CN1358091A - 雌激素受体－β配体 - Google Patents
雌激素受体－β配体 Download PDFInfo
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- CN1358091A CN1358091A CN00809003A CN00809003A CN1358091A CN 1358091 A CN1358091 A CN 1358091A CN 00809003 A CN00809003 A CN 00809003A CN 00809003 A CN00809003 A CN 00809003A CN 1358091 A CN1358091 A CN 1358091A
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- hydrogen
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- phenyl
- hydroxyl
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Abstract
一种与雌激素受体－β有关的疾病的治疗方法,包含给药某一治疗有效量的一种化合物的步骤,该化合物满足方程(KiαA/KiβA)/(KiαE/KiβE)>1,任选地有通式(I)。
Description
技术领域
本发明涉及一系列配体，更具体地说，涉及雌激素受体-β配体，它们与雌激素相比，对雌激素受体-β的选择性优于对雌激素受体-α的选择性，也涉及其生产方法和用于治疗与雌激素受体-β有关的疾病、尤其阿尔茨海默病、焦虑症、抑郁症、骨质疏松症、心血管疾病、类风湿关节炎或前列腺癌的用途。
背景
雌激素置换治疗(“ERT”)降低了阿尔次海默病的发病率，并改善了阿尔茨海默病患者的认识功能(Nikolov等人，Drugs of Today，34(11)，927-933(1998))。ERT也显示出对骨质疏松症和心血管疾病的有益效果，而且可能有抗焦虑和抗抑郁治疗性能。然而，ERT显示出有害的子宫和乳腺副作用，从而限制了它的使用。
ERT对绝经后妇女的有益效果，与雌激素在做了卵巢切除术的大鼠中对与认识功能、焦虑、抑郁、骨损、和心血管损害有关的模型的有益效果是相呼应的。雌激素在动物模型中也产生子宫和乳腺肥大，让人回忆起它对人体中这些组织的促有丝分裂效应。
ERT对绝经后妇女的有益效果，与雌激素在做了卵巢切除术的大鼠中对与认识功能、焦虑、抑郁、骨损、和心血管损害有关的模型的有益效果是相呼应的，具体地说，实验研究已经证实，雌激素通过提高胆碱能机能、增加神经营养酶(neurotrophin)/神经营养酶受体表达、改变淀粉样前体蛋白加工、提供对多种多样损害的神经保护、增加谷氨酸能突触传输、及其它效应，对中枢神经系统(“CNS”)产生影响。在临床前研究中雌激素效应的总体CNS形象，与其在改善认识功能和延缓阿尔茨海默病进展方面的临床效用是一致的。雌激素在子宫和乳腺组织中也产生促有丝分裂效果，表明它在人体中对这些组织的有害副作用。
人类、大鼠、和小鼠中的雌激素受体(“ER”)存在两种亚型，即ER-α和ER-β，两者在配体结合畴中各占约50％同一性(Kuiper等人，Endocrinology 139(10)4252-4263(1998))。这些亚型的同一性差异解释了如下事实：已经有人证实，一些小化合物对一种亚型的结合优先于对另一种亚型的结合(Kuiper等人)。
在大鼠中，相对于ER-α而言，ER-β强烈地表达于大脑、骨骼和血管上皮中，但微弱地表达于子宫和乳腺中。进而，ER-α失效(ERKO-α)小鼠是不生育的，而且显示出很少或没有生殖组织激素反应的证据。ER-β失效(ERKO-β)小鼠是能生育的，而且显示出乳腺和子宫组织的正常发育和机能。这些观察表明，选择性地以ER-β而不是ER-α为目标，可能会给若干重要的人类疾病例如阿尔茨海默病、焦虑症、抑郁症、骨质疏松症、和心血管病带来有益的效果而不会产生生殖系统副作用。对ER-β表达组织(中枢神经系统、骨骼等)而不对子宫和乳腺的选择性作用可以通过那些能与ER-β而不与ER-α选择性相互作用的药剂来实现。
本发明的目的是确认那些可用于治疗ERT对其有治疗效益的疾病的ER-β选择性配体。
本发明的另一个目的是确认那些有类似于ERT对大脑、骨骼和心血管机能的有益作用的ER-β选择性配体。
本发明的又一个目的是确认那些能提高认识机能和延缓阿尔茨海默病进展的ER-β选择性配体。
发明概要
本发明涉及使用有如下一般结构的化合物作为类似于ERT但缺少ERT所不希望的副作用的ER-β选择性配体。这些化合物尤其满足下式：
(KiαA/KiβA)/(KiαE/KiβE)＞1，较好满足
(KiαA/KiβA)/(KiαE/KiβE)＞30，更好满足
(KiαA/KiβA)/(KiαE/KiβE)＞100。式中KiαA是该配体在ER-α中的Ki值；KiβA是该配体在ER-β中的Ki值；KiαE是雌激素在ER-α中的Ki值；而KiβE是雌激素在ER-β中的Ki值。
发明详细说明
本发明涉及一种与雌激素受体-β相联系的疾病的治疗方法，包含给药某一治疗有效量的一种化合物的步骤，该化合物满足方程(KiαA/KiβA)/(KiαE/KiβE)＞1，式中KiαA是该激动剂在ER-α中的Ki值；KiβA是该激动剂在ER-β中的Ki值；KiαE是雌激素在ER-α中的Ki值；而KiβE是雌激素在ER-β中的Ki值。较好的是该化合物满足方程(KiαA/KiβA)/(KiαE/KiβE)＞100。与雌激素受体-β相联系的较好疾病选自阿尔茨海默病、焦虑症、抑郁症、骨质疏松症、心血管病、类风湿关节炎和前列腺癌。更好的是，该疾病是阿尔茨海默病或抑郁症。
本发明的化合物是如下结构的ER-β选择性配体：
在这个结构中，L1是-C(＝O)-、＝C(R6)-、-CH(R6)-、O、S、或NRa，较好的是-C(＝O)-、＝C(R6)-、-CH(R6)-或O；L2是＝C-或-CH-；L3是＝C(R6)-、-CH(R6)-或-C(＝O)-；而L4是-C(＝O)-、CH2、O、S、或NRa，较好的是-C(＝O)-、CH2或O，先决条件是：当L1是-C(＝O)-时L4是CH2、O、S或NRa；当L4是-C(＝O)-时L1是CH2、O、S或NRa；且当L3是-C(＝O)-时L1是＝C(R6)-或-CH(R6)-，而L4是O或NRa。此外，当L1是＝C(R6)-时L2是＝C-；当L1是-CH(R6)-时L2是-CH-；当L3是＝C(R6)-时，L2是＝C-；而当L3是-CH(R6)-时，L2是-CH-。＝代表一个单键或双键，因L1～L4的杂化而异。L2的结构只显示三个键，因为第四个键是一个连接R1的单键。
R1是经由一个单键连接到L2上的，而且是苯基、有取代苯基、以下定义的Het、或有取代Het。R1较好的是式中，R7是H、Cl、或甲基；R8是Br、Cl、F、Ra、ORa或烯丙基；R9是H、OH、NH2、Br、Cl；且R10是H或甲基；或者R8与R9可以组合成-OCH2O-，形成该苯基基团外部的一个次级5员环结构；或者R1是一个有如下结构的有取代或无取代杂环取代基：
更好的是无取代的
R2、R3、R4、和R5各自独立地是-Ra、-ORa、-SRa、-NRaRa、-NC(＝O)Ra、-NS(＝O)Ra、-NS(＝O)2Ra、卤素、氰基、-CF3、-CO2Ra、-C(＝O)Ra、-C(＝O)NHRa、硝基、-S(＝O)Ra或-S(＝O)2Ra，较好的是Ra、ORa、NR2 a、NC(＝O)Ra、CF3、或卤素，较好的是氢、羟基或甲基。
R6是Ra、苯基或CF3。
Ra每次出现时各自独立地是H或(C1-C5)烷基。
当L1是-C(＝O)-、且R2是羟基或氢、且R3是氢、且R4是羟基、且R5是氢、且R6是氢时，则R1不是对苯酚。
为了本发明之目的，“有取代”当用来修饰一个苯基或一个杂原子环时系指在一个或多个位置上独立地有下列基团取代的这样一个环：-Ra、-ORa、-SRa、-NRaRa、-NC(＝O)Ra、-NS(＝O)Ra、-NS(＝O)2Ra、卤素、氰基、-CF3、-CO2Ra、-C(＝O)Ra、-C(＝O)NHRa、硝基、-S(＝O)Ra、或-S(＝O)2Ra。
此外，为了本发明之目的，“Het”系指从下列选择的一个有取代或无取代的单环或双环式杂环：式中，交叉的键代表该杂环可以连接在它所交叉的那个环上的任何可用位置。
雌激素受体结合测定
一种化合物与ER结合的能力，是用它为与放射性标记雌激素〔125I〕-16α-碘-3，17β-雌二醇结合而竞争的能力衡量的(NEN，Cat#NEX-144)。该放射性配体以下称为〔125I〕-雌二醇。
把ER-β(Gen Bank Accession#X99101)或ER-α(Gen BankAccession #M12674)cDNA克隆成表达载体pSG5(Stratagene)，转变成大肠杆菌株DHαF，再阴离子交换树脂柱(Qiagen Cat.#12125)精制。受体蛋白质是用TNT T7快速偶合网状细胞溶胞产物系统(Promega Cat. #L 1170)进行这些质粒的离体转录和转译来制备的。网状细胞溶胞产物(12.5mL)用312.5μg ER-α和625μg ER-β质粒在30℃培养90分钟。然后，把编程的溶胞产物分成等分部分，于-80℃冷冻贮存。
各化合物以10pM-3μM范围内的半对数浓度用双份试样进行测试。各化合物先制备成1mM的DMSO储备溶液，然后用结合试验缓冲剂(以mM表示：20 HEPES、150 NaCl、1 EDTA、6-硫代甘油和10 Na2MoO4；10％(重量/体积)甘油，且pH＝7.9)在一个96孔平皿上稀释成一系列浓度递差三倍的20mL等分溶液。受体等分样品在冰上解冻、用结合试验缓冲剂适当稀释(见以下)。向每个孔中添加稀释的受体(每孔30μL)。用结合试验缓冲剂把〔125I〕-雌二醇从制造商的乙醇储备溶液稀释成900 pM工作溶液。最终试验体积是60μL、包括20μL一种按照本发明的化合物、30μL编程的网状细胞溶胞产物、和10μL 900pM〔125I〕-雌二醇。〔125I〕-雌二醇的最终浓度是150pM。含有最终试验混合物的平皿在一台振荡机上混合2分钟，并在4℃培养过夜(～16小时)。
通过在交联葡聚糖柱上过滤，将受体结合的和未结合的放射性配体分离。各柱(45μL床体积)是通过向96孔柱模板(Millipore MultiSereen Plates Cat#MAHVN 4510)中添加干柱介质(Pharmacia Cat#G-25)来制备的。然后，各柱用300μL结合试验缓冲剂饱和，并于4℃贮存。使用之前，贮存的柱以2000rpm旋转10分钟，然后用200μL新鲜的结合缓冲剂洗涤两次。然后，将结合试验混合物(每份50μL)加到各柱上，并立即向各该柱上加另外35μL的洗脱体积。然后，以2000rpm离心分离10分钟，从该柱上洗脱受体结合的放射性配体。向洗脱的放射性配体/受体复合物中添加一种闪烁鸡尾酒(145μL)，再用液体闪烁计数法测定放射性标记。
非专性结合是通过与150nM二甲基己烯雌酚(DES)竞争来界定的。结合亲合性表达为Ki，是利用Cheng-Prushoff公式按照通过使浓度与百分率专性结合(SB)的关系与如下方程拟合产生的IC50值计算的：
％SB＝最大值-(最大值-最小值)/(1+10(logIC50-log〔化合物〕))在本试验中，标准雌激素受体配体雌二醇和DES被检测为ER-β和ER-α的高亲合性(Ki＜1nM)非选择性配体。
要添加到该结合试验中的受体编程网状细胞溶胞产物的体积，是从对所制备的每批受体所做的两次测定独立地确定的。首先，利用该受体制剂的一系列稀释，确定各标准化合物的Ki。以这些受体稀释进行配体结合亲合性的Scatchard分析，产生了这些化合物的所报告Ki和可接受的信噪比(～10)。这些实验指出〔125I〕-雌二醇的KD为0.1～1nM、Bmax为5～30pmol。
给药和用途
本发明的化合物已显示对ER-β有优于对ER-α的高选择性，而且可能具有对ER-β的激动剂活性而无所不希望的子宫作用。因此，这些化合物和含有这些化合物的组合物可以作为治疗剂用于治疗诸如阿尔茨海默病等与ER-β有关的各种中枢神经系统疾病。
本发明也提供包含某一有效量的本发明化合物、包括其无毒的加成盐、酰胺和酯类的组合物，该组合物可以用来提供以上提到的治疗效益。这样的组合物也可以连同生理上可耐受的液体、凝胶或固体稀释剂、辅药和赋形剂一起提供。本发明化合物也与其它已知要用来作为上述或其它指征的治疗剂的化合物组合。
这些化合物和组合物可以由有资格的保健专业人员以类似于其它治疗剂的方式对人类给药，此外，还可以为了兽医用途而给其它哺乳动物例如家畜给药。典型地说，这样的组合物可以制备成注射剂，要么成为液体溶液剂要么成为悬浮液剂；还可以制备适合于在注射前溶解或悬浮于液体中的固体剂型。该制剂也可以乳化。该有效成分往往是与生理上可耐受而且与该有效成分兼容的稀释剂或赋形剂混合。适用的稀释剂和赋形剂是例如水、食盐水、葡萄糖、甘油等，及其组合。此外，如果希望，该组合物还可以含有少量辅助物质，例如润湿剂或乳化剂、稳定剂或pH缓冲剂等。
这些组合物惯常地是以非经肠方式、例如经由皮下注射或经由静脉内注射的方式给药。适用于其它给药方式的另一些配方包括栓剂、鼻内气雾剂、和在一些情况下的经口配方。对于栓剂来说，传统的粘结剂和赋形剂可以包括例如聚亚烷基二醇或甘油三酸酯；这样的栓剂可以从含有该有效成分的混合物形成。经口配方包括诸如通常采用的赋形剂，例如医药级甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。这些组合物的剂型为溶液剂、悬浮液剂、片剂、丸剂、胶囊剂、缓释配方或散剂。
本发明化合物可以配制成中性形式或盐形式的组合物。医药上可接受的无毒盐包括(与游离氨基基团生成的)和与无机酸例如盐酸或磷酸、或者有机酸例如乙酸、草酸、酒石酸、杏仁酸等生成的酸加成盐。与游离羧基基团生成的盐可以从无机碱例如氢氧化钠、钾、铵、钙、或铁以及有机碱例如异丙胺、三甲胺、2-乙胺基乙醇、组胺酸、普鲁卡因等衍生而成。
除了显示ER-β活性的本发明化合物外，本发明的化合物也可以作为中间体用于合成这样的有用化合物。
合成
本发明范围内的化合物可以用技术上众所周知的手段化学合成。以下实施例意在显示一般合成方案，它们可以用来通过采用各种商业上可得的起始原料而产生很多不同变化。这些实施例仅旨在作为关于如何在本发明范围内制作一些化合物的指南，而不应当解读为本发明范围的限制。
实施例
实施例1(路线A)
(3-溴-4-羟基苯基)-5，7-二羟基-4H-1-苯并吡喃-4-酮
1，3，5-三羟基苯甲醛(1.01g，6.25mmol)和3-溴-4-羟基苯乙酸(1.44g，6.25mmol)悬浮在POCl3(4mL)中。1分钟后，发生放热反应。让混合物冷却到室温。添加氯化锌(1M乙醚溶液，4.7mmol)，混合物在75℃加热1小时。冷却后，该混合物分配于乙酸乙酯与1M HCl水溶液中。有机层用食盐水洗涤、用MgSO4干燥。在硅胶上精制(MeOH/二氯甲烷，梯度)给出褐色固体状1-(2，4，6-三羟基苯基)-2-(3-溴-4-羟基苯基)乙酮(390mg)。
在氮气下向1-(2，4，6-三羟基苯基)-2-(3-溴-4-羟基苯基)乙酮(370mg)的DMF(5mL)溶液中滴加BF3-Et2O(0.83mL，6.55mmol)，随后添加甲磺酰氯(0.507mL，6.55mmol)。混合物在室温搅拌10分钟，在55℃加热30分钟。冷却后，该混合物分配于乙酸乙酯/1M HCl水溶液中。有机层用1M HCl和食盐水洗涤，用C18 HPLC精制，给出标题化合物(55mg)。
实施例2(化合物No.28：路线B)
3-(4-羟基苯基)-7-羟基-4-甲基香豆素
2，4-二羟基乙酰苯(1.1g，7.24mmol)、4-羟基苯乙酸(1.45g，9.5mmol)和乙酸钾(0.9g，9.2mmol)在乙酸酐(10mL)中的溶液在回流下加热18小时。冷却后，将混合物倾入冰水中。将固体滤出、用乙醚洗涤、在真空下干燥，给出3-(4-乙酰氧基苯基)-7-乙酰氧基-4-甲基香豆素(1.83g)。
3-(4-乙酰氧基苯基)-7-乙酰氧基-4-甲基香豆素(500mg)在THF(10mL)和1N氢氧化钠水溶液(10mL)中的悬浮液搅拌1小时。混合物用浓HCl酸化到pH＝1，用乙酸乙酯/水萃取。有机层用食盐水洗涤、用MgSO4干燥。溶剂蒸发、残渣用乙醚研制，给出标题化合物(140mg)。
HPLC条件(HPLC 4.6×250mm C18 5μm Vydax 218TP54柱，流量率1.5mL/分钟，乙腈/水0.1％TFA在30分钟内从10∶90到50∶50的线性梯度，UV检测：254nm)称为条件A。
HPLC条件(HPLC 2.1×30mm C18 3.5μm Zorbax快速拆分柱，流量率0.7mL/分钟，水-0.05％TFA 0.5分钟，然后90％乙腈水溶液/水0.05％TFA在9.5分钟内从0∶100到80∶20的线性梯度，UV检测)称为条件B。
按照这些路线，用有关起始原料，制备了下列化合物。
表1
表1(续)
表2：精制、性能、和合成路线
*化合物是商业上可得的。注a)：按照方法A制备；环化步骤是用三氟乙酸酐按照J.Med.Chem.1992，35，3519进行的。注b)：按照J.Org.Chem，1946，11，34中发展的方法，先用POCl3使对应2，4-二芳基丁酸环化，随后使甲氧基醚脱甲基化来制备。注c)：按照Aust.J.Chem，1978，31，1011制备。
| No. | L1 | L2 | L3 | L4 | R1 |
| 1 | C(＝O) | ＝C- | ＝CR6- | O | 3，4-二羟基苯基 |
| 2 | C(＝O) | ＝C- | ＝CR6- | O | 2-Cl-4-羟基苯基 |
| 3 | C(＝O) | ＝C- | ＝CR6- | O | 2-Me-4-羟基苯基 |
| 4 | C(＝O) | ＝C- | ＝CR6- | O | 3-F-4-羟基苯基 |
| 5 | C(＝O) | ＝C- | ＝CR6- | O | 3-Cl-4-羟基苯基 |
| 6 | C(＝O) | ＝C- | ＝CR6- | O | 3-Br-4-羟基苯基 |
| 7 | C(＝O) | ＝C- | ＝CR6- | O | 3-烯丙基-4-羟基苯基 |
| 8 | C(＝O) | ＝C- | ＝CR6- | O | 3-丙基-4-羟基苯基 |
| No. | L1 | L2 | L3 | L4 | R1 |
| 9 | C(＝O) | ＝C- | ＝CR6- | O | 3-甲氧基-4-羟基苯基 |
| 10 | C(＝O) | ＝C- | ＝CR6- | O | 3.5-二甲基-4-羟基苯基 |
| 11 | C(＝O) | ＝C- | ＝CR6- | O | 4-氟苯基 |
| 12 | C(＝O) | ＝C- | ＝CR6- | O | 3.4-(OCH2O)苯基 |
| 13 | C(＝O) | ＝C- | ＝CR6- | O | 4-氨基苯基 |
| 14 | C(＝O) | ＝C- | ＝CR6- | O | 2-萘基 |
| 15 | C(＝O) | ＝C- | ＝CR6- | O | 3-羟基苯基 |
| 16 | C(＝O) | ＝C- | ＝CR6- | O | 2-羟基苯基 |
| 17 | C(＝O) | ＝C- | ＝CR6- | O | 2-噻吩 |
| 18 | C(＝O) | ＝C- | ＝CR6- | O | 3-噻吩 |
| 19 | C(＝O) | ＝C- | ＝CR6- | O | 2-喹啉基 |
| 20 | C(＝O) | ＝C- | ＝CR6- | O | 4-溴苯基 |
| 21 | C(＝O) | ＝C- | ＝CR6- | O | 4-氯苯基 |
| 22 | C(＝O) | ＝C- | ＝CR6- | O | 4-羟基苯基 |
| 23 | C(＝O) | ＝C- | ＝CR6- | O | 4-羟基苯基 |
| 24 | C(＝O) | ＝C- | ＝CR6- | O | 3-F-4-羟基苯基 |
| 25 | C(＝O) | ＝C- | ＝CR6- | O | 4-羟基苯基 |
| 26 | C(＝O) | -CH- | -CHR6- | O | 4-羟基苯基 |
| 27 | C(＝O) | -CH- | -CHR6- | CH2 | 4-羟基苯基 |
| 28 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 29 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 30 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 31 | ＝CR6- | ＝C- | C(＝O) | O | 2-噻吩 |
| 32 | C(＝O) | ＝C- | ＝CR6- | O | 4-羟基苯基 |
| 33 | C(＝O) | ＝C- | ＝CR6- | O | 2-F-苯基 |
| 34 | C(＝O) | ＝C- | ＝CR6- | O | 苯基 |
| 35 | C(＝O) | ＝C- | ＝CR6- | O | 苯基 |
| 36 | O | ＝C- | ＝CR6- | C(＝O) | 4-羟基苯基 |
| No. | L1 | L1 | L3 | L4 | R1 |
| 37 | CH2 | -CH- | -CHR6- | C(＝O) | 4-羟基苯基 |
| 38 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 39 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 40 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 41 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 42 | ＝CR6- | ＝C- | C(＝O) | O | 4-Cl-苯基 |
| 43 | ＝CR6- | ＝C- | C(＝O) | O | 4-羟基苯基 |
| 44 | C(＝O) | ＝C- | ＝CR6- | O | 4-异丙氧基苯基 |
| 45 | C(＝O) | -CH- | -CHR6- | CH2 | 3-Br-苯基 |
| 46 | CH2 | -CH- | -CHR6- | O | 4-羟基苯基 |
| No. | R2 | R3 | R4 | R5 | R6 |
| 1 | OH | H | OH | H | H |
| 2 | OH | H | OH | H | H |
| 3 | OH | H | OH | H | H |
| 4 | OH | H | OH | H | H |
| 5 | OH | H | OH | H | H |
| 6 | OH | H | OH | H | H |
| 7 | OH | H | OH | H | H |
| 8 | OH | H | OH | H | H |
| 9 | OH | H | OH | H | H |
| 10 | OH | H | OH | H | H |
| 11 | OH | H | OH | H | H |
| 12 | OH | H | OH | H | H |
| 13 | OH | H | OH | H | H |
| 14 | OH | H | OH | H | H |
| 15 | OH | H | OH | H | H |
| 16 | OH | H | OH | H | H |
| No. | R2 | R3 | R4 | R5 | R6 |
| 17 | OH | H | OH | H | H |
| 18 | OH | H | OH | H | H |
| 19 | OH | H | OH | H | H |
| 20 | OH | H | OH | H | H |
| 21 | OH | H | OH | H | H |
| 22 | OH | H | OMe | H | H |
| 23 | Me | H | OH | H | H |
| 24 | H | H | OH | H | H |
| 25 | H | H | OH | H | CF3 |
| 26 | OH | H | OH | H | H |
| 27 | OH | H | OH | H | H |
| 28 | H | H | OH | H | Me |
| 29 | H | H | OH | H | Et |
| 30 | H | H | H | H | H |
| 31 | H | H | OH | H | H |
| 32 | OH | H | OH | OMe | H |
| 33 | OH | H | OH | H | H |
| 34 | OH | H | OH | H | Ph |
| 35 | H | H | OH | H | Ph |
| 36 | H | H | OH | H | H |
| 37 | H | H | OH | H | H |
| 38 | H | H | OH | H | H |
| 39 | OH | H | OH | H | H |
| 40 | H | H | H | OH | H |
| 41 | H | OH | H | H | H |
| 42 | H | H | OH | H | Me |
| 43 | H | H | OH | Me | Me |
| 44 | H | H | OH | H | CF3 |
| 45 | H | H | OH | H | H |
| No. | R2 | R3 | R4 | R5 | R6 |
| 46 | H | H | OH | H | H |
| No. | HPLCmin(方法) | MS(MH+) | ER-βKinM | ER-αKinM | 合成路线 |
| 1 | 2.15 | 605 | * | ||
| 2 | 5.76(B) | 305(35Cl) | 0.55 | 56 | A |
| 3 | 5.41(B) | 285 | 1.2 | 61 | A |
| 4 | 5.62(B) | 289 | 0.5 | 74 | A |
| 5 | 6.11(B) | 305(33Cl) | 1.2 | 1100 | A |
| 6 | 25.6(A) | 349(79Br) | 1.25 | 439 | A |
| 7 | 6.72(B) | 311 | 3.2 | ＞3000 | A |
| 8 | 7.08(B) | 313 | 0.75 | ＞3000 | A |
| 9 | 143 | ＞3000 | * | ||
| 10 | 25.4(A) | 299 | 25 | ＞3000 | A |
| 11 | 6.93(B) | 273 | 100 | ＞3000 | A |
| 12 | 22 | ＞3000 | * | ||
| 13 | 6 | ＞3000 | * | ||
| 14 | 7.86(B) | 305 | 150 | ＞3000 | A |
| 15 | 5.39(B) | 271 | 15 | 900 | A |
| 16 | 5.68(B) | 271 | 110 | ＞3000 | A |
| 17 | 1H NMR(DMSO-d6)：12.59(s，1H)，10.99(s，1H)，8.88(s，1H)，7.63(m，2H)，7.14(m，1H)6.44(s，1H)，6.27(s，1H). | 3.3 | ＞3000 | A | |
| 18 | 1H NMR(DMSO-d6)：12.92(s，1H)，10.93(s，1H)，8.72(s，1H)，8.07(s，1H)，7.64(m，1H).7.53(m，1H)，6.42(s，1H)，6.24(s，1H). | 17 | ＞3000 | A | |
| 19 | 5.26(B) | 306 | 122 | ＞3000 | A |
| 20 | 7.70(B) | 333(79Br) | 25 | ＞3000 | A |
| No. | HPLCmin(方法) | MS(MH+) | ER-βKinM | ER-αKinM | 合成路线 |
| 21 | 7.55(B) | 289(33Cl) | 42 | ＞3000 | A |
| 22 | 50 | ＞3000 | |||
| 23 | 5.20(B) | 269 | 0.5 | 200 | A |
| 24 | 4.91(B) | 273 | 3.3 | ＞3000 | A |
| 25 | 6.07(B) | 323 | 10 | 321 | 注a) |
| 26 | 3.7 | 1000 | * | ||
| 27 | 5.43(B) | 271 | 5.7 | 3000 | 注b) |
| 28 | 1H NMR(DMSO-d6)：10.47(m，1H)，9.55(m，1H)，7.67(d，1H)，7.1-6.7(m，6H)，2.22(m，3H)；MS：269 | 12 | 322 | B | |
| 29 | 5.57(B) | 283 | 4 | 80 | B |
| 30 | 6.01(B) | 239 | 140 | ＞3000 | B |
| 31 | 1H NMR(DMSO-d6)：10.68(s，1H)，8.44(s，1H)，7.75(m，1H)，7.60(m，2H)，7.16(m，1H)，6.87(dd，1H)，6.81(m，1H)；MS：245 | 108 | ＞3000 | B | |
| 32 | 33 | ＞3000 | * | ||
| 33 | 1H NMR(DMSOd-6)：12.66(s，1H)，10.98(s，1H)，8.42(s，1H)，7.48(m，2H)，7.27(m，2H)，6.44(d，1H，J＝2.1Hz)，6.26(d，1H，J＝2.1Hz)；MS：273 | 50 | ＞3000 | A | |
| 34 | 9.5 | 95 | |||
| 35 | 19 | 50 | * | ||
| 36 | 0.33 | 88 | * | ||
| 37 | 1H NMR(DMSOd-6)：9.61(s，1H)，9.52(s，1H)，7.26(d，1H，J＝2.7Hz)，7.21-7.13(m，3H)，6.99(dd，1H，J＝8.1Hz，J’＝2.7Hz)，6.71(d，2H，J＝8.4Hz)，3.26(m，1H)，3.07-2.80(m，3H)，2.64(m，1H)；MS：253(M-H)+ | 0.73 | 75 | 注c) | |
| No. | HPLCmin(方法) | MS(MH+) | ER-βKinM | ER-αKinM | 合成路线 |
| 38 | 1H NMR(DMSOd-6)：10.52(s，1H)，9.64(s，1H)，8.03(s，1H)，7.55(m，3H)，6.85-6.70(m，4H)；MS：255 | 4.9 | 220 | B | |
| 39 | 1H NMR(DMSOd-6)：10.63(s，1H)，10.33(s，1H)，9.60(s，1H)，7.95(s，1H)，7.50(d，2H，J＝8.4Hz)，6.80(d，2H，J＝8.4Hz)，6.28(s，1H)，6.22(s，1H)：MS：271 | 79 | ＞3000 | B | |
| 40 | 1H NMR(DMSOd-6)：10.18(s，1H)，9.73(s，1H)，8.08(s，1H)，7.60(d，2H，J＝8.4Hz)，7.17(m，2H)，7.06(m，1H)，6.85(d，2H，J＝8.4Hz)；MS：255 | 104 | ＞3000 | B | |
| 41 | 1H NMR(DMSOd-6)：9.72(s，2H)，8.05(s，1H)，7.58(d，2H，J＝8.4Hz)，7.25(d，1H，J＝8.7Hz)，7.07(d，1H，J＝2.7Hz)，7.00(dd，1H，J＝8.4Hz，J’＝2.7Hz)，6.84(d，2H，J＝8.4Hz)；MS：255 | 4.6 | 3000 | B | |
| 42 | 1H NMR(DMSOd-6)：10.56(s，1H)，7.50(d，2H，J＝7.8Hz)，7.42(d，1H，J＝8.7Hz)，7.33(d，2H，J＝7.8Hz)，6.84(dd，1H，J＝7.8Hz，J’＝2.1Hz)，6.75(d，1H，J＝2.1Hz)，2.21(s，3H)；MS：287(35Cl) | 51 | ＞3000 | B | |
| 43 | 1H NMR(DMSOd-6)：10.36(s，1H)，9.55(s，1H)，7.49(d，1H，J＝9Hz)，7.08(d，2H，J＝8.7Hz)，6.87(d，1H，J＝9Hz)，6.81(d，2H，J＝8.7Hz)，2.21(s，3H)，2.19(s，3H)；MS：283 | 24 | 500 | B | |
| 44 | 1H NMR(DMSOd-6)：11.11(s，1H)，7.93(d，1H，J＝8.7Hz)，7.16(d，2H，J＝8.4Hz)，7.03-6.93(m，4H)，4.66(m，1H)，1.30(d，6H，J＝6Hz)；MS：365 | 118 | 3000 | 注a) | |
| No. | HPLCmin(方法) | MS(MH+) | ER-βKinM | ER-αKinM | 合成路线 |
| 45 | 1H NMR(DMSOd-6)：10.39(s，1H)，7.78(d，1H，J＝8.4Hz)，7.42(m，2H)，7.28(t，1H，J＝7.8Hz)，7.19(d，1H，J＝7.8Hz)，6.75(dd，1H，J＝8.4Hz，J’＝2.4Hz)，6.69(d，1H，J＝2.4Hz)，3.86(m，1H)，3.00(m，1H)，2.85(m，1H)，2.4-2.1(m，2H)；MS：317(79Br) | 116 | 3000 | 注b) | |
| 46 | 2 | 155 | * | ||
Claims (13)
1.一种与雌激素受体-β有关的疾病的治疗方法，包含给药某一治疗有效量的一种满足如下方程的化合物的步骤：
(KiαA/KiβA)/(KiαE/KiβE)＞1，式中
KiαA是该激动剂在ER-α中的Ki值；
KiβA是该激动剂在ER-β中的Ki值；
KiαE是雌激素在ER-α中的Ki值；和
KiβE是雌激素在ER-β中的Ki值。
2.按照权利要求1的方法，其中，该化合物满足如下方程：
(KiαA/KiβA)/(KiαE/KiβE)＞100。
3.按照权利要求2的方法，其中，要治疗的疾病选自下列组成的一组：阿尔茨海默病、焦虑症、抑郁症、骨质疏松症、心血管病、类风湿关节炎和前列腺癌。
4.按照权利要求3的方法，其中，该化合物具有下式结构：式中
L1是-C(＝O)-、＝C(R6)-、-CH(R6)-、O、S、或NRa；
L2是＝C-或-CH-；
L3是＝C(R6)-、-CH(R6)-或-C(＝O)-；
L4是-C(＝O)-、CH2、O、S、或NRa；
式中
L1是-C(＝O)-时，L4是CH2、O、S、或NRa；
L4是-C(＝O)-时，L1是CH2、O、S、或NRa；
L3是-C(＝O)-时，L1是＝C(R6)-或-CH(R6)-，且L4是O或NRa；
L1是＝C(R6)-时，L2是＝C-；
L1是-CH(R6)-时，L2是-CH-；
L3是＝C(R6)-时，L2是＝C-；和
L3是-CH(R6)-时，L2是-CH-；
Ra每次出现时独立地是H或(C1-C5)烷基；
R1是苯基、有取代苯基或Het；
R2、R3、R4和R5独立地选自下列组成的一组：-Ra、-ORa、-SRa、-NRaRa、-NC(＝O)Ra、-NS(＝O)Ra、-NS(＝O)2Ra、卤素、氰基、-CF3、-CO2Ra、-C(＝O)Ra、-C(＝O)NHRa、硝基、-S(＝O)Ra和-S(＝O)2Ra；
R6是H、(C1-C5)烷基、苯基或CF3；和
式中，当L1是-C(＝O)-、且R2是羟基或氢、且R3是氢、且R4是羟基、且R5是氢、且R6是氢时，则R1不是对苯酚；以及
其任何医药上可接受的盐。
5.按照权利要求4的方法，其中，R1是Het。
6.按照权利要求4的方法，其中，
R1有如下结构
式中
R7是H、Cl或甲基；
R8是Br、Cl、F、Ra、ORa或烯丙基；
R9是H、OH、NH2、Br或Cl；和
R10是H或甲基；或
R8和R9组合形成-OCH2O-；或者
R1是下列之一的有取代或无取代基团：
7.按照权利要求1～6中任何一项的方法，其中，该疾病是阿尔茨海默病或抑郁症。
8.按照权利要求6的方法，其中，R2、R3、R4和R5独立地选自由Ra、ORa、NR2 a、NC(＝O)Ra、CF3
和卤素组成的一组。
9.按照权利要求8的方法，其中
R2是羟基或氢；R3是氢或甲基；R4是羟基或氢；和R5是氢或羟基。
10.按照权利要求8的方法，其中L4是-C(＝O)-。
11.按照权利要求8的方法，其中L3是-C(＝O)-。
12.按照权利要求8的方法，其中L1是-C(＝O)-。
13.按照权利要求9的方法，其中R1是下式的无取代基团：
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| US12990199P | 1999-04-16 | 1999-04-16 | |
| US60/129901 | 1999-04-16 |
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| US (1) | US6518301B1 (zh) |
| EP (1) | EP1173164A2 (zh) |
| JP (1) | JP2002542187A (zh) |
| KR (1) | KR20010108509A (zh) |
| CN (1) | CN1358091A (zh) |
| AR (1) | AR043085A1 (zh) |
| AU (1) | AU4128800A (zh) |
| BG (1) | BG106103A (zh) |
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| CZ (1) | CZ20013714A3 (zh) |
| EE (1) | EE200100526A (zh) |
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| IL (1) | IL145839A0 (zh) |
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| MX (1) | MXPA01010423A (zh) |
| NO (1) | NO20015015L (zh) |
| PL (1) | PL351314A1 (zh) |
| SK (1) | SK14762001A3 (zh) |
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| CN107667100A (zh) * | 2015-05-11 | 2018-02-06 | 肯塔基大学研究基金会 | 用于治疗癌症的抗肿瘤剂3‑芳基‑4h‑色烯‑4‑酮 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450134A (zh) * | 2012-05-31 | 2013-12-18 | 中国医学科学院药物研究所 | 香豆素衍生物的制备及其在防治脑部重大疾病中的应用 |
| CN103450134B (zh) * | 2012-05-31 | 2017-12-22 | 中国医学科学院药物研究所 | 香豆素衍生物的制备及其在防治脑部重大疾病中的应用 |
| CN107667100A (zh) * | 2015-05-11 | 2018-02-06 | 肯塔基大学研究基金会 | 用于治疗癌症的抗肿瘤剂3‑芳基‑4h‑色烯‑4‑酮 |
| CN113185486A (zh) * | 2015-05-11 | 2021-07-30 | 肯塔基大学研究基金会 | 用于治疗癌症的抗肿瘤剂3-芳基-4h-色烯-4-酮 |
| CN113185486B (zh) * | 2015-05-11 | 2024-05-10 | 肯塔基大学研究基金会 | 用于治疗癌症的抗肿瘤剂3-芳基-4h-色烯-4-酮 |
Also Published As
| Publication number | Publication date |
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| HUP0200740A3 (en) | 2004-08-30 |
| SK14762001A3 (sk) | 2002-10-08 |
| WO2000062765A2 (en) | 2000-10-26 |
| CA2370126A1 (en) | 2000-10-26 |
| KR20010108509A (ko) | 2001-12-07 |
| TR200102992T2 (tr) | 2004-12-21 |
| JP2002542187A (ja) | 2002-12-10 |
| IL145839A0 (en) | 2002-07-25 |
| US6518301B1 (en) | 2003-02-11 |
| EE200100526A (et) | 2002-12-16 |
| AU4128800A (en) | 2000-11-02 |
| MXPA01010423A (es) | 2002-03-27 |
| WO2000062765A3 (en) | 2001-09-07 |
| BG106103A (en) | 2002-05-31 |
| ZA200108409B (en) | 2003-03-26 |
| BR0009814A (pt) | 2002-01-08 |
| HUP0200740A2 (hu) | 2002-07-29 |
| AR043085A1 (es) | 2005-07-20 |
| IS6108A (is) | 2001-10-15 |
| NO20015015D0 (no) | 2001-10-15 |
| TR200201762T2 (tr) | 2002-10-21 |
| CZ20013714A3 (cs) | 2002-08-14 |
| EP1173164A2 (en) | 2002-01-23 |
| PL351314A1 (en) | 2003-04-07 |
| NO20015015L (no) | 2001-12-17 |
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