CN1057771C - 雄烯酮衍生物 - Google Patents
雄烯酮衍生物 Download PDFInfo
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- C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- 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
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- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
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- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
Abstract
本发明涉及式(1)的化合物,也称作17β-N-(2,5-双(三氟甲基)苯基氨基甲酰基-4-氮杂-5α-雄-1-烯-1-酮,其溶剂化物,它的制备方法,在其制备中使用的中间体,其药物制剂以及它在雄激素相关和调节的疾病的治疗方面的用途。
Description
本发明涉及特殊的17β-酰基苯胺-4-氮杂-5α-雄-1-烯-3-酮衍生物,作为一个惊人有效的选择性的1型和2型人体5α-还原酶的双重抑制剂。
发明背景
雄性激素在男性和女性中负责许多生理功能。雄激素作用由专门的胞内激素受体来调节,从受体用雄激素相关细胞表达。睾酮,主要的循环雄激素,是由睾丸的间质细胞在脑垂体衍生的促黄体生成激素(LH)的刺激下分泌的。然而,对于雄激素作用,在一些目标组织中,比如前列腺和皮肤,需要把睾酮的4,5-双键还原成为二氢睾酮(DHT)。在目标组织中,甾类5α-还原酶以NADPH依赖方式催化睾酮转化成DHT,如反应式A所示。
反应图A
在这些目标组织中需要DHT作为兴奋剂已经由研究甾类5α-还原酶缺乏个体所强调,缺乏个体具有发育不完全的前列腺,但不患寻常痤疮或男式秃(见McGinley,J.et al.,The Now England J.of Medicine,300,1233(1979))。这样,可以预料到在这些目标组织中抑制睾酮转化成DHT有助于治疗各种雄激素相关的疾病,例如,良性的前列腺增生、前列腺癌、痤疮、男式秃和多毛症。
另外,最近发现5α-还原酶的两个同功酶在人体中存在,这两个同功酶在其组织分布、对睾酮的亲合力、pH值分布及对抑制剂的敏感性方面不同(见Russell,D.W.et al.,J.Clin.Invest.,89,293(1992);Russell,D.W.et al.,Nature,354,159(1991))。由Imperato-McGinley研究的甾类5α-还原酶缺乏个体缺乏2型5α-还原酶(Russell,D.W.et al.,J.Clin.Invest.,90,799(1992);Russell,D.W.et al.,New England J.Med.,327,1216(1992)),这种酶是出现在前列腺中的占主导地位的同功酶,而l型同功在皮肤中占主导地位。同功酶特异性的相对值和5α-还原酶的两个同功酶的双重抑制剂取决于所治疾病的类型(良性的前列腺增生、前列腺癌、痤疮、男式秃或多毛症)以及疾病的阶段(预防与治疗)和在被治疗的病人身上的预期副作用(例如青春期男性普通痤疮的治疗)。
由于其潜在的有价值的治疗性,睾酮5α-还原酶抑制剂[在下文称“5α-还原酶抑制剂”]已成为世界范围内的活跃的研究课题。例如,见Hsia,S.and Voight,W.,J.Invest.Derm.,62,224(1973);Robaire,B.et al.,J.Steroid Biochem.,8,307 91977);Petrow,V.et al.,Steroids,38,121(1981);Liang,T.et al.,J.SteroidBiochem.,19,385(1983);Holt,D.et al.,J.Med.Chem.,33,937(1990);U.S.Patent No.4,377,584,U.S.patent No.4,760,071和U.S.Patent No.5,017,568。两个格外有价值的5α-还原酶抑制剂是MK-906(Merck),通称为finasteride,注册商标为Proscar及SKF-105657(SmithKline Beecham),如式B所示。
图B
通过4-氮杂甾类化合物(4-MA,式C)而不是通过药物finasteride的牛肾上腺和猪的粒层细胞3β-羟基-Δ5-甾类脱氢酶/3-酮-Δ5-甾类异构酶(3 BHSD)的有效抑制,(Tan,C.H.;Fong,C.Y.;Chan,W.K.Biochem.Biophys.Res.Comm.,144,166(1987)和Brandt,M.;Levy,M.A.Biochemistry,28,140(1989)),
图C
与3 BHSD在甾类生物合成中的关键作用(Potts,G.O.et al.,Steroids,32,257(1978))一起暗示出:1和2型5α-还原酶的最适宜的抑制剂也应对人体肾上腺3 BHSD有选择性。在5α-还原酶抑制剂中选择性的重要性已被在某种4-氮杂甾类化合物中,比如4-MA中的肝毒性的报告所强调(McConnell,J.D.TheProstate Suppl.,3,49(1990)和Rasmusson,G.H.et al.J.Med.Chem.,27,1690(1984))。
发明概述
本发明的其它方面是:
1.抑制睾酮-5α-还原酶的方法,包括使睾酮-5α-还原酶与式(I)的化合物接触。
2.治疗雄激素相关的或调节的疾病的方法,包括对需要这种治疗的病人施用有效药量的式(I)化合物。
3.含有式(I)的化合物作为活性成分的药物制剂。
4.治疗雄激素相关的或调节的疾病的方法,包括对需要这种治疗的病人施用有效药量的式(I)的化合物,并结合一个抗雄激素物质,比如氟硝丁酰胺。
5.治疗良性的前列腺增生的方法,包括对需要这种治疗的病人施用有效药量的式(I)化合物,并结合一个α1-肾上腺素功能的受体阻滞剂(例如特拉唑嗪)。
6.治疗良性前列腺增生的方法,包括对需要这种治疗的病人施用有效药量的式(I)化合物,并结合一个抗雌激素物质。发明详述
本领域的技术人员将懂得:许多有机化合物可以与溶剂形成配合物,它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。这些配合物称作“溶剂化物”。例如,一个与水形成的配合物称作“水合物”。化合物(I)的溶剂化物属于本发明的范围之内。
本领域的技术人员明白,许多有机化合物可以以多于一个结晶形式存在。例如,晶型可以因不同的溶剂化物而变化。这样,式(I)的化合物或其药物上可接受的溶剂化物的所有结晶形式均属于本发明的范围。
本发明的化合物可由US Patents 4,377,584(下文称“584”)和4,760,071(下文称“071”)中所述方法制备,二者在此作为参考。例如,式(I)的化合物可由反应式I和II所示的过程制备。
反应图I
在反应图I中,式(V)的化合物脱氢得到式(I)的化合物,这通过一个脱氢系统来完成,例如,用2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)和双(三甲基-甲硅烷基)三氟乙酰胺于干燥的二噁烷中在室温处理2~5小时,接着加热回流10~20小时(见Bhattacharya,A.et al.,J.Am.Chem.Soc.,110,3318(1988))。
式(V)的化合物可由反应式IA制备。
反应图IA
在反应式IA的步骤1中,3-氧代-4-雄烯-17β-羧酸(II)转化成式(III)的相应酰胺。这可以通过括化酸并与式(IIa)的苯胺反应来完成。例如,反应顺序可以是式(II)的化合物转化成相应的酰卤,这由用卤化剂比如氯化亚砜,在非质子传递溶剂中比如甲苯、二氯甲烷或四氢呋喃于-5~10℃在碱,比如吡啶存在下处理来完成。
中间体酰卤,例如酰氯,可与一式(IIa)的取代苯胺在25~70℃于一非质子溶剂比如四氢呋喃中反应,给出式(III)的酰胺。式(IIa)的化合物市场上可以买到(Aldrich Chemical Company,Milwaukee,WI 53201)。
在步骤2中,式(III)的化合物通过氧化,例如用高锰酸钠和高碘酸钠水溶液在碱条件下于叔丁醇中回流,转化为式(IV)的5-氧代-A-降-3,5-开环雄烷-3-酸衍生物。
在步骤3中,式(IV)的化合物用氨在乙二醇中回流,接着中间体4-氮杂-雄-5-烯-3-酮于乙酸中在60~70℃和40~60psi氢气压力下并在催化剂氧化铂存在下处理而转化成式(V)的4-氮杂-5α-雄烷-3-酮。
反应图II
用另一种方法,在反应式II中,式(I)的化合物可由式(VI)的3-氧代-4-氮杂-5α-雄-1-烯-17β-羧酸(Rasmusson,G.H.et al.,J.Med.Chem.,29,2298(1986)),按照反应式IA步骤1的方法来制备。
本领域的技术人员知道,在制备式(I)化合物或其溶剂化物的早期阶段,必须和/或需要保护分子中一个或多个敏感基团,以便阻止不希望有的副反应。
在式(I)的化合物的制备中使用的保护基团可以是在常规方法中使用的。例如见Protective Groups in Organic Chemistry Ed.J.F.W.McOmie,Plenum Press,London(1973)或Protective Groupsin Organic Synthesis,Theodora Green,John Wiley and Sons,NewYork(1981)。
任何存在的保护基团的去除可通过常规方法达到。芳烷基,比如苄基,可以在催化剂,例如披钯木炭的存在下通过氢解进行除去;酰基,比如N-苄氧羰基可以通过水解作用除掉,例如用乙酸中的溴化氢水解,或者通过还原作用除掉,例如通过催化加氢作用。
如所意识到的,在上述任何一般方法中,如上述的那样保护分子中的任何敏感基团是需要的或者甚至是必须的。因之,在任何上述过程之后,应进行通式(I)或其盐的有保护基的衍生物的脱保护反应步骤。
这样,本发明的另一方面是,如果必须和/或需要的话,在任何一般反应之后的任何合适反应中,可进行下列反应:
(i)任何保护基团的去除;
(ii)式(I)的化合物或其溶剂化物转化成为其药物上可接受的溶剂化物。
上述用来制备本发明的化合物的一般方法不但可用于制备过程中的最后主要步骤,也可用来在制备需要的化合物过程中的中间体阶段引入所需要的基团。因此应正确地估价到,在这种多阶段方法中,选择反应的顺序应使反应条件不致于影响到最终产品所需的分子中存在的基团。
式(I)的化合物和中间体化合物(II)-(VI),如在反应式I和II中所示,可用常规工艺方法纯化,例如色谱法或结晶法。体外试验甾类5α-还原酶
酶活性可用由下列物质衍生的微粒体测定:1)来自良性的前列腺(BPH)病人的前列腺组织;2)重组体杆状病毒感染的表达人1型5α-还原酶的SF9细胞;或者3)重组体杆状病毒感染的表达人2型5α-还原酶的SF9细胞。微粒体是通过组织或细胞的均化,接着由均浆的差速离心制备的。微粒体提取液用各种浓度的[1,2,6,7-3H]-睾酮,1mM NADPH及各种数量的式(I)的化合物,即试验化合物,在含有在0.5~240分钟内能够维持NADPH浓度的NADPH再生系统的缓冲液中来培养。进行不含试验化合物的相应培养作为对照研究。对于无性繁殖系1的IC50测验,试验组分除睾酮外在pH7.0进行预培养10分钟,接着加入100nM睾酮,试验继续进行10~120分钟。对无性繁殖系2的IC50测验,试验组分除睾酮外在pH6.0进行预培养20分钟,接着加入8nM睾酮,试验继续进行20~40分钟。在试验化合物存在下睾酮转化成DHT的百分率与对照研究的相应的转化比较,使用带放射化学检测的高压液相色谱(HPLC)进行估算的。这些试验的结果以IC50列于表1中。3β-羟基-Δ5-甾类脱氢酶/3-酮-Δ5-甾类异构酶
酶活性是使用由人肾上腺组织衍生的微粒体测量的。微粒体经将组织均化,接着将均浆差速离心来制备。微粒体提取液用不同浓度的脱氢表雄酮(DHEA)、1mM NAD+和这种量的式(I)的化合物,即试验化合物,于pH7.5缓冲液中培养1~60分钟。进行无试验化合物的相应培养作为对照研究。在试验化合物存在下,DHEA转化为雄二酮的百分率与对照研究中相应的转化进行比较,使用带放射化学检测的HPLC进行估算。这些试验的结果以Ki值,列于表1。
表15α-还原酶(5AR)和人肾上腺3β-羟基-Δ5-甾类脱氢酶/3
-酮-Δ5-甾类异构酶(3BHSD)在体外的抑制活性
IC50人 IC50人 Ki人肾上腺
1型5AR 2型5AR 3BHSD
<1nM <1nM >1000nM体内甾类5α-还原酶抑制剂的估计
甾类5α-还原酶抑制剂的体内活性可用慢性鼠模型测定(Brooks,J.R.et al.,Steroids,47,1(1986))。慢性模型使用阉割过的雄性鼠,每天用睾酮(20μg/鼠)皮下给药和用待测化合物(0.01~10mg/kg)或者媒介物口服7天。动物然后处死,称量其前列腺。受睾酮刺激的前列腺重量的减少表明了试验化合物的活性。用已知的甾类5α-还原酶抑制剂进行平行测验以保证试验方法的一致性。
本发明的甾类5α-还原酶抑制剂可用于雄激素相关疾病的治疗,例如良性和恶性的前列腺疾病,尤其是良性的前列腺增生,它以类似于其它的5α-还原酶抑制剂比如finasteride和SKF 105657的方式来治疗。然而,本发明的化合物与finasteride和SKF105657相比具有惊人长的半衰期和效力。与体外试验相关的在鼠体内和关于5α-还原酶抑制剂的人体临床数据请见Stoner,E.etal.,J.Steroid Biochem.Molec.Biol.37,375(1990);Brooks,J.R.etal.,Steroids,47,1(1986)和Rasmusson,G.H.et al.,J.Med.Chem.,29,2298(1986)。
本发明的化合物也可用于前列腺炎、前列腺癌、雄激素调节的皮肤病比如痤疮、多毛症和男式秃的治疗。其它有关激素的疾病,例如多囊的卵巢疾病也可用此化合物治疗。
当然,式(I)的化合物作为5α-还原酶抑制剂要求的有效用量将随被治疗的个别哺乳动物而变化,且最终要由医学或兽医的专业人员来决定。要考虑的因素包括疾病的情况、用药方法、配方性质、哺乳动物的体重和表面积、年龄及动物的一般情况。然而,对一个病人来说,适宜的有效5α-还原酶抑制剂量在大约每天每kg体重0.001~2mg范围内,优选每天约0.005~1mg/kg范围内。
每天总的剂量可以单一剂量或多次剂量给药,例如每天2~6次,或者在某一时期内通过静脉注射。在以上引用的范围之外的用量也属于本发明的范围,如果需要和必须的话,可以此用量给个别患者用药。例如对一个重75kg的哺乳动物来说,剂量范围是每天大约0.4mg~75mg,典型剂量是每天约10mg。由于本发明化合物的长的半衰期,对许多病人来说治疗仅需每隔一天或者设置每隔两天进行。如果需要多次剂量,典型治疗为给式(I)的化合物2.5mg,每天4次。
本发明的医用制剂包含一种活性化合物,即式(I)的化合物,其可接受的载体和任意地其它的治疗活性组分。载体必须是药物上可以接受,其意义在于与配方中的其它组分匹配,且对其受体无毒害。
因此,本发明进一步提供了包含式(I)的化合物及其药物可接受的载体的药物制剂。
制剂包括那些适于口腔的、局部的、直肠的或胃肠外的(包括皮下的、肌肉的和静脉的)给药制剂。优选适用于口服或胃肠外的给药。
这些制剂可以方便地以单位剂量形式存在,且可由任何药学技术上已知的方法制备。所有的方法包括把活性化合物与一个由一个或多个辅助组分组成的载体结合的步骤。总之,这些制剂是通过把活性化合物与一液态载体或者精细分配的固体载体均匀紧密地结合起来制备,然后,如果需要,把产品成型为所要的单位剂量形式。
本发明适合口服给药的制剂可制成分开的单元,比如胶囊、扁形囊剂、片剂或者锭剂,每个包含预定量的活性化合物;还可制成粉状或粒状剂;或者在含水液体或非水液体中的悬浮液或溶液,例如糖浆、酏剂、乳状液或饮剂。
片剂可通过压缩或压模制成,任意地带有一个或多个辅助成分。压缩药片可通过在适当的设备里以自由流动状态压缩活性化合物制备,例如粉或粒,任意地混合辅助成分,例如粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂。压模药片可通过在适当的设备里模压粉状的活性化合物与任何适当载体的混合物制备。
糖浆或悬浮液可由把活性化合物加入到浓缩的糖的水溶液中制备,例如蔗糖,其中也可以加入任何辅助成分。这种辅助成分可包括调味剂、阻碍糖结晶的试剂或增加其它成分的溶解性的试剂,例如作为多元醇如甘油或山梨醇。
用于直肠给药的制剂可以是带常规载体的栓剂,例如可可油或Witepsol S55(商标名Dynamite Nobel Chemical,Germany)可用作栓剂载体。
方便地适用于胃肠外给药的制剂包含制备活性化合物的无菌水溶液,此溶液最好与受体血液等渗压。这样,这些制剂可方便地含有蒸馏水、5%葡萄糖水溶液或盐水以及在这些溶剂中是有适宜溶解性的式(I)的化合物。有用的制剂也包括含有式(I)的化合物的浓缩液或固体,一旦用合适溶剂稀释后,便得到适于上述胃肠外给药的溶液。
局部制剂包括软膏、乳膏、凝胶和洗剂,这可由药学技术已知的常规方法制备。除了软膏、乳膏凝胶或洗液基质和活性成分外,这种局部制剂也可含有防腐剂、香料及其它活性药物剂。
除上述成分外,本发明的制剂可进一步地包括一个或多个用于药剂的任选的辅助成分,例如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、悬浮剂、防腐剂(包括抗氧剂)等等。
下述实施例说明了本发明的各方面,但不是对本发明的限制。在这些实施例中使用的符号和惯例与当代化学文献中使用的是一致的,例如美国化学会志(the Journal of the American ChemicalSociety)。
实施例1
17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄-1-烯-3-酮(图I的合成)A.17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-雄-4-烯-3-酮
往3-氧代-4-雄烯-17β-羧酸(Rasmusson,G.H.et al.,J.Med.Chem.,27,1690(1984))(17.2g,54.4mmol)、干燥的THF(180ml)和干燥的吡啶(7ml)的溶液中,在2℃下加入氯化亚砜(5.1ml,70.8mmol)。反应混合物在2℃下搅拌20分钟,然后室温搅拌40分钟。然后过滤反应混合物,固体用甲苯洗。滤液在真空下浓缩为油,用干燥的THF(150ml)和干燥的吡啶(7ml)稀释。往得到的黑色溶液中加入2,5-双-(三氟甲基)苯胺(9.4ml,59.8mmol),反应混合物回流5小时,用二氯甲烷稀释,连续地用1N HCl和盐水萃取,用硫酸钠干燥并过滤。把滤液浓缩并加进到一个含500g的硅胶的柱子,柱子用15-30%的醋酸乙酯-环己烷梯度洗脱,经浓缩后得到17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-雄-4-烯-3-酮,为灰白色的泡沫状物;产量:18.3g(64%)。B.17β-N-2,5-双(三氟甲基)苯基氨基甲酰基-5-氧代-A-降-3,5-开环雄烷-3-酸
往上述A部分中制备的17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-雄-4-烯-3-酮(18.3g,34.9mmol)、叔丁(275ml),碳酸钠(6.3g,50.8mmol)和水(36ml)的回流溶液中,在45分钟内加入高锰酸钾(0.38g,2.4mmol)、高碘酸钠(52.2g,245mmol)和水(311ml)的75℃的溶液。在再回流15分钟后,将此不均一的混合物冷却到室温,加入硅藻土(50g)。通过硅藻土床(50g)过滤反应混合物,固体用水洗,滤液在真空下浓缩以去除叔丁醇(约175ml)。结果得到的水溶液用36%HCl酸化到pH2,并用氯仿萃取4次。合并氯仿层并用水、盐水洗,用硫酸钠干燥后过滤,并在真空下浓缩得到灰白色的17β-N-2,5-双(三氟甲基)苯基氨基甲酰基-5-氧代-A-降-3,5-开环雄烷-3-酸;产量:20.5g(100%,粗产品)。此物质直接应用于如下的步骤C中。C.17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-雄-5-烯-3-酮
往如步骤B中所制备的17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-5-氧代-A-降-3,5-开环雄烷-3-酸(20.5g,34.8mmol)的无水乙二醇(100ml)悬浮液中,于室温下在5分钟内加入氨(约8ml,0.32mol)。得到的溶液在45分钟内加热到180℃,在180℃加热12分钟后,将反应混合物冷却到70℃,在5分钟内加入水(116ml),将得到的悬浮液冷却到7℃,搅拌10分钟,真空过滤。固体用水(60ml)洗,然后溶解于氯仿中并用水、盐水洗,用硫酸钠干燥,过滤并浓缩。残留物溶解在氯仿中,施加于一个110g硅胶的柱子,柱子用2~5%的异丙醇-氯仿梯度洗脱,得到灰白色的17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-雄-5-烯-3-酮,产量:16.5g(90%)。D.17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄烷-3-酮
往17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-雄-5-烯-3-酮(8.9g,16.7mmol)的醋酸(120ml)溶液中加入氧化铂(0.9g)。得到的混合物充氢气到50psi,并在60~70℃加热6小时。用氮气替代氢气后,通过硅藻土过滤反应混合物,硅藻土垫用醋酸(30ml)、氯仿(60ml)、甲苯(200ml)洗。滤液在真空下浓缩成油,加入甲苯(200ml),溶液在真空下浓缩成泡沫状物。此泡沫状物用醋酸乙酯-庚烷结晶,在真空下于85℃干燥1小时后得到17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄烷-3-酮,产量:4.78g(54%);m.p.245~247℃。对C27H32F6N2O2元素分析,计算值:C,61.12;H,6.08;N,5.28。测定值:C,61,13;H,6.12;N,5.21。E.17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄烷-1-烯-3-酮
往17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄烷-3-酮(7.24g,13.7mmol)和2,3-二氯-5,6-二氰基-1,4-苯醌(3.41g,15mmol)的干燥二噁烷(168ml)悬浮液中,在室温下加入双(三甲基-甲硅烷基)三氟乙酰胺(14.5ml,54.6mmol)。在室温搅拌7小时后,将反应混合物回流18小时。得到的黑色溶液冷却到室温并在真空下浓缩成黑色的油。往其它加入二氯甲烷(100ml)和1%的亚硫酸氢钠(40ml),此两相混合物快速搅拌15分钟后,过滤。分离两个滤液层,连续地用2N HCl和盐水洗二氯甲烷层,用硫酸钠干燥,过滤并浓缩成棕色油。此油用甲苯稀释,施加于一个300g硅胶的柱子上,并用12∶3∶1-9∶3∶1的甲苯∶丙酮∶乙酸乙酯梯度洗提,得到泡沫状物17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄-1-烯-3-酮;产量:3.38g(47%)。此物质由醋酸乙酯-庚烷(1∶1)结晶后得出白色固体;m.p.244-245℃。13C NMR(100MHz,CHCl3)δ171.31,166.77,151.04,136.35(q,J=1.4Hz),135.01(q,J=33.1Hz),126.73(q,J=5.4Hz),123.44(q,J=273.5Hz),123.03(q,J=273.2Hz),122.84,121.58(qq,J=30.4,1.0Hz),120.37(q,J=3.6Hz),120.29(q,J=3.9Hz),59.58,58.33,55.69,47.46,44.78,39.30,37.81,35.29,29.34,25.70,24.17,23.59,21.15,13.40,11.91.
C27H30F6N2O2元素分析:计算值:C,61.36;H,5.72;N,5.30。实测值:C,61.36;H,5.73;N,5.23
实施例2
17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄-1-烯-3-酮(反应式II的合成)
将3-氧代-4-氮杂-5α-雄-1-烯-17β羧酸(300g,0.95mol)在9升甲苯中的悬浮液机械搅拌并加热回流,而通过蒸馏1升甲苯被除去。混合物冷却至-2±2℃、并用甲苯(1L)、二甲基甲酰胺(10ml)和吡啶(191ml,2.37mole)稀释。往搅拌着的悬浮液中加入氯化亚砜(135g,1.14mole),保持温度在0℃以下。在0~20℃搅拌2小时后,加入2,5-双(三氟甲基)苯胺(238g,1.04mole)和二甲氨基吡啶(2.0g,0.016mole),混合物在100℃加热15-16小时。冷却至20℃后,甲苯溶液用1N氢氧化钠(2×1L)、盐水(1L),用硫酸镁干燥,过滤。用甲苯(100ml)洗涤固体后溶液在40~50℃(50~100mm)浓缩到体积大约是2L,加入乙腈(2L)混合物如上述进一步浓缩,直到结晶出现。产品浆状物在室温搅拌15~16小时,过滤收集并用2×50ml冷乙腈洗,得到粗产品。此粗产品通过溶解在温热甲醇(2L)中重结晶,接着加入乙腈并常压蒸馏直到得到厚的浆料。浆料在室温搅拌15~16小时,冷却至0~10℃,过滤收集产品,得到17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄-1-烯-3-酮,为白色结晶固体,243g(48%);m.p.245~245.5℃,此熔点与由例1的方法制备的产品的熔点相同。
实施例3药物制剂
“活性化合物”是式(I)的化合物(A)透皮组合物——1000片
成分 数量
活性化合物 40g
聚硅氧烷液体 450g
二氧化硅胶体 25g
聚硅氧烷液体和活性化合物混合在一起,加入二氧化硅胶体是为了提高粘度。此物质然后分布到一个随后热封的由下述物组成的聚合物叠层上:聚酯释放衬里、由聚硅氧烷或丙烯酸聚合物组成的皮肤接触粘合剂、聚烯烃控制膜(例如聚乙烯、聚乙酸二烯酯或聚氨基甲酸乙酯)以及由聚酯多叠层构成的不可渗透背衬膜。将得到的层压片然后切成10sg.cm的小块。(B)口服片剂——成1000片
成分 数量
活性化合物 20g
淀粉 20g
硬脂酸镁 1g
活性化合物和淀粉用水制成粒状,干燥。把硬脂酸镁加入到干燥的颗粒中,将混合物彻底掺合。将掺合好的混合物压成小片。(C)栓剂——或1000栓
成分 数量
活性化合物 25g
可可碱水杨酸钠 250g
Witepsol S55 1725g
非活性成分混合熔化。然后把活性化合物分散到熔化的混合物中,注入模具并冷却。(D)注射液——对1000个安瓿
成分 数量
活性化合物 5g
缓冲剂 适量
丙二醇 400mg
注射用水 600ml
活性化合物和缓冲剂于约50℃℃溶解在丙二醇中。然后加入注射用水,将得到的溶液过滤,装入针剂瓶,密封并通过高压杀菌消毒。(E)胶囊——对1000个胶囊
成分 数量
活性化合物 20g
果糖 450g
硬脂酸镁 5g
精细研磨的活性化合物与果糖和硬脂酸盐混合并封装入凝胶胶囊中。
Claims (9)
1. 17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-5α-雄-1-烯-3-酮或其药物上可接受的溶剂化物。
2.含权利要求1的化合物和其药物上可接受的载体的用于治疗或预防雄性激素相关的或调节的疾病的药物制剂。
3.权利要求1的化合物用于制造治疗和预防雄激素相关的或调节的疾病的药物的用途。
5.按照权利要求4的方法,其中在方法(B)中,式(VI)的化合物在与式(IIa)的化合物反应之前,用卤化剂在碱存在下处理。
6.体外抑制5α-睾酮还原酶的方法,包括使所说的酶与5α-睾酮抑制有效量的权利要求1的化合物接触。
7.权利要求3的用途是制备用于治疗哺乳动物的雄性激素相关的或调节的疾病的药物的用途。
8.按照权利要求7的用途其中雄性激素相关的或调节的疾病是良性的前列腺增生、前列腺癌、痤疮、男式秃和多毛症。
9.中间体17β-N-(2,5-双(三氟甲基))苯基氨基甲酰基-4-氮杂-雄-5烯-3-酮或其溶剂化物。
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