TW391952B - Guaiacoxypropanolamines with <alpha>/<beta>-adrenergic blocking activity - Google Patents

Description

A7 B7 V. Description of the invention (printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 丨 8ν.Λ 修 i

R = CH2CH = CH2. CH2 = CHCOOC2H5 CH2NHCO (CH2) 7 ch3 ch = chch3 The present invention discloses a method for synthesizing compounds, which comprises a guaiacol hydration reaction. The raw material is guaiacol ( guaiacol) and ethylene dibromide. After the reaction, adjust the pH (pH) to 7 ′ with sodium hydroxide solution, extract with aerosol, and concentrate the liquid with a silica gel-filled column to separate it with hexane: ethyl acetate. The liquid was extracted to obtain a white crystalline product (2- (2-methyloxybenzyloxy) ethyl> smell (2- (2-Methoxxyphenoxy_) ethylbromide). 2. 2- (2-methoxyphenoxy) Ethyl bromide, phthalimide and dimethylacetamide are subjected to amination reaction 'heated under reflux and poured into water, the precipitated solid is filtered and added to the potassium acid solution', and the obtained The mud was filtered, washed several times with water, and recrystallized from anhydrous alcohol to obtain a white crystalline product. The product and Hydrazine hydrate were taken up in anhydrous alcohol, heated to reflux and left to cool, filtered, concentrated, and then Extraction with aerobic simulation, concentration under reduced pressure, The packed column was separated, and ethyl acetate was used as an eluent to obtain an oily product, 2- (ethoxyphenethyl) ethylamine. Applicable to China cns) Θ (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___________ B7 V. Description of the Invention (i) The field of industrial application. The present invention is related to the synthesis of novel guaiacene based on the structure of propylpropanolamine. It has been pharmacologically confirmed by animal experiments. Has α / β-adrenergic blocker activity. Background Adrenergic no blockers have been used clinically for 26 years. 'Current' cold blockers are used in addition to cardiovascular diseases such as hypertension, angina pectoris, and ventricular arrhythmia. They are also used in the thyroid gland. Symptoms such as poisoning, myocardial hypertrophy, myocardial infarction, migraine, glaucoma, and gastrointestinal bleeding are widely used. However, traditional tadpole blockers still have some unavoidable 'such as: inhibiting β-muscle function, increasing peripheral and coronary vascular resistance and other side effects, which limit its clinical use, so angina pectoris caused by coronary artery spasm, It should not be treated with cold blockers. Drugs developed in recent years have 0: block, cold block drugs have begun to treat some cardiovascular diseases, it can reduce the side effects of traditional Lu blockers, on the other hand, it can also avoid alpha block The pulsatile tachycardia caused by vasodilators is generally referred to as the most typical α 'without blocking agent, which is ^ thornetolol (Trandate®), which is commonly used clinically for acute hypertension patient. This paper size is applicable to China National Standards (CNS) A4 specification (210X29 * 7mm) 3 (_Please read the note on the back and then this page) ——One—Order τ

Instruction of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 3. Synthesis of Epoxide; Ferulic acid is added as sulfuric acid as a catalyst, and anhydrous ethanol is heated to a boil. After the reaction is completed, sodium hydride aqueous solution is added to adjust the acidity. : (| H) value reached neutral, concentrated under reduced pressure and recrystallized with methanol to obtain ethyl 4-hydroxy-3-methoxycinnamic acid ethyl ester (4 to do 0 &gt; ^ -3-methoxycinnamic acid ethyl ester). The product was dissolved in an absolute ethanol solution containing sodium hydroxide. 'Epichlorohydrine was added to the reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The concentrated solution was filled in a silica gel column. The liquid was extracted and separated to obtain crude crystals. It was recrystallized with hexane repeatedly to obtain purified 4- (2,3-epoxypropoxy) · 3-methoxycinnamate ethyl acetate. 4. Synthesis of the product; 4- (2,3-epoxypropoxy &gt; 3-methoxy cinnamic acid ethyl ester and 2- (2-methoxybenzyloxy) ethylamine were dissolved in Anhydrous alcohol was reacted. The mixed solution was concentrated under reduced pressure, and the concentrated solution was separated by a column packed with Shixi gum, and concentrated to obtain a white crystalline product. It was then dissolved in an acetone solution of sodium hydroxide. After the reaction was completed, a silica gel tube was used. Column, separated, purified (^ [(i ethoxylvinylmethoxy) phenoxyfluorenyloxybenzyloxyethyl) amino] -2-propanol. Novel guaiacol hydroxy Propanolamine Compound Compounds 丨 ~ 4; Compound l ... (H (4-allyl-2 · fluorenyl) benzyloxy_3 _ [(2-methoxyphenoxyethyl) amino group- 2 Propanol (1-[(4_aiiyUmethDxy) pheiioxyI_: 3_ This paper rule applies to China's national standard (CNsyM regulations ^ -------- 7 (Please read the precautions on the back before filling this page)) ______I______ .--- 、-°. .I 1 ^ 1 II— -1 ^^ 1. A7 ____ B7 V. Description of the invention (2) The previous technology in SAR, structure activity relation ship Guaiacol ethylpropanol The structure of (guaiacolethylamine) has alpha blocker activity. Augestein et al., 1964; and Kierstead, Rw, et al., 1983, J. Med. Chem., Vol. 26, pp. 1561-69. Amylamine (aryloxyxyanolanol) is the basic structure of 10,000 blockers. In addition, many ingredients in traditional Chinese medicines contain aromatic rings, so it is interesting to find a component containing aromatic rings, including eugenol, isoeugenol (Is〇eugen〇1), ferulic acid (ferulicacid), capsaicin (capSaicj_n), first use a chemical reaction to introduce the propanol amine (propanol_amine) group; then introduce part of the guaiatropinyl ethyl The structure of guaiacol ethylainine 'makes it have the activity of an alpha blocker, and synthesize eugenodilol, j_soeeugencjiioi, ferulidilol, Capsinodilol, and further explore whether the synthesized compound has the activity of α, 10,000 blockers and explore its pharmacological effects. Purpose of the invention The primary purpose of the present invention is to reveal the novel guaiac tree experience The structure of propanolamine, as shown in formula I, the scale applies to Chinese national standard) Α4 is present (210X297 mm_) &quot; 4 A / A / ί) month B7 V. Description of the invention; ^. One :; eight. . · [(2-methoxyphenoxyethyl) amino] -2-propanol), referred to as eugenodilol ° Compound 2... (H (4-ethoxycarbonylvinyl-2-fluorenyloxy) phenoxy-3-[( 2-methoxyphenoxyethyl) amino] -2-propanol (1-[(4-ethoxycarbonyl · · · winter · ethenyl-2-methoxy) phenoxy] -3-[(2-metho ^ -phenoxyethyl) amino] -2-propanol) ° Compound 3 .... (l-[(4-nonylaminemethylmethyloxy) phenoxy_3-[(2-methyloxyphenoxy Ethyl) amino] -2-propanol (1-[(4-11〇1 ^ 仙 111 丨 (1 Coffee 6111) 4-2-methoxy) phenoxy] -3-[(2-methoxyphenoxyethyl) amino]- 2-propanol), abbreviated as capsinodilo compound 4 &quot;. (l-[(4-propenyl-2-methoxy) phenoxy-3-[(2-methoxyphenoxyethyl) amino] 2-propanol (l-[(4-propenyl-2-methoxy) · phenoxy] -3-[(2-methoxyphenoxyethyl) amino] -2-propanol), referred to as isoeugenodilol 〇 Compound 1M or its intermediate product is recrystallized After measuring the melting point (mp), or after purification The physical and chemical data such as elemental analysis, mass spectrometry (MS), infrared spectroscopy (IR), proton nuclear magnetic resonance spectroscopy (CDCI3 :), and ultraviolet absorption (ϋν) can be used to determine the structure of these compounds. Compounds with different dosages (1.0, 1.5, 3.0 mg / kg) can all act like a thief, and the action time is as standard (CNS) A4 size T &quot; 2i〇x297 as long as possible) 8 (Please read the precautions on the back before (Fill in this page) Printed by the Consumers 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs --- r ——, —line _ | Ί !: A7 B7 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

R = ch2ch = ch2 ch2 = chcooc2h5 CH2NHCO (CH2) 7 ch3. Ch = chch3 and synthesis method. Another object of the present invention is to confirm that the compound of formula I has α // 3-adrenergic blocker activity through animal experiments. The present invention still has another object. The pharmaceutical composition prepared by using the compound of formula I as a main ingredient and various excipients has an α / α-adrenergic agonist blocking activity. Description of the table: Table 1 The effect of blood pressure Table 2 Vasodilator effect Table 3 The effect of adrenaline inhibition on point 1 Table 4 Physicochemical data of compounds Figure 1 Detailed description of the compound synthesis method of the invention Guaiacol hydroxypropanolamine paper ruler China CNS} (Please read the precautions on the back before filling in this page)

Π 5 Μ Μ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs B7 V. Description of the invention (if):-;-Different concentrations of _ test chemical compound (1 / 10_s or ι〇_5μ), after action After 30 minutes, cumulative administration was completed with L-phenylephrine. EC50 values can be obtained by observing the inhibitory effects caused by test compounds at different concentrations. (b) Calculation of pA2 value: Calculation method of the right atrium experiment in vitro. As a result of the "adrenergic response" inhibitory effect, guinea pig isolated thoracic aorta, the cumulative administration of phenylephrine (l_phenylephrine) can cause blood vessel contraction, the test drug at a concentration of 10'lG · 5 and i (r4 M 'can suppress the effect of L-phenylephrine), and then learned from the Schild plot in Table 3: the test drug antagonizes L-phenylephrine in isolated blood vessels PA2 value obtained by the shrinkage effect of Example 1. Example 1 Synthesis of Compound-4: -phend: in: 4 mil sodium hydroxide, reacted at 7 (TC 1 (Please read the precautions on the back before filling this page )

17 A7 B7 V. Description of the invention (printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 丨 8ν.Λ 修 i

R = CH2CH = CH2. CH2 = CHCOOC2H5 CH2NHCO (CH2) 7 ch3 ch = chch3 The present invention discloses a method for synthesizing compounds, which comprises a guaiacol hydration reaction. The raw material is guaiacol ( guaiacol) and ethylene dibromide. After the reaction, adjust the pH (pH) to 7 ′ with sodium hydroxide solution, extract with aerosol, and concentrate the liquid with a silica gel-filled column to separate it with hexane: ethyl acetate. The liquid was extracted to obtain a white crystalline product (2- (2-methyloxybenzyloxy) ethyl> smell (2- (2-Methoxxyphenoxy_) ethylbromide). 2. 2- (2-methoxyphenoxy) Ethyl bromide, phthalimide and dimethylacetamide are subjected to amination reaction 'heated under reflux and poured into water, the precipitated solid is filtered and added to the potassium acid solution', and the obtained The mud was filtered, washed several times with water, and recrystallized from anhydrous alcohol to obtain a white crystalline product. The product and Hydrazine hydrate were taken up in anhydrous alcohol, heated to reflux and left to cool, filtered, concentrated, and then Extraction with aerobic simulation, concentration under reduced pressure, The packed column was separated, and ethyl acetate was used as an eluent to obtain an oily product, 2- (ethoxyphenethyl) ethylamine. Applicable to China cns) Θ (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Γ, Invention. ~~ ~~~~-EpicHiorohydrine 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 filled in a silica gel column, and hexane: ethyl acetate = 1: 9 is the eluent, and white crystals are obtained by separation. &gt;. '.¾ Take 0.03 mole 3- [4_ (2,3 · epoxypropoxy) _3_methoxy] phenylpropene (3- [4- (2,3-epoxypropoxy) -3 -methoxy] phenylpropene) and 5.0 g (0.03 mole) of 2- (2-methoxyoxyphenoxy) ethylamine (2_ (2_Meth〇xy-phenoxy) ethylamine) dissolved in 30 ml of absolute alcohol at room temperature Stir for 2 hours to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated solution was separated and concentrated using a silica-filled column to obtain a white crystalline product. Take an appropriate amount of sodium hydroxide and dissolve it in 0.1% propidium, 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 column of Shixijiao and separated by using an eluent of ethyl acetate: methanol = 1: 1 ratio. After purification, 1-[(4-propylpropyl-2-methoxy) phenoxy was obtained -3-[(2-methoxybenzyloxyethyl) amino-2-propanol (1-[(4-allyl-2-methoxy) phenoxy-3_ [(2-methoxy-phenoxyethyl) amino] -2 -propanol) Example 2 Synthesis of compound 3 The paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 meals) 18 (Please read the precautions on the back before filling out this page}-Binding. Thread

Instruction of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 3. Synthesis of Epoxide; Ferulic acid is added as sulfuric acid as a catalyst, and anhydrous ethanol is heated to boiling. After the reaction is completed, sodium hydride aqueous solution is added to adjust the acidity : (| H) value reached neutral, concentrated under reduced pressure and recrystallized with methanol to obtain ethyl 4-hydroxy-3-methoxycinnamic acid ethyl ester (4 to do 0 &gt; ^ -3-methoxycinnamic acid ethyl ester). The product was dissolved in an absolute ethanol solution containing sodium hydroxide. 'Epichlorohydrine was added to the reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The concentrated solution was filled in a silica gel column. The liquid was extracted and separated to obtain crude crystals. It was recrystallized with hexane repeatedly to obtain purified 4- (2,3-epoxypropoxy) · 3-methoxycinnamate ethyl acetate. 4. Synthesis of the product; 4- (2,3-epoxypropoxy &gt; 3-methoxy cinnamic acid ethyl ester and 2- (2-methoxybenzyloxy) ethylamine were dissolved in Anhydrous alcohol was reacted. The mixed solution was concentrated under reduced pressure, and the concentrated solution was separated by a column packed with Shixi gum, and concentrated to obtain a white crystalline product. It was then dissolved in an acetone solution of sodium hydroxide. After the reaction was completed, a silica gel tube was used. Column, separated, purified (^ [(i ethoxylvinylmethoxy) phenoxyfluorenyloxybenzyloxyethyl) amino] -2-propanol. Novel guaiacol hydroxy Propanolamine Compound Compounds 丨 ~ 4; Compound l ... (H (4-allyl-2 · fluorenyl) benzyloxy_3 _ [(2-methoxyphenoxyethyl) amino group- 2 Propanol (1-[(4_aiiyUmethDxy) pheiioxyI_: 3_ This paper rule applies to China's national standard (CNsyM regulations ^ -------- 7 (Please read the precautions on the back before filling this page)) ______I______ .---,-°. .I 1 ^ 1 II— -1- ^^ 1.

V. Description of the Invention (Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 0.03 Molar N- [4- (2,3-epoxypropoxy) _3_fluorenylbenzyl] _ Nonamidine (N- [4- (2,3_qx &gt; xypr〇 | x »^)-3-methc ^ benzyl] _nonanamide) and 0.09 mole 2- (2-methoxyphenoxy) ethylamine (2_ (2_

Methoxyphenoxy) ethylamine) was dissolved in 30 ml of anhydrous eyes 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 and concentrated using a column packed with Shixi gum 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 column of Shixijiao, and the solution was separated by using an ethyl acetate: methanol = 1: 1 ratio of eluent. After purification, (1-[(4-nonylaminofluorenyl-2-fluorenyloxy)] was obtained. Phenoxy-3-[(2-methoxyphenoxyethyl) amino] -2-propanol (1-[(4- nonanamidemethyl-2-methoxy) phenoxy] -3-[(2-methoxyphenoxyethyl ) amino] -2-propanol). Example 3 Synthesis of compound 2 Take 1 mol ferulic acid, add a small amount of sulfuric acid as a catalyst, and heat and boil for 48 hours after excess ethanol. Thin layer chromatography (TLC) to determine whether the reaction is complete. After the reaction is complete, add an aqueous solution of sodium hydride to adjust the pH value to reach mid-range. After concentration under reduced pressure, recrystallize with methanol to obtain ethyl 4-mercapto-3-methoxycinnamate. (4-hydroxy-3- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 19 (Please read the precautions on the back before filling this page) ------ Order--Γ- -r--line J ': .--- A / A / ί) month B7 V. Description of the invention; ^. A :; VIII .. · [[2-methoxyphenoxyethyl) amino] -2-propanol), abbreviated eugenodilol ° compound 2: .. (H (4-ethoxycarbonylethyl Phenyl-2-fluorenyloxy) phenoxy-3-[(2-fluorenoxyphenoxyethyl) amino] -2-propanol (1-[(4-ethoxycarbonyl ··· · winter ·· ethenyl-2-methoxy) phenoxy] -3-[(2-metho ^ -phenoxyethyl) amino] -2-propanol) ° Compound 3 .... (l-[(4-nonamidinemethylmethyloxy) Phenoxy_3-[(2-methoxyphenoxyethyl) amino] -2-propanol (1-[(4-11〇1 ^ 仙 111 丨 (1 Coffee 6111) 4-2- methoxy) phenoxy] -3-[(2-methoxyphenoxyethyl) amino] -2-propanol), abbreviated as capsinodilo compound 4 &quot;. (l-[(4-propenyl-2-methoxy) phenoxy-3- [(2-Methoxyphenoxyethyl) amino] -2-propanol (l-[(4-propenyl-2-methoxy) · phenoxy] -3-[(2-methoxyphenoxyethyl) amino] -2 -propanol), referred to as isoeugenodilol 〇 Compound 1M or its intermediate product after recrystallization to determine the melting point (mp), or the product after purification process to determine its elemental analysis, mass spectrometry (MS), infrared spectroscopy (IR), hydrogen nuclear magnetic resonance Physical and chemical data such as spectrum CDCI3 :), ultraviolet absorption (ϋν) can show that these compounds have a clear structure. Compounds with different doses of tincture (1.0, 1.5, 3.0 mg / kg) can all act on the thief, and the action time is as standard (CNS) A4 size T &quot; 2i〇x297 while taking advantage) 8 (Please read the precautions on the back before (Fill in this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs --- r ——, —line _ | Ί!

------------------------------------------... J methoxycinnamic acid ethyl ester ). One mole of the above product was dissolved in 100 ml of absolute ethanol containing sodium hydroxide and stirred at room temperature. Then add 5 mol epichlorohydrin (printed ichlorohydrine) to react at room temperature. After the reaction is completed, the solution is concentrated under reduced pressure. The concentrated solution is filled in a broken tube column, and hexane: ethyl acetate = 1: 9 is used for extraction. Liquid and separated to obtain crude crystals. Recrystallization from hexane was repeated to obtain purified 4- (2,3-epoxypropoxy) -3-methoxycinnamate. Take 0.03 mole 4- (2,3-epoxypropoxy) _3_methoxy cinnamic acid ethyl ester (4_ (2,3_ 印 oxypmpoxy) -3-methoxy_cinnamic acid ethyl ester) and 0.03 mole 2 -(2-methoxyphenoxy) ethylamine (2 · (2-Methoxyphenoxy) ethyl-amine) was 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 silica-filled column, and concentrated to obtain a white crystalline product. An appropriate amount of sodium hydroxide was dissolved in 0.1% acetone, and the white crystal product was dissolved and heated to boiling, and it was determined whether the reaction was complete by thin layer chromatography (TLC). The product was packed in a silica gel column, and was separated and purified using an ethyl acetate: methanol = 1: 1 ratio of eluent to obtain (1-[(4-ethoxycarbonylvinyl-2-fluorenyloxy) benzene. Oxy-3-[(2-methoxyoxybenzyloxyethyl) amino] -2-propanol (1-[(4-ethoxycarbonylethenyl-2-methoxy) phenoxy] -3-[(2-methoxy- pheno ^ ethyl) amino]-2-propanol) 0 scale is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) ~ (Please read the precautions on the back before filling this page) —Installation—Order-- -„--- So — .. 1. 20

The printing of employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs lasted for more than an hour; the blood house had a continuous decline in blood migration. In the guinea pig isolated thoracic aorta, administration of 10 A M phenylephrine (~ Phenylephrine) resulted in a contractile effect resulting from the administration of the compound ^ Table 2 shows the lion thin, and the phenomenon appears. In the isolated right atrium and left atrium of Tian Er mice, the cumulative administration of isoproterenol can increase the right atrial beating frequency and left atrial contractility, and the compounds are at concentrations of 10-7, 10-6, and 10. There is a competitive inhibitory effect on the action of lsoproterol. From the Schild plot in Table 3, the pA2 value of the compound on the effect of isoproterenol on the beating frequency of the right atrium and the contraction force of the left atrium was known. The compound of the present invention is added with various excipients, such as stearic acid, corn flour, starch, lactose, sodium methylcellulose, ethanol, glycerol, etc., or diluents, lubricants &lt; iubricants) , Flavor extenders, disintegrants, binders, or colorants, sweeteners to make lozenges or other solid preparations, and phosphate buffers can be made to adjust the pH value Injections or other liquids and various dosage forms. The solid dosage forms include tablets, lozenges, powders, capsules, sublingual tablets, granules and other dosage forms. The composition of this type of dosage form is an effective amount of injection dosage form, eye drop or various liquid dosage forms. The general dosage can be adjusted as the symptoms require, usually 50 mg to 300 mg per person, 3 paper rule per day ^ &quot; Applicable to China National Standard (CNS) A4 specification (210X297 mm) * Γ ·- ¾-&quot; I- I-nn--In n-1 ^ 1 I nn-^ I —L- II n ___I-L--h-,-1 --- .. € ^ (Please read the back first (Notes to fill out this page) 9

V. Description of the Invention (+ 乃 二 I Corruption Example 4 .....-......; :: ί: '-ϋ The synthesis of compound 4 is equal to Mor 4- (2,3- (4- (2,3-epoxypropoxy) -3-methoxy] block | enylpropene) # f2- (2 • methoxyphenoxy) ethylamine (2- (2-Meth ( jj§ | &gt; | ienoxy) ethylamine) Dissolved in 30 ml of water-free alcohol J. Stirred at room temperature for Γ hours to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated solution was filled with silicone gel. Separate the column and concentrate 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). Fill the product In a silica gel column, an ethyl acetate: methanol = 1: 1 ratio of the eluent was used for separation, and after purification, (1 · [(4_propenyl winter alkoxy) benzyloxy-3-[(2-methyl Oxyphenoxyethyl) amino] -2-propanol (l-[(4-propenyl-2-methoxy) -phenoxy] -3-[(2-methoxyphenoxyethyl) amino] -2-propanol) 〇 Example 5 Compound 1 Tablets Read First Read

Replenishment of the matters of interest X Gutter Printing compound 1 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Employees' cooperatives 50 mg Lactose 30 mg Starch 4 mg Magnesium stearate 6 mg Corn flour 10 mg According to the above prescription, a bond containing Compound 1 can be prepared The dosage form of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm 21 A7 —----- — B7) 5. Description of the invention (8) times. Discussion of pharmacological effects Heartbeat and blood pressure effects are great for males. White rats (Wistarstrain) weighed 3.0-450 g and were anesthetized by subcutaneous injection of 40 mg / kg pentobabarfcital, followed by tracheotomy and inserted into the catheter to keep the animals in the experiment. Breathing is smooth, which is also conducive to first aid. A femoral vein is intubated with a polyethylene tube (PE50) with an inner diameter of 0.85 mm and an outer diameter of 0.97 mm to facilitate the administration of drugs in the experiment; 3-way stopcock, one end is connected with a syringe filled with medicines; the other end is connected with a syringe filled with physiological saline. 'After giving the medicine, a little physiological saline can be injected immediately to avoid the medicine. Retention in the polyethylene tube (PE50) tube affects the accuracy of the experiment. The left femoral artery is also intubated with a polyethylene tube (PE50), the same use a three-way stopcock, one end is connected to the heparin solution, when the polyethylene tube (PE50 ) When there is an embolus in the tube, it can be used to unblock the tubing; the other end is connected to the Disposable Diaphragm Dome (TA1019), and then connected to the transmitter's amplifier, and the recorder records the effect of the drug on the blood pressure and heartbeat of the rat. Rats were administered test drugs at different doses of 1.0, 1.5, and 3.0 mg / k; g through the femoral vein to explore the effects of the drugs on heartbeat and blood pressure. This paper size applies CNs M standards (2 丨 QX297) (Centi) 10 189. year 1. A7 V. Description of the invention (21) Table 4 H (4-Fopropyl-2-methoxy) phenoxy-3-K2-methoxyphenoxyethyl) amine 2-propanol (l-[(4-a% l-2-methoxy) phenoxy] -3-[(2-methoxyphenoxy ethyl) amino] -2-propanol) XH-NMR (CDC13) 6: 2.93- 3.16 (m, 3.31-3.34 (d, 3.80-3.83 (m, 4.00-4.03 (mf 4.13-4.19 (m, 5.03-5.12 (m, 5.88-6.01 (m, 6.68-7.00 {m, 4H, CH2-NH -CH2); 2Hf Ar-CH2); 6H, OCH3 X 2}; 2Er Ar-OCH z); 3H, Ar-OCH2CH (OH)}; 2Er -CH = CH2); 1H, -CH = CH2); mr Ar); (Please read the notes on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Employees' Cooperative Printed MS m / s: 388 (Scan EI +). A113I. C22K29NO5 / mp. 46-48 ° C · l-[(4-ethoxyquinyl-2-methoxy) phenoxy -3-[(2-methoxyphenoxyethyl) amino] -2-propanol 1-[(4-ethoxy carbonylethenyl-2-methoxy) phenoxy] -3-[(2-meth〇5 ^ -phenoxydhyl) amino] -2-propariol) ^ -NMR (CDCI3) δ: 1.30-1.37 (ια, 3H, CH3); 3.13-3.18 (mr 4H, CH2-NH-CH2); 3.77-3.82 (m, 6Hf OCH3X 2); 4.06-4.08 (d, 2Hf Ar-OCH2); 4.15-4.19 (m, 3Hr Ar-OCH2CH (OH)); This paper size applies to China National Standard (CNS) A4 (210X297) 23) A7 _B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (9) Results Normal blood pressure Ib after normal anesthesia with pentobarbital sodium I 'was tested by femoral vein at different doses Drugs to observe the effects on heartbeat and blood pressure. The results are shown in Table 1. Compounds 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 longer than i hours; blood pressure also occurs. Continuous pressure to reduce pressure. For relaxation of guinea pigs in vitro, take any 300_450 grams of guinea pigs, knock them from the head with force, then put jk from the carotid artery, quickly remove the thoracic aorta, and place them in the cold Krebs solution to carefully remove the surrounding blood vessel wall Then cut the thoracic aorta into a circle of about 5 mm length, fix the aortic ring with two “H” -shaped platinum wires up and down, and place it in a 10-liter tube with 95% oxygen and 5% In the tissue trough of the rabbit dioxide mixture, one end is fixed to the bottom of the tissue trough, and the other is connected to a force transducer, and the isometric contraction is recorded via a recorder. Tension, 60 minutes after equilibration, first administer M phenylephrine to test the activity of the thoracic aorta, wash the phenylephrine after it is equilibrated, and then administer 10 phenephrine ^ lePhrine) to achieve the maximum shrinkage, wait for its balance. This paper size is suitable for towels: Countryside (CNS) A4 Specification (21 () &gt; &lt; 297 Gongchu) — ~~-* ίΓ ·-_______--- 1--install ^^ ----- order-- (Please read the notes on the back before filling Page) 11

Year X—Printed by the Consumer Cooperatives of the Ministry of Economic Affairs Bureau of the People's Republic of China ψ '· Invention Description (4.24-4.3lTC00CH2); 6.26-6.34 (df 1H, Ar-CH = CH) 6.86-7.〇9 ( m, 7H, Ar); 7.57-7.65 (d, 1H, Ar-CH = CH); MS m / s: 446 (Scan EI +). Anal. C24H31N07, mp. 94.6-96.4 ° C. (l-[( 4-nonylaminomethyl-2-methoxy) phenoxy-3-[(2-methoxyphenoxyethyl) amino] -2-propanol (l-[(4-nonanamidemethyl- 2- methoxy) phenoxy] -3-[(2-methoxy phenoxyethyl) amino] -2-propanol) iH-NMR (CDC13) 0.80-0.92 (m, 3H, CH3); 1 · 27 (s, 10H, CH2 X 5); 1.58-1 · 72 (m, 2H, ch2); 2.15-2.26 (m, 2H, CH2); 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-OCHa); 4.06-4.12 (m, 3H, Ar-OCH2CH (OH) 4.34-4.37 (df 2H, Ar-CH2); 5.76 (br, 1H, NH) • j 6.74-6.91 (m, 7H, Ar); MS m / s: 517 (Scan FAB +). Anal · C29H44N2O6, mp. 138-139 ° C. This paper standard is applicable to Chinese national standards (CNS) A4 size (210X29 * 7mm) 24 (Please read the precautions on the back before filling this page) Thread A7 B7 V. Description of the invention 10) After 'administering different concentrations of the test compound (10-5 or 10-6 or 10-7 M)', observe the inhibitory effect caused by the different concentrations of the test compound. Results In the guinea pig isolated thoracic aorta, administration The contraction effect of 10 β Μ phenylephrine (L-phenylephrine) will be caused by the administration of 10-6, 1CT5 and 10-4M compounds, as shown in Table 2 and a non-used-and shown the dose Related phenomena: ΜLING1 Adrenergic response inhibition (1) Guinea pig isolated right atrium experiment The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed a guinea pig weighing 300 ~ 45 grams and knocked hard Hit the head to faint 'then cut off the carotid artery to bleed' and then immediately cut open the chest cavity and quickly remove the entire heart 'set at room temperature (20 ~ 25). 〇 The left and right chambers are separated in a Krebs solution that has been mixed with gas (95% oxygen, 5% carbon dioxide). Take the spontaneously beating right atrium, clamp both ends with a frog heart clamp, fix one end to the bottom, and place it in a tissue bath filled with a mixed gas containing 10 liters of Krebs solution, and maintain the temperature at 32.5 ° C. Connect a force transducer and record the isometric contractions and beat frequency of the right atrium through a recorder (COULBOURN AT-High-Speed Videograph). Specimen given; paper rule 1 applicable ~: ^ national standard 隼 (〇 ^> 8 4 specifications (210; 297 ^ centimeter) '' — 12

V. Description of the invention (Z methoxy) phenoxy-3-[(2-methoxybenzyloxyethyl) A7 ... ........-.. / V / w-;,: 4, 卞 B7 „..Λ / 1., &Gt; 〆 一 _

Ά &lt;! I-一, -39195¾ (1-[(4-propenyl-2-amino) -2-propanol (1- [(4- propenyl-2-methoxy)-phenoxy] -3-[ (2-methoxyphenoxy ethy l) amino] -2-propanol) ^ -NMRCCDCla) δ: 1.11-1 · 25 (ια, 3H, CH3); 2.87-3.12 (m, 4H, CH2-NH-CH2); 3.84 (s, 6H, OCH3 X 2); 4.00- 4.14 (m, 2H, Ar-〇CH2); 4.00- 4.04 (m, 2H, Ar-OCH2); 4.13-4.16 (m, 3H, Ar-OCH2CH ( OH}); 6.04-6.37 (m, 2Ef -CH = CH); 6.84-6.95 (m, 7H, Ar); MS m / s: 388 (Scan EI +) ·

Anal.c22H29N05, mp. 90.2-91.6 ° C.! ^-IL · 丨 丨. 丨 丨 -------- 丨 丨 丨: ___ 丨 Line {Please read the precautions on the back before filling this page) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards and Standards of the Ministry of Labor 5 2 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) Printed by the Consumer Standards of the Central Standards of the Ministry of Economy of the Ministry of Economic Affairs A7 ______ B7 V. Description of the invention (11 ) Tension between 100 ~ 150 mg. After equilibrium, perform the following experiments: (a) Cumulative cone response-response curves are completed to evaluate the beta blocking activity of the test compound. · · · 'Each spontaneous beating of the isolated right atrium after equilibrium (approximately 60 minutes &gt;' Need to complete two separate B-agents M-agónist) isoproterenol (isoproterenol) accumulation Concentration curve. The experimental design is as follows: &lt; 1 &gt; The first curve directly gives isoproterenol (us〇proterenol) from low concentration to high concentration, increasing in order from 0.5 to 10 g units until the maximum response is reached; this is Control group. &lt; 2 &gt; The first time curve is the experimental group. Test compounds of different concentrations were first given (10-7 or 10-5 M; from low to high concentrations), and after 30 minutes of action, then isoproterenol (iSoprouteren 01 ) Complete cumulative administration. EC5 can be obtained by observing the inhibitory effects caused by different concentrations of the test compound. value. (b) Calculation of pA2 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 of the agent that achieves the same effect is taken as the vertical coordinate. The obtained data is rounded and linear regression is performed to obtain the abscissa intercept value of a regression line, that is, the pA2 value of the test compound. National paper standard (CNS) of this paper rule 槪 (((210X297 mm &gt; ~~~ --_ 13 (Please read the precautions on the back before filling in ^! ^) ----- Discussion 丨. A 7 B7 V. Description of the invention (i2) (2) Guinea pig isolated left atrium experiment The left atrium that does not spontaneously beat was obtained from the guinea pig isolated right atrium experiment. Under the same conditions, the wave pen 5 rasec is slightly larger than the threshold. (Threshold voltage) A square wave of about 1 volt stimulates the left atrium to cause a contractile response. The stimulation frequency is 0.5 · ζ and the resting tension is 0.5 grams. After the equilibrium (about 50 minutes), the following experiment is performed; (a ) The completion of cumulative concentration-response curves is the same as the experimental method of isolated right atrium. (B) The calculation of pA2 value is the same as the calculation method of isolated right atrium experiment. For / 5 1 epinephrine response ( (adrenergic response) The results of the inhibitory effect are printed on the right atrium and left atrium of guinea pigs by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Cumulative administration of isoproterenol can increase the right atrial beating frequency and left atrium And the compound can competitively inhibit the action of isoproterenol at concentrations ι0-7, 10-6, and ict5m. Then the Schild plot in Table 3 shows that the compound is antagonizing isopropyl The effect of adrenaline (isoproterenol) on the beating frequency of the right atrium and the contraction force of the left atrium is PA2. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 male thin) 14 A7 B7

V. Description of the invention (13) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, take guinea pigs weighing 300-450 grams and give an intraperitoneal injection of reserpine 5 h / fcg 18 to 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, and the trachea (about 4 cm in length) was removed along the neck, and placed at room temperature (about 22 ~ 25 °). 95% oxygen, 5% carbon dioxide) in a Krebs solution Petri dish 'carefully remove surrounding tissue'. Then cut the trachea into a spiral with three to four cartilage ring knots per revolution, divide it equally, and use a frog heart at both ends The clamp was clamped, and one end was fixed at the bottom and placed in a tissue bath filled with a mixed gas containing 20 ml of Krebs solution. The temperature was maintained at 32 ° C, and the other end was connected with a force transducer and passed through a recorder (COULBOURN). AT-High-Speed Videograph) Record the isometric contraction tension. The specimen is given a tension of 2 grams. After the balance is performed, the following experiment is performed. Β (a) Cumulative concentration response curve In the experiment, the trachea is first equilibrated (about 1 hour) to obtain spontaneous tension. Then, each aliquot of the trachea completes the secondary cumulative concentration response curve of isoproterenol. The first curve does not include the test compound as a control group; the second curve first adds the test 15 ( Please read the precautions on the back before ^^ this page) ----- * —Order *-»--- This paper size applies to China National Standard (CNS) A4 specification (210X297mm) A7 B7 V. Description of the invention (14) The cumulative concentration response curve was performed after the test compound was applied for 1 hour; this is the experimental group. (B) The calculation of pA2 value is the same as that of the right atrium experiment. The drug responds to β 2 adrenergic response. As a result, in the guinea pig isolated trachea obtained spontaneous tension, the cumulative administration of isoproterenol (isoproterenol) can relax the tension of the trachea, the compound at a concentration of 1 (Γ6, 1〇_5 and l〇- 4M can competitively inhibit the effect of isoproterenol. Then, according to the Schild plot in Table 3, it is known that pA2 obtained by antagonizing the relaxation effect of isoproterenol on the ex vivo trachea test drug. Cumulative concentration-response curve to the adrenergic response! Inhibition effect: The same as the vascular relaxation experiment, the isolated thoracic aorta of the guinea pig was removed and given a working weight of 60 grams for a balance of 60 minutes. Then, directly give L-phenylephrine from low concentration to high concentration, and increase it in order of 0.5 μg to reach the maximum response; this is used as the control group. Then the final paper size applies to China National Standard (CNS) 8 4 specifications (21〇 × 297 mm) '16 (Please read the precautions on the back before filling in this _

Printed by the Ministry of Economic Affairs of the Central Bureau of Consumers for Du MU Μ Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics for printing B7 V. Invention Description (if):-; ι〇_5μ), after 30 minutes of action, then cumulative administration with phenylephrine (L-phenylephrine). EC50 values can be obtained by observing the inhibitory effects caused by test compounds at different concentrations. (b) Calculation of pA2 value: Calculation method of the right atrium experiment in vitro. As a result of the "adrenergic response" inhibitory effect, guinea pig isolated thoracic aorta, the cumulative administration of phenylephrine (l_phenylephrine) can shrink blood vessels, the test drug at a concentration of 10'lG · 5 and i (r4 M 'can suppress the effect of L-phenylephrine), and then learned from the Schild plot in Table 3: the test drug antagonizes L-phenylephrine in isolated blood vessels PA2 value obtained by the shrinkage effect of Example 1. Example 1 Synthesis of Compound-4: -phend: in: 4 mil sodium hydroxide, reacted at 7 (TC 1 (Please read the precautions on the back before filling this page )

17 Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Γ, Invention. ~~ ~~~~-EpicHiorohydrine 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 filled in a silica gel column, and hexane: ethyl acetate = 1: 9 is the eluent, and white crystals are obtained by separation. &gt;. '.¾ Take 0.03 mole 3- [4_ (2,3 · epoxypropoxy) _3_methoxy] phenylpropene (3- [4- (2,3-epoxypropoxy) -3 -methoxy] phenylpropene) and 5.0 g (0.03 mole) of 2- (2-methoxyoxyphenoxy) ethylamine (2_ (2_Meth〇xy-phenoxy) ethylamine) dissolved in 30 ml of absolute alcohol at room temperature Stir for 2 hours to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated solution was separated and concentrated using a silica-filled column to obtain a white crystalline product. Take an appropriate amount of sodium hydroxide and dissolve it in 0.1% propidium, 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 column of Shixijiao and separated by using an eluent of ethyl acetate: methanol = 1: 1 ratio. After purification, 1-[(4-propylpropyl-2-methoxy) phenoxy was obtained -3-[(2-methoxybenzyloxyethyl) amino-2-propanol (1-[(4-allyl-2-methoxy) phenoxy-3_ [(2-methoxy-phenoxyethyl) amino] -2 -propanol) Example 2 Synthesis of compound 3 The paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 meals) 18 (Please read the precautions on the back before filling out this page}-Binding. Thread

V. Description of the Invention (Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 0.03 Molar N- [4- (2,3-epoxypropoxy) _3_fluorenylbenzyl] _ Nonamidine (N- [4- (2,3_qx &gt; xypr〇 | x »^)-3-methc ^ benzyl] _nonanamide) and 0.09 mole 2- (2-methoxyphenoxy) ethylamine (2_ (2_

Methoxyphenoxy) ethylamine) was dissolved in 30 ml of anhydrous eyes 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 and concentrated using a column packed with Shixi gum 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 column of Shixijiao, and the solution was separated by using an ethyl acetate: methanol = 1: 1 ratio of eluent. After purification, (1-[(4-nonylaminofluorenyl-2-fluorenyloxy)] was obtained. Phenoxy-3-[(2-methoxyphenoxyethyl) amino] -2-propanol (1-[(4- nonanamidemethyl-2-methoxy) phenoxy] -3-[(2-methoxyphenoxyethyl ) amino] -2-propanol). Example 3 Synthesis of compound 2 Take 1 mol ferulic acid, add a small amount of sulfuric acid as a catalyst, and heat and boil for 48 hours after excess ethanol. Thin layer chromatography (TLC) to determine whether the reaction is complete. After the reaction is complete, add an aqueous solution of sodium hydride to adjust the pH value to reach mid-range. After concentration under reduced pressure, recrystallize with methanol to obtain ethyl 4-mercapto-3-methoxycinnamate. (4-hydroxy-3- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 19 (Please read the precautions on the back before filling this page) ------ Order--Γ- -r--line J ': .--- Consumption cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs.

------------------------------------------... J methoxycinnamic acid ethyl ester ). One mole of the above product was dissolved in 100 ml of absolute ethanol containing sodium hydroxide and stirred at room temperature. Then add 5 mol epichlorohydrin (printed ichlorohydrine) to react at room temperature. After the reaction is completed, the solution is concentrated under reduced pressure. The concentrated solution is filled in a broken tube column, and hexane: ethyl acetate = 1: 9 is used for extraction. Liquid and separated to obtain crude crystals. Recrystallization from hexane was repeated to obtain purified 4- (2,3-epoxypropoxy) -3-methoxycinnamate. Take 0.03 mole 4- (2,3-epoxypropoxy) _3_methoxy cinnamic acid ethyl ester (4_ (2,3_ 印 oxypmpoxy) -3-methoxy_cinnamic acid ethyl ester) and 0.03 mole 2 -(2-methoxyphenoxy) ethylamine (2 · (2-Methoxyphenoxy) ethyl-amine) was 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 silica-filled column, and concentrated to obtain a white crystalline product. An appropriate amount of sodium hydroxide was dissolved in 0.1% acetone, and the white crystal product was dissolved and heated to boiling, and it was determined whether the reaction was complete by thin layer chromatography (TLC). The product was packed in a silica gel column, and was separated and purified using an ethyl acetate: methanol = 1: 1 ratio of eluent to obtain (1-[(4-ethoxycarbonylvinyl-2-fluorenyloxy) benzene. Oxy-3-[(2-methoxyoxybenzyloxyethyl) amino] -2-propanol (1-[(4-ethoxycarbonylethenyl-2-methoxy) phenoxy] -3-[(2-methoxy- pheno ^ ethyl) amino]-2-propanol) 0 scale is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) ~ (Please read the precautions on the back before filling this page) —Installation—Order-- -„--- So — .. 1. 20

V. Description of the Invention (+ 乃 二 I Corruption Example 4 .....-......; :: ί: '-ϋ The synthesis of compound 4 is equal to Mor 4- (2,3- (4- (2,3-epoxypropoxy) -3-methoxy] block | enylpropene) # f2- (2 • methoxyphenoxy) ethylamine (2- (2-Meth ( jj§ | &gt; | ienoxy) ethylamine) Dissolved in 30 ml of water-free alcohol J. Stirred at room temperature for Γ hours to carry out the amination reaction. The mixed solution was concentrated under reduced pressure, and the concentrated solution was filled with silicone gel. Separate the column and concentrate 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). Fill the product In a silica gel column, an ethyl acetate: methanol = 1: 1 ratio of the eluent was used for separation, and after purification, (1 · [(4_propenyl winter alkoxy) benzyloxy-3-[(2-methyl Oxyphenoxyethyl) amino] -2-propanol (l-[(4-propenyl-2-methoxy) -phenoxy] -3-[(2-methoxyphenoxyethyl) amino] -2-propanol) 〇 Example 5 Compound 1 Tablets Read First Read

Replenishment of the matters of interest X Gutter Printing compound 1 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Employees' cooperatives 50 mg Lactose 30 mg Starch 4 mg Magnesium stearate 6 mg Corn flour 10 mg According to the above prescription, a bond containing Compound 1 can be prepared The dosage form of this paper is applicable to the Chinese National Standard (CNS) A4, and it is 210X297 mm 21

7 7 · AB V. Description of the invention (? Completed) 'Change in blood (mmHg) Dose 1 mg / kg 1.5 mg / kg 3 mg / kg 1 -23.1 ± 4.5 -30.1 ± 3_6 • 38.1 ± 5.1 2 -37.5 ± 5.2 -44.2 ± 8.0 -52_4 ± 4.55 3 -32.6 ± 5.5 -41.7 ± 4.0 -52.0 ± 8.0 4 -24.9 ± 3.2 -29.5 ± 5.1 -36.4 ± 7.2 (Please read the precautions on the back before filling this page ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 6.13 7.20 ΙΟ ^ Μ ι〇 · 5μ ΙΟ ^ Μ 1 -62.8 ± 8.71 -51.7 ± 6.8 -39.7 ± 9.1 2 • 56.7 ± 5.1 -42.1 ± 9.1 -35.9 ± 7.9 3 -55.1 ± 7.4 -40.7 ± 8.4 -34.5 ± 4.2 4 -38: 1 ± 6.5 -30.1 ± 3.6 -23.4 ± 3.7. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 22 189.year 1. A7 V. Description of the invention (21) Table 4 H (4-Fopropyl-2-methoxy) phenoxy-3-K2-methoxyphenoxyethyl) amino-2-propanol (l -[(4-a% l-2-methoxy) phenoxy] -3-[(2-methoxyphenoxy ethyl) amino] -2-propanol) XH-NMR (CDC13) 6: 2.93-3.16 (m, 3.31-3.34 ( d, 3.80-3.83 (m, 4.00-4.03 {mf 4.13-4.19 (m, 5.03-5.12 (m, 5.88-6.01 (m, 6.68-7.00 {m, 4H, CH2-NH-CH2)); 2Hf Ar-CH2 ); 6H, OCH3 X 2}; 2Er Ar-OCHz); 3H, Ar-OCH2CH (OH)}; 2Er -CH = CH2); 1H, -CH = CH2); mr Ar); Please fill out this page again) MS MS / s: 388 (Scan EI +). A113I. C22K29NO5 / mp. 46-48 ° C · l-[(4-ethoxyquinyl Vinyl-2-methoxy) phenoxy-3-[(2-methoxyphenoxyethyl) amino] -2-propanol 1-[(4-ethoxy carbonylethenyl-2-methoxy) phenoxy ] -3-[(2-meth〇5 ^ -phenoxydhyl) amino] -2-propariol) ^ -NMR (CDCI3) δ: 1.30-1 · 37 (ια, 3H, CH3); 3.13-3.18 (mr 4H, CH2-NH-CH2); 3.77-3.82 (m, 6Hf OCH3X 2); 4.06-4.08 (d, 2Hf Ar-OCH2); 4.15-4.19 (m, 3Hr Ar-OCH2CH (OH)); Size of this paper Be applicable China National Standard (CNS) A4 Specification (210X297 mm) 23

Year X—Printed by the Consumer Cooperatives of the Ministry of Economic Affairs Bureau of the People's Republic of China ψ '· Invention Description (4.24-4.3lTC00CH2); 6.26-6.34 (df 1H, Ar-CH = CH) 6.86-7.〇9 ( m, 7H, Ar); 7.57-7.65 (d, 1H, Ar-CH = CH); MS m / s: 446 (Scan EI +). Anal. C24H31N07, mp. 94.6-96.4 ° C. (l-[( 4-nonylaminomethyl-2-methoxy) phenoxy-3-[(2-methoxyphenoxyethyl) amino] -2-propanol (l-[(4-nonanamidemethyl- 2- methoxy) phenoxy] -3-[(2-methoxy phenoxyethyl) amino] -2-propanol) iH-NMR (CDC13) 0.80-0.92 (m, 3H, CH3); 1 · 27 (s, 10H, CH2 X 5); 1.58-1 · 72 (m, 2H, ch2); 2.15-2.26 (m, 2H, CH2); 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-OCHa); 4.06-4.12 (m, 3H, Ar-OCH2CH (OH) 4.34-4.37 (df 2H, Ar-CH2); 5.76 (br, 1H, NH) • j 6.74-6.91 (m, 7H, Ar); MS m / s: 517 (Scan FAB +). Anal · C29H44N2O6, mp. 138-139 ° C. This paper standard is applicable to Chinese national standards (CNS) A4 size (210X29 * 7mm) 24 (Please read the precautions on the back before filling this page)

V. Description of the invention (Z methoxy) phenoxy-3-[(2-methoxybenzyloxyethyl) A7 ... ........-.. / V / w-;,: 4, 卞 B7 „..Λ / 1., &Gt; 〆 一 _

Ά &lt;! I-一, -39195¾ (1-[(4-propenyl-2-amino) -2-propanol (1- [(4- propenyl-2-methoxy)-phenoxy] -3-[ (2-methoxyphenoxy ethy l) amino] -2-propanol) ^ -NMRCCDCla) δ: 1.11-1 · 25 (ια, 3H, CH3); 2.87-3.12 (m, 4H, CH2-NH-CH2); 3.84 (s, 6H, OCH3 X 2); 4.00- 4.14 (m, 2H, Ar-〇CH2); 4.00- 4.04 (m, 2H, Ar-OCH2); 4.13-4.16 (m, 3H, Ar-OCH2CH ( OH}); 6.04-6.37 (m, 2Ef -CH = CH); 6.84-6.95 (m, 7H, Ar); MS m / s: 388 (Scan EI +) ·

Anal.c22H29N05, mp. 90.2-91.6 ° C.! ^-IL · 丨 丨. 丨 丨 -------- 丨 丨 丨: ___ 丨 Line {Please read the precautions on the back before filling this page) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards and Standards of the Ministry of Foreign Affairs of the People's Republic of China 5 2 This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

Claims (1)

Λ% Α8 Β8 C8 D8 Scope of patent application ... , (H (4-ethoxycarbonylvinyl · 2 # oxy) phenoxy, each [(2-methoxyphenoxyethyl) amine, mashed propanol (ΐ-[(4-ethoxycarbonyLethenyl-2- meth〇5iy) phenoxy] -3-[(2-mdhQ ^ -pJi ^ c ^ ethyL) ainin (^-2-propanol) 〇 &quot;-V;. '2 · — a compound, 1 tun 4 · ene Propylmethoxy) phenoxy-3 · [(2-methoxyphenoxyethyl) amine 棊 -2 -propanol ([(4-allyl-2-methoxy) phenoxy-3- 2 [( 2- methoxy-phenoxyethyl) amino] -2- propanol) ° 3. —kind of gold, (irK4-nonylamine f-group 4 ▼ oxy) phenoxy-3_ 1 (2-methoxyphenoxyethyl (Amino) amino] -2-salanol l-[(4-nonatriide-2-methoxy) phenoXy] -3-{(2-methoxypheno ^ ethyl) amino] -2_propanol). 4. A compound, (1-K4- is alkenyl_2-methoxy) phenoxy-HQ-methoxyphenylfluorenylcardiyl) pyrrolyl Jr 2 -diol (1 r [(4-propenyl -2-methj〇xy) -phenoxy] -3-[(2-methoxyphetioxyethyl) amino] -_ 2-propanol). 5.-A method for synthesizing the first patent compound in the scope of patent application, which includes: (1) the synthesis of epoxy compound (Epoxide); adding ferulic acid as a wall medium, and boiling after the absolute ethanol After the reaction is completed, an aqueous solution of sodium hydride is added to adjust the pH value to reach neutrality. After concentration under reduced pressure, the product is recrystallized with _A to obtain 4-hydroxy-3-methoxycinnamic acid ethyl ester (4-hydroxy-3 -methoxycinnamic acid ethyl pster) 〇 The product is dissolved in an absolute ethanol solution containing sodium hydroxide, and epichlorohydrine is added for reaction. After the reaction is completed, the solution is concentrated under reduced pressure. The concentrate is filled in Shixi A silica gel column was used for extraction with hexane: acetic acid to separate and obtain crude crystals. Repeatedly recrystallized with hexane to obtain purified 4> (2,3-epoxypropoxy) · 3-methoxycinnamate, (Please read the precautions on the back before filling in this page) Set the paper size printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs to apply the Chinese National Standard (CNS) Α4 specification (210X297 mm) 26 Λ% Α8 Β8 C8 D8 Patent application scope ... ........... 1. A compound, (H (4-ethoxycarbonylvinyl · 2 # oxy) phenoxy Each [(2-methoxyphenoxyethyl) amine mashed propanol (ΐ-[(4-ethoxycarbonyLethenyl-2-meth〇5iy) phenoxy] -3-[(2-mdhQ ^ -pJi ^ c ^ ethyL) ainin (^-2-propanol) 〇 • &quot;-V;. '2 · —Compounds, 1 屯 4 · Allylmethoxy) phenoxy_3 · [(2-methoxybenzene [(4-allyl-2-methoxy) phenoxy-3- 2 [(2-allyl-phenoxyethyl) amino] -2-propanol) ° 3.-a kind of gold , (IrK4-nonylamine f-group 4 ▼ oxy) phenoxy-3_ 1 (2-methoxyphenoxyethyl) amino] -2-salanol l-[(4-nona riide- 2-methoxy) phenoXy] -3-((2-methoxypheno ^ ethyl ) amino] -2_propanol). 4. A compound, (1-K4- is alkenyl_2-methoxy) phenoxy-HQ-methoxyphenylfluorenylcardiyl) pyrrolyl Jr 2 -diol (1 r [(4-propenyl -2-methj〇xy) -phenoxy] -3-[(2-methoxyphetioxyethyl) amino] -_ 2-propanol). 5.-A method for synthesizing the first patent compound in the scope of patent application, which includes: (1) the synthesis of epoxy compound (Epoxide); adding ferulic acid as a wall medium, and boiling after the absolute ethanol After the reaction is completed, an aqueous solution of sodium hydride is added to adjust the pH value to reach neutrality. After concentration under reduced pressure, the product is recrystallized with _A to obtain 4-hydroxy-3-methoxycinnamic acid ethyl ester (4-hydroxy-3 -methoxycinnamic acid ethyl pster) 〇 The product is dissolved in an absolute ethanol solution containing sodium hydroxide, and epichlorohydrine is added for reaction. After the reaction is completed, the solution is concentrated under reduced pressure. The concentrate is filled in Shixi A silica gel column was used for extraction with hexane: acetic acid to separate and obtain crude crystals. Repeatedly recrystallized with hexane to obtain purified 4> (2,3-epoxypropoxy) · 3-methoxycinnamate, (Please read the precautions on the back before filling in this page) Set the paper size printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs to apply the Chinese National Standard (CNS) A4 specification (210X297 mm) 26 Α8 Β8 C8 D8 S91952 VI. Patent application scope (2) Synthesis of products; take 4- (2,3-Epoxypropoxy) -3-methoxy 丨 Cinnamate Ethyl Acetate 2_ (2-Methoxyphenoxy) ethylamine is dissolved in absolute alcohol and reacts. The mixed liquid iron was concentrated under reduced pressure, and the concentrated solution was separated by a silica gel-filled column. The concentrated solution was sampled into a white crystalline product, and then dissolved in gaseous oxygen (a sodium acetone solution. After the reaction was completed, a tube of Shixi gum was used. After purification, (14 (4-ethoxycarbonylvinyl-2-fluorenyloxy) phenoxy-HOmethoxybenzylethyl) amino] -2-propanol is obtained. / Adrenergic blocking agent active pharmaceutical composition ', which is based on the first compound in the scope of patent application as the main component and added various excipients. 7. A kind of α // 5-adrenergic A pharmaceutical composition that blocks spade activity is based on the second compound in the scope of patent application as the main ingredient. Dare to add | an excipient. (Please read the precautions on the back before filling this page) Ε α 系 会 Α Master _ Medicine for the coating agent to break the item wins 3 Dou Fanfanlili ift i Printed Synthesis Group of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, the main subject of the medicine is the agent for the combination of medicines and drugs 4; Solitary The first image of the stimulus m Bu Cang Li ^-Feng shaped kidney application 3-with each β system ^ α added, J1 · Material version Paper size applies to China (CNS) A4 (210X297 mm) 27