CN1629156A - 吡啶基-和嘧啶基-哌嗪衍生物、其制备方法以及含有该衍生物的药物组合物 - Google Patents
吡啶基-和嘧啶基-哌嗪衍生物、其制备方法以及含有该衍生物的药物组合物 Download PDFInfo
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Abstract
本发明涉及下述通式的新化合物及其具有药理学活性的盐,如右式其中Ar,X,Y,R1,R2,n和A的定义如说明书中所述,本发明的化合物可用于治疗精神障碍。
Description
本申请是中国专利申请号为93117383.3、发明创造名称为《吡啶基-和嘧啶基-哌嗪衍生物、其制备方法以及含有该衍生物的药组合物》、申请日为1993年7月30日的中国发明专利申请的分案申请。
技术领域
目前所用的精神抑制剂会引起某些令人烦恼的锥体束外运动障碍(例如急性肌张力障碍反应和延迟的运动障碍),并且在改善精神***症的消极症状(例如受限的或迟钝的情绪唤醒)方面是无效的。抗抑制药的主要缺点是,它们不能减轻30-40%病人的压抑。***通常会上瘾。因此,迫切需要一种比现今临床上使用的药物更有效及付作用更小的治疗精神病的有效的药物。
背景技术
在药理学上对中枢神经***起作用的各种吡啶基-和嘧啶基哌嗪衍生物在现有技术中是已知的。可以提到某些有代表性的实例。氮哌酮是一种苯丁酮系列的精神安定药,它能对猪起镇静作用。丁螺旋酮是一种***。其安眠作用被认为是通过对5HT-受体的作用而被调节的。
氮哌酮
丁螺旋酮
U.S.P.No.4937245公开了通式C的化合物
其中A选自吡啶基或嘧啶基,例如
其中R6优选为氢,R7优选为在吡啶环的3-位上的氰基,酰氨基,甲氧基或氢取代基,该化合物用于治疗精神障碍如精神病,抑郁症及焦虑症。
发明内容
本发明涉及在药理学上对中枢神经***起作用的一种新的吡啶基-和嘧啶基-哌嗪衍生物,该衍生物的制备方法,以及含有该衍生物的药物组合物。
本发明提供的新化合物具有如下通式(1)的结构:
式中Ar可相同或不同,并选自:
式中的R3是氟或氢;
R1和R2可相同或不同,并选自氢或烷基;
n是2或3;
X是氨或次甲基;
当X是氮时,Y是亚甲基;
当X是次甲基或碳时,Y选自氮或氧,优选氧。
A选自下述的吡啶或嘧啶衍生物:
R4和R5可相同或不同,并选自氢,卤素,低级烷基,给电子基如低级烷氧基或羟基,吸电子基如氰基,硝基,三氟甲基,COOR6,CONR7R8或COB,其中R6是氢或低级烷基;R7和R8相同或不同,并选自氢,低级烷基或环烷基;
B选自:
其中m是1,2,3或4。
R9选自氢或低级烷基。本发明还包括上述化合物的药理学上的活性盐。在上述定义中使用的术语低级烷基是指直链和支链的,饱和和不饱和的具有1-5个碳原子的烃基;术语环烷基是指环状的饱和和不饱和的具有3-8个碳原子的烃基,术语低级烷氧基是指直链或支链的,饱和或不饱和的具有1-5个碳原子的烷氧基;术语卤素是指氟和溴。
式(1)化合物具有碱性,因之可以用适当的酸处理使之变成治疗上活性的酸加成盐;上述酸例如是无机酸如盐酸,氢溴酸,硫酸,硝酸和磷酸;或有机酸如乙酸,丙酸,乙醇酸(glycolic acid),乳酸,丙二酸,草酸,琥珀酸,富马酸,酒石酸,柠檬酸和pamoicacid。
反之,用碱处理可将其盐形变成游离碱形。
式(1)化合物及其治疗学上可接受的盐具有可贵的药理学性质;它们能用于治疗精神障碍如精神病,抑郁症及焦虑症;老年性痴呆,早老性痴呆,厌食,精神性药物滥用症。也能治疗动物的应激反应及焦虑症。
临床研究支持了5-羟色胺(5-HT)在精神障碍如精神病,抑郁症,焦虑及精神性药物滥用症的发病机理中是十分重要的。目前的相当多的活动被引向开发新的对精神有影响的药物,如5-HT1A***例如丁螺旋酮和ipsaprione,5HT2拮抗剂例如氟苯哌胺和ritanserin,5-HT摄入抑制剂例如氟苯氧丙胺和氟苯哌苯醚。
因为5-HT1A和5-HT2受体被发现在功能上是相互作用的,所以结合了5-HT1A激动剂和5-HT2拮抗剂活性的化合物对于治疗患精神紊乱的病人将是十分感兴趣的药物。
本发明的化合物对5-HT1A和5-HT2受体均表现出很高的亲合力。
虽然式(C)化合物和式(1)化合物对于5-羟色胺5-HT1A和5-HT2受体亚型均具有很高的亲合力,但十分惊异地发现,本发明的化合物从安全观点看是极优异的,这使它们可用于中枢神经***,特别是脑的血清素激活***的治疗。
于制药学上可接受的载体中的任何有效量的上述药理学上有活性的式(1)化合物均可按照通常的给药方式及通常的给药形式如溶液,乳液,片剂,胶囊和补片对需要治疗的人及动物给药,并且可以无菌溶液的形式进行非肠道给药。非肠道给药的制剂可以是水的或非水的等渗无菌注射溶液或悬浮液的形式。
当进行较轻微的治疗或当对体重较轻的患者给药时,虽然很少量的本发明的活性物质就是很有效的,但通常单位剂量是在0.5mg以上,这要根据被处置的病情,患者的年龄和体重以及对药物的反应而决定。
单位剂量可从0.1到100mg,优选1-10mg,目剂量优选1-50mg。正确的单剂量及日剂量当然应在内科医生及兽医的指导下按照标准的给药规定来确定。
通式(1)化合物可以用通常的方法制备:
方法1
式(II)化合物(其中Ar,X和Y定义如上述,L是适当的离去基如卤素和烷基或芳基磺酸酯)用式III化合物(其中R1,R2,A和n定义如上)处理,反应采用标准的N-烷基化方法完成。
方法2
将式IV化合物(其中Ar,R1,R2,X,Y及n定义如上)和式V,VI,VII,VIII化合物(其中R4和R5定义如上述,L是适当的离去基)反应。
方法3
式IX化合物(其中Ar定义如上述)与式X化合物(其中R1,R2,n和A定义如上述)反应,L是羟基或离去基)。
方法4
式XI化合物(其中Ar,n,R1和R2定义如上)与式V,VI,VII或VIII化合物反应,得到式XII的产物。
(其中Ar,n,R1和R2和A定义如上述),再将式XII化合物还原得所需产物式XIII化合物,
(其中Ar,R1,R2,n和A定义如上述)。
具体实施方式
下述实施例仅限于说明本发明的范围,而不是限制本发明的范围,尽管所例举的化合物对于我们所要达到的目的是特别有兴趣的。下述化合物的编号用a∶b表示,其中a表示说明所需化合物的制备方法的实放例号,b是指按照该实施例所制备的化合物号,因之化合物1∶2是指按照实施例1制备的第2号化合物。
化合物的结构用NMR,质谱及元素分析确证,熔点未经校正。
实施例1:1
1-{3-[双-(4-氟苯基)氨基]丙基}-4-(2-吡啶基)哌嗪二盐酸化合物
2.8g(0.01mol)3-[双-(4-氟苯基)氨基]丙基氯化物,3.3g(0.02mol)2-吡啶基哌嗪和0.1g碘和20ml甲苯一起于150℃(油浴)下搅拌48小时。冷却反应混合物达到~75℃后,加50ml甲苯和75ml水,将两相分离,水层用甲苯萃取三次。蒸发溶剂后,得到粗碱,再用闪式色谱法提纯并分离开油状物。将3.2g游离碱溶在40ml***中,加入于乙醇中的过量的盐酸沉出二盐酸化合物,用2-丙醇重结晶得3.2g标题化合物(1∶1),m.p 222-224℃。
实施例2:1
1-{3-(双-[4-氟苯基)氨基]丙基}-4-(3-羟基-2-吡啶基)哌嗪,盐酸化物。
6.6g(0.02mol)3-(N-4-吡啶基-4-氟苯氨基)丙基哌嗪,2.8g(0.22mol)2-氯-3-羟基吡啶和4.0g(0.0031mol)N,N-二异丙基乙基胺在二甲苯中于氮气氛下回流34小时。冷后将100ml甲苯和100ml水加到反应混合物中,将两相分开,水层用***洗三次,蒸发溶剂得到粗碱,将其用闪式色谱法提纯并分离,将晶体在乙醇-水(1∶1)中重结晶,将3g游离碱溶在30ml乙酸-乙酸乙酯(1∶4)中,用乙醇中的过量的盐酸沉出盐酸化物,重结晶后得2.2g标题化合物(2∶1),m.p205-207℃。
用基本上相同的方法可制备下列化合物。
2:2
1-{3-[双-(对氟苯基)氨基]丙基}-4-嘧啶基哌嗪盐酸化物,m.p.200-202℃;
2:3
1-{3-(N-4-吡啶基-4-氟苯氨基)丙基}-4-(3-氨基甲酰基-2-吡啶基)哌嗪,m.p120-121℃;
2:4
1-{3-(N-4-吡啶基-4-氟苯氨基)丙基}-4-(5-硝基-2-吡啶基)哌嗪1.5盐酸化物半水合物,m.P.225-228℃;
2:5
1-{3-[双-(对氟苯基)氨基]丙基}-4-(3-氨基甲酰基-2-吡啶基)哌嗪二盐酸化物,m.P.226-227℃;
2:6
1-{3-[双(对氟苯基)氨基]丙基}-4-(5-硝基-2-吡啶基)哌嗪盐酸化物,m.p.210-211℃;
2:7
1-{3-[双(对氟苯基)氨基]丙基}-4-(2-(吡啶-3-羧酸甲酯)基)哌嗪盐酸化物,m.P.181-182℃;
2:8
1-{3-[双(对氟苯基)氨基]丙基}-4-(6-氯-2-吡啶基)哌嗪盐酸化物,m.p.193-194℃;
2:9
1-{2-[(4,4′-二氟二苯甲基)氧]乙基}-4-(2-(吡啶基-3-羧酸甲酯)基)哌嗪二盐酸化物m.p 163-165℃;
2:10
1-{3-[双(对氟苯基)氨基]丙基}-4-(3-硝基-2-吡啶基)哌嗪盐酸化物,m.p.170-171℃;
2:11
1-{3-[双(对氟苯基)氨基]丙基}-4-(6-氟-2-吡啶基)哌嗪盐酸化物,m.p.190-191℃;
2:12
1-{2-[(4,4′-二氟二苯甲基)氧]乙基}-4-(6-氯-2-吡啶基)哌嗪盐酸化物,m.p 180-181℃。
实施例3:1
4-{2-[(4,4′-二氟二苯甲基)氧]乙基}-1-(2-吡啶基)哌嗪二盐酸化物。
4.1g(0.020mol)1-(2-羟乙基)-4-(2-吡啶基)哌嗪和2.4g(0.010mol)4-氟二苯甲基氯化物于165-170℃(油浴温度)氮气氛下搅拌45分钟,冷后往混合物中加60ml水和60ml甲苯,相分离后蒸发有机溶剂得到粗碱,将其用闪式色谱法提纯并以油状物游离出来。将2.2g游离碱溶在40ml乙酸乙酯中,用过量的乙醇中的盐酸沉出二盐酸化物,从异丙醇-***(3∶1)中重结晶得1.8g标题化合物(3∶1),m.p 167-168℃。
实施例4:1
1-{2-[4,4′-二氟二苯甲基)氨基]乙基}-4-(6-氯-2-吡啶基)哌嗪2.25盐酸化物。
6.5g(0.02mol)1-{2-[4,4′-二氟二苯亚甲基)氨基]乙基}哌嗪,3.0g(0.021mol)2,6-二氯吡啶,3.0g(0.025mol)K2CO3和0.1g碘和50ml二甲苯一起于140℃下搅拌16小时,冷后加100ml甲苯,将溶液过滤,用水洗三次,有机层用硫酸钠干燥;过滤。蒸发溶剂得8g 1-{2-[(4,4′-二氟二苯亚甲基)氨基]乙基}-4-(6-氯-2-吡啶基)哌嗪,为油状物。
8g(0.018mol)上述油状物溶于75ml甲醇中,加入3.5g(0.035mol)NaBH4并回流3小时,冷后加75ml水,用甲苯萃取;用硫酸钠干燥有机层,过滤,浓缩,得7.0g油状物,加入乙醇中的盐酸沉出盐酸化物,用2-丙醇重结晶得5.0g标题化合物(4∶1),m.p.235-236℃。
用实质上相同的方法制备下列化合物:
4:2
1-{2-[4,4′-二氟二苯甲基)氨基]乙基}-4-(2-(吡啶-3-羧酸乙酯)基)哌嗪2.25盐酸化物,m.P.224℃(分解);
4:3
1-{2-[(4,4′-二氟二苯甲基)氨基]乙基}-4-(3-羧基-2-吡啶基)哌嗪,m.p.229-230℃;
实施例5
本实施例说明式(II)化合物及其治疗学上的活性酸加成盐对于治疗精神病的能力。
试验1对于5-HT2受体的亲合力
结合试验实质上如Leysen等人(Mol.Pharmacol 21,301-14,1982)所述方法进行,使用3H-Ketanserin作配位体。
试验2 对5-HT1A受体的亲合力
结合试验实质上按照Peroutka S.J.(Brain Res.344,167,171,1985)所述方法进行。
表1 对5-HT2受体的亲合力
化合物 Ki(nM)
3∶1 11
1∶1 18
表2 对5-HT1A受体的亲合力
化合物 Ki(nM)
1∶1 1.7
实施例6
下述配方是本发明的所有药理学上的活性化合物的有代表性的配方,合适的胶囊配方实例为:
每个胶囊,mg
活性成份(盐形) 10
乳酸 250
淀粉 120
硬酯酸镁
5
总量 385
当活性成份的量较高时,可减少所用的乳酸的量。
适用的片剂配方实例
每片,mg
活性成份(盐形) 10
土豆淀粉 90
胶体硅 10
滑石 20
硬酯酸镁 2
5%明胶水溶液
25
总量 157
可以用活性物质的水溶性的制药学上可接受的盐的水溶液制备非肠道给药用的注射溶液,优选浓度约为0.5%-5%(重量),这种溶液还可以含稳定剂和/或缓冲剂,并且能以各种剂量单位的安瓿方便地提供。
Claims (14)
2.按照权利要求1的化合物,其中R1和R2分别是氢。
4.按照权利要求1的化合物,其中R4是氢,C1-C5烷基,三氟甲基,C1-C5烷氧基,甲酰氨基,硝基,羧基C1-C5烷基酯或氰基,并且R5是氢,C1-C5烷基,C1-C5烷氧基,硝基,卤素,氰基,羧基C1-C5烷基酯或甲酰氨基。
5.按照权利要求4的化合物,其中R4是氢并且R5是氢,C1-C5烷基,C1-C5烷氧基,硝基,卤素,氰基,羧基C1-C5烷基酯或甲酰氨基。
6.按照权利要求1的化合物,其中该化合物是所述化合物的二盐酸盐。
7.按照权利要求1的化合物,其中该化合物是1-{3-[双-(4-氟苯基)氨基]丙基}-4-(2-吡啶基)-哌嗪或其具有药理活性的二盐酸盐。
8.制备通式(1)化合物或其具有药理学活性的盐的方法:
其中Ar相同或不同并选自:
或
式中R3是氟,
R1和R2相同或不同并选自氢或C1-C5烷基,
n是2,
X是氮,
Y是亚甲基,
A选自下述嘧啶基或吡啶基或羧酸衍生物
或
式中R4和R5相同或不同并选自氢,卤素,C1-C5烷基,给电子基团:C1-C5烷氧基或羟基,吸电子基团:氰基,硝基,三氟甲基,COOR6或CONR7R8,其中R6是氢或C1-C5烷基,R7和R8相同或不同并选自氢,C1-C5烷基或C4-C6环烷基,
其特征在于将通式(II)化合物
式中Ar,X和Y的定义如上并且L是离去基,
和通式(III)化合物反应
式中R1,R2,n和A的定义如上,
或者将通式(IV)化合物
式中Ar,R1,R2,X,Y和n的定义如上,
和通式(V)或(VI)化合物进行反应
或者将通式IX化合物
式中Ar的定义如上并且L是离去基团或羟基,
和通式X化合物反应
式中R1,R2,n和A的定义如上。
9.一种药物组合物,该药物组合物含有权利要求1的通式(1)的一种或多种化合物作为其活性成分,并含有药学上可接受的载体。
10.一种药物组合物,该药物组合物包含对5-HT1A促效有效量或对5-HT2拮抗有效量的权利要求1的一种或多种化合物作为活性成分。
11.按权利要求10的药物组合物,其中所述的组合物是以含有0.1至100mg的所述化合物单位剂量形式。
12.按照权利要求10的药物组合物,其中所述的组合物是以含有1至10mg的所述化合物的单位剂量的形式。
13.按照权利要求10的药物组合物,其中所述的药物组合物是以片剂的形式。
14.按照权利要求10的药物组合物,其中所述的组合物是以胶囊的形式。
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SE9202265A SE9202265D0 (sv) | 1992-07-31 | 1992-07-31 | Novel- pyridyl and pyrimidylpiperazine derivatives |
SE9202265 | 1992-07-31 |
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CN93117383A Pending CN1087901A (zh) | 1992-07-31 | 1993-07-30 | 新的吡啶基-和嘧啶基哌嗪衍生物 |
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SE0201544D0 (sv) * | 2002-05-17 | 2002-05-17 | Biovitrum Ab | Novel compounds and thier use |
WO2004063150A2 (en) * | 2003-01-06 | 2004-07-29 | The General Hospital Corporation | Diagnostic and therapeutic alkyl piperidine/piperazine compounds and process |
WO2004083235A2 (en) | 2003-03-19 | 2004-09-30 | Exelixis Inc. | Tie-2 modulators and methods of use |
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FR2601366B1 (fr) * | 1986-07-10 | 1988-11-25 | Andre Buzas | Derives de la benzhydryloxyethyl-piperazine, procedes d'obtention et de compositions pharmaceutiques les contenant. |
US4766215A (en) * | 1987-02-27 | 1988-08-23 | American Home Products Corporation | Histamine H1 -receptor antagonists |
SE8701375D0 (sv) * | 1987-04-02 | 1987-04-02 | Leo Ab | Novel pyridyl- and pyrimidyl derivatives |
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US4994460A (en) * | 1989-06-01 | 1991-02-19 | Bristol-Myers Squibb Co. | Agents for treatment of brain ischemia |
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WO1994003430A1 (en) | 1994-02-17 |
JP3426601B2 (ja) | 2003-07-14 |
JPH07509711A (ja) | 1995-10-26 |
AU4594993A (en) | 1994-03-03 |
CA2141209C (en) | 2005-04-05 |
PT652867E (pt) | 2002-10-31 |
ATE219059T1 (de) | 2002-06-15 |
US6326371B1 (en) | 2001-12-04 |
DE69332023D1 (de) | 2002-07-18 |
IL106469A0 (en) | 1993-11-15 |
ZA935533B (en) | 1994-02-24 |
CA2141209A1 (en) | 1994-02-17 |
ES2178642T3 (es) | 2003-01-01 |
EP0652867A1 (en) | 1995-05-17 |
DK0652867T3 (da) | 2002-10-07 |
EP0652867B1 (en) | 2002-06-12 |
DE69332023T2 (de) | 2002-11-07 |
NZ254308A (en) | 1997-09-22 |
US5652240A (en) | 1997-07-29 |
AU679923B2 (en) | 1997-07-17 |
IL106469A (en) | 1997-02-18 |
CN1087901A (zh) | 1994-06-15 |
SE9202265D0 (sv) | 1992-07-31 |
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