CN110143995B - 氮杂环取代18β-甘草次酸衍生物及其制备和应用 - Google Patents
氮杂环取代18β-甘草次酸衍生物及其制备和应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及氮杂环取代18β‑甘草次酸衍生物及其制备和应用,还涉及包含氮杂环取代18β‑甘草次酸衍生物及其旋光异构体和药学上可接受的盐的药物组合物,及其它们在制备治疗和/或预防各种癌症的药物中的用途。本发明涉及的通式I所示的衍生物,及其旋光异构体和药学上可接受的盐结构如下:其中,X、Y、Z、m如权利要求书和说明书所述。
Description
技术领域:
本发明属于医药技术领域,具体涉及氮杂环取代18β-甘草次酸衍生物及其制备和应用,还涉及包含氮杂环取代18β-甘草次酸衍生物及其旋光异构体和药学上可接受的盐的药物组合物,及其它们在制备治疗和/或预防各种癌症的药物中的用途。
背景技术:
18β-甘草次酸是甘草中包含的主要成分甘草酸水解脱去两分子葡萄糖醛酸后的产物,属于齐墩果烷型五环三萜类化合物,具有广泛的药理活性。其中,18β-甘草次酸的抗肿瘤作用一直备受人们关注。但18β-甘草次酸水溶性差,生物利用度低,抗癌活性与现在临床应用的抗癌药物相比差距比较大。为增强其抗肿瘤活性,研究者设计和合成了许多18β-甘草次酸衍生物,其抗肿瘤活性具有显著提升。
含氮杂环是一类重要的生物活性物质,许多抗肿瘤化合物中都引入了含氮杂环来提高其活性。同样的,在五环三萜类化合物中引入含氮杂环后,抗肿瘤活性具有显著提高,其理化性质和成药性具有一定改善,因此在18β-甘草次酸中引入含氮杂环,有望获得具有良好抗肿瘤活性和理化性质的药物。
本发明人设计并合成了一系列氮杂环取代18β-甘草次酸衍生物,经细胞活性筛选,所合成的化合物具有较好的肿瘤细胞生长抑制活性。
发明内容:
本发明所解决的技术问题是提供氮杂环取代18β-甘草次酸衍生物及其制备方法,还提供了所述氮杂环取代18β-甘草次酸衍生物在制备预防和/或治疗肿瘤药物中的应用。
本发明涉及通式I所示的衍生物,及其旋光异构体或药学上可接受的盐:
X为卤素,卤代C1-C6烷基,C1-C4磺酰基;
Y为
Y左边连接甘草次酸骨架,右边连接含氮杂环;
Z为C,N,O,S;
当Z为C时,Z可以被R1、R2所取代,其中,
R1、R2可相同或不同,为氢原子,氧代,氨基,卤素,取代或未取代的C1-C6饱和或不饱和直链或支链烷基,取代或未取代的C1-C6饱和或不饱和直链或支链亚烷基,取代或未取代的C3-C7环烷基,所述烷基、亚烷基或环烷基可任选地用一个或多个选自以下的基团取代:羟基、氨基、卤素、二甲胺;
R1、R2也可为取代或未取代的C5-C6芳基或杂芳基,所述杂芳基可任选含有1-3个O、N或S的杂原子,所述芳基或杂芳基可任选地用一个或多个选自以下的基团取代:C1-C6烷基、C1-C6烷氧基、硝基、氰基、氨基、羟基、卤素;
R1、R2也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:羟基、氧代、氨基、卤素、C1-C4饱和或不饱和直链或支链烷基或亚烷基、C5-C10芳基、C5-C10芳基C1-C4烷基、C3-C7杂环基团、C3-C7杂环基团C1-C4烷基;
当Z为S时,Z可以被氢取代、氧代、被二氧代;
当Z为N时,Z可以被R3取代,其中,
R3可为氢,取代或未取代的C1-C6饱和或不饱和直链或支链烷基,所述烷基可任选地用一个或多个选自以下的基团取代:羟基、氨基、卤素、二甲胺;
R3也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:氢、羟基、氧代、氨基、卤素、C1-C4饱和或不饱和直链或支链烷基或亚烷基、C5-C10芳基、C5-C10芳基C1-C4烷基、C3-C7杂环基团、C3-C7杂环基团C1-C4烷基;
m为0-4的整数;
n为0-4的整数。
本发明优选通式I所示的化合物,及其旋光体或药学上可接受的盐,
其中,
X为F,Cl,Br,I,CF3;
Y为
Y左边连接甘草次酸骨架,右边连接含氮杂环;
Z为C,N,O,S;
当Z为C时,Z可以被R1、R2所取代,其中,
R1、R2可相同或不同,为氢原子,氧代,氨基,卤素,取代或未取代的C1-C6饱和或不饱和直链或支链烷基,取代或未取代的C1-C6饱和或不饱和直链或支链亚烷基,所述烷基、亚烷基或环烷基可任选地用一个或多个选自以下的基团取代:羟基、氨基、卤素、二甲胺;
R1、R2也可为取代或未取代的C5-C6芳基或杂芳基,所述杂芳基可任选含有1-3个O、N或S的杂原子,所述芳基或杂芳基可任选地用一个或多个选自以下的基团取代:C1-C6烷基、C1-C6烷氧基、硝基、氰基、氨基、羟基、卤素;
R1、R2也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:羟基、氧代、氨基、卤素、C1-C4饱和或不饱和直链或支链烷基或亚烷基、C5-C10芳基、C5-C10芳基C1-C4烷基、C3-C7杂环基团、C3-C7杂环基团C1-C4烷基;
当Z为S时,Z可以被氢取代、被氧代、被二氧代;
当Z为N时,Z可以被R3取代,其中,
R3可为氢,取代或未取代的C1-C6饱和或不饱和直链或支链烷基,所述烷基可任选地用一个或多个选自以下的基团取代:羟基、氨基、卤素、二甲胺;
R3也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:羟基、氧代、氨基、卤素、C1-C4饱和或不饱和直链或支链烷基或亚烷基、C5-C10芳基、C5-C10芳基C1-C4烷基、C3-C7杂环基团、C3-C7杂环基团C1-C4烷基;
m为0-4的整数;
n为0-4的整数。
本发明优选通式I所示的化合物,及其旋光体或药学上可接受的盐,
其中,
X为F,Cl,Br,I,CF3;
Y左边连接甘草次酸骨架,右边连接含氮杂环;
Z为C,N,O,S;
当Z为C时,Z可以被R1、R2所取代,其中,
R1、R2可相同或不同,为氢原子,氧代,氨基,卤素,取代或未取代的C1-C6饱和或不饱和直链或支链烷基,取代或未取代的C1-C6饱和或不饱和直链或支链亚烷基,取代或未取代的C3-C7环烷基,所述烷基、亚烷基或环烷基可任选地用一个或多个选自以下的基团取代:羟基、氨基、卤素、二甲胺;
R1、R2也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:羟基、氧代、氨基、卤素、C1-C4饱和或不饱和直链或支链烷基或亚烷基、C5-C10芳基、C5-C10芳基C1-C4烷基、C3-C7杂环基团、C3-C7杂环基团C1-C4烷基;
当Z为S时,Z可以被氢取代、被氧代、被二氧代;
当Z为N时,Z可以被R3取代,其中,
R3可为氢,取代或未取代的C1-C6饱和或不饱和直链或支链烷基,所述烷基可任选地用一个或多个选自以下的基团取代:羟基、氨基、卤素、二甲胺;
R3也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:羟基、氧代、氨基、卤素、C1-C4饱和或不饱和直链或支链烷基或亚烷基、C5-C10芳基、C5-C10芳基C1-C4烷基、C3-C7杂环基团、C3-C7杂环基团C1-C4烷基;
m为0-4的整数;
n为0-4的整数。
本发明优选通式I所示的化合物,及其旋光体或药学上可接受的盐,
其中,
X为F,Cl,Br,I,CF3;
Y左边连接甘草次酸骨架,右边连接含氮杂环;
Z为C,N,O,S;
当Z为C时,Z可以被R1、R2所取代,其中,
R1、R2可相同或不同,为氢原子,氨基,卤素;也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:羟基、氧代、氨基、卤素、C1-C4饱和或不饱和直链或支链烷基或亚烷基;
当Z为S时,Z可以被氢取代、被氧代、被二氧代;
当Z为N时,Z可以被R3取代,其中,
R3可为氢,取代或未取代的C1-C6饱和或不饱和直链或支链烷基,所述烷基可任选地用一个或多个选自以下的基团取代:羟基、氨基、卤素、二甲胺;也可为C3-C7饱和杂环基团,所述饱和杂环基团可含1-3个O、N或S的杂原子,所述饱和杂环基团可任选地用一个或多个选自以下的基团取代:羟基、氧代、氨基、卤素;
m为1-2的整数;
n为1-2的整数。
本发明优选通式I所示的化合物,及其旋光体或药学上可接受的盐,
其中,
X为F,Cl,Br,I,CF3;
Y左边连接甘草次酸骨架,右边连接含氮杂环;
n为1-2的整数。
特别优选的化合物包括:
N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶(实施例1)
N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-哌嗪(实施例2)
N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-吗啉(实施例3)
N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4,4-二氟哌啶(实施例4)
N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-硫代吗啉-1,1-过氧化物(实施例5)
N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-(3-氧杂环丁基)哌嗪(实施例6)
N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-羟乙基哌嗪(实施例7)
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶(实施例8)
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-哌嗪(实施例9)
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-吗啉(实施例10)
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4,4-二氟哌啶(实施例11)
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-硫代吗啉-1,1-过氧化物(实施例12)
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-(3-氧杂环丁基)哌嗪(实施例13)
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-羟乙基哌嗪(实施例14)
N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶(实施例15)
N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-哌嗪(实施例16)
N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-吗啉(实施例17)
N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4,4-二氟哌啶(实施例18)
N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-硫代吗啉-1,1-过氧化物(实施例19)
N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-(3-氧杂环丁基)哌嗪(实施例20)
N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-羟乙基哌嗪(实施例21)
1-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-3-(2-(硫代吗啉-1,1-过氧化物-4-基)乙基)脲(实施例22)
1-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-3-(2-(哌啶-1-基)乙基)脲(实施例23)
O-(2-(硫代吗啉-1,1-过氧化物-4-基)乙基)-N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-氨基甲酸酯(实施例24)
O-(2-(哌啶-1-基)乙基)-N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-氨基甲酸酯(实施例25)
N-(2-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)乙基)-硫代吗啉-1,1-过氧化物(实施例26)
N-(2-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)乙基)-哌啶(实施例27)。
本发明还包括本发明衍生物的前药。依据本发明,前药是通式I的衍生物,它们自身可能具有较弱的活性或甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解和另外的方式)被转化成相应的生物活性形式。
本发明包括药物组合物,该组合物含有通式I的氮杂环取代18β-甘草次酸衍生物,及其立体异构体和药物上可接受的盐和赋形剂。所述药物上可接受的赋形剂是指任何可用于药物领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明的药物组合物可配制成若干种剂型,其中含有药物领域中常用的一些赋型剂,例如,口服制剂(如片剂,胶囊剂,溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射用水可立即使用);局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。
通过体外活性筛选,我们发现本发明衍生物具有抗肿瘤活性,因此本发明衍生物可以用于制备治疗和/或预防各种癌症的药物,如乳腺癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、肝癌、膀胱癌、子宫癌、胰腺癌、卵巢癌、淋巴癌、卵巢癌、皮肤癌和血液癌。
本发明活性化合物可作为唯一的抗癌药物使用,或者与一种或多种其它抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实施例和制备例的范围并不以任何方式限制本发明的范围。
合成路线一:
试剂和条件:a)IBX,DMSO,85℃,6h;b)I2,pyridine,THF,reflux,overnight;c)SOCl2,amines,DIEA,dry-DCM,0℃~r.t.0.5h;d)Benzyl bromide,K2CO3,dry-DMF,r.t.,1h;e)FSO2CF2COOCH3,HMPA,CuI,dry-DMF,70℃,3.5h;f)TiCl4,dry-DCM,r.t.,2h;g)30%H2O2,10%NaOH,Acetone,r.t.,2h;h)KHF2,(CH2OH)2,140℃,36h.
合成路线二:
试剂和条件:a)SOCl2,NaN3,dry-DCM,DIEA,r.t.,2h;b)CHCl3,reflux,4h;c)amine,DIEA,THF,r.t.,6h;d)ROH,Cs2CO3,dry-DCM,r.t.,2~12h;e)conc.HCl,THF,r.t.,4h;f)RCl,K3PO4,KI,CH3CN,125℃,24h.
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。凡基于本发明上述内容所实现的技术均属于本发明的范围。
化合物的IR用Bruker IR-27G型色谱仪测定,核磁共振谱用Bruker ARX-600核磁共振波谱仪在CDCl3或DMSO-d6中以TMS为内标测定,低分辨质谱用Agilent 1100SL型离子阱质谱仪测定,高分辨质谱用Bruker micro-TOF-Q测定。
实施例1:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶的制备
步骤A:3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备
称取3.5g(7.48mmol)GA溶于150mL DMSO中,加入8.37g(30mmol)IBX,85℃回流搅拌4h。冷却至室温,倒入300mL 5%NaHCO3溶液中,析出白色固体。用乙醚萃取(150mL×3),合并有机层,用水洗,饱和氯化钠洗,无水硫酸钠干燥,减压浓缩得白色固体2.65g,收率:76%。1H NMR(600MHz,DMSO-d6)δ12.21(1H,s),7.64(1H,d,J=10.2Hz),5.72(1H,d,J=10.8Hz),5.52(1H,s),2.73(1H,s),2.17~2.06(2H,m),1.83~1.65(5H,m),1.60~1.53(3H,m),1.44~1.39(2H,m),1.38(3H,s),1.37~1.34(1H,m),1.31(3H,s),1.29~1.25(1H,m),1.21~1.16(1H,m),1.11(3H,s),1.10(3H,s),1.07(3H,s),1.02(3H,s),1.00~0.96(1H,m),0.78(3H,s).
步骤B:2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备
称取6.0g 3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸(12.9mmol)置于500mL茄形瓶中,加入300mL无水四氢呋喃溶解。随后加入I2 13.3g(51.6mmol)和吡啶6.23mL(77.4mmol),80℃下搅拌反应12h后,再补加I2 6.65g(25.8mmol)和吡啶3.12mL(38.7mmol),继续搅拌6h。冷却至室温,蒸干四氢呋喃,用乙酸乙酯溶解,硫代硫酸钠洗至金黄色,饱和氯化钠洗,无水硫酸钠干燥。减压浓缩后以环己烷:丙酮(V/V)=50:1为洗脱剂硅胶柱层析,分离得白色固体5.42g,收率:71%。Mp:286-288℃.1H NMR(600MHz,DMSO-d6)δ8.42(1H,s),5.53(1H,s),2.87(1H,s),2.16~2.08(2H,m),1.83~1.65(6H,m),1.59~1.50(3H,m),1.39(3H,s),1.39~1.34(2H,m),1.31(3H,s),1.29~1.25(1H,m),1.20~1.15(2H,m),1.11(3H,s),1.10(3H,s),1.08(6H,s),1.01~0.96(1H,m),0.78(3H,s).LC-MS:592.2[M-H]-.
步骤C:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶的制备
将0.25g 2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸(0.42mmol)溶于15mL SOCl2,置于室温搅拌1h,待酰氯制备完全,减压蒸干SOCl2。用15mL干燥二氯甲烷溶解,缓慢滴至二氯甲烷溶解的4-哌啶基哌啶溶液(0.11g,0.63mmol),升温至室温搅拌0.5h。萃取,用水洗,饱和氯化钠洗,无水硫酸钠干燥。减压蒸干溶剂,以二氯甲烷:甲醇(V/V)=50:1为洗脱剂硅胶柱层析,分离得白色固体0.19g,收率:61%。Mp:99-101℃.IR(KBr):3424.2,2930.8,2856.0,1679.5,1657.1,1628.9,1454.5,1416.4,1384.6,1326.7,1210.3,1122.2,1098.5,1015.9,975.4.1H NMR(600MHz,DMSO-d6)δ8.43(1H,s),5.60(1H,s),4.36~4.23(2H,m),2.87(1H,s),2.79~2.65(2H,m),2.48~2.40(5H,m),2.29~2.22(1H,m),2.18~2.09(1H,m),1.99~1.92(1H,m),1.87~1.80(1H,m),1.80~1.65(6H,m),1.59~1.52(2H,m),1.52~1.44(5H,m),1.44~1.39(2H,m),1.38(3H,s),1.36~1.34(1H,m),1.31(3H,s),1.29~1.21(4H,m),1.21~1.17(1H,m),1.16(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.01~0.96(1H,m),0.75(3H,s).13C NMR(150MHz,DMSO-d6)δ198.6,197.7,173.0,172.5,170.6,127.3,100.4,62.1,54.7,51.5,48.4,45.4,45.3,43.8,43.7,43.3,40.4,37.9,31.8,31.4,28.7,28.7,28.6,28.6,26.6,26.5,26.4,22.9,22.3,20.4,18.9,18.2.HRMS m/z calcd for C40H60IN2O3 +[M+H]+743.3643,found 743.3658.
实施例2:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-哌嗪的制备
按照实施例1的制备方法,用原料无水哌嗪替代实施例1中的原料4-哌啶基哌啶,制备标题化合物。Mp:150-153℃.IR(KBr):3424.4,2951.7,2867.5,1655.9,1628.6,1457.8,1412.5,1384.9,1319.7,1212.6,1099.8,1024.2,975.8.1H NMR(600MHz,DMSO-d6)δ8.43(1H,s),5.61(1H,s),3.52~3.41(4H,m),2.87(1H,s),2.69~2.59(4H,m),2.31~2.23(1H,m),2.17~2.09(1H,m),1.99~1.93(1H,m),1.88~1.82(1H,m),1.82~1.61(4H,m),1.59~1.50(2H,m),1.46~1.39(2H,m),1.38(3H,s),1.37~1.33(2H,m),1.32(3H,s),1.26~1.22(1H,m),1.20~1.17(1H,m),1.16(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.01~0.96(1H,m),0.75(3H,s).13C NMR(150MHz,DMSO-d6)δ198.7,197.8,173.3,172.7,170.7,127.4,100.5,60.2,54.7,51.5,48.4,46.4,45.5,45.4,43.9,43.8,43.4,40.5,37.9,32.5,31.9,31.5,28.8,26.6,26.5,23.0,22.4,20.5,19.0,18.3.HRMS m/z calcdfor C34H50IN2O3 +[M+H]+661.2861,found 661.2869.
实施例3:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-吗啉的制备
按照实施例1的制备方法,用原料吗啉替代实施例1中的原料4-哌啶基哌啶,制备标题化合物。Mp:302-304℃.IR(KBr):3424.2,2959.8,2872.7,1681.3,1648.1,1631.9,1385.7,1268.6,1210.7,1173.5,1117.3,1024.4,975.5.1H NMR(600MHz,DMSO-d6)δ8.43(1H,s),5.62(1H,s),3.62~3.48(8H,m),2.86(1H,s),2.30~2.24(1H,m),2.18~2.09(1H,m),1.99~1.93(1H,m),1.88~1.82(1H,m),1.82~1.63(4H,m),1.59~1.40(4H,m),1.38(3H,s),1.37~1.33(2H,m),1.32(3H,s),1.28~1.23(1H,m),1.17(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.02~0.96(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ198.8,197.8,173.7,172.6,170.7,127.4,100.5,66.8,54.8,51.5,48.4,45.5,45.4,43.9,43.8,43.6,43.4,37.8,32.3,31.9,31.5,28.8,28.8,26.6,26.5,23.0,22.4,20.4,19.0,18.3.HRMS m/z calcd for C34H49INO4 +[M+H]+662.2701,found 662.2729.
实施例4:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4,4-二氟哌啶的制备
按照实施例1的制备方法,用原料4,4-二氟哌啶替代实施例1中的原料4-哌啶基哌啶,制备标题化合物。Mp:306-309℃.IR(KBr):3423.6,2962.3,2873.2,1679.3,1633.9,1441.9,1409.0,1385.3,1364.1,1259.5,1212.4,1177.6,1112.2,1007.0,974.1,953.5.1HNMR(600MHz,DMSO-d6)δ8.43(1H,s),5.62(1H,s),3.71~3.55(4H,m),2.86(1H,s),2.33~2.26(1H,m),2.18~2.09(1H,m),2.01~1.89(5H,m),1.88~1.82(1H,m),1.82~1.63(4H,m),1.60~1.40(4H,m),1.38(3H,s),1.37~1.33(2H,m),1.32(3H,s),1.28~1.23(1H,m),1.19(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.02~0.96(1H,m),0.76(3H,s).13CNMR(150MHz,DMSO-d6)δ198.7,197.8,173.7,172.5,170.7,127.4,100.5,54.7,51.5,48.2,45.5,45.4,43.9,43.4,40.5,37.9,34.3,32.2,31.9,31.5,28.8,28.7,26.6,26.6,26.5,23.0,22.4,20.4,19.0,18.3.HRMS m/z calcd for C35H49F2INO3 +[M+H]+696.2720,found696.2711.
实施例5:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-硫代吗啉-1,1-过氧化物的制备
按照实施例1的制备方法,用原料硫代吗啉-1,1-过氧化物替代实施例1中的原料4-哌啶基哌啶,制备标题化合物。Mp:155-158℃.IR(KBr):3424.7,2953.1,2869.5,1652.7,1460.1,1404.9,1385.8,1321.8,1283.5,1126.1,1034.6,1008.0,975.7,949.4.1H NMR(600MHz,DMSO-d6)δ8.43(1H,s),5.66(1H,s),4.04~3.87(4H,m),3.19~3.06(4H,m),2.86(1H,s),2.34~2.28(1H,m),2.16~2.08(1H,m),1.98~1.91(1H,m),1.88~1.82(1H,m),1.82~1.62(4H,m),1.60~1.41(4H,m),1.38(3H,s),1.36~1.33(2H,m),1.32(3H,s),1.27~1.23(1H,m),1.21(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.02~0.97(1H,m),0.77(3H,s).13C NMR(150MHz,DMSO-d6)δ198.8,197.8,174.1,172.5,170.7,127.5,100.5,54.7,51.7,51.5,47.9,45.5,45.4,44.0,43.9,43.4,40.5,37.7,32.1,31.9,31.5,28.8,28.6,26.7,26.7,26.5,23.0,22.4,20.4,19.0,18.3.HRMS m/z calcd for C34H49INO5S+[M+H]+710.2371,found 710.2381.
实施例6:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-(3-氧杂环丁基)哌嗪的制备
按照实施例1的制备方法,用原料1-(3-氧杂环丁基)哌嗪替代实施例1中的原料4-哌啶基哌啶,制备标题化合物。Mp:120-122℃.IR(KBr):3430.4,2953.5,2930.2,2869.8,1678.2,1655.1,1630.8,1456.6,1410.7,1384.9,1318.6,1276.6,1247.4,1210.8,1115.2,1024.7,977.4.1H NMR(600MHz,DMSO-d6)δ8.43(1H,s),5.61(1H,s),4.58~4.51(2H,m),4.46~4.43(2H,m),3.63~3.51(4H,m),3.44~3.36(1H,m),2.86(1H,s),2.29~2.19(5H,m),2.19~2.08(1H,m),2.00~1.92(1H,m),1.89~1.82(1H,m),1.82~1.63(4H,m),1.60~1.40(4H,m),1.38(3H,s),1.36~1.34(1H,m),1.32(3H,s),1.26~1.22(2H,m),1.16(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.01~0.96(1H,m),0.75(3H,s).13C NMR(150MHz,DMSO-d6)δ198.7,197.8,173.5,172.6,170.7,127.4,100.5,74.7,58.8,54.7,51.5,49.9,48.4,45.5,45.4,43.9,43.8,43.7,43.4,40.5,37.9,32.4,31.9,31.5,31.4,28.8,26.8,26.6,26.6,26.6,23.0,22.4,20.4,18.9,18.3,14.5.HRMS m/z calcd forC37H54IN2O4 +[M+H]+717.3123,found 717.3116.
实施例7:N-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-羟乙基哌嗪的制备
按照实施例1的制备方法,用原料1-羟乙基哌嗪替代实施例1中的原料4-哌啶基哌啶,制备标题化合物。Mp:126-129℃.IR(KBr):3430.4,2930.7,1655.7,1630.3,1458.4,1414.4,1385.5,1324.4,1247.2,1212.6,1138.7,1008.5,975.5.1H NMR(600MHz,DMSO-d6)δ8.43(1H,s),5.62(1H,s),4.43(1H,s),3.59~3.45(6H,m),2.86(1H,s),2.44~2.32(6H,m),2.30~2.22(1H,m),2.17~2.09(1H,m),1.99~1.92(1H,m),1.89~1.81(1H,m),1.82~1.62(4H,m),1.60~1.40(4H,m),1.38(3H,s),1.37~1.34(1H,m),1.32(3H,s),1.25~1.18(2H,m),1.16(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.01~0.96(1H,m),0.75(3H,s).13C NMR(150MHz,DMSO-d6)δ198.7,197.8,173.4,172.6,170.7,127.4,100.5,60.6,58.8,55.4,54.7,53.9,51.5,48.4,45.5,45.4,43.9,43.8,43.7,43.4,40.5,37.9,32.4,31.9,31.5,28.8,26.6,26.6,23.0,22.4,20.4,19.0,18.3.HRMS m/z calcd forC36H54IN2O4 +[M+H]+705.3123,found 705.3147.
实施例8:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶的制备
步骤A:3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯的制备
称取5.0g(10.7mmol)3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸溶于100mL干燥的DMSO中,加入4.43g(32.1mmol)K2CO3,室温搅拌0.5h。随后加入1.4mL溴化苄(11.8mmol),继续搅拌2h。将反应液倒入300mL水中,搅拌15min,抽滤,水洗,干燥得白色固体5.35g,收率:90%。LC-MS:557.6[M+H]+,579.6[M+Na]+.
步骤B:2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯的制备
按照实施例1步骤B的制备方法,用原料3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯替代实施例1步骤B中的3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,制备标题化合物。Mp:158-161℃.1H NMR(600MHz,DMSO-d6)δ8.40(1H,s),7.45~7.29(5H,m),5.41(1H,s),5.22(1H,d,J=12.0Hz),5.08(1H,d,J=12.0Hz),2.84(1H,s),2.15~2.07(1H,m),2.01~1.96(1H,m),1.88~1.82(1H,m),1.79~1.68(5H,m),1.59~1.49(2H,m),1.46~1.40(1H,m),1.37(3H,s),1.36~1.32(2H,m),1.31(3H,s),1.24~1.16(2H,m),1.14(3H,s),1.10(3H,s),1.08(3H,s),1.05(3H,s),0.99~0.94(1H,m),0.71(3H,s).
步骤C:2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯的制备
将4.92g 2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯(7.2mmol)置于250mL三颈瓶中,用100mL干燥DMF溶解,避光条件下加入4.12g CuI(21.63mmol)。氮气保护,升温至70℃,再缓慢滴加17.3mL氟磺酰二氟乙酸甲酯(144.2mmol)和25mL HMPA(144.2mmol),继续搅拌4h。反应液稍冷后加入20mL饱和氯化铵溶液淬灭,冷却至室温,亚硫酸钠洗,2N HCl洗,水洗,饱和氯化钠洗,无水硫酸钠干燥。减压蒸干溶剂,以石油醚:乙酸乙酯(V/V)=20:1为洗脱剂硅胶柱层析,分离得白色固体3.3g,收率:73%。Mp:113-115℃.1H NMR(600MHz,DMSO-d6)δ8.20(1H,s),7.45~7.30(5H,m),5.43(1H,s),5.22(1H,d,J=12.0Hz),5.08(1H,d,J=12.0Hz),2.94(1H,s),2.16~2.07(1H,m),2.02~1.97(1H,m),1.88~1.82(1H,m),1.79~1.65(5H,m),1.61~1.55(2H,m),1.47~1.42(1H,m),1.38(3H,s),1.36~1.32(1H,m),1.31(3H,s),1.24~1.15(3H,m),1.14(3H,s),1.10(3H,s),1.08(6H,s),1.00~0.95(1H,m),0.72(3H,s).LC-MS:626.0[M+H]+,647.7[M+Na]+.
步骤D:2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备
将2.9g 2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯溶于20mL的干燥的二氯甲烷中,在0℃下向上述溶液中缓慢滴加32.5mL 1N TiCl溶液(32.5mmol),搅拌15min。转移至室温,继续搅拌2h。将反应液缓慢滴加至冰水中,用二氯甲烷萃取,水洗,饱和氯化钠洗,无水硫酸钠干燥。减压蒸干溶剂,以石油醚:乙酸乙酯(V/V)=10:1为洗脱剂硅胶柱层析,分离得白色固体2.2g,收率:91%。Mp:259-261℃.1H NMR(600MHz,DMSO-d6)δ12.21(1H,s),8.22(1H,s),5.55(1H,s),2.97(1H,s),2.17~2.07(2H,m),1.84~1.78(2H,m),1.78~1.63(5H,m),1.63~1.56(2H,m),1.40(3H,s),1.39~1.34(2H,m),1.32(3H,s),1.30~1.25(1H,m),1.23~1.16(1H,m),1.11(9H,s),1.09(3H,s),1.02~0.97(1H,m),0.79(3H,s).LC-MS:535.5[M+H]+,557.5[M+Na]+.
步骤E:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶的制备
按照实施例1步骤C的制备方法,用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-烯-30-羧酸,制备标题化合物。Mp:106-108℃.IR(KBr):3422.5,2931.0,2856.0,1688.7,1660.9,1455.6,1418.4,1368.1,1296.5,1215.4,1140.5,1014.0,976.5.1H NMR(600MHz,DMSO-d6)δ8.22(1H,s),5.62(1H,s),4.53~4.17(2H,m),2.97(1H,s),2.84~2.54(4H,m),2.31~2.22(1H,m),2.19~2.09(1H,m),2.01~1.93(1H,m),1.90~1.62(8H,m),1.62~1.47(6H,m),1.47~1.40(5H,m),1.39(3H,s),1.36~1.33(2H,m),1.32(3H,s),1.27~1.19(4H,m),1.17(3H,s),1.11(3H,s),1.10(3H,s),1.08(3H,s),1.02~0.97(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ199.2,198.7,173.1,172.9,164.3,127.4,123.7,121.9,62.3,54.1,50.5,50.0,48.4,45.4,45.3,44.0,43.9,43.8,40.5,38.2,38.0,32.4,31.9,31.8,31.2,29.7,29.5,28.8,28.1,26.8,26.7,26.6,23.0,22.6,21.6,20.2,18.9,18.2.HRMS m/z calcd for C41H60F3N2O3 +[M+H]+685.4551,found 685.4567.
实施例9:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-哌嗪的制备
按照实施例1步骤C的制备方法,用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料无水哌嗪替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:105-107℃.IR(KBr):3422.0,2955.3,2870.2,1688.1,1656.0,1458.8,1414.4,1386.9,1368.5,1296.7,1216.5,1139.1,1024.2,1009.2,977.3.1H NMR(600MHz,DMSO-d6)δ8.23(1H,s),5.63(1H,s),3.52~3.39(4H,m),2.97(1H,s),2.70~2.61(4H,m),2.31~2.25(1H,m),2.17~2.09(1H,m),2.00~1.93(1H,m),1.89~1.83(1H,m),1.81~1.54(6H,m),1.44~1.40(2H,m),1.39(3H,s),1.37~1.35(1H,m),1.32(3H,s),1.26~1.17(3H,m),1.16(3H,s),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.02~0.97(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ199.2,198.7,173.3,172.9,164.3,127.4,124.1,121.9,55.4,54.1,50.5,48.4,46.2,45.3,44.0,43.8,40.5,32.4,31.9,31.4,31.2,28.8,28.0,26.8,26.6,26.5,23.0,22.5,21.6,20.2,18.9,18.2.HRMS m/z calcd for C35H50F3N2O3 +[M+H]+603.3768,found 603.3769.
实施例10:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-吗啉的制备
按照实施例1步骤C的制备方法,用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料吗啉替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:98-101℃.IR(KBr):3431.1,2963.1,2870.8,1689.4,1648.8,1631.6,1455.6,1409.2,1386.3,1295.8,1269.9,1138.5,1120.0,1025.2,977.2.1H NMR(600MHz,DMSO-d6)δ8.22(1H,s),5.65(1H,s),3.63~3.47(8H,m),2.97(1H,s),2.32~2.25(1H,m),2.18~2.08(1H,m),2.00~1.93(1H,m),1.90~1.83(1H,m),1.83~1.63(6H,m),1.63~1.56(1H,m),1.47~1.40(1H,m),1.39(3H,s),1.37~1.33(1H,m),1.32(3H,s),1.26~1.18(2H,m),1.17(3H,s),1.11(6H,s),1.09(3H,s),1.02~0.97(1H,m),0.77(3H,s).13C NMR(150MHz,DMSO-d6)δ199.2,198.7,173.7,172.8,164.3,127.4,124.0,121.9,66.8,54.1,50.5,48.4,46.0,45.4,44.0,43.8,43.7,40.5,38.2,37.8,32.3,31.9,31.2,28.8,28.0,26.6,26.5,22.9,21.6,20.2,18.9,18.2.HRMS m/z calcd for C35H49F3NO4 +[M+H]+604.3608,found604.3612.
实施例11:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4,4-二氟哌啶的制备
按照实施例1步骤C的制备方法,用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料4,4-二氟哌啶替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:302-305℃.IR(KBr):3424.8,2964.4,2873.9,1688.7,1635.5,1411.1,1386.6,1366.1,1295.1,1216.5,1167.4,1134.7,1113.0,1083.9,975.2.1H NMR(600MHz,DMSO-d6)δ8.22(1H,s),5.64(1H,s),3.71~3.58(4H,m),2.97(1H,s),2.34~2.28(1H,m),2.18~2.10(1H,m),1.99~1.90(5H,m),1.88~1.83(1H,m),1.83~1.62(4H,m),1.62~1.55(2H,m),1.53~1.45(1H,m),1.45~1.40(1H,m),1.39(3H,s),1.37~1.34(2H,m),1.32(3H,s),1.28~1.20(1H,m),1.19(3H,s),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.02~0.97(1H,m),0.77(3H,s).13C NMR(150MHz,DMSO-d6)δ199.2,198.7,173.7,172.8,164.2,127.4,123.2,121.9,54.1,50.5,48.2,45.3,43.9,42.1,40.5,38.2,37.9,34.5,34.3,34.2,32.1,31.9,31.2,28.8,28.0,26.6,26.5,23.0,21.6,20.2,18.9,18.2.HRMS m/z calcd for C36H49F5NO3 +[M+H]+638.3627,found638.3639.
实施例12:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-硫代吗啉-1,1-过氧化物的制备
按照实施例1步骤C的制备方法,用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料硫代吗啉-1,1-过氧化物替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:157-160℃.IR(KBr):3421.3,2955.3,2932.1,2871.8,1688.3,1652.5,1386.7,1369.3,1324.1,1297.0,1215.0,1127.3,1034.8,1007.5,977.2,947.5.1H NMR(600MHz,DMSO-d6)δ8.22(1H,s),5.69(1H,s),4.03~3.87(4H,m),3.20~3.05(4H,m),2.97(1H,s),2.35~2.29(1H,m),2.17~2.08(1H,m),1.98~1.91(1H,m),1.88~1.82(1H,m),1.82~1.65(4H,m),1.62~1.55(2H,m),1.53~1.47(1H,m),1.45~1.40(1H,m),1.39(3H,s),1.36~1.33(2H,m),1.32(3H,s),1.28~1.24(1H,m),1.21(3H,s),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.03~0.98(1H,m),0.78(3H,s).13C NMR(150MHz,DMSO-d6)δ199.2,198.8,174.1,172.7,164.3,127.5,124.1,121.9,60.2,55.4,54.1,51.7,50.5,47.9,45.3,44.0,44.0,40.5,38.2,37.7,32.1,31.9,31.4,31.2,29.0,28.6,28.0,26.8,26.7,26.5,22.9,22.5,21.6,20.2,18.9,18.2.HRMS m/z calcd for C35H47F3NO5S-[M-H]-650.3133,found 650.3166.
实施例13:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-(3-氧杂环丁基)哌嗪的制备
按照实施例1步骤C的制备方法,用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料1-(3-氧杂环丁基)哌嗪替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:107-110℃.IR(KBr):3420.7,2953.3,2933.3,2871.7,1688.7,1654.1,1456.4,1385.0,1369.8,1296.4,1216.7,1139.9,1114.1,1025.0,1008.0,978.9.1H NMR(600MHz,DMSO-d6)δ8.23(1H,s),5.64(1H,s),4.57~4.50(2H,m),4.48~4.41(2H,m),3.63~3.51(4H,m),3.43~3.36(1H,m),2.97(1H,s),2.32~2.18(5H,m),2.18~2.09(1H,m),1.99~1.93(1H,m),1.88~1.82(1H,m),1.82~1.62(4H,m),1.62~1.55(2H,m),1.46~1.39(2H,m),1.38(3H,s),1.36~1.33(2H,m),1.32(3H,s),1.22~1.17(2H,m),1.16(3H,s),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.02~0.97(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ199.2,198.7,173.5,172.8,164.3,127.4,123.7,121.9,74.7,58.8,54.1,50.5,49.9,48.4,45.3,44.0,43.8,40.5,38.2,37.9,31.9,31.2,28.8,28.1,26.8,26.5,23.0,21.6,20.2,18.9,18.2.HRMS m/z calcd for C38H54F3N2O4 +[M+H]+659.4030,found 659.4033.
实施例14:N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-羟乙基哌嗪的制备
按照实施例1步骤C的制备方法,用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料1-羟乙基哌嗪替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:95-98℃.IR(KBr):3423.0,2953.6,2931.2,2871.2,1688.5,1656.1,1459.3,1415.3,1386.3,1368.2,1296.9,1216.5,1140.1,1009.0,977.4.1H NMR(600MHz,DMSO-d6)δ8.23(1H,s),5.64(1H,s),4.42(1H,s),3.57~3.45(6H,m),2.97(1H,s),2.44~2.31(6H,m),2.31~2.23(1H,m),2.18~2.08(1H,m),2.01~1.91(1H,m),1.88~1.83(1H,m),1.83~1.63(4H,m),1.63~1.54(2H,m),1.45~1.40(2H,m),1.39(3H,s),1.37~1.34(1H,m),1.32(3H,s),1.24~1.17(2H,m),1.16(3H,s),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.02~0.97(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ199.0,198.6,173.3,172.7,164.2,127.3,124.0,121.8,60.5,58.8,54.0,53.9,50.4,48.3,45.2,43.9,43.7,43.7,40.4,38.2,37.8,32.3,31.8,31.3,31.1,28.9,28.0,26.7,26.5,26.5,22.9,22.4,21.5,20.1,18.8,18.1,14.3.HRMS m/z calcd for C37H54F3N2O4 +[M+H]+647.4030,found 647.4048.
实施例15:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶的制备
步骤A:2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯的制备
称取7g 3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯(12.6mmol)溶于300mL丙酮中,加入12mL30%H2O2和10mL 10%NaOH溶液,室温搅拌6h。将反应液倒入700mL水中,析出白色固体,干燥。将上述环氧化物6.4g(13.3mmol),20.7g KHF2置于250mL茄形瓶中,加入100mL乙二醇溶解,140℃下搅拌36h。将反应液冷却至室温,倒入300mL水中,用二氯萃取,水洗,饱和氯化钠洗,无水硫酸钠干燥。减压蒸干溶剂,以石油醚:乙酸乙酯(V/V)=20:1为洗脱剂硅胶柱层析,分离得白色固体2.2g,两步收率:31%。Mp:208-210℃.1H NMR(600MHz,DMSO-d6)δ7.42~7.37(5H,m),7.33(1H,d,J=16.2Hz),5.41(1H,s),5.22(1H,d,J=12.0Hz),5.08(1H,d,J=12.0Hz),2.81(1H,s),2.14~2.07(1H,m),2.01~1.95(1H,m),1.88~1.82(1H,m),1.79~1.68(5H,m),1.58~1.53(2H,m),1.47~1.42(2H,m),1.39(3H,s),1.36(3H,s),1.34~1.29(2H,m),1.26~1.21(2H,m),1.14(3H,s),1.13(3H,s),1.07(3H,s),1.05(3H,s),0.98~0.94(1H,m),0.71(3H,s).LC-MS:575.5[M+H]+,597.6[M+Na]+.
步骤B:2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备
按照实施例2步骤D的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯替代实施例2步骤D中的2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯,制备标题化合物。Mp:94-96℃.1H NMR(600MHz,DMSO-d6)δ12.21(1H,s),7.35(1H,d,J=16.2Hz),5.52(1H,s),2.84(1H,s),2.16~2.08(2H,m),1.83~1.63(6H,m),1.63~1.51(3H,m),1.48~1.41(2H,m),1.40(3H,s),1.38(3H,s),1.32~1.25(2H,m),1.15(3H,s),1.11(3H,s),1.10(3H,s),1.05(3H,s),1.01~0.97(1H,m),0.78(3H,s).
步骤C:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶的制备
按照实施例1步骤C的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,制备标题化合物。Mp:130-133℃.IR(KBr):3421.2,2930.2,2855.0,1689.9,1656.0,1630.2,1453.9,1417.3,1385.1,1273.0,1210.6,1113.7,1036.2,1007.7,976.4.1H NMR(600MHz,DMSO-d6)δ7.35(1H,d,J=16.2Hz),5.59(1H,s),4.43~4.25(2H,m),2.84(1H,s),2.79~2.67(2H,m),2.49~2.33(3H,m),2.29~2.22(1H,m),2.18~2.08(1H,m),2.00~1.91(1H,m),1.87~1.60(8H,m),1.60~1.45(7H,m),1.45~1.41(2H,m),1.40(3H,s),1.37(3H,s),1.35~1.30(3H,m),1.28~1.22(3H,m),1.20~1.18(1H,m),1.16(3H,s),1.15(3H,s),1.09(3H,s),1.05(3H,s),1.02~0.97(1H,m),0.75(3H,s).13C NMR(150MHz,DMSO-d6)δ198.6,196.1,173.1,172.4,149.8,137.3,127.2,62.1,55.6,55.3,51.8,50.0,48.3,45.8,45.3,43.8,43.7,40.4,38.2,37.9,32.4,31.8,31.6,28.7,26.9,26.6,26.5,26.4,23.0,21.7,20.8,20.8,19.0,17.8.HRMS m/z calcd for C40H58FN2O3 -[M-H]-633.4437,found 633.4471.
实施例16:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-哌嗪的制备
按照实施例1步骤C的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料无水哌嗪替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:126-129℃.IR(KBr):3422.8,2927.3,2869.5,2738.5,1689.5,1648.3,1458.9,1413.6,1385.9,1366.3,1343.3,1212.9,1122.2,1035.6,1007.6,976.0.1H NMR(600MHz,DMSO-d6)δ7.35(1H,d,J=16.2Hz),5.61(1H,s),3.69~3.49(5H,m),2.84(1H,s),2.82~2.76(4H,m),2.29~2.22(1H,m),2.18~2.08(1H,m),1.99~1.90(1H,m),1.87~1.81(1H,m),1.81~1.65(4H,m),1.60~1.54(2H,m),1.48~1.42(2H,m),1.40(3H,s),1.37(3H,s),1.34~1.31(1H,m),1.25~1.23(2H,m),1.16(3H,s),1.15(3H,s),1.09(3H,s),1.05(3H,s),1.01~0.97(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ198.8,196.2,173.6,172.5,149.9,137.5,127.3,55.7,51.8,48.3,45.9,45.4,45.2,43.8,40.5,38.3,38.3,37.9,32.3,31.9,31.7,28.8,27.0,26.6,26.5,26.5,23.1,21.8,20.9,19.1,17.9.HRMS m/z calcd forC34H50FN2O3 +[M+H]+553.3800,found 553.3801.
实施例17:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-吗啉的制备
按照实施例1步骤C的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料吗啉替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:120-122℃.IR(KBr):3422.4,2955.4,2931.5,2868.6,1689.7,1631.6,1458.1,1411.3,1386.1,1365.1,1343.7,1267.7,1211.6,1117.3,1034.7,1007.0,976.5.1H NMR(600MHz,DMSO-d6)δ7.35(1H,d,J=16.2Hz),5.61(1H,s),3.65~3.46(8H,m),2.84(1H,s),2.30~2.24(1H,m),2.17~2.09(1H,m),1.99~1.92(1H,m),1.88~1.82(1H,m),1.82~1.62(4H,m),1.60~1.53(2H,m),1.48~1.41(2H,m),1.40(3H,s),1.37(3H,s),1.34~1.27(2H,m),1.21~1.18(1H,m),1.16(3H,s),1.15(3H,s),1.09(3H,s),1.05(3H,s),1.02~0.96(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ197.7,195.2,172.6,171.4,150.6,148.8,126.3,65.7,54.6,54.3,50.7,47.2,44.8,44.3,42.7,42.6,39.4,37.3,37.2,36.8,31.2,30.8,30.6,27.7,25.9,25.5,25.4,22.0,20.7,19.8,18.0,16.8.HRMS m/z calcd for C34H49FNO4 +[M+H]+554.3640,found 554.3631.
实施例18:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4,4-二氟哌啶的制备
按照实施例1步骤C的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料4,4-二氟哌啶替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:126-128℃.IR(KBr):3419.8,2928.9,2874.6,1690.1,1632.3,1404.0,1385.4,1271.8,1211.5,1174.2,1113.3,1036.3,1006.4,974.8.1H NMR(600MHz,DMSO-d6)δ7.35(1H,d,J=16.2Hz),5.61(1H,s),3.74~3.55(4H,m),2.84(1H,s),2.33~2.27(1H,m),2.17~2.08(1H,m),2.01~1.89(5H,m),1.87~1.81(1H,m),1.81~1.61(4H,m),1.59~1.54(2H,m),1.52~1.41(2H,m),1.40(3H,s),1.37(3H,s),1.35~1.29(2H,m),1.28~1.23(1H,m),1.19(3H,s),1.15(3H,s),1.09(3H,s),1.05(3H,s),1.02~0.96(1H,m),0.76(3H,s).13C NMR(150MHz,DMSO-d6)δ198.8,196.2,173.7,172.5,149.9,137.5,127.4,55.7,51.8,48.1,45.9,45.4,43.9,43.9,42.1,40.5,38.3,38.3,37.9,34.3,32.1,31.9,31.7,28.7,27.0,26.6,26.6,26.5,23.1,21.8,20.9,20.8,19.1,17.9.HRMS m/z calcd for C35H49F3NO3 +[M+H]+588.3659,found588.3676.
实施例19:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-硫代吗啉-1,1-过氧化物的制备
按照实施例1步骤C的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料硫代吗啉-1,1-过氧化物替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:137-140℃.IR(KBr):3421.4,2933.5,2873.2,1688.9,1646.3,1459.6,1405.6,1386.5,1366.4,1323.7,1283.7,1252.9,1211.1,1125.9,1035.9,1006.1,976.0,950.4.1HNMR(600MHz,DMSO-d6)δ7.35(1H,d,J=16.2Hz),5.65(1H,s),4.08~3.86(4H,m),3.17~3.07(4H,m),2.84(1H,s),2.34~2.28(1H,m),2.17~2.08(1H,m),1.99~1.91(1H,m),1.87~1.81(1H,m),1.81~1.62(4H,m),1.62~1.53(2H,m),1.53~1.42(2H,m),1.40(3H,s),1.37(3H,s),1.35~1.28(2H,m),1.20(3H,s),1.19~1.16(1H,m),1.15(3H,s),1.09(3H,s),1.05(3H,s),1.02~0.97(1H,m),0.77(3H,s).13C NMR(150MHz,DMSO-d6)δ198.8,196.2,174.1,172.4,149.9,137.5,127.5,55.7,55.4,51.8,51.8,47.9,45.9,45.4,44.0,43.9,40.5,38.3,38.3,37.7,32.1,31.9,31.7,28.6,27.0,26.7,26.4,23.0,21.8,20.8,19.1,17.9.HRMS m/z calcd for C34H49FNO5S+[M+H]+602.3310,found 602.3302.
实施例20:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-(3-氧杂环丁基)哌嗪的制备
按照实施例1步骤C的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料1-(3-氧杂环丁基)哌嗪替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:116-118℃.IR(KBr):3427.2,2950.5,2873.1,1688.8,1630.5,1490.9,1439.5,1402.8,1385.9,1274.0,1211.5,1173.5,1114.7,1006.6,979.9.1H NMR(600MHz,DMSO-d6)δ7.36(1H,d,J=16.2Hz),5.60(1H,s),4.58~4.50(2H,m),4.48~4.40(2H,m),3.64~3.50(4H,m),3.45~3.36(1H,m),2.84(1H,s),2.34~2.18(5H,m),2.18~2.07(1H,m),2.00~1.91(1H,m),1.87~1.81(1H,m),1.81~1.61(4H,m),1.61~1.52(2H,m),1.52~1.41(2H,m),1.40(3H,s),1.37(3H,s),1.35~1.29(2H,m),1.26~1.17(2H,m),1.16(3H,s),1.15(3H,s),1.09(3H,s),1.05(3H,s),1.01~0.95(1H,m),0.75(3H,s).13C NMR(150MHz,DMSO-d6)δ198.8,196.4,173.5,172.5,149.9,137.4,127.4,74.7,58.8,55.7,55.4,51.8,49.9,48.3,45.9,45.4,43.9,43.8,43.7,42.3,40.5,38.3,38.3,37.9,35.3,31.9,31.7,28.8,27.0,26.6,26.5,23.1,21.8,20.8,19.1,17.9.HRMS m/z calcd for C37H54FN2O4 +[M+H]+609.4062,found 609.4038.
实施例21:N-(2-氟代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-羟乙基哌嗪的制备
按照实施例1步骤C的制备方法,用原料2-氟代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例1步骤C中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸,用原料1-羟乙基哌嗪替代实施例1步骤C中的4-哌啶基哌啶,制备标题化合物。Mp:124-127℃.IR(KBr):3427.8,2932.3,2872.3,1689.0,1654.7,1458.9,1414.0,1386.1,1367.1,1345.6,1212.8,1127.3,1036.5,1007.1,976.6.1H NMR(600MHz,DMSO-d6)δ7.36(1H,d,J=16.2Hz),5.61(1H,s),4.42(1H,t,J=5.4Hz),3.60~3.43(6H,m),2.84(1H,s),2.42~2.32(6H,m),2.30~2.23(1H,m),2.17~2.08(1H,m),1.99~1.92(1H,m),1.87~1.81(1H,m),1.81~1.61(4H,m),1.61~1.52(2H,m),1.52~1.41(2H,m),1.40(3H,s),1.37(3H,s),1.35~1.31(1H,m),1.26~1.17(2H,m),1.16(3H,s),1.15(3H,s),1.09(3H,s),1.05(3H,s),1.01~0.96(1H,m),0.75(3H,s).13C NMR(150MHz,DMSO-d6)δ198.8,196.2,173.4,172.5,149.9,137.5,127.4,60.6,58.9,55.7,55.4,54.0,51.8,48.4,45.9,45.4,43.9,43.8,40.5,38.3,38.3,37.9,31.9,31.7,28.8,27.0,26.6,26.5,23.1,21.8,20.8,19.1,17.9.HRMS m/z calcd for C36H54FN2O4 +[M+H]+597.4062,found 597.4098.
实施例22:1-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-3-(2-(硫代吗啉-1,1-过氧化物-4-基)乙基)脲的制备
步骤A:2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-异氰酸酯的制备
将3.5g 2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-烯-30-羧酸(6.55mmol)溶于25mL SOCl2,室温搅拌0.5h。减压蒸去溶剂,用15mL干燥的二氯甲烷溶解,缓慢滴至NaN3(1.06g,16.4mmol)的二氯甲烷溶液,室温搅拌2h。将反应液用水萃取,饱和氯化钠洗,蒸干。将上述粗品溶于40mL三氯甲烷,回流反应6h。待反应液冷却至室温,减压蒸干溶剂,以石油醚:乙酸乙酯(V/V)=7:1为洗脱剂硅胶柱层析,分离得白色固体1.8g,收率:52%。Mp:281-284℃.1H NMR(600MHz,DMSO-d6)δ8.21(1H,s),5.66(1H,s),2.96(1H,s),2.27~2.21(1H,m),2.14~2.06(1H,m),2.01~1.94(1H,m),1.83~1.62(5H,m),1.62~1.55(2H,m),1.55~1.47(2H,m),1.43~1.39(3H,m),1.37(3H,s),1.32(3H,s),1.24~1.17(3H,m),1.12(3H,s),1.10(3H,s),1.09(3H,s),1.02~0.97(1H,m),0.87(3H,s).
步骤B:1-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-3-(2-(硫代吗啉-1,1-过氧化物-4-基)乙基)脲的制备
将0.15g 2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-异氰酸酯(0.28mmol)溶于25mL干燥的二氯甲烷,随后加入0.11g 4-(2-氨乙基)硫代吗啉-1,1-二氧化物(0.85mmol)和0.15mL DIPEA(0.85mmol),室温搅拌6h。将反应液用水洗,饱和氯化钠洗,无水硫酸钠干燥。减压蒸干溶剂,以二氯甲烷:甲醇(V/V)=50:1为洗脱剂硅胶柱层析,分离得白色固体0.14g,收率:71%。Mp:240-243℃.IR(KBr):3417.5,2952.8,2929.6,2871.4,1688.1,1656.4,1631.2,1565.0,1550.6,1455.8,1386.7,1368.3,1333.5,1297.7,1272.6,1215.4,1125.5,1039.6,1008.0,968.6.1H NMR(600MHz,DMSO-d6)δ8.22(1H,s),5.69~5.54(3H,m),3.15~3.01(6H,m),3.01~2.84(5H,m),2.57~2.51(2H,m),2.25~2.17(1H,m),2.17~2.06(1H,m),1.94~1.85(1H,m),1.85~1.64(5H,m),1.64~1.54(2H,m),1.51~1.39(3H,m),1.37(3H,s),1.32(3H,s),1.26~1.22(1H,m),1.21(3H,s),1.18~1.15(1H,m),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.00~0.92(1H,m),0.82(3H,s).13CNMR(150MHz,DMSO-d6)δ199.1,198.6,172.9,164.2,157.7,127.0,124.1,121.8,55.6,54.0,51.7,50.7,50.4,46.6,45.4,45.2,43.9,42.6,38.1,37.0,35.8,31.8,31.7,31.1,28.8,28.0,26.5,26.1,23.2,21.5,20.1,18.8,18.1.HRMS m/z calcd for C37H55F3N3O5S+[M+H]+710.3809,found 710.3821.
实施例23:1-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-3-(2-(哌啶-1-基)乙基)脲的制备
按照实施例22步骤B的制备方法,用原料1-(2-氨乙基)哌啶替代实施例22步骤B中的4-(2-氨乙基)硫代吗啉-1,1-二氧化物,制备标题化合物。Mp:204-206℃.IR(KBr):3418.7,2932.1,2860.4,1688.7,1657.8,1631.5,1567.4,1490.0,1441.5,1386.4,1368.5,1296.3,1271.6,1215.4,1142.7,1007.6,969.0.1H NMR(600MHz,DMSO-d6)δ8.22(1H,s),5.83~5.51(3H,m),3.21~3.01(2H,m),2.95(1H,s),2.48~2.26(5H,m),2.26~2.17(1H,m),2.17~2.04(1H,m),1.96~1.85(1H,m),1.85~1.63(5H,m),1.63~1.56(2H,m),1.56~1.46(5H,m),1.46~1.39(3H,m),1.37(3H,s),1.36~1.34(1H,m),1.32(3H,s),1.26~1.23(1H,m),1.21(3H,s),1.19~1.14(2H,m),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.00~0.92(1H,m),0.82(3H,s).1H NMR(600MHz,DMSO-d6)δ199.1,198.6,172.9,164.2,157.7,129.0,127.0,124.1,65.4,59.0,54.4,54.0,51.7,50.4,46.6,45.3,45.2,43.8,42.5,38.1,35.8,31.8,31.7,31.1,28.8,28.0,26.5,26.1,23.2,21.5,20.1,18.8,18.1.HRMS m/z calcd for C38H57F3N3O3 +[M+H]+660.4347,found 660.4341.
实施例24:O-(2-(硫代吗啉-1,1-过氧化物-4-基)乙基)-N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-氨基甲酸酯的制备
将0.2g 4-(2-羟乙基)硫代吗啉-1,1-二氧化物(1.13mmol)溶于15mL干燥的二氯甲烷,再加入0.37g Cs2CO3(1.13mmol),室温搅拌0.5h。随后将上述反应液中加入0.2g 2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-异氰酸酯(0.38mmol),继续搅拌12h。将反应液用水洗,饱和氯化钠洗,无水硫酸钠干燥。减压蒸干溶剂,以二氯甲烷:甲醇(V/V)=60:1为洗脱剂硅胶柱层析,分离得白色固体0.10g,收率:37%。Mp:118-121℃.IR(KBr):3397.1,2929.9,1723.3,1686.4,1655.2,1632.1,1451.3,1386.7,1334.4,1298.2,1271.3,1217.1,1125.6,1069.3,1008.1,971.0.1H NMR(600MHz,DMSO-d6)δ8.23(1H,s),6.86(1H,s),5.82(1H,s),4.12~3.96(2H,m),3.11~3.01(4H,m),3.01~2.91(5H,m),2.75~2.68(2H,m),2.32~2.23(1H,m),2.18~2.03(2H,m),1.86~1.62(5H,m),1.62~1.53(2H,m),1.46~1.38(2H,m),1.37(3H,s),1.35~1.33(1H,m),1.32(3H,s),1.26~1.20(2H,m),1.18(3H,s),1.10(6H,s),1.09(3H,s),1.00~0.92(1H,m),0.81(3H,s).13C NMR(150MHz,DMSO-d6)δ199.1,198.7,172.4,164.3,154.9,131.9,127.4,124.0,65.4,60.7,54.9,54.0,52.2,50.9,50.7,50.4,46.0,45.3,45.2,43.8,38.1,35.9,31.7,31.1,30.4,28.8,28.0,26.4,26.1,23.2,21.5,20.1,19.0,18.8,18.1,13.9.HRMS m/z calcd for C37H54F3N2O6S+[M+H]+711.3649,found 711.3633.
实施例25:O-(2-(哌啶-1-基)乙基)-N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-氨基甲酸酯的制备
按照实施例24的制备方法,用原料1-(2-羟乙基)哌啶替代实施例22步骤B中的4-(2-羟乙基)硫代吗啉-1,1-二氧化物,制备标题化合物。Mp:94-97℃.IR(KBr):3424.3,2983.2,2934.6,2870.3,1725.3,1689.3,1656.8,1629.7,1615.0,1492.5,1443.7,1387.5,1368.1,1296.5,1269.4,1216.6,1140.0,1068.9,1007.1,969.2.1H NMR(600MHz,DMSO-d6)δ8.22(1H,s),6.83(1H,s),5.82(1H,s),4.09~3.93(2H,m),2.94(1H,s),2.48~2.42(2H,m),2.42~2.31(4H,m),2.31~2.22(1H,m),2.16~2.01(2H,m),1.84~1.62(5H,m),1.62~1.54(2H,m),1.52~1.38(7H,m),1.37(3H,s),1.35~1.33(2H,m),1.32(3H,s),1.26~1.19(2H,m),1.17(3H,s),1.10(6H,s),1.09(3H,s),0.99~0.92(1H,m),0.80(3H,s).13C NMR(150MHz,DMSO-d6)δ199.1,198.7,172.4,164.2,155.0,131.9,127.3,123.6,65.4,60.8,57.9,54.6,54.0,52.1,50.4,46.0,45.3,45.2,43.8,38.1,35.8,31.7,31.1,28.8,28.0,26.4,26.1,25.9,24.3,23.1,21.5,20.1,18.8,18.1.HRMS m/z calcd for C38H56F3N2O4 +[M+H]+661.4187,found 661.4190.
实施例26:N-(2-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)乙基)-硫代吗啉-1,1-过氧化物的制备
步骤A:2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-氨基的制备
将0.75g 2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-异氰酸酯(1.41mmol)溶于30mL四氢呋喃,向上述溶液滴加3mL浓盐酸,室温搅拌4h。将反应液倒入150mL冰水中,用K2CO3溶液调节pH至7,搅拌,抽滤,干燥后得白色固体0.6g,收率:84%。LC-MS:506.5[M+H]+.
步骤B:N-(2-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)乙基)-硫代吗啉-1,1-过氧化物的制备
将0.3g 2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-氨基(0.59mmol),0.59g 4-(2-氯乙基)硫代吗啉-1,1-二氧化物(3.0mmol),0.5g KI(0.65mmol)和0.64g K3PO4(3.0mmol)溶于30mL干燥的乙腈。氮气保护,回流搅拌24h。将反应液冷却至室温,倒入100mL水中,用二氯萃取,水洗,饱和氯化钠洗,无水硫酸钠干燥。减压蒸干溶剂,以二氯甲烷:甲醇(V/V)=100:1为洗脱剂硅胶柱层析,分离得白色固体0.11g,收率:28%。LC-MS:667.4[M+H]+.
实施例27:N-(2-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)乙基)-哌啶的制备
按照实施例26步骤B的制备方法,用原料1-(2-氯乙基)哌啶替代实施例26步骤B中的4-(2-氯乙基)硫代吗啉-1,1-二氧化物,制备标题化合物。LC-MS:617.3[M+H]+.
本发明产物药理作用研究
体外抗肿瘤活性测试
1)细胞培养
人急性白血病细胞HL-60,前列腺癌细胞PC-3,乳腺癌细胞MCF-7,培养于含有10%(v/v)经加热灭活的胎牛血清、100U/mL青霉素、100μg/mL链霉素及2mmol/L谷氨酰胺的RPMI1640培养液或高糖DMEM培养液中。所有实验用细胞均于37℃、5%CO2饱和湿度培养箱中培养。
2)细胞生长抑制活性
化合物对HL-60细胞的生长抑制作用采用细胞计数法考察。将一定密度(1×105个/mL)的细胞悬液接种于24孔培养板,2mL/孔,加入不同浓度药物共同孵育72小时后于显微镜下计数,依以下公式求得细胞生长抑制率,并求得半数生长抑制浓度GI50(使细胞生长抑制率达50%时的药物浓度)。
化合物对实体瘤细胞PC-3和MCF-7的生长抑制作用采用MTT法考察。将一定密度(2~3×104个/mL)的细胞悬液接种于96孔培养板,100μL/孔,加入不同浓度化合物共同孵育96小时后再加入50μL的MTT溶液继续孵育3.5h,然后将96孔板内的液体全部弃掉倒扣在滤纸上充分吸干残留液体,之后每孔加入200μL DMSO于振荡器上震荡10min以溶解蓝紫色结晶物,最后使用酶标仪测570nm处吸光值,设A1(含200μL DMSO)为空白对照孔;依以下公式求得细胞生长抑制率,并求得半数生长抑制浓度GI50(使细胞生长抑制率达50%时的化合物浓度)。
表1化合物对HL-60,PC-3和MCF-7的GI50(μmol/L)值列表
Claims (5)
2.如下所述的衍生物或药学上可接受的盐,
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-哌啶基哌啶
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-哌嗪
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-吗啉
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4,4-二氟哌啶
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-硫代吗啉-1,1-过氧化物
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-(3-氧杂环丁基)哌嗪
N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)-4-羟乙基哌嗪
1-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-3-(2-(硫代吗啉-1,1-过氧化物-4-基)乙基)脲
1-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-3-(2-(哌啶-1-基)乙基)脲
O-(2-(硫代吗啉-1,1-过氧化物-4-基)乙基)-N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-氨基甲酸酯
O-(2-(哌啶-1-基)乙基)-N-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)-氨基甲酸酯
N-(2-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)乙基)-硫代吗啉-1,1-过氧化物
N-(2-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-基)乙基)-哌啶。
3.一种药物组合物,其特征在于:包含权利要求1或2所述的衍生物或药学上可接受的盐以及药学上可接受的赋形剂。
4.权利要求1或2所述的衍生物或药学上可接受的盐或权利要求3所述的药物组合物在制备治疗和/或预防抗肿瘤药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述的肿瘤为乳腺癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、肝癌、膀胱癌、子宫癌、胰腺癌、卵巢癌、淋巴癌、皮肤癌或血液癌。
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