TW293819B - Antiplatelet coumarin derivatives - Google Patents

Abstract

The novel compounds of formula I and II provided in this invention are the two types of derivatives, which was preperated from (alpha)-methylene-(gamma)-butyrolactones and coumarin. In view that these compounds are found to be potent inhibitors of platelet aggregation. Compounds of formula I and II in which R1, R2, R3 represents H, C 1-6 alkyl, in which R represents C1-6 alkyl, benzene, group which is optionally substituted by one or more R4, R5, R6. In which R4, R5, R6 represents C1-6 alkyl, C1-7 alkoxyl, halogens.

Description

203819 V. Invention description β (please read the precautions on the back before filling out this page). Because cerebrovascular disease has become a chronic disease that is the top ten cause of death in an aging society, and cerebrovascular disease is directly related to the function of platelets, especially the coagulation machine It is affected by other factors, abnormal coagulation occurs, or cardiovascular disease is induced by clinical thrombosis or vascular injury (Vascular injury), which often needs to be administered to interfere with platelet adhesion and aggregation, and release platelets. Platelet aggregation inhibitors that extend the active medium inhibit the occurrence of improper coagulation. Antiplatelet drugs are often used clinically for the prevention and treatment of vascular blood tests. Among them, aspirin (aSpjrjn), ejcosapentanic acid (EPA), dipyridamole (dipyridamole), and big ropi (tm〇) -pidine) is the most versatile, however, these drugs have their shortcomings, so Mengfa's more ideal new antiplatelet drugs are now valued by the medical community. • According to the research on the relationship between the known structure and biological activity, it is found that α-methine-γ-butyl lactone has an extra-ring unsaturated unit that can interact with the nucleophilic groups of large biochemical molecules (such as The thiol enzyme) undergoes a Michael addition reaction and is regarded as an alkylating agent. H-Nu

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Nu This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm)

A V. Description of the invention (〇: ', according to Pelter Andrew et al. 1 981 J. Chem. Soc., PerkinTrans. 1 page 2491 proposed compound 8- (4,5 7 ^ 7 (^ 〇- 5,5-(^ 〇16 化 7 卜 4-〇 father〇3-furanyl) -7-hydroxy-2-phenyl-4 /-/-1-benzopyran-4-one; according to V. Ν · Dholakia et al The compound Ethyl 8-methyl-4-oxo-3-phenyl-4 H-furo [3,2-c] [1] benzopyran-2-carboxylate, proposed in 1971 j Indian Chem. Soc. No other compounds have anti-platelet aggregation activity. The present invention is based on the formula of α_methylene γ-butyl lactone ring structure and coumarin as shown in the following formula (I, II>, where r, r, R 3 Respectively represent a hydrogen group and a C alkyl group, R represents a d 6 ^ group and a phenyl group substituted with at least R 4, R 5 and R 6, and R 4, R ^ and R 6 respectively represent a hydrogen group, a C 6 tiger group, C Bu? Oxygen burning base, Nansu 0 (please read the notes on the back before filling this page)

X. Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 Gongmeng) 5 -τ η

V. Description of the invention ((Κί) The preparation method of the coumarin derivative of the present invention is shown in (彳) by the coumarin (c〇_ar 丨 n) containing R1, R 2, R3 substituted in the acid-breaking clock. Substitute a halogenated ketone (HI) compound containing R substitution in a dangerous solution to obtain (2-oxoalkoxy) _2 · hydrogen-derived benzoin phenanthrene-2-yl (IV). (IV) Dissolve in anhydrous tetrahydrofuran, add zinc powder, hydroquinone, and ethyl (2-bromomethyl) aery 丨ate) 'Refonnatsky (Refonnatsky) reaction under heating and reflux to obtain the compound of formula (I, II). Coumarin derivatives (I, II) prepared according to the method of the present invention,

Wherein R 1, R 2, R3 represent hydrogen group, C bu 6 alkyl, R represents C ι_6 alkyl and phenyl substituted by at least r4, r5, r6, and R 4, R 5, R 6 represent hydrogen Group, C alkyl group, C} -7 oxyalkyl group, halogen. The more suitable coumarin derivatives are R j and R. , R? Stands for hydrogen, C, alkyl, R stands for C, " ° 1-3 1 '3 alkyl printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and printed at least by R 4, R 5, R 6 Substituted phenyl, and R 5 and R 6 respectively represent a hydrogen group, a C1-3 alkyl group, a CP3 oxyalkyl group, fluorine, gas, and bromine. Appropriate compounds of the present invention and each compound in the production process were measured for melting point (mp), infrared spectroscopy (丨 R), ultraviolet absorption (UV), nuclear magnetic resonance spectroscopy (NMR), elemental analysis and other physical properties data, and carried out in vitro Platelet aggregation activity test confirmed its activity. This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 6 S〇38i9 V. Description of the invention (1M) A, _J *

Year;) η W The coumarin derivatives of the present invention have platelet aggregation inhibitory activity, and are used to treat various human and animal cardiovascular diseases caused by abnormal blood agglutination and thrombosis. The compound of formula (I, π) can form salts with organic acids and pharmacologically acceptable acids, and add various excipients such as diluents, lubricating swords, wall odorants, and disintegrants ), Binders (binders), or colorants, sweeteners made into tablets or other solid preparations, and phosphate buffer to adjust the acid start: degree (pH) can be made into injections or other liquids and various Dosage form. The compound of formula (I, II) of the present invention can be tolerated by acid addition salts, and the pharmaceutical composition of tolerable acid addition salts can achieve the activity of inhibiting platelet aggregation, and the general dosage can be adjusted according to the symptoms. 'Usually 50 mg to 300 mg per person each time, 3 times a day. Explanation of the chart: Table (1) Anti-hemoglobin agglutination activity of coumarin derivatives The gold plate and coumarin derivatives were incubated at 37 ° C for 3 minutes and the agglutination activity exaggeration agent was added, so the percentage of agglutination was obtained as The average value of the number of tests in brackets is expressed. b. P 0.001 c. P 0.01 d · Pure effect of smooth muscle relaxation table (2) Anti-platelet agglutination activity of coumarin derivatives (3) Anti-blood agglutination activity of coumarin derivatives This paper size is applicable China ® Home Standard (CNS) A4 specification (210 X 297 mm) 7 C Please read the ii matters on the back and then fill out this page) Order A7 B7 printed by the Consumer Labor Cooperative of the Central Department of Economics of the Ministry of Economic Affairs Explanation (G 5) Figure (1) Preparation method of compound of formula (I, I)

This paper scale adopts the Chinese National Standard (CNS) A4 specification (210Xg97mm) A 7 B7 V. Invention description ((Jb) (一) [(2,3,4,5-Tetrahydro-2-methyl -4-Methylene-5-oxo-2-α-furan) Methoxy] nitrogen-Ί-benzoin-based birring_2 · que (2_)

0 ^ 0 la H3C, ζΟ 〇 ¥

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2b-2d ----------------------- 03. ........ *? ..... ί? · Ν / one * · (Please also read the notes on the back ^ 'this page) (12: = R2 = R3 = H c: Rj = R3 = H, R2 = CH3 d: Ri = R2 = R3 = CH3

Printed by Rz Employee Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

Scheme

Ri This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 0 2J3819 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Description of Invention (UT) --- ^ Sold, · coumarin ⑽, A silk coumarin ⑽ '7_ & base + methyl coumarin (eg, 7_ 丝 _ 3,4,8_ dimethyl coumarin (domain is the starting The raw material, as shown in Schemel, takes off the silk protons at the carbon age f_Zhongjian, and carries out the substitution reaction with the gas-substituted propionate to obtain the corresponding (2-oxopropoxy) -2 · hydro-1-benzoin Base brewing bilin-2-he (such as). Then, the compounds 2a-d were dropped into anhydrous tetrahydro α-furan, zinc powder and catalyst amount of hydroquinone and 2_ desert methyl propylene ethyl chloride were added ⑼ … ^ ㈣ 嶋 帶 帶 ^ The state is heated to reflux for Ref〇rmatsky (Ref〇rmatsky) reaction, you can get [(2,3,4,5-tetrahydro-2-methyl-4-methineoxy Substitute-2-〇furan) Methoxy] _2 · hydrogen-Ί · benzoin-based biryl-2-one (3a-d). Reaction example one: (, Jingxian first read the notes on the back and then fill in this page )

* 1T The size of this paper is applicable to China National Standard (CNS) A4 specification (210 xi). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Description of the invention (of) NMR (CDCI3): 62.36 (s, 3Hf CH3 ), 4.77 (s, 2H, 〇CH2), 5.57 (s, 1H.3-H), 7.28-7.36 (m, 2H, 6-and 8-H), 7.54-7.63 (m, 1H.7-H ), 7.88-7.94 (m, 1H, 5-H); Anal: Ci2Hi〇〇4, calcd. C: 66.05, Η: 4.62, Found C: 66.01, H: 4.64 ° (2) 7- (2 -Oxopropoxy) -2-gas-1-benzoin-based bilin-2_ 嗣 (2b). Combine 7-hydroxycoumarin (It) (1.62 g, 10 mmol) according to Compound 2 is synthesized and purified to obtain compound 2b, which is white needle crystals with a yield of 2.10 g (96.1./.). 111 Jie: 165-167〇〇; IR (KBr) vmax: 1709, 1620; UV (CHCI3Umax (| 〇ge); 308 (4.14), 244 (3.52); 1H-NMR (CDCI3): 62.31 (s, 3H , CH3), 4.65 (s, 2HfOCH2), 6.29 (d, 1H.3-H), 6.76 (d, 1H, 8-H), 6.88 (dd, 1H, 6-H), 7.42 (d, 1H, 5-H), 7.65 (d, 1H, 4-H); Anal: 〇12H10〇4. Calcd. C: 66.05, H: 4.62, Found C: 65.98, H: 4.61 ° (3) 4-methyl- 7- (2-oxopropoxy) -2-hydro-1-benzoyl acetylpyridine > 2-one ketone. 7-hydroxy-4-methyl-coumarin (Ια) (1.76 g, Millimoles), in accordance with the synthesis and purification method of compound k, compound can be obtained as white crystals, yield 1.63 l (70_3%) ° mp: 147-149〇C; IR (KBr) vmax: 1710, 1619; UV (CHCI3) ............. People ......-......... • 玎-(Please read the precautions on the back before writing this page) This paper size Applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) A7 B7 V. Description of invention (1 ^) kmax (l〇ge): 308 (4.13), 243 (3.45); lH · NMR (CDCI3): 6 2.31 (s, 3H, CH3), 2.41 (d, 3H, 4-CH3), 4.65 (s, 2H, OCH2), 6.17 (q, 1H.3-H), 6.76 (d, 1H, 8-H ), 6.89 (dd, 1H, 6-H), 7.54 (d, 1H, 5-H) -Anal: 〇 3Η12〇4, calcd. 0: 67.23, H: 5.21, Found C: 67.05t H: 5.29〇 (4) 7- (2-oxopropoxy) -3,4,8-trimethyl-2- Hydrogen-1-Benzoylpyrrolidine> 2-one (gdj. 7-Acetyl-3,4,8-trimethylcoumarin (id) (2_11 g, millimoles) 'according to the compound The synthesis and purification method can obtain compound M as a white crystalline powder with a yield of 2.34 g (90.1%). Mp: 173_175〇C; IR (KBr) vmax: 1742, 1698, 1604; UV (CHCI3) Xmax (log ε): 313 (4.11), 247 (3.60); Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling in this page) 1H-NMR (CDCI3): 52.20 (s, 3H, 3 -CH3), 2.33 (s, 3H, CH3), 2.37 (s, 3H, 4-CH3), 2.39 (s, 3H, 8-CH3), 4.62 (s, 2H, OCH2), 6.65 (d, 1H, 6-H), 7.40 (d, 1 H, 5-H); Anal: C15H16〇4, calcd. C: 69.22, H: 6.20, Found C: 69.03, H: 6.17 ° Reaction Example 2: (5) 4 -[(2,3,4,5-Tetrahydro-2-methyl-4-methine-5-oxo-2-furan) methoxy] -2-aza-1 -benzoyl benzole Lin_2_ 嗣 （4-[(2,3,4,5- ^ paper size is applicable to China National Standards (CNS) A4 specifications (210 X 297) «) B7 B7 Central Bureau of Standards, Ministry of Economic Affairs Consumer cooperatives Indian workers Dun V. invention is described in (〖Shang!)

Tetrahydro-2-methyl-4-methylene-5-〇x〇-2-furanyl) methoxy] -2H-1-benzopyran-2-one) (3a). Compound Yi_ (0.655 g, 3 mmol) Dissolve in anhydrous tetrahydrofuran (60 ml), add zinc powder (0.255 g, 3.9 mmol), p-phenylenediazine (6 mg), and 2-bromomethyl propenyl ethyl ester (ethyl 2 -(bromomethyl) acrylate) (0.78 g, 4 mmol), heated to reflux for 36 hours (to monitor the completion of the reaction by TLC), the reaction solution was cooled and poured into 300 ml of 5% glacial hydrochloric acid aqueous solution, with CH2Cl2 (75 ML X 3) extraction, the resulting organic solution was dried with saturated brine and dried with Na2S04 and concentrated under reduced pressure, the resulting residue was recrystallized from ethyl acetate 'to obtain light yellow granular crystals 3a' yield 0.656 g (76.4%) ° mp: 161-162 ° C; IR (KBr) vmax: 1766, 1703, 1627; UV (CHCI3) Xmax (log ε): 306 (3.79), 276 (4.01), 266 (4.05); 1H-NMR (CDCI3 ): δ 1.64 (s, 3H, 5, -CH3), 2.88 (dt, 1H, 4'-H), 3.19 (dt, 1 H, 4'-H), 4.08, 4.20 (two d, 2H, 0CH2 ), 5.67 (s, 1H, 3-H), 5.75 (t, 1H, vinylic H), 6.38 (t, 1H, vinylic H), 7.12-7.33 (m, 2H, 6 an d 8-H), 7.51-7.65 (m, 2H, 5 and 7-H); Anal: C " j6H * | 4〇5, calcd.C: 67.13, H: 4.93, Found 0: 67.14, H: 5.01 ° (6) 7-[(2,3,4,5-Tetrahydro-2-methyl-4-methine-5-oxo-2-furan) methoxy] · 2_hydrobenzoyl Acetylpyridine-2-one (3b). Apply compound 2b (0.63g, 3 mmol) to the Chinese standard (CNS) A4 specification (210X 297mm) according to the compound's paper size. 13 ----- ---- Cloth .............. Order (Please read the ii matters on the back before writing this page) SJ38j 9 Printed B7 by the Consumer Labor Cooperative of the Central Bureau of Standards of the Economic Village 5. Description of the invention (U) & synthesis reaction for 8 hours and purification method to obtain the compound run, as white crystals, yield 0.68 g (79.7%) ° mp: 123-1 24 〇C; IR (KBr) vmax : 1755, 1727, 1 626; UV (CHCI 3)

Xmax (log ε): 312 (4.18), 243 (3.58); 1H-NMR (CDC! 3): 51.58 (s, 3H, 5'-ΟΗ3), 2.79 (dt, 1H, 4'-Η), 3.18 (dt, 1H, 4'-H), 3.99, 4.09 (two d, 2H, OCH2), 5.69 (t, 1H, vinylic H), 6.26 (d, 1H, 3-H), 6.29 (t, 1H, vinylic H), 6.76-6.84 (m, 2H, 6 and8-H), 7.38 (d, 1H, 5-H), 7.65 (d, 1H, 4-H); Anal: Ci0H-j4〇5, calcd. C: 67.13, H: 4.93, Found C: 66.95, H: 5.10 ° (7) 7-[(2,3,4,5-tetrahydro-2-methyl · 4_methine-5-oxo -2-quinan) methoxy] -4 · -methylhydrogen-Ί-benzoylpyrrolidone (2 £ _). Compound 2 ^ (0.70 g, 3 mmol) according to compound 3 ^ The synthesis reaction for 24 hours and purification method can obtain compound aa, white crystals, yield 0_68 g (75.7%) 〇mp: 135-137〇C; IR (KBr) vmax: 1758, 1705, 1616; UV (CHCI3 )

Xmax (log ε): 320 (3.99), 242 (3.35); 1 H-NMR (CDCI3): 51.58 (s, 3H, 5'-CH3), 2_40 (d, 3H, 4.CH3), 2.79 (dt , 1H, 4'-H), 3.18 (dt, 1H, 4'-H), 3.98, 4.09 (twod, 2H, OCH2), 5.69 (t, 1H, vinylic H), 6.16 (q, 1H, 3- H), 6.30 (t, 1H, vinylic H), 6.78 (d, 1H, 8- H), 6.83 (dd, 1H, 6-H), 7.50 (d, 1H, 5-H); Anal: this paper The scale is applicable to the B National Standard (CNS) A4 specification (210 X 297 mm) ~ 14 • i .....-.....-................ ...... Order ............... 1 • (Read the precautions on the back before filling in this page) A 7 B7 V. Description of the invention (12) C17H1605 , calcd. C: 67.99, H: 5.37, Found C: 67.87, H: 5.63 ° (8) 7-[(2,3,4,5-tetrahydro-2-methyl-4-methylene-5 -Oxo-2 "furan) methoxy] · 3,4,8 · trimethyl_2_argon-bu benzoin acylpyridine ^ 2 * · ketone compound 2d. (0.78 g, 3 mmol) Ear), according to the synthesis reaction of compound M for 20 hours and purification method, compound M can be obtained as pale yellow crystals with a yield of 0.80 g (81 _4%). Mp: 1 63-165 ° C; IR (KBr) vmax: 1751, 1 699, 1 603; UV (CHCI3) λη3χ (Ι〇9 ε): 319 (4.18), 246 (3.71) 1H-NMR (CDCI3): 51.60 (s, 3H, 5 ^ 3), 2.18 (s, 3H, 3-CH3), 2.22 (s, 3H, 8-CH3), 2.36 (s, 3H, 4-CH3) , 2.81 (dtf 1H, 4'-H), 3.23 (dt, 1H, 4'-H), 3.99, 4.09 (twod, 2H, OCH2), 5.69 (t, 1H, vinylic H), 6.30 (t, 1H , vinylicH), 6.75 (d, 1H, 6-H), 7.38 (d, 1H, 5-H); Anal: C19H20O5, calcd. 0: 69.50, H: 6.14, Found by the Ministry of Economic Affairs Central Standards Bureau employee consumer cooperative (Please read the precautions on the back before writing this page) C: 69.22, H: 6.11 0 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 15 B7 V. Invention description aa) B7 II) [(2,3,4,5-Tetrahydro-4-methine-5-oxo-2-phenyl-2 -quinan) methoxy] _2 · hydro-Ί-benzoyl acetyl Production of bilinone (Pan)

CT, 〇 la

r3 C6H5

4b-M

lb-M ......... h .............. install ............... order ... ........... Line-({(Please read the precautions on the back before filling in this page) Printed r2 printed by Beigong Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

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k R! = Rj = R3 = H £: = R3 = H, R2 = CH3 = R2 = R3 = CH3 still using commercially available compounds 1a-1d as starting materials, as shown in Scheme 丨 丨The hydroxy protons are removed by treatment in acetone, and the paper standard of oc-brominated styrene is applicable to the Chinese National Standard (CNS) A4 specification (210X29 $ &%). bromoacetophenone) to carry out the substitution reaction, and the corresponding (2-oxo-2-phenylethoxy) -2-hydro-1-benzoin benzopyrine (4a-d) is known. Then, the compounds 4a-d were dissolved in anhydrous tetrahydrocarban (tet "ahydrofuran), and the powder and catalyst amount of hydroquinone and 2-ximethyl propanyl ethyl alcohol (ethyl 2- ( bromomethyl) acrylate) under heating and reflux to carry Refumas (1 ^ 〇 towel ^ 81 ^) reaction, you can get [(2,3,4,5-tetrahydro-4-hyridyl-5-oxo-2 -Phenyl-2- ηfuran) methoxy] -2-hydro-1 _benzoicylpyrin-2-one (5a-d) ° Reaction Example 3: (9) 4- (2-oxo -2-phenylethyloxy) -2-hydro-1-benzoin benzopyrine-2-one (4- (2-Oxo-2-phenylethoxy) -2 /-/-1 -benzopyran-2-one) (4a). Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back and then fill out this page). The commercially available 4-hydroxycoumarin (la) (1.62 g, 10% Mo Ear) and α-bromoacetophenone (1.99 g, 10 mmol) in 60 ml of acetone, potassium carbonate (5.53 g, 40 mmol) was added and heated to reflux for 3 hours. The treatment is the same as compound 2a. Needle crystals were recrystallized from ethyl alcohol. Yield 1.76 g (62.9%). Mp: 183-184〇C; IR (KBr) vmax: 1721, 1703, 1 626; UV (CHCI3)

Xmax (log ε): 306 (3.79), 253 (4.28); 1H-NMR (CDCI3): S5.50 (s, 2H, OCH2), 5.61 (s, 1H, 3-H), 7.26-7.35 (m , 2H, 6- and 8-H), 7.50-7.71 (m, the paper size is applicable to the China National Standard (CNS) A4 specification (210X297 mm) 17 A7 B7 V. Invention description (4H, 5-, 7- H and aromatic Η), 7.94-8.02 (m, 3Η, aromaticH); Anal: C * | 7 H-j2〇4, calcd. C: 72.85, H: 4.32, Found C: 72.85, H: 4.72 0 (10 ) 7- (2, oxo-2-phenethyloxy) -2-hydro-1-benzoyl acetylpyridine-2-one (7-hydroxycoumarin (It) (1.62 g, 10 mmol Mohr), according to the synthesis and purification methods of compound 4a, compound 4b can be obtained as pale yellow crystals with a yield of 1.53 g (73.1%). Mp: 163-165〇C; IR (KBr) vmax: 1728, 1702, 1 627; UV (CHCI3)

Xmax (log ε): 320 (4.16), 249 (4.13); 1H-NMR (CDCl3): 35.39 (s, 2H, OCH2), 6_27 (d, 1H, 3-H), 6.80 (d, 1H, 8 -H), 6.93 (dd, 1H, 6-H), 7.40 (d, 1H, 5-H), 7.49-7.68 (m, 4H, 4-H and aromatic H); Anal: C17H12O4, calcd. C: 72.85, H: 4.32, Found C: 72.98, H: 4.35 ° Printed by W Industrial and Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs :: _.........-...... V: Cloth ... ............. Order V (Please read the precautions on the back before filling in this page) (11) 4-methyl-7- (2-oxo-2-phenethyloxy ) -2-hydro-1-benzylpyridine-2-pyrene (4c). Combine 7-hydroxy-4-methylcoumarin (also) (1.76 g, 10 mmol) with ex-bromo Diphenylethyl ether (1.99 g, 10 mmol) was added to 60 ml of acetone, acid-broken acid (5.53 g, 40 mmol) was added and heated to reflux for 1 hour. The reaction solution was cooled and poured into 100 ml of water. Extracted with two gas methane pits (75 ml X2), collected organic solvent, dried and concentrated under reduced pressure, the paper scale is applicable to China National Standard (CNS) A4 specification (2l〇X297 | ^) " " " " ' A7 B7 5. Description of the invention (iG) The residue can be obtained by recrystallization from ethyl acetate 4C thereof, as white crystals, yield 2.86 g (97_2%). mp: 167-168〇C; IR (KBr) vmax: 1718, 17〇2, 1614; UV (CHCI3Umax (loge): 315 (4.14), 249 (4.10); 1H-NMR (CDCI3): δ 2.39 ( d, 3H, 4-CH3), 5.39 (s, 2H, OCH 2), 6.14 (q, 1H, 3-H), 6.80 (d, 1H, 8-H), 6.95 (dd, 1H, 6-H ), 7.49-7.63 (m, 4H, 5-H and aromatic H), 7.96-8.02 (m, 2H, aromatic H); Anal: C18H1404, calcd. C: 73.46, H: 4.79, Found C: 73.28, H : 4.77 ° (12) 7- (2-oxo-2-phenethyloxy) -3,4,8-trimethyl-2-hydro-1-benzylpyrrolidin-2-one (4 Tsuji ) · 7-hydroxy-3,4,8-trimethylcoumarin (M) (2.04 g, 10 mmol) can be obtained according to the synthesis and purification method of compound k, as a white crystalline powder , Yield 1.66 g (51.5%). Mp: 196-198 ° C; IR (KBr) vmax: 1 71 0, 1699, 1608; UV (CHCI3) Xmax (l〇g ε): 318 (4.16), 249 (4.16); 1 H-NMR (CDCI3): 62.18 (d, 3H, 30H3), 2.34 (s, 3H, 4 ^ H3), 2.38 (s, 3H, 8-CH3), 5.38 (s, 2H, OCH2 ), 6.70 (d, 1H, 6-H), 7.35 (d, 1H.5-H), 7.47-7.68 (m, 3H, aromatic H), 7.97-8.03 (m, 2H, aromatic H); Anal: 〇2〇Ηΐ8〇4, calcd. C: 74.52, H: 5.63, Found C: 74.45t H: 5.60 ° The paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 19 ················· (Please read the notes on the back before writing This page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy V. Description of the invention (1¾ Reaction Example 4: (13) 4-[(2,3,4,5-Tetrahydro-4-methine-5-oxo -2-phenyl-2-xiaran) methoxy] -2-hydro-1-benzylpyridine-2-one (4-[(2,3,4,5-T etrahydro-4-met hylene-5-οχο-2-phenyl · 2-furanyl) methoxy] -2H-1-benzopyran-2-one) (5a). Combine the compound (0.84 g, 3 mmol) according to the synthesis reaction of compound M 8 After hours and purification methods, the compound package can be obtained as white crystals with a yield of 0.90 g (86.4%). Mp: 212-214〇C; IR (KBr) vmax: 1766, 1717, 1 620; UV (CHCI3)

Xmax (log ε): 306 (3.89), 277 (4.10), 266 (4.14); 1H-NMR (CDCI3): 63.33 (dtJH, 4'-H), 3.66 (dt, 1H, 4'-H), 4.26, 4.32 (twod, 2H, OCH2), 5.60 (s, 1 H, 3- H), 5.79 (tf 1H, vinylic H), 6.42 (t, 1H, vinylic H), 7.20-7.61 (m, 9H, 5, 6, 7, 8-H, and aromatic H); Anal: 〇2i Η- | β〇5 0.25H 2〇, calcd. C: 71.48, H: 4.71,

Found C: 71.37, H: 4.67 ° (14) 7-[(2,3,4,5-tetrahydro-4-methine-5-oxo-2-phenyl-2-furan) methoxy 】 Hydrogen-Ί-benzoyl acylpyridine-2-one (5b). The compound (0.84 g, 3 moles), according to the synthesis reaction of compound M for 15 hours and the purification method can obtain the compound transport k, as a white powder crystal, yield 0.81 g (77_8%) 〇mp: 105-106〇C; IR (KBr) vmax: 1758, 1719, 1616; UV (CHCI3) This paper scale is applicable to the Chinese National Standard (CNS) A4 size (210X297mm) 20 · (please read the precautions on the back before filling in this page) Threading A7 B7 208819 V. Invention description (〗 1)

Xmax (l〇g ε): 321 (4.22), 243 (3.62); 1 Η-NMR (CDCI3): 6 3.24 (dt, 1H, 4'-Η), 3.66 (dt, 1H, 4'-H) , 4.17, 4-24 (twod, 2H, OCH2), 5.71 (t, 1H, vinylic H), 6.24 (d, 1H, 3-H), 6.31 (t, 1H, vinylic H), 6.72 (d, 1H , 8-H), 6.78 (dd, 1H, 6-H), 7.35 (d, 1H, 5-H), 7.40-7.52 (m, 5H, aromaticH), 7.62 (d, 1H, 4-H); Anal: C 21 H- | 0〇5, calcd. C: 72.41, H: 4.63, Found C: 72.30, H: 4.67 ° (15) 7-[(2,3,4,5-tetrahydro-4- Hypomethyl-5-oxo-2-phenyl-2-furan) methyloxy] _4_methyl_2_hydrobenzoyl benzopyrin-2-one (Μ). The compound 4α (0.74 g, 2.5 millimoles), according to the synthesis reaction of compound 3a for 18 hours and purification method, compound 5c. Can be obtained, which is a light yellow particle crystal with a yield of 0.76 g (84.5%). Yang: 168-169 ° C; IR (KBr) vmax: 1 773, 1 71 7, 1 609; UV (CHCI3) Xmax (loge): 320 (4.21), 242 (3.55); 1 H-NMR (CDCI3 ): 5 2.38 (d, 3H, 4-CH3), 3.23 (dt, 1H, 4'-H), 3.66 (dt, 1H, 4'-H), 4.17, 4.25 (two d, 2H, OCH2), 5.71 (t, 1 H, vinylic H), 6.13 (q, 1 Η, 3-H), 6.31 (t, 1H, vinylic H) f 6.72 (d, 1H, 8-H), 6.80 (dd, 1H, 6-H), 7.37-7.52 (m, 6H, 5-H and aromatic H); Anal: 〇22Η- | 8〇5 »calcd. C: 72.92, H: 5.01, Found C: 72.83, H: 5.16 ° The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 21 (please read the precautions on the back before filling this page)

、 1T Ministry of Economic Affairs Central Standards Bureau Shell Industry Consumer Cooperation Du Printed B7 V. Description of invention (〗 〖(16) 7-[(2,3,4,5-Tetrahydro-4-methine-5-oxo Substituted-2-phenyl-2-pyrano) methoxy] -3,4,8 · trimethyl-2-hydro-1-benzoylpyrrolidin-2-one (Μ). The compound 4d. (0.81 g, 2.5 mmol), according to the synthesis reaction of compound 3a for 20 hours and purification method, compound & can be obtained as white crystals with a yield of 0.71 g (72.5./.). 卬 ： 142-143 ° C; IR (KBr) vmax: 1 771, 1 698, 1 604; UV (CHCI3) Xmax (log ε): 309 (4.17), 258 (3.96); 1H-NMR (CDCI3): 5 2.18 (sf 3H, 3-CH3), 2.22 (s, 3H, 8_CH3), 2.34 (s, 3H, 4-CH3), 3.27 (dt, 1H, 4_-H), 3.71 (dt, 1H, 4'-H), 4.16, 4.23 (twod, 2H, OCH2), 5.73 (t, 1H, vinylic H), 6.34 (t, 1H, vinylic H), 6.69 (d, 1H, 6-H), 7.34 (d, 1H, 5-H) , 7.39-7.54 (m, 5H, aromatic H); Anal: C24 H22O5, calcd. C: 73.83, H: 5.68, Found 0: 73.61, H: 5.74 ° (Please read the notes on the back before filling this page ) Shi Yi............ The paper printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Standard (CNS) A4 size (210X297 male *) V. invention is described (YQ

II> [(2 '3,4,5-Tetrahydro_4_methine · 5 · oxo_2_phenyl_2_pyran) methyl] -2-gas-1 _benzoyl acetyl Production of Lin_2 • Keto derivatives (ζ)

6a.7a: R = pF 6b.7b: R = p-CI 6c.7c: R = ^ Br 6d.7d: R = p-Ph 6e.7e: R = p-OMe 6f.7f: R = m- OMe (please read the precautions on the back and then fill out this page). The preliminary results of the printing generation of the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy found 7-[(2,3,4,5-tetrahydro-4-methine * 5-Oxy ... benzylfuran) methoxy] -2-hydro-1-benzoyl benzopyrin-2-one has a significant anti-platelet aggregation effect, so the selected compound 1b is the main raw material 'such as Scheme 丨 丨 丨 丨As shown, decarboxylated protons were treated with acid-breaking in propylene, and substituted with acetophenone substituted with benzene ring of α-halide to obtain the corresponding (2-oxo-2-phenethyloxy> ; -2-hydro-1-benzyl acetylpyridine "2-keto derivative (6a-f) 〇 Then dissolve compound 6a-f in anhydrous tetrahydrofuran, add zinc powder and catalyst amount of p-benzene Diphenol and ethyl 2-bromomethacrylic acid (ethyl 2- This paper scale is applicable to China National Standard (CNS) A4 specifications (210 X 297f ¢) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ______B7 —_________ V. Inventions Description (H) (bromomethyl) acrylate) is heated to reflux Ma Si (

Reformatsky) reaction, you can get 7-[(2,3,4,5-tetrahydro_4_methine-5-oxo-2-phenyl-2-furan) methoxy] -2-hydrogen Benzoin Acetylpyridin "2-keto derivative (ZM). Reaction Example 5: (17) 7- (2-p-fluorophenyl-2-oxoethyloxy) -2-hydro-1-benzoyl benzopyrin-2-one (7- [2- (p- Fluorophenyl) -2_oxo-ethoxy) -2 //-1 -benzopyran-2-one) (6a).

Combine 7-hydroxycoumarin (Ik) (0.81 g, 5 mmol) with α- 气 -Ρ> 6 fluorobentophenone (a-chloro-p-fluoroacetophenone, 0.86 g, 5 mmol) in 50 ml of acetone, added acid-breaking (2 · 76 g, 20 mmol) and iodide (0.1 6 g, 1 mmol) as a catalyst, heated to reflux for 3 hours. The treatment method is the same as that of Compound 2 ^, which is recrystallized from ethyl acetate to obtain pale yellow crystals. Yield 1.25 g (83.5%) ° mp: 1 96- 197 ° C; IR (KBr) vmax: 1720, 1619; UV (CHCI3) Xmax (log ε): 319 (4.02), 2 50 (4.00) ; 1H-NMR (DMSO-d6): 6 5.74 (s, 2H, 0CH2), 6.31 (d, 1H) 3-H), 7.03 (dd, 1H, 6-H), 7.10 (d, 1H. 8- H), 7.43 (t, 2H, aromaticH) f 7.65 (d, 1H, 5-H), 8.00 (d, 1H, 4-H), 8.13 (dd, 2H, aromatic H); Anal: C17H11 FO4, calcd . 0: 68.46, H: 3.72, Found C: 68.23, H: 3.69 0 The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

0A (please read the precautions on the back before filling in this page) Formula ·. B7 5. Description of the invention (2¾ (18) 7- (2-p-gas phenyl-2-oxoethyloxy) -2-hydrogen Small benzoin acylpyridin ^ 2-ketone (6b) · Also with ϋ (5 millimoles) and oc-bromo-p-chloroacetophenone (a-bromo-p-chloroacetophenone), 1.17 grams, 5 millimoles Ear) According to the method of synthesis and purification of compound 6¾, it can be found in compound 6b as yellow crystals with a yield of 1.31 g (83.2%). mp: 192-194-«β%%» 〇C; IR (KBr) vmax: 1718, 1615; UV (CHCl3) Xmax (log ε): 31 9 (4.12), 258 (4.22); 1H-NMR (DMSO -d6): 55.74 (s, 2H, OCH2), 6.31 (d, 1H, 3-H), 7.03 (dd, 1H, 6-H), 7.li (d, 1H, 8-H), 7.65 ( d, 1H, 5-H), 7.67 (d, 2H, aromaticH) l8.00 (d, 1HI4-H) f8.06 (d, 2H, aromatic H); Anal: C17 Hu CIO4 0.25H 2〇, calcd . 0: 63.96, H: 3.63, Found C: 64.09, H: 3.49 0 (19) 7- (2-p-bromophenyl-2-oxoethyloxy) -2-hydro-1-benzoyl acetyl ratio Lin ~ 2- 嗣 (6c). With (5 millimoles) and α-bromobromoacetophenone (《-br 〇m 〇- p-bromoacetophenone) ^ 1.39 grams, 5 milligrams of shellfish consumption of the Central Standards Bureau of the Ministry of Economy Printed by the cooperative (please read the precautions on the back before filling in this page) Mohr) According to the compound synthesis and purification method, compound & can be obtained as white needle crystal, imou1 27jL (70_6%) 〇mp: 175-1 77 ° C; | R (KBr) vmax: 1699, 1615; UV (CHCI3) (l〇ge): 319 (4.22), 267j (4.33); 1H-NMR (CDCI3): 5 5.33 (s > 2H, OCH2), 6.27 (d, 1H. 3-H), 6.79 (d, 1H, 8-H) .6.91 (dd, 1H, 6-H), 7.40 (d, 1H, 5-H), 7.64 (d, 1H, the paper size With China National Standard (CNS > A4 size (210 X 297 mm) Central Bureau of Standards HIGHLAND consumer cooperatives A 7 B7 print run of Economic Affairs V. DESCRIPTION OF THE INVENTION

It is white crystal with a yield of 1.17 g (75.3%) ° mp: 159-161 ° C; IR (KBr) vmax: 171 8, 1700, 1 620; UV

_ I (CHCI 3) I 〇g ε): 3 1 5 (4.2 2), 2 7 1 (4.2 7); 1 H-NMR (CDCI3): 5 3.90 (s, 3H, OCH3), 5.33 (s, 2H, 〇CH2), 6.26 (d, 1H, 3-H), 6.79 (d, 1H, 8-H), 6.92 (dd, 1H, 6-H), 6.99 (d, 2H, aromaticH), 7.39 ( d, 1H.5-H), 7.63 (d, 1H, 4-H), 7.98 (d, 2H, aromatic H); Anal: C * j 8 Hi4〇5, calcd. C: 69.67, H: 4.55, Found C: 69.63, H: 4.57 ° (22) 7- (2-o-methoxyphenyl-2-oxoethyloxy) -2-hydro-1-benzoyl benzopyrine-2-one 丨 Μ 丨. Take 1_b (5 mmol) and a-bromo-m · methoxyacetophenone (lx-br 〇m ο--methoxyaeetophenoneyi. 15 g, 5 mmol) according to the synthesis and purification method of Compound M, namely Compound g is available as white crystals with a yield of 1.29 g (83.2%). 卬 卩 ： 172-173〇c; IR (KBr) vmax: 1743, 1 684, 1 622; UV (CHClf ^ max (丨 〇 g ε): 30 8 (4.21), 253 4.01); 1H-NMR (CDCI3): 6 3.88 (sf 3H, OCH3), 5.38 (s, 2H 〇CH2), 6.27 (d, 1H, 3-H ), 6.79 (d, 1H, 8-H), 6.93 (dd, 1H, 6-H), 7.16-7.22 (m, 1H, aromatic H), 7.38-7.59 (m, 4Hf 5-H and aromatic H) , 7.64 (d, 1H.4-H); Anal: C-jqH-j4〇5, calcd. 0: 69.67, H: 4.55, Found C: 69.44, H: 4.55 ° The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 27 (please read the precautions on the back before filling this page) Book 2J38I9 Central Ministry of Economic Affairs B7 printed by the Staff Consumer Cooperative of the Bureau of Standards 5. Description of invention (24 4-H), 7.67 (d, 2H, aromatic Η), 7.86 (d, 2H, aromatic H); Anal: Ci7H11Br04l calcd. 0: 56.85, H: 3.09, Found C-.56.81, H: 3.09 ° \ (20) 7- (2-p-Benzophenyl-2-oxoethyloxy) -2-hydrobenzoic acid benzopyrine-2-hydro Ketone (6_d). With K 5 mmol) and a-bromo_P_benzylphenone (α-br ό m 〇-p-phenylacetophenone), 1.38 g, 5 mmol) according to the synthesis of compound 6a and Purification method can obtain compound 6d., As pale yellow crystals, yield 1.58 g (88.8%) 〇〇 ^: 187-188〇C; IR (KBr) vmax: 1 729, 1700, 1626; UV (CH〇 丨3) Xmax (丨. g ε): 271 (4.38); 1H_NMR (CDC | 3): δ 5.41 (s, 2H, OCH2), 6.27 (d, 1H, 3-H), 6.83 (d, 1H, 8-H), 6.95 ( dd, 1H, 6-H), 7_40 (d, 1H, 5-H), 7.45-7.67 (m, 6H, 4-H and4'-phenylic H), 7.75 (d, 2H, aromatic H), 8- 07 (d, 2H, aromatic H); Anal: C 23 Η · | 6 〇4 0.25H2〇, calcd. C: 76.54, H: 4.61, Found 0: 76.64, H: 4.42 ° (21) 7- (2 -P-methoxyphenyl-2-oxoethyloxy) -2-hydro-1-benzyl acetylpyridine ^ 2-one (6e). With l "fe_ (5 millimoles) and a · bromine- P-methoxyacetophenone (a-bromo-p-methoxyacetophenone, 1_15 g, 5 mmol) can be obtained according to the synthesis and purification method of compound M (CNS) A4 specification (21GX297W) '26 ...............- y installed ............... (Please read the precautions on the back first (Fill in this page) A7 B7 5. Description of the invention (2¾ Reaction Example 6: (23) 7-[(2-p-fluorophenyl-2,3,4,5-tetrahydro-4-methylene-5-oxo Substituted-2-tlan) methoxy] hydrogen-Ί · benzoin acylpyrine · 2 · one 7 · {[2- (ρ-

Fluorophenyl) -2,3,4,5-tetrahydro-4-methylene-5-oxo-2-furanyl] methoxy} -2 H-1 -benzopyran-2-one (Za). Pack the compound _ (0.60 g, 2 mmol), according to the synthesis reaction of compound ^ for 18 hours and purification method, the compound can be obtained as pale yellow crystals with a yield of _63 g (85.9%> .mp: 157-159〇C; IR ( KBr) vmax: 1771, 1712, 1613; UV (CHCI3) λΓγιειχ (Ι〇9 ε): 320 (4.18), 253 (3.82); 1H-NMR (CDCI3): 5 3.21 (dt, 1H, 4'-H ), 3.65 (dt, 1H, 41-H), 4.13,4.22 (two d, 2H, OCH2), 5.73 (t, 1H, vinylic H), 6.26 (d, 1H, 3-H), 6.33 (t, 1H, vinylic H), 6.73 (d, 1H, 8-H), 6.78 (dd, 1H, 6-H), 7.14 (t, 2H, aromatic H), 7.36 (d, 1H, 5-H), 7.48 (dd, 2H, printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs ............... ^ ...- I · Left ... .... Order (please read the precautions on the back before filling this page) aromatic H), 7.63 (d, 1H, 4-H); Anal: C21H15F05 0.25H2〇, calcd. C: 68.01, H.4.21, Found 0: 68.19, H: 4.08 ° (24) 7-[(2-p-Phenyl-2,3,4,5-tetrahydro-4.methine_5_oxo_2_0furan) Oxy] -2-nitrogen · 1 -benzoin Base brew Biling "2-Meng (7b). Drop the compound (0.63 grams, 2 millimoles), according to the size of the compound on the paper, the Chinese Standard (CNS) A4 specification (210X297 mm) is applied ~ '~~ '28 A 7 B7 Fifth, the description of the invention (~) 24 hours of synthesis reaction and purification method can obtain the compound Zt, which is pale yellow (please read the precautions on the back before filling in this page) color crystal, yield 0.68 g ( 88.6%) ° mp: 202-204oC; IR (KBr) vmax: 1771, 1708, 1 608; UV (CHCI3)

Xmax (l〇g ε): 322 (4.13), 244 (3.58); 1H-NMR (CDQ3): δ 3.19 (dt, 1H, 4'-H), 3.64 (dt, 1H, 4'-H), 4.13, 4.21 (two d, 2H, OCH2), 5.73 (t, 1H, vintage H), 6.27 (d, 1H, 3-H), 6.33 (t, 1H, vintage H), 6.73 (d, 1H, 8 -H), 6.78 (dd, 1H, 6-H), 7.36 (d, 1H, 5-H), 7.39-7.43 (s, 4H, aromatic H), 7.63 (d, 1H, 4-H); Anal : C2iH15CI05 0.25H2〇, calcd. C: 65.12, H: 4.703,

Found C: 64.93, H: 3.93. (25 > 7-[(2-p-bromophenyl-2,3,4,5-tetrahydrogenated-4-methine-5-oxo-2-fluorofuran) methoxy] -2- Hydrogen-1-benzoin acetylpyridine-2-one (7c). Compound compound (0.72 g, 2 mmol), according to the synthesis reaction of compound M for 48 hours and purification method, compound weep is obtained, which is white economy Printed crystals of the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Production, yield 0.65 g (76.3%) ° mp: 206-208oC; IR (KBr) vmax: 1770, 1710, 1 610; UV (CHCI3)

Xmax (l〇g ε): 321 (4.20), 243 (3.68); 1H-NMR (CDa3): 6 3.18 (dt, 3.64 (dt, 1H, 4'-H), 4.13.4.21 (two d , 2H, OCH2), 5.73 (t, 1H, vinylic H), 6.27 (d, 1H.3-H), 6.33 (t, 1H, vinylic H), 6.73 (d, 1H.8-H), 6.78 ( dd, 1H, 6-H), 7.37 (d, 3H, 5-H and aromatic H), 7.58 (d, 2H, aromatic H) f 7.63 (d, 1 H, this paper scale is applicable to China National Standards (CNS) A4 size (210 X 297 mm) 20 B7 B7 Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Description of Invention Ο 4-Η); Anal: 〇21 Hi5Br〇5 〇.25Η 2〇, ca | cd. C: 58.42, H: 3.62, Found C: 58.53, H: 3.63 ° (26) 7-[(2-p-phenylphenyl-2,3,4,5-tetrahydro-4-methylene-4 -Oxo-2-pyran) methoxy] -2 -hydro-1 -benzoin-pyrin-2-one (Zi). The compound M (0.71 g, 2 mmol), according to compound ^ Synthesis reaction 56 hours and purification method can obtain compound M, as white crystals, yield 0.67 g (78 · 8%). Mp: 135-137〇C; IR (KBr) vmax: 1769, 1708, 1 613; UV (CHCI 3)

Xmax (l〇g ε): 322 (4.1 8), 253 (4.36); 1 H- H), 4.20, 4.29 (two d, 2H, OCH2), 5.73 (t, 1H, vintage H), 6.26 (d , 1H, 3-H), 6.33 (t, 1 H, vinylic H), 6.76 (d, 1H, 8-H), 6.81 (dd, 1H.6-H), 7.34-7.69 (01, 11H.4 -, 5- H and aromatic H); Anal: C27 H20O5 〇.25Η 2 〇, calcd. C: 75.60, H: 4.82, Found 0: 75.54, H: 4.81 0 (27) 7-[(2- p-A Oxyphenyl-2,3,4,5-tetrahydro-4-methine-5 · oxo-2 · kiran) methoxy] -2 -hydrogen-1 -benzoylpyridine-2- Ketone (Za) · Compound M (0.62 g, 2 mmol) can be obtained according to the synthesis reaction of compound M for 18 hours and purification method, as white crystals, yield 0.55 g (72.2%) 148-150 〇C; IR (KBr) vmax: 1778, 1714, 1615; UV (CHCI3)

Xmax (log ε): 320 (4.05), 245 (3.85); 1H- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 30 -i ............ ...... \ Λ ................ ordered (please read the precautions on the back before filling in this page) B7 B7 Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (2b) NMR (CDCI3): 5 3.21 (dt, lH, 4i-H), 3.62 (dt, 1H, 4, H), 3.84 (s, 3H, OCH3), 4.11, 4.22 (two d, 2H, OCH2), 5.70 (t, 1 H, vinylic H), 6.24-6.32 (m, 2H, 3-H and vinylic H), 6.73 (d, 1 Η, 8-H), 6.79 (dd, 1H, 6-H), 6.96 (d, 2H, aromatic H), 7.34-7.42 (m, 3H, 5-H and aromatic H), 7.63 (d, 1H, 4-H) .; Anal: 〇22Ηΐ8〇 6 0.25H2〇, calcd. C: 69.01, H: 4.87, Found C: 68.93, H: 4.83 ° (28) 7-[(2-O-methoxyphenyl-2,3,4,5'tetrahydro- 4-methine-5-oxo_2 · 〇furan) methoxy] 2-hydrogen-1-benzoyl acylpyridine · 2--Si (71). The compound red (0.62 g, 2 mmol) Ear), according to the synthesis reaction of the compound for 24 hours and purification method, the compound can be obtained as pale red crystals with a yield of 0.65 g (86.5./〇). mp: 121-122〇C; IR (KBr) vmax: 1758, 1714, 1 610; UV (CHCI3) ε): 322 (4.20), 248 (3.96); 1H-NMR (CDCI3): δ 3.23 (dt, 1Hf4'-H), 3.63 (dt, 1H, 4'-H), 3.84 (s, 3H, OCH3), 4.16, 4.25 (twod, 2H, OCH2), 5.71 (t, 1H, vinylic H), 6.26 ( d, 1H, 3-H), 6.31 (t, 1H, vinylic H), 6.73 (d, 1 Η, 8-H), 6.79 (dd, 1H, 6-H), 6.88-6.95 (m, 1H, aromatic H), 6.99-7.06 (m, 2H, aromatic H), 7.32-7.40 (m, 2H, 5-H and aromatic H), 7_62 (d, 1H, 4-H); Anal: 〇22Η18〇6 0_25H2O , calcd. C: 69.01, H: 4.87, Found C: 68.12, H: 4.93 0 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 31 (Please read the notes on the back before writing (This page)

1. 1T Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A 7 B7 5. Description of the invention (丄) The method of anti-platelet aggregation: (A) Preparation of platelet initiator ⑴ Thrombin (bovine) falls in 50% glycerol is 1 〇N old unit / m 丨 store for future use. (2) Collagen (bovin tendon) is dissolved in 15mM acetic acid aqueous solution, grinded into a homogenous suspension at 40C, then divided into img / ml solubility, stored at -70oC, and then re-dissolved before use to grind evenly . (3) PAF is dissolved in carbon tetrachloride (CCI4), stored at -20 ° C, and diluted with deionized water before use. (4) Sodium arachidonate (AA) is dissolved in deionized water and set aside. (B) Preparation of platelets The preparation of platelet suspension (Platelet suspension) according to the literature method, using 100mM EDTA and rabbit ear vein bleed bleeding at a ratio of 1:14, immediately centrifuged in the greenhouse at 120g for 10g The upper platelet-rich plasma was taken out and centrifuged at 500g for 10 minutes. After removing the plasma, the lower platelet was suspended with Tyrode solution containing EDTA (2mM) and Bovin serum albumin (3.5mg / ml). Centrifuge at a rotating speed for 10 minutes. The resulting platelets are suspended in Tyrode solution without EDTA, and the platelet count is adjusted to approximately 4.5 × 108 / ml with a Particle counter (Coulter). Finally, 1 mM calcium is added and left for 30 minutes. After that, experiment.

Tyrode solution (mM) composition: NaCI (136.8), KCI (2.8), NaH2P〇4 (0.33), NaHC03 (11 -9), MgCI2 (2.1), CaCI2 (1.0), glucose (11.2) and bovine serum… Γ ................--: y ----------------, yes (please read the precautions on the back before filling this page ) 32 A7 B7 2 ^ 3819 V. Description of the invention (: 1〇) albumin (0.35%) ° (C) Test of platelet coagulation and reaction with ATP release ...-....... 一 ' -Clothing ............... (please read the precautions on the back before filling in this page) According to the method for measuring the mixture of Born and Cross (1963), use Lumi-aggregometer ( Model 1020, Payton, Canada). Add 0.4 ml of platelet suspension to a small glass-coated tube coated with Silicone, and use a small magnetic rod to mix at 900 rpm. Unless otherwise specified, all antagonists are added 1 minute before the initiator is added. The method of expressing the degree of agglutination of the reaction process is as follows: Adding agglomeration initiator—absorbance agglutination after adding the absorbance before adding the agglomeration initiator (./.)=------ X 100% adding agglomeration initiator_Tyrode solution Absorbance of the previous absorbance In some experiments, the uciferase-luciferin mixture was added to 25 μ !, and the fluorescence generated by the reaction with ATP was used to determine the size of the platelet release reaction. The degree is expressed as a relative value. (⑺Calculation of IC50 Concentration of Inhibition The calculation method of inhibition of agglutination is as follows: Action Agglutination (%) Inhibition (%) = (1----) X 100% of control group agglutination (%) = %) The anti-platelet aggregation activity of the sample is shown in Table (1) (Table 1), the concentration and percentage of inhibition are plotted, and the 50% inhibitor amount is calculated by linear regression calculation, and IC50 is shown in Table (2) and Table (3) ). This paper scale is printed by China National Standard (CNS) A4 specification (210X297 mm) 33 C6 D6 Printed by βκ 工 consumer cooperative of Central Standards Bureau of Ministry of Economic Affairs

The size of clothing paper is in accordance with the Chinese National Standard (CNS) A4 wash grid (210 X 297 mm) ^ ωοΗΗιδι nHo = a :: g lnH (oQ〇oc \ 4HO = cc_ · ^? Hi £ fel

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CU ii phase call binding Λ (εο.ο + ι0,0 J · ° ε) 0.0 + ι0.0 qisod + loc; q «) 0d = F0.0 ο (εϋ + ιι1 / 98 q (e) rz + 10.98 (S) C \ I.0 = FS.6Z (εΗ.AZ + ι々.ε8

q {§.? 0.o · qwod + loc: q (inch) 0 ·? 0 · 0 q (inch) 9.9 + l8cvic \ JC, (§.50X9 u) 9 · t + ιιε. 00) 1¾ ucsll— H > l © l ^ l ^ l ^ 七 ^ (ε) 卜 2 + ιε · ιοο ^) ln; +! Co.cog E / or / ot 0 qo) e.L + lr6z (9) 0 · L + ICJ.ZOOsr / oor-l ^^^^: (ε) ε · ιη + 2 · 08 (ss. $ Co26l--lm / {l I; · 0_! § 省 螺 82 · 12 · 10,000 (Please first « (Read the back > / Notes and write this page again)

JL -installed-ordered. 2J3819 C6 D6 5. Description of invention (3¾ Table ⑵

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bi Rj = R2 = R3 = H c; R ^ = R3 = Ht R2 = CH3 d: R1 == CI, R2 = CH3 R3 = H Θ: R " | (please read the notes on the back before filling this page) Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, 1050 (pg / ml) compound arachidonic acid platelet aggregation factor 3a (R = CH3) 65.40 85.73 3b (R = CH3) > 20 59.71 (R = CH3) 34.07 44.05 ad (R = CH3) 5.94 35.20 3e (R = CH3) > 50 53.20 5a (R = C6H5) 2.86 36.01 5b (R = C6H5) 1.27 5.70 5c (R = C6H5) 5.06 54.43 M (R = C6H5) > 100 5e (R = C6H5) 3.94 The paper size is in accordance with Chinese National Standard (CNS) A 4 specifications (210 X 297 mm) 82. 12. 10, C6 __D6 5. Invention description) (Please read the precautions on the back first Item Write Table Page) Table ⑶ Central Bureau of Samples of the Ministry of Economic Affairs Shelley Consumer Cooperation Du Yin *

丨 C5〇 (gg / ml) Compound Arachidonic Acid Platelet Aggregation Factor 5b (R = 4-H) 1.27 5.70 la (R = 4-F) 1.36 5.89 7b (R = 4-CI) 1.62 15.04 IS. (R = 4 -Br) 3.25 14.21 Id (R = 4-Ph) > 5 Ze (R = 4-OMe) 3.40 12.58 71 (R = 3-OMe) 1.41 10.63 This paper is used in the troubled country «quasi (CNS) A 4 Specifications (210 X 297 mm) 82. 12. 10,000

Claims (1)

· ----- J Bulletin Γ ~ 6.Shen 1 * ~ a compound and its salt having the structure of the formula (ι) as shown below. Among them, R 2, R 3 represent hydrogen group, C Bu 6 pull, 'R represents cl6 alkyl and at least phenyl substituted with r4, r5, r6, and R r ruler represents hydrogen, C alkyl, C 4 5 6 1 1-7 oxyalkyl, halogen, respectively. (Please read the precautions on the back before filling this) Rs R = C ^ " R4 r6, C 1 _ 6 tiger base 2 such as the compounds and salts of the first item of the patent application scope, where R], R2, R3 represents a hydrogen group, 〇 Bu 6 alkyl group, R represents C! -6 alkyl group and at least R4, R5, R6 substituted phenyl group, and R4, R 5, R 6 respectively represent a hydrogen group, C Bu 6 alkyl基 、 C 卜 7 Oxygen burned i group, halogen. Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives a—a compound of the formula (II) shown below and its salts, where R represents Ci-6 alkyl and phenyl substituted with at least R4, R5, R6 And, R4, R5, R6 represent a hydrogen group, Ch-6 tiger group, Cp7 oxalonyl group, halogen. " The scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public A ,.), 7 B8 C8 D8 6. Scope of patent application 4 Compounds and their salts such as the application of the patent garden item 3, where R Represents C, β-tigeryl and phenyl substituted with at least R4, R5, and Chi-6, and R 4, R 5, and R 6 represent hydrogen, Cp6 alkyl, c-oxyalkyl, and halogen, respectively. 15—A method for manufacturing the compound of formula (I) and its salts, such as the first item in the scope of patent application, which consists of coumarin (coumarin) substituted with R i, R2, and R3 in carbonic acid. Substituted with halogenated sea bream (III) compound containing R substitution to obtain (2_oxo tiger oxy) -2-hydro-1-benzoin Qin cancer bilin · 2 · one (lν); Κ · ι, R_2 as defined in the patent application section; < *!. 5 y (please read the precautions on the back before filling in this page), 1T Printed by the Consumer Labor Cooperative of Central Falcon Bureau of the Ministry of Economic Affairs (iv) Dissolve compound (IV) in anhydrous tetrahydrofuran, add zinc powder and hydroquinone, 2-bromo Ethyl methyl ethyl ester (6 juice 7 丨 (2-13 "0yang 01116 ^^ 丨) 30" 7 this 6), heating and refluxing to perform Reformatsky reaction 〇'Ύ 0 This paper scale is applicable to the Chinese National Standard (CNS) Α4 specification (2 丨 0 > < 297 gong) 38 B B8 C8 D8 VI. Patent application scope 6. A compound of formula (II), such as the third item of the patent application scope And its salts, which are obtained by carrying out substitution reaction of halogenated ketone compounds containing R substitution with coumarin (c〇umarn) in an alkaline solution such as carbonate (2-oxoalkane) Oxy) benzoin-based bipyrin-2-one (IV); R as defined in the patent application country j 〇〇Zhonggong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Printing and Printing MM · Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs MM · „Training === ==. 811-. (Please read the precautions on the back before filling this page) Dissolve the compound (IV) in anhydrous tetranitrogen (uraf π) 'and add the diaper and dibenzhuang (bu y droq ui η ο η θ), 2- / odorous ethyl propylene ethyl alcohol (ethy 丨 (2- bromomethyl (acrylate), Reformatsky reaction by heating and refluxing 0 0 ^ 0 (IV) Zn, Br THF 39 The size of this paper is applicable to the Chinese National Standard (CNS) 84 specifications (210X297 mm) 2jHS19 η, C8 —— 一 _: _— DS VI. Patent application scope 7_ — A pharmaceutical composition with platelet aggregation inhibition, written It contains a pharmaceutically acceptable excipient and an effective amount of the compound of formula (I) and its salts such as the patent application model, where Rl, R_2, represents the wind * base, Cj_ 6 Dianji, R represents C 1_6 pit base And a phenyl group substituted with at least R 4, R 5, and R 6, and R 4, R 5, and R 6 respectively represent a hydrogen group, a C _ 6 alkyl group, a C 7-7 oxyalkyl group, and a halogen. 8. The pharmaceutical composition as claimed in item 7 of the patent scope, in which r 1, R2, respectively represent a hydrogen group, C 2 _ 6 burning group, R represents C Bu 6 alkyl group and at least substituted by R4, R5, R 6 The phenyl group, and r4, R5, ruler β represent a hydrogen group, Ci-β group, C] ~ 7 oxygen group, halogen. 9. A pharmaceutical composition with inhibition of platelet aggregation, which contains a pharmaceutically acceptable excipient and a compound of formula (Π) and its salts in a reasonable amount, such as _ 谙 Patent Fanyuan Item}, where R Represents c] — alkane ^ and phenyl substituted by at least R 4, R 5, R 6, and R 4, R 5, R 6 represent a hydrogen group, cT _6 alkyl group, C] _ 7 oxyalkyl group, boudoir Prime. The Central Standardization Bureau of the Ministry of Hydrology only cooperates with Xiaoji Printing Co., Ltd. 10. For the pharmaceutical composition of item 9 of the patent application, where R represents C 1-6 tiger group and benzene substituted by at least R4, R5, R 6 R 4, R 5, and ir s respectively represent a hydrogen group, ◦ 1 _ 6 alkyl group, c _ oxo burning group, and Yu element. 17