CN102050802A - N-(2-ethoxyl)ferulamide nitrate derivative with anoxia resisting pharmaceutical activity and preparation method thereof - Google Patents
N-(2-ethoxyl)ferulamide nitrate derivative with anoxia resisting pharmaceutical activity and preparation method thereof Download PDFInfo
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Abstract
The invention provides an N-(2-ethoxyl) ferulamide nitrate derivative (general formula I) with anoxia resisting pharmaceutical activities and a preparation method thereof. The N-(2-ethoxyl) ferulamide nitrate derivative has myocardial ischemia and anoxia resisting biological activities, wherein R represents (morpholine-4-yl)formyl group, (4-methyl-piperazine-1-yl)formyl group or (tetrahydro-sulfonyl-thiazine-4-yl)formyl group.
Description
Technical field
The present invention relates to a kind of medicine that is used for anti-hypoxia and treatment cardiovascular disorder and preparation method thereof.
Background technology
The nitrate esters medicine that with the pannonit is representative plays an important role in the treatment cardiovascular disorder.This type of drug main will increase the myocardial nutrition volume of blood flow and bring into play cardiovascular effect with reducing myocardial consumption of oxygen with dilating coronary blood vessel, is mainly used in the anginal treatment of acute and chronic clinically.The mechanism of nitrate esters medicine treatment cardiovascular disorder provides nitrogen protoxide relevant with it.Discover that NO has the effect of second messenger and neurotransmitter concurrently, therefore it is a kind of important carrier of new iuntercellular message exchange, in the treatment cardiovascular system diseases, NO regulates antiotasis and regulates the local organization blood flow by lax vascular smooth muscle and distributes.Outside this medicine decapacitation coronary artery dilating; still the effect that has the direct method protection ischemic myocardium that does not rely on the change of blood vessel kinetics; and can resist the kinds of experiments arrhythmia; can obviously resist myocardial ischemia-reperfusion injury; by the cyclic guanosine monophosphate concentration in NO approach rising blood plasma and the thrombocyte; performance cyclic guanosine monophosphate second messenger's effect; suppress the release of sarcoplasmic reticulum to calcium ion; reduce the calcium ion concn in blood plasma and the thrombocyte; the platelet aggregation that ADP is caused has the obvious suppression effect, is being widely used aspect the sclerosis of treatment coronary artery pasty state.But owing to be that biological half-life of nitrate esters medicine of representative is shorter relatively with the pannonit, the prolonged application untoward reaction is many, has limited the application of such medicine.Investigator of the present invention discloses a kind of N-(2-hydroxyethyl) asafoetide acid amides nitrate compound in No. the 99119659.7th, Chinese patent application, its action temperature and, long half time, result of treatment is good, illustrates that this compounds has broad application prospects in treatment cardiovascular disorder field.But this compound also has defectives such as extended storage stability difference.
The people enters the above plateau of 3000m fast, be subjected to the influence of low normal atmosphere and low oxygen partial pressure, generation is based on the acute high altitude reaction of breathing, digestion and central nervous system symptom, hypoxemia can cause the change of a series of physiological functions of human body, and hypoxemia is a most basic pathology link in numerous disease such as shock, cancer, the immunological disease generation evolution.Therefore develop anti-anoxic medicine, significant.
Summary of the invention
At the problems referred to above of prior art, the invention provides one group and have the active N-of anti-hypoxia pharmacology (2-hydroxyethyl) asafoetide acid amides nitrate derivatives, it has than better result of treatment of prior art and stability.
For achieving the above object, on the one hand, the invention provides N-(2-hydroxyethyl) the asafoetide acid amides nitrate derivatives or the acceptable salt of its medicine of a kind of general formula (I) expression, or its hydrate or solvate,
Wherein, R representative (morpholine-4-yl) formyl radical, (4-methyl-piperazine-1-yl) formyl radical or (tetrahydrochysene sulphonyl thiazine-4-yl) formyl radical.
On the other hand, the medicine that the invention provides a kind of anti-hypoxia and resist myocardial ischemia, it contains N-(2-hydroxyethyl) the asafoetide acid amides nitrate derivatives or the acceptable salt of its medicine of general formula (I) expression, or its hydrate or solvate are as effective constituent.
Again on the one hand, the invention provides N-(2-hydroxyethyl) asafoetide acid amides nitrate derivatives or the acceptable salt of its medicine as general formula (I) expression, or its hydrate or the application of solvate in the medicine for preparing anti-hypoxia and resist myocardial ischemia.
In addition, the invention provides the preparation method of following three kinds of particular compound:
(1) preparation method of 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate, it comprises the steps:
A. (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate and morpholine-4-acyl chloride reaction obtain (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate;
B. (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate and LiOHH
2O reaction obtains (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) vinylformic acid;
C. (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) vinylformic acid reacts with oxalyl chloride and DMF;
D.2-nitroxide-ethamine and Et
3The N reaction adds step C product and DMF subsequently, obtains 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate.
The preparation method of 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate preferably, comprises the steps: as mentioned above
A. in being the pyridine solution of (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate of 0.064～1.6mol/L, concentration adds 0.6～4.8 times of normal morpholine-4-acyl chlorides, the mixture stirred overnight at room temperature, steaming desolventizes, water is added in the residue, filter the back and obtain pink solid (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate;
B. be to add (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate in the mixture of 1: 0.1～10 methyl alcohol and tetrahydrofuran (THF) to volume ratio, strength of solution is 0.2～1.8mol/L, drips 1～6 times of normal LiOHH in-10～10 ℃ in above-mentioned solution
2The aqueous solution of O; Subsequently, mixture rises to room temperature and stirred 1～5 hour, and adding 1mol/L HCl to pH value is 3, filters the back and obtains white solid (3-(4-(morpholine-4-ketonic oxygen for)-3-methoxyl group) phenyl) vinylformic acid;
C. in being (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) acrylic acid dichloromethane solution of 0.1～3mol/L, concentration adds 1～10 times of normal oxalyl chloride in-10～10 ℃, and add several DMF, stir after 0.5～5 hour, mixture rises to room temperature and continues and stirred 0.5～5 hour, and evaporating solvent is also dry;
D. in being the dichloromethane solution of 0.1～2.5mol/L 2-nitroxide-ethamine, concentration adds 1～10 times of normal Et in-10～10 ℃
3N, and stirred 0.5～3 hour; In this solution, add and contain the dichloromethane solution of step C product, and add 5～10 DMF; Mixture rises to room temperature and stirs and spend the night; Evaporating solvent, add entry, the mixture dichloromethane extraction, dry, vacuum concentration, residue silicagel column purifying, elutriant are methylene dichloride: MeOH=10: 1～200: 1, obtain 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate.
(2) preparation method of 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (4-methyl-piperazine-1-yl) manthanoate, it comprises the steps:
In-10～10 ℃, drip the chloroformic solution of 0.5～5 times of normal 4-methyl-piperazine-1-carbonyl chlorine in concentration is the pyridine solution of (2-(3-(4-hydroxyl-3-methoxyl group) phenyl) acrylamide) ethyl nitric ether of 0.1～1.0mol/L, wherein the concentration of the chloroformic solution of 4-methyl-piperazine-1-carbonyl chlorine is 0.58～2.34mol/L; Rise to room temperature subsequently and stirred 4～24 hours, solvent removed in vacuo, residue is dissolved in the ethyl acetate, and uses saturated NaHCO
3The aqueous solution and salt water washing, drying concentrates, and uses the silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=1: 1～20: 1 obtains white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (4-methyl-piperazine-1-yl) manthanoate.
(3) preparation method of 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate, it comprises the steps:
A. (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate, DMAP, Et
3N and tetrahydrochysene thiazine-4-base formyl chloride reaction obtains 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
B.2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate and LiOH reactant aqueous solution obtain 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
C.2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate, DMF and oxalyl chloride reaction add 2-nitroxide-ethamine and triethylamine subsequently and obtain 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
D.2-the reaction of methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate and metachloroperbenzoic acid obtains 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate.
The preparation method of 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate preferably, comprises the steps: as mentioned above
A. to mol ratio 1: 1: 2 (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate, DMAP and Et in-10～10 ℃
3Drip the chloroformic solution of the tetrahydrochysene thiazine-4-base formyl chloride of equivalent in the mixture of N, wherein the concentration of the chloroformic solution of tetrahydrochysene thiazine-4-base formyl chloride is 0.3～3.0mol/L; In 40～100 ℃ of heating 4～20 hours,,, concentrate and obtain white solid 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate subsequently with the 2mol/L HCl aqueous solution and salt water washing, drying with the chloroform dilution;
B. be to add 0.5～10 times of normal LiOH aqueous solution in the methyl alcohol of 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate of 0.1～0.4mol/L and the THF solution to concentration, wherein, the volume ratio of methyl alcohol and THF is 1: 1; Gained solution stirring at room 4～24 hours; Thereafter use ethyl acetate extraction, drying concentrates, and obtains white solid 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
C. in being the dichloromethane solution of 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate of 0.1～1.0mol/L, concentration adds 5～10 DMF in-10～10 ℃, and drip 1～20 times of normal oxalyl chloride, stirring at room is 0.5～6 hour subsequently, desolventizes being lower than 40 ℃ of vacuum; Residue is dissolved in methylene dichloride, strength of solution is 0.2～2.0mol/L, and at-10～10 ℃ above-mentioned drips of solution added and to contain in the dichloromethane solution of 0.4～3.6 times of normal 2-nitroxide-ethamine and 1～16 times of normal triethylamine, wherein the concentration of 2-nitroxide-ethamine is 0.1～1.2mol/L, and the concentration of triethylamine is 0.5～6.0mol/L; Stirring at room reaction system 4～24 hours, dilute with methylene dichloride subsequently, water and salt water washing, dry, concentrate, residue silicagel column purifying, developping agent are methylene dichloride: methyl alcohol=10: 1～100: 1 obtains white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
D. in being the dichloromethane solution of 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate of 0-03～0.7mol/L, concentration adds 0.5～5 times of normal metachloroperbenzoic acid in-10～10 ℃ in batches, the mixture that obtains stirred 0.5～2 hour at-10～10 ℃, subsequently with methylene dichloride dilution, saturated NaHCO
3The aqueous solution and salt water washing, drying concentrates residue silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=1: 1～20: 1 obtains white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate.
N-of the present invention (2-hydroxyethyl) asafoetide acid amides nitrate derivatives has the biological activity of good anti-hypoxia and treatment cardiovascular disorder, and Bioexperiment shows that its anti-hypoxia effect is than asafoetide acid amides nitrate compound in the prior art high about 6.4～14.1%; And can obviously resist myocardial ischemia-reperfusion injury; Stability experiment shows that The compounds of this invention has stability in storage preferably, and therefore, this compound has a good application prospect at anti-hypoxia and treatment cardiovascular disorder field.
Embodiment
Synthesizing of embodiment 1.2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate
(1-1) 2-nitroxide-ethamine is synthetic
In the 200ml ether, drip the 48ml HNO of being fuming at-10 ℃
3, subsequently with thanomin (compound 1) (20g, ethyl acetate 0.33mmol) (160ml) drips of solution is added in the above-mentioned solution, mixture is warming up to 0 ℃, and stirs 1 hour, rises to room temperature subsequently and stir to spend the night.Obtain white solid after the filtration, obtain 2-nitroxide-ethamine (compound 2) (39.6g, productive rate 71.6%) after the petroleum ether.
(1-2) (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate is synthetic
To containing (3-(4-hydroxyl-3-methoxyl group) phenyl) vinylformic acid (compound 3) (45g, add the vitriol oil (7.5ml) in methyl alcohol 232mmol) (500ml) solution, mixture heating up was refluxed 16 hours, solvent removed in vacuo, residue is dissolved in ethyl acetate and uses saturated NaHCO
3The aqueous solution and salt water washing, dried over sodium sulfate concentrates, and obtains faint yellow oily crude product (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate (compound 4) (47g, productive rate 97.5%), its not purified direct use.
(1-3) (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate is synthetic
To containing compound 4 (20g, 96.2mmol) pyridine (300ml) solution in add morpholine-4-acyl chlorides (13.42ml, 115.44mmol), the mixture stirred overnight at room temperature, steam solvent, water is added in the residue, filter the back and obtain pink solid (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate (compound 5) (31.84g, crude product is purifying not).
(1-4) (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) is acrylic acid synthetic
(10g 31.2mmol), drips in above-mentioned solution in 0 ℃ and to contain LiOHH to add compound 5 in the mixture of 35ml methyl alcohol and 35ml THF (tetrahydrofuran (THF))
2O (3.927g, water 93.5mmol) (35ml) solution.Subsequently, mixture rises to room temperature and stirred 3 hours.Adding 1M HCl to pH value is 3.Filter the back and obtain white solid (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) vinylformic acid (compound 6) (4.7g, crude product is purifying not).
(1-5) 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate is synthetic
Step 1: in 0 ℃ to containing compound 6 (10g, 32.6mmol) methylene dichloride (115ml) solution in add oxalyl chloride (9.3ml, 97.8mmol), and add several DMF (N, dinethylformamide), stir after 0.5 hour, mixture rises to room temperature and continues and stirred 2 hours, and evaporating solvent is with drying.
Step 2: (7.17g adds Et in methylene dichloride 42.38mmol) (77ml) solution to 2-nitroxide-ethamine in 0 ℃
3(18.14ml 130.4mmol), and stirred 1 hour N.In this solution, add and contain methylene dichloride (115ml) solution of step 1 product, and add several DMF.Mixture rises to room temperature and stirs and spend the night.Evaporating solvent adds entry.The mixture dichloromethane extraction, drying, vacuum concentration.(elutriant is methylene dichloride: MeOH=100 to residue: 1) obtain 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate (compound c-10) (10g, 77.8%) with the silicagel column purifying.
1H?NMR(CDCl
3)：δ＝7.458-7.497(t，1H)，7.004-7.012(d，2H)，6.956(s，1H)，6.134(s，1H)，6.051-6.095(m，1H)，4.521-4.547(d，2H)，3.79(s，3H)，3.632-3.704(m，8H)，3.51(s，2H)。
Mass spectrum molecular ion peak 395.
Synthesizing of embodiment 2.2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (4-methyl-piperazine-1-yl) manthanoate
(2-1) (2-(3-(4-hydroxyl-3-methoxyl group) phenyl) acrylamide) ethyl nitric ether is synthetic
In 0 ℃, in 20 minutes, to containing compound 3 (20g, 103.1mmol), DMAP (N, N-dimethyl-4-aminopyridine 12.6g, 103.1mmol) (19g adds EDCI (1-(3-diformazan Propylamino)-3-ethyl carbodiimide 26g in methylene dichloride 113.4mmol) (500ml) mixture with compound 2,113.4mmol), mixture was 0 ℃ of stirring 30 minutes and add Et
3(41.6g, 412mmol), this reaction mixture rises to room temperature and stirred 16 hours N.Subsequently with methylene dichloride dilution, and with the 2N HCl aqueous solution and salt water washing, drying concentrates, and filtration obtains light yellow solid (2-(3-(4-hydroxyl-3-methoxyl group) phenyl) acrylamide) ethyl nitric ether (compound 7) (11g, productive rate 37.8%).
(2-2) 4-methyl-piperazine-1-carbonyl chlorine is synthetic
In 0 ℃, in 20 minutes, to triphosgene (4.86g, 16.4mmol) chloroform (50ml) solution in drip and to contain methyl-piperazine (compound 8) (4.7g, 46.8mmol) and DIEA (N, N-diisopropylethylamine 6.04g, chloroform 46.8mmol) (30ml) mixture, rise to room temperature subsequently and stirred 2 hours, vacuum is removed partial solvent.The not purified direct use of this crude product in solution.
(2-3) 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (4-methyl-piperazine-1-yl) manthanoate is synthetic
In-10 ℃, in 30 minutes, (11g, (crude product, chloroformic solution 46.8mmol) rise to room temperature subsequently and stirred 16 hours to drip 4-methyl-piperazine-1-carbonyl chlorine that previous step obtains in pyridine 39mmol) (150ml) solution to compound 7.Solvent removed in vacuo, residue are dissolved in the ethyl acetate and use saturated NaHCO
3The aqueous solution and salt water washing, dry, concentrate, (developping agent is a methylene dichloride: methyl alcohol=10: 1) with the silicagel column purifying, obtain white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (4-methyl-piperazine-1-yl) manthanoate (compound c-11) (5.5g, productive rate 35%).
1H?NMR(CDCl
3)：δ＝2.362(3H，s)，2.485(4H，s)，3.609(2H，s)，3.368(2H，m)，3.730(2H，s)，3.828(3H，s)，4.572(2H，t，J＝5.2Hz)，5.961(1H，d，J＝15.6Hz)，6.604(1H，t，J＝6Hz)，6.949(1H，d，J＝1.2Hz)，7.047(1H，d，J＝8.4Hz)，7.062(1H，d，J＝8.4Hz)，7.02(1H，d，J＝15.6Hz)。
Mass spectrum molecular ion peak 408.
Synthesizing of embodiment 3.2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate
(3-1) tetrahydrochysene thiazine-4-base formyl chloride is synthetic
In 0 ℃, in 30 minutes, to triphosgene (8.8g, 29.6mmol) chloroform (50ml) solution in drip and to contain tetrahydrochysene thiazine (compound 11) (8.7g, 84.5mmol) and DIEA (10.9g, chloroform 84.5mmol) (40ml) mixture rise to room temperature subsequently and stirred 2 hours.Vacuum is removed partial solvent, obtains crude product (tetrahydrochysene thiazine-4-yl) formyl chloride (compound 12), the not purified direct use of this crude product in solution.
(3-2) 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate is synthetic
In 0 ℃ to compound 4 (16.4g, 84.5mmol), DMAP (10.3g, 84.5mmol) and Et
3N (17.1g, drip the compound 12 (crude products that previous step obtains in mixture 169mmol), 84.5mmol) chloroform (100ml) solution, subsequently in 60 ℃ of heating 16 hours, with the chloroform dilution, with the 2mol/L HCl aqueous solution and salt water washing, drying, concentrate and obtain white solid 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate (compound 13) (28g, productive rate 98%).
(3-3) 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate is synthetic
(28.5g adds LiOH (253.5mmol, the 2.5M) aqueous solution, gained solution stirring at room 16 hours in methyl alcohol 84.5mmol) (200ml) and THF (200ml) solution to containing compound 13.With ethyl acetate extraction once, water is acidified to pH 4～5 with 2mol/L HCl, use twice of ethyl acetate extraction again, the combined ethyl acetate layer, drying concentrates, and obtains white solid 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate (compound 14) (20g, productive rate 74%), the not purified direct use of this crude product.
(3-4) 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate is synthetic
(19g adds 5 DMF in methylene dichloride 59mmol) (200ml) solution, and (30g, 236mmol), stirring at room is 2 hours subsequently, desolventizes being lower than 40 ℃ of vacuum to drip oxalyl chloride to compound 14 in 0 ℃.Residue is dissolved in the 100ml methylene dichloride, and 0 ℃ be added dropwise to contain 2-nitroxide-ethamine (11.9g, 71mmol) and triethylamine (23.8g is in methylene dichloride 236mmol) (200ml) solution.Stirring at room reaction system 16 hours, dilute with methylene dichloride subsequently, water and salt water washing, dry, concentrate, residue silicagel column purifying, developping agent are methylene dichloride: methyl alcohol=50: 1, obtain white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate (compound 15) (12g, productive rate 50%).
(3-5) compound 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate is synthetic
(11.2g, add m-CPBA in methylene dichloride 27.2mmol) (200ml) solution (59.8mmol), the mixture of acquisition stirred 1 hour at 0 ℃ for metachloroperbenzoic acid, 12.03g, subsequently with methylene dichloride dilution, saturated NaHCO in batches to compound 15 in 0 ℃
3The aqueous solution and salt water washing, dry, concentrate, residue silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=20: 1 obtains white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate (compound c-12) (5.5g, productive rate 45%).
1H?NMR(DMSO)：?
3.289(2H，s)，3.537(2H，m)，3.811(3H，s)，3.832(2H，s)，3.976(2H，s)，4.587(2H，t，J＝5.2Hz)，6.614(1H，d，J＝15.6Hz)，7.152(1H，m)，7.221(1H，d，J＝8.4Hz)，7.434(1H，d，J＝15.6Hz)，8.345(1H，t，J＝6Hz)。
Mass spectrum molecular ion peak 443.
The experiment of embodiment 4 mouse airtight anoxia tolerances
Get body weight 18～22g mouse, every group 10, male and female half and half, be divided into 5 groups at random: sample c-10 group, sample c-11 group, sample c-12 group, control group and acetyl asafoetide nitramine (the non-nit that draws of the embodiment of the invention 1～3 preparation, chemical name N-(2-hydroxyethyl) asafoetide acid amide nitric ether) group, control group is given and physiological saline, respectively being subjected to the reagent group to irritate stomach respectively by 16mg/kg gives and corresponding medicine, after 30 minutes, with the single 300ml ground wide-necked bottle that places of mouse, sealing (is put soda-lime 10g to absorb CO in the bottle
2And H
2O, pad filter paper is to absorb urine, wide-necked bottle is put a mouse for every bottle with the preceding correction capacity that all is filled with water), be index with the breath stopped, the survival time of record mouse.According to experimental group and control animals survival time, calculate animals survived time increment rate.The result is as shown in table 1, compares with the blank group, and the anti-hypoxia effect of compound of the present invention improves 22.2～31.1%; Compare with acetyl asafoetide nitramine group, the anti-hypoxia effect of compound of the present invention improves 6.4～14.1%.
Table 1 anti-hypoxia measurement result
The effect of 5 pairs of rat myocardial ischemia and reperfusions of embodiment
Get body weight 250～300g wistar male rat, after the abdominal injection 25% urethane 4.5ml/kg anesthesia, the promoting the circulation of qi cannula meets the breathing apparatus.Cut off left side 3,4 costicartilages, expose heart, with 3～No. 0 silk threads in the coronary artery anterior interventricular branch, on 1/3 intersection threading standby.Change with the standard I I continuous monitoring electrocardiogram(ECG that leads, the electrograph normal rat of coring experimentizes.Ischemia-reperfusion group (I/R group), rebasing with photoplate, two-wire ligation anterior interventricular branch is lifted on obviously with electrocardiogram(ECG S-T section, and the following myocardium colour-darkening of ligature is the myocardial ischemia sign, unclamps ligature after 30 minutes, recovers blood flow 60 minutes.Infarction size is measured in the dirty dyeing of coring.Sham operated rats: get above-mentioned processing rat, threading but not ligation, spacious putting 90 minutes; Respectively be subjected to reagent group dosage referring to table 2, administration was anaesthetized after 20 minutes, and all the other are handled with ischemic filling group again.The measurement result of table 2 shows, compares with control group, and sample c-10, sample c-11 and the sample c-12 myocardial infarct size of the embodiment of the invention 1～3 preparation obviously reduce, and its effect is with to give sorbitrate suitable.
Table 2 myocardial infarct size measurement result
Embodiment 6 stability tests
Acetyl asafoetide nitramine, sample c-10, c-11 and c-12 room temperature are placed, and measure content at the 0th, 3,6 month with HPLC respectively, the results are shown in Table 3.
Table 3 compound stability investigation table (content %)
Test result is as shown in table 3, and the result shows that sample c-10, c-11 and c-12 room temperature place after 6 months content and do not have or slightly descend, and acetyl asafoetide nitramine content descend obviously (7.3%).
Claims (8)
1. N-(2-hydroxyethyl) the asafoetide acid amides nitrate derivatives or the acceptable salt of its medicine of general formula (I) expression, or its hydrate or solvate,
Wherein, R representative (morpholine-4-yl) formyl radical, (4-methyl-piperazine-1-yl) formyl radical or (tetrahydrochysene sulphonyl thiazine-4-yl) formyl radical.
2. an anti-hypoxia and the medicine that resists myocardial ischemia, it contains N-(2-hydroxyethyl) the asafoetide acid amides nitrate derivatives or the acceptable salt of its medicine of general formula as claimed in claim 1 (I) expression, or its hydrate or solvate are as effective constituent.
3. N-(2-hydroxyethyl) the asafoetide acid amides nitrate derivatives or the acceptable salt of its medicine of the described general formula of claim 1 (I) expression, or its hydrate or the application of solvate in the medicine for preparing anti-hypoxia and resist myocardial ischemia.
4.2-the preparation method of methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate, it comprises the steps:
A. (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate and morpholine-4-acyl chloride reaction obtain (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate;
B. (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate and LiOHH
2O reaction obtains (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) vinylformic acid;
C. (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) vinylformic acid reacts with oxalyl chloride and DMF;
D.2-nitroxide-ethamine and Et
3The N reaction adds step C product and DMF subsequently, obtains 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate.
5. preparation method as claimed in claim 4, it comprises the steps:
A. in being the pyridine solution of (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate of 0.064～1.6mol/L, concentration adds 0.6～4.8 times of normal morpholine-4-acyl chlorides, the mixture stirred overnight at room temperature, steaming desolventizes, water is added in the residue, filter the back and obtain pink solid (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate;
B. be to add (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) methyl acrylate in the mixture of 1: 0.1～10 methyl alcohol and tetrahydrofuran (THF) to volume ratio, strength of solution is 0.2～1.8mol/L, drips 1～6 times of normal LiOHH in-10～10 ℃ in above-mentioned solution
2The aqueous solution of O; Subsequently, mixture rises to room temperature and stirred 1～5 hour, and adding 1mol/L HCl to pH value is 3, filters the back and obtains white solid (3-(4-(morpholine-4-ketonic oxygen for)-3-methoxyl group) phenyl) vinylformic acid;
C. in being (3-(4-(morpholine-4-ketonic oxygen generation)-3-methoxyl group) phenyl) acrylic acid dichloromethane solution of 0.1～3mol/L, concentration adds 1～10 times of normal oxalyl chloride in-10～10 ℃, and add several DMF, stir after 0.5～5 hour, mixture rises to room temperature and continues and stirred 0.5～5 hour, and evaporating solvent is also dry;
D. in being the dichloromethane solution of 0.1～2.5mol/L 2-nitroxide-ethamine, concentration adds 1～10 times of normal Et in-10～10 ℃
3N, and stirred 0.5～3 hour; In this solution, add and contain the dichloromethane solution of step C product, and add 5～10 DMF; Mixture rises to room temperature and stirs and spend the night; Evaporating solvent, add entry, the mixture dichloromethane extraction, dry, vacuum concentration, residue silicagel column purifying, elutriant are methylene dichloride: MeOH=10: obtain 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (morpholine-4-yl) manthanoate at 1～200: 1.
6.2-the preparation method of methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (4-methyl-piperazine-1-yl) manthanoate, it comprises the steps:
In-10～10 ℃, drip the chloroformic solution of 0.5～5 times of normal 4-methyl-piperazine-1-carbonyl chlorine in concentration is the pyridine solution of (2-(3-(4-hydroxyl-3-methoxyl group) phenyl) acrylamide) ethyl nitric ether of 0.1～1.0mol/L, wherein the concentration of the chloroformic solution of 4-methyl-piperazine-1-carbonyl chlorine is 0.58～2.34mol/L; Rise to room temperature subsequently and stirred 4～24 hours, solvent removed in vacuo, residue is dissolved in the ethyl acetate, and uses saturated NaHCO
3The aqueous solution and salt water washing, drying concentrates, and uses the silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=1: 1～20: 1 obtains white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (4-methyl-piperazine-1-yl) manthanoate.
7.2-the preparation method of methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate, it comprises the steps:
A. (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate, DMAP, Et
3N and tetrahydrochysene thiazine-4-base formyl chloride reaction obtains 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
B.2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate and LiOH reactant aqueous solution obtain 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
C.2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate, DMF and oxalyl chloride reaction add 2-nitroxide-ethamine and triethylamine subsequently and obtain 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
D.2-the reaction of methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate and metachloroperbenzoic acid obtains 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate.
8. preparation method as claimed in claim 7, it comprises the steps:
A. to mol ratio 1: 1: 2 (3-(4-hydroxyl-3-methoxyl group) phenyl) methyl acrylate, DMAP and Et in-10～10 ℃
3The chloroformic solution of the tetrahydrochysene thiazine of dropping and DMAP equivalent in the mixture of N-4-base formyl chloride, wherein the concentration of the chloroformic solution of tetrahydrochysene thiazine-4-base formyl chloride is 0.3～3.0mol/L; In 40～100 ℃ of heating 4～20 hours,,, concentrate and obtain white solid 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate subsequently with the 2mol/L HCl aqueous solution and salt water washing, drying with the chloroform dilution;
B. be to add 0.5～10 times of normal LiOH aqueous solution in the methyl alcohol of 2-methoxyl group-4-(3-methoxyl group-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate of 0.1～0.4mol/L and the THF solution to concentration, wherein, the volume ratio of methyl alcohol and THF is 1: 1; Gained solution stirring at room 4～24 hours; Thereafter use ethyl acetate extraction, drying concentrates, and obtains white solid 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
C. in being the dichloromethane solution of 2-methoxyl group-4-(vinylformic acid-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate of 0.1～1.0mol/L, concentration adds 5～10 DMF in-10～10 ℃, and drip 1～20 times of normal oxalyl chloride, stirring at room is 0.5～6 hour subsequently, desolventizes being lower than 40 ℃ of vacuum; Residue is dissolved in methylene dichloride, strength of solution is 0.2～2.0mol/L, and at-10～10 ℃ above-mentioned drips of solution added and to contain in the dichloromethane solution of 0.4～3.6 times of normal 2-nitroxide-ethamine and 1～16 times of normal triethylamine, wherein the concentration of 2-nitroxide-ethamine is 0.1～1.2mol/L, and the concentration of triethylamine is 0.5～6.0mol/L; Stirring at room reaction system 4～24 hours, dilute with methylene dichloride subsequently, water and salt water washing, dry, concentrate, residue silicagel column purifying, developping agent are methylene dichloride: methyl alcohol=10: 1～100: 1 obtains white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate;
D. in being the dichloromethane solution of 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene thiazine-4-yl) manthanoate of 0.03～0.7mol/L, concentration adds 0.5～5 times of normal metachloroperbenzoic acid in-10～10 ℃ in batches, the mixture that obtains stirred 0.5～2 hour at-10～10 ℃, subsequently with methylene dichloride dilution, saturated NaHCO
3The aqueous solution and salt water washing, drying concentrates residue silicagel column purifying, developping agent is a methylene dichloride: methyl alcohol=1: 1～20: 1 obtains white solid 2-methoxyl group-4-(3-(2-(nitroxide) ethylamino)-3-oxypropylene-1-yl) phenyl (tetrahydrochysene sulphonyl thiazine-4-yl) manthanoate.
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| CN102796040A (en) * | 2012-08-23 | 2012-11-28 | 天津药物研究院 | 1,4-disubstituted piperazine derivatives and their preparation method and use |
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| CN102796040B (en) * | 2012-08-23 | 2015-03-25 | 天津药物研究院 | 1,4-disubstituted piperazine derivatives and their preparation method and use |
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| CN105622488A (en) * | 2016-04-01 | 2016-06-01 | 南阳师范学院 | 4-cycloaminoalkoxy-3-methoxycinnamates, and preparation method and application thereof |
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