CN104529927B - One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene - Google Patents
One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene Download PDFInfo
- Publication number
- CN104529927B CN104529927B CN201510016137.0A CN201510016137A CN104529927B CN 104529927 B CN104529927 B CN 104529927B CN 201510016137 A CN201510016137 A CN 201510016137A CN 104529927 B CN104529927 B CN 104529927B
- Authority
- CN
- China
- Prior art keywords
- compound
- class
- present
- preparation
- halogeno
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 title abstract description 5
- -1 oxadiazoles sulfoxide compound Chemical class 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 30
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 abstract description 15
- 229940098892 Protease-activated receptor-1 antagonist Drugs 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000003146 anticoagulant agent Substances 0.000 description 7
- 210000001772 blood platelet Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 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
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 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 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-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
- 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
- 239000000556 agonist Substances 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
- 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 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
- 238000000034 method Methods 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
- ZFIDLIZAQNLPSV-FZCLLLDFSA-N (2S)-2-amino-2-cyclopentyl-N-(1-diphenoxyphosphorylethyl)acetamide Chemical compound C1([C@H](N)C(=O)NC(C)P(=O)(OC=2C=CC=CC=2)OC=2C=CC=CC=2)CCCC1 ZFIDLIZAQNLPSV-FZCLLLDFSA-N 0.000 description 1
- 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
- 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
- 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
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 102000007466 Purinergic P2 Receptors Human genes 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 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
- 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
- 230000010100 anticoagulation Effects 0.000 description 1
- 229940127218 antiplatelet drug 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
- 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
- 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
- 229940079593 drug Drugs 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
- 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
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- 238000012545 processing Methods 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
- 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
The present invention relates to the pharmaceutical field relevant to thrombotic diseases.Specifically, the present invention relates to a class containing the PAR-1 antagonist of oxadiazoles sulfoxide structure of halogeno-benzene, its preparation method and containing their pharmaceutical composition and their application in preparation treatment thrombotic diseases medicine.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to thrombus disease.Specifically, the present invention relates to the PAR-1 antagonist medicative class of thrombotic diseases being contained to the oxadiazoles sulfoxide structure of halogeno-benzene and preparation method thereof, and contain their pharmaceutical composition.
Background technology
Proteinase activated receptors 1 (ProteaseActivatedAcceptor-1, PAR-1) is the novel targets of the antiplatelet class antithrombotic reagent found recently.Proteinase activated receptors 1 is thrombin receptor again, zymoplasm by coagulation cascade activate after by PAR-1 receptor acting in thrombocyte thus activate thrombocyte, cause platelet aggregation thus cause thrombus and blood coagulation.Being rich in platelet component in the thrombus that PAR-1 causes, is the main reason of arterial thrombus.PAR-1 antagonist can block thrombin activation thrombocyte, thus interruption artery thrombosis, may be used for treatment acute coronary artery disease (AcuteCoronarySyndrome).Several PAR-1 inhibitor has been had to be in clinical study (ChackalamannilS., ThrombinReceptor (ProteaseActivatedReceptor-1) AntagonistsasPotentAntithromboticAgentswithStrongAntipla teletEffects, J.Med.Chem., 2006,49 (18), 5389-5403).
Traditional is divided three classes for the medicine preventing and treating thrombotic diseases.The first kind is anticoagulation class, be divided into direct thrombin inhibitor and indirect thrombin inhibitors, such medicine carrys out inhibition thrombosis by the different links acting on coagulation cascade, has and suppresses various thrombotic effect, as vitamin K antagon and Xa factor inhibitor etc.; Equations of The Second Kind is antiplatelet class, and as COX-1 inhibitor and adp receptor antagonist etc., such medicine is mainly used in preventing and treating arterial thrombus; 3rd class is fibrinolytic agent, is mainly used in the scleroproein formed in lysed blood.
Mostly antiplatelet drug is traditional arterial thrombus protective agents, as clopidogrel and acetylsalicylic acid etc.The shortcoming of these medicines is that bleeding risk is larger.And as the PAR-1 antagonist of newfound antiplatelet class antithrombotic reagent, then there is less bleeding risk, therefore this compounds can as the very promising medicine for the treatment of arterial thrombus.
The invention discloses the PAR-1 antagonist of a class containing the oxadiazoles sulfoxide structure of halogeno-benzene, may be used for the medicine preparing anti-arterial thrombus disease.
Summary of the invention
An object of the present invention is to provide a kind of there is good anti-thrombosis activity the compound with general formula I and pharmaceutically acceptable salt.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmaceutically acceptable salt thereof.
Another object of the present invention be to provide compound containing general formula I and pharmaceutically acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and the application in treatment arterial thrombus.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R is selected from halogenic substituent;
Preferably, R is selected from F, Cl, Br, I substituting group.
The preferably following compound with general formula I,
Further, the preferably following compound with general formula I,
Compound of Formula I of the present invention is synthesized by following steps:
Compound II per and compound III are reacted in the presence of a base, obtain compound IV; Compound IV oxidation obtains Compound I, and the definition of R as previously mentioned.。
The pharmacy acceptable salt of formula I of the present invention, include, but are not limited to the salt formed with various mineral acid example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrogen bromide etc., also comprise the salt formed as acetic acid, succsinic acid, toxilic acid, oxysuccinic acid and each seed amino acid etc. with various organic acid.
Compound of Formula I of the present invention has the antagonistic action of PAR-1, can be used as the medicine of effective constituent for the preparation of antithrombotic aspect.The activity of compound of Formula I of the present invention is verified by external model.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
The synthesis of A, IV-1
2.57g (10mmol) Compound II per-1,3.70g (10mmol) compound III and 4.15g (30mmol) solid carbonic acid potassium stir and spend the night in 20mL ethanol.Reaction mixture is poured in 200mL frozen water, stirs, regulates pH=4 with concentrated hydrochloric acid, the dichloromethane extraction of 50mL × 3, merge organic phase, brine It, anhydrous sodium sulfate drying, boil off solvent on a rotary evaporator, the resistates obtained, through column chromatography purification, obtains sterling IV-1, white solid, MS, m/z=569 ([M+Na]
+).
The synthesis of B, I-1
2.73g (5mmol) compound IV-1 is dissolved in 25mL methylene dichloride, stirs, slowly add 3.13g (20mmol) metachloroperbenzoic acid (mCPBA) at-10 DEG C.After reaction mixture stirs 1 hour at such a temperature, continue stirring under room temperature and spend the night.Reaction mixture is poured in 200mL frozen water, stirs, the dichloromethane extraction of 50mL × 3, merges organic phase, successively uses 3%NaHCO
3solution and brine It, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, and the resistates obtained, through column chromatography purification, obtains sterling I-1, white-yellowish solid, MS, m/z=580 ([M+NH
4]
+).
Embodiment 2-10
According to the method for embodiment 1, synthesize the following compounds with general formula I.
Embodiment 11 extracorporeal platelet aggregation inhibition test
In 96 orifice plates, the platelet aggregation of inducing at TRAP (Glycoprotein) concentrates the pharmacology test carrying out material.The sodium citrate solution of 3.13% is added in advance in syringe, then the blood of suction 20mL healthy volunteer, under 1500g centrifugal 20 minutes, separate being rich in hematoblastic blood plasma (PRP) and processing with the amount of 1 μ LPGE1 solution (ethanolic solns of 500 μ g/mL)/mLPRP.After at room temperature hatching 5 minutes, by its under 1200g centrifugal 20 minutes with except leucocyte-removing.To not transfer in the PP pipe of 15mL with 5mL/ part containing leukocytic PRP in batches, and centrifugally under 3600g make pellet platelets.Then, drain upper plasma, the pellet platelets deriving from 5mLPRP is suspended in 1mLTyrode (120mMNaCl, 2.6mMKCl, 12mMNaHCO3 again, 0.39mMNaH2PO4,10mMHEPES, 0.35%BSA, 5.5mM glucose, pH=7.4) in, and the platelet count of 3 × 105/ μ L is adjusted to Tyrode.By the 10mMCaCl2 solution-treated of this for 13mL cell suspension with 866 μ L, be drawn in 96 orifice plates with the amount of every hole 120 μ L, in the hole of 96 orifice plates, added 15 μ L material to be tested in advance.At room temperature hatch 30 minutes in dark, add 15 μ LTRAP solution (70-100 μM) as agonist, vibrate 20 minutes at 37 DEG C in SpectraMax, kinetics is noted down under 650nm, calculate the area under curve of negative control (tyrode/DMSO) and positive control (15 μ L agonist/DMSO), and difference is decided to be 100%.Aspirated with the form of serial dilution thing by compound to be tested, measure in duplicate, the same AUC measuring each material concentration, the AUC calculated compared with the control suppresses %.IC50 value is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %.Following table gives result.
| Compound | The suppression IC of platelet aggregation 50(nM) |
| Embodiment 1 compound | 4.6 |
| Embodiment 2 compound | 12.9 |
| Embodiment 3 compound | 11.4 |
| Embodiment 4 compound | 8.5 |
| Embodiment 5 compound | 15.1 |
| Embodiment 6 compound | 9.6 |
| Embodiment 7 compound | 7.1 |
| Embodiment 8 compound | 18.3 |
| Embodiment 9 compound | 16.7 |
| Embodiment 10 compound | 13.8 |
As can be seen from the above table, compound of the present invention all shows good restraining effect in platelet aggregation test.
Claims (3)
1. following compounds,
2. compound described in claim 1, is selected from,
3. the application of compound described in any one of claim 1-2 in preparation treatment thrombotic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016137.0A CN104529927B (en) | 2015-01-13 | 2015-01-13 | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016137.0A CN104529927B (en) | 2015-01-13 | 2015-01-13 | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104529927A CN104529927A (en) | 2015-04-22 |
| CN104529927B true CN104529927B (en) | 2016-04-06 |
Family
ID=52845604
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510016137.0A Active CN104529927B (en) | 2015-01-13 | 2015-01-13 | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104529927B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129369A (en) * | 2018-01-18 | 2018-06-08 | 天津小新医药科技有限公司 | Diphenyl thioacetic acid, the preparation method and its usage of P2Y12 receptor antagonists |
| CN108129370A (en) * | 2018-01-18 | 2018-06-08 | 天津小新医药科技有限公司 | A kind of P2Y12 receptor antagonists of itrile group diphenyl thioacetic acid structure and application thereof |
| CN108191723A (en) * | 2018-01-18 | 2018-06-22 | 天津小新医药科技有限公司 | A kind of P2Y12 receptor antagonists of nitro diphenyl thioacetic acid structure and application thereof |
| CN108191724A (en) * | 2018-01-18 | 2018-06-22 | 天津小新医药科技有限公司 | P2Y12 receptor antagonists of the thioacetic acid structure of diphenyl containing methoxy and application thereof |
| CN108191722A (en) * | 2018-01-18 | 2018-06-22 | 天津小新医药科技有限公司 | P2Y12 receptor antagonists of halogenated diphenyl thioacetic acid structure and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2380190A (en) * | 2001-08-28 | 2003-04-02 | Bayer Ag | Antiinflammatory heterocyclic sulphones |
| CN104086501A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist |
| CN104098520A (en) * | 2014-07-23 | 2014-10-15 | 张远强 | Phenyl triazole schiff base compound as well as preparation method and application thereof |
-
2015
- 2015-01-13 CN CN201510016137.0A patent/CN104529927B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2380190A (en) * | 2001-08-28 | 2003-04-02 | Bayer Ag | Antiinflammatory heterocyclic sulphones |
| CN104086501A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist |
| CN104098520A (en) * | 2014-07-23 | 2014-10-15 | 张远强 | Phenyl triazole schiff base compound as well as preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 1,3,4-噁二唑硫醚及（亚）砜类化合物的生物活性研究进展;邓华波等;《精细化工中间体》;20120430;第42卷(第2期);第1-8页 * |
| 作为潜在免疫抑制剂的2,5-二取代-1,3,4-噁二唑衍生物的合成与活性筛选;张志明;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20121015;第11页第3段，第44页图33 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129369A (en) * | 2018-01-18 | 2018-06-08 | 天津小新医药科技有限公司 | Diphenyl thioacetic acid, the preparation method and its usage of P2Y12 receptor antagonists |
| CN108129370A (en) * | 2018-01-18 | 2018-06-08 | 天津小新医药科技有限公司 | A kind of P2Y12 receptor antagonists of itrile group diphenyl thioacetic acid structure and application thereof |
| CN108191723A (en) * | 2018-01-18 | 2018-06-22 | 天津小新医药科技有限公司 | A kind of P2Y12 receptor antagonists of nitro diphenyl thioacetic acid structure and application thereof |
| CN108191724A (en) * | 2018-01-18 | 2018-06-22 | 天津小新医药科技有限公司 | P2Y12 receptor antagonists of the thioacetic acid structure of diphenyl containing methoxy and application thereof |
| CN108191722A (en) * | 2018-01-18 | 2018-06-22 | 天津小新医药科技有限公司 | P2Y12 receptor antagonists of halogenated diphenyl thioacetic acid structure and application thereof |
| CN108191724B (en) * | 2018-01-18 | 2021-06-29 | 天津小新医药科技有限公司 | P2Y12 receptor antagonist containing methoxydiphenyl thioacetic acid structure and application thereof |
| CN108129369B (en) * | 2018-01-18 | 2021-06-29 | 天津小新医药科技有限公司 | Diphenyl thioacetic acid of P2Y12 receptor antagonist, preparation method and application thereof |
| CN108191722B (en) * | 2018-01-18 | 2021-06-29 | 天津小新医药科技有限公司 | P2Y12 receptor antagonist with halogenated diphenyl thioacetic acid structure and application thereof |
| CN108129370B (en) * | 2018-01-18 | 2021-06-29 | 天津小新医药科技有限公司 | P2Y12 receptor antagonist with nitrile diphenyl thioacetic acid structure and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104529927A (en) | 2015-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104072434B (en) | Between position replace tetrazole acetophenone compound, Preparation Method And The Use | |
| CN104072436B (en) | The tetrazole acetophenone compound of para-orientation, Preparation Method And The Use | |
| CN104098520B (en) | Phenyltriazole schiff base compounds, Preparation Method And The Use | |
| CN104529927B (en) | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene | |
| CN104086503B (en) | PAR-1 antagonist and uses thereof | |
| CN104072438B (en) | Dialkoxy is for tetrazole acetophenone compound, Preparation Method And The Use | |
| CN104072437B (en) | Disubstituted tetrazole acetophenone compound, Preparation Method And The Use | |
| CN104072439B (en) | The tetrazole acetophenone compound of halogen substiuted, Preparation Method And The Use | |
| CN104086500B (en) | A kind of PAR-1 antagonist and uses thereof | |
| CN104086497B (en) | Triazole schiff base compounds, Preparation Method And The Use | |
| CN104086498B (en) | Compound, the Preparation Method And The Use of the triazole schiff bases class formation that end replaces | |
| CN104072432B (en) | Containing compound, the Preparation Method And The Use of phenyl substituted triazole schiff bases class formation | |
| CN104072431B (en) | The compound of the Phenyltriazole schiff bases structure that alkoxyl group replaces and purposes | |
| CN104086494B (en) | End disubstituted methyl-triazole schiff bases structural compounds, Preparation Method And The Use | |
| CN104513212B (en) | Oxadiazoles sulfoxide compound, the Preparation Method And The Use of one class nitrobenzene-containing | |
| CN104072435B (en) | The tetrazole acetophenone compound that two alkyl replaces and purposes | |
| CN104529930B (en) | One class nitrile group-containing Ben oxadiazole sulfoxide compound, Preparation Method And The Use | |
| CN104086502B (en) | Halo tetrazole acetophenone compound, Preparation Method And The Use | |
| CN104086495B (en) | End disubstituted triazole schiff bases structural compounds, Preparation Method And The Use | |
| CN104140398B (en) | Compound, the Preparation Method And The Use of methyl-triazole schiff bases class formation | |
| CN104529931B (en) | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of alcoxyl para-orientation benzene | |
| CN104529929B (en) | Containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of alcoxyl substituted benzene | |
| CN104496927B (en) | Diene tetrazole halobenzene compounds, Preparation Method And The Use | |
| CN104496925B (en) | Diene tetrazole compound, Preparation Method And The Use | |
| CN104496923B (en) | Oil of mirbane diene tetrazole compound, Preparation Method And The Use |
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 | ||
| 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 halogeno benzene, and preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160406 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
|
| 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: 20160406 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: 20190910 Address after: 064200 West of South Road of East Second Ring Road and South of Jianchang Street, Zunhua City, Tangshan City, Hebei Province Patentee after: Hebei Haohui Crushing Machinery Equipment Co., Ltd. Address before: Chancheng district has 528000 Taiwan public in Guangdong province Foshan City No. 32 first floor 1636, shop No. 1637 Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201014 Address after: 064200 No. 11, Block B, Fulidi Shang, Zunhua City, Tangshan City, Hebei Province Patentee after: Zunhua Penghai Mingrui Network Technology Co.,Ltd. Address before: 064200 West of South Road of East Second Ring Road and South of Jianchang Street, Zunhua City, Tangshan City, Hebei Province Patentee before: Hebei Haohui Crushing Machinery Equipment Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201229 Address after: Town group 221000, Xuzhou City, Xuzhou City, Jiangsu Province Patentee after: De Hao processings of farm products Co.,Ltd. of Pizhou City Address before: 064200 No.11, block B, Fuli bottom business, Zunhua City, Tangshan City, Hebei Province Patentee before: Zunhua Penghai Mingrui Network Technology Co.,Ltd. |