CN102268012B - Thiazole derivative and preparation method and application thereof - Google Patents
Thiazole derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicaments with an effect on resisting platelet aggregation, and provides a thiazole derivative of a structure in formula I and pharmaceutically acceptable salts thereof, wherein R1 is acetoxy and propionyloxy; R2 is hydrogen, methyl and ethyl; and R3 and R4 are hydrogen, chlorine, bromine, methyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, alkoxycarbonyl, carboxyl and formacyl. The invention also relates to a preparation method of the compound, and simultaneously discloses pharmaceutical compositions prepared from the compound or pharmaceutically acceptable salts thereof as active components, as well as applications of the pharmaceutical compositions as medicaments for resisting platelet aggregation.
Description
Technical field
The invention belongs to medical technical field, or rather, the pharmaceutical composition that relates to a class and there is thiazole derivative of antiplatelet aggregative activity and preparation method thereof, contain them and as the purposes of antiplatelet drug.
Background technology
Take in recent years 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, yet even low dose also may cause part population gastrointestinal discomfort sometimes,, also there is Aspirin Resistance in even serious gastrointestinal hemorrhage or hematencephalon in recent years.
Adenosine diphosphate (ADP) (ADP) is the important agonist that platelet activation, buildup effect amplify, and by blocking-up adp receptor, suppressing Platelet has become the important means that stops pathologic thrombosis (coronary heart disease, cerebro-vascular diseases, pulmonary infarction, thrombophlebitis etc.) and myocardial infarction, unstable angina pectoris, peripheral vascular disease, congestive heart failure etc.Adp receptor antagonist Ticlopidine (Ticlopidine) is first thienopyridine medicine, by the exploitation listing of French Sanofi company.Its by with the special sulfydryl receptors bind of P2Y type, suppress the activation of adp receptor.By changing the interaction of platelet membrane and interference membrane fiber proteinogen, glycoprotein iib/iiia acceptor on blocking platelet film, inhibition is reacted by the platelet aggregation of ADP and the induction of other platelet activating agents, is a kind of effect medicament for resisting platelet aggregation stronger than acetylsalicylic acid.Because Ticlopidine not only suppresses a certain platelet aggregation incitant, and suppressed accumulation process itself, in clinical, applied widely.Especially prevention cerebral infarction, treat stenocardia, prevent and treat myocardial infarction and improve the aspects such as peripheral vascular occlusive disease evident in efficacy.But the side effects such as Ticlopidine can cause neutrophil leucocyte minimizing, thrombopenia, bone marrow depression, hinders, thrombotic thrombocytopenic purpura (TTP).
Clopidogrel (Clopidogrel) is second thienopyridine medicine of French Sanofi company development, compare with Ticlopidine, many carboxymethyls on side chain only in structure, its action intensity and tolerance are all higher than Ticlopidine, and only anti-platelet activity is just high 6 times than Ticlopidine.Be applied to clinically treat atheromatosis, acute coronary syndrome, prevention intracoronary stent and plant restenosis and thrombotic complications etc. in people's postoperative support.In June, 1998, Britain went on the market in the U.S., and go on the market August calendar year 2001 in China.In multinomial broad scale research, clopidogrel, aspect the prognosis that improves ischemic events, is better than other drug, and ADR is few compared with Ticlopidine, and security is better than acetylsalicylic acid, thereby clopidogrel has replaced the application of Ticlopidine in many cases.But accept Effect of Clopidogrel in Treating, also occurred TTP and hemolytic uremic syndrome (HUS), the report of simultaneously relevant clopidogrel Resistant also had increase in recent years.Because clopidogrel is oily matter, alkalescence extremely a little less than, need could salify with strong acid, but it is unstable to meet moisture, and free alkali is separated out, purifying also has certain difficulty.And due to its strongly-acid, aspect preparation, be subject to certain restriction.
Synthetic method and summary about Thienopyridines are found in following document: CN101284838; CN101260112; CN1683373; US4681888; US4529596; GB1501797; WO02059128; US4174448; GB1561504; WO2004094374; JP6135970; JP63264588.
One of focus of studying as antiplatelet drug, needs more safe and effective this compounds of searching at present badly.
Summary of the invention
One object of the present invention is, in order to solve the problem of clopidogrel Resistant, develops a kind of thiazole derivative and pharmaceutical salts thereof of novel texture.
Another object of the present invention is, discloses the preparation method of a class thiazole derivative and pharmaceutical salts thereof.
A further object of the present invention is, discloses to take the pharmaceutical composition that thiazole derivative and pharmaceutical salts thereof be main active ingredient.
A further object of the invention is, thiazole derivative and pharmaceutical salts thereof are disclosed, application as antiplatelet drug aspect, particularly at the coronary syndrome causing because of platelet aggregation for the preparation of prevention or treatment, myocardial infarction, the purposes of the cardiovascular and cerebrovascular diseases medicament aspects such as myocardial ischemia.
Known through Preliminary pharmacological test, the compounds of this invention has superiority to a certain degree aspect drug effect and acute toxicity two.
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: C
1-C
4straight or branched alkyl.
R
3, R
4for: hydrogen, halogen, C
1-C
4straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be replaced by halogen; C
1-C
4straight or branched alkane alkyl-carbonyl; C
1-C
4straight or branched alkane carbalkoxy, acyl group, carboxylic acid group.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
R
1for: acetoxyl group, propionyloxy;
R
2for: methyl, ethyl;
R
3, R
4for: hydrogen, chlorine, bromine, methyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, alkyl carbonyl, carboxyl, formyl radical.
More preferably its pharmacy acceptable salt of following compound:
I-1 5-(2-(5-methylthiazol-2-base is amino)-2-oxoethyl)-2-acetoxyl group-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also;
I-2 2-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) kharophen)-5-acetoxyl group thiazole;
I-3 5-(2-(5-ethanoyl-4-methylthiazol-2-base is amino)-2-oxoethyl)-2-acetoxyl group-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also;
I-4 5-(2-(5-methyl 4-phenyl thiazol-2-yl is amino)-2-oxoethyl)-2-base acetoxyl group-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also;
I-5 5-(2-(5-bromo thiazole-2-base is amino)-2-oxoethyl-2-yl acetate-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also;
I-6 5-(2-oxygen-2-(5-(trifluoromethyl) thiazol-2-yl is amino) ethyl)-2-acetoxyl group-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also;
I-7 2-(2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) kharophen)-4-acetoxyl group thiazole;
I-8 5-(1-(5-formyl thiazole-2-base is amino)-1-oxygen butane-2-yl)-2-propionyloxy-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also.
Formula I compound pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.Wherein preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, etc.
The syntheti c route of formula I compound is as follows:
Wherein X is Cl, Br; R
1～R
4as aforementioned definitions.
Thiazole compound (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 hydrochloride 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, and 10～80 ℃ of reactions, make intermediate compound IV.Intermediate compound IV, take ethyl acetate, methylene dichloride, trichloromethane, toluene or acetonitrile etc. is 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, drip salt acid ether to pH be 2, 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 are preferably used 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 containing in pharmaceutical composition and unit dosage form (the compounds of this invention) 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.
Below by pharmacodynamic experiment, further illustrate the antithrombotic acitivity of the compounds of this invention.
A. 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 10mg/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).With PPP, adjust PRP, make its platelet count remain on 2 * 106/ml.Get PRP and add in test cup, 37 ℃ of temperature are incubated 10min.With PRP, return to zero, PPP adjusts 100%, and the ADP (final concentration is 5 μ M) of take is inductor, by turbidimetry, with SPA-3 type PPP platelet aggregation instrument, measures platelet aggregation percentage ratio, with t-check, carry out statistics comparison, compound sample the results are shown in Table 1 to rat platelet aggregation restraining effect.
Table 1 compound sample is to rat platelet aggregation restraining effect result
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.
By animal experiment, tentatively investigate the acute toxicity of the compounds of this invention.
The oral new compound of the present invention of mouse and clopidogrel 400mg/kg
-1d
-1after, the general behavior of mouse after administration and body weight have been carried out observing for one week.Result shows, mouse gives after above-mentioned 8 compounds, and heart rate, breathing and independent behaviour activity are showed no extremely, observes weight of mice normal through one week body weight.
Preliminary experiment result shows the LD of oral administration of compound I-7, I-8 and clopidogrel
50be respectively 3300mg/kg, 3359mg/kg and 3200mg/kg, visible I-7 and I-8 toxicity are slightly lower than clopidogrel.
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: the preparation of intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 11.4g 3-amino-2-methoxycarbonyl thiophene, after being dissolved with 50ml DMF, add 20.2g triethylamine, at-10 ℃～5 ℃, stir, drip the mixed solution of chloroacetyl chloride (16.9g) and methylene dichloride (30m1), after low-temp reaction 3h (flaggy demonstration reacts completely) stirring at room 1h, reaction solution is poured in 100ml cold water, fully stirred, filter, obtain brown solid (HPLC:86.5%).Rf=0.70[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-7, by 2-bromo butyryl bromide, replaces chloroacetyl chloride to obtain intermediate III-8 (particular compound is in Table 2).
Table 2 intermediate III-2～III-8 list
Reference example 2: the preparation of intermediate compound IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add successively 19.0g intermediate III-1,100mL acetonitrile and 20.2g triethylamine, add 19.0g 5,6,7 under nitrogen protection, 7a-tetramethylene sulfide is [3,2-c] pyridine-2 (4H)-one hydrochloride also.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 is separated with silica gel column chromatography, obtains white solid IV-1 (HPLC:97.9%).HRMS(m/z)[M+H]
+：310.0678。
Method with reference to reference example 2 can conveniently be prepared compound: intermediate compound IV-2～IV-8 (particular compound is in Table 3).
Table 3 intermediate compound IV-2～IV-8 list
Embodiment 1:
5-(2-(5-methylthiazol-2-base is amino)-2-oxoethyl)-2-acetoxyl group-4,5,6,7-tetramethylene sulfide is the preparation of [3,2-c] pyridine (Compound I-1) also
In the reaction flask that stirring, condenser, thermometer are housed, add successively 30.9g 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:98.9%).
1H?NMR(CDCl
3，400MHz)δ：2.265(s，3H，-OCH
3)，2.384-2.386(d，3H，-CH
3)，2.825-2.853(t，2H，-CH
2CH
2-)，2.924-2.952(t，2H，-CH
2CH
2N)，3.380(s，2H，-CH
2CONH-)，3.602(s，2H，-CH
2CH
2-)，6.287(s，1H，＝CH-)，7.050-7.053(d，1H，＝NCH＝)，10.211(s，1H，-NH)。HRMS(m/z)[M+H]
+：352.0784。
Method with reference to embodiment 1 can conveniently be prepared Compound I-2～I-7, with propionic anhydride, replaces diacetyl oxide to make Compound I-8 (particular compound is in Table 4).
Table 4 Compound I-2～I-8 list
Embodiment 2:
Compound I-1 one-tenth hydrochloride: get I-1 white solid product 3.1g, 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-3 one-tenth lactic acid salt: get I-3 white solid product 4.7g, be dissolved in 22mL anhydrous methanol.The molar lactic acid such as after being heated to reflux, add, continue at the lower about 1h of stirring reaction that refluxes.React complete, standing 24h under room temperature.Separate out yellow crystal, filter vacuum-drying, 230 ℃ of m.p. >.
For the pharmaceutical composition of thiazole derivative 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 be used any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 1-3.
Embodiment 4:
By following compositions, prepare hard gelatin capsule:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
Embodiment 5:
By following compositions, prepare tablet:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.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 6:
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves sorb ester and propylene glycol, add medicinal basic to regulate pH value to make its dissolving to 4-8.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilizing.
Embodiment 7:
The preparation of injection lyophilized powder:
The hydrochloride 100mg of Compound I-1
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate pH value to make its dissolving to 4-8 with medicinal basic.Add N.F,USP MANNITOL again, by the requirement of injection, carry out autoclaving, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, and sealing, obtains.
Claims (8)
1. compound or its pharmacy acceptable salt with formula I structure:
Wherein:
R
1for: acetoxyl group, propionyloxy;
R
2for: hydrogen, methyl, ethyl;
R
3, R
4for: hydrogen, chlorine, bromine, methyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, C
1-C
4alkyl carbonyl, carboxyl, formyl radical.
2. compound or its pharmacy acceptable salt, be selected from:
3. compound as claimed in claim 1 or 2 or its pharmacy acceptable salt, its pharmacy acceptable salt is: compound and mineral acid, organic acid salify.
4. compound as claimed in claim 3 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.
5. the preparation method of claim 1 Chinese style I compound, is characterized in that: compound III and 5,6; 7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-one hydrochloride under triethylamine exists; take acetonitrile as solvent, and 50～100 ℃ of reactions, make intermediate IV; intermediate IV be take acetonitrile as solvent; 10～40 ℃ by acid anhydrides acidylate, makes chemical compounds I, and wherein X is Cl or Br; acid anhydrides is diacetyl oxide or propionic anhydride, R
1～R
4as claim 1 definition,
6. a pharmaceutical composition for platelet aggregation-against, it comprises compound as claimed in claim 1 or 2 or its pharmacy acceptable salt and one or more pharmaceutical carriers for the treatment of significant quantity.
7. the compound described in claim 1 or 2 or its pharmacy acceptable salt are in the application aspect medicament for resisting platelet aggregation.
8. application as claimed in claim 7, the purposes aspect the cardiovascular and cerebrovascular diseases medicament causing because of platelet aggregation for the preparation for the treatment of.
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| 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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| CN101594864A (en) * | 2006-12-07 | 2009-12-02 | 第一三共株式会社 | Produce the method for solid preparation |
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| CN101594864A (en) * | 2006-12-07 | 2009-12-02 | 第一三共株式会社 | Produce the method for solid preparation |
| CN101260112A (en) * | 2008-04-11 | 2008-09-10 | 天津药物研究院 | Acethydrazide derivatives containing thieno[3.2-c]pyridine, preparation method and use thereof |
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