CN103804298A - 一类治疗青光眼的化合物及其用途 - Google Patents

一类治疗青光眼的化合物及其用途 Download PDF

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CN103804298A
CN103804298A CN201210457127.7A CN201210457127A CN103804298A CN 103804298 A CN103804298 A CN 103804298A CN 201210457127 A CN201210457127 A CN 201210457127A CN 103804298 A CN103804298 A CN 103804298A
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韩冰
徐文阁
武昕
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    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract

本发明公开了一类化合物及其药物组合物和新用途，所述新用途为治疗青光眼的药物中的用途。上述化合物治疗青光眼的作用效果非常显著。

Description

一类治疗青光眼的化合物及其用途
技术领域
本发明涉及一类治疗青光眼的化合物及其可药用盐和其类似物，由上述化合物及其可药用盐和其类似物制备的药物组合物，以及所述化合物或其可药用盐及其类似物在制备治疗青光眼的药物中的用途。
背景技术
青光眼是一种危害全世界人类健康的眼部疾病，所谓“青光”眼之名称，系自古罹患此病者以光线照射可见瞳孔有青色的反光而得名。主要分为原发性青光眼、继发性青光眼、先天性青光眼，患有此病症的患者主要表现为眼内压力(IOP)的增高。由于青光眼会导致不可逆性的视觉损失，因此世界卫生组织将其列为重大的致盲眼病。
目前科学界对于青光眼的发病原因尚无定论，公认为由多种原因造成，先天性青光眼主要由于遗传等因素，继发性青光眼主要由于糖尿病、血压不正常等诸多因素引起，由于产生原因不明，因此治疗的手段非常有限。手术手段痛苦较大且易复发，目前临床治疗上除去比较急性的青光眼病症运用小梁切除术外，大多数青光眼病症以药物治疗为主，临床上在治疗青光眼的药物主要有β受体阻断剂、前列腺素类似物、受体激动剂和一些中药等，但是这些药物的效果并不十分理想。由于患者群体很大且危害很大，青光眼已成为社会性的问题，亟需一种有效的药物进行治疗。
本发明人意外地发现一组化合物及其类似化合物或其可药用盐在制备治疗青光眼的药物上有意想不到的效果，目前对于这一类化合物治疗青光眼尚无报道。
发明内容
本发明提供了一组化合物及其类似化合物或其可药用盐在制备治疗青光眼的药物中的新用途。
本发明的技术方案如下：
本发明提供了一组可以治疗青光眼疾病的化合物或其可药用盐，及其类似物，所述化合物的结构如下：
Figure BSA00000805715200021
化合物(A)；
化合物(B)；
Figure BSA00000805715200023
化合物(C)；
Figure BSA00000805715200031
化合物(D)；
Figure BSA00000805715200032
化合物(E)。
上式化合物及其类似物或其可药用盐可以制备成经局部给药，胃肠道给药或是非胃肠道给药的各种制剂。所述制剂包括普通制剂、控释制剂、靶向制剂等。所述的局部给药制剂为经过眼部给药的粉针剂、水针剂、微球制剂、纳米制剂、脂质体制剂、树枝状高分子制剂、聚乙二醇修饰制剂、水凝胶制剂等。所述的非胃肠道给药制剂为适宜静脉注射、肌肉注射、皮下注射、骨髓注射、透皮给药、粘膜给药以及吸入给药的剂型。
本发明人研究发现此类化合物可极大地缓解青光眼症状，从药效学实验的结果看，此类化合物的效果超出目前临床应用的药物。此新化合物的开发将对青光眼的群体的恢复起到很大作用，对于解除病患和其家庭的痛苦具有重大的意义。
具体实施方式
本发明所用的化合物可以商购，也可以根据公开的制备方法进行制备，其并不限制本发明的治疗范围。
药物制备实施例
化合物(A)；
Figure BSA00000805715200042
化合物(B)；
Figure BSA00000805715200043
化合物(C)；
Figure BSA00000805715200051
化合物(D)；
Figure BSA00000805715200052
化合物(E)。
含化合物A针剂的制备：
①取甘露醇、磷脂、甘油、环糊精衍生物、二甲基亚砜和泊洛沙姆共50mg和100mg式(A)化合物在注射用水中混合并使之溶解；
②混匀溶解后待稳定后先用0.45um微孔滤膜粗滤，再用0.2um微孔滤膜过滤；
③分装入小西林瓶，加入其他冻干治疗剂和辅料；
④进行程序性冻干；
⑤进行热原、无菌、可见异物、不溶性微粒等相应检查，均符合要求后待用。
含化合物B针剂的制备：
①取甘露醇、磷脂、甘油、环糊精衍生物、二甲基亚砜和泊洛沙姆共50mg和1500mg式(B)化合物在注射用水中混合并使之溶解；
②混匀溶解后待稳定后先用0.45um微孔滤膜粗滤，再用0.2um微孔滤膜过滤；
③分装入小西林瓶，加入其他冻干治疗剂和辅料；
④进行程序性冻干；
⑤进行热原、无菌、可见异物、不溶性微粒等相应检查，均符合要求后待用。
含化合物C针剂的制备：
①取甘露醇、磷脂、甘油、环糊精衍生物、二甲基亚砜和泊洛沙姆共50mg和50mg式(C)化合物在注射用水中混合并使之溶解；
②混匀溶解后待稳定后先用0.45um微孔滤膜粗滤，再用0.2um微孔滤膜过滤；
③分装入小西林瓶，加入其他冻干治疗剂和辅料；
④进行程序性冻干；
⑤进行热原、无菌、可见异物、不溶性微粒等相应检查，均符合要求后待用。
含化合物D针剂的制备：
①取甘露醇、磷脂、甘油、坏糊精衍生物、二甲基亚砜和泊洛沙姆共50mg和2mg式(D)化合物在注射用水中混合并使之溶解；
②混匀溶解后待稳定后先用0.45um微孔滤膜粗滤，再用0.2um微孔滤膜过滤；
③分装入小西林瓶，加入其他冻干治疗剂和辅料；
④进行程序性冻干；
⑥进行热原、无菌、可见异物、不溶性微粒等相应检查，均符合要求后待用。
含化合物E针剂的制备：
①取甘露醇、磷脂、甘油、环糊精衍生物、二甲基亚砜和泊洛沙姆共50mg和500mg式(E)化合物在注射用水中混合并使之溶解；
②混匀溶解后待稳定后先用0.45um微孔滤膜粗滤，再用0.2um微孔滤膜过滤；
③分装入小西林瓶，加入其他冻干治疗剂和辅料；
④进行程序性冻干；
⑤进行热原、无菌、可见异物、不溶性微粒等相应检查，均符合要求后待用。
效果实施例
化合物(A-E)对大鼠闭角型青光眼的治疗实验
1.1实验动物及分组
实验采用成年雄性Wistar大鼠，体重220g左右。造模前，将动物随机分组：即空白对照组；模型组；化合物(A-E)组，每隔5天眼内注射给药一次，给药量0.1mg针剂/kg；阳性药组选择毛果芸香碱滴眼液，每天给药一次，一次一滴。所有给药持续15天。
1.2动物模型的建立
实验前腹腔注射大鼠4％水合氯醛(200mg.kg-1)，然后用1％的利多卡因局部麻醉大鼠角膜。高眼内压期间，保持每隔半小时腹腔注射4％水合氯醛0.2毫升使动物持续麻醉的状态。采用滑轮-缝线系统使大鼠右眼眼内压升高，同时左侧眼球做对照。将外科缝线两端各系一相同重的砝码，缝线中间系住一个圆圈用于环绕大鼠眼角巩膜缘后2毫米，两端的砝码通过滑轮对大鼠眼睛持续稳定施压。砝码施压为20克，持续压力6小时，造成大鼠闭角型青光眼模型。给药后饲养至第15天测定鼠眼压并记录。
1.3实验结果
实验结果见表1
表1各组给药治疗下的青光眼大鼠的眼压结果(mmHg，n＝10)
Figure BSA00000805715200071
与模型组比较*P＜0.05**P＜0.01
化合物(A-E)对兔开角型青光眼的治疗实验
2.1实验动物及分组
健康普通级青紫兰兔，雌雄各半，体重2.3kg左右，裂隙灯显微镜检查无眼前节病变。未造模前，随机选取实验兔20只，分别于每日多时间点测量兔双眼眼压并记录。连续观察一周后，以确定本组实验兔正常眼压范围。造模1周后，将模型动物随机分组：将动物随机分组：即空白对照组；模型组；化合物(A-E)组，每隔5天给药一次，每只兔眼内针剂给药0.5mg针剂；阳性药组选择选择三甲醋心安滴眼液，每天给药一次。所有给药持续15天。
2.2动物模型的建立
每组10只兔右眼角膜缘12点位前房穿刺，抽出房水0.2毫升。0.3％卡波姆和0.025％地塞米松0.2毫升经穿刺口注射至前房，左眼为对照眼，造模一周后开始给药。
2.3测量眼压
动物给药后，用眼压计测量给药后第15天眼内压并记录。
2.4实验结果
兔造模后眼压升高，各个药物治疗组的眼压均升高，显示造模型成功。给药后，各个药物组对眼内压升高均有抑制作用，其中化合物(A-E)组效果最为明显，且药物(A-E)组治疗效果均强于阳性药物组。
表2各组给药治疗下的兔眼压结果(n＝10)
Figure BSA00000805715200081
与模型组比较*P＜0.05**P＜0.01
综合上述实验结果得出结论：化合物(A)，(B)，(C)，(D)，(E)制备的药物均起到较好的治疗青光眼的作用。

Claims (6)

1.一类化合物或其可药用盐，及其类似物，所述化合物的结构如下：
Figure FSA00000805715100011
化合物(A)；
Figure FSA00000805715100012
化合物(B)；
Figure FSA00000805715100013
化合物(C)； 
Figure FSA00000805715100021
化合物(D)；
Figure FSA00000805715100022
化合物(E)。
2.一种药物组合物，其包括权利要求1所述的化合物及其可药用盐和其类似物。
3.权利要求2的药物组合物，其可以是普通制剂、控释制剂、靶向制剂等。
4.权利要求2的药物组合物，所述化合物及其可药用盐和其类似物制备成经局部给药，胃肠道给药或是非胃肠道给药的各种制剂。
5.权利要求4所述局部给药，为眼部给药的各种制剂。
6.权利要求2所述化合物及其可药用盐和其类似物在制备治疗青光眼的药物中的用途。 
CN201210457127.7A 2012-11-09 2012-11-09 一类治疗青光眼的化合物及其用途 Pending CN103804298A (zh)

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Publication number Priority date Publication date Assignee Title
WO2005012258A1 (ja) * 2003-07-30 2005-02-10 Kyowa Hakko Kogyo Co., Ltd. タンパク質キナーゼ阻害剤
WO2005030140A2 (en) * 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use
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Application publication date: 20140521