WO2021227897A1 - 一种一氧化氮供体型netarsudil衍生物及其制备方法和用途 - Google Patents

一种一氧化氮供体型netarsudil衍生物及其制备方法和用途 Download PDF

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WO2021227897A1
WO2021227897A1 PCT/CN2021/091526 CN2021091526W WO2021227897A1 WO 2021227897 A1 WO2021227897 A1 WO 2021227897A1 CN 2021091526 W CN2021091526 W CN 2021091526W WO 2021227897 A1 WO2021227897 A1 WO 2021227897A1
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compound
group
reaction
netarsudil
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黄张建
张奕华
吴建兵
毛宇婕
朱明超
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中国药科大学
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    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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    • 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
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  • the invention relates to the fields of medicinal chemistry and pharmacotherapy, and relates to a nitric oxide (NO) donor type Netarsudil derivative and a preparation method and application thereof, and specifically relates to the cooperation of NO donor and Netarsudil to relax the trabecular meshwork and regulate cytoskeletal remodeling Combination strategy, synthesis and evaluation of anti-glaucoma activity.
  • NO nitric oxide
  • This type of compound can be used for the increase in intraocular pressure caused by the increase in the resistance to the outflow of aqueous humor.
  • the present invention also relates to pharmaceutical combinations containing such compounds and their uses.
  • Glaucoma is a type of optic nerve disease caused by a variety of factors, characterized by persistent intraocular pressure (IOP) increase, optic nerve damage and visual field defects. It will eventually cause the death of retinal ganglion cells (RGCs) and deformation of the connective tissue that supports the optic disc, resulting in complete blindness. Glaucoma is the second largest irreversible blindness disease worldwide. According to statistics, there are currently more than 60 million patients. This number is expected to grow to 80 million in 2020 and 112 million in 2040. Clinically, lowering IOP is still the only way to prevent its further development and cause visual impairment or blindness.
  • IOP intraocular pressure
  • ROCK inhibitors HA-1077, H-1152P, AR-13324, Y-27632, Y-39983, AMA0076, etc.
  • ROCK inhibitor Netarsudil AR-13324
  • NET norepinephrine transporter
  • TM and SC The traditional route through TM and SC is the main route for the outflow of mammalian aqueous humor.
  • the resistance to the outflow of aqueous humor is produced by the inner wall of the SC and the microtubule area of the TM.
  • the structural characteristics of the cytoskeleton, mutual adhesion, SC cell permeability and TM cell secretion all play an important role in regulating the outflow of aqueous humor.
  • Netarsudil has the ability to destroy actin stress fibers and focal adhesions in TM cells, so Netarsudil can relax TM, increase SC permeability and reduce IOP.
  • Netarsudil can block the expression of fibrous markers induced by TGF- ⁇ 2 and has anti-fibrotic activity, which indicates that Netarsudil can change the fibrotic disease process related to the increase of IOP in TM.
  • steroid glaucoma can be treated with ROCK inhibitors. The mechanism behind this type of glaucoma is through the non-canonical Wnt pathway combined with ROR2/RhoA/ROCK. Yuan et al. determined that dexamethasone can activate this pathway, promote the cross-linking of the actin network, and cause structural changes in the TM cytoskeleton. Given the key role of Netarsudil on ROCK inhibition, it may be a viable treatment option for steroid glaucoma.
  • inhibiting NET can block the reuptake of norepinephrine in synapses, thereby increasing the intensity and duration of endogenous norepinephrine signaling. This mechanism may involve the production of aqueous humor. Since norepinephrine induces vasoconstriction, inhibiting NET can reduce blood flow in the blood vessels, thereby reducing the blood flowing into the ciliary body, thereby reducing the production of aqueous humor. Therefore, Netarsudil, as a NET inhibitor, can reduce IOP by inhibiting the production of aqueous humor.
  • the present invention provides a NO donor type Netarsudil derivative and its preparation method and application. Pharmacological experiments have proved that these compounds have a good effect of lowering intraocular pressure, therefore, they can be used to prevent and treat glaucoma.
  • NO can reduce the resistance of aqueous humor outflow through a variety of pathways, the most important of which is diastolic TM/SC. Some studies have also confirmed that NO can reduce the production of aqueous humor to a certain extent.
  • the present invention proposes to couple the NO donor compound nitrate or nitrosothiol compound and ROCK/NET to dually inhibit the active metabolite of Netarsudil, and the obtained compound has multiple effects on lowering intraocular pressure, which is better than a single effect.
  • the drug has a better treatment effect of glaucoma.
  • the present invention discloses a compound, which is a compound represented by general formula A or its optical isomers, enantiomers, diastereomers, racemates or racemic mixtures, or pharmaceutically Acceptable salt:
  • Linker represents an alkylene acyl group or an alkylene group, where the alkylene group is C1-C10 linear, branched, and contains a cyclic structure Or alkylene group, alkenylene group, alkynylene group, heterocyclic group containing ester bond, wherein the cyclic structure is saturated or unsaturated carbocyclic group or heterocyclic group.
  • the compound represented by formula A is selected from:
  • R 1 is selected from methylene, C2-C9 linear, branched or alkylene, alkenylene, alkynylene, heterocyclic group containing a cyclic structure, wherein the cyclic structure is a saturated or unsaturated carbocyclic ring Group, heterocyclic group.
  • R 1 represents ethylene, propylene, butylene, pentylene, or,
  • the compound is selected from:
  • R 2 and R 3 each independently represent an alkyl group, including a C2-C5 linear or branched chain alkyl group, or R 2 and R 3 together form a cyclic alkyl group.
  • the compound is selected from:
  • R 1 is selected from methylene, C2-C9 linear, branched or cyclic alkylene and alkenylene , Alkynylene, heterocyclic group, wherein the cyclic structure is saturated or unsaturated carbocyclic group, heterocyclic group.
  • the preparation method is characterized in that:
  • the solvent is selected from anhydrous acetonitrile, anhydrous dichloromethane, chloroform, ethyl acetate, redistilled acetone, anhydrous tetrahydrofuran, anhydrous N,N-dimethylformamide, two One or more of methyl sulfoxide or dioxane;
  • base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, pyridine, 4-methylaminopyridine, triethylamine, N ,N-Diisopropylmethylamine; the reaction temperature is -20°C to heating to reflux; and/or,
  • anhydrous dichloromethane is selected as the solvent; trifluoroacetic acid is selected as the acid; and the reaction temperature is from 0° C. to room temperature.
  • anhydrous dichloromethane is selected as the solvent, and the reaction temperature is room temperature.
  • anhydrous dichloromethane is selected as the solvent, and the reaction temperature is from 0° C. to room temperature.
  • a pharmaceutical composition which contains a therapeutically effective amount of the compound or its optical isomers, enantiomers, diastereomers, racemates or racemic mixtures, or pharmaceutical compositions thereof Acceptable salts and pharmaceutically acceptable carriers, adjuvants or vehicles.
  • the application of the compound of the present invention in the preparation of drugs for the prevention and/or treatment of diseases related to increased intraocular pressure is provided.
  • the diseases related to the increase in intraocular pressure include but are not limited to ocular hypertension, glaucoma, diabetic eye syndrome and the like.
  • the NO donor Netarsudil derivative is administered by eye drops to release Netarsudil and appropriate amount of NO in the eye.
  • the former inhibits ROCK and the latter activates the sGC-cGMP pathway, which synergistically produces diastolic trabecular meshwork, reduces intraocular pressure, increases blood flow, and protects The role of retinal ganglion cells.
  • the present invention designs and synthesizes NO-donor Netarsudil derivatives, which are proven to have dual-lowering IOP and protection of retinal ganglion cells by inhibiting ROCK and releasing NO, and it is non-irritating to the conjunctiva of New Zealand white rabbits.
  • Figure 1 shows the effect of I 1 ⁇ 2HCl and Netarsudil hydrochloride on rabbit eye conjunctiva after eye drops.
  • NO-donor Netarsudil compound releases NO in human trabecular meshwork cells (HTMC)
  • the NO release of the compound in HTMC cells was studied. Using DAF-FM DA fluorescent probes, it was found that compounds I 1 and II 3 released NO in a time-dependent manner (Table 1). Furthermore, at the time point of 24h, the NO in the cells was detected by flow cytometry, and it was found that compounds I 1 , I 2 , I 4 , and II 3 released more NO (Table 2). Among them, ISMN is isosorbide mononitrate.
  • Netarsudil compound I 1 has inhibitory effect on ROCK-I kinase or ROCK-II kinase
  • the reaction solution was extracted with EA, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain a pale yellow oily liquid I 1 (103 mg).
  • I 1 was dissolved in absolute ethanol, HCl was passed through it, and a white solid I 1 ⁇ 2HCl (112 mg) was obtained by the reaction.

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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Netarsudil衍生物及其制备方法和用途。这些衍生物保留了较强的ROCK抑制活性，在人小梁网细胞中可释放一定量的NO，二者协同降低新西兰白兔眼内压，且没有眼结膜的刺激性。本发明涉及此类NO供体型Netarsudil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

一种一氧化氮供体型Netarsudil衍生物及其制备方法和用途 技术领域
本发明涉及药物化学和药物治疗学领域，涉及一种一氧化氮(NO)供体型Netarsudil衍生物及其制备方法和用途，具体涉及NO供体和Netarsudil协同舒张小梁网，调节细胞骨架重构的联合用药策略、合成及抗青光眼活性评价。该类化合物可用于房水流出阻力增大而导致的眼内压升高。本发明还涉及含有这类化合物的药物组合及其用途。
背景技术
青光眼(Glaucoma)是一类多种因素导致的视神经疾病，以持续性的眼内压(IOP)升高、视神经损伤而视野缺损为主要特征。其最终会导致视网膜神经节细胞(RGCs)死亡及支撑视盘的结缔组织变形，从而造成完全的失明。青光眼是全球范围内第二大不可逆致盲疾病，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。临床上，降低IOP仍然是防止其进一步发展致视力损伤或失明的唯一手段。
目前，许多研究报道了ROCK抑制剂(HA-1077，H-1152P，AR-13324，Y-27632，Y-39983，AMA0076等)的细胞作用和降低IOP作用。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。
2017年12月，ROCK抑制剂Netarsudil(AR-13324)滴眼液由美国FDA批准上市。它是一种ROCK激酶和去甲肾上腺素转运体(NET)双重抑制剂，通过松弛小梁网(TM)和收缩睫状肌，减少房水流出阻力从而直接降低IOP，并且它还可以通过降低巩膜静脉压和减少房水的生成来降低IOP。
Figure PCTCN2021091526-appb-000001
研究证明，Netarsudil可以抑制人类ROCK-1(K i＝1nM)和ROCK-2(K i＝1nM)，比其他ROCK抑制剂更有效，如Y27632和fasudil。在对正常眼压的兔和猴进行的实验结果表明，0.04％Netarsudil显著降低眼压，在治疗的第3天，观察到兔和猴的最大眼压 降低值分别为8.1±0.7和7.5±1.1mmHg(两者均P<0.01)。研究发现，以不同的浓度对兔和猴单次、单侧局部给药，可以观察到明显的呈剂量依赖性降低眼压的作用。此外，Netarsudil和Latanoprost联合给药可产生更强的降低IOP作用，并且不良反应发生率与单独使用Netarsudil相当。2019年3月12日，美国FDA批准Rocklatan(Netarsudil/Latanoprost)的新药上市申请，临床上用于治疗青光眼和高眼压症。
通过TM和SC的传统途径是哺乳动物房水外流的主要途径。在正常眼和青光眼中，房水外流的阻力都是由SC的内壁和TM的近微管区产生的。细胞骨架结构特征，相互粘连作用，SC细胞通透性和TM细胞分泌都在调节房水外流中起着重要作用。Netarsudil具有破坏TM细胞中肌动蛋白应激纤维和粘着斑的能力，因此Netarsudil能够松弛TM，增加SC通透性从而降低IOP。此外，Netarsudil能阻断TGF-β2诱导的纤维标记物的表达能力，具有抗纤维化活性，这说明Netarsudil能够改变TM中与IOP升高相关的纤维化疾病过程。此外，类固醇性青光眼可以用ROCK抑制剂治疗，这类青光眼背后的机制是通过与ROR2/RhoA/ROCK结合的非经典Wnt途径。Yuan等确定地塞米松可以激活该途径，促进肌动蛋白网络的交联，并引起TM细胞骨架的结构改变。鉴于Netarsudil对ROCK抑制的关键作用，它可能是类固醇性青光眼的可行治疗选择。
研究证明抑制NET可以阻断去甲肾上腺素在突触中的再摄取，从而增加内源性去甲肾上腺素信号传导的强度和持续时间。这一机制可能涉及房水的生成，由于去甲肾上腺素诱导血管收缩，抑制NET可减少血管中血液流量，从而减少流入睫状体的血液，进而减少房水的生成。因此，Netarsudil作为一种NET抑制剂，可以通过抑制房水生成降低IOP。
发明内容
目的：本发明提供一种NO供体型Netarsudil衍生物及其制备方法和用途。药理实验证明，该类化合物具有良好的降眼压作用，因此，它们可用于预防和治疗青光眼。
近年来，NO/NO供体用于青光眼治疗的研究越来越多。大量文献证实，NO在IOP的控制中扮演着重要角色。NO及其信号通路的调节与房水动力学密切相关。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。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。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。
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，本发明提出将NO供体化合物硝酸酯或者亚硝基硫醇化合物和ROCK/NET双重抑制Netarsudil的活性代谢物偶联，得到的化合物具有多方面降眼压的作用，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，本发明公开了一种化合物，为通式A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：
Figure PCTCN2021091526-appb-000002
其中：m为2时，X为O；m为1时，X为S；Linker代表亚烷基酰基或亚烷基，其中亚烷基为C1-C10直链、支链、包含有环状结构或包含有酯键的亚烷基、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。
在一些实施例中，式A所示的化合物选自：
Figure PCTCN2021091526-appb-000003
Figure PCTCN2021091526-appb-000004
其中：
R 1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。
在一些实施例中，R 1代表亚乙基、亚丙基、亚丁基、亚戊基，或，
-R 1-为
Figure PCTCN2021091526-appb-000005
进一步的，所述化合物选自：
Figure PCTCN2021091526-appb-000006
R 2、R 3各自独立地代表烷基，包括C2-C5直链或支链烷基，或R 2、R 3共同构成环状烷基。
具体的，所述化合物选自：
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-4-(硝基氧基)丁酸酯(I 1)及其盐酸盐(I 1·2HCl)；
Figure PCTCN2021091526-appb-000007
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-5-(硝基氧基)戊酸酯(I 2)；
Figure PCTCN2021091526-appb-000008
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-6-(硝基氧基)己酸酯(I 3)；
Figure PCTCN2021091526-appb-000009
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]-苄基-琥珀酸单硝酸异山梨酯(I 4)
Figure PCTCN2021091526-appb-000010
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-4-[(硝基氧基)甲基]苯甲酸酯(I 5)
Figure PCTCN2021091526-appb-000011
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基[2-甲基-2-(亚硝基硫丙基)丙基]琥珀酸酯(II 1)
Figure PCTCN2021091526-appb-000012
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基[2-甲基-2-(亚硝基硫代)丁基]琥珀酸酯(II 2)
Figure PCTCN2021091526-appb-000013
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基[2-乙基-2-(亚硝基硫代)丁基]琥珀酸酯(II 3)
Figure PCTCN2021091526-appb-000014
{1-[(λ 2-氮杂亚基)(氧代)-λ 5-硫烷基]环己基}甲基{4-[3-氨基-1-(异喹啉-6-基氨基)-1-氧代丙烷-2-基]苄基}琥珀酸酯(II 4)
Figure PCTCN2021091526-appb-000015
第二方面，还提供式I、式II所示的化合物的制备方法，包括：
化合物III与化合物IV反应得到化合物V，化合物V氨基脱保护得到目标化合物I、II；合成路线如下：
Figure PCTCN2021091526-appb-000016
其中：m为2时，X为O；m为1时，X为S；R 1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。
在一些实施例中，所述的制备方法，其特征在于，
从化合物III制备化合物V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V制备化合物I、II的反应中，溶剂选择无水二氯甲烷；酸选择三氟乙酸； 反应温度为0℃至室温。
进一步的，在一些实施例中，从化合物III制备化合物V的反应中，溶剂选择无水二氯甲烷，反应温度为室温。
从化合物V制备化合物I、II的反应中，溶剂选择无水二氯甲烷，反应温度为0℃至室温。
这些化合物可按照常规分离技术加以纯化。
第三方面，提供一种药物组合物，其中含有治疗有效量的所述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。
NO供体型Netarsudil衍生物通过滴眼给药，在眼内释放Netarsudil和适量NO，前者抑制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Netarsudil衍生物，被证明可通过抑制ROCK并释放NO，产生双重降IOP和保护视网膜神经节细胞的作用，且对新西兰白兔眼结膜无刺激性。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。
附图说明
图1为I 1·2HCl与Netarsudil盐酸盐滴眼给药后对家兔眼结膜的影响。
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和II抗青光眼的药理实验方法与结果如下：
NO供体型Netarsudil化合物在人小梁网细胞(HTMC)中释放NO情况
研究了化合物在HTMC细胞中的NO释放。使用DAF-FM DA荧光探针发现化合物I 1和II 3以时间依赖性释放NO(表1)。进一步，选择24h这一时间点，用流式细胞仪检测细胞内NO的情况，发现化合物I 1、I 2、I 4、II 3释放的NO较多(表2)。其中， ISMN为单硝酸异山梨醇。
表1.化合物I 1和II 3在HTMC细胞中释放NO的情况
Figure PCTCN2021091526-appb-000017
表2 DAF-FM DA荧光探针检测TM细胞内化合物释放NO含量(流式)
Figure PCTCN2021091526-appb-000018
NO供体型Netarsudil化合物I 1对ROCK-I激酶或ROCK-II激酶具有抑制作用
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I 1对ROCK-I和ROCK-II激酶具有抑制作用，IC 50分别为24.40±3.22nM和15.70±0.44nM(表3)。表3化合物I 1和Netarsudil抑制ROCK-I及ROCK-II酶活性的IC 50
Figure PCTCN2021091526-appb-000019
Figure PCTCN2021091526-appb-000020
NO供体型Netarsudil衍生物I 1盐酸盐与Netarsudil盐酸盐对正常家兔眼内压的影响
实验方法：采用成年新西兰白兔(重量在2-3kg之间)，左眼滴加生理盐水，右眼滴加化合物I 1·2HCl(0.3％)或Netarsudil盐酸盐(0.3％)。使用非接触式眼压计分别测量0h、1h、2h、4h、8h、24h的眼内压(IOP)变化。实验发现，I 1在0-4h内可快速降低IOP，降低幅度与Netarsudil相当。(表4)。
值得注意的是，Netarsudil盐酸盐(0.3％)滴眼给药后2h即引起白兔眼结膜充血，并引起白色絮状分泌物增多(见图1，箭头部位)，这一副作用持续24h；而I 1·2HCl给药组并没有发生此类副作用。提示I 1·2HCl相比于Netarsudil具有更好的安全性。
表4化合物I 1·2HCl及Netarsudil盐酸盐对家兔眼内压的影响
Figure PCTCN2021091526-appb-000021
以上药理学数据显示，本发明涉及的一种有关NO供体型Netarsudil衍生物I 1能够发挥显著的抗青光眼作用且安全性较高，值得进一步研究。
实施例1
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-4-(硝基氧基)丁酸酯及其盐酸盐(I 1，I 1·2HCl)
Figure PCTCN2021091526-appb-000022
将4-(氮氧基)丁酸(77mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg,0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥， 过滤，滤液浓缩，柱层析纯化得Ⅴ 1(157mg)。将Ⅴ 1溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得淡黄色油状液体I 1(103mg)。将I 1溶于无水乙醇，向其中通入HCl，反应得到白色固体I 1·2HCl(112mg)。
I 1：MS:[M+H] +＝453.2. 1H NMR(CDCl 3,300MHz)δ:10.26(s,1H),9.09(s,1H),8.42(d,J＝5.73Hz,1H),8.33(s,1H),7.85(d,J＝8.79Hz,1H),7.56～7.51(m,2H),7.33(s,4H),5.10(s,2H),4.48(t,J＝6.23Hz,2H),3.76(dd,J 1＝6.96Hz,J 2＝4.32Hz,1H),3.46～3.39(m,1H),3.25～3.20(m,1H),2.48(t,J＝7.11Hz,2H),2.10～2.01(m,2H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:174.62,174.30,154.27,145.96,142.34,140.42,139.51,137.76,131.53,131.19,131.08,123.75,123.02,116.91,74.51,68.72,57.42,47.32,32.28,24.89.
I 1·2HCl： 1H NMR(D 2O,300MHz)δ:9.42(s,1H),8.45～8.44(m,1H),8.38(s,1H),8.31～8.08(m,2H),7.87～7.80(m,1H),7.59(s,4H),5.21(s,2H),4.46～4.40(m,2H),3.83～3.81(m,1H),3.62～3.60(m,1H),2.52～2.46(q,J＝7.02Hz,2H),2.13(d,J＝4.20Hz,1H),2.01～1.93(m,1H).
实施例2
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-5-(硝基氧基)戊酸酯(I 2)
Figure PCTCN2021091526-appb-000023
将5-(氮氧基)戊酸(85mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg，0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 2(161mg)。将Ⅴ 2溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有 机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得淡黄色油状液体I 2(106mg)。MS:[M+H] +＝467.1. 1H NMR(CDCl 3,300MHz)δ:10.37(s,1H),8.98(s,1H),8.34(d,J＝5.28Hz,1H),8.25(s,1H),7.70(d,J＝8.70Hz,1H),7.52～7.44(m,2H),7.39～7.29(m,4H),5.07(s,2H),4.42(t,J＝5.31Hz,2H),4.07～4.00(m,1H)3.52～3.49(m,1H),3.37～3.34(m,1H),2.38(t,J＝6.30Hz,2H),1.75～1.73(m,4H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:172.66,171.37,151.35,142.83,139.80,137.29,136.76,135.51,128.84,128.48,128.36,121.15,120.49,114.15,72.66,65.83,50.58,44.35,29.64,29.31,26.17,21.06.
实施例3
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-6-(硝基氧基)己酸酯(I 3)
Figure PCTCN2021091526-appb-000024
将6-(氮氧基)己酸(92mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg，0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 3(165mg)。将Ⅴ 3溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得淡黄色油状液体I 3(109mg)。MS:[M+H] +＝481.2. 1H NMR(CDCl 3,300MHz)δ:10.33(s,1H),9.03(s,1H),8.37(d,J＝5.64Hz,1H),8.29(s,1H),7.78(d,J＝8.79Hz,1H),7.49(d,J＝8.79Hz,2H),7.35～7.29(m,4H),5.07(s,2H),4.39(t,J＝6.54Hz,2H),3.85(s,1H),3.49～3.42(m,1H),3.21～3.18(m,1H),2.34(t,J＝7.34Hz,2H),2.15(s,2H),1.72～1.60(m,4H),1.27～1.26(m,2H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:173.06,171.63,151.51,143.09,139.82,137.51,136.85,135.53,128.78,128.58,128.39,121.16,120.46,114.23,72.97,65.72,54.60,53.41,44.63,33.87,26.45,25.15,24.30.
实施例4
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]-苄基-琥珀酸单硝酸异山梨酯(I 4)
Figure PCTCN2021091526-appb-000025
将4-单硝酸异山梨醇氧基-4-氧代丁酸(151mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg,0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 4(198mg)。将Ⅴ 4溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得白色胶状物I 4(135mg)。MS:[M+H] +＝595.2. 1H NMR(CDCl 3,300MHz)δ:10.30(s,1H),9.01(s,1H),8.37(d,J＝5.76Hz,1H),8.26(s,1H),7.76(d,J＝8.79Hz,1H),7.50～7.47(m,2H),7.36～7.29(m,4H),5.34～5.30(m,1H),5.19(s,1H),5.08(s,2H),4.93～4.89(m,1H),4.43～4.40(m,1H),4.00～3.82(m,5H),3.51～3.45(m,1H),3.24～3.19(m,1H),2.64(s,4H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:171.82,171.51,151.53,143.14,139.73,137.55,136.81,135.25,128.84,128.54,128.42,125.64,121.14,120.43,114.21,86.47,81.47,81.26,77.64,73.37,69.23,66.12,54.29,53.39,44.47,29.66,29.01.
实施例5
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基-4-[(硝基氧基)甲基]苯甲酸酯(I 5)
Figure PCTCN2021091526-appb-000026
将4-[(硝基氧基)甲基]苯甲酸(103mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg，0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 5(171mg)。将Ⅴ 5溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA 萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得白色固体I 5(114mg)。mp:>300℃.MS:[M+H] +＝501.2. 1H NMR(DMSO,300MHz)δ:10.59(s,1H),9.15(s,1H),8.40(d,J＝5.70Hz,1H),8.36(s,1H),8.05～7.99(m,3H),7.70(d,J＝8.79Hz,2H),7.58(d,J＝7.89Hz,2H),7.47～7.41(m,4H),5.64(s,2H),5.33(s,2H),4.03～3.98(m,2H),3.81(s,1H),1.98(s,2H). 13C NMR(75MHz,DMSO,25℃,TMS)δ:170.49,165.56,141.09,138.36,137.29,136.67,130.46,129.99,129.45,128.94,128.48,121.71,113.77,74.44,66.38.
实施例6
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基[2-甲基-2-(亚硝基硫丙基)丙基]琥珀酸酯(II 1)
Figure PCTCN2021091526-appb-000027
将4-[2-甲基-2-(亚硝基硫)丙氧基]-4-氧代丁酸(122mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg,0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 6(182mg)。将Ⅴ 6溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得淡绿色油状液体II 1(123mg)。MS:[M+H] +＝539.3. 1H NMR(CDCl 3,300MHz)δ:9.10(s,1H),8.40(d,J＝9.06Hz,1H),8.29(s,1H),7.83(d,J＝8.70Hz,1H),7.57(d,J＝4.89Hz,1H),7.46(d,J＝7.68Hz,1H),7.39～7.28(m,4H),5.09(s,2H),4.63(s,2H),4.15～4.08(m,1H),3.60～3.53(m,2H),2.65(s,4H),1.41(s,6H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:171.37,170.54,55.81,150.34,148.10,141.31,139.42,136.64,136.32,135.14,128.42,128.20,128.03,127.88,120.73,113.71,70.72,70.22,70.04,65.53,53.17,47.43,43.34,27.85,25.36,24.45,24.38.
实施例7
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基[2-甲基-2-(亚硝基硫代)丁基]琥珀酸酯(II 2)
Figure PCTCN2021091526-appb-000028
将4-[2-甲基-2-(亚硝基)丁氧基]-4-氧代丁酸(130mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg,0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 7(186mg)。将Ⅴ 7溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得淡绿色油状液体II 2(126mg)。MS:[M+H] +＝553.3. 1H NMR(CDCl 3,300MHz)δ:10.05(s,1H),9.12(s,1H),8.45(d,J＝5.88Hz,1H),8.33(s,1H),7.88(d,J＝8.64Hz,1H),7.57(d,J＝6.27Hz,1H),7.53(d,J＝8.40Hz,1H),7.35(s,4H),5.12(s,2H),4.70(d,J＝4.62Hz,2H),3.79～3.76(m,1H),3.48～3.25(m,2H),2.66(s,4H),1.37～1.33(m,7H),1.04(t,J＝7.35Hz,3H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:174.60,174.48,153.86,145.27,142.46,139.29,138.08,131.40,130.93,128.10,127.11,126.96,126.56,126.05,121.67,121.42,116.73,72.52,68.64,56.88,46.59,32.27,31.70,31.57,25.37,22.80,11.08.
实施例8
4-[3-氨基-1-(异喹啉-6-氨基)-1-氧丙烷-2-基]苄基[2-乙基-2-(亚硝基硫代)丁基]琥珀酸酯(II 3)
Figure PCTCN2021091526-appb-000029
将4-[2-乙基-2-(亚硝基硫代)丁氧基]-4-氧代丁酸(137mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg,0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。 有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 8(190mg)。将Ⅴ 8溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得淡绿色油状液体II 3(129mg)。MS:[M+H] +＝567.3. 1H NMR(CDCl 3,300MHz)δ:10.03(s,1H),9.08(s,1H),8.42(d,J＝4.85Hz,1H),8.29(s,1H),7.84(s,1H),7.54～7.48(m,2H),7.34(s,4H),5.10(s,2H),4.79(s,2H),3.84(s,1H),3.49～3.24(m,2H),2.65(s,4H),2.31～2.21(m,6H),1.02(t,J＝7.43Hz,3H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:171.83,171.70,171.45,151.59,143.273,139.61,137.44,136.86,135.36,128.87,128.58,128.41,125.70,121.09,120.39,114.25,67.62,66.06,63.08,54.79,54.30,44.39,29.00,27.77,8.05.
实施例9
{1-[(λ 2-氮杂亚基)(氧代)-λ 5-硫烷基]环己基}甲基{4-[3-氨基-1-(异喹啉-6-基氨基)-1-氧代丙烷-2-基]苄基}琥珀酸酯(II 4)
Figure PCTCN2021091526-appb-000030
将4-{{1-[(λ 2-氮杂亚基)(氧代)-λ 5-硫烷基]环己基}甲氧基}-4-氧代丁酸(143mg,0.52mmol)溶解于15mL的无水DCM中，加入EDCI(100mg,0.52mmol)，DMAP(6.4mg,0.052mmol)，化合物Ⅳ(200mg,0.47mmol)，0℃升至室温搅拌过夜。反应液EA萃取，饱和食盐水洗涤。有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得Ⅴ 9(193mg)。将Ⅴ 9溶解于无水DCM中，加入TFA(DCM:TFA＝10:1)，0℃反应2h，NaHCO 3将反应液pH调至7。反应液EA萃取，有机层用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得淡绿色油状液体II 4(132mg)。MS:[M-NO]＝549.3. 1H NMR(CDCl 3,300MHz)δ:10.17(s,1H),9.03(s,1H),8.38(d,J＝5.67Hz,1H),8.27(s,1H),7.78(d,J＝8.76Hz,1H),7.50～7.47(m,2H),7.36～7.29(m,4H),5.08(s,2H),4.72(s,2H),3.87～3.82(m,1H),3.50～3.43(m,1H),3.23～3.20(m,1H),2.63(s,4H),1.68～1.42(m,10H). 13C NMR(75MHz,CDCl 3,25℃,TMS)δ:171.87,171.82,171.51,151.52,143.12,139.69,137.43,136.81,135.51,135.34,128.82,128.71,128.53,128.38,121.12,120.89,120.43,119.06,118.81, 114.22,70.89,66.04,54.37,52.49,44.47,33.27,29.01,28.98,25.36,21.71.
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 (11)

  1. 一种化合物，为通式A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：
    Figure PCTCN2021091526-appb-100001
    其中：m为2时，X为O；m为1时，X为S；Linker代表亚烷基酰基或亚烷基，其中亚烷基为C1-C10直链、支链、包含有环状结构或包含有酯键的亚烷基、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。
  2. 根据权利要求1所述的化合物，其特征在于，式A所示的化合物选自：
    Figure PCTCN2021091526-appb-100002
    其中：
    R 1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。
  3. 根据权利要求2所述的化合物，其特征在于，所述化合物选自
    Figure PCTCN2021091526-appb-100003
    R 2、R 3各自独立地代表烷基，包括C2-C5直链或支链烷基，或R 2、R 3共同构成环状烷基。
  4. 根据权利要求2所述的化合物，其特征在于，R 1代表亚乙基、亚丙基、亚丁基、亚戊基，或，
    -R 1-为
    Figure PCTCN2021091526-appb-100004
  5. 根据权利要求1所述的化合物，其特征在于，所述化合物选自以下化合物：
    Figure PCTCN2021091526-appb-100005
    Figure PCTCN2021091526-appb-100006
    Figure PCTCN2021091526-appb-100007
  6. 式I、式II所示的化合物的制备方法，包括：
    化合物III与化合物IV反应得到化合物V，化合物V氨基脱保护得到目标化合物I、II；合成路线如下：
    Figure PCTCN2021091526-appb-100008
    其中：m为2时，X为O；m为1时，X为S；R 1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。
  7. 根据权利要求6所述的制备方法，其特征在于，
    从化合物III制备化合物V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V制备化合物I、II的反应中，溶剂选择无水二氯甲烷；酸选择三氟乙酸；反应温度为0℃至室温。
  8. 根据权利要求7所述的制备方法，其特征在于，
    从化合物III制备化合物V的反应中，溶剂选择无水二氯甲烷，反应温度为室温；
    从化合物V制备化合物I、II的反应中，溶剂选择无水二氯甲烷，反应温度为0℃至室温。
  9. 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及可药用的载体、佐剂或媒剂。
  10. 权利要求1-5任一项所述的化合物、权利要求9所述的药物组合物在制备预防和/或治疗与眼压升高有关疾病的药物中的应用。
  11. 根据权利要求10所述的用途，其特征在于，与眼压升高有关的疾病包括高眼压症、青光眼、糖尿病并发性眼症。
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