CN114524828A - 一种用于治疗神经重症的噻唑衍生物及其应用 - Google Patents
一种用于治疗神经重症的噻唑衍生物及其应用 Download PDFInfo
- Publication number
- CN114524828A CN114524828A CN202210166096.3A CN202210166096A CN114524828A CN 114524828 A CN114524828 A CN 114524828A CN 202210166096 A CN202210166096 A CN 202210166096A CN 114524828 A CN114524828 A CN 114524828A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- disease
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 7
- 150000007979 thiazole derivatives Chemical class 0.000 title abstract description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 230000000926 neurological effect Effects 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 9
- 102100032404 Cholinesterase Human genes 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 102100033639 Acetylcholinesterase Human genes 0.000 description 6
- 108010022752 Acetylcholinesterase Proteins 0.000 description 6
- 229940022698 acetylcholinesterase Drugs 0.000 description 6
- 102000003914 Cholinesterases Human genes 0.000 description 5
- 108090000322 Cholinesterases Proteins 0.000 description 5
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 5
- 229960004373 acetylcholine Drugs 0.000 description 5
- 229940048961 cholinesterase Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000005935 Sulfuryl fluoride Substances 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 2
- 150000008053 sultones Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WRIUFOROJHIQRC-UHFFFAOYSA-M 2-(2-iodoacetyl)oxyethyl-trimethylazanium;iodide Chemical compound [I-].C[N+](C)(C)CCOC(=O)CI WRIUFOROJHIQRC-UHFFFAOYSA-M 0.000 description 1
- GANZODCWZFAEGN-UHFFFAOYSA-N 5-mercapto-2-nitro-benzoic acid Chemical compound OC(=O)C1=CC(S)=CC=C1[N+]([O-])=O GANZODCWZFAEGN-UHFFFAOYSA-N 0.000 description 1
- KZPWRQDQRGSYBZ-UHFFFAOYSA-M C[N+](C)(C)CCSCCCCI.[I-] Chemical compound C[N+](C)(C)CCSCCCCI.[I-] KZPWRQDQRGSYBZ-UHFFFAOYSA-M 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241001262617 Japonica Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- 229910018503 SF6 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- -1 arylsulfonyl fluoride Chemical compound 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical group FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种具有治疗神经重症作用的噻唑衍生物，其对阿尔茨海默症等疾病具有很好的治疗与康复作用，与现有药物相比，显示出实质性的科学进步和突出的有益效果。
Description
技术领域
本发明涉及药物化学领域，具体涉及一种具有治疗神经重症作用的噻唑衍生物，本发明还涉及所述衍生物的制备方法、药物组合物及用途。
背景技术
阿尔茨海默氏病(Alzheimer's disease，AD)是一种发生在老年期或老年前期的神经重症，属于渐进性神经系统退化疾病，具有记忆力和其他认知障碍的逐步恶化，影响全球约4700万人。
改善疾病症状的最有效策略是使用胆碱酯酶(ChE)(称为乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)抑制剂)恢复乙酰胆碱(ACh)的水平。迄今为止，仅有的五种AD药物被FDA批准，其中四种是ChE抑制剂，其中卡巴拉汀，加兰他敏和多奈哌齐已在临床上使用。ChE是发现新的抗AD剂的最有价值和最主要的靶标之一。
哺乳动物体内除了AChE还存在着丁酰胆碱酯酶(BuChE)，研究发现，丁酰胆碱酯酶也参与乙酰胆碱的代谢过程，在调节ACh的水平也起到了重要的作用，因此，近年来也有学者认为BuChE是一个潜在的治疗靶点。
自1888年Erdmann引入“磺内酯”一词来描述羟基磺酸的内酯以来，磺内酯部分已逐渐被用作药物化学中的结构支架，并表现出色的生物学和药理活性，例如抗HIV-I和HIV-II，抗人巨细胞病毒，抗丁酰胆碱酯酶，抗碳酸酐酶。杂环结构也可以广泛用作合成复杂天然药物的磺烷基化剂。
本发明使用芳基磺酰氟和吡唑啉酮通过硫(VI)氟化物交换化学方法制备了一类新型的具有胆碱酯酶抑制活性的磺内酯-融合的吡唑骨架，这在现有技术中并无报道。
发明内容
本发明所要解决的技术问题是：
本发明的第一个方面，是提供一种式1所示化合物或其药学上可接受的盐，其具有如下结构：
优选地，所述药学上可接受的盐选自：盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐；
本发明的另一方面提供一种制备式1所示化合物的方法，其合成路线如下：
化合物2与化合物3在DBU作用下反应制得化合物1。
具体反应步骤如下：
向干燥的反应管(20mL)的溶液中加入硫磺酰氟化合物3(0.5mmol)和吡唑啉酮类化合物2(0.5mmol，1.0当量)，DBU(36mg溶于10mL CH2Cl2，2mL，5-30mol％)和无机碱(0.5mmol，1.0当量)。在通过TLC监测的情况下，将所得混合物在室温下搅拌8-12小时。产物通过硅胶柱色谱进行纯化(石油醚/二氯甲烷＝8:1)。
优选地，所述无机碱分别独立地选自碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾中的至少一种。
本发明的另一方面提供一种药物组合物，其包含式1所示的化合物或其药学上可接受的盐，以及药学上可接受的载体、赋形剂。
本发明另一方面涉及一种式1所示化合物或其药学上可接受的盐或包含其药物组合物在制备治疗或预防神经重症的药物中的应用；优选地，所述神经重症为阿尔茨海默症。
与现有技术相比，本发明的有益效果是：
(1)本发明提供了一类新的具有治疗神经重症作用的噻唑衍生物，拓宽了现有技术的范围，可作为先导化合物继续优化；
(2)本发明式1所示的化合物在药理试验中，显示出良好的治疗活性，能够用于预防和治疗阿尔茨海默症。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。本发明化合物可以用合成领域技术人员熟知的许多方法来制备。式1化合物可以使用下面列出的反应和技术连同合成有机化学领域已知的方法或本领域技术人员所理解的其变体来制备。优选的方法包括但不限于下面描述的那些方法。反应在适用于所用试剂和材料且适用于要实现的转化的溶剂中进行。此外，在下面描述的合成方法中，应理解所有建议的反应条件(包括溶剂、反应气氛、反应温度、实验持续时间和后处理程序的选择)都选择为该反应的标准条件，这应该被有机合成领域技术人员容易确认。并非所有落入给定类别的化合物可以与某些所述方法中需要的某些反应条件相容。对与反应条件相容的取代基的这些限制将对于本领域技术人员而言是显而易见的，并且可使用替代方法。
实施例1：化合物1的合成
向干燥的反应管(20mL)的溶液中加入硫磺酰氟化合物3(0.5mmol)和吡唑啉酮类化合物2(0.5mmol，1.0当量)，DBU(36mg溶于10mL CH2Cl2形成溶液，取3mL)和NaHCO3(42mg，0.5mmol，1.0当量)。在通过TLC监测的情况下，将所得混合物在室温下搅拌15小时。产物通过硅胶柱色谱进行纯化(石油醚/二氯甲烷＝7:1)。反应收率为66％，HPLC纯度为99.9％。
分子式：C9H7N3O4S2；ESI-MS：286.01[M+H]+
1H NMR(400MHz，CDCl3)：δ2.95(m，2H)，3.31(m，2H)，8.06(d，2H)，9.04(s，1H)。
实施例2：式1所示化合物的乙酰胆碱酯酶/丁酰胆碱酯酶活性测定实验
根据Ellman的方法，对鳗鱼的AChE(C3389-500UN；Sigma)和马血清的BuChE(C4290-1KU；Sigma)进行了测定。两种酶以及底物和DTNB显色剂均直接从Sigma公司购入并直接使用。实验在48孔板中进行，每个孔加入100μL 0.036U/mL的EeAChE或eqBuChE，以及100μL 0.1M(pH＝8)的磷酸盐缓冲液，加入不同浓度化合物100μL在37℃下孵育20分钟后，加入100μL 0.35mM碘代乙酰胆碱碘化物(ACh；A5751-1G；Sigma)或0.5mM碘代丁硫胆碱碘化物(BuCh；20820-1G；Sigma)和100μL 0.35mM的5,5'-二硫双-2-硝基苯甲酸(DTNB；D8130-1G；Sigma)，最终体积为500μL。胆碱酯酶与底物结合后与DTNB作用会产生黄色阴离子5-硫代-2-硝基苯甲酸，显色剂继续孵育20分钟后用酶标仪在410nm处测量吸光度变化，由抑制曲线(对数抑制剂浓度对抑制百分比)以图形方式确定IC50值。
结果显示，化合物1对AChE并无抑制活性，对BuChE的IC50值为0.24±0.03μM。可见，本发明的化合物1可能成为潜在的阿尔茨海默病治疗药物。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (6)
1.一种式1所示化合物或其药学上可接受的盐，其具有如下结构：
2.根据权利要求1所述的式1化合物或其药学上可接受的盐，所述药学上可接受的盐选自：盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐。
3.一种制备如权利要求1所述的式1所示化合物的方法，其反应路线如下：
化合物2与化合物3在DBU作用下反应制得化合物1。
4.一种药物组合物，其包含权利要求1-2任一项所述式1所示化合物或其药学上可接受的盐，以及药学上可接受的载体。
5.权利要求1-2任一项所述的式1所示的化合物或其药学上可接受的盐或权利要求4所述药物组合物在制备治疗或预防神经重症的药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述神经重症为阿尔茨海默症。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210166096.3A CN114524828B (zh) | 2022-02-22 | 2022-02-22 | 一种用于治疗神经重症的噻唑衍生物及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210166096.3A CN114524828B (zh) | 2022-02-22 | 2022-02-22 | 一种用于治疗神经重症的噻唑衍生物及其应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114524828A true CN114524828A (zh) | 2022-05-24 |
| CN114524828B CN114524828B (zh) | 2024-07-09 |
Family
ID=81623965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210166096.3A Active CN114524828B (zh) | 2022-02-22 | 2022-02-22 | 一种用于治疗神经重症的噻唑衍生物及其应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114524828B (zh) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN88103735A (zh) * | 1987-06-17 | 1988-12-28 | 三井东压化学株式会社 | 新的吡唑啉衍生物及以该化合物为活性成份治疗脑血管疾病的药物 |
| US20070142362A1 (en) * | 2005-12-20 | 2007-06-21 | Solvay Pharmaceuticals B.V. | 4,5-Dihydro-(1H)-pyrazole derivatives as cannabinoid CB1 receptor modulators |
| CN102695710A (zh) * | 2009-11-13 | 2012-09-26 | 默克雪兰诺有限公司 | 三环吡唑胺衍生物 |
| US20200129488A1 (en) * | 2017-06-01 | 2020-04-30 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and memantine |
| WO2021089781A1 (en) * | 2019-11-07 | 2021-05-14 | Inflazome Limited | Treatment or prevention of psychiatric brain disorders using the nlrp3 inhibitor n-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1 -isopropyl-1 h-pyrazole-3-sulfonamide |
-
2022
- 2022-02-22 CN CN202210166096.3A patent/CN114524828B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN88103735A (zh) * | 1987-06-17 | 1988-12-28 | 三井东压化学株式会社 | 新的吡唑啉衍生物及以该化合物为活性成份治疗脑血管疾病的药物 |
| US20070142362A1 (en) * | 2005-12-20 | 2007-06-21 | Solvay Pharmaceuticals B.V. | 4,5-Dihydro-(1H)-pyrazole derivatives as cannabinoid CB1 receptor modulators |
| CN102695710A (zh) * | 2009-11-13 | 2012-09-26 | 默克雪兰诺有限公司 | 三环吡唑胺衍生物 |
| US20200129488A1 (en) * | 2017-06-01 | 2020-04-30 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and memantine |
| WO2021089781A1 (en) * | 2019-11-07 | 2021-05-14 | Inflazome Limited | Treatment or prevention of psychiatric brain disorders using the nlrp3 inhibitor n-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1 -isopropyl-1 h-pyrazole-3-sulfonamide |
Non-Patent Citations (1)
| Title |
|---|
| 程勇等: "阿尔茨海默病的药物治疗", 《中国临床药理学杂志》, vol. 15, no. 4, pages 295 - 298 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114524828B (zh) | 2024-07-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101626688A (zh) | 茚满酮基胆碱酯酶抑制剂的组合物、合成和使用方法 | |
| EP0506532A1 (fr) | Nouveaux dérivés de l'indole, procédé de préparation et médicaments les contenant | |
| EP0839149B9 (fr) | Derives de la galanthamine, leur procede de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant | |
| RU2042663C1 (ru) | Производные бензола и их соли | |
| EP0732334A1 (fr) | Dérivés de pipéridine, leur procédé de préparation et leur application en thérapeutique | |
| BG61729B1 (bg) | 9-заместени-2-(2-норм-алкоксифенил)пурин-6-они | |
| EP1657244A1 (en) | 2-thiaquinolizidines as glycosidase and glycosyltransferase inhibitors | |
| JPS63310882A (ja) | ポリ酸素化されたラブダン誘導体及びその製造法 | |
| CN114524828B (zh) | 一种用于治疗神经重症的噻唑衍生物及其应用 | |
| CN114524827A (zh) | 一种用于治疗神经重症的吡唑衍生物及其应用 | |
| CN102438996B (zh) | 点击化学合成的具有分支结构的组蛋白去乙酰酶抑制剂 | |
| JP4162991B2 (ja) | Ｎｍｄａ受容体リガンドに対するプロドラッグ | |
| FI67700C (fi) | Foerfarande foer framstaellning av nya terapeutiskt anvaendbara fenyl-kinolizidiner | |
| JPH07508045A (ja) | オルニチン・デカルボキシラーゼ阻害性環式アミノオキシ化合物 | |
| EP0228314A2 (en) | Use of ethanol/amine derivatives in treating or preventing hyperlipemia | |
| JP4336299B2 (ja) | ５−リポキシゲナーゼ阻害活性を有する６−アルキルアミノ−２，２’−二重置換−７，８−二重置換−２ｈ−１−ベンゾピラン誘導体 | |
| EP2460803B1 (en) | Method for producing thiabenzoazulene propionic acid derivative | |
| AU2001285894A1 (en) | Prodrugs to NMDA receptor ligands | |
| US6392032B1 (en) | Heavily fluorinated sugar analogs | |
| US10633339B2 (en) | Tricyclic sulfone compound as a ROR gamma modulator | |
| CN111039963B (zh) | Wxfl10203614水溶性类似物及其合成方法 | |
| NO153494B (no) | Analogifremgangsaate for fremstilling av terapeutisk aktive cystinderivater. | |
| US20220235061A1 (en) | Triazolopyrimidine compound and salt, composition and use thereof | |
| CN115536511A (zh) | 1,4-二醛酮化合物、其合成方法及应用 | |
| SI7710060A8 (en) | Process for obtaining new benzamides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |