CN108129369A - Diphenyl thioacetic acid, the preparation method and its usage of P2Y12 receptor antagonists - Google Patents
Diphenyl thioacetic acid, the preparation method and its usage of P2Y12 receptor antagonists Download PDFInfo
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- CN108129369A CN108129369A CN201810050512.7A CN201810050512A CN108129369A CN 108129369 A CN108129369 A CN 108129369A CN 201810050512 A CN201810050512 A CN 201810050512A CN 108129369 A CN108129369 A CN 108129369A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
The present invention relates to the relevant drug field of angiocardiopathy.Specifically, the present invention relates to the P2Y12 receptor antagonists of one kind thioacetic acid containing diphenyl structure, preparation method and its applications in treatment angiocardiopathy especially thrombotic disease drug is prepared.Wherein, R1Selected from H, C1‑C6Alkyl；R2Selected from H, C1‑C6Alkyl, C3‑C8Cycloalkyl.
Description
Technical field
The present invention relates to the drug fields of vascular diseases treatment.In particular it relates to vascular diseases especially
The P2Y12 receptor antagonists of the medicative a kind of structure of thioacetic acid containing diphenyl of thrombotic disease tool, its preparation
Method and its purposes in pharmacy.
Background technology
The medical complication related with thrombosis occurs represents a kind of main cause of death.Some are with developing thrombus shape
Into related pathology example includes acute myocardial infarction, unstable angina pectoris and chronic stable angina pectoris, transience lacks
Blood breaking-out, cerebrovascular accident, peripheral vascular disease, pre-eclampsia and eclampsia, deep vein thrombosis formed, embolism (cerebral embolism,
Pulmonary embolism, coronary embolism, renal embolism etc.), disseminated intravascular coagulation or thrombotic thrombocytopenic purpura.It is invading
Still there are the danger that thrombosis and restenosis complication occurs, the invasive surgical operation during and after entering property surgical operation
Such as the peace of angioplasty, carotid endarterectomy, aortocoronary by-pass grafting or stent or vascular endoprostheses
It puts.
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：It circulating cells or is presented in blood flow along vascular wall
The damaging endothelial cell mediator discharged or the sub-endothelial matrix exposed during injury of blood vessel (such as collagen) blood
Bolt forms molecule.In addition, blood platelet can also be observed such as in narrow blood vessel under the blood flow conditions with shearing force
As activation.After activation, the cycle platelet adhesion reaction is simultaneously accumulated at injury of blood vessel, forms thrombus.In this process, blood
Generated thrombus is that volume is sufficiently large to blood flow in pipe, so as to which it be made partially or completely to be blocked.
In vein, thrombus can also be located to be formed slowly in obstruction or blood flow.Due to the property of these phlebothrombosises, can generate
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 of aggregation 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 by the red blood cell of damage and the endothelial cell of atherosclerosis wall in cycle, it is more specific and
Speech, as with compacted grains very high concentration store ADP in place of activation blood platelet secreted by.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 receptors are stated, are combined with the PLC β stimulations through G α q, are responsible for the mobilization of internal calcium storage, the change of platelet shape and in ADP
On moment aggregation.The P2Y12, the activation of inhibition and PI-3 kinases with the adenyl cyclase through G α i2 are combined, are 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 the use of P2Y12-/- mouse (Conley et al., Nature, 2001,409,202-207)
Described two receptors thrombus developing importance in vivo.In the mankind, P2Y12 gene defects and bleeding table are had been described above
Type is related with the significantly decline of the ADP- platelet aggregations induced.Human clinical put into practice in use clopidogrel it has been proved that
Represent the critical therapeutic strategy for the treatment of angiocardiopathy by Antagonist block P2Y12 receptors.Clopidogrel is thienopyridine
The prodrug of family, active metabolite are covalently bond to P2Y12 receptors, and lead to internal biologically active pdgf can not retroactive inhibition
(Savi et al., Biochem.Biophys.Res.Commun., 2001,283,379-383), the drug is in several clinical examinations
Middle its efficiency of display is tested, that is, reduces dangerous patient and cardiovascular unexpected danger occurs.
The invention discloses the P2Y12 receptor antagonists of one kind thioacetic acid containing diphenyl structure, these compounds can be used
In the drug for preparing treatment angiocardiopathy especially thrombotic disease.
Invention content
It is an object of the present invention to provide a kind of P2Y12 receptor antagonists of the excellent activity with general formula I.
It is a further object to provide prepare the method with compounds of formula I.
The content of present invention is specifically described in conjunction with the purpose of the present invention.
The present invention is with compounds of formula I with following structural formula：
Wherein, R1Selected from H, C1-C6Alkyl；
R2Selected from H, C1-C6Alkyl, C3-C8Cycloalkyl.
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention can be synthesized by following route：
It compound II and is reacted with triphenylphosphine, obtains salt III；Compound III is handled with n-BuLi, is obtained corresponding
Phosphonium ylide IV, the latter react in case of heating with compound V, obtain compound VI；Compound VI and bromine reaction, obtain
Two bromo-derivative VII；Compound VII reacts under alkaline condition with thioacetic acid, obtains compound I；R1And R2Institute as defined above
It states.
Compound of Formula I of the present invention has the antagonism of P2Y12 receptors, can be used as an active ingredient in the preparation of the heart
Vascular diseases especially thrombotic disease medicine.The activity of compound of Formula I of the present invention is by external people
The inhibition experiment of blood platelet aggregation is verified.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.Such as the dosage taken daily is about
In the range of 1mg-700mg/ people, it is divided into primary or is administered for several times.The dosage for actually taking compound of Formula I of the present invention can be by curing
It takes root and is determined according to related 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 according to the present invention is made should all
Within the protection domain required by the application claim.
The synthesis of 1 compound I-1 of embodiment
The synthesis of step 1. compound III-1
Compound II-1 (1.63g, 10mmol) and triphenylphosphine (2.62g, 10mmol) are dissolved in 30mL chloroforms, under stirring
It is refluxed overnight, a large amount of crystal is precipitated.Reaction mixture cools down, and collected by suction solid is dried in vacuo, obtains compound at room temperature
III-1, white crystalline solid, ESI-MS, m/z=345 ([M-Br]+)。
The synthesis of step 2. compound VI-1
Compound III-1 (3.40g, 8mmol) is dissolved in the THF of 50mL dryings, stirring, be cooled in nitrogen atmosphere-
20 DEG C, the hexane solution (5mL, 8mmol) of the n-BuLi of 1.6M is then slowly added dropwise with syringe, after being added dropwise, reaction
Mixture continues stirring 1 hour at such a temperature.Benzophenone (V-1,1.46g, 8mmol) is slowly added dropwise again with syringe to be dissolved in
Solution made of the THF of 5mL dryings, after being added dropwise, reaction mixture stirs half an hour at such a temperature, is then warming up to room
Temperature stirring 1 hour, finally stirred at reflux overnight again.Reaction mixture is carefully poured into 300mL ice water, and 50mL is used in stirring
×3CH2Cl2Extraction merges extraction phase, is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is steamed in rotation
It is evaporated on hair instrument, residue is purified using silica gel column chromatography, obtains compound VI-1, ESI-MS, m/z=249 ([M+H]+), in vain
Color solid.
The synthesis of step 3. compound VII-1
Compound VI-1 (0.99g, 4mmol) is dissolved in 10mL CH2Cl2In, Br is slowly added dropwise in stirring2(0.80g,5mmol)
With 1mL CH2Cl2The solution of preparation, after being added dropwise, reaction mixture is stirred at room temperature overnight, and TLC, which is checked, to be found to have reacted
Into.30mL ether and 20mL n-hexanes are added in into reaction mixture, is stirred 1 hour at room temperature, is filtered, collects solid, room temperature
Lower vacuum drying obtains compound VII-1, ESI-MS, m/z=409 ([M+H]+)。
The synthesis of step 4. compound I-1
Thioacetic acid (0.28g, 3mmol) is dissolved in 10mL ethyl alcohol, is stirred, 30% NaOH solution is slowly added dropwise
(1mL) then adds in compound VII-1 (0.82g, 2mmol), and reaction mixture flows back 24 hours in nitrogen atmosphere, TLC inspections
Discovery reaction is looked into complete.Reaction mixture is carefully poured into 200mL ice water, stirring, is adjusted pH=2-3 with concentrated hydrochloric acid, is used
50mL×3CH2Cl2Extraction merges extraction phase, is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is being revolved
Turn to be evaporated on evaporimeter, residue is purified using silica gel column chromatography, obtains compound I-1, ESI-MS, m/z=337 ([M-
H]-), white solid.
The synthesis of 2 compound I-2 of embodiment
The synthesis of step 1. compound III-2
Compound II-2 (1.77g, 10mmol) and triphenylphosphine (2.62g, 10mmol) are dissolved in 30mL chloroforms, under stirring
It is refluxed overnight, a large amount of crystal is precipitated.Reaction mixture cools down, and collected by suction solid is dried in vacuo, obtains compound at room temperature
III-2, white crystalline solid, ESI-MS, m/z=359 ([M-Br]+)。
The synthesis of step 2. compound VI-2
Compound III-2 (3.51g, 8mmol) is dissolved in the THF of 50mL dryings, stirring, be cooled in nitrogen atmosphere-
20 DEG C, the hexane solution (5mL, 8mmol) of the n-BuLi of 1.6M is then slowly added dropwise with syringe, after being added dropwise, reaction
Mixture continues stirring 1 hour at such a temperature.V-2 (1.68g, 8mmol) is slowly added dropwise again with syringe and is dissolved in 5mL dryings
Solution made of THF, after being added dropwise, reaction mixture stirs half an hour at such a temperature, is then warming up to that be stirred at room temperature 1 small
When, last stirred at reflux overnight again.Reaction mixture is carefully poured into 300mL ice water, stirring, with 50mL × 3CH2Cl2Extraction
It takes, merges extraction phase, be washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is steamed on a rotary evaporator
Dry, residue is purified using silica gel column chromatography, obtains compound VI-2, ESI-MS, m/z=291 ([M+H]+), canescence is solid
Body.
The synthesis of step 3. compound VII-2
Compound VI-2 (1.16g, 4mmol) is dissolved in 10mL CH2Cl2In, Br is slowly added dropwise in stirring2(0.80g,5mmol)
With 1mL CH2Cl2The solution of preparation, after being added dropwise, reaction mixture is stirred at room temperature overnight, and TLC, which is checked, to be found to have reacted
Into.30mL ether and 20mL n-hexanes are added in into reaction mixture, is stirred 1 hour at room temperature, is filtered, collects solid, room temperature
Lower vacuum drying obtains compound VII-2, ESI-MS, m/z=451 ([M+H]+)。
The synthesis of step 4. compound I-2
Thioacetic acid (0.28g, 3mmol) is dissolved in 10mL ethyl alcohol, is stirred, 30% NaOH solution is slowly added dropwise
(1mL) then adds in compound VII-2 (0.90g, 2mmol), and reaction mixture flows back 24 hours in nitrogen atmosphere, TLC inspections
Discovery reaction is looked into complete.Reaction mixture is carefully poured into 200mL ice water, stirring, is adjusted pH=2-3 with concentrated hydrochloric acid, is used
50mL×3CH2Cl2Extraction merges extraction phase, is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is being revolved
Turn to be evaporated on evaporimeter, residue is purified using silica gel column chromatography, obtains compound I-2, white solid, ESI-MS, m/z=
379([M-H]-)。
Embodiment 3-8
With reference to the method for embodiment 1,2, following compounds have been synthesized：
9 Compound ira vitro of embodiment is to the hematoblastic inhibiting effect of people's blood
Using the 20mL syringes of the sodium citrate buffered containing 2mL, blood is acquired from healthy volunteer.Blood is shifted
Into PA tube, and in room temperature centrifugation (100g) 5 minutes (braking for not using centrifuge).Then supernatant richness is collected
Thrombocyte plasma (PRP), dilution, and carry out platelet count before using it for aggregation and measuring.
The measurement (platelet aggregation instrument) of 37 DEG C of progress platelet aggregations in a glass tube.4 μ L are tested into compound (than needing
The DMSO solution of dense 100 times of the final concentration wanted) it is mixed with the PRP of 392 μ L brand-news, and be incubated 1 minute with stirring.Then to mixed
Close the ADP solution that 250 μM of 4 μ L are added in object.Lasting stirring, passes through 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 highly to represent
It calculates as a result, and being represented with suppression percentage.(inhibition on platelet aggregation) IC of the compounds of this invention50It is as shown in the table.
Can be seen that the compound of the present invention from upper table result has very strong antagonism to P2Y12, can be used as system
The drug of standby treatment angiocardiopathy especially thrombotic disease.
Claims (4)
1. the compound with general formula I,
Wherein, R1Selected from H, C1-C6Alkyl；
R2Selected from H, C1-C6Alkyl, C3-C8Cycloalkyl.
2. compound of Formula I defined in claim 1, is selected from,
3. synthesize the claim 1-2 methods as defined in any one for belonging to compounds of formula I：
It compound II and is reacted with triphenylphosphine, obtains salt III；Compound III is handled with n-BuLi, obtains corresponding phosphine leaf
Vertical moral IV, the latter react in case of heating with compound V, obtain compound VI；Compound VI and bromine reaction, obtain dibromo
For object VII；Compound VII reacts under alkaline condition with thioacetic acid, obtains compound I；R1And R2Definition such as claim
Described in 1-2.
4. claim 1-2 compound of Formula I as defined in any one is in terms for the treatment of thrombotic disease drug is prepared
Using.
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| CN105130893A (en) * | 2015-09-08 | 2015-12-09 | 大连理工大学 | 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative, preparation method and application in resisting aggregation of thrombocyte |
| CN104529927B (en) * | 2015-01-13 | 2016-04-06 | 佛山市赛维斯医药科技有限公司 | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene |
| CN106831866A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | One aryl oxidized phosphine P2Y12 receptor antagonists of class alcoxyl thiophene and application thereof |
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2018
- 2018-01-18 CN CN201810050512.7A patent/CN108129369B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529927B (en) * | 2015-01-13 | 2016-04-06 | 佛山市赛维斯医药科技有限公司 | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene |
| CN105111118A (en) * | 2015-08-14 | 2015-12-02 | 天津小新医药科技有限公司 | L-menthol P2Y12 receptor antagonists, preparation method therefor and use thereof |
| CN105130893A (en) * | 2015-09-08 | 2015-12-09 | 大连理工大学 | 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative, preparation method and application in resisting aggregation of thrombocyte |
| CN106831866A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | One aryl oxidized phosphine P2Y12 receptor antagonists of class alcoxyl thiophene and application thereof |
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