WO2000005193A1

WO2000005193A1 - GUAIACOXYPROPANOLAMINE DERIVATIVES WITH α/β-ADRENERGIC BLOCKING ACTIVITY

Info

Publication number: WO2000005193A1
Application number: PCT/CN1998/000132
Authority: WO
Inventors: Ing-Jun Chen; Tong-Ho Lin
Original assignee: Chen Ing Jun; Lin Tong Ho
Priority date: 1998-07-23
Filing date: 1998-07-23
Publication date: 2000-02-03
Also published as: AU8527798A

Abstract

The present invention relates to novel guaiacoxypropanolamine derivatives of formula (I): wherein R is CH2CH=CH2, CH=CHCOOC2H5, CH=CHCH3, CH2NHCO(CH2)7CH3; R3 is OH, OCH3, NHCH2CH3OCH3, CHR6; R4 is OCH3, OC2H5, CHR6; R6 is C1-C6 saturated alkyl, C1-C6 unsaturated alkyl; R2 is (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI). The said compounds of formula (I) have α/β-adrenergic blocking activity. The invention further relates to pharmaceutical composition comprising compound of formula (I) and pharmaceutical acceptable vehicle. The composition also has α/β-adrenergic blocking activity, and is useful in the treatment of acute hypertension.

Description

With oc / β-adrenergic block

Active guaiacoxypropanolamine derivative

Field of invention

The invention relates to a novel guaiacoxypropanolamine derivative, which has been confirmed by animal experiments to have pharmacologically α / β-adrenergic blocking activity, and also relates to a synthetic method of the derivative and a pharmaceutical combination containing the same Thing.

Background

Adrenergic beta blockers have been used clinically for 26 years. Currently, beta blockers have been used in thyroid disease in addition to cardiovascular diseases such as hypertension, angina pectoris, and supraventricular arrhythmia. Symptoms, such as myocardial hypertrophy, myocardial infarction, migraine, glaucoma, and gastrointestinal bleeding, are widely used. However, traditional beta blockers still have some unavoidable side effects, such as inhibiting myocardial function, increasing peripheral and coronary vascular resistance, etc., which limits its clinical use. Therefore, it is not appropriate to use beta blockers for angina pectoris caused by coronary artery spasm. Dispensing to treat. Drugs that have been developed in recent years and have α-blocking and β-blocking have begun to be used to treat some cardiovascular diseases. It can reduce the side effects of traditional β-blockers. On the other hand, it can also avoid oc-blockers. Repulsive tachycardia caused by vasodilation. The most typical alpha and beta blockers generally mentioned are labetalol (Trandate®), which is commonly used clinically in patients with acute hypertension.

current technology

Studies on the structure-activity relationship (SAR) showed that the structure of guaiacol ethylamine has the activity of an alpha blocker (Augestein et al. 1964); and Kierstead, RW et al. (J. Med. Chem.) Vol. 26 No.

Reported on pages 1561-69, aryloxypropanolamine is the basic structure of beta blockers. In addition, many of the ingredients in traditional Chinese medicines contain aromatic rings. Therefore, I am interested in finding an aromatic ring-containing ingredient, including eugenol, isoeugenium citronella, ferulic acid, and capsaicin. First, a propanolamine group is introduced by a chemical reaction. ; Then introduce part of the structure of guaiacol ethylamine to make it Has alpha blocker activity to synthesize eugenodilol, isoeugendilol, ferulidilol, capsinodilol, and further explore whether the synthesized compound It has the activity of alpha and beta blockers and explores its pharmacological effects.

Object of the invention

The primary object of the present invention is to provide novel guaiacoxypropanolamine derivatives, as shown in Formula I

Where R is CH ₂ CH = CH ₂ , CH = CHCOOC ₂ H ₅ , CH = CHCH, CH ₂ HCO (CH 2) ₇ CH ₃ ;

R ₃ is OH, OCH ₃ , NHCH ₂ CH ₃ OCIl3, CHR ₆ ;

R ₄ is OCH ₃ , OC ₂ H ₅ , CHR ₆ ;

Is d-G, bubble and alkyl, d-Cr, unsaturated fluorenyl-;

And its synthesis.

Another object of the present invention is to provide compounds of formula I which have been confirmed by animal experiments to have α / β-adrenergic blocking activity.

Another object of the present invention is to prepare a pharmaceutical composition having α / β-adrenergic blocking activity by adding various excipients as a main component of the compound of formula I.

Brief description of the drawings

FIG. 1 is a flowchart illustrating a method for synthesizing a compound.

Detailed description of the invention

The present invention provides a novel guaiacoxy propanolamine derivative as shown in Formula I,

Where R is CH ₂ CH = CH ₂ , CH = CHCOOC ₂ H ₅ , CH = CHCH, CH ₂ NHCO (CH

R ₃ is OH, OCH3, NHCH ₂ CH ₃ OCH ₃ , CHR ₆ ;

R ₄ is OCH ₃ , OC2H5, CHR ₆ ;

¾ is -Cf, bubble and fluorenyl, C _r C _{6 is} not bubble and fluorenyl;

N

The invention also relates to a method for synthesizing a novel guaiacoxypropanolamine compound of formula I, as shown in FIG. 1, which includes

1.) Synthesis of 4-oxoethylamine-3 -methoxybenzyl ethyl ester, heated from 4-hydroxy-3 -methoxybenzoate and dibromoethane to boiling in a three-necked flask, After stirring, sodium hydroxide was added; hexane / ethyl acetate mixture was used as the eluent, and the column was packed with silica gel for separation; an equimolar proportion of potassium phthalimide was added to the reaction, and the mixture was hydrated in an equimolar proportion. Hydrazine heating reaction

2.) Synthesis of epoxy compounds: Alkylated N-vanillinyl nonamide (Nonivamide), ferulic acid, or 4-hydroxy-3 -methoxy-1 -propenylbenzene, etc. in an alkaline ethanol environment The raw materials were reacted together, and epichlorohydrin was added to the mixture to fully react under reflux, and then concentrated under reduced pressure, and separated with a silica gel-filled column to obtain white crystals.

3.) Synthesis of N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxybenzoic acid) propoxy)-3 -methoxy 1-1 -propenylbenzene; The 4-oxoethylamine-3 -methoxybenzoate ethyl ester was subjected to an amination reaction with an epoxy compound in an equimolar ratio, and crystals were obtained after standing overnight.

The above novel guaiacoxypropanolamine compounds change some of the intermediate products with different substituents. For example, an epoxy compound can be heated with 4-oxyethylamine-3 -methoxymethoxycinnamate . During the reaction of dibromoethane with the brominated products of ferulic acid, vanillic acid, and guaiac, the 4 -oxoalkylamine on the product of dibromoethane can be replaced with other dibromo long chain alkanes. Base chain length. If necessary, esterification with methoxy-substituted guaiacol on the third carbon can obtain products with different methoxy groups. The novel guaiacoxypropanolamine compounds mainly include the following:

Compound 1 …… (1-[(4- -propyl- 2 -methoxy) benzyloxy]-3-[(2 -methoxyphenoxyethyl) amino] -propanol Bisphenol

Compound 2 ... (1-[(4 -Ethyl acrylate-2 -methoxy) benzyloxy]-3-[(2 -methoxyphenoxyethyl) amino] -propanol Diol

Compound 3 ... (1-[(4-nonanamide-2 -methoxy) benzyloxy]-3-[(2-methoxyphenoxyethyl) amino I-propanol, referred to as capsaicin

Compound 4 ... (1-[(4-propenyl-2 -methoxy) benzyloxy j-3-[(2-methoxyphenoxyethyl) amino j-propanol, referred to as isobutyl scent Double

Compound 5 ... N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3-methoxycinnamic acid) propoxy)-3 -methoxy]-1 -propenylbenzyl

Compound 6 ... N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxybenzylcarboxylic acid) propoxy) _ 3 -methoxybenzyl j -nonanamide

Compound 7 -.... N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3-methoxybenzoic acid) propoxy) _ 3 -methoxy]-1 -propenebenzene

Compound 8 ... N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3-methoxycinnamic acid) propoxy)-3 -methoxybenzyl I -nonanamide

Compound 9 ... N-[4-(2-hydroxy-3-(4-oxyacetoxybenzyloxyamino) propoxy)-3 -methoxyj-1 -propylene

Compound 10 ... N-[4-(4-ethylamino-1 -oxoacetic acid benzene) ethoxy j-1 -oxoacetic acid benzene

A compound of Formula I or an intermediate thereof was measured again after the crystalline melting point (MP), and then were measured or elemental analysis, mass spectrometry (MS), infrared spectroscopy (IR), proton nuclear magnetic resonance spectroscopy ⁽¹ H via the product of the purification process - NMR , CDCI ₃ ), ultraviolet absorption (UV) and other physical and chemical data can show that the compound has a clear structure.

Compounds 1 to 4 at different doses (1.0, 1.5, 3.0 mg / kg) can significantly reduce the heart rate in a dose-dependent manner, and the action time lasts for more than 1 hour; all of them produce a continuous blood pressure drop effect. In guinea pig isolated thoracic aorta, the contractile effect produced by administration of 10 μM L-phenylene 1 to 4 and the relaxation effect is shown in Table 2 and shows a dose-related phenomenon. In guinea pig isolated right atrium and left atrium, the cumulative administration of isoproterenol can increase the right atrial beating frequency and left atrial contractility, and compounds 1 to 4 at concentrations of 10 · ⁷ , 1 (Γ ⁶ and 10 · ⁵ Μ there is competitive inhibition of isoproterenol by the action of table 3 that the compound curve Schild 1 - 4 increase in the beating rate of the right atrium and isoproterenol antagonizing contractile force of the left atrium of pA ₂ value.

Various excipients are added to the compound of the present invention, such as magnesium stearate, corn flour, starch, lactose, sodium carboxymethyl cellulose, ethanol, glycerol, etc., or diluents, lubricants, flavoring agents, disintegration Agents, binders, or colorants, sweeteners are used to make lozenges or other solid preparations, and phosphate buffers can be used to adjust the pH value to make injections or other liquid preparations and various dosage forms. The solid dosage forms include tablets, lozenges, powders, capsules, sublingual tablets, granules, and the like. The composition of such dosage forms is an effective amount of injection, eye drops, or various liquid administration forms. The general dosage can be adjusted according to the symptoms, usually 50mg to 300mg per person, 3 times a day.

Discussion on pharmacological effects

Discussion on the effects of heartbeat and blood pressure

Male rats (Wistar strain) weighed 300 to 450 grams, were anesthetized with subcutaneous injection of sodium pentobarbital at 40 mg / kg, and then underwent tracheotomy, and the catheter was inserted to keep the experimental animals breathing smoothly, which is also conducive to first aid. Insert a polyethylene tube (PE50) with an inner diameter of 0.85mm and an outer diameter of 0.97mm into the femoral vein to facilitate the administration of experimental drugs; use a three-way stopcock, one end of which is connected with a syringe filled with drugs; the other end is filled with physiological salt In the water injection cylinder, a small amount of physiological saline can be injected immediately after the drug is administered to prevent the drug from staying in the polyethylene tube (PE50) and affecting the accuracy of the experiment. A polyethylene tube (PE50) was also inserted into the left femoral artery, and a three-way biopsy was used. One end was connected to a heparin solution. When a polyethylene tube (PE50) had an embolus, it could be used to unblock the tubing. Disposable Diaphragm Dome (TA1019), and then connected to the converter, through the amplifier, and finally recorded the effect of drugs on blood pressure and heartbeat of rats by a recorder. Rats were administered test drugs at different doses of 1.0, 1.5, and 3.0 mg / kg via the femoral vein, and the effects of the drugs on heartbeat and blood pressure were explored. result

Rats with normal blood pressure after anesthesia with sodium pentobarbital were administered different doses of test drugs from the femoral vein to observe the effects on heartbeat and blood pressure. The results are shown in Table 1. Compounds 1 to 4 at different doses (1.0, 1.5, 3.0 mg / kg) can significantly reduce the heart rate in a dose-dependent manner, and the duration of action lasts for more than 1 hour; it also produces blood pressure. Continuous blood pressure drop.

Evaluation of vascular relaxation in guinea pigs in vitro

Take 300-450 grams of guinea pigs, knock them from the head with force, and then bleed from the carotid arteries. Quickly remove the thoracic aorta, place them in ice-cold Krebs solution, and carefully remove the fatty connective tissue around the blood vessel wall. The thoracic aorta was cut into a 5mm long ring, and the aortic ring was fixed up and down with two "H" platinum wires. It was placed in a 10 ml tissue trough with 95% oxygen and 5% carbon dioxide gas mixture. One end It is fixed at the bottom of the tissue groove, and the other end is connected with a force transducer, and the isometric contraction is recorded by a recorder. The specimen was given 1 gram of tension. After equilibration for 60 minutes, 10 μM phenylephrine was first given to test the activity of the thoracic aorta. After it was equilibrated, the phenylephrine was washed away, and then 10 μM phenylephrine was used to achieve maximum contraction. wait until the equilibrium given different concentrations of test compound ^(10-5 or lO or 10 · ⁷ Μ), observe the inhibitory effect of different concentrations of test compound caused.

The result

The contractile effect of 10 μM L-phenylephrine administered to guinea pig isolated thoracic aorta will be produced as shown in Table 2 by the administration of 1 (T ⁶ , 10 ^-5 and 1 (T ⁴ Μ compounds 1 to 4). The effect of relaxation and presents a dose-related phenomenon.

Discussion on the inhibitory effect of ₃₁ adrenergic response

(1) Guinea pig right atrium experiment

Take a guinea pig weighing 300-450 grams, knock the head hard to faint, then cut off the carotid artery to bleed, then immediately cut the chest cavity, quickly remove the entire heart, and place it at room temperature (20 ~ 25 ° C). Gas (95% oxygen, 5% carbon dioxide) in Krebs solution, separate the left and right chambers. Take the spontaneously beating right atrium, clamp both ends with frog heart clips, and fix one end to the bottom, put it in a gas-filled and contain 10 ml Krebs solution In a fluid tissue bath, the temperature is maintained at 32.5, and the other end is connected to a force converter, and the right atrium isometric contraction and beating frequency are recorded by a recorder (COULBOURN AT-High-Speed Videograph). Specimens are given a tension between 100 and 150 mg. After equilibration, perform the following experiments:

(a) Preparation of cumulative concentration response curve

To evaluate the beta-blocking activity of the test compound, each spontaneous beating of the right atrium after equilibrium (approximately 60 minutes) requires two separate cumulative concentrations of β-agonist isoproterenol. The experimental design is as follows: <1> The first curve directly gives isoproterenol from low concentration to high concentration, and increases in order of 0.5 log units until the maximum response is reached; this is the control group. <2> The second curve is the experimental group. Administered to various concentrations of test compound ^(10-7 or 10 · ⁶ or 1 (T ⁵ M; at different concentrations from low concentrations to high concentrations), dried for 30 minutes, then complete the isoprenaline cumulative administration. The inhibitory effect of the test compound can be obtained as an EC ₅ value.

(b) Calculation of pA ₂ value

According to the method of Arunlakshana and Schild in 1959, the logarithmic value of the concentration of the test compound is used as the horizontal coordinate, and the logarithmic value of the dose ratio ¹ which achieves the same effect is used as the vertical coordinate. The obtained data are plotted and linear regression is performed. The abscissa intercept value of a regression line can be obtained, that is, the pA ₂ value of the test compound.

(2) Guinea pig left atrium experiment

A left atrium that does not spontaneously beat was obtained from an isolated right atrium experiment of guinea pigs. Under the same conditions, the left atrium was stimulated with a square wave with a width of 5 msec slightly greater than the threshold voltage of about 1 volt and caused a contractile response. Stimulation frequency is 0.5Hz and resting tension is 0.5g. After equilibration (about 50 minutes), perform the following experiments:

(a) The cumulative concentration response curve was made in the same way as the isolated right atrium.

(b) The calculation of pA ₂ value is the same as that of the right atrium experiment.

Results of inhibition of ₁ adrenergic response

In guinea pig isolated right atrium and left atrium, the cumulative administration of isoproterenol can increase the right atrial beating frequency and left atrial contractility, and compounds 1 to 4 at concentrations 1 (T ⁷ , 10 ⁶ and · 1 (Τ ⁵ Μ) Can competitively inhibit the effect of isoproterenol. Following from Table 3 According to the Schild curve, the pA ₂ value of compounds 1 to 4 on the effect of isoproterenol on the increase of the beating frequency of the right atrium and the contraction force of the left atrium was obtained.

Inhibition of β ₂ Adrenergic Response

Take guinea pigs weighing 300-450 grams, and give intraperitoneal injection of reserpine 5mg / kg 18-24 hours before the experiment. After the guinea pig was stunned, the carotid artery was cut off to bleed, and then the chest cavity was immediately cut off. The trachea (about 4 cm in length) was removed along the neck and placed at room temperature (about 22 ~ 25 °). 5% carbon dioxide) in Krebs solution, carefully remove the surrounding tissue, then cut the trachea into a spiral with three to four cartilage ring knots per turn, divide it equally, and clamp the ends with a frog heart clamp One end is fixed to the bottom, placed in a tissue bath filled with air mixture and containing 20 ml of Krebs solution, the temperature is maintained at 32.5 "C, and the other end is connected to a power converter via a recorder (COULBOURN AT-High-Speed Videograph ) Record the isometric contraction tension. The specimen is given a tension of 2 grams, and the following experiments are performed after equilibration.

(a) Cumulative concentration response curve

In the experiment, the trachea was first equilibrated (about 1 hour) to obtain the spontaneous tension, and then each aliquot of the trachea completed a second cumulative concentration-response curve of isoproterenol, in which the first curve was not added with the test compound as a control group. ; The second curve is after adding the test compound for 1 hour before performing the cumulative concentration response curve; this is the experimental group.

(b) Calculation of pA ₂ value

Calculation method of the right atrium experiment.

Results of the drug's response to β ₂ adrenergics

Resulting in spontaneous tension guinea pig isolated trachea, the cumulative administration of isoproterenol can have an effect trachea tension relaxation, Compounds 1 to 4 at a concentration of 1 (Γ ^6, 10 ⁵ and 1 (Γ ⁴ Μ lower, It can competitively inhibit the effect of isoproterenol, and then the Schild curve of Table 3 shows the pA ₂ value obtained by antagonizing the relaxant action of isoproterenol in the ex vivo trachea test drug.

Discussion on the inhibitory effect of α-adrenergic response

(a) Cumulative concentration response curve:

In the same vascular relaxation experiment, the isolated thoracic aorta of the guinea pig was removed and given 1 g of tension. After 60 minutes of equilibration, L-phenylephrine was directly administered from low concentration to high concentration, and increased in increments of 0.5 lo units until the maximum response was reached; this is the control group. Then, test compounds of different concentrations (10 · ⁷ or 1 (Γ ⁶ or 10 · ⁵ Μ) were given. After 30 minutes of action, cumulative administration was completed with L-phenylephrine, and the effects of test compounds at different concentrations were observed. Inhibition results in ECso values.

(b) Calculation of pA ₂ value:

Calculation method of the right atrium experiment.

Results of inhibition of α-adrenergic response

In the guinea pig thoracic aorta, cumulative dose L - phenylephrine can cause vascular contraction effect, the test drug concentrations ^10-6, ^10-5 and 1 (Γ ⁴ Μ at competitive can inhibit the L -The effect of phenylephrine, and the SchiW curve in Table 3 was used to determine the pA ₂ value obtained by testing the drug against the contractile effect of L-phenylephrine in isolated blood vessels.

Example 1

Synthesis of epoxy compounds

8 g of sodium hydroxide was dissolved in 100 ml of absolute ethanol, and 1 mol of 4-hydroxy-3 -methoxy-1 -propenylbenzene was dissolved in the above-mentioned ethanol solution containing sodium hydroxide, and the mixture was stirred at room temperature. Another 5 moles of epichlorohydrin was added, and the reaction was carried out at room temperature. It was determined whether the reaction was complete by thin layer chromatography (TLC).

After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrate was packed in a silica gel column, and hexane: ethyl acetate = 1: 9 was used as an eluent to separate and obtain white crude crystals. Repeated recrystallization from hexane. A purified N- [4- (2,3-epoxypropoxy) -3-methoxy] -1-propenylfluorene was obtained.

Example 2

Take 1 mole of ferulic acid, add an excess of absolute ethanol, and boil for 48 hours under heating. Add a small amount of sulfuric acid as a catalyst before heating. Thin layer chromatography (TLC) was used to determine whether the reaction was complete. After the reaction is completed, an aqueous sodium hydroxide solution is added to adjust the pH value to reach neutrality. After concentration under reduced pressure, it is recrystallized with methanol to obtain 4-hydroxy-3 -methoxymethoxycinnamate ethyl ester 0.2 moles of 4-hydroxy-3 ―Ethyl methoxycinnamate and 0.4 mole of dibromoethyl The alkane was placed in a three-necked flask and heated to boiling. After stirring, 125 ml of 1.6N sodium hydroxide was added within 30 minutes, and the mixture was stirred with heating until the layers were separated. After heating overnight, TLC was used to determine if the reaction was complete. The organic layer was repeatedly extracted with chloroform, and the organic layer was washed with 300 ml of 2N sodium hydroxide. Anhydrous sulfuric acid was added to stand overnight. After filtration, the solution was concentrated under reduced pressure. Separated with a silica gel-packed column, and hexane: ethyl acetate = 9: 1 was used as the eluent to obtain the intermediate 4-ethylethylbromo-3 monomethoxycinnamate.

After mixing an equal molar amount of ethyl 4-oxyethyl bromide 3-methoxycinnamate with potassium phthalimide, dissolve it in dimethylformamide, increase the temperature to 55 within five minutes and continue to maintain After thirty minutes, the temperature was lowered to room temperature. The organic layer was extracted with chloroform, washed with 0.2N sodium hydroxide, and anhydrous magnesium sulfate was added. After standing overnight, it was filtered and concentrated under reduced pressure. Recrystallization gave the intermediate 4-ethylethylphthalimide-3 ethyl methoxycinnamate.

Dissolve equimolar ethyl 4-oxyethylphthalimide-3 monomethoxycinnamate and hydrazine hydrate in absolute ethanol and heat to boiling for 45 minutes. Adding an appropriate amount of 18% hydrochloric acid produced a white precipitate. The white precipitate was removed by filtration, and the filtrate was washed with absolute ethanol. The filtrate was concentrated under reduced pressure, and then washed with 20% sodium hydroxide. After extraction with chloroform, the organic layer was taken, and anhydrous magnesium sulfate was added to stand overnight. After filtration, it was concentrated under reduced pressure to obtain ethyl 4-oxyethylamine-3 -methoxycinnamate.

Example 3

Synthesis of compound 5

Mix equal moles of 4-oxoethylamine-3 -methoxymethoxycinnamate with N-[4-(2, 3 -epoxypropoxy)-3 -methoxy]-1 -propenylbenzene Dissolve in 100 ml absolute ethanol, slightly increase the temperature for the amination reaction. After stirring overnight, it was allowed to stand to obtain white crystals, and the purified compound was obtained by recrystallization from methanol, N-[4-(2 -hydroxy-3-(4-oxoethylamino-3 -methoxycinnamate) propoxylate) Group) -3-methoxy] -1-propanylbenzene.

Dissolve an appropriate amount of sodium hydroxide in 0.1% acetone, and then dissolve it in N-[4-(2-hydroxy-3-(4-oxyethylamino-3 -methoxymethoxycinnamate) propoxy)-3- Methoxy I-1 -propenylbenzyl, heated to boiling, and measured by TLC Whether completely. The product was packed in a silica gel column and separated with an eluent of ethyl acetate: methanol = 1: 1 ratio, and the compound N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methyl) was obtained after purification. Oxycinnamic acid) propoxy)-3 -methoxy]-1 -propenylbenzyl.

Example 4

Synthesis of another epoxy compound

Weigh 10 grams (34 mmol) of N-vanillin nonanamide (Nonivamide), soak in an appropriate amount of absolute alcohol, and add equimolar sodium hydroxide. After reacting for 3 hours at 80, add 5 times molar epichlorine The alcohol was refluxed at room temperature for 2 hours; after the reaction, it was concentrated under reduced pressure, heated and dissolved, and filtered. The filtrate was allowed to stand overnight. The obtained crude crystals were recrystallized with absolute alcohol to obtain purified white crystals N-[4-(2, 3 -Epoxypropoxy) -3-methoxybenzyl] -nonanamide.

Example 5

Synthesis of compound 6

5 g (14.3 mol) of purified N-[4-(2, 3 -epoxypropoxy)-3 -methoxybenzyl] monononamide was dissolved in anhydrous methanol, and 3 times mol of Ethyl 4-oxyethylamine-3-methoxybenzoate was refluxed under nitrogen at 55 X for 4 hours; the resulting solution was directly concentrated under reduced pressure. After hot filtration, the filtrate was left to stand overnight. The crude crystal was repeatedly recrystallized with methanol to become a purified white crystal, that is, the compound N-[4-(2-hydroxy-3-(4-oxyethylamino-3-methoxybenzoate) propoxy)- 3-methoxybenzyl 1 nonanamide.

The purified compound N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxymethoxyethyl) propoxy)-3 -methoxybenzyl] -nonanamide Soluble in sodium hydroxide and acetone solution, stir and heat to 80 ° C for 2 hours, directly condense the solution under reduced pressure, and obtain crude crystals after standing; then recrystallize with methanol to obtain white crystals, namely compound N-[4 -(2-hydroxy-3-(4-oxoethylamino-3 -methoxybenzoic acid) propoxy)-3-methoxybenzyl]-nonamidamine.

Example 6

Take 1 mole of vanillic acid, add excess ethanol, boil for 48 hours with heating, add Add a small amount of sulfuric acid as a catalyst before heating. Thin layer chromatography (TLC) was used to determine whether the reaction was complete. After the reaction is completed, an aqueous sodium hydroxide solution is added to adjust the pH value to reach neutrality, and the solution is concentrated under reduced pressure, and then recrystallized with methanol to obtain 4-hydroxy-3 monomethoxybenzylformate.

Take 0.2 mol of 4-hydroxy-3 -methoxybenzylformate and 0.4 mol of dibromoethane in a three-necked flask and heat to a boil. After stirring, add 125 ml of 1.6N sodium hydroxide within 30 minutes, heat Stir until separated. After heating overnight, TLC was used to determine if the reaction was complete. The organic layer was repeatedly extracted with chloroform, and the organic layer was washed with 300 ml of 2N sodium hydroxide. Anhydrous magnesium sulfate was added to stand overnight. After filtration, the solution was concentrated under reduced pressure. Separation was performed on a silica gel-packed column, and hexane: ethyl acetate = 9: 1 was used as an eluent to obtain an intermediate product, 4-oxoethylbromo-3-methoxymethoxyethyl carboxylate.

After mixing equal molar amounts of ethyl 4-oxyethyl bromide 3-methoxybenzoate and potassium phthalimide, dissolve with dimethylformamide, increase the temperature to 55 C within 5 minutes and continue After maintaining for 30 minutes, the temperature was lowered to room temperature. The organic layer was extracted with chloroform, washed with 0.2N sodium hydroxide, and anhydrous magnesium sulfate was added. After standing overnight, it was filtered and concentrated under reduced pressure. Recrystallization gave the intermediate 4-ethylethylphthalimide- 3-methoxybenzoate.

Dissolve an equimolar amount of ethyl 4-oxoethylbenzimide-3 -methoxybenzoate and hydrazine hydrate in absolute ethanol and heat to boiling for 45 minutes. Adding an appropriate amount of 18% hydrochloric acid produced a white precipitate. The white precipitate was removed by filtration, and the filtrate was washed with absolute ethanol, concentrated under reduced pressure, and then washed with 20% sodium hydroxide. After extraction with chloroform, the organic layer was taken, and anhydrous magnesium sulfate was added to stand overnight. After filtration, it was concentrated under reduced pressure to obtain 4-oxoethylamine-3 -methoxybenzoic acid ethyl ester.

Example 7

Synthesis of compound 7

The purified N-[4-(2, 3-epoxypropoxy)-3-methoxy]-1-propylene was dissolved in 100 ml of absolute ethanol, and an equimolar amount of 4 monooxyethyl was added. Amine-3-methoxybenzoate. Raise the temperature slightly for the amination reaction. After stirring overnight, it was allowed to stand to obtain solid white crystals. After recrystallization from methanol, purified white crystals were obtained, that is, the compound N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -Ethyl methoxy benzoate) propoxy)-3-methoxy]-1-propylene.

The purified compound was dissolved in a 10% acetone-containing sodium hydroxide solution, heated to boiling, and determined by TLC to determine whether the reaction was complete. The product was packed in a silica gel column and separated with an eluent having a ratio of ethyl acetate: methanol = 1: 1, and the compound N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3- Methoxybenzylcarboxylic acid) propoxy)-3 -methoxy]-1 -propenebenzyl.

Example 8

Synthesis of compound 8

5 g (14.3 mol) of purified N-[4-(2, 3 -epoxypropoxy)-3 -methoxybenzyl] -nonanamide was dissolved in anhydrous methanol, and then 3 times moles were added. The 4-oxoethylamine-3 -methoxymethoxycinnamate was refluxed under nitrogen at 55 "for 4 hours; the resulting solution was directly concentrated under reduced pressure. After hot filtration, the filtrate was allowed to stand overnight to obtain The crude crystals were repeatedly recrystallized from methanol to become purified white crystals, namely the compound N-[4-(2-hydroxy-3-(4-oxyethylamino-3 -methoxymethoxycinnamate) propoxy)- 3-methoxybenzyl] -nonanamide.

The purified compound is dissolved in sodium hydroxide acetone solution, stirred and heated to 80 for 2 hours, and the reaction solution is directly concentrated under reduced pressure. After standing, crude crystals are obtained; and then recrystallized with methanol to obtain white crystals, that is, Compound N-[4-(2-hydroxy-3-(4-oxyethylamino-3 -methoxymethoxycinnamic acid) propoxy) -3-methoxybenzyl] -nonanamide.

Example 9

Synthesis of 2- (2-methoxyphenoxy) ethylamine

Take 0.2 mol (22.4 ml) of guaiacol and 0.4 mol (34.6 ml) of dibromoethane, heat to 100 ° C and stir vigorously, add 125 ml of 1.6N sodium hydroxide solution within 30 minutes, continue to heat and stir and Adjust the pH to reach 7, after cooling, the mixture was extracted with chloroform, the organic layer was washed with 2N sodium hydroxide, and then washed with saturated sodium chloride solution and magnesium sulfate. After concentration, the liquid was separated on a silica gel packed column, and Hexane: ethyl acetate = 9: 1 was used as the eluent to obtain a white crystalline product (2- (2-methoxybenzyloxy) ethyl bromide). 36 g (0.156 ml) of 2- (2-methoxyphenoxy) ethyl bromide and 27.3 g (0.186 mol) of phthalimide were dissolved in 100 ml of dimethylacetamide, and the mixture was heated under reflux with stirring. To 90. After 30 minutes, dissolve 10.45 g (0.186 mol) of potassium hydroxide in 30 ml of methanol, add to the mixture and heat to reflux for 1.5 hours. After cooling, pour the mixture into 300 ml of water. Filter the precipitated solid and add 10 200% potassium carbonate solution, heated and stirred to filter the obtained mud, washed with water several times, and recrystallized from anhydrous alcohol to obtain a white crystalline product.

Dissolve 21 g (0.071 mol) of the above product and 3.55 g (0.071 mol) of hydrazine hydrate in 70 ml of absolute alcohol, heat to reflux for 45 minutes, add 20 ml of 18% hydrochloric acid solution to the mixture and continue refluxing for 1 hour. Cool, filter and concentrate the residue to make it alkaline with 20% sodium hydroxide solution, and then extract with chloroform. After filtration, concentrate under reduced pressure, separate with a column packed with silica gel, and use ethyl acetate as the eluent to obtain Oily products 2

-(2-methoxyphenoxy) ethylamine.

Example 10

Synthesis of compound 1

Add 1 mole of 4-hydroxy-3 -methoxy-3 -propenylbenzene to a reaction flask containing 900 ml of ethanol, add equimolar sodium hydroxide, react at 70 ° C for 1 hour, and then add 5 times mole Epichlorohydrin was refluxed under the same conditions for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure. The concentrated solution was packed in a silica gel column, and hexane: ethyl acetate = 1: 9 was used as an eluent. White crystals were separated and obtained.

0.03 moles of N-[4-(2, 3-epoxypropoxy)-3-methoxy]

-3-propenylbenzene and 5.0 g (0.03 mol) of 2- (2-methoxyphenoxy) ethylamine were dissolved in 30 ml of absolute alcohol and stirred at room temperature for 2 hours to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated solution was separated on a column packed with silica gel, and concentrated to obtain a white crystalline product. Take an appropriate amount of sodium hydroxide in 0.1% acetone, dissolve the above white crystalline product, heat to boiling, and determine whether the reaction is complete by thin layer chromatography (TLC). The product was packed in a silica gel column and separated with an eluent having a ratio of ethyl acetate: methanol = 1: 1, and purified to obtain 1-[(4-allyl-2 -methoxy) phenoxy]-3- [(2-methoxyphenoxyethyl) amino1-propanol. Example 11

Synthesis of compound 3

0.03 moles of N-[4-(2, 3-epoxypropoxy)-3 -methoxybenzyl 1 -nonanamide and 0.09 moles of 2-(2-methoxybenzyloxy) ethylamine Dissolve in 30 ml of absolute alcohol and stir for 2 hours at room temperature to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated solution was separated on a column packed with silica gel, and concentrated to obtain a white crystalline product. Take an appropriate amount of sodium hydroxide in 0.1% acetone, dissolve the above white crystalline product, heat to boiling, and determine whether the reaction is complete by thin layer chromatography (TLC). The product was packed in a silica gel column and separated with an eluent of ethyl acetate: methanol = 1: 1 ratio, and after purification, 1-[(4-nonanamide-2 -methoxy) benzyloxy]-3-[ (2-methoxyphenoxyethyl) amino] -propanol.

Example 12

Synthesis of compound 2

Take 1 mole of ferulic acid, add a small amount of sulfuric acid as a catalyst and excess anhydrous ethanol, and heat to boil for 48 hours. TLC was used to determine whether the reaction was complete. After completion of the reaction, an aqueous sodium hydroxide solution was added to adjust the pH to reach neutrality, and the solution was concentrated under reduced pressure to recrystallize with methanol to obtain 4-hydroxy-3 -methoxycinnamate ethyl ester.

One mol of the above product was dissolved in 100 ml of absolute ethanol containing sodium hydroxide, and stirred at room temperature. 5 moles of epichlorohydrin was added to carry out the reaction at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The concentrated solution was packed in a silica gel column, and hexane: ethyl acetate = 1; Recrystallization from hexane was repeated to obtain purified N- [4- (2,3-epoxypropoxy) -3-methoxycinnamate.

0.03 moles of N-[4-(2, 3-epoxypropoxy)-3 -methoxycinnamate ethyl ester and 0.03 moles of 2-(2-methoxyphenoxy) ethylamine were dissolved In 30 liters of absolute alcohol, stir for 2 hours at room temperature to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated solution was separated on a column packed with silica gel, and concentrated to obtain a white crystalline product. Take an appropriate amount of sodium hydroxide in 0.1% acetone, dissolve the above white crystalline product, heat to boiling, and determine whether the reaction is complete by thin layer chromatography (TLC). The product was packed in a silica gel column and separated with an eluent of ethyl acetate: methanol = 1: 1 ratio. After purification, 1- [(4--Ethyl acrylate-2-methoxy) benzyloxy] -3-[(2-methoxybenzyloxyethyl) amino] -propanol.

Example 13

Synthesis of compound 4

Dissolve an equimolar amount of N-[4-(2, 3-epoxypropoxy)-3-methoxy]-3-propenylbenzene and 2-(2 -methoxybenzyloxy) ethylamine Stir in 30 ml of absolute alcohol for 2 hours at room temperature to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated condensate was separated on a column packed with silica gel, and concentrated to obtain a white crystalline product. Take an appropriate amount of sodium hydroxide in 0.1% acetone, dissolve the white crystal product above, heat to boiling, and determine whether the reaction is complete by thin layer chromatography (TLC). The product was packed in a silica gel column and separated with an eluent having a ratio of ethyl acetate: methanol = 1: 1, and 1-[(4-propenyl-2-methoxy) phenoxy)]-3-was obtained after purification. [(2-methoxybenzyloxyethyl) amino] -propanol.

Example 14

Synthesis of compound 9

0.2 moles of 1,4-dihydroxybenzene and equimolar bromoacetic acid were heated to boiling, and the reaction was determined to be complete by thin layer chromatography (TLC). After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and separated on a silica gel-packed column. Methanol: ethyl acetate = 2: 8 was used as an eluent to obtain 4-oxoacetic acid phenol as an intermediate product.

0.4 moles of 4-oxoacetic acid benzylphenol and 0.4 moles of dibromoethane were placed in a three-necked flask and heated to boiling. After stirring, 1.6 L of sodium hydroxide (125 N) was added, and the reaction was measured by thin layer chromatography (TLC). Whether completely. The organic layer was repeatedly extracted with chloroform, and the organic layer was washed with 300 ml of 2N sodium hydroxide. Anhydrous magnesium sulfate was added to stand overnight. After filtration, the solution was concentrated under reduced pressure. Separation was performed on a silica gel-packed column, and hexane: ethyl acetate = 9: 1 was used as an eluent to obtain 4-oxyacetic acid benzyloxyethyl bromide.

After mixing 4-oxyacetic acid oxyethyl bromide and equimolar potassium phthalimide, dissolve in dimethylformamide, increase the temperature to 55 C in 5 minutes, and continue to cool for 30 minutes. Room temperature. The organic layer was extracted with chloroform, washed with 0.2N sodium hydroxide, and anhydrous magnesium sulfate was added. After standing overnight, it was filtered and concentrated under reduced pressure. Recrystallization can be obtained Intermediate 4-oxyacetic acid, phenoxyethylphthalimide.

An equimolar amount of 4-oxoacetic acid phenoxyethylphthalimide and hydrazine hydrate were dissolved in absolute ethanol and heated to boiling for 45 minutes. Adding an appropriate amount of 18% hydrochloric acid produced a white precipitate. The white precipitate was removed by filtration, and the filtrate was washed with absolute ethanol, concentrated under reduced pressure, and then washed with 20% sodium hydroxide. The organic layer was extracted with chloroform, and anhydrous magnesium sulfate was added to stand overnight. After filtration, it was concentrated under reduced pressure to obtain 4-oxoacetic acid phenoxyethylamine.

Mix N-[4-(2, 3 -epoxypropoxy)-3 -methoxy 1-1-propenyl benzyl and equimolar 4 -oxoacetic acid phenoxyethylamine, soluble in absolute alcohol In 100 ml, it was stirred at room temperature for 2 hours to carry out the amination reaction. The mixture was concentrated under reduced pressure to determine whether the reaction was complete. The product was allowed to stand overnight, and filtered and concentrated under reduced pressure to obtain N-[4-(2 -hydroxy-3-(4 -oxoacetic acid phenoxyethylamino) propoxy) -3 -methoxy I-1 -propene. benzene.

Example 15

P-hydroxybenzaldehyde and equimolar nitromethane were heated to boiling, and thin layer chromatography (TLC) was used to determine whether the reaction was complete. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and separated on a column packed with silica gel. Hexane: ethyl acetate = 7: 3 was used as the eluent to obtain 4-ethylnitrophenol as an intermediate product.

Add 4-ethylnitrophenol to an appropriate amount of zinc powder and acetic acid, dissolve it in anhydrous alcohol, heat and boil, and determine whether the reaction is complete by thin layer chromatography (TLC). After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the product was allowed to stand overnight to obtain 4-ethylaminophenol. It was then boiled with equimolar bromoacetic acid to determine whether the reaction was complete by thin layer chromatography (TLC). After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the product was allowed to stand overnight to obtain 4-ethylamino-1 -oxoacetic acid benzene as an intermediate product.

Example 16

Synthesis of compound 10

Take 1 mole of 4-oxoacetic acid benzylphenol, add a small amount of sulfuric acid as a catalyst and excess anhydrous ethanol, and heat to boil for 48 hours. After the reaction is completed, an aqueous sodium hydroxide solution is added to adjust the pH value to reach neutrality, and the solution is concentrated under reduced pressure, and then recrystallized with methanol to obtain 4-oxoethyl acetophenone.

Place 0.2 moles of 4-oxoacetic acid benzylphenol and 0.4 moles of dibromoethane on three necks The bottle was heated to boiling, and after stirring, 125 ml of 1.6N sodium hydroxide was added, and it was determined whether the reaction was complete by thin layer chromatography (TLC). The organic layer was repeatedly extracted with chloroform, and the organic layer was washed with 300 L of 2N sodium hydroxide. Anhydrous magnesium sulfate was added to stand overnight, filtered, and concentrated under reduced pressure. Separation was performed on a silica gel-packed column, and hexane: ethyl acetate-9: 1 was used as an eluent to obtain 1-oxyethyl bromide 4-4-ethyl acetate benzene.

Mix 4-ethylamino-1 -oxoacetic acid benzene with equimolar 1-oxoethylbromo-4 -oxoacetate, dissolve in 100 ml of absolute alcohol, and stir at room temperature for 2 hours to carry out amination . The mixture was concentrated under reduced pressure to determine whether the reaction was complete. The product was allowed to stand overnight, and then filtered and concentrated under reduced pressure to obtain N- [4- (4-ethylamino-1-oxoacetic acid benzene) ethoxy] -1-oxoethyl acetate benzene.

Example 17

Compound 1 lozenge

Compound 1 50mg

Lactose 30mg

Starch 4mg

Magnesium stearate 6mg

Corn flour 10mg

According to the above formula, a lozenge dosage form containing Compound 1 can be prepared.

Table 2 Vasodilation

a: contrast

Table 4 Physical and chemical data of the compounds

Ν-[4-(2, 3 -epoxypropoxy)-3 -methoxy]-1 -propaneamidine

^Χ Η-NMR (CDC1 ₃ )

δ: 1.846 ~ 1.886 (d, 3H, Ar-CH = CH-CH ₃ ),

2.76 ~ 2.92 (m, 2H, Ar O-CH ₂ -HCACH ₂ ),

3.34 ~ 3.42 (m, 1H, Ar-0-CH ₂ -HCACH ₂ ),

3.882 (s, 3H, Ar-0-CH ₃ ),

4.05-4.09 (t, 4H, Ar-0-CH _2- ),

6.02-6.41 (m, IH, Ar-CH = CH-CH ₃ ),

6.842-6.893 (m, 3H, Ar-H),

7.262 (s, 1H, Ar-CH = CH-CH ₃ ) MS m / s: 220 (Scan EI +)

Elemental analysis (C ₁₃ H ₁₆ 0 ₃ ) (C, H, N)

4-Oxyethylbromo-3 -methoxymethoxycinnamate

XH-Bandit R (CDCI ₃ )

δ: 1.313-1.361 (t, 3H, Ar-CH = CH-COO-CH ₂ -C | ₃ ),

3.646 ~ 3.690 (t, 2H, Ar-0-CH ₂ -CH ₂ -Br),

3.901 (s, 3H, Ar-O CH ₃ ),

4.225 ~ 4.297 (m, 2H, Ar-O CH ₂ -CH ₂ -Br),

4.338-4.383 (t, 2H, Ar-CH = CH-COO-CH ₂ -CH ₃ ), 6.296-6.349 (d, 1H, Ar-CH = CH-COO-CH ₂ -CH ₃ ), 6.873 ~ 7.262 ( m, 3H, Ar-H),

7.595-7.647 (d, lh, Ar-CH = CH-COO-CH2-CH ₃ ), MS m / s: 328 (Scan EI +),

mp: 76.1-77.6

UV (CH ₃ OH) max (log8): 292 (4.27), 320 (4.33) nm,

Elemental analysis (C ₁₄ H ₁₇ 0 ₄ Br) (C, H, N)

4-Oxyethylphthalimide

JH-NMR (CDC1 ₃ )

δ: 1.304-1.352 (t, 3H, Ar-CH = CH-COO-CH ₂ -CH ₃ ),

3.796 (s, 3H, Ar-O CH ₃ ),

4.120-4.160 (t, 2H, Ar-0-CH ₂ -CH ₂ -N-),

4.216-4.250 (m, 2H, Ar-0-CH ₂ -¾-N-),

4.263 ~ 4.334 (m, 2H, Ar-CH = CH-COO-CH ₂ -CH ₃ ), 6.259-6.313 (m, 1H, Ar-CH = Cg-COO-CH ₂ -CH ₃ ), 6.902 ~ 7.880 ( m, 7H, Ar-H),

7.563-7.617 (m, 1H, Ar-CH = CH-COO-CH ₂ -CH ₃ ), MS m / s: 395 (Scan EI +), mp: 98.9 ~ 101.1 X

UV (CH ₃ OH) max (log £): 295 (4.22), 321 (4.27) nm,

Elemental analysis (C ₂₂ H ₂₁ 0 ₆ N) (C, H, N)

4-oxoethylamine-3 -methoxymethoxycinnamate

1 1-Bandit R (CDC1 ₃ )

δ: 1.313-1.361 (t, 3H, Ar-CH = CH-COO-CH ₂ -CH ₃ ),

3.122-3.157 (t, 2H, Ar-0-CH ₂ -CH ₂ -NH ₂ ),

3.892 (s, 3H, Ar-O CH ₃ ),

4.060-4.094 (m, 2H, Ar-0-CH ₂ -NH ₂ ),

4.224-4.296 (m, 2H, Ar-CH = CH-COO-CH ₂ -CH ₃ ),

6.286 ~ 6.339 (d, 1H, Ar-CH = CH-COO-CH ₂ -CH ₃ ), 6.861-7.095 (m, 7H, Ar-H),

7.598-7.651 (d, 1H, Ar-C = CH-COO-CH ₂ -CH ₃ ),

MS m / s: 265 (Scan EI +),

UV (CH ₃ OH) max (logs): 300 (4.23), 318 (4.33) nni,

Elemental analysis (C ₁₄ H ₁₉ 0 ₄ N) (C, H, N)

(N-[4-(2 -Hydroxy-3-(4 -oxyethylamino-3 -methoxymethoxycinnamate) propoxy)-3 -methoxy 1-1 -propenylbenzene

lR-wake up R (CDCI ₃ )

δ: 1.313-1.360 (t, 3H, Ar-CH = CH-COO-CH ₂ -CH ₃ ), 1.852-1.877 (m, 3H, Ar-CH = CHCH ₃ ),

2.2-2.7 (b, 1H, NH),

2.887 ~ 2.952 (m, 2H, Ar-0-CH ₂ -CH (OH) -CH ₂ -NH-), 3.100 ~ 3.135 (t, 2H, Ar-0-CH ₂ -CH ₂ -N-),

3.838 ~ 3.856 (d, 6H, Ar-0-CH ₃ ^x 2),

4.009 ~ 4.037 (t, 4H, Ar-0-CH ₂ -CH _2- ) _? --

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'(-¾3-¾3 0-JV' Ht ^ ') PSLS' £

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'(-H -¾3- (HO) H3-¾3 0-JtV' HI 90Z6

'( ^£ H3H3 = H3-JV Ή £' Ρ) 8Z £ 8.1 ~ 686Z Ι: 9

(HO D) So-Hi

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(SL 'H' 3) (O ^s ¾ "3) ^^^ a 90l ~ Z'S0I: dm '(+13 UB3S) S8t?: S / ui SIM

'(003-H3 = H3-JV' HI 'P) W9H6S

'(ΪΪ-JV' H9 'ω) £ 80'Δ ~ Z, ε8 · 9

'(-003-H3 = H3-JV' HI '«9S £" 9 ~ € £ e'9

'(¾3 H3 = H3-»V' HI 'P) 0ε · 9 ~ 08Γ9

'( ^C H3-H3 = H3-JV' HI '«69Γ9 ~ εΠ · 9

'( ^c H3-¾3003-H3 = H3-JV ⁽ HZ'"S63 ^ ~ SZ3 ^

'(-HM-¾3- (H0) H3-¾30-JV' HI Ί ") 08ΓΡ ~ 9ΡΓΡ € 100 / 86ND / JLD <I € 6150/00 OA \ UV (CH ₃ OH) max (logs): 264 (4.35), 297 (4.19) nm,

N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxymethoxycinnamate ethyl) propoxy)-3 -methoxybenzyl 1 -nonanamide

^ ― NMR (CDCIs)

δ: 0.87 (t, 3H, -CH ₃ );

1.28 (m, 10H,-(CH ₂ ) 5-);

1.31 (t, 3H, -COCH2-CH3);

1.65 (t, 2H, -CH2-);

2.20 (t, 2H, -CH _2- );

2.55 (br s, 1H, interchangeable, 0 |);

2.95 (m, 2H, -CH ₂ -NH-CH-);

3.11 (t, 2H, -CH (OH) -CH ₂ -NH-);

4.01 (s, 2H, Ar-O CH ₂ -CH _2- );

4.16 (m, 3H, Ar-0-CH ₂ -CH (OH)-);

4.27 (dd, 2H, Ar-COO-CH _2- );

4.37 (m, 2H, Ar-CH _2- );

5.81 (s, 1H, -NH-);

6.30 (d, 1H, Ar-CH = CH-);

6.78 ~ 7.05 (m, 6H, Ar ^x 2);

7.60 (d, 1H, Ar-CH = CH-),

mp 122.5-123.5 'C

UV (MeOH) λ max nm (log ε): 228 (4.40), 285 (4.28), 320 (4.32) MS m / s: 615 (M-)

Elemental analysis C ₃₄ H ₅ . N ₂ 0 ₈

N-[4-(2 -Hydroxy-3-(4 -Oxyethylamino-3 -methoxycinnamic acid) propoxy)-3 -methoxybenzyl] -nonylamine () ,,, .. 88776680m 3H Ar ~-(,, 23 4014.41c43m 2H AroocCH ---- n (,, 2233f 4.390toc 2H ArCHr ---- () ,,, 3.91sH? C 333 Ar- ¾ () ,,, 2r..665309t 2oC 37H ArHcrB-- ~-q¾ () ,,, 2 δ 1.1.7c37041tH ArooC 3H: ~ ---

) .420

3 I MS m / s: 302 (Scan ΕΓ),

mp: 70.9 ~ 71.2 X:

UV (CH ₃ OH) max (logs): 256 (4.08), 291 (3.77) nm, Elemental analysis (C ₁₂ H ₁₅ 0 ₄ Br) (C, H, N)

4-Ethoxyethyl o-benzyldimethylimine-3 ethyl

^X H-NMR (CDC1 ₃ )

δ: 1.353 ~ 1.399 (t, 3H, Ar-COO-CH ₂ -CH ₃ ),

3.826 (s, 3H, Ar-0-CH ₃ ),

4.137 ~ 4.178 (t, 4H, Ar-0-CH ₂ -CH ₂ -N-), 4.307 ~ 4.317 (m, 2H, Ar-O CH ₂ -CH2-N-), 4.330 ~ 4.354 (m, 2H, Ar-COO-CH ₂ -CH ₃ ), 6.913 ~ 7.884 (m, 7H, Ar-H),

MS m / s: 369 (Scan EI +),

mp: 157.1 ~ 158.2 °,

UV (CH ₃ OH) λπΐ3χ (logs): 257 (4.16), 292 (3.51) nm, elemental analysis (C _2. H ₁₉ 0 ₆ N) (C, H, N)

4-oxyethylamine-3 ethyl 3-methoxybenzoate

^-NMR (CDC1 ₃ )

δ: 1.360 ~ 1.407 (t, 3H, Ar-COO-CH ₂ -CH ₃ ),

3.138 ~ 3.172 (t, 2H, Ar-O CH _r ¾-NH ₂ ),

3.883 ~ 3.910 (d, 6H, Ar-O CH ₃ ),

4.079-4.113 (m, 2H, Ar-0-CH ₂ -NH ₂ ), 4.317 ~ 4.388 (m, 2H, Ar-COO-CH ₂ -CH ₃ ), 6.869 ~ 7.670 (m, 3H, Ar-H) ,

MS m / s: 239 (Scan EI +),

UV (CH ₃ OH ^ max (logs): 256 (3.99), 289 (3.73) nm, Elemental analysis (Ci ₂ H ₁₇ 0 ₄ N) (C, H, N)

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13 Bu S.

(z999SV ¾) 9 bu x J ί ~. 0 inch (S09Z9 εΓ0η 1 inch inch) (Η! Μ) ΛοY§ο su XBS3 ..

S8 / I () 8sMJMsaI:

n () (,, 2270i.204m 1HoCcOHC ArHHNH .----- (,, 22 40104.41tHc04oC ArH ~ --- 5 (,, 3d.8413.885〇c 36H Ar 2 ~-X

n (,, 22t.1183.154oC 32HrHcN A ~ ---- ¾ (() ,, 2T.922.957m 29CCOc 28H ArHHHHN ~ ---

(() ,, 25.s 12310HC- 4.323 ~ 4.395 (m, 2H, Ar-COO-CH ₂ -CH ₃ ),

6.052 ~ 6.169 (m, 1H, Ar-CH = CH-CH ₃ ),

6.303 ~ 6.358 (d, 1H, Ar-CH = CH-CH ₃ ),

6.838 ~ 7.670 (m, 6H, Ar-H),

MS m / s: 459 (Scan EI +),

mp: 111.2 ~ 112.6 X :,

UV (CH ₃ OH) max (Ioge): 217 (4.45), 256 (4.39) nm,

Elemental analysis (C ₂₅ H ₃₃ 0 ₇ N) (C, H, N)

N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxybenzoic acid) propoxy)-3 -methoxy]-1 -propenyl

JH-NMR (CDCI ₃ )

δ: 1.7990 ~ 1.8349 (d, 3H, Ar-CH = CHCH ₃ ),

2.6 ~ 2.7344 (m, 2H, Ar-0-CH ₂ -CH (OH) -CH ₂ -NH-),

2.8551 ~ 2.9148 (t, 2H, Ar-0-CH ₂ -C ₂ -N-),

3.7386 ~ 3.7618 (d, 6H, Ar-O CH ₃ ^x 2),

3.8780 ~ 3.9018 (t, 4H, Ar-0-CH ₂ -CH ₂ ),

3.9758 ~ 4.0309 (m, 1H, Ar-0-CH ₂ -CH (OH) -CH ₂ -NH-),

6.0906 ~ 6.2003 (m, 1H, Ar-CH = CH-CH ₃ ),

6.2847 ~ 6.3708 (d, IH, Ar-CH = CH-CH ₃ ),

6.8101 ~ 7.4045 (m, 6H, Ar-H),

MS m / s: 431 (Scan EI +),

UV (CH ₃ OH) max (logs): 254 (3.90) nm,

Elemental analysis (C ₂₃ H ₂₉ 0 ₇ N) (C, H, N)

(1-[(4- 4-propyl- 2 -methoxy) phenoxy 1-3-[(2- 2-methoxybenzyloxyethyl) amino j propanol)

JH-NMR (CDC1 ₃ )

δ: 2.93 ~ 3.16 (m, 4H, CH ₂ -NH-CH ₂ ); 3.31 ~ 3.34 (d, 2H, Ar-CH ₂ );

3.80 ~ 3.83 (m, 6H, OCH ₃ ^x 2);

4.00 ~ 4.03 (m, 2H, Ar-OCH ₂ );

4.13 ~ 4.19 (m, 3H, Ar-OCH ₂ CH (OH));

5.03 ~ 5.12 (m, 2H, -CH = CH ₂ );

5.88 ~ 6.01 (m, 1H, -CH = CH ₂ );

6.68-7.00 (m, 7H, Ar);

MS m / s: 388 (Scan EI ⁺ ),

Elemental analysis C ₂₂ H ₂₉ NO _s ,

mp. 46-48 °.

1-[(4 -Ethyl acrylate-2 -methoxy) benzyloxy]-3-[(2 -methoxyphenoxyethyl) amino I -propanol

^J H-Bandit R (CDC1 ₃ )

δ: 1.30 ~ 1.37 (m, 3H, CH ₃ );

3.13-3.18 (m, 4H, CH ₂ -NH-CH ₂ );

3.77 ~ 3.82 (m, 6H, OCH ₃ ^x 2);

4.06 ~ 4.08 (d, 2H, Ar-OCH ₂ );

4.15-4.19 (m, 3H, Ar-OCH ₂ CH (OH));

4.24 ~ 4.31 (COOCH ₂ );

6.26 ~ 6.36 (d, 1H, Ar-CH = CH);

6.86 ~ 7.09 (m, 7H, Ar);

7.57 ~ 7.65 (d, 1H, Ar-CH = CH);

MS m / s: 446 (Scan EI +).

Elemental analysis C ₂₄ H ₃₁ N0 ₇ ,

mp. 94.6-96.4.

1-[(4 -Nonamide_ 2 -methoxy) benzyloxy]-3-[(2-methoxyphenoxyethyl) amino] -propanol NMR (CDC)

0.80 ~ 0.92 (m, 3H, CH ₃ );

1.27 (s, 10H, CH ₂ x 5);

1.58 ~ 1.72 (m, 2H, CH ₂ );

2.15 ~ 2.26 (m, 2H, CH ₂ );

2.78 ~ 3.11 (m, 4H, CH2-NH-CH2);

3.82 ~ 3.84 (m, 6H, OCH3 x 2);

3.98 ~ 4.02 (m, 2H, Ar-OCH ₂ );

4.06-4.12 (m, 3H, Ar-OCH ₂ CH (OH));

4.34 ~ 4.37 (d, 2H, Ar-CH ₂ )

5.76 (br, 1H, NH);

6.74 ~ 6.91 (m, 7H, Ar);

MS m / s: 517 (Scan FAB +),

Elemental analysis C ₂₉ H ₄₄ N ₂ 0 ₆ ,

mp. 138-139.

1-[(4 -propenyl-2 -methoxy) phenoxy] phenyloxyethyl) amino] -propanol

JH― NMR (CDC1 ₃ )

δ: l.ll ~ 1.25 (m, 3H, CH ₃ );

2.87-3.12 (m, 4H, CH ₂ -NH-CH ₂ );

3.84 (s, 6H, OCH3 x 2);

4.00 ~ 4.14 (m, 2H, Ar-OCH ₂ );

4.00 ~ 4.04 (m, 2H, Ar-OCH ₂ );

4.13 ~ 4.16 (m, 3H, Ar-OCH ₂ CH (OH));

6.04 ~ 6.37 (m, 2H, -CH = CH);

6.84 ~ 6.95 (m, 7H, Ar);

MS m / s: 388 (Scan EI +).

Elemental analysis C ₂₂ H ₂₉ N0 ₅ ,

a 9Ί6-ZZΌ6 dm

ZeiOO / 86MD / 13d C61S0 / 00 OAV

Claims

1. A guaiacoxypropanolamine compound as shown in Formula I,

Where R is CH ₂ CH = CH ₂ , CH = CHCOOC ₂ H ₅ , CH = CHCH ₃ , CH ₂ NHCO (CH 2) ₇ CH ₃ ;

R ₃ is OH, OCH ₃ , HCH2CH3OCH3, CHR ₆ ;

R ₄ is OCH ₃ , OC ₂ H ₅ , CHR _fi ;

1 ^, is CrG, bubble and alkane ¾, dC _{6 is} not bubble and fluorenyl;

2. A method for synthesizing a guaiacoxypropanolamine compound represented by the formula I, comprising: a.) The synthesis of 4-oxyethylamine-3 3-methoxybenzoate ethyl ester from 4-hydroxy -3-Ethyl methoxybenzoate and dibromoethane are heated and stirred, and then sodium hydroxide is added; the hexane / ethyl acetate mixture is used as the eluent, and the column is filled with silica gel to separate; After heating the potassium benzaldiimide, the reaction is heated with an equimolar ratio of hydrazine hydrate;

b.) Synthesis of epoxy compound: Alkyl N-vanillyl nonanamide, or 4-hydroxy-3 -methoxy-1 -propenylbenzyl and other raw materials are reacted together in an alkaline ethanol environment, and then added to the table After fully reacting the chlorohydrin under reflux, it was concentrated under reduced pressure and separated with a column packed with silica gel to obtain white crystals;

c.) N-[4-(2 -Hydroxy-3-(4-oxoethylamino-3 -methoxybenzoic acid) propoxy)-3 -methoxyj-1 -propenyl The 4-oxoethylamine-3 -methoxybenzoic acid ethyl ester was subjected to an amination reaction with an epoxy compound in an equimolar ratio, and left overnight to obtain crystals.

3. A method for synthesizing a compound of formula I according to claim 2, comprising

a)) Synthesis of ethyl 4-oxyethylamine 3- 3-methoxycinnamate, heated by stirring with 4-hydroxy-3 3-methoxycinnamate ethyl ester and dibromoethane, sodium hydroxide was added; A hexane / ethyl acetate mixture was used as an eluent, and the mixture was separated on a silica gel-packed column; an equal molar ratio of potassium phthalimide was added to heat the reaction, and then the reaction was heated with an equimolar ratio of hydrazine hydrate;

b.) Synthesis of epoxy compound N-[4-(2, 3 -epoxypropoxy)-3 -methoxy 1-1 -propenylbenzene: The 4-hydroxy- 3-Methoxy-1-propenylbenzene reacted together, and after adding epichlorohydrin to fully react under reflux, it was concentrated under reduced pressure and separated with a column packed with silica gel to obtain white crystals;

c.) N-[4-(2 -Hydroxy-3-(4 -oxyethylamino-3 -methoxycinnamic acid) propoxy)-3 -methoxy]-1 -propenyl The 4-oxoethylamine-3 -methoxymethoxycinnamate ethyl ester was subjected to an amination reaction with an epoxy compound in an equimolar ratio, and left to stand overnight to obtain crystals.

4. A pharmaceutical composition having α / β-adrenergic blocking activity, which A compound of formula I as claimed in claim 1 is used as a main component and various excipients are added.

5. A compound is 1-[(4-allyl-2-methoxy) benzyloxy] -3-[(2-methoxyphenoxyethyl) amino] -propanol.

6. A compound is 1-[(4-nonanamide-2-methoxy) phenoxy j-3-[(2-methoxyphenoxyethyl) amino j-propanol.

7. A compound is 1-[(4-ethyl acrylate-2-methoxy) benzyloxy j-3-[[2-methoxybenzyloxyethyl) amino] -propanol.

8. A compound is 1-[(4-propenyl-2-methoxy) phenoxy j-3-[(2-methoxyphenoxyethyl) amino] -propanol.

9. A compound is N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxycinnamic acid) propoxy)-3 -methoxy]-1 -propenyl benzene.

10. A compound which is N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxybenzoic acid) propoxy)-3 -methoxybenzyl] -nonyl amine.

11. A compound is N-[4-(2 -hydroxy-3-(4 -oxyethylamino-3 -methoxybenzoic acid) propoxy)-3 -methoxy I-1 -propenebenzene .

12. A compound which is N- [4-(2-hydroxy-3-(4-oxoethylamino-3 -methoxycinnamic acid) propoxy)-3-methoxybenzyl I nonanamide.

13. A compound which is N- [4-(2-hydroxy-3-(4-oxoacetoxybenzyloxyethylamino) propoxy)-3_methoxy]-1-propeneben.

14. A compound is N- [4- (4-ethylamino-1-oxoacetic acid benzene) ethoxy] -1-oxoacetic acid benzene.