CN102653539B - Compound for resisting platelet aggregation and medicament combination thereof - Google Patents
Compound for resisting platelet aggregation and medicament combination thereof Download PDFInfo
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- CN102653539B CN102653539B CN201110048356.9A CN201110048356A CN102653539B CN 102653539 B CN102653539 B CN 102653539B CN 201110048356 A CN201110048356 A CN 201110048356A CN 102653539 B CN102653539 B CN 102653539B
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Abstract
The invention provides a compound with a structural formula, wherein R1, R2, and R3 are the same or different, and are hydrogen, and -CO-(CH2)n-Ar, Ar is an aryl, a substituted aryl, a substituted styryl or a substituted benzoyl, and n is an integer between 0-8; or R1, R2, and R3 are the same or different, and are -(CH2)n-Ar, Ar is a substituted pyrazinyl, and n is an integer between 0-8; and R1, R2, and R3 are not hydrogen simultaneously. The compound has the effect of resisting platelet aggregation.
Description
Technical field
The present invention relates to the medicine that a class has antiplatelet aggregative activity, and the drug regimen that contains them, medical technical field belonged to.
Background technology
Cordis and cerebral accident is the particularly healthy common diseases of the elderly of a kind of serious threat mankind, even if apply most advanced, perfect at present treatment means, still can there is more than 50% cerebrovascular accident survivor's life not take care of oneself completely, cardiovascular and cerebrovascular diseases has the feature of " sickness rate is high, mortality ratio is high, disability rate is high, recurrence rate is high, complication many "-" four is high by more than one ", at present, China's Patients with Cardiovascular/Cerebrovascular Diseases has exceeded 2.7 hundred million people.Mutual adhesion between thrombocyte is called gathering.ADP, suprarenin, zymoplasm and collagen etc. are all the hematoblastic poly-agent that causes.It is different that to cause the accumulation process performance that poly-agent causes different.As add ADP can directly cause platelet aggregation, and the ADP that the thrombocyte of assembling discharges can cause new platelet aggregation again.Thereby can occur that two are assembled ripple.Collagen itself can not directly cause platelet aggregation, can only after induced platelet discharges ADP, cause.Assemble that the mechanism occurring is known so far an arachidonic acid pathway, dense granule approach and platelet activating factor approach, known many factors are as Ca
2+all relevant with hematoblastic gathering with Fibrinogen.In the thrombocyte activating, the arachidonic acid in platelet membrane is free out, last under the effect of different enzymes, forms thromboxane A2 (TXA2).Thromboxane A2 is the strongest hitherto known poly-agent that causes, and the prostacyclin I2 (PGI2) that endotheliocyte discharges can raise cyclic amp (cAMP) level by activated adenyl cyclase, anticoagulant.Prevention is recommended anticoagulation medicine, particularly antiplatelet drug clinically with treatment embolism class diseases always.
Acetylsalicylic acid, chemical name 2-(acetoxyl group) phenylformic acid, has antithrombotic effect in vivo, and it can suppress hematoblastic release reaction, suppresses hematoblastic gathering, and this is relevant with the minimizing that TXA2 generates.Clinically for preventing the outbreak of cardiovascular and cerebrovascular diseases.
Ligustrazine, chemistry 2，3，5，6-tetramethylpyrazine by name, pharmaceutical research shows, Ligustrazine has vasodilation, anticoagulant, prevents thrombosis, improves the multiple effects such as cerebral ischemia.
Forulic acid, chemical name ferulic acid, has platelet aggregation-against, suppresses platelet 5-HT and discharges, and suppresses the generation of platelet thrombus element a2 (txa2), strengthens prostaglandin(PG) activity, analgesia, the effects such as alleviating vascular spasm.
The present invention selects the compounds such as acetylsalicylic acid, Ligustrazine, forulic acid as lead compound, has designed formula I compound, finds that it has efficiently, low toxicity, selectivity high.
Summary of the invention
Medicine and the pharmaceutical salts thereof of a class antiplatelet aggregative activity are the present invention relates to
Wherein R
1, R
2and R
3identical or different, be hydrogen ,-CO-(CH
2)
n-Ar, wherein Ar is the styryl of aryl, substituted aryl, replacement or the benzoyl of replacement, the integer that n is 0-8;
Or R
1, R
2and R
3identical or different, for-(CH
2)
n-Ar, wherein Ar is the pyrazinyl replacing, the integer that n is 0-8;
And R
1, R
2and R
3when different, be hydrogen.
Ar is selected from specifically: phenyl, 2-(acetoxyl group) benzoyl, (3,5,6;-trimethylpyrazine)-2 bases, 3,5-Dimethoxyphenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, styryl, 3-methoxyl-styrene, halogen substituted phenyl, naphthyl, furyl, thiazolyl.
Wherein preferred compound is:
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-bis-[2-(acetoxyl group) benzoyloxy]-pentamethylene;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5,6,-trimethylpyrazine-2 base)-methoxyl group]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5,6,-trimethylpyrazine-2 base)-methoxyl group]-oxyethyl group]-1,2-bis-[(3,5,6 ,-trimethylpyrazine-2 base)-methoxyl group]-pentamethylene;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-(3-methoxyl group 4-hydroxycinnamic acid base)-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-(ferulic acid base)-oxyethyl group]-1,2-bis-(ferulic acid base)-pentamethylene;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(4-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5-dimethoxy-4 '-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(4-methoxyl group-3-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[3-(4-hydroxyphenyl) acrylic]-oxyethyl group]-1,2-bis-[3-(4-hydroxyphenyl) acrylic]-pentamethylene;
The compounds of this invention is for the preparation for the treatment of and prevention platelet aggregation disease medicament, and these diseases comprise myocardial infarction, thrombotic apoplexy, local asphyxia, peripheral vascular disease or stenocardia.
The compounds of this invention and pharmaceutically acceptable thinner, auxiliary or carrier combinations, the preparation that formation can be taken, its agent shape can be solid (as tablet or filled capsules) for oral use, can the direct water-soluble liquid (as solution) of making after the compounds of this invention and all kinds of organic acid or mineral acid salify.These pharmaceutical compositions and unit dosage thereof can comprise all compositions that are configured to conventional ratio, comprise or do not comprise other active compound or principle.In the time being used as medicine, compound of the present invention is conventionally with the form administration of drug regimen.The method preparation that described drug regimen can be known with pharmaceutical industry, comprises at least one active compound.
The compounds of this invention and organic acid or mineral acid salify, organic acid organic acid is Citric Acid, acetylsalicylic acid and aspartic acid; Mineral acid is methylsulfonic acid, hydrochloric acid and sulfuric acid.
Compared with prior art, tool of the present invention has the following advantages:
The present invention relates to compound and have stronger anti-platelet activating factor effect than lead compound, its toxicity is low simultaneously, and security is higher.
Synthetic method is as follows: react with lead compounds such as acetylsalicylic acid, Ligustrazine, forulic acid respectively taking formula II compound as starting raw material.
Specific embodiment
Synthetic (the 1S of embodiment 1,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-pentamethylene glycol (A1)
(a), 2-(acetoxyl group)] Benzoyl chloride synthetic
By acetylsalicylic acid (12.6g, 0.07mol), thionyl chloride (25g, 0.2mol) add in there-necked flask, stir 30min post-heating, reaction 2h, produces hydrogenchloride and sulfur dioxide gas in reaction. then at the excessive sulfur oxychloride of reclaim under reduced pressure, obtain faint yellow transparent oily matter 1 (12.0g, 98%).
(b), target compound is synthetic
Modus ponens II compound (1.12g, 0.002mol), appropriate DMAP, joins in the methylene dichloride of 200mL, stir, above-mentioned oily matter 1 (0.43g, 0.002mol) adds in batches, heating reflux reaction 4h, and then the excessive solvent of reclaim under reduced pressure, gained residue is dissolved in tetrahydrofuran (THF), dropwise adds appropriate 64% acetic acid, room temperature reaction 12h under stirring.Drip the 5%NaOH aqueous solution, be adjusted to pH=7, solvent evaporated, silica gel column chromatography (CHCl
3: CH
3oH=10: 1) separate and obtain target compound.
MS(APCI)685(M+H
+，100％)。
Synthetic (the 1S of embodiment 2,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-bis-[2-(acetoxyl group) benzoyloxy]-pentamethylene (A2)
Modus ponens II compound (1.12g, 0.002mol), is dissolved in tetrahydrofuran (THF), dropwise adds appropriate 64% acetic acid, room temperature reaction 12h under stirring.Drip the 5%NaOH aqueous solution, be adjusted to pH=7, solvent evaporated, residue is dissolved in the methylene dichloride of 200mL, and appropriate DMAP adds 2-(acetoxyl group) in batches] Benzoyl chloride (1.5g, 0.007mol), heating reflux reaction 4h, then at the excessive solvent of reclaim under reduced pressure, residue silica gel column chromatography (CHCl
3: CH
3oH=10: 1) separate and obtain target compound.
MS(APCI)1009(M+H
+，100％)。
Synthetic (the 1S of embodiment 3,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5,6,-trimethylpyrazine-2 base)-methoxyl group]-oxyethyl group]-1,2-pentamethylene glycol (A3)
(a), 2-brooethyl-3,5,6-trimethylpyrazine synthetic
By dry Ligustrazine (5.0g, 0.037mol), NBS (6.7g, 0.038mol), benzoyl peroxide (0.01g), solvent C Cl
430mL, white light irradiation, oil bath is warming up to 80 DEG C, back flow reaction 10h, filter, solvent is fallen in underpressure distillation, and gained residue silicagel column separates (ethyl acetate: sherwood oil=10: 1), obtain 2-brooethyl-3,5,6-trimethylpyrazine (5.2g).
(b), target compound is synthetic
Press method described in embodiment 1, with 2-brooethyl-3,5,6-trimethylpyrazine and formula II compound are raw material, synthesising target compound.
MS(APCI)657(M+H
+，100％)。
Synthetic (the 1S of embodiment 4,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5,6,-trimethylpyrazine-2 base)-methoxyl group]-oxyethyl group]-1,2-bis-[(3,5,6 ,-trimethylpyrazine-2 base)-methoxyl group]-pentamethylene (A4)
Press method described in embodiment 2, with 2-brooethyl-3,5,6-trimethylpyrazine and formula II compound are raw material, synthesising target compound.
MS(APCI)925(M+H
+，100％)。
Synthetic (the 1S of embodiment 5,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-(ferulic acid base)-oxyethyl group]-1,2-pentamethylene glycol (A5)
(a), 3-methoxyl group-4-hydroxyl cinnamyl chloride is synthetic
According to the method for embodiment 1 (a), synthetic 3-methoxyl group-4-hydroxyl cinnamyl chloride taking ferulic acid and oxalyl chloride as raw material.
(b), target compound is synthetic
Press method described in embodiment 1, taking 3-methoxyl group-4-hydroxyl cinnamyl chloride and formula II compound as raw material, synthesising target compound.
MS(APCI)699(M+H
+，100％)。
Synthetic (the 1S of embodiment 6,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-(ferulic acid base)-oxyethyl group]-1,2-bis-(ferulic acid base)-pentamethylene (A6)
Press method described in embodiment 2, taking 3-methoxyl group-4-hydroxyl cinnamyl chloride and formula II compound as raw material, synthesising target compound.
MS(APCI)1051(M+H
+，100％)。
Synthetic (the 1S of embodiment 7,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(4-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol (A7)
(a), (4-hydroxyphenyl) formyl chloride is synthetic
According to the method for embodiment 1 (a), synthetic (4-hydroxyphenyl) formyl chloride taking (4-hydroxyphenyl) formic acid and oxalyl chloride as raw material.
(b), target compound is synthetic
Press method described in embodiment 1, taking (4-hydroxyphenyl) formyl chloride and formula II compound as raw material, synthesising target compound.
MS(APCI)699(M+H
+，100％)。
Synthetic (the 1S of embodiment 8,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5-dimethoxy-4 '-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol (A8)
(a), (3,5-dimethoxy-4 '-hydroxyphenyl) formyl chloride is synthetic
According to the method for embodiment 1 (a), be synthetic (4-hydroxyphenyl) formyl chloride of raw material with (3,5-dimethoxy-4 '-hydroxyphenyl) formic acid and oxalyl chloride.
(b), target compound is synthetic
Press method described in embodiment 1, with (3,5-dimethoxy-4 '-hydroxyphenyl) formyl chloride and formula II compound for raw material, synthesising target compound.
MS(APCI)703(M+H
+，100％)。
Synthetic (the 1S of embodiment 9,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(4-methoxyl group-3-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol (A9)
(a), (4-methoxyl group-3-hydroxyphenyl) formyl chloride is synthetic
According to the method for embodiment 1 (a), synthetic (4-methoxyl group-3-hydroxyphenyl) formyl chloride taking (4-methoxyl group-3-hydroxyphenyl) formic acid and oxalyl chloride as raw material.
(b), target compound is synthetic
Press method described in embodiment 1, taking (4-methoxyl group-3-hydroxyphenyl) formyl chloride and formula II compound as raw material, synthesising target compound.
MS(APCI)673(M+H
+，100％)。
Synthetic (the 1S of embodiment 10,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[3-(4-hydroxyphenyl) acrylic]-oxyethyl group]-1,2-bis-[3-(4-hydroxyphenyl) acrylic]-pentamethylene (A10)
(a), 3-(4-hydroxyphenyl) acrylate chloride is synthetic
According to the method for embodiment 1 (a), synthetic 3-(4-hydroxyphenyl) acrylate chloride taking 3-(4-hydroxyphenyl) vinylformic acid and oxalyl chloride as raw material.
(b), target compound is synthetic
Press method described in embodiment 2, taking 3-(4-hydroxyphenyl) acrylate chloride and formula II compound as raw material, synthesising target compound.
MS(APCI)1051(M+H
+，100％)。
The impact of the platelet aggregation rate of embodiment 11PAF induction
Experimental technique: get male new zealand rabbit, body weight 2.0-2.5kg.Dorsal position is fixed on operating table for rabbit, cuts off the neck rabbit hair, and subcutaneous injection 1% procaine hydrochloride injection local infiltration anesthesia is fixing after promoting circulation of blood cannula.After operation finishes, open bulldog clamp, blood is put into the test tube that contains 3.8% Trisodium Citrate, making blood and the ratio of 3.8% Trisodium Citrate volume is 9: 1.After being mixed, the anticoagulated blood of above-mentioned preparation prepares PRP and PPP by different centrifugal speeds.After the centrifugal 10min of 800rpm, draw upper plasma and obtain PRP; Obtain PPP by drawing upper plasma after centrifugal residual blood 2500rpm 10min.First get 250 μ l PPP and add in test cup, then put into test hole, press " PPP " key and calibrate.Then get 250 μ l PRP and add in test cup, preheating 1min in 37 DEG C of pre-temperature grooves, adds 10 μ L liquids after putting into test hole, adds immediately PAF inductor 10 μ L, to measure MA while pressing " beginning " key.4 passages of each mensuration, in the hope of average MA, result is as follows:
The impact of table 1 compound on platelet aggregation
Platelet aggregation-against experimental result shows: the activity of all compounds of the present invention is all strong compared with the activity of lead compound and deriveding group (A22), compared with prior art has efficient, low toxicity, feature that selectivity is high.
Synthetic (the 1S of embodiment 12,2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-pentamethylene diol hydrochloride
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-pentamethylene glycol (6.84g, 0.01mol) be dissolved in methyl alcohol, add 50mL ether solution of hydrogen chloride (0.2mol/L), fully stir evaporation section solvent, crystallisation by cooling, filter, dry, obtain target compound.
Embodiment 13 (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1, the preparation of 2-pentamethylene diol hydrochloride freeze-dried powder
Take synthetic (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3, 4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1, 2, 3-triazole [4, 5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1, 2-pentamethylene diol hydrochloride 8g, glycine 80g, N.F,USP MANNITOL 160g, inject water to 4000mL (1000 component), stir and be heated to 70 DEG C and make to dissolve, add 4g pin activated carbon, coarse filtration decarburization, afterwards with the filter of 0.22um millipore filtration essence, measure intermediate content, qualified rear filling in 10mL control cillin bottle, every bottle approximately fills 4mL, partly be pressed into butyl rubber match.Put into Freeze Drying Equipment and carry out lyophilize according to pre-designed freeze-drying curve.Drying process finishes rear compression plug, aluminium-plastic combined cover rolls lid, to obtain final product.
Embodiment 14 (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1, the preparation of 2-pentamethylene diol hydrochloride injection liquid
In weighing, take synthetic (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-pentamethylene diol hydrochloride 8g, glycine 80g, inject water to 10000mL (1000 component), stir and be heated to 60 DEG C and make to dissolve, regulating pH value with Citric Acid or Sodium Citrate is 6.0～8.0
Add 10g pin activated carbon, coarse filtration decarburization, rear with the filter of 0.22um millipore filtration essence, mensuration intermediate content, qualified rear filling in 10mL cillin bottle, every bottle approximately fills 10mL, compresses butyl rubber plug, rolls lid.100 DEG C of flowing steam sterilization 30min, lamp inspection is packed and be get final product; If sterile filling, tamponade, rolls lid, lamp inspection is packed and be get final product.
Claims (7)
1. a class formation is suc as formula the compound or pharmaceutically acceptable salt thereof of I,
Wherein R
1, R
2and R
3identical or different, be hydrogen ,-CO-Ar; Wherein Ar is selected from: 2-(acetoxyl group) benzoyl, (3,5,6;-trimethylpyrazine)-2 bases, ferulic acid base; 2-[(4-hydroxyphenyl) formyloxy; (3; 5-dimethoxy-4 '-hydroxyphenyl) formyloxy; (4-methoxyl group-3-hydroxyphenyl) formyloxy, 3-(4-hydroxyphenyl) acrylic, and R
1, R
2and R
3when different, be hydrogen.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, is characterized in that being selected from following compounds:
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[2-(acetoxyl group)] benzoyloxy-oxyethyl group]-1,2-bis-[2-(acetoxyl group) benzoyloxy]-pentamethylene;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5,6,-trimethylpyrazine-2 base)-methoxyl group]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5,6,-trimethylpyrazine-2 base)-methoxyl group]-oxyethyl group]-1,2-bis-[(3,5,6 ,-trimethylpyrazine-2 base)-methoxyl group]-pentamethylene;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-(ferulic acid base)-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-(ferulic acid base)-oxyethyl group]-1,2-bis-(ferulic acid base)-pentamethylene;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(4-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(3,5-dimethoxy-4 '-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[(4-methoxyl group-3-hydroxyphenyl) formyloxy]-oxyethyl group]-1,2-pentamethylene glycol;
(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-phenyl-difluoride base) cyclopropyl] amino]-5-(propyl dithiocarbamate)-3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl]-5-[2-[3-(4-hydroxyphenyl) acrylic]-oxyethyl group]-1,2-bis-[3-(4-hydroxyphenyl) acrylic]-pentamethylene.
3. the purposes in preparation treatment and prevention myocardial infarction, thrombotic apoplexy, local asphyxia or peripheral vascular disease medicine according to the compound or pharmaceutically acceptable salt thereof of claim 1-2 any one.
4. the purposes in preparation treatment and prevention angina drug according to the compound or pharmaceutically acceptable salt thereof of claim 1-2 any one.
5. a pharmaceutical composition, wherein comprises according to any one compound in claim 1-2 and pharmaceutically acceptable thinner, auxiliary or carrier.
6. according to the pharmaceutical salts of the compound described in claim 1-2 any one, it is characterized in that and organic acid or mineral acid salify.
7. pharmaceutical salts according to claim 6, is characterized in that with organic acid be Citric Acid, acetylsalicylic acid, aspartic acid or methylsulfonic acid; Mineral acid is hydrochloric acid or sulfuric acid.
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| CN105859720A (en) * | 2015-01-20 | 2016-08-17 | 上海方楠生物科技有限公司 | Method for preparing ticagrelor solution |
| CN113874377A (en) | 2019-05-13 | 2021-12-31 | 埃科莱布美国股份有限公司 | 1,2, 4-triazolo [1,5-a ] pyrimidine derivatives as copper corrosion inhibitors |
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| CN1334816A (en) * | 1998-12-04 | 2002-02-06 | 阿斯特拉曾尼卡有限公司 | Triazolo (4,5-D) pyrimidine compounds |
| WO2002038571A1 (en) * | 2000-11-09 | 2002-05-16 | Astrazeneca Ab | Novel compounds |
| WO2002096428A1 (en) * | 2001-05-31 | 2002-12-05 | Astrazeneca Ab | Pharmaceutical combinations |
| CN101883565A (en) * | 2007-12-03 | 2010-11-10 | 阿斯利康(瑞典)有限公司 | Triazolo [4,5-d] pyrimidine compounds for treatment of abdominal aortic aneurysms |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1334816A (en) * | 1998-12-04 | 2002-02-06 | 阿斯特拉曾尼卡有限公司 | Triazolo (4,5-D) pyrimidine compounds |
| WO2002038571A1 (en) * | 2000-11-09 | 2002-05-16 | Astrazeneca Ab | Novel compounds |
| WO2002096428A1 (en) * | 2001-05-31 | 2002-12-05 | Astrazeneca Ab | Pharmaceutical combinations |
| CN101883565A (en) * | 2007-12-03 | 2010-11-10 | 阿斯利康(瑞典)有限公司 | Triazolo [4,5-d] pyrimidine compounds for treatment of abdominal aortic aneurysms |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
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Effective date of registration: 20160930 Address after: 210016 Jiangsu Province, Nanjing city Zhongshan Road No. 323, 2 (former banshanyuan No. 12 Building 1 layer 1) Patentee after: JIANGSU CAREPHAR PHARMACEUTICAL CO., LTD. Address before: 210016 Jiangsu Province, Nanjing city Zhongshan Road No. 323, 2 (former banshanyuan No. 12 Building 1 layer 1) Patentee before: Qin Yinlin |