CN1033948C - 二氢螺旋烯酮在制备药物组合物中的应用 - Google Patents

二氢螺旋烯酮在制备药物组合物中的应用 Download PDF

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CN1033948C
CN1033948C CN90103713A CN90103713A CN1033948C CN 1033948 C CN1033948 C CN 1033948C CN 90103713 A CN90103713 A CN 90103713A CN 90103713 A CN90103713 A CN 90103713A CN 1033948 C CN1033948 C CN 1033948C
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estrogen
formula
chemical compound
contraception
compound
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CN1047299A (zh
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西比尔·贝耶
沃尔特·埃尔格
西野幸重
鲁道夫·韦卓特
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Bayer Pharma AG
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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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin

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Abstract

式I的化合物最好与雌激素共同用于制备药物，该种药物适宜于治疗绝经前(月经周期稳定)激素混乱和更年期的激素替代治疗，还适宜于治疗雄激素引起的紊乱和用于避孕。

Description

本发明涉及式I化合物在药物制备中的应用，
Figure C9010371300022
化合物I(二氢螺旋烯酮)在DE-A-2652761中除了作为利尿剂外，还作为一种醛固酮拮抗剂予以介绍。
由DE-A-3022337还可知道，化合物I在一定剂量条件下业已显示其抗醛固酮的作用，并且还具有明置的促孕素作用。因此，化合物I在单独使用或与雌激素组合为制剂时可用于避孕。
根据DE-A-3022337介绍，上述制剂可用于需要避孕但患有高血压或口服避孕药后会导致血压升高的妇女。因此，对血压容易升高的妇女也可采用激素避孕。
由EP-A-0253607可以知道，有一种药物组合物可用于绝经前(约从40岁起)妇女的替代治疗和避孕，这种药物组合物含有下列雌激素：
17β-雌二醇，
炔雌二醇，
炔雌醇其醚
和下列促孕素：
乙基羟基二降孕甾烯炔酮，
乙基羟基二降孕二烯炔酮，
脱氧炔诺酮，
3-酮脱氧炔诺酮，
炔诺酮。
由上所选择的组合物用于绝经前的过渡期，可平衡激素的混乱，并有助于缓解在这个时期由于妇女机体激素调整引起的疾病。同时，这种组合物可以保证在这个年龄区所需要的避孕保护。
由于已知各种原因和禁忌症象一类问题随着年龄的增长而增加，所以服用激素避孕药仅适用于大约35岁的妇女，这就使服用一定剂量进行绝经前的激素治疗和更年期的替代治疗，同时又能起到避孕作用则被视为问题。
除以上所述外，妇女随着年龄的增长，往往可以看到的禁忌症象是男性化现象，例如长胡须，声音深沉，皮肤不光洁；此外，常常还出现血压升高。
现已发现，式I化合物具有很高的抗雄激素活性组分，并且另外还具有令人惊奇的促孕素作用和抗醛固酮作用，在一定剂量条件下，该化合物配制剂还可用作口服避孕药。二氢螺旋烯酮大致具有与常规化合物环丙氯地孕酮同样高的抗雄激素活性(最高活性相同)。动物模拟：经过阉割的并由睾酮取代的小雄鼠)。
本发明的任务在于将式I化合物用于制备药物，这种药物适宜于治疗绝经前(月经周期稳定)激素混乱和更年期的激素替代治疗，并且适宜于治疗雄激素感应性紊乱和用于避孕。
优先将雌激素与式I化合物一起使用.至于究竟用合成雌激素还是天然雌激素，则决定于避孕作用为主还是替代治疗为主，前者优先用炔雌二醇或其他合成雌激素：后者则这种药物应含有天然雌激素。
但是，无论何种情况，这种药物都应保证中令妇女(约35-55岁)月经周期的稳定，同时在对雄激素感应性紊乱产生有益影响的条件下，保证在该年龄区还需要的避孕。当然，这种药物也适宜于年轻妇女，尤其是患高血压和男性化需要特殊避孕的妇女。这种应用是完全可能的，因为式I化合物同时将促孕素、抗醛固酮和抗雄激素的高活性结合于一体。至今所知，还没有一种药物同时具有这三种性质。
式I化合物的使用剂量应为每天0.5-50mg，尤以每天1-10mgf为佳。
就雌激素而言，至今所用的全部雌激素均可考虑。因此，雌激素的使用剂量最好能将本发明的雌激素用量与每天0.02-0.04mg的17α-炔雌二醇或0.5-4.0mg的戊酸雌二醇的用量相等。此外，17α-炔雌二醇酯和17α-炔雌二醇醚也都适宜用作雌激素组分，例如17α-乙炔基-7α-甲基-1，3，5(10)-雌三烯-1，3，17β-三醇(德国专利说明书1593509和德国公开说明书2818164)。此外，还有在DE-A-3628189中所述的14，17β-桥亚乙基-14β-雌三烯。雌激素和促孕素活性组分最好一起口服，但是也可单独服用和/或非经肠道或经皮肤给药。
本发明制剂的配制是以6β，7β； 15β，16β-二亚甲基-3-氧-4-雌烯-[17(β-1′)-螺旋-5′]-多氢呋喃-2′-酮为基础，按已知方法，将活性物质，需要时与雌激素结合，与药典中所用载体物质、稀释剂，需要时与矫味剂等进行加工配制并转变为所需剂型。从最好口服剂型而言，特别可以考虑的有片剂，糖衣丸，胶囊，丸剂，悬浮剂或溶液。非经肠道用药的剂型尤其可考虑油状溶液，例如芝麻油、蓖麻油和棉籽油溶液均很适用。为了提高溶解度，可加溶剂，如苯甲醇苄酯或苄醇。
下面将按不同实施例详细阐述若干制剂的配制。
实施例1
将20.0mg6β，7β；15β，16β-二亚甲基-3-氧-4-雌烯-[17(β-1′)-螺旋-5′]-多氢呋喃-2′-酮和0.05mg17α-炔雌二醇与140.45mg乳糖、59.5mg玉米淀粉、2.0mg硅胶(Aerosil)、2.5mg聚乙烯吡略烷酮25和0.5mg硬脂酸镁均匀混合，无需预先制粒即可压制成每片最终重量为225mg的片剂。
实施例2
按类似实施例1方法，将10mg6β，7β，15β，16β-二亚甲基-3-氧-4-雌烯-[17(β-1′)-螺旋-5′]-多氢呋喃-2′-酮和0.05mg17α-炔雌二醇与150.45mg乳糖、59.5mg玉米淀粉、2.0mg硅胶(Aerosil)、2.5mg聚乙烯吡咯烷酮25和0.5mg硬脂酸镁压制成最终重量为225mg的片剂。
实施例3
按类似实施例1的方法，将20mg6β，7β，15β，16β-二亚甲基-3-氧-4-雌烯-[17(β-l′)-螺旋-5′]-多氢呋喃-2′-酮与140.5mg乳糖、59.5mg玉米淀粉、2.0mg硅胶(Aerosil)、2.5mg聚乙烯吡咯烷酮25和0.5mg硬脂酸镁压制成每片最终重量为225mg的片剂。

Claims (3)

1.式(I)化合物在制备抗醛甾酮的、促孕的和抗雄激素的药物组合物中的应用，
2.根据权利要求1的式I化合物的应用，其中式I化合物与合成雌激素一起使用。
3.根据权利要求1的式I化合物的应用，其中式I化合物与天然雌激素一起使用。
CN90103713A 1989-05-16 1990-05-16 二氢螺旋烯酮在制备药物组合物中的应用 Expired - Lifetime CN1033948C (zh)

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DE3916112A DE3916112A1 (de) 1989-05-16 1989-05-16 Dihydrospirorenon als antiandrogen
DEP3916112.9 1989-05-16

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US5569652A (en) 1996-10-29
ZA903754B (en) 1991-02-27
NL300221I1 (nl) 2006-04-03
IE901738L (en) 1990-11-16
HU213408B (en) 1997-06-30
DE59010730D1 (de) 1997-08-07
DK0398460T3 (da) 1998-02-16
HUT54500A (en) 1991-03-28
PT94038B (pt) 1997-06-30
JPH0395121A (ja) 1991-04-19
GR3024861T3 (en) 1998-01-30
BR1101055A (pt) 2000-08-08
PT94038A (pt) 1991-01-08
EP0398460B1 (de) 1997-07-02
JP2848919B2 (ja) 1999-01-20
CN1047299A (zh) 1990-11-28
CA2016780A1 (en) 1990-11-16
DE122004000006I1 (de) 2006-06-08
ES2106728T3 (es) 1997-11-16
IL94416A0 (en) 1991-03-10
NL300221I2 (nl) 2006-11-01
DE3916112C2 (zh) 1992-04-30
AU5509490A (en) 1990-11-22
EP0398460A3 (de) 1991-09-25
LU91065I2 (fr) 2004-03-30
EP0398460A2 (de) 1990-11-22
ATE154881T1 (de) 1997-07-15
HU903045D0 (en) 1990-09-28
DE3916112A1 (de) 1990-11-22
DD294417A5 (de) 1991-10-02
AU642876B2 (en) 1993-11-04
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