CN1236313A - 新方法 - Google Patents
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Abstract
描述了治疗绝经后妇女心血管疾病的新方法。艾多昔芬是优选的化合物。
Description
发明领域
本发明涉及用于治疗和预防绝经后妇女心血管疾病的治疗剂,该治疗剂是组织选择性雌激素激动剂/拮抗剂化合物。
背景技术
对于绝经后妇女,绝经期发生的雌激素降低是心血管疾病发病率增加的一个重要病因。就包括LDL胆固醇和脂蛋白(a)(1p(a))血清浓度和纤维蛋白原血浆浓度的一些心血管疾病的独立发病因素而言,停经后进行雌激素治疗具有有利作用。参见Levenson J等,(1995),Arterioscler Thromb Vasc Biol,15,1263-1268;Kroon等,(1994),Thomb Hemost,71,420-423;Ettinger B(1990)Obstet GynecolClinics of North America,17,741-757;Mendoza S等(1994)JLab Clin Med 123,837-841。这些作用可部分解释流行病学观察到的现象,即雌激素治疗降低了心血管疾病的发病率。但是,预防性单独使用雌激素增加了子宫内膜癌症的危险性并还可能与乳腺癌发病率增加有关。基于这些原因并由于其麻烦的副作用(主要是乳房触痛和阴道出血),极少有妇女进行足以有利于保护心脏的长期HRT治疗。理想的治疗应维持雌激素对心血管的作用,但对生殖组织无不良作用。于是,人们努力开发具有组织选择性雌激素激动剂或拮抗剂性质的化合物。这样的组织选择性作用可产生雌激素对心血管疾病发病因素的有利作用,而没有对乳腺和子宫组织的不良作用。
发明概述
本发明提供了预防和治疗绝经后妇女心血管疾病的方法,该方法无明显的亲子宫作用,也不升高乳腺癌的发病率或引起阴道出血和乳房触痛机率的增加。此方法包括给有此需要的病人使用有效量的式Ⅰ化合物及其可药用的酸加成盐:其中X表示3位或4位碘或溴原子,符号R1和R2可相同或不同,表示C1-C3烷基,特别是甲基或乙基,或者R1表示氢原子而R2表示C1-C3烷基,或者R1和R2与它们连接的氮原子一起表示饱和杂环,一般是5或6元环,特别是1-吡咯烷基、哌啶子基、4-甲基哌啶子基或吗啉代基团。
发明详述
本发明提供了预防和治疗绝经后妇女心血管疾病的治疗方法,该方法使用一组先前已制备的并确定对治疗雌激素受体阳性乳腺癌有效的化合物。这些化合物以上述式Ⅰ描述并被描述于美国专利4839155中。
用于本治疗方法的优选的化合物为
(E)-1-[2-[4-[1-(4-碘代苯基)-2-苯基-1-丁烯基]苯氧基]吡咯烷
已知这些化合物结合雌激素受体并依所研究组织不同而引起雌激素激动或拮抗作用。通过对肝脏的雌激素激动作用(改变脂质分布(profile)和纤维蛋白原浓度)产生对心血管的有利作用。对动脉壁的雌激素激动作用也可有利于心血管疾病发病率的降低。
术语“心血管疾病”指动脉粥样硬化心血管疾病如心肌梗塞、中风、心绞痛、间歇性跛行、瞬间视觉缺失、瞬间局部缺血发作(TIA)和外周血管疾病。本发明方法可用于产生与降低动脉硬化发病率和降低升高的LDL胆固醇水平有关的血脂分布。此外,此方法可用于产生降低其它独立的心血管发病因素如血浆纤维蛋白原浓度和血清1p(a)浓度。
通过研究艾多昔芬对绝经后妇女心血管疾病的一些不同发病因素作用的研究,评价其降低心血管疾病发病率的能力。它们包括脂质分布的不同参数和凝集和纤维蛋白溶解的水平。
对绝经后妇女在3个月的研究中,将艾多昔芬的三个剂量(2.5、5和10mg/天)与安慰组比较。测定治疗前后不同脂参数、纤维蛋白原及其它凝集/纤维蛋白溶解参数水平的变化。此研究的结果描述如下。所有变化以相对基值的百分率变化描述。用下列符号表示与安慰组有统计学显著差异:*=p<0.01,**=p<0.001。
安慰组 | 2.5 | 5.0 | 10.0 | |
总胆固醇 | 0.5(1.1) | -0.9(1.1) | -4.2(1.2)* | -9.8(1.1)** |
LDL胆固醇 | 1.3(1.5) | -1.3(2.0) | -4.7(1.7)* | -15.2(1.6)** |
HDL胆固醇 | 2.4(1.4) | 2.7(1.5) | -1.4(1.5) | 0.8(1.7) |
HDL/LDL比 | 2.2(1.6) | 7.1(2.6) | 5.2(2.1) | 21.7(3.1)** |
脂蛋白(a) | 5.0(3.0) | -2.0(6.0) | 1.0(4.0) | -6.0(4.0) |
甘油三酯 | 1.3(3.8) | 1.8(3.9) | -3.2(3.6) | 3.8(3.8) |
纤维蛋白原 | 5.8(3.0) | -1.7(2.4) | -8.3(3.1)* | -16.9(2.4)** |
D-二聚体 | 0.0(3.1) | 4.7(4.3) | -2.1(2.7) | -7.1(2.7) |
因子Ⅶ | 5.4(2.4) | -10.1(2.4)** | -9.6(2.1)** | -11.1(1.6)** |
在同样的研究中,与安慰组比较阴道出血和乳房触痛的机率降低,且与安慰组的情况比较,接受艾多昔芬治疗的患者无组织学定义的子宫内膜增生。
这些结果表明对人来说艾多昔芬可产生所需的雌激素对心血管发病因素的有利作用,而对生殖组织无不良作用。
当本发明的化合物及其有活性的可药用盐口服时,可制成液体,如糖浆、混悬剂或乳液、片剂、胶囊及锭剂。
一般来说,液体制剂由本发明化合物或其可药用盐在适宜液体载体(一种或多种)中的悬浮液或溶液组成,液体载体有如乙醇、甘油、非水溶剂如聚乙二醇、油或水,其中添加助悬剂、防腐剂、香料或着色剂。
片剂形式的组合物可使用任何常规用于制备固体制剂的适宜药用载体(一种或多种)制备。这些载体的例子包括硬脂酸镁、淀粉、乳糖、蔗糖和纤维素。
胶囊形式的组合物可通过常规包囊方法制备。例如,可用标准载体制备含活性成分的小丸并再将其填充进硬明胶胶囊;或者,可用任何适宜的载体(一种或多种)制备分散液或混悬液,并再将此分散液或混悬液填充如软明胶胶囊,载体的例子有含水胶、纤维素、硅酸盐或油。
当本发明的化合物及其活性可药用盐非经胃肠道(即通过注射或输注)给药时,可制备为溶液或混悬液。
非经胃肠道给药组合物一般由活性成分在灭菌含水载体或非经胃肠道用油中的溶液或混悬液组成,非经胃肠道用油是如聚乙二醇、聚乙烯吡咯烷酮、卵磷脂、花生油或芝麻油。或者,可将此溶液冻干并恰在给药前再用适当溶剂重新配制。
当以此种方式给药时,典型的栓剂组合物含有本发明的化合物或其有活性的可药用盐,以及粘结剂和/或润滑剂如聚二醇类、明胶或可可脂或其它低熔点植物或合成蜡或脂肪。
典型的透皮制剂含有常规水性或非水载体,例如,霜剂、软膏、洗剂或糊剂,或为含药硬膏剂、贴剂或膜。
对于局部给药,所采用的药物组合物包括溶液、混悬液、软膏及固体插入物。典型的药用载体为,例如,水、水和与水混溶溶剂如低级烷醇或植物油的混合物,以及水混溶性眼科用无毒聚合物如纤维素衍生物如甲基纤维素。该药物制剂还可含有无毒辅剂如乳化剂、防腐剂、湿润剂和成形剂,如聚乙二醇类;抗菌剂成分如季铵化合物;缓冲成分如碱金属氯化物;抗氧剂如焦亚硫酸钠;及其它常规成分如脱水山梨醇单月桂酸酯。
优选地,该组合物是单位剂量形式。本发明化合物在药物剂量单位中的剂量是有效的、无毒的量,选自0.01-200mg/kg活性化合物,优选0.1-100mg/kg。所选剂量给需要治疗或预防心血管疾病或降低血浆胆固醇的患者每天使用1-6次,使用途径有口服、直肠给药、局部给药或注射,或者通过输液。给人使用的口服剂量单位优选含10至500mg活性化合物。较低剂量一般用于非经胃肠道给药。当对患者来说安全、有效、方便时,就口服给药。
当本发明的化合物按照本发明给药时,无不能接受的毒性作用。
实施例1
通过过筛、混合并按例如如下的比例将各组分填充入硬明胶胶囊,制备式(Ⅰ)活性化合物的口服给药的口服剂型。
组分 量(E)-1-[2-[4-[1-(4-碘代苯基)-2- 100mg苯基-1-丁烯基]苯氧基]吡咯烷
硬脂酸镁 10mg
乳糖 100mg
实施例2
将蔗糖、硫酸钙二水合物和口服活性式(Ⅰ)化合物混合并用10%明胶溶液制粒。将此湿颗粒过筛,干燥,并与淀粉、滑石和硬脂酸混合,过筛并压制成片剂。
组分 量(E)-1-[2-[4-[1-(4-碘代苯基)-2- 75mg苯基-1-丁烯基]苯氧基]吡咯烷
硫酸钙二水合物 100mg
蔗糖 15mg
淀粉 8mg
滑石 4mg
硬脂酸 2mg
实施例3
将(E)-1-[2-[4-[1-(4-碘代苯基)-2-苯基-1-丁烯基]苯氧基]吡咯烷50mg分散于25ml生理盐水中制备注射液。
Claims (6)
1.预防和治疗妇女绝经后心血管疾病的方法,包括给需要的患者使用有效量的式Ⅰ化合物。
2.根据权利要求1的方法,其中式Ⅰ化合物是(E)-1-[2-[4-[1-(4-碘代苯基)-2-苯基-1-丁烯基]苯氧基]吡咯烷。
3.根据权利要求1的方法,其中绝经后心血管疾病是心肌梗塞或中风。
4.式Ⅰ化合物在制备用于治疗妇女心血管疾病的药物方面的用途。
5.根据权利要求4的用途,其中式Ⅰ化合物是(E)-1-[2-[4-[1-(4-碘代苯基)-2-苯基-1-丁烯基]苯氧基]吡咯烷。
6.根据权利要求4的用途,其中疾病是心肌梗塞或中风。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2543996P | 1996-09-06 | 1996-09-06 | |
US60/025,439 | 1996-09-06 | ||
US5066697P | 1997-06-24 | 1997-06-24 | |
US60/050,666 | 1997-06-24 |
Publications (1)
Publication Number | Publication Date |
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CN1236313A true CN1236313A (zh) | 1999-11-24 |
Family
ID=26699738
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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CN97199492A Pending CN1236299A (zh) | 1996-09-06 | 1997-09-03 | 治疗包括骨质疏松的绝经后疾病的方法 |
CN97199493A Pending CN1236313A (zh) | 1996-09-06 | 1997-09-03 | 新方法 |
Family Applications Before (1)
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CN97199492A Pending CN1236299A (zh) | 1996-09-06 | 1997-09-03 | 治疗包括骨质疏松的绝经后疾病的方法 |
Country Status (16)
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EP (2) | EP0927029A4 (zh) |
JP (2) | JP2002515046A (zh) |
KR (2) | KR20000068472A (zh) |
CN (2) | CN1236299A (zh) |
AR (1) | AR008155A1 (zh) |
AU (2) | AU4247397A (zh) |
BR (2) | BR9711676A (zh) |
CA (2) | CA2264943A1 (zh) |
CO (2) | CO4920218A1 (zh) |
CZ (1) | CZ76699A3 (zh) |
IL (1) | IL128645A0 (zh) |
NO (2) | NO991097L (zh) |
PL (2) | PL332278A1 (zh) |
TR (2) | TR199900504T2 (zh) |
TW (1) | TW411273B (zh) |
WO (2) | WO1998009519A1 (zh) |
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WO1998034608A1 (en) * | 1997-02-11 | 1998-08-13 | Novo Nordisk A/S | Methods for treatment or prophylaxis of menopausal symptoms |
GB9827121D0 (en) * | 1998-12-09 | 1999-02-03 | Orion Corp | Agent for lowering endothelin levels |
DE19905961A1 (de) * | 1999-02-12 | 2000-08-17 | Stefan Neubauer | Verwendung von Östrogenen zur Behandlung der Herzinsuffizienz |
US6528681B2 (en) * | 2000-04-05 | 2003-03-04 | Bristol-Meyers Squibb Pharma Company | Halogenated triphenylethylene derivatives as selective estrogen receptor modulators |
TWI303990B (en) | 2000-10-17 | 2008-12-11 | Pfizer Prod Inc | New use of estrogen agonists/antagonists for improving vascular health |
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EP0260066B1 (en) * | 1986-09-11 | 1990-05-09 | National Research Development Corporation | Tamoxifen derivatives |
DE69316633T2 (de) * | 1992-09-15 | 1998-05-20 | Merrell Dow Pharma | Nichtmetabolisierbare clomiphene-analoge zur behandlung von tamoxifen-resistenten tumoren |
US5681835A (en) * | 1994-04-25 | 1997-10-28 | Glaxo Wellcome Inc. | Non-steroidal ligands for the estrogen receptor |
US5604248A (en) * | 1994-05-05 | 1997-02-18 | Eli Lilly And Company | Method for minimizing the uterotrophic effect of tamoxifen and tamoxifen analogs |
US5470883A (en) * | 1994-05-23 | 1995-11-28 | Stromberg; Brent V. | Method of treating peripheral vasoconstriction with tamoxifen citrate |
JPH11510479A (ja) * | 1995-06-07 | 1999-09-14 | ネオルックス コーポレイション | タモキシフェン類似体による心臓血管疾病の予防及び治療 |
HN1996000101A (es) * | 1996-02-28 | 1997-06-26 | Inc Pfizer | Terapia combinada para la osteoporosis |
US6069175A (en) * | 1996-11-15 | 2000-05-30 | Pfizer Inc. | Estrogen agonist/antagonists treatment of atherosclerosis |
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- 1997-09-03 JP JP51283798A patent/JP2002515046A/ja active Pending
- 1997-09-03 PL PL97332278A patent/PL332278A1/xx unknown
- 1997-09-03 CN CN97199492A patent/CN1236299A/zh active Pending
- 1997-09-03 CZ CZ99766A patent/CZ76699A3/cs unknown
- 1997-09-03 KR KR1019997001860A patent/KR20000068472A/ko not_active Application Discontinuation
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- 1997-09-03 CN CN97199493A patent/CN1236313A/zh active Pending
- 1997-09-03 EP EP97942388A patent/EP0927029A4/en not_active Withdrawn
- 1997-09-03 AU AU44097/97A patent/AU4409797A/en not_active Abandoned
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- 1997-09-03 EP EP97940773A patent/EP0929216A4/en not_active Withdrawn
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- 1997-09-03 WO PCT/US1997/015474 patent/WO1998009519A1/en not_active Application Discontinuation
- 1997-09-03 IL IL12864597A patent/IL128645A0/xx unknown
- 1997-09-03 WO PCT/US1997/015475 patent/WO1998009619A1/en not_active Application Discontinuation
- 1997-09-04 CO CO97051287A patent/CO4920218A1/es unknown
- 1997-09-04 CO CO97051289A patent/CO5070658A1/es unknown
- 1997-12-11 TW TW086112930A patent/TW411273B/zh active
-
1999
- 1999-03-05 NO NO991097A patent/NO991097L/no not_active Application Discontinuation
- 1999-03-05 NO NO991096A patent/NO991096D0/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
KR20000068473A (ko) | 2000-11-25 |
AU4247397A (en) | 1998-03-26 |
NO991096L (no) | 1999-03-05 |
CA2264943A1 (en) | 1998-03-12 |
PL332038A1 (en) | 1999-08-16 |
NO991097D0 (no) | 1999-03-05 |
AR008155A1 (es) | 1999-12-09 |
TW411273B (en) | 2000-11-11 |
BR9711676A (pt) | 1999-08-24 |
NO991097L (no) | 1999-03-05 |
JP2002515046A (ja) | 2002-05-21 |
TR199900506T2 (xx) | 1999-07-21 |
WO1998009519A1 (en) | 1998-03-12 |
NO991096D0 (no) | 1999-03-05 |
IL128645A0 (en) | 2000-01-31 |
JP2002515047A (ja) | 2002-05-21 |
AU4409797A (en) | 1998-03-26 |
BR9711681A (pt) | 1999-08-24 |
EP0929216A4 (en) | 2001-04-04 |
EP0927029A1 (en) | 1999-07-07 |
CA2264775A1 (en) | 1998-03-12 |
CZ76699A3 (cs) | 1999-08-11 |
CO4920218A1 (es) | 2000-05-29 |
EP0929216A1 (en) | 1999-07-21 |
CN1236299A (zh) | 1999-11-24 |
PL332278A1 (en) | 1999-08-30 |
TR199900504T2 (xx) | 1999-06-21 |
EP0927029A4 (en) | 2001-06-13 |
KR20000068472A (ko) | 2000-11-25 |
CO5070658A1 (es) | 2001-08-28 |
WO1998009619A1 (en) | 1998-03-12 |
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