CN1331082A - 有治疗前列腺增生药效的化合物及制备方法 - Google Patents

有治疗前列腺增生药效的化合物及制备方法 Download PDF

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CN1331082A
CN1331082A CN 00116781 CN00116781A CN1331082A CN 1331082 A CN1331082 A CN 1331082A CN 00116781 CN00116781 CN 00116781 CN 00116781 A CN00116781 A CN 00116781A CN 1331082 A CN1331082 A CN 1331082A
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李瑞麟
卢琦华
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Shanghai Aoqi Medical Technology Co.,Ltd.
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Shanghai Institute of Planned Parenthood Research
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Abstract

本发明公开了有治疗前列腺增生症药效的化合物。该类化合物为2α,17α－双乙炔基,A－失碳,5α－雄甾烷,2β,17β－双酯。本发明的化合物经动物实验证明药效好,副作用小,本发明提供了制备方法。

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有治疗前列腺增生药效的化合物及制备方法
本发明涉及药物化学，具体涉及一类有效治疗前列腺增生药效的化合物及制备方法。
目前世界各国男性随着年龄的增长，前列腺增生的发病率逐渐增加。据苏联学者1998年报道，前列腺增生发病率30岁以上达8％，40岁以上23％，50岁以上35～45％，60岁以上75％，70岁以上82％，80岁以上90％。现有治疗前列腺增生的药物，国内外品种甚多，1992年美国FDA批准默克公司生产的新药普罗斯卡(Proscar)，埃伯特公司生产的泰拉佐松(Turosteride)波罗乍松，Epristeride(爱普列特)，均有治疗效果，但需较长时期服用，停药后又将复发，且有不利的副作用。
本发明的目的在于克服上述不足之处，研制疗效好，副作用小的新药。
本发明公开了一类有治疗前列腺增生药效的新化合物，该类化合物具有下列通式III，具体有a、b、c、d四个化合物：
Figure A0011678100041
式中：
Figure A0011678100042
化合物IIIa(AHP—001)化合物IIIb(AHP—002)
Figure A0011678100044
化合物IIIc(AHP—003)
Figure A0011678100045
化合物IIId(AHP—004)
本发明的化合物经动物药理试验结果如下：
100g体重雄性大鼠以戊巴比妥钠麻醉，在无菌下切除双侧睾丸，一周后皮下注射丙酸睾丸酮0.5mg/只(5mg/kg)同时每天口服试验药，连续一个月，末次给药后24小时处死，取前列腺称重结果如下：
药名及用法 剂量(mg/kg)量 前列腺重量(mg)     P值
丙睾皮下注射     5.0     530.3     －
丙睾皮下注射＋AHP-001口服  5.0＋0.1     416.0     P＜0.01
丙睾皮下注射＋AHP-002  5.0＋0.1     412.0     P＜0.05
丙睾皮下注射＋AHP-002  5.0＋0.6     401.3     P＜0.05
动物药效试验结果表明本发明的化合物有较好的疗效，个别患者有严重前列腺增生症状的高龄患者，每晚小便需十次左右，服药7—10天后基本恢复正常，停药后10个月才发现有轻度复发的情况，最长为18个月，并且未见不良副作用。由此可见，本发明的化合物将能进一步作为治疗前列腺增生药物。
本发明的另一目的是提供了上述化合物的制备方法。该方法包括下列步骤：(1)制各2α，17α—双乙炔基，A—失碳，5α—雄甾烷，2β—17β—双羟基化合物(II)以A—失碳，5α—雄甾烷2，17—双酮(I)为起始原料，采用金属钾与叔丁醇反应生成叔丁醇钾，然后在四氢呋喃溶剂中加入原料，低温条件下通乙炔反应生成2α，17α—双乙炔基、A失碳、5α—雄甾烷，2β—17β—双羟基化合物(II)，或采用氢氧化钾粉末在四氢呋喃溶剂中低温通乙炔反应生成化合物II。(2)将化合物II在溶剂中与酸酐在20℃～100℃条件下搅拌反应1～12小时，生成2α，17α—双乙炔基，A—失碳5α—雄甾烷，2β，17β—双酯(化合物III)。
本发明的制备方法中，化合物HI的a、b、c、d的制备方法如下：(1)化合物II与琥珀酸酐在吡啶中以PTS为触媒，回流反应6—10小时，处理后得2β，17β—双乙炔基，A—失碳，5α—雄甾烷，2α，17α—双琥珀酸酯化合物IIIa(AHP—001)。(2)化合物II与琥珀酸酐，在吡啶中以AcoNa为触媒，回流反应2—3h，处理后得2α，17α—双乙炔基，A—失碳5α—雄甾烷，2β，17β—双羟基，2β—单琥珀酸酯化合物IIIb(AHP—002)(3)化合物II与琥珀酸酐在丙酸中以P.T.S.为触媒20℃搅拌反应12h左右，处理后得2α，17α—双乙炔基，A—失碳5α—雄甾烷，2β，17β—双羟基双丙酸酯化合物IIIc(AHP—003)。(4)化合物II与丁酸酐以P.T.S为解媒100℃搅拌反应1h，处理后得2α，17α—双乙炔基，A—失碳，5α—雄甾烷，2β，17β—双丁酸酯化合物IIId(AHP—004)。
实例1、制备2α，17α-双乙炔基—A失碳5α—雄烷，2β，17β—双羟基(II)
30g KOH粉末60mlTHF和O.2ml丙酮，冷至5℃以下通乙炔除尽空气后搅拌继续通乙炔至不吸收，然后保持5℃以下渐渐滴加10gA—失碳雄烷，2，17—双酮(I)溶于1OOmlTHF的冷溶液，通乙炔至板层层析见原料(I)消失，在搅拌下徐徐滴加18ml水冷却，防止突然升温，搅拌KOH溶解后，分去下层水层减压浓缩至干，加EtOCA溶解后水洗至中性，活性炭脱色，浓缩，用乙烷—苯重结晶得8g，mp169-70℃，[α]D-24±2°。
实例2、制备2α—双乙炔基A—失碳5α—雄烷2β，17β—双羟基双琥珀酸酯(AHP—001)
5g II，加20ml吡啶和15g琥珀酸酐0.5g P.T.s.搅拌回流10小时，加水50℃保温2小时，用EtOAC提取，水洗至中性浓缩，室温放置徐徐析出，固体滤出，用乙醇重结晶得1.5g mp 220—221℃[α]D24.6°(CHCL3)
实例3、制备2α，17α—双乙炔基，A—失碳5α—雄烷，2β，17β—双羟基2β—单琥珀酸酯(AHP—002)
1g II，加5ml吡啶和2g琥珀酸酐，0.1g醋酸钠，搅拌回流3hrs，同上法处理，粗品用甲醇—H2O重结晶得0.5g mp 217-219℃，[α]0-24.88(EtOH)。
实例4、制备2α，17α—双乙炔基，A—失碳，5α—雄甾烷，2β，17β—双羟基双丙酸酯(AHP—003)
lg II加3.5g丙酸酐，2g丙酸，0.1g P.T.S.溶解后20℃搅拌反应12小时，加水后室温放置渐渐析出结晶0.8g，用乙醇重结晶mp，152-153℃[α]0-32°。
实例5、制备2α，17α—双乙炔基，A—失碳，5α—雄甾烷，2β，17β—双羟基双丁酸酯(AHP—004)
1g II加20ml丁酸酐，0.5g P.T.S.100℃搅拌反应1小时，加水放置过夜，析出长针状结晶1.4g，用95％乙醇重结晶mp145-147℃。

Claims (3)

1、一种有治疗前列腺增生药效的化合物III，其特征在于该化合物III具有下列通式结构：式中：化合物IIIa(AHP—001)
Figure A0011678100023
化合物IIIb(AHP—002)化合物IIIc(AHP—003)
Figure A0011678100025
化合物IIId(AHP—004)
2、如权利要求1所述的一种有治疗前列腺增生药效的化合物III的制备方法，其特征在于该方法包括下列步骤：(1)制备2α，17α—双乙炔基，A—失碳，5α—雄甾烷，2β—17β—双羟基化合物(II)以A—失碳，5α—雄甾烷2，17—双酮(I)为起始原料，采用金属钾与叔丁醇反应生成叔丁醇钾，然后在四氢呋喃溶剂中加入原料，低温条件下通乙炔反应生成2α，17α—双乙炔基、A失碳、5α—雄甾烷，2β—17β—双羟基化合物(II)，或采用氢氧化钾粉末在四氢呋喃溶剂中低温通乙炔反应生成化合物(II)；(2)将化合物在溶剂中与酸酐在20℃～100℃条件下搅拌反应1～12小时，生成2α，17α—双乙炔基，A—失碳5α—雄甾烷，2β，17β—双酯(化合物III)。
3、根据权利要求1或2所述的一种有治疗前列腺增生药效的化合物III的制备方法，其特征在于其中所述的化合物IIIa、IIIb、IIIc、IIId是由下列方法制得的：(1)化合物II与琥珀酸酐在此吡啶中的PTS为触媒，回流反应6—10小时，处理后得2β，17β—双乙炔基，A—失碳，5α—雄甾烷，2α，17α—双琥珀酸酯化合物IIIa(AHP—001)；(2)化合物II与琥珀酸酐，在吡啶中以AcoNa为触媒，回流反应2—3h，处理后得2α，17α—双乙炔基，A—失碳5α—雄甾烷，2β，17β—双羟基，2β—单琥珀酸酯化合物IIIb(AHP—002)；(3)化合物II与琥珀酸酐在丙酸中以P.T.S.为触媒20℃搅拌反应12h左右，处理后得2α，17α—双乙炔基，A—失碳5α—雄甾烷，2β，17β—双羟基双丙酸酯化合物IIIc(AHP—003)；(4)化合物II与丁酸酐以P.T.S为解媒100℃搅拌反应1h，处理后得2α，17α—双乙炔基，A—失碳，5α—雄甾烷，2β，17β—双丁酸酯化合物IIId(AHP—004)。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102218069A (zh) * 2011-04-08 2011-10-19 上海奥奇医药科技有限公司 A-失碳-5α-雄甾烷化合物在制备抗恶性肿瘤药物中的应用
CN105434444A (zh) * 2014-09-29 2016-03-30 上海奥奇医药科技有限公司 一种A-失碳-5α雄甾烷化合物的口服制剂
WO2019041078A1 (en) * 2017-08-28 2019-03-07 Zhejiang Jiachi Pharmaceutical Development Ltd. ASYMMETRIC SYNTHESIS AND USES OF COMPOUNDS IN TREATMENT OF DISEASES
WO2022143897A1 (zh) * 2020-12-30 2022-07-07 上海奥奇医药科技有限公司 A-失碳-5α雄甾烷化合物的多晶型物

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102218069A (zh) * 2011-04-08 2011-10-19 上海奥奇医药科技有限公司 A-失碳-5α-雄甾烷化合物在制备抗恶性肿瘤药物中的应用
CN102218069B (zh) * 2011-04-08 2012-09-26 上海奥奇医药科技有限公司 A-失碳-5α-雄甾烷化合物在制备抗恶性肿瘤药物中的应用
CN105434444A (zh) * 2014-09-29 2016-03-30 上海奥奇医药科技有限公司 一种A-失碳-5α雄甾烷化合物的口服制剂
WO2016050193A1 (zh) * 2014-09-29 2016-04-07 陈雅君 一种A-失碳-5α雄甾烷化合物的口服制剂
US20170216313A1 (en) * 2014-09-29 2017-08-03 Yajun CHEN ORAL FORMULATION OF A-NOR-5a ANDROSTANE COMPOUND
JP2017530162A (ja) * 2014-09-29 2017-10-12 ヤージュン チェン Ａ−ノル−５αアンドロスタン化合物の経口投与製剤
US10537583B2 (en) * 2014-09-29 2020-01-21 Yajun CHEN Oral formulation of A-nor-5α androstane compound
WO2019041078A1 (en) * 2017-08-28 2019-03-07 Zhejiang Jiachi Pharmaceutical Development Ltd. ASYMMETRIC SYNTHESIS AND USES OF COMPOUNDS IN TREATMENT OF DISEASES
WO2019042192A1 (en) * 2017-08-28 2019-03-07 Zhejiang Jiachi Pharmaceutical Development Ltd. ASYMMETRIC SYNTHESIS AND USES OF COMPOUNDS IN TREATMENT OF DISEASES
WO2022143897A1 (zh) * 2020-12-30 2022-07-07 上海奥奇医药科技有限公司 A-失碳-5α雄甾烷化合物的多晶型物

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