CN105237474B - 6‑羟基‑7‑芳甲酰基喹啉酮类化合物的制备及其应用 - Google Patents
6‑羟基‑7‑芳甲酰基喹啉酮类化合物的制备及其应用 Download PDFInfo
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- CN105237474B CN105237474B CN201510645390.2A CN201510645390A CN105237474B CN 105237474 B CN105237474 B CN 105237474B CN 201510645390 A CN201510645390 A CN 201510645390A CN 105237474 B CN105237474 B CN 105237474B
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- Prior art keywords
- piperazinyls
- quinoline
- hydroxyls
- benzoyl
- compound
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Abstract
本发明属于医药技术领域,涉及6‑羟基‑7‑芳甲酰基喹啉酮类化合物及其应用。6‑羟基‑7‑芳甲酰基喹啉酮类化合物包括6‑羟基‑7‑芳甲酰基喹啉酮类化合物该类化合物的立体异构体和药学上适用的盐,其结构通式如下:6‑羟基‑7‑芳甲酰基喹啉酮类化合物以及该类化合物药学上适用的酸加成的盐可以与现有药物合并或单独使用作为***受体调节剂,用于治疗或预防与***功能相关的各种疾病,如:骨质疏松,癌症,尤其是乳腺癌,卵巢癌,骨肉瘤和子宫内膜癌。
Description
技术领域
本发明涉及6-羟基-7-芳甲酰基喹啉酮类化合物,其作为***受体调节剂的药物应用,及其制备方法。
背景技术
模拟***样作用的化合物具有广泛的治疗及预防作用,其中包括:缓解绝经期症状,治疗痤疮,治疗痛经和功能障碍性子宫出血,骨质疏松,***癌和预防心血管疾病。
研究发现***受体有两种类型:ERα和ERβ。配体与这两个亚型结合后,以不同的组织特异性发挥生理作用。
本领域需要的是与***替代疗法一样可产生阳性反应但无不良副作用或副作用减小的化合物,且对机体发挥组织特异性的***样作用。喹啉酮类衍生物因其具有与***类似的空间结构,可模拟***,在生物体内与***受体结合,发挥生理作用。
本发明的化合物是***受体的配体,可用于治疗或预防与***功能相关的各种疾病,其中包括:骨质疏松,癌症,尤其是乳腺癌,卵巢癌,骨肉瘤和子宫内膜癌。
***是人体中一类重要的激素化合物,当妇女进入绝经期后,体内***水平下降,由此引发更年期综合征、骨质疏松、老年痴呆症和心血管***等疾病。针对绝经后***水平下降,采取***替代疗法(est rogen replacement therapy,ERT),能够显著降低绝经后骨质疏松性骨折和冠心病的发生率(Turner RT,Riggs BL,Spelsberg TC.EndocrRev,1994,15(3):275-300;Mora S,Kershner DW,Vigilance CP,et al.Curr TreatOptions Cardiovasc Med,2001,3(1):67-79)。但是,ERT可能诱发乳腺癌和子宫内膜癌(Persson I,Weiderpass E,Bergkvist L,et al.Cancer Causes Control,1999,10(4):253-260)。为克服***致癌变的不良反应,人们又发展了雌、孕激素联合使用的性激素替代疗法(hormone replacement therapy,HRT),但长期的HRT治疗仍可能增加乳腺癌的发生率,即使使用孕激素,并非在所有的情况下均能克服由***所导致的子宫内膜癌的发生,这些不良反应限制了HRT的长期应用。选择性***受体调节剂(selective estrogenreceptor modulators,SERMs)对骨骼和心血管***具有***样作用,而对子宫和乳腺表现出抗***作用的药物。但是临床上使用的它莫西芬和雷洛昔芬能导致子宫内膜癌和热潮红等不良反应(Fisher B,Costantino JP,Wickerham DL,et al.J Nati Cancer Inst,1998,90:1371-1388;Walsh BW,Kuller LH,Wild RA,et al.J Am Med Assoc,1998,279:1445-1451)。
发明内容
本发明所解决的技术问题是提供一种如式I所示的化合物、其前体药物和药物活性代谢物,以及上述化合物的立体异构体及其药学上可接受的盐,并提供了其在制备预防和治疗***相关的疾病的药物中的应用。
其中X可以选自O;R1R2独立地选自氢、Cl-C4烷基、苄基、Cl-C4烷基取代的苄基、Cl-C4烷氧基取代的苄基、羟基和卤素取代的苄基、苯基、Cl-C4烷基取代的苯基、Cl-C4烷氧基取代的苯基、羟基和卤素取代的苯基、或R1R2与它们相连的氮原子一起组成1-吡咯烷基、1-哌啶基、4-吗啉基、4-苯基-1-哌嗪基、4-(4-甲基苯基)-1-哌嗪基、4-(4-氟苯基)-1-哌嗪基、4-(4-氯苯基)-1-哌嗪基、4-(4-溴苯基)-1-哌嗪基、4-(4-甲氧基苯基)-1-哌嗪基、4-(4-三氟甲基苯基)-1-哌嗪基或4-二苯甲基-1-哌嗪基。
优选地,R1R2与它们相连的氮原子一起组成二甲胺基,二乙胺基,1-吡咯烷基,1-哌啶基,4-吗啉基,4-苯基-1-哌嗪基,4-(4-甲基苯基)-1-哌嗪基,4-(4-氟苯基)-1-哌嗪基,4-(4-氯苯基)-1-哌嗪基,4-(4-溴苯基)-1-哌嗪基,4-(4-甲氧基苯基)-1-哌嗪基,4-(4-三氟甲基苯基)-1-哌嗪基或4-二苯甲基-1-哌嗪基。
本发明还提供了式I化合物和药学上可接受载体的药物组合物。本发明还预期包括含有药学上可接受的载体和本申请中具体公开的任意化合物的药物组合物。本发明还涉及制备本发明的组合物的方法。本发明还涉及能用于制备本发明化合物和药物组合物的方法。
本发明的化合物可以单独给予或优选与药学上可接受的载体或稀释剂,任选根据常规的制药习惯与已知辅剂联合,在药物组合物中给予。化合物经口服给予或经非胃肠道包括静脉内,肌肉内,腹膜内,皮下,直肠和局部途径给予。
在用于口服的片剂中,通常加入一般使用的载体包括乳糖和玉米淀粉,以及润滑剂如硬脂酸镁。对胶囊形式的口服药来说,可用的稀释剂包括乳糖和干燥的玉米淀粉。对根据本发明的治疗化合物的口服途径使用来说,被选化合物可以以例如片剂或胶囊的形式,或作为水溶液或混悬液而被给予。对片剂或胶囊形式的口服给药来说,活性药物成分能与可口服,无毒,药学上可接受的惰性载体组合,载体例如有乳糖,淀粉,蔗糖,葡萄糖,甲基纤维素,硬脂酸镁,磷酸二钙,硫酸钙,甘露醇,山梨醇等;对液体形式的口服给药来说,口服药物成分可与任意的可口服,无毒,药学上可接受的惰性载体例如乙醇,甘油,水等组合。此外,还可在混合物中加入适宜的粘合剂,润滑剂,崩解剂和着色剂。适宜的粘合剂包括淀粉,明胶,天然糖如葡萄糖或乳糖,玉米甜味剂,天然和合成的树胶如***胶,西黄蓍胶或海藻酸钠,羧甲基纤维素,聚乙二醇,蜡等。适宜的润滑剂包括油酸钠,硬脂酸钠,硬脂酸镁,苯甲酸钠,醋酸钠,氯化钠等。当水性混悬液口服使用时,可将活性成分与乳化剂和混悬剂组合。也可加入某些甜味剂或矫味剂。对肌内,腹膜内,皮下和静脉内使用来说,通常制备成活性成分的无菌溶液,溶液的pH应该适当的调节和缓冲。对静脉内使用来说,应当控制溶质的总浓度以使制剂维持等渗。
本发明的化合物还能以脂质体给药***的形式例如小型单层囊泡,单层大囊泡和多层囊泡的形式给予。脂质体可由各种磷脂例如胆固醇,硬脂胺或磷脂酰胆碱形成。
本发明的化合物还可以通过使用单克隆抗体作为单独载体而给予,其中化合物分子是被偶联的。本发明的化合物还可以与作为目标药物载体的可溶性聚合物偶联。这类聚合物可包括聚乙烯吡咯烷酮,吡喃共聚物,聚羟丙基甲基丙烯酰胺-苯酚,聚羟基-乙基天冬酰胺-苯酚或被棕榈酰基取代的聚氧化乙烯-聚赖氨酸。此外,本发明的化合物可以与一类可生物降解的用于实现药物控释的聚合物偶联,所述聚合物有例如聚乳酸,聚乙醇酸,聚乳酸和聚乙醇酸的共聚物,聚己内酯,聚羟基丁酸,聚原酸酯类,聚缩醛类,聚二氢吡喃,聚氰基丙烯酸酯和水凝胶的交联或两性嵌段共聚物。
本发明的化合物还可与已知的可用于治疗或预防以下疾病的药剂组合使用:骨质疏松,癌症,尤其是乳腺癌,卵巢癌,骨肉瘤和子宫内膜癌。目前公开的化合物与可用于治疗或预防在此公开疾病的药剂的联合也在本发明的范围内。本发明化合物和***。
“***”包括但不限于天然存在的***,合成的结合***,口服避孕药和硫酸化***。“***受体调节剂”指干扰或抵制***与受体结合的物质,无论机制如何。选择性5-羟色胺再摄取抑制剂通过增加脑中5-羟色胺的数量而发挥作用,其非限制性实例包括氟西汀,帕罗汀,舍曲林,西酞普兰和氟伏沙明,也能用于治疗与***功能有关的疾病。“芳香酶抑制剂”包括抑制芳香酶的化合物,其非限定性的选自:氨鲁米特,来曲唑,福美坦,依西美坦,阿他美坦,法倔唑,氟罗唑,伏氯唑。
有关本发明化合物的术语“给予”及其变体(例如“给予”化合物)的意思是将化合物或化合物的前药引入需要治疗的动物***中。当本发明的化合物或其前药与一种或多种其它活性剂(例如双膦酸盐化合物等)组合提供时,“给予”及其变体都可以被理解为包括同时和相继引入化合物或其前药以及其它药剂。本发明包括在其范围内的本发明化合物的前药。通常,这种前药是将本发明化合物的官能衍生物,其在体内易于转变为所需的化合物。这样,在本发明的治疗方法中,术语“给予”将包含用具体公开的化合物或可能未被具体公开的化合物,但是其能在给予患者后于体内转化为特定的化合物,以治疗所述的各种疾病。用于选择和制备适宜的前药衍生物的常规方法,在此引入作为参考。这些化合物的代谢物包括将本发明的化合物引入生物环境后产生的活性物质。
当本发明的化合物被给予人类受试中,日剂量将通常由处方医师确定,剂量一般根据患者个体的年龄,体重和反应以及患者症状的严重程度而变化。在一个示例性应用中,将适宜量的化合物给予接受治疗的哺乳动物。当用于所指示的作用时,本发明的口服剂量将为约0.01mg每kg体重每天(mg/kg/天)到约100mg/kg/天,优选0.01到10mg/kg/天,最优选0.1到5.0mg/kg/天。对口服给药来说,组合物优选以片剂的形式被提供,其中片剂包含0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100和500mg的活性成分,用于调节受治患者症状的剂量。药物一般包含约0.01mg到约500mg的活性成分,优选约1mg到约100mg活性成分。对于静脉注射,在恒速输注期间,最优选的剂量将为约0.1到约10mg/kg/分钟。本发明的化合物可以以每日一次的剂量给予,或者是可以将每日总剂量分为每日两次,三次或四次的剂量给予。此外,本发明的优选化合物可以以鼻内药物的形式通过局部使用适宜的鼻内载体,或通过经皮途径,使用本领域普通技术人员已知的经皮贴剂形式而给予。对于以经皮给药***的形式进行的给药来说,剂量给药在整个给药方案中当然将是连续的而不是间断的。
本发明的化合物能与其它可用于治疗***介导的状况的药剂组合使用。这种组合的各个成分能在治疗期间以不同的次数分别或同时以分开的形式或单一组合的形式给予。因此本发明能被理解为包含所有这样的同时或交替治疗的方案,而且术语“给予”也相应的按此解释。本发明化合物与其它可用于治疗组织蛋白酶介导状况的药剂的组合的范围,原则上包括与能用于治疗与***功能有关疾病的任意药物组合物的任意组合。
因此本发明还可以包括与第二种药剂组合的使用,其中第二种药剂选自:***,***受体调节剂,选择性5-羟色胺再摄取抑制剂,芳香酶抑制剂,及其药学上可接受的盐和混合物。
本发明的化合物能与其它可用于治疗由***介导的状况的药剂组合使用。这种组合的每个成分都能在治疗期间以不同的次数分别给予或同时以分开的形式或单一组合的形式给予。因此本发明应被理解为包含所有这样的同时或交替治疗的方案,而且术语“给予”也应按此解释。应该理解,本发明化合物与其它可用于治疗***介导状况的药剂的组合的范围原则上包括与能用于治疗与***功能有关疾病的任意药物组合物的任意组合。
使用本发明化合物的剂量方案将根据多种因素进行选择,这包括患者的类型,种属,年龄,体重,性别和医学状况;受治状况的严重程度;给药途径;患者的肾和肝功能;以及所用的特定化合物或其盐。普通技术医师,兽医或临床医师可容易的确定和开具需要预防,抗击或阻止状况发展的有效药量。
在本发明的方法中,在此详细描述的化合物能形成活性成分,并根据给药形式即口服片剂,胶囊,酏剂,糖浆剂等而与适当选择的适宜的药学稀释剂,赋形剂或载体(在此统称为‘载体’物质)混合,并符合常规的药学习惯。
本发明化合物的药学上可接受的盐类包括由无机或有机酸形成的常规无毒盐。常规的无毒盐包括源自无机酸例如盐酸,氢溴酸,硫酸,氨基磺酸,磷酸,硝酸等的盐,以及由有机酸例如醋酸,丙酸,琥珀酸,乙醇酸,硬脂酸,乳酸,苹果酸,酒石酸,柠檬酸,抗坏血酸,双羟萘酸,马来酸,羟基马来酸,苯乙酸,谷氨酸,苯甲酸,水扬酸,对氨基苯磺酸,2-乙酰氧基-苯甲酸,反丁烯二酸,甲苯磺酸,甲磺酸,乙烷二磺酸,草酸,羟乙磺酸,三氟醋酸等制备的盐类。本发明化合物的药学上接受的盐类能由包含酸性或碱性部分的本发明化合物经常规的化学方法合成。通常,碱性化合物的盐类能通过离子交换色谱法制备,或将游离碱与化学计量或过量的所期望的成盐无机或有机酸在适宜的溶剂或溶剂的各种组合中进行反应来制备。类似的,酸性化合物的盐类可通过与适宜的无机或有机碱进行反应来形成。
本发明的化合物能根据以下的一般方案使用适宜的物质来制备,并且通过随后的具体实施例进一步的举例说明。以下制备步骤的条件和方法的各种已知变化也能用于制备这些化合物。所有的温度均为摄氏度,除非另有指明。下面的流程描述了本发明几个代表性实施例的制备。
其中X可以选自H2或者O;R1R2独立地选自氢、Cl-C4烷基、苄基、Cl-C4烷基取代的苄基、Cl-C4烷氧基取代的苄基、羟基和卤素取代的苄基、苯基、Cl-C4烷基取代的苯基、Cl-C4烷氧基取代的苯基、羟基和卤素取代的苯基、或R1R2与它们相连的氮原子一起组成1-吡咯烷基、1-哌啶基、4-吗啉基、4-苯基-1-哌嗪基、4-(4-甲基苯基)-1-哌嗪基、4-(4-氟苯基)-1-哌嗪基、4-(4-氯苯基)-1-哌嗪基、4-(4-溴苯基)-1-哌嗪基、4-(4-甲氧基苯基)-1-哌嗪基、4-(4-三氟甲基苯基)-1-哌嗪基或4-二苯甲基-1-哌嗪基。
R1R2与它们相连的氮原子一起组成二甲胺基,二乙胺基,1-吡咯烷基,1-哌啶基,4-吗啉基,4-苯基-1-哌嗪基,4-(4-甲基苯基)-1-哌嗪基,4-(4-氟苯基)-1-哌嗪基,4-(4-氯苯基)-1-哌嗪基,4-(4-溴苯基)-1-哌嗪基,4-(4-甲氧基苯基)-1-哌嗪基,4-(4-三氟甲基苯基)-1-哌嗪基或4-二苯甲基-1-哌嗪基。
本发明所述化合物制备方法简单,收率稳定,制备的化合物能较好的预防和治疗***相关的疾病。
具体实施方式
以下述实例详细叙述本发明。但是,应当明白,本发明不限于具体叙述的下述实例。
实施例1:6-羟基-7-[4-(2-氧代-2-二乙胺基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮的制备
将3.26g(0.02mol)6-羟基喹啉酮,150mL二氯甲烷,2.24g(0.024mol)三乙胺加入250mL圆底烧瓶中,室温下搅拌均匀。搅拌下滴加含有对甲氧基苯甲酰氯的二氯甲烷溶液(对甲氧基苯甲酰氯3.74g,0.022mol;二氯甲烷40mL),匀速滴入反应液中,20min内滴加完毕。室温搅拌5h,TLC监测至反应完全,将反应液缓慢倒入50mL 1mol·L-1的盐酸中,抽滤,水30mL×3次洗涤滤饼,干燥。将滤液转移至分液漏斗中,分出有机层,水100mL×2洗涤,无水MgSO4干燥,过滤除去干燥剂,滤液减压蒸去有机溶剂,得白色固体,产量5.86g,收率98.7%。m.p.257-259℃;ESI-MS:m/z 297.1([M+H]+)。
在100mL圆底烧瓶中,加入6-(4-甲氧基苯甲酰氧基)-3,4-二氢-1H-喹啉-2-酮2.98g(0.012mol),无水三氯化铝(4.4g,0.034mol),安装空气冷凝管,装有无水CaCl2的球形干燥管,180℃油浴反应6h,TLC监测至反应完全,冷却至室温。加入适量冰水及1mol·L-1的盐酸溶液调节pH至2~3,浸泡过夜,打浆,抽滤并水洗产物至中性,得淡黄色固体,产量2.91g,收率97.7%。m.p.281-283℃;1H-NMR(600MHz,DMSO-d6)δ(ppm)10.38(s,1H),10.15(s,1H),9.90(s,1H),7.61(d,J=6.0Hz,2H),6.87-6.79(m,4H),2.88(t,J=12.0Hz,2H),2.43(t,J=12.0Hz,2H);ESI-MS:m/z 283.1([M+H]+)。
将6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮(3mmol),N,N-二乙基-2-氯乙酰胺(3.5mmol),碳酸钾(6.2g,45mmol)和碘化钾(0.1g,0.6mmol)和30mL丙酮加于圆底烧瓶中,加热回流12h后,TLC监测至反应完毕。抽滤,经柱层析[V(石油醚):V(乙酸乙酯)=1:3]分离得到黄色固体0.39g,收率33.23%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.19(s,1H),9.95(s,1H),7.68(d,J=9.0Hz,2H),7.00(d,J=9.0Hz,2H),6.88(s,1H),6.81(s,1H),4.92(s,2H),3.30(m,4H),2.88(t,J=15.0Hz,2H),2.43(t,J=15.0Hz,2H),1.17(t,J=13.8Hz,3H),1.04(t,J=14.4Hz,3H);MS(m/z):397.2([M+H]+)。
实施例2:6-羟基-7-{4-[2-氧代-2-(1-哌啶基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,1-氯乙酰哌啶,得到亮黄色固体0.43g,收率35.22%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.20(s,1H),9.92(s,1H),7.67(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,2H),6.89(s,1H),6.81(s,1H),4.93(s,2H),3.40(d,J=19.2Hz,4H),2.88(t,J=15.0Hz,2H),2.43(t,J=15.0Hz,2H),1.60(d,J=4.8Hz,2H),1.54(s,2H),1.44(s,2H);MS(m/z):409.2([M+H]+)。
实施例3:6-羟基-7-[2-氧代-(4-吗啉基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-氯乙酰吗啉,得到亮黄色固体0.19g,收率15.67%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.20(s,1H),9.92(s,1H),7.67(d,J=8.4Hz,2H),7.03(d,J=9.0Hz,2H),6.89(s,1H),6.81(s,1H),4.98(s,2H),3.60(d,J=28.8Hz,4H),3.46(s,4H),2.89(t,J=15.0Hz,2H),2.43(t,J=15.0Hz,2H);MS(m/z):411.2([M+H]+)。
实施例4:6-羟基-7-{4-[2-(1-哌啶基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(2-氯乙基)哌啶盐酸盐,得到亮黄色固体0.45g,收率38.07%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.13(s,1H),9.91(s,1H),7.68(d,J=7.8Hz,4H),7.31(t,J=15Hz,4H),7.20(t,J=15Hz,2H),6.99(d,J=8.4Hz,2H),4.16(t,J=15.0Hz,2H),2.88(t,J=15Hz,2H),2.67(t,J=11.4Hz,2H),2.43(t,J=14.4Hz,6H),1.49(m,4H),1.38(d,J=4.8Hz,2H);MS(m/z):395.2([M+H]+)。
实施例5:6-羟基-7-[2-(4-吗啉基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(2-氯乙基)吗啉盐酸盐,得到亮黄色固体0.30g,收率25.41%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.12(s,1H),9.91(s,1H),7.68(d,J=9.0Hz,2H),7.07(d,J=8.4Hz,2H),6.86(s,1H),6.80(s,1H),4.19(s,2H),3.58(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.72(s,2H),2.48-2.42(m,5H),2.19(s,1H);MS(m/z):397.2([M+H]+)。
实施例6:6-羟基-7-{4-[2-氧代-2-(4-二苯甲基-1-哌嗪基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-二苯甲基-1-氯乙酰哌嗪,得到亮黄色固体0.58g,收率33.67%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.13(s,1H),9.91(s,1H),7.66(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,4H),7.31(t,J=15Hz,4H),7.20(t,J=15Hz,2H),6.99(d,J=8.4Hz,2H),6.88(s,1H),6.81(s,1H),4.93(s,2H),4.36(s,1H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H);MS(m/z):576.2([M+H]+)。
实施例7:6-羟基-7-{4-[2-氧代-2-(苯甲胺基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,N-苄基-2-氯乙酰胺,得到亮黄色固体0.28g,收率21.69%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.14(s,1H),9.92(s,1H),8.72(t,J=18Hz,1H),7.70(d,J=13.8Hz,2H),7.27(m,5H),7.10(d,J=13.2Hz,2H),6.88(s,1H),6.81(s,1H),4.67(s,2H),4.36(d,J=9.6Hz,2H),2.89(t,J=22.8Hz,2H),2.43(t,J=22.2Hz,2H);MS(m/z):431.2([M+H]+)。
实施例8:6-羟基-7-{4-[2-氧代-2-(4-甲基苯基胺基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,N-(4-甲基苯基)-2-氯乙酰胺,得到亮黄色固体0.39g,收率30.51%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.17(s,1H),10.07(s,1H),9.91(s,1H),7.47(s,1H),7.41(d,J=12Hz,1H),7.20(t,J=23.4Hz,1H),7.11(d,J=13.2Hz,2H),6.91-6.85(m,2H),6.81(s,1H),4.81(s,2H),2.88(t,J=22.2Hz,2H),2.43(t,J=22.2Hz,2H),2.28(s,3H);MS(m/z):431.2([M+H]+)。
实施例9:6-羟基-7-[4-(2-氧代-2-二甲胺基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,N,N-二甲基-2-氯乙酰胺,得到亮黄色固体0.39g,收率30.51%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.19(s,1H),9.95(s,1H),7.68(d,J=9.0Hz,2H),7.00(d,J=9.0Hz,2H),6.88(s,1H),6.81(s,1H),4.92(s,2H),3.30(m,4H),2.98(s,6H);MS(m/z):367.2([M+H]+)。
实施例10:6-羟基-7-{4-[2-氧代-2-(4-苯基-1-哌嗪基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-苯基-1-氯乙酰哌嗪,得到亮黄色固体0.55g,收率31.64%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.13(s,1H),9.91(s,1H),7.66(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,4H),6.99(d,J=8.4Hz,2H),6.81(s,1H),4.93(s,2H),4.36(s,1H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H);MS(m/z):486.2([M+H]+)。
实施例10 6-羟基-7-{4-[2-氧代-4-(4-甲基苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(4-甲基苯基)-1-氯乙酰哌嗪,得到亮黄色固体0.50g,收率30.67%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.13(s,1H),9.91(s,1H),7.66(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,4H),6.99(d,J=8.4Hz,2H),6.81(s,1H),4.93(s,2H),4.36(s,1H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H)2.28(s,3H);MS(m/z):500.2([M+H]+)。
实施例11:6-羟基-7-{4-[2-氧代-4-(4-氟苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(4-氟苯基)-1-氯乙酰哌嗪,得到亮黄色固体0.48g,收率29.07%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.13(s,1H),9.91(s,1H),7.66(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,4H),6.99(d,J=8.4Hz,2H),4.93(s,2H),4.36(s,1H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H);MS(m/z):504.2([M+H]+)。
实施例12:6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(4-氯苯基)-1-氯乙酰哌嗪,得到亮黄色固体0.58g,收率29.12%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.05(s,1H),9.93(s,1H),7.66(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,4H),6.99(d,J=8.4Hz,2H),3.56(t,J=8.4Hz,4H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H);MS(m/z):520.2([M+H]+)。
实施例13:6-羟基-7-{4-[2-氧代-4-(4-溴苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(4-溴苯基)-1-氯乙酰哌嗪,得到亮黄色固体0.58g,收率29.12%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.05(s,1H),9.93(s,1H),7.66(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,4H),6.99(d,J=8.4Hz,2H),3.56(t,J=8.4Hz,4H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H);MS(m/z):564.1([M+H]+)。
实施例14:6-羟基-7-{4-[2-氧代-4-(4-甲氧基苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备
按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(4-甲氧基苯基)-1-氯乙酰哌嗪,得到亮黄色固体0.68g,收率32.87%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.13(s,1H),9.91(s,1H),7.66(d,J=7.8Hz,2H),7.54(d,J=7.8Hz,4H),6.99(d,J=8.4Hz,2H),6.81(s,1H),4.93(s,2H),4.36(s,1H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H)1.98(s,3H);MS(m/z):500.2([M+H]+)。
实施例15:6-羟基-7-{4-[2-氧代-4-(4-三氟甲基苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮的制备按照实施例1方法,由6-羟基-7-(4-羟基苯甲酰基)-3,4-二氢-1H-喹啉-2-酮,4-(4-三氟甲基苯基)-1-氯乙酰哌嗪,得到亮黄色固体0.38g,收率12.25%。1H-NMR(600MHz,DMSO-d6)δ(ppm)10.13(s,1H),9.91(s,1H),7.66(d,J=7.8Hz,2H),7.74(d,J=7.8Hz,4H),6.99(d,J=8.4Hz,2H),6.81(s,1H),4.93(s,2H),4.36(s,1H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H);MS(m/z):554.2([M+H]+)。
药物组合物
在下述制剂中,“活性成分”是指式1化合物,或其盐或溶剂化物。
实施例16:明胶胶囊
实施例17:片剂
实施例18:片剂
将活性组分,淀粉和纤维素通过45目U.S.筛并充分混合,将所得粉末与聚乙烯吡咯烷酮混合,然后通过14目U.S.筛,将这样得到的颗粒在50-60℃干燥并通过18目U.S.筛。将羧甲基纤维素钠,硬脂酸镁和滑石,先通过60目U.S.筛,然后加入至上述颗粒中,混合后,在压片机上压制成片剂。
实施例19:悬浮剂
将药物通过45目U.S.筛并与羧甲基纤维素钠及糖浆混合以形成均匀糊状物,将苯甲酸溶液,矫味剂,和着色剂用一些水稀释,并边搅拌边加入,然后加入足够量水以达到所需的体积。
实施例20:气溶胶
将活性成分与乙醇混合,并将所得混合物加入至部分的抛射剂22中,冷却至30℃,并转移至容器中。然后将所需量加入至不锈钢容器中并用剩余喷射剂稀释,然后安装阀门装置。
实施例21:栓剂
将活性组分通过60目U.S.筛并将其悬浮于预先熔化的饱和脂肪酸甘油酯类化合物中,然后将混合物倾入至标准的2g腔栓剂模中并冷却。
实施例22:可注射制剂
将以上溶液静脉内注射给药,速度约1mL每分钟。
药理药效实验
实施例23:***受体结合实验
***受体配体结合试验设计为采用闪烁亲近检测,使用含氚的***和重组表达的***受体。在杆状病毒表达***中生产全长重组人类ER-α及ER-β蛋白。ER-α及ER-β提取物在含有6mMα-单硫代甘油的磷酸缓冲盐水中以1:400稀释。将200μL等分样的稀释受体制备物加入96孔Flashplate板每一孔中。用Saran Wrap覆盖培养板,于4℃温育过夜。
第二天早上将20μL含有10%牛血清白蛋白的磷酸缓冲盐水等分试样加入至该96孔板的每一孔中,且使其在4℃温育2h。然后用200μL含有20mM Tris(pH7.2),1mM EDTA,10%丙三醇,50mM KCl及6mMα-单硫代甘油的缓冲液洗涤培养板。为在这些受体包被的培养板中进行测试,加入178μL相同缓冲液至96孔板的每一孔中。然后将20μL 10nM 3H-***溶液加入至该培养板的每一孔中。
在0.01nM到1000nM的浓度范围内评估测试化合物。测试化合物储液应在100%DMSO中制备为试验中测试所期望终浓度的100X。在96孔板测试孔中的DMSO量不应超过1%。最终加入至测试中的为配制于100%DMSO中的2μL测试化合物等分试样。密封这种板并使其在室温平衡3h。在为计数96孔板装备的闪烁计数器中计数板。
部分样品***受体结合实验抑制率列表如下(n=3):
实施例1-15的化合物表现出对ERα的结合亲和力在IC50=75至10000nm范围内,而对ERβ的结合亲和力在IC50=5至250nm的范围内。
在上述标准药理测试步骤中得到的结果表明,本发明的化合物是***化合物,某些化合物对ERα受体具有强烈的优先亲和力。本发明化合物从对ERα具有比ERβ高的优先亲和力到对两种受体同时具有几乎相当的亲和力变动。因此,本发明化合物具有各种至少部分基于其受体亲和力选择性特征的活性。另外,由于各种新受体配体络合物不同,因此它与各种辅调节蛋白之间的相互作用也是不相同的,本发明化合物根据所处细胞环境将显示出不同的调节活性。例如,在某些细胞类型中,某化合物可作为***激动剂,而在其它组织中,该化合物却是拮抗剂。具有上述活性的化合物通常被称为SERM(选择性***受体调节剂)。然而,与大多数***不同的是,很多SERM不引起子宫湿重的增加。这些化合物在子宫中具有抗***活性,因而在子宫组织中可以完全拮抗***激动剂的营养活性。然而,这些化合物在骨,心血管和中枢神经***中作为***激动剂。由于这些化合物具有上述的组织选择性,因而可用于治疗或预防由于***缺乏(在某些组织例如骨和心血管中)或***过量(在子宫或乳腺中)引起的或者与之相关的病理状态或综合症。
甚至超出上述细胞特异性调节作用之上,本发明化合物还潜在的对某种受体类型是激动剂,而对另一种受体却是拮抗剂。例如,对ERβ是拮抗剂,而对ERα是激动剂。这种***受体选择性激动剂拮抗剂活性为这一系列化合物提供了药理学上显著不同的***活性。
可以方便的利用标准药理学测试步测得本发明化合物的活性特征。下面简要概述了几种代表性测试步骤。本发明所述化合物均表现出与雷洛昔芬类似的生物活性。
实施例24:大鼠子宫营养/抗子宫营养测试步骤
可以在幼年大鼠子宫营养测试(4天)中测得化合物的***和抗***特性。将未发育成熟的大鼠(Sprague-Dawley大鼠)(雌性,18天大)分成六组测试。这些动物通过每天ip注射10μg化合物,100μg化合物,(100μg化合物和1μg 17β***)以检查抗***类,和1μg 17β***处理,使用50%DMSO/50%盐水作为注射媒介。这些动物在第四天通过CO2窒息处死,取出子宫,剥去过量油脂,除去所有液体,测得湿重,取出一角的一部分进行组织学分析,其余的用来分离出完整的RNA以评价补体成分3基因表达。
部分样品子宫增重列表如下(n=3):
实施例25:MCF-7/ERE抗增殖测试步骤
在DMSO中制备得到测试化合物的储备溶液(通常为0.1M),然后用DMSO进行10-100倍稀释使得操作溶液达到1-10mM。DMSO储备液储存于4℃(0.1M)或-20℃(<0.1M)下。使MCF-7细胞以每周两次通过生长培养基(D-MEM/F-12培养基)转代。细胞保持在置于5%CO2/95%湿空气培养器中的37℃通气烧瓶中。在治疗前一天,将细胞用生长培养基以25000/孔铺在96孔滴定板中,在37℃下培养过夜。
细胞在37℃下用50μL/孔的1/10稀释的腺病毒5-ERE-tk-荧光素酶在试验培养基(无酚磺酞的D-MEM/F-12培养基)中感染2h。然后将孔用150μλ试验培养基洗涤一次。最后,细胞分成多份复制品在37℃下处理24h,8孔/使用150μλ/孔媒介物(≤0.1%v/v DMSO)或者用试验培养基稀释≥1000倍的化合物治疗。
在1μM的单剂量下进行测试化合物的初期筛选,其中所测试化合物是单独的(激动剂模式)或者与0.1nM17β***联合(EC80:拮抗剂模式)。每个96孔滴定板还包括媒介物对照组(0.1%v/v DMSO)和激动剂对照组(0.1或1nM17β***)。在激动剂和/或拮抗剂模式中,对由10-14至10-5M对数增加的活性化合物进行剂量响应实验。根据这些剂量响应曲线,分别提到EC50和IC50值。各治疗组最后的滴定孔中含有5μL 3×10-5M ICC-182780(10-6M最终浓度)作为ER拮抗剂对照。
治疗后,将细胞在振荡器上用25μL/孔的1X细胞培养溶解试剂(PromegaCorporation)溶解15分钟。细胞溶解产物(20μL)转移至96孔光度计盘中,使用100μL/孔的荧光素酶底物(Promega Corporation)在MicroLumat LB 96P光度计(EG&G Berthold)中测量荧光素酶活性。在注入底物之前,对每个孔进行1s背景测量。在注入底物之后,测得延迟1s后10s内的荧光素酶活性。将这些来自光度计的数据用JMF软件(SAS Institute)分析;该程序减去来自每个孔荧光素酶活性的背景读数,然后计算每组治疗的平均和标准偏差。
上述荧光素酶数据通过对数转换,利用Huber M-估计器降低远离中心的经转换结果的权重。利用JMP软件来分析转换和加权后的数据进行单向ANOVA(D检验)。将化合物治疗组与激动剂模式中的媒介物对照组结果,或者拮抗剂模式中的阳性激动剂对照组结果(0.1nM17β-***)进行对比。对于最初的单剂量试验而言,如果化合物治疗组结果显著不同于相应的对照组的话(p<0.05),就将结果表达为相对于17β-***对照组的百分比。另外,利用JMP软件由非线形剂量-响应曲线确定EC50和/或IC50值。
部分样品MCF-7抗增殖测试列表如下(n=3):
实施例26:对乳腺癌细胞增殖的作用
以文献中易于得到的标准药理学实验方法,所述方法可评价本发明化合物治疗和抑制各种恶性肿瘤或者过度增殖疾病的能力。
切除卵巢的无胸腺nu/nu(裸)小鼠。肿瘤细胞注射前一天,用含0.36-1.7mgβ***(60或90天释放)的控释小丸或者安慰剂植入动物。采用10刻度精确转子,把小丸经皮下导入内雕纹区。接着,用1×107MCF-7细胞或者1×107BG-1细胞皮下注射到小鼠乳腺组织中。将细胞与等体积的基底胶(matrigel)混合,后者为一种基底膜基质制备液以增强肿瘤建立。在肿瘤细胞植入(抑制方案)后一天或者肿瘤已经达到某一体积(治疗方案)后通过给药可评价受试化合物。每天腹膜内或者口服给予在盐水中的1%吐温-80媒介物中的化合物。每3或7天评介肿瘤体积。
部分样品活性列表如下(n=3):
实施例27:对HOB细胞中IL-6和GM-CSF生产的作用
将人体破骨细胞HOB铺板在96孔皿内使其在常规HOB培养基(Ham氏F12,补充有28mM HEPES,Ph7.4,10%FCS,1.1mM CaCl2,2mM谷酰胺和1%抗生素-抗真菌剂)中的密度为7×103个细胞/孔。次日,细胞用化合物或载体处理(0.2%DMSO)处理30分钟,随后加入IL-1β(1ng/mL)和TNF-α(10ng/mL)。培养持续18至24小时。利用市售ELISA试剂盒测定培养基中IL-6和GM-CSF水平。本发明化合物显示出对IL-6和GM-CSF的抑制作用。
部分样品活性列表如下(n=3):
实施例28:对卵巢癌细胞SKOV3增殖的作用
对数生长期细胞用胰酶消化后,以6×103个/孔细胞数加人96孔培养板,置37℃、5%CO2培养箱中培养,第2天待大部分细胞贴壁后置人4℃恒温箱1h,以促成细胞同步化生长。吸去上清液,加人含10%新生小牛血清(FCS)RPMI1640培养液,200μL/孔,按实验设计分组。把无菌生理盐水配制的化合物注射液加入96孔中,每孔中加入200μL,使每孔的药物浓度分别为1mg/mL、2mg/mL和5mg/mI,以0mg/mL为阴性对照组。继续培养24、48、72h后,各孔分别加人20μL MTT溶液(浓度为5mg/mL),轻轻震荡培养板,放回培养箱内再孵育4h,然后吸尽上清液,于各孔中加二甲亚砜200μL,置震荡器上震荡5-10min,用酶标光度计测出每孔中波长为580nm的吸光值(A=580),A=580值与活细胞数量成正比。
部分样品活性列表如下(n=3):
Claims (12)
1.一种通式(I)的喹啉酮类化合物或其药学上可接受的盐,
其中X为O;
R1、R2独立地选自氢、Cl-C4烷基、苄基、Cl-C4烷基取代的苄基、Cl-C4烷氧基取代的苄基、羟基和卤素取代的苄基、苯基、Cl-C4烷基取代的苯基、Cl-C4烷氧基取代的苯基、羟基和卤素取代的苯基、或R1、R2与它们相连的氮原子一起组成1-吡咯烷基、1-哌啶基、4-吗啉基、4-苯基-1-哌嗪基、4-(4-甲基苯基)-1-哌嗪基、4-(4-氟苯基)-1-哌嗪基、4-(4-氯苯基)-1-哌嗪基、4-(4-溴苯基)-1-哌嗪基、4-(4-甲氧基苯基)-1-哌嗪基、4-(4-三氟甲基苯基)-1-哌嗪基或4-二苯甲基-1-哌嗪基。
2.如权利要求1所述的喹啉酮类化合物或其药学上可接受的盐,其中,
R1、R2与它们相连的氮原子一起组成二甲胺基,二乙胺基,1-吡咯烷基,1-哌啶基,4-吗啉基,4-苯基-1-哌嗪基,4-(4-甲基苯基)-1-哌嗪基,4-(4-氟苯基)-1-哌嗪基,4-(4-氯苯基)-1-哌嗪基,4-(4-溴苯基)-1-哌嗪基,4-(4-甲氧基苯基)-1-哌嗪基,4-(4-三氟甲基苯基)-1-哌嗪基或4-二苯甲基-1-哌嗪基。
3.如下的化合物或其药学上可接受的盐,选自:
6-羟基-7-[4-(2-氧代-2-二乙胺基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-2-(1-哌啶基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-[2-氧代-(4-吗啉基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-(1-哌啶基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-[2-(4-吗啉基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-2-(4-二苯甲基-1-哌嗪基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-2-(苯甲胺基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-2-(4-甲基苯基胺基)乙氧基]苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-[4-(2-氧代-2-二甲胺基乙氧基)苯甲酰基]-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-4-(4-甲基苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-4-(4-氟苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-4-(4-溴苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-4-(4-甲氧基苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮;
6-羟基-7-{4-[2-氧代-4-(4-三氟甲基苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3,4-二氢-1H-喹啉-2-酮。
4.一种药用组合物,该组合物含有权利要求1或2或3所述的化合物或药学上可接受的盐,及其药学上可接受的载体或稀释剂。
5.权利要求1、2或3所述的化合物或药学上可接受的盐在制备预防和治疗***相关疾病的药物中的应用。
6.权利要求4所述的药用组合物在制备预防和治疗***相关疾病的药物中的应用。
7.如权利要求5所述的应用,其特征在于,所述的***相关疾病为骨质疏松或癌症。
8.如权利要求6所述的应用,其特征在于,所述的***相关疾病为骨质疏松或癌症。
9.如权利要求7所述的应用,其特征在于,所述的癌症为乳腺癌、卵巢癌、骨肉瘤或子宫内膜癌。
10.如权利要求8所述的应用,其特征在于,所述的癌症为乳腺癌、卵巢癌、骨肉瘤或子宫内膜癌。
11.根据权利要求5、7或9所述的应用,其特征在于:以有效量的权利要求1或2或3所述的化合物或药学上可接受的盐接触***受体,抑制***受体。
12.根据权利要求6、8、10任何一项所述的应用,其特征在于:以有效量的权利要求4所述的药用组合物接触***受体,抑制***受体。
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