CN102268012A - Thiazole derivative and preparation method and application thereof - Google Patents
Thiazole derivative and preparation method and application thereof Download PDFInfo
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- CN102268012A CN102268012A CN2011102437743A CN201110243774A CN102268012A CN 102268012 A CN102268012 A CN 102268012A CN 2011102437743 A CN2011102437743 A CN 2011102437743A CN 201110243774 A CN201110243774 A CN 201110243774A CN 102268012 A CN102268012 A CN 102268012A
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Abstract
The invention belongs to the technical field of medicaments with an effect on resisting platelet aggregation, and provides a thiazole derivative of a structure in formula I and pharmaceutically acceptable salts thereof, wherein R1 is acetoxy and propionyloxy; R2 is hydrogen, methyl and ethyl; and R3 and R4 are hydrogen, chlorine, bromine, methyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, alkoxycarbonyl, carboxyl and formacyl. The invention also relates to a preparation method of the compound, and simultaneously discloses pharmaceutical compositions prepared from the compound or pharmaceutically acceptable salts thereof as active components, as well as applications of the pharmaceutical compositions as medicaments for resisting platelet aggregation.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to a class and have thiazole derivative of antiplatelet aggregative activity and preparation method thereof, contain their pharmaceutical composition and as the purposes of antiplatelet drug.
Background technology
In rising trend based on the sickness rate of the thrombotic disease of coronary artery thrombus and cerebral thrombosis in recent years, the serious harm human health.Platelet aggregation is a key link in the normal clotting mechanism, and hematoblastic adhesion, gathering, release reaction cause thrombosis.Therefore the anticoagulant medicine plays a significant role in the treatment thrombus disease, is the focus that people study always.
Clinically, acetylsalicylic acid is as the medicament for resisting platelet aggregation widespread use.Although acetylsalicylic acid can be tolerated by most people, yet even low dose also may cause part crowd gastrointestinal discomfort sometimes, even serious gastrointestinal hemorrhage or hematencephalon, the aspirin resistance phenomenon had also appearred in recent years.
Adenosine diphosphate (ADP) (ADP) is the important agonist that platelet activation, buildup effect amplify, and suppressing the thrombocyte effect by the blocking-up adp receptor has become the important means that stops pathologic thrombosis (coronary heart disease, cerebro-vascular diseases, pulmonary infarction, thrombophlebitis etc.) and myocardial infarction, unstable angina pectoris, peripheral vascular disease, congestive heart failure etc.Adp receptor antagonist Ticlopidine (Ticlopidine) is first thienopyridine medicine, by the exploitation listing of French Sanofi company.Its by with the special sulfydryl receptors bind of P2Y type, suppress the activation of adp receptor.By changing the interaction of platelet membrane and interference membrane fiber proteinogen, glycoprotein iib/iiia acceptor on the blocking platelet film, inhibition is a kind of effect medicament for resisting platelet aggregation stronger than acetylsalicylic acid by ADP and the reaction of other platelet activating agent inductive platelet aggregations.Because Ticlopidine not only suppresses a certain platelet aggregation incitant, and has suppressed accumulation process itself, is used widely in clinical.Especially the prevention cerebral infarction, treat stenocardia, prevent and treat myocardial infarction and improve aspect such as peripheral vascular occlusive disease evident in efficacy.But Ticlopidine can cause neutrophil leucocyte minimizing, thrombopenia, bone marrow depression, barrier, thrombotic thrombocytopenic purpura side effects such as (TTP) again.
Clopidogrel (Clopidogrel) is second thienopyridine medicine of French Sanofi company development, compare with Ticlopidine, many carboxymethyls on the side chain only on the structure, its action intensity and tolerance all are higher than Ticlopidine, and only anti-platelet activity is just high 6 times than Ticlopidine.Be applied to treat atheromatosis, acute coronary syndrome, prevention intracoronary stent clinically and plant people's postoperative in-stent restenosis and thrombotic complications etc.In June, 1998, Britain went on the market in the U.S., and go on the market in China August calendar year 2001.In multinomial broad scale research, clopidogrel is better than other drug aspect the prognosis that improves the ischemia incident, and ADR is few than Ticlopidine, and security is better than acetylsalicylic acid, thereby clopidogrel has replaced the application of Ticlopidine in many cases.TTP and hemolytic uremic syndrome (HUS) have also occurred but accept the clopidogrel treatment, the report of simultaneously relevant clopidogrel opposing also had increase in recent years.Because clopidogrel is oily matter, alkalescence extremely a little less than, need and strong acid could salify, but meet the moisture instability, free alkali is separated out, purifying also has certain difficulty.And because its strongly-acid has been subjected to certain restriction aspect preparation.
Synthetic method and summary about Thienopyridines are found in following document: CN101284838; CN101260112; CN1683373; US4681888; US4529596; GB1501797; WO02059128; US4174448; GB1561504; WO2004094374; JP6135970; JP63264588.
As one of focus of antiplatelet drug research, need more safe and effective this compounds of searching at present badly.
Summary of the invention
One object of the present invention is, in order to solve the problem of clopidogrel opposing, develops a kind of thiazole derivative and pharmaceutical salts thereof of novel texture.
Another object of the present invention is, discloses the preparation method of a class thiazole derivative and pharmaceutical salts thereof.
A further object of the present invention is that disclosing with thiazole derivative and pharmaceutical salts thereof is the pharmaceutical composition of main active ingredient.
A further object of the invention is, thiazole derivative and pharmaceutical salts thereof are disclosed, application as the antiplatelet drug aspect, particularly be used to prepare the coronary syndrome that prevention or treatment cause because of platelet aggregation, myocardial infarction, the purposes of cardiovascular and cerebrovascular diseases medicament aspects such as myocardial ischemia.
Through Preliminary pharmacological test as can be known, The compounds of this invention is in the superiority that has aspect drug effect and the acute toxicity two to a certain degree.
Now, content of the present invention is described in detail in conjunction with the object of the invention.
The present invention is specifically related to the compound and the pharmacy acceptable salt thereof of general formula I structure:
Wherein:
R
1For: C
1-C
4Straight or branched alkane carbonyl oxygen base.
R
2For: C
1-C
4The straight or branched alkyl.
R
3, R
4For: hydrogen, halogen, C
1-C
4The straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be replaced by halogen; C
1-C
4Straight or branched alkane alkyl-carbonyl; C
1-C
4Straight or branched alkane carbalkoxy, acyl group, carboxylic acid group.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
R
1For: acetoxyl group, propionyloxy;
R
2For: methyl, ethyl;
R
3, R
4For: hydrogen, chlorine, bromine, methyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, alkyl carbonyl, carboxyl, formyl radical.
More preferably following its pharmacy acceptable salt of compound:
I-1 5-(2-(5-methylthiazol-2-base is amino)-2-oxoethyl)-2-acetoxyl group-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also;
I-2 2-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) kharophen also)-5-acetoxyl group thiazole;
I-3 5-(2-(5-ethanoyl-4-methylthiazol-2-base is amino)-2-oxoethyl)-2-acetoxyl group-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also;
I-4 5-(2-(5-methyl-4-phenyl thiazole-2-base is amino)-2-oxoethyl)-2-base acetoxyl group-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also;
I-5 5-(2-(5-bromo thiazole-2-base is amino)-2-oxoethyl-2-yl acetate-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also;
I-6 5-(2-oxygen-2-(5-(trifluoromethyl) thiazol-2-yl amino) ethyl)-2-acetoxyl group-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also;
I-7 2-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) kharophen also)-4-acetoxyl group thiazole;
I-8 5-(1-(5-formyl thiazole-2-base is amino)-1-oxygen butane-2-yl)-2-propionyloxy-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also.
Formula I compound pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.Wherein preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, or the like.
The preparation route of formula I compound is as follows:
Wherein X is Cl, Br; R
1～R
4Definition as described above.
Thiazole compound (II), in DMF, with 2-halogen acyl halide compounds under the catalysis of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide or potassium hydroxide ,-30～10 ℃ of reactions make key intermediate III.Intermediate III is again with 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-keto hydrochloride is in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide or potassium hydroxide, with methylene dichloride, trichloromethane or acetonitrile is solvent, and 10～80 ℃ of reactions make intermediate compound IV.Intermediate compound IV is a solvent with ethyl acetate, methylene dichloride, trichloromethane, toluene or acetonitrile etc., and 0～40 ℃ by the acid anhydrides acidylate, makes Compound I.
Reaction makes all cpds or products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol, Virahol, ether or the DMSO dropping inorganic acid, organic acid makes pharmacy acceptable salt.
Specifically be that products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol, Virahol, ether or the DMSO, the dripping hydrochloric acid ether to pH be 2, make hydrochloride.Or products therefrom is dissolved in DMF, acetone, methyl alcohol or ethanol, molar lactic acid such as adding, its lactic acid salt.
This compounds is effective for the human disease that causes because of platelet aggregation of treatment.Although compound of the present invention can be without the direct administration of any preparation, described all cpds preferably uses with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions of The compounds of this invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of used compound or concentration are regulated in the scope of a broad.Usually, the scope of active compound amount is 0.5～90% (weight) of composition, and another preferred range is 0.5～70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention has the obvious suppression effect aspect platelet aggregation.
Further specify the antithrombotic acitivity of The compounds of this invention below by pharmacodynamic experiment.
A. to the rat platelet aggregation restraining effect
Medicine and preparation: compound is made into suspension with 0.5%CMC and uses for animals administer; Adenosine diphosphate (ADP) (ADP) (SERVA company, lot number 01993).
Animal: male rat, Tianjin Inst. of Materia Medica laboratory animal room provides, animal conformity certification number: No. the 001st, Tianjin animal word.
Instrument: PK121R type whizzer (Italian ALC International SPL product), SPA-3 type PPP platelet aggregation instrument (Shanghai Kodak testing tool factory).
Test method: male Wistar rat, about body weight 300g, per os is irritated stomach and is given new compound, and dosage is 10mg/kg, the administration volume is 10mL/kg, behind the 2h, etherization, aorta abdominalis blood sampling, 3.8% Sodium Citrate anti-freezing, whole blood is 9: 1 with the ratio of antithrombotics, the centrifugal 7min of 1000rpm, preparation platelet rich plasma (PPP).Transfer PRP with PPP, make its platelet count remain on 2 * 106/ml.Get PRP and add in the test cup, 37 ℃ of temperature are incubated 10min.Return to zero with PRP, PPP transfers 100%, is inductor with ADP (final concentration is 5 μ M), measures platelet aggregation percentage ratio by turbidimetry with SPA-3 type PPP platelet aggregation instrument, with t-check carrying out statistics relatively, compound sample the results are shown in Table 1 to the rat platelet aggregation restraining effect.
Table 1 compound sample is to rat platelet aggregation restraining effect result
By above pharmacological evaluation as seen, compound of the present invention can obviously suppress ADP inductive platelet aggregation.Therefore, they can be used for preventing or treating the coronary syndrome that causes because of platelet aggregation, myocardial infarction, cardiovascular and cerebrovascular diseases such as myocardial ischemia.
Tentatively investigate the acute toxicity of The compounds of this invention by animal experiment.
Oral new compound of the present invention of mouse and clopidogrel 400mg/kg
-1D
-1After, general behavior and the body weight of mouse after the administration have been carried out week observation.The result shows that after mouse gave above-mentioned 8 compounds, heart rate, breathing and independent behaviour activity there is no unusually, and is normal through all body weight observation weight of mice.
The preliminary experiment result shows the LD of oral administration of compound I-7, I-8 and clopidogrel
50Be respectively 3300mg/kg, 3359mg/kg and 3200mg/kg, visible I-7 and I-8 toxicity are lower than clopidogrel slightly.
Embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1HNMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Reference example 1: the preparation of intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 11.4g 3-amino-2-methoxycarbonyl thiophene, with 50ml DMF its dissolving back is added the 20.2g triethylamine,-10 ℃～5 ℃ are stirred down, drip the mixed solution of chloroacetyl chloride (16.9g) and methylene dichloride (30m1), behind low-temp reaction 3h (the flaggy demonstration reacts completely) the stirring at room 1h, reaction solution is poured in the 100ml cold water, fully stirred, filter, promptly get brown solid (HPLC:86.5%).The Rf=0.70[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2]
Method with reference to reference example 1 can conveniently prepare compound: intermediate III-2～III-7 replaces chloroacetyl chloride to get intermediate III-8 (particular compound sees Table 2) with 2-bromo butyryl bromide.
Table 2 intermediate III-2～III-8 tabulation
Reference example 2: the preparation of intermediate compound IV-1
Add 19.0g intermediate III-1,100mL acetonitrile and 20.2g triethylamine in the reaction flask that stirring, condenser, thermometer are housed successively, nitrogen protection adds 19.0g 5,6,7 down, and the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-keto hydrochloride also.Stop heating behind the backflow 3h, be cooled to room temperature.Adding distil water 100ml in reaction solution, ethyl acetate extraction (100ml * 3) merges organic phase, and anhydrous sodium sulfate drying filters, and filtrate decompression is steamed and is desolventized, and resistates separates with silica gel column chromatography, obtains white solid IV-1 (HPLC:97.9%).HRMS(m/z)[M+H]
+：310.0678。
Method with reference to reference example 2 can conveniently prepare compound: intermediate compound IV-2～IV-8 (particular compound sees Table 3).
Table 3 intermediate compound IV-2～IV-8 tabulation
Embodiment 1:
5-(2-(5-methylthiazol-2-base is amino)-2-oxoethyl)-2-acetoxyl group-4,5,6, the 7-tetramethylene sulfide is the preparation of [3,2-c] pyridine (Compound I-1) also
In the reaction flask that stirring, condenser, thermometer are housed, add 30.9g intermediate compound IV-1,100mL acetonitrile and a small amount of triethylamine successively; nitrogen protection drips diacetyl oxide down; 30 ℃ are stirred 3h, solvent evaporated, acetic acid ethyl dissolution; with saturated common salt water washing (50mL * 3); anhydrous sodium sulfate drying filters solvent evaporated; the anhydrous methanol recrystallization promptly gets white solid I-1 (HPLC:98.9%).
1H?NMR(CDCl
3，400MHz)δ：2.265(s，3H，-OCH
3)，2.384-2.386(d，3H，-CH
3)，2.825-2.853(t，2H，-CH
2CH
2-)，2.924-2.952(t，2H，-CH
2CH
2N)，3.380(s，2H，-CH
2CONH-)，3.602(s，2H，-CH
2CH
2-)，6.287(s，1H，＝CH-)，7.050-7.053(d，1H，＝NCH＝)，10.211(s，1H，-NH)。HRMS(m/z)[M+H]
+：352.0784。
Method with reference to embodiment 1 can conveniently prepare Compound I-2～I-7, replaces diacetyl oxide to make Compound I-8 (particular compound sees Table 4) with propionic anhydride.
Table 4 Compound I-2～I-8 tabulation
Embodiment 2:
Compound I-1 one-tenth hydrochloride: get I-1 white solid product 3.1g, be dissolved in the 10mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, drip 11.1% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under the ice-water bath.Filter, white solid, vacuum-drying, m.p.＞230 ℃.
Embodiment 3:
Compound I-3 one-tenth lactic acid salt: get I-3 white solid product 4.7g, be dissolved in the 22mL anhydrous methanol.Be heated to molar lactic acid such as the back adding that refluxes, continue at the about 1h of stirring reaction down that refluxes.Reaction finishes, and leaves standstill 24h under room temperature.Separate out yellow crystal, filter, vacuum-drying, m.p.＞230 ℃.
For the pharmaceutical composition of thiazole derivative of the present invention is described more fully, following example of formulations is provided below, described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment 1-3.
Embodiment 4:
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.After pressing recipe quantity mentioned component being mixed, be packed in the hard gelatin capsule.
Embodiment 5:
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 6:
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves sorb ester and propylene glycol, add medicinal basic and regulate the pH value and make its dissolving to 4-8.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 7:
The preparation of injection lyophilized powder:
The hydrochloride 100mg of Compound I-1
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate the pH value with medicinal basic and make its dissolving to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals, promptly.
Claims (8)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R
1For: acetoxyl group, propionyloxy;
R
2For: hydrogen, methyl, ethyl;
R
3, R
4For: hydrogen, chlorine, bromine, methyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, alkyl carbonyl, carboxyl, formyl radical.
2. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1, described compound is:
3. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1 or 2, its pharmacy acceptable salt is: formula I compound and mineral acid, organic acid salify.
4. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 3, its pharmacy acceptable salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate.
5. the preparation method of claim 1 Chinese style I compound is characterized in that: compound III and 5,6; 7, the 7a-tetramethylene sulfide also [3,2-c] pyridines-2 (4H)-keto hydrochloride in the presence of triethylamine; with the acetonitrile is solvent, and 50～100 ℃ of reactions make intermediate compound IV; intermediate compound IV is a solvent with acetonitrile etc.; 10～40 ℃ by the acid anhydrides acidylate, makes Compound I, and wherein X is Cl; Br, R
1～R
4As claim 1 definition,
6. the pharmaceutical composition of a platelet aggregation-against, it comprises compound or its pharmacy acceptable salt and one or more pharmaceutical carriers with formula I structure as claimed in claim 1 or 2 for the treatment of significant quantity.
7. claim 1 or 2 described compounds with formula I structure or its pharmacy acceptable salt are in the application that is used to prepare aspect the medicament for resisting platelet aggregation.
8. application as claimed in claim 7 is in the purposes that is used to prepare aspect the cardiovascular and cerebrovascular diseases medicament that treatment causes because of platelet aggregation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304561A (en) * | 2013-06-21 | 2013-09-18 | 天津药物研究院 | Compounds with antithrombotic effects |
| CN103896962A (en) * | 2014-03-20 | 2014-07-02 | 天津药物研究院 | Substituent piperazinyl-containing thienopyridine ester derivatives as well as preparation method and use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5036156A (en) * | 1989-09-29 | 1991-07-30 | Sanofi | Process for the preparation of α-bromo-phenylacetic acids |
| CN101260112A (en) * | 2008-04-11 | 2008-09-10 | 天津药物研究院 | Acethydrazide derivatives containing thieno[3.2-c]pyridine, preparation method and use thereof |
| CN101594864A (en) * | 2006-12-07 | 2009-12-02 | 第一三共株式会社 | Produce the method for solid preparation |
| CN102093385A (en) * | 2010-12-30 | 2011-06-15 | 天津药物研究院 | Schiff base compounds as well as preparation method and application of Schiff base compounds |
-
2011
- 2011-08-24 CN CN201110243774.3A patent/CN102268012B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5036156A (en) * | 1989-09-29 | 1991-07-30 | Sanofi | Process for the preparation of α-bromo-phenylacetic acids |
| CN101594864A (en) * | 2006-12-07 | 2009-12-02 | 第一三共株式会社 | Produce the method for solid preparation |
| CN101260112A (en) * | 2008-04-11 | 2008-09-10 | 天津药物研究院 | Acethydrazide derivatives containing thieno[3.2-c]pyridine, preparation method and use thereof |
| CN102093385A (en) * | 2010-12-30 | 2011-06-15 | 天津药物研究院 | Schiff base compounds as well as preparation method and application of Schiff base compounds |
Non-Patent Citations (2)
| Title |
|---|
| 周云松,等: "噻吩并四氢吡啶衍生物的合成及其抗血小板聚集活性研究", 《药学学报》 * |
| 成碟: "噻吩并吡啶类衍生物的设计、合成、活性评价及其药效团模型", 《天津大学博士学位论文》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304561A (en) * | 2013-06-21 | 2013-09-18 | 天津药物研究院 | Compounds with antithrombotic effects |
| CN103304561B (en) * | 2013-06-21 | 2016-06-01 | 天津药物研究院 | One class has the compound of anti thrombotic action |
| CN103896962A (en) * | 2014-03-20 | 2014-07-02 | 天津药物研究院 | Substituent piperazinyl-containing thienopyridine ester derivatives as well as preparation method and use thereof |
| CN103896962B (en) * | 2014-03-20 | 2016-09-14 | 天津药物研究院 | One class thienopyridine esters derivative containing substituted piperazinyl and its production and use |
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| CN102268012B (en) | 2014-04-09 |
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