CN104072432A - Compound containing phenyl substituted triazole schiff base structure, as well as preparation method and application thereof - Google Patents

Compound containing phenyl substituted triazole schiff base structure, as well as preparation method and application thereof Download PDF

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Publication number
CN104072432A
CN104072432A CN201410352128.4A CN201410352128A CN104072432A CN 104072432 A CN104072432 A CN 104072432A CN 201410352128 A CN201410352128 A CN 201410352128A CN 104072432 A CN104072432 A CN 104072432A
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compound
preparation
schiff base
general formula
application
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CN104072432B (en
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张远强
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Ma Yasu
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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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the field of drugs related to thrombotic diseases, belongs to the triazole schiff base compound of a kind of brand new skeleton, and a derivative thereof, and particularly relates to a kind of PAR-1 antagonist containing a phenyl substituted triazole schiff base structure, the preparation method thereof, drug compounds adopting the same, and the application thereof during the preparation of drugs for treating the thrombotic diseases. The structure of the component is shown in the Specification, and definitions of various substitutes are described in the Specification.

Description

Containing compound, the Preparation Method And The Use of phenyl substituted triazole schiff bases class formation
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 structure that the medicative class of thrombotic diseases is replaced containing phenyl 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 of a class containing the triazole schiff bases structure of phenyl 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 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 1be selected from alkyl, the cycloalkyl of C3-C5, the halogenic substituent of H, C1-C5.
The compound of general formula I and pharmaceutically acceptable salt, preferably certainly:
R 1be selected from alkyl, F, Cl, the Br of H, 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 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.
1.06 g (10 mmol) compound iIand 1.92g (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 = 295 ([M+H] +)。
1.48 g (5 mmol) compound iV-1, 1.85 g (5 mmol) compound vin 15 mL acetonitriles, stir and spend the night, then temperature rising reflux 3 hours with 2.07 g (15 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=583 ([M+NH 4] +).
embodiment 2-7
With reference to the method for embodiment 1, can synthesize and there is general formula ifollowing compounds:
embodiment 8 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 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, R1 is selected from alkyl, the cycloalkyl of C3-C5, the halogenic substituent of H, C1-C5.
2. claim 1 is defined has the compound of general formula I and acceptable salt pharmaceutically thereof,
Wherein, R1 is selected from alkyl, F, Cl, the Br of H, C1-C3.
3. the defined general formula of claim 2 icompound, is selected from following compounds:
4. compound described in claim 3, is selected from:
5. the defined general formula of claim 1-4 icompound and the pharmaceutically acceptable salt purposes aspect preparation treatment antithrombotic reagent.
CN201410352128.4A 2014-07-23 2014-07-23 Containing compound, the Preparation Method And The Use of phenyl substituted triazole schiff bases class formation Expired - Fee Related CN104072432B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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
CN102442965A (en) * 2010-09-30 2012-05-09 天津药物研究院 PAR-1 antagonists for the treatment of thrombotic disorders, process for their preparation and their use
CN103613553A (en) * 2013-12-09 2014-03-05 兴义民族师范学院 S-triazole Schiff base bisamide derivative as well as preparation method and usage thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
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
CN102442965A (en) * 2010-09-30 2012-05-09 天津药物研究院 PAR-1 antagonists for the treatment of thrombotic disorders, process for their preparation and their use
CN103613553A (en) * 2013-12-09 2014-03-05 兴义民族师范学院 S-triazole Schiff base bisamide derivative as well as preparation method and usage thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SAMUEL CHACKALAMANNIL: "Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
杨清翠等: "3-甲基-4-氨基-5-乙氧羰基甲硫基三唑席夫碱的合成及生物活性", 《化学通报》 *

Cited By (1)

* Cited by examiner, † Cited by third party
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

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