CN103304561B - One class has the compound of anti thrombotic action - Google Patents

Abstract

The present invention discloses compound and the pharmacy acceptable salt thereof that a class with structure shown in formula I has anti thrombotic action. Wherein, R can be hydrogen, methyl, ethyl, propyl group, sec.-propyl, nitro, cyano group, halogen, trifluoromethyl. The invention also discloses the preparation method of above-claimed cpd, and also disclose using this compound or its pharmacy acceptable salt as the pharmaceutical composition of active effective constituent, and they are as medicament for resisting platelet aggregation, particularly at the coronary syndrome caused because of platelet aggregation for the preparation of prevention or treatment, myocardial infarction, the application of the cardiovascular and cerebrovascular diseases medicament aspects such as myocardial ischemia.

Description

One class has the compound of anti thrombotic action

Technical field

The invention belongs to medical art, more properly say, relate to a class have the compound of anti thrombotic action and its preparation method, containing they pharmaceutical composition and as the purposes of antithrombotic reagent.

Background technology

In rising trend based on the sickness rate of coronary artery thrombus and the thrombotic disease of cerebral thrombosis, serious harm humans is healthy. Platelet aggregation is in normal coagulation mechanism a key link, and therefore the medicine of anticoagulant becomes the focus of antithrombotic reagent research.

The Ticlopidine (Ticlopidine) of Sanofi company of France exploitation listing is first adp receptor antagonist class antiplatelet drug, and it is by being combined with the special thiol acceptor of P2Y type, suppresses the activation of adp receptor, plays platelet aggregation-against effect. Owing to Ticlopidine not only suppresses a certain platelet aggregation incitant, and suppress accumulation process itself, applied widely in clinical. Especially at prevention cerebral infarction, treat stenocardia, prevent and treat myocardial infarction and improve in peripheral vascular occlusive disease etc. evident in efficacy. But follow-up research finds the side effects such as Ticlopidine can cause Neutrophilic granulocytopenia, thrombopenia, bone marrow depression, hinders, thrombotic thrombocytopenic purpura (TTP), less application in recent years.

Clopidogrel (Clopidogrel) is the 2nd Thienopyridines adp receptor antagonist pharmaceuticals of Sanofi company development, and compared with Ticlopidine, structure is many carboxymethyls on side chain only, and its action intensity and tolerance are all higher than Ticlopidine. Be applied to treatment atheromatosis on clinical, acute coronary syndrome, prevention intracoronary stent plant restenosis and thrombotic complications etc. in people's postoperative support. In multinomial broad scale research, clopidogrel, improving in the prognosis of ischemic events, is better than other drug, and ADR is few compared with Ticlopidine, and security is better than acetylsalicylic acid, and thus clopidogrel instead of the application of Ticlopidine in many cases. But accepting clopidogrel treatment and TTP and hemolytic uremic syndrome (HUS) also occurred, the report of relevant clopidogrel opposing simultaneously also had increase in recent years. Simultaneously owing to clopidogrel is oily matter, alkalescence is extremely weak, need to could become salt with strong acid, but it is unstable to meet moisture, and free alkali is precipitated out, and purifying also has certain difficulty. And due to its strongly-acid, in preparation, receive certain restriction.

The prasugrel (Prasugrel) that Japan the one or three is total to company and Li Lai company of U.S. joint development is the thienopyridine analog derivative that a class is new. Big quantity research confirms compared with clopidogrel, and prasugrel activity is stronger, and onset is faster, and between patient, response difference to this medicine is less. The controlled clinical trial result of itself and clopidogrel also shows, the death that it can reduce non-lethality heart trouble effectively and palsy causes, but causes patient's bleeding more. Owing to this product still has the closely related untoward reaction problem of some and its clinical efficacy, particularly due to higher hemorrhage risk, therefore, although FDA have approved prasugrel listing, but black frame is warned to warn hemorrhage risk to require it must add in new drug label, and suggestion suffers from reactivity Pathology bleeding, transient ischemic attack or palsy medical history or the patient comprising coronary artery bypass surgery that needs to perform the operation in the recent period does not take this medicine.

As the focus of antiplatelet drug research, mentioned above and Thienopyridines be in active, side effect or in physicochemical characteristic, all also there is certain deficiency, therefore, the present invention proposes the compound with antithrombotic acitivity that a class is different from Thienopyridines antiplatelet drug, to obtaining safe and effective medicine.

Summary of the invention

It is an object of the present invention to, disclose the compound with anti thrombotic action and the pharmaceutical salts thereof of a class novel texture.

Another object of the present invention is, discloses a class and has the compound of anti thrombotic action and the preparation method of pharmaceutical salts thereof.

Another object of the present invention is, open have the compound of anti thrombotic action and pharmaceutical salts thereof the pharmaceutical composition as main active ingredient taking a class.

A further object of the invention is, disclose a class and there is the application as antiplatelet drug aspect of the compound of anti thrombotic action and pharmaceutical salts thereof, particularly at the coronary syndrome caused 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.

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 formula I structure:

Wherein:

R can be hydrogen atom, methyl, ethyl, propyl group, sec.-propyl, nitro, cyano group, halogen atom, trifluoromethyl.

Wherein preferred following compound and pharmacy acceptable salt thereof:

Type I compound pharmacy acceptable salt refers to: salt formed by compound and mineral acid, organic acid. 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; gluconate, amino acid salts.

The syntheti c route of type I compound is as follows:

Wherein compound ii, III is commercially available prod, compound V reference literature (IndianJournalofChemistry, 2006(45B), 1453-1462) in synthetic method, the researchist in this area all can conveniently obtain.

Compound ii and III is under triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, taking methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile, DMF or toluene as solvent ,-10��80 DEG C of obtained compounds IV of reaction; Compound IV and compound V are taking methyl alcohol or ethanol as solvent, and under the existence of Potassium ethanoate or sodium-acetate, backflow is obtained by reacting compound VI; Compound VI and diacetyl oxide VII are obtained by reacting chemical compounds I under the effect of triethylamine, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide or potassium hydroxide.

The obtained various compound of reaction or be dissolved in DMF, acetone, methyl alcohol, ethanol or DMSO dripping products therefrom add mineral acid, organic acid make pharmacy acceptable salt.

Specifically products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol or DMSO, drips and add acidic alcohol to pH2, make hydrochloride. Or products therefrom is dissolved in DMF, acetone, methyl alcohol or ethanol, mole taurine such as add, obtain its taurate. Also this compound can be dissolved in DMF, acetone, methyl alcohol, ethanol or DMSO, drip the methanol solution adding the vitriol oil, adjust pH2-3, its vitriol obtained, etc.

The disease that this compounds causes because of platelet aggregation for the treatment mankind is effective. Although the compound of the present invention can without the direct administration of any preparation, but described various compounds preferably use in the form of a pharmaceutical preparation, and route of administration can be parenteral route (such 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 arbitrarily on technology of pharmaceutics acceptable auxiliary and vehicle 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 such as injection, pulvis etc.

The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can according to the situation of the state of an illness of patient, diagnosis specific be applied, the amount of compound used or concentration regulate in a wider scope. Usually, the weight range of active compound is 0.5��90%(weight of composition), another preferred scope is 0.5��70%.

The compound with structure shown in formula I of the present invention or its pharmacy acceptable salt, have obvious restraining effect in platelet aggregation, therefore can as potential antithrombotic reagent.

The antithrombotic acitivity of the compounds of this invention is described further below by pharmacodynamic experiment.

Test materials:

Medicine and preparation: the compounds of this invention, be made into suspension for animals administer with 1%CMCNa.

Animal: male rat, Tianjin Inst. of Materia Medica laboratory animal room provides, animal conformity certification number: No. 001st, Tianjin animal word.

Test method:

Male Wistar rat, about body weight 300g, gives the compounds of this invention 1-7 through mouth gavage, dosage is 100mg/kg, successive administration 3 times, 1 hour anesthesia (vetanarcol after last administration, 54mg/kg, ip) dorsal position fixes, separation right common carotid artery and left external jugular vein. Put into the silk thread of a root length 6cm in the stage casing of polyfluortetraethylene pipe, it is full of polyfluortetraethylene pipe with heparin-saline solution (50u/ml). After left external jugular vein is inserted in one end of polyfluortetraethylene pipe, accurately inject the anticoagulant heparin of 50u/kg by polyfluortetraethylene pipe, and then by the other end insertion right common carotid artery of polyfluortetraethylene pipe. Opening bulldog clamp, blood flow in polyfluortetraethylene pipe from right common carotid artery, returns left external jugular vein. Herba Clinopodii in after open blood flow 15min, takes out rapidly silk thread and weighs, and gross weight subtracts silk thread weight and namely obtains wet weight of thrombus. Carry out statistics with t-inspection to compare, the results are shown in following table:

Invention compound is on the impact of platelet aggregation

From test-results, the compound of the present invention can obviously suppress the formation of thrombus. Therefore, they can be used for preventing or treat the coronary syndrome because thrombosis causes, myocardial infarction, the cardiovascular and cerebrovascular diseases such as myocardial ischemia.

Getting final product stable existence through the known the compounds of this invention free alkali of stability study, after being prepared into the mineral acid such as hydrochloride, taurate or organic acid salt, its preparation stability is also all to some extent higher than the hydrosulfate of clopidogrel simultaneously.

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 detects through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC). Such as infrared spectra (IR) can be adopted subsequently, nuclear magnetic resonance spectrum (¹HNMR,¹³CNMR), mass spectrum (MS) etc. further confirm its structure.

Reference example 1:

Compound V

Get starting compound 2-cyano group-3-(2-thienyl) ethyl propenoate 50g(241mmol), thiosemicarbazide 22g(241mmol) and Anhydrous potassium carbonate 102g(724mmol) back flow reaction 4h in anhydrous methanol, let cool after reaction, regulate pH to neutral with dilute hydrochloric acid solution, have solid to precipitate out. Filtering, filter cake washing, drying, obtain clear crystal V (30.7g) with benzene recrystallization, receipts rate 68.7%. Fusing point 170 DEG C, is consistent with document, HPLC normalization method 98.9%.

Embodiment 1:

Compound IV-1

Get compound ii-1(10g, 61mmol) it is dissolved in 50mL methylene dichloride. Stir and fully dissolve. It is cooled to 0 DEG C. Drip the dichloromethane solution adding bromoacetyl bromide (III, 13.6g, 67mmol). Thermotonus 4h is kept after having dripped. After TLC detection reaction is complete, reaction solution is washed with water three times (30mL �� 3), divide and get organic layer, dry, filter, revolve steaming. By the time light yellow oil, without refining, namely can be used to cast single step reaction. The quality of products obtained therefrom is 16.5g, receipts rate 95%, purity 98.3%(HPLC normalization method), MS (m/z) [M+H]⁺: 284.0.

With reference to embodiment 1, following compound can be obtained

Embodiment 2:

Compound VI-1

Get compound IV-1(10g, 35mmol) it is dissolved in 50mL ethanol, add Potassium ethanoate (10.3g, 105mmol) after fully dissolving, it is heated to backflow, after reaction 6h, TLC detection reaction is complete. Reaction solution is let cool, in impouring water, has solid to precipitate out. Filter, dry, with ethyl acetate and sherwood oil 1:2 recrystallization, obtain product 10.5g, receipts rate 80.8%, purity 99.1%(HPLC normalization method), MS (m/z) [M+H]⁺: 371.1.

With reference to embodiment 2, following compound can be obtained

Embodiment 3:

Chemical compounds I-1

Get compound IV-1(5g, 13.5mmol), fully dissolve with 30mL methylene dichloride. It is down to 0 DEG C, adds triethylamine (2g, 20mmol), drip and add diacetyl oxide (2.1g, 20mmol), keep thermotonus 3h. TLC detection reaction terminates. In reaction solution impouring 30mL water, will divide and get organic phase, then wash three times (30mL �� 3). Organic layer is dry, filtration is steamed dry, obtains brown oil. Stirring with ethanol under room temperature, obtain white solid, filter, cold ethanol rinse used again by filter cake, obtains product 4.3g. Receipts rate 77.2%, purity 99.4%(HPLC normalization method), MS (m/z) [M+H]⁺: 413.1.

Embodiment 4:

Chemical compounds I-2

Get compound IV-2(5g, 13mmol), fully dissolve with 30mL methylene dichloride. It is down to 0 DEG C, adds triethylamine (2g, 20mmol), drip and add diacetyl oxide (2.1g, 20mmol), keep thermotonus 3h. TLC detection reaction terminates. In reaction solution impouring 30mL water, will divide and get organic phase, then wash three times (30mL �� 3). Organic layer is dry, filtration is steamed dry, obtains brown oil. Stirring with ethanol under room temperature, obtain white solid, filter, cold ethanol rinse used again by filter cake, obtains product 4.6g. Receipts rate 83.0%, purity 98.2%(HPLC normalization method), MS (m/z) [M+H]⁺: 427.2.

Embodiment 5:

Chemical compounds I-3

Get compound IV-3(5g, 13mmol), fully dissolve with 40mL tetrahydrofuran (THF). It is down to-10 DEG C, adds sodium hydroxide (1g, 26mmol), then drip and add diacetyl oxide (2.1g, 20mmol), keep thermotonus 5h. TLC detection reaction terminates. By reacting liquid filtering, filtrate is steamed dry, obtains reddish-brown oily matter. Stirring with methyl alcohol under room temperature, obtain white solid, filter, cold methanol drip washing used again by filter cake, obtains product 3.9g. Receipts rate 70.3%, purity 97.3%(HPLC normalization method), MS (m/z) [M+H]⁺: 427.1.

Embodiment 6:

Chemical compounds I-4

Get compound IV-4(5g, 13mmol), fully dissolve with 40mL tetrahydrofuran (THF). It is down to-10 DEG C, adds sodium hydroxide (1g, 26mmol), then drip and add diacetyl oxide (2.1g, 20mmol), keep thermotonus 5h. TLC detection reaction terminates. By reacting liquid filtering, filtrate is steamed dry, obtains reddish-brown oily matter. Stirring with methyl alcohol under room temperature, obtain white solid, filter, cold methanol drip washing used again by filter cake, obtains product 3.9g. Receipts rate 70.3%, purity 97.3%(HPLC normalization method), MS (m/z) [M+H]⁺: 427.1.

Embodiment 7:

Chemical compounds I-5

Get compound IV-5(5g, 11.1mmol), with the DMF stirred at ambient temperature of 20mL, fully dissolve. Adding salt of wormwood (4.55g, 33mmol), then drip and add diacetyl oxide (2.2g, 22mmol), after reaction 3h, TLC detection reaction terminates. By reacting liquid filtering, in filtrate impouring water, use dichloromethane extraction. Divide and get organic layer, dry, to filter, evaporated under reduced pressure obtains brown oil. Stirring with methyl alcohol under room temperature, obtain pale solid, filter, cold methanol drip washing used again by filter cake, obtains product 4.3g. Receipts rate 78.8%, purity 98.0%(HPLC normalization method), MS (m/z) [M+H]⁺: 491.0.

Embodiment 8:

Chemical compounds I-6

Get compound IV-6(5g, 10.3mmol), with the DMF stirred at ambient temperature of 20mL, fully dissolve. Adding sodium carbonate (4.2g, 30mmol), then drip and add diacetyl oxide (2.2g, 22mmol), after reaction 5h, TLC detection reaction terminates. By reacting liquid filtering, in filtrate impouring water, use dichloromethane extraction. Divide and get organic layer, dry, to filter, evaporated under reduced pressure obtains brown oil. Stirring with ethanol under room temperature, obtain pale solid, filter, cold ethanol rinse used again by filter cake, obtains product 4.0g. Receipts rate 80.5%, purity 99.2%(HPLC normalization method), MS (m/z) [M+H]⁺: 481.1.

Embodiment 9:

Chemical compounds I-7

Get compound IV-7(5g, 12mmol), fully dissolve with 30mL acetonitrile. It is warming up to 80 DEG C, adds saleratus (3.6g, 36mmol), then drip and add diacetyl oxide (2.5g, 24mmol), keep thermotonus 4h. TLC detection reaction terminates. By reacting liquid filtering, filtrate is steamed dry, obtains brown oil and sends out foaming material. Stirring with ethanol under room temperature, obtain light yellow solid, filter, cold ethanol rinse used again by filter cake, obtains product 3.5g. Receipts rate 63.7%, purity 98.5%(HPLC normalization method), MS (m/z) [M+H]⁺: 458.1.

Embodiment 10:

Chemical compounds I-8

Get compound IV-8(5g, 12.6mmol), fully dissolve with 30mL methylene dichloride. It is down to 0 DEG C, adds triethylamine (2.6g, 25mmol), drip and add diacetyl oxide (2.1g, 20mmol), keep thermotonus 3h. TLC detection reaction terminates. In reaction solution impouring 30mL water, will divide and get organic phase, then wash three times (30mL �� 3). Organic layer is dry, filtration is steamed dry, obtains brown oil. Stirring with ethanol under room temperature, obtain light yellow solid, filter, cold ethanol rinse used again by filter cake, obtains product 3.8g. Receipts rate 69.1%, purity 99.3%(HPLC normalization method), MS (m/z) [M+H]⁺: 438.3.

Embodiment 11:

Chemical compounds I-1 hydrochloric acid salt: get chemical compounds I-1(1g), it is dissolved in 10mL dehydrated alcohol. Ice-water bath is cooled to 5 DEG C, drips and adds 11.1% ethanol solution hydrochloride is 2 to pH, continues at stir about 1h under ice-water bath. Filtering, vacuum-drying, obtains white solid powder.

Embodiment 12:

Chemical compounds I-3 becomes taurate: get chemical compounds I-3(2.0g), it is dissolved in 20mL acetone. Add after being heated to backflow and wait mole taurine, continue at backflow time stirring reaction and be about 1.5h. React complete, in left at room temperature 24h. Precipitate out white crystals, filter, vacuum-drying.

Embodiment 13:

Chemical compounds I-5 becomes vitriol: gets chemical compounds I-5 product as light yellow solid (1.5g), is dissolved in 15mL methyl alcohol. Ice-water bath is cooled to 0 DEG C, drips and adds 10% sulfuric acid methanol solution is 3 to pH, continues at stir about 1h under ice-water bath. Filter, obtain white solid.

In order to a class of the present invention is described more fully have the pharmaceutical composition of the compound of anti thrombotic action, provide following example of formulations below, described embodiment only for illustration of, instead of for limiting the scope of the invention. Described preparation can use any active compound in the compounds of this invention and salt thereof, it is preferred to use compound described in embodiment 1-13 and salt thereof.

Embodiment 14:

Hard gelatin capsule is prepared by following compositions:

Preparation technology: supplementary material is dry in advance, crosses 100 order sieves for subsequent use. After mentioned component being mixed by recipe quantity, it is packed in hard gelatin capsule.

Embodiment 15:

Tablet is prepared by following compositions:

Preparation technology: supplementary material is dry in advance, crosses 100 order sieves for subsequent use. First the auxiliary material of recipe quantity is fully mixed even. By bulk drug, to increase progressively, dilution method is added in auxiliary material, and each added-time fully mixes even 2-3 time, ensures that medicine and auxiliary material fully mix even, crossing 20 order sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry particle is crossed 16 orders and is sieved whole grain, measure intermediates content, mix, compressing tablet on tabletting machine.

Embodiment 16:

The preparation of injection liquid:

Preparation method: get activeconstituents and join in the water for injection dissolving polysorbate and propylene glycol, adds medicinal basic adjust ph to 4��8 and makes it dissolve. Add gac, whip attachment 30min, carbon removal, essence filter, embedding, sterilizing.

Embodiment 17:

The preparation of injection lyophilized powder:

The taurate 100mg of chemical compounds I-3

Medicinal basic 0.1-7.0%

N.F,USP MANNITOL 55-85%

Preparation method: get activeconstituents and add water for injection, makes it dissolve by medicinal basic adjust ph to 4-8. Adding N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate carries out packing, adopts freeze-drying, and obtained loose block, sealing, to obtain final product.

Claims (11)

1. there is compound and the pharmacy acceptable salt thereof of structure shown in formula I:

Wherein:

R can be hydrogen, methyl, ethyl, propyl group, sec.-propyl, nitro, cyano group, halogen atom, trifluoromethyl.

2. type I compound as described in claim 1 is following compound:

3. type I compound as claimed in claim 1 or 2, pharmacy acceptable salt refers to: compound becomes salt with mineral acid, organic acid.

4. type I compound pharmacy acceptable salt as claimed in claim 3 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, gluconate.

5. the preparation method of type I compound in claim 1, it is characterised in that: this preparation method is by following three steps preparations:

(1) compound ii and III is under acid binding agent exists, in a solvent the obtained compound IV of reaction;

(2) compound IV and compound V are taking methyl alcohol or ethanol as solvent, and under the existence of Potassium ethanoate or sodium-acetate, backflow is obtained by reacting compound VI;

(3) compound VI and acetic anhydride obtain chemical compounds I;

R defines as previously mentioned.

6. preparation method according to claim 5, it is characterised in that, in step (1), acid binding agent is selected from triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide.

7. preparation method according to claim 5, it is characterised in that, in step (1), solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile, N, dinethylformamide or toluene.

8. preparation method according to claim 5, it is characterised in that, the temperature of reaction in step (1) is-10��80 DEG C.

9. a pharmaceutical composition for platelet aggregation-against, it comprises the type I compound of claim 1��2 arbitrary for the treatment of significant quantity or its pharmacy acceptable salt and one or more pharmaceutical carriers.

10. the type I compound of claim 1��2 arbitrary and pharmacy acceptable salt thereof are for the preparation of the application in medicament for resisting platelet aggregation.

11. apply as claimed in claim 10, the purposes in the cardiovascular and cerebrovascular diseases medicament caused because of platelet aggregation for the preparation for the treatment of.