CN102234284A - Fluorine-containing ticlopidine analogues, and preparation method and application thereof - Google Patents
Fluorine-containing ticlopidine analogues, and preparation method and application thereof Download PDFInfo
- Publication number
- CN102234284A CN102234284A CN2010101508855A CN201010150885A CN102234284A CN 102234284 A CN102234284 A CN 102234284A CN 2010101508855 A CN2010101508855 A CN 2010101508855A CN 201010150885 A CN201010150885 A CN 201010150885A CN 102234284 A CN102234284 A CN 102234284A
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- CN
- China
- Prior art keywords
- acid
- fluorine
- analogue
- ticlopidine
- acceptable 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.)
- Granted
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- 239000011737 fluorine Substances 0.000 title claims abstract description 37
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 35
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical class ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
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- 230000000638 stimulation Effects 0.000 description 1
- 238000013456 study Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to fluorine-containing ticlopidine analogues with a general formula (I), and a preparation method and application thereof. In the general formula (I), R1 is C1-C4 straight-chain or branched-chain alkyl, R2 is halogen or trifluoromethyl, R3 is hydrogen or fluorine, and n is an integer ranging from 0 to 4. The general formula (I) is shown in the specification.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to Ticlopidine analogue of fluorine and preparation method thereof, contain the pharmaceutical composition of these analogues and as the purposes of antithrombotic reagent.
Background technology
Cardiovascular and cerebrovascular diseases has become the principal disease of harm humans health at present, and thrombosis is the major complications and the lethal factor of this type of disease and atherosclerosis relative disease, researches and develops such medicine and has much prospect.
Ticlopidine is first adp receptor antagonist, belongs to thienopyridine on the chemical structure.Abroad at first by French Sanofi company in listing in 1978,1989 begin to enter China market, it is proved to be a kind of effective anti-thrombosis drug in the treatment of the heart, brain and surrounding blood vessel and microvascular disease, be used widely clinically.
Ticlopidine
But the Ticlopidine platelet aggregation-against is active low, and taking dose is big.
Simultaneously, the untoward reaction that causes is more, and blood system comprises: serious, the most frequent side effect of using the Ticlopidine appearance is aspect hematology, and cytopenia, granulopenia, aplastic anemia are all appeared in the newspapers.Ticlopidine can reduce hematoblastic ability of aggregation and prolong the bleeding time, hemostasis, nasal bleeding, menorrhagia, gastrointestinal hemorrhage etc. can occur.Gastrointestinal reaction: gastrointestinal complication is a most common side-effects, have nauseating, the vomiting and diarrhoea.Also can cause various skin allergyes such as skin rash, urticaria, maculopapule, fash erythema nodosum.Liver toxicity is arranged in addition, cause liver injury, even cause death.
Fluorine is the strongest atom of electronegativity, after introducing fluorine atom or fluoro-containing group in the organism, fluorine atom intensive electronegativity has strengthened the affinity interaction of fluorine and carbon, thereby changed the electrical effect and the mimic effect (Mimic effect) of fluorinated organic compound significantly, influenced the acid-basicity of compound internal structure.When fluorine atom has replaced the hydrogen atom in the compound, the solvability of its lipoid platform thing on microbial film is enhanced, and promotes its absorption and transmission speed in vivo, and physiological action is changed.
Import fluorine atom or trifluoromethyl on a certain key position of physiologically active substances such as pharmaceuticals, its effect obviously improves, and side effect is suppressed.The number of the fluorine-containing physiologically active substance of having developed so far is very many, enclose inside and outside fluorine-containing medicine at present and reach hundreds of, there are many medicines to become the principal item of some disease of treatment, some product annual sales amounts are above 1,000,000,000 dollars, at medicine circle very important position is arranged, as the fluoroquinolone antibiotics, because the introducing of fluorine, make its has a broad antifungal spectrum, activity not only far wins existing same veriety, and be better than the anti-infectives of other type at present commonly used, be one of antibiotic class drug research focus over nearly 20 years.In addition, also have 5 FU 5 fluorouracil series antineoplastic medicament, fluorine-containing NSAID (non-steroidal anti-inflammatory drug) or the like.
Summary of the invention
First purpose of the present invention provides fluorine-containing Ticlopidine analogue or its pharmacy acceptable salt with antithrombotic acitivity.
Second purpose of the present invention provides above-mentioned the have fluorine-containing Ticlopidine analogue of antithrombotic acitivity or the preparation method of its pharmacy acceptable salt.
The 3rd purpose of the present invention provides fluorine-containing Ticlopidine analogue or its pharmacy acceptable salt is the pharmaceutical composition of main active ingredient.
The 4th purpose of the present invention provides fluorine-containing Ticlopidine analogue or the application of its pharmacy acceptable salt in the medicine of preparation prevention or treatment thrombotic diseases.
Through Preliminary pharmacological test as can be known, The compounds of this invention has bigger superiority than Ticlopidine aspect antithrombotic acitivity, and other correlative studys are in progress.
The invention provides a kind of fluorine-containing Ticlopidine analogue or its pharmacy acceptable salt with following structural formula (I):
Wherein:
R
1: C
1-C
4The straight or branched alkyl;
R
2: halogen, trifluoromethyl;
R
3: hydrogen, fluorine;
N:0, the integer of 1-4.
Described straight or branched alkyl is methyl, ethyl, propyl group, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl-propyl.Preferable methyl, ethyl, propyl group, butyl, isobutyl-.
Described halogen is fluorine, chlorine, bromine.Preferred fluorine, chlorine.
Have in the fluorine-containing Ticlopidine analogue of structural formula (I), the structure of representative compound is as follows.
The fluorine-containing Ticlopidine analogue pharmacy acceptable salt of structural formula (I), be fluorine-containing Ticlopidine analogue and hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetate, propionic acid, propanedioic acid, butyric acid, lactic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, toxilic acid, the salt that phenylformic acid, succsinic acid, picric acid, tartrate, citric acid, fumaric acid form.
The preparation method of the fluorine-containing Ticlopidine analogue of structural formula (I):
In the presence of organic bases, compound (1) and compound (2) reacting generating compound (3) in aprotic solvent; In aprotic solvent, react production (I) compound with compound (4) again.
In above-mentioned reaction, R
1, R
2, R
3, the definition of n is with claim 1, and X is a chlorine or bromine.
In above-mentioned preparation method, compound (1) can obtain by two kinds of approach: according to US4, and 740,510 (1988-4-26) disclosed method, with 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine is that raw material makes; Commercially available product is arranged, and its commercially available product is its hydrochloride form, can directly use, and adds a certain amount of organic bases and gets final product.
Compound (2) is fluorine, chlorine, bromine, the replacement of trifluoromethyl list or polysubstituted phenmethyl chlorine (bromine), and the kind of commercially available product is a lot.Compound (4) is an acid anhydrides, and commercially available product is also all arranged.
Aprotic solvent refers to methylene dichloride, trichloromethane, tetrahydrofuran (THF), dimethyl formamide etc.
Triethylamine, the use of organic basess such as pyridine are The key factor extremely, if use the mineral alkali of reporting in the relevant document, particularly use inorganic strong alkali, as hydrogen sodium, potassium hydroxide, during sodium hydroxide, resultant is extremely complicated, is difficult to obtain compound (3) and end product formula (I) compound.
Formula (I) compound is dissolved in the organic solvent, makes pharmacy acceptable salt with mineral acid, organic acid reaction, this is a method conventional on the pharmaceutical chemistry.
Of the present invention have the fluorine-containing Ticlopidine analogue of structural formula (I) or a composition of its pharmacy acceptable salt and pharmaceutical excipient, is used for oral solid formulation, as tablet, and capsule etc., this is that pharmaceutical preparation is learned the conventional method that goes up.
Fluorine-containing Ticlopidine analogue or its pharmacy acceptable salt with structural formula (I) of the present invention has significant inhibitory effect to thrombosis.
Influence test to experimental artery thrombosis.
Laboratory animal: the healthy SD rat, male, the SPF level, body weight 240～260g is provided by Chinese Academy of Medical Sciences's Experimental Animal Center.Animal conformity certification number: the capital is moving is betrothed to (2002) No. 010.Blank group wherein, positive controls, each 10 of test group.
Medicine: hydrochloric acid Ticlopidine, compound N O.1-NO.6, white or off-white powder, content is greater than 99.5%.Face with before being mixed with 0.5% Xylo-Mucine suspendible soup and use concentration 10mg/ml for rat oral gavage.
Key instrument: the experimental thrombus in vivo of BT87-3 type forms determinator, and packet header medical college supervises the cardiovascular research chamber, and electrical maintenance scientific and technological development portion of packet header medical college makes.
Method and result:
Animal adaptability experimentizes after feeding for 1 week.Compound N O.1-NO.6, the hydrochloric acid Ticlopidine, by 30mg/kg administration every day, the blank group gives isopyknic 0.5% Xylo-Mucine, successive administration 3 days.Last administration 4 hours, with ketamine 0.11ml/kg, the new 0.15ml/kg mixing intramuscular injection anesthetized animal of speed dormancy, lie on the back and be fixed on the rabbit plate, operation on neck position preserved skin, sterilization, along tracheae medisection skin, peel off arteria carotis communis, electricity irritation thrombosis instrument turns on the power switch steady current in advance, with a fritter fatty tissue that fills up on the stimulating electrode from body, be placed on proximal part, temperature electrode is placed on distal end, and two electrodes hook blood vessel and blood vessel is maintained the original state and original position.On stimulation location, and cover wet gauze with a small amount of physiological saline point of the excellent libation at an ancient wedding ceremony of cotton, keep this section blood vessel moistening.The adjustment electric current is 1.8mA, opens the thorn energizing switch, stimulates 5min, does not have the burnt trace that obviously burns with vessel wall, and tube wall is fulgerized and located little flavescence, and the part attenuates, and the proximal part oedema is degree.
Influence to rat suppository formation
Above-mentioned influence test to experimental artery thrombosis shows that compound of the present invention and hydrochloric acid thiophene chloropyridine can obviously suppress thrombosis (p＜0.0) 1), compound activity of the present invention is better than the hydrochloric acid thiophene chloropyridine.Therefore, they can be used for preventing or treating the coronary syndrome that causes because of thrombosis, myocardial infarction, cardiovascular and cerebrovascular diseases such as myocardial ischemia.
Embodiment
The present invention is described further with embodiment below.
Reference example: hydrochloric acid Ticlopidine
Literature method is more, and (Chinese Journal of Pharmaceuticals, 28 (5): 197-199) wait people's method, with 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine and 2-chlorobenzyl chloride is that raw material makes to press Cen Junda.With dehydrated alcohol recrystallization three times, M.P 206.5-207 ℃, infrared spectrogram, proton nmr spectra, mass spectrum, ultimate analysis is consistent with reference substance.
Embodiment 1:
2-(acetoxyl group)-5-(2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.1) also
In three-necked bottle, add 5,6,7,7 successively
a-tetramethylene sulfide also [3,2-c] pyridone-2 hydrochloride (compound 1) (3.83g, 0.02mol), trichloromethane (25ml), triethylamine (4.5g), stir, be heated to 40 ℃, (3.78g 0.02mol) reacted 5 hours to add 2-fluorobenzene monobromomethane, add triethylamine (4g), diacetyl oxide (2.04g) again, continue reaction 2 hours.Add 20ml water, leave standstill after the stirring, tell the trichloromethane layer, through anhydrous sodium sulfate drying, the faint yellow oily thing behind the reclaim under reduced pressure trichloromethane separates with silicagel column, sherwood oil: ethyl acetate=3: 1 is an eluent, collect product, get 2-(acetoxyl group)-5-(2-luorobenzyl)-4,5 behind the decompression and solvent recovery, 6, the 7-tetramethylene sulfide is [3,2-c] pyridine 4.1g also, yield 67.2%.MS-ESI：306.1[M+H]。
Ultimate analysis: C, 62.84, H5.21, F6.19, N4.51 (theoretical value: C, 62.93, H5.28, F6.22, N4.59).
2-(acetoxyl group)-5-(2-luorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridines (NO.1) 1g are dissolved in the acetone of 20ml, and 0 ℃-5 ℃, add the hydrochloric acid diethyl ether solution to PH3, get white solid, i.e. hydrochloride.
By above-mentioned identical method, obtain 2-(acetoxyl group)-5-(3-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.2) and 2-(acetoxyl group)-5-(4-luorobenzyl)-4,5,6 also, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.3) also, and yield is respectively 68.9% and 69.6%.
Embodiment 2:
2-(acetoxyl group)-5-(2-fluoro-6-benzyl chloride base)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.4) also
In three-necked bottle, add 5,6,7,7 successively
a-tetramethylene sulfide also [3,2-c] pyridone-2 hydrochloride (compound 1) (3.83g, 0.02mol), methylene dichloride (20ml), pyridine (3.2g), stir, be heated to 35 ℃, (3.58g 0.02mol) reacted 4 hours to add 2-fluoro-6-chlorophenylmethyl chlorine, add pyridine (3.1g), diacetyl oxide (2.0g) again, continue reaction 1.5 hours.Add 22ml water, leave standstill after the stirring, tell dichloromethane layer, through anhydrous sodium sulfate drying, the colorless oil behind the reclaim under reduced pressure methylene dichloride is separated with silicagel column, sherwood oil: ethyl acetate=3: 1 is an eluent, collect product, get 2-(acetoxyl group)-5-(2-fluoro-6-benzyl chloride base)-4,5 behind the decompression and solvent recovery, 6, the 7-tetramethylene sulfide is [3,2-c] pyridine 3.6g also, yield 52.8%.MS-ESI：340.8[M+H]。
2-(acetoxyl group)-5-(2 fluoro-6-benzyl chloride base)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridines (NO.4) 1g is dissolved in the 18ml dehydrated alcohol, adds the equimolar vitriol oil, and decompression steams partial solvent, gets white solid, i.e. vitriol.
Embodiment 3:
2-(acetoxyl group)-5-(2, the 4-difluorobenzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.5) also
In three-necked bottle, add 5,6,7,7 successively
a-tetramethylene sulfide also [3,2-c] pyridone-2 hydrochloride (compound 1) (3.83g, 0.02mol), tetrahydrofuran (THF) (50ml), triethylamine (4.4g), stir, be heated to 38 ℃, add 2,4-difluoro phenmethyl chlorine (3.25g, 0.02mol) reacted 4.5 hours, add triethylamine (4.1g), diacetyl oxide (2.0g) again, continue reaction 1 hour.
Colorless oil behind the reclaim under reduced pressure tetrahydrofuran (THF), separate sherwood oil with silicagel column: ethyl acetate=3: 1 be an eluent, the collection product, get 2-(acetoxyl group)-5-(2, the 4-difluorobenzyl)-4,5,6 behind the decompression and solvent recovery, the 7-tetramethylene sulfide is [3,2-c] pyridine 4.3g also, yield 66.4%.MS-ESI：324.1[M+H]。
2-(acetoxyl group)-5-(2, the 4-difluorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridines (NO.5) 1g are dissolved in the 15ml anhydrous methanol, and 0 ℃-5 ℃, add ethanol solution hydrochloride to PH3, decompression steams partial solvent, gets white solid, i.e. hydrochloride.
By above-mentioned identical method, obtain 2-(acetoxyl group)-5-(2, the 5-difluorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.6), 2-(acetoxyl group)-5-(2,6-two fluoro-4-benzyl chloride bases)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.7) and 2-(acetoxyl group)-5-(2-fluoro-4-bromobenzyl)-4 also, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.8), yield is respectively 67.1%, 67.7% and 66.1% (MS-ESI:384.0[M+H]).
Embodiment 4:
2-(propionyloxy)-5-(2,4,5, the 6-ptfe benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.9) also
By the method that embodiment 1 provides, add equimolar 2,4,5,6-tetra fluoro benzene methyl chloride replaces 2-fluorobenzene monobromomethane, adds equimolar propionic anhydride again and replaces diacetyl oxide, obtain 2-(propionyloxy)-5-(2,4,5, the 6-ptfe benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine, yield 56.1%, MS-ESI:374.1[M+H].
By above-mentioned identical method, add and wait mole 2,3,4,5,6-pentafluoro-benzyl chloro is for 2,4,5,6-tetra fluoro benzene methyl chloride obtains 2-(propionyloxy)-5-(2,3,4,5, the 6-PFBBR)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.10), yield 60.6%, MS-ESI:392.1[M+H].
Embodiment 5:
2-(isobutyl acyloxy)-5-(2,3,5, the 6-ptfe benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.11) also
By the method that embodiment 2 provides, add equimolar 2,3,5,6-tetra fluoro benzene monobromomethane replaces 2-fluoro-6-chlorophenylmethyl chlorine, adds equimolar isobutyric anhydride again and replaces diacetyl oxide, obtain 2-(different propionyloxy)-5-(2,3,5, the 6-ptfe benzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine, yield 62.3%, MS-ESI:388.1[M+H].
By above-mentioned identical method, add and wait mole 2,4,5-trifluoro-benzene methyl chloro is for 2,3,5,6-tetra fluoro benzene methyl chloride obtains 2-(isobutyl acyloxy)-5-(2,4, the 5-trifluoro-benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.12) also, yield 64.8%, MS-ESI:370.1[M+H].
Embodiment 6:
2-(butyryl acyloxy)-5-(2-fluoro-5-trifluoromethyl benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.13) also
The method that provides by embodiment 3, add equimolar 2-fluoro-5-trifluoromethylbenzene monobromomethane and replace 2,4-difluoro phenmethyl chlorine adds equimolar butyryl oxide again and replaces diacetyl oxide, obtains 2-(butyryl acyloxy)-5-(2-fluoro-5-trifluoromethyl benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, yield 65.2%, MS-ESI:402.1[M+H].
By above-mentioned identical method, add and wait mole 2-fluoro-4-trifluoromethylbenzene monobromomethane to replace 2-fluoro-5-trifluoromethylbenzene monobromomethane, obtain 2-(butyryl acyloxy)-5-(2-fluoro-4-trifluoromethyl benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (NO.14) also, yield 63.5%, MS-ESI:402.1[M+H].
Claims (7)
1. fluorine-containing Ticlopidine analogue or its pharmacy acceptable salt with following structural formula (I):
Wherein:
R
1: C
1-C
4The straight or branched alkyl;
R
2: halogen, trifluoromethyl;
R
3: hydrogen, fluorine;
N:0, the integer of 1-4.
2. fluorine-containing according to claim 1 Ticlopidine analogue or its pharmacy acceptable salt, it is characterized in that described straight or branched alkyl is methyl, ethyl, propyl group, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl-propyl; Described halogen is fluorine, chlorine, bromine.
3. as fluorine-containing Ticlopidine analogue or its pharmacy acceptable salt as described in the claim 2, it is characterized in that described straight or branched alkyl is methyl, ethyl, propyl group, butyl, isobutyl-; Described halogen is fluorine, chlorine.
4. as fluorine-containing Ticlopidine analogue or its pharmacy acceptable salt as described in the claim 1 to 3, it is characterized in that, described pharmacy acceptable salt is fluorine-containing Ticlopidine analogue and hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetate, propionic acid, propanedioic acid, butyric acid, lactic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, toxilic acid, the salt of phenylformic acid, succsinic acid, picric acid, tartrate, citric acid, fumaric acid.
5. one kind has the fluorine-containing Ticlopidine analogue of structural formula (I) or the preparation force method of its pharmaceutically-acceptable salts according to claim 1, it is characterized in that:
In the presence of organic bases, compound (1) and compound (2) reacting generating compound (3) in aprotic solvent; In aprotic solvent, react production (I) compound with compound (4) again.
In above-mentioned reaction, R
1, R
2, R
3, the definition of n is with claim 1, and X is a chlorine or bromine.
6. antithrombotic pharmaceutical composition, it comprises each described fluorine-containing Ticlopidine analogue of claim 1 to 4 or its pharmacy acceptable salt and one or more pharmaceutical carriers, vehicle or the thinner for the treatment of significant quantity.
7. each described fluorine-containing Ticlopidine analogue of a claim 1 to 4 or the purposes of its pharmacy acceptable salt in the medicine of preparation prevention or treatment thrombotic diseases.
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| CN103360408A (en) * | 2012-04-11 | 2013-10-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel thienopyridine compounds and use thereof in medicine |
| CN106046021A (en) * | 2016-05-26 | 2016-10-26 | 天津药物研究院有限公司 | Thienopyridine derivative containing bromine and preparation method and application of thienopyridine derivative |
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|---|---|---|---|---|
| EP0573975A1 (en) * | 1992-06-08 | 1993-12-15 | Fuji Photo Film Co., Ltd. | 2-alkoxycarbonyl-5-o-chlorobenzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivative and process for producing the same |
| JP2006052208A (en) * | 2004-07-13 | 2006-02-23 | Dai Ichi Seiyaku Co Ltd | Prophylactic and therapeutic agent of thrombus/embolus by oral administration |
| CN101402643A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Industrial production method for prasugrel |
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|---|---|---|---|---|
| EP0573975A1 (en) * | 1992-06-08 | 1993-12-15 | Fuji Photo Film Co., Ltd. | 2-alkoxycarbonyl-5-o-chlorobenzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivative and process for producing the same |
| JP2006052208A (en) * | 2004-07-13 | 2006-02-23 | Dai Ichi Seiyaku Co Ltd | Prophylactic and therapeutic agent of thrombus/embolus by oral administration |
| CN101402643A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Industrial production method for prasugrel |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360408A (en) * | 2012-04-11 | 2013-10-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel thienopyridine compounds and use thereof in medicine |
| CN106046021A (en) * | 2016-05-26 | 2016-10-26 | 天津药物研究院有限公司 | Thienopyridine derivative containing bromine and preparation method and application of thienopyridine derivative |
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