A salidroside derivative, and a preparation method and use thereof

Abstract

The application provides a salidroside derivative, a preparation method and application thereof. The structure of the salidroside derivative is shown in formula I: wherein R1 is selected from H and carbonyl; R2 is selected from H and X is selected from O and NH; m is an integer of 3-6, and n is 0 or an integer of 3-6. The salidroside derivative has excellent antitumor activity, and the activity is obviously improved compared with salidroside. The preparation method of the salidroside derivative has mild reaction conditions, uses low-toxicity reagents, and has easily-obtained raw materials and convenient post-treatment.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry and pharmacology, and relates to a salidroside derivative, a preparation method thereof and use of the salidroside derivative in preparation of an anticancer drug. BACKGROUND

[0002] In recent years, the morbidity and mortality of cancer are showing a rapid upward trend, which seriously endangers the physical and mental health of human beings. Although the prevention, diagnosis and treatment means of cancer are rapidly developing, it is still one of the main killers leading to death.

[0003] The multi-target potential of natural products makes it an important research drug class. Salidroside is a compound extracted from the rhizomes or tubers of Rhodiola L. of the Crassulaceae family, and is an effective active ingredient of medicinal plants Rhodiola. Modern research shows that salidroside has anti-fatigue, immune regulation, anti-hypoxia, anti-radiation, anti-inflammatory, anti-virus, liver and kidney protection, anti-diabetic and other pharmacological effects. Although salidroside has anti-tumor activity, its activity needs to be improved.

[0004] SUMMARY

[0005] To solve the above technical problems existing in the prior art, the present application provides a salidroside furazan derivative and pharmaceutical use thereof.

[0006] The object of the present application is achieved by the following technical solutions.

[0007] The first object of the present application is to provide a salidroside furazan derivative, the structure of which is shown in formula I:

[0008]

[0009] wherein R1 is selected from H, a carbonyl group;

[0010] R2 is selected from H, X is selected from O, NH;

[0011] m is an integer of 3-6, and n is 0 or an integer of 3-6.

[0012] Further, the salidroside derivative is selected from the following compounds:

[0013]

[0014]

[0015]

[0016] A second object of the present application is to provide a pharmaceutical composition comprising the above-mentioned salidroside furazan derivative as an effective ingredient.

[0017] Further, the pharmaceutical composition is supplemented with a pharmaceutically acceptable carrier.

[0018] The salidroside derivative can be formulated into different dosage forms alone or in combination with one or more than one pharmaceutical carrier.

[0019] Further, the dosage form of the pharmaceutical composition is selected from tablets, capsules, dripping pills, granules, powders, lozenges, aqueous or oily suspensions, injections, patches, nano-preparations.

[0020] A third object of the present application is to provide the above-mentioned salidroside furazan derivative or the above-mentioned pharmaceutical composition or the use of the pharmaceutical composition in the preparation of a medicament for treating tumors.

[0021] Further, the salidroside furazan derivative or the pharmaceutical composition is used alone or in combination with an anti-tumor drug and / or radiotherapy.

[0022] Further, the anti-tumor drug is an anti-metabolic drug, an alkylating agent, an anti-tumor antibiotic, an anti-tumor plant drug, a hormone drug.

[0023] Further, the tumor is breast cancer, lung cancer, gastric cancer.

[0024] Another object of the present application is to provide a preparation method of the above-mentioned salidroside derivative,

[0025] When X is selected from O, NH, R1 is selected from H, and R2 is selected from H, the synthesis route is as follows:

[0026]

[0027] wherein n=0, m=3-6;

[0028] comprising the following steps:

[0029] Step (1), using anhydrous dichloromethane as a reaction solvent, using 1,8-diazabicycloundec-7-ene (DBU) as a catalyst, reacting 3,4-benzocycloacyl-1,2,5-oxadiazole-2-oxide with a brominated fatty alcohol compound represented by Br(CH2) m OH to generate compound II; wherein the molar ratio of 3,4-benzocycloacyl-1,2,5-oxadiazole-2-oxide and 1,8-diazabicycloundec-7-ene (DBU) is 1:1.5-1:4, preferably 1:3.

[0030] Step (2), the reaction solvent is N,N-dimethylformamide, the acid-binding agent is potassium carbonate, the catalyst is potassium iodide, the reaction of salidroside, aglycone tyrosol or 4-amino phenethyl alcohol and compound II generates salidroside derivatives; wherein the molar ratio of salidroside, tyrosol or 4-amino phenethyl alcohol and compound II is 1:1; the molar ratio of compound II and potassium carbonate is 1:4-1:6; the molar ratio of compound II and potassium iodide is 1:0.2.

[0031] When X is selected from O, R1 is selected from H, and R2 is selected from , the synthesis route is as follows:

[0032]

[0033] Wherein n=0, m=3-6;

[0034] Comprising the following steps:

[0035] Step (1), the reaction solvent is acetone, the base catalyst is triethylamine, the reaction of p-hydroxyphenyl acetic acid and a bromo aliphatic alcohol compound represented by Br(CH2) m OH generates compound III; wherein the molar ratio of tyrosol and the bromo aliphatic alcohol compound represented by Br(CH2) m OH is 1:3, the molar ratio of tyrosol and potassium carbonate is 1:4-1:6; the molar ratio of tyrosol and potassium iodide is 1:0.2.

[0036] Step (2), the reaction solvent is anhydrous dichloromethane, the catalyst is 1,8-diazabicycloundec-7-ene (DBU), the reaction of 3,4-diphenylacyl-1,2,5-oxadiazole-2-oxide and compound III generates salidroside derivatives; wherein the molar ratio of compound III and 3,4-diphenylacyl-1,2,5-oxadiazole-2-oxide is 1:2, the molar ratio of compound III and 1,8-diazabicycloundec-7-ene (DBU) is 1:1.5-1:4, preferably 1:3.

[0037] When X is selected from O, R1 is selected from carbonyl, and R2 is selected from , the synthesis route is as follows:

[0038]

[0039] Wherein m=3, n=3-6;

[0040] Comprising the following steps:

[0041] Step (1), the reaction solvent is acetone, the base catalyst is triethylamine, the reaction of p-hydroxyphenyl acetic acid and a bromo aliphatic alcohol compound represented by Br(CH2) nThe compound IV is reacted with the compound II to generate the compound V, wherein the molar ratio of the compound IV to the compound II is 1:1-1:2, the molar ratio of the compound IV to the potassium carbonate is 1:4-1:6, and the molar ratio of the compound IV to the potassium iodide is 1:0.2.

[0042] The compound V is reacted with 5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoic acid to generate the salidroside derivative under the conditions of EDCI, DMAP and nitrogen protection, wherein the molar ratio of the compound V to 5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoic acid is 1:3-1:5, the molar ratio of the compound V to EDCI is 1:1.5-1:2, and the molar ratio of the compound V to DMAP is 1:0.2.

[0043] The compound V is reacted with 5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoic acid to generate the salidroside derivative under the conditions of EDCI, DMAP and nitrogen protection, wherein the molar ratio of the compound V to 5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoic acid is 1:3-1:5, the molar ratio of the compound V to EDCI is 1:1.5-1:2, and the molar ratio of the compound V to DMAP is 1:0.2.

[0044] The present application has the following beneficial effects:

[0045] The present application aims to modify the structure of salidroside as a leading substance, and provides a series of salidroside furazan derivatives by introducing the NO donor group such as furazan nitroxide and the PARP inhibition group. The pharmacological experiment shows that the anti-tumor activity of the salidroside derivative of the present application is excellent, and the activity is obviously improved compared with salidroside. The preparation method of the salidroside derivative of the present application has mild reaction conditions, uses low-toxicity reagents, and has easy-to-obtain raw materials and convenient post-processing. DETAILED DESCRIPTION

[0046] The present application is further explained in combination with the following examples, but the examples do not limit the present application in any form.

[0047] Example 1

[0048] Step (1) Dissolve benzene thioacetic acid (16.8 g, 0.1 mol) in 75 mL of glacial acetic acid, drop 30% hydrogen peroxide solution (20.2 mL, 0.2 mol), stir at room temperature for 3 h, slowly drop fuming nitric acid (38 mL, 0.9 mol), the temperature should not exceed 40 °C during the drop process, drop for 1 h; after the drop is completed, the temperature is increased to 100 °C and the reaction is refluxed, the tail gas is absorbed by saturated NaOH solution, and the reaction is cooled to room temperature after 4 h. White needle-shaped crystals are precipitated, which are filtered and dried under an infrared lamp to obtain 3,4-diphenylacyl-1,2,5-oxadiazole-2-oxide 13.3 g, yield 51.1%.

[0049]

[0050] Step (2) Take 3,4-diphenylacyl-1,2,5-oxadiazole-2-oxide (200 mg, 0.546 mmol) in a reaction bottle, dissolve in anhydrous dichloromethane (3 mL), add 3-bromo-1-propanol (98.8 μL, 1.09 mmol), DBU (163.1 μL, 1.09 mmol) at 0 °C, and react at room temperature for 12 h. TLC detection shows that the reaction is complete; the reaction solution is rotary dried, and silica gel column chromatography (petroleum ether: ethyl acetate = 15:1, V:V) is used for separation to obtain compound A1 (white solid) 173 mg, yield 87.5%.

[0051]

[0052] Step (3) Take salidroside (300 mg, 1 mmol), compound A1 (376 mg, 1 mmol), anhydrous potassium carbonate (552 mg, 4 mmol) and potassium iodide (2 mg, 0.01 mmol) in a reaction bottle, dissolve in N,N-dimethylformamide (3 mL), react at room temperature for 12 h, and TLC detection shows that the reaction is complete; add 30 mL of water to the reaction solution, extract with ethyl acetate (30 mL x 3), combine the organic layers, wash with saturated sodium chloride solution (30 mL x 3), dry over anhydrous sodium sulfate, rotary evaporate the filtrate, and separate by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 2:1 V:V) to obtain compound I-1 (white solid) 107 mg, yield 18.4%.

[0053]

[0054] ESI-MS: 583.15 [M+H] +

[0055] 1H-NMR (400 MHz, DMSO-d6, TMS) δ ppm: 8.07-8.00 (m, 2H), 7.95-7.86 (m, 1H), 7.79-7.73 (m, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 5.01 (s, 1H), 4.93 (s, 1H), 4.91 (s, 1H), 4.49 (s, 1H), 4.18 (d, J = 7.7 Hz, 1H), 4.02-3.90 (m, 1H), 3.71-3.62 (m, 2H), 3.42 (d, J = 6.3 Hz, 1H), 3.12 (t, J = 8.8 Hz, 1H), 3.07 (dd, J = 5.9, 2.0 Hz, 1H), 3.03 (dd, J = 8.9, 2.8 Hz, 1H), 2.95 (dt, J = 12.1, 6.0 Hz, 1H), 2.88 (td, J = 7.0, 2.3 Hz, 2H), 2.49 (p, J = 1.9 Hz, 4H).

[0056] Example 2

[0057] The preparation method of Reference Compound I-1 was referred to, 4-bromo-1-butanol was used instead of 3-bromo-1-propanol, and other conditions were unchanged to prepare Compound I-2 (white solid) 210 mg in a yield of 35.2%.

[0058]

[0059] ESI-MS: 597.17 [M+H] +

[0060] 1H-NMR (400 MHz, DMSO-d6, TMS) δ ppm: 8.04-7.98 (m, 2H), 7.92-7.86 (m, 1H), 7.73 (dd, J = 8.4, 7.4 Hz, 2H), 7.21-7.14 (m, 2H), 6.88-6.82 (m, 2H), 5.01 (d, J = 4.9 Hz, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.93 (d, J = 4.9 Hz, 1H), 4.51 (t, J = 5.9 Hz, 1H), 4.46 (t, J = 6.1 Hz, 2H), 4.18 (d, J = 7.7 Hz, 1H), 4.01 (t, J = 6.2 Hz, 2H), 3.90 (ddd, J = 9.6, 8.2, 6.8 Hz, 1H), 3.67 (ddd, J = 11.8, 5.9, 2.0 Hz, 1H), 3.59 (ddd, J = 9.6, 8.3, 6.5 Hz, 1H), 3.47-3.41 (m, 1H), 3.15-3.11 (m, 1H), 3.09-3.02 (m, 2H), 2.96 (ddd, J = 8.9, 7.8, 4.8 Hz, 1H), 2.81-2.76 (m, 2H), 1.91 (dt, J = 11.3, 6.3 Hz, 2H), 1.86-1.78 (m, 2H).

[0061] Example 3

[0062] The compound I-3 (white solid) was prepared according to the preparation method of the reference compound I-1, using 5-bromo-1-pentanol instead of 3-bromo-1-propanol, and other conditions were the same. Yield: 192 mg, 22.5%.

[0063]

[0064] ESI-MS: 611.18 [M+H] + .

[0065] 1H-NMR (400 MHz, DMSO-d6, TMS) δ ppm: 7.96 (d, J = 7.4 Hz, 2H), 7.83 (t, J = 7.4 Hz, IH), 7.67 (t, J = 7.9 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.94 (d, J = 4.9 Hz, IH), 4.89 (d, J = 4.7 Hz, IH), 4.85 (d, J = 5.0 Hz, IH), 4.44 (t, J = 5.9 Hz, IH), 4.36 (t, J = 6.2 Hz, 2H), 4.12 (d, J = 7.8 Hz, IH), 3.90 (t, J = 6.3 Hz, 2H), 3.62-3.51 (m, 2H), 3.37 (dt, J = 11.6, 5.8 Hz, IH), 3.12-3.06 (m, IH), 3.00 (ddd, J = 13.5, 7.3, 3.4 Hz, 2H), 2.90 (dt, J = 8.6, 4.2 Hz, IH), 2.73 (td, J = 7.4, 3.3 Hz, 2H), 1.73 (dp, J = 22.2, 6.6 Hz, 4H), 1.46 (qd, J = 9.6, 8.9, 6.1 Hz, 2H).

[0066] Example 4

[0067] The reference compound I-1 was prepared according to the above method, except that 6-bromo-1-hexanol was used instead of 3-bromo-1-propanol, to give compound I-4 (white solid) 147.9 mg, yield 23.7%.

[0068]

[0069] ESI-MS: 625.2 [M+H] + .

[0070] 1H-NMR (300 MHz, DMSO-d6, TMS) δ ppm: 8.00-7.91 (m, 2H), 7.87-7.78 (m, 1H), 7.68 (m, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 4.95 (d, J = 4.8 Hz, 1H), 4.90 (d, J = 4.6 Hz, 1H), 4.86 (d, J = 4.8 Hz, 1H), 4.45 (t, J = 5.9 Hz, 1H), 4.34 (t, J = 6.3 Hz, 2H), 4.13 (dd, J = 7.8, 3.6 Hz, 1H), 3.92-3.80 (m, 3H), 3.63-3.56 (m, 1H), 3.40-3.35 (m, 1H), 2.73 (t, J = 7.0 Hz, 2H), 1.76-1.60 (m, 4H), 1.37 (p, J = 11.5, 8.7 Hz, 4H).

[0071] Example 5.

[0072] The preparation method of reference compound I-1 was referred to, and compound II-1 (white solid) 67.9 mg was prepared by replacing salidroside with tyrosol, and other conditions were unchanged, and the yield was 16.2%.

[0073]

[0074] ESI-MS: 421.10 [M+H] + .

[0075] 1 H-NMR (300 MHz, CDCl3, TMS) δ ppm: 8.00 (d, J = 7.8 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 4.64 (t, J = 6.2 Hz, 2H), 4.16 (t, J = 5.8 Hz, 2H), 3.84 (t, J = 6.5 Hz, 2H), 2.83 (t, J = 6.7 Hz, 2H), 2.35 (p, J = 6.3 Hz, 2H).

[0076] Example 6

[0077] The preparation method of reference compound I-1 was referred to, and compound II-2 (white solid) 52 mg was prepared by replacing salidroside with tyrosol and 3-bromo-1-propanol with 4-bromo-1-butanol, and other conditions were unchanged, and the yield was 11.9%.

[0078]

[0079] ESI-MS: 435.11 [M+H] + .

[0080] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.14-8.03 (m, 2H), 7.81-7.67 (m, 1H), 7.62 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.54 (t, J = 6.2 Hz, 2H), 4.07 (t, J = 6.0 Hz, 2H), 3.85 (t, J = 6.5 Hz, 2H), 2.84 (t, J = 6.5 Hz, 2H), 2.11 (dq, J = 7.9, 6.3 Hz, 2H), 2.00 (dq, J = 9.5, 6.1 Hz, 2H).

[0081] Example 7

[0082] The preparation method of reference compound I-1 was referred to, and compound II-3 (white solid) 52 mg was prepared by replacing salidroside with tyrosol and 3-bromo-1-propanol with 5-bromo-1-pentanol, and other conditions were unchanged. The yield was 11.9%.

[0083]

[0084] ESI-MS: 449.13 [M+H] + .

[0085] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.06 (dd, J = 8.5, 1.3 Hz, 2H), 7.78-7.69 (m, 1H), 7.60 (t, J = 7.9 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.45 (t, J = 6.4 Hz, 2H), 3.99 (t, J = 6.2 Hz, 2H), 3.82 (d, J = 7.4 Hz, 2H), 2.82 (t, J = 6.5 Hz, 2H), 1.96 (dq, J = 8.2, 6.6 Hz, 2H), 1.87 (dq, J = 8.2, 6.3 Hz, 2H), 1.72-1.63 (m, 2H).

[0086] Example 8

[0087] The preparation method of reference compound I-1 was referred to, and compound II-4 (white solid) 52 mg was prepared by replacing salidroside with tyrosol and 3-bromo-1-propanol with 6-bromo-1-hexanol, and other conditions were unchanged. The yield was 11.9%.

[0088]

[0089] ESI-MS: 463.15 [M+H] + .

[0090] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.05 (dd, J = 8.5, 1.3 Hz, 2H), 7.81-7.70 (m, 1H), 7.67-7.52 (m, 2H), 7.09-7.02 (m, 2H), 6.70-6.61 (m, 2H), 4.57 (t, J = 5.8 Hz, 2H), 3.80 (t, J = 6.6 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 2.76 (t, J = 6.5 Hz, 2H), 2.20 (dt, J = 12.4, 6.1 Hz, 2H).

[0091] Example 9

[0092] The preparation method of reference compound I-1 was referred to, 4-aminophenethyl alcohol was used to replace salidroside, 5-bromo-1-pentanol was used to replace 3-bromo-1-propanol, and other conditions were not changed. Compound III-2 (white solid) 51.8 mg was prepared in a yield of 11.6%.

[0093]

[0094] ESI-MS: 420.12 [M+H] + .

[0095] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.05 (dd, J = 8.5, 1.3 Hz, 2H), 7.81-7.70 (m, 1H), 7.67-7.52 (m, 2H), 7.09-7.02 (m, 2H), 6.70-6.61 (m, 2H), 4.57 (t, J = 5.8 Hz, 2H), 3.80 (t, J = 6.6 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 2.76 (t, J = 6.5 Hz, 2H), 2.20 (dt, J = 12.4, 6.1 Hz, 2H).

[0096] Example 10

[0097] The preparation method of reference compound I-1 was referred to, 4-aminophenethyl alcohol was used to replace salidroside, 5-bromo-1-pentanol was used to replace 3-bromo-1-propanol, and other conditions were not changed. Compound III-2 (white solid) 51.8 mg was prepared in a yield of 11.6%.

[0098]

[0099] ESI-MS: 448.15 [M+H] + .

[0100] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.07 (dd, J = 8.5, 1.3 Hz, 2H), 7.81-7.72 (m, 1H), 7.62 (dt, J = 8.4, 5.3 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 4.46 (t, J = 6.3 Hz, 2H), 3.81 (t, J = 6.7 Hz, 2H), 3.22-3.10 (m, 2H), 2.95-2.71 (m, 2H), 2.00-1.90 (m, 2H), 1.77-1.68 (m, 2H), 1.67-1.55 (m, 2H).

[0101] Example 11

[0102] The preparation method of reference compound I-1 was referred to, 4-aminophenethyl alcohol was used to replace salidroside, 6-bromo-1-hexanol was used to replace 3-bromo-1-propanol, and other conditions were not changed to prepare compound III-3 (white solid) 45.5 mg, yield 9.8%.

[0103]

[0104] ESI-MS: 462.16 [M+H] + .

[0105] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.07 (dd, J = 8.5, 1.3 Hz, 2H), 7.81-7.72 (m, 1H), 7.62 (dt, J = 8.4, 5.3 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 4.46 (t, J = 6.3 Hz, 2H), 3.81 (t, J = 6.7 Hz, 2H), 3.22-3.10 (m, 2H), 2.95-2.71 (m, 2H), 2.00-1.90 (m, 2H), 1.77-1.68 (m, 2H), 1.67-1.55 (m, 2H).

[0106] Example 12

[0107] Into a reaction flask was placed cholestanol (69 mg, 0.5 mmol) in dimethyl sulfoxide (3 mL), 3-bromo-1-propanol (98 μL, 1 mmol) was added, and the reaction was allowed to proceed at room temperature for 12 h. The reaction was monitored by TLC. The reaction mixture was diluted with 30 mL of water and extracted with 30 mL of ethyl acetate (3 times). The organic layer was washed with 30 mL of saturated sodium chloride solution (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 3,4-Diphenyl-1,2,5-oxadiazole-2-oxide (200 mg, 0.546 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 h. The reaction was monitored by TLC. The reaction mixture was purified by column chromatography on silica gel (eluted with petroleum ether: ethyl acetate = 4: 1 V:V) to give compound IV-1 (white solid) 44 mg in 13.7% yield.

[0108]

[0109] ESI-MS: 644.09 [M+H] + .

[0110] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 7.97 (ddd, J = 18.3, 8.5, 1.3 Hz, 4H), 7.77-7.67 (m, 2H), 7.54 (dtd, J = 8.6, 7.4, 1.8 Hz, 4H), 7.27 (s, 1H), 7.25 (s, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 4.65 (t, J = 6.1 Hz, 2H), 4.59 (t, J = 6.6 Hz, 2H), 4.18 (t, J = 5.9 Hz, 2H), 3.15 (t, J = 6.6 Hz, 2H), 2.37 (p, J = 6.0 Hz, 2H).

[0111] Example 13

[0112] Referring to the preparation method of compound IV-1, 4-bromo-1-butanol was used to replace 3-bromo-1-propanol, and other conditions were the same, to give compound IV-2 (white solid) 35 mg in 10.6% yield.

[0113]

[0114] ESI-MS: 658.10 [M+H] + .

[0115] 1H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.10-8.03 (m, 2H), 7.97 (dt, J = 7.2, 1.4 Hz, 2H), 7.80-7.72 (m, 2H), 7.65-7.54 (m, 4H), 7.31-7.22 (m, 2H), 6.96-6.89 (m, 2H), 4.60 (t, J = 6.6 Hz, 1H), 4.54 (t, J = 6.2 Hz, 1H), 4.09 (t, J = 6.0 Hz, 2H), 3.15 (t, J = 6.6 Hz, 2H), 2.13 (dq, J = 8.2, 6.4 Hz, 2H), 2.03 (td, J = 9.0, 8.5, 4.0 Hz, 2H).

[0116] Example 14

[0117] The preparation method of reference compound IV-1 was referred to, 5-bromo-1-pentanol was used to replace 3-bromo-1-propanol, and other conditions were unchanged to prepare compound IV-3 (white solid) 51 mg in a yield of 15.1%.

[0118]

[0119] ESI-MS: 672.12 [M+H] + .

[0120] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.10-8.03 (m, 2H), 7.97 (dt, J = 7.2, 1.4 Hz, 2H), 7.80-7.72 (m, 2H), 7.65-7.54 (m, 4H), 7.31-7.22 (m, 2H), 6.96-6.89 (m, 2H), 4.60 (t, J = 6.6 Hz, 1H), 4.54 (t, J = 6.2 Hz, 1H), 4.09 (t, J = 6.0 Hz, 2H), 3.15 (t, J = 6.6 Hz, 2H), 2.13 (dq, J = 8.2, 6.4 Hz, 2H), 2.03 (td, J = 9.0, 8.5, 4.0 Hz, 2H).

[0121] Example 15

[0122] The preparation method of reference compound IV-1 was referred to, 5-bromo-1-pentanol was used to replace 3-bromo-1-propanol, and other conditions were unchanged to prepare compound IV-3 (white solid) 51 mg in a yield of 15.1%.

[0123]

[0124] ESI-MS: 686.14 [M+H] + .

[0125] 1 H-NMR (400 MHz, CDC13, TMS) δ ppm: 8.07-8.03 (m, 2H), 7.96-7.92 (m, 2H), 7.78-7.70 (m, 2H), 7.64-7.58 (m, 2H), 7.58-7.52 (m, 2H), 7.24-7.20 (m, 2H), 6.92-6.87 (m, 2H), 4.58 (t, J = 6.7 Hz, 2H), 4.44 (t, J = 6.5 Hz, 2H), 3.99 (t, J = 6.3 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H), 1.92 (p, J = 6.7 Hz, 2H), 1.84 (q, J = 6.8 Hz, 2H), 1.60 (s, 1H), 1.58-1.55 (m, 2H).

[0126] Example 16

[0127] Into a reaction flask was placed 4-hydroxybenzoic acid (154 mg, immol) and dissolved in acetone (3 mL), 3-bromo-l-propanol (98 μL, 1 mmol) and triethylamine (100 μL) were added, and the mixture was stirred at room temperature for 6 h. TLC detection showed that the reaction was completed. The solution was dried by rotary evaporation. Dimethyl sulfoxide (3 mL) was added to dissolve the solution, and compound Al (376 mg, 1 mmol), anhydrous potassium carbonate (552 mg, 4 mmol), and potassium iodide (2 mg, 0.01 mmol) were added. The mixture was stirred at room temperature for 12 h. TLC detection showed that the reaction was completed. 30 mL of water was added to the reaction solution, and the mixture was extracted with 30 mL of ethyl acetate three times. The organic layers were combined and washed with 30 mL of saturated sodium chloride solution three times. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was dried by rotary evaporation. 5 mL of dichloromethane was added to dissolve the solution, and 5-[(3,4-dihydro-4-oxo-l-phthalazinyl) methyl]-2-fluorobenzoic acid (596 mg, 2 mmol), EDCI (274 mg, 1.5 mmol), and DMAP (24 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 6 h under nitrogen protection. TLC detection showed that the reaction was completed. The solution was dried by rotary evaporation, and the product was separated by silica gel column chromatography (eluent: dichloromethane:methanol = 90: 1 V:V) to obtain compound V-1 (white solid) 59 mg, yield 7.6%.

[0128]

[0129] ESI-MS: 773.19 [M+H] + .

[0130] 1H-NMR (400 MHz, CDC13, TMS) δ ppm: 10.61 (d, J = 17.7 Hz, 1H), 8.48 (ddt, J = 7.8, 4.1, 2.2 Hz, 1H), 8.06 - 8.03 (m, 1H), 8.01 - 7.97 (m, 1H), 7.90 (dt, J = 6.8, 2.4 Hz, 1H), 7.81 - 7.70 (m, 4H), 7.65 - 7.59 (m, 1H), 7.54 - 7.49 (m, 1H), 7.44 (td, J = 7.8, 4.7 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.18 - 7.15 (m, 1H), 7.08 (ddd, J = 10.0, 8.5, 1.1 Hz, 1H), 6.90 - 6.86 (m, 1H), 6.86 - 6.81 (m, 1H), 4.64 (t, J = 6.1 Hz, 1H), 4.53 (t, J = 6.2 Hz, 1H), 4.44 (t, J = 6.1 Hz, 1H), 4.38 (t, J = 6.1 Hz, 1H), 4.32 (d, J = 3.3 Hz, 2H), 4.29 - 4.27 (m, 2H), 4.17 (t, J = 6.0 Hz, 1H), 4.10 (t, J = 6.1 Hz, 1H), 3.59 (d, J = 6.1 Hz, 2H), 2.36 (p, J = 5.9 Hz, 1H), 2.22 (dp, J = 12.4, 6.1 Hz, 2H), 2.13 - 2.05 (m, 1H).

[0131] Example 17

[0132] The compound V-2 (white solid) 56 mg, yield 7.1% was prepared according to the procedure for the preparation of reference compound V-1, using 4-bromo-1-butanol instead of 3-bromo-1-propanol.

[0133]

[0134] ESI-MS: 787.20 [M+H] + .

[0135] 1H-NMR (400 MHz, CDC13, TMS) δ ppm: 10.12 (d, J = 21.6 Hz, 1H), 8.47 (dd, J = 5.9, 3.7 Hz, 1H), 8.07 (dd, J = 7.9, 3.3 Hz, 2H), 7.89 (d, J = 6.6 Hz, 1H), 7.77 (ddd, J = 12.0, 5.3, 2.3 Hz, 4H), 7.62 (t, J = 7.9 Hz, 2H), 7.44 (s, 1H), 7.23 - 7.18 (m, 2H), 7.14 - 7.05 (m, 1H), 6.87 (dd, J = 8.5, 4.2 Hz, 2H), 4.53 (td, J = 6.2, 2.7 Hz, 2H), 4.43 (t, J = 6.2 Hz, 1H), 4.38 (t, J = 5.8 Hz, 1H), 4.31 (d, J = 3.3 Hz, 2H), 4.26 (d, J = 6.3 Hz, 1H), 4.19 (t, J = 6.2 Hz, 1H), 4.11 (t, J = 6.1 Hz, 1H), 4.05 (t, J = 6.0 Hz, 1H), 3.59 (d, J = 3.3 Hz, 2H), 2.24 (t, J = 6.2 Hz, 1H), 2.10 (p, J = 6.5 Hz, 2H), 2.04 - 1.96 (m, 1H), 1.95 - 1.90 (m, 1H), 1.83 (q, J = 7.4, 6.9 Hz, 1H).

[0136] Example 18

[0137] The reference compound V-1 was prepared according to the method described in the reference compound V-1, using 5-bromo-1-pentanol instead of 3-bromo-1-propanol, and other conditions unchanged, to obtain compound V-3 (white solid) 68 mg, yield 8.5%.

[0138]

[0139] ESI-MS: 801.22 [M+H]+.

[0140] 1H-NMR (400 MHz, CDC13, TMS) δ ppm: 10.23 (d, J = 15.8 Hz, 1H), 8.48 (dd, J = 6.5, 2.6 Hz, 1H), 8.08 - 8.03 (m, 1H), 8.02 - 7.98 (m, 1H), 7.92 - 7.89 (m, 1H), 7.80 - 7.72 (m, 4H), 7.62 (t, J = 7.9 Hz, 1H), 7.53 (q, J = 8.2 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.23 (dd, J = 8.8, 2.6 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.09 (dd, J = 10.8, 8.0 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.83 (dd, J = 8.2, 5.7 Hz, 1H), 4.59 (dt, J = 44.4, 6.2 Hz, 1H), 4.45 (t, J = 6.1 Hz, 1H), 4.37 (t, J = 6.4 Hz, 1H), 4.30 (d, J = 9.4 Hz, 5H), 4.17 (t, J = 6.0 Hz, 1H), 4.15 - 4.10 (m, 1H), 3.99 - 3.93 (m, 2H), 3.62 - 3.56 (m, 2H), 2.27 - 2.17 (m, 2H), 1.84 (d, J = 8.8 Hz, 2H), 1.62 (s, 4H).

[0141] Example 19

[0142] The compound V-4 (white solid) 50 mg, yield 6.1% was prepared according to the preparation method of the reference compound V-1, using 6-bromo-1-hexanol instead of 3-bromo-1-propanol, and other conditions unchanged.

[0143]

[0144] ESI-MS: 815.23 [M+H]+.

[0145] 1H-NMR (400 MHz, CDC13, TMS) δ ppm: 10.63 (d, J = 5.9 Hz, 1H), 8.52-8.45 (m, 1H), 8.08-8.03 (m, 1H), 8.01-7.97 (m, 1H), 7.96-7.86 (m, 1H), 7.84-7.76 (m, 3H), 7.76-7.71 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.45-7.41 (m, 1H), 7.22 (dd, J = 8.5, 3.8 Hz, 1H), 7.17-7.13 (m, 1H), 7.08 (ddd, J = 10.2, 8.4, 1.7 Hz, 1H), 6.92-6.85 (m, 1H), 6.83-6.80 (m, 1H), 4.64 (t, J = 6.1 Hz, 1H), 4.45 (t, J = 6.1 Hz, 1H), 4.36 (d, J = 6.7 Hz, 1H), 4.32 (s, 2H), 4.28 (d, J = 6.2 Hz, 1H), 4.17 (t, J = 5.8 Hz, 1H), 4.13-4.08 (m, 1H), 3.97-3.92 (m, 2H), 3.58 (d, J = 3.6 Hz, 2H), 2.27-2.16 (m, 2H), 1.81 (dt, J = 7.5, 3.9 Hz, 2H), 1.69 (dd, J = 11.7, 5.1 Hz, 2H), 1.53 (p, J = 3.4 Hz, 2H), 1.30-1.26 (m, 2H).

[0146] Example 20

[0147] (I) In vitro anti-tumor cell proliferation experiment of the compound

[0148] The anti-tumor activity of the salidroside derivatives of the application was tested by tetrazolium blue colorimetric method (MTT method), and salidroside (SAL) and doxorubicin (Dox) were selected as positive control drugs.

[0149] Instruments: super-clean bench (SW-CJ-1FD, AIRTECH, Suqing Antai), constant-temperature CO2 incubator (3111, Thermo, USA), plate shaker (Kylin-bell lab Instruments), high-pressure sterilization pot (YXO.SG41.280, Shanghai Huaxian), centrifuge (SIGMA), multifunctional enzyme marker (POLARstar, Omega, USA).

[0150] Reagents: DMEM (KeyGEN), RPMI-1640 (KeyGEN), fetal bovine serum (GIBCO), trypsin (SIGMA), DMSO (SIGMA), MTT (Beyotime).

[0151] Cell lines: human breast cancer cell line MDA-MB-231, human breast cancer cell line MCF-7, human non-small cell lung cancer cell line A549, human gastric cancer cell BGC-823, human normal breast cell line MCF-10A; wherein BGC-823 cells are cultured with RPMI-1640 medium, MCF-10A cells, MCF-7 cells, A549 cells and MDA-MB-231 cells are cultured with DMEM (high sugar) medium (all purchased from Jiangsu Keygen Biotech Co., Ltd.).

[0152] Culture conditions: MDA-MB-231 (DMEM + 10% fetal bovine serum), MCF-7 (DMEM + 10% fetal bovine serum), A549 (DMEM + 10% fetal bovine serum), BGC-823 (RPMI1640 + 10% fetal bovine serum), MCF-10A (DMEM + 10% fetal bovine serum).

[0153] Method: The frozen cell lines were thawed and cultured in a constant temperature 37℃, 5% CO2 incubator, the liquid was changed once a day, and when they were in the exponential growth phase and in good condition, they were plated. 1 mL of 0.25% trypsin digestion solution was added and digested for 1-2 min, the cell state was observed under a microscope, and when the adherent cells were rounded and contracted, the digestion solution was removed, 1-2 mL of culture medium containing 10% fetal bovine serum was added to prepare a cell suspension, the cells were counted, and the amount of cell suspension required was calculated according to the number of cells per hole 5×10 3 4 cells and the total number of holes, 100 μL / hole was inoculated in a 96-well plate, the periphery was sealed with PBS solution, and it was cultured in a constant temperature 37℃, 5% CO2 incubator for 24 h.

[0154] An appropriate amount of test compound and DOX was weighed, dissolved with DMSO to prepare a mother liquor with a concentration of 10 mmol / L, then diluted with culture medium to prepare a series of solutions with concentrations of 0.25, 0.5, 1, 2, 4 μmol / L, and a blank control (DMSO was diluted with culture medium to a solution with a concentration of 4 μmol / L), 3 replicate holes were set for each drug concentration, and cultured for 48 h. MTT reagent (5 mg / mL) was added to the 96-well plate, 10 μL / hole, and incubated for another 4 h. The culture medium in the plate was removed, 150 μL of DMSO was added to each hole, the absorbance value of each hole was detected by a multifunctional enzyme label instrument at a wavelength of 570 nm, and the cell inhibition rate was calculated according to the following formula.

[0155] Cell inhibition rate % = [(blank control OD value - administration group OD value) / blank control group OD value] x 100%.

[0156] 3 screening results average value is the final inhibition rate, the IC50 value of the test drug is calculated (graphpad software), and the 3 repeated experiment results are the final IC50 value of the measured compound.

[0157] Table 1. Inhibition of MDA-MB-231, BGC-823, A549, MCF-7 and MCF-10A cell lines by test compounds

[0158]

[0159]

[0160] Note: NA means no test.

[0161] Based on Table 1, compared with rhodioloside, the rhodioloside derivatives of the present application have obvious improvement in the inhibition of MDA-MB-231, BGC-823, A549, MCF-7 tumor cell lines, and also show good selectivity. Compound V-1 has the best activity, and the IC50 value of MDA-MB-231 cell line is 0.002 ± 0.0002 μM, and the toxicity to normal human normal breast cell line MCF-10A is low, and the IC50 value is 8.227 ± 0.405 μM, which is expected to become a new anti-tumor candidate drug, and is worthy of further research.

[0162] The above only describes the preferred embodiments of the present application, and it should be noted that for ordinary skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A salidroside furazan derivative, characterized in that, The structure of the salidroside furazan derivative is shown as formula I: wherein, R1 is selected from H, carbonyl; R2is selected from H, X is selected from O, NH; m is an integer of 3-6, and n is 0 or an integer of 3-6.

2. The salidroside furazan derivative according to claim 1, characterized in that, The salidroside derivative is selected from the following compounds:

3. A pharmaceutical composition, characterized by, The pharmaceutical composition takes the salidroside furazan derivative of claim 1 as an effective component.

4. The pharmaceutical composition of claim 3, wherein, The pharmaceutical composition is supplemented with a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 3, wherein, The dosage form of the pharmaceutical composition is selected from tablets, capsules, dripping pills, granules, powders, lozenges, aqueous or oily suspensions, injections, patches, nano-preparations.

6. Use of the salidroside furazan derivative of claim 1 or the pharmaceutical composition of claim 3 in the preparation of a medicament for treating tumors.

7. Use according to claim 6, characterized in that, The salidroside furazan derivative or the pharmaceutical composition is used alone or in combination with an anti-tumor drug and / or radiotherapy.

8. Use according to claim 7, characterized in that, The anti-tumor drug is an anti-metabolic drug, an alkylating agent, an anti-tumor antibiotic, an anti-tumor plant drug, a hormone drug.

9. Use according to claim 6, characterized in that, The tumor is breast cancer, lung cancer, gastric cancer.

10. A method of preparing the rhodiolin furazan derivative of claim 1, characterized by, The preparation method is selected from one of the following (a)-(c): (a) when X is selected from O, NH, R1is selected from H, R2is selected from H, n = 0, m = 3-6; comprising the steps of: Step (1), compound II is prepared by reacting 3,4-benzocycloacetyl-1,2,5-oxadiazole-2-oxide with a bromo fatty alcohol compound represented by Br(CH2) m OH, using anhydrous dichloromethane as a reaction solvent and 1,8-diazabicycloundec-7-ene as a catalyst; wherein the molar ratio of 3,4-benzocycloacetyl-1,2,5-oxadiazole-2-oxide to 1,8-diazabicycloundec-7-ene is 1:1.5-1:4; and the compound II is Step (2), a salidiloside derivative is prepared by reacting salidiloside, aglycone tyrosol or 4-amino phenethyl alcohol with compound II, using N,N-dimethylformamide as a reaction solvent, potassium carbonate as an acid-binding agent and potassium iodide as a catalyst; wherein the molar ratio of salidiloside, tyrosol or 4-amino phenethyl alcohol to compound II is 1:1; the molar ratio of compound II to potassium carbonate is 1:4-1:6; and the molar ratio of compound II to potassium iodide is 1:0.

2. (b) when X is selected from O, R1 is selected from H, R2 is selected from n=0, m=3-6; comprising the following steps: step (1), with N,N-dimethylformamide as a reaction solvent, with potassium carbonate as an acid-binding agent, with potassium iodide as a catalyst, reacting tyrosol with a bromofatty alcohol compound represented by the formula Br(CH2) m OH to generate compound III; wherein the molar ratio of the tyrosol to the bromofatty alcohol compound represented by the formula Br(CH2) m OH is 1:3, the molar ratio of the tyrosol to potassium carbonate is 1:4-1:6; and the molar ratio of the tyrosol to potassium iodide is 1:0.

2. Step (2), the reaction solvent is anhydrous dichloromethane, 1,8-diazabicycloundec-7-ene is used as a catalyst, and 3,4-diphenylacyl-1,2,5-oxadiazole-2-oxide reacts with compound III to generate salidroside derivative; wherein, the molar ratio of compound III to 3,4-diphenylacyl-1,2,5-oxadiazole-2-oxide is 1:2, and the molar ratio of compound III to 1,8-diazabicycloundec-7-ene is 1:1.5-1:4; the compound III is (c) when X is selected from O, R1 is selected from carbonyl, and R2 is selected from m = 3, n = 3-6; comprising the following steps: step (1), reacting p-hydroxyphenylacetic acid with a bromo-aliphatic alcohol compound represented by the formula Br(CH2) n OH to generate compound IV, wherein the molar ratio of p-hydroxyphenylacetic acid to the bromo-aliphatic alcohol compound is 1:2; the volume ratio of the bromo-aliphatic alcohol compound to triethylamine is 1:1-1:1.5; the compound IV is step (2), reacting compound IV with compound II to generate compound V, wherein the molar ratio of compound IV to compound II is 1:1-1:2; the molar ratio of compound IV to potassium carbonate is 1:4-1:6; the molar ratio of compound IV to potassium iodide is 1:0.2; step (3), reacting compound V with 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid to generate a salidroside derivative under the conditions of EDCI, DMAP and nitrogen protection, wherein The molar ratio of the compound V to 5-[(3,4-dihydro-4-oxo-l-phthalazinyl) methyl]-2-fluorobenzoic acid is 1:3-1:5; the molar ratio of the compound V to EDCI is 1:1.5-1:2; the molar ratio of the compound V to DMAP is 1:0.2, and the compound V is 11. The method of claim 10, wherein, (a) In step (1), the molar ratio of 3,4-diphenylcycloacetyl-1,2,5-oxadiazole-2-oxide and 1,8-diazabicycloundec-7-ene is 1:

3.

12. The method of claim 10, wherein, (b) In step (2), the molar ratio of compound III and 1,8-diazabicycloundec-7-ene is 1:3.

Images