CN111518028B - 一种一氧化氮供体型ripasudil衍生物及其制备方法和用途 - Google Patents
一种一氧化氮供体型ripasudil衍生物及其制备方法和用途 Download PDFInfo
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- CN111518028B CN111518028B CN202010396041.2A CN202010396041A CN111518028B CN 111518028 B CN111518028 B CN 111518028B CN 202010396041 A CN202010396041 A CN 202010396041A CN 111518028 B CN111518028 B CN 111518028B
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- QSKQVZWVLOIIEV-NSHDSACASA-N ripasudil Chemical class C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(F)=C12 QSKQVZWVLOIIEV-NSHDSACASA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000002840 nitric oxide donor Substances 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 229950007455 ripasudil Drugs 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
- -1 ethylene, propylene, butylene Chemical group 0.000 claims description 13
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
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- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 6
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- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 claims description 4
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Ophthalmology & Optometry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物化学和药物治疗学领域,具体涉及一种一氧化氮(NO)供体型ripasudil衍生物及其制备方法和用途。该类衍生物保留了较强的ROCK抑制活性,抑制小梁网细胞肌球蛋白轻链磷酸化,舒张小梁网房水外排通路;释放的NO可舒张小梁网房水外排通路并抑制房水生成,二者协同降低眼内压,保护高眼压模型小鼠的视网膜神经节细胞。本发明涉及此类NO供体型ripasudil衍生物,或其药学上可接受的盐,他们的制备方法,含有这些化合物的药用组合物以及它们的医药用途,特别是在制备预防和/或治疗青光眼、高眼压等眼科疾病方面的应用。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及一种一氧化氮(NO)供体型ripasudil衍生物及其制备方法和用途。该类衍生物保留了较强的ROCK抑制活性,抑制小梁网细胞肌球蛋白轻链磷酸化,舒张小梁网房水外排通路;释放的NO可舒张小梁网房水外排通路并抑制房水生成,二者协同降低眼内压,保护高眼压模型小鼠的视网膜神经节细胞。本发明涉及此类NO供体型ripasudil衍生物,或其药学上可接受的盐,他们的制备方法,含有这些化合物的药用组合物以及它们的医药用途,特别是在制备预防和/或治疗青光眼、高眼压等眼科疾病方面的应用。
背景技术
青光眼(Glaucoma)是最主要的不可逆致盲眼病,是以视网膜神经节细胞及其轴突渐进变性进而导致视力损伤的一组视神经退行性疾病。目前据统计已有6000多万患者。该数字预计在2020年会增长到8000万,并在2040年达到1.12亿(Ophthalmology,2014,121(11):2081-2090;Lancet,2017,390(10108):2183-2193;Clin Exp Ophthalmol,2012,40(4):341-349)。病理性的眼内压(IOP)升高是最主要的致病危险因素,目前对于青光眼的治疗主要是通过降眼压药物或激光、手术降压来控制及延缓病情发展(Lancet,2015,385(9975):1295-304)。
Rho-相关蛋白激酶(ROCK)抑制剂,如HA-1077,H-1152P,K-115,Y-27632,Y-39983和AMA0076等可有效降低IOP。研究结果表明,ROCK抑制剂可有效降低正常眼压或高眼压动物模型中的IOP,而不会产生严重的副作用(Invest Ophthalmol Vis Sci,2007,48(7):3216-22;Curr Eye Res,2009,34(1):42-7;Curr Eye Res,2009,34(4):282-6;InvestOphthalmol Vis Sci,2014,55(2):1006-16)。
盐酸瑞法舒地尔二水合物(又称K-115),英文名:Ripasudil hydrochloridehydrate,该化合物专利由日本兴和株式会社申请(专利号为CN200580040971.8)。其游离碱为Ripasudil,化学名为4-氟-5-{[(2S)-2-甲基-1,4-二氮杂环庚烷-1-基]磺酰基}异喹啉,化学结构式:
分子式:C15H18FN3O2S,分子量:323.11。K-115是2014年12月于日本上市的滴眼液。它可以选择性抑制Rho相关的蛋白激酶2(ROCK-2),直接作用于小梁网、增加巩膜突的外流来发挥降低眼内压的作用(Drugs,2014,74(18):2211-2215)。研究人员之前已经在非临床实验中对K-115的作用进行了研究,K-115可以抑制人ROCK-1(IC50 0.051μmol/L)和ROCK-2(IC50 0.019μmol/L),比其他ROCK抑制剂Y27632和Fasudil更有效(Curr Eye Res,2014,39(8):813-22)。在对正常眼压的兔子和猴子进行的实验中,0.4%的剂量在临床上表现出降低眼压及治疗青光眼的作用。在之前的研究中,对于兔和猴局部、单侧、单次滴入K-115,可以观察到明显的呈剂量依赖的降低眼压作用(Sci Rep,2016,6:19640)。此外,K-115降低眼压的作用非常迅速,其最大作用(最低眼压)接近于浅层巩膜静脉压。这些结果表明,K-115是一个高效,能够选择性降低眼压的药物。0.4%的K-115滴入后可观察到房水外流显著增加;然而,并未发现K-115滴入对葡萄膜巩膜外流通路或房水流动速率有显著的影响(CurrEye Res,2014,39(8):813-22;J Ocul Pharmacol Ther,2016,32(7):405-14)。这些实验结果表明K-115降低眼压的作用是通过传统外流途径增强房水外流。
近年来,越来越多研究报道了一氧化氮(NO)可用于青光眼治疗的潜力。NO及其信号通路的调节与房水动力学密切相关(Invest Ophthalmol Vis Sci,2014,55(8):5005-15)。与健康受试者相比,高眼压症患者的NO生成减少,外源给予NO显示可降低患者的眼压(Invest Ophthalmol Vis Sci,1995,36(9):1774-84)。eNOS敲除小鼠或GCs活性受损的动物,与其野生型相比,具有较高的IOP,进一步证实NO信号在调节IOP中的重要性(InvestOphthalmol Vis Sci,2017,58(11):4826-4835)。初步机制研究证实,NO可通过多种通路减小房水流出阻力,其中最主要为舒张TM/SC。亦有部分研究证实,NO可一定程度减少房水的生成。
发明内容
目的:本发明提供一种NO供体型Ripasudil衍生物及其制备方法和用途,通过调节小梁网肌动蛋白细胞骨架舒张小梁网,并可通过释放NO发挥视神经节保护作用,可用于预防和/或治疗包含青光眼在内的以眼压升高为表现的原发性疾病或并发症。
临床研究表明,和单一药物治疗相比,2~3种不同作用机制的滴眼液联合使用可大程度地减少副作用,并有效地降低IOP。有鉴于此,本发明提出的具有舒张小梁网和调节小梁网细胞肌动蛋白骨架重构双重作用的药物,比单一作用的药物具有更好的青光眼治疗效果。
技术方案:为解决上述技术问题,本发明采用的技术方案为:
第一方面,本发明公开了一种NO供体型ripasudil衍生物,为通式I所示的化合物或其旋光异构体,对映体、非对映体、外消旋体或外消旋混合物,或其药学上可接受的盐或酯:
其中:式I中标明的一个手性中心,用***1表示,手性中心为R构型或S构型,
R1选自亚甲基,C2-C9直链、支链或包含有环状结构的亚烷基、亚烯基、亚炔基,杂环基,其中环状结构为饱和或不饱和碳环基、杂环基。
更为优选的,R1选自C2-C5直链、支链亚烷基;
进一步的,式I所示的化合物中,R1代表亚乙基、亚丙基、亚丁基、亚戊基,或,
O-R1-O为异山梨醇基手性中心*1为S构型。
在一些实施例中,所述化合物选自下列化合物:
(S)-4-(硝基氧)丁基-4-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(化合物编号:I1)及其盐酸盐(I1·HCl);
(S)-2-(硝基氧)乙基-4-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(化合物编号:I2)
(S)-3-(硝基氧)丙基-4-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(化合物编号:I3)
(S)-5-(硝基氧)戊基-1-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(化合物编号:I4)
(S)-1-单硝酸异山梨酯-1-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(化合物编号:I5)
下面药理实验中化合物的代号等同于此处代号所对应的化合物。
第二方面,提供本发明所述化合物的制备方法,包括:
化合物II与双(五氟苯基)碳酸III反应得到化合物IV,化合物IV与游离的ripasudil V反应得到目标化合物I;合成路线如下:
在一些实施例中,所述化合物的制备方法,
从化合物II制备化合物IV的反应中,溶剂选自无水乙腈,无水二氯甲烷,氯仿,乙酸乙酯,重蒸丙酮,无水四氢呋喃,无水N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种;碱选自碳酸钾,碳酸钠,碳酸氢钠,氢氧化钠,氢氧化钾,吡啶,4-甲氨基吡啶,三乙胺,N,N-二异丙基甲胺;反应温度为-20℃至加热回流;
从化合物IV制备化合物I的反应中,溶剂选自无水乙腈,无水二氯甲烷,氯仿,乙酸乙酯,重蒸丙酮,无水四氢呋喃,无水N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种;碱选自碳酸钾,碳酸钠,碳酸氢钠,氢氧化钠,氢氧化钾,吡啶,4-甲氨基吡啶,三乙胺,N,N-二异丙基甲胺;反应温度为-20℃至加热回流。
作为更优选,所述化合物的制备方法,
从化合物II制备化合物IV的反应中,溶剂选择无水四氢呋喃,反应温度为室温;
从化合物IV制备化合物I的反应中,溶剂选择无水四氢呋喃,反应温度为室温。
这些化合物可按照常规分离技术加以纯化。
第三方面,一种药物组合物,其中含有治疗有效量的权利要求1所述的通式I所示的NO供体型ripasudil衍生物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物,或其药学上可接受的盐及可药用的载体、佐剂或媒剂。
第四方面,提供本发明的化合物在制备预防和/或治疗与眼压升高有关的疾病药物中的应用。更为具体的,所述与眼压升高有关的疾病包括但不限于高眼压症、青光眼、糖尿病并发性眼症等。
此类NO供体型ripasudil衍生物通过滴眼给药,在眼内释放ripasudil和适量NO,前者ROCK,后者激活sGC-cGMP通路,协同产生舒张小梁网、降低眼内压、增加血流量以及保护视网膜神经节细胞的作用。
有益效果:本发明设计、合成了NO供体型ripasudil衍生物,一种新一代的一氧化氮供体和化合物,被证明可以分解成眼组织中的ripasudil(瑞法舒地尔)和NO,产生双重降IOP和保护视网膜神经节细胞的作用。含有目标化合物的药用组合物以及它们的医药用途,特别是在预防和治疗青光眼相关的疾病中,具有良好的应用前景。本发明提供NO供体型ripasudil衍生物联合治疗已成功应用于青光眼,例如青光眼这种高度复杂且进行性进展的疾病。
附图说明
图1:I1·HCl对人小梁网细胞(HTMC)肌球蛋白轻链磷酸化的抑制作用;
图2:I1·HCl对HTMC肌动蛋白细胞骨架的解聚作用;
图3:I1·HCl对HTMC cGMP水平的增加作用;
图4:I1·HCl滴眼给药后降低高眼压模型小鼠的眼内压;
图5:I1·HCl滴眼给药后保护高眼压模型小鼠的视网膜神经节细胞。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明具体描述,不应当理解为对本发明的限制。
本发明化合物I抗青光眼的药理实验方法与结果如下:
NO供体型ripasudil化合物对ROCK-I激酶或ROCK-II激酶具有明显抑制作用
研究了化合物对ROCK-I激酶或ROCK-II激酶的抑制作用。发现化合物I1,I1·HCl以及I2-I5对ROCK-I和ROCK-II激酶均具有抑制作用,其中化合物I1·HCl对ROCK-I和ROCK-II激酶的抑制作用最显著,IC50分别为34.19±1.21nM和16.61±1.14nM,并且比ripasudil的抑制作用更显著(n=5)(表1)。
表1.NO供体型ripasudil化合物对ROCK I和II的抑制活性
I1·HCl对HTMC肌球蛋白轻链磷酸化具有明显抑制作用
研究了I1·HCl对人小梁网细胞(HTMC)肌球蛋白轻链(MLC)磷酸化的影响。发现I1·HCl在10μM浓度下,在2h能显著抑制HTMC肌球蛋白轻链(MLC)的磷酸化(n=3)(图1)。
I1·HCl对HTMC F-actin具有明显解聚作用
研究了I1·HCl对人小梁网细胞(HTMC)肌动蛋白细胞骨架的影响。发现I1·HCl在10μM浓度下,在1h能显著促进HTMC F-actin的解聚,撤去药物后4h,该作用可以恢复(n=3)(图2)。
NO供体型ripasudil化合物在HTMC细胞中释放NO
研究了化合物对人小梁网细胞(HTMC)中NO的释放情况。发现化合物在1μM浓度下,24h后显著提高HTMC中NO的浓度(n=3)(表2)。
表2.NO供体型ripasudil化合物在HTMC细胞中释放NO的情况
NO供体型ripasudil化合物显著提高HTMC中cGMP的水平
研究了化合物对人小梁网细胞(HTMC)cGMP水平的影响。发现化合物在10μM浓度下,在24h能显著升高HTMC cGMP水平(n=3)(图3),提示这些化合物可在HTMC细胞中释放NO,NO进一步激活sGC,提高cGMP的水平。
I1·HCl的体内降眼压活性
实验方法:采用6-8周雄性C57BL/6J(C57)小鼠(体重:20-25g),应用1%戊巴比妥钠,按10mg/kg体重给药,使小鼠充分麻醉,左眼依次滴加托吡卡胺,丙美卡因和左氧氟沙星。对麻醉小鼠左眼的前房注射20μL 4.5μm磁珠造模,右眼未处理。注射一周后,眼内压(IOP)从基线10mmHg升至16-25mmHg。利用异氟烷和氧气和混合气体将小鼠麻醉,对左眼按10μL的剂量一次滴加I1·HCl(给药组,n=5,溶于10%的DMSO的PBS溶液,含I1·HCl0.26%),同时设立含等摩尔量ripasudil组(阳性对照组,n=5,10%的DMSO的PBS溶液,含ripasudil 0.2%),等摩尔量ripasudil+等摩尔量4-羟基丁基硝酸酯组(联合给药组,n=5,10%的DMSO的PBS溶液,含ripasudil 0.2%和4-羟基丁基硝酸酯0.07%)及PBS作为空白对照组(空白组,n=5)。于滴眼前及滴加后1,2,3,4,6小时测量IOP。如图4所示,与空白组相比,ripasudil组,I1·HCl组和联合给药组在给药后1,2,3小时均能显著降低IOP(P<0.001),而I1·HCl组降低IOP的持续时间比ripasudil组(P<0.05)和联合给药组(P<0.05)更长,在4h仍能显著降低IOP。这一结果提示,NO供体型ripasudil衍生物I1·HCl中NO和ROCK抑制剂片段发挥1+1>2的协同抗青光眼的作用。
I1·HCl保护视网膜神经节细胞作用
实验方法:采用6-8周雄性C57BL/6J(C57)小鼠(体重:20-25g),应用1%戊巴比妥钠,按10mg/kg体重给药,使小鼠充分麻醉,左眼依次滴加托吡卡胺,丙美卡因和左氧氟沙星。对麻醉小鼠左眼的前房注射20μL 4.5μm磁珠造模,右眼未处理。于造模后第二天开始对左眼按10μL的剂量滴加I1·HCl(给药组,n=4,溶于10%的DMSO的PBS溶液,含I1·HCl0.52%),同时设立PBS作为空白对照组(空白组,n=4),以及未造模组(n=4)。每日3次,每次间隔2h,持续7天。于造模后第九天实颈椎脱臼处死小鼠,将眼球固定后取视网膜,用RNABinding Protein with Multiple Splicing(RBPMS)对视网膜神经节细胞(RGCs)进行染色,并计数(图4)。与未造模组相比,造模组+PBS组RGCs数量明显减少(P<0.001);而与造模+PBS组相比,造模+I1·HCl组RGCs数量明显增多(P<0.001)(图5)。即,I1·HCl对视网膜神经节细胞具有明显的保护作用。
以上药理学数据显示,本发明涉及的一种NO供体型ripasudil衍生物及其制备方法和用途。该类衍生物保留了较强的ROCK抑制活性,I1的盐酸盐显著抑制小梁网细胞肌球蛋白轻链磷酸化,促进小梁网细胞F-actin的解聚,在前房注射磁珠的小鼠高眼压模型中,I1·HCl降低眼内压作用较ripasudil更为持久,且显著地保护了高眼压模型小鼠的视网膜神经节细胞。这些结果提示此类NO供体型ripasudil衍生物通过ROCK和NO两条通路,舒张房水的小梁网外排通路,协同产生强效的降低眼内压,保护视神经节细胞的作用,具有广阔的开发前景。
实施例1
(S)-4-(硝基氧)丁-4-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(I1)及其盐酸盐(I1·HCl)
将4-羟丁基硝酸酯(53mg,0.39mmol)溶解于5ml的无水THF中,加入双(五氟苯基)碳酸(200mg,0.51mmol),四丁基氟化铵(117μl,0.117mmol)室温搅拌2h,加入TEA(113μl,0.78mmol)游离的化合物V ripasudil(154.1mg,0.39mmol)室温搅拌过夜。反应液加入适量二氯甲烷(50mL)稀释,饱和碳酸氢钠溶液和饱和食盐水各洗涤3次。有机层用无水硫酸钠干燥,过滤,滤液浓缩后经快速硅胶柱层析制得I1。1H NMR(300MHz,CD3OD)δ9.25(s,1H),8.69–8.58(m,1H),8.55(d,J=5.1Hz,1H),8.52–8.44(m,1H),7.94–7.83(m,1H),4.56(t,J=6.1Hz,2H),4.24(t,J=6.1Hz,2H),4.01–3.85(m,3H),3.44–3.31(m,2H),3.11–2.90(m,2H),1.95–1.64(m,6H),0.83(d,J=6.6Hz,3H).ESI-HRMS[M+Na]+calcd for C20H25FN4NaO7S507.1326,found 507.1332,ppm error 1.2.
I1再溶解于适量丙酮(20ml)溶解,加入浓盐酸,过滤,滤饼烘干得I1的盐酸盐I1·HCl(40mg,26%)。
1H NMR(300MHz,CD3OD)δ9.61(s,1H),8.84–8.76(m,2H),8.71–8.66(m,1H),8.09(d,J=4.2Hz,1H),4.58(t,J=6.1Hz,2H),4.23(t,J=6.2Hz,2H),4.02–3.71(m,4H),3.50–3.38(m,1H),3.15–2.97(m,2H),1.94–1.67(m,6H),0.91(d,J=6.6Hz,3H).ESI-HRMS[M+H]+calcd for C20H26FN4O7S 485.1501,found 485.1498,ppm error 0.6.
实施例2
(S)-2-(硝基氧)乙基-4-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(I2)
将2-羟乙基硝酸酯(42mg,0.39mmol)溶解于5ml的无水THF中,加入双(五氟苯基)碳酸(200mg,0.51mmol),四丁基氟化铵(117μl,0.117mmol)室温搅拌2h,加入TEA(113μl,0.78mmol)游离的化合物V ripasudil(154.1mg,0.39mmol)室温搅拌过夜。反应液加入适量二氯甲烷(50mL)稀释,饱和碳酸氢钠溶液和饱和食盐水各洗涤3次。有机层用无水硫酸钠干燥,过滤,滤液浓缩后经快速硅胶柱层析制得I2(50mg,32%)。
1H NMR(300MHz,CD3OD)δ9.25(s,1H),8.73–8.62(m,1H),8.59–8.52(m,1H),8.52–8.44(m,1H),7.88(t,J=7.9Hz,1H),4.85–4.74(m,2H),4.58–4.34(m,2H),4.30–4.11(m,1H),4.00–3.86(m,2H),3.43–3.31(m,2H),3.15–2.90(m,2H),1.91–1.62(m,2H),0.76(d,J=6.6Hz,3H).ESI-HRMS[M+Na]+calcd for C18H21FN4NaO7S 479.1013,found 479.1023,ppmerror 2.1.
实施例3
(S)-3-(硝基氧)丙基-4-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(I3)
将3-羟丙基硝酸酯(47mg,0.39mmol)溶解于5ml的无水THF中,加入双(五氟苯基)碳酸(200mg,0.51mmol),四丁基氟化铵(117μl,0.117mmol)室温搅拌2h,加入TEA(113μl,0.78mmol)游离的化合物V ripasudil(154.1mg,0.39mmol)室温搅拌过夜。反应液加入适量二氯甲烷(50mL)稀释,饱和碳酸氢钠溶液和饱和食盐水各洗涤3次。有机层用无水硫酸钠干燥,过滤,滤液浓缩后经快速硅胶柱层析制得I3(50mg,32%)。
1H NMR(300MHz,CD3OD)δ9.25(s,1H),8.69–8.60(m,1H),8.60–8.52(m,1H),8.52–8.44(m,1H),7.88(t,J=7.9Hz,1H),4.74–4.57(m,2H),4.35–4.22(m,2H),4.04–3.88(m,3H),3.45–3.31(m,2H),3.12–2.89(m,2H),2.21–2.06(m,2H),1.83–1.55(m,2H),0.80(d,J=6.5Hz,3H).ESI-HRMS[M+Na]+calcd for C19H23FN4NaO7S,493.1169,found 493.1160,ppmerror 1.8.
实施例4
(S)-5-(硝基氧)戊基-1-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(I4)
将5-羟戊基硝酸酯(47mg,0.39mmol)溶解于5ml的无水THF中,加入双(五氟苯基)碳酸(200mg,0.51mmol),四丁基氟化铵(117μl,0.117mmol)室温搅拌2h,加入TEA(113μl,0.78mmol)游离的化合物V ripasudil(154.1mg,0.39mmol)室温搅拌过夜。反应液加入适量二氯甲烷(50mL)稀释,饱和碳酸氢钠溶液和饱和食盐水各洗涤3次。有机层用无水硫酸钠干燥,过滤,滤液浓缩后经快速硅胶柱层析制得I4(50mg,32%)。
1H NMR(300MHz,CD3OD)δ9.25(s,1H),8.68–8.58(m,1H),8.58–8.52(m,1H),8.52–8.44(m,1H),7.88(t,J=7.8Hz,1H),4.60–4.45(m,2H),4.34–4.19(m,2H),4.01–3.86(m,3H),3.45–3.32(m,2H),3.10–2.90(m,2H),1.91–1.40(m,8H),0.86(d,J=6.6Hz,3H).ESI-HRMS(M+Na)+calcd for C21H27FN4NaO7S 521.1482,found 521.1491,ppm error 1.7.
实施例5
(S)-1-单硝酸异山梨酯-1-((4-氟异喹啉-5基)磺酰基)-3-甲基-1,4-氮杂环庚烷-1-甲酸酯(I5)
将单硝酸异山梨酯(74.5mg,0.39mmol)溶解于5ml的无水THF中,加入双(五氟苯基)碳酸(200mg,0.51mmol),四丁基氟化铵(117μL,0.117mmol)室温搅拌2h,加入TEA(113μL,0.78mmol)游离的化合物V ripasudil(154.1mg,0.39mmol)室温搅拌过夜。反应液加入适量二氯甲烷(50mL)稀释,饱和碳酸氢钠溶液和饱和食盐水各洗涤3次。有机层用无水硫酸钠干燥,过滤,滤液浓缩后经快速硅胶柱层析制得I5(50mg,32%)。
1H NMR(300MHz,CD3OD)δ9.25(s,1H),8.79–8.61(m,1H),8.61–8.52(m,1H),8.52–8.44(m,1H),7.88(d,J=7.9Hz,1H),5.53–5.43(m,1H),5.18–5.11(m,1H),5.03–4.96(m,1H),4.55–4.49(m,1H),4.44–4.38(m,1H),4.07–3.90(m,6H),3.45–3.32(m,2H),3.09–2.93(m,2H),2.01–1.71(m,2H),0.70(d,J=6.5Hz,3H).ESI-HRMS(M+Na)+calcd forC22H25FN4NaO9S 563.1224,found 521.1212,ppm error 2.1。
以上所述仅是本发明的优选实施方式,应当指出:对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.一类化合物,为通式I所示的化合物,或其药学上可接受的盐:
其中:式I中标明的一个手性中心,用*1表示,手性中心为R构型或S构型;
R1选自亚甲基,C2-C9直链、支链的亚烷基。
2.根据权利要求1所述的化合物,其特征在于,式I所示的化合物中,手性中心*1为S构型;
R1代表亚乙基、亚丙基、亚丁基、亚戊基。
3.一种化合物,其特征在于,所述化合物选自以下化合物:
4.权利要求1所述化合物的制备方法,包括:
化合物II与化合物III反应得到化合物IV,化合物IV与游离的ripasudil V反应得到目标化合物I;合成路线如下:
5.根据权利要求4所述化合物的制备方法,其特征在于,
从化合物II制备化合物IV的反应中,溶剂选自无水乙腈,无水二氯甲烷,氯仿,乙酸乙酯,重蒸丙酮,无水四氢呋喃,无水N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种;碱选自碳酸钾,碳酸钠,碳酸氢钠,氢氧化钠,氢氧化钾,吡啶,4-甲氨基吡啶,三乙胺,N,N-二异丙基甲胺;反应温度为-20℃至加热回流;和/或,
从化合物IV制备化合物I的反应中,溶剂选自无水乙腈,无水二氯甲烷,氯仿,乙酸乙酯,重蒸丙酮,无水四氢呋喃,无水N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种;碱选自碳酸钾,碳酸钠,碳酸氢钠,氢氧化钠,氢氧化钾,吡啶,4-甲氨基吡啶,三乙胺,N,N-二异丙基甲胺;反应温度为-20℃至加热回流。
6.根据权利要求5所述化合物的制备方法,其特征在于,
从化合物II制备化合物IV的反应中,溶剂选择无水四氢呋喃,反应温度为室温;和/或,
从化合物IV制备化合物I的反应中,溶剂选择无水四氢呋喃,反应温度为室温。
7.一种药物组合物,其中含有治疗有效量的权利要求1-3任一项所述的化合物,或其药学上可接受的盐及可药用的载体。
8.权利要求1-3任一项所述的化合物在制备预防和/或治疗与眼压升高有关疾病的药物中的应用。
9.根据权利要求8所述的用途,其特征在于,与眼压升高有关的疾病为高眼压症、青光眼、糖尿病并发性眼症。
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