CN107857790A - 一种新型甾体类雄激素受体抑制剂、制备方法及其医药用途 - Google Patents
一种新型甾体类雄激素受体抑制剂、制备方法及其医药用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及一系列甾体类雄激素受体抑制剂、其制备方法及医药用途,特别是用于治疗雄激素受体相关疾病的药物,如依赖于雄激素的细胞增殖,多毛症,痤疮,雄激素脱发等。本发明中涉及化合物的结构通式如下式,通式中各基团定义详见说明书。
Description
技术领域
本发明涉及药物化学领域,具体涉及一系列甾体类雄激素受体抑制剂、它们的制备方法以及它们的医药用途,特别是用于制备治疗雄激素受体相关疾病如前列腺癌的药物。
背景技术
雄激素受体(Androgenic Receptor,AR)属于核受体家族,包含有四个主要区域:N端活性转录控制区域(NTD),DNA结合区域(DBD),铰链区及配体结合区(LBD)。AR主要在雄激素靶组织例如前列腺、骨骼肌、肝脏和中枢神经系统(CNS)中表达。在前列腺、肾上腺和附睾中观察到最大表达水平。AR可以由包括睾酮和5α-二氢睾酮(5α-DHT)在内的内源性雄激素的结合来激活。
前列腺癌(Prostate cancer,PCa)是发生于男性前列腺组织中的恶性肿瘤,是前列腺腺泡细胞异常无序生长的结果。前列腺癌的发病率具有明显的地理和种族差异。在欧美等发达国家和地区,它是男性最常见的恶性肿瘤,其死亡率居各种癌症的第二位;在亚洲,其发病率低于西方国家,但近年来呈迅速上升趋势。目前我国的前列腺癌发病率呈逐年上升趋势,且发现时以多呈中晚期。国家癌症中心发布2017年最新癌症数据显示前列腺癌发病率与城市化呈正相关,从小城市到大城市,发病趋势增加趋势明显。2017年小城市前列腺癌发病率<5/10万,而大城市发病率是小城市的4倍。
PCa的发生、发展与雄激素密切相关,内分泌治疗是目前晚期前列腺癌的主要治疗方法。大多数患者起初都对去势(手术或药物)或联合雄激素阻断治疗有效,但经过14~30个月的中位时间后,几乎所有患者病变都将逐渐发展为去势抵抗性前列腺癌(CRPC)。研究显示AR的过度表达与去势抵抗密切相关。约有三分之一的CPRC患者出现AR基因序列的扩增,进而引起AR表达增加。而主要发生在AR配体结合区的突变不仅导致雌激素等非AR活性物质发生激动作用,更严重的是导致比卡鲁胺等雄激素受体抑制剂产生激动活性,从而发生抵抗。最后,有研究发现CPRC患者前列腺中的雄激素水平仍为正常血清雄激素水平的25%。这可能是由于体内雄激素合成相关酶表达的增加进而引起内源性过度合成雄激素。因此,抑制雄激素受体活性和抑制雄激素合成是治疗CPRC的重要方法。
发明内容
本发明公开了具有通式一结构的甾体类抗雄激素化合物。经药理实验证明该类化合物具有良好的抗前列腺癌活性。
本发明通式的化合物结构如下:
其中R表示C2-C4的直链、支链烷烃或环烷烃;
其中虚线表示有无双键;其中X表示-OAc,-OH,=NOH或者=O;
其中A表示未取代或取代含N杂环。
本发明化合物的结构及编号如下:
药理实验及实施例中化合物的代号等同于以上代号所对应的化合物结构。
本发明的化合物可以由以下方法制备:
L201~L212
反应物和反应条件:i)POCl3,DMF,80℃,2h;ii)咪唑,K2CO3,DMF,80℃,4h;iii)NaBH4,MeOH,r.t.1h;iv)MsCl,Et3N,CH2Cl2,r.t.2h;v)胺,K2CO3,CH3CN,r.f.6h;vi)20%K2CO3,甲醇,r.f.1h;vii)Al(i-Pr)3,环己酮,甲苯,r.f.14h;viii)NH4OH-HCl,Et3N,EtOH,r.f.4h;ix)NaBH4,MeOH,r.t.1h.
L213~L224。
反应物和反应条件:i)POCl3,DMF,80℃,2h;ii)3-吡啶硼酸,K2CO3,THF,water,TBAB,(PPh3)2Cl2Pd,r.f.,10h;iii)NaBH4,MeOH,r.t.1h;iv)MsCl,Et3N,CH2Cl2,r.t.2h;v)胺,K2CO3,CH3CN,r.f.6h;vi)20%K2CO3,MeOH,r.f.1h;vii)Al(i-Pr)3,环丙酮,甲苯,r.f.14h;viii)NH4OH-HCl,Et3N,EtOH,r.f.4h;ix)NaBH4,MeOH,r.t.1h.
L225~L227
反应物和反应条件:i)POCl3,DMF,80℃,2h;ii)3-吡啶硼酸,K2CO3,THF,water,TBAB,(PPh3)2Cl2Pd,r.f.,10h;iii)NaClO2,Na2HPO3,2-甲基-1-丁烯,t-BuOH,0℃,2h;iv)20%K2CO3,MeOH,r.f.,1h;v)乙醇,PTS,80℃,4h。
下面是本发明的部分化合物的药理活性检测
MTT法测药物对前列腺癌细胞株(PC-3)增殖能力的抑制情况
前列腺癌细胞株PC-3抗增殖活性实验
1材料和方法
1.1实验材料
(1)细胞系
前列腺癌细胞PC-3(南京凯基生物技术公司)。
(2)试剂
筛选化合物由中国药科大学药化教研室提供。
RPMI1640培养基、双抗(Gibco),优级胎牛血清(天津灏洋,TBD);3-(4,5)-2噻唑-(2,5)-二甲基溴化四氢唑蓝(MTT)(南京生兴生物公司);DMSO(Amresco);其他试剂均为国产分析纯。
(3)主要实验仪器
CO2培养箱(美国Revco);全自动酶标仪(Labsystems Multiskan Ascent);40 CFL型荧光倒置显微镜(德国Carl Ziess Axiovert)。
1.2溶剂的配置方法
D-Hanks:NaCl 8.0g,KCl 0.4g,Na2HPO4·12H2O 0.13g,KH2PO40.06g,NaHCO30.35g,加1mL蒸馏水溶解,调pH至7.4,高压灭菌,4℃保存。
0.25%胰酶消化液:胰蛋白酶0.25g,加D-Hanks 100mL溶解,0.22μm滤器过滤,-20℃保存。RPMI1640培养液:RPMI1640培养基粉13.3g、NaHCO32.0g于1L蒸馏水中溶解,加入10%双抗,0.22μm滤膜过滤,使用时加入10%胎牛血清,4℃保存。
1.3实验方法
(1)细胞培养
用RPMI1640培养基于5%CO2,37℃孵育箱中培养,约两天更换一次培养基。细胞汇合度达到80%-90%时传代。传代时,倒掉旧培养基,D-Hanks洗两次(血清会影响胰酶的消化效果),加入少量0.25%胰蛋白酶,铺平瓶底,37℃下消化约3分钟,倒置显微镜下观察到细胞变圆,倒掉胰酶,D-Hanks洗一次,加入新鲜培养基,吹打混匀,分植入新的培养瓶中,继续培养。
冻存细胞时,收获对数生长期细胞(收集细胞前24h换液),冻存液(5%DMSO,95%RPMI1640)重悬细胞,调细胞密度为5×106-1×107个/mL,分装入无菌冻存管中,每管加1.5mL细胞悬液,做好标记和记录,冻存管在4℃放置20min,-20℃放置20min,在-80℃超低温冰箱过夜后移入液氮容器中。细胞复苏,从液氮容器中取出冻存管,迅速放入盛有40℃水的烧杯中,不时摇动,使之尽快融化,用酒精棉球消毒冻存管表面,吸出细胞悬液,移入离心管中,补加细胞培养液至10mL,继续培养。
细胞计数:取少量细胞混悬液与0.4%台盼蓝溶液等体积混合,用吸管吹打混匀,取少许(15uL-20uL)混合液滴入计数板与盖玻片的上方空隙中,注意不要产生气泡,于200倍低倍显微镜下观察,死细胞可被台盼蓝染色,而活细胞不会,移动计数板至看到计数方格,数出各对角四个大格的未染色细胞数,记录包括压右线和上线的细胞,下线和左线不计,细胞数/mL=25%格大格子细胞数×104。
(2)MTT检测法
收集对数期细胞,用RPMI1640培养液配成单个细胞悬液,调整细胞悬液浓度以每孔5000-10000个细胞接种到96孔板(边缘孔用D-Hanks填充)。培养24小时,吸去旧培养基,加入含药培养基200μL/孔,药物浓度分别为1×10-4mol/L,1×10-5mol/L,1×10-6mol/L,1×10-7mol/L,每组每个浓度设3个复孔;以含10%DMSO的RPMI1640培养液作为对照组,设12个复孔。培养48h后加入5mg/mL的MTT 20μL/孔,继续培养4h,吸出孔内液体,加入DMSO 150μL/孔,振摇5min使结晶物充分溶解,在酶联免疫检测仪上测定吸光度(A),测定波长为570nm。抑制率=[1-(实验组平均OD值/对照组平均OD值)]×100%。
2PC-3细胞株的细胞增殖抑制活性结果及讨论
前列腺癌细胞系PC-3来源于骨转移激素抵抗性前列腺癌组织,其AR表达为阴性,对雄激素不敏感。因此通过测试对于PC-3细胞株的抗增殖作用,可验证目标化合物是否可通过非雄激素效应产生细胞增殖抑制作用。
PC-3细胞MTT实验筛选结果
具体实施方式(所述实施例只是用来说明本发明,而不是用来限定本发明)
部分化合物的制备实例如下:
核磁共振氢谱仪为Bruker AV 500型(TMS为内标,氘代CDCl3或氘代DMSO为溶剂);质谱仪为岛津GCMS-QP2010型质谱仪或Mariner质谱仪;实验中柱层析均采用青岛海洋化工有限公司生产的100-200目硅胶做固定相;化学试剂均为市售化学纯或分析纯产品,出特殊说明外,未经处理直接使用。
实施例1
(3β)-17-氯-16-甲酰基-雄甾-5,16-二烯-3-醋酸酯(123)的制备
冰浴下PClO3(5.62ml,60mmol)缓慢滴加至20mlDMF中,0℃反应0.5h。醋酸去氢表雄酮(1g,3mmol)溶于20ml DMF中滴加至反应液,升温至80℃反应2h,TLC显示反应完全。反应液缓慢滴加至300ml 10%NH4OAc中水析,抽滤得白色固体1.20g,收率77.49%。ESI-MSm/z:377[M+H]+
实施例2
(3β)-17-(1-咪唑基)-16-甲酰基-雄甾-5,16-二烯-3-醋酸酯(144)的制备
化合物123(4.45g,11.83mmol),咪唑(3.20g,47.34mmol),K2CO3(6.53g,47.34mmol)溶于60ml无水DMF中,N2保护下80℃反应4h,TLC显示反应基本完全。反应液倒入300ml水中水析,得灰白色固体。异丙醇重结晶得白色晶体3.45g,收率71.28%。
实施例3
(3β)-17-(1-咪唑基)-16-羟甲基-雄甾-5,16-二烯-3-醋酸酯(145)的制备
化合物144(3.45g,8.45mmol)溶于35ml甲醇中,NaBH4(1.28g,33.82mmol)分批加入反应液中,0℃反应1h。TLC显示反应基本完全。旋干大部分甲醇后倒入100ml饱和食盐水中水析,得白色固体3.02g,收率86.62%。
实施例4
(3β)-17-(1-咪唑基)-16-甲磺酰甲基-雄甾-5,16-二烯-3-醋酸酯(146)的制备
化合物145(3.02g,7.32mmol)溶于45ml无水CH2Cl2中,冰浴下加入MsCl(2.19ml,29.27mmol),Et3N(4.9ml,35.14mmol),0℃下反应3h。TLC显示反应基本完全。反应液倒入50ml水中,分出有机层,水层用CH2Cl2萃取,合并有机层,干燥,旋干得黄色固体3.09g,收率94.98%。不经分离,直接下投。
实施例5
(3β)-17-(1-咪唑基)-16-正丙胺甲基-雄甾-5,16-二烯-3-醋酸酯(147)的制备
化合物146(0.4g,0.82mmol),正丙胺(0.2ml,2.46mmol)和K2CO3(0.34g,2.46mmol)KI(40mg)溶于8ml乙腈,室温搅拌过夜。TLC显示反应完全。旋干溶剂,反应液中加入10ml水,EA萃取,干燥,旋干得黄色固体0.28g,收率75.74%。
实施例6
(3β)-17-(1-咪唑基)-16-正丙胺甲基-3-羟基-雄甾-5,16-二烯(L201)的制备
化合物(150mg,0.36mmol)溶于3ml甲醇中,加入20%K2CO31ml,回流反应1h。TLC显示反应完成。旋掉大部分甲醇后倒入5ml饱和食盐水中水析得白色固体。柱层析纯化(DCM∶MeOH=150∶1)得白色固体78mg,收率57.34%。Data for L201:m.p.:78-79℃;1H NMR(CDCl3,300MHz)δ:7.42(s,1H,2-imidazole),7.13(s,1H,5-imidazole),6.90(s,1H,4-imidazole),5.41(s,1H,6-H),3.50(m,1H,-OH),3.21(s,2H,-CH 2NH),2.46(t,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.89(t,3H,-CH2CH 3)ppm;13C NMR(DMSO-d6,75MHz)δ:166.71,142.49,141.64,137.31,135.71,128.39,120.06,119.91,101.26,89.28,69.92,54.08,50.81,50.14,46.56,45.51,42.21,36.78,36.31,33.94,31.90,31.36,30.60,29.81,22.28,20.09,19.01,17.42,15.42,11.70ppm.HRMS(ESI):m/z[M+H]+.Calcd for C26H39N3O:410.3093;Found:410.3172.
实施例7
(3β)-17-(1-咪唑基)-16-正丙胺甲基-雄甾-4,16-二烯-3-酮(L202)的制备
化合物L201(0.74g,1.83mmol),异丙醇铝(0.38g,1.83mmol)溶于10ml甲苯中,加入环己酮(4ml,36.67mmol),回流反应12h。TLC显示反应完全。反应液冷却至室温,滤去不溶物,反应液倒入20ml水中,EA萃取,干燥,旋干,的黄色粗品。柱层析纯化(DCM∶MeOH=150∶1)得白色固体0.54g,收率72.97%。Data for L202:m.p.:118-120℃;1H NMR(CDCl3,300MHz)δ:7.38(s,1H,2-imidazole),7.27(s,1H,5-imidazole),7.00(s,1H,4-imidazole),6.22(s,1H,6-H),2.86(s,2H,-CH 2NH),2.66(t,2H,-NHCH 2CH2-),1.99(s,3H,19-CH3),0.78(s,3H,18-CH3),0.89(t,3H,-CH2CH 3)ppm;HRMS(ESI):m/z[M+H]+.Calcd for C26H37N3O:408.2941;Found:408.2683.
实施例8
(3β)-17-(1-咪唑基)-16-正丙胺甲基-雄甾-4,16-二烯-3-肟(L203)的制备
化合物L202(0.2mg,0.49mmol),盐酸羟胺(0.103g,1.48mmol)溶于4ml甲醇中,加入Et3N(205μl,1.48mmol),回流反应3h。TLC显示反应完全。反应液倒入20ml水中水析,得白色固体。柱层析纯化(DCM∶MeOH=100∶1)得白色固体0.15g,收率72.33%。Data for L203:m.p.:137-140℃;1H NMR(CDCl3,300MHz)δ:7.44(s,1H,2-imidazole),7.12(s,1H,5-imidazole),6.90(s,1H,4-imidazole),5.80(s,1H,4-H),3.19(s,2H,-CH 2NH),3.07(m,1H,-OH),1.05(s,3H,19-CH3),0.94(s,3H,18-CH3),0.88(t,3H,-CH2CH 3)ppm;13C NMR(DMSO-d6,75MHz)δ:203.23,193.84,186.38,137.34,135.88,118.08,108.39,100.35,72.50,62.04,55.37,53.60,46.61,29.56,22.00,15.47,11.64ppm.HRMS(ESI):m/z[M+H]+.Calcdfor C26H39N3O:423.3053;Found:423.3120.
实施例9
(3β)-17-(1-咪唑基)-16-正丙胺甲基-3-羟基-雄甾-5,16-二烯(L204)的制备
化合物L202(0.2g,0.49mmol)溶于2ml甲醇中,加入NaBH4(74mgg,1.96mmol),0℃反应1h。TLC显示反应基本完全。反应液倒入10ml饱和食盐水中水析,得白色固体。柱层析纯化(DCM∶MeOH=100∶1)得白色固体0.17g,收率85.27%。Data for L204:m.p.:92-94℃;1HNMR(CDCl3,300MHz)δ:7.39(s,1H,2-imidazole),7.10(s,1H,5-imidazole),6.86(s,1H,4-imidazole),5.31(s,1H,4-H),3.15(m,1H,-OH),3.17(s,2H,-CH 2NH),2.56(t,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.89(t,3H,-CH2CH 3)ppm;13C NMR(DMS0-d6,75MHz)δ:202.67,172.05,142.48,141.64,137.28,135.88,128.37,120.02,119.87,109.97,88.23,79.83,69.92,66.88,56.96,54.09,52.06,50.14,46.57,45.69,42.21,36.79,36.30,33.95,31.87,31.36,30.60,29.81,27.60,20.60,20.57,20.09,19.00,15.41,7.17,4.88ppm;HRMS(ESI):m/z[M+H]+.Calcd for C27H41N3O:424.3252;Found:424.3173.
实施例10
(3β)-17-(1-咪唑基)-16-异丁胺甲基-3-羟基-雄甾-5,16-二烯(L205)的制备
具体操作参照化合物L201,得白色固体,收率19.97%。Data for L205:m.p.:97-98℃;1H NMR(CDCl3,300MHz)δ:7.42(s,1H,2-imidazole),7.11(s,1H,5-imidazole),6.89(s,1H,4-imidazole),5.38(s,1H,6-H),3.54(m,1H,-OH),3.18(s,2H,-CH 2NH),2.27(t,2H,-NHCH 2CH-),1.01(s,3H,19-CH3),0.93(s,3H,18-CH3),0.89(t,6H,-CH(CH 3)2)ppm;13CNMR(DMSO-d6,75MHz)δ:202.67,172.05,142.48,141.64,137.28,135.88,128.37,120.02,119.87,109.97,88.23,79.83,69.92,66.88,56.96,54.09,52.06,50.14,46.57,45.69,42.21,36.79,36.30,33.95,31.87,31.36,30.60,29.81,27.60,20.60,20.57,20.09,19.00,15.41,7.17,4.88。
实施例11
(3β)-17-(1-咪唑基)-16-异丁胺甲基-雄甾-4,16-二烯-3-酮(L206)的制备
具体操作参照化合物L202,得白色固体,收率14.98%。Data for L206:m.p.:94-96℃;1H NMR(CDCl3,300MHz)δ:7.40(s,1H,2-imidazole),7.10(s,1H,5-imidazole),6.87(s,1H,4-imidazole),5.74(s,1H,4-H),3.20(s,2H,-CH 2NH),2.64(t,2H,-NHCH 2CH2-),1.07(s,3H,19-CH3),0.94(s,3H,18-CH3),0.86(t,6H,-CH(CH 3)2)ppm;HRMS(ESI):m/z[M+H]+.Calcd for C27H40N4O:437.3203;Found:437.3126.
实施例12
(3β)-17-(1-咪唑基)-16-异丁胺甲基-雄甾-4,16-二烯-3-肟(L207)的制备
具体操作参照化合物L203,得白色固体,收率11.51%。Data for L207:m.p.:107-109℃;1H NMR(CDCl3,300MHz)δ:7.46(s,1H,2-imidazole),7.14(s,1H,5-imidazole),6.92(s,1H,4-imidazole),5.81(s,1H,6-H),3.18(s,2H,-CH 2NH),2.42(t,2H,-NHCH 2CH2-),1.02(s,3H,19-CH3),0.96(s,3H,18-CH3),0.89(t,6H,-CH(CH 3)2)ppm;13C NMR(DMSO-d6,75MHz)δ:203.4,182.04,175.77,153.99,152.20,150.86,143.10,137.32,128.47,119.93,118.10,110.90,78.32,73.97,68.32,56.53,53.62,46.03,34.1833.50,32.50,31.49,27.29,20.51,18.41,17.27,15.47ppm.HRMS(ESI):m/z[M+H]+.Calcd for C27H41N3O:424.3252;Found:424.3173.
实施例13
(3β)-17-(1-咪唑基)-16-异丁胺甲基-3-羟基-雄甾-5,16-二烯(L208)的制备
具体操作参照化合物L203,得白色固体,收率13.03%。Data for L208:m.p.:82-83℃;1H NMR(CDCl3,300MHz)δ:7.43(s,1H,2-imidazole),7.13(s,1H,5-imidazole),6.90(s,1H,4-imidazole),5.41(m,2H,6-H,3-OH),3.61(m,1H,3-H),3.19(s,2H,-CH 2NH),1.07(s,3H,19-CH3),0.95(s,3H,18-CH3),0.89(m,6H,-CH2(CH 3)2)ppm;HRMS(ESI):m/z[M+H]+.Calcd for C27H41N3O:424.3252;Found:424.3173.
实施例14
(3β)-17-(1-咪唑基)-16-环丙胺甲基-3-羟基-雄甾-5,16-二烯(L209)的制备
具体操作参照化合物L201,得白色固体,收率16.39%。Data for L209:m.p.:127-129℃;1H NMR(CDCl3,300MHz)δ:7.46(s,1H,2-imidazole),7.14(s,1H,5-imidazole),6.92(s,1H,4-imidazole),5.41(s,1H,6-H),3.65(m,3H,3-H,-CH 2NH),3.23(s,1H,-NHCH),1.06(s,3H,19-CH3),0.95(s,3H,18-CH3),0.36(m,2H,-CH(CH 2)2-)ppm;13C NMR(DMSO-d6,75MHz)δ:142.40,141.62,137.30,135.85,128.35,120.08,119.98,114.50,69.91,54.08,52.02,50.14,46.53,45.36,42.20,36.77,36.30,33.93,32.06,31.36,30.60,30.05,29.80,20.08,19.01,15.33,7.16,6.08,5.87ppm.HRMS(ESI):m/z[M+H]+.Calcd for C27H39N3O:423.3092;Found:422.2715.
实施例15
(3β)-17-(1-咪唑基)-16-环丙胺甲基-雄甾-4,16-二烯-3-酮(L210)的制备
具体操作参照化合物L202,得白色固体,收率12.78%。Data for L210:m.p.:153-154℃;1H NMR(CDCl3,300MHz)δ:7.45(s,1H,2-imidazole),7.12(s,1H,5-imidazole),6.90(s,1H,4-imidazole),5.75(s,1H,4-H),3.27(s,2H,-CH 2NH),2.41(m,2H,-NHCH 2CH2-),1.17(s,3H,19-CH3),0.95(s,3H,18-CH3),0.36(m,2H,-CH(CH 2)2-)ppm.
实施例16
(3β)-17-(1-咪唑基)-16-环丙胺甲基-雄甾-4,16-二烯-3-肟(L211)的制备
具体操作参照化合物L203,得白色固体,收率11.50%。Data for L311:m.p.:105-107℃;1H NMR(CDCl3,300MHz)δ:7.42(s,1H,2-imidazole),7.13(s,1H,5-imidazole),6.90(s,1H,4-imidazole),5.41(s,1H,6-H),3.50(m,1H,-OH),3.21(s,2H,-CH 2NH),2.46(t,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.89(t,3H,-CH2CH 3)ppm;13C NMR(DMSO-d6,75MHz)δ:154.01,142.34,137.32,136.00,128.34,120.01,118.09,98.51,69.93,54.10,53.65,50.15,46.53,45.35,37.55,36.30,33.43,31.36,30.04,23.78,19.01,15.42,6.11,5.88ppm.HRMS(ESI):m/z[M+H]+.Calcd for C27H38N4O:435.3057;Found:435.2938.
实施例17
(3β)-17-(1-咪唑基)-16-环丙胺甲基-3-羟基-雄甾-5,16-二烯(L212)的制备
具体操作参照化合物L203,得白色固体,收率10.89%。Data for L312:m.p.:95-98℃;1H NMR(CDCl3,300MHz)δ:7.42(s,1H,2-imidazole),7.13(s,1H,5-imidazole),6.90(s,1H,4-imidazole),5.41(s,1H,6-H),3.50(m,1H,-OH),3.21(s,2H,-CH 2NH),2.46(t,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.89(t,3H,-CH2CH 3)ppm;13C NMR(DMSO-d6,75MHz)δ:169.68,152.11,148.98,147.76,144.90,141.22,139.82,135.64,131.63,128.78,123.08,121.95,105.56,73.13,57.82,55.54,49.94,48.52,37.70,36.33,34.81,33.07,31.02,30.03,27.32,21.00,20.23,18.86,16.12ppm.HRMS(ESI):m/z[M+H]+.Calcd for C27H39N3O:423.3092;Found:422.2715.
实施例18
(3β)-17-(3-吡啶基)-16-正丙胺甲基-3-羟基-雄甾-5,16-二烯(L213)的制备
具体操作参照化合物L201,得白色固体,收率13.69%。Data for L213:m.p.:87-90℃;1H NMR(CDCl3,300MHz)δ:8.57(s,1H,2-pyridine),8.56(s,1H,6-pyridine),7.48(s,1H,2-pyridine),7.34(s,1H,5-pyridine),5.41(s,1H,6-H),3.50(m,1H,3-H),3.21(s,2H,-CH2NH),2.74(t,2H,-NHCH 2CH2-),1.06(s,3H,19-CH3),0.94(s,3H,18-CH3),0.88(m,3H,-CH2CH 3)ppm;HRMS(ESI):m/z[M+H]+.Calcd for C28H40N2O:421.3141;Found:421.3068.
实施例19
(3β)-17-(3-吡啶基)-16-正丙胺甲基-雄甾-4,16-二烯-3-酮(L214)的制备
具体操作参照化合物L202,得白色固体,收率10.95%。Data for L214:m.p.:123-125℃;1H NMR(CDCl3,300MHz)δ:8.57(s,1H,2-pyridine),8.37(s,1H,6-pyridine),7.48(s,1H,2-pyridine),7.32(s,1H,5-pyridine),,5.41(s,1H,4-H),3.50(m,1H,-OH),3.21(s,2H,-CH 2NH),2.46(t,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.89(t,3H,-CH2CH 3)ppm.
实施例20
(3β)-17-(3-吡啶基)-16-正丙胺甲基-雄甾-4,16-二烯-3-肟(L215)的制备
具体操作参照化合物L203,得白色固体,收率10.89%。Data for L215:m.p.:111-113℃;1H NMR(CDCl3,300MHz)δ:8.51(s,1H,2-pyridine),8.36(s,1H,6-pyridine),7.67(s,1H,2-pyridine),7.45(s,1H,5-pyridine),5.43(s,1H,6-H),4.67(m,1H,3-H),4.11(t,2H,-CH 2NH),2.33(m,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.82(s,3H,18-CH3)ppm;13C NMR(DMSO-d6,75MHz)δ:170.47,147.02,129.08,113.11,111.15,101.45,92.68,86.84,55.39,55.21,53.77,47.32,43.29,42.03,37.75,36.02,35.33,33.80,33.11,32.28,31.60,31.29,25.26,24.65,24.34,23.12,21.02,18.12,13.30,11.27,5.39ppm.HRMS(ESI):m/z[M+H]+.Calcd for C28H39N3O:433.3091;Found:433.3322.
实施例22
(3β)-17-(3-吡啶基)-16-异丁胺甲基-3-羟基-雄甾-5,16-二烯(L217)的制备
具体操作参照化合物L201,得白色固体,收率15.47%。Data for L217:m.p.:110-112℃;1H NMR(CDCl3,300MHz)δ:8.53(m,2H,2,6-pyridine),7.46(s,1H,2-pyridine),5.42(s,1H,6-H),4.65(s,2H,-CH 2NH),3.34(m,1H,3-H),2.37(d,2H,-NHCH 2CH-),1.07(s,3H,19-CH3),0.93(s,3H,18-CH3),0.91(m,6H,-CH 3)ppm;HRMS(ESI):m/z[M+H]+.Calcd forC29H42N2O:435.3307;Found:435.3376.
实施例23
(3β)-17-(3-吡啶基)-16-异丁胺甲基-雄甾-4,16-二烯-3-酮(L218)的制备
具体操作参照化合物L202,得白色固体,收率13.76%。Data for L218:m.p.:104-105℃;1H NMR(CDCl3,300MHz)δ:7.42(s,1H,2-imidazole),7.13(s,1H,5-imidazole),6.90(s,1H,4-imidazole),5.41(s,1H,6-H),3.50(m,1H,-OH),3.21(s,2H,-CH 2NH),2.46(t,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.89(t,3H,-CH2CH 3)ppm;HRMS(ESI):m/z[M+H]+.Calcd for C29H40N2O:435.3570;Found:433.3060.
实施例24
(3β)-17-(3-吡啶基)-16-异丁胺甲基-3-羟基-雄甾-5,16-二烯(L220)的制备
具体操作参照化合物L203,得白色固体,收率11.24%。Data for L220:m.p.:91-93℃;1H NMR(CDCl3,300MHz)δ:8.53(s,1H,2-pyridine),8.39(s,1H,6-pyridine),7.77(s,1H,2-pyridine),7.55(s,1H,5-pyridine),5.43(s,1H,6-H),4.65(m,1H,3-H),3.56(s,1H,-OH);2.46(m,4H,-CH 2NHCH 2CH-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3)ppm;HRMS(ESI):m/z[M+H]+.Calcd for C29H42N2O:435.3307;Found:435.3376.
实施例25
(3β)-17-(3-吡啶基)-16-环丙胺甲基-3-羟基-雄甾-5,16-二烯(L221)的制备
具体操作参照化合物L201,得白色固体,收率19.87%。Data for L221:m.p.:82-83℃;1H NMR(CDCl3,300MHz)δ:8.52(s,1H,2-pyridine),8.38(s,1H,6-pyridine),7.67(s,1H,2-pyridine),7.47(s,1H,5-pyridine),5.42(s,1H,6-H),4.61(m,1H,-OH),3.21(s,2H,-CH 2NH),2.36(m,2H,-NHCH 2CH2-),1.06(s,3H,19-CH3),0.96(s,3H,18-CH3),0.81(m,3H,-CH2CH 3)ppm;13C NMR(DMSO-d6,75MHz)δ:175.66,156.01,148.99,143.48,136.41,124.47,91.97,62.64,52.06,34.12,21.90,7.18ppm.
实施例26
(3β)-17-(3-吡啶基)-16-环丙胺甲基-雄甾-4,16-二烯-3-酮(L222)的制备
具体操作参照化合物L202,得白色固体,收率15.49%。Data for L222:m.p.:94-95℃;1H NMR(CDCl3,300MHz)δ:8.54(m,1H,2,6-pyridine),7.13(m,1H,4,5-pyridine),5.41(s,1H,6-H),3.58(m,1H,4-H),3.21(m,3H,-CH 2NHCH-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.89(t,3H,-CH2CH 3),0.58(m,4H,-CH(CH3)2)ppm.
实施例27
(3β)-17-(3-吡啶基)-16-环丙胺甲基-雄甾-4,16-二烯-3-肟(L223)的制备
具体操作参照化合物L203,得白色固体,收率13.79%。Data for L323:m.p.:88-90℃;1H NMR(CDCl3,300MHz)δ:9.60(s,1H,-OH);8.67(s,1H,2-pyridine),8.54(m,1H,6-pyridine),7.54(m,1H,2,5-pyridine),5.41(s,1H,4-H),3.59(s,2H,-CH 2NH),2.46(t,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.91(s,3H,18-CH3),0.53(m,4H,-CH(CH 3)2)ppm.
实施例28
(3β)-17-(3-吡啶基)-16-环丙胺甲基-3-羟基-雄甾-5,16-二烯(L224)的制备
具体操作参照化合物L204,得白色固体,收率14.56%。Data for L224:m.p.:124-126℃;1H NMR(CDCl3,300MHz)δ:8.52(s,1H,2,6-pyridine),7.57(s,1H,2,5-pyridine),5.43(s,1H,4-H),4.28(m,1H,-NHCH(CH2)2-),2.87(t,2H,-CH 2NH),1.09(s,3H,19-CH3),0.91(s,3H,18-CH3),0.53(m,4H,-CH(CH 3)2)ppm.
实施例29
(3β)-17-(3-吡啶基)-3-羟基-雄甾-5,16-二烯-16-甲酸(150)的制备
具体操作参照化合物L201,得白色固体,收率95.38%。
实施例30
(3β)-17-(3-吡啶基)-3-羟基-雄甾-5,16-二烯-16-甲酸乙酯(L225)的制备
化合物150(0.2g,0.51mmol)溶于2ml乙醇中,加入PTS 20mg,回流反应3h,TLC显示反应完全。旋掉大部分乙醇,冷却结晶,得浅黄色晶体104mg,收率49.28%。Data for L224:m.p.:163-165℃;1H NMR(CDCl3,300MHz)δ:8.50(m,2H,2,6-pyridine),7.83(s,1H,2,5-pyridine),5.42(s,1H,6-H),3.76(t,2H,-OCH 2CH3),1.05(s,3H,19-CH3),0.82(s,3H,18-CH3)ppm;13C NMR(DMSO-d6,75MHz)δ:178.23,173.95,156.08,143.85,111.45,83.23,69.90,65.88,49.81,36.25,28.74.HRMS(ESI):m/z[M+H]+.Calcd for C27H37N2O3:423.2778;Found:423.2384.
实施例31
(3β)-17-(3-吡啶基)-3-羟基-雄甾-5,16-二烯-16-甲酸异丙酯(L226)的制备
具体操作参照化合物L225,得白色固体,收率52.28%Data for L226:m.p.:95-96℃;1H NMR(CDCl3,300MHz)δ:8.58(s,1H,2-pyridine),8.39(s,1H,6-pyridine),7.83(s,1H,2-pyridine),7.42(s,1H,5-pyridine),5.41(s,1H,6-H),4.67(m,1H,3-H),3.56(m,1H,-OCH(CH3)2),1.10(s,3H,19-CH3),0.95(s,3H,18-CH3)ppm;HRMS(ESI):m/z[M+H]+.Calcdfor C28H39N2O3:436.2934;Found:436.2850.
实施例32
(3β)-17-(3-吡啶基)-3-羟基-雄甾-5,16-二烯-16-甲酸正丁酯(L227)的制备
具体操作参照化合物L225,得白色固体,收率34.48%
Data for L227:m.p.:78=80℃;1H NMR(CDCl3,300MHz)δ:8.51(s,1H,2-pyridine),8.36(s,1H,6-pyridine),7.67(s,1H,2-pyridine),7.45(s,1H,5-pyridine),5.43(s,1H,6-H),4.67(m,1H,-OH),4.11(t,2H,-CH 2NH),2.33(m,2H,-NHCH 2CH2-),1.05(s,3H,19-CH3),0.82(s,3H,18-CH3)ppm.
Claims (8)
1.下列通式的化合物或者其药学上可接受的立体异构体:
其中R表示C2-C4的直链、支链烷烃或环烷烃;
其中虚线表示有无双键;
其中X表示-OAc,-OH,=NOH或者=O;
其中A表示未取代或取代含N杂环。
2.根据权利要求1所述的化合物,或者其药学上可接受的盐或其前药,其具有如下结构:
其中R表示C2-C4的直链、支链烷烃或环烷烃;
其中虚线表示有无双键;
其中X表示-OAc,-OH,=NOH或者=O。
3.根据权利要求1所述的化合物,或者其药学上可接受的盐或其前药,其具有如下结构:
其中R表示C2-C4的直链、支链烷烃或环烷烃;
其中虚线表示有无双键;
其中X表示-OAc,-OH,=NOH或者=O。
4.根据权利要求2所述的化合物或者其药学上可接受的立体异构体及其药学上可接受的盐。
5.根据权利要求3所述的化合物或者其药学上可接受的立体异构体及其药学上可接受的盐。
6.一种药物组合物,其中含有权利要求1至5中任一项的化合物或其药学上可接受的盐与药学上可接受的载体组成。
7.权利要求1至5中任一项的化合物或其药学上可接受的盐作为雄激素受体拮抗剂用于治疗雄激素受体相关疾病药物的应用。
8.权利要求12所述的应用,其特征是以下雄激素受体相关疾病中的任一种:(1)依赖于雄激素的细胞增殖,(2)多毛症,(3)痤疮,(4)雄激素脱发等。
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