Synthesis of sinomenine derivative and application of sinomenine derivative in resisting glioma

Abstract

The invention belongs to the technical field of medicines, and discloses synthesis of sinomenine derivatives and application of the sinomenine derivatives in resisting glioma. The invention specifically discloses a sinomenine derivative as shown in a formula I, a synthesis method thereof and an application of the sinomenine derivative in resisting glioma. A new method is provided for structural modification of sinomenine, and part of the compounds can well inhibit proliferation of brain glioma cells and have the potential of serving as anti-glioma drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. Specifically, the present invention relates to a sinomenine derivative, a preparation method thereof, and an application thereof in anti-human glioblastoma cells. Background Art

[0002] According to the statistics of the Central Brain Tumor Registry of the United States (CBTRUS) in 2020, glioblastoma (GBM, WHO grade IV) is the primary malignant central nervous system tumor with the highest incidence, accounting for 48.6% of intracranial tumors. In addition, the cancer prevalence data of the National Cancer Center of China in 2022 shows that the incidence of malignant brain tumors is on the rise year by year, with an average of 109,000 new cases and 58,500 death cases per year. GBM has the characteristics of "three highs and one low", namely high incidence, high mortality, high recurrence rate and low cure rate, and has always been one of the most difficult diseases to treat in neurosurgery. In the past 30 years, there has been no breakthrough in the treatment of GBM. For example, glioblastoma multiforme has a high degree of malignancy and rapid disease progression. Without treatment, most patients will die within 3 months. Even with the best treatment (including surgery, radiotherapy and chemotherapy), the average survival period of patients is only 12 months.

[0003] Temozolomide (TMZ), as the only first-line chemotherapy drug for high-grade GBM, has self-evident therapeutic significance. However, up to 95% of GBM patients may experience recurrence or drug resistance after receiving its treatment. Compounds from natural sources have novel structures and unique biological activities, and are important sources of drug lead compounds. Sinomenine (SIN), an isoquinoline alkaloid, has pharmacological activities such as anti-inflammatory, immunomodulatory, analgesic, anti-arrhythmic and anti-tumor. Sinomenine has many good biological characteristics, but there are still some clinical adverse reactions and a relatively short biological half-life. Therefore, the structural modification of sinomenine has become a research hotspot, aiming to develop highly efficient and low-toxic sinomenine derivatives and provide new options for the treatment of cancer clinically. Summary of the Invention

[0004] One object of the present invention is to provide a series of sinomenine derivatives.

[0005] Another object of the present invention is to provide a preparation method of the sinomenine derivative.

[0006] Another object of the present invention is to provide a composition containing the sinomenine derivative.

[0007] Another object of the present invention is to provide the application of the sinomenine derivative in the treatment and prevention of tumor drugs.

[0008] Term Definition

[0009] The terms used in this description for the present invention are only for describing specific embodiments and are not intended to limit the present invention. The nomenclature used herein and the laboratory operations in organic chemistry, medicinal chemistry, and biology described herein are well-known and commonly used in the art. Unless otherwise mentioned, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0010] As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a", "an", "the", and "said" are used to refer to both the singular and plural of the article, unless the context clearly indicates otherwise. For example, a compound includes one or more than one compound.

[0011] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items.

[0012] As used herein, the term "disease" or "disorder" refers to any change, interruption, or interference in the functioning of the body or some organs and / or causing symptoms.

[0013] As used herein, the term "treatment" aims to alleviate or eliminate the disease state or condition being targeted. If a subject has received a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, isomer, or pharmaceutical composition thereof according to the methods described herein, and one or more indications and symptoms of the subject show an observable and / or detectable reduction or improvement, then the subject has been successfully "treated". It should also be understood that the treatment of the disease state or condition described not only includes complete treatment but also includes cases where complete treatment is not achieved but some biologically or medically relevant results are obtained.

[0014] Technical Topic One

[0015] The present invention provides sinomenine derivatives having the structure shown in Formula I, their isomers, or their pharmaceutically acceptable salts:

[0016]

[0017] R represents:

[0018]

[0019] Wherein:

[0020] n represents the number of methylene groups, and n can be 1, 2, 3, 4, 5... 16;

[0021] R 1 、R 2 、R 3 、R 4 、R 5may respectively represent H, methyl, methoxy, hydroxy, F, Cl, Br, CF 3 , NO 2 . 2. The sinomenine derivative according to claim 1, wherein n represents the number of methylene groups, and n can be 1, 2, 3, 4, 5... 16; R 1 , R 2 , R 3 , R 4 , R 5 may respectively represent H, methyl, methoxy, hydroxy, F, Cl, Br, CF 3 , NO 2 .

[0022] In some preferred embodiments of the present invention, the derivative includes the following structure:

[0023]

[0024] In some preferred embodiments of the present invention, the medicinal salt is a salt formed by the derivative shown in formula I and an inorganic acid or an organic acid.

[0025] The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, barmic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, etc.

[0026] In some preferred embodiments of the present invention, the medicinal salt is hydrochloride or phosphate.

[0027] As used herein, "isomer" means that when the sinomenine derivative shown in formula I contains one or more asymmetric centers, the compounds of the present invention can exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, single diastereomers, geometric isomers, etc. These compounds can be represented by the symbols "R" or "S", depending on the configuration of the substituents around the stereogenic carbon atoms.

[0028] Technical Topic Two

[0029] The present invention also provides a method for synthesizing the compound shown in Formula I, comprising the following steps:

[0030]

[0031] Technical Topic Three

[0032] The present invention provides a composition comprising the sinomenine derivative shown in Formula I, its isomers or its pharmaceutically acceptable salts.

[0033] Furthermore, the "pharmaceutical composition" may further comprise one or more pharmaceutically acceptable carriers or excipients, and be prepared in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, medicinal wines, decoction extracts, lozenges, mixtures, suppositories, injections, inhalants or sprays, etc.

[0034] As used herein, "pharmaceutically acceptable carriers or excipients" include: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used with more than one function and with alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0035] For example: when used orally, it can be made into oral preparations such as tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules and pills, etc., containing fillers (such as sugar derivatives like lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives like corn starch, potato starch, dextrin and carboxymethyl starch; cellulose derivatives like crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives like magnesium aluminum metasilicate; phosphate derivatives like calcium phosphate; carbonate derivatives like calcium carbonate; sulfate derivatives like calcium sulfate, etc.), binders (such as gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (such as cellulose derivatives like sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, cetyl wax, boric acid, sodium benzoate, leucine), stabilizers (methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.), flavoring agents (such as common sweeteners, sour agents and fragrances, etc.).

[0036] When used parenterally, it can be formulated into an injection, including sterile powders for injection and solvents for injection. The carriers or excipients used include sterile water, Ringer's solution, and isotonic sodium chloride solution. Appropriate additives such as antioxidants, buffers, bacteriostatic agents, solubilizers, cosolvents, pH adjusters, and osmotic pressure regulators can also be added according to the nature of the drug. Solubilizers or cosolvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. When preparing freeze-dried powder injections, mannitol, glucose, etc. can also be added as supporting agents. When used for rectal administration, the drug can be formulated into suppositories, etc.

[0037] When used for pulmonary administration, the drug can be formulated into inhalants or sprays, etc. There are many resources available to those skilled in the art, which describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books like "Remington: The Science and Practice of Pharmacy", "Chinese Pharmaceutical Yearbook", "Pharmaceutics", etc.

[0038] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into ordinary preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations, and various particulate drug delivery systems.

[0039] Technical Topic Four

[0040] The present invention also provides the use of the sinomenine derivatives represented by formula I, their isomers, or their medicinal salts in the preparation of anti-tumor drugs.

[0041] Furthermore, the anti-tumor is selected from glioblastoma, and further, from human astrocytoma cells (U87). Detailed implementation manners

[0042] The present invention is illustrated below in conjunction with specific embodiments. These embodiments are not intended to limit the scope of the present invention, but to provide guidance for those skilled in the art to prepare and use the compounds and compositions of the present invention. The chemical names of the compounds described in this application are generally derived from ChemDraw Ultra (ChambridgeSoft) and / or generally follow the principles of IUPAC nomenclature.

[0043] The synthetic routes of the compounds in this embodiment part are as follows:

[0044]

[0045] Example 1

[0046]

[0047] 387.19 mg (1 mmol) of the compound 8-H-4-hydroxy-3-methoxy-17-methyl-9α,13α,14α-morphinan-6N,7N-quinoxaline, 300.54 (1.5 mmol) of dodecanoic acid, 383.4 mg (2.0 mmol) of EDCl and 36.81 mg (0.3 mmol) of DMAP were added to a 10.0 ml single-necked flask. 4.0 ml of DCM was added, and the reaction was magnetically stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. Work-up: The reaction mixture was washed with saturated ammonium chloride solution (5.0 ml x 1), and the organic phase was extracted with DCM (5.0 ml x 3) and then combined. The organic phase was dried over anhydrous Na 2 SO 4 After drying, it was concentrated, and the target compound (Q-1) was obtained as a yellow solid by column chromatography (DCM / MeOH = 100 / 4); Yield: 37.01%.

[0048] 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (brs, 1H), 7.87 - 7.80 (m, 1H), 7.64 - 7.54 (m, 2H), 6.95 (d, J = 8.53 Hz, 1H), 6.69 (d, J = 8.47 Hz, 1H), 4.41 (d, J = 17.26 Hz, 1H), 3.61 (s, 3H), 3.31 - 2.91 (m, 6H), 2.81 - 2.66 (m, 2H), 2.64 - 2.55 (m, 2H), 2.50 (s, 3H), 2.38 - 2.19 (m, 1H), 2.06 - 1.86 (m, 1H), 1.84 - 1.76 (m, 1H), 1.51 - 1.41 (m, 2H), 1.31 - 1.20 (m, 16H), 0.86 (t, J = 6.80 Hz, 3H).

[0049] 13 C NMR (100 MHz, CDCl 3 ) δ 172.43, 152.67, 149.76, 141.60, 141.15, 139.13, 131.39, 128.99, 128.88, 128.83, 128.32, 125.89, 110.93, 56.59, 55.88, 46.65, 45.52, 42.87, 39.90, 36.45, 34.81, 33.48, 32.06, 29.84, 29.81, 29.78, 29.72, 29.54, 29.50, 29.32, 24.97, 23.59, 22.82, 14.26.

[0050] ESI-MS (m / z): 570.40 (M + H)+ .

[0051] Example 2

[0052]

[0053] The preparation method was the same as that of Example 1, and the above yellow solid was obtained by using myristic acid instead of lauric acid; Yield: 42.65%.

[0054] 1 H NMR(400MHz,CDCl 3 )δ7.95(brs,1H),7.90 - 7.82(m,1H),7.65 - 7.57(m,2H),6.97(d,J = 8.38Hz,1H),6.71(d,J = 8.48Hz,1H),4.43(d,J = 17.30Hz,1H),3.62(s,3H),3.24 - 2.95(m,6H),2.83 - 2.70(m,2H),2.66 - 2.56(m,2H),2.52(s,3H),2.36 - 2.25(m,1H),2.11 - 1.91(m,1H),1.85 - 1.80(m,1H),1.53 - 1.37(m,2H),1.33 - 1.22(m,20H),0.878(t,J = 6.80Hz,3H).

[0055] 13 C NMR(100MHz,CDCl 3 )δ171.80,152.71,149.74,141.60,141.54,139.13,130.43,128.98,128.87,128.83,128.32,125.88,110.91,56.56,55.87,46.64,45.54,42.89,39.12,36.46,34.81,33.49,32.06,29.85,29.83,29.81,29.73,29.55,29.51,29.33,27.05,24.97,23.58,22.83,14.26.

[0056] ESI-MS(m / z):598.50(M + H) + .

[0057] Example 3

[0058]

[0059] The preparation method was the same as that of Example 1, and the above white solid was obtained by using palmitic acid instead of lauric acid; Yield: 70.20%.

[0060] 1 1H NMR (500 MHz, CDCl 3 ) δ 7.95 (brs, 1H), 7.89 - 7.81 (m, 1H), 7.64 - 7.58 (m, 2H), 6.97 (d, J = 8.49 Hz, 1H), 6.70 (d, J = 8.49 Hz, 1H), 4.43 (d, J = 17.21 Hz, 1H), 3.62 (s, 3H), 3.25 - 2.92 (m, 6H), 2.84 - 2.67 (m, 2H), 2.64 - 2.55 (m, 2H), 2.51 (s, 3H), 2.35 - 2.22 (m, 1H), 2.00 - 1.90 (m, 1H), 1.86 - 1.81 (m, 1H), 1.53 - 1.35 (m, 2H), 1.35 - 1.21 (m, 24H), 0.88 (t, J = 6.79 Hz, 3H);

[0061] 13 13C NMR (100 MHz, CDCl 3 ) δ 172.18, 152.79, 152.21, 149.72, 141.60, 141.24, 139.12, 130.46, 130.25, 128.97, 128.86, 128.82, 128.32, 125.88, 110.88, 56.51, 55.88, 46.62, 45.57, 42.93, 39.21, 36.49, 34.82, 33.52, 32.07, 29.85, 29.81, 29.73, 29.55, 29.50, 29.33, 24.97, 23.57, 22.83, 14.27;

[0062] ESI - MS (m / z): 626.50 (M + H) + 。

[0063] Example 4

[0064]

[0065] The preparation method was the same as that of Example 1, using trans - cinnamic acid instead of dodecanoic acid to obtain the above - mentioned white solid; Yield: 39.18%.

[0066] 1 1H NMR (400 MHz, CDCl 3)δ8.34(brs,1H),8.08(brs,1H),7.94 - 7.91(m,1H),7.83 - 7.81(m,2H),7.75 - 7.63(m,2H),7.61 - 7.48(m,3H),7.05(d,J=8.40Hz,1H),6.81(d,J=15.20Hz,1H),6.78(d,J=8.40Hz,1H),4.55(d,J=17.10Hz,1H),3.69(s,3H),3.37 - 2.93(m,6H),2.73 - 2.62(m,2H),2.56(s,3H),2.45 - 2.30(m,1H),2.13 - 1.86(m,2H);

[0067] 13 C NMR(100MHz,CDCl 3 )δ164.95,153.04,149.85,147.86,141.63,138.79,134.78,130.83,130.73,130.28,129.14,128.99,128.87,128.69,128.39,126.08,117.48,110.90,56.52,56.01,46.59,45.65,42.97,39.03,36.56,33.50,23.51;

[0068] ESI-MS(m / z):518.30(M + H) + 。

[0069] Example 5

[0070]

[0071] The preparation method was the same as that of Example 1, and the above pale yellow solid was obtained by using p-fluorocinnamic acid instead of dodecanoic acid; Yield: 59.10%.

[0072] 1 H NMR(400MHz,CDCl 3)δ8.28(brs,1H),8.00(brs,1H),7.91 - 7.85(m,1H),7.75(t,J=6.74Hz,2H),7.65 - 7.61(m,2H),7.18(t,J=8.53Hz,2H),7.00(d,J=8.51Hz,1H),6.73(d,J=8.50Hz,1H),6.69(d,J=16.08Hz,1H),4.48(d,J=17.19Hz,1H),3.63(s,3H),3.26 - 2.93(m,6H),2.64 - 2.55(m,2H),2.49(s,3H),2.34 - 2.27(m,1H),1.97 - 1.90(m,2H);

[0073] 13 C NMR(100MHz,CDCl 3 )δ164.76,164.31(d,J=250.50Hz),153.13,149.73,146.45,141.62,141.52,138.69,131.06,131.03,130.77,130.61,130.52,128.97,128.86,128.71,128.41,126.09,117.24,116.30(d,J=21.80Hz)110.83,56.38,55.97,46.53,45.72,43.21,43.02,39.16,36.60,33.52,23.45;

[0074] ESI - MS(m / z):536.30(M + H) + 。

[0075] Example 6

[0076]

[0077] The preparation method was the same as that of Example 1, and the above - mentioned yellowish - white solid was obtained by using 3 - fluorocinnamic acid instead of dodecanoic acid; Yield: 34.72%.

[0078] 1 H NMR(400MHz,CDCl 3)δ8.26(brs,1H),8.02(brs,1H),7.88(dd,J=8.13,1.69Hz,1H),7.68-7.61(m,2H),7.58-7.52(m,1H),7.50-7.44(m,2H),7.20-7.15(m,1H),7.02(d,J=8.46Hz,1H),6.75(d,J=16.00Hz,1H),6.74(d,J=8.80Hz,1H),4.46(d,J=17.15Hz,1H),3.64(s,3H),3.31-2.92(m,6H),2.72-2.60(m,2H),2.53(s,3H),2.41-2.30(m,1H),2.09-1.83(m,2H);

[0079] 13 C NMR(100MHz,CDCl 3 )δ164.86,163.25(d,J=245.50Hz),152.93,149.81,146.47,141.65,138.66,137.06,136.98,130.75,130.67,129.99,129.06,128.98,128.77,128.43,126.19,124.59,124.56,118.87,117.68(d,J=21.00Hz),115.00(d,J=22.00Hz),110.97,56.58,56.01,46.59,45.64,42.90,38.91,36.53,33.44,23.53;

[0080] ESI-MS(m / z):536.30(M+H) + 。

[0081] Example 7

[0082]

[0083] The preparation method was the same as that of Example 1, and the above pale yellow solid was obtained by using 2-fluorocinnamic acid instead of dodecanoic acid; Yield: 57.87%.

[0084] 1 H NMR(400MHz,CDCl 3)δ8.36(brs,1H),8.05(brs,1H),7.87(dd,J=8.11,1.68Hz,1H),7.79(t,J=7.51Hz,1H),7.69 - 7.57(m,2H),7.47 - 7.41(m,1H),7.30 - 7.15(m,2H),7.00(d,J=8.48Hz,1H),6.89(d,J=16.18Hz,1H),6.73(d,J=8.48Hz,1H),4.47(d,J=17.15Hz,1H),3.64(s,3H),3.30 - 2.93(m,6H),2.64 - 2.58(m,2H),2.50(s,3H),2.37 - 2.26(m,1H),2.01 - 1.86(s,2H);

[0085] 13 C NMR(100MHz,CDCl 3 )δ164.80,161.79(d,J=253.00Hz),152.99,149.74,141.60,140.17,138.75,132.31,132.22,130.75,130.45,129.56,128.97,128.85,128.29,126.11,124.70,124.66,122.89,122.78,120.08,116.48(d,J=21.80Hz),110.87,56.43,55.99,46.55,45.73,43.16,43.00,39.10,36.60,33.50,23.48;

[0086] ESI - MS(m / z):536.30(M + H) + 。

[0087] Example 8

[0088]

[0089] The preparation method was the same as that of Example 1, and the above - mentioned light - yellow solid was obtained by using p - nitro - cinnamic acid instead of dodecanoic acid; Yield: 41.59%.

[0090] 1 H NMR(400MHz,CDCl 3)δ8.38 - 8.35(m, 3H), 7.94 - 7.88(m, 4H), 7.66 - 7.62(m, 2H), 7.03(d, J = 8.48Hz, 1H), 6.87(d, J = 16.10Hz, 1H), 6.75(d, J = 8.51Hz, 1H), 4.43(d, J = 17.11Hz, 1H), 3.64(s, 3H), 3.28 - 2.96(m, 6H), 2.68 - 2.61(m, 2H), 2.52(s, 3H), 2.42 - 2.26(m, 1H), 2.04 - 1.87(m, 2H);

[0091] 13 C NMR(100MHz, CDCl 3 )δ163.95, 152.99, 149.63, 148.89, 144.82, 141.70, 141.50, 140.91, 138.44, 130.60, 129.22, 129.12, 129.03, 128.60, 128.53, 126.36, 124.43, 121.75, 110.95, 56.46, 56.00, 46.53, 45.79, 43.34, 42.98, 39.07, 36.60, 33.45, 23.47。

[0092] ESI - MS(m / z): 563.30(M + H) + 。

[0093] Example 9

[0094]

[0095] The preparation method was the same as that of Example 1, using 4 - methoxycinnamic acid instead of dodecanoic acid to obtain the above - mentioned white solid; Yield: 26.67%.

[0096] 1 H NMR(400MHz, CDCl 3)δ8.22(brs,1H),8.03(brs,1H),7.88(dd,J=8.08,1.73Hz,1H),7.72(d,J=8.24Hz,2H),7.69 - 7.59(m,2H),7.01(d,J=8.40Hz,2H),7.00(d,J=8.40Hz,1H),6.74(d,J=8.40Hz,1H),6.64(d,J=15.99Hz,1H),4.52(d,J=17.19Hz,1H),3.90(s,3H),3.64(s,3H),3.30 - 2.96(m,6H),2.72 - 2.60(m,2H),2.42 - 2.29(s,3H),2.34(m,1H),2.13 - 1.84(m,2H);

[0097] 13 C NMR(100MHz,CDCl 3 )δ165.91,161.92,152.98,150.00,147.59,141.62,138.93,130.65,130.44,129.00,128.87,128.40,127.51,126.02,114.81,114.59,110.95,56.65,56.02,55.59,46.65,45.51,42.85,38.81,36.48,33.45,23.55;

[0098] ESI-MS(m / z):548.40(M + H) + 。

[0099] Example 10

[0100]

[0101] The preparation method was the same as that of Example 1, and the above white solid was obtained by using 3 - methoxycinnamic acid instead of dodecanoic acid; Yield: 38.65%.

[0102] 1 H NMR(400MHz,CDCl 3)δ8.27(brs,1H),8.04(brs,1H),7.92 - 7.84(m,1H),7.70 - 7.59(m,1H),7.44 - 7.36(m,2H),7.33 - 7.28(m,1H),7.25 - 7.23(s,1H),7.06 - 6.94(m,2H),6.81 - 6.67(m,2H),4.50(d,J=17.07Hz,1H),3.91(s,3H),3.64(s,3H),3.32 - 2.90(m,6H),2.70 - 2.58(m,2H),2.52(s,3H),2.39 - 2.29(m,1H),2.05 - 1.91(m,2H);

[0103] 13 C NMR(100MHz,CDCl 3 )δ165.62,160.15,153.00,149.85,147.87,141.63,138.79,136.13,130.68,130.14,129.00,128.88,128.83,128.40,126.10,121.45,117.73,116.85,113.40,110.92,56.55,56.00,55.54,46.60,45.61,42.93,38.93,36.53,33.47,23.52;

[0104] ESI - MS(m / z):548.30(M + H) + 。

[0105] Example 11

[0106]

[0107] The preparation method was the same as that of Example 1, and the above - mentioned white solid was obtained by using 2 - methoxycinnamic acid instead of dodecanoic acid; Yield: 38.23%.

[0108] 1 H NMR(400MHz,CDCl 3)δ8.38(brs,1H),8.00(brs,1H),7.90 - 7.84(m,1H),7.76(d,J=7.66Hz,1H),7.66 - 7.58(m,2H),7.45 - 7.40(m,1H),7.09 - 7.05(m,1H),7.00(d,J=8.40Hz,2H),6.95(d,J=16.15Hz,1H),6.74(d,J=8.49Hz,1H),4.53(d,J=17.21Hz,1H),3.97(s,3H),3.64(s,3H),3.30 - 2.92(m,6H),2.68 - 2.57(m,2H),2.52(s,3H),2.40 - 2.28(m,1H),2.06 - 1.86(m,2H);

[0109] 13 C NMR(100MHz,CDCl 3 )δ166.48,159.00,152.93,149.98,143.45,141.64,141.59,139.07,132.03,130.76,130.29,128.95,128.92,128.74,128.33,125.96,123.66,120.91,118.17,111.38,110.91,56.59,56.01,55.66,46.67,45.53,42.93,38.99,36.54,33.52,23.57;

[0110] ESI - MS(m / z):548.30(M + H) + 。

[0111] Example 12 Antitumor Activity Test and Results

[0112] 1. Experimental Materials

[0113] Cells: Human glioma cell line U87

[0114] 2. Experimental Methods:

[0115] Reagents and Drugs: Accurately weigh sinomenine derivatives Q - 1 to Q - 11, dissolve them in dimethyl sulfoxide to prepare a stock solution with a sinomenine derivative concentration of 10 mM, store it at 80 °C, and dilute it to an appropriate concentration with fresh medium when used. The media used are 1640 or high - glucose DMEM medium.

[0116] A Concentration: 10 mM, dissolved in DMSO (-80 °C storage).

[0117] Concentration of B: Diluted from A to 1 mM, and the diluent is sterile normal saline (stored at -80 °C).

[0118] Concentration of C: Diluted from B to 100 μM, and the diluent is culture medium.

[0119] CCK-8 assay for cell proliferation: Cells in the logarithmic growth phase were seeded at 3000 cells per well in a 96-well plate and cultured in an incubator with 5% CO2 at 37 °C. After 24 hours, the culture medium was discarded and replaced with 1 - 5% serum culture medium. The original culture medium was discarded, 90 μL of 10% serum culture medium was added, and then 10 μL of the test drug was added to the culture plate and mixed well. The culture plate was incubated in the incubator for 72 hours, 10 μL of CCK-8 solution was added to each well, and then the culture plate was incubated in the incubator for 1 - 4 hours. The absorbance at 450 nm was measured using an enzyme-linked immunosorbent assay (ELISA) reader.

[0120] Calculation of inhibition rate, and the results are shown in Table 1.

[0121]

[0122] Further screening of the drug:

[0123] After determining the effect of the drug, further screening was carried out. Eight concentration gradients were set, a dose-response curve was plotted, and IC 50 was calculated. The results are shown in Table 2.

[0124] 3. Experimental results:

[0125] 2.1 The results of the in vitro anti-U87 inhibition rate of the compound of the present invention measured by Method 1 are shown in Table 1:

[0126] Table 1: Results of the in vitro anti-U87 inhibition rate of the compound of the example

[0127]

[0128] 2.2 The half-maximal inhibitory concentration IC 50 of the compound of the present invention against U87 in vitro measured by Method 1 is shown in Table 2:

[0129] Table 2: Results of the in vitro anti-U87 activity of the compound of the example

[0130] Number <![CDATA[IC 50 (μM)]]> Q-1 4.65 Q-2 4.25 Q-3 6.09 Q-4 7.15 Q-5 2.24 Q-6 5.56 Q-7 9.55 Q-8 5.69 Q-9 5.93 5-FU 27.97

Claims

1. An sinomenine derivative or a pharmaceutically acceptable salt thereof, characterized in that, it has the structure shown in Formula I: R represents: wherein: n represents the number of methylene groups, and n can be 1, 2, 3, 4, 5... 16; R 1 、R 2 、R 3 、R 4 、R 5 may respectively represent H, methyl, methoxy, hydroxy, F, Cl, Br, CF 3 , NO 2 .

2. The sinomenine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, n represents the number of methylene groups, and n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; R 1 、R 2 、R 3 、R 4 、R 5 can respectively represent H, methyl, methoxy, hydroxyl, F, Cl, Br, CF 3 , NO 2 .

3. The sinomenine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 2, characterized in that, selected from the following compounds:

4. The sinomenine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, the pharmaceutically acceptable salt is a salt formed by the structure shown in Formula I and an inorganic acid or an organic acid.

5. A method for preparing the sinomenine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, the method is realized through the following reaction route: The definition of R is the same as that defined in any one of claims 1-4.

6. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the sinomenine derivative shown in Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

7. Use of the sinomenine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-4 in the preparation of an anti-tumor drug.

8. The use according to claim 88, characterized in that, the tumor is selected from human brain astrocytoma.

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