CN104529930A - 一类含腈基苯的恶二唑亚砜化合物、其制备方法和用途 - Google Patents
一类含腈基苯的恶二唑亚砜化合物、其制备方法和用途 Download PDFInfo
- Publication number
- CN104529930A CN104529930A CN201510016230.1A CN201510016230A CN104529930A CN 104529930 A CN104529930 A CN 104529930A CN 201510016230 A CN201510016230 A CN 201510016230A CN 104529930 A CN104529930 A CN 104529930A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- application
- oxadiazole
- category
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 title abstract description 16
- 150000002825 nitriles Chemical class 0.000 title abstract 4
- -1 oxadiazole sulfoxide compounds Chemical class 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 abstract description 15
- 229940098892 Protease-activated receptor-1 antagonist Drugs 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 3
- 239000000890 drug combination Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000003146 anticoagulant agent Substances 0.000 description 8
- 210000001772 blood platelet Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 102100037136 Proteinase-activated receptor 1 Human genes 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 101710121440 Proteinase-activated receptor 1 Proteins 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000702 anti-platelet effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002560 nitrile group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 108010070519 PAR-1 Receptor Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000002020 Protease-activated receptors Human genes 0.000 description 2
- 108050009310 Protease-activated receptors Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000003790 Thrombin receptors Human genes 0.000 description 2
- 108090000166 Thrombin receptors Proteins 0.000 description 2
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OVBICQMTCPFEBS-SATRDZAXSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 OVBICQMTCPFEBS-SATRDZAXSA-N 0.000 description 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000032626 PAR-1 Receptor Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000007466 Purinergic P2 Receptors Human genes 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 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
- 208000024891 symptom Diseases 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及与血栓性疾病相关的药物领域。具体而言，本发明涉及一类含腈基取代苯的恶二唑亚砜结构的PAR-1拮抗剂、其制备方法、及含有它们的药物组合物以及它们在制备治疗血栓性疾病药物中的应用。
Description
技术领域
本发明涉及与血栓疾病相关的药物领域。具体而言，本发明涉及对血栓性疾病有治疗作用的一类含腈基取代苯等结构的的恶二唑亚砜结构的PAR-1拮抗剂及其制备方法，以及含有它们的药物组合物。
背景技术
蛋白酶激活受体1(Protease Activated Acceptor-1，PAR-1)是最近发现的抗血小板类抗血栓药物的新靶点。蛋白酶激活受体1又叫凝血酶受体，凝血酶被凝血连锁激活后通过PAR-1受体作用于血小板从而激活血小板，引起血小板聚集从而引起血栓和凝血。PAR-1引起的血栓中富含血小板成分，是动脉血栓的主要成因。PAR-1拮抗剂能阻断凝血酶激活血小板，从而阻断动脉血栓形成，可以用于治疗急性冠状动脉疾病(Acute Coronary Syndrome)。已经有几个PAR-1抑制剂处于临床研究(Chackalamannil S.,Thrombin Receptor(Protease Activated Receptor-1)Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects,J.Med.Chem.,2006,49(18),5389-5403)。
传统的用于防治血栓性疾病的药物分为三类。第一类是抗凝血类，分为直接凝血酶抑制剂和间接凝血酶抑制剂，该类药物通过作用于凝血连锁的不同环节来抑制血栓形成，具有抑制各种血栓形成的作用，如维生素K拮抗剂和Xa因子抑制剂等；第二类是抗血小板类，如COX-1抑制剂和ADP受体拮抗剂等，该类药物主要用于防治动脉血栓；第三类是纤维蛋白溶解剂，主要用于溶解血液中形成的纤维蛋白。
抗血小板药物多是传统的动脉血栓防治药物，如氯吡格雷和阿司匹林等。这些药物的缺点是出血风险比较大。而作为新发现的抗血小板类抗血栓药物的PAR-1拮抗剂，则具有较小的出血风险，因此这类化合物可以作为治疗动脉血栓的很有前景的药物。
本发明公开了一类含腈基取代苯等结构的恶二唑亚砜结构的PAR-1拮抗剂，可以用于制备抗动脉血栓疾病的药物。
发明内容
本发明的一个目的是提供一种具有良好抗血栓形成活性的具有通式I的化合物及其药学上可以接受的盐。
本发明的另一个目的是提供制备具有通式I的化合物及其药学上可以接受的盐的方法。
本发明的再一个目的是提供含有通式I的化合物及其药学上可以接受的盐作为有效成分，以及一种或多种药学上可接受的载体、赋形剂或稀释剂的药用组合物，及其在治疗动脉血栓方面的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式I的化合物具有下述结构式：
具有通式I结构的化合物及其药学上可以接受的盐，
其中，R选自-CN。
优选以下具有通式I的化合物，
本发明所述通式I化合物通过以下步骤合成：
化合物II和化合物III在碱存在下反应，得到化合物IV；化合物IV氧化得到化合物I，R的定义如前所述。。
本发明所述式I化合物的药学上可接受的盐，包括但是不限于与各种无机酸如盐酸、硫酸、硝酸、磷酸、氢溴酸等形成的盐，也包括与各种有机酸如乙酸、琥珀酸、马来酸、苹果酸以及各种氨基酸等形成的盐。
本发明所述通式I化合物具有PAR-1的拮抗作用，可作为有效成分用于制备抗血栓方面的治疗药物。本发明所述通式I化合物的活性是通过体外模型验证的。
本发明的通式I化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-500mg/人范围内，分为一次或数次给药。实际服用本发明通式I化合物的剂量可由医生根据有关的情况来决定。这些情况包括：被治疗者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
A、IV-1的合成
2.03g(10mmol)化合物II-1、3.70g(10mmol)化合物III和4.15g(30mmol)固体碳酸钾在20mL乙醇中搅拌过夜。反应混合物倾倒到200mL冰水中，搅拌，用浓盐酸调节pH＝4，50mL×3的二氯甲烷萃取，合并有机相，食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到纯品IV-1，白色固体，MS，m/z＝515([M+Na]+)。
B、I-1的合成
2.46g(5mmol)化合物IV-1溶于25mL二氯甲烷中，-10℃下搅拌，慢慢加入3.13g(20mmol)间氯过氧苯甲酸(mCPBA)。反应混合物在该温度下搅拌1小时后，室温下继续搅拌过夜。反应混合物倾倒到200mL冰水中，搅拌，50mL×3的二氯甲烷萃取，合并有机相，先后用3％NaHCO3溶液和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸去溶剂，得到的残余物经过柱层析纯化，得到纯品I-1，白色固体，MS,m/z＝526([M+NH4]+)。
实施例2-3
按照实施例1的方法，合成了具有通式I的下列化合物。
其中，实施例4为对比化合物(仍是申请人发现的全新结构)，以充分说明药理效果。
实施例5体外血小板聚集抑制试验
在96孔板中，在TRAP(凝血酶受体活化肽)诱导的血小板聚集中进行物质的药理学试验。注射器中预先加入3.13％的柠檬酸钠溶液，然后抽入20mL健康志愿者的血液，在1500g下离心20分钟，将富含血小板的血浆(PRP)分离出来并以1μL PGE1溶液(500μg/mL的乙醇溶液)/mL PRP的量进行处理。在室温下孵育5分钟后，将其在1200g下离心20分钟以除去白细胞。将不含白细胞的PRP以5mL/份分批转移到15mL的PP管中，并在3600g下离心使血小板沉淀。而后，滗出上层血浆，将得自5mL PRP的血小板沉淀重新混悬于1mL Tyrode(120mM NaCl，2.6mM KCl，12mM NaHCO3，0.39mM NaH2PO4，10mMHEPES，0.35％BSA，5.5mM葡萄糖，pH＝7.4)中，并用Tyrode调节至3×105/μL的血小板计数。将13mL这种细胞混悬液用866μL的10mM CaCl2溶液处理，以每孔120μL的量将其吸至96孔板中，在96孔板的孔中已经提前加入了15μL待测试物质。在室温下黑暗中孵育30分钟，加入15μL TRAP溶液(70-100μM)作为激动剂，在SpectraMax中37℃下振荡20分钟，在650nm下纪录动力学，计算阴性对照(tyrode/DMSO)和阳性对照(15μL激动剂/DMSO)的曲线下面积，并将差异定为100％。将待测试化合物以系列稀释物的形式吸移，一式两份地进行测定，同样测定各物质浓度的AUC，计算与对照相比的AUC抑制％。通过该抑制％按照4参数方程借助非线性回归分析计算IC50值。下表给出了结果。
| 化合物 | 血小板凝聚的抑制IC50(nM) |
| 实施例1化合物(I-1) | 7.6 |
| 实施例2化合物(I-2) | 10.4 |
| 实施例3化合物(I-3) | 12.5 |
| 实施例4化合物(对比例) | 14.7 |
从上表可以看出，本发明的化合物在血小板凝聚试验中均表现出较好的抑制作用，特别是I-1。
Claims (4)
1.具有通式I结构的化合物及其药学上可以接受的盐，
其中，R选自-CN。
2.权利要求1所定义的通式I化合物，选自下列化合物，
3.合成权利要求1-2任一所定义的通式I的化合物的方法：
化合物II和化合物III在碱存在下反应，得到化合物IV；化合物IV氧化得到化合物I，R的定义如权利要求1-2任一所述。
4.权利要求1-2所定义的通式I化合物及其药学上可以接受的盐在制备治疗血栓性药物方面的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016230.1A CN104529930B (zh) | 2015-01-13 | 2015-01-13 | 一类含腈基苯的噁二唑亚砜化合物、其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016230.1A CN104529930B (zh) | 2015-01-13 | 2015-01-13 | 一类含腈基苯的噁二唑亚砜化合物、其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104529930A true CN104529930A (zh) | 2015-04-22 |
| CN104529930B CN104529930B (zh) | 2016-03-09 |
Family
ID=52845607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510016230.1A Active CN104529930B (zh) | 2015-01-13 | 2015-01-13 | 一类含腈基苯的噁二唑亚砜化合物、其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104529930B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072436A (zh) * | 2014-07-23 | 2014-10-01 | 张远强 | 对位取代的四氮唑苯乙酮化合物、其制备方法和用途 |
| CN104072434A (zh) * | 2014-07-23 | 2014-10-01 | 张远强 | 间位取代的四氮唑苯乙酮化合物、其制备方法和用途 |
| CN104086501A (zh) * | 2014-07-23 | 2014-10-08 | 张远强 | 一种par-1拮抗剂、其制备方法和用途 |
-
2015
- 2015-01-13 CN CN201510016230.1A patent/CN104529930B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072436A (zh) * | 2014-07-23 | 2014-10-01 | 张远强 | 对位取代的四氮唑苯乙酮化合物、其制备方法和用途 |
| CN104072434A (zh) * | 2014-07-23 | 2014-10-01 | 张远强 | 间位取代的四氮唑苯乙酮化合物、其制备方法和用途 |
| CN104086501A (zh) * | 2014-07-23 | 2014-10-08 | 张远强 | 一种par-1拮抗剂、其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104529930B (zh) | 2016-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104072434A (zh) | 间位取代的四氮唑苯乙酮化合物、其制备方法和用途 | |
| CN104529927B (zh) | 一类含卤代苯的恶二唑亚砜化合物、其制备方法和用途 | |
| CN104072436A (zh) | 对位取代的四氮唑苯乙酮化合物、其制备方法和用途 | |
| CN104098520A (zh) | 苯基三唑希夫碱类化合物、其制备方法和用途 | |
| CN104086503B (zh) | Par-1拮抗剂及其用途 | |
| CN104072439A (zh) | 卤素取代的四氮唑苯乙酮化合物、其制备方法和用途 | |
| CN104072437A (zh) | 双取代的四氮唑苯乙酮化合物、其制备方法和用途 | |
| CN104086500B (zh) | 一种par-1拮抗剂及其用途 | |
| CN104529930B (zh) | 一类含腈基苯的噁二唑亚砜化合物、其制备方法和用途 | |
| CN104513212B (zh) | 一类含硝基苯的恶二唑亚砜化合物、其制备方法和用途 | |
| CN104086496B (zh) | 一种抗血栓化合物、其制备方法和用途 | |
| CN104529931B (zh) | 一类含烷氧对位取代苯的恶二唑亚砜化合物、其制备方法和用途 | |
| CN104529929B (zh) | 含烷氧取代苯的恶二唑亚砜化合物、其制备方法和用途 | |
| CN104086497A (zh) | 三唑希夫碱类化合物、其制备方法和用途 | |
| CN104496931A (zh) | 含胺基取代苯的恶二唑亚砜化合物、其制备方法和用途 | |
| CN104496932A (zh) | 一类含胺基对位取代苯的恶二唑亚砜化合物、其制备方法和用途 | |
| CN104529928A (zh) | 一类恶二唑亚砜化合物、其制备方法和用途 | |
| CN104086494A (zh) | 末端双取代的甲基三唑希夫碱结构化合物、其制备方法和用途 | |
| CN104086495A (zh) | 末端双取代的三唑希夫碱结构化合物、其制备方法和用途 | |
| CN104086493A (zh) | 末端取代的苯基三唑希夫碱结构的化合物及其用途 | |
| CN104072432A (zh) | 含苯基取代三唑希夫碱类结构的化合物、其制备方法和用途 | |
| CN104086498A (zh) | 末端取代的三唑希夫碱类结构的化合物、其制备方法和用途 | |
| CN104140398A (zh) | 甲基三唑希夫碱类结构的化合物、其制备方法和用途 | |
| CN104072431A (zh) | 烷氧基取代的苯基三唑希夫碱结构的化合物及用途 | |
| CN104496925B (zh) | 二烯四氮唑类化合物、其制备方法和用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: One category of oxadiazole sulfoxide compounds comprising nitrile benzene, and preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160309 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190604 Granted publication date: 20160309 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190704 Address after: Unit 216, A4 Floor, 218 Xinghu Street, Suzhou Industrial Park, Jiangsu Province Patentee after: Suzhou Naai Purification Technology Co., Ltd. Address before: 528000 Shops No. 1636 and 1637 on the First Floor of No. 32 Yantaigong, Chancheng District, Foshan City, Guangdong Province Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190830 Address after: Room 105-45957, No. 6 Baohua Road, Hengqin New District, Zhuhai City, Guangdong Province Patentee after: Zhuhai Hengqin Changmanou International Trade Co., Ltd. Address before: Unit 216, A4 Floor, 218 Xinghu Street, Suzhou Industrial Park, Jiangsu Province Patentee before: Suzhou Naai Purification Technology Co., Ltd. |