CN1192141A - 抑制黑素瘤的方法 - Google Patents
抑制黑素瘤的方法 Download PDFInfo
- Publication number
- CN1192141A CN1192141A CN96195876A CN96195876A CN1192141A CN 1192141 A CN1192141 A CN 1192141A CN 96195876 A CN96195876 A CN 96195876A CN 96195876 A CN96195876 A CN 96195876A CN 1192141 A CN1192141 A CN 1192141A
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- chemical compound
- melanoma
- acid
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- raloxifene
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- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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Abstract
一种抑制黑素瘤的方法,包括给病人单独服用有效量的通式(Ⅰ)的化合物,或单独服用适合药物的(Ⅰ)的盐或其溶剂化合物,或与一种或多种黑素瘤抑制剂一起服用。(Ⅰ)中R1和R3为独立H,－CH3,(a)或(b),(b)中Ar为选择性取代苯基,R2选自吡咯烷、六亚甲基氨和哌啶子基之一。
Description
发明背景
黑素瘤是一种主要位于皮肤表层的黑素细胞恶性瘤。黑素瘤主要发生在成人身上，一般由良性带颜色的痣恶化而成。任何面积增大，颜色变化或发痒等症状都预示着可能发生了恶性变化。黑素瘤引起的死亡一般约占所有癌症死亡中的1％。除在妇女中的肺癌外，黑素瘤的发病速度较其它瘤快。
黑素瘤的最大危险是其病毒通过淋巴管和血液循环转移到人体深层部位。人体的任何器官都可能被转移上，主要是转移到肺和肝上。尽管采用深切技术有时能令患者存活一段时间，但已转移到深层部位的黑素瘤很难用一般的治疗方法治愈。长期以来，黑素瘤病人成了探索新的化学疗法或改进生物技术疗法的临床试验者。
目前，经过近20年的试验，Dacarbazine(DTIC)被FDA认证为治疗黑素瘤的唯一制剂，组合使用化疗制剂，疗效并不比单独使用Dacarbazine疗效好。但只有15～25％的患者用Dacarbazine后有反应，且仅有5％的人治愈。因此有必要寻找更有效的治疗方式及另外的黑素瘤抑制剂。
发明概述
本发明提供了抑制黑素瘤的方法，该方法包括给病人单独服用有效量的通式(I)的化合物，或其药用盐或其溶剂化物，或与一种或多种黑素瘤抑制剂一起服用。式(I)中R1和R2为独立H，-CH3，
或
其中Ar为任选取代的苯基；R2选自吡咯烷、六亚甲基氨和哌啶子基。
发明详述
本发明涉及发现了有抑制黑素瘤作用的2-苯基-3-芳酰基苯并噻吩(苯并噻吩类)，其通式为(I)。
本发明提供了有效抑制黑素瘤的方法：给病人单独服用有效量的通式I的化合物，或其药用盐或其溶剂化物，或与一种或多种黑素瘤抑制剂一起服用。
“抑制”一词本意包含阻止、预防、限制、减慢、停止或逆转等，本发明中其意既包含药物治疗，又包含适当的预防作用。
本发明中raloxifene是化合物I的盐酸盐，R1和R3均为H，R2为1-哌啶基，它是一个核调节分子。已证明raloxifene结合在雌激素受体上，其作用是抗雌激素，因为它能阻碍雌激素激活子宫，诱发乳腺癌。事实上，在某些细胞中raloxifene确实阻碍了雌激素发挥作用，但在其它细胞中，雌激素能激活的基因，它也能激活，显示出与雌激素相同的药学特性，如治疗骨质疏松、高血脂等。因此，raloxifene既有抗雌激素的性质，又有主动剂-拮抗剂的性质。raloxifene表现出与雌激素不同的特性，现在被认为是raloxifene-雌激素受体络合物激活和/或抑制的基因，与雌激素-雌激素受体激活和/或抑制的基因不同。所以，尽管raloxifene与雌激素利用和竞争相同的受体，但二者对基因控制的药学结果却是难以预测，彼此也不相同。
一般该化合物加入赋形剂、稀释剂或载体，压缩成片剂，或酏剂或配制成溶液，以便患者口服，或肌肉或静脉注射。该化合物可穿透皮肤，因而可制成缓释剂等形式。
合成本发明中的化合物可参阅下列美国专利，专利号为：4133814，4418068，4380635。一般以具有一个6-羟基和一个2-(4-羟基苯基)的苯并[b]噻吩为原料，经保护性酰化，去保护得到通式1的化合物。上面提到的美国专利提供了合成这些化合物的实例。选择性取代的苯基包括苯基和一重或双重取代的苯基，取代基分别为C1-C6烷基，C1-C4烷氧基，羟基、硝基、氯、氟或三(氯或氟)甲基。
本发明方法中的化合物与大量的有机和无机酸及碱反应，形成适合药用的酸和碱加成盐，及生理上可用的盐，它们常用在药物化学中。典型使用的无机酸包括盐酸、氢溴酸、碘化氢、硝酸、硫酸、磷酸、连二磷酸等、所用有机酸有脂肪族单羧酸、二羧酸、苯基取代的链烷酸、羟基烷酸和羟基链烷双酸、芳香酸、脂肪族磺酸及芳香族磺酸。适合药用的盐包括乙酸盐、苯乙酸盐、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、O-乙酰基苯甲酸盐、2-萘苯甲酸盐、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、延胡索酸盐、乙醇酸盐、庚酸盐、脲酸盐、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，苯酸盐、邻苯二甲酸盐、四邻苯二甲酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯丙酸盐、水扬酸盐、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、氯代苯磺酸盐、乙基磺酸盐、2-羟乙基磺酸盐、甲基磺酸盐、1-萘磺酸盐、2-萘磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等。最好是用盐酸盐。
适合药用的酸及盐主要由通式I的化合物与等量或过量的酸反应而得。反应物一般置于共溶溶剂，如乙醚或苯中混合。约1小时至10天内产物盐从溶液中沉淀出来，过滤分离之或用常规方法除去溶剂，将盐分离出来。
合成盐常用的碱有：氢氧化铵、碱金属及碱土金属的氢氧化物、碳酸盐及伯、仲、叔脂肪族胺类、脂肪族二胺类。主要用的碱有：氢氧化铵、碳酸钾、甲胺、二乙胺、乙二胺及环己胺。
适于药用的盐的溶解性比其母体化合物的溶解性好，因而更适合于配制成液体或乳剂。
配制药方已有成熟的技术。例如化合物与普通的赋形剂、稀释剂或载体可制成片剂、胶囊、悬浮液、粉末等。适合于这类制剂的赋形剂、稀释剂及载体包括：填料和增容剂，如淀粉、糖、甘露糖醇及硅衍生物；粘合剂如羧甲基纤维素及其它纤维素衍生物，如藻酸盐、明胶及聚乙烯吡咯烷酮；润湿剂如甘油；粉碎剂如碳酸钙和碳酸氢钠；溶解抑制剂如石蜡；加速吸收剂如季铵盐化合物；表面活性剂如十六烷醇、硬脂酸甘油单酯；吸附载体如高岭土和膨润土；润滑剂如滑石、硬脂酸钙、硬脂酸镁和固态聚乙烯醇。
这些化合物也可配制成酏剂，或方便的口服液，或适于非肠道使用的溶液，如肌肉，皮下或静脉途径。另外，化合物也适合配成缓释片剂等。配制的制剂能在一段时间内仅在或优先在肠道的特定部位释放活性组分。包膜、外壳、保护基质可用聚合物材料或蜡做成。
本发明介绍了利用通式I的化合物抑制黑素瘤，抑制方式和特殊剂量由医生根据病人病情的严重程度，服用方式和其它因素来决定。一般来说，适用而有效的日剂量约为0.1至1000毫克，常用量为50至200毫克。病人每天服用一至三次，若需要可增加次数，这样可在一段时间内充分有效地抑制黑素瘤。本发明还包括通式I的化合物与一种或多种黑素瘤抑制剂一起服用。这类抑制剂包括Cisplatin、Dacarbazine和亚硝基脲氮芥。
通式I的化合物常以酸加成盐的形式服用，如同惯常服用带碱性基团如哌啶环的药。那样口服也有好处。为此口服剂量如下：
制剂
下列制剂中的“活性组分”指通式I的化合物。制剂1：胶囊
利用下面的制剂制成硬胶囊：组分 量(毫克/囊)活性组分 0.1-1000淀粉NF 0-650淀粉流动性粉末 0-650硅酮流体350厘沲 0-15将各组分混合，过45目美国筛，填充进硬胶囊。含raloxifene的制剂实例如下：制剂2：raloxifene胶囊组分 量(毫克/囊)raloxifene 1淀粉NF 112淀粉流动性粉末 225.3硅酮流体350厘沲 1.7制剂3：raloxifene胶囊组分 量(毫克/囊)raloxifene 5淀粉NF 108淀粉流动性粉末 225.3硅酮流体350厘沲 1.7制剂4：raloxifene胶囊组分 量(毫克/囊)raloxifene 10淀粉NF 103淀粉流动性粉末 225.3硅酮流体350厘沲 1.7制剂5：raloxifene胶囊组分 量(毫克/囊)raloxifene 50淀粉NF 150淀粉流动性粉末 397硅酮流体350厘沲 3.0上面的制剂可根据合理的变化作调整。用下列组分配制的片剂制剂如下：制剂6：片剂组分 量(毫克/片)活性组分 0.1-1000纤维素微晶 0-650二氧化硅 0-650硬脂酸 0-15
各组分混合后压缩成片剂。另一含0.1至1000毫克活性组分的片剂制剂如下：制剂7：片剂组分 量(毫克/片)活性组分 0.1-1000淀粉 45纤维素微晶 35聚乙烯吡咯烷酮(10％的水溶液) 4羧甲基纤维素钠 4.5硬脂酸镁 0.5滑石 1
活性组分、淀粉和纤维素过45目美国筛，混合均匀。聚乙烯吡咯烷酮溶液与上述粉末混合，过14目美国筛，得到的粒剂在50～60℃烘干后过18目美国筛。羧甲基纤维素钠、淀粉、硬脂酸镁和滑石混合，过60目美国筛后与粒剂混合，在片剂机上被压制成片剂。
每5毫升含0.1至1000毫克药剂的悬浮液制剂如下：制剂8：悬浮液组分 量(毫克/5毫升)活性组分 0.1-1000毫克羧甲基纤维素钠 50毫克糖浆 1.25毫克苯甲酸溶液 0.10毫升香料 适量颜料 适量纯净水 5毫升
活性组分过45目美国筛，与羧甲基纤维素钠及糖浆混合成糊状.苯甲酸溶液、香料及颜料用少许水稀释，加入到上述糊状物中，边加边搅加入足量的水定容。
试验
用细胞群繁殖法试验通式I的化合物的活性。在试验通式I的化合物短时间曝露在黑素瘤细胞上产生的作用时，将黑素瘤细胞的单细胞悬浮液，以每培养皿20000个细胞，培育到60毫米组织培养皿中(Corning，Corning NY)，允许它们接触2至4小时。将化合物加入培养皿中，孵育1小时，然后用磷酸盐缓冲盐水(Sigma Chemical Co.，St.Louis，MO)清洗三次，通过受胰蛋白作用收集细胞，再洗一次以除去药物，重新悬浮到5毫升含0.3％琼脂液的全培养液中(Difco，Detroit，MI)。悬浮液混合均匀，等分成三份，以每培养皿1毫升取样到预制的培养皿中，底层有固化的1％琼脂糖。室温下固化，并在37℃、增湿5％二氧化碳的条件下孵育。5天以后对连续细胞线，或7至14天以后对初级细胞，计数出大于125微摩尔/升的细胞群。
在试验通式I的化合物持续曝露在黑素瘤细胞上产生的作用时，以每毫升4000个细胞，将黑素瘤细胞悬浮于0.3％琼脂液中(Difco，Detroit，MI)，从中取样加入到含通式I的化合物和全培养液的试管里，如RPMI1640培养液(Irving Scientific，Santa Ana，CA)含10％胎牛血清(Hyclone，Logan，UT)、50微克/毫升庆大霉素(Gemini Bio-Products，Calabasas，CA)、2毫摩尔/升L-谷氨酰胺、10纳摩尔/升氢化可的松、5微克/毫升胰岛素、5微克/毫升转铁球蛋白、10纳摩尔/升雌甾二醇和5纳克/毫升硒(Sigma Chemical Co.，St.Louis，MO)，悬浮液混合均匀，等分成三份，以每培养皿1毫升取样至预制的培养皿中，底层含固化的1％琼脂糖。室温下固化，在37℃、增湿5％二氧化碳的条件下孵育。5天以后对连续细胞线，或7至14天以后对初级细胞，计数出大于125微摩尔/升的细胞群。
上述试验中至少有一个试验表明化合物的活性可用于抑制黑素瘤。
Claims (5)
1.一种抑制黑素瘤的方法，包括给需要的病人单独服用有效量的通式I的化合物，
或其药用盐或其溶剂化物，或与一种或多种黑素瘤抑制剂一起服用，式(I)中R1和R3为独立H，-CH3，
或
其中Ar为任选取代的苯基，R2选自吡咯烷、六亚甲基氨和哌啶子基。
2.权利要求1的方法，其中所说的化合物为其盐酸盐。
3.权利要求1的方法，其中所说的化合物是：
或其盐酸盐。
4.权利要求1的方法，其中所说的化合物与一种或多种cisplatin、dacarbazine或亚硝基脲氮芥一起服用。
5.权利要求1的方法，其中所说的黑素瘤是转移性的。
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| US08/466,673 | 1995-06-06 | ||
| US08/466,673 US5843974A (en) | 1995-06-06 | 1995-06-06 | Methods of inhibiting melanoma using Benzothiophenes as cytotoxic agents per se |
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| US6048847A (en) * | 1997-09-30 | 2000-04-11 | Dabur Research Foundation | Use of betulinic acid and its derivatives for inhibiting cancer growth and a method of monitoring this |
| US6228850B1 (en) * | 1997-09-30 | 2001-05-08 | Dabur Research Foundation | Antiangiogenic activity of betulinic acid and its derivatives |
| US6670345B1 (en) | 1997-09-30 | 2003-12-30 | Dabur Research Foundation | Betulinic acid derivatives for inhabiting cancer growth and process for the manufacture of betulinic acid |
| DK1175433T3 (da) | 1999-05-04 | 2005-09-19 | Strakan Int Ltd | Androgenglycosider og androgen aktivitet deraf |
| AU2005218759B2 (en) * | 2004-02-27 | 2009-07-16 | Antisense Pharma Gmbh | Pharmaceutical composition |
| CN101389345A (zh) * | 2004-03-19 | 2009-03-18 | 宾州研究基金会 | 治疗黑素瘤的组合方法和组合物 |
| CN116271053A (zh) | 2012-08-13 | 2023-06-23 | 洛克菲勒大学 | 治疗和诊断黑素瘤 |
| EP3091970B1 (en) | 2014-01-10 | 2020-10-28 | Rgenix, Inc. | Lxr agonists and uses thereof |
| US9758786B2 (en) | 2016-02-09 | 2017-09-12 | Autotelic, Llc | Compositions and methods for treating pancreatic cancer |
| US11214536B2 (en) | 2017-11-21 | 2022-01-04 | Inspirna, Inc. | Polymorphs and uses thereof |
| JP2023509845A (ja) | 2019-12-13 | 2023-03-10 | インスピルナ，インコーポレーテッド | 金属塩及びその使用 |
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| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
| US4656187A (en) * | 1981-08-03 | 1987-04-07 | Eli Lilly And Company | Treatment of mammary cancer |
| 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 |
| TW366342B (en) * | 1992-07-28 | 1999-08-11 | Lilly Co Eli | The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss |
| US5457113A (en) * | 1993-10-15 | 1995-10-10 | Eli Lilly And Company | Methods for inhibiting vascular smooth muscle cell proliferation and restinosis |
| KR950010891A (ko) * | 1993-10-15 | 1995-05-15 | 피터 지. 스트링거 | 내성 종양을 치료하는 방법 |
| UA32427C2 (uk) * | 1993-10-15 | 2000-12-15 | Елі Ліллі Енд Компані | Застосування бензотіофенів або їх фармацевтично прийнятних солей або сольватів для інгібування ангіогенезу і/або ангіогенних захворювань |
| US5476862A (en) * | 1993-12-21 | 1995-12-19 | Eli Lilly And Company | Methods of increasing thrombomodulin expression |
| US5622975A (en) * | 1995-06-01 | 1997-04-22 | Eli Lilly And Company | Methods for inhibiting vascular smooth muscle cell migration |
| US5726168A (en) * | 1995-10-12 | 1998-03-10 | Eli Lilly And Company | Lipophilic benzothiophenes |
| US5780497A (en) * | 1996-04-19 | 1998-07-14 | American Home Products Corporation | 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents |
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- 1996-06-06 EA EA199800015A patent/EA000680B1/ru not_active IP Right Cessation
- 1996-06-06 CN CN96195876A patent/CN1192141A/zh active Pending
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| CZ383197A3 (cs) | 1998-07-15 |
| PL323924A1 (en) | 1998-04-27 |
| MX9709466A (es) | 1998-02-28 |
| NO975580D0 (no) | 1997-12-03 |
| ZA964682B (en) | 1997-12-05 |
| HUP9901093A2 (hu) | 1999-10-28 |
| CA2223157A1 (en) | 1996-12-12 |
| KR19990022364A (ko) | 1999-03-25 |
| WO1996039135A1 (en) | 1996-12-12 |
| EA199800015A1 (ru) | 1998-06-25 |
| EA000680B1 (ru) | 2000-02-28 |
| EP0747053A3 (en) | 1997-01-29 |
| US5843974A (en) | 1998-12-01 |
| AU702716B2 (en) | 1999-03-04 |
| JPH11507371A (ja) | 1999-06-29 |
| IL118574A0 (en) | 1996-10-16 |
| NO975580L (no) | 1997-12-03 |
| EP0747053A2 (en) | 1996-12-11 |
| HUP9901093A3 (en) | 2000-02-28 |
| AU6109096A (en) | 1996-12-24 |
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