CN1091108C - 二苯亚甲基哌啶衍生物、其制备方法,含有它们的药物组合物及其用途 - Google Patents
二苯亚甲基哌啶衍生物、其制备方法,含有它们的药物组合物及其用途 Download PDFInfo
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Abstract
本发明涉及式(I)的二苯亚甲基哌啶衍生物,其中n是1或2;或者其药学上可接受的盐,在治疗中的用途,特别是用作多巴胺拮抗剂来治疗或预防精神病。
Description
技术领域
本发明涉及二苯亚甲基哌啶衍生物,含有它的药物组合物,其生产方法,以及治疗和预防精神病的方法。
背景技术
相关的二苯亚甲基哌啶衍生物是本领域中已知的。值得注意的是USP4,540,780及其分案USP4,666,905中公开的相关化合物,其中提到二苯亚甲基哌啶衍生物可用作止吐、抗组胺、肺、和镇痉剂。
本发明内容
其中n是1或2;或者其药学上可接受的盐。
更优选本发明的二苯亚甲基哌啶衍生物含有的两个氟原子与苯环对位相连。
及其药学上可接受的盐。
如体内阿朴吗啡攀登试验(ACT)所证实的那样,本发明的二苯亚甲基哌啶衍生物是具有很强抑制精神活性的多巴胺受体拮抗剂。多巴胺受体拮抗剂抑制由多巴胺激动剂如阿朴吗啡引起的啮齿动物行为效果的作用是一个已建立完善的预测这些药物在人体中的抗精神病功效的判断标准(参见例如W.C.Bowman和M.J.Rand,Text-book of Pharmacology,2nd ed.,1980,15,6)。在这方面一个特别相关的试验是ACT,它测定了多巴胺拮抗剂抑制由皮下注射阿朴吗啡引起的小鼠攀登行为的作用。在这项试验中的作用已被广泛用作抗精神病作用即抗精神分裂症作用的预测值(参见例如J.T.Strupczewski.等人,J.Med.Chem.,1995,38,1119)。
将本发明的化合物(表目1和2)与根据USP4,540,780的各种相关二苯亚甲基哌啶衍生物(表目3-15)相比,结果示于下表中:表I
Entry | R1 | m | X | Y | n | R2 | ACT(sc) |
本发明 | |||||||
1 | F | 3 | O | C | 1 | H | 0.5 |
2 | F | 3 | O | C | 2 | H | 0.5 |
根据US 4,540,780的化合物 | |||||||
3 | H | 3 | O | C | 1 | H | 2.1 |
4 | H | 3 | O | C | 2 | H | 1.1 |
5 | F | 4 | O | C | 1 | H | 3.7 |
6 | H | 2 | O | C | 2 | H | >22 |
7 | H | 4 | O | C | 2 | H | 3.6 |
8 | H | 5 | O | C | 2 | H | 7.4 |
9 | H | 3 | O | O | 2 | H | 5 |
10 | F | 3 | O | C | 2 | OH | 6.8 |
11 | H | 4 | O | C | 2 | (CH3)2 | >22 |
12 | H | 3 | O | C | 2 | (CH3)2 | >22 |
13 | F | 3 | H2 | C | 2 | H | >22 |
14 | H | 3 | H2 | C | 1 | H | >22 |
15 | H | 3 | H2 | C | 2 | H | >22 |
皮下给药后活性最高的表I的五种化合物经口服给药进行了ACT试验。结果示于表II。表II
表目 | ACT(皮下) | ACT(口服) |
12 | 0.50.5 | 2.81.4 |
347 | 2.11.13.6 | 472233.8 |
表II的结果表明,与根据USP4,540,780的二苯亚甲基哌啶衍生物相比本发明的化合物具有较好的口服活性。另外,随后所要求的化合物没有表现出强直性昏厥现象,这预示了它们没有不希望的锥体束外的副作用。
可以用本领域中已知的方法制备本发明的化合物,例如用与USP4,540,780公开的制备方法类似的方法。
适宜的生产方法是将4-双-(2-,3-,或4-氟苯基)亚甲基哌啶或其盐(例如盐酸盐),USP4,540,780公开了其合成方法,与1-(4-卤-1-氧代丁基)吡咯烷(n=1)或1-(4-卤-1-氧代丁基)哌啶(n=2)相缩合,其中卤是适宜的卤素原子如氯、溴或碘,然后将获得的化合物选择性地转化为药学上可接受的盐。
可以从反应混合物中以药学上可接受的盐的形式分离本发明的新化合物。也可以通过用有机或无机酸处理式I的游离碱来获得药学上可接受的盐,例如用HCl、HBr、HI、H2SO4、H3PO4、乙酸、丙酸、丙醇酸、马来酸、丙二酸、甲磺酸、富马酸、琥珀酸、酒石酸、柠檬酸、苯甲酸、和抗坏血酸。
本发明的化合物可以肠胃道或肠胃外给药,人体优选的每日剂量是每千克体重0.001-1毫克。与药用辅料混合,如标准文献中所述,Gennaro等人,Remington′s Pharmaceutical Sciences,(18th.ed.,Mack Publishing Company,1990,特别参见Par8:PharmaceuticalPreparations and Their Manufacture)化合物可被压成固体剂型,例如丸剂、片剂,或者被加工成胶囊或栓剂。通过药用液体,化合物还可以溶液、悬浮液、乳浊液的形式用作注射剂,或者用作气雾剂,如鼻腔气雾剂。
为了制成剂型,如片剂,考虑使用通常的添加剂如填充剂、着色剂、聚合粘合剂等等。通常可以使用不干扰活性化合物功效的任何药学上可接受的添加剂。可以与组合物一起给药的适宜载体包括乳糖、淀粉、纤维素衍生物等等,或者是它们的混合物,以适当数量使用。
具体实施方式
通过下面的实施例进一步阐述本发明。
实施例11-(三苯甲基)-4-哌啶羧酸乙酯的制备
将异哌啶甲酸乙酯(25g;0.165mol)在二氯甲烷(250ml)和三乙胺(50ml)中的溶液于水浴中冷却并分批加入三苯甲基氯(48.7g;0.175mol)。加入完毕后立即产生沉淀。将混合物在室温搅拌24小时,然后用水洗涤混合物,在硫酸钠上干燥并蒸发至干,得到黄色油状物(74.0g)。用甲基醇研制该油状物,得到乳色结晶状产物,产率97%(61.9g);m.p.164℃。α,α-双-(4-氯苯基-1-(三苯甲基)-4-哌啶甲醇的制备
将1-溴-4-氟代苯(154ml;1.402mol)的无水乙醚(640ml)溶液加入镁旋屑(34.1g;1.404mol)的无水乙醚(250ml)悬浮液中,在使得和缓回流的速率下在氮气中搅拌混合物。使溶液冷却,室温下搅拌45分钟,然后在冰浴中冷却。用40分钟以上的时间,向该溶液中逐滴加入1-(三苯甲基)-4-哌啶羧酸乙酯(90g,0.225mol)于无水四氢呋喃(1.2升)中的溶液。1小时后除去冷浴,使反应在室温放置过夜。然后回流加热反应混合物30分钟,倾入冰水中并将产物萃取到乙酸乙酯中。过滤萃取液除去不溶物,用水洗涤,在硫酸钠上干燥并蒸发生成油状物,将其用热的正己烷研制得到结晶产物(68.0g);m.p.243℃。4-[双-(4-氟苯基)-亚甲基]哌啶盐酸盐的制备
将α,α-双-(4-氟苯基)-1-(三苯甲基)-4-哌啶甲醇(67g;0.123mol)溶于盐酸(1升;2mol/升)中,并将溶液回流加热2小时。将溶液冷却,过滤收集沉淀的固体并悬浮于无水乙醚中。搅拌混合物1小时,过滤并从甲醇/乙醚中结晶固体得到的白色结晶状产物(28.3g);m.p.83℃。1-[4-[4-[双-(4-氟苯基)亚甲基]-1-哌啶基-1-氧代丁基]-吡咯烷盐酸盐的制备
将4-氯丁酰氯(0.68ml;6.07mmol)于无水二氯甲烷(10ml)中的溶液逐滴加入吡咯烷(0.57ml;6.83mmol)和三乙胺(1ml)于无水二氯甲烷(10ml)中的冰冷及搅拌下的溶液中。1小时后加入水,分离二氯甲烷溶液,用水洗涤,在硫酸钠上干燥并蒸发至干,得到1-(4-氯-1-氧丁基)-吡咯烷,将其与4-[双-(4-氟苯基)亚甲基]-哌啶盐酸盐(2.0g;6.2mmol)和碳酸钾(2.15g;15.55mmol)一起溶于二甲基甲酰胺中,将混合物于100℃加热2小时。将溶液倾入水中并用乙醚萃取产物。用水洗涤有机萃取物,在硫酸钠上干燥并蒸发至干,得到桔黄色胶状1-[4-[4-[双-(4-氟苯基)亚甲基]-1-哌啶-1-氧代丁基]-吡咯烷(2.33g)。将该产物溶于甲醇中,加入草酸(0.73g),使溶液结晶,得到1-[4-[4-[双-(4-氟苯基)-亚甲基]-1-哌啶基]-1-氧代丁基]-吡咯烷乙二酸盐。使该物质从甲醇/乙醚中重结晶得到物质(0.85g),其再转化为游离碱并在硅胶上层析。用二氯甲烷/甲醇洗脱得到纯物质,将其溶于乙醚中并用氯化氢气体处理。从甲醇/乙醚中结晶沉淀物,得到1-[4-[4-[双-(4-氟苯基)亚甲基]-1-哌啶-1-氧代丁基]-吡咯烷盐酸盐(0.40g);m.p.107℃。
与此类似,将纯化的游离碱溶于乙醚/甲醇(55/3,体积/体积)中,用甲磺酸(1.05摩尔当量)的乙醚溶液处理搅拌的溶液。产物沉淀为胶状物,其在搅拌下结晶。加入更多的乙醚后过滤固体并干燥,得到1-[4-[4-[双-(4-氟苯基)亚甲基]-1-哌啶基-1-氧代丁基]-吡咯烷甲磺酸盐;m.p.157-158℃。实施例21-[4-[4-[双-(4-氟苯基)亚甲基]-1-哌啶基-1-氧代丁基]哌啶(E)-2-丁二酸(1∶1)盐
在氮气氛下将4-氯丁酰氯的二氯甲烷溶液加入冰冷的哌啶(1.8ml;17.6mmol)与三乙胺(2.5ml)于二氯甲烷(40ml)的溶液中,在冷却下将混合物搅拌5分钟,然后在室温搅拌3小时。将溶液用水洗涤。在硫酸钠上干燥并蒸发得到浅黄色油状1-(4-氯-1-氧代丁基)哌啶(2.1g)。
将按照前面的实施例制备的4-[双(4-氟苯基)-亚甲基]哌啶盐酸盐(3.5g;11mmol)、上面的1-(4-氟-1-氧代丁基)-哌啶(2.1g;11mmol)和碳酸钾(3.3g;24mmol)在二甲基甲酰胺(40ml)中的混合物在80℃加热6小时并将反应混合物倾入水中。用乙醚萃取产物并将萃取液用水洗涤,在硫酸钠上干燥并蒸发得到胶状物,将其在硅胶上层析。用二氯甲烷/甲醇/氨水洗脱,得到游离碱型的产物,将其溶于乙酸乙酯中,并加入富马酸(0.25g)的甲醇溶液。将溶液在5℃下放置直至产生结晶,收集形成的晶体得到产物(0.88g);m.p.145℃。
实施例3小鼠阿朴吗啡攀登试验
经盐酸阿朴吗啡处理后的小鼠倾向于沿丝网筒壁采取竖直位置,站立或攀登。攀登行为被认为是由阿朴吗啡介导的多巴胺受体的激动引起的。许多药物影响攀登行为,但多巴胺拮抗剂通常在剂量上对其抑制而不干扰小鼠的自发运动活动和/或运动协调,调节这一攀登行为的测试化合物可具有抗精神病作用。
将小鼠随机分配进行各种处理。每个试验包括1+n个处理组:
1是对照组,12个小鼠经皮下接受阿朴吗啡和赋形剂,或者对照组的12个小鼠经皮下接受阿朴吗啡而经口腔接受赋形剂;n是(通常为4)化合物组,12个小鼠经皮下接受阿朴吗啡和测试化合物,或者化合物组的12个小鼠经皮下接受阿朴吗啡而经口腔接受测试化合物。
实验分三次进行,每次20只小鼠。
标记小鼠并称重,皮下注射测试化合物或赋形剂并将小鼠放在17×11×13cm的小Macrolon笼中。每笼5只小鼠;或者将测试化合物或赋形剂口腔给药并将小鼠放在29×11×13cm的Macrolon笼中。30分钟后,经已皮下注射赋形剂或测试化合物的小鼠皮下注射0.75mg/kg盐酸阿朴吗啡,或者经口腔给予赋形剂或测试化合物的小鼠皮下注射0.75mg/kg盐酸阿朴吗啡,并将小鼠分别放在丝网筒(直径12cm,高14cm)中。用阿朴吗啡处理后第10分钟观察每只小鼠的攀登行为,并按下列等级评分表示:
4只爪在地上 0分
1或2只爪抓壁 1分
3或4只爪抓壁 2分
用阿朴吗啡处理后第20分钟再次观察攀登行为并评分。
测定每个试验组的每只小鼠平均分数。对照组的分数应至少为1.0;否则,试验作废。每组的最后结果表示为对对照组的百分比。
对本发明测试化合物的试验结果示于表I(皮下注射测试化合物)和表II(口腔给予测试化合物)。
Claims (6)
2.权利要求1的二苯亚甲基哌啶衍生物,其中两个氟原子与苯环的对位相连。
4.含有权利要求1的二苯亚甲基哌啶衍生物和药学上可接受的辅料的药物组合物。
5.权利要求1的二苯亚甲基哌啶衍生物的制备方法,其中将4-双-(2-,3-,或4-氟苯基)亚甲基哌啶或其盐与1-(4-卤-1-氧代丁基)吡咯烷(n=1)或1-(4-卤-1-氧代丁基)-哌啶(n=2)缩合,其中卤为适宜的卤素原子如氯、溴或碘,之后将获得的化合物选择性转化为药学上可接受的盐。
6.权利要求1的二苯亚甲基哌啶衍生物用于生产治疗或预防精神病的药物的用途。
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PL (1) | PL183837B1 (zh) |
PT (1) | PT842170E (zh) |
RU (1) | RU2162846C2 (zh) |
TR (1) | TR199800027T1 (zh) |
TW (1) | TW419477B (zh) |
WO (1) | WO1997003065A1 (zh) |
ZA (1) | ZA965691B (zh) |
Families Citing this family (24)
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US6365604B1 (en) * | 1997-10-07 | 2002-04-02 | Akzo Nobel Nv | Antipsychotic substituted piperidine derivatives |
AU2517499A (en) * | 1998-01-09 | 1999-07-26 | Akzo Nobel N.V. | Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of movement disorders |
WO1999034801A1 (en) * | 1998-01-09 | 1999-07-15 | Akzo Nobel N.V. | Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of depression |
WO2000076513A1 (en) | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | Cyclopentyl modulators of chemokine receptor activity |
US6358979B1 (en) | 1999-06-11 | 2002-03-19 | Merck & Co., Inc. | N-cyclopentyl modulators of chemokine receptor activity |
AU5473400A (en) | 1999-06-11 | 2001-01-02 | Merck & Co., Inc. | Cyclopentyl modulators of chemokine receptor activity |
AU5469400A (en) | 1999-06-11 | 2001-01-02 | Merck & Co., Inc. | Cyclopentyl modulators of chemokine receptor activity |
AU5328500A (en) | 1999-06-11 | 2001-01-02 | Merck & Co., Inc. | N-cyclopentyl modulators of chemokine receptor activity |
WO2000076514A1 (en) | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | Cyclopentyl modulators of chemokine receptor activity |
KR20010113007A (ko) * | 2000-06-15 | 2001-12-24 | 주정호 | 항암제로서 유용한 n-치환된 피페리디닐우레아 유도체 및그의 제조방법 |
TW200303304A (en) * | 2002-02-18 | 2003-09-01 | Astrazeneca Ab | Chemical compounds |
US6770659B2 (en) * | 2002-08-26 | 2004-08-03 | Sk Corporation | Benzoyl piperidine compounds |
BR0316747A (pt) * | 2002-12-18 | 2005-10-18 | Fmc Corp | Piperidinas n-(arilmetil substituìdas)-4-(metil dissubstituìdas) e piperazinas |
SE0400208D0 (sv) * | 2004-02-02 | 2004-02-02 | Astrazeneca Ab | Chemical compounds |
TW200812582A (en) * | 2006-04-06 | 2008-03-16 | Astrazeneca Ab | Medicaments |
CA2958966C (en) | 2014-08-28 | 2020-01-14 | Asceneuron Sa | Substituted cyclic amines as glucosidase inhibitors |
WO2017106254A1 (en) * | 2015-12-18 | 2017-06-22 | Merck Sharp & Dohme Corp. | Glycosidase inhibitors and uses thereof |
US11261183B2 (en) | 2016-02-25 | 2022-03-01 | Asceneuron Sa | Sulfoximine glycosidase inhibitors |
US10696668B2 (en) | 2016-02-25 | 2020-06-30 | Asceneuron Sa | Acid addition salts of piperazine derivatives |
CA3012624A1 (en) | 2016-02-25 | 2017-08-31 | Asceneuron S.A. | Glycosidase inhibitors |
AU2017222958B2 (en) | 2016-02-25 | 2019-07-18 | Asceneuron S. A. | Glycosidase inhibitors |
US11213525B2 (en) | 2017-08-24 | 2022-01-04 | Asceneuron Sa | Linear glycosidase inhibitors |
US11731972B2 (en) | 2018-08-22 | 2023-08-22 | Asceneuron Sa | Spiro compounds as glycosidase inhibitors |
US11795165B2 (en) | 2018-08-22 | 2023-10-24 | Asceneuron Sa | Tetrahydro-benzoazepine glycosidase inhibitors |
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US4540780A (en) * | 1983-06-02 | 1985-09-10 | Warner-Lambert Company | Diphenylmethylene piperidines |
US4666905A (en) * | 1983-06-02 | 1987-05-19 | Warner-Lambert Company | Diphenylmethylene piperidines compositions and methods for their use |
Family Cites Families (1)
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US450780A (en) * | 1891-04-21 | Steam-engine |
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US4180583A (en) * | 1972-01-28 | 1979-12-25 | Richardson-Merrell Inc. | Olefinic 4-substituted piperidino derivatives as therapeutics |
US3922276A (en) * | 1974-12-11 | 1975-11-25 | Robins Co Inc A H | 1-Substituted-4-benzylidenepiperidines |
US4540780A (en) * | 1983-06-02 | 1985-09-10 | Warner-Lambert Company | Diphenylmethylene piperidines |
US4666905A (en) * | 1983-06-02 | 1987-05-19 | Warner-Lambert Company | Diphenylmethylene piperidines compositions and methods for their use |
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