CN1636154A - 二-取代的亚氨基杂环化合物 - Google Patents
二-取代的亚氨基杂环化合物 Download PDFInfo
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- CN1636154A CN1636154A CNA018005829A CN01800582A CN1636154A CN 1636154 A CN1636154 A CN 1636154A CN A018005829 A CNA018005829 A CN A018005829A CN 01800582 A CN01800582 A CN 01800582A CN 1636154 A CN1636154 A CN 1636154A
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- pyridyl
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Abstract
本发明提供了式(I)的二取代的亚氨基杂环化合物或其可药用的盐,其中:A是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基;X是氧原子、硫原子、碳原子或氮原子;基团-Y-X-表示选择性取代的亚烷基或环亚烯基;和B1和B2彼此独立地是氢原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基。这些化合物对α4β2烟碱乙酰基胆碱受体具有良好亲和力,将其活化从而对小脑机能障碍产生预防或治疗作用。
Description
技术领域
本发明涉及对烟碱乙酰胆碱受体显示亲和力和活化它们的化合物。本发明的化合物用于预防或治疗神经变性疾病,例如早老性痴呆和帕金森氏疾病、痴呆,例如脑血管痴呆,运动性共济失调,例如图雷特氏综合症、神经病学上的疾病,例如慢性小脑梗塞、神经病和精神病,例如焦虑和精神分裂症和由小脑损伤引起的小脑机能障碍。
背景技术
现在已经广泛已知烟碱存在许多药理学效果。这包括例如对中枢神经系统的胆碱能神经活化作用,如使乙酰基胆碱释放容易[Desarno P.& Gia cobini E.,J.Neurosci.Res.,22,194-200(1984)]和对单胺能神经系统的活化作用[Levin E.D.& Simon B.B.,Psychopharmacologh,138,217-230(1998)]。
还有报导称烟碱具有许多非常有用的小脑功能改善作用,例如增加小脑血液流动和脑中的葡萄糖摄入速率Decker M.W.et al.,LifeSic.,56,545-570(1995)。
还有报导称烟碱抑制β-肽的淀粉样蛋白形成,它被认为是早老性痴呆过程中神经元细胞死亡的原因[Salomon A.R.等,Biochemistry,35,13568-13578(1996)],和对由β-淀粉样蛋白(Aβ)引起的神经元细胞死亡具有细胞保护作用[Kihara T.等,Ann.Neurol.,42,156-163(1997)]。最近的研究建议烟碱作为炎性结肠炎的药物的可能性[Sandborn W.J.等,Ann.Intern.Med.126,364(1997)]。
另一方面,人们已知在早老性痴呆患者中,已知对认知,例如注意、学习、记忆和再认知起作用的重要神经元体系之一的乙酰基胆碱神经元的退化被改变,因而在小脑皮层和海马中烟碱乙酰基胆碱受体急剧下降[Nordberg A.等,J.Neurosci.Res.,31,103-111(1992)]。
已报导用烟碱乙酰基胆碱的激动剂或调制剂,通过活化烟碱异丁基胆碱受体以恢复乙酰基胆碱神经系统机制,有效治疗早老性痴呆的可能性[Newhouse P.A.等,Psychopharmacology,95,171-175(1988)]。
烟碱乙酰基胆碱受体属于由5个亚单元组成的离子通道神经递质受体,即,激动剂,例如乙酰基胆碱、烟碱等结合于受体以活化和打开其通道,从而导致阳离子,例如钠离子由细胞处流入以产生细胞刺激[Galzi J.L.& Changeux J.P.,Neuropharmacology,34563-582(1995)]。上述激动剂,例如乙酰基胆碱、烟碱等通过结合于存在于α亚单元中的特殊位置,所谓的激动剂结合位置显示其效果。
另一方面,人们已知通过增强乙酰基胆碱的作用活化细胞的化合物,例如雪花胺等等对烟碱乙酰基胆碱受体没有直接激动剂作用。这些化合物通过明显不同于激动剂结合位置的变构位置显示其效果[Schrattenholz A.等,Mol.Pharmacol.,49,1-6(1996)]。
如上所述,能够间接活化烟碱乙酰基胆碱受体的化合物称为调制剂,它被预期作为治疗各种神经疾病的有用药物[Lin N.-H & MeyerM.D.,Exp.Opin.Thr.Patents,8,991-1015(1998)]。
术语“激动剂”和“调制剂”以这些定义用于本说明书中。
烟碱乙酰基胆碱受体被认为不仅参与早老性痴呆,而且参与神经变性疾病,例如帕金森病和许多神经功能症和精神病,例如痴呆、焦虑、精神分裂症等[Barrantes F.J.,The Nicotic AcetylcholineReceptor,ed.Barrantes F.J.,Springer,1997,p175-212;LenaC. & Changeux J.-P.,J.Physiol.(Paris),92,63-74(1998)]。
尤其是,自从人们已知患有由小脑梗塞引起的脑血管痴呆的患者的小脑血流量下降以来[Takagi Shigeharu,gendai Iryo,28,1157-1160(1996);Tachibana H.等,H.Gerontol.,39,415-523(1984)],似乎存在将具有小脑血流量增加作用的烟碱乙酰基胆碱受体激动剂或调制剂应用于该治疗领域的药物的可能性。此外,最近的研究显示烟碱乙酰基胆碱受体的激动剂和其调制剂显示止痛活性[Bannon A.W.等,Science,279,77-81(1998)]。
作为烟碱乙酰基胆碱受体激动剂,烟碱本身的确有影响,例如,在烟碱向早老性痴呆患者给药后,观察到他们注意力或短时记忆的恢复,他们的疾病症状将改善[Newhousr P.A.等,Drugs & Aging,11,206-228(1997)]。然而,烟碱还具有缺点,例如广泛的识别瘾以及低生物有效性和对心血管系统的严重副作用。
因此,人们更加期望开发没有瘾、高的生物有效性和低的对心血管系统的副作用的烟碱乙酰基胆碱受体或调制剂作为药物以替代烟碱[Maelicke A.& Albuquerque E.X.,Drug Discovery Today,1,53-59(1996);Holladay M.W.等,J.Med.Chem.,40,4169-4194(1997)]。
作为烟碱乙酰基胆碱受体,已知存在一些亚型[Shacka J.J.&Robinson S.E.T.,Med.Chem.Res.,1996,444-464],主要是存在于中枢神经系统中的α4β2亚型受体。此外,在动力神经元的神经肌肉接合处存在的α1β1γδ(或α1β1εδ)亚型受体和在自主神经系统的神经节和肾上腺中存在的α3β4亚型受体。
胆碱能神经系统的活化和小脑血流量的增加作用被认为通过在中枢神经系统中的α4β2亚型受体发生,烟碱对心血管系统的上述效果通过影响存在于末梢神经系统中的受体亚型引起。
因此,开发对α1β1γδ亚型受体和α3β4亚型受体没有亲和力,但选择性地影响α4β2亚型受体的化合物作为没有副作用的药物是尤其有用的。
在这种情况下,已有许多提议以开发对中枢神经系统的烟碱乙酰基胆碱受体的选择性激动剂或调制剂作为实用的药物。它们包括,例如化合物,例如ABF-418[Arneric S.P.等,J.Pharmacol.Exp.Ther.,270,310-318(1994);Decker M.W.等,J.Pharmacol.Exp.Ther.,270,319-328(1994)]、ABT-089[Sulli van J.P.等,J.Pharmacol.Exp.Ther.,283,235-246(1997);Decker M.W.等,J.Pharmacol.Exp.Ther.,283,247-258(1997)]、GTS-21[ArendashG.W.等,Brain Res.,674,252-259(1995);Briggs C.A.等,Pharmacol Biochem.Behav.,57,231-241(1997)]、RJR-2403[Bencherif M.等,J.Pharmacol.Exp.Ther.,279,1413-1421(1996);Lippiello P.M.等,J.Pharmacol.Exp.Ther.,279,1422-1429(1996)]、SIB-1508Y[Cosford N.D.P.等,J.Med.Chem.,39,3235-3237(1996);Lloyd.G.K.等,Life Sci.,1601-1606(1995)]、SIB-1553A[Lloyd.G.K.等,Life Sci.,62,1601-1606(1995)]等。
其中,
R表示氢、选择性取代的酰基、烷基、芳基、芳烷基、杂芳基或杂芳烷基;
A表示氢、酰基、烷基或芳基系列的单官能团基团或表示连接于基团Z的双官能团基团;
E表示吸电子基团;
X表示-CH=或=N-基团,对于-C=基团可以连接于替代H原子的Z基团;
Z表示烷基、-O-R、-S-R或-NR2系列的单官能团基团或表示连接于A基团或X基团的双官能团基团。
然而,在上述专利公开中公开的化合物中,E基团限制于吸电子基团,因此,这些化合物明显不同于本专利申请公开的化合物。此外,在上述专利公开中未描述这些化合物能够选择性地活化α4β2烟碱乙酰基胆碱受体。
另一方面,作为杀虫剂的“吡虫啉”已知具有如本发明的化合物的类似骨架。已证实作为部分激动剂吡虫啉电生理学地影响PC12细胞的烟碱乙酰基胆碱受体[Nagata K.等,J.Pharmacol.Exp.Ther.,285,731-738(1998)]和吡虫啉本身或其代谢物和它们的类似物对小鼠脑中的烟碱乙酰基胆碱受体具有亲和力[Lee Chao S.& Casida E.,Pedtic,Biochem.Physiol.,58,77-88(1997);Tomizawa T.&Casida J.E.,J.Pharmacol.,127,115-122(1999);Latli B.等,J.Med.Chem.,42,2227-2234(1999)],然而,未报导吡虫啉衍生物选择性地活化α4β2烟碱乙酰基胆碱受体。
日本专利公开平10-226684公开了如下通式表示的[N-(吡啶基甲基)杂环]亚基胺,它们的可药用的盐和前药。
其中,
A表示-CH(R)-;
R3表示氢原子或选择性取代的C1-C6烷基;和
B表示下式的基团:
然而,在所述专利公开所公开的化合物中,在化合物中的亚氨基和基团Y未被取代,因此,这些化合物明显不同于本发明的化合物。已公开了上述化合物对烟碱乙酰基胆碱受体具有弱的亲和力;然而,未公开这些化合物对中枢神经系统的α4β2烟碱乙酰基胆碱受体具有选择性活化作用和用作烟碱乙酰基胆碱受体的激动剂或调制剂。
如上所述,人们已作了许多尝试以开发通过口服给药的选择性地活化中枢神经系统的α4β2烟碱乙酰基胆碱受体的激动剂或调制剂,但没有是令人满意的。
发明公开
因此,本发明提供了用于治疗通过活化烟碱乙酰基胆碱受体可预防或治愈的疾病的治疗或预防药物,所述药物具有选择性地结合中枢神经系统的α4β2烟碱乙酰基胆碱受体的能力,在心血管系统中没有不需要的副作用,例如高血压或心动过速。
更具体地说,本发明提供用于预防或治疗各种疾病的药物,所述疾病可通过活化烟碱乙酰基胆碱受体预防或治愈,如痴呆、老年性痴呆、老年前期痴呆、早老性痴呆、帕金森病、脑血管痴呆、AIDS相关的痴呆、在唐氏综合症中的痴呆、图雷特氏病、慢性小脑梗塞中的神经病、小脑损伤引起的机能障碍、焦虑、精神分裂症、郁抑、杭庭顿氏舞蹈病、疼痛等等。
通过对具有中枢神经系统的α4β2烟碱乙酰基胆碱受体的选择性结合能力的所调查的化合物的广泛研究,本发明人发现如下式(I)表示的化合物和它们的可药用的盐对中枢神经系统中的烟碱乙酰基胆碱受体具有高亲和力,作为激动剂或调制剂活化所述受体。
因此,作为本发明的一个方面,它提供了如下式(I)表示的二取代的亚氨基杂环化合物或其可药用的盐:
其中:
A是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基;
X是氧原子、硫原子、碳原子或氮原子;和
Y、B1和B2是,
(1)在X是氧原子的情况下,基团-Y-X-是-CH2-CH2-O-或-CH2-CH2-CH2-O-;B1是选择性取代的烷基;选择性取代的芳基;选择性取代的杂环基;和B2没有;
(2)在X是硫原子的情况下,基团-Y-X-是-CH2-CH2-S-或-C(R1)=C(R2)-S-(其中,R1和R2是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);B1是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基;和B2没有;
(3)在X是碳原子的情况下,基团-Y-X-是-CH=C(R3)-C(R4)=CH-、-CH(R5)-CH2-CH2-CH2-或-N=C(R6)-C(R7)=CH-(其中,R3、R4、R5、R6和R7是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);B1是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基;和B2是氢原子;和
(4)在X是氮原子的情况下,基团-Y-X-是-CH2-CH2-N(B2)-、-C(R8)=C(R9)-N(B2)-、-CH2-CH2-CH2-N(B2)-或-CH=C(R10)-C(R11)=N-(其中,R8、R9、R10和R11是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);B1和B2之一是氢原子,另一个是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基。
本发明的另一方面,它提供用于α4β2烟碱乙酰基胆碱受体的活化试剂,其含有式(I)的二取代的亚氨基杂环化合物或其可药用的盐作为活性成分。
作为本发明的另一方面,它提供了式(I)的二取代的亚氨基杂环化合物或其可药用的盐用于治疗或预防小脑循环疾病、神经变性等的用途。
进行本发明的最佳方法
可药用的盐的实例包括无机盐,例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、高碘酸盐等,和有机酸,例如富马酸盐、马来酸盐、草酸盐、柠檬酸盐、酒石酸盐、苹果酸盐、乳酸盐、琥珀酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐等。
在式(I)化合物中“A”表示的基团是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基团,所述选择性取代的烷基的优选实例包括甲基、乙基、苄基、4-氯苄基、3-吡啶基甲基、(6-氯-3-吡啶基)甲基、(6-甲基-3-吡啶基)甲基、(5,6-二氯-3-吡啶基)甲基、2-(6-氯-3-吡啶基)乙基等。
芳基的优选实例可包括苯基、萘基等。取代的芳基的合适取代基可包括C1-C4-低级烷基、卤素原子等,因此,所述取代的芳基包括甲基苯基、氯苯基、二氯苯基等。
“A”表示的术语“杂环基团”可以是含有相同或不同的1-3个杂原子,例如硫、氮、氧原子的5或6元杂环基团,实例包括噻吩、呋喃、吡喃、吡咯、吡唑、吡啶、密啶、吡嗪、哒嗪、咪唑、噁唑、异噁唑、噻唑、异噻唑、喹啉、异喹啉、四氢嘧啶等。
取代的杂环基团的合适取代基可包括C1-C4低级烷基、卤素原子等,因此,所述取代的杂环基团的实例可以是2-甲基吡啶、2-氯吡啶、2-氟吡啶、2-溴吡啶、3-溴吡啶、2,3-二氯吡啶、2-氯噻唑、3-甲基异噁唑等。
在式(I)化合物中“B1”表示的基团是氢原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基团,所述选择性取代的烷基的优选实例包括甲基、乙基、苄基、4-氯苄基、3-吡啶基甲基、(6-氯-3-吡啶基)甲基、(6-甲基-3-吡啶基)甲基、(5,6-二氯-3-吡啶基)甲基、2-(6-氯-3-吡啶基)乙基等。
芳基的优选实例可包括苯基、萘基等。取代的芳基的合适取代基可包括C1-C4低级烷基、卤素原子等,因此,所述取代的芳基包括甲基苯基、氯苯基、二氯苯基等。
“B1”表示的术语“杂环基团”可以是含有相同或不同的1-3个杂原子,例如硫、氮、氧原子的5或6元杂环基团,实例包括噻吩、呋喃、吡喃、吡咯、吡唑、吡啶、嘧啶、吡嗪、哒嗪、咪唑、噁唑、异噁唑、噻唑、异噻唑、喹啉、异喹啉、四氢嘧啶等。
取代的杂环基团的合适取代基可包括C1-C4低级烷基、卤素原子等,因此,所述取代的杂环基团的实例可以是2-甲基吡啶、2-氯吡啶、2-氟吡啶、2-溴吡啶、3-溴吡啶、2,3-二氯吡啶、2-氯噻唑、3-甲基异噁唑等。
在式(I)化合物中“X”表示的基团代表氧原子、硫原子、碳原子或氮原子,“X”与“Y”结合构成由“-Y-X-”表示的部分组分,它具有如下含义。
(1)在“X”是氧原子的情况下,术语“-Y-X-”是-CH2-CH2-O-或-CH2-CH2-CH2-O-;
(2)在“X”是硫原子的情况下,术语“-Y-X-”是-CH2-CH2-S-或-C(R1)=C(R2)-S-(其中,R1和R2是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);
(3)在“X”是碳原子的情况下,术语“-Y-X-”是-CH=C(R3)-C(R4)=CH-、-CH(R5)-CH2-CH2-CH2-或-N=C(R6)-C(R7)=CH-(其中,R3、R4、R5、R6和R7是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);
(4)在“X”是氮原子的情况下,术语“-Y-X-”是-CH2-CH2-N(B2)-、-C(R8)=C(R9)-N(B2)-、-CH2-CH2-CH2-N(B2)-或-CH=C(R10)-C(R11)=N-(其中,R8、R9、R10和R11是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基)。
由R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11表示的术语“卤素原子”可包括氟、氯、溴和碘。
术语“选择性取代的烷基”可包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基等。
术语“选择性取代的芳基”可以是未取代的苯基或被卤素原子或C1-C4低级烷基,例如甲基、乙基等取代的苯基,因此取代的苯基的实例包括甲基苯基、氯苯基、二氯苯基等。
术语“杂环基团”可以是含有相同或不同的1-3个杂原子,例如硫、氮、氧原子的5或6元杂环基团,实例包括噻吩、呋喃、吡喃、吡咯、吡唑、吡啶、嘧啶、吡嗪、哒嗪、咪唑、噁唑、异噁唑、噻唑、异噻唑、喹啉、异喹啉、四氢嘧啶等。
取代的杂环基团的合适取代基可包括C1-C4低级烷基、卤素原子等,因此,所述取代的杂环基团的实例可以是2-甲基吡啶、2-氯吡啶、2-氟吡啶、2-溴吡啶、3-溴吡啶、2,3-二氯吡啶、2-氯噻唑、3-甲基异噁唑等。
对于在式(I)中由“B2”表示的基团,在“X”是氧原子或硫原子的情况下,在式(I)中的基团“B2”没有;在“X”是碳原子的情况下,基团“B2”表示氢原子;和在“X”是氮原子的情况下,基团“B2”表示选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基团。
选择性取代的烷基、选择性取代的芳基和选择性取代的杂环基团的实例与基团“B1”的情况中的定义相同,仅在基团“B2”是选择性取代的烷基、选择性取代的芳基和选择性取代的杂环基团的情况下,基团“B1”必须是氢原子。
如下是式(I)的二取代的亚氨基杂环化合物的实例。
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-噻唑烷;
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-3,4,5,6-四氢-2H-1,3-噁嗪;
1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2,3,4,5,6-六氢嘧啶;
1,3-二[(6-氯-3-吡啶基)甲基]-2-亚氨基-1,2,3,4,5,6-六氢嘧啶;
1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2-二氢嘧啶;
5-氯-1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2-二氢吡啶;
1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-6-甲基哌啶;
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-2,3-二氢噻唑;
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-4-甲基-2,3-二氢噻唑;
1,3-二[(6-氯-3-吡啶基)甲基]-2-亚氨基-2,3-二氢咪唑;
3-(6-氯-3-吡啶基)甲基-2-甲基亚氨基噻唑烷;
3-(6-氯-3-吡啶基)甲基-2-苯基亚氨基-2,3-二氢噻唑;
1-(6-氯-3-吡啶基)甲基-2-亚氨基-3-甲基-2,3-二氢咪唑;
2-苄基亚氨基-3-(6-氯-3-吡啶基)甲基噻唑烷;
3-(6-氯-3-吡啶基)甲基-2-[2-(6-氯-3-吡啶基)乙基]-亚氨基噻唑烷。
本发明的式(I)表示的二取代的亚氨基杂环化合物可根据各种合成方法,例如如下方法1-3制备。
在如下反应方案中,基团A、B1、B2、X和Y具有如上所述的相同含义,和n是整数1或2。
方法1:
根据如下反应方案,式(II)化合物与式(III)化合物反应得到式(IV)表示的中间体化合物,随后得到的式(IV)中间体化合物再与化合物(V)或(VI)反应得到本发明的式(I)化合物。
其中,“Z”是离去基团,它加速A,例如卤素原子、对甲苯磺酰氧基、甲磺酰氧基、三氟甲基磺酰氧基、酰氧基、取代的酰氧基等与氨基或杂环的氮原子反应。虚线表示存在或不存在键,具有如下与数值“n”相关的含义,即,在数值“n”是1的情况下,双键位于杂环的碳原子和环外的氮原子之间,因此所述的氮原子相当于亚氨基,在数值“n”是2的另一种情况下,双键位于杂环的碳原子和表示碳或氮原子的“X”之间,因此,环外氮原子相当于作为杂环取代基的氨基。
用于该反应的化合物(II)可以是商业上获得的或能够用常用方法由已知化合物容易地制备。
为得到中间体化合物(IV)化合物(II)与化合物(III)的反应和为得到化合物(I),生成的中间体化合物(IV)与化合物(V)或(VI)的反应通常可以在合适的溶剂中,例如醇溶剂、酮溶剂、腈溶剂、酯溶剂、酰胺溶剂、烃溶剂和醚溶剂或它们的混合物中,并根据需要在有机碱或无机碱存在下,在-20℃-所使用的溶剂的回流温度之间的温度下进行。
醇溶剂的实例包括甲醇、乙醇、丙醇、2-丙醇、2-甲基-2-丙醇等。酮溶剂可包括丙酮、甲基乙基酮等。腈溶剂可包括乙腈、丙腈等,酯溶剂可以是乙酸乙酯。酰胺溶剂的实例包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、六甲基膦酰胺等。烃溶剂可包括芳烃,例如苯、甲苯等,或脂族烃,例如戊烷、己烷等。醚溶剂的实例可包括乙醚、二甲氧基乙烷、四氢呋喃、1,4-二噁烷等。
在反应中所使用的有机碱的实例可包括三乙胺、三甲基吡啶、二甲基吡啶、叔丁醇钾等,无机碱可包括碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾等。
方法2:
当化合物(I)的基团“A”和“B1”或“A”和“B2”是相同基团时,所述化合物(I)可根据如下反应方案通过化合物(II)与过量的化合物(III)的反应直接得到。
其中“Z”具有上述的相同含义,基团“A”和“B1”或“A”和“B2”是相同基团。
化合物(II)与化合物(III)的反应可在上述方法1中描述的相同溶剂中在相同的碱存在下进行,此外,反应温度和时间也与上述方法1中所述相同。
方法3:
当化合物(I)的基团“X”是硫原子时,所述化合物(I)可根据反应方案通过化合物(VII)与化合物(III)反应得到。
其中“X”是硫原子,“B2”没有,和“Z”具有上述相同含义。
用于该反应方案的化合物(VII)可以是商业上获得的或能够容易地用常规方法由已知化合物制备。
化合物(VII)与化合物(III)的反应可基本上在上述方法1或2的相同反应条件下进行,即用于方法1和2的溶剂和碱可用于该方法3。此外,方法1和2的反应温度和时间条件在该方法3中也是合适的。
如果需要,由此得到的本发明的式(I)化合物可用上述各种有机或无机酸转化为可药用的盐。此外,本发明的化合物(I)还可通过常规方法,例如重结晶、柱色谱法等纯化。
当本发明的式(I)化合物存在异构体形式时,每个异构体本身通过常规方法彼此分离。因此,应理解每个异构体本身以及异构体混合物应包括在本发明的化合物中。
本发明的式(I)化合物选择性地结合中枢神经系统中的烟碱乙酰基胆碱受体,作为激动剂或调制剂活化所述受体。因此,这些化合物用作预防或治疗各种疾病,例如痴呆、老年性痴呆、老年前期痴呆、早老性痴呆、帕金森病、脑血管痴呆、AIDS相关的痴呆、在唐氏综合症中的痴呆、图雷特氏病、慢性小脑梗塞中的神经病、小脑损伤引起的机能障碍、焦虑、精神分裂症、郁抑、杭庭顿氏舞蹈病、疼痛等等的药物。
本发明的式(I)化合物或其可药用的盐可以口服或以肠胃外制剂形式给药。用于口服给药的制剂可包括,例如片剂、胶囊、颗粒、细粉、糖浆等,用于肠胃外给药的制备可包括,例如用于注射或其它可药用的溶液的含有蒸馏水的注射溶液或悬浮液、用于经皮应用的斑、用鼻腔给药的喷雾、沉淀剂(depository)等。
这些制剂可通过在药物制剂领域中的技术人员已知的常规方法混合可药用的载体、赋形剂、增甜剂、稳定剂等形成。
可药用的载体或赋形剂的实例包括聚乙烯基吡咯烷酮、阿拉伯胶、明胶、山梨糖醇、环糊精、硬脂酸镁、滑石、聚乙二醇、聚乙烯基醇、二氧化硅、乳糖、结晶纤维素、蔗糖、淀粉、磷酸钙、植物油、羧甲基纤维素、羟丙基纤维素、月桂基硫酸钠、水、乙醇、甘油、甘露糖醇、糖浆等。
用于注射的溶液可以是含有葡萄糖等的渗溶液等,这些溶液可进一步含有合适的增溶剂,例如聚乙二醇等,缓冲剂、稳定剂、防腐剂、抗氧化剂等。
这些制剂可向人体和其它哺乳动物给药,优选的给药途径可包括口服途径、经眼途径、鼻腔途径、直肠途径、局部途径等。
给药剂量可随患者的年龄、体重、症状、给药途径等在宽范围内变化,对于成人患者通常要求的口服日剂量在约0.001-1000mg/每kg体重范围内,优选0.01-100mg/每kg体重,更优选0.1-10mg/每kg体重。
在肠胃外给药,例如静脉内注射的情况下,通常所需要的日剂量在约0.00001-10mg/每kg体重范围内,优选0.0001-1mg/每kg体重,更优选0.001-0.1mg/每kg体重,每天1或3次。
评价化合物对烟碱乙酰基胆碱受体的结合能力的方法随受体亚型不同而不同。化合物对α4β2烟碱乙酰基胆碱受体的结合能力用完全均化的大脑得到的大鼠脑膜检测,测定化合物对[3H]-金雀花碱与所述脑膜结合的抑制率。此外,化合物对α1β1γδ烟碱乙酰基胆碱受体的结合能力用均化的大鼠肌肉检测,测定化合物抗[3H]-α-银环蛇毒素与所述肌肉膜结合的抑制率。
在人体烟碱乙酰基胆碱受体的α4β2亚型中的激动剂效果通过如下方法测定,使用在爪蟾蜍(Xenopus Laevis)卵母细胞中制备的人体烟碱乙酰基胆碱受体,它以来自人体烟碱乙酰基胆碱受体的α4和β2亚单元的相应克隆cDNA的cRNA注入,采用膜电势保持法通过在灌注溶液中加入测试化合物测量电响应的表达。
实施例:
本发明通过如下实施例详细说明。
实施例1:用方法1合成
2-苄基亚氨基-3-(6-氯-3-吡啶基)甲基噻唑烷[化合物14]
将511mg(5mmol)2-氨基-2-噻唑和1.03g(5mmol)5-溴甲基-2-氯吡啶在50ml乙腈中的混合物在90℃回流下加热6小时,随后将反应混合物冷却到室温,减压除去溶剂。将得到的残余物与二氯甲烷和饱和碳酸氢钠水溶液混合,分离出有机层。水层用二氯甲烷提取,合并的有机层用硫酸镁干燥。减压除去溶剂,得到的残余物用氨基丙基涂覆的硅胶(Chromatorex NH-型;Fuji Silysia Chemical Ltd.)柱色谱法(洗脱液;己烷∶乙酸乙酯=2∶1)纯化得到623mg(收率;54.7%)3-(6-氯-3-吡啶基)甲基-2-亚氨基噻唑烷黄色油状物和173mg(收率;7.4%)3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基噻唑烷黄色油状物。
随后将228mg(1mmol)3-(6-氯-3-吡啶基)甲基-2-亚氨基噻唑烷、180mg(1.05mmol)苄基溴和276mg(2mmol)无水碳酸钾在10ml乙腈中的混合物在90℃回流下加热3小时。在将反应混合物冷却到室温后,减压除去溶剂。随后将得到的残余物与二氯甲烷和饱和碳酸氢钠水溶液混合,分离出有机层。水层用二氯甲烷提取,合并的有机层用硫酸镁干燥。减压除去溶剂,得到的残余物用氨基丙基涂覆的硅胶(Chromatorex NH-型;Fuji Silysia Chemical Ltd.)柱色谱法(洗脱液;己烷∶乙酸乙酯=2∶1)纯化得到217mg(收率;68.3%)2-苄基亚氨基-3-(6-氯-3-吡啶基)甲基噻唑烷无色油状物。将该产物溶解在甲醇中,向该溶液中加入79mg(0.681mmol)富马酸,减压浓缩混合物。得到的残余物用乙腈处理得到结晶,通过过滤收集结晶,真空干燥得到271mg标题化合物14的富马酸盐。
如下化合物根据实施例1中描述的相同方法合成。
化合物1:3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-噻唑烷;
化合物2:3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-3,4,5,6-四氢-2H-1,3-噁嗪;
化合物5:1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2-二氢嘧啶;
化合物8:3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-2,3-二氢噻唑;
化合物11:3-(6-氯-3-吡啶基)甲基-2-甲基亚氨基噻唑烷;
化合物13:1-(6-氯-3-吡啶基)甲基-2-亚氨基-3-甲基-2,3-二氢咪唑;
化合物15:3-(6-氯-3-吡啶基)甲基-2-[2-(6-氯-3-吡啶基)乙基]-亚氨基噻唑烷。
实施例2:通过方法2合成
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-4-甲基
-2,3-二氢噻唑[化合物9];
将228mg(2mmol)2-氨基-4-甲基噻唑和1.03g(5mmol)5-溴甲基-2-氯吡啶在30ml乙腈中的混合物在回流下在90℃加热8小时,随后将反应混合物冷却到室温,减压除去溶剂。将得到的残余物与二氯甲烷和饱和碳酸氢钠水溶液混合,分离出有机层。水层用二氯甲烷提取,合并的有机层用硫酸镁干燥。减压除去溶剂,得到的残余物用硅胶60(Merck Co.,Ltd.)柱色谱法(洗脱液;己烷∶乙酸乙酯=9∶1至4∶1)纯化得到600mg(收率;82.1%)粗产物黄色油状物。随后该粗产物再次用氨基丙基涂覆的硅胶(Chromatorex NH-型;Fuji SilysiaChemical Ltd.)柱色谱法(洗脱液;二氯甲烷)纯化,洗脱的产物通过用乙醚-异丙基醚处理结晶得到310mg(收率;42.4%)3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-4-甲基-2,3-二氢噻唑乳白色结晶。将200mg(0.548mmol)该产物溶解在甲醇中,向该溶液中加入64mg(0.551mmol)富马酸,减压浓缩混合物。得到的残余物用乙腈处理得到结晶,通过过滤收集结晶,真空干燥得到213mg标题化合物9的富马酸盐。
根据实施例2中描述的相同方法合成如下化合物。
化合物3:1-(6-氯-3-吡啶基)甲基-[(6-氯-3-吡啶基)甲基]亚氨基-1,2,3,4,5,6-六氢嘧啶;
化合物4:1,3-二[(6-氯-3-吡啶基)甲基]-2-亚氨基-1,2,3,4,5,6-六氢嘧啶;
化合物6:5-氯-1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2-二氢吡啶;
化合物7:1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-6-甲基哌啶;
化合物10:1,3-二[(6-氯-3-吡啶基)甲基]-2-亚氨基-2,3-二氢咪唑。
实施例3:通过方法3合成
3-(6-氯-3-吡啶基)甲基-2-苯基亚氨基-2,3-二氢噻唑[化合物12]
将176mg(1mmol)2-苯胺基噻唑和227mg(1.1mmol)5-溴甲基-2-氯吡啶在10ml乙腈中的混合物在回流下在90℃加热15小时,随后将反应混合物冷却到室温,减压除去溶剂。将得到的残余物与二氯甲烷和饱和碳酸氢钠水溶液混合,分离出有机层。水层用二氯甲烷提取,合并的有机层用硫酸镁干燥。减压除去溶剂,得到的残余物用硅胶60(Merck Co.,Ltd.)柱色谱法(洗脱液;二氯甲烷∶乙酸乙酯=30∶1至9∶1)纯化得到57mg(收率;18.9%)3-(6-氯-3-吡啶基)甲基-2-苯基亚氨基-2,3-二氢噻唑黄色结晶和240mg3-(6-氯-3-吡啶基)甲基-2-苯基亚氨基-2,3-二氢噻唑和2-苯胺基噻唑的产物混合物。随后该粗混合物用氨基丙基涂覆的硅胶(Chromatorex NH-型;Fuji SilysiaChemical Ltd.)柱色谱法(洗脱液;己烷∶乙酸乙酯=5∶1)纯化得到151mg(收率;50%)3-(6-氯-3-吡啶基)甲基-2-苯基亚氨基-2,3-二氢噻唑。将208mg(0.689mmol)合并的3-(6-氯-3-吡啶基)甲基-2-苯基亚氨基-2,3-二氢噻唑溶解在甲醇中,向该溶液中加入80mg(0.689mmol)富马酸,减压浓缩混合物。得到的残余物用乙腈处理得到结晶,通过过滤收集结晶,真空干燥得到192mg(收率;45.9%)标题化合物12的富马酸盐。
通过上述实施例得到的化合物的物化数据概述在如下表1-3中。
本发明的化合物(I)的效果用如下生物学实验评价。
生物学实验1:
对烟碱乙酰基胆碱受体的α4β2亚型的结合试验
本发明的化合物对烟碱乙酰基胆碱受体的α4β2亚单元的亲和力通过如下方法进行,它是Pabreza L.A.,Dhawan S.& Kellar K.J.,Mol.Pharm.,39,9-12(1990)和Anderson D.J.& Arneric S.P.,Eur.J.Pharm.,253,261-267(1994)描述的改进方法。
(1)
含有烟碱乙酰基胆碱受体的α4β2亚型的大鼠脑膜的制备
使用由Charles River Japan得到的Fischer-344系列雄性大鼠(体重:200-240g;9周龄),大鼠在室温控制为23±1℃和湿度55±5%的饲养笼内饲养1-4周,大鼠(每笼3-4只)每天在光下饲养12小时(从7:00-19:00),使其自由进食和饮水。
按如下进行含有烟碱乙酰基胆碱受体的α4β2亚型的大鼠脑膜的制备。即在断头杀死后马上取出大鼠脑,用冰冷的盐水溶液洗涤,随后用液氮在-80℃下冷冻,贮存直至使用。在融化冷冻的脑后,脑在10体积缓冲溶液(50mMTris-HCl,120mM NaCl,5mMKCl,1mMMgCl2,2mMCaCl2;pH7.4;4℃)用均浆器(HG30,Hitachi Kohki Ltd.)均化30秒,均浆在1000xG下在4℃离心10分钟。分离出得到的上清液,菌丝球用半体积的上述缓冲溶液重新均化,在相同条件下离心。合并的上清液在40000xG下在4℃再离心20分钟,菌丝球悬浮在缓冲溶液中,用于受体结合试验。
(2)
烟碱乙酰基胆碱受体的α4β2亚型结合实验
将含有400-600μg蛋白质的膜菌丝球的悬浮液加入含有试验化合物和[3H]-金雀花碱(2nM)的试管中,最终体积为200μl,在冰冷却的槽中培养75分钟。通过在Whatman GF/B过滤器上真空过滤分离样品,在样品过滤之前过滤器刚用0.5%聚乙烯亚胺预清洗,使用Brandel多支管细胞收获器。过滤器用缓冲溶液(3×1ml)快速清洗,过滤器在3ml澄清溶胶(clerasol) I(Nacalai Tesque Inc.)中计数,在10μM(-)-烟碱存在下培养测定非特异结合。
实验结果的分析用Accufit Competition Program(BeckmanLtd.)进行。
生物学实验2:
对烟碱乙酰基胆碱受体的α1β1γδ亚型的结合试验
本发明的化合物对烟碱乙酰基胆碱受体的α1β1γδ亚型的亲和力用如下方法测定,它是由Garcha H.S.Thomas P.,Spivak C.E.,Wonnacott S.& Stolerman I.P.,Psychropharmacology,110,347-354(1993)描述的改进方法。
(1)
含有烟碱乙酰基胆碱受体的α1β1γδ亚型的大鼠骨骼肌的制备
使用生物学实验中描述的基本上相同的动物。
烟碱乙酰基胆碱受体的α1β1γδ亚型的分离过程如下进行。即在断头杀死后马上取出大鼠后部骨骼肌,用冰冷的盐水溶液洗涤,随后用液氮在-80℃下冷冻,贮存直至使用。在融化冷冻的肌肉后,组织用缓冲溶液[2.5mM磷酸钠缓冲(pH:7.2),90mM NaCl,2mMKCl,1mMEDTA,2mM苄脒,0.1mM苄索氯铵,0.1mMPMSF,0.01%叠氮化钠](40% w/v)在Waring混合器[Waring混合器34BL97;WARINGPRODUCTS DIVISION DYNAMICS COPRO RATION OF AMERICA]中均化60秒,均浆在20000xG下在4℃离心60分钟。分离出上清液,将得到的菌丝球加入相同缓冲液(1.5ml/g湿重)中,在相同条件下均化。加入Triton X100(2% w/v),混合物在4℃搅拌3小时。在100000xG下在4℃离心60分钟得到作为上清液的大鼠肌肉提取物,用于受体结合试验。
(2)
烟碱乙酰基胆碱受体的α1β1γδ亚型的结合实验
受体结合实验进行如下,即,将含有600-900μg蛋白质的大鼠肌肉提取物加入含有试验化合物的试管中,在37℃下培养15分钟。随后向该混合物中加入1mM[3H]-α-环蛇毒素(α-Bgt),再培养2小时。通过在Whatman GF/B过滤器上真空过滤分离样品,在样品过滤之前过滤器刚用0.5%聚乙烯亚胺预清洗,使用Brandel多支管细胞收获器。过滤器用洗涤溶液(10mM KH2PO4,150mMNaCl,pH7.2,室温)(5×1ml)快速清洗,过滤器在3ml澄清溶胶(clerasol)I(NacalaiTesque Inc.)中计数,在1μMα-Bgt存在下培养测定非特异结合。含有α-Bgt(标记/非标记)的溶液通过使用含有0.25% BSA的缓冲溶液制备。在受体结合实验中,加入所述缓冲溶液以调节BSA的最终浓度至0.05%。
实验结果的分析用如生物学实验1中描述的相同方法进行。
表4显示本发明的化合物和作为比较化合物的(-)-烟碱的受体结合研究结果。
表4:
化合物No。 | 受体Ki的亲和力 | |
α4β2*1 | α1β1γδ**2 | |
1 | 16nM | 420μM |
2 | 22nM | (95%,56%) |
3 | 739nM | (77%,76%) |
4 | 475nM | (49%,30%) |
5 | (92%,23%) | n.d. |
6 | (94%,45%) | n.d. |
7 | (85%,75%) | (85%,52%) |
8 | 42nM | 840μM |
9 | 110nM | (78%,40%) |
10 | (89%,46%) | n.d. |
11 | (93%,18%) | n.d. |
12 | (109%,84%) | (86%,48%) |
13 | 15nM | 320μM |
14 | 123nM | (64%,20%) |
15 | 86nM | 479μM |
烟碱 | 1.6nM | 182μM |
*1:在圆括号内所示的数值显示分别在1μM和10μM试验化合物下控制[3H]-金雀花碱结合的%。
**2:在圆括号内所示的数值显示分别在1μM和10μM试验化合物下控制[3H]-α-Bgt结合的%。
n.d.:未测
生物学实验3:
对人体烟碱乙酰基胆碱受体的α4β2亚型的激动剂活性
本发明的化合物对人体烟碱乙酰基胆碱受体的α4β2亚型的激动剂活性用如下方法评价,它是由Papke R.L.,Thinschmide J.S.,Moulton B.A.,Meyer E.M.& Poirier A.,Br.J.Pharmacol.,120,429-438(1997)。
(1)
人体烟碱乙酰基胆碱受体的α4β2亚型的cRNA制备
人体烟碱乙酰基胆碱受体(hnACh-R)α4 cDNA和hnAC-R β2 cDNA的克隆根据常规方法通过合成各自相应于hnACh-R α4 cDNA和hnACh-R β2 cDNA的序列的DNA引物进行[Monteggia L.M.等,Gene,155,189-193(1995);和Anand R.,& Lindstrom J.,Nucl.AcidsRes.,18,4272(1990)],通过聚合酶链反应(PCR)分别得到hnACh-R α4 cDNA和hnACh-R β2 cDNA。得到的hnACh-R α4 cDNA和hnACh-Rβ2 cDNA被插入带有SP6 RNA启动子的cRNA表达载体(pSP64 polyA)以分别构成hnACh-R α4/pSP64 polyA和hnACh-R β2/pSP64 polyA。在通过用限制酶(EcoRI)由表达载体切割后,通过在帽类似物存在下影响SP6 RNA聚合酶进行转录以分别得到hnACh-R α4 cRNA和hnACh-R β2 cRNA。
(2)
在有爪蟾蜍卵母细胞中人体α4β2烟碱乙酰基胆碱受体亚型的表 达
卵母细胞由Kitanihouseibustukyohzai Co.,Ltd.购买,它已由有爪蟾蜍去核仁,用于该实验。
卵母细胞在无钙的改性Birth’s溶液(88mM NaCl,1mM KCl,2.4mM NaHCO3,0.82mM MgSO4,15mM HEPES,pH7.6)中在缓慢搅拌下在室温下用胶原酶(Sigma类型I;1mg/ml)处理90分钟,由组织中洗去酶。随后用摄子由卵泡中分离出卵母细胞,分离的卵母细胞放置在含有抗生素的改性Birth’s溶液(88mM NaCl,1mM KCl,2.4mMNaHCO3,0.82mM MgSO4,15mM HEPES,pH7.6,和0.1v/v%用于培养的青霉素和链霉素的混合物溶液;Sigma Co.)中。随后将处理的卵母细胞用自动注射器(NANOJECT;DRUMMOND SCIENTIFIC CO.)注射50nl调节的cRNA(1.0mg/ml),即每1个卵母细胞各自50ng hnACh-Rα4cRNA和hnACh-Rβ2 cRNA,在19℃下再培养4-14天。在卵母细胞中,通过注射的cRNA的翻译构成不均一五部分[(α4)2(β2)3],在细胞膜上构成离子通道受体。
(3)
对人体烟碱乙酰基胆碱受体的α4β2亚型的激动剂活性
通过膜电势保持方法记录对人体烟碱乙酰基胆碱受体的α4β2亚型的响应进行如下。即,将卵母细胞放置在总体积为50μl的记录盒中,以1ml/分钟的流量灌注含有阿托品(1μM)Ringer’s溶液(115mMNaCl,2.5mM KCl,1.8mM CaCl2,10mM HEPES,pH7.3),用两种电膜电势保持方法(CEZ-1250;Nihon Kohden Co.)将膜电势保持在-50mV。向灌注溶液中加入试验化合物,记录感应的向内电流的峰值强度。为规格化试验化合物的响应,在应用试验化合物之前和之后,记录乙酰基胆碱(Ach)的响应。通过在刚分离的卵母细胞中,观察到内部毒蕈碱乙酰基胆碱受体的响应,它是通过刺激受体,随着细胞内钙浓度的增加,通过活化钙依赖的氯化物离子通道产生的内部电流。然而,当用胶原酶或加入的1μM阿托品处理时,被证实这些响应完全消失。此外,没有注射cRNA的卵母细胞在用胶原酶处理后未显示Ach引起的响应。因此,在注射hnACh-R α4 cRNA和hnACh-R β2 cRNA的卵母细胞观察到的响应,即通过刺激受体由细胞内钠离子流入引起的向内电流应是人体烟碱乙酰基胆碱受体的α4β2亚型的新观察到的响应。
表5显示了本发明的化合物和参考化合物的(-)-烟碱的激动剂活性试验的结果。
表5:
化合物编号 | 激动剂效果 |
1 | 6% |
2 | 27% |
8 | 11% |
13 | 5% |
烟碱 | 146% |
这些数值显示与10μM乙酰基胆碱(100%)响应相比较,100μM试验化合物的响应的控制%。
如下是本发明的化合物(I)或可药用的盐的制剂实施例。
制剂实施例1(片剂):
化合物2 25g
乳糖 130g
结晶纤维素 20g
玉米淀粉 20g
3%羟丙基纤维素水溶液 100ml
硬脂酸镁 2g
将化合物、乳糖、结晶纤维素和玉米淀粉通过60目筛子过筛,均匀和加入捏和机中,在均匀的混合物中加入3%羟丙基纤维素水溶液,进一步捏和。产品通过16目筛子造粒,在50℃在空气中干燥,通过16目筛子重新造粒。向颗粒中加入硬脂酸镁,再次混合。将混合物压片得到重量为200mg和直径为8mm的片剂。
制剂实施例2(胶囊):
化合物2 25.0g
乳糖 125.0g
玉米淀粉 48.5g
硬脂酸镁 1.5g
将上述组分细粉碎,彻底混合以得到均匀混合物,将混合物填充在明胶胶囊中,每个胶囊200mg,得到胶囊。
制剂实施例3(注射液):
将化合物2的富马酸盐填充在250mg小瓶中,就地与约4-5ml可注射的蒸馏水混合以制备可注射的溶液。
工业应用
如上所述,本发明的化合物具有对中枢神经系统的α4β2烟碱乙酰基胆碱受体的高亲和力,作为激动剂或调制剂活化所述α4β2烟碱乙酰基胆碱受体。因此,本发明的化合物用于预防或治疗各种疾病,所述疾病可通过活化烟碱乙酰基胆碱受体预防或治愈。
更具体地说,本发明的用于α4β2烟碱乙酰基胆碱受体的活化剂用于预防或治疗各种疾病,例如痴呆、老年性痴呆、老年前期痴呆、早老性痴呆、帕金森病、脑血管痴呆、AIDS相关的痴呆、在唐氏综合症中的痴呆、图雷特氏病、慢性小脑梗塞中的神经病、小脑损伤引起的机能障碍、焦虑、精神分裂症、郁抑、杭庭顿氏舞蹈病、疼痛等等。
Claims (13)
1、下式(I)表示的二取代的亚氨基杂环化合物或其可药用的盐:
其中:
A是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基;
X是氧原子、硫原子、碳原子或氮原子;和
Y、B1和B2是,
(1)在X是氧原子的情况下,基团-Y-X-是-CH2-CH2-O-或-CH2-CH2-CH2-O-;B1是选择性取代的烷基;选择性取代的芳基;选择性取代的杂环基;和B2没有;
(2)在X是硫原子的情况下,基团-Y-X-是-CH2-CH2-S-或-C(R1)=C(R2)-S-(其中,R1和R2是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);B1是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基;和B2没有;
(3)在X是碳原子的情况下,基团-Y-X-是-CH=C(R3)-C(R4)=CH-、-CH(R5)-CH2-CH2-CH2-或-N=C(R6)-C(R7)=CH-(其中,R3、R4、R5、R6和R7是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);B1是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基;和B2是氢原子;和
(4)在X是氮原子的情况下,基团-Y-X-是-CH2-CH2-N(B2)-、-C(R8)=C(R9)-N(B2)-、-CH2-CH2-CH2-N(B2)-或-CH=C(R10)-C(R11)=N-(其中,R8、R9、R10和R11是氢原子、卤素原子、选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基);B1和B2之一是氢原子,另一个是选择性取代的烷基、选择性取代的芳基或选择性取代的杂环基。
2、权利要求1的式(I)表示的如下化合物和其可药用的盐:3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-噻唑烷;
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-3,4,5,6-四氢-2H-1,3-噁嗪;
1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2,3,4,5,6-六氢嘧啶;
1,3-二[(6-氯-3-吡啶基)甲基]-2-亚氨基-1,2,3,4,5,6-六氢嘧啶;
1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2-二氢嘧啶;
5-氯-1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-1,2-二氢吡啶;
1-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-6-甲基哌啶;
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-2,3-二氢噻唑;
3-(6-氯-3-吡啶基)甲基-2-[(6-氯-3-吡啶基)甲基]亚氨基-4-甲基-2,3-二氢噻唑;
1,3-二[(6-氯-3-吡啶基)甲基]-2-亚氨基-2,3-二氢咪唑;
3-(6-氯-3-吡啶基)甲基-2-甲基亚氨基噻唑烷;
3-(6-氯-3-吡啶基)甲基-2-苯基亚氨基-2,3-二氢噻唑;
1-(6-氯-3-吡啶基)甲基-2-亚氨基-3-甲基-2,3-二氢咪唑;
2-苄基亚氨基-3-(6-氯-3-吡啶基)甲基噻唑烷;
3-(6-氯-3-吡啶基)甲基-2-[2-(6-氯-3-吡啶基)乙基]-亚氨基噻唑烷。
3、α4β2烟碱乙酰基胆碱受体的活化剂,其含有权利要求1或2的化合物或其可药用的盐作为活性组分。
4、权利要求3的α4β2烟碱乙酰基胆碱受体活化剂,其中所述活化剂是α4β2烟碱乙酰基胆碱受体的激动剂或调制剂。
5、用于预防或治疗小脑循环疾病的药物,其含有权利要求3或4的α4β2烟碱乙酰基胆碱受体的活化剂。
6、用于预防或治疗神经变性疾病、痴呆、运动性共济失调、神经病和精神病的药物,其含有权利要求3或4的α4β2烟碱乙酰基胆碱受体的活化剂。
7、根据权利要求6的药物,其中所述神经变性疾病是早老性痴呆或帕金森氏疾病,所述痴呆是脑血管痴呆,所述运动性共济失调是图雷特氏综合症,所述神经病和精神病是焦虑和精神分裂症。
8、用于改善小脑代谢、神经传递功能疾病和记忆疾病、用于保护大脑或具有止痛效果的药物,其含有权利要求3或4的α4β2烟碱乙酰基胆碱受体的活化剂。
9、用于预防或治疗炎性肠疾病的药物,其含有权利要求3或4的α4β2烟碱乙酰基胆碱受体的活化剂。
10、权利要求1或2的化合物作为α4β2烟碱乙酰基胆碱受体活化剂的用途。
11、预防或治疗小脑循环疾病的方法,其包括给药权利要求3或4的α4β2烟碱乙酰基胆碱受体的活化剂。
12、预防或治疗神经变性疾病、痴呆、运动性共济失调、神经病和精神病的方法,其包括给药权利要求3或4的α4β2烟碱乙酰基胆碱受体的活化剂。
13、根据权利要求12的药物,其中所述神经变性疾病是早老性痴呆或帕金森氏疾病,所述痴呆是脑血管痴呆,所述运动性共济失调是图雷特氏综合症,所述神经病和精神病是焦虑或精神分裂症。
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WO2013144223A1 (en) | 2012-03-30 | 2013-10-03 | Basf Se | N-substituted pyrimidinylidene compounds and derivatives for combating animal pests |
JP2018511355A (ja) | 2015-01-28 | 2018-04-26 | クロノ セラピューティクス インコーポレイテッドChrono Therapeutics Inc. | 薬剤送達方法及びシステム |
US10679516B2 (en) | 2015-03-12 | 2020-06-09 | Morningside Venture Investments Limited | Craving input and support system |
JP2020503950A (ja) | 2017-01-06 | 2020-02-06 | クロノ セラピューティクス インコーポレイテッドChrono Therapeutics Inc. | 経皮薬剤送達の装置及び方法 |
CN107629045A (zh) * | 2017-11-10 | 2018-01-26 | 上海生农生化制品股份有限公司 | 一种噻虫啉的水相合成方法 |
AU2019279884A1 (en) | 2018-05-29 | 2020-12-10 | Morningside Venture Investments Limited | Drug delivery methods and systems |
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US3640952A (en) * | 1966-03-02 | 1972-02-08 | Mobay Chemical Corp | Polyesterurethanes stabilized with imino-oxazines |
DE1963193A1 (de) * | 1969-12-17 | 1971-06-24 | Bayer Ag | N-substituierte 2-Arylimino-oxazolidine,Verfahren zu ihrer Herstellung und ihre Verwendung als Ektoparasiticide |
US3787575A (en) * | 1970-12-17 | 1974-01-22 | Bayer Ag | N-substituted-2-arylimino-oxazolidines used as acaricides |
US4046909A (en) * | 1974-08-22 | 1977-09-06 | Mcneil Laboratories, Incorporated | Pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas as CNS depressants |
US4139537A (en) * | 1976-06-29 | 1979-02-13 | Cooper Laboratories, Inc. | 3-Aryloxy-1-(2- or 4-iminodihydro-1-pyridyl)-2-propanol antiarrhythmic compounds |
US4414211A (en) * | 1978-09-18 | 1983-11-08 | Mcneilab, Inc. | Heterocyclic derivatives of guanidine |
AU5263779A (en) * | 1978-11-29 | 1980-05-29 | Beecham Group Limited | Derivatives of thiazolidin-2-ylidene and oxazolidin-2-ylidene with hypoglycaemic acitivity |
EP0018134B1 (en) * | 1979-04-21 | 1984-03-14 | Beecham Group Plc | Dihydropyridine derivatives, processes for their preparation and pharmaceutical compositions containing them |
US4468403A (en) * | 1982-07-20 | 1984-08-28 | Canadian Patents & Development Limited | Analgesic substituted piperidylidene-2-sulfon(cyan)amide derivatives |
AU2717488A (en) * | 1987-11-19 | 1989-06-14 | Chevron Research Company | Ectoparasiticides |
DE4021439A1 (de) | 1989-12-14 | 1991-06-20 | Bayer Ag | 2-iminopyridin-derivate |
DE4011870A1 (de) * | 1990-04-12 | 1991-10-17 | Bayer Ag | Imidazolidinderivate |
DE4419587A1 (de) * | 1994-06-03 | 1995-12-07 | Bayer Ag | Heterocyclische Imino-Derivate |
DE69913520T2 (de) | 1998-06-01 | 2004-11-25 | Ortho-Mcneil Pharmaceutical, Inc. | Tetrahydronaphtalene verbindungen und deren verwendung zur behandlung von neurodegenerativen krankheiten |
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2000
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- 2001-03-21 KR KR1020017014894A patent/KR20010114273A/ko not_active Application Discontinuation
- 2001-03-21 US US09/979,162 patent/US6900202B2/en not_active Expired - Fee Related
- 2001-03-21 EP EP01914182A patent/EP1218371A2/en not_active Withdrawn
- 2001-03-21 CA CA002364268A patent/CA2364268A1/en not_active Abandoned
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JP2001261652A (ja) | 2001-09-26 |
EP1218371A2 (en) | 2002-07-03 |
AU781064B2 (en) | 2005-05-05 |
KR20010114273A (ko) | 2001-12-31 |
US6900202B2 (en) | 2005-05-31 |
WO2001070733A3 (en) | 2002-05-02 |
AU3954501A (en) | 2001-10-03 |
CA2364268A1 (en) | 2001-09-27 |
WO2001070733A2 (en) | 2001-09-27 |
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