CN1711107A - 由 Rho 激酶抑制剂和β阻断剂构成的青光眼治疗剂 - Google Patents

由 Rho 激酶抑制剂和β阻断剂构成的青光眼治疗剂 Download PDF

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CN1711107A
CN1711107A CNA2003801034679A CN200380103467A CN1711107A CN 1711107 A CN1711107 A CN 1711107A CN A2003801034679 A CNA2003801034679 A CN A2003801034679A CN 200380103467 A CN200380103467 A CN 200380103467A CN 1711107 A CN1711107 A CN 1711107A
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叶野正和
中岛正
松木雄
原英彰
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Abstract

本发明目的是提供一种具有新型作用机制的由Rho激酶抑制剂和β阻断剂组合得到的青光眼治疗剂。通过将Rho激酶抑制剂和β阻断剂组合可以使其各自的降低眼压的作用相互补充及/或增强。给药方式可以为并用给药，也可以制成合剂给药。

Description

由Rho激酶抑制剂和β阻断剂构成的青光眼治疗剂
技术领域
本发明涉及由Rho激酶抑制剂和β阻断剂组合构成的青光眼治疗剂。
背景技术
青光眼是一种由各种病因引起眼压升高、眼球内部组织(视网膜、视神经等)受到损害而导致的有致盲危险性的难治性眼科疾病。青光眼的治疗方法一般为降低眼压疗法，代表性的疗法有药物疗法、激光疗法、手术疗法等。
药物疗法中使用交感神经激动剂(肾上腺素等非选择性激动剂、阿可乐定(apraclonidine)等α2激动剂)、交感神经阻断剂(噻吗洛尔、苯呋洛尔、卡替洛尔(Carteolol)、尼普地洛(Nipradilol)、倍他索洛尔(Betaxolol)、左布诺洛尔(Levobunolol)或美替洛尔(Metipranolol)等β阻断剂、盐酸布那唑嗪等α1阻断剂)、副交感神经兴奋剂(匹鲁卡品等)、碳酸酐酶抑制剂(乙酰唑胺等)、前列腺素类(乌诺前列酮异丙酯、拉坦前列素、曲伏前列素、比马前列胺)等药物。
最近，作为基于新型作用机理的青光眼治疗药开发了Rho激酶抑制剂(国际公开WO00/09162号)。IOVS， 42(1)，137-144(2001)公开了Rho激酶抑制剂通过促进经由小梁网的房水流出以降低眼压，IOVS， 42(1)，137-144(2001)、IOVS， 42(5)，1029-1037(2001)中进一步公开了其作用机理为小梁细胞的细胞骨架的变化。
此前研究并报道了将具有降低眼压作用的药物相互组合使用以治疗青光眼。例如，日本专利2726672号公报报道了将交感神经阻断剂和前列腺素类物质组合进行给药的方法。另外，国际公开WO 02/38158号公开了将具有降低眼压作用的几种药物组合对眼睛给药以治疗青光眼的方法。
但是，所有报道都没有关于Rho激酶抑制剂的记载，当然也没有关于其与β阻断剂合用效果的记载。
如上所述，目前为止，完全没有关于将Rho激酶抑制剂与β阻断剂组合时的青光眼治疗效果的研究和报道。
发明内容
研究Rho激酶抑制剂和β阻断剂组合制成的青光眼治疗剂的效用是一个非常有趣的课题。
本发明人等深入地研究了将Rho激酶抑制剂和β阻断剂组合产生的效果，结果发现，将上述药物组合使用与各药物单独使用时相比，眼压降低作用有所增强及/或作用的持续性有所提高，从而完成了本发明。详细的试验方法和结果在后述的药理试验各项中进行说明，可以看出通过将Rho激酶抑制剂和β阻断剂相互组合，可以使眼压降低作用显著增强及/或作用的持续性显著提高。本发明可适用于治疗或预防伴随眼压升高的眼疾患。
通过将Rho激酶抑制剂和β阻断剂组合，对眼部进行给药，使眼压降低作用增强及/或其作用的持续性得以提高。因此，本发明为有效的青光眼治疗剂。
本发明为由Rho激酶抑制剂和β阻断剂的组合制成的青光眼治疗剂，其作用可以相互补充及/或增强。
给药方式可以为Rho激酶抑制剂和β阻断剂以各自的制剂形式给药，即合并给药；也可以将它们制成1种制剂给药、即以合剂的形式给药。
本发明中所述的Rho激酶抑制剂和β阻断剂也包括盐的形态。上述化合物含有氨基等碱性基团时，也可以与盐酸、硝酸等无机酸成盐，或者与草酸、琥珀酸、醋酸、马来酸等有机酸成盐；含有羧基等酸性基团时，也可以与钠、钾等碱金属成盐，或与钙等碱土类金属成盐。
另外，本发明中所述的Rho激酶抑制剂和β阻断剂也包括酯类等衍生物。酯类具体可以举出例如甲基酯、乙基酯、异丙基酯等烷基酯。
另外，本发明中的Rho激酶抑制剂和β阻断剂也可以水合物或溶剂合物的形态进行使用。
本发明的特征为将Rho激酶抑制剂和β阻断剂组合使用以治疗青光眼。
本发明中所述的Rho激酶抑制剂是指阻断随着Rho活化而被活化的丝氨酸/苏氨酸激酶的化合物。例如可以举出阻断ROKα(ROCK-II)、p160ROCK(ROKβ、ROCK-I)及其它具有丝氨酸/苏氨酸激酶活性的蛋白质的化合物。Rho激酶抑制剂具体可以举出WO 98/06433、WO 00/09162中公开的(R)-反式-N-(吡啶-4-基)-4-(1-氨基乙基)环己烷羧酰胺、(R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺等Rho激酶抑制剂；或者WO 97/23222、Nature，389，990-994(1997)中公开的1-(5-异喹啉磺酰基)高哌嗪、1-(5-异喹啉磺酰基)-2-甲基哌嗪等Rho激酶抑制剂；WO 01/56988中公开的(1-苄基吡咯烷-3-基)-(1H-吲唑-5-基)胺等Rho激酶抑制剂；WO 02/100833中公开的(1-苄基哌啶-4-基)-(1H-吲唑-5-基)胺等Rho激酶抑制剂；WO 02/076976中公开的N-[2-(4-氟苯基)-6，7-二甲氧基-4-喹唑啉基]-N-(1H-吲唑-5-基)胺等Rho激酶抑制剂；WO 02/076977中公开的N-4-(1H-吲唑-5-基)-6，7-二甲氧基-N-2-吡啶-4-基-喹唑啉-2，4-二胺等Rho激酶抑制剂；WO 99/64011中公开的4-甲基-5-(2-甲基-[1，4]苯甲二氮卓-1-磺酰基)异喹啉等Rho激酶抑制剂。
另一方面，β阻断剂只要是具有降低眼压的作用并对治疗青光眼有效的β阻断剂即可，作为具有降低眼压作用的β阻断剂的具体例，优选使用已作为青光眼治疗剂出售的噻吗洛尔、苯呋洛尔、卡替洛尔、尼普地洛、倍他索洛尔、左布诺洛尔或美替洛尔(Metipranolol)。
本发明中所述的青光眼有原发性开角型青光眼、正常眼压青光眼、房水分泌过多性青光眼、高眼压症、急性闭角型青光眼、慢性闭角型青光眼、混合型青光眼、类固醇性青光眼、淀粉样变性(amyloid)青光眼、新生血管性青光眼、恶性青光眼、晶状体的囊性青光眼、虹膜高褶型青光眼(plateau-iris syndrome)等。
作为实施本发明的制剂，可以是将Rho激酶抑制剂和β阻断剂各自进行配方的2种制剂，也可以为配合了各成分制成的1种制剂。上述制剂化不需要特殊的技术，可以利用广泛采用的技术进行制剂化。给药方式优选眼局部给药，剂型优选滴眼剂或眼软膏。
将Rho激酶抑制剂和β阻断剂分别进行制剂化时，可以依照各种公知的方法进行配制。例如Rho激酶抑制剂的制剂可以参照上述国际公开专利公报(WO 00/09162、WO 97/23222)中记载的制剂例进行配制。β阻断剂的制剂可以使用已作为青光眼治疗剂出售的噻吗洛尔、苯呋洛尔、卡替洛尔、尼普地洛、倍他索洛尔、左布诺洛尔或美替洛尔(Metipranolo)等制剂或符合其标准的产品。
Rho激酶抑制剂和β阻断剂二者配合的制剂也可以按照公知的方法进行配制。例如滴眼剂，可以根据需要使用氯化钠、浓甘油等等渗剂；磷酸钠、醋酸钠等缓冲剂；聚氧乙烯脱水山梨醇单油酸酯、硬脂酸聚烃氧40酯、聚氧乙烯硬化蓖麻油等表面活性剂；枸橼酸钠、乙二胺四乙酸钠等稳定剂；苯扎氯铵、对羟基苯甲酸酯等防腐剂等进行配制。
pH只要在眼科制剂所允许的范围内即可，优选pH在4～8的范围内。在后述的实施例项中记载了一部分制剂例作为参考，但本发明的范围并不限于后述制剂例。
本发明涉及一种组合使用Rho激酶抑制剂及β阻断剂、并给予患者有效剂量的药物的青光眼治疗方法。通过组合使用Rho激酶抑制剂及β阻断剂、并给予患者有效剂量的药物，可以使二者的作用得到互相补充及/或增强。本治疗方法优选使用的Rho激酶抑制剂为(R)-反式-N-(吡啶-4-基)-4-(1-氨基乙基)环己烷羧酰胺、(R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺、1-(5-异喹啉磺酰基)高哌嗪或1-(5-异喹啉磺酰基)-2-甲基哌嗪。本治疗方法优选的β阻断剂为噻吗洛尔、苯呋洛尔、卡替洛尔、尼普地洛、倍他索洛尔、左布诺洛尔或美替洛尔(Metipranolol)。
Rho激酶抑制剂及β阻断剂的给药量可以根据患者的症状、年龄、剂型、给药途径等决定。下面以滴眼给药为例进行简单说明。
Rho激酶抑制剂的给药量因药物的种类而不同，通常1日给药量在0.025～10000μg的范围内，可以每日给药1次，也可以分数次给药，用量可以根据患者的年龄、症状等进行适当的增减。
β阻断剂的给药量因药物的种类而不同，通常1日给药量在5～5000μg的范围内，可在1日内1次或分数次给药。具体而言，噻吗洛尔使用的1日剂量为5～1500μg、苯呋洛尔使用的1日剂量为10～2000μg，卡替洛尔使用的1日剂量为10～5000μg、尼普地洛使用的1日剂量为10～1250μg、倍他索洛尔使用的1日剂量为50～1000μg，左布诺洛尔使用的1日剂量为5～5000μg，美替洛尔使用的1日剂量为5～5000μg，上述用量可以根据患者的年龄、症状等进行适当的增减。另外，其它β阻断剂也可以基于同样的标准决定其用量。
上述给药量也适合将Rho激酶抑制剂与β阻断剂并用给药的情况，但在使用Rho激酶抑制剂和β阻断剂二者配合制得的制剂进行给药时，配制出适当地选择了配合比例的制剂，使1日给药量为上述各成分的用量或其以下，将该配合制剂1日1次或分数次给药。
附图说明
图1为表示各给药组眼压经时变化的曲线图。其中眼压以从初期眼压开始的变化值表示。
具体实施方式
以下以制剂例和药理试验作为实施例进行说明，其目的是为了更好地理解本发明，并不能限定本发明的范围。
实施例
[制剂例]
以下说明本发明中配合了Rho激酶抑制剂((R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺二盐酸盐)和β阻断剂(噻吗洛尔)的滴眼剂的普通制剂例。
滴眼剂(100ml中)
(R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4
-(1-氨基乙基)苯甲酰胺二盐酸盐             0.1g
马来酸噻吗洛尔                            0.34g
硼酸                                      0.2g
浓甘油                                    0.25g
苯扎氯铵                                  0.005g
稀盐酸                                    适量
氢氧化钠                                  适量
蒸馏水                                    适量
可改变上述配方中Rho激酶抑制剂和β阻断剂的种类及配合量，并且适当改变添加剂的用量，以配制出所需组成及所需浓度的滴眼液。
[药理试验]
为了检验Rho激酶抑制剂和β阻断剂组合的有效性，研究了将Rho激酶抑制剂和β阻断剂并用对实验动物进行给药时的眼压降低效果。Rho激酶抑制剂使用(R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺二盐酸盐[化合物A]，β阻断剂使用噻吗洛尔。
(试验化合物溶液的配制)
1.Rho激酶抑制剂溶液的配制
将Rho激酶抑制剂溶解于生理盐水之后，加入氢氧化钠来中和溶液(pH6.0～7.0)，从而配制出所需浓度的Rho激酶抑制剂溶液。
2.β阻断剂溶液的配制
直接使用市售的β阻断剂滴眼液，或者用生理盐水稀释，配制出所需浓度的β阻断剂溶液。
(试验方法)
以下研究了Rho激酶抑制剂和β阻断剂并用给药时的眼压降低效果。为了比较对照，也研究了Rho激酶抑制剂单独给药或者β阻断剂单独给药时的眼压降低效果。对照组中只给予基液(生理盐水)。
(实验使用的药剂和动物)
Rho激酶抑制剂溶液：0.1％化合物A溶液(滴眼量：50μl)
β阻断剂溶液：噻吗洛尔滴眼液(商品名：Timoptol 0.25％、滴眼量：50μl)
试验动物：日本白色家兔(种系：JW，性别：雄性，一组4只)
(给药方法及测定方法)
1.Rho激酶抑制剂和β阻断剂并用给药
1)给试验动物的双眼各滴1滴4％盐酸羟丁普鲁卡因滴眼液(商品名：诺维新(Benoxil)0.4％溶液)进行局部麻醉。
2)在临给予试验化合物之前测定眼压，作为初期眼压。
3)用Rho激酶抑制剂溶液对试验动物的一只眼滴眼给药(对侧眼不作处理)。由于不能同时以β阻断剂溶液进行滴眼给药，因而间隔少许时间(约5分钟)后对同一只眼进行β阻断剂溶液的滴眼给药。
4)在点眼给予Rho激酶抑制剂溶液后的1小时、2小时及4小时后分别对两眼点以1滴0.4％盐酸羟丁普鲁卡因滴眼液进行局部麻醉后，测定眼压。各测定3次眼压，其平均值在结果中示出。
2.Rho激酶抑制剂单独给药
用生理盐水代替β阻断剂溶液，除此之外，用与上述并用给药试验同样的方法进行试验。
3.β阻断剂单独给药
用生理盐水代替Rho激酶抑制剂溶液，除此之外，用与上述并用给药试验同样的方法进行试验。
4.对照组
用生理盐水代替Rho激酶抑制剂溶液及β阻断剂溶液，除此之外，用与上述并用给药试验同样的方法进行试验。
(结果及分析)
实验结果在图1中给出。眼压表示从初期眼压开始的变化值。
由图1可知，Rho激酶抑制剂和β阻断剂的并用组比药剂单独给药组，即Rho激酶抑制剂给药组或者β阻断剂给药组，具有更加良好的眼压降低作用，并且显示出提高上述作用持续性的效果。
另外，将说明书中记载的其他Rho激酶抑制剂和β阻断剂进行组合试验时，也可观察到和上述试验结果同样的倾向。
由此可以确认，通过将Rho激酶抑制剂和β阻断剂组合使用可以获得更良好的眼压降低效果及/或提高持续性的效果。
产业实用性
通过本发明，可提供一种将Rho激酶抑制剂和β阻断剂组合使用的青光眼治疗剂。

Claims (12)

1.一种青光眼治疗剂，由Rho激酶抑制剂与β阻断剂组合而成。
2.一种青光眼治疗剂，其特征为，是由Rho激酶抑制剂和β阻断剂组合而成，二者作用可相互补充及/或增强。
3.如权利要求1或2所述的青光眼治疗剂，其中所述的Rho激酶抑制剂为(R)-反式-N-(吡啶-4-基)-4-(1-氨基乙基)环己烷羧酰胺、(R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺、1-(5-异喹啉磺酰基)高哌嗪、或者1-(5-异喹啉磺酰基)-2-甲基哌嗪。
4.如权利要求1或2所述的青光眼治疗剂，其中所述的β阻断剂为噻吗洛尔、苯呋洛尔、卡替洛尔、尼普地洛、倍他索洛尔、左布诺洛尔或美替洛尔。
5.一种青光眼治疗方法，是将Rho激酶抑制剂和β阻断剂组合使用，并给予患者有效剂量的该组合物。
6.一种青光眼治疗方法，其特征为，将Rho激酶抑制剂和β阻断剂组合，给予患者有效剂量的该组合物，使二者作用相互补充及/或增强。
7.如权利要求5或6所述的青光眼治疗方法，其中所述的Rho激酶抑制剂为(R)-反式-N-(吡啶-4-基)-4-(1-氨基乙基)环己烷羧酰胺、(R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺、1-(5-异喹啉磺酰基)高哌嗪、或者1-(5-异喹啉磺酰基)-2-甲基哌嗪。
8.如权利要求5或6所述的青光眼治疗方法，其中所述的β阻断剂为噻吗洛尔、苯呋洛尔、卡替洛尔、尼普地洛、倍他索洛尔、左布诺洛尔或美替洛尔。
9.Rho激酶抑制剂和β阻断剂的组合在制备青光眼治疗剂中的用途。
10.Rho激酶抑制剂和β阻断剂的组合在制备青光眼治疗剂中的用途，其特征为，Rho激酶抑制剂和β阻断剂的作用相互补充及/或增强。
11.如权利要求9或10所述的Rho激酶抑制剂和β阻断剂的组合的用途，其中所述的Rho激酶抑制剂为(R)-反式-N-(吡啶-4-基)-4-(1-氨基乙基)环己烷羧酰胺、(R)-(+)-N-(1H-吡咯并[2，3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺、1-(5-异喹啉磺酰基)高哌嗪、或者1-(5-异喹啉磺酰基)-2-甲基哌嗪。
12.如权利要求9或10所述的Rho激酶抑制剂和β阻断剂的组合的用途，其中所述的β阻断剂为噻吗洛尔、苯呋洛尔、卡替洛尔、尼普地洛、倍他索洛尔、左布诺洛尔或美替洛尔。
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