CN1104243C - 芳化酶抑制剂用于制备治疗男性雄激素相对缺乏的药物的用途 - Google Patents

芳化酶抑制剂用于制备治疗男性雄激素相对缺乏的药物的用途 Download PDF

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CN1104243C
CN1104243C CN95195216A CN95195216A CN1104243C CN 1104243 C CN1104243 C CN 1104243C CN 95195216 A CN95195216 A CN 95195216A CN 95195216 A CN95195216 A CN 95195216A CN 1104243 C CN1104243 C CN 1104243C
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A·拉德勒麦尔
U-F·哈伯尼施特
F·纽马恩
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Abstract

本发明涉及芳化酶抑制剂用于制备治疗男性雄激素相对缺乏的药物。按照本发明优选用的选择性的芳化酶抑制剂有阿他美坦，福美司坦，喷特罗唑、阿美代司，法得罗唑，CGS 20267和/或伏罗唑。

Description

芳化酶抑制剂用于制备治疗男性 雄激素相对缺乏的药物的用途
本发明涉及芳化酶抑制剂用于制备治疗男性雄激素相对缺乏的药物的新用途。
男人随着老龄化，睾丸产生雄激素减少，体内雄激素水平降低。这与妇女的情况不同，妇女在切除卵巢后短时间内雌激素的产生下降，而男人要持续十多年而且是日益下降。然而已明确地证实，老龄男人组血清中睾酮的总水平比年轻男性值明显降低。伴随老龄化过程甾体激素结合球蛋白(SHBG)同时上升，而游离的未被结合的、因而具有生物活性的睾酮水平降低。此外还注意到，雌激素虽然是由雄激素直接转变而来，但其血清浓度并不依赖老龄化而下降。因此，激素环境发生了明显的偏移。
男人性激素环境的特征是雄激素明显地超过雌激素。在血循环中雄性素的主要成分睾酮在血清中的浓度范围是nmol/l，而雌激素如雌二醇的浓度范围仅为pmol/l。雄性激素明显优势主要在整个青春期过后的时期内，不过这种雄激素优势的特征是与年龄相关的。随着老龄化并且明显地表现于60岁以上，雄激素的优势减少，表1列出了由青年到老年(≥60岁)血清中睾酮与雌二醇公开发表的测定值：表1青年与老年血清中睾酮(T)/雌二醇(E2)的比值的对比
  文献     青年(＜60J.)   老年(＞60J.)   ％Δ(减小值)
Deslypere et al.1)     206∶1     128∶1     -38％
Pirke & Drr 2)     324∶1     174∶1     -46％
Bakcr et al.3)     372∶1     225∶1     -31％
Murano et al.4)上午下午 55∶1160∶1 98∶184∶1 -37％-48％
1)Deslvpere，J.P，et al.，Journal of Clinical Endocrinology and Metabolism，64，No.1，19872)Pirke，K.M.& Doerr，P.，Acta Endocrinologica，74(1973)，792-8003)Baker，H.W.G.et al.，Clinical Endocrinology，5(1976)，349-3724)Murano，E.P.et al.，Acta Endocrinologica，99(1982)，619-623
虽然所列出的睾酮与雌二醇的比值在不同的文献中部分地有明显的不同，这可归因于测定方法的不同，但老龄男人的睾酮相对的过量值比年青男人值下降30-50％。
睾酮相对缺乏会在多种方面产生不利的后果。例如可以设想，由于睾酮水平的下降，此时雌激素浓度总是保持稳定不变，在雄激素与雌激素之间的不均衡性是发生前列腺良性增生(BPH)的决定性因素。睾酮相对缺乏也会导致老龄人的一系列的障碍，而与雌激素作用无关。可提及有肌肉质量的下降，伴随机体工作能力受到限制，骨密度下降，个别人发展成骨质疏松，性欲和性功能下降，和植物神经紊乱。所有这些障碍常常称作男性更年期。
治疗可能由于雄激素缺乏的症侯的现行方法迄今是给外原性雄激素。口服给有效的雄激素和肌肉注射有贮库作用的睾酮长链酯。为了改善雄激素缺乏的症状所用的这些治疗方式当然不会充分地达到生理状态。
口服给药的物质或是睾酮衍生物，因而不是天然的睾酮(例如Proviron)或是给在生理条件下生成异常高水平的二氢睾酮(DHT)(例如Andriol)。DHT与睾酮不同，它对于前列腺良性增生以及雄激素引起的秃头有很大作用。
贮库剂型由于自库中的不均匀释放，迄今仍是未能满意解决的问题。在开始阶段睾酮水平的增高明显地在正常范围内，但在剂型释放的末期，睾酮值明显降低。
长期以来，人们知道由于内分泌调节系统男人的雄激素水平保持在恒定的水平，除雄激素外，还有雌激素的参与。给以雌激素样作用的药物剂量的物质，如己烯雌酚，可以大大地降低前列腺癌患者的垂体黄体生成素的释放，并且降低血清中睾酮水平到去势的水平。
根据前列腺癌患者用纯抗雄激素的治疗经验，以及老龄人如男性更年期患者，可有反馈的范围。若给以纯抗雄激素如氟他胺或Casodex，抑制了雄激素的中心阻止作用，则该老龄组的血清睾酮浓度与起始值相比反馈上升了大约50-60％。用纯抗雄激素连续一个月治疗前列腺素癌，该反馈的机能就会下降，即开始时明显提高的雄激素水平又下降了(Lund和Rasmussen，1988，Mahler和Denis，1990，Delaere和Van Thillo，1991)。
意外的是，老龄人雄激素的降低不会经过反馈机理的激活而受到阻止。其原因一方面是老龄者的睾丸功能一般减退，但另一方面也会因反馈机理表现出对性激素敏感性的提高(J.P.Deslypere et al，J.ClinicalEndocrinology and Mechanism，64，No.1，1987)。所以这归咎于老龄男人与年青人相比(见下)反调节机理不突出，以致长期应用时，与初始值相比，血清中雄激素浓度没有提高。
反之，皆知年青男人每天用抗雌激素(往往具有显著的部分雌激素作用)，长时间治疗时，睾酮值也会持久性升高(Treatment of MaleInfertility，Springer出版社，柏林，海德堡，纽约，1982；H.Fuse等，Archives of Andrology，31(1993)，139)。
根据理论上考虑，用抗雌激素治疗男性雄性素相对缺乏症似乎是不适宜的。用抗雌激素治疗时对雌激素水平没有影响，因为它阻断了雌激素对其受体的作用。使用抗雌激素作为受体阻断到由于不充分的应答，立即导致不适宜的效果，因为反调节作用发生的高雌激素浓度会直接作用于游离的受体。
抗雌激素治疗的另一个缺点是能否使所有依赖于雌激素的组织和器官同时将雌激素受体阻断是不确定的，这对于男性使用时的意义具有特异的雌激素作用，例如用最皆知的抗雌激素他莫昔芬所表现的那样。
本发明内容是提供适宜的物质，它可排除男人雄激素相对缺乏，而同时使雄激素和雌激素的比例同时接近生理水平，并避免了上述的缺点。
本发明内容是应用至少一种芳化酶抑制剂制备治疗男性雄激素相对缺乏的药物。
已经证明用芳化酶抑制剂用来治疗老龄男性的雄激素相对缺乏，意外地可长时间地提高雄激素水平。
由于逐渐降低了雌激素浓度，反调节作用引发刺激了雄激素的合成。该芳化酶抑制剂使男性的内源性睾酮/雌激素比例重新达到平衡，从而重新调节了雄激素的相对缺乏。
本发明的芳化酶抑制剂是这样的化合物，它抑制了芳化酶，阻止了由代谢前体生成雌激素(抑制生物合成)。所以各种可作为芳化酶底物的化合物都可考虑是芳化酶抑制剂，例如，在J.Clinical Endocrinologyand Metabolism  49，672(1979)所述的睾内酯(17α-氧杂-D-高雄甾-1，4-二烯-3，17-二酮)；在“Endocrinology”1973，Vol.92 No.3，873页叙述的化合物雄甾-4，6-二烯-3，17-二酮，雄甾-4，6-二烯-17β-醇-3-酮乙酸酯，雄甾-1，4，6-三烯-3，17-二酮，4-雄甾烯-19-氯-3，17-二酮，4-雄甾烯-3，6，17-三酮。
在德国专利3124780所述的19-炔化甾体，德国专利3124719叙述的10-(1，2-丙二烯基)-甾体，欧洲专利公开号No.100566叙述的19-硫代雄甾烷衍生物，在“Endocrinology”1977，Vol.100，No6，1684页和美国专利4235893叙述的4-雄甾烯-4-醇-3，17-二酮及其酯，德国专利3539244叙述的1-甲基-15α-烷基-雄甾-1，4-二烯-3，17-二酮；在德国专利3644358叙述的10β-炔基-4，9(11)-雌二烯衍生物，和欧洲专利0250262叙述的1，2β-亚甲基-6-亚甲基-4-雄甾烯-3，17-二酮。
用于本发明制备治疗男性雄激素相对缺乏的药物优选用选择性芳化酶抑制剂。所谓选择性芳化酶抑制剂是指其功能是芳化酶的底物、给以某剂量后除对芳化酶外对与临床相关的其它酶没有影响的化合物。
本发明典型的选择性芳化酶抑制剂宜用例如甾体化合物：1-甲基-雄甾-1，4-二烯-3，17-二酮(德国专利-A3322285；阿他美坦)，4-羟基-4-雄甾烯-3，17-二酮(福美司坦)，以及非甾体芳化酶抑制剂：(RS)-5-(4-氰苯基)-5，6，7，8-四氢-咪唑并(1，5α)-吡啶盐酸盐(Cancer Res.，48，834-838页，1988；法罗唑)，4-[氰基-α-(1，2，4-三唑-1-基)-苯基]-苯腈(CGS 20267)，5-[环戊叉-(1-咪唑基)-甲基]-噻吩-2-腈(EP-A 0 411735，喷托唑，2，2′-[5-(1H′，2′，4-三唑-1-基-甲基)-1，3-亚苯基]-双-(2′-甲基丙腈)(阿米代司)以及(6-[1-(4-氯苯基)-1，2，4-三唑-1-基)-甲基]-1-甲基-1H-苯并三唑)二盐酸盐(伏罗唑)。
上面所列的选择性芳化酶抑制剂并非只如此，也可考虑其它的在上述刊物和公开中发表的化合物及其它化合物，只要可适于上述的要求。
用芳化酶抑制剂治疗老龄男性数月后可降低反调节的刺激，与此学说相反，长时间研究的数据提示，用阿他美坦治疗良性前列腺增生病人，用药24-48周后睾酮浓度有显著性提高。
表2列出了多剂量研究与安慰剂治疗24周的对比结果(100mg/日，300mg/日和600mg/日)：表2：阿他美坦作用下的睾酮浓度(ng/ml)
    日剂量     开始值     24周后  Δ％(均值±SD)
    安慰剂     4.13     4.18   6.00±27.64
    100mg     4.41     5.57   29.57±34.70
    300mg     4.50     6.15   40.88±156.12
    600mg     3.78     5.40   41.19±37.62
表3和4列出了作用48周后的结果表3：阿他美坦作用下的睾酮浓度(ng/ml)
    日剂量     开姑值     48周后    Δ％(X±SD)
    安慰剂     4,6     4,1     -0,1±43,1
    400mg     4,2     5,4     42,9±53,5
表4：阿他美坦作用下的睾酮浓度(ng/ml)
    日剂量     开始值     48周后     Δ％(X±SD)
    安慰剂     4,6     4,6     2,8±26,9
    100mg     5,1     5,9     19,0±36,8
    300mg     4,7     6,6     41,7±46,4
由于逐渐降低了雌激素浓度，诱发了对雄激素生物合成的反调节性刺激作用。在一定程度上发生了内源性睾酮取代作用，从而将雄激素/雌激素的平衡又回复到“年青人”的范围内。这是用选择性的芳化酶抑制剂阿他美坦长时期治疗老龄男人(平均年龄60岁以上)已证实的结果。
在许多临床研究中，用阿他美坦治疗老龄男性的良性前列腺增生，以不同的剂量治疗，时间最长为48周。结果表明，用阿他美坦治疗的患者睾酮/雌二醇比例明显地向有利于睾酮方法移动。表5列出了阿他美坦治疗患者的4种研究和7个治疗组睾酮/雌二醇治疗前后的比值。表5：用阿他美坦治疗后睾酮/雌二醇比例的变化
    治疗组     开始值     治疗后(时间)    ％Δ
    100mg     248∶1     418∶1(48.周)   +41％
    300mg     236∶1     440∶1(48.周)   +46％
    400mg     207∶1     454∶1(48.周)   +54％
    200mg t.i.d.     116∶1     214∶1(8.周)   +46％
    100mg     196∶1     376∶1(24.周)   +48％
    300mg     199∶1     473∶1(24.周)   +58％
    600mg     170∶1     439∶1(24.周)   +61％
阿他美坦的治疗全都使睾酮/雌二醇平衡重新有利于雄激素成分。该作用在整个观察期间(最长直到48周)的治疗得到证实。每日剂量100mg-600mg虽然外周的雌激素下降，但在高剂量组的雄激素有较强的升高趋势。
设想在老龄组超过60岁的患者其睾酮降低的优势(雄激素相对缺乏)比年青男人降低大约30-50％，这导致“男性更年期”的症候。通过给以优选有选择性的芳化酶抑制剂，经刺激内源性的睾酮排代，而不必给以外源性激素，即重建了原来雄激素与雌激素之间的“强比例”。在老龄者有30-50％的比值比年青人值低，即永远还有50-70％的初始值为相应的“年青人”值。70岁患者的睾酮/雌二醇比值230∶1必然建立起新的平衡，范围是229∶1到460∶1，从而平衡了开始的30-50％的降低值。表6列出了在表4进行的阿他美坦研究的患者组的计算结果。表6：每日给予不同剂量的阿他美坦后计算的“年青的”睾酮/雌二醇范围与测定值的比较。
    日剂量     开始值     降低30-50％的计算的范围   用可他美坦后达到比值
    100mg     248∶1     354∶1→496∶1     418∶1
    300mg     236∶1     337∶1→472∶1     440∶1
    400mg     207∶1     296∶1→414∶1     454∶1
    100mg     196∶1     280∶1→392∶1     376∶1
    300mg     199∶1     284∶1→398∶1     473∶1
    600mg     170∶1     243∶1→340∶1     439∶1
每日用100mg一般可很好地达到目的范围。但用较高剂量时其结果在目的范围之上。
通过测定血清中睾酮和雌二醇的浓度，可以早期控制是否能达到所希望的激素平衡，并任选地调整剂量范围。
通常口服阿他美坦量为25-1000mg，优选为50-600mg，或生物等价量的其他芳化酶抑制剂，以治疗男性雄激素相对缺乏症。
芳化酶抑制剂可口服或胃肠道外用药。口服剂型优选为片剂、糖衣剂、胶囊剂，丸剂，悬浮剂或溶液，这些剂量用对于本领域技术人员所知的常规的方法，将所用的芳化酶抑制剂与口服剂型常规的添加剂和载体物质制成。
本发明制备的药剂中含有的有效成分阿他美坦，每个剂型单元为50-500mg，以及常规的助剂，载体和(或)稀释剂，或者用生物等价量的其它芳化酶抑制剂。
下面的实施倒是芳化酶抑制剂阿他美坦片剂的有代表性的处方：
实施例：100.0mg        1-甲基-雄甾-1，4-二烯-3，17-二酮140.0mg        乳糖70.0mg         玉米淀粉2.5mg          聚-N-乙烯基吡咯烷酮252.0mg          Aerosil0.5mg         硬脂酸镁315.0mg        片总重量，用常规方法压片。
应用芳化酶抑制剂治疗男性更年期可以降低雌激素浓度，该治疗上的易控制性其特征是用芳化酶抑制剂治疗，刺激睾酮生成而不必用抗雌激素。如已所述，用抗雌激素进行控制治疗，不可能在早期测定药效学参数。

Claims (2)

1.选择性芳化酶抑制剂的用途，用于制备治疗男性雄激素相对缺乏的药物的用途。
2.权利要求1的用途，该芳化酶抑制剂为阿他美坦。
CN95195216A 1994-09-22 1995-09-22 芳化酶抑制剂用于制备治疗男性雄激素相对缺乏的药物的用途 Expired - Fee Related CN1104243C (zh)

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