CN1313862A - 新的17-卤代的19-去甲甾醇类,制备方法和中间体,它们作为药物以及含有它们的药物组合物 - Google Patents
新的17-卤代的19-去甲甾醇类,制备方法和中间体,它们作为药物以及含有它们的药物组合物 Download PDFInfo
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- CN1313862A CN1313862A CN99809983A CN99809983A CN1313862A CN 1313862 A CN1313862 A CN 1313862A CN 99809983 A CN99809983 A CN 99809983A CN 99809983 A CN99809983 A CN 99809983A CN 1313862 A CN1313862 A CN 1313862A
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- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
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- Organic Chemistry (AREA)
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Abstract
本发明涉及式(Ⅰ)化合物,特别是其中X=卤素;Y=单键,O,NH,S,SO或SO2;Z=氢或卤素;n,R1,R2,R3和R4在说明书中定义。本发明还涉及用于制备所说化合物的方法和中间体,它们作为药物的用途以及含有它们的药物组合物。
Description
本发明涉及新的17-卤代的19-去甲甾醇类化合物,它们的制备方法和中间体,它们作为药物以及含有它们的药物组合物。
骨质疏松症是一种病理症状,其特征是骨质数量和质量减少,且足以自发地或由于偶然的极小的创伤导致椎骨或外围骨头骨折。虽然造成该病的起因有很多因素,但妇女绝经是构成骨质流失或骨质减少的其主要原因。
骨质减少表现为海绵状骨头构造的稀松和变化,其结果是增加了骨骼的易碎性和骨折的危险。绝经期后由于卵巢功能受到抑制使骨质流失急剧增加,达到每年3-5%,65岁后骨质流失减缓下来。
为了治疗,绝经期后荷尔蒙不足可以通过荷尔蒙补充疗法补充,其中雌激素在保护骨质方面起了主要作用。但是,长期用雌激素治疗有时会伴随产生对生殖器官不需要的副作用(如子宫内膜增生,乳腺癌等),这是该疗法的主要缺点,进而限制的它的使用。
因此,简便的方法是寻找有单纯的雌激素活性的除雌二醇之外的化合物,即该化合物具有保持骨质水平的雌激素活性,但根本没有或没有多少子宫内膜增生活性,也没有乳腺癌增生活性。
R1代表氢原子,(CH2)m-Ar,(CO)-Ar,(CH2)m-Alk或(CO)-Alk基团,
R2代表从含有1-6个碳原子的直链或支链饱和或不饱和烃衍生的基团,
X代表卤原子,
Y代表单键,O,NH,S,SO或SO2,
Z代表氢原子或卤原子,
n等于2,3,4或5,
R3和R4相同或不同,分别代表一个氢原子,(CH2)m′-Ar,(CH2)m′-Het或(CH2)m-Alk基团,或者
R3和R4与跟它们相连的氮原子一起构成芳香族或非芳香族的饱和或不饱和3-15员单环或多环杂环,该单环或多环杂环还任选地含有另外1-3个选自氧、硫和氮的杂原子,并且可以是非取代或取代的,
Ar代表含有6-18个碳原子的碳环芳基;Het代表含有1-9个碳原子和1-5个选自氧、硫和氮的杂原子的饱和或不饱和的芳香族或非芳香族杂环;Alk代表从饱和或不饱和的直链、支链或环状且含有1-12个碳原子的非芳香烃衍生的基团,Ar、Het或Alk基团可以是取代的或未取代的;m和m′代表0,1,2或3,
点划线代表可任选的第二个键,
卤素是指碘、溴、氯或氟。
卤素在4位时,优选为氯或溴。
卤素在17位时,优选为氟。
(CH2)m或(CH2)m′的涵义如下:单键(当m等于0时),CH2,(CH2)2和(CH2)3。
代表含有6-18个碳原子的碳环芳基的术语Ar是指芳香环烃衍生物,如苯基,萘基,菲基,或一个含有一个苯环的稠合的双环或三环烃,如2,3-二氢化茚基,茚基,二氢萘基,四氢萘基或芴基。连接在苯环平面上进行。优选苯基。
术语Het代表一个含有1-9个碳原子和1-5个选自氧、硫和氮的杂原子的饱和或不饱和的芳香族或非芳香族杂环,特别是下列基团:
-杂环单环基团,如噻吩基,呋喃基,吡喃基,吡咯基,咪唑基,吡唑基,吡啶基,吡嗪基,嘧啶基,哒嗪基,噻唑基,噁唑基,呋咱基,吡咯啉基,咪唑啉基,吡唑啉基,噻唑啉基、三唑基、四唑基、
-稠合的杂环,如苯并呋喃基,苯并噻吩基,苯并咪唑基,苯并噻唑基,萘并[2,3-b]噻吩基,噻蒽基,异苯并呋喃基,苯并吡喃基,呫吨基,苯并氧硫杂环己二烯基,吲嗪基,异吲哚基,3H-吲哚基,吲哚基,吲唑基,嘌呤基,喹嗪基,异喹啉基、喹啉基,2,3-二氮杂萘基,1,5-二氮杂萘基,喹喔啉基,喹唑啉基、噌啉基,蝶啶基,咔唑基,β-咔啉基,吖啶基,吩嗪基,吩噻嗪基,吩卓嗪基,二氢吲哚基,异二氢吲哚基,咪唑并吡啶基,咪唑并嘧啶基或由上述定义的单环杂环构成的稠合多环系统,如呋喃并[2,3-b]吡咯或噻吩并[2,3-b]呋喃,或
-饱和杂环,如吡咯烷,哌啶和吗啉。
术语Alk代表一个从饱和或不饱和的直链、支链或环形的非芳香烃衍生的基团,在脂肪烃情况下,代表烷基如甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,正戊基,正己基,2-甲基戊基,2,3-二甲基丁基,正庚基,2-甲基己基,2,2-二甲基戊基,3,3-二甲基戊基,3-乙基戊基,正辛基,2,2-二甲基己基,3,3-二甲基己基,3-甲基-3-乙基戊基,壬基,2,4-二甲基庚基或正癸基;链烯基如乙烯基,丙烯基,异丙烯基,烯丙基,2-甲基烯丙基,丁烯基或异丁烯基;或炔基如乙炔基,丙炔基,炔丙基,丁炔基或异丁炔基;在环形烃基的情况下,代表环烷基如环丙基,环丁基,环戊基,环己基或金刚烷基。
优选的是甲基和乙基。对于CO-Alk,优选COCH3和COEt;而对于CO-Ar,优选苯甲酰基,当m不是0时,(CH2)m-Ar将优选为苄基。
当R3和R4与跟它们相连的氮原子一起构成一个杂环时,特别是任选含有另外的选自氧和氮杂原子的单环或双环杂环,如下列的不饱和杂环:吡咯基,咪唑基,吲哚基,吡啶基,吡嗪基,嘧啶基,哒嗪基,噻唑基,噁唑基,呋咱啉基,吡唑啉基,噻唑啉基,或者更特别地,下列的饱和杂环:
当各种Alk,Ar,Het基团以及R3和R4与它们所带的氮原子形成的杂环被取代时,它们特别地被下列基团取代:卤素即氟,氯,溴或碘;烷氧基,如甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基;烷硫基,如甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基;氨基;烷基氨基,如甲氨基或乙氨基;二烷基氨基,如二甲氨基,二乙氨基,甲基乙基氨基,这些二烷基氨基都可以任选地以氧化形式存在;氨基烷基,如氨基甲基或氨基乙基;二烷基氨基烷基,如二甲基氨基甲基或乙基;二烷基氨基烷氧基,如二甲基氨基乙氧基;任选酰化的羟基;酰基,如乙酰基,丙酰基,丁酰基,苯甲酰基;游离的或酯化的羧基,如烷氧羰基,例如,甲氧羰基或乙氧羰基;氰基;三氟甲基;芳基,如苯基;芳烷基,如苄基,烷基,烯基或炔基,这些基团本身可以任选被上述卤素,烷基,烷氧基,烷硫基,氨基,烷基氨基或二烷基氨基取代。
当然,术语“取代的”表示可以存在一个或多个相同或不同的取代基。例如,当烷基是被一个或多个卤原子取代的甲基时,它尤其可以是CH2Cl,CH2F,CHF2和CF3。
在Het情况下,取代基可以在NH或碳原子的平面上。
当然,R1,R2,R3和R4以及n,m和m′的值是彼此独立的。
本发明自然要扩展到式(Ⅰ)化合物的盐,例如,与无机或有机酸在胺上形成的盐。所说酸可以是下列酸之一:盐酸,氢溴酸,硝酸,硫酸,磷酸,乙酸,甲酸,丙酸,苯甲酸,马来酸,富马酸,琥珀酸,酒石酸,柠檬酸,草酸,乙醛酸,天冬氨酸,链烷磺酸如甲磺酸或乙磺酸,芳基磺酸如苯磺酸或对甲苯磺酸,及芳基羧酸。当式(Ⅰ)化合物含有酸官能团时,本发明还扩展到可任选被取代的碱金属盐、碱土金属盐或铵盐。
本发明更具体的目的是上面定义的通式(Ⅰ)化合物及其加成盐,其中X是在α位的氟原子,而点划线不再代表第二个键(饱和甾醇中的D环)。
本发明的另一更具体的目的是上面定义的通式(Ⅰ)化合物及其加成盐,其中R1是氢原子,R2是甲基,Z可以是氢原子或氯原子,Y代表氧原子,而点划线不再代表第二个键。
本发明的特别具体的目的是上面定义的通式(Ⅰ)化合物及其加成盐,其中:
R3和R4相同或不同,分别代表一个含有1-6个碳原子的烷基,或者
本发明另一特别具体的目的是上面定义的通式(Ⅰ)化合物及其加成盐,其中X是在α位的氟原子,R1是氢原子,R2是甲基,Y是氧原子,Z是氢原子或氯原子,n等于2或3,
R3和R4相同或不同,分别代表一个含有1-6个碳原子的烷基,或者
R3和R4与跟它们相连的氮原子一起构成下列饱和杂环之一:而点划线不再代表第二个键。
最后,本发明的目的是式(Ⅰ)化合物及其与酸形成的加成盐,它们是:
17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌(estra)-1,3,5(10)-三烯-3-醇
17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇盐酸盐
17-α-氟-11-β-[4-[2-(1-二乙氨基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-α-氟-11-β-[4-[2-(1-吡咯烷基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
4-氯-17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-碘-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇
17-α-氟-11-β-[4-[2-(4-甲基-1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-α-氟-11-β-[4-[2-(4-甲基-1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇盐酸盐
17-α-氟-3-甲氧基-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯
17-α-氟-3-甲氧基-11-β-[4-[2-(1-吡咯烷基)乙氧基]苯基]-雌-1,3,5(10)-三烯
17-α-氟-3-甲氧基-11-β-[4-[2-(二乙氨基)乙氧基]苯基]-雌-1,3,5(10)-三烯
11-β-17-氯-11-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇
17-α-氯-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-碘-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇盐酸盐
17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇乳酸盐。
R2和Z定义如上,
或者
a)与肼作用,得到式(Ⅲb)化合物,
b)然后与卤化剂反应,得到式(Ⅰ′b)化合物,当RA代表-Ph-Y-(CH2)n-NR3R4时,它对应于某些式(Ⅰ)化合物,
然后,如果需要或如果必要的话,式(Ⅱ)、(Ⅲa)、(Ⅲb)、(Ⅰ′a)或(Ⅰ′b)化合物以保护或未保护形式,进行下列一个或多个反应:
-保护的OH基团的脱保护,
-OH基团的酰基化/烷基化反应,
-当RA代表-Ph-Y-(CH2)n-Hal或活化的-Ph-Y-(CH2)n-OH基团时,与任选地以盐形式存在的HNR3R4的反应,
-成盐反应。
17-酮还原为醇的按照标准方法进行,尤其是采用硼氢化物如硼氢化钠甲醇或乙醇溶液进行反应,或四氢化铝或四氢化锂进行反应。
这种还原反应尤其可以在17-β位得到醇。
接下来的卤化反应优选用试剂如XSO2C4F9在受阻碱如DBU(二氮杂双环十一烯)存在下进行,其中X优选氟。也可以使用其他本领域技术人员已知的卤化方法。
如果起始物质的羟基在β位,在亲核取代反应中就可以观察到本发明的构型转变。采用这种方法(卤化剂:全氟-1-丁烷磺酰氟(FSO2C4F9))特别可以得到氟在17-β位的式(Ⅰ)或(Ⅰ′a)化合物。
与肼的反应优选在碱如三乙胺存在下进行。接下来进行卤化反应,尤其是与碱性介质中的X2且特别是I2反应。
醇的活化反应是指引入能促进式(Ⅱ)、(Ⅲa)、(Ⅲb)、(Ⅰ′a)或(Ⅰ′b)化合物上的胺HNR3R4进行亲核取代反应的甲磺酸盐、甲苯磺酸盐或三氟甲磺酸盐,其中R3代表-Ph-Y-(CH2)n-OH基团。
从相应的醇生成甲磺酸盐、甲苯磺酸盐或三氟甲磺酸盐的反应在碱如三乙胺存在下进行。根据常规方法对该醇进行的卤原子取代反应也可以事先进行。
保护反应和脱保护反应采用的是本领域技术人员已知的方法。相当完整的综述包括在下列出版物中:《有机合成中的保护基》,T.W.Greene,John Wiley & Sons(1981)。
保护基P(OH→OP)可以代表一个含有1-4个碳原子的烷基,苄基,四氢吡喃基,RCRDRESi基团,其中RC,RD和RE可以相同或不同彼此独立地分别代表含有1-4个碳原子的烷基或苯基。特别具体的例子是Si(Me)2CMe3或-Si(Ph)2CMe3或-SiMe3基团。
例如,当P是四丁基二苯基甲硅烷基时,脱保护反应(OP→3位的OH)可以通过与四丁基氟化铵在四氢呋喃溶液中反应而进行。当P代表SO2C4F9时可以在氟化反应之后进行同样的反应。
当P是四氢吡喃基时,脱保护反应在酸水溶液存在下在醇溶剂中进行,优选在盐酸的甲醇溶液中进行。
式R3R4NH与式(Ⅱ)、(Ⅲa)、(Ⅲb)、(Ⅰ′a)或(Ⅰ′b)化合物胺的反应,其中R2代表-Ph-Y-(CH2)n-OH或-Ph-Y-(CH2)n-Hal基团,在适于亲核取代反应的标准条件下进行,特别是在非质子溶剂如四氢呋喃存在下进行。如果OH是活化的,则其特别优选是OSO2CH3,OSO2-Ph-pMe,OSO2CPh3。
3位OH基的烷基化或酰基化反应以及成盐反应按照本领域技术人员已知的标准方法进行。
通式(Ⅰ)化合物及其与可药用酸形成的加成盐尤其具有雌激素、抗雌激素和抗增生活性。
因此,本发明的式(Ⅰ)化合物可用于治疗与雌酮(激素)减退有关的疾病,如闭经,痛经,反复流产,经前疾病,用于治疗某些雌激素依赖型的病理疾病,如前列腺瘤或前列腺癌,乳腺癌和这些癌症的转移,或作为抗子宫营养剂治疗良性乳腺肿瘤,以及用于绝经期或绝经期前后的补充治疗。
在与绝经有关的症状和表现中特别具体的现象是热潮红,出汗,阴道萎缩和干燥,泌尿系统症状,以及骨质长期减少和骨折危险的增加,及雌激素提供的心血管保护的损失。
尤其是,式(Ⅰ)化合物及其与可药用酸或碱形成的加成盐可用于预防或治疗骨质疏松。
式(Ⅰ)化合物及其与可药用酸或碱形成的加成盐还可以用于预防或治疗人类的骨质疏松。
它们还可以用于预防或治疗第二类骨质疏松(如可的松型骨质疏松(cortisonal)或与不活动(immobilisation)相关的骨质疏松)。
式(Ⅰ)化合物及其与可药用酸或碱形成的加成盐尤其具有单纯的(dissociée)雌激素活性。
所谓单纯雌激素活性是指在骨质水平上具有雌激素活性,而在尿水平上只有最小的活性。因此不会造成子宫内膜增生(比雌二醇的活性低得多)。
而且,本发明化合物具有以下优点;
-它们在乳房水平上具有抗雌激素和/或抗增生活性。不同于雌二醇,本化合物不刺激人体乳房肿瘤细胞的生长,甚至可以抑制它们的生长。因此,本发明化合物对治疗有患乳腺癌风险(根据家族病史)的绝经期妇女特别有效,因此排除了使用雌二醇作补充治疗。
它们还可以用于治疗乳腺癌。
-它们使血清胆固醇含量降低到雌二醇所能达到的同等水平。因此,它们加强了心血管保护。
-最后,由于本发明化合物在泌尿系统水平上没有雌激素活性,它们不需要与拟孕酮类化合物联合给药。
因此,本发明的一个目的是用作药物的式(Ⅰ)化合物及其与可药用酸或碱形成的加成盐。
本发明更具体的目的是式(Ⅰ)化合物及其与可药用酸或碱形成的加成盐用作预防或治疗骨质疏松的药物。
本发明还涉及含有至少一种上述药物作为活性成分的药物组合物。
式(Ⅰ)化合物可通过消化道、非肠胃或局部途径给药,例如,经皮下给药。可以用常用方法将它们制成裸片或包衣片剂,明胶胶囊,颗粒,栓剂,子宫托,注射剂,软膏,乳膏,凝胶,微球,植入物,阴道内环,贴剂等形式。
可以将一种或多种活性成分与常用于这种药物组合物的赋形剂进行混合,所说赋形剂包括如滑石,阿拉伯胶,乳糖,淀粉,硬脂酸镁,椰子油,水性或非水性载体,动物或植物的脂肪物质,石蜡衍生物,二元醇,各种润湿剂、分散剂或乳化剂,防腐剂。
使用剂量根据所要治疗疾病和给药途径而变化,例如,对于成年人口服给药,剂量可以在为1-1000mg/天的范围内变化。
本发明的另一个目的是上述式(Ⅰ)化合物在用于制备涉及绝经期或绝经期前后进行荷尔蒙补充治疗药物的用途,该药物在泌尿系统几乎没有或根本没有活性,更具体地说,其特征在于该药物旨在预防或治疗骨质疏松。
式(Ⅱ)或(Ⅲa)化合物是本领域技术人员已知的或容易获得的。具体来说,Z=H,R2=Me和RA=-Ph-Y-(CH2)n-Hal的式(Ⅱ)化合物在国际专利申请WO 93/13123中(式Ⅱ化合物)有所论述;Z=H,R2=Me和RA=-Ph-Y-(CH2)n-OH的式(Ⅱ)化合物在欧洲专利0305242 B1中(式Ⅲ化合物)有所论述;Z=H,R2=Me和RA=-Ph-Y-(CH2)n-NR3R4的式(Ⅱ)化合物在欧洲专利0097572,法国补充证书2640977或欧洲专利0305242中有所论述。
其中Z代表一个卤原子的式(Ⅱ)化合物在国际专利申请WO9845316中有所论述,而且可以这样制备:从式(Ⅳ)化合物,通过与卤化剂作用得到式(Ⅴ)化合物,式(Ⅴ)化合物经过环A的芳构化剂的作用,然后与碱作用,得到其中Z代表卤原子的式(Ⅱ)化合物。
卤化剂如N-溴琥珀酰亚胺或N-氯琥珀酰亚胺与式(Ⅳ)化合物的作用具体是在偶极的非质子溶剂如二甲基甲酰胺存在下进行的。
皂化反应(碱作用)之前的芳构化反应是根据欧洲专利0097572所述标准方法进行的。优选用乙酸酐和乙酰溴混合物作芳构化剂,然后用碱如苏打的甲醇(溶液)作皂化剂。
本发明的另-个目的是式(Ⅰ′a),(Ⅲb)和(Ⅰ′b)的化合物作为中间产物。
下列实施例用以说明本发明而非限制它。
实施例中所述的溶剂分别为AcOEt(乙酸乙酯),TEA(三乙胺),CH2Cl2(二氯甲烷),CHCl3(氯仿),MeOH(甲醇),NH4OH(氢氧化铵),iPrOH(异丙醇)。
实施例1:17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
步骤A:还原反应
11-β-[4-(2-碘乙氧基)苯基]-雌-1,3,5(10)-三烯-3,17-β-二醇
于0℃将76mg硼氢化钠加到根据WO 93/13123所述方法制备的516mg 3-羟基-11-β-[4-(2-碘乙氧基)苯基]-雌-1,3,5(10)-三烯-17-酮的5ml MeOH和5ml THF的溶液中,在此温度搅拌5分钟,然后在室温搅拌1.5小时。加入20ml 0.1N HCl后观察结晶情况。得到460mg预期产物。Rf AcOEt/TEA 95/5=0.67NMR(CDCl3,300MHz)7.01和6.61(4H,2d,芳香烃11位的H);6.79(1H,d,H1);6.68(1H,d,H4);6.51(1H,dd,H2);4.11(2H,t,CH2O);3.94(1H,bt,H11));3.72(1H,bt,H17);3.33(2H,t,CH2I);0.37(3H,s,18-Me)。
步骤B:氟化反应
17-α-氟-11-β-[4-(2-碘乙氧基)苯基]-雌-1,3,5(10)-三烯-3-醇九氟丁磺酸盐
0℃和氮气下先后将0.45ml DBU和0.20ml全氟-1-丁烷磺酰氟(FSO2C4F9)加到步骤A制备的518mg甾醇的5ml甲苯和1ml二氯甲烷悬浮液中,并将所得溶液在室温保持30分钟。将反应物倒入20ml水中,用乙酸乙酯萃取,洗涤,干燥并减压蒸发,得到565mg粗产物。将其在Lichrosorb RP18上进行色谱纯化,用乙腈/水(85/15)混合物洗脱,得到350mg预期产物。Rf CH3CN/H2O 85/15=0.47在LKCl8F上(Whatman)M.p.=110℃NMR(CDCl3,250MHz)7.00(2H,m,H1和H4);6.93和6.63(4H,2d,AA′BB′,芳香烃11位的H);6.82(1H,dd,H2);4.44(1H,dd,J1=55.5Hz J2=5Hz,H17);4.14(2H,t,CH2O);4.03(1H,m,H11);3.35(2H,t,CH2I);0.23(3H,d,J=2Hz,CH3)。
步骤C:引入胺后进行脱保护
将0.4ml哌啶加到上步制备的甾醇的3ml THF溶液中,然后将反应物回流2小时,冷却后倒入10ml水中,用乙酸乙酯萃取,洗涤,干燥并减压蒸发,得到320mg粗产物。将其溶解于30ml THF,加入2ml四丁基氟化铵,然后加热回流7小时。冷却后将反应物倒入20ml碳酸氢钠饱和水溶液中,用乙酸乙酯萃取,洗涤,干燥并减压蒸发,得到405mg粗产物。将其在硅胶上进行色谱纯化,用AcOEt/TEA(95/5)混合物洗脱,得到160mg预期产物。Rf AcOEt/TEA 95/5 0.31在Merck的SiO2F254上。NMR(CDCl3 300MHz)6.95和6.48(4H,2d,AA′BB′,芳香烃11位的H);6.79(1H,d,H1);6.48(1H,d,H4);6.39(1H,dd,H2);4.44(1H,dd,J=56Hz和5Hz,H17);3.99(1H,bt,H11);4.26和3.99(2H,2m,CH2O),1.65和1.46(6H,m,哌啶γ和β位的CH2);1.20 to 3.20(20H,m骨架H+CH2N和哌啶α位的CH2);0.22(3H,d,J=2Hz,CH3)。IR(CHCl3)-OH 3597cm-1+缔合的-芳香烃1608,1582,1512,1503cm-1
实施例2:17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇盐酸盐
将2ml 4N HCl的乙酸乙酯溶液加到于0-+5℃的实施例1制备的氟化物的10ml乙酸乙酯溶液中,并观察结晶情况。得到1.6g白色晶体。Rf AcOEt/TEA 95/5=0.21在Merck的SiO2F254上。M.p.=216℃NMR(CDCl3 300MHz)6.95和6.43(4H,2d,AA′BB′,芳香烃11位的H);6.79(1H,d,H1);6.66(1H,d,H4);6.59(1H,dd,H2)4.43(1H,dd,J=56Hz和5Hz,H17);3.99(1H,bt,H11);4.26和3.87(2H,2m,CH2O);3.48(流动的1H,NH+);2.8 to 3.25(2H,m,CH2N+);0.22(3H,d,J=2Hz,CH3).IR(CHCl3)-OH 3598cm-1+缔合的-NH+吸收-芳香烃1610,1582,1512cm-1
实施例3:17-α-氟-11-β-[4-[2-(1-二乙氨基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
按照实施例1所述进行制备,但用二乙胺代替步骤C的哌啶,得到0.141g预期产物。Rf AcOEt/Et3N 99/1=0.15在Merck的SiO2F254上。NMR(CDCl3 300MHz)0.24(d,18位的CH3);1.05(t,CH3CH2N);2.64(q,CH3CH2N);2.83(t,O-CH2-CH2N);3.95(t,CH2O);4.00(bt,H11);4.44(dd,J=56Hz和5Hz,H17);6.32(d,H1),6.38(dd,H2);6.53(d,H4);6.57和6.96(AA′BB″,芳香烃11位的H);
实施例4:17-α-氟-11-β-[4-[2-(1-吡咯烷基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
按照实施例1所述进行制备,但用吡咯烷代替步骤C的哌啶,得到0.049g预期产物。Rf AcOEt/ET3N 95/5=0.18在Merck的SiO2F254上。NMR(CDCl3 300MHz)0.28(d,18位的CH3);2.70(m,吡咯烷);3.03(t,CH2N);3.98(t,CH2O);4.45(dd,H17):6.37(dd,H2);6.41(d,H4);6.50和6.96(AA′BB′,芳香烃11位的H);6.78(d,H1)
实施例5:4-氯-17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
步骤A:3-羟基-4-氯-3-[[二甲基(2,2-二甲基)乙基)甲硅烷基]氧基]-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-酮的保护
将1.3g叔丁基二甲基甲硅烷基氯加到4-氯-3-羟基-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-酮的30mlCH2Cl2溶液中,该酮化合物由NCS作用于相应的Δ4-5 9-10,3-酮衍生物,然后进行A环的芳构化反应而制得,并将反应物冷却到0℃,然后滴加1.13ml TEA。在0℃经5分钟后将反应物放至室温,并保持3小时,然后倒入100ml水中。干燥后减压蒸除有机相,得到4.55g粗产物。将其在硅胶上进行色谱纯化,用AcOEt/TEA(98/2)混合物洗脱,得到2.68g预期产物。Rf AcOEt/TEA 90/10=0.58在Merck的SiO2F254上。IR(CHCl3)C=O 1733cm-1芳香烃C-H 2936-2859cm-1
步骤B:还原反应
4-氯-3-[[二甲基-(2,2-二甲基乙基)甲硅烷基]氧基]-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-17-β-醇
将189mg NaBH4加到在冰浴中冷却的上步制备的甾醇的15ml甲醇溶液中,并在0-5℃搅拌5分钟,然后在室温搅拌30分钟。将反应物倒入100ml水中,用乙酸乙酯萃取,洗涤,干燥并减压蒸发,得到1.5g预期产物。Rf AcOEt/TEA 90/10=0.40在Merck的SiO2F254上。
步骤C:氟化然后脱保护
-氟化
在氮气和室温下将0.90ml DBU和0.04ml全氟丁磺酰氟加到上步制备的596mg甾醇的5ml甲苯和1ml CH2Cl2溶液中,然后将反应物搅拌2小时。倒入20ml水中,用二氯甲烷萃取,洗涤,干燥并减压蒸发,得到1.23g粗产物。将其在硅胶上进行色谱纯化,用AcOEt/TEA(98/2)混合物洗脱,分离出0.6g在3位保护的氟化产物。
-脱保护
将2ml Bu4NF加到上述氟化产物的3ml THF溶液中,然后加热回流4小时,冷却后倒入20ml水中。用二氯甲烷萃取,洗涤,干燥并减压蒸发,直到得到干的萃取物。将其在Lichrosorb RP18上进行色谱纯化,用MeOH/H2O/TEA(90/9/1)混合物洗脱,得到65mg预期产物。Rf MeOH H2O/TEA 90/9/1=0.23在LKC18F上(Whatman)NMR(CDCl3 300MHZ)6.91和6.61(4H,2d,芳香烃11位的H);6.80(1H,d,H1);6.61(1H,d,H2);4.34(1H,dd,J=5Hz和55.5Hz,H17);3.98(1H,被掩蔽的,H11);3.98(2H,t,CH2O);2.70(2H,t,CH2N);2.47(4H,m,哌啶N的α位的2CH2);1.58(4H,m,哌啶N的β位的2CH2);1.44(2H,m,哌啶N的γ位的1CH2);0.22(3H,d,J=2.5Hz,18-Me)。IR(CHCl3)OH 3537cm-1芳香烃1608,1581,1512cm-1
按照上述实施例所述方法制备以下产物:
实施例6:17-碘-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇Rf:0.33(AcOEt-TEA 90-10)。IR(CHCl3)OH:3600cm-1;芳香烃:1609,1580,1512cm-1。NMR(CDCl3,300MHz)0.46:(s,18位的CH3);3.95:(m,CH2O和H11);6.11:(H16);6.36:(dd,H2);6.44:(d,H4);6.71:(d,H1);≈6.50-≈6.94:(11位的芳香烃)。
实施例7:17-α-氟-11-β-[4-[2-(4-甲基-1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇Rf:0.22(AcOEt-TEA 99-1)。IR(CHCl3)OH:3599cm-1;芳香烃:1610,1581,1512(F)cm-1。NMR(CDCl3,300MHz)0.26:(s,18位的CH3);0.90:(d,哌啶基4位的CH3);≈3.97:(m,CH2O和H11);4.43:(dd,H17);6.38:(dd,H2);6.46:(d,H4);6.80:(d,H1);≈6.50-≈6.95:(11位的芳香烃)。
实施例8:17-α-氟-11-β-[4-[2-(4-甲基-1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇盐酸盐M.p.=200℃Rf:0.15(AcOEt-TEA 99-1)。NMR(DMSO,300MHz)0.16:(s,18位的CH3);0.90:(d,哌啶基4位的CH3);3.98:(bs,H11);4.25:(bs,CH2O);4.45:(dd,H17);6.31:(dd,H2);6.48:(d,J=2H4);6.71:(d,H1);6.71-7.02:(11位的芳香烃);8.97(s,3位的OH)。
实施例9:17-α-氟-3-甲氧基-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯Rf:0.23(MeOH-H2O-TEA 94-5-1)。IR(CHCl3)不存在OH;芳香烃:1610,1578,1512 1501cm-1。NMR(CDCl3,300MHz)0.22:(s,芳香烃18位的CH3);1.58:(m)and 2.47(m):哌啶;2.70:(t,CH2-N):3.73:(s,CH3-O);3.98:(t,CH2O);4.43:(dd,H17);6.50:(dd,H2);6.64:(bs,H4);6.88:(d,H1);≈6.62-≈6.97:(11位的芳香烃)。
实施例10:17-α-氟-3-甲氧基-11-β-[4-[2-(1-吡咯烷基)乙氧基]苯基]-雌-1,3,5(10)-三烯M.p.=132℃。Rf:0.21(MeOH-H2O-TEA 94-5-1)。IR(CHCl3)芳香烃:1610,1578,1512 1501cm-1。NMR(CDCl3,300MHz)0.22:(s,18位的CH3);1.78:(m)和2.58(m):pyrrolidine;2.83:(t,CH2-N):3.73:(s,CH3-O);3.99:(t,CH2O);4.43:(dd,H17);6.50:(dd,H2);≈6.65:(H4);6.89:(d,H1);≈6.64-≈6.97:(11位的芳香烃)。
实施例11:17-α-氟-3-甲氧基-11-β-[4-[2-(二乙氨基)乙氧基]苯基]-雌-1,3,5(10)-三烯Rf:0.20(MeOH-H2O-TEA 94-5-1)。IR(CHCl3)芳香烃:1610,1578,1512 1501cm-1。NMR(CDCl3,300MHz)0.22:(s,18位的CH3);1.04:(t)和2.61(q):N-Et2;2.82:(t,CH2-N):3.73:(s,CH3-O);3.94:(t,CH2O);4.43:(dd,H17);6.49:(dd,H2);6.64:(d,H4);6.88:(d,H1);≈6.62-≈6.96:(11位的芳香烃)。
实施例12:11-β-17-氯-11-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇Rf:0.25(CH2Cl2-MeOH-NH4OH 95-5-0.5)。NMR(CDCl3,300MHz)0.60:(s,18位的CH3);≈4.01:(m,CH2O和H11);5.60:(bd,H16);6.38:(dd,H2);6.45:(d,H4);6.70:(d,H1);≈6.50-≈6.93:(11位的芳香烃)。
实施例13:17-α-氯-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇Rf:0.10(CH2Cl2-MeOH-NH4OH 94-5-0.1)。NMR(CDCl3,300MHz)0.41:(s,18位的CH3);≈3.98:(m,CH2O和H11和H17);6.39:(dd,H2);6.48:(H4);6.79:(d,H1);≈6.48-≈6.94:(11位的芳香烃)。
实施例14:17-碘-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇盐酸盐M.p.=260℃。Rf:0.33(AcOEt-TEA 90-10)。NMR(DMSO,300MHz)0.29:(s,18位的CH3);4.02:(bt,H11);4.25:(bs,CH2O);6.15:(bs,H16);6.29:(dd,H2);6.48:(d,H4);6.64:(d,H1);≈6.73-≈7.01:(11位的芳香烃);8.94≈9.78:流动的H。
实施例15:17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇乳酸盐M.p.=138℃。NMR(CDCl3,300MHz)0.22:(d,18位的CH3);≈3.15;(CH2N);≈3.94:(m,CH2-O);≈3.98:(m,H11);4.43:(dd,H17);6.42:(dd,H2);6.78:(d,H1);≈6.48-≈6.97:(11位的芳香烃);1.36(d)和4.09(m):乳酸根。药物试验对乳房细胞增生的作用
在培养物中的MCF-7人体乳房细胞上进行本发明化合物的增生活性的研究,与雌二醇的增生活性进行比较。
为了证明雌二醇和/或试验化合物的拮抗作用,用空培养液,即无甾醇(补充了5%无甾醇血清,且没有酚红的DMEM,)培养液替代细胞维持的培养液(富含生长因子和甾醇)。正式试验前将细胞隔离(sevrage)2天。
在存在有要研究物质的培养物中培养7天后,通过测定DNA来评价细胞增生情况。在各试验中,10-10M的雌二醇的效果(雌二醇存在下细胞的生长不如溶剂存在下的细胞生长)定义为100%拮抗活性。本化合物的活性与此内部对照组进行对比。与只用溶剂观察到的细胞生长产生相同效果的化合物称为“无活性”,而使细胞生长低于只用溶剂所产生效果的化合物称为“抑制剂”。
活性 | |
雌二醇 | 拮抗剂 |
实施例1 | 无活性 |
实施例2 | 无活性 |
在切除了卵巢的3月龄雌大鼠身上进行本产品对骨头作用的研究
为了测定本发明化合物对骨质以及其形成和吸收活性的作用,在切除了卵巢的3月龄雌大鼠身上试验本化合物。动物都经过预防性处理。
动物:
种类 大鼠
品种 Sprague-Dawley
性别 雌性
体重 250-280g
动物分组编号 8
产品:
1受试产品:实施例1化合物
*载体:玉米油,0.5%甲基纤维素
*给药次数:一次/天;5天/周,共4周
*给药途径:口服该化合物
*体积:5ml/kg(p.o.)
*最后一次注射与处死之间的时间间隔:24小时
*给药次数:20
2参考化合物:17β雌二醇(玉米油/苄醇(99∶1)混合溶液中)按0.1或0.01mg/kg/每天的剂量和0.2ml/kg的体积经皮下方式给药。实验方案动物
在切除了卵巢的3月龄雌鼠身上进行研究。将动物放在空调房间中(温度20±2℃),分成4组放在盒子中。给动物随意喂食软化水和压缩食品(丸:A04CR-10 UAR)。手术
在用Imalgene 1000的麻醉条件下以100mg/kg的剂量和1ml/kg的体积,将体重约250g的3月龄雌鼠的卵巢切除。给雌大鼠腹膜内(i.p.)注射3mg/kg i.p.,体积为0.3ml/kg的Nembutal。
侧切开后将皮和肌肉剖开。结扎输卵管后切除各卵巢。
在同样条件下将“SHAM”对照组的大鼠麻醉。剖开皮和肌肉后,露出各卵巢,然后当场取下。处理
测定在预防性处理中本化合物的作用。卵巢切除术后立即进行给药。动物被分成8个组。
第1组:接受一种或多种载体的“SHAM”对照组大鼠
第2组:接受一种或多种载体的“OVX”对照组大鼠
第X组:分别接受限定剂量的一种或多种试验产品的“OVX”大鼠血样
在4周(研究期)结束时用断头机将动物斩首。离心后收集血清,并放在-20℃保存。
通过对500μl等分血清进行总胆固醇、甘油三酯和磷脂测定建立脂平衡。血清胆固醇水平的降低用相对于仅接受溶剂的卵巢切除动物的血清胆固醇水平的%表示。器官样品
处死动物后取出以下器官:-生殖道
取下子宫称重。其重量的增加表示为仅接受溶剂的卵巢切除动物的子宫重量的%。-骨质水平
用双光子倍能X射线吸收谱仪(DEXA)测量骨质(BMD,即骨矿物密度)。测量在切除和清理了所有软组织的骨头上进行。测量整个骨头和左胫骨接近顶端的干骺端部分的骨矿物密度。这个区域被确定是最富含小梁骨,因而对骨体积和骨矿物密度变化最敏感。
根据下式将结果表示为%形式:
剂量(mg/kg)给药途径 | 胫骨BMD% | 子宫重量% | 胆固醇% | |
OVX | 0 | |||
SHAM | 100 | |||
胆固醇 | 0.1sc | 139 | 220 | -3 |
实施例1 | 0.3po | 73 | 41 | -51 |
雌二醇 | 0.01sc | 95 | 317 | -16 |
实施例1 | O.1po0.3po1.0po | 577172 | 677093 | -49-59-61 |
Claims (17)
R1代表氢原子,(CH2)m-Ar,(CO)-Ar,(CH2)m-Alk或(CO)-Alk基团,
R2代表从含有1-6个碳原子的直链或支链饱和或不饱和烃衍生的基团,
X代表卤原子,
Y代表单键,O,NH,S,SO或SO2,
Z代表氢原子或卤原子,
n等于2,3,4或5,
R3和R4相同或不同,分别代表氢原子,(CH2)m′-Ar,(CH2)m′-Het或(CH2)m′-Alk基团,或者
R3和R4与跟它们相连的氮原子一起构成芳香族或非芳香族饱和或不饱和3-15员单环或多环杂环,其任选地含有另外1-3个选自氧、硫和氮的杂原子,并且可以是非取代或取代的,
Ar代表含有6-18个碳原子的碳环芳基;Het代表含有1-9个碳原子和1-5个选自氧、硫和氮的杂原子的饱和或不饱和的芳香族或非芳香族杂环;Alk代表从饱和或不饱和的直链、支链或环状且含有1-12个碳原子的非芳香烃衍生的基团,Ar、Het或Alk基团可以是取代的或未取代的;m和m′代表0,1,2或3,
点划线代表可任选的第二个键。
2.权利要求1所定义的通式(Ⅰ)化合物及其加成盐,其中X是α位的氟原子,而点划线不再代表第二个键。
3.权利要求1或2所定义的通式(Ⅰ)化合物及其加成盐,其中R1是氢原子,R2是甲基,Z是氢原子或氯原子,Y代表氧原子,而点划线不再代表第二个键。
4.权利要求1-3任一所定义的通式(Ⅰ)化合物及其加成盐,其中:
R3和R4相同或不同,分别代表含有1-6个碳原子的烷基,或者
R3和R4与跟它们相连的氮原子一起构成下列饱和杂环之一:
6.根据权利要求1-5任一的化合物,它们的名称为:
17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇盐酸盐
17-α-氟-11-β-[4-[2-(1-二乙氨基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-α-氟-11-β-[4-[2-(1-吡咯烷基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
4-氯-17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-碘-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇
17-α-氟-11-β-[4-[2-(4-甲基-1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-α-氟-11-β-[4-[2-(4-甲基-1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇盐酸盐
17-α-氟-3-甲氧基-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯
17-α-氟-3-甲氧基-11-β-[4-[2-(1-吡咯烷基)乙氧基]苯基]-雌-1,3,5(10)-三烯
17-α-氟-3-甲氧基-11-β-[4-[2-(二乙氨基)乙氧基]苯基]-雌-1,3,5(10)-三烯
11-β-17-氯-11-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇
17-α-氯-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇
17-碘-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10),16-四烯-3-醇盐酸盐
17-α-氟-11-β-[4-[2-(1-哌啶基)乙氧基]苯基]-雌-1,3,5(10)-三烯-3-醇乳酸盐。
R2和Z定义如上,
如果合适的话,经过OH官能团保护和/或活化之后,进行以下反应:
或者
然后,如果需要或如果必要,式(Ⅱ)、(Ⅲa)、(Ⅲb)、(Ⅰ′a)或(Ⅰ′b)化合物以保护或未保护形式,进行一个或多个下列反应:
-保护的OH基团的脱保护,
-OH基团的酰基化/烷基化反应,
-当RA代表-Ph-Y-(CH2)n-Hal或活化的-Ph-Y-(CH2)n-OH基团时,与任选地是盐形式的HNR3R4作用,
-成盐反应。
8.根据权利要求7的制备权利要求2所定义的通式(Ⅰ)化合物的方法,其中X代表17α位的氟原子,而点划线不再代表第二个键,其特征在于卤化剂是全氟-1-丁磺酰氟(FSO2C4F9)。
9.权利要求1所定义的式(Ⅰ)化合物及其与可药用酸或碱形成的加成盐作为药物。
10.权利要求2-5任一所定义的式(Ⅰ)化合物及其与可药用酸形成的加成盐作为药物。
11.权利要求6所定义的化合物及其与可药用酸形成的加成盐作为药物。
12.含有一种或多种权利要求9,10或11任一所定义的药物的药物组合物。
13.权利要求7或8所定义的通式(Ⅰ′a),(Ⅲb)或(Ⅰ′b)化合物作为新的中间产物。
14.权利要求1-6所定义的式(Ⅰ)化合物在制备用作绝经期或绝经期前后替代荷尔蒙治疗的药物中的用途,所说药物在泌尿系统水平上几乎没有或根本没有雌激素活性。
15.根据权利要求14的用途,其特征在于该药物用于预防或治疗骨质疏松。
16.权利要求11所定义的药物,用于预防或治疗骨质疏松。
17.权利要求11所定义的药物,用于心血管保护。
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FR9807898A FR2780060B1 (fr) | 1998-06-23 | 1998-06-23 | Nouveaux 19-nor steroides 17-halogenes, procede et intermediaires de preparation, application comme medicaments et compositions pharmaceutiques les renfermant |
FR98/07898 | 1998-06-23 |
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CN1313862A true CN1313862A (zh) | 2001-09-19 |
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CN99809983A Pending CN1313862A (zh) | 1998-06-23 | 1999-06-22 | 新的17-卤代的19-去甲甾醇类,制备方法和中间体,它们作为药物以及含有它们的药物组合物 |
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US (2) | US6423700B1 (zh) |
EP (1) | EP1090027B1 (zh) |
JP (1) | JP4509380B2 (zh) |
KR (1) | KR20010034919A (zh) |
CN (1) | CN1313862A (zh) |
AP (1) | AP1579A (zh) |
AR (1) | AR018916A1 (zh) |
AT (1) | ATE237628T1 (zh) |
AU (1) | AU771369B2 (zh) |
BR (1) | BR9912206A (zh) |
CA (1) | CA2336167A1 (zh) |
CZ (1) | CZ296246B6 (zh) |
DE (1) | DE69906972T2 (zh) |
DK (1) | DK1090027T3 (zh) |
DZ (1) | DZ2827A1 (zh) |
EA (1) | EA003325B1 (zh) |
ES (1) | ES2196879T3 (zh) |
FR (1) | FR2780060B1 (zh) |
HK (1) | HK1039945A1 (zh) |
HR (1) | HRP20000893A2 (zh) |
HU (1) | HUP0103194A3 (zh) |
ID (1) | ID27410A (zh) |
IL (1) | IL140416A (zh) |
MA (1) | MA26656A1 (zh) |
MY (1) | MY118101A (zh) |
NO (1) | NO318381B1 (zh) |
NZ (1) | NZ508535A (zh) |
PL (1) | PL345073A1 (zh) |
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FR2854402B1 (fr) * | 2003-04-29 | 2008-07-04 | Aventis Pharma Sa | Nouveau procede et intermediaires de preparation de composes 19-nor-steroides |
FR2854403B1 (fr) * | 2003-04-29 | 2008-07-11 | Aventis Pharma Sa | Nouveau procede et intermediaires de preparation de composes 19-nor-steroides 17-halogenes |
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US3079408A (en) * | 1963-02-26 | Ig-bisoxygenated iy-haloestra- | ||
US3264327A (en) * | 1962-07-27 | 1966-08-02 | Syntex Corp | 17alpha-fluoro-, 17beta-chlorofluoroacetoxy- and 17beta-methyl-delta4-and delta5-androstene derivatives |
US3413321A (en) * | 1966-06-03 | 1968-11-26 | Du Pont | Selected 17-fluoro-delta16 steroids |
FR2528434B1 (fr) * | 1982-06-11 | 1985-07-19 | Roussel Uclaf | Nouveaux 19-nor steroides substitues en 11b et eventuellement en 2, leur procede de preparation et leur application comme medicament |
FR2640977A2 (en) * | 1982-06-11 | 1990-06-29 | Roussel Uclaf | New position-11 substituted 19-norsteroids and their application as medicinal products. |
FR2685332A1 (fr) * | 1991-12-20 | 1993-06-25 | Roussel Uclaf | Nouveaux 19-nor sterouides ayant en position 11beta une chaine thiocarbonee, leur procede de preparation et les intermediaires et leur application a titre de medicaments. |
FR2757519B1 (fr) * | 1996-12-23 | 1999-06-11 | Hoechst Marion Roussel Inc | Steroides substitues en position 11, leur procede de preparation, leur application comme medicament et les compositions pharmaceutiques les renfermant |
FR2761992B1 (fr) * | 1997-04-09 | 1999-06-11 | Hoechst Marion Roussel Inc | Nouveaux steroides 4-halogenes, leur procede et intermediaires de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant |
FR2771096B1 (fr) * | 1997-11-17 | 2000-08-11 | Hoechst Marion Roussel Inc | Nouveaux 19-nor steroides, substitues en position 11beta, procede et intermediaires de preparation, application comme medicaments et compositions pharmaceutiques les renfermant |
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