CN102234284B - Fluorine-containing ticlopidine analogues, and preparation method and application thereof - Google Patents
Fluorine-containing ticlopidine analogues, and preparation method and application thereof Download PDFInfo
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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 analogues 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 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 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 large.
Simultaneously, the untoward reaction that causes is more, and blood system comprises: use that Ticlopidine occurs the most serious, side effect is aspect hematology the most frequently, cytopenia, granulopenia, aplastic anemia are all appeared in the newspapers.Ticlopidine can reduce hematoblastic ability of aggregation and extend the bleeding time, hemostasis, nasal bleeding, menorrhagia, gastrointestinal hemorrhage etc. can occur.Gastrointestinal reaction: gastrointestinal complication is modal side reaction, 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 lethal.
Fluorine is the strongest atom of electronegativity, after introducing fluorine atom or fluoro-containing group in organism, the strong electronegativity of fluorine atom has strengthened the affinity interaction of fluorine and carbon, thereby changed significantly electrical effect and the mimic effect (Mimic effect) of fluorinated organic compound, affected the acid-basicity of compound internal structure.When fluorine atom has replaced the hydrogen atom in the compound, the solvability of esterified thing of its class 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 the physiologically active substances such as pharmaceuticals, its successful improves, and side effect is suppressed.The number of the fluorine-containing physiologically active substance of having developed so far is very many, enclose at present inside and outside Drugs Containing Fluorine and reach hundreds of, there are many medicines to become the principal item of some disease for the treatment of, some product annual sales amounts are over 1,000,000,000 dollars, at medicine circle, very important position is arranged, as the fluoroquinolone antibiotics, introducing due to 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 Antibiotics 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) etc.
Summary of the invention
First purpose of the present invention is to provide fluorine-containing ticlopidine analogues or its pharmacy acceptable salt with antithrombotic acitivity.
Second purpose of the present invention is to provide above-mentioned the have fluorine-containing ticlopidine analogues of antithrombotic acitivity or the preparation method of its pharmacy acceptable salt.
The 3rd purpose of the present invention is to provide fluorine-containing ticlopidine analogues or its pharmacy acceptable salt is the pharmaceutical composition of main active ingredient.
The 4th purpose of the present invention is to provide fluorine-containing ticlopidine analogues 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 larger superiority than Ticlopidine aspect antithrombotic acitivity, and other correlative studys are in progress.
The invention provides a kind of fluorine-containing ticlopidine analogues 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 analogues of structural formula (I), the structure of representative compound is as follows.
The fluorine-containing ticlopidine analogues pharmacy acceptable salt of structural formula (I), be fluorine-containing ticlopidine analogues and hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 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 analogues of structural formula (I):
Under organic bases exists, compound (1) and compound (2) reacting generating compound (3) in aprotic solvent; React production (I) compound with compound (4) in aprotic solvent again.
In above-mentioned reaction, R
1, R
2, R
3, the definition of n is with claim 1, and X is chlorine or bromine.
In above-mentioned preparation method, compound (1) can obtain by two kinds of approach: according to US4,740,510 (1988-4-26) disclosed method, with 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine be 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 Multi substituted benzenes methyl chloride (bromine), and the kind of commercially available product is a lot.Compound (4) is 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 the organic basess such as pyridine is extremely crucial factor, if the mineral alkali of reporting in the use related documents, particularly use inorganic strong alkali, as hydrogen sodium, potassium hydroxide is 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 organic solvent, makes pharmacy acceptable salt with mineral acid, organic acid reaction, this is method conventional on pharmaceutical chemistry.
Of the present invention have the fluorine-containing ticlopidine analogues 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 method conventional on pharmaceutics.
Fluorine-containing ticlopidine analogues or its pharmacy acceptable salt with structural formula (I) of the present invention has significant restraining effect to thrombosis.
Impact test on 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: ticlopidine, compound N O.1-NO.6, white or off-white powder, content is greater than 99.5%.Be mixed with before use 0.5% Xylo-Mucine suspendible liquid for rat oral gavage, concentration 10mg/ml.
Key instrument: BT87-3 type instrument for detecting internal thrombosis, supervise medical college's cardiovascular research chamber, packet header, and packet header electrical maintenance scientific and technological development section of medical college makes.
Method and result:
Animal adaptability is tested after feeding for 1 week.Compound N O.1-NO.6, 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 speed new 0.15ml/kg mixing intramuscular injection anesthetized animal of sleeping, 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, the electricity irritation T hrombosis inducer turns on the power switch in advance, steady current, with a fritter fatty tissue that pads on 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 swab stick libation at an ancient wedding ceremony, keep this section blood vessel moistening.The adjustment electric current is 1.8mA, opens the thorn energizing switch, stimulates 5min, and without the burnt trace that obviously burns, tube wall is fulgerized and located little flavescence with vessel wall, and the part attenuates, and the proximal part oedema is degree.
Impact on rat suppository formation
Above-mentioned impact test demonstration on experimental artery thrombosis, 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, the cardiovascular and cerebrovascular diseases such as myocardial ischemia.
Embodiment
The present invention is described further with embodiment for the below.
Reference example: ticlopidine
Literature method is more, and (Chinese Journal of Pharmaceuticals, 28 (5): people's the method such as 197-199), 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] pyridine (NO.1) also
Add successively 5,6,7,7 in three-necked bottle
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 ℃, add 2-fluorobenzene monobromomethane (3.78g, 0.02mol) reaction 5 hours, add again triethylamine (4g), diacetyl oxide (2.04g), continue reaction 2 hours.Add 20ml water, standing after stirring, tell the trichloromethane layer, through anhydrous sodium sulfate drying, the faint yellow oily thing after the reclaim under reduced pressure trichloromethane separates with silicagel column, sherwood oil: ethyl acetate=3: 1 is eluent, collect product, get 2-(acetoxyl group)-5-(2-luorobenzyl)-4,5 after 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] pyridine (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)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.2) and 2-(acetoxyl group)-5-(4-luorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.3), yield is respectively 68.9% and 69.6%.
Embodiment 2:
2-(acetoxyl group)-5-(2-fluoro-6-chlorobenzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine (NO.4) also
Add successively 5,6,7,7 in three-necked bottle
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 ℃, add 2-fluoro-6-chlorophenylmethyl chlorine (3.58g, 0.02mol) reaction 4 hours, add again pyridine (3.1g), diacetyl oxide (2.0g), continue reaction 1.5 hours.Add 22ml water, standing after stirring, tell dichloromethane layer, through anhydrous sodium sulfate drying, the colorless oil after the reclaim under reduced pressure methylene dichloride is separated with silicagel column, sherwood oil: ethyl acetate=3: 1 is eluent, collect product, get 2-(acetoxyl group)-5-(2-fluoro-6-chlorobenzyl)-4,5 after 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-chlorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (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-(2,4-difluorobenzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine (NO.5) also
Add successively 5,6,7,7 in three-necked bottle
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-difluorobenzene methyl chloride (3.25g, 0.02mol) reacted 4.5 hours, then add triethylamine (4.1g), diacetyl oxide (2.0g), continue reaction 1 hour.
Colorless oil after the reclaim under reduced pressure tetrahydrofuran (THF), separate with silicagel column, sherwood oil: ethyl acetate=3: 1 is eluent, collects product, after decompression and solvent recovery 2-(acetoxyl group)-5-(2, the 4-difluorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine 4.3g, yield 66.4%.MS-ESI：324.1[M+H]。
2-(acetoxyl group)-5-(2,4-difluorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.5) 1g is dissolved in the 15ml anhydrous methanol, 0 ℃-5 ℃, adds 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 is [3,2-c] pyridine (NO.6), 2-(acetoxyl group)-5-(2 also, 6-two fluoro-4-chlorobenzyls)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.7) and 2-(acetoxyl group)-5-(2-fluoro-4-bromobenzyl)-4,5,6,7-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-(2,4,5,6-ptfe benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine (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, then adds equimolar propionic anhydride to replace 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 etc. moles 2,3,4,5,6-pentafluoro-benzyl chloro is for 2,4,5,6-tetra fluoro benzene methyl chloride obtains 2-(propionyloxy)-5-(2,3,4,5,6-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-(2,3,5,6-ptfe benzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine (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, then adds equimolar isobutyric anhydride to replace diacetyl oxide, obtain 2-(isopropyl acyloxy)-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 etc. moles 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)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (NO.12), 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] pyridine (NO.13) also
The method that provides by embodiment 3, add equimolar 2-fluoro-5-trifluoromethylbenzene monobromomethane to replace 2,4-difluorobenzene methyl chloride, then add equimolar butyryl oxide to replace diacetyl oxide, obtain 2-(butyryl acyloxy)-5-(2-fluoro-5-trifluoromethyl benzyl)-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also, yield 65.2%, MS-ESI:402.1[M+H].
By above-mentioned identical method, mole 2-fluoro-4-trifluoromethylbenzene monobromomethane such as add to replace 2-fluoro-5-trifluoromethylbenzene monobromomethane, obtain 2-(butyryl acyloxy)-5-(2-fluoro-4-trifluoromethyl benzyl)-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine (NO.14) also, yield 63.5%, MS-ESI:402.1[M+H].
Claims (7)
1. fluorine-containing ticlopidine analogues or its pharmacy acceptable salt with following structure formula I:
（Ⅰ）
Wherein:
R
1: C
1-C
4The straight or branched alkyl;
R
2: halogen, trifluoromethyl;
R
3: fluorine;
N:0, the integer of 1-4.
2. fluorine-containing ticlopidine analogues or its pharmacy acceptable salt as claimed in claim 1, 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; Described halogen is fluorine, chlorine, bromine.
3. fluorine-containing ticlopidine analogues or its pharmacy acceptable salt as claimed in claim 2, is characterized in that, described straight or branched alkyl is methyl, ethyl, propyl group, butyl, isobutyl-; Described halogen is fluorine, chlorine.
4. fluorine-containing ticlopidine analogues or its pharmacy acceptable salt as claimed in claim 1, it is characterized in that, described pharmacy acceptable salt is fluorine-containing ticlopidine analogues and hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 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 analogues of structure formula I or the preparation method of its pharmaceutically-acceptable salts as claimed in claim 1, it is characterized in that:
Under organic bases existed, compound (1) reacted in aprotic solvent with compound (2) and generates chemical combination
Thing (3); React again generation formula I compound in aprotic solvent with compound (4),
In above-mentioned reaction, R
1, R
2, R
3, the definition of n is with claim 1, and X is chlorine or bromine.
6. antithrombotic pharmaceutical composition, it comprises the described fluorine-containing ticlopidine analogues of claim 1 to 4 any one for the treatment of significant quantity or its pharmacy acceptable salt and one or more pharmaceutical excipients.
7. the described fluorine-containing ticlopidine analogues of claim 1 to 4 any one or the purposes of its pharmacy acceptable salt in the medicine of preparation prevention or treatment thrombotic diseases.
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Citations (3)
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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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2010
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Effective date of registration: 20120210 Address after: 300203, Tianjin Dagu South Road, respect 4, 3, Hexi District Applicant after: Tianjin Hankang Pharmaceutical Biotechnology Co., Ltd. Address before: 300203, Tianjin Dagu South Road, respect 4, 3, Hexi District Applicant before: Yan Jie |
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Effective date of registration: 20181010 Address after: 300409 88 Huashi Road, Beichen science and Technology Park, Tianjin Patentee after: TIANJIN HANRUI PHARMACEUTICAL CO., LTD. Address before: 300203 Tianjin Hexi District Dagu South Road 4, 3 Patentee before: Tianjin Hankang Pharmaceutical Biotechnology Co., Ltd. |