CN1215400A - 哌嗪和哌啶化合物 - Google Patents

哌嗪和哌啶化合物 Download PDF

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CN1215400A
CN1215400A CN97193520A CN97193520A CN1215400A CN 1215400 A CN1215400 A CN 1215400A CN 97193520 A CN97193520 A CN 97193520A CN 97193520 A CN97193520 A CN 97193520A CN 1215400 A CN1215400 A CN 1215400A
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R·W·菲恩斯特拉
C·G·科鲁塞
M·T·M·图尔普
W·库佩斯
S·K·龙
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Abstract

本发明涉及一组新的具有令人感兴趣的药物学性质的哌嗪和哌啶化合物。已经发现,式(a)化合物及其盐对多巴胺D2和5－羟色胺5－HT1A受体具有很强的亲和力,其中A代表5－7员杂环,其中1－3个杂原子选自O,N和S;R1代表氢或氟;R2是C1－4烷基,C1－4烷氧基或氧基,p是0,1或2;Z代表碳或氮,当Z是氮时虚线是单键,当Z是碳时虚线是单键或双键;R3和R4分别是氢或C1－4烷基;n的值为1或2;R5是卤素,羟基,C1－4烷氧基或C1－4烷基,q是0,1,2或3;Y是苯基,呋喃基或噻吩基,这些基团可以被1－3个羟基,卤素,C1－4烷氧基,C1－4烷基,氰基,氨基羰基,一－或二－C1－4烷基氨基羰基取代基取代。

Description

哌嗪和哌啶化合物
本发明涉及一组新的具有令人感兴趣的药理性质的哌嗪和哌啶化合物。
已经发现，式(a)化合物及其盐具有令人感兴趣的药理性质，
Figure A9719352000061
其中-A代表5-7员杂环，其中1-3个杂原子选自O,N和S,-R1代表氢或氟，-R2是C1-4烷基，C1-4烷氧基或氧基，p是0,1或2,-Z代表碳或氮，当Z是氮时虚线是单键，当Z是碳时虚线是单键或双键，-R3和R4分别是氢或C1-4烷基，-n的值为1或2,-R5是卤素，羟基，C1-4烷氧基或C1-4烷基，q是0,1,2或3,-Y是苯基，呋喃基或噻吩基，这些基团可以被1-3个羟基，卤素，C1-4烷氧基，C1-4烷基，氰基，氨基羰基，一-或二-C1-4烷基氨基羰基取代基取代。
优选的本发明化合物是其中A与苯基一起代表式b-m，其中R1和(R2)p,n是1,R3,R4,(R5)q,Y和Z定义如上的式(a)化合物及其盐。
Figure A9719352000062
Figure A9719352000071
特别优选的是其中A与苯基一起代表式(b)基团，或具有一个氧的杂环被取代的式(Ⅰ)基团，Y是被上述基团取代的苯基且n是1,R3和R4是氢，R5是羟基，甲氧基或卤素，q是0或1,Z是氮的式(a)化合物及其盐。
更加特别优选的是其中A与苯基一起代表具有一个氧的杂环被取代的式(Ⅰ)基团，q是0,Y是苯基的式(a)化合物及其盐。
根据EP0650964已知，下式化合物通过与5-HT受体结合作用于中枢神经系统，
Figure A9719352000072
其中R0是C1-4烷基，该化合物可以在苯基和/或杂环基和/或哌嗪基部分被取代。尤其是这些化合物与5-HT受体的亚型，即5-HT1A和5-HT1D受体结合。
现已出人意料地发现，本发明化合物对多巴胺D2和5-羟色胺5-HT1A受体(对两种受体类型pKi为7.0-9.5范围)表现出很强的亲和力。两者的结合对于治疗精神分裂症和其它精神病是有效的，而且，可用于所有病症(如阳性症，阴性症和两性失调)的更完全的治疗。
该化合物对于多巴胺D3-和D4-受体表现出部分激动或拮抗的各种活性。一些化合物对于多巴胺受体表现出类激动效果，但它们显然拮抗阿朴吗啡引起的小鼠攀援行为(口服，ED50值＜1mg/kg)。该化合物表现出5-HT1A受体激动的各种活性，而且不同程度的诱发5-羟色胺行为综合征。
本发明化合物在临床相关抗精神活动(例如有条件回避响应；Van derHeyden & Brodford，《大脑行为研究》(Behav.Brain Res.)，1988,31:61-67)，抗抑郁(例如低速率响应的增强差异；Van Hest等人，《神经药理学》(Paychopharmacology),1992,107:474-479)和抗焦虑(例如抑制紧张诱发的应激反应；Van der Poel等人，《神经药理学》(Paychopharmacology),1989,97:147-148)敏感治疗模型中是活性的。
相反，对临床相关多巴胺D2受体拮抗，所述化合物对于产生更啮齿动物的僵住症是低活性的并且比已有的抑制精神药剂诱发低的脊椎束外副作用。
这些化合物对5-HT1A受体固有的激动作用可具有降低诱发脊椎束外作用的趋势并且这种治疗作用在抗抑郁和抗焦虑行为敏感模型中已观察到。
本发明化合物对于治疗由于多巴胺能或血清素能(serotinergic)系统紊乱引起的中枢神经系统疾患或疾病，例如，帕金森疾病，攻击症，焦虑，孤僻症，眩晕，抑郁，识别和记忆紊乱，特别是精神分裂症和其它精神病是有价值的。
本化合物与适当的酸结合可以形成可药用酸加成盐，例如，盐酸，硫酸，磷酸，硝酸，以及有机酸，如柠檬酸，富马酸，马来酸，酒石酸，乙酸，苯甲酸，对甲苯磺酸，甲磺酸和萘磺酸。
可以通过常用方法用辅助物质如液体和固体载体材料将本发明化合物制成给药形式。
根据下述一些方法(A至E)得到本发明化合物。用于这些方法的哌嗪，高哌嗪和哌啶表示为Ⅰ-H至ⅩⅨ-H，其中Ⅰ-ⅩⅨ代表下列基团：
Figure A9719352000081
用于本发明化合物制备的哌啶ⅩⅧ-H和ⅩⅨ-H(见OA1)的合成方法类似于WO94-GB1507所述。
除了Ⅺ-H,Ⅻ-H和ⅩⅤ-H(见下文)之外，用于本发明化合物制备的哌嗪(见A1)的合成方法如EP0189612所述。
高哌嗪Ⅺ-H和哌嗪ⅩⅢ-H和ⅩⅤ-H是新的化合物，它们的制备方法如下(路线A.ⅰ-A.ⅲ)。Ⅺ-H的制备
Figure A9719352000092
ⅩⅢ-H的制备
Figure A9719352000101
                           路线A.ⅱ步骤1-3(路线A.ⅲ)：
7-硝基-吲哚已经在S.M.Parmerter等人，《美国化学会志(J.Am.Chem.Soc.)》,80(1958),4621-2中有所描述。步骤1,2和3的进行类似于EP0650964所述合成方法。ⅩⅤ-H的制备
Figure A9719352000102
路线A.ⅰ的步骤1-3和路线A.ⅲ的步骤1在实施例中详述，路线A.ⅲ的步骤2和3类似于EP0189612所述。
化合物Ⅰ-H至ⅩⅨ-H中N-H部分的H原子可以通过5种不同的化学方法(A,B,C,D和E，见下文)用Q基团置换，最后得到本发明化合物。A2给出Q1-Q34的涵义。
                    Q基团
Figure A9719352000111
合成路线A
化合物A1-A14和A16-A28按路线A1(见下文)所述进行合成。将哌嗪(Ⅰ-H至Ⅵ-H和Ⅷ-H至ⅩⅦ-H)与Q-X(X=Cl,Br,OMs)在乙腈中反应，Et(i-Pr)2N作为碱，在一些情况下加入Kl。可以用Et3N代替Et(i-Pr)2N。
Figure A9719352000121
                         路线A1
下列合成路线B-E并不限于哌嗪的的制备，也可用来制备哌啶。合成路线B
也可以根据路线B1(见下文)所述合成方法制备化合物。将哌嗪Ⅰ-H与2-苯基苯酚和甲醛在EtOH中反应。
Figure A9719352000122
                         路线B1合成路线C
根据路线C1(见下文)所述合成方法制备化合物C1-C4。将苯基哌嗪与几个间位取代的苯基-苯甲酰氯反应生成对应的酰胺。然后加入LiAlH4将酰胺还原成化合物C1-C4。
Figure A9719352000131
化合物C2和C3的制备如路线C2所示。
Figure A9719352000132
                           路线C2合成路线D
根据路线D1(见下文)所述合成方法制备化合物D1-D18和D21-D23。将芳基硼酸与芳族溴化物在碱性条件下在催化量的Pd(PPh3)4存在下反应。该所谓“铃木(Suzuki)”反应产生C-C偶合终产物D。
                        路线D1
根据路线D2所示变化的合成方法制备化合物D19和D20。
Figure A9719352000142
                        路线D2
在上述Suzuki反应发生之后用标准方法，例如，E2所述方法(路线E2)，经过水解除去保护性苄基(例如，用热浓HCl)。合成路线E
根据路线E1所述合成方法制备化合物E2和E3。尽管中间体不同，但同样采用合成路线D所述的Suzuki反应。
Figure A9719352000143
                        路线E1
根据路线E2所示变化的合成方法制备化合物E1。除了进行路线E1所述合成之外，还要进行保护性苄基的水解。
Figure A9719352000151
                     路线E2
下面实施例将详细描述式(a)化合物和一些中间体化合物的制备。实施例1方法A1(路线A1)：
将1.09(4.3mmol)哌嗪Ⅲ-H和1.29(4.7mmol)Q1-Br加到20mLCH3CN中，然后加入0.529(5.1mmol)Et3N和少量Kl。搅拌反应混合物，并在3个大气压的氮气中回流16小时。冷却混合物后真空除去溶剂，将留下的剩余物溶解于CH2Cl2，依次用0.5N NaOH和盐水(2X)洗涤。有机相用MgSO4干燥。除去干燥剂后真空除去溶剂，留下剩余物。快速柱色谱(SiO2，洗脱剂：CH2Cl2/MeOH 99/1)分离后得到化合物A11(游离碱，见表A1)。接着，将剩余物溶解于乙醚，并加入1当量1NHCl/EtOH。产生沉淀并生成0.98g(2.3mmol,52％)纯A11。HClm.p.:228-30℃.1H-NMR(CDCl3,δ):2.18 15(m,2H),3.09(宽峰，2H),3.3-3.7(宽峰组，6H),4.21(m,44H),4.30(s,2H),6.59(dd,J=1和8Hz,1H),6.71(dd,J=1和8Hz,1H),6.82(t,J=8Hz,1H),7.37(m,1H),7.47(m,2H),7.53(t,J=8Hz,1H),7.62-7.74(一组,4H),7.90(t,J=2Hz,1H),12.9(宽峰，1H)．
根据上述方法可用类似方法制成化合物A1-A14和A16-A28，见汇总表A1。类似于方法A5(见下文)用LiAlH4/THF还原化合物A14可制成化合物A15(化合物A14的还原反应不是在室温而是在回流温度进行)。
                                         d=分解
表A1
化合物编号 哌嗪 Q  X  盐     熔点℃
 A1  Ⅰ  1  Br  HCl  221-3
 A2  ⅩⅣ  1  Br  HCl  304-6
 A3  Ⅸ  1  Br  2HCl  258-60   d
 A4  Ⅹ  1  Br  2HCl  218-9
 A5  Ⅺ  1  Br  2HCl  188-9
 A6  ⅩⅣ  2  OMs  HCl  284-6    d
 A7  ⅩⅣ  3  OMs  碱  198-200
 A8  ⅩⅣ  4  OMs  HCl  265-70   d
 A9  Ⅵ  1  Br  FUM  ＞70     d
 A10  Ⅻ  1  Br  HCl  212-5
 A11  Ⅲ  1  Br  HCl  228-30
 A12  Ⅱ  1  Br  HCl  218-20
 A13  Ⅴ  1  Br  HCl  235-7
 A14  Ⅷ  1  Br  碱  180-2
 A15  Ⅶ  1  Br  HCl  150-6O
 A16  ⅩⅤ  1  Br  HCl  254-5    d
 A17  ⅩⅣ  5  OMs  HCl  251-2
 A18  ⅩⅣ  6  OMs  2HCl  177-80
 A19  ⅩⅣ  7  OMs  HCl  296-7    d
 A20  ⅩⅣ  8  Cl  HCl  260-1    d
 A21  ⅩⅣ  9  Cl  HCl  287-90   d
 A22  ⅩⅣ  10  Br  HCl  290-1    d
 A23  ⅩⅦ  1  Br  HCl  255-7    d
 A24  ⅩⅢ  1  Br  HCl  ＞245    d
 A25  Ⅳ  1  Br  FUM  90
 A26  ⅩⅥ  1  Br  HCl  275-9    d
 A27  ⅩⅧ  1  Br  HCl  243-5
 A28  ⅩⅨ  1  Br  HCl  183-6    d
用于方法A的中间体中间体Q-X：Q2-OH,Q3-OH和Q5-OH至Q9-OH：实施例(Q2-OH)，见路线A2：在碱性条件下和催化量Pd(PPh3)4存在下将芳基硼酸与芳族溴化物反应。该所谓“铃木(Suzuki)”反应产生C-C偶合的中间体Q-OH。所用硼酸很容易从相应的溴化物得到，例如，用D.Janietz等人，《合成(Synthesis)》,(1993),33所述一般方法制成，该文全部在此引作参考。方法A2(路线A2)：
Figure A9719352000171
                         路线A2
将10mL二甲氧基-乙烷在1个大气压的氮气中回流，之后，将溶剂冷却。然后，加入0.85mL(1.43g,8.8mmol)2-溴-噻吩，并在溶液中鼓入氮气10分钟。然后，在溶液中加入0.4g(0.35mmol,0.04eq)Pd(PPh3)4。搅拌10分钟后加入8.5mL 2N Na2CO3/H2O，然后在反应混合物中加入溶解在约2ml EtOH中的1.25g(8.2mmol)3-(羟基甲基)-苯基硼酸。将反应混合物加热至回流4小时，然后停止加热，在室温搅拌反应物16小时。用硅藻土滤出形成的沉淀，用EtOAc/H2O洗涤滤饼。用EtOAc萃取滤液，合并的有机相在MgSO4上干燥。除去干燥剂后蒸发滤液中的溶剂，得到2.1g油。快速色谱(SiO2，洗脱剂：甲基-叔丁醚/己烷1/1)分离后得到0.85g(4.5mmol,51％)所要产物Q2-OH。
用类似方法合并表A2给出的芳族溴化物和硼酸，制成下列间位取代的苄醇Q-OH。表A2
通过标准方法(例如，MsCl和Et3N的EtOAc)表A2中提到的所有Q-OH都可以被成功地转化成相应的甲苯磺酸酯。但是，对于Q8-OH和Q9-OH，不能得到相应的甲苯磺酸酯，但用HCl处理后可以得到相应的氯化物Q8-Cl和Q9-Cl。后二者在路线A1的反应中是极好的烷基化剂。中间体Q1-Br，见路线A3：
在催化量过氧化二苯甲酰存在下通过N-溴-琥珀酰胺(NBS)的作用对间-苯基-甲苯(S1=H)进行溴化。
Figure A9719352000191
                     路线A3万法A3(路线A3)：Q1-Br：将3g(29.8mmol)3-苯基-甲苯和5.3g(29.8mmol)N-溴-琥珀酰胺(NBS)溶解于30mL CCl4。加入少量二苯甲酰基过氧化物并将反应混合物回流10小时。在此期间加入极少量二苯甲酰基过氧化物。冷却后用CCl4和水稀释反应混合物。将此两相体系用2N NaOH碱化，然后搅拌。有机相用1N NaOH和水洗涤，然后MgSO4干燥。除去干燥剂后真空除去溶剂，留下8.0g剩余物。将其经柱色谱(SiO2，洗脱剂：Et2O/石油醚1/9)纯化，得到5.3g(21.5mmol,72％)纯中间体Q1-Br。
对于Q10-Br，可以通过类似方法A2的Suzuki反应由苯基硼酸和2-氟-5-溴-甲苯制成所要的2-氟-5-苯基-甲苯(S1=F)。见路线A3。Q4：实施例(Q4-OH)，见路线A4：
通过Mel/KOtBu的作用对3-苯基-4-羟基-苯甲酸(其制备方法见美国专利4873367)进行二甲基化，生成相应的甲氧基-苯甲酸甲酯，之后，可用LiAlH4将其还原成Q4-OH。方法A4(路线A4)：步骤1：将4.0g(19mmol)3-苯基-4-羟基-苯甲酸溶解于70mLDMF，并在其中加入4.6g(41mmol)KOtBu，然后将混合物搅拌30分钟。之后，加入3.0g(21mmol)Mel，在室温搅拌反应混合物14小时，在此期间加入第二批等量Mel。真空除去溶剂，将留下的剩余物溶解于EtOAc。所得溶液与2N NaOH混合在一起振动。有机相经Na2SO4干燥，除去干燥剂和溶剂后得到3.65g(16.0mmol,84％)相当纯的3-苯基-4-甲氧基-苯甲酸甲酯。它无需进一步纯化即可用于方法A5所述还原反应。
Figure A9719352000201
                      路线A4万法A5(路线A5)：步骤2：将0.68g(18mmol)LiAlH4加到20mL无水THF中，并在氮气中搅拌。接着，将溶解在60mL无水THF中的3.65g(16.0mmol)3-苯基-4-甲氧基-苯甲酸甲酯滴加到LiAlH4/THF混合物中。在室温继续搅拌1小时。冷却(冰/水)反应混合物，并加入混有THF的0.7mL水和1.4mL 2N NaOH。然后将混合物回流10分钟，之后，滤出盐。该盐用热THF洗涤，并将洗液与滤液合并。真空除去溶剂后得到3.1g(14.5mmol,90％)相当纯的Q4-OH。它无需进一步纯化即可用于甲苯磺酸Q4-OMs的制备。可将其用于路线A1的反应，最后得到化合物A8。实施例2方法B1(路线B1)：
将3.74g(17.0mmol)哌嗪Ⅰ-H和3.0g(17.0mmol)2-苯基-苯酚溶解于80mL无水EtOH。搅拌溶液时加入2.0ml(24.0mmol)37％的CH2O/H2O，搅拌持续48小时。之后，真空浓缩反应混合物，留下的剩余物进行快速柱色谱分离(SiO2，洗脱剂：CH2Cl2/石油醚1/1)。首先分离出2-苯基-苯酚的未反应部分，然后改变洗脱剂，将100％CH2Cl2换成CH2Cl2/MeOH 99/1，得到1.70g(4.2mmol,25％)混合物B1，为游离碱。m.p.:174-5℃,1H-NMR(CDCl3,δ):2.65(一组,8H),3.83(s,2H),4.27(m,4H),6.48(dd,J=1.5和J=8Hz,1H),6.59(dd,J=1.5和J=8Hz,1H),6.76(t,J=8Hz,1H),6.87(t,J=8Hz,1H),7,05(dd,J=1.5和J=8Hz,1H),7.28(dd,J=1.5和J=8Hz,1H),7.32(m,1H)7.42(t,J=8Hz 2H),7.61(m,2H),11.4(宽峰s,1H)．表B
化合物编号 哌嗪     Q     盐 熔点(℃)
    B1 Ⅰ     11     碱 174-5
实施例3方法C1(路线C1)步骤1：在氮气下，将0.8g(3.4mmol)3-(3-甲氧基-苯基)苯甲酸和0.65ml Et3N溶解在15ml THF中。将溶液冷却至0℃并在搅拌的同时加入0.42ml i-ButO(CO)Cl。30分钟后，将溶解在5ml无水THF中的0.71g(3.2mmol)Ⅰ-H加到上述溶液中。使反应混合物升至室温并继续搅拌16小时。之后将反应混合物用2N NaOH处理，然后用EtOAc萃取两相。用MgSO4干燥有机相。除去干燥剂后真空除去溶剂，将剩余物经过柱色谱分离(SiO2，洗脱剂：EtOAc/石油醚1/1)。产量：0.75g(1.7mmol,52％)相应的酰胺。步骤2：将0.9g LiAlH4悬浮在20ml无水THF中，将所得悬浮液升至回流温度之后向其中加入溶解在15ml无水THF中的0.7g(1.6mmol)酰胺(步骤1的产物)。继续回流15分钟后，将反应混合物冷却(冰/水)并且非常小心加入0.9g H2O。接着加入1.8ml 2N NaOH和0.9g H2O，然后将混合物再回流20分钟。冷却至室温并过滤得到剩余物，将其用EtOAc洗涤。合并滤液并用MgSO4干燥洗液。除去干燥剂后真空除去溶剂，将剩余物经过柱色谱分离(SiO2，洗脱剂：EtOAc)。产量：0.57g(1.4mmol,85％)纯游离碱C1。将其溶解在EtOAc并通过加入1NHCl/MeOH转化为HCl盐，得到0.5g纯C1.HCl。m.p.:165-7(dec.).1H-NMR(CDCl3,δ):3.24(宽峰，2H),3.42-3.58(一组，4H),3.64-3.84(宽峰，2H),3.90(s,3H),4.26(m,4H),4.30(s,2H),6.67(宽峰d,J=8Hz,2H),6.79(t,J=8Hz,1H),6.93(m,1H),7.23(m,2H),7.38(t,J=8Hz,1H),7.52(t,J=8Hz,1H),7.65(宽峰d,J=8Hz,1H),7.69(宽峰d,J=8Hz,1H),7.92(宽峰s,1H),13.2(宽峰，1H)。方法C2(路线C2)步骤1和2：该反应类似于方法C1，步骤1和2(路线C1)。步骤3：将1.1g(2.4mmol)乙酸酯悬浮在150ml EtOH和15ml H2O中，然后加入1.5g(37.5mmol)NaOH。将反应混合物搅拌16小时然后真空除去EtOH。将剩余部分用饱和NH4Cl溶液处理并用CH2Cl2萃取。将合并的有机相用饱和NaHCO3溶液洗涤并用MgSO4干燥。除去干燥剂后真空除去溶剂，剩余物中0.97g(2.3mmol,97％)含有相应的纯苯酚衍生物。步骤4：将0.98g(2.3mmol)苯酚衍生物(步骤3得到的)溶解在15ml丙酮中，向其中加入1.5g粉末K2CO3。搅拌，加入0.3ml(CH3)2SO4，然后将反应混合物回流2小时。当反应混合物达到室温后，真空除去溶剂。向剩余部分加入30ml H2O，然后将反应混合物煮沸45分钟。冷却反应混合物后用CH2Cl2萃取。有机相用MgSO4干燥。除去干燥剂后真空除去溶剂，剩余物为0.95g(2.2mmol,96％)相应的纯O-甲基化的苯酚衍生物。
化合物C4的合成类似类似于C2所述。
表C中概括下列化合物。表C                                       d=分解
化合物编号 哌嗪     Q     盐 熔点(℃)
    C1     Ⅰ     6     HCl 165-7d
    C2     Ⅰ     12     碱 197-8
    C3     Ⅰ     4     HCl ＞148d
    C4     ⅩⅣ     12     HCl 255～7
用于路线C的中间体
Figure A9719352000231
                     路线C3
3-(3-甲氧基-苯基)苯甲酸(路线C3)类似于W.G.Dauben等人《美国化学会志》(J.Am.Chem.Soc.,)75,(1953),4969-73所述方法制备。3-苯基-4-乙酰氧基-苯甲酸(路线C3)从3-苯基-4-羟基苯甲酸用标准方法制备，参见路线3。该化合物的合成已经公开在美国专利4873367中。实施例4方法D1(路线D1)：
在氮气下，将0.4g(2.8mmol)4-溴-苯酚溶解在5ml甲苯中。向该溶液中加入溶解在5ml热EtOH中的97.5mg(0.084mmol,0.3当量)Pd(PPh3)4,2.8ml 2N Na2CO3和1.0g(2.8mmol)硼酸d1(S5=H)。将所得混合物在90℃剧烈搅拌4小时。反应混合物达到室温后，将其用EtOAc和少量水稀释。然后用EtOAc萃取，将合并的有机相用盐水洗涤并用MgSO4干燥。除去干燥剂后真空除去溶剂，将得到的1.52g剩余物经过柱色谱分离(SiO2，洗脱剂：EtOAc/石油醚1/1)。产量：0.53g(1.3mmol,47％)纯游离碱D22。将游离碱转化为其二盐酸盐(从EtOH/乙醚结晶)得到D22.2HCl。m.p.:222-7℃.1H-NMR(d6-DMSO/CDCl34/1,δ):3.14-3.30(宽峰一组，4H),
3.34-3.56(一组宽峰，4H),4.23(m,4H),4.42(d,J=4Hz,2H),6.46-6.58(一组,
2H),6.73(t,J=8Hz,1H),6.89(m,2H),7.47(t,J=7Hz,1H),7.52-7.66(一组4H)
7.99(t,J=1Hz,1H),9.40(宽峰,OHN+HH2O),11.5(宽峰,1H)．
类似上述合成得到下列化合物(表D)。表D                                  d=分解
化合物编号 哌嗪     Q     盐     熔点℃
    D1     Ⅰ     9     HCl     185    d
    D2     Ⅰ     8     HCl     193    d
    D3     Ⅰ     16     碱     141-3
    D4     Ⅰ     17     碱     132-3
    D5     Ⅰ     18     HCl     178-80 d
    D6     Ⅰ     2     2HCl     199-201
    D7     Ⅰ     19     2HCl     188-90 d
    D8     Ⅰ     3     2HCl     228-30
    D9     Ⅰ     20     base     177-8
    D10     Ⅰ     21     2HCl     208-12 d
    D11     Ⅰ     22     2HCl     218-22
    D12     Ⅰ     23     2HCl     216-9
    D13     Ⅰ     24     2HCl     ＞192  d
    D14     Ⅰ     25     2HCl     ＞230  d
    D15     Ⅰ     26     2HCl     ＞200  d
    D16     Ⅰ     27     2HCl     215-7  d
    D17     Ⅰ     28     2HCl     185-91
    D18     Ⅰ     29     2HCl     208-12
    D19     Ⅰ     30     2HCl     glass
    D20     Ⅰ     31     2HCl     ＞200  d
    D21     Ⅰ     32     碱     124-5
    D22     Ⅰ     33     2HCl     222-7
    D23     Ⅰ     34     HCl     234-5
用于路线D的中间体
用于路线D1和D2的溴化物容易用标准方法得到或者其为商品。用于D1和D2中的硼酸容易经过相应的溴化物(路线3)得到，其一般方法参见D.Janietz等人，《合成》(Synthesis),(1993),33，其全文在此引作参考。
所用溴化物(S5=H,OCH2Ph，路线D3)的合成类似于方法E3(路线E3)中所述方法。实施例5方法E1(路线E1)：
将5.1g(12.0mmol)1-[(2-甲氧基-5-溴-苯基)甲基]-4-(2,3-二氢-1,4-苯并二氧环己环(benzodioxin)-5-基]哌嗪溶解在20ml甲苯中，向其中加入12ml 2N Na2CO3/H2O和0.45g(0.39mmol,0.03eq)Pd(PPh3)4。然后将溶解在3ml温乙醇中的1.46g(12.0mmol)苯基-硼酸加到溶液中。将反应混合物在85℃剧烈搅拌。4小时后使两相反应混合物达到室温，然后分离有机部分(甲苯)。水相用EtOAc萃取。分别用水和盐水洗涤合并的甲苯和EtOAc相，然后用Na2SO4干燥有机相。除去干燥剂后真空除去溶剂，将剩余物经过柱色谱分离(SiO2，洗脱剂：Et2O/石油醚1/2)。将分离的游离碱E2溶解在EtOAc/EtOH1/1中并将该溶液用1当量1N HCl/EtOH处理。产量：1.43g(3.2mmol,26％)E2.HCl。
    m.p.:240-2℃(分解),1H-NMR(d6-DMSO/CDCl34/1,δ):3.1-3.3(一组4H),3.48(一组，4H),3.93(s,3H),4.23(m,4H),4.41(d,J=5Hz,2H),6.48(dd,J=1Hz,J=8Hz,1H),6.55(dd,J=1Hz,J=8Hz,1H),6.73(t,J=8Hz,1H),7.20(d,J=9Hz,1H)-,7.32(m,1H),7.40(t,J=8Hz,2H),7.71(m,2H),7.75(dd,J=2Hz,J=9Hz,1H),8.04(d,J=2Hz,1H),11.1(br,1H )．方法E2(路线E2)：
将3.0g(5.9mmol)O-苄基保护的化合物E1溶解在35ml浓HCl中，然后将该混合物搅拌并回流45分钟。再加入30ml浓HCl并继续回流45分钟。之后使混合物达到室温并真空除去溶剂。将剩余物用饱和的NaHCO3溶液处理并用EtOAc萃取。用盐水洗涤有机相然后用MgSO4干燥。除去干燥剂后真空除去溶剂，将剩余物经过柱色谱分离(SiO2，洗脱剂：Et2O/MeOH95/5)。分离游离碱E1并通过用1N HCl/EtOH处理转化为盐酸盐。从EtOH/H2O中重结晶得到1.45g(3.2mmol,54％)E1.HCl。
上述化合物概括在表E中。表E                                 d=分解
化合物编号 哌嗪     Q     盐  熔点(℃)
    E1     Ⅰ     13     HCl  ＞190    d
    E2     Ⅰ     14     HCl  240-2    d
    E3     ⅩⅣ     15     HCl  271-3    d
用于路线E中的中间体
在路线E1中给出的用于Suzuki反应的溴化物可以从苄基-哌嗪和其中X可以代表Cl,Br或OMs的所取代的3-溴-苯基-甲基-X中间体(参见E3)合成。
Figure A9719352000271
                         路线E3方法E3(路线E3)：
将6.6g(23.0mmol)(2-甲氧基-5-溴-苯基)-甲基溴化物和5.4g(21mmol)Ⅰ-H.HCl加到80ml CH3CN中，然后加入5.2g(51.0mmol)Et3N和少量KI。将反应混合物搅拌并保持回流温度16小时。之后将反应混合物过滤并真空浓缩滤液。将剩余物经过柱色谱分离(SiO2，洗脱剂：Et2O/石油醚1/2)，最终得到5.1g(12.2mmol,58％)纯1-[(2-甲氧基-5-溴-苯基)甲基]-4-(2,3-二氢-1,4-苯并二氧环己环-5-基)哌嗪。
所用硼酸容易经过相应的溴化物得到，其一般方法参见D.Janietz等人，《合成》(Synthesis),(1993),33，其全文在此引作参考。根据路线A.i制备Ⅺ-H中间体：步骤1(路线A.i)：
将5.1g(25mmol)1-(苯基甲基)-六氢-5H-1,4-二-吖庚因(diazepin)-5-酮(其制备参见Dickerman等人，《有机化学杂志》(J.org.Chem.)19,(1954))和7.39g(37.5mmol)7-溴苯并呋喃和3.45g(25mmol)干燥的K2CO3和0.48g(2.5mmol)CuI一起放入烧瓶中并在120℃加热90分钟同时搅拌混合物。反应混合物达到室温后，加入40ml甲苯。用硅藻土过滤所得悬浮液，将剩余物用温甲苯洗涤。合并洗液并真空蒸发滤液得到12.4g棕色油。将其用CH2Cl2稀释并分别用2N NaOH,NaHCO3(饱和)和水处理。用MgSO4干燥有机相，除去干燥剂后真空蒸发溶剂，得到11.7g棕色油。将所得剩余物经过快速色谱分离(SiO2，洗脱剂：CH2Cl2/MeOH 98/2)并得到5.7g(83％)所需产物。步骤2(路线A.ⅰ)：
将溶解在40ml无水THF中的5.9g(18.6mmol)步骤1的产物滴加到2.14g(55.8mmol)LiAlH4的100ml Et2O混合物中，继续搅拌3小时。之后将反应混合物分别用2.1ml H2O的THF,4.2ml 2N NaOH和2.4mlH2O处理。继续搅拌2小时，然后用硅藻土过滤混合物，分别用THF和CH2Cl2洗涤剩余物。合并洗液并真空蒸发滤液得到5.4g棕色油。将所得剩余物经过快速色谱分离(SiO2，洗脱剂：CH2Cl2/MeOH 98/1)并得到4.83g(85％)二吖庚因类似物。步骤3(路线A.ⅰ)：
将4.83g(15.8mmol)步骤2的产物溶解在65ml 1,2-二氯乙烷，同时搅拌。在氮气和2-4℃下，10分钟内将溶解在25ml 1,2-二氯乙烷的2.3g(15.8mmol)Cl(CO)O(CHCl)CH3(“ACE-氯化物)加到上述溶液中。然后将反应混合物回流10小时。之后真空浓缩反应混合物得到5.1g剩余物。将其用MeOH稀释并将所得溶液回流16小时。反应混合物达到室温后，真空除去溶剂得到4.2g剩余物，将其经过快速色谱分离(SiO2，洗脱剂：CH2Cl2/MeOH/NH4OH 92/7.5/0.5)，得到2.8g(82％)1-(7-苯并呋喃基)六氢-1,4-二吖庚因。制备ⅩⅤ-H，参见路线A.ⅲ：步骤1(路线A.ⅲ)：
将3.94g(21.9mmol)7-硝基-苯并噁唑啉酮(用于后面化合物的制备，参见欧洲专利EPO189612，并在此引作参考)溶解在40ml DMSO中，然后加入1.72g85％粉末KOH(26.2mmol)。搅拌并冷却(水)，滴加溶解在6ml DMSO中的3.72g(26.2mmol)Mel。继续在室温搅拌16小时，在此期间再加入Mel(0.5g)。加完后，用水稀释反应混合物然后用CH2Cl2萃取。分别用水和盐水洗涤合并的有机相然后用MgSO4干燥有机相。除去干燥剂后真空蒸发溶剂，得到4.1g固体剩余物。快速柱色谱分离(SiO2，洗脱剂：CH2Cl2)得到3.6g(85％)纯3-甲基-7-硝基-2-苯并噁唑啉酮。

Claims (9)

1．下式化合物及其盐其中-A代表5-7员杂环，其中1-3个杂原子选自O,N和S,-R1代表氢或氟，-R2是C1-4烷基，C1-4烷氧基或氧基，p是0,1或2,-Z代表碳或氮，当Z是氮时虚线是单键，当Z是碳时虚线是单键或双键，-R3和R4分别是氢或C1-4烷基，-n的值为1或2,-R5是卤素，羟基，C1-4烷氧基或C1-4烷基，q是0,1,2或3,-Y是苯基，呋喃基或噻吩基，这些基团可以被1-3个羟基，卤素，C1-4烷氧基，C1-4炕基，氰基，氨基羰基，一-或二-C1-4烷基氨基羰基取代基取代。
2．根据权利要求1的化合物及其盐，其特征在于A与苯基一起代表式b-m，
Figure A9719352000022
Figure A9719352000023
Figure A9719352000024
Figure A9719352000025
Figure A9719352000026
Figure A9719352000027
Figure A9719352000028
Figure A97193520000211
Figure A97193520000213
其中R1和(R2)p如权利要求1定义，n是1,R3,R4,(R5)q,Y和Z如权利要求1定义。
3．根据权利要求2的化合物及其盐，其特征在于A与苯基一起代表式(b)基团，或具有一个氧的杂环被取代的式(Ⅰ)基团，Y如权利要求1定义的被取代的苯基且Z是氮。
4．根据权利要求3的化合物及其盐，其特征在于R3和R4是氢，R5是氢，羟基，甲氧基或卤素，Y如权利要求3的定义。
5．根据权利要求4的化合物及其盐，其特征在于A与苯基一起代表具有一个氧的杂环被取代的式(Ⅰ)基团，R5是氢，Y是苯基。
6．制备权利要求1的化合物的方法
a)式(n)化合物
Figure A9719352000031
与下式化合物反应
Figure A9719352000032
其中X是离去基团；或
b)式(n)化合物与下式化合物
Figure A9719352000033
和甲醛反应；或
c)式(n)化合物与下式化合物反应
Figure A9719352000041
然后进行酮基还原；或
d)下式化合物
Figure A9719352000042
与化合物Y-Br反应；或
e)下式化合物
Figure A9719352000043
与下式化合物反应
                   B(OH)2-Y其中结构式中的符号具有权利要求1中的含义。
7．药物组合物，至少含有一种作为活性成分的权利要求1定义的化合物。
8．制备药物组合物的方法，其特征在于通过将权利要求1的化合物制成适当的给药形式制备权利要求7的组合物。
9．治疗CNS疾病的方法，其特征在于使用权利要求1的化合物。
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DK0889889T3 (da) 2007-01-29
CZ306898A3 (cs) 1999-01-13
NO320970B1 (no) 2006-02-20
JP3989554B2 (ja) 2007-10-10
PL329123A1 (en) 1999-03-15
BRPI9708389B8 (pt) 2015-12-08
SK285119B6 (sk) 2006-06-01
NZ331860A (en) 2000-04-28
ZA972639B (en) 1997-10-02
BR9708389A (pt) 2000-01-04
HUP9902471A3 (en) 2000-04-28
NO984533D0 (no) 1998-09-28
CZ294413B6 (cs) 2004-12-15
CN1100055C (zh) 2003-01-29
BR9708389B1 (pt) 2009-12-01
PL189256B1 (pl) 2005-07-29
DE69736704T2 (de) 2007-09-13
US6225312B1 (en) 2001-05-01
TR199801942T2 (xx) 2000-08-21
UA52656C2 (uk) 2003-01-15
ATE340173T1 (de) 2006-10-15
RU2178414C2 (ru) 2002-01-20
HU227454B1 (en) 2011-06-28
PT889889E (pt) 2007-01-31
EP0889889A1 (en) 1999-01-13
EP0889889B1 (en) 2006-09-20
DE69736704D1 (de) 2006-11-02
NO984533L (no) 1998-11-02
WO1997036893A1 (en) 1997-10-09
ES2271967T3 (es) 2007-04-16
AU708053B2 (en) 1999-07-29
TW422846B (en) 2001-02-21
CA2250347A1 (en) 1997-10-09
HUP9902471A2 (hu) 2000-03-28
IL126187A0 (en) 1999-05-09
CA2250347C (en) 2006-02-21
SK133198A3 (en) 1999-02-11
AU2029497A (en) 1997-10-22
JP2000507949A (ja) 2000-06-27

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