CN101100480A - 新颖的依托孕烯酯 - Google Patents
新颖的依托孕烯酯 Download PDFInfo
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Abstract
本发明提供新的孕激素酯、特别是依托孕烯十二烷酸酯，及其用途，既用于男性和女性避孕，也用于男性和女性HRT。另外，也涉及该酯在女性妇科学障碍的治疗和预防中的用途，所述障碍例如子宫内膜异位、月经过多、月经频多、经前期综合征和痛经。
Description
本申请是申请日为2003年5月22日、申请号为03812375.4、发明创造名称为“新颖的依托孕烯酯”的申请的分案申请。
技术领域
本发明涉及(男性与女性)避孕、(女性与男性)激素替代疗法(HRT)和妇科学障碍治疗/预防领域。
背景技术
男性和女性的避孕方法对世界范围的生殖健康而言是很重要的。
不过，迄今尚无有效果和有效率的男性避孕方法可以利用。
男性避孕寻求通过抑制促性腺素促黄体激素(LH)和促卵泡激素(FSH)而抑制精子发生。这导致睾丸内睾酮的耗尽和精子发生的停止。
孕激素的给药导致垂体促性腺素的剂量依赖性抑制，睾酮水平的降低和精子发生的可逆抑制。需要一种外源性雄激素以补偿所减少的睾酮水平。按照相同的方式，男性HRT得以实现，导致睾酮被外源性雄激素代替，所述外源性雄激素对前列腺比内源性睾酮更加安全。
孕激素与雄激素一起用作男性避孕剂是已知的(Guerin和Rollet(1988)，International Journal of Andrology 11，187-199)。
不过，依托孕烯的特定酯用于男性避孕和男性HRT尚未被提出。
另外，孕激素与雌激素一起用于女性避孕是已知的(M.Tausk，J.H.H.Thijssen，Tj.B.van Wimersma Greidanus，“Pharmakologie derHormone”，Georg Thieme Verlag，Stuttgart，1986)。
孕激素被广泛用于女性避孕和女性HRT。在避孕时，孕激素-雌激素组合口服避孕剂是最广泛使用的。这样一种组合的给药导致很多效果：它阻滞排卵，它干扰子宫内膜的阶段性发育(这减少成功植入的机会)，并且它导致宫颈粘液变得如此之粘，以致它阻碍精子透入。大多数仅含孕激素的丸剂(POP)仅仅致力于最后提到的那种效果。
女性HRT致力于内源性雌激素的补充，用于治疗围绝经期与绝经后病症(热潮红、阴道干燥)，预防长期雌激素缺乏的症状。后者包括骨质疏松、冠状动脉疾病、泌尿生殖失禁，可能还有阿尔茨海默氏病和结肠直肠癌。长期无节制雌激素给药的缺点是子宫内膜增生的相关性增加，这继而可以增加子宫内膜癌的危险。为此，在长期制度中共同给以孕激素，因为它们能够减少子宫内膜上皮的增殖活性和诱发分泌转化。
不过，尚未提出依托孕烯的特定酯用于女性避孕、女性HRT和妇科学障碍的治疗/预防。
本发明描述新的依托孕烯酯，即依托孕烯癸酸酯、依托孕烯十一烷酸酯和依托孕烯十二烷酸酯，已经惊人地发现它们比其他依托孕烯酯具有更好的药动学行为。这些酯使作用持续时间长的孕激素的单剂给药成为可能。
发明内容
本发明提供新的孕激素酯，即依托孕烯癸酸酯、依托孕烯十一烷酸酯和依托孕烯十二烷酸酯，及其用途，既用于男性和女性避孕，也用于男性和女性HRT。
另外，也涉及这些酯在女性妇科学障碍的治疗和预防中的用途，所述障碍例如子宫内膜异位、月经过多、月经频多、经前期综合征和痛经。
附图说明
图1
依托孕烯庚酸酯、依托孕烯壬酸酯、依托孕烯癸酸酯、依托孕烯十一烷酸酯、依托孕烯十二烷酸酯、依托孕烯十三烷酸酯和依托孕烯十五烷酸酯的化学结构。
图2a
依托孕烯、依托孕烯庚酸酯、依托孕烯壬酸酯和依托孕烯十一烷酸酯的一次肌内(IM)注射对雄性完整兔中依托孕烯血浆水平的影响。N＝3的平均值和SEM。
图2b
依托孕烯庚酸酯、依托孕烯壬酸酯、依托孕烯癸酸酯、依托孕烯十一烷酸酯、依托孕烯十二烷酸酯、依托孕烯十三烷酸酯的一次肌内(IM)注射对雄性完整兔中依托孕烯血浆水平的影响。N＝3的平均值和SEM。
具体实施方式
本发明提供化合物依托孕烯癸酸酯、依托孕烯十一烷酸酯和依托孕烯十二烷酸酯。
本发明涉及避孕和/或HRT试剂盒，包含避孕和/或治疗有效量的依托孕烯癸酸酯和/或依托孕烯十一烷酸酯和/或依托孕烯十二烷酸酯，用于男性和女性的避孕和HRT。
本发明进一步提供避孕和/或治疗有效量的依托孕烯癸酸酯和/或依托孕烯十一烷酸酯和/或依托孕烯十二烷酸酯在药物制备中的用途，所述药物用于避孕和/或HRT。在一种优选的实施方式中，所述药物用于男性避孕和/或男性HRT。在另一种实施方式中，所述药物用于女性避孕和/或女性HRT。
本发明进一步涉及避孕和/或HRT的方法，包括对受治疗者给以避孕和/或治疗有效量的依托孕烯癸酸酯和/或依托孕烯十一烷酸酯和/或依托孕烯十二烷酸酯。在一种优选的实施方式中，所述受治疗者是男性受治疗者。在另一种实施方式中，所述受治疗者是女性受治疗者。
本发明另外提供治疗有效量的依托孕烯癸酸酯和/或依托孕烯十一烷酸酯和/或依托孕烯十二烷酸酯在药物制备中的用途，所述药物用于治疗和/或预防女性妇科学障碍，例如子宫内膜异位、月经过多、月经频多、经前期综合征和痛经。
本发明进一步涉及女性妇科学障碍的治疗和/或预防方法，所述障碍例如子宫内膜异位、月经过多、月经频多、经前期综合征和痛经，该方法包含对女性受治疗者给以治疗有效量的依托孕烯癸酸酯和/或依托孕烯十一烷酸酯和/或依托孕烯十二烷酸酯。
本发明的化合物可以经由技术人员可利用的任意适合途径给药。
在口服给药的情况下，涉及固体剂量单元，例如片剂或胶囊剂。可以将本发明化合物用药学上可接受的载体制成制剂，例如标准参考文献所述：Gennaro et al，Remmington：The Science and Practice of Pharmacy，(20th ed.，Lippincott Williams&Wilkins，2000，尤其参见第5部分：Pharmaceutical Manufacturing)。可以将本发明化合物和药学上可接受的载体压制成固体剂量单元，例如丸剂、片剂，或者加工成胶囊剂或栓剂。借助药学上适合的液体，化合物也可以作为注射制备物以溶液、悬液、乳液的形式应用，或者作为喷雾剂应用，例如鼻用喷雾剂。就制备剂量单元而言，例如片剂，涉及常规添加剂的使用，例如填充剂、着色剂、聚合粘合剂、润滑剂、流动增强剂、助流剂等。一般而言，可以使用不干扰活性化合物的功能的任何药学上可接受的添加剂。本发明化合物还可以被包含在植入物、阴道环、贴剂、凝胶剂等中。
适合于与组合物一起给药的载体包括乳糖、淀粉、纤维素衍生物等，或者它们的混合物，适量使用。
所要给药的本发明化合物或其药物组合物的给药剂量与制度将依赖于所要达到的治疗效果，将因给药途径和接受给药的个别受治疗者的年龄与条件和/或其中使用该化合物或其药物组合物的特定避孕或HRT制度而异。典型的剂量是0.001-5mg/kg体重。
下列实施例进一步描述本发明，它们决不打算限制所要求保护的发明的范围。
实施例-依托孕烯C7、C9、C10、C11、C12和C13酯在兔子中的动力
学
制备下列依托孕烯酯，在兔子中进行试验：
·依托孕烯庚酸酯
·依托孕烯壬酸酯
·依托孕烯癸酸酯
·依托孕烯十一烷酸酯
·依托孕烯十二烷酸酯
·依托孕烯十三烷酸酯
也制备了依托孕烯十五烷酸酯。
图1显示这些化合物的化学结构。
作为参照，依托孕烯也包括在内。
依托孕烯酯的制备
从醇制备酯的一般方法可以参见例如Greene，T.W.等，″Protectivegroups in organic synthesis″，John Wiley&Sons，NY，1999(第三版)。从叔醇(象依托孕烯)制备酯可以借助若干技术来实现，例如：
1)叔醇、羧酸、三氟乙酸-酸酐，DE 1013284(1956)；2)叔醇、酰氯、吡啶，Watson，T.G.等，Steroids 41，255(1983)；3)叔醇、酰氯、T10Et，Shafiee，A.等，Steroids 41，349(1983)；4)叔醇、羧酸-酸酐、TsOH、苯，Johnson，A.L.，Steroids，20，263(1972)；和5)叔醇、羧酸-酸酐、DMAP、CH2Cl2：Shafiee，A.等，Steroids 41，349(1983)。
(17α)-13-乙基-11-亚甲基-17-[[(1-氧代壬基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯壬酸酯)的制备
a)将壬酸(1.95g)的无水甲苯(8ml)溶液冷却至0℃，用三氟乙酸酐(2.6g)处理。搅拌30分钟后，加入(17α)-13-乙基-17-羟基-11-亚甲基-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯，2.0g)的无水甲苯(15ml)溶液，将反应混合物在室温下搅拌17小时。将反应混合物用水、饱和碳酸氢钠水溶液、水和盐水洗涤。将有机相经硫酸钠干燥，在减压下浓缩。残余物经过柱色谱纯化(甲苯/乙酸乙酯95∶5)。将产物(2.08g)溶于乙酸乙酯(40ml)，冷却至0℃，与氢氧化钠水溶液(1M，13ml)搅拌2小时。混合物用乙酸乙酯萃取；合并有机相，用冰冷的氢氧化钠水溶液(1M)、水和盐水洗涤，干燥，在减压下浓缩。柱色谱处理得到(17α)-13-乙基-11-亚甲基-17-[[(1-氧代壬基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(1.25g)。1H-NMR(CDCl3)：δ5.89(m，1H)，5.08(bs，1H)，4.85(bs，1H)，2.82(ddd，1H，J＝14.8，9.5和6.3Hz)，2.73(d，1H，J＝12.8Hz)，2.69-2.19(m)，2.63(s，1H)，2.11(m，1H)，1.90-1.21(m)，1.15(m，1H)，1.05(t，3H，J＝7.5Hz)，0.88(t，3H，J＝7.1Hz)。测量质量[M+H]+465.3358。计算质量[M+H]+465.3363。
按照类似于上述工艺的方式，制备了依托孕烯庚酸酯、依托孕烯癸酸酯、依托孕烯十一烷酸酯、依托孕烯十二烷酸酯、依托孕烯十三烷酸酯和依托孕烯十五烷酸酯：
b)(17α)-13-乙基-11-亚甲基-17-[[(1-氧代庚基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯庚酸酯)。1H-NMR(CDCl3)：δ5.89(m，1H)，5.08(bs，1H)，4.85(bs，1H)，2.82(ddd，1H，J＝14.8，9.5和6.3Hz)，2.73(d，1H，J＝12.6Hz)，2.68-2.19(m)，2.63(s，1 H)，2.11(m，1H)，1.90-1.24(m)，1.15(m，1H)，1.05(t，3H，J＝7.5Hz)，0.89(t，3H，J＝7.1Hz)。测量质量[M+H]+437.3027。计算质量[M+H]+437.3050。
c)(17α)-13-乙基-11-亚甲基-17-[[(1-氧代癸基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯癸酸酯)。1H-NMR(CDCl3)：δ5.89(bs，1H)，5.08(bs，1H)，4.84(bs，1H)，2.82(m，1H)，2.73(d，1H，J＝12.6Hz)，2.67-2.18(m)，2.63(s，1H)，2.11(m，1H)，1.90-1.21(m)，1.15(m，1H)，1.06(t，3H，J＝7.5Hz)，0.88(t，3H，J＝7.1Hz)。测量质量[M+H]+479.3508。计算质量[M+H]+479.3519。
d)(17α)-13-乙基-11-亚甲基-17-[[(1-氧代十一烷基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯十一烷酸酯)。1H-NMR(CDCl3)：δ5.89(m，1H)，5.08(bs，1H)，4.85(bs，1H)，2.82(ddd，1H，J＝14.8，9.5和6.3Hz)，2.73(d，1H，J＝12.6Hz)，2.68-2.18(m)，2.63(s，1H)，2.11(m，1H)，1.90-1.21(m)，1.06(t，3H，J＝7.5Hz)，0.88(t，3H，J＝7.1Hz)。测量质量[M+H]+493.3664。计算质量[M+H]+493.3676。
e)(17α)-13-乙基-11-亚甲基-17-[[(1-氧代十二烷基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯十二烷酸酯)。1H-NMR(CDCl3)：δ5.89(bs，1H)，5.08(bs，1H)，4.85(bs，1H)，2.82(m，1H)，2.73(d，1H，J＝12.6Hz)，2.65-2.18(m)，2.64(s，1H)，2.11(m，1H)，1.90-1.20(m)，1.15(m，1H)，1.06(t，3H，J＝7.5Hz)，0.88(t，3H，J＝7.1Hz)。测量质量[M+H]+507.3829。计算质量[M+H]+507.3832。
f)(17α)-13-乙基-11-亚甲基-17-[[(1-氧代十三烷基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯十三烷酸酯)。1H-NMR(CDCl3)：δ5.89(bs，1H)，5.08(bs，1H)，4.85(bs，1H)，2.82(m，1H)，2.73(d，1H，J＝12.6Hz)，2.65-2.18(m)，2.64(s，1H)，2.11(m，1H)，1.90-1.20(m)，1.15(m，1H)，1.06(t，3H，J＝7.5Hz)，0.89(t，3H，J＝7.1Hz)。测量质量[M+H]+521.4007。计算质量[M+H]+521.3989。
g)(17α)-13-乙基-11-亚甲基-17-[[(1-氧代十五烷基)氧基]-18，19-二去甲孕-4-烯-20-炔-3-酮(依托孕烯十五烷酸酯)。1H-NMR(CDCl3)：δ5.89(bs，1H)，5.08(bs，1H)，4.85(bs，1H)，2.82(m，1H)，2.73(d，1H，J＝12.6Hz)，2.65-2.19(m)，2.63(s，1H)，2.11(m，1H)，1.90-1.20(m)，1.15(m，1H)，1.06(t，3H，J＝7.5Hz)，0.89(t，3H，J＝7.1Hz)。测量质量[M+H]+549.4278。计算质量[M+H]+549.4302。
兔中的药动学研究
就肠胃外用药后不同依托孕烯酯的药动学行为测定而言，在阉割兔模型中选择i.m.用药代替s.c.。简而言之，按20mg/kg给兔子注射一次(第1天)所示依托孕烯酯的花生油溶液(浓度40mg/ml)。在第1、2、3、4、5、6、7、8、10、12、14、21、28、35、49、63、77、92、 106、120和133天，从耳动脉收集血液到含有EDTA的试管中。制备EDTA血浆(1500g，15min)，贮存在-20℃下。利用LC-MSMS，测定这些样品中的母体化合物(依托孕烯)含量。这种新测定法的下限是0.5nmol/l，得到0-250nmol/l的线性曲线，相关系数为0.9998。
如图2a所示，依托孕烯本身导致非常高的峰水平(200nmol/l)，在28天内下降至1nmol/l以下的依托孕烯水平。依托孕烯庚酸酯也引起高的依托孕烯初始峰水平(120nmol/l)。依托孕烯壬酸酯引起较低的峰水平，依托孕烯血清水平长时间维持在1nmol/l以上。与图2a中的其他两种酯相比，依托孕烯十一烷酸酯引起在初始峰水平(八天后最大值为13nmol/l)与作用持续时间(超过92天在1nmol/l以上)之间的最佳平衡。
如图2b所示，依托孕烯癸酸酯在5天后产生24nmol/l的初始峰水平，而依托孕烯十二烷酸酯在8天后产生9nmol/l的初始峰水平。利用依托孕烯十三烷酸酯，没有观察到依托孕烯初始水平。
从图2a和2b可以看到，优选的依托孕烯酯是依托孕烯癸酸酯、依托孕烯十一烷酸酯和依托孕烯十二烷酸酯。
Claims (1)
1.依托孕烯十二烷酸酯。
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| DE19540253C2 (de) * | 1995-10-28 | 1998-06-04 | Jenapharm Gmbh | Mehrphasenpräparat zur Kontrazeption auf der Basis natürlicher Estrogene |
| DK1087986T3 (da) | 1998-06-19 | 2002-06-17 | Akzo Nobel Nv | Testosteronderivat |
| AU4513099A (en) | 1998-06-19 | 2000-01-10 | Akzo Nobel N.V. | Cycloalkyl-carboxylic acid esters of 7.alpha.methyl-estr-4-en-3-one 17.beta.-ol (19-nor 7.alpha.-methyltestosterone) |
| US6180682B1 (en) | 1999-01-26 | 2001-01-30 | Virgil A. Place | Buccal drug delivery system for use in male contraception |
| TW200400041A (en) * | 2002-05-30 | 2004-01-01 | Akzo Nobel Nv | Use of new etonogestrel esters |
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2003
- 2003-05-19 TW TW092113489A patent/TW200403065A/zh unknown
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