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WO2018032666A1 - 治疗中枢神经系统退行性疾病或脑肿瘤的化合物及其应用 - Google Patents

治疗中枢神经系统退行性疾病或脑肿瘤的化合物及其应用 Download PDF

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WO2018032666A1
WO2018032666A1 PCT/CN2016/109199 CN2016109199W WO2018032666A1 WO 2018032666 A1 WO2018032666 A1 WO 2018032666A1 CN 2016109199 W CN2016109199 W CN 2016109199W WO 2018032666 A1 WO2018032666 A1 WO 2018032666A1
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皮荣标
涂亚林
陈秋荷
杨晓红
王胜男
陈景考
文石军
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Sun Yat Sen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine, and relates to a compound, a drug combination and a application thereof for treating a central nervous system degenerative disease or a brain tumor.
  • the present invention also relates to a process for the preparation of a series of dual target inhibitors of SGK1 and JNK having antioxidative effects and their use, which can be formulated into suitable pharmaceutical dosage forms for the treatment of central nervous degenerative diseases and brain tumors.
  • Serum and Glucocorticoid-Inducible Kinase1 is a silk/threonine protein kinase discovered by Webster et al. in 1993 by differential expression of glucocorticoid-induced transcription of rat breast cancer cells.
  • the transcript level of SGK1 rises rapidly within 30 minutes, so it is called serum and glucocorticoid-regulated protein kinase; SGK1 and protein kinase B (PKB/Akt)
  • the messenger is highly homologous, and in addition to its phosphorylation/dephosphorylation regulatory mechanisms similar to most protein kinases, SGK1 is also regulated by the rapid transcriptional phase.
  • SGK1 is regulated by a variety of hormones and growth factors, such as glucocorticoids, serum, mineralocorticoids, peptide hormone CRH, etc. can quickly induce the expression of SGK1. More and more studies have shown that SGK1 may be a functional junction of multiple cell signal transduction pathways and cellular phosphorylation cascades, and there are signal transductions involved in ion channel regulation, cell survival, differentiation, proliferation and apoptosis. Guide a variety of physiological functions.
  • JNK c-Jun N-terminal kinase
  • MAPK mitogen-activated protein kinase
  • SNK signaling pathway can be activated by various factors such as cytokines, growth factors and stress, and plays a vital role in cell regulation such as cell proliferation and differentiation, apoptosis and stress response. Dysfunction of the JNK signaling pathway can cause various diseases such as ischemia-reperfusion injury, chronic inflammation, neurodegeneration, diabetes and tumors.
  • JNK inhibitors are considered to be potential drugs for diseases such as neurodegenerative diseases and brain tumors.
  • Lipoic acid is one of the most effective natural antioxidants known and is known as a “universal antioxidant”. It is a cofactor for pyruvate dehydrogenase and a metabolic antioxidant that can be converted into reduced dihydrolipoic acid (DHLA) in the body by scavenging free radicals and reactive oxygen species; chelated metal ions, It has an antioxidant effect with other antioxidants in the body.
  • DHLA reduced dihydrolipoic acid
  • Lipoic acid has the characteristics of low molecular weight and amphiphilicity, making it easy to penetrate the blood-brain barrier and exert an antioxidant effect in the central nervous system. Therefore, it is considered to be an effective way to treat neurodegenerative diseases.
  • lipoic acid is not stable enough in the body, and its target is relatively simple. It has only anti-oxidation effect and is difficult to be used alone in the complicated CNS disease. Clinically, it is mainly used in combination with other drugs, or as a pharmacophore for multi-target drug development.
  • both SGK1 and JNK are highly expressed in diseases such as central nervous system degenerative diseases and brain tumors, and inhibition of SGK1 or JNK can improve the course of diseases such as central nervous system degenerative diseases and brain tumors to some extent, while antioxidants are It also plays a positive role in the treatment of central nervous system degenerative diseases.
  • Complex diseases such as central nervous system degenerative diseases and tumors with complex pathogenesis and interaction factors are difficult to achieve treatment or improve the condition through a single drug.
  • the treatment of such diseases is increasingly expected to be applied to multi-targeted drugs that can simultaneously act on multiple targets associated with pathogenesis.
  • the present invention aims to develop a small molecule compound having simultaneous inhibition of SGK1 and JNK and having an anti-oxidation effect, thereby achieving additive or synergistic effects in the treatment of diseases such as central nervous system degenerative diseases and brain tumors, and at the same time reducing joint
  • diseases such as central nervous system degenerative diseases and brain tumors
  • the purpose of medication is inconvenient, the interaction between drugs and other adverse factors.
  • the invention relates to a compound of formula (I) or a tautomer, pharmaceutically acceptable salt, prodrug or solvate thereof.
  • X is:
  • Y is:
  • the compounds of the present invention are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • pharmaceutically acceptable salts, derivatives, solvates, prodrugs any pharmaceutically acceptable salt, ester, solvate, or other compound which, upon administration to a recipient, provides (directly or indirectly) a compound described herein.
  • non-pharmaceutically acceptable salts are also within the scope of the invention, as those which may be used in the preparation of pharmaceutically acceptable salts and salts, the preparation of the prodrugs and derivatives may be carried out by methods known in the art.
  • a pharmaceutically acceptable salt of a compound provided herein can be synthesized from the parent compound by conventional methods, the parent compound containing a base or an acid moiety.
  • the salt is prepared, for example, by combining these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or a mixture of both.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salt include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and organic acid addition salts such as acetate, maleate.
  • the base addition salt include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum, and lithium salts; and organic bases such as, for example, ethylenediamine, ethanolamine, N,N-dialkylethanolamine, triethanolamine, and hydrochloric acid. Glycosamine and basic amino acid salts.
  • Preferred derivatives or prodrugs are those which, when used in a patient, increase the bioavailability of the compounds of the invention (e.g., by allowing the orally administered compound to be more readily absorbed into the blood) or enhancing the parent compound relative to the parent substance.
  • Those that are delivered to a biological compartment such as the brain or lymphatic system).
  • prodrug any compound of the prodrug of a compound of formula (I) is within the scope of the invention, and the term "prodrug" is used in its broadest sense and includes those derivatives which are converted in vivo to the compounds of the invention. These derivatives will be apparent to those skilled in the art and include, depending on the functional groups present in the molecule, the following derivatives which are not limited to the compounds of the invention: esters, amino acid esters, phosphoric acid, metal salt sulfuric acid, carbamates and amides.
  • the compound of the present invention may be in the form of a crystalline form as an advantageous compound or as a solvate, and it is intended that both forms are included in the scope of the present invention.
  • Methods of solvation are well known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a specific embodiment, the solvate is a hydrate.
  • the reaction product can be purified by a conventional method such as crystallization or chromatography.
  • a conventional method such as crystallization or chromatography.
  • these isomers can be separated by conventional techniques such as preparative chromatography. If a chiral center is present, the compound may be prepared in racemic form, or the individual enantiomers may be prepared by enantiospecific synthesis or by resolution.
  • a preferred pharmaceutical form is a crystalline form, including such forms in pharmaceutical compositions.
  • the additional ionic or solvent portion should also be non-toxic.
  • the compounds of the invention may exist in different polymorphs, and it is intended that the invention include all such forms.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or excipient for administration to a patient medicine.
  • compositions of the invention can be used with other drugs to provide a combination therapy.
  • Other drugs may form part of the same composition or may be provided as separate compositions for simultaneous or simultaneous administration.
  • reagents and methods involved in the examples are all reagents and methods commonly used in the art.
  • DCM is dichloromethane
  • TFA is trifluoroacetic acid
  • EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DMAP is 4-dimethylaminopyridine.
  • Lipoic acid (50.00 mg, 242.34 ⁇ mol) was dissolved in DMF (3 mL), EDCI (139.37 mg, 727.01 ⁇ mol), HOBt (39.29 mg, 290.80 ⁇ mol) and triethylamine (100.78 ⁇ L, 727.01 ⁇ mol) at room temperature After stirring for 10 minutes, the yellow solid obtained by the above reaction (71.61 mg, 315.04 ⁇ mol) was added in one portion, and the mixture was stirred under argon atmosphere for 6 hours at room temperature. The aqueous phase was added with saturated NaHCO 3 solution and extracted with ethyl acetate.
  • Logarithmic growth phase HT-22 cells were digested with 0.25% trypsin, resuspended in complete medium, counted under a microscope and adjusted to a cell concentration of 10 ⁇ 10 4 cells/mL, and seeded with 96-well cell culture plates. 100 ⁇ L/well was cultured overnight to allow the cells to adhere. The medium in the 96-well plate was aspirated, and various concentrations of the compound were added to a 96-well plate at 100 ⁇ L/well. After pre-incubation for 30 min, 2 ⁇ L of 100 mM L-glutamate was added. The model group was not added with the test compound, and 2 ⁇ L of 100 mM L-glutamate was directly added.
  • HT-22 cells were treated with DMEM + 10% fetal calf serum and placed in a 5% CO2 incubator at 37 °C.
  • the cells were seeded in a poly-lysine-coated 24-well plate at a suitable density; after the cells were attached, the PT109 prepared in the medium was added to the corresponding wells, and after treatment for 30 minutes, 2 mM glutamic acid was added. 10h.
  • the cells were collected, and the cells were incubated with DHE dye for about 30 minutes, the DHE dye was washed, and the fluorescence intensity of DHE was detected by a high-content system.
  • the experimental results show that PT109 can significantly reduce ROS-induced ROS elevation at 10 ⁇ M.
  • PT109 has better selectivity for SGK1 and JNK at 10 ⁇ M.
  • V d is the volume of the receiving cell
  • V a is the volume of the receiving cell
  • A is the membrane area
  • t is the permeation time
  • [drug] acceptor is the absorbance of the receiving cell
  • [drug] equilibrium is the theoretical equilibrium absorbance.

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Abstract

本发明涉及治疗中枢系统退行性疾病或脑肿瘤的化合物、药物组合物及其应用，该化合物具有式(I)的结构，这些化合物可作为具有抗氧化作用的SGK1和JNK的双靶点抑制剂，而被制成适当的药物剂型用于中枢神经退行性疾病、脑肿瘤的治疗。

Description

治疗中枢神经系统退行性疾病或脑肿瘤的化合物及其应用 技术领域
本发明属于医药领域，涉及治疗中枢神经系统退行性疾病或脑肿瘤的化合物、药物组合及其应用。本发明还涉及一系列具有抗氧化作用的SGK1和JNK的双靶点抑制剂的制备方法及其应用，它们可被制成适当的药物剂型用于中枢神经退行性疾病、脑肿瘤的治疗。
背景技术
血清和糖皮质激素调节蛋白激酶1(Serum and Glucocorticoid‐Inducible Kinase1,SGK1)是1993年Webster等通过糖皮质激素诱导转录大鼠乳腺癌细胞的表达差异筛选发现的一种丝/苏氨酸蛋白激酶；当细胞受到糖皮质激素或者血清刺激后，SGK1的转录水平在30分钟内迅速升高，因此称之为血清和糖皮质激素调节蛋白激酶；SGK1与蛋白激酶B(PKB/Akt)等第二信使具有高度同源性，除了具有和绝大多数蛋白激酶相似的磷酸化/去磷酸化调节机制外，SGK1还受到快速转录阶段的调节。据文献报道，SGK1受到多种激素和生长因子的调节，如糖皮质激素、血清、盐皮质激素、多肽类激素CRH等均能快速诱导SGK1的表达。越来越多的研究表明，SGK1可能是多种细胞信号转导通路和细胞磷酸化级联反应的一个功能性交汇点，存在参与离子通道调节、细胞存活、分化、增殖和凋亡的信号转导等多种生理功能。近来研究发现其与脑变性疾病如脑缺血、癫痫、阿尔茨海默病(AD)、帕金森氏病(PD)和脑肿瘤等密切相关，在中枢神经系统发育、神经元变性、凋亡和脑肿瘤的发生发展过程中起着重要作用。SGK1的表达及活性异常增加参与了多种疾病的发生及发展过程，SGK1的抑制剂被认为可能是治疗这些疾病的潜在的有用的药物。
c‐Jun氨基末端激酶(c‐Jun N‐terminal kinase,JNK)家族是1990年被发现的促分裂原活化蛋白激酶(mitogen‐activated protein kinase,MAPK)超家族成员之一，属于进化上保守的丝氨酸/苏氨酸蛋白激酶。JNK信号通路可被细胞因子、生长因子和应激等多种因素激活，在细胞增殖与分化、细胞凋亡和应激反应等多种细胞调控方面起着至关重要的作用。JNK信号通路功能失调可造成缺血再灌注损伤、慢性炎症、神经退行性变、糖尿病和肿瘤等多种疾病。近年来的研究发现过度激活的JNK信号通路与阿尔茨海默病、帕金森氏病密切相关，而敲除或JNK抑制剂则能改善AD和PD疾病模型的症状。有研究发现胶质瘤患者JNK高表达，且JNK的表达量与胶质瘤的恶性程度和胶质瘤患者的愈后密切相关。另外，JNK的抑制剂被发现能降低神经胶质瘤干细胞的自我更新能力，促进胶质瘤干细胞朝不具有致瘤能力的胶质样或神经元样的细胞分化。因此，JNK抑制剂被认为是神经退行性疾病和脑肿瘤等疾病的潜在药物。
硫辛酸(lipoic acid,LA)是已知天然抗氧剂中效果最强的一种，被誉为“万能抗氧剂”。 它是丙酮酸脱氢酶的辅助因子，也是代谢性抗氧剂，在生物体内可以转化为还原型的二氢硫辛酸(DHLA)，它可以通过清除自由基和活性氧；螯合金属离子、与其他体内的抗氧剂作用等途径达到抗氧化作用。硫辛酸具有分子量低和两亲性的特点，使得它容易透过血脑屏障，从而在中枢神经系统发挥抗氧化作用，因此，它被认为是治疗神经退行性疾病的有效途径。但是硫辛酸在体内不够稳定，作用靶点较为单一，仅具有抗氧化作用，难以单独用于发病机制错综复杂的CNS疾病。临床上主要与其他药物联合使用，或作为多靶点药物研发的药效团。
由以上可以发现，SGK1和JNK均在中枢神经退行性疾病和脑肿瘤等疾病中高表达，抑制SGK1或JNK则能一定程度上改善中枢神经退行性疾病和脑肿瘤等疾病的病程，而抗氧化剂在治疗中枢神经退行性疾病中也起到了积极的作用。中枢神经退行性疾病和肿瘤等发病机制复杂且发病因素之间相互影响的复杂性疾病很难通过单一药物达到治疗或改善病情的目的。随着系统生物和网络药理学的发展，人们越来越将这类疾病的治疗寄希望于能同时作用于与发病机制相关的多个靶点的多靶点药物上。基于此，本发明旨在开发具有同时抑制SGK1和JNK并具有抗氧化作用的小分子化合物，达到在中枢神经退行性疾病、脑肿瘤等疾病的治疗中起到相加或协同作用，同时减少联合用药带来的用药不方便、药物之间的相互作用等不良因素的目的。
发明内容
基于以上研究和多靶点药物研发理论，我们合成并筛选了一系列具有SGK1和JNK双靶点抑制作用的小分子化合物。
本发明涉及式(Ⅰ)的化合物或其互变异构体、药用盐、前药或溶剂化物。
Figure PCTCN2016109199-appb-000001
其中结构式通式(Ⅰ)中
X为：
Figure PCTCN2016109199-appb-000002
Y为：
Figure PCTCN2016109199-appb-000003
Z为：
Figure PCTCN2016109199-appb-000004
除非另外指明，本发明的化合物还意欲包括区别仅在于存在一个或多个同位素富集的原子的化合物。例如，用氘或氚替换氢，或者用13C或14C‐富集的碳原子替换碳原子，或15N‐富集的氮原子替换氮原子的化合物属于本发明的范围内。
属于“药用盐、衍生物、溶剂化物，前药”是指任何药用盐、酯、溶剂化物，或经施用于接受者后能够提供(直接或间接)本文所述化合物的其他化合物。然而，应当理解非药用盐也属于本发明的范围内，因为那些可能用于制备药用盐和盐，前药和衍生物的制备可以通过本领域已知的方法进行。例如，本发明提供的化合物的药用盐可以通过常规方法由母体化合物合成，该母体化合物含有碱或酸部分。通常，该盐例如通过将游离酸或碱形式的这些化合物与化学计算量的适当碱或酸在水中或在有机溶剂中或在两者的混合物中制备。通常，非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。酸加成盐的实例包括无机酸加成盐例如，盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐，和有机酸加成盐例如，乙酸盐、马来酸盐、富马酸盐、柠檬酸盐、草酸盐、琥珀酸盐、酒石酸盐、苹果酸盐、扁桃酸盐和对甲苯磺酸盐。碱加成盐的实例包括无机盐如例如钠、钾、钙、铵、镁、铝和锂盐；和有机碱如例如乙二胺、乙醇胺、N,N‐二烷基乙醇胺、三乙醇胺、葡糖胺和碱性氨基酸盐。
优选的衍生物或前药是相对于母体物质，当将这些化合物使用于患者时提高本发明化合物的生物利用度(例如通过使得口服给药的化合物更容易被吸收到血液中)或增强母体化合物向生物区室(例如脑或淋巴系统)的传递的那些。
式(Ⅰ)化合物前药的任何化合物属于本发明的范围内，术语“前药”以其最广泛的意义使用并且包括在体内转化为本发明化合物的那些衍生物。这些衍生物对于本领域技术人员是显而易见的，并且根据分子中存在的官能团，包括不限于本发明化合物的下列衍生物：酯、氨基酸酯、磷酸、金属盐硫酸、氨基甲酸酯和酰胺。
本发明的化合物可以是作为有利化合物或作为溶剂化物的晶体形式，意欲将两种形式都包括在本发明的范围内。溶剂化的方法是本领域公知的。适当的溶剂化物是药用溶剂化物。在一个具体实施方案中，溶剂化物是水合物。
如果需要，可以通过常规方法如结晶法或色谱法纯化反应产物。当用于制备本发明化合物的上述方法产生立体异构体的混合物时，这些异构体可以通过常规技术如制备色谱法分离。如果存在手性中心，化合物可能以外消旋形式制备，或者可以通过对映特异性合成或通过拆分来制备单个的对映异构体。
一种优选的药用形式是结晶形式，包括药物组合物中的这种形式。如果是盐和溶剂化物，另外的离子或溶剂部分也应当是非毒性。本发明的化合物可以存在不同的多晶型物，意欲本发明包括所有这些形式。
由上述发明式(Ⅰ)表示的典型化合物、其盐、它们的溶剂化物或前药显示良好的血脑屏障透过率，较强的SGK1和JNK抑制作用。因此，本发明另一方面涉及治疗、改善或预防神经退行性疾病的方法，该方法包含向需要这种治疗的患者施用治疗有效量的式(Ⅰ)的化合物或其药物组合物。
本发明另外提供药物组合物，其包含本发明的化合物，或其药用盐、衍生物、前药或立体异构体，以及药用载体、辅剂或赋形剂，以用于向患者给药。
本发明的化合物和组合物可以与其它药物一起使用以提供联合治疗。其它药物可以形成相同组合物的一部分，或者可以作为同时或不同时给药的分开的组合物提供。
附图说明
图1.化合物对谷氨酸诱导的HT22死亡的保护作用。***P<0.001，**P<0.01，**P<0.05与谷氨酸组比较；###P<0.001与正常组比较。
图2.化合物PT109对ROS的影响。
具体实施方式
提供下列实施例进一步举例说明本发明，它们不应当认为是对本发明范围的限定。除非特别说明，实施例中所涉及的试剂、方法均为本领域常用的试剂和方法。其中，DCM为二氯甲烷，TFA为三氟乙酸，EDCI为1‐(3‐二甲氨基丙基)‐3‐乙基碳二亚胺盐酸盐，DMAP为4‐二甲氨基吡啶。
实施例1
Figure PCTCN2016109199-appb-000005
5‐(1,2‐二硫环戊烷‐3‐基)‐N‐(2‐(异喹啉‐5‐磺酰胺)乙基)戊酰胺【5‐(1,2‐dithiolan‐3‐yl)‐N‐(2‐(isoquinoline‐5‐sulfonamido)ethyl)pentanamide】(PT019)的制备：
合成路线：
Figure PCTCN2016109199-appb-000006
按照上述PT019的合成路线，将异喹啉‐5‐磺酸置于圆底烧瓶中，加入6mL二氯亚砜和一滴DMF，回流三个小时。用旋转蒸发仪除去二氯亚砜，向剩余固体中加入DCM，过滤，固体用DCM洗涤三次后经真空干燥箱干燥得到白色固体中间体2(1g,产率91.9％)。
在冰浴条件下，将中间体2(130.00mg,571.01μmol)缓慢地加入含有乙二胺(381.30μL,5.71mmol)的DCM(6mL)溶液中，撤去冰浴后室温反应3h。反应完成后用水洗去剩余的乙二胺，有机相用旋转蒸发仪除去溶剂，剩余物在乙醚中重结晶得到棕黄色固体中间体3(91.8mg,产率60％)。1H NMR(400MHz,DMSO)δ9.48(s,1H),8.70(d,J＝6.1Hz,1H),8.47–8.40(m,2H),8.34(dd,J＝7.4,1.1Hz,1H),7.87–7.80(m,1H),2.77(t,J＝6.5Hz,2H),2.46(t,J＝6.5Hz,2H).
将中间体3(100mg,397.92μmol)，硫辛酸(98.52mg,477.51μmol)，DMAP(4.86mg,39.79μmol)溶于DCM(6mL)中，将Et3N(165.48μL,1.19mmol)和EDCI(114.42mg,596.88μmol)加入溶液中，反应在室温下搅拌过夜后加入DCM(30mL)稀释，用水(10mL)终止反应。分离后，水相用DCM(15mL×3)萃取。合并的有机相用饱和的食盐水(10mL×1)洗涤。在Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到黄色粘稠油状物PT019(168mg,产率96％)。1H NMR(400MHz，CDCl3)δ9.36(s,1H),8.70(d,J＝6.1Hz,1H),8.48–8.35(m,2H),8.22(d,J＝8.2Hz,1H),7.77–7.65(m,1H),5.94(dd,J＝10.0,4.8Hz,2H),3.56(dt,J＝14.8,6.3Hz,1H),3.34(dd,J＝11.1,5.8Hz,2H),3.14(dddd,J＝22.8,16.0,8.9,5.5Hz,4H),2.46(dt,J＝12.3,6.5Hz,1H),2.16–2.03(m,2H),1.91(td,J＝13.7,6.9Hz,1H),1.61–1.53(m,2H),1.48–1.32(m,2H).13C NMR(101MHz,CDCl3)δ174.29,153.28,145.02,134.25,133.69,133.23,131.17,129.08,126.08,117.36,56.46,43.28,40.28,39.38,38.49,36.14,34.50,28.78,25.21.纯度：97％(高效液相色谱法)。
实施例2
Figure PCTCN2016109199-appb-000007
5‐(1,2‐二硫环戊烷‐3‐基)‐N‐(3‐(异喹啉‐5‐磺酰胺)丙基)戊酰胺【5‐(1,2‐dithiolan‐3‐yl)‐N‐(3‐(isoquinoline‐5‐sulfonamido)propyl)pentanamide】(PT046)的制备：
合成路线：
Figure PCTCN2016109199-appb-000008
按照上述PT046的合成路线，在冰浴条件下，将实施例1中获得到中间体2(600.00mg,2.27mmol)缓慢地加入含有1,3‐丙二胺(1.89mL,22.72mmol)的DCM(6mL)溶液中，撤去冰浴后室温反应3h.反应完成后用水洗去剩余的乙二胺，有机相用旋转蒸发仪除去溶剂，剩余物在乙醚中重结晶得到棕黄色固体中间体4(300mg,产率43.8％)。
将中间体4(77.16mg,290.80μmol)，硫辛酸(50.00mg,242.34μmol)，DMAP(2.96mg,24.23μmol)溶于DCM(6mL)中，将Et3N(6mL)和EDCI(69.68mg,363.50μmol)加入溶液中，反应在室温下搅拌过夜后加入DCM(30mL)稀释，用水(10mL)终止反应。分离后，水相用DCM(15mL×3)萃取。合并的有机相用饱和的食盐水(10mL×1)洗涤。在Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到黄色粘稠油状物PT046(19.2mg,产率17.5％)。1H NMR(400MHz,CDCl3)δ9.34(s,1H),8.70(d,J＝6.1Hz,1H),8.47(d,J＝6.1Hz,1H),8.41(dd,J＝7.3,1.1Hz,1H),8.19(d,J＝8.2Hz,1H),7.73–7.63(m,1H),6.49(t,J＝6.5Hz,1H),5.82(t,J＝5.9Hz,1H),3.52–3.43(m,1H),3.28(dd,J＝12.2,6.3Hz,2H),3.20–3.04(m,2H),2.92(dd,J＝12.2,6.4Hz,2H),2.48‐2.38(m,1H),2.11(t,J＝7.3Hz,2H),1.94–1.77(m,4H),1.70–1.62(m,1H),1.55–1.46(m,2H),1.40–1.28(m,2H).13C NMR(101MHz,CDCl3)δ174.10,153.16,145.16,135.06,133.35,132.85,131.26,129.05,125.94,117.55,56.42,40.27,39.73,38.48,36.26,35.80,34.48,30.10,28.76,25.25.纯度：96％(高效液相色谱法)。
实施例3
Figure PCTCN2016109199-appb-000009
5‐(1,2‐二硫环戊烷‐3‐基)‐N‐(4‐(异喹啉‐5‐氨基)环己基)戊酰胺【5‐(1,2‐dithiolan‐3‐yl)‐N‐(4‐(isoquinolin‐5‐ylamino)cyclohexyl)pentanamide】(PT109)的制备：
合成路线：
Figure PCTCN2016109199-appb-000010
按照上述PT109的合成路线，将化合物5(442.31mg,2.07mmol)，5‐氨基异喹啉(230.00mg,1.60mmol)和无水Na2SO4(1.13g,7.98mmol)溶于冰醋酸(10mL)中，在冰浴条件下加入氰基硼氢化钠(200.50mg,3.19mmol)，撤掉冰浴，反应在室温搅拌下过夜。反应完成后用旋转蒸发仪除去冰醋酸，剩余物中加入饱和NaHCO3溶液，水相用DCM萃取。合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到黄色固体化合物6(372mg,产率68.3％)。1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.46(s,1H),7.53(s,1H),7.49–7.39(m,1H),7.30(s,1H),6.77(s,1H),4.71–4.12(m,2H),3.55(m,3H),2.27(d,J＝12.0Hz,1H),2.14(d,J＝12.6Hz,1H),2.06–1.88(m,2H),1.82(m,2H),1.46(s,9H),1.34(m,3H).
将化合物6(45.51mg,133.28μmol)溶解在DCM(1mL)中，加入TFA(1mL)，室温下搅拌3小时。反应完成后用旋转蒸发仪除去TFA，剩余物中加入硫辛酸(25.00mg,121.17μmol)，HOBt(18.01mg,133.28μmol)和EDCI(34.84mg,181.75μmol)，加入含有三乙胺(50.39μL,363.50μmol)的无水DCM，室温下搅拌过夜，反应完成后加水(10mL)萃灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到黄色油状物PT109(39.3mg，产率75.5％)。m.p.131.4℃.1H NMR(400MHz,CDCl3)δ9.14(s,1H),8.44(d,J＝5.9Hz,1H),7.54(d,J＝5.9Hz,1H),7.46(t,J＝7.9Hz,1H),7.30(d,J＝8.1Hz,1H),6.77(d,J＝7.7Hz,1H),6.00(d,J＝7.4Hz,1H),4.01(d,J＝7.4Hz,1H),3.70(s,1H),3.62–3.48(m,1H),3.24–3.02(m,2H),2.43(tt,J＝20.8,10.4Hz,1H),2.20(t,J＝7.3Hz,2H),2.00–1.78(m,7H),1.70(m,7H),1.56–1.37(m,3H).13C NMR(100MHz,CDCl3)δ173.25,171.31,153.00,143.11,131.58,130.07,129.03,127.30,125.40,114.24,56.46,45.00,43.66,41.11,40.28,38.53,34.73,33.13,29.19,28.93,25.06.纯度：100％(高效液相色谱法)。
实施例4
Figure PCTCN2016109199-appb-000011
5‐(1,2‐二硫环戊烷‐3‐基)‐1‐(3‐(异喹啉‐5‐氨基)哌啶‐1‐基)戊烷‐1‐酮【5‐(1,2‐dithiolan‐3‐yl)‐1‐(3‐(isoquinolin‐5‐ylamino)piperidin‐1‐yl)pentan‐1‐one】(PT128)的制备：
合成路线：
Figure PCTCN2016109199-appb-000012
按照上述PT128的合成路线，将化合物7(497.52mg,2.50mmol)，5‐氨基异喹啉(300.00mg,2.08mmol)溶解在钛酸异丙酯(5mL)中，室温下搅拌30分钟后加入无水乙醇(5mL)稀释，冰浴条件下加入氰基硼氢化钠(261.53mg,4.16mmol)，反应在室温下搅拌3个小时。用硅藻土过滤去除固体物，加入饱和NaHCO3溶液淬灭反应，水相用乙酸乙酯萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到黄色固体化合物8(566.00mg,产率83％)。
将化合物8(200.00mg,610.83μmol)溶解在DCM(1mL)中，加入TFA(1mL)，室温下搅拌3小时。反应完成后用旋转蒸发仪除去TFA，加入饱和NaHCO3溶液(10mL)，水相用乙酸乙酯萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到黄色固体(130.00mg,产率93.6％)。
将硫辛酸(50.00mg,242.34μmol)溶解到DMF(3mL)中，加入EDCI(139.37mg,727.01μmol)，HOBt(39.29mg,290.80μmol)和三乙胺(100.78μL,727.01μmol)在室温下搅拌10分钟后一次性加入上述反应得到的黄色固体(71.61mg,315.04μmol)，室温氩气保护搅拌6小时，加入饱和NaHCO3溶液水相用乙酸乙酯萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到棕黄色油状物(53mg,产率52.6％)。1H NMR(400MHz,DMSO)δ9.12(s,1H),8.40(s,1H),8.14–8.02(m,1H),7.46(d,J＝4.7Hz,1H),7.28(t,J＝7.0Hz,1H),6.93–6.80(m,1H),6.12–5.98(m,1H),4.63(d,J＝12.4Hz,1H),4.03(d,J＝11.9Hz,1H),3.85(d,J＝12.0Hz,1H),3.62(s,2H),3.51(s,1H),3.24–2.99(m,4H),2.91(s,1H),2.43–2.30(m,2H),2.15(dd,J＝38.2,16.6Hz,3H),1.93–1.65(m,5H),1.63–1.33(m,7H),1.22(s,1H).纯度：99％(高效液相色谱法)。
实施例5
Figure PCTCN2016109199-appb-000013
1‐(5‐(1,2‐二硫环戊烷‐3‐基)戊酰基‐N‐(异喹啉‐5‐基)哌啶‐4‐甲酰胺【1‐(5‐(1,2‐dithiolan‐3‐yl)pentanoyl)‐N‐(isoquinolin‐5‐yl)piperidine‐4‐carboxamide】(PT106)的制备：
合成路线：
Figure PCTCN2016109199-appb-000014
按照上述PT106的合成路线，将化合物9(1g,7.74mmol)溶解在NaOH溶液(2M,10mL)中，在冰浴条件下缓慢加入溶解了BOC酸酐(2.53g,11.61mmol)的THF(10mL)溶液，反应在室温下搅拌1小时，用旋转蒸发仪除去THF，水相用稀盐酸调节pH值至5‐6，然后用乙酸乙酯萃取，合并的有机相用无水Na2SO4干燥并过滤，滤液用旋转蒸发仪浓缩，真空干燥后得到白色固体化合物10(1.78g,7.76mmol,产率100％)。
将化合物10(279.89mg,1.22mmol)，5‐氨基异喹啉(160.00mg,1.11mmol)，DMAP(13.56mg,110.98μmol)溶解在无水DCM(8ml)中，常温下加入三乙胺(461.50μL,3.33mmol)和EDCI(319.12mg,1.66mmol)，室温下搅拌过夜；反应完成后加水(10mL)淬灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到白色固体中间体11(174.30mg,490.39μmol,产率44.2％)。1H NMR(400MHz,CDCl3)δ9.27(s,1H),8.57(d,J＝6.0Hz,1H),8.16(d,J＝7.2Hz,1H),7.84(d,J＝8.2Hz,1H),7.64‐7.57(m,3H),4.37–4.10(m,2H),2.86(s,2H),2.59(s,1H),2.05‐2.01(m,2H),1.89‐1.79(m,2H),1.48(s,9H).
将中间体11(85.00mg,239.15μmol)溶解在DCM(1mL)中，加入TFA(1mL)，室温下搅拌3小时。反应完成后用旋转蒸发仪除去TFA，剩余物中加入硫辛酸(59.21mg,286.98μmol)，DMAP(2.92mg,23.91μmol)和EDCI(91.69mg,478.29μmol)，加入含有三乙胺(99.45μL,717.44μmol)的无水DCM，室温下搅拌过夜，反应完成后加水(10mL)萃灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到黄色油状物PT106(77mg,173.57μmol,产率72.6％)。1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.51(d,J＝5.9Hz,1H),8.12(s,1H),8.06(d,J＝7.4Hz,1H),7.81(d,J＝8.1Hz,1H),7.60‐7.56(m,2H),4.65(d,J＝12.8Hz,1H),3.96(d,J＝13.3Hz,1H),3.59‐3.52(m,1H),3.23–3.05(m,3H),2.76‐2.67(m,11.2Hz,2H),2.48‐2.40(m,1H),2.38–2.27(m,2H),2.05(d,J＝12.5Hz,2H),1.96–1.84(m,5H),1.84–1.74(m,2H),1.70‐1.59(m,4H),1.52–1.40(m,2H).13C NMR(100MHz,CDCl3)δ173.34,171.40,153.09,143.20,131.67,130.16,129.12,127.39,125.49,114.33,56.55,45.09,43.75,41.20,40.37,38.62,34.82,33.22,29.19,25.15.纯度：96％(高效液相色谱法)。
实施例6
Figure PCTCN2016109199-appb-000015
4‐(5‐(1,2‐二硫环戊烷‐3‐基)戊酰胺)‐N‐(异喹啉‐5‐基)苯甲酰胺【4‐(5‐(1,2‐dithiolan‐3‐yl)pentanamido)‐N‐(isoquinolin‐5‐yl)benzamide】(PT133)的制备：
合成路线：
Figure PCTCN2016109199-appb-000016
按照上述PT133的合成路线，将化合物12(200.00mg,1.39mmol)，5‐氨基异喹啉(427.86mg,1.80mmol)，DMAP(16.95mg,138.72umol)，三乙胺(576.87μL,4.16mmol)溶解在无水DCM中，室温下搅拌30分钟后一次性加入EDCI(797.80mg,4.16mmol)，回流反应过夜；反应完成后加水(10mL)淬灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到白色固体中间体13(426,1.17mmol,产率84.5％)。1H NMR(400MHz,DMSO)δ10.36(s,1H),9.71(s,1H),9.35(s,1H),8.52(d,J＝5.9Hz,1H),8.03(t,J＝8.3Hz,3H),7.88(d,J＝7.3Hz,1H),7.82(d,J＝5.6Hz,1H),7.72(t,J＝7.7Hz,1H),7.63(d,J＝8.1Hz,2H),1.51(s,9H).
将中间体13(80.00mg,220.14μmol)溶解在DCM(1mL)中，加入TFA(1mL)，室温下搅拌3小时。反应完成后用旋转蒸发仪除去TFA，剩余物中加入硫辛酸(54.50mg,264.16μmol)，DMAP(2.69mg,22.01μmol)和EDCI(126.60mg,660.41μmol)，加入含有三乙胺(91.54μL,660.41μmol)的无水DCM(6mL)，室温下搅拌过夜，反应完成后加水(10mL)萃灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到白色固体PT133(54.40mg,120.46μmol,产率54.7％)。m.p.172.6℃.1H NMR(400MHz,DMSO)δ10.41(s,1H),10.20(s,1H),9.38(s,1H),8.53(d,J＝6.0Hz,1H),8.08–8.03(m,3H),7.91(d,J＝7.3Hz,1H),7.85(d,J＝6.0Hz,1H),7.78(s,1H),7.76(d,J＝2.3Hz,1H),7.73(d,J＝7.8Hz,1H),3.69‐3.60(m,1H),3.21‐3.13(m,3H),2.46–2.35(m,3H),1.83‐1.93(m,1H),1.78–1.55(m,4H),1.47‐1.42(m,2H).13C NMR(100MHz,DMSO)δ172.11,166.12,152.97,143.15,142.98,133.77,131.84,129.33,128.73,127.80,127.66,126.00,118.72,116.89,113.08,56.59,38.60,36.80,34.64,28.82,25.24.纯度：97％(高效液相色谱法)。
实施例7
Figure PCTCN2016109199-appb-000017
4‐(5‐(1,2‐二硫环戊烷‐3‐基)戊酰胺)N‐(吡啶‐4‐基)苯甲酰胺【4‐(5‐(1,2‐dithiolan‐3‐yl)pentanamido)‐N‐(pyridin‐4‐yl)benzamide】(PT119)的制备：
合成路线：
Figure PCTCN2016109199-appb-000018
按照上述PT119的合成路线，将化合物14(1.00g,5.15mmol)溶解在DCM(2mL)中，加入TFA(2mL)，室温下搅拌3小时。反应完成后用旋转蒸发仪除去TFA，得到4‐氨基吡啶三氟乙酸盐粗品。
将4‐氨基吡啶三氟乙酸盐(300.00mg,1.45mmol)，N‐BOC‐4‐氨基苯甲酸(377.99mg,1.59mmol)，DMAP(17.69mg,144.84μmol)溶解在无水DCM(6mL)中，室温下加入三乙胺(602.30μL,4.35mmol)和EDCI(416.48mg,2.17mmol)，室温下搅拌过夜，反应完成后加水(10mL)萃灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到白色固体中间体15(140mg,446.78μmol,产率30.85％)。1H NMR(400MHz,DMSO)δ10.41(s,1H),9.72(s,1H),8.45(d,J＝4.6Hz,2H),7.90(d,J＝8.3Hz,2H),7.77(d,J＝4.9Hz,2H),7.60(d,J＝8.3Hz,2H),1.49(s,9H).
将中间体15(50.00mg,159.57μmol)溶解在DCM(1mL)中，加入TFA(1mL)，室温下搅拌3小时。反应完成后用旋转蒸发仪除去TFA，剩余物中加入硫辛酸(32.92mg,159.57μmol)，HOBt(25.87mg,191.48μmol)和EDCI(45.88mg,239.35μmol)，加入含有三乙胺(66.36μL,478.70μmol)的无水DMF(4mL)溶液，室温下搅拌过夜，反应完成后加水(10mL)萃灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到白色固体PT119(48mg,119.54μmol,产率74.91％)。m.p.159.9℃.1H NMR(400MHz,DMSO)δ10.44(s,1H),10.21(s,1H),8.45(s,2H),7.94(d,J＝7.4Hz,2H),7.75(d,J＝9.1Hz,4H),3.63(s,1H),3.15(d,J＝20.1Hz,2H),2.36(s,3H),1.90‐1.86(m,1H),1.61(s,4H),1.42(s,2H).13C NMR(100MHz,DMSO)δ171.64,165.72,150.19,146.05,142.75,128.86,128.11,118.20,113.94,56.07,38.08,36.27,34.11,28.27,24.69.纯度：97％(高效液相色谱法)。
实施例8
Figure PCTCN2016109199-appb-000019
1‐(5‐(1,2‐二硫环戊烷‐3‐基)戊酰胺)‐N‐(吡啶‐4‐基)哌啶‐4‐甲酰胺【1‐(5‐(1,2‐dithiolan‐3‐yl)pentanoyl)‐N‐(pyridin‐4‐yl)piperidine‐4‐carboxamide】(PT134)的制备：
合成路线：
Figure PCTCN2016109199-appb-000020
按照上述PT134的合成路线，将实施例7中获得的4‐氨基吡啶三氟乙酸盐(200.00mg,965.58μmol)，化合物10(265.66mg,1.16mmol)，DMAP(11.80mg,96.56μmol)溶解在无水DCM(6mL)中，加入三乙胺(401.53μL,2.90mmol)和EDCI(555.31mg,2.90mmol)，室温下搅拌过夜，反应完成后加水(10mL)萃灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到白色固体中间体16(281mg,920.19μmol,产率95.3％)。1H NMR(400MHz,DMSO)δ10.29(s,1H),8.40(d,J＝4.8Hz,2H),7.56(d,J＝4.8Hz,2H),3.99(d,J＝14.2Hz,3H),2.86‐2.67(m,2H),1.79(d,J＝12.9Hz,2H),1.51‐1.45(m,2H),1.40(s,9H).将化合物16(140.00mg,458.46μmol)溶解在DCM(1mL)中，加入TFA(1mL)，室温下搅拌3小时。反应完成后用旋转蒸发仪除去TFA，剩余物中加入硫辛酸(113.51mg,550.15μmol)，DMAP(5.60mg,45.85μmol)和EDCI(263.66mg,1.38mmol)和DMF(1mL)，最后加入溶解了三乙胺(190.65μL,1.38mmol)的无水DCM(6mL)，室温下搅拌过夜，反应完成后加水(10mL)萃灭，水相用DCM萃取，合并的有机相用饱和的食盐水(10mL×1)洗涤，在无水Na2SO4干燥后旋蒸除去溶剂，残留物经硅胶柱色谱纯化得到棕黄色油状物PT134(154.3mg,392.06μmol,产率85.52％)。1H NMR(400MHz,CDCl3)δ8.47(d,J＝5.3Hz,2H),8.34(s,1H),7.51(d,J＝5.4Hz,2H),4.59(d,J＝13.4Hz,1H),3.94(d,J＝13.5Hz,1H),3.66–3.48(m,1H),3.25–3.01(m,3H),2.68(t,J＝12.2Hz,1H),2.59–2.41(m,2H),2.35(t,J＝7.4Hz,2H),1.94‐1.91(m,2H),1.81‐1.79(m,1H),1.72‐1.63(m,6H),1.52‐1.45(m,3H).13C NMR(100MHz,CDCl3)δ173.78,171.51,150.35,145.93,113.98,56.53,45.02,43.83,41.17,40.37,38.61,34.79,33.21,29.14,25.19.纯度：98％(高效液相色谱法)。
实施例9：生物学评估
化合物对谷氨酸诱导的HT22死亡的保护作用
取对数生长期HT‐22细胞，以0.25％胰酶消化后，完全培养基重悬，显微镜下细胞计数板计数并调整细胞浓度为10×104个/mL，接种96孔细胞培养板，100μL/孔，培养过夜，使细胞贴壁。将96孔板中培养基吸走，加入不同浓度的化合物到96孔板中，100μL/孔。预孵育30min后，加入2μL 100mM L‐glutamate。模型组不加待测化合物，直接加入2μL 100mM L‐glutamate。孵育24h后，每孔加入10μL 5mg/mL MTT，孵育1h，弃去上清，加DMSO 100μL/孔，振荡使生成物formazan充分溶解，在酶标仪上测定各孔吸光度值，测定波长570nm。采用公式化合物促进细胞的存活率(％)＝100％*(A待测化合物‐A模型组)/(A模型组‐A空白)计算细胞存活率。结果见附图1。从结果可以看出，除化合物PT119外，其他化合物均能在一定的浓度下逆转谷氨酸诱导的HT‐22细胞的死亡。
实施例10：生物学评估
PT109对ROS的影响
采用DHE染色检测氧自由基的生成情况。HT‐22细胞用DMEM+10％胎牛血清，并置于37℃，含5％CO2孵箱中。将细胞以合适的密度种在多聚赖氨酸包被的24孔板；待细胞贴壁后，分别用培养基配制好的PT109加入对应的孔中，处理30min后，加入2mM谷氨酸处理10h。收集细胞，并用DHE染料孵育细胞30min左右，洗净DHE染料，用高内涵系统检测DHE的荧光强度。实验结果显示PT109在10μM条件下能明显减少由谷氨酸诱导的ROS升高。
实施例11：生物学评估
PT109对SGK1和JNK的抑制作用
通过life Technologies公司的激酶筛选商业化服务检测PT109对SGK和JNK的抑制作用。结果如表1所示：PT109对SGK1、SGK2和SGK3的IC50为分别为1.34μM、5.6μM和26.4μM，对SGK1有较好的选择性；对JNK1、JNK2和JNK3的IC50分别为0.285μM、0.143μM和0.831μM。
表1 PT109对JNK和SGK1的抑制作用
Figure PCTCN2016109199-appb-000021
实施例12：生物学评估
PT109的激酶选择性
通过life Technologies公司的激酶筛选服务检测PT109对其他激酶(包括JNK和SGK1)的抑制作用(化合物9的浓度为10μM，重复两次取平均值)，考察化合物对JNK和SGK1的选择性。结果如表2所示：PT109在10μM的条件下对SGK1和JNK具有较好的选择性。
表2 PT109对其他激酶的筛选结果
Figure PCTCN2016109199-appb-000022
Figure PCTCN2016109199-appb-000023
实施例13：生物学评估
体外血脑屏障透过率
1)取4μL 2％(PBL)溶液加于MAIPn 4550的96孔板的疏水膜上，滴加过程中注意移液枪头勿接触膜表面以防破坏膜结构；
2)迅速(10min内)定量吸取200μL待测样品液(0.1mg/ml)加入到96孔板中的膜上方作为给药池，膜另一侧加入200μL PBS(pH＝7.4)为接受池，注意保持接受液与膜的充分接触；
3)室温静止120min后，小心移除给药池，用UV光谱仪测试接受池内化合物吸光度值(250‐500nm)；
4)吸取100μL待测样品液与100μL PBS充分混匀，作为理论平衡溶液，测试其吸光度值(250‐500nm)，需要用acceptor板测试；
5)根据公式计算logPe值：
Figure PCTCN2016109199-appb-000024
式中Vd是接受池的体积，Va是接受池的体积，A是膜面积，t是渗透时间，[drug]acceptor是接受池的吸光度，[drug]equilibrium是理论平衡吸光度。
注：Pe×10‐6cm s‐1值大于5.3，则化合物能够透过血脑屏障，小于2.4被定义为不能透过血脑屏障。由结果表3可知，PT109具有较好的血脑屏障透过率。
表3 PT109的血脑屏障透过率
Compound Pe(×10‐6cm s‐1) Prediction M.W cLogP
PT109 11.93±0.08 CNS+ 429.19 4.26

Claims (6)

  1. 一种具有下述结构式的化合物或其药用盐：
    Figure PCTCN2016109199-appb-100001
    式(I)
    其中，
    X选自：
    Figure PCTCN2016109199-appb-100002
    Y选自：
    Figure PCTCN2016109199-appb-100003
    Z选自：
    Figure PCTCN2016109199-appb-100004
  2. 一种药物组合物，包括如权利要求1所述的任一化合物或其药用盐，以及药学上可接受的载体或赋形剂。
  3. 权利要求1的任一化合物或其药用盐在制备治疗中枢神经系统退行性疾病或脑肿瘤的药物中的应用。
  4. 根据权利要求3所述的应用，所述中枢神经系统退行性疾病包括阿尔茨海默病或帕金森氏病。
  5. 根据权利要求3所述的应用，所述脑肿瘤包括胶质瘤。
  6. 一种具有抗氧化作用的SGK1和JNK双靶点抑制剂，其包含权利要求1所述的任一化合物或其药用盐。
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