CN1053605A - 具有局部麻醉和止痛作用的新取代4-苯基-4-哌啶甲酰胺的制备方法 - Google Patents
具有局部麻醉和止痛作用的新取代4-苯基-4-哌啶甲酰胺的制备方法 Download PDFInfo
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Abstract
用作局部麻醉剂和止痛药的式IV化合物及其制
备方法、其药物制剂及其应用。
Description
本发明涉及既具有局部麻醉作用又具有止痛作用的新化合物、其制备方法及其在制备药物制剂中的应用。
哌替啶是一种常用的止痛药。它还具有微弱的局部麻醉作用。哌替啶在脊柱施用后,麻醉作用和止痛作用常常都不足,因此目前改用丁哌卡因和芬太尼或吗啡的配伍体。阿片类止痛药有几个严重的缺点,例如产生耐受性、成瘾、有呼吸抑制的危险。因此,需要在产生局部麻醉的同时保留止痛作用的药剂。这类药剂应当在手术中于脊柱注射或硬膜外注射后作为局部麻醉剂使用。随后,这些化合物会大大减轻手术后痛苦。
Hardy.D.G.等人描述了某些具有止痛活性的哌替啶类似物的构效关系(J.Med.Chem.8:847-851,1965)。瑞典专利96980描述了1-甲基-1-苯基哌啶-4-羧酸和它的两种酰胺。但该文献中没有提到具体的药物作用,只提到这些化合物可用于制造某些新药物。由法国专利2156470可知,1-(3,3-二苯基丙基)哌啶的一些衍生物由于脂溶性高,只能具有止痛剂活性而不能具有局部麻醉剂活性。有文献描述了1-丁基-4-苯基-4-哌啶羧酸的某些酰胺(Acta Pol Pharm 36(4):439-4,《化学文摘》93(1980)7970V)。这些酰胺看来具有止痛作用,但不具有局部麻醉作用。
现已发现,具有下式Ⅳ的化合物或其可药用的盐,不仅具有意外良好的脊柱麻醉剂和硬膜外麻醉剂作用,而且还具有额外的止痛作用,这种止痛作用在麻醉作用开始下降后仍长时间持续。这样便无需做活性化合物的配伍,从而避免了与上述危险有关的危险。本发明的化合物为由下式Ⅳ限定的化合物及其可药用的盐:
其中
R1为含2-6个碳原子的烷基或烷氧烷基R4O-(CH2)m-,其中R4为含1-4个碳原子的烷基,m为2-4;R2和R3相同或不同,各为最多含6个碳原子的烷基,或者R2和R3一起形成(CH2)n链,其中n为4-6,或R2和R3中有一个为氢和含1-6个碳原子的直链或支链烷基。
优选的本发明化合物中,R1、R2和R3为烷基。
特别优选的化合物中,R1为己基,R2为甲基或乙基,R3为乙基。
优选的本发明盐为可药用的盐。特别优选的是盐酸盐。
上述式Ⅳ化合物是如下制备的:
其中A、R1、R2和R3如上所限定。
A为CN或-CO2C2H5、R如上所限定的式Ⅰ化合物,是由相应的仲胺(R1=H)制备的,但R1为CH3、A为CO2C2H5的化合物除外,后者就是市场上有售的化合物哌替啶。式Ⅱ化合物可以直接由A为-CO2C2H5的式Ⅰ化合物与烷基胺反应来制备(参见实施例1),也可按与式Ⅳ化合物相同的方式来制备。式Ⅳ化合物的制备方法是:先将式Ⅰ化合物水解成式Ⅲ的羧酸,然后使其与草酰氯和适当的胺反应,生成式Ⅳ化合物。
实施例Ⅰ1-Ⅰ6描述了式Ⅳ化合物制备过程中的中间体。
化合物Ⅰ
实施例Ⅰ1
1-己基-4-苯基-4-哌啶羧酸
乙酯盐酸盐
将去甲哌替啶(23.5克,0.10摩尔)、碘己烷(23.5克,0.11摩尔)、无水Na2CO3(11.7克,0.11摩尔)和乙腈(250毫升)在搅拌下加热回流1.5小时。将该混合物过滤除去溶剂。将残渣溶于CH2Cl2,用100毫升1N NaOH洗涤该溶液,然后用水洗涤,最后干燥(K2CO3)。然后向该溶液中加入HCl的乙醚溶液,而后除去溶剂,残渣用乙酸乙酯重结晶,得到22.5克盐酸盐,m.p.156-158℃。m.p.文献值为158℃(J.Med.chem.8:847-851,1965)。
实施例Ⅰ2
1-[4-乙氧丁基]-4-苯基-4-哌啶
羧酸乙酯盐酸盐
将去甲哌替啶(15.63克,67毫摩尔)、4-乙氧丁基氯(10.67克,70毫摩尔)、Na2CO3(7.77克,73毫摩尔)、KI(0.6克)和乙腈(150毫升)于搅拌下加热回流72小时。将该混合物过滤并除去溶剂。将残渣溶于乙醚,用水洗涤该溶液并干燥(MgSO4)。蒸馏得到17.9克沸点为160-163℃/0.05mmHg的碱,其沸点文献值为180℃/1mmHg(J.Chem.Soc.3062,1958),其盐酸盐的熔点为143-145℃。
实施例Ⅰ3
1-(2-乙氧基乙基)-4-氰基-4-
苯基哌啶
如实施例Ⅰ2所述,由4-氰基-4-苯基哌啶和2-溴乙基乙基醚制备标题化合物,但不用KI,回流反应时间为6小时。该化合物的沸点为130-135℃/0.005mmHg。
化合物Ⅲ
实施例Ⅰ4
1-己基-4-苯基-4-哌啶羧酸
盐酸盐
将1-己基-4-苯基-4-哌啶羧酸乙酯(22.5克,64毫摩尔)、20%盐酸(225毫升)和乙酸(70毫升)的混合物加热回流30小时。冷却后,将该混合物倾入200毫升冰水中,过滤并空气干燥后,得到12.9克酸。蒸发滤液,残渣用乙腈处理,又得到4克酸。用乙腈重结晶,得到16.9克酸,熔点为193-195℃。该酸含有结晶溶剂。
实施例Ⅰ5
1-[4-乙氧基丁基]-4-苯基-4-哌啶
羧酸盐酸盐
将1-[4-乙氧基丁基]-4-苯基-4-哌啶羧酸乙酯(17.9克,53.7毫摩尔)、2N NaOH(55毫升)和乙醇(6毫升)的混合物于搅拌下加热回流24小时。用乙醚萃取该溶液,然后用稀盐酸酸化。蒸发溶剂,残渣用丙酮萃取。将该丙酮溶液过滤,蒸发溶剂。结晶残余物置真空干燥器中用CaCl2干燥,用THF-乙酸乙酯重结晶。产量为11.7克,熔点131-133℃。
实施例Ⅰ6
1-(2-乙氧基乙基)-4-苯基-4-
哌啶羧酸盐酸盐
将实施例Ⅰ3的氰化物(5.6克)、KOH(5.6克)、乙醇(39毫升)和水(17毫升)的混合物,在高压釜中于140℃下加热6小时。反应混合物用浓盐酸酸化,将沉淀出的盐过滤并蒸发滤液。残渣用热丙酮淋洗。由丙酮萃取液中得到4.2克标题化合物,m.p.150-155℃。
化合物Ⅱ
实施例Ⅱ
N-丁基-1-甲基-4-苯基-4-哌啶
甲酰胺
将哌替啶盐酸盐(2.56克,9毫摩尔)和丁胺(5毫升)在高压釜中于180℃加热3天。将反应混合物在10毫升1N NaOH和乙醚之间振荡,并干燥(MgSO4)乙醚萃取液。蒸发溶剂,残渣在氧化铝上层析,用乙酸乙酯作洗脱剂。结晶产物(1.0克)用正己烷重结晶,得到0.59克,熔点73-76.5℃。
实施例Ⅲ
N-乙基-1-己基-4-苯基-4-哌啶
甲酰胺
如上所述,由1-己基-4-苯基-4-哌啶羧酸乙酯盐酸盐(3.54克,10毫摩尔)和乙胺(2.25克,50毫摩尔)制备标题化合物,反应时间为2天。粗产物(1.0克)用异丙醚重结晶,得到0.81克,熔点92-94℃。盐酸盐熔点为221-223℃(由含2%水的丙酮结晶)。
化合物Ⅳ
一般制备方法:在搅拌下,将草酰氯(4毫升)滴加到哌啶羧酸(化合物Ⅲ)(5-6毫摩尔)的CH2Cl2(20毫升)溶液中。将反应混合物于50℃下搅拌2小时。蒸发溶剂,加入几毫升甲苯,再蒸发掉溶剂。将残渣溶于CH2Cl2(10毫升),将该溶液在搅拌下滴加到适当胺(35-42毫摩尔)的CH2Cl2(20毫升)溶液中,并置冰水中冷却。然后在室温下将反应混合物搅拌几小时,再加1N NaOH(20毫升)振荡,加水振荡一次,干燥(K2CO3),蒸发溶剂。
在若干情况下,精制碱在转化成盐酸盐之前用层析等方法进一步纯化。
下面的表1列出了本发明的一些化合物。
表1
盐酸盐
化合物 R1R2R3m.p℃
1) CH3H C4H973-76.5
2) C6H13H CH3252-254
3) C6H13H C2H5221-223
4) C6H13H CH(CH3)2145-148
5) C6H13CH3CH3155.5-158.5
6) C6H13CH3C2H5137-141
7) C6H13C2H5C2H5151-154
8) C6H13(CH2)5217-219
9) C2H5O(CH2)4CH3CH3125-128
10) C2H5O(CH2)4CH3C2H5115-117
11) C2H5O(CH2)4(CH2)5130-132
12) C2H5OCH2-CH2C2H5C2H5142-144
13) C3H7O(CH2)2C2H5C2H5
14) C4H9O(CH2)2C2H5C2H5
药物制剂
为制备药物制剂,将新化合物溶于适于注射用的液体稀释剂中。所用的制剂为水溶液,其中含有以盐酸盐计为2.5-40.0毫克/毫升的活性化合物。
生物学研究
脊椎麻醉
用小鼠测试本发明化合物的脊椎麻醉作用。以六只动物为一组,测试了对照化合物哌替啶;化合物2)-8)的原料,即1-己基-4-苯基-4-哌啶羧酸乙酯盐酸盐(实施例Ⅰ1);以及化合物9)和10)的原料,即1-[4-乙氧基丁基]-4-苯基-4-哌啶羧酸乙酯盐酸盐(实施例Ⅰ2),这些化合物在前面引用的J.Med.Chem中有记载。结果示于下面的表2。
表2
给小鼠蛛网膜下注射5微升试验溶液后运动原阻断和全麻(摇尾)平均持续时间(分)。持续时间由注射时开始计算。
化合物 浓度(%)运动原阻断 摇尾持续
持续时间(分)时间(分)
10 3 1 10 15
4 14 35
5 14 20
6 20 40
7 27 50
15 8 19 40
9 3 10
10 6 10
11 6 10
12 3 10
20 Ⅰ1 15 40
Ⅰ2 5 25
3 2 22 30
4 24 30
25 5 21 25
6 36 55
7 48 85
8149 >120
9 6 10
30 10 7 10
11 12 35
12 6 10
Ⅰ2 10 15
哌替啶 4 15
35 1 4 17 20
哌替啶 10 25
1动物因受刺激而发出吱吱叫声。
由表2可见,本发明化合物具有比已知麻醉药哌替啶更强的局部麻醉作用。由于这种局部麻醉作用伴有良好的止痛作用,本发明化合物比哌替啶更有价值。用这些化合物代替一种止痛药和一种麻醉剂的配伍也能产生良好效果。
目前已知的实施本发明最佳方法是使用化合物6或7。
Claims (9)
2、根据权利要求1的化合物,其中R1、R2和R3为烷基。
3、根据权利要求2的化合物,其中R1为己基,R2为甲基,R3为乙基。
4、根据权利要求2的化合物,其中R1为己基,R2和R3均为己基。
5、一种用于以硬膜外或鞘内途径控制阻断的药物制剂,它含有根据权利要求1的化合物。
6、一种用于麻醉和止痛的药物制剂,它含有根据权利要求1的化合物。
7、根据权利要求1的化合物在制备具有麻醉和止痛作用的药物制剂中的应用。
9、一种诱发麻醉作用或止痛作用的方法,包括给需要局部麻醉和止痛的哺乳动物(包括人)施用有效量的权利要求1化合物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1043990C (zh) * | 1993-09-17 | 1999-07-07 | 杏林制药株式会社 | 咪唑啉酮衍生物、其酸的加成盐及老年痴呆症的治疗药物 |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
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SE9400447D0 (sv) * | 1994-02-11 | 1994-02-11 | Astra Ab | New compounds |
SE9404438D0 (sv) * | 1994-12-21 | 1994-12-21 | Astra Ab | New process |
US5931809A (en) | 1995-07-14 | 1999-08-03 | Depotech Corporation | Epidural administration of therapeutic compounds with sustained rate of release |
US7799337B2 (en) | 1997-07-21 | 2010-09-21 | Levin Bruce H | Method for directed intranasal administration of a composition |
US20020102291A1 (en) * | 1997-12-15 | 2002-08-01 | Noven Pharmaceuticals, Inc. | Compositions and method for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate |
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JP2006511554A (ja) * | 2002-12-13 | 2006-04-06 | スミスクライン ビーチャム コーポレーション | Ccr5アンタゴニストとしてのピペリジン誘導体 |
WO2008045564A2 (en) * | 2006-10-12 | 2008-04-17 | Epix Delaware, Inc. | Carboxamide compounds and their use as antagonists of the chemokine ccr2 receptor |
RU2010128543A (ru) | 2007-12-11 | 2012-01-20 | Сайтопатфайндер, Инк. (Jp) | Карбоксамидные соединения и их применение в качестве агонистов хемокиновых рецепторов |
US8473062B2 (en) | 2008-05-01 | 2013-06-25 | Autonomic Technologies, Inc. | Method and device for the treatment of headache |
US8412336B2 (en) | 2008-12-29 | 2013-04-02 | Autonomic Technologies, Inc. | Integrated delivery and visualization tool for a neuromodulation system |
US9320908B2 (en) | 2009-01-15 | 2016-04-26 | Autonomic Technologies, Inc. | Approval per use implanted neurostimulator |
US8494641B2 (en) | 2009-04-22 | 2013-07-23 | Autonomic Technologies, Inc. | Implantable neurostimulator with integral hermetic electronic enclosure, circuit substrate, monolithic feed-through, lead assembly and anchoring mechanism |
EP3914246A1 (en) | 2019-01-22 | 2021-12-01 | ICM (Institut du Cerveau et de la Moelle Épinière) | Local anesthetic for the treatment of neurological symptoms resulting from brain dysfunctions |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE96980C1 (zh) | ||||
US2486796A (en) * | 1943-06-25 | 1949-11-01 | Ciba Pharm Prod Inc | Esters of 1-alkyl-4-hydroxyphenylpiperidyl-4-ketones |
US3334106A (en) * | 1964-10-20 | 1967-08-01 | Aldrich Chem Co Inc | N(aryl)n(hydrocarbyl)-omega-(4-phenyl-4-piperidinocarbonylheteroamine) alkanoamide |
US3539580A (en) * | 1967-06-26 | 1970-11-10 | Janssen Pharm | 4-aryl-4-aminoalkoxy-piperidines |
CH501622A (de) * | 1968-12-20 | 1971-01-15 | Ciba Geigy Ag | Verfahren zur Herstellung von neuen Piperidinderivaten |
US3737538A (en) * | 1968-12-30 | 1973-06-05 | Ciba Geigy Corp | Antitussive compositions and method with isonipecotic acid derivatives |
FR2156470A2 (en) * | 1971-10-21 | 1973-06-01 | Synthelabo | 1-(3,3-diphenyl-1-propyl)-4-aryl-piperidines - as analgesics spasmolytic and anti-tussive agents |
ZA899436B (en) * | 1988-12-12 | 1990-08-29 | Ciba Geigy | Piperidine derivatives |
US5100903A (en) * | 1989-05-12 | 1992-03-31 | Anaquest, Inc. | N-aryl-n-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds |
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CN1043990C (zh) * | 1993-09-17 | 1999-07-07 | 杏林制药株式会社 | 咪唑啉酮衍生物、其酸的加成盐及老年痴呆症的治疗药物 |
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