One class halogeno-benzene MENTHOL class P2Y12 receptor antagonist and application thereofTechnical field
The present invention relates to the drug world for the treatment of cardiovascular disease.In particular it relates to outstanding to cardiovascular diseaseIt is the P2Y12 receptor antagonists that thrombotic disease has MENTHOL structure of the medicative class containing halogeno-benzene structureAgent, its preparation method, and the purposes in pharmacy.
Background technology
The medical complication relevant with there are thrombosiss represents a kind of main cause of death.Some and development thrombosis shapeInclude that acute myocardial infarction, unstable angina pectoriss and chronic stable angina pectoris, transience lack into relevant pathology exampleBlood outbreak, cerebrovas-cularaccident, peripheral vascular disease, preeclampsia and eclamposia, dvt formed, thromboembolism (cerebral embolism,Pulmonary infarction, coronary thrombosiss, renal infarction etc.), disseminated inravascular coagulation or thrombotic thrombocytopenic purpura.InvadingStill there are the danger that thrombosiss and restenosiss complication occur, the invasive surgical operation during and after entering property surgical operationSuch as angioplasty, carotid endarterectomy, aorto-coronary bypass grafting or support or the peace of vascular endoprosthesesPut.
Artery thrombosis can occur after vascular damaged or atheromatous plaque rupture.Platelet is in these thrombosisNecessary effect is played in formation.Platelet can pass through following substance activating：In blood flow circulating cells or along blood vessel wall presentThe amboceptor that discharged of damaging endotheliocyte, or during blood vessel injury exposed sub-endothelial matrix (such as collagen) bloodBolt forms molecule.Additionally, platelet can also be observed such as in narrow blood vessel under the blood flow conditions with shearing forceAs activate.After activation, the circulation platelet adhesion is simultaneously accumulated at blood vessel injury, forms thrombosis.In this process, bloodProduced thrombosis are that volume is sufficiently large to blood flow in pipe, so that it is partially or completely blocked.
In vein, thrombosis can also slowly be located to be formed in obstruction or blood flow.Due to these venothrombotic properties, it can be producedThe embolus moved in vascular system.These emboluses thus the blood flow in more remote blood vessel can be blocked, the blood vessel such as lungTremulous pulse or coronary artery.
Verified 5'- adenosine diphosphate (ADP)s (ADP) are platelet activation and the principal mediator assembled for many researchs, in thrombosisPlay in the startup of formation and progress decisive role (Maffrand et al., Thromb.Haemostas., 1988,59,225-230).ADP is discharged in circulation by the endotheliocyte of the erythrocyte that damages and atherosclerosiss wall, it is more specific andSpeech, by secreted by the activation platelet with compacted grains in place of very high concentration stores ADP.The platelet aggregation of ADP- inductionsTriggered by it and in the combination of two species specificity purinergic receptor P2Y1 and P2Y12 of the endoglin expression of human blood platelets.InstituteP2Y1 receptors are stated, is stimulated with the PLC β of Jing G α q and combine, be responsible for mobilization, the change of platelet shape that internal calcium stores and in ADPOn moment aggregation.The P2Y12, the activation of suppression and PI-3 kinases with the adenyl cyclase of Jing G α i2 is combined, and is responsible forThe amplification of response and the stabilisation of aggregation.P2Y1-/- transgenic mice (Gachet et al., J.Clin.Invest., 1999,104,1731-1737) prove with using for P2Y12-/- mice (Conley et al., Nature, 2001,409,202-207)Described two receptors thrombosis developing importance in vivo.In the mankind, P2Y12 genetic flaws and bleeding table are had been described aboveType is relevant with the notable decline of the platelet aggregation that ADP- is induced.Human clinical practice used in clopidogrel it has been proved thatThe critical therapeutic strategy for the treatment of cardiovascular disease is represent by Antagonist block P2Y12 receptors.Clopidogrel is thienopyridineThe prodrug of family, its active metabolite is covalently bond to P2Y12 receptors, and cause internal biologically active pdgf can not retroactive inhibition(Savi et al., Biochem.Biophys.Res.Commun., 2001,283,379-383), the medicine is in some clinical examinationsMiddle its efficiency of display is tested, that is, reduces adventurous patient's generation cardiovascular unexpectedly dangerous.
The invention discloses the P2Y12 receptor antagonists of MENTHOL structure of the class containing halogeno-benzene structure, these chemical combinationThing can be used to prepare the medicine for the treatment of cardiovascular disease especially thrombotic disease.
The content of the invention
It is an object of the present invention to provide a kind of P2Y12 receptor antagonists of the excellent activity with formula I.
It is a further object to provide preparing the method with compounds of formula I.
It is also another object of the present invention to provide containing compounds of formula I as effective ingredient and its in treatment cardiovascularDisease application especially in terms of thrombotic disease.
Present invention is specifically described in conjunction with the purpose of the present invention.
The present invention has following structural formula with compounds of formula I：
Wherein, X is selected from halogenic substituent.
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention can be synthesized by following route：
In the presence of a base reacting by heating generates compound IV for compound II and compound III；Compound IV reducing agents are alsoOriginal obtains compound V；Compound V reacts in the presence of a base with chloracetyl chloride, obtains compound VI；Compound VI is in the presence of a baseWith sulfhydryl compound VII reactions, corresponding I is obtained；X is defined as described above.
Compound of Formula I of the present invention has the antagonism of P2Y12 receptors, can be used to prepare the heart as effective ingredientAngiopathy especially thrombotic disease medicine.The activity of compound of Formula I of the present invention is by external peopleThe inhibition test of blood platelet aggregation is verifying.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The dosage for example taken daily is aboutIn the range of 1mg-700mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking compound of Formula I of the present invention can be by curingTake root according to relevant situation for determining.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only forIllustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all shouldWithin the protection domain required by the application claim.
The synthesis of the compound I-1 of embodiment 1
The synthesis of step 1. compound IV
1.56g (10mmol) compound II is dissolved in 15mL DMF, the lower stirring of ice-water bath cooling, is dividedly in some parts 0.48g(12mmol, 60%) solid NaH are stirred 30 minutes under room temperature.1.86g (10mmol) 2,4- dinitro compound III are added, andStir 3 hours under room temperature afterwards, TLC shows that reaction is completed.Reactant mixture is carefully poured in 200mL frozen water, stirring, uses 50mL×3CH2Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is steamed in rotationSend out and be evaporated on instrument, residue uses silica gel column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=323 ([M+H]+)。
The synthesis of step 2. compound V
2.26g (7mmol) compound IV is dissolved in 20mL dehydrated alcohol, stirring, adds 0.1g 10%Pd/C, is then pressedCarry out being hydrogenated with normal temperature and pressure according to standard operation, complete after 12 hours.Reactant mixture is carefully poured in 200mL frozen water, is stirredMix, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, filterLiquid is evaporated on a rotary evaporator, and residue uses silica gel column chromatography purification, obtains compound V, white solid, ESI-MS, m/z=263 ([M+H]+)。
The synthesis of step 3. compound VI
1.31g (5mmol) compound V is dissolved in the dichloromethane of 15mL dryings, the lower stirring of ice-water bath cooling, is added1.52g (15mmol) triethylamine, then slowly Deca 0.56g (5mmol) chloracetyl chloride and 1mL dry methylene chlorides prepare it is moltenLiquid, after completion of dropping, stirring was continued at room temperature overnight for reactant mixture, and TLC shows that reaction is completed.Reactant mixture carefully inclinesIn pouring 200mL frozen water into, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, successively the hydrochloric acid and salt water washing with 1%,Anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and residue is pure using silica gel column chromatographyChange, obtain compound VI, white solid, ESI-MS, m/z=339 ([M+H]+)。
The synthesis of step 4. compound I-1
1.02g (3mmol) compound VI, 0.38g (3mmol) VII-1 and 0.91g (9mmol) triethylamine are dissolved in 10mL to be doneIn dry dichloromethane, stirring was continued at room temperature overnight for reactant mixture, and TLC shows that reaction is completed.Reactant mixture is carefulIn pouring into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, successively the hydrochloric acid with 1% and salt washingWash, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and residue uses silica gel column chromatographyPurification, obtains compound I-1, white solid, ESI-MS, m/z=431 ([M+H]+)。
Embodiment 2-11
With reference to the method for embodiment 1, compound listed in Table is synthesized.
The Compound ira vitro of embodiment 12 is to the hematoblastic inhibitory action of human blood
Using the 20mL syringes of the sodium citrate buffered containing 2mL, from healthy volunteer blood is gathered.Blood is shiftedInto polypropylene tube, and (100g) 5 minutes (not using the braking of centrifuge) is centrifuged in room temperature.Then supernatant richness is collectedThrombocyte plasma (PRP), dilution, and carried out platelet count before aggregation measurement is used it for.
37 DEG C of measurements (platelet aggregation instrument) for carrying out platelet aggregation in glass tubing.By 4 μ L test compounds (than needingThe DMSO solution of dense 100 times of the final concentration wanted) mix with the PRP of 392 μ L brand-news, and with stirring incubation 1 minute.Then to mixedThe ADP solution of 250 μM of 4 μ L is added in compound.Persistently stir, by the method recording light variable density according to G.V.R.Born(Born, Nature, 1962,194,927), monitor the measurement of aggregation 6 to 8 minutes.Using the aggregation amplitude meter represented with heightResult is calculated, and is represented with suppression percentage.The inhibition on platelet aggregation IC of the compounds of this invention50It is as shown in the table.
The compound that can be seen that the present invention from upper table result has very strong antagonism to P2Y12, can be used as systemThe medicine of standby treatment cardiovascular disease especially thrombotic disease.