CN1307563A - N-苯基-n′-苯丙基哌嗪衍生物及其制备方法 - Google Patents
N-苯基-n′-苯丙基哌嗪衍生物及其制备方法 Download PDFInfo
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- CN1307563A CN1307563A CN99808050A CN99808050A CN1307563A CN 1307563 A CN1307563 A CN 1307563A CN 99808050 A CN99808050 A CN 99808050A CN 99808050 A CN99808050 A CN 99808050A CN 1307563 A CN1307563 A CN 1307563A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及由式(1)表示的N-苯基-N’-苯丙基哌嗪衍生物,其中R1代表低级烷基;R2代表低级烷氧基;R3代表氰基、羧基或吲哚羰基;药物;和制备该衍生物的方法。本发明化合物具有有效的α1-肾上腺素受体阻滞活性,因此可用于高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛和由良性前列腺增生引起的尿路梗阻和尿频的预防或治疗。
Description
技术领域
本发明涉及苯基哌嗪衍生物及其制备方法,该衍生物具有极好的α1-肾上腺素受体阻滞活性,可用作药物。
背景技术
α1-肾上腺素受体可导致血管扩张或减少血管阻力,其阻滞剂已知可作为高血压(特发性高血压或肾性高血压)、充血性心脏衰竭、心肌缺血、心律不齐和心绞痛等疾病预防和治疗药物。许多种化合物已被报道可用作这样的阻滞剂。此外,α1-肾上腺素受体已被发现在很大程度上参与膀胱颈的收缩作用(《泌尿科学杂志》134,396(1985)),因此,该受体阻滞剂作为一种能够选择性治疗由良性前列腺增生(BPH)引起的尿路梗阻、尿频和其他症状的药物,已使人们对其产生兴趣。例如,盐酸哌唑嗪和乌拉地尔(英国专利1156973、德国专利1942405、WO 89/12634、WO 90/03972)已被用作治疗高血压或由BPH引起的尿路梗阻的药物,盐酸坦洛新也已被用作治疗由BPH引起的尿路梗阻的药物(日本专利申请未审公开110665/1981)。
不过,常规的α1-肾上腺素受体阻滞剂没有必然地表现出对上述症状的充分的预防和治疗效果,已知还可能导致副作用,例如起立性低血压和意识丧失。为了克服这些缺点,仍然需要研制新的药物。
发明的公开
本发明人发现,特定的N-苯基-N’-苯丙基哌嗪衍生物表现出极好的α1-肾上腺素受体阻滞活性,因此可用作药物。在该发现的基础上完成了本发明。
相应地,本发明提供了由式(1)代表的N-苯基-N’-苯丙基哌嗪衍生物:
(其中R1代表低级烷基;R2代表低级烷氧基;R3代表氰基、羧基或吲哚羰基)或其盐,以及制备该衍生物或其盐的方法。
本发明还提供了药物,包含由式(1)代表的N-苯基-N’-苯丙基哌嗪衍生物或其盐作为活性组分。
本发明还提供了α1-肾上腺素受体阻滞剂,该阻滞剂包含由式(1)代表的N-苯基-N’-苯丙基哌嗪衍生物或其盐作为活性组分。
本发明进一步提供了药物组合物,含有由式(1)代表的N-苯基-N’-苯丙基哌嗪衍生物或其盐作为活性组分,和药学上可接受的载体。
本发明进一步提供了由式(1)代表的N-苯基-N’-苯丙基哌嗪衍生物或其盐作为药物的用途。
本发明进一步提供了用于治疗高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛或由BPH引起的尿路梗阻和尿频的方法,其特征在于将由式(1)代表的N-苯基-N’-苯丙基哌嗪衍生物或其盐给药。
由本发明人提交的WO 95/26955和WO 99/03831描述了吲哚丁酸酯衍生物具有α1-肾上腺素受体阻滞活性,但是没有描述式(1)化合物的活性。
实施发明的最佳方式
在本发明中,术语“低级”指直链、支链或环状含碳基团中的碳原子数为1至6。
相应地,术语“低级烷基”指C1-C6直链、支链或环状烷基。这种烷基的特例包括甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、仲丁基、叔丁基、环丁基、戊基、1-甲基丁基、2-甲基丁基、异戊基、叔戊基、1,2-二甲基丙基、新戊基、1-乙基丙基、环戊基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、异己基、1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-甲基-1-乙基丙基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,2,2-三甲基丙基和环己基。其中,C1-C4直链或支链烷基是优选的,甲基是最优选的。
术语“低级烷氧基”指C1-C6直链、支链或环状烷氧基。这种烷氧基的特例包括甲氧基、乙氧基、丙氧基、环丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、环丁氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、异戊氧基、叔戊氧基、1,2-二甲基丙氧基、新戊氧基、1-乙基丙氧基、环戊氧基、己氧基、1-甲基戊氧基、2-甲基戊氧基、3-甲基戊氧基、异己氧基、1-乙基丁氧基、2-乙基丁氧基、1,1-二甲基丁氧基、1,2-二甲基丁氧基、1,3-二甲基丁氧基、2,2-二甲基丁氧基、2,3-二甲基丁氧基、3,3-二甲基丁氧基、1-甲基-1-乙基丙氧基、1-乙基-2-甲基丙氧基、1,1,2-三甲基丙氧基、1,2,2-三甲基丙氧基和环己氧基。其中,C1-C4直链或支链烷氧基是优选的,甲氧基是最优选的。
在本发明中,术语“吲哚羰基”指在一端与吲哚键合的羰基。这种吲哚羰基的特例包括(吲哚-1-基)羰基、(吲哚-2-基)羰基、(吲哚-3-基)羰基、(吲哚-4-基)羰基、(吲哚-5-基)羰基、(吲哚-6-基)羰基和(吲哚-7-基)羰基。其中,(吲哚-3-基)羰基是最优选的。
在式(1)中,R1优选为甲基,R2优选为甲氧基,R3优选为氰基、羧基或(吲哚-3-基)羰基,最优选为氰基或羧基。
本发明化合物(1)与酸或碱形成盐。与酸形成的盐的例子包括与无机酸形成的盐,酸例如氢氯酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸;与有机酸形成的盐,酸例如甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸和乙磺酸;与酸性氨基酸形成的盐,酸例如天冬氨酸和谷氨酸。与碱形成的盐的例子包括与无机碱形成的盐,例如钠盐、钾盐、镁盐、钙盐、铝盐和锌盐;铵盐。
本发明涵盖化合物(1)的各种溶剂化物或多晶形,进一步涵盖化合物(1)的外消旋变体和R-与S-立体异构体以及旋光活性物。
(其中R1和R2与上述相同。)
可按已知方法制备的4’-低级烷基-3-氯苯基乙基酮(2)利用诸如硼氢化钠等硼氢化物进行还原,从而得到3-氯-1-(4-烷基苯基)-1-丙醇(3)。反应可以在诸如甲醇或乙醇等醇溶剂中、在冷却条件、室温、温暖条件或加热下进行。所得3-氯-1-(4-烷基苯基)-1-丙醇(3)可以通过旋光拆分的方法分离为包括各种旋光异构体和R-与S-异构体在内的异构体,该方法用到一种旋光拆分剂,例如旋光活性的扁桃酸、酒石酸、二苯甲酰酒石酸或二(对甲苯甲酰)酒石酸。
若向化合物(2)中加入(R)-5,5-二苯基-2-甲基-3,4-亚丙基(propano)-1,3,2-氧杂氮杂硼杂环戊烷(oxazaborolidine)和硼烷-二乙基苯胺配合物以进行二者之间的反应,则可以生成3-氯-1-(4-烷基苯基)-1-丙醇(3)的S-异构体。同样,向化合物(2)中加入(S)-5,5-联苯-2-甲基-3,4-亚丙基-1,3,2-氧杂氮杂硼杂环戊烷和硼烷-二乙基苯胺配合物,并使化合物进行反应,从而得到3-氯-1-(4-烷基苯基)-1-丙醇(3)的R-异构体。在每个下列反应中利用R-异构体和S-异构体,可以生成本发明化合物(1)的R-异构体和S-异构体。在上述还原作用中,可以加入硼氢化钠、硫酸二甲酯和N,N-二乙基苯胺,以代替硼烷-二乙基苯胺配合物。
若向化合物(3)中加入1-(2-低级烷氧基苯基)哌嗪衍生物(4)、碘化钾和一种碱、并使混合物进行反应,则可以生成N-(3-羟基-3-苯基丙基)哌嗪衍生物(5)。碱的例子包括金属碳酸盐类,例如碳酸钾和碳酸钠;三烷基胺类,例如三乙胺和二异丙基乙胺;吡啶类,例如吡啶、二甲基吡啶和4-二甲氨基吡啶。反应通常在不影响反应的溶剂中进行,例如N,N-二甲基甲酰胺、二甲基亚砜、丙酮或二氯甲烷。反应可以在室温、温暖条件或加热下进行。
N-(3-羟基-3-苯基丙基)哌嗪衍生物(5)与对氟苄腈反应,从而得到其中R3是氰基的本发明化合物(1a)。反应通常在一种碱的存在下进行,例如氢氧化钠、氢氧化钾、叔丁醇钾或氢化钠;反应在有或没有不影响反应的溶剂的存在下进行,例如N,N-二甲基甲酰胺、二甲基亚砜或四氢呋喃。反应可以在冷却条件、室温、温暖条件或加热下进行。
其中R3是氰基的本发明化合物(1a)的水解作用提供了其中R3是羧基的本发明化合物(1b)。反应通常在诸如氢氧化钾或氢氧化钠等碱的存在下,在诸如甲醇、乙醇或四氢呋喃等溶剂或上述溶剂之一与水的混合溶剂中进行。反应在温暖条件、加热或加热回流下进行。
其中R3是羧基的本发明化合物(1b)与一种卤化剂反应,例如亚硫酰氯、草酰氯、三氯化磷或五氯化磷,从而活化了化合物(1b)的羧基,进一步与单独制备的、吲哚与有机金属化合物之间的反应产物反应,从而得到其中R3是吲哚羰基的本发明化合物(1c)。化合物(1b)羧基的活化反应可以在有或没有不影响反应的溶剂的存在下进行,例如含卤溶剂,如二氯甲烷和氯仿。反应可以在室温、温暖条件或加热下进行。在吲哚与有机金属化合物之间的反应产物制备中,利用一种不影响反应的溶剂,例如含卤溶剂,如二氯甲烷、氯仿或1,2-二氯乙烷;醚,如二乙醚、四氢呋喃或二噁烷;苯,如甲苯或二甲苯。有机金属化合物的例子包括有机锂化合物、有机铝化合物、有机锌化合物和有机镁化合物。有机锂化合物的特例包括甲基锂和丁基锂;有机铝化合物的特例包括三甲基铝和三乙基铝;有机锌化合物的特例包括二甲基锌和二乙基锌;有机镁化合物的特例包括氯化甲基镁、氯化乙基镁、溴化甲基镁、溴化乙基镁、碘化甲基镁和碘化乙基镁。反应可以在有或没有一种锌化合物的存在下进行。优选地,反应在锌化合物的存在下进行,锌化合物的例子包括氯化锌、溴化锌和碘化锌。反应可以在冷却条件、室温、温暖条件或加热下进行。
本发明所得N-苯基-N’-苯丙基哌嗪衍生物(1)可以按照常规方法与酸或碱转化为盐。
本发明所得N-苯基-N’-苯丙基哌嗪衍生物(1)及其盐涵盖各种溶剂化物和多晶形。通过对原料、不对称还原和使用诸如旋光活性扁桃酸、酒石酸、二苯甲酰酒石酸或二(对甲苯甲酰)酒石酸等旋光拆分剂的旋光拆分进行适当选择,能够生成不同的外消旋变体、各种旋光异构体和R-与S-异构体。
所得本发明化合物(1)具有极好的α1-肾上腺素受体阻滞活性和较高的安全性。因此,该化合物可用作高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛和由BPH引起的尿路梗阻和尿频的预防和治疗剂。
本发明化合物(1)可以形成药物组合物,例如通过与药学上可接受的载体进行配制,用于口服给药或肠胃外给药。口服给药时,化合物(1)通过与适当添加剂混合,可以形成片剂、粉末、颗粒或胶囊,添加剂包括赋形剂,例如乳糖、甘露糖醇、玉米淀粉和结晶纤维素;粘合剂,例如纤维素衍生物、阿拉伯胶和明胶;崩解剂,例如羧甲基纤维素-Ca;润滑剂,例如滑石和硬脂酸镁。所得固体制剂利用一种包衣剂可以形成肠溶制剂,包衣剂例如羟丙基甲基纤维素邻苯二甲酸酯、乙酸羟丙基甲基纤维素琥珀酸酯、乙酸纤维素邻苯二甲酸酯或甲基丙烯酸酯共聚物。肠胃外给药时,化合物(1)通过与例如水、乙醇、甘油和常规的表面活性剂混合可以形成注射液;或者通过与栓剂基质形成栓剂。
剂量可以根据年龄、体重、症状、治疗效果、给药方式和给药周期而异。一般来说,在口服给药的情况下,本发明化合物(1)的给药量是1-2000mg/天,优选为10-300mg/天,每天给药一次或分2-3次给药。
实施例
下面将通过实施例来描述本发明,实施例不应被解释为对发明的限制。
实施例1
二盐酸(S)-4-[3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)丙氧基]苄腈的制备
步骤1
4’-甲基-3-氯苯基乙基酮的制备
按照A.A.Khalaf等所述方法(Bulletin de la Societe de France,No 7-8,II 285-291,1984)制备目标化合物。
将氯化铝(480g)悬浮在二氯甲烷(1125ml)中。向悬浮液中滴加硝基甲烷(195ml),所得混合物在室温下搅拌一小时。随后,向其中滴加甲苯(321ml),混合物在室温下搅拌一小时。进一步在10-15℃下向混合物中滴加3-氯丙酰氯(289ml),所得混合物在室温下搅拌2小时。反应混合物在冰浴中冷却后,在搅拌下向混合物中加入冰、然后是二氯甲烷、水和浓氢氯酸。分层,有机层按顺序用1N氢氯酸、饱和碳酸氢钠和饱和盐水洗涤,经无水硫酸钠干燥,然后在减压下蒸发溶剂。残余物从己烷与乙酸乙酯的溶剂混合物中重结晶,从而得到457.9g目标化合物,为白色晶体。熔点:77.5-78.5℃
步骤2
(S)-3-氯-1-(4-甲基苯基)-1-丙醇的制备
在氩气氛下,将4’-甲基-3-氯苯基乙基酮(18.2g)和(R)-5,5-联苯-2-甲基-3,4-propano-1,3,2-oxazabololidine(277mg)溶于四氢呋喃(100ml)。在水冷却下向溶液中滴加硼烷-二乙基苯胺配合物(18ml),所得混合物在相同温度下搅拌1.5小时。反应混合物在冰浴中冷却后,滴加甲醇(50ml),混合物在相同温度下搅拌30分钟。在搅拌下向其中加入1N氢氯酸,之后向混合物中加入氯化钠进行盐析,然后用乙酸乙酯萃取。用1N氢氯酸、饱和碳酸氢钠和盐水洗涤后,有机层经无水硫酸钠干燥。在减压下蒸发溶剂,从而得到17.4g标题化合物,为无色固体。
熔点:48-50℃
1H-NMR(CDCl3)δ:1.90~1.94(1H,m),2.00~2.13(1H,m),
2.16~2.30(1H,m),3.50~3.60(1H,m),3.67~3.78(1H,m),
4.90(1H,quint),7.15~7.30(4H,m)
IR(KBr)cm-1:3300
MS(EI)m/e:184,186(M+)
[α]D(C=1,CHCl3):-22.5°
步骤3
(S)-3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)-1-丙醇的制备
将(S)-3-氯-1-(4-甲基苯基)-1-丙醇(17.4g)、盐酸1-(2-甲氧基苯基)哌嗪(22.9g)、碘化钾(49.8g)和三乙胺(45ml)悬浮在N,N-二甲基甲酰胺(230ml)中。悬浮液在60℃下搅拌16小时。将反应混合物倒入水中。向其中加入饱和碳酸氢钠,然后用乙酸乙酯萃取。有机层用盐水洗涤并经无水硫酸钠干燥后,在减压下蒸发溶剂。残余物从己烷与乙酸乙酯的溶剂混合物中重结晶,从而得到22.8g目标化合物,为浅粉红色晶体。
熔点:127.5-128.5℃
1H-NMR(CDCl3)δ:1.86~1.96(2H,m),2.34(3H,s),2.62~2.96(6H,m).
3.14(4H,br),3.86(3H,s),4.94(1H,t),6.84~7.06(4H,m),7.15(2H,d),
7.23~7.32(2H,m)
IR(KBr)cm-1:3400
MS(FAB)m/e:341(MH+)
[α]D(C=1,CHCl3):-60.8°
步骤4
二盐酸(S)-4-[3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)丙氧基]苄腈的制备
将(S)-3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)-1-丙醇(22.7g)和对氟苄腈(8.88g)溶于N,N-二甲基甲酰胺(230ml)。在冰浴冷却下向溶液中加入叔丁醇钾(11.2g),所得混合物在相同温度下搅拌10分钟。将反应混合物倒入水中,向其中加入1N氢氯酸,调pH为6,然后用乙酸乙酯萃取。有机层用盐水洗涤并经无水硫酸钠干燥后,在减压下蒸发溶剂。将残余物溶于二乙醚,向其中加入4N氢氯酸-二噁烷溶液,然后减压浓缩。在搅拌下向残余物中加入乙醇与二乙醚的溶剂混合物,之后过滤收集所沉淀的晶体。所收集的晶体用二乙醚与乙酸乙酯的混合溶剂洗涤,从而得到32.5g目标化合物,为浅粉红色晶体(收率95%)。
熔点:169.5-170.5℃(分解)
1H-NMR(CDCl3)δ:2.33(3H,s),2.50~2.62(2H,m),3.25~3.42(2H,m),
3.50~3.65(4H,m),4.08(3H,s),4.34~4.57(2H,m),5.13(2H,t),5.52(1H,t),
6.91(2H,d),7.02~7.26(6H,m),7.44~7.52(3H,m),8.22(1H,dd),
13.90(1H,brs)
IR(KBr)cm-1:3450,3360,2361,2228,1605
MS(FAB)m/e:442(MH+)
[α]D(C=1,CHCl3):0.30°
实施例2
(S)-4-[3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)丙氧基]苯甲酸的制备
在加热下,将二盐酸(S)-4-[3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)丙氧基]苄腈(32.0g)溶于75%乙醇水溶液(320ml)。向溶液中加入氢氧化钾(81.9g),混合物回流20小时。反应混合物减压浓缩。将残余物悬浮在水中,向其中加入浓氢氯酸,调pH为6。随后,混合物用二氯甲烷萃取。有机层按顺序用饱和碳酸氢钠和盐水洗涤,经无水硫酸钠干燥。在减压下蒸发溶剂。向残余物中加入甲醇,加热溶解残余物。所得混合物放冷,从而得到24.5g目标化合物,为浅粉红色晶体(收率86%)。
熔点:188-189℃(分解)
1H-NMR(CDCl3)δ:2.14~2.26(2H,m),2.31(3H,s),2.50~2.62(1H,m),
2.84~3.25(9H,m),3.84(3H,s),5.35(1H,t),6.72(2H,d),6.81~7.02(4H,m),
7.12(2H,d),7.24(2H,d),7.60(2H,d),8.30(1H,br)
IR(KBr)cm-1:3450,1655,1603
MS(FAB)m/e:461(MH+)
[α]D(C=1,CHCl3):-35.0°
实施例3
向二氯甲烷(100ml)中加入(S)-4-[3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)丙氧基]苯甲酸(10.0g)。向溶液中加入亚硫酰氯(2ml),混合物在室温下搅拌10分钟。在搅拌下向反应混合物中加入二氯甲烷和饱和碳酸氢钠,然后分层。有机层用盐水洗涤并经无水硫酸镁干燥后,在减压下蒸发溶剂,从而得到酰氯。
另外,向二氯甲烷(30ml)中加入吲哚(3.06g)。在冰浴冷却下向溶液中加入3M溴化甲基镁-二乙醚溶液(8.7ml),所得混合物然后在相同温度下搅拌10分钟。随后,向其中加入1M氯化锌-二乙醚(52.2ml),混合物加热至室温。混合物在室温下搅拌20分钟。向混合物中加入预先得到的酰氯的二氯甲烷溶液(100ml),在室温下搅拌一小时。反应完成后,在搅拌下向其中加入甲醇(50ml),之后,将混合物倒入氯仿(200ml)中。混合物按顺序用1N氢氯酸、水、饱和碳酸氢钠和盐水洗涤,经无水硫酸镁干燥。在减压下蒸发溶剂。将残余物溶于乙酸乙酯与甲醇的溶剂混合物。向所得溶液中加入4N氢氯酸-二噁烷,过滤收集所沉淀的晶体,从而得到10.5g目标化合物,为浅粉红色晶体(收率81%)。
熔点:163-166℃(分解)
1H-NMR(DMSO-d6)δ:2.20~2.60(5H,m),3.08~3.67(10H,m),
3.80(3H,s),5.56~5.64(1H,m),6.88~7.09(6H,m),7.16~7.27(4H,m),
7.38(2H,d),7.48~7.55(1H,m),7.72(2H,d),7.88(1H,d),8.17~8.23(1H,m)
IR(KBr)cm-1:3320,2290,1609
MS(FAB)m/e:560(MH+)
[α]D(C=1,MeOH):-15.4°
另外,向盐酸(S)-3-[4-[3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)丙氧基]苯甲酰基]吲哚(2.0g)的二氯甲烷悬浮液中加入饱和碳酸氢钠,使其重新分配。有机层用盐水洗涤,经无水硫酸镁干燥,之后在减压下蒸发溶剂。残余物从乙酸乙酯与二异丙醚的溶剂混合物中重结晶,从而得到1.4g(S)-3-[4-[3-[4-(2-甲氧基苯基)哌嗪-1-基]-1-(4-甲基苯基)丙氧基]苯甲酰基]吲哚,为浅黄色晶体。
熔点:168-170℃
1H-NMR(CDCl3)δ:1.95~2.15(1H,m),2.20~2.40(1H,m),
2.33(3H,s),2.60(2H,brs),2.68(4H,brs),3.12(4H,brs),3.86(3H,s),
5.33(1H,dd),6.82~7.05(6H,m),7.15(2H,d),7.25~7.33(4H,m),
7.37~7.45(1H,m),7.62(1H,d),7.74(2H,d),8.30~8.40(1H,m),
8.72(1H,brs)
IR(KBr)cm-1:1599
MS(FAB)m/e:560(MH+)
[α]D 20(C=1.0,MeOH):-28.1°
α1-肾上腺素受体阻滞活性
将兔子放血至死,摘除尿道前列腺部和前列腺,制作平滑肌条。将每条悬浮在37℃的含Krebs溶液的器官浴中,其中已经通入95%O2和5%CO2。通过等长传感器(Nihon Koden:TB-651T)在笔型记录器(Nihon Denki San’ei产品:RECTI HORIZ 8K)上记录1g休止张力下的等长收缩。
将平滑肌条平衡60分钟后,利用一定浓度(10-5M)的苯福林诱发收缩。随后,器官浴用生理溶液洗涤,以60分钟间隔的休止期重复上述操作,直到获得平滑肌条的恒定收缩反应。下面,以渐增方式向器官浴中加入苯福林(10-7-3×10-4M),从而得到浓度-反应曲线(对照)。继洗涤平滑肌条的60分钟休止期后,将供试样本(含有供试药物的DMSO溶液;10-7-10-5M)处理30分钟,得到苯福林的收缩-反应曲线。
生理溶液的组成如下:NaCl 118.4mM,KCl 4.7mM,MgCl2 1.2mM,CaCl2 2.5mM,NaHCO3 25.0mM,葡萄糖1.1mM和KH2PO4 1.2mM。
在所有情况下,在供试样本用平滑肌条处理前10分钟,向生理溶液中加入10-5M普萘洛尔(β-肾上腺素受体拮抗剂)。
根据pA2(在拮抗剂的存在下,为了达到在没有拮抗剂的存在下所需相同的作用而要求两倍促效剂浓度的拮抗剂摩尔浓度的负对数)的计算结果评价每种供试药物在α1-肾上腺素受体阻滞活性方面的效力。结果表示在表1中。
表1
pA2 | ||
前列腺 | 尿道 | |
实施例1 | 8.00 | 8.44 |
实施例2 | 8.67 | 8.73 |
实施例3 | 6.89 | 6.29 |
制剂例1
将实施例1化合物(20g)、乳糖(315g)、玉米淀粉(125g)和结晶纤维素(25g)均匀混合。向其中加入7.5%羟丙基纤维素水溶液(200ml)。所得混合物用装有孔径0.5mm筛的挤出机造粒。所制备的颗粒立即用球形造粒机整圆,然后干燥,得到颗粒剂。
制剂例2
利用流化造粒机,将制剂例1中制备的颗粒用具有下列组成的膜衣溶液(1.9kg)包衣,从而得到肠溶颗粒剂。
包衣溶液的组成:羟丙基甲基纤维素邻苯二甲酸酯(5.0%)、硬脂酸(0.25%)、二氯甲烷(50.0%)和乙醇(44.75%)。
制剂例3
将实施例2化合物(20g)、乳糖(100g)、玉米淀粉(36g)、结晶纤维素(30g)、羧甲基纤维素钙(10g)和硬脂酸镁(4g)均匀混合。利用捣棒直径为7.5mm的单冲压片机将所得混合物制成片剂,片重200mg。
制剂例4
将制剂例3中制备的片剂用具有下列组成的包衣溶液进行喷雾包衣,从而得到肠膜衣片,每片用10mg包衣溶液。
包衣溶液的组成:羟丙基甲基纤维素邻苯二甲酸酯(8.0%)、maibaset(0.4%)、二氯甲烷(50.0%)、漂白蜂蜡(0.1%)和异丙醇(41.5%)。
制剂例5
将实施例3化合物(200g)、聚山梨酯80(20g)和中链脂肪酸甘油三酯(1780g)混合,完全溶解。随后,按照利用制软胶囊液体的旋转法将所得溶液制成软胶囊剂,每粒含200mg溶液,该制软胶囊液体含有明胶(100份)、稠甘油(30份)、对羟基苯甲酸乙酯(0.4份)和对羟基苯甲酸丙酯(0.2份)。
制剂例6
实施例2化合物 100mg
乙酸钠 2mg
乙酸(调pH为5.8) 适量
蒸馏水 余量
总计 10ml/瓶
按常规方法加工上述成分,得到注射剂。
工业实用性本发明的苯基哌嗪衍生物表现出有效的α1-肾上腺素受体阻滞作用,且安全性高,因此可用于高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛以及由BPH引起的尿路梗阻、尿频和其他症状。
Claims (15)
2、根据权利要求1的N-苯基-N’-苯丙基哌嗪衍生物或其盐,其中R3是氰基或羧基。
3、药物,包含如权利要求1或2所述的N-苯基-N’-苯丙基哌嗪衍生物或其盐作为活性组分。
4、α1-肾上腺素受体阻滞剂,包含如权利要求1或2所述的N-苯基-N’-苯丙基哌嗪衍生物或其盐作为活性组分。
5、根据权利要求3的药物,用作高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛和由良性前列腺增生引起的尿路梗阻和尿频的预防或治疗剂。
6、药物组合物,包含如权利要求1或2所述的N-苯基-N’-苯丙基哌嗪衍生物或其盐和药学上可接受的载体。
7、根据权利要求6的药物组合物,用作高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛和由良性前列腺增生引起的尿路梗阻和尿频的预防或治疗剂。
8、如权利要求1或2所述的N-苯基-N’-苯丙基哌嗪衍生物或其盐作为药物的用途。
9、根据权利要求8的用途,其中该药物用作高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛和由良性前列腺增生引起的尿路梗阻和尿频的预防或治疗剂。
10、高血压、充血性心脏衰竭、心肌缺血、心律不齐、心绞痛和由良性前列腺增生引起的尿路梗阻和尿频的治疗方法,其特征在于,用如权利要求1或2所述的N-苯基-N’-苯丙基哌嗪衍生物或其盐的给药。
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CN1172919C (zh) * | 2002-06-03 | 2004-10-27 | 上海医药工业研究院 | 芳烷醇哌嗪衍生物及其在制备抗抑郁症药物中的应用 |
HUP0700353A2 (en) * | 2007-05-18 | 2008-12-29 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
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