WO2022033047A1 - 一种长效的psd-95抑制剂 - Google Patents

一种长效的psd-95抑制剂 Download PDF

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Publication number
WO2022033047A1
WO2022033047A1 PCT/CN2021/085166 CN2021085166W WO2022033047A1 WO 2022033047 A1 WO2022033047 A1 WO 2022033047A1 CN 2021085166 W CN2021085166 W CN 2021085166W WO 2022033047 A1 WO2022033047 A1 WO 2022033047A1
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Prior art keywords
fmoc
arg
compound
lys
ser
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PCT/CN2021/085166
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English (en)
French (fr)
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黄晓兵
周述靓
代景莹
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成都奥达生物科技有限公司
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Publication of WO2022033047A1 publication Critical patent/WO2022033047A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a long-acting PSD-95 inhibitor and use thereof.
  • Acute ischemic stroke is one of the diseases with the highest fatality and disability rates in the world, and there is currently no effective clinical treatment. Cerebral ischemia can cause a cascade of reactions from energy deprivation to cell death. The early events mainly include excitotoxicity and oxidative stress, and the late events are mainly inflammation and apoptosis. At present, a large number of basic and clinical researches are devoted to intervening the signaling molecules related to stroke pathology to develop effective neuroprotective therapy. As the initial link of stroke pathology, excitotoxicity is the primary target of stroke therapy.
  • PSD-95 protein in the postsynaptic density (PSD) can bridge the NMDA receptor with a variety of toxic signaling molecules in the cell, and inhibit the PSD-95 to make the NMDA receptor and PSD-95 protein. Dissociation, both attenuated excitotoxicity without affecting NMDA receptor activity and synaptic function.
  • NA-1 a PSD-95 inhibitor
  • PSD-95 postsynaptic density protein 95
  • the purpose of the present invention is to provide patients with a long-acting PSD-95 inhibitor, reduce the frequency of administration, and reduce the cost of patients.
  • the present invention provides a long-acting PSD-95 inhibitor and use thereof.
  • the present invention first provides a compound shown in structure I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex formed by the compound, and a medicine based on the compound. precursor, or any mixture of the above.
  • AA1 in structure I is Lys, or Dap, or Orn, or Dab, or Dah;
  • AA2 in Structure I is NH2 , or is OH;
  • R in structure I is cholesteryl succinate monoester, or 2-cholesteryl acetic acid, or 2-cholesteryl propionic acid, or 3-cholesteryl propionic acid, or HO 2 C(CH 2 ) n1 CO-( ⁇ Glu ) n2 -(PEG n3 (CH 2 ) n4 CO) n5 -.
  • n1 is an integer from 10 to 20;
  • n2 is an integer from 1 to 5;
  • n3 is an integer from 1 to 30;
  • n4 is an integer from 1 to 5;
  • n5 is an integer from 1 to 5;
  • the present invention also provides pharmaceutical compositions comprising compounds according to the present invention, as well as providing pharmaceutical compositions of compounds of the present invention for use in the manufacture of pharmaceuticals for the treatment of diseases.
  • the pharmaceutical composition is used in the preparation of neuroprotective drugs after ischemic brain injury.
  • any chemical structure within the scope of the description herein, whether in part or in the whole structure containing similar structures above, includes all possible enantiomers and diastereomers of the compound, including Any single stereoisomer (eg, pure geometric isomer, pure enantiomer, or pure diastereomer) and any mixture of these isomers are included.
  • Any single stereoisomer eg, pure geometric isomer, pure enantiomer, or pure diastereomer
  • racemic and stereoisomeric mixtures can also be further resolved into their constituent enantiomers or stereoisomers by those skilled in the art using continuous separation techniques or chiral molecular synthesis methods body.
  • Compounds of structural formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds.
  • single enantiomer or diastereomer, such as optical isomer can be obtained by asymmetric synthesis method or racemate separation method.
  • Resolution of the racemates can be accomplished by various methods, such as conventional recrystallization with a resolution-promoting agent, or by chromatography.
  • compounds of formula I also include cis and/or trans isomers with double bonds.
  • the compounds of the present invention include, but are not limited to, compounds of structural formula I and all of their various pharmaceutically usable forms.
  • the different pharmaceutically acceptable forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the aforementioned substances and the aforementioned forms of these compounds. any mixture.
  • the above-mentioned prodrugs include ester or amide derivatives of compounds represented by structural formula I contained in the compounds.
  • the compound represented by the structure I provided by the present invention has stable properties, is a long-acting PSD-95 inhibitor, and has a significant protective effect on nerves after ischemic brain injury.
  • the present invention discloses a PSD-95 inhibitor and use thereof, and those skilled in the art can learn from the content of this paper and appropriately improve relevant parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the method of the present invention has been described by the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the compounds and preparation methods described herein without departing from the content, spirit and scope of the present invention, to achieve and Apply the technology of the present invention.
  • the preparation method includes: preparing a peptide resin by a solid-phase polypeptide synthesis method, and then subjecting the peptide resin to acidolysis to obtain a crude product, and finally purifying the crude product to obtain a pure product; wherein the step of preparing the peptide resin by the solid-phase polypeptide synthesis method is to pass the solid-phase peptide synthesis method on the carrier resin.
  • the corresponding protected amino acids or fragments in the following sequences are sequentially connected by the coupled synthesis method to prepare the peptide resin:
  • the dosage of the Fmoc-protected amino acid or the protected amino acid fragment is 1.2-6 times of the total moles of the resin charged; preferably 2.5-3.5 times.
  • the substitution value of the carrier resin is 0.2-1.0 mmol/g resin, and the preferred substitution value is 0.3-0.5 mmol/g resin.
  • the solid-phase coupling synthesis method is as follows: the protected amino acid-resin obtained in the previous step is subjected to a coupling reaction with the next protected amino acid after removing the Fmoc protecting group.
  • the deprotection time for de-Fmoc protection is 10-60 minutes, preferably 15-25 minutes.
  • the coupling reaction time is 60-300 minutes, preferably 100-140 minutes.
  • the coupling reaction needs to add a condensation reagent, and the condensation reagent is selected from DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, benzotriazole hexafluorophosphate -1-yl-oxytripyrrolidinophosphorus, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate , benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate or O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoro
  • One of boronate esters preferably N,N-diisopropylcarbodiimide.
  • the molar amount of the condensation reagent is 1.2-6 times, preferably 2.5-3.5 times, the total moles of
  • the coupling reaction needs to add an activating reagent, and the activating reagent is selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, preferably 1-hydroxybenzotriazole.
  • the dosage of the activating agent is 1.2-6 times, preferably 2.5-3.5 times, the total moles of amino groups in the amino resin.
  • the reagent for removing Fmoc protection is a PIP/DMF (piperidine/N,N-dimethylformamide) mixed solution, and the mixed solution contains piperidine in an amount of 10-30% (V ).
  • the dosage of the de-Fmoc protecting reagent is 5-15 mL per gram of amino resin, preferably 8-12 mL per gram of amino resin.
  • the peptide resin is subjected to acid hydrolysis while removing the resin and the side chain protecting group to obtain a crude product:
  • the acid hydrolyzing agent used during the acidolysis of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1,2-ethanedithiol (EDT) and water, and the volume ratio of the mixed solvent is: TFA It is 80-95%, EDT is 1-10%, and the balance is water.
  • the volume ratio of the mixed solvent is: TFA is 89-91%, EDT is 4-6%, and the balance is water.
  • the volume ratio of the mixed solvent is: TFA is 90%, EDT is 5%, and the balance is water.
  • the dosage of the acid hydrolyzing agent is 4-15 mL of acid hydrolyzing agent per gram of peptide resin; preferably, 7-10 mL of acid hydrolyzing agent is required per gram of peptide resin.
  • the cleavage time using the acid hydrolyzing agent is 1 to 6 hours at room temperature, preferably 3 to 4 hours.
  • High performance liquid chromatography was used for purification.
  • the chromatographic packing for purification was 10 ⁇ m reversed-phase C18, the mobile phase system was 0.1% TFA/water solution-0.1% TFA/acetonitrile solution, and the flow rate of the 77mm*250mm column was 90mL/min.
  • Gradient system elution, cyclic injection purification take the crude product solution and load it into the chromatographic column, start the mobile phase elution, collect the main peak and evaporate the acetonitrile to obtain the purified intermediate concentrate;
  • High performance liquid chromatography was used for salt exchange, the mobile phase system was 1% acetic acid/water solution-acetonitrile, the chromatographic packing for purification was 10 ⁇ m reversed-phase C18, and the flow rate of the 77mm*250mm column was 90mL/min (according to different specifications. chromatographic column, adjust the corresponding flow rate); adopt gradient elution, cyclic sample loading method, load sample into the chromatographic column, start mobile phase elution, collect the main peak of salt change and use analytical liquid phase to detect the purity, combine the solution of the main peak of salt change, reduce Concentrate under pressure to obtain pure acetic acid aqueous solution, and obtain pure product after freeze-drying.
  • Peptide sequence n protect amino acids 1 Fmoc-Lys(Alloc) 2 Fmoc-Val 3 Fmoc-Asp(OtBu)
  • the activated first protected amino acid solution is added to the resin from which Fmoc has been removed, and the coupling reaction is carried out for 60-300 minutes, filtered and washed to obtain a resin containing one protected amino acid.
  • the first protected amino acid solution of the activated side chain is added to the resin from which Alloc has been removed, and the coupling reaction is carried out for 60-300 minutes, filtered and washed to obtain a resin containing the first protected amino acid of the side chain.
  • the second to third protected amino acids and monoprotected fatty acids corresponding to the side chain are sequentially connected to obtain a peptide resin.
  • the purified intermediate concentrate was filtered with a 0.45 ⁇ m filter membrane for use, and high performance liquid chromatography was used for salt exchange.
  • the mobile phase system was 1% acetic acid/water solution-acetonitrile, and the chromatographic packing for purification was 10 ⁇ m reversed-phase C18, 30mm*250mm
  • the flow rate of the chromatographic column is 20mL/min (the corresponding flow rate can be adjusted according to the chromatographic column of different specifications); the gradient elution, cyclic sample loading method is adopted, the sample is loaded into the chromatographic column, the mobile phase elution is started, and the main peak of salt exchange is collected.
  • the purity was detected by analytical liquid phase, the main peak solution of salt exchange was combined, and concentrated under reduced pressure to obtain pure acetic acid aqueous solution, which was freeze-dried to obtain 8.5 g of pure product with a purity of 98.1% and a total yield of 25.3%.
  • the molecular weight was 3361.8 (100% M+H).
  • Peptide sequence n protect amino acids 1 Fmoc-Lys(Alloc) 2 Fmoc-Val 3 Fmoc-Asp(OtBu) 4 Fmoc-Ser(tBu) 5 Fmoc-Glu(OtBu) 6 Fmoc-Ile 7 Fmoc-Ser(tBu) 8 Fmoc-Ser(tBu) 9 Fmoc-Leu 10 Fmoc-Lys(Boc) 11 Fmoc-Arg(Pbf) 12 Fmoc-Arg(Pbf) 13 Fmoc-Arg(Pbf) 14 Fmoc-Gln(Trt)
  • Peptide sequence n protect amino acids 1 Fmoc-Lys(Alloc) 2 Fmoc-Val 3 Fmoc-Asp(OtBu) 4 Fmoc-Ser(tBu) 5 Fmoc-Glu(OtBu) 6 Fmoc-Ile 7 Fmoc-Ser(tBu) 8 Fmoc-Ser(tBu) 9 Fmoc-Leu 10 Fmoc-Lys(Boc) 11 Fmoc-Arg(Pbf)
  • Peptide sequence n protect amino acids 1 Fmoc-Lys(Alloc) 2 Fmoc-Val 3 Fmoc-Asp(OtBu) 4 Fmoc-Ser(tBu) 5 Fmoc-Glu(OtBu) 6 Fmoc-Ile
  • Percent cerebral infarct volume right infarct volume/right brain volume x 100%.
  • Rats were given adaptive training (rotation speed was 4 revolutions per second, lasting 1 minute) before the test using a wheeled fatigue rotarod. During the test, the rotational speed of the rotarod was gradually increased from 4 rpm to 40 rpm within 5 minutes, and the time from the rat on the rotarod to fall was recorded (over 300 seconds, recorded as 300 seconds). Detection time: before modeling, 24 hours after reperfusion, and 3 days.
  • Detection method The test rats were placed in the new object recognition box to move freely for 10 minutes, and the total distance of the rat's activities, the number of times of entering the central area, and the percentage of exercise time in the central area were recorded. Detection time: before modeling, 24 hours after reperfusion, and 3 days.
  • the rats in each group moved about 5 meters within 10 minutes in the autonomous activity box, and there was no significant difference between the groups (P>0.05).
  • the average value of the exercise distance of the rats in each group was the same.
  • the compound 1 group significantly improved the motor function of rats at 24 hours after ischemia-reperfusion.
  • Each compound was divided into two administration groups: SD rats, 4 males in each group, 8 rats in total.
  • Intravenous tail vein group the dose was 1 mg/kg, and blood was collected from the orbital vein of the rats before the drug (0h) and 30min, 1h, 2h, 4h, 8h, 24h, 48h, 96h, and 144h after the drug, and centrifuged. Plasma sample.
  • Subcutaneous administration group the dose was 1 mg/kg, blood was collected from the orbital vein of the rats before the drug (0h) and 1h, 2h, 3h, 4h, 8h, 24h, 48h, 96h, 144h after the administration, and the plasma was separated by centrifugation. sample.
  • the plasma concentrations of the corresponding compounds in the plasma samples of SD rats were determined by LC/MS, respectively.
  • the half-life of subcutaneous (SC) administration of compounds in SD rats is shown in the following table:

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Abstract

本发明公开了一种长效PSD-95抑制剂，本发明还公开了该长效PSD-95抑制剂在制备用于缺血性脑损伤后的神经保护的药物中的用途。

Description

一种长效的PSD-95抑制剂
本申请要求于2020年08月11日提交中国专利局、申请号为202010799838.7、发明名称为“一种长效的PSD-95抑制剂”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种长效的PSD-95抑制剂及其用途。
背景技术
急性缺血性脑卒中是全世界致死率、致残率最高的疾病之一，目前临床上缺乏有效的治疗方法。脑缺血可引起从能量剥夺到细胞死亡的级联反应，早期事件主要包括兴奋性毒性和氧化应激，晚期事件则以炎症反应和细胞凋亡为主。目前，大量的基础和临床研究致力于干预脑卒中病理相关的信号分子，以开拓有效的神经保护治疗。兴奋性毒性作为脑卒中病理的起始环节，是卒中治疗的首要靶点。
脑缺血后,兴奋性谷氨酸过度释放并可持续作用于N-甲基-D-天冬氨酸受体，从而启动一系列下游有害信号通路，例如细胞内Ca2+超载、自由基的产生等,最终导致神经细胞死亡。最新研究显示，突触后致密区(postsynaptic density,PSD)的PSD-95蛋白可使NMDA受体与细胞内的多种毒性信号分子桥联，抑制PSD-95使NMDA受体与PSD-95蛋白解离,既可减轻兴奋性毒性，又不影响NMDA受体活性和突触功能。
Nerinetide(NA-1)是一种PSD-95抑制剂，可干扰突触后密度蛋白95(PSD-95)，通过终止细胞内NO自由基的产生来实现，在临床前缺血性脑卒中模型中可减少脑缺血再灌注的梗死面积，并改善其功能预后。
由于Nerinetide在体内半衰期短，患者每天需要大剂量用药，患者顺应性差，临床费用高。本发明的目的就是为患者提供长效的PSD-95抑制剂，减少给药频率，降低患者费用。
发明内容
本发明提供了一种长效的PSD-95抑制剂及其用途。
为实现上述目的，本发明首先提供了一种结构I所示的化合物，该化合物所成的可药用的盐、溶剂化物、螯合物或非共价复合物，基于该化合物基础上的药物前体，或上述形式的任意混合物。
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-
Lys-Leu-Ser-Ser-Ile-Glu-Ser-Asp-Val-AA1(R)-AA2
结构I
结构I中的AA1为Lys,或为Dap，或为Orn，或为Dab，或为Dah；
结构I中的AA2为NH 2，或为OH；
结构I中的R为丁二酸胆固醇单酯，或为2-胆固醇乙酸，或为2-胆固醇丙酸，或为3-胆固醇丙酸，或为HO 2C(CH 2) n1CO-(γGlu) n2-(PEG n3(CH 2) n4CO) n5-。
其中：n1为10至20的整数；
n2为1至5的整数；
n3为1至30的整数；
n4为1至5的整数；
n5为1至5的整数；
本发明还提供了包括根据本发明化合物的药物组合物，以及提供了本发明化合物的药物组合物用于制备治疗疾病的药物用途。
作为优选，所述药物组合物在制备缺血性脑损伤后的神经保护药物中的用途。
本发明所涉及到的更多内容在以下有详细描述，或者有些也可以在本发明的实施例中体会。
除非另有所指，本文中所用来表示不同成分的数量、反应条件，在任意情况下都可解读为“大致的”、“大约的”意思。相应的，除有明确的特指外，在下述以及权利要求中所引用的数字参数都是大致的参数，在各自的实验条件下由于标准误差的不同，有可能会得到不同的数字参数。
本文中，当一个化合物的化学结构式和化学名称有分歧或疑义时，以化学结构式确切定义此化合物。本文所描述的化合物有可能含有一个或 多个手性中心，和/或者双键以及诸如此类的结构，也可能存在立体异构体，包括双键的异构体(比如几何异构体)、旋光对映异构体或者非对映异构体。相应的，在本文描述范围内的任意化学结构，无论是部分或整体结构中含有上述类似结构，都包括了此化合物的所有可能的对映异构体和非对映异构体，其中也包括了单纯的任一种立体异构体(如单纯的几何异构体、单纯的对映异构体或者单纯的非对映异构体)以及这些异构体的任意一种混合物。这些消旋异构体和立体异构体的混合物由本领域技术人员利用不停的分离技术或手性分子合成的方法也可进一步被拆分成其组成成分的对映异构体或立体异构体。
结构式I的化合物包含了，但并不仅限于，这些化合物的光学异构体、消旋体和/或其他的混合物。上述情况下，其中单一的对映异构体或非对映异构体，如有旋光的异构体，可以用不对称合成的方法或消旋体拆分的方法获得。消旋体的拆分可用不同的方法实现，如常规的用助拆分的试剂重结晶，或用色谱方法。另外，结构式I的化合物也包含了带双键的顺式和/或反式的异构体。
本发明所述化合物包含但不限于，结构式I所示化合物以及他们所有的在药学上可用的不同形式。这些化合物的药学上可用的不同形式包括各种可药用的盐、溶剂化物、络合物、螯合物、非共价的复合物、基于上述物质基础上的药物前体和上述这些形式的任意混合物。
上述所述药物前体包括含在所述化合物内，如结构式I所示化合物的酯或者酰胺衍生物。
本发明提供的结构I所示的化合物性质稳定，是一种长效的PSD-95抑制剂，对缺血性脑损伤后的神经具有显著的保护作用。
具体实施方式
本发明公开了一种PSD-95抑制剂及其用途，本领域技术人员可以借鉴本文内容，适当改进相关参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不 脱离本发明内容、精神和范围内对本文所述的的化合物和制备方法进行改动或适当变更与组合，来实现和应用本发明技术。
本发明中涉及的英文缩写所对应的中文名称见下表所示：
英文缩写 中文名称 英文缩写 中文名称
Fmoc 9-芴甲氧羰基 OtBu 叔丁氧基
tBu 叔丁基 Boc 叔丁氧羰酰基
Trt 三苯甲基 Pbf (2,3-二氢-2,2,4,6,7-五甲基苯并呋喃-5-基)磺酰基
Ala 丙氨酸 Leu 亮氨酸
Arg 精氨酸 Lys 赖氨酸
Asn 天冬酰胺 Met 甲硫氨酸
Asp 天冬氨酸 Phe 苯丙氨酸
Cys 半胱氨酸 Pro 脯氨酸
Gln 谷酰胺 Ser 丝氨酸
Glu 谷氨酸 Thr 苏氨酸
Gly 甘氨酸 Trp 色氨酸
His 组氨酸 Tyr 酪氨酸
Ile 异亮氨酸 Val 缬氨酸
Dap 2,3-二氨基丙酸 Dab 2,4-二氨基丁酸
Orn 鸟氨酸 Dah 2,7-二氨基庚酸
Dhthr 脱羟基苏氨酸 Dhval 2,3-二脱氢缬氨酸
实施例1化合物1的制备
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Lys-Leu-Ser-Ser-
Ile-Glu-Ser-Asp-Val-Lys(AEEA-AEEA-γGlu-18烷二酸)-NH 2
制备方法，包括：采用固相多肽合成法制备肽树脂，肽树脂再经酸解得到粗品，最后粗品经过纯化得到纯品；其中固相多肽合成法制备肽树脂的步骤为在载体树脂上通过固相偶联合成法依次接入下列序列中相对 应的保护氨基酸或片段，制备肽树脂：
上述制备方法中，所述的Fmoc-保护氨基酸或保护氨基酸片段的用量为所投料树脂总摩尔数的1.2～6倍；优选为2.5～3.5倍。
上述制备方法中，所述的载体树脂取代值为0.2～1.0mmol/g树脂，优选的取代值为0.3～0.5mmol/g树脂。
作为本发明优选的方案，所述固相偶联合成法为：前一步反应得到的保护氨基酸-树脂脱去Fmoc保护基后再与下一个保护氨基酸偶联反应。所述的去Fmoc保护的脱保护时间为10～60分钟，优选的为15～25分钟。所述的偶联反应时间为60～300分钟，优选的为100～140分钟。
所述的偶联反应需添加缩合试剂，缩合试剂选自DIC(N,N-二异丙基碳二亚胺)、N,N-二环己基碳二亚胺，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐或O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯中的一种；优选的为N,N-二异丙基碳二亚胺。所述缩合试剂的摩尔用量为氨基树脂中氨基总摩尔数的1.2～6倍，优选为2.5～3.5倍。
所述的偶联反应需添加活化试剂，活化试剂选自1-羟基苯并三唑或N-羟基-7-氮杂苯并三氮唑，优选的为1-羟基苯并三唑。活化试剂的用量为氨基树脂中氨基总摩尔数的1.2～6倍，优选的为2.5～3.5倍。
作为本发明优选的方案，所述的脱去Fmoc保护的试剂为PIP/DMF(哌啶/N,N-二甲基甲酰胺)混合溶液，混合溶液中含哌啶为10～30％(V)。去Fmoc保护试剂的用量为每克氨基树脂5～15mL，优选的为每克氨基树脂8～12mL。
优选的，肽树脂经酸解同时脱去树脂及侧链保护基得到粗品：
进一步优选的，所述肽树脂酸解时采用的酸解剂为三氟醋酸(TFA)、1,2-乙二硫醇(EDT)和水的混合溶剂，混合溶剂的体积配比为：TFA为80～95％，EDT为1～10％，余量为水。
更进一步优选的，混合溶剂的体积配比为：TFA为89～91％、EDT为4～6％，余量为水。最优的，混合溶剂的体积配比为：TFA为90％、 EDT为5％，余量为水。
所述酸解剂用量为每克肽树脂需要4～15mL酸解剂；优选的，每克肽树脂需要7～10mL酸解剂。
使用酸解剂裂解的时间为室温条件下1～6小时，优选的为3～4小时。
进一步的，粗品经高效液相色谱纯化、冻干得到纯品，具体方法为：
取粗品，加水搅拌，调pH值至完全溶解，溶液用0.45μm混合微孔滤膜过滤，纯化备用；
采用高效液相色谱法进行纯化，纯化用色谱填料为10μm的反相C18，流动相系统为0.1％TFA/水溶液-0.1％TFA/乙腈溶液，77mm*250mm的色谱柱流速为90mL/min，采用梯度系统洗脱，循环进样纯化，取粗品溶液上样于色谱柱中，启动流动相洗脱，收集主峰蒸去乙腈后，得纯化中间体浓缩液；
取纯化中间体浓缩液，用0.45μm滤膜滤过备用；
采用高效液相色谱法进行换盐，流动相系统为1％醋酸/水溶液-乙腈，纯化用色谱填料为10μm的反相C18，77mm*250mm的色谱柱流速为90mL/min(可根据不同规格的色谱柱，调整相应的流速)；采用梯度洗脱，循环上样方法，上样于色谱柱中，启动流动相洗脱，收集换盐主峰并用分析液相检测纯度，合并换盐主峰溶液，减压浓缩，得到纯品醋酸水溶液，冷冻干燥后得纯品。
1、肽树脂的合成
使用Rink Amide BHHA树脂为载体树脂，通过去Fmoc保护和偶联反应，依次与下表所示的保护氨基酸偶联，制得肽树脂。本实施例使用的保护氨基酸相对应的保护氨基酸如下所示：
接肽顺序n＝ 保护氨基酸
1 Fmoc-Lys(Alloc)
2 Fmoc-Val
3 Fmoc-Asp(OtBu)
4 Fmoc-Ser(tBu)
5 Fmoc-Glu(OtBu)
6 Fmoc-Ile
7 Fmoc-Ser(tBu)
8 Fmoc-Ser(tBu)
9 Fmoc-Leu
10 Fmoc-Lys(Boc)
11 Fmoc-Arg(Pbf)
12 Fmoc-Arg(Pbf)
13 Fmoc-Arg(Pbf)
14 Fmoc-Gln(Trt)
15 Fmoc-Arg(Pbf)
16 Fmoc-Arg(Pbf)
17 Fmoc-Lys(Boc)
18 Fmoc-Lys(Boc)
19 Fmoc-Arg(Pbf)
20 Fmoc-Gly
21 Boc-Tyr(tBu)
侧链-1 Fmoc-AEEA
侧链-2 Fmoc-AEEA
侧链-3 Fmoc-γGlu-OtBu
侧链-4 18烷二酸单叔丁酯
(1)接入主链第1个保护氨基酸
取0.03mol第1个保护氨基酸和0.03mol HOBt，用适量DMF溶解；另取0.03mol DIC，搅拌下慢慢加入至保护氨基酸DMF溶液中，于室温环境中搅拌反应30分钟，得到活化后的保护氨基酸溶液，备用。
取0.01mol的Rink amide MBHA树脂(取代值约0.4mmol/g)，采用20％PIP/DMF溶液去保护25分钟，洗涤过滤得到去Fmoc的树脂。
将活化后的第1个保护氨基酸溶液加入到已去Fmoc的树脂中，偶联反应60～300分钟，过滤洗涤，得含1个保护氨基酸的树脂。
(2)接入主链第2～35个保护氨基酸
采用上述接入主链第1个保护氨基酸同样方法，依次接入上述对应的第2～35个保护氨基酸，得含主链35个氨基酸的树脂。
(3)接入侧链第1个保护氨基酸
取0.03mol侧链第1个保护氨基酸和0.03mol HOBt，用适量DMF溶解；另取0.03mol DIC，搅拌下慢慢加入至保护氨基酸DMF溶液中，于室温环境中搅拌反应30分钟，得到活化后的保护氨基酸溶液。
取2.5mmol四三苯基膦钯和25mmol苯硅烷，用适量二氯甲烷溶解，去保护4小时，过滤洗涤，得到去Alloc的树脂备用。
将加入活化后的侧链第1个保护氨基酸液加入到已去Alloc的树脂，偶联反应60～300分钟，过滤洗涤，得含侧链第1个保护氨基酸的树脂。
(4)接入侧链第2～3个保护氨基酸
采用上述接入主链第1个保护氨基酸同样方法，依次接入侧链对应的第2～3个保护氨基酸和单保护脂肪酸，得到肽树脂。
2、粗品的制备
取上述肽树脂，加入体积比为TFA︰水︰EDT＝95︰5︰5的裂解试剂(裂解试剂10mL/克树脂)，搅拌均匀，室温搅拌反应3小时，反应混合物使用砂芯漏斗过滤，收集滤液，树脂再用少量TFA洗涤3次，合并滤液后减压浓缩，加入无水乙醚沉淀，再用无水乙醚洗沉淀3次，抽干得类白色粉末即为粗品。
3、纯品的制备
取上述粗品，加水搅拌溶解，溶液用0.45μm混合微孔滤膜过滤，纯化备用。采用高效液相色谱法进行纯化，纯化用色谱填料为10μm的反相C18，流动相系统为0.1％TFA/水溶液-0.1％TFA/乙腈溶液，30mm*250mm的色谱柱流速为20mL/min，采用梯度系统洗脱，循环进样纯化，取粗品溶液上样于色谱柱中，启动流动相洗脱，收集主峰蒸去乙腈后，得纯化中间体浓缩液；
纯化中间体浓缩液用0.45μm滤膜滤过备用，采用高效液相色谱法进行换盐，流动相系统为1％醋酸/水溶液-乙腈，纯化用色谱填料为10μm的反相C18，30mm*250mm的色谱柱流速为20mL/min(可根据不同规格的色谱柱，调整相应的流速)；采用梯度洗脱，循环上样方法，上样于色谱柱中，启动流动相洗脱，收集换盐主峰并用分析液相检测纯度，合并换盐主峰溶液，减压浓缩，得到纯品醋酸水溶液，冷冻干燥，得纯品8.5g，纯度为98.1％，总收率为25.3％。分子量为3361.8(100％M+H)。
实施例2化合物2的制备
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Lys-Leu-Ser-Ser-Ile-
Glu-Ser-Asp-Val-Lys(丁二酸胆固醇单酯)-NH 2
制备方法同实施例1，使用的保护氨基酸如下表:
接肽顺序n＝ 保护氨基酸
1 Fmoc-Lys(Alloc)
2 Fmoc-Val
3 Fmoc-Asp(OtBu)
4 Fmoc-Ser(tBu)
5 Fmoc-Glu(OtBu)
6 Fmoc-Ile
7 Fmoc-Ser(tBu)
8 Fmoc-Ser(tBu)
9 Fmoc-Leu
10 Fmoc-Lys(Boc)
11 Fmoc-Arg(Pbf)
12 Fmoc-Arg(Pbf)
13 Fmoc-Arg(Pbf)
14 Fmoc-Gln(Trt)
15 Fmoc-Arg(Pbf)
16 Fmoc-Arg(Pbf)
17 Fmoc-Lys(Boc)
18 Fmoc-Lys(Boc)
19 Fmoc-Arg(Pbf)
20 Fmoc-Gly
21 Boc-Tyr(tBu)
侧链-1 丁二酸胆固醇单酯
得纯品7.7g，纯度为97.1％，总收率为24.7％。分子量为3114.6(100％M+H)。
实施例3化合物3的制备
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Lys-Leu-Ser-Ser-Ile-
Glu-Ser-Asp-Val-Lys(PEG 5CH 2CO-γGlu-18烷二酸)-NH 2
制备方法同实施例1，使用的保护氨基酸如下表:
接肽顺序n＝ 保护氨基酸
1 Fmoc-Lys(Alloc)
2 Fmoc-Val
3 Fmoc-Asp(OtBu)
4 Fmoc-Ser(tBu)
5 Fmoc-Glu(OtBu)
6 Fmoc-Ile
7 Fmoc-Ser(tBu)
8 Fmoc-Ser(tBu)
9 Fmoc-Leu
10 Fmoc-Lys(Boc)
11 Fmoc-Arg(Pbf)
12 Fmoc-Arg(Pbf)
13 Fmoc-Arg(Pbf)
14 Fmoc-Gln(Trt)
15 Fmoc-Arg(Pbf)
16 Fmoc-Arg(Pbf)
17 Fmoc-Lys(Boc)
18 Fmoc-Lys(Boc)
19 Fmoc-Arg(Pbf)
20 Fmoc-Gly
21 Boc-Tyr(tBu)
侧链-1 Fmoc-PEG 5CH 2COOH
侧链-2 Fmoc-γGlu-OtBu
侧链-3 18烷二酸单叔丁酯
得纯品9.3g，纯度为98.7％，总收率为27.8％。分子量为3349.2(100％M+H)。
实施例4化合物4的制备
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Lys-Leu-Ser-Ser-Ile-
Glu-Ser-Asp-Val-Lys(2-胆固醇胆乙酸)-NH 2
制备方法同实施例1，使用的保护氨基酸如下表:
接肽顺序n＝ 保护氨基酸
1 Fmoc-Lys(Alloc)
2 Fmoc-Val
3 Fmoc-Asp(OtBu)
4 Fmoc-Ser(tBu)
5 Fmoc-Glu(OtBu)
6 Fmoc-Ile
7 Fmoc-Ser(tBu)
8 Fmoc-Ser(tBu)
9 Fmoc-Leu
10 Fmoc-Lys(Boc)
11 Fmoc-Arg(Pbf)
12 Fmoc-Arg(Pbf)
13 Fmoc-Arg(Pbf)
14 Fmoc-Gln(Trt)
15 Fmoc-Arg(Pbf)
16 Fmoc-Arg(Pbf)
17 Fmoc-Lys(Boc)
18 Fmoc-Lys(Boc)
19 Fmoc-Arg(Pbf)
20 Fmoc-Gly
21 Boc-Tyr(tBu)
侧链-1 2-胆固醇胆乙酸
得纯品7.2g，纯度为97.6％，总收率为23.4％。分子量为3072.8(100％M+H)。
实施例5体内活性的测定
6-10周SD大鼠，通过线栓法造成大鼠大脑中动脉闭塞(MCAO)局灶性脑缺血，缺血2小时后拔出线栓实现再灌注。再灌注即刻给药，静脉注射，单次给药，溶剂对照组给予等量生理盐水。
1、脑梗死体积
MCAO再灌注后3天，解剖各组存活大鼠，预冷的PBS灌注心脏，取脑组织，使用1％红四氮唑(TTC)进行染色，计算梗死体积百分比。
脑梗死体积百分比＝右侧梗死体积/右侧大脑体积×100％。
脑梗死体积百分比
Figure PCTCN2021085166-appb-000001
Figure PCTCN2021085166-appb-000002
MCAO再灌注3天后，安乐死所有存活大鼠，将脑组织进行TTC染色，观察各组脑梗死区域并计算脑梗死体积百分比：右侧大脑梗死体积/右侧大脑体积×100％。与假手术组比较，溶剂对照组脑梗死体积显著升高(**P＜0.001)。与溶剂对照组比较：化合物1，化合物2，化合物3，化合物4尾静脉注射15mg/kg，大鼠脑梗死体积均有不同程度下降，其中化合物1和化合物3对脑梗死体积的缓解程度略优于化合物1和化合物4
2、运动能力测试
使用轮式疲劳转棒在试验前均给予大鼠适应性的训练(旋转速度为4转/秒，持续1分钟)。测试时在5分钟内，转棒的转速逐渐从4转/秒增加至40转/秒，记录大鼠在转棒上维持至跌倒的时间(超过300秒，记录为300秒)。检测时间：造模前、再灌注后24小时，3天。
轮式疲劳转棒测试
Figure PCTCN2021085166-appb-000003
Figure PCTCN2021085166-appb-000004
使用轮式疲劳转棒测试大鼠运动能力。测试时间5分钟内，转棒的转速逐渐从4转/秒增加至40转/秒，记录大鼠在转棒上维持的时间(超过300秒，记录为300秒)。造模前，各组大鼠运动功能无差异(P＞0.05)。缺血再灌注24小时，溶剂对照组大鼠运动功能显著低于假手术组(P＝0.006)，化合物1，化合物2，化合物3给药组大鼠转棒维持时间平均值比溶剂对照组均有升高，其中化合物1对运动能力改善最为明显，且显著优于化合物4(P＝0.021)。缺血再灌注后第3天，化合物1，化合物2和化合物3转棒维持时间平均值高于化合物4组。
3、自主活动能力检测
检测方法：将试验大鼠的置于新物体识别箱中自由活动10min，记录大鼠鼠活动的总路程、进入中心区次数、中心区运动时间百分比。检测时间：造模前、再灌注后24小时，3天。
自主活动能力检测
Figure PCTCN2021085166-appb-000005
Figure PCTCN2021085166-appb-000006
MCAO再灌注造模前，各组大鼠在自主活动箱中10min内运动距离约为5米，组间无显著差异(P＞0.05)。缺血再灌注24小时后，化合物1组大鼠运动距离平均值高于溶剂对照组，且显著高于化合物3组(P＝0.041)和化合物14组(P＝0.029)。缺血再灌注72小时后，各组大鼠运动距离平均值相当。化合物1组在缺血再灌注后24小时对大鼠运动功能改善明显。
实施例6初步药代特性的测定
将每个化合物分两个给药组：SD大鼠，每组雄各4只，共8只。
尾静脉静注组：剂量为1mg/kg，分别于药前(0h)、以及给药后30min、1h、2h、4h、8h、24h、48h、96h、144h大鼠眼眶静脉取血，离心分离血浆样本。
皮下给药组：剂量为1mg/kg，分别于药前(0h)、以及给药后1h、2h、3h、4h、8h、24h、48h、96h、144h大鼠眼眶静脉取血，离心分离血浆样本。
用液质联用法分别测定SD大鼠血浆样本中相应化合物的血药浓度，静脉和皮下给药后，化合物SD大鼠皮下(SC)给药半衰期见下表：
化合物 t 1/2(h)
化合物1 8.3
化合物2 7.6
化合物3 8.8
化合物4 7.2

Claims (6)

  1. 一种结构I所示的化合物：
    Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-
    Lys-Leu-Ser-Ser-Ile-Glu-Ser-Asp-Val-AA1(R)-AA2
    结构I
    结构I中的AA1为Lys,或为Dap，或为Orn，或为Dab，或为Dah；
    结构I中的AA2为NH 2，或为OH；
    结构I中的R为丁二酸胆固醇单酯，或为2-胆固醇乙酸，或为2-胆固醇丙酸，或为3-胆固醇丙酸，或为HO 2C(CH 2) n1CO-(γGlu) n2-(PEG n3(CH 2) n4CO) n5-，
    其中：n1为10至20的整数；
    n2为1至5的整数；
    n3为1至30的整数；
    n4为1至5的整数；
    n5为1至5的整数。
  2. 根据权利要求1所述的化合物，包含该化合物所成的可药用的盐、溶剂化物、螯合物或非共价复合物，基于该化合物基础上的药物前体，或上述形式的任意混合物。
  3. 权利要求1和2所述的化合物，在制备治疗疾病的药物中的应用。
  4. 根据权利要求3所述的应用，其特征在于，所述药物为治疗缺血性脑损伤后的神经保护的药物。
  5. 一种用于缺血性脑损伤后的神经保护的药物，其包括权利要求1或2所述的化合物和药学上可接受的辅料。
  6. 一种缺血性脑损伤后神经保护的方法，其特征在于，给予权利要求1或2所述的化合物或权利要求5所述的药物。
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