CN1213372A - 杂环稠合的吗啡类衍生物(ⅱ) - Google Patents
杂环稠合的吗啡类衍生物(ⅱ) Download PDFInfo
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- CN1213372A CN1213372A CN97192879A CN97192879A CN1213372A CN 1213372 A CN1213372 A CN 1213372A CN 97192879 A CN97192879 A CN 97192879A CN 97192879 A CN97192879 A CN 97192879A CN 1213372 A CN1213372 A CN 1213372A
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Abstract
取代的式(Ⅰ)单杂环稠合吗啡类衍生物是强效及选择性的δ阿片激动剂及拮抗剂,并具有麻醉剂及用于治疗通常可用δ阿片受体激动剂及拮抗剂治疗的病理病症的作用,其中n=0或1,X、Y、R1-R8如本申请中所定义。
Description
本发明涉及新的吗啡类化合物,其制备方法及其医药方面的用途。
至少三类阿片受体(μ、δ和κ)的存在是公知的并见于文献报道,并且全部三类受体似乎存在于许多动物包括人类的中枢及外周神经系统中(Lord J.A.H.等,Nature 1997,267,495)。
全部三类阿片受体亚型的激活可导致动物模型的无痛觉感。特别是,肽的δ激动剂的研究显示δ受体的激活可导致啮齿类、灵长类动物的无痛觉感,并可诱导人的临床麻醉(D.E.Moulin等,Pain,1985,23,213)。已有证据提示对于δ激动剂的较少嗜好可产生通常伴随μ和κ激活的副作用(Galligan等,J.Pharm.Exp.Ther.,1984,229,641)。
US 5223507及US 5225417(G.D.Searle&Co.)公开了双环稠合的吗啡类化合物,据认为它是具有作为麻醉剂治疗用途的δ阿片激动剂。
WO 94/07896(Toray Ind.Inc.)公开了用作免疫抑制剂,抗过敏及抗炎剂的吲哚稠合的吗啡类化合物。
现在我们已经发现一类新的取代单杂环稠合吗啡类衍生物,由于其为强效的和选择性δ阿片激动剂和拮抗剂,因而具有作为麻醉剂、防止器官移植及皮肤移植时排斥反应的免疫抑制剂、抗过敏及抗炎剂、脑细胞保护剂、治疗药物及酒精滥用、胃炎、腹泄、心血管及呼吸道疾病、咳漱、精神病及癫痫的药物,一句话治疗那些通常可用δ阿片受体激动剂及拮抗剂治疗的病理性病症的药物,因而具有潜在的治疗用途。
根据本发明提供了式(Ⅰ)化合物,或其溶剂化物或盐,所述式(Ⅰ)如下:其中,R1为氢、直链或支链C1-6烷基、C3-7环烷基、C4-6环烷基烷基,后三个基团中的每一个任选由羟基(当C≥2时)、C3-5链烯基、芳基、芳烷基或呋喃-2或3-基烷基或(CH2)mCOR(其中m是0-5及R为直链或支链C1-6烷基、羟基、C1-5烷氧基、OC3-6链烯基或烷基芳基)、NR10R11(其中R10和R11可以相同或不同,并且每一个为氢、直链或支链C1-6烷基、C4-6环烷基烷基、C3-5链烯基、芳基或芳烷基)取代;或者R1为A-B基团,其中A表示C1-10亚烷基及B表示取代的或未取代的芳基或杂芳基;R2为氢、羟基或C1-5烷氧基(优选甲氧基)、卤素、硝基、NR10R11、SR10,其中R10及R11的定义同上述,此外R10是COR1,优选乙酰基;R3为氢、直链或支链C1-6烷基(优选乙基)、羟基、C1-5烷氧基(优选甲氧基)、卤素(优选溴)或(CH2)mCOR(其中m和R的定义同上)、SR10、硝基、NR10R11、NHCOR10、NHSO2R10(其中R10及R11的定义同上述,优选氢或甲基);R4和R5可以相同或不同,各自独立为氢、羟基、C1-5烷氧基(优选甲氧基、O-苯氧基)或可一起形成氧基团(-O-);或R4与R3一起形成亚甲基二氧基团(-OCH2O-);R6为基团:或含有多至三个杂原子如O、S及N并由具有上述定义的R3取代的五或六元杂芳基团,该环上有多至3个R3基团,或者R6为C(Z)R12基团,其中Z是氧或硫,R12是直链或支链的C1-18烷基、羟基、直链或支链C1-18烷氧基、芳烷氧基或NR13R14,其中R13及R14(可以相同或不同)为氢、直链或支链的C1-6烷基、C3-7环烷基、C4-6环烷基烷基,后三个基团中的每一个任选由多至三个氟原子或羟基团(C≥2)、C3-6链烯基、芳基、芳烷基或任选取代的杂环取代或R13及R14可以一起形成可插入氧或NR1的C3-6烷环,其中R1的定义同上;或R6是CH2WA基团,其中W是氧、硫或NR14,及A是氢、直链或支链的烷基或COR14(其中R14的定义如上且优选为甲基);或R6为COCOR12基团,其中R12具有与上相同的定义并优选为C1-18烷氧基;或R6为NR13R14基团,其中R13和R14具有与上相同的定义,或R13可以为(CH2)mCOR基团,其中m和R具有与上相同的定义;或R6为P(Z)R12基团,其中Z和R12具有与上相同的定义,以及优选Z=O和R12=C1-18烷氧基;或R6为S(O)iR12基团,其中i=1,2及R12具有与上相同的定义。R7为氢、C1-18烷基、C2-18链烯基、卤素、卤代-C1-6烷基、(CH2)mCOR其中m和R具有与上相同的定义或为基团:或含有多至三个杂原子如O、S及N并由具有上述定义的R3取代的五或六元杂芳基团;R8为氢、C1-6烷基,优选甲基;n是0或1;当n=0时,X和Y独立为氧、硫、CH或R6-或R7-取代的碳原子、及NR9(其中所述R9为氢、直链或支链的C1-6烷基、C3-7环烷基、C4-6环烷基烷基,其中后三个基团中的每一个任选由羟基取代(当C≥2时),或可含有NR10R11基团,其中所述R10及R11具有与上相同的定义)、C3-5链烯基、芳基、芳烷基、或(CH2)mCOR(其中m是0-5及R代表羟基、C1-5烷氧基、OC3-6链烯基或烷基芳基、NR10R11,其中R10和R11(可以相同或不同)为氢、直链或支链的C1-6烷基、C4-6环烷基烷基);及当n=1时,则X和Y均为N,或N和CH。当R1是芳基时,优选为苯基,当其为芳烷基时,优选为苯基-C1-6烷基。R1的实施例为氢、甲基、乙基、丙基、异丙基、烯丙基、苄基、苯基-乙基、CH2CH2OH、CH2COOH、CH2COOEt、CH2CONH2及COMe。R2的实施例为氢、羟基及甲氧基。R3的实施例为氢、羟基、乙基、溴、羟基、甲氧基、乙氧基、异丙氧基、COMe及OCH2COOH。R4和R5的实施例为氢、羟基、乙酰氧基、甲氧基、O-苯基、一起作为氧基或R4与R3一起为亚甲基二氧基。R6的实施例为CONH2、CONMe2、CONEt2、CON(i-Pr)2、CON(i-Pr)CH2Ph、CON(i-Pr)(CH2)2OH、CON(CH2CF3)(i-Pr)、COOMe、COOEt、COO-n-Pr、COO-i-Pr、及COO-i-Bu、COOCH(i-Pr)2、CSNEt2、CSN(i-Pr)2、COOH、COMe、CO-i-Pr、CO-i-Bu、CO-t-Bu、CO-3-戊基、COPh、及PO(OEt)2。R7的实施例为甲基、异丙基、三氟甲基、CH2COOH及CH2COOEt。R8的实施例为氢。R9的实施例为氢、甲基、CH2COOH、CH2COOEt、CH2CONHCH2Ph、CH2CONHMe、CH2CONMe2。X的实施例为NR9,其中R9与上述实施例相同,及S。Y的实施例为CR7,其中R7与上述实施例相同。优选的式(Ⅰ)化合物的基团是其中n=0,X是NH及Y是CH或R6-或R7取代的碳原子,其中R6是-C(Z)-R12基团(其中R12是C1-6烷基、C1- 4烷氧基)或NR13R14,其中R13及R14的定义同上及Z是氧;R7是甲基或卤代-C1-2烷基。
特别优选的式(Ⅰ)化合物为其中R6是CONEt2、CON(i-Pr)2或COO-i-Bu,R7是甲基,及R9是氢、甲基或CH2COOH。
式(Ⅰ)化合物或其盐或溶剂化物优选为药学可接受的或基本上纯的形式。药学可接受的形式特别是指不包括常规药用添加剂例如稀释剂及载体的药学可接受的浓度或纯度,也不包括在常规剂量下有毒的物质。
基本上纯的形式一般含有至少50%(不包括常规药用添加剂),优选75%,更优选90%及最优选95%的式(Ⅰ)化合物或其盐或溶剂化物。
一种优选的药学可接受的形式为结晶形式,包括此种形式的药用组合物。在盐及溶剂化物的情况下加入的离子及溶剂部分也必须是无毒的。
式(Ⅰ)化合物药学可接受的盐的实施例包括用常规药用酸的酸加成盐,所用常规酸例如,马来酸、盐酸、氢溴酸、磷酸、乙酸、富马酸、水杨酸、柠檬酸、乳酸、扁桃酸、酒石酸、琥珀酸、苯甲酸、抗坏血酸及甲磺酸。
式(Ⅰ)化合物可以多于一种的立体异构形式存在,本发明扩展至全部此类形式及其混合物,包括外消旋体。
本发明也提供了制备式(Ⅰ)化合物或其溶剂化物或盐的制备方法,包括式(a)化合物与式(b)化合物缩合,及然后使式(Ⅰ)化合物任选转变成其盐或溶剂化物。所述式(a)及式(b)化合物如下:其中,式(a)中,K为H、Br、COR7、=CHOH或=NOH;式(b)中,Q为COR7、CHClR7、COR7、SH或NH2,及J是=NNHPh、=O、=H2或=CHR7,其中R7及R6具有与上述相同的定义。当K=H、Q=COR7及J==NNHPh时,优选的反应条件是于60-100℃的温度范围内在AcONa存在下的AcOH/Zn。当K=COR7、Q=SH及J==H2时,优选的反应条件是ⅰ)于RT下在醇介质中的干燥HCl,ⅱ)强碱,例如MeONa在MeOH中。当K=H、Q=CHClR7及J==O时,优选的反应条件是NaH在THF中。
式(Ⅰ)化合物或其盐或溶剂化物可以通过下述一般反应图式介绍的方法或通过其改进的方法,使用容易得到的原料、试剂及常规合成步骤制备。如果期望获得本发明的特定对映体,可从所需对映体原料开始及进行不包括消旋化过程的反应合成,或可由手性合成或由手性辅助剂的衍生化制备,其中所得的非对映体混合物可被分离并可通过裂解其辅助基团以得到纯的所需对映体。此外,当分子中含有碱性官能基例如氨基或酸性官能基例如羧基时,使用合适的旋光酸或旋光碱生成非对映异构体盐,然后经分级结晶拆分非对映异构体盐及随后回收纯的对映体。
式(Ⅰ)化合物(其中n=0,X=NH及Y为R7-取代的碳原子)可如图式1所述由式(Ⅱ)酮与式(Ⅲ)腙起始(Organic Reactions,1959,3-142),在Zn及CH3COONa存在下,以CH3COOH为溶剂(Khimiya Geterot.Soed.,1972,342)而得到:
流程1式(Ⅰ)化合物(其中n=0,X=NH及Y为R6取代的碳原子)可如图式2所述由式(Ⅳ)(J.Org.Chem,1964,29,3459)卤代酮与式(Ⅴ)酮(Can.J.Chem.,1970,48,1689)在NH4OH存在下环化得到:
流程2式(Ⅰ)化合物(其中n=0,X=O及Y为R7取代的碳原子)可如图式3所述由式(Ⅱ)酮与式(Ⅵ)α-卤代酮(优选α-氯代酮)在碱(J.Org.Chem.,1984,49,2317)存在下环化得到:
流程3式(Ⅰ)化合物(其中n=0,X=O及Y为R6取代的碳原子)可如图式4所述由式(Ⅳ)溴代酮与式(Ⅴ)酮于醇中在碱(优选EtONa)存在下环化(J.Chem.Soc.PerkinI,1972,2372)得到:
流程4式(Ⅰ)化合物(其中n=0,X=S及Y为R7取代的碳原子)可如图式5所述由通式(Ⅶ)β-二酮(由酮(Ⅱ)和式R7-COOEt的酯起始经Claisen反应合成;J.Am.Chem.Soc.,1945,67,1510;J.Med.Chem.1982,25,983)与式(Ⅷ)巯基衍生物在HCl存在下制备(DE1,088,507;C.A.,1962,56,456;Synthesis,1992,526):
流程5式(Ⅰ)化合物(其中n=0,Y=S及X为R6取代的碳原子)可如图式6所述通过α-巯基酮(Ⅸ)(由溴代酮(Ⅳ)和H2S/KOH起始制备,J.Am.Chem.Soc.,1985,107,4175)与式(Ⅹ)炔衍生物,在溶剂如DMSO中,在碱如t-BuOK存在下反应(Chem Ber.,1964,97,2109)得到:
流程6式(Ⅰ)化合物(其中n=0,X及Y均为N)可如图式7所述由肟基衍生物(ⅩⅤ)及式(ⅩⅥ)R6-R7-取代的亚胺氯(imidoyl chlorides)在碱性介质中,接着用在回流甲苯中的H+处理中间产物(J.Org.Chem.,1993,58,7092)而得到:
流程7式(Ⅰ)化合物(其中n=1,X=N及Y=CH)可如图式8所述由羟基亚甲基酮(Ⅺ)(由酮(Ⅱ)与HCOOEt在碱存在下缩合制备;Org.Synth.Coll.,1963,4,536)与烯胺(Ⅻ)反应(J.Ind.Chem.Soc.,1935,12,289)得到:
流程8式(Ⅰ)化合物(其中n=1,X=Y=N)可如图式9所述由羟基亚胺酮(ⅩⅢ)(由酮(Ⅱ)与亚硝酸异戊酯/t-BuOK按J.Med.Chem.,1991,34,1715所述的方法制得)与乙二胺(ⅩⅣ)起始,并接着对在碱性介质中使中间体芳香化(Chem.Ber.,1967,100,555)而得到:
流程9式(Ⅰ’)化合物(其中n=0,X=NH及Y为R6-或R7-取代的碳原子)可如一般图式10所述通过使用烷基化试剂R9Br在DMF中的NaH存在下转化成通式(Ⅰ)的其它化合物(其中吡咯氮由R9基团取代):
通式(Ⅰ’)化合物(其中R4=OH及R5=H)可如图式11所述按照上述图式所述由已知的式(Ⅱ)酮或(作为另一种选择)由通式(Ⅰ)化合物(其中R4及R5一起形成氧基团(-O-))经与Zn在沸腾MeOH/HCl或沸腾AcOH中反应制得:
流程11式(Ⅰ)化合物(其中n=0、X=S及Y=N,R6为NR13R14,其中R13是(CH2)mCOR基团(m=0)及R14是氢)可如图式12所述由溴代酮(Ⅳ)在碱存在下(优选Na2CO3)与在异丙醇中的硫脲环合(J.Chem.Soc.,1945,455),接着使所得的胺与合适的酰基氯或与相应的羧酸在偶合剂如DCC存在下酰化得到:
通式(Ⅰ)化合物(其中R6为C(Z)R12基团(其中Z是硫))可由化合物(其中Z为氧)经与硫杂化剂例如Lawesson试剂反应制得。
通式(Ⅰ)化合物(其中R6为CH2WA)可由通式(Ⅰ)化合物经文献中公知的R6基团如酯酰胺、硫代酰胺(tioamides)的常规化学反应制得。
通式(Ⅰ)化合物可与合适的有机或无机酸反应而转变成其药学上可接受的盐。
式(Ⅰ)化合物的溶剂化物可通过在合适的溶剂中结晶或重结晶生成。例如,水合物可通过在水溶液,或含水有机溶剂的溶液的结晶或重结晶生成。
非药学上可接受的式(Ⅰ)化合物的盐或溶剂化物可用于生产药学上可接受的盐或溶剂化物的中间体。因而这样的盐或溶剂化物也成为本发明的一部分。
一般来说,可作为选择性δ受体配体的式(Ⅰ)化合物可以用作麻醉剂、预防器官移植及皮肤移植排斥反应的免疫抑制剂、抗过敏及抗炎剂、脑细胞保护剂、治疗药物及酒精滥用、减少胃分泌、用于腹泄、心血管及呼吸道疾病、咳漱和呼吸抑制、精神病及癫痫发作及其它神经紊乱(此后称作‘病症’)的药物。特别是在标准试验中作为δ激动剂的式(Ⅰ)化合物的活性显示它们具有作为改善或消除疼痛的麻醉剂的潜在的治疗用途。
按照本发明也可提供用作活性治疗物质的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物。
按照本发明进一步提供包括式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物,及药学上可接受的载体的药用组合物。
本发明也提供式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物在用于治疗所述病症的药品的生产中的用途。
此种药品及本发明的组合物可以通过本发明化合物与适当的载体混合制得。它可以包含常规形式的稀释剂、粘合剂、填充剂、崩解剂、调味剂、着色剂、润滑剂或防腐剂。
这些常规赋形剂可以用于例如在治疗所述病症的已知药物的组合物的制备中。
优选本发明的药用组合物为单位剂量形式及应用于医学或兽医学领域所采用的形式。例如,此种制剂可以是附有用作治疗所述病症药物的文字印刷说明书的包装形式。
本发明化合物的合适剂量范围取决于所用的化合物及患者的病情。特别是也取决于药效与吸收性的关系及给药的次数及途径。
本发明化合物或组合物可配制成任何途径给药的制剂形式,优选单一剂型或者是病人可以单一剂量自己服用的形式。有利的是,所述组合物适于口服、直肠、局部、胃肠外、静脉或肌肉内给药。制剂可设计成缓慢释放有效成分的形式。
组合物可为例如片剂、胶囊、香囊剂(sachets)、小瓶剂(vials)、粉剂、颗粒剂、锭剂、可复制的粉剂,或液体制剂,例如溶液或悬浮液,或栓剂。
所述组合物例如适于口服的组合物可含有常规赋形剂诸如粘合剂例如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶,或聚乙烯吡咯烷酮;填充剂例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘油;制片润滑剂例如硬脂酸镁;崩解剂例如淀粉、聚乙烯吡咯烷酮、淀粉甘醇酸钠或微晶纤维素;或药学上可接受的凝固剂例如十二烷基硫酸钠。
固体制剂可通过混合、填充、制片等常规方法得到。反复混合操作可使活性试剂分散至应用大量添加剂的组合物中。当所述组合物是片剂、粉剂或锭剂时,可以使用任何适于配制固体药用组合物的载体,实例如硬脂酸镁、淀粉、葡萄糖、乳糖、蔗糖、米粉及白垩粉。片剂可以按照常规药用实践中公知的方法包衣,特别是包肠溶衣。所述组合物可为易吸收的胶囊的形式例如包含所述化合物的明胶的形式,如果需要,还含有载体或其它赋形剂。
用于口服的组合物如液体可为,例如乳剂、糖浆或酏剂的形式,或可作为使用前用水或其它合适的溶媒重新组合的干燥产物存在。此种液体组合物可含有常规添加剂诸如悬浮剂例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化食用脂肪;乳化剂例如卵磷脂、脱水山梨醇单油酸酯,或阿拉伯胶;水的或非水溶媒包括食用油例如杏仁油、精馏椰子油、油酯例如甘油酯,或丙烯乙二醇、或乙醇、甘油、水或常规盐水;防腐剂例如对羟基苯甲酸甲酯或丙酯或山梨酸;及如果需要还可含有常规的调味剂或着色剂。
本发明化合物也可以通过非口服途径给药。按照常规药用方法,所述组合物可制成例如作为栓剂用于直肠给药。它们也可以配制成在水的或非水溶液中,在药学上可接受的液体如灭菌的无热原水或胃肠道外可接受的油或液体混合物的悬浮液或乳液中的可注射形式。所述液体可含有抑菌剂、抗氧剂或其它防腐剂、提供使所述溶液与血液等渗的缓冲剂或溶质、增稠剂、悬浮剂或其它药学上可接受的添加剂。此种形式将以单位剂量形式如安瓿或一次性的注射装置或以多剂量形式如可以抽出合适剂量的瓶或可以用于制备注射剂型的固体形式或浓缩物形式存在。
本发明化合物也可以通过鼻或口的途径吸入给药。此种给药可通过使用包括优选悬浮于例如烃抛射剂中的本发明化合物及合适的载体的喷雾制剂进行。
优选的喷雾制剂包括微米化的化合物粒子与表面剂、溶剂或防止悬浮粒子沉降的分散剂的结合。优选所述化合物的粒度为2-10微米。
本发明化合物给药的另外的形式包括利用皮肤膏贴制剂的透皮传递。优选的制剂包括使本发明化合物分散于粘附于皮肤的压力敏感的胶粘剂中,进而使所述化合物由所述胶粘剂通过皮肤扩散传递至患者。为了获得经皮吸收的稳定速率,可以使用本领域中已知的压力敏感的胶粘剂如天然橡胶或硅氧烷。
如上所述,所述化合物的有效剂量取决于所用的特定化合物,患者的病情及给药的次数及途径。一般单位剂量为20-1000mg,优选30-50mg,特别优选50、100、150、200、250、300、350、400、450或500mg。所述组合物可以一天给药一次或多次,例如每天2、3或4次,对于70kg的成人,全部的日剂量通常为100-3000mg。此外单位剂量也可含有2-20mg的活性成分并且(如果需要)可多次给药以达到上述日剂量。
当按照本发明给药时,期望本发明的化合物没有毒性作用。
本发明也提供治疗和/或预防脯乳动物,特别是人类的所述病症的方法,其包括给予需要此种治疗和/或预防的脯乳动物以有效量的式(Ⅰ)化合物或其药学上可接受的盐或溶剂化物。
作为选择性δ配体的本发明化合物的活性由下述放射配体结合分析确定。
小鼠脑膜由Kosterlitz所述的方法制得(Br.J Pharmacol.,1981,73,939.)。优选的δ配体[3H]-[D-Ala2,D-Leu5]-脑腓肽(DADLE)以在40nM未标记的μ配体[D-Ala2,MePhe4,Gly-ol5]脑腓肽(DAMGO)存在下的KD浓度(1.3nM)进行评估。所述μ配体[3H]-DAMGO(Eur.J.Pharmacol.,1989,166,213)的结合及κ配体[3H]-U69593(Excerpta Medica,1990,211)的结合以0.5nM进行。非特异结合是在纳络酮(10μm)存在下对全部氚化的配体测得的。结合常数表示为抑制百分数并符合下述方程:f(x)=100·X/(IC50+X),其中X为cold drug浓度值。所得的IC50用于按照Cheng和Prusoff关系(relation)计算抑制常数(Ki)(Biochem.Pharmcol,1973,22,3099)。
本发明化合物δ激动剂/拮抗剂活性以如下述的在NG108-15细胞系中的cAMP生物分析法测定。
使NG108-15细胞于37℃在5%CO2及95%空气的潮湿气氛中在补充有含2mM谷氨酰胺,2%HATx50添加物,50ug链霉素和50I.U.青霉素/ml的胎牛血清的DMEM(使用无丙酮酸钠的4500mg/l葡萄糖)中生长,并用在无Ca/Mg磷酸盐缓冲盐水中的机械搅拌的1MEDTA收获融合的细胞。每两天换一次培养基在实验前一天将所述细胞分散于17mm培养板(约10×106个细胞/板)。1天后,除去生长培养基并用由hepesNaOH200nM,pH7.4,含有(mmol/l)NaCl(125),KCl(5),KH2PO4(0.4),MgSO4及CaCl2(1.2),NaHCO3(25),葡萄糖(12)缓冲的改良Krebs-Ringer培养基洗涤细胞两次。培养基也包括1mM 3-异丁基-1-甲基黄质(isobuthyl-1-methylxantine)(IBMX)。实验于室温下进行。培养10分钟后掺入IBMX,NG108-15细胞用1μmforskolin及所述待测化合物处理10分钟。通过加入冷的0.4N HClO4使该反应中止。15分钟后,小心收集冷的上清液并用1M K2CO3中和。于4℃培养过夜后所述实验管以9000rpm离心5分钟并将100ul等分试样通过使用商业购得的125I cAMP RIA标准试剂诊断盒(Amersham Inc.)测定cAMP含量。得自初始培养板的小颗粒溶于NaOH0.5N及其蛋白质含量用Bradfort所述的方法测定(Anal.Biochem.1976,72,248)。所得数据标准化成蛋白质含量。
本发明所述的最强效的化合物显示对δ受体的亲合力的范围为0.5-200nM,对δ的选择性的范围为对其它阿片受体类型的20-1500倍。在cAMP抑制生物分析中这些化合物也显示强的δ激动剂或拮抗剂的性质。选择性δ激动剂(由选择性δ拮抗剂纳曲酮(Nalrindole)拮抗)显示IC50的范围为1-500mnM。例如,实施例10的化合物显示Kiδ=2.9nM,Kiμ/Kiδ=840及Kiκ/Kiδ=600。实施例1的化合物显示对forskolin-刺激的在NG108-15细胞(IC50=15nM)(完全由选择性δ拮抗剂纳曲酮所拮抗,100nM)中的cAMP抑制的激动剂活性。
小鼠腹部狭窄(abdomianl constriction)(MAC)(Proc.Soc.Exp.Biol.Med,1957,95,729),大鼠摆尾(tail-flick)(MTF)(J.Pharm.Exp.Ther.,1941,72,74)及大鼠温水摆尾(tail-flick warm water)(MTF-WW)(LifeSci.,1986,39,1795)用来对本发明化合物的抗痛觉能力进行评价。
下述制备1-7介绍得到作为本发明一部分的通式(Ⅱ)的新酮的合成途径。特别是4,5-环氧基-17-甲基-3-乙烯基吗啡烷-6-酮、4,5-环氧基-3-(1-乙氧基乙烯基)-17-甲基吗啡烷-6-酮、4,5-环氧基-3-乙基-17-甲基吗啡烷-6-酮、3-溴-4,5-环氧基-14-羟基-17-甲基吗啡烷-6-酮及3-溴-4,5-环氧基-17-甲基吗啡烷-6-酮为新化合物并被用作制备实施例28、30、33、35、41、52、61及64化合物的原料。其它用作原料的酮在文献中是公知的。制备8介绍用作制备实施例89化合物原料的通式(Ⅲ)新的磷酰腙的制备。实施例1介绍由通式(Ⅱ)的相应酮与相应通式(Ⅲ)已知腙起始的制备本发明通式(Ⅰ)化合物的方法。实施例2、49及52介绍由相应式(Ⅰ)化合物的化学转移依次制备的通式(Ⅰ)化合物的制备方法。实施例105描述通式(Ⅰ)化合物(其中n=0,X=S及Y为取代的碳原子)的制备。此处介绍的实施例可按照如实施例1、2、49、52及105所述相同的步骤制备。
实施例1-105的化合物归纳在化学表中。制备通式(Ⅱ)化合物(其中R3=CH=CH2及C(OEt)=CH2)的一般过程。制备14,5-环氧基-17-甲基-3-三氟甲基磺酰基氧基吗啡烷-6-酮
在氮气下将5.5g(19.3mmol)4,5-环氧基-3-羟基-17-甲基吗啡烷-6-酮溶于20ml吡啶中。将该溶液冷至0℃并滴加入3.56ml(21.2mmol)三氟甲基磺酸酐。该溶液于0℃搅拌5分钟,然后温热至室温过夜。将该反应混合物倒至水中并用AcOEt萃取该水相。有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析,分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱,得6.26g标题产物。N.M.R.300MHz(CDCl3):δ7.0(d,1H),6.7(d,1H),4.7(s,1H).3.2(m,1H),3.1(d,1H),2.7-2.3(m,8H),2.1(m,2H),1.9-1.7(m,2H),1.3-1.1(m,1H).MS(TSP)m/z=417.2(M+)制备24,5-环氧基-17-甲基-3-乙烯基吗啡烷-6-酮
在氮气下将2g(4.8mmol)4,5-环氧基-17-甲基-3-三氟甲基磺酰氧基吗啡烷-6-酮溶解于25ml二甲基甲酰胺中,然后加入1.46ml(5mmol)乙烯基三丁基锡、1.6g(38.4mmol)LiCl、0.337g(0.48mmol)双(三苯基膦)钯(Ⅱ)氯化物及0.5g(1.9mmol)三苯基膦。该反应混合物加热至100℃3小时,然后将该反应混合物倒至水中并用AcOEt萃取该水相。有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析纯化,分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱,得1.1g标题产物。N.M.R.300MHz(CDCl3):δ7.1(d,1H),6.8-6.6(m,2H),6.0(d,1H),5.4(d,1H),4.6(s,1H),3.2-1.7(m,13H),1.2(m,2H).MS(TSP)m/z=295.1(M+)制备34,5-环氧基-3-(1-乙氧基乙烯基)-17-甲基吗啡烷-6-酮
2.5g(6.0mmol)4,5-环氧基-17-甲基-3-三氟甲基磺酰基氧基吗啡烷-6-酮、2.1ml(6.2mmol)(1-乙氧基乙烯基)三丁基锡、2g(48mmol)LiCl、0.42g(0.6mmol)双(三苯基膦)钯(Ⅱ)氯化物及0.63g(2.4mmol)三苯基膦在25ml二甲基甲酰胺中如制备2所述处理。所得粗品反应混合物经快速层析纯化,分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱,得1.95g标题产物。I.R.(KBr):2932,1728,1674 cm-1.N.M.R.300MHz(CDCl3):δ7.4(d,1H),6.6(d,1H),5.2(s,1H),4.65(s,1H),4.45(s,1H),3.9(q,2H),3.2-1.4(m,18H).MS(TSP)m/z=339.1(M+).制备44,5-环氧基-3-乙基-17-甲基吗啡烷-6-酮
将1.2g(4.06mmol)4,5-环氧基-17-甲基-3-乙烯基吗啡烷-6-酮溶于150ml无水乙醇中。加入1g10%Pd-碳并将该反应混合物于室温在Parr装置中在35psi下氢化8小时。滤除催化剂并真空除去溶剂,得到0.77g标题化合物。N.M.R.300 MHz(CDCl3):δ6.9(d,1H),6.6(d,1H),4.6(s,1H),3.2-1.7(m,18H),0.9(m,2H).MS(TSP)m/z=297.1(M+)制备通式(Ⅱ)化合物(其中R3=Br)的一般过程。制备53-溴-4,5-环氧基-17-甲基吗啡烷-6-醇
将3.1g(11.4mmol)4,5-环氧基-17-甲基吗啡烷-6-醇溶于150ml冰乙酸中并滴加入11.4ml1M在AcOH中的Br2溶液。1小时后,真空除去AcOH,残留物溶于水中,该水溶液用饱和NaHCO3溶液调至pH7并用AcOEt萃取。有机相用Na2SO4干燥并真空除去溶剂。得3.6g标题产物。I.R.(KBr):3580,2930,1452 cm-1.N.M.R.300 MHz(CDCl3):δ7.2(d,1H),6.6(d,1H),4.6(d,1H),4.0(m,1H),3.1(m,1H),2.9(d,1H),2.5-1.5(m,12H),1.1(m,1H).MS(TSP)m/z=349.0(M-1)制备63-溴-4,5-环氧基-14-羟基-17-甲基吗啡烷-6-酮
如制备5中所述用3.8ml 1M在AcOH中的Br2溶液处理1.1g(3.8mmol)4,5-环氧基-14-羟基-17-甲基吗啡烷-6-酮在50ml冰AcOH中的溶液,得1.1g标题产物。I.R.(KBr):3348,2910,1738 cm-1.制备73-溴-4,5-环氧基-17-甲基吗啡烷-6-酮
于-55℃在氮气下,将在4.8ml CH2Cl2中的1.6ml DMSO溶液缓慢加至在21mlCH2Cl2中的0.9ml草酰氯溶液中。2分钟后加入在20mlCH2Cl2中的3.6g(10.3mmol)3-溴-4,5-环氧基-17-甲基吗啡烷-6-醇,然后于15分钟后,加入6.6ml Et3N。将该反应混合物于2小时内温热至室温,然后,用50ml H2O使之骤冷。分离各相,有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析,分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱,得2.87g标题产物。I.R.(KBr):2940,1716,1446cm-1.N.M.R.300MHz(CDCl3):δ7.2(d,1H),6.6(d,1H),5.4(s,1H),3.3(m,1H),2.95(d,1H),2.6-1.7(m,12H),1.2(m,1H).MS(TSP)m/z=347.0(M-1)制备81-苯基亚肼基-2-氧丙基膦酸二乙酯
于0-10℃将7.1g(0.0517mol)K2CO3及0.0257mol苯基重氮氯化物加至5.0g(0.0257mol)二乙基(2-氧丙基)膦酸二乙酯在25ml乙醇/水4∶1中的溶液中。搅拌所得悬浮液直至温度达室温。然后加入30ml水和100mlCH2Cl2。有机相用Na2SO4干燥并真空蒸发得7g红色油状标题化合物,其可直接用于下一步骤中。C13H19N2O4PIR(neat):3498,1716,1666,1268,1026cm-1N.M.R.300MHz(CDCl3):12.9(bs,1H);7.5-7.0(m,5H),4.2(m,4H);2.3(s,3H);1.5(m,6H).实施例1[8R-(4bS*,8α,8aβ,12bβ)]-11(N-苄基-N-异丙基氨基羰基)-7,10-二甲基-1-甲氧基-5,6,7,8,12,12b-六氢-(9H)-4,8-亚甲基苯并呋喃[3,2-e]吡咯并[2,3-g]异喹啉盐酸盐
将0.65g(2.17mmol)7,8-二氢可待因酮盐酸盐,2.2g(6.51mmol)N-苄基-N-异丙基-2-苯基腙-3-氧代butiramide溶于10ml冰乙酸及0.54g(6.51mmol)CH3COONa的混合物中。所得反应混合物加热至60℃,然后在氮气下分次加入0.57g(8.6mmol)锌粒。使该混合物回流2小时,然后冷至室温。通过倾倒除去所得盐并用乙酸洗涤。收集该酸性溶液然后调至pH8并用AcOEt提取数次。干燥所得有机相并真空蒸发至干。所得残留物经使用硅胶(15-25u)中压层析纯化并用AcOEt/MeOH/浓NH4OH 90∶10∶0.5的混合物作洗脱剂纯化。所得产物溶于丙酮/MeOH1∶1的混合物并将溶液用HCl/Et2O调pH至酸性。过滤所得沉淀,洗涤并干燥得到0.5g标题化合物。M.P.=304℃分解。实施例2[8R-(4bS*,8α,8aβ,12bβ)]-11(二乙基氨基硫代羰基)-7,10-二甲基-1-甲氧基-5,6,7,8,12,12b-六氢-(9H)-4,8-亚甲基苯并呋喃[3,2-e]吡咯并[2,3-g]异喹啉盐酸盐
将1g(2.3mmol)[8R-(4bS*,8α,8aβ,12bβ)]-11(二乙基氨基羰基)-7,10-二甲基-1-甲氧基-5,6,7,8,12,12b-六氢-(9H)-4,8-亚甲基苯并呋喃[3,2-e]吡咯并[2,3-g]异喹啉,0.950g(2.3mmol)Lawesson试剂溶于40ml甲苯中并将混合物回流4小时。真空除去溶剂,然后残留物溶于CH2Cl2中并用s.s.NaHCO3洗涤。有机层用Na2SO4干燥。蒸发除去溶剂后,残留物经硅胶快速层析(CH2Cl2/MeOH/NH4OH(浓)86∶10∶0.6)纯化,然后产物溶于丙酮。所得溶液用HCl/Et2O调至pH酸性。过滤沉淀物,在炭存在下溶于沸腾的MeOH 30分钟。滤除该炭,并将该溶液蒸发至干。残留物用沸腾Et2O研磨得到0.41g标题化合物。M.P.>250℃。
实施例73化合物按照上述相同方法制备。实施例49[8R-(4bS*,8α,8aβ,12bβ)]-11-异丙基羰基-7,10,12-三甲基-1-甲氧基-5,6,7,8,12,12b-六氢-(9H)-4,8-亚甲基苯并呋喃[3,2-e]吡咯并[2,3-g]异喹啉盐酸盐
于氮气下将0.52g(1.2mmol)[8R-(4bS*,8α,8aβ,12bβ)]-11(异丙基羰基)-7,10-二甲基-1-甲氧基-5,6,7,8,12,12b-六氢-(9H)-4,8-亚甲基苯并呋喃[3,2-e]吡咯并[2,3-g]异喹啉(实施例34)溶于5mlDMF中。在保持0℃温度的同时分次加入0.051g 60%NaH。30分钟后滴加入0.2gMeI溶于1mlDMF的溶液。1小时后用碎冰使该反应骤停。所得溶液用Et2O萃取。有机层用Na2SO4干燥,然后真空除去溶剂。使生成的残留物溶于丙酮中,所得溶液用Et2O/HCl调至pH酸性。依次蒸发该溶剂并将所得残留物用沸腾Et2O研磨。将该固体过滤,洗涤并干燥得到0.25g标题化物。M.P.240-243℃。
实施例62和82的化合物按照上述方法制备。
实施例74,79及80按照相同方法使用溴乙酸乙酯作烷化剂制备。所得乙基酯依次在酸性条件下水解成上述实施例的相应酸的衍生物。实施例52[10R,4bS-(4bb,9ab)]-3-溴-7-二异丙基氨基羰基-8,14-二甲基-4b,5,9,9a,10,11-六氢-4-羟基-(6H)-10,4b-(亚氨基桥亚乙基)菲并[3,2-b]吡咯
于氮气下将0.3g(0.58mmol)[8R-(4bS*,8α,8ab,12bb)]-1-溴-11-异丙基氨基羰基-7,10-二甲基-5,6,7,8,12,12b-六氢-(9H)-4,8-亚甲基苯并呋喃[3,2-e]吡咯并[2,3-g]异喹啉(实施例30)溶于10ml冰AcOH中并加入0.15g(1.8mmol)AcONa。反应混合物加热至80℃并分次加入0.23g(3.5mmol)锌粒。该反应混合物加热回流4小时,然后倒至冰中,用浓NH4OH调pH至9并用CH2Cl2萃取。有机相用Na2SO4干燥并真空除去溶剂。所得粗品反应混合物经快速层析纯化,分别用CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7的混合物洗脱,所得固体在Et2O中研磨,得0.15g标题产物。实施例105[8R-(4bS*,8α,8aβ,12bβ)]-11-甲氧基羰基-7,10-二甲基-1-甲氧基-5,6,7,8,9,12b-六氢-4,8-亚甲基苯并呋喃[3,2-e]噻吩并[2,3-g]异喹啉盐酸盐
将7-乙酰基-4,5-环氧基-1-甲氧基-17-甲基吗啡烷-6-酮(1g,2.9mmol)(J.Med.Chem.1982,25,983)在MeOH(40ml)中的溶液冷至-10℃并将干燥HCl鼓泡进入该系统直至饱和(约1h)。然后加入硫代乙醇酸(0.4ml,5.8mmol),继续于-10℃鼓泡HCl 4小时。该反应混合物于RT下放置6天。真空蒸发该溶剂,用浓NH4OH处理残留物并用AcOEt萃取。分离有机层,用水洗涤,干燥(Na2SO4)并真空蒸发。所得粗产物直接用于下一步骤。
将2N MeONa(10ml)加至上述产物于12ml MeOH中的溶液中并于氮气下保持24小时。蒸除溶剂并用冰-冷水处理残留物。用6N HCl酸化该混合物至pH=1。用AcOEt洗涤后,水层用NaOH处理至pH=9并用AcOEt萃取。干燥溶剂,蒸发并将粗产物经硅胶层析(CH2Cl2/MeOH/浓NH4OH;95∶5∶0.5)纯化。所得产物用HCl/Et2O处理,得55mg标题产物。
Claims (13)
1.式(Ⅰ)化合物,或其溶剂化物或其盐:其中,R1为氢、直链或支链C1-6烷基、C3-7环烷基、C4-6环烷基烷基,后三个基团中的每一个任选由羟基(当C≥2时)、C3-5链烯基、芳基、芳烷基或呋喃-2或3-基烷基或(CH2)mCOR(其中m是0-5及R为直链或支链C1-6烷基、羟基、C1-5烷氧基、OC3-6链烯基或烷基芳基)、NR10R11(其中R10和R11可以相同或不同,并且每一个为氢、直链或支链C1-6烷基、C4-6环烷基烷基、C3-5链烯基、芳基或芳烷基)取代;或者R1为A-B基团,其中A表示C1-10亚烷基及B表示取代的或未取代的芳基或杂芳基;R2为氢、羟基或C1-5烷氧基、卤素、硝基、NR10R11、SR10,其中R10及R11的定义同上述,此外R10是COR1;R3为氢、直链或支链C1-6烷基、羟基、C1-5烷氧基、卤素或(CH2)mCOR(其中m和R的定义同上)、SR10、硝基、NR10R11、NHCOR10、NHSO2R10(其中R10及R11的定义同上述);R4和R5可以相同或不同,各自独立为氢、羟基、C1-5烷氧基、O-苯氧基或可一起形成氧基团(-O-);或R4与R3一起形成亚甲基二氧基基团(-OCH2O-);R6为基团:或含有由具有上述定义的R3取代的多至三个杂原子的五或六元杂芳基团,该环上有多至3个R3基团,或者R6为C(Z)R12基团,其中Z是氧或硫,R12是直链或支链的C1-18烷基、羟基、直链或支链C1-18烷氧基、芳基烷氧基或NR13R14,其中R13及R14(可以相同或不同)为氢、直链或支链的C1-6烷基、C3-7环烷基、C4-6环烷基烷基,后三个基团中的每一个任选由多至三个氟原子或羟基基团(C≥2)、C3-6链烯基、芳基、芳烷基或任选取代的杂环取代;或R13及R14可以一起形成可插入氧或NR1的C3-6烷环,其中R1的定义同上;或R6是CH2WA’基团,其中W是氧、硫或NR14,及A’是氢、直链或支链的烷基或COR14(其中R14的定义如上);或R6为COCOR12基团,其中R12具有与上相同的定义;或R6为NR13R14基团,其中R13和R14具有与上相同的定义,或R13可以为(CH2)mCOR基团,其中m和R具有与上相同的定义;或R6为P(Z)R12基团,其中Z和R12具有与上相同的定义;或R6为S(O)iR12基团,其中i=1,2及R12具有与上相同的定义。R7为氢、C1-18烷基、C2-18链烯基、卤素、卤代-C1-6烷基、(CH2)mCOR其中m和R具有与上相同的定义或为基团:或含有具有上述定义的R3取代的多至三个杂原子的五或六元杂芳基团;R8为氢、C1-6烷基;n是0或1;当n=0时,则X和Y独立为氧、硫、CH或R6-或R7-取代的碳原子、及NR9(其中所述R9为氢、直链或支链的C1-6烷基、C3-7环烷基、C4-6环烷基烷基,其中后三个基团中的每一个任选由羟基取代(当C≥2时),或可含有NR10R11基团(其中所述R10及R11具有与上相同的定义)、C3-5链烯基、芳基、芳烷基、或(CH2)mCOR(其中m是0-5及R代表羟基、C1-5烷氧基、OC3-6链烯基或烷基芳基、NR10R11,其中R10和R11(可以相同或不同)各自为氢、直链或支链的C1-6烷基、C4-6环烷基烷基);及当n=1时,则X和Y均为N,或N和CH。
2.权利要求1的化合物,其中R1是氢、甲基、乙基、丙基、异丙基、丙烯基、苄基、苯基乙基、CH2CH2OH、CH2COOH、CH2COOEt、CH2CONH2或COMe。
3.权利要求1或2的化合物,其中R3是氢、羟基、乙基、溴、羟基、甲氧基、乙氧基、异丙氧基、COMe或CH2COOH。
4.权利要求1-3的化合物,其中R4和R5各自为氢、羟基、乙酰氧基、甲氧基、O-苯基、或一起形成氧基、或R4与R3一起为亚甲基二氧基。
6.权利要求1的化合物,其中,n=0,X是NH及Y是CH或R6-或R7取代的碳原子,其中R6是-C(Z)-R12基团及其中所述R12是C1-6烷基、C1-4烷氧基或NR13R14并且其中所述R13及R14的定义同权利要求1及Z是氧;及R7是甲基或卤代-C1-2烷基。
7.选自实施例1-105的权利要求1的化合物。
8.包括按照权利要求1-7中的任一项的化合物及药学上可接受的载体的药用组合物。
9.按照权利要求1-7中的任一项的用作活性治疗物质的化合物。
10.按照权利要求1-7中的任一项的用作麻醉剂、预防器官移植及皮肤移植排斥反应的免疫抑制剂、抗过敏及抗炎剂、脑细胞保护剂、治疗药物及酒精滥用、减少胃分泌、治疗腹泄、心血管及呼吸道疾病、咳漱和呼吸抑制、精神病及癫痫发作及其它神经紊乱的化合物。
11.按照权利要求1-7中的任一项的化合物在生产用作麻醉剂、防止器官移植及皮肤移植排斥反应的免疫抑制剂、抗过敏及抗炎剂、脑细胞保护剂、治疗药物及酒精滥用、减少胃分泌、治疗腹泄、心血管及呼吸道疾病、咳漱和呼吸抑制、精神病及癫痫发作及其它神经紊乱的药物中的用途。
12.治疗和/或预防哺乳动物,特别是人罹患权利要求11定义的病症的方法,包括给需要此种治疗和/或预防的哺乳动物服用有效量的按照权利要求1-7中的任一项的化合物。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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ITMI960029 IT1282950B1 (it) | 1996-01-10 | 1996-01-10 | Derivati eterociclo-condensati di morfinoidi |
ITMI96A000029 | 1996-01-10 | ||
ITMI96A002291 | 1996-11-05 | ||
IT96MI002291 IT1287130B1 (it) | 1996-11-05 | 1996-11-05 | Derivati eterociclo-condensati di morfinoidi |
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CN1213372A true CN1213372A (zh) | 1999-04-07 |
CN1090190C CN1090190C (zh) | 2002-09-04 |
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CN97192879A Expired - Fee Related CN1090190C (zh) | 1996-01-10 | 1997-01-08 | 杂环稠合的吗啡类衍生物,制备方法和用途 |
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US (1) | US6365594B1 (zh) |
EP (1) | EP0880526B1 (zh) |
JP (1) | JP2000503019A (zh) |
KR (1) | KR19990077125A (zh) |
CN (1) | CN1090190C (zh) |
AR (1) | AR005423A1 (zh) |
AT (1) | ATE229958T1 (zh) |
AU (1) | AU706370B2 (zh) |
BR (1) | BR9707136A (zh) |
CA (1) | CA2242609A1 (zh) |
CZ (1) | CZ218298A3 (zh) |
DE (1) | DE69717967T2 (zh) |
ES (1) | ES2188888T3 (zh) |
HU (1) | HUP9900974A3 (zh) |
IL (1) | IL125226A0 (zh) |
NO (1) | NO983169L (zh) |
NZ (1) | NZ326331A (zh) |
PL (1) | PL327943A1 (zh) |
TR (1) | TR199801348T2 (zh) |
TW (1) | TW357148B (zh) |
WO (1) | WO1997025331A1 (zh) |
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1997
- 1997-01-08 AR ARP970100077A patent/AR005423A1/es unknown
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- 1997-01-08 NZ NZ326331A patent/NZ326331A/xx unknown
- 1997-01-08 AT AT97901009T patent/ATE229958T1/de not_active IP Right Cessation
- 1997-01-08 ES ES97901009T patent/ES2188888T3/es not_active Expired - Lifetime
- 1997-01-08 US US09/101,213 patent/US6365594B1/en not_active Expired - Fee Related
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- 1997-01-08 AU AU14410/97A patent/AU706370B2/en not_active Ceased
- 1997-01-08 KR KR1019980705261A patent/KR19990077125A/ko not_active Application Discontinuation
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- 1997-01-08 WO PCT/EP1997/000120 patent/WO1997025331A1/en not_active Application Discontinuation
- 1997-01-08 PL PL97327943A patent/PL327943A1/xx unknown
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- 1997-01-08 JP JP9524871A patent/JP2000503019A/ja not_active Withdrawn
- 1997-01-08 EP EP97901009A patent/EP0880526B1/en not_active Expired - Lifetime
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1298720C (zh) * | 2005-03-18 | 2007-02-07 | 中国科学院上海有机化学研究所 | C环连接有五元杂环的青藤碱衍生物和合成方法 |
CN101210016B (zh) * | 2006-12-29 | 2011-07-20 | 中国科学院上海药物研究所 | 一类杂环并吗啡喃类化合物、制备方法及用途 |
CN112047951A (zh) * | 2020-10-16 | 2020-12-08 | 吉林大学 | 手性螺[吡咯-2,2’-呋喃]化合物及其制备方法 |
Also Published As
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HUP9900974A2 (hu) | 1999-08-30 |
HUP9900974A3 (en) | 2000-09-28 |
AR005423A1 (es) | 1999-06-23 |
EP0880526A1 (en) | 1998-12-02 |
TW357148B (en) | 1999-05-01 |
JP2000503019A (ja) | 2000-03-14 |
ES2188888T3 (es) | 2003-07-01 |
KR19990077125A (ko) | 1999-10-25 |
BR9707136A (pt) | 1999-08-31 |
ATE229958T1 (de) | 2003-01-15 |
AU706370B2 (en) | 1999-06-17 |
AU1441097A (en) | 1997-08-01 |
PL327943A1 (en) | 1999-01-04 |
EP0880526B1 (en) | 2002-12-18 |
CA2242609A1 (en) | 1997-07-17 |
CZ218298A3 (cs) | 1999-08-11 |
DE69717967T2 (de) | 2003-08-28 |
TR199801348T2 (xx) | 1998-10-21 |
WO1997025331A1 (en) | 1997-07-17 |
NZ326331A (en) | 2000-01-28 |
CN1090190C (zh) | 2002-09-04 |
DE69717967D1 (de) | 2003-01-30 |
NO983169L (no) | 1998-09-09 |
US6365594B1 (en) | 2002-04-02 |
IL125226A0 (en) | 1999-03-12 |
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