CN1167703C - 氮杂二环氨基甲酸酯及其作为α-7烟碱性乙酰胆碱受体激动剂的用途 - Google Patents
氮杂二环氨基甲酸酯及其作为α-7烟碱性乙酰胆碱受体激动剂的用途 Download PDFInfo
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Classifications
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- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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Abstract
本发明提供式(I)化合物，其中n、A、R1、R2和R3如说明书中的定义，并提供其制备方法。式(I)化合物可用作药物。
Description
本发明涉及新的氮杂二环氨基甲酸酯、其制备方法、其药物用途和含有其的药物组合物。
更具体地，本发明提供游离碱或酸加成盐形式的式I化合物
其中n是1或2，R1、R2和R3独立地是氢或(C1-4)烷基，A是具有下组化学式的基团：
其中m是1、2或3，X是O、S、NH或CH2，R4和R5独立地是氢、卤素、羟基，(C1-4)烷基、(C1-4)烷氧基、(C1-4)烷硫基、(C1-4)烷基氨基、硝基、三氟甲基或苯基。
卤素是指氟、溴、氯或碘。
所有的烷基、烷氧基和烷硫基均是分支或直链基团。它们优选是甲基、甲氧基、或甲硫基。
由于式I化合物和其盐中存在的不对称碳原子，故这些化合物可以以旋光体或旋光异构体的混合物的形式，如外消旋混合物的形式存在。所有的旋光异构体和它们的混合物，包括外消旋混合物，都是本发明的一部分。
在再一方面，本发明提供制备式I化合物和其盐的方法，包括步骤：使式II化合物
其中n、R1和R2如上定义，与式III化合物
其中R3和A如上定义，及N，N’-羰基二咪唑或二(N-琥珀酰亚胺基)碳酸酯反应；和回收所获游离碱或酸加成盐形式的式I化合物。
根据优选实施方案，在第一步中使式III化合物与N，N’-羰基二咪唑反应，然后使所获化合物与式II化合物反应。
或者，可以使式II化合物与式IV化合物
其中R3和A如上定义，反应。
这些反应可以根据常规方法，如描述在实施例中的方法进行。
可以按已知程序处理根据上述方法的反应混合物和纯化由此获得的化合物。
可以按已知方式从游离碱制备酸加成盐，且反之亦然。
旋光纯形式的式I化合物可以从相应的外消旋物根据熟知的程序获得。或者，可以使用旋光纯的起始物。
式II、III和IV起始物是已知的，或可以从已知化合物根据常规方法获得。
在体外检测和动物试验中，式I化合物和其可药用酸加成盐(下文称作本发明药剂)表现出有价值的药物学性质，因此被用作药物。
具体地，本发明药剂是α7烟碱性乙酰胆碱受体(nAChR)激动剂。
在功能试验中，本发明药剂表现出对α7nAChR有高亲和性，见如下试验：
a)使用稳定表达人α7nAChR的大鼠垂体细胞系进行功能试验以分析对人α7nAChR的亲和性。使用刺激受体后的钙流入作为读出数据。在此试验中，本发明药剂表现出大约5至大约8的pEC50值。
b)为了评价本发明药剂对人神经元nAChRα4β2的活性，使用稳定表达人α4β2亚型的人上皮细胞系进行相似的功能试验。在此试验中，本发明药剂表现出对α7nAChR亚型具有选择性。
c)为了评价本发明化合物对烟碱性受体的“神经节亚型”和肌肉型的活性，使用稳定表达人神经节亚型受体的人上皮细胞系或内源性表达人肌肉型烟碱性受体的细胞系进行类似的功能试验。在这些试验中，本发明药剂表现出对神经节和肌肉烟碱性受体亚型没有或几乎没有活性。
在表现出感觉门控(sensory gating)缺损的小鼠模型(DBA/2小鼠)(描述在S.Leonard等，精神分裂症通报(Schizophrenia Bulletin)22，431-445(1996))中，本发明药剂在大约10至大约40μM浓度时诱导显著的感觉门控。
因此，本发明药剂可以用于治疗精神障碍，如精神分裂症、躁狂症、抑郁和焦虑，和用于治疗神经变性病，如老年痴呆、阿尔茨海默氏病和其它智力损伤障碍如注意缺陷多动症(ADHD)、帕金森病、亨廷顿舞蹈病、肌萎缩性侧索硬化、多发性硬化。α7nAChR激动剂在神经变性病中的用途参见文献，如Wang等，J.Biol.Chem.275，5626-5632(2000)。
对于上述适应症，当然，随着例如所用化合物、宿主、给药模式和所治疗疾病的性质和严重性的不同，适宜的剂量将不同。然而，一般地，对于动物显示出以约0.01至约100，优选约0.1至约50mg/kg动物体重的每日剂量可获得满意的结果。对于较大哺乳动物，如人，所显示的日剂量在约1至约500mg范围内，优选约5至约300mg的本发明药剂，其可以方便地以例如分开的给药量一天给药多达4次，或可以以缓释形式给药。
本发明药剂可以通过任何方便的途径给药，尤其是通过胃肠道途径，优选口服，例如以片剂或胶囊形式给药，或通过胃肠外途径，例如以注射溶液或悬浮液的形式给药。
优选的化合物是(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸1-(2-氟苯基)-乙酯的立体异构体，其琥珀酸盐具有83-84℃的熔点，并且其具有+14.6°的旋光性(c＝1；水，20℃，589nm)，是实施例61的化合物。
根据前述，本发明还提供用于作为药物，例如用于治疗上述任何疾病的本发明药剂。
本发明还提供包含本发明药剂以及至少一种药物载体或稀释剂的药物组合物。该组合物可以按常规方式制备。单位剂型含有例如约0.25至约150，优选约1至约25mg的根据本发明的化合物。
而且，本发明提供本发明药剂在制备用于治疗上述任何疾病的药物中的用途。
再一方面，本发明提供给需要治疗上述任何疾病的对象进行治疗的方法，该方法包括给该对象施用治疗有效量的本发明药剂。
以下实施例举例说明本发明。
实施例1：(1-氮杂二环[2.2.2]辛-3-基)氨基甲酸1-苯基乙酯咪唑-1-羧酸1-苯基乙酯
向1.21ml(10.0mmol)DL-1-苯基乙醇的10ml四氢呋喃溶液中，加入1.70g(10.5mmol)N，N’-羰基二咪唑。将此白色悬浮液加热至50℃并在此温度下搅拌40分钟。将反应混合物冷却并蒸发。通过快速层析(己烷/乙酸乙酯80/20)纯化粗产物，得到无色油状标题产物。
(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸1-苯基乙酯
向0.50g(2.31mmol)咪唑-1-羧酸1-苯基乙酯的5ml二甲基甲酰胺中加入0.46g(2.31mmol)3-氨基奎宁环二盐酸盐和0.49g(4.62mmol)碳酸钠。将此悬浮液加热至80℃并在此温度下搅拌18小时。然后将反应混合物冷却并用水和乙酸乙酯抽提。将合并的有机相干燥并蒸发。干燥油性残余物，将其溶解在乙醚中并用4M盐酸二氧六环溶液酸化。滤出沉淀的晶体，用乙醚进行洗涤然后使之干燥，得到标题产物。Mp＝71-72℃(分解)。
实施例2：(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸苄基酯
将996mg(5.0mmol)3-氨基奎宁环二盐酸盐缓慢地加入676mg(15.5mmol)氢化钠(55％分散体)在二甲基甲酰胺(15ml)中的搅拌悬浮液中。之后，室温再搅拌该悬浮液90分钟，然后缓慢地加入0.72ml(5.1mmol)苄氧甲酰氯。室温下再放置2小时后，小心地加入水以淬灭悬浮液。然后70℃/16毫巴蒸发溶剂。将残余物溶解在水和乙酸乙酯中。分离有机相并用乙酸乙酯重复提取水相两次。干燥合并的有机相并进行蒸发，产生油性粗产物，将此产物溶解在二氧六环中然后加入0.72ml 4M盐酸。从二氧六环/乙醚中使沉淀的产物重晶体，得到标题产物的盐酸盐。Mp＝192-193℃。
实施例3：(R)-(+)-(1-氮杂二环[2.2.2]辛-3-基)氨基甲酸苄基酯
用石油醚洗涤0.33g(7.5mmol)氢化钠(55％分散体)并通过分离(倾析)除去溶剂。然后，小心地将氢化钠悬浮在二甲基甲酰胺(12.5ml)中。向此悬浮物中加入0.50g(2.5mmol)(R)-(+)-3-氨基奎宁环二盐酸盐。然后室温下对初始放热反应进行一小时的搅拌，然后15分钟内向反应混合物中加入0.39ml(2.75mmol)苄氧甲酰氯。室温下对再次的初始放热反应进行90分钟的搅拌，然后将混合物倾倒入10％盐水(NaCl/水溶液)中，之后用甲苯抽提4次。将合并的有机相干燥并蒸发。将粗油性残余物溶解在二氧六环(5ml)中然后加入0.31ml 4M盐酸。然后室温搅拌混合物直到产物沉淀。滤出晶体，用二氧六环和乙醚洗涤并干燥，得到标题产物。Mp＝228-229℃。旋光性+6.3°(c＝0.5，水)。
实施例4：(S)-(-)-(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸苄基酯
用石油醚洗涤0.33g(7.5mmol)氢化钠(55％分散体)并通过分离(倾析)除去溶剂。然后，小心地将氢化钠悬浮在二甲基甲酰胺(12.5ml)中。向此悬浮物中加入0.50g(2.5mmol)(S)-(-)-3-氨基奎宁环二盐酸盐。然后室温对初始放热反应进行一小时的搅拌，然后15分钟内向反应混合物中加入0.39ml(2.75mmol)苄氧甲酰氯。室温下对再次的初始放热反应进行90分钟的搅拌，然后将混合物倾倒入10％盐水(NaCl/水溶液)中，之后用甲苯抽提4次。将合并的有机相干燥并蒸发。将粗油性残余物溶解在二氧六环(5ml)中然后加入0.31ml 4M盐酸。然后室温搅拌混合物直到产物沉淀。滤出晶体，用二氧六环和乙醚洗涤并干燥，得到标题产物。Mp＝221-223℃。旋光性-8.0°(c＝0.5，水)。
实施例5：(1-氮杂二环[2.2.2]辛-3-基)氨基甲酸4-丁基苄基酯
向0.47ml(2.75mmol)(4-丁基苯基)甲醇的15ml二氯甲烷溶液中加入1.05ml(7.5mmol)三乙胺和0.80g二-(N-琥珀酰亚胺基)碳酸酯。室温搅拌此初始悬浮液45分钟，得到清澈的溶液。将此混合物滴加至0.32g(2.5mmol)3-氨基奎宁环和0.52ml(1.5mmol)三乙胺的10ml二氯甲烷溶液中。随后室温再搅拌反应混合物2小时。之后用20ml水洗涤此混合物。分离有机相，并对其进行干燥和蒸发。将粗产物溶解在5ml二氯甲烷中并用盐酸在乙醚中的饱和溶液进行酸化。加入50ml乙醚以沉淀白色产物。滤出晶体，用乙醚洗涤然后干燥，得到标题产物。Mp＝174-175℃(分解)。
其中n是2、R1和R2是氢、A是取代的苯基的以下式I化合物可以按类似于实施例1、2或5的方式制备。
| 实施例 | R3 | R4 | R5 | Mp/旋光性 |
| 6 | H | 邻-OMe | H | 89-90℃(盐酸盐) |
| 7 | H | 2-OMe | 3-OMe | 93-95℃(盐酸盐) |
| 8 | H | 对-苯基 | H | 193-195℃(盐酸盐) |
| 9 | H | 邻-Br | H | 203-204℃(盐酸盐) |
| 10 | H | 邻-NO2 | H | 177-178℃(盐酸盐) |
| 11 | H | 对-NO2 | H | 89-90℃(盐酸盐) |
| 12 | H | 2-OMe | 5-Br | 147-149℃(盐酸盐) |
| 13 | H | 间-苯氧基 | H | 82-83℃(盐酸盐) |
| 14 | H | 邻-Cl | H | 82-83℃(盐酸盐) |
| 15 | H | 3-NO2 | 5-NO2 | 93-94℃(盐酸盐) |
| 16 | H | 3-Cl | 4-Cl | * |
| 17 | H | 间-OMe | H | 139-140℃(盐酸盐) |
| 18 | H | 3-NO2 | 4-Me | 86-88℃(盐酸盐) |
| 19 | H | 3-Me | 5-Me | 183-184℃(盐酸盐) |
| 20 | H | 对-CF3 | H | 143-144℃(盐酸盐) |
| 21 | H | 邻-Me | H | 174-176℃(盐酸盐) |
| 22 | H | 对-Me | H | 194-196℃(盐酸盐) |
| 23 | H | 对-异丙基 | H | 235℃(盐酸盐) |
| 24 | Me | 对-Me | H | 168-170℃(盐酸盐) |
| 25顺/反外消旋混合物 | Me | H | H | 71-72℃(盐酸盐) |
| 26立体异构体-1 | Me | H | H | 182-184℃(盐酸盐)；旋光性：+32.4°(c＝1；水，24℃，589nm) |
| 27立体异构体-2 | Me | H | H | 151-152℃(琥珀酸盐)；旋光性：-9.7°(c＝1；甲醇，22℃，589nm) |
| 28立体异构体-3 | Me | H | H | 旋光性：+12.5°(c＝1；甲醇，20℃，589nm) |
| 29立体异构体-4 | Me | H | H | 117-119℃(延胡索酸盐)；旋光性：-25.0°(c＝1；甲醇，20℃，589nm) |
| 30 | H | 3-OMe | 5-OMe | 179-180℃(盐酸盐) |
| 31 | H | 3-Me | 4-NO2 | 165-167℃(盐酸盐) |
| 32 | Me | 2-Cl | 4-Cl | 212-214℃(盐酸盐) |
| 33 | H | 对-乙基 | H | 208-209℃(盐酸盐) |
| 34 | H | 对-Br | H | 190-191℃(盐酸盐) |
| 35 | H | 3-CF3 | 5-CF3 | 157-158℃(盐酸盐) |
| 36 | H | 对-SMe | H | 164-166℃(盐酸盐) |
| 37 | H | 2-NO2 | 5-Me | 198-199℃(盐酸盐) |
| 38 | H | 3-OMe | 4-OMe | 221-223℃(盐酸盐) |
| 39 | H | 2-Cl | 6-Cl | 251-252℃(盐酸盐) |
| 40 | H | 对-CO2Me | H | 220-222℃(盐酸盐) |
| 41 | Me | 对-叔丁基 | H | 232-233℃(盐酸盐) |
| 42 | 乙基 | H | H | ** |
| 43 | Me | 对-Cl | H | 132-135℃(盐酸盐) |
| 44 | Me | 邻-Me | H | 219-220℃(盐酸盐) |
| 45 | Me | 对-Br | H | 163-165℃(盐酸盐) |
| 46 | Me | 3-Cl | 4-Cl | 240-241℃(盐酸盐) |
| 47 | Me | 对-F | H | 219-220℃(盐酸盐) |
| 48 | H | 间-Br | H | 186-187℃(盐酸盐) |
| 49 | H | 间-Me | H | 174-175℃(盐酸盐) |
| 50 | H | 间-苄氧基 | H | 168-169℃(盐酸盐) |
| 51 | H | 2-Cl | 5-Cl | 205-207℃(盐酸盐) |
| 52 | H | 2-OMe | 5-OMe | 162-163℃(盐酸盐) |
| 53 | H | 2-NO2 | 4-Cl | 204-205℃(盐酸盐) |
| 54顺/反外消旋混合物 | Me | 邻-Cl | H | 230-232℃(盐酸盐) |
| 55立体异构体-1 | Me | 邻-Cl | H | 229-230℃(盐酸盐)；旋光性：-8.6°(c＝1；水，20℃，589nm) |
| 56立体异构体-2 | Me | 邻-Cl | H | 255-257℃(盐酸盐)；旋光性：+26.8°(c＝1；水，22℃，589nm) |
| 57立体异构体-3 | Me | 邻-Cl | H | 229-230℃(盐酸盐)；旋光性：+8.9°(c＝1；水，20℃，589nm) |
| 58立体异构体-4 | Me | 邻-Cl | H | 257-258℃(盐酸盐)；旋光性：-30.9°(c＝1；水，22℃，589nm) |
| 59立体异构体-1 | Me | 邻-F | H | 83-84℃(琥珀酸盐)；旋光性：+15.4°(c＝1；水，20℃，589nm) |
| 60立体异构体-2 | Me | 邻-F | H | 146-147℃(琥珀酸盐)；旋光性：+2.5°(c＝1；水，20℃，589nm) |
| 61立体异构体-3 | Me | 邻-F | H | 83-84℃(琥珀酸盐)；旋光性：+14.6°(c＝1；水，20℃，589nm) |
| 62立体异构体-4 | Me | 邻-F | H | 136-137℃(琥珀酸盐)；旋光性：-4.8°(c＝1；水，20℃，589nm) |
Me＝甲基
*IS：在1695cm-1处有羰基吸收
**IS：在1712cm-1处有羰基吸收
实施例63：(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸苯并[1，3]间二氧杂环戊烯-5-基甲酯
类似于实施例1、2或5制备。
Mp(盐酸盐)＝186-187℃。
实施例64：(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸苯并[1，3]间二氧杂环戊烯-4-硝基-5-基甲酯
类似于实施例1、2或5制备。
Mp(盐酸盐)＝216-218℃。
实施例65：(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸3，4，5-三甲氧基苄基酯
类似于实施例1、2或5制备。
Mp(盐酸盐)＝211-212℃。
实施例66：(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸苯并[1，2，5]噻二唑-5-基甲酯
类似于实施例1、2或5制备。
IS：在1718cm-1处有羰基吸收。
Claims (8)
1.游离碱或酸加成盐形式的式I化合物
其中n是1或2，R1、R2和R3独立地是氢或C1-4烷基，而A是具有下组化学式的基团：
其中m是1、2或3，X是O、S、NH或CH2，R4和R5独立地是氢、卤素、羟基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、硝基、三氟甲基或苯基。
2.权利要求1的游离碱或酸加成盐形式的化合物，其是(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸1-(2-氟苯基)-乙酯的立体异构体。
3.权利要求1的游离碱或酸加成盐形式的化合物，其是(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸1-(2-氟苯基)-乙酯的立体异构体，其琥珀酸盐具有83至84℃的熔点。
4.权利要求1的游离碱或酸加成盐形式的化合物，其是(1-氮杂二环[2.2.2]辛-3-基)-氨基甲酸1-(2-氟苯基)-乙酯的立体异构体，其琥珀酸盐具有83至84℃的熔点，且其具有+14.6°的旋光性，测定条件：c＝1；水，20℃，589nm。
5.制备权利要求1的式I化合物或其盐的方法，包括步骤：使式II化合物
其中n、R1和R2如权利要求1的定义，和式III化合物
其中R3和A如权利要求1的定义，及N，N’-羰基二咪唑或二(N-琥珀酰亚胺基)碳酸酯反应；和回收得到的游离碱或酸加成盐形式的式I化合物。
6.制备权利要求1的式I化合物或其盐的方法，包括步骤：使式II化合物
其中n、R1和R2如权利要求1的定义，与式IV化合物反应：
其中R3和A如权利要求1的定义；和回收得到的游离碱或酸加成盐形式的式I化合物。
7.药物组合物，其包含游离碱或可药用酸加成盐形式的权利要求1的化合物、以及药物载体或稀释剂。
8.游离碱或可药用酸加成盐形式的权利要求1的化合物在制备用于治疗精神障碍和神经变性病的药物中的用途。
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