CN105085347B - MENTHOL class P2Y12 receptor antagonist of one class nitrile group-containing and application thereof - Google Patents
MENTHOL class P2Y12 receptor antagonist of one class nitrile group-containing and application thereof Download PDFInfo
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Abstract
The present invention relates to the drug world relevant to cardiovascular disease.Specifically, the present invention relates to the P2Y12 receptor antagonist of L menthol structure of a class nitrile group-containing, 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 a medicative class nitrile group-containing
Receptor antagonist, its preparation method, and the purposes in pharmacy.
Background technology
The medical complication relevant with there is thrombosis represents a kind of main cause of death.Some with development blood
Bolt forms relevant pathology example and includes acute myocardial infarction, unstable angina pectoris and chronic stable heart strand
Bitterly, transient ischemic attack, cerebrovas-cularaccident, peripheral vascular disease, preeclampsia and eclamposia, deep are quiet
Arteries and veins thrombosis, thromboembolism (cerebral embolism, pulmonary infarction, coronary thrombosis, renal infarction etc.), dispersivity blood
Intravascular coagulation or thrombotic thrombocytopenic purpura.Generation blood is still had during and after invasive surgical operation
Bolt is formed and the danger of restenosis complication, described invasive surgical operation such as angioplasty, carotid artery intima
Excision, aorto-coronary bypass grafting or support or the arrangement of vascular endoprostheses.
Artery thrombosis can occur after vascular damaged or atheromatous plaque rupture.Platelet is at these
Thrombosis plays the effect of necessity.Platelet can pass through following substance activating: in blood flow circulating cells or
The amboceptor that the damaging endotheliocyte presented along blood vessel wall is discharged, or in being exposed during blood vessel injury
The thrombosis molecule of sub-endothelial matrix (such as collagen).Additionally, platelet also can have the blood of shearing force
Activate as viewed in narrow blood vessel under the conditions of stream.After activation, described circulation platelet adhesion is also
Accumulate at blood vessel injury, form thrombosis.In this process, in blood vessel, produced thrombosis is volume to blood flow
Sufficiently large, so that it is partially or completely blocked.
In vein, thrombosis also can be located to be formed at obstruction or blood flow slowly.Due to these venothrombotic character, its
The embolus of movement in vascular system can be produced.These emboluses thus the blood in more remote blood vessel can be blocked
Stream, described blood vessel such as pulmonary artery or coronary artery.
Many researchs have turned out the principal mediator that 5'-adenosine diphosphate (ADP) (ADP) is platelet activation and gathering,
Thrombotic startup and progress in play decisive role (Maffrand et al., Thromb.Haemostas.,
1988,59,225-230).ADP is discharged into by the erythrocyte of infringement and the endotheliocyte of atherosclerosis wall
In circulation, more specifically, the activation platelet institute in place of ADP is stored by with compacted grains in very high concentration
Secretion.The platelet aggregation of ADP-induction is fast with two species specificity of the endoglin expression at human blood platelets by it
The combination of purine energy receptor P2Y1 and P2Y12 is triggered.Described P2Y1 receptor, stimulates with the PLC β through G α q
Associating, is responsible for mobilization, the change of platelet shape and the gathering of the moment on ADP that internal calcium stores.Institute
Stating P2Y12, suppression and kinase whose activation of PI-3 with the adenyl cyclase through G α i2 are combined, and are responsible for response
The stabilisation amplified and assemble.P2Y1-/-transgenic mice (Gachet et al., J.Clin.Invest., 1999,104,
1731-1737) use with P2Y12-/-mice (Conley et al., Nature, 2001,409,202-207) proves
The two receptor developing importance of thrombosis in vivo.In the mankind, have been described above P2Y12 gene
Defect is relevant with the notable decline of the platelet aggregation that hemorrhage phenotype and ADP-are induced.In Human clinical puts into practice
Use clopidogrel it has been proved that represent the pass for the treatment of cardiovascular disease by Antagonist block P2Y12 receptor
Key therapeutic strategy.Clopidogrel is the prodrug of thienopyridine family, and its active metabolite is covalently bond to
P2Y12 receptor, causes irreversible suppression (Savi et al., the Biochem.Biophys. of internal biologically active pdgf
Res.Commun., 2001,283,379-383), this medicine shows its usefulness in some clinical trials, i.e. drops
Low adventurous patient occurs cardiovascular the most dangerous.
The invention discloses the P2Y12 receptor antagonist of the MENTHOL structure of a class nitrile group-containing, these compounds
Can be used for the medicine of preparation treatment cardiovascular disease especially thrombotic disease.
Summary of the invention
It is an object of the present invention to provide the P2Y12 receptor antagonist of a kind of excellent activity with formula I.
It is a further object to provide the method that preparation has compounds of formula I.
It is also another object of the present invention to provide containing compounds of formula I as effective ingredient and in treatment
Application in terms of cardiovascular disease especially thrombotic disease.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has compounds of formula I and has a following structural formula:
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention can be synthesized by following route:
Compound II and compound III reacting by heating in the presence of a base generate compound IV；Compound IV is with also
Former dose of reduction obtains compound V；Compound V reacts with chloracetyl chloride in the presence of a base, obtains compound VI；
Compound VI reacts with sulfhydryl compound VII in the presence of a base, obtains the I of correspondence.
Compound of Formula I of the present invention has the antagonism of P2Y12 receptor, can use as effective ingredient
In preparation cardiovascular disease especially thrombotic disease medicine.Compound of Formula I of the present invention
Activity is to be verified 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 that such as every day takes
Amount, about in the range of 1mg-700mg/ people, is divided into once or is administered for several times.Actual take formula Iization of the present invention
The dosage of compound can be determined according to relevant situation by doctor.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only
For illustrating, and it is not intended to limit the present invention.Those skilled in the art are made according to the teachings of the present invention
Various changes all should be within the protection domain required by the application claim.
The synthesis of embodiment 1 compound I-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, adds in batches
Enter 0.48g (12mmol, 60%) solid NaH, stir 30 minutes under room temperature.Add 1.86g (10mmol)
2,4-dinitro compound III, then stir 3 hours under room temperature, and TLC display reaction completes.Reactant mixture
Carefully pouring in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses
Saline washs, and anhydrous sodium sulfate is dried.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 under normal temperature and pressure, complete after 12 hours.Reactant mixture is carefully toppled over
Entering in 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, washs with saline,
Anhydrous sodium sulfate is dried.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 that 15mL is dried, the lower stirring of ice-water bath cooling,
Add 1.52g (15mmol) triethylamine, the most slowly drip 0.56g (5mmol) chloracetyl chloride and 1mL does
The solution of dry dichloromethane preparation, after dropping, stirring was continued at room temperature overnight for reactant mixture, TLC
Display reaction completes.Reactant mixture carefully pours in 200mL frozen water, and stirring, with 50mL × 3
CH2Cl2Extraction, merges extraction phase, and hydrochloric acid and saline with 1% wash successively, and anhydrous sodium sulfate is dried.Take out
Filtering desiccant, filtrate is evaporated on a rotary evaporator, and 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, 0.41g (3mmol) VII-1 and 0.91g (9mmol) triethylamine is 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 carefully pours in 200mL frozen water, and stirring, with 50mL × 3CH2Cl2Extraction
Taking, merge extraction phase, hydrochloric acid and saline with 1% wash successively, and anhydrous sodium sulfate is dried.Sucking filtration removes dry
Drying prescription, 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=438 ([M+H]+)。
Embodiment 2-4
With reference to the method for embodiment 1, synthesize compound listed in Table.
Embodiment 4 Compound ira vitro inhibitory action hematoblastic to human blood
Use the 20mL syringe of the sodium citrate buffered containing 2mL, gather blood from healthy volunteer.Will
Blood is transferred in polypropylene tube, and centrifugal (100g) 5 minutes (not using the braking of centrifuge) in room temperature.Then
Collect supernatant platelet rich plasma (PRP), dilution, and carried out blood before using it for assembling measurement
Platelet number.
37 DEG C of measurements (platelet aggregation instrument) carrying out platelet aggregation in glass tubing.4 μ L are tested compound
(than the DMSO solution of dense 100 times of the final concentration needed) mixes with the PRP of 392 μ L brand-news, and incubates with stirring
Educate 1 minute.Then in mixture, add the ADP solution of 4 μ L 250 μMs.Continuously stirred, by according to G.
The method recording light variable density (Born, Nature, 1962,194,927) of V.R.Born, the measurement that monitoring is assembled
6 to 8 minutes.Use the gathering magnitude determinations result represented with height, and represent with suppression percent.The present invention
The inhibition on platelet aggregation IC of compound50As shown in the table.
| Compound | IC50(nM) |
| Compound R-1 (embodiment 4) | 734 |
| I-1 | 291 |
| I-2 | 352 |
| I-3 | 379 |
From upper table result it can be seen that the compound of the present invention has the strongest antagonism to P2Y12, can
Using the medicine as preparation 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. synthesis claim 1-2 arbitrary defined in belong to the method for compounds of formula I:
Compound II and compound III reacting by heating in the presence of a base generate compound IV；Compound IV is with also
Former dose of reduction obtains compound V；Compound V reacts with chloracetyl chloride in the presence of a base, obtains compound VI；
Compound VI reacts with sulfhydryl compound VII in the presence of a base, obtains corresponding compound I.
4. the defined compound of Formula I of one of claim 1-2 is in terms of preparation treatment thrombotic disease medicine
Application.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19830430A1 (en) * | 1998-07-08 | 2000-01-13 | Hoechst Marion Roussel De Gmbh | New sulfur-substituted sulfonylamino-carboxylic acid N-arylamide derivatives useful as guanylate cyclase activators in treatment of e.g. cardiovascular disorders, asthma and diabetes |
| CN1318054A (en) * | 1998-09-14 | 2001-10-17 | 阿斯特拉曾尼卡有限公司 | Novel compounds |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19830430A1 (en) * | 1998-07-08 | 2000-01-13 | Hoechst Marion Roussel De Gmbh | New sulfur-substituted sulfonylamino-carboxylic acid N-arylamide derivatives useful as guanylate cyclase activators in treatment of e.g. cardiovascular disorders, asthma and diabetes |
| CN1318054A (en) * | 1998-09-14 | 2001-10-17 | 阿斯特拉曾尼卡有限公司 | Novel compounds |
Non-Patent Citations (1)
| Title |
|---|
| 现代手性药物的合成与发展;刘二畅等;《广东药学院学报》;20041225(第06期);全文 * |
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Effective date of registration: 20190311 Address after: 515636 Head Dragon Stork Road, Longhu Town, Chaoan District, Chaozhou City, Guangdong Province Patentee after: Guangdong Qiangji Pharmaceutical Co. Ltd. Address before: Room 302 A-58, Block 3, E3, Saida Emerging Industrial Park, Xiqing District, Tianjin Patentee before: TIANJIN XIAOXIN PHARMACEUTICAL TECHNOLOGY CO., LTD. |