CN100582103C - 作为搔痒治疗药有效的4-(2-呋喃甲酰基)氨基哌啶类化合物 - Google Patents
作为搔痒治疗药有效的4-(2-呋喃甲酰基)氨基哌啶类化合物 Download PDFInfo
- Publication number
- CN100582103C CN100582103C CN200480012521A CN200480012521A CN100582103C CN 100582103 C CN100582103 C CN 100582103C CN 200480012521 A CN200480012521 A CN 200480012521A CN 200480012521 A CN200480012521 A CN 200480012521A CN 100582103 C CN100582103 C CN 100582103C
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- Prior art keywords
- ethyl
- cyclohexyl
- furoylamide
- piperidin
- picoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明提供一种用通式(I)表示的化合物或其可药用盐,见右式(I)。[式中,R1是5-甲基吡啶-2-基、对甲苯基、均三甲苯基,R2是通式(II)~(IX)。(式中,R3是C1~C4烷基,R4是H、C1~C4烷基,R5是H、3-吡啶基甲基、4-吡啶基甲基,R6是2,4-二羟基苄基、3-吡啶基甲基、4-吡啶基甲基),或者当R1是均三甲苯基时,R2是式(X)。]。该化合物具有止痒作用,其对于昆虫叮咬的反应、相对于环境变应原的反应,或者因皮肤感染、外部寄生虫感染或肾透析患者引起的刺痒及搔痒有预防、治疗作用。
Description
技术领域
本发明涉及一种作为搔痒治疗药有效的新型4-(2-呋喃甲酰基)氨基哌啶类化合物和其制造方法,以及其作为药品的使用。
背景技术
阿片样物质受体是具有吗啡样作用的、药物特异性结合的受体,存在于中枢和肠道神经等中。在阿片样物质受体中已知有μ、δ及κ三种类型。μ受体具有镇痛、呼吸抑制、幸福感、精神·身体依赖、耐性、抑制消化道功能、心搏徐缓、便秘、缩瞳作用等。与之对应,δ受体具有镇痛、精神·身体依赖、情绪性作用等,κ受体具有镇痛、镇静、心搏徐缓、利尿、厌恶感、缩瞳作用等。
在WO 03/035645中记载了作为μ受体拮抗药发挥作用的4-(2-呋喃甲酰基)氨基哌啶衍生物。该化合物族具有强烈的μ受体拮抗作用,由于其具有对末梢的选择性,因此,其作为便秘症及过敏性肠症候群等的消化道功能不全的治疗药是有用的。但是,虽然该化合物族具有强烈的阿片样物质μ受体拮抗作用,对便秘、恶心呕吐等的μ受体激动药的副作用和特发性便秘、术后肠梗阻、麻痹性肠梗阻、过敏性肠症侯群是有效的,但由于对治疗刺痒或搔痒的效果还没有完全认定,或者说即使认定也是不充分的,因此,期望发明更强力的搔痒治疗药。
另外,美国特许公开公报US2003-004340A记载了如下内容:结合于阿片样物质(opiate;鸦片剂)受体(例如μ、κ及δ受体)的化合物对这些刺痒或搔痒的治疗是有用的。
发明内容
本发明者为了提供一种没有副作用、具有强力搔痒治疗效果的化合物,进行了深入研究,结果发现,将WO03/035645中记载的4-(2-呋喃甲酰基)氨基哌啶衍生物的结构进行部分改变,得到的用下面的通式(I)表示的化合物或其可药用盐具有强力的搔痒治疗作用,
[式中,R1是5-甲基吡啶-2-基、对甲苯基、均三甲苯基,R2是通式(II)~(IX)
(式中,R3是C1~C4烷基,R4是H、C1~C4烷基,R5是H、3-吡啶基甲基、4-吡啶基甲基,R6是2,4-二羟基苄基、3-吡啶基甲基、4-吡啶基甲基),或者当R1是均三甲苯基时,R2是式(X)。]。
包含于通式(I)的化合物例如有:
N-[1-[2-[1-[2-[双(吡啶-3-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-[双(吡啶-4-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-(1-氧代-2-异吲哚满基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-(2,4-二羟基苄氨基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-(吗啉代)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-(3-环己基-3-羟丙基)哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
N-[1-[(3-甲氧羰基-1-三环[3.3.1.13,7]癸基)甲基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
[1-[2-[4-[N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺]哌啶-1-基]乙基]环己基]乙酸二乙基膦酰基甲亚胺酸酐
[1-[2-[4-(N-均三甲苯基-2-呋喃甲酰胺)哌啶-1-基]乙基]环己基]乙酸
N-[1-[2-(1-乙基环己基)乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
N-[1-[2-[1-(4-甲氧基-3-甲氧基甲基丁基)环己基]乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
N-[1-[2-[1-(4-甲氧基-3-羟甲基丁基)环己基]乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
或其可药用盐等。
在本发明化合物中,包含一个以上手性中心的化合物可以作为对映体及非对映异构体存在。非对映异构体可以通过常用技术例如分别结晶法或色谱法进行分离。各种立体异构体可以通过该化合物的外消旋混合物或其它混合物的分离,用常用技术例如分别结晶法或HPLC等进行单离。在不引起外消旋或差向异构化的条件下,所希望的光学异构体可以通过适当的光学活性起始原材料的反应进行调制。或者,所希望的光学异构体可以通过使用适当手性支持体的外消旋体的HPLC,或者在适当的场合通过合适的光学活性酸或碱和外消旋体发生反应形成的非对映异构体的分别结晶法,通过离析来调制。本发明包括分离了的每个异构体以及异构体的混合物、二者的用途。
用通式(I)表示的化合物的所有保护衍生物及前药、活性代谢物均包括在本发明的范围内。
本发明化合物可以用以WO03/035645中公开的4-(2-呋喃甲酰基)氨基哌啶衍生物的制造法为基准的方法进行制造。
在本发明通式(I)表示的化合物的医药中容许的酸加成盐可以通过通常的方法制造。例如:将游离碱的溶液和适当的酸直接或用合适的溶剂处理,通过随后的过滤或通过减压下反应溶剂的蒸发可以分离出来。用同样的方法,通过将本发明通式(I)表示的化合物的溶液用合适的碱进行处理,可以得到可药用的碱加成盐。盐的两种类型可以用离子交换树脂技术形成或相互变化。酸加成盐例如有:和盐酸、氢溴酸、硫酸、磷酸等无机酸的形成盐类;和乙酸、琥珀酸、草酸、苹果酸、酒石酸、富马酸、马来酸、柠檬酸、丙二酸、乳酸、甲磺酸、对甲苯磺酸、苯乙醇酸、辛二酸、邻苯二甲酸、对苯二甲酸等有机酸形成的盐类。碱加成盐例如有:和钠盐、钾盐、各种铵盐等无机或有机碱形成的盐类。
如上所述的本发明的化合物对动物及人的刺痒及搔痒的治愈或预防是有用的。刺痒或搔痒是使人及动物感觉相当痛苦的一般皮肤科症状,已知有伴随内因性、外因性的疾病的刺痒。内因性、外因性的疾病例如有:慢性肾功能不全、原发性胆汁型肝硬化、胆管闭塞、胆汁郁积、肝炎、真性红血球增多症、淋巴肿大、白血病、何杰金氏病、多发性骨髓症、缺铁症、细胞肥大症、甲状腺功能亢进症、甲状腺功能低下症、类癌症侯群、糖尿病、恶性肿瘤、精神病、寄生虫感染症、干皮症、疥癣、疱疹状皮炎、特异反应性皮炎、单纯性慢性苔癣、银屑病、扁平苔癣、接触性皮炎、痱子、虫咬、荨麻疹、毛囊炎、晒伤、多形性日光疹、水泡性类疱疮、真菌感染、菌状息肉肿、脂溢性皮炎等。
本发明化合物特别对动物及人起因于过敏性皮炎、特异反应等的搔痒皮肤病及透析患者的搔痒、接触性皮炎、银屑病、湿疹及昆虫咬伤等的刺痒及搔痒的治愈性治疗或预防是有用的。
而且,本发明化合物有望通过阻断阿片样物质μ受体,作为便秘及恶心呕吐等μ受体激动药的副作用和特发性便秘、术后肠梗阻、麻痹性肠梗阻、过敏性肠症侯群等的治疗药及预防药。
在使用该通式(I)表示的化合物作为药品时,可以制成各种给药形式的制剂。亦即该制剂可以以口服药片、糖衣药片、硬质糖浆、软质糖浆、肠溶制剂、溶液、乳浊液或悬浊液的液剂形态给药。另外,非口服给药时,可以以注射剂、栓剂、灌肠剂、溶液、乳浊液或悬浊液的液剂形态给药。另外,也可以以美国专利公报USP5567773及USP5888494公开的局部覆盖膜形成组合物和美国专利公报USP5798093及USP5811078公开的喷雾制剂的形态给药。
本发明化合物可以单独给药,或和用于治疗或预防疾患、减轻或抑制症状的一种以上的药物并用给药。这样的药物的例子(该例子是为说明所作的提示,但并不限于此,也不需做解释)有:抗寄生虫剂例如有:芬普尼、禄芬隆、益达胺、阿维菌素(例如:阿佛菌素、依维菌素、多拉菌素)、倍脉心、有机磷酸酯、拟除虫菊酯;抗组胺剂例如有:扑尔敏、三甲利定、苯海拉明、抗敏安;抗真菌剂例如有:康唑、酮康唑、伊曲康唑、灰黄霉素、两性霉素B;抗菌剂例如有:恩诺沙星、麻保沙星、氨必西林、阿莫西林;消炎剂例如有:强的松、倍他米松、地塞米松、卡洛芬、苯酮苯丙酸;膳食补充剂例如有:γ-亚麻油酸;以及缓和药等。因而,本发明进一步提供包含本发明化合物及上述列出的化合物作为并用制剂的制品,该制品在治疗鸦片受体介导的疾病时,个别或连续的使用。
在调制这些制剂时,可以添加用于制剂的、惯用的添加剂,例如:赋形剂、稳定剂、防腐剂、溶解剂、润湿剂、乳化剂、润滑剂、甜味剂、着色剂、香味剂、张力调节剂、缓冲剂、抗氧化剂等进行制剂化。
本发明的阿片样物质μ受体阻断剂的给药方法、给药量可以根据各种制剂形态、患者性别、疾患程度进行适当选择,有效成分的每日给药量为1~1000mg。
下面,显示本发明化合物的生物学活性的测定结果。
1.止痒效果的测定
本发明化合物的止痒效果用小鼠P物质搔痒模型测定(测定法是T.Andoh et al.,The Jounal of Pharmacology and ExperimentalTherapeutics Vol.286,No.3,1140-1145(1998)及T.Andoh etal.,European Journal of Pharmacology Vo.436(2002)235-239记载的)。在实验的前日或前日之前,在轻度乙醚麻醉下,对小鼠(ICR系,6周龄,雄性)的吻侧背部进行剃毛及在后肢放置磁石(直径1mm×3mm)。在实验当日,将本发明化合物或作为比较的WO03/035645记载的化合物10mg/kg(腹腔内或口服给药)对小鼠给药,30分钟后在轻度乙醚麻醉下,将P物质100nmol/site(50μl)对吻侧背部进行皮下给药。从P物质给药2分钟后开始用搔痒测定装置(NS-SCT16型株式会社ニユ-ロサイエンス)及MicroAct(デ-タ制御·集录解析用软件株式会社ニユ-ロサイエンス)记录30分钟的搔痒行动。得到的数据在阈值0.05V,事件间隔0.05sec,最大频率20.00Hz,最小频率5.00Hz,最小持续时间0.30sec的条件进行分析。相对于30分钟的对照(溶剂)组的平均搔痒次数、从本发明化合物给药组的平均搔痒次数算出搔痒次数抑制率(%)。需要说明的是,比对照组搔痒次数多的组表示为-X%。表1记载了各化合物的搔痒次数抑制率(%)。为了比较,同时也显示了WO03/035645记载的下列化合物的止痒效果。
表1:止痒效果的测定
根据以上结果可知,与WO03/035645公开的化合物相比,本发明化合物具有非常高的止痒效果。
2.对自发运动量的作用的研究
对小鼠的自发运动量的作用进行了研究。用的是6周龄雄性ICR小鼠。本发明化合物溶解于蒸馏水或20% cremophor EL(SIGMA综合目录,C5135,Sigma-Aldrich社),以10mg/kg的用量腹腔内给药。从给药30分钟后开始用自发运动量测定器(Scanet MV-20MT(有)メルクエスト)测定自发运动量。在测定机器内放置塑料制的罩子(W220×D320×H135mm),化合物给药30分钟后,将小鼠放入罩内进行30分钟测定,记录显示小鼠的总运动量的计数。以对照组(蒸馏水或20%cremophor EL)的自发运动量为100%,从各化合物给药后的自发运动量的平均值算出抑制率。各化合物的自发运动抑制率如表2所示。
表2:自发运动抑制率
根据该结果可知,本发明化合物的止痒作用没有起因于自发运动抑制(镇静)的副作用。
3.对μ受体的拮抗作用
通过豚鼠回肠纵肌标本的电场刺激法测定本发明化合物的μ拮抗活性(pA2值)。
纵肌标本是将豚鼠(Hartley系,雄性)放血致死后摘出回肠制作而成的。记录在装满20mL营养液(Krebs-Henselite液,37℃,通入95%O2-5%CO2气体)的马格纳斯装置中、在0.5g的负荷下悬挂的标本的等尺性收缩。将标本在营养液中平衡1小时以上,用能够得到最大收缩的电压进行电场刺激(0.1Hz,1msec duration)。在收缩稳定后累积地添加μ受体激动药的吗啡,洗涤后,暂停1小时。再次进行电场刺激、待收缩稳定后,添加本发明化合物,添加后15分钟时累积地添加吗啡。从记录电场刺激收缩的图,测定吗啡添加前后的收缩量(mm),根据计算式1算出收缩抑制率(%)。
计算式1:收缩抑制率(%)=[(a-b)/a]×100
a:吗啡添加前的收缩量(mm)
b:吗啡添加后的收缩量(mm)
以吗啡的对数浓度为横轴,以收缩抑制率(%)为纵轴作曲线,制成本发明化合物不存在及存在下的吗啡浓度反应曲线。在吗啡浓度反应曲线的收缩抑制率为50%之处,测定从本发明化合物不存在下到存在下的吗啡反应曲线的距离(mm)。以该距离为基础,将计算式2的Log(CR-1)的值从van Rossum简易表求出,算出pA2的值。
计算式2:Log(CR-1)=Log[B]+pA2
[B]:本发明化合物的浓度
本发明化合物对μ受体的拮抗活性(pA2值)如表3所示。
表3:对μ受体的拮抗活性
实施例编号 | pA<sub>2</sub>值 |
实施例1-2 | 8.06 |
实施例2-2 | 8.28 |
实施例4 | 7.74 |
实施例5-7 | 6.55 |
实施例6-4 | 7.91 |
实施例7-3 | 7.52 |
实施例8 | 8.15 |
实施例9-5 | 7.52 |
实施例10-8 | 7.52 |
WO03/035645 EX 2-3 | 8.14 |
WO03/035645 EX 3A-3 | 7.64 |
WO03/035645 EX 3B-1 | 8.26 |
WO03/035645 EX 3G-2 | 8.12 |
WO03/035645 EX 2-18 | 8.86 |
WO03/035645 EX 5B-1 | 8.66 |
WO03/035645 EX 2-17 | 8.38 |
根据该结果可知,本发明化合物对μ受体具有拮抗作用。因而,本发明化合物通过阻断鸦片μ受体,可以期待其具有治疗及预防便秘及恶心呕吐等μ受体激动药的副作用和特发性便秘、术后肠梗阻、麻痹性肠梗阻及过敏性肠症候群等的效果。
具体实施方式
下面,展示处方例。
处方例1
明胶硬胶囊剂
实施例记载化合物 | 20mg |
玉米淀粉 | 200mg |
硬脂酸镁 | 10mg |
合计 | 230mg |
将各成分均匀混合,填充到明胶硬胶囊中、制成内容量为460mg的明胶硬胶囊剂。
处方例2
明胶硬胶囊剂
实施例记载的化合物 | 20mg |
玉米淀粉 | 89mg |
结晶纤维素 | 89mg |
硬脂酸镁 | 2mg |
合计 | 200mg |
将各成分均匀混合,填充至明胶硬胶囊中、制成内容量为200mg的明胶硬胶囊剂。
处方例3
明胶软胶囊剂
(药液) | |
实施例记载的化合物 | 20mg |
中链脂肪酸triglide(トリグリド) | 160mg |
聚环氧乙烷固化蓖麻油60 | 20mg |
小计 | 200mg |
(皮膜) | |
明胶 | 100mg |
甘油 | 30mg |
对羟基苯甲酸甲酯 | 0.2mg |
对羟基苯甲酸丙酯 | 0.05mg |
精制水 | 适量 |
小计 | 140mg |
合计 | 340mg |
采用旋转式软胶囊制造机,用预先加热溶解了的皮膜溶液制成皮膜,将预先均匀溶解了的药液成分包覆成型后,进行充分干燥。
处方例4
片剂
实施例记载的化合物 | 10mg |
玉米淀粉 | 45mg |
结晶纤维素 | 35mg |
聚乙烯基吡咯烷酮(作为10%水溶液) | 4mg |
羧甲基纤维素钠 | 4.5mg |
硬脂酸镁 | 0.5mg |
滑石粉 | 1mg |
合计 | 100mg |
将主药、淀粉、纤维素过筛,进行充分混合。将聚乙烯基吡咯烷酮水溶液混合在该粉末中,然后用No.14目筛网过筛。将这样制造的粒状物在50~60℃干燥,用No.18目筛网过筛。然后将事先通过N0.60目筛网的羧甲基纤维素钠、硬脂酸镁及滑石粉加入该粒状物中,进行混合后,用压片机制造各重量为100mg的片剂。
处方例5
片剂
实施例记载的化合物 | 250mg |
结晶纤维素 | 400mg |
甲状腺 | 10mg |
硬脂酸镁 | 5mg |
合计 | 665mg |
将各成分均匀混合,用压片机制造各重量为665mg的片剂。每给药量5mL中含有活性成分5mg的悬浊液通过如下方法制造。
悬浊液
实施例记载的化合物 | 5mg |
羧甲基纤维素钠 | 50mg |
单糖浆 | 1.25mL |
安息香酸水溶液 | 0.10mL |
芳香剂 | 适量 |
精制水 | 使得总量达到5ml的添加量 |
合计 | 5mL |
将主药用No.45目筛网过筛,和羧甲基纤维素钠及单糖浆混合,制成膏。将安息香酸水溶液、芳香剂用一定量的精制水稀释,边搅拌边加入到得到的膏中。然后加入精制水达到所需要的容量。
下面,通过实施例对本发明作进一步说明。这些只是用于举例说明本发明的,并不限定本发明。
制造例1
N-[2-[1-[2-[4-(对甲苯胺基)哌啶-1-基]乙基]环己基]乙基]邻苯二甲酰亚胺
在含有4-(对甲苯胺基)哌啶(0.73g,3.85mmol)、N-[2-[1-(甲酰甲基)环己基]乙基]邻苯二甲酰亚胺(0.77g,2.57mmol)、乙酸(0.30mL,5.14mmol)的1,2-二氯乙烷(10mL)溶液中,加入三乙酰氧基硼氢化钠(0.82g,3.85mmol),在室温搅拌1.5小时。加入饱和碳酸氢钠水溶液,用氯仿-乙醇溶液(10∶1)进行萃取。干燥(无水硫酸钠)后在减压的条件下除去溶剂。将得到的残渣用硅胶柱层析(Merck Art9385 25g,氯仿∶甲醇=20∶1)进行精制,得到无色油状物(1.32g)的标题化合物。
1H-NMR(CDCl3)δ:1.35-1.63(m,16H),2.05-2.08(m,2H),2.15-2.23(m,2H),2.23(s,3H),2.42-2.46(m,2H),2.94-2.98(m,2H),3.25-3.30(m,1H),3.64-3.68(m,2H),6.53(d,2H,J=8.3Hz),6.97(d,2H,J=7.8Hz),7.69-7.72(m,2H),7.81-7.86(m,2H).
制造例2
N-[2-[1-[2-[4-[N-(对甲苯基)-2-呋喃甲酰胺]哌啶-1-基]乙基]环己基]乙基]邻苯二甲酰亚胺
在含有N-[2-[1-[2-[4-(对甲苯胺)哌啶-1-基]乙基]环己基]乙基]邻苯二甲酰亚胺(202mg,0.43mmol)、三乙胺(0.14mL,1.00mmol)的二氯甲烷(2mL)溶液中,加入2-呋喃甲酰氯(0.055mL,0.55mmol),在室温搅拌1小时。将反应液依次用10%柠檬酸水溶液、饱和碳酸氢钠水溶液、饱和食盐水洗涤,干燥(无水硫酸钠),减压浓缩。将得到的残渣用硅胶柱层析(NH Silica Chromatorex DM2035 10g,己烷∶乙酸乙酯=7∶3)进行精制,得到无色无定形固体(142mg)的标题化合物(收率58%)。
1H-NMR(CDCl3)δ:1.25-1.60(m,16H),1.85-1.89(m,2H),2.14-2.21(m,2H),2.35-2.42(m,2H),2.39(s,3H),3.02-3.06(m,2H),3.59-3.64(m,2H),4.75-4.84(m,1H),5.38(s,1H),6.13(dd,1H,J=1.5Hz,3.4Hz),7.02(d,2H,J=7.8Hz),7.18(d,2H,J=7.8Hz),7.35(s,1H),7.68-7.70(m,2H),7.81-7.83(m,2H).
制造例3
N-[1-[2-[1-(2-氨乙基)环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
在含有N-[2-[1-[2-[4-[N-(对甲苯基)-2-呋喃甲酰胺]哌啶-1-基]乙基]环己基]乙基]邻苯二甲酰亚胺(1.91g,3.36mmol)的乙醇(30mL)悬浊液中,加入肼一水合物(0.49mL,10.0mmol),加热回流2.5小时。将反应液冷却至室温,滤去不溶物,将滤液减压浓缩。将得到的残渣用硅胶柱层析(NH Silica Chromatorex DM2035 25g,氯仿)进行精制,得到无色油状物(1.64g)的标题化合物(定量)。
1H-NMR(CDCl3)δ:1.23-1.57(m,16H),1.83-1.86(m,2H),2.04-2.12(m,2H),2.22-2.27(m,2H),2.39(s,3H),2.59-2.64(m,2H),2.94-2.98(m,2H),4.72-4.81(m,1H),5.37(s,1H),6.13(dd,1H,J=2.0Hz,3.4Hz),7.01(d,2H,J=7.8Hz),7.17(d,2H,J=7.8Hz),7.34(d,1H,J=2.0Hz).
实施例1-1
N-[1-[2-[1-[2-[双(吡啶-3-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
在含有N-[1-[2-[1-(2-氨乙基)环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(130mg,0.30mmol)、3-吡啶甲醛(80mg,0.75mmol)、乙酸(70μL,1.20mmol)的1,2-二氯乙烷(5mL)溶液中,加入三乙酰氧基硼氢化钠(212mg,1.00mmol),搅拌18小时。在反应液中加入饱和碳酸氢钠水溶液,用氯仿进行萃取。将有机层用饱和食盐水洗涤、干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。将残渣用硅胶柱层析(NH Silica Chromatorex DM2035 5g,氯仿)进行精制,得到无色油状物(178mg,0.29mmol)的标题化合物(收率96%)。
1H-NMR(CDCl3)δ:1.13-1.51(m,16H),1.79-1.89(m,4H),2.03-2.08(m,2H),2.35-2.39(m,2H),2.39(s,3H),2.76-2.80(m,2H),3.57(s,4H),4.68-4.76(m,1H),5.37(s,1H),6.14(dd,1H,J=1.5Hz,3.4Hz),7.00(d,2H,J=7.8Hz),7.17(d,2H,J=8.3Hz),7.24-7.29(m,2H),7.35(d,1H,J=1.5Hz),7.67-7.70(m,2H),8.51(dd,2H,J=2.0Hz,4.9Hz),8.56(d,1H,J=2.0Hz).
实施例1-2
N-[1-[2-[1-[2-[双(吡啶-3-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺四盐酸盐
在含有N-[1-[2-[1-[2-[双(吡啶-3-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(178mg,0.29mmol)的乙酸乙酯(2mL)-乙醇(2mL)溶液中,加入4N盐酸/乙酸乙酯溶液(0.35mL,1.4mmol),在室温搅拌20分钟。将反应液减压浓缩,在得到的残渣中加入乙酸乙酯,滤出析出的结晶,减压干燥,得到白色固体(197mg,0.26mmol)的标题化合物(收率89%)。
1H-NMR(DMSO-d6)δ:1.04-2.03(m,10H),2.39(s,3H),2.98-3.07(m,4H),3.45-3.54(m,2H),4.74-4.80(m,1H),5.40(s,1H),6.33(dd,1H,J=1.5Hz,3.4Hz),7.17(d,2H,J=8.3Hz),7.30(d,2H,J=8.3Hz),7.67(s,1H),7.82(brs,2H),8.57(d,2H,J=7.8Hz),8.80(d,2H,J=4.9Hz),9.04(brs,2H),10.22(br,1H).
实施例2-1
N-[1-[2-[1-[2-[双(吡啶-4-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
在含有N-[1-[2-[1-(2-氨乙基)环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(131mg,0.30mmol)、4-吡啶甲醛(80mg,0.75mmol)、乙酸(70μL,1.20mmol)的1,2-二氯乙烷(5mL)溶液中,加入三乙酰氧基硼氢化钠(212mg,1.00mmol),搅拌18小时。在反应液中加入饱和碳酸氢钠水溶液,用氯仿进行萃取。将有机层用饱和食盐水洗涤、干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。将残渣用硅胶柱层析(NH Silica Chromatorex DM2035 5g,氯仿)进行精制,得到无色油状物(171mg,0.28mmol)的标题化合物(收率92%)。
1H-NMR(CDCl3)δ:1.13-1.52(m,16H),1.81-1.85(m,2H),1.94-2.00(m,2H),2.08-2.13(m,2H),2.35-2.39(m,2H),2.39(s,3H),2.79-2.82(m,2H),3.57(s,4H),4.69-4.77(m,1H),5.37(s,1H),6.14(dd,1H,J=1.5Hz,3.4Hz),7.00(d,2H,J=8.3Hz),7.17(d,2H,J=8.3Hz),8.54(dd,1H,J=1.5Hz,4.4Hz),7.29-7.35(m,5H).
实施例2-2
N-[1-[2-[1-[2-[双(吡啶-4-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺四盐酸盐
在含有N-[1-[2-[1-[2-[双(吡啶-4-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(171mg,0.28mmol)的乙酸乙酯(2mL)-乙醇(2mL)溶液中,加入4N盐酸/乙酸乙酯溶液(0.35mL,1.4mmol),在室温搅拌10分钟。在反应液中加入乙酸乙酯(3mL),在水浴中搅拌20分钟,滤得析出的结晶,减压干燥,得到白色固体(136mg,0.18mmol)的标题化合物(收率64%)。
1H-NMR(DMSO-d6)δ:1.08-1.75(m,16H),1.98-2.03(m,2H),2.38(s,3H),2.50-2.55(m,2H),2.79-2.86(m,2H),3.04-3.10(m,2H),3.38-3.51(m,2H),4.04(brs,4H),4.73-4.83(m,1H),5.41(s,1H),6.33(dd,1H,J=1.5Hz,3.4Hz),7.16(d,2H,J=8.3Hz),7.30(d,2H,J=8.3Hz),7.66(s,1H),8.01(d,4H,J=3.0Hz),8.82(brs,4H),9.99(br,1H).
实施例3-1
N-[1-[2-[1-[2-(1-氧代-2-异吲哚满基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
在含有N-[1-[2-[1-(2-氨乙基)环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(226mg,0.52mmol)的1,2-二氯乙烷(3mL)溶液中,加入2-甲酰基安息香酸甲酯(254mg,1.55mmol)、乙酸(89μL,1.55mmol)、三乙酰氧基硼氢化钠(265mg,1.25mmol),在室温搅拌3小时。将反应液用氯仿稀释,依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤。将有机层干燥(无水硫酸钠)、减压浓缩,将得到的残渣用硅胶柱层析(NH Silica Chromatorex DM2035 10g,己烷∶乙酸乙酯=7∶3~1∶1)进行精制,得到无色无定形固体(194mg,0.26mmol)的标题化合物(收率67%)。
1H-NMR(CDCl3)δ:1.30-1.60(m,16H),1.87(d,2H,J=12.2Hz),2.14(t,2H,J=11.2Hz),2.31-2.36(m,2H),3.02(d,2H,J=11.7Hz),3.53-3.58(m,2H),4.36(s,2H),4.73-4.82(m,1H),5.35(brs,1H),6.13(dd,1H,J=1.5Hz,2.9Hz),7.02(d,2H,J=8.3Hz),7.18(d,2H,J=8.3Hz),7.35(d,1H,J=1.0Hz),7.42-7.47(m,2H),7.50-7.54(m,1H),7.83(d,1H,J=7.3Hz).
实施例3-2
N-[1-[2-[1-[2-(1-氧代-2-异吲哚满基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺 盐酸盐
将含有N-[1-[2-[1-[2-(1-氧代-2-异吲哚满基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(167mg,0.30mmol)溶解于乙酸乙酯-乙醇=1∶1(4mL)中,加入4N盐酸/乙酸乙酯溶液(0.25mL,1.00mmol)。在室温搅拌5分钟后,将反应液减压浓缩。将得到的残渣溶解于乙醇(10mL)中,减压浓缩至约0.5mL后,加入2-丙醇(10mL),减压浓缩,得到淡褐色无定形(124mg,0.21mmol的标题化合物(收率70%)。
1H-NMR(DMSO-d6)δ:1.26-1.47(m,10H),1.50-1.55(m,2H),1.69-1.78(m,4H),2.04-2.07(m,2H),3.00-3.20(m,4H),3.47-3.61(m,4H),4.51(s,2H),4.78-4.85(m,1H),5.51(d,1H,J=3.4Hz),6.32(dd,1H,J=2.0Hz,3.4Hz),7.17(d,2H,J=8.3Hz),7.31(d,2H,J=8.3Hz),7.45-7.49(m,1H),7.57-7.61(m,2H),7.63-7.67(m,2H),9.57(br,1H).
实施例4
N-[1-[2-[1-[2-(2,4-二羟基苄氨基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺二盐酸盐
在含有N-[1-[2-[1-(2-氨乙基)环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(100mg,0.23mmol)和2,4-二羟基苯甲醛(79mg,0.57mmol)的1,2-二氯乙烷(3mL)溶液中,加入乙酸(34μL,0.57mmol)和三乙酰氧基硼氢化钠(121mg,0.57mmol),在室温搅拌16小时。在反应液中加入饱和食盐水,用氯仿-乙醇溶液=9∶1进行萃取。将有机层干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。将残渣周硅胶柱层析(NH Silica Chromatorex DM2035 10g,氯仿∶甲醇=50∶1)进行精制,得到无色油状物(49mg,0.09mmol)(收率38%)。将该物质溶解于乙酸乙酯(3mL),加入4N盐酸/乙酸乙酯溶液(0.1mL,0.40mmol)。室温搅拌30分钟、冰浴下搅拌30分钟,滤得析出的结晶,减压干燥,得到无色结晶(43mg,0.07mmol)的标题化合物(收率78%)。
1H-NMR(DMSO-d6)δ:1.16-1.26(m,4H),1.31-1.46(m,6H),1.51-1.77(m,6H),2.02-2.06(m,2H),2.36(s,3H),2.71-2.89(m,2H),2.98-3.16(m,4H),3.53-3.57(m,2H),3.94(brs,2H),4.76-4.80(m,1H),5.49(d,1H,J=2.9Hz),6.25(dd,1H,J=2.4Hz,8.3Hz),6.31-6.33(m,1H),6.41(d,1H,J=2.0Hz),7.15-7.18(m,3H),7.30(d,2H,J=8.3Hz),7.62(d,1H,J=1.0Hz),7.92(br,1H),8.71(br,1H),9.45(s,1H),9.72(br,1H),9.89(s,1H).
IR(KBr)cm-1:3407,2928,2644,1619,1556,1511,1469,1407,1342,1312,1188,1111,757.
实施例5-1
1-[1-[2-(叔丁基二苯基甲硅烷氧基)乙基]环己基]乙醛
在含有2-[1-[2-(叔丁基二苯基甲硅烷氧基)乙基]环己基]乙醇(810mg,1.97mmol)、碘代苯二乙酸(700mg,2.17mmol)的二氯甲烷(10mL)溶液中,加入2,2,6,6-四甲基哌啶1-氧自由基(31mg,0.20mmol),在室温搅拌4小时。将反应液依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤、干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。得到褐色油状物(1.29g)的标题化合物。该物质不精制用于下面的工序。
1H-NMR(CDCl3)δ:1.03(s,9H),1.33-1.45(m,10H),1.77(t,2H,J=6.8Hz),2.34(d,2H,J=2.9Hz),3.76(t,2H,J=7.3Hz),7.31-7.45(m,6H),7.65-7.71(m,4H),9.78(t,1H,J=2.9Hz).
实施例5-2
4-[2-[1-[2-(叔丁基二苯基甲硅烷氧基)乙基]环己基]乙基]吗啉
在含有1-[1-[2-(叔丁基二苯基甲硅烷氧基)乙基]环己基]乙醛(1.29g,ca.1.97mmol)、吗啉(0.26mL,2.98mmol)、乙酸(0.23mL,4.02mmol)的1,2-二氯乙烷(5mL)溶液中,加入三乙酰氧基硼氢化钠(0.63g,2.98mmol),在室温搅拌2.5小时。在反应液中加入饱和碳酸氢钠水溶液,用氯仿进行萃取。将有机层用饱和食盐水洗涤、干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。得到褐色油状物(1.31g)的标题化合物。该物质不精制用于下面的工序。
1H-NMR(CDCl3)δ:1.04(s,9H),1.18-1.37(m,12H),1.59(t,2H,J=7.8Hz),2.15-2.20(m,2H),2.32(brs,4H),3.65-3.73(m,6H),7.31-7.45(m,6H),7.63-7.72(m,4H).
实施例5-3
4-[2-[1-[2-羟乙基]环己基]乙基]吗啉
在含有4-[2-[1-[2-(叔丁基二苯基甲硅烷氧基)乙基]环己基]乙基]吗啉(1.31g,ca.1.97mmol)的甲醇(10mL)溶液中,在室温下加入浓盐酸(0.5mL,6.0mmol),进一步搅拌4.5小时。将反应液减压浓缩,在得到的残渣中加入1N盐酸(10mL),用二乙醚进行萃取。在水层加入5N氢氧化钠水溶液至pH为12,用二乙醚进行萃取。将有机层干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。得到无色油状物(448mg)的标题化合物(收率94%,两步)。
1H-NMR(CDCl3)δ:1.26-1.61(m,14H),2.32(t,2H,J=6.8Hz),2.47(brs,4H),3.40(br,1H),3.66-3.72(m,6H).
实施例5-4
4-[2-[1-(甲酰基甲基)环己基]乙基]吗啉
在含有4-[2-[1-[2-羟乙基]环己基]乙基]吗啉(439mg,1.82mmol)、碘代苯二乙酸(644mg,2.00mmol)的二氯甲烷(10mL)溶液中,加入2,2,6,6-四甲基哌啶1-氧自由基(32mg,0.20mmol),在室温搅拌14小时。将反应液依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤、干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。得到褐色油状物(625mg)的标题化合物。该物质不经精制、用于下面的工序。
1H-NMR(CDCl3)δ:1.31-1.67(m,12H),2.32-2.52(m,6H),3.66-3.72(m,6H),9.80(s,1H).
实施例5-5
4-[2-[1-[2-[4-(对甲苯胺)哌啶-1-基]乙基]环己基]乙基]吗啉
在含有4-[2-[1-(甲酰基甲基)环己基]乙基]吗啉(625mg,ca.1.82mmol)、4-(对甲苯胺)哌啶(519mg,2.73mmol)、乙酸(0.21mL,3.64mmol)的1,2-二氯乙烷(10mL)溶液中,加入三乙酰氧基硼氢化钠(579mg,2.73mmol),搅拌3小时。在反应液中加入饱和碳酸氢钠水溶液,用氯仿进行萃取。将有机层用饱和食盐水洗涤、干燥(无水硫酸钠)后,在减压下蒸馏除去溶剂。将残渣用硅胶柱层析(Merck Art 938530g,氯仿∶甲醇=1∶0~10∶1)进行精制,得到无色油状物(346mg)的标题化合物(收率48%)。
1H-NMR(CDCl3)δ:1.24-1.53(m,16H),2.00-2.46(m,15H),2.89-2.92(m,2H),3.23-3.31(m,1H),3.66-3.74(m,2H),3.73(s,3H),6.52(d,2H,J=8.3Hz),6.97(d,2H,J=7.8Hz).
实施例5-6
N-[1-[2-[1-[2-(吗啉代)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
在含有4-[2-[1-[2-[4-(对甲苯胺)哌啶-1-基]乙基]环己基]乙基]吗啉(319mg,0.77mmol)的二氯甲烷(5mL)溶液中,在冰浴下依次加入三乙胺(0.21mL,1.50mmol)、2-呋喃甲酰氯(0.10mL,1.00mmol),在室温搅拌16小时。将反应液减压浓缩,将得到的残渣用硅胶柱层析(Merck Art 9385 20g,氯仿∶甲醇=20∶1~氯仿∶甲醇∶氨水=10∶1∶0.1)进行精制,得到无色油状物(283mg)的标题化合物(收率72%)。
1H-NMR(CDCl3)δ:1.24-1.57(m,16H),1.84-1.87(m,2H),2.07-2.13(m,2H),2.23-2.30(m,4H),2.39(s,3H),2.39-2.46(m,4H),2.95-2.98(m,2H),3.69-3.72(m,4H),4.73-4.81(m,1H),5.38(d,1H,J=2.4Hz),6.13(dd,1H,J=1.5Hz,3.4Hz),7.01(d,2H,J=8.3Hz),7.18(d,2H,J=8.3Hz),7.34(s,1H).
实施例5-7
N-[1-[2-[1-[2-(吗啉代)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺二盐酸盐
在含有N-[1-[2-[1-[2-(吗啉代)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺(283mg,0.56mmol)的乙酸乙酯(4mL)溶液中,加入4N盐酸/乙酸乙酯溶液(0.5mL,2.0mmol),在室温搅拌10分钟(生成白色沉淀)。在反应液中加入乙醇(0.5mL)(沉淀溶解),减压浓缩,得到白色无定形固体(283mg)的标题化合物(收率87%)。
1H-NMR(DMSO-d6)δ:1.17-1.47(m,10H),1.57-1.77(m,6H),1.99-2.03(m,2H),2.39(s,3H),3.01-3.15(m,8H),3.43-3.46(m,2H),3.59-3.62(m,2H),3,78-3.81(m,2H),3.84-3.96(m,2H),4.75-4.81(m,1H),5.39(s,1H),6.33(dd,1H,J=1.5Hz,3.4Hz),7.16(d,2H,J=7.8Hz),7.30(d,2H,J=8.3Hz),7.66(s,1H),10.22(brs,1H),11.38(brs,1H).
MS(ESI)m/z:508(M+H)+.
实施例6-1
1-(3-环己基-3-羟丙基)-4-(5-甲基吡啶-2-基)氨基哌啶
将4-(5-甲基吡啶-2-基)氨基哌啶(394mg,2mmol)、碳酸氢钠(277mg,3.2mmol)、3-环己基-3-羟丙基-4-溴代苯磺酸酯(932mg,2.4mmol)的1,2-二甲氧基乙烷(10mL)的混合物回流8小时。在反应液中加入NH silica Chromatorex DM1020 5g减压浓缩。将残渣用硅胶柱层析(NH Silica Chromatorex DM2035 60g,己烷∶乙酸乙酯=1∶1)进行精制,得到淡黄色固体的标题化合物405mg(收率59.6%)。
1H-NMR(CDCl3)δ:0.94-1.06(m,2H),1.07-1.34(m,4H),1.40-1.80(m,8H),1.90-2.08(m,4H),2.16(s,3H),2.28-2.40(m,1H),2.54-2.68(m,2H),2.74-2.88(m,1H),3.02-3.15(m,1H),3.46-3.53(m,1H),3.57-3.68(m,1H),4.12-4.22(m,1H),6.29(d,1H,J=8.8Hz),7.22(dd,1H,J=2.0Hz,8.8Hz),7.89(d,1H,J=2.0Hz)
实施例6-2
1-(3-叔丁基二甲基甲硅烷氧基-3-环己基丙基)-4-(5-甲基吡啶-2-基)氨基哌啶
在含有1-(3-环己基-3-羟丙基)-4-(5-甲基吡啶-2-基)氨基哌啶(405mg,1.22mmol)、三乙胺(0.20mL)、4-二甲基氨基吡啶(30mg,0.24mmol)的二氯甲烷(5mL)溶液中,在冰浴下加入叔丁基二甲基甲硅烷基氯化物(203mg,1.5mmol),在室温搅拌18小时。在反应液中加入三乙胺(0.20mL)、4-二甲基氨基吡啶(30mg,1.5mmol)、叔丁基二甲基甲硅烷基氯化物(203mg,1.5mmol),进一步在室温搅拌70小时。在反应液中加入NH silica Chromatorex DM1020,减压浓缩。将残渣用硅胶柱层析(NH Silica Chromatorex DM2035 60g,己烷∶乙酸乙酯=4∶1)进行精制,得到无色油状物的标题化合物423mg(收率77.7%)。
1H-NMR(CDCl3)δ:0.030(s,3H),0.033(s,3H),0.89(s,9H),0.85-1.25(m,5H),1.30-1.40(m,1H),1.39-1.56(m,2H),1.57-1.78(m,7H),2.00-2.08(m,2H),2.08-2.20(m,2H),2.16(s,3H),2.28-2.47(m,2H),2.80-2.88(m,2H),3.44-3.50(m,1H),3.52-3.64(m,1H),4.23(brd,1H,J=8.0Hz),6.30(d,1H,J=8.3Hz),7.23(dd,1H,J=2.0Hz,8.3Hz),7.88(d,1H,J=2.0Hz)
实施例6-3
N-[1-(3-叔丁基二甲基甲硅烷氧基-3-环己基丙基)哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
在含有1-(3-叔丁基二甲基甲硅烷氧基-3-环己基丙基)-4-(5-甲基吡啶-2-基)氨基哌啶(423mg,0.95mmol)、三乙胺(0.264mL)的二氯甲烷(4mL)溶液中,在冰浴下滴入2-呋喃甲酰氯(0.14mL,1.4mmol),在室温搅拌18小时。在反应液中加入NH silica ChromatorexDM1020,减压浓缩。将残渣用硅胶柱层析(NH Silica ChromatorexDM2035 60g,己烷∶乙酸乙酯=4∶1)进行精制,得到油状物的标题化合物458mg(收率89.4%)。
1H-NMR(CDCl3)δ:0.00(s,6H),0.86(s,9H),0.80-1.37(m,6H),1.50-1.66(m,7H),1.67-1.75(m,2H),1.89-1.96(m,2H),2.06-2.15(m,2H),2.22-2.31(m,1H),2.38(s,3H),2.36-2.45(m,1H),2.90-2.96(m,2H),3.37-3.44(m,1H),4.73(tt,1H,J=4.0Hz,12.3Hz),5.93(d,1H,J=3.4Hz),6.18(dd,1H,J=1.5Hz,3.4Hz),6.98(d,1H,J=7.8Hz),7.22(d,1H,J=1.5Hz),7.50(dd,1H,J=2.5Hz,7.8Hz),8.37(d,1H,J=2.5Hz)
实施例6-4
N-[1-(3-环己基-3-羟丙基)哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺盐酸盐
在N-[1-(3-叔丁基二甲基甲硅烷氧基-3-环己基丙基)哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺(423mg,0.95mmol)的THF(5mL)溶液中,加入氟化四丁基铵(1.0M THF溶液,2mL),在室温搅拌18小时。在反应液中追加氟化四丁基铵(1.0M THF溶液,2mL),在50℃搅拌8小时。将反应液减压浓缩,将残渣用硅胶柱层析(MerckArt 9385 100g,氯仿∶甲醇=20∶1)进行精制,得到淡桃色结晶的标题化合物单体264mg(收率73.2%)。将结晶溶解于乙酸乙酯5.0mL中,当加入4N盐酸-乙酸乙酯溶液0.4mL时结晶析出。过滤结晶,得到淡桃色固体目的物164mg(收率41.8%)。
1H-NMR(CDCl3)δ:0.92-1.38(m,6H),1.59-1.78(m,4H),1.80-1.95(m,3H),2.24-2.42(m,4H),2.48(s,3H),2.82-2.94(m,2H),3.09-3.22(m,2H),3.51-3.65(m,2H),3.74-3.81(m,1H),4.95-5.05(m,1H),6.26-6.33(m,2H),7.20-7.23(m,1H),7.27(d,1H,J=7.8Hz),7.84(dd,1H,J=2.0Hz,7.8Hz),8.44(d,1H,J=2.0Hz),11.15(brs,1H)
MS(ESI)m/z:426(M+H)+
实施例7-1
3-羟甲基三环[3.3.1.13,7]癸烷-1-甲酸甲酯
将1,3-金刚烷二甲酸二甲酯(1.00g,3.96mmol)溶解于四氢呋喃(5mL)中,在冰浴下滴入氢化二异丁基铝(0.95M;5.0mL,4.75mmol),进一步在冰浴下搅拌3小时。反应后,在室温滴入水(0.2mL),然后滴入15%NaOH水溶液.(0.2mL),搅拌30分钟。然后加入水(0.6mL)及无水硫酸镁搅拌,滤掉不溶物,在减压下蒸馏除去溶剂,对得到的残渣进行层析(Merck Art 9385 50g,己烷∶乙酸乙酯=3∶2),得到无色油状物(0.1648g,0.735mmol)的标题化合物(收率19%)。
1H-NMR(DMSO-d6)δ:1.39-1.41(m,4H),1.54(s,2H),1.55-1.65(m,2H),1.66-1.80(m,4H),2.00-2.07(m,2H),3.02(d,2H,J=5.9Hz),3.57(s,3H),4.29(t,1H,J=5.9Hz).
实施例7-2
3-[4-(5-甲基吡啶-2-基)氨基哌啶-1-基甲基]三环[3.3.1.13,7]癸烷-1-甲酸甲酯
将3-羟甲基三环[3.3.1.13,7]癸烷-1-甲酸甲酯(0.1648g,0.735mmol)及吡啶(0.0829g,1.05mmol)溶解于二氨甲烷(5mL)中,在冰浴下滴入三氟甲磺酸酐(0.185mL,1.11mmol),搅拌1小时。在反应液中加入水(10mL),用乙酸乙酯(20mL)萃取,依次用1NHCl(10mL)、饱和NaHCO3水溶液.(10mL)、盐水(10mL)洗涤,用无水硫酸镁干燥后,混合4-(5-甲基吡啶-2-基)氨基哌啶(0.2995g,1.57mmol),在减压下蒸馏除去溶剂。将得到的黄色油状物在60℃加热1小时。对其进行层析(Merck Art 9385 50g,二氯甲烷∶甲醇∶氨水=97∶3∶0.2),得到白色固体(0.2398g,0.603mmol)的标题化合物(收率82%)。
1H-NMR(DMSO-d6)δ:1.35-1.48(m,6H),1.51-1.63(m,4H),1.68-1.83(m,6H),1.98(s,2H),1.89-2.06(m,2H),2.07(s,3H),2.22-2.31(m,2H),2.63-2.71(m,2H),3.51-3.61(m,1H),3.58(s,3H),5.90(d,1H,J=7.8Hz),6.35(d,1H,J=8.3Hz),7.14(dd,1H,J=2.0Hz,8.3Hz),7.75(d,1H,J=2.0Hz).
实施例7-3
N-[1-(3-甲氧羰基-1-三环[3.3.1.13,7]癸基)甲基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺盐酸盐
将3-[4-(5-甲基吡啶-2-基)氨基哌啶-1-基甲基]三环[3.3.1.13,7]癸基-1-甲酸甲酯(0.2248g,0.565mmol)溶解于二氯甲烷(5mL)中,在室温加入三乙胺(0.12g,1.21mmol)。然后在冰浴下滴入2-呋喃甲酰氯(0.071mL,0.724mmol)后,在室温搅拌16小时。将反应液不进行前处理进行层析(Merck Art 9385 100g,二氯甲烷∶甲醇∶氨水=98∶2∶0.1~97∶3∶0.2),得到无色油状物(0.2675g,0.544mmol)的标题化合物单体(收率96%)。进而进行盐酸盐化,得到白色固体(0.2951g,0.522mmol)的标题化合物(收率96%)。
1H-NMR(DMSO-d6)δ:1.55-1.66(m,6H),1.67-1.80(m,6H),1.90-2.10(m,6H),2.37(s,3H),2,83-2.90(m,2H),3.21-3.41(m,2H),3.45-3.52(m,2H),3.59(s,3H),4.69-4.80(m,1H),5.87-5.94(m,1H),6.34-6.36(m,1H),7.24-7.28(m,1H),7.55-7.56(m,1H),7.73-7.77(m,1H),8.39-8.41(m,1H)
IR(KBr)cm-1:2919,1725,1644,1627,1239,754
MS(ESI)m/z:492(M+H)+.
实施例8
[1-[2-[4-[N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺]哌啶-1-基]乙基]环己基]乙酸二乙基膦酰基甲亚胺酸酐
将[1-[2-[4-[N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺]哌啶-1-基]乙基]环己基]乙酸(0.2004g,0.442mmol)的N,N-二甲基甲酰胺(4mL)溶液中,加入二乙基偶磷氰酸盐(0.2170g,1.33mmol)、三乙胺(0.1628g,1.61mmol)、2-氨基-2-羟甲基-1,3-丙二醇(0.0877g,0.724mmol),在室温搅拌5天。在反应液中加入乙酸乙酯(50mL)后,水洗(20mL×2),用无水硫酸镁干燥后,在减压下蒸馏除去溶剂,对得到的残渣进行层析(Merck Art.9385 50g,二氯甲烷∶甲醇∶氨水=95∶5∶0.3),得到无色油状物(0.1543g,0.250mmol)的标题化合物单体(收率57%)。进一步进行盐酸盐化,得到白色固体(0.1630g,0.224mmol)的标题化合物(收率90%)。
1H-NMR(DSMO-d6)δ:1.20-1.38(m,11H),1.45-1.59(m,3H),1.78-1.98(m,6H),1.99-2.08(m,2H),2.37(s,3H),2.90-3.00(m,2H),3.03-3.16(m,2H),3.42-3.51(m,2H),4.15-4.27(m,4H),4.69-4.80(m,1H),5.90(d,1H,J=3.4Hz),5.99(s,1H),6.35(dd,1H,J=2.0Hz,3.4Hz),7.23(d,1H,J=7.8Hz),7.55(d,1H,J=2.0Hz),7.73(dd,1H,J=2.5Hz,7.8Hz),8.39(d,1H,J=2.4Hz),9.69-9.82(br,1H);IR(KBr)cm-1:3444,2995,2936,2503,1650,1620,1556,1472,1327,1294,1273,1029,993,977,771MS(ESI)m/z:599(M+H)+.
实施例9-1
4-(均三甲苯基氨基)哌啶-1-甲酸叔丁酯
在含有4-氧代哌啶-1-甲酸叔丁酯(5.00g,25.1mmol)、2,4,6-三甲基苯胺(3.56g,26.3mmol)、乙酸(2.9mL,50.2mmol)的二氯甲烷(50mL)溶液中,加入三乙酰氧基硼氢化钠(7.98g,37.6mmol),在室温搅拌3.5小时。在反应液中加入饱和碳酸氢钠水溶液(150mL)后,搅拌至发泡平息。将有机层分离,将水层用氯仿(100ml)萃取。将有机层合并,用饱和食盐水(100mL)洗涤、干燥(Na2SO4)后,在减压下蒸馏除去溶剂,将残渣用硅胶柱层析(Merck Art 9385 50g,己烷∶乙酸乙酯=9∶1)进行精制,得到褐色油状物(5.71g)的标题化合物(收率71%)。
1H-NMR(CDCl3)δ:1.24-1.42(m,2H),1.46(s,9H),1.87-1.91(m,2H),2.16(s,6H),2.21(s,3H),2.68-2.73(m,2H),2.96-3.02(m,1H),4.08(br,2H),6.81(s,2H).
实施例9-2
4-(均三甲苯基氨基)哌啶
在4-(均三甲苯基氨基)哌啶-1-甲酸叔丁酯(5.71g,17.9mmol)的二氯甲烷(30mL)溶液中,加入三氟乙酸(10mL),在室温搅拌22小时后进行减压浓缩。将残渣溶解于甲醇(10mL),加入甲苯(20mL)再进行减压浓缩。将残渣用硅胶柱层析(NH Silica Chromatorex DM2035 75g,己烷∶乙酸乙酯=4∶1~1∶1~氯仿∶甲醇=10∶1)进行精制,得到褐色固体(3.57g)的标题化合物(收率65%,两步)。
1H-NMR(CDCl3)δ:1.74-1.85(m,2H),2.11-2.18(m,2H),2.23(s,3H),2.24(s,6H),2.86(br,2H),3.09-3.19(m,1H),3.41-3.49(m,2H),6.83(s,2H).
实施例9-3
[1-[2-[4-(均三甲苯基氨基)哌啶-1-基]乙基]环己基]乙酸甲酯
将含有4-(均三甲苯基氨基)哌啶(250mg,1.15mmol)、[1-(2-溴乙基)环己基]乙酸甲酯(371mg,1.38mmol)、碳酸钾(318mg,2.3mmol)的N,N-二甲基甲酰胺(3mL)的悬浊液在80℃搅拌10小时。在反应液中加入氯仿(10mL),过滤不溶物后,将滤液进行减压浓缩。将残渣溶解于二甲苯(10mL)中,进行减压浓缩。将残渣用硅胶柱层析(Merck Art9385 10g,己烷∶乙酸乙酯=7∶3~氯仿∶甲醇=10∶1)进行精制,得到褐色油状物(243mg)的标题化合物(收率53%)。
1H-NMR(CDCl3)δ:1.37-1.47(m,12H),1.58-1.62(m,2H),1.89-1.97(m,4H),2.23(s,6H),2.23(s,3H),2.29(s,2H),2.32-2.35(m,2H),2.88-2.96(m,3H),3.63(s,3H),6.80(s,2H).
实施例9-4
[1-[2-[4-(N-均三甲苯基-2-呋喃甲酰胺)哌啶-1-基]乙基]环己基]乙酸甲酯
在含有[1-[2-[4-(均三甲苯基氨基)哌啶-1-基]乙基]环己基]乙酸甲酯(225mg,0.56mmol)、三乙胺(0.23mL,1.68mmol)的二氯甲烷(1mL)溶液中,在冰浴下滴入2-呋喃甲酰氯(0.11mL,1.12mmol)后,在室温搅拌4小时。将反应液用氯仿(2mL)稀释,依次用饱和碳酸氢钠水溶液(2mL)、10%柠檬酸水溶液(2mL),饱和食盐水(2mL)洗涤、干燥(Na2SO4)后,在减压下蒸馏除去溶剂。将残渣用硅胶柱层析(NHSilica Chromatorex DM2035 15g,己烷∶乙酸乙酯=4∶1)进行精制,得到白色固体(187mg)的标题化合物(收率68%)。
1H-NMR(CDCl3)δ:1.32-1.58(m,14H),1.99-2.11(m,4H),2.13(s,6H),2.28(s,2H),2.32(s,3H),2.30-2.35(m,2H),2.94-2.98(m,2H),3.62(s,3H),4.26-4.34(m,1H),5.23(d,1H,J=3.9Hz),6.13(dd,1H,J=2.0Hz,3.9Hz),6.91(s,2H),7.52(s,1H).
实施例9-5
[1-[2-[4-(N-均三甲苯基-2-呋喃甲酰胺)哌啶-1-基]乙基]环己基]乙酸 盐酸盐
在[1-[2-[4-(N-均三甲苯基-2-呋喃甲酰胺)哌啶-1-基]乙基]环己基]乙酸甲酯(159mg,0.32mmol)的甲醇(10mL)溶液中,加入2N氢氧化钠水溶液(1.6mL,3.2mmol)后,在室温搅拌13小时。在反应液中加入2N氢氧化钠水溶液(1.0mL,2.0mmol),在室温搅拌24小时、在40℃搅拌2小时。在反应液中加入乙酸(0.35mL)后进行减压浓缩,将得到的残渣用氯仿∶乙醇(100∶20v/v,10mL×3)萃取,将有机层干燥(Na2SO4)、进行减压浓缩,得到白色固体的标题化合物单体(229mg)。
进一步进行盐酸盐化,得到标题化合物(148mg)(收率90%,两步)。
1H-NMR(DMSO-d6)δ:1.23-1.42(m,10H),1.75-1.82(m,2H),1.87-2.04(m,4H),2.12(s,6H),2.17(s,2H),2.29(s,3H),2.98-3.08(m,4H),3.46-3.49(m,2H),4.30-4.37(m,1H),5.34(brs,1H),6.31-6.32(m,1H),7.02(s,2H),7.68(s,1H),10.25(br,1H)
IR(KBr)cm-1:3444,2931,2854,2638,2537,1733,1713,1633,1557,1469,1392,1351,1313,1238,1187,1037,751
MS(ESI)m/z:481(M+H)+.
实施例10-1
2-[1-(2-羟乙基)环己基]乙醇
将氢化铝锂(11.4g,0.300mmol)混悬于四氢呋喃(300mL)中,在室温下滴入1,1-环己二乙酸(30.0g,0.150mmol)的四氢呋喃溶液(200mL)。滴入完成后,在冰浴下搅拌5分钟,在冰浴下用5分钟滴入水(11.5mL)。搅拌10分钟后,用5分钟滴入15%氢氧化钠水溶液(11.5mL)。加入二乙醚(500mL,特级)搅拌5分钟后,加入水(34.5mL)。在冰浴下搅拌2小时后,加入钙铁石,过滤。将滤液减压浓缩,与甲苯共沸,得到无色油状物(21.7g)的标题化合物。
1H-NMR(CDCl3)δ:1.23-1.50(m,10H),1.64(t,4H,J=7.2Hz),1.96-2.17(m,2H),3.72(t,4H,J=7.2Hz).
实施例10-2
2-[1-(2-叔丁基二苯基甲硅烷氧基乙基)环己基]乙醇
在2-[1-(2-羟乙基)环己基]乙醇(21.7g,0.126mol)的二氯甲烷(280mL)溶液中,在冰浴下滴入叔丁基氯代二苯基硅烷(34.4mL,0.132mol)。在室温搅拌14小时后,加入25%氯化铵水溶液(300mL),进行萃取。将有机层用饱和氯化钠水溶液洗涤后,将有机层用无水硫酸镁干燥、过滤后,进行减压浓缩。将残渣用硅胶柱层析(Merck Art9385 500g,己烷∶乙酸乙酯=4∶1)进行精制,得到无色油状物(36.8g)的标题化合物(两步 收率60%)。
1H-NMR(CDCl3)δ:1.05(s,9H),1.19-1.43(m,10H),1.48-1.55(m,3H),1.61(t,2H,J=7.6Hz),3.56(t,2H,J=7.6Hz),3.70(t,2H,J=7.6Hz),7.35-7.47(m,6H),7.64-7.73(m,4H).
实施例10-3
甲磺酸2-[1-(2-叔丁基二苯基甲硅烷氧基乙基)环己基]乙酯
在2-[1-[2-叔丁基二苯基甲硅烷氧基乙基]环己基]乙醇(3.24g,7.80mmol)的二氯甲烷(25mL)溶液中,加入三乙胺(2.20mL,15.8mmol),在冰浴下滴入甲磺酰氯(0.91mL,11.7mmol)。在室温搅拌40分钟后,加入饱和碳酸氢钠水溶液(300mL),用氯仿进行萃取后,将有机层用饱和氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤、减压浓缩,得到黄色油状物(3.97g)的标题化合物。
1H-NMR(CDCl3)δ:1.04(s,9H),1.58-1.61(m,2H),1.73(t,2H,J=7.3Hz),2.92(s,3H),3.69(t,2H,J=7.3Hz),4.20(t,2H,J=7.8Hz),7.37-7.46(m,6H),7.66-7.68(m,4H).
实施例10-4
叔丁基-2-(1-乙基环己基)乙氧基二苯基硅烷
将氢化铝锂(0.30g,7.80mmol)混悬于四氢呋喃(15mL)中,在室温下用10分钟滴入甲磺酸2-[1-[2-叔丁基二苯基甲硅烷氧基乙基]环己基]乙酯(3.97g,7.80mmol)的四氢呋喃(10mL)溶液。进一步搅拌10分钟后,进行45分钟加热回流。在冰浴下依次滴入水(0.30mL)、15%氢氧化钠水溶液(0.30mL)、水(0.90mL),加入二乙醚(25mL)搅拌16小时后,加入钙铁石,进一步搅拌1小时进行过滤。将滤液减压浓缩,得到无色油状物(3.02g)的标题化合物。
1H-NMR(CDCl3)δ:0.67(t,3H,J=7.3Hz),1.07(s,9H),1.20-1.46(m,14H),1.58-1.73(m,2H),3.69(t,2H,J=7.3Hz),7.34-7.44(m,6H),7.65-7.69(m,4H).
实施例10-5
2-(1-乙基环己基)乙醇
在叔丁基-2-(1-乙基环己基)乙氧基二苯基硅烷(3.02g,7.65mmol)的四氢呋喃(20mL)溶液中,在室温下加入氟化四丁基铵1.0M四氢呋喃溶液(7.70mL,7.70mmol),搅拌2小时。进一步加入氟化四丁基铵1.0M四氢呋喃溶液(7.70mL,7.70mmol),搅拌14小时。在反应液中加入1N盐酸(20mL),用乙酸乙酯进行萃取。将有机层用饱和氯化钠水溶液洗涤后,将有机层用无水硫酸镁干燥。将过滤后减压浓缩得到的残渣用硅胶柱层析(Merck Art 9385 100g,己烷∶乙酸乙酯=6∶1)进行精制,得到无色油状物(708mg)的标题化合物(3步 收率57%)。
1H-NMR(CDCl3)δ:0.80(t,3H,J=7.8Hz),1.22-1.32(m,6H),1.36-1.45(m,6H),1.54-1.60(m,2H),1.60-1.65(m,1H),3.65(t,2H,J=7.8Hz).
实施例10-6
(1-乙基环己基)乙醛
在2-(1-乙基环己基)乙醇(708mg,4.53mmol)的二氯甲烷(15mL)溶液中,在室温下加入碘代苯二乙酸(1.61g,4.98mmol)后,加入2,2,6,6-四甲基哌啶1-氧自由基(70.8mg,0.450mmol),搅拌15小时。在反应液中加入二乙醚,依次用10%硫代硫酸钠水溶液、1N盐酸、饱和碳酸氢钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤后,进行减压浓缩,得到橙色油状物(1.54g)的标题化合物。
1H-NMR(CDCl3)δ:0.86(t,3H,J=7.8Hz),1.39-1.50(m,12H),2.32(d,2H,J=2.9Hz),9.84(t,1H,J=3.4Hz).
实施例10-7
1-[2-(1-乙基环己基)乙基]-4-(5-甲基吡啶-2-基)氨基哌啶
在4-(5-甲基吡啶-2-基)氨基哌啶二氢溴酸盐(1.60g,4.53mmol)的1,2-二氯乙烷(7mL)溶液中加入三乙胺(1.30mL,9.06mmol)后,搅拌30分钟后,加入(1-乙基环己基)乙醛(1.54g,4.53mmol)的1,2-二氯乙烷(8mL)溶液,搅拌15分钟。在冰浴下加入三乙酰氧基硼氢化钠(0.96g,4.53mmol)搅拌5分钟后,在室温搅拌1小时。在反应液中加入25%氯化铵水溶液、氯仿及3N氢氧化钠水溶液,用氯仿萃取,将有机层用饱和氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤后,进行减压浓缩。将得到的残渣用硅胶柱层析(Merck Art.9385100g,氯仿∶甲醇=95∶5)进行精制,得到褐色油状物(1.37g,4.16mmol)的标题化合物(两步收率92%)。
1H-NMR(CDCl3)δ:0.77(t,3H,J=7.8Hz),1.21-1.30(m,5H),1.35-1.48(m,8H),1.48-1.60(m,2H),2.06(d,2H,J=13.6Hz),2.13-2.19(m,2H),2.16(s,3H),2.26-2.30(m,2H),2.90(d,2H,J=10.8Hz),3.55-3.63(m,1H),4.24(d,1H,J=8.3Hz),6.30(d,1H,J=8.3Hz),7.23(dd,2H,J=2.4Hz,8.3Hz),7.89(s,1H).
MS(ESI)m/z:330(M+H)+.
实施例10-8
N-[1-[2-(1-乙基环己基)乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
在1-[2-(1-乙基环己基)乙基]-4-(5-甲基吡啶-2-基)氨基哌啶(1.31g,3.98mmol)的二氯甲烷(13mL)溶液中,加入三乙胺(1.33mL,9.55mmol)。在冰浴下加入2-呋喃甲酰氯(0.47mL,4.78mmol),搅拌2小时。在反应液中加入25%氯化铵水溶液,用氯仿萃取,将有机层用饱和氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤后,进行减压浓缩。将得到的残渣用硅胶柱层析(NH Silica ChromatorexDM2035 80g,己烷∶乙酸乙酯=2∶1)进行精制,得到淡黄色固体(1.52g,3.59mmol)的标题化合物(收率90%)。
1H-NMR(CDCl3)δ:0.74(t,3H,J=7.8Hz),1.18-1.33(m,6H),1.36-1.40(m,8H),1.56-1.66(m,2H),1.95(d,2H,J=12.2Hz),2.08(t,2H,J=12.2Hz),2.20-2.24(m,2H),2.40(s,3H),2.99(d,2H,J=11.7Hz),4.74(tt,1H,J=4.3Hz,12.2Hz),5.92(d,1H,J=7.8Hz),6.19(d,1H,J=1.9Hz,3.4Hz),6.99(d,1H,J=7.8Hz),7.22(d,1H,J=1.5Hz),7.50(dd,1H,J=2.4Hz,8.3Hz),8.38(d,1H,J=1.5Hz).
MS(ESI)m/z:424(M+H)+.
实施例11-1
N-[1-[2-[1-(4-甲氧基-3-甲氧基甲基丁基)环己基]乙基)哌啶-4-基)-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
在N-[1-[2-[1-(4-羟基-3-羟基甲基丁基)环己基]乙基)哌啶-4-基)-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺(1.00g,2.01mmol)的N,N-二甲基甲酰胺(3mL)溶液中,在冰浴下加入氢化钠(60%分散于矿物油中)(179mg,4.47mmol)搅拌40分钟。然后加入碘化甲烷(0.15mL,2.41mmol),搅拌1小时后,加入饱和碳酸氢钠水溶液(10mL)。用乙酸乙酯萃取,用饱和氯化钠水溶液(10mL)洗涤后,用无水硫酸镁干燥。将过滤后减压浓缩得到的残渣用硅胶柱层析(NH Silica ChromatorexDM2035 150g,己烷∶乙酸乙酯=1∶1~氯仿∶甲醇=8∶2)进行精制,得到标题化合物(100mg)和N-[1-[2-[1-(4-甲氧基-3-羟基甲基丁基)环己基]乙基)哌啶-4-基)-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺的呋喃羧酸酯(91mg)。
N-[1-[2-[1-(4-甲氧基-3-甲氧基甲基丁基)环己基]乙基)哌啶-4-基)-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
1H-NMR(CDCl3)δ:1.18-1.30(m,8H),1.30-1.45(m,8H),1.57-1.66(m,2H),1.66-1.75(m,1H),1.94(d,2H,J=11.2Hz),2.06(t,2H,J=11.7Hz),2.22-2.25(m,2H),2.38(s,3H),2.97(d,2H,J=11.7Hz),3.29-3.37(m,10H),4.73(tt,1H,J=3.9Hz,8.3Hz),5.93(d,1H,J=3.4Hz),6.19(dd,1H,J=1.0Hz,3.4Hz),7.00(d,1H,J=7.8Hz),7.22(d,1H,J=1.5Hz),7.51(dd,1H,J=2.5Hz,7.8Hz),8.37(d,1H,J=2.5Hz).
N-[1-[2-[1-(4-甲氧基-3-羟基甲基丁基)环己基]乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺的呋喃羧酸酯
1H-NMR(CDCl3)δ:1.20-1.45(m,16H),1.54-1.62(m,2H),1.89-2.04(m,4H),1.89-1.97(m,1H),2.13-2.22(m,2H),2.38(s,3H),2.94(d,2H,J=11.7Hz),3.33(s,3H),3.39(d,2H,J=6.4Hz),4.27(dd,1H,J=5.4Hz,10.7Hz),4.34(dd,1H,J=5.4Hz,10.7Hz),4.71(t,1H,J=8.3Hz),5.90(d,1H,J=3.4Hz),6.19(dd,1H,J=2.0Hz,3.4Hz),6.55(dd,1H,J=1.9Hz,3.4Hz),6.90(d,1H,J=7.8Hz),7.16(dd,1H,J=1.0Hz,3.4Hz),7.23(d,1H,J=1.0Hz),7.51(dd,1H,J=2.5Hz,7.8Hz),8.37(d,1H,J=2.5Hz).
实施例11-2
N-[1-[2-[1-(4-甲氧基-3-羟基甲基丁基)环己基]乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
在N-[1-[2-[1-(4-甲氧基-3-羟基甲基丁基)环己基]乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺的呋喃羧酸酯(60mg,0.10mmol)的甲醇(1.5mL)溶液中,加入3N氢氧化钾水溶液(0.5mL,1.50mmol),搅拌2小时。反应完成后加入水,用乙酸乙酯萃取,将有机层用饱和氯化钠水溶液洗涤,将有机层用无水硫酸镁干燥。将过滤后减压浓缩得到的残渣用硅胶柱层析(NH Silica Chromatorex DM203530g,乙酸乙酯)进行精制,得到无色无定形固体(58mg,0.10mmol)的标题化合物(定量收率)。
1H-NMR(CDCl3)δ:1.10-1.26(m,8H),1.28-1.38(m,8H),1.57-1.66(m,2H),1.63-1.88(m,2H),1.94(d,2H,J=11.7Hz),2.05-2.12(m,2H),2.16-2.22(m,2H),2.38(s,3H),2.97(m,2H),3.34(s,3H),3.35-3.38(m,1H),3.51(dd,1H,J=3.9Hz,8.8Hz),3.59(dd,1H,J=6.8Hz,10.7Hz),3.67(dd,1H,J=3.9Hz,10.7Hz),4.73(t,1H,J=12.2Hz),5.93(d,1H,J=3.4Hz),6.19(dd,1H,J=1.5Hz,3.4Hz),6.99(d,1H,J=8.3Hz),7.22(d,1H,J=1.5Hz),7.50(dd,1H,J=1.5Hz,7.8Hz),8.37(d,1H,J=2.0Hz).
工业实用性
根据本发明得到的新型4-(2-呋喃甲酰基)氨基哌啶衍生物,其对人及动物双方的过敏性反应,例如相对跳蚤咬伤等昆虫类咬伤的反应、相对室尘的螨或花粉等环境变应原的反应,由细菌及真菌引起的皮肤感染、外部寄生虫感染或肾透析患者引起的刺痒或搔痒有预防或治疗作用。
Claims (4)
1、下列化合物或其可药用盐:
N-[1-[2-[1-[2-[双(吡啶-3-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-[双(吡啶-4-基甲基)氨基]乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-(1-氧代-2-异吲哚满基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-(2,4-二羟基苄氨基)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-[2-[1-[2-(吗啉代)乙基]环己基]乙基]哌啶-4-基]-N-(对甲苯基)-2-呋喃甲酰胺
N-[1-(3-环己基-3-羟丙基)哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
N-[1-[(3-甲氧羰基-1-三环[3.3.1.13,7]癸基)甲基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
[1-[2-[4-[N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺]哌啶-1-基]乙基]环己基]乙酸二乙基膦酰基甲亚胺酸酐
[1-[2-[4-[N-均三甲苯基-2-呋喃甲酰胺]哌啶-1-基]乙基]环己基]乙酸
N-[1-[2-(1-乙基环己基)乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
N-[1-[2-[1-(4-甲氧基-3-甲氧基甲基丁基)环己基]乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺
N-[1-[2-[1-(4-甲氧基-3-羟甲基丁基)环己基]乙基]哌啶-4-基]-N-(5-甲基吡啶-2-基)-2-呋喃甲酰胺。
2、一种药品,其以如权利要求1记载的化合物或其可药用盐为有效成分,根据需要配合制剂上容许的药品添加物而形成。
3、如权利要求2记载的药品,其是一种治疗搔瘁症的药品。
4、如权利要求3记载的药品,其中,搔瘁是指相对昆虫叮咬的反应、相对环境变应原的反应、由细菌及霉菌引起的皮肤感染、外部寄生虫感染或肾透析患者引起的搔痒。
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JO2642B1 (en) | 2006-12-08 | 2012-06-17 | جانسين فارماسوتيكا ان. في | Dopamine 2 receptor antagonists are rapidly hydrolyzed |
US7842616B2 (en) * | 2007-01-22 | 2010-11-30 | Advanced Technology Development Facility, Inc. | Methods for fabricating semiconductor structures |
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