CN102351878A - Isoxazole derivatives as well as preparation method and application thereof - Google Patents
Isoxazole derivatives as well as preparation method and application thereof Download PDFInfo
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- CN102351878A CN102351878A CN2011102437758A CN201110243775A CN102351878A CN 102351878 A CN102351878 A CN 102351878A CN 2011102437758 A CN2011102437758 A CN 2011102437758A CN 201110243775 A CN201110243775 A CN 201110243775A CN 102351878 A CN102351878 A CN 102351878A
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- compound
- acceptable salt
- formula
- pharmacy acceptable
- platelet aggregation
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- GHLVMBXOBZVJIC-UHFFFAOYSA-N CC(C)c1n[o]c(N)c1 Chemical compound CC(C)c1n[o]c(N)c1 GHLVMBXOBZVJIC-UHFFFAOYSA-N 0.000 description 1
- BMDFCFKINGWUMV-UHFFFAOYSA-N CC(C)c1n[o]c(NC(CCl)=O)c1 Chemical compound CC(C)c1n[o]c(NC(CCl)=O)c1 BMDFCFKINGWUMV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of platelet aggregation inhibiting drugs, and provides isoxazole derivatives with a structure shown in the formula I and pharmaceutically acceptable salts thereof. In the formula I, R<1> is acetoxyl; R<2> is H, methyl or ethyl; and R<3> and R<4> are H, methyl, isopropyl, cyanomethyl, ethoxycarbonyl or chlorophenyl. The invention also relates to a preparation method of the compounds, and simultaneously discloses pharmaceutical compositions with the compounds or pharmaceutically acceptable salts of the compounds as the active effective ingredient, and application of the pharmaceutical compositions used as platelet aggregation inhibiting drugs.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to one type and have Isoxazole derivative of antiplatelet aggregative activity and preparation method thereof, contain their pharmaceutical composition and as the purposes of medicament for resisting platelet aggregation.
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.
Adp receptor antagonist Ticlopidine, clopidogrel also come with some shortcomings clinically.
Need more safe and effective such medicine of searching at present badly.
Summary of the invention
One object of the present invention is, discloses a kind of Isoxazole derivative and pharmaceutical salts thereof of novel texture.
Another object of the present invention is, discloses the preparation method of Isoxazole derivative and pharmaceutical salts thereof.
A further object of the present invention is that disclosing with one type of Isoxazole derivative and pharmaceutical salts thereof is the pharmaceutical composition of main active ingredient.
A further object of the invention is; One type of Isoxazole derivative 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: hydrogen, C
1-C
4The straight or branched carbalkoxy.
R
2For: hydrogen, C
1-C
4The straight or branched alkyl.
R
3, R
4For: hydrogen, C
1-C
4The straight or branched alkyl, C
1-C
4Straight or branched alkyl cyanic acid, phenyl, halogeno-benzene, C
1-C
4The straight or branched carbalkoxy.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
R
1For: hydrogen, methanoyl, acetoxyl group.
R
2For: hydrogen, methyl, ethyl.
R
3, R
4For: hydrogen, methyl, sec.-propyl, first cyanic acid, ethoxycarbonyl, chlorinated benzene.
More preferably following its pharmacy acceptable salt of compound:
I-1 5-(2-((3-isopropyl oxazole-5-yl) amino)-2-oxoethyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-2-yl acetate also;
I-2 5-(2-(4-(first cyanic acid) isoxzzole-5-base is amino)-2-oxoethyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-2-yl acetate also;
I-3 5-((2-(3,5-dimethyl isoxazole-4-yl) amino)-2-oxoethyl)-2-acetoxyl group-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also;
I-4 5-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) kharophen also)-4-ethoxycarbonyl isoxzzole;
I-5 5-(2-(2-acetoxyl group-6,7-dihydro-thiophene be [3,2-c] pyridines-5 (4H)-yl) kharophen also)-3-methyl-4-ethoxycarbonyl isoxzzole;
I-6 5-(2-(5-methyl isoxzzole-3-base is amino)-2-oxoethyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-2-yl acetate also;
I-7 5-(1-(3-(2-chloro-phenyl-) isoxzzole-5-base is amino)-1-oxo butyl-2-yl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine-2-base propionic ester 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 or the like.
The preparation route of formula I compound is following:
Wherein X is Cl, Br; R
1~R
4Like aforementioned definitions.
Intermediate III and 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridines-2 (4H)-keto hydrochloride are solvent with the acetonitrile in the presence of morpholine etc., and 30~60 ℃ of reactions make intermediate compound IV.Intermediate compound IV, 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 or the DMSO, dripping hydrochloric acid ethanol to pH be 2, process hydrochloride.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 Clopidogrel Hydrogensulfate and analogue thereof, and dosage is 10mg/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.Return to zero with PRP; 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; Carry out statistical comparisons with the t-check, compound sample is seen table 1 to rat platelet aggregation restraining effect result.
Table 1 compound sample is to rat platelet aggregation restraining effect result
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.
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: the preparation of intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 12.6g 3-sec.-propyl-5-amido isoxazole; With 50ml 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 (30m1); Behind low-temp reaction 3h (the flaggy demonstration reacts completely) the stirring at room 1h, reaction solution is poured in the 100ml 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-6 replaces chloroacetyl chloride to get III-7 (table 2 is seen in the compound tabulation) with 2-bromo butyryl bromide.
Table 2 intermediate III-2~III-7 tabulation
Embodiment 1: the preparation of intermediate compound IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add 20.2g intermediate III-1,100mL acetonitrile and 20.2g morpholine successively, nitrogen protection adds 19.1g 5,6,7,7a-tetramethylene sulfide [3,2-c] pyridines-2 (4H)-keto hydrochloride down.Stop heating behind the 40-50 ℃ of reaction 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 white solid IV-1 (HPLC:95.5%).HRMS(m/z)[M+H]
+:322.1220。
Method with reference to embodiment 1 can conveniently prepare compound: intermediate compound IV-2~IV-7 (particular compound is seen table 3).
Table 3 intermediate compound IV-2~IV-7 tabulation
Embodiment 2:5-(2-(5-methyl isoxzzole-3-base is amino)-2-oxoethyl)-4,5,6, the 7-tetramethylene sulfide is the preparation of [3,2-c] pyridine-2-yl acetate (compound I-6) also
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, and 30 ℃ are stirred 3h, solvent evaporated; The anhydrous methanol recrystallization promptly gets light yellow solid I-6 (HPLC:99.2%).
1H?NMR(CDCl
3,400MHz):2.266(s,3H,CH
3COO-),2.387-2.388(d,3H,-CH
3),2.816-2.842(t,2H,-CH
2CH
2-),2.908-2.936(t,2H,-CH
2CH
2-),3.309(s,2H,-CH2CO-),3.592(s,2H,-CH
2-),6.290(s,1H,-CH=),6.709-6.711(d,1H,-CH=C(O-)-CH
3),9.640(s,1H,-NH-);HRMS(m/z)[M+H]
+:336.1013。
Method with reference to embodiment 2 can conveniently prepare compound I-1~I-5, replaces diacetyl oxide to make compound I-7 (particular compound is seen table 4) with propionic anhydride.
Table 4 compound I-1~I-5 tabulation
Embodiment 3:
Compound I-1 one-tenth hydrochloride: get I-1 white solid product 4.5g, be dissolved in the 20mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, drip 11.0% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under the ice-water bath.Filter, get white solid.
For the pharmaceutical composition of Isoxazole derivative 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 1-3.
Embodiment 4:
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 5:
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 6:
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 and regulate the pH value and make its dissolving to 4-8.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
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%
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 (8)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R
1For: acetoxyl group, propionyloxy;
R
2For: hydrogen, methyl, ethyl;
R
3, R
4For: hydrogen, methyl, sec.-propyl, cyanogen methyl, ethoxycarbonyl, chlorinated benzene.
3. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1 or 2, its pharmacy acceptable salt is: formula I compound and mineral acid, organic acid salify.
4. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 3, 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; It is characterized in that: intermediate III and 5,6,7; 7a-tetramethylene sulfide [3; 2-c] pyridine-2 (4H)-keto hydrochloride in the presence of morpholine, is a solvent with the acetonitrile; 30-60 ℃ react intermediate compound IV; After the acid anhydrides acidylate, make compound I again, wherein X is Cl or Br, R
1~R
4Like claim 1 definition,
6. the pharmaceutical composition of a platelet aggregation-against, it comprises compound or its pharmacy acceptable salt and one or more pharmaceutical carriers with formula I structure as claimed in claim 1 or 2 of treating significant quantity.
7. claim 1 or 2 described compounds with formula I structure or its pharmacy acceptable salt are in the application that is used to prepare aspect the medicament for resisting platelet aggregation.
8. application as claimed in claim 7 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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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 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003035652A1 (en) * | 2001-10-26 | 2003-05-01 | Merck Generics [Uk] Limited | A PROCESS FOR PREPARING ENANTIOMERICALLY PURE α-PHENYL-α-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YL)-ACETIC ACID DERIVATIVES |
CN102093385A (en) * | 2010-12-30 | 2011-06-15 | 天津药物研究院 | Schiff base compounds as well as preparation method and application of Schiff base compounds |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003035652A1 (en) * | 2001-10-26 | 2003-05-01 | Merck Generics [Uk] Limited | A PROCESS FOR PREPARING ENANTIOMERICALLY PURE α-PHENYL-α-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YL)-ACETIC ACID DERIVATIVES |
CN102093385A (en) * | 2010-12-30 | 2011-06-15 | 天津药物研究院 | Schiff base compounds as well as preparation method and application of Schiff base compounds |
Non-Patent Citations (1)
Title |
---|
SHUANG ZHI, 等: "N-(5-Ethylsulfanyl-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetamide", 《ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE》, vol. 67, 30 June 2011 (2011-06-30) * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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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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