CN103251601A - 羧胺三唑(cai)乳清酸盐在黄斑变性中的用途 - Google Patents

羧胺三唑(cai)乳清酸盐在黄斑变性中的用途 Download PDF

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CN103251601A
CN103251601A CN2013100054685A CN201310005468A CN103251601A CN 103251601 A CN103251601 A CN 103251601A CN 2013100054685 A CN2013100054685 A CN 2013100054685A CN 201310005468 A CN201310005468 A CN 201310005468A CN 103251601 A CN103251601 A CN 103251601A
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拉希达.A.卡马利
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Abstract

本文涉及羧胺三唑(CAI)乳清酸盐在黄斑变性中的用途。本文涉及用于治疗与年龄相关的黄斑变性和其他血管生成依赖的疾病的方法和羧胺三唑乳清酸盐组合物。

Description

羧胺三唑(CAI)乳清酸盐在黄斑变性中的用途
此案是申请日为2007年12月5日、申请号为200780045466.1、发明名称为“羧胺三唑(CAI)乳清酸盐在黄斑变性中的用途”的发明申请的分案申请。
技术领域
本发明涉及通过给药血管生成抑制剂羧胺三唑(carboxyamidotriazole)或5-氨基-1,2,3-三唑乳清酸盐（CAI乳清酸盐）而治疗与年龄相关的黄斑变性。本发明还涉及治疗血管生成依赖的疾病(angiogenesis-dependent disease)的组合物和方法。
发明背景
在美国和其他国家中，与年龄相关的黄斑变性(macular degeneration)是导致50岁以上人群失明的主要原因。已知两种类型的与年龄相关的黄斑变性：1)新生血管性(neovascular)，也被称为渗出性与年龄相关的黄斑变性，及2)非新生血管性(nonneovascular)，也被称为非渗出性与年龄相关的黄斑变性。新生血管性黄斑变性涉及血管生成。本文所使用的术语“血管生成(angiogenesis)”是指在组织或器官中的新的血管的生成。动物(包括人)在正常的生理条件下，只有在例如伤口愈合、胎儿及胚胎发育和黄体、子宫内膜、胎盘形成的非常特殊的情况下才会有血管生成。血管生成的控制是血管生成促进和抑制的高度有序的系统。已发现在某些病症中对血管生成的控制发生了改变，在许多情况下，与这些疾病有关的病理损伤与失控的血管生成有关。
由血管生成介导的疾病的一个实例是眼部新生血管性疾病。此疾病的特征在于新生血管侵袭例如视网膜或角膜的眼部结构。这是导致失明的最常见的原因，并涉及20多种眼部疾病。在高龄相关的黄斑变性中，相关的视觉疾病由脉络膜毛细血管向内生长通过Bruch膜上的缺陷所引起，并伴随着在视网膜色素上皮细胞下的微管组织的增殖。血管生成损伤也与糖尿病性视网膜症、早产儿视网膜症、角膜移植排斥反应、新生血管性青光眼和晶状体后纤维组织增生症有关。与角膜新生血管形成相关的其他疾病包括但不局限于：病毒性角(膜)结膜炎、维生素A缺乏、隐形眼镜超戴症、特硬性角膜炎、上方角膜缘角结膜炎、翼状胬肉干燥性角膜炎(pterygium keratitis sicca)、干燥症、红斑痤疮、水泡(phylectenulosis)、梅毒、分支杆菌感染、脂质变性、化学品灼伤、细菌性溃疡、真菌性溃疡、单纯疱疹感染、带状疱疹感染、原虫感染、卡波西肉瘤(Kaposi sarcoma)、蚕食性角膜溃疡、Terrien角膜边缘变性、边缘角质层分离（mariginal keratolysis）、类风湿性关节炎、全身性红斑狼疮、多动脉炎、创伤、Wegener结节症、巩膜炎、Steven′s Johnson症、类天疱疮放射状角膜切除(periphigoid radial keratotomy)及角膜移植排斥反应。
与视网膜/脉络膜新生血管有关的疾病包括但不局限于：糖尿病性视网膜症、黄斑变性、镰状细胞贫血、结节症、梅毒、弹性假黄色瘤、乳头乳晕湿疹样癌、静脉阻塞、动脉阻塞、颈动脉阻塞疾病、慢性葡萄膜炎/玻璃体炎、分枝杆菌感染、Lyrne′s疾病、系统性红斑狼疮、早产儿视网膜病变、视网膜静脉周围炎(Eales disease)、贝切特病(Bechets disease)、引起视网膜炎或脉络膜炎的感染、眼拟组织胞浆菌病、先天性黄斑变性(Bests disease)、近视、视窝(optic pits)、隐性(遗传性)黄斑营养不良(Stargarts disease)、扁平部睫状体炎、慢性视网膜剥离、高粘滞综合征、弓形虫病、创伤和激光治疗后并发症。其他疾病包括但不局限于与潮红（新生血管形成的角度）有关的疾病和由微管或纤维组织不正常的增殖（包括所有形式的增生性玻璃体视网膜病变）所引起的疾病。
另一种涉及血管生成的疾病是类风湿性关节炎(rheumatoid arthritis)。在关节滑膜衬里中的血管发生了血管生成。除了形成血管网外，内皮细胞还释放可导致血管翳生成和软骨组织破坏的因子和反应性氧。涉及血管生成的因子可导致和有助于维持慢性类风湿性关节炎的炎症状态。
与血管生成有关的因子在骨关节炎(osteoarthritis)中也具有作用。通过血管生成相关的因子活化软骨细胞可导致关节的损伤。在晚期阶段，血管生成因子将导致新骨的形成。防止骨损伤的治疗性干预可阻止疾病的进程，并缓解关节炎患者的症状。
慢性炎症也涉及病理性血管生成。此类病症例如溃疡性结肠炎和节段性回肠炎，其新血管表现出向炎症组织内生长的组织学变化。巴尔通体病是一种发现于南美洲的细菌感染疾病，其可导致一种特征在于血管内皮细胞增殖的慢性状态。与血管生成有关的另一类病理性作用是动脉粥样硬化。在血管腔内形成的斑块已显示出具有促进血管生成的活性。
因此，需要新的能抑制血管生成和治疗血管生成依赖的疾病的方法和组合物。
羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐（CAI乳清酸盐）基于其抗血管生成、抗增殖、抗转移作用而用作抗肿瘤剂，正处于临床研发阶段（Kohn等，Cancer Res 52:3208-3212,(1992)；Bauu等，J.Pharm Exp Ther 292:31-37(2000)及Purow等，Cancer Investigation 22:577-587,(2004)）。在于1999年1月19日公布的美国专利第5,861,406号案和于1999年7月15日公布的美国专利第5,912,346号案中，说明了以氨基咪唑甲酰胺和CAI三唑的盐治疗和预防肿瘤。具体地，在Dunning大鼠前列腺癌模型中，发现CAI的乳清酸盐与CAI相比具有改善的抗肿瘤活性。CAI乳清酸盐的抗肿瘤活性的增强的机理并没有得到说明，但是据估计与肝中环核苷酸的活性改变有关。
发明概述
本发明涉及血管生成抑制剂羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐及其使用方法。具体地，此抑制剂具有强的抗黄斑变性活性(anti-maculardegeneration activity)。
本发明提供了通过给予足以抑制血管生成的剂量的包含羧胺三唑或5-氨基1,2,3-三唑乳清酸盐（CAI乳清酸盐）的组合物至患有不期望的血管生成的动物或人，治疗由不期望和不可控制的血管生成介导的疾病和过程(processes)的方法和组合物。具体地本发明用于治疗或抑制黄斑变性。
本发明涉及以下内容：
(1).治疗个体黄斑变性的方法，其包括：向个体给予黄斑变性抑制量的羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐。
(2).羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐抑制血管生成的方法，其中该血管生成引起血管生成依赖性疾病。
(3).(2)的方法，其中血管生成依赖性疾病是眼部新生血管疾病、糖尿病性视网膜症、早产儿视网膜症、角膜移植排斥反应、新生血管性青光眼、晶状体后纤维组织增生症、潮红、实体瘤、血生肿瘤、白血病、肿瘤转移、良性肿瘤、听神经瘤、神经纤维瘤、沙眼、及化脓性肉芽肿、类风湿性关节炎、牛皮癣、Osler-Webber症、心肌血管生成、斑块新生血管形成、毛细血管扩张、血友病患者关节炎、血管纤维瘤、创面肉芽形成。
(4).(1)的方法，其中有效、安全形式和剂量的羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐以口服给药。
(5).(2)的方法，其中有效、安全形式和剂量的羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐以口服给药。
附图简述
图1说明了内皮细胞(HUVEC)增殖实验结果
发明详述
本发明涉及羧胺三唑或5-氨基1,2,3-三唑乳清酸盐（CAI乳清酸盐），及当将其在体外加入正在增殖的内皮细胞中而抑制内皮细胞增殖的能力。本发明CAI乳清酸盐可用于治疗血管生成相关的疾病，尤其是黄斑变性及血管生成依赖的疾病。
血管生成相关的疾病可使用本发明抑制内皮细胞增殖化合物来诊断和治疗。血管生成相关的疾病包括但不局限于：眼部血管生成疾病(ocularangiogenic disease)，例如,糖尿病性视网膜症(diabetic retinopathy)、早产儿视网膜症(retinopathy of rematurity)、黄斑变性、角膜移植排斥反应(corneal graftrejection)、新生血管性青光眼(neovascular glaucoma)、晶状体后纤维组织增生症(retrolental fibroplasias)、潮红(rubeosis)；血管生成依赖的癌症，包括例如实体瘤、血生肿瘤（blood born tumors，例如白血病）、及肿瘤转移；良性肿瘤，例如血管瘤、听神经瘤、神经纤维瘤、沙眼、及化脓性肉芽肿；类风湿性关节炎；牛皮癣；Osler-Webber症；心肌血管生成(myocardialangiogenesis)；斑块内新生血管生成(plaque neovascularization)；毛细血管扩张(telangiectasia)；血友病患者的关节炎(hemophiliac joints)；血管纤维瘤(angiofibroma)；及创面肉芽形成(wound granulation)。本发明抑制内皮细胞增殖的蛋白也可用于治疗过量或不正常的刺激内皮细胞而导致的疾病。这些疾病包括但不局限于肠粘连、动脉粥样硬化、硬皮症、增生性瘢痕（即瘢痕疙瘩）。其也可用于治疗作为例如猫爪病（Rochele minalia quintosa）和溃疡（幽门螺杆菌）病理结果的血管生成的疾病。
实施例
实施例1
使用在美国专利第5,861,406号案中说明的方法制备羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐（CAI乳清酸盐）。CAI乳清酸盐的分子量是581。
实施例2
羧胺三唑乳清酸盐对血管生成的抑制
以三种不同浓度的羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐（CAI乳清酸盐）处理人脐静脉内皮细胞(HUVEC)3天。计量在不同处理条件下的每一培养物的细胞数量。该实验进行了三次，并且数据以平均＋/-标准偏差表示。羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐（CAI乳清酸盐）以剂量相关的方式抑制血管生成（图1）。
本发明不受限于在意图说明本发明一方面的实施例中公开的实施方案的范围，及功能相同的任何方法也在本发明范围之内。事实上，除了本文说明和展示的改变外，通过前述说明，本发明的各种改变对本领域技术人员而言将是显而易见的。这些改变将落在权利要求的范围之内。
本领域技术人员可使用本文说明的常规的实验、本发明的具体的实施方案的任何等价物而认识或能确认。所述等价物将包含在权利要求之内。

Claims (4)

1.羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐在制备给药于个体有效量的组合物来抑制黄斑变性中的用途。
2.权利要求1的用途，其中有效剂量的羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐以口服或局部给药。
3.权利要求2的用途，其中有效和安全剂量的羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐以口服或局部给药。
4.羧胺三唑或5-氨基-1,2,3-三唑乳清酸盐在制备给药于个体有效量的组合物来抑制血管生成中的用途，其中血管生成是选自下列疾病的治疗中的靶标：眼部新生血管疾病、糖尿病性视网膜症、早产儿视网膜症、角膜移植排斥反应、新生血管性青光眼、晶状体后纤维组织增生症、潮红、心肌血管生成、斑块新生血管形成、毛细血管扩张、血友病患者关节炎、血管纤维瘤、创面肉芽形成。
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