CN1055687C - 新的哌嗪甲酰胺 - Google Patents

新的哌嗪甲酰胺 Download PDF

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CN1055687C
CN1055687C CN93116827A CN93116827A CN1055687C CN 1055687 C CN1055687 C CN 1055687C CN 93116827 A CN93116827 A CN 93116827A CN 93116827 A CN93116827 A CN 93116827A CN 1055687 C CN1055687 C CN 1055687C
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L·阿伯兰莫
C·诺维
T·隆德斯泰特
K·G·奥尔森
M·布罗斯基
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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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明涉及下述通式新化合物及其药理学活性的盐
这些新化合物用于治疗精神疾病。

Description

新的哌嗪甲酰胺
急迫需要一种有效的治疗精神病症的药物，与现今临床使用的药物相比它更为有效并具有更小的付作用。现今使用的抗精神病药产生一定范围麻烦的锥体束外移动病症(例如急性张力障碍反应和迟发运动障碍)并且在改善分裂症付症状(例如限制或减弱情绪唤起)方面是不良的。现今这些抗抑郁药的主要缺点是它们不能使30-40％患者的抑郁减轻。抗焦虑药通常与成瘾性有关。
现有技术中已知多种对中枢神经系统有药理学活性的哌嗪衍生物。可以举出一些典型的实例。
美国专利4308387公开了氟苯哌胺，它在临床研究中显示出有用的抗精神病性能。
氟苯哌胺具有边缘轮廓作用。
                     Amperozide
按照本发明提供了具有通式(I)的新化合物及其药理学活性的盐
Figure C9311682700111
其中Ar相同或不同并选自其中R3是卤素或氢，R1和R2相同或不同并选自氢或烷基；n是2或3，X是氮或次甲基，当X是氮时Y是亚甲基，当X是次甲基时，Y选自氮或氧，A选自如下羧酸衍生物；
Figure C9311682700113
其中R4和R5相同或不同并选自氢，烷基，环烷基或芳基。Z选自硫或氧。R6选自其中m是1，2，3或4。R7选自氢或低级烷基。在前述定义中使用的术语低级烷基意指包括直链和支链，饱和和不饱和具有1至5个碳原子的烃基，术语环烷基意指包括具有3至8个碳原子的饱和和不饱和环烃基，术语低级烷氧基意指包括直链或支链，饱和或不饱和具有1至5个碳原子的烷氧基，术语卤素意指包括氟和溴。
式(I)化合物具有碱性，并且理所当然，通过用适合的酸处理它们能转化为其具有治疗活性的酸加成盐，例如用无机酸如氢氯酸、氢溴酸、硫酸、硝酸和磷酸，或用有机酸如乙酸、丙酸、乙醇酸、乳酸、丙二酸、草酸、琥珀酸、富马酸、酒石酸、柠檬酸和双羟萘酸。
相反地，通过用碱处理盐形式能转化为游离碱形式。
式(I)化合物和其药学上可接受的盐具有有价值的药理学性质，使其能用于治疗精神病症如精神病、抑郁病、焦虑和滥用镇静剂。也能治疗动物的紧张和焦虑。
本发明化合物显示出影响精神过程的性质。
已发现它们是选择性5-HT2拮抗剂。
具有通式(I)的化合物可通过一般方法制备。方法1使其中Ar，X和Y如先前定义和L是适合的离去基团如卤素和烷基或芳基磺酸盐的式(II)化合物与式中R1，R2，A和n如先前定义的式(III)化合物反应。用标准的N-烷基化方法可使反应进行。方法2
Figure C9311682700132
Figure C9311682700133
使其中Ar，R1，R2，X，Y，Z和n如上述定义的式IV化合物与式中R4，R5，R6和Z如上述定义和L是适合的离去基团的式V，VI化合物反应。方法3
                    O＝C＝N-R4
                       VII使式IV化合物与其中R4如上述定义的式VII化合物反应。方法4使其中Ar如上述定义的式VIII化合物与式中n和A如上述定义的式IX化合物反应。L是羟基或离去基团。方法5使其中Ar，n，R3和R4如上述定义的式X化合物与式V或VI化合物反应得到式XI产物
Figure C9311682700151
其中Ar，n，R1，R2如上述定义。还原化合物XI，得到式XII化合物，
Figure C9311682700152
其中Ar，R3，R4，n和A如上述定义。方法6
Figure C9311682700153
使其中Ar，X，Y，R1，R2和Z如上述定义的式XIII化合物与仲胺反应，得到由式(I)所描述的产物。方法7使式IV化合物与三光气(XIV)反应，得到其中Ar，n，X，Y，R1和R2如上述定义的式(XV)产物，将其与仲胺反应得到式(I)所描述的产物。
用下述实施例来说明但不是限制本发明范围，虽然所举出的化合物对我们预定的目的是特别重要的。这些化合物由数字符号来标明，a∶b；在此a意指实施例号码，其中叙述了所述化合物的制备，b是指按照那个实施例制备的化合物的顺序。这样化合物1∶2意指按照实施例1制备的第二个化合物。
化合物的结构由NMR，质谱和元素分析证实。当给出熔点时，这些熔点是未较正的。实施例1：1
1-{3-[双(p-氟苯基)氨基]丙基}-N-乙基-4-哌嗪-甲酰胺氢氯化物
将4.7g(0.3mol)N-乙基哌嗪甲酰胺，13.4g(0.036mol)3-[双(p-氟苯基)氨基]丙基碘和5g(0.060mol)NaHCO3于乙醇中回流48小时。冷却后过滤反应混合物。蒸去溶剂得到粗碱。
将3.2g游离碱溶于40ml乙醚中。用过量的乙醇中的盐酸沉淀出其氢氯化物。在2-丁酮中重结晶，得到2.7g标题化合物(1：1)m.p.164-165℃。实施例2：14-{2-[(4，4′-二氟二苯甲基)氧基]-乙基-}-N-n-辛基-1-哌嗪甲酰胺氢氯化物
将5.6g(0.017mol)2-[(4，4′-二氟二苯甲基)氧基]乙基哌嗪，4.5g(0.018mol)苯基-辛基氨基甲酸酯和2.8g碳酸钾与60ml甲苯一起搅拌并回流1小时，过滤反应滤反应混合物。用水将滤液洗涤三次然后用盐水洗涤。用硫酸钠干燥有机层并过滤。蒸发从滤液中除去溶剂，得到一种油。将6.5g油溶于70ml乙酸乙酯中。用过量的乙醇中的盐酸沉淀出其氢氯化物。从异丙醇/乙醚中重结晶，得到5.3g标题化合物(2：1)，m.p.171-172℃。
基本上以同一方法用于制备如下化合物。2：21-[2-[(4，4′-二氟二苯甲基)氨基]乙基]-4-(N-异丙基氨基甲酰基)哌嗪2.25氢氯化物m.p.192-193℃。实施例3：14-[2-[(4，4′-二氟二苯甲基)氧基]乙基]-N-乙基-1-哌嗪甲酰胺氢氯化物
将5g 2-[(4，4′-二氟二苯甲基)氧基]乙基哌嗪和100ml乙醚置于三颈瓶中。将1.1g异氰酸乙酯溶于20ml乙醚并一滴一滴加入烧瓶中。室温下将反应混合物搅拌2小时。蒸去溶剂。将残余物溶于乙醚。用过量的乙醇中的盐酸沉淀出其氢氯化物。从异丙醇中重结晶，得到4.5g标题化合物(3：1)，m.p.191-192℃。
基本上，用同一种方法制备下述化合物。3：24-[2-[(4，4′-二氟二苯甲基)氧基]乙基]-N-环己基-1-哌嗪甲酰胺氢氯化物m.p.199-200℃。3：34-[2-[(4，4′-二氟二苯甲基)氧基]乙基]-N-苯基-1-哌嗪甲酰胺氢氯化物m.p.211-212℃。3：44-[2-[(4，4′-二氟二苯甲基)氧基]乙基]-N-甲基-1-哌嗪硫代甲酰胺氢氯化物m.p.193-194℃。3：51-[3-(N-4-吡啶基-4-氟苯胺基)丙基]-N-乙基-4-哌嗪甲酰胺二草酸盐m.p.172-173℃。3：61-[3-(N-吡啶基-4-氟苯胺基)丙基]-N-苯基-4-哌嗪甲酰胺二富马酸盐m.p.151-155℃。3：71-[3-(N，N-二(p-氟苯基)氨基)丙基]-N-环己基-4-哌嗪甲酰胺氢氯化物，水合物167-170℃。3：81-[3-(N，N-二(p-氟苯基)氨基)丙基]-N-苯基-4-哌嗪甲酰胺氢氯化物，半水合物187-190℃。3：91-[3-(N，N-二(p-氟苯基)氨基)丙基]-N-苯基-4-哌嗪硫代甲酰胺1.5氢氯化物m.p.187-188℃。3：101-[3-(N-吡啶基-4-氟苯胺基)丙基]-N-环己基-4-哌嗪甲酰胺二富马酸盐m.p.175℃(分解)实施例3b：14-{2-[(4，4-二氟二苯甲基)氧基]乙基}-1-哌嗪甲酰胺氢氯化物
将4-{[2-[(4，4-二氟二苯甲基)氧基]乙基}-哌嗪(4.0g 0.012mol)的20ml冰醋酸溶液冷至0℃，于此时，将溶于20ml水中的氰酸钾3g(0.036mol)加入。将所得溶液于室温搅拌24小时，然后用100ml水稀释，加入20％碳酸氢钠水溶液至PH为7，然后用200ml乙酸乙酯萃取三次。用盐水洗涤合并的有机层，用无水硫酸钠干燥并蒸去溶剂。将4g(0.011mol)残余物用硅胶柱色谱法纯化(二氯甲烷∶甲醇10∶0.9)合并有关的极馏分(pole fraction)并浓缩，得到3g油。加入20ml乙醇并冷却后，将该物质固化。过滤收集形成的固体并用两份20ml的冷乙醇洗涤。将固体溶于乙醚并加入在乙醇中的5-NHCl。从乙醇∶乙醚中重结晶得到白色固体。得3g标题化合物(3b：1)m.p.116-119℃。实施例4：14-{[2-[(4，4′-二氟二苯甲基)氧基]乙基]}-N-甲基-1-哌嗪甲酰胺氢氯化物
在氮气氛下，于165-170℃(油浴温度)，将3.7g(0.020mol)1-(2-羟乙基)-N-甲基-1-哌嗪甲酰胺和2.4g(0.010mol)4-氟二苯甲基氯搅拌45分钟。冷却后，将60ml水和60ml甲苯加入反应混合物。分离各相。蒸发有机溶剂得到粗碱，用快速色谱法纯化并离析出油状物。将2.0g游离碱于20ml乙醚。用过量乙醇中的盐酸沉淀出其二氢氯化物。在异丙醇∶乙醚3∶1中重结晶，得到1.5g标题化合物(4：1)，m.p.202-203℃。实施例5：11-{2-[(4，4′-二氟二苯甲基)氨基]乙基}-N-环己基-4-哌嗪甲酰胺2.25氢氯化物
将3.2g(0.01ml)1-[ 2-[(4，4′-二氟亚二苯甲基)氨基]乙基]哌嗪和80ml乙醚置于三颈烧瓶中。将1.4g(0.01ml)异氰酸环己酯溶于乙醚并一滴一滴加入烧瓶。室温下将反应混合物搅拌2小时并形成结晶。然后滤出产物。将2.2g(0.05ml)结晶溶于20ml甲醇，加入1.0g(0.03ml)NaBH4并回流1小时。冷却后，蒸去溶剂并将残物溶于水和乙醚中。用水洗涤乙醚层三次并干燥。用过量乙醇中的盐酸沉淀出其氢氯化物。从异丙醇中重结晶，得到1.8g标题化合物(5：1)m.p.196-197℃。
基本上，用同一方法制备下述化合物。5：21-[2-[(4，4′-二氟二苯甲基)氨基]乙基]-4-(N-丁基氨基甲酰基)哌嗪2.25氢氯化物m.p.165-167℃。5：31-[2-[(4，4-二氟二苯甲基)氨基]乙基]-N-苯基-4-哌嗪硫代甲酰胺m.p.133-134℃。实施例6：11-{2-[(4，4′-二氟二苯甲基)氧基]乙基}-(4-吗啉代-羰基)哌嗪氢氯化物
将10g 4-[2-[(4，4′-二氟二苯甲基)氧基]乙基]-p-硝基苯基哌嗪氨基甲酸酯于140℃与20ml吗啉一起加热12小时。蒸发过量的吗啉。将残余物溶于乙醚并用盐水，10％NaOH，盐水洗涤。蒸发溶剂，得到油状粗碱。将该油溶于乙醚，用乙醇中的盐酸，沉淀出其氢氯化物。从甲醇/丙酮1∶10中重结晶，得到8.0g标题化合物(6：1)，m.p.208-209℃。
基本上，用同一方法制备下述化合物。6：21-[2-[(4，4′-二氟二苯甲基)氧基]乙基]-4-(吡咯烷基-羰基)哌嗪氢氯化物m.p.170-171℃。6：31-[2-[(4，4′-二氟二苯甲基)氨基]乙基]-4-(4-甲基哌啶子基羰基)哌嗪2.5氢氯化物m.p.219-221℃。6：41-[2-[(4，4′-二氟二苯甲基)氨基]乙基]-4-(N，N-二戊基氨基甲酰基)哌嗪2.5氢氯化物m.p.113-115℃。6：51-[3-(N，N-二(p-氟苯基)氨基)丙基]-N，N-二乙基-4-哌嗪甲酰胺氢氯化物m.p.141-142℃。实施例7：11-{2-[(4，4′-二氟二苯甲基)氧基]乙基}-4-(N，N-二乙基氨基甲酰基)哌嗪氢氯化物
于5-10℃，将5g(0.015mol)1-[2-(4，4′-二氟二苯甲基)氧基]乙基]哌嗪，50ml甲苯和3ml(0.02mol)三乙胺的溶液子1小时滴加到1.5g(0.005mol)三光气的100ml甲苯溶液中。将混合物置于室温16小时，然后用1NaOH和水洗涤，用硫酸钠干燥。蒸发溶剂得到油状粗碱。将该油溶于乙醚中，用过量盐酸在乙醇中沉淀出氢氯化物。从乙酸乙酯∶2-丁酮(3∶1)中重结晶，得到2.5g标题化合物(7：1)m.p.158-160℃(分解)。
基本上，用，同一方法制备下述化合物。7：21-[2-[(4，4′-二氟二苯甲基)氧基]乙基]-4-(N，N-二丙氨基甲酰基)哌嗪氢氯化物m.p.125-127℃。实施例8试验1.对5-HT2受体的亲和力
基本上按LeySen等(Mol.Pharmacol.21，301-14，1982)所述用3H-Ketanserin作配位体进行亲合测定。试验2.对D2-受体的亲和力
基本上按LeySen等(Mol.Pharmacol.21，301-14，1982)所述用3H-螺环哌啶作酮配位体进行亲合测定。表1
化合物                 5-HT2                     D2
                       Hi(nM)                    Ki(nM)
3：1                   60                        ＞10000
3：4                   20                        1600
6：2                   15                        1780
氟苯哌胺               17                        540
给出表1中列出的化合物其目的并非是为了限制本发明，仅是对式(I)范围内化合物的有用的药理学活性的举例。实施例9
下述制剂对本发明所有药理学活性化合物是代表性的。适合的胶囊的实例。
                                              每个胶囊，mg
活性成分  以盐形式                                  10
乳糖                                                250
淀粉                                                120
硬脂酸镁                                            5
总量                                                385在活性成分高含量下，可降低所用乳糖的量。适合的片剂的实例
                                                  每片，mg
活性成分  以盐形式                                     10
马铃薯淀粉                                             90
胶体二氧化硅                                           10
滑石                                                   20
硬脂酸镁                                               2
5％明胶水溶液                                          25
总量                                                   157
注射用非肠道施用溶液可制成活性物质的水溶性药学上可接受的盐的水溶液，优选浓度约0.5％至5％(重量)。这些溶液也可含稳定剂和/或缓冲剂并可方便地提供多种剂量单位的安瓿。

Claims (9)

1.具有通式(I)的新化合物及其药理学上可接受的盐
Figure C9311682700021
其中Ar相同或不同并选自
Figure C9311682700022
其中R3是卤素或氢，R1和R2相同或不同并选自氢或低级烷基，n是2或3，X是氮或次甲基，当X是氮时Y是亚甲基，当X是次甲基时Y选自氮或氧，A选自下述羧酸衍生物
Figure C9311682700023
其中的R4和R5相同或不同并选自氢，烷基，环烷基或芳基，Z选自硫或氧，R6选自
Figure C9311682700031
其中m是1，2，3或4，R7选自氢或低级烷基。
2.按照权利要求1的化合物，其中n是2。
3.按照权利要求1或2的化合物，其中R1和R2是氢。
4.按照权利要求3的化合物，其中X是次甲基。
5.按照权利要求4的化合物，其中Y是氧。
6.按照权利要求5的化合物，其中R4和R5选自氢或低级烷基。
7.按照权利要求5的化合物，其中R2是吡咯烷。
8.制备具有通式(I)的化合物及其药理学可接受的盐的方法
Figure C9311682700032
其中Ar相同或不同选自其中R3是卤素或氢，R1和R2相同或不同选自氢或烷基，n是2或3，X是氮或次甲基，当X是氮时，Y是亚甲基，当X是次甲基时，Y选自氮，氧或硫，A选自下述羧酸衍生物其中R4和R5相同或不同并选自氢，烷基，环烷基或芳基，Z选自硫或氧，R6选自
Figure C9311682700043
其中m是1，2，3或4，R7选自氢或低级烷基，其中使具有通式(II)的化合物
Figure C9311682700051
其中Ar，X和Y如上定义，L是离去基团，与具有通式(III)的化合物反应
Figure C9311682700052
其中R1，R2，n和A如上定义或其中使具有通(IV)的化合物其中Ar，R1，R2，X，Y和n如前述定义，与具有通式(V)或(VI)的化合物反应
Figure C9311682700061
其中Z，R4和R5如前述定义，L是离去基团，或其中使如上述定义的化合物IV与具有式VII的化合物反应O＝C＝N-R4
VII其中R4如前述定义，或其中使具有通式VIII的化合物其中Ar如前述定义，L是离去基团或羟基，与通式IX的化合物反应
Figure C9311682700071
其中R1，R2，n和A如前述定义，
Figure C9311682700072
Figure C9311682700073
或其中使Ar，n，R3和R4如上述定义的式X化合物与式V或VI化合物反应，得到式XI产物
Figure C9311682700081
其中Ar，n，R1、R2和A如前述定义，还原化合物XI得到期望的产物式XII化合物
Figure C9311682700082
其中Ar，R3，R4，n和A如前述定义或其中使如前所述Ar，X，Y，R1，R2和Z如前述定义的式VIII化合物与仲胺反应，
Figure C9311682700091
或其中使如上所述的式IV化合物与三光气(XIV)反应，得到(XV)产物，其中Ar，n，X，Y，R1和R2如前述定义，使其与仲胺反应。
9.药物组合物，含有作为活性成分的一个或多个具有通式(I)的化合物，优选与药学上可接受的载体一起，如果需要，还含有其它药理学上的活性剂。
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