CN105153192A - Substituted tetrahydrothienopyridine derivative and application thereof - Google Patents

Substituted tetrahydrothienopyridine derivative and application thereof Download PDF

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CN105153192A
CN105153192A CN201510553507.4A CN201510553507A CN105153192A CN 105153192 A CN105153192 A CN 105153192A CN 201510553507 A CN201510553507 A CN 201510553507A CN 105153192 A CN105153192 A CN 105153192A
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compound
formula
carbon
clopidogrel
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CN105153192B (en
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张维威
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Nanjing Major Biotechnology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

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Abstract

The invention discloses a substituted tetrahydrothienopyridine derivative, application thereof, and pharmaceutically acceptable acidic salt, solvate or hydrate as shown in a general formula (I), wherein R1, R2 and X are as defined in the description. In addition, the invention further discloses a synthesis method of the compound, medicine combinations and application thereof to preparation of medicines for inhibiting platelet aggregation and preventing or treating thrombus and embolism related diseases.

Description

The tetrahydro thienopyridine derivative replaced and application thereof
Technical field
The invention belongs to field of pharmaceutical chemistry technology, more particularly, relate to a kind of tetrahydro thienopyridine derivative of novel replacement, the acceptable acid salt of pharmacy, solvate or hydrate, their preparation method, pharmaceutical composition and their purposes in the medicine for the preparation of anticoagulant, prevention or treatment thrombus and embolism relative disease.
Background technology
Clopidogrel is the medicament for resisting platelet aggregation of widespread use clinically, and in the research to its internal metabolism process, the clopidogrel proto-drug finding that there is 85% is inactive clopidogrel carboxylic acid derivative through liver hydrolysis metabolism; In addition, metabolism is not had to be that the clopidogrel of nonactive meta-bolites also needs to rely on P450 enzyme system metabolism activation, due to the difference that P450 enzyme system in Different Individual liver expresses, make the clopidogrel relying on the metabolism onset of P450 enzyme system on clinical therapeutic efficacy, produce larger individual difference, the individuality that P450 metabolic activity is weak, take clopidogrel poor efficiency or invalid, produce " clopidogrel Resistant " on-the-spot, the cardiovascular event incidences such as thrombosis can not get reducing.
Prasugrel is the another one medicament for resisting platelet aggregation that Japan three is total to drugmaker and the exploitation of Lilly drugmaker, although do not have similar " drug resistance " compared with clopidogrel, rapid-action, active strong, has larger bleeding risk.
So rapid-action, active strong, do not have drug resistance, the medicament for resisting platelet aggregation that bleeding risk is little becomes clinical active demand simultaneously.
Summary of the invention
The invention provides a kind of tetrahydro thienopyridine derivative of novel replacement, as medicament for resisting platelet aggregation, prevention or the development for the treatment of in thrombus and embolism relative disease; These medicines have the features such as rapid-action, active strong, bleeding risk is little and difference between biont is little.
The object of this invention is to provide a kind of tetrahydro thienopyridine derivative of novel replacement, it is by the active metabolite identical with clopidogrel of esterase (but not relying on P450 enzyme system in liver) the metabolism generation in blood.Because the ubiquity of esterase in blood of human body, avoid " clopidogrel Resistant " phenomenon of clopidogrel.
Second object of the present invention is to provide the preparation method of above-mentioned tetrahydro thienopyridine derivative.
3rd object of the present invention is to provide the pharmaceutical composition comprising above-mentioned tetrahydro thienopyridine derivative.
4th object of the present invention is to provide above-mentioned tetrahydro thienopyridine derivative or pharmaceutical composition for the preparation of anticoagulant, or the purposes in the medicine of prevention or treatment thrombus and embolism relative disease.
Specifically, the invention provides a kind of tetrahydro thienopyridine derivative of replacement, as the compound of general formula I, or its pharmaceutically acceptable acid salt, solvate or hydrate:
Wherein:
R 1for the straight or branched alkyl of 1-6 carbon, the cycloalkyl of a 3-6 carbon or OR 3;
R 2for tauryl, stearyl-, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or linolenyl;
R 3for the straight or branched alkyl of 1-6 carbon or the cycloalkyl of 3-6 carbon;
R 4for hydrogen, the straight or branched alkyl of a 1-6 carbon or the cycloalkyl of 3-6 carbon; With
X is hydrogen, chlorine, fluorine, bromine or iodine;
n＝0-6。
In a kind of preferred embodiment of the present invention, formula I provided by the invention, wherein, R 1for cyclopropyl or methoxyl group or oxyethyl group.
In a kind of preferred embodiment of the present invention, formula I provided by the invention, wherein, R 2for
R 4for hydrogen, the straight or branched alkyl of a 1-6 carbon or the cycloalkyl of 3-6 carbon; N=0-6.
In a kind of preferred embodiment of the present invention, formula I provided by the invention, wherein, X is chlorine or fluorine.
In a kind of preferred embodiment of the present invention, formula I provided by the invention, wherein, R 1for cyclopropyl or methoxyl group, oxyethyl group;
R 2for
R 4for hydrogen, the straight or branched alkyl of a 1-6 carbon or the cycloalkyl of 3-6 carbon; N=0-6; With
X is chlorine or fluorine.
In a kind of more preferred of the present invention, formula I provided by the invention, wherein, R 1for methoxyl group;
R 2for
R 4for hydrogen, the straight or branched alkyl of a 1-6 carbon or the cycloalkyl of 3-6 carbon; N=0-6; With
X is chlorine.
In a kind of preferred embodiment of the present invention, formula I provided by the invention, wherein, R 2for tauryl, stearyl-, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or linolenyl.
In a kind of preferred embodiment of the present invention, formula I provided by the invention, wherein, R 1for cyclopropyl or methoxyl group or oxyethyl group;
R 2for tauryl, stearyl-, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or linolenyl; With
X is chlorine or fluorine.
In a kind of more preferred of the present invention, formula I provided by the invention, wherein, R 1for methoxyl group;
R 2for tauryl, stearyl-, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or linolenyl; With
X is chlorine.
In particularly preferred embodiment of the present invention, compound provided by the invention is selected from the one in following compound, or its pharmaceutically acceptable acid salt, solvate or hydrate:
In embodiments of the invention, described derivative provided by the invention comprises enantiomer and the racemic modification of formula I.
In embodiments of the invention, derivative of the present invention comprises formula I or its pharmaceutically acceptable acid salt, includes but not limited to the salt that compound and following acid are formed: hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, citric acid, tartrate, phosphoric acid, lactic acid, acetic acid, toxilic acid, fumaric acid, oxysuccinic acid, tussol, methylsulfonic acid, Phenylsulfonic acid, tosic acid, oxalic acid or succsinic acid.
In embodiments of the invention, formula I provided by the invention, wherein, the straight or branched alkyl of a described 1-6 carbon is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group or hexyl.
In embodiments of the invention, formula I provided by the invention, wherein, the cycloalkyl of a described 3-6 carbon is selected from cyclopropane base, tetramethylene base, pentamethylene base or cyclohexyl.
Second aspect, the invention provides the preparation method of above-mentioned substituted-tetrahydro thienopyridine derivative formula I or its pharmaceutical acceptable acid formula salt, solvate or hydrate, comprises the following steps:
Formula II compound and formula III compound or formula IV compound react, and obtain formula I
Wherein, the R in formula II compound, formula III compound and formula IV compound 1, R 2, X defined such as formula in I, Z is leavings group, as chlorine, pentafluranol base, nitro phenolic group etc.
As the preferred embodiment of one, the invention provides the tetrahydro thienopyridine derivative formula I of above-mentioned replacement or the preparation method of its pharmaceutical acceptable acid formula salt, solvate or hydrate, described method comprises and is dissolved in organic solvent by formula II compound or its salt, add alkali under cooling in batches, then react with formula III compound, obtain formula I, can be further purified by ordinary method such as recrystallization, column chromatography etc. if necessary.Here, described alkali can be mineral alkali or organic bases, can be selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine or DIPEA etc.
Especially, the ends such as the compounds of this invention such as MJ10605 are contained to the compound of reactive group, corresponding protecting group can be adopted, as 9-fluorenylmethyloxycarbonyl protection, and after one-tenth ester condensation reaction, increase and use piperidines deprotection steps.
The third aspect, the present invention goes back providing package comprises formula I or its acid salt pharmaceutically accepted, solvate or hydrate pharmaceutical composition containing the aforementioned substituted-tetrahydro thienopyridine derivative for the treatment of significant quantity, and this pharmaceutical composition can also comprise pharmaceutically acceptable carrier or thinner.This pharmaceutical composition is by intravenous administration, organize administration, Intraperitoneal medication, oral administration or intranasal administration by being injected into.This pharmaceutical composition can have the form being selected from solution, dispersion, suspension, powder, capsule, tablet, pill, time-release capsules, time release tablet and time release pill.The dosage of this pharmaceutical composition is 5-5000mg/ day.
Fourth aspect, the invention provides acid salt, solvate or hydrate that above-mentioned substituted-tetrahydro thienopyridine derivative pharmaceutically accepts such as formula I or its for the preparation of platelet aggregation-against, prevention or treatment thrombus and embolism relative disease, the purposes especially in prevention or the postoperative thrombotic medicine for the treatment of atheromatosis, myocardial infarction, stenocardia, apoplexy, ischemia cerebral thrombosis, peripheral arterial disease, acute coronary artery syndrome or calcification score.
Compared with prior art, the tetrahydro thienopyridine derivative of novel replacement of the present invention has significant anticoagulant effect, and its antiplatelet aggregative activity is even significantly better than clopidogrel.
Compound of the present invention, by the active metabolite identical with clopidogrel of esterase (but not relying on P450 enzyme system in liver) the metabolism generation in blood, avoids " clopidogrel Resistant " phenomenon of clopidogrel.
In addition, in body, release experiment shows, new substituted tetrahydro thienopyridine derivative of the present invention can effectively be converted into pharmacologically active metabolite in vivo and play a role, and the precursor 2-oxygen base-clopidogrel concentration of active metabolite is significantly higher than clopidogrel.
Accompanying drawing explanation
Fig. 1 male SD rat (n=3) gavage gives the Plasma Concentration (ng/mL) of 2-oxygen base-clopidogrel after the compounds of this invention of 2mg/kg and bisulfate clopidogrel.
After the administration in continuous 5 days of Fig. 2 male SD rat, L-Arginine compares (20 μm of ol/LADP inductions).
Embodiment
Carry out exemplary illustration embodiment of the present invention by the following examples, for the ordinary skill in the art, under the teachings of the present invention, according to prior art, to the improvement that embodiment of the present invention is carried out, still belong in protection scope of the present invention.
The source of the raw materials of compound used in embodiment is: all reagent is bought by Reagent Company, starting raw material (2S)-2-(2-chloro-phenyl-)-2-(2-oxygen-5,6,7,7a-tetramethylene sulfide is [3,2-c] pyridyl also) methyl acetate with reference to Chinese patent application 201210333184.4 method by 2-chloro mandelic acid methyl esters benzene sulfonate synthesize and through split obtain.
Hydrogen nuclear magnetic resonance modal data is gathered by BrukerAV-300 nuclear magnetic resonance spectrometer and processes.
Embodiment 1
The synthesis of cyclohexyloxy
Sodium hydride (8.79g) by 60% is suspended in tetrahydrofuran (THF) (500ml), add hexalin (10g), mixture stirs 30 minutes at 0 DEG C, then adds bromoacetic acid (13.9g), adds rear back flow reaction 2 hours.Water is added in reaction solution, Rotary Evaporators removes organic solvent, the aqueous solution is diluted with water to 200ml, with methyl tertiary butyl ether washing, with 1N hcl acidifying water layer, extract with methyl tertiary butyl ether, be separated organic layer, anhydrous magnesium sulfate drying, reduction vaporization falls organic solvent, obtain oily matter (cyclohexyloxy) (12.9g), yield 81.6%. 1H-NMR(CDCl 3)δ：1.18～1.47(5H,m),1.52～1.63(1H,m),1.72～1.85(2H,m),1.90～2.03(2H,m),3.36～3.47(1H,m),4.13(2H,s)。
Embodiment 2
The synthesis of MJ10601
Cyclohexyloxy (1.58g) 10ml sulfur oxychloride suspendible, 60 DEG C are reacted 2 hours, remove solvent under reduced pressure, obtain cyclohexyloxy Acetyl Chloride 98Min., by (2S)-2-(2-chloro-phenyl-)-2-(2-oxygen-5, 6, 7, 7a-tetramethylene sulfide also [3, 2-c] pyridyl) methyl acetate (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), add 0.3ml triethylamine, cyclohexyloxy Acetyl Chloride 98Min. (0.18g) is dripped at 0 DEG C, after dropping terminates, be warming up to room temperature reaction 3 hours, reaction solution is poured in 30ml water, ethyl acetate (30ml × 3) aqueous phase extracted, merge organic phase, wash with saturated sodium bicarbonate aqueous solution, use saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness organic phase obtains oily matter 0.7g.Adopt silica gel column chromatography to be separated and obtain white solid 0.25g, yield 52.3%.MS(m/z)：478.2[M+1]+； 1H-NMR(DMSO-d6)δ：1.16～1.43(5H,m),1.51～1.63(1H,m),1.72～1.86(2H,m),1.89～2.05(2H,m),2.66～2.91(m，4H),3.35～3.69(m,3H),3.71(s，3H),4.14(2H，s),4.91(s,1H),6.25(s,1H),7.21～7.68(m,4H)。
Embodiment 3
The synthesis of propoxy-acetic acid
Sodium hydride (8.79g) by 60% is suspended in tetrahydrofuran (THF) (500ml), add n-propyl alcohol (6g), mixture stirs 30 minutes at 0 DEG C, then adds bromoacetic acid (13.9g), adds rear back flow reaction 2 hours.Water is added in reaction solution, Rotary Evaporators removes organic solvent, the aqueous solution is diluted with water to 200ml, with methyl tertiary butyl ether washing, with 1N hcl acidifying water layer, extract with methyl tertiary butyl ether, be separated organic layer, anhydrous magnesium sulfate drying, reduction vaporization falls organic solvent, obtain oily matter (propoxy-acetic acid) (10.9g), yield 92.3%. 1H-NMR(CDCl 3)δ：0.89(3H,t),1.51(2H,m),3.37(2H,t),4.12(2H,s)。
Embodiment 4
The synthesis of MJ10602
Propoxy-acetic acid (1.18g) 10ml sulfur oxychloride suspendible, 60 DEG C are reacted 2 hours, remove solvent under reduced pressure, obtain propoxy-Acetyl Chloride 98Min., by (2S)-2-(2-chloro-phenyl-)-2-(2-oxygen-5, 6, 7, 7a-tetramethylene sulfide also [3, 2-c] pyridyl) methyl acetate (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), add 0.3ml triethylamine, propoxy-Acetyl Chloride 98Min. (0.14g) is dripped at 0 DEG C, after dropping terminates, be warming up to room temperature reaction 3 hours, reaction solution is poured in 30ml water, ethyl acetate (30ml × 3) aqueous phase extracted, merge organic phase, wash with saturated sodium bicarbonate aqueous solution, use saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness organic phase obtains oily matter 0.8g.Adopt silica gel column chromatography to be separated and obtain white solid 0.21g, yield 47.9%.MS(m/z)：438.1[M+1]+； 1H-NMR(DMSO-d6)δ：0.88(3H,t),1.51(2H,m),2.65～2.91(m，4H),3.34～3.68(m,4H),3.71(s，3H),4.13(2H,s),4.93(s,1H),6.26(s,1H),7.23～7.68(m,4H)。
Embodiment 5
The synthesis of 2-(tetrahydropyrans-4-oxygen base) acetic acid
Sodium hydride (8.79g) by 60% is suspended in tetrahydrofuran (THF) (500ml), add tetrahydropyrans-4-alcohol (10.2g), mixture stirs 30 minutes at 0 DEG C, then adds bromoacetic acid (13.9g), adds rear back flow reaction 2 hours.Water is added in reaction solution, Rotary Evaporators removes organic solvent, the aqueous solution is diluted with water to 200ml, with methyl tertiary butyl ether washing, with 1N hcl acidifying water layer, extract with methyl tertiary butyl ether, be separated organic layer, anhydrous magnesium sulfate drying, reduction vaporization falls organic solvent, obtain oily matter (2-(tetrahydropyrans-4-oxygen base) acetic acid) (10.9g), yield 69.0%. 1H-NMR(CDCl 3)δ：1.58～1.91(4H,m),3.23(1H,m),3.41～3.65(4H,m),4.21(2H,s)。
Embodiment 6
The synthesis of MJ10603
2-(tetrahydropyrans-4-oxygen base) acetic acid (1.60g) 10ml sulfur oxychloride suspendible, 60 DEG C are reacted 2 hours, remove solvent under reduced pressure, obtain 2-(tetrahydropyrans-4-oxygen base) Acetyl Chloride 98Min., by (2S)-2-(2-chloro-phenyl-)-2-(2-oxygen-5, 6, 7, 7a-tetramethylene sulfide also [3, 2-c] pyridyl) methyl acetate (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), add 0.3ml triethylamine, 2-(tetrahydropyrans-4-oxygen base) Acetyl Chloride 98Min. (0.18g) is dripped at 0 DEG C, after dropping terminates, be warming up to room temperature reaction 3 hours, reaction solution is poured in 30ml water, ethyl acetate (30ml × 3) aqueous phase extracted, merge organic phase, wash with saturated sodium bicarbonate aqueous solution, use saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness organic phase obtains oily matter 1.1g.Adopt silica gel column chromatography to be separated and obtain white solid 0.23g, yield 47.9%.MS(m/z)：480.2[M+1] +； 1H-NMR(DMSO-d6)δ：1.61～1.89(m,4H)，2.66～2.91(m，4H),3.25(s,1H),3.38～3.75(m,6H),3.71(s，3H),4.21(s,2H),4.96(s,1H),6.23(s,1H),7.22～7.68(m,4H)。
Embodiment 7
The synthesis of sec.-propyl ethoxyacetic acid
Sodium hydride (8.79g) by 60% is suspended in tetrahydrofuran (THF) (500ml), add Virahol (6g), mixture stirs 30 minutes at 0 DEG C, then adds bromoacetic acid (13.9g), adds rear back flow reaction 2 hours.Water is added in reaction solution, Rotary Evaporators removes organic solvent, the aqueous solution is diluted with water to 200ml, with methyl tertiary butyl ether washing, with 1N hcl acidifying water layer, extract with methyl tertiary butyl ether, be separated organic layer, anhydrous magnesium sulfate drying, reduction vaporization falls organic solvent, obtain oily matter sec.-propyl ethoxyacetic acid (10.3g), yield 87.3%. 1H-NMR(CDCl 3)δ：1.15(6H,d),3.21(1H,m),4.33(2H,s)。
The synthesis of embodiment 8MJ10604
Sec.-propyl ethoxyacetic acid (1.18g) 10ml sulfur oxychloride suspendible, 60 DEG C are reacted 2 hours, remove solvent under reduced pressure, obtain sec.-propyl oxygen base Acetyl Chloride 98Min., by (2S)-2-(2-chloro-phenyl-)-2-(2-oxygen-5, 6, 7, 7a-tetramethylene sulfide also [3, 2-c] pyridyl) methyl acetate (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), add 0.3ml triethylamine, sec.-propyl oxygen base Acetyl Chloride 98Min. (0.18g) is dripped at 0 DEG C, after dropping terminates, be warming up to room temperature reaction 3 hours, reaction solution is poured in 30ml water, ethyl acetate (30ml × 3) aqueous phase extracted, merge organic phase, wash with saturated sodium bicarbonate aqueous solution, use saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness organic phase obtains oily matter 0.9g.Adopt silica gel column chromatography to be separated and obtain white solid 0.22g, yield 49.2%.MS(m/z)：438.2[M+1] +； 1H-NMR(DMSO-d6)δ：1.14(d,6H),2.63～2.91(m，4H),3.12(m,1H),3.36～3.66(m,2H),3.73(s，3H),4.37(s,2H),4.96(s,1H),6.27(s,1H),7.22～7.69(m,4H)。
Embodiment 9
The synthesis of MJ10611
By (2S)-2-(2-chloro-phenyl-)-2-(2-oxygen-5, 6, 7, 7a-tetramethylene sulfide also [3, 2-c] pyridyl) methyl acetate (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), add 0.3ml triethylamine, hexadecanoyl chloride (0.4g) is dripped at 0 DEG C, after dropping terminates, be warming up to room temperature reaction 3 hours, reaction solution is poured in 30ml water, ethyl acetate (30ml × 3) aqueous phase extracted, merge organic phase, wash with saturated sodium bicarbonate aqueous solution, use saturated common salt water washing, anhydrous sodium sulfate drying, evaporate to dryness organic phase obtains oily matter 1.3g.Adopt silica gel column chromatography to be separated and obtain white solid 0.45g, yield 43.3%.MS(m/z)：576.2[M+1] +； 1H-NMR(DMSO-d6)δ：0.92(t,3H),1.25～1.32(m,24H),1.53(m，2H),2.53(t,2H),2.67～3.12(m,4H),3.39～3.68(m,2H),3.75(s，3H),4.96(s,1H),6.25(s,1H),7.23～7.68(m,4H)。
Embodiment 10
The preparation of MJ10601 hydrochloride
Compound MJ10601 (478mg) is dissolved in anhydrous tetrahydro furan, stirs borehole cooling to 0 DEG C, pass into dry hydrogen chloride gas, collect and separate out solid, obtain off-white powder (316mg), yield 61.4%.
The different acid of other salt reacts preparation in anhydrous organic solvent.
Embodiment 11 platelet aggregation-against is tested:
The preparation of test solution: get bisulfate clopidogrel appropriate, add 0.5%CMC-Na solution, grinding, the suspension of obtained 0.6mg/ml, 2.0mg/ml, to obtain final product.Same method, gets compound MJ10601, MJ10602 appropriate, the suspension of obtained 0.2mg/ml, 0.6mg/ml; Get compound MJ10604, MJ10611 appropriate, the suspension of obtained 0.6mg/ml, to obtain final product.
Animal: SD rat, male, 250-270g.Totally 54, be divided into 9 groups, often organize 6.Rat gives each test liquid by the volume gavage of 5ml/kg, converts respectively supply examination thing dosage to be 1-10mg/kg.Control group gives equal-volume 0.5%CMC-Na solution.
Method and result: after gastric infusion 2 hours, each rat femoral gets blood, mixes with suitable proportion with 3.8% liquor sodii citratis, centrifugal 7 minutes (1000rpm), obtained platelet rich plasma (PRP); Get another part of whole blood, with method with 3000rpm centrifugal 5 minutes, obtained platelet poor plasma (PPP).Add PPP in PRP appropriate, make final PC be 5 × 10 9--10 × 10 9/ L.With 5 μm of ADP (adenosine diphosphate (ADP)) test solutions in right amount for inductor adds in test fluid, on platelet aggregation instrument, measure the max platelet rate in 5 minutes, and calculate L-Arginine according to this.
L-Arginine=100% × (control group max platelet rate mean value-test group animal max platelet rate)/control group max platelet rate mean value, the results are shown in Table 1.
The restraining effect of table 1 pair rat platelet aggregation
* compare with clopidogrel 3mg/kg group and have pole significant difference (p<0.01)
# compares with clopidogrel 10mg/kg group significant difference (p<0.05)
Above-mentioned test-results display, test group curative effect of medication is almost 6 times that wait dosage Clopidogrel Hydrogensulfate, and the difference of this effect between different animals, test medication is obviously little compared with clopidogrel.
Pharmacokinetic in embodiment 12 body
Research shows, clopidogrel in vivo first metabolism activation generate 2-oxygen base-clopidogrel, 2-oxygen base-clopidogrel more further hydrolysis generate active metabolite.The formation reaction of 2-oxygen base-clopidogrel is the rate-limiting step of metabolism, so the growing amount of 2-oxygen base-clopidogrel is the key index evaluating this compounds activity in vivo.
The present inventor is by investigating rat after gavage gives compound MJ10601, MJ10602, MJ10604, MJ10611 and bisulfate clopidogrel respectively, their metabolite 2-oxygen base-clopidogrel through time process, metabolism can produce 2-oxygen base-clopidogrel in vivo after investigating compound administration, and evaluate their growing amount.
Healthy male SD rat 15 (body weight 250-270g), is divided into 5 groups, and often organize 3, gavage gives compound MJ10601, MJ10602, MJ10604, MJ10611 and bisulfate clopidogrel (2mg/kg) respectively.Do not show any abnormalities after administration, animal tolerates the compound of this dosage in prompting.Gather plasma sample in different time points, after organic solvent process, adopt the concentration of 2-oxygen base-clopidogrel in LC-MS/MS blood plasma, the results are shown in Figure 1.After rat takes test compounds and bisulfate clopidogrel, the pharmacokinetic parameter of 2-oxygen base-clopidogrel calculates according to non-compartment model, the results are shown in Table 2.
Table 2 male SD rat gavage gives the pharmacokinetic parameter of 2-oxygen base-clopidogrel after test compounds and bisulfate clopidogrel
Pharmacokinetic shows, test compounds can effectively be converted into pharmacologically active metabolite in vivo and play a role, and gavage produces the precursor 2-oxygen base-clopidogrel AUC of active metabolite higher than bisulfate clopidogrel group after giving MJ10601, MJ10602, MJ10604, MJ10611.
Meanwhile, the change of main pharmacokinetic parameter (as AUC etc.) between more each animal, investigational agent RSD is significantly less than clopidogrel group.
More than research shows, test compounds can be converted into 2-oxygen base-clopidogrel and further metabolism activation in vivo, and the individual difference of metabolism is little compared with clopidogrel group, and the specific enzymes dependency of medicine is less, and the possibility producing clopidogrel Resistant is less; In addition, the amount of the active metabolite precursor 2-oxygen base-clopidogrel produced in vivo due to test compounds is significantly higher than clopidogrel group when waiting quality, being expected to by reducing dosage, under rapid-action, that curative effect is high prerequisite, reducing the untoward reaction that nonactive metabolism produces.Except above compound, the AUC of 2-oxygen base-clopidogrel that the preferred compound metabolism that the present invention relates to produces also is greater than the AUC of the 2-oxygen base-clopidogrel waiting bisulfate clopidogrel generation under dosage, is all better than bisulfate clopidogrel group waiting L-Arginine under dosage conditions.
Platelet aggregation-against test after embodiment 13 multiple dosing
Trial-product gavage is given normal SD rats 5 days by this test, compares the restraining effect of trial-product different time points to 20 μm of olADP induced platelet aggregation.
Test with 54 male SD rats, be divided into 3 large groups at random, every large group 18, give 19.65mg/kg bisulfate clopidogrel, 2mg/kgMJ10611,1.52mg/kgMJ10602 respectively, successive administration 5 days, fasting 8 ~ 12h before last administration, every large component 6 group after administration in 5th day, often organize 3 and test 20 μm of ol/LADP induced platelet aggregation rates in 0.17h, 2h, 4h, 6h, 12h, 24h, testing method is shown in embodiment 11, calculates L-Arginine according to this.
L-Arginine=100% × (control group max platelet rate mean value-test group animal max platelet rate)/control group max platelet rate mean value, the results are shown in Table 3, Fig. 2.
Inhibition on platelet aggregation after the administration in continuous 5 days of table 3 male SD rat
Test-results show, compound of the present invention with the dosed administration of intimate clopidogrel 1/10, the thrombocyte restraining effect of generation and clopidogrel basically identical.

Claims (10)

1. formula I, or the acceptable acid salt of its pharmacy, solvate or hydrate:
Wherein:
R 1for the straight or branched alkyl of 1-6 carbon, the cycloalkyl of a 3-6 carbon or OR 3;
R 2for tauryl, stearyl-, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or linolenyl;
R 3for the straight or branched alkyl of 1-6 carbon or the cycloalkyl of 3-6 carbon;
R 4for hydrogen, the straight or branched alkyl of a 1-6 carbon or the cycloalkyl of 3-6 carbon;
X is hydrogen, chlorine, fluorine, bromine or iodine;
n＝0-6。
2. compound according to claim 1, wherein, R 1for cyclopropyl, methoxyl group or oxyethyl group.
3. compound according to claim 1, wherein, R 2for
R 4for hydrogen, the straight or branched alkyl of a 1-6 carbon or the cycloalkyl of 3-6 carbon; N=0-6.
4. compound according to claim 1, wherein, R 2for tauryl, stearyl-, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or linolenyl.
5. compound according to claim 1, wherein, X is chlorine or fluorine.
6. be selected from a compound for having structure, or the acceptable acid salt of its pharmacy, solvate or hydrate:
7., for the preparation of a method for compound according to any one of claim 1-6, comprise the following steps:
Formula II compound and formula III compound or formula IV compound react, and obtain formula I
Wherein, the R in formula II compound, formula III compound and formula IV compound 1, R 2, X as in claim 1 formula I define, Z is leavings group.
8. a pharmaceutical composition, described pharmaceutical composition comprises the compound according to any one of claim 1-6.
9. the compound according to any one of claim 1-6 or pharmaceutical composition as claimed in claim 8 are for the preparation of anticoagulant, or the purposes in the medicine of prevention or treatment thrombus and embolism relative disease.
10. purposes as claimed in claim 9, wherein, describedly prepare anticoagulant, or prevention or treatment thrombus and embolism relative disease comprise prevention or treatment stenocardia, atheromatosis, myocardial infarction, apoplexy, ischemia cerebral thrombosis, peripheral arterial disease or acute coronary artery syndrome or the postoperative thrombosis of calcification score.
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