CN105152996B - L-menthol type P2Y12 receptor antagonists and application thereof - Google Patents
L-menthol type P2Y12 receptor antagonists and application thereof Download PDFInfo
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- CN105152996B CN105152996B CN201510502504.8A CN201510502504A CN105152996B CN 105152996 B CN105152996 B CN 105152996B CN 201510502504 A CN201510502504 A CN 201510502504A CN 105152996 B CN105152996 B CN 105152996B
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Abstract
The invention relates to the field of drugs for related cardiovascular diseases, in particular to P2Y12 receptor antagonists containing L-menthol structures, a preparation method of the P2Y12 receptor antagonists and an application of the P2Y12 receptor antagonists in preparation of drugs for treating cardiovascular diseases, particularly, thromboembolic diseases. The compound has a general formula shown in the specification, wherein R is selected from C1-C3 alkyl.
Description
Technical field
The present invention relates to the drug world for the treatment of cardiovascular disease.In particular it relates to outstanding to cardiovascular disease
It is that thrombotic disease has a medicative class P2Y12 receptor antagonists, its preparation side containing MENTHOL structure
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 shape
Include that acute myocardial infarction, unstable angina pectoriss and chronic stable angina pectoris, transience lack into relevant pathology example
Blood 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.Invading
Still there are the danger that thrombosiss and restenosiss complication occur, the invasive surgical operation during and after entering property surgical operation
Such as angioplasty, carotid endarterectomy, aorto-coronary bypass grafting or support or the peace of vascular endoprostheses
Put.
Artery thrombosis can occur after vascular damaged or atheromatous plaque rupture.Platelet is in these thrombosis
Necessary effect is played in formation.Platelet can pass through following substance activating：In blood flow circulating cells or along blood vessel wall present
The amboceptor that discharged of damaging endotheliocyte, or during blood vessel injury exposed sub-endothelial matrix (such as collagen) blood
Bolt forms molecule.Additionally, platelet can also be observed such as in narrow blood vessel under the blood flow conditions with shearing force
As activate.After activation, the circulation platelet adhesion is simultaneously accumulated at blood vessel injury, forms thrombosis.In this process, blood
Produced 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 produced
The embolus moved in vascular system.These emboluses thus the blood flow in more remote blood vessel can be blocked, the blood vessel such as lung
Tremulous pulse or coronary artery.
Verified 5'- adenosine diphosphate (ADP)s (ADP) are platelet activation and the principal mediator assembled for many researchs, in thrombosis
Play in the startup of formation and progress decisive role (Maffrand etal., 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 and
Speech, by secreted by the activation platelet with compacted grains in place of very high concentration stores ADP.The platelet aggregation of ADP- inductions
Triggered by it and in the combination of two species specificity purinergic receptor P2Y1 and P2Y12 of the endoglin expression of human blood platelets.Institute
P2Y1 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 ADP
On 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 for
The amplification of response and the stabilisation of aggregation.P2Y1-/- transgenic mice (Gachet etal., 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 above
Type is relevant with the notable decline of the platelet aggregation that ADP- is induced.Human clinical practice used in clopidogrel it has been proved that
The critical therapeutic strategy for the treatment of cardiovascular disease is represent by Antagonist block P2Y12 receptors.Clopidogrel is thienopyridine
The 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 examinations
Middle its efficiency of display is tested, that is, reduces adventurous patient's generation cardiovascular unexpectedly dangerous.
The invention discloses a class contains the P2Y12 receptor antagonists of MENTHOL structure, these compounds 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 cardiovascular
Disease 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, R is selected from C1-C3Alkyl.
More preferably compounds of 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 also
Original 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 base
With sulfhydryl compound VII reactions, corresponding I is obtained；R 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 ingredient
Angiopathy especially thrombotic disease medicine.The activity of compound of Formula I of the present invention is by external people
The 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 about
In 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 curing
Take 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 for
Illustrate, 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 should
Within 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, and
Stir 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 rotation
Send 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 pressed
Carry 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 stirred
Mix, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, filter
Liquid 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 added
1.52g (15mmol) triethylamine, then slowly Deca 0.56g (5mmol) chloracetyl chloride and 1mL dry methylene chlorides prepare it is molten
Liquid, after completion of dropping, stirring was continued at room temperature overnight for reactant mixture, and TLC shows that reaction is completed.Reactant mixture carefully inclines
In 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 chromatography
Change, 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, 0.52g (3mmol) VII-1 and 0.91g (9mmol) triethylamine are dissolved in 10mL to be done
In dry dichloromethane, stirring was continued at room temperature overnight for reactant mixture, and TLC shows that reaction is completed.Reactant mixture is careful
In pouring into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, successively the hydrochloric acid with 1% and salt washing
Wash, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and residue uses silica gel column chromatography
Purification, obtains compound I-1, white solid, ESI-MS, m/z=443 ([M+H]+)。
Embodiment 2-8
With reference to the method for embodiment 1, compound listed in Table is synthesized.
The Compound ira vitro of embodiment 9 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 shifted
Into polypropylene tube, and (100g) 5 minutes (not using the braking of centrifuge) is centrifuged in room temperature.Then supernatant richness is collected
Thrombocyte 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 needing
The 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 mixed
The 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 height
Result 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.
| Compound | IC50(nM) |
| I-1 | 131 |
| I-2 | 328 |
| I-3 | 440 |
| I-4 | 524 |
| I-5 | 619 |
| I-6 | 271 |
| I-7 | 185 |
| I-8 | 392 |
The compound that can be seen that the present invention from upper table result has very strong antagonism to P2Y12, can be used as system
The medicine of standby treatment cardiovascular disease especially thrombotic disease.
Claims (4)
1. there is the compound of general formula I,
Wherein, R is selected from C1-C3Alkyl.
2. compound of Formula I defined in claim 1, selected from following compounds,
3. the arbitrary defined method for belonging to compounds of formula I of claim 1-2 is synthesized：
In the presence of a base reacting by heating generates compound IV for compound II and compound III；Compound IV reducing agents are reduced
To compound V；Compound V reacts in the presence of a base with chloracetyl chloride, obtains compound VI；Compound VI in the presence of a base with mercapto
Based compound VII reacts, and obtains correspondence compound I；The definition of R is as described in claim 1-2 is arbitrary.
4. compound of Formula I defined in one of claim 1-2 in terms for the treatment of thrombotic disease medicine is prepared should
With.
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| AU761983B2 (en) * | 1998-07-08 | 2003-06-12 | Sanofi-Aventis Deutschland Gmbh | Sulfur substituted sulfonylaminocarboxylic acid N-arylamides, their preparation,their use and pharmaceutical preparations comprising them |
| SE9803107D0 (en) * | 1998-09-14 | 1998-09-14 | Astra Pharma Prod | Novel Compunds |
| WO2003080564A1 (en) * | 2002-03-20 | 2003-10-02 | Schering Aktiengesellschaft | Menthol substituted antithrombotic pai-1 inhibitors |
| US8354116B2 (en) * | 2007-06-18 | 2013-01-15 | Biochemics, Inc. | Bifunctional synthetic molecules |
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