CN1216036A - 新型苯并环己酮或苯并吡喃酮衍生物及其制备方法 - Google Patents

新型苯并环己酮或苯并吡喃酮衍生物及其制备方法 Download PDF

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CN1216036A
CN1216036A CN98800075A CN98800075A CN1216036A CN 1216036 A CN1216036 A CN 1216036A CN 98800075 A CN98800075 A CN 98800075A CN 98800075 A CN98800075 A CN 98800075A CN 1216036 A CN1216036 A CN 1216036A
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吉浜诚
中越雅道
中村纯二
中山正次
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Abstract

本发明提供可用作对各种雄性和雌性激素依赖性疾病的预防和/或治疗药的新型苯并环己酮或苯并吡喃酮衍生物及其制备方法。新型苯并环己酮或苯并吡喃酮衍生物如通式(Ⅰ)所示。(其中R1和R2分别表示氢、羟基、烷氧基或芳烷氧基,R3～R7分别表示氢、羟基、碳数1～6的直链或支链烷基、烷氧基或芳烷氧基、卤素、氨基或R3和R4、R4和R5、R5和R6、R6和R7结合的亚烷二氧基,A表示亚甲基或氧。)此外,该衍生物是通过特定的苯并环己酮或苯并吡喃酮衍生物和特定的苯甲醛衍生物反应制得的。

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新型苯并环己酮或苯并吡喃酮衍生物及其制备方法
本发明涉及新型苯并环己酮或苯并吡喃酮衍生物及其制备方法。本发明的新型苯并环己酮或苯并吡喃酮衍生物具有17-β羟基类固醇脱氢酶(以下称为17β-HSD)阻断活性，利用其活性可使之作为雄性和雌性激素依赖性疾病的预防和/或治疗药物，具体的说就是作为前列腺癌、前列腺肥大症、男性化症、乳腺癌、乳腺疾病、子宫癌、子宫内膜异位、卵巢癌等各种雄性和雌性激素依赖性疾病的预防和/或治疗药物很有用。
近年来，我国出现前列腺癌和前列腺肥大等雄性激素依赖性疾病以及乳腺癌和子宫内膜异位等雌性激素依赖性疾病的患病率增加的问题。例如，据1984年度的统计，前列腺癌的死亡率为每10万人3.9人，是美国非白人的1/10，但是因医疗技术的进步使平均寿命上升以及饮食的欧美化使其逐步上升，1993年为每10万人6.7人，接近欧美的水平。据预测2015年的前列腺癌死亡数将约为1990年的4倍，这是所有癌症中最坏的增加率。
已经有许多事实表明，通过降低血中的雄性激素水平可以使雄性激素依赖性疾病患者的主观和客观症状均得到改善。所以，对这些疾病进行治疗的同时也用各种手段降低血中的雄性激素水平，例如去势、给予脑下垂体分泌的促性腺激素释放激素LH-RH的激动剂从而使脑下垂体脱敏致LH-RH分泌能力降低而血中雄性激素水平达去势水平、给予抗雄性激素药拮抗雄性激素受体从而控制雄性激素的作用等，事实上这些措施的临床效果已得到广泛承认。然而，由于去势导致QOL的降低，因此仅限于很少的病例。此外LH-RH的激动剂具有激动剂特有的点燃现象(暂时性的雄性激素增加)而导致骨痛和排尿障碍等副作用，以及来源于肾上腺的雄性激素持续存在而带来的再燃等问题。更进一步，抗雄性激素药显示出在给药中因雄性激素受体变异而导致治疗效果降低的现象。因此最近提出了更有效的内分泌疗法，“雄性激素完全阻断疗法”。此方法通过几种内分泌疗法的组合，目的在于完全阻断血中的雄性激素，从而预期有更好的治疗效果。
C19甾体中具有最强雄性激素活性的睾丸酮可以用17β-HSD从底物雄烯二酮生物合成。所以，阻断了此17β-HSD就能直接降低血中睾丸酮的浓度，可望对上述雄性激素依赖性疾病有较好的治疗效果。此外这个酶也是C18甾体中具最强雌性激素活性的雌二醇的生物合成酶，所以它对乳腺癌和子宫内膜症等雌性激素依赖性疾病也会有同样的治疗效果。
到目前，作为17β-HSD的阻断剂，有甾体化合物也有非甾体化合物。作为非甾体化合物，例如有生物化学和生物物理研究通讯(Biochemical and Biophysical Research Communications，215卷，1137-1144页，1995年)记载的黄酮和异黄酮类，甾体生物化学杂志(Journal of Steroid Biochemistry，23卷，357-363页，1985年)记载的脂肪酸等。但是这些化合物的活性并不令人满意，因此人们希望得到有更高活性的物质。
鉴于上述情况，本发明者们进行锐意的探索，结果发现具优良17β-HSD阻断活性的新型化合物。因此，本发明的目的在于提供新型的苯并环己酮或苯并吡喃酮衍生物及其制备方法。
本发明涉及新型苯并环己酮或苯并吡喃酮衍生物及其制备方法。本发明的新型苯并环己酮或苯并吡喃酮衍生物具有17-β羟基类固醇脱氢酶(17β-HSD)阻断活性，利用其活性可使之作为雄性和雌性激素依赖性疾病的预防和/或治疗药物，具体的说就是作为前列腺癌、前列腺肥大症、男性化症、乳腺癌、乳腺疾病、子宫癌、子宫内膜异位、卵巢癌等各种雄性和雌性激素依赖性疾病的预防和/或治疗药物很有用。
本发明的衍生物为下述通式(Ⅰ)
Figure A9880007500061
(其中R1和R2分别表示氢、羟基、烷氧基或芳烷氧基，R3～R7分别表示氢、羟基、碳数1～6的直链或支链烷基、烷氧基或芳烷基、卤素、氨基或R3和R4、R4和R5、R5和R6、R6和R7结合的亚烷二氧基，A表示亚甲基或氧。)所示的新型苯并环己酮或苯并吡喃酮衍生物。
此外，本发明的特征在于，新型苯并环己酮或苯并吡喃酮衍生物的制备是将下述通式(Ⅱ)所示的苯并环己酮或苯并吡喃酮衍生物和下述通式(Ⅲ)所示的苯甲醛衍生物用有机溶剂溶解，在酸性条件下加热回流，再将反应液精制而得。
Figure A9880007500062
(其中R1和R2分别表示氢、羟基、烷氧基或芳烷氧基，A表示亚甲基或氧。)
Figure A9880007500063
(其中R3～R7分别表示氢、羟基、碳数1～6的直链或支链烷基、烷氧基或芳烷氧基、卤素、氨基或R3和R4、R4和R5、R5和R6、R6和R7结合的亚烷二氧基。)
通式(Ⅰ)所示的本发明新型苯并环己酮或苯并吡喃酮衍生物，具体可列举以下的化合物。(化合物的序号和图1～3记载的实施例的序号一致。)(1)2-〔(3,4-二羟基苯基)亚甲基〕-6-羟基-1-苯并环己酮(2)2-(苯基亚甲基)-6-羟基-1-苯并环己酮(3)2-〔(3-羟基苯基)亚甲基〕-6-羟基-1-苯并环己酮(4)2-〔(4-羟基苯基)亚甲基〕-6-羟基-1-苯并环己酮(5)2-〔(2-甲氧基苯基-4-羧酸)亚甲基〕-6-羟基-1-苯并环己酮(6)2-〔(4-二甲基氨基苯基)亚甲基〕-6-羟基-1-苯并环己酮(7)2-〔(3,4-二甲氧基苯基)亚甲基〕-6-羟基-1-苯并环己酮(8)2-〔(3,5-二甲氧基苯基)亚甲基〕-6-羟基-1-苯并环己酮(9)2-〔(4-溴苯基)亚甲基〕-6-羟基-1-苯并环己酮(10)2-〔(4-氯苯基)亚甲基〕-6-羟基-1-苯并环己酮(11)2-〔(4-氟苯基)亚甲基〕-6-羟基-1-苯并环己酮(12)6-羟基-2-亚胡椒基-1-苯并环己酮(13)2-〔(3,4-苯并二噁烷)-6-亚甲基〕-6-羟基-1-苯并环己酮(14)2-〔(3,4-二羟基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮(15)7-羟基-3-亚胡椒基-4(4H)-苯并吡喃酮(16)3-〔(1,4-苯并二噁烷)-6-亚甲基〕-7-羟基-4(4H)-苯并吡喃酮(17)3-〔(3,4-二甲氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮(18)3-〔(3-乙氧基-4-甲氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮(19)3-〔(3-甲氧基-4-乙氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮(20)3-〔(3,4-二乙氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮(21)3-〔(3-甲基-4-甲氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮(22)2-甲氧基-〔(3-甲氧基-4-乙氧基苯基)亚甲基〕-6-甲氧基-1-苯并环己酮
本发明衍生物除了上述化合物外还包括这些化合物的立体异构体、以及和碱形成的盐。作为与碱形成的盐，例如有和无机碱形成的钠盐、钾盐、镁盐、钙盐、铝盐等，有和低级烷基胺或低级醇胺等有机碱、赖氨酸、精氨酸、鸟氨酸等碱性氨基酸形成的盐或铵盐等。更进一步，衍生物也可形成水和物、低级醇等的溶剂合物和多晶形结晶等。
本发明的衍生物可按以下方法制得。例如，将上述苯并环己酮或苯并吡喃酮衍生物(Ⅱ)和苯甲醛衍生物(Ⅲ)用甲醇、乙醇、或丙醇等溶剂溶解，加入浓盐酸加热回流1～24小时，然后冷却，将析出的结晶滤过，就得到本发明衍生物(Ⅰ)。此外，无结晶析出时加入水使结晶析出，滤过后干燥，就得到目的物本发明衍生物。还有，可在甲醇、乙醇、或丙醇等溶剂中加入氢氧化钠或氢氧化钾，搅拌1～24小时后用盐酸调成酸性，将析出的结晶滤过，就得到目的物本发明衍生物。更进一步，也可在甲醇、乙醇、丙醇、或醚等有机溶剂的氯化氢饱和的溶液中，在冷却、室温下放置、或加热下，搅拌1～24小时，再加入水使目的化合物结晶析出，将析出的结晶滤过，就得到本发明衍生物。
将本发明衍生物对人和动物作为药物经口和非经口安全地给予。非经口给药例如有静脉注射、肌内注射、皮下注射、腹腔注射、经皮给药、经肺给药、经鼻给药、经肠给药、口腔内给药、经粘膜给药等，其制剂例如有注射剂、栓剂、气雾剂、经皮吸收带(tape)等。作为经口给药制剂，例如有片剂(包括糖衣片、包衣片、口腔粘膜用片)、散剂、胶囊剂(包括软胶囊)、颗粒剂(包括包衣的)、丸剂、糖锭剂、液体药剂、或其药剂学上允许的缓释制剂。作为经口给药用液体剂形，例如有混悬剂、乳剂、糖浆剂(包括干糖浆)、酏剂等。
这些制剂按众所周知的制剂学制法准备，将药物和药理学上允许的载体、赋形剂、崩解剂、润滑剂、着色剂等一起作成药品组合物作为制剂给予。作为这些制剂所用的载体和赋形剂，例如有乳糖、葡萄糖、蔗糖、甘露醇、马铃薯淀粉、玉米淀粉、碳酸钙、磷酸钙、硫酸钙、结晶纤维素、甘草粉末、黄龙胆粉末等，作为粘合剂，例如有淀粉、西黄耆胶、明胶、糖浆、聚乙烯醇、聚乙烯醚、聚乙烯吡咯烷酮、羟丙基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素等，作为崩解剂例如有淀粉、琼脂、明胶粉末、羧甲基纤维素钠、羧甲基纤维素钙、结晶纤维素、碳酸钙、碳酸氢钠、海藻酸钠等，作为润滑剂例如有硬脂酸镁、滑石、氢化植物油、聚乙二醇等，作为着色剂可加入允许往药品中添加的着色剂。
对于片剂、颗粒剂，可根据需要用蔗糖、明胶、羟丙基纤维素、精制虫胶、明胶、甘油、山梨醇、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、邻苯二甲酸纤维素乙酸酯、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸甲酯、甲基丙烯酸聚合物等作成包衣，或用两种以上的这些物质形成的物质层作成包衣。另外也可用乙基纤维素合明胶等的物质作成胶囊。而且在调制注射剂时，根据主药的需要加入pH调节剂、缓冲剂、稳定化剂、助溶剂等，按常规方法制成各种注射剂。
本发明衍生物对患者的给药因症状的程度、患者的年龄、健康状态、体重等条件的不同而不同，并没有特殊的限定，一般可以是成人每天约1mg～1000mg，优选50～200mg经口或非经口1天1次或1次以上给予。
此外，本发明衍生物在半导体装置等的制备过程中，可作为能给出高灵敏度分辨力、良好显像性、耐热性和具优良抗蚀形状的抗蚀图的正型光致抗蚀剂组合物使用。
图1为表示实施例结果的图。
图2为表示实施例结果的图。
图3为表示实施例结果的图。
下面就实施例对本发明进行详细的说明，但本发明并不仅限于这些例子。实施例12-〔(3,4-二羟基苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和3,4-二羟基苯甲醛0.85g，回流2.5小时后，冷却到室温再加入水357ml，滤取析出的结晶。结晶在减压下用五氧化二磷干燥6小时，得到目的物1.25g。FABMASS(M+1)；2831H-NMR(in DMSO-d6)；2.83(2H,m),3.02(2H,m),6.66(1H,d,J=2.1Hz),6.75(1H,dd,J=8.5,2.4Hz),6.79(1H,d,J=7.9Hz),6.83(1H,dd,J=8.3,1.9Hz),6.94(1H,d,J=1.8Hz),7.49(1H,s),7.81(1H,d,J=8.5Hz),9.09(1H,s),9.35(1H,s),10.31(1H,s)实施例22-(苯基亚甲基)-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和苯甲醛0.42ml，回流2小时后，冷却到室温再加入水400ml，滤取析出的结晶。结晶在减压下用五氧化二磷干燥6小时，得到目的物0.756g。FABMASS(M+1)；2511H-NMR(in DMSO-d6)；2.83(2H,m),3.02(2H,m),6.66(1H,s)、6.76(1H,d,J=8.6Hz),7.44(4H,m),7.62(1H,s),7.84(1H,d,J=8.8Hz),10.37(1H,s)实施例32-〔(3-羟基苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和3-羟基苯甲醛0.903g，回流1小时后，冷却到室温再加入水400ml，滤取析出的结晶。结晶在减压下用五氧化二磷干燥6小时，得到目的物0.92g。FABMASS(M+1)；2671H-NMR(in DMSO-d6)；2.83(2H,m),2.99(2H,m),6.66(1H,d,J=2.4Hz)、6.76(2H,m),6.98(2H,m),7.23(1H,t,J=7.0Hz),7.53(1H,s,),7.84(1H,d,J=8.4Hz),9.54(1H,s),1实施例42-〔(4-羟基苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和4-羟基苯甲醛0.903g，回流1小时后，冷却到室温再加入水200ml放置1小时后，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物0.941g。FABMASS(M+1)；2671H-NMR(in DMSO-d6)；2.81(2H,m),3.00(2H,m),6.65(1H,d,J=2.4Hz)、6.75(1H,dd,J=8.5,2.1Hz),6.84(2H,d,J=8.5Hz),7.35(1H,d,J=8.8Hz),7.55(1H,s,),7.82(1H,d,J=8.5Hz).9.84(1H,s),10.33(1H,s)实施例52-〔(2-甲氧基苯基-4-羧酸)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和4-甲酰基-2-甲氧基苯乙酰化物1.44g，回流1小时后，冷却到室温再加入水400ml放置2小时后，滤取析出的结晶。结晶在减压下用五氧化磷干燥4小时，得到目的物0.671g。FABMASS(M+1)；3251H-NMR(in DMSO-d6)；2.82(2H,m),3.05(2H,m)3.81(3H,s),6.66(1H,d,J=2.1Hz)、6.75(1H,dd,J=8.2,2.1Hz),6.85(1H,d,J=7.9Hz),6.98(1H,dd,J=8.2,1.8Hz),7.07(1H,d,J=1.8Hz),7.58(1H,s,),7.83(1H,d,J=8.5Hz)实施例62-〔(4-二甲基氨基苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和4-二甲基氨基苯甲醛0.97g，回流1.5小时后，冷却到室温再加入水400ml，滤取析出的结晶。结晶在减压下用五氧化二磷干燥6小时，得到目的物0.885g。FABMASS(M+1)；2941H-NMR(in DMSO-d6)；2.81(2H,m),2.98(6H,s),3.03(2H,m),6.66(1H,d,J=2.5Hz)、6.75(1H,dd,J=8.5,2.4Hz),6.83(1H,d,J=8.8Hz),7.40(1H,d,J=8.8Hz),7.58(1H,s),7.82(1H,d,J=8.5Hz)实施例72-〔(3,4-二甲氧基苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和3,4-二甲氧基苯甲醛1.23g，回流1.5小时后，冷却到室温，滤取析出的结晶。结晶在减压下用五氧化二磷干燥5.5小时，得到目的物1.60g。FABMASS(M+1)；3111H-NMR(in DMSO-d6)；2.82(2H,m),3.06(2H,m),3.80(6H,s),6.66(1H,d,J=2.1Hz)、6.76(1H,dd,J=8.5,2.4Hz),7.01(1H,d,J=8.8Hz),7.07(2H,m),7.60(1H,s),7.84(1H,d,J=8.5Hz),10.19(1H,s)实施例82-〔(3,5-二甲氧基苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和3,5-二甲氧基苯甲醛1.23g，回流1.5小时后，冷却到室温，滤取析出的结晶。结晶在减压下用五氧化磷干燥4小时，得到目的物1.276g。FABMASS(M+1)；3111H-NMR(in DMSO-d6)；2.82(2H,m),2.93(2H,s),3.83(3H,s),3.87(3H,s),6.57(1H,dd,J=8.2,2.1Hz)、6.63(1H,dd,J=8.6,2.1Hz),6.77(1H,dd,J=8.5,2.4Hz),7.29(1H,d,J=8.5Hz),7.83(1H,s),7.84(1H,d,J=8.5Hz)实施例92-〔(4-溴苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和4-溴苯甲醛1.37g，回流1小时后，冷却到室温再加入水250ml，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物0.72g。FABMASS(M+1)；3301H-NMR(in DMSO-d6)；2.82(2H,m),2.97(2H,m),6.66(1H,d,J=1.5Hz)、6.77(1H,dd,J=8.5,2.4Hz),7.43(2H,d,J=8.5Hz),7.56(1H,s),7.61(2H,d,J=8.5Hz),7.85(1H,d,J=8.5Hz),10.42(1H,s)实施例102-〔(4-氯苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和4-氯苯甲醛1.03g，回流1.5小时后，冷却到室温再加入水250ml，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物0.77g。FABMASS(M+1)；2851H-NMR(in DMSO-d6)；2.82(2H,m),2.98(2H,m),6.66(1H,d,J=2.1Hz)、6.77(1H,dd,J=8.5,2.2Hz),7.48(5H,m),7.59(1H,s),7.85(1H,d,J=8.5Hz),10.41(1H,s)实施例112-〔(4-氟苯基)亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和4-氟苯甲醛0.79ml，回流1.5小时后，冷却到室温再加入水300ml，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物0.65g。FABMASS(M+1)；2691H-NMR(in DMSO-d6)；2.81(2H,m),2.98(2H,m),6.66(1H,d,J=2.2Hz)、6.77(1H,dd,J=8.5,2.5Hz),7.25(2H,m),7.53(2H,m),7.61(1H,s),7.84(1H,d,J=8.5Hz),10.41(1H,s)实施例126-羟基-2-亚胡椒基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和胡椒醛1.11g，回流0.5小时后，冷却到室温，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物1.63g。FABMASS(M+1)；2951H-NMR(in DMSO-d6)；2.82(2H,m),3.01(2H,m),6.06(2H,s)、6.65(1H,d,J=2.1Hz),6.75(1H,dd,J=8.5,2.4Hz),6.98(1H,d,J=7.9Hz),7.02(1H,dd,J=9.4,1.1Hz),7.08(1H,d,J=1.5Hz),7.55(1H,s),7.82(1H,d,J=8.5Hz),10.37(1H,s)实施例132-〔(3,4-苯并二噁烷)-6-亚甲基〕-6-羟基-1-苯并环己酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入6-羟基-1-苯并环己酮1.0g和3,4-苯并二噁烷-6-甲醛1.21g，回流1小时后，冷却到室温，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物1.57g。FABMASS(M+1)；3091H-NMR(in DMSO-d6)；2.81(2H,m),3.00(2H,m),4.26(4H,m),6.65(1H,d,J=2.4Hz),6.75(1H,dd,J=8.5,2.1Hz),6.90(1H,d,J=8.2Hz),6.98(1H,dd,J=8.5,1.8H2),7.01(1H,d,J=2.1Hz),7.52(1H,s),7.82(1H,d,J=8.6Hz),10.36(1H,s)实施例142-〔(3,4-二羟基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮的制备
往浓盐酸25ml和甲醇35ml的混合液中中加入7-羟基-4(4H)-苯并吡喃酮0.5g和3,4-二羟基苯甲醛0.42g，回流2.5小时后，冷却到室温再加入水250ml放置18小时后，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物0.61g。FABMASS(M+1)；2851H-NMR(in DMSO-d6)；5.34(2H,d,J=1.6Hz),6.29(1H,d,J=2.1Hz),6.53(1H,dd,J=8.6,2.2Hz),6.74(1H,dd,J=8.2,1.8Hz)；6.82(2H,m),7.51(1H,s),7.71(1H,d,J=8.8Hz),9.19(1H,s),9.55(1H,s),10.57(1H,s)实施例157-羟基-3-亚胡椒基-4(4H)-苯并吡喃酮的制备
往浓盐酸50ml和甲醇75ml的混合液中中加入7-羟基-4(4H)-苯并吡喃酮1.0g和胡椒醛1.0g，回流2小时后，冷却到室温再加入水200ml放置1小时后，滤取析出的结晶。结晶在减压下用五氧化二磷干燥4小时，得到目的物0.266g。FABMASS(M+1)；2971H-NMR(in DMSO-d6)；5.33(2H,d,J=1.6Hz),6.09(1H,s),6.31(1H,d,J=2.1Hz),6.53(1H,dd,J=8.8,2.5Hz),6.93(1H,dd,J=7.9,1.2Hz),7.02(2H,m),7.59(1H,s),7.72(1H,d,J=8.8Hz),10.64(1H,s)实施例163-〔(1,4-苯并二噁烷)-6-亚甲基〕-7-羟基-4(4H)-苯并吡喃酮的制备
往浓盐酸50ml和甲醇40ml的混合液中中加入7-羟基-4(4H)-苯并吡喃酮1.0g和1,4-苯并二噁烷-6-羧基醛(carboxyaldehyde)1.2g，回流1.5小时后，冷却到室温，滤取析出的结晶。结晶在减压下用五氧化磷干燥4小时，得到目的物1.066g。FABMASS(M+1)；3111H-NMR(in DMSO-d6)；4.29(4H,m),5.33(2H,d,J=1.6Hz),6.31(1H,d,J=2.1Hz),,6.53(1H,dd,J=8.8,2.4Hz),6.89～6.96(3H,m),7.56(1H,s),7.72(1H,d,J=8.5Hz),10.62(1H,s)实施例173-〔(3,4-二甲氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮的制备
往浓盐酸50ml和甲醇40ml的混合液中中加入7-羟基-4(4H)-苯并吡喃酮1.0g和3,4-二甲氧基苯甲醛1.22g，回流1.5小时后，冷却到室温再加入水100ml放置30分钟后，滤取析出的结晶。结晶在减压下用五氧化磷干燥7小时，得到目的物0.255g。FABMASS(M+1)；3131H-NMR(in DMSO-d6)；3.80(3H,s),3.81(3H,s),5.39(2H,d),6.32(1H,d,J=2.1Hz),6.54(1H,dd,J=8.8,2.2Hz),6.97～7.05(3H,m),7.63(1H,s),7.73(1H,d,J=8.8Hz)实施例183-〔(3-乙氧基-4-甲氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮的制备
往7-羟基-4(4H)-苯并吡喃酮1.0g和3-乙氧基-4-甲氧基苯甲醛1.30g中加入氯化氢饱和的甲醇15ml，搅拌22.5小时后，加入水100ml滤取析出的结晶。将此结晶加入30ml的55℃的甲醇中，过滤后所得的结晶在减压下用五氧化磷干燥4小时，得到目的物0.415g。FABMASS(M+1)；3271H-NMR(in DMSO-d6)；1.33(3H,t),3.81(3H,s),4.05(2H,q),5.38(2H,d),6.31(1H.d,J=2.5Hz),6.53(1H,dd,J=8.5,2.1Hz),6.96～7.05(3H,m),7.62(1H,s),7.73(1H,d,J=8.5Hz)实施例193-〔(3-甲氧基-4-乙氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮的制备
往7-羟基-4(4H)-苯并吡喃酮1.0g和3-甲氧基-4-乙氧基苯甲醛1.30g中加入氯化氢饱和的甲醇20ml，搅拌18小时后，加入水100ml滤取析出的结晶。将此结晶加入100ml的55℃的甲醇中，搅拌15分钟后，过滤后所得的结晶在减压下用五氧化磷干燥4小时，得到目的物0.216g。FABMASS(M+1)；3271H-NMR(in DMSO-d6)；1.33(3H,t),3.80(3H,s),4.05(2H,q),5.38(2H,d),6.31(1H,d,J=2.1Hz),6.53(1H,dd,J=8.5,2.1Hz),6.93～7.03(3H,m),7.63(1H,s),7.73(1H,d,J=8.8Hz)实施例203-〔(3,4-二乙氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮的制备
往7-羟基-4(4H)-苯并吡喃酮1.0g和3,4-二乙氧基苯甲醛1.58ml中加入氯化氢饱和的甲醇20ml，搅拌72小时后，加入水100ml滤取析出的结晶。将此结晶加入60ml的55℃的甲醇中，搅拌15分钟后，过滤所得的结晶在减压下用五氧化磷干燥4小时，得到目的物0.762g。FABMASS(M+1)；3411H-NMR(in DMSO-d6)；1.33(6H,t),4.07(4H,q),5.37(2H,d),6.31(1H,d,J=2.4Hz),6.53(1H,dd,J=8.8,2.4Hz),6.93～7.02(3H,m),7.62(1H,s),7.73(1H,d,J=8.6Hz)实施例213-〔(3-甲基-4-甲氧基苯基)亚甲基〕-7-羟基-4(4H)-苯并吡喃酮的制备
往7-羟基-4(4H)-苯并吡喃酮1.0g和3-甲基-4-甲氧基苯甲醛0.87g中加入氯化氢饱和的甲醇20ml，搅拌72小时后，加入水100ml滤取析出的结晶。将此结晶加入50ml的55℃的甲醇中，搅拌15分钟后，过滤所得的结晶在减压下用五氧化磷干燥4小时，得到目的物0.447g。FABMASS(M+1)；2971H-NMR(in DMSO-d6)；2.17(3H,s),3.83(3H,s),5.35(2H,d),6.31(1H,d,J=2.2Hz),6.53(1H,dd,J=8.6,2.2Hz),7.02(1H,d,J=8.5Hz),7.24(2H,m),7.59(1H,s),7.73(1H,d,J=8.6Hz)实施例222-甲氧基〔(3-甲氧基-4-乙氧基苯基)亚甲基〕-6-甲氧基-1-苯并环己酮的制备
将6-甲氧基-1-苯并环己酮1.0g和3-甲氧基-4-乙氧基苯甲醛1.27g加入60ml浓盐酸和50 ml甲醇的混合液中，回流2.5小时。反应液冷却到室温，加入乙酸乙酯100ml后，用100ml水洗2次后，再用100ml饱和食盐水洗2次。将乙酸乙酯溶液用硫酸镁脱水后，在减压和40℃下浓缩至20ml，滤取析出的结晶，在减压下用五氧化磷干燥4小时，得到目的物0.89g。FABMASS(M+1)；3391H-NMR(in CDCl3)；1.46(3H,t),2.89(2H,m),3.10(2H,m),3.83(3H,s),3.86(3H,s),4.22(2H,q,4H2),6.67(1H,d,J=8.2Hz),6.83(1H,dd,J=8.3,1.9Hz),6.85(1H,d,J=8.2Hz),6.65(1H,d,J=1.8Hz),7.00(1H,dd,J=8.5,2.1Hz),7.65(1H,s),8.07(1H,d,J=8.8Hz)体外17β-HSD阻断活性实验
试验实施例1～22所得的化合物(以下称为被测物质)的17β-HSD阻断活性。即,将被测物质分别用乙醇溶解，使之最浓度为260nM并装入试管，用氮气使之干固。再往其中加入含100mM氯化钾、1mM乙二胺四乙酸、0.SmM还原型烟酰胺腺嘌呤二核苷酸(全部自和光纯药公司)、1μM〔4-14C〕雌酮(NEN研究产品公司制)的10mM磷酸缓冲液(pH7.5)590μl，和E.A.Thompson等的方法(生物化学杂志J.Biol.Chem.，249卷，5364～5372页，1974年)制备的人胎盘所得的微粒体10μl，在37℃下振荡30分钟进行反应。反应结束后直接加入二氯甲烷2ml并充分搅拌，以3000rpm离心5分钟，将所得下层液(二氯甲烷层)移入别的试验管，用氮气进行干固。再往其中加入含20μg雌酮和20μg雌二醇的乙醇100μl，吸取20μl在TLC板(硅胶60F254，默克公司制)上点样。将此TLC板用苯∶丙酮(4∶1)展开后，在紫外线下切取相当于雌酮、雌二醇的点，加入液体闪烁混合液(filter count(注册商标)；惠普公司制)，用液体闪烁计数器求出残余的〔4-14C〕雌酮的量和反映17β-HSD酶活性的〔4-14C〕雌二醇的生成量。此外，不加被测物质而进行相同的操作并作为对照组。将对照组的17β-HSD酶活性阻断率作为0％，从而算出被测物质17β-HSD酶活性阻断的百分率。结果如图1～3所示。
从以上结果可以确认本发明化合物(被测物质)具有优良的17β-HSD阻断活性。所以，本发明提供了具优良17β-HSD阻断活性的新型苯并环己酮或苯并吡喃酮衍生物及其制备方法。利用本发明化合物的活性可使之作为雄性和雌性激素依赖性疾病的预防和/或治疗药物，具体的说就是作为前列腺癌、前列腺肥大症、男性化症、乳腺癌、乳腺疾病、子宫癌、子宫内膜异位、卵巢癌等各种雄性和雌性激素依赖性疾病的预防和/或治疗药物很有用。而且本发明化合物也可被利用作成正型光致抗蚀剂组合物，其应用范围很广。

Claims (5)

1．下述通式(Ⅰ)所示的新型苯并环己酮或苯并吡喃酮衍生物，
Figure A9880007500021
其中R1和R2分别表示氢、羟基、烷氧基或芳烷氧基，R3～R7分别表示氢、羟基、碳数1～6的直链或支链烷基、烷氧基或芳烷氧基、卤素、氨基或R3和R4、R4和R5、R5和R6、R6和R7结合的亚烷二氧基，A表示亚甲基或氧。
2．根据权利要求1记载的新型苯丙环己酮或苯并吡喃酮衍生物的制备方法，其特征在于，将下述通式(Ⅱ)所示的苯并环己酮或苯并吡喃酮衍生物和下述通式(Ⅲ)所示的苯甲醛衍生物用有机溶剂溶解，在酸性条件下加热回流，再将反应液精制而得；
Figure A9880007500022
通式(Ⅱ)中R1和R2分别表示氢、羟基、烷氧基或芳烷氧基，A表示亚甲基或氧；
Figure A9880007500023
通式(Ⅲ)中R3～R7分别表示氢、羟基、碳数1～6的直链或支链烷基、烷氧基或芳烷氧基、卤素、氨基或R3和R4、R4和R5、R5和R6、R6和R7结合的亚烷二氧基。
3．以权利要求1记载的新型苯并环己酮或苯并吡喃酮衍生物为有效成分的药物。
4．以权利要求1记载的新型苯并环己酮或苯并吡喃酮衍生物为有效成分的激素依赖性疾病预防药物。
5．以权利要求1记载的新型苯并环己酮或苯并吡喃酮衍生物为有效成分的激素依赖性疾病治疗药物。
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