CN1138042A - 治疗偏头痛的吲哚烷基-吡啶基和嘧啶基哌嗪的1,2,5-噻二唑衍生物 - Google Patents
治疗偏头痛的吲哚烷基-吡啶基和嘧啶基哌嗪的1,2,5-噻二唑衍生物 Download PDFInfo
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- CN1138042A CN1138042A CN96105542A CN96105542A CN1138042A CN 1138042 A CN1138042 A CN 1138042A CN 96105542 A CN96105542 A CN 96105542A CN 96105542 A CN96105542 A CN 96105542A CN 1138042 A CN1138042 A CN 1138042A
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- A—HUMAN NECESSITIES
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Abstract
式I的一系列新的吲哚基烷基哌嗪基吡啶和嘧啶5-(3,4-二氨基-1,2,5-噻二唑和S-氧化物)的衍生物被用于减轻血管性头痛。
在式I中,X选自S,SO和SO2。
Description
本发明总的来说涉及具有药物和生物作用性能的杂环化合物及其制备与用途。本发明特别涉及1,4-二取代哌嗪衍生物,其中一个取代基为1,2,5-噻二唑、1,2,5-噻二唑-1-氧化物或1,2,5-噻二唑-1,1-二氧化物取代的吲哚-3-基-烷基基团,另一个取代基为吡啶环或嘧啶环。这些化合物具有独特的血清素构型以及代谢稳定性,这就使它们可用于治疗血管性头痛如偏头痛或簇形头痛。
Dowie等人在出版的专利申请GB2,124,210中公开了可用于治疗偏头痛的一系列3-烷基氨基-吲哚衍生物。在后来的Oxford的专利申请GB2,162,522(1986年2月5日出版)中,特别要求保护这系列化合物中的一种。在文献中,此特定的化合物被叫做Sumatriptan(i)。
其中R4为芳基、吡啶基或喹啉基。
在US4,954,502中,Smith等人公开了一系列结构式(iii)的1,4-二取代哌嗪衍生物,这些衍生物可用作抗抑郁剂。
吲哚取代基R3和R4为氢原子、烷基、烷氧基、烷硫基、卤原子、羰基酰胺和三氟甲基。
在US5,077,293中,Smith等人提供了另一系列的治疗抑郁症的1,4-二取代哌嗪,其中吡啶基由嘧啶基来代替。
最相关的文献当属我们先前的专利申请USSN08/122,266,公开了治疗偏头痛的结构式(V)的化合物。
这些化合物均未提及本发明的新的吡啶基或嘧啶基哌嗪的5-噻二唑(及其氧化物)取代的吲哚-3-基-烷基衍生物可用于治疗偏头痛和簇形头痛。
偏头痛是各种类型头痛中的一种,它还包括簇形头痛和其它被认为从病原学看与血管有联系的头痛。这些头痛通常被归类为血管性头痛。有关近来头痛及其治疗方法可参见:Chepter13:“Drugs Used to Treat Migraineand Other Headaches”is Drug Evaluations,6th Edn.,1986,pages 239-253,American Medecal Association,W.B.Saunders Co.Philadelphia,PA。
频繁且无规律的头痛折磨着许多人,这种头痛常常是非常剧烈而且时间不长。治疗这类头痛的典型方法是服用温和的止痛药,如阿司匹林或对乙酰氨基酚。这类头痛非常常见,尽管使人感到痛苦和烦恼,但极少使人致残或衰弱。然而,血管类型的慢性复发头痛通常会使患者疼痛难忍而抱怨医生,这种头痛经常会使人致残。
尽管对于头痛还没有一个公认的分类体系,本发明的血管性头痛主要是指偏头痛和簇形头痛。偏头痛包括通常类型或传统类型的头痛,还包括本领域技术人员熟悉的偏头痛的变异类型。另外如中毒性血管头痛和高血压性头痛、慢性阵发性偏头痛,还有一些肌肉收缩头痛以及血管与肌肉混全的头痛,都可归类于与血管相关的头痛而且都可以利用本发明来治疗。本领域的技术人员应当理解,没有一种单个的治疗方法对于所有被诊断为相同头痛症状的患者是有效的,因此有必要提出有关头痛分类的不定因素。
过去最常用于治疗头痛的药物分为如下几组:
麦角生物碱,
β-阻滞剂,
钙通道阻滞剂,
抗抑郁药,以及
上述药剂的混合物,
血管性头痛至今不能完全治愈,其原因就在于缺少一种对所有患者同一类型头痛均有效的治疗方法。最近能得到的抗偏头痛药物Sumatriptan在治疗患者偏头痛方面取得了一些成功,但仍存在一些不足。进一步的复杂性还在于用于治疗偏头痛的药物长期使用时能造成依赖性,这类药如麦角胺宁。本发明另一个重要的考虑是使当今使用的比较有效的治疗偏头痛药剂如麦角和羟甲丙基甲基麦角酰胺能够在长效服用时具有有限的副作用。
因此,需要一种安全且有效的药物用来治疗偏头痛及其相关疾病,既能治愈可怕的头痛又能减轻既定的头痛。
本发明的目的是使用新的5-(3,4-双氨基-1,2,5-噻二唑-1-氧化物)-取代的吡啶基和嘧啶基哌嗪吲哚-3-基-烷基衍生物治疗血管性头痛,特别是偏头痛和簇形头痛;本发明的目的还在于提供其制备方法及其药物组合物和医疗用途。
本发明的方法是试图减轻血管性或与血管性相关的头痛,其中偏头痛和簇形头痛是最熟知的具体例症。本方法实质上包括了给需要此类治疗的患者服用5-噻二唑(或S-氧化物)取代的吡啶基或嘧啶基哌嗪吲哚-3-基-烷基衍生物、或其可药用的盐和/或溶剂化物。对于本方法的服法,口服或经鼻(transnasal)施用含目的抗偏头痛药剂的药物组合物为优选。
在式I中,R1为选自氢原子、卤原子、低级烷基和低级烷氧基的取代基。
R2、R3和R5各自独立地选自氢原子和低级烷基。在优选的化合物中,R2和R3不能同时为低级烷基。
R4为低级烷氧基。
R6为选自氨基、低级烷基氨基、双-低级烷基氨基和低级烷氧基。
m可取整数1~3或0,n可取整数1~5。在优选的化合物中,m取0,n取3。
X为选自S、SO和SO2,优选的化合物中X为SO。
Y和Z各自为选自IV和CH,但Y和Z不可同时为CH。
另外,式I化合物还包含了所有可药用酸加成盐和/或溶剂化物,本发明还包括立体异构体以及光学异构体,如对映体混合物及个别对映体和非对映体。由于本发明系列中特定化合物的结构非对称性,因而出现了上述异构体。单一异构体的分离是通过使用本领域专业人员公知的方法完成的。
术语“低级烷基”是指含1~4个碳原子的直链和支链碳基团。这些基团是碳链,它们可以是甲基、乙基、丙基、异丙基、1-丁基、1-甲基丙基、2-甲基丙基。
低级烷氧基是指与氧原子相连的C1-4烷基基团。噻二唑基也包含亚砜(SO)和砜(SO2)的衍生物。
选择适当的Y和Z,吡啶环或者嘧啶环是确定的。
本发明可药用的酸加成盐是指那些抗衡离子对盐的毒性或药理活性不能具有很大作用的盐,这些盐本身也是式I为基础上的药物等同物。它们对医疗用途通常是优先的。在有些情况下,它们的具有的一些物理性能使得在药物制剂中更需要这些盐,如溶解性、不吸湿性、与片剂相关的可压缩性以与用于药物目的其它成分的相容性。这些盐通常是通过混合式I的碱与被选择的酸形成的,其中在含过量常用隋性溶剂的溶液中反应为优选,所述溶剂如水、乙醚、苯、甲醇、乙醇、乙酸乙酯和乙腈。在式I物质中一个盐的阴离子被另一个阴离子置换的条件下,上述盐也可通过复分解或用离子交换树脂处理制得。所述置换的条件是允许通过如从溶液中沉淀成从溶剂萃取或者通过从离子交换树脂洗脱或保留于离子交换树脂分离所需的物质形式。为了生成式I物质的盐,可药用的酸包括硫酸、磷酸、盐酸、氢溴酸、氢碘酸、柠檬酸、乙酸、苯甲酸、肉桂酸、富马酸、扁桃酸、硝酸、粘酸、马来酸、羟乙磺酸、棕榈酸、庚酸等等。
式I化合物可以通过采用方案A和B所示的合成工艺和化合物制备而得。
特定的化合物及其合成还将在下文的特别实例部分详细讨论。
在合成方案中,R1至R6、X、Y、Z、m和n如上文定义,符号Q代表合成的有机离去基团部分,如甲苯磺酰基、甲磺酰基、卤离子、硫酸根、磷酸根等等。
方案A提出了X为SO或SO2时式I化合物的合成工艺。方案B是X为S时的合成工艺。所述合成工艺是由式(6)的5-氨基取代的中间产物进行的,其中杂环取代的哌嗪部分已经引入到了分子结构中。合成路径的修正不仅可以确定噻二唑部分所需的R6取代基(如所示的R4或NR2R3),而且还可以确定所需R5取代基是
H还是烷基。为了合成R5为烷基的产物,在方案A和B进一步反应之前,中间产物(6)应是单-N-烷基化的。
方案A揭示的合成工艺实质上包括合成具有与5位吲哚环相连的终端氨基的吲哚基烷基哌嗪基杂环部分,如化合物(6)。该中间产物与3,4-二烷氧基噻二唑的1-氧化物或1,1-二氧化物(3)反应生成R6为烷氧基(R4)的式I产物。利用胺取代噻二唑的烷氧基部分即可得到该产物,R6为氨基的式I产物如化合物(I-2)。如上所述,为了得到中间产物以及R5为烷基基团的产物,中间产物(6)可以在其5-吲哚基-氨基终端N-烷基化。
方案B的工艺包括了含噻二唑环的产物(X仅为S)的合成。此工艺先前公开在关于一系列组胺H2-受体拮抗剂的U.S.4,440,933和4,600,779中,在此只是应用。这些美国专利在此引作参考。方案B实质上揭示了化合物(6)中间产物与1,2-二烷氧基取代的乙二酰亚胺反应生成式(7)中间化合物。化合物(7)与N,N′-硫代二苯邻二甲酰亚胺皮应生成噻二唑的类似物产物(I-3)。与方案A相同,化合物(I-3)的噻二唑基烷氧基取代基(R6=R4)也可被胺取代而生成R6为氨基的式(I-4)产物。
方案C涉及用于方案A和B的中间化合物的合成路线;作为实例,方案C提出了为这些方案提供起始中间化合物的一些特殊的合成工艺。
方案A、B和C采用的反应及其应用对于有机合成领域的专业人员是熟悉的,反应条件和反应物的改良都应当是可以理解的。熟练的合成化学专家一定知道如何利用这些工艺去制备特殊的式I化合物,包括本发明所包含的却未具体公开的其它化合物。对于本领域技术人员来讲,为制备相同化合物,方法稍有变化也应当是显然的。为得到更详细的描述,有代表性的合成实例将在下文的特别实例部分提供。
通过累集数据表明血清素与病理生理学联系在一起,所述数据包括偏头痛发作后血清素代谢物排泄的增加和偏头痛发作过程中血小板血清素含量的减少。这后一作用对偏头痛显得很特别,而不是痛苦和紧张的结果。(Anthony等人,“plasma Serotonin in migraine andstress”,Arch Neurol.1967,16:544-552)。更重要地,在患偏头痛时,肌肉注射利血平会降低血浆血清素并诱导典型的偏头痛类型的头痛。这种诱导的头痛可通过静脉缓慢注射血清素肌酸酐硫酸盐而得到减轻。(Kimball等人,“Effect of serotonin in migraine patients,”NeurologyN.Y.1960,10:107-111)。
尽管血清素在治疗偏头痛方法中已显示出其效果,但由于副作用其在偏头痛中使用已被排除。所述副作用如坐立不安、恶心、虚弱、呼吸深快、面部潮红以及机能异常。(Lance等,“The control of Cranial arteries byhumoral mechanisms and its relation to the migrainesyndrome,”Headache,1967,7:93 -102)。因此,能够治疗偏头痛而又没有其它作用的更特殊的血清素药剂是潜在的用于治疗偏头痛药物。收集的结果已得到了如下的概念:具有血清素受体5-HT1D亚型选择性的化合物在治疗偏头痛方面具有临床作用。为此,本发明的化合物表明了与5-HT1D位点的极强的亲和性。我们感兴趣的式I化合物具有很大的潜能,其中这些化合物的IC50值小于100毫微摩尔(nmolar)。优选化合物的IC50值在10毫微摩尔以下。
5-HT1D结合性能的确定是通过采用如Heuring和Peroutka,J.Neurosci.7(3),1987,894-903中描述的方法完成的,只是有很小的改变。使用氚化血清素可以确定本发明化合物体外的IC50(nM)试验值。
除了5-HT1D结合试验数据,本发明化合物在犬隐静脉的静脉模型中诱发收缩的能力进一步揭示了其在治疗血管性头痛的有用性。优选的化合物已证明其潜能与血清素本身相当或高于血清素本身。另外,本发明化合物显示其在体外鼠肝匀浆中的潜能远远大于早期公开在USSN08/122,266中吲哚-squarate系列化合物的能力。所有上述药理试验均表明本发明化合物对治疗偏头痛有效。
本发明的另一方面提供了一种治疗偏头痛的方法,该方法包括给患者系统服用治疗有效量式I化合物或其可药用的盐。期望服用式I化合物能够治愈早期阶段发作的偏头痛,还能治疗既定的血管性头痛。
式I化合物的服法和剂量与参考文献GB2,162,522A中的参考化合物Sumatriptan可采用相同的方式。尽管本化合物可通过鼻内施用和口服,其剂量和剂量规范都必须视情况仔细施用,应当具有极好的职业判断并考虑到受者的年龄、体重和病情、施用途径以及疾病的性质和严重性。当非肠道施用时,每天剂量大约从0.05至10mg/kg,0.1至2mg/kg优选;口服时,每天剂量大约从1至50mg/kg,大约5至20mg/kg优选。在有些情况下,较小的剂量就能获得足够的治疗效果,而在另一些情况下则需较大的剂量。系统施用是指口服、鼻内施用、直肠施用和非肠道施用(即肌内、静脉内和皮下施用)。一般地,结果会发现为了达到同样的效果,口服本发明的化合物所需活性成分的剂量比通过鼻内或非肠道给药的剂量要大。根据好的临床经验,优选的是在一定浓度水平上服用本化合物,既能治疗偏头痛产生作用而又不造成任何有害或不适当的副作用。
为了治疗偏头痛,本发明的化合物既可以作为单个治疗剂,又可以与其它治疗剂混合。作为治疗,化合物经常是以药物组合物形式给出,该组合物包含治疗偏头痛剂量的式I化合物或其可药用的盐以及可药用的载体。每单位剂量含大约1至500mg有效成分的药物组合物为优选,组合物通常被制备成片剂、锭剂、胶囊、粉剂、水或油悬浮剂、糖浆、酏剂和水溶液。
当然,使用的药物组合物的性质取决于所需的给药路径。例如,口服药物应是片剂或胶囊形式,可含常规的赋形剂如粘合剂(如淀粉)和湿润剂(如月桂基硫酸钠)。含常规药物载体的式I化合物的溶液或悬浮液将用于鼻内和非肠道给药的组合物,如水溶液用于静脉内注射、油性悬浮液用于肌内注射。
构成本发明的化合物及其制备方法和生物作用将从下述的实施例中表现得更完全,这些实施例给出仅仅是说明本发明,而不是限制本发明的大小或范围。在用来说明上文合成过程的下面实施例中,温度是以摄氏度表示,熔点未经修正。核磁共振(NMR)光谱特征是指化学位移(δ)。该位移是以相对于四甲基硅烷作为参比标准的ppm值表示的。在1NHMR光谱数据中各种位移报告的相对面积对应于分子中特定官能基类型的氢原子数目。对于多重性,位移的特征被描述为宽单峰(bs)、单峰(s)、多重峰(m)、七重峰(hept)、四重峰(q)、三重峰(t)、或双峰(d)。使用的缩略词有DMSO-d6(氘代二甲基亚砜)、CDCl3(氘代氯仿),此外均为惯用语。红外(IR)光谱描述仅仅包括具有官能基团鉴定值的吸收波数(cm-1)。使用净相或溴化钾(KRr)作为稀释剂来确定IR。以重量百分数表达元素分析结果。
下列的实施例详细描述了式I化合物的制备以及各步工艺的合成中间产物。对于本领域的技术人员来讲,物质和方法的修正均可制备本发明公开的其它化合物,这是显然的。从上文的描述及下文的实施例可以相信本领域的技术人员有能力最充分地利用本发明。另外,合成特定中间产物以及在3位和4位具有氨基取代基的1,2,5-噻二唑化合物的实例已经公开了。参见如Crenshaw和Algieri,U.S.4,374,248和U.S.4,600,779;Montzka,U.S.4,440,933。这些美国专利在此引出作为参考,从而为确定本发明中间产物和产物提供了可能性。
A.中间化合物的制备
包含在本发明方案中的制备合成中间产物的一些有代表性的步骤在下文中给出了。大多数起始物质和确定的中间产物在市场上能够购到或者其合成工艺在化学文献中已经能够得到,因此有机合成化学领域中的技术人员能够充分利用它们。
实施例1
5-[(5-硝基-1H-吲哚-3-基)甲基]-2,2-二甲基-1,3-二噁烷-4,6-二酮
应用Flaugh的工艺步骤(D.S.Farlow,M.E.Flaugh,S.D.Horvath,E.R.Lavignino,P.Pranc,Org.Prep,Proc,Int.,1981,13,39.)。这样在室温下,将5-硝基吲哚(50.0g,0.32mol)、Meldrum酸(46.0g,0.32mol)、37%甲醛水溶液(26.0ml,0.32mol)和脯氨酸(1.8g,0.016mol)的200ml乙腈溶液搅拌18小时。过滤所得的粘稠黄色浆液,并用乙腈清洗滤饼,然后用丙酮、最后用乙醚清洗。在真空中干燥此物质,得到亮黄色固体标题化合物(80.0g,81%),熔点182℃(分解)。浓缩母液,然后用水稀释,收集所得固体并如前述清洗和干燥,得到暗黄色固体二次产物(7.0g)。总产率=87.0g(89%):IR(KBr)3330,1767,1732cm-1;1HNMR(DMSO-d6,200MHz)δ11.64(s,1H),8.63(d,J=2.2Hz,1H),7.96(dd,J=9.0,2.2Hz,1H),7.49(d,J=9.0Hz,1H),7.33(d,J=2.2Hz,1H),4.84(t,J=4.6Hz,1H),3.45(d,J=4.5Hz,2H),1.78(s,3H),1.55(s,3H).元素分析C15H14N2O6计算值:C,56.60;H,4,43;N,8.80.实测值:C,56.62;H,4.41;N,8.91.
实施例2
5-硝基-3-(1H-吲哚)丙酸乙酯
向[5-(5-硝基吲哚-3-基)甲基]-2,2-二甲基-1,3-二噁烷-4,6-二酮(10.0g,0.031mol)的吡啶(80ml)和无水乙醇(20ml)混合物的溶液中加入0.1g铜粉,在氩气气氛中加热回流混合物2小时。过滤冷却后的混合物,蒸发滤液。用乙醚-二氯甲烷研制所得的残留物,得到固体标题化合物(7.3g,89%)。熔点118-121℃:IR(KBr)3330,1730cm-1;1HNMR(DMSO-d6,200MHz)δ11.59(brs,1H),8.53(d,J=2.2Hz,1H),7.97(dd,J=9.0,2.3Hz,1H),7.49(d,J=9.0Hz,1H),7.40(d,J=2.1Hz,1H),4.03(q,J=7.1Hz,2H),3.02(t,J=7.4Hz,2H),2.67(t,J=7.4Hz,2H),1.13(t,J=7.1Hz,3H).
实施例3
3-(3-羟基丙基)-5-硝基-1H-吲哚
在0℃、氩气气氛中,向95%LiAlH4(2.20g,0.058mol)的60ml无水四氢呋喃(THF)悬浮液中加入5-硝基-3-吲哚丙酸乙酯
0.028mol)的100ml无水THF溶液,搅拌20分钟后,混合物通过小心加入3ml H2O骤冷。搅拌所得悬浮液10分钟,然后过滤,滤饼用另加的THF清洗。蒸发滤液,在乙醚中溶解残留物并干燥(Na2SO4)和蒸发,用己烷研制所得固体,从而得到黄色固体标题化合物(4.30g,70%),熔点107-110℃:IR(KBr)3480,3180,1625cm-1;1HNMR(CDCl3,200MHz)δ8.60(d,J=2.1Hz,1H),8.35(brs,1H),8.11(dd,J=9.0,2.2Hz,1H),7.38(d,J=8.9Hz,1H),7.16(m,1H),3.75(t,J=6.2Hz,2H),2.91(t,J=7.2Hz,2H),2.07-1.93(m,2H),1.37(br s,1H).
实施例4a
3-(3-溴丙基)-5-硝基-1H-吲哚
在0℃,氩气气氛中,向三苯基膦(6.70g,0.025mol)的80ml乙腈溶液中加入3-[3-羟基丙基]-5-硝基-1H-吲哚(实施例3)(4.30g,0.020mol)的75ml乙腈溶液,再加入CBr4(9.00g,0.027mol)的25ml乙腈溶液。在室温下搅拌混合物3小时,再蒸发并通过色谱纯化残留物(SiO2/乙酸乙酯-己烷,1∶9然后1∶4)得到固体标题化合物(4.60g,84%),熔点92-95℃:IR(纯)3420,1330cm-1,1HNMR(CDCl3,200MH)δ8.59(d,J=2.1Hz,1H),8.40(brs,1H),8.13(dd,J=9.0,2.2Hz,1H),7.40(d,J=9.1Hz,1H),7.21(d,J=2.2Hz,1H),3.45(t,J=6.4Hz,2H),2.99(t,J=7.2Hz,2H),2.26(m,2H).
实施例4b
3-[3-碘丙基]-5-硝基-1H-吲哚
将3-[3-羟基丙基]-5-硝基-1H-吲哚(1.13g,5.06mmol)的20ml乙腈溶液冷却至0℃,依次利用三乙胺(1.05ml,7.59mmol)和甲磺酰氯(0.43ml,5.6mmol)处理,搅拌混合物30分钟。反应混合物利用30ml水骤冷,有机相萃取到乙酸乙酯中。干燥(MgSO4)有机萃取物并真空浓缩。将粗的残留物溶解在20ml含KI(1.7g,10.1mmol)的乙腈中,并加热回流3小时。冷却反应混合物,在真空除去溶剂。残留物溶解在100ml乙酸乙酯中并用水洗。干燥(MgSO4)产乙酸乙酯相,残留物通过快速柱色谱纯化(20%乙酸乙酯的己烷溶液),从而得黄色固体标题化合物(1.37g,4.20mmol,83%):熔点95-98℃;1HNMR(DMSO-d6,300MHz)δ8.53(d,J=2.3Hz,1H),7.97(dd,J=2.3,9.0Hz,1H),7.51(d,J=9.0Hz,1H),7.43(s,1H),3.30(t,J=6.7Hz,2H),2.84(t,J=7.7Hz,2H),2.11(m,2H);IR(KBr)1330,1510,810cm-1;MS(m/e)330(M+).元素分析:C11H11IN2O2计算值:C,40.02,H3.36,M8.48.实测值:C,40.26;H,3.27;N,8.51.
实施例5a
3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-硝基-1H-吲哚
在氩气气氛中,将5-硝基-3-(3-溴丙基)吲哚(0.57,2.0mmol)、1-(5-甲氧基-4-吡啶)哌嗪(0.47g,2.4mmol)、KI(0.40g,2.4mmol)和二异丙基乙胺(1.75ml,10.0mmol)混合物的20ml乙腈溶液加热回流6小时。用乙酸乙酯稀释冷却过的反应混合物,并清洗(H2O,盐水)。利用二氯甲烷反相萃取水相;清洗(H2O,盐水)合并有机相,并干燥(Na2SO4)和蒸发。所得残留物通过色谱纯化(SiO2/CH2Cl2-MeOH,95∶5)得到固体,再利用二氯甲烷-己烷研制得到黄色固体标题化合物(0.55g,70%),熔点163-166℃:IR(KBr)3440,3175,1578,1320cm-1;1HNMR(CDCl3,200MHz)δ8.60(d,J=2.1Hz,1H),8.47(brs,1H),8.33(s,1H),8.11(dd,J=9.0,2.2Hz,1H),8.47(brs,1H),8.33(s,1H),8.11(dd,J=9.0,2.2Hz,1H),7.89(s,1H),7.38*d,J=9.0Hz,1H),7.18(d,J=2.0Hz,1H),3.86(s,3H),3.8-3.9(m,4H),2.86(t,J=7.4Hz,2H),2.59(t,J=4.9Hz,4H),2.50(t,J=7.5Hz,2H),2.05-1.90(m,2H).元素分析:C20H24N6O3.H2O.0.1CH2Cl2 计算值:C,57.08;H,6.24;N,19.87.实测值:C,57.37;H,5.85;N,19.53.
实施例5b
3-[3-[4-(3-甲氧基-4-吡啶基)-1-哌嗪基]丙基]-5-硝基-1H-吲哚
将3-[3-碘丙基]-5-硝基-1H-吲哚(1.4g,4.2mmol)、1-(3-甲氧基-4-吡啶基)-哌嗪(0.98g,5.09mmol)和K2CO3(1.4g,10.2mmol)混合物的30ml乙腈溶液加热回流4小时。冷却反应混合物,搅拌12小时。分离溶剂,残留物溶解在乙酸乙酯和水中。分离水层并用乙酸乙酯萃取。干燥(MgSO4)并浓缩有机萃取物,通过快速硅胶色谱纯化(5%甲醇的二氯甲烷溶液作为洗脱液)胶质残余物。得到黄色固体标题化合物(0.6g,36%):IR(KBr)3600,2400,1600,1520,1330,1250,815cm-1;1HNMR(DMSO-d6,300MHz)δ8.52(d,J=2.2Hz,1H),8.10(s,1H),8.02(d,J=5.3Hz,1H),7.96(dd,J=2.3,9.0Hz,1H),7.48(d,J=9.0Hz,1H),7.42(s,1H),6.81(d,J=5.4Hz,1H),3.84(s,3H),3.21(brs,4H),3.07(dd,J=6.4,14.7Hz,2H),2.79(t,J=14.7Hz,2H),2.66(br s,4H),1.97(m,2H);MS(M/e)395(M+).
实施例5c
3-[3-[4-(2-吡啶基)-1-哌嗪基]丙基]-5-硝基-1H-吲哚
将3-[3-溴丙基]-5-硝基-1H-吲哚(1.4g,4.2mmol)、1-(2-吡啶基)-哌嗪(0.98g,5.09mmol)和K2CO3(1.4g,10.2mmol)混合物的30ml乙腈溶液加热回流4小时。冷却反应混合物,分离溶剂,残留物溶解在乙酸乙酯和水中。分离水层并用乙酸乙酯萃取。干燥(MgSO4)并浓缩有机萃取物,通过快速硅胶色谱纯化(5%甲醇的二氯甲烷)胶质残余物,得到黄色固体标题化合物(0.6g,36%):IR(KBr)3182,1520,1330cm-1;1HNMR(DMSO-d6,300MHz)δ8.52(d,J=2.24Hz,1H),8.80(dd,J=1.8,4.8Hz,1H),7.95(dd,J=2.25,9.0Hz,1H),7.52-7.49(m,2H),7.41(s,1H),6.79(d,J=8.6Hz,1H),6.60(t,J=6.6Hz,1H),3.46(t,J=4.7Hz,4H),2.78(t,J=7.4Hz,2H),2.42(t,J=5.0Hz,1H),2.34(t,J=6.9Hz,4H),1.82(dt,J=7.4,46.9Hz,2H);MS(m/e)365(M+.元素分析:C20H23N5O2计算值:C,65.73,H,6.34,N,19.16;实测值C,65.35,H,6.26,N,18.87.
实施例5d
3-[3-[(3-甲氧基-2-吡啶基)-1-哌嗪基]丙基]-5-硝基-1H-吲哚
将3-(3-溴丙基)-5-硝基-1H-吲哚(0.88g,3.11mmol)、K2CO3(0.43g,3.11mmol)、KI(0.52g,3.11mmol)和1-(3-甲氧基-2-吡啶基)哌嗪(0.60g,3.11mmol)混合物的50ml乙腈溶液加热回流5小时。冷却、过滤并浓缩混合物。通过快速柱色谱法纯化(以5%甲醇的二氯甲烷作为洗脱液)残留物,得到黄色泡沫标题化合物(1.2g,99%):IR(KBr)3300,1520,1330,1240cm-1;1HNMR(DMSO-d6,300MHz)δ8.54(d,J=2.2Hz,1H),7.97(dd,J+2.2,9.9Hz,1H),7.77(m,1H),7.50(d,J=9.0Hz,1H),7.44(s,1H),7.24(d,J=7.75Hz,1H),6.90(m,1H),3.78(s,3H),3.33(brs,2H),2.80(t,J=7.3Hz,2H),1.93(m,2H);MS(m/e)395(M+)。
实施例6
3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-氨基-1H-吲哚
向3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-硝基-吲哚(0.550g,1.39mmol)的乙醇(120ml)和THF(40ml)混合物的溶液中加入10%钯-炭(0.30g)。在40psi下将混合物在帕尔摇动器上氢化18小时。然后通过硅藻土过滤混合物,用另加的乙醇-THF清洗催化剂,蒸发滤液,得到实质上很纯的褐色泡沫标题化合物(0.557g,100%)。用过量的甲醇HCl处理此物质的样品(0.143g),用丙酮稀释得到的溶液,从而得到沉淀。过滤沉淀,然后从乙醇结晶得到0.100g略带紫色的固体,熔点192℃(分解):IR(KBr)3410,3200,1630,1540cm-1;1HNMR(DMSO-d6,200MHz)δ11.22(br s,1H),10.20(brs,2H),8.60(m,1H),8.20(m,1H),8.20(s,1H),7.55(d,J=1.6Hz,1H),7.45(d,J=8.6Hz,1H),7.35(d,J=2.1Hz,1H),7.07(dd,J=8.6,1.9Hz,1H),4.89-4.82(m,2H),3.91(s,3H),3.8-3.0(br m,8H),2.76(m,2H),元素分析:C20H26N60.4HCl.H2O计算值:C,45.29;H,6.08;N,15.85.实测值:C,45.32;H,5.97;N,15.59.
实施例7
4-甲基-5-氨基-3-(3-羟基丙基)吲哚
A.4-甲基吲哚
在氩气气氛下,将3-硝基-邻-二甲苯(13.4ml,0.1mol)、二甲基甲酰胺二甲醇缩醛(40ml,0.3mol)和吡咯烷(10ml,0.12mol)混合物的200ml无水DMF溶液加热到120~130℃(油浴温度)21小时。将冷却的混合物注入到冷水(400ml)中,并用乙醚(4×200ml)萃取。清洗(H2O,4×100ml)、干燥(Na2SO4)和蒸发醚溶液,得到暗红色粘的油状物。该油状物用150ml乙酸乙酯溶解,加入1.5g 10%的钯-炭,并在50psi下在Parr摇动器中氢化1小时。然后过滤反应混合物,用另加的乙酸乙酯洗涤催化剂,蒸发滤液得到暗红紫色油状物。通过快速色谱纯化(SiO2/二氯甲烷-石油醚,1∶1)该油状物得到纯的淡黄褐色4-甲基吲哚(8.85g,68%)油状物:1H NMR(DMSO-d6,200MHz)δ11.04(brs,1H),7.29(t,J=2.7Hz,1H).7.21(d,J=7.7Hz,1H),6.96(t,J=7.2Hz,1H),6.75(dt,J=6.9,0.8Hz),1H),6.43(m,1H),2.46(s,3H).
B.1-乙酰基-4-甲基二氢吲哚
向4-甲基吲哚(7.433g,0.0567mol)的100ml冰醋酸中在1.5小时内分批加入NaCNBH3。然后真空浓缩反应混合物,加入水,再用10N NaOH碱化溶液。利用乙酸乙酯(X3)萃取所得的混合物,清洗(盐水)、干燥(Na2SO4)并蒸发有机萃取物,得到油状物,快速色谱纯化(SiO2/乙酸乙酯-己烷,1∶4)该油状物得到纯的油状4-甲基二氢吲哚(6.962g,92%):1HNMR(DMSO-d6,200MHz)δ6.78(t,J=7.6Hz,1H),6.33(d,J=7.4Hz,1H),6.30(d,J=7.6Hz,1H),5.36(brs,1H),3.38(t,J=8.5Hz,2H),2.81(t,J=8.5Hz,2H),2.11(s,3H).
所得油状物(6.945g,0.0522mol)在10ml乙酸酸酐中溶解。放热反应接着发生了,并在15分钟后,混合物已经固化。随后在真空中分离挥发物,得到固体。利用乙醚研制该物质,得到6.317g白色结晶固体1-乙酰基-4-甲基二氢吲哚,熔点110-111℃。蒸发上清液,用己烷研制所得的残留物,得到另外的2.191g纯产品。总产量=8.508g(93%):IR(neat)1649cm-1;1HNMR(DMSO-d6,200MHz)δ7.86(d,J=7.9Hz,1H),7.03(t,J=7.7Hz,1H),6.80(d,J=7,5Hz,1H),4.08(t,J=8.5Hz,2H),3.03(t,J=8.5Hz,2H),2.18(s,3H),2.13(s,3H).元素分析:C11H13NO计算值:C,75.39;H,7.48;N,8.00.实测值:C,75.41;H,7.53;N,7.95.
C.4-甲基-5-硝基二氢吲哚
将1-乙酰基-4-甲基二氢吲哚(8.260g,0.0372mol)的50ml浓硫酸溶液冷却至5℃,然后滴加HNO3以维持内部温度5-10℃。滴加完成后,混合物保温15分钟,然后注入500ml碎冰块,搅拌所得的浆状物直至冰块全部溶解。然后过滤悬浮液,用水清洗滤饼,残留物在二氯甲烷中溶解。分离有机相,用二氯甲烷(X3)反萃取水相。干燥(Na2SO4)并蒸发合并的有机相,得到暗黄色固体。色谱纯化(9×10cmSiO2填塞/二氯甲烷,然后二氯甲烷-乙腈,95∶5)该固体,得到1-乙酰基-4-甲基-5-硝基二氢吲哚和1-乙酰基-4-甲基-7-硝基二氢吲哚的不可分混合物(8.09g,78%),其比例为9∶1(大约):1HNMR(DMSO-6,200MH)δ7.98(d,J=8.9Hz,0.88H),7.89(d,J=8.9Hz,0.88H),7.54(d,J=8.3Hz,0.12H),7.03(d,J=8.3Hz,0.12H),4.18(t,J=8.7Hz,2H),3.14(t,J=8,7Hz,2H),2.37(s,3H),2.19(s,3H).
向1-乙酰基-4-甲基-5(7)硝基二氢吲哚(8.049g,0.0366mol)的75ml甲醇悬浮液中加入25mlClaisen碱(参见Fieser & Fieser,Reagents for OrganicSynthesci,Vol.1,Pg.153),在蒸汽浴上温热所得混合物,直至变成均质。浓缩冷却后的反应混合物,用水稀释,过滤所得的悬浮液,得到橙褐色固体。用二氯甲烷(X3)萃取滤液,干燥(Na2SO4)并蒸发有机萃取物,得到固体。色谱纯化(SiO2/乙醚-己烷,1∶1,然后氯仿)合并的固体得到两部分。部分1用乙醚溶解,溶液用脱色炭处理,过滤(硅藻土)并蒸发得到暗橙色固体4-甲基-7-硝基二氢吲哚(0.575g,9%,熔点125-、127℃;IR(KBr)3395,1623,1596cm-1;1HNMR(DMSO-d6,200MHz)δ7.83(brs,1H),7.55(d,J=8.8Hz,1H),6.36(d,J=8.8Hz,1H),3.75(t,J=8.6Hz,1H),2.99(t,J=8.6Hz,2H),2.15(s,3H),元素分析:C9H10N2O2计算值:C,60.66;H,5.66;N,15.72.实测值:C,60.99;H,5.71;N,15.48.
部分2再经色谱纯化(氯仿),得到的固体再用乙醚研制,得到橙色结晶固体4-甲基-5-硝基二氢吲哚(4.813g,74%),熔点169-171℃:IR(KBr)3330,1598cm-1;1HNMR(DMSO-d6,200MHz)δ7.85(d,J=8.8Hz,1H),7.04(brs,1H),6.33(d,J-8.8Hz,1H),3.63(t,J=8.8Hz,1H),2.98(t,J=8.8Hz,2H),2.38(s,3H).元素分析:C9H10N2O2计算值:C,60.66;H,5.66;N,15.72,实测值LC,60.66;H,5.47;N,15.74.
D.4-甲基-5-硝基吲哚
向4-甲基-5-硝基二氢吲哚(4.767g,0.0268mol)的100ml甲醇悬浮液中立即加入2,3-二氯-5,6-二氰基-1,4-苯醌(6.697g,0.0295mol),在室温下搅拌所得混合物1小时。然后蒸发反应混合物,用二氯甲烷溶解残留物。利用饱和NaHCO3水溶液(X4)洗涤溶液,并干燥(Na2SO4)和蒸发,得到固体。从乙酸乙酯-己烷(-20℃)中结晶该固体,得到绿黄色针状标题化合物(4.161g)。熔点:179-180℃色谱纯化(SiO2/乙酸乙酯-己烷,1∶1)母液,又得到0.417g纯产物。总产量=4.578g(97%):IR(KBr)3318,1604,1585cm-1;1HNMR(DMSO-d6,200MHz)δ11.72(brs,1H),7.81(d,J=9.0Hz,1H),7.56(t,J=2.8Hz,1H),7.39(d,J=8.9Hz,1H),6.79(m,1H),2.75(s,3H)。元素分析:C9H8N2O2计算值:C,61.35;H,4.58;N,15.90.实测量:C,61.32;H,4.40;N,15.96.
E.5-(4-甲基-5-硝基吲哚-3-基甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮
采用Flaugh的步骤。由此在室温下,将4-甲基-5-硝基吲哚(0.880g,5.00mmol)、Meldrum酸(0.864g,6.00mmol)、37%甲醛水溶液(0.5ml,6.0mmol)和D,L-脯氨酸(0.029g,0.25mmol)的25ml乙腈溶液搅拌72小时。得到的黄色浆状物在-20℃环境下保存,然后过滤冷混合物。用冷的乙腈和乙醚清洗滤饼,然后真空干燥,得到金丝雀黄固体标题化合物(1.055g,64%),熔点196-198℃(分解):IR(KBr)3338,1782,1742cm-1;1HNMR(DMSO-d6,200MHz)δ11.46(brs,1H),7.61(d,J=8.9Hz,1H),7.32(d,J=8.9Hz,1H),7.25(d,J=2.4Hz,1H),4.74(t,J=5.0Hz,1H),3.64(d,J=4.9Hz,1H),2.80(s,3H),1.84(s,3H),1.69(s,3H),元素分析:C16H16N2O6计算值:C,57.83;H,4.85;N,8.43.实测量:C,57.42;H,4.68;N,8.52.
F.4-甲基-5-硝基-3-吲哚丙酸乙酯
在氩气气氛中,向5-[(4-甲基-5-硝基吲哚-3-基)甲基]-2,2-二甲基-1,3-二噁烷-4,6-二酮(1.009g,3.04mmol)的吡啶(18ml)和无水乙醇(2ml)混合物的溶液中加入0.05g铜粉,并将混合物加热回流2小时。过滤冷却了的混合物,真空蒸发滤液,得到粘稠褐色油状物。用乙酸乙酯溶解该物质,清洗(1N HCl,饱和NH4Cl水溶液、盐水)、干燥(Na2SO4)并蒸发该溶液,得到黄色固体。用乙醚研制,得到褐色固标题化合物(423mg)。通过蒸发上清液并再用乙醚研制,可回收另外的166mg产品。总产量=671mg(80%)。从乙酸乙酯-己烷中结晶出分析样品,得到褐色晶体,熔点105-106℃:IR(KBr)3340,1717,1517,1335cm-1;1HNMR(DMSO-d6,200MHz)δ11.47(brs,1H),7.63(d,J=9.0Hz,1H),7.30(d,J=8.6Hz,1H),7.28(s,1H),4.06(q,J=7.1Hz,2H),3.18(t,J=7.1Hz,2H),2.77(s,3H),2.68(m,2H),1.16(t,J=7.1Hz,3H).元素分析:C14H16N2O4计算值:C,60.86;H,5.84;N,10.14.实测值:C,60.76;H,5.74;N,10.00
G.4-甲基-5-硝基-3-(3-羟基丙基)吲哚
在0℃,氩气气氛下,向95%LiAlH4(0.378g,9.44mmol)的10ml无水THF悬浮液中加入4-甲基-5-硝基-3-吲哚丙酸乙酯(0.650g,2.36mmol)的2ml无水THF溶液。5分钟后移去冷却浴,在室温下继续搅拌30分钟。通过顺序加入0.4ml水、0.4ml 15%NaOH水溶液及1.2ml水,使反应骤冷。用乙酸乙酯稀释所得的悬浮液,然后过滤,再用另外的乙酸乙酯清洗滤饼。蒸发滤液,色谱纯化(SiO2/二氯甲烷-乙酸乙酯,2∶1)残留物,得到固体标题化合物(0.458g,83%),从乙酸乙酯-已烷结晶出分析样品,得到黄橙色针状物,熔点129-130℃:IR(KBr)3543,3210,1616,1520,1330cm-1;1HNMR(DMSO-d6,200MHz)δ11.43(brs,1H),7.63(d,J=8.9Hz,1H),7.30(d,J=8.7Hz,1H),7.29(s,1H),4.51(t,J=5.2Hz,1H),5.20(dt,J=6.2,5.4Hz,2H),2.91(t,J=7.7Hz,2H),2.78(s,3H),1.78(m,2H).元素分析:C12H14N2O3计算值:C,61.52;H,6.02;N,11.96.实测值:C,61.23;H,5.85;N,11.90.
H.4-甲基-5-氨基-3-(3-羟基丙基)吲哚
4-甲基-5-硝基-3-(3-羟基丙基)吲哚(0.365g,1.56mmol)的20ml无水乙醇溶液中加入10%钯-炭(0.150g),在50Psi下,将混合物在Parr摇动器上氢化0.5小时。通过硅藻土填塞过滤混合物,用另外的乙醇清洗催化剂,蒸发滤液得到固体标题化合物(0.280g,88%)。从乙酸乙酯结晶出分析样品,得到米色针状物,熔点141-142℃:IR(KBr)3388,3180,1618cm-1;1HNMR(DMSO-d6,200MHz)δ10.20(brs,1H),6.87(d,J=8.8Hz,1H),6.83(s,1H),6.50(d,J=8.3Hz,1H),4.43(t,J=5.2Hz,1H),4.12(s,2H),3.47(dt,J=6.4,5.3Hz,2H),2.79(t,J=7.7Hz,2H),2.31(s,3H),1.73(m,2H).元素分析C12H16N2O计算值:C,70.55;H,7.90;N,13.72.实测值:C,70.41;H,7.89;N,13.55.
实施例8
3,4-二甲氧基-1,2,5-噻二唑-1,1-二氧化物
在1分钟内,将3,4-二甲氧基-1,2,5-噻二唑(1.48g,10.1mmol)[根据J.Org.Chem.,40,2749(1975)中描述的步骤制备]的20ml氯仿溶液加入搅拌的间-氯过苯甲酸(4.11g,20.3mmol,测定85%)的60ml氯仿溶液中。在环境温度下搅拌1小时后,将混合物加热至回流温度8小时,然后在环境温度下搅拌1小时。用NaHCO3水溶液和水萃取反应混合物,干燥(Na2SO4)有机相,减压过滤和蒸发有机相。用甲醇处理残留物并过滤,得到1.03g产品。从甲醇中重结晶得到标题化合物,熔点200~202℃:元素分析:C4H6N2O4S计算值:C,26.97;H,3.39;N,15.72;S,18.00;实测量:C,26.82;H,3.18,N,16.09;S,18.00.
实施例9
3,4-二甲氧基-1,2,5-噻二唑-1-氧化物
在氮气气氛中,将草二亚胺酸二甲基酯(4.0gm,34.5mmol)和吡啶(5.71ml,5.58gm,70.6mmol)的8mlCH2Cl2溶液滴加到亚硫酰氯(2.61ml,4.25gm,34.7mmol)的18mlCH2Cl2冷溶液中,其中滴加速度以控制反应温度保持在0~15℃。在环境温度下搅拌20分钟之后,用2份11ml的0.055NHCl水溶液清洗反应混合物。用2份20ml的CH2Cl2萃取水相,干燥合并的有机相,在减压下将有机相蒸干。从异丙醇中重结晶固体残留物,得到3.0gm标题化合物,熔点137-139℃。
B.式I产物
1.式I-1产物(X=SO,SO2)
实施例10
在室温下,将3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-氨基吲哚(0.366g,1.0mmol)和3,4-二甲氧基-1,2,5-噻二唑-1-氧化物(3)(0.162g,1.0mmol,参见US4,374,248)的20ml甲醇溶液搅拌30分钟,然后加热回流4小时。蒸发冷却了的混合物,利用二氯甲烷研制残留物,得到0.323g固体。色谱纯化(SiO2/CH2Cl2-MeOH,95∶5,然后CHCl2-MeOH-NH4OH,95∶4.5∶0.5)该物质得到黄色固体标题化合物(0.150g,30%),熔点164℃(分解):IR(KBr)3330(br),1605,1580,1130cm-1;1HNMR(DMSO-d6,400MHz)δ10.85(s,1H),10.38(s,1H),8.23(s,1H),8.18(s,1H),8.02(s,1H),7.7(d,J=8.7Hz,1H),7.34(d,J=8.7Hz,1H),7.17(s,1H),4.17(s,3H),3.83(s,3H),3.68(brs,4H),2.69(t,J=7.4Hz,2H),2.37(t,J=7.4Hz,2H),1.84(m,2H).元素分析:C23H28N8O3S.H2O计算值:C,53.68;H,5.88;N,21.78.实测值:C,53.87;H,5.88;N,21.63.
2.式I-2产物
实施例11
在-10℃约30分钟内,将无水二甲胺吹进50ml无水乙醇中。在此冷溶液中加入3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-(1-氧代-1-甲氧基-1,2,5-噻二唑-3-基)氨基吲哚(实施例8)(0.190g,0.38mmol)溶液,然后在室温下搅拌所得溶液1小时。蒸发反应混合物,得到灰白色固体,色谱纯化(SiO2/CH2Cl2-MeOH,95∶5,然后CH2Cl2-MeOH-NH4OH,95∶4.5∶0.5至90∶9∶1)该固体,得到灰白色固体标题化合物(0.130g,62%),熔点150℃(分解):IR(KBr)3310(br),1628,1608,1575cm-1;1HNMR(DMSO-d6,200MHz)δ10.88(br S,0.5H),9.88(brs,0.5H),8.51(brs,1H),8.23(s,1H),8.11(s,1H),8.02(s,1H),7.38(s,2H),7.18(s,1H),3.83(s,3H),3.70(brs,4H),3.00(s,3H),2.71(m,2H),2.50(m,9H),1.86(m,2H).元素分析:C24H31N9O2S.1.9H2O.0.04CH2Cl2计算值:C,52.76;H,6.42;N,23.04.实测值:C,52.37;H,6.02;N,23.50.
实施例12
3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-(1-氧代-4-甲基氨基-1,2,5-噻二唑-3-基)氨基吲哚
在-10℃,约30分钟内,将无水甲胺吹进50ml无水乙醇中。在此冷溶液中加入3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-(1-氧代-4-甲氧基-1,2,5-噻二唑-3-基)氨基吲哚(实施例8)(0.200g,0.40mmol)溶液,在室温下搅拌所得溶液3小时。然后蒸发反应混合物,得到固体,研制该固体得到浅黄色固体纯产物(0.120g,60%)。从含水DMSO中重结晶该物质,得到浅黄色固体标题化合物(0.100g,47%),熔点150-158℃:IR(KBr)3310(br),1626,1608,1575cm-1;1HNMR(DMSO-d6,200MHz)δ10.86(br s,1H),9.84(brs,1H),8.47(brs,1H),8.22(s,1H),8.09(s,1H),8.01(s,1H),7.37(s,2H),7.17(s,1H),3.82(s,3H),3.67(br s,4H),3.00(brs,3H),2.70(m,2H),2.54-2.33(m,6H),1.83(m,2H).元素分析:C23H29N9O2S.1.3H2O.0.15C2H6OS计算值:C,52.72;H,6.17;N,23.76.实测值:C,52.90;H,6.21;N,23.39.
实施例13
在-10℃、约15分钟内,将无水氨吹进40ml无水乙醇中。在此冷溶液中加入3-[3-[4-(5-甲氧基-4-嘧啶基)-1-哌嗪基]丙基]-5-(1-氧代-4-甲氧基-1,2,5-噻二唑-3-基)氨基吲哚(实施例8)(0.175g,0.35mmol)的10ml无水乙醇溶液,在室温下搅拌所得的溶液1小时。然后蒸发反应混合物,得到黄色胶体。色谱纯化(SiO2/CH2Cl2-MeOH-NH4OH,90∶9∶1)该物质得到黄色胶体,接着用过量的甲醇HCl处理。蒸发所得溶液,残留物用丙酮研制,得到为黄色固体的标题化合物的盐酸盐(0.160g,76%),熔点158℃(分解):IR(KBr)3380(br),3200(br),1628,1574,1543cm-1,1HNMR(DMSO-d6,200MHz)δ10.0-11.3(m,2H),8.64(brs,1H),8.29(br s,1H),8.20(brs,1H),7.60(m,1H),7.35(d,J=8.7Hz,1H),6.96-7.22(m,1H),4.89(m,2H),3.90(s,3H),3.62(m,4H),3.16(m,4H),2.77(m,2H),2.14(m,2H).元素分析:C22H27N9O2S.2HCl.2.2H2O.0.2CH4O计算值:C,44.40;H,5.74;N,21.00.实测值.C,44.44;H,6.14;N,21.25.
C.生物试验步骤
实施例14
犬侧向隐静脉中的激动剂研究
侧向隐静脉是从麻醉狗中获得的,并经粘接材料修整过,将脉管切成2-3mm的环节,安置在组织浴中的不锈钢钢丝上,该组织浴含有20ml改进的Kreb缓冲液,并向内不断充进5%CO2/95%O2气体,保温37℃。静态张力人为地调节至1g,并保持,直至达到稳定基线,平衡1小时。在平衡期间,组织浴溶液每15分钟调换一次。
将酮色林、阿托品和美吡拉敏以浓度为1μm加入以阻滞5-HT2、胆碱能作用和组胺作用。15分钟后,当存在抗拮药时,血清素浓度响应曲线以累积形式存在。总之,组织浴清洗数次,张力调节在1g,组织在45-60分钟期限内返回平衡。抗拮药又加到组织浴中,15分钟后,产生被选择试验的化合物的浓度响应曲线。每个脉管节仅暴露于一种试验化合物中。
试验化合物的活性以在相同血管性制剂中相对于5-HT(任意指定值1.0)的相对效能和效力的形式表示。
方案A
方案B
方案C
中间体合成
Claims (14)
2.根据权利要求1的化合物,其中Y和Z为N。
3.根据权利要求1的化合物,其中X为SO。
4.根据权利要求3的化合物,其中R1、R2、R3和R5为氢原子。
5.根据权利要求3的化合物,其中m为0,n为3。
6.根据权利要求3的化合物,其中R4为甲氧基。
7.根据权利要求3的化合物,其中R1、R2、R3和R5为氢原子,R4为甲氧基;Y和Z为N;m为0,n为3。
8.根据权利要求7的化合物,该化合物选自其中R6为氨基、甲氨基、二甲氨基和甲氧基的化合物组成的组。
9.一种治疗血管性头痛的方法,该方法包括给血管性头痛患者施用治疗有效量的权利要求1的化合物。
10.一种治疗血管性头痛的方法,该方法包括给血管性头痛患者施用治疗有效果的权利要求3的化合物。
11.一种治愈血管性头痛的方法,该方法包括给开始患有血管性头痛的病人施用预防有效量的权利要求1的化合物。
12.一种治愈血管性头痛的方法,该方法包括给开始患有血管性头痛的病人施用预防有效量的权利要求3的化合物。
13.一种适用于给血管性头痛病潜在患者或患者系统给药的单位剂量形式的药物组合物,它包含药用载体以及约1~500mg权利要求1的化合物。
14.一种适用于给血管性头痛病潜在的患者或患者系统给药的、单位剂量形式的药物组合物,它包含药用载体以及约1~500mg权利要求3的化合物。
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JPH10501212A (ja) * | 1994-05-19 | 1998-02-03 | メルク シヤープ エンド ドーム リミテツド | 5−ht▲下1d▼−アルファ作働薬としてのインドール−3−イルアルキルのピペラジン、ピペリジンおよびテトラヒドロピリジン誘導体 |
GB9415575D0 (en) * | 1994-08-02 | 1994-09-21 | Merck Sharp & Dohme | Therapeutic agents |
GB9501865D0 (en) * | 1995-01-31 | 1995-03-22 | Merck Sharp & Dohme | Therapeutic agents |
US8022095B2 (en) | 1996-08-16 | 2011-09-20 | Pozen, Inc. | Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs |
US5872145A (en) * | 1996-08-16 | 1999-02-16 | Pozen, Inc. | Formulation of 5-HT agonist and NSAID for treatment of migraine |
US6586458B1 (en) | 1996-08-16 | 2003-07-01 | Pozen Inc. | Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs |
US7189753B1 (en) | 1997-11-06 | 2007-03-13 | Cady Roger K | Preemptive prophylaxis of migraine |
US7332183B2 (en) * | 2002-12-26 | 2008-02-19 | Pozen Inc. | Multilayer dosage forms containing NSAIDs and triptans |
AU2004247076A1 (en) * | 2003-06-06 | 2004-12-23 | Glaxo Group Limited | Composition comprising triptans and NSAIDs |
EP3027607B1 (en) | 2013-07-29 | 2020-08-26 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use thereof |
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US3468882A (en) * | 1966-10-07 | 1969-09-23 | Sterling Drug Inc | Phenylhydrazone derivatives as intermediates for preparing indoles |
NL189197C (nl) * | 1979-09-04 | 1993-02-01 | Bristol Myers Squibb Co | 3,4-digesubstitueerde-1,2,5-thiadiazool-1-oxiden en 1,1-dioxiden, bereiding daarvan alsmede farmaceutische preparaten. |
US4600779A (en) * | 1982-03-29 | 1986-07-15 | Bristol-Myers Company | Substituted 3,4-diamino-1,2,5-thiadiazoles having histamine H2 -receptor antagonist activity |
GR79215B (zh) * | 1982-06-07 | 1984-10-22 | Glaxo Group Ltd | |
US4440933A (en) * | 1983-03-16 | 1984-04-03 | Bristol-Myers Company | Process for preparing 1,2,5-thiadiazoles |
GB2162522B (en) * | 1984-08-01 | 1988-02-24 | Glaxo Group Ltd | An indole derivative |
US4954502A (en) * | 1988-06-10 | 1990-09-04 | Bristol-Myers Squibb Company | 1-indolyalkyl-4-(substituted-pyridinyl)piperazines |
FR2635104B1 (fr) * | 1988-08-03 | 1992-04-30 | Synthelabo | Derives d'indolone, leur preparation et leur application en therapeutique |
FR2672052B1 (fr) * | 1991-01-28 | 1995-05-24 | Esteve Labor Dr | Derives d'aryl (ou heteroaryl)-piperazinyl-alkyl-azoles, leur preparation et leur application en tant que medicaments. |
US5077293A (en) * | 1990-06-29 | 1991-12-31 | Bristol-Myers Squibb Co. | 1-indolyalkyl-4-(alkoxypyrimidinyl)piperazines |
CA2043709C (en) * | 1990-06-29 | 2002-01-22 | David W. Smith | Antimigraine alkoxypyrimidine derivatives |
DE4101686A1 (de) * | 1991-01-22 | 1992-07-23 | Merck Patent Gmbh | Indolderivate |
CA2084531A1 (en) * | 1991-12-19 | 1993-06-20 | David W. Smith | Antimigraine 4-pyrimidinyl and pyridinyl derivatives of indol-3yl-alkyl piperazines |
CA2130078A1 (en) * | 1993-09-16 | 1995-03-17 | Jonas A. Gylys | Antimigraine cyclobutenedione derivatives of indolylalkyl-pyridinyl and pyrimidinylpiperazines |
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CN1063177C (zh) | 2001-03-14 |
RU2165420C2 (ru) | 2001-04-20 |
IL117224A (en) | 2000-06-29 |
US5618816A (en) | 1997-04-08 |
NO960699D0 (no) | 1996-02-22 |
HUP9600498A2 (en) | 1997-10-28 |
NO305248B1 (no) | 1999-04-26 |
CA2169804A1 (en) | 1996-09-03 |
PL313022A1 (en) | 1996-09-16 |
AU4581996A (en) | 1996-09-12 |
AR002281A1 (es) | 1998-03-11 |
KR960034200A (ko) | 1996-10-22 |
HUP9600498A3 (en) | 1998-10-28 |
ZA961392B (en) | 1997-08-21 |
HU9600498D0 (en) | 1996-04-29 |
IL117224A0 (en) | 1996-06-18 |
AU707770B2 (en) | 1999-07-22 |
EP0729958A2 (en) | 1996-09-04 |
EP0729958A3 (zh) | 1996-10-02 |
CZ46896A3 (en) | 1996-09-11 |
NO960699L (no) | 1996-09-03 |
NZ286090A (en) | 1997-12-19 |
JPH08253479A (ja) | 1996-10-01 |
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