CN1259056C - 腺苷a3受体激动剂用于抑制病毒复制的用途 - Google Patents
腺苷a3受体激动剂用于抑制病毒复制的用途 Download PDFInfo
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- CN1259056C CN1259056C CNB028037715A CN02803771A CN1259056C CN 1259056 C CN1259056 C CN 1259056C CN B028037715 A CNB028037715 A CN B028037715A CN 02803771 A CN02803771 A CN 02803771A CN 1259056 C CN1259056 C CN 1259056C
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Abstract
本发明涉及一种活性成分抑制病毒在细胞中复制的用途，所述活性成分选自一组腺苷受体系统的激动剂。特别是，本发明提供了用于抑制病毒在细胞中复制的组合物和方法，该方法包括呈递给细胞有效量的活性成分。根据一种实施方案，其中的腺苷激动剂是A3受体激动剂(A3RAg)。本发明尤其可用于(但并不限于)抑制HIV病毒在人类细胞中的复制。
Description
发明领域
总的来说，本发明涉及抗感染领域。更具体而言，涉及用于抑制病毒在细胞内复制的药物组合物及医疗用途。
在先技术
以下是与本发明相关的在先技术的清单，它们描述了本发明领域内的技术发展水平。本文中，通过在括号内列出这些参考文献在该清单中的序号，来确认对这些文献的引用。
1.Linden J.美国实验生物学会联合会会志(The FASEB J.)5：2668-2676(1991)；
2.Stiles G.L.临床研究(Clin.Res.)38：10-18(1990)；
3.Stolfi R.L.等，癌症研究(Cancer Res.)43：561-566(1983)；
4.Soderback U.等，临床科学(Clin.Sci.)81：691-694(1994)；
5.Gilbertsen R.B.药剂作用(Agents actions)22：91-98(1987)；
6.Bouma M.G.等，免疫学杂志(J Immunol.)153：4159-4168(1994)；
7.Rozengurt E.实验细胞研究(Exp.Cell Res.)139：71-78(1982)；
8.Gonzales F.A.等，美国国家科学院院报(PNAS USA)87：9717-9721(1990)；
9.Sandberg G.和Fredholm B.B.胸腺(Thymus)3：63-75(1981)；
10.Pastan I.H.等，生物化学年评(Annu.Rev.Biochem.)44：491-495(1975)；
11.R.Cole和J.de Vellis.1997年。载于：《神经细胞培养方案》(Protocols for neural cell culture)。S.Fedoroff和A.Richardson编写，Human Press，Totowa，NJ，117-130页。
12.S.Gartner和M.Popovic.1990年。载于：《HIV研究技巧》(Techniques on HIV research)。A.Aldovini和B.D.Walker编写。Stockton Press，New York，NY，53-70页。
13.V.W.Yong和J.P.Antel.1997年。载于：《神经细胞培养方案》(Protocols for neural cell culture)。S.Fedoroff和A.Richardson编写，Humana Press，Totowa，NJ，157-172页。
14.US5,688,774.
15.US5,773,423.
16.US6,048,865.
17.WO95/02604.
18.WO99/20284.
19.WO99/06053.
发明背景
人体1型和2型免疫缺陷病毒(HIV-1和HIV-2)是导致人患上获得性免疫缺陷综合征(AIDS)的逆转录病毒。AIDS由HIV感染个体中低水平的CD4阳性T淋巴细胞引起。
HIV-1可感染T淋巴细胞、单核细胞/巨噬细胞、树突细胞和小胶质细胞。所有这些细胞都表达可充当HIV-1和HIV-2受体的表面糖蛋白CD4。HIV-1是否有效进入到靶细胞中取决于病毒的被膜糖蛋白gp120与CD4的结合。此外，有几种趋化因子受体起HIV共同受体的作用，并决定HIV-1毒株对各种细胞型的有效感染。结合后，HIV-1被膜糖蛋白介导病毒与宿主细胞膜的融合来完成进入过程。一旦到达细胞内部，就开始病毒复制过程。然后通过芽殖过程，复制的病毒从受感染细胞中释放，最终造成受感染细胞溶解破坏。这一过程重复许多次，显著减少了体内该种靶细胞的数目。这种严重且威胁生命的物态，常常最终导致受感染个体的死亡。
腺苷是存在于血浆和其他胞外液体中的一种嘌呤核苷。它由各种细胞型释放到胞外空间中，通过结合细胞膜上的G蛋白联合受体而发挥其他细胞的作用(1-2)。腺苷与其受体的相互作用引发信号转导途径，主要增进腺苷酸环化酶效应器系统，该系统利用cAMP作为第二信使。G蛋白联合腺苷受体分为A1、A2a、A2b和A3四组。A1和A3受体与Gi蛋白偶联，由此抑制腺苷酸环化酶，导致细胞内cAMP浓度降低。A2a和A2b受体与Gs蛋白偶联，由此激活腺苷酸环化酶，从而升高cAMP浓度(3)。
胞外腺苷的生理学作用包括抑制细胞因子释放、抑制血小板聚集、诱导产生促红细胞生成素和调制淋巴细胞功能(4-6)。腺苷还与某些中枢神经系统(CNS)功能的调制、伤口愈合、利尿以及控制疼痛等有关。腺苷能在很多正常细胞型中诱导增殖(7-10)。
发明概述
本发明是基于这样的发现，即腺苷受体激动剂能抑制细胞内病毒的复制。于是，本发明提供了一种抑制病毒在细胞内复制的方法，该方法包括呈递给细胞有效量的至少一种腺苷A3受体激动剂(A3RAg)。
本发明的激动剂是腺苷A3受体的完全或部分激动剂。本文中，如果化合物能完全抑制腺苷酸环化酶(A3)，则称其为腺苷A3受体的“完全激动剂”；如果化合物能部分抑制腺苷酸环化酶(A3)，则称其为腺苷A3受体的“部分激动剂”。
本发明还提供了用于抑制细胞内病毒复制的药物组合物，该组合物包含有效量的所述至少一种A3RAg。还提供了所述活性成分(即A3RAg)用于制备这种药物组合物的用途。
本发明尤其可用于(但并不限于)抑制HIV病毒在人类细胞中的复制。
发明详述
为实现本发明目的所需的药学或治疗学“有效量”考虑本领域公知的因素后确定。该用量必须能有效地达到预期的治疗作用，该作用取决于治疗的类型和方式。对于技术人员来说，很显然，有效量应当能有效地降低细胞内病毒复制的速率，能降低临床样本中病毒颗粒的浓度，或者能改善受到病毒感染的个体的状况，能改善或消除能被本领域技术人员接受为适宜量度的症状或任何其它指征。有效量的一个实例是每日给药约1μg/kg体重至约10mg/kg体重范围内的A3RAg。A3RAg的这种用量一般每日给药一次。当然，有的时候，日剂量也可以在一天内分成几次给药。有时数天的剂量也可以结合成一剂药，每几天给药一次，特别是当以持续释放制剂给药时。
在一个实施方案中，活性成分是核苷衍生物。术语“核苷”是指包含糖(优选核糖或脱氧核糖)，或者嘌呤或嘧啶碱，或者糖与嘌呤或嘧啶碱优选通过N-糖基键彼此结合成的组合物的任何化合物。术语“核苷衍生物”在本文中表示天然产核苷，合成核苷，或为了得到具有所需生物效应的衍生物，通过在其中一次或多次插入、缺失、外环或内吞取代一个或多个基团进行了化学修饰或进行了构象修饰的核苷。
按照本发明的一个实施方案，活性成分是下列通式(I)表示的核苷衍生物：
其中：
-R1是烷基、羟基烷基、羧基烷基或氰基烷基，或下列通式(II)化合物：
其中：
-Y是碳原子的氧，硫；
-X1是H，烷基，RaRbNC(＝O)-或HORc-，其中Ra和Rb可以相同，也可不同，分别选自氢，氨基；或者取代或未取代的烷基，卤烷基，氨基烷基，BOC-氨基烷基，和环烷基，或者二者结合共同形成含有2-5个碳原子的杂环。Rc选自下列基团：烷基，氨基，卤烷基，氨基烷基，被护氨基烷基(例如：-BOC氨基烷基)，和环烷基；
-X2是H，羟基，烷基氨基，烷酰氨基或羟烷基；
-X3和X4各自独立地为氢，羟基，氨基，酰氨基，叠氮基，卤素，烷基，烷氧基，羧基，次氨基，硝基，三氟代，芳基，烷芳基，硫代，酯，硫酯，醚，硫醚，-OCOPh，-OC(＝S)OPh，或者X3和X4均为氧并与＞C＝S相连形成5元环，或者X2和X3形成式(III)的环：
其中R’和R”独立地为低级烷基；
-R2选自下列基团：氢，卤素，烷基醚，氨基，肼基，烷基氨基，烷氧基，硫代烷氧基，吡啶基硫基，烯基，炔基，硫代，和烷硫基；和
-R3是-NR4R5基，其中：
-R4是氢或选自烷基、取代烷基或芳基-NH-C(Z)-的基团，其中Z是O，S，或NRa，Ra含义同上文；和
-R5选自下列基团：杂芳基-NRa-C(Z)-，杂芳基-C(Z)-，烷芳基-NRa-C(Z)-，烷芳基-C(Z)-，芳基-NR-C(Z)-和芳基-C(Z)-，Ra和Z为上文中所确定的含义；或者，当R4为氢时，R5为R-或S-1-苯乙基，苄基，苯乙基或酰苯胺，上述所有基团均可选地在一个或多个位置上被选自下列成员的取代基取代：烷基，氨基，卤素，卤代烷基，硝基，羟基，乙酰氨基，烷氧基，和磺酸或其盐；
或者当R4为苯并二噁烷甲基，糠基(fururyl)，L-丙基丙氨酰氨基苄基，β-丙氨酰氨基-苄基，T-BOC-β-丙氨酰氨基-苄基，苯氨基，氨基甲酰基，苯氧基或环烷基时，R5为下列化学式所示基团：
或者上文所定义化合物的适宜的盐，例如其三乙铵盐。
活性成分优选为通式(IV)的核苷衍生物：
其中X1、R2、R4和R5如上文所定义，和
按照本发明的这种实施方案，优选的活性成分可以一般地称之为N6-苄基腺苷-5’-乌龙酰胺(uronamides)及其衍生物，据认为，它们是A3选择性腺苷受体激动剂。这类衍生物的实例是N6-2-(4-氨基苯基)乙基腺苷(APNEA)，N6-(4-氨基-3-碘代苄基)腺苷-5’-(N-甲基乌龙酰胺)(AB-MECA)和1-脱氧-1-{6-[((3-碘代苯基}甲基)氨基]-9H-嘌呤-9-基}-N-甲基-β-D-核糖呋喃乌龙酰胺，后者在本领域中也称作N6-3-碘代苄基-5’-甲基甲酰胺基腺苷或N6-(3-碘代苄基)腺苷-5’-N-甲基-乌龙酰胺，在本文中简写为IB-MECA。IB-MECA的氯化衍生物(R2＝Cl)也构成该基团的一部分，在本文中称之为Cl-IB-MECA，IB-MECA和Cl-IB-MECA是目前所优选的。
按照本发明的另一种实施方案，活性成分可以是一般地称之为N6-苄基-腺苷-5’-烷基乌龙酰胺-N1-氧化物或N6-苄基腺苷-5’-N-二烷基乌龙酰胺(dialyluron-amide)-N1-氧化物的腺苷衍生物。
上面所定义的某些化合物以及它们的合成步骤可以在上文所列的出版物14-19中找到，这些文献结合在此作为参考。
本文中所用的烃链可包括直链或支链。特别是，术语“烷基”指的是一价直链、支链环烷基，优选具有1-20个碳原子，更优选1-10个碳原子(″低级烷基″)，首选1-6个原子。该术语代表的实例可以是，诸如甲基，乙基，正丙基，异丙基，正丁基，异丁基，正己基，等等。
术语“亚烷基”和“低级亚烷基”指的是相应于烷烃的二价基。另外，如本文中所用的，带有从烷烃衍生的名称的其他基团，诸如烷氧基，烷酰基，烯基，环烯基等，当用“低级”修饰时，具有10个或更少碳原子的碳链。在这些情况下，当最小碳原子数大于1时，例如烯基(最少2个碳原子)和环烷基(最少3个碳原子)，应当理解为“低级”意味着至少是最小碳原子数。
本文中所用的术语“取代烷基”指的是带有如上文所定义的1-4个取代基、优选1-3个取代基的烷基。本文中所用的带有前缀“取代”的其他基团将包括上文所列的一个或多个取代基。
本文中所用的术语“烷氧基”指的是基团“烷基-O-”，其中烷基如上文所定义。
本文中所用的术语“烯基”指的是优选具有2-10个碳原子、更优选具有2-6个碳原子、且具有至少1个、优选1-2个烯基不饱和位点的烯基。而术语“炔基”指的是优选具有2-10个碳原子、更优选具有2-6个碳原子、且具有至少1个、优选1-2个炔基不饱和位点的炔基。
本文中所用的术语“芳基”指的是6-14个碳原子的不饱和芳族碳环基团，它具有单环(例如苯基)或多个缩合(稠合)环(例如萘基或蒽基)。优选的芳基包括苯基、萘基等等。除非对于芳基取代基有另外的定义，否则这些芳基可以可选地被1-5个取代基、优选被1-3个取代基取代，诸如上文中提到的那些取代基。
本文中所用的术语“环烷基”指的是具有单环或多个缩合环的、3-12个碳原子的环烷基。举例来说，这类环烷基包括：单环结构的，诸如环丙基，环丁基，环戊基，环辛基，等等；或多环结构的，诸如金刚烷基，等等。
本文中所用的术语“杂芳基”指的是具有1-15个碳原子和在至少一个环内(如果有1个以上环的话)具有选自氧、氮和硫的1-4个杂原子的芳族碳环基团。除非另有说明，否则这些杂芳基可以可选地被1-5个、优选1-3个如上文所述的取代基取代。
当然，对于含有1个或多个取代基的上述任何一个基团，应当理解，这些基团不含从空间结构上说不切实际和/或不可能合成的任何取代或取代模式。
作为活性成分的、如上文所定义的A3RAg，有时可以含有保护基或阻断基。术语“保护基”或“阻断基”指的是当其与该化合物的1个或多个羟基、氨基或羧基结合时，能防止在这些基团上发生反应的任何基团。且保护基能采用常规的化学或酶解步骤除去，从而恢复成羟基、氨基或羧基。优选的可去除的氨基阻断基包括常规取代基，诸如叔丁氧基羰基(t-BOC)(如上文所示)以及其他基团，诸如苄氧基羰基(CBZ)等，它们可以利用与产物的性质相一致的常规条件除去。
按照本发明，A3RAg可以如上文所定义，也可以是其盐或溶剂化物的形式，特别是其生理学上可接受的盐和溶剂化物。另外，当含有1个和多个不对称碳原子时，活性成分可以包括上述活性成分的异构体和非对映异构体或其混合物。
上述活性成分的可药用盐包括从可药用无机和有机酸衍生的那些。适宜的酸的实例包括盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、醋酸、柠檬酸、甲磺酸、蚁酸、苯甲酸、丙二酸、萘-2-磺酸和苯磺酸。
A3RAg可以作为非活性物质(例如药物前体)给药，并且可以只在利用天然过程经过进一步修饰后，在受治疗者体内的特定部位具有活性。在任何情况下，衍生物都将是保留了本发明药物组合物的治疗功能的。这类药物前体也包括在本文所用的术语“活性成分”的含义内。类似地，术语“A3RAg”也应理解为包括肯定缺乏激动剂活性、但能在体内被激活的药物前体。
在选择用于本发明的腺苷A3受体激动剂时，可以看候选组分是否具有能以和IB-MECA或CI-IB-MECA类似的方式抑制病毒复制的能力来筛选这类化合物。适宜的筛选方法是在下文的实验结果部分描述的那种体外测定法。不过，也可以使用本身已知的各种其他测定法。
本发明的药物组合物可以只包含A3RAg本身，也可以与其他成分结合，这些成分可以是技术人员熟知的药学上可接受的载体、稀释剂、赋形剂、添加剂和/或助剂，例如，目的是为了向该药物组合物中加入调味剂、着色剂、润滑剂等。显然，本发明可采用的药学上可接受的载体、稀释剂、赋形剂、添加剂一般指的是惰性的、无毒的固体或液体填充剂、稀释剂或包胶囊物质，优选它们不会与本发明组合物范围内的化合物发生反应。
许多A3RAg口头给药是有效的。因此，根据活性成分的不同，本发明的药物组合物可以配制成口服制剂。这类口服组合物可以进一步包含药学上可接受的、适宜口服给药的载体、稀释剂、赋形剂、添加剂或助剂。
本发明的药物组合物按照良好的医学实践，在考虑了患者个体的临床情况、给药部位和方法、给药方案、患者的年龄、性别、体重以及医师公知的其他因素后给药。
本发明组合物可以各种方式给药。可以口服给药，皮下或非肠道给药包括静脉内、动脉内、肌内、腹膜内给药，或者鼻内给药，以及利用本领域熟练技术人员公知的鞘内方式和输液技术给药。
治疗时间的长短视疾病过程的长短和活性剂的效力而定。治疗方案可以是在若干天或更长的时间内单剂或多剂给药。
当以非肠道途径给药本发明组合物时，一般将其配制成单位剂量注射用剂型(溶液、悬液、乳液)。适于注射用的药物制剂包括无菌水溶液或分散体，以及用于重新构成无菌注射用溶液或分散体的无菌粉末。所用的载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇、脂质聚乙二醇等)等的溶剂或分散介质，它们的适宜混合物以及植物油。
有时也可以用非含水载体诸如棉籽油、芝麻油、橄榄油、大豆油、玉米油、葵花籽油或花生油，和酯诸如肉豆蔻酸异丙酯等作为活性成分的溶剂系统。
另外，还可以加入能够增强组合物的稳定性、无菌性和等渗性的各种添加剂，包括抗菌防腐剂、抗氧化剂、螯合剂和缓冲剂。可以利用各种抗细菌和抗真菌剂来确保防止微生物的作用，例如尼泊金酯类，氯丁醇、苯酚、山梨酸等。
为了用于口服给药，活性成分可以配制成片剂、悬液、溶液、乳液、胶囊、粉末剂、糖浆剂等形式。这些剂型可以用药剂师熟知的技术制得。
下面将借助实施例，并参考下述实验结果以及附图，对本发明作进一步描述。应当理解，本文所采用的术语是描述性而不是限制性的。
尽管前面只详细描述了本发明的几个具体实施方案，但本领域技术人员应当理解，本发明并不限于此。在不背离本文所公开的发明的范围和实质的条件下，有可能进行某些形式和细节的变化。
实验结果
材料和方法：制备初级人胎儿星形胶质细胞和小胶质细胞。
利用在Cole和de Vellis11以及Yong和Antel13的方法基础上修正后的程序，从16-20周龄的人胎儿脑组织制备纯化的初级人胎儿星形胶质细胞和小胶质细胞。脑组织用冰冷的、含有抗生素庆大霉素和两性霉素B的Hank’s平衡盐溶液(HBSS)洗涤。除去血管和脑膜，将组织切成小片。切碎后，组织在0.05％胰岛素中进行培养，使其酶促解离，并令其数次通过75μm尼龙筛滤器，机械使其分裂。将所得单细胞悬浮液洗涤，沉淀并以在DMEM：含有10％胎牛血清、胰岛素、庆大霉素和L-谷氨酰胺的F12中、2-10×106/162cm2/烧瓶的密度铺板。生长7-10天后，将其置于旋转混合器上，在37℃培养箱中，以200rpm振摇过夜，从而分离出小胶质细胞。除去未附着的细胞，使之粘附于新烧瓶1-3小时。附着后，洗涤细胞，并再次用含有10％胎牛血清、胰岛素、庆大霉素、L-谷氨酰胺和N1补充剂的培养基培养。星形胶质细胞在含有15％胎牛血清、胰岛素、庆大霉素和L-谷氨酰胺以及小胶质细胞的培养基中，从附着细胞开始进行次培养，并通过反复旋转振摇分离。培养后的星形胶质细胞和小胶质细胞以2.5×105/孔的密度铺在6孔平板上，用于随后的感染试验。
HIV-1病毒的制备
脑衍生的初级HIV-1分离物SF162和JR-FL基本上如Gartner和Popovic12所述，在人外周血单核细胞(PBMC)中进行培养。利用ficoll梯度从人血沉棕黄层分离PBMC，并以在含有10％胎牛血清和庆大霉素的RPMI中、2.5×106/ml的密度铺板。细胞通过加入5ug/ml植物血凝集素(PHA)刺激48小时。之后，细胞用SF162或JR-FL感染并培养7-10天，直到利用p24 ELISA测定法在上清液中检测到高效价的HIV-1。当病毒的生产达到最佳时，使细胞沉淀，含有HIV-1的上清液作为等分试样，在-70℃下储存直到使用。对储存的等分试样进行P24ELISA测定，以确定病毒效价。
初级人胎儿星形胶质细胞和小胶质细胞的感染以及用CI-IB-MECA
的治疗
将2.5×105个小胶质细胞或星形胶质细胞铺到6孔平板的每个孔中。第二天，细胞用新鲜培养基清洗并重新培养。向每孔中加入2×104p24单位的SF162或JR-FL病毒，总量为1ml的病毒接种体。在对照实验中，不加入病毒。细胞在37℃下用病毒培养过夜，用PBS充分洗涤，用2ml新鲜培养基再次培养。培养物每24小时用0.01μM浓度的IB-MECA或Cl-IB-MECA处理。按照指示，在感染后的一定时间取出500μl的培养基，储存在-70℃下，用于后面的分析。将每次的培养基除去，加入一定体积的新鲜培养基。在对照实验中，省略IB-MECA和Cl-IB-MECA。
p24 ELISA测定
利用商业上可购得的p24 ELISA试剂盒(NEN/Dupont)，按照制造商的指示，对收集的50μl上清液进行ELISA测定，以检测HIV-1病毒核心蛋白p24。
结果
从表1-3可以看出，与未用IB-MECA或Cl-IB-MECA.(HIV)处理的对照品相比，在用IB-MECA(HIV和IB-MECA)或Cl-IB-MECA(HIV和Cl-IB-MECA)处理的HIV感染细胞中，从HIV感染细胞收集的培养基中存在的p24蛋白的量明显下降。
表1显示了IB-MECA和Cl-IB-MECA对JR-FL感染的星形胶质细胞中HIV复制的作用，其中从HIV感染5天后的细胞培养物测定培养基中的p24蛋白(pg/mL)。
表2显示了IB-MECA和Cl-IB-MECA对SF162感染的星形胶质细胞中HIV复制的作用，其中p24蛋白(pg/mL)如上所示进行测定。
表3显示了IB-MECA和Cl-IB-MECA对SF126感染的小胶质细胞/SF中HIV复制的作用，其中从HIV感染5天和10天后的细胞培养物测定培养基中的p24蛋白(pg/mL)。
表1
| 星形胶质细胞/JR-FL | |
| 治疗 | p24pg/mL 5天 |
| 无HIV | 12.64 |
| HIV | 22.83 |
| HIV和IB-MECA 0.01 | 3.02 |
| HIV和Cl-IB-MECA 0.01 | 8.45 |
表2
| 星形胶质细胞/SF-162 | |
| 治疗 | p24pg/mL 5天 |
| 无HIV | -12.96 |
| HIV | 313.38 |
| IB-MECA 0.01 | 137.58 |
| Cl-IB-MECA 0.01 | 288.77 |
表3
| 小胶质细胞/SF | ||
| p24pg/mL | ||
| 感染5天后 | 感染10天后 | |
| 无HIV | -12.64 | -12.64 |
| HIV | 267.99 | 209.18 |
| IB-MECA 0.01 | 81.33 | 62.79 |
| IB-MECA 0.1 | 82.29 | 54.80 |
| Cl-IB-MECA 0.01 | 127.03 | 111.05 |
| Cl-IB-MECA 0.0.1 | 10.81 | 80.37 |
Claims (2)
1、IB-MECA或Cl-IB-MECA在制备用于抑制病毒复制的药物组合物中的用途。
2、权利要求1的用途，其中的病毒是HIV。
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|---|---|---|---|
| US26165901P | 2001-01-16 | 2001-01-16 | |
| US60/261,659 | 2001-01-16 |
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| BR (1) | BR0206492A (zh) |
| CA (1) | CA2434906C (zh) |
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| HK (1) | HK1064948A1 (zh) |
| IL (1) | IL156704A0 (zh) |
| WO (1) | WO2002055085A2 (zh) |
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| US20020115635A1 (en) * | 2001-02-21 | 2002-08-22 | Pnina Fishman | Modulation of GSK-3beta activity and its different uses |
| US7414036B2 (en) | 2002-01-25 | 2008-08-19 | Muscagen Limited | Compounds useful as A3 adenosine receptor agonists |
| AR049384A1 (es) | 2004-05-24 | 2006-07-26 | Glaxo Group Ltd | Derivados de purina |
| DK1758596T3 (da) | 2004-05-26 | 2010-07-26 | Inotek Pharmaceuticals Corp | Purinderivater som adenosin-A1-receptoragonister og fremgangsmåder til anvendelse deraf |
| US7863253B2 (en) | 2004-09-20 | 2011-01-04 | Inotek Pharmaceuticals Corporation | Purine Derivatives and methods of use thereof |
| GT200500281A (es) * | 2004-10-22 | 2006-04-24 | Novartis Ag | Compuestos organicos. |
| CA2585581A1 (en) * | 2004-11-22 | 2006-05-26 | King Pharmaceuticals Research & Development Inc. | Enhancing treatment of hif-1 mediated disorders with adenosine a3 receptor agonists |
| GB0500785D0 (en) * | 2005-01-14 | 2005-02-23 | Novartis Ag | Organic compounds |
| GB0514809D0 (en) | 2005-07-19 | 2005-08-24 | Glaxo Group Ltd | Compounds |
| CA2627319A1 (en) | 2005-11-30 | 2007-06-07 | Prakash Jagtap | Purine derivatives and methods of use thereof |
| GB0607953D0 (en) * | 2006-04-21 | 2006-05-31 | Novartis Ag | Organic compounds |
| GB0607944D0 (en) * | 2006-04-21 | 2006-05-31 | Novartis Ag | Organic compounds |
| KR20080110925A (ko) | 2006-04-21 | 2008-12-19 | 노파르티스 아게 | 아데노신 ａ２ａ 수용체 효능제로서 사용하기 위한 퓨린 유도체 |
| GB0607950D0 (en) | 2006-04-21 | 2006-05-31 | Novartis Ag | Organic compounds |
| EP1889846A1 (en) | 2006-07-13 | 2008-02-20 | Novartis AG | Purine derivatives as A2a agonists |
| EP1903044A1 (en) | 2006-09-14 | 2008-03-26 | Novartis AG | Adenosine Derivatives as A2A Receptor Agonists |
| BRPI0718792A2 (pt) * | 2006-11-10 | 2013-12-03 | Novartis Ag | Compostos orgânicos |
| ES2641190T3 (es) | 2007-03-14 | 2017-11-08 | Can-Fite Biopharma Ltd. | Procedimiento de síntesis de IB-MECA |
| US20090088403A1 (en) * | 2007-05-07 | 2009-04-02 | Randy Blakely | A3 adenosine receptors as targets for the modulation of central serotonergic signaling |
| DK2227234T3 (da) | 2007-10-15 | 2014-08-11 | Can Fite Biopharma Ltd | Fremgangsmåde til induktion af hepatocytproliferering og anvendelserderaf |
| US9199102B2 (en) | 2009-07-21 | 2015-12-01 | Oradin Pharmaceutical Ltd. | A3 adenosine receptor ligands for modulation of pigmentation |
| SG10201502588UA (en) | 2010-01-11 | 2015-05-28 | Inotek Pharmaceuticals Corp | Combination, kit and method of reducing intraocular pressure |
| MX2012010724A (es) | 2010-03-26 | 2012-11-12 | Inotek Pharmaceuticals Corp | Metodo para reducir la presion intraocular en seres humanos empleando n6-ciclopentiladenosina (cpa), derivados de cpa o profarmacos de los mismos. |
| US9073960B2 (en) | 2011-12-22 | 2015-07-07 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US20150018299A1 (en) * | 2012-01-23 | 2015-01-15 | Can-Fite Biopharma Ltd. | Treatment of liver conditions |
| US9278991B2 (en) | 2012-01-26 | 2016-03-08 | Inotek Pharmaceuticals Corporation | Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)} methyl nitrate and processes of preparation thereof |
| USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| MX2015001644A (es) * | 2012-08-09 | 2015-08-14 | Can Fite Biopharma Ltd | Ligandos del receptor de adenosina a3 para su uso en el tratamiento de una disfuncion sexual. |
| CN105188714A (zh) | 2013-03-15 | 2015-12-23 | 伊诺泰克制药公司 | 眼用配制品 |
| IL242723B (en) | 2015-11-23 | 2019-12-31 | Can Fite Biopharma Ltd | A3 adenosine receptor ligand for the treatment of ectopic fat accumulation |
| WO2017185061A1 (en) | 2016-04-21 | 2017-10-26 | Astrocyte Pharmaceuticals, Inc. | Compounds and methods for treating neurological and cardiovascular conditions |
| WO2019157317A1 (en) | 2018-02-09 | 2019-08-15 | Astrocyte Pharmaceuticals, Inc. | Compounds and methods for treating addiction and related disorders |
| JP2022502405A (ja) | 2018-09-26 | 2022-01-11 | アストロサイト ファーマシューティカルズ， インコーポレイテッド | 多形化合物およびその使用 |
| IL272078A (en) | 2020-01-16 | 2021-07-29 | Can Fite Biopharma Ltd | Cannabinoids for use in therapy |
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| US5443836A (en) * | 1993-03-15 | 1995-08-22 | Gensia, Inc. | Methods for protecting tissues and organs from ischemic damage |
| US5688774A (en) * | 1993-07-13 | 1997-11-18 | The United States Of America As Represented By The Department Of Health And Human Services | A3 adenosine receptor agonists |
| EP0708781B1 (en) * | 1993-07-13 | 2001-10-04 | THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, Department of Health and Human Services | A 3 adenosine receptor agonists |
| US6048865A (en) * | 1997-07-29 | 2000-04-11 | Medco Research, Inc. | N6 -substituted-adenosine-5'-uronamides as adenosine receptor modulator |
| EP1019427A4 (en) | 1997-07-29 | 2000-07-19 | Medco Res Inc | N? 6 -SUBSTITUES-ADENOSINE-5'-URONAMIDES USEFUL AS MODULATORS OF ADENOSINE RECEPTORS |
| WO1999020284A1 (en) | 1997-10-23 | 1999-04-29 | Trustees Of The University Of Pennsylvania | Methods for reducing ischemic injury of the heart via the sequential administration of monophosphoryl lipid a and adenosine receptor agents |
| IL133680A0 (en) | 1999-09-10 | 2001-04-30 | Can Fite Technologies Ltd | Pharmaceutical compositions comprising an adenosine receptor agonist or antagonist |
| US8076303B2 (en) * | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
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| Publication number | Publication date |
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| HK1064948A1 (en) | 2005-02-08 |
| EP1365776B1 (en) | 2005-04-13 |
| US20040106572A1 (en) | 2004-06-03 |
| BR0206492A (pt) | 2004-02-10 |
| JP2004517864A (ja) | 2004-06-17 |
| WO2002055085A2 (en) | 2002-07-18 |
| DE60203702D1 (de) | 2005-05-19 |
| CA2434906C (en) | 2008-08-19 |
| WO2002055085A3 (en) | 2002-12-19 |
| EP1365776A2 (en) | 2003-12-03 |
| AU2002219497B2 (en) | 2004-08-26 |
| CA2434906A1 (en) | 2002-07-18 |
| CN1489470A (zh) | 2004-04-14 |
| ATE292973T1 (de) | 2005-04-15 |
| IL156704A0 (en) | 2004-01-04 |
| JP4012070B2 (ja) | 2007-11-21 |
| US7589075B2 (en) | 2009-09-15 |
| DE60203702T2 (de) | 2006-03-02 |
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