CN101973930B - Dihydropyridine derivative for selectively relaxing brain blood vessel as well as synthetic method and application thereof - Google Patents
Dihydropyridine derivative for selectively relaxing brain blood vessel as well as synthetic method and application thereof Download PDFInfo
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- CN101973930B CN101973930B CN2010105066172A CN201010506617A CN101973930B CN 101973930 B CN101973930 B CN 101973930B CN 2010105066172 A CN2010105066172 A CN 2010105066172A CN 201010506617 A CN201010506617 A CN 201010506617A CN 101973930 B CN101973930 B CN 101973930B
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- pyridine derivative
- dihydrogen pyridine
- dihydropyridine
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Abstract
The invention discloses a dihydropyridine derivative for selectively relaxing brain blood vessels as well as a synthetic method and application thereof, wherein the chemical name of the derivative is (E)-4-[2-(3-tert-pentyloxy-3-oxy-1-propenyl]phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the derivative is synthesized through the reaction of o-phthalaldehyde and a corresponding Wittig reagent, Hantzsch reaction and the like. The compound has high selectivity for relaxing the brain blood vessels, simultaneously shows the function of lowering pressure and has the application of treating diseases related to the blood-supply insufficiency of the brain blood vessels.
Description
Technical field
The invention belongs to the medicament research and development field, relate to the cerebrovascular medicine of a kind of selectivity diastole, cerebrovascular dihydrogen pyridine derivative of especially a kind of selectivity diastole and preparation method and use thereof.
Background technology
At present, hypertension and cerebral blood supply insufficiency have become the modal vascular disease in the world, also are one of maximum prevailing disease, and human beings'health in serious harm.According to the statistical information of China Ministry of Health, the morbidity of China's cerebro-vascular diseases is 7/1000ths.According to investigations, along with Beijing society, rapid economy development, and the continuous aging of population, cerebrovascular disease becomes first of the citizen's cause of the death of capital gradually.Account for whole dead ratios to cerebro-vascular diseases in 2009 and reach 27.53%, cerebro-vascular diseases has become pose a health risk genuine " No.1 killer " now.Hypotensive and medicine vasodilation of clinical application at present mainly contains nitrate esters, β-adrenergic agents thing, angiotensin-convertion enzyme inhibitor, calcium channel blocker and Chinese patent medicine etc., and wherein dihydropyridine calcium channel blocker nitrendipine, amlodipine, Lacidipine (62 and felodipine are clinical the most commonly used.Calcium channel blocker is the main medicine of treatment hypertension and vasodilation, both can singly be used as a line medicine, also can with the other drug coupling.The characteristics of its antihypertensive function are: to low renin type (comprising the elderly) hypertension better effects if; Hypotensive effect is rapid, dihydropyridines particularly, and the selectivity of vasodilation effect is high; Metabolism there is not obvious influence.
The calcium-channel antagonists nimodipine can be regulated the level of intracellular Ca2+ effectively, makes it to keep normal physiological function.Particularly outstanding to cerebrovascular effect, can be used for cerebral vasospasm due to prevention and treatment ischemic cerebrovascular disease, migraine, the slight subarachnoid hemorrhage, sudden deafness, light moderate essential hypertension.But the nimodipine drug effect is not strong, once needs more than the oral 40mg; The nimodipine transformation period is short, and needs were oral 3 times on 1st.
Therefore, seek a kind of simple in structure, be easy to synthesize, efficient, long-acting, can the selectivity diastole cerebrovascular, the dihydropyridine calcium channel blocker of certain hypotensive effect is arranged again, it is still significant to be applied to treat the heart, cerebrovascular disease.
Summary of the invention
The objective of the invention is to overcome the shortcoming of above-mentioned prior art; Cerebrovascular dihydrogen pyridine derivative of a kind of selectivity diastole and preparation method and use thereof are provided; This verivate is 1; 4 dihydropyridine calcium channel antagonists, it is high to cerebrovascular selectivity, has characteristics such as efficient, long-acting, that toxic action is little.
The objective of the invention is to solve through following technical scheme:
The cerebrovascular dihydrogen pyridine derivative of this selectivity diastole is characterized in that, structural formula is as with shown in the following formula (I):
The present invention provides a kind of compound method of dihydrogen pyridine derivative as stated: at first make OPA and corresponding Wittig reagent condensation; Products therefrom reacts in alcohol with amino ethyl crotonate under acid catalysis and obtains (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2; 6-dimethyl--1; 4-dihydropyridine-3, the 5-diethyl dicarboxylate is said dihydrogen pyridine derivative.
The compound method of above-described dihydrogen pyridine derivative specifically may further comprise the steps:
1) in organic solvent, make OPA and equimolar Wittig reagent react obtain (E)-2 '-formyl radical cinnamic acid tert-pentyl ester;
2) under acid catalysis; The amino ethyl crotonate of (E)-2 '-formyl radical cinnamic acid tert-pentyl ester and twice molar weight is reacted obtain (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2 in alcohol; 6-dimethyl--1,4-dihydropyridine-3,5-diethyl dicarboxylate.
Above-mentioned organic solvent is methylene dichloride, chloroform or THF.
Above-mentioned Wittig reagent is inferior tert.-amyl acetate of triphenyl phosphonium base or the inferior phosphine acyl acetic acid tert-pentyl ester of diethoxy.
Above-mentioned acid is trifluoroacetic acid or trichoroacetic acid(TCA), its consumption be said (E)-2 '-formyl radical cinnamic acid tert-pentyl ester molar weight 1-2 doubly.
Compound provided by the invention can the selectivity diastole cerebrovascular when lower concentration; Dosage can bring high blood pressure down when increasing, and the present invention advocates that also a kind of above-mentioned dihydrogen pyridine derivative with structural formula (I) is used to prepare the purposes of treatment cerebrovascular blood supply insufficiency disease medicament and antihypertensive drug.
The present invention has following beneficial effect:
The present invention filters out the have structural formula compound of (I) from design synthetic multiple dihydropyridine calcium channel antagonist, this kind compound is not only simple in structure, and good and hypotensive effect arranged to cerebrovascular selectivity.The compound method of synthetic this compound realizes that easily production cost is low in addition.And the medicine that utilizes this compound to process is compared with nimodipine tablet, and is higher to cerebrovascular selectivity, and the blood pressure lowering effect aspect has efficient, long lasting characteristics.
Description of drawings
Fig. 1 is the diastole action diagram of ZCM-298 of the present invention to 60mmol/L potassium ion preshrinking blood vessel;
Fig. 2 is the diastole action diagram of ZCM-298 of the present invention to U46619 preshrinking blood vessel.
Embodiment
Below in conjunction with accompanying drawing the present invention is done and to describe in further detail:
The present invention at first proposes the cerebrovascular dihydrogen pyridine derivative of a kind of selectivity diastole, and this kind dihydrogen pyridine derivative can be used in the medicine of preparation treatment cerebral blood supply insufficiency disease, and its structural formula is suc as formula shown in (I):
Its chemistry of the described structural formula of formula (I) (E)-4-by name [2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2,6-dimethyl--1,4-dihydropyridine-3,5-diethyl dicarboxylate.
The compound method of above dihydrogen pyridine derivative (or (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2,6-dimethyl--1,4-dihydropyridine-3,5-diethyl dicarboxylate) is following:
At first make OPA and corresponding Wittig reagent condensation; Products therefrom reacts in alcohol with amino ethyl crotonate under acid catalysis and obtains (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2; 6-dimethyl--1; 4-dihydropyridine-3, the 5-diethyl dicarboxylate is said dihydrogen pyridine derivative.
Describe the compound method of dihydrogen pyridine derivative of the present invention in detail below in conjunction with embodiment:
Embodiment 1
In the present embodiment, the compound method of dihydrogen pyridine derivative, specifically carry out according to following steps:
1) in dichloromethane solvent, make the inferior tert.-amyl acetate reaction of OPA and equimolar triphenyl phosphonium base obtain (E)-2 '-formyl radical cinnamic acid tert-pentyl ester;
2) under trifluoroacetic acid catalysis; The amino ethyl crotonate of above-mentioned (E)-2 '-formyl radical cinnamic acid tert-pentyl ester that obtains and twice molar weight is reacted obtain (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2 in alcohol; 6-dimethyl--1; 4-dihydropyridine-3, the 5-diethyl dicarboxylate; The consumption of said trifluoroacetic acid is 1 times of molar weight of (E)-2 '-formyl radical cinnamic acid tert-pentyl ester.
Embodiment 2
In the present embodiment, the compound method of dihydrogen pyridine derivative, specifically carry out according to following steps:
1) in chloroform solvent, make the inferior phosphine acyl acetic acid tert-pentyl ester reaction of OPA and equimolar diethoxy obtain (E)-2 '-formyl radical cinnamic acid tert-pentyl ester;
2) under trichoroacetic acid(TCA) catalysis; The amino ethyl crotonate of above-mentioned (E)-2 '-formyl radical cinnamic acid tert-pentyl ester that obtains and twice molar weight is reacted obtain (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2 in alcohol; 6-dimethyl--1; 4-dihydropyridine-3, the 5-diethyl dicarboxylate; The consumption of said trichoroacetic acid(TCA) is 2 times of molar weight of (E)-2 '-formyl radical cinnamic acid tert-pentyl ester.
Embodiment 3
In the present embodiment, the compound method of dihydrogen pyridine derivative, specifically carry out according to following steps:
1) in tetrahydrofuran solvent, make the inferior tert.-amyl acetate reaction of OPA and equimolar triphenyl phosphonium base obtain (E)-2 '-formyl radical cinnamic acid tert-pentyl ester;
2) under trichoroacetic acid(TCA) catalysis; The amino ethyl crotonate of above-mentioned (E)-2 '-formyl radical cinnamic acid tert-pentyl ester that obtains and twice molar weight is reacted obtain (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2 in alcohol; 6-dimethyl--1; 4-dihydropyridine-3, the 5-diethyl dicarboxylate promptly has the verivate of structural formula (I); The consumption of wherein said trichoroacetic acid(TCA) is 1 times of molar weight of (E)-2 '-formyl radical cinnamic acid tert-pentyl ester.
Below with (E)-4-of the present invention [2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2; 6-dimethyl--1; 4-dihydropyridine-3; The 5-diethyl dicarboxylate (hereinafter to be referred as: ZC-298) concrete synthetic instance and preparation of drug combination further specify the present invention, but the invention is not restricted to these embodiment.
Embodiment 4
(E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2,6-dimethyl--1,4-dihydropyridine-3,5-diethyl dicarboxylate's (ZCM-298) is synthetic:
The 0.64g OPA is dissolved in the 30mL methylene dichloride, adds the inferior tert.-amyl acetate of 1.88g triphenylphosphine then, make mixture stirring at room reaction 5h under nitrogen protection; Rotary evaporation removes and desolvates again, and the gained residue is dissolved in the 15mL ethanol, and ice bath is cooled to 0 ℃; Add the 2.72g ethyl, after waiting to dissolve, add the 3.6g trichoroacetic acid(TCA) again; 30min is stirred in continuation, and (eluent is a sherwood oil: ETHYLE ACETATE=8: 1), get yellow solid matter in directly column chromatography separation after system concentrates; Adopt recrystallization from ethyl acetate/petroleum ether, obtain white particulate crystallization 1.22g.Productive rate 54.46%.MP：164-167℃。EI-MS：470(M+1)。
1H?NMR(300MHz，CDCl
3)δ：0.96(t，3H，-CH
3)，1.13(t，6H，2×-CH
3)，1.50(s，6H，2×-CH
3)，1.85(q，2H，-CH
2-)，2.33(s，6H，2×-CH
3)，3.93(q，2H，-OCH
2-)，4.02(q，2H，-OCH
2-)，5.32(s，1H，CH)，5.65(s，1H，-NH-)，6.27(d，1H，J＝15.78，＝CH-)，7.12(t，1H)，7.25(t，1H)，7.40(d，1H)，7.48(d，1H)[Ar-H]，8.44(d，1H，J＝15.84，-CH＝)。
(E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2,6-dimethyl--1,4-dihydropyridine-3,5-diethyl dicarboxylate's (ZCM-298) is synthetic:
In reaction flask, add the 2.60g OPA, 7.59g triphenylphosphine alkene tert.-amyl acetate, the 110mL methylene dichloride stirs room temperature reaction 5h under the nitrogen protection.Removal of solvent under reduced pressure adds the 60mL absolute ethyl alcohol, stirs, and system is cooled off with ice-water bath, adds the 5.26g ethyl again, and the 3.7mL trifluoroacetic acid adds the cooling of continued ice-water bath and stirs 30min down.System concentrates rear pillar chromatographic separation (sherwood oil: ETHYLE ACETATE=8: 1), get yellow solid matter 5.28g, productive rate 58.0%.After the re-crystallizing in ethyl acetate, MP:164-167 ℃.EI-MS：470(M+1)。
Below specifically introduce the preparation that contains the ZCM-298 pharmaceutical prepn that the present invention proposes
One, the composition of ZCM-298 tablet and preparation
With 1000 in ZCM-298 tablet of the present invention of preparation is example, and the bulk drug that it is used and the composition of auxiliary material and proportioning are following:
ZCM-298 2.0g
Starch 50g
Dextrin 36g
10% starch slurry is an amount of
Cross-linked polyvinylpyrrolidone 10g
Magnesium Stearate 1g
Method for making: ZCM-298 is pulverized, cross 80 mesh sieves, mix with starch and dextrin; Add starch slurry and process softwood, after granulating with 14 mesh sieves, put 60～80 ℃ of dry backs with the whole grain of 12 mesh sieves; After adding cross-linked polyvinylpyrrolidone and Magnesium Stearate mixing, use the tabletting machine compressing tablet, promptly get.Every heavy 100mg contains ZCM-298 2mg.
Two, capsular composition of ZCM-298 and preparation
With 1000 of ZCM-298 capsules of the present invention of preparation is example, and the bulk drug that it is used and the composition of auxiliary material and proportioning are following:
ZCM-298 6.0g
Starch 60g
Dextrin 32g
10% starch slurry is an amount of
Method for making: ZCM-298 is pulverized, crosses 80 mesh sieves, mix, add starch slurry and process softwood with starch and dextrin, after the granulation of 14 mesh sieves, put 60～80 ℃ of dryings after, insert in the capsulae vacuus, promptly get.The heavy 100mg of every capsules content contains ZCM-2986mg.
This tablet can be used for treating cerebrovascular disease, be grown up 1 time on the 1st, 1 time 1.
This capsule can be used for treating mild or moderate hypertension, be grown up 1 time on the 1st, 1 time 1.
Should be noted that only also unrestricted the present invention of above embodiment in order to explanation the present invention.Although with preferred embodiment the present invention has been carried out detailed explanation, those of ordinary skill in the art should be appreciated that and under not departing from the scope of the present invention, can make amendment, be out of shape the present invention or be equal to replacement, all belongs to protection scope of the present invention.
In order to verify that ZCM-298 that the present invention proposes is to cerebrovascular selectivity diastole effect; To (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2; 6-dimethyl--1,4-dihydropyridine-3,5-diethyl dicarboxylate (being ZCM-298) has carried out the vasodilator test.
Get the SD rat, CO
2Anesthesia is put to death, and separates coronary artery, aorta abdominalis, brain basal arteries and the Renal artery, immerses in the cold Krebs liquid, and artery is cut into the long annulus section of 1mm.The vascular circle of handling well is enclosed within on the steel wire of two 60 μ m, one of them connects tonotransducer, and another connects micromatic setting (regulating load tension force).Install the back through bridging amplifier, antiotasis is shown in graphoscope.Arterial ring is inserted 37 ℃ of Myograph thermostatic baths that contain Krebs liquid 2mL, and lasting feeding contains 95%O
2And 5%CO
2Mixed gas, pH keeps 7.4.Before the experiment, arterial ring tranquillization load 1-5mN, every 20min changes liquid 1 time, stablizes 1.5h.With K
+-Krebs liquid (contains 60mmol/L K
+) check arterial ring shrinkability, twice shrinkage amplitude differs less than 10% and is used for experiment.Write down 60mmol/L K earlier
+The contraction that causes, steadily the back adds the ZCM298 of the different concentration that add up.Calculate diastolic rate with [shrinkage amplitude before (shrinkage amplitude before the medicine-medicine post shrinkage amplitude)/medicine] * 100%.Same quadrat method, record 10
-5The vasoconstriction that mmol/L U46619 causes is observed the vasorelaxation action that ZCM298 that different concns adds up causes again.Fig. 1 and Fig. 2 show compound ZCM-298 diastole 60mmol/L K respectively
+The effect of 4 kinds of arterial rings that shrink with U46619.Its diastole effect to the brain basal arteries is the strongest, is coronary artery, mesenteric artery and the Renal artery secondly.Compound ZCM-298 sees Fig. 1 and Fig. 2 to the diastole effect of 4 kinds of arterial rings.
In order to verify the hypotensive effect that the present invention relates to compound ZCM-298, select the positive contrast medicine of Lacidipine (62, adopt clear-headed spontaneous hypertensive rat (SHR) to observe its blood pressure lowering effect.
Medicine: Lacidipine (62, ZCM-298, self-control, purity＞98%.Use DMSO 99.8MIN.: ethanol: 0.5% tween-80=1: 1: 8 (volume ratio) is mixed with medicine respectively the solution to be tried of 2.0mg/100mL.
Administering mode: irritate stomach
Dosage: 0.2mg/kg
Animal: 8 of SHR rats
Instrument: BP-6 animal non-invasive blood pressure tester, Chengdu TME Technology Co., Ltd. produces.
Experimental technique: open BP-6 animal non-invasive blood pressure tester, regulate the test box temperature about 37 ℃.With the rat mouse cage of packing into, integral body is put into test box.The mouse tail is passed pulse detector (being the intasome of air bag and sphygmograph transducer), stablize 10～15min caudal artery is fully expanded.After signal to be tested was steady, applied voltage test was read systolic pressure.Repeat 3 times, average, be the preceding blood pressure of administration.Take out animal, press the 10mL/kg gastric infusion, put in the blood pressure tester again, after signal to be tested was steady, applied voltage test was read systolic pressure and diastolic pressure.Test respectively about 30min 2 times after the administration, get average, be blood pressure after the administration.Table 1 result shows that ZCM-298 has the effect of tangible reduction SHR rat blood pressure.
Table 1.ZCM-298 irritates the hypotensive effect
of stomach to the SHR rat
Compare * * P＜0.01 with control group
Claims (6)
1. the cerebrovascular dihydrogen pyridine derivative of selectivity diastole is characterized in that, structural formula is as with shown in the following formula (I):
Synthesizing of this dihydrogen pyridine derivative: at first make OPA and corresponding Wittig reagent condensation; Products therefrom reacts in alcohol with amino ethyl crotonate under acid catalysis and obtains (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2; 6-dimethyl--1; 4-dihydropyridine-3, the 5-diethyl dicarboxylate is said dihydrogen pyridine derivative.
2. the compound method of dihydrogen pyridine derivative according to claim 1 is characterized in that, specifically may further comprise the steps:
1) in organic solvent, make OPA and equimolar Wittig reagent react obtain (E)-2 '-formyl radical cinnamic acid tert-pentyl ester;
2) under acid catalysis; The amino ethyl crotonate of (E)-2 '-formyl radical cinnamic acid tert-pentyl ester and twice molar weight is reacted obtain (E)-4-[2-(uncle's 3-pentyloxy-3-oxygen-1-propenyl] phenyl-2 in alcohol; 6-dimethyl--1,4-dihydropyridine-3,5-diethyl dicarboxylate.
3. the compound method of dihydrogen pyridine derivative according to claim 2 is characterized in that, said organic solvent is methylene dichloride, chloroform or THF.
4. the compound method of dihydrogen pyridine derivative according to claim 2 is characterized in that, described Wittig reagent is inferior tert.-amyl acetate of triphenyl phosphonium base or the inferior phosphine acyl acetic acid tert-pentyl ester of diethoxy.
5. the compound method of dihydrogen pyridine derivative according to claim 2 is characterized in that, described acid is trifluoroacetic acid or trichoroacetic acid(TCA), its consumption be said (E)-2 '-formyl radical cinnamic acid tert-pentyl ester molar weight 1-2 doubly.
6. the said purposes of dihydrogen pyridine derivative in preparation cerebral blood supply insufficiency disease medicament of a claim 1 with structural formula (I).
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| CN101691351B (en) * | 2009-09-30 | 2012-03-28 | 西安交通大学 | Synthesis method of 4-aminopropenylphenyl-1,4-dihydropyridine and medicinal application thereof |
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