CN104496931A - Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof - Google Patents
Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof Download PDFInfo
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- CN104496931A CN104496931A CN201510016277.8A CN201510016277A CN104496931A CN 104496931 A CN104496931 A CN 104496931A CN 201510016277 A CN201510016277 A CN 201510016277A CN 104496931 A CN104496931 A CN 104496931A
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- oxadiazole
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- substituted benzene
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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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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the field of medicines related with thrombotic diseases, in particular to PAR-1 antagonists which contain the amino substituted benzene and are of an oxadiazole sulfoxide structure, a preparation method thereof, medicine combinations containing the PAR-1 antagonists and applications of the PAR-1 antagonists in preparing medicines for treating thrombotic diseases. The formula is as follows, wherein the definition of R is as described in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to thrombus disease.Specifically, the present invention relates to PAR-1 antagonist of the isostructural oxadiazoles sulfoxide structure of the medicative class amino-contained substituted benzene of thrombotic diseases and preparation method thereof, and containing 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 amino-contained substituted benzene isostructural 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:
There is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R
1, R
2independently be selected from the alkyl of H, C1-C5, the cycloalkyl of C3-C6.
Preferably, R
1, R
2independently be selected from the alkyl of H, C1-C3.
Further, preferred following compounds,
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, R
1, R
2definition as previously mentioned.
The pharmacy acceptable salt of formula I of the present invention, 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.
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
2.21g (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=533 ([M+Na]
+).
The synthesis of B, I-1
2.55g (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 solid, MS, m/z=544 ([M+NH
4]
+).
Embodiment 2-3
According to the method for embodiment 1, synthesize the following compounds with general formula I.
Wherein, embodiment 4 is control compounds (being still the brand new that applicant finds), to absolutely prove pharmacological effect.
Embodiment 5 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 (I-1) | 6.8 |
| Embodiment 2 compound (I-2) | 12.1 |
| Embodiment 3 compound (I-3) | 10.3 |
| Embodiment 4 compound (comparative example) | 14.7 |
As can be seen from the above table, compound of the present invention all shows good restraining effect, particularly I-1 in platelet aggregation test.
Claims (5)
1. there is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R
1, R
2independently be selected from the alkyl of H, C1-C5, the cycloalkyl of C3-C6.
2. the compound of claim general formula I and pharmaceutically acceptable salt thereof,
Wherein, R
1, R
2independently be selected from the alkyl of H, C1-C3.
3. the compound of Formula I that defines of claim 1, is selected from following compounds,
4. synthesize the method for the compound of arbitrary the defined general formula I of claim 1-3:
Compound II per and compound III are reacted in the presence of a base, obtain compound IV; Compound IV oxidation obtains Compound I, R
1, R
2definition as arbitrary in claim 1-3 as described in.
5. the compound of Formula I that defines of claim 1-3 and the pharmaceutically application of acceptable salt in preparation treatment thrombotic medicine thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016277.8A CN104496931A (en) | 2015-01-13 | 2015-01-13 | Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016277.8A CN104496931A (en) | 2015-01-13 | 2015-01-13 | Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof |
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|---|---|
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2380190A (en) * | 2001-08-28 | 2003-04-02 | Bayer Ag | Antiinflammatory heterocyclic sulphones |
| CN104086501A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist |
| CN104098520A (en) * | 2014-07-23 | 2014-10-15 | 张远强 | Phenyl triazole schiff base compound as well as preparation method and application thereof |
-
2015
- 2015-01-13 CN CN201510016277.8A patent/CN104496931A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2380190A (en) * | 2001-08-28 | 2003-04-02 | Bayer Ag | Antiinflammatory heterocyclic sulphones |
| CN104086501A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist |
| CN104098520A (en) * | 2014-07-23 | 2014-10-15 | 张远强 | Phenyl triazole schiff base compound as well as preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| 任玉杰等: "新型抗凝血药合成及应用研究", 《上海应用技术学院学报（自然科学版）》 * |
| 张志明: "作为潜在免疫抑制剂的2,5 - 二取代-1 , 3 , 4 -噁二唑衍生物的合成与活性筛选", 《中国优秀硕士学位论文医药卫生科技辑》 * |
| 邓华波等: "1，3，4-噁二唑硫醚及（亚）砜类化合物的生物活性研究进展", 《精细化工中间体》 * |
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Application publication date: 20150408 |