CN104072431B - The compound of the Phenyltriazole schiff bases structure that alkoxyl group replaces and purposes - Google Patents

The compound of the Phenyltriazole schiff bases structure that alkoxyl group replaces and purposes Download PDF

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Publication number
CN104072431B
CN104072431B CN201410352029.6A CN201410352029A CN104072431B CN 104072431 B CN104072431 B CN 104072431B CN 201410352029 A CN201410352029 A CN 201410352029A CN 104072431 B CN104072431 B CN 104072431B
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phenyltriazole
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schiff bases
par
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CN104072431A (en
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张远强
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Lu Jun
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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)

Abstract

The present invention relates to the pharmaceutical field relevant to thrombotic diseases.The invention belongs to triazole schiff base compounds and the derivative thereof of the brand-new skeleton of a class, the PAR-1 antagonist of Phenyltriazole schiff bases structure replaced in particular to a class end alkoxy group, its preparation method and containing their pharmaceutical composition and their purposes in preparation treatment thrombotic diseases medicine.

Description

Compound with alkoxy substituted phenyl triazole Schiff base structure and application
Technical Field
The invention relates to the field of medicines related to thrombotic diseases. The invention belongs to triazole Schiff base compounds with a brand-new framework and derivatives thereof, and particularly relates to PAR-1 antagonists with a terminal alkoxy substituted phenyl triazole Schiff base structure, a preparation method thereof and a pharmaceutical composition containing the same, wherein the PAR-1 antagonists have a therapeutic effect on thrombotic diseases.
Background
The protease activated receptor 1 (ProteaActivatedAcceptor-1, PAR-1) is a new target of the recently discovered anti-platelet antithrombotic drugs. The protease activated receptor 1 is called thrombin receptor, and after thrombin is activated by the coagulation chain, the thrombin acts on platelets through a PAR-1 receptor to activate the platelets, so that the platelets are aggregated to cause thrombosis and coagulation. The thrombus caused by PAR-1 is rich in platelet components and is the main cause of arterial thrombosis. PAR-1 antagonists block the activation of platelets by thrombin and thus block arterial thrombosis and can be used for the treatment of acute coronary artery disease (AcutesoronarySyndrome). Several PAR-1 inhibitors have been in clinical study (Chackalamannil S., Thrombin Receptor (ProteaActivatedReceptor-1) AntagonisstsA ScientticoagentswithStrongAntiemplateEffects,J.Med.Chem.,2006,49(18),5389-5403)。
the traditional medicines for preventing and treating thrombotic diseases are divided into three categories. The first class is the anticoagulant class, which is divided into direct thrombin inhibitors and indirect thrombin inhibitors, the drugs inhibit thrombosis by acting on different links of the coagulation linkage, and have the effect of inhibiting various thrombosis, such as vitamin K antagonists, Xa factor inhibitors and the like; the second category is anti-platelet, such as COX-1 inhibitor, ADP receptor antagonist and the like, and the drugs are mainly used for preventing and treating arterial thrombosis; the third type is a fibrinolytic agent, which is mainly used to dissolve fibrin formed in blood.
Most antiplatelet drugs are traditional arterial thrombosis prevention drugs, such as clopidogrel, aspirin and the like. The disadvantage of these drugs is the relatively high risk of bleeding. PAR-1 antagonists, which are newly discovered antiplatelet antithrombotic agents, have smaller bleeding risks, so the compounds can be used as promising drugs for treating arterial thrombosis.
The invention discloses a PAR-1 antagonist with a terminal alkoxy substituted phenyl triazole Schiff base structure, which can be used for preparing medicines for resisting arterial thrombosis diseases.
Disclosure of Invention
It is an object of the present invention to provide a compound of formula (I) having good antithrombotic activityIAnd pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a process for the preparation of a compound of the formulaIAnd pharmaceutically acceptable salts thereof.
It is a further object of the present invention to provide a composition comprisingIThe compound and the pharmaceutically acceptable salt thereof as effective components, and one or more pharmaceutically acceptable carriers, excipients or diluents, and application thereof in treating arterial thrombosis.
The present disclosure will now be described in detail for the purpose of the invention.
The compounds of the present invention having the general formula I have the following structural formula:
(I)
wherein,
R1selected from: H. a halogen substituent;
R2selected from: C1-C5 alkyl and C3-C5 cycloalkyl.
Compounds of formula I and pharmaceutically acceptable salts thereof, are preferably selected from:
wherein,
R1selected from: H. f, Cl and Br substituents;
R2selected from: C1-C3 alkyl.
Preferably the following has the general formulaIThe compound of (a) to (b),
further, the following compounds having the general formula (III)IThe compound of (a) to (b),
the general formula of the inventionIThe compound was synthesized by the following steps:
compound (I)IIAnd compoundsIIIReacting under the catalysis of acid or alkali to obtain Schiff baseIVIVAndVreacting in the presence of a base to obtain a compoundI
The invention is of the formulaIPharmaceutically acceptable salts of the compounds include, but are not limited to, salts with various inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and the like, and also salts with various organic acids such as acetic acid, succinic acid, maleic acid, malic acid, and various amino acids, and the like.
The general formula of the inventionIThe compound has PAR-1 antagonistic effect, and can be used as effective component for preparing antithrombotic therapeutic medicine. The general formula of the inventionIThe activity of the compounds was verified by in vitro models.
The general formula of the inventionIThe compounds are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 1mg to 500mg per person, divided into one or more administrations. Practical administration of the inventionIThe dosage of the compound can be determined by a physician in the light of the relevant circumstances. These include: the physical state of the subject, the route of administration, the age, body weight, individual response to the drug, severity of the symptoms, and the like.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
Example 1
Reaction raw materials: self-made and conventional method.
1.36g (10mmol) of the CompoundII-1And 2.10g (10mmol) of the compoundIII-1Dissolved in 20mL of glacial acetic acid and refluxed at elevated temperature overnight. After the reaction mixture was slightly cooled, it was poured into 200mL of ice water, stirred, suction filtered to collect the solid, recrystallized from absolute ethanol, and vacuum dried at room temperature to give the productIV-1White crystals. The MS is a Mobile Station (MS),m/z=329([M+H]+)。
1.65g (5mmol) of the CompoundIV-11.85g (5mmol) of the compoundVAnd 2.07g (15mmol) of solid potassium carbonate in 15mL acetonitrile were stirred overnight, followed by heating and refluxing for 3 hours. Pouring the reaction mixture into 200mL of ice water after slightly cooling, stirring, adjusting the pH to =4 with concentrated hydrochloric acid, extracting with 50mL of x 3 dichloromethane, combining the organic phases, washing with brine, drying over anhydrous sodium sulfate, evaporating the solvent on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure productI-1The white solid, MS,m/z=635([M+NH4]+)。
examples 2 to 8
With reference to the procedure of example 1, a compound having the general formulaIThe following compounds of (a):
example 9 in vitro platelet aggregation inhibition assay
Pharmacological testing of the substances was performed in 96-well plates, with TRAP (thrombin receptor activating peptide) -induced platelet aggregation. The syringe was primed with a 3.13% sodium citrate solution and then 20mL of blood was drawn from healthy volunteers at 1500gPlatelet Rich Plasma (PRP) was separated by centrifugation for 20 minutes and treated with 1. mu.L of LPGE1 solution (500. mu.g/mL of ethanol solution)/mLPRP. After 5 min incubation at room temperature, it was centrifuged at 1200g for 20 min to remove leukocytes. PRP without leukocytes was transferred in 5mL portions to 15mL PP tubes and pelleted by centrifugation at 3600 g. Then, the upper plasma was decanted, and the platelet pellet from 5 mlprep was resuspended in 1mLTyrode (120mMNaCl, 2.6mMKCl, 12mMNaHCO3, 0.39mMNaH2PO4, 10 mhepes, 0.35% BSA, 5.5mM glucose, pH =7.4) and adjusted to a platelet count of 3 × 105/μ L with Tyrode. 13mL of this cell suspension are treated with 866. mu.l of a 10mM CaCl2 solution and pipetted into a 96-well plate in an amount of 120. mu.l per well, into whose wells 15. mu.l of the test substance have been added beforehand. Incubate in the dark at room temperature for 30 min, add 15 μ LTRAP solution (70-100 μ M) as agonist, shake at 37 ℃ for 20 min in SpectraMax, record kinetics at 650nm, calculate the area under the curve for negative control (tyrode/DMSO) and positive control (15 μ L agonist/DMSO), and set the difference to 100%. Compounds to be tested were pipetted as serial dilutions and assayed in duplicate, the AUC for each substance concentration was also determined and% AUC inhibition compared to control was calculated. The IC50 values were calculated from the% inhibition by means of non-linear regression analysis according to the 4-parameter equation. The following table gives the results:
as can be seen from the above table, the compounds of the present invention showed significant inhibition in the platelet aggregation assay.

Claims (5)

1. A compound with a structure shown in a general formula I and pharmaceutically acceptable salts thereof,
wherein,
R1selected from: H. a halogen substituent;
R2selected from: C1-C5 alkyl.
2. A compound of formula I as defined in claim 1,
wherein,
R1selected from: H. f, Cl and Br substituents;
R2selected from: C1-C3 alkyl.
3. A compound of the general formula I as defined in claim 2, selected from the group consisting of,
4. a compound of the general formula I as defined in claim 3, selected from the group consisting of,
5. use of a compound of general formula I as defined in claims 1 to 4 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of antithrombotic diseases.
CN201410352029.6A 2014-07-23 2014-07-23 The compound of the Phenyltriazole schiff bases structure that alkoxyl group replaces and purposes Expired - Fee Related CN104072431B (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 (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102442965A (en) * 2010-09-30 2012-05-09 天津药物研究院 PAR-1 (protease-activated receptor-1) antagonists for treating thrombotic diseases, as well as preparation and application thereof
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

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ES2239806T3 (en) * 1997-06-19 2005-10-01 Bristol-Myers Squibb Pharma Company XA FACTOR INHIBITORS WITH A P1 NEUTRAL SPECIFICITY GROUP.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102442965A (en) * 2010-09-30 2012-05-09 天津药物研究院 PAR-1 (protease-activated receptor-1) antagonists for treating thrombotic diseases, as well as preparation and application thereof
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
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;杨清翠等;《化学通报》;20131231;第76卷(第8期);第758-761页 *
Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects;Samuel Chackalamannil;《Journal of Medicinal Chemistry》;20060907;第49卷(第18期);第5389-5403页 *

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