CN104086496B - A kind of antithrombotic compound, Preparation Method And The Use - Google Patents

A kind of antithrombotic compound, Preparation Method And The Use Download PDF

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CN104086496B
CN104086496B CN201410352063.3A CN201410352063A CN104086496B CN 104086496 B CN104086496 B CN 104086496B CN 201410352063 A CN201410352063 A CN 201410352063A CN 104086496 B CN104086496 B CN 104086496B
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preparation
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par
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CN104086496A (en
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张远强
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Co Ltd Of Jining Huaneng Pharmaceutical Factory
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/101,2,4-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
    • C07D249/12Oxygen or sulfur atoms

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  • 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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to medical art, relate to a kind of PAR-1 antagonist of formula I structure, its preparation method and containing their pharmaceutical composition and their purposes in preparation treatment thrombotic diseases medicine.

Description

A kind of antithrombotic compound, Preparation Method And The Use
Technical field
The invention belongs to medical art.In particular to a kind of PAR-1 antagonist of new texture, its preparation method and containing their pharmaceutical composition and their purposes in preparation treatment thrombotic diseases medicine.
Background technology
Proteinase activated receptors 1 (Protease Activated Acceptor-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 (Acute Coronary Syndrome).Several PAR-1 inhibitor has been had to be 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 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 a kind of new triazole Schiff bases PAR-1 antagonist, 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 compound and pharmaceutically acceptable salt.
Another object of the present invention be to provide a kind of there is good anti-thrombosis activity compound and the method for pharmaceutically acceptable salt, 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 formula I has following structural formula:
I
The method of synthesis above-claimed cpd is:
Compound iIand compound iIIacid or alkali catalysis under react, obtain schiff bases iV; iVwith vbe obtained by reacting compound in the presence of a base i.
Formula of the present invention ithe pharmacy acceptable salt of compound, 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.
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.The activity of formula I of the present invention is verified by external model.
Formula I of the present invention is effective in quite wide dosage range.The dosage taken such as every day, within the scope of 1 mg-500 mg/ people, is divided into once or administration for several times.The actual dosage taking formula I 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
Reaction raw materials: self-control, ordinary method.
1.80 g (10 mmol) Compound II per and 1.92g (10 mmol) compound III are dissolved in 20 mL Glacial acetic acid, and temperature rising reflux spends the night.After reaction mixture is slightly cold, pour in 200 mL frozen water, stir, collected by suction solid, recrystallization from dehydrated alcohol, ambient temperature in vacuum is dry, obtains product IV, white crystal.MS, m/z = 293([M+H]+)。
1.47 g (5 mmol) compound IV, 1.85 g (5 mmol) compound V and 2.07 g (15 mmol) solid carbonic acid potassium stir and spend the night in 15 mL acetonitriles, then temperature rising reflux 3 hours.Be poured in 200 mL frozen water after reaction mixture is slightly cold, stir, regulate pH=4 with concentrated hydrochloric acid, the dichloromethane extraction of 50 mL × 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 I, white solid, MS, m/z=611 ([M+NH4]+).
control compounds and preparation thereof
for further illustrating the pharmacological action of comparing the compounds of this invention, the present invention, with reference to the method for embodiment 1, has prepared following formula: compound
Concrete preparation method is as follows:
1.94g (10 mmol) Compound II per and 1.92g (10 mmol) compound III are dissolved in 20 mL Glacial acetic acid, and temperature rising reflux spends the night.After reaction mixture is slightly cold, pour in 200 mL frozen water, stir, collected by suction solid, recrystallization from dehydrated alcohol, ambient temperature in vacuum is dry, obtains product IV, white crystal.MS, m/z = 307([M+H]+)。
1.53g (5 mmol) compound IV, 1.85 g (5 mmol) compound V and 2.07 g (15 mmol) solid carbonic acid potassium stir and spend the night in 15 mL acetonitriles, then temperature rising reflux 3 hours.Be poured in 200 mL frozen water after reaction mixture is slightly cold, stir, regulate pH=4 with concentrated hydrochloric acid, the dichloromethane extraction of 50 mL × 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 I, white-yellowish solid, MS, m/z=675 ([M+NH4]+).
embodiment 2 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, then the blood of suction 20 mL healthy volunteer, 1500 in syringe glower centrifugal 20 minutes, separate being rich in hematoblastic blood plasma (PRP) and processing with the amount of 1 μ L PGE1 solution (ethanolic solns of 500 μ g/mL)/mL PRP.After at room temperature hatching 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 in batches, and centrifugally under 3600 g make pellet platelets.Then, drain upper plasma, the pellet platelets deriving from 5 mL PRP is suspended in again 1 mL Tyrode (120 mM NaCl, 2.6 mM KCl, 12 mM NaHCO3,0.39 mM NaH2PO4,10 mM HEPES, 0.35% BSA, 5.5 mM glucose, pH=7.4) in, and the platelet count of 3 × 105/ μ L is adjusted to Tyrode.By the 10 mM CaCl2 solution-treated of this cell suspension of 13 mL 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 L TRAP solution (70-100 μM) as agonist, vibrate 20 minutes under 37 ° of C in SpectraMax, kinetics is noted down under 650 nm, 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%.Compound I to be tested aspirated with the form of dilution, measure in duplicate, measure the AUC of each material concentration, the AUC calculated compared with the control suppresses %.By suppressing % according to parametric equation and by nonlinear regression analysis, calculate IC50 value.Following table gives result:
As can be seen from the above table, Compound I of the present invention shows obvious platelet aggregation inhibitor effect.

Claims (3)

1. formula I and pharmaceutically acceptable salt,
2. synthesize the method for compound described in claim 1:
Compound II per and compound III are reacted under the catalysis of acid or alkali, obtain schiff bases IV; IV and V is obtained by reacting Compound I in the presence of a base.
3. compound described in claim 1 and the pharmaceutically purposes of acceptable salt in preparation treatment antithrombotic reagent.
CN201410352063.3A 2014-07-23 2014-07-23 A kind of antithrombotic compound, Preparation Method And The Use Active CN104086496B (en)

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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

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6518254B1 (en) * 2002-04-11 2003-02-11 Henry Joseph Niemczyk Ribonucleoside-TRIBOSE
CN101747322A (en) * 2010-01-20 2010-06-23 贵州大学 Pyridazinone derivatives with 1,2,4-triazole schiff base, preparation method and application thereof
CN102329273A (en) * 2011-07-15 2012-01-25 中国科学院海洋研究所 Schiff base containing nitrogenous heterocyclic compound and preparation method and application thereof
CN103739594A (en) * 2012-10-17 2014-04-23 南京大学 Schiff base derivatives containing pyrazine ring and triazole structure and preparation method of the derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6518254B1 (en) * 2002-04-11 2003-02-11 Henry Joseph Niemczyk Ribonucleoside-TRIBOSE
CN101747322A (en) * 2010-01-20 2010-06-23 贵州大学 Pyridazinone derivatives with 1,2,4-triazole schiff base, preparation method and application thereof
CN102329273A (en) * 2011-07-15 2012-01-25 中国科学院海洋研究所 Schiff base containing nitrogenous heterocyclic compound and preparation method and application thereof
CN103739594A (en) * 2012-10-17 2014-04-23 南京大学 Schiff base derivatives containing pyrazine ring and triazole structure and preparation method of the derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Synthesis, spectral characterization, in vitro antibacterial, antifungal and cytotoxic activities of Co (II), Ni (II) and Cu (II) complexes with 1, 2, 4-triazole Schiff bases;Bagihalli G B, Avaji P G, Patil S A, et al.;《European journal of medicinal chemistry》;20080229;第43卷(第12期);2639-2649 *
Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects;Chackalamannil S.;《Journal of medicinal chemistry》;20060831;第49卷(第18期);5389-5403 *

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