CN104447624A - Nitrile group and phenyl group-containing trans-cyclohexane amide compound and application thereof - Google Patents
Nitrile group and phenyl group-containing trans-cyclohexane amide compound and application thereof Download PDFInfo
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- CN104447624A CN104447624A CN201410635567.6A CN201410635567A CN104447624A CN 104447624 A CN104447624 A CN 104447624A CN 201410635567 A CN201410635567 A CN 201410635567A CN 104447624 A CN104447624 A CN 104447624A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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Abstract
The invention belongs to the field of medicines associated with thrombotic diseases, and particularly relates to a nitrile group and phenyl group-containing PAR-1 (pretease activated receptor-1) antagonist and application of antagonist in preparation of medicines for treating thrombotic diseases, wherein the nitrile group and phenyl group-containing PAR-1 antagonist has a structure of a formula (I) as shown in the specification.
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 of the trans cyclohexane amide structure of the medicative a kind of nitrile group-containing phenyl of thrombotic diseases and the application 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 the PAR-1 antagonist of the trans cyclohexane amide structure of the nitrile group-containing phenyl of a kind of formula (I) structure,
It 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 compound containing trans cyclohexane amide structure and pharmaceutically acceptable salt thereof of formula (I) structure.
Another object of the present invention is to provide compound containing general formula I and the pharmaceutically application of acceptable salt in treatment arterial thrombus thereof.
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:
Formula I of the present invention is synthesized by the following method:
The method of preparation formula (I) compound is as follows:
Step is described as follows:
(1) Compound II per is converted into corresponding acyl chlorides II-C, and the reagent of use is selected from SOCl2, (COCl) 2, PCl5 and PCl3.
(2) II-C reacts with compound III in the presence of a base, obtains Compound I.
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.
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 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 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 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.
The preparation of embodiment 1 the compounds of this invention I
In a 100mL round-bottomed flask, add the SOCl that 1.84g (10mmol) Compound II per and 10mL heavily steam
2, then under agitation temperature rising reflux 3 hours.
Reaction mixture under reduced pressure steams excessive SOCl
2resistates II-C dissolves with the methylene dichloride of 20mL drying, gained mixture stirs under ice-water bath cooling, slowly drip the solution that the methylene dichloride that is dissolved in 5mL drying by 1.87g (10mmol) III and 3.04g (30mmol) triethylamine is made, continue at room temperature to stir to spend the night.TLC shows reaction to be completed.
Reaction mixture pours in frozen water, stirs, and with the dichloromethane extraction of 50mL × 3, merges extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, boil off solvent on a rotary evaporator, the resistates column chromatography purification obtained, obtains product I, white-yellowish solid.ESI-MS，m/z＝355([M+H]
+)。
The preparation of embodiment 2 control compounds I-2
For contrasting the drug effect of this compound further, this invention describes following formula control compounds I-2 (new compound, not yet open) and preparation method thereof and pharmacological datum:
Its preparation method is as follows:
In a 100mL round-bottomed flask, add the SOCl that 1.84g (10mmol) Compound II per and 10mL heavily steam
2, then under agitation temperature rising reflux 3 hours.
Reaction mixture under reduced pressure steams excessive SOCl
2resistates II-C dissolves with the methylene dichloride of 20mL drying, gained mixture stirs under ice-water bath cooling, slowly drip the solution that the methylene dichloride that is dissolved in 5mL drying by 2.07g (10mmol) III-2 and 3.04g (30mmol) triethylamine is made, continue at room temperature to stir to spend the night.TLC shows reaction to be completed.
Reaction mixture pours in frozen water, stirs, and with the dichloromethane extraction of 50mL × 3, merges extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, boil off solvent on a rotary evaporator, the resistates column chromatography purification obtained, obtains product I-2, white solid.ESI-MS，m/z＝375([M+H]
+)。
Embodiment 3 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 NaHCO
3, 0.39mM NaH
2pO
4, 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 CaCl of this for 13mL cell suspension with 866 μ L
2solution-treated, is 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 LTRAP 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 %.IC is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %
50value.Following table gives result.
As can be seen from the above table, compound of the present invention all shows restraining effect in platelet aggregation test, and with regard to drug effect, the compounds of this invention I is better than control compounds I-2.
Claims (2)
1. there is compound and the pharmaceutically acceptable salt thereof of formula I structure,
2. profit requires compound described in 1 and the pharmaceutically purposes of acceptable salt in preparation treatment thrombotic medicine thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635567.6A CN104447624B (en) | 2014-11-02 | 2014-11-02 | The trans cvclohexvl alkyl amide compound of nitrile group-containing phenyl and purposes |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635567.6A CN104447624B (en) | 2014-11-02 | 2014-11-02 | The trans cvclohexvl alkyl amide compound of nitrile group-containing phenyl and purposes |
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| Publication Number | Publication Date |
|---|---|
| CN104447624A true CN104447624A (en) | 2015-03-25 |
| CN104447624B CN104447624B (en) | 2016-08-17 |
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| CN201410635567.6A Expired - Fee Related CN104447624B (en) | 2014-11-02 | 2014-11-02 | The trans cvclohexvl alkyl amide compound of nitrile group-containing phenyl and purposes |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998054164A1 (en) * | 1997-05-30 | 1998-12-03 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
| WO2006057868A1 (en) * | 2004-11-29 | 2006-06-01 | Eli Lilly And Company | Antithrombotic diamides |
-
2014
- 2014-11-02 CN CN201410635567.6A patent/CN104447624B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998054164A1 (en) * | 1997-05-30 | 1998-12-03 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
| WO2006057868A1 (en) * | 2004-11-29 | 2006-06-01 | Eli Lilly And Company | Antithrombotic diamides |
Non-Patent Citations (2)
| Title |
|---|
| S. P. WEBSTER ET AL.: "Discovery and biological evaluation of adamantyl amide 11β-HSD1 inhibitors", 《BIOORG. MED. CHEM. LETT.》, vol. 17, 25 February 2007 (2007-02-25), pages 2838 - 2840 * |
| 王育才等: "《临床医师诊疗全书》", 31 January 1992, article "临床医师诊疗全书", pages: 550 * |
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| CN104447624B (en) | 2016-08-17 |
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