CN1096459C - (r)-5-溴-n-(1-乙基-4-甲基六氢-1h-1,4-二氮杂䓬-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺,其制备方法及含有该化合物的医药组合物 - Google Patents
(r)-5-溴-n-(1-乙基-4-甲基六氢-1h-1,4-二氮杂䓬-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺,其制备方法及含有该化合物的医药组合物 Download PDFInfo
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- CN1096459C CN1096459C CN96195988A CN96195988A CN1096459C CN 1096459 C CN1096459 C CN 1096459C CN 96195988 A CN96195988 A CN 96195988A CN 96195988 A CN96195988 A CN 96195988A CN 1096459 C CN1096459 C CN 1096459C
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Abstract
式(I)所代表的化合物及其生理上可接受的酸加成盐。此类化合物具有基于强烈血清素S<sub>3</sub>和多巴胺D<sub>2</sub>受体拮抗作用的优异止吐效果,因此,可作为一种止吐剂用于治疗或预防各种疾病,以及药物给药所伴随的许多消化性症状等。
Description
技术领域
本发明涉及对血清素S3(以下也称之为5-HT3)和多巴胺D2这两种受体显示强烈拮抗作用的新型(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺,其制备方法及含有该化合物的医药组合物。
技术背景
在特开平5-92959号公报中,广泛公开了下式(A)所示的化合物〔式中,R1的R2相同或不同,各系指氢原子、低级烷基、有取代基的低级烷基等,R3相同或不同,各系指氢原子、低级烷基等,R5相同或不同,各系指氢原子、卤原子、低级烷氧基、氨基、单取代或二取代的氨基等,Het系指单环杂芳基或除1H-吲唑基以外的二环杂芳基,q系指0、1或2,s系指1、2或3,B系指-CXNR6(CH2)r-等,其中R6系指氢原子、低级烷基,X系指氧原子或硫原子,r系指0、1、2或3,m系指1、2、3或4,n系指1、2或3〕,并记载Het可以表示吡啶基,但作为Het是3-吡啶基的化合物具体记载的,只有下式所示的实施例37化合物。这种实施例37化合物在3-吡啶基是无取代的且六氢-1H-1,4-二氮杂的4位有甲基这一点上,与后述式(I)所示的本发明化合物是结构上明显不同的。
此外,上述公报中记载了上述式(A)的化合物对血清素S3(5-HT3)受体有拮抗作用,可用于治疗和预防急性·慢性胃炎、胃·十二指肠溃疡等疾病中的食欲不振、恶心、呕吐、腹胀等,或抗癌剂给药时、射线照射时、动摇病(晕车)等的恶心或呕吐,但关于多巴胺D2受体拮抗作用没有任何记载。
而且,在WO 93/08186中,公开了下式(B)所示的化合物(式中,R1表示C1-6烷氧基、C3-8环烷氧基或C3-8环烷基C1-4烷氧基;R2表示氢、卤素、C1-6烷基、C1-6烷氧基或如果希望也可以有1个或2个C1-6烷基取代的氨基;R3表示氢、卤素或C1-6烷基;L表示O或NH;而Z表示二氮杂环或氮杂双环侧链),并记载了上述化合物作为5-HT3拮抗剂可用于治疗或预防疼痛、呕吐、中枢神经系统障碍和胃肠障碍,但关于多巴胺D2受体拮抗作用没有任何记载。
上述WO 93/08186中,作为二氮杂环Z的适当实例之一,引用了上述特开平5-92959号公报专利系列(patent family)中的EP-A-358903,但在WO 93/08186中上述式(A)所示具有二氮杂环侧链的化合物没有任何具体的说明,因此,WO 93/08186没有以任何方式提到本发明化合物。
另一方面,属于多巴胺D2受体拮抗剂的多潘立酮〔化学名:5-氯-1-〔1-〔3-(2,3-二氢-2-氧代-1H-苯并咪唑-1-基)丙基〕-4-哌啶基〕-1,3-二氢-2H-苯并咪唑-2-酮;例如,请参阅Merck Index第11版3412(1989)〕对各种消化器官症状伴随的呕吐或小儿上呼吸道感染症伴随的呕吐是有效的,但对氯氨铂(cisplatin)等抗癌剂给药时引起的呕吐不能说有令人满意的效果。
最近,作为对抗癌剂给药时引起的呕吐有选择性且强力抑制作用的药剂,已开发了血清素S3受体拮抗剂,现在,盐酸格雷西酮〔化学名:桥-1-甲基-N-(9-甲基-9-氮杂双环〔3.3.1〕壬-3-基)-1H-吲唑-3-羧酰胺盐酸盐;例如,请参阅Merck Index第11版4443(1989)〕、盐酸恩丹西酮〔化学名:1,2,3,9-四氢-9-甲基-3-〔(2-甲基-1H-咪唑-1-基)甲基〕-4H-咔唑-4-酮盐酸盐;例如,请参阅Merck Index第11版6802页(1989)〕、以及盐酸阿渣雪酮(azasetron)〔化学名:(±)-N-1-氮杂双环〔2.2.2〕辛-3-基-6-氯-3,4-二氢-4-甲基-3-氧代-2H-1,4-苯并
嗪-8-羧酰胺盐酸盐;例如,请参阅Drugs of the Future,18(3),206-211(1993)〕已在临床上使用。然而,这些血清素S3受体拮抗剂据说其临床应用主要限于抗癌剂等给药时引起的呕吐,而对迟延性呕吐(late emesis)的效果不太令人满意。
因此,对特定呕吐有效的药剂虽然存在,但尚未开发出能强力抑制由于种种原因而引起的呕吐的、适用范围广的止吐剂,因而期待着广谱止吐剂的开发。
发明内容
本发明者等人在对强力而选择性的血清素S3受体拮抗物质进行一系列研究的过程中,考虑到除血清素S3受体拮抗作用外还具有多巴胺D2受体拮抗作用的物质对各种呕吐是有效的,合成了能赋予对血清素S3受体有拮抗作用的六氢-1H-1,4-二氮杂製衍生物以多巴胺D2受体拮抗作用的各种六氢-1H-1,4-二氮杂製衍生物,并进行了筛选,其结果,这次发现下式(I):所示的(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺符合上述目的,而且有广谱止吐作用。
因此,本发明提供上述式(I)所示的(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺及其生理上可接受的酸加成盐。此外,本发明也提供了该化合物的制备方法。进而,本发明还提供了含有该化合物的医药组合物。本发明进一步提供用于该化合物制备的中间体。
式(I)所示化合物的生理上可接受酸加成盐,可以列举诸如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐等无机酸盐,以及草酸盐、马来酸盐、富马酸盐、丙二酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、甲磺酸盐等有机盐。
式(I)化合物及其生理上可接受的酸加成盐也会以水合物和/或溶剂合物形式存在,这些水合物和/或溶剂合物也包含在本发明的化合物范围内。
作为式(II)化合物的反应性衍生物,可以列举诸如低级烷基酯(尤其甲酯)、活性酯、酸酐、酰卤(尤其酰氯)等。作为活性酯的具体实例,可以列举对硝基苯酯、2,4,5-三氯苯酯、N-羟基琥珀酰亚胺酯等。作为酸酐,可以用对称酸酐或混合酸酐中任何一种,而作为混合酸酐的具体实例,可以列举与氯碳酸乙酯、氯碳酸异丁酯这样的氯碳酸烷酯的混合酸酐,与氯碳酸苄酯这样的氯碳酸芳烷酯的混合酸酐,与氯碳酸苯酯这样的氯碳酸芳酯的混合酸酐,与异戊酸、新戊酸这样的链烷酸的混合酸酐等。
在用式(II)化合物本身作为起始物质的情况下,可以在诸如N,N′-二环己基碳化二亚胺、1-乙基-3-(3-二甲胺基丙基)碳化二亚胺盐酸盐、N,N′-羰基二咪唑、N,N′-羰基二琥珀酰亚胺、1-乙氧羰基-2-乙氧基-1,2-二氢喹啉、二苯基磷酰叠氮、丙磺酸酐、苯并三唑-1-基氧-三(二甲胺基)鏻·六氟磷酸盐等缩合剂的存在下进行上述反应。
式(II)化合物或其反应性衍生物与式(III)化合物的反应可在溶剂中或无溶剂下进行。作为可使用的溶剂,可以列举诸如苯、甲苯、二甲苯这样的芳香族烃类,二乙醚、四氢呋喃、二噁烷这样的醚类,二氯甲烷、氯仿这样的卤代烃类,乙醇、异丙醇这样的醇类,乙酸乙酯,丙酮,乙腈,二甲基甲酰胺,二甲基亚砜,乙二醇,水等,这些溶剂可以分别单独使用或两种以上混合使用。本反应必要时可在碱的存在下进行,作为此时可使用的碱的具体实例,可以列举氢氧化钠、氢氧化钾等氢氧化物碱,碳酸钠、碳酸钾等碳酸盐碱,碳酸氢钠、碳酸氢钾等碳酸氢盐碱,三乙胺、三丁胺、二异丙基乙胺、N-甲基吗啉等有机碱等。反应温度通常可以在约-30℃~约200℃、较好在约-10℃~约150℃~约150℃的范围内。此外,式(III)化合物相对于式(II)化合物或其反应性衍生物1摩尔而言,一般可以以1摩尔~3摩尔、较好1摩尔~1.5摩尔的比例供给反应,但因情况而异也可以以大过剩量使用,以兼备作为碱的作用。
作为起始物质使用的式(II)化合物,可以用诸如以下反应路线1中所示步骤制备。各步骤的具体条件见后述参考例1。
上述式中,R1系指直链或枝化的C1~C6烷基。
而作为起始物质使用的式(III)化合物是先有文献中无记载的新型化合物,可以用诸如以下反应路线2中所示步骤制备。各步骤的具体条件见后述实施例2。
反应路线2
上述式中Et系指乙基,Z1系指叔丁氧羰基、三苯甲基、乙酰基等氨基保护基,Z2因情况而异,系指也可以有氯原子、溴原子、甲氧基或硝基取代的苄氧羰基,R2系指氢原子、卤原子、C1~C3烷基或C1~C3烷氧基,R1的含义同前。
上述式(III)化合物因制备方法而异,也可以以酸加成盐形式得到。作为这种酸加成盐,可以列举诸如上述生理上可接受的酸加成盐,具体地说,可以列举盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐等无机酸盐,以及草酸盐、马来酸盐、富马酸盐、丙二酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、苯甲酸盐、甲磺酸盐等有机酸盐。
按照式(I)化合物的上述制法,起始物质式(III)化合物的立体配置在生成物式(I)化合物中可以保持其原样。
用上述制法生成的式(I)化合物,可以用色谱法、重结晶、再沉淀等常用方法分离、精制。
式(I)化合物和式(III)化合物、因反应·处理条件而异,可以以游离碱或酸加成盐形式得到。酸加成盐可以通过常法,例如用碳酸盐碱、氢氧化物碱这样的碱处理,变成游离碱,另一方面,游离碱也可以按照常法用各种酸处理而转化成酸加成盐。
具体实施方式
以下显示本发明化合物和下列对照化合物的药理试验结果,并说明本发明化合物的药理作用特征。
(1)多潘立酮(domperidone):在临床上作为止吐剂或消化道机能改善剂使用的选择性多巴胺D2受体拮抗剂。
(2)盐酸恩丹西酮(ondanserton hydrochloride):作为止吐剂在抗癌剂给药时临床使用的选择性血清素S3受体拮抗剂。
(3)盐酸格雷西隆(graniserton hydrochloride):作为止吐剂在抗癌剂给药时临床使用的选择性血清素S3受体拮抗剂。
(4)盐酸灭吐灵(又名胃复胺、盐酸甲氧氯普胺、metoclopramidehydrochloride):作为止吐剂或消化道机能改善剂在世界上广泛使用的药剂〔化学名:4-氨基-5-氯-N-〔2-(二乙胺基)乙基〕-2-甲氧基苯甲酰胺·二盐酸盐一水合物;例如,请参阅Merck Index第11版6063(1989)〕。
A.关于对多巴胺D2受体和血清素S3受体的作用
试验例1:多巴胺D2受体结合作用和血清素S3受体结合作用(离体受体结合试验)
根据Creese,I.等人〔参照Eur.J.Pharmacol.,46,337(1977)〕和Peroutka,S.J.与Hamik,A.〔参照Eur.J.Pharmacol.,148,297(1988)〕的方法,分别进行多巴胺D2和血清素S3受体结合试验。用从大鼠脑制备的粗突触膜级分作为受体标本,而用〔3H〕螺哌酮(spiperone)(D2)和〔3H〕キ-パジン(S3)作为标记配体。含有受体标本和各自的标记配体的缓冲液(最终体积1ml)在各种浓度的试验化合物的存在下经过一定时间培育后,受体上结合的放射性配体用细胞收集器(勃兰德公司制)分离在过滤器上。用液体闪烁计数管测定过滤器上的放射活性,求出总结合量。并以同时测定的、无标记配体〔螺哌酮(D2)和喹哌嗪(Quipazine)〕过量存在下的结合量为非特异性结合量,从总结合量与这一数量之差求出特异性结合量。用概率单位(probit)法算出试验化合物使标记配体的特异性结合抑制50%的浓度(IC50值)。结果列于以下表1。
试验2:von Bezold-Jarisch反射抑制作用(抗血清素S3作用)
本试验按照Fozard等人的方法〔参照Arch.Pharmacology,326,36-44(1984)〕进行。Wistar品系雄性大鼠(体重250-350g)用尿烷(1.5g/kg,经腹腔内)麻醉,进行背位固定。导出心电图(次级诱导),通过心率计把心跳数记录在墨水书写式示波器上。若经静脉内给药10~30μg/kg 2-甲基血清素(血清素S3兴奋剂),则会引起一过性的心率减少,即von Bezold-Jarisch反射。每隔15分钟重复给药一定量的2-甲基血清素,达到稳定的反应之后,在2-甲基血清素给药3分钟前经静脉内给药试验化合物。算出相对于试验化合物给药前的反应而言的给药后反应抑制率,用概率单位法求出抑制50%的有效量(ED50值)。结果列于以下表1中。表1
试验化合物 | 试验例1IC50(nM) | 试验例2ED50(μg/kg)von Bezold-Jarisch反射抑制作用 | |
D2 | S3 | ||
实施例1化合物 | 11.7 | 1.0 | 1.9 |
多潘立酮 | 14 | >100 | >10000 |
盐酸恩丹西酮 | >100000 | 4.2 | 1.1 |
盐酸格雷西隆 | >100000 | 2.0 | 0.26 |
盐酸灭吐灵 | 630 | 880 | 181 |
从以上表1中所示结果可以看出,实施例1化合物,作为选择性多巴胺D2受体拮抗剂,有与众所周知的多潘立酮同样或更优异的多巴胺D2受体结合作用,而作为选择性血清素S3受体拮抗剂,有比众所周知的盐酸恩丹西酮和盐酸格雷西隆更强的血清素S3受体结合作用,即使在von Bezold-Jarisch反射抑制作用方面,也有与盐酸恩丹西酮相匹敌的优异作用。此外,作为对血清素S3和多巴胺D2受体两者都显示结合作用的止吐剂,盐酸灭吐灵是已知的,但对这两种受体的结合作用比实施例1化合物弱得多。
因此,本发明化合物对血清素S3和多巴胺D2这两种受体都有强拮抗作用,可以期待作为能抑制由于种种原因引起的呕吐的广谱止吐剂使用。
B.关于止吐作用
试验例3:对阿朴吗啡诱发呕吐的抑制作用
用一组3~4只载体狗(体重8~15kg),考察试验化合物对阿朴吗啡诱发的呕吐的抑制作用。这种试验一般用来作为多巴胺阻断剂的检测法。溶解或悬浮在0.5%黄蓍胶溶液中的预定用量试验化合物经口给药,2小时后从背部皮下注射盐酸阿朴吗啡(0.3mg/kg),然后数1小时内的呕吐次数。将试验化合物给药组的呕吐次数与对照组的呕吐次数加以比较,算出抑制率,用概率单位法求出抑制50%的有效量(ED50值)。结果列于以下表2中。
试验例4:对雪貂氯氨铂诱发呕吐的作用
用体重1kg左右的雄性雪貂(美国马歇尔公司)。为了经静脉内给药,实验3~4日前在戊巴比妥麻醉下在颈静脉内安装套管。试验组经口给药溶解或悬浮在0.5%黄蓍胶溶液中的预定用量试验化合物,30分钟后经小套管向静脉内给药氯氨铂(西格玛公司制)10mg/kg(生理食盐液3ml/kg)。记录氯氨铂给药后起3小时时间内诱发的呕吐次数,算出试验化合物的抑制率,用概率单位法求出抑制50%的有效量(ED50值)。结果列于以下表2中。
试验例:对狗氯氨铂诱发呕吐的作用
用一组4~5只载体狗(体重10~12kg),考察试验化合物对氯氨铂诱发的呕吐的抑制作用。试验组经口给药溶解或悬浮在0.5%黄蓍胶溶液中的预定用量试验化合物,30分钟后经静脉内给药氯氨铂(西格玛公司制)3mg/kg(生理食盐液3ml/kg)。记录氯氨铂给药后起5小时时间内诱发的呕吐次数,算出试验化合物的抑制率,用概率单位法求出抑制50%的有效量(ED50值)。结果列于以下表2中。表2
试验化合物 | 试验例3阿朴吗啡诱发呕吐狗ED50,mg/kg | 试验例4氯氨铂诱发呕吐雪貂ED50,mg/kg | 试验例5氯氨铂诱发呕吐狗ED50,mg/kg |
实施例1化合物 | 0.19 | 0.03 | 0.29 |
多潘立酮 | 0.02 | >10 | >3 |
盐酸恩丹西酮 | >10 | 0.1 | 0.16 |
盐酸灭吐灵 | 0.45 | 0.98 | 3.96 |
从以上表2中所示结果可以看出,实施例1化合物,在基于多巴胺D2受体拮抗作用的阿朴吗啡诱发呕吐方面不如属于选择性多巴胺D2受体拮抗剂的多潘立酮,但确实显示优异的抑制作用,而且值得一提的是,在基于血清素S3受体拮抗作用的氯氨铂诱发呕吐方面,显示出与属于选择性血清素S3受体拮抗剂的盐酸恩丹西酮几乎同等的强力抑制作用。即,实施例1化合物,从血清素S3和多巴胺D2两受体拮抗作用均衡良好兼备强力的优异特性来看,显示出具有广谱止吐作用。
此外,实施例1化合物,与对血清素S3和多巴胺D2两受体显示弱结合作用的盐酸灭吐灵相比,也显示强止吐作用,尤其对氯氨铂诱发呕吐显示出强得多的抑制作用,显然在其效果上可以看出有意义的差别。
C.关于中枢作用
试验例6:探索行动抑制作用
使用各组均为5只的std-ddy系雄性小鼠(体重20~25g)。经口给药溶解或悬浮在0.5%黄蓍胶溶液中的试验化合物,2小时后把每只小鼠各放入Animex运动量测定装置(Farad公司制)上的测定笼(23×35×30cm)中,测定3分钟的探索行动量。求出试验化合物给药组的探索行动量(计数/3分钟)的平均值,与对照组的该量值比较,算出抑制率,再用概率单位法求出抑制50%的有效量(ED50值)。
实施例1化合物和盐酸灭吐灵的ED50值分别是48.5mg/kg和22.4mg/kg,实施例1化合物与盐酸灭吐灵相比,显示出中枢抑制作用较弱。
从以上试验结果可以看出,式(I)化合物及其生理上可接受的酸加成盐,显示出以强烈血清素S3和多巴胺D2受体拮抗作用为基础的优异止吐作用,可以作为适用范围广的止吐剂用于处置或预防各种疾病、给药等所伴随的消化器官症状。具体地说,可用于急性·慢性胃炎、逆流性食道炎、胃·十二指肠溃疡、胃神经症、胃下垂、胃切除后综合症、强皮症、糖尿病、食道·胆道系统疾病、小儿周期性呕吐症、上气道感染症等疾病中的恶心、呕吐、食欲不振、腹胀感、上腹不快感、腹痛、胸闷、暧气等的处置或预防,或过敏性肠综合征、便秘、乳幼儿下痢症的处置或预防。此外,还可以用于各种抗癌剂或左旋多巴(Levodopa)制剂给药时或属于麻药性镇痛剂的吗啡给药时、或放射性照射时的恶心或呕吐的处置或预防。进而,还可作为抗精神病剂或抗不安剂,用于对迷幻性药物(吗啡、烟碱、苯异丙胺)中毒的处置或预防。
作为式(I)化合物及其生理上可接受的酸加成盐的给药途径,可以是经口给药、非经口给药或经直肠内给药中的任何一种,其给药量因化合物种类、给药方法、患者症状、年龄等而异,但在诸如作为止吐剂使用的情况下,通常在0.01~10mg/kg/日,较好在0.1~3mg/kg/日的范围内是适当的,而在作为抗精神病剂使用的情况下,通常在3~50mg/kg日、较好在5~30mg/kg日的范围内是适当的。
式(I)化合物或生理上可接受的酸加成盐,在用于如上所述医药用途的情况下,通常是以与制剂用载体混合、调制的制剂形式给药的。作为制剂用载体,可以使用制剂领域中常用且不与本发明化合物反应的无毒物质。具体地说,可以列举诸如柠檬酸、谷氨酸、甘氨酸、乳糖、肌醇、葡萄糖、甘露糖醇、葡萄聚糖、山梨糖醇、环糊精、淀粉、部分α化淀粉、白糖、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、硅铝酸镁、合成硅酸铝、结晶纤维素、羧甲基纤维素钠、羟丙基淀粉、羧甲基纤维素钙、离子交换树脂、甲基纤维素、明胶、阿拉伯树胶、绒膜促性腺激素(pullulan)、羟丙基纤维素、低取代度羟丙基纤维素、羟丙基甲基纤维素、聚乙烯基吡咯烷酮、聚乙烯醇、藻酸、藻酸钠、轻质无水硅酸、硬脂酸镁、滑石、黄蓍胶、膨润土、硅铝酸镁盐、羧乙烯基聚合物、氧化钛、脱水山梨糖醇脂肪酸酯、硫酸月桂酯·钠、甘油、脂肪酸甘油酯、精制羊毛脂、甘油明胶、缩聚山梨醇油酸酯、聚乙二醇、植物油、蜡、丙二醇、乙醇、苄醇、氯化钠、氢氧化钠、盐酸、水等。
作为剂型,可以列举锭剂、胶囊剂、颗粒剂、散剂、糖浆剂、悬浮剂、注射剂、栓剂等。这些制剂可以按照常用方法调制。而且,当呈液体制剂时,还可以呈溶解或悬浮于水或适当溶剂中的形式。此外,锭剂和颗粒剂也可以用众所周知的方法包衣。
这些制剂可以以0.01%以上、较好0.1~70%的比例含有式(I)化合物或其生理上可接受的酸加成盐。这些制剂还可以含有治疗上有价值的其它成分。
以下列举参考例和实施例更具体地说明本发明,但本发明不限于这些实施例。化合物鉴定是用元素分析值、质谱、红外(IR)光谱、核磁共振谱(NMR)等进行。
此外,以下参考例和实施例中,也使用了如下省略号以简化描述。
J:结合常数
s:单线态
d:双线态
t:三线态
m:多线态
br-s:宽幅单线态
ee:对映体过剩率
参考例1
5-溴-2-甲氧基-6-甲胺基-3-吡啶羧酸的制备
(1)2,6-二氟吡啶50g溶解在四氢呋喃200ml中,在-70℃滴加1.6M正丁基锂四氢呋喃溶液326ml。在同一温度搅拌1小时后,向反应液中分批每批少许添加干冰29g的块状物。然后在同一温度搅拌30分钟后,升温至约5℃,加冰水500ml。反应液用乙酸乙酯洗涤2次,水层用浓盐酸调至pH3之后,用氯仿萃取。萃取液用饱和食盐水洗涤、用无水硫酸镁干燥后、减压蒸出溶剂。滤取析出的结晶,此结晶用二乙醚-正己烷重结晶,得到2,6-二氟-3-吡啶羧酸63g,熔点170-171℃。
(2)以上生成物63g、甲醇700ml和浓硫酸5ml的混合物加热回流20小时。减压蒸出溶剂、残渣用冰水稀释之后,用氯仿萃取。萃取液用水洗涤、用无水硫酸镁干燥后,减压浓缩溶剂。残渣用硅胶柱色谱法分离,氯仿洗脱、精制,得到油状物2,6-二氟-3-吡啶羧酸甲酯64g。
(3)在-20℃~-25℃,向以上生成物38g的乙醇500ml溶液中滴加20%甲胺的乙醇溶液72g。在同一温度搅拌5小时之后,升温至室温,反应液减压浓缩。向浓缩液中滴加冰水,滤取析出的固体,此固体水洗、干燥后用二乙醚-正己烷(2∶3)混合液重结晶,得到2-氟-6-甲胺基-3-吡啶羧酸甲酯15.7g。熔点156~159℃。
(4)向以上生成物15.7g的甲醇400ml溶液中加叔丁醇钾19.1g,加热回流3小时。冷却后,反应液减压浓缩,然后向残渣中添加碳酸氢钠水溶液、滤取析出的固体,此固体水洗后干燥,得到2-甲氧基-6-甲胺基-3-吡啶羧酸甲酯16.3g。熔点120~122℃(用正己烷-二乙醚重结晶)。
(5)向以上生成物7.3g的二甲基甲酰胺70ml溶液中添加N-溴琥珀酰亚胺7.0g,在80℃加热4小时。向反应液中加冰水,滤取析出的固体,此固体水洗后干燥,得到5-溴-2-甲氧基-6-甲胺基-3-吡啶羧酸甲酯9.8g。熔点136~138℃(用正己烷-二乙醚重结晶)。
(6)向以上生成物20g的甲醇溶液100ml中添加含氢氧化钠3.1g的水溶液200ml,加热回流1.5小时。冷却后,减压蒸出甲醇,然后用浓盐酸调成酸性。滤取析出的固体,此固体水洗后干燥,得到目的化合物18.9g。熔点224~225℃。
1H-NMR光谱(DMSO-d6,δppm):2.92(3H,d,J=5Hz),3.88(3H,s),7.08(1H,d,J=5Hz),7.98(1H,s),12.08(1H,s)。
实施例1
(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂製-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·二富马酸盐的制备:
(1)5-溴-2-甲氧基-6-甲胺基-3-吡啶羧酸18.0g、N,N′-羰基二咪唑11.7g和二甲基甲酰胺50ml的混合液在室温搅拌8小时。向此混合液中添加(R)-6-氨基-1-乙基-4-甲基六氢-1H-1,4-二氮杂製13.0g,在室温搅拌15小时。反应液减压浓缩,向其中添加2N氢氧化钠水溶液,然后用氯仿萃取。萃取液用水洗涤、用无水硫酸镁干燥后,溶剂减压浓缩。残渣用硅胶柱色谱法分离、用氯仿-甲醇(15∶1)混合液洗脱·精制,用二乙醚重结晶,得到(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂製-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·1/4水合物19.6g。熔点52~55℃。
该化合物在下列条件的高压液体色谱法(HPLC)上显示保持时间23.6分钟,光学纯度在99%ee以上。
〔HPLC条件〕
HPLC柱:CHIRALPAK AS(ダイセル、Daicel即大世吕化学工业公司制);内径4.6mm×250mm
移动相:正己烷-乙醇-二乙胺(940∶30∶2)
流速:0.8ml/分钟
温度:25℃
检测:UV 254nm
(2)以上生成物19g用富马酸处理而成为二富马酸盐,用乙醇重结晶,得到目的化合物23g。熔点152~155℃。
1H-NMR光谱(DMSO-d6,δppm):1.02(3H,t,J=7Hz),2.43(3H,s),2.5-3.0(10H,m),2.93(3H,d,J=5Hz),3.98(3H,s),4.14(1H,m),6.60(4H,s),6.99(1H,d,J=5Hz),8.09(1H,s),848(1H,d,J=8Hz),12.80(2H,br-s)。
参考例2
(S)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂製-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·二富马酸盐的制备:
(1)实施例1(1)中的(R)-6-氨基-1-乙基-4-甲基六氢-1H-1,4-二氮杂製代之以使用(S)-6-氨基-1-乙基-4-甲基六氢-1H-1,4-二氮杂製,与实施例1(1)一样进行反应、处理,得到(S)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂製-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·一水合物。
熔点67~68℃(用二乙醚-石油醚重结晶)。
该化合物在与实施例1相同条件下的HPLC上显示保持时间27.5分钟,光学纯度在99%ee以上。
(2)以上生成物用富马酸处理以制成二富马酸盐,用乙醇重结晶,得到目的化合物。熔点152~155℃。
实施例2
(R)-6-氨基-1-乙基-4-甲基六氢-1H-1,4-二氮杂的制备
(1)向N′-甲基-N-(3-甲基苄基)乙二胺1602g的氯仿1200ml溶液中,在冰冷却下滴加二碳酸二叔丁酯2180g的氯仿3500ml溶液。在室温搅拌18小时后,减压蒸出反应液,向残渣中添加甲苯和冰水,在冰冷却下,在内温4℃以下滴加10%柠檬酸水溶液,使水层变成酸性。分离的甲苯层用水萃取,得到的水层与酸性水溶液合并,用甲苯洗涤。水层用48%氢氧化钠水溶液调成碱性后,用甲苯再萃取。萃取液用水、饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸出溶液,得到油状物N′-叔丁氧羰基-N′-甲基-N-(3-甲基苄基)乙二胺1860g。
(2)以上生成物50g与(S)-2-甲氧羰基-1-苄氧羰基氮丙啶53g混合,在80℃搅拌20小时,得到粗制的(R)-2-(苄氧羰基)氨基-3-〔N-〔2-〔N′-(叔丁氧羰基)-N′-甲基氨基〕乙基〕-N-(3-甲基苄基)〕氨基丙酸甲酯。
(3)向以上粗制的生成物中添加10%氯化氢乙醇溶液750ml,在30~40℃搅拌2小时。滤去不溶物,减压蒸出溶剂,残渣溶于500ml水中,水层用二乙醚洗涤。水层用碳酸氢钠中和后,用氯仿萃取。萃取液用无水硫酸镁干燥后、减压蒸出溶剂,得到粗制的(R)-2-(苄氧羰基)氨基-3-〔N-(2-甲胺基乙基)-N-(3-甲基苄基)〕氨基丙酸甲酯79g。生成物的一部分制成草酸盐,用乙醇-二乙醚重结晶,得到上述甲酯的草酸盐。熔点185~190℃。
(4)上述粗制的甲酯物39g溶解在乙醇70ml中,在0℃~10℃向其中滴加2N氢氧化钠水溶液70ml,然后在室温搅拌16小时。减压蒸出乙醇,水溶液用浓盐酸调至pH8,用氯仿萃取。萃取液用无水硫酸镁干燥后、减压蒸出溶剂,得到粗制的(R)-2-(苄氧羰基)氨基-3-〔N-(2-甲胺基乙基)-N-(3-甲基苄基)〕氨基丙酸36.4g。生成物的一部分精制,得到结晶。熔点170~175℃。
(5)上述粗制的生成物36.4g溶解在二氯甲烷180ml中,添加1-乙基-3-(3-二甲胺基丙基)碳化二亚胺盐酸盐18.2g,在室温搅拌20小时。反应液水洗,用无水硫酸镁干燥后,减压蒸出溶剂,残渣用二乙醚-正己烷重结晶,得到(S)-3-(苄氧羰基)氨基-1-甲基-4-(3-甲基苄基)六氢-2-氧代-1,4-二氮杂22g。熔点70~71℃。
(6)向上述生成物40.8g的二氯甲烷400ml溶液中滴加氯碳酸1-氯乙酯18.0g,在室温搅拌3小时。减压蒸出溶剂,向残渣中添加甲醇100ml,加热回流1小时。减压蒸出甲醇后,向残渣中加水,用二乙醚洗涤,水层用氢氧化钠水溶液调成碱性之后,用氯仿萃取。萃取液用无水硫酸镁干燥后,减压蒸出溶剂,得到粗制的(S)-3-(苄氧羰基)氨基-1-甲基六氢-2-氧代-1,4-二氮杂。
(7)向以上粗制的生成物中添加甲醇600ml和三乙胺21.2g,进一步在冰冷却下添加80%乙醛水溶液11.6g,搅拌2小时。然后在同一温度下分批每批少许添加硼氢化钠3.97g,在冰冷却下搅拌1小时,进一步在室温搅拌16小时。减压蒸出溶剂,用氯仿萃取。萃取液用饱和食盐水洗涤、用无水硫酸镁干燥后,减压蒸出溶剂。残渣用硅胶柱色谱法分离、用氯仿-甲醇(15∶1)洗脱、精制,得到油状物(S)-3-(苄氧羰基)氨基-5-乙基-1-甲基六氢-2-氧代-1,4-二氮杂28g。
(8)向上述生成物28g中添加48%氢溴酸水溶液140ml,在60℃加热搅拌2小时。冷却后,反应液用二乙醚洗涤2次,水层用碳酸钾调成碱性后,用氯仿萃取。萃取液用无水硫酸镁干燥后,减压蒸出溶剂,得到油状物(S)-3-氨基-5-乙基-1-甲基六氢-2-氧代-1,4-二氮杂19g。
(9)在冰冷却下向上述生成物23g的四氢呋喃300ml溶液中滴加1 M甲硼烷四氢呋喃溶液1000ml后,在室温搅拌16小时。在冰冷却下,添加1N盐酸500ml后,加热回流1小时。冷却后,减压蒸出溶剂,残渣用二乙醚洗涤2次,水层用碳酸钾调成碱性之后,用氯仿萃取。萃取液用无水硫酸镁干燥后,减压蒸出溶剂,得到油状物形式的目的化合物19g。
参考例3
(S)-6-氨基-1-乙基-4-甲基六氢-1H-1,4-二氮杂的制备
实施例2(2)的(S)-2-甲氧羰基-1-苄氧羰基氮丙啶代之以使用(R)-2-甲氧羰基-1-苄氧羰基氮丙啶,与实施例2(2)~(9)一样进行反应、处理,得到目的化合物。
制剂例1
锭剂制备(5mg锭剂)(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·二富马酸盐 5g乳糖 80g玉米淀粉 30g结晶纤维素 25g羟丙基纤维素 3g轻质无水硅酸 0.7g硬脂酸镁 1.3g
以上成分用常法混合、造粒,以每锭145mg压片,制成1000锭(片)。
制剂例2
散剂制备(1%散)(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·二富马酸盐 10g乳糖 960g羟丙基纤维素 25g轻质无水硅酸 5g
以上成分用常法混合后,制成散剂。
制剂例3
注射剂制备(0.5%注射溶液)(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·二富马酸盐 10g山梨糖醇 100g注射用水 适量
总量2000ml
(R)-5-溴-N-(1-乙基-4-甲基六氢-1H-1,4-二氮杂-6-基)-2-甲氧基-6-甲胺基-3-吡啶羧酰胺·二富马酸盐和山梨糖醇在一部分注射用水中溶解后,添加其余注射用水,进行全量配制。此溶液用膜过滤器(0.22μm)过滤,滤液灌注到2ml安瓿中,然后在121℃灭菌20分钟。
产业上利用的可能性
如上所说明的,式(I)所示的本发明化合物及其生理上可接受的酸加成盐,显示出基于强烈血清素S3和多巴胺D2受体拮抗作用的优异止吐作用,可作为止吐剂用于各种疾病、药物给药等所伴随的种种消化器官症状的处置或预防。具体地说,可用于急·慢性胃炎、逆流性食道炎、胃·十二指肠溃疡、胃神经症、胃下垂、胃切除后综合症、强皮症、糖尿病、食道·胆道系统疾病、小儿周期性呕吐症、上气道感染症等疾病中的恶心、呕吐、食欲不振、腹胀感、上腹不快感、腹痛、胸闷、暧气等的处置或预防,以及过敏性肠综合征、便秘、乳幼儿下痢症的处置或预防。进而,还可用于各种抗癌剂或左旋多巴制剂给药时或麻药性镇痛剂吗啡给药时、或放射性照射时的恶心或呕吐的处置或预防。此外,本发明化合物还可用作抗精神病剂或抗不安剂。
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GB0216027D0 (en) * | 2002-07-10 | 2002-08-21 | Arachnova Therapeutics Ltd | New therapeutic use |
US20040048874A1 (en) * | 2001-05-22 | 2004-03-11 | Bardsley Hazel Judith | New therapeutic use of 4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D]pyrimidine |
ITBO20020198A1 (it) * | 2002-04-12 | 2003-10-13 | Univ Bologna | Derivati 2 , 5 bis diammino 1 , 4 benzochenionici utili per il trattamento della malattia di alzheimer , metodo per la loro preparazione ed |
AU2004204825B2 (en) * | 2003-01-13 | 2007-07-19 | Dynogen Pharmaceuticals, Inc. | Method of treating functional bowel disorders |
US20040147510A1 (en) * | 2003-01-13 | 2004-07-29 | Dynogen Pharmaceuticals, Inc. | Method of treating nausea, vomiting, retching or any combination thereof |
DE602004007225T2 (de) * | 2003-04-04 | 2008-03-06 | Dynogen Pharmaceuticals Inc., Waltham | Methode zur behandlung von erkrankungen der unteren harnwege |
US20060293309A1 (en) * | 2005-03-28 | 2006-12-28 | Dynogen Pharmaceuticals, Inc. | Method of treating disorders and conditions using peripherally-restricted antagonists and inhibitors |
CN102333763A (zh) | 2009-03-31 | 2012-01-25 | 善利亚新药工业股份有限公司 | 1,5-苯二氮䓬衍生物的制备方法 |
EP2818463A1 (en) | 2010-08-26 | 2014-12-31 | Kowa Co., Ltd. | Production method of 1,4-diazepane derivatives |
EP3102565B1 (en) * | 2014-02-03 | 2019-01-02 | Mylan Laboratories Ltd. | Processes for the preparation of intermediates of raltegravir |
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