CN1199398A - 1-[2-(2,3-二氢-1h-茚-1-基)乙基]-4-(萘-1基)哌嗪衍生物,它们的制备方法及其在治疗中的应用 - Google Patents
1-[2-(2,3-二氢-1h-茚-1-基)乙基]-4-(萘-1基)哌嗪衍生物,它们的制备方法及其在治疗中的应用 Download PDFInfo
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- CN1199398A CN1199398A CN96197512A CN96197512A CN1199398A CN 1199398 A CN1199398 A CN 1199398A CN 96197512 A CN96197512 A CN 96197512A CN 96197512 A CN96197512 A CN 96197512A CN 1199398 A CN1199398 A CN 1199398A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
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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
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Abstract
满足通式(Ⅰ)的化合物,其中X代表氢原子、羟基、C1-C3烷氧基或环丙基甲氧基,Y代表氢原子、羟基或甲氧基。治疗应用。
Description
X代表氢原子、羟基、C1-C3烷氧基或环丙基甲氧基,Y代表氢原子、羟基或甲氧基。
本发明的这些化合物能够以碱或加合盐的状态存在。
另外,这些化合物在其结构中可以具有一个非对称碳原子;因此它们可以呈纯的对映体或这些对映体混合物形式存在。
与通式(I)化合物化学结构类似的化合物是可作为中枢神经系统药物使用的,这些化合物已在EP-0490772专利申请和US-3729474中描述过。
根据本发明,可以采用由下述第1-3种方案说明的方法制备通式(I)的化合物。
根据第一种方案,用诸如像氢化锂铝、甲硼烷、甲硼烷-四氢呋喃或甲硼烷-二甲硫配合物或氢化铝的碱金属氢化物或金属氢化物之类的简单或复合还原剂,在例如甲苯、二甲苯、乙醚、四氢呋喃、二噁烷之类的芳族或醚化惰性溶剂中,在30-140℃具体取决于溶剂的温度下,处理通式(II)的1H-茚-3-乙酸衍生物,其式中Y’代表氢原子或甲氧基,生成通式(III)的醇。
然后,在诸如三乙胺或吡啶之类的有机碱存在下,并可选地存在一种惰性溶剂,在温度0-40℃用4-甲基苯磺酰氯处理这种醇,得到通式(IV)衍生物。
其后,可选地在如甲苯、二甲苯、N,N-二甲基甲酰胺或1-甲基吡咯烷-2-酮之类的高沸点溶剂中,在温度100-150℃下,优选地是在130℃下,让通式(IV)衍生物与其X如前面所定义的通式(V)哌嗪衍生物进行反应,得到通式(VI)衍生物。
如果希望得到其Y代表羟基的通式(I)最终化合物,可在例如二氯甲烷之类的惰性非质子溶剂中,在温度-70℃至-5℃下用三溴化硼使其Y’代表甲氧基的通式(VI)化合物进行去甲基化作用。
最后,采用催化氢化作用还原通式(VI)化合物。
第二种方案
根据第二种方案,在例如三乙胺或吡啶之类的有机碱存在下,可选地在一种惰性溶剂中,在温度0-40℃让其Y如前面所定义的通式(VII)的2,3-二氢-1H-茚-1-乙醇衍生物与4-甲基苯磺酰氯进行反应,得到通式(VIII)衍生物。
最后,可选地在如甲苯或二甲苯之类的高沸点溶剂中,在温度100-150℃下,让通式(VIII)衍生物与其X如前面所定义的通式(V)哌嗪衍生物进行反应。
第三种方案
根据第三种方案,在例如像二氯甲烷或四氢呋喃等的含氯溶剂或醚化溶剂之类的惰性溶剂中,在温度20-50℃下,用N,N’-羰基二咪唑处理其Y如前面所定义的通式(IX)的、消旋的或光学纯的2,3-二氢-1H-茚-1-乙酸衍生物,以得到相应的咪唑化物(imidazolide),然后用其X如前面所定义的通式(V)哌嗪衍生物处理咪唑化物(imidazolide),以得到一种通式(X)的酰胺,最后,在例如甲苯、四氢呋喃或二噁烷之类的芳族或醚化惰性溶剂中,在30-140℃,依溶剂性质而定的温度下,采用例如氢化锂铝等的碱金属或金属氢化物之类的单一的或复合的还原剂处理通式(X)的哌嗪衍生物。
其X和Y每个都代表羟基的通式(I)化合物可以采用通常的方法得到,例如在如二氯甲烷之类的惰性溶剂中,在温度-20℃至+40℃下,采用如三溴化硼之类的试剂处理其X和Y每个都代表甲氧基的相应化合物。
在C.A.76(23)140279S,C.A.104(1)5652q和J.Chem.Soc.PerkinTrans.(1972),1(7),941中描述了通式(II)起始酸:在锌粉存在下,在Reformatsky反应条件下,用溴代乙酸乙酯处理2,3-二氢-1H-茚-1-酮(Y=H,在市场上可购到)或6-甲氧基-2,3-二氢-1H-茚-1-酮(Y=OCH3,在J.Org.Chem.(1970),35(3),647和J.Org.Chem.(1977),42(12),2155中有介绍),得到一种(6-Y-2,3-二氢-1H-茚-1-亚基)乙酸乙酯和5-Y-1H-茚-3-乙酸乙酯的混合物。然后这种混合物在碱性醇介质中水解得到通式(II)的酸。
通式(VII)2,3-二氢-1H-茚-1-乙醇衍生物可以根据J.Pharm.Sc.(1974),63,848描述的方法得到。
人们已知通式(V)哌嗪衍生物,并可以由例如在EP-0343050、EP-0354093和EP-0434561专利申请中,在J.Med.Chem.(1986),29(11),2379、J.Med.Chem.(1988)31(10)1968和J.Med.Chem.(1991),34(8),2623中描述的方法得到。
根据在J.Am.Chem.Soc.(1952),74,2274描述的方法,由上面提到的通式(II)的起始酸酯的混合物催化氢化,接着水解,或催化氢化这些酸本身,可以得到通式(IX)消旋酸。
根据J.Am.Chem.Soc.(1992),114,2181描述的方法,采用例如(+)-或(-)-α-苯基-乙基胺之类的光学纯手性胺拆分,由相应的消旋化合物可以得到光学纯的通式(IX)起始酸。采用如脂酶之类的酶,对映选择性(enantioselective)水解例如假单胞菌或猪肝丙酮粉末,由相应的消旋酯也可以得到光学纯的通式(IX)起始酸。
下面的实施例详细说明制备本发明的化合物。
元素的微量分析和IR和NMR谱证实所得到产物的结构。
在这些实施例题目括弧中所标出的数字对应于较后表中第一栏的数字。实施例1(第3号化合物)
(E)-2-丁烯二酸-1-[2-(6-甲氧基-2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
1.1 5-甲氧基-1H-茚-3-乙醇
制备在50毫升乙醚中0.76克(0.02摩尔)氢化锂铝的悬浮液,加入2.04克(0.01摩尔)5-甲氧基-1H-茚-3-乙酸溶液,搅拌该混合物,再加热该混合物回流32小时。
让该混合物冷却,用1.6毫升10%酒石酸钾钠复盐水溶液进行水解,让其加热沸腾1小时,过滤,用四氢呋喃洗涤残余物,并在减压下蒸发该滤液。
得到1.8克油状残余物,并蒸馏纯化残余物。
得到1.55克可在后续步骤中原样使用的黄色液体。
1.2.4-甲基苯磺酸-2-(5-甲氧基-1H-茚-3-基)乙酯
将1.27克(0.0067摩尔)5-甲氧基-1H茚-3-乙醇溶解在11毫升无水吡啶中,搅拌该混合物,并用冰浴进行冷却,一点一点地添加1.4克(0.0073摩尔)4-甲基苯磺酰氯,在冷却下保持搅拌一夜,然后在室温下搅拌4小时。
将这种溶液倒入16毫升10N盐酸和48克冰的混合物中,用乙醚处理所得到的这种混合物,分离有机相,该有机相用水洗涤,用硫酸镁进行干燥,过滤并在减压下蒸发滤液。
得到1.94克可在后续步骤中原样使用的无色油状产物。
1.3.1-[2-(5-甲氧基-1H茚-3-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪
将2.07克(0.006摩尔)4-甲基苯磺酸-2-(5-甲氧基-1H-茚-3-基)乙酯和2.90克(0.012摩尔)1-(7-甲氧基萘-1-基)哌嗪混合。搅拌该混合物,将该混合物置于氩气氛下,并在130℃油浴中加热2小时。
用二氯甲烷溶解该混合物,用水、稀氢氧化钠溶液,再用水洗涤该溶液,该溶液用硫酸镁干燥,过滤,再在减压下蒸发其滤液。
得到4.08克油,采用硅胶柱色谱纯化该油,用二氯甲烷/丙酮(92/8)混合物洗脱。
得到2.09克化合物。
1.4.(E)-2-丁烯二酸-1-[2-(6-甲氧基-2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
将0.9克(0.0021摩尔)1-[2-(5-甲氧基-1H-茚-3-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪溶解在40毫升乙醇中,加入0.17毫升(1当量)氯仿和0.4克含10%钯的碳,再在Parr设备中在约0.3兆帕压力下进行氢化。
当吸收理论量的氢时,采用过滤分离该催化剂,并在减压下蒸发该滤液。其残余物用二氯甲烷和水溶解,加入碳酸钾,分离该有机相,并用水洗涤,用硫酸钠干燥,再在减压下蒸去该溶剂。
得到0.76克油状产物,将其溶于Z醇加入0.21克(1当量)富马酸,分离沉淀的盐,并让该盐在乙醇中重结晶。
熔点:133-135℃实施例2(第2号化合物)
(E)-2-丁烯二酸-1-[2-(2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
2.1. 4-甲基苯磺酸-2-(2,3-二氢-1H-茚-1-基)乙酯
将2.2克(0.0136摩尔)2,3-二氢-1H-茚-1-乙醇溶解在25毫升无水吡啶中,搅拌该溶液,用冰浴冷却该溶液,并一点一点地加入2.6克(0.0136摩尔)4-甲基苯磺酰氯,保持在0℃搅拌1小时,然后在室温下搅拌3小时。
将得到的溶液倒入50毫升10N盐酸和100克冰的混合物中,加入乙醚,分离有机相,该有机相用水洗涤,用硫酸镁干燥,过滤并在减压下蒸去该溶剂。
得到2.5克在后续步骤中可原样使用的无色油状产物。
2.2.(E)-2-丁烯二酸-1-[2-(2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
制备1.1克(0.0035摩尔)4-甲基苯磺酸-2-(2,3-二氢-1H-茚-1-基)乙酯和1.7克(0.007摩尔)1-(7-甲氧基萘-1-基)哌嗪的混合物,并在氩气氛下在130℃油浴中加热该混合物3小时。
该混合物经冷却后,用氢氧化钠水溶液处理,并用二氯甲烷萃取。
该有机相用水洗涤,用硫酸镁干燥,再过滤并在减压下蒸去该溶剂。
得到2.2克油状产物,采用硅胶柱色谱提纯该产物,用二氯甲烷/丙酮(97/3)混合物洗脱。
得到1.3克纯化的碱溶解在丙-2-醇和乙醚混合物中,将其添加0.4克富马酸溶解在热的丙-2-醇中的溶液,加热该混合物,再缓慢冷却。
在乙醇中重结晶后,最后得到1.2克富马酸盐。
熔点:185-186℃。
实施例3(第13号化合物)
(E)-2-丁烯二酸-(-)-1-[2-(6-甲氧基-2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
3.1.(±)-2,3-二氢-6-甲氧基-1H-茚-1-乙酸
将4.97克(0.028摩尔)5-甲氧基-1H-茚-3-乙酸溶解在100毫升冰冷的乙酸中,加入2.6克含10%钯的碳,再在Parr设备中在约0.3兆帕压力下进行氢化。
当吸收理论量的氢时,采用过滤分离该催化剂,并在减压下蒸发该滤液。其残余物用环己烷多次溶解,蒸发以便除去所有微量的乙酸,在减压下干燥后,得到4.04克固体。
熔点:90-92℃。
3.2.(-)-2,3-二氢-6-甲氧基-1H-茚-1-乙酸
a)将4.04克(0.02摩尔)(±)-2,3-二氢-6-甲氧基-1H-茚-1-乙酸溶解在70毫升丙酮中,加入2.06克(0.017摩尔)(R)-α-苯乙基胺,在室温下搅拌该混合物4小时。
过滤收集白色的固体,该白色固体在丙酮中重结晶多次,直到熔点不变。
熔点:166.5-167.5℃
[α]D 20:-9.2·(C=0.31;CH3OH)。
b)用0.25N氢氧化钠溶液处理如此得到的盐,其pH升到10,用苯萃取释放出的胺,再用浓盐酸酸化该含水相,直到pH=1,然后用乙醚萃取三次。含醚的有机相用水洗涤,用硫酸钠干燥,在减压下蒸去其溶剂,其固体再在己烷和石油醚的混合物中重结晶。
熔点:88-89℃。
[α]D 20:-40.0·(C=0.80;CH3OH)ee=99.3%(HPLC)。
3.3(-)-1-[(2,3-二氢-6-甲氧基-1H-茚-1-基)乙酰基]-4-(7-甲氧基萘-1-基)哌嗪
在氮气氛下,在7毫升无水四氢呋喃中加入0.26克(1.3毫摩尔)(-)-(2,3-二氢-6-甲氧基-1H-茚-1-乙酸,分数份小份加入0.265克(1.6毫摩尔)N,N’-羰基二咪唑,并在室温下搅拌该混合物1小时30分钟。加入0.336克(1.4毫摩尔)4-(7-甲氧基萘-1-基)哌嗪在2毫升无水四氢呋喃中的溶液,并在室温下搅拌该混合物16小时。在减压下蒸去其溶剂,用水和二氯甲烷溶解该残余物,分离有机相,该有机相用饱和氯化钠水溶液洗涤,再用水洗涤,用硫酸钠干燥,在减压下蒸去其溶剂,采用硅胶柱色谱提纯该残余物,用二氯甲烷/丙酮(97/3)混合物洗脱。
得到0.49克化合物
熔点:57-60℃
[α]D 20:-25.8·(C=0.48;CH3OH)。
3.4.(E)-2-丁烯二酸-(-)-1-[2-(6-甲氧基-2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
在氮气氛下,在3毫升无水四氢呋喃中加入0.06克(1.6毫摩尔)氢化锂铝,滴加0.4克(0.93毫摩尔)(-)-1-[(2,3-二氢-6-甲氧基-1H-茚-1-基)乙酰基]-4-(7-甲氧基萘-1-基)哌嗪在2毫升无水四氢呋喃中的溶液,加热该混合物回流2小时30分钟。
加入5毫升乙酸乙酯,搅拌15分钟,过滤该混合物,在减压下蒸发该滤液,用乙酸乙酯和饱和氯化钠水溶液溶解该残余物,其有机相经分离后,用水洗涤,用硫酸钠干燥,再在减压下蒸去该溶剂。
得到0.38克油状产物,将其油状产物溶解在丙-2-醇中,加入0.1克富马酸溶解于热丙-2-醇中的溶液,加热该混合物,再让其缓慢冷却。在乙醇中重结晶后得到0.3克富马酸盐。
熔点:171-172℃
[α]D 20:-22.0·(C=0.40;CH3OH)ee>99.8%(HPLC)。实施例4(第14号化合物)
(E)-2-丁烯二酸-(+)-1-[2-(6-甲氧基-2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
4.1.(+)-2,3-二氢-6-甲氧基-1H-茚-1-乙酸
a)将实施例3.2.a)中所得到的来自于盐重结晶的母液合并,在减压下蒸去溶剂,将该残余物溶解在水中,用0.25N氢氧化钠水溶液将pH调整到10,用苯萃取释放的胺,酸化该含水相并用乙醚萃取三次。含醚的有机相用水洗涤,用硫酸钠干燥,再在减压下蒸去溶剂。得到2.8克在己烷中重结晶的固体。
b)将1.95克(0.95毫摩尔)这种固体溶解在20毫升丙酮中,往这种溶液中滴加1.1克(0.9毫摩尔)(S)-α-苯乙基胺在5毫升丙酮中的溶液,在室温下搅拌该混合物1小时30分钟。过滤收集固体,该固体经干燥后在丙酮中重结晶几次,直到熔点不变,得到0.8克盐。
熔点:165.5-167.5℃,
[α]D 20:+11.5·(C=0.46;CH3OH)
c)用0.25N氢氧化钠溶液处理0.76克这种盐直到pH=10,用苯萃取释放的胺,用浓盐酸将这种含水相酸化直至pH=1,用乙醚萃取三次,含醚的有机相用饱和氯化钠水溶液洗涤,用硫酸钠干燥,在减压下蒸去溶剂,该残余物在己烷中重结晶,得到0.42克化合物。
熔点:86.5-87.5℃
[α]D 20:+20.9·(C=0.66;CH3OH)ee=95.2%(HPLC)。
4.2.(+)-1-[2-(2,3-二氢-6-甲氧基-1H-茚-1-基)乙酰基]-4-(7-甲氧基萘-1-基)哌嗪
使用实施例3.3中描述的方法,由0.36克(1.7毫摩尔)(+)-2,3-二氢-6-甲氧基-1H-茚-1-乙酸和0.464克(1.9毫摩尔)4-(7-甲氧基萘-1-基)哌嗪得到0.62克化合物。
熔点:55-58℃
[α]D 20:+26.1·(C=0.54;CH3OH)
4.3.(E)-2-丁烯二酸-(+)-1-[2-(6-甲氧基-2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
使用实施例3.4中描述的方法,由0.535克(1.2毫摩尔)(+)-1-[(2,3-二氢-6-甲氧基-1H-茚-1-基)乙酰基]-4-(7-甲氧基萘-1-基)哌嗪和0.1克(2.6毫摩尔)氢化锂铝得到0.47克胺,由该胺制备出0.495克富马酸盐。
熔点:169-170℃
[α]D 20:+23.0·(C=0.46;CH3OH),ee=95.4%(HPLC)。实施例5(第11号化合物)
(E)-2-丁烯二酸-(R)-(+)-1-[2-(2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
5.1.(±)-2,3-二氢-1H-茚-1-乙酸乙酯
将12克(0.06摩尔)在J.Am.Chem.Soc.(1952),74,2274中描述的(2,3-二氢-1H-亚茚-1-基)乙酸乙酯和1H-茚-3-乙酸乙酯混合物溶解在250毫升乙醇中,再加入1.5克含10%钯的碳,在Parr设备中在约0.3兆帕压力下进行氢化。
当吸收理论量的氢时,采用过滤分离该催化剂,再在减压下蒸去该溶剂,蒸馏该残余物。得到11.8克可原样使用的液体。
沸点:160℃(270帕/2毫米汞柱)。
5.2.(R)-(+)-2,3-二氢-1H-茚-1-乙酸乙酯
24克(0.117摩尔)(±)-2,3-二氢-1H-茚-1-乙酸乙酯在160毫升二异丙醚和160毫升0.01M磷酸盐缓冲液(磷酸二氢钾和磷酸氢二钠)中的溶液(pH=7.8)里,加入2.88克假单胞菌属的脂酶PS(AmanoTM),搅拌该混合物24小时,并且加入5N氢氧化钠水溶液使其pH保持不变。
将pH调整到9,用二异丙醚萃取该混合物三次,有机相用硫酸镁干燥,并在减压下蒸去溶剂,得到10.8克化合物。
[α]D 20:+11.6·(C=1.05;CHCl3),ee=99%(HPLC)。
5.3.(R)-(+)-2,3-二氢-1H-茚-1-乙酸
23.5克(0.11摩尔)(R)-(+)-2,3-二氢-1H-茚-1-乙酸乙酯和32.6克(0.58摩尔)氢氧化钾混合物在600毫升水与乙醇混合物(50/50)中加热回流1小时。
在减压下蒸去乙醇,用乙醚萃取含水相,用浓盐酸酸化该含水相直到pH=1,用乙醚萃取三次,有机相用水洗涤,用硫酸钠干燥,在减压下蒸去溶剂,得到18克可在正-己烷中重结晶的固体。
熔点:78.5-80.5℃
[α]D 20:+8.1·(C=1.21;CH3COCH3),ee=99%(HPLC)。
5.4.(R)-(+)-1-[(2,3-二氢-1H-茚-1-基)乙酰基]-4-(7-甲氧基萘-1-基)哌嗪
采用实施例3.3.中描述的方法,由2.3克(13毫摩尔)(R)-(+)-2,3-二氢-1H-茚-1-乙酸和3.4克(14毫摩尔)4-(7-甲氧基萘-1-基)哌嗪得到4.3克化合物。
熔点:121-123℃
[α]D 20:+8.5·(C=0.46;CH3COCH3)。
5.5.(E)-2-丁烯二酸-(R)-(+)-1-[2-(2,3-二氢-1H-茚-1-基)乙基]-4-(7-甲氧基萘-1-基)哌嗪酯(1∶1)
采用实施例3.4.中描述的方法,4.2克(10毫摩尔)(R)-(+)-1-[(2,3-二氢-1H-茚-1-基)乙酰基]-4-(7-甲氧基萘-1-基)哌嗪与0.4克(10毫摩尔)氢化铝锂作用,然后与0.96克(8.3毫摩尔)富马酸作用,得到3.7克化合物。
熔点:177-179℃
[α]D 20:+3.9·(C=1;CH3OH),ee=97.5%(HPLC)。
下面的表说明本发明某些化合物的化学结构和物理性质。
表
注解
编号 | X | Y | 异构 | 盐 | 熔点(℃) |
1 | H | H | RS | fum.(1∶1) | 198-200 |
2 | OCH3 | H | RS | fum.(1∶1) | 185-186 |
3 | OCH3 | OCH3 | RS | fum.(1∶1) | 133-135 |
4 | OCH2CH3 | H | RS | fum.(1∶1) | 182-183 |
5 | OCH2CH3 | OCH3 | RS | fum.(1∶1) | 104-105 |
6 | OCH2CH2CH3 | OCH3 | RS | fum.(1∶1) | 97-98 |
7 | OCH(CH3)2 | OCH3 | RS | fum.(1∶1) | 155,5-157 |
8 | OCH2cC3H5 | H | RS | fum.(1∶1) | 169,5-171 |
9 | OH | OCH3 | RS | HCl(1∶1) | 271-273,5 (d) |
10 | OH | OH | RS | HCl(1∶1) | 168-170 |
11 | OCH3 | H | R(+) | fum.(1∶1)mes.(1∶1) | 177-179129,5-131 |
12 | OCH3 | H | S(-) | fum.(1∶1) | 174,5-177,5 |
13 | OCH3 | OCH3 | (-) | fum.(1∶1) | 171-172 |
14 | OCH3 | OCH3 | (+) | fum.(1∶1) | 169-170 |
在栏“X”中,“OCH2cC3H5”代表环丙基甲氧基。
在栏“Sel”中,“-”代表一种呈碱状态的化合物,“fum.”代表富马酸盐,或(E)-2-丁烯二酸盐,“HCl”代表氢氯化物和“mes.”代表甲二磺酸盐,或甲磺酸盐;括弧中所表明的比是碱与酸的摩尔比。
在栏“F(℃)”中,“(d)”代表有分解的熔点。
本发明化合物构成证明它们作为治疗物质是有意义的试验内容。
于是,根据由Sauger和Schoemaker在Psychopharmacology(1992),108,85-92中描述的方案,离体试验了这些化合物对老鼠海马中存在的5-HT1A类型血清素源性受体的亲合力。这些化合物可置换在5-HT1A受体上特定标记配位体,[3H]-8-羟基-2-(二-正-丙基氨基)-1,2,3,4-四氢化萘(下面用“[3H]-8-OH-DPAT”表示,Gozlan等人在Nature(1983),305,140-142中描述过),的键合。
使用的动物是重160-200克的Sprague-Dawley雄性鼠。切下头部后,取出脑,切除海马。该组织在10个体积用盐酸将其pH调节到7.4的50mM三羟甲基氨基甲烷缓冲液中(即每毫升100毫克新鲜组织),用Ultra-Turrax PolytronTM设备以最高速度的一半磨碎30秒。在4℃三次洗涤已均化的组织,这些组织每次以48000×g离心10分钟,其残渣在该冷的、新鲜的缓冲液中再制成悬浮液。最后,让最后的残渣在该缓冲液中制成悬浮液,以达到每毫升50mM缓冲液为100毫克起始组织的浓度。然后在37℃继续培育10分钟。
在最终体积为1毫升含有10μM优降灵和3μM帕罗西汀的缓冲液中,通过培育100微升膜悬浮液测定与[3H]-8-OH-DPAT(1纳摩尔)键合。
在37℃培育15分钟后,用Whatman GF/BTM滤纸过滤回收这些膜,用5毫升冰冷的缓冲液以等分量分三次进行洗涤。在该闪烁液体中提取这些滤纸,并采用液体闪烁照相法测定其放射性。特定的[3H]-8-OH-DPAT键合定义为在这些滤纸上所保留的放射性的量,并且该放射性的量可能受到在10μM5-羟基色胺中共-培育作用的抑制。在1nM[3H]-8-OH-DPAT浓度条件下,该特定的键合为用滤纸所回收的90%总放射性。
对于每个所研究化合物的浓度,测定抑制与[3H]-8-OH-DPAT键合的百分数,然后测定IC50浓度,即抑制50%该键合的浓度。
IC50值为1-300nM。
本发明的化合物也构成有关它们对在牛的尾状核中存在的5-HT1D血清素源性受体的亲合力进行离体研究的内容,该亲合力通过特定的标记配位体,[3H]-5-羟基色胺的置换予以证明,基本如Heuring和Peroutka在J.Neurosci.,(1987),7,804-903所描述的那样。
将牛的尾状核(Collectorgane,Paris)保存在-80℃直到使用。在10个体积用盐酸将其pH调节到7.4的50mM三羟甲基氨基甲烷缓冲液中(即每毫升100毫克新鲜组织),该组织用Ultra-Turrax PolytronTM设备以最高速度的一半磨碎30秒。在4℃两次洗涤已均化的组织,并且以40000×g离心10分钟,该残渣每次都在冷的缓冲液中再制成悬浮液。最后,让最后的残渣在该缓冲液中制成悬浮液,以达到每毫升50mM缓冲液为100毫克起始组织的浓度,在37℃继续培育15分钟。然后,这种膜悬浮液以40000×g离心10分钟,将这种残渣在8个体积含有三羟甲基氨基甲烷(50mM)、抗坏血酸(0.1%)、氯化钙(4mM)、优降灵(μM)美舒麦角(100nM)和8-羟基-二丙基氨基-1,2,3,4-四氢化萘(100nM)的培育介质中再制成悬浮液,其介质的pH用盐酸调节到7.4。
在最终体积为1毫升的培育介质中通过培育100微升膜悬浮液测定与[3H]-5-羟基色胺(2nM)键合。
在37℃培育30分钟,接着在0-4℃培育5分钟后,用WhatmanGF/BTM滤纸过滤回收这些膜,用1毫升冰冷的三羟甲基氨基甲烷缓冲液以等分量分两次进行洗涤,其pH用盐酸调节到7.4。
在该闪烁液体中提取这些滤纸,并采用液体闪烁照相法测定其放射性。特定的[3H]-5-羟基色胺键合定义为在这些滤纸上所保留的放射性的量,其放射性的量可能受到0.1μM5-羟基色胺共-培育作用的抑制。在2nM[3H]-5-羟基色胺浓度条件下,特定的键合为用该滤纸所回收的70%总放射性。
对于所研究化合物的每个浓度,测定了与[3H]-5-羟基色胺键合的抑制百分数,然后测定IC50浓度,即抑制50%该键合的浓度。
在这个试验中,最强活性的本发明化合物的IC50低于40nM。
本发明这些化合物也构成在老鼠大脑皮质的(5-HT2)血清素源性受体上螺环哌定苯键合置换的离体试验内容。
对于这个试验,取出老鼠的大脑,解剖其大脑皮质,并在每升含有50毫摩尔pH7.4的三羟甲基氨基甲烷/HCl缓冲溶液、120毫摩尔氯化钠和5毫摩尔氯化钾的10个体积混合物中,在0℃下进行均化。已均化的混合物以40000×g离心10分钟,然后重复两次,回收残渣,其残渣在同样的缓冲液混合物中制成悬浮液进行洗涤,再均化并离心。为了完成该试验,按照每1毫升缓冲液为100毫克湿组织将最后的残渣稀释在同样的缓冲液混合物中。
这时,这种组织在10微摩尔/升优降灵存在下在37℃预培育10分钟,然后在浓度0.3纳摩尔/升3H-螺环哌丁苯(比活度:每毫摩尔15-30居里)和待研究化合物存在下在37℃下培育20分钟。
然后用Whatman GF/BTM滤纸过滤回收这些膜,用5毫升冷的缓冲液洗涤两次。该滤纸所保留的放射性是采用液体闪烁照相法测定的。
为了估算出这些化合物的活性,建立了特定的3H-螺环哌丁苯键合的抑制百分数随不同的置换药品浓度变化曲线。
用图解法确定了IC50浓度,即抑制50%特定键合浓度。
特定的键合定义为用100微摩尔/升5-HT置换的键合。
本发明化合物IC50浓度位于50-1500nM。
最后,本发明这些化合物构成有关它们对猪的脉络丛中存在的5-HT1C血清素源性受体的亲合力的离体试验内容,并且基本上如Pazos等人在Eur.J.Pharmacol.,(1984),106,539-546和Yagalof和Hartig在Mol.Pharmacol.,(1986),26,120-125中所描述的,这种亲合力是由一种特定的标记配位体([3H]-美舒麦角)键合置换予以证明的。
将该脉络丛(Collectorgane,Paris)保存在-80℃直到使用。在10个体积蔗糖(0.32M)中,在温度0-4℃下,该组织用PotterTM均化器开动10-15次(800转/分)进行均化。这种膜悬浮液以1000×g(4℃)离心10分钟,上层清液以30000×g(4℃)离心20分钟。将这种残渣在用盐酸使其pH调节到7.4的10个体积的50mM三羟甲基氨基甲烷缓冲液中制成悬浮液,然后在37℃培育15分钟。最后,这种悬浮液以30000×g(4℃)离心20分钟,并将这种残渣溶解在28个体积含有三羟甲基氨基甲烷缓冲液(50mM)、抗坏血酸(0.1%)、氯化钙(4mM)和优降灵(10μM)的培育缓冲液中,该缓冲液的pH用盐酸调节到7.4。
在最后500微升培育介质中培育100微升膜悬浮液,可测定与[3H]-美舒麦角的键合。
在37℃培育30分钟,接着在0-4℃培育5分钟后,用WhatmanGF/BTM滤纸过滤回收这些膜,这些滤纸预先用0.05%聚乙烯亚胺处理30分钟,每次用1毫升50mM冷的三羟甲基氨基甲烷缓冲液洗涤两次,该缓冲液用盐酸将其pH调节到7.4。
在闪烁液中提取这些滤纸,并且用液体闪烁照相法测定该放射性。[3H]-mesulergine特定键合定义为这些滤纸保留的放射性的量,该放射性可能受到与10μM 5-羟基色胺共-培育的抑制。在1nM[3H]-美舒麦角浓度,特定键合为90%用滤纸所回收的总放射性。
对于每个所研究化合物的浓度,测定了与[3H]-美舒麦角键合的抑制百分数,然后测定了IC50浓度,即抑制50%该键合的浓度。
本发明这些化合物在这个试验中的IC50浓度为5-500nM。
这些试验的结果表明,本发明化合物对5HT1A、5HT1D和5HT1C类型的血清素源性受体具有很强的亲合力,以及对5HT2具有中等的亲合力。
这些结果使人想到这些化合物可用于治疗与5HT1A、5HT1D、5HT1C和/或5HT2类型的血清素源性受体机能障碍相关的任何疾病,具体地用于治疗焦虑、抑郁症,其中包括精神病性抑郁症、睡眠紊乱、恐怖症、恐慌症、强迫观念与行为紊乱、由于滥用或戒酒或毒品所引起的紊乱、产生性的或短缺性的精神分裂症、由精神安定剂诱发的急性或慢性锥体束外综合症、性行为紊乱,调节摄取营养,还用于治疗诸如偏头痛和高血压之类的血管或心血管疾病。
为此目的,这些化合物与适当的赋形剂配合可以呈任何肠或肠胃道外用药的适当形式,例如片剂、糖衣丸、胶囊、囊、栓剂、口服或注射的溶液或悬浮液,其剂量为每天服用1-1000毫克活性物质。
Claims (4)
1.满足下述通式(I)的化合物:式中:
X代表氢原子、羟基、C1-C3烷氧基或环丙基甲氧基,Y代表氢原子、羟基或甲氧基,
这些化合物以碱或加合盐状态存在,呈纯的对映体形式或对映体混合物形式。
2.根据权利要求1所述化合物的制备方法,其特征在于:
a)用一种还原剂处理通式(II)的1H-茚-3-乙酸衍生物:式中Y’代表氢原子或甲氧基,以便生成通式(III)的醇:然后用4-甲基-苯磺酰氯处理这种醇,以得到通式(IV)衍生物:再让通式(IV)衍生物与通式(V)哌嗪衍生物进行反应:式中X是如权利要求1中所定义,以得到通式(VI)衍生物:,然后如果希望得到其中Y代表羟基的通式(I)最终化合物,让其中Y’代表甲氧基的通式(VI)化合物进行去甲基化作用,最后采用催化氢化还原通式(VI)化合物,或b)让通式(VII)的2,3-二氢-1H-茚-1-乙醇衍生物:其中Y如权利要求1中所定义,与4-甲基苯磺酰氯进行反应,以得到通式(VIII)衍生物:最后让通式(VIII)衍生物与通式(V)哌嗪衍生物进行反应:式中X如权利要求1中所定义,或
3、药物,其特征在于它由一种根据权利要求1所述的化合物组成。
4、药物组合物,其特征在于它含有与一种赋形剂配合的权利要求1所述的化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9509684A FR2737724B1 (fr) | 1995-08-09 | 1995-08-09 | Derives de 1-[2-(2,3-dihydro-1h-inden-1-yl)ethyl]-4- (naphtalen-1-yl) piperazine, leur preparation et leur application en therapeutique |
FR95/09684 | 1995-08-09 |
Publications (1)
Publication Number | Publication Date |
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CN1199398A true CN1199398A (zh) | 1998-11-18 |
Family
ID=9481836
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN96197512A Pending CN1199398A (zh) | 1995-08-09 | 1996-08-01 | 1-[2-(2,3-二氢-1h-茚-1-基)乙基]-4-(萘-1基)哌嗪衍生物,它们的制备方法及其在治疗中的应用 |
Country Status (20)
Country | Link |
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US (1) | US5929078A (zh) |
EP (1) | EP0843670A1 (zh) |
JP (1) | JP2000501699A (zh) |
KR (1) | KR19990035954A (zh) |
CN (1) | CN1199398A (zh) |
AR (1) | AR003222A1 (zh) |
AU (1) | AU707372B2 (zh) |
BR (1) | BR9609977A (zh) |
CA (1) | CA2228843A1 (zh) |
CO (1) | CO4750833A1 (zh) |
CZ (1) | CZ36898A3 (zh) |
FR (1) | FR2737724B1 (zh) |
HU (1) | HUP9802546A3 (zh) |
IL (1) | IL123187A0 (zh) |
NO (1) | NO980529L (zh) |
NZ (1) | NZ315363A (zh) |
PL (1) | PL324966A1 (zh) |
SK (1) | SK16798A3 (zh) |
WO (1) | WO1997006155A1 (zh) |
ZA (1) | ZA966772B (zh) |
Families Citing this family (2)
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TWI242011B (en) | 1997-03-31 | 2005-10-21 | Eisai Co Ltd | 1,4-substituted cyclic amine derivatives |
US8106074B2 (en) | 2001-07-13 | 2012-01-31 | Pierre Fabre Medicament | Pyridin-2-yl-methylamine derivatives for treating opiate dependence |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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BE358300A (zh) * | 1928-04-28 | |||
US2927924A (en) * | 1958-04-03 | 1960-03-08 | Lilly Co Eli | Novel phenethyl-substituted piperazines |
NL132357C (zh) * | 1966-09-03 | |||
DE2037852C3 (de) * | 1970-07-30 | 1980-06-26 | Boehringer Sohn Ingelheim | Neue Piperazinderivate und Verfahren zu ihrer Herstellung |
EP0737189B1 (en) * | 1993-12-28 | 1999-07-28 | PHARMACIA & UPJOHN COMPANY | Heterocyclic compounds for the treatment of cns and cardiovascular disorders |
FR2716193B1 (fr) * | 1994-02-16 | 1996-04-05 | Synthelabo | Dérivés de 1[2-(1h-inden-3-yl)ethyl]-4-(naphtalen-1-yl)piperazine, leur préparation et leur application en thérapeutique. |
-
1995
- 1995-08-09 FR FR9509684A patent/FR2737724B1/fr not_active Expired - Fee Related
-
1996
- 1996-08-01 HU HU9802546A patent/HUP9802546A3/hu unknown
- 1996-08-01 CZ CZ98368A patent/CZ36898A3/cs unknown
- 1996-08-01 BR BR9609977A patent/BR9609977A/pt not_active Application Discontinuation
- 1996-08-01 NZ NZ315363A patent/NZ315363A/xx unknown
- 1996-08-01 US US09/011,807 patent/US5929078A/en not_active Expired - Fee Related
- 1996-08-01 CN CN96197512A patent/CN1199398A/zh active Pending
- 1996-08-01 EP EP96927120A patent/EP0843670A1/fr not_active Withdrawn
- 1996-08-01 IL IL12318796A patent/IL123187A0/xx unknown
- 1996-08-01 KR KR1019980700615A patent/KR19990035954A/ko not_active Application Discontinuation
- 1996-08-01 CA CA002228843A patent/CA2228843A1/en not_active Abandoned
- 1996-08-01 JP JP9508161A patent/JP2000501699A/ja active Pending
- 1996-08-01 WO PCT/FR1996/001216 patent/WO1997006155A1/fr not_active Application Discontinuation
- 1996-08-01 AU AU67053/96A patent/AU707372B2/en not_active Ceased
- 1996-08-01 SK SK167-98A patent/SK16798A3/sk unknown
- 1996-08-01 PL PL96324966A patent/PL324966A1/xx unknown
- 1996-08-06 CO CO96041580A patent/CO4750833A1/es unknown
- 1996-08-08 ZA ZA9606772A patent/ZA966772B/xx unknown
- 1996-08-08 AR ARP960103928A patent/AR003222A1/es unknown
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1998
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Also Published As
Publication number | Publication date |
---|---|
AU6705396A (en) | 1997-03-05 |
CZ36898A3 (cs) | 1998-05-13 |
FR2737724A1 (fr) | 1997-02-14 |
US5929078A (en) | 1999-07-27 |
HUP9802546A2 (hu) | 1999-02-01 |
WO1997006155A1 (fr) | 1997-02-20 |
IL123187A0 (en) | 1998-09-24 |
ZA966772B (en) | 1997-02-19 |
JP2000501699A (ja) | 2000-02-15 |
CA2228843A1 (en) | 1997-02-20 |
NO980529L (no) | 1998-04-14 |
NO980529D0 (no) | 1998-02-06 |
FR2737724B1 (fr) | 1997-09-05 |
SK16798A3 (en) | 1998-08-05 |
NZ315363A (en) | 1998-10-28 |
EP0843670A1 (fr) | 1998-05-27 |
KR19990035954A (ko) | 1999-05-25 |
AR003222A1 (es) | 1998-07-08 |
HUP9802546A3 (en) | 1999-10-28 |
CO4750833A1 (es) | 1999-03-31 |
MX9801057A (es) | 1998-05-31 |
PL324966A1 (en) | 1998-06-22 |
BR9609977A (pt) | 1999-01-12 |
AU707372B2 (en) | 1999-07-08 |
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