CN101495117B - 含酰胺化合物的水性液体制剂 - Google Patents
含酰胺化合物的水性液体制剂 Download PDFInfo
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- CN101495117B CN101495117B CN2007800285930A CN200780028593A CN101495117B CN 101495117 B CN101495117 B CN 101495117B CN 2007800285930 A CN2007800285930 A CN 2007800285930A CN 200780028593 A CN200780028593 A CN 200780028593A CN 101495117 B CN101495117 B CN 101495117B
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Abstract
本发明的目的是促进具有Rho激酶抑制活性的化合物对局部部分的渗透,并且提供甚至在减少给药频率时也能够维持给定的药物浓度的水性液体制剂。本发明通过水性液体制剂解决上述问题,所述水性液体制剂含有由下式(I)表示的化合物
Description
技术领域
本发明涉及一种含酰胺化合物的水性液体制剂。更具体地,本发明涉及一种包含具有Rho激酶抑制活性的酰胺化合物作为活性成分的眼用制剂,其促进所述活性成分的眼内渗透。
背景技术
青光眼由眼球的异常高的内部压力引起,其中,所述异常高的压力使得眼渐渐变得模糊或伤害眼,这又使视力可能渐渐衰退至失明。通常,水状液在眼球中连续循环,并且保持恒定的眼内压力(10-20mmHg)。所述压力由血液和淋巴细胞的循环,眼球壁的弹性,控制神经的行为等保持。它们中的任何一项的异常导致眼内压力的升高,这可能发展青光眼。
为了防止眼内压力升高或降低升高了的眼内压力的目的,对于青光眼的预防和治疗,已经使用了各种药物。已知的用于青光眼的治疗的滴眼剂包括交感激动剂,例如肾上腺素,地匹福林等。另外,β-肾上腺素阻滞剂,例如噻吗洛尔,吲哚洛尔等,被广泛地使用,原因在于它们通过抑制房水的产生而有利地降低眼内压力,并且不对瞳孔作用。α1-肾上腺素阻滞剂的房水流出促进效果的最近建议还暗示了盐酸布那唑嗪等作为青光眼的新的治疗药的潜在用途(非专利文献1)。
同时,已经报道具有Rho激酶抑制活性的化合物对各种高血压模型动物显示了降血压的效果(非专利文献2)。Rho激酶已经被确认存在于角膜上皮细胞中(非专利文献3)。
作为具有Rho激酶抑制活性的化合物,已经报道了将要随后提及的式(I)的化合物(专利文献1)。专利文献1中描述的化合物已知作为下列药剂有用:用于循环器官例如冠状动脉,大脑动脉,肾动脉,外周动脉等的病症的预防和治疗的药剂(例如,高血压的治疗药,心绞痛的治疗药,肾和外周循环病症的治疗药,脑血管收缩的抑制药等),有效力的并持久的哮喘治疗药,以及进一步在眼科学领域中,对于视网膜病变有用。另外,专利文献2公开式(I)的化合物对青光眼的预防或治疗有用,专利文献3公开该化合物对视觉功能障碍的治疗有用,并且专利文献4公开该化合物对角膜敏感性的恢复有用。
如上所述,各种对青光眼的预防或治疗有效的成分是已知的。重要的是促进它们渗透到房水中,以维持功效。例如,专利文献5公开了具有6至10个碳原子的直链脂肪酸,具有6至10个碳原子的烷基磺酸,磷酸或柠檬酸或它们的盐的加入,以增强布那唑嗪或哌唑嗪(prazosin)的角膜渗透性。专利文献6公开了C3-C7脂肪酸或它们的盐用于促进β阻滞剂(卡替洛尔,噻吗洛尔等)的角膜渗透性的用途。非专利文献4公开了对兔滴注噻吗洛尔和辛酸的离子对,以增加渗透到房水中的噻吗洛尔的量。而且,专利文献7公开了一种用于青光眼的治疗的含有黄原酸胶和碳酸酯脱水酶抑制剂的眼科组合物。专利文献8公开了一种在对眼滴注时变成凝胶的眼用液体组合物,所述眼用液体组合物具有不大于120mM的总的离子强度,含有特定的黄原酸胶,并且没有豆角胶(locust bean gum)。作为要被包含在所述组合物中的药物,在其中描述了抗青光眼药(噻吗洛尔,溴莫尼定,拉坦前列素等)。
专利文献1:WO98/06433
专利文献2:WO00/09162
专利文献3:WO02/083175
专利文献4:WO2005/118582
专利文献5:JP-A-63-301822
专利文献6:WO99/22715
专利文献7:JP-A-2001-508035
专利文献8:JP-A-2002-510654
非专利文献1:日本眼科纪要(Folia Ophthalmologica Japonica),第42卷,第710-714页,1990年
非专利文献2:Masayoshi Uehata等,自然(Nature),第389卷,第990-994 页,1997年
非专利文献3:Nirmala SundarRaj等,IOVS,第39(7)卷,第1266-1272页,1998年
非专利文献4:药物与生物医学分析杂志(J.Pharm.Biomed.Anal.),第7卷,第4期,第433-439页,1989年
发明内容
本发明要解决的问题
本发明的一个目的是促进具有Rho激酶抑制活性的化合物对局部部分的渗透,并且提供一种甚至在减少给药频率时也能够维持给定的药物浓度的水性液体制剂。
解决问题的手段
考虑到上述问题,本发明人已经进行了深入细致的研究,并且发现了一种促进具有Rho激酶抑制活性的化合物的局部渗透的混合成分,这导致了本发明的完成。因此,本发明涉及下列内容。
(1)一种水性液体制剂,其包含由下式(I)表示的酰胺化合物:
其中,
Ra是下式所示基团
在式(a)和(b)中,
R是氢,烷基,或在环上任选具有取代基的环烷基,环烷基烷基,苯基或芳烷基,或由下式表示的基团
其中,R6是氢,烷基或式:-NR8R9
其中,R8和R9相同或不同,并且分别是氢,烷基,芳烷基或苯基,R7是氢,烷基,芳烷基,苯基,硝基或氰基,或R6和R7组合表示形成杂环的基团,所述形成杂环的基团在环中任选还具有氧原子,硫原子或任选取代的氮原子,
R1是氢,烷基,或在环上任选具有取代基的环烷基,环烷基烷基,苯基或芳烷基,
或R和R1与相邻的氮原子一起组合成为形成杂环的基团,所述形成杂环的基团在环中任选还具有氧原子,硫原子或任选取代的氮原子,
R2是氢或烷基,
R3和R4相同或不同,并且分别是氢,烷基,芳烷基,卤素,硝基,氨基,烷基氨基,酰氨基,羟基,烷氧基,芳烷氧基,氰基,酰基,巯基,烷硫基,芳烷硫基,羧基,烷氧基羰基,氨基甲酰基,烷基氨基甲酰基或叠氮基,并且
A是由下式表示的基团
其中,R10和R11相同或不同,并且分别是氢,烷基,卤代烷基,芳烷基,羟基烷基,羧基或烷氧羰基,或R10和R11表示组合形成环烷基的基团,并且l,m和n分别是0或1-3的整数,
在式(c)中,
L是氢,烷基,氨基烷基,单或二烷基氨基烷基,四氢糠基,氨基甲酰基烷基,苯二甲酰亚氨基烷基,脒基或由下式表示的基团
其中,B是氢,烷基,烷氧基,芳烷基,芳烷氧基,氨基烷基,羟基烷基,烷酰氧基烷基,烷氧基羰基烷基,α-氨基苄基,呋喃基,吡啶基,苯基,苯基氨基,苯乙烯基或咪唑并吡啶基,
Q1是氢,卤素,羟基,芳烷氧基或噻吩基甲基,
W是亚烷基,
Q2是氢,卤素,羟基或芳烷氧基,
X是亚烷基,
Q3是氢,卤素,羟基,烷氧基,硝基,氨基,2,3-二氢呋喃基或5-甲基-3-氧代-2,3,4,5-四氢哒嗪-6-基;
并且Y是单键,亚烷基或亚烯基,并且
在式(c)中,
虚线是单键或双键,并且
R5是氢,羟基,烷氧基,烷氧基羰基氧基,烷酰氧基或芳烷氧基羰基氧基;
Rb是氢,烷基,芳烷基,氨基烷基或单或二烷基氨基烷基;并且
Rc是任选取代的含氮杂环,
它们的异构体和/或它们的药用酸加成盐(以下有时称为本化合物),以及离子对试剂或水溶性聚合物。
(2)如上述(1)所述的水性液体制剂,其中所述离子对试剂是山梨酸,辛酸或N-月桂酰基-L-谷氨酸或其药理学可接受的盐。
(3)如上述(1)所述的水性液体制剂,其中所述水溶性聚合物是黄原酸胶。
(4)如上述(1)-(3)中任一项所述的水性液体制剂,其中由所述式(I)表示的化合物是(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺·一盐酸盐。
(5)如上述(1)-(4)中任一项所述的水性液体制剂,所述水性液体制剂是滴眼剂。
(6)一种促进由上述(1)的式(I)表示的化合物,其异构体和/或其药用酸加成盐的眼内渗透的方法,所述方法包括向含有由所述式(I)表示的化合物,或其异构体和/或其药用酸加成盐的水溶液中加入离子对试剂或水溶性聚合物。
(7)一种预防或治疗选自由下列疾病组成的组中的一种疾病的方法:由睫状肌的持续异常紧张引起的青光眼,视力疲劳和假性近视,由视网膜神经或视神经的损伤或退化引起的视觉功能病症,由对角膜神经的损伤引起的角膜敏感性功能障碍,以及由角膜敏感性功能障碍引起的干眼病,所述方法包括,与离子对试剂或水溶性聚合物一起,对受试者施用有效量的由上述(1)的式(I)表示的化合物,其异构体和/或其药用酸加成盐。
(8)如上述(7)所述的方法,其中所述离子对试剂是山梨酸,辛酸或N-月桂酰基-L-谷氨酸或其药理学可接受的盐。
(9)如上述(7)所述的方法,其中所述水溶性聚合物是黄原酸胶。
(10)如上述(7)-(9)中任一项所述的方法,其中由所述式(I)表示的所述化合物是(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺·一盐酸盐。
(11)如上述(7)-(10)中任一项所述的方法,所述方法涉及滴眼剂。
(12)由上述(1)的式(I)表示的化合物,其异构体和/或其药用酸加成盐,以及离子对试剂或水溶性聚合物用于制备水性液体制剂的用途,所述水性液体制剂用于预防或治疗选自由下列疾病组成的组中的一种疾病:由睫状肌的持续异常紧张引起的青光眼,视力疲劳和假性近视,由视网膜神经或视神经的损伤或退化引起的视觉功能病症,由对角膜神经的损伤引起的角膜敏感性功能障碍,以及由角膜敏感性功能障碍引起的干眼病。
(13)如上述(12)所述的用途,其中所述离子对试剂是山梨酸,辛酸或N-月桂酰基-L-谷氨酸或其药理学可接受的盐。
(14)如上述(12)所述的用途,其中所述水溶性聚合物是黄原酸胶。
(15)如上述(12)-(14)中任一项所述的用途,其中由所述式(I)表示的所述化合物是(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺·一盐酸盐。
(16)如上述(12)-(15)中任一项所述的用途,所述用途涉及滴眼剂。
(17)一种商业包装(package),包括上述(1)-(5)中任一项所述的水性液体制剂以及陈述所述水性液体制剂可以或应当被用于预防或治疗选自由下列疾病组成的组中的一种疾病的书面资料:由睫状肌的持续异常紧张引起的青光眼,视力疲劳和假性近视,由视网膜神经或视神经的损伤或退化引起的视觉功能病症,由对角膜神经的损伤引起的角膜敏感性功能障碍,以及由角膜敏感性功能障碍引起的干眼病。
发明效果
根据本发明的水性液体制剂,促进了作为活性成分的本化合物的眼内渗透,可以在眼内组织中长期保持活性成分的治疗有效浓度,并且可以减少给药频率。根据本发明,与含有相同浓度的活性成分的已知制剂相比,可以提供在下列方面优良的制剂:活性成分的作用部位可到达性,成分的有效使用,以及给药频率的减少。而且,根据本发明,甚至含有低浓度的活性成分的制剂也能够显示与已知制剂的功效相等的功效,并且延长给药间隔。因而,可以提供在长期给药下特别对患者带来较小负担的制剂。
附图简述
图1是显示在滴注给药后的房水中的化合物A的浓度的图。
图2是显示在滴注给药后的结膜中的化合物A的浓度的图。
实施本发明的最佳方式
在本发明中,Rho激酶是指随着Rho的活化而被活化的丝氨酸/苏氨酸激酶。例如,示例的有ROKα(ROCKII:Leung,T.等,生物化学杂志(J.Biol.Chem.),270,29051-29054,1995),p160 ROCK(ROKβ,ROCK-I:Ishizaki, T.等,The EMBO J.,15(8),1885-1893,1996)以及其它具有丝氨酸/苏氨酸激酶活性的蛋白质。
在本发明中,可以单独使用具有Rho激酶抑制活性的化合物的一种,或在必须时,可以同时使用它们的几种。
在本发明中,式(I)的各个符号定义如下。
在R和R1的烷基是具有1至10个碳原子的直链或支链烷基,例如,甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,戊基,己基,庚基,辛基,壬基,癸基等,优选具有1至4个碳原子的烷基。
在R和R1的环烷基具有3至7个碳原子,并且例如,环丙基,环丁基,环戊基,环己基,环庚基等。
在R和R1的环烷基烷基是其中环烷基部分是上述具有3至7个碳原子的环烷基并且所述烷基部分是具有1至6个碳原子的直链或直链烷基(甲基,乙基,丙基,异丙基,丁基,戊基,己基等)的环烷基烷基,并且可以提及环丙基甲基,环丁基甲基,环戊基甲基,环己基甲基,环庚基甲基,环丙基乙基,环戊基乙基,环己基乙基,环庚基乙基,环丙基丙基,环戊基丙基,环己基丙基,环庚基丙基,环丙基丁基,环戊基丁基,环己基丁基,环庚基丁基,环丙基己基,环戊基己基,环己基己基,环庚基己基等。
在R和R1的芳烷基是其中烷基部分是具有1至4个碳原子的烷基的芳烷基,并且例如苯基烷基,例如苄基,1-苯基乙基,2-苯基乙基,3-苯基丙基,4-苯基丁基等。
在R和R1的环上的任选取代的环烷基,环烷基烷基,苯基和芳烷基的取代基是卤素(例如,氯,溴,氟和碘),烷基(与在R和R1的烷基相同),烷氧基(具有1至6个碳原子的直链或支链烷氧基,例如甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,仲丁氧基,叔丁氧基,戊氧基,己氧基等),芳烷基(与在R和R1的芳烷基相同)或卤代烷基(由1-5个卤素取代的在R和R1的烷基,并且示例为氟甲基,二氟甲基,三氟甲基,2,2,2-三氟乙基,2,2,3,3,3-五氟丙基等),硝基,氨基,氰基,叠氮基等。
由R和R1与邻近的氮原子一起组合形成的基团形成杂环,所述杂环任选在环中还具有氧原子,硫原子或任选取代的氮原子,优选是5或6-元环及其化合的环。它们的实例包括1-吡咯烷基,哌啶基,1-哌嗪基,吗 啉基,硫代吗啉基,1-咪唑基,2,3-二氢噻唑-3-基等。任选取代的氮原子的取代基示例为烷基,芳烷基,卤代烷基等。如本文中所使用的,烷基,芳烷基和卤代烷基如对于R和R1所定义。
在R2的烷基如对于R和R1所定义。
在R3和R4的卤素,烷基,烷氧基和芳烷基如对于R和R1所定义。
在R3和R4的酰基是具有2至6个碳原子的烷酰基(例如,乙酰基,丙酰基,丁酰基,戊酰基,新戊酰基等),苯甲酰基,或其中烷酰基部分具有2至4个碳原子的苯基烷酰基(例如,苯基乙酰基,苯基丙酰基,苯基丁酰基等)。
在R3和R4的烷基氨基是其中烷基部分是具有1至6个碳原子的直链或支链烷基的烷基氨基。其实例包括甲氨基,乙氨基,丙氨基,异丙氨基,丁氨基,异丁氨基,仲丁氨基,叔丁氨基,戊氨基,己氨基等。
在R3和R4的酰基氨基是其中酰基部分是具有2至6个碳原子的烷酰基,苄基或烷酰基部分是具有2至4个碳原子的苯基烷酰基等的酰基氨基,例如,乙酰氨基,丙酰氨基,丁酰氨基,戊酰氨基,新戊酰氨基,苯甲酰氨基,苯基乙酰氨基,苯基丙酰氨基,苯基丁酰氨基等。
在R3和R4的烷硫基是其中烷基部分是具有1至6个碳原子的直链或支链烷基的烷硫基,例如,甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,仲丁硫基,叔丁硫基,戊硫基,己硫基等。
在R3和R4的芳烷氧基是其中烷基部分是具有1至4个碳原子的烷基的芳烷氧基,例如,苄氧基,1-苯基乙氧基,2-苯基乙氧基,3-苯基丙氧基,4-苯基丁氧基等。
在R3和R4的芳烷硫基是其中烷基部分是具有1至4个碳原子的烷基的芳烷硫基,例如,苯甲硫基,1-苯基乙硫基,2-苯基乙硫基,3-苯基丙硫基,4-苯基丁硫基等。
在R3和R4的烷氧基羰基是其中烷氧基部分是具有1至6个碳原子的直链或支链烷氧基的烷氧基羰基,例如,甲氧基羰基,乙氧基羰基,丙氧基羰基,异丙氧基羰基,丁氧基羰基,异丁氧基羰基,仲丁氧基羰基,叔丁氧基羰基,戊氧基羰基,己氧基羰基等。
在R3和R4的烷基氨基甲酰基是由具有1至4个碳原子的烷基单或二 取代的氨基甲酰基,例如,甲基氨基甲酰基,二甲基氨基甲酰基,乙基氨基甲酰基,二乙基氨基甲酰基,丙基氨基甲酰基,二丙基氨基甲酰基,丁基氨基甲酰基,二丁基氨基甲酰基等。
在R5的烷氧基如对于R和R1所定义。
在R5的烷氧基羰基氧基是其中烷氧基部分是具有1至6个碳原子的直链或支链烷氧基的烷氧基羰基氧基,例如,甲氧基羰基氧基,乙氧基羰基氧基,丙氧基羰基氧基,异丙氧基羰基氧基,丁氧基羰基氧基,异丁氧基羰基氧基,仲丁氧基羰基氧基,叔丁氧基羰基氧基,戊氧基羰基氧基,己氧基羰基氧基等。
在R5的烷酰氧基是其中烷酰基部分是具有2至6个碳原子的烷酰基的烷酰氧基,例如,乙酰氧基,丙酰氧基,丁酰氧基,戊酰氧基,新戊酰氧基等。
在R5的芳烷氧基羰基氧基是其中芳烷基部分是具有C1-C4烷基的芳烷基的芳烷氧基羰基氧基,例如,苄氧基羰基氧基,1-苯基乙氧基羰基氧基,2-苯基乙氧基羰基氧基,3-苯基丙氧基羰基氧基,4-苯基丁氧基羰基氧基等。
在R6的烷基如对于R和R1所定义;在R8和R9的烷基如对于R和R1所定义;并且在R8和R9的芳烷基如对于R和R1所定义。
在R7的烷基如对于R和R1所定义,并且在R7的芳烷基如对于R和R1所定义。
由R6和R7组合形成的基团形成杂环,所述杂环在环中任选还具有氧原子,硫原子或任选取代的氮原子,所述基团例如咪唑-2-基,噻唑-2-基,噁唑-2-基,咪唑啉-2-基,3,4,5,6-四氢吡啶-2-基,3,4,5,6-四氢嘧啶-2-基,1,3-噁唑啉-2-基,1,3-噻唑啉-2-基,或具有取代基例如卤素,烷基,烷氧基,卤代烷基,硝基,氨基,苯基,芳烷基等的任选取代的苯并咪唑-2-基,苯并噻唑-2-基,苯并噁唑-2-基等。如本文中所使用的,卤素,烷基,烷氧基,卤代烷基和芳烷基如对于R和R1所定义。
上述任选取代的氮原子的取代基例如为烷基,芳烷基,卤代烷基等。如本文中所使用的,烷基,芳烷基和卤代烷基如对于R和R1所定义。
在R10和R11的羟基烷基是由1至3个羟基取代的具有1至6个碳原子 的直链或支链烷基,例如,羟甲基,2-羟乙基,1-羟乙基,3-羟丙基,4-羟丁基等。在R10和R11的烷基如对于R和R1所定义;在R10和R11的卤代烷基和烷氧基羰基如对于R和R1所定义。由R10和R11组合形成的环烷基与在R和R1的环烷基相同。
在L的烷基如对于R和R1所定义。
在L的氨基烷基是由氨基取代的具有1至6个碳原子的直链或支链烷基,例如,氨基甲基,2-氨基乙基,1-氨基乙基,3-氨基丙基,4-氨基丁基,5-氨基戊基,6-氨基己基等。
在L的单或二烷基氨基烷基是由具有1至4个碳原子的烷基单或二取代的氨基烷基,例如,甲基氨基甲基,二甲基氨基甲基,乙基氨基甲基,二乙基氨基甲基,丙基氨基甲基,二丙基氨基甲基,丁基氨基甲基,二丁基氨基甲基,2-二甲基氨基乙基,2-二乙基氨基乙基等。
在L的氨基甲酰基烷基是由氨基甲酰基取代的具有1至6个碳原子的直链或支链烷基,例如,氨基甲酰基甲基,2-氨基甲酰基乙基,1-氨基甲酰基乙基,3-氨基甲酰基丙基,4-氨基甲酰基丁基,5-氨基甲酰基戊基,6-氨基甲酰基己基等。
在L的苯二甲酰亚氨基烷基是由邻苯二甲酰亚胺取代的具有1至6个碳原子的直链或支链烷基,它的实例包括苯二甲酰亚氨基甲基,2-苯二甲酰亚氨基乙基,1-苯二甲酰亚氨基乙基,3-苯二甲酰亚氨基丙基,4-苯二甲酰亚氨基丁基,5-苯二甲酰亚氨基戊基,6-苯二甲酰亚氨基己基等。
在B的烷基如对于R和R1所定义。
在B的烷氧基如对于R和R1所定义。
在B的芳烷基如对于R和R1所定义。
在B的芳烷氧基如对于R3和R4所定义。
在B的氨基烷基如对于L所定义。
在B的羟烷基如对于R10和R11所定义。
在B的烷酰基氧基烷基是其中具有1至6个碳原子的直链或支链烷基被具有拥有2至6个碳原子的烷酰基部分的烷酰基氧基取代的烷酰基氧基烷基,例如,乙酰基氧基甲基,丙酰基氧基甲基,丁酰基氧基甲基,戊酰基氧基甲基,新戊酰基氧基甲基,乙酰基氧基乙基,丙酰基氧基乙基,丁 酰基氧基乙基,戊酰基氧基乙基,新戊酰基氧基乙基等。
在B的烷氧基羰基烷基是其中具有1至6个碳原子的直链或支链烷基被具有拥有1至6个碳原子的烷氧基部分的烷氧基羰基取代的烷氧基羰基烷基,例如,甲氧基羰基甲基,乙氧基氧基甲基,丙氧基羰基甲基,异丙氧基羰基甲基,丁氧基羰基甲基,异丁氧基羰基甲基,仲丁氧基羰基甲基,叔丁氧基羰基甲基,戊氧基羰基甲基,己氧基羰基甲基,甲氧基羰基乙基,乙氧基羰基乙基,丙氧基羰基乙基,异丙氧基羰基乙基,丁氧基羰基乙基,异丁氧基羰基乙基,仲丁氧基羰基乙基,叔丁氧基羰基乙基,戊氧基羰基乙基,己氧基羰基乙基等。
在Q1,Q2和Q3的卤素如对于R和R1所定义。
在Q1和Q2的芳烷氧基如对于R3和R4所定义。
在Q3的烷氧基如对于R和R1所定义。
在W,X和Y的亚烷基是具有1至6个碳原子的直链或支链亚烷基,例如,亚甲基,亚乙基,三亚甲基,亚丙基,四亚甲基,五亚甲基,六亚甲基等。
在Y的亚烯基是具有2至6个碳原子的直链或支链亚烯基,例如,1,2-亚乙烯基,1,3-亚丙烯基,亚丁烯基,亚戊烯基等。
在Rb的烷基如对于R和R1所定义。
在Rb的芳烷基如对于R和R1所定义。
在Rb的氨基烷基如对于L所定义。
在Rb的单或二烷基氨基烷基如对于L所定义。
在Rc的含氮杂环,当它是单环时,例如为吡啶,嘧啶,哒嗪,三嗪,吡唑,***等,并且当它是稠合环时,例如为吡咯并吡啶(例如,1H-吡咯并[2,3-b]吡啶,1H-吡咯并[3,2-b]吡啶,1H-吡咯并[3,4-b]吡啶等),吡唑并吡啶(例如,1H-吡唑并[3,4-b]吡啶,1H-吡唑并[4,3-b]吡啶等),咪唑并吡啶(例如,1H-咪唑并[4,5-b]吡啶等),吡咯并嘧啶(例如,1H-吡咯并[2,3-d]嘧啶,1H-吡咯并[3,2-d]嘧啶,1H-吡咯并[3,4-d]嘧啶等),吡唑并嘧啶(例如,1H-吡唑并[3,4-d]嘧啶,吡唑并[1,5-a]嘧啶,1H-吡唑并[4,3-d]嘧啶等),咪唑并嘧啶(例如,咪唑并[1,2-a]嘧啶,1H-咪唑并[4,5-d]嘧啶等),吡咯并三嗪(例如,吡咯并[1,2-a]-1,3,5-三嗪,吡咯并[2,1-f]-1,2,4-三嗪),吡唑 并三嗪(例如,吡唑并[1,5-a]-1,3,5-三嗪等),***并吡啶(例如,1H-1,2,3-***并[4,5-b]吡啶等),***并嘧啶(例如,1,2,4-***并[1,5-a]嘧啶,1,2,4-***并[4,3-a]嘧啶,1H-1,2,3-***并[4,5-d]嘧啶等),噌啉,喹唑啉,喹啉,吡啶并哒嗪(例如,吡啶并[2,3-c]哒嗪等),吡啶并吡嗪(例如,吡啶并[2,3-b]吡嗪等),吡啶并嘧啶(例如,吡啶并[2,3-d]嘧啶,吡啶并[3,2-d]嘧啶等),嘧啶并嘧啶(例如,嘧啶并[4,5-d]嘧啶,嘧啶并[5,4-d]嘧啶等),吡嗪并嘧啶(例如,吡嗪并[2,3-d]嘧啶等),萘啶(例如,1,8-萘啶等),四唑并嘧啶(例如,四唑并[1,5-a]嘧啶等),噻吩并吡啶(例如,噻吩并[2,3-b]吡啶等),噻吩并嘧啶(例如,噻吩并[2,3-d]嘧啶等),噻唑并吡啶(例如,噻唑并[4,5-b]吡啶,噻唑并[5,4-b]吡啶等),噻唑并嘧啶(例如,噻唑并[4,5-d]嘧啶,噻唑并[5,4-d]嘧啶等),噁唑并吡啶(例如,噁唑并[4,5-b]吡啶,噁唑并[5,4-b]吡啶等),噁唑并嘧啶(例如,噁唑并[4,5-d]嘧啶,噁唑并[5,4-d]嘧啶等),呋喃并吡啶(例如,呋喃并[2,3-b]吡啶,呋喃并[3,2-b]吡啶等),呋喃并嘧啶(例如,呋喃并[2,3-d]嘧啶,呋喃并[3,2-d]嘧啶等),2,3-二氢吡咯并吡啶(例如,2,3-二氢-1H-吡咯并[2,3-b]吡啶,2,3-二氢-1H-吡咯并[3,2-b]吡啶等),2,3-二氢吡咯并嘧啶(例如,2,3-二氢-1H-吡咯并[2,3-d]嘧啶,2,3-二氢-1H-吡咯并[3,2-d]嘧啶等),5,6,7,8-四氢吡啶并[2,3-d]嘧啶,5,6,7,8-四氢-1,8-萘啶,5,6,7,8-四氢喹啉等。当这些环形成氢化芳族环时,环中的碳原子可以是羰基,并且包括例如,2,3-二氢-2-氧代吡咯并吡啶,2,3-二氢-2,3-二氧代吡咯并吡啶,7,8-二氢-7-氧代-1,8-萘啶,5,6,7,8-四氢-7-氧代-1,8-萘啶等。优选吡啶,吡咯并吡啶。
这些环可以被下列取代基取代,例如卤素,烷基,烷氧基,芳烷基,卤代烷基,硝基,氨基,烷基氨基,氰基,甲酰基,酰基,氨基烷基,单或二烷基氨基烷基,叠氮基,羧基,烷氧基羰基,氨基甲酰基,烷基氨基甲酰基,烷氧基烷基(例如,甲氧基甲基,甲氧基乙基,甲氧基丙基,乙氧基甲基,乙氧基乙基,乙氧基丙基等),任选取代的肼基等。
如本文中所使用的,任选取代的肼基的取代基包括烷基,芳烷基,硝基,氰基等,其中烷基和芳烷基如对于R和R1所定义,并且例如为甲基肼基,乙基肼基,苄基肼基等。
式(I)的化合物示例为下列化合物及其盐。
(1)4-(2-吡啶基氨基甲酰基)哌啶
(2)1-苄氧基羰基-4-(4-吡啶基氨基甲酰基)哌啶
(3)1-苯甲酰基-4-(4-吡啶基氨基甲酰基)哌啶
(4)1-丙基-4-(4-吡啶基氨基甲酰基)哌啶
(5)[3-(2-(2-噻吩基甲基)苯氧基)-2-羟丙基]-4-(4-吡啶基氨基甲酰基)哌啶
(6)4-(4-吡啶基氨基甲酰基)哌啶
(7)1-苯甲基-4-(4-吡啶基氨基甲酰基)-1,2,5,6-四氢吡啶
(8)3-(4-吡啶基氨基甲酰基)哌啶
(9)1-苄基-3-(4-吡啶基氨基甲酰基)哌啶
(10)1-(2-(4-苄氧基苯氧基)乙基)-4-(N-(2-吡啶基)-N-苄基氨基甲酰基)哌啶
(11)1-甲酰基-4-(4-吡啶基氨基甲酰基)哌啶
(12)4-(3-吡啶基氨基甲酰基)哌啶
(13)1-异丙基-4-(4-吡啶基氨基甲酰基)哌啶
(14)1-甲基-4-(4-吡啶基氨基甲酰基)哌啶
(15)1-己基-4-(4-吡啶基氨基甲酰基)哌啶
(16)1-苄基-4-(4-吡啶基氨基甲酰基)哌啶
(17)1-(2-苯乙基)-4-(4-吡啶基氨基甲酰基)哌啶
(18)1-(2-(4-甲氧基苯基)乙基)-4-(4-吡啶基氨基甲酰基)哌啶
(19)1-(2-(4-甲氧基苯基)乙基)-4-(2-吡啶基氨基甲酰基)哌啶
(20)1-(2-(4-氯代苯基)乙基-4-(4-吡啶基氨基甲酰基)哌啶
(21)1-二苯基甲基-4-(2-吡啶基氨基甲酰基)哌啶
(22)1-[2-(4-(5-甲基-3-氧代-2,3,4,5-四氢哒嗪-6-基)苯基)乙基]-4-(2-吡啶基氨基甲酰基)哌啶
(23)1-(4-(4,5-二氢-2-呋喃基)苯基)-4-(4-吡啶基氨基甲酰基)哌啶
(24)1-(2-硝基苯基)-4-(4-吡啶基氨基甲酰基)哌啶
(25)1-(2-氨基苯基)-4-(4-吡啶基氨基甲酰基)哌啶
(26)1-烟酰基-4-(4-吡啶基氨基甲酰基)哌啶
(27)1-异烟酰基-4-(4-吡啶基氨基甲酰基)哌啶
(28)1-(3,4,5-三甲氧基苯甲酰基)-4-(4-吡啶基氨基甲酰基)哌啶
(29)1-乙酰基-4-(4-吡啶基氨基甲酰基)哌啶
(30)1-(3-(4-氟苯甲酰基)丙基)-4-(4-吡啶基氨基甲酰基)哌啶
(31)1-(3-(4-氟苯甲酰基)丙基)-4-(2-吡啶基氨基甲酰基)哌啶
(32)1-(1-(4-羟基苯甲酰基)乙基)-4-(2-吡啶基氨基甲酰基)哌啶
(33)1-(1-(4-苄氧基苯甲酰基)乙基)-4-(2-吡啶基氨基甲酰基)哌啶
(34)1-(2-(4-羟基苯氧基)乙基)-4-(2-吡啶基氨基甲酰基)哌啶
(35)1-(4-(4-氟苯基)-4-羟丁基)-4-(4-吡啶基氨基甲酰基)哌啶
(36)1-(1-甲基-2-(4-羟基苯基)-2-羟乙基)-4-(2-吡啶基氨基甲酰基)哌啶
(37)1-肉桂酰基-4-(2-吡啶基氨基甲酰基)哌啶
(38)1-(2-羟基-3-苯氧基丙基)-4-(4-吡啶基氨基甲酰基)哌啶
(39)1-(2-羟基-3-苯氧基丙基)-4-(3-吡啶基氨基甲酰基)哌啶
(40)1-(2-羟基-3-苯氧基丙基)-4-(2-吡啶基氨基甲酰基)哌啶
(41)1-(2-苯基乙基)-4-[N-(2-吡啶基)-N-(2-(N,N-二甲基氨基)乙基)氨基甲酰基]哌啶
(42)1-苄氧基羰基-4-(2-吡啶基氨基甲酰基)哌啶
(43)1-(3-氯苯基)氨基甲酰基-4-(4-吡啶基氨基甲酰基)哌啶
(44)1-[N-(2-吡啶基)-N-(2-(N,N-二甲基氨基)乙基)氨基甲酰基]哌啶
(45)1-甲基-4-(4-吡啶基氨基甲酰基)-1,2,5,6-四氢吡啶
(46)1-烟酰基-3-(4-吡啶基氨基甲酰基)哌啶
(47)1-[2-(4-氟苯甲酰基)乙基]-4-(4-吡啶基氨基甲酰基)哌啶
(48)1-(6-氯-2-甲基咪唑并[1,2-a]吡啶-3-羰基)-4-(4-吡啶基氨基甲酰基)哌啶
(49)1-(4-硝基苄基)-4-(4-吡啶基氨基甲酰基)哌啶
(50)1-己基-4-(4-吡啶基氨基甲酰基)哌啶
(51)1-苄氧基羰基-4-(2-氯-4-吡啶基氨基甲酰基)哌啶
(52)4-(2-氯-4-吡啶基氨基甲酰基)哌啶
(53)1-(2-氯烟酰基)-4-(4-吡啶基氨基甲酰基)哌啶
(54)3-(2-氯-4-吡啶基氨基甲酰基)哌啶
(55)1-(4-苯二甲酰亚氨基丁基)-4-(4-吡啶基氨基甲酰基)哌啶
(56)1-(3,5-二-叔丁基-4-羟基肉桂酰基)-4-(4-吡啶基氨基甲酰基)哌啶
(57)1-氨基甲酰基甲基-4-(4-吡啶基氨基甲酰基)哌啶
(58)1-苄氧基羰基-4-(5-硝基-2-吡啶基氨基甲酰基)哌啶
(59)4-(5-硝基-2-吡啶基氨基甲酰基)哌啶
(60)反式-4-苄氧基甲酰胺基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(61)反式-4-氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(62)反式-4-甲酰氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(63)反式-4-二甲基氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(64)N-苯亚甲基-反式-(4-吡啶基氨基甲酰基)环己基甲基胺
(65)反式-4-苄基氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(66)反式-4-异丙基氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(67)反式-4-烟酰基氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(68)反式-4-环己基氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(69)反式-4-苄氧基甲酰胺基-1-(4-吡啶基氨基甲酰基)环己烷
(70)反式-4-氨基-1-(4-吡啶基氨基甲酰基)环己烷
(71)反式-4-(1-氨基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(72)反式-4-氨基甲基-顺式-2-甲基-1-(4-吡啶基氨基甲酰基)环己烷
(73)(+)-反式-4-(1-苄氧基甲酰胺基丙基)-1-环己烷羧酸
(74)(+)-反式-4-(1-苄氧基甲酰胺基丙基)-1-(4-吡啶基氨基甲酰基)环己烷
(75)(-)-反式-4-(1-苄氧基甲酰胺基丙基)-1-(4-吡啶基氨基甲酰基)环己烷
(76)(+)-反式-4-(1-氨基丙基)-1-(4-吡啶基氨基甲酰基)环己烷
(77)(-)-反式-4-(1-氨基丙基)-1-(4-吡啶基氨基甲酰基)环己烷
(78)(-)-反式-4-(1-苄氧基甲酰胺基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(79)(+)-反式-4-(1-苄氧基甲酰胺基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(80)(+)-反式-4-(1-氨基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(81)(-)-反式-4-(1-氨基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(82)反式-4-(4-氯苯甲酰基)氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(83)反式-4-氨基甲基-1-(2-吡啶基氨基甲酰基)环己烷
(84)反式-4-苄氧基甲酰胺基甲基-1-(2-吡啶基氨基甲酰基)环己烷
(85)反式-4-甲基氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(86)反式-4-(N-苄基-N-甲基氨基)甲基-1-(4-吡啶基氨基甲酰基)环己烷
(87)反式-4-氨基甲基-1-(3-吡啶基氨基甲酰基)环己烷
(88)反式-4-氨基甲基-1-[(3-羟基-2-吡啶基)氨基甲酰基]环己烷
(89)反式-4-苄氧基甲酰胺基甲基-1-(3-吡啶基氨基甲酰基)环己烷
(90)反式-4-苄氧基甲酰胺基甲基-1-[(3-苯甲氧基-2-吡啶基)氨基甲酰基]环己烷
(91)反式-4-苯二甲酰亚氨基甲基-1-(4-吡啶基氨基甲酰基)环己烷
(92)反式-4-苄氧基甲酰胺基甲基-1-(3-甲基-4-吡啶基氨基甲酰基)环己烷
(93)反式-4-氨基甲基-1-(3-甲基-4-吡啶基氨基甲酰基)环己烷
(94)4-(反式-4-苯甲氧基甲酰胺基甲基环己基羰基)氨基-2,6-二甲基吡啶-N-氧化物
(95)4-(反式-4-氨基甲基环己基羰基)氨基-2,6-二甲基吡啶-N-氧化物
(96)反式-4-氨基甲基-1-(2-甲基-4-吡啶基氨基甲酰基)环己烷
(97)反式-4-(1-苄氧基甲酰胺基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(98)反式-4-(1-氨基-1-甲基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(99)反式-4-(2-氨基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(100)反式-4-(2-氨基-1-甲基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(101)反式-4-(1-氨基丙基)-1-(4-吡啶基氨基甲酰基)环己烷
(102)反式-4-氨基甲基-反式-1-甲基-1-(4-吡啶基氨基甲酰基)环己烷
(103)反式-4-苄基氨基甲基-顺式-2-甲基-1-(4-吡啶基氨基甲酰基)环己烷
(104)反式-4-(1-苄氧基甲酰胺-1-甲基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(105)反式-4-苄氧基甲酰胺基甲基-1-(N-甲基-4-吡啶基氨基甲酰基)环己烷
(106)反式-4-(1-乙酰胺-1-甲基乙基)-1-(4-吡啶基氨基甲酰基)环己烷
(107)反式-N-(6-氨基-4-嘧啶基-4-氨基甲基环己烷甲酰胺
(108)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-氨基甲基-环己烷甲酰胺
(109)(+)-反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)环己烷甲酰胺
(110)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基-1-甲基乙基)环己烷甲酰胺
(111)反式-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-氨基甲基-环己烷甲酰胺
(112)(+)-反式-N-(1H-吡唑并[3,4-b]吡啶-4-yl)-4-(1-氨基乙基)环己烷甲酰胺
(113)反式-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-(1-氨基-1-甲基乙基)环己烷甲酰胺
(114)(+)-反式-N-(2-氨基-4-吡啶基)-4-(1-氨基乙基)-环己烷甲酰胺
(115)反式-N-(1H-吡唑并[3,4-d]嘧啶-4-基)-4-氨基甲基环己烷甲酰胺
(116)(+)-反式-N-(1H-吡唑并[3,4-d]嘧啶-4-基)-4-(1-氨基乙基)环己烷甲酰胺
(117)反式-N-(1H-吡唑并[3,4-d]嘧啶-4-基)-4-(1-氨基-1-甲基乙基)环己烷甲酰胺
(118)反式-N-(4-嘧啶基)-4-氨基甲基环己烷-甲酰胺
(119)反式-N-(3-氨基-4-吡啶基)-4-氨基甲基环己烷-甲酰胺
(120)反式-N-(7H-咪唑并[4,5-d]嘧啶-6-基)-4-氨基甲基环己烷甲酰胺
(121)反式-N-(3H-1,2,3-***并[4,5-d]嘧啶-7-基)-4-氨基甲基环己烷甲酰胺
(122)反式-N-(1-苄基-1H-吡唑并[3,4-b]吡啶-4-基)-4-氨基甲基环己烷甲酰胺
(123)反式-N-(1H-5-吡唑基)-4-氨基甲基环己烷甲酰胺
(124)反式-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-氨基甲基环己烷甲酰胺
(125)反式-N-(4-哒嗪基)-4-氨基甲基环己烷甲酰胺
(126)反式-N-(7H-吡咯并[2,3-d]嘧啶-4-基)-4-氨基甲基环己烷甲酰胺
(127)反式-N-(2-氨基-4-吡啶基)-4-氨基甲基环己烷甲酰胺
(128)反式-N-(噻吩并[2,3-d]嘧啶-4-基)-4-氨基甲基环己烷甲酰胺
(129)反式-N-(5-甲基-1,2,4-***并[1,5-a]密啶-7-基)-4-氨基甲基环己烷甲酰胺
(130)反式-N-(3-氰基-5-甲基吡唑并[1,5-a]嘧啶-7-基-4-氨基甲基环己烷甲酰胺
(131)反式-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-(1-氨基-1-甲基乙基)环己烷甲酰胺
(132)反式-N-(2-(1-吡咯烷基)-4-吡啶基)-4-氨基甲基环己烷甲酰胺
(133)反式-N-(2,6-二氨基-4-密啶基)-4-氨基甲基环己烷甲酰胺
(134)(+)-反式-N-(7-甲基-1,8-萘啶-4-基)-4-(1-氨基乙基)环己烷甲酰胺
(135)反式-N-(1-苄氧基甲基吡咯并[2,3-b]吡啶-4-基)-4-氨基甲基环己烷甲酰胺
(136)(+)-反式-N-(1-甲基吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)环己烷甲酰胺
(137)反式-N-苄基-N-(2-苄基氨基-4-吡啶基)-4-(1-氨基-1-甲基乙基)环己烷甲酰胺
(138)反式-N-(2-叠氮基-4-吡啶基)-4-氨基甲基环己烷甲酰胺
(139)反式-N-(2,3-二氢-1H-吡咯并[2,3-b]吡啶-4-基)-4-氨基甲基环己烷甲酰胺
(140)反式-N-(2,3-二氢-1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基-1-甲基乙基)环己烷甲酰胺
(141-1)反式-N-(2-羧基-4-吡啶基)-4-氨基甲基环己烷甲酰胺
(141-2)(R)-(+)-反式-N-(3-溴-1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)环己烷甲酰胺
(142)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-胍基甲基环己烷甲酰胺
(143)反式-N-(1H-吡咯并[3,4-b]吡啶-4-基)-4-胍基甲基环己烷甲酰胺
(144)反式-N-(4-吡啶基)-4-胍基甲基环己烷甲酰胺
(145)反式-N-(1-甲基吡咯并[2,3-b]吡啶-4-基)-4-(胍基甲基)环己烷甲酰 胺
(146)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(2-咪唑啉-2-基)氨基甲基环己烷甲酰胺
(147)反式-N-(1-苯甲氧基甲基吡咯并[2,3-b]吡啶-4-基)-4-胍基甲基环己烷甲酰胺
(148)反式-N-(2-氨基-4-吡啶基)-4-胍基甲基环己烷甲酰胺
(149)反式-N-(1-苄氧基甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(2-咪唑啉-2-基)氨基甲基环己烷甲酰胺
(150)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-苄基胍基甲基)环己烷甲酰胺
(151)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-苯基胍基甲基)环己烷甲酰胺
(152)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-丙基胍基甲基)环己烷甲酰胺
(153)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-辛基胍基甲基)环己烷甲酰胺
(154)反式-N-(1-苄氧基甲基吡咯并[2,3-b]吡啶-4-基)-4-(2-苄基-3-乙基胍基甲基)环己烷甲酰胺
(155)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(咪唑-2-基)氨基甲基环己烷甲酰胺
(156)反式-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(噻唑-2-基)氨基甲基环己烷甲酰胺
(157)(R)-(+)-N-(4-吡啶基)-4-(1-氨基乙基)苯甲酰胺
(158)N-(4-吡啶基)-4-(1-氨基-1-甲基乙基)苯甲酰胺
(159)N-(4-吡啶基)-4-氨基甲基-2-苄氧基苯甲酰胺
(160)N-(4-吡啶基)-4-氨基甲基-2-乙氧基苯甲酰胺
(161)(R)-(-)-N-(4-吡啶基)-4-(1-氨基乙基)-3-硝基苯甲酰胺
(162)(R)-(-)-N-(4-吡啶基)-3-氨基-4-(1-氨基乙基)苯甲酰胺
(163)(R)-(+)-N-(4-吡啶基)-4-(1-氨基乙基)-3-氯苯甲酰胺
(164)N-(4-吡啶基)-3-氨基甲基苯甲酰胺
(165)(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺
(166)(R)-(+)-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺
(167)N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-胍基甲基苯甲酰胺
(168)N-(4-吡啶基)-4-胍基甲基苯甲酰胺
(169)(R)-(+)-N-(4-吡啶基)-4-(1-氨基乙基)-3-氟苯甲酰胺
(170)N-(4-吡啶基)-4-氨基甲基苯甲酰胺
(171)N-(4-吡啶基)-4-氨基甲基-2-羟基苯甲酰胺
(172)N-(4-吡啶基)-4-(2-氨基乙基)苯甲酰胺
(173)N-(4-吡啶基)-4-氨基甲基-3-硝基苯甲酰胺
(174)N-(4-吡啶基)-3-氨基-4-氨基甲基苯甲酰胺
(175)(S)-(-)-N-(4吡啶基)-4-(1-氨基乙基)苯甲酰胺
(176)(S)-(-)-N-(4-吡啶基)-2-(1-氨基乙基)苯甲酰胺
(177)(R)-(+)-N-(4-吡啶基)-4-(1-氨基乙基)-2-氯苯甲酰胺
(178)(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基-4-(1-(3-丙基胍基)乙基)苯甲酰胺
(179)(R)-(-)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)-3-叠氮基苯甲酰胺
(180)(R)-(+)-N-(4-吡啶基)-4-(1-氨基乙基)-2-硝基苯甲酰胺
(181)(R)-(-)-N-(4-吡啶基)-4-(1-氨基乙基)-3-乙氧基苯甲酰胺
(182)(R)-(+)-N-(3-碘-1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺
(183)(R)-(+)-N-(3-碘-1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)-3-叠氮基苯甲酰胺
(184)(R)-(-)-N-(4-吡啶基)-4-(1-氨基乙基)-3-羟基苯甲酰胺
(185)N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-胍基甲基-3-硝基苯甲酰胺
(186)(R)-N-(1H-吡咯并[3,4-b]吡啶-4-基)-4-(1-胍基乙基)-3-硝基苯甲酰胺
(187)(R)-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-(1-氨基乙基)-2-硝基苯甲酰胺
(188)N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-胍基苯甲酰胺
(189)(R)-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-(1-氨基乙基)-3-硝基苯甲酰胺
(190)(R)-N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-(1-胍基乙基)苯甲酰胺
(191)N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-(1-氨基-2-羟乙基)苯甲酰胺
(192)N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-氨基甲基-3-硝基苯甲酰胺
(193)N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-哌啶甲酰胺
(194)N-(1H-吡唑并[3,4-b]吡啶-4-基)-4-哌啶甲酰胺
(195)N-(1H-吡唑并[3,4-b]吡啶-4-基)-1-氨基乙酰基-4-哌啶甲酰胺
(196)N-(1-甲氧基甲基-1H-吡唑并[3,4-b]吡啶-4-基)-4-哌啶甲酰胺
(197)N-(2,3-二氢-1H-吡咯并[2,3-b]吡啶-4-基)-4-哌啶甲酰胺
(198)N-(1H-吡咯并[2,3-b]吡啶-4-基)-1-(2-苯基乙基)-4-哌啶甲酰胺
(199)N-(1H-吡咯并[2,3-b]吡啶-4-基)-1-脒基-4-哌啶甲酰胺
(200)N-(1H-吡咯并[2,3-b]吡啶-4-基)-1-(3-苯基丙基)-4-哌啶甲酰胺
(201)N-(1H-吡咯并[2,3-b]吡啶-4-基)-1-苄基-4-哌啶甲酰胺
(202)N-(1H-吡唑并[3,4-b]吡啶-4-基)-1-(2-苯基乙基)-4-哌啶甲酰胺
(203)N-(1H-吡唑并[3,4-b]吡啶-4-基)-1-(3-苯基丙基)-4-哌啶甲酰胺
优选的是化合物(80),(109),(110),(112),(115),(142),(143),(144),(145),(153),(157),(163),(165),(166)和(179)。
该化合物可以是药用酸加成盐,其中所述酸例如为无机酸例如盐酸,氢溴酸,硫酸等,以及有机酸例如甲磺酸,富马酸,马来酸,扁桃酸,柠檬酸,酒石酸,水杨酸等。具有羧基的化合物可以用金属例如钠,钾,钙,镁,铝等转化成盐,用氨基酸例如赖氨酸等转化成盐。此外,1水合物,2水合物,1/2水合物,1/3水合物,1/4水合物,2/3水合物,3/2水合物,6/5水合物等被包括在本发明中。优选地,该化合物是(R)-(+)-N(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺一盐酸盐。
该化合物可以通过例如在JP-A-62-89679,JP-A-3-218356,JP-A-5-194401,JP-A-6-41080,WO95/28387,WO98/06433等中所述的方法合成。
当由式(I)表示的酰胺化合物具有光学异构体,它的消旋体或顺-反异构 体时,它们的全部可以被用于本发明中。这些异构体可以通过常规方法分离,或可以使用所述异构体的起始材料制备。
本化合物对包括人,牛,马,狗,小鼠,大鼠等的哺乳动物具有眼内压力降低作用,视盘血液流动改善作用以及房水流出促进作用。因此,它们可以被用作各种类型的青光眼的预防和治疗的药剂,例如,原发性开角型青光眼,正常眼压青光眼,分泌过多青光眼,高眼压症,急性闭角型青光眼,慢性闭角型青光眼,高褶型虹膜综合征,混合型青光眼,类固醇青光眼,囊膜性青光眼,色素青光眼,淀粉样变性相关继发性青光眼,新生血管性青光眼,恶性青光眼等的预防和治疗的药剂。
由于本化合物抑制哺乳动物例如人,牛,马,狗,小鼠,大鼠等的睫状肌的收缩,因此本发明的水性液体制剂被用作用于由睫状肌等的持续异常紧张引起的视力疲劳和假性近视的预防或治疗的药剂。
由于本化合物对包括人,牛,马,狗,小鼠,大鼠等的哺乳动物具有视网膜神经节细胞轴突延长作用和视神经细胞再生作用,因此化合物被认为是改善由视网膜神经或视神经的损伤,退化等引起的视觉功能病症的化合物。因此,本发明的水性液体制剂被认为在下列方面是有效的:在由归因于视网膜炎症等的损伤等(视网膜神经病,视网膜血管闭塞,静脉周炎视网膜,伊尔斯病,局部缺血眼病,视网膜小动脉微动脉瘤,由高血压肾病和血液病引起的视网膜病变,糖尿病视网膜病变,视网膜营养不良,斑点营养不良,脉络膜视网膜病变,斑点退化,斑点水肿,视网膜色素上皮脱离,退化视网膜劈裂症,视网膜母细胞瘤,视网膜色素上皮瘤等)所引起的视觉障碍方面的视觉功能改善;在由视神经的退化,损伤所引起的视觉障碍(视觉神经炎,视盘的毛细管血管瘤,局部缺血视觉神经病,视网膜神经纤维层的缺陷,视网膜视神经萎缩,视觉神经的神经断伤,创伤性视觉神经病,淤血***(choked disc),视盘的缺损,视觉神经发育不全,毒性视神经萎缩等)方面的视觉功能改善;在归因于由升高的眼内压力(青光眼等)等所引起的视神经萎缩,退化等的视觉障碍方面的视觉功能改善;以及另外,在视网膜移植以及视神经移植中的视神经再生方面的包括视网膜神经节细胞的视细胞的增殖和功能维持。
由于本化合物促进哺乳动物例如人,牛,马,狗,小鼠,大鼠等的角 膜神经前突的形成,因此本发明的水性液体制剂对于由角膜神经损伤所引起的角膜敏感性功能障碍或由角膜敏感性功能障碍所引起的干眼病的改善是有用的。具体地,它被用作用于下列病症的预防或治疗的药剂:白内障外科,激光屈光性角膜切削术(PRK),激光角膜磨镶术(LASIK),LASEK或角膜移植以后的角膜敏感性功能障碍,由角膜神经退化引起的角膜敏感性功能障碍例如神经性麻痹角膜病变,角膜溃疡,糖尿病角膜病变等,干眼症状等。
本发明的水性液体制剂的特征在于含有用于促进活性成分的眼内渗透的离子对试剂。
在本发明中,所述离子对试剂是指在液相中与本化合物形成离子对的试剂。该离子对试剂根据本发明的水性液体制剂的pH而适当选择,使得在液相中可以与本化合物(活性成分)形成离子对。例如,当pH为约7时,可以使用山梨酸,辛酸,N-月桂酰基-L-谷氨酸,脱氢乙酸或糖精或其药理学可接受的盐,优选山梨酸,辛酸或N-月桂酰基-L-谷氨酸或其药理学可接受的盐。当pH为约5时,可以使用乙酰色氨酸,糖精,山梨酸,辛酸或脱氢乙酸或其药理学可接受的盐,优选糖精或其药理学可接受的盐。上述盐的实例包括碱金属盐,例如钠盐,钾盐等。
当本发明的水性液体制剂被用作滴眼剂时,优选将该液体制剂的pH调节到约7。因而,离子对试剂优选选自山梨酸,辛酸,N-月桂酰基-L-谷氨酸及其药理学可接受的盐。
本化合物和上述离子对试剂以摩尔比计的混合比通常为本化合物∶离子对试剂=1∶0.01-1∶100,优选1∶0.1-1∶10。根据离子对试剂的选择和上述混合比,有效地在本发明的水性液体制剂中形成离子对,并且可以促进本化合物的眼内渗透。
在另一个实施方案中,本发明的水性液体制剂的特征在于包含用于促进活性成分的眼内渗透的水溶性聚合物。
所述水溶性聚合物的实例包括黄原酸胶,透明质酸,聚乙二醇,聚乙烯吡咯烷酮,羟丙基甲基纤维素,甲基纤维素,羟乙基纤维素,褐藻酸,聚谷氨酸,壳聚糖,羧甲基纤维素,它们的盐,羧基乙烯基聚合物,聚乙烯醇等。优选的是能够提供适当的水性液体制剂粘度的黄原酸胶。
例如,黄原酸胶的平均分子量通常为100,000-50,000,000,优选200,000-20,000,000,特别优选1,000,000-10,000,000。作为黄原酸胶,使用商购自日本住友制药株式会社(Dainippon Sumitomo Pharma Co.,Ltd.)的ECHO GUM系列例如ECHO GUM T,ECHO GUM F等,商购自San-Ei GenF.F.I.公司的SAN-ACE系列例如SAN-ACE NXG-S等,商购自三妆化研株式会社(SANSHO Co.,Ltd.)的KERTOROL系列例如KERTOROL CG,KERTOROL CG-T等等,并且优选ECHO GUM T和KERTOROL CG-T。
水溶性聚合物(例如,黄原酸胶)在本发明的水性液体制剂中的浓度通常为0.02-1.0w/v%,优选0.1-0.5w/v%。
含有水溶性聚合物的本发明的水性液体制剂的粘度,如通过E型旋转粘度计(10rpm)测量的,通常不小于30mPa·s。具有此范围的粘度的水性液体制剂是优选的,因为例如,在眼内局部给药过程中容易操作,并且在液体制剂眼内存留方面优良。
例如,当使用黄原酸胶时,浓度在1.0w/v%内的滴眼剂是优选的,原因在于它保持了适当的制剂静态粘度,在例如滴注等的给药(动态)条件下具有低的粘度,并且容易操作。它在水性液体制剂的制备过程中也是优选的,原因在于粘度适当,并且在普通条件下可以进行通过过滤灭菌。
本发明的水性液体制剂经口或肠胃外给药。给药形式的实例包括经口给药形式例如糖浆剂等和肠胃外给药形式例如外用制剂(例如,溶液,混悬剂或乳剂注射,滴眼剂等)。它优选以眼局部给药形式使用,并且特别优选以滴眼剂的形式使用。
具有上述剂型的制剂通过可以将本化合物与用于配制制剂所必需的添加剂例如典型的载体,赋形剂,粘合剂,稳定剂等混合,并且按照常规方法制备。例如,将本化合物与药用载体(例如,赋形剂,粘合剂,崩解剂,矫正剂,矫味剂,乳化剂,稀释剂,增溶剂等)混合,以得到适于口服或肠胃外制剂形式的以糖浆剂,液体制剂,乳剂,混悬剂,注射剂(例如,液体制剂,混悬剂等),滴眼剂等的形式的药物组合物或药物制剂。
在制备液体制剂时,使用添加剂,例如氯化钠,葡萄糖,山梨醇,甘油,丙二醇,乙醇等。
在制备注射剂时,使用无菌水溶液例如生理盐水,等渗液,油等。必要时,可以同时使用适当的悬浮剂例如羧甲基纤维素钠,非离子表面活性剂,增溶剂(例如,苯甲酸苯甲酯,苯甲醇)等。
而且,在制备滴眼剂时,使用特别是无菌的注射用水溶液的水溶液或混悬剂。滴眼剂可以适当地包含各种添加剂,例如,缓冲剂,稳定剂,润湿剂,乳化剂,悬浮剂,表面活性剂,等渗剂,防腐剂和增稠剂。
缓冲剂例如可以是磷酸盐缓冲剂,硼酸盐缓冲剂,柠檬酸盐缓冲剂,酒石酸盐缓冲剂,乙酸盐缓冲剂,氨基酸等。
稳定剂例如可以是乙二胺四乙酸钠,柠檬酸等。
润湿剂例如可以包括甘油等。
混悬剂例如可以是羟丙基甲基纤维素,甲基纤维素等。
表面活性剂例如可以是聚山梨酯80,聚氧乙烯氢化蓖麻油等。
等渗剂例如可以是糖类例如山梨醇,葡萄糖,甘露醇等,多元醇例如甘油,丙二醇等,盐类例如氯化钠等,等。
防腐剂例如可以是季铵盐例如苯扎氯铵,苄索氯铵等,对羟基苯甲酸酯例如对羟基苯甲酸甲酯,对羟基苯甲酸乙酯等,苯甲醇,苯乙醇,山梨酸及其盐,硫柳汞,氯丁醇等。
增稠剂例如可以是羟乙基纤维素,羟丙基纤维素,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素,及其盐等。
在作为滴眼剂使用时,通常将pH调节到约4-9,优选约6-8.5。
本发明的水性液体制剂以制剂计通常以0.0001-10w/v%,优选0.001-1w/v%,更优选0.01-0.1w/v%的比例包含活性成分。尽管剂量和给药频率取决于症状,年龄,体重和给药形式而变化,但是当将它用作成人用滴眼剂时,将以0.0001-10w/v%,优选0.001-1w/v%的比例含有本化合物的制剂给药每日数次,优选每日1-2次,更优选每日一次,每次几滴,优选1-3滴。
实施例
以下,通过参考实施例和试验例具体解释本发明,所述实施例和试验例不被解释为是限制性的。
实施例1-3和比较例1
滴眼剂的制备
根据表1中所示的配方,制备含有具有Rho激酶抑制作用的化合物,即(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺·一盐酸盐(化合物A)的滴眼剂。实施例1-3中的化合物A和离子对试剂的混合比(摩尔比)是1∶2。
表1
成分 | 实施例1 | 实施例2 | 实施例3 | 比较例1 |
化合物A | 0.0565g | 0.0565g | 0.0565g | 0.0565g |
辛酸钠 | 0.052g | - | - | - |
山梨酸钠 | - | 0.047g | - | - |
N-月桂酰基-L-谷 氨酸钠 | - | - | 0.11g | - |
磷酸二氢钠 | 0.1g | 0.1g | 0.1g | 0.1g |
氯化钠 | 0.85g | 0.85g | 0.85g | 0.85g |
苯扎氯铵 | 0.005g | 0.005g | 0.005g | 0.005g |
氢氧化钠/氯化氢 | 平衡量 | 平衡量 | 平衡量 | 平衡量 |
无菌净化水 | 平衡量 | 平衡量 | 平衡量 | 平衡量 |
总量 | 100ml | 100ml | 100ml | 100ml |
pH | 7.0 | 7.0 | 7.0 | 7.0 |
试验例1
通过添加离子对试剂,化合物A进入到房水中的渗透试验
通过滴注(50μL,一次,n=4)将实施例1-3和比较例1的滴眼剂分别对雄性白兔(体重2.1-2.7kg)的眼给药。通过给药过量的戊巴比妥钠溶液,使兔在滴注给药后1小时安乐死。用生理盐水洗涤眼的外部,并且用具有27G注射针头的注射器对房水取样。将回收的房水用0.45μm色谱盘(chromato disc)过滤,并且将滤液用作试液。在下列条件下进行HPLC,并且测量化合物A的浓度。
<HPLC条件>
检测器:紫外吸收比色计(测量波长:248nm)
柱:YMC-Pack ODS A-302(4.6mm×15cm,5μm)
柱温:接近40℃的恒定温度
流动相:甲醇∶0.02mol/L高氯酸钠(pH 2.5)=18∶82的混合溶液
流速:1.0mL/min
注射体积:50μL
<结果>
结果显示于表2中。
表2
组 | 房水中的化合物A的浓度(ng/mL)* |
比较例1 | 23.7±14.7 |
实施例1 | 44.0±5.7 |
实施例2 | 46.6±23.3 |
实施例3 | 49.1±47.0 |
*每个值显示平均值±标准偏差
如表2中所示,与比较例1给药组中的房水中的化合物A的浓度相比,实施例1给药组,实施例2给药组和实施例3给药组中的房水中的化合物A的浓度增加。由此阐明的是,向含有化合物A的水性液体制剂中加入作为离子对试剂的辛酸钠,山梨酸钠或N-月桂酰基-L-谷氨酸钠,促进了化合物A进入到房水中的渗透。
实施例4和比较例2
滴眼剂的制备
根据表3中所示的配方,制备含有化合物A的滴眼剂。
表3
成分 | 实施例4 | 比较例2 |
化合物A | 0.0565g | 0.0565g |
黄原酸胶(ECHO GUMT:注册商标,日本住友制药株式会社 (Dainippon Sumitomo Pharma Co.,Ltd.)) | 0.2g | - |
磷酸二氢钠 | 0.1g | 0.1g |
氯化钠 | 0.85g | 0.85g |
氢氧化钠/氯化氢 | 平衡量 | 平衡量 |
无菌净化水 | 平衡量 | 平衡量 |
总量 | 100ml | 100ml |
pH | 7.0 | 7.0 |
[0397] 试验例2
在加入水溶性聚合物的情况下,化合物A的眼内组织渗透试验
通过滴注(50μL,一次,n=5)将实施例4和比较例2的滴眼剂分别对雄性白兔(体重2.2-2.6kg)的眼给药。通过给药过量的戊巴比妥钠溶液,使兔在滴注给药后1小时或2小时安乐死。用生理盐水洗涤眼的外部,并且对房水和结膜取样。用具有27G注射针头的注射器对房水取样,向房水(100μL)中加入甲醇(10μL)和随后的内标溶液(10μL),将混合物在氮气流下干燥,溶解在甲醇(20μL)以及随后的流动相溶液A(180μL)中,并且用作房水试液。提取结膜,加入乙腈(5mL)并且切碎结膜,以及将上层清液(4.5mL)分离。将其在氮气流下干燥,并且溶解在随后的稀释溶液(500μL)中。向此溶液(100μL)中加入甲醇(10μL)和内标溶液(10μL),并且将混合物在氮气流下干燥。将残余物溶解在甲醇(20μL)和流动相溶液A(180μL)中,并且用作结膜试液。在下列条件下进行HPLC,并且测量每一个试液中的化合物A的浓度。
<HPLC条件>
检测器:MS/MS
柱:Capcell Pak UG-120S-3(2.0mm×5cm,5μm)
保护柱:Rheodyne Column Inlet Filter(3mm ID釉料)
柱温:30℃
流动相溶液A:10mM甲酸铵的0.1%甲酸水溶液
流动相溶液B:乙腈
注射体积:20μL
稀释溶液:甲醇∶生理盐水=1∶9的混合溶液
内标溶液:内标物((+)-反式-4-(1-氨基乙基)-1-(4-吡啶基氨基甲酰基)环己烷·二盐酸盐·一水合物),约1.4μg/mL甲醇溶液。
表4
MS/MS条件:电离化法:汽轮离子喷雾(turbo ion spray),阳离子模式
物质 | Q1(m/z) | Q3(m/z) |
化合物A | 281 | 264 |
内标物 | 248 | 95 |
表5
梯度条件
时间(min) | 流速(mL/min) | 流动相溶液A的比例 (v/v%) | 流动相溶液B的比例 (v/v%) |
0.0 | 0.25 | 100 | 0 |
7.0 | 0.25 | 80 | 20 |
7.0 | 0.25 | 100 | 0 |
15.0 | 0.25 | 100 | 0 |
<结果>
结果显示于表6中。
表6
*每个值显示平均值±标准偏差
如表6中所示,与比较例2给药组中的房水中的化合物A的浓度相比,在滴注后1小时和2小时的实施例4给药组中的房水中的化合物A的浓度都增加。与比较例2给药组中的结膜中的化合物A的浓度相比,在滴注后1小时和2小时的实施例4给药组中的结膜中的化合物A的浓度都增加。由此阐明的是,向含有化合物A的水性液体制剂中加入作为水溶性聚合物的黄原酸胶,促进了化合物A进入到眼内组织中的渗透。
试验例3
在加入水溶性聚合物的情况下,化合物A的眼内组织渗透试验
以与试验例2中的方法相同的方式对实施例4和比较例2的滴眼剂进行试验,并且在滴注(n=3)后6小时和12小时测量房水和结膜中的化合物A的浓度。
<结果>
结果显示于表7中。
表7
*每个值显示平均值±标准偏差
如表7中所示,在滴注后6小时和12小时,实施例4给药组中的房水中的化合物A的浓度比比较例2给药组中的房水中的化合物A的浓度增加2倍以上。在滴注后6小时,实施例4给药组中的结膜中的化合物A的浓度比比较例2给药组中的结膜中的化合物A的浓度增加约2倍。由此阐明的是,向含有化合物A的水性液体制剂中加入作为水溶性聚合物的黄原酸胶,促进了化合物A进入到眼内组织中的渗透,并且其效果长期维持。
在滴注后,上述试验例2和试验例3中的房水中的化合物A的浓度和结膜中的化合物A的浓度分别显示于图1和图2中。
工业适用性
根据本发明的水性液体制剂,促进了作为活性成分的本化合物的眼内渗透,可以在眼内组织中长期保持活性成分的治疗有效浓度,并且可以减少给药频率。根据本发明,与含有相同浓度的活性成分的已知制剂相比,可以提供在下列方面优良的制剂:活性成分的作用部位可到达性,成分的有效使用,以及给药频率的减少。而且,根据本发明,甚至含有低浓度的活性成分的制剂也能够显示与已知制剂的功效相等的功效,并且延长给药间隔。因而,可以提供在长期给药下特别对患者带来较小负担的制剂。
本申请基于在日本提交的专利申请号2006-209102(提交日:2006年7月31日),将其内容通过此引用而全部结合在此。
Claims (3)
1.一种水性液体制剂,所述水性液体制剂包含由下式(I)表示的酰胺化合物:
其中,
Ra是下式所示基团
在所述式(b)中,
R是氢或具有1至10个碳原子的直链或支链烷基,
R1是氢或具有1至10个碳原子的直链或支链烷基,
R3和R4相同或不同,并且分别是氢或具有1至10个碳原子的直链或支链烷基,
A是由下式表示的基团
其中,R10和R11相同或不同,并且分别是氢或具有1至10个碳原子的直链或支链烷基,并且1,m和n分别是0或1-3的整数,
Rb是氢或具有1至10个碳原子的直链或支链烷基;并且
Rc是吡啶,吡咯并吡啶,吡唑并吡啶,咪唑并吡啶,吡咯并嘧啶,吡唑并嘧啶,咪唑并嘧啶,吡咯并三嗪,吡唑并三嗪,***并吡啶,或***并嘧啶,
它们的异构体和/或它们的药用酸加成盐,以及离子对试剂或水溶性聚合物,其中所述离子对试剂是山梨酸、辛酸或N-月桂酰基-L-谷氨酸或其药理学可接受的盐,所述水溶性聚合物是黄原酸胶,
其中式(I)的酰胺化合物的浓度为0.0001-10w/v%,
水溶性聚合物的浓度为0.02-1.0w/v%,
式(I)的酰胺化合物与离子对试剂的摩尔比为1∶0.01-1∶100。
2.根据权利要求1所述的水性液体制剂,其中由所述式(I)表示的化合物是(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺,由所述式(I)表示的化合物的药用酸加成盐是(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨基乙基)苯甲酰胺一盐酸盐。
3.根据权利要求1-2中任一项所述的水性液体制剂,所述水性液体制剂是滴眼剂。
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- 2007-07-30 KR KR1020097003798A patent/KR20090057223A/ko not_active Application Discontinuation
- 2007-07-30 WO PCT/JP2007/064916 patent/WO2008016016A1/ja active Application Filing
- 2007-07-30 EP EP07791601A patent/EP2050449A4/en not_active Withdrawn
- 2007-07-30 CA CA002659687A patent/CA2659687A1/en not_active Abandoned
- 2007-07-30 BR BRPI0714782-1A patent/BRPI0714782A2/pt not_active IP Right Cessation
- 2007-07-30 CN CN2007800285930A patent/CN101495117B/zh not_active Expired - Fee Related
- 2007-07-30 RU RU2009107191/15A patent/RU2476219C2/ru not_active IP Right Cessation
- 2007-07-30 AU AU2007279766A patent/AU2007279766A1/en not_active Abandoned
- 2007-07-30 JP JP2008527745A patent/JPWO2008016016A1/ja active Pending
- 2007-07-30 MX MX2009001037A patent/MX2009001037A/es not_active Application Discontinuation
- 2007-07-30 US US12/309,813 patent/US20090247552A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
---|---|
KR20090057223A (ko) | 2009-06-04 |
MX2009001037A (es) | 2009-05-15 |
CA2659687A1 (en) | 2008-02-07 |
AU2007279766A1 (en) | 2008-02-07 |
RU2009107191A (ru) | 2010-09-10 |
RU2476219C2 (ru) | 2013-02-27 |
EP2050449A1 (en) | 2009-04-22 |
EP2050449A4 (en) | 2010-10-06 |
CN101495117A (zh) | 2009-07-29 |
JPWO2008016016A1 (ja) | 2009-12-24 |
US20090247552A1 (en) | 2009-10-01 |
BRPI0714782A2 (pt) | 2013-07-16 |
WO2008016016A1 (en) | 2008-02-07 |
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