CN104529928A - One category of oxadiazole sulfoxide compounds, and preparation method and application thereof - Google Patents
One category of oxadiazole sulfoxide compounds, and preparation method and application thereof Download PDFInfo
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- CN104529928A CN104529928A CN201510016160.XA CN201510016160A CN104529928A CN 104529928 A CN104529928 A CN 104529928A CN 201510016160 A CN201510016160 A CN 201510016160A CN 104529928 A CN104529928 A CN 104529928A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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Abstract
The invention relates to the field of drugs associated with thrombotic diseases, in particular to a category of PAR-1 antagonists comprising structures such as nitrobenzene, a preparation method of the PAR-1 antagonists, and application of drug combinations comprising the nitrobenzene and the nitrobenzene in preparation of the drugs for treating the thrombotic diseases. Please see the formula in the specification, wherein R is selected from -NO2.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to thrombus disease.Specifically, the present invention relates to the PAR-1 antagonist medicative class of thrombotic diseases being contained to oxadiazoles sulfoxide structure and preparation method thereof, and contain their pharmaceutical composition.
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 the PAR-1 antagonist of a class containing oxadiazoles sulfoxide structure, 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 the compound with general formula I and pharmaceutically acceptable salt.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmaceutically acceptable salt thereof.
Another object of the present invention be to provide compound containing general formula I and pharmaceutically acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, 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 general formula I has following structural formula:
Wherein, R is selected from the alkyl of H, C1-C5, the cycloalkyl of C3-C6.
Preferably, R is selected from the alkyl of H, C1-C3, the cycloalkyl of C3-C5.
The preferably following compound with general formula I,
Further, the preferably following compound with general formula I,
Compound of Formula I of the present invention is synthesized by following steps:
Compound II per and compound III are reacted in the presence of a base, obtain compound IV; Compound IV oxidation obtains Compound I, and the definition of R as previously mentioned.
Compound of Formula I of the present invention 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 compound of Formula I of the present invention is verified by external model.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention 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
The synthesis of A, IV-1
1.92g (10mmol) Compound II per-1,3.70g (10mmol) compound III and 4.15g (30mmol) solid carbonic acid potassium stir and spend the night in 20mL ethanol.Reaction mixture is poured in 200mL frozen water, stirs, regulates pH=4 with concentrated hydrochloric acid, the dichloromethane extraction of 50mL × 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 IV-1, white solid, MS, m/z=504 ([M+Na]
+).
The synthesis of B, I-1
2.41g (5mmol) compound IV-1 is dissolved in 25mL methylene dichloride, stirs, slowly add 3.13g (20mmol) metachloroperbenzoic acid (mCPBA) at-10 DEG C.After reaction mixture stirs 1 hour at such a temperature, continue stirring under room temperature and spend the night.Reaction mixture is poured in 200mL frozen water, stirs, the dichloromethane extraction of 50mL × 3, merges organic phase, successively uses 3%NaHCO
3solution and brine It, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, and the resistates obtained, through column chromatography purification, obtains sterling I-1, white-yellowish solid, MS, m/z=515 ([M+NH
4]
+).
Embodiment 2-7
According to the method for embodiment 1, synthesize the following compounds with general formula I.
Embodiment 8 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 in syringe, then the blood of suction 20mL healthy volunteer, under 1500g 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 1200g centrifugal 20 minutes with except leucocyte-removing.To not transfer in the PP pipe of 15mL with 5mL/ part containing leukocytic PRP in batches, and centrifugally under 3600g make pellet platelets.Then, drain upper plasma, the pellet platelets deriving from 5mL PRP is suspended in again 1mL Tyrode (120mM NaCl, 2.6mM KCl, 12mM NaHCO3,0.39mM NaH2PO4,10mMHEPES, 0.35%BSA, 5.5mM glucose, pH=7.4) in, and the platelet count of 3 × 105/ μ L is adjusted to Tyrode.By the 10mM CaCl2 solution-treated of this for 13mL cell suspension 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 at 37 DEG C in SpectraMax, kinetics is noted down under 650nm, 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%.Aspirated with the form of serial dilution thing by compound to be tested, measure in duplicate, the same AUC measuring each material concentration, the AUC calculated compared with the control suppresses %.IC50 value is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %.Following table gives result.
| Compound | The suppression IC of platelet aggregation 50(nM) |
| Embodiment 1 compound | 4.8 |
| Embodiment 2 compound | 14.7 |
| Embodiment 3 compound | 6.1 |
| Embodiment 4 compound | 22.5 |
| Embodiment 5 compound | 18.3 |
| Embodiment 6 compound | 11.9 |
| Embodiment 7 compound | 13.0 |
As can be seen from the above table, compound of the present invention all shows good restraining effect in platelet aggregation test.
Claims (6)
1. there is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R is selected from the alkyl of H, C1-C5, the cycloalkyl of C3-C6.
2. the compound with general formula I that claim 1 defines and pharmaceutically acceptable salt,
R is selected from the alkyl of H, C1-C3, the cycloalkyl of C3-C5.
3. the compound of Formula I that defines of claim 2, is selected from following compounds,
4. the compound of Formula I that defines of claim 3, is selected from following compounds,
5. synthesize the method for the compound of arbitrary the defined general formula I of claim 1-4:
Compound II per and compound III are reacted in the presence of a base, obtain compound IV; Compound IV oxidation obtains Compound I, as described in the definition of R is as arbitrary in claim 1-4.
6. the compound of Formula I that defines of claim 1-4 and the pharmaceutically application of acceptable salt in preparation treatment thrombotic medicine thereof.
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Application publication date: 20150422 |