CN106749408A - A kind of aryl oxidized phosphine P2Y12 receptor antagonists of nitrothiophene and application thereof - Google Patents
A kind of aryl oxidized phosphine P2Y12 receptor antagonists of nitrothiophene and application thereof Download PDFInfo
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- CN106749408A CN106749408A CN201710070041.1A CN201710070041A CN106749408A CN 106749408 A CN106749408 A CN 106749408A CN 201710070041 A CN201710070041 A CN 201710070041A CN 106749408 A CN106749408 A CN 106749408A
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- 229940127424 P2Y12 Receptor Antagonists Drugs 0.000 title abstract description 6
- JIZRGGUCOQKGQD-UHFFFAOYSA-N 2-nitrothiophene Chemical compound [O-][N+](=O)C1=CC=CS1 JIZRGGUCOQKGQD-UHFFFAOYSA-N 0.000 title abstract description 5
- 125000003118 aryl group Chemical group 0.000 title abstract description 5
- 229910000073 phosphorus hydride Inorganic materials 0.000 title description 2
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 9
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- 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
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- 238000000034 method Methods 0.000 claims description 4
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- 206010047249 Venous thrombosis Diseases 0.000 description 1
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- LRBIYQBRHZQHOJ-UHFFFAOYSA-N [O-][N+](c1c(C=O)[s]c(Cl)c1)=O Chemical compound [O-][N+](c1c(C=O)[s]c(Cl)c1)=O LRBIYQBRHZQHOJ-UHFFFAOYSA-N 0.000 description 1
- CQSLEHIAAJPNSO-UHFFFAOYSA-N [O-][N+](c1c(CN2CCCCC2)[s]c(Cl)c1)=O Chemical compound [O-][N+](c1c(CN2CCCCC2)[s]c(Cl)c1)=O CQSLEHIAAJPNSO-UHFFFAOYSA-N 0.000 description 1
- CAWGOJUZEHPYRV-UHFFFAOYSA-N [O-][N+](c1c(CN2CCCCC2)[s]c([O](c2ccccc2)c2ccccc2)c1)=O Chemical compound [O-][N+](c1c(CN2CCCCC2)[s]c([O](c2ccccc2)c2ccccc2)c1)=O CAWGOJUZEHPYRV-UHFFFAOYSA-N 0.000 description 1
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- 239000005557 antagonist Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
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- 201000011461 pre-eclampsia Diseases 0.000 description 1
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- 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
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- 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
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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
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- 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 present invention relates to the drug field related to angiocardiopathy.Specifically, the present invention relates to a kind of P2Y12 receptor antagonists of the aryl oxidized phosphine structure containing nitrothiophene, its preparation method and its application in preparation treatment angiocardiopathy especially thrombotic disease medicine.
Description
Technical field
The present invention relates to the drug field for the treatment of cardiovascular disease.In particular it relates to outstanding to angiocardiopathy
It is that thrombotic disease has a kind of medicative P2Y12 receptor antagonists containing the aryl oxidized phosphine structure of nitrothiophene
Agent, Preparation Method And The Use.
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 breaking-out, 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 be by following substance activating：In blood flow circulating cells or along vascular wall present
The amboceptor that is 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 sufficiently large volume to blood flow in pipe, so that it is partially or completely blocked.
In vein, thrombus can also be located to be formed slowly in obstruction or blood flow.Due to the property of these phlebothrombosises, it can be produced
The embolus moved in vascular system.These emboluses can thus block the blood flow in more remote blood vessel, 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
Played in the startup of formation and progress decisive role (Maffrand et al., Thromb.Haemostas., 1988,59,
225-230).ADP is discharged into circulation by the red blood cell and the endothelial cell of atherosclerosis wall for damaging, it is more specific and
Speech, as secreted by the activation blood platelet with compacted grains in place of very high concentration storage ADP.The platelet aggregation of ADP- inductions
The combination of two species specificity the purinergic receptor P2Y1 and P2Y12 by it and in the endoglin expression of human blood platelets is triggered.Institute
P2Y1 acceptors are stated, combine with stimulating through the PLC β of G α q, be responsible for mobilization, the change of platelet shape and in ADP that internal calcium is stored
On moment aggregation.The P2Y12, the activation of suppression and PI-3 kinases with the adenyl cyclase through 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) proved 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 put into practice in use 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 dangerous patient and cardiovascular unexpected danger is occurred.
The invention discloses a kind of P2Y12 receptor antagonists containing the aryl oxidized phosphine structure of nitrothiophene, these compounds
Can be used to prepare the medicine for the treatment of 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 Formulas I.
Method it is a further object to provide the compound with Formulas I is prepared.
It is it is also another object of the present invention to provide the compound containing Formulas I as active ingredient and its cardiovascular in treatment
Disease application especially in terms of thrombotic disease.
Present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the present invention with Formulas I has following structural formula：
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 by reduction；Chemical combination
Thing IV first at low temperature with n-BuLi treatment, the aryl lithium intermediate for obtaining again with diphenyl phosphine chloride reaction, obtain compound
V；Compound V oxidizer treatments obtain compound I.
Compound of formula I of the present invention has the antagonism of P2Y12 acceptors, can be used to prepare painstaking effort as active ingredient
Pipe disease especially thrombotic disease medicine.The activity of compound of formula I of the present invention is by external human blood blood
The suppression of platelet aggregation is tested to verify.
Compound of formula I of the invention is effective in comparatively wide dosage range.The dosage for example taken daily about exists
In the range of 1mg-700mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking formula I can be by doctor's root
Determined according to relevant situation.
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 NaCNBH3(1.26g, 20mmol), is stirred for 5 hours at room temperature, and TLC display reactions are completed.
Reactant mixture is carefully poured into 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 dry THF of 15mL, 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 stirring 1 hour at such a temperature.Diphenyl phosphorus chloride (1.32g, 6mmol) is slowly added dropwise again with syringe to be dissolved in
The solution that the dry THF of 7mL are made, 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 into 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 at 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 into 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 (1.92g, 10mmol) are dissolved in 10mL methyl alcohol, room temperature
Under be stirred overnight, then add NaCNBH3(1.26g, 20mmol), is stirred for 5 hours at room temperature, and TLC display reactions are completed.
Reactant mixture is carefully poured into 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=261 ([M+H]+)。
The synthesis of step 2. compound V-2
Compound IV-2 (1.56g, 6mmol) is dissolved in the dry THF of 15mL, 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 stirring 1 hour at such a temperature.Diphenyl phosphorus chloride (1.32g, 6mmol) is slowly added dropwise again with syringe to be dissolved in
The solution that the dry THF of 7mL are made, 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 into 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 solid, ESI-MS, m/z=411 ([M+H]+)。
The synthesis of step 3. compound I-2
Compound V-2 (0.82g, 2mmol) is dissolved in 10mL glacial acetic acid, is stirred at 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 into 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, 209-211 DEG C of fusing point, ESI-MS, m/z=427 ([M+H]+)。
The Compound ira vitro of embodiment 3 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.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 be incubated 1 minute with stirring.Then to mixed
The ADP solution of 250 μM of 4 μ L is added in compound.Lasting stirring, by the method recording light variable density according to G.V.R.Born
(Born, Nature, 1962,194,927), monitors the measurement of aggregation 6 to 8 minutes.Use 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) |
| The compound of embodiment 1 | 328 |
| The compound of embodiment 2 | 86 |
Can be seen that compound of the invention from upper table result has very strong antagonism to P2Y12, can be as system
The medicine of standby treatment angiocardiopathy especially thrombotic disease.
Claims (3)
1. there is the compound of Formulas I structure,
2. the method for synthesizing compound described in claim 1：
Compound II and compound III first react generation enamine intermediates, and the latter obtains compound IV by reduction；Compound IV
First at low temperature with n-BuLi treatment, the aryl lithium intermediate for obtaining again with diphenyl phosphine chloride reaction, obtain compound V；Change
Compound V oxidizer treatments obtain compound I.
3. application of the compound described in claim 1 in terms for the treatment of thrombotic disease medicine is prepared.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101868469A (en) * | 2007-11-29 | 2010-10-20 | 埃科特莱茵药品有限公司 | Phosphonic acid derivates and their use as P2Y12 receptor antagonists |
| CN102405220A (en) * | 2009-04-22 | 2012-04-04 | 埃科特莱茵药品有限公司 | Thiazole derivatives and their use as p2y12 receptor antagonists |
| CN104447867A (en) * | 2013-09-17 | 2015-03-25 | 天士力控股集团有限公司 | Thienopiperidine derivative, preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101868469A (en) * | 2007-11-29 | 2010-10-20 | 埃科特莱茵药品有限公司 | Phosphonic acid derivates and their use as P2Y12 receptor antagonists |
| CN102405220A (en) * | 2009-04-22 | 2012-04-04 | 埃科特莱茵药品有限公司 | Thiazole derivatives and their use as p2y12 receptor antagonists |
| CN104447867A (en) * | 2013-09-17 | 2015-03-25 | 天士力控股集团有限公司 | Thienopiperidine derivative, preparation method and application thereof |
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