CN1271356A - 作为相应抗真菌剂前药的四氢呋喃磷酸酯-和羟基酯 - Google Patents
作为相应抗真菌剂前药的四氢呋喃磷酸酯-和羟基酯 Download PDFInfo
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- CN1271356A CN1271356A CN98809550A CN98809550A CN1271356A CN 1271356 A CN1271356 A CN 1271356A CN 98809550 A CN98809550 A CN 98809550A CN 98809550 A CN98809550 A CN 98809550A CN 1271356 A CN1271356 A CN 1271356A
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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Abstract
公开了式(Ⅰ)的化合物,其中G是H或PO3H2,或其可药用盐、含有这些化合物的药物组合物以及用这些化合物或含有它们的药物组合物治疗或预防真菌感染的方法。
Description
发明背景
本发明涉及四氢呋喃抗真菌磷酸酯,即5-[[2(S)-[4-[4-[4-[4-[[(R-顺)-5-(2,4-二氟苯基)-四氢-5-(1H-1,2,4-三唑-1-基甲基)-3-呋喃基]甲氧基]苯基]-1-哌嗪基]苯基]-4,5-二氢-5-氧代-1H-1,2,4-三唑-1-基]-1(S)-甲基丁基]氧基]-5-氧代丁基磷酸酯,并涉及四氢呋喃抗真菌丁酸酯,即(-)-2(S)-[4-[4-[4-[4-[[(R-顺)-2-(2,4-二氟苯基)-四氢-2-(1H-1,2,4-三唑-1-基甲基)-4-呋喃基]甲氧基]苯基]-1-哌嗪基]苯基]-4,5-二氢-5-氧代-1H-1,2,4-三唑-1-基]-1(S)-甲基丁基4-羟基丁酸酯,及其可药用盐,含有这些抗真菌剂的药物组合物以及用它们在患者中治疗或预防真菌感染的方法。
国际申请WO96/38443(公开于1996年12月5日)和WO95/17407(公开于1995年6月29日)公开了多种四氢呋喃抗真菌剂和其磷酸酯,但是其中没有公开本发明的四氢呋喃抗真菌化合物。
对广谱抗真菌剂存在需求,这些抗真菌剂具有适于非肠道给药的溶解度,并具有治疗和/或预防系统真菌感染、特别是对曲霉属(Aspergillus)、念珠菌属(Candida)、隐球酵母属(Cyrptococcus)以及机会感染的有利活性。
发明概述
式II的本发明化合物的可药用盐如二N-甲葡糖胺(“NMG”)盐由式II.2NMG表示,它是水溶性前药,其在体内转变为活性代谢物III,该代谢物在体内也可转变为式IV表示的抗真菌剂,其按照如下反应过程:
在体内式II的化合物水解为式III的化合物;III再在体内水解为式IV的化合物。II和III的水解主要发生在血清中和组织(肝、肺和肾)中。III水解为IV主要发生在血清中。
以存在于水中的其二NMG盐即式II.2NMG表示的形式,给小鼠静脉使用式II的化合物,在小鼠中提供了式IV化合物的优异的血浆浓度。见表1-3。
当化合物II的二NMG盐(II.2NMG)的水溶液给小鼠静脉给药时,其与式V化合物的二NMG盐(公开于WO95/17407第15页右下部)作平行对照,得自本发明的式II化合物二NMG盐的式IV化合物的药代动力学参数意外地优于得自式V的先有技术化合物的二NMG盐的式IV化合物的。结果见表3。
表1
静脉使用存在于灭菌水中的20mg/kg式IV化合物后(其剂量相当于式II表示的本发明化合物的二NMG盐),在混合小鼠1血浆(2只小鼠/混合体)中,式IV化合物的浓度。
μg/ml
hr 混合体1 混合体2 平均值 %CV30(未给药) 0.0002 0.000 0.0000.017(1min) 0.171 0.164 0.168 2.950.05(3min) 0.378 0.297 0.338 16.90.083(5min) 0.798 0.817 0.808 1.660.25(15min) 1.57 2.72 2.15 37.90.5(30min) 3.02 2.34 2.68 17.9
1hr. 4.46 3.95 4.21 8.58
3hr. 5.16 5.63 5.40 6.16
6hr. 5.96 3.59 4.78 35.1
24hr. 0.915 0.992 0.954 5.71Cmax(μg/ml) 5.40Tmax(hr) 3AUC(0-24hr) 79.1(μg.hr/ml)
1雄性Charles River小鼠,平均体重18-20g,得自CharlesRiver Wilmington,MA 01887
2低于低限量0.05μg/ml的值报告为0。
3%CV是变量百分系数,其是变性的相对量度。参见Steele andTorrie,“统计学原理和方法”,(1980),第二版,McGraw-Hill,NY,第27页。
表2
静脉使用存在于灭菌水中的20mg/kg式IV化合物后(其剂量相当于式V表示的现有技术化合物的二NMG盐),在混合小鼠1血浆(2只小鼠/混合体)中,式IV化合物的浓度。
μg/ml
hr 混合体1 混合体2 平均值 %CV40(未给药) 0.0001 0.000 0.000 -0.017(1min) 0.000 0.000 0.000 -0.05(3min) 0.738 0.663 0.723 11.70.083(5min) 1.04 1.43 1.24 22.30.25(15min) 1.22 0.407 0.814 70.60.5(30min) 1.99 ---3 1.99 -
1hr. 2.73 2.63 2.68 2.64
3hr. 0.923 2.51 1.72 65.4
6hr. 2.59 1.90 2.25 21.7
24hr. 0.447 0.515 0.481 10.0Cmax(μg/ml) 2.68Tmax(hr) 1AUC(0-24hr) 36.7(μg.hr/ml)
1雄性Charles River小鼠,平均体重18-20g,得自CharlesRiver,Wilmington,MA 01887
2低于低限量0.05μg/ml的值报告为0。
3检测器和计算机的连接中断,因此没有该值。
%CV是变量百分系数,其是变性的相对量度。参见Steele andTorrie,“统计学原理和方法”,(1980),第二版,McGraw-Hill,NY,第27页。
表3
给小鼠静脉使用存在于灭菌水中的20mg/kg式IV化合物后(其剂量相当于式II和V表示的化合物的二NMG盐),在小鼠1血浆(2只小鼠/混合体)中,式IV化合物的药代动力学(PK)参数。
式IV化合物的PK参数使用的化合物 Cmax Tmax AUC2 生物利用度
(μg/ml) (hr) (μg.hr/min) (%)式II.2NMG 5.40 3 79.1 65式V.2NMG 2.68 1 36.7 30
1雄性Charles River小鼠,平均体重18-20g,得自CharlesRiver,Wilmington,MA 01887。
2从时间0至24小时检测的曲线下面积(μg.hr/min)。
表3总结并比较了表1和2给出的药代动力学参数。得自本发明化合物的二NMG盐(II.2NMG)的式IV化合物的药代动力学参数优于得自现有技术式V化合物的二NMG盐的式IV化合物的药代动力学值。
对静脉注射了本发明式II表示的本发明化合物的鼠血浆分析得到的式IV化合物的药代动力学参数,惊人地出乎意料地优于静脉注射式IV表示的现有技术化合物的鼠血浆得到的数值(见表1-3)。
术语“机会真菌”包括隐球酵母属(Cryptococcus)、组织胞浆菌属(Histoplasma)、芽生菌属(Blastomyces)、球孢菌属(Coccidioides)、镰孢属(Fusarium)、毛霉属(Mucor)、副球孢子菌属(Paracoccidioides)、产色芽生菌(Fonsecaea)、瓶霉属(Wangiella)、孢子丝菌(Sporothrix)、肺囊虫(Pneumocystis)、丝胞酵母属(Trichosporon),这通过在适当的动物种如小鼠、大鼠或兔的体外和/或体内活性表明。本发明的化合物预计对原生动物们、细菌、革兰氏阴性、革兰氏阳性、厌氧菌的很多属和种具有活性,包括Legionella Borrelia、支原体属(Mycoplasma)、密螺旋体属(Treponema)、Gardnerella、毛滴虫属(Gardnerella)和锥体虫属(Trypanosoma)。
式I-III表示的本发明的化合物预期对人和动物的如下病原体具有广谱抗真菌活性:曲霉属、芽生菌属、念珠菌属、隐球酵母属、球孢菌属、表皮癣菌属(Epidermophyton)、产色芽生菌属、镰孢属、毛霉属、糖酵母属(Saccharomyces)、球拟酵母属(Torulopsis)、发癣菌属(Trichophyton)、丝胞酵母属、孢子丝菌和肺囊虫。
式III和IV的化合物-式II化合物的体内转变产物-在小鼠体内实验具有抗真菌活性,且此活性比现存的抗真菌剂如伊曲康唑和氟康唑以及Saksena等在US 5039676和国际专利申请No.93/09114中特别公开的唑系化合物出人意料地好。
式II、III和IV化合物对念珠菌属的41个种、曲霉属的31个种和隐球酵母属的9个种的体外抗真菌活性总结于表5。根据对MICs(mcg/ml)的几何平均数的比较,式III和IV化合物的体外抗真菌活性彼此相似;II的体外活性低得多。式II化合物在两个小鼠模型中表现出良好的体内活性。10mg/kg剂量的II使系统白色念珠菌感染的小鼠在第9天100%存活,而使肺烟曲霉感染的小鼠70%存活;伊曲康唑在此小鼠曲霉肺感染模型中无活性。此小鼠曲霉肺感染模型按照David Loebenberg等的“抗真菌剂Sch 39304的活性对映体Sch42427的体外和体内活性”,Antimicrobial Agents andChemotherapy(1992),Vol.36,pp.498-501进行。
对人组织和血清的药代动力学研究表明式II的化合物通过式III表示的代谢物代谢为式IV的化合物。在cynomologus猴以二NMG盐的形式进行式II化合物静脉内(IV)输液时,血浆浓度表现出表4总结的药代动力学(PK)性质。
表4
II.2NMG静脉输液后Cynomolgus猴PK水平
化合物 Cmax(μg/ml) AUC1
II 40.7 3.98
III 4.8 4.41
IV 1.04 24.11
1.从时间0至48小时测量曲线下面积,即AUC(0-48小时),单位为μg.hr/ml。
式I-III抗真菌化合物和这些化合物的药物组合物预计对哺乳动物、特别是人具有抗过敏、抗炎和免疫调节活性、广谱抗感染活性,例如,抗细菌、抗原虫和抗线虫活性。
本发明还提供了治疗或预防真菌感染的组合物,其中含有抗真菌有效量的式I化合物或其可药用盐以及可药用载体或稀释剂。
本发明的药物组合物还可以含有杀真菌有效量的其它抗真菌化合物如细胞壁活性的化合物。术语“细胞壁活性的化合物”在本文中指干扰真菌细胞壁的任何化合物,包括但不限于化合物如阜孢霉素类,echinocandins和阿库来菌素类以及真菌细胞壁抑制剂如烟霉素,以及US 5006513描述的其它化合物,将该文献引入作为参考。
表5
体外抗真菌活性(mcg/ml)
化合物 微生物 G平均 范围MICs1 | |||
IIIIII | 曲霉种类2(n=30)念珠菌种类3(n=41)2新型隐球酵母3(n=9)3 | 5.97.51.9 | 0.5 to >321 to >320.125 to 32 |
IIIIIIIII | 曲霉种类2(n=30)念珠菌种类3(n=41)新型隐球酵母3(n=9) | 0.20.30.09 | 0.0313 to 2≤0.0156 to 80.0156 to 0.5 |
IVIVIV | 曲霉种类2(n=30)念珠菌种类3(n=41)新型隐球酵母3(n=9) | 0.10.20.04 | ≤0.0156 to 1≤0.0156 to 8≤0.0150 to 0.5 |
1几何平均MICs
2按照Espinel-Ingroff′s方法检测的抗曲霉属的体外活性
3按照对NCCLS标准M27A的方法检测的体外活性。
本发明化合物的可药用盐包括可药用的碱加成盐。
适用于本发明的可药用碱为能与式I或II的酸性抗真菌化合物形成可药用盐的那些碱,包括适宜的有机和无机碱。适宜的有机碱包括伯、仲和叔烷基胺、烷醇胺、芳胺、烷基芳胺和环胺。有机胺的实例包括可药用的碱,其选自氯普鲁卡因、普鲁卡因、哌嗪、葡糖胺、N-甲基葡糖胺、N,N-二甲基葡糖胺、亚乙基二胺、二乙醇胺、二异丙基胺、二乙基胺、N-亚苄基二胺、二乙醇胺、二异丙基胺、二乙基胺、N-苄基-2-苯乙胺、N,N′-二苄基亚乙基二胺、胆碱、克立咪唑、三乙胺(“Et3N”)、三(羟甲基)氨基甲烷或D-葡糖胺。优选的有机碱包括N-甲基葡糖胺(“NMG”)、二乙醇胺和三(羟甲基)氨基甲烷(“TRIS”)。更优选在本发明中使用两个当量的NMG。适宜的无机碱还包括碱金属氢氧化物如氢氧化钠。
本发明的药物组合物可以适应于任何给药形式,例如,口服、非肠道如SC,IM,IV和IP、局部或阴道给药或通过吸入(口或鼻内)。通过将式II化合物或一个或两个当量的可药用碱如NMG形成式II.2NMG的可接受盐与适宜的惰性可药用载体或稀释剂混合制备这些组合物。
适宜的组合物的实例包括用于口服的固体或液体组合物,如片剂、胶囊、丸剂、粉剂、颗粒、溶液、栓剂、糖锭、锭剂、小丸剂、混悬剂或乳剂。固体载体可以是一种或多种物质,它们也可作为稀释剂、矫味剂、增溶剂、润滑剂、助悬剂、粘合剂或片剂崩解剂;它也可以是包封物质。在粉剂中,载体是细粒度固体,其与细粒度的活性化合物混合。在片剂中,此活性化合物与具有需要粘合性的载体以适当比例混合并压制为所需的形状和大小。
可以按照本领域熟知的方法制备局部剂型,并可以含有多种组分、赋形剂和添加剂。局部使用的制剂包括软膏、霜剂、洗剂、粉剂、气雾剂、子宫托和喷雾剂。
为了制备栓剂,先将低熔点蜡如脂肪酸甘油酯的混合物或可可脂熔化,并通过搅拌将活性组分均匀地分散在其中。然后将此熔融的均匀混合物倒入适宜尺寸的模中,让其冷却并固化。
液体制剂包括溶液剂、混悬剂和乳剂。例如,对于非肠道注射可以提及水-丙二醇溶液。液体制剂也可以在每分子带有2至11个羟丙基的含适量羟丙基的α、β或γ环糊精、聚乙二醇如PEG-200或丙二醇的溶液中配制,,此溶液中也可以含水。适于口服的含水溶液剂可以通过在水中加入活性组分并按照需要加入适宜的着色剂、矫味剂、稳定剂、甜味剂、增溶剂和增稠剂来制备。适于口服的含水混悬剂可以通过将细粒度的活性组分分散在水中制备。特别优选的含水药物组合物可以由式I化合物与羟丙基-β-环糊精一起在水中制备。α-、β-和γ-环糊精的衍生物例如羟丙基-β-环糊精的用途描述于N.Bodor的US4983586、Pitha的US 4727064和日本药物国际专利申请PCT/EP84/00417中。
本发明的药物组合物可以通过将可药用载体如羟丙基-β-环糊精在水中混合,并向其中加入抗真菌有效量的本发明化合物制备。将如此形成的溶液过滤,并任选地通过熟知方法例如旋转蒸发或冻干除去水。此溶液的形成可以在约15℃至35℃温度下进行。水一般是灭菌水并还可以含有可药用盐和缓冲剂,例如,磷酸盐或枸橼酸盐以及防腐剂。式I的抗真菌化合物与羟丙基-β-环糊精的摩尔比为约1∶1至1∶80,优选1∶1至1∶2。一般来说,羟丙基-β-环糊精是过量的。
还包括在临使用前转变为液体制剂以口服或非肠道给药的固体制剂。该预转变为液体剂型的固体制剂除活性物质如本发明的化合物和任选存在的细胞壁活性化合物(特别是真菌细胞壁抑制剂如烟霉素)外,可以含有矫味剂、着色剂、稳定剂、缓冲剂、合成或天然甜味剂、分散剂、增稠剂、增溶剂等。用于制备此液体制剂的溶剂可以是水、等渗水、乙醇、甘油、聚乙二醇、丙二醇等,及其混合物。
静脉、肌内或皮下注射的非肠道给药剂型常是灭菌溶液的形式,并可以含有盐或葡萄糖以使此溶液等渗。
供人抗真菌使用的局部制剂形式为含有式I化合物(浓度通常为约0.1%至约20%,优选约0.5%至约10%重量)和无毒可药用局部给药载体的药物制剂,其直到症状改善前将其每天一次或多次施用于被感染的皮肤。
总之,供人抗真菌用口服剂型的用量为约1mg/每千克体重/每天至约30mg/每千克体重/每天,以单剂量或分开的剂量给药,优选约1mg/每千克体重至约20mg/每千克体重/每天,并首选约1mg/每千克体重至约10mg/每千克体重/每天。
总之,供人抗真菌用非肠道给药剂型的用量为约1mg/每千克体重/每天至约30mg/每千克体重/每天,以单剂量或分开的剂量给药,优选约1mg/每千克体重至约20mg/每千克体重/每天,并首选约1mg/每千克体重至约8mg/每千克体重/每天。
静脉(IV)输液是优选的给药途径。优选200-450mg的单剂量或分开的剂量,每天两次IV输液。首选200-250mg每天两次IV输液。
当然,本发明抗真菌用化合物的准确剂量、给药频率和时期会依患者的性别、年龄和病症以及临床医生确诊的感染严重性变化。
实验
实施例1
制备式II化合物及式II.2NMG盐
向搅拌的、10g(14mmol)式IV化合物(按照1996年12月5日公开的WO96/38443的实施例32的方法制备)和2.27g(1.3eq)的碱4-(N,N-二甲基氨基)吡啶(“DMAP”)在200ml二氯甲烷的混合物中,滴加4-溴丁酰氯(1.3eq,18.6mmol,3.44g)并室温下搅拌所得反应混合物至由薄层色谱(“TLC”)确定反应完全。将此反应混合物在饱和碳酸氢钠水溶液和乙酸乙酯(“EtOAc”)之间分配。分离有机相,用水洗涤并用硫酸镁干燥。除去有机溶剂并在硅胶色谱柱上用乙酸乙酯作为洗脱剂纯化所得残余物,得到8.58g溴化物VI,为白色固体。
步骤(B)
向搅拌的、步骤A的溴化物VI(3.44g,4.0mmol)的200ml干燥的苯溶液中,加入二苄基磷酸银(由Sigma Chemical Co.,St.Louis提供)(2.0eq,8.2mmol,3.14g)并将所得反应混合物加热回流20小时。将此反应混合物冷却并过滤,将此滤液在乙酸乙酯和10%盐酸之间分配。分离有机相,用水洗涤,用硫酸镁干燥,并减压浓缩得到残余物。将此残余物在硅胶色谱柱上用乙酸乙酯∶甲醇(20∶1(v/v))作为洗脱剂纯化得到0.976g起始物溴化物VI和1.221g所需二苄基磷酸酯VII,为淡棕色固体。
室温下,将10%钯碳(0.60g)和步骤B的二苄基磷酸酯VII(1.2g,1.14mmol)在乙醇(40ml)和乙酸(“HOAc”)(40ml)的搅拌的悬浮液置于氢气氛下过夜(或16小时)。然后,用硅藻土垫将此反应混合物过滤并用甲醇彻底洗涤此固体垫。将合并的滤液减压浓缩得到0.976g化合物II,为淡棕色固体。
1H nmr:δH(CD3OD),8.38(s,1),8.06(s,1),7.77(s,1),7.42-7.48(m,2),7-34-7.42(m,1)7.06-7.23(m,5),6.96-7.03(m,1),6.83-6-90(m,2),5.13-5.22(m,1)4.67(s,2),4.09-4.17(m,2),3.70-3.91(m,4),3.39-3.45(m,4),3.24-3.30(m,4),2.50-2.65(m,2),2.30-2.38(m,2),2.14-2.22(m,1),1.74-1.98(m,4),1.30(d,3)和0.88(t,3).
FABMS(实测值:[MH+]867.3404;理论值:[MH+]867.3406)。
向步骤C的产物II(0.940g,1.08mmol)中加入存在于10ml水中的N-甲基葡糖胺(2eq,2.17mmol,0.423g)。将所得溶液过滤并在氮气流下浓缩此滤液,得到1.396g式II.2NMG表示的二NMG盐,为淡棕色固体。
1H nmr:δH(CD3OD),8.37(s,1),8.08(s,1),7.76(s,1),7.42-7.46(m,2),7.34-7.41(m,1),7.11-7.16(m,2),6.96-7.02(m,3),6.80-6.90(m,3),5.14-5.22(m,1),4.66(s,2),4.10-4.16(m,2),3.96-4.03(m,2),3.60-3.87(m,14),3.35-3.40(m,4),3.18-3.23(m,4),2.88-3.01(m,4),2.50-2.65(m,2),2.56(s,6),2.34-2.41(m,2),2.15-2.22(m,1),1.76-1.96(m,4),1.30(d,3)和0.87(t,3).
实施例2
制备式III的化合物:2(S)-[4-{4-{4-{4-[[(R-顺)-2-(2,4-二氟苯基)-四氢-2-(1H-1,2,4-三唑-1-基甲基)-4-呋喃基]甲氧基]苯基]-1-哌嗪基]苯基]-4,5-二氢-5-氧代-1H-1,2,4-三唑-1-基]-1-(S)-甲基丁基-4-羟基-丁酸酯
向搅拌的、0.29g 60%氢化钠在矿物油中的分散液(1eq,0.19g的氢化钠)在5ml二甲基甲酰胺(“DMF”)中的混悬液中,室温氮气氛下加入1.00g(7.7mmol)4-羟基丁酸钠盐。将所得反应混合物搅拌30分钟并加入1.36g(1eq,0.94ml)苄基溴。将所得反应混合物搅拌过夜。用水处理后,分离粗品并将其在硅胶色谱柱上用乙酸乙酯-己烷(1∶20,v/v)作为洗脱剂纯化,制备了0.271g苄基酯,4-苄氧基丁酸苄基酯。
向0.27g(0.95mmol)步骤(A)苄基酯在3ml甲醇和1ml水溶液中的搅拌的混合物中,一次性地加入氢氧化钠(2eq,1.9mmol,73mg)。将所得混合物搅拌3小时,然后减压浓缩。将所得残余物在乙醚(Et2O)和水之间分配。分离出水相,用乙醚洗涤,用盐酸酸化,并加入二氯甲烷。用硫酸镁干燥此有机相并浓缩得到0.153g 4-苄氧基丁酸,为无色油状物。
向1.0g步骤(B)得到的4-苄氧基丁酸、0.507mmol,3.62g式IV化合物(按照1996年12月5日公开的WO96/38443的实施例32的方法制备)和0.82g碱4-(N,N-二甲基氨基)吡啶(“DMAP”)在50ml二氯甲烷中的混合物中,加入1.26g二环己基碳二亚胺(“DCC”),并将所得反应混合物室温下搅拌至由薄层色谱(“TLC”)确定反应彻底(4小时)。将此反应混合物在5%枸橼酸和乙酸乙酯之间分配。分离有机相,用水洗涤并用硫酸镁干燥。除去有机溶剂并将所得残余物在硅胶色谱柱上用乙酸乙酯作为洗脱剂进行纯化,得到2.8g苄基醚VIII。H1 NMR与结构VIII一致。FABMS(实测值:[MH]+,877.4182 C48H55N8O6F2要求877.4213);[α]D 24=(-)56.5°(c,1.01;CHCl3);1H nmr:δH(CDCl3),8.12(s,1),7.80(s,1),7.58(d,1),7.24-7.43(m,8),6.75-7.01(m,8),5.18-5.27(m,1),4.64(A of AB,1),4.52(B of AB,1),4.44(s,2),4.16-4.24(m,1),4.09-4.14(m,1),3.76-3.81(m,1),3.68-3.74(m,1),3.59-3.65(m,1),3.41-3.46(m,2),3.30-3.36(m,4),3.18-3.24(m,4),2.51-2.66(m,2),2.34-2.40(m,2),2.05-2.12(m,1),1.74-1.99(m,4),1.29(d,3),和0.89(t,3).
步骤(D)
向搅拌的1.0g苄基醚VIII(按照实施例2步骤(C)制备)和1ml甲酸的40ml甲醇溶液中,加入0.5g钯黑催化剂。将所得反应混合物加热回流15分钟。将此反应混合物冷却至室温并过滤除去Pd催化剂。用甲醇洗涤滤出的催化剂。将合并的甲醇浓缩并在硅胶色谱柱上用在乙酸乙酯中的5%甲醇作为洗脱剂进行纯化,得到0.7g式III的醇。
FABMS(实测值:[MH]+787.3743.C41H49N8O6F2要求787.3714);[α]D 24=(-)64.80(c,1.03;CHCl3);1H nmr:δH(CDCl3),8.11(s,1),7.80(s,1)7.64(s,1),7.35-7.45(m,3),6.99-7.05(m,2),6.89-6.95(m,2),6.75-6.89(m,4),5.19-5.27(m,1),4.65(A of AB,1),4.51(B ofAB,1),4.18-4.24(m,1),4.08-4.15(m,1),3.75-3.81(m,1),3.68-3.73(m,1),3.53-3.65(m,3),3.32-3.40(m,4),3.18-3.26(m,4),2.51-2.66(m,2),2.34-2.41(m,2),2.04-2.12(m,1),1.88-1.99(m,1),1.74-1.84(m,3),1.32(d,3)和0.90(t,3).
向搅拌的实施例2步骤(D)的醇III(0.140g,0.18mmol)和四唑(0.53mmol,3eq,0.037g)的5ml二氯甲烷溶液中,滴加N,N-二异丙基二苄基磷酰胺(1.5eq,0.27mmol,0.0922g),并将所得反应混合物室温搅拌1小时。然后,向此搅拌的反应混合物中加入叔丁基过氧化氢(3eq,90μl,5.5M异辛醇溶液),并再继续搅拌3小时。将所得反应混合物在10%硫代硫酸钠水溶液和乙醇之间分配。分离有机相,用饱和碳酸氢钠水溶液洗涤并用无水硫酸钠干燥。将此有机相浓缩并在硅胶色谱柱上用乙酸乙酯-甲醇(20∶1,v/v)作为洗脱剂进行纯化,得到0.1389g二苄基磷酸酯化合物,其1H NMR确定的结构与实施例1步骤B的式VII一致。
按照实施例1步骤(C)的方法,处理实施例2步骤(C)的化合物VII,得到式II的标题化合物。
Claims (20)
2.含有抗真菌有效量的权利要求1的化合物和可药用载体的药物组合物。
3.权利要求2的药物组合物,其特征是适于非肠道给药。
4.权利要求2的药物组合物,其特征是适于静脉内给药。
5.权利要求2的药物组合物,其特征是适于静脉输液。
6.治疗或预防患者的真菌感染的方法,其中包括给所述患者使用抗真菌有效量的权利要求1的化合物。
7.治疗或预防患者的真菌感染的方法,其中包括给所述患者非肠道使用抗真菌有效量的权利要求1的化合物。
9.含有抗真菌有效量的权利要求8的化合物和可药用载体的药物组合物。
10.权利要求9的药物组合物,其特征是适于非肠道给药。
11.权利要求9的药物组合物,其特征是适于静脉内给药。
12.权利要求9的药物组合物,其特征是适于静脉输液。
13.治疗或预防患者的真菌感染的方法,其中包括给所述患者使用抗真菌有效量的权利要求9的化合物。
14.治疗或预防患者的真菌感染的方法,其中包括给所述患者非肠道使用抗真菌有效量的权利要求9的化合物或其可药用盐。
17.含有抗真菌有效量的权利要求16的化合物和可药用载体的药物组合物。
18.权利要求17的药物组合物,其特征是适于非肠道给药。
19.治疗或预防患者的真菌感染的方法,其中包括给所述患者使用抗真菌有效量的权利要求16的化合物。
20.治疗或预防患者的真菌感染的方法,其中包括给所述患者非肠道使用抗真菌有效量的权利要求16的化合物。
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ZA (1) | ZA988688B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112521378A (zh) * | 2019-12-26 | 2021-03-19 | 上海英诺富成生物科技有限公司 | 抗真菌水溶性前药及其制备方法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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AU1915500A (en) | 1998-11-20 | 2000-06-13 | Bristol-Myers Squibb Company | Water soluble prodrugs of azole compounds |
CN102906087B (zh) * | 2010-05-19 | 2016-03-23 | 桑多斯股份公司 | 制备手性三唑酮的方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5693626A (en) * | 1993-12-21 | 1997-12-02 | Schering Corporation | Tetrahydrofuran antifungals |
ATE204875T1 (de) * | 1993-12-21 | 2001-09-15 | Schering Corp | Fungizide tetrahydrofurane |
-
1998
- 1998-09-22 KR KR1020007003196A patent/KR20010024297A/ko not_active Application Discontinuation
- 1998-09-22 CA CA002304624A patent/CA2304624C/en not_active Expired - Fee Related
- 1998-09-22 IL IL13446998A patent/IL134469A0/xx unknown
- 1998-09-22 EP EP98961721A patent/EP1027349B1/en not_active Expired - Lifetime
- 1998-09-22 JP JP2000512827A patent/JP3473949B2/ja not_active Expired - Fee Related
- 1998-09-22 TR TR2000/00753T patent/TR200000753T2/xx unknown
- 1998-09-22 DE DE69828524T patent/DE69828524T2/de not_active Expired - Lifetime
- 1998-09-22 MY MYPI98004343A patent/MY133775A/en unknown
- 1998-09-22 PE PE1998000905A patent/PE120799A1/es not_active Application Discontinuation
- 1998-09-22 ID IDW20000551A patent/ID28294A/id unknown
- 1998-09-22 WO PCT/US1998/018508 patent/WO1999015522A1/en not_active Application Discontinuation
- 1998-09-22 ZA ZA988688A patent/ZA988688B/xx unknown
- 1998-09-22 HU HU0004616A patent/HUP0004616A3/hu unknown
- 1998-09-22 PT PT98961721T patent/PT1027349E/pt unknown
- 1998-09-22 ES ES98961721T patent/ES2232974T3/es not_active Expired - Lifetime
- 1998-09-22 AU AU16981/99A patent/AU1698199A/en not_active Abandoned
- 1998-09-22 PL PL98339488A patent/PL339488A1/xx unknown
- 1998-09-22 NZ NZ502709A patent/NZ502709A/en unknown
- 1998-09-22 AT AT98961721T patent/ATE286502T1/de not_active IP Right Cessation
- 1998-09-22 SK SK391-2000A patent/SK3912000A3/sk unknown
- 1998-09-22 BR BR9812671-7A patent/BR9812671A/pt not_active IP Right Cessation
- 1998-09-22 CN CN98809550A patent/CN1125066C/zh not_active Expired - Fee Related
- 1998-09-22 AR ARP980104741A patent/AR015458A1/es unknown
- 1998-09-23 CO CO98055163A patent/CO5011088A1/es unknown
-
2000
- 2000-03-24 NO NO20001557A patent/NO20001557L/no not_active Application Discontinuation
- 2000-08-17 HK HK00105167A patent/HK1025960A1/xx not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112521378A (zh) * | 2019-12-26 | 2021-03-19 | 上海英诺富成生物科技有限公司 | 抗真菌水溶性前药及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
IL134469A0 (en) | 2001-04-30 |
DE69828524T2 (de) | 2005-12-29 |
EP1027349B1 (en) | 2005-01-05 |
MY133775A (en) | 2007-11-30 |
EP1027349A1 (en) | 2000-08-16 |
BR9812671A (pt) | 2000-08-22 |
HK1025960A1 (en) | 2000-12-01 |
PT1027349E (pt) | 2005-05-31 |
ID28294A (id) | 2001-05-10 |
AU1698199A (en) | 1999-04-12 |
CA2304624C (en) | 2007-06-19 |
TR200000753T2 (tr) | 2001-01-22 |
DE69828524D1 (de) | 2005-02-10 |
ZA988688B (en) | 1999-03-23 |
KR20010024297A (ko) | 2001-03-26 |
WO1999015522A1 (en) | 1999-04-01 |
ES2232974T3 (es) | 2005-06-01 |
CN1125066C (zh) | 2003-10-22 |
JP2001517665A (ja) | 2001-10-09 |
NZ502709A (en) | 2001-11-30 |
AR015458A1 (es) | 2001-05-02 |
HUP0004616A3 (en) | 2002-04-29 |
CA2304624A1 (en) | 1999-04-01 |
PE120799A1 (es) | 1999-12-01 |
CO5011088A1 (es) | 2001-02-28 |
SK3912000A3 (en) | 2000-08-14 |
ATE286502T1 (de) | 2005-01-15 |
PL339488A1 (en) | 2000-12-18 |
HUP0004616A2 (hu) | 2002-03-28 |
NO20001557D0 (no) | 2000-03-24 |
JP3473949B2 (ja) | 2003-12-08 |
NO20001557L (no) | 2000-03-24 |
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