CN100435785C - 抑制iapp的化合物或其可药用酯或其可药用盐的制药应用 - Google Patents

抑制iapp的化合物或其可药用酯或其可药用盐的制药应用 Download PDF

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CN100435785C
CN100435785C CNB008107203A CN00810720A CN100435785C CN 100435785 C CN100435785 C CN 100435785C CN B008107203 A CNB008107203 A CN B008107203A CN 00810720 A CN00810720 A CN 00810720A CN 100435785 C CN100435785 C CN 100435785C
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tetrahydroisoquinoline
iapp
group
tetrahydro isoquinolyl
sulfonic acid
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CN1377260A (zh
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W·A·沙雷克
D·F·韦弗
X·孔
A·古普塔
D·米格内奥尔特
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Bellus Health International Ltd
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Bellus Health International Ltd
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Abstract

本发明提供了可用于治疗淀粉样变性的方法和组合物。本发明特别提供了用于抑制、预防或治疗例如胰岛中淀粉样蛋白沉积的方法和组合物，其中所述淀粉样蛋白沉积物是与胰岛淀粉样多肽(IAPP)有关的淀粉样蛋白沉积或沉积物。本发明方法包括给个体施用能抑制与IAPP有关的淀粉样蛋白沉积物的治疗化合物。因此，本发明组合物和方法可用于在发生这样的淀粉样蛋白沉积的病症例如糖尿病中抑制淀粉样变性。

Description

抑制IAPP的化合物或其可药用酯或其可药用盐的制药应用
依据35U.S.C.119(e)条款，本申请要求下列两件未结案的美国临时申请的优先权：其中一件的申请号是60/135,545，于1999年5月24日提交；另一件的申请号是60/143,123，于1999年7月9日提交。这两件申请的全文引入本文以作参考。本申请还涉及在1999年10月26日公布的美国专利5,972,328，该专利全文引入本发明以作参考。
发明背景
淀粉样变性是指特征为存在淀粉样蛋白的病症。淀粉样蛋白是一个类名，它是指一类不同但是特异的细胞内和细胞外蛋白沉积物，其与多种不同疾病有关。虽然其出现不同，但是所有淀粉样蛋白沉积物都具有共同的形态特征，包括它们可用特定染料(例如刚果红)染色，并且染色后在偏振光中具有独特的双折射外观(有时特征为“红-绿”)。它们还具有共同的超微结构特征和共同的X-射线衍射以及红外光谱。
淀粉样变性在临床上可分为原发型、继发型、家族型和/或独立型。独立型淀粉样变性是趋于牵涉单一器官系统的淀粉样变性。不同的淀粉样变性还可以通过沉积物中存在的蛋白的类型来表征。例如，神经变性疾病例如瘙痒病、牛海绵状脑炎、Creutzfeldt-Jakob疾病等的特征是在中枢神经系统中出现和积聚着耐蛋白酶形式的蛋白酶传染性因子蛋白(称为AScr或PrP-27)。类似地，阿尔茨海默氏病-另一种神经变性疾病的特征是亲刚果性(congophilic)血管病、神经炎斑块和神经原纤维缠结，所有这些都具有淀粉样蛋白的特征。在该病症中，斑块和血管淀粉样蛋白是由β蛋白形成的。其它疾病例如在青少年和成人中开始发作的糖尿病、长期血液透析的并发症和长期炎症或浆细胞恶液质的后发病的特征是淀粉样蛋白的系统积聚。在每一这些病症中，不同的淀粉样蛋白原性蛋白参与淀粉样蛋白沉积。
已知胰岛淀粉样多肽(IAPP)能够形成原纤维，这样的原纤维沉积在II型糖尿病患者的胰腺中，形成沉积物。一旦这些淀粉样蛋白沉积物已形成，没有任何能在原位显著减少或清除沉积物的已知治疗或疗法.
发明概述
本发明提供了可用于治疗淀粉样变性的方法和组合物。本发明特别公开了用于抑制、预防和治疗例如胰岛中淀粉样蛋白沉积的方法和组合物，其中欲治疗的淀粉样蛋白沉积物是例如与胰岛淀粉样多肽(IAPP)有关的具有至少一些β-折叠结构的淀粉样蛋白沉积物。本发明方法包括给个体施用能抑制、减轻或分裂淀粉样蛋白沉积物例如与IAPP有关的淀粉样蛋白沉积物的治疗化合物。因此，本发明组合物和方法可用于在发生这样的淀粉样蛋白沉积的病症例如糖尿病中抑制淀粉样变性。
在一个实施方案中，提供了在个体中抑制淀粉样蛋白沉积、特别是与IAPP有关的淀粉样蛋白沉积的方法，其中是给所述个体施用有效量的IAPP抑制化合物或其可药用盐，以抑制所述与IAPP有关的淀粉样蛋白沉积。这样的化合物包括下述通式化合物或其可药用酯、酸或盐：
其中C是碳，N是氮，l、m、o、p和q独立地为0或1；n是0-3的整数；W是氢或者在生理pH为阴离子的基团；Y是在生理pH为阴离子的基团；R1和R2独立地为氢、烷基、在生理pH为阴离子的基团，或者R1和R2与它们所连接的氮可以一起形成未取代或取代的在杂环中有3-7个原子的杂环；R3是氢、卤素、巯基或羟基；R4、R5、和R6独立地为氢或卤素；且A是氢或C1-C6烷基。
优选的治疗化合物包括3-(3-羟基-1-丙基)氨基-1-丙磺酸；2-氨基-5-磷酸戊酸(2-amino-5-phosphovaleric acid)；4-苯基-1-(3’-磺基丙基)-1，2，3，6-四氢吡啶；环己基氨基磺酸；O-磷酸-L-丝氨酸；六氟戊二酸；3-氨基-2-羟基-1-丙磺酸；8-甲氧基-5-喹啉磺酸；和3-二甲基氨基-1-丙磺酸，在附图10-14中描述的化合物，和它们的可药用酯、酸或盐。
在另一个实施方案中，提供了在个体中抑制淀粉样蛋白沉积、特别是与IAPP有关的淀粉样蛋白沉积的方法，其中是给所述个体施用有效量的IAPP抑制化合物或其可药用酯、酸或盐，以抑制所述与IAPP有关的淀粉样蛋白沉积。这样的化合物包括下述通式化合物：
Figure C0081072000071
其中A1、A2、A3、A4、A5和A6独立地为亚烷基、0、S或-NH-；m和n(对于每个独立的A基团)独立地为0或1；l、p和q独立地为0、1或2；R7、R8、R9、R10、R11、R12、R13、和R14独立地为氢、烷基、脂环基、杂环基或芳基，并且相邻的R基团(例如R7和R8)可形成未取代或取代的环或杂环。在一个实施方案中，R13可以是阴离子。
优选的治疗化合物包括1，2，3，4-四氢异喹啉和在附图1-9中描述的化合物.
在另一实施方案中，本发明涉及在患有与IAPP有关的淀粉样蛋白沉积的个体中减轻淀粉样蛋白沉积的方法，该方法包括给所述个体施用有效量的IAPP抑制化合物或其可药用酯、酸或盐，以减轻与IAPP有关的淀粉样蛋白沉积。
本发明治疗化合物是通过能有效地抑制与IAPP有关的淀粉样蛋白沉积的途径给个体施用的。合适的给药途径包括口服、透皮、皮下、舌下、颊、静脉内和腹膜内注射。治疗化合物可以与可药用载体一起给药。
本发明还提供了用于治疗淀粉样变性的药物组合物。所述药物组合物包含能有效地抑制与IAPP有关的淀粉样蛋白沉积的量的本发明治疗化合物与可药用载体。
附图概述
附图1-14描述的是在说明书中描述的化合物的示例性化学结构。
发明详述
通过下述定义来更充分地阐述本发明。
“淀粉样蛋白”包括与IAPP有关的淀粉样蛋白，其包括但不限于基本上由IAPP亚单位构建的β-折叠淀粉样蛋白。“抑制”淀粉样蛋白沉积包括阻止或停止与IAPP有关的淀粉样蛋白形成例如原纤维形成，抑制或减缓已患有淀粉样变性的个体中的与IAPP有关的淀粉样蛋白进一步沉积，和减轻或逆转患有进行性淀粉样变性的个体中的与IAPP有关的淀粉样蛋白沉积。对淀粉样蛋白沉积的抑制是相对于未治疗个体、或者相对于治疗前的治疗个体确定的，例如通过在临床上测定糖尿病患者胰腺功能的改善来确定的。
本发明治疗化合物的适用的可药用酯、酸或盐在本发明范围内，例如碱金属盐、碱土金属盐、较高化合价阳离子盐(例如铝盐)、多阳离子反荷离子盐或铵盐。当化合物是阴离子化合物时，优选的可药用盐是钠盐。也包括其它盐，例如在其可药用范围内的盐酸盐、柠檬酸盐、酒石酸盐。
本发明治疗化合物可以在可药用载体中施用。本文所用的“可药用载体”包括与化合物的活性相容并且对于个体来说是生理可接受的任何以及所有溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。可药用载体的实例是缓冲标准盐水(0.15M NaCl)。对于任何常规介质或辅剂，除了其必须与治疗化合物相容以外，还要考虑其在适于药物施用的组合物中的应用。还可以向本发明组合物中掺入补充活性化合物。
本文所用的“阴离子基团”是指在生理pH带负电荷的基团。优选的阴离子基团包括羧酸根、硫酸根、磺酸根、亚磺酸根、氨基磺酸根、四唑基、磷酸根、膦酸根、亚膦酸根、和硫代膦酸根或其官能等同物。阴离子基团的“官能等同物”包括生物电子等排物，例如羧酸根的生物电子等排物。生物电子等排物包括标准的生物电子等排物和非标准的生物电子等排物。标准和非标准的生物电子等排物是本领域已知的(参见例如Silverman，R.B.The Organic Chemistry of drugDesign and Drug Action，Academic Press，Inc.：San Diego，CA，1992，pp.19-23)。特别优选的阴离子基团是羧酸根。
术语“烷基”包括饱和脂族基团，包括直链烷基、支链烷基、环烷基(脂环族烷基)、烷基取代的环烷基、和环烷基取代的烷基。在优选的实施方案中，直链或支链烷基在其骨架中具有30或少于30个碳原子(例如对于直链是C1-C30，对于支链是C3-C30)，更优选在骨架中具有20或少于20个碳原子。同样，环烷基可在其环结构中具有4-10个碳原子，更优选具有5、6或7个碳原子。
此外，术语烷基既包括“未取代的烷基”，也包括“取代的烷基”，取代的烷基是指在烃骨架的一个或多个碳上具有取代基以代替氢的烷基。这样的取代基可包括例如卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸酯、烷基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、烷氧基、磷酸酯、膦酸酯基(phosphonato)、次磷酯基(Phosphinato)、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯、硫酸酯、磺酸酯、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、或芳族或杂芳族基团。本领域技术人员应当理解，如果适当的话在烃链上被取代的部分自身可以被取代。环烷基可以被例如上述取代基取代。“芳烷基”是被芳基取代的烷基(例如苯基甲基(苄基))。
在本文中，术语“芳基”包括5-元和6-元芳族基团，其中可包含0-4个杂原子，例如苯、吡咯、呋喃、噻吩、咪唑、唑、噻唑、三唑、四唑、吡唑、吡啶、吡嗪、哒嗪和嘧啶等。芳基还包括多环稠合芳基例如萘基、喹啉基、吲哚基等。在环结构中具有杂原子的芳基也可以称为“芳杂环”、“杂芳基”或“杂芳族化合物”。芳环可以在一个或多个环位点上被如上所述的取代基取代，例如被卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸酯、烷基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、烷氧基、磷酸酯、膦酸酯基、次磷酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯、硫酸酯、磺酸酯、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、或芳族或杂芳族基团取代。芳基还可以与非芳族的脂环或杂环稠合或桥接以形成多环(例如四氢萘)。
术语“链烯基”和“炔基”包括不饱和脂族基团，其在链长和取代方面与上述烷基类似，但是分别含有至少一个双键和三键。
除非具体指明碳原子的数目，“低级烷基”是指如上所定义的烷基，但是在其骨架结构中具有1-10个、更优选1-6个碳原子。同样，“低级链烯基”和“低级炔基”具有类似链长。优选的烷基是低级烷基。
术语“杂环基”或“杂环基团”包括3-元-10-元环结构、更优选4-元-7-元环，所述环结构包含1-4个杂原子。杂环基包括吡咯烷、四氢呋喃、硫杂环戊烷(thiolane)、哌啶、哌嗪、吗啉、内酯、内酰胺例如氮杂环丁烷酮、磺内酰胺、磺酸内酯等。杂环可以在一个或多个环位点上被如上所述的取代基取代，例如被卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸酯、烷基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、烷氧基、磷酸酯、膦酸酯基、次磷酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯、硫酸酯、磺酸酯、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、或芳族或杂芳族基团取代。
术语“多环基”或“多环基团”包括两个或更多个环(例如环烷基、环烯基、环炔基、芳基和/或杂环)，其中有两个或更多个碳原子是两个相邻环所共有的，例如这些环是“稠合环”。经由非相邻原子连接的环称为“桥接”环。多环的每个环都可以被如上所述的取代基取代，例如被卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸酯、烷基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、烷氧基、磷酸酯、膦酸酯基、次磷酸酯基、氟基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯、硫酸酯、磺酸酯、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、或芳族或杂芳族基团取代。
术语“杂原子”包括除了碳或氢之外的任何元素的原子。优选的杂原子是氮、氧、硫和磷。
本文所用术语“芳基醛”包括式Ar-C(O)H化合物，其中Ar是芳基(如上所述的芳基)，且-C(O)H是甲酰基或醛基。
应当指出，某些本发明化合物的结构包括不对称碳原子。因此应当理解，除非另有指明，否则由于这样的不对称而产生的异构体(例如所有对映异构体和非对映异构体)包括在本发明范围内。通过标准分离技术和通过立体化学控制的合成能够以基本上纯的形式获得这样的异构体。此外，在适当时，烯烃或炔烃可包括E-或Z-几何构型。
在实施方案中，本发明方法和组合物抑制、预防和治疗胰岛中的淀粉样蛋白沉积，其中所要治疗的淀粉样蛋白沉积是与胰岛淀粉样多肽(IAPP)有关的淀粉样蛋白沉积物，例如具有至少一些β-折叠结构的淀粉样蛋白沉积物。本发明方法包括给个体施用能抑制、减轻或分裂与IAPP有关的淀粉样蛋白沉积物的治疗化合物。因此，本发明组合物和方法可用于在发生这样的淀粉样蛋白沉积的病症例如糖尿病中抑制淀粉样变性。
在一个实施方案中，提供了在个体中抑制与IAPP有关的淀粉样蛋白沉积的方法，其中是给所述个体施用有效量的IAPP抑制化合物或其可药用酯、酸或盐，以抑制所述与IAPP有关的淀粉样蛋白沉积。这样的化合物包括下述通式化合物或其可药用酯、酸或盐：
Figure C0081072000121
其中C是碳，N是氮，l、m、o、p和q独立地为0或1；n是0-3的整数；W是氢或者在生理pH为阴离子的基团；Y是在生理pH为阴离子的基团；R1和R2独立地为氢、烷基、在生理pH为阴离子的基团，或者R1和R2与它们所连接的氮可以一起形成未取代或取代的在杂环中有3-7个原子的杂环；R3是氢、卤素、巯基或羟基；R4、R5、和R6独立地为氢或卤素；且A是氢或C1-C6烷基。
在一个实施方案中，W优选为-COOH；Y优选为-COOH、-SO3H、-PO3H2、或-OP(O)(OH)2；R1优选为H、Me或羟基丙基；R2优选为H、Me或-SO3H；R3优选为H、F、或OH；当R1和R2与它们所连接的氮一起形成未取代或取代的杂环时，优选的基团包括
R4、R5和R6优选为H或F；A优选为H、CH、CF2或烷基，所述烷基可以是取代或未取代的直链、支链或环状烷基例如环己基。
优选的治疗化合物包括3-(3-羟基-1-丙基)氨基-1-丙磺酸；2-氨基-5-磷酸戊酸；4-苯基-1-(3’-磺基丙基)-1，2，3，6-四氢吡啶；环己基氨基磺酸；O-磷酸-L-丝氨酸；六氟戊二酸；3-氨基-2-羟基-1-丙磺酸；8-甲氧基-5-喹啉磺酸；和3-二甲基氨基-1-丙磺酸，在附图10-14中描述的化合物，和它们的可药用酯、酸或盐。
在另一个实施方案中，提供了在个体中抑制与IAPP有关的淀粉样蛋白沉积的方法，其中是给所述个体施用有效量的IAPP抑制化合物或其可药用酯、酸或盐，以抑制所述与IAPP有关的淀粉样蛋白沉积。这样的化合物包括下述通式化合物或其可药用酯、酸或盐：
Figure C0081072000131
其中A1、A2、A3、A4、A5和A6独立地为亚烷基、0、S或-NH-；m和n(对于每个独立的A基团)独立地为0或1；l、p和q独立地为0、1或2；R7、R8、R9、R10、R11、R12、R13、和R14独立地为氢、烷基、脂环烃基、杂环基或芳基，并且相邻的R基团(例如R7和R8)可形成未取代或取代的环或杂环。在一个实施方案中，R13可以是阴离子。
优选的治疗化合物包括1，2，3，4-四氢异喹啉和在附图1-9中描述的化合物。
本发明另一方面包括用于治疗淀粉样变性的药物组合物。在本发明方法中，可将如上所述的治疗化合物以能有效地抑制淀粉样变性或减轻淀粉样蛋白沉积的量掺入到药物组合物的可药用载体中。
在本发明方法中，是通过给个体施用本发明治疗化合物来抑制个体中的淀粉样蛋白沉积。术语个体包括其中发生淀粉样变性的活生物体。个体的实例包括人、无尾猿、猴子、奶牛、绵羊、山羊、狗、猫、小鼠、大鼠、和其转基因变种。可用已知方法以能有效地抑制个体中淀粉样蛋白沉积或减轻淀粉样蛋白沉积的剂量和治疗持续时间给欲治疗的个体施用本发明组合物。达到治疗效果所需的治疗化合物的有效量可随因素例如在个体中的治疗位点已沉积的淀粉样蛋白的量、个体的年龄、性别、和体重、以及治疗化合物抑制个体中淀粉样蛋白沉积或减轻淀粉样蛋白沉积的能力而变。可调节给药方案以提供最佳治疗反应。例如，几份均分剂量可每日施用，或者可随着治疗情境的急迫程度有比例地降低剂量。
活性化合物可通过诸如口服、舌下、颊、透皮、皮下、静脉内、和腹膜内给药这样的途径施用。根据给药途径，可用材料将活性化合物包衣以保护化合物不受酸、酶以及其它可使化合物失活的天然条件的影响。
可将本发明化合物配制以确保在体内正确分布。例如，可将本发明治疗化合物配制在脂质体中。对于制备脂质体的方法，参见例如美国专利4,522,811；5,374,548；和5,399,331。脂质体可包含一个或多个能选择性地转运到具体细胞或器官(“靶向部分”)内并因此提供了药物的靶向递送(参见例如V.V.Ranade(1989)J.Clin.Pharmacol.29：685)。靶向部分的实例包括叶酸盐或生物素(参见例如Low等人的美国专利5,416,016)；甘露糖苷(Umezawa等人，(1988)Biochem.Biophys.Res.Commun.153：1038)；抗体(P.G.Bloeman等人.(1995)FEBS Lett.357：140；M.Owais等人.(1995)Antimicrob.Agents Chemother.39：180)；表面活性蛋白A受体(Briscoe等人.(1995)Am.J.Physiol.1233：134)；gp120(Schreier等人.(1994)J.Biol.Chem.269：9090)；还参见K.Keinanen；M.L.Laukkanen(1994)FEBS Lett.346：123；J.J.Killion；I.J.Fidler(1994)Immunomethods 4：273。在优选的实施方案中，将本发明治疗化合物配制成脂质体；在更优选的实施方案中，脂质体包括靶向部分。
为了通过除非胃肠道途径之外的途径施用治疗化合物，可能需要用防止化合物失活的材料将化合物包衣或者将治疗化合物与这样的材料一起施用。例如，可将治疗化合物在适当载体例如脂质体或稀释剂中施用给个体。可药用稀释剂包括盐水和适当缓冲溶液。脂质体包括水包油包水CGF乳剂以及常规脂质体(Strejan等人，(1984)J.Neuroimmunol.7：27)。
治疗化合物还可以非胃肠道、舌下、颊、腹膜内、脊柱内、或脑内给药。分散体可在例如甘油、液体聚乙二醇、和其混合物、以及油中制备。在常规贮存和使用条件下，这些制剂可含有防腐剂以防止微生物生长。
适于注射使用的药物组合物包括无菌水溶液(溶于水的)或分散体和用于临时配制无菌注射溶液或分散体的无菌粉末。在所有情况下，组合物都必须是无菌的，并且是其程度使得能够进行注射的流体。其在制备和贮存条件下必须是稳定的，并且必须被保护以防止受微生物例如细菌和真菌作用的污染。载体可以是溶剂或分散介质，其中含有例如水、乙醇、多元醇(例如甘油、丙二醇、和液体聚乙二醇等)、其合适的混合物、和植物油。可例如通过使用包衣例如卵磷脂、通过维持所需的粒径(对于分散体)、和通过使用表面活性剂来保持适当流动性。防止微生物的作用可通过各种抗菌剂和抗真菌剂例如paraben、氯丁醇、苯酚、抗坏血酸、硫汞撒等来实现。在许多情况下，组合物优选包含等渗剂例如糖、氯化钠、或聚醇例如甘露醇和山梨醇。注射组合物的延迟吸收作用可通过在组合物中包含能延迟吸收的物质例如硬脂酸铝或明胶来实现。
无菌注射溶液可通过按照需要将所需量的治疗化合物掺入在具有一种上述组分或上述组分混合物的适当溶剂中、然后过滤灭菌而制得。一般情况下，分散体可通过将治疗化合物掺入到含有基本分散体基质和所需其它上述组分的无菌载体中而制得。对于用于制备无菌注射溶液的无菌粉末，优选的制备方法是真空干燥和冷冻干燥，其能由过滤灭菌的溶液获得活性组分(即治疗化合物)和任何其它所需组分的粉末。
治疗化合物可口服给药，例如用惰性稀释剂或可同化的食用载体口服给药。还可以将治疗化合物和其它组分包封在硬壳或软壳明胶胶囊中，压制成片，或者直接掺入到个体的饮食中。对于口服治疗给药，可将治疗化合物与赋形剂混合，并以吞咽片、舌下/颊片、锭剂、胶囊、酏剂、悬浮剂、糖浆剂、糯米纸囊剂等的形式给药。当然，治疗化合物在组合物和制剂中的百分比可以变化。治疗化合物在这样的治疗用组合物中的量是能获得适当剂量的量。
尤其有利的是将非胃肠道给药用组合物配制成易于给药和剂量均匀性的单位剂型。本文所用的单位剂型是指适于作为单位剂量用于所治疗的个体的物理不连续单位；各单位含有经计算能产生所需治疗作用的预定量的治疗化合物以及所需的药物载体。关于本发明单位剂型的具体要求由并直接取决于(a)治疗化合物的独特特征以及想要达到的特定治疗作用，和(b)在混合用于治疗个体中淀粉样蛋白沉积的化合物的领域中的内在限制。
活性化合物是以足以抑制个体中淀粉样蛋白沉积的治疗有效剂量给药的。相对于未治疗个体或在治疗前的相同个体，“治疗有效剂量”优选抑制淀粉样蛋白沉积和/或减少淀粉样蛋白沉积物至少约20％、更优选至少约40％、甚至更优选至少约60％、特别更优选至少约80％。
可在能够预测在人疾病中抑制淀粉样蛋白沉积或减少淀粉样蛋白沉积物的动物模型系统中测定化合物抑制淀粉样蛋白沉积或减少淀粉样蛋白沉积物的能力。化合物抑制淀粉样蛋白沉积的能力也可以通过使用例如ELISA分析在体外测定化合物抑制淀粉样蛋白沉积的能力来评价。可通过硫黄素T(ThT)分析、圆二色性(CD)或红外(IR)光谱法进一步测定化合物对淀粉样蛋白的二级结构的作用。
CD和IR光谱法是特别有用的技术，因为所获得的信息能通过确定化合物对淀粉样蛋白折叠和/或原纤维形成的结构作用而直接测定出测试化合物预防或逆转淀粉样变性的能力。这与以前已知的测定淀粉样蛋白前体的细胞运输或淀粉样蛋白与细胞外基质蛋白之间的相互作用、仅间接提供潜在淀粉样蛋白抑制活性的方法不同。还应当指出，CD和IR光谱法还可检测能提高例如淀粉样蛋白β-折叠、从而稳定淀粉样蛋白原纤维的化合物。
淀粉样蛋白沉积是多步过程。因此，用于治疗淀粉样变性的活性剂具有多种潜在作用方式。抑制淀粉样蛋白沉积的活性剂可以以一种或多种下述途径起作用，提供这些途径仅是举例说明而不是限制：
1.抑制或延迟溶液中蛋白的折叠；
2.抑制或延迟低聚淀粉样肽聚集/延长成原纤维和/或沉积物；和
3.分裂/溶解/修饰淀粉样蛋白原纤维和/或沉积物；
类型1和2相当于阻止形成淀粉样蛋白沉积物(减缓或停止淀粉样蛋白沉积)，类型3相当于除去或修饰已经形成的沉积物(除去或减少现存的淀粉样蛋白沉积物)。
通过下述实施例来进一步举例说明本发明，但这些实施例不是限制本发明。
实施例1
通过硫黄素T光谱法测定淀粉样蛋白原纤维形成的速度
硫黄素T(ThT)结合形成β-折叠的淀粉样蛋白，使组织切片和原纤维在体外表现出黄色荧光。ThT荧光的测定可用作在不同条件下的淀粉样蛋白原纤维形成的灵敏测定。该测定方法已用于实验中以测定本发明化合物对淀粉样蛋白原纤维形成的影响。
方法
将合成的人IAPP(Bachem)溶于40％三氟乙醇中，并冷冻干燥成方便量取的等分试样。制备LAPP，然后立即通过将其溶于40％1，1，1，3，3，3-六氟-2-丙醇(HFIP)的水中以使肽维持α螺线构象并且可溶来进行测定。制备ThT(2.5mM)的贮备液，即7.9mg在10mLTris-HCl pH 7.0中的溶液，并过滤(0.22μm)。将溶液保持在黑暗中直至使用。在440nm激发(狭缝5nm)、482nm发射(狭缝10nm)以及搅拌下测定荧光。将25ml ThT贮备液(终浓度为62.5μM)加到肽样本中，并在比色杯中补至1mL。将样本搅拌5分钟，然后读取数据。在最初的时间点(制备样本后5分钟)开始测定，然后在接下来的4-6小时和于室温培养过夜后定时测定。
使用该方法发现，本文所公开的一些化合物(或如上所述的其盐)，即3-(3-羟基-1-丙基)氨基-1-丙磺酸；2-氨基-5-磷酸戊酸；4-苯基-1-(3’-磺基丙基)-1，2，3，6-四氢吡啶；环己基氨基磺酸；O-磷酸-L-丝氨酸；六氟戊二酸；8-甲氧基-5-喹啉磺酸；3-氨基-2-羟基-1-丙磺酸；和3-二甲基氨基-1-丙磺酸，以及1，2，3，4-四氢异喹啉能抑制或阻止与IAPP有关的原纤维集合。
实施例2
依据本发明公开内容，通过测定存在或不存在β-折叠构象，进行圆二色性以确定一些治疗化合物阻止或抑制与IAPP有关的原纤维形成的活性。所得结果列在表1中。
如下所述进行该测定：
仪器和参数
仪器：JASCO J-715分光偏振计
小池/比色杯：具有1.0mm通路长度的Hellma石英(QS)
室温
波长间隔：250nm-190nm
分辨率：0.1nm
带宽：1.0nm
响应时间：1秒
扫描速度：20nm/分钟
光谱运行数目：5
该测定-一种共培养方法测定了化合物或物质抑制淀粉样蛋白原纤维集合的能力，例如测试在可溶性IAPP存在下淀粉样蛋白β-折叠构象的存在。在和不在(即仅有水)缓冲剂存在下测定样本，这样做是测定使用离子缓冲剂(通常是磷酸盐)是否观察到竞争性作用。
A.仅在水中测定
加入比例为1∶10[肽∶化合物]的所用组分；向含有化合物的水溶液中加入10μL浓度为10mg/mL的IAPP贮备液(最终是100μg肽)，使终体积为400μl。测定最终分析溶液的pH以确保没有任何波动，并使用如上所述的参数累计光谱。
B.在磷酸盐缓冲液中测定
加入所需量的化合物以在10mM磷酸盐缓冲液，pH 7中获得1∶10的摩尔比。向含有化合物的该磷酸盐缓冲溶液中加入10μL浓度为10mg/mL的IAPP贮备液(最终是100μg肽)，使终体积为400μl。测定最终分析溶液的pH以确保没有任何波动，并使用如上所述的参数累计光谱。
在这两个分析中，按各自的测试组测定对照样本。该对照仅在400μl类似终体积的水或缓冲液中含有肽。首先收集对照的光谱(第一次测定)，最后收集测试组(最后测定)，以确保在测定期间肽不进行广泛聚集。使用对照组的光谱以与用处理样本获得的测定结果进行比较。
共培养：
制备1mg/mL的IAPP在10mM磷酸盐缓冲液，pH 7中的新鲜贮备液。加入所需量的化合物以在10mM磷酸盐缓冲液，pH 7中获得1∶10的摩尔比。在室温培养3天。用10mM磷酸盐缓冲液，pH 7将体积补足至400μL。测定最终分析溶液的pH以确保没有任何波动，并使用如上所述的参数累计光谱。
测定类似对照以进行比较。
数据分析
独立收集光谱图(对照和处理)，并测定在218nm的椭圆率改变。其最小值直接与样本中存在的β-折叠的量相关。记录正向和负向中的变化，并用相对值(“有活性”或“无活性”)表示所测定的化合物的活性。
表1
  化合物   活性
  3-(3-羟基-1-丙基)氨基-1-丙磺酸   有活性
  DL-2-氨基-5-磷酸戊酸   有活性
  1，2，3，4-四氢异喹啉盐酸盐   有活性
  环己基氨基磺酸钠盐   有活性
  O-磷酸-L-丝氨酸   有活性
  六氟戊二酸   有活性
  8-甲氧基-5-喹啉磺酸钠盐   有活性
  4-苯基-1-(3’-磺基丙基)-1，2，3，6-四氢吡啶钠盐   有活性
  3-氨基-2-羟基-1-丙磺酸   有活性
  3-二甲基氨基-1-丙磺酸   有活性
实施例3
下面描述本发明化合物-钠盐形式的4-苯基-1-(3’-磺基丙基)-1，2，3，6-四氢吡啶的合成。
在室温向4-苯基吡啶(15.5g，0.1mol)在丙酮(100mL)内的溶液中加入1，3-丙磺内酯(12.2g，0.1mol)。然后将该混合物在回流温度加热过夜。将所得悬浮液冷却至室温。通过过滤收集固体，并用丙酮洗涤。向该固体(31g)在甲醇(500mL)内的溶液中分批加入硼氢化钠(10g，260mmol)，并将该混合物在室温搅拌2小时。加入蒸馏水(50mL)以破坏过量硼氢化钠。将该混合物用甲醇(200ml)稀释，并用Amberlite IR-120离子交换树脂(H+形式，300g)中和。形成了白色沉淀。通过过滤除去沉淀和树脂，并在约100℃用蒸馏水(400mL)处理。将该混合物过滤，并用热的蒸馏水(2×200mL)洗涤。合并滤液和洗涤液，并浓缩至干。将残余物与甲醇(3×200mL)一起蒸发，然后从乙醇-水{8∶2(v/v)}中重结晶，获得了4-苯基-1-(3’-磺基丙基)-1，2，3，6-四氢吡啶，其为白色结晶(26g，93％)。其1H；和13C NMR光谱与结构相一致。
向上面所得4-苯基-1-(3’-磺基丙基)-1，2，3，6-四氢吡啶(5.6g，20mmol)在乙醇(180mL)内的溶液中加入氢氧化钠(1.2g，30mmol)。将该悬浮液在回流温度加热30分钟。然后将该混合物冷却至室温。通过过滤收集第一批产物(3.9g，64％)。将滤液浓缩至干，用乙醇将残余物重结晶，获得了第二批产物(2.0g，32％)。
1H NMR(400MHz，D2O)：δ1.85(五重峰，2H，J8.7，7.7Hz，2H-2′)，2.39-2.45(m，4H，2H-3′and 2H-3)，2.59(t，2H，J 5.6Hz，2H-2)，2.80(t，2H，J7.7Hz，2H-1′)，3.00(brs，2H，2H-6)，6.00(brs，1H，H-5)，7.18-7.36(m，5H，Ar).13C NMR(100.6MHz，D2O)：δ23.90(C-2′)，29.01(C-3)，51.69，51.76(C-2，C-3′)，54.45(C-6)，58.12(C-1′)，123.75(C-5)，127.31，130.01，131.24(Ar)，136.89(C-4)，142.47(Ar).
等同物
本领域技术人员将认识到，或者能够使用至多常规实验来得到本文所描述的具体操作的多个等同物。这样的同等物在本发明范围内，并且为下述权利要求所覆盖。在本申请中引用的所有参考文献、公开的专利、和出版的专利申请都引入本发明以作参考。

Claims (8)

1.下式抑制IAPP的化合物或其可药用酯或其可药用盐在制备用于在个体中治疗特征是与IAPP有关的淀粉样蛋白沉积的疾病的药物或在个体中减少或抑制与IAPP有关的淀粉样蛋白沉积的药物中的应用：
其中A1、A2、A3、A4、A5和A6独立地为C1-C30亚烷基、O、S或-NH-；
m为1；
每个n对于每个独立的A基团独立地为0或1；
l、p和q为1；和
R7、R8、R9、R10、R11、R12、R13和R14独立地为氢或C1-C30的直链或支链的烷基。
2.抑制IAPP的化合物或其可药用酯或其可药用盐在制备用于在个体中治疗特征是与IAPP有关的淀粉样蛋白沉积的疾病的药物或在个体中减少或抑制与IAPP有关的淀粉样蛋白沉积的药物中的应用，其中所述化合物选自
1，2，3，4-四氢异喹啉；
3-[2-(1，2，3，4-四氢异喹啉基)]-1-丙磺酸
3-[2-(6，7-二甲氧基-1，2，3，4，-四氢异喹啉基)]-1-丙磺酸
3-[2-(6-甲氧基-1，2，3，4-四氢异喹啉基)]-1-丙磺酸
4-[2-(6，7-二甲氧基-1，2，3，4-四氢异喹啉基)]-1-丁磺酸
4-[2-(6-甲氧基-1，2，3，4-四氢异喹啉基)]-1-丁磺酸
3-[2-(1，2，3，4-四氢异喹啉基)]-1-丙基硫代膦酸
3-[2-(6-甲氧基-1，2，3，4-四氢异喹啉基)]-1-丙磺酸
3-[2-(8-甲氧基-1，2，3，4-四氢异喹啉基)]-1-丙磺酸
1，2，3，4-四氢-8-异喹啉磺酸
3-[2-(6-二甲基氨基-1，2，3，4-四氢异喹啉基)]-1-丙磺酸
3-[2-(6-氯-1，2，3，4-四氢异喹啉基)]-1-丙磺酸
4-[2-(1，2，3，4-四氢异喹啉基)]-1-丁磺酸
1，2，3，4-四氢-5-异喹啉磺酸
1，2，3，4-四氢异喹啉
3-[2-(3-羧基-1，2，3，4-四氢异喹啉基)]-1-丙磺酸
4-[2-(1，2，3，4-四氢异喹啉基)]-1-丁磺酸
3-[7-甲氧基-2-(1，2，3，4-四氢异喹啉基)]丙基膦酸
3-[6-甲氧基-2-(1，2，3，4-四氢异喹啉基)]丙基膦酸
3-[8-甲氧基-2-(1，2，3，4-四氢异喹啉基)]丙基膦酸
3-[2-(3-甲氧基羰基-1，2，3，4-四氢异喹啉基)]丙基膦酸
3-[6-甲氧基-2-(1，2，3，4-四氢异喹啉基)]丙基膦酸
3-[7-甲氧基-2-(1，2，3，4-四氢异喹啉基)]丙基膦酸
N-膦酰基乙酰基-6-甲氧基-1，2，3，4-四氢异喹啉
6-甲氧基-1，2，3，4-四氢异喹啉
N-磺基乙酰基-1，2，3，4-四氢异喹啉
N-乙基-1，2，3，4-四氢异喹啉
N-丙基-1，2，3，4-四氢异喹啉
N-丙基-6-甲氧基-1，2，3，4-四氢异喹啉
6-甲氧基-1，2，3，4-四氢异喹啉
7-甲氧基-1，2，3，4-四氢异喹啉
6，7-二甲氧基-1，2，3，4-四氢异喹啉
1，2，3，4-四氢异喹啉-6-腈
1，2，3，4-四氢异喹啉-7-腈
(1，2，3，4-四氢异喹啉-1-基)膦酸
7-(2，2，2-三氟乙酰基)-1，2，3，4-四氢异喹啉
7-乙酰基-1，2，3，4-四氢异喹啉
1，2，3，4-四氢异喹啉-7-甲酸
1，2，3，4-四氢异喹啉-7-甲酰胺
7-羟基甲基-1，2，3，4-四氢异喹啉
7-甲基-1，2，3，4-四氢异喹啉
7-羟基-1，2，3，4-四氢异喹啉
7-(甲磺酰基)氨基-1，2，3，4-四氢异喹啉
7-(甲磺酰基)氨基甲基-1，2，3，4-四氢异喹啉
7-硝基-1，2，3，4-四氢异喹啉
1，2，3，4-四氢异喹啉-7-磺酰胺
7-三氟甲基-1，2，3，4-四氢异喹啉
7-甲硫基-1，2，3，4-四氢异喹啉。
3.权利要求1或2的应用，其中所述与IAPP有关的淀粉样蛋白沉积物存在于胰岛中。
4.权利要求1或2的应用，用于抑制IAPP原纤维形成。
5.权利要求1或2的应用，用于抑制所述与IAPP有关的淀粉样蛋白沉积。
6.权利要求1或2的应用，用于治疗特征是与IAPP有关的淀粉样蛋白沉积的疾病。
7.权利要求1或2的应用，用于减少与IAPP有关的淀粉样蛋白沉积。
8.权利要求1或2的应用，其中所述个体患有糖尿病。
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Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040208875A1 (en) * 1995-03-15 2004-10-21 Queen's University At Kingston Method for treating amyloidosis
BR0010099A (pt) * 1999-04-28 2002-06-04 Univ Kingston Métodos para modular a agregação de amilóides em um indivìduo, para o tratamento de um estado doentio associado com amiloidose, composição para modular amiloidose, e, métodos para inibir os depósitos de amilóide associados com iapp em um indivìduo, para inibir fibrilogenese iapp em um indivìduo, para reduzir os agregados de amilóides associados com iapp em um indivìduo, para modular dano associado com amilóides em células, e para modular amiloidose in vivo ou ex vivo
US6562836B1 (en) * 1999-05-24 2003-05-13 Queen's University Of Kingston Methods and compounds for inhibiting amyloid deposits
CA2375628A1 (en) * 1999-07-09 2001-01-18 Isis Innovation Limited Compounds for inhibiting diseases and preparing cells for transplantation
BR0213139A (pt) 2001-10-04 2004-08-10 Elan Pharm Inc Composto, método de tratamento ou prevenção de doenças e de preparação de um composto, uso de um composto e composição farmacêutica
US7345068B2 (en) 2002-02-07 2008-03-18 Hitoshi Endou Aromatic amino acid derivatives and medicinal compositions
WO2004058686A1 (en) 2002-04-30 2004-07-15 Elan Pharmaceuticals, Inc. Hydroxypropyl amides for the treatment of alzheimer’s disease
EP1511710B1 (en) * 2002-05-31 2013-11-20 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer s disease, type 2 diabetes, and parkinson s disease
US20050154011A1 (en) * 2003-02-20 2005-07-14 The Procter & Gamble Company Tetrahydroisoquinolnyl sulfamic acids
US20040204383A1 (en) * 2003-04-11 2004-10-14 Gabor Tigyi Lysophosphatidic acid analogs and inhibition of neointima formation
US20070010573A1 (en) * 2003-06-23 2007-01-11 Xianqi Kong Methods and compositions for treating amyloid-related diseases
US7414076B2 (en) * 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
CN1839118B (zh) * 2003-06-23 2010-06-16 贝卢斯健康(国际）有限公司 治疗淀粉样相关疾病用的方法与组合物
US7244764B2 (en) * 2003-06-23 2007-07-17 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7253306B2 (en) * 2003-06-23 2007-08-07 Neurochem (International) Limited Pharmaceutical drug candidates and methods for preparation thereof
EP1644325A2 (en) * 2003-06-23 2006-04-12 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
AU2011250847B2 (en) * 2003-06-23 2013-06-20 Bhi Limited Partnership Methods and compositions for treating amyloid-related diseases
SI1646659T1 (sl) * 2003-06-23 2014-07-31 Kiacta Sarl Postopek za pripravo spojin 1,3-propan disulfonske kisline
WO2005079830A1 (en) * 2004-02-23 2005-09-01 Paul Fraser Inhibitors of amyloid fibril formation and uses thereof
NZ552397A (en) 2004-07-15 2011-04-29 Amr Technology Inc Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
BRPI0517790A (pt) * 2004-11-12 2008-10-21 Neurochem Int Ltd métodos e composições fluoradas para tratar doenças relacionadas à amilóide
EP1817305A2 (en) * 2004-11-16 2007-08-15 Neurochem (International) Limited Compounds for the treatment of cns and amyloid associated diseases
US8044100B2 (en) * 2004-12-22 2011-10-25 Bellus Health Inc. Methods and compositions for treating amyloid-related diseases
DE602006011299D1 (de) * 2005-04-07 2010-02-04 Astrum Therapeutics Pty Ltd Verbindungen zur behandlung von amyloidose und verhinderung des tods von beta-zellen bei diabetes mellitus typ 2
AU2006235123A1 (en) * 2005-04-07 2006-10-19 Astrum Therapeutics Pty. Ltd. Complementary compositions to reduce blood glucose levels and treat diabetes
TW200716088A (en) * 2005-04-15 2007-05-01 Neurochem Int Ltd Formulations and methods for treating amyloidosis
EP1893576A4 (en) * 2005-05-27 2010-03-17 Univ Kingston TREATMENT OF PROTEIN DISORDERING
US20070049638A1 (en) * 2005-07-21 2007-03-01 Neurochem (International) Limited Polymorphic forms of 3-amino-1-propanesulfonic acid
ES2352801T3 (es) * 2005-12-22 2011-02-23 Kiacta Sàrl Tratamiento de nefropatía diabética.
ES2891278T3 (es) 2006-10-12 2022-01-26 Bhi Lp Métodos, compuestos, composiciones y vehículos para suministrar ácido 3-amino-1-propanosulfónico
US8148398B2 (en) * 2006-12-06 2012-04-03 Cornell Research Foundation, Inc. Intermediate duration neuromuscular blocking agents and antagonists thereof
CA2673022A1 (en) * 2006-12-22 2008-07-03 Bellus Health (International) Limited Methods, compounds, and compositions for treating metabolic disorders and diabetes
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
KR101755178B1 (ko) * 2008-11-14 2017-07-06 비에이치아이 리미티드 파트너쉽 유기 영양 염, 제조 방법 및 용도
WO2010107488A1 (en) 2009-03-17 2010-09-23 Cornell University Reversible nondepolarizing neuromuscular blockade agents and methods for their use
WO2010132442A1 (en) * 2009-05-12 2010-11-18 Albany Molecular Reserch, Inc. 7-([1,2,4,]triazolo[1,5,-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydroisoquinoline and use thereof
EP2429295B1 (en) 2009-05-12 2013-12-25 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
EP2429293B1 (en) 2009-05-12 2014-10-29 Bristol-Myers Squibb Company CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF
IN2012DN00352A (zh) * 2009-06-16 2015-08-21 Bikam Pharmaceuticals Inc
CN102471248B (zh) 2009-08-10 2015-01-07 Bhi有限合伙公司 用于递送1,3-丙二磺酸的方法、化合物和组合物
US9220700B2 (en) 2009-08-19 2015-12-29 Cornell University Cysteine for physiological injection
WO2011156389A2 (en) * 2010-06-07 2011-12-15 The Regents Of The University Of California The islet amyloid polypeptide toxic oligomer is a biomarker of heart or kidney failure in type-2 diabetes mellitus
KR101905436B1 (ko) 2010-08-16 2018-10-08 코그놉틱스, 인코포레이티드 아밀로이드 단백질을 검출하기 위한 시스템 및 방법
US9095631B2 (en) 2011-05-24 2015-08-04 Universita Degli Studi Di Bari “Aldo Moro” Tetrahydroisoquinoline compounds for use in the diagnosis and treatment of neurodegenerative diseases
JP6126118B2 (ja) * 2011-11-30 2017-05-10 ビカム ファーマスーティカルス，インコーポレイテッド オプシン結合性リガンド、組成物、及び使用方法
LT3052096T (lt) * 2013-10-03 2018-04-10 Kura Oncology, Inc. Erk inhibitoriai ir jų panaudojimo būdai
US10532977B2 (en) * 2015-06-01 2020-01-14 Indiana University Research And Technology Corporation Small molecule inhibitors of protein tyrosine phosphatases and uses thereof
CA3029811A1 (en) * 2016-07-08 2018-01-11 Arizona Board Of Regents On Behalf Of The University Of Arizona Indoline derivatives and method for using and producing the same
US20230148589A1 (en) * 2020-03-31 2023-05-18 Lg Chem, Ltd. Composition for protecting islet transplantation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0236251A2 (fr) * 1986-03-05 1987-09-09 Universite Louis Pasteur (Strasbourg I) (amino-2 benzyl)-2 tétrahydro-1,2,3,4 isoquinoléines, procédés pour leur obtention et compositions pharmaceutiques les contenant
US5164295A (en) * 1991-03-06 1992-11-17 The Upjohn Company Method for identifying amyloid protein-extracellular matrix protein affinity altering compounds
WO1994022437A2 (en) * 1993-03-29 1994-10-13 Queen's University At Kingston Method for treating amyloidosis
DE4313118A1 (de) * 1993-04-22 1994-10-27 Hoechst Ag Verwendung von 1,2,3,4-Tetrahydroisochinolin-Derivaten als Antimykotika
WO1996028187A1 (en) * 1995-03-15 1996-09-19 Queen's University At Kingston Method for treating amyloidosis
WO1996037612A1 (en) * 1995-05-23 1996-11-28 Pfizer Inc. Transgenic animal models for type ii diabetes mellitus
WO1997009976A2 (en) * 1995-09-01 1997-03-20 Washington University Method of reducing neurotoxic injury with zinc chelators

Family Cites Families (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3872125A (en) 1973-03-03 1975-03-18 Sandoz Ag 3-substituted-4-aryl isoquinolines
FR2384751A1 (fr) 1977-03-23 1978-10-20 Francaise Coop Pharma Nouveaux derives de la taurine a activite neuro-musculaire renforcee
CA1140049A (en) 1977-12-22 1983-01-25 Dke J.E. Helgstran Pharmaceutical preparations from derivatives of hydroxycarbonylphosphonic acid
FR2457281A1 (fr) 1979-05-23 1980-12-19 Meram Lab Nouveaux derives de l'acide 3-aminopropanesulfonique ayant une activite membranaire renforcee
US5087618A (en) 1982-05-18 1992-02-11 University Of Florida Redox carriers for brain-specific drug delivery
US4540564A (en) 1982-05-18 1985-09-10 University Of Florida Brain-specific drug delivery
FR2529546A1 (fr) 1982-07-05 1984-01-06 Meram Lab Nouveaux sels d'amino-(et imino-)acides a, o-sulfoniques n-substitues, vecteurs cationiques de haute penetration cellulaire
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
IT1193590B (it) 1983-01-07 1988-07-08 Loris Jacopo Bononi Derivati amino-alchil-solfonici,procedimento per la loro preparazione e composizioni farmaceutiche che li contengono
US5374548A (en) 1986-05-02 1994-12-20 Genentech, Inc. Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor
MX9203291A (es) 1985-06-26 1992-08-01 Liposome Co Inc Metodo para acoplamiento de liposomas.
SE454299B (sv) * 1986-10-08 1988-04-18 Westermark P Sats innehallande polypeptid som finns i pankreasoamyloid och/eller antikroppar riktade mot polypeptiden
US5166320A (en) 1987-04-22 1992-11-24 University Of Connecticut Carrier system and method for the introduction of genes into mammalian cells
US5108921A (en) 1989-04-03 1992-04-28 Purdue Research Foundation Method for enhanced transmembrane transport of exogenous molecules
US5194654A (en) 1989-11-22 1993-03-16 Vical, Inc. Lipid derivatives of phosphonoacids for liposomal incorporation and method of use
US5463092A (en) 1989-11-22 1995-10-31 Vestar, Inc. Lipid derivatives of phosphonacids for liposomal incorporation and method of use
DE3940410A1 (de) 1989-12-04 1991-06-06 Schering Ag Neue verwendung von nmda-rezeptor-antagonisten
FR2657164B1 (fr) 1990-01-16 1992-04-03 Cit Alcatel Installation de detection de fuite a pompe holweck a prise intermediaire.
US5242932A (en) 1991-12-17 1993-09-07 The Rockefeller University Treatment of amyloidosis associated with alzheimer disease
US5385915A (en) 1990-05-16 1995-01-31 The Rockefeller University Treatment of amyloidosis associated with Alzheimer disease using modulators of protein phosphorylation
DE4021066A1 (de) 1990-07-03 1992-01-09 Hoechst Ag Langzeitprophylaxe gegen erkrankungen, die durch viren oder durch unkonventionelle viren verursacht werden
ATE231723T1 (de) 1991-02-22 2003-02-15 Howard K Shapiro Verwendung von pharmazeutischen wirkstoffen zur behandlung von krankheitssymptomen neurologischer erkrankungen und etiologisch verwandter symptomenkomplexe
IT1245907B (it) * 1991-05-17 1994-10-25 Alfa Wassermann Spa Uso dei glicosaminoglicani nel trattamento della nefropatia diabetica e della neuropatia diabetica.
US5276059A (en) 1992-07-10 1994-01-04 The United States Of America As Represented By The Department Of Health And Human Services Inhibition of diseases associated with amyloid formation
EP0611966A1 (en) * 1993-02-19 1994-08-24 Bayer Corporation Method, composition and device for measuring the ionic strength or specific gravity of a test sample
US5643562A (en) 1993-03-29 1997-07-01 Queen's University Of Kingston Method for treating amyloidosis
US5972328A (en) * 1993-03-29 1999-10-26 Queen's University At Kingston Method for treating amyloidosis
WO1994027602A1 (en) 1993-06-01 1994-12-08 Cortex Pharmaceuticals, Inc. Use of metabotropic receptor agonists in progressive neurodegenerative deseases
US5576419A (en) * 1993-06-30 1996-11-19 Regents Of The University Of Minnesota Mild solid-phase synthesis of aligned branched triple-helical peptides
AU7642494A (en) 1993-08-31 1995-03-22 Gliatech Inc. Inhibition of beta amyloid binding to glycosaminoglycans for treatment of alzheimer's disease
US5858326A (en) * 1995-06-06 1999-01-12 Neurochem, Inc. Methods of increasing amyloid deposition
CA2242851A1 (en) 1995-08-17 1997-02-27 The Ontario Cancer Institute Protein fibril assembly assay
JPH0995444A (ja) * 1995-10-02 1997-04-08 Teijin Ltd アミロイド蛋白凝集阻害剤
US5972956A (en) 1995-11-02 1999-10-26 Warner-Lambert Company Inhibition of amyloidosis by 9-acridinones
AU703540B2 (en) 1996-03-26 1999-03-25 Meddiss, Incorporated Methods for inducing analgesia or anesthesia and treating or preventing ischemic injury of tissues in general
US6043283A (en) 1996-09-20 2000-03-28 Baylor College Of Medicine Tyramine compounds and their neuronal effects
US5927328A (en) * 1996-09-26 1999-07-27 Masco Corporation Self closing faucet with timing mechanism
WO1998013046A1 (en) 1996-09-27 1998-04-02 Guilford Pharmaceuticals Inc. Naaladase compositions and methods for treating glutamate abnormality and effecting neuronal activity in animals
SE9604582D0 (sv) 1996-12-13 1996-12-13 Astra Ab Novel compounds
US5869469A (en) 1997-08-18 1999-02-09 Queen's University At Kingston Phosphonocarboxylate compounds for treating amyloidosis
WO1999008685A1 (en) * 1997-08-18 1999-02-25 Queen's University At Kingston Phosphono-carboxylate compounds for treating amyloidosis
ATE241365T1 (de) * 1997-08-28 2003-06-15 Univ Washington Saccharid-enthaltende zubereitungen zur behandlung von alzheimerschen erkrankung und von weiteren amyloidosen
US5952389A (en) 1998-01-13 1999-09-14 Synchroneuron Methods of treating tardive dyskinesia and other movement disorders
US6166320A (en) * 1998-03-19 2000-12-26 Toyota Jidosha Kabushiki Kaisha Tandem solar cell
US6310073B1 (en) 1998-07-28 2001-10-30 Queen's University At Kingston Methods and compositions to treat glycosaminoglycan-associated molecular interactions
WO2000057707A1 (en) 1999-03-15 2000-10-05 Proteotech, Inc. Methods of treating alzheimer's disease and other amyloidoses using hypericum perforatum and derivatives thereof
BR0010099A (pt) 1999-04-28 2002-06-04 Univ Kingston Métodos para modular a agregação de amilóides em um indivìduo, para o tratamento de um estado doentio associado com amiloidose, composição para modular amiloidose, e, métodos para inibir os depósitos de amilóide associados com iapp em um indivìduo, para inibir fibrilogenese iapp em um indivìduo, para reduzir os agregados de amilóides associados com iapp em um indivìduo, para modular dano associado com amilóides em células, e para modular amiloidose in vivo ou ex vivo
US6562836B1 (en) * 1999-05-24 2003-05-13 Queen's University Of Kingston Methods and compounds for inhibiting amyloid deposits
CA2375628A1 (en) 1999-07-09 2001-01-18 Isis Innovation Limited Compounds for inhibiting diseases and preparing cells for transplantation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0236251A2 (fr) * 1986-03-05 1987-09-09 Universite Louis Pasteur (Strasbourg I) (amino-2 benzyl)-2 tétrahydro-1,2,3,4 isoquinoléines, procédés pour leur obtention et compositions pharmaceutiques les contenant
US5164295A (en) * 1991-03-06 1992-11-17 The Upjohn Company Method for identifying amyloid protein-extracellular matrix protein affinity altering compounds
WO1994022437A2 (en) * 1993-03-29 1994-10-13 Queen's University At Kingston Method for treating amyloidosis
DE4313118A1 (de) * 1993-04-22 1994-10-27 Hoechst Ag Verwendung von 1,2,3,4-Tetrahydroisochinolin-Derivaten als Antimykotika
WO1996028187A1 (en) * 1995-03-15 1996-09-19 Queen's University At Kingston Method for treating amyloidosis
WO1996037612A1 (en) * 1995-05-23 1996-11-28 Pfizer Inc. Transgenic animal models for type ii diabetes mellitus
WO1997009976A2 (en) * 1995-09-01 1997-03-20 Washington University Method of reducing neurotoxic injury with zinc chelators

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CA2373093C (en) 2010-01-19
CA2684016A1 (en) 2000-11-30
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US7393875B2 (en) 2008-07-01
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US7786174B2 (en) 2010-08-31
ATE466571T1 (de) 2010-05-15
US20080227767A1 (en) 2008-09-18
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