CN1111988A - 取代的芳族甾类化合物控制生育力的用途及其药物组合物 - Google Patents
取代的芳族甾类化合物控制生育力的用途及其药物组合物 Download PDFInfo
- Publication number
- CN1111988A CN1111988A CN95103086A CN95103086A CN1111988A CN 1111988 A CN1111988 A CN 1111988A CN 95103086 A CN95103086 A CN 95103086A CN 95103086 A CN95103086 A CN 95103086A CN 1111988 A CN1111988 A CN 1111988A
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- CN
- China
- Prior art keywords
- triolefin
- ethyoxyl
- female steroid
- dimethylamino
- alcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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Abstract
本发明的目的是式(I)化合物及其可药用的酸加
成盐的用途,以获得控制生育力特别是控制雄性生育
力的药物:其中各取代基定义参见说明书。
Description
本发明涉及在3位被二取代的氨基烷氧基链取代的芳族甾类化合物的用途,以获得控制生育力特别是雄性生育力的药物,以及涉及含有这些甾类化合物的药物组合物。
本发明的一个目的是式(Ⅰ)化合物及其可药用的酸加成盐的用途以获得控制生育力特别是控制雄性生育力的药物:
其中R1和R2可相同或不同且各自代表具有1至8个碳原子的烷基或苄基,或R1和R2与它们所连的氮一起形成5或6元饱和杂环,该杂环任选含有选自氧和氮的另一杂原子:在α或β位的R3代表甲基:n表示2至10的整数;R4和R5一起形成氧代,或R4代表氢原子、羟基或具有至多12个碳原子的酰氧基,R5代表氢原子、羟基、具有至多12个碳原子的酰氧基、各自具有至多8个碳原子的烷基、链烯基或炔基;R5和R7一起形成氧代,或R5和R7可相同或不同,且各自代表氢原子、羟基或具有至多12个碳原子的酰氧基;或者R5和R6一起形成双键且R4和R7是氢原子。
当R1、R2和R5代表含有1至8个碳原子的烷基时,该烷基是甲基、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,优选甲基、乙基、异丙基。
当R1和R2与它们所连的氮一起形成任选含有选自氧和氮的另一杂原子的5或6元饱和杂环时,该杂环优选哌啶子基、吗啉代、哌嗪子基(piperazino)或吡咯烷子基(pyrrolidino)。
所谓具有至多12个碳原子的酰氧基优选指的是选自乙酰氧基、丙酰氧基、丁酰氧基、己酰氧基和苯甲酰氧基的基团。还可提及的是甲酰氧基。
所述具有至多8个碳原子的链烯基举例如下:乙烯基、烯丙基、1-丙烯基、丁烯基、戊烯基或己烯基。
所述具有至多8个碳原子的炔基举例如下:乙炔基、丙炔基、丁炔基、戊炔基或己炔基。
本发明自然地扩展到式(Ⅰ)化合物的可药用的酸加成盐,例如与下列酸形成的盐: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、二羟乙酸、天冬氨酸、链烷磺酸如甲或乙磺酸,芳基磺酸如苯或对甲苯磺酸以及芳基羧酸。优选盐酸盐。
在8、9和14位的波浪线是指氢在(8α、9α、14α)位或(8β、9β、14β)位。
本发明的一个更具体的目的是上面定义的且其中在β位的R3是甲基的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途。
本发明的一个更具体的目的是上面定义的对应于通式(ⅠA)的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途:
其中R1、R2和n如上所定义。
本发明的一个更具体的目的是上面定义的对应于通式(ⅠB)的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途:
其中R1、R2、R5和n如上所定义。
本发明的一个更具体的目的是上面定义的对应于通式(ⅠC)的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途:
其中R1和R2可相同或不同且各自代表具有1至8个碳原子的烷基,n如上所定义;以及
a)R4代表氢原子和R5代表羟基,
b)或者R4和R5一起形成氧代,
c)或者R4和R5都代表氢原子。
本发明的一个更具体的目的是上面定义的对应于通式(ⅠD)的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途:
其中R1、R2和n如上所定义。
本发明的一个更具体的目的是上面定义的对应于通式(ⅠE)的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途:
其中R1、R2和n如上所定义。
本发明的一个更具体的目的是上面定义的对应于通式(ⅠF)的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途:
其中R1、R2和n如上所定义:R4和R5一起形成氧代,或者R4和R5可相同或不同并各自代表氢原子、羟基或具有至多12个碳原子的酰氧基;R6和R7一起形成氧代;或者R6和R7可相同或不同并各自代表氢原子、羟基或具有至多12个碳原子的酰氧基;或者R5和R6一起形成双键且R4和R7是氢原子。
本发明的一个更具体的目的是其中R1和R2是相同的并代表甲基或乙基的上面定义的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途。
本发明的一个更具体的目的是其中n等于2的上面定义的通式(Ⅰ)化合物及其可药用的酸加成盐的上述用途。
本发明的一个十分具体的目的是通式(Ⅰ)的下列化合物的上述用途:
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮盐酸盐,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮盐酸盐,
3-[2-(1-哌啶基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-(4-吗啉基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[3-(二甲氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[3-(二乙氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[4-(二甲氨基)丁氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[5-(二甲氨基)戊氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[5-(二乙氨基)戊氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[10-(二甲氨基)癸氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-[甲基(苯基甲基)氨基]乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[3-[双(苯基甲基)氨基]丙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(17β)-3-[2-[甲基(苯基甲基)氨基]乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17β)-3-[3-(二甲氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17β)-3-[3-(二乙氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二乙氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-16-酮,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-16-酮,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-16-酮盐酸盐,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(1-哌啶基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[3-(1-哌啶基)丙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯盐酸盐,
3-[2-(4-吗啉基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10),16-四烯,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10),16-四烯,
(17α)-3-[3-(二甲氨基)丙氧基]-17-甲基雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]-17-甲基雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-[甲基(苯基甲基)氨基]乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-17-丙基雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-17-丙基雌甾-1,3,5(10)-三烯-17-醇盐酸盐,
(17α)-3-[3-(二甲氨基)丙氧基]-17-(1-丙烯基)雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-17-(1-丙烯基)雌甾-1,3,5(10)-三烯-17-醇盐酸盐,
(17α)-3-[2-(二甲氨基)乙氧基]-19-去甲孕甾-1,3,5(10),20-四烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10),20-四烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇盐酸盐,
(17α)-3-[2-(二乙氨基)乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[3-(二乙氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[2-[甲基(苯基甲基)氨基]乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[2-[甲基(苯基甲基)氨基]乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇盐酸盐,
(17α)-3-[3-[甲基(苯基甲基)氨基]丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(8α,9β,13α,14β)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(8α,9β,13α,14β)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(8α,9β,13α,14β)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯,
(8α,9β,13α,14β)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯,
(8α,9β,13α,14β)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯盐酸盐,
(8α,9β,13α,14β,17α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(13α)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(13α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(13α)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯,
(13α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯。
在法国专利1,338,308及增补专利90803和90804、美国专利3,212,971、英国专利984,028和984,029中描述了式(Ⅰ)产物的合成。
已知式(Ⅰ)产物具有抗血脂或降低血胆固醇的性质。
本申请人已致力于并揭示了式(Ⅰ)产物在精子的钙流调节方面的新性质。
本发明的产物具有:
1)对σ受体的强亲和力(参见药理试验),和
2)使钙流入精子的活性。
试验结果表明在固定于σ受体的产物中,一些通过刺激钙流入精子产生作用,另一些则通过抑制所刺激的钙的流入产生作用,或通过黄体酮(一种结合在σ受体上的分子)不产生作用。
具有激动活性的式(Ⅰ)产物刺激钙流入精子。因此它们可用于治疗特征在于精子生育力不足的某些不育症。
具有拮抗活性的式(Ⅰ)产物抑制钙流入精子。因此它们可有效地用于控制顶体反应,由此必然影响精子的生育力。所以这些化合物可用作避孕药特别是雄性避孕药。
这些化合物也可用于兽医领域作为家养动物(如狗、猫……)的雄性避孕药,或用于限制有害动物特别是啮齿动物或鸽子的繁殖。
有用的剂量随所治疗的疾病的性质和给药途径而变化。例如,一个成年人口服的日剂量为10至1000mg。
本发明扩展至含有至少一种上面定义的药物化合物作为活性成份的药物组合物。
可经消化道、非胃肠或局部途径特别是对于妇女例如可通过经皮途径,或在兽医领域可通过注射特别是皮下注射途径使用式(Ⅰ)化合物。这些化合物可被配制成普通剂型或糖包衣片剂、胶囊剂、粒剂、栓剂、注射制剂、阴道栓剂、软膏剂、乳油剂、凝胶剂、微球粒剂、植入剂、贴剂,这些剂型可按常规方法制备。
一种或多种活性成份可与常用于这些药物组合物的赋形剂混合,例如滑石粉、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、可可脂、含水或非水载体、来源于动物或植物的脂肪物质、石蜡衍生物、乙二醇类、各种润滑剂、分散剂或乳化剂、防腐剂。
因此,本发明的一个目的是含有上述药物化合物的药物组合物。
药理试验
方法
人精子的制备
人精液来自健康供者。用Percoll梯度(47.5-95%)离心分离出运动的精子,然后再悬浮于含有下列成份的高渗BWW介质中:166mM NaCl、5mM KCl、1.3mM CaCl2、1.2mM KH2PO4、1.2mM MgSO4、5.5mM葡萄糖、21mM乳酸钠、0.25mM丙酮酸钠、25mM NaHCO3、20mM Hepes和0.8%HSA(410mosm/升),室温下pH7.4。
细胞内钙的测定
将运动的精子在BWW/HSA获能介质中培养至少2小时,然后用Fura 2-AM(最终浓度2μm)在37℃下培养(浓度5-10×106/ml)45分钟。用不含HSA的BWW离心洗涤10分钟后,将精子再悬浮,浓度为4×106/ml。在37℃下用荧光分光计以激发波长340和380nm(PTIM 2001-Kontron)或340、360和380nm(Hitachi F 2000-B.Braun Science Tec.)测定荧光信号。在505nm处记录荧光发射。将溶于无水乙醇中的被试验的黄体酮或产物加到最终浓度为0.1%乙醇的培养介质中。当发现黄体酮的拮抗作用时,在黄体酮之前2分钟将产物加到介质中。在各剂量加完后,将5μm伊屋诺霉素加到试样中测定最大的荧光信号,然后用0.05% Triton X-100使精子渗透,并加入10mM EGTA(pH9.5)以便测定最小的荧光信号。按照Grunkiewicz等人所述的方法(Grunkiewicz G.,Poenie M.和Tsien R.Y.(1985)J.Biol.Chem.260,3440-3450),用上面所得的数值计算细胞内钙([Ca2+]i)的浓度。细胞内钙浓度的结果用相对于任意设定为1的基准之值来表示。
σ受体:相对结合亲和力的测定
用大鼠脑和睾丸膜制剂评估相对结合亲和力。
膜的制备:
使用来自Iffa Credo且重大约200g的雄性Sprague-Dawley大鼠。使动物断头致死,取出脑和睾丸,并用Ultrathurax在4℃下在10至25体积的50mM Tris-HCl缓冲液(pH7.7)中均化。将均化浆在4℃ 30,000g下离心15分钟,然后通过再悬浮(在相同的缓冲液中)和在相同条件下的离心分离洗涤小丸3次。将用此方法得到的膜在-80℃下贮存。
培养:
所用的σ受体的标记是具有比活性3404 GBq/mmol的NEN的3H PPP(丙基-3-(3-羟基苯基)哌啶)。
将膜再悬浮于50mM Tris-HCl缓冲液(pH8.0)中以便得到睾丸的蛋白浓度大约为0.6mg/ml,脑的蛋白浓度大约为1mg/ml。用3nM3H PPP在逐渐增加参考产物(氟哌啶醇)或试验产物浓度的情况下将匀浆等份试样在25℃下培养(总体积0.5ml)90分钟。培养结束后,使用预先用0.05%聚乙烯亚胺预处理过的Whatman GF/C过滤器快速过滤,将结合在膜上的3H PPP与游离的3H PPP分离。然后用5ml Tris-HCl缓冲液洗涤沉淀两次。加入20ml闪烁液体Aqualyte(Baker)后,进行放射性计数。
相对结合亲和力(RBA)的计算:
绘出下列两条曲线:结合的氚化标记物百分数100×B/BO作为未标记的参考产物的浓度对数的函数或作为未标记的试验产物的浓度对数的函数。
确定下列等式的直线:
I50=100(BO/BO+Bmin/BO)/2
I50=100(1+Bmin/BO)/2=50(1+Bmin/BO)
BO=在无任何未标记的产物存在下结合的氚化标记物的浓度。
B=在未标记的产物浓度为X时结合的氚化标记物的浓度。
Bmin=在极大过量的未标记的参考产物(5,000nm)存在下结合的氚化标记物的浓度。
直线I50和曲线的交点用来计算在受体上抑制50%的氚化标记物的特异性结合时未标记的参考产物(CH)和未标记的试验产物(CX)的浓度。试验产物的相对结合亲和力由如下公式确定:
RBA=100(CH)/(CX)
氟哌啶醇的RBA任意设定为100。
对σ受体的相对结合亲和力
脑(鼠) 睾丸(鼠)
参考:氟哌啶醇 100.0 100.0
黄体酮 0.7 0.3
雌甾酮 <0.06
(8α,9β,13α,14β)-3-[2-(二 23.0 0.5
甲氨基)乙氧基]雌甾-1,3,5(10)-
三烯(pdt X)
3-[2-(二乙氨基)-乙氧基] 85.0 12.5
雌甾-1,3,5(10)-三烯-17-酮
(pdt W)
3-[2-(1-哌啶基)乙氧基] 28.0
雌甾-1,3,5(10)-三烯-17-酮
(13α)-3-[2-(二乙氨基)乙氧基] 39.0
雌甾-1,3,5(10)-三烯-17-酮
3-[2-(1-哌啶基)乙氧基] 54.0
雌甾-1,3,5(10)-三烯
(8α,9β,13α,14β)-3-[2-(二 28.0
乙氨基)乙氧基]雌甾-1,3,5(10)-
三烯盐酸盐
(17α)-3-[2-(二乙氨基)乙氧基] 24.0
-19-去甲孕酮-1,3,5(10)-三烯
-20-炔-17-醇
由黄体酮和产物W诱导细胞内钙([Ca2+]i)浓度的增加
黄体酮(10-5M) 产物W(10-5M)
实验1 4.25 3.56
实验2 6.60 2.55
这些结果用相对于设定为1的基准值来表示。
初始基准为:
实验1=200nm、实例2=250nm。
对于([Ca2+]i),产物X的有效剂量
产物X
10-7M 10-8M 5×10-6M 10-5M 2×10-5M
实验1 1.50 1.63 2.55 7.20 8.50
实验2 1.38 1.78 5.56 12.00 8.00
这些结果用相对于设定为1的基准值来表示。
对于[Ca2+]i,10-5M黄体酮和10-5M产物X的
作用比较,平均值±SEM n=3
黄体酮 产物X
4.90±0.92 4.80±0.92
这些结果用相对于设定为1的基准值来表示。
结论:
对人精子细胞内钙的作用
浓度为10-5M的黄体酮诱导[Ca2+]i的短暂增加,接着是第二阶段,其中[Ca2+]i稍大于基准值。
产物X引起[Ca2+]i的剂量依赖性增加,产物X为10-5M时达到等于由黄体酮引起的强度。与用黄体酮时所观察到的情况相反,该作用是长期的。
对σ受体的相对结合亲和力(RBA)
本发明的产物和黄体酮能够置换3H PPP。用大鼠脑膜计算的RBA也已用于评估睾丸,并结果已列入上述表中。
脑和睾丸的RBA值不同可以用在这两种器官中各种类型的σ受体位点的不同分布来解释。
因此,这些产物如产物X作为激动剂时可激刺顶体反应,所以可用于特征在于精子生育力不足的某些不育症。
Claims (14)
1、式(Ⅰ)化合物及其可药用的酸加成盐的用途,以获得控制生育力特别是雄性生育力的药物:
其中R1和R2可相同或不同且各自代表具有1至8个碳原子的烷基或苄基,或R1和R2与它们所连的氮一起形成5或6元饱和杂环,该杂环任选含有选自氧和氮的另一杂原子;在α或β位的R3代表甲基;n表示2至10的整数;R4和R5一起形成氧代,或R4代表氢原子、羟基或具有至多12个碳原子的酰氧基,R5代表氢原子、羟基、具有至多12个碳原子的酰氧基、各自具有至多8个碳原子的烷基、链烯基或炔基;R6和R7一起形成氧代,或R6和R7可相同或不同,且各自代表氢原子、羟基或具有至多12个碳原子的酰氧基;或者R5和R6一起形成双键且R4和R7是氢原子。
2、根据权利要求1,由权利要求1定义的且其中在β位的R3是甲基的通式(Ⅰ)化合物及其可药用的酸加成盐的用途。
9、根据权利要求1,由权利要求1-8的任一项定义的且其中R1和R2是相同的并代表甲基或乙基的通式(Ⅰ)化合物及其可药用的酸加成盐的用途。
10、根据权利要求1,由权利要求1-9的任一项定义的且其中n等于2的通式(Ⅰ)化合物及其可药用的酸加成盐的用途。
11、根据权利要求1,由权利要求1定义的通式(Ⅰ)的下列化合物的用途:
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮盐酸盐,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮盐酸盐,
3-[2-(1-哌啶基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-(4-吗啉基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[3-(二甲氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[3-(二乙氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[4-(二甲氨基)丁氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[5-(二甲氨基)戊氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[5-(二乙氨基)戊氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[10-(二甲氨基)癸氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[2-[甲基(苯基甲基)氨基]乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
3-[3-[双(苯基甲基)氨基]丙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(17β)-3-[2-[甲基(苯基甲基)氨基]乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17β)-3-[3-(二甲氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17β)-3-[3-(二乙氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二乙氨基)丙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-16-酮,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-16-酮,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-16-酮盐酸盐,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(1-哌啶基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[3-(1-哌啶基)丙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯盐酸盐,
3-[2-(4-吗啉基)乙氧基]雌甾-1,3,5(10)-三烯,
3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10),16-四烯,
3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10),16-四烯,
(17α)-3-[3-(二甲氨基)丙氧基]-17-甲基雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]-17-甲基雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[2-[甲基(苯基甲基)氨基]乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-17-丙基雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-17-丙基雌甾-1,3,5(10)-三烯-17-醇盐酸盐,
(17α)-3-[3-(二甲氨基)丙氧基]-17-(1-丙烯基)雌甾-1,3,5(10)-三烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-17-(1-丙烯基)雌甾-1,3,5(10)-三烯-17-醇盐酸盐,
(17α)-3-[2-(二甲氨基)乙氧基]-19-去甲孕甾-1,3,5(10),20-四烯-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10),20-四烯-17-醇,
(17α)-3-[2-(二甲氨基)乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[3-(二甲氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇盐酸盐,
(17α)-3-[2-(二乙氨基)乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[3-(二乙氨基)丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[2-[甲基(苯基甲基)氨基]乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(17α)-3-[2-[甲基(苯基甲基)氨基]乙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇盐酸盐,
(17α)-3-[3-[甲基(苯基甲基)氨基]丙氧基]-19-去甲孕甾-1,3,5(10)-三烯-20-炔-17-醇,
(8α,9β,13α,14β)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(8α,9β,13α,14β)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(8α,9β,13α,14β)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯,
(8α,9β,13α,14β)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯,
(8α,9β,13α,14β)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯盐酸盐,
(8α,9β,13α,14β,17α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-醇,
(13α)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(13α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯-17-酮,
(13α)-3-[2-(二甲氨基)乙氧基]雌甾-1,3,5(10)-三烯,
(13α)-3-[2-(二乙氨基)乙氧基]雌甾-1,3,5(10)-三烯,
12、含有至少一种权利要求1所述的化合物的药物组合物。
13、含有至少一种权利要求2-10所述的化合物的药物组合物。
14、含有至少一种权利要求11所述的化合物的药物组合物。
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1994
- 1994-03-24 FR FR9403460A patent/FR2717690B1/fr not_active Expired - Fee Related
-
1995
- 1995-03-08 US US08/401,078 patent/US5554604A/en not_active Expired - Fee Related
- 1995-03-20 AU AU14956/95A patent/AU698349B2/en not_active Ceased
- 1995-03-22 DE DE69517356T patent/DE69517356T2/de not_active Expired - Fee Related
- 1995-03-22 EP EP95400630A patent/EP0676202B1/fr not_active Expired - Lifetime
- 1995-03-22 ES ES95400630T patent/ES2147267T3/es not_active Expired - Lifetime
- 1995-03-22 AT AT95400630T patent/ATE193650T1/de not_active IP Right Cessation
- 1995-03-22 PT PT95400630T patent/PT676202E/pt unknown
- 1995-03-22 DK DK95400630T patent/DK0676202T3/da active
- 1995-03-23 RU RU95104235/14A patent/RU2176506C2/ru not_active IP Right Cessation
- 1995-03-23 KR KR1019950006180A patent/KR100367805B1/ko not_active IP Right Cessation
- 1995-03-23 HU HU9500846A patent/HUT72085A/hu unknown
- 1995-03-23 CN CN95103086A patent/CN1055391C/zh not_active Expired - Fee Related
- 1995-03-23 JP JP08868995A patent/JP3678454B2/ja not_active Expired - Fee Related
- 1995-03-24 CA CA002145469A patent/CA2145469A1/fr not_active Abandoned
- 1995-12-11 US US08/570,134 patent/US5672595A/en not_active Expired - Fee Related
- 1995-12-11 US US08/570,135 patent/US5635498A/en not_active Expired - Fee Related
-
1996
- 1996-03-14 US US08/616,162 patent/US5580864A/en not_active Expired - Fee Related
-
1997
- 1997-01-17 US US08/785,203 patent/US5739124A/en not_active Expired - Fee Related
-
2000
- 2000-07-05 GR GR20000401567T patent/GR3033882T3/el not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
ATE193650T1 (de) | 2000-06-15 |
US5739124A (en) | 1998-04-14 |
EP0676202A2 (fr) | 1995-10-11 |
EP0676202A3 (fr) | 1995-12-27 |
DK0676202T3 (da) | 2000-10-16 |
HU9500846D0 (en) | 1995-05-29 |
CN1055391C (zh) | 2000-08-16 |
FR2717690B1 (fr) | 1996-04-26 |
FR2717690A1 (fr) | 1995-09-29 |
AU1495695A (en) | 1995-10-05 |
US5554604A (en) | 1996-09-10 |
US5672595A (en) | 1997-09-30 |
JPH07285988A (ja) | 1995-10-31 |
DE69517356D1 (de) | 2000-07-13 |
ES2147267T3 (es) | 2000-09-01 |
CA2145469A1 (fr) | 1995-09-25 |
AU698349B2 (en) | 1998-10-29 |
RU95104235A (ru) | 1996-11-27 |
HUT72085A (en) | 1996-03-28 |
US5635498A (en) | 1997-06-03 |
KR950031078A (ko) | 1995-12-18 |
RU2176506C2 (ru) | 2001-12-10 |
EP0676202B1 (fr) | 2000-06-07 |
KR100367805B1 (ko) | 2003-08-02 |
DE69517356T2 (de) | 2000-12-14 |
GR3033882T3 (en) | 2000-11-30 |
PT676202E (pt) | 2000-09-29 |
JP3678454B2 (ja) | 2005-08-03 |
US5580864A (en) | 1996-12-03 |
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