CN104072435A - Alkyl disubstituted tetrazole acetophenone compound and preparation method and use thereof - Google Patents
Alkyl disubstituted tetrazole acetophenone compound and preparation method and use thereof Download PDFInfo
- Publication number
- CN104072435A CN104072435A CN201410352064.8A CN201410352064A CN104072435A CN 104072435 A CN104072435 A CN 104072435A CN 201410352064 A CN201410352064 A CN 201410352064A CN 104072435 A CN104072435 A CN 104072435A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- general formula
- par
- present
- 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
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 7
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 title description 2
- -1 tetrazole acetophenone compound Chemical class 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 8
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 abstract description 15
- 239000000556 agonist Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 108091005804 Peptidases Proteins 0.000 abstract description 2
- 239000004365 Protease Substances 0.000 abstract description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract description 2
- 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
- 102100037136 Proteinase-activated receptor 1 Human genes 0.000 description 5
- 229940098892 Protease-activated receptor-1 antagonist Drugs 0.000 description 4
- 101710121440 Proteinase-activated receptor 1 Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000000702 anti-platelet effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- 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
- 238000006243 chemical reaction Methods 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
- 239000000470 constituent Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 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
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-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
- 239000007995 HEPES buffer Substances 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- 239000003513 alkali Substances 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
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000006285 cell suspension Substances 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
- 238000004440 column chromatography Methods 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
- 238000001035 drying Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 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
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000006698 induction 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
- 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
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 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
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation 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
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 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
- 239000002904 solvent Substances 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
- 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
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to the field of medicines related to thrombotic diseases, in particular to an alkyl disubstituted PAR-1 (Protease Activated Acceptor-1) agonist containing a tetrazole acetophenone structure, a preparation method thereof, a medicine composition containing the PAR-1 agonist and application of the PAR-1 agonist to preparation of medicines for treating thrombotic diseases. The formula (I) and the definition of R group are shown in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to thrombus disease.Particularly, the present invention relates to PAR-1 antagonist containing tetrazole methyl phenyl ketone structure that the two alkyl of the medicative class of thrombotic diseases are replaced and preparation method thereof, and the pharmaceutical composition that contains them.
Background technology
Proteinase activated receptors 1 (Protease Activated Acceptor-1, PAR-1) is the novel targets of the antiplatelet class antithrombotic reagent of recent findings.Proteinase activated receptors 1 is again thrombin receptor, thereby zymoplasm activates thrombocyte by PAR-1 receptor acting in thrombocyte after being activated by coagulation cascade, thereby causes that platelet aggregation causes thrombus and blood coagulation.In the thrombus that PAR-1 causes, being rich in thrombocyte composition, is the main reason of arterial thrombus.PAR-1 antagonist can be blocked thrombin activation thrombocyte, thereby interruption artery thrombosis can be used for the treatment of acute coronary disease (Acute Coronary Syndrome).There are several PAR-1 inhibitor in clinical study (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).
Traditional medicine for preventing and treating thrombotic diseases is divided three classes.The first kind is anticoagulation class, be divided into direct thrombin inhibitor and indirect thrombin inhibitors, such medicine suppresses thrombosis by the different links that act on coagulation cascade, has the various thrombotic effects of inhibition, 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; The 3rd class is fibrinolytic agent, the scleroproein that is mainly used in forming in lysed blood.
Mostly antiplatelet drug is traditional arterial thrombus control medicine, 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, there is less bleeding risk, therefore this compounds can be used as the very promising medicine for the treatment of arterial thrombus.
The invention discloses the PAR-1 antagonist containing tetrazole methyl phenyl ketone structure that the two alkyl of a class replace, can be for the preparation of the medicine of anti-arterial thrombus disease.
Summary of the invention
An object of the present invention is to provide a kind of general formula that has with good anti-thrombosis activity
icompound and acceptable salt pharmaceutically thereof.
Another object of the present invention is to provide preparation and has general formula
icompound and the method for acceptable salt pharmaceutically thereof.
A further object of the present invention is to provide and contains general formula
icompound and pharmaceutically acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and application aspect 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:
(?I?)
Wherein,
Wherein,
R1 is selected from F, Cl, Br, I;
R2 is selected from the alkyl of C1-C3.
Preferably, there is general formula
icompound,
。
Further, the preferred following general formula that has
icompound,
?。
General formula of the present invention
icompound synthesizes by following steps:
。
Compound
iIand compound
iIIunder the catalysis of acid or alkali, react, obtain compound (
i).
Formula of the present invention
ithe pharmacy acceptable salt of compound, include, but are not limited to the salt forming with various mineral acid example hydrochloric acids, sulfuric acid, nitric acid, phosphoric acid, Hydrogen bromide etc., also comprise the salt forming as acetic acid, succsinic acid, toxilic acid, oxysuccinic acid and each seed amino acid etc. with various organic acids.
General formula of the present invention
icompound has the antagonistic action of PAR-1, can be used as the medicine of effective constituent for the preparation of antithrombotic aspect.General formula of the present invention
ithe activity of compound is verified by external model.
General formula of the present invention
icompound is effective in quite wide dosage range.The dosage of taking for example every day, within the scope of 1 mg-500 mg/ people, is divided into once or administration for several times.Actually take general formula of the present invention
ithe dosage of compound can be decided according to relevant situation by doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, individual reaction to medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
embodiment 1
。
Reaction raw materials: self-control, ordinary method.
1.92 g (10 mmol) compound
iI-1, 3.70 g (10 mmol) compound
iII-1in 20 mL acetonitriles, stir and spend the night, then temperature rising reflux 3 hours with 4.15 g (30 mmol) solid carbonic acid potassium.
After reaction mixture is slightly cold, be poured in 200 mL frozen water, stir, regulate pH=4, the dichloromethane extraction of 50 mL × 3 with concentrated hydrochloric acid, merge organic phase, salt solution washing, anhydrous sodium sulfate drying, on Rotary Evaporators, boil off solvent, the resistates obtaining, through column chromatography purification, obtains sterling
i-1, white solid, MS,
m/z=504 ([M+Na]
+).
embodiment 2-5
According to the method for embodiment 1, synthesize and there is general formula
ifollowing compounds.
embodiment 6 extracorporeal platelet aggregation inhibition tests
In 96 orifice plates, concentrate at the platelet aggregation of TRAP (Glycoprotein) induction the pharmacology test that carries out material.In syringe, add in advance 3.13% sodium citrate solution, then suction 20 mL healthy volunteers' blood, 1500
glower centrifugal 20 minutes, will be rich in that hematoblastic blood plasma (PRP) is separated and process with the amount of 1 μ L PGE1 solution (ethanolic solns of 500 μ g/mL)/mL PRP.At room temperature hatch after 5 minutes, by its under 1200 g centrifugal 20 minutes with except leucocyte-removing.To not transfer in the PP pipe of 15 mL with 5 mL/ parts containing leukocytic PRP, and the centrifugal thrombocyte that makes precipitates under 3600 g in batches.Then, drain upper plasma, the thrombocyte precipitation that derives from 5 mL PRP is suspended in to 1 mL Tyrode (120 mM NaCl, 2.6 mM KCl, 12 mM NaHCO3 again, 0.39 mM NaH2PO4,10 mM HEPES, 0.35% BSA, 5.5 mM glucose, pH=7.4) in, and be adjusted to the platelet count of 3 × 105/ μ L with Tyrode.The 10 mM CaCl2 solution-treated by this cell suspension of 13 mL with 866 μ L, are drawn in 96 orifice plates with the amount of every hole 120 μ L, have added in advance 15 μ L material to be tested in the hole of 96 orifice plates.At room temperature in dark, hatch 30 minutes, add 15 μ L TRAP solution (70-100 μ M) as agonist, in SpectraMax, under 37 ° of C, vibrate 20 minutes, under 650 nm, note down kinetics, calculate the area under curve of negative control (tyrode/DMSO) and positive control (15 μ L agonist/DMSO), and difference is decided to be to 100%.Compound to be tested is inhaled and moved with the form of serial dilution thing, measure in duplicate, measure equally the AUC of each material concentration, the AUC calculating compared with the control suppresses %.Calculate IC50 value according to 4 parametric equations by nonlinear regression analysis by this inhibition %.Following table has provided result.
As can be seen from the above table, compound of the present invention all shows obvious restraining effect in platelet aggregation test.
Claims (4)
1. there is general formula
ithe compound of structure and pharmaceutically acceptable salt,
(?I?)
Wherein,
Wherein,
R1 is selected from F, Cl, Br, I;
R2 is selected from the alkyl of C1-C3.
2. the defined general formula of claim 1
icompound, is selected from following compounds,
?
。
3. the defined general formula of claim 2
icompound, is selected from following compounds,
?。
4. the defined general formula of claim 1-3
icompound and the pharmaceutically acceptable salt purposes aspect preparation treatment thrombotic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410352064.8A CN104072435B (en) | 2014-07-23 | 2014-07-23 | The tetrazole acetophenone compound that two alkyl replaces and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410352064.8A CN104072435B (en) | 2014-07-23 | 2014-07-23 | The tetrazole acetophenone compound that two alkyl replaces and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104072435A true CN104072435A (en) | 2014-10-01 |
| CN104072435B CN104072435B (en) | 2015-11-04 |
Family
ID=51594083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410352064.8A Expired - Fee Related CN104072435B (en) | 2014-07-23 | 2014-07-23 | The tetrazole acetophenone compound that two alkyl replaces and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104072435B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529928A (en) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | One category of oxadiazole sulfoxide compounds, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998057937A2 (en) * | 1997-06-19 | 1998-12-23 | The Du Pont Merck Pharmaceutical Company | Inhibitors of factor xa with a neutral p1 specificity group |
| US20110105490A1 (en) * | 2009-10-29 | 2011-05-05 | Han-Cheng Zhang | 2,3-dihydro-1h-isoindol-1-imine derivatives useful as thrombin par-1 receptor antagonist |
| CN102241621A (en) * | 2010-05-11 | 2011-11-16 | 江苏恒瑞医药股份有限公司 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
-
2014
- 2014-07-23 CN CN201410352064.8A patent/CN104072435B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998057937A2 (en) * | 1997-06-19 | 1998-12-23 | The Du Pont Merck Pharmaceutical Company | Inhibitors of factor xa with a neutral p1 specificity group |
| US20110105490A1 (en) * | 2009-10-29 | 2011-05-05 | Han-Cheng Zhang | 2,3-dihydro-1h-isoindol-1-imine derivatives useful as thrombin par-1 receptor antagonist |
| CN102241621A (en) * | 2010-05-11 | 2011-11-16 | 江苏恒瑞医药股份有限公司 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529928A (en) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | One category of oxadiazole sulfoxide compounds, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104072435B (en) | 2015-11-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104072436B (en) | The tetrazole acetophenone compound of para-orientation, Preparation Method And The Use | |
| CN104072434B (en) | Between position replace tetrazole acetophenone compound, 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 | |
| CN104072438B (en) | Dialkoxy is for tetrazole acetophenone compound, Preparation Method And The Use | |
| CN104086503B (en) | PAR-1 antagonist and uses thereof | |
| 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 | |
| CN104072435B (en) | The tetrazole acetophenone compound that two alkyl replaces and purposes | |
| CN104086502B (en) | Halo tetrazole acetophenone compound, Preparation Method And The Use | |
| CN104086494B (en) | End disubstituted methyl-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 | |
| CN104086495B (en) | End disubstituted triazole schiff bases structural compounds, Preparation Method And The Use | |
| CN104086496B (en) | A kind of antithrombotic compound, Preparation Method And The Use | |
| 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 | |
| CN104072431A (en) | Compound of phenyl triazole Schiff base structure substituted for alkoxy and application | |
| CN104086493A (en) | Compounds with terminally-substituted phenyl triazole Schiff base structures and applications of compounds | |
| CN104529930B (en) | One class nitrile group-containing Ben oxadiazole sulfoxide compound, Preparation Method And The Use | |
| CN104513212B (en) | Oxadiazoles sulfoxide compound, the Preparation Method And The Use of one class nitrobenzene-containing | |
| CN104529928A (en) | One category of oxadiazole sulfoxide compounds, and preparation method and application thereof | |
| CN104496931A (en) | Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof | |
| CN104496932A (en) | Oxadiazole sulfoxide compound containing alkyl-para-substituted phenyl, preparation method thereof and application thereof |
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 | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170727 Address after: 510640 Guangdong City, Tianhe District Province, No. five, road, public education building, unit 371-1, unit 2401 Patentee after: Guangdong Gaohang Intellectual Property Operation Co., Ltd. Address before: 528000 Guangdong, Foshan District, Pu Lan Road, the first floor of the first floor, No. 5, Chancheng Patentee before: Zhang Yuanqiang |
|
| CB03 | Change of inventor or designer information |
Inventor after: Fan Xinmei Inventor before: Zhang Yuanqiang |
|
| CB03 | Change of inventor or designer information | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170818 Address after: 030600, 2, 78, South Street, South Village, Guo fort, Yuci District, Jinzhong, Shanxi Patentee after: Fan Xinmei Address before: 510640 Guangdong City, Tianhe District Province, No. five, road, public education building, unit 371-1, unit 2401 Patentee before: Guangdong Gaohang Intellectual Property Operation Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151104 Termination date: 20180723 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |