CN100443477C - 作为雌激素药物的取代苯并唑和类似物 - Google Patents
作为雌激素药物的取代苯并唑和类似物 Download PDFInfo
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- CN100443477C CN100443477C CNB028278186A CN02827818A CN100443477C CN 100443477 C CN100443477 C CN 100443477C CN B028278186 A CNB028278186 A CN B028278186A CN 02827818 A CN02827818 A CN 02827818A CN 100443477 C CN100443477 C CN 100443477C
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- benzoxazole
- alcohol
- hydroxy phenyl
- compound
- fluoro
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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Abstract
本发明提供具有式(I)结构的式(I)的雌激素受体调节剂或者其药学上可接受的盐,其中R1、R2、R2a、R3、R3a和R4以及X如在说明书中定义。
Description
本发明背景
本发明涉及用作雌激素药物的取代苯并噁唑。
已很好地证明哺乳动物组织内雌激素的多效作用,现在意识到雌激素可影响许多器官系统[Mendelsohn和Karas,New EnglandJournal of Medicine 340:1801-1811(1999),Epperson等,PsychosomaticMedicine 61:676-697(1999),Crandall,Journal of Womens Health &Gender Based Medicine 8:1155-1166(1999),Monk和Brodaty,Dementia&Geriatric Cognitive Disorders 11:1-10(2000),Hurn和Macrae,Journalof Cerebral Blood Flow&Metabolism 20:631-652(2000),Calvin,Maturitas 34:195-210(2000),Finking等,Zeitschrift fur Kardiologie 89:442-453(2000),Brincat,Maturitas 35:107-117(2000),Al-Azzawi,Postgraduate Medical Journal 77:292-304(2001)]。雌激素能够以几种方式对组织发挥作用,并且最具优良特征的作用机制为它们与导致基因转录变化的雌激素受体相互作用。雌激素受体为配体-激活的转录因子并且属于核激素受体超家族。这一家族的其它的成员包括孕酮、雄激素、糖皮质激素和盐皮质激素受体。一旦与配体结合,这些受体二聚化并且通过直接结合于DNA的特异性序列(称作应答元素)或者通过与其它的转录因子(例如AP1)相互作用,然后它直接结合于特异性DNA序列,可激活基因转录。[Moggs and Orphanides,EMBO Reports 2:775-781(2001),Hall等,Journal ofBiologicalchemistry 276:36869-36872(2001),McDonnell,Principles Of MolecularRegulation.351-361页(2000)]。一类“共调节”蛋白也可以与配体-结合的受体相互作用并且进一步调节它的转录活性[McKenna等,Endocrine Reviews 20:321-344(1999)]。它也显示雌激素受体能够以配体-依赖的和独立的方式抑制NFκB-介导的转录。[Quaedackers等,Endocrinology 142:1156-1166(2001),Bhat等,Journal of SteroidBiochemistry&Molecular Biology 67:233-240(1998),Pelzer等,Biochemical&Biophysical Research Communications 286:1153-7(2001)]。
通过磷酸化也可激活雌激素受体。通过生长因子例如EGF介导这种磷酸化并在配体不存在下,引起基因转录变化[Moggs和Orphanides,EMBO,Reports 2:775-781(2001),Hall等,Journal ofBiological chemistry 276:36869-36872(2001)]。
雌激素借以影响细胞颇具特点的方法是通过所谓的膜受体。这样受体的存在是有争论的,但它很好证实雌激素可非常迅速引起得自细胞的非基因组应答。担负传导这些作用的分子实体尚未明确分离,但有证据提示它至少与雌激素受体的核形成相关[Levin,Journal ofApplied Physiology 91:1860-1867(2001),Levin,Trends inEndocrinology&Metabolism 10:374-377(1999)]。
迄今已发现两种雌激素受体。15年前已克隆第一种雌激素受体且现在称为ERα[Green等,Nature 320:134-9(1986)]。最近才发现第二种形式的雌激素受体且称为ERβ[Kuiper等,Proceedings of theNational Academy of Sciences of the United States of America 93:5925-5930(1996)]。ERβ的最初研究集中在对多种配体定义它的亲合性,并且确实观察到与ERα的某些差异。在啮齿动物上良好绘制ERβ的组织分布且不与ERα相一致。组织例如小鼠和大鼠子宫主要表达ERα,而小鼠和大鼠肺主要表达ERβ[Couse等,Endocrinology 138:4613-4621(1997),Kuiper等,Endocrinology 138:863-870(1997)]。甚至在相同器官内,ERα和ERβ的分布可以被划分区域。例如,在小鼠卵巢中,ERβ在颗粒细胞中高度表达,并且ERα被限制于卵泡膜和基质细胞[Sar和Welsch,Endocrinology 140:963-971(1999),Fitzpatrick等,Endocrinology 140:2581-2591(1999)]。然而,存在受体共同表达的实例和有来自体外实验的证据,表明ERα和ERβ能够形成杂化二聚体[Cowley等,Journal of Biological chemistry 272:19858-19862(1997)]。
已描述大量化合物模拟或者阻断17β-雌二醇的活性。具有与17β-雌二醇大致相同生物作用的化合物,最有效的内源性雌激素,被称作“雌激素受体激动剂”。那些当与17β雌二醇组合给予时阻断其作用的化合物被称作“雌激素受体拮抗剂”。事实上,存在雌激素受体激动剂与雌激素受体拮抗剂活性之间的统一体并且在某些组织中确实有某些化合物作为雌激素受体激动剂起作用而在其它组织中作为雌激素受体拮抗剂起作用。这些具有混合活性的化合物被称作选择性雌激素受体调节剂(SERMS)并且在治疗上是有用的药物(例如EVISTA)[McDonnell,Journal of the Society for GynecologicInvestigation 7:S10-S15(2000),Goldstein等,Human ReproductionUpdate 6:212-224(2000)]。相同化合物可具有细胞-特异性作用的准确的原因未被推测,但受体构象和/或共调节蛋白的环境的差异已被提示。
曾经一段时期已知当结合配体时,雌激素受体采取不同的构象。然而,仅在最近才揭示这些变化的连续性和微细区别。通过与各种配体共结晶已解决ERα和ERβ的三维结构并且清晰显示当立体阻碍受体-共调节蛋白相互作用所需要的蛋白序列时,在雌激素受体拮抗剂存在下双螺旋12的改变[Pike等,Embo 18:4608-4618(1999),Shiau等,Cell 95:927-937(1998)]。另外,噬菌体展示技术已用于在不同配体存在下鉴定与雌激素受体相互作用的肽[Paige等,Proceedings of the National Academy of Sciences of the United States ofAmerica 96:3999-4004(1999)]。例如,肽被鉴定以区分结合于全长雌激素受体激动剂17β-雌二醇和二乙基己烯雌酚的ERα。不同的肽显示结合于ERα和ERβ的氯芪酚之间的区别。这些数据指明每一配体潜在地以独一无二的和意想不到的可能具有独特生物活性的构象装配受体。
如以上所述,雌激素影响全部生物过程。另外,描述性别差异时(例如发病率、攻击应答等),解释包括男性和女性之间的雌激素水平上的差异是可能的。
本发明描述
本发明提供具有下面结构的式I的雌激素化合物或者其药学上可接受的盐,
其中
R1为氢、羟基、卤素、1-6个碳原子的烷基、1-6个碳原子的三氟烷基、3-8个碳原子的环烷基、1-6个碳原子的烷氧基、1-6个碳原子的三氟烷氧基、1-6个碳原子的硫烷基、1-6个碳原子的磺烷基、1-6个碳原子的磺酰烷基、6-10个碳原子的芳基、具有1-4个选自O、N或者S的杂原子的5或者6-元杂环、-NO2、-NR5R6、-N(R5)COR6、-CN、-CHFCN、-CF2CN、2-7个碳原子的链炔基或者2-7个碳原子的链烯基,其中烷基或者链烯基部分由羟基、-CN、卤素、1-6个碳原子的三氟烷基、1-6个碳原子的三氟烷氧基、-COR5、-CO2R5、-NO2、CONR5R6、NR5R6或者N(R5)COR6任选取代;
R2和R2a每个独立为氢、羟基、卤素、1-6个碳原子的烷基、1-4个碳原子的烷氧基、2-7个碳原子的链烯基、或者2-7个碳原子的链炔基、1-6个碳原子的三氟烷基、或者1-6个碳原子的三氟烷氧基,其中烷基或者链烯基部分由羟基、-CN、卤素、1-6个碳原子的三氟烷基、1-6个碳原子的三氟烷氧基、-COR5、-CO2R5、-NO2、CONR5R6、NR5R6或者N(R5)COR6任选取代;
R3、R3a和R4每个独立为氢、1-6个碳原子的烷基、2-7个碳原子的链烯基、2-7个碳原子的链炔基、卤素、1-4个碳原子的烷氧基、1-6个碳原子的三氟烷基或者1-6个碳原子的三氟烷氧基,其中烷基或者链烯基部分由羟基、-CN、卤素、1-6个碳原子的三氟烷基、1-6个碳原子的三氟烷氧基、-COR5、-CO2R5、-NO2、CONR5R6、NR5R6或者N(R5)COR6任选取代;
R5、R6每个独立为氢、1-6个碳原子的烷基、6-10个碳原子的芳基;
X为O、S或者NR7;
R7为氢、1-6个碳原子的烷基、6-10个碳原子的芳基、-COR5、-CO2R5或者-SO2R5。
当本发明化合物含碱性部分时,自有机和无机酸可形成药学上可接受的盐,例如,所述酸为:乙酸、丙酸、乳酸、枸橼酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、萘甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、甲磺酸、萘磺酸、苯磺酸、甲苯磺酸、樟脑磺酸,和类似的已知可接受的酸。当本发明的化合物含酸性部分时,自有机和无机碱也可形成盐,例如碱金属盐(例如钠、锂或钾)、碱土金属盐、铵盐、在每一烷基含1-6个碳原子的烷基铵盐和在每一烷基含1-6个碳原子的二烷基铵盐,和在每一烷基含1-6个碳原子的三烷基铵盐。
术语烷基、链烯基和链炔基包括分支和直链两者的部分。实例包括甲基、乙基、丙基、丁基、异丙基、仲丁基、叔丁基、乙烯基、烯丙基、乙炔基、1-甲基乙烯基等。当烷基或者链烯基部分被取代时,它们通常可为单-、二-、三-或者全-取代。卤素取代基的实例包括1-溴代乙烯基、1-氟代乙烯基、1,2-二氟乙烯基、2,2-二氟乙烯基、1,2,2-三氟乙烯基、1,2-二溴乙烷、1,2-二氟乙烷、1-氟-2-溴乙烷、CF2CF3、CF2CF2CF3等。术语卤素包括溴、氯、氟和碘。术语芳基意指苯基、1-萘基或者2-萘基。优选的5-6元杂环包括呋喃、噻吩、吡咯、异吡咯、吡唑、咪唑、三唑、二硫杂环戊二烯、氧硫杂环戊二烯、异噁唑、噁唑、噻唑、异噻唑、噁二唑、呋咱、噁三唑、二噁唑、噁噻唑、四唑、吡喃、吡啶、哒嗪、嘧啶、吡嗪、三嗪、噁嗪、噁噻嗪或者噁二嗪。更优选杂环为呋喃、噻吩或者噻唑。
在本发明的化合物当中,优选式I的化合物或者其药学上可接受的盐具有以下结构:
其中
R1为2-7个碳原子的链烯基,其中链烯基部分由羟基、-CN、卤素、1-6个碳原子的三氟烷基、1-6个碳原子的三氟烷氧基、-COR5、-CO2R5、-NO2、CONR5R6、NR5R6或者N(R5)COR6任选取代;
R2和R2a每个独立为氢、羟基、卤素、1-6个碳原子的烷基、1-4个碳原子的烷氧基、2-7个碳原子的链烯基、2-7个碳原子的链炔基、1-6个碳原子的三氟烷基、或者1-6个碳原子的三氟烷氧基,其中烷基、链烯基或者链炔基部分由羟基、-CN、卤素、1-6个碳原子的三氟烷基、1-6个碳原子的三氟烷氧基、-COR5、-CO2R5、-NO2、CONR5R6、NR5R6或者N(R5)COR6任选取代;
R3和R3a每个独立为氢、1-6个碳原子的烷基、2-7个碳原子的链烯基、2-7个碳原子的链炔基、卤素、1-4个碳原子的烷氧基、1-6个碳原子的三氟烷基、或者1-6个碳原子的三氟烷氧基,其中烷基、链烯基或者链炔基部分由羟基、-CN、卤素、1-6个碳原子的三氟烷基、1-6个碳原子的三氟烷氧基、-COR5、-CO2R5、-NO2、CONR5R6、NR5R6或者N(R5)COR6任选取代;
R5、R6每个独立为氢、1-6个碳原子的烷基、6-10个碳原子的芳基;
X为O、S或者NR7;
R7为氢、1-6个碳原子的烷基、6-10个碳原子的芳基、-COR5、-CO2R5或者-SO2R5。
更优选X为O,且仍然更优选X为O,而R1为2-3个碳原子的链烯基,它由羟基、-CN、卤素、1-6个碳原子的三氟烷基、1-6个碳原子的三氟烷氧基、-COR5、-CO2R5、-NO2、CONR5R6、NR5R6或者N(R5)COR6任选取代。
如在本发明中使用时,就提供本发明覆盖的化合物或者物质而论,术语“提供”意指直接给予这样的化合物或者物质,或者给予在体内形成有效量的化合物或者物质的前药、衍生物或者类似物。
如在本发明中使用时,术语“ERβ选择性配体”意指在测量对ERα和ERβ结合亲合力的标准药理学实验方法中配体对ERβ的结合亲合力(如通过IC50测量的,其中17β-雌二醇的IC50在ERα与ERβ之间相差不大于3倍)比其对ERα的结合亲和力至少大约10倍。优选ERβ选择性配体对ERβ具有结合亲和力,它比其对ERα的结合亲和力至少大约20倍。更优选ERβ选择性配体对ERβ具有结合亲和力,它比其对ERα的结合亲和力至少大约50倍。另外优选的是ERβ选择性配体为非-亲子宫和非-激乳腺的。
如在本发明中使用时,术语“非-亲子宫的”意指在标准药理学实验方法中产生的湿子宫重量增加小于在相同方法中对最大有效剂量的17β-雌二醇或17α-乙炔基-17β-雌二醇所观察到的子宫重量增加的50%。优选增加湿子宫重量小于对雌二醇所观察到的湿子宫重量增加的25%,并且更优选湿子宫重量增加小于对雌二醇所观察到的湿子宫重量增加的10%。最优选与避免亲子宫活性的对照组(例如媒介组)相比较非-亲子宫的ERβ选择性配体将不显著(p>0.05)增加湿子宫重量。
如在本发明中使用时,术语“非-激乳腺的”意指在标准药理学实验方法中产生的酪蛋白激酶II mRNA增加小于相同方法中对最大有效剂量下17β-雌二醇或者17α-乙炔基-17β-雌二醇所观察到的酪蛋白激酶II mRNA增加的50%。优选酪蛋白激酶II mRNA增加小于对雌二醇所观察到的25%,并且更优选酪蛋白激酶II mRNA增加小于对雌二醇所观察到的10%。最优选与避免激乳腺活性的对照组(例如媒介组)相比较激乳腺的ERβ选择性配体将不显著(p>0.05)增加酪蛋白激酶II mRNA。
本发明也提供ERβ选择性配体在治疗或者抑制关节炎、炎性肠疾病和子宫内膜异位中的用途。更具体地说,ERβ选择性配体用于治疗或者抑制类风湿性关节炎、骨关节炎或者椎关节病,和克郎氏病、溃疡性结肠炎、不确定的结肠炎、感染性结肠炎或者溃疡性直肠炎。本发明另外提供ERβ选择性配体在治疗或者抑制关节肿胀或者糜烂,或者在治疗或者抑制继发于关节镜或者外科手术方法的关节损伤中的用途。优选ERβ选择性配体为非-亲子宫和非-激乳腺的。
在制备本发明的化合物中使用的试剂可以为市场上可以得到的或者可通过在文献中描述的标准方法制备。
在另一方面,本发明涉及制备本发明化合物的方法,方法包括下面当中的一个:
(a)使下式化合物
其中R1、R2、R2a和X如上定义,与下式化合物反应
其中R3和R3a如上定义,并且Y为卤素、-OH或者1-6个碳原子的烷氧基;
或者
(b)使如上定义的式II化合物转变为其药学上可接受的盐;
或者
(c)拆分式II化合物的异构体混合物以分离式II化合物或者其药学上可接受的盐的对映体。
例如按照下面的合成流程(I-VIII),可以制备本发明的化合物。
流程I
在流程I中,在三乙胺存在下,用市场上可以得到的苯甲酰氯2处理市场上可以得到的二甲氧基苯胺1,产生酰胺3。在亚硫酰氯存在下回流,自市场上可以得到的苯甲酸4也可以制备所需要的苯甲酰氯2。在高温(200℃)下,用吡啶盐酸盐处理,酰胺3转变为酚基苯并噁唑5。
流程II
在流程II中,用在乙酸中的Br2/NaOAc溴化市场上可以得到的硝基-酚6,产生溴代苯酚7。用在EtOAc中的Ra-Ni催化氢化7,得到苯胺8。在吡啶存在下8与苯甲酰氯9(市场上可以得到的,或者自相应的苯甲酸和亚硫酰氯制备)偶合,产生酰胺-酯10。在高温(150℃)下,于酸性条件下(对-甲苯磺酸),实现10至苯并噁唑11的转化。用在二氯甲烷中的三溴化硼使11脱甲基,得到酚基苯并噁唑12。
流程III
在流程III中,在高温(150℃)下,用在对-二甲苯中的苯甲酸13和硼酸处理,使苯胺8转变为苯并噁唑14。用在二氯甲烷中的三溴化硼使14脱甲基,得到酚基苯并噁唑15。
流程IV
在流程IV中,用乙酸中的硝酸使16硝化,产生17,后者在Ra-Ni存在下用氢还原,得到苯胺18。以在流程II中描述的类似的方法,免除在高温(200℃)下用吡啶盐酸盐实现脱甲基步骤,把苯胺18转变为苯并噁唑19。
流程V
在流程V中,用在N,N-二甲基甲酰胺中的叔丁基二甲基甲硅烷基氯化物/咪唑/4-二甲基氨基吡啶把苯并噁唑20的羟基保护为甲硅烷基醚21(R3=Me3C(CH3)2Si),或者用在二氯甲烷中的乙酸酐/4-二甲基氨基吡啶保护为酯21(R3=CH3CO)。在20℃-150℃的温度范围内,伴随用于硼酸偶合反应的碱(即Na2CO3)存在下,在对-二甲苯、甲苯、四氢呋喃、二甲氧基甲烷或者1,2-二甲氧基乙烷中,在钯催化剂[即二氯双(三-邻-甲苯基膦)钯(II)或者四重(三苯基膦)钯(0)]存在下,苯并噁唑20和21与各种试剂(即三丁基(乙烯基)锡、三丁基(烯丙基)锡、三丁基(2-呋喃基)锡、硼酸或者氯化锌)偶合,产生苯并噁唑22和23。
用氢氟酸(48wt.%在水中)或者四丁基氟化铵使22(R3=Me3C(CH3)2Si)的甲硅烷基醚脱保护,产生苯并噁唑24。用在二噁烷中的碳酸钾使22(R3=CH3CO)皂化,产生苯并噁唑24。在高温(200℃)下,用二氯甲烷或者吡啶盐酸盐中的三溴化硼将苯并噁唑23(R=CH3)脱甲基,得到苯并噁唑24。
流程VI
在流程VI中,在低温(-78℃)下,用正丁基锂处理苯并噁唑24,随后加入亲电试剂(即CNCO2Et,Ph(CH3)NCHO,Etl等),产生化合物25。用三溴化硼(R=CH3)或者四丁基氟化铵(R=Me3C(CH3)2Si)将25脱保护,得到苯并噁唑26[R=CHO,CO2Et,CH2CH3,C(CH3)2OH]。
在高温(200℃)下,用吡啶盐酸盐处理叔醇25(R=C(CH3)OH),产生1-甲基-乙烯基苯并噁唑27。用H2/Pd-C还原27,得到异丙基类似物28。
流程VII
在流程VII中,用在甲醇中的硼氢化钠还原苯并噁唑29,产生醇30。用三溴化硼在CH2Cl2中处理30一小时,得到苯并噁唑31,延长(18小时)处理得到溴化物32。在N,N-二甲基甲酰胺中的氰化钾和18-冠-6醚处理下,把溴化物32转变成乙腈33。
流程VIII
在流程VIII中,首先用在DMF中的氰化铜(I)处理溴代苯并噁唑35(R=CH3),产生相应的芳基-腈,后者用三溴化硼处理,得到苯并噁唑36。自第二种合成途径也可制备苯并噁唑36,其中在钯催化剂[即四重(三苯基膦)钯(0)]存在下,用氰化锌处理苯并噁唑35,得到相应的芳基-腈,后者用三溴化硼脱甲基,产生苯并噁唑36。用溴化铜(I)和在DMF中的新鲜制备的甲醇钠处理苯并噁唑35(R=H),产生甲氧基-苯并噁唑37。用乙腈中的N-溴代琥珀酰亚胺将37溴代,得到单溴代苯并噁唑38(主要产物)和二溴代苯并噁唑39(小量产物)。
标准药理实验方法易于测定所给出的受试化合物的活性分布。以下简短概述几种有代表性的实验方法并且可以包括本发明代表性化合物的数据。所有试验,除放射配体结合试验以外,可用于检测化合物的雌激素受体激动剂或者拮抗剂活性。通常,通过比较化合物对参比物雌激素(例如17β-雌二醇、17α-乙炔基,17β-雌二醇、雌酮、二乙基己烯雌酚等)的活性可测量雌激素受体激动剂活性。通常,通过用参比物雌激素共处理受试化合物并比较单独用参比物雌激素得到的结果,可测量雌激素受体拮抗剂活性。在美国专利4418068和5998402中也提供SERMs的标准药理实验方法,其通过引用结合到本文中。
对ERα和Erβ结合亲合力的评价
在常规放射配体结合试验中,评价本发明的代表性实施例与17β-雌二醇竞争ERα和ERβ两种受体的能力。这个实验方法为技术人员测定对ERα或者ERβ受体的相对结合亲合力提供方法学。下面简短描述所采用的方法。
结合选择性特征的受体提取物的制备。采用作为模板的全长cDNA和含当保持用于表达的合适的读框时亚克隆的合适的限制位点的引物,通过PCR得到配体结合区,在此便利定义为DNA结合区的全序列的下游。这些模板含人ERα的氨基酸M250-V595[Green等,Nature 320:134-9(1986)]和人ERβ的M214-Q530[Ogawa等,Biochemical&Biophysical Research Communications 243:122-6(1998)]。把人ERβ克隆到带有C-末端Flag标记物的Ncol-BamH1片段的pET15b(Novagen,Madison WI)中。除加入N-末端His标记物以外,按照人ERβ克隆人ERα。通过两条谱带的完整序列,检定采用的所有构造的序列。
BL21(DE3)细胞被用于表达人蛋白质。一般10mL过夜培养基被用于接种1L含100μg/mL阿莫西林的LB媒介物的培养基。在37℃下孵育过夜后,把IPTG加入到最终浓度为1mM并在25℃下孵育2小时。经离心(1500xg)收获细胞,冲洗沉淀并重悬浮在100mL的50mM Tris-Cl(pH7.4)、150mM NaCl中。在12000psi下,通过弗氏压碎器两次,裂解细胞。通过在4℃下,于12000xg下离心30分钟澄清溶胞产物并在-70℃下储备。
用于特异性[3H]-雌二醇结合的提取物的评价。用1mM EDTA补充的Dulbecco氏磷酸盐缓冲盐水(Gibco,1x最终浓度)作为试验缓冲液。为使用于试验中的受体的量最佳化,把[3H]-17β-雌二醇(NewEngland Nuclear,最终浓度=2nM)±0.6μM二乙基己烯雌酚和100μL大肠杆菌溶胞产物的各种稀释液加至高亲和掩蔽微滴板(EG&GWallac)上的每孔中。最终试验体积为120μL且DMSO的浓度≤1%。室温下孵育5-18小时后,吸出未结合的材料且用约300μL试验缓冲液把板冲洗3次。冲洗后,将135μL液体闪烁混合剂(Optiphase Supermix,EG&G Wallac)加至每孔中,把板密封并且搅拌至少5分钟以使闪烁物与残余冲洗缓冲液混合。通过液体闪烁计数(EG&G Wallac Microbeta Plus)评价结合的放射活性。
测定提供最大特异性结合的每一受体制备液的稀释液后,采用受体制备液的各种稀释液,通过估计未标记17β-雌二醇的IC50进一步使试验最佳化。对未标记的17β-雌二醇的IC50,选择每一受体制备液的最终工作稀释液为2-4nM。
配体结合竞争试验方法。最初将受试化合物溶于DMSO中并且DMSO在结合试验中的最终浓度≤1%。每一受试化合物的8个稀释液被用作[3H]-17β-雌二醇的未标记的竞争剂。通常,一系列化合物稀释液应在人ERα和ERβ上同时试验。结果作为测量的DPM对受试化合物的的浓度做图。对剂量-应答曲线拟合,把转化的、称重的数据的四参数对数模型拟合并且IC50定义为化合物减少最大[3H]-雌二醇结合达50%的浓度。
本发明的代表性实施例对ERα和ERβ(通过IC50测量)的结合亲合力显示在表(1)中。
在以上描述的标准药理学实验方法中得到的结果证实本发明的化合物结合雌激素受体的两种亚型。对ER βIC50s一般比较低,指明这些化合物优选为ERβ选择性配体,但也被认为对ER α有活性。基于,至少部份基于它们的受体亲合力选择性概况,本发明的化合物会呈现一定范围内的活性。因为本发明的化合物结合ER-β比结合ER-α具有更高的亲合力,它们用于治疗或者抑制可通过ER-β调节的疾病。另外,因为每一受体配体复合物是独一无二的,并且因此它与各种共调节蛋白的相互作用是独一无二的,依细胞内容物而定本发明的化合物应呈现不同的和不可预见的活性。例如,在某些细胞类型中,化合物作为雌激素受体激动剂起作用,而在其它的组织中作为雌激素受体拮抗剂起作用是可能的。具有这样活性的化合物有时被称为SERMs(选择性雌激素受体调节剂)。然而,不像许多雌激素那样,许多SERMs不引起子宫湿重增加。这些化合物在子宫是抗雌激素的且可在子宫组织中完全拮抗雌激素受体激动剂的营养作用。然而,这些化合物在骨、心血管和中枢神经系统中作为雌激素受体激动剂起作用。由于这些化合物的这个组织选择性性质,它们在治疗或者抑制其引起或者与雌激素缺乏(在某些组织例如骨或者心血管中)或者雌激素过量(在子宫或者乳腺中)有关的哺乳动物疾病症状或者综合征上是有用的。另外,本发明的化合物也具有对一种受体类型作为雌激素受体激动剂起作用而对另一种受体类型作为雌激素受体拮抗剂起作用的潜在性。例如,已证实化合物通过ERβ可拮抗17β-雌二醇的作用而呈现具有ERα的雌激素受体激动剂活性[Sun等,Endocrinology 140:800-804(1999)]。这样的ERSAA(雌激素受体选择性激动剂拮抗剂)活性在这一系列化合物中提供药理学上独特的雌激素活性。
金属硫蛋白II mRNA的调节
按照Harris[Endocrinology 142:645-652(2001)]描述,通过ERβ但非ERα起作用的雌激素可向上调节在Saos-2细胞中的金属硫蛋白II mRNA水平。自这一试验方法得到的结果可与自下面描述的试验方法(ERE报道基因试验方法)得到的结果相结合,以产生本发明化合物的选择性分布(也参见WO 00/37681)。本发明代表性化合物的数据显示在表(2)中。
在MCF-7乳腺癌细胞中采用ERE-报道基因试验方法评价受试化合物
在DMSO中制备受试化合物的储备液(通常0.1M),然后用DMSO稀释至10-100倍以制备1或者10mM的工作溶液。在4℃(0.1M)或者-20℃(<0.1M)下储备DMSO储备液。每周用生长培养基[含10%(v/v)热灭活胎牛血清、1%(v/v)青霉素-链霉素和2mM glutaMax-1的D-MEM/F-12培养基]将MCF-7细胞传代两次。在37℃下,在5%CO2/95%湿润的空气孵育箱中,于通气烧瓶中维持细胞。处理前一天,在25000细胞/孔下,用生长培养基将细胞铺展在96孔板上并在37℃下孵育过夜。
在37℃下,于实验培养基[含10%(v/v)热灭活活性炭剥离的胎牛血清、1%(v/v)青霉素-链霉素、2mM glutaMax-1和1mM丙酮酸钠的无酚红的D-MEM/F-12培养基]中,用50μl/孔的腺病毒5-ERE-tk-荧光素酶的1∶10稀释液把细胞转染2小时。然后,用150μl的实验培养基把孔洗涤一次。最后,在37℃下,以8孔/复制用150μl/孔的媒介物(≤0.1%v/v DMSO)或者化合物处理所述细胞24小时,后者稀释≥1000倍成为实验培养基。
单独试验(雌激素受体激动剂模型)或者与0.1nM 17β-雌二醇(EC80;雌激素受体拮抗剂模型)组合,在单次剂量1μM下初步筛选受试化合物。每个96孔板也包含媒介物对照组(0.1%v/v DMSO)和雌激素受体激动剂对照组(0.1或者1nM 17β-雌二醇)。在活性化合物以log自10-14增至10-5M,在雌激素受体激动剂和/或雌激素受体拮抗剂模型上进行剂量-应答实验。自这些剂量-应答曲线,分别生成EC50和IC50值。在每一治疗组中最后一孔含作为雌激素受体拮抗剂对照组的5μl的3×10-5M ICI-182780(10-6M最后浓度)。
处理后,用25μl/孔的1X细胞培养基溶胞试剂(PromegaCorporation)将所述细胞于摇床上溶胞15分钟。把细胞溶胞产物(20μl)转移至96孔发光计板,采用100μl/孔的萤光素酶底物(PromegaCorporation),在MicroLumat LB 96P发光计(EG&G Berthold)中测量萤光素酶活性。注射底物前,对每孔进行1秒背景测量。注射底物后,1秒延迟后测量萤光素酶活性10秒。自发光计把数据传递至Macintosh个人微机并采用JMP软件(SAS研究所)分析;程序自每孔萤光素酶测量值减去背景读数然后测定每处理组的平均值和标准差。
通过对数换算萤光素酶数据,并且Huber M-估算法被用于使外围转换的观察重量下降。JMP软件用于分析单向ANOVA(Dunnett’s试验)的转化的和称重的数据。在雌激素受体激动剂模型中,化合物处理组与媒介物对照组结果相比较,或者在雌激素受体拮抗剂模型中与阳性雌激素受体激动剂对照组结果(0.1nM 17β-雌二醇)相比较。对最初的单次剂量实验,如果化合物处理结果显著区别于合适的对照组(p<0.05),那么结果以相对于17β-雌二醇对照组的百分率报道[即((化合物-媒介物对照组)/(17β-雌二醇对照组-媒介物对照组))×100]。JMP软件也用于自非线性剂量-应答曲线测定EC50和/或IC50值。
亲子宫活性的评价
按下面的标准药理学实验方法,可测量受试化合物的亲子宫活性。
方法1:自Taconic得到性未成熟(18天龄)Sprague-Dawley大鼠并提供未加以禁止的酪蛋白基质饮食(Purina Mills 5K96C)和水。在第19、20和21天,用17α-乙炔基-17β-雌二醇(0.06μg/大鼠/天)、受试化合物或者媒介物(50%DMSO/50%Dulbecco’s PBS)皮下给予大鼠。为评价雌激素受体拮抗剂活性,化合物与17α-乙炔基-17β-雌二醇(0.06μg/大鼠/天)一同给药。每组6只大鼠并且最后一次注射后约24小时通过CO2窒息和气胸使它们安乐死。摘除子宫并去除有关脂肪且排出任何内流体后称重。组织样品也可被速冻用于分析基因表达(例如补体因子3mRNA)。自本发明代表性化合物得到的结果显示在表(3)中。
表3:所选择的化合物在大鼠亲子宫试验方法中的评价
化合物 | 平均子宫重量(mg)±SEM |
媒介物 | 21.4±1.59 |
17α-乙炔基,17β-雌二醇(0.06μ | 85.5±3.1 |
g/大鼠) | |
实施例12(2mg/大鼠)+17α-乙炔基,17β-雌二醇(0.06μg/大鼠) | 60.2±4.0 |
实施例41(2mg/大鼠) | 30.3±1.5 |
实施例41(2mg/大鼠)+17α-乙炔基,17β-雌二醇(0.06μg/大鼠) | 76.6±3.0 |
实施例24(2mg/大鼠) | 14.18±1.1 |
实施例24(2mg/大鼠)+17α-乙炔基,17β-雌二醇(0.06μg/大鼠) | 80.7±5.3 |
媒介物 | 30.5±3.2 |
17α-乙炔基,17β-雌二醇(0.06μg/大鼠) | 104.7±5.4 |
实施例20(2mg/大鼠) | 39.2±0.7 |
实施例20(2mg/大鼠)+17α-乙炔基,17β-雌二醇(0.06μg/大鼠) | 95.9±5.5 |
实施例21(2mg/大鼠) | 38.8±1.7 |
实施例21(2mg/大鼠)+17α-乙炔基,17β-雌二醇(0.06μg/大鼠) | 93.9±5.9 |
方法2:自Taconic得到性未成熟(18天龄)129SvE小鼠并提供未加以禁止的酪蛋白基质饮食(Purina Mills 5K96C)和水。在第22、23、24和25天,用化合物或者媒介物(玉米油)皮下给予小鼠。每组6只小鼠并且最后一次注射后约6小时通过CO2窒息和气胸使它们安乐死。摘除子宫并去除有关脂肪且排出任何内流体后称重。自本发明代表性化合物得到以下结果(表(4))。
表4:所选择的化合物在小鼠亲子宫试验方法中的评价
化合物 | 平均子宫重量±SEM |
媒介物 | 10.2±2.1 |
17β-雌二醇(50mg/kg) | 41.7±3.6 |
实施例21(20mg/kg) | 12.1±1.7 |
媒介物 | 11.7±0.5 |
17β-雌二醇(50mg/kg) | 41.9±2.9 |
实施例24(50mg/kg) | 10.7±0.9 |
媒介物 | 9.6±0.4 |
17β-雌二醇(50mg/kg) | 40.0±2.0 |
实施例24(50mg/kg) | 10.3±0.7 |
媒介物 | 9.4±0.4 |
17β-雌二醇(50mg/kg) | 35.6±4.4 |
实施例25(50mg/kg) | 9.7±1.0 |
媒介物 | 13.7±2.0 |
17β-雌二醇(50mg/kg) | 40.5±5.84 |
实施例12(50mg/kg) | 13.7±0.82 |
实施例20(50mg/kg) | 13.1±0.86 |
媒介物 | 9.6±0.36 |
17β-雌二醇(50mg/kg) | 40.0±2.0 |
实施例34(50mg/kg) | 10.3±0.69 |
媒介物 | 9.8±1.2 |
17β-雌二醇(50mg/kg) | 42.9±4.8 |
实施例26(50mg/kg) | 9.0±0.3 |
实施例42(50mg/kg) | 9.5±0.6 |
实施例64(50mg/kg) | 9.8±0.7 |
骨质疏松和类脂调节(心脏保护)的评价
术后1天自Taconic Farms得到切除卵巢或者假手术的雌性Sprague-Dawley大鼠(重量范围240-275g)。在一个室中按12/12(白天/昼夜)时间表将它们按3或者4只大鼠/笼饲养并且任意提供食物(Purina 5K96C大鼠食物(chow))和水。到达后1天对所有研究组开始治疗并且大鼠每周给药7天,连续6周。一组不接受任何治疗的年龄相当的假手术大鼠用作每项研究的完整的雌激素饱满对照组。
在50%DMSO(JT Baker,Phillipsburg,NJ)/1x Dulbecco’s磷酸盐水(GibcoBRL,Grand Island,NY)的媒介物中,在定义的以致于治疗体积为0.1mL/100g体重的浓度下,制备所有的受试化合物。把17β-雌二醇溶于玉米油(20μg/mL)中并皮下传递,0.1mL/大鼠。按照组平均体重测量值,所有剂量在三周间隔内调整,并且皮下给药。
开始治疗5周后和研究终止1周前,评价每只大鼠的骨质密度(BMD)。在采用XCT-960M(pQCT,Stratec Medizintechnik,Pforzheim,Germany)麻醉的大鼠上评价近端胫骨的总的和小梁的密度。如下进行测量:扫描前15分钟,腹膜内注射45mg/kg氯胺酮、8.5mg/kg赛拉嗪、和1.5mg/kg乙酰丙嗪麻醉每只大鼠。
把右后爪通过25mm直径的聚碳酸酯管并粘贴于丙烯酸框,使踝关节在90°角和膝关节在180°角。聚碳酸酯管被附着于活动的平台以保持它垂直于pQCT的孔径。调整平台以致于股骨的远端和胫骨的近端处于扫描区。运行二维搜索图象10mm长和0.2mm的线性分辨率。在监测器上展示搜索图象后,胫骨的近端被固定。自这一点3.4mm远开始pQCT扫描。pQCT扫描为1mm厚,具有0.140mm的轴(三维像素)径,并由145个贯穿切片的投射物组成。
在pQCT扫描完成后,在监测器上展示图象。包括胫骨但不包括腓骨的研究区域被概述。采用迭代算法,数学上去除软组织。以mg/cm3报道剩余的骨密度(总密度)。以同心螺旋数学上揭去骨外部55%。以mg/cm3报道其余的骨密度(小梁密度)。
BMD评价1周后,通过CO2窒息和气胸使大鼠安乐死并采集血液用于胆固醇测定。摘除子宫并去除有关脂肪和排出任何内流体后称重。采用Cholesterol/HP试剂盒,用Boehringer-Mannheim Hitachi 911临床分析仪测定总胆固醇。采用Dunnet’s试验的单向方差分析,比较统计学意义。
用本发明的代表性化合物得到下面的结果(表(5))。
表5:给予选择的本发明化合物后切除卵巢的大鼠体内骨矿物质密度的评价
化合物 | 总骨矿物质密度(平均值mg/cm<sup>3</sup>±SEM) | 小梁骨矿物质密度(平均值mg/cm<sup>3</sup>±SEM) |
媒介物 | 543.49±14.24 | 353.96±13.46 |
17β-雌二醇(2μg/大鼠) | 639.49±14.47 | 453.28±24.93 |
实施例24(10mg/kg) | 517.56±9.67 | 321.16±9.04 |
实施例21(10mg/kg) | 501.40±11.97 | 312.34±19.73 |
实施例20(10mg/kg) | 525.51±7.93 | 287.56±17.56 |
实施例21(10mg/kg)+17β-雌二醇(2μg/大鼠) | 682.41±24.01 | 491.43±36.43 |
假手术(非操作) | 685.28±15.68 | 510.96±16.99 |
抗氧化活性的评价
自屠宰场得到猪主动脉,冲洗,迁移到冷却的PBS中,并收获主动脉内皮细胞。为收获细胞,打结主动脉的肋间血管且把主动脉的一端夹紧。将新鲜、灭菌过滤的0.2%胶原酶(Sigma Type I)放入血管中,然后夹紧血管的另一端以形成密闭的系统。把主动脉于37℃下孵育15-20分钟,之后收集胶原酶溶液并于2000xg下离心5分钟。将每份沉淀悬浮于7mL由用活性炭剥离的FBS(5%)、NuSerum(5%)、L-谷氨酰胺(4mM)、青霉素-链霉素(1000U/ml,100μg/ml)和庆大霉素(75μg/ml)补充的无酚红DMEM/Ham’s F12培养基组成的内皮细胞培养基中,在100mm培养皿上接种并在5%CO2中于37℃孵育。20分钟后,用PBS冲洗细胞并加入新鲜的培养基,24小时再次重复这一操作。约1周后,使细胞汇合。内皮细胞一周定期喂饲两次,当汇合时,胰蛋白酶消化并以1∶7的比率接种。在待评价化合物(5μM)存在下,将细胞介导的12.5μg/mL LDL氧化于37℃下进行4小时。按照通过分析游离醛的TBARS(硫代巴比妥酸活性物质)方法[Yagi,Biochemical Medicine 15:212-6(1976)]测量,其结果表达成氧化过程的百分比抑制率。
黄体酮受体mRNA调节标准药理学实验方法
这个实验方法可用于评价本发明的化合物的雌激素或者抗雌激素活性[Shughrue等,Endocrinology 138:5476-5484(1997)]。本发明代表性化合物的数据显示在表(6)中。
表6.本发明代表性化合物对调节大鼠脑的视前区中黄体酮mRNA的作用
化合物(10mg/kg) | 黄体酮受体mRNA(任意单位;平均值±stdev) |
媒介物 | 22.0±10.1 |
实施例21 | 110.5±19.3 |
实施例20 | 238.6±36.3 |
实施例12 | 256.2±42.3 |
媒介物 | 189.2±27.2 |
实施例34 | 511.5±23.7 |
实施例25 | 447.0±60.7 |
实施例26 | 467.8±66.7 |
实施例64 | 431.3±65.6 |
大鼠热潮红实验方法
以标准药理实验方法可评价受试化合物对热潮红的作用,这个方法测量受试化合物减弱尾巴皮肤温度增加的能力,该温度当采用纳洛酮使吗啡成瘾的大鼠毒品急剧戒断时发生[Merchenthaler等,Maturitas 30:307-16(1998)]。通过受试化合物与参照雌激素一同给药,它也用于检测雌激素受体拮抗剂活性。自本发明的代表性化合物得到下面的数据(表(7))。
表7;所选择的本发明化合物在大鼠热潮红模型中的作用
化合物 | 注射纳洛酮15分钟温度变化(平均值±SEM) |
媒介物 | 4.63±0.79 |
17α-乙炔基,17β-雌二醇(0.3mg/kg) | 2.12±1.14 |
实施例20(15mg/kg) | 5.28±0.71 |
实施例41(15mg/kg) | 5.25±0.72 |
在离体大鼠主动脉环上血管舒缩功能的评价
Sprague-Dawley大鼠(240-260克)分成4组:
1.正常未切除卵巢组(完整)
2.切除卵巢(ovex)媒介物治疗组
3.切除卵巢17β-雌二醇治疗组(1mg/kg/天)
4.用受试化合物治疗切除卵巢动物(各种剂量)
治疗前约3周把动物切除卵巢。每只动物通过胃管接受悬浮在含1%吐温-80的蒸馏后的去离子水中的17β-雌二醇硫酸酯(1mg/kg/天)或者受试化合物。媒介物治疗的动物接受与在药物治疗组中使用的媒介物体积相当的媒介物。
通过吸入CO2使动物安乐死并放血。迅速除去胸主动脉并放入含有下面组合的37℃的生理溶液中,包括(mM):通入最终pH7.4的CO2-O2(95%/5%)的NaCl(54.7)、KCl(5.0)、NaHCO3(25.0)、MgCl2 2H2O(2.5)、D-葡萄糖(11.8)和CaCl2(0.2)。自外表面除去血管外膜并把血管切成2-3mm宽的环。将环悬浮于一端连接于浴的底部且另一端连接于力量传感器的10mL组织浴中。使1克静止的张力放置于环上。把环平衡1小时,获得并分析信号。
平衡后,把环暴露于增加浓度的苯基厄福伦(10-8-10-4M)中并且记录张力。然后用新鲜的缓冲液冲洗浴3次。洗脱后,将200mM L-NAME加入到组织浴中并平衡30分钟。然后重复苯基厄福伦浓度应答曲线。
心脏保护活性的评价
自Taconic Farms得到载脂蛋白E-缺乏的C57/B1J(apo E KO)小鼠。严格按照IACUC指南下进行所有动物方法。切除卵巢的雌性apoE KO小鼠,4-7周龄,被饲养在鞋-盒笼子中并允许随意进食和饮水。动物根据重量随机分组(每组n=12-15只小鼠)。使用Precise-dosingProtocol将饮食中的受试化合物或者雌激素(在1mg/kg/天下的17β-雌二醇硫酸酯)给予动物,其中每周测量所消耗的饮食的量,基于动物重量相应调整剂量。所采用的饮食为Western-style餐(57U5),它由Purina制备并包含0.50%胆固醇、20%猪油和25IU/KG维生素E。采用12周一个疗程的这一方案给予/喂饲动物。对照组动物喂饲Western-style餐但不接受化合物。研究期间结束时,使动物安乐死并得到血浆样品。首先用盐水,然后用中性缓冲的10%福尔马林溶液就地灌注心脏。
为测定血脂和脂蛋白,采用酶促方法,分别用市场上可以得到的来自Boehringer Mannheim和Wako Biochemicals的试剂盒测定总胆固醇和甘油三酯,并采用Boehringer Mannheim Hitachii 911分析仪分析。采用FPLC体积分级分离,进行血浆脂蛋白的分离和定量。简言之,过滤50-100mL血清并把它注射到串连的Superose 12和Superose 6柱中,在恒定流速下,用1mM EDTA钠和0.15M NaCl洗脱。采用Waters MillenniumTM软件,对表示VLDL、LDL和HDL的每条曲线的面积积分,通过每对应的色谱峰的相对百分比面积,经总胆固醇值放大使每一脂蛋白馏分定量。
对主动脉粥样硬化的定量,小心分离主动脉且在操作前于福尔马林固定剂中放置48-72小时。采用Oil Red O染色剂,鉴定动脉粥样硬化的损伤。把血管短暂去染色,然后采用配备与作为图像捕集软件的IMAQ Configuration Utility(National Instrument)相谐的Sony3CCD视频摄象系统的Nikon SMU800显微镜成像。采用常规阈值用途软件包(Coleman Technologies),沿着主动脉弓定量损伤en面。采用程序的阈值功能,在血管上,具体地说,在含主动脉弓的区域,从头臂干的近边至左锁骨下动脉的远边,进行自动化损伤评估。按照严格地在定义的内腔区域内包含的损伤百分率表达主动脉粥样硬化数据。
认知增强的评价
在每连续5天中,把摘除卵巢的大鼠(n=50)置于8-臂的径臂迷宫中驯化10分钟。驯化和试验前使动物禁水。100μL等分试样的水放于每臂末端用作补充。通过使动物进入一个饵诱的臂,完成在径臂迷宫中的获胜-转换任务得。饮水后,动物退出臂并重新进入中心室,在那里它可以进入先前访问的臂或者进入新的臂。当动物选择进入新的臂时,记录正确的应答。每只动物每天给出5次试验,连续3天。最后一次习得试验后,将动物安排下面4组中的一组:
1.阴性对照组:注射10%DMSO/芝麻油媒介物,一天一次,连续6天(1mL/kg,SC)
2.阳性对照组:用17β-雌二醇苯甲酸酯注射2天并且第2次注射后试验4天(每只大鼠注射10μg/0.1mL下的17β-雌二醇苯甲酸酯)
3.雌二醇:17β-雌二醇应每天注射,连续6天(20μg/kg,SC)
4.受试化合物:每天注射,连续6天(剂量变化)。
所有注射应在习得实验的最后一天开始。组1、3和4的最后一次注射应在工作记忆试验前2小时发生。
工作记忆试验为延迟的与样品非-匹配的任务(DNMS),采用15、30或者60秒的延迟。这个任务为习得实验的变体,其中大鼠被放置于中心室并且使之进入前面的一个臂。一旦大鼠半途旅行经过第一个臂,第二个臂就会开启,并且大鼠再次需要选择这个臂。当它半途旅行经过第二个臂时,两扇门关闭并且延迟开始。一旦延迟终止,最初的两扇门和第三个新门同时开启。当动物半途旅行经过第三个,新的臂时,记录正确的应答。当动物半途旅行经过第一个或者第二个臂时,记录不正确的应答。在每三次延迟间隔中的一个,每只动物应接受5次试验,每只动物总共15次试验。
对胸膜炎作用的评价
按照Cuzzocrea的方法[Endocrinology 141:1455-63(2000)],可评价减少实验性诱导大鼠胸膜炎的症状的能力。
对谷氨酸诱导细胞毒性(神经保护)的保护作用的评价
采用谷氨酸攻击,在体外标准药理试验方法中可评价本发明的化合物的神经保护活性[Zaulyanov等,Cellular&MolecularNeurobiology 19:705-18(1999);Prokai等,Journal of MedicinalChemistry 44:110-4(2001)]。
在乳房终蕾试验方法中的评价
雌激素需要全导管伸长和乳房导管分支,及在黄体酮影响下接着小叶-蜂窝状终蕾的发展。在这个试验方法中,按照以下标准药理试验方法,评价所选择的本发明化合物的促乳激素活性。28天年龄Sprague-Dawley大鼠(Taconic Farms)被卵巢切除并且休息9天。在12-小时光/暗周期中饲养动物,喂饲基于酪蛋白的Purina实验室啮齿类动物食物5K96(Purina,Richmond,IN)并允许自由饮水。然后皮下给予大鼠媒介物(50%DMSO(JT Baker,Phillipsburg,NJ)/50%1xDulbecco氏磷酸缓冲盐水(GibcoBRL)、17β-雌二醇(0.1mg/kg)或者受试化合物(20mg/kg)6天。最后3天,也皮下给予大鼠黄体酮(30mg/kg)。第7天,使大鼠安乐死并切除乳房脂垫。分析这一脂肪垫用于酪蛋白激酶II mRNA作为终蕾增殖的标记物。通过真-时间RT-PCR分析酪蛋白激酶II mRNA。简言之,按照制造商的说明书,Trizol(GibcoBRL)后分离RNA。采用无DNA-试剂盒(Ambion),用DNAse I处理样品,并且采用Taqman Gold方法(PE AppliedBiosystems),通过真-时间RT-PCR测量酪蛋白激酶II mRNA水平。
采用酪蛋白激酶II mRNA特异性引物对(5’引物,CACACGGATGGCGCATACT,3’引物,CTCGGGATGCACCATGAAG)和定做的探针(TAMRA-CGGCACTGGTTTCCCTCACATGCT-FAM),以三份分析总共50ng的RNA。采用由PE Applied Biosystems供应的引物和探针,酪蛋白激酶II mRNA水平被归一化为包含在每一样品反应中的18s核糖体RNA中。对本发明的代表性化合物得到下面的结果(表(8))。
用HLA大鼠标准药理实验方法评价炎性肠道疾病
以模拟人炎性肠道疾病的HLA大鼠标准药理实验方法评价本发明的代表性化合物。下面简短描述所采用的方法和得到的结果。自Taconic得到雄性HLA-B27大鼠并不限制进食(PMI Lab餐5001)和水。每天观察粪质量并按照以下标准分级:腹泻=3;软粪=2;正常粪=1。研究结束时,收集血清并在-70℃下贮存。制备结肠切片以用于组织分析并对另外的部分分析髓过氧化物酶活性。
在研究A中,用下面列出的方案之一皮下给予大鼠(22-26周龄),每天一次,连续7天。每组5只大鼠,并且安乐死之前两小时给予最后剂量。
·媒介物(50%DMSO/50%Dulbecco氏PBS)
·实施例24(50mg/kg)
得自研究A的结果显示在表(9)中。给予媒介物的大鼠整个研究过程中继续具有腹泻。用实施例24治疗的大鼠粪质量得到改善。
在研究B中,如下口服给予大鼠(8-10周龄),连续26天。
·媒介物(2%吐温-80/0.5%甲基纤维素)
·实施例25(第1-14天10mg/kg;然后在第15天增至20mg/kg)
·实施例34(10mg/kg)
得到下面的结果(表(10))并在用本发明的代表性化合物治疗的所有大鼠中显示改善的粪便特性。
表10:用媒介物或者本发明的代表性化合物口服治疗的HLA大鼠的粪特性的评价。所报道的值为组平均分数。
在研究C中,每天用下面列出的制剂之一口服给予大鼠(8-10周龄),每天一次,连续46天。每组4只大鼠,并且安乐死之前两小时给予最后剂量。
·媒介物(2%吐温-80/0.5%甲基纤维素)
·实施例21(第1-18天10mg/kg;然后在第19天增至20mg/kg)
·实施例24(第1-24天10mg/kg;然后在第25天增至20mg/kg)
获得以下结果(表(11))并显示给予ERβ选择性化合物所有的动物改善的粪特性。
表11:用媒介物或者本发明的代表性化合物口服治疗的HLA大鼠的粪分数。所报道的值为组平均分数。
组织分析:把结肠组织浸泡在10%中性缓冲的福尔马林中。每片结肠分割为4个样品用于评价。在Tissue Tek真空浸润加工器中将福尔马林固定的组织加工(Miles公司;West Haven,Connecticut)以用于石蜡埋植。将样品切成5μm,然后用苏木精和伊红(H&E)染色用于采用在Boughton-Smith后改进的计分法的双盲组织评价。完成评分后,样品为非盲的,并且数据作表且通过带有多平均比较的ANOVA线性模型分析。结肠组织的切片被用于评价几种疾病适应症和所给出的相关分数。如在表(12)(两种皮下给药研究的组合,包括研究A)中显示的,在减少组织损伤的几种测量中实施例24是有效的。
也组织上检测得自研究B的肠组织(参见上面)。如下显示(表(13)),两个化合物显著减少总疾病分数。
也组织上检测得自研究C的肠组织(参见上面)。如下显示(表(14)),实施例24显著减少总疾病分数。尽管统计学上不显著,实施例21在所有疾病参数上的分数低于媒介物治疗的大鼠的相应的分数。
两种模型关节炎的评价
佐剂诱发关节炎的Lewis大鼠试验。按照标准便利操作方法,饲养60只雌性,12周龄,Lewis大鼠。它们任意接受标准方案的食物和水。通过标明项目组和动物编号的笼卡区别每只动物。通过不易涂抹的墨水记号笔在尾巴上标记每只动物编号。研究前至少10-21天,使它们麻醉并且通过标准无菌手术技术切除卵巢。
弗氏完全佐剂(Sigma Immuno Chemicals,St.Louis,MO)被用于诱发关节炎,每mL含热杀和干燥的1mg结核分支杆菌、0.85mL矿物油和0.15mL单油酸甘露糖醇酯(批号084H8800)。
下面是两种实验方法的实例。抑制实验方法:30只大鼠于尾根部皮内注射0.1mL的弗氏完全佐剂。把动物随机分为4组,每组6只大鼠。每天,各组接受媒介物(50%DMSO(JT Baker,Phillipsburg,NJ)/1x Dulbecco’s磷酸盐缓冲盐水(GibcoBRL,Grand Island,NY)或者受试化合物(皮下给予)。所有大鼠第1天开始治疗。本发明代表性化合物的数据显示在表(15)中。
治疗实验方法:30只大鼠于尾根部皮内注射0.1mL的弗氏完全佐剂。把动物随机分为4组,每组包括6只大鼠。每天,各组接受媒介物(50%DMSO(JT Baker,Phillipsburg,NJ)/1x Dulbecco’s磷酸缓冲盐水(GibcoBRL,Grand Island,NY)或者受试化合物(皮下给予)。所有大鼠在佐剂注射后第8天开始治疗。本发明代表性化合物的数据显示在表(16)、(17)和(18)中。
采用Abacus Concepts Super ANOVA(Abacus Concepts公司,Berkeley,CA)进行统计学分析。研究的所有参数经历组间Duncan’s新的多元回归试验的方差分析。数据被表达为平均值±标准差(SD),如果p<0.05,认为差异显著。
按照下面的疾病指数:后足爪红斑、后足爪肿胀、关节触痛和运动及体姿,每天监测关节炎严重性的程度。将0-3的整数分数用于定量红斑(0=正常足爪,1=稍微红斑,2=中度红斑,3=严重红斑)和肿胀(0=正常足爪,1=稍微肿胀,2=中度肿胀,3=严重肿胀的后足爪)的水平。每天最大分数为12。
在研究结束时,用CO2使大鼠安乐死,尸体剖检时摘除下肢并在10%缓冲的福尔马林中固定,并且跗关节脱钙并包埋在石蜡中。用苏木精和伊红或者番红O-坚牢绿染色液将组织切片染色。
将玻片编码以致于检验者对治疗组并不了解。在滑膜增殖、炎性细胞浸润和血管翳形成的基础上评价得自跗关节的滑膜组织[Poole和Coombs,International Archives of Allergy&Applied Immunology 54:97-113(1977)],阐述如下。
类目 | 等级 |
1.滑膜衬细胞 | |
a.无变化 | 0 |
b.细胞增大,稍微增厚 | 1 |
c.细胞增大,数目增加,中度增厚。无绒毛存在 | 2 |
d.细胞增大,增厚,绒毛存在 | 3 |
2.纤维组织形成 | |
a.无变化 | 0 |
b.纤维组织形成存在于衬细胞下 | 1 |
c.小区域的疏松结缔组织由纤维组织替代 | 2 |
d.疏松结缔组织由纤维组织替代 | 3 |
3.炎性细胞 | |
a.偶尔可以观察到,散落在贯穿所选择的区域 | 0 |
b.细胞以小数目存在或者存在于衬细胞层中或者恰好处于衬细胞层下和/或在血管周围。 | 1 |
c.小量粘着采集的细胞可以存在 | 2 |
d.大量的细胞存在于囊中并且存在于衬细胞层中或者恰好处于衬细胞层下。 | 3 |
4.血管翳 | |
a.不可检测 | 0 |
b.可检测 | 1 |
另外,采用下面显示的Mankin氏组织学分级系统[Mankin等,Journal of Bone&Joint Surgery-American Volume 53:523-37(1971)]评价关节软骨和骨。
类目 | 等级 |
1.结构 | |
a.正常 | 0 |
b.表面不规则 | 1 |
c.血管翳和表面不规则 | 2 |
d.裂开到过渡带 | 3 |
e.裂开到边缘带 | 4 |
f.裂开到钙化带 | 5 |
g.完全结构破坏 | 6 |
2.细胞 | |
a.正常 | 0 |
b.弥散性细胞过多 | 1 |
c.细胞集落 | 2 |
d.细胞过多 | 3 |
3.番红-O染色法 | |
a.正常 | 0 |
b.稍微减少 | 1 |
c.中度减少 | 2 |
d.严重减少 | 3 |
e.未见到染色 | 4 |
4.潮标完整性 | |
a.接触 | 0 |
b.经血管穿透 | 1 |
对HLA-B27大鼠关节炎模型的评价。在模拟人关节炎的HLA-B27大鼠标准药理实验方法中评价本发明的代表性化合物。下面简短描述所采用的方法和得到的结果。雄性HLA-B27大鼠得自Taconic并提供未加以禁止食物(PMI实验室饮食5001)和水。如以上对佐剂诱导的关节炎的Lewis大鼠模型描述,评价关节分数和组织学。
研究1:每天用下面列出的制剂之一口服给予大鼠(8-10周龄)一次,连续46天。每组4只大鼠,并且安乐死之前两小时给予最后剂量。
·媒介物(2%吐温-80/0.5%甲基纤维素)
·实施例21(第1-18天10mg/kg;然后在第19天增至20mg/kg)
·实施例24(第1-24天10mg/kg;然后在第25天增至20mg/kg)
对本发明的代表性化合物得到下面的结果(表(19)和(20))。
研究2:给大鼠(8-10周龄)口服下面列出的制剂之一,连续26天。每组4只大鼠,并且安乐死之前两小时给予最后剂量。
·媒介物(2%吐温-80/0.5%甲基纤维素)
·实施例25(第1-14天10mg/kg;然后在第15天增至20mg/kg)
·实施例34(10mg/kg)
对本发明的代表性化合物得到下面的结果(表(21))。
致癌体内模型的评价
以文献中易于得到的标准药理学实验方法,所述方法包括下面的两个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。
乳腺癌。自Charles River Laboratories(Wilmington,MA)得到切除卵巢的无胸腺nu/nu(裸)小鼠。肿瘤细胞注射前一天,用含0.36-1.7mg17β-雌二醇(60或者90天释放,Innovative Research of America,Sarasota,FL)的时辰释放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天评价肿瘤体积。
结肠癌。以Smirnoff[Oncology Research 11:255-64(1999)]的实验方法可评价治疗或者抑制结肠癌的能力。
以两种体内实验方法评价神经保护作用
蒙古沙土鼠的瞬时总体缺血。采用下面的实验方法,可测量受试化合物预防或者治疗应答于氧剥夺/再灌注的脑损伤作用。
雌性蒙古沙土鼠(60-80g;Charles River Laboratories,Kingston,NY)在Wyeth-Ayerst动物护理中心(AAALAC认证)饲养,伴随12小时光照,12小时黑暗光周期并且自由进食自来水和低雌激素酪蛋白食物(Purina;Richmond,IN)。顺应后(3-5天),用异氟烷(2-3%与O2的混合物)麻醉沙土鼠,摘除卵巢(第0天)。第二天(第1天)早晨开始,每天用媒介物(10%ETOH/玉米油)、17β-雌二醇(1mg/kg,sc)或者实验化合物皮下治疗沙土鼠。第6天,用异氟烷麻醉沙土鼠(n=4-5/组),通过中线颈切口使常见颈动脉主动脉肉眼可视并用非-创伤显微动脉瘤夹钳同时闭合两条主动脉5分钟。闭合后,移去夹钳以使脑再灌注并且用创伤夹钳封闭颈切口。沙土鼠局部缺血手术之前,所有动物禁食过夜,这个步骤便利于始终如一的局部缺血损伤。第12天,沙土鼠暴露于致死剂量的CO2中,并在干冰上冷冻脑且在-80℃下贮存。用于这些研究的动物方法被综述并且得到Radnor/Collegeville AnimalCare和Wyeth-Ayerst Research的Use Committee(RACUC/CACUC)批准。
通过neurogranin mRNA的就地杂交分析,评价神经元保护的程度。简言之,在凝胶包衣的载玻片上收集20μm冠状恒冷箱切片,干燥并在-80℃下贮存。加工时,把干燥的载玻片箱温热至室温,将载玻片后固定在4%低聚甲醛中,用乙酸酐处理,然后用氯仿和乙醇脱脂和脱水。之后用200μl(6×106DPM/载玻片)在50%甲酰胺杂交混合液中的用于Neurogranin(35S-UTP标记的NG-241,基质99-340)的反义或者意义(对照组)核糖探针把所加工的切片-计数载玻片杂交,并且在55℃下于湿润的载玻片室中孵育过夜而不必盖玻片。第二天上午,收集支架上的载玻片,把它们浸泡在2x SSC(0.3M NaCl,0.03M枸橼酸钠,pH 7.0)/10mM DTT中,用RNase A(20μg/ml)处理并在67℃下于0.1x SSC中冲洗(2×30min)以除去非特异性标记物。脱水后,将载玻片暴露于BioMax(BMR-1,Kodak)X-射线胶片中过夜。
neurogranin杂交信号水平被用于定量评价损伤后在CA1区神经元缺失的程度并评价17β-雌二醇和实验化合物的效力。选择neurogranin mRNA用于这些研究,因为它在包括CA1的海马神经元中高度表达,但是在存在于这个脑区的神经胶质和其它细胞类型中缺乏。因此,存在的neurogranin mRNA的量的测量值表示存活的神经元。neurogranin杂交信号的相对光密度测量值得自带有基于图象分析系统(C-Imaging公司,Pittsburgh,PA)的计算机的胶片放射自显影图。使得自每只动物的6个切片(相隔40μm)的结果平均化并做统计学评估。各种数值作为平均值±SEM被报道。单向方差分析被用于检验neurogranin mRNA的水平差异并且在结果部分中的非-差异的所有陈述暗示p>0.05。
自本发明的代表性化合物得到下面的结果(表(22))。
小鼠中脑主动脉闭合
按照由Dubal[参见Dubal等,Proceedings of the National Academyof Sciences of the United States of America 98:1952-1957(2001),Dubal等,Journal of Neuroscience 19:6385-6393(1999)]描述的实验方法,可评价神经保护作用。
排卵抑制标准药理实验方法
本实验方法用于测定受试化合物是否能够抑制或者改变排卵的时间。它也可用于测定排卵的卵母细胞数目[Lundeen等,J SteroidBiochem Mol Biol 78:137-143(2001)]。自本发明的代表性化合物得到下面的数据(表(23))。
子宫内膜异位标准药理实验方法的评价
自出版的方法[Bruner-Tran等,Journal of Clinical Investigation 99:2851-2857(1997)]对这个方法稍加改进。简言之,体外用10nM的17β-雌二醇处理正常人子宫内膜组织(周期天数~12)过夜,然后植入切除卵巢的无胸腺裸小鼠。为这些研究的目的,如在本文中描述的,小鼠不接受雌激素/安慰剂植入剂。使损伤建立至少10天,然后开始每天口服给药并持续至少15天。值得一提的是所有小鼠在给药开始时具有肉眼可见的损伤。在尸体剖检下,测定带有损伤的小鼠的数目以及每只小鼠的损伤。
在10mg/kg剂量下,以这个方法将实施例24的化合物评价三次。在每个实验方法中,在尸体剖检下,给予实施例24化合物的小鼠比那些给予媒介物的小鼠具有更少的损伤。例如,在研究1中,媒介物组中的4只小鼠中每一只具有至少1处损伤并且在这一组中总共有10处损伤。相反,实施例24治疗的6只小鼠中仅有2只具有任何损伤并且每只动物仅发现1处损伤。因此,由于所有的小鼠在治疗开始时具有损伤,实施例24的化合物在6只小鼠中有4只引起损伤。
基于在标准药理试验方法中得到的结果,本发明的化合物为雌激素受体调节剂用于治疗或者抑制至少部分由雌激素缺乏或者过量介导的,或者可通过采用雌激素药物治疗或者抑制的症状、紊乱或者疾病状态。本发明的化合物特别用于治疗其中所产生的内源性雌激素水平被大大减少的绝经前后(peri-menopausal)、绝经或经绝后的患者。经绝一般定义为最后的天然月经期且特征为卵巢功能的停止,导致在血流中循环的雌激素显著减少。当在此所使用时,经绝也包括可以是由手术的、化学的、或者导致过早减少或者卵巢功能停止的疾病症状引起的雌激素产生减少的情况。
本发明的化合物也用于抑制或者治疗雌激素缺乏的其它结果,包括:热潮红、阴道或阴门萎缩、萎缩性阴道炎、阴道干燥、瘙痒、交媾困难、排尿困难、尿繁、尿失禁、尿道感染。其它的生殖道用途包括治疗或者抑制功能性子宫出血。所述化合物也用于治疗或者抑制子宫内膜异位症。
本发明的化合物在脑中也是有活性的并且因此用于抑制或者治疗阿尔滋海默氏病、认知衰退、减少的性欲、老年性痴呆、神经退化性疾病、抑郁症、焦虑症、失眠症、精神分裂症和不育症。本发明的化合物也用于治疗或者抑制良性或者恶性异常组织生长,包括肾小球硬化症、前列腺肥大、子宫平滑肌瘤、乳腺癌、硬皮病、纤维瘤病、子宫内膜癌、多囊卵巢综合征、子宫内膜息肉、良性乳房疾病、子宫内膜异位、卵巢癌、黑素瘤、前列腺癌、结肠癌、CNS癌症,例如神经胶质瘤或者星母细胞瘤(astioblastomia)。
本发明的化合物具有心血管保护作用且为抗氧化剂,并用于降低胆固醇、甘油三酯、Lp(a)和LDL水平;抑制或者治疗高胆固醇血症、高脂血症、心血管疾病、动脉粥样硬化、外周血管疾病、再狭窄和血管痉挛,并且抑制由于导致免疫介导的血管损伤的细胞过程引起的血管壁损伤。本发明的化合物也用于治疗与炎症或者自动免疫疾病有关的疾病,包括炎性肠疾病(克郎氏病、溃疡性结肠炎、不确定的结肠炎)、关节炎(类风湿性关节炎、椎关节病、骨关节炎)、胸膜炎、局部缺血/再灌注损伤(例如中风、移植性排斥、心肌缺血等)、哮喘、巨细胞性动脉炎、前列腺炎、葡萄膜炎、牛皮癣、多发硬化症、系统性红斑狼疮和脓毒症。
本发明的化合物也用于治疗或者抑制眼疾病,包括白内障、葡萄膜炎和黄斑变性并用于治疗皮肤疾病例如衰老、脱发和痤疮。
本发明的化合物也用于治疗或者抑制代谢疾病例如II型糖尿病、脂质代谢、食欲(例如神经性厌食症和贪食症)。
本发明的化合物也用于治疗或者抑制出血性疾病例如遗传出血性毛细管扩张、功能性子宫出血和格斗出血性休克。
本发明的化合物用于其中闭经是有利的疾病状态,例如白血病、子宫内膜切除、慢性肾病或肝病或者血凝固疾病或紊乱。
本发明的化合物可用作避孕药物,特别是当与孕激素联合使用时。
当给药用于治疗或者抑制具体的疾病状态或者紊乱时,应理解有效剂量可依使用的具体化合物、给药模式、所治疗的疾病和疾病的严重性以及与所治疗的个体相关的多种身体因素而定。可在约0.1mg/天-1000mg/天的口服剂量下有效给予本发明的化合物。优选以单剂量或以两次或更多次分开的计量给予约10mg/天-600mg/天,更优选给予约50mg/天-600mg/天。预期设想的每天剂量随着给药途径而变化。
这样的剂量可以任何用于使在此的活性化合物向着接受者的血流的方式给药,包括口服、借助植入、非肠道(包括静脉内、腹膜内、关节内和皮下注射)、直肠、鼻内、局部、眼(借助眼滴剂)、阴道和经皮。
含有本发明的活性化合物的口服制剂可包含任何常规使用的口服形式,包括片剂、胶囊、颊下含片制剂、锭剂、糖锭剂和口服液体、悬浮液或溶液剂。胶囊可含有活性化合物与惰性填充剂和/或稀释剂的混合物,例如药学上可接受的淀粉(例如玉米、马铃薯或木薯淀粉)、蔗糖、人工甜味剂、粉末纤维素、例如结晶和微晶纤维素、矫味剂、明胶、树胶等。通过常规压制、湿法制粒或干法制粒方法并使用药学上可接受的稀释剂、粘合剂、润滑剂、崩解剂、表面修饰剂(包括表面活性剂)、悬浮剂或者稳定剂,包括(但不限于)硬脂酸镁、硬脂酸、滑石粉、十二烷基硫酸钠、微晶纤维素、羧甲基纤维素钙、聚乙烯吡咯烷酮、明胶、藻酸、阿拉伯胶、黄原胶、枸橼酸钠、复合硅酸盐、碳酸钙、甘氨酸、糊精、蔗糖、山梨醇、磷酸二钙、硫酸钙、乳糖、高岭土、甘露醇、氯化钠、滑石粉、干燥淀粉和粉末化蔗糖可制备有用的片剂。优选的表面修饰剂包括非离子和阴离子表面修饰剂。表面修饰剂的代表性实例包括(但不限于)羟聚体188、苯扎氯铵、硬脂酸钙、十六醇十八醇混合物、聚西托醇乳化蜡、山梨糖醇酯、胶体二氧化硅、磷酸盐、十二烷基硫酸钠、硅酸铝镁和三乙醇胺。在此的口服制剂可使用标准延迟或定时释放制剂,以改变活性化合物的吸收。口服制剂也可包括给予在水或果汁中的活性组分,如果需要,包含合适的稳定剂或者乳化剂。
在某些情况中,将所述化合物以气溶胶的形式直接给予气道是合乎需要的。
本发明的化合物也可以非肠道或腹膜内给药。也可以在水中与适宜的表面活性剂如羟基丙基纤维素混合制备作为游离碱或药理学上可接受的盐的这些活性化合物的溶液剂或悬浮剂。也可以用甘油、液体聚乙二醇和它们在油中的混合物制备分散剂。在常规的贮存和使用条件下,这些制剂含有防腐剂以抑制微生物的生长。
适合于注射使用的药用形式包括灭菌水溶液剂或分散剂和用于临时制备灭菌可注射水溶液剂或分散剂的灭菌粉末。在所有情况中,所述制剂必须是灭菌的和必须是流体以达到易于注射的程度。在制备和贮存的条件下它必须是稳定的并且必须在抗微生物例如细菌和真菌的污染作用下保存。载体可以为溶剂或分散介质,包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、它们合适的混合物和植物油。
为了本公开的目的,经皮给药被理解为包括所有的穿过身体表面和身体通道的内衬包括上皮和粘膜组织的给药。使用本化合物或其药学上可接受的盐,以洗剂、霜剂、泡沫剂、贴剂、悬浮剂、溶液剂和栓剂(直肠和阴道),可实施这样的给药。
通过使用含有所述活性化合物和对所述活性化合物惰性的载体的经皮贴剂可实现经皮给药,该载体对皮肤无毒,并使得药物经皮肤传递全身吸收进入血流。所述载体可采取任何数目的形式,例如霜剂和软膏剂、糊剂、凝胶剂和封闭装置(occlusive devices)。霜剂和软膏剂可为水包油或油包水型的粘稠液体或半固体乳剂。由分散于含有活性组分的石油或亲水石油中的可吸收粉末组成的糊剂也可以是合适的。多种封闭装置可用于把活性组分释放进入血流,例如包含贮库的半透膜,后者含有含或不含载体的活性成分,或者含有活性成分的基质。在文献中已知其它的封闭装置。
从传统材料,包括可可脂,伴随加入或不加入蜡以改变栓剂的熔点,和甘油,可制备栓剂。也可使用水溶性栓剂基质,例如不同分子量的聚乙二醇。
以下描述本发明代表性实施例的制备。
实施例1
2-(5-羟基-1,3-苯并噁唑-2-基)苯-1,4-二醇
步骤a)N-(2,5-二甲氧基苯基)-2,5-二甲氧基苯甲酰胺。
将2,5-二甲氧基苯甲酸(5.0g,27.5mmol)和亚硫酰氯(15mL)的混合物回流1小时。真空除去挥发物。把残余物溶于THF(20mL)中并加入到2,5-二甲氧基苯胺(4.6g,30.2mmol)、三乙胺(5mL,35.9mmol)和THF(40mL)的冷的(0℃)溶液中。将混合物搅拌30分钟,倾入到水中,用HCl(2N)酸化并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(己烷/EtOAc 2/1)纯化,得到白色固体(8.1g,93%收率,m.p.121-123℃);MS m/e 318(M+H)+。
对C17H19NO5分析:
理论值:C,64.34;H,6.03;N,4.41
实测值:C,64.29;H,5.95;N,4.44
步骤b)2-(5-羟基-1,3-苯并噁唑-2-基)苯-1,4-二醇。
在200℃下,将N-(2,5-二甲氧基苯基)-2,5-二甲氧基苯甲酰胺(1.0g,3.1mmol)和吡啶盐酸盐(2.0g,17.3mmol)的混合物搅拌1小时。把混合物冷却至室温并加入HCl(10mL,2N)。然后用EtOAc提取混合物并经MgSO4干燥有机提取液。蒸发并经快速层析法(己烷/EtOAc 2/1)纯化,得到白色固体(0.8g,76%收率,m.p.309-311℃);MS m/e 242(M-H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,63.98;H,3.71;N,5.62
实施例2
3-(5-羟基-1,3-苯并噁唑-2-基)苯-1,2-二醇
以与在实施例1中描述的基本相同的方法,从2,5-二甲氧基苯胺和2,3-二甲氧基苯甲酸制备标题化合物。得到为褐色固体的产物,m.p.239-241℃;MS m/e 244(M+H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,63.86;H,3.90;N,5.74
实施例3
2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例1中描述的基本相同的方法,从2,5-二甲氧基苯胺和3-氟-4-甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.262-268℃;MS m/e 244(M-H)+。
对C13H8FNO3分析:
理论值:C,63.68;H,3.29;N,5.71
实测值:C,64.01;H,3.25;N,5.63
实施例4
2-(3-氯-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例1中描述的基本相同的方法,从2,5-二甲氧基苯胺和3-氯-4-甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.254-256℃;MS m/e 260(M-H)+。
对C13H8ClNO3分析:
理论值:C,59.67;H,3.08;N,5.35
实测值:C,59.59;H,3.02;N,5.25
实施例5
2-(2-氯-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例1中描述的基本相同的方法,从2,5-二甲氧基苯胺和2-氯-4-甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.253-255℃;MS m/e 262(M+H)+。
对C13H8ClNO3分析:
理论值:C,59.67;H,3.08;N,5.35
实测值:C,59.79;H,2.87;N,5.36
实施例6
2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-6-醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和3-氟-4-甲氧基苯甲酸制备标题化合并得到为白色固体的产物,m.p.269-271℃;MS m/e 244(M-H)+。
对C17H17NO3分析:
理论值:C,63.68;H,3.29;N,5.71
实测值:C,63.53;H,3.71;N,5.38
实施例7
2-(3-叔丁基-4-羟基苯基)-1,3-苯并噁唑-6-醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和3-叔丁基-4-甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.220-222℃;MS m/e 284(M+H)+。
对C17H17NO3分析:
理论值:C,72.07;H,6.05;N,4.94
实测值:C,72.03;H,6.43;N,4.72
实施例8
2-(6-羟基-1,3-苯并噁唑-2-基)苯-1,4-二醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和2,5-二甲氧基苯甲酸制备标题化合物并得到为褐色固体的产物,m.p.278-280℃;MS m/e 244(M+H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,64.09;H,3.14;N,5.65
实施例9
3-(6-羟基-1,3-苯并噁唑-2-基)苯-1,2-二醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和2,3-二甲氧基苯甲酸制备标题化合物并得到为褐色固体的产物,m.p.256-258℃;MS m/e 244(M+H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,63.91;H,3.98;N,5.72
实施例10
4-(6-羟基-1,3-苯并噁唑-2-基)苯-1,2-二醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和3,4-二甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.282-284℃;MS m/e 242(M-H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,63.57;H,3.68;N,5.63
实施例11
2-(3-氯-4-羟基苯基)-1,3-苯并噁唑-6-醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和3-氯-4-甲氧基苯甲酸制备标题化合物并得到为灰白色固体的产物,m.p.254-256℃;MS m/e 262(M+H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,63.57;H,3.68;N,5.63
实施例12
2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例1中描述的基本相同的方法,从2,5-二甲氧基苯胺和4-甲氧基苯甲酰氯制备标题化合物并得到为浅黄色固体的产物,m.p.264-267℃;MS m/e 228(M+H)+。
对C13H9NO3分析:
理论值:C,68.72;H,3.99;N,6.16
实测值:C,67.87;H,4.05;N,6.23
实施例13
4-(5-羟基-1,3-苯并噁唑-2-基)苯-1,3-二醇
以与在实施例1中描述的基本相同的方法,从2,5-二甲氧基苯胺和2,4-二甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.大于300℃;MS m/e 242(M-H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,63.92;H,3.74;N,5.56
实施例14
2-(4-羟基苯基)-1,3-苯并噁唑-6-醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和4-甲氧基苯甲酰氯制备标题化合物并得到为白色固体的产物,m.p.大于300℃;MS m/e 226(M-H)+。
对C13H9NO3分析:
理论值:C,68.72;H,3.99;N,6.16
实测值:C,68.09;H,4.01;N,6.05
实施例15
4-(6-羟基-1,3-苯并噁唑-2-基)苯-1,3-二醇
以与在实施例1中描述的基本相同的方法,从2,4-二甲氧基苯胺和2,4-二甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.293-296℃;MS m/e 242(M-H)+。
对C13H9NO4分析:
理论值:C,64.20;H,3.73;N,5.76
实测值:C,64.43;H,3.77;N,5.74
实施例16
6-氯-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)N-(4-氯-2,5-二甲氧基苯基)-3-氟-4-甲氧基苯甲酰胺。
以与在实施例1步骤a中描述的基本相同的方法,从4-氯-2,5-二甲氧基苯胺和3-氟-4-甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.197-199℃;MS m/e 340(M+H)+。
对C16H15ClFNO4分析:
理论值:C,56.56;H,4.45;N,4.12
实测值:C,56.33;H,4.35;N,4.05
步骤b)N-(4-氯-2,5-二羟基苯基)-3-氟-4-羟基苯甲酰胺。
将三氟化硼二甲硫复合物(70mL)加入到N-(4-氯-2,5-二甲氧基苯基)-3-氟-4-甲氧基苯甲酰胺(1.75g,5.15mmol)和CH2Cl2(35mL)的混合物中。搅拌20小时后,在氮气流下,在防护罩中蒸发溶剂和过量的试剂。用冰和HCl(1N)的混合物吸收残余物并用EtOAc提取。用HCl(1N)洗涤有机层,经MgSO4干燥。蒸发并经快速层析法(CH2Cl2/己烷/EtOAc 5/3/2,和AcOH 10mL每1升的洗脱溶剂)纯化,得到白色固体(1.4g,91%收率,m.p.254-256℃);MS m/e 296(M-H)+。
对C13H9ClFNO4分析:
理论值:C,52.46;H,3.05;N,4.71
实测值:C,51.98;H,2.98;N,4.56
步骤c)6-氯-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例1步骤b中描述的基本相同的方法,从N-(4-氯-2,5-二羟基苯基)-3-氟-4-羟基苯甲酰胺和吡啶盐酸盐制备标题化合物并得到为白色固体的产物,m.p.258-260℃;MS m/e 278(M-H)+。
对C13H17ClFNO3分析:
理论值:C,55.83;H,2.52;N,5.01
实测值:C,55.35;H,2.59;N,4.91
实施例17
6-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例16中描述的基本相同的方法,从4-溴-2,5-二甲氧基苯胺和3-氟-4-甲氧基苯甲酸制备标题化合物并得到为白色固体的产物,m.p.224-226℃;MS m/e 322(M-H)+。
对C13H17BrFNO3分析:
理论值:C,48.18;H,2.18;N,4.32
实测值:C,48.69;H,2.36;N,4.59
实施例18
6-氯-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例16中描述的基本相同的方法,从4-氯-2,5-二甲氧基苯胺和4-甲氧基苯甲酰氯制备标题化合物并得到为灰白色固体的产物,m.p.260-262℃;MS m/e 260(M-H)+。
对C13H8ClNO3分析:
理论值:C,59.67;H,3.08;N,5.35
实测值:C,59.09;H,3.06;N,5.11
实施例19
5-氯-2-(4-羟基苯基)-1,3-苯并噁唑-6-醇
以与在实施例16中描述的基本相同的方法,从5-氯-2,4-二甲氧基苯胺和4-甲氧基苯甲酰氯制备标题化合物并得到为灰白色固体的产物,m.p.254-256℃;MS m/e 262(M+H)+。
对C13H8ClNO3分析:
理论值:C,59.67;H,3.08;N,5.35
实测值:C,59.40;H,2.97;N,5.22
实施例20
7-溴-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)2-溴-4-甲氧基-6-硝基苯酚。
将在乙酸(20mL)中的溴(16.0g,100mmol)加入到4-甲氧基-2-硝基苯酚(16.9g,100mmol)、乙酸钠(16.4g,200mmol)和乙酸(100mL)的混合物中。把混合物在室温下搅拌30分钟,然后在70℃下搅拌2小时,倾入到含有浓硫酸(10mL)的水(1.51)中。过滤沉淀的固体并结晶(从氯仿/己烷中),得到棕色固体,m.p.116-118℃;MS m/e 246(M-H)+。
对C7H6BrNO4分析:
理论值:C,33.90;H,2.44;N,5.65
实测值:C,34.64;H,2.16;N,5.43
步骤b)2-氨基-6-溴-4-甲氧基苯酚。
将阮内镍(2.5g)加入到2-溴-4-甲氧基-6-硝基苯酚(8.8g,35.5mmol)的EtOAc(100mL)溶液中。在帕尔装置中,于25磅/平方英寸的氢气压下,把混合物振摇2.5小时。通过硅藻土过滤反应混合物并真空浓缩,得到灰色固体(7.4g,96%收率,95-97℃);MS m/e 218(M+H)+。
对C7H8BrNO2分析:
理论值:C,38.56;H,3.70;N,6.42
实测值:C,38.32;H,3.77;N,6.24
步骤c)2-溴-4-甲氧基-6-[(4-甲氧基苯甲酰基)氨基]苯基-4-甲氧基苯甲酸酯
将无水吡啶(37.0mL,468.5mmol)滴加入到2-氨基-6-溴-4-甲氧基苯酚(20.0g,91.7mmol)、4-甲氧基苯甲酰氯(38.9g,229.0mmol)和CH2Cl2(250mL)的冷的(0℃)混合物中(机械搅拌的)。在加入吡啶期间形成沉淀。把混合物搅拌30分钟,然后加入乙醚(250mL)。滤出沉淀的固体并用乙醚洗涤。用水吸收固体并搅拌20分钟。然后滤出固体并干燥,得到灰白色固体(42.5g,95%收率,m.p.73-75℃);MS m/e484(M-H)+。
对C23H20BrNO6分析:
理论值:C,56.80;H,4.15;N,2.88
实测值:C,56.50;H,3.78;N,2.83
步骤d)7-溴-5-甲氧基-2-(4-甲氧基苯基)1,3-苯并噁唑。
途径a)
伴随连续除去水(迪安-斯达克榻分水器),将2-溴-4-甲氧基-6-[(4-甲氧基苯甲酰基)氨基]苯基4-甲氧基苯甲酸酯(42.0g,86.4mmol)、对甲苯磺酸单水合物(32.8g,172.8mmol)和无水对二甲苯(800mL)的悬浮液回流1小时。在回流温度下,最初的悬浮液变为棕色溶液。把混合物冷却至室温并用NaOH(2N)洗涤。经MgSO4干燥有机层。蒸发并从丙酮/乙醚中结晶,得到灰白色固体(23.5g,82%收率,m.p.139-141℃);MS m/e 334(M+H)+。
对C15H12BrNO3分析:
理论值:C,53.91;H,3.62;N,4.19
实测值:C,53.83;H,3.37;N,4.01
途径b)
使用迪安-斯达克榻分水器,将2-氨基-6-溴-甲氧基苯酚(100mg,0.46mmol)、4-甲氧基苯甲酸(77mg,0.50mmol)和硼酸(31mg,0.5mmol)在对二甲苯(9mL)中的混合物回流24小时。把混合物冷却至室温并真空浓缩。经快速层析法(30%EtOAc/石油醚)纯化残余物,得到浅桃红色固体(99mg,65%收率,m.p.136-138℃);MS m/e 334(M+H)+。
对C15H12BrNO3分析:
理论值:C,53.91;H,3.62;N,4.19
实测值:C,53.78;H,3.55;N,4.01
步骤e)7-溴-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇。
途径a)
将三溴化硼(1M,89.9mL,89.8mmol)滴加入到7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(10.0g,29.94mmol)和CH2Cl2(50mL)的冷的(-70℃)悬浮液中。使混合物温热至室温。在温热期间,悬浮液变为深色溶液。把混合物在室温下搅拌2天,然后缓慢倾入到冷的(0℃)乙醚(1000mL)中。于20分钟内,向新的混合物中缓慢加入甲醇(200mL)。然后把混合物倾入到水(1.51)中。用水把有机层洗涤三次,经MgSO4干燥。蒸发并从丙酮/乙醚/己烷中结晶,得到灰白色固体(8.4g,92%收率,m.p.298-299℃);MS m/e 306(M+H)+。
对C13H8BrNO3分析:
理论值:C,51.01;H,2.63;N,4.58
实测值:C,50.96;H,2.30;N,4.42
途径b)
将三溴化硼(0.25mL,2.7mmol)滴加入到7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(130mg,0.39mmol)和二氯甲烷(1.5mL)的冷的(-78℃)混合物中。使反应混合物逐渐恢复到室温并搅拌1小时。将混合物倾入到冰中并用EtOAc提取。用盐水洗涤有机提取液并经MgSO4干燥。蒸发并快速层析化(30-40%EtOAc/石油醚),得到为浅桃红色固体的产物(102mg,86%收率),m.p.295-298℃;MS m/e 304(M-H)+。
对C13H8BrNO3分析:
理论值:C,51.01;H,2.63;N,4.58
实测值:C,51.06;H,2.77;N,4.36
实施例21
7-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)2-溴-6-[(3-氟-4-甲氧基苯甲酰基)氨基]-4-甲氧基苯基3-氟-4-甲氧基苯甲酸酯。
将3-氟-4-甲氧基苯甲酸(39.0g,229mmol)、亚硫酰氯(100mL)和N,N-二甲基甲酰胺(0.5mL)的混合物回流1小时。真空除去挥发物。用苯吸收固体(两次)并真空除去挥发物。把残余物溶于CH2Cl2(100mL)中并加入到2-氨基-6-溴-4-甲氧基苯酚(20.0g,91.7mmol)和CH2Cl2(150mL)的冷的(0℃)混合物中(机械搅拌的)。将无水吡啶(37.0mL,468.5mmol)滴加入到新的混合物中。在加入吡啶期间形成沉淀。把混合物搅拌30分钟,然后加入乙醚(250mL)。滤出沉淀的固体并用乙醚洗涤。用水吸收固体并搅拌20分钟。然后滤出固体并干燥,得到灰白色固体(46.5g,97%收率,m.p.184-186℃);MS m/e 520(M-H)+。
对C23H18BrF2NO6分析:
理论值:C,52.89;H,3.47;N,2.68
实测值:C,52.79;H,3.23;N,2.63
步骤b)7-溴-2-(3-氟-4-甲氧基苯基)-5-甲氧基-1,3-苯并噁唑。
伴随连续除去水(迪安-斯达克榻分水器),将2-溴-6-[(3-氟-4-甲氧基苯甲酰基)氨基]-4-甲氧基苯基3-氟-4-甲氧基苯甲酸酯(46.0g,88.1mmol)、对-甲苯磺酸单水合物(33.5g,177.2mmol)和无水对-二甲苯(1 l)的悬浮液回流3小时。在回流温度下,最初的悬浮液变为棕色溶液。滤出固体并用乙醚洗涤。把固体悬浮于乙醚(200mL)中,搅拌10分钟,滤出并干燥,得到褐色固体(25.1g,m.p.175-177℃)。将乙醚层浓缩至20mL,得到2.5g另外的产物(90%总收率)。MS m/e 352(M+H)+。
对C15H11BrFNO3分析:
理论值:C,51.16;H,3.15;N,3.98
实测值:C,51.10;H,2.92;N,3.89
步骤c)7-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例20步骤e中描述的基本相同的方法,制备标题化合物并得到为白色固体的产物,m.p.265-267℃;MS m/e 332(M-H)+。
对C13H7BrFNO3分析:
理论值:C,48.18;H,2.18;N,4.32
实测值:C,48.19;H,2.29;N,4.19
实施例22
7-溴-2-(2-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)2-氟-4-甲氧基苯甲酸。
向Ag2O(13.5g,58.4mmol)、NaOH(19.5g,487mmol)和水(200mL)的温热(55℃)混合物中加入2-氟-4-甲氧基苯甲醛(15g,97.4mmol)。把混合物搅拌1小时,滤出并用热水(10mL)洗涤沉淀的固体。伴随剧烈搅拌下,把滤液缓慢加入到冷的(0℃)HCl(5N)中。过滤沉淀的固体,用水洗涤并干燥,得到白色固体(13.6g,82%收率,m.p.194-196℃);MS m/e 169(M-H)+。
对C8H7FO3分析:
理论值:C,56.48;H,4.15
实测值:C,56.12;H,4.12
步骤b)7-溴-2-(2-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例21中描述的基本相同的方法,从2-氟-4-甲氧基苯甲酸制备标题化合物,并得到为白色固体的产物,m.p.248-250℃;MS m/e 324(M+H)+。
对C13H7BrFNO3分析:
理论值:C,48.18;H,2.18;N,4.32
实测值:C,47.89;H,1.95;N,4.18
实施例23
7-溴-2-(2,3-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)2,3-二氟-4-甲氧基苯甲酸甲酯。
将碘甲烷(10.7mL,172.5mmol)加入到2,3-二氟-4-羟基苯甲酸(10.0g,57.5mmol)、碳酸锂(12.7g,172.5mmol)和N,N-二甲基甲酰胺(100mL)的混合物中。把混合物在40℃下搅拌12小时,然后倾入到水中并用EtOAc提取。有机提取液经MgSO4干燥。蒸发并经快速层析法(己烷/EtOAc 5/1)纯化,得到白色固体(10.2g,88%收率,m.p.66-68℃);MS m/e 203(M+H)+。
对C9H8F2O3分析:
理论值:C,53.47;H,3.99
实测值:C,53.15;H,3.83
步骤b)2,3-二氟-4-甲氧基苯甲酸。
将氢氧化钠(2N,50mL)加入到2,3-二氟-4-甲氧基苯甲酸甲酯(10.0g,49.5mmol)、THF(100mL)和MeOH(100mL)的混合物中。把混合物在室温下搅拌6小时,用HCl(2N)酸化。滤出沉淀的固体,用水洗涤并干燥,得到白色固体(8.9g,96%收率,m.p.194-196℃);MSm/e 187(M-H)+。
对C8H6F2O3分析:
理论值:C,51.08;H,3.21
实测值:C,50.83;H,2.92
步骤c)7-溴-2-(2,3-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例21中描述的基本相同的方法,从2,3-二氟-4-甲氧基苯甲酸制备标题化合物,并得到为白色固体的产物,m.p.258-260℃;MS m/e 342(M+H)+。
对C13H6BrF2NO3分析:
理论值:C,45.64;H,1.77;N,4.09
实测值:C,45.33;H,1.62;N,4.02
实施例24
2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇
途径a)
步骤a)7-溴-5-{[叔丁基(二甲基)甲硅烷基]氧基}-2-(4-{[叔丁基(二甲基)甲硅烷基]氧基}-3-氟苯基)-1,3-苯并噁唑。
将叔丁基(氯代)二甲基硅烷(23.2g,154mmol)分批加入到7-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇(16.6g,51.4mmol)、咪唑(17.5g,257mmol)、N,N-二甲基吡啶-4-胺(1.0g,8.1mmol)和DMF(300mL)的混合物中。把混合物搅拌3小时,倾入到水中并用乙醚提取。有机提取液经MgSO4干燥。蒸发并经快速层析法(己烷/EtOAc 50/1)纯化,得到白色固体(27.5g,97%收率,m.p.98-99℃);MS m/e 552(M+H)+。
对C25H35BrFNO3Si2分析:
理论值:C,54.34;H,6.38;N,2.53
实测值:C,54.06;H,6.52;N,2.24
步骤b)5-{[叔丁基(二甲基)甲硅烷基]氧基}-2-(4-{[叔丁基(二甲基)甲硅烷基]氧基}-3-氟苯基)-7-乙烯基-1,3-苯并噁唑。
将二氯双(三-邻-甲苯基膦)钯(II)(0.63g,0.79mmol)加入到7-溴-5-{[叔丁基(二甲基)甲硅烷基]氧基}-2-(4-{[叔丁基(二甲基)甲硅烷基]氧基}-3-氟苯基)-1,3-苯并噁唑(14.7g,26.6mmol)、三丁基(乙烯基)锡(10.5g,33.25mmol)和对-二甲苯(85mL)的混合物中。把反应混合物在90℃下搅拌24小时,冷却至室温,用乙醚(100mL)稀释并用活性炭处理。通过MgSO4过滤混合物并浓缩。经快速层析法(己烷/EtOAc50/1)纯化,得到白色固体(11.8g,89%收率,m.p.93-95℃);MS m/e 500(M+H)+。
对C27H38FNO3Si2分析:
理论值:C,64.89;H,7.66;N,2.80
实测值:C,64.59;H,7.70;N,2.73
步骤c)2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇。
将氢氟酸(48wt.%在水中,1mL)加入到5-{[叔丁基(二甲基)甲硅烷基]氧基}-2-(4-{[叔丁基(二甲基)甲硅烷基]氧基}-3-氟苯基)-7-乙烯基-1,3-苯并噁唑(1.5g,3.0mmol)、THF(6mL)和乙腈(3mL)的溶液中。把反应混合物在65℃下搅拌8小时,然后倾入到水中。滤出沉淀的固体并干燥。从丙酮/乙醚中结晶该产物,得到白色固体(0.72g,81%收率,m.p.249-251℃);MS m/e 272(M+H)+。
对C15H10FNO3分析:
理论值:C,66.42;H,3.72;N,5.16
实测值:C,66.31;H,3.85;N,4.96
途径b)
2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇。
将二氯双(三-邻-甲苯基膦)钯(II)(0.87g,1.1mmol)加入到7-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇(7.16g,22.1mmol)、三丁基(乙烯基)锡(10.5g,33.25mmol)和乙二醇二乙醚(65mL)的混合物中。将该反应混合物在115℃下搅拌48小时,冷却至室温并用活性炭处理。通过MgSO4过滤混合物并浓缩。经酸性硅胶上的快速层析法(己烷/EtOAc/CH2Cl2/1/1/1)纯化,得到白色固体(4.35g,72%收率,m.p.250-252℃);MS m/e 272(M+H)+。
对C15H10FNO3分析:
理论值:C,66.42;H,3.72;N,5.16
实测值:C,66.03;H,3.68;N,5.09
途径c)
步骤a)4-[5-(乙酰氧基)-7-溴-1,3-苯并噁唑-2-基]-2-氟苯基乙酸酯。
将乙酸酐(1.0mL,9.95mmol)加入到7-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇(1.24g,3.8mmol)、N,N-二甲基吡啶-4-胺(1.1g,9.18mmol)和1,4-二噁烷(13mL)的冷的(0℃)溶液中。使反应混合物温热至室温并搅拌20小时。向该反应混合物中加入水(50mL),用EtOAc提取并经MgSO4干燥。蒸发并从EtOAc/己烷中结晶,得到灰白色固体(0.87g,56%收率);MS m/e 408(M+H)+。
对C17H11BrFNO5分析:
理论值:C,50.02;H,2.72;N,3.43
实测值:C,49.58;H,2.59;N,3.37
步骤b)2-[4-(乙酰氧基)3-氟苯基]-7-乙烯基-1,3-苯并噁唑-5-基乙酸酯。
将二氯双(三-邻-甲苯基膦)钯(II)(46mg,0.06mmol)加入到4-[5-(乙酰氧基)-7-溴-1,3-苯并噁唑-2-基]-2-氟苯基乙酸酯(0.8g,1.98mmol)、三丁基(乙烯基)锡(0.9g,2.8mmol)和对-二甲苯(9mL)的混合物中。将所述反应混合物在130℃下搅拌5小时,冷却至室温,用乙醚(10mL)稀释并用活性炭处理。通过MgSO4过滤混合物并浓缩。经快速层析法(己烷/EtOAc 5/1)纯化,得到白色固体(0.4g,56%收率,m.p.154-156℃);MS m/e 356(M+H)+。
对C19H14FNO5分析:
理论值:C,64.23;H,3.97;N,3.94
实测值:C,63.94;H,3.78;N,3.76
步骤c)2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇。
将碳酸钾(55mg)加入到2-[4-(乙酰氧基)-3-氟苯基]-7-乙烯基-1,3-苯并噁唑-5-基乙酸酯(0.14g,0.39mmol)和1,4-二噁烷(3mL)的溶液中。将所述混合物在90℃下搅拌1小时,倾入到水中,用HCl(2N)酸化并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并从EtOAc/己烷中结晶,得到白色固体(0.06g,46%收率,m.p.250-252℃);MS m/e272(M+H)+。
对C15H10FNO3分析:
理论值:C,66.42;H,3.72;N,5.16
实测值:C,66.32;H,3.47;N,5.18
实施例25
2-(2-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇。
以与在实施例24途径a)中描述的基本相同的方法,从7-溴-2-(2-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇制备标题化合物并得到为白色固体的产物,m.p.274-275℃;MS m/e 272(M+H)+。
对C15H10FNO3分析:
理论值:C,66.42;H,3.72;N,5.16
实测值:C,66.18;H,3.47;N,4.97
实施例26
2-(2,3-二氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇。
以与在实施例24途径b)中描述的基本相同的方法,从7-溴-2-(2,3-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇制备标题化合物并得到为灰白色固体的产物,m.p.276-278℃;MS m/e 290(M+H)+。
对C15H9F2NO3分析:
理论值:C,62.29;H,3.14;N,4.84
实测值:C,61.90;H,3.05;N,4.52
实施例27
2-(4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇。
以与在实施例24途径b)中描述的基本相同的方法,从7-溴-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇制备标题化合物并得到为白色固体的产物,m.p.249-250℃;MS m/e 254(M+H)+。
对C15H11NO3分析:
理论值:C,70.99;H,4.39;N,5.52
实测值:C,70.75;H,4.34;N,5.46
实施例28和29
4-溴-2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇(实施例28)和4,6-二溴-2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇(实施例29)。
将N-溴代琥珀酰亚胺(0.49g,2.77mmol)加入到2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇(0.75g,2.77mmol)和乙腈(30mL)的混合物中。将所述反应混合物在室温下搅拌16小时,倾入到水中并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(己烷/EtOAc/CH2Cl2 2/1/1)纯化,得到(a)为白色固体的产物(0.45g,m.p.226-228℃);MS m/e 349(M+H)+。
对C15H9BrNO3分析:
理论值:C,51.45;H,2.59;N,4.00
实测值:C,51.08;H,2.40;N,3.90
和(b)为白色固体的产物(0.18g,m.p.272-274℃);MS m/e 428(M+H)+。
对C15H8Br2NO3分析:
理论值:C,41.99;H,1.88;N,3.26
实测值:C,42.25;H,1.90;N,3.14
实施例30
7-(1,2-二溴乙基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇步骤a)5-甲氧基-2-(4-甲氧基苯基)-7-乙烯基-1,3-苯并噁唑。
以与在实施例24途径c)步骤b)中描述的基本相同的方法,从7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑制备标题化合物并得到为白色固体的产物,MS m/e 282(M+H)+。
对C17H15NO3分析:
理论值:C,72.58;H,5.37;N,4.98
实测值:C,72.33;H,5.26;N,4.72
步骤b)7-(1,2-二溴乙基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇。
将三溴化硼(0.85mL,8.95mmol)滴加入到5-甲氧基-2-(4-甲氧基苯基)-7-乙烯基-1,3-苯并噁唑(0.31g,1.12mmol)和CH2Cl2(4mL)的冷的(-78℃)混合物中。使混合物温热至室温。于室温下搅拌18小时后,将所述混合物缓慢倾入到冷的(0℃)乙醚(20mL)中。然后向该混合物中缓慢加入甲醇(10mL)。把新的混合物用水洗涤(三次)并经MgSO4干燥。蒸发并经快速层析法(己烷/EtOAc 3/1)纯化,得到浅黄色固体(0.27g,59%收率,m.p.175-177℃);MS m/e 412(M+H)+。
对C15H11Br2NO3分析:
理论值:C,43.62;H,2.68;N,3.39
实测值:C,43.85;H,2.44;N,3.33
实施例31
7-(1-溴代乙烯基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
将1,8-二氮杂双环[5.4.0]十一碳-7-烯(0.25g,1.65mmol)加入到7-(1,2-二溴乙基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇(0.4g,0.96mmol)和乙腈(4mL)的溶液中。将该反应混合物搅拌24小时,倾入到冷的(0℃)HCl(1N,10mL)中并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(CH2Cl2/己烷/异丙醇15/5/1)纯化,得到白色固体(185mg,58%收率,m.p.228-230℃);MS m/e 332(M+H)+。
对C15H10BrNO3分析:
理论值:C,54.24;H,3.03;N,4.22
实测值:C,54.27;H,2.94;N,4.20
实施例32
7-(1-溴代乙烯基)-2-(2-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例29-30中描述的基本相同的方法,从7-溴-2-(2-氟-4-甲氧基苯基)-5-甲氧基-1,3-苯并噁唑制备标题化合物并得到为灰白色固体的产物,m.p.235-237℃;MS m/e 350(M+H)+。
对C15H9BrFNO3分析:
理论值:C,51.45;H,2.59;N,4.00
实测值:C,51.63;H,2.38;N,3.98
实施例33
7-(1-溴代乙烯基)-2-(2,3-二-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例29-30中描述的基本相同的方法,从7-溴-2-(2,3-二氟-4-甲氧基苯基)-5-甲氧基-1,3-苯并噁唑制备标题化合物,得到为灰白色固体的产物,m.p.240-242℃;MS m/e 366(M-H)+。
对C15H8BrF2NO3分析:
理论值:C,48.94;H,2.19;N,3.80
实测值:C,49.63;H,2.33;N,3.61
实施例34
7-烯丙基-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例24途径c步骤b中描述的基本相同的方法,从7-溴-2-(3-氟-4-甲氧基苯基)-5-甲氧基-1,3-苯并噁唑、烯丙基三丁基锡和二氯双(三-邻-甲苯基膦)钯,随后按照实施例20步骤e)脱甲基化,制备标题化合物。得到为浅桃红色固体的要求的产物,m.p.169-171℃;MSm/e 284(M-H)+。
对C16H12FNO3分析:
理论值:C,67.37;H,4.24;N,4.91
实测值:C,67.37;H,4.16;N,4.66
实施例35
7-乙炔基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
将四重(三苯基膦)钯(0)(52mg,0.045mmol)加入到7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(0.3g,0.9mmol)、碘化铜(I)(17.1mg,0.09mmol)、乙炔基(三甲基)硅烷(0.2g mg,2mmol)和三乙胺(12mL)的混合物中。将所述混合物在110℃下搅拌4小时,倾入到氯化铵水溶液中并用EtOAc/THF(1/1)提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(己烷/EtOAc 6/1)纯化,得到灰白色固体(0.27g,85%收率)。将该产物溶于CH2Cl2(2mL)中,冷却至-78℃并滴加三溴化硼(0.6mL)。使该混合物温热至室温。于室温下搅拌18小时后,将所述混合物缓慢倾入到冷的(0℃)乙醚(10mL)中。然后向该混合物中缓慢地加入甲醇(3mL)。将新的混合物用水洗涤(三次)并经MgSO4干燥。蒸发并经快速层析法(己烷/EtOAc 3/1)纯化,得到黄色固体(86mg,38%收率,m.p.229-231℃);MS m/e 252(M+H)+。
对C15H9NO3分析:
理论值:C,71.71;H,3.61;N,5.58
实测值:C,71.39;H,3.49;N,5.32
实施例36
2-(4-羟基苯基)-7-丙基-1,3-苯并噁唑-5-醇
将四重(三苯基膦)钯(0)(70mg,0.06mmol)加入到7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(0.4g,1.2mmol)、溴代(丙基)锌(0.5M在THF中,3.6mL,1.8mmol)和THF(4mL)的混合物中。将所述混合物在室温下搅拌48小时,倾入到HCl(1N)中并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(己烷/EtOAc 6/1)纯化,得到灰白色固体(0.14g)。将该产物溶于CH2Cl2(2mL)中,冷却至-78℃并滴加三溴化硼(0.35mL)。使该混合物温热至室温。于室温下搅拌18小时后,把混合物缓慢倾入到冷的(0℃)乙醚(10mL)中。然后向混合物中缓慢加入甲醇(3mL)。将新的混合物用水洗涤(三次)并经MgSO4干燥。蒸发并经快速层析法(己烷/EtOAc 4/1)纯化,得到白色固体(90mg,27%收率,m.p.110-112℃);MS m/e 270(M+H)+。
对C16H15NO3分析:
理论值:C,71.36;H,5.61;N,5.20
实测值:C,71.02;H,5.58;N,4.94
实施例37
7-丁基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例35中描述的基本相同的方法,从7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑和溴代(丁基)锌制备标题化合物。得到为白色固体的要求的产物,m.p.125-127℃;MS m/e 282(M-H)+。
对C17H17NO3分析:
理论值:C,72.07;H,6.05;N,4.94
实测值:C,72.78;H,5.87;N,4.69
实施例38
7-环戊基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例35中描述的基本相同的方法,从7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑和溴代(环戊基)锌制备标题化合物。得到为白色固体的要求的产物,m.p.220-222℃;MS m/e 296(M+H)+。
对C18H17NO3分析:
理论值:C,73.20;H,5.80;N,4.74
实测值:C,73.05;H,5.74;N,4.59
实施例39
5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-甲酸乙酯
步骤a)7-溴-5-{[叔丁基(二甲基)甲硅烷基]氧基}-2-(4-{[叔丁基(二甲基)甲硅烷基]氧基}苯基)-1,3-苯并噁唑。
以与在实施例24途径a步骤a中描述的基本相同的方法,从7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑和叔丁基(氯代)二甲基硅烷制备标题化合物。得到为白色固体的要求的产物,m.p.90-91℃;MS m/e 534(M+H)+。
对C25H36BrNO3Si2分析:
理论值:C,56.16;H,6.79;N,2.62
实测值:C,55.66;H,6.86;N,2.68
步骤b)5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-甲酸乙酯
将正丁基锂(2.5M,0.3mL,0.75mmol)滴加入到7-溴-5-{[叔丁基(二甲基)甲硅烷基]氧基}-2-(4-{[叔丁基(二甲基)甲硅烷基]氧基}苯基)-1,3-苯并噁唑(0.4g,0.75mmol)和THF(4mL)的冷的(0℃)溶液中。使该混合物温热至40℃,然后搅拌2小时。然后向所述反应混合物中加入在THF(1mL)中的[(氰基羰基)氧基]乙烷(84mg)并使反应混合物温热至0℃,搅拌1小时。用氯化铵水溶液猝灭该反应,用EtOAc提取,经MgSO4干燥。蒸发并经快速层析法(己烷/CH2Cl2/异丙醇18/2/1)纯化,得到无色的油(340mg)。将产物溶于THF(3.5mL)中并用四丁基氟化铵(1M在THF中,1.4mL)处理。将所述混合物搅拌30分钟,倾入到HCl(1N)中并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(己烷/CH2Cl2/异丙醇5/2/1)纯化,得到白色固体(119mg,53%收率,m.p.305-307℃);MS m/e 300(M+H)+。
对C16H13NO5分析:
理论值:C,64.21;H,4.38;N,4.68
实测值:C,64.04;H,4.43;N,4.40
实施例40
2-(4-羟基苯基)-7-苯基-1,3-苯并噁唑-5-醇
步骤a)5-甲氧基-2-(4-甲氧基苯基)-7-苯基-1,3-苯并噁唑
将7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(200mg,0.60mmol)和四重(三苯基膦)钯(0)(63mg,0.03mmol)溶于甲苯(5mL)中并在氮气氛下,于室温搅拌10分钟。加入苯硼酸(110mg,0.90mmol),随后加入碳酸钠水溶液(2M,1.5mL)和乙醇(2mL)。将所述混合物回流12小时,用水稀释并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(20-40%EtOAc/石油醚)纯化,得到为浅桃红色固体的标题化合物,mp 92℃;MS m/e 332(M+H)+。
对C21H17NO3分析:
理论值:C,76.12;H,5.17;N,4.23
实测值:C,75.86;H,5.08;N,4.07
步骤b)2-(4-羟基苯基)-7-苯基-1,3-苯并噁唑-5-醇
按照实施例20步骤e(途径b)的方法制备标题化合物,并得到为紫色固体的产物,m.p.255-258℃;MS m/e 302(M-H)+。
对C19H13NO3×0.25H2O分析:
理论值:C,74.14;H,4.42;N,4.55
实测值:C,73.81;H,4.40;N,4.35
实施例41
5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-腈
步骤a)5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑-7-腈。
在干燥氮气下,将7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(200mg,0.60mmol)在无水N,N-二甲基甲酰胺(1.5mL)中的溶液与氰化铜(I)(80mg,0.90mmol)搅拌并加热至回流4小时。将所述混合物冷却并倾入到过量的乙二胺四乙酸水溶液中。分离粗品产物,从(30%EtOAc/石油醚)中得到为褐色针晶的腈(164mg,98%收率);m.p.180-183℃;MS m/e 281(M+H)+。
对C16H12N2O3×0.2H2O分析:
理论值:C,66.84;H,4.48;N,9.74
实测值:C,66.63;H,4.33;N,9.60
步骤b)5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-腈
按照实施例20步骤e(途径b)的方法制备标题化合物,并得到为浅桃红色固体的产物,mp 297-303℃;MS m/e 253(M+H)+。
对C14H8N2O3×0.5H2O分析:
理论值:C,64.37;H,3.47;N,10.72
实测值:C,64.44;H,3.49;N,9.92
实施例42
5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-甲酰胺
从实施例40步骤b的反应物分离为作为浅褐色固体的小量产物的标题化合物,m.p.325℃;MS m/e 271(M+H)+。
对C14H10N2O4×0.5H2O分析:
理论值:C,60.22;H,3.97;N,10.03
实测值:C,59.71;H,3.91;N,9.84
实施例43
2-(4-羟基苯基)-7-甲氧基-1,3-苯并噁唑-5-醇
将7-溴-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇(100mg,0.33mmol)和溴化铜(I)(56mg,0.39mmol)在无水N,N-二甲基甲酰胺(1.5mL)中的混合物与新鲜制备的甲醇钠(15wt%在甲醇中,1ml)搅拌并加热至120℃4小时。将所述混合物冷却并用HCl(1N,5ml)稀释。用乙酸乙酯分离粗品产物,随后快速层析化(40%-50%EtOAc/石油醚),得到为灰白色固体的标题化合物(50mg,60%收率,mp 225-228℃);MS m/e258(+H)+。
对C14H11NO4×0.75H2O分析:
理论值:C,62.11;H,4.65;N,5.17
实测值:C,62.53;H,4.73;N,5.02
实施例44
7-乙基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)7-乙基-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑。
将正丁基锂(2.5N,0.43mL,1.08mmol)滴加入到7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(300mg,0.90mmol)和THF(2mL)的冷的(-78℃)混合物中。将该混合物搅拌0.5小时。把碘乙烷(0.14mL,1.8mmol)滴加入到混合物中。使反应混合物温热至室温并搅拌2小时。用氯化铵水溶液猝灭该反应,倾入到水中并用EtOAc提取。用盐水洗涤有机提取液并经MgSO4干燥。蒸发并快速层析化(20%EtOAc/石油醚),得到为浅棕色固体的产物(231mg,91%收率):m.p.85℃;MSm/e 284(M+H)+。
对C17H17NO3×0.2H2O分析:
理论值:C,70.28;H,6.17;N,4.94
实测值:C,70.12;H,5.74;N,4.82
步骤b)7-乙基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
按照实施例20步骤e(途径b)的方法制备标题化合物并得到为浅棕色固体的产物(98%收率),m.p.110-115℃;MS m/e 256(M+H)+。
实施例45
7-乙基-2-(2-乙基-4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)7-乙基-5-甲氧基-2-(2-乙基-4-甲氧基苯基)-1,3-苯并噁唑。
按照实施例43步骤a的方法,使用两当量的正丁基锂制备标题化合物,并且将粗品产物直接用于下一步骤。
步骤b)7-乙基-2-(2-乙基-4-羟基苯基)-1,3-苯并噁唑-5-醇
按照实施例20步骤e(途径b)的方法,从7-乙基-5-甲氧基-2-(2-乙基-4-甲氧基苯基)-1,3-苯并噁唑制备标题化合物,并得到为灰色固体的产物(87%收率);MS m/e 284(M+H)+。
实施例46
5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-甲醛
步骤a)5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑-7-甲醛。
按照实施例43步骤a的方法,使用N-甲基N-甲酰苯胺作为亲电试剂制备标题化合物,得到浅橙色固体(94%,m.p.153-155℃);MSm/e 284(M+H)+。
对C16H13NO4分析:
理论值:C,67.84;H,4.63;N,4.94
实测值:C,67.58;H,4.53;N,4.75
步骤b)5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-甲醛
按照实施例20步骤e(途径b)的方法,从5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑-7-甲醛制备标题化合物,并得到为深黄色固体的产物(99%收率,m.p.273-275℃);MS m/e 256(M+H)+。
对C14H9NO4×0.25H2O分析:
理论值:C,64.74;H,3.69;N,5.39
实测值:C,64.32;H,3.59;N,5.18
实施例47
7-(羟基甲基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)5-甲氧基-7-(羟基甲基)-2-(4-甲氧基苯基)-1,3-苯并噁唑
在0℃下,将硼氢化钠(66.8mg,1.76mmol)加入到5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑-7-甲醛(250mg,0.88mmol)的无水MeOH(8mL)溶液中。将该反应混合物搅拌30分钟,然后真空蒸发。把残余物溶于乙醚中并用水和盐水洗涤,经MgSO4干燥并过滤。蒸发并快速层析化(50%EtOAc/石油醚),得到产物(210mg,83%收率),将其直接用于下一步反应。
步骤b)7-(羟基甲基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇。
按照实施例20步骤e(途径b)的方法,从5-甲氧基-7-(羟基甲基)-2-(4-甲氧基苯基)-1,3-苯并噁唑制备标题化合物并得到为浅棕色固体的产物,m.p.282℃(分解);MS m/e 258(M+H)+。
对C14H11NO4×0.5H2O分析:
理论值:C,63.16;H,4.54;N,5.26
实测值:C,63.33;H,4.36;N,5.04
实施例48
7-(溴代甲基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
按照实施例20步骤e(途径b)的方法,从5-甲氧基-7-(羟基甲基)-2-(4-甲氧基苯基)-1,3-苯并噁唑,同时在三溴化硼存在下延长搅拌,制备标题化合物,并得到为浅棕色固体的产物,m.p.250-260℃(分解);MS m/e 321(M+H)+。
对C14H10BrNO3分析:
理论值:C,52.52;H,3.15;N,4.38
实测值:C,52.26;H,3.17;N,4.07
实施例49
[5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-基]乙腈
向7-(溴代甲基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇(122mg,0.40mmol)的N,N-二甲基甲酰胺(1.5mL)溶液中加入18-冠-6-醚(202mg,0.80mmol)和氰化钾(131mg,2mmol)。搅拌反应混合物2小时,然后倾入到水中并用EtOAc提取。用盐水洗涤有机提取液并经MgSO4干燥。蒸发并快速层析化(50%-60%EtOAc/石油醚),得到为灰色固体的产物(80mg,75%收率),m.p.170-180℃;MS m/e 265(M-H)+。
对C15H10N2O3×1.5H2O分析:
理论值:C,61.43;H,4.47;N,9.55
实测值:C,61.41;H,4.21;N,9.19
实施例50
7-(1-羟基-1-甲基乙基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇]
步骤a)2-[5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑-7-基]丙烷-2-醇
按照实施例43步骤a的方法,从7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑,使用丙酮作为亲电试剂制备标题化合物,得到白色固体(78%收率,m.p.149℃);MS m/e 314(M+H)+。
对C18H19NO4分析:
理论值:C,68.99;H,6.11;N,4.47
实测值:C,68.78;H,6.13;N,4.35
步骤b)7-(1-羟基-1-甲基乙基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇]
按照实施例20步骤e(途径b)的方法,从2-[5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑-7-基]丙烷-2-醇制备标题化合物,并得到为深棕色固体的产物(90%收率,m.p.180-185℃);MS m/e 286(M+H)+。
对C16H15NO4×0.5H2O分析:
理论值:C,65.30;H,5.48;N,4.76
实测值:C,65.03;H,5.20;N,4.72
实施例51
2-(4-羟基苯基)-7-异丙烯基-1,3-苯并噁唑-5-醇
将吡啶盐酸盐加热至(400mg)加热至190℃。向该融化物中加入2-[5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑-7-基]丙烷-2-醇(114mg,0.36mmol)并搅拌反应物2小时。将该混合物冷却至室温,溶于水中并用EtOAc提取。合并有机层并先后用HCl(1N)、水和盐水洗涤,经MgSO4干燥。蒸发并经快速层析法(50%-60%EtOAc/石油醚)纯化,得到为浅棕红色固体的产物(40mg,41%收率),m.p.225-228℃;MSm/e 268(M+H)+。
对C16H13NO3×0.5H2O分析:
理论值:C,69.56;H,5.11;N,5.06
实测值:C,69.46;H,5.22;N,4.56
实施例52
2-(4-羟基苯基)-7-异丙基-1,3-苯并噁唑-5-醇]
将2-(4-羟基苯基)-7-异丙烯基-1,3-苯并噁唑-5-醇(64mg,0.24mmol)溶于EtOAc(5mL)和无水乙醇(5mL)的混合物中并在含有氩气的惰性气氛下放置。向该混合物中加入10%Pd-C(25mg)。将溶液在帕尔装置中于25磅/平方英寸下氢化3小时。将所述溶液通过硅藻土过滤并用乙醇冲洗。浓缩滤液并经快速层析法(50%EtOAc/石油醚)纯化残余物,得到为褐色固体的产物(58mg,90%收率),m.p.200℃;MSm/e 270(M+H)+。
实施例53
7-溴-2-(4-羟基-3-(三氟甲基)苯基)-1,3-苯并噁唑-5-醇
步骤a)2-溴-4-甲氧基-6-{[4-甲氧基-3-(三氟甲基)苯甲酰基]氨基}苯基4-甲氧基-3-(三氟甲基)苯甲酸酯。
以与在实施例20步骤c中描述的基本相同的方法,从2-氨基-6-溴-4-甲氧基苯酚和4-甲氧基-3-三氟甲基苯甲酰氯制备标题化合物。得到为灰白色固体的产物,m.p.205-208℃;MS m/e 622(M+H)+。
对C25H18BrF6NO6分析:
理论值:C,48.25;H,2.92;N,2.25
实测值:C,48.47;H,2.76;N,2.16
步骤b)7-溴-5-甲氧基-2-(4-甲氧基-3-(三氟甲基)苯基)-1,3-苯并噁唑。
以与在实施例20步骤d(途径a)中描述的基本相同的方法,从2-溴-4-甲氧基-6-{[4-甲氧基-3-(三氟甲基)苯甲酰基]氨基}苯基4-甲氧基-3-(三氟甲基)苯甲酸酯和对甲苯磺酸单水合物制备标题化合物。得到为灰白色固体的产物,m.p.183-185℃;MS m/e 402(M+H)+。
对C16H11BrF3NO3分析:
理论值:C,47.79;H,2.76;N,3.48
实测值:C,47.60;H,2.50;N,3.37
步骤c)7-溴-2-(4-羟基-3-(三氟甲基)苯基)-1,3-苯并噁唑-5-醇
按照实施例20步骤e(途径b)的方法,从7-溴-5-甲氧基-2-(4-甲氧基-3-(三氟甲基)苯基)-1,3-苯并噁唑制备标题化合物,并得到为浅黄色固体的产物(50%收率,m.p.200-210℃);MS m/e 372(M-H)+。
对C14H7BrF3NO3×0.5H2O分析:
理论值:C,43.89;H,2.10;N,3.65
实测值:C,43.59;H,2.04;N,3.6
实施例54
7-(2-呋喃基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
步骤a)7-(2-呋喃基)-5-甲-2-(4-甲氧基苯基)-1,3-苯并噁唑
将7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑(300mg,0.90mmol)和二氯双(三-邻-甲苯基膦)钯(II)(71mg,0.09mmol)溶于对二甲苯(3mL)中并在氮气氛下,于室温搅拌10分钟。加入2-(三丁基甲锡烷基)呋喃(449mg,1.26mmol)并将该混合物回流4小时。将混合物冷却至室温,用饱和氯化铵溶液稀释并用EtOAc提取。先后用水和盐水洗涤有机提取液并经MgSO4干燥,浓缩。经快速层析法(20%-30%EtOAc/石油醚)纯化,得到为白色固体的标题化合物(99%收率,m.p.120-121℃);MS m/e 322(M+H)+。
对C19H15NO4分析:
理论值:C,71.02;H,4.71;N,4.36
实测值:C,70.23;H,4.7;N,4.19
步骤b)7-(2-呋喃基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇
按照实施例50的方法制备标题化合物并得到为浅桃红色固体的产物(64%收率,m.p.283-287℃);MS m/e 294(M+H+)。
对C17H11NO4分析:
理论值:C,69.62;H,3.78;N,4.78
实测值:C,69.11;H,3.6;N,4.64
实施例55
2-(3-氟-4-羟基苯基)-7-(2-呋喃基)-1,3-苯并噁唑-5-醇
步骤a)2-(3-氟-4-甲氧基苯基)-7-(2-呋喃基)-5-甲氧基-1,3-苯并噁唑
按照实施例53步骤a的方法,从7-溴-5-甲氧基-2-(4-甲氧基-3-(三氟甲基)苯基)-1,3-苯并噁唑制备标题化合物,并得到为琥珀色结晶的产物(73%收率,m.p.155℃);MS m/e 340(M+H)+。
对C19H14FNO4分析:
理论值:C,67.25;H,4.16;N,4.13
实测值:C,66.88;H,3.97;N,4.04
步骤b)2-(3-氟-4-羟基苯基)-7-(2-呋喃基)-1,3-苯并噁唑-5-醇
按照实施例50的方法,从2-(3-氟-4-甲氧基苯基)-7-(2-呋喃基)-5-甲氧基-1,3-苯并噁唑制备标题化合物,并得到为灰色固体的产物(81%收率,m.p.245-250℃);MS m/e 312(M+H)+。
对C17H10FNO4×0.7C3H6O分析:
理论值:C,65.04;H,4.37;N,3.79
实测值:C,64.84;H,4.29;N,3.70
实施例56
2-(4-羟基苯基)-7-噻吩-2-基-1,3-苯并噁唑-5-醇
步骤a)5-甲氧基-2-(4-甲氧基苯基)-7-噻吩-2-基)-1,3-苯并噁唑
按照实施例53步骤a的方法,从7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑和2-(三丁基甲锡烷基)噻吩制备标题化合物。得到为白色固体的产物(95%收率),m.p.95-100℃);MS m/e 338(M+H)。
步骤b)2-(4-羟基苯基)-7-噻吩-2-基-1,3-苯并噁唑-5-醇
按照实施例50的方法,从5-甲氧基-2-(4-甲氧基苯基)-7-噻吩-2-基)-1,3-苯并噁唑制备标题化合物,并得到为灰色固体的产物(80%收率,m.p.278-280℃);MS m/e 310(M+H)+。
对C17H11NO3S×0.25H2O分析:
理论值:C,65.06;H,3.69;N,4.46
实测值:C,64.93;H,3.84;N,4.21
实施例57
2-(4-羟基苯基)-7-(1,3-噻唑-2-基)-1,3-苯并噁唑-5-醇
步骤a)5-甲氧基-2-(4-甲氧基苯基)-7-(1,3-噻唑-2-基)-1,3-苯并噁唑。
按照实施例53步骤a的方法,从7-溴-5-甲氧基-2-(4-甲氧基苯基)-1,3-苯并噁唑和2-(三丁基甲锡烷基)噻唑制备标题化合物。得到为灰白色固体的产物(93%收率,m.p.132-136℃);MS m/e 339(M+H)+。
对C18H14N2O3S分析:
理论值:C,63.89;H,4.17;N,8.28
实测值:C,63.53;H,3.94;N,8.15
步骤b)2-(4-羟基苯基)-7-(1,3-噻唑-2-基)-1,3-苯并噁唑-5-醇。
按照实施例50的方法,从5-甲氧基-2-(4-甲氧基苯基)-7-(1,3-噻唑-2-基)-1,3-苯并噁唑制备标题化合物,并得到为黄色固体的产物(55%收率,m.p.245-255℃);MS m/e 311(M+H)+。
对C16H10N2O3S×1.5H2O分析:
理论值:C,56.97;H,3.88;N,8.30
实测值:C,57.24;H,3.95;N,7.50
实施例58
2-(3-氟-4-羟基苯基)-5-羟基-1,3-苯并噁唑-7-腈
按照实施例35的方法,从7-溴-2-(3-氟-4-甲氧基苯基)-5-甲氧基-1,3-苯并噁唑和氰化锌制备标题化合物。得到为白色固体的产物,m.p.308-310℃,MS m/e 269(M-H)+。
对C14H7FN2O3×1.5H2O分析:
理论值:C,61.01;H,2.77;N,10.16
实测值:C,60.68;H,2.46;N,9.77
实施例59和60
4-溴-2-(4-羟基苯基)-7-甲氧基-1,3-苯并噁唑-5-醇(实施例59)
4,6-二溴-2-(4-羟基苯基)-7-甲氧基-1,3-苯并噁唑-5-醇(实施例60)
按照实施例28的方法,从2-(4-羟基苯基)-7-甲氧基-1,3-苯并噁唑-5-醇和N-溴代琥珀酰亚胺制备标题化合物。得到为白色固体的产物(a),m.p.246-248℃,MS m/e 336(M+H)+。
对C14H10BrNO4×.1H2O分析:
理论值:C,49.49;H,3.08;N,4.12
实测值:C,49.28;H,2.89;N,3.87
得到为白色固体的产物(b),m.p.260-262℃,MS m/e 414(M+H)+。
对C14H9Br2NO4分析:
理论值:C,40.52;H,2.19;N,3.37
实测值:C,40.21;H,2.00;N,3.3
实施例61
7-溴-2-(3,5-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇
以与在实施例21中描述的基本相同的方法,从3,5-二氟-4-甲氧基苯甲酸和2-氨基-6-溴-4-甲氧基苯酚制备标题化合物,并得到为白色固体的产物,m.p.270-272℃;MS m/e 340(M-H)+。
对C13H6BrF2NO3分析:
理论值:C,45.64;H,1.77;N,4.09
实测值:C,45.81;H,1.73;N,3.89
实施例62
2-(3,5-二氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇
以与在实施例24途径b中描述的基本相同的方法,从7-溴-2-(3,5-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇制备标题化合物,并得到为白色固体的产物,m.p.160-262℃;MS m/e 288(M-H)+。
对C15H9F2NO3×0.1H2O分析:
理论值:C,61.52;H,3.23;N,4.78
实测值:C,61.53;H,3.10;N,4.72
实施例63
7-溴-2-(4-羟基-2-甲基苯基)-1,3-苯并噁唑-5-醇
以与在实施例21中描述的基本相同的方法,从4-甲氧基-2-甲基苯甲酸和2-氨基-6-溴-4-甲氧基苯酚制备标题化合物,并得到为浅紫色固体的产物,m.p.120-135℃;MS m/e 320(M+H)+。
对C14H10BrNO3分析:
理论值:C,52.52;H,3.15;N,4.38
实测值:C,52.24;H,2.97;N,4.15
实施例64
2-(3-氟-4-羟基苯基)-7-(1-氟乙烯基)-1,3-苯并噁唑-5-醇
将氟化氢吡啶(1.14mL)滴加入到2-[4-(乙酰氧基)-3-氟苯基]-7-乙烯基-1,3-苯并噁唑-5-基乙酸酯(0.25g,0.7mmol)在环丁砜(3mL)中的冷的(0℃)溶液中。将反应混合物搅拌5分钟,然后一批加入1,3-二溴-5,5-二甲基咪唑烷-2,4-二酮(120mg)。将混合物在室温下搅拌24小时,用HCl(1N)稀释并用EtOAc提取。经MgSO4干燥有机层。蒸发并经快速层析法(CH2Cl2/异丙醇0.3%)纯化,得到为白色固体的7-(2-溴-1-氟乙基)-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇(0.25g,m.p.185-186℃)。用乙腈(2mL)吸收该产物并加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(150mg)。将所述反应混合物搅拌24小时,倾入到冷的(0℃)HCl(1N,10mL)中并用EtOAc提取。经MgSO4干燥有机提取液。蒸发并经快速层析法(20%EtOAc/己烷)纯化,得到白色固体(160mg,m.p.213-214℃);MS m/e 290(M+H)+。
对C15H9BrF2NO3×0.3H2O分析:
理论值:C,61.15;H,3.28;N,4.75
实测值:C,60.84;H,3.41;N,4.57
Claims (20)
2.权利要求1的化合物,其中R1为2-3个碳原子的链烯基,它由卤素任选取代。
3.权利要求1的化合物,其为2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
4.权利要求1的化合物,其为2-(2-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
5.权利要求1的化合物,其为2-(2,3-二氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
6.权利要求1的化合物,其为4-溴-2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
7.权利要求1的化合物,其为4,6-二溴-2-(3-氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
8.权利要求1的化合物,其为7-(1-溴代乙烯基)-2-(2-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
9.权利要求1的化合物,其为7-(1-溴代乙烯基)-2-(2,3-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
10.权利要求1的化合物,其为7-烯丙基-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
11.权利要求1的化合物,其为2-(3,5-二氟-4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
12.权利要求1的化合物,其为2-(3-氟-4-羟基苯基)-7-(1-氟乙烯基)-1,3-苯并噁唑-5-醇或其药学上可接受的盐。
13.一种化合物,它为
a)2-(5-羟基-1,3-苯并噁唑-2-基)苯-1,4-二醇;
b)3-(5-羟基-1,3-苯并噁唑-2-基)苯-1,2-二醇;
c)2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇;
d)2-(3-氯-4-羟基苯基)-1,3-苯并噁唑-5-醇;
e)2-(2-氯-4-羟基苯基)-1,3-苯并噁唑-5-醇;
f) 2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-6-醇;
g)2-(3-叔丁基-4-羟基苯基)-1,3-苯并噁唑-6-醇;
h)2-(6-羟基-1,3-苯并噁唑-2-基)苯-1,4-二醇;
i)3-(6-羟基-1,3-苯并噁唑-2-基)苯-1,2-二醇;
j)4-(6-羟基-1,3-苯并噁唑-2-基)苯-1,2-二醇;
k)2-(3-氯-4-羟基苯基)-1,3-苯并噁唑-6-醇;
l)4-(5-羟基-1,3-苯并噁唑-2-基)苯-1,3-二醇;
m)4-(6-羟基-1,3-苯并噁唑-2-基)苯-1,3-二醇;
n)6-氯-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇;
o)6-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇;
p)6-氯-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
q)5-氯-2-(4-羟基苯基)-1,3-苯并噁唑-6-醇;
r)7-溴-2-(3-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇;
s)7-溴-2-(2-氟-4-羟基苯基)-1,3-苯并噁唑-5-醇;
t)7-溴-2-(2,3-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇;
u)2-(4-羟基苯基)-7-乙烯基-1,3-苯并噁唑-5-醇;
v)7-(1,2-二溴乙基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
w)7-(1-溴代乙烯基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
x)7-乙炔基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
y)2-(4-羟基苯基)-7-丙基-1,3-苯并噁唑-5-醇;
z)7-丁基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
aa)7-环戊基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
bb)5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-甲酸乙酯;
cc)2-(4-羟基苯基)-7-苯基-1,3-苯并噁唑-5-醇;
dd)2-(4-羟基苯基)-7-甲氧基-1,3-苯并噁唑-5-醇;
ee)7-乙基-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
ff)7-乙基-2-(2-乙基-4-羟基苯基)-1,3-苯并噁唑-5-醇;
gg)5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-甲醛;
hh)7-(羟基甲基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
ii)7-(溴代甲基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
jj)[5-羟基-2-(4-羟基苯基)-1,3-苯并噁唑-7-基]乙腈;
kk)7-(1-羟基-1-甲基乙基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇];
ll)2-(4-羟基苯基)-7-异丙烯基-1,3-苯并噁唑-5-醇;
mm)2-(4-羟基苯基)-7-异丙基-1,3-苯并噁唑-5-醇];
nn)7-溴-2-(4-羟基-3-(三氟甲基)苯基)-1,3-苯并噁唑-5-醇;
oo)7-(2-呋喃基)-2-(4-羟基苯基)-1,3-苯并噁唑-5-醇;
pp)2-(3-氟-4-羟基苯基)-7-(2-呋喃基)-1,3-苯并噁唑-5-醇;
qq)2-(4-羟基苯基)-7-噻吩-2-基-1,3-苯并噁唑-5-醇;
rr)2-(4-羟基苯基)-7-(1,3-噻唑-2-基)-1,3-苯并噁唑-5-醇;
ss)2-(3-氟-4-羟基苯基)-5-羟基-1,3-苯并噁唑-7-腈;
tt)4-溴-2-(4-羟基苯基)-7-甲氧基-1,3-苯并噁唑-5-醇;
uu)4,6-二溴-2-(4-羟基苯基)-7-甲氧基-1,3-苯并噁唑-5-醇;
vv)7-溴-2-(3,5-二氟-4-羟基苯基)-1,3-苯并噁唑-5-醇;
或它们的学上可接受的盐。
14.权利要求1-13中任何一项要求的化合物在制备用于在需要的哺乳动物中治疗或抑制与雌激素缺乏或者雌激素过量有关的病症、障碍或疾病的药物中的用途。
15.权利要求1-13中任何一项要求的化合物在制备用于在需要的哺乳动物中治疗或抑制炎性肠道疾病、克郎氏病、溃疡性直肠炎或结肠炎的药物中的用途。
16.权利要求14的用途,其中所述病症、障碍或疾病是阴道或阴门萎缩、萎缩性阴道炎、阴道干燥、瘙痒、交媾困难、排尿困难、频繁排尿、尿失禁、尿道感染。
17.权利要求1-13中任何一项要求的化合物在制备用于在需要的哺乳动物中治疗或抑制血管舒缩症的药物中的用途。
18.权利要求1-13中任何一项要求的化合物在制备用于在需要的哺乳动物中治疗或抑制子宫内膜异位的药物中的用途。
19.一种药用组合物,其包含作为唯一非活性成分的如在权利要求1-13中任何一项要求的化合物和药用载体。
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