CN102351877B - Thiophene derivative, its preparation method and its application - Google Patents
Thiophene derivative, its preparation method and its application Download PDFInfo
- Publication number
- CN102351877B CN102351877B CN201110231476.2A CN201110231476A CN102351877B CN 102351877 B CN102351877 B CN 102351877B CN 201110231476 A CN201110231476 A CN 201110231476A CN 102351877 B CN102351877 B CN 102351877B
- Authority
- CN
- China
- Prior art keywords
- compound
- acceptable salt
- pharmacy acceptable
- formula
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the anti-platelet aggregation effect medicine technical field, and provides a thiophene derivative with a general formula I structure and its pharmaceutically acceptable salt, wherein R1-R5 are defined according to claim. The invention also relates to a preparation method of the derivative, and simultaneously discloses a pharmaceutical composition by taking the derivative or its pharmaceutically acceptable salt as an active and effective component, and an application of the derivative or its pharmaceutically acceptable salt in anti-platelet aggregation medicines.
Description
Technical field
The invention belongs to medical technical field, or rather, the pharmaceutical composition that relates to a class and there is thiophene derivant of antiplatelet aggregative activity and preparation method thereof, contain them and the purposes as antiplatelet drug.
Background technology
In recent years take coronary artery thrombus and cerebral thrombosis as the sickness rate of main thrombotic disease in rising trend, serious harm human health.Platelet aggregation is a key link in normal clotting mechanism, and hematoblastic adhesion, gathering, release reaction cause thrombosis.Therefore anticoagulant medicine plays a significant role in treatment thrombus disease, is the focus that people study always.
Clinically, acetylsalicylic acid is as medicament for resisting platelet aggregation widespread use.Although acetylsalicylic acid can be tolerated by most people, even but sometimes low dose also may cause part population gastrointestinal discomfort,, also there is in recent years Aspirin Resistance in even serious gastrointestinal hemorrhage or hematencephalon.
Adenosine diphosphate (ADP) (ADP) is the important agonist that platelet activation, buildup effect are amplified, and suppressing Platelet by 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, is a kind of effect medicament for resisting platelet aggregation stronger than acetylsalicylic acid.Clopidogrel (Clopidogrel) is second thienopyridine medicine of French Sanofi company development, and its action intensity and tolerance are all higher than Ticlopidine.But accept Ticlopidine, there is certain defect in Effect of Clopidogrel in Treating.
One of focus of studying as antiplatelet drug, needs more safe and effective this compounds of searching at present badly.
Contriver has found that in research process a class has the thiophene derivant of antiplatelet aggregative activity.
Summary of the invention
One object of the present invention is, discloses a kind of thiophene derivant and pharmaceutical salts thereof of novel texture.
Another object of the present invention is, discloses the preparation method of thiophene derivant and pharmaceutical salts thereof.
A further object of the present invention is, discloses the pharmaceutical composition take thiophene derivant and pharmaceutical salts thereof as main active ingredient.
A further object of the invention is, thiophene derivant and pharmaceutical salts thereof are disclosed, as the application of antiplatelet drug aspect, particularly at the coronary syndrome causing because of platelet aggregation for the preparation of prevention or treatment, myocardial infarction, myocardial ischemia, the purposes of cardiovascular and cerebrovascular diseases medicament aspect.
Now, in conjunction with the object of the invention, content of the present invention is described in detail.
The present invention is specifically related to 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: hydrogen, C
1-C
4straight or branched alkyl.
R
3for: C
1-C
4straight or branched alkyl, C
3-C
6cycloalkyl, this alkyl or cycloalkyl is replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, thienyl, itrile group, nitro, phenyl;
R
4, R
5for: hydrogen; C
1-C
4straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4straight or branched alkyl replaces; Cyano group; Methylthio group; Methylsulfonyl.
Preferably following compound and pharmacy acceptable salt thereof:
Wherein:
R
1for: hydrogen, acetoxyl group, propionyloxy;
R
2for: hydrogen, methyl, ethyl;
R
3for: methyl, ethyl;
R
4, R
5for: hydrogen; The tertiary butyl; Trifluoromethyl; Phenyl; Chlorophenyl; Nitrophenyl; Cyano group; Methylthio group; Methylsulfonyl.
More preferably its pharmacy acceptable salt of following compound:
I-1 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-2-methoxycarbonyl thiophene;
I-2 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) the acetamido)-5-tertiary butyl)-2-methoxycarbonyl thiophene;
I-3 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-4-phenyl-5-(trifluoromethyl)-2-methoxycarbonyl thiophene;
I-4 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-5-phenyl-2-methoxycarbonyl thiophene;
I-5 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-5-(4-fluorophenyl)-2-methoxycarbonyl thiophene;
I-6 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-5-(3-nitrophenyl)-2-methoxycarbonyl thiophene;
I-7 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-5-(4-tert-butyl-phenyl)-2-methoxycarbonyl thiophene;
I-8 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-4-cyano group-5-(methylthio group)-2-ethoxycarbonyl thiophene;
I-9 4-(methylsulfonyl)-5-(methylthio group)-3-(2-(2-(propionyloxy)-6; 7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) amide-based small)-2-methanoyl thiophene.
Compound of Formula I 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 etc.
The syntheti c route of formula I compound is as follows:
Wherein X is Cl, Br; R
1～R
5as aforementioned definitions
Thiophenes (II), in DMF, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide ,-30～10 ℃ of reactions make key intermediate III with 2-halogen acyl halide compounds.Intermediate III is again with 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-one is under the acid binding agent such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide exists, take methylene dichloride, trichloromethane or acetonitrile as solvent, 10～80 ℃ of reactions, make intermediate compound IV.Intermediate compound IV, take ethyl acetate, methylene dichloride, trichloromethane, toluene or acetonitrile etc. as solvent, 0～40 ℃ by acid anhydrides acidylate, makes Compound I.
Reaction make various compounds or products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, Virahol, ether or DMSO drip mineral acid, organic acid is made pharmacy acceptable salt.
Specifically products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, Virahol, ether or DMSO, drips salt acid ether to pH2, make hydrochloride.Or products therefrom is dissolved in to DMF, acetone, methyl alcohol or ethanol, and the molar lactic acid such as add, obtain its lactic acid salt.
The disease that this compounds causes because of platelet aggregation for the treatment mankind is effective.Although compound of the present invention can be without the direct administration of any preparation, described various compounds preferably use with the form of pharmaceutical preparation, and route of administration can be parenteral route (as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one 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 such as 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 etc.
The amount of the active ingredient (the compounds of this invention) containing in pharmaceutical composition and unit dosage form can specifically be applied according to the situation of patient's the state of an illness, diagnosis, and the amount of compound used or concentration regulate in a wider scope.Conventionally, 0.5～90% (weight) that the scope of active compound amount is composition, another preferred scope is 0.5～70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention has obvious restraining effect aspect platelet aggregation.
Further illustrate the antithrombotic acitivity of the compounds of this invention below by pharmacodynamic experiment.
To rat platelet aggregation restraining effect
Medicine and preparation: compound is made into suspension for animals administer with 0.5%CMC; 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. 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, body weight 300g left and right, per os gavage gives new compound, and dosage is 15mg/kg, administration volume is 10mL/kg, after 2h, etherization, aorta abdominalis blood sampling, 3.8% Sodium Citrate anti-freezing, whole blood is 9: 1 with the ratio of antithrombotics, and the centrifugal 7min of 1000rpm prepares platelet rich plasma (PPP).Adjust PRP with PPP, make its platelet count remain on 2 × 106/ml.Get PRP and add in test cup, 37 ℃ of temperature are incubated 10min.With PRP zeroing, PPP adjusts 100%, take ADP (final concentration is as 5 μ M) as inductor, measures platelet aggregation percentage ratio by turbidimetry with SPA-3 type PPP platelet aggregation instrument, carries out statistics comparison with t-check.The results are shown in following table.
To rat platelet aggregation restraining effect
From above pharmacological evaluation, compound of the present invention can obviously suppress the platelet aggregation of ADP induction.Therefore, they can be used for the coronary syndrome that prevention or treatment cause because of platelet aggregation, myocardial infarction, the cardiovascular and cerebrovascular diseases such as myocardial ischemia.
Tentatively investigate the acute toxicity of the compounds of this invention by animal experiment.
Preliminary experiment result shows the LD of oral administration of compound I-1 and clopidogrel
50be respectively 3360mg/kg and 3210mg/kg.
Embodiment
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that 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 confirmed its structure.
reference example 1:
Intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 15.7g 3-amino-2-methoxycarbonyl thiophene, after being dissolved with 100ml DMF, add 20.2g triethylamine, at-10 ℃～5 ℃, stir, drip the mixed solution of chloroacetyl chloride (16.9g) and methylene dichloride (30ml), after low-temp reaction 3h (flaggy demonstration reacts completely) stirring at room temperature 1h, reaction solution is poured in 200ml cold water, fully stir, filter, obtain brown solid (HPLC:90.5%).Rf=0.66[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2]
Method with reference to reference example 1 can conveniently be prepared compound: intermediate III-2～III-8.With 2-bromo butyryl bromide replace chloroacetyl chloride obtain intermediate III-9.
reference example 2:
Intermediate compound IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add successively 23.3g intermediate III-1,100mL acetonitrile and 20.2g triethylamine, under nitrogen protection, add 19.0g 5,6,7,7a-tetramethylene sulfide [3,2-c] pyridine-2 (4H)-one hydrochloride.After backflow 3h, stop heating, be cooled to room temperature.To adding distil water 100ml in reaction solution, ethyl acetate extraction (100ml × 3), merges organic phase, anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed and desolventized, resistates separates with silica gel column chromatography, obtains yellow solid IV-1 (HPLC:94.8%).HRMS(m/z)[M+H]
+：353.0624。
Method with reference to reference example 2 can conveniently be prepared compound: intermediate compound IV-2～IV-9.
embodiment 1:
3-(2-(2-acetoxyl group-6,7-dihydro-thiophene [3,2-c] pyridine-5 (4H)-yl) kharophen)-2-methoxycarbonyl thiophene (Compound I-1)
In the reaction flask that stirring, condenser, thermometer are housed, add successively 35.2g intermediate compound IV-1,100mL acetonitrile and a small amount of triethylamine; under nitrogen protection, drip diacetyl oxide; 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; anhydrous methanol recrystallization, obtains white solid I-1 (HPLC:99.3%).
1H?NMR(CDCl
3，400MHz)δ：2.263(s，3H，-CH
3COO-)，2.900-2.940(m，4H，-CH
2CH
2-)，3.350(s，2H，-CH
2CO-)，3.652(s，2H，-CH
2N(CH
2-)
2)，3.766(s，3H，CH
3OOC-)，6.309(s，1H，-CH＝C-O-)，7.442-7.456(d，1H，-CHS-)，8.163-8.177(d，1H，-CH＝CHS-)，11.324(s，1H，-CONH-)。HRMS(m/z)[M+H]
+：395.0730。
Method with reference to embodiment 1 can conveniently be prepared Compound I-2～I-8.With propionic anhydride replace diacetyl oxide make Compound I-9.
embodiment 2:
Compound I-1 one-tenth hydrochloride: get I-1 white solid product 3.4g, be dissolved in 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 ice-water bath.Filter, obtain white solid, vacuum-drying, 230 ℃ of m.p. >.
embodiment 3:
Compound I-5 one-tenth vitriol: get I-5 white solid product 4.3g, be dissolved in 20mL acetone.Ice-water bath is cooled to 5 ℃, drip 9.8% sulfuric acid acetone soln to pH be 3, continue at stir about 1h under ice-water bath.Filter, obtain pink solid, vacuum-drying, 230 ℃ of m.p. >.
embodiment 4:
Compound I-9 one-tenth lactic acid salt: get I-2-3 light yellow solid product 4.7g, be dissolved in 20mL anhydrous methanol.After being heated to reflux, the molar lactic acid such as add, continue at the lower about 1h of stirring reaction that refluxes.React complete, under room temperature, leave standstill 24h.Separate out yellow crystal, filter vacuum-drying, 230 ℃ of m.p. >.
For the pharmaceutical composition of thiophene derivant of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, described embodiment is only for explanation, rather than for limiting the scope of the invention.Described preparation can use any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 1-4.
embodiment 5:
Prepare hard gelatin capsule by following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
embodiment 6:
Prepare tablet by following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.First the auxiliary material of recipe quantity is fully mixed.Bulk drug is added in auxiliary material to increase progressively dilution method, and each added-time fully mixes 2-3 time, guarantees that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dry particle is crossed 16 mesh sieves and is arranged, measure intermediate content, mix compressing tablet on tabletting machine.
embodiment 7:
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 to regulate pH value to 4～8 to make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilizing.
embodiment 8:
The preparation of injection lyophilized powder:
The lactic acid salt 100mg of Compound I-9
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate pH value to make its dissolving to 4-8 with medicinal basic.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, and sealing, to obtain final product.
Claims (9)
1. there is compound or its pharmacy acceptable salt of formula I structure:
Wherein:
R
1for: C
1-C
4straight or branched alkane carbonyl oxygen base;
R
2for: hydrogen, C
1-C
4straight or branched alkyl;
R
3for: C
1-C
4straight or branched alkyl, C
3-C
6cycloalkyl, this alkyl or cycloalkyl is replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, thienyl, itrile group, nitro, phenyl;
R
4, R
5for: hydrogen; C
1-C
4straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4straight or branched alkyl replaces; Cyano group; Methylthio group; Methylsulfonyl.
2. the compound of formula I structure as claimed in claim 1 or its pharmacy acceptable salt, the compound of its Chinese style I structure is:
Wherein:
R
1for: acetoxyl group, propionyloxy;
R
2for: hydrogen, methyl, ethyl;
R
3for: methyl, ethyl;
R
4, R
5for: hydrogen; The tertiary butyl; Trifluoromethyl; Phenyl; Chlorophenyl; Nitrophenyl; Cyano group; Methylthio group; Methylsulfonyl.
3. compound as claimed in claim 1 or its pharmacy acceptable salt, the compound of described formula I structure is:
4. formula I compound as claimed in claim 1 or its pharmacy acceptable salt, its pharmacy acceptable salt is: formula I compound and mineral acid, organic acid salify.
5. formula I compound as claimed in claim 4 or its pharmacy acceptable salt, 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.
6. as the preparation method of claim 1 Chinese style I compound, it is characterized in that: thiophenes II, in DMF, with 2-halogen acyl halide compounds at triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, under the catalysis of sodium hydroxide or potassium hydroxide,-30～10 ℃ of reactions make key intermediate III, intermediate III and 5, 6, 7, 7a-tetramethylene sulfide [3, 2-c] pyridine-2(4H)-one, at triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, under sodium hydroxide or potassium hydroxide exist, with methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane, acetonitrile or toluene are solvent, 10-100 ℃ of reaction, after acid anhydrides acidylate, make chemical compounds I,
Wherein X is Cl, Br; R
1～R
5as claim 1 defines.
7. a pharmaceutical composition for platelet aggregation-against, the formula I compound that it comprises claim 1～3 any one for the treatment of significant quantity or its pharmacy acceptable salt and one or more pharmaceutical carriers.
8. the formula I compound of claim 1～3 any one or its pharmacy acceptable salt are in the application aspect medicament for resisting platelet aggregation.
9. application as claimed in claim 8, the purposes aspect the cardiovascular and cerebrovascular diseases medicament causing because of platelet aggregation for the preparation for the treatment of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110231476.2A CN102351877B (en) | 2011-08-12 | 2011-08-12 | Thiophene derivative, its preparation method and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110231476.2A CN102351877B (en) | 2011-08-12 | 2011-08-12 | Thiophene derivative, its preparation method and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102351877A CN102351877A (en) | 2012-02-15 |
| CN102351877B true CN102351877B (en) | 2014-07-09 |
Family
ID=45575545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110231476.2A Active CN102351877B (en) | 2011-08-12 | 2011-08-12 | Thiophene derivative, its preparation method and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102351877B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066310A (en) * | 2018-01-21 | 2019-07-30 | 上海星叶医药科技有限公司 | Tanshinone IIA thiophene pyridine compounds and their and its preparation method and application |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665042B (en) * | 2012-09-21 | 2016-03-16 | 北京普禄德医药科技有限公司 | Optically active 2-hydroxy tetrahydro thienopyridine derivative and its production and use |
| CN103163095A (en) * | 2013-03-25 | 2013-06-19 | 江南大学 | Visual multifunctional detection method based on nano-silver |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1021449B1 (en) * | 1997-10-06 | 2002-01-02 | Sanofi-Synthelabo | Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates |
| CN101701020A (en) * | 2009-11-04 | 2010-05-05 | 天津药物研究院 | Amide derivate, preparation method and application thereof |
-
2011
- 2011-08-12 CN CN201110231476.2A patent/CN102351877B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1021449B1 (en) * | 1997-10-06 | 2002-01-02 | Sanofi-Synthelabo | Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates |
| CN101701020A (en) * | 2009-11-04 | 2010-05-05 | 天津药物研究院 | Amide derivate, preparation method and application thereof |
Non-Patent Citations (6)
| Title |
|---|
| N-(5-Ethylsulfanyl-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetamide;Zhi Shuang等;《Acta Crystallographica, Section E: Structure Reports Online》;20110601;第67卷;第o1490，sup1-sup8页，参见第1页背景文献、图，第sup-1页实验部分 * |
| Zhi Shuang等.N-(5-Ethylsulfanyl-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetamide.《Acta Crystallographica, Section E: Structure Reports Online》.2011,第67卷第1页. |
| 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》.2011,第46卷(第1期),第70-74页，参见第71页scheme1，第73页实验部分1.2.4,1.3. |
| 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;周云松等;《药学学报》;20110131;第46卷(第1期);第70-74页，参见第71页scheme1，第73页实验部分1.2.4和1.3节 * |
| 抗血小板药物新进展;陈航等;《心血管病学进展》;20090228;第30卷(第1期);第105-109页，参见第107页3.3.1节 * |
| 陈航等.抗血小板药物新进展.《心血管病学进展》.2009,第30卷(第1期),全文. |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066310A (en) * | 2018-01-21 | 2019-07-30 | 上海星叶医药科技有限公司 | Tanshinone IIA thiophene pyridine compounds and their and its preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102351877A (en) | 2012-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101402641B (en) | Oxime derivatives containing thienopyridine, preparation method and application thereof | |
| TW200825094A (en) | Therapeutic pyrazolyl thienopyridines | |
| JP5575979B2 (en) | Thienopyridine ester derivatives containing cyano groups, their preparation, use and compositions | |
| CN104447867A (en) | Thienopiperidine derivative, preparation method and application thereof | |
| CN102351877B (en) | Thiophene derivative, its preparation method and its application | |
| CN102093385B (en) | Schiff base compounds as well as preparation method and application of Schiff base compounds | |
| CN101974015A (en) | Ester compound and preparation method and application thereof | |
| CN107922448B (en) | Deuterated thienopiperidine derivative, preparation method and application thereof | |
| CN105367582B (en) | Bilobalide B derivates and its application in drug | |
| CN102268012B (en) | Thiazole derivative and preparation method and application thereof | |
| CN105026399B (en) | As the pyrrolo-triazine class compound of potassium channel inhibitors | |
| CN102351878B (en) | Isoxazole derivatives as well as preparation method and application thereof | |
| CN101830911B (en) | Thienopyridine derivatives, preparation method and application thereof | |
| CN103420890B (en) | 3-pyrrole carboxylic acid derivatives, and preparing method and application thereof | |
| CN102796040B (en) | 1,4-disubstituted piperazine derivatives and their preparation method and use | |
| CN102268013B (en) | Thiadiazole derivative as well as preparation method and application thereof | |
| CN102796093B (en) | Thiomorpholine-containing pyrrole derivatives and their preparation method and use | |
| CN101781310B (en) | Thiofuran-pyridine [3, 2-c] contained acethydrazide derivative and preparation method and application thereof | |
| CN102796077A (en) | Compound with diuretic effect | |
| CN103304561B (en) | One class has the compound of anti thrombotic action | |
| CN103896962B (en) | One class thienopyridine esters derivative containing substituted piperazinyl and its production and use | |
| CN102875566B (en) | Thiophene derivatives with anti-gastric ulcer effect | |
| CN102875567B (en) | Piperazine compound and preparation and usage thereof | |
| CN116898850A (en) | Pharmaceutical preparation of oxopyridazine amide derivatives, and preparation method and medical application thereof | |
| CN116898808A (en) | FXIa pharmaceutical composition, and preparation method and medical application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |