CN106674282A - Aryl phosphine oxide P2Y12 receptor antagonist, and preparation method and application thereof - Google Patents
Aryl phosphine oxide P2Y12 receptor antagonist, and preparation method and application thereof Download PDFInfo
- Publication number
- CN106674282A CN106674282A CN201710070028.6A CN201710070028A CN106674282A CN 106674282 A CN106674282 A CN 106674282A CN 201710070028 A CN201710070028 A CN 201710070028A CN 106674282 A CN106674282 A CN 106674282A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- blood
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Aryl phosphine oxide Chemical compound 0.000 title claims abstract description 4
- 102100026171 P2Y purinoceptor 12 Human genes 0.000 title abstract description 9
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000002464 receptor antagonist Substances 0.000 title abstract description 3
- 229940044551 receptor antagonist Drugs 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 55
- 208000007536 Thrombosis Diseases 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 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 4
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
- 230000008859 change Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 150000002081 enamines Chemical class 0.000 claims description 2
- 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
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 208000001435 Thromboembolism Diseases 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 14
- 238000000605 extraction Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 210000001772 blood platelet Anatomy 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 239000000376 reactant Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 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
- 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000000370 acceptor Substances 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 210000004204 blood vessel Anatomy 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-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
- 230000002792 vascular Effects 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
- 229940127424 P2Y12 Receptor Antagonists Drugs 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102100037600 P2Y purinoceptor 1 Human genes 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000004087 circulation Effects 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
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 206010003178 Arterial thrombosis 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
- 206010011084 Coronary artery embolism Diseases 0.000 description 1
- 102100037241 Endoglin Human genes 0.000 description 1
- 108010036395 Endoglin Proteins 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
- 101001098232 Homo sapiens P2Y purinoceptor 1 Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 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
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 108010014270 Purinergic P2Y12 Receptors Proteins 0.000 description 1
- 206010063544 Renal embolism Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 201000007023 Thrombotic Thrombocytopenic Purpura 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
- 230000003321 amplification Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000003143 atherosclerotic effect Effects 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
- 238000013172 carotid endarterectomy Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 229920001436 collagen Polymers 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
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 208000002296 eclampsia Diseases 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
- 238000011534 incubation 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
- 210000004072 lung Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 201000011461 pre-eclampsia Diseases 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response 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
- 239000006228 supernatant Substances 0.000 description 1
- 238000012360 testing method Methods 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
- 238000012549 training Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of drugs associated with cardiovascular diseases, and in particular relates to an aryl phosphine oxide P2Y12 receptor antagonist, and a preparation method and application thereof in preparation of drugs for treating cardiovascular diseases, especially thromboembolic diseases. The formula is as shown in the specification, wherein R is selected from H and C1-C10 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 angiocardiopathy
It is that thrombotic disease has P2Y12 receptor antagonist of the medicative class containing aryl oxidized phosphine structure, its preparation
Method and purposes.
Background technology
The medical complication relevant with there is thrombosis represents a kind of main cause of death.Some and development thrombus shape
Include that acute myocardial infarction, unstable angina pectoris and chronic stable angina pectoris, transience lack into relevant pathology example
Blood outbreak, cerebrovas-cularaccident, peripheral vascular disease, pre-eclampsia and eclampsia, dvt formed, embolism (cerebral embolism,
Pulmonary embolism, coronary embolism, renal embolism etc.), disseminated intravascular coagulation or thrombotic thrombocytopenic purpura.Invading
Still there are the danger that thrombosis and ISR complication occur, the invasive surgical operation during and after entering property surgical operation
Such as angioplasty, carotid endarterectomy, aortocoronary by-pass grafting or support or the peace of vascular endoprostheses
Put.
Arterial thrombosis can occur after vascular damaged or atheromatous plaque rupture.Blood platelet is in these thrombus
Necessary effect is played in formation.Blood platelet can pass through following substance activating：In blood flow circulating cells or along vascular wall present
The amboceptor that discharged of damaging endothelial cell, or during injury of blood vessel exposed sub-endothelial matrix (such as collagen) blood
Bolt forms molecule.Additionally, blood 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 reaction is simultaneously accumulated at injury of blood vessel, forms thrombus.In this process, blood
Produced thrombus is that volume is sufficiently large to blood flow in pipe, so that it is partially or completely blocked.
In vein, thrombus 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
Artery or coronary artery.
Verified 5'- adenosine diphosphate (ADP)s (ADP) are platelet activation and the principal mediator assembled for many researchs, in thrombus
Play 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 endothelial cell of the red blood cell that damages and atherosclerotic wall, it is more specific and
Speech, by secreted by the activation blood 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 acceptors 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 et al., J.Clin.Invest., 1999,
104,1731-1737) prove with using for P2Y12-/- mouse (Conley et al., Nature, 2001,409,202-207)
Described two acceptors thrombus developing importance in vivo.In the mankind, P2Y12 gene defects 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 angiocardiopathy is represent by Antagonist block P2Y12 acceptors.Clopidogrel is thienopyridine
The prodrug of family, its active metabolite is covalently bond to P2Y12 acceptors, 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, is reduced adventurous patient and cardiovascular unexpected danger is occurred.
The invention discloses a class contains the P2Y12 receptor antagonists of aryl oxidized phosphine structure, these compounds can be used to make
The medicine of standby treatment angiocardiopathy 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 active ingredient, and its in treatment painstaking effort
The application especially in terms of thrombotic disease of pipe 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 H, C1-C10Alkyl.
It is preferred that below general formula I,
Wherein, R1Selected from H, C1-C4Alkyl.
It is further preferred that compounds of formula I has following structure,
Compound of Formula I of the present invention can be synthesized by following route：
Compound II and compound III first react generation enamine intermediates, and the latter obtains compound IV through reduction；Chemical combination
Thing IV first at low temperature with n-BuLi processs, the aryl lithium intermediate for obtaining again with diphenyl phosphine chloride reaction, obtain compound
V；Compound V oxidizer treatments obtain compound I；R is defined as described above.
Compound of Formula I of the present invention has the antagonism of P2Y12 acceptors, can be used to prepare the heart as active ingredient
Vascular diseases especially thrombotic disease medicine.The activity of compound of Formula I of the present invention is by external people
The suppression of blood platelet aggregation is tested to verify.
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
Compound II (0.85g, 10mmol) and compound III-1 (1.47g, 10mmol) are dissolved in 10mL methyl alcohol, room temperature
Under be stirred overnight, then add NaCNBH3It is stirred under (1.26g, 20mmol), room temperature 5 hours, TLC shows that reaction is completed.
Reactant mixture is carefully poured in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, is washed with salt
Wash, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and residue uses silica gel column chromatography
Purifying, obtains compound IV-1, white solid.ESI-MS, m/z=216 ([M+H]+)。
The synthesis of step 2. compound V-1
Compound IV-1 (1.29g, 6mmol) is dissolved in the THF of 15mL dryings, stirring, and -78 are cooled in nitrogen atmosphere
DEG C, the hexane solution (3.75mL, 6mmol) of the n-BuLi of 1.6M is then slowly added dropwise with syringe, after completion of dropping, reaction
Mixture continues at such a temperature stirring 1 hour.Diphenyl phosphorus chloride (1.32g, 6mmol) is slowly added dropwise again with syringe to be dissolved in
Solution made by the THF that 7mL is dried, after completion of dropping, reactant mixture is stirred half an hour at such a temperature, is then warming up to room
Temperature is stirred for overnight.Reactant mixture is carefully poured in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction
Phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and residue is used
Silica gel column chromatography is purified, and obtains compound V-1, white solid.ESI-MS, m/z=366 ([M+H]+)。
The synthesis of step 3. compound I-1
Compound V-1 (0.73g, 2mmol) is dissolved in 10mL glacial acetic acid, is stirred under room temperature, and 30% H is slowly added dropwise2O2Water
Solution (1mL), after completion of dropping, stirring was continued at room temperature overnight for reactant mixture, and TLC has found that reaction is completed.Reaction mixing
Thing is carefully poured in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sulphur
Sour sodium is dried.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, is obtained
Compound I-1, white solid, 212-214 DEG C of fusing point, ESI-MS, m/z=382 ([M+H]+)。
The synthesis of the compound I-2 of embodiment 2
The synthesis of step 1. compound IV-2
Compound II (0.85g, 10mmol) and compound III-2 (1.60g, 10mmol) are dissolved in 10mL methyl alcohol, room temperature
Under be stirred overnight, then add NaCNBH3It is stirred under (1.26g, 20mmol), room temperature 5 hours, TLC shows that reaction is completed.
Reactant mixture is carefully poured in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, is washed with salt
Wash, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and residue uses silica gel column chromatography
Purifying, obtains compound IV-2, white solid.ESI-MS, m/z=230 ([M+H]+)。
The synthesis of step 2. compound V-2
Compound IV-2 (1.15g, 6mmol) is dissolved in the THF of 15mL dryings, stirring, and -78 are cooled in nitrogen atmosphere
DEG C, the hexane solution (3.75mL, 6mmol) of the n-BuLi of 1.6M is then slowly added dropwise with syringe, after completion of dropping, reaction
Mixture continues at such a temperature stirring 1 hour.Diphenyl phosphorus chloride (1.32g, 6mmol) is slowly added dropwise again with syringe to be dissolved in
Solution made by the THF that 7mL is dried, after completion of dropping, reactant mixture is stirred half an hour at such a temperature, is then warming up to room
Temperature is stirred for overnight.Reactant mixture is carefully poured in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction
Phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and residue is used
Silica gel column chromatography is purified, and obtains compound V-2, white-yellowish solid, ESI-MS, m/z=380 ([M+H]+)。
The synthesis of step 3. compound I-2
Compound V-2 (0.76g, 2mmol) is dissolved in 10mL glacial acetic acid, is stirred under room temperature, and 30% H is slowly added dropwise2O2Water
Solution (1mL), after completion of dropping, stirring was continued at room temperature overnight for reactant mixture, and TLC has found that reaction is completed.Reaction mixing
Thing is carefully poured in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sulphur
Sour sodium is dried.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, is obtained
Compound I-2, white solid, 237-239 DEG C of fusing point, ESI-MS, m/z=396 ([M+H]+)。
Embodiment 3-6
With reference to the operating procedure of embodiment 1, compound listed in Table is synthesized.
The Compound ira vitro of embodiment 7 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 PA 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 tube.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.(inhibition on platelet aggregation) IC of the compounds of this invention50It is as shown in the table.
| Compound | IC50(nM) | Compound | IC50(nM) |
| The compound of embodiment 1 | 328 | The compound of embodiment 4 | 161 |
| The compound of embodiment 2 | 72 | The compound of embodiment 5 | 455 |
| The compound of embodiment 3 | 125 | The compound of embodiment 6 | 809 |
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 angiocardiopathy especially thrombotic disease.
Claims (5)
1. there is the compound of general formula I,
Wherein, R is selected from H, C1-C10Alkyl.
2. claim 1 is defined has compounds of formula I,
Wherein, R1Selected from H, C1-C4Alkyl.
3. compound of Formula I defined in claim 2, is selected from：
4. the arbitrary defined method for belonging to compounds of formula I of claim 1-3 is synthesized：
Compound II and compound III first react generation enamine intermediates, and the latter obtains compound IV through reduction；Compound IV
First at low temperature with n-BuLi processs, the aryl lithium intermediate for obtaining again with diphenyl phosphine chloride reaction, obtain compound V；Change
Compound V oxidizer treatments obtain compound I；The definition of R is as described in claim 1-3 is arbitrary.
5. compound of Formula I defined in one of claim 1-3 in terms for the treatment of thrombotic disease medicine is prepared should
With.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710070028.6A CN106674282A (en) | 2017-02-09 | 2017-02-09 | Aryl phosphine oxide P2Y12 receptor antagonist, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710070028.6A CN106674282A (en) | 2017-02-09 | 2017-02-09 | Aryl phosphine oxide P2Y12 receptor antagonist, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106674282A true CN106674282A (en) | 2017-05-17 |
Family
ID=58860789
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710070028.6A Pending CN106674282A (en) | 2017-02-09 | 2017-02-09 | Aryl phosphine oxide P2Y12 receptor antagonist, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106674282A (en) |
-
2017
- 2017-02-09 CN CN201710070028.6A patent/CN106674282A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106831866A (en) | One aryl oxidized phosphine P2Y12 receptor antagonists of class alcoxyl thiophene and application thereof | |
| CN107001363B (en) | Dihydro indolizine ketone derivatives | |
| CN105111118B (en) | L-menthol P2Y12 receptor antagonists, preparation method thereof and use thereof | |
| JP2022513919A (en) | Substituted oxopyridine derivatives for the treatment and / or prevention of thrombotic or platelet embolic disease and / or thrombotic or platelet embolic complications | |
| CN104529927B (en) | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene | |
| TW201022238A (en) | Method for treating or preventing thrombosis using dabigatran etexilate or a salt thereof with improved efficacy over conventional warfarin therapy | |
| KR102209441B1 (en) | Compound having inhibitory effect for platelet aggregation and salt thereof, and composition comprising the same for prevention or treatment of thrombotic disease | |
| CN106674282A (en) | Aryl phosphine oxide P2Y12 receptor antagonist, and preparation method and application thereof | |
| CN107400131A (en) | Eliquis derivative and its production and use | |
| CN106831868A (en) | A kind of aryl oxidized phosphine P2Y12 receptor antagonists of amido thiophene and application thereof | |
| CN106749408A (en) | A kind of aryl oxidized phosphine P2Y12 receptor antagonists of nitrothiophene and application thereof | |
| CN106831867A (en) | A kind of aryl oxidized phosphine P2Y12 receptor antagonists of cyano-thiophene and application thereof | |
| CN106831869A (en) | Aryl oxidized phosphine P2Y12 receptor antagonists of amido thiophene and application thereof | |
| CN106831871A (en) | Aryl oxidized phosphine P2Y12 receptor antagonists of one class nitrothiophene and application thereof | |
| CN105152996B (en) | L-menthol type P2Y12 receptor antagonists and application thereof | |
| CN105111119B (en) | Halogenobenzene L-menthol P2Y12 receptor antagonists and application thereof | |
| CN106831870A (en) | Aryl oxidized phosphine P2Y12 receptor antagonists of one class cyano-thiophene and application thereof | |
| JP2018520128A (en) | Deuterated thienopiperidine derivatives, methods of preparation, and uses thereof | |
| CN105085346B (en) | MENTHOL class P2Y12 receptor antagonist of amino-contained and application thereof | |
| CN105085345B (en) | MENTHOL class P2Y12 receptor antagonist containing nitro and application thereof | |
| CN105085347B (en) | MENTHOL class P2Y12 receptor antagonist of one class nitrile group-containing and application thereof | |
| US4555522A (en) | Antithrombotic and/or antihypertensive compositions | |
| CN108129370A (en) | A kind of P2Y12 receptor antagonists of itrile group diphenyl thioacetic acid structure and application thereof | |
| CN108191723A (en) | A kind of P2Y12 receptor antagonists of nitro diphenyl thioacetic acid structure and application thereof | |
| CN108191724A (en) | P2Y12 receptor antagonists of the thioacetic acid structure of diphenyl containing methoxy and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170517 |