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CN-121974971-A - Tanshinone IIA derivative and application thereof

CN121974971ACN 121974971 ACN121974971 ACN 121974971ACN-121974971-A

Abstract

The invention discloses a tanshinone IIA derivative, a preparation method and application thereof, wherein the invention provides a set of chemical synthesis route of a system for overcoming the defects of poor water solubility, low bioavailability and to-be-improved antitumor activity of tanshinone IIA, and a series of novel derivatives with various structures and general structures and medicinal salts thereof are prepared by carrying out structural modification on tanshinone IIA parent nucleus. The core of the technical scheme is that after the specific functional group is introduced into the derivative, the water solubility and stability of the compound are obviously improved, particularly excellent colorectal cancer resistance activity is shown, the proliferation of tumor cells and the growth of tumors in an animal model can be effectively inhibited, and no obvious toxic or side effect is seen. The invention also provides a pharmaceutical composition containing the derivative and application of the pharmaceutical composition in preparing medicines for preventing, relieving or treating colorectal cancer, and provides an important candidate compound for developing high-efficiency and low-toxicity novel medicines for resisting colorectal cancer.

Inventors

  • SONG CHANGFENG
  • LI JIYU
  • MANG ZHIGUO
  • BAI JING

Assignees

  • 上海市浦东医院（复旦大学附属浦东医院）
  • 贵州药法自然医药科技有限公司

Dates

Publication Date
20260505
Application Date
20251208

Claims (10)

  1. 1. The preparation method of the tanshinone IIA derivative is characterized by comprising the following synthetic routes: ; Namely: a) Mixing tanshinone IIA, acetic acid, 2, 6-tetramethylpiperidine oxide and chlorobenzene, reacting under heating, and post-treating after the reaction to obtain a compound 1; b) Reacting the compound 1 with pyridine p-toluenesulfonate in toluene, and performing post-treatment after the reaction is finished to obtain a compound 2; c) Reacting the compound 2 with selenium dioxide in 1, 4-dioxane, and performing aftertreatment after the reaction is finished to obtain a compound 3; d) Reacting the compound 3 with N-bromosuccinimide in dichloromethane, and performing post-treatment after the reaction is finished to obtain tanshinone IIA derivative 4; e) Reacting the compound 3 and paraformaldehyde in acetic acid under a closed condition, and performing alkali treatment after the reaction to obtain tanshinone IIA derivative 6; f) Reacting tanshinone IIA derivative 6 with dess-martin periodate in dichloromethane to obtain tanshinone IIA derivative 10; g) Reacting tanshinone IIA derivative 10, hydrogen peroxide, disodium hydrogen phosphate buffer solution and sodium chlorite in acetonitrile to obtain tanshinone IIA derivative 11; h) Reacting the tanshinone IIA derivative 6 with thionyl chloride in dichloromethane to obtain a tanshinone IIA derivative 8; i-1) reacting the compound 3, an amine compound or hydrochloride thereof with paraformaldehyde in acetic acid to prepare tanshinone IIA derivatives 5- (1-2), 5- (5-9), 5- (11-17) and 5- (20-32); i-2) carrying out reductive amination reaction on the tanshinone IIA derivative 10, an amine compound or hydrochloride thereof in 1, 2-dichloroethane to obtain tanshinone IIA derivatives 5- (3-4), 5-10 and 5- (18-19); i-3) reacting the tanshinone IIA derivative 8, an amine compound or hydrochloride thereof with triethylamine in dichloromethane to prepare tanshinone IIA derivative 5- (33-39); j-1) reacting tanshinone IIA derivative 6, organic acid acyl chloride and triethylamine in dichloromethane to prepare tanshinone IIA derivative 7- (1-12); j-2) taking tanshinone IIA derivative 6 and di (p-nitrobenzene) carbonate as raw materials, reacting in methylene dichloride in the presence of 4-dimethylaminopyridine and triethylamine, and then adding amine compounds for reaction to prepare tanshinone IIA derivative 7- (13-26); k) Reacting tanshinone IIA derivative 8 with sodium methoxide in a mixed solvent of dichloromethane and methanol to obtain tanshinone IIA derivative 9; l) reacting tanshinone IIA derivative 11, amine compound, triethylamine and 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate in dichloromethane to prepare tanshinone IIA derivative 12 series compound 12- (1-13); m) reacting tanshinone IIA derivative 11 with oxalyl chloride in dichloromethane under the catalysis of N, N-dimethylformamide to form acyl chloride, and then reacting with methanol and triethylamine in dichloromethane to obtain tanshinone IIA derivative 13; Wherein: R 1 、R 2 is independently selected from any one of C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, benzene ring or substituted benzene ring, wherein the substituent on the benzene ring is any one of F, cl, br, trifluoromethyl, amino, cyano, ester group, nitro, methoxy or hydroxy, and the number of the substituent is 1-3, or R 1 、R 2 and C, N, O also form a 3-6 membered ring, wherein N atoms on the ring are connected with C 1-6 alkyl, C 1-6 cycloalkyl, benzene ring and aromatic heterocycle, and H atoms connected with the C atoms on the ring are substituted by C 1-6 alkyl, F, cl, br, benzene ring, 3-6 membered heterocyclic group, C 1-6 alkyl, C 2-6 alkenyl and C 3-6 cycloalkyl; R 3 is H or is substituted with at least one R a group, said R a group being any of C 1-8 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-8 alkyl, C 1-8 alkoxy, -C 1-8 alkyl OC 1-8 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, N (C 1-8 alkyl) 2 , amino, cyano, aldehyde, carboxyl, NHC 1-8 alkyl, nitro, C 1-8 alkoxy, hydroxyl or-COC 1-8 alkyl; R 4 is selected from any one of C 1-6 alkyl, C 2-6 alkenyl and C 3-6 cycloalkyl; R 5 、R 6 is independently selected from any one of C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group and N (C 1-8 alkyl) 2 , wherein the carbon chain of the alkyl is further linked through N, O, the hydrogen of the alkyl is substituted by C 1-6 cycloalkyl, benzene ring and aromatic heterocyclic ring, or R 1 、R 2 and C, N, O together form a 3-6 membered ring, and the N atom on the ring is connected with C 1-6 alkyl, C 1-6 cycloalkyl, benzene ring and aromatic heterocyclic ring; R 7 is selected from any one of C 1-6 alkyl, C 2-6 alkenyl and C 3-6 cycloalkyl.
  2. 2. The method of manufacturing according to claim 1, characterized in that: The structural formulas of tanshinone IIA derivatives 5- (1-2), 5- (5-9), 5- (11-17) and 5- (20-32) are respectively as follows: The structural formulas of tanshinone IIA derivatives 5- (3-4), 5-10 and 5- (18-19) are respectively as follows: the structural formulas of the tanshinone IIA derivatives 5- (33-39) are respectively as follows: the structural formulas of the tanshinone IIA derivatives 7- (1-12) are respectively as follows: the structural formulas of the tanshinone IIA derivatives 7- (13-26) are respectively as follows: the structural formulas of the tanshinone IIA derivatives 12- (1-13) are respectively as follows: 。
  3. 3. The method of manufacturing according to claim 1, characterized in that: in the step a), the reaction temperature is 100-130 ℃, and the molar ratio of tanshinone IIA, acetic acid and 2, 6-tetramethylpiperidine oxide is 1:1.5-3:1.5; in the step b), the reaction temperature is 100-120 ℃, and the molar ratio of the compound 1 to the tosylate is 1:1-1.5; in the step C), the reaction temperature is 90-110 ℃, and the molar ratio of the compound 2 to the selenium dioxide is 1:1-1.1; In the step d), the reaction is carried out at 10-30 ℃, and the molar ratio of the compound 3 to the N-bromosuccinimide is 1:1-1.5; in the step e), the sealing condition is a tube sealing reaction, the temperature of the reaction is 80-100 ℃, and the alkali used for alkali treatment is potassium carbonate; in the step f), the reaction is carried out at 10-30 ℃, and the molar ratio of the tanshinone IIA derivative 6 to the dess-Martin periodate is 1: (1-1.5); in the step g), the volume concentration of the hydrogen peroxide is 25-35%, the pH value of the buffer solution is 1.5-2.5, and the reaction is carried out at room temperature; in the step h), the reaction is carried out at the temperature of 10-30 ℃, and the molar ratio of the tanshinone IIA derivative 6 to the thionyl chloride is 1:1-1.5; In the step i-1), the reaction temperature is 50-70 ℃, and the molar ratio of the compound 3 to the amine compound to the paraformaldehyde is 1:1-1.5:1-2; In the step i-2), the reductive amination reaction is carried out at the temperature of 10-30 ℃, and the molar ratio of the tanshinone IIA derivative 10, the amine compound and the sodium triacetoxyborohydride is 1:1-1.5:1.5-2.5; In the step i-3), the reaction temperature is 20-40 ℃, and the molar ratio of the tanshinone IIA derivative 8, the amine compound and the triethylamine is 1:1-1.5:1.5:2.5; in the step j-1), the reaction is carried out at the temperature of ice bath to room temperature, and the molar ratio of the tanshinone IIA derivative 6 to the organic acid acyl chloride to the triethylamine is 1:1-1.5:1.5-3; in the step j-2), the reaction is carried out at the temperature of ice bath to room temperature, and the molar ratio of the tanshinone IIA derivative 6 to the di (p-nitrobenzene) carbonate to the amine compound to the 4-dimethylaminopyridine to the triethylamine is 1:1.5-2.5:2-3:0.05-0.15:1-1.5; in the step k), the volume ratio of dichloromethane to methanol is 1:1, the reaction temperature is 0-20 ℃, and the molar ratio of tanshinone IIA derivative 8 to sodium methoxide is 1:1.5-2.5; in the step l), the reaction is carried out at the temperature of 10-30 ℃, and the molar ratio of the tanshinone IIA derivative 11, the amine compound, the triethylamine and the 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate is 1:1-1.5:1-1.5:1.2-1.8; in the step m), the reaction for forming acyl chloride is carried out at the temperature of 10-30 ℃, and the molar ratio of the tanshinone IIA derivative 11 to the oxalyl chloride to the methyl alcohol to the triethylamine is 1:4-6:1.5-2.5:1.5-2.5.
  4. 4. A method of preparation according to claim 3, characterized in that: in the step a), the temperature of the reaction is 120 ℃, and the molar ratio of the tanshinone IIA, acetic acid and 2, 6-tetramethylpiperidine oxide is 1:2:1.2; in step b), the temperature of the reaction is 110 ℃, and the molar ratio of the compound 1 to the tosylate is 1:1.2; in step C), the temperature of the reaction is 100 ℃, and the molar ratio of the compound 2 to the selenium dioxide is 1:1.05; In step d), the reaction is carried out at 20℃and the molar ratio of the compound 3 to N-bromosuccinimide is 1:1.2. In step e), the temperature of the reaction is 90 ℃; In step f), the reaction is carried out at 20 ℃, the molar ratio of tanshinone IIA derivative 6 to dess-martin periodate being 1:1.2; in step g), the hydrogen peroxide is present in a volume concentration of 30%; In the step h), the reaction is carried out at 20 ℃, and the molar ratio of the tanshinone IIA derivative 6 to the thionyl chloride is 1:1.2; In the step i-1), the temperature of the reaction is 60 ℃, and the molar ratio of the compound 3, the amine compound and the paraformaldehyde is 1:1.2:1.5; In the step i-2), the reductive amination reaction is carried out at 20 ℃, and the molar ratio of the tanshinone IIA derivative 10, the amine compound and the sodium triacetoxyborohydride is 1:1.2:2.0; in the step i-3), the temperature of the reaction is 30 ℃, and the molar ratio of the tanshinone IIA derivative 8, the amine compound and the triethylamine is 1:1.2:2.0. In the step j-1), the molar ratio of the tanshinone IIA derivative 6, the organic acid chloride and the triethylamine is 1:1.2:2; In the step j-2), the molar ratio of the tanshinone IIA derivative 6, the di (p-nitrobenzene) carbonate, the amine compound, the 4-dimethylaminopyridine and the triethylamine is 1:2:2.5:0.1:1.2; In the step k), the temperature of the reaction is 10 ℃, and the molar ratio of the tanshinone IIA derivative 8 to sodium methoxide is 1:2; In the step l), the reaction is carried out at 20 ℃, and the molar ratio of the tanshinone IIA derivative 11, amine compounds, triethylamine and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate is 1:1.2:1.2:1.5; in step m), the reaction for forming acyl chloride is carried out at 20 ℃, and the molar ratio of the tanshinone IIA derivative 11, the oxalyl chloride, the methanol and the triethylamine is 1:5:2:2.
  5. 5. The method of manufacturing according to claim 1, characterized in that: The post-treatment comprises the steps of washing with water, washing with saturated saline, separating out an organic layer, drying with anhydrous sodium sulfate, concentrating under reduced pressure to remove an organic solvent, and purifying the crude product by silica gel column chromatography.
  6. 6. A tanshinone IIA derivative and its pharmaceutically acceptable salt, characterized in that: the tanshinone IIA derivative is prepared by the preparation method of any one of claims 1-5; The tanshinone IIA derivative medicinal salt is an addition salt prepared by reacting an alkaline tanshinone IIA derivative with an alkaline nitrogen atom in a structure and a pharmaceutically acceptable inorganic acid or organic acid, wherein the alkaline tanshinone IIA derivative is prepared by the preparation method of any one of claims 1-5.
  7. 7. The tanshinone IIA derivative pharmaceutically acceptable salt thereof according to claim 6 wherein: the pharmaceutically acceptable inorganic acid is: Hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid and/or nitric acid; the pharmaceutically acceptable organic acids are: Formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic 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, pamoic acid, pectate acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic 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, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptylic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, and/or thiocyanic acid.
  8. 8. A composition comprising a tanshinone IIA derivative or a pharmaceutically acceptable salt thereof according to claim 6 and an edible or pharmaceutically acceptable carrier or adjuvant.
  9. 9. Use of a tanshinone IIA derivative or a pharmaceutically acceptable salt thereof according to claim 6 or a composition according to claim 8 in the manufacture of a food or medicament for the prevention, alleviation and/or treatment of colorectal cancer.
  10. 10. The use according to claim 9, wherein said tanshinone IIA derivative or pharmaceutical salt thereof or said tanshinone IIA derivative or pharmaceutical salt composition thereof is formulated into oral tablet, capsule, granule, syrup, injectable powder, solution, or as functional additive in food, skin care product, cosmetic and/or health care product.

Description

Tanshinone IIA derivative and application thereof Technical Field The invention relates to a tanshinone IIA derivative and application thereof, and belongs to the technical field of preparation and application of tanshinone IIA derivatives. Background Tanshinone IIA (English: tanshinoneIIA) is prepared from Saviae Miltiorrhizae radix (Chinese medicinal materials)The fat-soluble diterpenoid quinone component with the most main and strongest activity extracted from rhizome has a unique phenanthrenequinone structure and is a key substance for playing a pharmacological role of the red sage root. Modern pharmacological research shows that tanshinone IIA has various cardiovascular protection effects of protecting vascular endothelial cells, resisting arrhythmia and atherosclerosis, improving microcirculation, protecting cardiac muscle, inhibiting and relieving platelet aggregation, increasing coronary flow, improving organism hypoxia tolerance and the like. In addition, the compound also shows wide anti-tumor activity, has inhibition effect on various cancer cells such as liver cancer, lung cancer, breast cancer, gastric cancer and the like, and the action mechanism of the compound relates to a plurality of links such as regulation of cell cycle, inhibition of cell proliferation, induction of apoptosis, inhibition of tumor invasion and metastasis, inhibition of angiogenesis, reversion of tumor multidrug resistance and the like, and in recent years, research also finds that tanshinone IIA imidazole derivatives which are synthesized by introducing an imidazole ring design can activate release of ROS and regulate PTEN/AKT signal paths and inhibit formation of invasive pseudopodia by taking tanshinone IIA as a parent structure, thereby effectively inhibiting proliferation and metastasis of cancer cells in a triple-negative breast cancer zebra fish transplantation tumor model (see research results published by Mei Wenjie team in Journal of MEDICINAL CHEMISTRY) "Design and SAR of Withangulatin A Analogues that Act as Covalent TrxR Inhibitors through the Michael Addition Reaction Showing Potential in Cancer Treatment"）. Although tanshinone IIA has wide pharmacological activity, certain physical and chemical properties of the tanshinone IIA severely limit the wider clinical application. The main manifestation is that tanshinone IIA has extremely high fat solubility and extremely poor water solubility, which leads to difficult dissolution and absorption of the drug, low bioavailability and short half-life, so that the drug effect is difficult to fully exert, compared with most antitumor drugs, the antitumor activity of tanshinone IIA still needs to be further improved, so that the structure of tanshinone IIA is necessary to be optimized or a novel delivery system is adopted (see Li Na, deng Qian and Jiang Jianjun, "research progress of antitumor effect of tanshinone IIA" clinical study of traditional Chinese medicine 2022, vol.14Issue (18): 133-136). In order to overcome the defects, various methods have been explored in the prior art, including the aspects of formulation improvement, the in-vitro dissolution speed and degree of the medicine are increased by the technologies of solid dispersion, inclusion technology, self-microemulsifying medicine release system, superfine particle preparation, supercritical fluid anti-solvent technology and the like, so that the oral bioavailability is improved, and the tanshinone IIA inclusion compound for injection prepared by adopting HP-beta-CD as an inclusion material is remarkably improved in water solubility. In terms of structural modification, besides the tanshinone IIA imidazole derivative, the prior art also relates to preparation and research of tanshinone IIA sulfonate, such as a continuous preparation method of tanshinone IIA sodium sulfonate based on a single-tube thin-layer liquid membrane reactor (application publication number: CN 120349367A) developed by the university of Huadong, and the first biological pharmaceutical company on the sea applies for a patent (publication number: CN 119912516A) of a related substance of tanshinone IIA sodium sulfonate and a refining method thereof, aiming at improving the quality standard of tanshinone IIA sodium sulfonate. However, these prior art techniques still have respective limitations, for example, the formulation modifications may involve complex processes and high costs, the long-term stability of certain delivery systems has yet to be examined, and structural modifications have to be focused on changes in potential toxicity while improving activity. Therefore, research and development of novel tanshinone IIA derivatives, preparations or preparation processes capable of comprehensively improving water solubility, stability, bioavailability and pharmacological activity is still a technical problem to be solved in the art. Disclosure of Invention In order to overcome the defects of the prior art, the invention aims to develop a