CN1049349A - 新的2-氧代-3，8-二氮杂螺[4，5]癸烷衍生物，含有这些衍生物的药物配方及其制备方法 - Google Patents
新的2-氧代-3，8-二氮杂螺[4，5]癸烷衍生物，含有这些衍生物的药物配方及其制备方法 Download PDFInfo
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- CN1049349A CN1049349A CN90106982A CN90106974A CN1049349A CN 1049349 A CN1049349 A CN 1049349A CN 90106982 A CN90106982 A CN 90106982A CN 90106974 A CN90106974 A CN 90106974A CN 1049349 A CN1049349 A CN 1049349A
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- oxo
- decane
- diazaspiro
- derivatives
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
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- 238000000034 method Methods 0.000 claims description 38
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- 238000006243 chemical reaction Methods 0.000 claims description 22
- -1 2-oxo-3,8-diazaspiro [4,5] decane Alkane Chemical class 0.000 claims description 19
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Abstract
本发明涉及新的治疗有效的式(I)的2-氧代
-3，8-二氮杂螺(4，5)癸烷衍生物，其异构体，溶剂化
物，酸加成物和季铵盐，
式中各基团定义详见说明书。
本发明进一步涉及含这些化合物的药物配方及
其制备方法。
式I的各化合物对中枢神经系统有抗缺氧作用，
因此可用于预防和治疗识别功能紊乱以及躁狂，焦虑
不安，精神运动性的焦虑，老年性和多发梗塞性痴呆
以及阿尔茨海默(Alzheimer′s)病。
Description
本发明涉及新的、有治疗活性的由式(I)代表的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物，其异构体，溶剂化物，水合物，酸加成物和季铵盐以及含这些化合物的药物配方其中R代表氢：C1-18烷基，C2-6环烷基，碳环C6-10-芳基或碳环C6-10芳基-C1-4芳基，在后两种基团中的芳环部分分有一个或多个，相同或不同的卤素取代，或者有一个或多个C1-4烷基或C1-4烷氧基取代；R1和R2中的一个代表羟基，另一个代表甲基；R3和R4可相同或不同，代表氢，一个或多个卤素，C1-4烷基，C1-4烷氧基，三卤甲基或由C1-4链烷酸任意酯化的羟基；以及n是1或2，
本发明也涉及以上化合物和配方的制备方法以及治疗方法。后者包括用治疗有效量的式(I)的化合物或药用酸加成物或其季铵盐给病人以影响缺氧症，组织乏氧性缺血症。
式(I)的化合物可以立体异构体形式，如几何异构体以及外消旋体，分开的光学异构体或其混合物形式存在，所有这些异构体都可成为各种溶剂化物和水合物。所有这些化合物和混合物都在本发明范围内。
文献中已叙述过一些治疗上有效的2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷衍生物，以下出版物报告了这类化合物；C.A.71，91359d(1969)；C.A.78，33876q(1973)；C.A.81，33153c和105368b(1974)；C.A.95，161765，(1981)；以及DE专利申请号2,013,729，2,013,668和2,163,000和BE专利申请号773,934，774,170，786,631，825,444；GB专利申请号1,100,281；已公布的ML专利申请号7,214,689及US专利申请号3,555,033，3,594,386，4,244,961，和4,255,422。
本发明式(I)的化合物与至今已知的类似衍生物间的主要差别表现为在螺癸烷骨架的4-位上取代基和3-位上的任意选择性取代基的性质。
另一方面本发明提供了式(I)的化合物及其酸加合物和季铵盐的制备方法，该方法包括：
e)式(II)(其中R，R1和R2如上规定)的
2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物与式(III)的二苯基烯烃衍生物反应其中R3，R4和n如上所规定，y代表卤素或者为C1-4烷基磺酰氧基或芳基磺酰氧基；或
b)式(VII)(其中R3，R4和n如上规定)的4-乙酰基-4-羟基啶衍生物与式R-NCO的异腈酸酯反应，其中R为如上所规定的但氢除外，
然后将所得式(VIII)(其中R，R3，R4和n如上所规定)的4-乙酰基-4-氨甲酰氧基哌啶衍生物环合，或
c)将式VIII的4-乙酰基-4-氨甲酰氧基哌啶衍生物环合，其中R3，R4和n如上面规定，R如对式R-NCO中的R所规定的；或
d)式(VI)(其中R3，R4和n如上规定)的
化合物与式R-NH2的胺反应，其中R如式(I)所规定或
e)式(IV)(其中R，R3，R4和n如上规定)
的4-亚甲基-2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物在酸性介质中水合，然后，若需要的话用已知的方法，把所得式(II)的化合物的功能基转变成另外的基团其中R，R1，R2，R3，R4和n如式(I)所规定，和/或所得式(I)(其中R，R1，R2，R3，R4和n如上规定)的化合物与酸反应得酸加成盐，和/或用碱处理式(I)(其中R，R1，R2，R3，R4和n如上规定)的所得的盐化合物就释放出游离碱，和/或把所得式(I)(其中R，R1，R2，R3，R4和n如上规定)的化合物转变成其季铵盐。
在本发明的方法(a)中，式(II)的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物与式(III)的二苯烯衍生物进行反应，其中y代表甲磺酰氧基或甲苯磺酰氧基或卤素，最好是氯或溴。完成该反应最好在惰性有机溶剂中，在能结合反应中释放出的酸的碱存在下进行。适宜的溶剂为脂肪烷醇类如乙醇，异丙醇或丁醇；芳烃类如氯苯或甲苯；醚类如二丁醚或二噁烷；叔-脂酰胺类如二甲基甲酰胺或二甲基乙酰胺；酮类如丙酮，甲基乙基酮或甲基异丁基酮；而以上溶剂的混合物也可应用。为结合反应中释放出的酸，可用无机碱或叔-有机碱如碱金属或碱土金属的碳酸盐或碳酸氢盐以及有机碱如三乙胺二甲基苯胺或吡啶；为此目的，即使式II的化合物过量也是适宜的。该反应可在室温和反应混合物的沸点之间的温度下进行；还可任意选择地加催化剂。适宜的催化剂是碱金属碘化物。最好在惰性气体如氮气或氩气下进行反应。
关于本发明的b)法，式(VII)的4-乙酰基-4-羟基哌啶衍生物与式R-NCO异氰酸酯反应，这样产生的式( )的4-乙酰基-4-氨甲酰基哌啶衍生物再进行环合。接第一步的缩合反应用已知的方法进行/Houbsn-Weyl：有机化学方法(Mstteden dsr Organischsn Chemie)Vol。VIII/3，137-147页(1952)/。所得4-乙酰基-4-氨甲酰氧基-哌啶衍生物最好在碱存在下进行环合。碱金属的醋酸盐，碳酸盐，醇盐，氢氧化物和/或权有机碱，例如吡啶，三丙胺或甲基吡啶都可用作环合的碱催化剂；有机碱也可用作反应溶剂。更适宜的溶剂是比如脂肪醇类如甲醇，乙醇，丙醇或丁醇；脂肪族、脂环或芳香烃类如二氯甲烷、己烷、环己烷、苯，甲苯或二甲苯；酸性酰胺类如二甲基甲酰胺或N-甲基吡咯烷酮；醚类如二丁醚或二噁烷；腈类如乙腈；亚砜类如二甲基亚砜；以及以上溶剂的混合物。反应也可在无任何溶剂，例如在熔融状态进行。为了促进环合，可适当提高温度：反应最好在40℃和反应混合物沸点之间完成。在惰性气体如氩或氮气下进行反应是适宜的。按照最好的方案是，由式(VII)的4-乙酰基-4-羟基哌啶衍生物与式R-NCO异腈酸酯反应得到的式(VIII)的，4-乙酰基-4-氨甲酰氧基哌啶衍生物不必分离，而在同样反应混合物中，在适当碱存在下直接进行环合。
关于本发明的方法c)，按在方法b)的第二步中叙述的方法进行。
按本发明的方法d)，式(VI)的化合物与式R-NH2的氨反应。该反应在适宜的溶剂中或没有任何溶剂的情况下进行。适宜的溶剂例如脂肪，脂环或芳脂烷醇类如乙醇，丁醇，环己醇，苄醇；脂肪或芳香烃类如己烷，庚烷，二甲苯，氯苯或硝基苯；醚类例如二噁烷或二-正-丁基醚；叔有机碱例如甲基吡啶，三乙胺或吡啶；即使式R-NH2胺过量也可作为反应溶剂。该步骤可在室温和反应混合物沸点之间的温度进行，最好在惰性气体例如氩或氮气下反应。
根据本发明的方法a)，水合作用在含水介质中，在矿酸和/或有机酸存在下进行。适宜的酸是，例如卤氢酸，硫酸，磷酸，甲酸，芳磺酸，草酸等等。该反应最好在5℃和反应混合物的沸点之间的温度进行。
如果需要的话，用方法a)-4)所得式(I)的化合物都可用已知的方法转变成另外的化合物，这些也包括在式(I)的范围内。
如果需要，式(I)的化合物可用已知的方法转变成酸加成物和季胺盐。为了制备酸加成盐，无机酸或有机酸如氢卤酸，例如盐酸和氢溴酸；硫酸，磷酸以及甲酸，乙酸，丙酸，草酸，乙醇酸，马来酸，富马酸，琥珀酸，酒石酸，抗坏血酸，柠檬酸，苹果酸，水杨酸，乳酸，苯甲酸，肉桂酸，天冬氨酸，谷氨酸，N-乙酰基天冬氨酸或N-乙酰基谷氨酸以及烷基磺酸如甲烷磺酸、芳磺酸，例如对甲苯磺酸等等都可应用。
盐的形成用这样的方法进行，即把相应的酸加到在惰性溶剂例如乙醇中制备的式(I)化合物的溶液中，以后形成的盐最好加与水不相混合的有机溶剂例如乙醚使沉淀出来。
为了制备季铵盐，低级卤代烷，卤代烯或卤苄或烷基硫酸酯都可应用。季铵化作用可在有机溶剂如丙酮，乙腈，乙醇或这些溶剂的混合物中适宜地进行，反应温度范围是由室温至溶剂的沸点的温度。
所得酸加成物或季铵盐可过滤分离出来，若需要可用重结晶法来精制。
相反地，可用碱处理其盐而释放出相应的游离碱。
本发明的方法所使用的起始物质部分是已知的，或者可用已知的方法制备。用作原料的式(VII)和(VIII)的化合物是新的，也具自己的生物活性。
式III的化合物可按以下的参考文献来制备：Ber.55，3406(1922)；Ann.Chem. 555，80(1952)；GB专利申请号683,950；药学杂志 82，1088(1952)；J.chem.Soc.4066(1959)；Coll.Czechoslov.Chem.Comman.38，3379(1973)。
式(II)的化合物的制备在匈牙利专利申请号4092/89中描述过。
式(IV)的化合物可由式(II)(其中R1和R2一起代表亚甲基，R如上规定)的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物与式(III)的二苯烯衍生物反应制备。
式(V)和(VIII)的氨基甲酸酯类可用式(III)或(VII)的化合物分别与上述式R-NOG异腈酸酯反应得到。
式(VI)的化合物可由式(V)的4-氨甲酰氧基-4-乙炔基哌啶衍生物在酸性介质中环合，生成的亚胺化合物然后与水反应而制得。
由4-乙炔基-4-羟基哌啶衍生物水合可合成式(VII)的4-乙酰基-4-羟基哌啶衍生物/参看：Houban-Weylla有机化学方法Vol VII/2，826页至835页(1973)/或者用碱处理式(VI)的4-亚甲基-2-氧代-1，3-二氧杂-8-氮杂螺〔4，5〕癸烷衍生物来合成。
例如在匈牙利专利申请号166,769或Farmaro(Pavia)Ed Sci 12，34(1957)中叙述的适宜取代的4-哌啶酮衍生进行乙炔化反应来制备式(IX)的化合物。
根据本发明式(I)的新化合物及其盐具有价值的药理性质；例如对中枢神经系统具有选择性的多巴胺能样作用，并有抗缺氧，抗组织缺氧症，抗局部缺血，抗遗忘症的作用。由于其多巴胺能样作用，就抑制大脑皮层和皮层下的中枢多巴胺(以下简称DA)受体。这些化合物及其盐类对各种起因的大脑缺氧/缺血引起的原发损伤，例如由于缺氧和长期生存在严重缺氧条件下的哺乳类动物诱发的大脑水肿记忆损伤有保护作用。式(I)的化合物可广泛地用于预防性治疗，并用于治疗各种疾病如躁狂，各种起因的焦虑不安，精神运动性焦虑，运动机能亢进，老年性痴呆和多发梗塞性痴呆，早老性痴呆，识别功能紊乱，局部缺血性损伤等。
用下述方法研究了本发明式(I)的新化合物的药理作用1.对脱水吗啡诱发的运动机能亢进和刻板动作的抑制作用
脱水吗啡诱发大鼠和各种动物出现活动亢进和刻板行为的特有症状/J.Pharm.Pharmacol.19，627(1957)；J.Neurol.Trans、40，97(1977)；J.Psychiat.R：s.11，1(1974)；J.Pharm.Pharmacol，25，1003(1973)；Naturs 263，338(1976)/。
体重160-180g的雄性Hannover-Wistar大鼠用于这些试验。受试化合物悬浮于2％吐温80溶液，加蒸馏水稀释至所要的浓度。给大鼠5ml/Kg体积的相应剂量。对照组给不含受试物的上述溶液。
给口服受试化合物2.5mg/Kg1小时后的大鼠皮下注射脱水吗啡盐酸盐1mg/Kg。
给脱水吗啡15分钟后，把动物放入由微处理机控制的5-波道行为观察装置内，测定动物的协调及刻板运动15分钟。氯氮平(Chlozaprms)(化学称8-氯-11-(4-甲基-1-哌嗪基)-5H-二苯并-〔b，e〕〔1，4〕二氮杂)的剂量2.5mg/Kg用作对照药。结果以与对照相比两种运动型的百分数表示。
进而用G.Stille和H.Leuner(Arxmeim-Forsch21，252(1971))的方法研究了这些化合物对致僵住症(诱发的僵住症)的作用。在这些实验中，用90-110g体重的雄性Wtstar大鼠，口服不同剂量的受试物。给药后每小时登记僵住的动物数，共6小时。提起动物前肢向上放在有8cm高的水平杆的装置上，若其这种异常体位在30秒内不能矫正，就认这样的动物是患有僵住症。由僵住症活物的百分数计算ED50值。结果列于表1
表中所用缩写如下：LMA8有运动活动性n8动物数P.O8口服给药S.E.8均数标准误A8 8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3，4-二甲基-4-羟基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕-癸烷盐酸盐B.：3-苄基-8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐
表1化合物 脱水吗啡诱发的活动性的抑制 致僵住作用 n
LMA 刻板动作 ED50 mg/kg
对照百分数 P.OA -40 0 ＞300 5B -25 +15 ＞300 5氯氮平 -25 +11 31.9 5对照：LMA： 100％(438.9±54.7sec±S.E.)刻板动作： 100％(105.0±13.7sec±S.E.)
由表I可明显的看到，口服本发明式(I)的化合物2.5mg/Kg就能降低脱水吗啡诱发的运动机能亢进，有与参照药相同或显著高于参照药的效果，而对刻板动作与参照药氯氮平(Clozapina)相似无抑制作用。致僵住作用比参照药至少好10倍。可以预料，本发明式(I)的新化合物的锥体束外的副作用将是不常见或者不发生。2.对记忆的缺氧损伤的抑制作用
在这些实验中使用体重210-230g雄性自发(遗传性)高血压的大鼠。在6-频道的穿棱一盒内，3天期间训练30个周期研完主动性回避行为。在单个周期内应用1Hz频率的间歇性光刺激15秒钟做为条件刺激，0.8mA的电刺激10秒钟做为非条件刺激，在信号间的时间为15秒。
在第四天，实验前1小时，给动物口服10mg/Kg的受试化合物。在这些实验中用两个对照组，其中之一用安慰剂处理，另一组用安慰剂并使处于缺氧条件下。吡咯醋酰胺(化学名2-氧代-1-四氢吡咯乙酰胺)和二氢麦角碱用做参照药。动物的行动在缺氧条件下进行检查，缺氧条件是这样造成的，用含6％氧和94％氮气的混合气体流经盒子其速度为200mL/分/盒子。记数条件圈避性反应(以下简称GAR)。化合物对缺氧记忆损伤的防护作用以下式来计算。防护作用％-(治疗组条件性回避反应 X-)-(安慰剂+缺氧条件性回避反应 X-)
×100(安慰剂条件性回避反应 X-)-(安慰剂+缺氧条件组回避反应 X-)其中保护作用就是抑制缺氧损伤的效果以百分数表示；CAR X表示受试动物组条件反应数的平均值。
化合物对缺氧记忆损伤的保护作用与对照组相比以百分数表示，并列于表23.抑制低压缺氧
体重200-220g自发高血压的雄性大鼠用于这些研究。每组3只动物，放入6升体积的干燥器内，在20秒内减压至170Hgmm(22.66KPa)并继续保持该压力。实验前1小时，给动物口服各种剂量的受试化合物。测定ED50值(即与用安慰剂处理的对照组相比延长受试动物存活时间50％的剂量)并列于表3
用于表2和表3的缩写如下：C：3-苄基-8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐PIR：吡咯醋酰胺DHE：二氢麦角碱
表2化合物 剂量 对遗忘症损害的保护作用
mg/kg P.OC 10 64 6PIR 500 85 6DHE 10 63 6
表3化合物 对低压缺氧的保护作用 nC 23.7 10PIR 293.0 10DHE 50.0x 104.抑制大脑水肿
用以下方法研究了受试化合物抑制大脑水肿的效果/Ann。Pherm.Fr.42，431(1984)/
每组7只体重180-200g雄性Hannouet-Wtstar大鼠，每天用2.5mg/Kg三乙基锡氯化物(以下简称TET)处理5天诱发脑水肿/TET(Msrch-Schuchardt，Darmstadt，FRG)在搅拌下溶于蒸馏水，每天上午7点给动物口服搅拌的溶液/
参照药和受试化合物在0.5％(按重量计)的羧甲基纤维素溶液中用Ultra Turrar搅拌器搅匀并在给药期间也要搅匀再给。在TET处理后第1小时和第6小时，按0.5ml/100g体重剂量口服这些化合物。对照组给TET的溶剂(即蒸馏水)和受试化合物的载体(即0.5％(按重量计)的羧甲基纤维素溶液)，按上述同样的时间间隔和剂量给与。
在处理的第5天，在最后一次给受试化合物后两小时将动物断头，迅速取出整个脑子，用(按重量计的)0.9％的冷氯化钠溶液洗涤，用滤纸除去水，称脑湿重精确到10mg，放在预先称重的铝箔上。随后，在90℃干燥92小时，然后称总(毛)重(即脑干重与铝箔一起的重量)。由脑的湿、干重的差分别计算出脑的水含量和其变化该变化以保护的百分数表示如下：
其中(TET-K0)表示用TET和载体处理的动物的脑的平均水含量；
(TET-V)表示用TET和受试化合物处理的动物脑平均水含量；(Veg-K0)表示用蒸馏水和载体处理动物的脑的平均水含量。
脑的水含量和干重变化的偏差用Studeat′，“t”测试相比。这里也以吡咯醋酰胺和二氢麦角碱用作参照药物。结果列于表4。
用于表4的缩写如下：TET：三乙基锡氯化物dw：蒸馏水Veh：赋形剂(0.5％按重量计的羧甲基纤维素溶液)D：8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-〔2-(3，4-二甲氧基苯基)乙基〕-4-甲基-2-氧代-1-氧杂-3，8-二杂螺-〔4，5〕癸烷马来酸酯E：8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐 表4处理 剂量 保护作用
umol/kg ％dw+Veh - -TET+Veh - -TET化合物C 25 97.9
″ 50 102.0
″ 100 88.1
″ C 100 102.2
″ E 100 114.3TET+PIR 100 16.7TET+DHE 30x 25.6*在以上实验中DHE给药剂量为30mg/Kg
根据以上研究，本发明的化合物能以好的效果保护动物不受由于缺氧而产生的遗忘症和记忆损伤的影响并以低剂量延长在严重缺氧情况下动物的生存时间。
在中枢神经系统，三乙基锡氯化物诱发了严重的脑水肿，增加了脑水含量以及严重的脑代谢活动损伤，细胞呼吸，氧化磷酸化，谷氨酸酯，琥珀酸酯，葡萄糖等的氧化受到抑制。这在缺氧和局部缺血的情况下对这些严重改变也进行了观察；这些改变基本上表现为发生大脑水肿，其后果是识别功能紊乱，痴呆等。本发明的化合物完全抑制了大脑水肿的发展而参照药没有这种保护效果。
本发明的化合物可转变成药物配方，这些配方的制剂可口服，直肠给药和/或非肠道给药。为口服给药，配方可配制成片剂，糖衣丸或胶囊。为了制备口服配方制剂，乳糖或淀粉可用做载体。明胶，羧甲纤维素钠，甲基纤维素，聚乙烯吡咯烷酮或淀粉胶都是适合的粘合剂或成粒剂。崩解剂主要是和土豆淀粉或微晶纤维素，不过超支链淀粉或甲醛醇蛋白等也可应用。滑石粉，胶状硅酸，硬脂精，硬酯酸钙或硬酯酸镁等等都是适宜的防粘剂和润滑剂。液体口服配方可配制成悬浮液，糖浆或酏剂，这些剂型可含水、乙二醇，油，醇类以及着色剂和调味剂。
片剂可通过压制湿颗粒来制备。活性成分与载体和适当的与部分崩解添加剂的混合物，与粘合剂的水溶液，醇或水醇的溶液混合在适当的装置制粒，然后干燥颗粒。随后，混合另外的崩解剂、润滑剂和防粘添加剂成至干颗粒，将这样的混合物压制成片。假如需要，还可提供带沟的片剂以使服用方便。片子也可由含活性成分和适当添加剂的混合物直接制备。用普通惯用的药物添加剂，例如保护剂，调味或着色剂如糖，纤维素衍生物(甲基-或乙基纤维素，羧甲基纤维素钠等)，聚乙烯吡咯烷酮，磷酸钙，碳酸钙，食物色素，着色硝基纤维素，芳香剂，氧化铁，色素等将片剂任意选择地转成糖衣片。胶囊制剂配方是将活性成分与添加剂的混合物装入胶囊来制备。
为直肠给药，本发明配方配制成含载体的栓剂，即所谓“动物脂栓剂基质”再加上活性成分。做为载体，植物油脂如硬化植物油，C12-18脂肪酸三甘油脂(最好载体是带有商业名字Wttapsol)都可应用。把活性成分均匀地分布在熔化的载体物中然后模制成栓剂。
对非胃肠道给药，本发明配方可配制成注射液。为制备这些注射液，活性成分可分别溶在蒸馏水和/或各种有机溶剂，例如乙二醇醚，可加溶解剂，如聚氧乙烯山梨糖醇酐-月桂酸酯或-油酸酯或-硬脂酸酯(吐温20，吐温60或吐温80)。注射液还可含有各种辅剂，例如防腐剂如乙二胺四乙酸酯，pH-调解剂和缓冲物，如果需要可加局部麻醉剂如利多卡因盐酸盐。在装安瓿以前，含本发明配方的注射液要过滤，过滤后的注射液要灭菌。
本发明也涉及治疗哺乳动物(包括人)识别功能紊乱的方法。该方法包括给病人有效量的式(I)的活性成分，或其药用盐酸加成盐，或其季铵盐。根据病的类型，严重程度和病人的状态，每天剂量可在0.1-40mg/Kg之间变化，可以每天给一次或分成几次口服，直肠给药或非消化道给药。
借助于以下非限制性实例更详细的来阐明本发明。
实例18-〔3，3-双(4-氟苯基)-2-丙烯基〕-4-羟基〕-4-甲基-2-氧代-3-正-丙基-1-氧杂-3，8-二氮杂螺〔〔4，5〕-癸烷的制备
在室温搅拌下1小时内，将9.3g 3.3-双(4-氟苯基)-2-丙烯基溴化物溶在50ml丙酮的溶液分批地加到合6.85g 4-羟基-4-甲基-2-氧代-3-正-丙基-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷和4.29无水碳酸钾在68ml无水丙酮的混合物中，然后反应混合物在室温再搅拌1小时。滤掉无机盐后，减压除去溶剂，将残余物溶于苯，用水洗涤，无水硫酸钠干燥，然后减压蒸发至其体积的十分之一。加正-己烷至残余物中使沉淀。滤出结晶，干燥得标题化合物，86％产量，m.p.：128-129℃元素分析：C26H20F2N3O3
C H F N理论值： 68.40 6.62 8.32 6.14％实测值： 68.44 6.79 8.50 6.12％
把乙醚氯化氢溶液加到游离碱的乙醚溶液中使盐酸盐沉出，m.p.：233-235℃
以下化合物可用适当的原料用类似的方法制备。8-(3，3-二苯基-2-丙烯基)-4-羟基-3-异丙基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：219-221℃；3-〔3，3-双(4-氟苯基〕-4-羟基-3-异丙基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：255-260℃
实例23-正丁基-8-(3，3-二苯基-2-丙烯基)-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐的制备
在搅拌下把92ml 3摩尔/升的盐酸溶液滴加到5.2g的3-正-丁基-8-(3，3-二苯基-2-丙烯基)-4-亚甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷在10.4ml 99％的甲酸溶液中。以后在0-5℃搅拌反应混合物30分钟。滤出结晶后，用水洗涤，干燥，得标题产物，97％产量，m.p.：104-106℃元素分析：C27H24N2O2
C H N理论值： 74.62 7.89 6.45％实测值： 74.55 8.01 6.56％
实例38-(4，4-双(4-氟苯基)-3-丁烯基)-4-羟基-3-异丙基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐的制备
11.3g 8-〔4，4-双(4-氟苯基)-3-丁烯基〕-s-异丙基-4-亚甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷与100ml 1摩尔/升盐酸在室温搅拌18小时，然后滤出沉淀的结晶，用水洗涤，冷却至5℃，减压干燥得标题化合物盐酸盐，产量96％，m.p.：252-255℃(分解)
加饱合碳酸氢钠水溶液释放游离碱，再提取入氯仿。有机层用水洗涤，无水硫酸镁干燥并且减压蒸去溶剂。残余物由苯重结晶后，得标题化合物游离碱，87％产率m.p.：175-176℃元素分析：C27H22F2N3O3
C H F N理论值： 68.91 6.86 8.08 6.95％实测值： 69.12 6.94 8.13 6.10％
实例48-(3，3-二苯基-2-丙烯基)-4-羟基-4-甲基-2-氧代-3-丙基-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐的制备
含12.6g 4-乙酰基-1-(3，3-二苯基-2-丙烯基)-4-丙基氨甲酰氧基哌啶和0.4g甲醇钠在80ml甲醇中的溶液在氩气下回流4-5小时，然后减压除去溶剂。残余物与50ml1.0摩尔/升盐酸在0℃-5℃搅拌15分钟。结晶滤出后，用冰冷水洗涤，干燥，得标题化物盐酸盐，产率82.4％，m.p：132-134℃元素分析：C26H28N2O2
C H N理论值： 74.25 7.67 6.66％实测值： 74.40 7.65 6.53％
实例58-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-乙基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐的制备
7.0g 8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-乙基-4-亚甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔45〕癸烷与320ml 0.1摩尔/升盐酸煮沸搅拌1小时。反应混合物冷至5℃，过滤，结晶沉淀用水洗涤，干燥，得标题化合物盐酸盐，产率92.6％，m.p.：238-240℃(分解)
加氢氧化钠水溶液由盐酸盐释放出游离碱。元素分析：C26H20F2N2O3理 C H F N理论值： 68.40 6.62 8.32 6.14％实测值： 68.36 6.68 8.50 6.25％
实例68-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-癸基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐的制备
在搅拌的同时将5.5ml癸胺分批加到10.3g 8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-亚甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷在20ml苯的溶液中。反应温和地放热，反应混合物的温度升到44-45℃。然后将反应混合物在室温搅拌18-20小时。滤出结晶沉淀，用己烷洗涤并干燥。加乙醚氯化氢溶液将碱转变成盐酸盐，得标题化合物盐酸盐，产率78.6％，m.p.：140-141℃元素分析：C24H42F2N2O3
C H F N理论值： 71.86 8.15 6.68 4.93％实测值： 71.88 8.33 6.61 5.11％
以下化合物可用适当的原料及类似的方法制备。8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-〔2-(34-二甲氧基苯基)乙基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷m.p.：143-144℃；其马来酸盐在129-132℃分解，8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-3-丙基-1-氧杂-3，8-二氮杂螺〔4，55〕癸烷盐酸盐，m.p.：247-250℃(分解)；8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3 -环己烷基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔45〕癸烷盐酸盐，m.p.：256-258℃(分解)；8-〔3，3-双(4-氟苯基)-2-丙烯基〕-3-丁基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：228-230℃(分解)；3-苄基-8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：179-181℃(分解)；8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：155-157℃(分解)；8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-3-(1-萘基)-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p：230-233℃(分解)；3，4-二甲基-8-(3，3-二苯基-2-丙烯基)-4-羟基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：211-213℃(分解)；8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-叔丁基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：220-224℃(分解)；8-〔3，3-双(4-苯苯基)-2-丙烯基〕-3，4-二甲基-4-羟基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.238-240℃(分解)；8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-3-苯基-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.：179-181℃(分解)；8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3，4-二甲基-4-羟基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷，m.p.：144-144℃，盐酸盐203-204℃分解；8-〔3，3-双(4-氟苯基)-2-丙烯基〕-3，4-二甲基-4-羟基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.241-244℃(分解)和8-〔4，4-双(4-氟苯基)-3-丁烯基-3-丁基-4-羟-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，m.p.： 2 2 9-2 3 1℃(分解)。
实例73-(4-氯苯基)-8-(3，3-二苯基-2-丙烯基)-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐的制备
含有6.4g 4-乙酰基-1-(3，3-二苯基-2-丙烯基)-4-羟基哌啶和3.4g 4-氯苯基异腈酸酯在30ml三丙胺中的溶液，在氩气及搅拌下温和的回流3小时，然后减压蒸去溶剂，加苯至残余物后，不溶物滤出，苯液经硅胶层过滤，减压蒸发。粗产物由乙醇和己烷重结晶，以活性炭澄清，所得游离碱加氯化氢二异丙醚溶液转成盐酸盐。得标题化合物盐酸盐，产率47.3％，m.p.227-230℃(分解)元素分析：C28H28ClN2C3
C H Cl N理论值： 71.22 5.98 7.25 5.73％实测值： 71.29 6.14 7.40 5.60％
实例88-〔4，4-双(4-氯苯基)-3-丁烯基〕-3-丁基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐的制备
含有7.27g 3-丁基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷，12.89g4，4-双(4-氯苯基)-3-丁烯基溴化物，4.98g无水碳酸钾和0.6g碘化钾在73ml甲基异丁基酮的溶液，在氩气及搅拌下缓缓回流6小时。冷下来后，滤除无机盐，用甲基异丙基酮洗涤，滤液用水洗至中性，无水硫酸镁干燥，减压除去溶剂。残余物由乙醇重结晶，所得产物溶于乙醚，加乙醚氯化氢溶液，盐酸盐沉出，得标题化合物盐酸盐产率79.3％，m.p.：230-233℃(分解)元素分析：C28H24Cl2N2C3
C H Cl N理论值：64.89 6.62 13.70 5.41％实测值：65.04 6.66 13.62 5.48％
实例98-〔3，3-双(4-氟苯基)-2-丙烯基〕-4-羟基-4-甲基-2-氧代-3-丙基-I-氧杂-8，8-二氮杂螺〔4，5〕癸烷8-鎓碘化物的制备
4.1g 8-〔3，3-双(4-氟苯基)-2-丙烯基〕-4-羟基-4-甲基-2-氧代-3-丙基-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷和0.7ml碘甲烷在400ml甲基异丙基酮中的混合物回流2小时。冷下来后，滤出结晶沉淀，用二异丙醚洗涤，冷至0℃，干燥，得标题季铵盐产率91.3％，m.p.：232-233℃
实例10
本发明的新化合物可转成以下配方a)片剂的制备
50.0g活性成分与92g乳糖，40g土豆淀粉，4g聚乙烯四氢吡咯，6g滑石粉，1g硬脂酸镁，1g胶体；二氧化硅(高分散度硅胶)和6g超支链链淀粉混合，制粒后，得到的颗粒压制成含50mg活性成分的片子。b)糖衣片的制备
上述制备的片子以已知的方法用含糖和滑石粉涂层包衣后，得到的糖衣片用蜂蜡和巴西蜡棕树蜡的混合物磨光，得糖衣片每片重250mgc)胶囊的制备
100g活性成分通过与30g月桂基硫酸钠，280g淀粉，280g乳糖；4克胶体二氧化硅(高分散度硅胶)和6g硬脂酸镁混合，混合物过筛装入明胶胶囊，每个含100mg活性成分。d)栓剂的制备
(注：所有量是-个栓剂的计算量)
100mg活性成分通过与200.0mg乳糖，1700.0mg栓剂基质(例如Wttepsol 4)一起混合熔化。冷至35℃，活性成分和乳糖的混合物再用匀浆器混合，然后倒入冷的锥形模具内，每个栓剂重为2000mg。e)悬浮液的制备
100ml悬浮液的组分：
活性成分 1.00g
氢氧化钠 0.26g
柠檬酸 0.30g
尼泊金(4-羟基苯甲酸甲酯钠盐) 0.10g
Carbupol(聚丙烯酸) 0.30g
96％乙醇 1.00g
红莓香料 0.60g
山梨醇(70％水溶液) 71.00g
蒸馏水加至 100.00ml
在剧烈搅拌下将聚羧乙烯(Carbopol)小批地加到尼泊金和柠檬酸在20ml蒸馏水的溶液中，得到的溶液放置10-12小时，随后把以上给出量的氢氧化钠溶在1ml蒸馏水中，然后在搅拌下滴入山梨醇水溶液和红莓香料的乙醇溶液。将活性成分小部分地加入这种混合物中，用浸入式匀浆器使其悬浮。最后用蒸馏水加至100ml并通过胶体研磨机得到糖浆悬浮液。
Claims (10)
1.新的式(I)2-氧代-3，8-二氮杂螺〔45〕癸烷衍生物，这些衍生物的异构体，溶剂化物，水合物，酸加成盐和季铵盐，其中R等于氢，C1-12烷基，C2-6环烷基，碳环C6-10芳基或碳环C6-10芳基-C1-4烷基，后两个基团在其芳环部分可任意地由一个或多个，相同或不同的卤素或1个或多个C1-4烷基或C1-4烷氧基取代；R1和R2中的一个代表羟基另一个是甲基；R3和R4相同或不同，它们代表氢，一个或多个卤素，C1-4烷基，C1-4烷氧基，三卤甲基或由C1-4烷酸任意酯化的羟基；以及n是1或2。
2.由以下化合物组成的组里选择的一个化合物及其异构体，溶剂化物，水合物，其他酸加合物和季铵盐，8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3，4-二甲基-4-羟基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-叔丁基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，8-〔4，4-双(4-氟苯基)-3-丁烯基〕-3-丁基-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，5〕癸烷盐酸盐，3-苄基-8-〔4，4-双(4-氟苯基)-3-丁烯基〕-4-羟基-4-甲基-2-氧代-1-氧杂-3，8-二氮杂螺〔4，55〕癸烷盐酸盐。
3.一种药物组合物，其包括将一个或多个式(I)2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物或其药用酸加成盐或季铵盐(其中R，R1，R2，R3，R4和n如权利要求1所定义)与载体，稀释剂，稳定剂，pH调节剂，渗透压调节剂和/或普通用于制药工业的调配添加剂一起混合。
4.新的式(I)的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物，其异构体，溶剂化物，水合物，酸加成物和季铵盐的制备方法
其中R为氢，C1-12烷基，C2-6环烷基，碳环C6-10-芳基或碳环C6-10芳基-C1-4烷基，后两种基团的芳环部分可任意的由一个或多个，相同或不同的卤素或一个或多个C1-4烷基或C1-4烷氧基取代；R1和R2中的一个代表羟基，另一个代表甲基；R3，R4可相同或不同，它们代表氢，一个或多个卤素，C1-4烷基，C1-4烷氧基，三卤甲基或由C1-4烷酸任意酯化的羟基；及n是1或2，该方法包括
a)式(II)(其中R，R1和R2如上面所规定)
的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物与式(III)的二苯基烯衍生物反应其中R3，R4和n如上规定，y为卤素或C1-4烷基磺酰氧基或芳基磺酰氧；或
b)式(VII)(其中R3，R4中n如上规定)的4-乙酰基-4-羟哌啶衍生物与式R-NCO异腈酸酯反应(其中R按如上规定，除氢)然后所得式(VIII)4-乙酰基-4-氨甲酰氧基哌啶衍生物进行环合，
其中R，R3，R4和n如上规定，或
c)式(VIII)的4-乙酰基-4-氨甲酰氧基哌啶衍生物环合，其中R3，R4和n如上规定，R如R-NCO式中所规定；或
d)式(VI)(其中R3，R4和n如上面规定)的化合物与式R-NH2的胺反应，其中R如式(I)规定；或
e)式(IV)(其中R，R3，R4和n如上面规定的)的4-亚甲基-2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物在酸性介质中水合如果需要，所得式(I)(其中R，R1，R2，R3，R4和n如式I规定)的化合物的功能基可用已知的方法转变成另外的功能基和/或
所得式(I)(其中R，R1，R2，R3，R4和n如上规定)的化合物与酸反应得酸加成盐和/或用碱处理式(I)(其R，R1，R2，R3，R4和n如上规定)的化合物所得的盐，释放出其游离碱形式和/或将所得式(I)(其中R，R1，R2，R3R4，和m如上规定)的化合物转化成其季铵盐。
5.如权利要求4中方法a)所要求的方法，其包括将式II(其中R如式(I)所规定的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物与式(III)(其中Y为卤素，最好为氯或溴，R3和R4及n如式I规定)的二苯基烯衍生物反应。
6.如权利要求4中方法a)所要求的方法，其包括将式(II)(其中R，R1和R2如式(I)规定)的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物与式(III)(其中Y为甲磺酰氧基或对-甲苯磺酰氧基及R3，R4和n如式I规定)的二苯烯衍生物反应。
7.权利要求4或权利要求5中方法a)所要求的方法，其包括在碘化钾存在下，在酮类溶剂中进行该反应，用碳酸钾为酸结合剂。
8.如权利要求4中方法b)所要求方法，其包括将式(VII)(其中R3，R4和n如式I所规定)的4-乙酰基-4-羟基哌啶衍生物与异腈酸酯R-NCO进行反应以及将所得式(VIII)(其中R，R3，R4和n如式I规定)的4-乙酰基-4-氨甲酰氧基哌啶衍生物在三异丙胺介质中，在反应混合物的沸点条件下进行环合。
9.药物组合物的制备方法，其包括将式作为活性成分的式(I)的一或多个2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物(其中R，R1，R2，R3，R4和n如权利要求1所定义)与载体，稀释剂，稳定剂，pH-调节剂，渗透压调节剂(等渗透)和/或普通用于制药工业的调配添加剂相混合并将其转变成药物组合物。
10.治疗哺乳动物识别功能紊乱的方法，其特征为，单独的或以药物组合物形式给哺乳动物(包括人)以治疗有效剂量的式(I)(其中R，R1，R2，R3，R4和n如权利要求1所规定)的2-氧代-3，8-二氮杂螺〔4，5〕癸烷衍生物或其药用酸加成物或其季铵盐。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102459278A (zh) * | 2009-06-16 | 2012-05-16 | 默沙东公司 | 取代的-1,3,8-三氮杂螺[4.5]癸烷-2,4-二酮 |
| CN107001367A (zh) * | 2014-09-16 | 2017-08-01 | 克罗诺斯治疗有限公司 | 用于治疗例如注意力缺陷障碍(add)的作为人多巴胺主动转运体(dat)蛋白抑制剂的2‑[双(4‑氟苯基)甲基]‑2,7‑二氮杂螺[4.5]癸烷‑10‑酮衍生物和有关化合物 |
| CN107108625A (zh) * | 2014-09-16 | 2017-08-29 | 克罗诺斯治疗有限公司 | 螺环衍生物 |
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| US4985437A (en) * | 1986-12-17 | 1991-01-15 | Glaxo Group Limited | Medicaments |
| YU150489A (sh) * | 1989-08-10 | 1992-12-21 | W.L. Gore & Co. Gmbh. | Uređaj za ispitivanje odevnih predmeta na nepromočivost |
| HU204529B (en) * | 1989-08-10 | 1992-01-28 | Richter Gedeon Vegyeszet | Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them |
| US5534520A (en) * | 1990-04-10 | 1996-07-09 | Fisher; Abraham | Spiro compounds containing five-membered rings |
| US5852029A (en) * | 1990-04-10 | 1998-12-22 | Israel Institute For Biological Research | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity |
| EP0492020A1 (en) * | 1990-12-21 | 1992-07-01 | Merrell Dow Pharmaceuticals Inc. | Use of certain esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one and related compounds for treating cognitive disorders |
| GB9206989D0 (en) * | 1992-03-31 | 1992-05-13 | Glaxo Group Ltd | Chemical compounds |
| US5756743A (en) * | 1996-04-10 | 1998-05-26 | Hoechst Marion Roussel Inc. | Spiro cyclopent b!indole-piperidines! |
| US6100256A (en) * | 1996-12-02 | 2000-08-08 | Merck Sharp & Dohme Ltd. | Use of NK-1 receptors antagonists for treating schizophrenic disorders |
| SE9604786D0 (sv) | 1996-12-20 | 1996-12-20 | Astra Pharma Inc | New compounds |
| US6974825B1 (en) | 1996-12-20 | 2005-12-13 | Astrazeneca Canada Inc. | Compounds with analgesic effect |
| SE9904675D0 (sv) | 1999-12-20 | 1999-12-20 | Astra Pharma Inc | Novel compounds |
| SE0101771D0 (sv) | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
| SE0101770D0 (sv) * | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
| SE0101773D0 (sv) * | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
| SE0101769D0 (sv) | 2001-05-18 | 2001-05-18 | Astrazeneca Ab | Novel compounds |
| KR20030087248A (ko) * | 2002-05-08 | 2003-11-14 | (주)씨엔아이 | 온라인을 통한 상거래 기초항목의 설정기능을 갖는 상거래관리장치 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL127065C (zh) * | 1964-04-22 | |||
| CH601304A5 (zh) * | 1974-02-12 | 1978-07-14 | Buskine Sa | |
| BE790675A (fr) * | 1971-10-29 | 1973-04-27 | Science Union & Cie | Nouveaux derives de l'oxa-1 diaza-3,8 spiro (4,5) decane |
| FR2615515B1 (fr) * | 1987-05-22 | 1989-06-30 | Adir | Nouveaux derives du spiro 4, 5 decane, leur procede de preparation et les compositions pharmaceutiques les renfermant |
| HU204530B (en) * | 1989-08-10 | 1992-01-28 | Richter Gedeon Vegyeszet | Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them |
| HU204529B (en) * | 1989-08-10 | 1992-01-28 | Richter Gedeon Vegyeszet | Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them |
| YU150489A (sh) * | 1989-08-10 | 1992-12-21 | W.L. Gore & Co. Gmbh. | Uređaj za ispitivanje odevnih predmeta na nepromočivost |
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1989
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1990
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- 1990-08-10 US US07/566,279 patent/US5132309A/en not_active Expired - Fee Related
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102459278A (zh) * | 2009-06-16 | 2012-05-16 | 默沙东公司 | 取代的-1,3,8-三氮杂螺[4.5]癸烷-2,4-二酮 |
| CN107001367A (zh) * | 2014-09-16 | 2017-08-01 | 克罗诺斯治疗有限公司 | 用于治疗例如注意力缺陷障碍(add)的作为人多巴胺主动转运体(dat)蛋白抑制剂的2‑[双(4‑氟苯基)甲基]‑2,7‑二氮杂螺[4.5]癸烷‑10‑酮衍生物和有关化合物 |
| CN107108625A (zh) * | 2014-09-16 | 2017-08-29 | 克罗诺斯治疗有限公司 | 螺环衍生物 |
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