CN1159195A - (22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺的差向异构体 - Google Patents
(22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺的差向异构体 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
本发明涉及以下差向异构体:可用作睾酮5α-还原酶抑制剂的(22R)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺和(22S)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺,并且涉及它们的制备方法和含有它们的药物组合物。
Description
本发明涉及通式(I)和(II)两种差向异构体,即(22R)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺[通式(I)化合物]和(22S)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺[通式(II)化合物]。
通式(I)和(II)化合物的代谢产物和代谢前体都在本发明范围内。
比例为1∶1的通式(I)和(II)的差向异构体混合物即化合物(22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺(实验室代码FCE 28260)已在我们前一国际专利申请W094/03475(参见第15页化合物41和第45页实施例5)中公开,而(22R)或(22S)的单一差向异构体没有在其中具体说明。
已证明该差向异构体混合物是体内及体外都有效的睾酮5α-还原酶抑制剂(参见WO94/03475第33页表(I)中数据),因此可用于需要降低雄激素活性的病例,例如治疗良性前列腺增生、乳腺和前列腺癌以及某些皮肤-头发(skin-hair)变化,例如治疗粉刺、脂溢性皮炎、妇女多毛症和男子秃顶。
我们已将两种差向异构体从其差向异构体混合物中分离出,并且评价了它们作为睾酮5α-还原酶抑制剂的活性。
该两种差向异构体可按照WO94/03475中描述的方法制备,然后分离差向异构体混合物。可通过高压液相色谱法(HPLC)进行所述分离。
另外,通过将3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酸与先前已拆分过的单一对映体1,1,1-三氟-2-苯基丙-2-基胺反应可获得彼此独立的单一差向异构体。
此外,由于将3-氧代-雄甾-4-烯-17β-羧酸与(±)-1,1,1-三氟-2-苯基丙-2-基胺反应而获得的相应差向异构体酰胺比相应的3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺差向异构体更易于分离,所以单一纯度的差向异构体可有利地按如下获得:
a)将3-氧代-雄甾-4-烯-17β-羧酸或其衍生物与(±)-1,1,1-三氟-2-苯基丙-2-基胺反应;
b)分离所得(22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-雄甾-4-烯-17β-羧酰胺的两种差向异构体(例如通过硅胶上的快速色谱法);
c)按照已知反应分别将所得的差向异构体转化为最终的通式(I)和(II)差向异构体。
以下反应方案I(C(22)位的绝对构型是推测的)描述了这一合成途径:
方案Id)NaOH,H2O,二噁烷/回流/3he)(COCl)2,T甲苯/RT/3hf)(±)-PhCF3(CH3)CNH2,吡啶,CHCl3/回流/5hg)色谱分离h)KMnO4,NalO4,tBuOH/35-40℃/2h
方案I(续)i)NH3,(CH2OH)2/0-180℃/2hl)H2/PtO2,AcOH/40-50psi/45-50°m)(PhSeO)2O,PhCl/回流/5h
如下文所述,体外抑制人前列腺睾酮5α-还原酶的生物试验意外地表明,一种差向异构体(分别测试)的活性是另一种的约两倍,而差向异构体混合物如所预料的具有中间活性。
因此,本发明的目的是上述两种通式(I)和(II)差向异构体以及它们作为5α-还原酶抑制剂的用途。
这些差向异构体可用于需要降低雄激素活性的病例,例如治疗和/或化学预防良性前列腺增生和前列腺癌。另外,这些差向异构体也可用于治疗乳腺癌和某些皮肤-头发变化,例如治疗粉刺、脂溢性皮炎、妇女多毛症和男子秃顶。
另外,本发明涉及含有通式(I)或(II)的差向异构体之一或者其混合物(其中一种差向异构体的含量大大超过另一种)以及一种或多种可药用载体和/或稀释剂的药物组合物。
含有本发明化合物的药物组合物通常按照常规方法制备,并且以适当药物形式给药,例如WO94/03475中所述的那些之一。
以下实施例进一步阐明本发明。
实施例1
(22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺
氮气下,经30分钟在3-氧代-4-氮杂-5α-雄甾烷-17β-羧酸(7克)的氯仿(100毫升)悬浮液中滴加入亚硫酰氯(SOCl2)(35毫升)的氯仿(15毫升)溶液,在冰水浴中保持反应混合物在约+3℃。室温下搅拌悬浮液1小时,然后真空蒸发挥发性化合物。得到白色固体。
将该固体悬浮在氯仿(330毫升)中,将悬浮液冷却至+3℃;加入吡啶(1.78毫升),然后加入(±)-1,1,1-三氟-2-苯基丙-2-基胺(7.1克),将反应混合物加热至60℃并保持4小时,然后于室温搅拌过夜。将反应混合物倒入氯化铵饱和水溶液(500毫升)中,分离有机层,水层用二氯甲烷萃取(2×100毫升)。合并的有机萃取物用水洗涤,以硫酸钠干燥,真空除去溶剂。将粗品在硅胶上通过快速色谱纯化(洗脱液:二氯甲烷/丙酮70∶30),从而得到7.036克(22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺[差向异构体比例50∶50,HPLC(柱:Partisphere C8,4.6×250mm;洗脱液:乙腈/水50∶50;流速:1mL/分钟;检测器:210nm UV)]。
实施例2
通过制备型HPLC将该混合物分离成单一差向异构体
仪器:PrepLC/System 500(Water Associates)
柱:2PrepPAK-500/SILICA
洗脱液:甲苯/乙酸/甲醇100∶3∶3
流速:150毫升/分钟
检测器:折射率
因为X射线结晶学尚没有确定单一差向异构体的绝对构型,因此用实验室代码FCE 29330和FCE 29331分别区分第一个洗脱下来的差向异构体(Rfsup.)和第二个洗脱下来的化合物(Rfinf.)。FCE 29330NMR(CDCl3)δ:7.50-7.33(m,5H,Ph),6.78(d,1H,H(1)),5.87(bs,1H,NH(21)),5.82(dd,1H,H(2)),5.48(bs,1H,NH(4)),3.33(dd,1H,H(5a)),2.07(s,3H,C(CF3)CH3Ph),0.98(s,3H,Me(19)),0.72(s,3H,Me(18)).[α]D+46.7°(c0.89,无水EtOH)FCE 29331NMR(CDCl3)δ:7.50-7.33(m,5H,Ph),6.78(d,1H,H(1)),5.90(bs,1H,NH(21)),5.82(dd,1H,H(2)),5.48(bs,1H,NH(4)),3.33(dd,1H,H(5a)),2.04(s,3H,C(CF3)CH3Ph),0.98(s,3H,Me(19)),0.68(s,3H,Me(18)).[α]D+58.3°(c0.061,无水EtOH)
实施例3
将外消旋(±)-1,1,1-三氟-2-苯基丙-2-基胺拆分成单一对映体
用(+)-O,O,-二苯甲酰基-D-酒石酸处理外消旋(±)-1,1,1-三氟-2-苯基丙-2-基胺;从异丙醇中结晶出非对映体盐。5次结晶后,得到部分拆分的胺,其中主要是(+)-对映体[对映体比例:(+)/(-)=88/12]。
类似地,从异丙醇中将外消旋胺与(-)-O,O’-二苯甲酰基-L-酒石酸的非对映体盐结晶5次后,得到富含(-)-对映体的胺[对映体比例:(+)/(-)=12/88]。
实施例4
将3-氧代-4-氮杂-5α-雄甾烷-17β-羧酸与富含(+)-对映体的胺[对映体比例:(+)/(-)=88/12]反应,得到FCE 29331和FCE 29330混合物,其中FCE29331/FCE 29330的差向异构体比例为88/12(HPLC确定)。
将3-氧代-4-氮杂-5α-雄甾烷-17β-羧酸与富含(-)-对映体的胺[对映体比例:(+)/(-)=12/88]反应,得到FCE 29331和FCE 29330混合物,其中FCE29331/FCE 29330的差向异构体比例为12/88(HPLC确定)。
实施例5
(22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-雄甾-4-烯-17β-羧酰胺(化合物(VI))
在冷却至10℃的3-氧代-雄甾-4-烯-17β-羧酸(化合物(IV))(2.00克)的甲苯(28毫升)和吡啶(0.640毫升)悬浮液中经10分钟加入草酰氯(0.68毫升)的甲苯(4毫升)溶液。除去冷却浴,将混合物于室温搅拌1.5小时。在低于40℃的温度减压除去挥发性化合物。将所得酰氯(化合物(V))溶于氯仿(100毫升),于冰水浴中冷却;加入三乙胺(0.876毫升),然后加入(±)-1,1,1-三氟-2-苯基丙-2-基胺(2.375克)的氯仿(4毫升)溶液。加热回流反应混合物4小时。将反应混合物倒入冷却的饱和氯化钠水溶液(200毫升)中,用二氯甲烷萃取(3×100毫升);有机萃取物用水洗涤,以硫酸钠干燥,减压除去溶剂。得到2.150克标题化合物。
在硅胶上通过快速色谱分离两种差向异构体(洗脱液:正己烷/乙酸乙酯70∶30),得到770毫克较少保留(Rfsup.)的差向异构体和700毫克较多保留(Rfinf.)的差向异构体。
按照类似方法,用富含(+)-对映体的胺[对映体比例(+)/(-)=88/12]可获得Rfinf.和Rfsup.差向异构体间具有相同差向异构体比例的最终化合物。该事实表明(+)-胺产生Rfinf.差向异构体。
类似地,用富含(-)-对映体的胺可得到富含Rfsup.差向异构体的最终化合物。
化合物(VIb)(Rfsup.)NMR(CDCl3)δ:7.50-7.30(m,5H,Ph),5.86(bs,1H,NH(21)),5.75(m,1H,H(4)),2.08(s,3H,C(CF3)CH3Ph),1.20(s,3H,Me(19)),0.76(s,3H,Me(18)).[α]D+187°(cl,无水EtOH)
化合物(VIa)(Rfinf.)NMR(CDCl3)δ:7.50-7.30(m,5H,Ph),5.90(bs,1H,NH(21)),5.75(m,1H,H(4)),2.04(s,3H,C(CF3)CH3Ph),1.20(s,3H,Me(19)),0.72(s,3H,Me(18)).[α]D +126°(c1,无水EtOH)
17β-[N-(1,1,1-三氟-2-苯基丙-2-基)氨基甲酰基]-5-氧代-4-去甲-3,5-断雄烷-3-酸(Rfinf.)(化合物(VIIa))
于约40℃,在N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-雄甾-4-烯-17β-羧酰胺(Rfinf.)(化合物(VIa))(1.70克;3.486毫摩尔)的叔丁醇(40毫升)溶液和2M碳酸钠水溶液(2.09毫升)中经约5分钟同时滴加入2%高锰酸钾水溶液(1.8毫升)和0.75M偏高碘酸钠水溶液(30毫升),加入的速率应使反应混合物一直保持粉红色。在40℃搅拌1小时15分钟后,将反应混合物冷却至室温,过滤,通过真空蒸发将叔丁醇从滤液中除去(收集到40毫升溶剂)。然后将溶液冷却至约0℃,用水稀释,以1N盐酸酸化并用乙酸乙酯(4×30毫升)和二氯甲烷(2×30毫升)萃取;收集到的有机萃取物用水(2×30毫升)、盐水(20毫升)洗涤,用硫酸钠干燥。蒸发溶剂后得到固体状泡沫,通过快速色谱纯化(洗脱液∶正己烷/乙酸乙酯50∶50)而得到1.656克白色固体化合物。NMR(CDCl3)δ:7.30-7.50(m,5H,Ph),5.90(bs,1H,NH),2.04(s,3H,C(CF3)CH3Ph),1.12(s,3H,Me(19)),0.71(s,3H,Me(18)).MS(FAB+)(m/z):508[M+H]+,490[M-H2O+H]+,336[M-C(CF3)CH3Ph+2H]+,173 PhCH3(CF3)C+[α]D+108.2°(c1,无水乙醇 )
按照类似方法,以N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-雄甾-4-烯-17β-羧酰胺(Rfsup.)(化合物(VIb))开始,可得到差向异构体化合物(化合物VIIb):NMR(CDCl3)δ:7.30-7.50(m,5H,Ph),5.88(bs,1H,NH),2.08(s,3H,C(CF3)CH3Ph),1.14(s,3H,Me(19)),0.78(s,3H,Me(18)).[α]D +80°(c1,无水乙醇)
N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-雄甾-5-烯-17β-羧酰胺(Rfinf.)(化合物(VIIIa))
在0℃用无水氨气将17β-[N-(1,1,1-三氟-2-苯基丙-2-基)氨基甲酰基]-5-氧代-4-去甲-3,5-断雄烷-3-酸(Rfinf.)(化合物(VIIa))(1.540克)的无水乙二醇(35毫升)悬浮液饱和:断酸完全溶解。将所得溶液经1小时10分钟缓慢加热至180℃,并在该温度保持20分钟。然后经0.5小时使温度达室温。在彻底搅拌下将黄色溶液冷却至约0℃:最终化合物开始沉淀。用水(30毫升)稀释后,于0℃继续搅拌0.5小时,过滤沉淀物,用水洗涤。得到1.36克淡褐色固体,在硅胶上通过快速色谱纯化(洗脱液∶正己烷/乙酸乙酯50∶50),得到1.090克标题化合物。NMR(CDCl3)δ:7.50-7.30(m,5H,Ph),5.88(bs,1H,NH),4.81(m,1H,H(6)),2.06(s,3H,C(CF3)CH3Ph),1.12(s,3H,Me(19)),0.71(s,3H,Me(18)).[α]D+48.5°(c1,无水乙醇)
按照类似方法,以17β-[N-(1,1,1-三氟-2-苯基丙-2-基)氨基甲酰基]-5-氧代-4-去甲-3,5-断雄烷-3-酸(Rfsup.)(化合物(VIIb))开始,得到差向异构体化合物(化合物VIIIb):NMR(CDCl3)δ:7.50-7.30(m,5H,Ph),5.88(bs,1H,NH),4.78(m,1H,H(6)),2.09(s,3H,C(CF3)CH3Ph),1.12(s,3H,Me(19)),0.74(s,3H,Me(18)).[α]D -2°(c1,无水乙醇)
N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾烷-17β-羧酰胺(Rfinf.)(化合物(IXa))
45℃时,在PtO2(Adams’催化剂)(140毫克)存在下于45psi压力的氢气下将N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-雄甾-5-烯-17β-羧酰胺(Rfinf.)(化合物(VIIIa))(700毫克)的冰醋酸(45毫升)溶液氢化1小时。将反应混合物冷却至室温,滤除催化剂,减压除去溶剂。用二氯甲烷溶解残余物,用1N硫酸、盐水、碳酸钠水溶液、盐水、水洗涤,硫酸钠干燥,真空除去溶剂。将所得粗制固体在硅胶上通过快速色谱纯化(洗脱液:甲苯/乙酸乙酯/甲醇75∶20∶5)而得到420毫克标题化合物。NMR(CDCl3)δ:7.50-7.30(m,5H,Ph),5.88(bs,1H,NH(21)),5.55(bs,1H,NH(4)),3.06(dd,1H,H(5a)),2.05(s,3H,C(CF3)CH3Ph),0.92(s,3H,Me(19)),0.68(s,3H,Me(18)).[α]D +12°(c1,无水乙醇)
按照类似方法,从N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-5-烯-17β-羧酰胺(Rfsup.)(化合物(VIIIb))开始,得到差向异构体化合物(化合物(IXb)):NMR(CDCl3)δ:7.50-7.30(m,5H,Ph),5.88(bs,1H,NH(21)),5.55(bs,1H,NH(4)),3.06(dd,1H,H(5a)),2.05(s,3H,C(CF3)CH3Ph),0.92(s,3H,Me(19)),0.71(s,3H,Me(18)).[α]D+62°(c1,无水乙醇)
N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺(Rfinf.)(FCE 29331)
在N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾烷-17β-羧酰胺(Rfinf.)(化合物(IXa))(106毫克)的氯苯(5毫升)溶液中加入苯基亚硒酸酐(108.3毫克)。将溶液回流5小时,同时通过Marcusson装置除去水。蒸发溶液,将残余物溶于二氯甲烷中,用碳酸钠水溶液、饱和氯化钠溶液及水洗涤,硫酸钠干燥。蒸发溶剂后,将粗品通过快速色谱纯化(洗脱液:甲苯/乙酸乙酯/甲醇75∶20∶5)而得70毫克标题化合物。NMR(CDCl3)δ:7.50-7.33(m,5H,Ph),6.78(d,1H,H(1)),5.90(bs,1H,NH(21)),5.82(dd,1H,H(2)),5.48(bs,1H,NH(4)),3.33(dd,1H,H(5a)),2.04(s,3H,C(CF3)CH3Ph),0.98(s,3H,Me(19)),0.68(s,3H,Me(18)).[α]D+46°(c1,CHCl3)
按照类似方法,从N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾烷-17β-羧酰胺(Rfsup.)(化合物(IXb))开始,得到差向异构体化合物FCE29330:NMR(CDCl3)δ:7.50-7.33(m,5H,Ph),6.78(d,1H,H(1)),5.87(bs,1H,NH(21)),5.82 dd,1H,H(2)),5.48(bs,1H,NH(4)),3.33(dd,1H,H(5a)),2.07(s,3H,C(CF3)CH3Ph),0.98(s,3H,Me(19)),0.72(s,3H,Me(18)).[α]D+21°(c1,CHCl3)
如该实施例所示,从(+)-胺获得FCE 29331,而FCE 29330是从(-)-胺获得的。
体外5α-还原酶抑制试验
用来自增生人前列腺组织匀浆的粒状部分作为酶源评价对5α-还原酶的抑制。在140,000×g将前列腺组织匀浆离心而制备粒状部分。将所得颗粒洗涤数次后再悬浮在缓冲液中,以含有约10mg蛋白质/毫升的等分保存在-80℃。
在pH 5.5的40mM TRIS-HCl缓冲液中于0.5毫升的终体积进行5α-还原酶试验,该缓冲液含有1mM二硫苏糖醇、5mM NADPH、1uM[14C]睾酮、等分酶制剂和不同浓度的抑制剂。在37℃孵育30分钟后,加入2毫升冷乙醚终止反应,分离有机相,于氮气下蒸发,再悬浮于乙酸乙酯中。在硅胶F 254板(Merck)上TLC分离该提取物中的睾酮代谢产物,用氯仿、丙酮和正己烷(2∶1∶2)作为展开溶剂系统。
记录板上的放射性,通过TLC-分析仪(Berthold)描绘的定量图分析。通过比较5α-还原代谢产物(5α-二氢睾酮、3α-和3β-雄甾烷二醇)区域中的14C-放射性和睾酮及5α-还原代谢产物区域的总放射性计算睾酮5α-还原作用分数。50%降低对照5α-还原酶活性所需每一化合物的浓度(IC50)通过绘制%抑制对抑制剂浓度的对数值(log)来确定。
单一差向异构体FCE 29330和FCE 29331所得结果以及外消旋混合物FCE 28260所得结果如下表1所示。
表1
FCE 28260的立体异构体对人前列腺
5α-还原酶的体外抑制
化合物 IC50(nM)
FCE 28260 12
FCE 29330 17
FCE 29331 8
从表1所示结果可看出,差向异构体FCE 29331的活性是另一差向异构体FCE 29330活性的约2倍。混合物FCE 28260,正如所料,表现出中间活性。
Claims (9)
1.通式(I)和(II)的差向异构体:即(22R)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺[通式(I)化合物]和(22S)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺[通式(II)化合物]。
2.一种制备权利要求1的通式(I)或(II)的差向异构体的方法,包括从相应差向异构体混合物中分离单一差向异构体。
3.一种制备权利要求1的通式(I)或(II)的差向异构体的方法,包括将3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酸与先前已拆分的1,1,1-三氟-2-苯基丙-2-基胺的单一对映体反应。
4.一种制备权利要求1的通式(I)或(II)的差向异构体的方法,包括:
a)将3-氧代-雄甾-4-烯-17β-羧酸或其衍生物与(±)-1,1,1-三氟-2-苯基丙-2-基胺反应;
b)分离所得(22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-雄甾-4-烯-17β-羧酰胺的两种差向异构体;
c)按照已知反应分别将所得的差向异构体转化为最终的通式(I)和(II)差向异构体。
5.一种含有权利要求1的通式(I)或(II)的差向异构体之一或者其混合物以及一种或多种可药用载体和/或稀释剂的药物组合物,其中在混合物中一种差向异构体的含量大大超过另一种。
6.一种权利要求1的通式(I)或(II)化合物,用作睾酮5α-还原酶抑制剂。
7.一种权利要求1的通式(I)或(II)化合物,用作为抗雄激素药物。
8.一种权利要求1的通式(I)或(II)化合物,用在治疗和/或化学预防良性前列腺增生或前列腺癌中。
9.一种权利要求1的通式(I)或(II)化合物,用在治疗乳腺癌、粉刺、脂溢性皮炎、妇女多毛症和/或男子秃顶中。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT95MI001587A IT1275594B1 (it) | 1995-07-21 | 1995-07-21 | Epimeri del (22rs)-n-(1,1,1-trifluoro-2-fenilprop-2-il)-3-osso -4-aza-5alfa-androst-1-ene-17beta-carbossammide |
ITMI95A001587 | 1995-07-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1159195A true CN1159195A (zh) | 1997-09-10 |
Family
ID=11372032
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96190785A Pending CN1159195A (zh) | 1995-07-21 | 1996-06-28 | (22RS)-N-(1,1,1-三氟-2-苯基丙-2-基)-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-羧酰胺的差向异构体 |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP0782582A1 (zh) |
JP (1) | JPH10506411A (zh) |
KR (1) | KR970706298A (zh) |
CN (1) | CN1159195A (zh) |
AR (1) | AR003967A1 (zh) |
AU (1) | AU6418396A (zh) |
BR (1) | BR9606527A (zh) |
CA (1) | CA2199273A1 (zh) |
EA (1) | EA199700045A1 (zh) |
HU (1) | HUP9702465A3 (zh) |
IL (1) | IL120343A0 (zh) |
IT (1) | IT1275594B1 (zh) |
MX (1) | MX9701948A (zh) |
NO (1) | NO971196L (zh) |
PL (1) | PL319351A1 (zh) |
WO (1) | WO1997004002A1 (zh) |
ZA (1) | ZA965678B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100355772C (zh) * | 2005-12-28 | 2007-12-19 | 天津大学 | 具有5α-还原酶抑制活性的甾体化合物及其制备方法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000013509A1 (en) * | 1998-09-09 | 2000-03-16 | Merck & Co., Inc. | Method of determining and reducing the risk of bph-related urologic events |
ES2237408T3 (es) * | 1999-01-25 | 2005-08-01 | Smithkline Beecham Corporation | Antiandrogenos y procedimientos para tratar una enfermedad. |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9216284D0 (en) * | 1992-07-31 | 1992-09-16 | Erba Carlo Spa | Fluorinated 17beta-substituted 4-aza-5alpha-androstane-3-one derivatives |
-
1995
- 1995-07-21 IT IT95MI001587A patent/IT1275594B1/it active IP Right Grant
-
1996
- 1996-06-28 MX MX9701948A patent/MX9701948A/es unknown
- 1996-06-28 AU AU64183/96A patent/AU6418396A/en not_active Abandoned
- 1996-06-28 CA CA002199273A patent/CA2199273A1/en not_active Abandoned
- 1996-06-28 WO PCT/EP1996/002830 patent/WO1997004002A1/en not_active Application Discontinuation
- 1996-06-28 CN CN96190785A patent/CN1159195A/zh active Pending
- 1996-06-28 BR BR9606527A patent/BR9606527A/pt not_active Application Discontinuation
- 1996-06-28 KR KR1019970701797A patent/KR970706298A/ko not_active Application Discontinuation
- 1996-06-28 HU HU9702465A patent/HUP9702465A3/hu unknown
- 1996-06-28 IL IL12034396A patent/IL120343A0/xx unknown
- 1996-06-28 JP JP9506217A patent/JPH10506411A/ja active Pending
- 1996-06-28 EP EP96923968A patent/EP0782582A1/en not_active Withdrawn
- 1996-06-28 PL PL96319351A patent/PL319351A1/xx unknown
- 1996-07-04 ZA ZA965678A patent/ZA965678B/xx unknown
- 1996-07-19 AR ARP960103652A patent/AR003967A1/es unknown
-
1997
- 1997-03-14 NO NO971196A patent/NO971196L/no unknown
- 1997-04-18 EA EA199700045A patent/EA199700045A1/ru unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100355772C (zh) * | 2005-12-28 | 2007-12-19 | 天津大学 | 具有5α-还原酶抑制活性的甾体化合物及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
AU6418396A (en) | 1997-02-18 |
ZA965678B (en) | 1997-01-24 |
HUP9702465A2 (hu) | 1998-05-28 |
JPH10506411A (ja) | 1998-06-23 |
MX9701948A (es) | 1997-06-28 |
ITMI951587A1 (it) | 1997-01-21 |
NO971196D0 (no) | 1997-03-14 |
ITMI951587A0 (it) | 1995-07-21 |
IT1275594B1 (it) | 1997-08-06 |
KR970706298A (ko) | 1997-11-03 |
AR003967A1 (es) | 1998-09-30 |
IL120343A0 (en) | 1997-06-10 |
CA2199273A1 (en) | 1997-02-06 |
HUP9702465A3 (en) | 1998-11-30 |
PL319351A1 (en) | 1997-08-04 |
EA199700045A1 (ru) | 1997-12-30 |
NO971196L (no) | 1997-03-14 |
EP0782582A1 (en) | 1997-07-09 |
BR9606527A (pt) | 1997-12-23 |
WO1997004002A1 (en) | 1997-02-06 |
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