CN1088205A - 苯并噻吩及其相关物的改进 - Google Patents
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Abstract
本发明提供了用于通过抑制骨损失来治疗或预
防骨质疏松症的化合物、方法和药方。可以使用这些
化合物、方法和配方而不出现雌激素治疗所伴生的不
利效果,因而可有效地预防或治疗骨质疏松症。
Description
本发明涉及一种发现,即一组2-苯基-3-芳酰基苯并噻吩可用于防止骨损失。
骨损失的机理还不太清楚,但就实际效果而言,该疾病起因于新的健康骨的形成与老骨的再吸收(reseoption)之间的失衡,这导致了骨组织的净损失。这种骨损失包括骨中矿物质含量和蛋白质基质成分的减少,并造成骨折率的增加,主要是大腿骨和前臂及脊椎骨折率的增加。这些骨折又会引起总体发病率的上升,身材和灵活性的明显损失,在许多情况下,还会由于并发症而使死亡率升高。
骨损失发生在多种人身上,包括绝经后的妇女、作过子宫切除手术的病人、正长期服用或曾经长期服用过皮质类固醇的病人、患柯兴综合症的病人和患性腺发育不全的病人。
未受抑制的骨损失可以引起骨质疏松症,这是一种较重的令人虚弱的疾病,其主要特点是骨质损失(密度降低且骨间隙变大)而骨头体积不减少,产生多孔性和易碎性。
最常见的一类骨质疏松症发现由绝经后的妇女所患,仅美国就有估计两千万至两千五百万妇女受影响。绝经后骨质疏松症的一个重要特点是由于卵巢停止产生雌性激素而造成骨质大量而迅速的损失。的确,数据清楚地表明,雌性激素能够限制骨质疏松性骨损失的发展,在美国和许多其它国家,对绝经后骨质疏松症进行雌性激素补偿治疗是受到承认的。然而,尽管雌性激素对骨头是有益的。但即使很低量的、长期的雌性激素治疗也会牵涉到许多疾病,包括增加患子宫癌和乳腺癌的危险,因而使得许多妇女拒绝这种治疗。最近提出的医疗方法试图减少患癌的危险,例如联合服用孕激素和雌激素,这使得病人不得不经受有规律地排血,而这正是大多数老年妇女所不能接受的。考虑到雌激素疗法显著的不良效应和雌激素对消除现有骨损失的有限能力,因而需要开发可对骨头产生所需作用但不引起不良效应的替代的骨损失疗法。
利用与雌激素受体发生相互作用的抗雌激素化合物来满足这种需要的偿试没有获得多大成功,原因也许是由于这些化合物一般具有混合的兴奋剂/拮抗物作用。也即,虽然这些化合物对抗雌激素与受体的相互作用,但这些化合物本身也可以在那些具有雌性激素受体的组织中引起雌激素作用。因此,有些抗雌激素也具有与雌激素疗法相同的不良效果。
本发明提供了一种抑制骨损失但没有伴随雌激素治疗的不良效应的方法,因而可以用来对骨质疏松症进行有效且可以接受的治疗。
在本发明配方和方法中作活性组分的2-苯基-3-芳酰基苯并噻吩是由C.David Jones和Tulio Suarez首次作为反受精剂开发的(见US专利4,133,814,1979年1月9日出版)。这组中的某些化合物发现可用来抑制乳房肿瘤生长。
Jones后来发现,一组有关的化合物可用于抗雌激素和抗雄激素治疗,特别是用于处理乳房和前列腺肿瘤(见US专利4,418,068,1983年11月29日出版)。这些化合物中的一种,即n为O、R和R1为羟基、R2为哌啶子基环的式Ⅰ化合物,已作过一段短时间的治疗乳腺癌的临床试验。该化合物称为raloxifene,以前叫keoxifene。治疗服用时,raloxifene优选以盐的形式服用,最优选作为盐酸盐服用。
本发明提供了一种治疗骨损失的新方法,包括给需要治疗的人施用有效量的式Ⅰ的化合物或其药学上可接受的盐,
式中:
n为0,1或2;
R和R1各自为氢、羟基、C1-C6烷氧基、C1-C6酰氧基、C1-C6烷氧基-C2-C6-酰氧基、R3取代的芳氧基、R3取代的芳酰基氧基、R4取代的羰氧基、氯或溴;
R2为选自吡咯烷子基(pyrrolidino)、哌啶子基、或六亚甲基亚氨基的杂环;
R3为C1-C3烷基、C1-C3烷氧基、氢、或卤素;
R4为C1-C6烷氧基或芳氧基。
本发明也提供了一种用于抑制骨损失的药物配方,含有一种式Ⅰ的化合物,其中R、R1、R2和n如前所述,其含量以提高或保持骨密度为准,并含有药学上可接受的载体。
本发明涉及一种发现,即式Ⅰ的一组2-苯基-3-芳酰基苯并噻吩(苯并噻吩)可用于治疗骨质疏松症。式Ⅰ的苯并噻吩抑制由于缺乏内源雌激素而引起的骨损失,例如发生在由于自然、外科或其它过程而造成月经停止的妇女身上的骨损失。较少发生在男人身上的骨密度和质量的减少,同样与激素调节的损失相关,这也是本发明方法所要治疗的目标之一。
式Ⅰ的苯并噻吩是一系列非甾族化合物,对第一性靶组织中常见的雌激素受体有高的亲合性。然而,它们导致这些组织中最小的雌激素响应,实际上是天然雌激素如雌二醇的有效的拮抗药。当给完好或受雌激素治疗的动物服用时,式Ⅰ的苯并噻吩能够对抗第一性靶组织中的经典的雌激素响应而不会明显降低骨密度,并且它们能防止雌激素不足的动物的骨损失。这二歧现象(dichotomy)表明对特定靶细胞有选择性兴奋剂/拮抗药作用,这在处理更年期综合症时似乎是非常需要的。因此,该发现的真正益处在于,式Ⅰ的苯并噻吩抑制骨损失但不会引出第一性靶组织中明显的雌激素响应。因而,本发明提供了一种抑制骨损失的方法,包括给需要治疗的人施用式Ⅰ的化合物,其量以抑制骨损失但不会明显地影响第一性靶组织为准。这些特征的组合使得可以用来长期治疗慢性病,且出现通常雌激素补偿治疗的不良效应的危险较小。
式Ⅰ苯并噻吩的生物学作用很复杂,也许与血液中可测出的母体化合物无关。临床试验中人口服本发明优选的苯并噻吩raloxifene(以其盐酸盐服用)后,在这些受试者的血清中测不出该母体化合物。已经确认,口服之后,该化合物即广泛地共轭成葡糖苷酸形式,并迅速从血流中清除出来。虽然在人类身体中测不出生物终点,但重要的是该化合物不是生物上可利用的。
已针对实验动物进行了若干生物利用率试验以测定生物活性。动物研究表明,即使raloxifene在动物血浆中广泛共轭的条件下,raloxifene在抑制氚化雌二醇的子宫吸收和对雌二醇的正常子宫营养(uterotrophic)效应方面都是最有效的。而且,从服过raloxifene的人体尿液分离出的共轭物,当静脉注射给鼠时显示了明显的抗雌素激/抗子宫营养活性,以类似于母体化合物的方式抑制了氚化雌二醇与鼠子宫雌激素受体的相互作用。这些研究提示共轭的化合物可能已经在作用位置转化成母体形式,大概是由于β-葡糖苷酸酶的作用。这种转化可能有助于化合物的活性。β-葡糖苷酸酶是相当普遍的,它在骨变型的再吸收过程中被认为是有活性的,如果需要活性,估计可用它来将共轭化合物转化成母体形式。因此,式Ⅰ苯并噻吩的共轭对其作为骨损失抑制剂的生物有效性不一定有害。
因此,本发明提供的治疗方法是通过给需要抑制骨损失的人施用一定剂量的式Ⅰ化合物或其药学上可接受的盐来实现的,所述剂量应足以有效地抑制骨损失。该方法的一种特殊好处是可以避免有潜在危害和不可接受的雌激素副效应。该方法所预期的抑制骨损失包括医药治疗和/或预防性处理两方面,如果合适的话。
该方法还包括与雌激素结合施用式Ⅰ给出的化合物。这里所用术语雌激素是指与通常认为是17β-雌二醇的天然作用分子活性谱图类似的任何化合物。这些化合物的例子包括雌三醇、雌酮、乙炔基雌二醇、premarin(由天然资源分离出的共轭雌激素的工业制品-Ayerst)等。而且,由于式Ⅰ化合物的选择性兴奋剂/拮抗物性质,这种结合可以提供雌激素治疗的所有益处,而不会出现单用雌激素治疗时伴有的不利效果。
用于描述式Ⅰ化合物的一般化学术语有其常用含义。例如,术语“C1-C3烷基”包括诸如甲基、乙基、丙基和异丙基。术语“C1-C6烷氧基”包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基和己氧基,还包括支链结构如异丙氧基和异丁氧基。
术语“C1-C6酰氧基”包括甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰氧基、己酰氧基等,还包括支链结构例如2,2-二甲基丙酰氧基和3,3-二甲基丁酰氧基。
术语“C1-C6-烷氧基-C2-C6-酰氧基”设想为例如甲氧基乙酰氧基、甲氧基丙酰氧基、甲氧基丁酰氧基、甲氧基戊酰氧基、甲氧基己酰氧基、乙氧基乙酰氧基、乙氧基丙酰氧基、乙氧基丁酰氧基、乙氧基戊酰氧基、乙氧基己酰氧基、丙氧基乙酰氧基、丙氧基丙酰氧基、丙氧基丁酰氧基等等。
还应理解,这里所用的术语例如烷基和烷氧基结构也包括环烷基和环烷氧基,这种结构中的碳原子数至少为3。
术语“R3取代的芳氧基”和“R3取代的芳酰氧基”包括例如苯氧基、噻吩氧基、呋喃氧基、萘氧基、苯甲酰氧基、噻吩甲酰氧基、呋喃甲酰氧基、萘甲酰氧基等等,其中R3取代基可为氢、羟基、C1-C3烷基、C1-C3烷氧基、或卤素。
术语“R4取代的羰氧基”(这里R4取代基可以是C1-C6烷氧基或芳氧基)包括如甲氧基羰氧基、乙氧基羰氧基、丙氧基羰氧基、丁氧基羰氧基、戊氧基羰氧基、己氧基羰氧基、苯氧基羰氧基、噻吩氧基羰氧基、呋喃氧基羰氧基和萘氧基羰氧基这样的碳酸盐结构。
本发明优选的实施方式包括使用式Ⅰ的化合物,其中R和R1不是氢、烷氧基、芳氧基、氯或溴,因而表示酯和碳酸盐构型。其它优选实施方式包括使用R和R1相同的式Ⅰ化合物。用于实施本发明时,某些R2基团具有优选性能。例如,本发明的优选实施方式包括使用R2为哌啶子基、或吡咯烷子基、尤其是哌啶子基的式Ⅰ化合物。哌啶子基和吡咯烷子基化合物进一步优选的分组包括R和R1不是氢的化合物,特别是R和R1为羟基的化合物。本发明最优选的实施方式是使用reloxifene,尤其是当作为盐酸盐施用时。
本发明方法所用的化合物都可用已有方法制备,例如用US专利4,133,814和US专利4,418,068详述的方法。通常,该方法由带6-羟基和2-(4-羟苯基)基团的苯并[b]噻吩开始。该起始化合物被保护、烷基化和脱保护,形成R和R1均为羟基的式Ⅰ化合物。如果需要,式Ⅰ化合物可以生成醚、酯和碳酸盐。上述US专利提供了制备这类化合物的例子。可用于本发明的另一些衍生物的特殊制备在下面的制备部分概括描述。为了适应特定取代基的反应性官能团,必须对上述方法进行改变。对本领域技术人员来说,这些改变是既明显又容易弄清的。
本发明方法所用的化合物可与许多有机和无机的酸和碱形成药学可接受的酸和碱加成盐,包括药物化学中常用的药理学可接受的盐。这些盐也是本发明的组成部分。用于形成这些盐的典型无机酸包括氢氯酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等等。也可以使用由有机酸得到的盐,有机酸如脂族单和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷双酸、芳香族酸、脂族和芳香族磺酸。这类药学上可接受的盐包括乙酸盐、苯基乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、邻乙酸基苯甲酸盐、萘-2-苯甲酸盐、溴化物、异丁酸盐、苯基丁酸盐、β-羟基丁酸盐、丁炔-1,4-二酸盐(dioate)、己炔-1,4-二酸盐、癸酸盐、辛酸盐、氯化物盐、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、乙醇酸盐、庚酸盐、马尿酸盐、乳酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二甲酸盐(teraphthalate)、磷酸盐、一氢磷酸盐、二氢磷酸盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯基丙酸盐、水杨酸盐、癸二酸盐、琥珀酸盐、辛二酸盐、硫酸盐、硫酸氢盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磺酸盐、苯磺酸盐、对溴苯基磺酸盐、氯苯磺酸盐、乙烷磺酸盐、2-羟基乙烷磺酸盐、甲烷磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等等。
此外,有些式Ⅰ化合物可以和水或有机溶剂如乙醇形成溶剂化物。这些溶剂化物也可用于本发明的方法。
药学可接受的酸加成盐一般通过使式Ⅰ化合物与等摩尔或过量的酸反应形成。反应物一般在共同溶剂如二乙醚或苯中化合。该盐一般在约1小时至10天内由溶液沉淀出来,可以通过过滤或用常见方式汽提出溶剂而分离出来。
一般用来形成盐的碱包括氢氧化铵和碱金属及碱土金属氢氧化物,碳酸盐和碳酸氢盐、以及脂族和芳族胺、脂族二胺和羟基烷基胺。特别适用于制备加成盐的碱包括氢氧化铵、碳酸钾、碳酸氢钠、氢氧化钙、甲基铵、二乙胺、1,2-乙二胺、环己胺和乙醇胺。
与原化合物相比较,药学可容盐一般增强了溶解度特性,因而常常更适合于配制成液体或乳液。
本发明还提供了可用于抑制骨损失的药物配方,含有一种式Ⅰ的化合物或其药学可容盐,加上一或多种药学可接受的赋形剂。该药物配方可由现有技术已知的方法配制。例如,将化合物与常用赋形剂、稀释剂、或载体一起配制,成形为片剂、胶囊、悬浮剂、粉剂等。适用于该配方的赋形剂、稀释剂和载体的例子包括:填充剂和扩充剂如淀粉、糖、甘露糖醇和硅衍生物;粘合剂如羧甲基纤维素和其它纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;增湿剂如甘油;崩解剂如琼脂、碳酸钙和碳酸氢钠;缓溶剂如石蜡;回吸(resorption)加速剂如季铵化合物;表面活性剂如鲸蜡醇、单硬脂酸甘油脂;吸附载体如高岭土和膨润土;润滑剂如滑石、硬脂酸钙和硬脂酸镁,和固体聚乙二醇。
该化合物也可配制成便于口服的酏剂或溶液,或作为肠胃外给药用的溶液,例如经肌内、皮下或静脉内注射。此外,该化合物也非常适合配制成持续释放的剂型等。该配方也可制成只在或优先在肠道的特定部分释放活性成分,该过程可能在一定时间期限内进行。包层、胶囊或保护性基料例如可由聚合材料或蜡制成。
按照本发明,治疗或抑制骨损失所用式Ⅰ化合物的具体剂量取决于疾病的严重程度、给药的方式和其它由治病医生决定的相关因素。通常,式Ⅰ化合物的有效剂量为约0.1至约1000mg,一般约50至400mg,最优选约50至200mg。这种剂量可给需治疗者每天分一至三次给药,或根据需要分更多次,以有效地抑制骨损失过程。
通常优选以酸加成盐的形式施用式Ⅰ的化合物,因为习惯上施用的药物带有一个像哌啶子基这样的碱性基团。给老年人(例如在×射线分析中呈现骨损失的男性或绝经后女性)口服这种化合物也是有利的。为此,可以使用以下的口服剂型。
配方
在下述配方中,“活性成分”指式Ⅰ化合物。
配方1:明胶胶囊
用下列物质制备硬明胶胶囊:
成份 量(mg/胶囊)
活性成份 0.1-1000
淀粉,NF 0-650
可流动淀粉粉末 0-650
350厘沲的硅氧烷流体 0-15
混合这些成份,过45目US筛,并填入硬明胶胶囊中。
已制备了含raloxifene 盐酸盐的特殊胶囊配方的例子,包括如下成分:
配方2:Raloxifene胶囊
成份 量(mg/胶囊)
Raloixfene氢氯化物 1
淀粉,NF 112
可流动淀粉粉末 225.3
350厘沲的硅氧烷流体 1.7
配方3:Raloxifene胶囊
成份 量(mg/胶囊)
Raloixfene 5
淀粉,NF 108
可流动淀粉粉末 225.3
350厘沲的硅氧烷流体 1.7
配方4:Raloxifene胶囊
成份 量(mg/胶囊)
Raloixfene氢氯化物 10
淀粉,NF 103
可流动淀粉粉末 225.3
350厘沲的硅氧烷流体 1.7
配方5:Raloxifene胶囊
成份 量(mg/胶囊)
Raloixfene氢氯化物 50
淀粉,NF 150
可流动淀粉粉末 397
350厘沲的硅氧烷流体 3.0
上述具体配方可以按照规定的合理范围改变。
用下述成份制备了片剂制品:
配方6:片剂
成份 量(mg/片)
活性剂成份 0.1-1000
纤维素,微晶 0-650
二氧化硅,烘制(fumed) 0-650
硬脂酸 0-1.5
混合各成份,并压制成片剂。
另外还制备了下述各含0.1-1000mg活性成份的药片:
配方7:片剂
成份 量(mg/片)
活性剂成份 0.1-1000
淀粉 45
纤维素,微晶 35
聚乙烯吡咯烷酮(作为10%水溶液) 4
羧甲基纤维素钠 4.5
硬脂酸镁 0.5
滑石 1
使活性成份、淀粉和纤维素通过45目U.S.筛并彻底混合。使得到的粉末与聚乙烯吡咯烷酮溶液混合,然后通过14目U.S.筛。在50°-60℃干燥所得粒状物,并通过18目U.S.筛。先使羧基甲基淀粉钠、硬脂酸镁和滑石通过60号U.S.筛,然后加到粒状物中,混合后,用制片机压制得到片剂。
按下法制得了每5ml剂量含0.1-1000mg药剂的悬浮液:
配方8:悬浮液
成份 量(mg/5ml)
活性剂成份 0.1-1000mg
羧基甲基纤维素钠 50mg
糖浆 1.25mg
苯甲酸溶液 0.10ml
香料 q.v.
色素 q.v.
纯净水至 5ml
使药剂通过45目U.S.筛,并与羧基甲基纤维素钠和糖浆混合,形成光滑的混合膏。用一些水稀释苯甲酸溶液、香料和色素,并搅拌加入。然后加入足量的水以得到所需体积。
可用于本发明配方和方法的示例性化合物如表1所示。
23 1 OH 哌啶子基 HCl
24 2 OH 哌啶子基 HCl
25 1 H 哌啶子基 HCl
26 0 OH 吡咯烷子基 碱
27 0 OH 吡咯烷子基 HCl
28 1 OH 吡咯烷子基 HCl
29 2 OH 吡咯烷子基 HCl
30 0 H 吡咯烷子基 HCl
31 0 OH 六亚甲基亚氨基 HCl
32 1 OH 六亚甲基亚氨基 HCl
33 2 OH 六亚甲基亚氨基 HCl
34 0 OCH3哌啶子基 HCl
在下列制备中,化合物编号与表1中相对应。
化合物1的制备:
6-(4-氟苯甲酰基氧基)-2-[4-(4-氟苯甲酰基氧基)苯基]-苯并[b]噻吩-3-基-[4-(2-(哌啶-1-基)乙氧]苯基]-甲烷酮
使Raloxifene氢氯化物(也叫6-羟基-2-(4-羟苯基)-苯并[b]噻吩-3-基-4-[2-(哌啶-1-基)乙氧苯基]-甲烷酮氢氯化物)(5.1g,10mmol)悬浮于250ml无水四氢呋喃(TFH),加入7.1g(70mmol)三乙胺和约10mg4-(N,N-二甲基氨基)吡啶。在冰浴中冷却悬浮液,并放入氮气氛中。先使4-氟苯甲酰基氯(4.75g,30mmol)溶于20ml无水TFH中,在20分钟期间慢慢加入。搅拌反应混合物,使之在18小时内慢慢升至室温。然后过滤,在真空条件下将滤液蒸发成胶。将这样得到的粗产物溶解在少量氯仿中,用以线性梯度溶剂洗脱的硅胶柱进行色谱分离(HPLC),开始用氯仿洗脱,最后用氯仿甲醇混合物(19:1(V/V))。合并含用薄层色谱(硅胶,氯仿-甲醇(9:1))法确定的所需产物的各馏份,并蒸发成胶。由乙醚中结晶最终产物,得到3.21g化合物1。
PMR:与结构一致
FDMS:m/e=717M+
对C42H33F2NO6S的元素分析:
理论值:C,70.29;H,4.60;N,1.95
实验值:C,70.05;H,4.60;N,1.89
分子量:717
制备2
化合物2的制备:
6-(4-氟苯甲酰基氧基)-2-[4-(4-氟苯甲酰基氧基)-苯基]-苯并[b]噻吩-3-基-[4-(2-(哌啶-1-基)乙氧基]苯基]-甲烷酮氢氯化物。
使化合物1(5.15g,7.18mmol)溶于25ml THF,加入150ml乙醚。用干HCl气体鼓泡通入溶液,形成白色胶状沉淀物。滗析除去液体,使残渣在醋酸乙酯中结晶,其中加入少量乙醇以形成溶液。过滤产物,用乙醚冲洗,干燥得到4.41g白色粉末状化合物2。
PMR:与结构一致
对C42H34ClF2NO6S的元素分析:
理论值:C,66.88;H,4.54;N,1.86
实验值:C,66.59;H,4.39;N,1.60
分子量:753.5
制备3
化合物3的制备:
6-(环丙基羰氧基)-2-[4-(环丙基羰氧基)-苯基]苯并[b]噻吩-3-基-[4-[2-(哌啶-1-基)乙氧基]-苯基]甲烷酮。
用与制备1相似的方法制备标题化合物,但用环丙基羰基氯,且产物不结晶。产物=2.27g
PMR:与结构一致
FDMS:m/e=610M+
制备4
化合物4的制备:
6-(环丙基羰氧基)-2-[4-(环丙基羰氧基)-苯基]苯并[b]噻吩-3-基-[4-[2-哌啶-1-基)乙氧基]-苯基]甲烷酮氢氯化物。
按制备2所述用化合物3制备化合物4。
制备5
化合物5的制备:
6-(n-丁酰氧基)-2-[4-(n-丁酰氧基)苯基]苯并[b]噻吩-3-基-[4-[2-(哌啶-1-基)乙氧基)苯基]甲烷酮。
用制备1的方法制备化合物5,但起始物质是n-丁酰氯,得到4.12g油状最终产物。
PMR:与结构一致
FDMR:m/e=614(M+1)
制备6
化合物6的制备:
6-(n-丁酰氧基)-2-[4-(n-丁酰氧基)苯基]苯并[b]噻吩-3-基[4-[2-哌啶-1-基)乙氧基]苯基]甲烷酮氢氯化物。
使化合物5(4.12g)溶于醋酸乙酯(50ml)中,加入HCl乙醚溶液直到沉淀停止。滗析出液体,用二乙醚研制白色胶状残渣并过滤。干燥残渣得到1.33g化合物6。
PMR:与结构一致
对C36H40ClNO6S的元素分析:
理论值:C,66.50;H,6.20;N,2.15
实验值:C,66.30;H,6.28;N,1.98
分子量:650.24
制备7
化合物7的制备:
6-(2,2-二甲基丙酰氧基)-2-[4-(2,2-二甲基丙酰氧基)苯基]苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]苯基]甲烷酮
用制备1的方法制备化合物7,但使用2,2-二甲基丙酰基氯。
制备8
化合物8的制备:
6-(2,2-二甲基丙酰氧基)-2-[4-(2,2-二甲基丙酰氧基)苯基]苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]苯基]甲烷酮氢氯化物。
按制备2所述,由化合物7制备化合物8。
FDMS:m/e=614(M-HCl-1)
对C38H44ClNO6S的元素分析:
理论值:C,67.29;H,6.54;N,2.07
实验值:C,67.02;H,6.54;N,1.90
分子量:678.29
制备9
化合物9的制备:
6-(3,3-二甲基丁酰氧基)-2-[4-(3,3-二甲基丁酰氧基)-苯基]苯并[b]噻吩-3-基[4-[2-哌啶-1-基)乙氧基]-苯基]甲烷酮。
用制备1的方法制备化合物9,但使用3,3-二甲基丁酰氯。
制备10
化合物10的制备:
6-(3,3-二甲基丁酰氧基)-2-[4-(3,3-二甲基丁酰氧基)-苯基]苯并[b]噻吩-3-基[4-[2-哌啶-1-基)乙氧基]-苯基]甲烷酮氢氯化物。
按制备2所述,由化合物9制备化合物10。
FDMS:m/e=669(M-HCl-1)
对C40H48ClNO6S的元素分析:
理论值:C,68.02;H,6.85;N,1.98
实验值:C,67.75;H,6.83;N,2.04
分子量:706.35
制备11
化合物11的制备:
6-(4-甲基苯甲酰氧基)-2-[4-(4-甲基苯甲酰氧基)-苯基]苯并[b]噻吩-3-基[4-[2-哌啶-1-基)乙氧基]-苯基]甲烷酮氢氯化物。
用与制备2类似的方法由游离碱制备化合物11。
FDMS:m/e=710(M-HCl-1)
对C44H40ClNO6S的元素分析:
理论值:C,70.81;H,5.39;N,1.88
实验值:C,71.10;H,5.39;N,1.94
分子量:746.33
制备12
化合物12的制备:
6-苯甲酰氧基-2-[4-(苯甲酰氧基)苯基]苯并[b]噻吩-3-基[4-[2-哌啶-1-基)乙氧基]-苯基]甲烷酮。
按制备1所述,由适当的酰基氯制备化合物12。
FDMS:m/e=682(M+1)
对C42H35NO6S的元素分析:
计算值:C,73.80;H,5.14;N,2.05
实验值:C,73.27;H,5.27;N,1.94
分子量:681.8
制备13
化合物13的制备:
6-(n-丁氧基酰基氧基)-2-[4(n-丁氧基酰基氧基)苯基]-苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]-苯基]甲烷酮。
以类似于制备1所述的方式制备化合物13,区别是用n-氯甲酸丁酯代替酰基氯。得到6.13g油状产物。
PMR:与结构一致
FDMS:m/e=674(M+1)
制备14
化合物14的制备:
6-(n-丁氧羰氧基)-2-[4(n-丁氧羰氧基)苯基]-苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]苯基]-甲烷酮氢氯化物。
以类似于制备6所述的方式将化合物13转化为氢氯化物盐。
PMR:与结构一致
对C38H44ClNO8S的元素分析:
计算值:C,64.26;H,6.24;N,1.97
实验值:C,63.97;H,6.34;N,1.98
分子量:710.29
制备15
化合物15的制备:
6-(苯氧基羰氧基)-2-[4(苯氧基羰氧基)苯基]苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]苯基]甲烷酮。
用类似于制备13所述的方式制备该化合物,但使用合适的酰基酯。得到3.59g褐色非晶形粉末状最终产物。
PMR:与结构一致
FDMS:m/e=713(M+)
制备16
化合物16的制备:
6-(苯氧基羰氧基)-2-[4(苯氧基羰氧基)苯基]苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]苯基]甲烷酮氢氯化物。
以类似于制备6所述的方式将化合物15转化成氢氯化物盐。
PMR:与结构一致
对C38H44ClNO8S的元素分析:
计算值:C,67.24;H,4.84;N,1.87
实验值:C,66.94;H,4.96;N,1.84
分子量:750.27
制备17
化合物17的制备:
6-(萘甲酰氧基)-2-[4(1-萘甲酰氧基)苯基]苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基)苯基]甲烷酮。
按制备1所述用合适的酰基卤制备化合物17。得到3.5g白色非晶形粉末。
PMR:与结构一致
FDMS:m/e=781(M+)
对C50H39NO6S的元素分析:
计算值:C,76.80;H,5.03;N,1.79
实验值:C,76.53;H,5.20;N,1.53
分子量:781.94
制备18
化合物18的制备:
6-(甲氧基乙酰氧基)-2-[4(甲氧基乙酰氧基)苯基]苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]苯基]甲烷酮。
如制备1所述用合适的酰基卤制备化合物18。得到3.61g胶质固体。
PMR:与结构一致
FDMS:m/e=618(M+1)
制备19
化合物19的制备:
6-(甲氧基乙酰氧基)-2-[4(甲氧基乙酰氧基)苯基]苯并[b]噻吩-3-基[4-[2-(哌啶-1-基)乙氧基]苯基]甲烷酮氢氯化物。
如制备2所述由3.5g化合物18制备化合物19。得到1.65g非晶形白色粉末。
PMR:与结构一致
FDMS:m/e=618(M+1)
对C34H36NO8S的元素分析:
计算值:C,62.43;H,5.55;N,2.14
实验值:C,62.23;H,5.63;N,2.15
下面用非限定实施例说明本发明的方法和配方。
例1
在说明方法的实施例中,绝经后骨质疏松症的模型用来确定进行不同处理对股骨密度的效果。
以CHarles River实验室(运送:MI)获得75日龄雌性Sprague Dawley鼠(重量范围在225至275g)。使它们3只一组圈养,并可随意进食(钙含量约1%)和饮水。室温维持在22.2℃±1.7℃,最低湿度为40%。室内光照周期为12小时亮12小时暗。
到达后一周,在麻醉状态下对鼠作两侧卵巢切除手术(44mg/kg克它命和5mg/kgXylazine(Butler,Indianapolis,IN)肌内用药)。手术当天麻醉苏醒后开始用药物载体、雌激素或式Ⅰ化合物进行治疗,口服剂量在0.5ml1%的羧甲基纤维素(CMC)中管饲。外科手术时和此后每周确定一次体重,并按体重变化调整用药剂量。对每一试验组平行评估药物载体或雌激素治疗的切除卵巢(ovex)和未切除卵巢(完整)的鼠,作为阴性和阳性对照物。
每天治疗鼠达35天(每治疗组6只鼠),在第36天通过断头术将鼠杀死。如所述测出,35天的时间周期已足以使骨密度最大程度的降低。鼠死时,取出子宫,切去外部组织,在确定湿重之前,挤出流体成分,以证实与完全切除卵巢有关的雌激素缺乏。由于卵巢切除术,子宫重量一般减少约75%。然后将子宫放在10%中性缓冲的福尔马林中以进行后面的组织分析。
切除右股骨并在距髌骨槽1mm的顶部干骺端处用单光子吸光测光法扫描。光密度计测量的结果以作为骨矿物质含量和骨宽度函数的骨密度的计算值表示。
RALOXIFENE对骨密度的影响
表2汇集了五个分开试验的对照处理的结果。总体来讲,与不手术药物载体处理对照相比,鼠的卵巢切除手术使得股骨密度减少约25%。以口服活性形式乙炔基雌二醇(EE2)服用的雌激素按剂量不同防止了骨损失,但同时对子宫也施加了刺激作用,结果以100μm/kg服用时,子宫重量接近不手术鼠的子宫重量。报导的结果是对30只鼠测量的平均值±平均的标准误差。
在这些研究中,作为氢氯化物服用的raloxifene也按剂量不同防止了骨损失;在这些动物中,相对于切除卵巢的对照物仅仅最小程度地增加了子宫重量。表3列出了使用raloxifene的5次试验的结果。对应的,每个都反映了30只鼠的反应,由此对该模型绘出了典型的对raloxifene的剂量响应曲线。结果作为平均值±平均值的标准误差来报导。
表2
骨密度(mg/cm/cm) 子宫重量(mg)
卵巢切除对照 170±3 127±5
(0.5mlcMc口服)
不手术对照 220±4 545±19
(0.5mlcmc口服)
EE2 100μg/kg,口服 210±4 490±11
表3
骨密度(mg/cm/cm) 子宫重量(mg)
卵巢切除对照 171±3 127±5
(0.5mlcmc口服)
不手术对照 222±3 540±22
(0.5mlcmc口服)
raloxifene0.01mg/kg,口服 176±3 150±5
raloxifene0.10mg/kg,口服 197±3 196±5
raloxifene1.00mg/kg,口服 201±3 199±5
raloxifene10.00mg/kg,口服 199±3 186±4
例2
单独服用作为氢氯化物的Raloxifene或与乙炔基雌二醇结合服用。单独用Raloxifene处理的鼠的子宫重量或多或少地高于卵巢切除对照物,但大大低于乙炔基雌二醇处理的鼠,后者接近于不手术对照物。与此相反的是,raloxifene处理明显降低了卵巢切除鼠的骨损失,当与乙炔基雌二醇结合使用时,并不明显降低雌激素对骨密度的保护作用。结果列于表4中。
表4
试验A 骨密度(mg/cm/cm) 子宫重量(mg)
卵巢切除对照 162±4 142±18
(0.5ml cmc 口服)
不手术对照 219±5 532±49
(0.5ml cmc 口服)
EE2 100μm/kg口服 202±6 450±17
EE2 100μg/kg+
204±2 315±10
raloxifene0.10mg/kg,口服
EE2 100μg/kg+
200±5 250±21
raloxifene1mg/kg,口服
试验B 骨密度(mg/cm/cm) 子宫重量(mg)
卵巢切除对照 165±8 116±6
(0.5ml cmc 口服)
不手术对照 220±4 605±69
(0.5ml cmc 口服)
EE2 100μg/kg,口服 215±11 481±24
raloxifene1mg/kg,+
EE2 100μg/kg,口服 197±7 263±17
raloxifene1mg/kg 198±11 202±5
例3
将raloxifene抑制骨损失的能力与三苯氧胺(tamoxifen)(SIGMA,St.Louis,Mo)相对比。目前用于治疗某些癌症的众所周知的抗雌激素三苯氧胺(Tamoxifen)已证明可抑制骨损失(见例如Love,R.等,1992“三苯氧胺对患乳腺癌绝经后妇女骨矿物质密度的影响”,N Eng J Med 326:852;Turner,R,等,1988“三苯氧胺抑制缺卵巢激素鼠由破骨细胞传递的有小梁结构的骨的再吸收”,Endo 122:1146)。如前例那样给卵巢切除鼠口服较窄范围剂量的raloxifene和三苯氧胺。虽然这两种药剂都有抑制股骨密度降低的能力,同时仅仅诱发适度的子宫营养活性,如子宫重量增加所确定的那样(表5),若干组织参数的对比表明了用这些药剂处理的鼠之间的明显差别(表6)。
上皮高度的增加是治疗药剂促进发情能力的象征,并可能与增加子宫癌症发病率有关。当如例1所述服用raloxifene时,仅有一种剂量与卵巢切除对照相比上皮高度有统计意义上可测到的增加。这与用三苯氧胺和雌激素所得到的结果相反。在所有剂量下,三苯氧胺增加的上皮高度都等于不手术鼠,比用raloxifene看到的响应增加约6倍。雌二醇处理将上皮高度增加大于不手术鼠的厚度。
还通过评估嗜曙红细胞渗入子宫基质层的反响应(表6)来评定促使发情的能力。Raloxifene不引起在卵巢切除鼠基质层观察到的嗜曙红细胞数目的任何增加,而三苯氧胺使该响应明显增加。如所预计的那样,雌二醇引起嗜曙红细胞渗入的大量增加。
在对基质和子宫肌层厚度的影响方面,raloxifene和三苯氧胺之间没有可测出的差别。两者引起这些测定值的增加额都比雌激素的影响小得多。
汇积所有四个参数的促使发情能力的总标度说明,raloxifene的雌情性远小于三苯氧胺。
表5
骨密度(mg/cm/cm) 子宫重量(mg)
卵巢切除对照 171±5 126±17
(0.5ml cmc 口服)
不手术对照 208±4 490±6
(0.5ml cmc 口服)
EE2 100μg/kg,口服 212±10 501±37
raloxifene1mg/kg,口服 207±13 198±9
三苯氧胺1mg/kg,口服 204±7 216±18
表6
上皮高度 基质的嗜 子宫肌层 基质的
曙红细胞 厚度 膨胀
卵巢切除对照 1.24 1.00 4.42 10.83
(0.5ml cmc 口服)
不手术对照 2.71 4.17 8.67 20.67
(0.5ml cmc 口服)
EE2 100μg/kg,口服 3.42 5.17 8.92 21.17
raloxifene1mg/kg 1.67 1.17 5.42 14.00
三苯氧胺1mg/kg 2.58 2.83 5.50 14.17
例4
按例1所述给鼠口服式Ⅰ的其它化合物。表7列出了1mg/kg剂量每种化合物的影响,表示为抑制骨损失的百分数和子宫重量增加百分数。
表7
化合物号 抑制骨损失%a 子宫重量增加%b
2 86 26
6 24 19
8 66 24
10 52 24
11 26 28
12 60 15
14 121 32
16 108 25
18 21 17
27 25 1
34 26 -6
a 抑制骨损失百分数=(处理的卵巢切除(ovex)动物的骨密度-未处理卵巢切除(ovex)动物的骨密度÷(雌激素处理的卵巢切除(ovex)动物的骨密度-未处理的卵巢切除(ovex)动物的骨密度)×100
b 子宫重量增加百分数=(已处理卵巢切除动物的子宫重量-卵巢切除动物的子宫重量)÷(雌激素处理卵巢切除动物的子宫重量-卵巢切除动物的子宫重量)×100。
例5
由骨质疏松症引起的骨折率与骨矿物质密度有相反的关系。然而,骨密度的改变发生得很慢,要等数月或几年才能得到有意义的测定值。然而,通过测定几种反映骨骼代谢变化的快速响应的生化参数,可以证明式Ⅰ化合物如raloxifene对骨矿物质密度和骨损失有积极作用。为达此目的,对至少160个患者进行现行的raloxifene试验研究(作为氢氯化物服用),并将所述患者随机分成四个治疗组:雌激素,两种不同剂量的raloxifene和安慰剂。每天治疗患者达8周。
治疗前、中、和后分别收集血和尿。另外,在研究开始和结束时分别测定子宫上皮组织。分别把服用雌激素和安慰剂作为阳性和阴性的对照。
患者是健康的绝经后(手术引起或自然的)妇女,年龄45-60岁,她们一般被认为是要求用雌激素代用品治疗骨质疏松症的侯选者。这包括有完整子宫的妇女,她们最后一次已经超六个月但未超过6年。
在研究开始时将已经受过下列药物系统治疗的患者排除于研究之列:维生素D、皮质类固醇、血脂过少药(hypolipidemics)、氯噻嗪(thiazides)、抗痛风剂、水杨酸盐、吩噻嗪、磺酸盐、四环素、新霉素和抗肠虫药。在开始研究前三月内受过任何雌激素、孕激素或雄激素治疗的患者;曾受过降血钙素、氟化物或双磷酸盐治疗的患者;有糖尿病的患者;在以前五年内有过癌病史的患者;有不能诊断或异常生殖器出血的患者;患或患过血栓栓塞疾病的患者;肝或肾功能受过损害的患者;甲状腺功能不正常的病人;药物或心理冒险性弱的患者;或饮酒过量或滥用药物的患者。
雌激素治疗组的病人服药0.625mg/日,两个raloxifene组服药剂量为200和600mg/日,各组均口服胶囊制剂。用648mg碳酸钙药片给所有病人作为补充钙,在研究过程中每天早晨服2片。
研究是双盲设计的。研究者和病人都不知道病人属于哪一治疗组。
对每个病人的基本检查包括定量测量尿钙、肌酸酐、羟脯氨酸和交联的吡啶并灵(pyridinoline)。测定血样以确定血清中osteocalcin、骨特殊碱性磷酸酶、raloxifene和raloxifene代谢物的浓度。基本测量还包括检测子宫,包括子宫的活组织检查。
在医生治疗研究期间,重复测量上述反应治疗的参数。上述列出的与骨吸收有关的生化标志全都表明,与未处理的个体相比,由于服用雌激素而得到抑制。Raloxifene也预期可在缺少雌激素的个体中抑制这些标志,因为raloxifene从治疗开始后即有效地抑制骨损失。
在随后的长期研究中可通过使用光子吸光测定法和测定与医疗相关的骨折率来直接测定骨密度。
Claims (6)
2、Raloxifene或其药学可容盐用于抑制人类骨损失。
3、Raloxifene氢氯化物用于抑制人类骨损失。
4、权利要求1、2或3的化合物用于治疗诊断为患骨疏松症的人。
5、权利要求1、2或3的化合物的应用,其中预防性施用该化合物。
6、用于抑制人类骨损失的药方,含有如权利要求1至3之一所定义的式(Ⅰ)化合物。
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WO2007095851A1 (fr) * | 2006-02-20 | 2007-08-30 | Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences | Composés hétérocycliques à 5 chaînons insaturés, procédés d'utilisation et de préparation de ceux-ci |
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