CN1084516A - 氮杂环和氮杂双环亚烷基羟胺 - Google Patents
氮杂环和氮杂双环亚烷基羟胺 Download PDFInfo
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- CN1084516A CN1084516A CN93108003.7A CN93108003A CN1084516A CN 1084516 A CN1084516 A CN 1084516A CN 93108003 A CN93108003 A CN 93108003A CN 1084516 A CN1084516 A CN 1084516A
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- Prior art keywords
- azabicyclo
- compound
- oct
- azanol
- formula
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- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 12
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- -1 1-azabicyclo [2.2.2]-oct-3-yl Chemical group 0.000 claims description 25
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及一类有药理活性的氮杂环和氮杂双
环亚烷基羟胺(式(I),其中A,n,R1和R2的具体含
义都在说明书中定义),它们作为胆碱能类药用于治
疗神经和精神性疾病,包括它们的制备过程和含有它
们的药用组合物。
Description
本发明涉及一类有药物活性的氮杂环和氮杂双环亚烷基羟胺,包括它们的制备方法和含有它们的药物组合物。这些新化合物刺激皮质胆碱能的神经传递,因此可用于治疗神经和精神性疾病,这些疾病的临床表现是由于胆碱能的传递受损引起的。
认识障碍表现为健忘、神经混乱、记忆丧失和感情纷乱等特征。它们可能是由衰老引起,或者是在病理条件下由脑器官疾病引起。这些精神病的病因和病理尚不清楚。虽然有几个神经传递系统(乙酰胆碱,去甲肾上腺素,多巴胺,5-羟色胺,GABA,等等)受损,这些系统在脑细胞间的突触交流间起一定作用并且与识别功能有关,但是胆碱能系统的中心作用是主要原因[Coyle,J.J.et al,Science,219,1184(1983);Briley M.et al.,Pharmacopsych.23,75(1990)]。由胆碱能缺损引起的疾病包括:早老和老年性痴呆(也叫做阿耳茨海默氏痴呆),杭廷顿氏舞蹈病,迟发性运动机能障碍,运动机能亢进,躁狂和图雷特氏综合症。这些紊乱疾病的许多症状都与观察到的乙酰胆碱合成下降和特殊脑区(如大脑皮层和海马)的胆碱能神经元受损或缺失有关[Davies et al.,The Lancet 2,1403(1976);Perry et al.,J.Neurol.Sci.32,247(1977)]。
根据这一“胆碱能假设”,采用了不同的办法恢复乙酰胆碱水平或模仿天然传递介质的作用来治疗上述疾病[Kuman V.et al.,Int.J.Clin.Pharrnacol.29,23(1991)]。已有人提出,乙酰胆碱酯酶抑制剂(如毒扁豆碱或9-氨基四氢吖啶)可以通过阻断灭活酶来增加突触裂口处乙酰胆碱的有效量[Drachnan D.A.et al.,Arch.Neurol.37,674(1980);Summers W.K.et al.,New Engl.J.Med.315,1241(1986)]。也试验了一些能够促进乙酰胆碱合成或将其从贮存囊中释放的化合物[Etienne P.“用卵磷酯治疗阿耳茨海默氏痴呆”在Alzheimer′s disease,编者:Reisberg B.出版:Free Press New York,1983;Davis H.P.et al.,Exp.Aging Res.9,211(1983)]。但是提高与胆碱能路径有关的CNS(中枢神经系统)功能的最直接的途径,看来是直接刺激胆碱能蕈毒碱受体本身。在患有以上那些疾病时,这些受体可能丢失或受破坏,但是,逐渐增加的证据表明,对患有痴呆症的病人,蕈毒碱受体各部位的损失程度不同:位于大脑皮层和海马的前突触胆碱能末端的明显降低,并不伴随着后突触蕈毒碱受体的重大变化或丢失。[Quirion R.,J.of Neuroch.1914(1988);Caulfield M.P.et al.,The Lancet,1227(1982)]。
利用药物激活中心蕈毒碱部位迄今为止非常有限或者令人失望,因为作用环境非常不利。大部分已知的蕈毒碱促效药都含有季铵基团(例如卡巴可),因此推测外周给药后不会穿透血脑屏障。槟榔碱,喹核醇乙酸酯和RS86等含有一个叔胺基,能够进入脑中。但是,已经发现因激活外周蕈毒碱受体而带来的副作用(瞳孔缩小,流泪,能动性纷乱和对心脏的影响),另外,前两个化合物的作用时间很短,因为它们含有一个非常易于水解的酯基[Davidson M.et.al.,Current Research in Alzheimer Therapy,Giacobini E.and Becker R.Editors;Taylor-Francis,New York 333(1988)]。
最近至少发现五种结构不同的蕈毒碱受体亚型([Bonner J.J.et al.,Science 237,527(1987);Bonner J.J. et al.,Neurochem.1,403(1988)];并且按照功能试验划分为三个亚型(M1,M2和M3)(Bridsall N.N.et al.,“蕈毒碱受体亚型的命名”在Subtypes of Muscarinic Receptors Ⅳ;Levine R.R.Editor,Trends Pharmac.Sci.Ⅶ),重新引起人们对拟胆碱能途径的兴趣。
因此,最近在拟胆碱能领域研究的目标是选择性激活M1蕈毒碱受体亚型,它位于胆碱能神经元的后突触部位,并且象上面所说的那样,仍然存在于受损大脑区。努力探索的另一目标是不能激活M2和M3亚型,因为后者将刺激外周胆碱能产生负作用。考虑到很多进入中枢神经系统的药仍残存在外周区,这方面尤其相关。另外,缺乏M2亚型促进活性也将有利地伴随着对同一受体亚型的微弱的拮抗效应。有人推测,乙酰胆碱的释放受反馈机制的消极调节,该机制由内源性促进剂作用于M2亚型的前突触蕈毒碱受体而介导。因此,直接刺激M1受体的有益作用将伴随着乙酰胆碱释放量的增加而提高。
已经发现一类新的化合物具有好的蕈毒碱受体亲和性,并能刺激同样的受体,这正是本发明的目的。在本发明中,这些化合物的另一个有利特点是它们激活M1、M2和M3蕈毒碱受体亚型的能力是不同的,这归因于它们本身所固有的功效不同。因此,本文所提供的一些适当的化合物能够选择性作用于M1受体部位而不作用于M2和M3。另外一些特殊的化合物的选择性刺激M1亚型活性甚至可以因拮抗M2亚型而增加。
这些新化合物可用于治疗或预防与中枢胆碱能缺损有关的疾病。特别是它们的应用有助于治疗认识障碍,与年龄有关的记忆缺损,不同形式的痴呆,阿耳茨海默氏痴呆,杭廷顿氏舞蹈病,迟发性运动机能障碍,运动机能亢进,图雷特综合症。另外,作为中心作用的蕈毒碱的试剂,本发明中的化合物也能用作止痛剂治疗疼痛。
根据本发明,我们提供通式(Ⅰ)所代表的化合物:
其中:
A代表4-8元的氮杂环烷基,或7-9元氮杂双环烷基,N-可任选地被C1-3烷基取代;
n代表1或0;
R1和R2独立地代表:氢;任选地被烷氧基、烷巯基、氰基或卤素取代的直链或支链C1-6烷基;C2-6烯基;C2-6炔基;卤素;任选地被卤素、C1-3烷基、C1-3烷氧基取代的芳基;C6-12芳烷基;杂环芳基;或者与它们所连接的碳原子一起组成一个4-7元环;侧链-(CH2)n-O-N=C-R1R2连接在不靠近氮杂环烷或氮杂双环烷中的氮原子的碳原子上。
氮杂环烷残基A实例(并非局限于此)有:1-氮杂环丁-3-基,1-氮杂环戊-3-基,1-氮杂环己-3-基,1-氮杂环己-4-基,和N-可任选地被C1-3烷基取代的1-氮杂环戊-3-基。
非局限性的氮杂双环烷残基A例子有:1-氮杂双环[2.2.1]-庚-3-基,1-氮杂双环[2.2.2]-辛-3-基,1-氮杂双环[3.2.1]-辛-3-基,1-氮杂双环[3.2.1]-辛-6-基,1-氮杂双环[3.3.1]-壬-3-基,和N-任选地被C1-3烷基取代的8-氮杂双环[3.2.1]-辛-3-基。
在式(Ⅰ)的化合物中,当R1和R2代表直链和支链C1-6烷基时,它可以是,例如,甲基,乙基,正丙基,异丙基,丁基,戊基,己基,2-甲基戊基和类似的基团。当R1和R2代表任选地含取代基的烷基时,它们可以是:甲氧乙基,甲硫乙基,乙硫乙基,或氰乙基。卤素指的是氟、氯、溴和碘。比较好的卤素是氟、氯和溴,特别是氟和氯。当R1和R2代表C2-6烯基时,它可以是,例如,烯丙基或3-甲基-丁烯-2-基。当R1和R2代表C2-6炔基时,它可以是,例如,炔丙基。当R1和R2代表芳基时,它可以是,例如,苯基,可以任选地被甲基,乙基,甲氧基,乙氧基,氟,氯或溴取代。当R1和R2代表C6-12芳烷基时,它可以是,例如,苄基。当R1和R2是杂环芳基时,它可以是,例如,含有1-3个杂原子的5-6元环,如呋喃,吡啶,哒嗪或噁二唑。当R1和R2与它们所连接的碳原子一起代表一个4-7元环时,它可以是,例如,环丁烷或环戊烷。根据本发明,含有一个或多个非对称碳原子的化合物可以以确定构型的光学活性对映体形式存在,或者作为特殊的非对映体或非对映体混合物存在,也可以是一个全外消旋混合物。另外,本发明中的一些化合物能够作为内式或外式异构体存在;这里的术语“内式”指的是那些在次甲基桥-(CH2)n的反位含有羟胺侧链。另外,肟基是本发明化合物中的一部分,根据肟基的特点,也可以存在别的几何异构现象。具有E或Z构型的化合物来自肟基的异构现象。具有这类异构现象的化合物能够以单一的形式或者是混合物的形式得到;在特殊情况下,一种异构体可以转变成另一种异构体。很显然,本发明复盖了所有这些光学的和几何型的异构体以及它们的混合物。
根据本发明,比较好的一组化合物是通式(Ⅰ)所代表的化合物,其中,A是氮杂双环烷基,n是0,R1为氢、低级C1-2烷基,或卤素,并且R2是氢或任选地被烷氧基或卤素取代的低级C1-3烷基,是C2-6炔基或卤素。
根据本发明,最好的化合物如下:
R(-)-O-(1-氮杂双环[2.2.2]-辛-3-基-N-亚乙基-羟胺,盐酸盐。(化合物2)
(±)-外式-O-(1-氮杂双环[3.2.1]-辛-6-基)-N-亚乙基羟胺,盐酸盐。(化合物22)
(±)-外式-O-(1-氮杂双环[2.2.1]-庚-3-基)-N-亚乙基羟胺,富马酸盐。(化合物20)
(±)-外式-O-(1-氮杂双环[3.2.1]-辛-3-基)-N-亚乙基羟胺,富马酸盐。(化合物24)
S(±)-O-(1-氮杂双环[2.2.2]-辛-3-基)-N-(2,2,2-三氟亚乙基)-羟胺,富马酸盐。(化合物7)
举例来说,通式(Ⅰ)所代表的化合物可以按照如下方法制备,这构成本发明的另一特点。
式(Ⅰ)的化合物由O-取代的氮杂环基或氮杂双环基羟胺(式Ⅱ)与羰基衍生物(式Ⅲ)反应得到。
在这里,A,n,R1和R2与以上定义的相同。这一反应在下列溶剂中能够方便地进行,可选溶剂有甲醇、乙醇、异丙醇等含羟基的溶剂;四氢呋喃或甲苯溶剂;比较好的溶剂是甲醇。反应温度通常保持在0℃和所选溶剂的沸点之间,最好在室温。式(Ⅱ)所代表的中间体化合物作为起始原料可以是自由碱,或者在想要时采用它们的盐类衍生物。
上述方法中的式(Ⅱ)中间体化合物,可以通过还原通式(Ⅳ)所示的O-取代的羟基-邻苯二甲酰衍生物而制备。
其中,A和n与以上定义一样。
这个方法可以用适当的还原剂(如水合肼或乙酰胺)进行,最好是用水合肼在醇的溶剂(如甲醇,乙醇和异丙醇,最好是甲醇)中进行。整个过程的反应温度保持在10℃-80℃之间,最好是室温。
通式Ⅳ所代表的邻苯二甲酰衍生物可以方便地从适当的式(Ⅴ)所示的氮杂环或氮杂双环羟基衍生物和羟基邻苯二甲酰亚胺(Ⅵ)制得,制备方法参照已知的Mitsunobu反应过程[Mitsunobu O.,Synthesis 1(1981)]。
其中,A和n与上面定义相同。
缩合-脱水过程在无水的非质子传递溶剂(如乙醚或四氢呋喃)中,在室温或低于室温的条件下,用三苯基膦作为脱水剂和用DEAD(二乙基偶氮二羧酸酯)作为活化剂进行。
上述步骤中所用的关键中间体(Ⅲ)和(Ⅴ)(羟基衍生物)可以直接买到或者根据文献记载方法制备得到。
根据不同的选择,式(Ⅰ)化合物能够通过式(Ⅶ)化合物和式(Ⅷ)的肟反应得到:
比处R1,R2,A和n与上面定义相同,X是适当的离去基,如甲磺酸基或对甲苯磺酸基或卤素,最好是氯。
这一反应在质子性或非质子性溶剂(甲醇、乙醇或二甲基甲酰胺,最好是甲醇)中进行,用钠或氢化钠活化肟基。反应温度维持在30~100℃之间,最好在60℃。式(Ⅷ)所代表的肟类化合物,可以通过前面所说的式Ⅲ羰基化合物与盐酸羟胺在甲醇中室温反应得到,这一方法非常成熟(Organic Functional Groups Preparation,Vol.Ⅲ Sec.Edition by Sadler and Karo,Academic Press S.Diego,1989)。式(Ⅰ)所代表的化合物可以在想要的情况下,用普通的方法转变成药用的有机或无机酸盐,例如以该化合物为碱与对应的酸溶液在适当的溶剂中反应。
药用酸盐的实例包括与下列酸形成的盐:盐酸、富马酸、马来酸、琥珀酸、柠檬酸、酒石酸、磷酸、硫酸、水杨酸、乳酸、葡糖酸、天冬氨酸或甲磺酸[参见如Berg S.M.et al.“Pharmaceutical Salts”in J.Pharm.Sci,66,1(1977)]。
比较好的酸是盐酸、酒石酸和富马酸。
正象以上已经提到的那样,式(Ⅰ)所示的这类新化合物具有有利的药物活性,因为它们能够以固有功效刺激不同的蕈毒碱受体亚型M1、M2和M3,这些功效对每一亚型都是特殊的。因此,这类化合物能够用来治疗或防预与中枢胆碱能缺损有关的病症。它们的应用将特别有利于治疗认识障碍,与年龄有关的记忆受损,不同的痴呆症,阿耳茨海默氏症,杭廷顿氏舞蹈病,迟发性运动机能障碍,运动机能亢进,图雷特综合症。另外,作为中心作用的蕈毒碱剂,本发明所涉及的这些化合物也能够作为止痛剂用于治疗疼痛。
本发明所涉及化合物的给药方法可以是口服,非肠道给药或直肠给药,服用剂量为每日0.01-100毫克/千克体重,最好是0.5-10毫克/千克体重,给药可控制在每天1-4次。
药用配方制剂是本发明的另一特点,包括片剂、药丸、胶囊、粉末、颗粒、无菌非肠道溶液、或栓剂。
在固体的药用组合物中,连同它们的作用机制一起考虑,可以选用适当的药用载体,如,玉米淀粉、乳糖、山梨糖醇、硬脂酸镁,等等。在口服或注射时,适用于溶解这类化合物的液体包括,水溶液,调味糖浆,和用油或其它赋形剂作成的乳化液。分散剂和悬浮剂也可以采用。
为防止外周副作用,在药用组合物中加入外周作用胆碱能拮抗剂(如N-甲基东莨菪碱,或溴环扁吡酯或普鲁本辛)可能是有利的。
药理
“在体外”通过在三种带有M1、M2和M3受体亚型的三种组织(分别是老鼠大脑皮层,心和下颌下腺)的受体结合研究,评估了化合物(Ⅰ)对M1、M2和M3蕈毒碱受体亚型的亲和性。用三种功能模型[老鼠上颈神经节(M1),豚鼠前房(M2),和豚鼠回肠(M3)]检验了化合物(Ⅰ)作用于M1、M2和M3受体亚型的效力和本身的活性。
受体结合研究(Receptor binding Studies)
组织制备:移去老鼠组织,清洗,并在Na+-Mg2+-HEPES缓冲液(pH=7.4,nM:NaCl,100;MgCl2,10;HEPES,20)中先后用Ultra-Turrax最大速度匀浆30秒(重量/体积:大脑皮层,1∶100;全心,1∶2000;下颌唾液腺,1∶200),Potter-Elvehjem匀浆机处理30次,最后用双层干酪布过滤。
结合实验:不同化合物的结合曲线都从它们与对应受体的竞争性实验中导出,大脑皮层蕈毒碱受体用0.5nM[3H]哌吡二氮
标记,心脏和下颌腺蕈毒碱受体用0.3nM[3H]NMS标记。每份1毫升匀浆在标记配体和不同浓度的冷配体存在下30℃保温45分钟。用Eppendorf微量离心管在室温下离心(12000转/分)3分钟终止保温。所得小片用1.5毫升盐水洗涤两次移去自由的放射活性,洗后的小片放干。剪下含小片的离心管末端并加入200微升组织溶解剂(Lumasolve,Lumac),放置过夜。加入4毫升液闪烁溶液(LipoLuma,Lumac)后计数放射活性。进行三份试验,并且当在保温介质中含有1μM的3-奎宁环基苯偶酰酯外消旋混合物(QNB)时,非特异性结合可被定义为小片中被结合或诱捕的放射活性。非特异性结合分别平均低于30%和10%。用Cheng and Prusoff方程对放射配体占位转换校正后,就可以算出抑制常数(Ki)(参见Cheng Y.et al Biochem.Pharmacol.22,3099,1973)。表Ⅰ报告了实验结果。
功能研究
将重150-200克的雄性Sprague-Dawley老鼠用尿烷麻醉(1.2克/千克),切除上颈神经节。每一个神经节都在显微镜下剥去外鞘,然后浸入三室浴器中。神经节身体放在中心室中,节前神经(颈交感神经)和节后神经(内颈动脉)躯干分别通过一个加有润滑脂的狭槽伸入两边的两个隔室中。向中间的隔室(体积约0.5ml)中连续灌注Krebs-Henseleit溶液(25℃,事先用含5%二氧化碳的氧气平衡),在两边的隔室中静止放入同样的溶液。所用介质是含有如下组成的水溶液(mM):NaCl,124.1;KCl,4.8;NaHCO3,24.8;CaCl2,2.5;MgSO4,1.2;KH2PO4,1.2;葡萄糖,10。灌药后引起的神经节电位变化通过插在盛有神经节身体(接地)和节后神经干的隔室中的Ag/AgCl电极记录。电位经放大后在电位测绘仪上记录。经30分钟稳定期后,将1μM蕈毒碱每间隔15分钟过冷75秒,直至观察到连续两次等大小的去极化应答为止(通常3-4次)。在每次实验中所测得的最后一次应答被认为是标准的最大应答。等返回至稳定的基线后,过冷一种激动剂,并使其浓度以半对数摩尔浓度增长(如,1,3,10μM),直至引起最大应答,过冷时间为75秒。这些操作通常间隔10-15分钟,但是万一返回基线较慢,所用时间会更长。当测得最大应答后,哌吡二氮
在0.1μM过冷60分钟,然后再测定在过冷介质中有哌吡二氮
存在时激动剂浓度-应答曲线。通过用最小乘方线性回归分析第一次浓度-应答曲线可以计算出产生50%最大应答(EC50)所需的激动剂的浓度。将1μM蕈毒碱的标准最大应答作为1,激动剂的最大应答与之比较后即得到相对最大值(RM)。为了确证对激动剂应答中蕈毒碱的性质,在EC50水平计算出了剂量-比率(当核对完曲线上的平行点后,用哌吡二氮
从右侧取替激动剂的浓度-应答曲线)。按照Furchgott所描述的方法计算出对哌吡二氮
(PA2)的亲和值(Handlook of Experimental Pharmarcdogy,Vol.33,H.Blaschko & E.Muschall(Eds.),283-335,Springer-Verlog,Berlin,1972):pA2=-log([拮抗剂]/剂量-比率-1)。
表Ⅱ报告了实验结果:
表Ⅱ
“体外”功能研究
*RM=相对最大值,与1μM蕈毒碱的效应定为1作对照
下面的例子给出了本发明中的一些化合物,但是并不限制本发明的范围:
实例1
R(-)N-[1-氮杂双环[222]-辛-3-基)-氧]-邻苯二甲酰亚胺在无水THF(750ml)中加入S(+)-1-氮杂双环[222]-辛-3-醇(37.5克)[Eur.J.Med.Chem.14,111(1979)],三苯基膦(77.3克),N-羟基-邻苯二甲酰亚胺(48.1克)和分子筛(70克),所得混合物室温搅拌2小时,冰浴冷却。然后滴加二乙基偶氮二羧酸酯(DEAD)(51.4克),所得溶液搅拌过夜。加入水(300ml)后,过滤除去分子筛;真空减压除去THF,残余物用10%盐酸水溶液酸化,乙酸乙酯洗涤两次。水层用K2CO3碱化,并用乙酸乙酯彻底萃取。合并有机层,并干燥和蒸发至干,得到所要化合物,白色固体(33.5克)。
M.p.>280℃(乙醇,盐酸盐)
MS(C.I.)=273 m/e [M+H]
[α]D=-36.34°(c=1%在1N HCl中)
根据上述步骤,制备了下列化合物:
S(+)N-[1-氮杂双环[222]-辛-3-基)-氧]-邻苯二甲酰亚胺,起始原料是R(-)1-氮杂双环[222]-辛-3-醇[Eur.J.Med.Chem.14,111(1979)]。
M.p.>280℃(乙醇,盐酸盐)
MS(C.I.)=273 m/e [M+H]
[α]D=+36.15°(C=1%在1N HCl中)
(±)-内式-N-[(1-氮杂双环[221]-庚-3-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-外式-1-氮杂双环[221]-庚-3-醇[J.Org.Chem.34,3674(1969)]
M.p.220-225℃(分解)(盐酸盐)
MS(C.I.)=259 m/e [M+H]
(±)-外式-N-[(1-氮杂双环[221]-庚-3-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-内式-1-氮杂双环[221]-庚-3-醇[EP 427390]
M.p.145-150℃
MS(C.I.)=259 m/e [M+H]
(±)-内式-N-[(1-氮杂双环[321]-辛-6-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-外式-1-氮杂双环[321]-辛-6-醇[J.Org.Chem.33,4376(1968)]
M.p.>250℃(盐酸盐)
MS(C.I.)=273 m/e [M+H]
(±)-外式-N-[(1-氮杂双环[321]-辛-6-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-内式-1-氮杂双环[321]-辛-6-醇[J.Org.Chem.33,4376(1968)]
M.p.148-152℃
MS(C.I.)=273 m/e [M+H]
(±)-内式-N-[(1-氮杂双环[321]-辛-3-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-外式-1-氮杂双环[321]-辛-3-醇[J.Org.Chem.33,4376(1968)EP257741]
M.p.=110-118℃分解
MS(C.I.)=273 m/e [M+H]
(±)-外式-N-[(1-氮杂双环[321]-辛-3-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-内式-1-氮杂双环[321]-辛-3-醇[J.Org.Chem.33,4376(1968)]
M.p.=108-111℃
MS(C.I.)=273 m/e [M+H]
(±)-内式-N-[(1-氮杂双环[331]-壬-3-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-外式-1-氮杂双环[321]-壬-3-醇[J.Amer.Chem.Soc.89,1431(1967),EP257741]
M.p.=135-140℃
MS(C.I.)=287 m/e [M+H]
(±)-外式-N-[(1-氮杂双环[331]-壬-3-基)-氧]-邻苯二甲酰亚胺,起始原料是(±)-内式-1-氮杂双环[331]-壬-3-醇[J.Amer.Chem.Soc.89,1431(1967)]
M.p.=160℃分解
MS(C.I.)=287 m/e [M+H]
R(-)-N-[(1-氮杂双环[222]-辛-3-基)-甲氧]-邻苯二甲酰亚胺,起始原料是R(-)-1-氮杂-3-羟基-甲基-双环[222]辛烷[EP 458214]
M.p.=85-95℃(异丙醚)
MS(C.I.)=287 m/e [M+H]
[α]D=-27.49°(c=1%在1N HCl中)
S(+)-N-[(1-氮杂双环[222]-辛-3-基)-甲氧]-邻苯二甲酰亚胺,起始原料是S(+)-1-氮杂-3-羟基-甲基-双环[222]辛烷[EP 458214]
M.p.=90-95℃(异丙醚)
MS(C.I.)=287 m/e [M+H]
[α]D=-25.93°(c=1%在1N HCl中)
N-[(1-乙基-1-氮杂环丁-3-基)-氧]-邻苯二甲酰亚胺,起始原料是1-乙基-1-氮杂环丁-3-醇[见实例2]
N-[(1-氮杂环丁-3-基)-氧]-邻苯二甲酰亚胺,起始原料是1-氮杂环丁-3-醇[Synth.Comm.20,407(1990)]
N-[(1-甲基-1-氮杂环己-4-基)-氧]-邻苯二甲酰亚胺
M.p.95℃
MS(C.I.)=261 m/e [M+H]
(±)-N-[(1-甲基-1-氮杂环庚-3-基)-氧]-邻苯二甲酰亚胺,起始原料是1-甲基-1-氮杂环庚-3-醇[见实例3]
M.p.=70-72℃
MS(C.I.)=275 m/e [M+H]
外式-N-[(8-甲基-8-氮杂双环[321]-辛-3-基)-氧]-邻苯二甲酰亚胺
M.p.=255℃(分解)(异丙醇,盐酸盐)
MS(C.I.)=287 m/e [M+H]
(±)-N-[(1-甲基-1-氮杂环戊-3-基)-氧]-邻苯二甲酰亚胺
M.p.87-91℃
MS(C.I.)=247 m/e [M+H]
实例2
1-乙基-1-氮杂环丁-3-醇
实例3
a)N-甲基-N-(乙氧羰基甲基)-5-氨基戊酸,乙酯
5-溴代戊酸乙酯(30克)分批加入充分搅拌的、在甲苯(220毫升)中肌氨酸盐酸盐(22克)和三乙胺(29克)的悬浮液中。反应混合物回流20小时后,在5℃冷却。加入5%的盐酸水溶液(200毫升),分出有机层并排出,水溶液用17%Na2CO3溶液碱化,并将分出的油状物用乙醚溶解。有机溶液用水洗涤后干燥,蒸发至干,得粗品标题化合物,用蒸馏法纯化,得17.5克,b.p.120-125℃(0.5mmHg)。
b)1-甲基-1-氮杂-2-乙氧羰基-环庚-3-酮
在搅拌下,将上述中间体(8克)的甲苯(65ml)溶液滴入回流的叔丁醇钾无水甲苯溶液中。反应混合物再回流10分钟后,室温冷却。加入5%盐酸水溶液(50ml),分出有机溶液并排出。水层用17%碳酸钠溶液盐化,并将生成的油状物用乙酸乙酯萃取出来,该溶液经蒸发干燥,得到粗品中间体(5.78克)可以直接用于下步反应。
I.R.(nujol)=羰基吸收带1710和1740cm-1。
c)1-甲基-1-氮杂环庚-3-酮
将该乙氧羰基中间体(5.68克)在浓盐酸(56ml)中的溶液回流7小时,室温冷却。加入15%氢氧化钠水溶液至溶液的pH=9。生成的油状物用乙酸乙酯萃取,干燥,蒸发,得到黄色油状物(2.8克),为脱羧的酮衍生物。
1H-NMR和M.S.与推测结构一致;
d)1-甲基-1-氮杂环庚-3-醇
上述中间体(3.5克)在无水四氢呋喃中的溶液冷至5℃,分批加入LiAlH4(1.04克)。反应混合物再搅拌1小时,然后滴加入含水(0.5ml)的四氢呋喃(30ml)溶液。滤去生成的盐,有机溶液蒸发后得到标题化合物,为一微黄色油状物(3.5克)。1H-NMR和M.S.与推测结构一致。
实例4
R(-)-O-(1-氮杂双环[222]辛-3-基)-羟胺二盐酸盐
在无水乙醇(300ml)中溶解R(-)-N-[(1-氮杂双环[222]-辛-3-基)-氧]-邻苯二甲酰亚胺(31.5克)和85%水合肼(13.3ml)。所得混合物室温搅拌过夜,滤除固体,滤液蒸干。残余物溶于水并用冰水浴冷却,用10%HCl溶液酸化;搅拌4小时后滤除固体。蒸干滤液,所得粗品用乙醇结晶得到白色固体,为标题中化合物。
M.p.195-200℃
MS(C.I.)=143 m/e [M+H]
[α]D=-39.53°(c=1%在1N HCl中)
按照上面描述的方法步骤,由适当的中间体开始,制备出下列各化合物。
S(+)-O-(1-氮杂双环[222]-辛-3-基-羟胺二盐酸盐
M.p.200-205℃(分解)
MS(C.I.)=143 m/e [M+H]
[α]D=+40°(c=1%在1N HCl中)
(±)-内式-O-(1-氮杂双环[221]-庚-3-基-羟胺二盐酸盐
M.p.210-215℃(分解)
MS(C.I.)=129 m/e [M+H]
(±)-外式-O-(1-氮杂双环[221]-庚-3-基-羟胺二盐酸盐
M.p.165-170℃
MS(C.I.)=129 m/e [M+H]
(±)-内式-O-(1-氮杂双环[321]-辛-6-基)-羟胺二盐酸盐
M.p.210-215℃(分解)
MS(C.I.)=142 m/e [M+H]
(±)-外式-O-(1-氮杂双环[321]-辛-6-基)-羟胺
浓油
MS(C.I.)=143 m/e [M+H]
(±)-内式-O-(1-氮杂双环[321]-辛-3-基)-羟胺二盐酸盐
M.p.205-210℃(分解)
MS(C.I.)=143 m/e [M+H]
(±)-外式-O-(1-氮杂双环[321]-辛-3-基)-羟胺二盐酸盐
M.p.183-185℃(分解)
MS(C.I.)=143 m/e [M+H]
(±)-内式-O-(1-氮杂双环[331]-壬-3-基)-羟胺二盐酸盐
M.p.185-189℃(分解)
MS(C.I.)=157 m/e [M+H]
(±)-外式-O-(1-氮杂双环[331]-壬-3-基)-羟胺二盐酸盐
M.p.200-205℃(分解)
MS(C.I.)=157 m/e [M+H]
R(-)-O-[(1-氮杂双环[222]-辛-3-基)-甲基]-羟胺二盐酸盐
M.p.110-120℃(分解)
MS(C.I.)=157 m/e [M+H]
[α]D=-21.59°(c=1%在1N HCl中)
S(+)-O-[(1-氮杂双环[222]-辛-3-基)-甲基]-羟胺二盐酸盐
吸湿性固体
MS(C.I.)=157 m/e [M+H]
[α]D=+21.22°(c=1%在1N HCl中)
O-(1-乙基-1-氮杂环丁-3-基)-羟胺二盐酸盐
O-(1-氮杂环丁-3-基)-羟氨二盐酸盐
O-(1-甲基-1-氮杂环己-4-基)-羟氨二盐酸盐
M.p.195℃(分解)
MS(C.I.)=131 m/e [M+H]
(±)-O-(1-甲基-1-氮杂环庚-3-基)-羟胺二盐酸盐浓油
MS(C.I.)= 145m/e [M+H]
(±)-O-(1-甲基-1-氮杂环己-3-基)-羟氨二盐酸盐
M.p.205-210℃(分解)
MS(C.I.)=131 m/e [M+H]
外式-O-(8-甲基-8-氮杂双环[321]-辛-3-基)-羟胺二盐酸盐
M.p.185℃(分解)
MS(C.I.)=157 m/e [M+H]
(±)-O-(1-甲基-1-氮杂环戊-3-基)-羟胺二盐酸盐
M.p.162-6℃(分解)
MS(C.I.)=177 m/e [M+H]
实例5
S(+)-O-(1-氮杂双环[222]-辛-3-基)-N-亚乙基-羟胺盐酸盐(化合物1)
将S(+)-O-(1-氮杂双环[222]-辛-3-基)-羟胺二盐酸盐(0.6克)、甲醇(10cc)和钠(64毫克)的悬浮液,室温搅拌至金属钠完全消失。冷却后滴加乙醛(0.16毫升),反应液0-5℃搅拌过夜。蒸除甲醇,残余物溶于水并用乙酸乙酯洗涤。水相用Na2CO3碱化后,以CHCl3萃取,合并有机层,干燥后蒸干。残余物溶于乙酸乙酯后加入无水HCl的乙醚溶液,得到标题化合物的盐酸盐。固体过滤后真空干燥。
得到纯的标题化合物为一白色固体(0.31克)。
M.p.165-170℃
MS(C.I.)=169 m/e [M+H]
[α]D=+38.70°(c=1%在1N HCl中)
1H-NMR(CDCl3):1.7÷2.3(4H,m);1.85(3H,d);2.52(1H,m);3.1÷3.7(6H,m);4.51(1H,m);6.84和7.46(1H,2q);12.27(1H,b)
元素分析:C9H17ClN2O
C H N Cl
实测值% 52.54 8.40 13.65 17.24
计算值% 52.81 8.37 13.69 17.32
根据上述步骤制备出下列各化合物
R(-)-O-(1-氮杂双环[222]-辛-3-基)-N-亚乙基-羟胺盐酸盐
(化合物2)
M.p.158-161℃
MS(C.I.)=169 m/e [M+H]
[α]D=+40.128°(c=1%在1N HCl中)
1H-NMR(CDCl3):1.7÷2.3(4H,m);1.85(3H,d);2.51(1H,m);3.1÷3.7(6H,m);4.54(1H,m);6.84和7.46(1H,2q);12.20(1H,b)
元素分析:C9H17ClN2O
C H N Cl
实测值% 52.31 8.42 13.57 17.27
计算值% 52.81 8.37 13.69 17.32
S(+)-O-(1-氮杂双环[222]-辛-3-基)-N-亚丙基-羟胺盐酸盐
(化合物3)
M.p.147℃
MS(C.I.)=183 m/e [M+H]
[α]D=+40.9°(c=1%在1N HCl中)
1H-NMR(CDCl3):1.08(3H,t);1.7÷2.6(7H,m);3.1÷3.5(6H,m);4.53(1H,m);6.72和7.45(1H,2t);12.18(1H,b)
元素分析:C10H19ClN2O
C H N Cl
实测值% 54.39 8.81 12.70 16.12
计算值% 54.91 8.76 12.81 16.21
R(-)-O-(1-氮杂双环[222]-辛-3-基)-N-亚丙基-羟胺盐酸盐
(化合物4)
M.p.150℃
MS(C.I.)=183 m/e [M+H]
[α]D=-42.33(c=1%在1N HCl中)
1H-NMR(CDCl3):1.08(3H,t);1.7÷2.6(7H,m);3.1÷3.7(6H,m);4.53(1H,m);6.72和7.45(1H,2t);12.31(1H,b)
元素分析:C10H19ClN2O
C H N Cl
实测值% 54.40 8.76 12.77 16.15
计算值% 54.91 8.76 12.81 16.21
S-O-(1-氮杂双环[222]-辛-3-基)-N-亚异丙基-羟胺盐酸盐
(化合物5)
M.p.160-162℃(分解)
MS(C.I.)=197 m/e [M+H]
[α]D=+35.1(c=1%在乙醇中)
1H-NMR[DMSO+CDCl3]:10.86(b,1H);7.41(d,1H);4.48(m,1H);2.9÷3.7(6H);2.3÷2.6(2H);1.89(m,4H);1.05(d,6H)
元素分析:C11H21ClN2O
C H N Cl
实测值% 55.18 8.35 11.91 15.12
计算值% 56.76 9.09 12.04 15.23
R(-)-O-(1-氮杂双环[222]-辛-3-基)-N-亚异丙基-羟胺盐酸盐
(化合物6)
M.p.165℃(分解)
MS(C.I.)=197 m/e [M+H]
[α]D=-33.4(c=1%在乙醇中)
1H-NMR[DMSO]:10.92(b,1H);7.47(d,1H);4.45(m,1H);3.0÷3.8(6H);2.50(m,1H);2.29(m,1H);1.6÷2.2(4H);1.03(d,6H)
元素分析:C11H21ClN2O
C H N Cl
实测值% 55.21 9.07 11.71 15.17
计算值% 56.76 9.09 12.04 15.23
S(+)-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2,2-三氟亚乙基-羟胺富马酸盐
(化合物7)
M.p.128-132℃(分解)
MS(C.I.)=223 m/e [M+H]
[α]D=+31.3(c=1%在乙醇中)
1H-NMR[DMSO]:8.25(q,1H);-7.3(b,2H);6.51(s,2H);4.60(m,1H);3.40(m,1H);2.8÷3.1(5H);2.23(m,1H);1.5÷1.9(4H)
元素分析:C13H17F3N2O5
C H N
实测值% 46.01 5.12 8.10
计算值% 46.16 5.07 8.28
R(-)-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2,2-三氟亚乙基)-羟胺富马酸盐
(化合物8)
M.p.138-140℃(分解)
MS(C.I.)=223 m/e [M+H]
[α]D=-31.5(c=1%在乙醇中)
1H-NMR[DMSO]~8.8(b,2H);8.26(q,1H);6.51(s,2H);4.63(m,1H);3.41(m,1H);2.8÷3.2(5H);2.25(m,1H);1.5÷2.0(4H)
元素分析:C13H17F3N2O5
C H N
实测值% 46.22 5.11 8.19
计算值% 46.16 5.07 8.28
(±)-O-(1-氮杂双环[222]-辛-3-基)-N-(苯亚甲基)-羟胺盐酸盐
(化合物9)
M.p.207-209℃
MS(C.I.)=231 m/e [M+H]
1H-NMR[CDCl3]12.42(b,1H);8.12(s,1H);7.2÷7.6(5H);4.68(m,1H);3.0÷3.7(6H);2.62(m,1H);1.6÷2.4(4H)
元素分析:C14H19ClN2O
C H N Cl
实测值% 62.81 7.27 10.43 13.23
计算值% 63.02 7.19 10.50 13.29
(±)-O-[(1-氮杂双环[222]-辛-3-基)-甲基-N-(苯亚甲基)-羟胺盐酸盐
(化合物10)
M.p.200℃
MS(C.I.)=245 m/e [M+H]
1H-NMR[CDCl3]12.12(b,1H);8.03(s,1H);7.2÷7.7(5H);4.20(d,2H);1.8÷3.7(12H)
元素分析:C15H21ClN2O
C H N Cl
实测值% 63.98 7.61 9.88 12.58
计算值% 64.16 7.54 9.98 12.63
实例6
R(-)-O-(1-氮杂双环[222]辛-3-基)-N-异亚丙基-羟胺盐酸盐
(化合物11)
将丙酮(0.24毫升)滴入冷的(10℃)R(-)-O-(1-氮杂双环[222]-辛-3-基)-羟胺盐酸盐(0.7克)的甲醇(15毫升)溶液中。该溶液在10℃搅拌2小时后,再室温搅拌36小时,蒸除甲醇,残余物溶于乙酸乙酯,然后蒸发至干。残余物用乙酸乙酯结晶,得到白色固体(0.58克),为标题化合物。
M.p.130-132℃
MS(C.I.)=183 m/e [M+H]
[α]D=-41.65°(c=1%在1N HCl中)
1H-NMR(DMSO+CDCl3):1.6÷2.1(4H,m);1.84(3H,s);1.85(3H,s);2.35(1H,m);2.9÷3.7(6H,m);4.47(1H,m);6.40(1H+HDO,b);10.82(1H,b)
元素分析:C10H20Cl2N2O
C H N Cl
实测值% 46.53 7.97 10.81 27.55
计算值% 47.07 7.90 10.98 27.79
按照上述方法,从适当的中间体开始制备出下列化合物
S(+)-O-(1-氮杂双环[222]-辛-3-基)-N-异亚丙基-羟胺二盐酸盐
(化合物12)
M.p.135-140℃
MS(C.I.)=183 m/e [M+H]
[α]D=+41.4°(c=1%在1N HCl中)
1H-NMR(DMSO+CDCl3):1.6÷2.1(4H,m);1.84(3H,s);1.85(3H,s);2.35(1H,m);2.9÷3.7(6H,m);4.47(1H,m);6.26(1H+HDO,b);10.73(1H,b)
元素分析:C10H20Cl2N2O
C H N Cl
实测值% 47.11 7.95 11.17 27.49
计算值% 47.07 7.90 10.98 27.79
R(-)-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2-二氟亚乙基)-羟胺二富马酸盐
(化合物13)
M.p.130-135℃(分解)
MS(C.I.)=205 m/e [M+H]
1H-NMR[DMSO]9.20(b,2H);7.91(m,1H);6.53(s,2H);6.56(m,1H);4.59(m,1H);3.47(m,1H);2.9÷3.3(5H);2.27(m,1H);1.5÷2.0(4H)
元素分析:C13H18F2N2O5
C H N
实测值% 48.60 5.70 8.68
计算值% 48.75 5.66 8.75
S(+)-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2-二氟亚乙基)-羟胺盐酸盐
(化合物14)
M.p.110℃(分解)
MS(C.I.)=205 m/e [M+H]
1H-NMR[CDCl3]7.51(m,1H);6.11(m,1H);4.65(m,1H);3.58(m,1H);3.2÷3.5(5H);2.56(m,1H);1.7÷2.3(4H)
元素分析:C9H15ClF2N2O
C H N Cl
实测值% 44.80 6.35 11.55 14.62
计算值% 44.91 6.28 11.64 14.73
R(-)-O-(1-氮杂双环[222]-辛-3-基)-N-(2-氟亚乙基)-羟胺富马酸盐
(化合物15)
M.p.118℃(分解)
MS(C.I.)=187 m/e [M+H]
1H-NMR[DMOS]7.75和7.26(2m,1H);6.50(s,2H);6.4(b,2H);5.30和4.99(2m,2H);4.50(m,1H);3.41(m,1H);2.9÷3.2(5H);2.25(b,1H);1.5÷2.0(4H)
元素分析:C13H19FN2O5
C H N
实测值% 51.83 6.25 9.31
计算值% 51.65 6.34 9.27
S(+)-O-(1-氮杂双环[222]-辛-3-基)-N-(2-氟亚乙基)-羟胺富马酸盐
(化合物16)
M.p.118℃(分解)
MS(C.I.)=187 m/e [M+H]
1H-NMR[DMSO]8.56(b,2H);7.69和7.15(2m,1H);6.54(s,2H);5.25和4.95(2m,2H);4.41(m,1H);3.36(m,1H);2.7÷3.2(5H);2.23(m,1H);1.4÷2.1(4H)
元素分析:C13H19FN2O5
C H N
实测值% 51.40 6.40 9.17
计算值% 51.65 6.34 9.27
R(-)-O-(1-氮杂双环[222]-辛-3-基)-N-环亚丁基-羟胺盐酸盐
(化合物17)
M.p.185-190℃(分解)
MS(C.I.)=195 m/e [M+H]
[α]D=-36.35(c=1%在乙醇中)
1H-NMR[DMSO+CDCl3]:10.62(b,1H);4.69(m,1H);3.1÷3.9(6H);0.7÷2.7(11H)
元素分析:C11H19ClN2O
C H N Cl
实测值% 57.11 8.32 12.17 15.01
计算值% 57.26 8.30 12.14 15.36
S(+)-O-(1-氮杂双环[222]-辛-3-基)-N-环亚丁基-羟胺盐酸盐
(化合物18)
M.p.190-195℃(分解)
MS(C.I.)=195 m/e [M+H]
[α]D=-34.79(c=1%在乙醇中)
1H-NMR[DMSO+CDCl3]10.79(b,1H);4.44(m,1H);2.7÷3.7(10H);2.32(m,1H);1.6÷2.2(6H)
元素分析:C11H19ClN2O
C H N Cl
实测值% 55.60 8.32 12.08 15.23
计算值% 57.26 8.30 12.14 15.36
(±)-内式-O-(1-氮杂双环[221]-庚-3-基)-N-亚乙基-羟胺富马酸盐
(化合物19)
M.p.160℃
MS(C.I.)=155 m/e [M+H]
1H-NMR[DMSO]:8.8(宽,2H);6.99(m,2H);7.51和6.94(2q,1H);4.79(m,1H);3.43(m,1H);3.17(m,1H);2.8÷3.1(4H);2.60(m,1H);1.6÷2.0(2H);1.79和1.80(2d,3H)
元素分析:C12H18N2O5
C H N
实测值% 53.47 6.80 10.35
计算值% 53.32 6.71 10.37
(±)-外式-O-(1-氮杂双环[221]-庚-3-基)-N-亚乙基-羟胺富马酸盐
(化合物20)
M.p.175℃
MS(C.I.)=155 m/e [M+H]
1H-NMR[DMSO+CDCl3]:9.40(b,2H);6.57(s,2H);6.84和7.41(2q,1H);4.25(m,1H);2.4÷3.3(7H);1.81(m,1H);1.78(d,3H);1.24(m,1H)
元素分析:C12H18N2O5
C H N
实测值% 52.98 6.71 10.18
计算值% 53.32 6.71 10.37
(±)-内式-O-(1-氮杂双环[321]-辛-6-基)-N-亚乙基-羟胺富马酸盐
(化合物21)
M.p.135-140℃(分解)
MS(C.I.)=169 m/e [M+H]
1H-NMR[CDCl3]:10.6(b,2H);7.48和6.85(2q,1H);6.81(s,2H);5.09(m,1H);4.04(m,1H);3.3÷3.6(3H);3.0÷3.3(2H);2.73(b,1H);2.21(m,1H);1.7÷2.1(3H);1.86和1.88(2d,3H)
元素分析:C13H20N2O5
C H N
实测值% 54.84 7.25 9.74
计算值% 54.92 7.09 9.85
(±)-外式-O-(1-氮杂双环[321]-辛-6-基)-N-亚乙基-羟胺盐酸盐
(化合物22)
M.p.170-173℃
MS(C.I.)=169 m/e [M+H]
1H-NMR[CDCl3]:12.84(b,1H);8.03(s,1H);7.2÷7.7(5H);4.20(d,2H);1.8÷3.7(12H)
元素分析:C9H17ClN2O
C H N Cl
实测值% 52.15 8.40 13.59 17.9
计算值% 52.80 8.37 13.69 17.2
(±)-内式-O-(1-氮杂双环[321]-辛-3-基)-N-亚乙基-羟胺富马酸盐
(化合物23)
M.p.125-127℃(分解)
MS(C.I.)=169 m/e [M+H]
1H-NMR[DMSO]:9.2(b,2H);6.94(q,1H);6.47(s,2H);4.31(b,1H);3.41和3.50(d,m,2H);3.23(m,2H);3.01和3.12(m,d,2H);2.50(m,1H);1.9÷2.2(4H);1.81(d,3H)
元素分析:C13H20N2O5
C H N
实测值% 54.43 7.11 9.75
计算值% 54.92 7.09 9.85
(±)-外式-O-(1-氮杂双环[321]-辛-3-基)-N-亚乙基-羟胺富马酸盐
(化合物24)
M.p.119-121℃(分解)
MS(C.I.)=169 m/e [M+H]
1H-NMR[DMSO+CDCl3]:9.46(b,2H);7.39和6.82(2q,1H);6.53(s,2H);4.46(m,1H);2.5÷3.6(7H);1.4÷2.3(4H);1.75和1.77(2d,3H)
元素分析:C13H20N2O5
C H N
实测值% 53.60 6.93 9.42
计算值% 53.73 6.87 9.53
(±)-内式-O-(1-氮杂双环[331]-壬-3-基)-亚乙基-羟胺富马酸盐
(化合物25)
M.p.吸湿性固体
MS(C.I.)=183 m/e [M+H]
1H-NMR[DMSO]:8.3(b,2H);7.51和6.93(2q,1H);6.50(s,2H);4.37(m,1H);3.60(m,1H);3.0÷3.3(5H);2.51(m,1H);2.23(m,1H);2.04(b,1H);1.4÷1.9(4H);1.81和1.82(2d,3H)
元素分析:C14H22N2O5
C H N
实测值% 56.04 7.34 9.19
计算值% 56.36 7.43 9.39
(±)-外式-O-(1-氮杂双环[331]-壬-3-基)-亚乙基-羟胺盐酸盐
(化合物26)
M.p.155-160℃(分解)
MS(C.I.)=183 m/e [M+H]
1H-NMR[CDCl3]:12.68(b,1H);7.41和6.80(2q,1H);4.98(m,1H);3.60(m,1H);3.2÷3.5(5H);1.8÷2.5(7H);1.82和1.83(2d,3H)
元素分析:C10H19ClN2O
C H N Cl
实测值% 54.00 8.61 12.57 16.10
计算值% 54.91 8.76 12.81 16.21
外式-O-(8-甲基-8-氮杂双环[321]-辛-3-基)-N-亚乙基-羟胺富马酸盐
(化合物27)
M.p.145℃(分解)
MS(C.I.)=183 m/e [M+H]
1H-NMR[CDCl3]:11.40(b,2H);6.82(s,2H);7.40和6.75(2q,1H);4.44(m,1H);3.98(b,2H);2.78(s,3H);2.1÷2.4(6H);1.95(d,2H);1.81和1.82(2d,3H)
元素分析:C14H22N2O5
C H N
实测值% 56.28 7.49 9.36
计算值% 56.36 7.43 9.39
R(-)-O-[1-氮杂双环[221]-辛-3-基)]-甲基-N-亚甲基-羟胺
(化合物50)
S(+)-O-[1-氮杂双环[221]-辛-3-基)]-甲基-N-亚甲基-羟胺
(化合物51)
实例7
R(-)-O-(1-氮杂双环[222]-辛-3-基)]-甲基-N-亚乙基-羟胺盐酸盐
(化合物28)
R(-)-O-[(1-氮杂双环[222]-辛-3-基)-甲基]羟胺二盐酸盐(1.5克)、甲醇(25毫升)和金属钠(300毫克)混合物,室温搅拌至金属钠完全溶解,冰水浴冷却后,滴加乙醛(0.37毫升),反应液室温搅拌2小时,然后蒸发至干。残余物用水溶解,并以乙酸乙酯洗涤。水层用Na2CO3碱化并用CHCl3萃取。合并有机层,干燥,蒸干。粗品溶于乙酸乙酯中,加入无水HCl的乙醚溶液,得到目标化合物盐酸盐。滤出固体并真空干燥。得到纯标题化合物(0.34克),是一白色固体。
M.p.135-140℃
MS(C.I.)=183 m/e [M+H]
[α]D=-39.46°(c=1%在1N HCl中)
1H-NMR(CDCl3)1.7÷2.8(6H,m),1.81和1.84(3H,2d),2.9÷3.7(6H,m),4.03和4.13(2H,2d),6.76和7.39(1H,2q),12.05(1H,b)
元素分析:C10H19ClN2O
C H N Cl
实测值% 54.18 8.82 12.63 16.15
计算值% 54.91 8.76 12.81 16.24
按照上述过程,以适当的中间体为原料,制备出下列各化合物
S(+)-O-[(1-氮杂双环[222]-辛-3-基)-甲基]-N-亚乙基-羟胺盐酸盐
(化合物29)
M.p.145-150℃
MS(C.I.)=183 m/e [M+H]
[α]D=+41.63°(c=1%在1N HCl中)
1H-NMR(CDCl3)1.7÷2.7(6H,m),1.80和1.84(3H,2d),2.9÷3.7(6H,m),4.04和4.12(2H,2d),6.76和7.39(1H,2q),12.08(1H,b)
元素分析:C10H19ClN2O
C H N Cl
实测值% 54.42 8.79 12.66 16.18
计算值% 54.91 8.76 12.81 16.24
O-(1-乙基-1-氮杂环丁-3-基)-N-亚乙基-羟胺
(化合物31)
(±)-O-(1-甲基-1-氮杂环戊-3-基)-N-亚乙基-羟胺草酸盐
(化合物33)
M.p.105-109℃(分解)
MS(C.I.)=143 m/e [M+H]
1H-NMR[DMSO]10.24(b,2H);7.47和6.95(2q,1H);4.81(m,1H);3.2÷3.6(4H),2.80(s,3H);2.30(m,1H);2.07(m,1H);1.78和1.80(2d,3H)
元素分析:C9H16N2O5
C H N
实测值% 46.39 7.04 11.80
计算值% 46.55 6.94 12.06
(±)-O-(1-甲基-1-氮杂环庚-3-基)-N-亚乙基-羟胺马来酸盐
(化合物35)
M.p.95-100℃(分解)
MS(C.I.)=171 m/e [M+H]
1H-NMR[CDCl3]7.48和6.85(2q,1H);6.29(s,2H);4.53(b,1H);3.1÷3.7(b,4H),2.92(s,3H);1.6÷2.2(6H);1.87(d,3H)
元素分析:C13H22N2O5
C H N
实测值% 54.12 7.75 9.59
计算值% 54.53 7.74 9.78
O-(1-甲基-1-氮杂环己-4-基)-N-亚乙基-羟胺富马酸盐
(化合物37)
M.p.90-95℃(分解)
MS(C.I.)=157 m/e [M+H]
1H-NMR[DMSO+CDCl3]10.64(b,2H);6.80和7.42(2q,1H);6.57(s,2H);4.12(m,1H);2.4÷3.1(4H);2.46(s,3H);1.79(d,3H);1.7÷2.2(4H)
元素分析:C12H20N2O5
C H N
实测值% 52.67 7.59 10.22
计算值% 53.93 7.40 10.29
(±)-O-(1-甲基-1-氮杂环己-3-基)-N-亚乙基-羟胺盐酸盐
(化合物39)
M.p.150-157℃(分解)
MS(C.I.)=157 m/e [M+H]
1H-NMR[CDCl3]12.7和11.7(2b,1H);7.80,7.36和6.83(3m,1H);4.48(m,1H);3.58(m,2H);2.84(s,3H);2.6÷3.2(2H);1.5÷2.4(4H);1.82和1.83(2d,3H)
元素分析:C8H17ClN2O
C H N Cl
实测值% 49.56 8.99 14.44 18.32
计算值% 49.87 8.89 14.54 18.40
R-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2,2-三氯-亚乙基)-羟胺盐酸盐
(化合物40)
M.p.225℃(分解)
MS(C.I.)=272 m/e [M+H]
[α]D=-30.0(c=1%在乙醇中)
1H-NMR[CDCl3]12.24(b,1H);7.90(s,1H);4.73(m,1H);3.70(m,1H);3.2÷3.6(5H);2.61(b,1H);1.8÷2.3(4H)
元素分析:C9H14Cl4N2O
C H N Cl
实测值% 34.80 4.65 8.99 46.18
计算值% 35.09 4.58 9.09 46.05
S-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2,2-三氯-亚乙基)-羟胺盐酸盐
(化合物41)
M.p.225℃(分解)
MS(C.I.)=272 m/e [M+H]
[α]D=+31.3(c=1%在乙醇中)
1H-NMR[CDCl3]12.55(b,1H);7.84(s,1H);4.70(m,1H);3.62(m,1H);3.2÷3.5(5H);2.62(b,1H);1.7÷2.3(4H)
元素分析:C9H14Cl4N2O
C H N Cl
实测值% 34.47 4.50 8.84 46.11
计算值% 35.09 4.58 9.09 46.05
R-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2-二氯-亚乙基)-羟胺富马酸盐
(化合物42)
M.p.170-172℃(分解)
MS(C.I.)=238 m/e [M+H]
[α]D=-30.73(c=1%在乙醇中)
1H-NMR[DMSO+CDCl3]8.18(b,2H);7.81和7.32(2d,1H);7.16和6.79(2d,1H);6.56(s,2H);4.49(m,1H);3.42(m,1H);2.8÷3.2(5H);2.26(m,1H);1.5÷2.0(4H)
元素分析:C13H18Cl2N2O5
C H N Cl
实测值% 44.04 5.20 8.01 19.95
计算值% 44.21 5.14 7.93 20.08
S-O-(1-氮杂双环[222]-辛-3-基)-N-(2,2-二氯-亚乙基)-羟胺富马酸盐
(化合物43)
M.p.172-174℃(分解)
MS(C.I.)=238 m/e [M+H]
[α]D=-31.61(c=1%在乙醇中)
1H-NMR[DMSO+CDCl3]9.75(b,2H);7.81和7.34(2d,1H);7.16和6.80(2d,1H);6.56(s,2H);4.47(m,1H);3.44(m,1H);2.8÷3.2(5H);2.24(m,1H);1.5÷2.0(4H)
元素分析:C13H18Cl2N2O5
C H N Cl
实测值% 44.00 5.22 7.85 20.19
计算值% 44.21 5.14 7.93 20.08
R-O-(1-氮杂双环[222]-辛-3-基)-N-(1-氟-亚乙基)-羟胺富马酸盐
(化合物46)
M.p.118-121℃(分解)
MS(C.I.)=187 m/e [M+H]
[α]D=-29.7(c=1%在乙醇中)
1H-NMR[DMSO]6.52(s,2H);4.43(m,1H);3.42(m,1H);2.9÷3.2(5H);2.27(m,1H);2.19和2.04(2d,3H);1.5÷2.0(4H)
元素分析:C13H19FN2O5
C H N
实测值% 51.35 6.40 9.18
计算值% 51.65 6.34 9.27
S-O-(1-氮杂双环[222]-辛-3-基)-N-(1-氟-亚乙基)-羟胺富马酸盐
(化合物47)
M.p.140℃(分解)
MS(C.I.)=187 m/e [M+H]
[α]D=+28.87(c=1%在乙醇中)
1H-NMR[DMSO]8.2(b,2H);6.53(s,2H);4.35(m,1H);3.42(m,1H);2.9÷3.2(5H);2.18和2.04(2d,3H);1.5÷2.0(4H);2.28(m,1H)
元素分析:C13H19FN2O5
C H N
实测值% 51.13 6.45 9.12
计算值% 51.65 6.34 9.27
S-O-(1-氮杂双环[222]-辛-3-基)-N-亚甲基-羟胺盐酸盐
(化合物48)
M.p.80-90℃(分解,吸湿性固体)
MS(C.I.)=155 m/e [M+H]
[α]D=+25.78(c=1%在甲醇中)
1H-NMR[DMSO]10.86(b,1H);7.16(d,1H);6.75(d,1H);4.56(m,1H);3.0÷3.6(6H);1.5÷2.4(5H)
元素分析:C6H16Cl2N2O
C H N Cl
实测值% 41.94 7.19 12.20 31.32
计算值% 42.30 7.10 12.33 31.22
R-O-(1-氮杂双环[222]-辛-3-基)-N-亚甲基-羟胺盐酸盐
(化合物49)
M.p.145-150℃(分解)
MS(C.I.)=155 m/e [M+H]
[α]D=-26.32(c=1%在甲醇中)
1H-NMR[DMSO]7.16(d,1H);6.74(d,1H);4.56(m,1H);3.56(m,1H);3.6(b,1H);3.0÷3.3(5H);2.30(m,1H);1.6÷2.0(4H)
元素分析:C8H16Cl2N2O
C H N Cl
实测值% 41.96 7.21 12.30 31.04
计算值% 42.30 7.10 12.33 31.22
实例8
内式-O-(8-甲基-8-氮杂双环[321]-辛-3-基)-N-亚乙基-羟胺盐酸盐
(化合物44)
在金属钠(0.237克)的乙醇溶液(10毫升)中,分批加入乙醛肟(1.97毫升),搅拌15分钟后,加入内式-8-甲基-3-氯-8-氮杂双环[321]-辛烷(5.16克)[J.Am.Chem.Soc.80,4677(1958)]。所得溶液回流15小时,然后冰水浴冷却,并用HCl乙醇溶液调节pH至9。滤除无机盐,并将滤液蒸发至干。粗品残渣用闪式柱层析(硅胶)纯化(洗脱剂:95∶5∶0.5=CH2Cl2∶CH3OH∶NH4OH30%)。所得粗品溶于乙酸乙酯,加入无水HCl乙醚溶液,然后蒸发至干,用乙醚结晶后得到固体的标题化合物(0.13克)。
M.p.160℃
MS(C.I.)=183 m/e [M+H]
1H-NMR(DMSO+CDCl3)1.81(3H,d);2.0÷3.4(8H,m);2.68(3H,d);3.82(2H,b);4.26(1H,m);6.86和7.44(1H,2q);11.36(1H,b)
元素分析:C10H19ClN2O
C H N Cl
实测值% 53.55 8.83 12.49 15.98
计算值% 54.91 8.76 12.81 16.21
按照以上所述步骤制备出下列各化合物
O-(1-甲基-1-氮杂环己-4-基)-N-异亚丙基-羟胺盐酸盐
(化合物45)
M.p.140℃
MS(C.I.)=171 m/e [M+H]
1H-NMR(DMSO+CDCl3)1.8÷2.4(10H,m);2.73(3H,d);2.7÷3.6(4H,m);4.26(1H,m);10.92(1H,b)
元素分析:C9H19ClN2O
C H N Cl
实测值% 51.54 9.30 13.25 16.88
计算值% 52.29 9.26 13.53 17.15
实例9
a)(±)N-[(1-氮杂环己-3-基)-氧]邻苯二甲酰亚胺
在1,2-二氯乙烷(50ml)中的N-[(1-甲基-1-氮杂环己-3-基)-氧]邻苯二甲酰亚胺(1.1克)和1,8-双(二甲氨基)萘(质子海绵)(0.9克),在5℃冷却后,滴入二氯甲酸1-氯-乙基酯(0.6毫升)。反应液室温搅拌过夜,然后依次用烯的Na2CO3水溶液和稀盐酸水溶液洗涤。有机层干燥并蒸发至干。粗品残渣溶于甲醇(50毫升)中,并将所得溶液回流2小时蒸发至干,得到粗品中间体(0.9克,用乙酸乙酯和乙醚混合物结晶,m.p.233-236℃),产品的纯度可以直接用于下步反应;
b)(±)O-(1-氮杂环己-3-基)-羟胺二盐酸盐
上述中间体(0.87克)溶于无水乙醇中(35ml),在搅拌下滴入85%水合肼水溶液。反应液在室温再搅拌3小时,过滤,将澄清滤液用10%盐酸水溶液酸化,并蒸发至干。用乙醇结晶后就得到标题化合物(0.45克),为一白色固体,m.p.158-161℃。
实例10
O-(1-氮杂环己-4-基)-N-亚乙基-羟胺盐酸盐
(化合物36)
在1,2-二氯乙烷中加入O-(1-甲基-1-氮杂环己-4-基)-N-亚乙基羟胺(0.4克)和1,8-双(二甲氨基)萘(质子海绵)(0.55克),在5℃冷却,然后在搅拌下滴加氯甲酸1-氯乙基酯(0.34毫升),并室温搅拌过夜。然后加入Na2CO3水溶液,分出有机层并用5%盐酸水溶液洗涤,蒸干,残余物用甲醇溶解并回流1小时,蒸干,得到标题化合物的盐酸盐粗品,用乙酸乙酯结晶得1.80克。
M.p.130-140℃(分解)
MS(C.I.)=143 m/e [M+H]
1H-NMR[DMSO+CDCl3]9.16(b,2H);7.45和6.85(2q,1H);4.25(m,1H);3.07(m,4H);1.97(m,4H);1.80(d,3H)
元素分析:C7H15ClN2O
C H N Cl
实测值% 46.81 8.56 15.48 19.70
计算值% 47.06 8.46 15.60 19.84
根据上述步骤,以适当的中间体为原料,制备出下列各化合物
O-(1-氮杂环丁-3-基)-N-亚乙基-羟胺
(化合物30)
(±)O-(1-氮杂环戊-3-基)-N-亚乙基-羟胺,草酸盐
(化合物32)
M.p.150℃(分解)
MS(C.I.)=129 m/e [M+H]
1H-NMR[DMSO]9.27(b,3H);7.46和6.96(2q,1H);4.78(m,1H);3.1÷3.4(4H);2.08(m,2H);1.77和1.80(2d,3H)
元素分析:C8H14N2O5
C H N
实测值% 42.98 6.31 12.62
计算值% 44.03 6.47 12.84
(±)O-(1-氮杂环庚-3-基)-N-亚乙基羟胺,盐酸盐
(化合物34)
M.p.110℃(分解)
MS(C.I.)=157 m/e [M+H]
1H-NMR[CDCl3]9.89(b,1H);9.36(b,1H);7.57和6.83(2q,1H);4.58(m,1H);3.2÷3.6(4H);1.6÷2.3(6H);1.86和1.91(2d,3H)
元素分析:C8H17ClN2O
C H N Cl
实测值% 50.10 8.99 14.27 18.25
计算值% 49.87 8.89 14.54 18.40
(±)-O-(1-氮杂环己-3-基)-N-亚乙基-羟胺盐酸盐
(化合物38)
M.p.98-100℃(分解)
MS(C.I.)=143 m/e [M+H]
1H-NMR[CDCl3]9.84(b,1H);9.22(b,1H);7.60和6.84(2q,1H);4.45(m,1H);3.0÷3.4(4H);1.7÷2.2(4H);1.85和1.96(2d,3H)
元素分析:C7H15ClN2O
C H N Cl
实测值% 46.45 8.52 15.58 19.78
计算值% 47.06 8.46 15.60 19.84
实例11
片剂
-活性组分 50mg 100mg
-乳糖 100mg 200mg
-玉米淀粉 4mg 8mg
-硬脂酸镁 0.95mg 1.08mg
制备方法:活性组分、乳糖和一份玉米淀粉混合后,并用10%玉米淀粉糊颗粒化。所得颗粒过筛,干燥,并与剩余的玉米淀粉和硬脂酸镁混合。然后将所得颗粒分别压成每片含50mg和100mg活性组分的片剂。
Claims (11)
1、通式(Ⅰ)的化合物,或其盐、光学和几何异构体、非对映异构体及其混合物,
其中:
A代表4-8元环的氮杂环烷残基,或者7-9个原子的氮杂双环烷基,N-可任选地被C1-3烷基取代;
n代表1或0;
R1和R2独立地代表:氢;任选地被烷氧基、烷巯基、氰基或卤素取代的直链或支链烷基;C2-6烯基;C2-6炔基;卤素;任选地被卤素、C1-3烷基、C1-3烷氧基取代的芳基;C6-12芳烷基;杂环芳基;或者与它们所相连的碳原子一起构成一个4-7元环;侧链-(CH2)n-O-N=C-R1R2与不靠近氮杂环烷或氮杂双环烷中的氮原子的碳原子相连。
2、权利要求1的化合物,其中,该氮杂环烷残基 A是1-氮杂环丁-3-基,1-氮杂环戊-3-基,1-氮杂环己-3-基,1-氮杂环己-4-基和1-氮杂环庚-3-基,并且N-可任选地被C1-3烷基取代。
3、权利要求1的化合物,其中,该氮杂双环烷基A是1-氮杂双环[2.2.1]-庚-3-基,1-氮杂双环[2.2.2]-辛-3-基,1-氮杂双环[3.2.1]-辛-3-基,1-氮杂双环[3.2.1]-辛-6-基,1-氮杂双环[3.3.1]-壬-3-基和8-氮杂双环[3.2.1]-辛-3-基,N-任选地被C1-3烷基取代。
4、按前述权利要求的通式(Ⅰ)的化合物,其中,A是氮杂双环烷基,n是0,R1是氢,低级C1-2烷基或卤素,并且R2是氢或低级C1-3烷基(可以任选地含有一个烷氧基或卤素),C2-6炔基或卤素。
5、按前述权利要求的化合物,选自:
R(-)-O-(1-氮杂双环[222]辛-3-基)-N-亚乙基-羟胺,盐酸盐;
(±)-外式-O-(1-氮杂双环[321]辛-6-基)亚乙基-羟胺,盐酸盐;
(±)-外式-O-(1-氮杂双环[221]庚-3-基)-N-亚乙基-羟胺,富马酸盐;
(±)-外式-O-(1-氮杂双环[321]辛-3-基)-N-亚乙基-羟胺,富马酸盐;
S(+)-O-(1-氮杂双环[222]辛-3-基)-N-(2,2,2-三氟亚乙基)-羟胺,富马酸盐。
6、权利要求1-5的通式(Ⅰ)化合物的药用酸式加成盐。
7、权利要求6中所述的盐,其中,药用酸是盐酸,酒石酸,或富马酸。
9、权利要求8的方法,其特征是该羟基溶剂选自甲醇、乙醇、异丙醇。
10、药物组合物,包括有效量的权利要求1的式(Ⅰ)化合物或其药用酸式加成盐作为活性组分,与药用载体、稀释剂或赋形剂。
11、权利要求10的药物组合物,用于治疗神经或精神障碍性疾病,特别是认识障碍,与年龄有关的记忆性损伤,不同形式的痴呆,阿耳茨海默氏病,杭廷顿氏舞蹈病,迟发性运动机能障碍,运动机能亢进,图雷特氏综合症。
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ITMI921571A IT1255179B (it) | 1992-06-26 | 1992-06-26 | Azaciclo e azabiciclo alchiliden idrossilamine |
ITMI92A001571 | 1992-06-26 |
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AU (1) | AU4325393A (zh) |
IT (1) | IT1255179B (zh) |
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US9878989B2 (en) | 2015-06-26 | 2018-01-30 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
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1992
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- 1993-06-14 WO PCT/EP1993/001493 patent/WO1994000448A1/en active Application Filing
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AU4325393A (en) | 1994-01-24 |
TW225523B (zh) | 1994-06-21 |
ITMI921571A1 (it) | 1993-12-26 |
ITMI921571A0 (it) | 1992-06-26 |
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