TW503235B - Derivatives of magnolol and their bioactivity - Google Patents

Abstract

This invention is related to novel Magnolol derivatives which have the following formula (I) and (II). As formula (I) shown, where R is the group selected from R1 is the group selected from formula; R2 is the group selected from formula; R3 is the group selected from halogen group, hydrogen, methoxyl group, ethoxyl group, propoxyl group, and NO2. The n is 0, 1, 2, 3. The Magnolol derivatives have antioxidation, and antihypertension.

Description

V. Description of the invention (1)

The present invention discloses a magnolol series compound, a synthesis method and its activity; the synthesis method not only improves the disadvantages of low yield, but also modifies the structure to exert anti-oxidative activity, anti-free radical activity, and lower blood pressure. BACKGROUND OF THE INVENTION "Oxidative stress" is a complex term. Simple and axiomatic, under the balance system of oxidation and antioxidant, the degree of oxidation is better than 10 antioxidants. This is because most cells require oxygen in order to survive, and reactive oxygen is what causes oxidation. Although there are many physiological self-defense antioxidants in the human body, including many enzymes and non-enzyme antioxidants, due to the increasingly serious pollution in today's living environment, the probability of promoting oxidation is also increasing. When the anti-oxidant system cannot fight 15, the damage caused by oxidation will accumulate in the body. According to Halliwell B. in 1991, j; No. 91, page MS_23S, there are more than 50 diseases at present, the cause of which is the injury caused by oxidation. Therefore, it is urgent to find and study such antioxidants, including synthetic or natural antioxidants. 20

503235 V. Description of the invention (2) magnolol, also known as magnoliol, is one of the main active ingredients of magnolia (M ^ o /). 丨 " 4years Your X such as m. Phrm⑽ No. 47, p.-553 revealed that when screening the antioxidant capacity of the medicinal ingredients, it was found that magnolol's anti-lipid peroxidation ability was' 5 approximately _0 times that of vitamin E. Thereafter After systematic research on Chinese medicine and its active ingredients, no more traditional Chinese medicine ingredients have been found than the antioxidative effect of honokiol. Therefore, honoki is used to protect cells against lipid peroxidation. It is a new type of antioxidant with the most development potential. 10 Reads the oxo domain free radicals, but there are also some, such as the singlet oxygen molecule ㈣et xygen; A) and hydrogen peroxide (HA). Different oxygen homogenates have the same half-life ‘of which silk radicals (· ΟΗ) are the most active and the shortest half-life since the city’, so it also has the most damage to the human body. Peroxide radicals have a longer half-life. This is the reason why peroxy radicals can diffuse to other places. Its generation is caused by other free radicals attacking unsaturated fatty acids (P0lyunsaturated fatty adds; pupAs). form. When peroxy radicals are born, lipid peroxidation begins. Yueyue's superemulsifying effect is the main mechanism for the damage of oxygen free radicals to the human body. ^^ Listed in the central nervous system, page 6 A: \ 8.030 pt. D. Ptd Description of the invention (3) In terms of system, Oxidation can cause damage to the brain and spinal cord, leading to the development of degenerative diseases, such as stroke, Parkinson's disease, and the like. On the cardiovascular side, endothelial cells can be destroyed, and the function of blood vessels is impaired, resulting in many cardiovascular diseases such as hypertension. 5 Injuries caused by myocardial ischemia (ischemia) and reperfusion (erfbsion) caused by hemorrhagic infarction are also related to lipid peroxidation. In blood, the cell membrane of blood cells can be ruptured, resulting in hemolysis. The cause of many serious diseases is lipid peroxidation. What exactly is lipid peroxidation? 10 When tissue cells are damaged, such as trauma, inflammation, etc., they can cause cell death. When Lai ruptures, the transition metal ions are released from the cells. These transition metal ions have redox capacity, which can lead to the generation of free radicals, which in turn triggers lipid peroxidation. In addition, these injuries will also activate epoxidized plum (cycl〇xygenase) and lipooxidized plum 15 (Π15yg_e), and these two enzymes will act on unsaturated moon fatty acids, generate free radicals, and can also trigger lipid Peroxidation. Field blood sclerosis, infarction | or abnormally contracted blood vessels, causing blood ^ f / ^ (perilision) ^ ii4c ^ m ^ jfc (my〇cardial ischemia) ° Country 20 Myocardial ischemia will be caused ^ # 不 整 而Enchanting ☆, based on research material Α.Λ8. 030 pt.d.ptd Page 7 503235 5. Description of the invention (f) If it is believed to be peroxidation damage due to oxygen free radicai . When myocardial ischemia, adenosine triacetate (Ατρ) is degraded into hypoxanthine and purine, and through the action of xanthine oxidase, superoxide anion is produced

5 (superoxide anion), and then through the redox capacity of the transition metal to generate hydroxyl radicals (hydroxyl radicals), these two free radicals will attack the cell membrane, which will produce lipid peroxidation, and expand the damage of tissue cells. When the blood cannot be perfused normally, the medicine usually given is nothing more than a vasodilator, a blood test lysing agent ', or a surgical operation to reperfusion. 10 Although reperfusion can provide oxygen to hypoxic cells, as shown in Figure 1, the entry of large amounts of oxygen makes lipid peroxidation more severe.

Free radicals can directly or indirectly attack the phospholipids of the cell membrane, resulting in lipid peroxidation. It is particularly easy to attack C2: 4 and C22: 6 unsaturated fatty acids, change the structure of the 15 cell membrane, and then disrupt cell functions. It can be seen from Figure 2 that lipid peroxidation is a chain reaction. If the reaction cannot be prevented in time, the damage will be chained. When free radicals attack unsaturated fatty acids, the Yuebi knife will rearrange and form conjugated diene.

W V. Description of the invention (5) (hydr. Ah ide), the most motivated purpose is to tilt down and record the second malt (mal ° ndialdehyde), so the calculation of the content of malondialdehyde (MDA) is Generally used to evaluate the degree of lipid peroxidation. In 1995, Uk〇, E. a., Et al. Yu Xia, "Xiao No. ⑺ 第 ⑹ Na Na page was only published in ~ patients with hemorrhagic diseases, including those with complications of heart blood T lesions, their blood A large amount of malondialdehyde (MDA) can be detected in polysaccharide and vascular tissues, such as patients with diabetes, hypertension, and arteriosclerosis. The content of malondialdehyde (MDA) in aging cells is also higher than that of normal cells. High. Research findings K) Malonic acid can react with some important molecules in the body, such as amino acids, proteins and nucleic acids, and cause harm to the human body. Previous technology 15 Magnolia is a plant of the Magnoliaceae family. In Sichuan, Guizhou, Xiangbei, Shaanxi, Jianjian, etc. Shennong Materia Medica contains: "Houpu attends strokes, typhoid headaches, hot rolls, consternation, Qijin therapy, dead muscles, and deworming." Liang Tao Hongjing's famous doctor said ... "" Hupok Wenzhong Yiqi, sputum and qi, cholera and abdominal pain fullness, cold inversion in the stomach, vomiting in the chest, bleeding diarrhea. " " Magnol phenol (masnol〇i) is in 1930, Japanese scholar Suzuo Sugii was extracted from the bark of medicinal parts of Magnolia officinalis in China. The thick batch contained in Magnolia officinalis

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The content is reported to be high, which accounts for about the dry weight of Magnolia; ^ # _, &, 77 —. In traditional medicine, humans have π and cardiovascular disease. In 1990, C.M. et al. Pointed out that its main component is Magnolia officinalis, 1/47, pp. 1153-1161, "intracellular flow, intravascular smooth muscle relaxation, anti-platelet callouts, and Inhibit serotonin secretion. ,1994? La, S •, et al. Unveiled a small number of different thick secrets (-1) as shown in Figure 3 in the ship shot No. Π page 273_277, and their knots also belong to the sword structure, which is different from hopu The relationship is isomers. Iso-Magnolol, Lo, YC, 1994 also proved to have strong anti-lipid peroxidation ability, but its activity was slightly inferior to magnolol. Methods for the synthesis of magnolol 15 Many literatures describe various methods for the synthesis of magnolol; for example, I9%

Feringa B. et al. Reported in a series of synthetic methods of magnolol with p-acrylic ether as starting material, as shown in Fig. 4, in 乂 rg c / 2, No. 98, η72 · 3373. The system is to remove p-allylanisde and boron tribromide-methyl sulfide complex to remove the methyl group and remove the methyl group to form p-allylphenol; chavic〇1) ; In the test environment, and then with potassium ferricyanide (potassium ferricyanide; K3Fe (CN) 6)

A: \ 8.030 pt. D. Ptd Page 10 503235 5. Explanation of the invention (7) Redox reaction is carried out to produce 2-C21 hydroxy-5- (2-propenyl) phenyl] -4- (2 propionyl ) Fen ((2- [2-hydroxy-5- (2-propenyl) phenyl] -4- (2-propenyl) phenol; magnolol) ° 5 In addition, KuPchan S · M · et al. In 1978 c% No. 43, page 4076-408, reveals a series of magnolol synthesis methods starting from p-propenylanisole (Kallylanisole) as shown in Figure 5. It is based on the use of dichloromethane as a bath, adding trifluororacetic acid (TFA) and triflutriacetic acid anhydride (TFAA), and oxidizing vanadium oxyfluoride (100 xytrifluoride; VOF3). Under the reduction reaction, p-methoxy-2 2- [2-methoxy-5-(2-propenyl) phenyl] -4- (2-propenyl) benzene (1-methoxy_2_ [2_meth〇 xy_5- (2-propenyi) phenyl] _4_ (2-pr〇pen_) Boron tribromide-methyl sulfide complex is used to remove the fluorenyl group to form 2- [2-hydroxy-5- (2-propene (Phenyl) phenyl] -4- (2-propenyl 15-yl) phenol ((2- [2 妨 droxy-5- (2-pr〇penyl) phenylH- (2-pro ^^ magnolol). He Dongying et al. 985 Taiwan Science No. 40, page 3M5 reveals a two-directional synthesis method as shown in Figure 6. The advantage of this method is that the synthetic route 20 is short, and the test drug is relatively; the disadvantage is that the yield is too low (0_25%). '' 'End products and by-products

The physical and chemical properties are too similar, which makes separation and purification difficult and cannot be mass-produced

Agharahimi, M.R., et al. Disclosed the synthetic method shown in Fig. 7 in I " 5 years / c / 2/2 60th page 1856-1863. The advantage of this method is that the yield rate can be 40% higher than the synthetic method of He Dongying et al. It is easier to purify because no by-products occur. Disadvantages are that the process is long, the reagents used are expensive, and the reaction conditions need to be performed under anhydrous, oxygen-free and low-temperature conditions, which has less industrial use value. / '10 The magnolol's basic structure is a combination of two phenolic rings, which is a bisphenol (biphenol) compound. Just 4 years in the literature, the anti-lipid peroxidation capacity of Magnolia officinalis is 15 thousand times that of vitamin E. The structure of magnolol is simpler than many known antioxidants. Therefore, this study used magnolol, a highly effective and simple structure, as a lead compound for structural modification. 15

Antioxidant ability of magnolol From previous research, through the method of “Clearer 1”, it has been shown that magnolol has much lower antioxidant capacity than vitamin E. However, if the method of measuring "chain breaker" is used, it is shown that magnolol has a stronger antioxidant effect than vitamin E.

Five, the invention said ΐΐντ --- --- type antioxidants. It can be seen from Figures 8, 9, and 10 that honokiol is significantly stronger than vitamin E in anti-lipid peroxidation, and is a disruptor of a powerful chain reaction. Magnolia shame plays a role of "clearer" in Figures 10, 11, and 12. It can be seen from the figure that the antioxidant capacity at this stage is much lower than that of vitamin E. OBJECTS OF THE INVENTION 10 The main purpose of the present invention can be divided into three parts; firstly, the novel synthesis method of magnolol is disclosed to improve the low-yield synthesis method in the literature. Second, it reveals two new series of compounds, such as formula I and formula II. OH ΟΗ

The above R refers to the following groups NM 丨 —; and & optional

Use Κ · ί: Η2-) ιι-οαϊ2-η2, — (called ―CH

ΑΛ8 · 〇3〇 pt.d.ptd Page 13

Thirdly, it reveals that the pharmacological activity test of the new Magnolia officinalis two series of compound 1 shellfish compounds has good antioxidant activity, anti-free radical activity J1, and has the effect of lowering blood pressure, which can be developed into cardiovascular drugs. Column description Table 1 Physical properties and chemical properties of 2- [3-substituted methyl-2-hydroxy-5- (2-propenyl) phenyl (2-propenyl) pan compounds. Table 2 2- [2- Physical and chemical properties of (3-substituted 2-hydroxypropoxy) -5- (2-propenyl) benzyl] -4- (2-propenyl) phenol series compounds

A: \ 8.030 pt. D. Ptd Page 14 Diphenylnitro_PPH) Test of antioxidant ability to scavenge free radicals. Table Illustrates the activity of lowering blood pressure. . Lipid peroxidation: the rugged structure of dimagneol (magnet) and iso- magnolol. Figure 4. FeringaB. Et al. Synthetic magnolol. Figure 5. KupchanS.M. Et al. Synthetic magnolol. Method of synthesizing Magnolia officinalis by He Dongyang Xunren Figure 7 Aghamhimi, MR · et al. Method of synthesizing Magnolia Officinalis Fig. 8 Magnus (magndd, ·) and Vitamin E Oxygen capacity (n = 6) Figure Nine magnolol (Lu) and vitamin E (a_Tcxx) pheiOU〇 ability to inhibit malondialdehyde (μ〇α) in myocardial mitochondria (n = 6) Magnolol (ginseng) and vitamin e (a_T〇c〇pher〇1A) inhibit the ability of myocardial mitochondria to produce conjugated diene (n = 3)

Magnolol (♦) and Vitamin E (a-Tocopherol, 503235 V. Description of the Invention (12) ▲) After reacting with the diphenylnitro trap (DPPH) for 90 minutes, the ability to scavenge the diphenylnitro trap free radicals (n = 3) Figure twelve magnolia ^ (magnoll, spring) and vitamin E (α-Tocopherol, ▲) h divided ^-the ability of the free radicals of the radical shokeyphine 'to test the concentration of 200 μM, ( η = 3) Figure 13 Ability of the compound of the present invention to scavenge diphenylnitro trap radicals (η = 3) Figure 14 Ability of the compound of the present invention to scavenge diphenylnitro trap free radicals (η = 3) Figure 15 Ability of the compound to produce malondiol (η-3) 15 20 Detailed description of the invention The present invention can be mainly divided into three parts; one is a novel σ-forming method of magnolol, and the other is a novel magnolol. A large series of compounds, three of which are novel magnolia _ big _ compounds, which have good antioxidant activity 'anti-radical activity' and lower blood pressure, and can be developed into cardiovascular drugs.

ΑΛ8.030 pt.dptd page 16 " In order to achieve the purpose of the present invention, detailed analysis of the reverse synthesis of thick secrets, we will know that :: direction of the hand to synthesize magnolol,-first is to synthesize p-propenol, and then ^ money 1-position leads to acrylic. According to 1992 Singh, B, et al. In J; c / Dirty No. 35, No. 4,858_4, the ship reported that a series of derivatives containing Marizil (Mannic-based hopes, in which Pyridylmethylnepan ((1_py_dine sentence!) Deleted ^ naphthd · HC1) has a strong 々-type blood-lowering activity. The synthesized compound Magnolia officinalis 5 as a skeleton is introduced into a series of horses that may have activities such as lowering blood pressure. Mannich bases are expected to have good antioxidant activity, as well as cardiovascular activity such as lowering blood pressure. The compounds synthesized by the present invention as the backbone compound are selected by two methods including: The first is to take magnolol and formic acid, add a second amine derivative, and heat and stir under acidic conditions to fully react, then concentrate under reduced pressure, and then purify and recrystallize. (Mannich) salt, 2- [3-substituted fluorenyl group of formula j-5_ (2-propenyl) phenyl Ml propyl group [3-substituted methyl.2-hydroxy-5 < 2.propenyl ) phenyl] «4 < 2-pr〇penyl) 15 Phen〇1S). Another series of synthetic methods are to dissolve honokiol in tetrahydrofuran, and under experimental conditions, add gas methyl hydrazone finely to the reaction; all preliminarily add μμ-2,3-cyclo Oxypropane, heated to reflux; added hexahydropyridine derivatives, heated to reflux, concentrated under reduced pressure, purified and recrystallized to obtain each intermediate product, and purified by Shixi column chromatography to obtain the formula 孓 [2_ρ 503235 V. Description of the invention (14) Substituted 2-propenylpropoxy) _5_ (2_propenyl) phenyl) _4_ (2_propenyl) pan (2_P_ (3-substituted ^ 2-hydroxypropoxy) -5 < 2 -propenyl) phenyl-4- (2-propen ^ -phenols]) 〇

ΟΗ I 1 I 10 The above-mentioned R means the following groups-0-A-r, ^ compounds of the formula 酚 and formula π honokiol, whose structures are shown below.

_ (_ CH2-) n-C-CHrR27 (CH2) "c Η CH factory 蛘 (CH2) n- 15; and R2 is optional

N = (χ Ν CHr 蛘 (CH ^

ο ο ′ Wherein r3 can be selected from halogen, hydrogen, methyloxy, ethyloxy, propyloxy, N02, η is a natural number of 0, i, 2, 3.

A: \ 8. 030 nt Price page 18 503235 V. Description of invention (15) 15

Therefore, r can still represent the following groups r ~ \ N —N Ν ′ R3 W

—N N-CH2 ·

Ο ο 〇-〇-r3 -Ο -Ν Ν '

Ν Ν

The compound prepared by the present invention is purified by a purification method or after crystallization, respectively (mp), elemental analysis, mass spectrometry (infrastructure), infrared spectrum (melon), nuclear magnetic resonance spectrum (1H side R, also donkey), and ultraviolet absorption. (uv) and other physical and chemical information. —The two series of compounds of formula 1 and formula ΠHupanpan synthesized by the present invention have been tested in Example 24,-本 r #-fifteen, twenty-six music theory activity test, the results are shown in Figure 25 2-20 Γ Figure 15 'and the compounds shown in Table 3 are like free radicals

Α: \ 8. 030 pt. D. Ptd _ Park Ye, also better than the clinical drugs Trolox and General

Page 19 503235 V. Description of the invention (16) Probucol is stronger. Example 25 The anti-lipid peroxidative activity test was performed on the whole brain tissue of SD rats. The results showed that the compounds Ec_5, Ec_6, EG_9, EC_lG, mo, and EC-25 have higher anti-lipid peroxidative activity than Magnolia. Phenol is strong, and EC_is0 is equivalent to honokiol. The changes in blood pressure and heartbeat are shown in Table 4. The compound of the present invention is added with various excipients, such as magnesium stearate, corn meal, starch, lactose, sodium methylcellulose hydroxycellulose, ethanol, glycerol, etc., or 10 diluents and lubricants. , Flavoring agents, dismtegmnts, binders, or coloring agents, sweeteners to make lozenges or other solid preparations, and phosphate-based buffers to adjust the pH value can be made into injections or Other liquids and various dosage forms. The solid dosage forms include tablets, lozenges, powders, capsules, sublingual tablets, granules, and the like. The pharmaceutically acceptable acid addition salt of the present invention 15 and the pharmaceutical product of the pharmaceutically acceptable acid addition salt, except In addition to solid dosage forms for oral administration and rectal administration, they can also be prepared as effective amounts of injection forms, liquid dosage forms, parenteral injection forms or ointment forms directly applied to the affected area. General dosage 503235 5. Description of the invention (17) ---- It can be adjusted according to the symptoms, usually 50 mg to 300 mg per person,

I 3 times a day. 5 Beifang β Example 1 Synthesis of magnolol IS · 6 g (0.100 mol) 2, 2, -biphenol was placed in a 500 ml reaction flask, and 24.2 g (0.200 mol) of propylene bromide was added. And 〇20g (1500mm) of copper (II) chloride, add 30ml of water 'and fill with nitrogen, heat and reflux for 10 hours, and then add a saturated sodium bicarbonate aqueous solution' to neutralize the reaction The resulting bromic acid was extracted with ethyl acetate and water, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (ether: hexane = 1: purified on white crystalline product, and weighed to obtain MG). (28.5%). The melting point and physical and chemical properties of magnolol of this product are the same as those of pure products of natural origin. Examples 2 to 8 15.1 EC-2, EC-3, EC-4, EC-5, EC- 9, EOIO, EC-11 2-[3-substituted fluorenyl-2-hydroxy-5- (2-propenyl) phenyl] -4 4- (2-propenyl) phenol (2- [3-substituted methyl- 2But droxy_5 fenpropeny_ ^ prcpenyl) phen〇is) General synthesis method 20 Take 0 · 200δ (0 · 752ηιη101) honokiol dissolved in 10ml of ethanol, add 0.83 mmol of the second amine derivative, and heat and stir Five hours, concentrated under reduced pressure, and recrystallized to obtain each product EC-2, EC. , EC_4, ec_5, Ec_9 Page 21 A: \ 8.030 ptd.ptd 503235 V. Description of the invention (18) EC-10, ECM1 analysis data are shown in Table 1. Example Nine 2-[2-Methoxymethyloxy-5- (2-propenyl)] phenyl-4- (2-propenyl) 5 S ^ (2- [2-methoxymethoxy-5- (2 -propenyl)] phenyl-4- (2-prc) penyl) phenol, EC-7) Take 0.20 g (0.752 mmol) of honokiol and dissolve it in 10 ml of tetrahydrofuran and place it in a reaction flask. in. Take 0.020 g (0.883 mmol) of sodium hydride and dissolve it in 1 ml of tetrahydrofuran. This solution was slowly added to the reaction flask, stirred at room temperature for 15 minutes, and allowed to stand for 5 minutes. Good; drop for 1 hour 'at the end. Slowly add 60.5 mg (0.572 mmol) of chloromethylfluorenyl ether, stir at room temperature for 12 hours, and concentrate to dryness under reduced pressure. After drying, perform column chromatography (EA : Hexane = 1: 5) Purification, the weight of the obtained product was 162 g, yield 81%. 15 UV (EtOH) λ max · 290 5 214 nm. MS (El, 70 eV): m / z (%) = 310 [M +] (100%) IR (KBr): 3320, 3210, 2924, 1644, 1589 , 1504, 1410, 1200, 1010, 912, 820 cm · 1 20 'H-NMR (300 MHz ^ CDC13) 5: 3.42 (3H? S, CHpCH2), 3.45 (4H? D, J 2 5 · 2Ηζ, 2 X CH2CH = CH2), 5.12 (4H, m, 2 X CH2CH = CH2), 5.16 (2H, s, OCH2〇), 6.05 (2H, m, 2X CH2CH = CH2), 6.20 (1H, s, OH), 7.00-7.23 (6H, m, 6 X Ar-H)

A: \ 8. 030 pt. D. Ptd Page 22 503235 5. Description of the invention (19) 13C-NMR (75 MHz, CDC13) (5: 40.5, 57.0, 96.6, 116J, 116.6, 117.2, 117.8, 126 · 6,129 · 0, 130.0, 131.8, 132.9, 135.8, 137.90, 152.5.

Rf (ΕΑ: Hexane = 1: 5) = 0.50 5 Elemental analysis: Molecular formula C2 () H2203 Theoretical value C, 77.39; H, 7.14 Actual value C, 77.11; H, 7.19 Example 10 10

H ethylene oxide-2-ylfluorenyloxy) -2-[(2-fluorenyloxy-5- (2-propanyl) phenyl] -4- (2-propylenyl) benzene (L- ^ oxiranJ-ylmethoxy ^-^-methoxy methoxy-5- (2 enzyme propenyl) phenyl] Draw '(2 significant propenyl) benzene, EC-8) 15

Take 0.20 g (0.64 mmol) of the product EC-7 from Example 9 and dissolve it in 10 ml of ethanol, put it in a reaction flask, and add 476.5 mg (5.1 mmol) of 1-chloro-2, 3 -Propylene oxide, stir well, heat and reflux for 2 hours, stand, and concentrate to dryness under reduced pressure. Purify the product by chopping column chromatography (EA: Hexane = 1: 5). The weight of the product is 0.21 g 20. Yield 100%. UV (EtOH) λ max: 285 > 217 nm. MS (El, 70 eV): m / z (%) = 366 [M +] (100%) IR (KBr): 3289, 308 2950, 1640, 1504 , 1410, 1350, 1270, 25 1010, 912, 840, 820 cnT1. ^ -NMR (300 MHz, CDC13) 5: 2.76 (2H, d, J = 2.8 Hz, CH2OCH),

A: \ 8.030 pt. D. Ptd page 23 503235 5. Explanation of the invention (20) 3.36 (3H, s5 CHPCH2), 3.39 (4H, d, J = 8.7 Hz, 2X CH2CH = CH2), 5 · 05 (4H, m, 2XCH2CH = CH2), 5.07 (2H, s, OCH2〇), 6.01 (2¾ m, 2 X CH2CH = CH2)? 6.91-7.15 (6H, m, 6 X Ar-H) 5 I3c -NMR (75 MHz, CDC13) (5: 40.0, 50.8, 56.4, 69.9, 96.2, 113.7, 116.1, 116 · 3, 129.3, 129.0, 132.4, 133.2, 138.3, 154.0, 154.99.

Rf (EA: Hexane = 1: 5) = 0.40 Elemental analysis: molecular formula c23h26o4 10 theoretical value C, 75.38; H, 7.15 actual value C, 75.39; H, 7.28 Examples H to twenty-three 15 2— [2— ( 3-substituted 2-hydroxypropoxy) -5- (2-propenyl) phenyl] -4- (2-propenyl) pan (2- [2- (3-substituted 2-hydroxypropoxyy5-(> piOpeiiyl ) phenyl-4- (2-propenyl) phenols, EC-130 ~ EO250) 1.2 g (3.28 mmol) of the product EC-8 of Example 10 was dissolved in 50 ml of methanol, and 20 were added to 6.56 noodles. Hexahydrogen derivative (if it is an argonized derivative, an equal amount of sodium bicarbonate needs to be added to remove hydrochloric acid), heated to reflux for 5 hours, concentrated under reduced pressure, purified and recrystallized to obtain each intermediate Product. The intermediate product was directly reacted without the structural identification. Take 3 ~ 10mm of the above intermediate product respectively, and dissolve it in Τρρ: ρ Pr〇H = 1

503235 V. Description of the invention (21) ------- After that, add a saturated carbonated oil solution to neutralize it, and then partition it into water and ethyl acetate. The organic layer is concentrated under reduced pressure. Analytical purification, the following second series of products EC-130, EC_14〇, EC_15〇, Ec i60, this loss, EC-180 > EC-190 ^ EC-200 ^ C-21〇.EC-220 > EC-23〇.EC-240 ^ EC-25〇5 5 Analytical data are shown in Table 2. Example Twenty-four Diphenyl Nitro Trap (DPPH) Test Antioxidant activity According to the method disclosed in I% 6-year Mellors, A. et al., J. Imitation 0 / c ~ m, Issue 10, p. 4353, Phenyl nitrate (Dppfi) was dissolved in ethanol and configured to 100 / zM. The test subject was dissolved in ethanol, which was configured as 100 # m, 50 # m, 20 / zM and 10 // M. The test specimen was added to the diphenylnitro trap in the dry mail winter piciyhydrazyl (DPPH). Medium, stir evenly, let stand for% minutes, measure its absorbance at a wavelength of 517nm, and estimate the activity of scavenging free radicals from the measured absorbance. 15 Example 25 Antilipid peroxidation activity period according to I% 6 years Teng, CM, et al. Wu Wu Pharmarca ^ 3〇3 Μ page 25 A: \ 8.030 pt. D. Ptd i 503235 V. Description of the invention (22) The method disclosed on page I29439, taking 8 weeks offender Rat whole brain tissue, with cerebellum removed. Rinse with ice-cold krebs buffer and homogenize with a Dow homogenize! *. Centrifuge at low speed for 10 minutes at low temperature. Add ιιο // M the compound to be tested for activity and let stand for 10 minutes. 2 called m 5 ferrous ion was added and reacted at 37 for 30 minutes to induce lipid peroxidation. Add 10 // M ice-cold three-gas acetic acid solution and 200 / zM thiobarbituricacid as the coloring agent, react for 1 minute under boiling water, take it out, wait for it to cool, and then add 1ml of n-butyl Alcohol, centrifuge for 5 minutes, take out the organic layer, and measure its absorbance at 532nm to estimate its anti-lipid peroxidation activity. 10 Example 26 The antihypertensive test of peripheral drug administration is in accordance with I " 3 year Tao , RL ·, et al., No. 243, pp. 135-15, disclosed the method of taking male rats with spontaneously hypertensivr rats aged 10 weeks and weighing about 25-30 g, and intraperitoneally injecting 50 mg / kg After pentobarbital anesthesia, femoral artery and femoral vein were inserted

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tube. Heparin-filled pdyethyiene'g (PE-5G) was inserted into the femoral artery and connected to a pressure transducer (G. Shestatham PMID) to detect gray pressure, while the heartbeat used blood pressure Connected to a heartbeat monitor (Tach〇meter, Grass Co.), the change was recorded by a high-grade (g · M〇㈣7d physiological polygraph), and a saline-filled catheter was inserted into the femoral vein. For dosing and replenishing body fluids. For tracheal intubation (PE ·) to prevent the trachea from being blocked by sputum and for supplying oxygen. After the operation is completed, wait for the animal's blood pressure and heartbeat to stabilize for 30 minutes, and open platinum for administration. 0.4 mg / 2 00 g of the drug to be tested was injected through the venous cannula, and the remaining drug on the catheter wall was flushed with 0. 10 physiological saline, and the changes in heartbeat and blood pressure were recorded.

Mean blood pressure (MBP) calculation: [(systolic blood pressure-diastolic blood pressure) / 3] + diastolic blood pressure 15

503235

A: \ 8.030 pt. D. Ptd Page 28 503235 V. Description of the invention (25) EC-2 R -〇UVEtOH Max (nm) 303 218 MS (El, 70 eV) m / z (%) 349 (M \ 38) 237 (100) ER (cnrl) KBr 3248, 3080, 2975,1644, 1470, 1316,1148, 1072, 912,834 lH-NMR (300 MHz, CDC13) (5 (ppm) 1.60 (4H, m, 2 XNCH2CH2) 2.75 (4¾ m, 2XNCH2) 3.39 (4H, cU = 6.8Hz, 2XCH2CH = CH2) 3.58 (2H, s, ArCH2N) 5.08 (4H, d5 J = 7.0 Hz, 2XCH2CH = CH2) 6.00 (2H, m, 2XCH2CH = CH2) 6.91-7.20 (5H, m, 5xAr-H) l3C-NMR (75 MHz, CDCI3) < 5 (ppm) 24.7, 40.10, 56.1, 113.5, 116.0, 116.7, 117.5, 126.6, 129.4 , 130.4, 132.9, 143.2, 154.1, 155.4 Rf (Acetone: Hexane = 1: 1) 0.45 Melting point (ec) 110-111 Column chromatography extraction solvent Acetone: Hexane = 1: 1 Molecular formula C23H27NO2

A: \ 8.030 pt.dptd Page 29 503235 V. Description of the invention (26) EC-4 R h3co 'UVEtOH max (nm) 288 216 MS (El, 70eV) m / z (%) 470 (M +, 6.0) 150 (100) JR (cm * 1) KBr 3284, 3080, 2948, 2895, 2816, 1644, 1594, 1504, 1470, 1246, 918, 750 lH-NMR (300 MHz, CDC13) δ (ppm) 2.40 (4H , t, J = 6.8Hz3 CH2N (CH2) 2) 2.92 (4H, t, J = 6.81Hz, (CH2) 2NAr) 3.28 (4H, d, J = 4.5 Hz, 2xCH2CH = CH2) 3.54 (2H, s, ArCH2N) 3.79 (1H, s, OCH5) 5.02 (4H, d, J = 9.9 Hz, 2xCH2CH = CH2) 5.92 (2H, m, 2xCH2CH = CH2) 6.66-6.97 (9¾ m, 9χΑτ-Η) 13CNMR ( 75 MHz, CDCI3) δ (ppm) 48.2, 52.9, 61.1, 115.5, 116.8, 121.1, 127.9, 128.2, 128.5, 129.8, 130.6, 131.4, 138.8, 153.9, 155.2 Rf (Acetone: Hexane = 1: 5) 0.24 soluble (Point cc) 111-112 拄 Chromatographic extraction solvent EA: Hexane = 1: 5 Molecular formula c3〇h34n2〇3

A: \ 8.030 pt.d. ptd Page 30 503235 V. Description of the invention (27)

Page 31 EC-5 R—ί /) UVEtOH 293 into max (nm) 266 MS (El, 70eV) 365 (Μ +, 13) m / z (%) 236 (100) IR (cm4) KBr 3234, 3080, 3060, 2984, 2959, 2900, 2857, 1635, 1608,1504,1468, 1237,1128,993,910, 876 lH-NMR 2.32 (4Η, t, J = 5.0 Hz, 2xNCH2CH20) (300 MHz, CDC13) 3.38 (4Η, d, J = 4.5 Hz, 2xCH2CH = CH2) δ (ppm) 3.51 (2H, s, ArCH2N) 3.62 (4H, t, J = 5.0 Hz, 2xNCH2CH2〇) 5.07 (4H, d, J = 5 · 2 Hz, 2xCH2CH = CH2) 5.97 (2¾ is called 6.89-7.26 (5H, m, 5 > &Ar; H) l3C-NMR 46.7, 68.1, 115.7, 116.1, 116.3, 121.3, 127.6, 128.8, (75 MHz, CDCI3) δ (ppm) 130.1, 131.4, 140.2, 141.6, 153.7, 155.4 Rf (Acetone: Hexane = 1: 3) -0.45 melting point 〇c) 119-110.5 Column elution solvent EA: Hexane = 1: 3 Molecular formula C23H27NO3 A: \ 8. 030 pt. D. Ptd 503235 V. Description of the invention (28) EC-9 R -οϋ UVEtOH 298 λ max (nm) 247 216 MS (El, 70eV) 441 (M +, 47) m / z (%) 279 (100) IR ^ m- ^ KBr 3416, 3074, 3026, 1658, 1554, 1282, 1264, 1120, 1043, 1002,912,828 lH-NMR 2.76 (4H, m, CH2N (CH2) 2) ( 300 MHz, CDC13) 3.02 (4H, t, J = 7.01, (CH2) 2NAr) δ (ppm) 3.41 (4H, d, J = 4.5 Hz, 3.86 (2H, s5 AtCH2N) 5.09 (4H, d, J = 3.4 Hz, 2xCH2CH = CH2) 6.00 ( 2¾ m, 2xCH2CH = CH2) 6.62-8.21 (9H, m, 9χΑτ-Η) l3C-NMR 30.3, 40.1, 45.6, 52.8, 62.1, 107.7, 114.5, 116.0, (75 MHz, CDCI3) 119.1, 121.2, 128.8, 129.8,131.6,132.5,138.2, < 5 (ppm) 152.2,153.1,159.6 Rf (Acetone: Hexane = 1: 5) 0.18 Melting point rc) 103-104 Elution chromatography solvent EA: Hexane = 1: 5 Molecular formula C ^ H31N302

A: \ 8. 030 pt. D. Ptd Page 32 503235 V. Description of the invention (29)

EC-10 R UVEtOH into max (nm) 290 214 MS (El, 70eV) m / z (%) 499 (Μ ", 15) 135 (100) IR (cm4) KBr 3220, 3080, 2956, 2900, 2816, 1644,1608,1498, 1442, 1238,1044,1008, 918, 820 lH-NMR (300 MHz, CDC13) δ (ppm) 2.63 (4H, m, 2xCH2NCH2) 3.36 (4H, m, 2 > < CH2NAr) 3.81 (2H, s, ArCH2N) 4.14 (4H, d, J = 7.1 Hz, 2xCH2CH = CH2) 5.10 (4H, d, J = 3.4 Hz, 2xCH2CH = CH2) 5.94 (2H, s, 2x〇CH2〇) 6.02 (2H, m, 2xCH2CH = CH2) 6.74-7.17 (8H, m, 8 > < Ar-H) l3C-NMR (75 MHz, CDCI3) < 5 (ppm) 40.1, 53.0, 61.9, 63.0, 101.5, 108.5, 109.9, 116.3, 119.1, 121.3, 122.8, 127.4, 128.6, 129.7, 131.9, 132.1, 138.6, 148.3, 152.5, 153.2 Rf (Acetone: Hexane = 1: 3) 0.24 Melting point (ec) 109-110 Column chromatography Extraction solvent EA: Hexane = 1: 3 Molecular formula c31h35n2o4 Page 33 A: \ 8. 030 pt. D. Ptd 503235 5. Description of the invention (30)

EC-11 R -0 ^ 3 UVEtOH 299 into max (nm) 211 MS (El, 70eV) 442 (Μ '63) m / z (%) 279 (100) IR (cirfl) KBr 3422, 3225, 2934, 2816 , 1665, 1565, 1504, 1246, 1050,1008,910,828 lH-NMR 3.37 (4Η, d, J-5.0 Hz, 2xCH2CH = CH2) (300 MHz, CDCI3) 3.85 (2H, s5 ArCH2N) < 5 (ppm ) 5.08 (4H, d, J = 7.8 Hz, 2xCH2CH = CH2) 5.30 (2H, s, 2xAr〇H) 6.00 (2H, m, 6.53-8.33 (8H, m, 8 > < Ar-H) l3C- NMR 30 · 2, 40.1, 43.9, 52.9, 62.2, 111.0, 116.0, 119.1, (75 MHz, CDCI3) 121.2, 126: 9, 128.8, 129.8, 131.7, 132.1, 133.0, δ (ppm) 138.5, 152.2, 153.1, 158.3 , 162.0 Rf (Acetone: Hexane = 1: 1) 0.30 Run point 〇c) 98-100 column chromatography extraction solvent EA: Hexane = 1: 3 Molecular formula CANA

A: \ 8. 030 pt. D. Ptd Page 34 503235 V. Description of the invention (31) Table II EC-130; R = —:

EC-250

OCH,

Μ Α: \ 8. 030 pt. D. Ptd p.35 503235 5. Description of the invention (32) EC-130 R -0-0 UVEtOH 290 max. (Nm) 212 MS (El, 70 eV) 485 (M +, 7} m / z (%) 176 (100) IR (cm * l) KBr 3324, 3172, 3080, 2974, 2900, 2816, 1734, 1534, 1484, 1422, 1279, 1244, 1128, 1002, 926, 821 3.39 (4H, d, J = 5.8 Hz, 2xCH2CH = CH2) (300 MHz, CDC13) 3.51 (4H, t, J = 4.8 Hz, (CH2) 2NAr) δ (ppm) 5.07 (4H, d, J = 16.8 Hz, 2xCH2CH = CH2) 5.99 (2H, m, 2xCH2CH = CH2) 6.96-6.99 (1H51, J = 5.34, Pyridine-H!) 7.05-7.17 (1H, t, J = 8.73, Pyridine-Ηί) 8.18 -8.21 (1H, m, J = 5.1, Pyridine-Hf) l3C-NMR 40.0, 45.8, 53.7, 66.0, 71.8, 107.6, 113.4, 114.1, (75 MHz, CDCI3) 116.1, 118.5, 129.6, 131.9, 133.0, 134.5,138.1, < 5 (ppm) 148.5,152.5, 153.9,160.0 Rf (Acetone: Hexane = 1: 1) 0.40 melting point 〇c) 97-99 Column chromatography extraction solvent EA: Hexane = 1: 3 Molecular formula C30H35N3O3 Page 36 A: \ 8.030 pt. D. Ptd

503235 V. Description of Invention (33)

EC-140 R -〇-〇H3C (/ UVEtOH 284 into max (nm) 209 MS (El, 70 eV) 514 (M +, 6) m / z (%) 205 (100) IR (cinl) KBr 3366, 3256 , 3080, 2942, 2828, 1644, 1594, 1504, 1282, 1246, 1128, 1008, 918, 785 lH-NMR 3.09 (4H, t, J = 5.1 Hz, (CH2) 2NAr) (300 MHz, CDC13) 3.21 (1H, s5 CH2CH〇H) < 5 (ppm) 3.39 (4H, d, J = 5.8 Hz, 2xCH2CH = CH2) 3.73 (3H, s, OCH2) 3.94 (2H, s, -OCH2-) 5.09 (4H, d, J = 2 · 7 Hz, 2xCH2CH = CH2) 5.99 (2H, m, 2xCH2CH = CH2) 6.82-7.40 (10H, m, 10xAr-H) 13C-NMR 40.3, 52.9, 61.2 , 115.6,116.8,121.1,127.9,128.2, (75 MHz, CDCi3) < 5 (ppm) 128.8, 129.8,130.3,131.4,138 / 7,153.9,155.4 Rf (Acetone: Hexane = 1: 2) 0.24 Melting point (ec ) 132-133 column chromatography extraction solvent EA: Hexane = 1: 3 Molecular formula ^ 32 ^ 38 ^ 2〇4 Page 37 A: \ 8.030 pt. D. Ptd 503235 5. Description of the invention (34) EC-150 R -〇-〇 ^ f UVEtOH 289 into max (nm) 208 MS (El, 70 eV) 502 (Μ ") m / z (%) 193 (100) ER (cnrl) KBr 3318, 3171, 2942, 2900, 2829 , 1644,1607, 1518, 1462,1419,1224, 1282,1088, 926, 834 lH -NMR 2.73 (2H, cU = 5.0 Hz, CHCI ^ N) (300 MHz, CDC13) 3.01 (4H, t, J = 4.4 Hz, (CH2) 2NAr) δ (ppm) 3.39 (4H, 4 J = 4.7 Hz, 2xCH2CH = CH2) 5.07 (4H, d, J = 2.5 Hz, 2xCH2CH = CH2) 5.99 (2H, m, 2 > < CH2CH = CH2) 6.71-7.23 (10H, m, 1〇χΑτ-Η) 13C-NMR 40.2, 50 · 9, 54.1, 60.4, 66.0, 71.8, 76.8, 113.5, 115.9, (75 MHz, CDC13) 116.5, 118.7, 158.2, 128.8, 130.7, 133.0, 137.6, δ (ppm) 137.4, 148.4 , 152.5,153.8,159.4 Rf (Acetone: Hexane = 1: 1) 0.60 Melting point 〇c) 144-145.5 'Column chromatography extraction solvent Acetone: Hexane = 1: 2 Molecular formula c31h35n2o3f Page 38 A: \ 8.030 pt. D . ptd

503235 V. Description of the invention (35) EC-160 R-UVEtOH 289 max (nm) 244 232 MS (El, 70 eV) 486 (Μ +) m / z (%) 176 (100) IR (cm-1) KBr 3338, 3228, 3075, 2942, 2814, 1558, 1554, 1456, 1364, 1260, 1134,988,924,806 lH-NMR 2.60 (2Η, d, J = 5.3 Hz, CHCI ^ N) (300 MHz, CDC13) 3.38 ( 4H, d, J = 5.7 Hz, 2xCH2CH = CH2) (5 (ppm) 3.80 (4H, t5 J = 4.8 Hz, (CH2) 2NAr) 5.07 (4H, d, J = 2.5 Hz, 2xCH2CH = CH2) 5.99 ( 2H, m, 2xCH2CH = CH2) 6.51-7.15 (7H, m ^ Ar-H) 8.31 (2H, d, J = 3.87, Pyrimidine-H46) l3C-NMR 40.0, 44.2, 53.7, 60.7, 66.0, 71.8, 110.6 , 113.4, (75 MHz, CDCI3) 116.1, 118.4, 127.3, 128.3, 129.7, 131.9, 133.0, δ (ppm) 134.5, 137.4, 152.5, 153.9, 158.3, 162.1 Rf (Acetone: Hexane = 1: 2) 0.32 Melting point (° c) 92-95 column chromatography extraction solvent Acetone: Hexane = 1: 2 Molecular formula C29H34N4O3

A: \ 8. 030 pt. D. Ptd Page 39

503235 V. Description of Invention (36)

EC-170 R -ΌΌ UVEtOH max (nm) 288 212 MS (El, 70 eV) m / z (%) 484 (M〇175 (100) IR (cm * 1) KBr 3310, 3172, 2934 , 2822,1644, 1602,1504,1455, 1282, 1232, 1148,1088,926, 834 lH-NMR (300 MHz, CDC13) (5 (ppm) 2.60 (2H, d, J = 5.4 Hz, CHCH ^ N ) 3.17 (4H, t, J = 4.8 Hz, (CH2) 2NAr) 3.39 (4H, d, J = 6.6 Hz, 2xCH2CH = CH2) 5.09 (4H, d, J = 13 Hz, 2xCH2CH = CH2) 6.01 (2H, m, 2xCH2CH = CH2) 6.87-7.32 (9H, m, 9 > < Ar-H) liC-NMR (75 MHz, CDCI3) δ (ppm) 40.1, 49.8, 53.9, 60.5, 66.0, 71.8, 113.4, 116.1, 116.5, 116.7, 118.5, 120.4, 127.4, 128.3, 129.7, 131.9, 133.0, 138.4, 151.7, 152.5, 153.9 Rf (Acetone: Hexane = 1: 2) 0.38 melting point rc) 125-126 chromatography Solvent Acetone: Hexane = 1: 2 Molecular formula C3iH36N203 A: \ 8.030 pt.d.ptd 503235 V. Description of the invention (37) EC-180 R-0 name UVEtOH 288 into max (nm) 212 MS (El, 70 eV) 574 (Mm / z (%) 167 (100) IR (cm-1) KBr 3346, 3273, 3080, 2927, 2822, 1644, 1608, 1506, 1420, 1280, 1149, 1008, 926, 825 'H- NMR 2.07 (1H, s, Ci ^ CHOH) (300 MHz, CD C13) 2.61 (2H, d, J = 5.7 Hz, CHCH2N) < 5 (ppm) 3.38 (4H, d, J = 6.6 Hz, 2xCH2CH = CH2) 4.21 (1H, s, ArOH) 5.07 (4¾ 4 J = 7 · 7 Hz, 2xCH2CH = CH2) 6.00 (2H, m, 0.98-7.43 (16¾ m, 16xAr-H) 13c-nmr 40.0, 52.5, 60.3, 65.7, 71.8, 113.3, 116.1, 118.7, (75 MHz, CDCI3 ) 127.5, 128.5, 129.1, 129.8, 133.0, 134.5, 138.0, < 5 (ppm) 143.2,152.5, 153.8 Rf (Acetone: Hexane = 1: 2) 0.37 melting point fC) 128-130 column chromatography eluent Acetone : Hexane = 1: 2 Molecular formula 匸 38 仏 # 2〇3

A: \ 8.030 pt. D. Ptd p. 41 503235 5. Description of the invention (38) EC-190 R UVEtOH 286 into max (nm) 213 MS (El, 70 eV) 518 (NT) m / z (%) 208 (100) IR (cm-1) KBr 3360, 3256, 3074, 2942, 2829, 1644, 1587, 1504, 1282, 1128, 1001, 912, 820 lH-NMR 2.06 (1H, s, CH2CH〇H) (300 MHz, CDC13) 2.24-2.80 (8H, m, (CH2) 2N and (CH2) 2NAr) δ (ppm) 3.05 (2H, d, J = 4.8 Hz, CHCH2N) 3.39 (4H, d5 J = 3.6 Hz, 5.07 (4H, d, J = 7.7 Hz, 2xCH2CH = CH2) 5.14 (1H, s, Ar〇H) 6.00 (2H, m, 2xCH2CH = CH2) 6.99-7.45 (10H, m, 1〇χΑτ-Η) 13c- nmr 40.0, 51.7, 54.0, 60.5, 65.9, 71.8, 113.4, 116.1, (75 MHz, CDCI3) 118.5, 120.6, 124.4, 127.4, 128.3, 129.8, 131.8, δ (ppm) 134.0, 138.0, 149.6, 152.5, 153.9 Rf (Acetone: Hexane = 1: 2) 0.30 Melting point 〇c) 103-104.5 Column chromatography eluent Acetone: Hexane = 1: 2 Molecular formula c31h35n2o3ci Page 42 A: \ 8. 030 pt. D. Ptd

503235 V. Description of Invention (39)

A: \ 8.030 pt.d.ptd EC-200 R _0_ < aF UV EtOH 288 into max (nm) 214 MS (El, 70 eV) 610 (NT) M / z (%) 233 (100) IR (cm4) KBr 3346, 270, 3080, 2928, 2822, 1644, 1608, 1512, 1420, 1279, 1226, 1155, 1008, 926, 834 ^ -NMR 2.07 (1H, s, CH2CH〇H) (300 MHz, CDC13 ) 2.30-2.44 (8H, m, (CH2) 2N and (CH2) 2NAr) 0 (ppm) 3.39 (4H, d, J = 6.3 Hz, ZxCHzCHCiy 4.20 (1H, s5 ArOH) 5.07 (4H, d, J = 7.7 Hz, 2xCH2CH = CH2) 6.00 (2H, m, 2xCH2CH = CH2) 6.90-7.37 (14H, m, 14xAr-H) l3C-NMR 40.0, 52.3, 54.0, 60.3, 65.8, 71.7, 75.0, 113.3, 115.9, (75 MHz, CDCI3) 116.1, 118.6, 129.5, 131.9, 132.9, 133.4, 134.5, < 5 (ppm) 138.4, 152.5, 153.8, 160.8, 164.0 Rf (Acetone: Hexane = 1: 2) 0.28 Melting point (t: ) 125-127 拄 Chromatographic extraction solvent Acetone: Hexane = 1: 2 Molecular formula C38H40N2O3F 2 Page 43 503235 V. Description of the invention (40) ------- --- ~ ----- EC-210 R w kA〇> UVEtOH 288 max (nm) 216 MS (El, 70 eV) 542 (M +) — m / z (° / 〇) 233 (100) IR (cm · 1) KBr 3416, 3228, 3080, 2942, 2822, 1644, 1608, 1504, 14 40,1282,1254, 1156,1036,1008,918, 812 lH-NMR 2.34-2.47 (8H, m, (CH2) 2N and (CH2) 2NAr) (300 MHz, CDC13) 3.37-3.40 (4H, m, 2xCH2CH = CH2 and NCH2Ar) < 5 (ppm) 4.14 (2H, d, J = 6.9 Hz, OCH2CH) 5.08 (4H, d, J = 6.3 Hz, 2xCH2CH = CH2) 5.94 (2H, s, OCH2〇) 6.02 ( 2H, m, 2xCH2CH = CH2) 6.75-7.16 (9H, m, 9xAr-H) l3C-NMR 40.0, 53.4, 60.4, 63.2, 65.9, 71.9, 101.5, 108.4, (75 MHz, CDCI3) 110.1, 113.4, Π6 .4,118.6,122.8,128.4,129.7, (5 (ppm) 131.9,132.9,138.5, 147.2,148.2,152.6,154.0 Rf (Acetone: Hexane = 1: 3) 0.22 melting point rc) 115-116 column chromatography solvent extraction Acetone: Hexane = 1: 3 Molecular formula C33H38N2O5

503235 V. Description of the invention (41) EC-220 R —1 / no2 UVEtOH 380 into max (nm) 289 211 MS (El, 70 eV) 529 (M +) m / z (%) 220 (100) IR (cm- l) KBr 3318, 3170, 3080, 2892, 2830, 1644, 1602, 1502, 1330, 1246, 1120, 1002, 926, 833 lH-NMR 2.50-2.71 (8H, m, (0¾) ^ and (CH ^ aNAr ) (300 MHz, CDCi3) 3.39-3.41 (6H, m, 2xCH2CH = CH2 and NCH2Ar) δ (ppm) 5.10 (4H, d, J = 8.8 Hz, 2xCH2CH = CH2) 6.00 (2H, m, 2xCH2CH = CH2 ) 6.81-7.20 (8H, m, 10xAr-H) 8.15 (2H, d, J = 9.27, 2 > < Pin 02, 13C-NMR 40.0, 53.4, 60.4, 63.2, 65.9, 71.9, 101.5, 108.4, (75 MHz, CDC13) 110.1, 113.4, 116.4, 118.6, 122.8, 128.4, 129.7, δ (ppm) 131.9, 132.9, 138.5, 147.2, 148.2, 152.6, 154.0 Rf (Acetone: Hexane = 1: 2) 0.37 Melting point 〇c) 160-163 column chromatography extraction solvent Acetone: Hexane = 1: 2 molecular formula. 32 印 # 3〇5

A: \ 8. 030 pt. D. Ptd Page 45 503235 5. Description of the invention (42) EC-230 R -〇 吾 —-UVEtOH max (am) 211 MS (El, 70 eV) 608 (M +) m / z (%) 201 (100) IRCcm- ^ KBr 3346, 3276, 3080, 2927, 2822, 1644, 1608, 1504, 1402, 1279,1232, 1090, 1008, 926, 820 lH-NMR 3.38 (4H, 4 J = 6.6 Hz, 2xCH2CH = CH2) (300 MHz, CDCl3) 4.10 (2H, d, J = 5.2 Hz, OCH2CH) δ (ppm) 5.06 (4H, d, J = 4.3 Hz, 2xCH2CH = CU2) 5.98 (2H , m, 2xCH2CH = CH2) 6.94-7.32 (15H, m, 15xAr-H) l3C-NMR 32.6, 38.3, 40.0, 53.2, 55.9, 60.6, 65.8, 71.9, 113.4, (75 MHz, CDCI3) 116.0, 118.7, 126.4, 128.8, 129.6, 131.8, 133.0, (5 (ppm) 138.0, 141.4, 152.6, 153.9 Rf (Acetone: Hexane = 1: 2) 0.32 Melting point (to 120-123 column chromatography eluent Acetone: Hexane = 1 : 2 molecular formula ^ 32 ^ 41 ^ 2〇3 ^

A: \ 8.030 pt. D. Ptd Page 46 503235 V. Description of the invention (43) EC-240 R UVEtOH 288 max (nm) 209 MS (El, 70 eV) 496 (Μ +) m / z (%) 188 (100) IR (cm1) KBr 3422, 3242, 3078, 3026, 2928, 2850, 1644, 1608, 1504, 1454, 1419, 1282, 1246, 1128, 918, 750 ^ -NMR 2.35-2.65 (8Η , M, (CH2) 2N and (CH ^ yAr) (300 MHz, CDC13) 3.36-3.40 (6H, m, 2xCH2CH = CH2 and NCH2Ar) δ (ppm) 5.07 (4H, d, J = 4.4 Hz, 2xCH2CH = CH2) 5.98 (2H, m, 2xCH2CH = CH2) 6.97-7.37 (llH, m, 11 xAr-H) 13C-NMR 40.0, 52.1, 60.5, 65.7, 71.7, 133.4, 166.1, 118.4, (75 MHz, CDCi3) 127.8, 128.3, 129.2, 129.7, 131.8, 132.9, 137.9, < 5 (ppm) 141.7, 142.5, 152.5, 153.9 Rf (Acetone: Hexane = 1: 3) 0.25 melting point 〇c) 85-87 column chromatography Solvent Acetone: Hexane = 1: 3 Molecular formula ^ 32 ^ 38N2〇3

A: \ 8.030 pt.d.ptd Page 47 503235 V. Description of the invention (44) EC-250 R UVEtOH 288 max (nm) 217 MS (El, 70 eV) 514 (M〇m / z (%) 205 (100) IRCcm- ^ KBr 3365, 3256, 3080, 2945, 2829, 1644, 1594, 1504, 1282, 1246, 1128, 1008, 918, 758 'H-NMR 3.10 (4H, t, J = 4.5 Hz , (CH2) 2NAr) (300 MHz, CDC13) 3.37 (4H, d, J = 7.6Hz, IxCHzCHCHy < 5 (ppm) 3.79 (3H, s, 0CH2) 5.07 (4H, d, J = 7.2 Hz , 2xCH2CH = CH2) 6.00 (2H, m, 2xCH2CH = CH2) 6.81-7.38 (10H, m, 10xAr-H) l3C-NMR 40.0, 53.1, 60.8, 115.6, 116.8, 117.5, 121.4, 127.6, (75 MHz, CDCi3) 128.4, 129.0, 129.8, 130.3, 131.7, 138.5, 152.8, < 5 (ppm) 154.2, 155.6 Rf (Acetone: Hexane = 1: 2) 0.34 melting point 〇c) 124-128 column chromatography Solvent Acetone: Hexane = 1: 2 Molecular formula C32H38N2O4 A: \ 8. 030 pt. D. Ptd

Page 48 503235

A: \ 8.030 pt. D. Ptd p. 49 503235

A: \ 8. 030 pt. D. Ptd Page 50

Claims (1)

503235 Page 51 503235 _Case No. 88103202_Year Month and Date_ VI. Scope of patent application 2. —A kind of Magnolia spp. Compound as shown in formula II, The above R refers to the following groups-N N-h & optional-(CH2_) n_CH2-R2 ,, Among them, R3 can be selected from halogen, hydrogen, methyloxy, ethyloxy, propyloxy, Ν02, and the natural value of η is ϋ 1T, 2 3.—A method for preparing Magnolia officinale compounds as shown in Formula I of the first patent application, which includes Page 52 503235 No. 8810 Take VI. Patent scope OH OH Month Θ Correction R 丨 丨 I 丨 1 Take magnolol and formaldehyde, add a second amine derivative and heat and reflux under acidic conditions (PH3-5) After stirring for 3-10 hours, it was concentrated under reduced pressure, and then purified and recrystallized to obtain a Mannich base, 2_ [3_substituted methyl-2-hydroxy-5- (2-propene) of formula j (Phenyl) phenyl] icel (2-propenyl) phenol (2_ [3_substituted methyl ^ -hydroxy-S ^ -propenyl) phenyl] -4- (2-propenyl) phenols) 〇4 · Formula 2 The method for the combination of magnolol shown in n includes OHΗOH ^ '1 II || Dissolving magnolol in tetrahydrofuran, under the experimental conditions of magnolol · · NaH = n! Methyl ether was added at 20-40. (: Reaction for 12-36 hours; add pre-distilled 1-chloro-2,3-epoxypropane uniformly, and heat to reflux __ 8 hours; add ~ add hexahydropyridine derivative and heat to reflux for 2_12 hours , Concentrated under reduced pressure, purified and recrystallized to obtain each intermediate product; purified by Shixi column chromatography, Phenol ^ (2-propenyl) of formula π can be obtained-page 53 It is based on item 1 of the scope of application for patents. Various pharmaceutical compositions with lowering blood pressure are added according to the needs of various dosage forms. Magnolol series compounds are the main ingredients and excipients. Excipients have a blood pressure-lowering composition, which is the material of Magnolia officinalis No. 2 as a domain component, and various types are added with each type. 7. A pharmaceutical composition with antioxidant activity , Its fine towel material benefit range 1 Xiang Houpu series of compounds are the main ingredients, and various excipients are added according to the needs of various dosage forms. 8. A pharmaceutical composition with anti-oxidant activity, which is based on the 2nd simplest compound in the scope of the patent application, and it is added with various excipients according to the needs of various dosage forms. • A pharmaceutical composition with anti-free radical activity, which is based on the No. 1 compound of Magnolia officinalis in the scope of patent application, and various excipients are added according to the needs of various dosage forms. n A pharmaceutical composition with anti-m activity, which is based on the main ingredient of Magnolia spp. series compounds in the scope of patent application, and various excipients are added according to the needs of various dosage forms. Page 54