CN1119530A - 抑制骨损失和降低血清胆固醇的方法 - Google Patents
抑制骨损失和降低血清胆固醇的方法 Download PDFInfo
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- CN1119530A CN1119530A CN95100021A CN95100021A CN1119530A CN 1119530 A CN1119530 A CN 1119530A CN 95100021 A CN95100021 A CN 95100021A CN 95100021 A CN95100021 A CN 95100021A CN 1119530 A CN1119530 A CN 1119530A
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- Prior art keywords
- raloxifene
- cholesterol
- bone
- estrogen
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
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Abstract
本发明公开了抑制骨损失或吸收及降低血清胆固醇的方法,该方法包括给需要治疗的人施用低剂量式I化合物或其可药用盐或溶剂化物。本发明还包括单位剂型的药物制剂,每一单位剂量含有低剂量活性成分。
Description
本发明涉及用低剂量的特定2-苯基-3-芳酰基苯并噻吩抑制骨损失和降低血清胆固醇的方法。
I.骨损失(bone loss)
目前为公众关心的主要骨疾病或疾症包括绝经后骨质疏松、卵巢切除术患者、老年骨质疏松、长期进行皮质类固醇治疗的患者、糖皮质激素或类固醇治疗的副作用、库欣综合征患者、性腺发育不全、类风湿关节炎中关节周围糜烂、骨关节炎、佩吉特病、骨质缺乏、骨软化、恶性高钙血、因骨转移所致骨质减少、牙周病和甲状旁腺机能亢进。所有这些病症的特征都是骨损失,是由于骨降解(骨吸收)与健康的新骨形成失调造成的。这种骨倒转(Turnover of bone)正常情况下持续一生,并且骨以这种机制再生。但是,上述疾病将使该平衡倾向于骨损失,这样,骨吸收的量不能充分地被新骨补充,于是造成净的骨损失。
一种最常见的骨疾病是绝经后骨质疏松,仅在美国就有大约2000-2500万妇女患有此病。随着循环雌激素含量下降,绝经后妇女的骨倒转速度增加,由此导致净的骨损失。不同骨的骨倒转速度不同,在富集小梁骨的部位,例如椎骨和股骨头处骨倒转速度最快。紧接着绝经之后,这些部位骨损失的量可能为4-5%。所造成的骨量减少和骨空间增大导致骨折的危险升高,因为骨的力学完整性迅速衰退。
目前在美国,由于骨质疏松使得2000万人患有可检测的椎骨骨折,并且因为骨质疏松每年有250,000人髋骨骨折。后一种情况在头两年死亡率为12%,并且30%这样的患者在骨折后需要家庭护理。因此,骨疾病的特征是显著的死亡率、幸存者生活质量大大下降以及给家庭造成巨大的经济负担。
几乎上述所有疾症都可得益于用抑制骨吸收的药物治疗。骨吸收是通过特定的所谓破骨细胞的活性而进行。破骨细胞的独特性在于它既能够吸收骨的羟磷灰石矿物质,也能吸收骨的有机基质。它们与以前称为破软骨细胞的软骨吸收细胞等同。由于这一原因,折骨骨吸收的有效抑制剂也将抑制类风湿性关节炎以及骨关节炎中所出现的细胞介导的软骨降解。
旨在阻止净骨损失的治疗包括使用雌激素。已经清楚地表明,雌激素终止了绝经后出现的骨损失,并且限制了骨质疏松的发展;但是患者不愿配合,因为雌激素有副作用。这些副作用包括月经恢复、乳房痛、患子宫癌的危险增加,以及可能增加患乳腺癌的危险。
另外也已采用降钙素来治疗骨质疏松患者。橙红色的降钙素直接抑制哺乳动物破骨细胞的吸收活性,在意大利和日本它已经被普遍地处方使用。但是,对于多数人来说降钙素过于昂贵,实际上无法使用,并且效力也短暂。也说是说破骨细胞通过下调降钙素受体能够“逃避”降钙素的吸收抑制作用。因此,目前的临床数据表明,用降钙素进行长期治疗对于终止绝经后的骨损失不可能长期有效。
II.血清胆固醇
所有的哺乳动物细胞均需要胆固醇作为其细胞膜的结构成分,并用于非甾醇最终产物。甾类激素合成也需要胆固醇。但是胆固醇的性质,即其在水中的不可溶性,既使胆固醇在细胞膜中是有用的,也使得它可能成为致死性因子。如果胆固醇聚集在错误的地方,例如在动脉壁内,那么它不能容易地移动,它的存在会导致形成动脉粥样硬化的斑块。已经证明,与低密度脂蛋白相关连的血清胆固醇浓度增高是动脉粥样硬化形成和发展的主要因素。
在哺乳动物中,血清脂蛋白是由胆固醇和胆固醇酯类、甘油三酯类、磷脂类和脱辅基蛋白类组成。血清或血浆脂蛋白包括几部分。血浆脂蛋白的主要组成部分或种类有极低密度脂蛋白(VLDL)、低密度脂蛋白(LDL)、中等密度脂蛋白(IDL)以及高密度脂蛋白(HDL)。这些脂蛋白在大小、密度以及核心中甘油三酯类与胆固醇酯类的相对比例等方面都各不相同,并且其表面的脱辅基蛋白类的性质也是相互有区别的。
在哺乳动物中,血清胆固醇既从外源饮食来源得到,也通过内源合成得到。胆固醇的内源合成包括一套复杂的酶催化反应和通常称之为甲羟戊酸酯途径的调控机制。由于胆固醇(甲羟戊酸酯代谢的主要最终产物)衍生自由受体介导的胞内作用而进入细胞的血浆低密度脂蛋白,并还衍生自在细胞内的合成作用,因此,细胞在调节甲羟戊酸酯合成中面临复杂的问题。每个细胞必须平衡这些外部和内部的来源,以便维持甲羟戊酸酯合成,同时避免甾醇过分聚积。这种平衡是通过甲羟戊酸酯合成中至少2个连续作用的酶(3-羟基-3-甲基戊二酰基辅酶A(HMG-CoA)合成酶和HMG-CoA还原酶)以及LDL受体的反馈调节而实现的。在没有LDL的情况下,哺乳动物细胞保持上述2种酶的高活性,以此合成用于产生胆固醇和非甾醇产物的甲羟戊酸酯。如果有LDL存在(来自于外源性来源),那么HMG-CoA合成酶和还原酶活性受到抑制,并且细胞产生较少量甲羟戊酸酯用于生成非甾醇最终产物。
大量的证据表明治疗高血脂蛋白可以降低或预防动脉粥样硬化并发症。除了维持正常体重和使血浆中类脂类浓度降至最低的饮食之外,治疗策略还包括消除使高血脂蛋白加重的因素,以及服用降低脂蛋白血浆浓度的治疗剂,其方法是通过减少脂蛋白的产生,或者通过提高脂蛋白从血浆中清除的效率。
目前出售的治疗血胆固醇过多的最有希望的一类药物是通过抑制HMG-CoA还原酶而起作用,此酶是内源性胆固醇合成的限速酶。该类药物可竞争性地抑制上述酶的活性。最后,降低了胆固醇的内源合成,并且通过正常的体内平衡机制,血浆胆固醇通过LDL受体而被吸收,结果恢复了细胞内胆固醇的平衡。
相对体内的其他细胞,肝细胞在维持血清胆固醇体内平衡方面起着关键性作用,它通过释放LDL的前体和通过受体介导作用从血清中吸收LDL。在人和动物模型中,在肝脏LDL受体和LDL-相关的血清胆固醇含量之间似乎存在相反的关系。一般来讲,较高的肝细胞受体数量导致较低的LDL-相关的血清胆固醇含量。释放到肝细胞中的胆固醇可以以胆固醇酯类的形式贮存,转变成胆汁酸类并释放到胆小管中,或者进入羟胆固醇库内。据信,正是该羟胆固醇库与LDL受体的基因和包含在胆固醇合成途径中的酶的最终产物阻遏作用有关。
已知当细胞有过量的胆固醇(或许以羟胆固醇的形式)供给时,那么LDL受体基因的转录作用会被阻遏。在LDL受体启动子区内的被称为甾醇应答元素的DNA序列,似乎与这种甾醇最终产物阻遏作用有关。该甾醇应答元素已被广泛地研究(Brown,Goldstein和Russell,美国专利4,745,060和4,935,363),并且看来象是由存在于LDL受体编码区5′端上的16个碱基对序列组成。该甾醇应答元素可以插进通常对胆固醇不产生应答的基因中,因而把甾醇最终产物阻遏作用赋予该嵌合基因。这种阻遏作用的确切机理尚不清楚。但是有大量的证据表明,胆固醇生物合成中的极性中间体和天然存在的以及合成的羟基甾醇类可阻遏含有甾醇应答元素的基因。
有人认为,羟基胆固醇结合蛋白起受体的作用。当该受体与羟基甾醇结合时,它对甾醇应答元素起作用,通过类似于甾类激素受体超基因家庭成员的作用机理控制转录作用。
在其中冠状动脉心脏病是主要健康问题的人群中,妇女的发病率明显地低于男人。在较年青年龄组,例如在35和44岁之间的男人和妇女中,这是特别肯定的事实。
一般来讲,血浆脂蛋白代谢受性腺类固醇的循环浓度的影响。由于性腺状况的变化或由于服用外源的性腺类固醇而引起的血清雌激素和雄激素浓度的改变是与血清脂蛋白含量的改变相关连的。受雌激素和雄激素影响的该变化一般支持下述看法:即脂蛋白的性别差异是由于男人和妇女之间激素不同所造成的。
性腺类固醇与血浆脂蛋白之间的通常被人们接受的关系是雄激素降低HDL浓度而提高LDL,因此成为男人与妇女相比HDL含量低和LDL含量高的原因。而认为雌激素对脂蛋白有相反的影响,也就是使HDL上升并使LDL降低。这些性类甾醇引起的脂蛋白浓度的差异被认为是与男人相比,妇女的心血管疾病发生率较低的原因。在绝经之后,妇女丧失了雌激素的保护作用,使心血管疾病的发生率增加到男性的水平。绝经后服用雌激素的妇女,与同年龄不服用雌激素的妇女相比较,一般患心血管疾病的比例较低。雌激素(特别是口服时)可降低血浆LDL含量并提高血浆HDL含量。
雌激素降低LDL含量和提高HDL含量的机理尚不清楚。一般来讲,脂蛋白血浆浓度的变化是由于其合成速度或其分解代谢速度的变化引起的。例如,雌激素可通过提高从血浆中清除LDL的程度来降低LDL含量,因为在动物中雌激素可增加肝脏LDL受体的数量。
虽然雌激素对血清LDL具有有益的作用,甚至在极低浓度时也有这种有益作用,但是长期用雌激素治疗与多种疾病有连带关系,包括增加了患子宫癌,或许还有乳腺癌的危险,从而使许多妇女避免接受这种治疗。近来建议的设法减少引起患上述癌危险的治疗方案,例如服用孕激素与雌激素的组合物,使患者经受定期(子宫)出血,这对大多数年龄较大的妇女来说是不愿接受的。此外,合并应用孕酮和雌激素看来要减弱雌激素引起的血清胆固醇降低作用。对于用与雌激素治疗有关的明显不希望产生的副作用的关切,支持了需要研究另一治疗高血胆固醇的方法,该方法应对血清LDL具有所希望的作用,但是不引起不希望有的作用。
通过应用通常称为抗雌激素的化合物以满足上述要求的努力得到了有限的成功,这或许是由于这些化合物通常显示出激动剂/拮抗剂的混合性作用,这些抗雌激素化合物能与雌激素受体相互作用,和/或与已称为抗雌激素结合位点(AEBS)的部位相结合。也就是说,虽然这些化合物可以拮抗雌激素与受体之间的相互作用,但是这些化合物本身可以对具有雌激素受体的那些组织(如子宫)引起雌激素应答。因此,某些抗雌激素剂如三苯氧胺能引起与雌激素治疗有关的同样不良反应。
本发明还包括降低血清胆固醇的方法,该方法包括以约50-150mg/天的量施用式I化合物。
本发明还包括剂量单位形式的药物制剂,每一剂量含有约50-150mg式I化合物。
本发明涉及下述发现:约50-150mg/天剂量的式I化合物可用于降低血清胆固醇含量和抑制骨吸收及骨损失。本发明提供的治疗方法是:以约50-150mg/天的量给需要该治疗的人施用式I化合物或其可药用盐或溶剂化物,以降低血清胆固醇含量或抑制骨损失或吸收。
术语“抑制”定义为包括其通常可接受的含义,包括阻止、防止、遏制和减缓、终止或逆转疾病的进程、严重程度、控制和/或治疗已有的状况。本发明方法包括适当的医疗和/或(如果需要)预防治疗。一般来讲,可以将本发明化合物与普通的赋形剂、稀释剂或载体一起进行配制并压成常用的口服给药的片剂,或者配制成酏剂或溶液剂;或者通过肌内或静脉途径给药。本发明化合物可以经皮给药,还适于配制成持续释放等剂型。
本发明方法适用于男性和女性。实际上缺乏雌激素应答的男性可以使用本发明方法,而不会出现雌激素或雌激素兴奋剂女性化应答,例如男子女性型乳房。但是,本发明方法优选用于妇女,特别是雌激素缺乏的妇女。
本发明方法中的活性成分2-苯基-3-芳酰基苯并噻吩化合物最早由C.David Jones和Tulio Suarez制成,用作抗受精剂(antifertility agent)(US Patent 4,133,814,1979年1月9日出版)。已发现该组中的某些化合物适用于抑制乳腺癌的生长。
之后Jones发现了一组适用于抗雌激素治疗和抗雄激素治疗、特别是治疗乳腺癌和前列腺癌的相关化合物(US Patent 4,418,068,1983年11月29日出版)。对这些化合物之一,即式I化合物的盐酸盐进行短时间的治疗乳腺癌临床试验。该化合物称为雷洛昔芬,以前称作Keoxifene。
雷洛昔芬目前在人体临床实验上用于骨质疏松和降脂。Draper等人(“Effects of Raloxifene on Biochemical Markers of Boneand Lipid Metabolism in Healthy Post-Menopausal Wonen,”Fourth International Symposium on Osteoporosis,Hong Kong,1993年3月29日)讨论了雷洛昔芬可用于抑制骨吸收和降低血清胆固醇方面的某些有益发现。试验剂量为200mg/天和600mg/天。如EP-A-584952(1994年3月2日公开)所示(相应于美国申请07/920933,1992年7月28日申请,(docket X-7947)),优选的范围是200mg-600mg/天。尽管200-600mg/天的剂量范围提供了足够的应答并且是可药用的,但是目前发现,与较高的剂量范围相比,约50mg/天至约150mg/天的较低剂量范围出人意料地得到了等价的效果。
雷洛昔芬已表明与雌激素受体结合,并且最初被认为是这样一种分子:即从其功能和药理学上说,它是抗雌激素,因为它阻断雌激素激活子宫组织和雌激素依赖型乳腺癌的能力。在某些细胞中雷洛昔芬的确阻断了雌激素的作用;然而在其他各类细胞中,雷洛昔芬和雌激素一样,激活相同基因并显示同样药理学(例如骨质疏松、高脂血)。与雌激素-雌激素受体复合物对基因的活化作用和/或抑制作用相反,雷洛昔芬所显示的不同于雌激素的独特特征目前被认为是由于雷洛昔芬-雌激素受体复合物对各种基因功能的独特活化和/或抑制作用。因此,尽管雷洛昔芬和雌激素使用且竞争同样的受体,但是它们调节基因和药理学结果是难以预见的并且是彼此不同的。
一般而言,该化合物与常用的赋形剂、稀释剂或载体配制,并压成片或配成便于口服的酏剂或溶液剂,或通过肌内或静脉内给药。该化合物可经皮或阴道内给药,并可制成持续释放等剂型。
本发明方法中所使用的化合物可以按既定的方法(例如US4,133,814、4,418,068和4,380,635中所述的方法,这些专利引入本文作为参考)制备。一般,该方法用具有6-羟基和2-(4-羟苯基)的苯并[b]噻吩开始。将起始化合物的羟基保护、将3位酰基化并使产物脱保护,得到式I化合物。在上述美国专利中提供了这些化合物的制备实例。
用于本发明方法的化合物可以与各种有机和无机酸和碱反应生成药学上适用的酸和碱加成盐,药学上适用的酸和碱加成盐包括通常用于药物化学中的生理上适用的盐。所述的盐也是本发明的一部分。生成所述盐的常用无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可用由有机酸得到的盐,可以应用的有机酸有例如脂肪族一和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸,芳香族酸、脂肪族和芳香族磺酸。因而所述药学上适用的盐包括乙酸盐、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、邻乙酰氧基苯甲酸盐、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、己炔-1,4-二酸盐、癸酸盐、辛酸盐、氯化物、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、羰基乙酸盐、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、对苯二酸盐(Teraphthalate)、磷酸盐、磷酸一氢盐、磷酸二氢盐、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、对溴苯磺酸盐、氯苯磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、甲磺酸盐、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。优选盐酸盐。
药学上适用的酸加成盐通常由式I化合物与等摩尔或过量的酸反应而制得。通常使反应物于互溶剂如乙醚或苯中进行混合。盐通常约在约1小时至10天内从溶液中折出,可经过滤分离,或按常规方法除去溶剂。
通常用于形成盐的碱包括氢氧化铵,碱金属和碱土金属氢氧化物、碳酸盐和碳酸氢盐,以及脂肪族伯、仲和叔胺,脂肪族二胺。在制备加成盐中尤其适用的碱包括氢氧化钠、氢氧化钾、氢氧化铵、碳酸钾、甲胺、二乙胺、1,2-乙二胺和环己胺。
与衍生它们的化合物比较,药学上适用的盐通常具有增强的溶解性性能,因此常常更适用于配制如液体剂或乳剂。
药用制剂可按本技术领域已知的方法制备。例如,可将该化合物与普通的赋形剂、稀释剂或载体进行配制,并制成片剂、胶囊、悬浮液、粉剂等。适用于上述制剂的赋形剂、稀释剂和载体的实例包括如下:填充剂和增量剂如淀粉、糖、甘露糖醇和硅衍生物;粘合剂如羧甲基纤维素和其他纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;润湿剂如甘油;崩解剂如碳酸钙和碳酸氢钠;溶解阻滞剂如石蜡;吸收促进剂如季铵化合物;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,以及固态聚乙基乙二醇。
该化合物也可配制成便于口服的酏剂或溶液剂、或适于非肠道给药的溶液剂,例如经肌内、皮下或静脉内途径给药。此外,该化合物也非常适合配制成持续释放等剂型。该制剂也可这样构成,使他们仅仅或最好在肠道的特定部位,可能在一定的时间内释放活性成分。包衣、包膜和保护基质可以由例如聚合物质或蜡制成。
本发明的剂量范围是约50-150mg/天,优选60-150mg/天,最优选60-100mg/天。本发明具体的剂量是50、55、60、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145和150mg/天。
该组合物优选配制成单位剂量形式,每一剂量含有约50-150mg,优选上面所列出的量。术语“单位剂量形式”是指可物理分离的单位,例如片剂和胶囊,它适于作为单元剂量、特别是单元日剂量,供人或其他哺乳动物使用,每一单位含有与合适的药物赋形剂结合的预定量的活性物质,其量可产生所需的疗效。
给人施用约50-150mg/天剂量的用药时间取决于疾病的严重程度、病人健康状况和有关因素,这些将由主治医生确定。期望的疗程为至少6个月,更通常为至少一年,优选连续用药。
采用下列剂量范围的制剂实施例:
制剂制剂1:明胶胶囊
用下列成分制备硬明胶胶囊:
成分 | 用量(mg/胶囊) |
雷洛昔芬淀粉,NF可流动的粉末状淀粉硅氧烷流体(350厘沲) | 50-1500-6500-6500-15 |
将各成分混合,通过美国45号筛,装填入硬明胶胶囊。
胶囊制剂实施例包括下述制剂制剂2:雷洛昔芬胶囊
制剂3:雷洛昔芬胶囊
成分 用量(mg/胶囊)雷洛昔芬 100淀粉,NF 103可流动的淀粉粉末 225.3硅氧烷流体(350厘沲) 1.7制剂5:雷洛昔芬胶囊
制剂6:雷洛昔芬胶囊
成分雷洛昔芬淀粉,NF可流动的淀粉粉末硅氧烷流体(350厘沲) | 用量(mg/胶囊)60112225.31.7 |
成分雷洛昔芬淀粉,NF可流动的淀粉粉末硅氧烷流体(350厘沲) | 用量(mg/胶囊)75109225.31.7 |
制剂4:雷洛昔芬胶囊 |
成分雷洛昔芬淀粉,NF可流动的淀粉粉末硅氧烷流体(350厘沲) | 用量(mg/胶囊)1251503973.0 |
成分雷洛昔芬淀粉,NF可流动的淀粉粉末硅氧烷流体(350厘沲) | 用量(mg/胶囊)1501503973.0 |
根据所提供的合理变化,可以对上述具体制剂进行改变。
用下列成分制备片剂:制剂7:片剂
成分 用量(mg/片)雷洛昔芬 60微晶纤维素 0-650煅制的二氧化硅 0-650硬脂酸 0-15制剂8:片剂
制剂9:片剂
制剂11:片剂
将各成分混合并压成片。
成分雷洛昔芬微晶纤维素煅制的二氧化硅硬脂酸 | 用量(mg/片)750-6500-6500-15 |
成分雷洛昔芬微晶纤维素煅制的二氧化硅硬脂酸 | 用量(mg/片)1000-6500-6500-15 |
制剂10:片剂 | |
成分雷洛昔芬微晶纤维素煅制的二氧化硅硬脂酸 | 用量(mg/片)1250-6500-6500-15 |
成分 | 用量(mg/片) |
雷洛昔芬微晶纤维素煅制的二氧化硅硬脂酸 | 1500-6500-6500-15 |
另外,如下制备每片含50-150mg活性成分的片剂:制剂12:片剂
制剂13:片剂
制剂14:片剂
制剂15:片剂
制剂16:片剂
成分 | 用量(mg/片) |
雷洛昔芬淀粉微晶纤维素聚乙烯吡咯烷酮(10%水溶液)羧甲基纤维素钠硬脂酸镁滑石 | 60453544.50.51 |
成分 | 用量(mg/片) |
雷洛昔芬淀粉微晶纤维素聚乙烯吡咯烷酮(10%水溶液)羧甲基纤维素钠硬脂酸镁滑石 | 75453544.50.51 |
成分 | 用量(mg/片) |
雷洛昔芬淀粉微晶纤维素聚乙烯吡咯烷酮(10%水溶液)羧甲基纤维素钠硬脂酸镁滑石 | 100453544.50.51 |
成分 | 用量(mg/片) |
雷洛昔芬淀粉微晶纤维素聚乙烯吡咯烷酮(10%水溶液)羧甲基纤维素钠硬脂酸镁滑石 | 125453544.50.5 |
成分 | 用量(mg/片) |
雷洛昔芬淀粉微晶纤维素聚乙烯吡咯烷酮(10%水溶液)羧甲基纤维素钠硬脂酸镁滑石 | 150453544.50.51 |
将活性成分、淀粉和纤维素通过美国45号筛并充分混合。将聚乙烯吡咯烷酮溶液与所得的粉末混合,然后通过美国14号筛。将制备的颗粒于50°-60℃干燥,并通过美国18号筛。然后将预先通过美国60号筛的羧甲基纤维素钠、硬脂酸镁和滑石加入此颗粒中,混合后将颗粒在压片机上压片,得到片剂。
每5ml含50-150mg药物的悬浮液如下制备:制剂17:悬浮液
制剂18:悬浮液
制剂19:悬浮液
制剂20:悬浮液
制剂21:悬浮液
成分 | 用量(mg/5ml) |
雷洛昔芬羧甲基纤维素钠糖浆苯甲酸溶液调味剂着色剂加纯化水 至 | 60mg50mg1.25mg0.1ml适量适量5ml |
成分 | 用量(mg/5ml) |
雷洛昔芬羧甲基纤维素钠糖浆苯甲酸溶液调味剂着色剂加纯化水 至 | 75mg50mg1.25mg0.1ml适量适量5ml |
成分 | 用量(mg/5ml) |
雷洛昔芬羧甲基纤维素钠糖浆苯甲酸溶液调味剂着色剂加纯化水 至 | 100mg50mg1.25mg0.1ml适量适量5ml |
成分 | 用量(mg/5ml) |
雷洛昔芬羧甲基纤维素钠糖浆苯甲酸溶液调味剂着色剂加纯化水 至 | 125mg50mg1.25mg0.1ml适量适量5ml |
成分 | 用量(mg/5ml) |
雷洛昔芬羧甲基纤维素钠糖浆苯甲酸溶液调味剂着色剂加纯化水 至 | 150mg50mg1.25mg0.1ml适量适量5ml |
将药物通过美国45号筛,并与羧甲基纤维素钠和糖浆混合制成调匀的糊状物。苯甲酸溶液、调味剂和着色剂用一部分水稀释,并在搅拌下加入糊状物中。然后加入足够的水至所需体积。
下列实施例说明本发明所用化合物的制备。
实施例1
6-羟基-2-(4-羟苯基)-3-[4-(2-哌啶子
基乙氧基)苯甲酰基]苯并[b]噻吩
将4g6-甲磺酰氧基-2-(4-甲磺酰氧基苯基)-3-[4-(2-哌啶子基乙氧基)-苯甲酰基]苯并[b]噻吩盐酸盐与100ml变性乙醇和10ml 5N氢氧化钠混合,在氮气氛下搅拌回流1.5小时。将反应混合物真空蒸发至干,将残余物溶于200ml水中,并用300ml乙醚洗涤。将水层真空脱气,然后鼓泡通入氟,排出所有微量的乙醚。用1N盐酸酸化混合物,然后用过量碳酸氢钠碱化。过滤收集沉淀,用冷水洗涤,得到2.4g粗产品。将其在2×30cm硅胶柱上纯化,先用700ml 55%甲醇的氯仿溶液洗脱,然后用1升10%甲醇的氯仿溶液洗脱。首先洗出杂质,合并含有产物的馏份并真空蒸发,得到1.78g黄色油状物。将此油状物溶于6ml丙酮中,接种晶种并在冷冻机中激冷,得到1.2g纯产物,m.p.(熔点)143-147℃。该产物的特性证实如下:
nmr谱(100mHz,在dmso-d6中)δ1.20-1.65(6H,m,N(CH2CH2)2CH2);2.30-2.45(4H,m,N(CH2CH2)2CH2);2.60(2H,t,J=6Hz,OCH2CH2N);4.06(2H,t,J=6Hz,OCH2CH2N);6.68(2H,d,J=9H,芳族O至OH);6.85(1H,q,JH4-H5=9Hz,JH5-H7=2Hz,H5,苯并噻吩环):6.90(2H,d,J=9Hz,芳族o至OCH2CH2N);7.18(2H,d,J=9Hz,芳族m至OH);7.25(1H,d,J=9Hz,H4,苯并噻吩环);7.66(2H,d,J=9Hz,芳族o至CO):9.72(2H,宽s,OH)。在乙醇中的紫外谱:λmax(ε):290nm(34,000)。电子碰撞质谱Mt m/e 473。
实施例2
6-羟基-2-(4-羟苯基)-3-[4-(2-哌啶子
基乙氧基)苯甲酰基]苯并[b]噻吩
将3.6g6-甲磺酰氧基-2-(4-甲磺酰氧基苯基)-3-[4-(2-哌啶子基乙氧基)苯甲酰基]苯并[b]噻吩溶于100ml四氢呋喃和40ml甲醇中,加入10ml 5N氢氧化钠。在室温下搅拌该混合物16小时,然后按上述实施例1的方法操作,得到3.5g黄色固体。不纯产物在硅胶上经柱色谱纯化,用5%甲醇-30%甲醇的氯仿溶液梯度洗脱。蒸发含产物的馏份,得到1.85g油状产物,用丙酮重结晶,得到1.25g纯产物,m.p.141-144℃。
实施例3
6-羟基-2-(4-羟苯基)-3-[4-(2-哌啶子
基乙氧基)苯甲酰基]苯并[b]噻吩盐酸盐
在氮套中,将3g 4-(2-哌啶子基乙氧基)苯甲酸盐酸盐、2滴二甲基甲酰胺、2.5ml亚硫酰氯和40ml氯苯的混合物在70-75℃加热约1小时。蒸掉过量的亚硫酰氯和15-20ml溶剂。将剩余的悬浮液冷却至室温,向其中加入100ml二氯甲烷、2.7g6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩和10g氯化铝。搅拌该溶液约1小时,加入7.5ml乙硫醇,再搅拌该混合物45分钟。加入40ml四氢呋喃,然后加入15ml 20%盐酸。放热回流。加入50ml水和25ml饱和氯化钠水溶液。搅拌该混合物并使其冷却至室温。过滤收集沉淀,相继用30ml水、40ml 25%四氢呋喃水溶液和35ml水洗涤。在40℃将固体真空干燥,得到5.05g产物,用核磁共振进行鉴定。
δ1.7(6H,m,N(CH2CH2)2CH2);2.6-3.1(2H,m,NCH2);3.5-4.1(4H,m,NCH2):4.4(2H,m,OCH2);6.6-7.4(9H,m,芳族);7.7(2H,d,芳族o至CO);9.8(2H,m,OH)。
试验结果
对大约160名健康的绝经后妇女进行8周平行、双盲对照研究。本研究中所用雷洛昔芬的剂量是10、50和200mg。10mg剂量对任何骨标记都没有显著活性(见表I)。由于经过一段时间许多骨标记出现,所以当在长期研究中进行评估时,50mg/天剂量的雷洛昔芬很可能有足够的活性。
表I
骨代谢标记的基线值和基线至终点的组平均(±SEM)变化(GGGC)
缩写:n=任何一种标记的受试患者最大数;SEM=标准平均误差。*与对照组比较统计学上有显著(p<0.0051)差异(双尾(two-tailed)比较)。
标记 | 雷洛昔芬对照 10mg(n=42) (n=42) | 雷洛昔芬50mg(n=42) | 雷洛昔芬200mg(n=41) |
血清基线变化血清基线变化 | 碱性磷酸酶(U/L)77.31(±3.53) 78.71(±3.12)-1.10(±2.08) 0.21(±1.56)osteocalcin(ng/ml)3.94(±0.21) 3.86(±0.19)-0.63(±0.16) -0.27(±0.13) | 73.86(±2.69)-4.78(±1.52)3.65(±0.21)-0.81(±0.15) | 79.07(±2.77)-5.93*(±1.48)4.21(±0.21)-1.21*(±0.18) |
血清脂含量受50和200mg雷洛昔芬剂量影响(表II)。在50mg雷洛昔芬治疗的患者中观察到与200mg剂量治疗患者中可比的LDL胆固醇下降。用雷洛昔芬治疗的患者的HDL含量无变化。在50mg和200mg剂量雷洛昔芬治疗患者中都观察到HDL∶LDL比例和总血清胆固醇含量的统计学显著下降。
表II血清脂的基线值和基线至终点的组平均(±SEM)变化(GGGC)
缩写:LDL-C=低密度脂蛋白胆固醇;HDL-C=高密度脂蛋白胆固醇;n=任何一种标记的受试者最大数;SEM=标准平均误差。#统计学上显著(p<0.050)大于其他所有治疗(双尾(two-tailed)比较)。*与对照组相比统计学上有显著(p<0.050)差异(双尾比较)。
对照变量 (n=42)LDL-C (mmol/L)基线 3.67(±0.11)变化 0.02(±0.08)HDL-C (mmol/L)基线 1.41(±0.06)变化 -0.03(±0.03)HDL-C∶LDL-C比例基线 0.40(±0.02)变化 -0.01(±0.01)总胆固醇 (mmol/L)基线 5.69(±0.12)变化 0.01(±0.09) | 雷洛昔芬10mg(n=42)4.11#(±0.17)0.05(±0.10)1.41(±0.06)0.01(±0.02)0.37(±0.03)0.00(±0.01)6.18#(±0.19)0.01(±0.10) | 雷洛昔芬50mg(n=42)3.55(±0.16)-0.23*(±0.06)1.35(±0.05)0.04(±0.02)0.42(±0.03)0.03*(±0.01)5.82(±0.21)-0.23*(±0.08) | 雷洛昔芬200mg(n=41)3.68(±0.13)-0.17(±0.07)1.32(±0.05)0.02(±0.02)0.38(±0.02)0.03*(±0.01)5.71(±0.14)-0.15(±0.08) |
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Families Citing this family (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
TW366342B (en) * | 1992-07-28 | 1999-08-11 | Lilly Co Eli | The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss |
USRE38968E1 (en) * | 1992-07-28 | 2006-02-07 | Eli Lilly And Company | Methods for inhibiting bone loss using 6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thien-3-yl-4-[2-(piperidin-1-yl) ethoxyphenylimethanone hydrochloride |
USRE39049E1 (en) | 1992-07-28 | 2006-03-28 | Eli Lilly And Company | Methods for inhibiting bone loss |
US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US5770609A (en) | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US6197789B1 (en) | 1995-06-07 | 2001-03-06 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
CA2162586C (en) | 1993-05-13 | 2006-01-03 | David J. Grainger | Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells |
US6319914B1 (en) | 1993-11-05 | 2001-11-20 | Apollo Biopharmaceuticals, Inc. | Cytoprotective effect of polycyclic phenolic compounds |
US5554601A (en) * | 1993-11-05 | 1996-09-10 | University Of Florida | Methods for neuroprotection |
US5478847A (en) | 1994-03-02 | 1995-12-26 | Eli Lilly And Company | Methods of use for inhibiting bone loss and lowering serum cholesterol |
US5512583A (en) * | 1995-01-30 | 1996-04-30 | Eli Lilly And Company | Methods of decreasing serum calcium levels |
US5856340A (en) | 1995-02-28 | 1999-01-05 | Eli Lilly And Company | Method of treating estrogen dependent cancers |
US5726168A (en) * | 1995-10-12 | 1998-03-10 | Eli Lilly And Company | Lipophilic benzothiophenes |
US6458811B1 (en) * | 1996-03-26 | 2002-10-01 | Eli Lilly And Company | Benzothiophenes formulations containing same and methods |
EP0910369B1 (en) * | 1996-03-26 | 2010-04-21 | Eli Lilly And Company | Benzothiophenes, formulations containing same, and methods |
US5888963A (en) * | 1996-04-18 | 1999-03-30 | Auckland Uniservices Limited | Treatment of bone disorders with adrenomedullin |
US6440421B1 (en) | 1996-04-18 | 2002-08-27 | Auchkland Uniservices Limited | Treatment of bone disorders with adrenomedullin or adrenomedullin agonists |
US5747509A (en) * | 1996-06-03 | 1998-05-05 | Schering Aktiengesellschaft | Method for lowering plasma levels of lipoprotein(a) |
KR20000022040A (ko) * | 1996-06-20 | 2000-04-25 | 보오드 오브 리젠츠, 더 유니버시티 오브 텍사스 시스템 | 약학적 활성 제제를 제공하기 위한 화합물, 방법 및 그의 용도 |
GB9624800D0 (en) * | 1996-11-29 | 1997-01-15 | Lilly Co Eli | Methods of preventing breast cancer |
KR19980033284A (ko) * | 1996-10-30 | 1998-07-25 | 피터지.스트링거 | 개선된 유방암 예방법 |
KR100522646B1 (ko) * | 1996-10-30 | 2005-12-21 | 일라이 릴리 앤드 캄파니 | 유방암의예방방법 |
CZ300261B6 (cs) * | 1996-10-30 | 2009-04-01 | Eli Lilly And Company | Použití hydrochloridové soli raloxifenu pro prípravu léciva pro prevenci rakoviny prsu |
US6069175A (en) * | 1996-11-15 | 2000-05-30 | Pfizer Inc. | Estrogen agonist/antagonists treatment of atherosclerosis |
EP1027027B1 (en) | 1997-09-26 | 2006-12-20 | Auckland Uniservices Limited | Use of amylin, adrenomedullin and analogues thereof for treating cartilage defects |
US6096781A (en) | 1997-11-14 | 2000-08-01 | Eli Lilly And Company | 2-arylbenzo[B]thiophenes useful for the treatment of estrogen deprivation syndrome |
US6054446A (en) | 1997-12-24 | 2000-04-25 | Sri International | Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use |
KR20010042531A (ko) * | 1998-04-08 | 2001-05-25 | 피터 지. 스트링거 | 랄록시펜의 폐 및 경비 전달 |
US20040186185A1 (en) * | 1998-05-07 | 2004-09-23 | Steiner Mitchell S. | Method for treatment and chemoprevention of prostate cancer |
US6465445B1 (en) | 1998-06-11 | 2002-10-15 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
US7005428B1 (en) | 1998-06-11 | 2006-02-28 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
US6258826B1 (en) | 1998-10-13 | 2001-07-10 | Eli Lilly And Company | Pharmaceutical formulations and applications thereof for the treatment of estrogen deprivation syndrome |
ATE301129T1 (de) | 1999-05-04 | 2005-08-15 | Strakan Int Ltd | Androgen glykoside und die androgenische aktivität davon |
US6326365B1 (en) | 1999-07-20 | 2001-12-04 | Apollo Biopharmaceutics, Inc. | Methods of prevention and treatment of ischemic damage |
US6339078B1 (en) | 1999-07-20 | 2002-01-15 | University Of Florida Research Foundation, Inc. | Methods of prevention and treatment of ischemic damage |
US20020013327A1 (en) * | 2000-04-18 | 2002-01-31 | Lee Andrew G. | Compositions and methods for treating female sexual dysfunction |
AR029538A1 (es) * | 2000-07-06 | 2003-07-02 | Wyeth Corp | Composiciones farmaceuticas de agentes estrogenicos |
WO2002034266A1 (en) * | 2000-10-25 | 2002-05-02 | Eli Lilly And Company | Method for inhibiting cataracts |
US6599921B2 (en) | 2001-02-22 | 2003-07-29 | Nanodesign, Inc. | Non-steroidal estrogen receptor ligands |
EP1312363A1 (en) * | 2001-09-28 | 2003-05-21 | Pfizer Products Inc. | Methods of treatment and kits comprising a growth hormone secretagogue |
EP2316468A1 (en) | 2002-02-22 | 2011-05-04 | Shire LLC | Delivery system and methods for protecting and administering dextroamphetamine |
US7342884B2 (en) * | 2002-03-13 | 2008-03-11 | Harmonic, Inc. | Method and apparatus for one directional communications in bidirectional communications channel |
JP3887588B2 (ja) * | 2002-08-30 | 2007-02-28 | 株式会社リガク | X線回折による応力測定法 |
US7964734B2 (en) | 2002-09-30 | 2011-06-21 | A/S Gea Farmaceutisk Fabrik | Raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these |
US20060106010A1 (en) * | 2003-05-27 | 2006-05-18 | Black Larry J | Methods for inhibiting bone loss |
BRPI0414448A (pt) * | 2003-09-19 | 2006-11-14 | Pfizer Prod Inc | composições farmacêuticas e métodos compreendendo combinações de derivados de 2-alquilideno-19-nor-vitamina d e um agonista/antagonista de estrogênio |
BRPI0417621A (pt) * | 2003-12-17 | 2007-04-10 | Pfizer Prod Inc | terapia de combinação contìnua com agonistas seletivos do receptor ep4 de prostaglandina e um estrogênio para o tratamento de estados que se apresentem com baixa massa óssea |
US20050137264A1 (en) * | 2003-12-22 | 2005-06-23 | Patel Ashish A. | Modafinil compositions |
US20050203086A1 (en) * | 2004-03-04 | 2005-09-15 | Pfizer Inc. | Methods of treatment using an EP2 selective receptor agonist |
EP1732528A1 (en) * | 2004-04-08 | 2006-12-20 | Wyeth | Bazedoxifene acetate solid dispersion formulations |
US7504394B2 (en) * | 2004-04-08 | 2009-03-17 | Wyeth | Bazedoxifene ascorbate |
US20060068010A1 (en) * | 2004-09-30 | 2006-03-30 | Stephen Turner | Method for improving the bioavailability of orally delivered therapeutics |
DK1729735T3 (da) * | 2004-11-10 | 2007-10-08 | Teva Pharma | Fremgangsmåde til fremstilling af sammenpressede, faste doseringsformer, som er velegnede til brug sammen med lægemidler med lav vandoplöselighed og sammenpressede, faste doseringsformer fremstillet derved |
US8367105B2 (en) | 2004-11-10 | 2013-02-05 | Teva Pharmaceutical Industries, Ltd. | Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby |
UA89513C2 (uk) * | 2004-12-03 | 2010-02-10 | Элан Фарма Интернешнл Лтд. | Стабільна композиція з наночастинок ралоксифену гідрохлориду |
US20060270641A1 (en) * | 2005-05-31 | 2006-11-30 | Steiner Mitchell S | Method for chemoprevention of prostate cancer |
EP2271320A4 (en) * | 2008-04-02 | 2011-05-18 | Reddys Lab Ltd Dr | PHARMACEUTICAL RALOXIFY FORMULATIONS |
EP2448562B1 (en) | 2009-07-02 | 2013-11-06 | Synthon B.V. | Raloxifene composition |
US8501690B2 (en) | 2010-04-30 | 2013-08-06 | John G. Stark | Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue |
JP5508311B2 (ja) * | 2011-02-28 | 2014-05-28 | テバ ファーマシューティカル インダストリーズ リミティド | 低水溶性薬物とともに使用することによく適した圧縮固体状投与形態の製造方法およびそれにより製造された圧縮固体状投与形態 |
MD20140054A2 (ro) | 2011-12-16 | 2014-10-31 | Olema Pharmaceuticals, Inc. | Compuşi noi de benzopiran, compoziţii şi utilizări ale acestora |
WO2014203129A1 (en) | 2013-06-19 | 2014-12-24 | Olema Pharmaceuticals, Inc. | Combinations of benzopyran compounds, compositions and uses thereof |
WO2014203132A1 (en) | 2013-06-19 | 2014-12-24 | Olema Pharmaceuticals, Inc. | Substituted benzopyran compounds, compositions and uses thereof |
AU2016331065B2 (en) | 2015-10-01 | 2021-04-29 | Olema Pharmaceuticals, Inc. | Tetrahydro-1H-pyrido(3,4-b)indole anti-estrogenic drugs |
EP3386968A4 (en) | 2015-12-09 | 2019-09-25 | The Board of Trustees of the University of Illinois | BENZOTHIOPHEN-BASED SELECTIVE ESTROGEN RECEPTOR-DOWN-REGULATING PREPARATIONS |
WO2017197055A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Heterocyclic degronimers for target protein degradation |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | C3 CARBON-BASED GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
EA201990187A1 (ru) | 2016-07-01 | 2019-07-31 | Г1 Терапьютикс, Инк. | Антипролиферационные средства на основе пиримидина |
WO2018081168A2 (en) | 2016-10-24 | 2018-05-03 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective mixed estrogen receptor downregulators |
BR112019013814A2 (pt) | 2017-01-06 | 2020-01-21 | G1 Therapeutics Inc | método para tratamento de câncer ou de um tumor em um indivíduo, composição farmacêutica, combinação, e, kit. |
AU2018217809A1 (en) | 2017-02-10 | 2019-08-22 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
AU2018291026B2 (en) | 2017-06-29 | 2022-09-01 | G1 Therapeutics, Inc. | Morphic forms of GIT38 and methods of manufacture thereof |
CN113453679A (zh) | 2018-12-20 | 2021-09-28 | C4医药公司 | 靶向蛋白降解 |
JP2023509375A (ja) | 2019-12-20 | 2023-03-08 | シーフォー セラピューティクス, インコーポレイテッド | Egfrの分解のためのイソインドリノン及びインダゾール化合物 |
WO2024030968A1 (en) | 2022-08-03 | 2024-02-08 | Brystol-Myers Squibb Company | Compounds for modulating ret protein |
WO2024097980A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein inhibitors |
WO2024097989A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein degraders |
Family Cites Families (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4185108A (en) | 1977-05-10 | 1980-01-22 | Westwood Pharmaceuticals Inc. | Antiosteoporotic agents |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
IL65379A0 (en) | 1981-04-03 | 1982-05-31 | Lilly Co Eli | Process for preparing acylated benzothiophenes |
GB2097788B (en) | 1981-04-03 | 1985-04-24 | Lilly Co Eli | Benzothiophene compounds and process for preparing them |
EP0068563A3 (en) | 1981-06-23 | 1983-06-15 | THE PROCTER & GAMBLE COMPANY | Heterocyclic acetic acid compounds and compositions for treating bone diseases |
US4729999A (en) | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
US4970237A (en) | 1987-03-20 | 1990-11-13 | Yale University | Use of clomiphene to increase bone mass in premenopausal women |
US5075321A (en) * | 1987-03-24 | 1991-12-24 | University Of Pennsylvania | Methods of treating diseases characterized by interactions of IgG-containing immune complexes with macrophage Fc receptors using antiestrogenic benzothiophenes |
US5395842A (en) | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
US5208031A (en) | 1989-06-06 | 1993-05-04 | Kelly Patrick D | Sexual lubricants containing zinc as an anti-viral agent |
US5011853A (en) | 1989-08-25 | 1991-04-30 | Washington University | Compounds for treatment of cholinergic neurotoxins |
US5118667A (en) | 1991-05-03 | 1992-06-02 | Celtrix Pharmaceuticals, Inc. | Bone growth factors and inhibitors of bone resorption for promoting bone formation |
DE4122484A1 (de) * | 1991-07-06 | 1993-01-07 | Teves Gmbh Alfred | Schaltungsanordnung zur erkennung von radsensordefekten |
DE4123368C1 (zh) | 1991-07-15 | 1992-11-05 | Bergwerksverband Gmbh, 4300 Essen, De | |
JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
WO1993011074A1 (en) * | 1991-11-25 | 1993-06-10 | Healthguard, Incorporated | Multistage coaxial encapsulated filter assembly |
TW366342B (en) * | 1992-07-28 | 1999-08-11 | Lilly Co Eli | The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss |
TW383306B (en) * | 1992-12-22 | 2000-03-01 | Lilly Co Eli | New use of 2-phenyl-3-aroylbenzothiophenes in lowering serum cholesterol |
US5482949A (en) | 1993-03-19 | 1996-01-09 | Eli Lilly And Company | Sulfonate derivatives of 3-aroylbenzo[b]thiophenes |
US5445941A (en) | 1993-06-21 | 1995-08-29 | Eli Lilly And Company | Method for screening anti-osteoporosis agents |
CZ285522B6 (cs) | 1993-06-24 | 1999-08-11 | Eli Lilly And Company | Farmaceutický prostředek pro snížení koncentrace glukosy v krvi |
TW303299B (zh) | 1993-07-22 | 1997-04-21 | Lilly Co Eli | |
US5441947A (en) | 1993-08-25 | 1995-08-15 | Eli Lilly And Company | Methods of inhibiting vascular restenosis |
US5468773A (en) | 1993-08-25 | 1995-11-21 | Eli Lilly And Company | Methods for inhibiting bone loss and cartilage degradation using wortmannin and its analogs |
US5457116A (en) | 1993-10-15 | 1995-10-10 | Eli Lilly And Company | Methods of inhibiting uterine fibrosis |
US5461065A (en) | 1993-10-15 | 1995-10-24 | Eli Lilly And Company | Methods for inhibiting endometriosis |
RU2135176C1 (ru) | 1993-12-14 | 1999-08-27 | Эли Лилли Энд Компани | Водорастворенный комплекс включения соединений бензотиофена с водорастворимым циклодекстрином, способ его получения и фармацевтическая композиция |
US5462949A (en) | 1993-12-21 | 1995-10-31 | Eli Lilly And Company | Methods of inhibiting fertility in women |
US5591753A (en) | 1994-01-28 | 1997-01-07 | Eli Lilly And Company | Combination treatment for osteoporosis |
US5478847A (en) | 1994-03-02 | 1995-12-26 | Eli Lilly And Company | Methods of use for inhibiting bone loss and lowering serum cholesterol |
US5811120A (en) | 1994-03-02 | 1998-09-22 | Eli Lilly And Company | Solid orally administerable raloxifene hydrochloride pharmaceutical formulation |
US5972383A (en) | 1994-03-02 | 1999-10-26 | Eli Lilly And Company | Solid orally administerable raloxifene hydrochloride pharmaceutical formulation |
US5629425A (en) | 1994-09-19 | 1997-05-13 | Eli Lilly And Company | Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene |
CO4410190A1 (es) | 1994-09-19 | 1997-01-09 | Lilly Co Eli | 3-[4-(2-AMINOETOXI)-BENZOIL]-2-ARIL-6-HIDROXIBENZO [b] TIOFENO CRISTALINO |
US6458811B1 (en) | 1996-03-26 | 2002-10-01 | Eli Lilly And Company | Benzothiophenes formulations containing same and methods |
US6713494B1 (en) | 1996-08-28 | 2004-03-30 | Eli Lilly And Company | Amorphous benzothiophenes, methods of preparation and methods of use |
US6096781A (en) | 1997-11-14 | 2000-08-01 | Eli Lilly And Company | 2-arylbenzo[B]thiophenes useful for the treatment of estrogen deprivation syndrome |
ID24978A (id) | 1997-11-14 | 2000-08-31 | Lilly Co Eli | 2-ARYL-3-AROYLBENZO (b) THIOPHENES BERGUNA UNTUK PENGOBATAN SINDROM DEPRIVASI ESTROGEN |
US6258826B1 (en) | 1998-10-13 | 2001-07-10 | Eli Lilly And Company | Pharmaceutical formulations and applications thereof for the treatment of estrogen deprivation syndrome |
-
1994
- 1994-03-02 US US08/205,012 patent/US5478847A/en not_active Ceased
-
1995
- 1995-01-10 SG SG1996003344A patent/SG46354A1/en unknown
- 1995-02-07 PE PE1995261225A patent/PE44895A1/es not_active Application Discontinuation
- 1995-02-07 CA CA002141999A patent/CA2141999A1/en not_active Abandoned
- 1995-02-07 NZ NZ270460A patent/NZ270460A/xx unknown
- 1995-02-07 ZA ZA95976A patent/ZA95976B/xx unknown
- 1995-02-07 NZ NZ314699A patent/NZ314699A/en unknown
- 1995-02-07 CZ CZ95313A patent/CZ31395A3/cs unknown
- 1995-02-09 IL IL11259395A patent/IL112593A0/xx unknown
- 1995-02-10 EP EP95300842A patent/EP0674903A1/en not_active Withdrawn
- 1995-02-14 PH PH49963A patent/PH31420A/en unknown
- 1995-02-16 MY MYPI95000392A patent/MY130157A/en unknown
- 1995-02-27 PL PL95307463A patent/PL307463A1/xx unknown
- 1995-02-28 CO CO95007823A patent/CO4340681A1/es unknown
- 1995-02-28 NO NO950774A patent/NO950774L/no not_active Application Discontinuation
- 1995-02-28 KR KR1019950003983A patent/KR950031069A/ko not_active Application Discontinuation
- 1995-02-28 RU RU95102778/14A patent/RU2100024C1/ru not_active IP Right Cessation
- 1995-02-28 RU RU96119781/14A patent/RU2150275C1/ru not_active IP Right Cessation
- 1995-02-28 UA UA99116044A patent/UA32636C2/uk unknown
- 1995-03-01 AU AU13551/95A patent/AU702575B2/en not_active Ceased
- 1995-03-01 YU YU13695A patent/YU13695A/sh unknown
- 1995-03-01 CN CN95100021A patent/CN1119530A/zh active Pending
- 1995-03-01 HU HU9500634A patent/HUT72638A/hu unknown
- 1995-03-01 JP JP7041769A patent/JP2818384B2/ja not_active Expired - Fee Related
- 1995-03-01 BR BR9500784A patent/BR9500784A/pt not_active Application Discontinuation
- 1995-04-14 US US08/422,417 patent/US5641790A/en not_active Expired - Lifetime
- 1995-04-14 US US08/422,289 patent/US5610168A/en not_active Expired - Lifetime
-
1997
- 1997-01-27 US US08/788,984 patent/US5747510A/en not_active Expired - Lifetime
-
1998
- 1998-04-17 JP JP10107550A patent/JPH10291932A/ja active Pending
- 1998-04-17 JP JP10107549A patent/JPH10310525A/ja active Pending
-
2003
- 2003-02-27 US US10/375,274 patent/USRE39050E1/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH10291932A (ja) | 1998-11-04 |
HU9500634D0 (en) | 1995-04-28 |
SG46354A1 (en) | 1998-02-20 |
NZ270460A (en) | 1999-07-29 |
NO950774D0 (no) | 1995-02-28 |
NZ314699A (en) | 2000-07-28 |
CO4340681A1 (es) | 1996-07-30 |
RU2100024C1 (ru) | 1997-12-27 |
PH31420A (en) | 1998-10-29 |
RU95102778A (ru) | 1996-11-27 |
PE44895A1 (es) | 1995-12-20 |
BR9500784A (pt) | 1995-10-24 |
JPH10310525A (ja) | 1998-11-24 |
CA2141999A1 (en) | 1995-09-03 |
EP0674903A1 (en) | 1995-10-04 |
US5747510A (en) | 1998-05-05 |
AU702575B2 (en) | 1999-02-25 |
JPH07267861A (ja) | 1995-10-17 |
IL112593A0 (en) | 1995-05-26 |
RU2150275C1 (ru) | 2000-06-10 |
US5478847A (en) | 1995-12-26 |
NO950774L (no) | 1995-09-04 |
MY130157A (en) | 2007-06-29 |
ZA95976B (en) | 1996-08-07 |
UA32636C2 (uk) | 2001-02-15 |
PL307463A1 (en) | 1995-09-04 |
YU13695A (sh) | 1999-07-28 |
CZ31395A3 (en) | 1995-11-15 |
JP2818384B2 (ja) | 1998-10-30 |
AU1355195A (en) | 1995-09-07 |
US5641790A (en) | 1997-06-24 |
HUT72638A (en) | 1996-05-28 |
US5610168A (en) | 1997-03-11 |
USRE39050E1 (en) | 2006-03-28 |
KR950031069A (ko) | 1995-12-18 |
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