A kind of pyridone derivative and its preparation method and application
A derivative, pyridone technology, applied in the field of chemistry and medicine, can solve the problems of many side reactions, drug resistance, gemcitabine therapy is no longer effective, etc., and achieve good practicability.
Active Publication Date: 2022-02-18
NANJING UNIV
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Problems solved by technology
Prior to 2011, despite numerous trials testing gemcitabine in combination with other agents, there had been no significant progress in the treatment of advanced pancreatic cancer
In recent years, breakthroughs have been made in the clinical application of targeted inhibitors such as Kras, EGFR, and COX-2, which can significantly improve the prognosis of pancreatic cancer patients, but further research is still needed due to high cost and many side effects
Currently, gemcitabine is still the "gold standard" treatment for advanced pancreatic cancer. The drug can block tumor cell division and promote cell death; however, many patients die within months, usually because the cancer cells find a way to avoid the drug gemcitabine's effect Therefore, there is an urgent need to develop clinical chemotherapy drugs with a new structure and mechanism of action for the treatment of pancreatic cancer to alleviate the resistance of existing chemotherapy drugs. Drug properties, prolong the life of pancreatic cancer patients and improve their quality of life
Method used
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Embodiment 1
[0030] 1. The preparation of compound S8, the reaction formula is:
[0031]
[0032] 1) Preparation of Compound S2
[0033] Synthesis of 3-isobutoxy-2-cyclohexenone (S2) from 1,3-cyclohexanedione (S1): Add 1,3-cyclohexanedione (50mmol, 1.0eq) into a 250mL reaction flask , p-toluenesulfonic acid monohydrate (3mmol, 0.06eq), isobutanol (200mmol, 4.0eq) and toluene (200mL), and reflux overnight at 120°C in a water trap. After the reaction was completed, the solvent and excess isobutanol were distilled off under reduced pressure, separated and purified by column chromatography to obtain 3-isobutoxycyclohexenone (S2) in a yellow oily liquid with a yield of 95%.
[0034] 2) Preparation of compound S3a / S3b / S3c / S3d
[0035] Under the protection of nitrogen, add 2mol / LLDA THF solution (30mmol, 15mL, 1.2eq) to freshly distilled THF (100mL) cooled to -78°C, and add S2 (25mmol, 1.0eq) THF solution dropwise at -78°C (20mL). React for 1 h and slowly return to 0°C, then cool to -78°C,...
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The invention discloses a pyridone derivative and its preparation method and application thereof. The pyridone derivative is mainly derived from R 1 , R 2 , R 3 These three substituent groups are structurally modified, where R 1 The modification of R is mainly through allyl, isopentenyl, geranyl, p-fluorobenzyl, etc.; R 2 The modification is mainly through hydroxyethyl, hydroxypropyl, aminoethyl, aminopropyl, etc.; R 3 Modifications in the literature mainly focus on ethers with certain structural features. The pyridone derivatives of the present invention have obvious inhibitory effect on pancreatic cancer cell PANC-1 under anaerobic state, but have no effect on the cell under normal nutritional state (indicating no cytotoxicity). The preparation method of the pyridone derivatives of the present invention firstly synthesizes the basic core bicyclo[3.3.1]nonanone, and reacts with a series of alcoholamines or diamines under the catalysis of toluenesulfonic acid to prepare a class of The pyridone derivatives, which have obvious inhibitory effect on pancreatic cancer, have very good practicability.
Description
technical field [0001] The invention belongs to the technical field of chemistry and medicine, and in particular relates to a pyridone derivative and its preparation method and application. Background technique [0002] Pancreatic cancer, known as the "King of Cancer" by the medical community, is the cancer with the worst prognosis among all malignant tumors. The mortality rate of patients is as high as 95%-98% one year after diagnosis, that is to say, about 95%. Pancreatic cancer patients live less than a year from diagnosis to death, and it is very rare that they can live more than five years. Surgical resection is the best treatment for pancreatic cancer after diagnosis, but more than 80% to 85% of pancreatic cancer patients are diagnosed at an advanced stage. For these patients, chemotherapy is an acceptable solution. Before 2011, despite numerous trials trying to combine gemcitabine with other drugs, there had been no significant progress in the treatment of advanced p...
Claims
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IPC IPC(8): C07D215/22C07D409/12C07D215/36C07D405/12A61K31/435A61K31/4709A61P35/00
CPCA61P35/00C07D215/22C07D215/36C07D405/12C07D409/12
Inventor 吴静沈奇李建新
Owner NANJING UNIV