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CN-121974868-A - Camphor compound containing 1,3, 4-thiadiazole structure and its preparation method and use

CN121974868ACN 121974868 ACN121974868 ACN 121974868ACN-121974868-A

Abstract

In order to overcome the defects of Aurovertin B, the invention designs the camphor compound containing the 1,3, 4-thiadiazole structure by adopting a skeleton transition strategy, wherein the structural formula of the camphor compound containing the 1,3, 4-thiadiazole structure is shown as the formula (I): (I) The compound has better activity and safety than Aurovertin B, and has good application prospect in the field of three-yin breast cancer medicaments.

Inventors

  • ZHAN ZHAJUN
  • Li Jinghuo
  • LU JINJIAN
  • YUAN LINGJIE
  • MA LIEFENG

Assignees

  • 浙江工业大学

Dates

Publication Date
20260505
Application Date
20260304

Claims (10)

  1. 1. The camphor compound containing the 1,3, 4-thiadiazole structure is characterized in that the structural formula of the camphor compound containing the 1,3, 4-thiadiazole structure is shown as the formula (I): (I) in the formula (I), R 1 is 、 、 、 、 、 、 、 、 Or (b) One of the following; Wherein, the Wherein the X group is one of H, C-C3 alkyl, nitro, C1-C3 alkoxy, halogen or cyano.
  2. 2. The camphor-based compound according to claim 1, wherein the camphor-based compound having a1, 3, 4-thiadiazole structure has a structure represented by any one of the structures I-1~I-38: 。
  3. 3. the method for preparing the camphor-based compound according to claim 1, comprising the steps of: (1) Adding sodium carbonate and potassium permanganate into water for dissolution, dropwise adding an organic solvent A in which ((1S, 4R) -7, 7-dimethyl-2-oxo-bicyclo [2.2.1] heptyl-1-yl) methanesulfonyl chloride compound shown in a formula (II) is dissolved under stirring at 10-30 ℃, heating to 60-80 ℃ for reaction for 0.5-4 hours after reacting at 10-30 ℃, cooling to 10-30 ℃ after the reaction is finished, adding excessive Na 2 SO 3 , dropwise adding diluted sulfuric acid until the reaction solution is colorless, extracting the obtained reaction solution by using ethyl acetate, collecting an organic layer, adding a drying agent, filtering, and concentrating the obtained filtrate under reduced pressure to obtain a camphol carboxylic acid compound shown in the formula (III), wherein the ratio of the ((1S, 4R) -7, 7-dimethyl-2-oxo-bicyclo [2.2.1] heptyl-1-yl) methanesulfonyl chloride compound to sodium carbonate and potassium permanganate substance is 1-2:2 mass per volume of the organic solvent A shown in the formula (II) is 1-2:4 mass/volume per volume of the organic solvent A shown in the formula (II); (2) Adding an aromatic aldehyde structure compound shown in a formula (IV) and thiosemicarbazide into an organic solvent B, uniformly stirring, adding an acid catalyst, reacting for 2-4 hours at 60-80 o ℃ after the reaction is finished, monitoring the end of the reaction by TLC, cooling the obtained reaction liquid B to 10-30 ℃, adding water for dilution, carrying out suction filtration, and vacuum drying the obtained filter cake to obtain an aryl iminothiourea derivative crude product shown in a formula (V), wherein the ratio of the aromatic aldehyde structure compound shown in the formula (IV) to ((1S, 4R) -7, 7-dimethyl-2-oxo bicyclo [2.2.1] heptyl-1-yl) methanesulfonyl chlorourea compound shown in the formula (II) is 1:1:1-2, and the volume consumption of the organic solvent B is 5-60 ml/g based on the mass of the aromatic aldehyde structure compound shown in the formula (IV), and the acid catalyst is glacial acetic acid; (3) Dissolving the crude aryliminothiourea derivative shown in the formula (V) in an organic solvent C, adding anhydrous FeCl 3 to react for 2-12 hours at 60-80 ℃, monitoring the end of the reaction by TLC, concentrating under reduced pressure, adding water into the obtained crude product C, extracting for a plurality of times by using ethyl acetate, mixing organic phases, washing by using saturated sodium chloride solution, adding anhydrous sodium sulfate for drying, filtering, concentrating the filtrate under reduced pressure to obtain the crude product C, purifying by using a silica gel column chromatography of a petroleum ether/ethyl acetate system to obtain a compound of the arylthiodiazole amine shown in the formula (VI), wherein the ratio of ((1S, 4R) -7, 7-dimethyl-2-oxo-bicyclo [2.2.1] heptyl-1-yl) methanesulfonyl chloride compound to the amount of the anhydrous FeCl 3 is 1:3-6, and the organic solvent B is ethanol, wherein the volume consumption of the organic solvent C is 5-60 ml/g based on the mass of the compound shown in the formula (II); (4) Adding an organic solvent D into the camphorcyclocarboxylic acid compound shown in the formula (III) prepared in the step (1), the arylthiadiazole amine compound shown in the formula (VI) prepared in the step (3), N-methylimidazole (NMI), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (TCFH), mixing for 12-48 hours at 10-30 ℃, monitoring the end of the reaction by TLC, and performing post-treatment on the obtained reaction solution to obtain the camphol compound shown in the formula (I), wherein the ratio of the amounts of the arylthiadiazole amine shown in the formula (VI), the camphol cyclocarboxylic acid compound shown in the formula (III), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate and N-methylimidazole is 1-2:2-3, the organic solvent D is acetonitrile, and the volume amount of the organic solvent D is 5-60 ml/g calculated by the mass of the compound shown in the formula (II); r 1 in the formulae (IV), (V) and (VI) is 、 、 、 、 、 、 、 、 Or (b) One of the following; Wherein, the Wherein the X group is one of H, C-C3 alkyl, nitro, C1-C3 alkoxy, halogen or cyano.
  4. 4. The method for preparing camphor-like compounds as claimed in claim 3, wherein the post-treatment method in the step (4) comprises the steps of adding water into the reaction solution after the reaction is finished, extracting with ethyl acetate, collecting an organic layer, adding a drying agent, drying, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography using a mixed solution of petroleum ether and acetone as an eluent to obtain camphor-like compounds. The drying agent in the step (1) and the step (4) is one of anhydrous sodium sulfate or anhydrous magnesium sulfate.
  5. 5. A process for preparing camphol-type compounds as claimed in claim 3, wherein the volume ratio of petroleum ether to acetone as eluent is 4:1.
  6. 6. The method for producing a camphor-based compound according to claim 3, wherein the ratio of the ((1S, 4R) -7, 7-dimethyl-2-oxo-bicyclo [2.2.1] heptyl-1-yl) methanesulfonyl chloride to sodium carbonate and potassium permanganate in the step (1) is 1:3:2, and the reaction temperature is 70 to 80 C, reacting for 1-2 h, wherein the concentration of the dilute sulfuric acid is 3-8 mol/L.
  7. 7. The method for producing a camphor-based compound according to claim 3, wherein the ratio of the amount of the aromatic aldehyde to the amount of the thiosemicarbazide in the step (2) is 1:1-2, and the reaction temperature is 60-80 And C, reacting for 2-4 hours.
  8. 8. The method for preparing camphor-based compounds according to claim 3, wherein the ratio of the amount of the aryliminothiourea to the amount of the anhydrous FeCl 3 in the step (3) is 1:3-4, and the reagents used for amide condensation are N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (TCFH) and N-methylimidazole (NMI). The ratio of the amounts of the substances of the arylthiadiazole amine, the camphorcarboxylic acid, the TCFH and the NMI is 1-1.2:1:1:2-3, the reaction temperature is 10-30 ℃, and the reaction is carried out for 12-24 hours.
  9. 9. The use of a camphor-like compound according to claim 1 for the preparation of a medicament for the treatment of tumours.
  10. 10. The use of camphor-like compounds according to claim 1 for preparing medicaments for treating tumors, characterized in that the tumors are triple negative breast cancers.

Description

Camphor compound containing 1,3, 4-thiadiazole structure and its preparation method and use Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to a camphor compound containing a1, 3, 4-thiadiazole structure, and a preparation method and application thereof. Background Breast cancer is one of the common malignant tumors of females, and greatly endangers the life safety of females. Triple Negative Breast Cancer (TNBC) is a type of breast cancer, meaning that cancer tissue immunohistochemical examination results in breast cancer that is negative for all of the Estrogen Receptor (ER), the Progestogen Receptor (PR) and the proto-oncogene (Her-2), accounting for about 15% -20% of all breast cancer types. The current molecular mechanism research on TNBC pathogenesis is limited, a definite therapeutic target is lacked, and the transfer potential is high, the prognosis is extremely poor, and the survival rate of the advanced TNBC patients within 5 years is extremely low due to the high recurrence risk. Clinically conventional breast cancer treatment methods, such as hormone therapy and Her-2 targeted therapy, have little therapeutic effect on TNBC, clinical treatment schemes are limited, traditional chemotherapy is still the main stream method for treating TNBC, and currently first-line chemotherapeutics clinically used are mainly anthracyclines, taxol, cyclophosphamide, platinum and the like, however, the traditional chemotherapy has obvious defects such as drug resistance, various toxic and side effects and the like. The only drug currently used to significantly extend the overall survival of TNBC patients is Trodelvy approved by the FDA in 2020, trodelvy is an ADC drug targeting Trop-2 protein and linked to topoisomerase I inhibitor SN-38 for the treatment of advanced TNBC patients. Despite the significant advances in TNBC treatment marked by the marketing of Trodelvy, there is currently insufficient molecular mechanism of TNBC pathogenesis and clinically available therapies remain limited. Thus, there is a need to find potential targeted drugs for the treatment of TNBC. Aurovertin B (AVB) is a polyketide ATP synthase inhibitor of microbial origin, having a unique [ 3.2.1 ] bicyclooctane structural fragment in its structure. Pharmacological studies show that Aurovertin B can obviously inhibit the growth and metastasis of TNBC cells in vitro and in vivo, and is a potential candidate drug for resisting the triple negative breast cancer. However, the high-fat-solubility polyketide has the defects of poor bioavailability, high toxicity, narrow treatment window and the like. In addition, the specificity, complexity and natural source limitations of the framework bring great challenges to the structural modification of the framework, and greatly limit the commercial development and utilization of the framework. In order to overcome the defects of Aurovertin B, the invention designs the camphor compound containing the 1,3, 4-thiadiazole structure by adopting a skeleton transition strategy. The camphor skeleton is selected to replace [ 3.2.1 ] dicyclo-octane ring in AVB, the camphor ring is used as a hydrophobic group, the space structure of the camphor ring is similar to that of the [ 3.2.1 ] dicyclo-octane ring, and the carbonyl part of the camphor ring can possibly keep hydrogen bond interaction force. For the intermediate linking chain moiety, thiadiazoles are used instead. Furthermore, in AVBSubstitution of the pyrone structure with a different aromatic group, aimed at preserving the potential-Interaction. Compared with Aurovertin B, the synthesized compound has better water solubility and can improve the bioavailability of the medicine. The activity evaluation shows that part of the compounds related to the invention have better activity and safety than Aurovertin B. Aurovertin B structural formula Disclosure of Invention The invention provides a camphor compound containing a 1,3, 4-thiadiazole structure, and a preparation method and application thereof. In a first aspect, the invention provides a camphor compound containing a1, 3, 4-thiadiazole structure, wherein the structural formula of the camphor compound containing the 1,3, 4-thiadiazole structure is shown as the formula (I): (I) in the formula (I), R 1 is 、、、、、、、、Or (b)One of the following; Wherein, the Wherein the X group is one of H, C-C3 alkyl, nitro, C1-C3 alkoxy, halogen or cyano. Preferably, the camphor compound containing the 1,3, 4-thiadiazole structure has a structure shown in any one of I-1~I-38: In a second aspect, the present invention provides a method for preparing the above compound, comprising the steps of: (1) Adding sodium carbonate and potassium permanganate into water for dissolution, dropwise adding an organic solvent A in which ((1S, 4R) -7, 7-dimethyl-2-oxo-bicyclo [2.2.1] heptyl-1-yl) methanesulfonyl chloride compound shown in a formula (II) is dissolved under stirring at 10-30 ℃,