CN105085346B - MENTHOL class P2Y12 receptor antagonist of amino-contained and application thereof - Google Patents
MENTHOL class P2Y12 receptor antagonist of amino-contained and application thereof Download PDFInfo
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- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical class CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 title description 4
- 239000002464 receptor antagonist Substances 0.000 title description 3
- 229940044551 receptor antagonist Drugs 0.000 title description 3
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 39
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- -1 sulfhydryl compound VII Chemical compound 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 9
- 229940127424 P2Y12 Receptor Antagonists Drugs 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000001772 blood platelet Anatomy 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 7
- 210000004204 blood vessel Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000004623 platelet-rich plasma Anatomy 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960003009 clopidogrel Drugs 0.000 description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 210000003725 endotheliocyte Anatomy 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 102100037241 Endoglin Human genes 0.000 description 1
- 108010036395 Endoglin Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108091006068 Gq proteins Proteins 0.000 description 1
- 102000052606 Gq-G11 GTP-Binding Protein alpha Subunits Human genes 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102100037600 P2Y purinoceptor 1 Human genes 0.000 description 1
- 108050008996 P2Y purinoceptor 1 Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 102000007074 Phospholipase C beta Human genes 0.000 description 1
- 108010047834 Phospholipase C beta Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 102000016927 Purinergic P2Y1 Receptors Human genes 0.000 description 1
- 108010028935 Purinergic P2Y1 Receptors Proteins 0.000 description 1
- 206010038470 Renal infarct Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 201000007023 Thrombotic Thrombocytopenic Purpura Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 201000011461 pre-eclampsia Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to the drug world related to cardiovascular disease.Specifically, the present invention relates to the P2Y12 receptor antagonists of the L menthol structures of a class amino-contained, its preparation method and the application in preparation treatment cardiovascular disease especially thrombotic disease medicine.
Description
Technical field
The present invention relates to the drug world for the treatment of cardiovascular disease.In particular it relates to cardiovascular disease
Sick especially thrombotic disease has the P2Y12 of the MENTHOL structure of medicative class amino-contained
Receptor antagonist, 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 blood
Bolt forms relevant pathology example includes that acute myocardial infarction, unstable angina pectoriss and the chronic stable heart are twisted
Bitterly, transient ischemic attack, cerebrovas-cularaccident, peripheral vascular disease, preeclampsia and eclamposia, deep are quiet
Arteries and veins thrombosiss, thromboembolism (cerebral embolism, pulmonary infarction, coronary thrombosiss, renal infarction etc.), dispersivity blood
Intravascular coagulation or thrombotic thrombocytopenic purpura.Still there is generation blood during and after invasive surgical operation
Bolt forms the danger with restenosiss complication, the invasive surgical operation such as angioplasty, carotid artery intima
The placement of excision, aorto-coronary bypass grafting or support or vascular endoprostheses.
Artery thrombosis can occur after vascular damaged or atheromatous plaque rupture.Platelet is at these
Necessary effect is played in thrombosiss.Platelet can pass through following substance activating：In blood flow circulating cells or
The amboceptor discharged by the damaging endotheliocyte presented along blood vessel wall, or institute is exposed interior during blood vessel injury
The thrombosiss molecule of sub-endothelial matrix (such as collagen).Additionally, platelet can also be in the blood with shearing force
Activate as what is observed in narrow blood vessel under the conditions of stream.After activation, the circulation platelet adhesion is simultaneously
Accumulate at blood vessel injury, form thrombosis.In this process, thrombosis produced in blood vessel are volumes to blood flow
Sufficiently large, so which is partially or completely blocked.
In vein, thrombosis can also be located to be formed in obstruction or blood flow slowly.Due to these venothrombotic properties, its
The embolus moved in vascular system can be produced.These emboluses thus the blood in more remote blood vessel can be blocked
Stream, the blood vessel such as pulmonary artery or coronary artery.
Many research principal mediators that verified 5'- adenosine diphosphate (ADP)s (ADP) are platelet activation and assemble,
It is thrombotic startup and be in progress in play decisive role (Maffrand et al., Thromb.Haemostas.,
1988,59,225-230).The endotheliocyte of erythrocyte and atherosclerosiss wall of the ADP by infringement is discharged into
In circulation, more specifically, by the activation platelet institute with compacted grains in place of very high concentration stores ADP
Secretion.The platelet aggregation of ADP- inductions is fast with two species specificity of the endoglin expression in human blood platelets by which
The combination of purine energy receptor P2Y1 and P2Y12 is triggered.The P2Y1 receptors, are stimulated with the PLC β of Jing G α q
Joint, is responsible for mobilization, the change of platelet shape and the aggregation of the moment on ADP of internal calcium storage.Institute
P2Y12 is stated, the activation of suppression and PI-3 kinases with the adenyl cyclase of Jing G α i2 is combined, and is responsible for response
The stabilisation amplified and assemble.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 genes are had been described above
Defect is relevant with the notable decline of the platelet aggregation that bleeding phenotype and ADP- are induced.In Human clinical's practice
Using clopidogrel it has been proved that the pass for the treatment of cardiovascular disease is represent by Antagonist block P2Y12 receptors
Key therapeutic strategy.Prodrug of the clopidogrel for thienopyridine family, its active metabolite are covalently bond to
P2Y12 receptors, cause internal biologically active pdgf can not retroactive inhibition (Savi et al., Biochem.Biophys.
Res.Commun., 2001,283,379-383), the medicine shows its efficiency in some clinical trials, that is, drop
It is unexpectedly dangerous to there is cardiovascular in low adventurous patient.
The invention discloses the P2Y12 receptor antagonists of the MENTHOL structure of a class amino-contained, 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：
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention can be synthesized by following route：
Reacting by heating generates compound IV in the presence of a base for compound II and compound III；Compound IV is with also
Former agent reduction obtains compound V；Compound V is reacted with chloracetyl chloride in the presence of a base, obtains compound VI；
Compound VI is reacted with sulfhydryl compound VII in the presence of a base, obtains corresponding I.
Compound of Formula I of the present invention has the antagonism of P2Y12 receptors, can use as effective ingredient
In preparing cardiovascular disease especially thrombotic disease medicine.Compound of Formula I of the present invention
Activity is verifying by the inhibition test of external human blood platelet aggregation.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The agent for example taken daily
Amount about in the range of 1mg-700mg/ people is divided into and being administered once or for several times.Formula Iization of the present invention is taken actually
The dosage of compound can be determined according to relevant situation by doctor.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only
For illustrating, and it is not intended to limit the present invention.Those skilled in the art's training centre of the invention is made
Various change all should be within the protection domain required by the application claim.
The synthesis of 1 compound I-1 of embodiment
The synthesis of step 1. compound IV
1.56g (10mmol) compound II is dissolved in 15mL DMF, and ice-water bath cooling is lower to stir, in batches plus
(12mmol, 60%) solid NaH are stirred 30 minutes under room temperature to enter 0.48g.Add 1.86g (10mmol)
2,4- dinitro compound III, then stir 3 hours under room temperature, and TLC shows that reaction is completed.Reactant mixture
Carefully pour in 200mL frozen water, stir, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses
Salt water washing, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, remaining
Thing 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,
Then according to standard operation carries out being hydrogenated with normal temperature and pressure, complete after 12 hours.Reactant mixture is carefully toppled over
Enter in 200mL frozen water, stir, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses salt water washing,
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 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, and ice-water bath cooling is lower to stir,
1.52g (15mmol) triethylamine is added, then slowly Deca 0.56g (5mmol) chloracetyl chloride and 1mL are dry
The solution that dry dichloromethane is prepared, after completion of dropping, stirring was continued at room temperature overnight for reactant mixture, TLC
Show that reaction is completed.Reactant mixture is carefully poured in 200mL frozen water, stirring, with 50mL × 3
CH2Cl2Extraction, merge extraction phase, successively with 1% hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Take out
Desiccant is filtered, filtrate is evaporated on a rotary evaporator, residue uses silica gel column chromatography purification, is changed
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 molten
In the dichloromethane that 10mL is dried, stirring was continued at room temperature overnight for reactant mixture, and TLC shows instead
Should complete.Reactant mixture is carefully poured in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction
Take, merge extraction phase, successively with 1% hydrochloric acid and salt water washing, anhydrous sodium sulfate drying.Sucking filtration removes dry
Drying prescription, filtrate are evaporated on a rotary evaporator, and residue uses silica gel column chromatography purification, obtains compound I-1,
White solid, ESI-MS, m/z=428 ([M+H]+)。
Embodiment 2-4
With reference to the method for embodiment 1, compound listed in Table is synthesized.
4 Compound ira vitro of embodiment is to the hematoblastic inhibitory action of human blood
Using the 20mL syringes of the sodium citrate buffered containing 2mL, blood is gathered from healthy volunteer.Will
Blood is transferred in polypropylene tube, and (100g) 5 minutes (not using the braking of centrifuge) is centrifuged in room temperature.Then
Supernatant platelet rich plasma (PRP) is collected, is diluted, and entered promoting the circulation of blood before aggregation measurement is used it for
Platelet number.
37 DEG C of measurements (platelet aggregation instrument) for carrying out platelet aggregation in glass tubing.By 4 μ L test compounds
(DMSO solution of dense 100 times of the final concentration than needing) is mixed with the PRP of 392 μ L brand-news, and is incubated with stirring
Educate 1 minute.Then the ADP solution of 250 μM of 4 μ L is added in mixture.Persistently stir, by according to G.
(Born, Nature, 1962,194,927), monitor the measurement of aggregation to the method recording light variable density of V.R.Born
6 to 8 minutes.Using the aggregation magnitude determinations result represented with height, and represented with suppression percentage.The present invention
The inhibition on platelet aggregation IC of compound50It is as shown in the table.
| Compound | IC50(nM) |
| Compound R -1 (embodiment 4) | 734 |
| I-1 | 327 |
| I-2 | 375 |
| I-3 | 392 |
The compound that the present invention be can be seen that from upper table result has very strong antagonism to P2Y12, can
Using as the medicine for preparing treatment cardiovascular disease especially thrombotic disease.
Claims (4)
1. there is the compound of general formula I,
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：
Reacting by heating generates compound IV in the presence of a base for compound II and compound III；Compound IV is with also
Former agent reduction obtains compound V；Compound V is reacted with chloracetyl chloride in the presence of a base, obtains compound VI；
Compound VI is reacted with sulfhydryl compound VII in the presence of a base, obtains correspondence compound I.
4. compound of Formula I defined in one of claim 1-2 is in terms for the treatment of thrombotic disease medicine is prepared
Application.
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