CN104086498A - Compounds with terminally-substituted triazole Schiff base structures as well as preparation methods and applications of compounds - Google Patents
Compounds with terminally-substituted triazole Schiff base structures as well as preparation methods and applications of compounds Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 title claims description 32
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000003146 anticoagulant agent Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000002785 anti-thrombosis Effects 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 11
- 229940098892 Protease-activated receptor-1 antagonist Drugs 0.000 abstract description 7
- 239000002262 Schiff base Substances 0.000 abstract description 7
- -1 triazole Schiff base compounds Chemical class 0.000 abstract description 6
- 102000002020 Protease-activated receptors Human genes 0.000 abstract description 4
- 108050009310 Protease-activated receptors Proteins 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000005557 antagonist Substances 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 210000001772 blood platelet Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 102100037136 Proteinase-activated receptor 1 Human genes 0.000 description 5
- 0 *c1ccccc1 Chemical compound *c1ccccc1 0.000 description 4
- 101710121440 Proteinase-activated receptor 1 Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- 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
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 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
- 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
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 239000003513 alkali Substances 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
- 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
- 239000000203 mixture Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000630 rising effect Effects 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
- 125000006273 (C1-C3) alkyl group Chemical group 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- 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
- 150000004753 Schiff bases Chemical class 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
- 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
- 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
- 239000013078 crystal Substances 0.000 description 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 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
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 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
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 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
- 239000000047 product Substances 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
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000013207 serial dilution Methods 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
- 238000000967 suction filtration Methods 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
- 230000001732 thrombotic effect Effects 0.000 description 1
- 238000001291 vacuum drying 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
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the field of thrombotic disease related drugs, belongs to triazole Schiff base compounds with brand new structures and derivatives of the triazole Schiff base compounds and particularly relates to PAR (Protease Activated Receptor)-1 antagonists with terminally-substituted triazole Schiff base structures, preparation methods of the PAR-1 antagonists, pharmaceutical compositions containing the PAR-1 antagonists and applications of the PAR-1 antagonists to preparation of drugs for treating thrombotic diseases. All substituent groups are defined as the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to thrombus disease.The invention belongs to triazole schiff base compounds and the derivative thereof of the brand-new skeleton of a class, particularly, relate to PAR-1 antagonist of the triazole schiff bases class formation that the medicative class end of thrombotic diseases is 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 have been 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 is divided three classes for preventing and treating the medicine of thrombotic diseases.The first kind is anticoagulation class, be divided into direct thrombin inhibitor and indirect thrombin inhibitors, such medicine suppresses thrombosis by acting on the different links of 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, have less bleeding risk, so this compounds can be used as the very promising medicine for the treatment of arterial thrombus.
The invention discloses the PAR-1 antagonist of the triazole schiff bases class formation of a class end replacement, 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 the 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,
R is selected from the alkyl of C1-C5, the cycloalkyl of C3-C5, OR
1, R wherein
1be selected from the cycloalkyl of alkyl and the C3-C5 of C1-C5.
The compound of general formula I and pharmaceutically acceptable salt, preferably certainly:
R be selected from C1-C3 alkyl,, OR
1, R wherein
1be selected from the alkyl of C1-C3.
Preferably, there is general formula
icompound,
。
Further preferred following compounds,
。
General formula of the present invention
icompound synthesizes by following steps:
。
Compound
iIand compound
iIIunder the catalysis of acid or alkali, react, obtain schiff bases
iV;
iVwith
vunder alkali exists, reaction obtains 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 effective constituent for the preparation of the medicine 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 for example taking 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, the 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.
1.20 g (10 mmol) compound
iIand 1.16g (10 mmol) compound
iII-1be dissolved in 20 mL Glacial acetic acid, temperature rising reflux spends the night.After reaction mixture is slightly cold, pour in 200 mL frozen water, stir, suction filtration is collected solid, recrystallization from dehydrated alcohol, and vacuum-drying under room temperature, obtains product
iV-1, white crystal.MS,
m/z = 233 ([M+H]
+)。
1.17 g (5 mmol) compound
iV-1, 1.85 g (5 mmol) compound
vstir and spend the night in 15 mL acetonitriles with 2.07 g (15 mmol) solid carbonic acid potassium, then temperature rising reflux is 3 hours.
After reaction mixture is slightly cold, be poured in 200 mL frozen water, stir, with concentrated hydrochloric acid, regulate pH=4, the dichloromethane extraction of 50 mL * 3, 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, faint yellow solid, MS,
m/z=525 ([M+NH
4]
+).
embodiment 2-8
With reference to the method for embodiment 1, can synthesize and there is general formula
ifollowing compounds:
。
embodiment 9 extracorporeal platelet aggregation inhibition tests
In 96 orifice plates, at the platelet aggregation of TRAP (Glycoprotein) induction, concentrate the pharmacology test that carries out material.In syringe, add in advance 3.13% sodium citrate solution, suction 20 mL healthy volunteers' blood then, 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 containing leukocytic PRP, with 5 mL/ parts, not transfer in the PP pipe of 15 mL, 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 with Tyrode, be adjusted to the platelet count of 3 * 105/ μ L.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 %.By this inhibition %, according to 4 parametric equations, by nonlinear regression analysis, calculate IC50 value.Following table has provided result:
| Compound | The inhibition IC50 (nM) of platelet aggregation |
| Embodiment 1 compound | 1.9 |
| Embodiment 2 compounds | 2.5 |
| Embodiment 3 compounds | 3.9 |
| Embodiment 4 compounds | 1.4 |
| Embodiment 5 compounds | 2.4 |
| Embodiment 6 compounds | 3.0 |
| Embodiment 7 compounds | 4.2 |
| Embodiment 8 compounds | 3.8 |
As can be seen from the above table, compound of the present invention shows obvious restraining effect in platelet aggregation test.
Claims (5)
1. there is general formula
ithe compound of structure and pharmaceutically acceptable salt,
（I）
Wherein,
R is selected from the alkyl of C1-C5, the cycloalkyl of C3-C5, OR
1, R wherein
1be selected from the cycloalkyl of alkyl and the C3-C5 of C1-C5.
2. claim 1 is defined has the compound of general formula I and acceptable salt pharmaceutically thereof,
Wherein,
R is selected from alkyl, the OR of C1-C3
1, R wherein
1be selected from the alkyl of C1-C3.
3. the defined general formula of claim 2
icompound, is selected from following compounds,
。
4. the defined general formula of claim 3
icompound, is selected from following compounds,
。
5. the defined general formula of claim 1-4
icompound and the pharmaceutically acceptable salt purposes aspect preparation treatment antithrombotic reagent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410352081.1A CN104086498B (en) | 2014-07-23 | 2014-07-23 | Compound, the Preparation Method And The Use of the triazole schiff bases class formation that end replaces |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410352081.1A CN104086498B (en) | 2014-07-23 | 2014-07-23 | Compound, the Preparation Method And The Use of the triazole schiff bases class formation that end replaces |
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| Publication Number | Publication Date |
|---|---|
| CN104086498A true CN104086498A (en) | 2014-10-08 |
| CN104086498B CN104086498B (en) | 2015-11-18 |
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|---|---|---|---|
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| 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 |
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