CN1202087C - 酰基－哌嗪基－嘧啶衍生物,它们的制备和作为药物的应用 - Google Patents

酰基－哌嗪基－嘧啶衍生物,它们的制备和作为药物的应用 Download PDF

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CN1202087C
CN1202087C CNB988084589A CN98808458A CN1202087C CN 1202087 C CN1202087 C CN 1202087C CN B988084589 A CNB988084589 A CN B988084589A CN 98808458 A CN98808458 A CN 98808458A CN 1202087 C CN1202087 C CN 1202087C
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piperazinyl
pyrimidine
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J·克伯拉阿卓纳
D·瓦挪密尼克
J·夫里格拉科斯塔萨
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Abstract

通式(I)的酰基-哌嗪基-嘧啶衍生物，其中X是O或S；R1是烷氧基或三氟甲基基团；R2是烷基，环烷基，杂环烷基，芳基，芳烷基，杂芳基或杂芳烷基。X是O的通式(I)化合物可由嘧啶衍生物与哌嗪衍生物的反应获得，或通过哌嗪-嘧啶衍生物与羧酸或其盐或其衍生物反应获得。X是S的通式(I)化合物可通过使X是O的通式(I)化合物与Lawesson试剂或五硫化磷反应制备。通式(I)化合物显示了镇静剂、镇痉剂、安眠药和常规麻醉剂的活性，可用作人或兽药。

Description

酰基-哌嗪基-嘧啶衍生物，它们的制备和作为药物的应用
本发明涉及新的通式(I)的酰基-哌嗪基-嘧啶类化合物，涉及其生理上可接受的盐，其制备方法，和它们作为人用药和/或兽药在治疗中的应用，本发明还涉及含有所述化合物的药物组合物。
Figure C9880845800111
本发明的目的化合物可作为医药工业的中间体用于药物的制备。
在欧洲专利申请EP 382 637和EP 497 659中描述了具有抗焦虑和镇定性质的通式(II)的烷基-哌嗪基-嘧啶衍生物。
Figure C9880845800112
现发现在嘧啶的4-位引入取代基和以酰基取代基代替烷基取代基可得到新的通式(I)化合物。所述的新化合物显示出很有用的生物活性，可作为人用药和/或兽药用于治疗。本发明化合物可用作作用于哺乳动物，包括人类的中枢神经系统的药物，特别是，所述的新化合物可用作镇静剂、镇痉剂、安眠药和常规的麻醉剂。
图1说明了一些本发明化合物的镇静剂活性的测试结果，其是通过运动活性的降低测定的。
本发明提供了的新化合物能够引起强烈的镇静作用，如当它们以适当的方法和适当的剂量用药时可作为安眠药、镇痉剂、镇痛剂、肌肉松弛剂、止咳剂、抗焦虑剂、抗精神病药、抗抑郁剂、抗脑局部缺血药、抗偏头痛药、用于睡眠失调的药物、用于神经变性疾病的药物、用于认知失调和阿尔茨海默氏病的药物，以及能够引起和保持麻醉的药物。
通式(I)表示的本发明的化合物和它们生理上可接受的盐：
Figure C9880845800121
其中
X是氧或硫原子；
R1是C1-4烷氧基或三氟甲基基团；
R2是C1-6烷基基团；C3-6饱和的环烷基；环由3-6个原子组成的杂环烷基，其中的杂原子选自氧、硫或氮，并可选择性的N-取代；由1、2或3个相同或不同的，选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的取代基选择取代的苯基；由苯基基团取代的C1-3烷基构成的芳烷基，其中的苯基被1、2或3个相同或不同的，选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的取代基选择取代；选择取代的杂芳基，其由5或6杂原子环，或是有1或2个选自氧、硫或氮的杂原子和具有9-10个原子的稠合杂芳环系统构成，该系统由选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的前述取代基选择取代；以及杂芳烷基，所述杂芳烷基是杂芳基取代的1-3个碳原子的烷基，所述的杂芳基由5或6元杂芳环，或是有1或2个选自氧、硫或氮的杂原子和9-10员稠合杂芳环系统构成，该系统由选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的前述取代基选择取代。
本发明中术语C1-4“烷氧基”表示基团OR3，其中R3是含有1-4个碳原子的饱和直链或支链的碳链，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁氧基或叔丁氧基。
术语“烷基”表示饱和的直链或支链烃基衍生的基团。术语C1-6烷基表示含有1-6个碳原子的直链或支链烷基，如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基和己基。
术语C3-6饱和“环烷基”表示3-6个碳原子的饱和环，如环丙基、环丁基、环戊基、或环己基。
术语“杂环烷基”表示其中的杂原子例如是氧原子或硫原子的3-6个原子的环，例如2-吖丙啶基、2-四氢呋喃基、3-四氢呋喃基、2-四氢噻吩基、3-四氢噻吩基，或其中的氮原子可以是取代或未取代的，例如2-氮杂环丁烷基、2-哌啶基、3-哌啶基或4-哌啶基。
术语“芳基”表示未取代的或由1、2或3个相同或不同的，例如氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的取代基取代的苯基基团，例如2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-氨基苯基、3-氨基苯基、4-氨基苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-乙酰氨基苯基、3-乙酰氨基苯基、4-乙酰氨基苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-(三氟甲基)苯基、3-(三氟甲基)苯基、4-(三氟甲基)苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2，3-二氟苯基、3，4-二氟苯基、2，4-二氟苯基、2，3-二溴苯基、3，4-二溴苯基、2，4-二溴苯基、2，3-二甲基苯基、3，4-二甲基苯基、2，4-二甲基苯基、2，3-二甲氧基苯基、3，4-二甲氧基苯基、2，4-二甲氧基苯基。
术语“芳烷基”表示由芳基基团取代的1-3个碳原子的直链或支链的链，按照前述定义的包括了取代基的“芳基”，例如是苯甲基、1-苯基乙基、2-苯基乙基、3-苯基乙基、3-苯基丙基，和其它芳环被例如氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的取代基取代的基团。
术语“杂芳基”表示取代或未取代的5或6元杂芳环，或是有1或2个例如氮、氧或硫的杂原子和9或10员稠合杂芳环系统，取代基是例如氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基，这些基团例如是2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、3-甲基-2-噻吩基、5-甲基-2-噻吩基、3-甲氧基-2-噻吩基、3-氯-2-噻吩基、5-氯-2-噻吩基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-吲哚基、3-吲哚基、2-苯并[b]噻吩基、3-苯并[b]噻吩基、3-氯-2-苯并[b]噻吩基、吡唑基、咪唑基、嘧啶基、哒嗪基、吡嗪基、苯并咪唑基、喹啉基、噁唑基和噻唑基。
术语“杂芳烷基”表示被杂芳基取代的1-3个碳原子的烷基，“杂芳基”按照前述定义，并带有取代基，例如2-噻吩甲基、2-苯并[b]噻吩甲基和3-(4-氯吡唑基)丙基。
通式(I)的新化合物可含有不对称碳原子，因此可制备成光学异构体或外消旋体。用常规的方法可将化合物(I)的外消旋体拆分为它们的光学异构体，例如用手性色谱或分步结晶分离该化合物的非对映异构体的盐。类似地，它们也可以由手性前体进行不对称合成获得。
本发明还涉及通式(I)化合物生理上可接受的盐，特别是与无机酸如盐酸、氢溴酸、磷酸、硫酸、硝酸的加成盐，和与有机酸如对甲苯磺酸或甲磺酸的加成盐。
其中X是氧原子，R1和R2如上文定义的通式(I)的新衍生物可按照下述方法A或方法B制备。
方法A：
通式(I)化合物可通过使R1如上文定义的式(III)氯代嘧啶衍生物与X和R2如上文定义的通式(IV)的哌嗪衍生物反应制备。
Figure C9880845800141
反应在例如下述有机溶剂中进行：卤代烃如二氯甲烷或氯仿，线性的或环状的醚如1，2-二甲氧基乙烷、四氢呋喃或二噁烷，质子惰性的极性溶剂如吡啶、二甲亚砜或二甲基甲酰胺，或其它任何适合于进行芳族亲核取代反应的溶剂。反应可在无机或有机碱如脂族胺，优选三乙胺或N-甲基吗啉存在下，在搅拌下于室温至溶剂的沸点的温度范围进行10分钟-24小时，优选条件是进行30分钟-5小时。
方法B：
使其中R1和R2如上文定义的式(V)的胺：
Figure C9880845800151
与其中R2如上文定义的通式R2COOH(VI)的羧酸进行反应，或与所述酸的盐或其衍生试剂R2COY(VII)进行反应。
Figure C9880845800152
盐的实例包括碱金属盐如钠盐和钾盐，碱土金属盐如钙盐或镁盐，铵盐，以及与有机碱如三乙胺、三甲胺、吡啶和甲基吡啶的盐。
通式R2COY(VII)的衍生试剂，其中Y是优选为氯原子或溴原子的卤原子，叠氮基(-N3)，1-咪唑基，O-CO-R4基团，其中R4为1-6个碳原子的烷基或芳基，优选被一个或几个卤原子取代，或基团OR5，其中R5表示一个或两个环的芳基基团，该基团被一个或几个卤原子或硝基取代，优选的基团是4-硝基苯基、2，4-二硝基苯基、五氯苯基、五氟苯基、1-苯并三唑基、或N-琥珀酰亚胺。类似地，用前述衍生试剂代替，可通过使式(V)的胺与通式(VI)的羧酸反应直接制备通式(I)化合物。在此情况下，优选反应在由活化羰基的试剂如N，N’-二环己基碳化二亚胺、二异丙基碳化二亚胺或3-(3-二甲氨基)苯基-1-乙基碳化二亚胺(ethycarbdiimide)存在下进行反应。此反应还可用所述的碳化二亚胺在1-苯并三唑或N-羟基琥珀酰亚胺存在下进行。通式(VI)的酸和通式(V)的胺也可以在N，N’-羰基二咪唑或丙膦酸酐(propanophosphonic acid anhydride)存在下直接反应。
反应在例如下述有机溶剂中进行：卤代烃如二氯甲烷或氯仿，线性的或环状的醚如1，2-二甲氧基乙烷、四氢呋喃或二噁烷，质子惰性的极性溶剂如吡啶、二甲亚砜或二甲基甲酰胺，或其它任何类型的适合于进行芳族亲核取代反应的溶剂。反应可在无机或有机碱如脂族胺，优选三乙胺或N-甲基吗啉存在下，在搅拌下于室温至溶剂的沸点的温度范围进行10分钟-24小时，优选条件是进行30分钟-5小时。
方法C：
其中X是硫原子，R1和R2如上文定义的通式(I)新衍生物可按照下述方法制备。
将其中X是氧原子，R1和R2如上文定义的通式(I)化合物用Lawesson’s试剂(2，4-双(4-甲氧基苯基)-1，3，2，4-二硫杂二磷杂桥亚乙基-2，4-二硫化物(disulphuro))或用五硫化磷进行处理得到X是硫原子的相应硫代酰胺。
Figure C9880845800161
反应在例如下述有机溶剂中进行：甲苯、苯、庚烷、吡啶或四氢呋喃，连续进行振荡，于室温至溶剂的沸点的温度范围反应1-24小时，优选在80℃进行1-16小时。
方法D：
通式(I)化合物的盐可在适当的溶剂如甲醇、乙醇、乙醚、乙酸乙酯、乙腈或丙酮中，通过与无机酸如盐酸、氢溴酸、磷酸、硫酸、硝酸的反应，或通过与有机酸如对甲苯磺酸或甲磺酸的反应，以及通过通常的沉淀技术或相应盐的结晶获得。
本发明还提供了药物组合物，其中含有至少一种通式(I)化合物或一种通式(I)化合物的生理上可接受的盐，以及药学上可接受的赋形剂。本发明还涉及通式(I)化合物和其生理上可接受的盐在制备对哺乳动物中枢神经系统，包括在人体中枢神经系统具有活性的药物中的应用，特别是在制备镇静剂、镇痉剂、安眠药和常规麻醉剂的药物中的应用。
在下面的实施例中按照本发明的方法制备了本发明的新化合物，同时也描述了应用于不同领域时的一些典型的形式，以及应用本发明化合物的药物制剂。
方法A：
实施例1制备2-[4-(2-呋喃羰基)-1-哌嗪基]-4-甲氧基嘧啶
将1.0g(6.92mmol)2-氯-4-甲氧基嘧啶，1.49g(8.30mmol)1-(2-呋喃基羰基)哌嗪和1.39g(13.84mmol)三乙胺于20ml正丁醇中的溶液缓慢搅拌过夜。减压蒸发溶剂，粗产物用氯仿稀释，用水洗涤，有机相用硫酸钠干燥，蒸发至干得到粗产物，将其用硅胶色谱纯化，以乙酸乙酯/石油醚70∶30为洗脱液，得到油，该油在静置后固化。将此固体悬浮于石油醚，得到1.4g(4.86mmol)2-[4-(2-呋喃羰基)-1-哌嗪基]-4-甲氧基嘧啶，m.p.＝85-86℃。
方法B：
实施例3制备4-甲氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶
将1.0g(5.15mmol)4-甲氧基-2-(1-哌嗪基)嘧啶和1ml(7.18mmol)三乙胺于30ml二氯甲烷中的溶液冷却至0℃，缓慢加入0.76g(5.18mmol)2-噻吩羰基氯化物，使溶液在0℃保持1小时，然后使温度升至室温。有机相用水洗涤，硫酸钠干燥，减压蒸发溶剂。粗产物溶于乙醚，结晶得到1.0g(3.28mmol)4-甲氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶，m.p.＝71-73℃。
实施例12制备4-甲氧基-2-[4-(3-噻吩羰基)-1-哌嗪基]嘧啶
在冷却至0℃的1.0g(7.81mmol)3-噻吩甲酸和1ml(7.86mmol)三乙胺的30ml二氯甲烷溶液中加入0.84g(7.81mmol)氯甲酸乙酯。使混合物在0℃保持20分钟，然后向其中加入1.5g(7.81mmol)4-甲氧基-2-(1-哌嗪基)嘧啶的30ml二氯甲烷溶液。使温度升至室温，溶液继续搅拌2小时，有机相用水洗涤，硫酸钠干燥，减压蒸发溶剂。得到的油用乙醚处理，得到的固体在乙醇/水中重结晶，得到0.8g(2.63mmol)4-甲氧基-2-[4-(3-噻吩羰基)-1-哌嗪基]嘧啶，m.p.＝90-92℃。
实施例20制备2-[4-(2-吲哚羰基)-1-哌嗪基]-4-甲氧基嘧啶
在0.83g(5.15mmol)吲哚-2-羧酸的15ml无水THF溶液中，加入0.83g(5.15mmol)N，N’-羰基二咪唑。30分钟后，向其中加入1.0g(5.15mmol)4-甲氧基-2-(1-哌嗪基)嘧啶，连续搅拌过夜。减压除去溶剂，加水，过滤沉淀并干燥，得到1.7g(5.04mmol)2-[4-(2-吲哚羰基)-1-哌嗪基]-4-甲氧基嘧啶，m.p.＝202-203℃。
方法C：
实施例54制备4-甲氧基-2-(4-硫代苯甲酰基-1-哌嗪基)嘧啶
将0.56g(1.9mmol)2-(4-苯甲酰基-1-哌嗪基)-4-甲氧基嘧啶溶于25ml无水甲苯，加入0.46g(1.14mmol)Lawesson’s试剂(2，4-双(4-甲氧基苯基)-1，3，2，4-二硫杂二磷杂桥亚乙基-2，4-二硫化物)。混合物在80-90℃加热16小时。加入乙醚，残余物用碱水洗涤，有机萃取物用硫酸钠干燥，减压蒸发溶剂。得到的粗产物用乙醚-石油醚结晶，得到160mg(0.5mmol)2-(4-硫代苯甲酰基-1-哌嗪基)-4-甲氧基嘧啶，m.p.＝125-129℃。
方法D：
实施例2制备2-[4-(2-呋喃羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐
将1.0g(3.47mmol)2-[4-(2-呋喃羰基)-1-哌嗪基]-4-甲氧基嘧啶溶于乙酸乙酯，加入几滴乙醚/盐酸，过滤干燥如此得到的沉淀，得到1.07g(3.29mmol)2-[4-(2-呋喃羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐(chlorohydrate)，m.p.＝162-164℃。
实施例4制备4-甲氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐
将1.0g(3.29mmol)4-甲氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]-嘧啶溶于丙酮，加入几滴乙醚/盐酸，过滤干燥如此得到的沉淀，得到1.05g(3.08mmol)4-甲氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐，m.p.＝143-145℃。
实施例13制备4-甲氧基-2-[4-(3-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐
将0.8g(2.63mmol)4-甲氧基-2-[4-(3-噻吩羰基)-1-哌嗪基]-嘧啶溶于乙醇，加入几滴乙醚/盐酸，过滤干燥如此得到的沉淀，得到0.6g(1.76mmol)4-甲氧基-2-[4-(3-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐，m.p.＝154-156℃。
表1
Figure C9880845800221
Figure C9880845800231
Figure C9880845800251
Figure C9880845800261
Figure C9880845800291
Figure C9880845800301
Figure C9880845800321
Figure C9880845800331
Figure C9880845800341
Figure C9880845800351
Figure C9880845800371
Figure C9880845800381
Figure C9880845800401
Figure C9880845800411
Figure C9880845800421
小鼠的安眠活性
按照David Sudgen(J.Pharmacol.Exp.Ther.，1983，227，3)描述的改进方法研究了本发明产物的安眠活性，评价它们增加由巴必妥诱导的睡眠时间的能力。
在施用巴必妥(150mg/Kg，i.v.)15分钟后，小鼠用所研究的产物处理，起始剂量100mg/Kg(i.p.)，测定活性最好的产物的半数剂量效率(DE50)，一些本发明化合物的结果列于表2，以安宁为参照物。
         表2  增加由巴必妥诱导的睡眠时间的能力
实施例           ％活性(睡眠)            DE50(mg/kg)
                 剂量100mg/kg
  2                   93                    14.4
  4                   100                   8.7
  5                   73                    39
  8                   97                    9.7
  9                   67                    28.1
  10                  74                    11.6
  11                  89                    10.5
  13                  77                    41.3
  15                  86                    8.2
  17                  56                    84.2
  18                  82                    27.3
  22                  57                    75
  24                  69                    41.5
  26                  60                    74.1
  30                  75                    37.2
  32                  73                    56.5
  34                  98                    7
  55                  70                    31
  57                  100                   1.6
59                101                14
61                102                4.5
63                103                4
65                100                7.7
67                96                 15
69                97                 10
73                98                 9.5
81                99                 8.3
83                100                5.3
87                101                10
89                102                8
91                81                 10
92                98                 8
94                84                 5.2
96                97                 3
安宁              54                 84.5
常规麻醉活性
在小鼠的尾静脉注射需要研究的产物，以便对小鼠的常规麻醉活性进行研究。记录睡眠开始和持续时间，一些本专利申请化合物的结果列于表3，随着动物后来的恢复，结果表明相对参照化合物而言(丙泊酚)，它们显示了明显的麻醉活性。
            表3 i.v.给药时小鼠的麻醉活性
  实施例 剂量(mg/kg)   起效(s) 持续时间(分钟)
    2     8040     立即12     5.30.6
    4     8040     立即15     7.41.3
    15     8040     2015     1.91.4
    30     8040     3030     7.91.8
    34     8040     立即No     1.50
    57     80     立即     1 1
    59     80     20     3.4
    61     80     10     1.6
    65     80     20     8.6
    63     80     立即     14.8
    71     80     60     5.6
    73     80     立即     9
    77     80     立即     10
    79     80     立即     19
    81     80     立即     10
    85     80     立即     8.4
    87     80     立即     10
    89     80     立即     4
    91     80     立即     7
    92     80     立即     5
    96     80     立即     6
    101     80     立即     2
    丙泊酚     10612080     3020No     6.23.90
镇静活性
此实验对本发明一些产物对小鼠运动活性的镇静作用进行了研究。实验按照T.G.Heffneren，J.Pharm.Exp.Ther.，1989，251，105-112所述的技术进行。把大鼠分成4组，用摄像设备和用SMART程序(Letica S.A.)进行影像分析测量小鼠主动方式的运动以便对小鼠的运动活性进行测定。在把产物通过i.p.给药5分钟后开始测量活性，并连续进行20分钟。结果(图1)说明了试验化合物的镇静活性。
肌肉松弛活性
通过评价本发明产物对小鼠腹部紧张度的作用对本发明产物的肌肉松弛活性进行研究。研究按照S.TRWING(Gordon Res.Conf.OnMedicinal Chem..，1959，p133)所述的方法进行。
进行研究的小鼠通过i.p.以80mg/Kg的剂量给药本发明产物，在给药后不同的时间(1/2，1，2，3，4和5小时)，相对于对照动物而言，通过观察肌肉张力评价研究动物的身体紧张度和腹部紧张度。
表4列出的结果表明许多本发明化合物都具有显著的肌肉松弛剂活性，它们的作用时间比作为参照化合物的丙泊酚和吡唑旦更长。
      表4  Irwing小鼠实验的松弛活性
           [剂量＝80mg/kg，i.p.]
  实施例            ％肌肉松弛时间
          1/2H   1H     2H     3H    4H    5H
    4     100    90     10     0     0     0
    34    60     70     80     85    40    40
    57    100    100    100    80    55    0
    63    100    100    90     75    20    0
    71    100    100    100    40    10    0
    73    100    100    100    0     0     0
    75    100    100    100    80    80    60
    77    100    100    100    60    0     0
    79    100    100    100    65    0     0
    83    90     90     90     70    50    0
    92    100    100    100    0     0     0
  丙泊酚  100    100    70     0     0     0
止痛活性
对本发明产物的止痛活性进行了研究，通过苯基苯醌诱导小鼠的旋转实验评价其作用，该实验按照Siegmund E.和其同事所描述的方法(Proc.Soc.Exp.Biol.Med.，1957，95：729-731)进行。
以i.p.注射5mg/Kg苯基苯醌1小时后，使小鼠接受不同剂量本发明产物。记录其后15分钟内小鼠的旋转次数，并与对照组的旋转情况进行比较，得到实施例4化合物的DE50(半数剂量效率)。在皮下或口服给药的情况下，此化合物比阿斯匹林显示出更好的止痛活性。
        表5 止痛活性，防止苯基苯醌诱导的小鼠旋转
    实施例 DE50(mg/kg，s.c.) DE50(mg/kg，o.a.)
    阿斯匹林     84     120
    4     48     72
药物制剂
1、注射剂(im/iv)：
    实施例4化合物                  5mg
    氯化钠                         适量
    HCl 0.1N或NaOH                 适量
    注射用水c.s.p.                 3ml
2、胶囊
    实施例4化合物                  0.5-4.0mg
    胶体二氧化硅                   0.5mg
    硬脂酸镁                       1.0mg
    乳糖c.s.p.                     100mg
3、片剂
    实施例4化合物                  0.5-4.0mg
    胶体二氧化硅                   0.5mg
    硬脂酸镁                       1.0mg
    交联羧甲基纤维素钠             60mg
    乳糖c.s.p.                     100mg
    制剂B(湿颗粒)
    实施例4化合物                  0.5-4.0mg
    胶体二氧化硅                   0.5mg
    硬脂酸镁                       1.0mg
    聚维酮K-30                     5.0mg
    羧甲基淀粉钠                   5.0mg
    微晶纤维素                     20mg
    乳糖c.s.p.                     100mg

Claims (20)

1.通式(I)的酰基-哌嗪基-嘧啶衍生物和它们生理上可接受的盐：
Figure C988084580002C1
其中
X是氧或硫原子；
R1是C1-4烷氧基或三氟甲基基团；
R2是C1-6烷基基团；C3-6饱和的环烷基；环由3-6个原子组成的杂环烷基，其中的杂原子选自氧、硫或氮；由1、2或3个相同或不同的，选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的取代基选择取代的苯基；由苯基基团取代的C1-3烷基构成的芳烷基，其中的苯基被1、2或3个相同或不同的，选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的取代基选择取代；选择取代的杂芳基，其由5或6杂原子环，或是有1或2个选自氧、硫或氮的杂原子和具有9-10个原子的稠合杂芳环系统组成，该系统由选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的前述取代基选择取代；以及杂芳烷基，所述杂芳烷基是杂芳基取代的1-3个碳原子的烷基，所述的杂芳基由5或6元杂芳环，或是有1或2个选自氧、硫或氮的杂原子和9-10员稠合杂芳环系统组成，该系统由选自氟、氯、溴、氨基、乙酰氨基、硝基、甲基、三氟甲基和甲氧基的前述取代基选择取代。
2.按照权利要求1的化合物，其中R1是甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁氧基或叔丁氧基。
3.按照权利要求1的化合物，其中R2是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基或己基。
4.按照权利要求1的化合物，其中R2是环丙基、环丁基、环戊基或环己基。
5.按照权利要求1的化合物，其中R2是2-吖丙啶基、2-四氢呋喃基、3-四氢呋喃基、2-四氢噻吩基、3-四氢噻吩基、2-氮杂环丁烷基、2-吡咯烷基、3-吡咯烷基、2-哌啶基、3-哌啶基或4-哌啶基。
6.按照权利要求1的化合物，其中R2是2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-氨基苯基、3-氨基苯基、4-氨基苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-乙酰氨基苯基、3-乙酰氨基苯基、4-乙酰氨基苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-(三氟甲基)苯基、3-(三氟甲基)苯基、4-(三氟甲基)苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2，3-二氟苯基、3，4-二氟苯基、2，4-二氟苯基、2，3-二溴苯基、3，4-二溴苯基、2，4-二溴苯基、2，3-二甲基苯基、3，4-二甲基苯基、2，4-二甲基苯基、2，3-二甲氧基苯基、3，4-二甲氧基苯基、2，4-二甲氧基苯基。
7.按照权利要求1的化合物，其中R2是芳环选择取代的苯甲基、1-苯基乙基、2-苯基乙基、3-苯基乙基、3-苯基丙基。
8.按照权利要求1的化合物，其中R2是2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、3-甲基-2-噻吩基、5-甲基-2-噻吩基、3-甲氧基-2-噻吩基、3-氯-2-噻吩基、5-氯-2-噻吩基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-吲哚基、3-吲哚基、2-苯并[b]噻吩基、3-苯并[b]噻吩基、3-氯-2-苯并[b]噻吩基、吡唑基、咪唑基、嘧啶基、哒嗪基、吡嗪基、苯并咪唑基、喹啉基、噁唑基或噻唑基。
9.按照权利要求1的化合物，其中R2是2-噻吩甲基、2-苯并[b]噻吩甲基或3-(4-氯吡唑基)丙基。
10.按照权利要求1的化合物，该化合物是选自下列一组的化合物：
2-[4-(2-呋喃羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-呋喃羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐，
2-(4-乙酰基-1-哌嗪基)-4-甲氧基嘧啶，
2-{4-[4-(4-氯吡唑基)丁酰基]-1-哌嗪基)-4-甲氧基嘧啶，
2-{4-[4-(4-氯吡唑基)丁酰基]-1-哌嗪基)-4-甲氧基嘧啶盐酸盐，
2-(4-苯甲酰基-1-哌嗪基)-4-甲氧基嘧啶，
2-(4-环丙基羰基-1-哌嗪基)-4-甲氧基嘧啶，
2-[4-(2-呋喃羰基)-1-哌嗪基]-4-(三氟甲基)嘧啶，
2-[4-(2-噻吩羰基)-1-哌嗪基]-4-(三氟甲基)嘧啶，
4-甲氧基-2-[4-(3-噻吩羰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(3-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐，
2-[4-(5-甲基-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(5-甲基-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(3-甲氧基-2-噻吩羰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(3-甲氧基-2-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐，
2-[4-(2-苯并[b]噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-苯并[b]噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(2-吲哚羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-氯-2-苯并[b]噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-氯-2-苯并[b]噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(2-吡咯羰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(2-吡咯羰基)-1-哌嗪基]嘧啶盐酸盐，
4-甲氧基-2-[4-(2-噻吩乙酰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(2-噻吩乙酰基)-1-哌嗪基]嘧啶盐酸盐，
2-[4-(3-甲基-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-甲基-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(3-氯-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-氯-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(3-吲哚羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-苯并[b]噻吩乙酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(5-氯-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(5-氯-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(4-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
4-甲氧基-2-[4-(4-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(4-氟苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(4-氟苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(4-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(4-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(3-甲氧基苯甲酰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(3-甲氧基苯甲酰基)-1-哌嗪基]嘧啶盐酸盐，
2-[4-(3-氟苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-氟苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(3-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(2-甲氧基苯甲酰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(2-甲氧基苯甲酰基)-1-哌嗪基]嘧啶盐酸盐，
2-[4-(2-氟苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-氟苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(2-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-氯苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(2-四氢呋喃羰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-(4-噻吩苯甲酰基-1-哌嗪基)嘧啶，
4-甲氧基-2-[4-(2-四氢呋喃羰基)-1-哌嗪基]嘧啶盐酸盐，
4-甲氧基-2-(4-硫代苯甲酰基-1-哌嗪基)嘧啶盐酸盐，
2-(4-苯甲酰基-1-哌嗪基)-4-甲氧基嘧啶，
4-甲氧基-2-{4-[4-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶，
4-甲氧基-2-{4-[4-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶盐酸盐，
4-甲氧基-2-{4-[3-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶，
4-甲氧基-2-{4-[3-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶盐酸盐，
4-甲氧基-2-{4-[2-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶，
4-甲氧基-2-{4-[2-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶盐酸盐，
4-甲氧基-2-(4-烟酰基-1-哌嗪基)嘧啶，
4-甲氧基-2-(4-烟酰基-1-哌嗪基)嘧啶二盐酸盐，
2-(4-异烟酰基-1-哌嗪基)嘧啶，
2-(4-异烟酰基-1-哌嗪基)嘧啶二盐酸盐，
2-[4-(1-咪唑羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(1-咪唑羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-(4-烟酰基-1-哌嗪基)-4-(三氟甲基)嘧啶，
2-(4-烟酰基-1-哌嗪基)-4-(三氟甲基)嘧啶盐酸盐，
4-甲氧基-2-[4-(2-吡啶羰基)-1-哌嗪基]嘧啶，
4-甲氧基-2-[4-(2-吡啶羰基)-1-哌嗪基]嘧啶二盐酸盐，
4-乙氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶，
4-乙氧基-2-[4-(2-噻吩羰基)-1-哌嗪基]嘧啶盐酸盐，
2-[4-(3-氯-2-噻吩羰基)-1-哌嗪基]-4-乙氧基嘧啶，
2-[4-(3-氯-2-噻吩羰基)-1-哌嗪基]-4-乙氧基嘧啶盐酸盐，
4-乙氧基-2-{4-[2-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶，
4-乙氧基-2-{4-[2-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶盐酸盐，
2-[4-(2-甲基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-甲基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(4-氟苯甲酰基)-1-哌嗪基]-4-异丙氧基嘧啶，
2-[4-(4-氟苯甲酰基)-1-哌嗪基]-4-异丙氧基嘧啶盐酸盐，
4-异丙氧基-2-{4-[2-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶，
4-异丙氧基-2-{4-[2-(三氟甲基)苯甲酰基]-1-哌嗪基}嘧啶盐酸盐，
2-[4-(3-氯-2-噻吩羰基)-1-哌嗪基]-4-异丙氧基嘧啶，
2-[4-(3-氯-2-噻吩羰基)-1-哌嗪基]-4-异丙氧基嘧啶盐酸盐，
2-[4-(环己基羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(环己基羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-乙氧基-2-[4-(4-氟苯甲酰基)-1-哌嗪基]嘧啶，
4-乙氧基-2-[4-(4-氟苯甲酰基)-1-哌嗪基]嘧啶盐酸盐，
2-[4-(2-噻唑羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-氨基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-氨基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(3-氟-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(3-氟-2-噻吩羰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
2-[4-(4-甲氧基-2-嘧啶基)-1-哌嗪基羰基]苯甲酸，
2-[4-(2-乙酰氧基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(2-羟基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，
2-[4-(4-甲氧基-2-嘧啶基)-1-哌嗪基羰基]苯甲酸钠，
2-[4-(2-羟基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶盐酸盐，
4-甲氧基-2-[4-(2-甲氧基苯甲酰基)-1-哌嗪基]-4-甲氧基嘧啶，和
4-乙氧基-2-[4-(2-吡啶羰基)-1-哌嗪基]嘧啶。
11.制备按照权利要求1通式(I)化合物的方法，其中X是氧原子，该方法包括使R1如权利要求1定义的式(III)氯代嘧啶衍生物：
Figure C988084580008C1
与通式(IV)的哌嗪衍生物反应：
Figure C988084580008C2
其中R2如权利要求1定义，以及X表示氧原子。
12.制备按照权利要求1通式(I)化合物的方法，其中X是氧原子，该方法包括使R1如权利要求1定义的式(V)的胺：
与式R2COOH(VI)的羧酸，或与所述酸的盐进行反应，其中R2如权利要求1定义。
13.制备按照权利要求1通式(I)化合物的方法，其中X是氧原子，该方法包括使R1如权利要求1定义的式(V)的胺：
Figure C988084580009C1
与式R2COY(VII)的衍生试剂进行反应，其中R2如权利要求1定义，Y表示卤原子，叠氮基，1-咪唑基，O-CO-R4基团，其中R4为被一个或几个卤原子选择取代的1-6个碳原子的烷基或芳基基团，或基团OR5，其中R5表示芳基基团或一个或两个环，该基团被一个或几个卤原子或硝基取代，或N-琥珀酰亚胺。
14.制备按照权利要求1通式(I)化合物的方法，其中X是硫原子，该方法包括使其中X是氧原子的通式(I)化合物与Lawesson’s试剂(2，4-双(4-甲氧基苯基)-1，3，2，4-二硫杂二磷杂桥亚乙基-2，4-二硫化物)或与五硫化磷进行反应。
15.制备按照权利要求1通式(I)化合物的盐的方法，该方法包括使通式(I)化合物与无机酸或有机酸在适当的溶剂进行反应。
16.药物组合物，其中含有至少一种权利要求1-10中任意一项的通式(I)化合物或一种通式(I)化合物的生理上可接受的盐，另外还含有药学上可接受的赋形剂。
17.权利要求1-10任意一项的通式(I)化合物或其生理上可接受的盐在制备对哺乳动物的中枢神经系统具有活性的药物中的应用。
18.权利要求17的应用，其中通式(I)化合物或其生理上可接受的盐用于制备对哺乳动物具有镇静剂、镇痉剂、镇痛剂、肌肉松弛剂、止咳剂、抗焦虑剂、抗精神病药、抗抑郁剂、抗脑局部缺血药、抗偏头痛药活性的药物，以及用于制备用于治疗睡眠失调、神经变性疾病、认知失调和阿尔茨海默氏病的药物、安眠药和常用麻醉剂的药物。
19.权利要求17的应用，其中所述哺乳动物包括人。
20.权利要求18的应用，其中所述哺乳动物包括人。
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