CN1058390C - 苯并噻吩类化合物的用途 - Google Patents

苯并噻吩类化合物的用途 Download PDF

Info

Publication number
CN1058390C
CN1058390C CN94117172A CN94117172A CN1058390C CN 1058390 C CN1058390 C CN 1058390C CN 94117172 A CN94117172 A CN 94117172A CN 94117172 A CN94117172 A CN 94117172A CN 1058390 C CN1058390 C CN 1058390C
Authority
CN
China
Prior art keywords
acid
chemical compound
angiogenesis
preparation
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN94117172A
Other languages
English (en)
Other versions
CN1105361A (zh
Inventor
J·P·星
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of CN1105361A publication Critical patent/CN1105361A/zh
Application granted granted Critical
Publication of CN1058390C publication Critical patent/CN1058390C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pyrane Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrrole Compounds (AREA)

Abstract

抑制血管生成和/或血管原性疾病的方法，包括给需要治疗的患者施用有效量具有以下通式的化合物或其药用盐或其溶剂化物：
其中，各代号意义详见说明书。

Description

苯并噻吩类化合物的用途
血管生成(或新血管形成)，即血管的发育，在胚胎发育、炎症反应、转移物的发育(肿瘤诱导的血管生成即TIA)、糖尿病性视网膜病、关节炎性淋巴结炎的形成及牛皮癣中起着重要的作用。例如，在肿瘤性血管生成过程中，形成了由一群肿瘤细胞诱导的毛细血管芽。这些毛细血管芽最终在肿瘤块中发育成微循环网。根据转移性幼芽在表面及器官中的植入后情况存在两种重要类型的肿瘤血管生成。
第一类或原发性血管生成是增殖的肿瘤细胞块的初始血管形成，它被认为是肿瘤细胞存活和转移性寄存物进一步生长的必要条件。
第二类或继发性血管生成表现为在生长的肿瘤块外周血管以波纹起伏状出现的现象。这第二类血管生成是新的微循环区扩大、成为供应不断扩展和浸润的肿瘤生长所必需的。
很明显，如果一种化学物质能抑制血管生成，不论它是通过竞争性抑制一种血管生成因子的方式或是通过其它的机理，它都将对肿瘤的生长、视网膜病或类风湿性关节炎的发展或牛皮癣病变的发展产生不利的影响。
本发明提供抑制血管生成和/或血管原性疾病的方法，包括给需要治疗的患者施用有效量的下列通式I的化合物及其药用盐和溶剂化物：其中：
R1和R3分别独立地为H、-CH3、
Figure C9411717200052
基)或
Figure C9411717200053
，其中Ar是任选取代的苯基；
R2选自吡咯烷基和哌啶子基。
本发明涉及下述发现：所选择的一组2-苯基-3-芳酰基苯并噻吩化合物(苯并噻吩)，即通式I中的那些化合物可用于抑制血管生成和/或血管原性疾病。实施本发明提供的治疗方法是通过给予需要治疗的患者一剂有效地抑制血管生成和/或血管原性疾病的通式I的化合物或其药用盐或其溶剂化物。术语“抑制”定义为包括通常被接受的含义。即包括预防性地治疗易患血管生成和/或血管原性疾病的个体，并控制和/或治疗已出现的血管生成和/或血管原性疾病。照此说来，本发明的方法包括恰当的医疗性治疗和/或预防性处理。
一般来说，本发明的化合物用普通的赋形剂、稀释剂或载体配制，并压成片，或配成便于口服或肌内或静脉内给药的酏剂或溶液剂。所说化合物还可经透皮施用，并可配成缓释剂型等。
用于本发明方法中的化合物可根据成熟的方法制备。例如在US4,133,814、US 4,418,068和US 4,380,635中已详细描述的方法，上述专利文献都并入本文作为参考。总的说来，该方法以具有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、去保护，形成通式I的化合物，在上文所述的美国专利中提供了制备这类化合物的实施例。被取代的苯基包括用C1-C6烷基、C1-C4烷氧基、硝基、氯、氟或三(氯或氟)甲基取代一次或二次的苯基。
本发明方法中所用的化合物与许多种类的有机和无机酸和碱形成可药用的酸加成盐和碱加成盐，并包括制药工业常用的生理可接受盐。用于形成这些盐的典型的无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可以使用有机酸衍生的盐，如脂族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸、芳香酸、脂族和芳族磺酸。所说可药用盐因此包括乙酸盐、苯乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸、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、邻-乙酰基苯甲酸盐、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-1，4-二羧酸盐、己炔-1，4-二羧酸盐、癸酸盐、辛酸盐、氯化物，肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、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、三邻苯二甲酸盐(teraphthalate)、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、对溴苯碳酸盐、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，优选的盐为盐酸盐。
药用酸加成盐典型地是通过将通式I的化合物与等摩尔或过量的酸反应形成的。反应物一般在互溶剂如二乙基醚或苯中结合。在约1小时至10天内盐正常地从溶剂中沉淀出来，并且借助过滤将盐分离或者用常规方法除去溶剂。
用于生成盐的碱通常包括氢氧化铵和碱金属和碱土金属氢氧化物、碳酸盐和碳酸氢盐以及脂族胺和伯胺、仲胺、叔胺、脂族二胺和羟基烷胺。在制备加成盐中尤其适用的碱包括氢氧化铵、碳酸钾、碳酸氢钠、氢氧化钙、甲胺、二乙胺、1，2-乙二胺、环己胺和乙醇胺。
药用盐一般来讲与衍生它的化合物相比具有溶解性更强的特征，因此它们更适于制成液体或乳剂配方。
通过本领域已知的方法可以配制药物制剂。例如，本发明化合物可用普通赋形剂、稀释液或载体配制，并制成片剂、胶囊剂、悬浮制、粉剂等。适于这些制剂的赋形剂、稀释剂和载体包括下列物质：填充剂和增量剂如淀粉、蔗糖、甘露糖醇及硅衍生物；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；湿润剂如甘油；崩解剂如碳酸钙和碳酸氢钙；溶解抑制剂如石蜡；消溶促进剂如季铵化合物；表面活性剂如十六烷醇、单硬脂酸甘油酯；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、和固态聚乙基1，2-乙二醇。
本发明的化合物也可配制成便于口服的酏剂或溶液剂，或配成适于肠外如适于肌内、皮下或静脉内施用的溶液剂。此外，本发明的化合物非常适于作为缓释剂型等制剂。这样构成的制剂使之可在一段时间内只释放活性成分或者优选在肠道特定部位释放活性成分。可以制备包衣、包膜和保护性基质，例如由聚合物或蜡制得。
根据本发明，治疗血管生成和血管原性疾病所需的特定剂量将依赖于病情的严重程度、施药途径和由主治医生决定的相关因素。一般说来，可被接受的和有效的日剂量约0.1-1000mg，更典型地为约50-200mg/天。将上述剂量给需要治疗的患者每日施用一次至三次，或按需要分更多次施用以有效地抑制血管生成和血管原性疾病。
如同施用带碱性基团如哌啶子基环的药物时的习惯做法一样，通常优选施用酸加成盐形式的通式I化合物。经口服将这种化合物施用于病人是有益的。为此，可使用下列口服剂型。
                        制剂
在下面的制剂中，“活性成分”指通式I的化合物。制剂1：明胶胶囊
用下面的物质制备硬质明胶胶囊：
    成    分                                    量(mg/胶囊)
    活性成分                                    0.1-1000
    淀粉，NF                                    0-650
    淀粉，可流动的粉末                          0-650
    硅氧烷液(Silicone fluid)，350厘沲           0-15
将上述成分混合，过No.45目美国筛，并填入硬质明胶胶囊中。
已经制得的其中R2为哌啶子基的通式I化合物(raloxifene)的特定胶囊制剂的实施例包括如下所示的配方：制剂2：Raloxifene胶囊
  成  分                                量(mg/胶囊)
Raloxifene                                  1
淀粉，NF                                    112
淀粉，可流动的粉末                          225.3
硅氧烷液，350厘沲                           1.7制剂3：Raloxifene胶囊
  成  分                                量(mg/胶囊)
Raloxifene                                  5
淀粉，NF                                    108
淀粉，可流动的粉末                          225.3
硅氧烷液，350厘沲                           1.7制剂4：Raloxifene胶囊
成    分                                    量(mg/胶囊)
Raloxifene                                      10
淀粉，NF                                        103
淀粉，可流动的粉末                              225.3
硅氧烷液，350厘沲                               1.7制剂5：Raloxifene胶囊
成    分                                    量(mg/胶囊)
Raloxifene                                      50
淀粉，NF                                        150
淀粉，可流动的粉末                              397
硅氧烷液，350厘沲                               3.0
上述特定制剂可根据所提供的合理变化进行改变。
用下列成分制备片剂制剂：制剂6：片剂
成    分                                      量(mg/片)
活性成分                                      0.1-1000
纤维素，微晶体                                0-650
二氧化硅，雾化的                              0-650
硬脂酸                                        0-15
将上述各成分混合，并压制成片。
可以选择地是，按如下配方制成每片含有0.1-1000mg活性成分的片剂：制剂7：片剂
   成    分                           量(mg/片)
   活性成分                           0.1-1000
   淀粉                               45
   纤维素，微晶体                     35
   聚乙烯吡咯烷酮                     4
   (以10％水溶液形式)
   羧甲基纤维素钠                     4.5
   硬脂酸镁                           0.5
   滑石                               1
将活性成分，淀粉和纤维素通过No.45目U.S.筛，并充分混合。将聚乙烯吡咯烷酮溶液与所产生的粉末混合然后通过No.14目U.S.筛，于50-60℃干燥所产生的颗粒，并通过No.18目U.S.筛。然后将已先通过No.60目U.S.筛的羧甲基淀粉钠、硬脂酸镁和滑石加至前述颗粒中。混合后经压片机压制成片。
按如下配方配制每5ml剂量含0.1-1000mg药物的悬液剂：制剂8：悬液剂
   成    分                             含量(mg/5ml)
   活性成分                             0.1-1000mg
   羧甲基纤维素钠                       50mg
   糖浆                                 1.25mg
   苯甲酸溶液                           0.1ml
   调味剂                               适量
   色素                                 适量
   加纯化水至                           5ml
药物通过No.45目U.S.筛，并与羧甲基纤维素钠和糖浆混合形成匀状糊。用水稀释苯甲酸溶液、调味剂和色素，边搅拌边加入制好的糊中，然后加入足量的水至所需体积。
                       试验过程
基本上用Buzney等人描述的方法(Buzney et al.，RetinalVascular Endothelia Cell and Pericytes：Differential GrowthCharacteristics in vitro，Invest.Ophthalmol.Visual，Sci.24：470-483(1983))制备初级肾毛细血管内皮细胞培养物，并如Voyta等人所述(Voyta ed al.，Identification and Isolationof Endothelial Cells Based on their Increased uptakeof Acetylated-low desity Lipoprotein.J.Cell Biol.99：2034-2040，(1981))除去污染细胞。
或者，获取牛心脏内皮细胞(American Type CultureCollection；Rockville MD 20852)用于测定。无论来源如何，将所得的内皮细胞以10,000细胞/孔的细胞密度种入24孔组织培养板中，其中每孔含有补充了10％牛血清、100U/ml青霉素、100ug/ml链霉素、2mM L-谷氨酸和20ng/ml成纤维细胞生长因子的Dulbecco改性的Engle培养基(GIBCO；Grand Island，N.Y.)。过夜培养后，向各个生长孔中加入各种不同量的本发明化合物。为了进行比较，测试了在0.1-4μg/ml范围内已知能抑制内皮细胞和血管生成的天然PF-4，用作阳性对照样。使内皮细胞培养物在湿润的组织培养箱中于37℃、5％ CO2条件下生长4天。然后经胰蛋白酶处理后逐个收集培养物，并用AmCoulter计数器(Coulter Electronics，Inc.；Opa Locka FL 33054)计数。
上述试验中的活性表明本发明的化合物在治疗血管生成和/或血管原性疾病中具有潜力。

Claims (4)

1.式(I)化合物或其可药用盐或溶剂化物在制备用于抑制血管生成和/或血管原性疾病的药物中的用途，条件是，这种疾病不包括治疗乳房或前列腺肿瘤或类风湿性关节炎，其中：R1和R3分别独立地为氢、-CH3、
Figure C9411717200022
或
Figure C9411717200023
其中Ar是被C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟、三氯甲基或三氟甲基任选取代一次或两次的苯基；
R2选自吡咯烷基和哌啶子基。
2.按权利要求1的用途，其中所说的化合物是其盐酸盐。
3.按权利要求1的用途，其中所说的化合物适用于预防性给药。
4.按权利要求1的用途，其中所说的化合物是下式的化合物或其盐酸盐。
CN94117172A 1993-10-15 1994-10-12 苯并噻吩类化合物的用途 Expired - Fee Related CN1058390C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13770393A 1993-10-15 1993-10-15
US137,703 1993-10-15

Publications (2)

Publication Number Publication Date
CN1105361A CN1105361A (zh) 1995-07-19
CN1058390C true CN1058390C (zh) 2000-11-15

Family

ID=22478690

Family Applications (1)

Application Number Title Priority Date Filing Date
CN94117172A Expired - Fee Related CN1058390C (zh) 1993-10-15 1994-10-12 苯并噻吩类化合物的用途

Country Status (23)

Country Link
US (1) US5610166A (zh)
EP (1) EP0652000B1 (zh)
JP (1) JPH07149644A (zh)
KR (1) KR950010889A (zh)
CN (1) CN1058390C (zh)
AT (1) ATE205712T1 (zh)
AU (1) AU677701B2 (zh)
CA (1) CA2118097A1 (zh)
CZ (1) CZ287535B6 (zh)
DE (1) DE69428325T2 (zh)
DK (1) DK0652000T3 (zh)
ES (1) ES2161238T3 (zh)
HU (1) HU220607B1 (zh)
IL (1) IL111289A (zh)
NO (1) NO313403B1 (zh)
NZ (1) NZ264674A (zh)
PH (1) PH31260A (zh)
PT (1) PT652000E (zh)
RU (1) RU94036771A (zh)
SI (1) SI0652000T1 (zh)
TW (1) TW303367B (zh)
UA (1) UA32427C2 (zh)
ZA (1) ZA948027B (zh)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5811447A (en) 1993-01-28 1998-09-22 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US6515009B1 (en) 1991-09-27 2003-02-04 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US6251920B1 (en) 1993-05-13 2001-06-26 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
WO1996040098A2 (en) * 1995-06-07 1996-12-19 Neorx Corporation Prevention and treatment of cardiovascular pathologies with tamoxifen analogues
ATE406909T1 (de) 1993-05-13 2008-09-15 Poniard Pharmaceuticals Inc Prävention und behandlung von pathologien, die mit einer abnormalen proliferationglatter muskelzellen verbunden sind
US5492927A (en) * 1993-12-21 1996-02-20 Eli Lilly And Company Non-peptide tachykinin receptor antagonists to treat allergy
US5484808A (en) * 1995-02-09 1996-01-16 Eli Lilly And Company Methods of inhibiting cell-cell adhesion
US5843974A (en) * 1995-06-06 1998-12-01 Eli Lilly And Company Methods of inhibiting melanoma using Benzothiophenes as cytotoxic agents per se
US5532254A (en) * 1995-06-07 1996-07-02 Eli Lilly And Company Modulation of calcium channels using benzothiophenes
KR100523755B1 (ko) 1997-06-24 2005-10-26 얀센 파마슈티카 엔.브이. 혈관형성을 저해하는 티아디아졸릴 피리다진 유도체
US6537554B1 (en) 1998-09-10 2003-03-25 Curagen Corporation Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis
AU777770C (en) 1999-05-04 2005-11-10 Strakan International Limited Androgen glycosides and androgenic activity thereof
KR100675252B1 (ko) * 2000-03-08 2007-02-08 한국생명공학연구원 신규 7,8-디히드로-잔테논-8-카르복실산 유도체 및 이를생산하는 신규 미생물
US20030104573A1 (en) * 2000-09-11 2003-06-05 Shimkets Richard A. Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis
US6632835B2 (en) 2001-02-22 2003-10-14 Nanodesign Inc. Dibenzo[c]chromen-6-one derivatives as anti-cancer agents
ITMI20011495A1 (it) * 2001-07-12 2003-01-12 Pharmaproducts Uk Ltd Sali di calcio ad attivita' citotossica
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
ITMI20041279A1 (it) * 2004-06-24 2004-09-24 Pharmaproducts Uk Ltd Uso di calcio trifluoroacetato per la preparazione di medicamenti ad effetto anti-angiogenetico

Citations (2)

* Cited by examiner, † Cited by third party
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
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4380635A (en) * 1981-04-03 1983-04-19 Eli Lilly And Company Synthesis of acylated benzothiophenes
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
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Also Published As

Publication number Publication date
AU677701B2 (en) 1997-05-01
JPH07149644A (ja) 1995-06-13
DE69428325D1 (de) 2001-10-25
ZA948027B (en) 1996-04-15
NO943875D0 (no) 1994-10-13
DK0652000T3 (da) 2001-11-12
HU9402955D0 (en) 1995-02-28
HU220607B1 (hu) 2002-03-28
EP0652000A1 (en) 1995-05-10
ES2161238T3 (es) 2001-12-01
KR950010889A (ko) 1995-05-15
CN1105361A (zh) 1995-07-19
CZ287535B6 (en) 2000-12-13
NO313403B1 (no) 2002-09-30
US5610166A (en) 1997-03-11
PH31260A (en) 1998-06-18
CZ253294A3 (en) 1995-05-17
TW303367B (zh) 1997-04-21
CA2118097A1 (en) 1995-04-16
DE69428325T2 (de) 2002-06-20
ATE205712T1 (de) 2001-10-15
SI0652000T1 (en) 2002-06-30
EP0652000B1 (en) 2001-09-19
IL111289A0 (en) 1994-12-29
NO943875L (no) 1995-04-18
PT652000E (pt) 2002-01-30
UA32427C2 (uk) 2000-12-15
RU94036771A (ru) 1996-11-10
NZ264674A (en) 1999-06-29
AU7579194A (en) 1995-05-04
IL111289A (en) 1999-09-22
HUT71108A (en) 1995-11-28

Similar Documents

Publication Publication Date Title
CN1058390C (zh) 苯并噻吩类化合物的用途
CN1102388C (zh) 用羟基咔唑化合物抑制平滑肌的移行与增生
CN1049335C (zh) 苯并噻吩类化合物的制药用途
CN1072931C (zh) 抑制细胞－细胞粘连的方法
US5447941A (en) Methods of inhibiting pulmonary hypertensive diseases with raloxifene and related benzothiophenes
EP0771200B1 (en) Use of raloxifene and its analogs for the manufacture of a medicament for the treatment of viral diseases
CN1105359A (zh) 抑制平滑肌细胞增殖和再狭窄的方法
CN1095663C (zh) 抑制低密度脂蛋白氧化和动脉粥样硬化的方法
CN1108093A (zh) 抑制血管舒缩症状和护理有关绝经后综合征心理障碍的方法
CN1053102C (zh) 苯并噻吩衍生物在制备抑制软骨退化的药物方面的用途
CN1107332A (zh) 抑制绝经后妇女的中枢神经系统问题的方法
CN1107705A (zh) 提高绝经后妇女性欲的方法
CN1076968C (zh) 苯并噻吩类化合物在制备防治假骨变性的药物中的用途
CN1108103A (zh) 抑制特纳综合征的方法
CN1107702A (zh) 抑制卵巢发育不全、青春发育延迟或性幼稚型的方法
CN1108099A (zh) 抑制性早熟的方法
JPH11507371A (ja) メラノーマを阻止する方法
CN1107707A (zh) 抑制体重增加或诱发体重减轻的方法
US6300343B1 (en) Method of treatment
AU716655B2 (en) Methods of inhibiting plasminogen activator inhibitor 1
CN1169116A (zh) 抑制环境雌激素的方法
CN1177295A (zh) 抑制生长激素作用的方法
NZ508532A (en) Method for promoting smoking cessation or reduction or preventing relapse smoking
CN1209746A (zh) 抑制肌腱膜纤维瘤病(硬纤维瘤)的方法
CN1108092A (zh) 提高巨噬细胞功能的方法

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee