CN1156998A - 雌-1,3,5(10)-三烯衍生物,其制备方法及含有这些化合物的药物组合物 - Google Patents
雌-1,3,5(10)-三烯衍生物,其制备方法及含有这些化合物的药物组合物 Download PDFInfo
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- CN1156998A CN1156998A CN95194914A CN95194914A CN1156998A CN 1156998 A CN1156998 A CN 1156998A CN 95194914 A CN95194914 A CN 95194914A CN 95194914 A CN95194914 A CN 95194914A CN 1156998 A CN1156998 A CN 1156998A
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- triolefins
- hydroxies
- sulphonate
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Abstract
本发明涉及新的在3位带有R-SO2-O基团的雌-1,3,5(10)-三烯氨基磺酸酯,其中R为R1R2N-基团,其中R1和R2各自独立地为氢原子,C1-C5烷基或与N原子一起为C4-C6聚亚甲基亚氨基或吗啉代残基。本发明化合物适于激素避孕和更年期激素替代疗法(HRT)以及治疗妇科和男科疾病。因此本发明化合物仅呈现低的肝雌激素效应。还描述了制备本发明化合物和制备药物组合物的方法。
Description
本发明涉及新的雌-1,3,5(10)-三烯氨基磺酸酯。
雌激素在激素避孕和更年期激素替代疗法(HRT)中及治疗妇科疾病(例如乳腺癌)和男科疾病(例如前列腺癌)中起主要作用。
在HRT和避孕中,雌激素主要与孕激素(gestagen)如左炔诺孕酮,去氧孕烯,孕二烯酮,drospirorenone,炔诺酮,环丙孕酮乙酸酯,氯地孕酮和地诺孕素结合使用。
为了避孕,要求雌激素能可靠地抑制卵泡成熟和排卵。它们还将替代大受抑制的雌二醇的内源性卵巢分泌。此种替代是维持人工月经周期和性器官的其他功能所必须的,但这并不能单独由孕激素令人满意地达到。
内源性雌激素还在雌性生物中具有重要的中枢神经和代谢功能。
正常的雌激素水平对个体的舒适和安宁具有关键性作用(L.Zichella;绝经妇女的临床管理,国际受精和绝经研究杂志(Int.J.of Fertil.and Menop.Studies),38,增补第1期[1993],15-22)。其通过各种机理的存在有助于防止心血管疾病的产生,例如通过在血液中产生“有益”类型的脂蛋白(G.Samsioe;激素替代疗法与心血管疾病;国际受精和绝经研究杂志,38,增补第1期[1993],23-29),抑制脂质掺入血管壁(T.B.Clarkson;孕酮与孕激素对动脉壁的实验效果;妇科内分泌学(Gynecol.Endocrinol.),6:增补第1期[1992],15),通过对血管紧张的有益作用降低血压(R.A.Lobo;雌激素和心血管疾病;纽约科学院年报(Ann.New York Acad.Sciences),592[1990],286-294),减小重要血管段的灌住阻力,减小对血管肌的收缩刺激(C.Jiang等;17β-雌二醇在兔对内皮素-1的冠状动脉收缩的急性作用;美国生理学杂志(Am.J.Physiol.),263[1992],H271-H275)。在雌激素作用下的血管内壁释放出对抗血块聚集的因子(前列环素)。
雌激素另外还在保持骨骼结构上对妇女来说必不可少。它们的缺乏可能引起骨退化(骨质疏松)(C.Christiansen;使用激素替代疗法预防和治疗骨质疏松;国际受精和绝经研究杂志,38,增补第1期[1993],45-54)。雌激素的这些后面的“中枢神经”和“代谢”作用是HRT中的主要方面。
尽管雌激素治疗具有许多积极方面,但仍然具有某些对雌激素的治疗用途产生限制或可能产生不希望有的效应的未解决问题。
天然雌激素(雌二醇,雌酮,雌酮硫酸酯,雌二醇的酯,雌三醇)的生物利用率在口服后倾向于降低(K.B.Lokind等;17β-雌二醇和各种酯类前药在大鼠中的口服生物利用率;国际药物杂志(Int.J.Pharmaceutics),76[1991],177-182)。这一最低量具有高度个体可变性,因此不能建议通常有效的剂量。天然雌激素(雌二醇)用于激素避孕已因这些药代动力学限制得到不利评价(W.Kuhnz等;年轻妇女单次静脉内和口服施用17β-雌二醇后雌二醇,游离和总雌酮的药代动力学;药物研究(Arzneimittel Forschung/Drug Res.),43(II),9[1993],966-973)。从血液中快速消除这些物质是另一问题。在HRT中雌激素替代治疗对各个接受者必须反复再调整。迄今各种努力尚不能开发出具有改进的生物利用率的雌二醇前药(K.B.Lokind等;见上)。
合成雌激素也具有严重的缺点。乙炔雌二醇(EE)是最重要的合成改性的雌激素甾族化合物。它是在口服激素避孕中起主要作用的雌激素。除了EE外,在少数情况中使用美雌醇,它是一种在生物体中代谢成EE的“前药”(J.W.Goldzieher;乙炔雌激素的药代动力学和代谢的某些方面及其临床并发症;美国妇产科学杂志(Am.J.Obstet.Gynecol.),163[1990],318-322)。当口服给药(于人)时,EE的生物利用率要比上述天然雌激素好得多,但取决于各个接受者,其口服生物利用率可能急剧降低。在药效学上,Goidzieher强调曲线下面积(AUC)的可变性以及半衰期和达到最大血液浓度所经过的时间的可变性所暗示的不利结果。在其研究中,用药后0-24小时记录的最大AUC达到2121pg×h/ml。最小AUC为284pg×h/ml。Hümpel等说明了在6-7倍附近的AUC的类似分散(M.Hümpel等;在妇女使用两种低剂量联后的口服避孕药中血清乙炔雌二醇,结合性激素的球蛋白,结合类皮质激素的球蛋白和皮质醇水平的比较;激素研究(Horm.Res.),33[1990],35-39)。
口服施用的活性物质在吸收之后采取的途径是从肠腔经肝进入生物体。这一事实对雌激素药物非常适当,因为肝是雌激素的靶器官,而且因此它们的口服给药可导致强烈的肝内雌激素效应。在人的肝中由雌激素调节的分泌活动包括转运蛋白,CBG,SHBG和TBG,血管紧张素原,各种在血液凝固中起主要生理作用的因子,以及脂蛋白的合成。
然而,如果通过绕过肝来将天然雌激素供给雌性生物,比如说通过经皮施用,则上述肝功能不受影响且保持不变(U.Larsson-Cohn等人;绝经后激素替代治疗的某些生化结果;多疑更年期(The ControversialClimateric),编辑:P.A.van Keep等;MTP出版有限公司[1982])。口服给予治疗当量的天然雌激素导致各种肝参数的明显变化:SHBG,CBG,血液紧张素,HDL(高密度脂蛋白)升高(J.C.Stevenson等;口服与经皮激素替代疗法;国际受精和绝经研究杂志,38,增补第1期[1993],30-35)。由马雌激素混合物(所谓的结合雌激素)得到的肝雌激素效应被清楚地发现比天然雌激素所引起的那些要更强(C.A.Mashchak等;各种雌激素制剂的药效学性能比较,美国妇产科学杂志,144[1982],511-518)。乙炔雌二醇和DES可产生甚至更强的肝激素效应。与抗促性腺激素性能有关,EE在肝中的雌激素效应为口服给予的天然雌激素的8-10倍。因此,存在高度不利的性能分离(B.vonSchoultz等;雌激素治疗和肝功能-经口和胃肠外给药的代谢作用;前列腺(The Prostate),14[1989],389-395)。
下列研究表明通过降低避孕药中的EE剂量并不能避免不希望有的肝雌激素效应。EE从30μg降至20μg,各剂量均与150μg相同孕激素结合,在3个月后不能降低显著增加的血管紧张素水平且在6个月后最好只给出稍微降低的值(A.Basdevant等;在含去氧孕烯的口服避孕药中将乙炔雌二醇剂量由30mcg降至20mcg的止血和代谢作用;避孕(Contraception),48[1993],193-204)。
致命的血栓栓塞并发症已知是在男性的前列脉癌的高剂量雌激素治疗中的一个现实问题(B.von Schoultz等,见上)。
口服激素避孕的策略由或多或少降低的EE在肝中的潜在副作用确定。
一方面需要考虑避孕药的有效性和维持规则月经,而另一方面要考虑潜在副作用高,所以控制所需的EE血液水平如同走钢丝。相当百分数的妇女不能使用口服避孕药,因为它们的耐受限度被月经异常或与雌激素相关的副作用超出。
心血管疾病的危险,甚至具有致命结果,明显地随激素避孕药而增加(V.Wynn;口服避孕药和冠脉疾病;生殖医学杂志(J.Reprod.Med.),36,增补第3期[1991],219-225)。某些危险因子取决于年龄(J.I.Mann;口服避孕药和年轻妇女的心肌梗塞;甾族避孕药的药理学(Pharmacol.Steroid.Contracept.Drugs),编辑:S.Garrattini和H.W.Berendes,Raven出版社,New York[1977],289-296)。因此数家卫生管理局已警告年龄超过35岁的妇女不要使用激素避孕药。对于年龄超过35岁的使用激素避孕药的吸烟女性来说患心血管疾病的危险甚至更大(F.A.Leidenberger;妇科医生的临床内分泌学(KlinischeEndokrinologie fur Frauenartze);382-383;J.I.Mann;见上)。在口服避孕药的使用者中发现致命性心血管疾病的危险为对照群体的5-6倍(F.A.Leidenberger;同上)。这些数据表明大量的性成熟妇女仅能以不合理的高危险服用常规的激素避孕药或根本不能服用。
最近的研究表明上述问题应归因于激素避孕药中的雌激素组分,而不是孕激素组分(Skouby等;妇产科学杂志(J.Obstet.Gynecol.),[1990],1535-1537)。在一次“舆论会议”上,得出如下结论:患致命性心肌梗塞的真正危险并不取决于使用长短。这些发现似乎证实致命的结块并不归因于心脏动脉壁的慢性损伤(动脉粥样硬化),而是归因于对肝中止血功能的急性作用(R.A.Lobo;见上)。因此,降低雌激素对肝的作用似乎是一种消除激素避孕的上述危险和应用时的相关局限的方法。
所述EE的危险对天然雌激素,即肝雌激素效应低于EE的雌激素来说明显得以消除(R.A.Lobo;见上)。
对HRT通常需要基于最近技术使用天然激素单个地调整剂量。在本文中已证实治疗伴随有与过度剂量或不足剂量的危险有关的主要不确定性。
因此本发明的目的是提供不具有上述不利特性和副作用的雌-1,3,5(10)-三烯衍生物。
根据本发明,该目的通过提供具有通式I的雌-1,3,5(10)-三烯衍生物而得到满足:式中R为R1R2N基团,其中R1和R2各自独立地为氢原子,C1-C5烷基,或与氮原子一起为C4-C6聚亚甲基亚氨基或吗啉代残基,R3为氢原子或C1-C5烷基,R4为氢原子,羟基,酯化羟基,C1-C5卤代烷基或C1-C5烷氧基,R5和R6各自为氢原子或一起为亚甲基,R7,R8和R9各自独立地为氢原子或羟基,以及环B含有一根或两根双键或R8为具有至多5个碳原子的炔基或R8和R9一起为氧原子或R5和R8为1,2-亚乙烯基或1,2-亚乙基。
本发明的在3位碳原子上带有R-SO2-O基团且其中R起上述作用的雌-1,3,5(10)-三烯衍生物在6和7,7和8,8和9,9和11,8和14,14和15和/或15和16位碳原子之间可含有额外双键。
本发明的在3位碳原子上带有R-SO2-O基团且其中R起上述作用的雌-1,3,5(10)-三烯衍生物可在6,7,11,15,16和/或17位碳原子上含有氧代基团。
本发明的在3位碳原子上带有R-SO2-O基团且其中R起上述作用的雌-1,3,5(10)-三烯衍生物可在6,7,9,11,14,16和/或17位碳原子上带有额外的羟基,且这些羟基可被酯化或醚化。此类酯化通过常用的生理相容无机酸或有机酸的衍生物进行。它们可以是磷酸,硫酸,草酸,马来酸,富马酸,乳酸,酒石酸,苹果酸,柠檬酸,水杨酸,戊酸,己二酸和苯甲酸。更适用的酸可参见例如“药物研究进展(Fortschritte der Arzneimittelforschung)”,Vol.10,第224-225页,Birkhauser Verlag,Basel and Stuttgart,1966,和药物科学杂志(Journal of Pharmaceutical Sciences),Vol.66,第1-5页(1977)。醚化利用至多具有6个碳原子的脂族醇的常见衍生物进行。
本发明的在3位碳原子上带有R-SO2-O基团且其中R起上述作用的雌-1,3,5(10)-三烯衍生物可在6,7,11,14,15,16和/或17位碳原子上被至多具有5个碳原子的烷基,亚烷基,链烯基和炔基取代,且这些基团又可以相同方式被烷基,亚烷基,链烯基或炔基或卤素取代。
本发明的在3位碳原子上带有R-SO2-O基团且其中R起上述作用的雌-1,3,5(10)-三烯衍生物可在14和15或14和17位碳原子之间被至多具有3个碳原子的亚烷基或亚链烯基取代。
本发明的在3位碳原子上带有R-SO2-O基团且其中R起上述作用的雌-1,3,5(10)-三烯3-氨基磺酸酯衍生物例如可为如下化合物:17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二-乙基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基吡咯烷基(pyrrolidino)磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基吗啉代磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10),7-四烯-3-基N,N-二甲基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10),6,8-五烯-3-基N,N-二乙基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10),8-四烯-3-基N,N-二甲基氨基磺酸酯,11β-氯代甲氧基-17β-羟基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,17β-羟基-14α,15α-亚乙烯基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯,14α,17α-亚乙基-17β-羟基雌-1,3,5(10)-三烯-3-基吡咯烷基磺酸酯,16α,17β-二羟基-14α,17α-亚乙基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯,17β-羟基-7α-甲基雌-1,3,5(10)-三烯-3,11β-二基3-N,N-二甲基氨基磺酸酯-11-硝酸酯,17β-羟基-11β-甲氧基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基N,N-二甲基氨基磺酸酯,17β-羟基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基氨基磺酸酯,17β-羟基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基N-甲基氨基磺酸酯,17β-羟基雌-1,3,5(10),7-四烯-3-基N,N-二乙基氨基磺酸酯,17β-羟基雌-1,3,5(10),6,8-五烯-3-基N,N-二甲基氨基磺酸酯,17α-羟基-14α,15α-亚甲基雌-1,3,5(10),8-四烯-3-基氨基磺酸酯,17-氧代雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,17-氧代雌-1,3,5(10)-三烯-3-基氨基磺酸酯,11β-甲氧基-17-氧代雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,17β-羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基雌-1,3,5(10),6,8-五烯-3-基氨基磺酸酯,17α-羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,雌-1,3,5(10)-三烯-3,17β-二基3-氨基磺酸酯17-戊酸酯,雌-1,3,5(10)-三烯-3,17β-二基3,17-二(氨基磺酸酯),16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基吗啉代磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,11β-氯代甲氧基-17β-羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基-14α,17α-亚乙烯基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,14α,17α-亚乙基-17β-羟基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,16α,17β-二羟基-14α,17α-亚乙基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基-7α-甲基雌-1,3,5(10)-三烯-3,11β-二基3-氨基磺酸酯-11-硝酸酯,17β-羟基-11β-甲氧基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基氨基磺酸酯。
还特别优选R7和R9为羟基的通式I的雌-1,3,5(10)-三烯衍生物。
还特别优选R5和R6一起为1,2-亚乙基或亚甲基的通式I的雌-1,3,5(10)-三烯衍生物。
根据本发明,特别优选如下雌-1,3,5(10)-三烯衍生物:17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,和16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯。
此外,本发明涉及一种生产本发明雌-1,3,5(10)-三烯衍生物的方法,其特征在于按通常已知的方法用适当取代的氨基磺酰氯酯化雌-1,3,5(10)-三烯衍生物的3-OH基团而将其转化。
该转化通常在用作相转移催化剂的季铵盐存在下以两相体系进行。转化温度为室温至100℃之间。使用常见的两相体系作溶剂,如氯仿-水,二氯甲烷-水,甲苯-水等。
本发明的另一主题是涉及含有通式I的雌-1,3,5(10)-三烯衍生物作活性成分的药物组合物,这些组合物可能根据需要含有助剂和载体。
本发明的药物组合物还可含有一种或多种上述孕激素,如左炔诺孕酮,去氧孕烯,孕二烯酮,drospirorenone,炔诺酮,环丙孕酮乙酸酯,氯地孕酮或地诺孕素。
本发明的药物组合物也可制成多级或组合产品形式。
例如用于避孕的组合产品包括可以是几种组分的组合的第一级,这些组分是生物(biogenic)雌激素,合成雌激素,孕激素和/或本发明的雌-1,3,5(10)-三烯衍生物,以及一个或几个额外的级,该级可包括药物上安全的安慰剂或生物或合成孕激素或生物或合成雌激素或本发明的雌-1,3,5(10)-三烯衍生物,或几种组分的组合,这些组分是生物雌激素,合成雌激素,孕激素,本发明的雌-1,3,5(10)-三烯衍生物,或合成雌激素或本发明的雌-1,3,5(10)-三烯衍生物和孕激素的组合。
例如生物雌激素具有雌二醇,雌酮,雌烷,雌三醇以及其它生物雌激素中的一种组分或至少一种在摄取后迅速使上述雌激素组分中的一种立即分离出的化合物。
本发明的合成雌激素具有至少一种选自乙炔雌二醇,美雌醇和其他合成雌激素中的组分或至少一种在摄取后迅速使上述雌激素组分中的一种立即分离出的化合物。
本发明的孕激素具有至少一种选自左炔诺孕酮,去氧孕烯,黄体酮,炔诺酮乙酸酯,氯地孕酮,孕二烯酮,环丙孕酮乙酸酯和其他天然和/或合成孕激素的组分或至少一种在摄取后迅速使上述孕激素组分中的一种立即分离出的化合物。
本发明的另一主题是涉及生产可用于激素避孕,更年期激素替代疗法和治疗妇科疾病和男科疾病如乳腺癌和前列腺癌的药物组合物的方法。
本发明的另一主题是涉及片剂,缓释片剂,包衣片剂,丸剂,胶囊剂,包膜片剂和缓释包膜片剂形式的药物组合物。
这些药物以通常已知且已确定的方法按所需使用方式和合适的剂量制备,使用常见的固态或液态载体或稀释剂和常见的药物助剂。优选口服制剂。此类制剂可为片剂,包膜片剂,包衣片剂,胶囊剂,丸剂,粉剂或储存制剂。
合适的片剂例如可通过将活性物质与已知助剂如惰性稀释剂象葡萄糖,糖,山梨醇,甘露糖醇,聚乙烯吡咯烷酮,崩解剂如玉米淀粉或藻酸,粘结剂如淀粉或明胶,润滑剂如硬脂酸镁或滑石和/或用来达到储存效果的试剂如羧基聚亚甲基,羧甲基纤维素,纤维素乙酸酯对苯二甲酸酯或聚乙酸乙烯酯混合而制得。片剂也可由几层组成。
包衣片剂可以通过用常见的涂覆剂如聚乙烯吡咯烷酮或紫胶,阿拉伯胶,滑石,二氧化钛或糖涂覆类似于片剂制得的核而制备。涂层可为几层,而且可使用对片剂所述的助剂。
其中含有活性物质的胶囊剂例如可通过混合活性物质与惰性载体如乳糖或山梨醇,并将其包封在明胶胶囊中而得到。
然而,由于用于医药用途的常规雌激素衍生物的严重缺陷,迫切需要没有这些缺陷的化合物。
令人惊奇地发现本发明的化合物就其雌激素效力而言优于EE,伴随着在子宫中最大生殖雌激素效应且肝雌激素效应不比天然雌激素-雌二醇强。与天然和合成雌激素相比,本发明化合物提供的这一相互影响因素(constellation)将得到明显改善的治疗性能。
含本发明的雌-1,3,5(10)-三烯衍生物的避孕药可能对使用激素避孕的局限进行全新的定义,因为它们对止血系统很少有或根本没有作用。
含本发明的雌-1,3,5(10)-三烯衍生物的避孕药因其雌激素效应急剧降低而可以对循环控制足够高的剂量应用,结果比常规EE避孕药所达到的好。
在目前的激素替代疗法中使用EE因所涉及的副作用而受到严格反对。非天然(生物)雌激素所存在的危险因本发明的雌-1,3,5(10)-三烯衍生物的出现而不复存在。不同于在目前的激素替代疗法中占主导地位的天然雌激素,提供了显著优越的可控性优点,因为口服生物利用率被清楚地界定,且不再具有生物雌激素的主要个体可变性。
在切除卵巢的大鼠中证实了肝雌激素效应:将成年雌性试验动物(种畜:HSD/WIN:WU)切除卵巢(第14天)。每天口服一次试验物质的治疗在切除卵巢2周后开始。
所有动物按随机方法分组。该实验为区组设计。所有动物在试验前和试验后称重两次。
治疗开始和结束定为第1天(=d1)或第7天(=d7)。在第8天杀死动物。取出几种器官(子宫,肾上腺,肝)并称重,放入深冻条件(-196℃)下供进一步研究。
在治疗前(d0)以及在(d4)和(d8)用乙醚麻醉从眼球后血管丛取血。用所得血清测定IGF1,血管紧张素I,胆固醇和HDL胆固醇。测定方法:IGF1-RIA bioMérieux Co.;血管紧张素-肾素活性的改良RIA-Sorin Co.;胆固醇/HDL-酶试验,光度法,Dr.Bruno Lange GmbH提供的试剂。
所得结果给于表1。
口服本发明的雌-1,3,5(10)-三烯衍生物对子宫的效力等同或优于乙炔雌二醇(EE)。另外对肝雌激素效应参数的影响不存在或显著低于类似剂量的乙炔雌二醇(EE)。
本发明雌-1,3,5(10)-三烯衍生物的血液水平比类似物质雌二醇(E2),乙炔雌二醇(EE)和雌三醇(E3)要高得多。
表1:
口服雌激素作用
对性功能和肝参数的影响
物质 | 剂量/dμg/动物p.o. | 子宫重量(mg) | 总胆固醇(mg/dl血浆) | HDL胆固醇(mg/dl血浆) | 血管紧张素I(ng/mg血浆) | 血液水平(pg/ml血清) |
雌二醇(E2) | 10 | 182 | 84.3 | 54.1 | 344.6 | 19.2 |
乙炔雌二醇(EE) | 10 | 353 | 41.9 | 24.3 | 639.6 | 28.9 |
雌三醇(E3) | 10 | 302 | 70.9 | 42.7 | 495.9 | 8.815 |
J983 | 10 | 349 | 75.5 | 48.3 | 413.2 | 33.2 |
J989 | 10 | 183 | 95.8 | 52.5 | 412.9 | 42.875 |
J982 | 10 | 193 | 83.3 | 50.8 | 421.5 | 46.4 |
J984 | 10 | 246 | 89.6 | 47.8 | 405.3 | 75.8 |
本发明由如下实施例说明。实施例1:雌-1,3,5(10)-三烯衍生物的N,N-二取代3-氨基磺酸酯的一般合成方法
将指定用于酯化的雌-1,3,5(10)-三烯衍生物,氨基磺酰氯,碱金属氢氧化物或碱土金属氢氧化物以及作相转移催化剂的季铵盐在剧烈搅拌下加到适当的有机溶剂和水的混合物中。继续搅拌直到由分析方法(薄层色谱法)显示酯化完全,当需要缩短反应时间时,工作温度为50-100℃是可行的。然后分离两相。水相反萃取,合并的有机萃取液连续用稀盐酸,饱和碳酸氢钠溶液和水洗涤。然后在无水硫酸钠上干燥萃取液并在减压下蒸发干燥。残余物从适当溶剂中重结晶。实施例2(=J983):17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯的制备
将2g14α,15α-亚甲基雌-1,3,5(10)-三烯-3,17β-二醇悬浮于30ml甲苯,4ml水,0.32g苄基三乙基氯化铵,2.94mlN,N-二乙基氨基磺酰氯和2.1ml40%氢氧化钠溶液中并搅拌和加热2小时至80℃的内部温度。
冷却至室温后按实施例1所述进行处理。由此得到的粗产物在硅胶(粒径:0.063-0.2mm)上进行色谱分离。用氯仿/乙酸乙酯9∶1洗脱和从甲醇重结晶之后得到标题化合物。熔点:68-73℃;1H-NMR:0.26(m,CH2),0.99(s,18-H),3.38(q,7.2Hz,CH3-CH2-N),3.55(dd,Σ16Hz),7.31(d,8.8Hz,1-H)ppm(CDCl3)。实施例3(=J989):16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯的制备
搅拌120ml水,1.58g苄基三乙基氯化铵,7.44mlN,N-二甲基氨基磺酰氯和4ml40%氢氧化钠溶液并在80℃温度下加入2g雌三醇在800ml甲苯中的溶液中。继续加热至80℃。在该过程中通过加入40%氢氧化钠溶液维持反应溶液的pH值为10。所有起始化合物反应完全后冷却至室温并按实施例1所述进行处理。所得残余物从丙酮/正己烷重结晶得到标题化合物。熔点:180-181℃;1H-NMR:0.67(s,18-H),2.89(s,CH3-N),3.32(m,17-H),3.84(m,16-H),4.64,4.71(各为d,4.9Hz,各为OH),7.34(d,8.8Hz,1-H)ppm(D6-DMSO)。实施例4(=J982):17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯的制备
按实施例1所述在30ml二氯甲烷和6.6ml水的混合物中进行1g14α,15α-亚甲基雌-1,3,5(10)-三烯-3,17β-二醇,2.4g氢氧化钠,0.24g氯化三乙基苄基铵和3.6mlN,N-二甲基氨基磺酰氯的反应。在反应产物的处理,色谱纯化和从丙酮中重结晶之后得到标题化合物。熔点:193-196℃;1H-NMR:0.255(m,CH2),0.99(s,18-H),2.98(s,CH3-N),3.55(dd,∑16Hz,17-H),7.32(d,8.6Hz,1-H)ppm(CDCl3)。实施例5(=J984):16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯的制备
按实施例1所述在800ml甲苯和128ml水的混合物中进行2g雌三醇,5.2g氢氧化钠,1.72g氯化三乙基苄基铵和9.75mlN,N-二乙基氨基磺酰氯的反应。在处理,色谱纯化和从丙酮重结晶后得到标题化合物。熔点:121-124℃;1H-NMR:0.67(s,18-H),1.11(t,7.1Hz,CH3-CH2-H),3.33(q,7.1Hz,CH3-CH2-N),3.83(m,16-H),4.65,4.72(均为d,4Hz,3.5Hz,16-OH,17-OH),7.33(d,8.4Hz,1-H)ppm(D6-DMSO)。实施例6:
雌-1,3,5(10)-三烯衍生物的N-单取代和N-未取代3-氨基磺酸酯的一般合成方法。搅拌碱(三乙胺或2,6-二叔丁基-4-甲基吡啶)和单取代或N-未取代氨基磺酰氯搅拌并逐一加入雌-1,3,5(10)-三烯衍生物在适当溶剂(二氯甲烷,吡啶或二甲基甲酰胺)中的溶液中。反应温度应不超过+20℃。起始材料的完全转化可由薄层色谱法在1-3个小时之后记录。为了处理,用稀盐酸水溶液,饱和碳酸氢钠水溶液和水洗涤反应溶液并在无水硫酸钠上干燥,在旋转真空蒸发仪中蒸发至干。在硅胶上通过柱色谱法和/或通过重结晶提纯残余物。实施例7(=J1044):14α,15α-亚甲基雌二醇的3-(N-甲基)氨基磺酸酯的制备
按实施例6所述在吡啶(12.7ml)和2,6-二叔丁基-4-甲基吡啶(5.1g)的溶液中进行亚甲基雌酮(1.17g)和(N-甲基)氨基磺酰氯(1ml)的反应。处理之后用柱色谱法(氯仿/乙酸乙酯9/1)提纯粗产物并从丙酮/正己烷重结晶得到14α,15α-亚甲基雌酮-(N-甲基)氨基磺酸酯。
在氩气保护,除去水分和搅拌下将由硼氢化钠(1g)和三氟化硼-乙醚配合物(3.5ml)在四氢呋喃(44ml)中制备的甲硼烷溶液(25ml)在0-5℃下分批加入14α,15α-亚甲基雌酮-(N-甲基)氨基磺酸酯(809.5g)在四氢呋喃(15ml)中的溶液中。反应溶液在滴入冰水之前在0-5℃下放置20小时。在处理,柱色谱分离(氯仿/乙酸乙酯9/1)和从丙酮重结晶之后得到标题化合物。熔点:192-193.5℃;1H-NMR:0.20(m,CH2),0.2555(m,CH2),0.89(s,H-18),2.71(d,3.8Hz,CH3-NH),3.43(m,H-17),4.43(d,5.3Hz,OH),7.39(d,8.5Hz,H-1),8.12(m,NH)ppm(D6-DMSO)。实施例8(=J1011):雌酮-(N-甲基)氨基磺酸酯的制备
按实施例6所述在二氯甲烷(1200ml)和三乙胺(28.2ml)的溶液中进行雌酮(3g)和N-甲基氨基磺酰氯(3ml)的反应。处理之后粗产物从丙酮/正己烷中重结晶,得到标题化合物。熔点:192.5-196.5℃;1H-NMR:0.91(s,H-18),2.95(d,5.1Hz,CH3-NH),4.58(m,NH),7.30(d,8.2Hz,H-1)ppm(CDCl3)。实施例9(=J1012):雌二醇-(N-甲基)氨基磺酸酯的制备
用硼氢化钠(624.2mg)在四氢呋喃(20ml)和甲醇(20ml)的混合物中还原雌酮-(N-甲基)氨基磺酸酯(1g)。处理后粗产物从丙酮/正己烷中重结晶得到标题化合物。熔点:194-198.5℃;1H-NMR:0.78(s,H-18),2.94(d,5.2Hz,CH3-NH),4.53(m,NH),3.73(dd,∑16.9Hz,H-17),7.30(d,8.4Hz,H-1)ppm(CDCl3)。实施例10(=J1036):17α-乙炔雌二醇-3-(N-甲基)氨基磺酸酯的制备
如实施例6所述在二氯甲烷(25ml)和2,6-二叔丁基-4-甲基吡啶(3.3g)的溶液中进行17α-乙炔雌二醇-17-三甲基甲硅烷基醚(1g)与(N-甲基)氨基磺酰氯(0.72ml)的反应。反应溶液通过在1∶1稀盐酸水溶液中搅拌5小时而使甲硅烷基醚完全断裂,然后用柱色谱法(甲苯/氯仿/甲醇80/15/5)纯化粗产物并从丙酮/正己烷重结晶得到标题化合物。熔点:156-162.5℃;1H-NMR:0.88(s,H-18),2.61(s,≡CH),2.94(d,5.2Hz,CH3-NH),4.53(m,NH),7.31(d,8.8Hz,H-1)ppm(CDCl3)。实施例11(=J994):雌酮-氨基磺酸酯的制备
将雌酮(1g)溶于二甲基甲酰胺(20ml)中。然后将氨基磺酰氯(2.14g)加入该溶液中。搅拌6小时后在水中沉淀,从乙酸乙酯中重结晶产物得到标题化合物。熔点:199-202℃;1H-NMR:0.83(s,H-18),7.35(d,8.7Hz,H-1),7.9(s,NH2)ppm(D6-DMSO)。实施例12(=J995):雌二醇-3-氨基磺酸酯的制备
在四氢呋喃(28ml)和甲醇(28ml)的溶液中用硼氢化钠(960mg)还原雌酮-氨基磺酸酯(1.4g)。处理后从丙酮中重结晶粗产物得到标题化合物。熔点:211-213℃;1H-NMR:0.67(s,H-18),3.53(t,d 7.9Hz,4.7Hz,H-17);4.55(d,4.8Hz,OH),7.34(d,8.6Hz,H-1),7.90(s,NH2)ppm(D6-DMSO)。实施例13(=J1018):14α,15α-亚甲基雌二醇-3-氨基磺酸酯的制备
按实施例6所述在二氯甲烷(3ml)和2,6-二叔丁基-4-甲基吡啶(180mg)的溶液中进行14α,15α-亚甲基雌二醇-17-叔丁基二甲基甲硅烷基醚(100mg)与氨基磺酰氯(145mg)的反应。处理之后粗产物用柱色谱法(甲苯/丙酮4/1)提纯并从丙酮/正己烷中重结晶,从而得到14α,15α-亚甲基-17β-叔丁基二甲基甲硅烷氧基雌-1,3,5(10)-三烯-3-基氨基磺酸酯。
将14α,15α-亚甲基-17β-叔丁基二甲基甲硅烷氧基雌-1,3,5(10)-三烯-3-基氨基磺酸酯(2.2g)溶于四氢呋喃(100ml)中。往该溶液中加入乙酸/水/四氢呋喃3/1/1(220ml)的混合物。在产物处理,柱色谱纯化(环己烷/乙酸乙酯3/2)和在丙酮/正己烷中重结晶前将反应溶液在室温下放置7天。熔点:210-214℃;1H-NMR:0.20(m,CH2),0.26(m,CH2),0.89(s,H-18),3.4(m,H-17),4.41(d,5.2Hz,OH),7.39(d,8.8Hz,H-1),7.90(s,NH2)ppm(D6-DMSO)。实施例14(=J1028):17α-乙炔雌二醇-3-氨基磺酸酯的制备
按实施例6所述在二氯甲烷(40ml)和三乙胺(16ml)的溶液中进行17α-乙炔雌二醇-17-三甲基甲硅烷基醚(1.5g)与氨基磺酰氯(8g)的反应。断裂甲硅烷基醚基团和处理之后,粗产物用柱色谱法(氯仿/乙酸乙酯7/3)纯化并从丙酮/正己烷重结晶得到标题化合物。熔点:209-211℃;1H-NMR:0.76(s,H-18),3.35(s,≡CH),5.35(s,OH),7.35(d,8.7Hz,H-1),7.89(s,NH2)ppm(D6-DMSO)。实施例15(=J1034):
雌三醇-3-氨基磺酸酯的制备
按实施例6所述在二氯甲烷(13ml)和三乙胺(15.5ml)的溶液中进行雌三醇-16,17-二(叔丁基二甲基甲硅烷基)醚(2g)与氨基磺酰氯(7.9g)的反应。在处理后粗产物按实施例13进行甲硅烷基醚断裂,然后用柱色谱法(氯仿/甲醇/乙酸90/13/1)纯化分离的物质,并从丙酮/正己烷重结晶得到标题化合物。熔点:208-213℃;1H-NMR:0.67(s,H-18),3.30(m,H-17),3.84(m,H-16),4.7(m,OH),7.32(d,8.4Hz,H-1)ppm(D6-DMSO)。实施例16(=J1040):雌三醇-3-(N-甲基)氨基磺酸酯的制备
按实施例6所述在二氯甲烷(51ml)和2,6-二叔丁基-4-甲基吡啶(4.05g)的溶液中进行雌三醇-16,17-二(叔丁基二甲基甲硅烷基)醚(1.7g)与(N-甲基)氨基磺酰氯(0.87ml)的反应。处理之后粗产物用柱色谱法(甲苯/氯仿/甲醇80/15/5)纯化,随后按实施例13进行甲硅烷基醚断裂。分离的物质经柱色谱纯化(氯仿/甲醇/乙酸90/13/1)和从丙酮/正己烷重结晶得到标题化合物。熔点:199-202℃;1H-NMR:0.67(s,H-18),2.70(s,NH-CH3),3.30(m,H-17),3.84(m,H-16),4.7(m,OH),7.33(d,8.7Hz,H-1)ppm(D6-DMSO)。实施例17(=J1050):17α-雌二醇-3-氨基磺酸酯的制备
按实施例6所述在二氯甲烷(70ml)和2,6-二叔丁基-4-甲基吡啶(3.6g)的溶液中进行17α-雌二醇-叔丁基二甲基甲硅烷基醚(1.94g)与氨基磺酰氯(2.75g)的反应。粗产物在处理之后用柱色谱法(甲苯/丙酮4/1)提纯并从丙酮/正己烷中重结晶。将由此得到的17α-叔丁基二甲基甲硅烷氧基雌-1,3,5(10)-三烯-3-基氨基磺酸酯按实施例13进行甲硅烷基醚断裂。从分离物质的柱色谱分离(甲苯/乙酸乙酯/氯仿6/3/1)和在丙酮/正己烷中重结晶得到标题化合物。熔点:192-196℃;1H-NMR:0.62(s,H-18),3.59(d,5.5Hz,H-17),7.36(d,8.8Hz,H-1),7.88(s,NH2)ppm(D6-DMSO)。实施例18(=J1010):14α,15α-亚甲基雌酮-氨基磺酸酯的制备
按实施例6所述在二氧甲烷(50ml)和三乙胺(7.7ml)的溶液中进行14α,15α-亚甲基雌酮(765mg)与氨基磺酰氯(11.7g)的反应。在处理之后通过柱色谱法(氯仿/乙酸乙酯9/1)提纯粗产物,并用丙酮/正己烷进行重结晶,从而得到标题化合物.熔点:191-195℃;1H-NMR:-0.40(m,CH2),0.80(m,CH2),1.12(s,H-18),7.40(d,8Hz,H-1),7.93(s,NH3)ppm(D6-DMSO)。实施例19(=J1021)11β-甲氧基雌酮-氨基磺酸酯的制备
将氢化钠分批(0.4g,80%)加入11β-甲氧基雌酮(2g)在二甲基甲酰胺(37ml)中的溶液中。氢气的放出结束后,加入氨基磺酰氯(6.2g),并室温搅拌反应混合物-夜。然后在水中沉淀,并通过柱色谱法(氯仿/丙酮7/3)提纯产物。从丙酮/正己烷中重结晶得到标题化合物。熔点:191-195℃;1H-NMR:0.99(s,H-18),3.20(s,CH3O),4.24(m,H-11),7.26(d,8.7Hz,H-1),7.93(s,NH2)ppm(D6-DMSO)。实施例20(=J1038)雌-1,3,5(10)-三烯-3,17β-二基-3-氨基磺酸酯,17-戊酸酯的制备
按实施例6所述进行溶于二甲基甲酰胺(37ml)中的雌二醇-17-戊酸酯(2g)与氢化钠(336mg,80%)和氨基磺酰氯(6.47g)的反应。在处理,柱色谱分离(氯仿/乙酸乙酯9/1)和从丙酮/正己烷重结晶之后得到标题化合物。熔点:107-108℃;1H-NMR:0.78(s,H-18),0.87(t,7.3Hz,CH3-(CH2)3-CO),2.29(t,7.2Hz,C3H7-CH2-CO),4.63(dd,∑15.5Hz,H-17),7.34(d,8.4Hz,H-1),7.89(s,NH2)ppm(D6-DMSO)。实施例21(=J1051)17α-羟基-14α,15α-亚甲基雌-1,3,5(10),8-四烯-3-基氨基磺酸酯的制备
按实施例6所述进行14α,15α-亚甲基-17α-三甲基甲硅烷氧基雌-1,3,5(10)-三烯-3-醇(100mg)在二氯甲烷(3ml)和2,6-二叔丁基-4-甲基吡啶(180mg)的溶液中与氨基磺酰氯(145mg)的反应。在断裂甲硅烷基醚基团和处理之后,通过柱色谱法(环己烷/乙酸乙酯3/2)提纯粗产物,并从丙酮/正己烷中重结晶。白色泡沫;Fp 189-194℃;1H-NMR:0.46(m,CH2),0.92(s,H-18),1.28(m,CH2),3.90(d,∑6.0Hz,H-17)ppm(CDCl3),7.35(d,8.8Hz,H1),7.88(s,NH)(D6-DMSO)。实施例22(=J992)雌酮-(N,N-二甲基)氨基磺酸酯的制备
将雌酮(1g)与二氯甲烷(30ml),水(3ml),苄基三乙基氯化铵(0.24g),N,N-二甲基氨基磺酰氯(3.6ml)和氢氧化钠溶液(40%,6ml)一起在室温下搅拌2小时。然后按实施例1进行处理,产物从乙酸乙酯中重结晶。熔点:192-194℃;1H-NMR:0.91(s,H-18),2.98(s,N-CH3),7.28(d,9.9Hz,H-1)ppm(CDCl3)。实施例23(=J991)雌二醇-3-(N,N-二甲基)氨基磺酸酯的制备
按实施例22所述进行雌二醇(1g)的反应。在从氯仿/甲醇中重结晶产物前进行处理。熔点:204-208℃;1H-NMR:0.78(s,H-18),2.98(s,N-CH3),3.72(dd,∑16Hz),7.28(d,9.9Hz,H-1)ppm(CDCl3)。实施例24(=J1052)14α,15α-亚甲基雌二醇-3-吡咯烷基磺酸酯的制备
按实施例22所述在14α,15α-亚甲基雌二醇(1.05g)与二氯甲烷(30ml),水(3ml),苄基三乙基氯化铵(0.24g),吡咯烷基磺酰氯(4.5ml)和氢氧化钠溶液(40%,8ml)之间进行反应。按实施例1处理后得到标题化合物。无定形固态物质;1H-NMR:0.20(m,CH2),0.26(m,CH2),0.89(s,H-18),3.33(m,-CH2-N-CH2-),3.4(m,H-17),4.41(d,5.2Hz,OH),7.36(d,8.7Hz,H-1)ppm(D6-DMSO)。实施例25(=J1053)雌三醇-3-吗啉代磺酸酯的制备
按实施例3在甲苯(800ml)与水(120ml)的混合物中进行雌三醇(2g)与吗啉代磺酰氯(9.2ml),苄基三乙基氯化铵(1.58g)和氢氧化钠溶液(40%,6.5ml)的反应。按实施例1处理后得到标题化合物。熔点:188-192℃;1H-NMR:0.67(s,H-18),3.28-3.36(m,H-17,-CH2-N-CH2-),3.65-3.68(m,-CH2-O-CH2-),4.7(m,OH),7.37(d,8.8Hz,H-1)ppm(D6-DMSO)。实施例26(=J1054)马萘雌酮-氨基磺酸酯的制备
如实施例11所述用氨基磺酰氯在二甲基甲酰胺溶液中酯化马萘雌酮(1g)并处理。稍呈黄色的树脂;1H-NMR:0.69(s,H-18),7.23,7.56(d,8.4Hz,d,8.5Hz,H-6和H-7),7.82(d,9.8Hz,H-1),7.9(s,NH2)ppm(D6-DMSO)。
Claims (4)
2.根据权利要求1的雌-1,3,5(10)-三烯衍生物,即17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基吡咯烷基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基吗啉代磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10),7-四烯-3-基N,N-二甲基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10),6,8-五烯-3-基N,N-二乙基氨基磺酸酯,17β-羟基-14α,15α-亚甲基雌-1,3,5(10),8-四烯-3-基N,N-二甲基氨基磺酸酯,11β-氯代甲氧基-17β-羟基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,17β-羟基-14α,17α-亚乙烯基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,14α,15α-亚乙基-17β-羟基雌-1,3,5(10)-三烯-3-基吡咯烷基磺酸酯,16α,17β-二羟基-14α,17α-亚乙基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯,17β-羟基-7α-甲基雌-1,3,5(10)-三烯-3,11β-二基3-N,N-二甲基氨基磺酸酯-11-硝酸酯,17β-羟基-11β-甲氧基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基N,N-二甲基氨基磺酸酯,17β-羟基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基氨基磺酸酯,17β-羟基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基N-甲基氨基磺酸酯,17β-羟基雌-1,3,5(10),7-四烯-3-基N,N-二乙基氨基磺酸酯,17β-羟基雌-1,3,5(10),6,8-五烯-3-基N,N-二甲基氨基磺酸酯,17α-羟基-14α,15α-亚甲基雌-1,3,5(10),8-四烯-3-基氨基磺酸酯,17-氧代雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,17-氧代雌-1,3,5(10)-三烯-3-基氨基磺酸酯,11β-甲氧基-17-氧代雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,17β-羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基雌-1,3,5(10),6,8-五烯-3-基氨基磺酸酯,17α-羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,雌-1,3,5(10)-三烯-3,17β-二基3-氨基磺酸酯,17-戊酸酯,雌-1,3,5(10)-三烯-3,17β-二基3,17-二(氨基磺酸酯),16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二乙基氨基磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N,N-二甲基氨基磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基吗啉代磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,16α,17β-二羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,11β-氯代甲氧基-17β-羟基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基-14α,17α-亚乙烯基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,14α,17α-亚乙基-17β-羟基雌-1,3,5(10)-三烯-3-基N-甲基氨基磺酸酯,16α,17β-二羟基-14α,17α-亚乙基雌-1,3,5(10)-三烯-3-基氨基磺酸酯,17β-羟基-7α-甲基雌-1,3,5(10)-三烯-3,11β-二基3-氨基磺酸酯-11-硝酸酯,17β-羟基-11β-甲氧基-19-去甲-17α-孕甾-1,3,5(10)-三烯-20-炔-3-基氨基磺酸酯。
3.制备根据权利要求1或2的雌-1,3,5(10)-三烯衍生物的方法,其特征在于使雌-1,3,5(10)-三烯衍生物按本身己知方式与适当取代的氨基磺酰氯反应,使该雌-1,3,5(10)-三烯衍生物的3-OH基团酯化。
4.含有根据权利要求1或2且可与药物上安全的助剂和载体组合的雌-1,3,5(10)-三烯衍生物的药物组合物。
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DD207447A3 (de) * | 1982-04-02 | 1984-02-29 | Jenapharm Veb | Mittel zur chemosterilisation von schadnagetieren |
FR2533570B1 (fr) * | 1982-09-23 | 1985-07-12 | Centre Nat Rech Scient | Complexes organometalliques d'oestrogenes et leur application au dosage des recepteurs hormonaux |
RU2087479C1 (ru) * | 1989-11-29 | 1997-08-20 | Шеринг Аг | Эстратриены, содержащие мостик |
GB9118478D0 (en) * | 1991-08-29 | 1991-10-16 | Imperial College | Steroid sulphatase inhibitors |
DE4222316A1 (de) * | 1992-07-03 | 1994-01-05 | Schering Ag | Verfahren zur Herstellung von Etheno- und Ethano-16â,17µ-Steroiddiolen und deren Derivaten |
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1994
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1995
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- 1995-07-03 CA CA002196694A patent/CA2196694A1/en not_active Abandoned
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- 1995-07-03 WO PCT/DE1995/000877 patent/WO1996005216A1/de active IP Right Grant
- 1995-07-03 EP EP95925679A patent/EP0775155B1/de not_active Expired - Lifetime
- 1995-07-03 HU HU9700389A patent/HUT77610A/hu unknown
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105753924A (zh) * | 2016-02-03 | 2016-07-13 | 中国药科大学 | 新型甾体类选择性雌激素受体调节剂、其制备方法及其医药用途 |
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