5-fluorouracil derivatives, preparation methods and uses thereof

Abstract

Disclosed is a 5-fluorouracil derivative having the molecular structure shown in general formula VI, in which Ra and Rb groups are an alkoxy group or a fluorine-substituted alkoxy group having 1, 2, 3, or 4 carbon atoms, and are mono-, bis-, tri-, tetra- or penta-substituted on a phenyl group; a linking group L1 is an alkyl or alkenyl group having 1, 2, 3, or 4 carbon atoms, a linking group L2 is oxygen, or an alkyl or alkoxy group having 1, 2, 3, or 4 carbon atoms, or an amino acid, or an alkyl group having 1, 2, 3, or 4 carbon atoms containing an amino moiety, or a furyl group, and an X group is O or —NH—. Further disclosed is a method for preparing such a derivative and a use of the same in the treatment of cancer, tumor diseases, and diseases caused by abnormal neovascularization in a human or non-human mammal, and a medicament or a composition containing the 5-fluorouracil derivative.

Claims

1. A compound of formula VI: ##STR00010## wherein: 1) Ra is a mono-substituted, di-substituted, tri-substituted, tetra-substituted or penta-substituted phenyl group, in which one or more hydrogens are substituted by (C1-C4) alkoxy or fluorine-substituted (C1-C4) alkoxy; 2) Rb is a mono-substituted, di-substituted, tri-substituted, or tetra-substituted phenyl group, in which one or more hydrogens are substituted by (C1-C4) alkoxy or fluorine-substituted (C1-C4) alkoxy; 3) the linking group L1 is —CH═CH— or —CH.sub.2CH.sub.2−; 4) the linking group L2 is —CH.sub.2−, —CH.sub.2−CH.sub.2−, or —CH.sub.2CH.sub.2CH.sub.2−; 5) the group X is independently selected from the group of a bond, 0, and —NH—.

2. The compound according to claim 1, wherein: 1) Ra is a tri-substituted phenyl group, in which three hydrogens are substituted by —OMe, —OCF.sub.3, —OCF.sub.2H or —OCFH.sub.2, 2) Rb is a mono-substituted phenyl group, in which one hydrogen is substituted by —OMe, or —OEt.

3. The compound according to claim 1, characterized in that its structure characteristic is shown as formula I: ##STR00011## wherein: 1) each R1, R2 or R3 is independently (C1-C4) alkoxy, or fluorine-substituted (C1-C4) alkoxy; 2) R4 is (C1-C4) alkoxy or fluorine-substituted (C1-C4) alkoxy.

4. The compound according to claim 3, wherein: each R1, R2, R3 or R4 is independently —OCH.sub.3, —OC.sub.2H.sub.5, —OCF.sub.3, —OCF.sub.2H or —OCFH.sub.2.

5. The compound according to claim 1, wherein said compound is selected from the group consisting of: Compound Ia: (Z)-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-methoxy-5-(3,4,5-trimethoxystyryl (phenyl) acetamide, Compound Ib: 3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-methoxy-5-(3,4,5-trimethoxyphenethyl(phenyl) acetamide, Compound Ic: (Z)-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-methoxy-5-(3,4,5-trimethoxystyryl(phenyl) propanamide, Compound Id: 3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-methoxy-5-(3,4,5-trimethoxyphenethyl(phenyl) propanamide, Compound Ie: (Z)4[3]]4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-methoxy-5-(3,4, 5-trimethoxystyryl(phenyl)butyrylamide, Compound If: 4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-methoxy-5-(3,4, 5-trimethoxyphenethyl(phenyl)butyrylamide, Compound Ig: N-(2-ethoxy-5-(3,4,5-trimethoxyphenethyl(phenyl)-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide, Compound Ih: N-(2-ethoxy-5-(3,4,5-trimethoxyphenethyl(phenyl)-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) propanamide, Compound Ii: (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)-phenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate, Compound Ij: 2-methoxy-5-(3,4,5-trimethoxyphenethyl)-phenyl: 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate, Compound Ik: (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)-phenyl-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate, Compound Il: 2-methoxy-5-(3,4,5-trimethoxyphenethyl)-phenyl-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate, Compound Im: (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)-phenyl-4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)butyrate, Compound In: 2-ethoxy-5-(3,4,5-trimethoxyphenethyl)-phenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate, and Compound Io: 2-ethoxy-5-(3,4,5-trimethoxyphenethyl)-phenyl-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate.

6. A pharmaceutical composition containing the compound of claim 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that it is a dosage form selected from the group consisting of: lyophilized powder, powder, injection, liposome, emulsion, microcapsule, suspension or solution for intravenous administration; granules, tablets, capsules or syrup for oral administration; and suppository.

Description

DETAILED DESCRIPTION

(1) This invention provides preparation methods of compounds with formula I, which are obtained by carboxyl condensation of raw materials II and intermediates III under the action of condensation reagent, as follows:

(2) ##STR00006##

(3) Wherein:

(4) 1) Each R1, R2 or R3 is independently (C1-C4) alkoxy, or fluorine-substituted (C1-C4) alkoxy.

(5) 2) Each R4 is independently selected from (C1-C4) alkoxy, or fluorine-substituted (C1-C4) alkoxy.

(6) 3) The linking group L1 is independently (C1-C4) alkyl or (C1-C4) alkenyl.

(7) 4) Each L2 is independently selected from the group of a bond, O, (C1-C4) alkyl, (C1-C4) alkoxy, amino acid, (C1-C4) alkyl with amino, or furanyl.

(8) 5) Each X is independently selected from the group of a bond, O, NH.

(9) 6) The condensation reagent is independently DCC, EDCI, BOP, PyBOP, HBTU or HATU, preferably DCC.

(10) In this embodiment, the synthesis route of raw material II of stilbenes and diphenylethanes is as follows:

(11) ##STR00007##

(12) 1) Each R1, R2 or R3 is independently (C1-C4) alkoxy, or fluorine-substituted (C1-C4) alkoxy.

(13) 2) Each R4 is independently selected from (C1-C4) alkoxy, or fluorine-substituted (C1-C4) alkoxy.

(14) The detailed synthesis method about raw material II of stilbenes and diphenylethanes used in the invention has been described in patents US2012/0046492A1 and CN103539642 by the inventor.

(15) The intermediate III of 5-fluorouracil involved in this embodiment is a known compound, which is prepared by the following steps slightly improved according to literature:

(16) 1) 5-fluorouracil (5-FU) reacts with raw material IV to afford intermediate V.

(17) 2) Intermediate V is hydrolyzed to afford intermediate III.

(18) ##STR00008##

(19) Wherein, Y in raw material IV is selected from chlorine, bromine or iodine, preferably chlorine and bromine. The linking group L2 is the group of a bond, —O—, —C.sub.nH.sub.2n— (n=1, 2, 3, 4), —OC.sub.nH.sub.2n— (n=1, 2, 3, 4), amino acid, (C1-C4) alkyl with amino, or furanyl.

(20) Each R is hydrogen, methyl, ethyl, propyl or isopropyl, preferably hydrogen, methyl and ethyl.

(21) In order to further understanding of the technical content of the invention, the synthesis methods of raw material II of stilbenes or diphenylethanes and 5-fluorouracil intermediate III used in the invention are illustrated with examples as follows:

Preparation of Raw Material II of Stilbenes or Diphenylethanes

Example 1: Preparation of 3′-amino-3,4,4′,5-tetramethoxystilbene (IIa)

Step 1: Synthesis of 3′-nitro-3,4,4′,5-tetramethoxystilbene

(22) Under nitrogen, 3,4,5-trimethoxybenzylbromotriphenylphosphonate (4.42 g, 8.5 mmol) was suspended in anhydrous tetrahydrofuran (50 ml). the mixture was cooled to −20° C., and n-butyl lithium solution (8 ml, 2.5 m) was added dropwise slowly. After adding, the reactant was keep stirring for 3 h. A tetrahydrofuran (10 mL) solution of 3-nitro-4-methoxy benzaldehyde (1.5 g, 8.3 mmol) was added to the reaction solution through a drop funnel. After adding, the reaction was keep for 5 h, the reactant was raised to room temperature and reacted overnight. While TLC test showed that the reaction was complete, water (50 ml) was added to quench reaction and the organic solution was separated. The water layer was exacted by ethyl acetate (50 ml). The organic phase was combined and washed with water for 2 or 3 time, and was dried with anhydrous sodium sulfate. The oil was obtained by rotary evaporation. The residue was crystallized with anhydrous ethanol to obtain a solid of 3′-nitro-3,4,4′, 5-tetramethoxystilbene (1.6 g, 46%). 1H-NMR (500 MHz, CDCl3) δ8.03 (s, 1H), 7.68 (d, J=5 Hz, 1H), 7.11 (d, J=10 Hz, 1H), 7.00 (m, 2H), 6.75 (s, 2H), 4.01 (s, 3H), 3.94 (s, 6H), 3.90 (s, 3H).

Step 2: Preparation of 3′-amino-3,4,4′, 5-tetramethoxystilbene

(23) 3′-nitro-3,4,4′,5-tetramethoxystilbene (1.4 g, 4.0 mmol) obtained in step 1 was dissolved in acetic acid (10 ml). Zinc powder (6.5 g) was added the solution, and the reactant was stirred and reacted at room temperature for 2 h. While TLC test showed that the reaction was complete, the mixture was filtrated. The filtration was pour to water (50 ml). The water layer extracted with dichloromethane (3*50 mL). The combined organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water once respectively, dried with anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the product IIa (0.9 g, 70.2%). 1H-NMR (500 MHz, CDCl3) δ6.95 (s, 1H), 6.91 (m, 3H), 6.89 (d, J=5 Hz, 1H), 6.80 (d, J=5 Hz, 1H), 6.73 (s, 2H), 3.93 (s, 3H), 3.90 (s, 6H), 3.88 (s, 3H).

Example 2: Preparation of 3′-amino-3,4,4′,5-tetramethoxy diphenylethane (IIb)

(24) 3′-nitro-3,4,4′,5-tetramethylstilbene (1.4 g, 4.0 mmol) prepared in step 1 of example 1 was dissolved with ethyl acetate (30 mL), and 10% Pd—C catalyst (200 mg) was added. The reaction system was replaced with hydrogen three times. The hydrogenate reaction was maintained at room temperature for 4 h. While the reaction detected by TLC was complete the reactant was filtered. The filtrate was concentrated under vacuum. The crude residue was subjected to column chromatography to afford the product IIb (1 g, 78.0%). 1H-NMR (500 MHz, CDCl3) δ6.95 (s, 1H), 6.91 (m, 3H), 6.89 (d, J=5 Hz, 1H), 6.80 (d, J=5 Hz, 1H), 6.73 (s, 2H), 3.93 (s, 3H), 3.90 (s, 6H), 3.88 (s, 3H).

Example 3: Preparation of 3′-amino-4′-ethoxy-3,4,5-trimethoxy stilbene (IIc)

Step 1: Preparation of 3′-nitro-4′-ethoxy-3,4,5-trimethoxystilbene

(25) (3,4,5-trimethoxybenzyl)triphenylphosphonium bromide (15 g, 28.7 mmol) was suspended in anhydrous tetrahydrofuran (300 mL) under argon. The mixture was cooled to −15° C., and n-butyllithium cyclohexane solution (1.6 mol/L, 22 mL) was added dropwise. After the reactant was stirred for 1 hour, tetrahydrofuran (24 mL) solution of 4-ethoxy-3-nitrobenzaldehyde (5.7 g, 29 mmol) was slowly dropped into the reaction solution. The reactant was stirred for 1 hour and then stirred overnight at room temperature. While TLC test showed that the reaction was complete, water was added to quench reaction and the organic solution was separated. Three fours of the solvent was removed by concentration. The remaining mother liquor was crystallized using 4 times anhydrous ethanol in ice bath and then filtered to afford light yellow solid of the product (6.8 g, 65%).

Step 2: Synthesis of 3′-amino-4′-ethoxy-3,4,5-trimethoxystilbene

(26) 3′-nitro-4′-ethoxy-3,4,5-trimethoxystilbene (1.4 g, 4.0 mmol) obtained in step 1 was dissolved in acetic acid (10 ml). Zinc powder (6.5 g) was added into the solution, and the reactant was stirred at room temperature for 2 h. While TLC test showed that the reaction was complete, the mixture was filtrated. The filtration was pour to water (50 ml) and neutralized with sodium hydroxide until pH=9. The organic layer extracted with dichloromethane was washed with saturated brine dried with anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the product IIc (1.1 g).

Example 4: Preparation of 3′-amino-4′-ethoxy-3,4,5-trimethoxy diphenylethane (IId)

(27) 3′-amino-4′-ethoxy-3,4,5-trimethoxystilbene (2 g) prepared in step 2 of example 3 was dissolved with ethyl acetate (50 mL), and 10% Pd—C catalyst (500 mg) was added. The reaction system was replaced with hydrogen three times. The hydrogenate reaction was maintained at room temperature for 4 h. While the reaction detected by TLC was complete the reactant was filtered. The filtrate was concentrated under vacuum to afford the product II d.

(28) 1H-NMR (500 MHz, CDCl3) δ7.14 (d, 1H, 2′-H), 6.88 (d, 1H, 6′-H), 6.68 (d, 1H, 5′-H), 6.60 (s, 2H, 2, 6-H); 4.48 (brs, 2H, NH2); 4.08 (q, 2H, —CH2), 3.77 (s, 3H, 4-OCH3), 3.75 (s, 6H, 3, 5-OCH3), 2.85 (d, 1H, J=12.5 Hz, la-H); 2.78 (d, 1H, J=12.5 Hz, la′-H), 1.56 (3H, t; CH3); MS (m/Z): 331 (M+); HRMS, Calcd: 331.1784, found: 331.1753.

Example 5: Preparation of 3′-hydroxyl-3,4,4′,5-tetramethoxy diphenylethane (IIe)

Step 1: Synthesis of 3′-benzyloxy-3,4,4′,5-tetramethoxystilbene

(29) Dried THF (50 mL) and (3,4,5-trimethoxybenzyl)triphenyl phosphonium bromide (4.42 g, 8.5 mmol) were added to a three-necked flask filled by nitrogen and cooled to −20° C. After the mixture was stirred for 1 h, 2.5M n-butyllithium (8 mL) was added slowly and the reactant continued stirring for 3 h. A THF (10 mL) solution of 3-benzyloxy-4-methoxybenzaldehyde (1.21 g, 5 mmol) was dropped and the resulting reaction mixture was stirred for 5 h. The mixture was warmed to room temperature and stirred overnight. After reaction detected by TLC was complete, water (100 mL) was added to stop the reaction and the organic liquid was separated. The water layer was extracted with EA (50 mL). The combined organic phases was washed with water for 2-3 times, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue was disposed with anhydrous ethanol (15 mL) to afford the product (1.2 g, 59%). 1H-NMR (500 MHz, CDCl3) δ3.91 (s, 9H); 5.20 (s, 2H); 6.70 (s, 2H); 6.83 (d, J=16.5 Hz, 1H); 6.90 (m, 2H); 7.08 (t, J=8.5 Hz, 2H); 7.32 (t, J=7.5 Hz, 1H); 7.39 (t, J=7.5 Hz, 2H); 7.48 (d, J=7.5 Hz, 2H).

Step 2: Preparation of 3′-hydroxyl-3,4,4′5-tetramethoxy diphenylethane (IIe)

(30) Anhydrous ethanol (60 mL) and 3′-benzyloxy-3,4,4′,5-tetramethoxystilbene (2.03 g, 5 mmol) were added to a three-necked flask filled with hydrogen at room temperature. 10% Pd—C (0.5 g) was added and acetic acid (1 mL) was added dropwise. After the reactant reacted for 4 hours, TLC detection showed that the reaction was complete. Pd—C was removed by filtration and the filtrate was concentrated to remove most of the solvent. The residue was leave overnight in refrigerator. A lot of crystals precipitated was filtered to afford the product Ie (1.4 g, 88%). 1H-NMR (500 MHz, CDCl3), δ2.82 (s, 4H); 3.85 (d, J=10 Hz, 12H); 5.61 (s, 1H); 6.38 (s, 2H); 6.65 (dd, J=2.0 Hz, J=8.0 Hz, 1H); 6.77 (d, J=8.0 Hz, 1H); 6.81 (d, J=2.0 Hz, 1H).

Example 6: Preparation of 3′-hydroxyl-4′-ethoxy-3,4,5-trimethoxy diphenylethane (IIf)

Step 1: Preparation of 3′-benzyloxy-4′-ethoxy-3,4,5-trimethoxystilbene

(31) 3,4,5-trimethoxybenzyl triphenylphosphonium bromide (20 g, 38.2 mmol) was suspended in anhydrous tetrahydrofuran (150 mL). Solid potassium tert-butoxide (7.5 g, 66.5 mmol) was added to the reaction solution in batches with stirring. The raw materials were gradually dissolved after stirring at room temperature for 30 min, and the reaction system turned to blood red. Tetrahydrofuran (70 mL) solution dissolved 4-ethoxy-3-benzyloxybenzaldehyde (10.5 g, 41.0 mmol) was added through dropping funnel. The mixture was stirred at room temperature for another 1 h after dropping. After reaction detected by TLC was complete, deionized water (140 mL) was added and the organic liquid was separated. The water layer was extracted with diethyl ether (2*300 mL). The combined organic phases was dried with anhydrous magnesium sulfate and filter cake was washed diethyl ether (50 mL). The filtrate was concentrated to afford oily matter (25 g). The oily matter was disposed with anhydrous ethanol (20 mL) to afford a pale yellow solid (14.1 g). The solid was recrystallized by anhydrous ethanol (25 mL) and then washed with anhydrous ether (10 mL), dried to afford a pale yellow powder of pure 3′-benzyloxy-4′-ethoxy-3,4,5-trimethoxy stilbene (10.6 g, 61.6%).

Step 2: Preparation of 3′-hydroxyl-4′-ethoxy-3,4,5-trimethoxy diphenylethane (IIf)

(32) Ethyl acetate (200 mL) and 3′-benzyloxy-4′-ethoxy-3,4,5-trimethoxy stilbene (10.6 g, 25.8 mmol) prepared in step 1 were added to a flask filled with hydrogen. 10% Pd—C (1 g) was added. The reaction system was replace with hydrogen three times, then the reactant reacted for 1 hours at room temperature. The mixture was filtrated and the filtrate was concentrated. The residue was recrystallized with 40 mL ethanol and washed with ethanol to afford the product IIf of white crystal (6.7 g, 83%)

Preparation of Intermediates III 5-Fluorouracil

Example 1: Preparation of 2-(5-fluorouracil) acetic acid (IIIa)

(33) Potassium hydroxide (19.2 g, 0.34 mol), water (80 mL) and 5-fluorouracil (13.0 g, 0.1 mol) were added to a flask. The reactant was stirred to dissolve and was warmed to 80° C. Bromide acetic acid (18.1 g, 0.13 mol) was slowly added dropwise and then reactant was stirred for 4 hours. While the reaction detected by TLC was complete, the mixture was cooled to room temperature and the pH of the mixture was adjusted to 2 with concentrated hydrochloric acid. Solid precipitated with ice bath cooling was filtrated and recrystallized using hot water to afford product IIIa (12.1 g, 64.4%). 1H-NMR (500 MHz, D2O) δ7.72 (d, J=5 Hz, 1H), 4.43 (s, 2H).

Example 2: Preparation of 3-(5-fluorouracil) Propionic acid (IIIb)

Step 1: Preparation of 3-(5-fluorouracil) ethyl propionate

(34) 5-fluorouracil (13.0 g, 0.1 mol), DMF (300 mL), ethyl 3-bromopropanoate (21.5, 0.12 mol) and potassium carbonate (13.8 g, 0.1 mol) were added to a flask. The mixture was stirred for 18 hours at room temperature. While the reaction detected by TLC was complete, the reactant was poured to water. The water layer was extracted with ethyl acetate. The organic phase was washed by saturation brine 2 or 3 times, dried by sodium sulfate and concentrated at vacuum. The yellow oil was subjected to column chromatography to afford a colorless crystal of 3-(5-fluorouracil) ethyl propionate (12.5 g, 54.3%). 1H-NMR (500 MHz, CDCl3) δ9.94 (s, 1H), 7.58 (d, J=5 Hz, 1H), 4.18 (q, J=5 Hz, 2H), 3.98 (t, J=5 Hz, 2H), 2.80 (t, J=5 Hz, 2H), 1.28 (t, J=5 Hz, 3H).

Step 2: Preparation of 3-(5-fluorouracil) Propionic acid (IIIb)

(35) Distilled water (40 mL), 3-(5-fluorouracil) ethyl propionate (4.6 g, 20 mmol) and 2M sodium hydroxide (20 mL) were added to flask and stirred. The reactant was heated to reflux for 2 h. While the reaction detected by TLC was complete, the mixture was adjusted with concentrated hydrochloric acid to pH=1. Solid obtained by concentrated was recrystallized with water to afford white solid of IIIb (2.6 g, 64.4%). 1H-NMR (500 MHz, D2O) δ7.82 (d, J=5 Hz, 1H), 3.92 (t, J=5 Hz, 2H), 2.73 (t, J=5 Hz, 2H).

Example 3: Preparation of 4-(5-fluorouracil) butyric acid (IIIc)

Step 1: Preparation of 4-(5-fluorouracil) ethyl butyrate

(36) According to step 1 in Example 2 of Preparation of intermediates III, ethyl 4-bromobutanoate was reacted with 5-fluorouracil to afford 4-(5-fluorouracil) ethyl butyrate. 1H-NMR (500 MHz, CDCl3) δ9.08 (s, 1H), 7.34 (d, J=5 Hz, 1H), 4.17 (q, J=5 Hz, 2H), 3.81 (t, J=5 Hz, 2H), 2.41 (t, J=5 Hz, 2H), 2.04 (m, 2H), 1.29 (t, J=5 Hz, 3H).

Step 2: Preparation of 4-(5-fluorouracil) butyric acid (IIIc)

(37) According to step 2 in Example 2 of Preparation of intermediates III, 4-(5-fluorouracil) ethyl butyrate was hydrolysised with 1M Sodium hydroxide solution to afford 4-(5-fluorouracil) butyric acid (IIIc). 1H-NMR (500 MHz, CDCl3) δ7.78 (d, J=5 Hz, 1H), 3.73 (t, J=5 Hz, 2H), 2.37 (t, J=5 Hz, 2H), 1.91 (m, 1H).

Preparation Embodiment for 5-Fluorouracil Derivative in Technical Solution 1

Embodiment 1: Preparation of (Z)-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(2-methoxy-5-(3,4,5-trimethoxystyryl)-phenyl)acetamide (Ia)

(38) 3,4,4′,5-tetramethoxy-3′-aminostilbene (IIa, 0.5 g, 1.57 mmol), 2-(5-fluorouracil) acetic acid (IIIa, 1.0 g, 5.31 mmol) and 30 mL anhydrous methylene chloride were added into a flask filled with nitrogen. The mixture was stirred to dissolve, DCC (0.8 g) was added and was stirred at room temperature for 24 hours. While the reaction detected by TLC was complete, the mixture was filtered and filtrate was concentrated. The residue was subjected to column chromatography to afford product Ia (0.26 g). 1H-NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.44 (d, J=5 Hz, 1H), 6.91 (d, J=5 Hz, 1H), 6.83 (d, J=5 Hz, 1H), 6.40 (s, 2H), 4.54 (s, 2H), 3.91 (s, 3H), 3.84 (s, 9H), 2.84 (s, 4H). 13C-NMR (100 MHz, DMSO-d6) δ166.23, 158.10, 157.84, 153.46, 150.25, 149.41, 140.78, 138.51, 137.40, 133.36, 131.83, 131.50, 129.96, 128.01, 127.48, 126.89, 123.61, 119.35, 111.85, 104.02, 60.49, 56.30, 50.77; HRMS-ESI (m/z): [M+H]+ (Calcd for C24H25N3O8F) 486.1677; Found 486.1667. [M+Na]+ (Calcd for C24H24N3O8FNa) 508.1496; Found 508.1494. FTIR (KBr, cm-1) 1126.43, 1217.08, 1251.80, 1267.23, 1352.10, 1419.61, 1444.68, 1463.97, 1492.90, 1506.41, 1543.05, 1589.34, 1660.71, 1699.29, 1712.79, 2985.81, 3026.31, 3061.03.

Embodiment 2: Preparation of 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(5-(3,4,5-trimethoxyphenethyl)-2-methoxyphenyl)-acetamide (Ib)

(39) According to Embodiment 1, 3,4,4′,5-tetramethoxy-3′-amino diphenylethane (IIb, 0.5 g, 1.57 mmol) was reacted with 2-(5-fluorouracil) acetic acid (IIIa, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Ib (0.35 g). 1H-NMR (500 MHz, CDCl3) δ8.76 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.44 (d, J=5 Hz, 1H), 7.23 (d, J=5 Hz, 1H), 6.96 (s, 2H), 6.91 (d, J=5 Hz, 1H), 6.73 (s, 2H), 4.56 (s, 2H), 3.95 (s, 3H), 3.93 (s, 6H), 3.88 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ166.00, 158.10, 157.84, 153.07, 150.23, 148.03, 140.76, 138.50, 137.64, 136.00, 133.88, 131.83, 131.50, 126.96, 124.75, 122.10, 111.47, 106.03, 60.36, 56.17, 50.73, 38.27, 37.11. HRMS-ESI (m/z): [M+H]+ (Calcd for C24H27N3O8F) 488.1833; Found 488.1845. [M+Na]+ (Calcd for C24H26N3O8FNa) 510.1652; Found 510.1646; FTIR (KBr, cm-1) 1002.98, 1024.20, 1126.43, 1217.08, 1251.80, 1267.23, 1352.10, 1382.96, 1419.61, 1444.68, 1463.97, 1492.90, 1506.41, 1543.05, 1589.34, 1660.71, 1699.29, 1712.79, 3026.31.

Embodiment 3: Preparation of 3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(5-(3,4,5-trimethoxystyryl)-2-methoxyphenyl)-propanamide (Ic)

(40) According to Embodiment 1, 3,4,4′,5-tetramethoxy-3′-aminophenylethane (IIa, 0.5 g, 1.57 mmol) was reacted with 3-(5-fluorouracil) Propionic acid (IIIb, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Ic (0.29 g). 1H-NMR (300 MHz, DMSO-d6) δ11.77 (s, 1H), 9.31 (s, 1H), 8.07 (s, 1H), 8.00 (d, J=3 Hz, 1H), 7.27 (d, J=3 Hz, 1H), 7.13 (d, J=15 Hz, 1H), 7.01 (d, J=6 Hz, 1H), 6.93 (s, 1H), 6.87 (s, 2H), 3.89 (t, J=6 Hz, 2H), 3.79 (s, 9H), 3.63 (s, 3H), 2.78 (t, J=6 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6) δ169.36, 158.04, 157.79, 153.47, 150.07, 149.89, 140.78, 138.51, 137.43, 133.39, 131.29, 130.96, 129.87, 127.99, 127.53, 126.98, 123.50, 120.75, 111.83, 104.05, 60.49, 56.29, 56.20, 45.25, 35.28. HRMS-ESI (m/z): [M+H]+ (Calcd for C24H26N2O8F) 500.1883; Found 500.1905. [M+Na]+ (Calcd for C24H25N2O8FNa) 522.1652; Found 522.1655; FTIR (KBr, cm-1) 834.52, 1012.73, 1028.85, 1117.61, 1159.22, 1176.58, 1198.32, 1248.56, 1325.34, 1353.69, 1424.23, 1465.11, 1471.69, 1534.29, 1586.20, 1662.64, 1685.79, 1714.83, 2913.27, 3023.45.

Embodiment 4: Preparation of 3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) N-(5-(3,4,5-trimethoxyphenethyl)-2-methoxyphenyl)-propanamide (Id)

(41) According to Embodiment 1, 3,4,4′,5-tetramethoxy-3′-amino diphenylethane (IIb, 0.5 g, 1.57 mmol) was reacted with 3-(5-fluorouracil) Propionic acid (IIIb, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Id (0.32 g). 1H-NMR (500 MHz, CDCl3) δ8.34 (s, 1H), 8.21 (s, 1H), 7.79 (s, 1H), 7.69 (d, J=5 Hz, 1H), 6.90 (d, J=5 Hz, 1H), 6.82 (d, J=5 Hz, 1H), 6.44 (s, 2H), 4.11 (t, J=5 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 6H), 3.85 (s, 3H), 2.92 (t, J=5 Hz, 2H), 2.88 (d, J=5 Hz, 4H). 13C-NMR (100 MHz, DMSO-d6) δ169.36, 167.88, 158.11, 157.86, 153.46, 153.38, 149.91, 140.69, 138.53, 137.42, 133.38, 131.22, 129.87, 127.98, 127.53, 126.96, 123.49, 120.75, 111.82, 104.04, 60.48, 56.29, 56.20, 49.99, 32.05, 30.72, 25.81. HRMS-ESI (m/z): [M+H]+ (Calcd for C24H26N2O8F) 502.1990; Found 502.2035. [M+Na]+ (Calcd for C24H25N2O8FNa) 524.1809; Found 524.1810; FTIR (KBr, cm-1) 804.32, 1010.70, 1028.06, 1118.71, 1159.22, 1176.58, 1192.01, 1242.16, 1323.17, 1357.89, 1427.32, 1460.11, 1471.69, 1485.19, 1512.19, 1539.20, 1593.20, 1662.64, 1685.79, 1708.93, 2843.07, 3003.17.

Embodiment 5: Preparation of 4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(5-(3,4,5-trimethoxystyryl)-2-methoxyphenyl)-butanamide (Ie)

(42) According to Embodiment 1, 3,4,4′,5-tetramethoxy-3′-aminophenylethane (IIa, 0.5 g, 1.57 mmol) was reacted with 4-(5-fluorouracil) butyric acid (III c, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Ie (0.29 g). 1H-NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.44 (d, J=5 Hz, 1H), 6.91 (d, J=5 Hz, 1H), 6.83 (d, J=5 Hz, 1H), 6.40 (s, 2H), 4.54 (s, 2H), 3.91 (s, 3H), 3.84 (s, 9H), 2.84 (s, 4H). 13C-NMR (100 MHz, DMSO-d6) δ171.03, 158.05, 157.80, 153.46, 150.07, 141.14, 138.87, 137.39, 133.42, 130.78, 130.45, 129.83, 128.10, 127.85, 126.86, 123.17, 120.35, 111.70, 106.43, 104.03, 60.49, 56.30, 56.22, 55.98, 47.88, 33.26, 24.57. HRMS-ESI (m/z): [M+H]+ (Calcd for C26H29N2O8F) 514.1990; Found 514.1971. [M+Na]+ (Calcd for C26H28N2O8FNa) 536.1809; Found 536.1810. FTIR (KBr, cm-1) 866.04, 891.11, 968.27, 1016.49, 1029.99, 1116.78, 1159.22, 1184.29, 1201.65, 1215.15, 1236.37, 1253.73, 1284.59, 1328.95, 1350.17, 1363.67, 1421.54, 1429.25, 1471.69, 1506.41, 1529.55, 1581.63, 1668.43, 1685.79, 1718.58, 2943.37, 3047.53.

Embodiment 6: Preparation of 4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(5-(3,4,5-trimethoxyphenethyl)-2-methoxyphenyl)-butanamide (If)

(43) According to Embodiment 1, 3,4,4′,5-tetramethoxy-3′-aminodiphenylethane (IIb, 0.5 g, 1.57 mmol) was reacted with 4-(5-fluorouracil) butyric acid (IIIc, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product If (0.37 g). 1H-NMR (500 MHz, CDCl3) δ8.61 (s, 1H), 8.44 (s, 1H), 7.86 (d, J=5 Hz, 1H), 7.22 (d, J=5 Hz, 1H), 6.99 (2H, s), 6.90 (d, J=10 Hz, 1H), 6.76 (s, 2H), 3.90 (s, 3H), 3.86 (s, 6H), 3.85 (s, 3H), 2.55 (t, J=5 Hz, 2H), 2.17 (t, J=5 Hz, 2H), 1.27 (m, 2H). 13C-NMR (100 MHz, DMSO-d6) δ170.90, 158.02, 157.77, 153.04, 150.43, 150.09, 141.25, 139.34, 137.18, 132.38, 129.95, 129.87, 128.68, 127.79, 123.15, 113.09, 106.32, 60.47, 56.30, 55.98, 47.39, 33.79, 32.11, 30.54, 24.06. HRMS-ESI (m/z): [M+H]+ (Calcd for C26H31N2O8F) 516.2146; Found 516.2138. [M+Na]+ (Calcd for C26H30N2O8FNa) 538.1965; Found 538.1968. FTIR (KBr, cm-1) 891.11, 968.27, 1016.49, 1029.99, 1116.78, 1159.22, 1184.29, 1201.65, 1215.15, 1236.37, 1253.73, 1284.59, 1328.95, 1350.17, 1363.67, 1421.54, 1429.25, 1471.69, 1506.41, 1529.55, 1581.63, 1668.43, 1685.79, 1718.58, 2943.37, 3047.53.

Embodiment 7: Preparation of N-(5-(3,4,5-trimethoxyphenethyl)-2-ethoxyphenyl)-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (Ig)

(44) According to Embodiment 1, 3,4,5-trimethoxy-3′-amino-4′-ethoxy diphenylethane (IIc, 0.5 g, 1.57 mmol) was reacted with 2-(5-fluorouracil) acetic acid (IIIc, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Ig (0.36 g). 1H-NMR (300 MHz, DMSO-d6) δ11.86 (s, 1H), 9.37 (s, 1H), 8.06 (d, J=6 Hz, 1H), 7.86 (s, 1H), 6.91 (m, 2H), 6.49 (s, 2H), 4.56 (s, 2H), 4.05 (q, J=6 Hz, 2H), 3.69 (s, 6H), 3.56 (s, 3H), 2.72 (s, 4H), 1.24 (t, J=6 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6) δ165.93, 158.08, 157.83, 153.06, 150.23, 147.20, 140.78, 138.51, 137.65, 135.99, 133.84, 131.81, 131.47, 127.71, 127.19, 124.84, 122.21, 119.58, 112.66, 110.05, 106.04, 64.48, 60.37, 56.18, 50.80, 38.25, 37.13, 15.04. HRMS-ESI (m/z): [M+H]+ (Calcd for C26H31N2O8F) 502.1990; Found 502.1956. [M+Na]+ (Calcd for C26H30N2O8FNa) 524.1809; Found 524.1812. FTIR (KBr, cm-1) 1010.70, 1045.42, 1093.64, 1145.72, 1161.15, 1172.72, 1234.44, 1251.80, 1269.16, 1311.59, 1328.95, 1363.67, 1396.46, 1427.32, 1452.40, 1465.90, 1514.12, 1593.20, 1683.86, 1720.50, 1743.65, 2929.87, 2943.37, 2964.59, 3003.17, 3064.89.

Embodiment 8: Preparation of N-(5-(3,4,5-trimethoxyphenethyl)-2-ethoxyphenyl)-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanamide (Ih)

(45) According to Embodiment 1, 3,4,5-trimethoxy-3′-amino-4′-ethoxy diphenylethane (IIc, 0.5 g, 1.57 mmol) was reacted with 3-(5-fluorouracil) propanoic acid (IIIc, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Ig (0.41 g). 1H-NMR (300 MHz, DMSO-d6) δ11.77 (s, 1H), 9.05 (s, 1H), 7.98 (d, J=6 Hz, 2H), 7.74 (s, 1H), 6.88 (s, 2H), 6.49 (s, 2H), 3.99 (q, J=6 Hz, 2H), 3.88 (t, J=3 Hz, 2H), 3.70 (s, 6H), 3.58 (s, 3H), 2.77 (t, J=6 Hz, 2H), 2.73 (s, 4H), 1.28 (t, J=6 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6) δ172.71, 169.12, 158.02, 157.76, 153.08, 149.88, 147.79, 137.69, 136.00, 133.73, 131.29, 130.96, 127.38, 124.88, 123.12, 119.43, 112.68, 110.16, 106.01, 64.41, 60.36, 56.14, 45.20, 38.12, 37.01, 35.23, 14.98. HRMS-ESI (m/z): [M+H]+ (Calcd for C26H31N3O7F) 516.2146;

(46) Found 516.2138. [M+Na]+ (Calcd for C26H30N3O7FNa) 538.1965; Found 538.1963. FTIR (KBr, cm-1) 806.25, 908.47, 1006.84, 1045.42, 1089.78, 1120.64, 1143.79, 1182.36, 1197.79, 1217.08, 1232.51, 1249.87, 1290.38, 1311.59, 1342.46, 1352.10, 1377.17, 1396.46, 1419.61, 1431.18, 1458.18, 1469.76, 1487.12, 1506.41, 1537.27, 1593.20, 1662.64, 1683.86, 1699.29, 1716.65, 2933.73, 3089.96.

Embodiment 9: Preparation of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)-phenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (Ii)

(47) 3,4,4′,5-tetramethoxy-3′-hydroxystilbene (CA4, 0.5 g, 1.57 mmol), 2-(5-fluorouracil) acetic acid (IIIa, 1.0 g, 5.31 mmol), anhydrous methylene chloride (30 mL) and DCC (0.5 g) were added into a flask filled with nitrogen. The mixture was stirred for 24 hours at room temperature. The reactant was filtrated while the reaction detected by TLC was complete. The filtration was concentrated and the residue was dissolved in EA. The solution was wished by saturated brine 3 times, dried by anhydrous sodium sulfate and concentrated at vacuum. The crude was subjected to column chromatography to afford product Ii (0.26 g, 34%). 1H-NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 7.33 (d, J=5 Hz, 1H), 7.18 (d, J=5 Hz, 1H), 6.99 (d, J=5 Hz, 1H), 6.89 (d, J=5 Hz, 1H), 6.51 (m, 4H), 4.67 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.72 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ: 165.55, 157.51, 157.25, 152.97, 149.72, 149.69, 141.65, 139.28, 138.68, 137.00, 132.44, 130.15, 129.81, 128.99, 128.66, 128.29, 122.74, 112.14, 105.77, 60.83, 55.98, 55.83, 48.53; HRMS-ESI (m/z): [M+H]+ (Calcd for C24H24N2O8F) 487.1517; Found 487.1557. [M+Na]+ (Calcd for C24H23N2O8FNa) 509.1336; Found 509.1332; FTIR (KBr, cm-1) 1217.08, 1236.37, 1336.67, 1373.32, 1382.96, 1456.26, 1523.76, 1589.34, 1647.21, 1666.50, 1680.00, 1693.50, 1728.22, 2929.87, 3334.92.

Embodiment 10: Preparation of 2-methoxy-5-(3,4,5-trimethoxyphenethyl)-phenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (Ij)

(48) According to Embodiment 9, 3,4,4′,5-tetramethoxy-3′-hydroxy diphenylethane (IIe, 0.5 g, 1.57 mmol) was reacted with 2-(5-fluorouracil) acetic acid (IIIa, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Ij (0.35 g). 1H-NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 7.36 (d, J=5 Hz 1H), 7.03 (d, J=5 Hz 1H), 6.90 (d, J=5 Hz, 1H), 6.85 (s, 1H), 6.34 (s, 2H), 4.74 (s, 2H), 3.84 (m, 12H), 2.86 (s, 4H). 13C-NMR (100 MHz, DMSO-d6) δ 166.75, 157.99, 157.73, 153.06, 150.02, 149.10, 141.06, 138.89, 138.77, 137.51, 136.02, 134.66, 130.77, 130.43, 127.48, 122.82, 113.34, 106.07, 60.37, 56.35, 56.16, 48.91, 37.96, 36.49. HRMS-ESI (m/z): [M+H]+ (Calcd for C24H26N2O8F) 489.1673; Found 489.1690. [M+Na]+ (Calcd for C24H25N2O8FNa) 511.1493; Found 511.1489; FTIR (KBr, cm-1) 815.89, 975.98, 1004.91, 1024.20, 1124.50, 1151.50, 1170.79, 1242.16, 1269.16, 1330.88, 1381.03, 1421.54, 1463.97, 1510.26, 1589.34, 1668.43, 1701.22, 1774.51, 2841.15, 2933.73, 3003.17, 3070.68.

Embodiment 11: Preparation of (Z)-5-(3,4,5-trimethoxystyryl)-2-methoxyphenyl-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate (Ik)

(49) According to Embodiment 9, 3,4,4′,5-tetramethoxy-3′-hydroxy stilbene (CA4, 0.5 g, 1.57 mmol) was reacted with 3-(5-fluorouracil) propanoic acid (IIIb, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Ik (0.38 g). 1H-NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 7.58 (d, J=5 Hz, 1H), 7.17 (d, J=5 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J=10 Hz, 1H), 6.50 (s, 2H), 6.50 (d, J=5 Hz, 2H), 4.07 (t, J=10 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.73 (s, 6H), 3.03 (t, J=5 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6) δ 169.28, 158.03, 157.77, 153.04, 150.25, 149.93, 140.85, 139.12, 138.58, 137.22, 132.32, 131.17, 130.84, 130.03, 129.95, 128.62, 127.90, 123.10, 113.13, 106.35, 60.49, 56.28, 55.98, 44.42, 32.51. HRMS-ESI (m/z): [M+H]+ (Calcd for C25H26N2O8F) 501.1673; Found 501.1687. [M+Na]+ (Calcd for C25H25N2O8FNa) 523.1493; Found 523.1501. FTIR (KBr, cm-1) 844.82, 896.90, 1022.27, 1130.29, 1136.07, 1159.22, 1209.37, 1217.08, 1242.16, 1274.95, 1307.74, 1328.95, 1377.17, 1419.61, 1442.75, 1463.97, 1510.26, 1577.77, 1680.00, 1691.57, 1708.93, 1728.22, 1749.44, 2972.31, 3051.39.

Embodiment 12: Preparation of 5-(3,4,5-trimethoxyphenethyl)-2-methoxyphenyl-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate (I1)

(50) According to Embodiment 9, 3,4,4′,5-tetramethoxy-3′-hydroxy diphenylethane (IIe, 0.5 g, 1.57 mmol) was reacted with 3-(5-fluorouracil) propanoic acid (IIIb, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Il (0.41 g). 1H-NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.61 (d, J=10 Hz, 1H), 7.04 (d, J=5 Hz, 1H), 6.91 (d, J=5 Hz, 1H), 6.85 (s, 1H), 6.36 (s, 2H), 4.10 (t, J=10 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 6H), 3.80 (s, 3H), 3.08 (t, J=10 Hz, 2H), 2.86 (s, 4H). 13C-NMR (100 MHz, DMSO-d6) δ169.38, 158.05, 157.79, 153.07, 149.95, 149.21, 140.87, 139.16, 138.60, 137.55, 136.02, 134.58, 131.24, 130.90, 127.14, 122.98, 113.00, 106.05, 60.37, 56.15, 44.54, 37.89, 36.49, 32.60. HRMS-ESI (m/z): [M+H]+ (Calcd for C25H28N2O8F) 503.1830; Found 503.1848. [M+Na]+ (Calcd for C25H27N2O8FNa) 525.1649; Found 525.1645. FTIR (KBr, cm-1) 804.32, 1006.84, 1026.13, 1112.93, 1122.57, 1130.29, 1147.65, 1217.08, 1234.44, 1249.87, 1269.16, 1313.52, 1325.10, 1363.67, 1427.32, 1440.83, 1452.40, 1467.83, 1512.19, 1519.91, 1593.20, 1651.07, 1691.57, 1726.29, 1757.15, 2939.52, 2962.66, 2999.31, 3064.89.

Embodiment 13: Preparation of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)-phenyl-4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)butanoate (Im)

(51) According to Embodiment 18, 3,4,4′,5-tetramethoxy-3′-hydroxy stilbene (CA4, 0.5 g, 1.57 mmol) was reacted with 4-(5-fluorouracil) butyric acid (IIIc, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Im (0.37 g). 1H-NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 7.42 (d, J=5 Hz, 1H), 7.16 (d, J=5 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J=5 Hz, 1H), 6.52 (s, 2H), 6.50 (d, J=5 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.74 (s, 6H), 2.63 (t, J=10 Hz, 2H), 2.11 (t, J=5 Hz, 2H), 1.27 (m, 2H). 13C-NMR (100 MHz, DMSO-d6) δ170.90, 158.02, 157.77, 153.04, 150.43, 150.09, 139.34, 137.18, 132.38, 129.95, 129.87, 128.68, 127.79, 123.15, 113.09, 106.32, 60.47, 56.30, 55.98, 47.39, 30.54, 24.06. HRMS-ESI (m/z): [M+H]+ (Calcd for C26H28N2O8F) 515.1830; Found 515.1835. [M+Na]+ (Calcd for C26H27N2O8FNa) 537.1649; Found 537.1647; FTIR (KBr, cm-1) 846.75, 883.40, 1024.20, 1134.14, 1155.36, 1174.65, 1205.51, 1240.23, 1276.88, 1317.38, 1328.95, 1357.89, 1381.03, 1421.54, 1452.40, 1512.19, 1581.63, 1616.35, 1627.92, 1662.64, 1689.64, 1720.50, 1741.72, 2933.73.

Embodiment 14: Preparation of 5-(3,4,5-trimethoxyphenethyl)-2-ethoxyphenyl 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (In)

(52) According to Embodiment 9, 3,4,5-tetramethoxy-3′-hydroxy 4′-ethoxydiphenylethane (IIf, 0.5 g, 1.57 mmol) was reacted with 2-(5-fluorouracil)acetate acid (IIIa, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product In (0.38 g). 1H-NMR (300 MHz, DMSO-d6) δ11.99 (s, 1H), 8.13 (s, 1H), 7.05 (d, J=6 Hz, 1H), 7.01 (s, 1H), 6.98 (d, J=6 Hz, 1H), 6.47 (s, 2H), 4.73 (s, 2H), 3.96 (q, J=6 Hz, 2H), 3.69 (s, 6H), 3.57 (s, 3H), 2.75 (d, J=6 Hz, 4H), 1.24 (t, J=6 Hz, 3H); 13C-NMR (100 MHz, DMSO-d6) δ166.68, 157.98, 157.73, 153.06, 149.98, 148.33, 139.28, 137.52, 136.02, 134.67, 130.74, 130.40, 128.42, 127.49, 127.43, 124.80, 122.72, 119.49, 114.47, 110.11, 106.08, 64.63, 60.38, 56.16, 48.85, 37.93, 36.51, 14.99; HRMS-ESI (m/z): [M+H]+ (Calcd for C.sub.25H.sub.28N.sub.2O.sub.8F) 503.1830;

(53) Found. 503.1848. [M+Na]+ (Calcd for C25H27N2O8FNa) 525.1649; Found 525.1644; FTIR (KBr, cm-1) 808.17, 902.69, 960.55, 975.98, 1002.98, 1041.56, 1116.78, 1168.86, 1242.16, 1265.30, 1330.88, 1346.31, 1381.03, 1419.61, 1456.26, 1510.26, 1589.34, 1666.50, 1699.29, 1714.72, 1778.37, 2939.52, 2981.95, 3066.820.

Embodiment 15: 5-(3,4,5-trimethoxyphenethyl)-2-ethoxyphenyl-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate (Io)

(54) According to Embodiment 9, 3,4,5-tetramethoxy-3′-hydroxy 4′-ethoxydiphenylethane (IIf, 0.5 g, 1.57 mmol) was reacted with 3-(5-fluorouracil) propanoic acid (IIIb, 1.0 g, 5.31 mmol). The crude was subjected to column chromatography to afford product Io (0.35 g). 1H-NMR (300 MHz, DMSO-d6) δ11.81 (s, 1H), 8.07 (s, 1H), 6.98 (m, 3H), 6.46 (s, 2H), 3.92 (t, J=6 Hz, 2H), 3.68 (s, 6H), 3.57 (s, 3H), 2.95 (t, J=6 Hz, 2H), 2.74 (s, 4H), 1.24 (t, J=6 Hz, 3H); 13C-NMR (100 MHz, DMSO-d6) δ 169.38, 158.03, 157.77, 153.06, 149.94, 148.40, 140.85, 139.58, 138.58, 137.57, 136.01, 134.59, 131.28, 130.94, 127.08, 122.91, 114.16, 106.05, 64.38, 60.38, 56.15, 44.54, 37.88, 36.51, 32.51, 14.91; HRMS-ESI (m/z): [M+H]+ (Calcd for C26H30N2O8F) 517.1986;

(55) Found. 517.2008. [M+Na]+ (Calcd for C26H29N2O8FNa) 539.1806; Found 539.1807; FT-IR (KBr, cm-1) 806.25, 1004.91, 1043.49, 1101.35, 1126.43, 1159.22, 1182.36, 1211.30, 1228.66, 1253.73, 1325.10, 1350.17, 1359.82, 1386.82, 1415.75, 1435.04, 1469.76, 1492.90, 1543.05, 1595.13, 1660.71, 1693.50, 1728.22, 2939.52, 3034.03.

Effects of Embodiments

(56) In order to illustrate the anticancer and antitumor activities of the 5-fluorouracil derivatives provided by the invention, bioactivity experiments are employed to illustrate as shown in the followings:

(57) Compound Activity Test 1

(58) Evaluation of In Vitro Antitumor Activity of Hela Cervical Cancer Tumor Cell Lines with Compounds (MTT Method)

(59) 1.1. Test Methods

(60) The cells were cultured in RPMI1640 medium containing 200 mL/L fetal bovine serum so that the cells were kept at logarithmic growth. The cells were inoculated to 96-well plate, with a density of 4˜8×10.sup.4/ml, 37° C., and pre-cultured for 24 hours with added drugs. The drugs were set at 6 concentrations, each has 3 holes. After 48 hours of consequent effect, the nutrient solution was then removed and the cells were left for air-drying. Each hole was then added with cold 500 g/L trichloroacetic acid (TCA) 50 μL (final concentration of 100 g/L). After setting for 60 minutes, it was then rinsed for 4-5 times with ionized water and dried. Each hole then was added with 4 g/L SRB 100 μL left for 30 mins. Then it was rinsed with 10 mL/L acetic acid for 4 times, dried. Then 10 mmol Tris-base 200 μL per hole was added, then shaked and mixed, subsequently, oscillating on the plate oscillator for 5 min. The enzyme-linked immunoassay was used to determine the A value. To calibrate, a blank control was used, with a wavelength of 490 nm. Tumor inhibition rate (%)=(Average A value of the control cell hole−Average A value of the drugged hole A)/Average A value of the control cell hole×100%. The positive control cell holes were CA4, CB1, and CB1N. To calculate the IC50 value, the Logit method was used according to the cell growth inhibition rate of different concentrations of the drug.

(61) 1.2. Test Results

(62) TABLE-US-00001 TABLE 1 In vitro proliferation inhibition activity of embodiment compound (Ia-Io) against Hela cervical cancer cell line (IC50/nmol/L) Compound Substituent group IC.sub.50 number L.sub.1 L.sub.2 R X (nmol/L) Ia —CH═CH— —CH.sub.2— OMe NH 45.99 Ib —CH.sub.2CH.sub.2— —CH.sub.2— OMe NH 29.12 Ic —CH═CH— —CH.sub.2CH.sub.2— OMe NH 28.99 Id —CH.sub.2CH.sub.2— —CH.sub.2CH.sub.2— OMe NH 29.83 Ie —CH═CH— —CH.sub.2CH.sub.2CH.sub.2— OMe NH 68.82 If —CH.sub.2CH.sub.2— —CH.sub.2CH.sub.2CH.sub.2— OMe NH 28.80 Ig —CH═CH— —CH.sub.2— OEt NH 47.12 Ih —CH.sub.2CH.sub.2— —CH.sub.2CH.sub.2— OEt NH >370 Ii —CH═CH— —CH.sub.2— OMe O 31.41 Ij —CH.sub.2CH.sub.2— —CH.sub.2— OMe O 32.33 Ik —CH═CH— —CH.sub.2CH.sub.2— OMe O 29.57 Il —CH.sub.2CH.sub.2— —CH.sub.2CH.sub.2— OMe O 29.61 Im —CH═CH— —CH.sub.2CH.sub.2CH.sub.2— OMe O 30.03 In —CH.sub.2CH.sub.2— —CH.sub.2— OEt O 39.98 Io —CH.sub.2CH.sub.2— —CH.sub.2CH.sub.2— OEt O 34.25 CA4 / / / / 400 5-FU / / / / 113.24 All data contained three parallel samples with ± S.D. in each group.

(63) 1.3 Experimental Results Analysis

(64) Using CA4 and 5-fluorouracil as positive control drugs, the in vitro proliferation inhibition activity of 5-fluorouracil derivative (la-Jo) with the invention was evaluated for Hela cervical cancer cell line (MTT method). The IC50 values of 5-fluorouracil and CA4 were 113.24 nM and 400 nM under the same test conditions respectively, while the IC50 values of all splices were below 70 nM, in which the best active compound Ic inhibited the proliferation activity of Hela cervical cancer cell line in vitro was 4 times compared to 5-fluorouracil and 14 times compared to CA4.

(65) Compound Activity Test II

(66) Evaluation of In Vitro Antitumor Activity of Compounds on Multiple Tumor Cell Lines (CCK-8 Method)

(67) 2.1. Experimental Methods

(68) Take the living cells with more than 90% cells for testing. The cell proliferation inhibition test was performed using the EnoGeneCell™ Counting Kit-8 (CK-8) cell viability test kit. The cell was digested, counted and prepared into a cell suspension with a concentration of 1×10.sup.5/mL. 100 μL cell suspension (1×10.sup.4 cells per hole) was added to each hole in the 96-well plate. The 96-well plate was cultured in a 37° C., 5% CO.sub.2 incubator for 24 hours. With every hole added with 100 μL respective drugged cultured medium, control groups were set up, including negative control group, solvent control group, and positive control group. Each group has 5 holes. The 96-well plates were cultured at 37° C., in 5% CO.sub.2 incubator for 72 hours. Afterward, 10 μL CCK-8 solution was added to each hole, and the culture plate was incubated in the incubator for 4 hours, and the OD value at 450 nm was determined by enzyme labeling instrument. The inhibition rate and IC50 value of these compounds on tumor cells such as human gastric cancer cell MGC-803, human liver cancer cell HepG2, human lung cancer cell A549 and human breast cancer cell MDA-MB-231 were calculated.

(69) 2.2 Experimental Results

(70) TABLE-US-00002 TABLE 2 The inhibition rate and IC50 value of compounds on the proliferation activity of multiple tumor cell lines in vitro. IC.sub.50(umol/L) Compounds MGC-803 HepG2 A549 MDA-MB-231 5-FU 62.5 0.004 34.89 97.04 CA4 0.02058 1285 0.00254 0.0033 Ia 64.15 0.01245 27.53 111.8 Ib 1.86 <0.19 <0.19 3.21 Ic 48.5 150.5 57.93 122.2 Id 50.64 110.5 38.02 70.19 Ig 25.82 39.4 59.86 60.22 Ih 23.18 170.7 15.23 60.56 Ii <0.0003 0.02278 <0.0003 0.3997 Ij <0.0003 0.1414 <0.0003 15.41 Ik <0.0003 7.333 <0.0003 80.65 Il <0.0003 0.0004 <0.0003 0.00025 In 19.29 468.3 4.257 101.7 Io 0.6092 0.0017 0.0003 2.57

(71) 2.3 Experimental Results Analysis

(72) All the tested 5-fluorouracil derivatives showed inhibitory activity against human gastric cancer cells MGC-803, human hcc cells HepG2, human lung cancer cells A549, and human breast cancer cell MDA-MB-231. Compared with the positive drugs CA4 and 5-fluorouracil, the spliced 5-fluorouracil derivatives showed significantly improved activity, indicating that the spliced product of 5-fluorouracil derivatives had synergistic effect in vivo. Upon further observation, the number of alkyl carbons (n=1, 2, 3, 4) on the linked base L2 has some effect on the activity of the product. Overall, the activity is better when n=2.

(73) Compound Activity Test III

(74) Antitumor rate of oral administration of the compound towards MGC-803 mice with transplanted tumor

(75) 3.1 Experimental Methods

(76) After 1 week of adaptation, the mice were inoculated with gastric cancer MGC-803 tumor tissue subcutaneously. After the tumor grew for 100-300 mm.sup.3, the animals were randomly grouped. For the drug group, each group of each compound had 6 mice, and 12 mice were in the control group. The intragastric administration was employed and the dosage of Ii, Ij, Ik and Il was 25 and 50 mg/kg. The positive control was CA4, the administration time was d0, d2, d4, d6, d8, d10, d12 days, 7 times in total. The tumor size was measured 3 times per week, together with mice weight. The mice were executed 14 days after inoculation and the tumor mass was taken and measured for its weight. The tumor inhibition rate was calculated as tumor weight inhibition rate, and the formula is tumor weight inhibition rate %=(1-treatment group average tumor weight/control group average tumor weight)×100%.

(77) 3.2. Experimental Results

(78) According to the administration plan, the above compounds can significantly inhibit the growth of transplanted tumors in MGC-803 mice. About 8 days after administration, ii, ij, ik, il administration group showed that the tumors had a tendency to shrink. The tumor inhibition rate of 50 (mg/kg) dose was over 80%.

(79) TABLE-US-00003 TABLE 3 Tumor inhibition rate of MGC-803 mice transplanted with oral administration drugs (%) Group Ii Ij Ik Il Dosage (mg/kg) 25 50 25 50 25 50 25 50 Tumor inhibition rate (%) 62 85 53 80 48 75 65 90

(80) 3.3. Experimental Results Analysis

(81) Four compounds with strong in vitro activity (ii, ij, ik, il) were selected for the test of the tumor inhibition rate of MGC-803 mice transplanted tumor. When the tumor inhibition rate was over 80% at oral administration of 50 mg/kg, and the effective oral dose was about one tenth of the 5-fluorouracil 1D50 value (230 mg/kg), provided that it is safe. Tests and calculations have proved that a wider range of 5-500 mg/kg is also effective. The specific situation should be selected according to the type of cancer or tumor and the severity of the condition, as 25 mg/kg and 50 mg/kg are just the relatively better choice.

(82) Toxicity Test of Compounds

(83) Acute Toxicity Test of Single Gastric Administration in Mice

(84) 4.1. Experimental Methods

(85) Kunming mice (weight 17-22 g, equal male and female) were randomly grouped according to body weight, with 10 mice maximum per dose group in the experiment. And with a maximum dose of 1500 mg/kg, and a ratio of 0.9, the mice were divided into 10 dose groups. The dosages of the tested drugs were 1500, 1350, 1215, 1093, 984, 885, 797, 717, 645, and 581 mg/kg. Given by single intraperitoneal injection and a single intragastric injection, observations were done after 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 24 h respectively. The mortality rate was recorded. Afterward, the groups were observed once everyday, and the mortality rate was recorded for 14 days. On day 15, the living mice were sacrificed for pathological dissection.

(86) 4.2. Experimental Results

(87) After a single dose of intragastric administration and a high dose of 40 min-1 hr, there were casualties, and no obvious residual solution was found in dissection, indicating that the drug was absorbed quickly. The remaining mice died mainly on the first 2 days after a single intraperitoneal injection, and no mice died after the 5th day. Dissections upon dead mice showed that there was no anomaly on the viscera including heard, lungs, liver, spleen, kidneys, etc. The alive mice showed diarrhea, yet not severe, indicating that the tested drugs mainly cause acute toxic effect with no obvious delayed toxicity.

(88) TABLE-US-00004 TABLE 4 Results of acute toxicity test for a single intragastric administration in mice Compound Ii Ij Ik Il 5-FU CA4 Erianin LD.sub.50 (mg/kg) 1059 1015 1185 1228 230 1276 2531 95% Confidence 815- 789- 840- 1050- 210- 1047- 2511- Limit 1395 1298 1138 1438 250 1255 2553

(89) 4.3 Experimental Results Analysis

(90) From the experimental results shown in table 4, it can be seen that the tested compounds ii, ij, ik, il had acute LD50 above 1000 mg/kg, and the toxicity is very low. This means the 5-fluorouracil derivatives of the invention (distyrene and diphenylethane fragments spliced with 5-fu twins) had low toxicity (lower than 5-FU, and similar to CA4), which means it is quite safe.

(91) Summary of Experiments on Bioactivity Testing

(92) 5-Fluorouracil is an anti-metabolic anti-tumor drug with a broad anti-tumor spectrum. Side effects such as bone marrow suppression and severe gastrointestinal reactions etc. has reduced patients' tolerance to the treatment. This type of compound has high water solubility and low liposolubility. Styrene/alkane compounds, as a class of tubulin inhibitors, have tumor vascular targeting effect, with high liposolubility and poor water solubility.

(93) This invention creatively splices two kinds of antitumor drugs with different mechanisms of action in the form of chemical bonds, and designs a novel synthetic route to synthesize the compounds of these specific novel structures (new structure). Through the above biological activity tests on the in vitro activity of the typical cancer cell line and the tumor inhibition activity in mice, the advantages of the proposed 5-fluorouracil derivatives with two kinds of antitumor drugs were shown, which served its purpose of creating a synergistic effect. Therefore, this compound can improve the pharmaceutical properties of two kinds of antitumor drugs, and improve the anti-tumor activity and oral bioavailability of the styrene/alkane compounds. Furthermore, through vascular targeting effect of styrene/alkane fragments, 5-fluorouracil can be directed to tumor cells, thereby reducing the toxic side effects of 5-fluorouracil.

(94) As a common knowledge of experts in this field, the molecular structure of the 5-fluorouracil derivative of this invention contains a distyrene and diphenylethane class fragment, which has the same effect as the tubulin aggregation inhibitor CA4. So the 5-fluorouracil derivative of this invention can be used as a tubulin aggregation inhibitor, or as a preparation agent for tubulin aggregation inhibitor production.

(95) As described in the background, the 5-fluorouracil derivatives of The invention can interfere with tubulin aggregation and thus inhibit the formation of tumor blood vessels, so they can also be used as anti-tumor vascular disruptors or as a preparation agent for the production of anti-tumor vascular disruptors.

(96) Furthermore, because of its inhibitory effect on angiogenesis, it must also be able to treat diseases caused by abnormal neovascularization, or to prepare drugs for the treatment of diseases caused by abnormal neovascularization. Current known diseases of such kind include rheumatoid arthritis, diabetic retinopathy, precocious retinopathy, retinal venous occlusion, psoriasis, erythematous acne, Kaposi sarcoma, specific reactive keratitis, keratoconjunctivitis, neovascular glaucoma, bacterial ulcer, fungal ulcer, simple scar rash infection, zoster infection, protozoa infection, mycobacterium infection, polyarteritis, sarcoid tumor, scleritis, flushing, xerostomia and xerophthalmia syndrome, systemic lupus erythematosus, AIDS syndrome, syphilis.

(97) The 5-fluorouracil derivative provided by the invention has inhibitory activity on human gastric cancer cells MGC-803, human liver cancer cells HepG2, human lung cancer cells A549 and human breast cancer cells MDA-MB-231, and it is not difficult to predict its therapeutic effect on other clinical cancers, tumors, including lung cancer, non-small cell carcinoma, liver cancer, pancreas cancer, stomach cancer, bone cancer, esophagus cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sebaceous gland carcinoma, sebaceous gland carcinoma, papillary carcinoma Cystic carcinoma, papillary carcinoma, cystic carcinoma, cystic carcinoma, myeloid carcinoma, bronchial carcinoma, osteocyte carcinoma, epithelial carcinoma, cholangiocarcinoma, choriocarcinoma, embryo cancer, spermatogonial carcinoma, Wilms carcinoma, glial carcinoma, astrocytoma, neuroblastoma, craniopharyngioma, ependymoma, pinealoma, hematoblastoma, vocal cord neuroma, meningioma, neuroblastoma, optic neuroma, retinocytoma, neurofibromatosis, fibrosarcoma, fibroblastoma, fibroadenoma, fibrochondroma, fibrocystic tumor, fibromylinoma, fibroosteoma, fibromyxa, fibromyxa, fibromatosis, fibro papilloma, fibroid, papilloma, sarcoma, mucous sac, myxochondroma, myxosarcoma, myxosarcoma, myxochondrosarcoma, mucinous adenoma, myxoma, myxocytoma, myxocytoma, myxocytoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma, lipoma Litoma, chondrosarcoma, chondroma, chondromyoma, chordoma, chorionic adenoma, villoepithelioma, chorionic cell tumor, osteosarcoma, osteoblastoma, osteochondroma, osteochondroma, osteocystoma, osteo dentinoma, bone fibroma, osteofibroma, hemangioma, hemangioma, hemangioma, hemangioma, hemangioma, hemangioma, hemangioma, hemangichondroma, hemangioblastoma, hemangioblastoma, hemangioblastoma, hemangioma, hemangioma, hemangioma, hemangioma, hemangioma, hemangioblastoma, hemangioblastoma, hemangioma, hemangioblastoma, hemangioblastoma, hemangioperioma, hemangioblastoma, hemangioblastoma, lymphosarcoma, lymphadenoma, lymphangioma, lymphoma, lymphoma, lymphoma, lymphangioma, lymphangioma, lymphangioma, hemangioblastoma, hemangioblastoma, hemangioblastoma, hemangioblastoma, endothelioma, synovialoma, synovial sarcoma, mesoma, leiomyoma, leiomyoma, leiomyoma, leiomyoblastoma, leiomyoblastoma, leiomyoblastoma leiomyoma, leiomyoma, rhabdomyosarcoma, rhabdomyosarcoma, rhabdomyosarcoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic cell/erythrocytosis, lymphoma, or multiple myeloma.

(98) Furthermore, kunming mice were used in the experiment to demonstrate that the compound had a significant in vivo inhibitory effect on the transplanted tumor in MGC-803 mice. And it would also be able to demonstrate therapeutic effect on cancer and tumor in other non-human mammals.

(99) In addition, other than the above anti-tumor and anti-cancer effects, this invention can also be administered alone or in combination with other anti-cancer and anti-tumor drugs as a composition (compound) to treat tumor or cancer. See Cancer Principles and Practice of Oncology specifically (edited by V. T. Devita and S. Hellman, 6th ed. (2001), Lipincott Williams & Wilkins Publishers).

(100) General technicians in the field should be able to identify which combination of drugs can be used based on the specific characteristics of the drug and the cancer involved. These anticancer agents include, but are not limited to: HDAC inhibitors, estrogen receptor regulators, androgen receptor regulators, retinoid receptor regulators, cytotoxicity/cell growth inhibitors, anti-proliferative agents, isoprene-based protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenic inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducers and agents that interfere with cell cycle checkpoints.

(101) In conclusion, this new invention of new structural compound obtained by splicing the two types of antitumor drugs has the advantages of the two types of antitumor drugs, as well as the synergistic effect, with a bright application and development prospect.

(102) The above embodiment is a preferred case of the invention and is not used to limit the protection range of the invention.