CN102351877A - Thiophene derivative, its preparation method and its application - Google Patents
Thiophene derivative, its preparation method and its application Download PDFInfo
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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, relate to one type and have thiophene derivant of antiplatelet aggregative activity and preparation method thereof, contain their pharmaceutical composition and as the purposes of antiplatelet drug.
Background technology
Be that master's the sickness rate of thrombotic disease is in rising trend with 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 possibly 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 through 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, 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 all are higher than Ticlopidine.But accept the treatment of Ticlopidine, clopidogrel and have certain defective.
As one of focus of antiplatelet drug research, need more safe and effective this compounds of searching at present badly.
The contriver has found one type of thiophene derivant with antiplatelet aggregative activity in research process.
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 that disclosing with thiophene derivant and pharmaceutical salts thereof is the pharmaceutical composition of main active ingredient.
A further object of the invention is; Thiophene derivant 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; Myocardial ischemia, the purposes of cardiovascular and cerebrovascular diseases medicament aspect.
Combine the object of the invention at present, content of the present invention is set forth in detail.
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: hydrogen, C
1-C
4The straight or branched alkyl.
R
3For: C
1-C
4The straight 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
4The straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4The straight or branched alkyl replaces; Cyanic acid; Methylthio group; Methylsulfonyl.
Preferred 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; Cyanic acid; Methylthio group; Methylsulfonyl.
More preferably following its pharmacy acceptable salt of compound:
I-1 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) acetamido also)-2-methoxycarbonyl thiophene;
I-2 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) the acetamido also)-5-tertiary butyl)-2-methoxycarbonyl thiophene;
I-3 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) acetamido also)-4-phenyl-5-(trifluoromethyl)-2-methoxycarbonyl thiophene;
I-4 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) acetamido also)-5-phenyl-2-methoxycarbonyl thiophene;
I-5 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) acetamido also)-5-(4-fluorophenyl)-2-methoxycarbonyl thiophene;
I-6 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) acetamido also)-5-(3-nitrophenyl)-2-methoxycarbonyl thiophene;
I-7 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) acetamido also)-5-(4-tert-butyl-phenyl)-2-methoxycarbonyl thiophene;
I-8 3-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) acetamido also)-4-cyanic acid-5-(methylthio group)-2-ethoxycarbonyl thiophene;
I-9 4-(methylsulfonyl)-5-(methylthio group)-3-(2-(2-(propionyloxy)-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) amide-based small also)-2-methanoyl thiophene.
The 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 or the like.
The preparation route of formula I compound is following:
Wherein X is Cl, Br; R
1～R
5Like aforementioned definitions
Thiophenes (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 hydrogencarbonate, 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)-ketone is in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate, 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 processes 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 is processed hydrochloride to pH2.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 (like vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions of The compounds of this invention is following: use standard and conventional technology; Acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.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, Ucar 35, 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-s 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 through pharmacodynamic experiment.
To the rat platelet aggregation restraining effect
Medicine and preparation: compound is made into suspension with 0.5%CMC and supplies animals administer to use; 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 15mg/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.With the PRP zeroing, 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, carries out statistical comparisons with the t-check.The result sees the following form.
To the rat platelet aggregation restraining effect
Visible by above pharmacological evaluation, 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 through animal experiment.
The 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 done further explanation, embodiment only is indicative, means that never it limits scope of the present 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 implementation example 1:
Intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 15.7g 3-amino-2-methoxycarbonyl thiophene; With 100ml 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 (30ml); Behind low-temp reaction 3h (the flaggy demonstration reacts completely) the stirring at room 1h, reaction solution is poured in the 200ml cold water, fully stirred; Filter, promptly get brown solid (HPLC:90.5%).The Rf=0.66[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2]
Method with reference to reference implementation example 1 can conveniently prepare compound: intermediate III-2～III-8.Replace chloroacetyl chloride to get intermediate III-9 with 2-bromo butyryl bromide.
Reference implementation example 2:
Intermediate compound IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add 23.3g intermediate III-1,100mL acetonitrile and 20.2g triethylamine successively, nitrogen protection adds 19.0g 5,6,7,7a-tetramethylene sulfide [3,2-c] pyridines-2 (4H)-keto hydrochloride down.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 yellow solid IV-1 (HPLC:94.8%).HRMS(m/z)[M+H]
+：353.0624。
Method with reference to reference implementation example 2 can conveniently prepare compound: intermediate compound IV-2～IV-9.
Embodiment 1:
3-(2-(2-acetoxyl group-6,7-dihydro-thiophene [3,2-c] pyridines-5 (4H)-yl) kharophen)-2-methoxycarbonyl thiophene (compound I-1)
In the reaction flask that stirring, condenser, thermometer are housed, add 35.2g 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: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 prepare compound I-2～I-8.Replace diacetyl oxide to make compound I-9 with propionic anhydride.
Embodiment 2:
Compound I-1 one-tenth hydrochloride: get I-1 white solid product 3.4g, 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-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 the ice-water bath.Filter, pink solid, vacuum-drying, m.p.＞230 ℃.
Embodiment 4:
Compound I-9 one-tenth lactic acid salt: get I-2-3 light yellow solid product 4.7g, be dissolved in the 20mL 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 under room temperature, leaves standstill 24h.Separate out yellow crystal, filter, vacuum-drying, m.p.＞230 ℃.
For the pharmaceutical composition of thiophene derivant of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, said embodiment only is used for explanation, rather than is used to limit scope of the present invention.Said 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 1-4.
Embodiment 5:
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, and it is subsequent use to cross 100 mesh sieves.After pressing recipe quantity mentioned component being mixed, be packed in the hard gelatin capsule.
Embodiment 6:
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, and it is subsequent use 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 7:
The preparation of injection liquid:
Preparing method: get activeconstituents and join in the water for injection that dissolves sorb ester and Ucar 35, add medicinal basic adjusting pH value to 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
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%
Preparing 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, filtrating is carried out packing, adopts freeze-drying, makes loose block, seals, and promptly gets.
Claims (9)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R
1For: C
1-C
4Straight or branched alkane carbonyl oxygen base;
R
2For: hydrogen, C
1-C
4The straight or branched alkyl;
R
3For: C
1-C
4The straight 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
4The straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4The straight or branched alkyl replaces; Cyanic acid; Methylthio group; Methylsulfonyl.
2. the compound of formula I structure as claimed in claim 1 or its pharmacy acceptable salt, the compound of formula I structure is preferred:
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; Cyanic acid; Methylthio group; Methylsulfonyl.
3. compound as claimed in claim 1 or its pharmacy acceptable salt, the compound of said 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. like 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; Yellow soda ash; Sodium hydrogencarbonate; 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)-ketone; At triethylamine; Pyridine; Salt of wormwood; Yellow soda ash; Sodium hydrogencarbonate; Sodium hydroxide or potassium hydroxide exist down, with methyl alcohol; Ethanol; Ethyl acetate; Methylene dichloride; Trichloromethane; Acetonitrile or toluene are solvent, 10-100 ℃ of reaction; After the acid anhydrides acidylate, make compound I
Wherein X is Cl, Br; R
1～R
5Define like claim 1.
7. the pharmaceutical composition of a platelet aggregation-against, it comprises each formula I compound or its pharmacy acceptable salt and one or more pharmaceutical carriers of claim 1～3 of treating significant quantity.
8. each formula I compound or its pharmacy acceptable salt of claim 1～3 is in the application that is used to prepare aspect the medicament for resisting platelet aggregation.
9. application as claimed in claim 8 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 (3)
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| CN103163095A (en) * | 2013-03-25 | 2013-06-19 | 江南大学 | Visual multifunctional detection method based on nano-silver |
| CN103665042A (en) * | 2012-09-21 | 2014-03-26 | 北京普禄德医药科技有限公司 | Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof |
| 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 |
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| 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 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103665042A (en) * | 2012-09-21 | 2014-03-26 | 北京普禄德医药科技有限公司 | Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof |
| 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 |
| 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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