CN101052641A - 6H-[1]苯并吡喃并[4,3-b]喹啉及其作为雌激素药物的用途 - Google Patents
6H-[1]苯并吡喃并[4,3-b]喹啉及其作为雌激素药物的用途 Download PDFInfo
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- CN101052641A CN101052641A CNA2005800379553A CN200580037955A CN101052641A CN 101052641 A CN101052641 A CN 101052641A CN A2005800379553 A CNA2005800379553 A CN A2005800379553A CN 200580037955 A CN200580037955 A CN 200580037955A CN 101052641 A CN101052641 A CN 101052641A
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- alkyl
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Abstract
本发明提供了具有式I结构的6H-[1]苯并吡喃并[4,3-b]喹啉化合物。本发明还提供了包含所述化合物的组合物、使用所述化合物的方法以及所述化合物的制备方法。
Description
发明领域
本发明涉及6H-[1]苯并吡喃并[4,3-b]喹啉化合物,它们作为雌激素药物的用途以及它们的制备方法。
发明背景
雌激素在哺乳动物组织中的多效性作用已被很好地证明,现在了解到雌激素可影响许多器官系统(参见Mendelsohn and Karas,NewEngland Journal of Medicine 340:1801-1811(1999),Epperson,et al.,Psychosomatic Medicine 61:676-697(1999),Crandall,Journal ofWomens Health & Gender Based Medicine 8:1155-1166(1999),Monkand Brodaty,Dementia & Geriatric Cognitive Disorders 11:1-10(2000),Hurn and Macrae,Journal of Cerebral Blood Flow & Metabolism20:631-652(2000),Calvin,Maturitas 34:195-210(2000),Finking,etal.,Zeitschrift fur Kardiologie 89:442-453(2000),Brincat,Maturitas35:107-117(2000),Al-Azzawi,Postgraduate Medical Journal 77:292-304(2001))。雌激素可以几种方式对组织发挥作用,最具特征性的作用机制为其与雌激素受体相互作用导致基因转录的改变。雌激素受体为配体活化的转录因子,属于细胞核激素受体超家族。该家族中的其它成员包括黄体酮、雄激素、糖皮质激素和盐皮质激素受体。在与配体结合后,这些受体发生二聚化,并可通过直接与DNA上的特定序列(称为反应元件)结合或通过与其它转录因子(如AP1)相互作用再直接与特定的DNA序列结合来活化基因转录(参见Moggsand Orphanides,EMBO Reports 2:775-781(2001),Hall,et al.,Journalof Biological Chemistry 276:36869-36872(2001),McDonnell,Principles of Molecular Regulation 351-361(2000))。“辅调节”蛋白类也可与配体结合受体相互作用,进一步调节其转录活性(参见McKenna,et al.,Endocrine Reviews 20:321-344(1999))。据显示,雌激素受体还可以配体依赖型和非依赖型方式抑制NFκB-介导的转录(参见Quaedackers,et al.,Endocrinology 142:1156-1166(2001),Bhat,et al.,Journal of Steroid Biochemistry & Molecular Biology 67:233-240(1998),Pelzer,et al.,Biochemical & Biophysical ResearchCommunications 286:1153-7(2001))。
雌激素受体还可被磷酸化作用活化。磷酸化作用由生长因子如EGF介导,在没有配体存在时引起基因转录变化(参见Moggs andOrphanides,EMBO Reports 2:775-781(2001),Hall,et al.,Journal ofBiological Chemistry 276:36869-36872(2001))。
一种不太具特征性的雌激素影响细胞的方式为通过所谓的膜受体。这种受体的存在是有争论的,但已很好地证明雌激素可从细胞中引起非常快速的非基因组应答(non-genomic responses)。负责转导这些作用的细胞实体尚未被确定分离,但是有证据显示其至少与雌激素受体的细胞核形式相关(参见Levin,Journal of Applied Physiology91:1860-1867(2001),Levin,Trends in Endocrinology & Metabolism10:374-377(1999))。
目前已发现两种雌激素受体。第一种雌激素受体约于15年前被克隆,现在被称为ERα(参见Green,et al.,Nature 320:134-9(1986))。第二种雌激素受体是最近才发现的,被称作ERβ(参见Kuiper,et al.,Proceedings of the National Academy of Sciences of theUnited States of America 93:5925-5930(1996))。早先对ERβ的研究集中在定义其对许多种配体的亲和力方面,的确发现与ERα的一些不同之处。已经在啮鼠动物中清楚绘制了ERβ的组织分布图,其与ERα的并不一致。组织如小鼠和大鼠的子宫主要表达ERα,而其它组织如小鼠和大鼠的肺主要表达ERβ(参见Couse,et al.,Endocrinology 138:4613-4621(1997),Kuiper,et al.,Endocrinology138:863-870(1997))。即使在同样的器官中,ERα和ERβ的分布也可被区分。例如,在大鼠卵巢中,ERβ在颗粒细胞中高度表达,ERα则限于在鞘和基质细胞中表达(参见Sar and Welsch,Endocrinology 140:963-971(1999),Fitzpatrick,et al.,Endocrinology140:2581-2591(1999))。但是,有两种受体共表达的例子,在体外研究中有证据表明ERα和ERβ可形成异二聚体(参见Cowley,et al.,Journal of Biological Chemistry 272:19858-19862(1997))。
已描述过许多可拟或阻滞17β-雌二醇活性的化合物。与17β-雌二醇,即最有效的内源性雌激素,具有大致相同的生物效应的化合物被称为“雌激素受体激动剂”。那些与17β-雌二醇联用时阻滞其功效的化合物被叫做“雌激素受体拮抗剂”。实际上,在雌激素受体激动剂和雌激素受体拮抗剂活性之间具有连续区(continuum),的确,一些化合物在一些组织中表现为雌激素受体激动剂,而在另一些组织中则表现为雌激素受体拮抗剂。这些具有混合活性的化合物被称为选择性雌激素受体调节剂(SERMS),为治疗上有用的药物(如EVISTA)(参见McDonnell,Journal of the Society for GynecologicInvestigation 7:S10-S15(2000),Goldstein,et al.,Human ReproductionUpdate 6:212-224(2000))。同样的化合物可具有细胞特异性作用的确切原因尚未被阐明,但是可能与受体构象和/或辅调节蛋白的环境的差别有关。
大家已经知道当与配体结合时,雌激素受体采用不同的构象。但是,这些变化的结果和微妙之处最近才被揭示。ERα和ERβ的三维结构已通过与各种配体共结晶得以解析,其清楚地显示出在雌激素受体拮抗剂存在下螺旋12的复位,其在空间上阻碍受体-辅调节蛋白相互作用所需的蛋白序列(参见Pike,et al.,Embo 18:4608-4618(1999),Shiau,et al.,Cell 95:927-937(1998))。此外,已用噬菌体展示技术来鉴别在不同配体存在下与雌激素受体相互作用的肽(参见Paige,et al.,Proceedings of the National Academy of Sciences of theUnited States of America 96:3999-4004(1999))。例如,鉴定了一种肽,该肽在ERα与全雌激素受体激动剂和与二乙基己烯雌酚的结合之间有所不同。不同的肽在氯米酚与ERα和ERβ的结合之间也显示出不同。这些资料表明每个配体都可能使受体处于可能具有不同生物活性的独特的和不可预知的构象。
如上所述,雌激素会影响一整套(panoply)生物学过程。此外,当描述性别差异(如发病频率、对刺激的应答等)时,其解释有可能涉及男性和女性之间雌激素水平的差异。知道了这些化合物的重要性,就了解了对新型雌激素药物的需要。本发明涉及这些以及其它重要的目标。
发明简述
本发明提供了可用作雌激素药物的6H-[1]苯并吡喃并[4,3-b]喹啉化合物。在某些实施方案中,所述化合物具有式I结构:
其中:
A和A′各自独立为OH、H或OR;
每个R独立选自C1-C6烷基、烯基、苄基、酰基、芳酰基、-C(=O)-OR′、磺酰基和磷酰基,其中每个R′独立选自C1-C6烷基、C2-C7烯基、C2-C7炔基或C3-C10环烷基,各自任选被1-3个选自C1-C6烷基或卤素的取代基取代;
R1和R2独立选自H、卤素、C1-C6烷基、C1-C6全卤代烷基、CF3、C2-C7烯基和C1-C6烷氧基;
R3、R4、R5和R6各自独立选自H、卤素、CF3、C1-C6全卤代烷基、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、CN、-CHO、酰基、苯基、芳基和杂芳基;
其中R3、R4、R5和R6的烷基或烯基部分各自可任选被最多3个独立选自下述基团的取代基取代:卤素、OH、CN、三氟烷基、三氟烷氧基、NO2或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的炔基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、-CHO、酰基、三氟烷基、三烷基甲硅烷基或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的苯基、芳基或杂芳基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、烷基、烷氧基、全氟烷基或全氟烷氧基;
每个R10独立选自卤素、C1-C6烷基、C2-C7烯基、-OH、C1-C6烷氧基、-CN、-CHO、-NO2、氨基、C1-C6烷基氨基、二-(C1-C6)烷基氨基、巯基(thiol)和C1-C6烷硫基;和
n为0、1、2或3;
条件是:
A和A′中至少一个不为H;
如果n为0,则R3不为卤素;和
R3、R4和R5中至少一个为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、-CN、-CHO、酰基、苯基、芳基或杂芳基;
或其N-氧化物或其药学可接受盐或其前药。
本发明化合物为雌激素受体调节剂,可用于治疗或抑制至少部分由雌激素缺乏或过量而介导的或可通过使用雌激素药物而被治疗或抑制的症状、病症或疾病状态。因此,在一些方面,本发明涉及本发明化合物在治疗或预防如骨质疏松症、炎性肠病、Crohn′s病、溃疡性直肠炎、结肠炎、雌激素依赖性癌症、高胆固醇血症、高脂血症、心血管疾病、动脉粥样硬化、老年性痴呆、Alzheimer′s病、焦虑症、神经退化性疾病、不育症或关节炎的疾病中的用途。
发明详述
本发明提供了6H-[1]苯并吡喃并[4,3-b]喹啉化合物,包含所述化合物的组合物和所述化合物作为雌激素药物的用途。本发明化合物可有效治疗和预防预雌激素受体特别是ERβ相关的疾病。在一些实施方案中,本发明的雌激素化合物具有下面的式I结构:
其中:
A和A′各自独立为OH、H或OR;
每个R独立选自C1-C6烷基、烯基、苄基、酰基、芳酰基、-C(=O)-OR′、磺酰基和磷酰基,其中每个R′独立选自C1-6烷基、C2-C7烯基、C2-C7炔基或C3-C10环烷基、各自任选被1-3个选自C1-C6烷基或卤素的取代基取代;
R1和R2独立选自H、卤素、C1-C6烷基、C1-C6全卤代烷基、CF3、C2-C7烯基和C1-C6烷氧基;
R3、R4、R5和R6各自独立选自H、卤素、CF3、C1-C6全卤代烷基、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、CN、-CHO、酰基、苯基、芳基和杂芳基;
其中R3、R4、R5和R6的烷基或烯基部分各自可任选被最多3个独立选自下述基团的取代基取代:卤素、OH、CN、三氟烷基、三氟烷氧基、NO2或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的炔基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、-CHO、酰基、三氟烷基、三烷基甲硅烷基或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的苯基、芳基或杂芳基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、烷基、烷氧基、全氟烷基或全氟烷氧基;
每个R10独立选自卤素、C1-C6烷基、C2-C7烯基、-OH、C1-C6烷氧基、-CN、-CHO、-NO2、氨基、C1-C6烷基氨基、二-(C1-C6)烷基氨基、巯基和C1-C6烷硫基;和
n为0、1、2或3;
条件是:
A和A′中至少一个不为H;
如果n为0,则R3不为卤素;和
R3、R4和R5中至少一个为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、-CN、-CHO、酰基、苯基、芳基或杂芳基;
或其N-氧化物或其药学可接受盐或其前药。
在一些实施方案中,A和A′各自为OH。在另一些实施方案中,A和A′之一为OH,A和A′中的另外一个为OR。在另一些实施方案中,A和A′之一为OH,A和A′中的另外一个为O-C1-C6烷基。在另一些实施方案中,A和A′各自为OR。在再另外的实施方案中,A和A′各自为-O-C1-C6烷基。在再另外的实施方案中,A和A′之一为H,A和A′中的另外一个为OH或OR。在另外的实施方案中,A和A′之一为H,A和A′中的另外一个为OH或O-C1-C6烷基。
在一些实施方案中,R3和R5各自独立为H、卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO、酰基或如前所述的任选取代的苯基。在一些这样的实施方案中,R3不为H。
在一些实施方案中,R3为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、-O-C1-C6烷基(即C1-C6烷氧基)、全氟烷基和CN;且R5为H、卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、C1-C6烷氧基、全氟烷基和CN。在一些这样的实施方案中,R3的苯基任选被最多3个选自下述基团的取代基取代:F、Cl、Br、CN、OCH3和CF3。
在一些实施方案中,R3为卤素、C2-C7炔基或-CN。在另一些实施方案中,R3和R5各自独立为卤素、C2-C7炔基或-CN。
在一些实施方案中,R1和R2之一为卤素。在一些优选的实施方案中,R1和R2之一为氟。在另一些实施方案中,R1和R2之一为卤素,R1和R2中的另外一个为H。在另一些实施方案中,R1和R2之一为氟,R1和R2中的另外一个为H。在另一些实施方案中,R1和R2各自独立为卤素。在另一些实施方案中,R1和R2各自为氟。在另一些实施方案中,R1和R2各自为H。
在一些实施方案中,R4为H、卤素或-CN,优选为H。
在一些实施方案中,R3为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、C1-C6烷氧基、全氟烷基和CN;R5为H、卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、C1-C6烷氧基、全氟烷基和CN;且R1和R2之一为卤素;且R4为H、卤素或-CN。
在一些实施方案中,优选其中A和A′各自为OH,R1、R2、R4、R5和R6为氢,且R3为卤素,或R3为OH,或R3为C2-C7烯基,或R3为CN,或R3为C2-C7炔基,或R3为C1-C6烷基,或R3为任选取代的苯基,优选其中所述苯基的取代基为卤素、C1-C6烷氧基、全氟烷基或CN的那些化合物。
在每个上述实施方案的一些实施方案中,n为1。
在一些实施方案中,本发明提供了包含一种或多种本发明化合物或其药学可接受盐、螯合物、络合物或前药的组合物。
应了解,本发明的化合物可以本文提到的结构式描述的游离碱形式或以其盐和/或其水合物形式,特别是以其药学可接受盐形式存在。药学可接受盐为本领域中已知的,水合物也是如此,本领域中熟练技术人员会发现很方便用领域中公认的技术来制备这样的盐。当本发明化合物包含碱性部分时,可从有机和无机酸形成药学可接受盐,如乙酸、丙酸、乳酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、邻苯二甲酸、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酸。当本发明化合物包含酸性部分时,也可从有机和无机碱形成盐,如碱金属盐(如钠、锂或钾)、碱土金属盐、铵盐、包含1-6个碳原子的烷基铵盐或在每个烷基中包含1-6个碳原子的二烷基铵盐,和在每个烷基中包含1-6个碳原子的三烷基铵盐。示例性的盐还包括酸加成盐如HCl、H2SO4、HBr、HI、HNO3、H3PO4、NaH2PO4、Na2HPO4、H3PO3、NaH2PO3、Na2HPO4、H2SO4、NaHSO4,羧酸如乙酸、丙二酸、癸酸、月桂酸、二氯乙酸、三氯乙酸等,以及其它药学可耐受的盐。水合物包括半水合物、一水合物、二水合物等。除非本文另有修改,游离碱结构式的使用包括其盐和/或水合物。
本发明还包括本文公开的化合物的N-氧化物衍生物。这些N-氧化物可由制备类似化合物的方法制备。如,可用过酸、过氧化氢、碱金属过氧化物或烷基过氧化物来氧化所述化合物。有效的N-氧化物衍生物为其中喹啉环上的氮原子形成N-氧化物基团的化合物。
本发明还包括前药衍生物。“前药衍生物”或“前药”是指在体内可转化为相应的本发明化合物的非衍生形式的本发明化合物的衍生物。
除非另有说明,本文所用术语“烷基”,无论是单独使用还是作为其它基团的一部分,是指包括但不限于包含1-12个碳原子优选1-6个碳原子的直链和支链脂肪族烃链。例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等都包含在术语“烷基”中。
在本文的定义中所用的碳原子的数目是指所述部分的碳主链或碳支链,但并不包括所述部分的取代基的碳原子,如烷氧基取代基等。
本文所用术语“烯基”,无论单独使用还是作为其它基团的一部分,是指脂肪族烃链,其包括但不限于具有2-8个碳原子如2-7个碳原子的直链和支链并包含至少一个双键。优选地,烯基部分具有1或2个双键。如乙烯基、烯丙基、1-甲基乙烯基等都包含在术语“烯基”内。这样的烯基部分可以E或Z构象存在,本发明的化合物包含两种构象。
本文所用术语“炔基”,无论单独使用还是作为其它基团的一部分,是指脂肪族烃链,其包括但不限于具有2-8个碳原子如2-7个碳原子的直链和支链并包含至少一个三键。优选地,炔基部分具有1或2个三键。如,乙炔基、丙炔基等都包含在术语“炔基”内。
术语“酰基”是指烷基羰基部分,如其中烷基如本文所定义。术语“苄基”具有其常规意义为苯基甲基。术语“芳酰基”是指通过羰基连接的芳基部分,如苯甲酰基。
提到变量R1、R2 R3、R4、R5、R6、A和A′时本文所描述的烷基、烯基、炔基、芳基、环烷基、杂芳基、芳酰基、酰基和苯基可任选被一个或多个取代基取代,优选被最多3个取代基取代。所述取代基为独立选择的,包括硝基、氰基、卤素、羟基、羧基、烷基、烯基、炔基、环烷基、芳基、杂芳基、烷氧基、芳基氧基、杂芳基氧基、烷基烷氧基、烷氧基烷氧基、全氟烷基、全氟烷氧基、芳基烷基、烷基芳基、羟基烷基、烷氧基烷基、烷硫基、S(O)s-芳基(其中s=0-2)、S(O)s-杂芳基(其中s=0-2)或-C(=O)-OR′,其中R′如前所述。在本发明某些实施方案中,优选的取代基包括卤素、OH、CN、三氟烷基、三氟烷氧基、全氟烷基、全氟烷氧基、芳基烷基、烷基芳基、NO2和苯基,其中所述苯基任选被最多3个独立选择的如前所述的R10基团取代。
例如,当烷基或烯基部分被取代时,它们通常被单-、二-、三-或全取代。卤素取代基的实例包括1-溴乙烯基、1-氟乙烯基、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-氟乙烷、1-氟-2-溴乙烷、CF2CF3、CF2CF2CF3等。
术语“卤素”包括氟、氯、溴和碘。
示例性的环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基等。在一些实施方案中,所述环烷基具有3-10个碳原子。优选的环烷基具有3-7个碳原子。本文所用的环烷基还包括不饱和环烷基,即环烯基。示例性的不饱和环烷基包括环戊烯基、环己烯基、环庚烯基等。
芳基为具有至少一个不包含杂(即非碳)环原子的芳香性环的部分。术语“芳基”包括单-和多环芳香性环系,如包含6-15个碳原子的芳香性环系,如苯基、萘基等。芳基可具有与芳香性环稠合的完全或部分饱和环。因此,示例性的芳基包括苯基、萘基、芘基、5,6,7,8-四氢萘-1-基等。
术语杂芳基是指包含至少一个选自O、N和S的非碳环原子(如1-3个杂原子)且具有如5-14个环原子的芳香环系。示例性的杂芳基包括吡咯基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、喹啉基、喹喔啉基、喹唑啉基、噻吩基(thiophenyl)、呋喃基、唑基、噻唑基、噻吩基(thienyl)、吡喃基、噻喃基、苯并呋喃基、吲哚基、吲唑基、苯并咪唑基、苯并噻唑基、苯并吡喃基、苯并噻喃基、吲唑基、吡啶并吡咯基等。
在一些实施方案中,A或A′的-C(=O)-OR′部分的R′基团为C1-C6烷基。在一些实施方案中,R′为C1-4烷基。在一些实施方案中,该-C(=O)-OR′部分为叔丁氧基羰基(BOC)。
关于提供本发明覆盖的化合物或物质,其中所用术语“提供”是指直接给予这样的化合物或物质或给予可在体内形成有效量的所述化合物或物质的前药、衍生物或类似物。
根据在下面描述的标准药理学试验程序得到的结果,本发明化合物为雌激素受体调节剂,可有效用于治疗或抑制至少部分由雌激素缺乏或过量介导的或可通过使用雌激素药物而被治疗或抑制的症状、病症或疾病状态。本发明化合物可特别有效用于治疗内源性雌激素产生水平大大降低的围绝经期、绝经期或绝经后患者。绝经期通常被定义为最后的自然月经周期,以卵巢功能停止为特征,导致血流中循环雌激素的实质减少。本文所用绝经(期)还包括由外科手术、化疗或导致卵巢功能过早降低或停止的疾病引起的雌激素生成减少的病症。
因此,本发明化合物可有效用于治疗或抑制骨质疏松症和抑制骨脱矿质作用,其可能由个体的新骨组织形成和旧组织再吸收不均衡而导致骨的净流失引起。这样的骨缺失在一定范围的人群中发生,特别是绝经后女性、卵巢双侧切除的女性、正在接受或接受过长期皮质类固醇疗法的患者、性腺发育不全的患者和患Cushing′s综合征的患者。也可用这些化合物满足患有骨折、骨结构缺陷和接受与骨相关的手术和/或假体植入的个体对骨包括牙齿和口腔骨替代的特别需要。除了上述问题外,这些化合物可用于治疗或抑制骨关节炎、脊椎关节病、低钙血症、高钙血症、Paget′s病、骨软化症、骨钙质缺乏、多发性骨髓瘤和对骨组织具有有害作用的其它形式的癌症。
本发明化合物还可有效用于治疗或抑制继关节镜或手术操作而发生的关节损伤。
本发明化合物还可有效用于治疗或抑制良性或恶性异常组织增生包括前列腺肥大、子宫平滑肌瘤、乳腺癌、子宫内膜异位(endometriosis)、子宫内膜癌、多囊性卵巢综合征、子宫内膜息肉、良性乳房疾病、子宫腺肌病(adenomyosis)、卵巢癌、黑素瘤、前列腺癌、结肠癌、CNS癌如神经胶质瘤或成星形细胞瘤(astioblastomia)。
本发明化合物具有心血管保护作用,它们可有效用于降低胆固醇、甘油三酯、Lp(a)脂蛋白和低密度脂蛋白(LDL)水平;抑制或治疗高胆固醇血症;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;并可抑制引起免疫介导的血管损伤的由细胞事件导致的血管壁损伤。这些心血管保护特性,在用雌激素治疗绝经后患者来抑制骨质疏松症时,和对适于用雌激素疗法的男性具有重要的意义。
本发明化合物还是抗氧化剂,因此可有效用于治疗和抑制自由基诱导的疾病状态。其中抗氧化疗法肯定有疗效的特定情况有癌症、中枢神经系统病症、Alzheimer′s病、骨病、衰老、炎性疾病、外周血管疾病、类风湿性关节炎、自身免疫性疾病、呼吸性窘迫、肺气肿、哮喘、胸膜炎、眼葡萄膜炎、脓毒症、出血性休克、预防再灌注损伤(prevention of reperfusion injury)、病毒性肝炎、慢性活动性肝炎、肺结核、银屑病、全身性红斑狼疮、成人呼吸性窘迫综合征、中枢神经系统外伤和中风。
本发明化合物还可有效用于提供认知增强,并用于治疗或抑制老年性痴呆、Alzheimer′s病、认知减退、神经退化性疾病,提供神经保护或认知增强。
本发明化合物还可有效用于治疗或抑制炎性肠病、溃疡性直肠炎、Crohn′s病和结肠炎;绝经相关性病症如血管舒缩症(vasomotorsymptoms)包括热潮红、阴道或外阴萎缩、萎缩性阴道炎、阴道干燥、瘙痒症、性交困难、排尿困难、尿频、尿失禁、泌尿道感染、肌痛、关节痛、失眠、易激症(irritability)等;男性型秃发;皮肤萎缩;痤疮;II型糖尿病;功能障碍性子宫出血;和不育症。
本发明化合物可有效用于其中闭经为有利的疾病状态,如白血病、子宫内膜切除、慢性肾病或肝病或血凝固疾病或病症。
本发明化合物可被用作避孕药,特别是与黄体酮联用时。
当用于治疗或抑制特定的疾病状态或症状时,应了解有效剂量可根据所用的特定化合物、给药方式、所治疗的病症及其严重程度以及与所治疗个体相关的各种物理因素而有所不同。本发明化合物的有效给药口服剂量为约0.1mg/天-1,000mg/天。优选地,给药剂量可为约10mg/天-600mg/天,更优选为约50mg/天-600mg/天,单次剂量或两次或多次分份剂量。计划日剂量根据给药方式可有所不同。
所述剂量可以任何有利于使活性化合物进入受者血流的方式给药,包括口服、经由埋植剂、胃肠外(包括静脉、腹膜内和皮下注射)、直肠、鼻内、阴道和经皮给药。
包含本发明活性化合物的口服制剂可包括任何常规口服形式,包括片剂、胶囊剂、含剂(buccal forms)、含片(troches)、锭剂和口服液体、混悬液和或溶液。胶囊剂可包含活性化合物与惰性填充剂和/或稀释剂如药学可接受淀粉(如玉米、马铃薯或木薯淀粉)、糖、人工甜味剂、粉状纤维素如晶状和微晶纤维素、面粉、明胶、树胶(gums)等。有效的片剂制剂可由常规压片、湿法制粒或干法制粒制备,可使用药学可接受稀释剂、粘合剂、润滑剂、崩解剂、表面修饰剂(surface modifying agents)(包括表面活性剂)、悬浮剂或稳定剂,包括但不限于硬脂酸镁、硬脂酸、滑石粉、月桂基硫酸钠、微晶纤维素、羧甲基纤维素钙、聚乙烯基吡咯烷酮、明胶、海藻酸、金合欢胶、黄原胶、柠檬酸钠、硅酸盐复合物、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、干淀粉和糖粉。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帕洛沙姆188、苯扎氯铵、硬脂酸钙、十六醇十八醇混合物(cetostearlalcohol)、聚乙二醇单鲸蜡基醚乳化蜡(cetomacrogol emulsifyingwax)、山梨坦酯、胶体二氧化硅、磷酸盐(phosphates)、十二烷基硫酸钠、硅酸镁铝和三乙醇胺。本文的口服制剂可使用标准延迟或时间释放制剂(time release formulations)以改变活性化合物的吸收。所述口服制剂还可包括根据需要将活性成分在包含合适的稳定剂或乳化剂的水或果汁中给药。
在一些情况下,可能需要将化合物通过气雾剂形式直接给药至呼吸道。
本发明化合物还可胃肠外给药或腹膜内给药。这些游离碱形式的活性化合物或其药学可接受盐的溶液剂或混悬剂可在适当混有表面活性剂如羟丙基纤维素的水中制备。分散液也可在甘油、液态聚乙二醇及其在油中的混合物中制备。在普通贮存和使用条件下,这些制剂包含防止微生物生长的防腐剂。
适于注射用途的药用形式包括无菌水溶液或分散液和可临时制备为无菌注射液或分散液的无菌粉末。在所有情况下,所述形式都必须为无菌的并必须有使其容易注射的足够的流动性。其在生产和贮存条件下必须是稳定的并必须能防止微生物如细菌和真菌的污染作用。所述载体可为溶剂,或包含如水、乙醇多元醇(如甘油、丙二醇和液态聚乙二醇)、其合适的混合物和植物油的分散介质。
为了本公开的目的,经皮给药被理解为包括所有通过皮肤表面和身体通道内层(inner linings)包括上皮和粘膜组织给药的方式。该给药方式可用本发明化合物、其N-氧化物、其前药或其药学可接受盐以洗液、乳膏、泡沫、贴剂、混悬剂、溶液剂和栓剂(直肠和阴道)形式进行。
经皮给药可通过使用包含活性药物和载体的透皮贴剂来完成,所述载体对活性化合物为惰性的,对皮肤无毒并可使全身吸收的药物通过皮肤进入血流。所述载体可为任何形式,如乳膏和软膏、糊剂、凝胶和封存装置(occlusive devices)。所述乳膏和软膏可为水包油或油包水型粘稠液体或半固体乳液。由可吸收的粉末分散于石油或亲水性石油包含活性成分构成的包含活性成分的糊剂也是合适的。可使用多种封存装置以将所述活性药物释放入血流,如包有包含活性成分与载体或无载体的储库或包含活性成分的基质的半透性膜。其它封存装置为文献中已知的。
可由传统材料来制备栓剂,所述材料包括可可脂、甘油和用来改变栓剂的熔点的可添加或不添加的蜡。也可用水溶性栓剂基质,如各种分子量的聚乙二醇。
本发明化合物的合成
本发明化合物由有机化学领域中已知的方法制备。在本发明化合物的制备中,所用的试剂可购买得到或可由文献中描述的标准方法制备。
在下面的方案1-4中描述了本发明代表性实施例的合成。方案1-4中的合成方法A-M在下面的实施例中描述。
方案1
方案2
方案3
方案4
实施例
本发明代表性化合物的合成:通用方法
Aldrich Sure SealTM溶剂,无水不需进一步纯化,可用于本文描述的反应,可得自Aldrich Chemical Company(St.Louis,MO)。所有的反应在氮气下进行。色谱法采230-400目的硅胶(Merck Grade 60,Aldrich Chemical Company)。薄层色谱用得自EM Science的硅胶60F254进行。1H和19F NMR光谱用Bruker AM-400或Bruker DPX-300仪器(Bruker,Billerica,MA)在氘化溶剂如CDCl3、DMSO-d6或丙酮-d6中进行。化学位移(δ)以距四甲基硅烷(TMS)低场处距离的百万分之一(ppm)表示。熔点在Thomas-Hoover仪器上测定,未经校正。红外(IR)光谱用Perkin-Elmer衍射光栅或Perkin-Elmer 784分光光度计(Perkin-Elmer,Shelton,CT)记录。质谱用Kratos MS 50或Finnigan8230质谱仪记录。化合物命名通常使用Beilstein AutonomTM方案。
实施例1
3-(3-甲氧基-苯氧基)-丙酸(1)
方法A:向3-溴丙酸(14.70g,118mmol)在水(100mL)中的混合物中缓慢加入NaHCO3(8.40g,100mmol),所得混合物搅拌5分钟。向该溶液中加入70-mL3-甲氧基苯酚(14.70g,96mmol)的NaOH(4.67g,119mmol)水溶液,所得混合物在100℃下加热3小时。冷至室温后,将反应混合物用1N HCl酸化,用Et2O萃取。用NaHCO3(3x)水溶液洗涤Et2O层。水层再次用1N HCl酸化,用Et2O萃取。用水、盐水洗涤Et2O层,干燥(Na2SO4),过滤,浓缩,得到棕色固体粗品,将其重结晶(Et2O/-20℃),得到黄色固状纯产物。产量:17.0g(23%)。1H-NMR(300MHz,CDCl3):δ2.85(t,J=6.3Hz,2H),3.79(s,3H),4.24(t,J=6.3Hz,2H),6.50(m,3H),7.18(t,J=8.2Hz,1H),11.45(br,1H);MS(ESI)m/z 195([M-H]-);元素分析计算值:C10H12O4:C:61.22,H:6.16.实测值:C:61.24,H:6.12。
实施例2
7-甲氧基-色原烷-4-酮(2)
方法B:在0℃向包含3-(3-甲氧基-苯氧基)-丙酸(1)(7.00g,35.6mmol)的反应器中缓慢加入三氟甲磺酸(15mL)。将反应混合物搅拌3小时,同时使其升至室温。冷至0℃后,用碎冰猝灭反应混合物,然后用Et2O(2×300mL)萃取。用水(2x)、NaHCO3水溶液、水、盐水洗涤有机层,然后干燥(Na2SO4),过滤,浓缩,得到油状粗品,将其用硅胶色谱法纯化,得到黄色固状纯产物。产量:4.26g(67%).1H-NMR(300MHz,CDCl3):δ2.76(t,J=6.3Hz,2H),3.84(s,3H),4.52(t,J=6.3Hz,2H),6.41(d,J=2.3Hz,1H),6.58(dd,J=8.8,2.3Hz,1H),7.84(d,J=8.8Hz,1H);MS(ESI)m/z 179([M+H]+)。
实施例3
3,9-二甲氧基-6H-色原烯并(CHROMENO)[4,3-b]喹啉-7-醇(3)
方法C:将2-氨基-5-甲氧基苯甲酸(1.839g,11.00mmol)和7-甲氧基-色原烷-4-酮(2)(1.960g,11.00mmol)的在Ph2O(10mL)中的混合物在170℃下加热1小时,在200℃下加热7小时。冷至室温后,加入己烷。过滤收集形成的黄色沉淀物,用己烷和Et2O充分洗涤,真空干燥。产量:2.171g(64%)。mp 298℃(dec.);1H-NMR(300MHz,DMSO-d6)δ3.82(s,3H),3.84(s,3H),5.17(s,2H),6.64(d,J=2.4Hz,1H),6.79(dd,J=8.7,2.4Hz,1H),7.31(dd,J=9.0,2.9Hz,1H),7.50(d,J=2.8Hz,1H),7.74(d,J=9.0Hz,1H),7.99(d,J=8.7Hz,1H),11.56(s,1H);MS(ESI)m/z 308([M-H]-),310([M+H]+);HRMS(ESI+)计算值C18H15NO4310.1074([M+H]+),实测值310.1068。
实施例4
7-氯-3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉(4)
方法C:将3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉-7-醇(3)(124mg,0.400mmol)和POCl3(1mL)的混合物加热回流1小时。冷却后,减压除去过量的POCl3。向固体残留物中缓慢加入水,然后缓慢加入K2CO3水溶液,反应混合物用EtOAc萃取。用盐水洗涤有机层,然后干燥(Na2SO4),过滤,浓缩,得到固体粗品,将其通过硅胶短垫(a short pad of silica gel),重结晶(热庚烷/-20℃),得到黄色粉末状纯产物。产量:124mg(95%);mp 190-191℃;1H-NMR(300MHz,CDCl3)δ3.85(s,3H),3.97(s,3H),5.50(s,2H),6.53(d,J=2.4Hz,1H),6.71(dd,J=8.7,2.4Hz,1H),7.35(dd,J=8.9,2.8Hz,1H),7.38(d,J=3.2Hz,1H),7.98(d,J=8.8Hz,1H),8.29(d,J=8.7Hz,1H);MS(ESI)m/z 328/330([M+H]+);HRMS(ESI+)计算值C18H14ClNO3328.0735([M+H]+),实测值328.0728;元素分析计算值C18H14ClNO3:C:65.96,H:4.31,N:4.27.实测值:C:65.71,H:4.17,N:3.92。
实施例5
7-溴-3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉(5)
方法E.将3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉-7-醇(3)(1.025g,3.31mmol)和POBr3(1.430g,5.00mmol,1.5当量)在DMF(15mL)中的混合物在70℃加热30分钟。冷至室温后,缓慢加入水,然后缓慢加入K2CO3水溶液,反应混合物用温CHCl3(2x)萃取。用水(2x)和盐水洗涤有机层,然后干燥(Na2SO4),通过硅胶短垫过滤,浓缩得到黄色固状粗品,将其重结晶(热EtOAc/-20℃)得到黄色针状纯产物。产量:1.127g(91%);mp 196-197℃;1H-NMR(300MHz,CDCl3)δ3.85(s,3H),3.98(s,3H),5.48(s,2H),6.53(d,J=2.4Hz,1H),6.71(dd,J=8.7,2.5Hz,1H),7.35(dd,J=9.0,2.7Hz,1H),7.39(d,J=2.7Hz,1H),7.97(d,J=9.0Hz,1H),8.30(d,J=8.7Hz,1H);MS(ESI)m/z 372/374([M+H]+);HRMS(ESI+)计算值C18H14BrNO3372.0230([M+H]+),实测值372.0228;元素分析计算值C18H14BrNO3:C:58.08,H:3.79,N:3.76.实测值:C:57.94,H:3.68,N:3.73。
实施例6
7-氯-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(6)
方法F:向7-氯-3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉(4)(68mg,0.21mmol)的1,2-二氯乙烷(3mL)溶液中缓慢加入BBr3(1.0M,1mL,1mmol)的CH2Cl2溶液。将反应混合物在室温下搅拌30分钟,然后在40℃下搅拌2小时。在冰浴中冷却后,在剧烈搅拌下非常缓慢地加入NaHCO3水溶液以猝灭反应,所得反应混合物用EtOAc萃取。用盐水洗涤有机层,然后干燥(Na2SO4),通过硅胶短垫过滤,浓缩得到黄色固体,将其重结晶(THF/己烷)。产量:56mg(90%);mp 235℃(dec.);1H-NMR(300MHz,DMSO-d6)δ5.47(s,2H),6.40(s,1H),6.60(d,J=8.0Hz,1H),7.34(d,J=2.1Hz,2H),7.89(d,J=9.6Hz,1H),8.09(d,J=8.6Hz,1H),10.10(s,1H),10.35(s,1H);HRMS(ESI+)计算值C16H10ClNO3 300.0422([M+H]+),实测值300.0411。
实施例7
7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)
方法G:向7-溴-3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉(5)(881mg,2.37mmol)的1,2-二氯乙烷(20mL)溶液中缓慢加入AlCl3(3.16g,23.7mmol)和EtSH(2.7mL,36mmol),将反应混合物在室温下搅拌3小时。在冰浴中冷却后,在剧烈搅拌下非常缓慢地加入NaHCO3水溶液以猝灭反应,所得反应混合物用EtOAc萃取。通过Celite过滤形成沉淀物。用盐水洗涤有机层,然后干燥(Na2SO4),过滤,浓缩,得到黄色固状粗品,将其用硅胶色谱法纯化得到橙色固状纯产物。产量:478mg(59%);mp 240℃(dec.);1H-NMR(300MHz,DMSO-d6)δ5.44(s,2H),6.41(d,J=2.3Hz,1H),6.59(dd,J=8.6,2.3Hz,1H),7.33(dd,J=8.7,2.6Hz,1H),7.35(s,1H),7.88(d,J=8.7Hz,1H),8.09(d,J=8.6Hz,1H),10.09(s,1H),10.35(s,1H);MS(ESI)m/z 342/344([M-H]-),344/346([M+H]+);HRMS(ESI+)计算值C16H10BrNO3 343.9917([M+H]+),实测值343.9911。
实施例8
3,9-二羟基-7-乙烯基-6H-色原烯并[4,3-b]喹啉(8)
方法H:将7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)(34.5mg,0.100mmol)、三丁基(乙烯基)锡(38mg,0.120mmol,1.2当量)和Pd(PPh3)4(11.6mg,0.0100mmol,10mol%)在甲苯(1.5mL)中的混合物在氮气下回流,直至消耗完所有的起始原料(1-2小时)。通过Celite过滤,并通过硅胶短垫纯化,得到橙色粉末状纯产物。产量:24mg(83%);mp 160℃(dec.);1H-NMR(400MHz,DMSO-d6)δ5.36(s,2H),5.47(dd,J=17.9,1.4Hz,1H),5.91(dd,J=11.6,1.4Hz,1H),6.38(d,J=2.3Hz,1H),6.58(dd,J=8.5,2.3Hz,1H),7.10(dd,J=17.7,11.6Hz,1H),7.22(d,J=2.5Hz,1H),7.26(dd,J=9.1,2.6Hz,1H),7.84(d,J=8.9Hz,1H),8.10(d,J=8.5Hz,1H),9.94(s,1H),9.95(s,1H);MS(ESI)m/z 290([M-H]-),292([M+H]+);HRMS(ESI+)计算值C18H13NO3 292.0968([M+H]+),实测值292.0962。
实施例9
3,9-二羟基-7-[(三甲基甲硅烷基)乙炔基]-6H-色原烯并[4,3-b]喹啉(9)
方法I:将7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)(51.6mg,0.150mmol)、(三甲基甲硅烷基乙炔基)三丁基锡(70mg,0.180mmol,1.2当量)和Pd(PPh3)4(17mg,0.015mmol,10mol%)在甲苯(2mL)中的混合物在氮气下回流,直至消耗完所有的起始原料(1-2小时)。通过Celite过滤,并通过硅胶短垫纯化,得到红色固状纯产物。产量:54mg(99.6%);mp 160℃(dec.);1H-NMR(300MHz,acetone-d6)δ0.43(s,9H),5.53(s,2H),6.52(d,J=2.3Hz,1H),6.71(dd,J=8.6,2.3Hz,1H),7.42(dd,J=9.1,2.7Hz,1H),7.61(d,J=2.7Hz,1H),7.97(d,J=9.0Hz,1H),8.26(d,J=8.6Hz,1H),8.94(s,1H),9.16(s,1H);MS(ESI)m/z 360([M-H]-),362([M+H]+);HRMS(ESI+)计算值C21H19NO3Si 362.1207([M+H]+),实测值362.1207。
实施例10
3,9-二羟基-7-乙炔基-6H-色原烯并[4,3-b]喹啉(10)
方法J:向3,9-二羟基-7-[(三甲基甲硅烷基)乙炔基]-6H-色原烯并[4,3-b]喹啉(9)(54mg,0.15mmol)的MeOH(2mL)溶液中加入K2CO3(104mg,0.75mmol,5当量),将反应混合物搅拌30分钟。用NH4Cl(5mL)水溶液猝灭反应混合物。减压除去甲醇(MeOH),用EtOAc萃取反应混合物。用水和盐水洗涤有机层,然后干燥(Na2SO4),过滤,浓缩,得到黄色固状粗品,将其通过硅胶短垫纯化,得到酒红色(burgundy)粉末纯产物。产量:27mg(63%);mp220℃(dec.);1H-NMR(300MHz,DMSO-d6)δ5.27(s,1H),5.46(s,2H),6.41(d,J=2.1Hz,1H),6.59(dd,J=8.5,2.1Hz,1H),7.31(dd,J=9.1,2.6Hz,1H),7.41(d,J=2.5Hz,1H),7.87(d,J=9.0Hz,1H),8.09(d,J=8.5Hz,1H),10.04(s,1H),10.23(s,1H);MS(ESI)m/z 288([M-H]-),290([M+H]+);HRMS(ESI+)计算值C18H11NO3 290.0812([M+H]+),实测值290.0808。
实施例11
3,9-二羟基-7-乙基-6H-色原烯并[4,3-b]喹啉(11)
方法K:将3,9-二羟基-7-乙炔基-6H-色原烯并[4,3-b]喹啉(10)(13mg,0.045mmol)和Pd/C(10wt.%)在EtOAc/THF(1.5mL)中的混合物在氢气(1atm,气球)下搅拌30分钟。通过Celite过滤反应混合物,浓缩,得到黄色固体,将其重结晶(EtOAc/己烷/-20℃)。产量:13mg(98%)。mp 145℃(dec.);1H-NMR(300MHz,DMSO-d6)δ1.18(t,J=7.4Hz,3H),2.95(q,J=7.6Hz,2H),5.41(s,2H),6.38(d,J=2.2Hz,1H),6.56(dd,J=8.5,2.3Hz,1H),7.24(dd,J=8.3,2.4Hz,1H),7.26(s,1H),7.82(d,J=9.0Hz,1H),8.09(d,J=8.5Hz,1H),9.90(s,1H),9.93(s,1H);MS(ESI)m/z 292([M-H]-),294([M+H]+);HRMS(ESI+)计算值C18H15NO3 294.1125([M+H]+),实测值294.1123。
实施例12
7-氰基-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(12)
方法L:将7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)(47mg,0.14mmol)、CuCN(370mg,4.13mmol)在无水DMF(2mL)中的混合物在密封管中在200℃下加热,直至消耗完所有的起始原料(5小时)。冷至室温后,通过Celite过滤反应混合物,用EtOAc冲洗。向滤液中加入水,用EtOAc萃取反应混合物。用水(2x)和盐水洗涤有机层,然后干燥(Na2SO4),过滤,浓缩,得到固体粗品,将其用硅胶色谱法纯化得到棕色粉末状纯产物。产量:9mg(23%);1H-NMR(300MHz,DMSO-d6)δ5.52(s,2H),6.44(d,J=2.1Hz,1H),6.63(dd,J=8.6,2.1Hz,1H),7.27(d,J=2.4Hz,1H),7.41(dd,J=9.1,2.5Hz,1H),7.98(d,J=9.1Hz,1H),8.09(d,J=8.6Hz,1H),10.19(s,1H),10.63(s,1H);MS(ESI)m/z 289([M-H]-),291([M+H]+);HRMS(ESI+)计算值C17H10N2O3 291.0764([M+H]+),实测值291.0758。
实施例13
7-(4-氯苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(13)
方法M:将7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)(40mg,0.12mmol)和Pd(PPh3)4(7mg,0.006mmol,5mol%)在DME(3mL)中的混合物在室温下搅拌10分钟。向该混合物中依次加入4-氯苯基硼酸(boronic acid)(22mg,0.14mmol,1.2当量)和Na2CO3水溶液(2Msoln,5当量),使反应混合物回流,直至消耗完所有的起始原料(2-3小时)。冷却后,加入NH4Cl水溶液,用EtOAc萃取反应混合物。用水和盐水洗涤有机层,然后干燥(Na2SO4),过滤,浓缩,得到固体粗品,将其通过硅胶短垫纯化,得到红色粉末状纯产物。产量:41mg(94%);mp 215-218℃(dec.);1H-NMR(400MHz,DMSO-d6)δ5.01(s,2H),6.36(d,J=2.2Hz,1H),6.60(dd,J=8.7,2.2Hz,1H),6.62(d,J=2.5Hz,1H),7.26(dd,J=9.1,2.6Hz,1H),7.41(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),7.90(d,J=9.0Hz,1H),8.15(d,J=8.4Hz,1H),9.82(s,1H),9.98(s,1H);MS(ESI)m/z 374/376([M-H]-),376/378([M+H]+);HRMS(ESI+)计算值C22H14ClNO3 376.0735([M+H]+),实测值376.0728。
实施例14
7-(4-氰基苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(14)
该化合物按照方法M采用4-氰基苯基硼酸从7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)制备。象牙色粉末;产率:96%;mp295℃(dec.);1H-NMR(400MHz,DMSO-d6)δ4.99(s,2H),6.36(d,J=2.3Hz,1H),6.53(d,J=2.7Hz,1H),6.61(dd,J=8.7,2.3Hz,1H),7.27(dd,J=9.1,2.6Hz,1H),7.62(d,J=8.5Hz,2H),7.91(d,J=9.0Hz,2H),8.09(d,J=8.3Hz,1H),8.16(d,J=8.6Hz,1H),9.86(s,1H),9.99(s,1H);MS(ESI)m/z 365([M-H]-),367([M+H]+);HRMS(ESI+)计算值C23H14N2O3 367.1077([M+H]+),实测值367.1074。
实施例15
3,9-二羟基-7-(4-甲氧基苯基)-6H-色原烯并[4,3-b]喹啉(15)
该化合物按照方法M采用4-甲氧基苯基硼酸从7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)制备。黄色粉末;产率:84%;mp 195℃(dec.);1H-NMR(400MHz,DMSO-d6)δ3.87(s,3H),5.03(s,2H),6.36(d,J=2.2Hz,1H),6.60(dd,J=8.5,2.5Hz,1H),6.73(d,J=2.6Hz,1H),7.16(d,J=8.6Hz,2H),7.24(dd,J=9.0,2.6Hz,1H),7.30(d,J=8.6Hz,2H),7.89(d,J=9.0Hz,1H),8.15(d,J=8.6Hz,1H),9.80(s,1H),9.98(s,1H);MS(ESI)m/z 370([M-H]-),372([M+H]+);HRMS(ESI+)计算值C23H17NO4 372.1230([M+H]+),实测值372.1226。
实施例16
3,9-二羟基-7-[4-(三氟甲基)苯基]-6H-色原烯并[4,3-b]喹啉(16)
该化合物按照方法M采用4-三氟甲基苯基硼酸从7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)制备。黄色粉末;产率:95%;mp175-177℃(dec.);1H-NMR(400MHz,DMSO-d6)δ5.00(s,2H),6.36(d,J=2.3Hz,1H),6.56(d,J=2.6Hz,1H),6.61(dd,J=8.6,2.2Hz,1H),7.26(dd,J=9.1,2.6Hz,1H),7.64(d,J=7.9Hz,2H),7.92(d,J=9.0Hz,1H),7.98(d,J=8.1Hz,2H),8.16(d,J=8.6Hz,1H),9.84(s,1H),10.00(s,1H);19F-NMR(400MHz,DMSO-d6)δ-61.43(s);MS(ESI)m/z 408([M-H]-),410([M+H]+);HRMS(ESI+)计算值C23H14F3NO3 410.0999([M+H]+),实测值410.0992。
实施例17
7-(3-氯苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(17)
该化合物按照方法M采用3-氯苯基硼酸从7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)制备。橙色粉末;产率:94%;mp 162-165℃(dec.);1H-NMR(400MHz,DMSO-d6)δ5.01(s,2H),6.36(d,J=2.3Hz,1H),6.60(dd,J=8.5,2.2Hz,1H),6.61(d,J=2.6Hz,1H),7.26(dd,J=9.1,2.6Hz,1H),7.35(m,1H),7.50(d,J=1.0Hz,1H),7.64(dd,J=3.9,1.6,Hz,2H),7.90(d,J=9.1Hz,1H),8.15(d,J=8.8Hz,1H),9.86(s,1H),9.98(s,1H);MS(ESI)m/z 374/376([M-H]-),376/378([M+H]+);HRMS(ESI+)计算值C22H14ClNO3 376.0735([M+H]+),实测值376.0721。
实施例18
3,9-二羟基-7-(3-甲氧基苯基)-6H-色原烯并[4,3-b]喹啉(18)
该化合物按照方法M采用3-甲氧基苯基硼酸从7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)制备。黄色粉末;产率:87%;mp 155-158℃(dec.);1H-NMR(400MHz,DMSO-d6)δ3.82(s,3H),4.99(d,J=14.2Hz,1H),5.04(d,J=14.2Hz,1H),6.35(d,J=2.3Hz,1H),6.60(dd,J=8.6,2.3Hz,1H),6.71(d,J=2.7Hz,1H),6.90(m,1H),6.92(d,J=1.6Hz,1H),7.12(m,1H),7.24(dd,J=9.1,2.7Hz,1H),7.52(dd,J=8.2,7.9Hz,1H),7.89(d,J=9.1Hz,1H),8.15(d,J=8.6Hz,1H),9.80(s,1H),9.96(s,1H);MS(ESI)m/z 370([M-H]-),372([M+H]+);HRMS(ESI+)计算值C23H17NO4 372.1230([M+H]+),实测值372.1223。
实施例19
7-(3-氰基苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(19)
该化合物按照方法M采用3-氰基苯基硼酸从7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉(7)制备。黄色粉末;产率:74%;mp 275℃(dec.);1H-NMR(400MHz,DMSO-d6)δ4.98(d,J=14.2Hz,1H),5.03(d,J=14.2Hz,1H),6.36(d,J=2.3Hz,1H),6.54(d,J=2.6Hz,1H),6.61(dd,J=8.6,2.3Hz,1H),7.27(dd,J=9.1,2.6Hz,1H),7.74(dt,J=7.8,1.4Hz,1H),7.82(t,J=7.7Hz,1H),7.92(d,J=9.1Hz,1H),7.94(d,J=1.6Hz,1H),8.05(dt,J=7.7,1.4Hz,1H),8.16(d,J=8.6Hz,1H),9.87(s,1H),10.00(s,1H);MS(ESI)m/z 365([M-H]-),367([M+H]+);HRMS(ESI+)计算值C23H14N2O3 367.1066([M+H]+),实测值367.1083。
药理学实验方法
雌激素活性的证明
评价了本发明的代表性实例与17β-雌二醇对ERα和ERβ竞争的能力。所用试验方法使人们可确定特定的化合物是否与雌激素受体结合(因此为“雌激素的”),是否对ERα或ERβ具有选择性。下面的表1中显示了代表性化合物实施例的结果,以IC50值表示。IC50被定义为降低总17β-雌二醇结合50%的化合物浓度。简要地描述了所用方法。制备表达人ERα或ERβ雌激素受体配体结合域(D、E和F)的大肠杆菌(E.coli)粗溶胞产物。将两种受体和化合物在加有1mM乙二胺四乙酸(EDTA)的1X Dulbecco′s磷酸盐缓冲盐水(DPBS)中稀释。采用高结合掩蔽的微孔滴定板(high binding masked microtiterplate),将100uL受体(1uG/孔)与2nM[3H]-17β-雌二醇和各种浓度的化合物结合。在室温下5-15小时之后,用DPBS/1mM EDTA洗涤板,通过液体闪烁计数确定结合放射性。
表1本发明代表性化合物的结合亲和力和受体选择性;以IC50表示
Cpd | R3 | ERβ(nM) | ERα(nM) | α/β |
678910111213141516171819 | ClBrCH=CH2C=C-TMSC=CHEtCN4-Cl-Ph4-CN-Ph4-MeO-Ph4-CF3-Ph3-Cl-Ph3-MeO-Ph3-CN-Ph | 3.33.631225375.05.6160826113713086150 | 886354816913166403090142035760905058201130 | 2718180.8313719176444108 |
在该药理学试验方法中得到的结果证明了本发明化合物为雌激素化合物,许多化合物都对ERβ受体具有强优选的亲和力。本发明涵盖对ERβ比对ERα具有高度优选亲和力至对两种受体具有几乎相等亲和力的化合物。因此,本发明化合物的活性范围,至少部分以其受体亲和力选择性曲线(profile)为基础,将有一定跨度。此外,由于每个新型受体配体复合物都是独一无二的,因此,其与各种辅调节蛋白的相互作用也是独一无二的,本发明化合物将根据其所在的细胞背景(cellular context)展现出不同的调节行为。例如,在一些细胞类型中,化合物可表现为雌激素激动剂,而在其它组织中,表现为雌激素拮抗剂。具有这样活性的化合物有时被称为SERM(选择性雌激素受体调节剂)。但是,与很多雌激素不同,许多SERM不能增加子宫湿重。这些化合物在子宫中为抗雌激素的,在子宫组织中可完全拮抗雌激素激动剂的营养作用。但是,这些化合物在骨、心血管和中枢神经系统中却充当雌激素激动剂的角色。由于这些化合物的这种组织选择性性质,它们可有效用于治疗或预防哺乳动物如人类如女性的由雌激素缺乏(如在某些组织如骨或心血管中)或雌激素过量(如在子宫或乳腺中)引起的或与之相关的疾病状态或综合征。
甚至除了这样的细胞特异性调节之外,本发明化合物还具有对一种受体类型表现为激动剂而对另一种受体表现为拮抗剂的功效。例如,已证明化合物可为ERβ拮抗剂同时又为ERα激动剂(参见Meyers,Marvin J.et al.,J.Med.Chem.42(13):2456-2468(1999))。在该系列化合物中,这样的ERSAA(雌激素受体选择性激动剂拮抗剂)活性提供了药理学上独特的雌激素活性。
可用其它药理学试验方法容易地测定本发明代表性化合物的活性曲线。以下简要地概述了几种代表性的试验方法。在美国专利Nos.4,418,068和5,998,402中也提供了对SERM的药理学试验方法,其各自通过引用以其整体结合到本文中。
大鼠子宫营养/抗子宫营养试验方法
所述化合物的雌激素和抗雌激素特性可由未成熟大鼠子宫营养分析(4天)来测定(参见L.J.Black and R.L.Goode,Life Sciences 26:1453(1980))。将未成熟Sprague-Dawley大鼠(雌性18天大)分为6组进行测试。每天用50%DMSO/50%盐水作为注射载体的10μg化合物、100μg化合物、100μg化合物+1μg 17β-雌二醇(用来检测抗雌激素能力)和1μg 17β-雌二醇对所述动物进行腹膜内(ip)注射。在第四天,用CO2窒息处死动物,取出它们的子宫并剥去多余的油脂,除去任何流质,测定湿重。将一个角的一小部分用来进行组织学分析,剩余部分用来分离总RNA以评价补体成分3的基因表达。
六(6)周卵巢切除大鼠试验方法-骨和心血管保护
得自Taconic(Greenwood,NY)的卵巢切除或假卵巢切除手术1天后的雌性Sprague Dawley CD大鼠(重量范围240-275g)。将其置于房间中分为3或4只大鼠/笼,实行12/12(光线/黑暗)时间表,无限制提供食物(Purina Mills5K96C大鼠食物)和水。动物到来1天后开始所有的试验处理,每周给予7天,共进行6周。每个试验有一组未接受任何处理的年龄相当的假手术大鼠作为未作处理的、雌激素充分的(intact,estrogen replete)对照组。
所有的处理在1%Tween 80的生理盐水溶液中制备成确定的浓度,以使所述处理体积为0.1mL/100g体重。将17β雌二醇溶于玉米油(20μg/mL)中,皮下给药0.1mL/大鼠。所有的剂量根据组平均体重测量结果每隔三周调整一次。
处理开始5周后,试验结束1周前,评价每只大鼠的骨矿物质密度(BMD)。采用XCT-960M(pQCT)(Stratec Medizintechnik,Pforzheim,Germany)在麻醉大鼠中评价胫骨近端的总密度和骨小梁密度。如下进行测定:在扫描前5分钟,向每只大鼠腹膜内注射45mg/kg氯胺酮、8.5mg/kg塞拉嗪和1.5mg/kg乙酰丙嗪进行麻醉。
将右后肢通过直径为25mm的聚碳酸酯管,用带子绑在丙烯酸树脂支架上,使踝关节成90°角,膝关节成180°角。将聚碳酸酯管附着于可支持它与pQCT的孔保持垂直的滑动台。调节所述台,以使股骨远端和胫骨近端在扫描范围内。二维探查性图象(scout view)在长度为10mm和线分辨率为0.2mm下进行。当监控器上显示探查性图象之后,定位胫骨近端。从距该点3.4mm远处开始pQCT扫描。PQCT扫描厚1mm,三维象素(voxel)(三维象素)大小为0.140mm,由145个穿过切片(slice)的投影组成。
完成pQCT扫描后,图像在监控器上显示。划出包括胫骨但不包括腓骨的相关区。用迭代算法自动除去软组织。报告用mg/cm3表示剩余骨的密度(总密度)。在同心螺旋(concentric spiral)中剥去所述骨的55%外部分。报告用mg/cm3表示的剩余骨的密度(骨小梁密度)。BMD评价一周后,通过二氧化碳窒息处死大鼠,采集血液进行胆固醇检测。取出子宫,称重。采用Cholesterol/HP试剂盒用Boehringer-Mannheim Hitachi 911临床用分析仪测定总胆固醇。采用单向方差分析法(ANOVA)与Dunnet′s测试进行统计学比较。
MCF-7/ERE抗增殖试验方法
在DMSO中制备试验化合物的母液(通常为0.1M),然后用DMSO稀释10-100倍以使操作溶液为1或10mM。将DMSO母液在4℃(0.1M)或-20℃(<0.1M)下储存。用生长培养基[包含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]使MCF-7细胞一周传代2次。将所述细胞置于通气烧瓶(vented flasks)中在5%CO2/95%加湿空气孵育箱内保持37℃。在处理前一天,将所述细胞与生长培养基一起以25,000/孔置入96孔板中在37℃下孵育过夜。
将细胞在37℃用50μl/孔的1∶10稀释的腺病毒5-ERE-tk-荧光素酶在实验培养基[包含10%(v/v)热灭活活性炭处理的胎牛血清、1%(v/v)青霉素-链霉素、2mM glutaMax-1、1mM丙酮酸钠的无酚红D-MEM/F-12培养基]中感染2小时。然后将所述细胞用150μl实验培养基洗涤一次。最后,将细胞用150μl/孔的载体(≤0.1%v/vDMSO)或在实验培养基中稀释≥1000-倍的化合物在37℃下处理24小时,每组平行处理8孔。
试验化合物的初期筛选以1μM的单剂量进行,其单独进行试验(激动剂模式)或与0.1nM 17β-雌二醇联用(EC80;拮抗剂模式)进行试验。每个96孔板还包括载体对照组(0.1%v/v DMSO)和激动剂对照组(0.1或1nM 17β-雌二醇)。剂量反应实验以激动剂和/或拮抗剂模式,用10-14M到10-5M对数增长的活性化合物进行。从这些剂量反应曲线可分别得出EC50和IC50值。每个处理组的最终的孔包含5μl的3×10-5M ICI-182,780(10-6M终浓度)作为ER拮抗剂对照。
处理后,将细胞与25μl/孔的1X细胞培养溶解试剂(PromegaCorporation)在振摇器上溶解15分钟。将溶胞产物(20μl)转移到96孔光度计(luminometer)平板,在MicroLumat LB 96P光度计(EG & GBerthold)中用100μl/孔的荧光酶底物(Promega Corporation)测定荧光酶活性。在注射底物前,对每个孔进行1秒背景测量。注射底物后,在1秒延迟后测定荧光酶活性10秒。将所得数据从光度计传输到Macintosh个人电脑,并用JMP软件(SAS Institute)分析;该程序从每个孔的荧光酶值测定减去背景读数,然后确定每个处理的均值和标准差
将荧光酶数据进行对数转化,使用Huber M-估计器(estimator)下调逸出的转化观测值的权重。用JMP软件分析转化和加权的数据用于单向ANOVA(Dunnett′s检验)。将化合物处理组与激动剂模式的载体对照组结果或与拮抗剂模式的阳性激动剂对照组结果(0.1nM17β-雌二醇)相比较。对于开始的单剂量实验,如果化合物处理组结果与适当的对照组有显著性差异(p<0.05),则所述结果以相对于17β-雌二醇对照组的百分率[即((化合物-载体对照)/(17β-雌二醇对照-载体对照))×100]表示。还用JMP从非线性剂量反应曲线确定EC50和/或IC C50值。
抑制LDL氧化-抗氧化剂活性
将得自屠宰场的猪主动脉洗涤,置入预冷的磷酸盐缓冲盐水(PBS)中,采集主动脉内皮细胞。为了采集所述细胞,要避免(tiedoff)主动脉的肋间脉管(the intercostal vessels of the aorta),并将主动脉的一端夹住。在脉管中置入新鲜的无菌过滤的0.2%胶原酶(SigmaType I),然后夹位脉管的另一端以形成封闭系统。将该主动脉在37℃下孵育15-20分钟,然后收集胶原酶溶液在2000x g离心5分钟。将每个沉淀物悬浮于7mL内皮细胞培养基中,该培养基包含加有活性炭处理的胎牛血清(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(gentimicin)(75μg/ml)的无酚红DMEM/Ham′s F12,在100mm培养皿中接种,在5%CO2中在37℃下孵育。20分钟后,将细胞用PBS冲洗,加入新鲜培养基,在24小时后再次重复该操作。约1周后细胞融合。通常一周喂饲内皮细胞两次,当融合时,用胰蛋白酶作用,并以1∶7比率接种。使细胞介导的12.5μg/mL LDL氧化作用在待评价化合物(5μM)存在下在37℃下进行4小时。用分析游离醛的TBARS(丙二酰硫脲反应性物质(thiobarbituric acid reactivesubstances))方法测定氧化过程的抑制百分率,并用该抑制率表示结果(Yagi K.,Biochem Med 15:212-216(1976))。
D12下丘脑细胞试验程序
D12大鼠下丘脑细胞亚克隆自RCF17亲代细胞系并冷冻储存。使它们在DMEM∶F12(1∶1)、glutaMAX-1(2mM)、青霉素(100U/ml)-链霉素(100mg/ml)和10%FBS中常规生长。将所述细胞以亚融合密度(1-4×106细胞/150mm培养皿)置于包含2-10%活性炭处理的FBS无酚红培养基(DMEM∶F12、glutaMAX、青霉素-链霉素)中。24小时后用包含2%活性炭处理过的血清的培养基再次喂饲(refed)细胞。为了测试激动剂活性,将细胞用10nM 17β-雌二醇或各种剂量的试验化合物(1mM或1pM-1mM范围)处理。为了测试拮抗剂活性,将细胞用0.1nM 17β-雌二醇在没有或有不同剂量(100pM-1mM)的试验化合物存在下处理。对照培养皿也用DMSO处理作为阴性对照。激素加入48小时后,细胞溶解,进行结合试验程序
对于每个结合试验程序,将100-150mg蛋白与10nM 3H-R5020+100-倍过量的R5020在150mL体积中孵育。在96孔板上制备一式3份反应物(3个有R5020,3个没有R5020)。首先加入蛋白提取物,接着加入3H-R5020或3H-R5020+100x未标记的R5020。将反应在室温下进行1-2小时。通过加入100mL冷5%活性炭(Norit SX-4)、pH 7.4的0.5%葡聚糖69K(Pharmacia)的TE溶液终止反应。5分钟后,在室温下离心(5分钟,1000RCF,4℃)分离结合和未结合的配体。除去上清液(~150ml),转移到闪烁瓶中。然后加入闪烁液(Beckman Ready Protein+),在闪烁计数器中将样品计数1分钟。
CNS视前区的孕酮受体
将六十(60)日龄的雌性Sprague-Dawley大鼠切除卵巢。将所述动物装在配有12小时光线、12小时黑暗光周期的笼中,可自由使用自来水和啮齿类动物食物。
将切除卵巢的动物随机分组,注射载体(50%DMSO,40%PBS,10%乙醇载体)、17β-雌二醇(200ng/kg)或试验化合物。另外的动物在注射17β-雌二醇前1小时注射试验化合物以评价该化合物的拮抗特性。皮下(sc)注射6小时后,用致死剂量的CO2处死动物,收集它们的大脑并冷冻。
将从动物收集的组织在恒冷切片机上在-16℃切片,收集在甲硅烷包被的载玻片上。然后将装有切片的载玻片在保持在42℃的载玻片加热器上干燥,并在-80℃下储存于干燥的载玻片盒中。在处理前,将干燥的载玻片盒缓慢升至室温(用12-16小时升至-20℃;再用2小时升至4℃;再用1小时升至室温)以避免载玻片上的冷凝形成,并因此使组织和RNA的降解最小化。将干燥的载玻片装在金属支架上,在4%多聚甲醛(pH 9.0)中后固定(post-fixed)5分钟,并用如前所述的方法处理。
将包含大鼠PR cDNA 9(配体结合区域)的815bp片段的质粒线性化,并用来产生可与大鼠PR mRNA的一部分互补的S 35-UTP标记的探针。将处理过的装有切片的载玻片与200ml包含核糖核酸探针(4-6×106DPM/片)和50%甲酰胺的杂交混合物杂交,并在55℃的加湿室中孵育过夜。第二天早上,将该载玻片置于浸在2xSSC(0.15M NaCl、0.015M柠檬酸钠;pH 7.0)/10mM DTT的金属支架上。将支架全部转移到大容器中,在2xSSC/10mM DTT中在室温和轻微搅拌下洗涤15分钟。然后将载玻片在Rnase缓冲液中在37℃下洗涤30分钟,在37℃下用RNase A(2mg/ml)处理30分钟,然后在室温1xSSC中洗涤15分钟。然后,将载玻片在0.1xSSC在65℃下洗涤(2×30分钟)以除去非特异性标记,在室温0.1xSSC中冲洗15分钟,用梯度系列的乙醇∶乙酸铵(70%、95%和100%)脱水。将风干的载玻片在x-射线胶片上曝光3天,然后显影处理。将得自所有动物的载玻片一起杂交、洗涤、曝光并显影处理以消除条件上的测定间差异引起的差别。
大鼠热潮红-CNS作用
切除卵巢的60日龄的Sprague-Dawley大鼠,经下面的手术得到。至少要在第一次处理前8天做手术。将动物在12/12小时光线/黑暗周期下各自装笼,给予无限量的标准大鼠食物和水。
在每个试验中包括两个对照组。根据mg/kg平均组体重在10%DMSO的芝麻油溶液中(sc试验)或在1.0%Tween 80的盐水溶液中((po)试验)配置剂量。给予动物剂量范围为0.01-10mg/kg平均组体重的试验化合物。每个试验中包括载体和乙炔基雌二醇(EE)对照(0.1mg/kg,sc或0.3mg/kg,po)的对照组。当测定化合物的拮抗剂活性时,对于sc或po试验分别同时给予0.1或0.3mg/kg的EE。试验化合物一直给药到测定尾部皮肤温度的那天。
在4天的适应期之后,用感兴趣的化合物每天一次处理动物。每处理组有10动物。可在颈部的颈背处sc注射0.1ml或po 0.5ml体积的化合物。在处理的第三天,皮下植入吗啡微型片(75mg硫酸吗啡)。在处理的第五天,再植入1或2个吗啡微型片。在第八天,给约半数的动物注射氯胺酮(80mg/kg,肌肉注射),将与MacLab数据获得系统(API仪器,Milford,MA)连接的热电偶绑在距尾根处约1英寸的尾巴上。该系统可连续测量尾部皮肤的温度。测定温度基线15分钟,然后皮下给予纳洛酮(1.0mg/kg)(0.2mL)以阻滞吗啡的作用,1小时后测定尾部皮肤温度。在第九天,安排对剩余的动物进行同样的分析。
分离的大鼠主动脉环的血管舒缩功能
将Sprague-Dawley大鼠(240-260g)分成4组:
1.正常未切除卵巢的(intact)
2.切除卵巢的(ovex)用载体处理的
3.切除卵巢的用17-β雌二醇处理的(1mg/kg/天)
4.切除卵巢的用试验化合物处理(即1mg/kg/天)的动物。
在处理前约3周对动物进行卵巢切除。通过胃管饲法给予每只动物1mg/kg/天硫酸17-β雌二醇或悬浮于含1%Tween-80的蒸馏的、去离子水的试验化合物。给予载体处理动物药物处理组中所用的适当体积的载体。
通过吸入CO2和放血法处死动物。快速移出它们的胸主动脉并置于具有下述成分的37℃的生理溶液中(mM):NaCl(54.7)、KCl(5.0)、NaHCO3(25.0)、MgCl2-2H2O(2.5)、D-葡萄糖(11.8)和充有95%/5%CO2-O2的CaCl2(0.2),终pH为7.4。将血管外膜从外表面除去,将血管切成2-3mm宽的环。将所述环悬浮于10mL组织浴中,环的一端与所述浴的底部相连另一端与力传感器相连。在所述环上加1g的静息张力。将环保持平衡1小时,同时获取信号并分析。
平衡后,将所述环暴露于递增浓度的去氧肾上腺素(10-8-10-4M)并记录张力。然后用新鲜缓冲液冲洗浴3次。洗净后,将200mML-NAME加入到组织浴中,保持平衡30分钟。然后重复去氧肾上腺素浓度反应曲线。
8-臂放射状迷宫-认知增强作用
采用刚到的雄性重200-250g的Sprague-Dawley,CD大鼠(Charles River,Kingston,NY)。将大鼠装在自由饮食标准实验室食物和水的笼中一周,每笼六只。所居住的饲养室保持22℃,12/12小时光/暗周期循环,光照在6:00AM开始。习惯了该设施后,将动物单独饲养并使其保持自由进食时体重的85%。一旦达到稳定重量,将大鼠置于8臂放射迷宫中适应环境。
对Peele和Baron(Pharmacology,Biochemistry,and Behavior29:143-150(1988))设计的迷宫做了改动,形成8臂迷宫结构。将迷宫提高到75.5cm高度,该迷宫包括环状区域和周围的8个臂,8个臂从中心伸出,呈放射状,相互间等距。每个臂长58cm,高13cm。开始每个时间段之前,将透明有机玻璃筒降低,以使实验动物进入迷宫的中心部分。迷宫的每个臂装配有3套光电池,通过数据采集装置,最终与计算机相连。光电池用来示踪大鼠在迷宫中的活动。颗粒喂食器放在每个臂末端的食物杯上方,当臂的外部光电池在给定的时间段内第一次活化时,喂食器给出两个45mg的巧克力颗粒。迷宫置于测试室中,用黑和白色几何图形贴在每个壁上作为视觉提示。在训练和测试程序的整个过程中,都可听到白噪声(~70db)。
训练程序包括5个阶段,每个阶段的每天的时间段持续5-10分钟。在将大鼠放进迷宫中心部分与将透明筒升高开始计时之间加上10秒钟的延迟时间。在阶段1期间,两只限食的大鼠被置于迷宫中,45mg的巧克力食物粒散在分布于迷宫的8个臂中。在阶段II期间,将每只大鼠单独置于迷宫中10分钟,食物粒散在分布于各臂的食物杯的中部光电池处。在阶段III期间,将每只大鼠置于迷宫中10分钟,食物粒仅置于各臂的食物杯周围。在阶段IV,给每只大鼠10分钟从每个臂收集两个食物粒。重进入臂被认为是错误。将大鼠每天以该方式训练直到它们达到在连续3天的训练中总错误小于或等于2个的表现标准。总适应和训练时间为约3周。
试验化合物在磷酸盐缓冲盐水中制备,以1ml/kg的体积给药。用东莨菪碱HBr(0.3mg/kg sc)作为损伤剂,使错误率增加(失忆)。在任何给定的试验日首次暴露于迷宫前的30分钟,腹膜内给予试验化合物,同时给予东莨菪碱。
为了评价试验化合物,设计了可重复测量的8×8平衡拉丁方,以用最少的试验动物达到高实验效率的目的。八个试验时间段,每周两个,在每个时间段随机进行8种处理(载体、东茛菪碱、3个剂量的试验化合物与东茛菪碱联用)。每个处理之间的时间保持一致。因此,每个处理的残余效果可被估计并从直接处理效果中除去。按照ANOVA,采用对校正均数的Dunnett′s双向检验进行多重比较。
在首次面对迷宫期间未在5分钟内做4次正确选择的动物,或在第二次面对迷宫结束时总计未做8个选择的动物被认为在所述时间段“超时”(″timed-out″)。从分析中排除任何给予超过一剂量的实验化合物后“超时”的动物。
神经保护作用
对在原代皮质神经元培养物中的细胞时间依赖型死亡的抑制作用(Inhibition of Time-Dependent Death of Cells in Primary CorticalNeuron Cultures)
用变动的Monyer et al.,Brain Research 483:347-354(1989)中描述的方法从0-1日龄的大鼠脑制备原代皮质神经元(Primary corticalneurons)。将分散的脑组织在DMEM/10%PDHS(怀孕供体马血清)中生长3天,然后用阿糖胞苷(ARC)处理2天以除去污染的神经胶质细胞。在第5天,除去ARC培养基,用DMEM/10%PDHS代替。在使用前将神经元细胞再培养4-7天。
对照原代神经元培养物在培养中的第12-18天显示出程序性细胞死亡。在第9天向保持在DMEM和10%PDHS中的6个培养物中加入试验化合物并保持剩下的培养作为对照之后,在第12天和16天对12个培养物的乳酸脱氢酶(LD)的水平进行评价。LD用Wroblewski et al.,Proc.Soc.Exp.Biol.Med.90:210-213(1955)中描述的方法的变更方法来测定。LD为胞质酶,通常在临床和基础研究中用于测定组织生存能力。培养基中LD的增加与细胞死亡直接相关。
对抗由低血糖引起的细胞毒性的神经保护作用
将得自美国组织培养中心(ATCC)的C6神经胶质瘤细胞以1×106细胞/ml的浓度置于装在FALCON25cm2组织培养烧瓶中的含FBS的RPMI培养基中。在低血糖开始前4小时,弃去维持培养基,用合适的培养基洗涤单层两次,然后在无血清或无血清加试验化合物中在37℃下孵育4小时。在加入合适的葡萄糖处理之前,用Kreb′s Ringer磷酸盐缓冲液洗涤单层2次。RPMI培养基包含2mg葡萄糖/mL;将烧瓶分为6组,每组接受100%葡萄糖(2mg/ml)、80%葡萄糖(1.6mg/ml)、60%葡萄糖(1.2mg/ml)或0%葡萄糖(缓冲剂)或添加有试验化合物。将所有烧瓶孵育20小时,然后用锥虫蓝进行总、活和死细胞数目评价。
对抗兴奋毒性氨基酸的神经保护作用(Neuroprotection AgainstExcitotoxic amino Acids)
将包含SK-N-SH成神经瘤细胞的五个培养皿用试验化合物处理,并将5个培养皿用RPMI培养基处理。四小时后,将所有细胞用NMDA(500μM)处理5分钟。测定总活细胞和死细胞。
对抗缺氧缺糖的神经保护作用(Neuroprotection Against Oxygen-Glucose Deprivation)-分析固缩核来测定细胞凋亡(Analysis of pyknoticnuclei to measure apoptosis)
将从E18大鼠胎儿制备的皮质神经元以100,000细胞/孔的密度置于用聚-D-赖氨酸(poly-D-lysine)(10ng/ml)和血清预包被的8孔小室载玻片中。将细胞置于包含10%FCS的高糖DMEM中,并置于充有10%CO2/90%空气的37℃的孵育箱中。第二天,通过用包含B27添加物的高糖DMEM更换培养基来除去血清,并将细胞置于孵育箱中不再变化培养基直至实验的那天。在第6天,将载玻片分为两组:对照组和OGD组。对照组的细胞接受含葡萄糖和定制的B27(无抗氧化剂)的DMEM。OGD组的细胞接受在真空下除气15分钟的含定制B27的无葡萄糖DMEM。将细胞在气密室中用90%N2/10%CO2冲洗10分钟,并在37℃下孵育6小时。6小时后,将对照组和OGD组细胞进行培养基更换,将其置于包含载体(DMSO)或在含定制B27的含葡萄糖DMEM中的试验化合物的培养基中。将细胞送回含氧量正常的37℃的孵育箱。24小时后,将细胞在4℃下在4%PFA中固定10分钟,用Topro(荧光细胞核结合染料)染色。用激光扫描细胞计数器通过测定固缩核来评价细胞凋亡。
作为细胞死亡指征的LDH释放的测定
将从E18大鼠胎儿制备的皮质神经元以150,000细胞/孔的密度置于用聚-D-赖氨酸(10ng/ml)和血清预包被的48孔培养皿中。将细胞置于包含10%FCS的高糖DMEM中,并置于充有10%CO2/90%空气的37℃的孵育箱中。第二天,通过用包含B27添加物的高糖DMEM更换培养基来除去血清。在第6天,将细胞分为两组:对照组和OGD组。对照组的细胞接受含葡萄糖和定制的B27(无抗氧化剂)的DMEM。OGD组的细胞接受在真空下除气15分钟的含定制B27的无葡萄糖DMEM。在气密室中将细胞用90%N2/10%CO2冲洗10分钟,并在37℃下孵育6小时。6小时后,将对照组和OGD组细胞进行培养基更换,将其置于包含载体(DMSO)或在含定制B27的含葡萄糖DMEM中的试验化合物的培养基中。将细胞送回含氧量正常的37℃的孵育箱。24小时后,通过检测细胞释放到培养基中的LDH(乳酸脱氢酶)来评价细胞死亡。对于LDH测定,将50μl培养基等分试样转移到96孔板中。加入140μl 0.1M磷酸钾缓冲液(pH7.5)和100μl 0.2mg/ml NADH后,将板在室温下置于黑暗中20分钟。通过加入10μl丙酮酸钠开始反应。将板立即在Thermomax板读数器(Molecular Devices)中在340nM处读数。每6秒记录吸光度(NADH浓度的指数),记录5分钟,用表示NADH消失速率的斜率来计算LDH活性:
LDH活性(U/ml)=(ΔA/min)(TCF)(20)(0.0833)/(.78)
其中:
0.0833=正比常数,和
0.78=仪器光径长(cm)。
HLA大鼠试验方法-Crohn′s病和炎性肠病
得自Taconic的雄性HLA-B27大鼠,提供无限制使用的食物(Purina MillsLabDiet500l)和水。在试验开始时,大鼠为22-26周龄。
给大鼠每天皮下注射一剂下面列出的制剂之一,进行7天。每组5只动物,最后一剂在处死前2小时给予。
·载体(50%DMSO/50%Dulbecco′s PBS);
·17α-乙炔基-17β-雌二醇(10μg/kg);或
·试验化合物。
根据下面的标准每天观察粪便性质并评分:腹泻=3;软便=2;正常便=1。在试验操作最后,采集血清并在-70℃下保存。制备结肠切片以进行组织学分析,其它部分用于髓过氧化物酶活性分析。
下面的方法用于测定髓过氧化物酶的活性。收集结肠组织并快速在液氮中冷冻。用整个结肠的代表性样品来确保样品间的一致性。将所述组织储存在-80℃待用。然后,将组织称重(约500mg),并在1∶15w/v of 5mM H2KPO4(pH 6)洗涤缓冲液中匀浆化。将该组织在Sorvall RC 5B离心机中在2-8℃以20,000xg离心沉淀45分钟。然后弃去上清液。将组织重悬浮于含10mM EDTA和0.5%Hex溴化铵的2.5mL(1∶5w/v)的50mM H2KPO4中并匀浆化以帮助细胞内MPO溶解。将组织在液氮中冷冻,在37℃的水浴中解冻,并进行15秒钟的声处理以确保膜溶解。将该程序重复3次。然后将样品置于冰上20分钟,在2-8℃以12,000xg离心15分钟。按照下面的步骤分析上清液。
通过将含0.167邻联茴香胺/ml的2.9mL的50mM H2KPO4与0.0005%H2O2加入反应管中而制得试验混合物。当过氧化氢降解时,邻联茴香胺被氧化并在460nm处以浓度依赖方式吸收。将该混合物加热至25℃。向反应管中加入一百(100)μL组织上清液,在25℃下孵育1分钟,然后取1ml转移到一次性塑料管中。在反应时间内每2分钟在460nm处相对于包含2.9mL反应混合物和100μL0.5%溴化铵溶液的空白测定光密度(OD)。
酶活性单位通过将在460nm处的吸收度与用纯化人MPO 31.1单位/管绘制的标准曲线比较来定量。将MPO重新溶解并用含10mM EDTA和0.5%Hex溴化铵的50mM H2KPO4连续稀释成4个已知浓度。将样品吸收度与该曲线相比较以确定活性。
如下进行组织学分析。将结肠组织浸于10%中性缓冲的福尔马林中。将每个结肠样品分为四个样品进行评价。将福尔马林固定的组织在真空抽滤机中处理以进行石蜡包埋。将样品在以5μm厚度切片,然后用苏木精和伊红(H&E)染色,采用有所改动的Boughton-Smith评价标准进行组织学盲评。评分完成后,使样品脱盲,将数据列表,用多重均值比较通过ANOVA线性模型进行分析。
根据本文描述标准药理学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,可有效用于治疗或抑制至少部分由雌激素缺乏或过量介导的或可通过使用雌激素药物来治疗或抑制的症状、病症和疾病状态。
在此专利文件中提到的每个专利、申请和印刷的出版物,包括书,都通过引用以其整体结合到本文中。该申请要求了2004年9月7日提交的序列号为60/607,766的美国临时申请的优先权,其通过引用以其整体结合到本文中。
本领域熟练技术人员会了解对本发明的优选实施方案可做许多不偏离本发明精神的改变和修饰。所有这些变更都在本发明的范围内。
Claims (61)
1.一种具有下述结构的式I化合物:
其中:
A和A′各自独立为OH、H或OR;
每个R独立选自C1-C6烷基、烯基、苄基、酰基、芳酰基、-C(=O)-OR′、磺酰基和磷酰基,其中每个R′独立选自C1-C6烷基、C2-C7烯基、C2-C7炔基或C3-C10环烷基,各自任选被1-3个选自C1-C6烷基或卤素的取代基取代;
R1和R2独立选自H、卤素、C1-C6烷基、C1-C6全卤代烷基、CF3、C2-C7烯基和C1-C6烷氧基;
R3、R4、R5和R6各自独立选自H、卤素、CF3、C1-C6全卤代烷基、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、CN、-CHO、酰基、苯基、芳基和杂芳基;
其中R3、R4、R5和R6的烷基或烯基部分各自可任选被最多3个独立选自下述基团的取代基取代:卤素、OH、CN、三氟烷基、三氟烷氧基、NO2或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的炔基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、-CHO、酰基、三氟烷基、三烷基甲硅烷基或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的苯基、芳基或杂芳基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、烷基、烷氧基、全氟烷基或全氟烷氧基;
每个R10独立选自卤素、C1-C6烷基、C2-C7烯基、-OH、C1-C6烷氧基、-CN、-CHO、-NO2、氨基、C1-C6烷基氨基、二-(C1-C6)烷基氨基、巯基和C1-C6烷硫基;和
n为0、1、2或3;
条件是:
A和A′中至少一个不为H;
如果n为0,则R3不为卤素;和
R3、R4和R5中至少一个为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、-CN、-CHO、酰基、苯基、芳基或杂芳基;
或其N-氧化物或其药学可接受盐或其前药。
1.权利要求1的化合物,其中A和A′各自为OH。
2.权利要求1的化合物,其中A和A′之一为OH,A和A′中的另外一个为OR。
3.权利要求1的化合物,其中A和A′之一为OH,A和A′中的另外一个为O-C1-C6烷基。
4.权利要求1的化合物,其中A和A′各自为OR。
5.权利要求5的化合物,其中A和A′各自为-O-C1-C6烷基。
6.权利要求1的化合物,其中A和A′之一为H,A和A′中的另外一个为OH或OR。
7.权利要求1的化合物,其中A和A′之一为H,A和A′中的另外一个为OH或O-C1-C6烷基。
8.权利要求1-8中任一项的化合物,其中R3和R5各自独立为H、卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO、酰基或如前所述的任选取代的苯基。
9.权利要求9的化合物,其中R3不为H。
10.权利要求1-8中任一项的化合物,其中R3为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、C1-C6烷氧基、全氟烷基和CN;且R5为H、卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、C1-C6烷氧基、全氟烷基和CN。
11.权利要求11的化合物,其中所述R3的所述苯基任选被最多3个选自下述基团的取代基取代:F、Cl、Br、CN、OCH3和CF3。
12.权利要求1-8中任一项的化合物,其中R3为卤素、C2-C7炔基或-CN。
13.权利要求1-8中任一项的化合物,其中R3和R5各自独立为卤素、C2-C7炔基或-CN。
14.权利要求1-14中任一项的化合物,其中R1和R2之一为卤素。
15.权利要求1-14中任一项的化合物,其中R1和R2之一为氟。
16.权利要求1-14中任一项的化合物,其中R1和R2之一为卤素,R1和R2中的另外一个为H。
17.权利要求1-14中任一项的化合物,其中R1和R2之一为氟,R1和R2中的另外一个为H。
18.权利要求1-14中任一项的化合物,其中R1和R2各自独立为卤素。
19.权利要求1-14中任一项的化合物,其中R1和R2各自为H。
20.权利要求1-14中任一项的化合物,其中R1和R2各自为氟。
21.权利要求1-21中任一项的化合物,其中R4为H、卤素或-CN。
22.权利要求1-21中任一项的化合物,其中R4为H。
23.权利要求1-8中任一项的化合物,其中:
R3为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、C1-C6烷氧基、全氟烷基和CN;
R5为H、卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、-CN、-CHO或任选被最多3个选自下述基团的取代基取代的苯基:卤素、C1-C6烷氧基、全氟烷基和CN;
R1和R2之一为卤素;且R4为H、卤素或-CN。
24.权利要求2的化合物,其中R3为卤素,且R1、R2、R4、R5和R6为氢。
25.权利要求2的化合物,其中R3为OH,且R1、R2、R4、R5和R6为氢。
26.权利要求2的化合物,其中R3为C2-C7烯基,且R1、R2、R4、R5和R6为氢。
27.权利要求2的化合物,其中R3为CN,且R1、R2、R4、R5和R6为氢。
28.权利要求2的化合物,其中R3为C2-C7炔基,且R1、R2、R4、R5和R6为氢。
29.权利要求6的化合物,其中R3为C1-C6烷基,且R1、R2、R4、R5和R6为氢。
30.权利要求6的化合物,其中R3为任选取代的苯基,且R1、R2、R4、R5和R6为氢。
31.权利要求31的化合物,其中所述苯基的所述取代基选自卤素、C1-C6烷氧基、全氟烷基和CN。
32.权利要求1-23或25-32中任一项的化合物,其中n为1。
33.权利要求24的化合物,其中n为1。
34.一种化合物,其为:
a)3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉-7-醇;
b)7-氯-3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉;
c)7-溴-3,9-二甲氧基-6H-色原烯并[4,3-b]喹啉;
d)7-氯-3,9-二羟基-6H-色原烯并[4,3-b]喹啉;
e)7-溴-3,9-二羟基-6H-色原烯并[4,3-b]喹啉;
f)3,9-二羟基-7-乙烯基-6H-色原烯并[4,3-b]喹啉;
g)3,9-二羟基-7-[(三甲基甲硅烷基)乙炔基]-6H-色原烯并[4,3-b]喹啉;
h)3,9-二羟基-7-乙炔基-6H-色原烯并[4,3-b]喹啉;
i)3,9-二羟基-7-乙基-6H-色原烯并[4,3-b]喹啉;
j)7-氰基-3,9-二羟基-6H-色原烯并[4,3-b]喹啉;
k)7-(4-氯苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉;
l)7-(4-氰基苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉;
m)3,9-二羟基-7-(4-甲氧基苯基)-6H-色原烯并[4,3-b]喹啉;
n)3,9-二羟基-7-[4-(三氟甲基)苯基]-6H-色原烯并[4,3-b]喹啉;
o)7-(3-氯苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉;
p)3,9-二羟基-7-(3-甲氧基苯基)-6H-色原烯并[4,3-b]喹啉;
q)7-(3-氰基苯基)-3,9-二羟基-6H-色原烯并[4,3-b]喹啉;
或其药学可接受盐、螯合物、络合物或前药。
35.一种组合物,所述组合物包含权利要求35的化合物。
36.一种组合物,所述组合物包含权利要求1-35中任一项的化合物。
37.一种治疗或抑制需要其的哺乳动物的骨质疏松或抑制骨脱矿质作用的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
38.一种治疗或抑制需要其的哺乳动物的肠炎、Crohn′s病、溃疡性直肠炎或结肠炎的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
39.一种降低需要其的哺乳动物的胆固醇、甘油三酯、Lp(a)或LDL水平;抑制或治疗需要其的哺乳动物的高胆固醇血症;高脂血症;心血管疾病;动脉粥样硬化(atheroclerosis);外周血管疾病;再狭窄或血管痉挛;或抑制需要其的哺乳动物的血管损伤的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
40.一种向需要其的哺乳动物提供认知增强作用或神经保护作用;或治疗或抑制需要其的哺乳动物的老年痴呆、Alzheimer′s病、认知减退、中风、焦虑症或神经退化性疾病的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
41.一种治疗或抑制需要其的哺乳动物的自由基诱导的疾病状态的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
42.一种治疗或抑制需要其的哺乳动物的阴道或外阴萎缩;萎缩性阴道炎;阴道干燥;瘙痒症;性交困难;排尿困难;尿频;尿失禁;泌尿道感染的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
43.一种治疗或抑制需要其的哺乳动物的血管舒缩症的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
44.权利要求44的方法,其中所述血管舒缩症为热潮红。
45.一种使需要其的哺乳动物避孕的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
46.一种治疗或抑制需要其的哺乳动物的类风湿性关节炎、骨质疏松或脊椎关节病的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
47.一种治疗或抑制需要其的哺乳动物的继关节镜或手术操作而发生的关节损伤的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
48.一种治疗或抑制需要其的哺乳动物的不育症的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
49.一种治疗或抑制需要其的哺乳动物的局部缺血、再灌注损伤、哮喘、胸膜炎、多发性硬化症、全身性红斑狼疮、肌痛、关节痛、失眠症、易激症、眼葡萄膜炎、脓毒症、出血性休克或II型糖尿病的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
50.一种治疗或抑制需要其的哺乳动物的低钙血症、高钙血症、Paget′s病、骨软化症、骨钙质缺乏、多发性骨髓瘤的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
51.一种治疗或抑制需要其的哺乳动物的良性或恶性异常组织增生包括前列腺肥大、子宫平滑肌瘤、乳腺癌、子宫内膜异位、子宫内膜癌、多囊性卵巢综合征、子宫内膜息肉、良性乳房疾病、子宫腺肌病、卵巢癌、黑素瘤、前列腺癌、结肠癌或CNS癌的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
52.权利要求52的方法,其中所述良性或恶性异常组织增生为前列腺肥大、子宫平滑肌瘤、乳腺癌、癌症、多囊性卵巢综合征、子宫内膜息肉、良性乳房疾病、子宫腺肌病、卵巢癌、黑素瘤、前列腺癌、结肠癌或CNS癌。
53.权利要求53的方法,其中所述CNS癌为神经胶质瘤或成星形细胞瘤。
54.一种治疗或抑制需要其的哺乳动物的癌症、中枢神经系统病症或外伤、骨病、衰老、炎性疾病、外周血管疾病、自身免疫性疾病、呼吸性窘迫、肺气肿、病毒性肝炎、慢性活动性肝炎、肺结核、银屑病、成人呼吸性窘迫综合征的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
55.一种治疗或抑制需要其的哺乳动物的皮肤萎缩、痤疮或男性型秃发的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
56.一种治疗或抑制需要其的哺乳动物的白血病、子宫内膜切除、慢性肾脏疾病、肝病或血凝固疾病或病症的方法,所述方法包括向所述哺乳动物提供有效量的权利要求1-35中任一项的一种或多种化合物。
57.一种制备式IV化合物的方法:
其中:
A和A′各自独立为OH、H或OR;
每个R独立选自C1-C6烷基、烯基、苄基、酰基、芳酰基、-C(=O)-OR′、磺酰基和磷酰基,其中每个R′独立选自C1-C6烷基、C2-C7烯基、C2-C7炔基或C3-C10环烷基,各自任选被1-3个选自C1-C6烷基或卤素的取代基取代;
R1和R2独立选自H、卤素、C1-C6烷基、C1-C6全卤代烷基、CF3、C2-C7烯基和C1-C6烷氧基;
R3、R4、R5和R6各自独立选自H、卤素、CF3、C1-C6全卤代烷基、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、CN、-CHO、酰基、苯基、芳基和杂芳基;
其中R3、R4、R5和R6的烷基或烯基部分各自可任选被最多3个独立选自下述基团的取代基取代:卤素、OH、CN、三氟烷基、三氟烷氧基、NO2或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的炔基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、-CHO、酰基、三氟烷基、三烷基甲硅烷基或苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3、R4、R5和R6的苯基、芳基或杂芳基部分各自可任选被最多3个选自下述基团的取代基取代:卤素、-CN、烷基、烷氧基、全氟烷基或全氟烷氧基;
每个R10独立选自卤素、C1-C6烷基、C2-C7烯基、-OH、C1-C6烷氧基、-CN、-CHO、-NO2、氨基、C1-C6烷基氨基、二-(C1-C6)烷基氨基、巯基和C1-C6烷硫基;和
n为0、1、2或3;
条件是:
A和A′中至少一个不为H;
如果n为0,则R3不为卤素;和
R3、R4和R5中至少一个为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、-CN、-CHO、酰基、苯基、芳基或杂芳基;
或其N-氧化物或其药学可接受盐或其前药。
包括以下步骤:
a)提供式II的化合物:
和;
b)将式II化合物与式III化合物反应:
产生式IV化合物。
58.权利要求58的方法,还包括将式IV化合物与修饰试剂接触形成式I化合物的步骤:
其中:
R3选自H、卤素、CF3、C1-C6全卤代烷基、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、CN、-CHO、酰基、苯基、芳基和杂芳基;
其中R3的烷基或烯基部分任选被最多3个独立选自下述基团的取代基取代:卤素、OH、CN、三氟烷基、三氟烷氧基、NO2和苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3的炔基部分任选被最多3个选自下述基团的取代基取代:卤素、-CN、-CHO、酰基、三氟烷基、三烷基甲硅烷基和苯基,其中所述苯基任选被最多3个独立选择的R10基团取代;
其中R3的苯基、芳基或杂芳基部分任选被最多3个选自下述基团的取代基取代:卤素、-CN、烷基、烷氧基、全氟烷基或全氟烷氧基;
条件是:
A和A′中至少一个不为H;
如果n为0,则R3不为卤素;和
R3、R4和R5中至少一个为卤素、C1-C6烷基、C2-C7烯基、C2-C7炔基、C3-C7环烷基、C1-C6烷氧基、-CN、-CHO、酰基、苯基、芳基或杂芳基;
或其N-氧化物或其药学可接受盐或其前药。
59.权利要求58的方法的产物。
60.权利要求59的方法的产物。
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Publication number | Priority date | Publication date | Assignee | Title |
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DE202004021953U1 (de) | 2003-09-12 | 2013-06-19 | Vessix Vascular, Inc. | Auswählbare exzentrische Remodellierung und/oder Ablation von atherosklerotischem Material |
MXPA06015270A (es) * | 2004-07-01 | 2007-03-15 | Wyeth Corp | Compuestos tetraciclicos como ligandos de estrogeno. |
US8396548B2 (en) | 2008-11-14 | 2013-03-12 | Vessix Vascular, Inc. | Selective drug delivery in a lumen |
US9125667B2 (en) | 2004-09-10 | 2015-09-08 | Vessix Vascular, Inc. | System for inducing desirable temperature effects on body tissue |
US9713730B2 (en) | 2004-09-10 | 2017-07-25 | Boston Scientific Scimed, Inc. | Apparatus and method for treatment of in-stent restenosis |
CA2613703A1 (en) | 2005-06-28 | 2007-01-04 | Cv Therapeutics, Inc. | Abca1 elevating compounds |
US20070191442A1 (en) * | 2006-02-14 | 2007-08-16 | Wyeth | Aqueous Pharmaceutical Formulations of ER-beta Selective Ligands |
US8019435B2 (en) | 2006-05-02 | 2011-09-13 | Boston Scientific Scimed, Inc. | Control of arterial smooth muscle tone |
EP2455036B1 (en) | 2006-10-18 | 2015-07-15 | Vessix Vascular, Inc. | Tuned RF energy and electrical tissue characterization for selective treatment of target tissues |
EP2076198A4 (en) | 2006-10-18 | 2009-12-09 | Minnow Medical Inc | Inducing Desired Temperatreating Effects on Body Weave |
CA2672428A1 (en) * | 2006-12-27 | 2008-07-03 | Cv Therapeutics, Inc. | Abca1 elevating compounds |
US9604931B2 (en) | 2007-01-22 | 2017-03-28 | Gtx, Inc. | Nuclear receptor binding agents |
BRPI0806371A2 (pt) | 2007-01-22 | 2011-09-13 | Gtx Inc | agentes ligação de receptor nuclear |
US9623021B2 (en) * | 2007-01-22 | 2017-04-18 | Gtx, Inc. | Nuclear receptor binding agents |
AU2009314133B2 (en) | 2008-11-17 | 2015-12-10 | Vessix Vascular, Inc. | Selective accumulation of energy with or without knowledge of tissue topography |
JP2013523318A (ja) | 2010-04-09 | 2013-06-17 | べシックス・バスキュラー・インコーポレイテッド | 組織の治療のための発電および制御の装置 |
US9192790B2 (en) | 2010-04-14 | 2015-11-24 | Boston Scientific Scimed, Inc. | Focused ultrasonic renal denervation |
US8473067B2 (en) | 2010-06-11 | 2013-06-25 | Boston Scientific Scimed, Inc. | Renal denervation and stimulation employing wireless vascular energy transfer arrangement |
US9084609B2 (en) | 2010-07-30 | 2015-07-21 | Boston Scientific Scime, Inc. | Spiral balloon catheter for renal nerve ablation |
US9358365B2 (en) | 2010-07-30 | 2016-06-07 | Boston Scientific Scimed, Inc. | Precision electrode movement control for renal nerve ablation |
US9463062B2 (en) | 2010-07-30 | 2016-10-11 | Boston Scientific Scimed, Inc. | Cooled conductive balloon RF catheter for renal nerve ablation |
US9408661B2 (en) | 2010-07-30 | 2016-08-09 | Patrick A. Haverkost | RF electrodes on multiple flexible wires for renal nerve ablation |
US9155589B2 (en) | 2010-07-30 | 2015-10-13 | Boston Scientific Scimed, Inc. | Sequential activation RF electrode set for renal nerve ablation |
US8974451B2 (en) | 2010-10-25 | 2015-03-10 | Boston Scientific Scimed, Inc. | Renal nerve ablation using conductive fluid jet and RF energy |
US9220558B2 (en) | 2010-10-27 | 2015-12-29 | Boston Scientific Scimed, Inc. | RF renal denervation catheter with multiple independent electrodes |
US9028485B2 (en) | 2010-11-15 | 2015-05-12 | Boston Scientific Scimed, Inc. | Self-expanding cooling electrode for renal nerve ablation |
US9668811B2 (en) | 2010-11-16 | 2017-06-06 | Boston Scientific Scimed, Inc. | Minimally invasive access for renal nerve ablation |
US9089350B2 (en) | 2010-11-16 | 2015-07-28 | Boston Scientific Scimed, Inc. | Renal denervation catheter with RF electrode and integral contrast dye injection arrangement |
US9326751B2 (en) | 2010-11-17 | 2016-05-03 | Boston Scientific Scimed, Inc. | Catheter guidance of external energy for renal denervation |
US9060761B2 (en) | 2010-11-18 | 2015-06-23 | Boston Scientific Scime, Inc. | Catheter-focused magnetic field induced renal nerve ablation |
US9023034B2 (en) | 2010-11-22 | 2015-05-05 | Boston Scientific Scimed, Inc. | Renal ablation electrode with force-activatable conduction apparatus |
US9192435B2 (en) | 2010-11-22 | 2015-11-24 | Boston Scientific Scimed, Inc. | Renal denervation catheter with cooled RF electrode |
US20120157993A1 (en) | 2010-12-15 | 2012-06-21 | Jenson Mark L | Bipolar Off-Wall Electrode Device for Renal Nerve Ablation |
US9220561B2 (en) | 2011-01-19 | 2015-12-29 | Boston Scientific Scimed, Inc. | Guide-compatible large-electrode catheter for renal nerve ablation with reduced arterial injury |
EP2734259B1 (en) | 2011-07-20 | 2016-11-23 | Boston Scientific Scimed, Inc. | Percutaneous device to visualize, target and ablate nerves |
CN103813829B (zh) | 2011-07-22 | 2016-05-18 | 波士顿科学西美德公司 | 具有可定位于螺旋引导件中的神经调制元件的神经调制系统 |
WO2013055826A1 (en) | 2011-10-10 | 2013-04-18 | Boston Scientific Scimed, Inc. | Medical devices including ablation electrodes |
US9420955B2 (en) | 2011-10-11 | 2016-08-23 | Boston Scientific Scimed, Inc. | Intravascular temperature monitoring system and method |
WO2013055815A1 (en) | 2011-10-11 | 2013-04-18 | Boston Scientific Scimed, Inc. | Off -wall electrode device for nerve modulation |
US9364284B2 (en) | 2011-10-12 | 2016-06-14 | Boston Scientific Scimed, Inc. | Method of making an off-wall spacer cage |
WO2013059202A1 (en) | 2011-10-18 | 2013-04-25 | Boston Scientific Scimed, Inc. | Integrated crossing balloon catheter |
EP2768563B1 (en) | 2011-10-18 | 2016-11-09 | Boston Scientific Scimed, Inc. | Deflectable medical devices |
CN104023662B (zh) | 2011-11-08 | 2018-02-09 | 波士顿科学西美德公司 | 孔部肾神经消融 |
WO2013074813A1 (en) | 2011-11-15 | 2013-05-23 | Boston Scientific Scimed, Inc. | Device and methods for renal nerve modulation monitoring |
US9119632B2 (en) | 2011-11-21 | 2015-09-01 | Boston Scientific Scimed, Inc. | Deflectable renal nerve ablation catheter |
US9265969B2 (en) | 2011-12-21 | 2016-02-23 | Cardiac Pacemakers, Inc. | Methods for modulating cell function |
CN104254368B (zh) | 2011-12-23 | 2016-10-12 | 维西克斯血管公司 | 重建身体通道的组织或身体通路附近的组织的方法及设备 |
WO2013101452A1 (en) | 2011-12-28 | 2013-07-04 | Boston Scientific Scimed, Inc. | Device and methods for nerve modulation using a novel ablation catheter with polymeric ablative elements |
US9050106B2 (en) | 2011-12-29 | 2015-06-09 | Boston Scientific Scimed, Inc. | Off-wall electrode device and methods for nerve modulation |
WO2013169927A1 (en) | 2012-05-08 | 2013-11-14 | Boston Scientific Scimed, Inc. | Renal nerve modulation devices |
WO2014032016A1 (en) | 2012-08-24 | 2014-02-27 | Boston Scientific Scimed, Inc. | Intravascular catheter with a balloon comprising separate microporous regions |
US9173696B2 (en) | 2012-09-17 | 2015-11-03 | Boston Scientific Scimed, Inc. | Self-positioning electrode system and method for renal nerve modulation |
WO2014047411A1 (en) | 2012-09-21 | 2014-03-27 | Boston Scientific Scimed, Inc. | System for nerve modulation and innocuous thermal gradient nerve block |
WO2014047454A2 (en) | 2012-09-21 | 2014-03-27 | Boston Scientific Scimed, Inc. | Self-cooling ultrasound ablation catheter |
EP2906135A2 (en) | 2012-10-10 | 2015-08-19 | Boston Scientific Scimed, Inc. | Renal nerve modulation devices and methods |
US9693821B2 (en) | 2013-03-11 | 2017-07-04 | Boston Scientific Scimed, Inc. | Medical devices for modulating nerves |
US9956033B2 (en) | 2013-03-11 | 2018-05-01 | Boston Scientific Scimed, Inc. | Medical devices for modulating nerves |
US9808311B2 (en) | 2013-03-13 | 2017-11-07 | Boston Scientific Scimed, Inc. | Deflectable medical devices |
US10265122B2 (en) | 2013-03-15 | 2019-04-23 | Boston Scientific Scimed, Inc. | Nerve ablation devices and related methods of use |
CN105473090B (zh) | 2013-03-15 | 2019-05-03 | 波士顿科学国际有限公司 | 重建身体通道的组织或邻近身体通道的组织的方法及装置 |
JP6139772B2 (ja) | 2013-03-15 | 2017-05-31 | ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. | 電極パッドと共に使用するための制御ユニットおよび漏電を推定するための方法 |
WO2014205388A1 (en) | 2013-06-21 | 2014-12-24 | Boston Scientific Scimed, Inc. | Renal denervation balloon catheter with ride along electrode support |
EP3010436A1 (en) | 2013-06-21 | 2016-04-27 | Boston Scientific Scimed, Inc. | Medical devices for renal nerve ablation having rotatable shafts |
US9707036B2 (en) | 2013-06-25 | 2017-07-18 | Boston Scientific Scimed, Inc. | Devices and methods for nerve modulation using localized indifferent electrodes |
US9833283B2 (en) | 2013-07-01 | 2017-12-05 | Boston Scientific Scimed, Inc. | Medical devices for renal nerve ablation |
WO2015006573A1 (en) | 2013-07-11 | 2015-01-15 | Boston Scientific Scimed, Inc. | Medical device with stretchable electrode assemblies |
CN105377169B (zh) | 2013-07-11 | 2019-04-19 | 波士顿科学国际有限公司 | 用于神经调制的装置和方法 |
EP3049007B1 (en) | 2013-07-19 | 2019-06-12 | Boston Scientific Scimed, Inc. | Spiral bipolar electrode renal denervation balloon |
CN105392435B (zh) | 2013-07-22 | 2018-11-09 | 波士顿科学国际有限公司 | 具有扭绞球囊的肾神经消融导管 |
US10342609B2 (en) | 2013-07-22 | 2019-07-09 | Boston Scientific Scimed, Inc. | Medical devices for renal nerve ablation |
EP3035879A1 (en) | 2013-08-22 | 2016-06-29 | Boston Scientific Scimed, Inc. | Flexible circuit having improved adhesion to a renal nerve modulation balloon |
CN105555218B (zh) | 2013-09-04 | 2019-01-15 | 波士顿科学国际有限公司 | 具有冲洗和冷却能力的射频(rf)球囊导管 |
US10952790B2 (en) | 2013-09-13 | 2021-03-23 | Boston Scientific Scimed, Inc. | Ablation balloon with vapor deposited cover layer |
US11246654B2 (en) | 2013-10-14 | 2022-02-15 | Boston Scientific Scimed, Inc. | Flexible renal nerve ablation devices and related methods of use and manufacture |
US9687166B2 (en) | 2013-10-14 | 2017-06-27 | Boston Scientific Scimed, Inc. | High resolution cardiac mapping electrode array catheter |
JP6259098B2 (ja) | 2013-10-15 | 2018-01-10 | ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. | 医療デバイスおよび同医療デバイスを製造する方法 |
US9770606B2 (en) | 2013-10-15 | 2017-09-26 | Boston Scientific Scimed, Inc. | Ultrasound ablation catheter with cooling infusion and centering basket |
JP6259099B2 (ja) | 2013-10-18 | 2018-01-10 | ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. | 可撓性を備える導電性ワイヤを備えるバルーン・カテーテル、並びに関連する使用および製造方法 |
JP2016534842A (ja) | 2013-10-25 | 2016-11-10 | ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. | 除神経フレックス回路における埋め込み熱電対 |
EP3091922B1 (en) | 2014-01-06 | 2018-10-17 | Boston Scientific Scimed, Inc. | Tear resistant flex circuit assembly |
US11000679B2 (en) | 2014-02-04 | 2021-05-11 | Boston Scientific Scimed, Inc. | Balloon protection and rewrapping devices and related methods of use |
EP3424453A1 (en) | 2014-02-04 | 2019-01-09 | Boston Scientific Scimed, Inc. | Alternative placement of thermal sensors on bipolar electrode |
Family Cites Families (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3518273A (en) | 1966-08-03 | 1970-06-30 | Warner Lambert Pharmaceutical | Benzopyranquinolinol derivatives and process for their production |
US3518258A (en) | 1967-05-09 | 1970-06-30 | Warner Lambert Pharmaceutical | Pyrano(3,2-i)quinolizine and process for the production |
US3493579A (en) | 1967-05-29 | 1970-02-03 | Little Inc A | 1,4-ethano-5h-(1)benzopyrano (3,4-b)pyridines |
US3541100A (en) | 1967-12-14 | 1970-11-17 | American Cyanamid Co | Benzheteroazolo(2,3-a)isoquinolium salts |
US3518272A (en) | 1968-02-05 | 1970-06-30 | Warner Lambert Pharmaceutical | Tetrahydro benzopyranoquinolines and process for their production |
US3600375A (en) | 1968-03-25 | 1971-08-17 | Dow Chemical Co | Azomethanodioxocins |
US3551565A (en) | 1968-04-26 | 1970-12-29 | Geigy Chem Corp | Pharmaceutical compositions and uses of oxazinoisoquinoline derivatives |
US4418068A (en) | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
SU1051092A1 (ru) | 1982-07-05 | 1983-10-30 | Ростовский Ордена Трудового Красного Знамени Государственный Университет Им.М.А.Суслова | Способ получени тиохиндолинов |
GB8500605D0 (en) | 1985-01-10 | 1985-02-13 | Secretary Trade Ind Brit | Damped spring |
JPS63238079A (ja) | 1987-03-24 | 1988-10-04 | Masatoshi Yamato | キノリン系化合物、その製造法及びその化合物を有効成分とする抗癌剤 |
JPH0720867B2 (ja) | 1987-05-26 | 1995-03-08 | キッセイ薬品工業株式会社 | 骨粗鬆症治療剤 |
MX13270A (es) | 1987-10-05 | 1993-06-01 | Pfizer | Procedimiento para la preparacion de derivados de 4-aminopiridina |
JPH02256667A (ja) | 1988-12-27 | 1990-10-17 | Masatoshi Yamato | 縮合キノリン系化合物およびその製造方法 |
US5223506A (en) | 1991-06-04 | 1993-06-29 | Glaxo Inc. | Cyclic antitumor compounds |
WO1994020869A1 (en) | 1993-03-12 | 1994-09-15 | Ppg Industries, Inc. | Novel benzopyrans |
US5428040A (en) | 1993-08-31 | 1995-06-27 | The Du Pont Merck Pharmaceutical Company | Carbocyclic fused-ring quinolinecarboxylic acids useful as immunosuppressive agents |
AU3731895A (en) | 1994-09-28 | 1996-04-19 | Shaman Pharmaceuticals, Inc. | Cryptolepine analogs with hypoglycemic activity |
PT800519E (pt) | 1994-12-22 | 2004-03-31 | Ligand Pharm Inc | Compostos moduladores de receptores de esteroides e metodos |
DK0792292T4 (da) | 1995-09-08 | 2009-07-20 | Karobio Ab | Orphan-receptor |
US5998402A (en) | 1996-04-19 | 1999-12-07 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
WO1998045272A1 (en) | 1997-04-07 | 1998-10-15 | Latrobe University | Topoisomerase inhibitors |
US7157568B1 (en) | 1997-08-05 | 2007-01-02 | American Home Products Corporation | Human estrogen receptor-β |
US6110962A (en) | 1998-05-12 | 2000-08-29 | American Home Products Corporation | 11-aryl-benzo[B]naphtho[2,3-D]furans and 11-aryl-benzo[B]naphtho[2,3-D]thiophenes useful in the treatment of insulin resistance and hyperglycemia |
GB9814620D0 (en) | 1998-07-06 | 1998-09-02 | Karobio Ab | Vasculoprotector |
WO2000059897A2 (en) | 1999-04-06 | 2000-10-12 | Akzo Nobel N.V. | Esters and carbonates of 2-(4-hydroxyphenyl)-6(or 5)-hydroxy-benzothiophene derivatives as selective estrogenic compounds |
WO2000061230A2 (en) | 1999-04-09 | 2000-10-19 | Karo Bio Ab | Estrogen receptors-beta antagonism and bone diseases |
EP1173164A2 (en) | 1999-04-16 | 2002-01-23 | AstraZeneca AB | Estrogen receptor-beta ligands |
GB9913649D0 (en) | 1999-06-11 | 1999-08-11 | Karobio Ab | Estrogen receptor |
AU7622000A (en) | 1999-10-01 | 2001-05-10 | Institute Of Molecular And Cell Biology | Compounds for the treatment of viral-mediated diseases |
WO2001064665A1 (en) | 2000-03-01 | 2001-09-07 | Akzo Nobel N.V. | Chroman derivatives as estrogenic compounds |
JP2003528858A (ja) | 2000-03-27 | 2003-09-30 | アクゾ・ノベル・エヌ・ベー | エストロゲン関連治療用のノンステロイド系四環式化合物 |
WO2002030407A1 (en) | 2000-10-13 | 2002-04-18 | Astrazeneca Ab | ESTROGEN RECEPTOR-β LIGANDS |
GB2361642A (en) | 2000-10-24 | 2001-10-31 | Karobio Ab | Estrogen receptor beta (ERbeta) agonists for use in cancer treatment |
US7256201B2 (en) | 2000-12-07 | 2007-08-14 | Astrazeneca Ab | Selective estrogen receptor-β ligands |
US20070004713A1 (en) | 2000-12-07 | 2007-01-04 | Bernard Barlaam | Therapeutic benimidazole compounds |
EP1345914A1 (en) | 2000-12-22 | 2003-09-24 | AstraZeneca AB | Therapeutic compounds |
EP1365768B1 (en) | 2001-02-27 | 2008-05-07 | Bayer Schering Pharma Aktiengesellschaft | Use of er-beta selective antagonists as contraceptives |
JP3562481B2 (ja) | 2001-04-02 | 2004-09-08 | 株式会社村田製作所 | 射出成形方法および射出成形機 |
GB2374412A (en) | 2001-04-11 | 2002-10-16 | Karobio Ab | Hypertension treatment and assay |
US6559177B2 (en) | 2001-04-19 | 2003-05-06 | Wyeth | 5, 11-Dioxa-benzo[b]fluoren-10-one and 5-oxa-11-thia-benzo[b]fluoren-10-ones as estrogenic agents |
US6589980B2 (en) | 2001-05-17 | 2003-07-08 | Wyeth | Substituted 10,11-benzo[b]fluoren-10-ones as estrogenic agents |
CA2467013C (en) | 2001-11-19 | 2010-08-10 | Eli Lilly And Company | Substituted benzopyrans as selective estrogen receptor-beta agonists |
EP1478631A1 (en) | 2001-11-28 | 2004-11-24 | AstraZeneca AB | Therapeutic compounds |
UA83620C2 (ru) | 2001-12-05 | 2008-08-11 | Уайт | Замещенные бензоксазолы и их аналоги как эстрогенные агенты |
US6960607B2 (en) | 2001-12-13 | 2005-11-01 | Wyeth | Naphthyl benzoxazoles and benzisoxazoles as estrogenic agents |
TW200301107A (en) | 2001-12-13 | 2003-07-01 | Wyeth Corp | Substituted 6H-dibenzo[c,h]chromenes as estrogenic agents |
US6903238B2 (en) | 2001-12-13 | 2005-06-07 | Wyeth | Substituted indenones as estrogenic agents |
US6835745B2 (en) | 2002-01-15 | 2004-12-28 | Wyeth | Phenyl substituted thiophenes as estrogenic agents |
US20030158169A1 (en) | 2002-01-24 | 2003-08-21 | Wyeth | Method of treating hemorrhagic shock or systemic inflammatory response syndrome |
US20040002524A1 (en) | 2002-06-24 | 2004-01-01 | Richard Chesworth | Benzimidazole compounds and their use as estrogen agonists/antagonists |
WO2004073610A2 (en) | 2003-02-13 | 2004-09-02 | Merck & Co., Inc. | Estrogen receptor modulators |
DK1626974T3 (da) | 2003-04-21 | 2008-11-17 | Lilly Co Eli | Substituerede benzopyraner som selektive östrogenreceptor-beta-agonister |
EP1618102B1 (en) | 2003-04-21 | 2010-02-10 | Eli Lilly And Company | Substituted benzopyrans as selective estrogen receptor-beta agonists |
DE10318896A1 (de) | 2003-04-22 | 2004-11-25 | Schering Ag | 8beta-Vinyl-11beta-(omega-substituierte)alkyl-estra-1,3,5(10)-triene |
US7279600B2 (en) | 2003-05-02 | 2007-10-09 | Wyeth | Hydroxy-biphenyl-carbaldehyde oxime derivatives and their use as estrogenic agents |
CL2004000985A1 (es) | 2003-05-16 | 2005-01-14 | Wyeth Corp | Compuestos derivados de fenilquinolinas; composicion farmaceutica, proceso de preparacion; y uso para tratar osteoporosis, enfermedad de paget, dano vascular, osteoartritis, cancer oseo, cancer ovarico, cancer prostatico, hipercolesterolemia, aterosc |
US7250440B2 (en) | 2003-08-12 | 2007-07-31 | Wyeth | (Hydroxyphenyl)-1H-indole-3-carbaldehyde oxime derivatives as estrogenic agents |
US20070099880A1 (en) | 2003-11-24 | 2007-05-03 | Blizzard Timothy A | Estrogen receptor modulators |
US7157492B2 (en) | 2004-02-26 | 2007-01-02 | Wyeth | Dibenzo chromene derivatives and their use as ERβ selective ligands |
CA2569152A1 (en) | 2004-06-10 | 2005-12-29 | Merck & Co., Inc. | Estrogen receptor modulators |
-
2005
- 2005-09-06 US US11/219,940 patent/US7354927B2/en not_active Expired - Fee Related
- 2005-09-06 WO PCT/US2005/031696 patent/WO2006029146A2/en active Application Filing
- 2005-09-06 EP EP05813086A patent/EP1789420A2/en not_active Withdrawn
- 2005-09-06 CA CA002578164A patent/CA2578164A1/en not_active Abandoned
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- 2005-09-06 AU AU2005282554A patent/AU2005282554A1/en not_active Abandoned
- 2005-09-06 CN CNA2005800379553A patent/CN101052641A/zh active Pending
- 2005-09-06 JP JP2007531265A patent/JP2008512458A/ja active Pending
- 2005-09-06 MX MX2007002789A patent/MX2007002789A/es active IP Right Grant
- 2005-09-06 BR BRPI0514974-6A patent/BRPI0514974A/pt not_active IP Right Cessation
- 2005-09-06 RU RU2007106870/04A patent/RU2007106870A/ru not_active Application Discontinuation
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- 2007-02-22 IL IL181514A patent/IL181514A0/en unknown
- 2007-03-06 ZA ZA200701950A patent/ZA200701950B/xx unknown
- 2007-03-07 EC EC2007007302A patent/ECSP077302A/es unknown
- 2007-03-14 NO NO20071364A patent/NO20071364L/no not_active Application Discontinuation
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AU2005282554A1 (en) | 2006-03-16 |
US7354927B2 (en) | 2008-04-08 |
MX2007002789A (es) | 2007-04-24 |
EP1789420A2 (en) | 2007-05-30 |
JP2008512458A (ja) | 2008-04-24 |
RU2007106870A (ru) | 2008-10-20 |
BRPI0514974A (pt) | 2008-07-01 |
IL181514A0 (en) | 2007-07-04 |
WO2006029146A3 (en) | 2006-04-27 |
KR20070061536A (ko) | 2007-06-13 |
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