CN85106225A - 吲哚衍生物的制备方法及其在医疗上的应用 - Google Patents
吲哚衍生物的制备方法及其在医疗上的应用 Download PDFInfo
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- CN85106225A CN85106225A CN85106225.3A CN85106225A CN85106225A CN 85106225 A CN85106225 A CN 85106225A CN 85106225 A CN85106225 A CN 85106225A CN 85106225 A CN85106225 A CN 85106225A
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Abstract
描述了用于治疗和/或预防由于颅脑血管扩张所引起的疼痛特别是偏头痛的结构式(I)之化合物;或其生理上可接受的盐和溶剂化物。
化合物(I)可通过使结构式(II)之化合物环化而制得。
Description
本发明是关于一种用于治疗偏头痛的吲哚衍生物、其制备方法、含该吲哚衍生物的医药组合物及其在医疗上的应用。
偏头痛与颅脑血管系统的过度扩张有关,已知的治疗方法包括投服有血管收缩作用的化合物,如麦角胺。但麦角胺是一种非选择性血管收缩剂,可使全身血管收缩而具有潜在危险和副作用。也可服用止痛剂治疗偏头痛,通常是与一种止吐剂联合使用,但这种方法的治疗价值是有限的。
因此要求有一种治疗偏头痛的安全而有效的药物,其可用于予防或缓解业已出现的头痛,而且有选择性血管收缩活性的化合物是可达到这一功效的。
此外,在偏头痛情况下,一般是由病人服药的,故特别期望能口服用药。因此它应具有良好的生物可利用度并可有效地由胃肠道吸收,以便促使症状缓解。这种药物经口服时也应是安全的(即无毒性作用)。
其中R1代表氢原子或C1-6烷基或C3-6烯基,R2代表氢原子或C1-3烷基,C3-6烯基,芳基,芳(C1-4)烷基或C5-7环烷基,R3代表氢原子或C1-3烷基,R4或R5可以是相同的或不相同的,各代表一个氢原子或C1-3烷基或丙烯基,或者R4和R5一同形成一个芳亚烷基;AIK代表含有2个或3个碳原子的亚烷基键,其可以是未被取代的或由不超过2个的C1-2烷基取代的一以及其生理上可接受的盐和溶剂化物。
如在英国专利申请2124210A号中所指出的,有上述结构构式的化合物能选择性地缩窄经麻醉狗的颈动脉床,故可用于治疗偏头痛。
我们现已发现,有一种特殊的化合物,虽然Fallwath in属于英国专利申请2124210A号所描述和提出权利要求的一组化合物之范围内,但在文本中并没有专门地公开,该化合物所具有的特殊的优点。据此,我们发现通过选择两个特殊的取代基-即吲哚环第5位上的甲氨基磺酰甲基和第3位上的N,N-二甲基氨乙基取代基,即可得到治疗偏头痛所要求的高度优越性的化合物。
根据本发明的化合物是用于治疗和/或予防由颅脑血管扩张所引起的疼痛,特别是偏头痛和相关的病痛如多发性头痛。
如在经麻醉狗身上所作实验所显示的,在静脉注射结构式(I)之化合物后,其表现出显著地和有选择性地缩窄颈动脉血管床的作用。这种强有力的和选择性的血管收缩剂作用也已在体外实验中得到证明。在经麻醉狗身上所作进一步实验显示,结构式(I)之化合物在经十二指肠内给药后可十分高效和稳定地由胃肠道吸收,迅速地引起颈动脉血管床的持续性收缩。
结构式(I)之化合物在其治疗偏头痛的有效剂量时,对血压和心率没有明显影响,对肺部也没有明显的支气管收缩剂作用。
经口服结构式(1)之化合物是和静脉内给药同样安全的。
结构式(1)之化合物所具有的这些性质,在治疗偏头痛是非常需要的,而且正如前述试验所证明的,化合物(I)有着显著的优点,其优越性超过了以前如在已分布的美国专利申请2124210A号所述的、在偏头痛的治疗中所使用的化合物。结构式(I)之化合物可以一种恒定的方式由胃肠道有效地吸收,是它的一个特殊优点。
而且,以豚鼠所作试验表明,在口服给药后,结构式(I)之化合物可促进胃排空,故可缓解胃淤积胃淤积是偏头痛经常伴随发生的一种症状。所以结构式(I)之化合物缓解胃淤积的作用,是该化合物在治疗偏头痛中的又一个有利的性质。
适用的结构式(I)之化合物的生理上可接受的盐,包括与有机或无机酸所形成的酸加成盐,如盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、甲磺酸盐、柠檬酸盐、苯甲酸盐、延胡索酸盐、马来酸盐和琥珀酸盐。在结构式(I)之化合物的制剂中,其它盐也可能是有用的,如硫酸肌酐加合物以及与甲苯-P-磺酸形成的盐。
根据本发明的化合物(I)的盐是与二羧酸如琥珀酸所成的,该盐可与一个或两个羧酸基成盐,即该盐每含1mole酸,即含1或2mole化合物(I)。根据本发明的优选的盐是琥珀酸盐,最好是1∶1琥珀酸盐。
再一方面,本发明提供了一个通过投服结构式(I)之化合物或其生理上可接受的盐或其溶剂化物,治疗患有或易感由颅脑血管收缩所引起的疼痛,如偏头痛或多发性头痛之病人的方法。该治疗方法中,最好是口服本发明之化合物。
此外,本发明还提供了一种医学上使用的医药组合物,其包含结构式(1)之化合物和/或其生理上可接受的盐或溶剂化物(如水合物),可经任何方便的途经给药。这样组合物可以简便的方法用一种或多种医药上可接受的载体或赋形剂配制。根据本发明的化合物可配制成口服、舌下、胃肠道外、直肠或鼻内给药的剂型,或配成适于吸入或吹入给药的剂型。最好是以适于口服的剂型配制。
口服给药的医药组合物可用常规方法制成片剂或胶囊剂,所用的医药上可接受的赋形剂有粘合剂(如予糊化玉米淀粉,聚乙烯吡咯烷酮或羟丙基甲基纤维素);填料(如乳糖、蔗糖、甘露醇、玉米淀粉、微晶纤维素或磷酸氢钙);润滑剂(如硬脂酸、聚乙二醇、硬脂酸镁、滑石或硅石);崩解剂(如马铃薯淀粉、淀粉乙醇酸钠或Croscarmellose sodium);或湿润剂(如十二烷基硫酸钠)。可用本技术领域内已知的方法将片剂包被糖衣。供口服的液体制剂,可用的剂型如含水或含油溶液、糖浆剂、酏剂、乳剂或混悬剂,或者是可作为干燥产品存在,临用前以水或其它适当赋形剂构成之。这样的液体制剂可与医药上可接受的添加物用常规方法制成,所用添加物有助悬剂(如山梨醇糖浆、纤维素衍生物、葡萄糖/糖浆、白明胶、硬脂酸鋁凝胶、或氢化的食用脂肪);乳化剂(如卵磷脂、阿拉伯胶或脱水山梨酯-油酸酯);非含水赋形剂(如杏仁油、含油酯、乙醇或分镏的植物油);以及防腐剂(如甲基或丙基对位羟基苯甲酸酯或山梨酸)。液体剂剂也可含有适当量的常用缓冲剂、调味剂、着色剂和甜味剂。
本发明之化合物用于治疗偏头痛,成人(约70公斤体重)口服建议剂量为每次服用有效成份0.1mg至100mg,例如0.5mg至50mg,最好是2mg至40mg,每天可服至8次,一般是每天1至4次。应注意根据病人的年令、体重、以及病情而给予不同的剂量除非另外说明,一般此剂量中化合物(1)的重量应是指游离碱而言。
本发明之化合物可配制成胃肠道外给药的注射剂,最好是静脉内或皮下注射,例如快速浓注(bolus injection)或连续静脉内输注。注射用制剂可制成单位剂量形式的,如安瓶或多剂量包装(multi-dose containers)形先,并加防腐剂。该组合物可以是在含油或含水赋形剂中的混悬液,溶液或乳化液,并可含有调配剂如助悬剂、稳定剂和/或扩散剂,和/或调整溶液张力的试剂。或者,将有效成分制成粉末形式,使用前用一种适当的赋形剂如灭菌的无热原水溶解而成溶液剂。
注射给药时全天剂量可在50mg至50mg范围,如0.5至20mg,可分成2,3或4次注射。
本发明的化合物适于作直肠给药的组合物,如栓剂或滞留灌肠剂,可含有通常使用的栓剂基质,如可可脂或其它甘油酯。
作舌下给药的片剂可以相似于口服给药的片剂的方法进行配制。
本发明的化合物用于鼻内给药可作为液体喷雾或滴入形式使用。
本发明之化合物当作直肠内,舌下或鼻内给药时,用于治疗成人(平均体重约70公斤)偏头痛的剂量,可相似于前述口服给药的剂量。
根据本发明的化合物作为吸入剂给药时,是由加压包装中很方便地以气雾剂喷雾形式释放的,同时要使用一种气雾剂基质,如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适当的气体,或可由喷雾器中释放。在以加压气雾剂形式使用时,剂量单位可通过一个定量释放的阀来确定。在吸入器或吹入器中使用的白明胶等的胶囊和药筒可制成含有本发明之化合物和一种适当的粉末基质如乳糖或淀粉的粉末混合物。
最好将气雾剂配方调制好,以便使由加压气雾剂中放出的标定剂量或每次喷出的剂量含有0.2mg至2mg本发明之化合物,并且使通过吸入器或吹入器内胶囊或药筒投服的每一剂含有0.2mg至20mg本发明之化合物。每天可给药几次,如2至8次,每次可给1,2或3剂。通过吹入给药的全天剂量相似于口服给药的剂量。
如需要时,本发明之化合物可与一种或多种其它治疗剂如止痛药、抗炎药和抗恶心药联合使用。
结构式(1)之化合物及其生理上可接受的盐和溶剂化物(如水合物)可按下文中所略述的一般方法制备。
根据一般方法(A),结构式(I)的化合物可通过使结构式(II)之化合物环化而制得。
该反应很便于在含水或不含水的反应介质中,于10-200℃最好50-125℃的温度下进行。
对方法(A)中特别适用的突出要点描述如下。
环化作用是在含有多磷酸酯的反应介质中完成的,该反应介质可含有一种或多种有机溶剂,最好是卤代烃。如氯仿、二氯甲烷、二氯乙烷、二氯二氟甲烷,或其混合物。多磷酸酯为酯的混合物,其可根据(“Reagents for organic Synthesis”)(Fieserand Fieser,John wiley and Sons 1967)一文中所述的方法,由五氧化二磷、二乙基醚和氯仿制得。
另外,环化作用可在一种酸催化剂存在下,在含水或不含水的介质中进行。当使用含水介质时,其可能是一种含水有机溶剂,如含水醇(如甲醇、乙醇或异丙醇)或含水醚(如二噁烷或四氢呋喃),也可用这些溶剂与酸催化剂的混合物,酸催化剂可以是一种无机酸如浓盐酸或浓硫酸,或一种有机酸如乙酸(有些情况下,酸催化剂也可起反应性溶剂作用)。在无水反应介质中,其可包括一种或多种醇或醚(如前已述及的)或酯(如乙酸乙酯),酸催化剂一般是某种路易斯酸,如三氟化硼、氯化锌或氯化镁。
根据该环化方法的一个特别实施例,结构式(I)之化合物可由
下列结构式(III)之化合物
或它的某种盐(如盐酸盐),与结构式(IV)之化合物或其盐或其被保护衍生物(例如一种缩醛,如以二烷基或环状缩醛与适当的烷基原甲酸酯或二醇所形成的,或作为亚硫酸氢盐加成复合物被保护的)直接反应而制得。化合物(II)的环化反应可使用前述的适宜的条件来进行,(Fischer-IndolSynthesis,B.Robinson P488-Wiley,1982)。值得注意的是,在该环化方法(A)的实施例中,结构式(II)之化合物是作为一个中间体而形成的,并且在原位反应而形成所需要的结构式(I)之化合物。
如需要时,可通过以结构式(III)之化合物或其盐或其被保护衍生物与结构式(IV)之化合物或其盐或其被保护衍生物反应,作为一种中间体而分离出结构式(II)之化合物,反应可在水中或适当的溶剂如含水醇(如甲醇)或含水醚(如二噁烷)中,于一适当温度,如10-30℃下完成。如果使用结构式(IV)之化合物的缩醛,则反应必须是在一种有机或无机酸(如乙酸或盐酸)存在下完成。
结构式(III)之化合物可按英国专利申请2124210A号中所述的方法制备。
如在下列一般方法(B)和(C)中所说明的,可用常规技术将二甲基氨基取代基引入3位,其包括在3位上改变取代基或直接将氨烷基取代基引入3位。
适当的可置换原子或基团Y包括卤原子(如氯、溴或碘);基因OR6,这里OR6可以是由羧酸或磺酸衍生得来的酰氧基,如乙酰氧基、氯乙酰氧基、二氯乙酰氧基、三氟乙酰氧基、对位硝基苯甲酰氧基、对位甲苯磺酰氧基或甲基磺酰氧基; Y也可为NR7R8R9EΘ基团其中R7、R8和R9各代表一个C1-3烷基,E-代表一个阴离子,如卤素离子(如氯,溴,碘离子)。
置换反应可很方便的在一种惰性有机溶剂(其中可以有水)中进行,这种溶剂的例子包括醇,如乙醇;环醚,如二噁烷或四氢呋喃;无环醚,如二乙醚;酯,如乙酸乙酯;酰胺,如N,N-二甲基甲酰胺;酮,如丙酮、甲基乙基酮或甲基异丁基酮。该过程可在-10至+150℃,最好20至100℃的温度下进行。
Y为卤原子的结构式(V)之化合物,可由结构式(III)之肼在含水醇(如甲醇)或含有一种酸(如乙酸或盐酸)的含水醚(如二噁烷)中,与结构式(VI)
OHC(CH2)3Y (VI)的醛(或其被保护衍生物)反应而制得,或者可由结构式(VII)之化合物与适当的卤化剂如三卤化磷、亚硫酰氯或N-溴丁二酰亚胺和三苯基膦,在适当的溶剂如吡啶或四氢呋喃中反应而制得。结构式(VII)之化合物也被用于制备其中的Y是基团OR6的结构式(V)之化合物,即使用常规技术以得自羧酸或磺酸的活化剂(如酸酐或磺酰氯)使之酰化。醇(VII)可按已公布的英国专利申请2150932A号所述的方法,通过环化适当的腙而制得。
如在下文一般方法(E)中所述的,其中的Y代表基团NR7R8R9EΘ的结构式(V)之化合物,可由相应的伯胺与一种适当的烷基化试剂进行反应而制得。
结构式(I)之化合物也可用另一个一般方法(C)制备,其包括使通式(VIII)
之化合物(其中W是能被还原产生所需要的二甲氨基乙基的基团)或基盐或其被保护衍生物还原。
所需要的-(CH2)-2和二甲胺部分可通过以适当方式各自地或一同发生的还原步骤形成。
可还原为-(CH2)-2部分的基团包括相应的不饱和基团和含有一个或多个羰基和/或羟基的基团。基团W可以是其本身被还原为二甲氨基乙基部分的基团。这样的基团的例子包括-CH2)2N(CH3)COR10(其中R10代表氢原子,烷氧基或芳烷氧基);-COCON(CH3)2;
-CH2CON(CH3)2;-CH(OH)CH2N(CH3)2;以及
-COCH2N(CH3)2。
W也可代表一个在二甲胺存在下经还原产生二甲氨基乙基部分的基团,如-CH2CN和-CH2CHO。
制备结构式(I)之化合物的一个特别适用的方法就是在一种适当的还原剂存在下,用甲醛使相应的氨基或甲氨基衍生物产生还原性甲基化反应。可取的是当用伯胺为原料时,应至少使用两当量的甲醛。如必要时,可首先使甲醛与胺缩合,之后进行还原反应而得到此中间体。
可通过常规方法还原结构式(VIII)之化合物,如可通过催化氢化作用或使用一种还原剂如碱金属或碱土金属的氢硼化物或氰基氢硼化物。环原作用可很便利地在有机反应介质中完成,其可包括一种或多种有机溶剂。适用的溶剂有醇,如乙醇或丙醇;环醚,如二噁烷或四氢呋喃;无环醚,如二乙醚;胺,如二甲基甲酰胺;酯,如乙酸乙酯,以及腈如乙腈。
应注意到的是可根据基团W的性质来选择还原剂和反应条件。
可用于上述的结构式(VIII)之化合物(基中的W代表基团-CH(OH)CH2N(CH3)2)还原过程的适当还原剂包括在有金属催化剂(如阮内镍)存在下的氢,或贵金属催化剂(如铂、氧化铂、钯或铑)存在下的氢,而这些则可载于活性碳、硅藻土或矾土等载体上。在使用阮内镍时,也可用肼作为氢源。该反应过程宜于在醇((如乙醇)、醚(如二噁烷或四氢呋喃)、酰胺(如二甲基甲酰胺)或酯(如乙酸乙酯)等溶剂中,于-10至+50℃,最好-5至+30℃的温度下进行。
其中的W代表基团-CH(OH)CH2N(CH3)2或-COCH2N(CH3)2的结构式(VIII)之化合物,也可用一种碱金属或碱土金属的氢硼化物或氰基氢硼化物如氢硼化钠、氢硼化钙或氰基氢硼化钠、氰基氢硼化钙来催化还原反应,该过程宜于在一种醇如丙醇、乙醇或甲醇中,于10至100℃,最好50至100℃的温度下进行。在某些例子中,还原反应也可于氯化钴存在下,用一种氢硼化物催化完成。
也可在一种碱金属或碱土金属的氢硼化物或氰基氢硼化物催化下用甲醛使相应于结构式(I)的氨乙基或甲氨乙基化合物产生还原性甲基化反应。反应可在含水或不含水反应介质—常是在上述的醇、醚(如二噁烷或四氢呋喃)中,于有或没有水存在情况下进行。在该具体实施本发明的方法中,反应可于一种酸如乙酸存在时,于0至100℃,最好5至50℃的温度下完成。
其中的W代表基团-(CH2)2N(CH3)CHO,-CH2CON(CH3)2,-CH(OH)CH2N(CH3)2,-COCON(CH3)2和-COCH2N(CH3)2的结构式(VIII)之化合物的还原作用也可使用一种金属氢化物如氢化鋁锂。该过程可在醚类溶剂如四氢呋喃中,且通常于-10至+100℃,最好是50至100℃的温度下进行。
一般方法(C)的一个特殊的具体实施方案包括W是基团-CH2CN的结构式(VIII)之化合物的还原作用,其可于二甲胺存在下,在有一种催化剂如载于活性碳上的钯或载于矾土上的铑存在下,由氢催化完成。反应可在一适当的溶剂如一种醇(甲醇或乙醇)中进行。
结构通式(VIII)之化合物的原料或中间体可使用已公布的英国专利申请2124210号中所述的相似方法制备,或者按下述方法(5)来改变5位取代基制备。
依据另一个一般方法(D),可由结构式(IX)
之化合物(基中X代表一个离去原子或基团)或其盐。与甲胺反应来制备结构式(I)之化合物。
结构通式(IX)之化合物中适当离去基团或基团X的例子有卤原子(如氟、氯或溴原子)或基团OR11,这里R11代表烃基如芳基(例如苯基)。该芳基可以是未被取代的或由一个或多个取代基如卤原子;硝基;氰基;氨基;烷基(如甲基);烷氧基(如甲氧基);酰基(如乙酰基)或烷氧羰基(如乙氧基羰基)取代的。
反应可于在一种溶剂存在下,并可在含水或不含水反应介质中进行。
反应介质可以是一种或多种有机溶剂,包括醚,如二噁烷或四氢呋喃;胺,如N,N-二甲基甲酰胺或N-甲基吡咯烷酮;醇,如甲醇或乙醇;酯,如乙酸乙酯;腈,如乙腈;卤代烃,如二氯甲烷;以及叔胺,如三乙胺或吡啶,介质中可存在或不存在水。在某些情况下,甲胺本身即可作为溶剂。
必要时氨群作用可于一种碱如碱金属碳酸盐或碳酸氢盐(如碳酸钠或碳酸钾,碳酸氢钠或碳酸氢钾);叔胺(如三乙胺或吡啶);醇盐(如叔丁醇钠)或氢化物(如氢化钠)存在下完成。
反应可于-20至+150℃的温度下进行。
的化合物(其中X的定义如前;W是基团CH2CN或CH2CHO)或其盐或其被保护衍生物还原而制成。反应是于二甲胺存在下,依据上述一般方法(C)完成的。
其中的X代表卤原子的结构式(IX)之化合物,可用相应的磺酸衍生物或其盐与一种卤化剂如卤化磷或卤氧化磷在惰性有机溶剂,如溶于二氯甲烷的五氯化磷中反应制备。X是OH的结构式(IX)的之磺酸可通过酸或碱催化的结构式(IX)的酯(即其中的X代表基团OR11的化合物)水解而制备。
结构式(X)之化合物和结构式(IX)之磺酸衍生物(其中的X是羟基)可按已公开的欧洲专利申请145459号和(“A Chemi-stry of Heterocyclic Compounds-Indoles PartII”Chapter VI edifed by W.J Hamilton (1972)Wiey Intersoience,New York)一文中所述的相类方法制备。
又根据一般方法(E),结构式(I)之化合物可由结构式(XI)之化合物(其中R12、R13和R14各代表氢式甲基,R12、R13和R14中至少一个是氢)与一种甲基化试剂反应制得。用于该反应的甲基化试剂包括甲基卤(如甲基碘)、甲基甲苯磺酸酯,或硫酸二甲酯。值得注意的是应使用足够量的甲基化试剂,以引入所要求之数目的甲基。因此,如当R12、R13和R14中有两个代表氢时,则至少应使用2当量的甲基化试剂。该反应最好在一种碱存在下,于一种惰性有机溶剂如酰胺(如二甲基甲酰胺)、醚(如四氢呋喃)或芳香烃(如甲苯)中进行。适当的碱包括碱金属氢化物,如氢化钠或氢化钾;碱金属酰胺,如氨基化钠;碱金属碳酸盐,如碳酸钠;或碱金属醇盐,如甲醇钠或甲醇钾、乙醇盐或叔丁醇盐;或氟化四丁铵。当使用甲基卤作甲基化试剂时,反应亦可在一种酸清除剂如丙烯或环氧乙烷存在下完成。该反应可于0至60℃,最好20至40℃的温度下进行。
结构式(XI)之化合物可按本文所述方法(A)-(E)中的任何一种方法制备,亦可按已公布的英国专利申请2124210A号中所述的方法制备。
吸电子基团R16包括-SO2Ra、-COa 2、CORa、CHO和CN,此中Ra烃基,如烷基、芳基或芳烷基。R16最好是苯氧磺酰基。
其中R15代表甲基的化合物(XII),可在含水乙醇胺中,于50至200℃的温度下经加热处理而脱烷基化。用一种碱包括碱金属碳酸盐如碳酸钠,或碱金属氢氧化物如氢氧化钠处理,即可除去基团-CH2CH2R16。
其中的R15代表甲基的结构式(XII)之化合物,可按一般方法(E)所述,通过使相应于化合物(I)的3-氨基乙基或3-甲氨基乙基化合物烷基化而制得。
其中的R15代表基团-CH2CH2R16的结构式(XII)之化合物,可用相应的3-氨基乙基或3-甲氨基乙基化合物与结构式(XIII)
H2C=CHC16 (XIII)之化合物反应来制备,之后再按上述方法将产物烷基化。与结构式(XIII)之化合物的反应可在一种含水介质中,于0-50℃的温度下完成。
结构式(I)之化合物也可依据另一个一般方法(G)来制备,其包括使相应的结构式(XIV)
之二氢吲哚脱氢。该脱氢过程可依常规方法经催化或使用一种适当的氧化剂完成。
用于该过程的氧化剂包括醌,如2,3-二氢-5,6-二氰基-1,4-苯醌或2,3,5,6-四氯-1,4-苯醌;以及二氧化锰。二氢吲哚(XIV)的催化脱氢作用可使用钯、铂或镍催化剂完成,如使用载于活性碳上的钯、磨碎的钯、氧化铂或阮内镍等。
当使用氧化剂时,脱氢反应可于含水或不含水反应介质中进行。可使用的溶剂包括烃,如苯或二甲苯;酰胺,如N,N-二甲基甲酰胺;醚,如四氢呋喃或二噁烷;醇,如甲醇或乙醇;卤代烃,如二氯甲烷;以及水或其混合物。反应可在-50至+150℃的温度下进行。催化脱氢可于有或没有溶剂情况下,一般于高温如100至300℃时完成,因此,可用的溶剂为高沸点溶剂,包括高沸点烃如二甲苯或异丙基甲苯;以及高沸点醚,如苯基醚。尤其应根据所用的氧化剂或脱氢催化剂来严格掌握反应条件。
化合物,通过在金属催化剂如载于活性炭上的钯存在下用氢还原,以及在喹啉存在下脱羧,得到相应的3-氰甲基-2-羧基吲哚之后在二甲胺存在下,按前述一般方法(C)还原。结构式(XV)之化合物本身可按常规方法制备,如可由结构成(XVI)之苯胺与氯醛和羟胺反应,得到肟基酰替苯胺,再用硫酸处理使之环化,并在一种碱如三乙胺存在下,于适当溶剂如二噁烷中,使所得到的靛红与氰基乙酸缩合。
依照另一个一般方法(H),根据本发明的结构式(I)之化合物或其盐,可使通式(I)之化合物的被保护衍生物或其盐经历一个除去保护基的反应而制得。
在制备结构式(I)之化合物及其盐的反应过程早期阶段,应将分子中的任何敏感基团保护起来,以避免产生付反应,如防止吲哚氮与芳烷基(如苯甲基)反应。
其后可通过常规方法解离保护基。据此,一个芳烷基如苯甲基可于一种催化剂(如载于活性炭上的钯)或钠和液态氨的存在下,经氢解作用而裂解。
正如将被意识到的,前述一般方法(A)到(G)中的某些方法,必定或可望能保护如刚刚述及的分子中的任何敏感基团。因此,包括使结构式(I)之被保护衍生物及其盐产生去保护作用在内的的反应步骤,可继前述方法(A)至(G)的任何一种方法之后完成。
所以,根据本发明的另外一个方面,如需要时,可继方法(A)至(G)之后完成任何适当反应系列中的下述反应:
(I)除去任何的保护基;以及
(II)将结构式(I)之化合物或其盐转化成其生理上可接受的盐或溶剂化物(如水合物)。
倘期望作为生理上可接受的盐,如一种酸加成盐分离到结构式(I)之化合物,即可通过以一种适当的酸(如琥珀酸或盐酸)处理结构式(I)之游离碱而制得,且最好是在适当溶剂(如含水乙醇)中以等当量酸处理。
上面指出的制备本发明之化合物的一般方法除了被用作制备程序中的最后主要步骤外,在制备所需要求的化合物中也可用于在中间阶段引入所要求的基团。例如,可在环化之前或环化之后于5位上形成甲氨基磺酰甲基,以形成吲哚环。因此须意识到,在这种多阶段方法中,应注意选择好反应顺序,以便使反应条件不至影响到期望存在于终产物分子中的基团。
下列这些例子旨在阐明根据本发明的以3-(2-(二甲氨基)乙基)-N-甲基-1H-吲哚-5-甲磺酰胺琥珀酸盐(1∶1)作为活性成分的医药配方。在这些例子中,活性成分的重量即为琥珀酸盐的重量。口服片剂A.
直接压片
1.
mg/片
制40g混合物
活性成分 49 15.08g
硬脂酸镁(英国药典) 0.650 0.20g
无水乳糖 81 24.92g
将活性成分过筛并与无水乳糖和硬脂酸镁混匀。用装配有8.0mm凹型冲头的Manesty F3压片机将所得的混合物压制成片。2.
mg/片
制140g混合物
活性成分 49 14.0g
硬脂酸镁(英国药典) 0.7 0.20g
微晶纤维素(法国标准) 91 26.0g
将活性成分过筛并与微晶纤维素和硬脂酸镁混匀。用装配有8.0mm凹型冲头的Manesty F3压片机将所得的混合物压制成片。B
湿式成粒
mg/片
活性成分 7.0
乳糖(英国药典) 146.5
淀粉(英国药典) 30.0
予糊化玉米淀粉(英国药典) 15.0
硬脂酸镁(英国药典)
1.5
压缩重量 200.0
使活性成分通过一个适当的筛并与乳糖、淀粉和予糊化玉米淀粉相混合。加入适当体积的净化水并使粉未成粒。干燥后,筛选颗粒并与硬脂酸镁调混。之后用适当直径的冲头将颗粒压制成片。
通过改变活性成分对乳糖的比例或改变压缩重量并使用适当的冲头,可制出其它强度的片剂。
用标准技术,以适当的薄膜形成材料如羟丙基甲基纤维素,可制成薄膜包衣的片剂。另外,也可将药片制成糖衣片或肠溶片。胶囊
mg/胶囊活性成分 49.00*淀粉1500 150.00硬脂酸镁
1.00充填重量 200.00*为一种直接可压缩淀粉
将活性成分过筛并与各赋形剂混合。用适当的机械将混合物装入大小为2号的硬白明胶胶囊内。改变充填重量或必要时改变胶囊的型号,可制成其它剂量的胶囊。糖浆
末展示蔗糖
mg/5ml剂量
活性成分 49.00
羟丙基甲基纤维素(美国药典) 22.5
净化水(英国药典)加至 5.0ml
使羟丙基甲基纤维素分散于热水中,冷却之后与含有活性成分和其它配方成分的水溶液混合。调整所得溶液的体积并混匀。经过滤澄清糖浆。
混悬液
将一硬脂酸鋁分散于大约90%的分馏之椰子油中。将所得的悬液于搅拌下加热到115℃,之后冷却。加入甜味剂、调味剂和着色剂并将活性成分适当地分散于其中。用剩余的分馏之椰子油将混悬液补足体积并混匀之。舌下含片
mg/片
活性成分 49.00
可压缩糖(法国标准) 50.5
硬脂酸镁(英国药典) 0.5
压缩重量 100.0
将活性成分通过适当的筛,与赋形剂混合并用适当的冲头压片。改变活性成分对赋形剂的比率或压缩重量并使用相适配的冲头,可制成其它强度的含剂。
用于直肠给药的栓剂
活性成分 49.0mg
*Witepsol H15 加至 1.0g
*Adepssolidus Ph.Eur.的专利品
将分散于融熔的Witepsol中的活性成分悬液用适当的机械装入可容1g的栓模中。用作静脉内给药的注射剂
mg/ml
活性成分 0.896
氯化钠静脉内
灌注液(英国药典0.9%W/V) 加至1ml
批量 2500ml
将活性成分溶解于一部分氯化钠静脉内灌注液中,用氯化钠静脉内灌注液调整溶液体积,并彻底混匀。将溶液装入透明的I型10ml玻璃安瓶并于液面上空间充氮下经熔融玻璃而封口。用高压灭菌器将安瓶于121℃灭菌,时间不少于15分钟。吸入用制剂 吸入用药筒
mg/筒活性成分(微粉化的) 0.56乳糖(英国药典) 25.00
用流体能磨将活性成分微粉化为微细颗粒,之后在高能混合器内与标准压片级乳糖混合。在一适当的胶囊封装机上将粉末混合物装入3号硬明胶囊内。使用粉剂吸入器如Glaxo Rotahaler给药(药筒内容)。可计量剂量的加压气雾剂
混悬气雾剂
mg/量剂量
每筒
活性成分 0.280 73.92mg
油酸(英国药典) 0.020 5.28mg
三氯氟甲烷(英国药典) 23.64 5.67mg
二氯二氟甲烷(英国药典) 61.25 14.70g
用流体能磨将活性成分微粉化为微细颗粒。于10-15℃下将油酸与三氯甲烷混合,并将微粉化的药物加入该溶液,以高剪力混合器混合之。将此混悬液量入鋁质气雾剂筒中并将适当的释放85mg混悬液的计量阀卷于筒上,再通过阀将二氯二氟甲烷加压装入筒内。鼻内喷雾剂
每次喷出重量 100mg(相当于7mg活性成分)
将活性成分、防腐剂和氯化钠溶于部分水中,用于将溶液调到适当体积并彻底混匀。
可用酸或碱将PH调至使活性成分有最适稳定性和/或有利于活性成分溶解的PH值。另外,也可使用适当的缓冲盐。
通过下列实施例对本发明作进一步的阐述。所有温度均为摄氏度。“Hyflo”是一种助滤剂。“反应瓶”(“Reacfivials”)是带有螺旋帽及特氟隆贴面瓶盖衬垫的4ml有黑啤酒色壁之玻璃瓶。由Pierce和Warriner(英国)有限公司提供。除另外说明者外,均使用常规方法用硅胶(Merck Kieselge l60,Art.7734)进行层析,或者在硅胶(Merck 9385)板上作“闪光”层析(W.C.Still,M.Kahn A.Mitra,
J.Org. Chem.,2923,
43,1978)以及用硅胶(Macherly-Nagel,Polygram)作薄层层析(t.l.c.)。用于层析或t.l.c的洗脱液以下列缩写字表示:
(A)乙酸乙酯-异丙醇-水-0.88氨25∶15∶8∶1
(B)二氯甲烷-乙醇-0.88氨 100∶8∶1
(C)乙醚
(D)二氯甲烷-乙醇-0.88氨 20∶8∶1
(E)二氯甲烷-乙醇-0.88氨 200∶8∶1
(F)二氯甲烷-乙醇-0.88氨 50∶8∶1
(G)乙醇-乙酸乙酯-0.88氨-水 25∶15∶2∶2
(H)异丙醇-氯仿-水-0.88氨 25∶15∶2∶2
(I)二氯甲烷-乙醇-0.88氨89∶10∶1
(J)二氯甲烷-甲醇97∶3
(K)乙酸乙酯-己烷60∶40
(L)二氯甲烷-甲醇95∶5
(M)乙醚-己烷4∶1
(N)二氯甲烷-乙醇-0.88氨25∶8∶1
(O)乙酸-乙酸乙酯1∶99
(P)二氯甲烷-乙醇-0.88氨150∶8∶1
通过t.l.c方法用紫外光(u.v.)检测以及喷洒试剂如高锰酸钾(KMnO4),以常规检验中间体的纯度。另外通过喷洒硫酸高铈(CeIV)水溶液检定吲哚中间体,喷洒碘铂酸(IPA)或硫酸高铈溶液检定色胺。用Varian EM390核磁共振仪于90MHz、或用Bruker AK或WM250核磁共振仪于250MHz测得质子(1H)核磁共振(n.m.r)谱。 S=单峰,d=双重峰,t=三重峰,q=四重峰,m=多重峰。制备1
(1)
N-甲基-4-(2-(2-(苯基硫代)亚乙基) 肼基)苯甲磺酰胺
将溶于无水乙醇(180ml)的(苯基硫代)乙醛(6.05g)之溶液于10分钟内加到溶于水(180ml)的4-肼基-N-甲基-苯甲磺酰胺盐酸化物(10g)之溶液中,并进行冷却。加完醛之后,将混合物于5°搅拌14小时。过滤出沉淀的固体,用水(200ml)、乙烷(200ml)洗涤,真空干燥得到题目化合物(10.95g)熔点110-112°。T.I.C.(B)Rf0.5(KMnO4)。(II)
N-甲基-3-(苯基硫代)-1H-吲哚-5-甲 磺酰胺
将溶于无水乙醇(300ml)中的阶段(I)之产物(5g)的溶液用氯化氢气体饱和(约30分钟),同时在冰水浴中冷却,于环境温度下搅拌3小时之后过滤。于空真中浓缩滤液并层析(闪光,E)以提供一种泡沫状物,将其用醚研制而固化一种非晶形粉未(2.17g)。样品由己烷-二氯甲烷中重结晶得到题目化合物,熔点133-134°。T.I.C.(B):Rf0.5(KMzO4)。
(III)
N-甲基-1H-吲哚-5-甲磺酰胺
向溶于无水乙醇(50ml)的阶段(II)之产物(460mg)的溶液中加入阮内镍(4.6g,于水中的50%淤浆,用去离子水(60ml)洗至中性),并在氮气环境下将反应混合物回流总共16小时。冷却至环境温度后,除去上清并用乙醇(2×50ml,使其在N2气环境下缓和回流15分钟)提取阮内镍。通过一个砂-硅灌土垫过滤合并的提取物并于真空中浓缩。层析残留物(闪光,E),分离出一种油(187mg),将其由乙醚-己烷中结晶出来,得到题目化合物(90mg),熔点127-129°。T.I.C.(B)Rf0.50(KMnO4)。制备2
5-(((甲氨基)磺酰基)甲基)-1H-吲哚-3-乙酸
将3-(氰甲基)-N-甲基-1H-吲哚-5-甲磺酰胺(1.0g)与溶于水(15ml)和乙醇(25ml)的氢氧化钾(4.5g)在氮气环境下回流并搅拌加热16小时。减压蒸发除去乙醇,用水(20ml)稀释含水残留物并用乙酸乙酯(2×30ml)洗涤。用2 N盐酸(50ml)酸化水层并用乙酯(3×50ml)提取;其后用盐水洗涤有机层,干燥(MgSO4)并蒸发之,得到一种油状物(1.25g)。用干醚研制得到固体题目化合物(0.767g),熔点126-133°。T.I.C.(0):Rf 0.7(CeIV)制备3
3-(2-(二甲氨基)乙基)-2,3-二
氢-N-甲基-1H-吲哚-5-甲磺酰胺
向悬将于三氟乙酸(15ml)中的-10°的3-(2-(二甲氨基)乙基)-N-甲基-1H-吲哚-5-甲磺酰胺(0.5g)悬液内加保持在低于+2°温度下的盐水-四氢呋喃配合物(45ml,1M)。于0°将所得之悬浮液搅拌5分钟,倾入饱和的碳酸钾(50ml)中并用乙醇(2×20ml)提取之。蒸发乙醇提取物并用柱层析法(A)纯化残留物,得到油状的题目化合物(80mg)。T.I.C.(N):Rf 0.53(IRA,CeIV)。
除特别指明者外,下述实施例均为阐述3-(2-(二甲氨基)乙基)-N-甲基-1H-吲哚-5-甲磺酰胺及其盐的制备。实施例1
与琥珀酸生成的化合物(2∶1)(半琥珀酸盐)
将溶于甲醇之二甲胺(200ml,15%W/W)和乙醇之二甲胺(300ml,33%W/W)的3-(氰甲基)-N-甲基-1H-吲哚-5-甲磺酰胺(16.5g)溶液于室温下通过于乙醇(100ml)中载于活性炭(10%,16g)上的预还原之氧化钯,氢化24小时。通过hyflo过滤悬浮液并于真空中蒸发,得到一种固体物(16g),将其用乙酸乙酯(500ml)研制。过滤收集固体物(13.5g),溶解于热无水乙醇(200ml)中并过滤之。向热溶液内加入溶于甲醇(50ml)的琥珀酸(2.7g)溶液。过滤除去所形成的晶体,得到题目化合物(12.2g),熔点158-159°。T.I.C.(D):Rf 0.5(IPA)。
元素分析结果(%):C 54.0;H 6.7;N 11.7
(C14H21N3O2S)2·C4H6O4需要:C 54.2;H 6.8N 11.9
1H n.m.r.:δ(D MSO-d6),2.37(2,S,CH2CO2H),2.0(6H,S,N(CH3)2),2.58(3H,S,NHCH3),2.7-3.0(4H,m,CH2CH2N),4.38(2H,S,CH2SO2),6.85(1H,brs,NHCH3),芳族信号在7.11(1H,brd),7.22(1Hbrs),7.36(1H,d),7.55(1H,brs)和10.94(1H,brs)。实施例2
与琥珀酸生成的化合物(1∶1)
将溶于甲醇(37.5ml)和乙酸(2.246g)的3-(2-氨乙基)-N-甲基-1H-吲哚-甲磺酰胺(2g)和氰基氢硼化钠(0.564g)溶液于大约12°用溶于甲醇(8.85ml)的36%(W/V)甲醛水溶液处理。将所得溶液于22°搅拌2小时,之后加入2N氢氧化钠溶液(6.5ml)和氢硼化钠(0.1g)。向反应混合物中加入2N盐酸(7ml)之后蒸发除去甲醇,并用水稀释(至25ml)。加固体碳酸钾使PH达到7,用乙酸乙酯洗该溶液并用水洗乙酸乙酯提取物。合并水层和洗液,用碳酸钾饱和和并用乙酸乙酯提取之。干燥(用MgSO4)乙酸乙酯提取液并蒸馏,得到固体残留物(1.8g)。由异丙醇(16.7ml)中重结晶出1.67g残留物,得到1.307g结晶碱,将其中的1.297g溶解于IMS(13ml)中,并用溶于IMS(13ml)的热的琥珀酸(0.518g)溶液处理。冷却所得的溶液,过滤沉淀的固体并干燥之,得到题目化合物(1.737g),熔点165-166°。n.m。r和t.l.c((G),Rf0.5(IPA))与实施例1的产物一致。实施例3
3-(2-(二甲氨基)乙基)-N-甲基
-1H-吲哚-5-甲磺酰胺(碱)
将溶于水(100ml)的氢硼化钠(7.1g)溶液和溶于甲醇(50ml)的甲醛水溶液(30%,W/V,50ml)于15-21°、0.75小时内加到溶于甲醇(200ml)的3-(2-氨乙基)-N-甲基-1H-吲哚-5-甲磺酰胺(10g)溶液中。加入盐酸(2N,75ml)并于真空中将混合物浓缩至150ml。再加盐酸(2N,50ml)。用碳酸钾(60g)使混合物碱化并用乙酸乙酯(2×150ml)提取。干燥(用MgSO4)合并之提取物并于真空中浓缩,得到固态的题目化合物(10.7g),熔点169-171°。T.I.C(G):Rf 0.5(u.V),n.m.r.谱与实施例1之产物一致。
实施例4
(I)
N,N-二甲基-5-(2-(甲氨基)磺酰基)甲基) -d-氧代-1H-吲哚-3-乙酰胺
于氮气环境下,将草酰氯(0.112ml)加到经搅拌的混有苯邻二甲酰亚胺(约40%,W/W)的N-甲基-1H-吲哚-5-甲磺酰胺(270mg)在无水四氢呋喃中的溶液内,并于室温下继续搅拌1.75小时。将气态二甲胺成气泡通过反应混合物15分钟,于室温下继续搅拌15分钟。将混合物倾入2N盐酸(50ml)中并用乙酸乙酯(3×20ml)提取;用盐水洗涤有机层、干燥(用MgSO4)并蒸发得到泡沫状物(222mg)。用闪光层析法(G)纯化,得到固体的题目化合物(126mg),熔点157-159°。T.I.C(L):Rf 0.15(u.V.)。(II)
3-(2-(二甲氨基)乙基)-N-甲基-1H-吲 哚-5-甲磺酰胺
将阶段(II)的产物(77g)与无水四氢呋喃(15ml)和 氢化锂鋁(90mg)的混合物于氮气环境下回流加热4小时。冷却至室温后,于氮气环境下小心地加入水(0.09ml),之后加入2N含水氢氧化钠(0.18ml)和另一份水(0.18ml)。过滤除去沉淀物,蒸发滤液得到一种油状物(53mg),其n.m.r.谱和t.l.c.表明与实施例1的产物相同。实施例5
(I)
3-(氯乙酰基)-N-甲基-1H-吲哚-5-甲 磺酰胺
经30秒的时间并于0°向N,N-二乙基氯乙酰胺(800mg)中加入磷酰氯(250μl)。加完后,于0℃将混合物搅拌15分钟,之后于室温下搅拌20分钟。于0℃加入制备1的产物(300mg)并将混合物升温至60°,借以使之溶解。在该温度下将混合物搅拌2小时,之后倾入水(约5g)和氯仿(5ml)中并剧烈搅拌1小时。滤除固体物,用水(50ml)和己烷(100ml)洗涤并于真空中干燥,得到题目化合物(192mg)。
T.I.C(B):Rf 0.42(KMnO4)
1H n,m.r. :δ(DMSO-d6),2.58(3H,d,NHCH3),4.45(2H,S,CH2SO2),4.92(2H,S,CH2Cl),6.88(1H,q,NH)以及芳族信号7.29(1H,dd),7.54(1H,d),8.23(1H,brs),8.50(1H,d)和12.30(1H,brs,吲哚NH)。
(II)
3-((二甲氨基)乙酰基)-N-甲基-1H-吲 哚-5-甲磺酰胺
将溶于乙醇之二甲胺(30ml,于乙醇中33%)的阶段(I)之产物(160mg)的溶液加热回流2小时。冷却至环境温度,于真空中除去溶剂,层析(B)分离残留物得到题目化合物(55mg),熔点230°(分解)。T.I.C.(B):Rf 0.14(IPA)。
(III)
3-(2-(二甲氨基)乙基)-N-甲基-1H-吲 哚-5-甲磺酰胺
向悬浮于1-丙醇(5ml)中的阶段(II)之产物(46.5mg)的悬浮液内加入氢硼化钠(62mg)。将反应混合物回流3小时,之后再加另一份氢硼化钠(60mg)。再回流1小时之后,将混合物冷却至环境温度并用2NHCI(10ml)使之急冷。用乙酸乙酯(5ml)洗该水溶液,之后中和(用饱和NaHCO3溶液)并用乙酸乙酯(3×15ml)提取。干燥(用MgSO4)合并的提取液并真空中蒸发,层析(F)纯化残留物得到题目化合物(2mg),其为一种胶质物,t.l.c.((F).Rf0.34,(KMnO4))和n.m.r谱表明其与实施例1的产物相同。实施例6
(I)
N,N-二甲基-5-(((甲氨基)磺酰)甲基) -1H-吲哚-3-乙酰胺
向溶于四氢呋喃(20ml)的制备2之产物(0.3g)的溶液内加入1,1′-羰基二咪唑(0.24g)并于室温下搅拌1小时。之后将其用二甲胺饱和的四氢呋喃(20ml)处理,并于环境温度下放置16小时。用浓氢氧化铵(d0.88,1ml)处理所得的悬浮液,蒸发去除溶剂并经柱层析(B)纯化残留物,得到非晶形固体题目化合物(0.18g)。
T.I.C(B):Rf 0.4(CeIV)。
1Hn.m.r.:δ(DM SO-d6),2.56(3H,NH
Me),2.84和3.04(6H,S+S,CON
Me 2),3.74(2H,S,CH2CO),4.33(2H,S,OH2SO2)6.81(1H,q,
NHMe),芳族信号在7.11(1H,dd),7.23(1H,d),7.35(1H,d),7.57(1H,brs)及11.00(1H.brs,吲哚NH)。
(III)
3-(2-(甲氨基)乙基)-N-甲基-1H-吲 哚-5-甲磺酰胺
将阶段(I)的产物(0.17g)加入干四氢呋喃(10ml)和氢化锂鋁(0.29g)的混合物中,并将所得混合物加热回流16小时。过量的氢化锂鋁经加水(2ml)而被分解,使反应混合物在饱和碳酸钾(10ml)和乙醇(10ml)之间分配,并将乙醇层蒸发至干。经柱层析(F)纯化残留物,得到油状的题目化合物(0.12g),其n.m.r谱和T.I.C表明与实施例1的产物相同。实施例7
(I)
苯甲基·甲基(2-(5-(((甲氨基)磺酰)甲基) -1H-吲哚-3-基)乙基)氨基甲酸酯
向溶于碳酸钠(2N,15ml)和四氢呋喃(10ml)的N-甲基-3-((2-甲氨基)乙基)-1H-吲哚-5-甲磺酰胺(0.55g)之冷(冰浴)溶液内加入苄基氯甲酸酯(0.3ml)并于室温下将所得悬浮液搅拌过夜。之后将其倾入水内,用氯代甲烷(3×30ml)提取,干燥(用MgSO4)提取液并浓缩之。经柱层析(C)纯化残留物,得到泡沫状题目化合物(0.5(0.58g)。
T.I.C.(C):Rf 0.3(CeIV,KMnO4)。
1Hn.m.r.:δ(DMSO-d6,于330K),2.58(3H,S,NH
Me)2.93(3H,S,N-
Me),2.98(2H,m,NCH2CH2),3.60(2H,m,NCH2CH2),4.35(2H,S,CH2SO2),5.12(2H,S,CH2Ph),6.59(1H,brs,NHCH3),且芳族信号在7.1-7.2(2H,m),7.3-7.5(6H,m),7.58(1H,brs)和10,80(1H,brs,吲哚NH)。
(II)
3-(2-(二甲氨基)乙基)-N-甲基-1H-吲 哚-5-甲磺酰胺
于回流条件下,将阶段(I)之产物(0.2g)与在干四氢呋喃(50ml)中的氢化锂鋁(0.3g)的混合物加热6小时,之后冷却并通过加水(5ml)使过量的氢化锂鋁分解,所得的悬液用固体碳酸钾饱和并用乙醇(2×30ml)提取。蒸发除去溶剂并经柱层析(F)纯化残留物,得到一种油状物(67mg),n.m.r和t.l.c((D),Rf0.5)显示其与实施例1的产物相同。实施例8
与琥珀酸(2∶1)形成的化合物
(I)
4-(2-(4-(二甲氨基)亚丁基)肼基)-N -甲苯-甲磺酰胺
将4,4-二甲氧基-N,N-二甲基丁酰胺(8.32g)加到经搅拌的悬浮于水(25ml)和2N盐酸(5ml)中的4-肼基-N-甲苯甲磺酰胺盐酸化物(10g)之混悬液内。再加入2N盐酸(25ml),将所得溶液(PH1.5-2)于室温下搅拌2.5小时。加氯仿(150ml)之后再加25ml等分量的2N碳酸钠溶液(150ml)。使溶液分层并进一步用氯仿(150ml)提取水层。干燥(用MgSO4)合并之有机提取液并空真浓缩,得到泡沫状题目化合物(12.4g)。T.I.C.矾土。(E),Rf 0.45。
(II)
3-(2-(二甲氨基)乙基)-N-甲基-1H-吲 哚-5-甲磺酰胺,与琥珀酸(2∶1)形成的化合物
于室温下将多磷酸酯(20g)与溶于氯仿(80ml)的阶段(I)之产物(4g)的混合物搅拌4小时。用水(2×100ml)提取反应混合物,用氯仿(50ml)洗含水提取物,之后将其用固体碳酸钾碱化至PH11并用乙酸乙酯(3×100ml)提取之。干燥(用MgSO4)合并之有机提取物并真空浓缩而留下泡沫状物(2.5g),经层析(F)得到色胺油状物(1.1g),静置而缓缓形成结晶。将溶于热甲醇(ml)的琥珀酸(0.22g)加到溶于无水乙醇(21ml)的色胺(1.1g)之热溶液中,搅拌下将混合物加热回流而得到溶液。经搅拌将溶液冷却至室温,将所得之悬液进一步于水浴中冷却2小时。滤除固体物,用乙醇(25ml)洗并真空干燥,得到题目化合物(0.83g),熔点152-155°,n.m.r谱和t.l.c((D),Rf0.5,(IPA))表明其相同于实施例1之化合物。实施例9
(I)
3-(2-羟乙基)-N-甲基-1H-吲哚-5- 甲磺酰胺
将制备2之产物(0.5g)与存在于干四氢呋喃中的氢化锂鋁(1g)的混合物加热回流16小时。加水(2ml)使过量的氢化物分解并使所得之悬液在饱和碳酸钾(10ml)和乙醇(10ml)之间分配。将有机层蒸发至干并经柱层析(B)纯化残留物,得到固态的题目化合物(0.2g)。
T.I.C.(P) Rf 0.2(KMnO4,CeIV)。
1H n.m.r.δ(DMSO-d6),2.56(3H,d,NH
Me),2.87(2H,m,CH2CH2OH),3.67(2Hm,CH2CH2OH),4.37(2H,S,CH2SO2),6.81(1H,m,
NHMe),且芳族信号在7.09和10.90之间。
(II)
3-(2-(二甲氨基)乙基)-N-甲基-1H -5-甲磺酰胺
向溶于吡啶(2ml)中的阶段(I)之产物(70mg)的冷溶液(水-盐浴)内加入溶于吡啶(3ml)的亚硫酰氯的冷溶液(冰-盐浴),并将所得溶液搅拌0.5小时,此期间温度升至+10°。之后用水使之骤冷,用浓盐酸酸化并用二氯甲烷(3×20ml)提取。蒸发溶剂得到油状物3-(2-氯乙基)-N-甲基-1H-吲哚-5-甲磺酰胺(30mg),将其溶解于乙醇之二甲胺(33%W/V,5ml)中并于活化瓶中于100 °加热4小时。蒸发溶剂得到一种油状物,经t.l.c.((F),Rf 0.35)分析表明其含有实施例1的产物。
在另一实验中,经层析(B)纯化后得到纯的油状产物3-(2-氯乙基)-N-甲基-1H-吲哚-甲磺酰胺。
1Hn.m.r.δ(DMSO-d6).2.60(3H,d,NH
Me),3.20(2H,m,CH2CH2Cl),3.90(2H,m,CH2CH2Cl),4.40(2H,S,CH2SO2)6.87(1H,brs,NHMe),且芳族信号在7.15和11.08之间。实施例10
使甲胺成泡通过溶于无水吡啶的苯基3-(2-(二甲氨基)乙基)-1H-吲哚-5-甲磺酰胺(0.223g)的溶液。之后在热压器内于120°(油浴温度)将溶液加热16小时。经旋转蒸发除去吡啶并层析(F)纯化残留的胶质物。蒸发适当的馏份得到部分结晶的胶质物(0.11g),经刮除固化物得到粉末(0.1g),熔点169-172°,n.m.r谱和t.l.c。((F).Rf 0.4(IPA))表明其与实施例1的产物相同。实施例11
用氯化四正丁铵(1m,溶于四氢呋喃,0.16ml)处理溶于无水四氢呋喃(5ml)的3-(2-(二甲氨基)乙基)-1H-吲哚-5-甲磺酰胺溶液并于室温下搅拌25分钟。加氧化丙烯(0.01243ml),之后加甲基碘(0.005ml)并于室温下搅拌该溶液。3小时后,T.I.C.((N),Rf0.7)表明存在有实施例1之产物。实施例12
向溶于乙醇(10ml)的N-甲基-3-(2-(甲氨基)乙基)-1H-吲哚-5-甲磺酰胺(0.3g)溶液内加入甲基碘(0.07ml)并于室温下将所得溶液搅拌过夜。之后用稀盐酸将其酸化至PH1,用乙酸乙酯(25ml)提取,使酸性层分配于饱和碳酸钾(20ml)和乙醇(20ml)之间。蒸发乙醇层并经柱层析(F)纯化残留物,得到一种油状物(30mg),n.m,r.和t.l.c.((D),Rf 0.5)分析表明其相同于实施例1的产物。实施例13
将碘代甲烷(0.16ml)加到搅拌下的3-(2-氨乙基)-N-甲基-1H-吲哚-5-甲磺酰胺(0.2g)与溶于甲醇(10ml)的碳酸氢钠(0.14g)之混合物中。于22°将混合物搅拌2小时并于回流下搅拌16小时。再加碘代甲烷(0.5ml)并于回流下将混合物搅拌2小时以上。过滤混合物,并减压蒸馏除去溶剂,得到含N,N,N-三甲基-5-(((甲氨基)磺酰基)甲基)-1H-吲哚-3-碘化乙铵的油状物。加入50%含水乙醇胺(20ml)并将混合物回流加热1小时。蒸馏除去水并将所得溶液于100°加热1小时。加入水(25ml)、乙酸乙酯(25ml)和无水碳酸钾(10g)。震荡混合物并使其分离成三个相。收集最上面的乙酸乙酯层,用水(5ml)洗,经MgSO4干燥并于减压下蒸馏除去溶剂,得到胶质状的题目化合物(0.1g),T.I.C.((D),Rf 0.75,(IPA))表明其相同于实施例1的产物。实施14
向溶于二噁烷(20ml)的制备3之产物(40mg)的溶液内加入2,3-二氯-5,6-二氰基-1,4-苯醌(35mg)并将混合物于回流下加热2小时。冷却,使混合物分配于饱和碳酸钾(20ml)和乙醇(20ml)之间,蒸发有机层得到一种油状物(10mg),t.l.c.((F),Rf0.31)表明其含有实施例1的产物。实施例15
(I)
3-(氰甲基)-N-甲基-1-(苯基甲基)-1H -吲哚-5-甲磺酰胺
将3-(氰甲基)-N-甲基-1H-吲哚-5-甲磺酰胺(0.4g)溶解于重蒸馏的二甲基甲酰胺(10ml)中并用氢化钠(0.132g,于油中80%分散剂)处理。0.5小时后将搅拌的悬浮液冷却至-30℃并用蒸馏的苄基氯(0.19g)处理。将混合物升温至10°,搅拌1小时后倾入冰(10g)中。过滤悬浮液,收集固体物并用水(20ml)和环己烷(30ml)洗。经层析(M)纯化固体物,合并适当的部分并真空浓缩至20ml,借此重结晶出固体物,收集并干燥之得到题目化合物((0.12g),熔点133-135°。T.I.C.(M):Rf0.4(KMnO4)。
(III)
3-(2-(二甲氨基)乙基)-N-甲基-1-(苯 基甲基)-1H-吲哚-5-甲磺酰胺
将溶于乙醇之二甲胺(3ml,33%W/W)的阶段(I)之产物(100mg)的溶液于21°通过予还原的载于碳(100mg,于乙醇(10ml)中)上的10%的氧化钯,使之氢化4小时。过滤(用hyflo)除去催化剂并于真空中使溶剂蒸发,得到一种胶状物(100mg),将其层析(B)纯化得到题目化合物(0.85mg),为一种泡沫状物。T.I. C.(B):Rf0.3。
(III)
3-(2-(二甲氨基)乙基)-N-甲基-1H-吲 哚-5-甲磺酰胺
向冷却至-60°的搅拌之钠(约15mg)在液态氨(3ml)中的溶液内逐滴加入溶于四氢呋喃(1ml)的阶段(II)之产物。5分钟后加入甲醇(0.5ml)和氯化铵(0.2g)并于40°蒸发除去氨。于真空中浓缩混合物得到一种固体物,经层析(F)纯化得到粉末状题目化合物(20mg),熔点160-165°,n.m.r.和t.l.c.((F),Rf 0.4)表明其相同于实施例1的化合物。实施例16
与延胡索酸生成的化合物(2∶1)
用溶于IMS(8.0ml)的延胡索酸(128mg)的热溶液液处理单份的溶于IMS(7ml)的实施例3之产物(590.8mg)的热溶液。将混合物冷却至25°。将冰冷却下的所得之悬浮液搅拌30分钟并过滤。用IMS(2ml)洗滤饼并真空干燥得到题目化合物(619mg),熔点204.5-206°(分解)。元素分析结果(%):C54.1;H6.7;N11.7(C14H21N3O2S)2,C4H4O4需要:C54.4;H6.6;N11.9。
实施例17
与苯甲酸生成的化合物
用苯甲酸(244mg)在IMS(2ml)中的热溶液处理单份的实施例3之产物(590.8mg)在IMS(7ml)中的热溶液。将溶液冷却至25°。于冰致冷下将所得悬浮液搅拌20分钟并过滤。用IMS(0.5ml)洗滤饼并于真空中干燥得到题目化合物(653mg),熔点173-175°。元素分析结果(%):C60.3;H6.6;N9.9。C14H21N3O2S·C7H6O2需要:C60.4;H6.5;N10.1,实施例18
与甲磺酸生成的化合物(1∶1)
将溶于热IMS(3ml)的甲磺酸(0.213g)溶液加到经搅拌的溶于热IMS(9ml)的实施例3之产物(0.597g)的溶液内。将所得搅拌下的溶液经1小时冷却至室温,再于水浴浴中冷却20分钟,之后过滤混合物,得到固体的题目化合物(0.642g),熔点186-188.5°。元素分析结果(%):C46.0;H6.6;N10.6。C14H21N3O2S·CH4O3S需要:C64.0;H6.4;N10.7。T.I.C.(H):Rf 0,23(痕量杂质),0.52;(IPA,CeIV)。实施例19
与琥珀酸生成的化合物(1∶1)
将溶于IMS(10ml)的琥珀酸(1.26g)的热澄清溶液加到搅拌的实施例3之产物(3.14g)在IMS(60ml)中制成的热澄清溶液内。几乎可立即结晶出固体物,并将混合物冷却至30°。于冰浴中将混合物进一步冷却(45分钟)。滤去固体物,用冷乙醇(35ml)洗并真空干燥,得到题目化合物(4.17g),熔点164-165°。T.I.C.(D):Rf0.7(IPACe)。Hn.m.r.和压I.C.证明该产物含有5.52%(W/W)乙醇(0.52mole)。元素分析结果(%):C51.7;H6.95;N9.8。C14H21N3O2S·C4H6O4·0.52C2H6O需要:C52.25;H6.95;N9.6。实施例20
与盐酸生成的化合物(1∶1)
将浓盐酸(0.18ml)加到65℃搅拌的实施例3之产物在IMS中制成的溶液内。将混合物冷却至25°而结晶出固体物。加以水冷却并过滤收集固体物。用IMS(2×1ml)洗滤饼并于减压下干燥,得到题目化合物(517mg),熔点214-215°。T.I.C(G):Rf 0.47(IPA)。
元素分析结果(%):C50.75; H6.8;N12.6。
C14H21N3O2S·HCI需要:C50.5;H6.7;N12.7。
Claims (11)
或其医药上可接受的盐或溶剂化物的方法,其包括
(A)环化结构式(II)之化合物
(其中Y是容易被置换的基团)或其被保护衍生物与二甲胺反应;或
(其中W是能够被还原以形成二甲氨基乙基的基团)或其盐或其被保护衍生物;或
(D)以结构式(IX)之化合物
(其中X代表离去原子或基团)或其盐与甲胺反应;或
(其中R12、R13和R14各代表氢或甲基,且R12、R13和R14之中至少有一个是氢)与甲基化试剂反应;或
(其中R15是甲基或基团-CH2CH2R16,这里R16是吸电子基团且EΘ是阴离子)脱甲基化;或
脱氢,或
(H)使结构式(I)之化合物的被保护衍生物或其盐经反应除去一个或多个保护基;
且如必要时,使所得的结构式(1)之化合物或其盐进一步进
行下列的一种或两种反应—
(I)除去任何保护基,或
(II)将结构式(1)之化合物或其盐转化为其生理上可提受的盐或溶剂化物。
2、根据权利要求1的方法,其中生理上可接受的盐是一种与有机酸或无机酸所形成的酸加成盐。
3、根据权利要求2的方法,其中生理上可接受的盐是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、甲磺酸盐、柠檬酸盐、苯甲酸盐、延胡索酸盐、马来酸盐或琥珀酸盐。
4、根据权利要求3的方法,其中生理上可接受的盐是1∶1琥珀酸盐。
5、根据权利要求1的方法,其中处理步骤(C)包括在一种适当的还原剂存在下,用甲醛使结构式(1)之化合物的氨乙基或甲氨基乙基还原甲基化。
6、根据权利要求5的方法,其中还原剂是一种碱金属或碱土金属的氢硼化物或氰基氢硼化物。
7、根据权利要求6的方法,其中还原剂是氢硼化钠。
8.一种用于治疗易感或患有偏头痛的方法,其中包括提供(如权利要求1中所定义的)化学式(I)的化合物或其生理上可接受的盐或溶剂化物的一个有效剂量。
9.一种用于治疗易感或患有偏头痛的方法,其中包括提供一个药用配方,该配方包括至少一个选自如权利要求1中所定义的化学式(I)的化合物和其生理上可接受的盐和溶剂化物,与最少一个药用上可接受的载体或赋形剂。
10.按照权利要求8或9的方法,其中所提供的该化合物或药用的配方是口服的。
11.制备一种药用配方的方法,其中包括至少一种选自如权利要求1所定义结构式(I)的化合物及其生理上可接受的盐和溶剂化物与至少一种医药上可以接受的载体或赋形剂。
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JP (2) | JPH062733B2 (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102827062A (zh) * | 2012-09-17 | 2012-12-19 | 扬子江药业集团四川海蓉药业有限公司 | 苹果酸阿莫曲坦的制备方法 |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8332437D0 (en) * | 1983-12-06 | 1984-01-11 | Glaxo Group Ltd | Chemical compounds |
GB8419575D0 (en) * | 1984-08-01 | 1984-09-05 | Glaxo Group Ltd | Chemical compounds |
GB8430624D0 (en) * | 1984-12-04 | 1985-01-09 | Glaxo Group Ltd | Chemical compounds |
NL8503337A (nl) * | 1984-12-04 | 1986-07-01 | Glaxo Group Ltd | Indoolderivaten. |
GB8600397D0 (en) * | 1986-01-08 | 1986-02-12 | Glaxo Group Ltd | Chemical compounds |
GB8601959D0 (en) * | 1986-01-28 | 1986-03-05 | Glaxo Group Ltd | Indole derivatives |
US5270333A (en) * | 1986-01-28 | 1993-12-14 | Glaxo Group Limited | Indole derivatives |
PT88255B (pt) * | 1987-08-13 | 1995-03-01 | Glaxo Group Ltd | Processo para a preparacao de derivados do indole |
GB8719167D0 (en) * | 1987-08-13 | 1987-09-23 | Glaxo Group Ltd | Chemical compounds |
US5225431A (en) * | 1987-10-23 | 1993-07-06 | Burroughs Wellcome Co. | Therapeutic substituted indole compounds and compositions thereof |
JPH01312506A (ja) * | 1988-06-13 | 1989-12-18 | Mitsui Petrochem Ind Ltd | カラーフィルター |
MC2210A1 (fr) * | 1990-06-07 | 1992-11-26 | Wellcome Found | Composes heterocycliques therapeutiques,leur utilisation et procede pour les preparer |
GB9209882D0 (en) * | 1992-05-07 | 1992-06-24 | Glaxo Lab Sa | Compositions |
GB9211277D0 (en) | 1992-05-28 | 1992-07-15 | Glaxo Group Inc | Pharmaceutical compositions |
ES2055651B1 (es) * | 1992-07-20 | 1995-03-01 | Vita Invest Sa | Procedimiento para la obtencion de nuevas amidinas derivadas de 3-aminoetilindoles. |
IT1264813B1 (it) * | 1993-07-28 | 1996-10-10 | Oxon Italia Spa | Procedimento per la preparazione di alcansolfonammidi |
EP0875513A1 (en) * | 1997-04-14 | 1998-11-04 | Eli Lilly And Company | Substituted heteroaromatic 5-HT 1F agonists |
US7189753B1 (en) | 1997-11-06 | 2007-03-13 | Cady Roger K | Preemptive prophylaxis of migraine |
GB9926250D0 (en) * | 1999-11-06 | 2000-01-12 | Knoll Ag | Chemical process |
US20030017175A1 (en) * | 2001-07-05 | 2003-01-23 | R.T. Alamo Ventures I, Inc. | Sublingual administration of dihydroergotamine for the treatment of migraine |
US20030198669A1 (en) * | 2001-07-05 | 2003-10-23 | R.T. Alamo Ventures I, Llc | Compositions and methods for rapid dissolving formulations of dihydroergotamine and caffeine for the treatment of migraine |
US6685951B2 (en) | 2001-07-05 | 2004-02-03 | R. T. Alamo Ventures I, Inc. | Administration of dihydroergotamine as a sublingual spray or aerosol for the treatment of migraine |
JP4897221B2 (ja) * | 2002-12-20 | 2012-03-14 | チバ ホールディング インコーポレーテッド | アミン類の合成及びその合成のための中間体 |
WO2004099141A1 (en) * | 2003-05-12 | 2004-11-18 | Ramesh Babu Potluri | A novel process for preparation of indole derivatives |
EP1765300A2 (en) * | 2004-06-10 | 2007-03-28 | Duramed Pharmaceuticals, Inc. | Formulations of sumatriptan for absorption across biological membranes, and methods of making and using the same |
CN101247853B (zh) | 2005-04-13 | 2014-11-12 | 轴突公司 | 具有nos抑制活性的取代的吲哚化合物 |
AR060451A1 (es) * | 2006-04-13 | 2008-06-18 | Neuraxon Inc | Compuestos de indol 1,5 y 3,6-sustituidos con actividad inhibitoria de nos |
WO2008056378A2 (en) * | 2006-11-09 | 2008-05-15 | Natco Pharma Limited | Novel process for the preparation of naratriptan hydrochloride |
MX2009008582A (es) * | 2007-02-11 | 2009-10-30 | Map Pharmaceuticals Inc | Metodo para la administracion terapeutica de dihidroergotamina para permitir un rapido alivio de la migraña mientras se minimiza el perfil de efectos secundarios. |
NZ586082A (en) | 2007-11-16 | 2013-03-28 | Neuraxon Inc | Indole compounds and methods for treating visceral pain |
CA2705833A1 (en) * | 2007-11-16 | 2009-05-22 | Subhash C. Annedi | 3,5-substituted indole compounds having nos and norepinephrine reuptake inhibitory activity |
AU2008321353A1 (en) * | 2007-11-16 | 2009-05-22 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Methods for treating visceral pain |
US20110171141A1 (en) * | 2009-06-26 | 2011-07-14 | Kellerman Donald J | Administration of dihydroergotamine mesylate particles using a metered dose inhaler |
NZ599344A (en) * | 2009-09-25 | 2015-02-27 | Reddy’S Lab Ltd Dr | Formulations comprising triptan compounds |
US11337962B2 (en) | 2009-09-25 | 2022-05-24 | Upsher-Smith Laboratories, Llc | Formulations comprising triptan compounds |
CN103619805A (zh) * | 2011-05-27 | 2014-03-05 | 国立大学法人德岛大学 | 苄胺衍生物 |
EP3628325A1 (en) | 2011-07-22 | 2020-04-01 | The University of Chicago | Treatments for migraine and related disorders |
AU2013361337A1 (en) | 2012-12-21 | 2015-07-09 | Map Pharmaceuticals, Inc. | 8'-Hydroxy-Dihydroergotamine compounds and compositions |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3322787A (en) * | 1964-09-25 | 1967-05-30 | Merck & Co Inc | Alpha-hydrazino-beta-(3-indolyl) alkanoic acid derivatives |
US3472870A (en) * | 1966-08-29 | 1969-10-14 | Mead Johnson & Co | Sulfonamidotryptamines |
US3468882A (en) * | 1966-10-07 | 1969-09-23 | Sterling Drug Inc | Phenylhydrazone derivatives as intermediates for preparing indoles |
IT1036004B (it) * | 1968-05-21 | 1979-10-30 | Abc Ist Biolog Chem Spa | Acidt 3 indolil adetoidrossamici |
US3730723A (en) * | 1971-06-17 | 1973-05-01 | Eastman Kodak Co | Direct positive processes utilizing silver halide surface image emulsions containing desensitizers |
US4283410A (en) * | 1978-06-15 | 1981-08-11 | Miles Laboratories, Inc. | 3-Amino or amido-2-(1H-indol-3-yl) propanoic acid derivatives |
ZA795239B (en) * | 1978-10-12 | 1980-11-26 | Glaxo Group Ltd | Heterocyclic compounds |
ZW19381A1 (en) * | 1980-08-12 | 1983-03-09 | Glaxo Group Ltd | Heterocyclic compounds |
ZA815540B (en) * | 1980-08-12 | 1983-03-30 | Glaxo Group Ltd | Heterocyclic compounds |
ES8300699A1 (es) * | 1980-08-12 | 1982-11-01 | Glaxo Group Ltd | Procedimiento para la preparacion de derivados del indol. |
GR79215B (zh) * | 1982-06-07 | 1984-10-22 | Glaxo Group Ltd | |
GB8332437D0 (en) * | 1983-12-06 | 1984-01-11 | Glaxo Group Ltd | Chemical compounds |
NL8503337A (nl) * | 1984-12-04 | 1986-07-01 | Glaxo Group Ltd | Indoolderivaten. |
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Cited By (1)
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CN102827062A (zh) * | 2012-09-17 | 2012-12-19 | 扬子江药业集团四川海蓉药业有限公司 | 苹果酸阿莫曲坦的制备方法 |
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