CN1413105A - 新的治疗方法 - Google Patents
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Abstract
一种治疗哺乳动物,例如人的与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病或病症的方法,该方法包括给需此治疗的哺乳动物施用有效的、无毒的且可药用量的PPARγ激动剂,如化合物(I)。
Description
本发明涉及一种治疗方法,尤其是一种治疗与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病或病症的方法。
公开号为0306228的欧洲专利申请涉及某些具有抗高血糖和降血脂活性的噻唑烷二酮衍生物。EP 0306228公开的一种具体的噻唑烷二酮:5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮(下文称化合物(I))。WO 94/05659公开了式(I)化合物的某些盐,包括其实施例1公开的马来酸盐。
式(I)是一类已知称为“格列他腙(glitazones)”或“噻唑烷二酮”的抗高血糖药的实例。
欧洲专利申请公开0008203、0139421、0032128、0428312、0489663、0155845、0257781、0208420、0177353、0319189、0332331、0332332、0528734、0508740;国际专利申请公开92/18501、93/02079、93/22445以及美国专利5104888和5478852也公开了某些噻唑烷二酮类。
上述出版物的内容均引入本文以供参考。
已知γ-异构型的过氧物酶体增殖剂-活化的受体(下文称PPAR-γ)是核受体大家族的成员,该大家族包括甾体、甲状腺和视黄醛衍生物激素的受体(Evans,Science 240,889-895,1988)。从Chawla等还可知道PPARγ在脂肪细胞分化期间早早地被表达(Endocrinology135,798-800,1994)。从J.Biol.Chem.,270,12963-12966还获知噻唑烷二酮,如化合物(I)是PPARγ激动剂。
现在我们发现在活化的中性白细胞中PPARγ表达得到显著上调。因此,预期PPARγ激动剂抑制活化的中性白细胞功能,因此对受益于抑制中性白细胞活性或数量的疾病和病症具有潜在的应用价值。治疗病症包括本文列出的疾病,包括:痛风、关节炎、哮喘、慢性阻塞性肺病、肠应激综合症、银屑病和痤疮。
在与中等至高等强度的紫外光线接触后,中性白细胞是浸润皮肤真皮和表皮层的一类主要细胞。这些细胞能引起组织损伤,在某些严重情况下还延迟皮肤的愈合。因此认为PPARγ激动剂可用于预防和/或治疗由于过度紫外线辐射或阳光照射引起的皮肤真皮和/或表皮层的损伤。另外认为它们有助于损伤后皮肤的愈合。
因此,本发明提供一种治疗哺乳动物,例如人的与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病或病症的方法,该方法包括给需此治疗的哺乳动物施用有效的、无毒的且可药用量的PPARγ激动剂,如化合物(I)。
另一方面,本发明提供PPARγ激动剂,如化合物(I)用于制备治疗哺乳动物,如人的与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病或病症的药物的用途。
与中性白细胞数量增加和/或中性白细胞过度活化有关的适宜疾病或病症包括呼吸道、骨骼与关节、皮肤、胃肠道、其它组织的疾病或病症和系统性疾病、同种移植物排斥反应及某些癌症。优选呼吸道疾病或病症。优选骨骼与关节的疾病或病症。优选皮肤疾病或病症。优选其它组织的疾病或病症及系统性疾病。优选与同种移植物排斥反应有关的病症。优选某些癌症。
适宜的呼吸道疾病或病症包括:阻塞性呼吸道疾病,包括慢性阻塞性肺病(COPD);哮喘,如支气管哮喘、变应性哮喘、内因性、外因性和灰粉性哮喘,尤其是慢性或习惯性哮喘(如后期哮喘或呼吸道过度反应);支气管炎;急性变应性、特应性鼻炎和慢性鼻炎,包括干酪性鼻炎、肥厚性鼻炎、脓性鼻炎、干性鼻炎和药物性鼻炎;膜性鼻炎,包括格鲁布性鼻炎、纤维蛋白性鼻炎和假膜性鼻炎以及腺病性鼻炎;季节性鼻炎,包括神经性鼻炎(季节性变应性鼻炎)和血管舒缩性鼻炎;肉状瘤病,农民肺和相关性疾病,纤维化肺(fibricici lung)及自发间质性肺炎。特定的呼吸道疾病或病症是说明所列的不包括所列其它成员的具体疾病或病症。
适宜的骨骼和关节疾病或病症包括:类风湿关节炎、血清反应阴性的脊椎性关节病(包括强直性脊椎炎、银屑病关节炎和Reiter病)、Behcet病、Sjogren综合症和系统性硬化症。特定的骨骼和关节疾病或病症是上述所列的各种具体疾病或病症,但不同时包括所列其它成员。
适宜的皮肤疾病或病症包括银屑病、特应性皮炎、接触性皮炎和其它湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性天疱疮、大疱性表皮松解、荨麻疹、干皮病、血管炎、红斑、皮下嗜酸性细胞增多症、色素层炎、斑性脱发和春季结膜炎。优选的皮肤疾病或病症是上面所列的各种具体疾病或病症,但不同时包括所列其它成员。
适宜的胃肠道疾病或病症包括:腹腔疾病、直肠炎、嗜酸性细胞性胃肠炎、肥大细胞增生、节段性回肠炎、溃疡性结肠炎、具有来自肠道的远程作用的与食物有关的过敏症,如偏头痛、鼻炎和湿疹。优选的胃肠道疾病是上面所列的各种具体疾病或病症,但不同时包括所列其它成员。
适宜的其它组织和系统性疾病包括:多发性硬化、动脉粥样硬化、获得性免疫缺乏综合症(AIDS)、红斑狼疮、系统性狼疮、红斑(erythtmatosus)、桥本甲状腺炎、重症肌无力、I型糖尿病、肾病综合症、嗜酸性细胞增多性筋膜炎、IgE过多综合症、结节性麻风、Sezary综合症和自发性血小板减少性紫癜。优选的其它组织和系统性疾病是上面所列的各种具体疾病,但不同时包括所列其它成员。
适宜的与同种移植物排斥反应有关的病症包括与下列有关的疾病:肾、心脏、肝脏、肺、骨髓、皮肤和角膜移植后的急慢性病症;和慢性移植物抗宿主疾病。特定的与同种移植物排斥反应有关的病症是上面所列的各种具体病症,但不同时包括所列其它成员。
适宜的癌症包括:非小细胞肺癌(NSCLC)和鳞状肉瘤。特定的癌症是非小细胞肺癌(NSCLC)。特定的癌症是鳞状肉瘤。
另一方面,还包括下列病症或疾病:囊性纤维化、中风、心脏、脑和外周肢体的再灌注性损伤及败血病、痛风、关节炎、哮喘、慢性阻塞性肺病、肠应激综合症、银屑病和痤疮。特定的病症或疾病是上面所列的各种具体病症或疾病,但不同时包括所列其它成员。
如上所示,与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病皮肤病症是由于过度紫外线辐射或阳光照射引起的皮肤真皮和/或表皮层损伤。因此,本发明还涉及一种预防和/或治疗哺乳动物,如人的由于过度紫外线辐射或阳光照射引起的皮肤真皮和/或表皮层损伤的方法,该方法包括该需此治疗的哺乳动物施用,优选局部施用有效的、无毒的和可药用量的PPARγ激动剂,如化合物(I)。
本发明还提供一种促进或有助于损伤后皮肤愈合的方法,该方法包括给需此治疗的哺乳动物施用,优选局部施用有效的、无毒的和可药用量的PPARγ激动剂,如化合物(I)。
适宜的PPARγ激动剂是化合物(I)或其可药用衍生物。
其它适宜的PPARγ激动剂包括(+)-5-[[4-[(3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基]苯基]甲基]-2,4-噻唑烷二酮(或曲格列酮);5-[[4-(1-甲基环己基)甲氧基]苄基]噻唑烷-2,4-二酮(或齐格列酮);5-[4-[2-(5-乙基吡啶-2-基)乙氧基]苄基]噻唑烷-2,4-二酮(或吡格列酮);和5-[(2-苄基-2,3-二氢苯并吡喃)-5-基甲基]噻唑烷-2,4-二酮(或恩格列酮);或者它们的可药用衍生物。
应该理解,PPARγ激动剂,如化合物(I)以包括其可药用衍生物的可药用形式给药。
当相对于PPARγ激动剂来讲适当时,适宜可药用衍生物包括可药用盐、酯或溶剂化物。
适宜的可药用盐或溶剂化物形式的化合物(I)包括EP 0306228中和WO 94/05659中描述的那些。化合物(I)的优选可药用盐是马来酸盐。化合物(I)的优选可药用溶剂化物是水合物。
其它可药用衍生物公开于标准的参考书中,如英国和美国药典、Remington’s Pharmaceutical Sciences(Mack Publ ishing Co.)和Martindale The Extra Pharmacopoeia(London,The PharmacuticalPress)或上述出版物。
PPARγ激动剂可用已知方法制备,例如上面提及的出版物中公开的方法。
因此,化合物(I)及其可药用形式可用已知方法制备,例如EP0306228和WO 94/05659中公开的方法。
化合物(I)可以数种互变异构体形式存在,术语化合物(I)包括所有这些互变异构体单体或其混合物。化合物(I)包含一个手性碳原子,因此可以多达两种立体异构体形式存在,术语化合物(I)包括所有这些异构体单体或其混合物,包括外消旋体。
本文采用的术语“可药用”包括人用或兽用:例如术语“可药用”包括可兽药用的化合物。
为避免产生疑问,当本文指称一定数量,包括mg量的可药用形式的化合物(I)时,该数量是指化合物(I)本身的,例如2mg化合物(I)马来酸盐是指含2mg化合物(I)的马来酸盐。
可采用常规方法,如Current Protocols in Immunology,Vol I,Suppl 1,Unit 6.12.3.中公开的方法证明中性白细胞的活化,该文献引入本文以供参考。
按照Current Protocols in Immunology,Vol I,Suppl 1,Unit7.23.1中所述,中性白细胞可从人血中分离,该文献引入本文以供参考。
本发明的方法中,活性药物优选以药物组合物形式给药。
因此,本发明提供用于治疗哺乳动物,如人的与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病或病症的药物组合物,该组合物含有PPARγ激动剂,如化合物(I)和可药用载体。
组合物适于以任何适宜的方式给药,例如口服给药、非胃肠给药、舌下或透皮给药。
组合物可以是片剂、胶囊、粉剂、颗粒、锭剂、栓剂、重建粉剂或液体制剂,如口服或者无菌非胃肠溶液或悬浮液。
为获得给药的均匀性,本发明的组合物优选是单位剂量形式的。
口服给药的单位剂量形式可以是片剂和胶囊,它们可含有常规赋形剂,例如粘合剂,如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶或聚乙烯吡咯烷酮;填充剂,如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨醇或甘油;压片润滑剂,如硬脂酸镁;崩解剂,如淀粉、聚乙烯吡咯烷酮、淀粉甘醇酸钠或微晶纤维素;或者可药用润湿剂,如月桂基硫酸钠。
基于例如所选择的特定药物以及疾病或病症的性质或严重程度的因素,单位剂量形式的组合物优选含有与日剂量相适宜的量。
PPARγ激动剂,如化合物(I)的适宜剂量,包括单位剂量是参考文献例如英国和美国药典、Remington’s Pharmaceutical Sciences(Mack Publishing Co.)和Martindale The Extra Pharmacopoeia(London,The Pharmacutical Press)或上述出版物中针对这些化合物描述的或提及的已知剂量或单位剂量。
在本发明的治疗方法中,PPARγ激动剂按照上述参考文献或出版物中描述的或提及的已知方案给药。
在本发明的治疗方法中,药物每天给药1-6次,但最优选每天给药1或2次。
固体口服组合物可采用常规的混合、填充或压片方法制备。采用重复混合操作可使活性成分均匀分布于使用大量填充剂的组合物中。当然,这类操作是本领域常规操作。片剂可按照普通制药实践中的熟知方法进行包衣,尤其是用肠溶衣包衣。
口服液体制剂可以是,例如乳液、糖浆或酏剂形式,或者可呈在使用前用水或其它适宜载体重建的干燥产品形式。这类液体制剂可含有常规添加剂,例如悬浮剂,如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化食用脂肪;乳化剂,如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶;非水性载体(可包括食用油),如杏仁油、精馏椰子油、油性酯,如甘油、丙二醇或乙醇的酯;防腐剂,如对羟基苯甲酸甲酯或丙酯或者山梨酸;并且如果需要还可含有常规分调味剂或着色剂。
对于非胃肠给药,根据使用的浓度,可用化合物和无菌载体通过将化合物悬浮于或溶于载体中来制备单位剂型形式的流体制剂。在溶液的制备中,可将化合物溶于注射用水中,进行无菌过滤后,填充到适宜的小瓶或安瓿中,再密封。有益的辅剂是可溶于载体的局麻剂、防腐剂和缓冲剂。为提高稳定剂,组合物在填充到小瓶中后,可进行冷冻并真空除去水。非胃肠悬浮液可采用基本相同的方法制备,不同的是将化合物(I)悬浮于,而不是溶于载体中,并且不采用过滤灭菌。在悬浮于无菌载体之前,化合物可通过与环氧乙烷接触进行灭菌。为有助于化合物均匀分布,组合物中包含表面活性剂或润湿剂是有益的。
依据给药方法的不同,组合物含有0.1-99%(重量),优选10-60%(重量)的活性物质。
如上所示,PPARγ激动剂也可以以适于局部应用的可药用形式给药。
局部应用PPARγ激动剂特别适于治疗皮肤疾病或病症,包括上面提及的那些疾病或病症;以及预防和/或治疗由于过度紫外线辐射或阳光照射引起的皮肤真皮和/或表皮层损伤。皮肤疾病或病症优选是银屑病。
另一方面,本发明提供一种优选用于治疗皮肤疾病或病症的适于局部给药的药物组合物,该组合物含有PPARγ激动剂和可药用载体。
适于局部应用的适宜可药用载体包括可安全地局部或透皮施用于人或非人类哺乳动物的与活性化合物相容的任何物质,包括溶剂、稀释剂、防腐剂、透皮促进剂、聚合物、缓冲剂、香精、增稠剂、胶凝剂、表面活性剂和乳化剂。这类物质公开于标准参考书,如英国和美国药典、Remington’s Pharmaceutical Sciences(MackPublishing Co.);Martindale The Extra Pharmacopoeia(London,The Pharmaceutical Press);Harry’s Cosmeticology(LeonardHill Books)和Brian W Barry的Drugs and Pharmaceutical Science,Vol 18,Dermatological Formulations“Percutaneous Absorption”,pub Marcel Deker(ISBN 0/8247/1729/5)或者上面提及的出版物。
对于局部给药,可含有0.001-10%w/w,例如1-2%制剂重量的活性物质。但是,制剂可含有多达10%w/w,但优选含有小于5%w/w,更优选0.1-1%w/w的活性物质。
适于局部给药的本发明组合物可采用上述参考书中公开的方法,配制成适于局部应用的常规剂型,例如洗剂、搽剂、凝胶剂、乳剂、软膏剂、滴剂、溶液或喷雾剂。
用于皮肤的洗剂或搽剂还可包含加速干燥或冷却皮肤的物质,例如乙醇或丙酮;和/或保湿剂,如甘油或者油类,如蓖麻油或花生油。
本发明的乳剂、软膏剂或糊剂是外用的活性成分的半固体制剂。它们可如下制备:借助适宜的机械,将细粉或粉末形式的活性成分本身或者以其水性或非水性的溶液或悬浮液形式与油性或非油性基质混合。所述基质可含有烃类,如硬的、软的或液体石蜡、甘油、蜂蜡、金属皂;粘质物;天然产的油,如杏仁油、玉米油、花生油、蓖麻油或橄榄油;羊毛脂或其衍生物或者脂肪酸,如硬脂酸或油酸;以及醇类,如丙二醇或聚乙二醇。
本发明的滴剂可含有无菌的水性或油性溶液或悬浮液,它们可如下制备:将活性成分溶于包含适宜的杀细菌剂和/或杀真菌剂和/或任何其它适宜的防腐剂,以及优选包含表面活性剂的水溶液中。将所得溶液过滤使其澄明后,转移到适宜的容器中,然后密封并用高压灭菌法或者保持在98-100℃灭菌半小时。或者,溶液可经过滤灭菌,然后采用无菌技术转移到容器中。适于包含在滴剂中的杀菌剂或杀真菌剂的实例是硝酸苯汞或乙酸苯汞(0.002%)、氯苄烷铵(0.01%)和洗必太(0.01%)。用于制备油性溶液的适宜溶剂包括甘油、稀乙醇和丙二醇。
在局部治疗中,药物可每天应用1-6次,但最优选每天1或2次。
本发明还提供适于局部给药的药物组合物,它含有PPARγ激动剂作为活性治疗剂及适于局部应用的可药用载体。
如果需要,该组合物可以是写有或印刷有使用说明的包装形式。
该组合物按照例如下列标准参考书中公开的常规方法配制:英国和美国药典、Remington’s Pharmaceutical Sciences(MackPublishing Co.);Martindale The Extra Pharmacopoeia(London,The Pharmaceutical Press)(例如参见第31版341页及其中所引用文献);和Harry’s Cosmeticology(Leonard Hill Books)或者上面提及的出版物中公开的方法。
现已确认,上述剂量范围内的本发明组合物和方法没有毒副作用。
下列实施例说明本发明,而非以任何方式限制本发明。效果证明
附图1所示结果证明:
(附图1A):在人中性白细胞加入培养皿期间(在1-4小时采集数据),PPARγ mRNA快速并显著地增多并且用GM-CSF处理导致进一步增多(附图1A)。
(附图1B):用1μM化合物(I)处理降低了加入中性白细胞后4小时观察到的凝胶酶B mRNA表达增强。零时(TO)是指加入天然人中性白细胞前的表达。
附图2:化合物(I)抑制MMP-9的释放
用逆流式离心淘析法分离中性白细胞得到至少98%纯度的中性白细胞,将其加入到加有1%BSA的RPMI 1640中。细胞在48孔培养板中培养并在铺板1小时内附着在孔内。从实验开始就加入化合物(I)(附图2中称为BRL49653)。4小时后,取出培养基,进行人MMP-9ELISA分析(Amersham)。将数据(采自4个不同个体的)直接合并是不合适的,为了绘图将数据统一为占无化合物对照的百分数。星号是指对统一化之前的原始数据进行配对学生t检验的p<0.05。化合物(I)对MMP-9释放抑制作用的IC50为10.6nM(通过用Statistica拟合4参数对数曲线计算)。
Claims (11)
1、一种治疗哺乳动物,例如人的与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病或病症的方法,该方法包括给需此治疗的哺乳动物施用有效的、无毒的且可药用量的PPARγ激动剂,如化合物(I)。
2、权利要求1的方法,其中与中性白细胞数量增加和/或中性白细胞过度活化有关的疾病或病症选自:呼吸道、骨骼与关节、皮肤、胃肠道、其它组织的疾病或病症和系统性疾病、同种移植物排斥反应及某些癌症。
3、权利要求1或2的方法,其中的呼吸道疾病或病症包括:阻塞性呼吸道疾病,包括慢性阻塞性肺病(COPD);哮喘,如支气管哮喘、变应性哮喘、内因性、外因性和灰粉性哮喘,尤其是慢性或习惯性哮喘(如后期哮喘或呼吸道过度反应);支气管炎;急性变应性、特应性鼻炎和慢性鼻炎,包括干酪性鼻炎、肥厚性鼻炎、脓性鼻炎、干性鼻炎和药物性鼻炎;膜性鼻炎,包括格鲁布性鼻炎、纤维蛋白性鼻炎和假膜性鼻炎以及腺病性鼻炎;季节性鼻炎,包括神经性鼻炎(季节性变应性鼻炎)和血管舒缩性鼻炎;肉状瘤病,农民肺和相关性疾病,纤维化肺及自发间质性肺炎。
4、权利要求1-3任一项的方法,其中的骨骼和关节疾病或病症包括:类风湿关节炎、血清反应阴性的脊椎性关节病、Behcet病、Sjogren综合症和系统性硬化症。
5、权利要求1-3任一项的方法,其中的皮肤疾病或病症包括银屑病、特应性皮炎、接触性皮炎和其它湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性天疱疮、大疱性表皮松解、荨麻疹、干皮病、血管炎、红斑、皮下嗜酸性细胞增多症、色素层炎、斑性脱发和春季结膜炎。
6、权利要求1-3任一项的方法,其中的胃肠道疾病或病症包括:腹腔疾病、直肠炎、嗜酸性细胞性胃肠炎、肥大细胞增生、节段性回肠炎、溃疡性结肠炎、具有来自肠道的远程作用的与食物有关的过敏症。
7、权利要求1-3任一项的方法,其中的其它组织和系统性疾病包括:多发性硬化、动脉粥样硬化、获得性免疫缺乏综合症(AIDS)、红斑狼疮、系统性狼疮、红斑、桥本甲状腺炎、重症肌无力、I型糖尿病、肾病综合症、嗜酸性细胞增多性筋膜炎、IgE过多综合症、结节性麻风、Sezary综合症和自发性血小板减少性紫癫。
8、权利要求1-3任一项的方法,其中的与同种移植物排斥反应有关的病症包括与下列有关的疾病:肾、心脏、肝脏、肺、骨髓、皮肤和角膜移植后的急慢性病症;以及慢性移植物抗宿主疾病。
9、权利要求1-3任一项的方法,其中的癌症包括:非小细胞肺癌(NSCLC)和鳞状肉瘤。
10、权利要求1-9任一项的方法,其中的PPARγ激动剂是5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮(“化合物(I)”)或其可药用衍生物。
11、权利要求1-9任一项的方法,其中的PPARγ激动剂是5-[4-[2-(5-乙基吡啶-2-基)乙氧基]苄基]噻唑烷-2,4-二酮(或称为吡格列酮)。
Applications Claiming Priority (2)
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GBGB9908647.2A GB9908647D0 (en) | 1999-04-15 | 1999-04-15 | Novel compounds |
GB9908647.2 | 1999-04-15 |
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CN1413105A true CN1413105A (zh) | 2003-04-23 |
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CN00809014A Pending CN1413105A (zh) | 1999-04-15 | 2000-04-17 | 新的治疗方法 |
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EP (2) | EP1593379A3 (zh) |
JP (1) | JP2003516310A (zh) |
KR (1) | KR20010108506A (zh) |
CN (1) | CN1413105A (zh) |
AP (1) | AP2001002291A0 (zh) |
AT (1) | ATE319437T1 (zh) |
AU (1) | AU4583000A (zh) |
BG (1) | BG106104A (zh) |
BR (1) | BR0009776A (zh) |
CA (1) | CA2370127A1 (zh) |
CZ (1) | CZ20013688A3 (zh) |
DE (1) | DE60026508T2 (zh) |
DK (1) | DK1274407T3 (zh) |
DZ (1) | DZ3151A1 (zh) |
EA (1) | EA200101089A1 (zh) |
ES (1) | ES2256003T3 (zh) |
GB (1) | GB9908647D0 (zh) |
HK (1) | HK1053788A1 (zh) |
HR (1) | HRP20010746A2 (zh) |
HU (1) | HUP0300479A2 (zh) |
ID (1) | ID30339A (zh) |
IL (1) | IL145875A0 (zh) |
MA (1) | MA25351A1 (zh) |
MX (1) | MXPA01010428A (zh) |
NO (1) | NO20014950L (zh) |
PL (1) | PL364720A1 (zh) |
PT (1) | PT1274407E (zh) |
SK (1) | SK14532001A3 (zh) |
TR (1) | TR200102977T2 (zh) |
WO (1) | WO2000062766A2 (zh) |
YU (1) | YU77901A (zh) |
ZA (1) | ZA200108446B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107073079A (zh) * | 2014-09-08 | 2017-08-18 | 达纳-法伯癌症研究所公司 | 包括给予PPAR‑γ激动剂的治疗癌症的方法 |
CN116531374A (zh) * | 2023-04-20 | 2023-08-04 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | 吡格列酮及其盐在制备用于治疗系统性红斑狼疮的产品中的应用 |
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GB9913782D0 (en) * | 1999-06-14 | 1999-08-11 | Smithkline Beecham Plc | Novel compounds |
EP1331934B1 (de) * | 2000-11-09 | 2006-03-29 | Phenion GmbH & Co KG | Ppar-alpha,beta-aktivatoren zur behandlung von alopecia areata und vitiligo |
GB0030845D0 (en) * | 2000-12-18 | 2001-01-31 | Smithkline Beecham Plc | Novel treatment |
GB2373725A (en) * | 2001-03-30 | 2002-10-02 | Novartis Ag | Use of a PPAR gamma agonist in the production of a medicament for the prevention or treatment of diseases associated with IL-10 production |
EP1465622A1 (en) * | 2001-11-26 | 2004-10-13 | Arachnova Therapeutics Ltd. | Use of ppar activators for the treatment of pulmonary fibrosis |
DE10204398A1 (de) * | 2002-02-04 | 2003-08-14 | Univ Goettingen Georg August | Neue Verwendung von Liganden der 'Peroxisome Proliferator-Activated receptors'(PPAR) |
US6992093B2 (en) | 2002-05-02 | 2006-01-31 | Los Angeles Biomedical Research Institute At Harbor Ucla Medical Center | Method of inhibiting lipofibroblast to myofibroblast transdifferentiation |
US8293479B2 (en) | 2002-05-02 | 2012-10-23 | Los Angeles Biomedical Research Institute At Harbor Ucla Medical Center | Use of parathyroid hormone-related protein(PTHRP) in the diagnosis and treatment of chronic lung disease and other pathologies |
US20030220300A1 (en) * | 2002-05-14 | 2003-11-27 | Hwang Cheng Shine | Reduction of hair growth |
ITRM20050389A1 (it) | 2005-07-22 | 2007-01-23 | Giuliani Spa | Composti e loro sali specifici per i recettori ppar ed i recettori per l'egf e loro uso in campo medico. |
KR101333089B1 (ko) | 2006-05-22 | 2013-11-27 | 재단법인 아산사회복지재단 | 로지글리타존을 유효성분으로 함유하는 흡연-유발 만성폐쇄성 폐질환 예방 또는 치료용 약제학적 조성물 |
US8236786B2 (en) | 2008-08-07 | 2012-08-07 | Pulmagen Therapeutics (Inflammation) Limited | Respiratory disease treatment |
WO2010015818A1 (en) * | 2008-08-07 | 2010-02-11 | Argenta Discovery Limited | Respiratory disease treatment |
GB0913672D0 (en) | 2009-08-05 | 2009-09-16 | Argenta Discovery Ltd | Glitazones |
UA107562C2 (uk) | 2008-12-05 | 2015-01-26 | Спосіб лікування псоріазу | |
NZ594157A (en) | 2008-12-30 | 2013-07-26 | Pulmagen Therapeutics Inflammation Ltd | Sulfonamide compounds for the treatment of respiratory disorders |
HUE032999T2 (hu) | 2009-02-16 | 2017-11-28 | Nogra Pharma Ltd | Alkilamido vegyületek és azok alkalmazása |
WO2010150014A1 (en) | 2009-06-24 | 2010-12-29 | Pulmagen Therapeutics (Inflammation) Limited | 5r- 5 -deuterated glitazones for respiratory disease treatment |
WO2011098746A1 (en) | 2010-02-09 | 2011-08-18 | Pulmagen Therapeutics (Inflammation) Limited | Crystalline acid addition salts of ( 5r) -enanti0mer of pioglitazone |
GB201002243D0 (en) | 2010-02-10 | 2010-03-31 | Argenta Therapeutics Ltd | Respiratory disease treatment |
GB201002224D0 (en) | 2010-02-10 | 2010-03-31 | Argenta Therapeutics Ltd | Respiratory disease treatment |
MX364220B (es) | 2012-02-09 | 2019-04-16 | Nogra Pharma Ltd | Metodos de tratamientos de fibrosis. |
EP2844242A1 (en) | 2012-04-18 | 2015-03-11 | Nogra Pharma Limited | Methods of treating lactose intolerance |
KR20190095372A (ko) * | 2017-01-13 | 2019-08-14 | 토비시 파마슈티칼 컴패니 리미티드 | 호중구 활성화 조절제 |
KR20210125047A (ko) | 2019-02-08 | 2021-10-15 | 노그라 파마 리미티드 | 3-(4'-아미노페닐)-2-메톡시프로피온산, 및 그의 유사체 및 중간체의 제조 방법 |
JP2020145939A (ja) * | 2019-03-12 | 2020-09-17 | 日本製粉株式会社 | アレルギー性鼻炎抑制用組成物 |
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GB9611947D0 (en) * | 1996-06-07 | 1996-08-07 | Glaxo Group Ltd | Medicaments |
JPH10139665A (ja) * | 1996-09-12 | 1998-05-26 | Sankyo Co Ltd | トログリタゾンを含有するグルタチオン還元酵素活性増強剤 |
DE69739828D1 (de) * | 1996-12-11 | 2010-05-12 | Dana Farber Cancer Inst Inc | Methoden und pharmazeutische Zusammensetzungen zur Inhibition des Tumorwachstums |
EP0963199A1 (en) * | 1996-12-31 | 1999-12-15 | The Salk Institute For Biological Studies | Treatment of disease states which result from neoplastic cell proliferation using ppar-gamma activators and compositions useful therefor |
FR2773075B1 (fr) * | 1997-12-31 | 2000-05-05 | Cird Galderma | Utilisation d'activateurs de ppar-gamma en dermatologie |
US6028088A (en) * | 1998-10-30 | 2000-02-22 | The University Of Mississippi | Flavonoid derivatives |
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1999
- 1999-04-15 GB GBGB9908647.2A patent/GB9908647D0/en not_active Ceased
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2000
- 2000-04-11 DZ DZ003151A patent/DZ3151A1/xx active
- 2000-04-17 PL PL00364720A patent/PL364720A1/xx not_active Application Discontinuation
- 2000-04-17 AT AT00927425T patent/ATE319437T1/de not_active IP Right Cessation
- 2000-04-17 CZ CZ20013688A patent/CZ20013688A3/cs unknown
- 2000-04-17 SK SK1453-2001A patent/SK14532001A3/sk unknown
- 2000-04-17 MX MXPA01010428A patent/MXPA01010428A/es unknown
- 2000-04-17 CA CA002370127A patent/CA2370127A1/en not_active Abandoned
- 2000-04-17 DE DE60026508T patent/DE60026508T2/de not_active Expired - Lifetime
- 2000-04-17 CN CN00809014A patent/CN1413105A/zh active Pending
- 2000-04-17 IL IL14587500A patent/IL145875A0/xx unknown
- 2000-04-17 AU AU45830/00A patent/AU4583000A/en not_active Abandoned
- 2000-04-17 EA EA200101089A patent/EA200101089A1/ru unknown
- 2000-04-17 AP APAP/P/2001/002291A patent/AP2001002291A0/en unknown
- 2000-04-17 KR KR1020017013106A patent/KR20010108506A/ko not_active Application Discontinuation
- 2000-04-17 EP EP05076787A patent/EP1593379A3/en not_active Withdrawn
- 2000-04-17 ID IDW00200102237A patent/ID30339A/id unknown
- 2000-04-17 HU HU0300479A patent/HUP0300479A2/hu unknown
- 2000-04-17 WO PCT/GB2000/001499 patent/WO2000062766A2/en not_active Application Discontinuation
- 2000-04-17 ES ES00927425T patent/ES2256003T3/es not_active Expired - Lifetime
- 2000-04-17 PT PT00927425T patent/PT1274407E/pt unknown
- 2000-04-17 BR BR0009776-4A patent/BR0009776A/pt not_active IP Right Cessation
- 2000-04-17 DK DK00927425T patent/DK1274407T3/da active
- 2000-04-17 YU YU77901A patent/YU77901A/sh unknown
- 2000-04-17 JP JP2000611903A patent/JP2003516310A/ja active Pending
- 2000-04-17 EP EP00927425A patent/EP1274407B1/en not_active Expired - Lifetime
- 2000-04-17 TR TR2001/02977T patent/TR200102977T2/xx unknown
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2001
- 2001-10-11 NO NO20014950A patent/NO20014950L/no not_active Application Discontinuation
- 2001-10-12 MA MA26355A patent/MA25351A1/fr unknown
- 2001-10-15 HR HR20010746A patent/HRP20010746A2/hr not_active Application Discontinuation
- 2001-10-15 ZA ZA200108446A patent/ZA200108446B/xx unknown
- 2001-11-13 BG BG106104A patent/BG106104A/xx unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107073079A (zh) * | 2014-09-08 | 2017-08-18 | 达纳-法伯癌症研究所公司 | 包括给予PPAR‑γ激动剂的治疗癌症的方法 |
CN116531374A (zh) * | 2023-04-20 | 2023-08-04 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | 吡格列酮及其盐在制备用于治疗系统性红斑狼疮的产品中的应用 |
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