CN117285591A - 选择性抑制ADP的2-Trp-AA-四氢咔啉-3-羧酸类化合物及其制备和应用 - Google Patents
选择性抑制ADP的2-Trp-AA-四氢咔啉-3-羧酸类化合物及其制备和应用 Download PDFInfo
- Publication number
- CN117285591A CN117285591A CN202310960788.XA CN202310960788A CN117285591A CN 117285591 A CN117285591 A CN 117285591A CN 202310960788 A CN202310960788 A CN 202310960788A CN 117285591 A CN117285591 A CN 117285591A
- Authority
- CN
- China
- Prior art keywords
- trp
- carboxylic acid
- carboline
- tetrahydro
- residue
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 17
- 230000002401 inhibitory effect Effects 0.000 title description 9
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 claims abstract description 26
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 206010003178 Arterial thrombosis Diseases 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical group OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims abstract description 10
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical group OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 10
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims abstract description 10
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract description 10
- 150000001413 amino acids Chemical class 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 12
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 24
- 229940114079 arachidonic acid Drugs 0.000 description 12
- 235000021342 arachidonic acid Nutrition 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 239000002504 physiological saline solution Substances 0.000 description 8
- 208000007536 Thrombosis Diseases 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 108010003541 Platelet Activating Factor Proteins 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 108090000190 Thrombin Proteins 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- 210000001367 artery Anatomy 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000004623 platelet-rich plasma Anatomy 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000411 inducer Substances 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical group CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- WXYGVKADAIJGHB-ZDUSSCGKSA-N (2s)-3-(1h-indol-2-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound C1=CC=C2NC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CC2=C1 WXYGVKADAIJGHB-ZDUSSCGKSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000002627 tracheal intubation Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- NZCPCJCJZHKFGZ-AAEUAGOBSA-N Trp-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 NZCPCJCJZHKFGZ-AAEUAGOBSA-N 0.000 description 1
- KBUBZAMBIVEFEI-ZFWWWQNUSA-N Trp-His Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CNC=N1 KBUBZAMBIVEFEI-ZFWWWQNUSA-N 0.000 description 1
- DXYQIGZZWYBXSD-JSGCOSHPSA-N Trp-Pro Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)N1CCC[C@H]1C(O)=O DXYQIGZZWYBXSD-JSGCOSHPSA-N 0.000 description 1
- TYYLDKGBCJGJGW-WMZOPIPTSA-N Trp-Tyr Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=C(O)C=C1 TYYLDKGBCJGJGW-WMZOPIPTSA-N 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 108010029384 tryptophyl-histidine Proteins 0.000 description 1
- 108010084932 tryptophyl-proline Proteins 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了具有选择性抑制腺苷二磷酸(ADP)2‑Trp‑AA‑3S‑四氢‑β‑咔啉‑3‑羧酸类化合物,所述的化合物的结构式如下，式中AA代表的氨基酸分别选自L‑Pro残基,L‑Tyr残基,L‑Gln残基以及L‑His残基，本发明进一步公开了所述化合物的制备方法以及其在治疗动脉血栓性疾病中的应用。实验证明,本发明的ADP选择性抑制剂有良好的抗动脉血栓作用。因而提出本发明为抗动脉血栓提供了有效的技术手段。
Description
技术领域
本发明涉及选择性抑制腺苷二磷酸(ADP)的2-Trp-AA-四氢咔啉-3-羧酸类化合物，涉及它们的制备方法以及在治疗动脉血栓性疾病中的应用。本发明属于生物医药领域。
背景技术
动脉栓塞已成为目前发病率高和死亡率高的疾病之一。动脉血栓形成对暂时性脑缺血发作,急性冠状动脉综合症,心肌梗塞和心房颤动负责。在房颤中有18％-47％病人患有冠状动脉疾病,在伴随冠状动脉疾病的房颤患者中有大约20％接受经皮冠状动脉介入治疗。动脉血栓形成还对人工心脏瓣膜,动静脉瘘和其他手术后的动脉血栓及不稳定型心绞痛负责。例如肝移植手术之后,患者面临肝脏动脉血栓风险。此外,抗磷脂综合症患者也面临动脉血栓风险。动脉血栓形成与血小板聚集关联。通常诱发血小板聚集的诱导剂,包括血小板活化因子(PAF),腺苷二磷酸(ADP),凝血酶(TH)及花生四烯酸(AA)。而发现腺苷二磷酸的选择性抑制剂是抗动脉血栓药物研究的重要方向。发明人在研究中筛选到以下结构的2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸(式中AA为L-Pro残基,L-Tyr残基,L-Gln残基及L-His)选择性抑制ADP诱发的血小板聚集。
在大鼠丝线法动脉血栓模型上4种2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸显示优秀的抗动脉血栓活性。根据这些发现,发明人提出了本发明。
发明内容
本发明要解决的技术问题是提供具有选择性抑制ADP的四类2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物，实验证明,由本发明制备的2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物选择性抑制腺苷二磷酸(ADP)，并具有优秀的抗动脉血栓作用。为了达到所述的技术效果,本发明采用了以下四个技术手段。
第一个技术手段是确认了本发明的2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物，其结构式如下：
式中AA代表的氨基酸分别选自：L-Pro残基,L-Tyr残基,L-Gln残基或L-His。
第二个技术手段是提出了制备所述的2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸的方法,该方法包括以下步骤:
1)制备3S-四氢-β-咔啉-3-羧酸；
2)制备Boc-Trp-AA,AA为L-Pro残基,L-Tyr残基,L-Gln残基及L-His；
3)制备2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸,其中AA为L-Pro残基,L-Tyr残基,L-Gln残基及L-His；
4)制备2-Trp-AA-3S-四氢-β-咔啉-3-羧酸,其中AA为L-Pro残基,L-Tyr残基,L-Gln残基及L-His。
第三个技术手段是确认所述的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物对腺苷二磷酸(ADP)的选择性抑制作用。
第四个技术手段是确认所述的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物对ADP诱发的血小板聚集的选择性抑制作用。
第五个技术手段是确认所述的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸对动脉血栓的优秀的抑制作用。
相较于现有技术，本发明的有益效果是：
本发明在咔啉的结构基础上对其进行修饰，制备得到了一类具有上述结构的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸，实验发现，该类化合物表现出了良好的抑制腺苷二磷酸(ADP)的活性以及抑制动脉血栓的作用。
本发明的提出为动脉血栓的治疗提供了新的治疗药物，丰富了人们对于治疗动脉血栓的药物选择。
附图说明
图1为2-Trp-AA-3S-四氢-β-咔啉-3-羧酸的合成路线图:i)CH2O,H2SO4；ii)DCC,HOBt,N-甲基吗啉,Boc-Trp-AA；iii)浓度为4N的氯化氢的乙酸乙酯溶液。
具体实施方式
为了进一步阐述本发明,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进行具体描述,不应当理解为对本发明的限制。
实施例1制备3S-四氢-β-咔啉-3-羧酸(1)
往400mL水中缓慢加入0.2mL浓硫酸。往得到的稀硫酸水溶液中加入5.0g(24.5mmol)L-Trp,超声振荡至L-Trp完全溶解。往得到的溶液中加入10mL浓度为35％的甲醛水溶液。反应混合物室温搅拌6小时,薄层层析(乙酸乙酯/乙醚,20/1)监测到L-Trp消失,终止反应。反应液中缓慢滴加浓氨水,调节至pH6,静置30分钟。滤出生成的沉淀并用水洗,滤出的无色固体平铺于培养皿,于空气中干燥,得到5.05g(95％)标题化合物,为无色固体。ESI-MS(m/e):217[M+H]+。
实施例2制备Boc-Trp AA
采用常规的DCC法,从Boc-Trp与Pro-O-CH3,Tyr-O-CH3,Gln-O-CH3及His-O-CH3制得Boc-Trp-Pro-O-CH3,Boc-Trp-Tyr-O-CH3,Boc-Trp-Gln-O-CH3及Boc-Trp-His-O-CH3。0℃将Boc-Trp-Pro-O-CH3,Boc-Trp-Tyr-O-CH3,Boc-Trp-Gln-O-CH3及Boc-Trp-His-O-CH3在2N的氢氧化钠水溶液中皂化,得到Boc-Trp-Pro,ESI-MS:402[M+H]+；Boc-Trp-Tyr,ESI-MS:468[M+H]+；Boc-Trp-Gln,ESI-MS:433[M+H]+及Boc-Trp-His,ESI-MS:442[M+H]+。它们的收率都达到91％,它们的纯度都超过98％,它们都是已知化合物,不做检测直接用于后面的合成反应。
实施例3制备3S-[2-(Boc-Trp-Pro)]-四氢-β-咔啉-3-羧酸(2a)
0℃下往3.03g(14mmol)3S-四氢-β-咔啉-3-羧酸与5.6g(14mmol)Boc-Trp-Pro及150mL无水四氢呋喃的溶液中加2.0g(14.8mmol)N-羟基苯并三唑(HOBt),3.1g(14.8mmol)二环己基羰二亚胺(DCC)。反应混合物0℃搅拌30分钟。然后用N-甲基吗啉(NMM)调pH8。反应混合物0℃搅拌6小时,薄层层析(乙酸乙酯/甲醇,20/1)监测到3S-四氢-β-咔啉-3-羧酸消失,终止反应。反应混合物过滤,滤液减压浓缩至干,残留物用200mL乙酸乙酯溶解。得到的溶液依次用5％碳酸氢钠水溶液洗(30mL×3),饱和氯化钠水溶液洗(30mL×3),5％盐酸水溶液洗(30mL×3),饱和氯化钠水溶液洗(30mL×3)。分离乙酸乙酯层,用无水硫酸钠干燥12小时,过滤,滤液减压浓缩至干,得到7.55g(90％)标题化合,为无色粉末。ESI-MS:600[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.891(s,1H),11.675(s,1H),10.791(s,1H),7.582(d,J＝7.6Hz,1H),7.352(d,J＝7.7Hz,1H),7.395(s,1H),7.332(d,J＝7.9Hz,1H),7.213(d,J＝7.9Hz,1H),7.211(s,1H),7.064(t,J＝7.2Hz,1H),6.981(t,J＝7.2Hz,1H),6.933(t,J＝7.2Hz,1H),6.912(t,J＝7.2Hz,1H),4.925(t,J＝5.6Hz,1H),4.856(t,J1＝6.1Hz,1H),4.553(s,2H),4.402(d,J＝5.6Hz,1H),3.522(t,J＝5.7Hz,2H),3.312(d,J＝5.6Hz,2H),2.332(m,J＝5.6Hz,2H),2.023(m,J＝5.6Hz,2H),3.042(d,J＝6.1Hz,2H),1.424(s,9H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝171.91,170.72,169.35,160.22,136.53,136.22,130.43,127.45,127.31,123.11,121.78,121.72,119.86,119.83,118.85,118.75,111.16,111.13,109.87,104.77,79.65,67.83,66.03,57.33,49.53,38.15,29.63,28.45,28.44,28.43,28.12,24.13,22.65。
实施例4制备3S-[2-(Trp-Pro)]-四氢-β-咔啉-3-羧酸(3a)
将5.6g(9.3mmol)3S-[2-(Boc-Trp-Pro)]-四氢-β-咔啉-3-羧酸溶于50mL氯化氢的乙酸乙酯溶液(4N),反应混合物室温搅拌60分钟。薄层层析(乙酸乙酯/甲醇,20/1)监测到3S-[2-(Boc-Trp-Pro)]-四氢-β-咔啉-3-羧酸消失,终止反应。反应混合物减压浓缩,残留物溶于50mL乙酸乙酯,再减压浓缩。该操作重复5次,得到4.55g(98％)标题化合物,为无色粉末。FT-ICR-MS:500.2298[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.892(s,1H),11.673(s,1H),10.793(s,1H),8.861(s,2H),7.583(d,J＝7.6Hz,1H),7.351(d,J＝7.7Hz,1H),7.333(d,J＝7.9Hz,1H),7.212(d,J＝7.9Hz,1H),7.201(s,1H),7.065(t,J＝7.2Hz,1H),6.982(t,J＝7.2Hz,1H),6.932(t,J＝7.2Hz,1H),6.911(t,J＝7.2Hz,1H),4.855(t,J1＝6.1Hz,1H),4.551(s,2H),4.402(t,J＝6.9Hz,1H),3.952(t,J＝5.6Hz,1H),3.512(t,J＝6.9Hz,2H),3.312(d,J＝5.6Hz,2H),2.331(m,J＝6.9Hz,2H),2.022(m,J＝6.9Hz,2H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝173.31,171.72,169.36,136.52,136.23,130.44,127.43,127.32,123.01,121.77,121.73,119.85,119.84,118.86,118.76,111.15,111.14,107.17,104.89,67.85,66.05,52.63,49.52,38.13,29.83,27.72,24.15,22.64。
实施例5制备3S-[2-(Boc-Trp-Tyr)]-四氢-β-咔啉-3-羧酸(2b)
采用实施例3的操作从3.03g(14mmol)3S-四氢-β-咔啉-3-羧酸与6.05g(14mmol)Boc-Trp-Tyr得到8.4g(90％)标题化合物,为无色粉末。ESI-MS:666[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.891(s,1H),11.671(s,1H),10.786(s,1H),9.086(s,1H),8.321(s,1H),7.582(d,J＝7.6Hz,1H),7.392(s,1H),7.355(d,J＝7.9Hz,1H),7.333(d,J＝7.9Hz,1H),7.211(s,1H),7.213(d,J＝7.9Hz,1H),7.061(t,J＝7.2Hz,1H),6.981(t,J＝7.2Hz,1H),6.962(t,J＝7.2Hz,2H),6.933(t,J＝7.2Hz,1H),6.912(t,J＝7.2Hz,1H),6.681(t,J＝7.2Hz,2H),4.924(t,J＝5.6Hz,1H),4.922(t,J＝5.6Hz,1H),4.851(t,J1＝6.1Hz,1H),4.454(s,2H),3.452(d,J1＝5.6Hz,2H),3.314(d,J1＝5.6Hz,2H),3.045(d,J1＝6.1Hz,2H),1.421(s,9H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝171.95,171.72,170.06,155.95,155.75,136.52,136.23,130.40,130.21,130.20,129.22,127.44,127.32,123.15,121.77,121.71,119.84,119.82,118.81,118.80,115.82,115.81,111.15,111.13,109.72,104.95,79.55,67.88,59.53,55.13,38.03,37.75,28.41,28.40,28.39,27.85,22.63。
实施例6制备3S-[2-(Trp-Tyr)]-四氢-β-咔啉-3-羧酸(3b)
采用实施例4的操作从5.4g(8.1mmol)3S-[2-(Boc-Trp-Tyr)]-四氢-β-咔啉-3-羧酸得到4.26g(93％)标题化合,为无色粉末。FT-ICR-MS:566.2403；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.892(s,1H),11.672(s,1H),10.782(s,1H),9.083(s,1H),8.861(s,2H),8.322(s,1H),7.581(d,J＝7.6Hz,1H),7.353(d,J＝7.9Hz,1H),7.332(d,J＝7.9Hz,1H),7.212(s,1H),7.212(d,J＝7.9Hz,1H),7.063(t,J＝7.2Hz,1H),6.982(t,J＝7.2Hz,1H),6.962(d,J＝7.2Hz,1H),6.961(t,J＝7.2Hz,1H),6.931(t,J＝7.2Hz,1H),6.912(t,J＝7.2Hz,1H),6.682(t,J＝7.2Hz,1H),6.681(t,J＝7.2Hz,1H),4.921(t,J＝5.6Hz,1H),4.852(t,J1＝6.1Hz,1H),4.456(s,2H),3.952(t,J1＝5.6Hz,1H),3.443(d,J1＝5.6Hz,2H),3.313(d,J1＝5.6Hz,2H),3.043(d,J1＝6.1Hz,2H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝171.93,171.73,170.05,155.74,136.51,136.22,130.41,130.22,130.21,129.23,127.43,127.31,123.13,121.75,121.72,119.85,119.83,118.83,118.81,115.83,115.82,111.14,111.13,107.12,104.93,67.85,56.73,55.13,38.04,37.74,27.45,22.62。
实施例7制备3S-[2-(Boc-Trp-Gln)]-四氢-β-咔啉-3-羧酸(2c)
采用实施例3的操作从3.03g(14mmol)3S-四氢-β-咔啉-3-羧酸与5.84g(14mmol)Boc-Trp-Gln得到7.94g(90％)标题化合物,为无色粉末。ESI-MS:631[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.892(s,1H),11.673(s,1H),10.789(s,1H),8.321(s,1H),7.582(d,J＝7.6Hz,1H),7.391(s,1H),7.351(d,J＝7.9Hz,1H),7.333(d,J＝7.9Hz,1H),7.203(s,1H),7.213(d,J＝7.9Hz,1H),7.062(t,J＝7.2Hz,1H),7.033(s,2H),6.981(t,J＝7.2Hz,1H),6.931(t,J＝7.2Hz,1H),6.912(t,J＝7.2Hz,1H),4.853(t,J＝5.6Hz,1H),4.922(t,J＝5.6Hz,1H),4.440(t,J1＝6.1Hz,1H),4.555(s,2H),3.314(d,J1＝5.6Hz,2H),3.045(d,J1＝6.1Hz,2H),2.071(m,J1＝6.1Hz,2H),2.051(t,J1＝6.1Hz,2H),1.421(s,9H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝173.56,171.90,171.66,169.32,155.97,136.52,136.21,130.41,127.41,127.31,123.13,121.71,121.69,119.84,119.82,118.81,118.80,111.14,111.13,109.72,104.93,79.55,67.87,59.55,54.62,38.03,32.61,28.41,28.40,28.39,27.87,27.85,22.63。
实施例8制备3S-[2-(Trp-Gln)]-四氢-β-咔啉-3-羧酸(3c)
采用实施例4的操作从5.6g(8.89mmol)3S-[2-(Boc-Trp-Gln)]-四氢-β-咔啉-3-羧酸得到4.2g(90％)标题化合物,为无色粉末。FT-ICR-MS:531.2356[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.891(s,1H),11.671(s,1H),10.787(s,1H),8.861(s,2H),8.321(s,1H),7.581(d,J＝7.6Hz,1H),7.352(d,J＝7.9Hz,1H),7.332(d,J＝7.9Hz,1H),7.201(s,1H),7.212(d,J＝7.9Hz,1H),7.061(t,J＝7.2Hz,1H),7.031(s,2H),6.982(t,J＝7.2Hz,1H),6.932(t,J＝7.2Hz,1H),6.911(t,J＝7.2Hz,1H),4.852(t,J＝5.6Hz,1H),4.441(t,J1＝6.1Hz,1H),4.553(s,2H),3.951(t,J1＝5.6Hz,1H),3.315(d,J1＝5.6Hz,2H),3.042(d,J＝5.6Hz,2H),2.072(m,J1＝6.1Hz,2H),2.052(t,J1＝6.1Hz,2H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝173.57,171.91,171.69,169.33,136.53,136.22,130.43,127.42,127.32,123.12,121.73,121.72,119.83,119.81,118.82,118.81,111.13,111.12,107.13,104.93,67.85,56.72,54.62,38.05,32.63,27.86,27.45,22.64。
实施例9制备3S-[2-(Boc-Trp-His)]-四氢-β-咔啉-3-羧酸(2d)
采用实施例3的操作从3.03g(14mmol)3S-四氢-β-咔啉-3-羧酸与5.25g(14mmol)Boc-Trp-His得到8.1g(90％)标题化合物,为无色粉末。ESI-MS:640[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝13.091(s,1H),12.891(s,1H),11.671(s,1H),10.788(s,1H),8.732(s,1H),8.322(s,1H),7.662(s,1H),7.582(d,J＝7.6Hz,1H),7.391(s,1H),7.351(d,J＝7.9Hz,1H),7.332(d,J＝7.9Hz,1H),7.203(s,1H),7.213(d,J＝7.9Hz,1H),7.061(t,J＝7.2Hz,1H),6.981(t,J＝7.2Hz,1H),6.931(t,J＝7.2Hz,1H),6.912(t,J＝7.2Hz,1H),4.924(t,J＝5.6Hz,1H),4.922(t,J＝5.6Hz,1H),4.852(t,J1＝6.1Hz,1H),4.454(s,2H),3.314(d,J1＝5.6Hz,2H),3.181(t,J＝5.6Hz,2H),3.043(d,J1＝6.1Hz,2H),1.421(s,9H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝171.95,171.73,170.16,155.95,136.52,136.23,136.21,131.42,130.43,127.41,127.31,123.11,121.71,121.69,119.84,119.82,118.81,118.80,117.91,111.14,111.13,109.72,104.93,79.55,67.88,59.53,54.82,38.05,30.84,28.41,28.40,28.39,27.85,22.64。
实施例10制备3S-[2-(Trp-His)]-四氢-β-咔啉-3-羧酸(3d)
采用实施例4的操作由5.6g(8.8mmol)3S-[2-(Boc-Trp-His)]-四氢-β-咔啉-3-羧酸得4.32g(91％)标题化合物,为无色固体。FT-ICR-MS:540.2359[M+H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝13.071(s,1H),12.890(s,1H),11.670(s,1H),10.791(s,1H),8.731(s,1H),8.862(s,2H),8.322(s,1H),7.661(s,1H),7.581(d,J＝7.6Hz,1H),7.350(d,J＝7.9Hz,1H),7.331(d,J＝7.9Hz,1H),7.211(d,J＝7.9Hz,1H),7.201(s,1H),7.060(t,J＝7.2Hz,1H),6.980(t,J＝7.2Hz,1H),6.930(t,J＝7.2Hz,1H),6.911(t,J＝7.2Hz,1H),4.921(t,J＝5.6Hz,1H),4.851(t,J1＝6.1Hz,1H),4.452(s,2H),3.951(t,J＝5.6Hz,1H),3.313(d,J1＝5.6Hz,2H),3.173(d,J1＝5.6Hz,2H),3.051(t,J1＝6.1Hz,2H)；13CNMR(75MHz,DMSO-d6):δ/ppm＝171.93,171.71,170.15,136.51,136.25,136.23,131.32,130.41,127.42,127.32,123.10,121.72,121.70,119.85,119.83,118.82,118.81,117.93,111.15,111.12,107.13,104.93,67.87,56.72,54.82,38.03,30.83,27.45,22.65。
实施例11评价抗血小板聚集活性
将新鲜的猪颈动脉血用3.8％枸橼酸钠(按体积比1/9)抗凝。1000g离心10分钟得富血小板血浆(PRP),3000g离心10分钟得贫血小板血浆(PPP)。用贫血小板血浆调节富血小板血浆,使富血小板血浆中的血小板数适合测定抗血小板聚集活性。3a-d用生理盐水溶解。往比浊管中加0.24mL调节过的富血小板血浆,再加5μL生理盐水溶液或3a-d的生理盐水溶液(5μL,浓度为0.1μM,10μM,15μM,20μM)。调好吸光度的基线,加入5μL四种诱导因子的生理盐水溶液观察血小板在5分钟内的最大聚集率(Am)。四种诱导剂是血小板活化因子(PAF,终浓度为50μM),腺苷二磷酸(ADP,终浓度为500μM),凝血酶(TH,终浓度为50IU/L)及花生四烯酸(AA,终浓度为7.5mg/mL)。最大聚集率是对应于聚集曲线波峰的值。每个浓度平行测定6次,形成血小板聚集曲线。根据血小板聚集曲线确定,3a-d抑制血小板活化因子,腺苷二磷酸,凝血酶及花生四烯酸诱发的血小板聚集的IC50(见表1)。表1的数据表明,3a-d抑制ADP诱发的血小板聚集的IC50值最小,3a-d是ADP的选择性抑制剂。
表1 3a-c抑制4种诱导剂诱发的血小板聚集的IC50(均值±SD,μM)
| 化合物 | ADP | TH | PAF | AA |
| 3a | 1.24±0.05 | 21.55±0.27 | 22.55±0.28 | 22.58±0.26 |
| 3b | 1.26±0.06 | 22.43±0.29 | 23.31±0.29 | 23.31±0.27 |
| 3c | 1.17±0.04 | 22.26±0.28 | 21.46±0.27 | 21.38±0.24 |
| 3d | 1.32±0.06 | 23.11±0.30 | 21.91±0.26 | 21.47±0.25 |
n＝6
实施例12评价抗动脉血栓活性
1)将聚乙烯管拉成一端为斜口的细管,定长为10.0cm,分别为右颈静脉(管径较粗)及左颈动脉(管径较细)插管；中段聚乙烯管定长为8.0cm,血栓线压在颈动脉插管方向,插管前需在管中充满肝素。
2)将体重为200±20g的雄性SD大鼠在手术前适应环境并禁食一天。随机分为生理盐水组(空白对照,口服剂量为0.3mL/100g,10只大鼠),阿司匹林组(阳性对照,口服剂量为167μmol/kg,10只大鼠),3a-d的生理盐水溶液组(口服剂量为0.1μmol/kg,10只大鼠)。口服30分钟后,大鼠腹腔注射20％乌拉坦溶液麻醉(7mL/kg),2分钟之后开始手术。手术中将大鼠仰卧位于固定板上,剪开颈部皮肤,分离右颈总动脉及左颈静脉,血管下压一根精确称重的丝线,结扎远心端,在静脉的远心端处剪一小口,将插管插入静脉端,注射肝素,而后取下注射肝素的注射器,系线固定,再用动脉夹夹住动脉近心端,在动脉的远心端剪一小口,将动脉端结扎,系线固定后松开动脉夹,建立体外循环旁路。循环15分钟后先剪断静脉观察血液循环是否正常,若血液循正常从动脉端取出附有血栓的丝线,用滤纸吸干未凝固血液,精确称附有血栓的丝线重,将附有血栓的丝线的重量减丝线的重量得到血栓的重量,数据列入表2。表中的血栓重量表明,在0.1μmol/kg口服剂量下3a-d有效抑制大鼠患动脉血栓症(与生理盐水及口服剂量为16.7μmol/kg的阿司匹林比p<0.01)。这是意想不到的技术效果。
表2 3a-d对大鼠动脉血栓的影响
a)与生理盐水及口服剂量为16.7μmol/kg的阿司匹林比p<0.01；b)与生理盐水比p>0.05；n＝10。
Claims (5)
1.具有下式结构的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物，其特征在于，所述化合物中AA代表的氨基酸选自L-Pro残基,L-Tyr残基,L-Gln残基以及L-His,
2.制备权利要求1所述的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物的方法,其特征在于，所述的制备方法包括以下步骤:
1)制备3S-四氢-β-咔啉-3-羧酸；
2)制备Boc-Trp-AA,AA为L-Pro残基,L-Tyr残基,L-Gln残基及L-His；
3)制备2-Boc-Trp-AA-3S-四氢-β-咔啉-3-羧酸,其中AA为L-Pro残基,L-Tyr残基,L-Gln残基及L-His；
4)制备2-Trp-AA-3S-四氢-β-咔啉-3-羧酸,其中AA为L-Pro残基,L-Tyr残基,L-Gln残基及L-His。
3.权利要求1所述的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物在制备腺苷二磷酸抑制剂中的应用。
4.权利要求3所述的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物对在制备腺苷二磷酸诱发的血小板聚集的药物中的应用。
5.权利要求1所述的2-Trp-AA-3S-四氢-β-咔啉-3-羧酸类化合物在制备抗动脉血栓药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310960788.XA CN117285591A (zh) | 2023-08-01 | 2023-08-01 | 选择性抑制ADP的2-Trp-AA-四氢咔啉-3-羧酸类化合物及其制备和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310960788.XA CN117285591A (zh) | 2023-08-01 | 2023-08-01 | 选择性抑制ADP的2-Trp-AA-四氢咔啉-3-羧酸类化合物及其制备和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117285591A true CN117285591A (zh) | 2023-12-26 |
Family
ID=89252484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310960788.XA Pending CN117285591A (zh) | 2023-08-01 | 2023-08-01 | 选择性抑制ADP的2-Trp-AA-四氢咔啉-3-羧酸类化合物及其制备和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117285591A (zh) |
-
2023
- 2023-08-01 CN CN202310960788.XA patent/CN117285591A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3009573B2 (ja) | アミノアルギニンの分離および身体内の酸化窒素生成を遮断するための用途 | |
| US20090131677A1 (en) | Substituted beta-phenyl-alpha-hydroxy-propanoic acid, synthesis method and use thereof | |
| US9890193B2 (en) | Compounds having triple activities of thrombolysis, antithrombosis, and radical scavenging, synthesis, and use thereof | |
| EP0490818A1 (en) | 6-cyclohexyl-2'-0-methyl-adenosine hydrate and uses thereof | |
| CN114716346B (zh) | 一种4-硝基苯胺衍生物及其应用 | |
| EP0811616B1 (de) | Salze des 3-(2-(4-(4-(Amino-imino-methyl)-phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)-acetylamino)-3-phenyl-propionsäure-ethylesters | |
| CN117285591A (zh) | 选择性抑制ADP的2-Trp-AA-四氢咔啉-3-羧酸类化合物及其制备和应用 | |
| CN116874557A (zh) | 2-Trp-AA-四氢咔啉-3-羧酸类化合物及其PAF抑制剂的应用 | |
| CN116970032A (zh) | 2-Trp-AA-四氢咔啉-3-羧酸类AA抑制剂及抗血栓应用 | |
| CN116970031A (zh) | 2-Trp-AA-四氢咔啉-3-羧酸类TH抑制剂、其及抗血栓的应用 | |
| FI79526C (fi) | Foerfarande foer framstaellning av de optiska antipoderna av ( )-1,7-difenyl-3-metylaza-7-cyan-8-metyl- nonan, vilka aer terapeutiskt anvaendbara. | |
| CN108948146B (zh) | 1R-甲基-β-四氢咔啉酰-K(ARPAK)-RGDV,其合成,活性和应用 | |
| CN116947857A (zh) | 选择性抑制凝血酶(th)的氨基酸修饰的四环化合物、及其制备和应用 | |
| EP2899186B1 (en) | New hydroxysafflor yellow pharmaceutical salts | |
| CN116947858A (zh) | 选择性抑制adp的四种氨基酸修饰的化合物、及其制备和应用 | |
| CN116947859A (zh) | 选择性抑制花生四烯酸的氨基酸修饰的四环化合物、及其制备和应用 | |
| CN116903622A (zh) | 选择性抑制paf的氨基酸修饰的四环化合物及其制备和应用 | |
| JPS63104960A (ja) | α−［（フェニルメトキシ）メチル］ピリジンアルカノール誘導体 | |
| JPH0368845B2 (zh) | ||
| WO2004002403A2 (en) | Sterols bearing pendant allosteric effectors of hemoglobin, and uses thereof | |
| US9624254B2 (en) | Hydroxysafflor yellow pharmaceutical salts | |
| JPH0699311B2 (ja) | 抗血管レン縮剤および血管弛緩剤 | |
| CN1249295A (zh) | 具有心血管药理活性的合成化合物及制备方法 | |
| CN111848724B (zh) | 茶氨酰四氢咪唑并吡啶-6-甲酰酸性氨基酸的制备,活性和应用 | |
| CN106589060B (zh) | N-(pak)-2,3-二羟基异喹啉-7-甲酰-rgdv/f,其合成,活性及应用 |
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 |