在培养物或全生物体中生长的工程细胞中启动其它生物事件。
特别是,Ariad的PCT申请WO 96/06097、WO 97/31898、WO97/31899和Holt,D.A.,等人(Bioorg.Med.Chem.,1998,6(8),1309-1335)公开了一些化合物,这些化合物包括下述结构代表的一系列多聚化剂:
共同属于Cephalon,Inc.和Kyowa Hakko Kogyo Co.,Ltd.(统称为“Cephalon”)的专利描述了在治疗神经变性疾病中具有潜在临床应用性的小分子神经营养剂。
特别是,Cephalon的U.S.专利5,756,494、5,621,101和5,461,146、以及PCT申请WO 96/13506和WO 94/02488公开了一系列吲哚并咔唑蛋白激酶抑制剂,据述这些抑制剂对中枢胆碱能神经元、脊神经节和脊髓有神经营养作用。下述结构是这些化合物的典型代表:
上述活性剂没有一种经证实对人神经变性疾病具有治疗或预防效力。因此,存在着对于具有这种效力的活性剂的迫切且未满足的需要。
附图简述
附图1表示的是,使用大鼠面神经压迫模型,本发明化合物30的体内生物活性。在该模型中,压缩面神经引起该侧面部上的腮须肌肉麻痹。在另一侧上的未处理的面神经用作内对照。结果证明,与载体和内对照相比,用化合物30治疗使得麻痹一侧的腮须动作恢复得更快。与载体和内对照相比的麻痹一侧的腮须动作恢复速度显示在该附图中。
发明概述
本发明提供了具有下述结构的化合物或其可药用盐,其中
(a)R1选自H、COCOR2、COOR3和SO2R3,
(i)R2选自O-C1-6直链或支链烷基、C1-6直链或支链烷基、
C1-6直链或支链链烯基、C5-7环烷基、2-噻吩基、3-噻
吩基或苯基,所述苯基具有1-3个独立地选自下列的
取代基:H、低级烷基、低级烷氧基、羟基和卤素,且
(ii)R3是苯基烷基,所述苯基具有1-3个独立地选自下列
的取代基:H、低级烷基、低级烷氧基、羟基和卤素;
(b)
是4-6元杂环,其中在所述杂环中有不超过一个环原子是O或S;
(d)A选自COO(CH2)mAr、
(此处的R1与在(a)部分中描述的R1相同或不同)、
CONR4(CH2)mAr、(CH2)mO(CH2)nAr和(CH2)nAr,
(i) R4是H或C1-4烷基;
(ii) Ar选自2-吡啶基、3-吡啶基、4-吡啶基和苯基,所
述苯基具有1-3个独立地选自下列的取代基:H、低
级烷基、低级烷氧基、羟基和卤素;
(iii) m是1-4;且
(iv) n是0-4。
本发明还提供了具有下述结构的化合物或其可药用盐,其中R″是C(1-4)-直链或支链烷基。
(a)R1选自H、COCOR2、COOR3和SO2R3,
(i)R2选自O-C1-6直链或支链烷基、C1-6直链或支链烷基、
C1-6直链或支链链烯基、C5-7环烷基、2-噻吩基、3-噻
吩基或苯基,所述苯基具有1-3个独立地选自下列的
取代基:H、低级烷基、低级烷氧基、羟基和卤素,且
(ii)R3是苯基烷基,所述苯基具有1-3个独立地选自下列
的取代基:H、低级烷基、低级烷氧基、羟基和卤素;
本发明还提供了刺激神经元生长的方法,包括使神经元与有效量的一种本发明化合物接触。本发明还提供了包含一种本发明化合物和可药用载体的药物组合物。
本发明还提供了治疗患有其特征是由疾病或创伤引起的神经元损伤的病症的个体的方法,包括给所述个体施用治疗有效量的本发明药物组合物。最后,本发明还提供了抑制个体中其特征是由疾病引起的神经元损伤的病症发作的方法,包括给所述个体施用预防有效量的本发明药物组合物。发明详述
本发明提供了具有令人惊奇的神经营养活性的新的吡咯烷和哌啶。这些化合物、以及相关药物组合物和方法可用于治疗和预防神经疾病例如帕金森氏病、阿尔茨海默氏病、中风、多发性硬化、肌萎缩性侧索硬化、糖尿病性神经病和贝尔麻痹。
具体来说,本发明提供了具有下述结构的化合物
或其可药用盐,其中
(a)R1选自H、COCOR2、COOR3和SO2R3,
(i)R2选自O-C1-6直链或支链烷基、C1-6直链或支链烷基、
C1-6直链或支链链烯基、C5-7环烷基、2-噻吩基、3-噻
吩基或苯基,所述苯基具有1-3个独立地选自下列的
取代基:H、低级烷基、低级烷氧基、羟基和卤素,且
(ii)R3是苯基烷基,所述苯基具有1-3个独立地选自下列
的取代基:H、低级烷基、低级烷氧基、羟基和卤素;
(b)
是4-6元杂环,其中在所述杂环中有不超过一个环原子是O或S;
(此处的R1与在(a)部分中描述的R1相同或不同)、
CONR4(CH2)mAr、(CH2)mO(CH2)nAr和(CH2)nAr,
(i) R4是H或C1-4烷基;
(ii) Ar选自2-吡啶基、3-吡啶基、4-吡啶基和苯基,所
述苯基具有1-3个独立地选自下列的取代基:H、低
级烷基、低级烷氧基、羟基和卤素;
(iii)m是1-4;且
(iv) n是0-4。
在优选的实施方案中,这一化合物选自本发明化合物4、14、30、31、35、38、43、44、55、56、58、60、62和64。
本发明还提供了具有下述结构的化合物或其可药用盐,其中
(a)R1选自H、COCOR2、COOR3和SO2R3,
(i) R2选自O-C1-6直链或支链烷基、C1-6直链或支链烷基、
C1-6直链或支链链烯基、C5-7环烷基、2-噻吩基、3-噻
吩基或苯基,所述苯基具有1-3个独立地选自下列的
取代基:H、低级烷基、低级烷氧基、羟基和卤素,且
(ii) R3是苯基烷基,所述苯基具有1-3个独立地选自下列
的取代基:H、低级烷基、低级烷氧基、羟基和卤素;
(b)
是4-6元杂环,其中在所述杂环中有不超过一个环原子是O或S;
(c)
是5元杂环,其中所述杂环具有2-3个选自N、O和S的杂原子,至少一个这样的杂原子是N;且
(d)B是(CH2)nAr或
,其中n为0-4。
在优选的实施方案中,该化合物选自本发明化合物24、26、37和59。
本发明化合物可以作为游离碱分离出来并使用。本发明化合物还可以作为可药用盐分离出来并使用。这样的盐的实例包括氢溴酸盐、氢碘酸盐、盐酸盐、高氯酸盐、硫酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、扁桃酸盐、甲磺酸盐、羟乙磺酸盐(hydroethanesulfonic)、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己烷氨基磺酸盐和葡糖二酸盐。
本发明还提供了刺激神经元生长的方法,包括使神经元与有效量的一种本发明化合物接触。所述接触可例如在体外或体内进行。
本发明还提供了包含一种本发明化合物和可药用载体的药物组合物。
可药用载体是本领域技术人员众所周知的,并包括但不限于约0.01-约0.1M、优选0.05M的磷酸盐缓冲液或0.8%盐水。这样的可药用载体可以是水或非水溶液、悬浮液和乳液。非水溶剂的实例有丙二醇、聚乙二醇、植物油例如橄榄油、和可注射用的有机酯例如油酸乙酯。水载体包括水、乙醇、醇/水溶液、甘油、乳液或悬浮液,包括盐水和缓冲介质。口服载体可以是酏剂、糖浆剂、胶囊、片剂等。典型固体载体是惰性物质例如乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、甘露醇等。非胃肠道给药用载体包括氯化钠溶液、林格氏葡萄糖溶液、葡萄糖和氯化钠、乳酸盐林格氏溶液和不挥发油。静脉内载体包括液体和营养补充物、电解质补充物例如以林格氏葡萄糖溶液为基质的电解质补充物等。还可以含有防腐剂和其它添加剂,例如抗微生物剂、抗氧化剂、螯合剂、惰性气体等。可以按照需要使用本领域已知的常规技术将所有载体与崩解剂、稀释剂、制粒剂、润滑剂、粘合剂等混合。
本发明还提供了治疗患有其特征是由疾病或创伤引起的神经元损伤的病症的个体的方法,包括给所述个体施用治疗有效量的本发明药物组合物。
本文所用术语“个体”包括但不限于任何动物或人工改型的动物。在优选的实施方案中,个体是人。
本发明组合物的施用可用任意本领域技术人员已知的各种不同方法来完成或进行。本发明化合物可例如静脉内、局部、肌内、口服、皮下施用,并且可直接施用到脑脊髓流体和/或脑中。在优选的实施方案中,本发明药物组合物是口服施用。此外,给药可包括在合适的时间内给个体施用多个剂量。可依据常规方法来决定给药方案。
特征是神经元损害的病症有很多,其包括但不限于下述病症:阿尔茨海默氏病、皮克病、弥漫性雷维小体病(diffuse Lewy bodydisease)、进行性核上性麻痹(Steel-Richardson综合征)、多系统变性(Shy-Drager综合征)、运动神经元疾病包括肌萎缩性侧索硬化、变性共济失调、皮层基底变性、Guam ALS-帕金森氏-痴呆并发症、亚急性致硬化性全脑炎、亨廷顿氏舞蹈病、帕金森氏病、synucleinopathies、原发性进行性失语症、条纹状黑质变性、3型Machado-Joseph病/脊髓小脑运动失调和橄榄体脑桥小脑变性、Gilles De La Tourette’s病、延髓和假延髓病麻痹、脊柱和脊髓延髓肌肉萎缩(Kennedy’s病)、原发性侧索硬化、家族性痉挛性截瘫、Werdnig Hoffmann病、Kugelberg-Welander病、Tay-Sach’s病、Sandhoff病、家族性痉挛病、Wohlfart-Kugelberg-Welander病、痉挛性麻痹、进行性多灶性脑白质病、和朊病毒疾病(包括Creutzfeldt-Jakob、Gerstmann-Strussler-Scheinker病、Kuru和致死性家族性失眠症)。
其它病症包括但不限于弥散性白质病(Binswanger氏病)、头部创伤和弥散性脑损伤、脊髓损伤、颅内和脊柱内损伤(包括但不限于挫伤、穿透、剪切、压迫和撕裂)、脑缺血或梗塞导致的中风、栓塞性闭塞和血栓形成性闭塞、和任何类型的颅内出血(包括但不限于硬膜外、硬膜下、蛛网膜下和大脑内出血)。
另外的病症包括但不限于脱髓鞘性疾病例如多发性硬化;多神经根神经炎(格-巴二氏综合征);亚急性脱髓鞘性多神经病;急性散播性脑脊髓炎、急性出血性脑白质炎或全身性红斑狼疮引起的脑损伤;与多灶性脑损伤、神经病和/或脊髓病有关的贝切特氏综合征;与神经损伤或萎缩或脊髓病有关的肉样瘤病;导致脑、脊髓、神经损伤、脑膜神经根炎、和/或脊髓病的细菌或病毒感染;亚急性混合变性;横贯性脊髓炎;利伯氏遗传性神经病;亚急性坏死性脑病(Leigh氏病);具有脱髓鞘作用的线粒体脑病;异染性脑白质病变;克拉贝氏病;Fabry氏病;肾上腺白质营养不良(adrenoleukodystrophy);视神经脊髓炎(德维克氏综合征);脱髓鞘性神经鞘疾病;颅和外周神经病,包括但不限于Déjerine-Sottas神经病及其变型;Charcot-Marie-Tooth病及其变型;遗传性多神经病;感觉和运动神经病;轴索神经病;肾上腺脊髓神经病;雷弗素姆氏病;由于卟啉症、急性或慢性毒素/药物中毒而导致的涉及轴索、脱髓鞘、感觉、运动和/或自主障碍的神经病;弗里德希氏共济失调;共济失调性毛细管扩张;和异染性脑白质营养不良;慢性神经病,包括但不限于糖尿病和其它代谢失调和血内蛋白异常(代谢性神经病,包括由于酒精中毒所致的那些);和炎性/免疫过程(炎性神经病、与带状疱疹有关的神经病、和麻疯病性神经炎)。
其它病症,包括但不限于外周或颅神经创伤性神经病、贝尔麻痹和其它面神经病、三叉神经病、前庭神经病、副神经病、迷走神经病、舌咽神经病、视神经病、眼球运动神经病、多颅神经麻痹、丛病、根疾病、自发性臂丛神经炎、神经丛炎、多灶性神经病、和自主神经系统神经病。
在一个本发明实施方案中,所治疗的病症是与疾病引起的,并选自帕金森氏病、阿尔茨海默氏病、中风、多发性硬化、肌萎缩性侧索硬化、糖尿病性神经病和贝尔麻痹。在另一个实施方案中,所治疗的病症是由于脑、脊髓、或外周神经创伤引起的。
最后,本发明还提供了抑制个体中其特征是疾病引起的神经元损伤的病症发作的方法,包括给所述个体施用预防有效量的本发明药物组合物。
在一个实施方案中,所抑制的病症选自帕金森氏病、阿尔茨海默氏病、中风、多发性硬化、肌萎缩性侧索硬化、糖尿病性神经病和贝尔麻痹。
本文所用的药物组合物的“治疗有效量”是足以停止、逆转或减轻病症进行的量。药物组合物的“预防有效量”是足以抑制病症发作,即消除、改善和/或延迟病症发作的量。确定本发明药物组合物的治疗和预防有效量的方法是本领域已知的。施用给人的药物组合物的有效量可例如通过数学方法从动物实验结果来确定。
在一个实施方案中,治疗和/或预防有效量是足以递送约0.01mg/kg-约200mg/kg体重本发明化合物的剂量。在另一个实施方案中,治疗和/或预防有效量是足以递送约0.1mg/kg-约100mg/kg体重本发明化合物的剂量。在优选的实施方案中,治疗和/或预防有效量是足以递送约1mg/kg-约30mg/kg体重本发明化合物的剂量。
通过下述实验详述可更好地理解本发明,但是本领域技术人员很容易理解,这些实验详述仅是举例说明在权利要求书中更全面描述的本发明。此外,在整个本申请中提及了多篇不同出版物。将这些出版物的公开内容引入本发明以作参考,来更全面地描述本发明所属于的领域的状态。实验详述
I.一般合成方法
本发明代表性化合物可依据下述一般合成方法来合成,并在下述合成方案1中说明。在这些合成方案中,交替地使用阿拉伯和罗马数字来表示不同化合物。通过阿拉伯数字在该节中提及的化合物不与通过阿拉伯数字在表1中以及本文别处提及的具体化合物相混淆。
合成方案1
通式1a化合物[其中
和
具有本文所用含义;Z是(C1-C6)-直链或支链烷基、(C1-C6)-直链或支链链烯基或(C5-C7)环烷基、或苯基;其中该苯环具有1-3个独立地选自氢、低级烷基、低级烷氧基、羟基和卤素的取代基;Y是A或低级烷氧基羰基;且A具有本文所用含义]可这样制得:根据下述草氨酸酯的活性,将通式1b化合物:[其中
和
具有本文所用含义;R是(C1-C6)-直链或支链烷基;Y是A或低级烷氧基羰基;且A具有本文所用含义]与适当保护的格式试剂在惰性溶剂例如四氢呋喃或乙醚中于约-78℃-约0℃温度下反应约2小时-约6小时。
合成方案2
或者,化合物1a和1b[其中
和
具有本文所用含义;R是(C1-C6)-直链或支链烷基;Y是A或低级烷氧基羰基;A具有本文所用含义;且Z是(C1-C6)-直链或支链烷基、(C1-C6)-直链或支链链烯基或(C5-C7)环烷基、2-噻吩基、3-噻吩基、或苯基;其中该苯环具有1-3个独立地选自氢、低级烷基、低级烷氧基、羟基和卤素的取代基]可这样制得:将通式2化合物:[其中
和A具有本文所用含义]与适当保护的乙醛酰氯或烷基草酰氯在惰性溶剂例如二氯甲烷中反应约2小时-约6小时。一般情况下,该反应在有机胺例如二异丙基乙基胺或三乙胺存在下于约0℃-约37℃进行。
对于定义如上的化合物1a,该转化还可以这样进行:在偶联剂例如二异丙基碳化二亚胺、二环己基碳化二亚胺、或苯并三唑-1-基氧基三(二甲基氨基)鏻六氟磷酸盐(Castro’s试剂)存在下,将定义如上的化合物2与适当保护的乙醛酸在惰性溶剂例如四氢呋喃、二甲基甲酰胺、或二氯甲烷中于约0℃-约37℃缩合2小时-约24小时。
合成方案3
通式3化合物[其中
和A具有本文所用含义;且R3是苯基烷基;其中该苯环具有1-3个独立地选自氢、低级烷基、低级烷氧基、羟基和卤素的取代基]可这样制得:将定义如上的化合物2与苯基烷基磺酰氯在惰性溶剂例如二氯甲烷中反应约2小时-约24小时。一般情况下,该反应在有机胺例如二异丙基乙基胺或三乙胺存在下于约0℃-约37℃温度下进行。
合成方案4
定义如上的化合物2可由定义如上的通式4化合物通过按照标准方法除去N-苄氧基羰基而制得:这样的方法包括使用贵金属催化剂例如钯/炭在醇溶剂中于室温(RT)催化氢化约4小时-约24小时,或者与三溴化硼在惰性溶剂例如二氯甲烷中于约-78℃-约25℃温度下反应约2小时-约6小时,或者与强酸例如氢溴酸在乙酸中于约20℃-约100℃反应约2小时-约6小时。对于后一方法,产物通常是作为氢溴酸盐分离出来。
合成方案5
通式5a化合物[其中
、m、和Ar具有本文所用含义]可这样制得:将定义如上的通式5b化合物与芳族或杂芳族醇例如3-羟基吡啶反应。该反应一般在偶氮二甲酸衍生物例如偶氮二甲酸二乙酯或1,1’-(偶氮基二羰基)二哌啶和膦衍生物例如三苯基膦或三正丁基膦存在下在惰性溶剂例如四氢呋喃或甲苯中进行约12-约24小时。该反应温度可以为约20℃-约65℃。
合成方案6
通式6a和6b化合物[其中
、R4、m、和Ar具有本文所用含义;R是COCOR2、COOR3或SO2R3;且R2和R3具有本文所用含义]可这样制得:将通式6c化合物[其中
和
具有本文所用含义;R是COCOR2、COOR3或SO2R3;且R2和R3具有本文所用含义]与芳基烷基胺或芳基烷醇衍生物反应。该反应是通过加入试剂例如二苯基磷酰基叠氮化物、氯甲酸异丙烯酯、或氯甲酸异丁酯与有机胺碱例如三乙胺或二异丙基乙基胺在惰性溶剂例如四氢呋喃或二甲基甲酰胺中经由酰基叠氮化物或混合酸酐中间体进行的。还可以加入酰化催化剂例如二甲基氨基吡啶。该反应一般在约0℃-约25℃温度下进行约12-约24小时。
合成方案7
化合物5b可通过用金属氢化物还原剂例如硼氢化锂或硼氢化钠/氯化锂混合物将化合物7还原而制得:[其中
和m具有本文所用含义;且R是低级烷基]。该反应一般在醇溶剂例如乙醇或甲醇中、加入或不加入四氢呋喃、于约室温-约65℃温度下进行约24小时-约72小时。
合成方案8
化合物6c可这样制得:将通式8化合物[其中
和
具有如上所述的含义;R是COCOR2、COOR3或SO2R3;R2和R3具有本文所用含义;且R′是低级烷基]与碱金属氢氧化物或碱金属碳酸盐例如氢氧化锂、氢氧化钠或碳酸钾在混合水溶剂体系例如四氢呋喃/水或乙醇/水中于约室温-约80℃温度下进行约3小时-约24小时。
合成方案9
通式9a化合物[其中
和m具有本文所用含义;且R是低级烷基]可这样制得:将定义如上的通式9b化合物与α-溴酮基酯例如溴丙酮酸乙酯或γ-溴乙酰乙酸乙酯在醇溶剂例如乙醇中缩合。该反应可在约20℃-约80℃进行约2小时-约24小时。
合成方案10
定义如上的通式10a化合物可按照类似方法制得:将化合物9b与定义如上的通式10b化合物在醇溶剂例如乙醇中于约80℃温度下缩合约3小时-约24小时。
合成方案11
定义如上的化合物10b可这样制得:将定义如上的通式11化合物与溴化氢在惰性溶剂例如乙醚中反应。该反应一般在约0℃-约25℃温度下进行直至N2释放完全。
合成方案12
化合物11可通过下述方法由通式12化合物制得:[其中
具有如上所述的含义]将化合物12的酰氯衍生物与重氮甲烷或三甲基甲硅烷基重氮甲烷在有机碱例如三乙胺或二异丙基乙基胺存在下反应。该反应一般在惰性溶剂例如四氢呋喃、乙腈、或二者的混合物中于约0℃-约25℃温度下进行约2小时-约24小时。所述酰氯可用文献中的标准方法由相应的酸制得,例如通过将相应的酸与草酰氯在惰性溶剂例如二氯甲烷或四氢呋喃中在催化量的二甲基甲酰胺存在下反应而获得。
合成方案13
通式13化合物[其中
具有本文所用含义;且R是低级烷基]可这样制得:将化合物12与衍生自异氰基乙酸烷基酯的阴离子在极性惰性溶剂例如二甲基甲酰胺中反应约12小时-24小时。通常使用碱金属碳酸盐例如碳酸钾以生成所需阴离子。为了促进反应,通过与二苯基磷酰基叠氮化物反应来将化合物12羧酸在原位转化成活性反应物例如酰基叠氮化物。
合成方案14
通式14a化合物[其中
、和Ar具有如上所述的含义;R是COCOR2、COOR3或SO2R3;且R2和R3具有本文所用含义]可这样制得:在偶联剂例如水溶性碳化二亚胺、二异丙基碳化二亚胺或二环己基碳化二亚胺存在下,在惰性溶剂例如二甘醇二甲醚或二氧杂环己烷中,将通式14b化合物[其中Ar具有本文所用含义]与通式14c化合物反应[其中
具有如上所述的含义;R是COCOR2、COOR3或SO2R3;且R2和R3具有本文所用含义]该反应通常在约50℃-约110℃进行约5小时-约24小时。
化合物14b可通过将芳烷基腈与羟基胺盐酸盐在极性质子溶剂例如乙醇中在无机碱例如碳酸钾存在下反应而制得。该反应通常在约20℃-约100℃温度下进行约12小时-约72小时。
合成方案15
通式15a化合物[其中R是COCOR2、COOR3或SO2R3;R2和R3具有本文所用含义;V是(CH2)nAr或
;且Ar具有本文所用含义]可这样制得:将通式15b化合物[其中R是COCOR2、COOR3或SO2R3;R2和R3具有本文所用含义;V是(CH2)nAr或
;且Ar具有本文所用含义]与环化脱氢试剂反应,例如与在吡啶中的亚硫酰氯反应,与六甲基二硅氮烷在氟化四正丁基铵和咪唑存在下反应,与Et3N+S(O)2N-COOMe(Burgess试剂)反应,或者在三乙胺存在下与三氟甲磺酸酐反应。对于在吡啶中的亚硫酰氯,与该二酰基肼衍生物的初始反应是在约0℃进行约2小时-约6小时。闭环成噁二唑的随后反应在惰性溶剂例如甲苯中于约80℃-约150℃进行约3小时-约24小时。二酰基肼衍生物与六甲基二硅氮烷的反应通常在惰性溶剂例如甲苯或氯苯中于约80℃-约150℃进行约6小时-72小时。对于Burgess试剂,与该二酰基肼衍生物的反应通常在惰性溶剂例如四氢呋喃中于约室温进行约24小时-约72小时。该二酰基肼衍生物与三氟甲磺酸酐和三乙胺的反应通常在惰性溶剂例如二氯甲烷、四氢呋喃、或乙醚中于约0℃-约25℃温度下进行约1小时-约24小时。
合成方案16
化合物15b可这样制得:将化合物14c的混合酸酐或酰氯衍生物[其中具有如上所述的含义;R是COCOR2、COOR3或SO2R3;且R2和R3具有本文所用含义]与通式16a化合物反应[其中V是(CH2)nAr或
;且Ar具有本文所用含义]。该反应一般在惰性溶剂例如四氢呋喃或二氯甲烷中、加入或不加入叔胺碱例如三乙胺或二异丙基乙基胺、于约0℃-约25℃进行约6小时-约24小时。所述混合酸酐或酰氯衍生物可用文献中的标准方法由相应的酸制得,例如通过将相应的酸与氯甲酸异丁酯或氯甲酸乙酯在三乙胺或二异丙基胺存在下反应,或者将相应的酸与草酰氯在惰性溶剂例如二氯甲烷或四氢呋喃中在催化量的二甲基甲酰胺存在下反应而获得。
对于定义如上的化合物15b,该转化还可以这样实现:在偶联剂例如二异丙基碳化二亚胺、二环己基碳化二亚胺、或苯并三唑-1-基氧基三(二甲基氨基)鏻六氟磷酸盐(Castro’s试剂)存在下,将定义如上的化合物16a与化合物14c在惰性溶剂例如四氢呋喃、二甲基甲酰胺、或二氯甲烷中于约0℃-约37℃缩合2小时-约24小时。化合物16a[其中V是(CH2)nAr或
;且Ar具有本文所用含义]可由相应的低级烷基酯衍生物通过与肼在醇溶剂例如乙醇中于回流温度下反应约6小时-约24小时而制得。或者,化合物16a可这样制得:经由三甲基甲硅烷基酯中间体,将相应的羧酸衍生物与肼在惰性溶剂例如二氯甲烷、四氢呋喃、或二甲基甲酰胺中于约0℃-约25℃温度下反应约1小时-约24小时。甲硅烷基酯可用本领域技术人员常用的方法在原位制得,例如将羧酸与N,O-二(三甲基)乙酰胺在约0℃-约25℃温度下反应约1小时-约6小时。
合成方案17
通式17化合物[其中
具有本文所用含义;R是COCOR2、COOR3或SO2R3;且R2和R3具有本文所用含义]可这样制得:将化合物14c的混合酸酐或酰氯[其中
具有本文所用含义;R是COCOR2、COOR3或SO2R3;且R2和R3具有本文所用含义]与约0.5-1当量肼一水合物在约0℃-约25℃反应约4小时-约24小时。
该反应一般在惰性溶剂例如四氢呋喃或二氯甲烷中、加入或不加入叔胺碱例如三乙胺或二异丙基乙基胺来进行。所述混合酸酐或酰氯衍生物可用文献中的标准方法由相应的酸制得,例如通过将相应的酸与氯甲酸异丁酯或氯甲酸乙酯在三乙胺或二异丙基胺存在下反应,或者将相应的酸与草酰氯在惰性溶剂例如二氯甲烷或四氢呋喃中在催化量的二甲基甲酰胺存在下反应而获得。
在化合物3的合成中使用的苯基烷基磺酰氯,在化合物6a和6b的合成中使用的芳基烷基胺和芳基烷醇衍生物,通式12化合物,在化合物16a的合成中使用的芳烷基羧酸低级烷基酯衍生物,和在化合物14b的制备中使用的芳烷基腈当不能商购获得时,可依据文献通过常规合成方法用标准试剂和反应条件由易得原料制得。
应当理解,当A是
,时,其中
和R1具有本文所用含义,本发明化合物可包含两个R1基团。因此,许多上述反应可通过向适当反应物中加入另外一当量的试剂来同时在两个R1上进行。此外,可通过使用本领域技术人员已知的适当保护基方法来选择性地修饰其中一个R1,而不修饰另一个R1。
当本发明化合物具有至少一个手性中心时,它们可作为对映体存在。当化合物具有两个或更多个手性中心时,它们还可以作为非对映体存在。应当理解,所有这样的异构体及其混合物都在本发明范围内。此外,对于这些化合物,一些晶形可作为多晶型物存在,并且这样的多晶型物也包括在本发明范围内。此外,某些化合物可以与水或常用有机溶剂形成溶剂化物(例如水合物),并且这样的溶剂化物也包括在本发明范围内。
II.所选的本发明化合物
在优选的本发明实施方案中,本发明化合物选自下表所示的化合物。
III.具体合成方法
作为本发明代表的具体化合物可按照下述实施例制得。为了清楚起见,在下述实施例中制得的本发明化合物通过术语“化合物”和附在其后面的适当数字表示(例如“化合物1”)。在本发明化合物的合成中的中间体称为“参考实施例”。没有采取任何尝试来优化这些反应的产率。本领域技术人员应当知道如何通过常规改变反应时间、温度、溶剂和/或试剂来提高这样的产率。
一些参考实施例的产物可用作制备一种以上本发明化合物的中间体。在这些情况下,选择用于制备本发明此后化合物的中间体在本领域技术人员的能力范围内。
向N-苄氧羰基-L-脯氨酸(9.96g,40.0mmol)和碳酸钾倍半水合物(26.50g,160.0mmol)在DMF(60mL)内的冷(0℃)的悬浮混合物中加入二苯基磷酰基叠氮化物(12.0mL,55.6mmol)和异氰基乙酸甲酯(7.30mL,80.3mmol)。移去冰浴,并将该反应混合物在室温(RT)搅拌约20小时。加入盐水,并将该反应混合物过滤。用CHCl3/CH3OH(9∶1,150mL)萃取该滤液。将有机溶液用H2O(3×)、盐水(4×)洗涤,用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用2%CH3OH的CHCl3溶液洗脱,获得了所示噁唑(7.47g,产率56%),为浅棕色油状物,NMR表明其是45∶55旋转异构体混合物。
CIMS MH+=331(100%).1H NMR(300MHz,DMSO-d6)δ1.95-2.00(m,3H),2.30-2.45(m,1H),3.45-3.60(m,2H),3.71(s,0.55×3H),3.82(s,1.35H),4.91(d,Jab=12.82,1.1H),5.03(d,Jab=12.82,0.9H),5.45-5.48(m,0.45H),5.52-5.54(m,0.55H),7.02(br s,1H),7.26-7.34(m,4H),8.32-8.39(m,1H).
参考实施例2
向参考实施例1的甲酯(7.27g,22.6mmol)在THF/H2O混合物(2∶1,270mL)内的冷(0℃)溶液中加入氢氧化锂(594.7mg,24.8mmol)。将所得混合物在约室温搅拌过夜。将该反应混合物用4.80g柠檬酸在100mL水中的溶液酸化,用CHCl3(2×150mL)萃取。将合并的有机萃取液用Na2SO4干燥,过滤并浓缩,获得了所示甲酸(6.66g,产率93%),为白色薄片状固体。
CIMS M-1=315M-45=271(100%).1H NMR(300MHz,DMSO-d6),a 45∶55旋转异构体混合物,δ1.95-2.05(m,3H),2.25-2.40(m,1H),3.35-3.60(m,2H),4.91(d,Jab=12.82,0.55×2H),5.03(d,Jab=12.82,0.45×2H),5.45-5.48(m,0.45×1H),5.52-5.54(m,0.55×1H),7.00(br s,1H),7.20-7.45(m,5H),8.25-8.35(m,1H).
向参考实施例2的噁唑-4-甲酸(632.3mg,2.00mmol)与三乙胺(0.62mL,4.45mmol)在DMF(2mL)内的冷(0℃)溶液中加入二苯基磷酰基叠氮化物(0.48mL,2.22mmol)和3-氨基甲基吡啶(0.22mL,2.16mmol)。将所得混合物在约室温搅拌约1天,用水(25mL)稀释,并用EtOAc(2×25mL)萃取。将合并的有机萃取液用水(6×50mL)洗涤,用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用100%EtOAc洗脱,获得了化合物1(0.49g,产率60%),为无色不流动油状物。
MS(loop pos)MH+=407(100%);M+Na=429(10%).1H NMR(300MHz,CDCl3),a 45∶55旋转异构体混合物,δ1.90-2.15(m,3H),2.30-2.45(m,1H),3.55-3.70(m,2H),4.45-4.65(m,2H),4.85-5.20(m,2H),5.65-5.70(m,0.45×1H),5.75-5.80(m,0.55×1H),7.0(br s,1H),7.20-7.40(m,6H),8.45-8.50(m,1H),8.55-8.60(m,1H).
将化合物1(0.39g,0.96mmol)和10%钯/炭(0.05g)在CH3OH(25mL)中的不均匀混合物在50psi氢气压力下于约室温振摇约3小时。将该混合物经由硅藻土床过滤,并用CH3OH洗涤滤饼。将合并的滤液真空浓缩,获得了化合物2(0.25g,产率96%),为不流动油状物,不用进一步纯化使用。
MS(loop pos)MH+=273(100%).1H NMR(300MHz,CDCl3),δ1.8-2.2(m,4H),2.95-3.05(m,1H),3.10-3.20(m,1H),4.554.70(m,2H),4.90(t,J=7.00Hz,1H),7.20-7.35(m,2H),7.60-7.75(m,3H),8.53(d,J=4.13Hz,1H),8.62(s,1H).
向化合物2(0.25g,0.91mmol)与三乙胺(140mL,1.00mmol)在二氯甲烷(10mL)内的冷(0℃)溶液中加入α-甲苯磺酰氯(184.2mg,0.966mmol)。在约室温搅拌约6小时后,将该反应混合物用35.6mg磺酰氯与30mL三乙胺处理。将该反应混合物用二氯甲烷(40mL)稀释,用水(2×50mL)洗涤,用硫酸钠干燥,过滤并浓缩至干。通过制备TLC以色谱法纯化粗产物,用100%EtOAc洗脱,获得了化合物3(0.17g,产率44%),为taffy固体。
MS(loop pos)MH+=427(100%).1HNMR(300MHz,CDCl3)δ1.72-1.80(m,1H),1.95-2.11(m,2H),2.27-2.36(m,1H),3.07-3.15(m,1H),3.44-3.52(m,1H),4.27(d,Jab=13.97Hz,1H),4.41(d,Jab=13.96Hz,1H),4.44-4.71(m,3H),5.72-5.77(m,1H),7.28-7.45(m,6H),7.69-7.72(m,2H),8.53(d,J=4.13Hz,1H),8.62(s,1H).
向参考实施例2的噁唑-4-甲酸(1.26g,4.00mmol)、三乙胺(0.62mL,4.445mmol)、DMAP(49.5mg,0.405mmol)和3-吡啶基甲醇(0.39mL,4.02mmol)在THF(20mL)内的冷(0℃)溶液中加入氯甲酸异丙烯酯(0.48mL,4.39mmol)。温热至约室温后,将该深黄色不均匀的反应混合物在约室温搅拌约20小时。将该反应用EtOAc稀释,用水洗涤,并用1N盐酸萃取。用无水碳酸钠将该酸性水溶液碱化,并用氯仿(2×100mL)萃取。将该氯仿溶液用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用100%EtOAc洗脱,获得了化合物4(0.61g,产率37%),为无色不流动油状物。MS(loop pos)MH+=408(100%).1H NMR(300MHz,CDCl3)δ1.98-2.10(m,3H),2.25--2.45(m,1H),3.50-3.70(m,2H),4.86-5.39(m,4H),5.59-5.61(m,1H),5.65-5.85(m,1H),7.05(br s,1H),7.30-7.35(m,5H),7.66-7.80(m,2H),8.58-8.71(m,2H).
向参考实施例1的甲酯(3.66g 11.0mmol)与氯化锂(2.50g,58.9mmol)在EtOH/THF混合物(4∶3;175mL)内的溶液中分两批加入硼氢化钠(2.10g,55.0mmol)。将所得不均匀混合物在约室温搅拌约3天。用NH4Cl水溶液(200mL)处理该反应混合物,并用CHCl3(3×150mL)萃取。将该有机溶液用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用3%CH3OH的CHCl3溶液洗脱,获得了所示醇(2.87g,产率86%),为无色油状物。
MS(loop pos)MH+=303(100%);1HNMR(300MHz,CDCl3)δ1.90-2.10(m,1H),2.15-2.40(m,3H),3.45-3.70(m,2H),4.40-4.50(m,1H),4.60-4.80(m,2H),4.90-5.15(m,2H),5.20-5.30(m,1H),7.30-7.35(m,5H),7.35(s,5H),7.75(s,1H).
化合物5
向参考实施例3的噁唑-4-甲醇(2.34g,7.74mmol)、三苯基膦(3.05g,11.6mmol)和3-羟基吡啶(1.11g,11.7mmol)在THF(60mL)内的冷(0℃)溶液中加入DEAD(1.86mL,11.7mmol)。将所得混合物在约室温搅拌过夜,并浓缩至干。通过硅胶色谱纯化该油状物,用3%CH3OH的CHCl3溶液洗脱,获得了含有副产物的化合物5的粗产物。将该油状物溶于CH2Cl2(50mL)中,并用1N盐酸(5×80mL)洗涤。将该酸性水溶液用NaHCO3/Na2CO3碱化,并萃取到CHCl3(3×50mL)中。将该CHCl3溶液用Na2SO4干燥,过滤并浓缩,获得了化合物5(0.47g),为油状物,该油状物在静置时会固化。该化合物不用进一步纯化直接使用。
MS(loop pos)MH+=380(100%).1H NMR(300MHz,CDCl3)1∶1旋转异构体混合物,δ1.90-2.10(m,2H),2.15-2.30(m,2H),3.45-3.65(m,2H),4.40-4.60(m,1H),4.95-5.30(m,4H),7.10-7.25(m,2H),7.30(s,5H),7.75-8.00(m,1H),8.15(br s,0.5×1H),8.25-8.30(m,1H),8.40(br s,0.5×1H).
将化合物5的粗产物(0.43g)与10%钯/炭(0.05g)在CH3OH(35mL)中的不均匀混合物在约54psi氢气压力下于约室温振摇约6.5小时。将混合物经由硅藻土床过滤;并用CH3OH洗涤滤饼。将滤液真空浓缩,获得了残余物。通过硅胶色谱纯化粗产物,用CHCl3∶CH3OH∶NH4OH(90∶9∶1)洗脱,获得了化合物6(0.10g),为油状物。MS(loop pos)MH+=246(100%)。
向化合物6(0.10g,0.41mmol)与三乙胺(70mL,0.50mmol)在CH2Cl2(10mL)内的冷(0℃)溶液中加入乙基草酰氯(70mL,0.63mmol)。将该反应混合物搅拌约2小时,用另外的CH2Cl2(50mL)稀释,并用NaCl水溶液(3×50mL)洗涤,用Na2SO4干燥,过滤并浓缩,获得了化合物7(0.10g,产率71%),为油状物,不用进一步纯化直接用于下一步骤。MS(loop pos)MH+=346(100%)。
向化合物7(0.10g,0.29mmol)在THF(10mL)内的冷(-78℃)溶液中加入在乙醚中的过量1,1-二甲基丙基氯化镁(1M,1.40mL),并在约-78℃搅拌约2小时。将该反应混合物用NH4Cl水溶液(25mL)处理,并用EtOAc(2×50mL)萃取。将该EtOAc溶液用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用1∶1 EtOAc∶己烷洗脱,获得了化合物8(55.5mg,产率52%),为油状物。
MS(loop pos)MH+=372(100%).1H NMR(300MHz,DMSO-d6),旋转异构体混合物(3至1),δ0.66(t,J=7Hz,0.25×3H),0.75(t,J=7Hz,0.75×3H),0.80(s,0.25×3H),0.88(s,0.25×3H),1.07(s,0.75×3H),1.10(s,0.75×3H),1.56-1.59(m,2H),1.88-1.98(m,2H),2.08-2.29(m,2H),3.42-3.60(m,2H),4.93(d,J=12Hz,0.25×1H),4.99(d,J=12Hz,0.25×1H),5.08(d,J=12Hz,0.75×1H),5.18(d,J=12Hz,0.75×1H),5.34-5.38(m,1H),7.47-7.54(m,1H),7.32-7.39(m,1H),8.18-8.20(m,1H),8.34-8.35(m,1H)8.35(s,0.75×1H),8.41(s,0.25×1H).
参考实施例4
将参考实施例1的甲酯(2.00g,6.00mmol)与10%钯/炭(0.20g)在CH3OH(40mL)中的不均匀混合物在54psi氢气压力下于约室温振摇约20小时。将该混合物经由硅藻土床过滤,用CH3OH(75mL)洗涤滤饼。将合并的滤液浓缩,获得了所示吡咯烷(1.20g,产率100%),为黄色固体。
MS(loop pos)MH+=197(100%).1H NMR(300MHz,CDCl3),δ2.10-2.25(m,3H),2.40-2.50(m,1H),3.40-3.60(m,2H),3.95(s,3H),5.40-5.50(m,1H),7.95(s,1H).
参考实施例5
向参考实施例4的吡咯烷(1.18g,6.00mmol)和三乙胺(0.94mL,6.74mmol)在CH2Cl2(100mL)内的冷(0℃)混合物中加入在CH2Cl2(25mL)内的乙基草酰氯(0.80mL,8.70mmol)。将所得反应混合物在约室温搅拌约2小时,用NaCl水溶液(3×75mL)洗涤,并用Na2SO4干燥。将CH2Cl2过滤并浓缩,获得了残余物,通过色谱法纯化(用35%己烷的EtOAc溶液洗脱),获得了所示草氨酸酯(1.23g,产率72%),为油状物,该油状物会固化。
1H NMR(300MHz,CDCl3),1∶1.5旋转异构体混合物,δ1.35(t,J=7Hz,0.6×3H),1.20(t,J=7Hz,0.4×3H),1.95-2.20(m,3H),2.40-2.50(m,1H),3.40-3.60(m,2H),3.89(s,0.6×3H),3.91(s,0.4×3H),4.00-4.15(m,0.4×2H),4.29-4.40(m,0.6×2H),5.70-5.75(m,0.6×1H),5.90-5.95(m,0.4×1H),7.75(s,0.6×1H),7.80(s,0.4×1H).
参考实施例6
向参考实施例5的草氨酸酯(0.87g,3.08mmol)在无水THF(10mL)内的冷(-78℃)溶液中加入在乙醚中的过量1,1-二甲基丙基氯化镁(1M,4.60mL,4.60mmol),并将所得混合物在约-78℃搅拌约3小时。用NH4Cl水溶液(25mL)处理该反应混合物,并用EtOAc(2×25mL)萃取。将该EtOAc溶液用Na2SO4干燥,过滤并浓缩至干。用284.5mg草氨酸酯和1.50mL二甲基丙基氯化镁重复该反应。通过硅胶色谱纯化合并的粗产物,用1∶1 EtOAc∶己烷洗脱,获得了所示草酰胺(0.95g,产率96%),为无色油状物。
MS(loop pos)MH+=323(90%).1HNMR(300MHz,CDCl3),旋转异构体混合物(3至1),δ0.70(t,J=7.4Hz,0.25×3H),0.80(t,J=7.4Hz,0.75×3H),1.00(s,0.25×3H),1.05(s,0.25×3H),1.15(s,0.75×6H),1.65-1.75(m,2H),1.90-2.20(m,0.75×2H),2.35-2.50(m,0.25×2H),3.55-3.70(m,0.75×1H),3.75-3.80(m,0.25×1H),3.90(s,1H),5.70-5.80(m,1H),7.75(s,0.75×1H),7.80(s,0.25×1H).
参考实施例7
将参考实施例6的4-甲氧羰基噁唑(0.93g,2.88mmol)和氢氧化锂(76.9mg,3.21mmol)在THF/H2O混合物(2∶1;30mL)中的溶液在约0℃搅拌约1小时,在约室温搅拌约22小时。将该反应混合物用Et2O(2×75mL)洗涤,用柠檬酸水溶液(pH=1.0)酸化,并用CHCl3(3×50mL)萃取。将该氯仿溶液用Na2SO4干燥,过滤并浓缩,获得了油状物。用乙醚将该油状物覆盖,并放置在高度真空下,获得了所示甲酸(0.80g,产率90%),为白色固体。
MS(loop neg)M-1=307(100%).1H NMR(300MHz,THF-d8),旋转异构体混合物(2.5至1),δ0.70(t,J=7.4Hz,0.30×3H),0.85(t,J=7.4Hz,0.70×3H),0.92(s,0.30×3H),0.95(s,0.30×3H),1.15(s,0.70×6H),1.45-1.65(m,2H),1.90-2.20(m,3H),2.30-2.40(m,1H),3.50-3.65(m,2H),5.65-5.73(m,0.7×1H),5.75-5.80(m,0.3×1H),7.9(s,0.7×1H),8.00(s,0.3×1H).
化合物9
向参考实施例7的噁唑-4-甲酸(0.31g,1.00mmol)、三乙胺(0.17mL,1.22mmol)、DMAP(12.1mg,0.099mmol)和3-吡啶基甲醇(0.11mL,1.13mmol)在THF(15mL)内的冷(0℃)溶液中加入氯甲酸异丙烯酯(0.12mL,1.10mmol)。温热至室温后,将该深黄色不均匀反应混合物在约室温搅拌约20小时。将该反应用水稀释,并萃取到氯仿(2×50mL)中。将该CHCl3溶液用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用3%CH3OH的CHCl3溶液洗脱,获得了化合物9(222.8mg,产率56%),为浅黄色不流动油状物。
MS(loop pos)MH+=400(100%).1HNMR(300MHz,DMSO-d6),旋转异构体混合物(3至1),δ0.62(t,J=7.4Hz,0.25×3H),0.76(t,J=7.4Hz,0.75×3H),0.83(s,0.25×3H),0.86(s,0.25×3H),1.11(s,0.75×6H),1.44-1.49(m,0.25×2H),1.58(q,J=7.41,7.42,7.41Hz,0.75×2H),1.88-2.04(m,3H),2.25-2.34(m,1H),3.34-3.61(m,2H),5.31-5.39(m,2H),5.52-5.59(m,1H),7.42-7.46(m,1H),7.89-7.91(m,1H),8.44(s,0.75×1H),8.50(s,0.25×1H),8.57(d,J=4.56Hz,1H),8.69(s,1H).
化合物10
向参考实施例7的噁唑-4-甲酸(308.2mg,1.00mmol)和三乙胺(310mL,2.22mmol)在DMF(2mL)内的冷(0℃)溶液中加入二苯基磷酰基叠氮化物(480mL,1.16mmol)和3-氨基甲基吡啶(110mL,2.16mmol)。将所得混合物在约室温搅拌约1天,用水(25mL)稀释,并用EtOAc(2×50mL)萃取。将该EtOAc溶液用Na2SO4干燥,过滤并浓缩。通过硅胶色谱纯化粗产物(用5%CH3OH的CHCl3溶液洗脱,获得了化合物10(310mg,产率78%),为油状物。MS(loop pos)MH+=399(100%).1H NMR(300MHz,DMSO-d6),旋转异构体混合物(2至1),δ0.65(t,J=7.4Hz,0.33×3H),0.75(t,J=7.4Hz,0.67×3H),0.85(s,0.33×3H),0.90(s,0.33×3H),1.15(s,0.67×6H),1.45-1.65(m,2H),1.80-2.00(m,3H),2.25-2.40(m,1H),3.40-3.60(m,2H),4.35-4.50(m,2H),5.60-5.65(m,0.67×1H),5.70-5.75(m,0.33×1H),7.20-7.30(m,2H),7.55-7.75(m,1H),8.50-8.65(m,2H),8.90-9.00(m,1H).
参考实施例8
将N-CBz-L-脯氨酰胺(1.12g,4.51mmol)和2,4-二(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂环戊烷(diphosphetane)-2,4-二硫化物(Lawesson’s试剂;911.3mg,2.25mmol)在苯(20mL)中的不均匀混合物于回流状态下搅拌约1小时。然后加入933.0mgLawesson’s试剂,并将该反应继续回流1小时。将该反应混合物浓缩,获得了硫代酰胺粗产物。用EtOH(10mL)将该残余物溶解,用溴丙酮酸乙酯(300uL,1.00mmol)处理,并搅拌回流过夜。冷却至室温后,将该反应混合物用固体K2CO3处理,搅拌约10分钟并浓缩。用CHCl3(50mL)将残余物溶解,用H2O(2×)洗涤,并用Na2SO4干燥,过滤并浓缩。通过硅胶色谱纯化粗产物,用2%CH3OH的CHCl3溶液洗脱,获得了所示噻唑(0.63g,产率39%),为浅黄色油状物。
MS(loop pos)MH+=361(50%),M+Na=383(100%).1H NMR(300MHz,DMSO-d6),旋转异构体混合物,δ1.23(t,J=7.32,7.66,3H),1.93-2.37(m,3H),3.50-3.59(m,2H),4.30(q,J=7.04,7.05,7.08Hz,2H),4.94-5.22(m,3H),7.08-7.38(m,5H),8.32(s,0.33H),8.41(s,0.67H).
参考实施例9
将参考实施例8的乙酯(0.55g,1.53mmol)与氢氧化锂(37.5mg,1.56mmol)在THF/H2O混合物(2∶1;6mL)中的溶液在约0℃搅拌约1小时,在约室温搅拌约2小时。用氯化钠水溶液将该反应混合物稀释,用CHCl3(2×15mL)洗涤,用柠檬酸(427mg)酸化,然后用CHCl3(2×20mL)萃取。将该CHCl3溶液用Na2SO4干燥,过滤并浓缩,获得了所示甲酸(0.51g,产率100%),为油状物,不用进一步纯化直接使用。
MS(loop neg)M-1=331(50%).1HNMR(300MHz,DMSO-d6),δ1.93-2.35(m,3H),2.25-2.40(m,1H),3.39-3.50(m,2H),4.94-5.21(m,3H),4.94-5.22(m,3H),7.04-7.12(m,1H),7.25-7.37(m,4H),8.33(s,1H),13.0(br s,1H).
化合物11
向参考实施例9的噻唑-4-甲酸(0.51g,1.53mmol)和三乙胺(0.48mL,3.44mmol)在DMF(3mL)内的冷溶液中加入二苯基磷酰基叠氮化物(376mL,1.72mmol)和3-氨基甲基吡啶(180mL,1.77mmol),将所得混合物在约室温搅拌约1天,用水(25mL)稀释,并用EtOAc(2×25mL)萃取。将该EtOAc溶液用水(6×50mL)洗涤,用Na2SO4干燥,过滤并浓缩。通过硅胶色谱纯化粗产物,用100%EtOAc洗脱,获得了化合物11(0.44g,产率68%),为无色不流动油状物。
MS(loop pos)MH+=423(100%)M+Na=445(10%).1H NMR(300MHz,CDCl3)δ1.90-2.05(m,2H),2.15-2.45(m,2H),3.45-3.70(m,2H),4.60-4.65(m,2H),4.95-5.25(m,3H),5.65-5.85(m,1H),7.05(br s,1H),7.20-7.40(m,5H),7.66-7.70(m,1H),7.55-7.65(m,1H),8.00-8.05(m,1H),8.50-8.65(m,2H).
化合物12
将化合物11(0.38g,0.90mmol)与30%溴化氢的乙酸(2mL)在混合物于约室温搅拌约2小时。从该反应混合物中沉淀出了产物的二氢溴酸盐。向该反应混合物中加入乙醚,并通过过滤收集化合物12(407.8mg,产率100%),为米色吸湿性固体。
MS(looppos)MH+=289(100%).1H NMR(300MHz,DMSO-d6),δ1.95-2.25(m,3H),2.40-2.50(m,2H),3.30-3.40(m,1H),3.45-3.55(m,1H),4.65-4.70(m,2H),5.15-5.25(m,1H),7.90-8.10(m,1H),8.40(s,1H),8.50-8.55(m,1H),8.80-8.85(m,1H),8.90(s,1H),9.15-9.30(m,1H),9.35-9.45(m,1H),9.75-9.90(m,1H).
向化合物12的二氢溴酸盐(203.0mg,0.453mmol)和三乙胺(210mL,1.50mmol)在二氯甲烷(4mL)内的冷(0℃)溶液中加入α-甲苯磺酰氯(95.0mg,0.498mmol)。3小时后,再向该反应混合物中加入DMAP(10mg)、三乙胺(100mL)和α-甲苯磺酰氯(44.8mg)。将该反应混合物搅拌过夜。真空除去溶剂和挥发性物质。通过制备TLC纯化粗产物,用5%CH3OH的CHCl3溶液洗脱,获得了化合物13(67.6mg,产率34%),为米色固体。
MS(loop pos)MH+=443(100%).1H NMR(300MHz,CDCl3),δ1.90-2.05(m,2H),2.10-2.20(m,2H),3.30-3.50(m,2H),4.3(s,2H),4.60-4.70(m,2H),4.85-4.95(m,1H),7.10-7.20(m,1H),7.30-7.45(m,5H),7.50-7.65(m,1H),7.70-7.75(m,1H),8.05(s,1H),8.50-8.55(m,1H),8.60(s,1H).
参考实施例10
将参考实施例8 N-CBz保护的2-吡咯烷基-4-甲氧羰基噻唑(3.33g,9.25mmol)在CH3CO2H(10mL)中的溶液用30%HBr的CH3CO2H(4mL)溶液处理,并在室温搅拌约6小时。用乙醚将沉淀出的吡咯烷基噻唑二氢溴酸盐覆盖,并通过过滤收集。用乙醚洗涤该白色固体,在真空烘箱中于约室温干燥过夜,获得了作为二氢溴酸盐的所示吡咯烷(2.48g,产率69%)。
MS(loop pos)MH+=227(100%).元素分析C10H14N2O2S-2.0HBr:计算值C 30.95,H 4.15,N 7.22,S 8.26,Br41.69;实测值C 31.18,H 4.07,N 7.11,S 7.91,Br41.84.1H NMR(300MHz,DMSO-d6),δ1.31(t,J=7.12,7.21Hz,3H),2.03-2.21(m,3H),2.50-2.53(m,1H),3.33-3.35(m,2H),4.33(q,J=7.04,7.05,7.08Hz,2H),5.10(t,J=6.94,6.94Hz,1H),8.66(s,1H),9.2-9.5(m,2H),9.80(br s,1H).
向参考实施例10的吡咯烷(1.53g,5.00mmol)在CH2Cl2(100mL)内的冷(0℃)混合物中加入三乙胺(1.70mL,1.21mmol)和乙基草酰氯(0.82mL,7.34mmol)。将所得反应混合物于约室温搅拌约2小时,用氯化钠水溶液(2×150mL)洗涤,用Na2SO4干燥,过滤并浓缩,获得了草氨酸酯(1.45g,产率89%),为油状物,不用进一步纯化直接使用。
MS(loop pos)MH+=327(100%).1H NMR(300MHz,DMSO-d6),2∶1旋转异构体混合物,δ1.20-1.35(m,6H),1.8-2.2(m,3H),2.30-2.45(m,1H),3.65-3.80(m,2H),4.20-4.35(m,4H),5.35-5.40(m,0.67×1H),5.59-5.61(m,0.33×1H),8.42(s,0.67×1H),8.47(s,0.33×1H).
向参考实施例11的草氨酸酯(1.39g,4.26mmol)在无水THF(25mL)内的冷(-78℃)溶液中加入在乙醚中的过量1,1-二甲基丙基氯化镁(1M,7.80mL,7.80mmol),并将所得混合物在约-78℃搅拌约5小时。将该反应混合物用NH4Cl水溶液处理(25mL),并用EtOAc(2×25mL)萃取。将该EtOAc溶液用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用35%EtOAc的己烷溶液洗脱,获得了草酰胺(1.01g,产率67%),为白色固体。
MS(loop pos)MH+=353(100%).1H NMR(300MHz,DMSO-d6),4∶1旋转异构体混合物,δ0.65(t,J=7.1Hz and 1Hz,0.20×3H),0.75(t,J=7.10Hz,7.10Hz,0.80×3H),0.95(s,0.10×3H),0.97(s,0.10×3H),1.15(s,0.80×6H),1.25(t,J=7.10Hz,7.10Hz,3H),1.55-1.70(m,2H),1.85-2.00(m,2H),2.05-2.15(m,1H),2.25-2.40(m,1H),3.35-3.60(m,1H),4.33(q,J=7.04,7.05,7.08Hz,2H),5.30-5.40(m,1H),8.40(s,0.80×1H),8.45(s,0.20×1H).
将参考实施例12的乙酯(0.95g,2.70mmol)与氢氧化锂(71.9mg,3.00mmol)在THF/H2O混合物(2.5∶1;35mL)中的溶液在约0℃搅拌约1小时,在约室温搅拌约20小时。将该反应混合物用乙醚(2×50mL)洗涤,并用柠檬酸水溶液酸化。用CHCl3(2×75mL)萃取沉淀出的甲酸。将该CHCl3溶液用Na2SO4干燥,过滤并浓缩,获得了所示甲酸(0.81g,产率93%),为白色固体,不用进一步纯化直接使用。
MS(loop neg)M-1=323.1HNMR(300MHz,DMSO-d6),4∶1旋转异构体混合物,δ0.65(t,J=7.1Hz和1Hz,0.20×3H),0.75(t,J=7.10Hz,7.10Hz,0.80×3H),0.95(s,0.10×3H),0.97(s,0.10×3H),1.15(s,0.80×6H),1.55-1.70(m,2H),1.85-2.00(m,2H),2.05-2.15(m,1H),2.25-2.40(m,1H),3.35-3.60(m,1H),5.30-5.40(m,1H),8.35(s,0.80×1H),8.40(s,0.20×1H)13.5(s,1H).
向参考实施例13的噻唑-4-甲酸(322.2mg,1.00mmol)和三乙胺(310mL,2.22mmol)在DMF(3mL)内的冷(0℃)溶液中加入二苯基磷酰基叠氮化物(250mL,1.16mmol)和3-氨基甲基吡啶(110mL,1.08mmol)。将所得混合物在约室温搅拌约1天,用氯化钠水溶液(25mL)洗涤,并用CHCl3(3×25mL)萃取。将该CHCl3溶液用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物(用100%EtOAc洗脱),获得了0.44g化合物14,为无色不流动油状物。然后通过锥形制备TLC板纯化该油状粗产物,用5%CH3OH在CHCl3中的混合物洗脱,获得了化合物14(271.8mg,产率66%),为无色玻璃状物。
MS(loop pos)MH+=415(100%).1HNMR(300MHz,DMSO-d6),4∶1旋转异构体混合物,δ0.64(t,J=7.45Hz,7.45Hz,0.20×3H),0.78(t,J=7.40Hz,7.40Hz,0.80×3H),0.95(s,0.10×3H),0.97(s,0.10×3H),1.15(s,0.80×6H),1.45-1.65(m,2H),1.90-2.05(m,2H),2.10-2.20(m,1H),2.25-2.40(m,1H),3.42-3.48(m,1H),3.50-3.58(m,1H),4.47(d,J=6.28Hz,2H),5.31-5.33(m,0.20×1H),5.37-5.40(m,0.80×1H),7.33-7.37(m,1H),7.70-7.73(m,1H),8.21(s,0.80×1H),8.25(s,0.20×1H),8.44-8.46(m,1H),8.54(br s,1H),9.00(t,J=6.17,6.20Hz,1H).
向参考实施例13的噻唑-4-甲酸(322.6mg,1.00mmol)、三乙胺(0.17mL,1.22mmol)、DMAP(13.0mg,0.100mmol)和3-吡啶基甲醇(0.11mL,1.13mmol)在THF(15mL)内的冷(0℃)溶液中加入氯甲酸异丙烯酯(0.12mL,1.10mmol)。温热至室温后,将该不均匀反应混合物在约室温搅拌约20小时。将该反应用水洗涤,并用EtOAc(2×25mL)萃取。将该EtOAc溶液用Na2SO4干燥,过滤并浓缩至干。通过锥形制备TLC板纯化粗产物,用3%CH3OH在CHCl3中的混合物洗脱,获得了化合物15(240.0mg,产率59%),为浅黄色固体。
MS(loop pos)MH+=416(100%).1H NMR(300MHz,DMSO-d6),4∶1旋转异构体混合物,δ0.64(t,J=7.45Hz,7.45Hz,0.20×3H),0.78(t,J=7.40Hz,7.40Hz,0.80×3H),0.98(s,0.10×3H),1.00(s,0.10×3H),1.14(s,0.80×3H),1.15(s,0.80×3H),1.53-1.65(m,2H),1.94-1.99(m,2H),2.05-2.15(m,1H),2.31-2.38(m,1H),3.44-3.56(m,2H),5.37(m+s,3H),7.42-7.46(m,1H),7.88-7.90(d,J=7.70Hz,1H),8.54-8.59(m+s,2H),8.69(s,1H).
向参考实施例8的4-甲氧羰基噻唑(3.64g,10.0mmol)和氯化锂(2.12g,50.0mmol)在EtOH(100mL)和THF(75mL)内的溶液中加入氢氧化钠(1.94g,51.3mmol)。6小时后,向该反应混合物中再加入224mg LiCl和205mg NaBH4,并再搅拌约18小时。用氯化铵水溶液处理该反应混合物,并用氯仿(3×100mL)萃取。将该CHCl3溶液用Na2SO4干燥,过滤并浓缩至干。通过硅胶色谱纯化粗产物,用5%CH3OH在CHCl3中的混合物洗脱,获得了所示醇(2.39g,产率75%),为无色油状物。
MS(loop pos)MH+=319(100%).1H NMR(300MHz,CDCl3),δ1.85-2.05(m,3H),2.10-2.40(m,2H),2.60-2.70(m,1H),3.40-3.55(m,1H),3.60-3.70(m,1H),4.65-4.75(m,2H),5.05-5.30(m,3H),7.05(br s,1H),7.10(br s,1H),7.20-7.40(m,3H).
将参考实施例14的噻唑-4-甲醇(2.17g,6.83mmol)与三苯基膦(3.38g,12.8mmol)、偶氮二甲酸二乙酯(1.64mL,10.4mmol)和3-羟基吡啶(0.97g,10.2mmol)在THF(110mL)中合并,并按照与制备化合物5相同的方法进行处理。该反应获得了化合物16(2.08g)与肼副产物的粗产物,为油状物。
MS(loop pos)MH+=396(100%).1H NMR(300 MHz,DMSO-d6),δ1.85-2.05(m,3H),2.10-2.40(m,1H),3.40-3.55(m,2H),4.90-5.20(m,5H),7.05(br s,1H),7.10(br s,1H),7.30-7.60(m,5H),8.12-8.15(m,1H),8.35-8.37(m,1H),9.00(s,1H).
将化合物16的粗产物(1.85g)与30%HBr在CH3CO2H(12mL)中的混合物于约室温搅拌约2小时。将该反应混合物用水(25mL)稀释,并用Et2O(3×75mL)萃取。用碳酸钠水溶液将该酸性水层碱化,并用CHCl3(10×100mL)萃取该高度水溶性的游离碱。将水层浓缩至潮湿的固体,并用CHCl3(3×125mL)萃取。将合并的CHCl3溶液干燥(Na2SO4),过滤并浓缩,获得了化合物17(0.55g),为油状物。
MS(loop pos)MH+=262(40%).1H NMR(300MHz,DMSO-d6),δ1.67-1.84(m,2H),2.10-2.22(m,1H),2.82-3.00(m,2H),3.43(brs,1H),4.41-4.45(m,1H),5.16(s,2H),7.31-7.36(m,1H),7.47-7.51(m,1H),7.55(s,1H),8.18(d,J=4.36Hz,1H),8.37(d,J=2.86Hz,1H).
化合物18
按照与制备化合物7相同的方法处理在CH2Cl2(100mL)中的化合物17(0.55g,2.00mmol)、三乙胺(0.69mL,4.95mmol)和乙基草酰氯(0.35mL,3.13mmol),获得了化合物18(0.33g,产率46%),为油状物。
MS(loop pos)MH+=362(100%).1H NMR(300MHz,DMSO-d6),3∶2旋转异构体混合物,δ1.05(t,J=7.40Hz,7.41Hz,0.40×3H),1.25(t,J=7.41,7.40Hz,0.60×3H),1.80-2.15(m,3H),2.25-2.45(m,1H),3.55-3.75(m,2H),4.00(q,J=7.12Hz,7.13Hz,7.10Hz,0.4×2H),4.30(q,J=7.12Hz,7.13Hz,7.10Hz,0.60×2H),5.20(s,2H),5.32-5.39(m,0.60×1H),5.40-5.55(m,0.40×1H),7.32-7.40(m,1H),7.45-7.52(m,1H),7.69(s,0.60×1H),7.75(s,0.40×1H),8.19(d,J=4.36Hz,1H),8.38-8.39(m,1H).
化合物19
按照与制备化合物8相同的方法处理在THF(10mL)中的化合物18(0.31g,0.86mmol)和1,1-二甲基丙基氯化镁(1M,2.25mL,2.25mmol),获得了化合物19(0.17g,产率51%),为黄色油状物。
MS(loop pos)MH+=388(100%).1H NMR(300MHz,DMSO-d6),4∶1旋转异构体混合物,δ0.65(t,J=7.41Hz,7.42Hz,0.20×3H),0.79(t,J=7.37,7.40Hz,0.80×3H),0.93(s,0.10×6H),0.97(s,0.10×6H),1.16(s,0.40×6H),1.17(s,0.40×6H),1.63(q,J=7.40,7.42,7.45Hz,2H),1.95-1.97(m,2H),2.07-2.13(m,1H),2.26-2.36(m,1H),5.20(s,2H),5.34-5.40(m,1H),7.32-7.36(m,1H),7.49-7.53(m,1H),7.70(s,0.80×1H),7.76(s,0.20×1H),8.19(d,J=3.96Hz,1H),8.38(br s,1H).
参考实施例15
向乙酰乙酸乙酯(65mL,510mmol)在无水Et2O(100mL)内的冷(0℃)溶液中加入溴(26.40mL,512.4mmol)。将该反应混合物在约室温静置约1天,然后倒在冰上,并用无水Na2CO3洗涤直至呈碱性。将该乙醚溶液用盐水洗涤,并用氯化钙干燥约4天。将该乙醚溶液过滤并浓缩,获得了81.66g浅棕色油状物,并用碳酸钾固体稳定。
1H NMR(300MHz,CDCl3)δ1.50(t,J=7.40,7.40Hz,3H),3.70(s,2H),4.00(s,2H),4.20(q,J=7.40,7.40Hz,2H).
参考实施例16
将参考实施例8的N-CBz-脯氨酸硫代酰胺(4.36g,16.5mmol)、和参考实施例15的90%γ-溴乙酰乙酸乙酯(4.80g,22.5mmol)在乙醇(170mL)中的溶液于回流状态下搅拌约2小时。将该反应混合物浓缩至干。通过硅胶色谱纯化残余物,用1%CH3OH在CHCl3中的混合物洗脱,获得了所示噻唑(6.25g,产率100%),为油状物。
MS(loop pos)MH+=375(40%).1HNMR(300MHz,DMSO-d6),δ1.15-1.25(m,3H),1.80-2.10(m,3H),2.25-2.40(m,1H),3.35-3.55(m,2H),3.75(s,2H),4.05(q,J=7.40,7.42,7.45Hz,2H),4.95-5.20(m,3H),7.10(br s,1H),7.25-7.40(m,5H).
参考实施例17
将参考实施例16的乙酯(3.01g,8.00mmol)、氯化锂(1.72g,40.6mmol)和硼氢化钠(1.51g,mmol)在EtOH/THF(4∶3;175mL)中合并,并按照与制备参考实施例14产物相同的方法处理,获得了所示醇(2.40g,产率90%),为浅黄色油状物。
1H NMR(300MHz,DMSO-d6),δ1.80-2.05(m,3H),2.20-2.40(m,1H),2.80(t,J=6.52,6.52Hz,2H),3.40-3.60(m,2H),3.65-3.70(m,2H),4.65(t,1H(OH),4.90-5.20(m,3H),7.05(br s,1H),7.15(br s,1H),7.25-7.40(m,4H).
化合物20
按照与制备化合物5相同的方法处理在THF(20mL)中的参考实施例17的噻唑-4-乙醇(1.51g,4.55mmol)、三苯基膦(2.37g,9.04mmol)、偶氮二甲酸二乙酯(1.00mL,6.35mmol)和3-羟基吡啶(0.60g,6.31mmol),获得了化合物20的粗产物(0.82g),为油状物。
MS(loop pos)MH+=410(100%).1HNMR(300MHz,DMSO-d6),δ1.90-2.02(m,3H),2.20-2.40(m,1H),3.15(t,J=6.52,6.52Hz,2H),3.47-3.60(m,2H),4.30-4.40(m,2H),4.93-5.20(m,3H),7.05(br s,1H),7.20-7.70(m,7H),8.15(d,J=4.3Hz,1H),8.28-8.32(m,1H).
按照与制备化合物17相同的方法处理化合物20(0.71g)和30%HBr在CH3CO2H(5mL)中的溶液,获得了化合物21(0.85g),为吸湿性二氢溴酸盐。
MS(loop pos)MH+=276(100%).1H NMR(300MHz,DMSO-d6),δ1.90-2.20(m,3H),2.40-2.50(m,1H),3.25-3.40(m+t,J=6.52,6.52Hz,4H),4.60(t,J=6.52,6.52Hz,2H),5.00-5.10(m,1H),7.60(s,1H),7.95-8.05(m,1H),8.25-8.30(m,1H),8.65(d,J=4.3Hz,1H),8.80(s,1H),9.10-9.25(br s,1H),9.75-9.90(br s,1H).
按照与制备化合物7相同的方法处理在CH2Cl2(25mL)中的化合物21(0.78g,1.78mmol)、三乙胺(0.63mL,4.52mmol)和乙基草酰氯(0.30mL,2.68mmol),获得了化合物22(0.42g,63%),为油状物。
MS(loop pos)MH+=376(100%).1H NMR(300MHz,DMSO-d6),3∶2旋转异构体混合物,δ1.20-1.30(m,3H),1.95-2.10(m,3H),2.25-2.45(m,1H),3.15(q,J=7.40,7.42,7.45Hz,2H),3.50-3.75(m,2H),4.20-4.40(m,4H),5.30-5.35(m,0.60×1H),5.50-5.55(m,0.40×1H),7.25-7.33(m,1H),7.35-7.40(m,2H),8.15-8.18(m,1H),8.20-8.22(m,1H),(q,J=7.40,7.42,7.45Hz,2H).
化合物23
按照与制备化合物8相同的方法处理在THF(25mL)中的化合物22(0.41g,1.09mmol)和1,1-二甲基丙基氯化镁(1M,3.00mL,3.00mmol),获得了化合物23(224.4mg,产率51%),为油状物。
MS(loop pos)MH+=402(100%).1H NMR(300MHz,DMSO-d6),4∶1旋转异构体混合物,δ0.63(t,J=7.41Hz,7.42Hz,0.20×3H),0.79(t,J=7.37,7.40Hz,0.80×3H),0.89(s,0.10×6H),0.93(s,0.10×6H),1.15(s,0.40×6H),1.16(s,0.40×6H),1.59-1.64(m,2H),1.95-2.08(m,3H),2.23-2.33(m,1H),3.16(t,J=6.30Hz,6.30Hz,2H),3.40-3.57(m,2H),4.36(t,J=6.64,6.64Hz,2H),5.30-5.37(m,1H),7.29-7.41(m,3H),8.16(d,J=4.25Hz,1H),8.26-8.29(m,1H).
化合物24
方法A
向(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸(4.557g,18.89mmol,按照在WO 96/40633中描述的方法制得的)在四氢呋喃(130mL)内的冷却至约-15℃(MeOH/冰浴)的搅拌溶液中加入三乙胺(1.908g,2.63mL,18.89mmol),然后加入氯甲酸乙酯(2.05g,1.806mL,18.86mmol)。在约-15℃-约-10℃搅拌约30分钟后,通过过滤除去沉淀的固体,加入四氢呋喃将滤液和洗涤液的体积调节至约170mL。
在搅拌下于0℃向该混合酸酐溶液中(85mL,9.32mmol)加入肼一水合物(0.48mL,9.79mmol)。将该混合物搅拌,温热至约室温并保持过夜。真空除去溶剂后,通过硅胶柱色谱纯化残余物,用50%乙酸乙酯/二氯甲烷洗脱,获得了化合物24(0.64g,产率28.7%),为无色固体,将其从乙醚/戊烷中重结晶,熔点为177-178℃。CIMS 479(MH+),501(M+Na+)。1H NMR(300MHz,CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
9.06(br s,2H),4.61(m,2H),3.50-3.46(m,4H),2.40-2.36(m,2H),2.13-1.94(m,6H),1.83-1.64(m,4H),1.25和1.21(分别是s,分别是6H),0.87(t,3H).IR(KBr)cm-1:3261,2970,1706,1684,1636.元素分析C24H38N4O6的计算值:C,60.23;H,8.00;N,11.71。实测值:C,60.30;H,8.03;N,11.58。
在室温向(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸(2.4229g,10mmol,按照在WO 96/40633中描述的方法制得的)在四氢呋喃(50mL)内的搅拌溶液中依次加入三乙胺(4.18mL,30mmol)、乙基二甲基氨基丙基碳化二亚胺盐酸盐“EDC.HCl’(1.917g,10mmol)和羟基苯并三唑水合物”HOBt.H2O“(1.53g,10mmol)。约5分钟后,加入肼在四氢呋喃中的溶液(1M,5mL,5mmol),并将该混合物搅拌约18小时。真空除去四氢呋喃(<35℃),将残余物溶解在二氯甲烷中,并依次用水、1%盐酸水溶液、和水洗涤,并干燥(Na2SO4)。过滤后,真空除去二氯甲烷,通过硅胶柱色谱纯化残余物,用1.5%甲醇在二氯甲烷中的混合物纯化,获得了化合物24(产率18%),[α]25 D-95.8°(c=0.33,CHCl3),该化合物在各方面与通过方法A获得的化合物相同。
使用方法A来制备化合物25-29。
方法A-化合物25
使用(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-哌啶甲酸(基本上按照在WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的),分离到了化合物25,为无色固体(产率38%),熔点为180-181℃(乙醚/戊烷)。CIMS 507(MH+),529(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.07(br m,2H),5.17(d,2H),4.29-4.08(m,2H),3.39(d,4H),2.89(t,1H),2.40-2.05(m,3H),1.89-1.44(m,10H),1.23和1.22(分别是s,分别是6H),0.90(t,6H).IR(KBr)cm-1:3309,2969,1699,1646,1610.元素分析C26H42N4O6的计算值:C,61.64;H,8.36;N,11.06。实测值:C,61.45;H,8.58;N,10.76。
使用(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-氮杂环丁烷甲酸(基本上按照在WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的),分离到了化合物26,为透明的粘性泡沫状物(产率35%),熔点<58℃,[α]25 D-93.4°(CHCl3)。CIMS 451(MH+),473(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
9.70(br s,2H),5.02(d,d,2H),4.34-4.18(m,4H),2.85-2.73(m,2H),2.61-2.49(m,2H),1.84-1.73(m,6H),1.25和1.23(分别是s,分别是6H),0.84(t,6H).IR(KBr)cm-1:3498,3247,2972,1703,1636.
使用(3S)-2-(1,2-二氧代-3,3-二甲基戊基)-1,2,3,4-四氢异喹啉甲酸(基本上按照在WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的),分离到了化合物27,为无色固体(产率41%,乙醚/戊烷),熔点为108-110℃;[α]25 D-55.12°(CHCl3)。CIMS 603(MH+),625(M+Na)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)7.22-7.03(m,8H),5.25-4.95(m,2H),4.51-4.25(m,4H),3.16-3.10(m,2H),1.72-1.66(m,2H),1.22和1.21(分别是s和分别是6H),0.89(t,6H).IR(KBr)cm-1:3219,2969,1701,1639.元素分析C34H42N4O6的计算值:C,67.75;H,7.02;N,9.30。实测值:C,67.54;H,7.04;N,9.13。
使用(4R)-3-(1,2-二氧代-3,3-二甲基戊基)-4-噻唑烷甲酸(基本上按照在WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的),分离到了化合物28,为无色泡沫状物(产率39.8%),熔点为77-82℃(乙醚/戊烷);[α]25 D-15.6°(c=0.276,CHCl3)。CIMS 515(MH+),537(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.93(br s,2H),5.05-4.98(m,2H),4.54-4.43(m,4H),3.59-3.54(m,2H),3.25-3.21(9m,2H),1.78-1.74(m,4H),1.25和1.23(分别是s,分别是6H),0.88(t,3H).IR(KBr)cm-1:3270,2970,1703,1642,1418.元素分析C22H34N4O6的计算值:C,51.34;H,6.66;N,10.89。实测值:C,51.52;H,6.67;N,11.06。
使用(2S)-1-苄氧基羰基-2-吡咯烷甲酸,分离到了化合物29,为无色泡沫状物,其熔点范围不确定。[α]25 D-56.1°(CHCl3)。CIMS495(MH+),518(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
9.11(br s,2H),7.36(br s,10H),5.23-5.149m,4H),4.41(br s,2H),3.55-3.44(m,4H),2.36-1.94(m,8H).IR(KBr)cm-1 3496,1704,1499,1420,1358.
还按照方法C制备化合物28和29。
方法C-化合物28
用约20分钟向(4R)-3-(1,2-二-氧代-3,3-二甲基戊基)-4-噻唑烷甲酸(1.63g,6.29mmol)在二氯甲烷(100mL)内的溶液(在冰浴中冷却)中加入草酰氯(0.72mL,8.25mmol)在二氯甲烷(5mL)中的溶液。将该混合物在约室温搅拌约2小时,通过在40℃以下真空蒸发除去溶剂。将残余物真空下充分干燥约1小时后,将其溶解在无水四氢呋喃(50mL)中。用约30分钟在约0℃向该搅拌溶液中加入1M肼在四氢呋喃中的溶液(3.15mL,3.15mM)和三乙胺(1.32mL,9.47mM);将该混合物在约室温搅拌过夜。约24小时后,通过真空蒸发除去溶剂,将残余物在1N盐酸和二氯甲烷之间分配。将有机层干燥(Na2SO4),并真空蒸发。通过闪式硅胶色谱法纯化粗产物,用2%甲醇在二氯甲烷中的混合物洗脱,获得了化合物28(1.18g,产率73%),[α]25 D-15.6°(c=0.276,CHCl3),其在各方面与在方法A中获得的真实样品相同。
在氮气氛下,用约20分钟向Z-脯氨酸(10g,40.12mmol)在二氯甲烷(100mL)内的冷却至约0℃的溶液中滴加草酰氯(4.19mL,48mmol),然后加入二甲基甲酰胺(3滴)。在约室温搅拌约2小时后,将该混合物真空蒸发至干,并在高度真空下干燥约30分钟。将残余物溶解在无水四氢呋喃(THF,160mL)中;用约2分钟将该溶液加到1M肼在四氢呋喃内的溶液(40mL,40mM)中,然后在约室温搅拌约18小时。将该混合物真空蒸发至干。把残余物置于乙酸乙酯(300mL)中,依次用1%盐酸和水洗涤,将有机层干燥(Na2SO4),过滤并真空蒸发,获得了无色油状残余物。通过闪式硅胶色谱纯化粗产物,用2%甲醇/二氯甲烷洗脱,获得了化合物29(8.8g,产率88.7%),[α]25 D-56.1°(c=1.0,CHCl3),为无色泡沫状物,其与在方法A中获得的真实样品相同。
按照方法D、E、和F制备化合物30。
方法D-化合物30
在剧烈搅拌下,向化合物24(0.567g,1.185mmol)在无水乙醚(400mL)内的冷溶液中加入吡啶(0.12mL,3.35mmol),然后加入亚硫酰氯(0.120mL,1.66mmol)。将该混合物在约0℃搅拌约2小时后,通过过滤除去沉淀的固体,用无水乙醚迅速洗涤,将合并的滤液在低于40℃温度下真空蒸发至干。将残余物(0.6235g泡沫状物)溶解在无水甲苯(25mL)中,并在氮气氛下加热回流约3小时。将甲苯真空蒸发,通过硅胶/CH2Cl2柱色谱纯化残余物,用1%甲醇/二氯甲烷洗脱,获得了本标题化合物30(0.354g,产率63.6%),为无色固体,从乙醚/戊烷中重结晶,熔点为123-124℃;[α]24 D-74.6°(c=0.8,CHCl3)。CIMS 461(MH+),483(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式异构体)
5.32(d,d,J=3.0,7.6),3.59(m,4H),2.33-2.07(m,8H),1.80-1.65(m,4H),1,23和1.20(分别是s,分别是6H),0.86(t,6H).IR(KBr)cm-1:2972,1704,1641.元素分析C24H38N4O5的计算值:C,62.59;H,7.88;N,12.16。实测值:C,62.68;H 7.75;N,12.14。
方法E-化合物30
向化合物24(0.112g,0.234mM)在氯苯(10mL)内的溶液中加入六甲基二硅氮烷(0.123mL,0.585mM)、咪唑(10mg)和氟化四丁基铵(10mg),并将该混合物在氮气氛下加热回流约72小时。通过色谱法纯化粗产物,获得了化合物30,薄层色谱和质谱数据表明其与在方法D中描述的真实样本相同。
方法F-化合物30
向化合物24(0.2018g,0.42mmol)在四氢呋喃(10mL)内的溶液中分三批加入(甲氧基羰基氨磺酰基)三乙胺氢氧化物内盐(Burgess试剂,总共0.3014g,1.265mmol),约每30分钟加入一批。然后将该混合物在约室温搅拌约72小时。真空除去溶剂后,通过闪式色谱法纯化该反应残余物,获得了化合物30,薄层色谱和质谱数据表明其与在方法D中描述的真实样本相同。
参考实施例18
将3-(3-吡啶基)丙腈(7.5g,56.75mM)、羟基胺盐酸盐(5.915g,85.12mM)和无水碳酸钾(15.686g,113.5mM)在乙醇(200mL)中的混合物在氮气氛下搅拌并加热回流约64小时。冷却后,通过过滤除去固体,并将滤液真空蒸发至干,获得了粘稠的琥珀色油状残余物(8.95g)。在二氯甲烷(300mL)中研制,过滤,然后真空除去二氯甲烷,获得了非常粘稠的油状残余物(5.84g)。将不溶于二氯甲烷的部分溶解在甲醇中,过滤,并真空蒸发,获得了粘稠的半固体偕胺肟残余物(3.09g);CIMS 166(MH+)。
向(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸(4.557g,18.89mmol,按照在WO 96/40633中描述的方法制得的;2.02g,8.37mmol)在二(乙二醇)一甲醚(二甘醇二甲醚,30mL)的溶液中依次加入参考实施例18的偕胺肟(1.383g,8.37mM)和1-(二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐“EDC″(3.21g,16.743mmol),将该混合物搅拌,并在油浴中于氮气氛下在约50℃加热约20小时,然后在约110℃加热约5小时。冷却后,将该反应混合物在水与二氯甲烷之间分配,将有机相干燥(Na2SO4),并真空蒸发,获得了粘稠的残余物(3.727g)。通过硅胶/二氯甲烷色谱纯化,用1%甲醇/二氯甲烷洗脱,获得了化合物31,为粘稠的油状物(0.39g,产率12.5%)。CIMS 371(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.47(s,2H),7.52(d,1H,J=7.6),7.24-7.20(m,1H),5.32(d,d,1H),3.64(t,2H),3.06(M,4H),2.42-2.33(m,1H),2.19-2.06(m,3H),1.82-1.61(m,2H),1.24和1.22分别是s,分别是3h),0,87(t,3H).IR(KBr)cm-1;2970,1704,1645,1580,1425.元素分析C20H26N4O3的计算值:C,64.84;H,H,7.07;N,15.12。实测值:C,64.43;H,6.95;N,14.89。
将3-(3-吡啶基)丙酸乙酯(5.92g,33.08mM)、无水肼(20mL,大大过量)和乙醇(100mL)的混合物在氮气氛下加热回流约18小时。通过真空蒸发除去溶剂,用乙醚研制残余物,并冷藏。收集结晶固体,用少量乙醚洗涤,获得了酰肼,为无色固体结晶。熔点为87-90℃。
CIMS 166(MH+).1H NMR(DMSO)δ9.04(s,1H),8.43-8.39(m,2H),7.61(d,1H),7.32-7.28(m,1H),2.83(t,2H),2.35(t,2H).IR(KBr)cm-1:3325,3231,3004,1667,1630.元素分析C8H11N3O的计算值;C,58.17;H,6.71;N,25.44。实测值:C,57.94;H,6.49;N,25.28。
化合物32
使用方法A的操作,采用一当量参考实施例19的一酰基肼以代替未取代的肼,获得了化合物32(产率73%),为无色固体,熔点为90-92℃(乙醚/戊烷)。CIMS 389(MH+)。1H NMR(旋转异构体混合物,CDCl3)δ(对于主要的反式旋转异构体)
9.3(s,1H),8.83(s,1H),8.44(s,2H),7.54(d,1H),7.27-7.18(m,1H),4.59-4.56(m,1H),3.48(t,2H),2.99(2H),2.57(t,2H),2.09-1.92(m,4H),1.80-1.63(m,2H),1.23(s,3H),1.20(s,3H),0.86(t,3H).IR(KBr)cm-1:3258,2971,1703,1637.元素分析C20H28N4O4.0.5H2O的计算值:C,60.44;H,7.35;N,14.10。实测值:C,60.67;H,7.07;N,14.32。
使用方法F的操作,采用化合物32作为反应物,获得了化合物33(产率71.6%),为无色固体,CIMS 371(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.49(d,2H),7.54(d,2H),7.26-7.22(m,1H),5.30(t,2H),3.15(s,4H),2.35-2.04(m,4H),1.77-1.59(m,3H),1.23(s,3H),1.21(s,3H),0.86(t,3H).元素分析C20H26N4O3的计算值:C,64.84;H,7.07;N,15.12。实测值:C,64.45;H,7.07;N,15.12。
采用方法A的操作,但是使用一当量3-(3,4,5-三甲氧基苯基)丙酰基肼以代替肼,获得了化合物34(产率81.4%),为无色玻璃状泡沫。CIMS 478(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
9.06(br s,1H),7.99(br s,1H),6.42(s,2H),4.61(m,1H),3.84(s,6H),3.82(s,3H),3.48(t,2H),2.93(t,2H),2.54(t,2H),2.38-2.35(m,1H),2.06-1.93(m,3H),1.80-1.65(m,2H),1.24(s,3H),1.21(s,3H),0.86(t,3H).IR(KBr)cm-1:3273,2970,1703,1639,1127.
采用方法F的操作,使用化合物34作为反应物,获得了化合物35(产率99%),为无色粘稠的油状物。CIMS 460(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
5.31(d,d 1H),3.85(s 6H),3.82(s,3H),3.61-3.59(m,1H),3.25-3.00(m,4H),2.40-2.25(m,1H),2.25-1.90(m,4H),1.80-1.60(m 2H),1.23(s,3H),1.21(s,3H),0.86(t,3H).IR cm-1:2968,1702,1644,1590,1508,1459,1423,1127.元素分析C24H33N3O6.0.6H2O的计算值:C,61.29;H,7.33;N,8.93。实测值:C,61.29;H,7.17;N,8.93。
使用方法A的操作和(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-哌啶甲酸(基本上按照在WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的),并使用参考实施例19的酰肼以代替肼,获得了化合物36(产率71.5%),为无色泡沫状固体。熔点为48-52℃。CIMS 403(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.64(s,1H),8.47-8.43(m,3H),7.56-7.53(m,1H),7.25-7.20(m.1H),5.17(d,1H),3.39(d,1H),3.03-2.98(m,2H),2.61-2.55(m,2H),2.30-2.20(m,1H),1.85-1.51(m,8H),1.23(s,3H),1.22(s,3H),0.89(t,3H).IR(KBr)cm-1:3272,2969,1701,1638,1445.元素分析C21H3ON4O4.0.3H2O的计算值:C,61.84;H,7.56;N,13.74。实测值:C,61.88;H,7.40;N,13.70。
化合物37
使用方法A的操作和(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-哌啶甲酸(基本上按照在WO 96/40633中描述的制备(2S)-1-(1,2-二-氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的),并使用3-(3,4,5-三甲氧基苯基)丙酰基肼以代替肼,获得了化合物37(产率98%),为无色玻璃状固体,熔点为52-55℃。CIMS 492(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.25(br s,1H),7.71(br s,1H),6.43(d,2H),5.17(d,1H),3.85(s,6H),3,83(s,3H),3.38(m,1H),3.0-2.90(m,2H),2.50-2.40(m,2H),2.33(br t,1H),1.8-1.6(m,8H),1.24(s,3H),1.23(s,3H).IR(KBr)cm-1:3293,2967,2941,1701,1640,1591,1509,1459,1127.元素分析C25H37N3O7.0.75H2O的计算值:C,59.45;H,7.68;N,8.32。实测值:C,59.47;H,7.55;N,8.36。
采用方法F的操作,使用化合物36作为反应物,获得了化合物38,为无色油状物(产率96%)。CIMS 385(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.49(d,2H),7.56(d,1H),7.27-7.22(m 2H),5.93(d,1H),3.21-3.11(m,4H),2.35(d,1H),2.0-1.50(m,8H),1.24(s,3H),1.21(s,3H),0.90(t,3H).IR(KBr)cm-1:2967,2942,2877,1700,1644,1585,1434.元素分析C21H28N4O3的计算值:C,65.60;H,7.34;N,14.57。实测值:C,65.37;H,7.43;N,14.41。
化合物39
采用方法F的操作,使用化合物37作为反应物,获得了化合物39(产率64.8%),为无色粘稠的油状物。CIMS 474(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
6.42(s,2H),5.93(d,1H),3.84(s,6H),3.82(s,3H),3.40(br d,1H),3.25-3.00(m,4H),2.36(br d,1H),2.0-1.50(m,8H),1.24(3H),1.22(s,3H),0.90(t,3H).IR(KBr)cm-1:3502,2966,2942,1772,1700,1644,1590,1509,1462,1240,1128.元素分析C25H35N3O6.2H2O的计算值:C,58.92;H,7.71;N,8.25。实测值:C,59.05;H,7.45;N,8.57。
在约0℃、氮气氛下,向N-苄氧羰基-L-脯氨酸(2.0g,8.0mmol)在无水二氯甲烷(20mL)内的溶液中滴加草酰氯(1.22g,9.6mmol),然后加入2滴DMF。将该溶液搅拌约3小时,温热至约25℃,然后浓缩。将所得酰氯溶解在THF∶乙腈(1∶1,20mL)中,并在约0℃、氮气氛下用三乙胺(0.87g,8.6mmol)处理。将该溶液搅拌约10分钟,并滴加三甲基甲硅烷基重氮甲烷(2.0M己烷溶液,7.8mL)。将该溶液在约0℃搅拌约2小时,温热至约25℃,并再搅拌约17小时。将该溶液用乙酸乙酯稀释,用饱和碳酸氢钠和水洗涤,干燥(MgSO4),并浓缩。通过硅胶柱色谱纯化粗产物,用40%乙酸乙酯在戊烷中的混合物洗脱,获得了该重氮酮(1.15g,产率53%),为黄-橙色油状物。1H NMR(CDCl3;顺式-反式酰胺旋转异构体混合物):
δ1.88-2.09,2.17-2.38(2br m,4H);3.58(m,2H),3.81,4.03,4.17(s,AB四重峰,2H,J=4.0),4.61(m,1H),5.13(m,2H),7.32(m,5H).
在氮气氛下,向参考实施例20的N-苄氧羰基-L-脯氨酸α-重氮酮(1.0g,3.6mmol)在无水乙醚(10mL)内的溶液中滴加饱和HBr乙醚溶液,直至停止释放出氮气。将该溶液在约25℃搅拌约1小时,然后用饱和NaHCO3、H2O和饱和NaCl洗涤,干燥(MgSO4)并浓缩。通过硅胶柱色谱纯化粗产物,用40%乙酸乙酯在戊烷中的混合物洗脱,获得了所示溴酮(0.49g,产率42%),为澄清油状物。1H NMR(CDCl3;顺式-反式酰胺旋转异构体混合物):
δ1.84-2.30(br m,4H);3.58(m,2H);4.32(m,1H);5.17(m,2H);5.28(t,1H);7.35(m,5H).
化合物40
向参考实施例8的硫代酰胺(0.40g,1.5mmol)在无水乙醇(15mL)内的溶液中滴加在无水乙醇(2mL)中的参考实施例21的N-苄氧基羰基-L-脯氨酸α-溴甲基酮(0.49g,1.5mmol)。将所得溶液在氮气氛下加热回流约3小时。将该溶液冷却至约25℃,并浓缩。将所得残余物置于乙醚/饱和NaHCO3中。分离出水相,并用乙醚萃取数次。合并有机层,干燥(MgSO4)并浓缩。通过硅胶柱色谱纯化粗产物,并用40%乙酸乙酯在戊烷中的混合物洗脱,获得了化合物40(0.51g,产率69%),为澄清的油状物。1H NMR(CDCl3;顺式-反式酰胺旋转异构体的混合物):
δ 1.93(m,4H);2.20(br m,4H);3.61(br m,4H);5.18(br m,6H);6.74,6.85(s,s,1H);7.13(m,2H);7.27(m,4H);7.39(m,4H).
化合物41
在约0℃,向化合物40(0.48g,0.97mmol)在无水二氯甲烷(20mL)内的溶液中滴加1.0M BBr3在二氯甲烷(5mL)中的溶液。将该溶液在约0℃搅拌约1小时,然后温热至约25℃,并搅拌约2小时。通过滴加H2O(25ml)来终止该反应。分离各层,用水萃取有机相。通过滴加1N NaOH将合并的水相调节至约pH 11,然后浓缩。过滤出所得盐,并用乙酸乙酯充分洗涤。将有机滤液干燥(MgSO4)并浓缩,获得了化合物41(0.067g,产率31%),为黄色油状物。1H NMR(CDCl3):δ1.88(m,6H);2.17(m,1H);2.31(m,1H);3.05(m,2H);3.16(m,2H);4.24(m,1H);4.57(m,1H);6.99(s,1H).
化合物42
在约0℃,向化合物41(0.067g,0.30mmol)在无水二氯甲烷(5mL)内的溶液中加入三乙胺(0.13g,1.28mmol)。搅拌约15分钟后,滴加甲基草酰氯(0.10g,0.84mmol)在二氯甲烷(2mL)中的溶液。将该溶液在约0℃搅拌约1.5小时,然后用H2O洗涤,干燥(MgSO4),并浓缩,获得了化合物42(0.115g,产率97%),为黄色油状物。1H NMR(CDCl3;4种顺式-反式酰胺旋转异构体混合物)δ1.96-2.48(系列重叠的br m’s,8H);3.62-4.00(系列重叠的br m’s,4H);3.67,3.72,3.76,3.91(2个重叠的s,s,s,系列重叠的s,6H);5.44,5.71(br m,2H);6.91,6.93,6.98,7.07(s,s,s,s,1H)。
化合物43
在约-78℃,向化合物42(0.115g,0.29mmol)在无水THF(5mL)内的溶液中滴加二甲基丙基氯化镁(1.0M乙醚溶液,0.754mL)。将该溶液在约-78℃搅拌约3小时,然后倒入饱和氯化铵(25mL)中,并用乙酸乙酯萃取。将有机相合并,干燥(MgSO4),并浓缩。通过硅胶柱色谱纯化粗的残余物,用40%乙酸乙酯在戊烷中的混合物洗脱,获得了化合物43(0.075g,产率55%),为白色固体,熔点为127-129℃。1H NMR(CDCl3;顺式-反式酰胺旋转异构体混合物)δ0.60-1.02(系列重叠的s和m,10H);1.12-1.21(系列重叠的s,8H);1.66(m,4H);1.88-2.29(重叠的br m’s,8H);3.38-3.70(br m,4H);5.15,5.29,5.37,5.42(m,m,m,m,2H);6.81,6.84,6.91,6.96(s,s,s,s,1H)。元素分析C25H37N3O4S的计算值:C,63.13;H,7.84;N,8.83。实测值:C,62.94;H,7.80;N,8.67。
采用方法F的操作,使用化合物25作为反应物,获得了化合物44(产率63%),为无色固体,熔点为102-105℃(乙醚/戊烷)。CIMS489(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
5.98(d,2H),3.46-3.17(m,4H),2.33(d,2H),1.94-1.40(m,12H),1.25和1.21(分别是s,分别是6H),0.87(t,6H).IR(KBr)cm-1:1702,1639,1578,1550,1441.元素分析C26H40N4O5.0.6H2O:C,62.53;H,8.32;N,11.22。实测值:C,62.52;H,8.09;N,11.14。
采用方法D的操作,使用化合物29作为反应物,获得了化合物45(产率68%),为粘稠的油状物;[α]=-87.4°(CHCl3)。CIMS 477(MH+),499(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
7.35-7.19(m,10H),5.20-5.0(m,6H),3.80-3.40(m,4H),2.40-1.85(m,8H).IR(KBr)cm-1:3584,2956,1705,1584,1498,1446,1410,1355.元素分析C26H28N4O5.0.25H2O的计算值:C,64.92;H,5.97;N,11.65。实测值:C,64.92;H,5.88;N,11.81。
化合物46
方法G
将化合物45(3.06g,6.46mmol)在甲醇(125mL)中的溶液在10%Pd/C催化剂(580mg)存在下于15psi压力下氢化约4小时。经由硅藻土垫过滤以除去催化剂,将滤液真空蒸发至干,获得了无色、非常粘稠的油状物(1.28g,产率95%)。
CIMS209(MH+),231(M+Na+).1H NMR(CDCl3)δ4.46(q,2H),3.17-3.01(m,4H),3.17-3.01(m,6H).IR(纯品)cm-1:3313,2966,2875,1651,1584,1410,1337,1170,1084.
化合物47
采用方法D的操作,使用大大过量的吡啶和亚硫酰氯(分别是22和11当量)以及化合物27作为反应物,获得了化合物47(产率80%),为无色泡沫状物,[α]=-55.12°(c=0.254,CHCl3)。CIMS585(MH+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
7.22-6.91(m,8H),6.15-6.10(m,2H),4.41(m,2H),3.45-3.20(m,4H),1.81-1.69(m,4H),1.25和1.22(分别是s,分别是6H),0.90(t,6H).IR(KBr)cm-1:2969,2928,2879,1702,162,1586,1556,1499,1429.元素分析C34H42N4O5.0.5C5H12的计算值:C,70.76;H,7.58;N,8.92。实测值:C,70.93;H,7.38;N,8.92。
化合物48
向化合物46(0.107g,0.514mmol)在二氯甲烷(10mL)内的溶液中依次加入二异丙基乙基胺(2.87mL,1.65mmol)、二异丙基碳化二亚胺(0.323mL)、1-羟基-7-氮杂苯并三唑(0.280g,2.06mmol)和在二氯甲烷(5mL)中的噻吩-2-乙醛酸(0.320g,2.056mmol)。将该混合物在氩气氛下于约室温搅拌约20小时。将该混合物真空蒸发至干,把残余物置于二氯甲烷(20mL)中,然后依次用5%盐酸、水和饱和碳酸氢钠水溶液洗涤。将有机层干燥(Na2SO4),过滤并蒸发至干,获得了残余物。通过硅胶柱色谱纯化粗产物,用1.5%甲醇在二氯甲烷中的混合物洗脱,获得了化合物48(产率65%),为泡沫状固体,熔点为74-76℃。CIMS 485(MH+),507(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.05-7.96(m,2H),7.81-7.74(m,2H),7.21-7.11(m,2H),5.46-5.42(m,2H),3.87-3.66(m,4H),2.47-1.99(m,8H).IR(KBr)cm-1:3092,2955,2310,1658,1584,1561,1513,1441,1406,1353,1252,1167.元素分析C22H20N4O5S2的计算值:C,54.53;H,4.16;N,11.56。实测值:C,54.49;H,4.08;N,11.34。
化合物51
在氩气氛下,用约30分钟向化合物46(0.431g,2.071mmol)和三乙胺(0.65mL,4.66mmol)在二氯甲烷(20mL)内的冰冷搅拌溶液中加入在二氯甲烷(9mL)中的氯氧代乙酸甲酯(0.54mL,5.8mmol)。将该混合物在约0℃搅拌约2小时后,如下所述对该反应混合物进行后处理:用盐水(3×50mL)洗涤,将有机层干燥(Na2SO4),过滤,并真空蒸发至干,获得了化合物51,为泡沫状物(0.815g,产率95%)。CIMS 381(MH+),403(M+Na+)。
化合物49
在氩气氛下,用约15分钟向化合物51(0.375g,0.986mmol)在四氢呋喃(7mL)内的搅拌且于约-78℃冷却的溶液中滴加溴化环己基镁的乙醚溶液(1mL,2M,2mmol)。在约-78℃搅拌约3小时后,如下所述对该反应混合物进行后处理:倒入饱和氯化铵水溶液中,用乙酸乙酯萃取,将有机层干燥(Na2SO4),过滤并真空浓缩至。通过硅胶柱色谱纯化所得粗产物,用0.75%甲醇在二氯甲烷中的混合物洗脱,获得了化合物49(29mg,产率5.8%),为无色固体,熔点为132-133℃。CIMS 485(MH+),507(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
5.33-5.27(m,2H),3.88-3.59(m,4H),2.44-1.69(m,20H),1.38-1.00(m,6H).IR(KBr)cm-1:2880,2927,2852,1706,1641,1582,1560,1445.元素分析C26H36N4O5.0.35H2O的计算值:C,63.61;H,7.54;N,11.41。实测值:C,63.96;H,7.59;N,11.08。
化合物50
采用方法A的操作,但是使用1当量N-苄氧羰基脯氨酸酰肼(CAS#53157-63-4)以代替肼。获得了化合物50,为无色固体(产率56%)。熔点为145-146℃。CIMS 443(MH+-CO),487(MH+),485(M-H)。[α]=-96.1°(c=0.254,CHCl3)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体):
9.05(br s,1H),8.98(br s,1H),7.36(s,5H),5.23-5.11(m,2H),3.70-3.40(m,4H),2.41(br s,2H),2.30-1.80(m,6H),1.79-1.42(m,2H),1.25和1.22(分别是s,分别是3H),0.87(t,3H).IR(KBr)cm-1:3307,3272,2966,2884,1731,1699,1651,1444.元素分析C25H34N4O6的计算值:C,61.71;H,7.04;N,11.51。实测值:C,62.09;H,7.20;N,11.28。
采用方法D的操作,使用化合物26作为反应物,获得了化合物52,为无色粘稠的油腻物质(产率75.8%)。CIMS 433(MH+),455(M+Na+)。1H NMR(旋转异构体混合物,CDCl3)δ(对于主要的反式旋转异构体)
5.86-5.53(d,2H),4.48-4.35(m,2H),4.27-4.14(m,2H),2.93-2.80(m,2H),2.73-2.50(m,2H),1.84-t.60(m,4H),1.21(s,12H),0.82(t,6H).IR(KBr)cm-1:2970,2880,1704,1651,1583,1564,1461,1423,1385.
化合物53
采用方法D的操作,使用化合物50作为反应物,获得了化合物53,为无色粘稠的油状物(产率89%)。CIMS 469(MH+),491(M+Na+)。[α]=-92.7°(c=0.246,CHCl3).1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
7.36-7.20(m,5H),5.20-5.03(m,2H),3.70-3.50(m,2H),2.40-1.80(m,4H),1.80-1.60(m,2H).IR(纯品)cm-1:2968,2881,1702,1641,1584,1411,1356.元素分析C25H32N4O5的计算值:C,64.09;H,6.88;N,11.96。实测值:C,64.20;H,6.87;N,11.83。
使用方法I的操作,但是使用α-甲苯磺酰氯来代替氯氧代乙酸甲酯,获得了化合物54(产率59%),为无色固体,熔点为144-145℃。CIMS 517(MH+),539(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
7.49-7.46(m,4H),7.40-7.37(m,6H),5.04(q,2H),4.41(q,4H),3.39-3.31(9m,2H),3.14-3.07(m,2H),2.33-2.12(m,4H),2.09-1.94(m,4H).IR(KBr)cm-1:1574,1554,1495,1455,1410,1332,1140.元素分析C24H28N4O5S2的计算值:C,55.80;H,5.46;N,10.84。实测值:C,55.73;H,5.42;N,10.76。化合物55
采用方法G的操作,使用化合物53作为反应物,获得了化合物55,为无色粘稠的油状物(产率90%)。[α]=-35.5°(c=0.414,CHCl3)。CIMS 335(MH+),357(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
5.32(dd,2H),4.46(m,2H),3.61(dt,4H),3.36-3.03(m,4H),2.40-1.60(m,6H),1.24和1.21(分别是s,分别是3H),0.86(t,3H).IR(纯品)cm-1:3342,2969,2880,1703,1642,1586,1586,1428.元素分析C17H26N4O3的计算值:C,61.06;H,7.84;N,16.75。实测值:C,60.75;H,7.64;N,16.68。
化合物56
使用方法H的方法,但是使用3,4,5-三甲氧基苯基乙醛酸以代替噻吩-2-乙醛酸,获得了化合物56,为无色固体,熔点为79-83℃(产率56%)。[α]=-0.9°(c=0.260,CHCl3)。CIMS 653(MH+),675(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
7.34(s,4H),5.41(d,d,2H),3.95(s,6H),3.93(s,12H),3.68(t,4H),3.48-2.20(m,8H).IR(KBr)cm-1:2944,2839,1770,1715,1677,1650,1583,1416,1330,1126.元素分析C32H36N4O11的计算值:C,58.89;H,5.56;N,8.58。实测值:C,58.64;H,5.75;N,8.35。
使用方法I的操作,但是使用化合物55作为反应物,并使用α-甲苯磺酰氯来代替氯氧代乙酸甲酯,获得了化合物57,为粘稠的油状物(产率72%)。[α]=-28.6°(c=0.49,CHCl3)。CIMS 489(MH+),511(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
7.49-7.46(m,2H),7.38-7.36(m,4H),5.39-5.32(m,1H),5.10-5.06(m,1H),4.39(q,2H),3.71-3.58(m,2H),3.40-3.31(m,1H),3.11-3.00(m,1H),2.38-1.92(m,9H),1.79-1.59(m,2H),1.23和1.20(分别是s,分别是3H),0.84(t,3H).IR(纯品)cm-1:2971,2881,1703,1644,1584,1562,1427,1342.元素分析C24H32N4O5S的计算值:C,59.00;H,6.60;N,11.47。实测值:C,59.24;H,6.58;N,11.39。化合物58
采用方法F的操作,使用化合物28作为反应物,获得了化合物58(产率44%),为无色粘稠的油状物。[α]=-12°(c=0.308,CHCl3)。CIMS 497(MH+),519(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
5.90-5.83(m,2H),4.64-4.48(m,4H),3.53-3,34(m,4H),1.74(m,4H),1.26和1.23(分别是s,分别是6H),0.88(t,6H);IRcm-1 2966,1798,1651.元素分析C22H32N4O5S2的计算值:C,53.20;H,6.49;N,11.28。实测值:C,53.36;H,6.58;N,10.64。
采用方法C的操作,但是使用(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸(按照WO 96/40633中描述的方法制得的)以替代(4R)-3-(1,2-二氧代-3,3-二甲基戊基)-4-噻唑烷甲酸,用烟酰肼替代肼,获得了化合物59,为无色固体,熔点为161-163℃(产率42%)。CIMS 361(MH+),383(M+Na+).1H NMR(CDCl3)δ9.06(d,1H),8.74(m,1H),8.14(d,1H),7.37(m,1H),4.68(m,1H),3.52(t,2H),2.39(m,1H),2.14(m,2H),2.00(m,1H),1.81-1.61(m,4H).IR(KBr)cm-1:3296,2965,2883,1702,1664,1640,1590,1518.元素分析C18H24N4O4的计算值:C,59.99;H,6.71;N,15.55。实测值:C,59.88;H,6.63;N,15.38。
采用方法F的操作,使用化合物59作为反应物,获得了化合物60,为无色固体(产率79%),熔点为96-97℃。CIMS 343(MH+),365(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
9.25(d,1H),8.78(m,1H),8.34(dd,1H),7.47(m,1H),5.43(d,d,1H),3.67(t,2H),2.47-2.08(m,2H),1.85-1.73(m,2H),1.26和1.23(分别是s,分别是3H),0.87(t,3H).IR(KBr)cm-1:2969,2883,1701,1638,1431.元素分析C18H22N4O3的计算值:C,63.14;H,6.48;N,16.36。实测值:C,62.91;H,6.37;N,16.27。
采用方法A的操作,使用(2S)-1-(1,2-二氧代-3,3-二甲基丁基)-2-吡咯烷甲酸(基本上按照WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的)作为反应物,获得了化合物61,为无色固体(产率28%),熔点为108-110℃。CIMS 451(MH+),473(M+Na+),449(M-H)。[α]=-116.1°(c=0.274,CHCl3)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
9.11(s,2H),4.62(m,2H),3.47(t,4H),2.50-2.37(m,2H),2.15-1.85(m,4H),1.29(s,18H).IR(KBr)cm-1:3279,2976,2879,1707,1639,1446.元素分析C22H34N4O6.0.35H2O的计算值:C,57.84;H,7.66;N,12.26.实测值:C,58.10;H,7.75;N,11.98。
化合物61
采用方法B的操作,使用(2S)-1-(1,2-二氧代-3,3-二甲基丁基)-2-吡咯烷甲酸(基本上按照WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的)作为反应物,并使用N-甲基吗啉(NMM)作为碱以替代三乙胺“Et3N″,获得了化合物61(产率73%),其在各方面均与通过方法A获得的化合物相同。
采用方法D的操作,使用化合物61作为反应物,获得了化合物62(产率42.5%),熔点为138-141℃。[α]=-82.5°(c=0.282,CHCl3)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
5.34-5.29(m,2H),3.63-3.55(m,4H),2.40-2.00(m,8H),1.27(s,18H).IR(KBr)cm-1:2958,1705,1636,1582,1560,1438.元素分析C22H32N4O5的计算值:C,61.09;H,7.46;N,12.95。实测值:C,61.05;H,7.44;N,12.88。
采用方法H的操作,但是使用二甲基丙酮酸以替代噻吩-2-乙醛酸,获得了化合物62(0.030g,产率13.5%),其在各方面均与通过方法D获得的化合物相同。
采用方法A的操作,但是使用(2R)-1-(1,2-二氧代-3,3-二甲基戊基)-2-哌啶甲酸(基本上按照WO 96/40633中描述的制备(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸的方法制得的)作为反应物以替代(2S)-1-(1,2-二氧代-3,3-二甲基戊基)-2-吡咯烷甲酸,并使用氯甲酸异丁酯来替代氯甲酸乙酯,获得了化合物63,为无色泡沫状固体(产率37%),熔点为179-180℃。[α]=+101°(c=0.474,CHCl3)。CIMS 479(MH+),501(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
9.13(br s,2H),4.61(dd,2H),3.49(m,4H),2.39-2.34(m,2H),2.16-1.86(m,6H),1.84-1.61(m,4H),1.25和1.21(分别是s,分别是6H),0.87(t,6H).IR(KBr)cm-1:3263,2970,2880,1705,1684,1636,1614,1567,1444.元素分析C24H38N4O5的计算值:C,60.23;H,8.00;N,11.71。实测值:C,59.96;H,7.92;N,11.55。
化合物64
采用方法D的操作,使用化合物63作为反应物,获得了化合物64,为乳白色固体(产率85%),熔点为123-124℃。[α]=+72.2°(c=0.248,CHCl3)。CIMS 461(MH+),483(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
5.32(dd,2H),3.68-3.53(m,4H),2.41-2.02(m,8H),1.83-1.58(m,4H),1.23和1.20(分别是s,分别是3H),0,86(t,6H).IR(KBr)cm-1:2973,1705,1639,1574,1463,1432,1383,1096.元素分析C24H36N4O5的计算值:C,62.59;H,7.88;N,12.16。实测值:C,62.74;H,7.81;N,12.10。
采用方法B的操作,但是使用吡啶甲基酰肼以替代肼,获得了化合物65,为乳白色固体(产率71%),熔点为182-185℃。[α]=-67.0°(c=0.26,CHCl3)。CIMS 361(MH+),383(M+Na+)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
10.00(br s,1H),9.39(br s,1H),8.57(d,1H),8.15(d,1H),7.86(dt,1H),7.48-7.44(m,1H),4.75-4.71(m,1H),3.53-3.47(m,2H),2.52-2.39(m,1H),2.34-1.88(m,4H),1.85-1.67(m,4H),1.28和1.24(分别是s,分别是3H),0.89(t,3H).IR(KBr)cm-1:3270,2972,2880,1703,1640.元素分析C18H24N4O4.0.5H2O的计算值:C,58.52;H,6.82;N,15.17。实测值:C,58.53;H,6.44;N,14.90。
采用方法F的操作,使用化合物65作为反应物,获得了化合物66,为无色固体结晶(产率75%),熔点为70-72℃。CIMS 343(MH+),365(M+Na+)。[α]=-36.8°(c=0.280,CHCl3)。1H NMR(CDCl3,旋转异构体混合物)δ(对于主要的反式旋转异构体)
8.77(d,1H),8.23(d,1H),7.89(d,t 1H),5.45(dd 1H),3.76-3.62(m,2H),2.44-2.05(m,4H),1.86-1.63(m,2H),1.27和1.23(分别是s,分别是3H),0.87(t,3H).IR(KBr)cm-1:2973,1701,1636,1588,1562,1552,1463,1441.元素分析C18H22N4O3.0.25H2O的计算值:C,62.32;H,6.54;N,16.15。实测值:C,62.24;H,6.38;N,16.36。
IV.生物测定与活性
实施例1和4的体外活性结果显示在表2中。实施例2和3详细描述了制备在实施例4中使用的细胞培养物的方法。实施例5的体外活性结果显示在表3中。实施例6的体内活性结果显示在附图1中。
A.体外生物活性
实施例1
脊神经节(DRG)培养物
从新生或1天大小的CD大鼠中切下来DRG,并置于放在冰上的PBS内。用无菌铺平板培养基洗涤2次后,用#7曲形钳将DRG转移到用聚鸟氨酸/昆布氨酸包被的6-孔平板(Becton Dickinson Labware)的空孔中。然后非常轻微地加入3ml/孔铺平板培养基以不影响DRG。铺平板培养基是Leibovitz’s L-15培养基(Gibco)加0.6%葡萄糖,33mM KCl,10%FCS,10mM Hepes和青霉素/链霉素/谷酰胺。在约37℃于5%CO2的培养过夜后,用3mL/孔含有载体(DMSO,1/200,000)、阳性对照(2-4ng/mL NGF)或测试化合物(50-250nM)的测定培养基[Leibovitz’s L-15培养基加0.6%葡萄糖,1%FCS,1%N-2补充物(Gibco),10μM ara-C,10mM Hepes,和青霉素/链霉素/谷酰胺]来替换该培养基。所有培养基都是在当天新制备的。在第1-5天通过显微镜测定DRG的轴突分枝。在最适的条件下,载体处理没有引起从DRG的轴突分枝。如果本发明化合物引起≥1个DRG直径的轴突则认为实验为阳性(+)。
B.细胞培养物测定
实施例2
原始大鼠海马细胞
从18天大小的大鼠胚胎脑中切下来海马细胞,并用胰蛋白酶(1mg/mL)分离和研制。将细胞以30,000个细胞/孔的浓度接种到填充有100μL MEM和10%FBS的96-孔平板中。在培养的第7天,用4%低聚甲醛将细胞固定,并进行免疫荧光测定。
实施例3
人M17成神经细胞瘤细胞
将M17人成神经细胞瘤在具有1×NEAA和10%FBS的1∶1的EMEM和Ham’s F12中培养。培养基含有1×PSN抗生素,并每隔一天交换一次,使细胞经过接近融合的对数期。
表2
体外神经营养活性化合物 DRG 大鼠海马 M17
细胞反应 细胞反应1 - NA 1033 - NA NA4 + 111,123 134,1118 NT NA NA9 NT NA NA10 NT NA NA11 + NA NA13 - NA 10214 NT 116 112,10815 NT NA NA19 NT 109 11024 +,+,+,+,- 119,104,108 12325 NT 108 11126 NT 133 NA27 NT NA NA28 NT NA NT29 NT NA NA30 +,+,+,+,+ 161,118,130 112,10331 +,+,+,+,+,+,- 124 11132 NT NA 10333 NT 112 10434 NT 113 10635 NT 126 10636 NT NA 11037 NT 130 11138 NT 129 10539 NT NA 11243 NT 120 10844 NT NA 11845 NT NA NA46 NT NA NA47 NT NA NT48 NT 113 NT49 NT NA NT50 NT 110 NT51 NT 107 NT52 NT 110 NT53 NT NA NT54 NT 113 NT55 NT 116 NT56 NT 118,116 NT57 NT NA NT58 NT 142 NT59 NT 116 NT60 NT 114 NT62 NT 120 NT63 NT 110 NT64 NT 122 NT
+=对每个实验为阳性结果
-=对每个实验为阴性结果
NA=没有活性
NT=没有测试
实施例4
轴突分枝测定
将培养物与标准马血清(1∶50;Vector Labs)一起培养约20分钟,洗涤,然后与原始抗体、微管相关蛋白2(抗-鼠MAP-2;1∶1000;Chemicon)在约室温培养约2小时。与原始抗体培养后,将培养物洗涤,并与荧光素抗-鼠IgG(吸收的大鼠;1∶50;Vector Labs)培养约1小时。与荧光素培养后,将培养物洗涤,并在PBS中在荧光平板读数器上读数(激发:485nm;发射:530nm)。如果轴突分枝反应大于在同一平板上的平均DMSO处理对照反应,则化合物视为有活性。测试化合物的反应以占DMSO处理对照的百分比表示。信噪分离是一致的:DMSO对照孔的荧光比空白孔大至少2倍。
实施例5
烟碱性乙酰胆碱受体结合测定
使用得自大鼠脑皮层、纹状体和海马的突触膜粗制备物实现3H-野靛碱与神经原烟碱性乙酰胆碱受体结合。将新鲜或冷冻的膜在50体积的10mM HEPES(N-2-羟基乙基哌嗪-N’-2-乙磺酸,pH 7.4)中均化,并以42,000g离心。将P2部分重悬在40体积的10mM HEPES中,并以42,000g离心。重复该步骤,并将P2部分重悬在25体积(例如1g组织悬浮在25mL中)的由下述组分构成的培养基中:Na+-HEPES缓冲液(10mM,pH 7.4),5mM MgCl2,0.01%粉化的牛血清白蛋白(BSA)和100mM NaCl。为了开始结合反应,用吸量管将本发明化合物(100μl)、Na-HEPES缓冲的培养基(400μL)、3H-野靛碱(250μL)和生物膜悬浮液(250μL)加到试管中,将其中的内容物混合,然后在约23℃培养约40分钟。通过使用Brandel Cell Harvester过滤来终止结合反应;对于每份样本,使用Wallac LKB 1205 Betaplate液体闪烁计数器定量测定结合的3H-野靛碱的量。所有化合物都是以一式四份以10μM筛选。使用10μM(+)-epibatidine阻断所有3H-野靛碱与α-4,β-2烟碱性乙酰胆碱受体(α4β2nAChR)的结合来确定非特异性结合。如下所述计算各测试化合物的活性:校正非特异性结合后,计算特异性结合(总结合减去非特异性结合)的抑制百分比。以5个浓度进一步测定各活性化合物以产生浓度-抑制曲线。通过使用标准回归程序进行数据的非线性回归分析来计算IC50值。
表3
测试化合物对烟碱性乙酰胆碱受体的结合亲和力(IC50nM)化合物 IC50(nM)6 80117 63.8
本发明提供了使用化合物6和17以及包含相同化合物的药物组合物来治疗帕金森氏病、阿尔茨海默氏病、焦虑、注意力不足活动过强症、“ADHD”、Turret氏综合征、吸烟成瘾和疼痛。
C.体内生物活性
实施例6
大鼠面神经压迫模型
用氯胺酮(60mg/kg)/赛拉嗪(6mg/kg)将Long-Evans大鼠麻醉。暴露出面神经,并用钳子在单侧茎突乳突孔机械压迫面神经,把相反的未损伤一侧用作内对照。神经压迫引起腮须肌肉麻痹,由此降低了在损伤一侧的腮须动作(从麻醉恢复后即刻观察到的)。手术后大鼠以约20mg/kg的剂量口服接受测试化合物,每天给药2次,给药15天。对照大鼠仅接受载体。每组测试3-8只大鼠。在不同手术后时间每天记录腮须动作的恢复,记录最长达2周时间,并且如附图1所示。
Claims (29)
(a)R1选自H、COCOR2、COOR3和SO2R3,
(i)R2选自O-C1-6直链或支链烷基、C1-6直链或支链烷基、
C1-6直链或支链链烯基、C5-7环烷基、2-噻吩基、3-噻
吩基或苯基,所述苯基具有1-3个独立地选自下列的
取代基:H、低级烷基、低级烷氧基、羟基和卤素,且
(ii)R3是苯基烷基,所述苯基具有1-3个独立地选自下列
的取代基:H、低级烷基、低级烷氧基、羟基和卤素;
(b)
是4-6元杂环,其中在所述杂环中有不超过一个环原子是O或S;
(此处的R1与在(a)部分中描述的R1相同或不同)、
CONR4(CH2)mAr、(CH2)mO(CH2)nAr和(CH2)nAr,
(i) R4是H或C1-4烷基;
(ii) Ar选自2-吡啶基、3-吡啶基、4-吡啶基和苯基,所述苯
基具有1-3个独立地选自下列的取代基:H、低级烷基、
低级烷氧基、羟基和卤素;
(iii)m是1-4;且
(iv)n是0-4。
3.权利要求1的化合物,它具有下述结构
4.权利要求1的化合物,它具有下述结构
8.权利要求1的化合物,它具有下述结构
9.权利要求1的化合物,它具有下述结构其中各个R1彼此相同或不同。
13.权利要求9的化合物,它具有下述结构
14.权利要求9的化合物,它具有下述结构
15.权利要求9的化合物,它具有下述结构
(a)R1选自H、COCOR2、COOR3和SO2R3,
(i)R2选自O-C1-6直链或支链烷基、C1-6直链或支链烷基、C1-6
直链或支链链烯基、C5-7环烷基、2-噻吩基、3-噻吩基或苯
基,所述苯基具有1-3个独立地选自下列的取代基:H、
低级烷基、低级烷氧基、羟基和卤素,且
(ii)R3是苯基烷基,所述苯基具有1-3个独立地选自下列的取
代基:H、低级烷基、低级烷氧基、羟基和卤素;
(c)
是5元杂环,其中所述杂环具有2-3个选自N、O和S的杂原子,至少一个这样的杂原子是N;且
19.权利要求18的化合物,它具有下述结构
20.权利要求18的化合物,它具有下述结构
23.刺激神经元生长的方法,包括使神经元与有效量的 1、17或18的化合物接触。
24.包含权利要求1、17或18的化合物与可药用载体的药物组合物。
25.治疗患有其特征是疾病或创伤引起的神经元损伤的病症的个体的方法,包括给所述个体施用治疗有效量的权利要求24的药物组合物。
26.权利要求25的方法,其中所述病症是由疾病引起的,并选自帕金森氏病、阿尔茨海默氏病、中风、多发性硬化、肌萎缩性侧索硬化、糖尿病性神经病和贝尔麻痹。
27.权利要求25的方法,其中所述病症是由脑、脊髓、或外周神经创伤引起的。
28.抑制个体中其特征是疾病引起的神经元损伤的病症发作的方法,包括给所述个体施用预防有效量的权利要求24的药物组合物。
29.权利要求28的方法,其中所述病症选自帕金森氏病、阿尔茨海默氏病、中风、多发性硬化、肌萎缩性侧索硬化、糖尿病性神经病和贝尔麻痹。
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- 2000-06-14 CA CA002379149A patent/CA2379149A1/en not_active Abandoned
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- 2000-06-14 WO PCT/US2000/016221 patent/WO2001004116A2/en not_active Application Discontinuation
- 2000-06-14 JP JP2001509726A patent/JP2003504367A/ja active Pending
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- 2000-06-14 US US09/593,852 patent/US6809107B1/en not_active Expired - Lifetime
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- 2000-06-14 CZ CZ200265A patent/CZ200265A3/cs unknown
- 2000-06-14 RU RU2002103340/04A patent/RU2241709C2/ru not_active IP Right Cessation
- 2000-06-14 PL PL00352432A patent/PL352432A1/xx not_active Application Discontinuation
- 2000-06-14 BR BR0012327-7A patent/BR0012327A/pt not_active Application Discontinuation
- 2000-06-14 EP EP00939836A patent/EP1202990A2/en not_active Withdrawn
- 2000-06-14 IL IL14750500A patent/IL147505A0/xx active IP Right Grant
- 2000-06-14 MX MXPA02000330A patent/MXPA02000330A/es unknown
- 2000-06-14 KR KR1020027000348A patent/KR20020027486A/ko not_active Application Discontinuation
- 2000-07-07 AR ARP000103484A patent/AR034541A1/es unknown
- 2000-09-18 TW TW089113459A patent/TW589311B/zh not_active IP Right Cessation
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2002
- 2002-01-07 IL IL147505A patent/IL147505A/en not_active IP Right Cessation
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107207488A (zh) * | 2014-12-17 | 2017-09-26 | 伦敦皇家学院 | 作为视黄酸受体β(RARβ)激动剂的双环杂芳基‑杂芳基‑苯甲酸化合物 |
CN107207488B (zh) * | 2014-12-17 | 2020-11-17 | 伦敦皇家学院 | 作为视黄酸受体β(RARβ)激动剂的双环杂芳基-杂芳基-苯甲酸化合物 |
CN114591295A (zh) * | 2022-03-04 | 2022-06-07 | 贵州大学 | 含吡啶盐的n-(吲哚酰基)-n’-(取代的)的丙基酰肼类衍生物、其制备方法及应用 |
CN114591295B (zh) * | 2022-03-04 | 2023-11-07 | 贵州大学 | 含吡啶盐的n-(吲哚酰基)-n’-(取代的)的丙基酰肼类衍生物、其制备方法及应用 |
Also Published As
Publication number | Publication date |
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CZ200265A3 (cs) | 2002-07-17 |
JP2003504367A (ja) | 2003-02-04 |
RU2241709C2 (ru) | 2004-12-10 |
BR0012327A (pt) | 2002-07-02 |
WO2001004116A2 (en) | 2001-01-18 |
HUP0202249A2 (hu) | 2002-12-28 |
US6809107B1 (en) | 2004-10-26 |
PL352432A1 (en) | 2003-08-25 |
HUP0202249A3 (en) | 2003-01-28 |
IL147505A0 (en) | 2002-08-14 |
AR034541A1 (es) | 2004-03-03 |
CA2379149A1 (en) | 2001-01-18 |
KR20020027486A (ko) | 2002-04-13 |
TW589311B (en) | 2004-06-01 |
WO2001004116A3 (en) | 2001-08-23 |
MXPA02000330A (es) | 2004-05-21 |
AU5485500A (en) | 2001-01-30 |
AU781235B2 (en) | 2005-05-12 |
EP1202990A2 (en) | 2002-05-08 |
IL147505A (en) | 2006-07-05 |
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