CN1306426A - 化合物的止痒活性新用途 - Google Patents
化合物的止痒活性新用途 Download PDFInfo
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- CN1306426A CN1306426A CN98810066A CN98810066A CN1306426A CN 1306426 A CN1306426 A CN 1306426A CN 98810066 A CN98810066 A CN 98810066A CN 98810066 A CN98810066 A CN 98810066A CN 1306426 A CN1306426 A CN 1306426A
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- Prior art keywords
- xanthine
- chemical compound
- methyl
- nitro
- butyl
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Abstract
8-取代的黄嘌呤衍生物,其用于预防或治疗瘙痒的疾病或病症。
Description
发明领域
本发明涉及用于治疗和控制瘙痒的化合物。
发明背景
瘙痒是很多皮肤炎症疾病,尤其是牛皮癣和特应性皮炎的常见症状。此症状一直难以模拟。最近,公开了外周引起的痒病的行为模型(Woodward等,外周引起的痒病行为模型的特征暗示血小板活化因子是潜在的瘙痒原,J.Pharmacol.Exp.Therap.272:758-765,1995)。此模型导出了其它变型,如本文所述。
由于对此情况没有特别有效的治疗,故此领域仍需要具有抗瘙痒活性的化合物。
发明概述
本发明涉及PDE4抑制剂,优选式(Ⅰ)的化合物预防、治疗和控制需要此治疗的哺乳动物(包括人)患有的瘙痒症的新用途,该方法包括给所述哺乳动物使用有效量的式(Ⅰ)化合物。
本发明的式(Ⅰ)化合物在本文中描述。
附图简述
图Ⅰ显示了化合物Ⅰ--1,3-二-环丙基甲基-8-氨基-黄嘌呤在花生四烯酸引起的瘙痒模型中的抗瘙痒活性。
发明详述
本发明已发现PDE4抑制剂,它们作为一类化合物,不论其结构如何,都具有抗瘙痒活性。由于瘙痒是很多不同疾病的关键症状,故使用PDE4抑制剂控制瘙痒具有极大的价值。
尽管PDE4化合物具有多种不同的结构,但是它们有共同的特征,即抑制PDE4同工酶。本领域技术人员运用熟知和固定的检测方法,可以确定某化合物是否是PDE4同工酶的抑制剂,是否可用于本发明中。此处使用的适宜的PDE4化合物包括,但不限于,下列文献公开的化合物:WO92/00968;PCT/US91/08229;WO92/05175;WO92/05176;WO92/11260;WO93/01014;PCT/US92/03613;WO93/07111;PCT/US93/02045;WO93/19748;WO93/19750;WO93/19751;WO93/19747;WO93/19749;WO93/19720;WO94/20079;WO95/00139;WO95/08581;WO95/09308;WO95/09623;WO95/09836;WO95/09624;WO95/09837;WO95/09627;WO95/24381;WO95/27692;WO96/19995;WO96/20158;WO96/20153;WO96/19980;WO96/19988;WO96/19977;WO96/20161;WO96/20157;PCT/US95/16707;WO96/20690;WO96/20159;WO96/19983;WO96/19984;WO96/19985;WO96/19990;WO96/19994;WO96/20163;WO96/20156;WO96/19986;WO96/20174;WO96/19979;WO96/20160;WO96/20175;WO96/19993;WO96/20162;WO96/19978;WO96/23754;WO96/36594;WO97/03945;US5734051和US5420154。检测PDE4活性的适当实验也描述于上述文献中,它们的公开内容全部引入本文作为参考。
一种特别的PDE4,CP80633描述于J.M.Hanifin等,J.Invest.Dermatol,107:51-56(1996)。优选,所用方法不包括化合物CP80633。
若该哺乳动物需要此治疗,式(Ⅰ)的化合物也可于除人以外的哺乳动物瘙痒的兽医治疗中。治疗,可以是对动物的医治和预防。
本发明的式(Ⅰ)化合物及其药用盐描述于美国专利5734051并由如下结构式表示:其中R1和R2彼此独立地表示烷基或下式部分
-(CH2)m-A;
m是数字0至3;
A是未取代或取代的环烃基;
R3是卤素、硝基或-NR4R5;
R4和R5独立地表示氢原子、烷基、烷基羰基或者与它们连接的氮原子一起形成选择性取代的杂环。
优选R1和R2都表示-(CH2)m-A。优选A部分表示C3-C8环烷基,特别是C3-C6环烷基并优选不取代。更优选A是环丙基或环丁基部分。优选m是0或1。任何环烃的适宜的选择性取代基包括C1-C6烷基或卤原子。
R1或R2的优选基团是含1至6个碳原子的烷基,特别是甲基、乙基、丙基或正丁基。更优选是正丁基。
当R3是卤素时,优选此取代基是溴或氯。
当R3是-NR4R5,且R4和R5表示烷基或烷基羰基时,优选R4和R5之一是氢。
适宜的杂环包括饱和或不饱和的单环或稠环杂环基团,每个环含5至7个环原子,其中环原子还可最多含有两个其它选自O、N或S的杂原子。
优选的杂环基团包括5至7元单环,更优选5至6元,首选6元环。优选的杂环基团是吡咯烷基、哌啶基或吗啉基环。
特别举例性式(Ⅰ)化合物为:
1,3-二-正丁基-8-硝基黄嘌呤;
1,3-二-环丙基甲基-8-硝基黄嘌呤;
1,3-二-环丁基甲基-8-硝基黄嘌呤;
1,3-二-环戊基甲基-8-硝基黄嘌呤;
1,3-二-环己基甲基-8-硝基黄嘌呤;
1,3-二-正-丁基-8-氨基黄嘌呤;
1,3-二-环丙基甲基-8-氨基黄嘌呤;
1,3-二-环丁基甲基-8-氨基黄嘌呤;
1,3-二-环戊基甲基-8-氨基黄嘌呤;
1,3-二-环己基甲基-8-氨基黄嘌呤;
1,3-二-环丙基-8-氨基黄嘌呤;
1,3-正丁基-8-乙酰氨基黄嘌呤;
1,3-二-正丁基-8-氯黄嘌呤;
1,3-二正丁基-8-溴黄嘌呤‘
1,3-二-环丙基甲基-8-氯黄嘌呤;
1,3-二-环己基-8-氯黄嘌呤;
1,3-二-正丁基-8-哌啶子基黄嘌呤;
1,3-二-环丙基甲基-8-吗啉代黄嘌呤;
1,3-二-正丁基-8-吡咯烷基黄嘌呤;
1,3-二-环丙基甲基-8-吡咯烷基黄嘌呤;
1,3-二-环丙基甲基-8-哌啶基黄嘌呤;
1,3-二-环己基甲基-8-哌啶基黄嘌呤;
1,3-二-环己基甲基-8-溴黄嘌呤;及
1,3-二-环己基-8-硝基黄嘌呤;或其药用盐。
用于本发明方法的最优选的式(Ⅰ)化合物是1,3-二-环丙基甲基-8-氨基黄嘌呤或其药用盐。
术语“烷基”在本文中,不论单独或作为其它基团的一部分(例如烷基羰基)使用,包括直链或支链含1至12个碳原子(除非链长有限制)的基团,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基等。
除非特别指明,术语“环烃”在本文中指含3至8个碳原子的单环或稠环。环烃的每个环最多可含8个碳原子。本文中,术语“环烷基”或“环烷基烷基”可与术语“环烃”互换。环烷基和环烷基烷基包括但不限于环丙基、环丙基-甲基、环戊基或环己基。
术语“卤代”在本文中指所有的卤原子,即氯、氟、溴和碘。
制备方法
式(Ⅰ)化合物的制备可由本领域技术人员按照本文中给出出处的方法进行,该方法描述于Maschler等的英国专利申请号8906792.0(1989年3月23日申请)和美国专利5734051,其全部公开内容整体引入作为参考。
治疗方法
式(Ⅰ)的化合物或其药用盐还可以用于制备预防和治疗由过分或不规则瘙痒加剧或引起的人或其它哺乳动物的任何疾病的药物。
式(Ⅰ)的化合物可以用于局部治疗或预防具有瘙痒症状的局部疾病。
式(Ⅰ)的化合物描述于Maschler等的英国专利申请号8906792.0(1989年3月23日申请)和美国专利5734051,用于治疗与嗜酸性细胞数量增加有关的疾病,例如,增生性皮肤病,即牛皮癣、特应性皮炎、非特应性皮炎、原发性接触性皮炎、过敏性接触性皮炎或过敏性疾病如特异反应性、uticaria、湿疹、鼻炎、脂溢性皮炎,以及家畜动物的兽疥癣。式(Ⅰ)的化合物还公开于PCT/US91/08734和PCT/US93/01496(WO93/06699公开),将其公开内容整体引入作为参考,它们用于治疗肿瘤坏死介导的疾病。
式(Ⅰ)的化合物可以与其它用于治疗或控制瘙痒的试剂如甾类化合物同时使用。
本领域技术人员应意识到治疗作用需要的单核因子活性干涉试剂的实际用量当然随所选试剂、给药途径、疾病的本质和严重性以及接受治疗的哺乳动物特别是人的特定病症而变化,并最终由医生决定。本领域技术人员还应意识到此试剂的最佳用量和单剂量的给药间隔由所治疗病症的特性和程度、给药的形式,途径和部位、以及接受治疗的特定患者决定,而此最佳剂量可以通过常规技术测定。本领域技术人员还应意识到最佳疗程,即在一定天数内该试剂每天给药次数可以由本领域技术人员用治疗判定实验的常规方法确定。
式(Ⅰ)的化合物可以口服(当通过此途径给药有活性时)、局部、非肠道或吸入给药,给药形式为此试剂与标准药用载体按照常规方法混合制备的常规剂型,给药量足以产生治疗活性。
所用药用载体可以由本领域技术人员容易地确定,他们应意识到此确定依赖于多种熟知的因素,如所用特定单核因子活性干涉试剂的本质、用量和特性,以及需要的给药形式和途径。所用这些载体在本文中另行描述。
为了用式(Ⅰ)的化合物或其药用盐治疗人或其它哺乳动物,一般将其按照标准药学操作配制为药物组合物。
本发明的药物组合物应含有有效、无毒量的式(Ⅰ)化合物及药用载体或稀释剂。式(Ⅰ)化合物给药用常规剂型,通过将足以分别产生活性量的式(Ⅰ)化合物与标准药用载体按照常规方法混合制备。这些方法包括混合、制粒和压制,或者将适当的组份溶解制成需要的制剂。
所用药用载体可以是,例如,固体或液体。固体载体的实例为乳糖、石膏粉、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸等。液体载体的实例为糖浆、花生油、橄榄油、聚乙二醇、椰油、水等。同样,载体或稀释剂可以包括本领域熟知的时间延迟物质,如甘油单硬脂酸酯或甘油二硬脂酸酯,它们可单独或与蜡混合使用。
式(Ⅰ)化合物及其药用盐可以用于多种药物剂型中。药用盐的制备由化合物的本质决定,并可以用本领域技术人员容易使用的常规技术制备。因此,如果使用固体载体,该制剂可以是片剂、置于硬明胶胶囊中的粉末或微粒形式、或糖锭或锭剂。固体载体的用量变化范围很大,但是优选约25mg至约1g。当使用液体载体时,该制剂可以是糖浆、乳剂、软明胶胶囊、灭菌注射液如安瓿或非水液体混悬剂。当此组合物是胶囊形式时,任何常规包封技术是适宜的,例如,用在硬明胶胶囊壳中用上述载体。当此组合物是软明胶胶囊形式时,可以考虑任何常规用于制备分散液或混悬剂的药用载体,例如,含水树胶、纤维素、硅酸盐或油,并可将其掺混入软明胶胶囊壳中。糖浆一般由此化合物或盐在液体载体中的混悬剂或溶液组成,例如,乙醇、聚乙二醇、椰油、甘油或水,其中添加矫味剂或着色剂。
局部给药起治疗作用需要的式(Ⅰ)化合物的量,当然随所选化合物、炎症的本质和严重性以及接受治疗的动物变化,并最终由医生决定。
术语“非肠道”在本文中包括静脉、肌肉内、皮下、鼻内、直肠内、阴道内或腹膜内给药。非肠道给药的皮下和肌肉内形式一般是优选的。这种给药的适当剂型可通过常规技术制备。
典型的非肠道组合物由该化合物或盐在灭菌水或选择性含有非肠道用油的非水载体中的溶液或混悬液组成,其中非肠道用油如聚乙二醇、聚乙烯吡咯烷酮、卵磷脂、花生油或芝麻油。非肠道给药的日剂量适宜地为约0.001mg/kg至40mg/kg,优选约0.01mg/kg至20mg/kg的式(Ⅰ)化合物或其药用盐,以游离碱计。
式(Ⅰ)的化合物可以口服。口服的日剂量适宜地为约.1mg/kg至1000mg每天。给药量适宜地为约0.001mg/kg至40mg/kg,优选约0.01mg/kg至20mg/kg的式(Ⅰ)化合物或其药用盐,以游离碱计。该活性组份可以每天使用1至6次,足以发挥活性作用。
式(Ⅰ)的化合物还可以吸入给药。“吸入”指鼻内及口腔吸入给药。此给药的适宜剂型,例如气雾剂或计量吸入剂,可以按照常规技术制备。吸入给药的日剂量适宜地为约0.001mg/kg至40mg/kg,优选约0.01mg/kg至20mg/kg的式(Ⅰ)化合物或其药用盐,以游离碱计。
溶液、混悬液或乳液形式的典型吸入组合物可以以干粉的形式给药,或用常规抛射剂如二氯二氟甲烷或三氯氟甲烷以气雾剂的形式给药。
优选此组合物是单位剂型的形式,例如片剂、胶囊或计量的气雾剂,以便患者可以自己使用单个剂量。
式(Ⅰ)的化合物还可以局部给药。局部给药指非系统性给药并包括将式(Ⅰ)的化合物施用于表皮外、口腔及慢慢滴入耳、眼和鼻,且此时该化合物不显著地进入血流。局部给药的日剂量适宜地为0.001mg/kg至100mg/kg,优选0.1至20mg/kg的式(Ⅰ)化合物或其药用盐,以游离碱计。
系统性给药指口服、静脉、腹膜内和肌肉内给药。
虽然活性组份可能单独以原化合物的形式给药,但是优选其存在于药物制剂中。对于局部给药,该活性组份可以占此制剂重量的0.001%至10%w/w,例如,1%至2%,虽然其可以占到10%w/w,但是优选不超过5%w/w,并更优选0.1%至1%w/w。
本发明的局部制剂含有活性组份和一种或多种药用载体(一种或多种)以及选择性存在的任何其它治疗组份(一种或多种)。载体(一种或多种)必须是可接受的,即与该制剂的其它组份相合并且不损害患者。
适于局部给药的制剂包括适于透过皮肤到达炎症部位的液体或半液体制剂,例如,搽剂、洗剂、霜剂、软膏或糊剂,以及适于给眼、耳或鼻给药的滴剂。
本发明的滴剂可以含有灭菌水或油溶液或混悬液,并可以通过将此活性组份溶解于适宜的杀细菌剂和/或杀真菌剂和/或任何其它适宜的防腐剂的水溶液中制备,并优选含有表面活性剂。所得溶液再过滤澄清、转移至随后可密封的适合的容器中并通过高压釜或在98-100℃保持半小时灭菌。或者,该溶液可以通过过滤除菌并无菌转移至容器中。适于滴剂的杀细菌剂和杀真菌剂的实例为硝酸苯汞或醋酸苯汞(0.002%)、苯扎氯铵(0.01%)和醋酸洗必泰(0.01%)。制备油溶液的适宜的溶剂包括甘油、稀乙醇和丙二醇。
本发明的洗剂包括适于施用于皮肤或眼的那些。眼用洗剂可以含有灭菌水溶液,其中选择性地含有杀细菌剂,并可以通过与制备滴剂相似的方法制备。施用于皮肤的洗剂或搽剂还可以含有加速干燥或清凉皮肤的试剂如乙醇或丙酮,及/或增湿剂如甘油或某种油如蓖麻油或花生油。
本发明的霜剂、软膏或糊剂是此活性组份的外用半固体制剂。它们可通过将细颗粒或粉末形式的活性组份单独混合或将其在含水或非水流体中的溶液或混悬液混合,借助于适当的机器,加入润滑性或非润滑性基质。此基质可以含有烃如硬、软或液体石蜡,甘油,蜂蜡,金属皂;胶浆;天然油如杏仁、玉米、花生、蓖麻或橄榄油;羊毛脂或其衍生物,或脂肪酸如硬脂酸或油酸,以及同时使用的醇如丙二醇或聚乙二醇。此制剂中可以加入任何适宜的表面活性剂如阴离子、阳离子或非离子表面活性剂,如脱水山梨醇酯或其聚氧乙烯衍生物。还可以含有助悬剂如天然树胶、纤维素衍生物或无机物如二氧化硅,以及其它组份如羊毛脂。
本领域技术人员应意识到此药用载体或稀释剂的形式或特性由与其混合的活性组份式(Ⅰ)化合物的量、给药途径以及其它熟知因素决定。
本领域技术人员应意识到式(Ⅰ)化合物或其药用盐的最佳量和单个剂量的给药间隔由被治疗本质的本质和程度、给药的形式,途径及部位、以及接受治疗的特定患者决定,且此最佳量可以通过常规技术测定。本领域技术人员还应意识到最佳疗程,即在固定的天数内式(Ⅰ)化合物或其药用盐的每天给药次数,可以由本领域技术人员用常规疗程判定实验确定。
制剂实施例
掺混本发明化合物的药物制剂可以以多种形式并与多种赋形剂一起制备。液体制剂的实例如下:
1.通过将此化合物溶解于水或其它适宜的载体中,其中加入或不加防腐剂如苯甲酸,制备含式(Ⅰ)化合物的溶液,以便每次使用都能转运所需的药量。此化合物的存在量为约10μg至约30μg/毫升载体。
2.通过将此化合物以约1至约10mg每毫升PEG 400的量溶解,其中含或不含BHA/BHT防腐剂,制备式(Ⅰ)化合物的溶液。或者,可以将此溶液填充入软明胶胶囊中以制备固体口服剂型,或以糖浆的形式使用。
3.含式(Ⅰ)化合物,如1,3-二-环丙基甲基-8-氨基黄嘌呤的固体制剂,已通过将50mg的该化合物与多种浓度(mg)的甘露醇、羟丙甲基纤维素、磷酸二钙、淀粉(Starch1500)和硬脂酸镁(作为润滑剂)混合,填入大小适当的胶囊中制备,或者如果需要可将此组合物压为片剂。该组份的多种制剂列于表1,编号1至6。
应用实施例
将Woodward等著述中描述的方法(出处同上)中的鼠模型的原型,作为本发明的鼠模型。该小鼠模型的可取之处是对花生四烯酸反应的皮肤炎症,其通过抓或摩擦行为指示瘙痒。
简言之,给Balb/c小鼠左耳局部使用存在于20μl冷丙酮中的花生四烯酸(2mg/耳)。然后,将被处理的小鼠单个放置于4L烧杯中。适应2分钟后,在10分钟内记录抓和摇头的次数。通过计算平均值和标准偏差来分析数据。用学生t检验确定平均值中的统计学差异。对花生四烯酸反应的炎症的生化药学暗示干细胞脱粒及廿烷类炎性递质释放(即白三烯和前列腺素类)。速激肽和血小板活化因子也可以参与此反应。用花生四烯酸也显示了4型磷酸二脂酶(PDE4)抑制剂的抗炎活性(Griswold,D.E.等,吡咯并咪唑,SK&F105809的药理学,体内抗炎活性和对递质产生的抑制,Biochemical Pharmacology42:825-831,1991),将该公开内容全部引入作为参考。
特定方法:
给重19-23克的雄性Balb/c小鼠(n=6/治疗组)的左耳局部使用存在于20μl冷丙酮中的花生四烯酸(2mg/耳)。施用后立即,给相同的耳朵施用25μl的载体或被测化合物。剂量为5至1000μg/耳。然后,将处理后的小鼠单独置于4L烧杯中。适应2分钟后,在10分钟内记录抓和摇头的次数。通过计算平均值和标准偏差来分析数据。用学生t检验确定平均值中的统计学差异。
有利的是,如此可确定不同结构的PDE4抑制剂在此模型中是否显示了止痒活性。如上所述,三个此PDE4抑制剂确实显示了显著的止痒活性。
PDE4抑制剂的局部止痒活性
治疗(100μg/耳) | 瘙痒抑制率(%) |
BRL61063 | 61.4*** |
咯利普兰(Rolipram) | 75.8*** |
CP80633 | 49.7*** |
***较载体对照统计学显著性p<0.001,BRL61063同化合物Ⅰ。
本说明书中引用的所有的出版物,包括但不限于专利和专利申请,被引入作为参考,如同上述对单个出版物各自特别并单独指出的那样。
上述说明书充分公开了本发明,包括其优选的实施方案。对本文特别公开的实施方案的修改或改进在下述权利要求书的范围内。相信本领域技术人员不用进一步劳动可以用上述说明书,完全实施本发明。因此,本文的实施例只是用来举例说明而不是以任何方式限制本发明的范围。本发明的实施方案,其中独占性或特权要求保护如下。
Claims (22)
1.给需要的哺乳动物治疗瘙痒的方法,包括给所述哺乳动物使用有效量的除CP80633以外的PDE4抑制剂。
3.权利要求2的方法,其中R1表示-(CH2)m-A。
4.权利要求2的方法,其中R1和R2都表示-(CH2)m-A。
5.权利要求4的方法,其中A表示取代的或不取代的C3-C8环烷基。
6.权利要求4的方法,其中m表示1。
7.权利要求6的方法,其中A表示取代的或不取代的环丙基、环丁基、环戊基或环己基。
8.权利要求7的方法,其中A表示环丙基或环丁基。
9.权利要求8的方法,其中R3是硝基或-NR4R5,其中R4是氢原子而R5是氢原子或烷基羰基。
10.权利要求9的方法,其中R4或R5是氢原子。
11.权利要求10的方法,其中A表示环丙基。
12.权利要求2的方法,其中化合物选自:
1,3-二-正丁基-8-硝基黄嘌呤;
1,3-二-环丙基甲基-8-硝基黄嘌呤;
1,3-二-环丁基甲基-8-硝基黄嘌呤;
1,3-二-环戊基甲基-8-硝基黄嘌呤;
1,3-二-环己基甲基-8-硝基黄嘌呤;
1,3-二-正丁基-8-氨基黄嘌呤;
1,3-二-环丙基甲基-8-氨基黄嘌呤;
1,3-二-环丁基甲基-8-氨基黄嘌呤;
1,3-二-环戊基甲基-8-氨基黄嘌呤;
1,3-二-环己基甲基-8-氨基黄嘌呤;
1,3-二-环丙基-8-氨基黄嘌呤;
1,3-正丁基-8-乙酰氨基黄嘌呤;
1,3-二-正丁基-8-氯黄嘌呤;
1,3-二正丁基-8-溴黄嘌呤‘
1,3-二-环丙基甲基-8-氯黄嘌呤;
1,3-二-环己基-8-氯黄嘌呤;
1,3-二-正丁基-8-哌啶子基黄嘌呤;
1,3-二-环丙基甲基-8-吗啉代黄嘌呤;
1,3-二-正丁基-8-吡咯烷基黄嘌呤;
1,3-二-环丙基甲基-8-吡咯烷基黄嘌呤;
1,3-二-环丙基甲基-8-哌啶基黄嘌呤;
1,3-二-环己基甲基-8-哌啶基黄嘌呤;
1,3-二-环己基甲基-8-溴黄嘌呤;及
1,3-二-环己基-8-硝基黄嘌呤;或如果适当则选其药用盐。
13.权利要求2的方法,其中化合物是1,3-二-环丙基甲基-8-氨基黄嘌呤或其药用盐。
14.权利要求2或13的方法,其中所述化合物口服、非肠道、局部或吸入给药。
15.权利要求14的方法,其中所述化合物是局部给药。
16.权利要求1的方法,其中该化合物与有效量的第二种止痒化合物一起局部使用。
17.权利要求1的方法,其中所述化合物描述于WO92/00968;PCT/US91/08229;WO92/05175;WO92/05176;WO92/11260;WO93/01014;PCT/US92/03613;WO93/07111;PCT/US93/02045;WO93/19748;WO93/19750;WO93/19751;WO93/19747;WO93/19749;WO93/19720;WO94/20079;WO95/00139;WO95/08581;WO95/09308;WO95/09623;WO95/09836;WO95/09624;WO95/09837;WO95/09627;WO95/24381;WO95/27692;WO96/19995;WO96/20158;WO96/20153;WO96/19980;WO96/19988;WO96/19977;WO96/20161;WO96/20157;PCT/US95/16707;WO96/20690;WO96/20159;WO96/19983;WO96/19984;WO96/19985;WO96/19990;WO96/19994;WO96/20163;WO96/20156;WO96/19986;WO96/20174;WO96/19979;WO96/20160;WO96/20175;WO96/19993;WO96/20162;WO96/19978;WO96/23754;WO96/36594;WO97/03945;US5734051和US5420154。
18.给需要的哺乳动物治疗瘙痒的方法,该方法包括给所述哺乳动物瘙痒有效量的化合物1,3-二-环丙基甲基-8-氨基黄嘌呤或其药用盐。
19.权利要求18的方法,其中所述化合物经口服、非肠道、局部或吸入给药。
20.权利要求19的方法,其中所述化合物经局部给药。
21.权利要求18的方法,其中所述化合物与有效量的第二种止痒化合物一起局部使用。
22.权利要求21的方法,其中第二种止痒化合物是甾类化合物。
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AU6825898A (en) * | 1997-03-07 | 1998-09-29 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Novel tetrazoles |
BR9810409A (pt) * | 1997-03-18 | 2000-08-22 | Basf Ag | Métodos e composições para a modulação de responsividade a corticosteróides |
AU8106598A (en) * | 1997-06-03 | 1998-12-21 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Benzonaphthyridine |
-
1998
- 1998-10-15 AR ARP980105131A patent/AR015966A1/es not_active Application Discontinuation
- 1998-10-16 EP EP98953608A patent/EP1030666A4/en not_active Withdrawn
- 1998-10-16 CN CN98810066A patent/CN1306426A/zh active Pending
- 1998-10-16 AU AU10938/99A patent/AU740875B2/en not_active Ceased
- 1998-10-16 CA CA002306985A patent/CA2306985A1/en not_active Abandoned
- 1998-10-16 JP JP2000516677A patent/JP2001520196A/ja not_active Withdrawn
- 1998-10-16 IL IL13558198A patent/IL135581A0/xx unknown
- 1998-10-16 TR TR2000/01040T patent/TR200001040T2/xx unknown
- 1998-10-16 CO CO98060225A patent/CO4810374A1/es unknown
- 1998-10-16 WO PCT/US1998/021886 patent/WO1999020280A1/en not_active Application Discontinuation
- 1998-10-16 BR BR9814080-9A patent/BR9814080A/pt not_active IP Right Cessation
- 1998-10-16 PL PL98341062A patent/PL341062A1/xx unknown
- 1998-10-16 HU HU0003792A patent/HUP0003792A3/hu unknown
- 1998-10-16 ZA ZA989450A patent/ZA989450B/xx unknown
- 1998-10-16 CZ CZ20001376A patent/CZ20001376A3/cs unknown
- 1998-10-16 NZ NZ503551A patent/NZ503551A/en unknown
- 1998-10-16 KR KR1020007004053A patent/KR20010031149A/ko not_active Application Discontinuation
-
2000
- 2000-04-10 NO NO20001847A patent/NO20001847L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101389612B (zh) * | 2006-02-21 | 2011-09-21 | 卫材R&D管理有限公司 | 喹唑啉衍生物 |
Also Published As
Publication number | Publication date |
---|---|
CA2306985A1 (en) | 1999-04-29 |
NO20001847D0 (no) | 2000-04-10 |
PL341062A1 (en) | 2001-03-26 |
CZ20001376A3 (cs) | 2002-06-12 |
AU1093899A (en) | 1999-05-10 |
EP1030666A1 (en) | 2000-08-30 |
BR9814080A (pt) | 2000-09-26 |
TR200001040T2 (tr) | 2001-01-22 |
NZ503551A (en) | 2002-05-31 |
WO1999020280A1 (en) | 1999-04-29 |
IL135581A0 (en) | 2001-05-20 |
KR20010031149A (ko) | 2001-04-16 |
HUP0003792A3 (en) | 2001-12-28 |
AU740875B2 (en) | 2001-11-15 |
ZA989450B (en) | 1999-04-19 |
AR015966A1 (es) | 2001-05-30 |
CO4810374A1 (es) | 1999-06-30 |
JP2001520196A (ja) | 2001-10-30 |
HUP0003792A2 (hu) | 2001-10-28 |
EP1030666A4 (en) | 2002-10-16 |
NO20001847L (no) | 2000-04-10 |
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