CN101037430B - (-)-美普他酚双配基衍生物和/或其盐类及其制备方法和用途 - Google Patents
(-)-美普他酚双配基衍生物和/或其盐类及其制备方法和用途 Download PDFInfo
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- CN101037430B CN101037430B CN2006100294778A CN200610029477A CN101037430B CN 101037430 B CN101037430 B CN 101037430B CN 2006100294778 A CN2006100294778 A CN 2006100294778A CN 200610029477 A CN200610029477 A CN 200610029477A CN 101037430 B CN101037430 B CN 101037430B
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- meptazinol
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- JLICHNCFTLFZJN-OAHLLOKOSA-N 3-[(3s)-3-ethyl-1-methylazepan-3-yl]phenol Chemical compound C=1C=CC(O)=CC=1[C@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-OAHLLOKOSA-N 0.000 title claims abstract description 32
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- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 abstract description 12
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- MPJUSISYVXABBH-UHFFFAOYSA-N 3-(3-ethyl-1-methylazepan-3-yl)phenol;hydron;chloride Chemical compound Cl.C=1C=CC(O)=CC=1C1(CC)CCCCN(C)C1 MPJUSISYVXABBH-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical group ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 2
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 2
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
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- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AYMUQTNXKPEMLM-UHFFFAOYSA-N 1-bromononane Chemical class CCCCCCCCCBr AYMUQTNXKPEMLM-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- AGQKYUPKNZGEQS-UHFFFAOYSA-N C(C)(=O)OC=C.C(O)(=O)Cl Chemical compound C(C)(=O)OC=C.C(O)(=O)Cl AGQKYUPKNZGEQS-UHFFFAOYSA-N 0.000 description 1
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- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
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- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
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- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
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- 238000001291 vacuum drying Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
本发明属制药领域，涉及光学纯(-)-美普他酚双配基衍生物或其盐类，制备方法及其用途。本发明以(-)-美普他酚为原料，经N-去甲基反应制得(-)-N-去甲基美普他酚，而后由(-)-N-去甲基美普他酚与二酰氯或二卤代烃缩合成为(-)-美普他酚双配基衍生物。经鼠脑乙酰胆碱酯酶抑制活性测试显示，(-)-美普他酚双配基衍生物盐酸盐的活性与(-)-盐酸美普他酚相比有明显的提高，其中(-)-美普他酚双配基衍生物当A为CH2，n为7时活性最强，是(-)-美普他酚的1.10×104倍，有望开发成为治疗指数高、毒副作用小的早老性痴呆治疗药物。
Description
技术领域
本发明属制药领域，涉及光学纯(-)-美普他酚双配基衍生物和/或其盐类及其制备方法和用途。
背景技术
美普他酚(Meptazinol)，分子式C15H23NO，化学名为3-(3-乙基-1-甲基-1H-六氢氮杂卓-3-基)苯酚，是1986年上市的镇痛药物，其镇痛活性与喷他佐辛、度冷丁及右丙氧酚相当，但比吗啡稍弱，与其他阿片类镇痛药相比，其呼吸抑制和成瘾性等副作用极低，故不属“麻药”管理范畴。已知美普他酚可适用于急慢性疼痛，如创伤、术后、产科和癌痛等，特别用于分娩镇痛安全有效，不影响新生儿的健康。上市后临床疗效可靠，于1998年为英国药典收载。
临床上使用的是盐酸美普他酚的外消旋体，有研究，以光学纯的酒石酸或其衍生物为拆分剂，对外消旋美普他酚进行化学拆分获得光学纯美普他酚或其盐类，经毛细管电泳方法确证e.e.值＞99％，左旋体通过单晶X衍射确定了它的绝对构型为(3S)。经小鼠脑乙酰胆碱酯酶抑制活性测定，获得的(-)-美普他酚盐酸盐具备乙酰胆碱酯酶抑制的药理活性，结果表明左旋体或其盐类值得进行乙酰胆碱酯酶抑制剂的开发研究。
乙酰胆碱酯酶抑制剂是目前FDA批准用于治疗早老性痴呆的主要临床药物，能够有效缓解患者的痴呆症状。近几年，根据乙酰胆碱酯酶存在底部(三合一酶催化中心)和口部(外周阴离子位点)两个重要的活性位点的特点，设计和合成了许多活性提高的乙酰胆碱酯酶抑制剂双配基和双功能团衍生物，包括双分子他克林，双分子石杉碱乙等。国内外目前尚未有美普他酚的双配基药物的研究报道。
发明内容
本发明的目的是提供光学纯(-)-美普他酚双配基衍生物和/或其药学上可接受的盐。
本发明的另一目的是提供光学纯(-)-美普他酚双配基衍生物及其盐类的制备方法。
本发明的进一步目的是提供上述光学纯(-)-美普他酚双配基衍生物及其盐类对乙酰胆碱酯酶优良的抑制活性，以及用于早老性痴呆的治疗的用途。
本发明以(-)-美普他酚为活性单元，运用计算机辅助对接方法，设计和合成了(-)-美普他酚双配基衍生物，使便与酶的两个活性部位：催化中心和外周阴离子位点，同时作用，研究双配基链长与活性的构效关系。寻找新的活性更强的乙酰胆碱酯酶抑制剂，以进一步开发成为治疗指数高、毒副作用小的早老性痴呆治疗药物
本发明涉及的(-)-美普他酚双配基衍生物具有(I)的结构通式：
A为C＝O，CH2；n为0～10；
所述盐的酸根可以是无机酸，也可以是有机酸。
本发明采用下述制备方法合成上述(-)-美普他酚双配基衍生物及其盐类，合成路线如(II)所示：
1.(-)-美普他酚去N-甲基的反应：(-)-美普他酚与卤甲酸酯在惰性溶剂中，碱存在下反应制得中间体(-)-N-烷氧甲酰基-N-去甲基美普他酚，然后再通过水解反应制得(-)-N-去甲基美普他酚。
所述惰性溶剂选自四氢呋喃(THF)、氯仿、二氯甲烷、苯、甲苯、N，N-二甲基甲酰胺(DMF)或者上述溶剂的混合物中；所述卤甲酸酯选自氯甲酸乙酯、氯甲酸乙烯酯、氯甲酸苯酯或者氯甲酸三氯乙酯；所述碱选自碳酸氢钾或钠；所述水解反应可以在硫酸水溶液或水合肼溶液或四氢呋喃水溶液条件下进行。
所述惰性溶剂优选氯仿；所述卤甲酸酯优选氯甲酸乙酯；所述碱优选碳酸氢钾；所述水解反应优选50％硫酸水溶液条件下进行。
2.(-)-美普他酚双配基酰胺衍生物(A为C＝O，n为0～10)的制备方法是，(-)-N-去甲基美普他酚在惰性溶剂中，碱的存在下，与二酰卤反应制得。
所述惰性溶剂选自四氢呋喃(THF)、乙醚、氯仿、二氯甲烷、苯、甲苯、N，N-二甲基甲酰胺(DMF)或者上述溶剂的混合物；所述碱选自吡啶、三乙胺、4-二甲氨基吡啶(DMAP)、二异丙基乙胺、碳酸钾或钠、氢氧化钾或钠等。所述二酰卤选自二酰氯、二酰溴等。
所述惰性溶剂优选二氯甲烷；所述碱优选三乙胺；所述二酰卤优选二酰氯。
3.(-)-美普他酚双配基衍生物(A为CH2，n为0～10)的制备方法是，(-)-N-去甲基美普他酚在惰性溶剂中，碱的存在下，与二卤代烷反应制得。
所述惰性溶剂选自乙腈、四氢呋喃(THF)、乙醚、氯仿、二氯甲烷、苯、甲苯、N，N-二甲基甲酰胺(DMF)或者上述溶剂的混合物；所述碱选自吡啶、三乙胺、4-二甲氨基吡啶(DMAP)、二异丙基乙胺、碳酸钾或钠、氢氧化钾或钠等。所述二卤代烷选自二氯代烷、二溴代烷、二碘代烷等。
所述惰性溶剂优选乙腈；所述碱优选三乙胺；所述二酰卤优选二溴代烷。
4.(-)-美普他酚双配基衍生物(A为CH2，n为0～10)的另一制备方法是，由(-)-美普他酚双配基酰胺衍生物(A为C＝O，n＝0～10)在干燥的醚类溶剂中经氢化铝锂还原反应制得。
所述溶剂选自四氢呋喃(THF)、乙醚、1，4-二氧六环等，优选四氢呋喃。
5.所得的(-)-美普他酚双配基衍生物(A为CH2，n为0～10)，与各种无机酸或有机酸成盐制得其盐类。无机酸可以是盐酸、氢溴酸、氢碘酸或硫酸等，有机酸可以是酒石酸、马来酸或富马酸等。
所述美普他酚按照中国专利CN200410017499的方法制备。光学纯(-)-美普他酚根据中国专利CN200610025390.3提供的方法获得。
本发明对合成的(-)-美普他酚双配基衍生物及其盐类的乙酰胆碱酯酶抑制活性进行测试。
AChE抑制活性测试方法：
取大鼠脑组织称重后，加9倍生理盐水制成10％匀浆，3500转/分离心10分钟，取上清液于-20℃保存。根据乙酰胆碱酯酶水解乙酰胆碱，生成胆碱及乙酸，胆碱与琉基显色剂反应生成黄色化合物，比色法检测胆碱数量，从而以水解产物胆碱的数量反映乙酰胆碱酯酶活力的实验原理，按南京建成生物技术有限公司提供的乙酰胆碱酯酶(AChE)试剂盒说明书测定乙酰胆碱酯酶活性。不同浓度待测药与大鼠脑匀浆上清液反应20分钟后测定乙酰胆碱酯酶活性，以计算其抑制乙酰胆碱酯酶的IC50值。
AChE抑制活性测试结果：
(-)-美普他酚盐酸盐对大鼠脑匀浆中乙酰胆碱酯酶的抑制活性IC50＝32.5μM，其(-)-美普他酚双配基衍生物(A＝CH2，n＝0～10)盐酸盐的结果表明，当连接链含碳数＜9时，乙酰胆碱酯酶的抑制活性随着链含碳数的增加而提高，当连接链含碳数＞9时，活性随链含碳数增加而降低，当连接链含碳数＝7时，活性最强。
表1是(-)-美普他酚双配基衍生物(A＝CH2，n＝0～10)对大鼠脑匀浆中乙酰胆碱酯酶的抑制活性。
表1.
经大鼠脑乙酰胆碱酯酶抑制活性实验证实，(-)-美普他酚双配基衍生物对乙酰胆碱酯酶的抑制活性与(-)-盐酸美普他酚相比有很大的提高，有5个化合物活性提高1000倍左右，其中(-)-美普他酚双配基衍生物盐酸盐当A为CH2，n为7时活性最强，IC50为2.94nM，是(-)-盐酸美普他酚的1.1万倍。结果表明，本发明所设计的(-)-美普他酚双配基衍生物是新型的活性很强的乙酰胆碱酯酶抑制剂，有望被开发成为治疗指数高、毒副作用小的早老性痴呆治疗药物。
附图说明
图1是.(-)-美普他酚双配基衍生物(A＝CH2，n＝0～10)对大鼠脑匀浆中乙酰胆碱酯酶的抑制活性与连接链含碳数的构效关系。
具体实施方式
下面用制备实施例进一步说明本发明，但不限制本发明。
实施例1 (-)-N-去甲基美普他酚的制备
(-)美普他酚20.9g(89.70mmol)，KHCO3157g(1.57mol)，氯仿2000ml混合，40℃加入氯甲酸苯酯97ml(0.77mol)，回流反应3hr。放冷，加水1000ml，分液，氯仿层浓缩得浅黄色油状物。油状物溶解在1400ml甲醇中，加入K2CO3138g(1mol)的1000ml水溶液，氮气保护下室温反应18hr。滴加6N HCl(270ml)调节pH至5，减压浓缩蒸去甲醇，加乙醚1200ml、800ml提取，合并醚层，无水Na2SO4干燥。过滤，蒸除溶剂，得棕黄色油状物34g。硅胶柱层析分离，含乙醚-氯仿溶液梯度洗脱，得(-)N-去甲基-N-苯氧甲酰基美普他酚29g，浅黄色油状物，收率95％。
(-)N-去甲基-N-苯氧甲酰基美普他酚22g(64.9mmol)和85％水合肼170ml(2.98mol)混合，N2保护下回流反应4hr。冷却，加水200ml，乙醚600ml，200ml×2提取，合并有机层，无水Na2SO4干燥。过滤，浓缩至干，得棕黄色油状物21g。硅胶柱层析纯化，洗脱剂乙醇-氯仿梯度洗脱，所得(-)-去甲基美普他酚为一白色至黄色油状物6.07g，收率43％。
1HNMR(DMSO-d6)9.42(H，s，OH)，7.16(H，t)，6.74～6.65(3H，m)，3.49(H，d)，3.21(H，d)，3.08～3.00(2H，m)，2.14(H，m)，1.77～1.55(7H，m)，0.49(3H，t)
LC-MS(ESI) 220.1[M+1]+
实施例2 同法可制备化合物(A＝CH2，n＝0～1和4～10)及其盐酸盐
N，N’-(1，9-亚壬基)-双-(-)-N-去甲美普他酚盐酸盐的制备
(-)-N-去甲基美普他酚0.89g(4.06mmol)热溶解在11ml乙腈中，加入三乙胺1.13ml(8.12mmol)，加入1，9-二溴壬烷423μL(2.03mmol)，回流反应2小时。冷却，蒸除溶剂，加饱和碳酸钠溶液10ml，氯仿20ml，10ml×3提取。合并氯仿层，适量无水硫酸钠干燥。过滤，浓缩到干得棕色油状物1.60g，硅胶柱层析分离，洗脱剂(乙酸乙酯∶石油醚＝1∶2)，得浅黄色油状物0.71g，收率62.3％。
上述产物0.67g溶解在20ml无水乙醚中，pH9，过滤，滤液滴加无水HCl-乙醚溶液10.6ml，调节pH至4，析出白色粉末。过滤，少量无水乙醚洗，放入P2O5干燥器真空干燥，放置过夜，得到白色粉末0.62g，收率81.9％，mp.118～124℃，[α]D＝-39.13°(c＝0.32，MeOH)。
1HNMR(DMSO-d6)10.10(brs，1/2H，NH+，重水交换消失)，9.95(brs，1/2H，NH+，重水交换消失)，9.56～9.44(m，2H，Ar-OH，重水交换消失)，8.41(brs，1/2H，NH+，重水交换消失)，8.34(brs，1/2H，NH+，重水交换消失)，7.19～7.11(m，2H，Ar-H)，6.84～6.64(m，6H，Ar-H)，3.82(d，H，J＝14.09Hz，N-CH2)，3.53(d，H，J＝13.7Hz，N-CH2)，3.38～3.27(m，3H，N-CH2)，3.15～3.04(m，7H，N-CH2)，2.38～2.32(m，H，CH2)，2.10～2.01(m，3H，CH2)，1.79～1.70(m，12H，CH2)，1.54～1.27(m，14H，CH2)，0.47(t，6H，CH3)
LC-MS(ESI) [M+1]+563.5；[M+2]2+282.3
实施例3 N，N’-(1，4-丁二酰基)-双-(-)-N-去甲美普他酚的制备
(-)-N-去甲基美普他酚1.45g(6.63mmol)溶解在25ml无水二氯甲烷中，加无水三乙胺1.84ml(12.23mmol)。冰盐浴冷却下，缓慢滴加丁二酰氯382μL(3.30mmol)的10ml无水二氯甲烷溶液，温度控制在～0℃。滴加完毕，0℃搅拌15分钟。用水5ml、2N HCl 5ml和水5ml洗涤。水层合并，用二氯甲烷10ml×3提取，合并二氯甲烷层，适量无水硫酸钠干燥。过滤，蒸除溶剂得到墨绿色泡沫1.85g，硅胶柱层析，石油醚-乙酸乙酯剃度洗脱，得到产品为浅黄颗粒晶0.73g，收率41.4％，mp 117～120℃。
1HNMR(DMSO-d6)8.79(s，2H，Ar-OH，重水交换消失)，7.19(t，2H，Ar-H)，6.78～6.70(m，6H，Ar-H)，4.88(d，2H，J＝14.66Hz，N-CH2)，3.59(m，2H，J1＝11.73Hz，J2＝6.23Hz，N-CH2)，3.08(d，2H，J＝15.03Hz，N-CH2)，2.91(t，2H，J＝11.73Hz，N-CH2)，2.83(d，2H，J＝13.56Hz，N-CH2)，2.39(dm，2H，J＝7.7Hz，CH2)，2.33(d，2H，J＝13.2Hz，N-CH2)，1.82～1.48(m，14H，CH2)，0.68(t，6H，J＝7.33Hz，CH3)
LC-MS(ESI) [M+1]+ 521.3
实施例4 N，N’-(1，4-亚丁基)-双-(-)-N-去甲美普他酚盐酸盐的制备
在无水THF15ml中加入LiAlH4粉末0.20g(5.26mmol)，冰水浴冷却下，缓慢滴入N，N’-(1，4-丁二酰基)-双-(-)-N-去甲基美普他酚0.56g(1.08mmol)的15ml无水THF溶液，回流反应1hr。冷却，依次滴加0.28ml水的3ml THF溶液、15％ NaOH溶液0.28ml、水0.84ml。过滤，滤液浓缩到干，加水15ml，氯仿30ml，滴加10％ NH4Cl水溶液1.5ml，调节pH≈9。水层用氯仿10ml×4提取，合并有机层，适量无水硫酸钠干燥。过滤，蒸除溶剂得橙色油状物0.55g，硅胶柱层析(洗脱剂甲醇∶氯仿)纯化得橙色油状产品0.19g，收率35.8％。
N，N’-(1，4-亚丁基)-双-(-)-(N-去甲基美普他酚)0.19g加无水乙醚20ml溶解，滴加无水HCl-乙醚溶液2.2ml，析出类白色粉末。过滤，少量无水乙醚洗，P2O5干燥器真空干燥过夜，得盐酸盐0.12g，收率55％，mp.110～115℃，[α]D＝-51.96°(c＝0.092，MeOH)。
1HNMR(DMSO-d6)9.98(brs，1/2H，NH+，重水交换消失)，9.77(brs，1/2H，NH+，重水交换消失)，9.56-9.43(m，2H，Ar-OH，重水交换消失)，8.46(brs，1H，NH+，重水交换消失)，7.21-7.13(m，2H，Ar-H)，6.85-6.65(m，6H，Ar-H)，3.83(t，H，J＝13.3Hz，N-CH2)，3.52(t，H，J＝13.7，N-CH2)，3.36-3.15(m，10H，N-CH2)，2.38(m，H，CH2)，2.10-1.46(m，19H，CH2)，0.49(t，6H，CH3)
LC-MS(ESI)[M+1]+ 493.3 [M+2]2+ 247.2
Claims (3)
1.具有如下的结构通式的(-)-美普他酚双配基衍生物和/或其盐类在制备治疗早老性痴呆症药物中的用途：
其中：A为CH2，n＝6、7、8、9或10；
所述盐是无机酸盐或有机酸盐。
2.按权利要求1所述的用途，其特征在于，n＝7。
3.按权利要求1或2所述的用途，其特征在于，所述盐是盐酸盐。
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| CN102617471B (zh) * | 2011-01-31 | 2014-07-09 | 复旦大学 | 左旋美普他酚双分子衍生物和/或其盐及其制备方法和用途 |
| CN102816151B (zh) * | 2011-06-09 | 2014-09-17 | 上海市计划生育科学研究所 | 左旋美普他酚衍生物、其制备方法和其制药用途 |
| CN105622509B (zh) * | 2014-11-06 | 2017-12-29 | 复旦大学 | 左旋美普他酚茚酮衍生物和/或其盐类及其制备方法和用途 |
| CN106316954B (zh) * | 2015-06-24 | 2018-11-20 | 上海市计划生育科学研究所 | 制备光学纯(+)-或(－)-n-去甲基美普他酚的方法 |
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| CN1569839A (zh) * | 2004-05-14 | 2005-01-26 | 复旦大学 | 美普他酚前体药物和盐类及其制备方法 |
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| GB1495778A (en) * | 1975-06-18 | 1977-12-21 | Wyeth John & Brother Ltd | Hexahydroazepines |
| US4242346A (en) * | 1979-12-19 | 1980-12-30 | Smithkline Corporation | Bis-2N-alkylene tetrahydroisoquinoline compounds |
| US20030119060A1 (en) * | 2001-08-10 | 2003-06-26 | Desrosiers Peter J. | Apparatuses and methods for creating and testing pre-formulations and systems for same |
| CN1271057C (zh) | 2004-04-07 | 2006-08-23 | 复旦大学 | 一种制备1－甲基－3－乙基－3－(3－羟基苯基)－六氢－1h－氮杂䓬盐酸盐的方法 |
| CN1984910A (zh) * | 2004-07-16 | 2007-06-20 | 詹森药业有限公司 | 适用于神经变性疾病治疗的哌啶、哌嗪或者吗啉或它们的7元类似物的二聚化合物 |
| CN1850804B (zh) | 2006-03-31 | 2011-02-16 | 复旦大学 | 光学纯美普他酚或其盐类及其制备方法 |
| CN1974558B (zh) * | 2006-12-20 | 2011-07-27 | 复旦大学 | (+)-美普他酚双配基衍生物或/和其盐类及其制备方法 |
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| CN1569839A (zh) * | 2004-05-14 | 2005-01-26 | 复旦大学 | 美普他酚前体药物和盐类及其制备方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2008019572A1 (en) | 2008-02-21 |
| EP2048134A4 (en) | 2010-11-17 |
| EP2048134A1 (en) | 2009-04-15 |
| US8232270B2 (en) | 2012-07-31 |
| CN101037430A (zh) | 2007-09-19 |
| JP2009544633A (ja) | 2009-12-17 |
| JP5118696B2 (ja) | 2013-01-16 |
| EP2048134B1 (en) | 2015-09-23 |
| US20100035861A1 (en) | 2010-02-11 |
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