CN1360591A - 具有麻醉剂活性的3α-羟基-3β-甲氧基甲基-21-杂环取代的类固醇 - Google Patents
具有麻醉剂活性的3α-羟基-3β-甲氧基甲基-21-杂环取代的类固醇 Download PDFInfo
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- CN1360591A CN1360591A CN00808360A CN00808360A CN1360591A CN 1360591 A CN1360591 A CN 1360591A CN 00808360 A CN00808360 A CN 00808360A CN 00808360 A CN00808360 A CN 00808360A CN 1360591 A CN1360591 A CN 1360591A
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- C—CHEMISTRY; METALLURGY
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- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- 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
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- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
本发明涉及式(I)化合物或其药学上可接受的盐、药物前体或溶剂化物,其中:R1是H或甲基;R2是5α-或5β-H;R3是可选取代的N-连接的杂芳基或-X-R4基;R4是可选取代的碳连接的杂芳基;而X是O、S或N。本发明还涉及3α-羟基-3β-甲氧基甲基-取代的类固醇作为镇静剂/安眠剂和用于诱导麻醉的用途。
Description
发明背景
发明领域
本发明涉及医药化学领域以及用于调节脑兴奋性的新颖的类固醇衍生物和方法。更具体地说,本发明涉及3α-羟基-3β-甲氧基甲基-21-取代的-5α-(和5β-)孕烷-20-酮,它具有可取的用作镇静剂/安眠剂和麻醉剂的性能。
相关背景技术
天然产生的神经活性类固醇不适合作为镇静剂/安眠剂,因为它们的口服生物利用度不佳,据推测是由于它们迅速的首过代谢导致的(Hogenkamp.D.J.等,《医药化学杂志》40:61-72(1997))。加入3β-取代产生了在动物体内不显示强口服活性的神经活性类固醇,但它们通常会持续过长的时间以致无法作为有用的镇静剂/安眠剂。镇静剂/安眠剂在人体内应当具有<5小时的消除半衰期,以避免残留的次日效应和连续每晚给药后的蓄积(Nicholson,A.N.,《药物》31:164-176(1986))。然而,我们已发现:3β-甲氧基甲基-取代的类固醇在保持了其他3β-取代的神经活性类固醇的口服活性的同时还具有使得它们能用作镇静剂/安眠剂和麻醉剂的持续作用时间。
发明概述
本发明涉及3α-羟基-3β-甲氧基甲基-21-取代的-5α-(和5β-)孕烷-20-酮,它们具有尤为可取的可用作镇静剂/安眠剂和麻醉剂的性能。
本发明还涉及式I化合物作为麻醉剂的用途。
本发明的第一个方面涉及式I表示的新颖的甲氧基甲基-取代的类固醇。
本发明的第二个方面涉及作为镇静剂-安眠剂的新颖的式I化合物。
本发明的第三个方面是提供一种通过对需要这种治疗的哺乳动物给药式I化合物来诱导麻醉的方法。
本发明的第四个方面是提供一种药物组合物,它含有有效量的式I化合物,并混合有一种或多种药学上可接受的载体或稀释剂。
发明详述
本发明是这样一种发现的结果:新颖的式I表示的3β-甲氧基甲基-3α-羟基-取代的类固醇具有使得它们尤其可用作镇静剂/安眠剂和麻醉剂的持续作用时间。
R1是H或甲基;
R2是5α-或5β-H;
R3是可选取代的N-连接的杂芳基或-X-R4基;
R4是可选取代的碳连接的杂芳基;和
X是O、S或N。
一组优选的式I化合物是其中R4为可选取代的碳连接的二环杂芳基而X=O的化合物。
另一组优选的式I化合物是其中:R4为可选取代的碳连接的杂芳基;而X=S。
另一组优选的是其中R3为可选取代的N-连接的单环杂芳基的式I化合物。优选的神经活性类固醇包括3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮和21-(5’-氨基-[1,3,4]-噻二唑-2-基硫基)-3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮。
更优选的一组式I化合物是其中R4为可选取代的碳连接的二环杂芳基的N-氧化物,并且X=O的化合物。
其他更优选的组包括其中R3为可以可选地被取代的N-连接的咪唑或四唑的式I化合物。
尤为优选的是以下化合物:3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮及其盐酸盐。3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5β-孕烷-20-酮及其盐酸盐。3α-羟基-3β-甲氧基甲基-21-(2’-四唑基)-5α-孕烷-20-酮和3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮,N-氧化物。
在本发明的这一方面中有用的化合物非限制性地包括:
3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮;
3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5β-孕烷-20-酮;
3α-羟基-3β-甲氧基甲基-21-(2’-四唑基)-5α-孕烷-20-酮;
3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮,N-氧化物,和
21-(5’-氨基-[1,3,4]-噻二唑-2-基硫基)-3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮。
有用的芳基是C6-14芳基,尤其是C6-10芳基。典型的C6-14芳基包括苯基、萘基、菲基、蒽基、茚基、薁基、联苯、亚联苯基和芴基。
有用的环烷基是C3-8环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
有用的饱和或部分饱和的碳环基是如上定义的环烷基,以及环烯基,诸如环戊烯基、环庚烯基和环辛烯基。
有用的杂芳基包括以下任何一种:噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、苯并吡喃基、呫吨基、吩氧硫杂环己二烯基(phenoxanthiinyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、四唑基、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹喔啉基(quinozalinyl)、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基(acrindinyl)、萘嵌间二氮杂苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异噁唑基、呋咱基、吩噁嗪基、噻二唑基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、1,2-苯并异噁唑-3-基、苯并咪唑基、2-羟吲哚基和2-氧代苯并咪唑基。
有用的卤或卤素基包括氟、氯、溴和碘。
有用的烷基包括直链和支链C1-10烷基,更优选C1-6烷基。典型的C1-10烷基包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基。还可考虑的是取代在本发明化合物苯环上的两个相邻位置上的1,3-亚丙基。
有用的链烯基是C2-6链烯基,优选C2-4链烯基。典型的C2-4链烯基包括乙烯基、丙烯基、异丙烯基、丁烯基和仲丁烯基。
有用的炔基是C2-6炔基,优选C2-4炔基。典型的C2-4炔基包括乙炔基、丙炔基、丁炔基和2-丁炔基。
有用的芳烷基包括被任何一种上述C6-14芳基取代的任何一种上述C1-10烷基。有用的芳烷基包括苄基、苯乙基和萘甲基。
有用的芳烯基包括被任何一种上述C6-14芳基取代的任何一种上述C2-4链烯基。
有用的芳炔基包括被任何一种上述C6-14芳基取代的任何一种上述C2-4炔基。有用的芳炔基包括苯基乙炔基和苯基丙炔基。
有用的环烷基烷基包括被任何一种上述环烷基取代的任何一种上述C1-10烷基。
有用的卤烷基包括被一个或多个氟、氯、溴或碘原子取代的C1-10烷基,例如氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基和三氯甲基。
有用的羟烷基包括被羟基取代的C1-10烷基,例如羟甲基、羟乙基、羟丙基和羟丁基。
有用的烷氧基包括被一个上面所提到的C1-10烷基取代的氧。
有用的烷硫基包括被一个上面所提到的C1-10烷基取代的硫。
有用的酰氨基是与氨基氮连接的任何C1-6酰基(链烷酰基),例如乙酰氨基、丙酰氨基、丁酰氨基、戊酰氨基、己酰氨基以及芳基取代的C1-6取代酰基。
有用的酰氧基是与氧(-O-)基连接的任何C1-6酰基(链烷酰基),例如乙酰氧基、丙酰氧基、丁酰氧基、戊酰氧基、己酰氧基等等。
有用的饱和或部分饱和的杂环基包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异苯并二氢吡喃基、苯并二氢吡喃基、吡唑烷基、吡唑啉基、特窗酰基(tetronoyl)和四氨酰基(tetramoyl)。
有用的杂环烷基包括被任何一种上述杂环基取代的任何一种上述C1-10烷基。
有用的氨基包括-NH2、-NHR5和-NR5R6,其中R5和R6是如上定义的C1-10烷基或环烷基。
有用的氨基羰基是被-NH2、-NHR5和-NR5R6取代的羰基,其中R5和R6是C1-10烷基。
式I中任何一个杂芳基环上的可选取代基包括以下任何一种:上述卤素、卤代烷基、芳基、杂环基、环烷基、杂芳基、烷基、链烯基、炔基、芳烷基、芳烯基、芳炔基、杂芳基烷基、杂芳基烯基、杂芳基炔基、环烷基烷基、杂环烷基、羟烷基、氨基烷基、羧基烷基、烷氧基烷基、硝基、氨基、脲基、氰基、酰氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、羧基、氨基羰基和烷基巯基。优选的可选取代基包括:卤素、卤代烷基、羟烷基、氨基烷基、硝基、烷基、烷氧基和氨基。
某些式I化合物可以作为旋光异构体存在,本发明包括这类旋光异构体的外消旋混合物以及可以按照本领域普通技术人员熟知的方法加以分离的单个对映体。
药学上可接受的加成盐的实例包括无机和有机酸加成盐,诸如盐酸盐、氢溴化物、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐、醋酸、二氯乙酸和草酸盐。
药物前体的实例包括带有可选取代基(包括羟烷基或氨基烷基)的式I化合物的酯或酰胺,它们可以通过使这类化合物与酸酐诸如琥珀酸酐反应来制备。
本发明化合物可以用本领域技术人员已知的方法加以制备。
在本发明范围内的组合物包括其中含有可有效地达到其预定目的量的本发明化合物的所有组合物。虽然个体的需要不同,但每种组分有效量最佳范围的确定都是本领域中的常识。一般说来,用于治疗失眠时,根据哺乳动物的体重计算每天用量,则这些化合物可以0.0025至50mg/kg的剂量对哺乳动物(例如人)口服给药,或者给药等当量的其药学上可接受的盐。用于肌内注射时,剂量一般是口服剂量的大约一半。
单位口服剂量可包含约0.01至约50mg、优选约0.1至约10mg的化合物。单位剂量可以作为每片含有约0.1至约10、一般是约0.25至50mg的化合物或其溶剂化物的一个或多个片剂每天给药一次或多次。
化合物除了作为未经加工的化学药品给药外,本发明化合物还可作为药物制剂的一部分给药,所述药物制剂含有合适的药学上可接受的载体,包括有助于将化合物加工成可药用制剂的赋形剂和助剂。优选地,制剂、特别是可口服给药并可用于优选给药类型的那些制剂(诸如片剂、糖衣丸和胶囊剂)、以及可以直肠给药的制剂(诸如栓剂)、再加上用于通过注射或口服给药的适宜的溶液,都含有从约0.01至99%、优选从约0.25至75%的活性化合物,以及赋形剂。
在本发明的范围内还包括本发明化合物的无毒的药学上可接受的盐。酸加成盐是通过将本发明的特定杂芳基化合物的溶液与药学上可接受的无毒的酸(诸如盐酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸、二氯乙酸等)的溶液混合而形成的。碱式盐是通过将本发明的杂芳基化合物的溶液与药学上可接受的无毒的碱(诸如氢氧化钠、氢氧化钾、氢氧化胆碱、碳酸钠等)的溶液混合而形成的。
本发明的药物组合物可以对能体验到本发明化合物的有益作用的任何动物给药。在这样的动物中最重要的是哺乳动物,例如人,尽管本发明并不打算仅限于此。
本发明的药物组合物可以用能达到它们预定目的的任何一种方式给药。例如,可以通过胃肠外、皮下、静脉内、肌内、腹膜内、经皮或经颊途径给药。另一方面,或者并行地,可以通过口服途径给药。给药剂量将取决于接受者的年龄、健康状况和体重,并行治疗的种类,如果有的话,治疗频率以及所需作用的性质。
本发明的药物制剂以自身已知的方式生产,例如利用常规的混合、制粒、制糖衣丸、溶解或冷冻干燥过程。于是,用于口服的药物制剂可以这样得到:将活性化合物,其可有利地微粉化,与固体赋形剂混合;可选地研磨所得混合物并对该颗粒混合物进行加工,如果希望或需要,在加入了合适的助剂后进行加工,从而得到片剂或糖衣丸芯。
合适的赋形剂特别是:填充剂诸如糖类,例如乳糖或蔗糖,甘露糖醇或山梨糖醇,纤维素制剂和/或磷酸钙,例如磷酸三钙或磷酸氢钙,以及粘合剂诸如淀粉糊剂,使用例如玉米淀粉、小麦淀粉、稻米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要,可以加入崩解剂(诸如上述淀粉以及羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸)或其盐,诸如藻酸钠。助剂尤其是流动调节剂和润滑剂,例如二氧化硅、滑石、硬脂酸或其盐,诸如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。糖衣丸芯有合适的包衣,如果需要,该包衣是能抗胃液的。为此目的,可以使用浓缩糖溶液,它可可选地含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和适宜的有机溶剂或溶剂混合物。为了生产抗胃液的包衣,使用合适的纤维素制剂(诸如乙酰纤维素邻苯二甲酸酯或羟丙甲基纤维素邻苯二甲酸酯)的溶液。例如,为了鉴别或为了描绘活性化合物剂量的联合形式的特征,可以向片剂或糖衣丸芯包衣中加入染料或颜料。
可以口服的其他药物制剂包括由凝胶制成的推入配合式胶囊,以及由明胶和增塑剂(诸如甘油或山梨糖醇)制成的软密封胶囊。推入配合式胶囊可含有颗粒形式的活性化合物,它们可以与填充剂(诸如乳糖)、粘合剂(诸如淀粉)、和/或润滑剂(诸如滑石或硬脂酸镁)、以及可选的稳定剂混合。在软胶囊中,活性化合物优选溶解或悬浮于合适的液体(诸如脂肪油或液体石蜡)中。另外,可以加入稳定剂。
可以直肠应用的合适的药物制剂包括例如栓剂,它由一种或多种活性化合物与栓剂基质的结合物组成。合适的栓剂基质是例如天然或合成的甘油三酯或石蜡烃。此外,也有可能使用由活性化合物与基质的结合物组成的明胶直肠胶囊。合适的基质材料包括例如液体甘油三酯、聚乙二醇或石蜡烃。
用于胃肠外给药的适宜制剂包括水溶性形式的活性化合物的水溶液,例如水溶性盐和碱性溶液。另外,可以给药活性化合物的悬浮液作为适当油性的注射悬浮液。合适的亲脂性溶剂或载体包括脂肪油,例如芝麻油,或合成脂肪酸酯,例如油酸乙酯或甘油三酯或聚乙二醇-400(化合物可溶于PEG-400)。含水注射悬浮液可含有能增加该悬浮液粘度的物质,包括例如羧甲基纤维素钠、山梨糖醇和/或葡聚糖。可选地,悬浮液还可含有稳定剂。
下列实施例是说明而不是限制本发明的方法和组合物的。常在临床治疗中遇到并且对本领域技术人员来说显而易见地,对各种条件和参数的其他合适的修饰和改变都在本发明的精神实质和范围内。
3α-羟基-3β-甲氧基甲基-5α-和5β-孕烷-20-酮从(3R)-螺[环氧乙烷-2’,5α-或5β-孕烷]-20-酮和甲醇钠制备,如Hogenkamp等所述,见“3β-取代的-3α-羟基孕烷-20-酮的合成和体外活性:GABAA受体的变构调节剂”,《医药化学杂志》40:61-72(1997)。21-取代的类固醇从相应的使用带有催化HBr的存在于MeOH中的Br2从20-甾酮类合成的21-溴代类固醇制备。
实施例1
3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮21-溴-3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮
向在室温下搅拌着的3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮(30.0g,82.9mmol)的900mL甲醇溶液中加入3滴48%HBr水溶液。然后在2小时内滴加溴(13.9g,87.1mmol)的200mL甲醇溶液,在此期间使反应避光。又经过30分钟后,TLC(1%丙酮/二氯甲烷)指示已不存在原料并形成了少量极性产物。将该反应物浓缩至大约300mL,然后加入CH2Cl2(400mL),并将该反应物倒入含有200mL水的分液漏斗中。使相分离,水相用CH2Cl2(3×100mL)萃取。将有机相合并,用200mL饱和NaHCO3水溶液洗涤,用Na2SO4干燥,减压浓缩,得到淡黄色泡沫状溴化物。不进行进一步的纯化。3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮
向在上面制得的溴化物(36.7g,82.9mmol)的800mL CH3CN悬浮液中加入咪唑(28.2g,415mmol),该反应在氩气下加热至回流。回流1小时后反应完全(TLC,95∶4.5∶0.5 CH2Cl2∶MeOH∶三乙胺(TEA))。使反应冷却至室温,然后真空浓缩。将所得油状物溶于600mL CH2Cl2,用稀NaHCO3溶液(4×200mL)洗涤,用Na2SO4干燥并真空浓缩。经快速色谱法在硅胶上纯化,用95∶4.5∶0.5 CH2Cl2∶MeOH∶TEA洗脱,得到18g标题化合物,为白色固体,mp185-187℃(真空毛细管)。
计算值C36H40N2O3:C,72.86;H,
9.41;N,6.54实测值:C,72.64;H,9.35;N,6.42.1H NMR(300MHz,
CDCl3)δ 7.40(s,1H),7.08(s,1H),6.84(s,1H),4.72(d,1H,J=17.7Hz),
4.64(d,1H,J=18Hz),3.39(s,3H),3.18(s,2H),2.57(t,1H,J=8.7Hz),
0.76(s,3H),0.66(s,3H).
实施例2
3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮,盐
酸盐
向溶于35mL CH2Cl2中的3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮(1.00g,2.33mmol)的溶液中通入氯化氢气体(Aldrich)7分钟。形成白色沉淀。真空除去溶剂,得到1.10g盐酸盐,为白色固体,mp 230-233℃。1H NMR(300MHz,CDCl3)δ 9.66(s,1H),7.31(s,1H),7.05(s,1H),5.45(d,1H,J=18Hz),5.26(d,1H,J=18Hz),3.39(s,3H),3.19(s,2H),2.72(t,1H,J=8.7Hz),0.76(s,3H),0.70(s,3H).
实施例3
3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5β-孕烷-20-酮
向3α-羟基-3β-甲氧基甲基-5β-孕烷-20-酮(2.0g,5.53mmol)的100mL MeOH溶液中加入1滴48%HBr水溶液,之后在1小时内滴加溴(955mg,5.97mmol)的MeOH溶液。TLC(2%丙酮/CH2Cl2)指示反应完全。该反应物用50mL CH2Cl2稀释并在各100mL的CH2Cl2和饱和NaHCO3水溶液之间分配。将水层分离并用CH2Cl2(3×25mL)洗涤。将合并后的有机层干燥(Na2SO4)并真空浓缩。所得残余物溶于CH3CN(100mL)并用固体咪唑(5当量;1.88g,27.6mmol)处理。回流1小时后,使该反应物冷却并浓缩至干。残余物在CH2Cl2和饱和NaHCO3水溶液之间分配。将水层分离并用CH2Cl2(3×25mL)洗涤。将合并后的有机层干燥(Na2SO4)并真空浓缩。经快速色谱法在硅胶上纯化,用95∶4.5∶0.5 CH2Cl2∶MeOH∶TEA洗脱,得到1.9g标题化合物,为固体。
1H NMR(CDCl3,300MHz)δ 7.42(s,1H),7.10(s,1H),6.86(s,1H),4.69(m,
2H),3.40(m,5H),2.57(t,1H),0.94 (s,3H),0.67(s,3H).
实施例4
3α-羟基-3β-甲氧基甲基-21-(2’-四唑基)-5α-孕烷-20-酮
存在于无水THF(15mL)中的21-溴-3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮(1.70g,3.85mmol)、IH-四唑(Aldrich;0.27g,3.85mmol)和碳酸钾(2.60g,19.3mmol)在氩气下在回流下加热过夜。然后该混合物在水(50mL)和EtOAc(75mL)之间分配。将有机层分离,用水洗涤,用Na2SO4干燥并蒸发。残余物用硅胶色谱法纯化,用EtOAc/己烷(1∶1)洗脱,得到830mg(50%)标题化合物,mp 165-167℃。1H NMR(300MHz,CDCl3)δ 8.56(s,1H),5.45(s,2H),3.39(s,3H),3.19(s,2H),0.77(s,3H),0.71(s,3H).
实施例5
21-(5’-氨基-[1,3,4]-噻二唑-2-基硫基)-3α-羟基-3β-甲氧基
甲基-5α-孕烷-20-酮
将21-溴-3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮(4.00g,9.72mmol)溶于200mL乙腈并一次性加入固体5-氨基-[1,3,4]-噻二唑-2-硫醇(1.42g,10.7mmol)。加入净三乙胺(1.49mL,10.7mmol)得到澄清溶液。在室温下搅拌30分钟后,有白色沉淀形成,TLC(3∶1己烷∶丙酮)显示反应完全。将该混合物冷却至0℃,沉淀通过过滤分离并用乙腈洗涤。所得固体真空干燥,得到3.86g(80%)标题化合物,为白色固体,mp 169-172℃。1H NMR(CDCl3):δ 5.07(bs,2H),4.11(s,2H),3.39(s,3H),3.18(s,2H),2.74(t,1H),0.75(s,3H),0.64(s,3H).计算值C25H39N3O3S2:C,60.82;H,7.96;N,8.51;S 12.99.实测值:C,60.70;H,7.79;N,8.51;S,12.67.
实施例6
3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-
酮,N-氧化物3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮
在室温下向6-羟基喹啉(Acros,99+%;4.74g,32.6mmol)在600mL乙腈中的悬浮液中加入叔丁醇钾的1.0M THF溶液(32.6mL,32.6mmol)。搅拌15分钟后,加入在实施例2中制备的21-溴化物固体(12.0g,27.2mmol)并使该反应物在室温下搅拌过夜。TLC分析(1∶1己烷/乙酸乙酯)显示溴化物已完全消耗并形成了极性更大的UV活性产物。加入水(~750mL)并将所得混合物搅拌15分钟。将该悬浮液真空过滤得到标题化合物(12.6g,91%),为黄褐色固体,mp 178-180℃。该物质的样品进行燃烧分析,得到以下结果:对C32H43NO4-1/8H2O的计算值:C,75.67;H,8.58;N,2.76。实测值:C,75.31;H,8.74;N,2.63。3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮N-氧化物
向在上面制得的喹啉(12.0g,23.7mmol)的400mL二氯甲烷溶液中加入3-氯过苯甲酸(Aldrich,57-83%;6.53g,~26mmol),所得溶液在室温下搅拌过夜。TLC(1∶1二氯甲烷/乙酸乙酯)指示喹啉已完全消耗并形成了极性更大的产物。将该反应物转移到分液漏斗中并用饱和NaHCO3水溶液(3×250mL)洗涤。合并后的有机层用Na2SO4干燥并真空浓缩。所得橘色固体用各100mL的己烷和乙腈研制过夜。将该混合物真空过滤得到浅黄褐色固体产物(9.59g,78%),mp:在180℃下变软,在197-200℃下熔化。该物质的样品进行燃烧分析,得到以下结果:对C32H43NO5-1/2 H2O的计算值:C,72.42;H,8.35;N,2.64。实测值:C,72.40;H,8.48;N,2.44。从EtOAc/MeOH重结晶得到标题化合物,为浅黄褐色棱晶,mp 210-212℃(真空毛细管)。
1H NMR(300MHz,CDCl3)
δ 8.68(d,1H,J=9.6Hz),8.39(d,1H,J=6.3Hz),7.59(d,1H,J=8.4Hz),
7.44(dd,1H,J=2.6,9.4Hz),7.24(m,1H),7.00(d,1H,J=2.4Hz),4.71(d,
1H,J=16.5Hz),4.62(d,1H,J=16.5Hz),3.39(s,3H),3.18(s,2H),2.83(t,
1H),0.76(s,3H),0.70(s,3H).
实施例7
3α-羟基-3β-甲氧基甲基-取代的类固醇的作用持续时间
下表I中比较了结构非常相关的各对3β-甲基和3β-甲氧基甲基类固醇的体外效能[抑制[35S]-叔丁基二环硫代磷酸酯(TBPS)的结合的能力],旋转棒TD50(半数试验动物不能在旋转的棒上停留1分钟时的剂量)和所有试验动物都能通过旋转棒试验前时间的长度(作用持续时间)。用于测量本发明化合物的体外和体内活性的这些方法完全公开在美国专利5,232,917中。TBPS测定得到了化合物的体外效能,而旋转棒测定评价了化合物的镇静剂/安眠剂活性。既然化合物的作用持续时间取决于剂量并将在更高的剂量下延长,于是在所有动物都没有通过旋转棒试验的最低剂量下测量作用持续时间。对于作用持续时间>240分钟的化合物,在240分钟时通过旋转棒试验的动物数记在圆括号中。在每对化合物中,3β-甲基类固醇具有大于240分钟的生物学持续作用时间,而相应的每个3β-甲氧基甲基类固醇的作用持续时间下降至180分钟或更短。此外,3β-甲基类固醇显示在240分钟时只有不到一半的动物通过旋转棒试验,这提示其作用持续时间明显更长。在表I中所列的2个一对的3β-甲氧基甲基和3β-甲基类固醇中,前者比后者有更短的作用持续时间,尽管体外效能要强2倍。因此,特定的3β-甲氧基甲基-取代的神经活性类固醇提供了独特而出乎意料的药动学性能,使得它们尤其可用作镇静剂/安眠剂和麻醉剂。
表I.3β-甲基和3β-甲氧基甲基类固醇对大鼠的体外效能和生物学作用持续时间的比较a
化合物 | 3β-基 | TBPSIC50(nM) | RR TD50口服(mg/kg) | 作用持续时间(分钟) |
3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮 | MeOCH2 | 138 | 28 | 140 |
3α-羟基-21-(1’-咪唑基)-3β-甲基-5α-孕烷-20-酮 | Me | 97 | 31 | >240(3/8通过) |
3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮,N-氧化物 | MeOCH2 | 25 | 29 | 84 |
3α-羟基-3β-甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮,N-氧化物 | Me | 46 | 15 | >240(1/8通过) |
3α-羟基-3β-甲氧基甲基-21-(2’-四唑基)-5α-孕烷-20-酮 | MeOCH2 | 24 | 35 | 120 |
3α-羟基-3β-甲基-21-(2’-四唑基)-5α-孕烷-20-酮 | Me | 44 | 4.5 | >240(0/8通过) |
21-(5’-氨基-[1,3,4]-噻二唑-2-基硫基)-3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮 | MeOCH2 | 48 | 40 | <90 |
3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5β-孕烷-20-酮 | MeOCH2 | 174 | 30 | <180 |
aIC50是抑制[35S]-叔丁基二环硫代磷酸酯(TBPS)的50%特异性结合的类固醇的剂量。RR TD50是在大鼠旋转棒试验中半数动物未能通过该试验时的剂量。在所有动物都未能通过旋转棒试验的最低剂量下测量的作用持续时间是所有试验动物再一次通过旋转棒试验所需的时间。
现已对本发明进行了充分的描述,本领域普通技术人员将理解:本发明可以在宽泛且等价范围内的条件、制剂和其他参数下实施,而不会影响本发明或其任何一种实施方案的保护范围。本文中提到的所有专利和出版物都完全地整个结合在此作为参考。
Claims (13)
2、权利要求1化合物,其中:
R3是可选取代的N-连接的单环杂芳基。
3、权利要求1化合物,其中:
R3是-X-R4;
R4是可选取代的碳连接的二环杂芳基;和
X=O。
4、权利要求2化合物,其中:
R3是可选取代的(1’-咪唑基)或可选取代的(2’-四唑基)。
5、权利要求3化合物,其中:
R4是碳连接的可选取代的喹啉或异喹啉或相应的N-氧化物;和
X=O。
6、权利要求1化合物,其中:
R3是-X-R4;
R4是碳连接的单环杂芳基;和
X=S。
7、权利要求4化合物,它是3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5α-孕烷-20-酮或3α-羟基-21-(1’-咪唑基)-3β-甲氧基甲基-5β-孕烷-20-酮或其药学上可接受的盐。
8、权利要求4化合物,它是3α-羟基-3β-甲氧基甲基-21-(2’-四唑基)-5α-孕烷-20-酮。
9、权利要求5化合物,它是3α-羟基-3β-甲氧基甲基-21-(喹啉-6-基氧基)-5α-孕烷-20-酮,N-氧化物。
10、权利要求6化合物,它是21-(5’-氨基-[1,3,4]-噻二唑-2-基硫基)-3α-羟基-3β-甲氧基甲基-5α-孕烷-20-酮。
11、一种药物组合物,它包含权利要求1化合物和药学上可接受的载体。
12、减轻或预防受治疗动物的失眠症的方法,包括对需要这种治疗的所述受治疗动物给药有效量的权利要求1化合物。
13、对需要这种处理的受治疗动物诱导麻醉的方法,包括对需要处理的所述受治疗动物给药有效量的权利要求1化合物。
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- 2000-04-28 CA CA002372342A patent/CA2372342A1/en not_active Abandoned
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2001
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2002
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107404877A (zh) * | 2014-10-16 | 2017-11-28 | 萨奇治疗股份有限公司 | 靶向cns 障碍的组合物和方法 |
CN112940066A (zh) * | 2014-10-16 | 2021-06-11 | 萨奇治疗股份有限公司 | 靶向cns障碍的组合物和方法 |
CN112961206A (zh) * | 2014-10-16 | 2021-06-15 | 萨奇治疗股份有限公司 | 靶向cns障碍的组合物和方法 |
CN113473991A (zh) * | 2018-08-31 | 2021-10-01 | 普拉西斯精密医药公司 | Gabaa阳性别构调节剂的盐和结晶形式 |
CN113226326A (zh) * | 2018-12-17 | 2021-08-06 | 细胞内治疗公司 | 有机化合物 |
Also Published As
Publication number | Publication date |
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NZ515779A (en) | 2003-11-28 |
PL351438A1 (en) | 2003-04-22 |
CA2372342A1 (en) | 2000-11-09 |
US20040034002A1 (en) | 2004-02-19 |
NO20015262L (no) | 2001-12-19 |
YU77701A (sh) | 2005-07-19 |
KR20020013530A (ko) | 2002-02-20 |
HUP0201818A2 (en) | 2002-10-28 |
EP1177206A1 (en) | 2002-02-06 |
MXPA01010915A (es) | 2002-11-07 |
AU780989B2 (en) | 2005-04-28 |
ZA200109847B (en) | 2003-02-26 |
CN1187367C (zh) | 2005-02-02 |
HUP0201818A3 (en) | 2004-04-28 |
HK1047594A1 (en) | 2003-02-28 |
AU4810400A (en) | 2000-11-17 |
JP2002543218A (ja) | 2002-12-17 |
US20050171074A1 (en) | 2005-08-04 |
NO20015262D0 (no) | 2001-10-26 |
WO2000066614A1 (en) | 2000-11-09 |
CZ20013867A3 (cs) | 2002-07-17 |
WO2000066614A8 (en) | 2001-03-15 |
IL146230A0 (en) | 2002-07-25 |
NO321536B1 (no) | 2006-05-22 |
BR0010060A (pt) | 2002-01-15 |
RU2243232C2 (ru) | 2004-12-27 |
UA73736C2 (en) | 2005-09-15 |
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