CN104356094B - Trans cvclohexvl alkyl amide compound, its preparation method and in purposes pharmaceutically - Google Patents
Trans cvclohexvl alkyl amide compound, its preparation method and in purposes pharmaceutically Download PDFInfo
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- CN104356094B CN104356094B CN201410635539.4A CN201410635539A CN104356094B CN 104356094 B CN104356094 B CN 104356094B CN 201410635539 A CN201410635539 A CN 201410635539A CN 104356094 B CN104356094 B CN 104356094B
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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 present invention relates to the drug world relevant to thrombotic disease.Specifically, the present invention relates to the class PAR-1 antagonist containing trans cyclohexane amide structure, its preparation method and their application in preparation treatment thrombotic disease medicine.R is selected from C3-C8Cycloalkyl.
Description
Technical field
The present invention relates to the drug world relevant to thrombus disease.Specifically, the present invention relates to PAR-1 antagonist containing trans cyclohexane amide structure of the medicative class of thrombotic disease and preparation method thereof, containing they pharmaceutical composition and in purposes pharmaceutically.
Background technology
Proteinase activated receptors 1 (ProteaseActivatedAcceptor-1, PAR-1) is the novel targets of recently discovered antiplatelet class antithrombotic reagent.Proteinase activated receptors 1 is again thrombin receptor, and thrombin passes through PAR-1 receptor acting in platelet thus activating platelet after being activated by coagulation cascade, causes platelet aggregation thus causing thrombosis and blood coagulation.Rich in platelet component in the thrombosis that PAR-1 causes, it it is the main reason of arterial thrombus.PAR-1 antagonist can block thrombin activation platelet, thus interruption artery thrombosis, it is possible to it is used for treating acute coronary artery disease (AcuteCoronarySyndrome).Several PAR-1 inhibitor has been had to be in clinical research (ChackalamannilS., ThrombinReceptor (ProteaseActivatedReceptor-1) AntagonistsasPotentAntithromboticAgentswithStrongAntipla teletEffects, J.Med.Chem., 2006,49 (18), 5389-5403).
The medicine being traditionally used for preventing and treating thrombotic disease is divided three classes.The first kind is anticoagulation class, it is divided into direct thrombin inhibitor and indirect thrombin inhibitor, such medicine carrys out inhibition thrombosis by acting on the different links of coagulation cascade, has the various thrombotic effects of suppression, such as vitamin K antagon and Xa factor inhibitor etc.；Equations of The Second Kind is antiplatelet class, and such 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, be mainly used in lysed blood formed fibrin.
Mostly antiplatelet drug is traditional arterial thrombus protective agents, such as clopidogrel and aspirin etc..The shortcoming of these medicines is that bleeding risk is relatively 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 class PAR-1 antagonist containing trans cyclohexane amide structure, they may be used for preparing the medicine of anti-arterial thrombus disease.
Summary of the invention
It is an object of the present invention to provide a kind of compound with formula I with good anti-thrombosis activity and pharmaceutically acceptable salt thereof.
It is a further object to provide preparation and there is the compound of formula I and the method for pharmaceutically acceptable salt thereof.
It is also another object of the present invention to provide the compound containing formula I and pharmaceutically acceptable salt as effective ingredient, and the Pharmaceutical composition of one or more pharmaceutically acceptable carriers, excipient or diluent, and the application in treatment arterial thrombus.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of formula I and has following structural formula:
Wherein, R is selected from C3-C8Cycloalkyl.
Further, R preferably is selected from cyclopropane base, cyclohexyl.
Further, it is preferable that there is the compound of formula I below,
Compound of Formula I of the present invention synthesizes by the following method:
Compound II per and Compound II per I reaction under condensing agent exists, obtains product I；Described condensing agent is selected from DCC (N, N '-dicyclohexyl carbodiimide), EDC (N-ethyl-N '-dimethylamino carbodiimides), CDI (carbonyl dimidazoles) etc..
The pharmaceutically acceptable salt of compound of formula I of the present invention, include, but are not limited to the salt formed with various mineral acid example hydrochloric acids, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid etc., also include the salt formed with various organic acid such as acetic acid, succinic acid, maleic acid, malic acid and each seed amino acid etc..
Compound of Formula I of the present invention has the antagonism of PAR-1, can as effective ingredient for preparing the medicine of antithrombotic aspect.The activity of compound of Formula I of the present invention is verified by external model.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or is administered for several times.The actual dosage taking compound of Formula I of the present invention can be determined according to relevant situation by doctor.These situations include: the condition of patient, route of administration, age, body weight, individual reaction to medicine, the order of severity etc. of symptom.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only for illustrating, and it is not intended to limit the present invention.Those skilled in the art all should within the protection domain required by the application claim according to the various changes that the teachings of the present invention is made.
The preparation of embodiment 1 compound I-1
In one 100mL round-bottomed flask, the THF that addition 1.84g (10mmol) Compound II per, 1.68g (10mmol) Compound II per I-1 and 20mL dry, gained mixture is stirring under ice-water bath cools down, after adding 2.48g (12mmol) DCC, continue at room temperature to stir overnight.TLC shows that reaction completes.
Reactant mixture pours in frozen water, stirring, with the dichloromethane extraction of 50mL × 3, merges extracted organic phase, using saturated common salt water washing, anhydrous sodium sulfate dries, and boils off solvent on a rotary evaporator, the residue column chromatography purification obtained, obtains product I-1, white solid.ESI-MS, m/z=335 ([M+H]+)。
The preparation of embodiment 2 compound I-2
In one 100mL round-bottomed flask, the THF that addition 1.84g (10mmol) Compound II per, 1.26g (10mmol) Compound II per I-2 and 20mL dry, gained mixture is stirring under ice-water bath cools down, after adding 2.48g (12mmol) DCC, continue at room temperature to stir overnight.TLC shows that reaction completes.
Reactant mixture pours in frozen water, stirring, with the dichloromethane extraction of 50mL × 3, merges extracted organic phase, using saturated common salt water washing, anhydrous sodium sulfate dries, and boils off solvent on a rotary evaporator, the residue column chromatography purification obtained, obtains product I-2, white solid.ESI-MS, m/z=293 ([M+H]+)。
Embodiment 3 extracorporeal platelet aggregation inhibition test
In 96 orifice plates, concentrate the pharmacology test carrying out material at TRAP (Glycoprotein) platelet aggregation induced.Syringe is previously added the sodium citrate solution of 3.13%, then the blood of suction 20mL healthy volunteer, it is centrifuged 20 minutes under 1500g, will be enriched in hematoblastic blood plasma (PRP) and separate and process with the amount of 1 μ LPGE1 solution (alcoholic solution of 500 μ g/mL)/mLPRP.After at room temperature hatching 5 minutes, it is centrifuged under 1200g 20 minutes to remove leukocyte.PRP without leukocyte is transferred to 5mL/ part in the PP pipe of 15mL in batches, and centrifugal under 3600g make pellet platelets.Then, drain upper plasma, the pellet platelets deriving from 5mLPRP is suspended in 1mLTyrode (120mMNaCl, 2.6mMKCl, 12mMNaHCO again3, 0.39mMNaH2PO4, 10mMHEPES, 0.35%BSA, 5.5mM glucose, pH=7.4) in, and regulate the platelet count to 3 × 105/ μ L with Tyrode.By this for the 13mL cell suspension 10mMCaCl with 866 μ L2Solution-treated, is drawn in 96 orifice plates with the amount of every hole 120 μ L, has added 15 μ L materials to be tested in the hole of 96 orifice plates in advance.At room temperature dark is hatched 30 minutes, add 15 μ LTRAP solution (70-100 μM) as agonist, SpectraMax vibrates 20 minutes at 37 DEG C, 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%.Compound to be tested is aspirated with the form of serial dilution thing, is measured in duplicate, the same AUC measuring each material concentration, calculate AUC compared with the control and suppress %.IC is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %50Value.Following table gives result.
| Compound | The suppression IC of platelet aggregation50(μM) |
| Compound I-1 | 3.8 |
| Compound I-2 | 7.1 |
As can be seen from the above table, the compound of the present invention all shows inhibitory action in platelet aggregation test, and for drug effect, compound I-1 is better than I-2.
Claims (4)
1. there is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R is selected from cyclopropane base, cyclohexyl.
2. the compound of Formula I that claim 1 is defined, is selected from,
3. the method for the compound of Formula I that synthesis any one of claim 1-2 is defined:
Compound II per and Compound II per I reaction under condensing agent exists, obtains product I；Described condensing agent is selected from N, N '-dicyclohexyl carbodiimide, N-ethyl-N '-dimethylamino carbodiimides, carbonyl dimidazoles, described in the definition of R such as claim 1,2.
4. any one of claim 1-2 is defined compound of Formula I and the pharmaceutically acceptable salt purposes in preparation treatment thrombotic medicine.
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| CN201410635539.4A CN104356094B (en) | 2014-11-02 | 2014-11-02 | Trans cvclohexvl alkyl amide compound, its preparation method and in purposes pharmaceutically |
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| CN201410635539.4A CN104356094B (en) | 2014-11-02 | 2014-11-02 | Trans cvclohexvl alkyl amide compound, its preparation method and in purposes pharmaceutically |
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| CN104356094A CN104356094A (en) | 2015-02-18 |
| CN104356094B true CN104356094B (en) | 2016-06-29 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE69835430T2 (en) * | 1997-05-30 | 2007-03-08 | Takeda Pharmaceutical Co. Ltd. | Sulphonamide derivatives, their preparation and their use |
| WO2006057868A1 (en) * | 2004-11-29 | 2006-06-01 | Eli Lilly And Company | Antithrombotic diamides |
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