CN-117586227-B - Pirfenidone derivative and preparation method and application thereof

Abstract

The invention discloses a pirfenidone derivative and a preparation method and application thereof. The structural formula of the pirfenidone derivative is shown as a formula (I), wherein R 1 、R 2 、R 3 、R 4 can be the same or different and are independently selected from any group ：-CH 3 、-CH 2 OH、-CH 2 NH 2 、-CF 3 、-CH 2 NR 5 R 6 ;, R 5 、R 6 can be the same or different and are independently selected from any group-CH 3 、-C 2 H 5 . Compared with pirfenidone, the compound has better lung function improving effect and can meet the clinical requirement of treating pulmonary fibrosis (IPF).

Inventors

• WANG WEI
• LU YONGZHANG
• TAN JINHUI

Assignees

• 广东中科药物研究有限公司

Dates

Publication Date

20260508

Application Date

20231123

Claims (9)

1. 1. A compound represented by formula (II):
2. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (II) is any of hydrochloride, nitrate, mesylate, phosphate, citrate, fumarate, sulfate, succinate, tartrate, citrate, hydrobromide, hydroiodide, acetate, lactate, benzoate, cinnamate, salicylate, malonate, glutarate, malate.
3. 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (II) has the structural formula (III): The X is selected from acid radical anions generated when any acid is ionized, such as hydrochloric acid, nitric acid, methanesulfonic acid, phosphoric acid, citric acid, fumaric acid, sulfuric acid, succinic acid, tartaric acid, citric acid, hydrobromic acid, hydroiodic acid, acetic acid, lactic acid, benzenesulfonic acid, cinnamic acid, salicylic acid, malonic acid, glutaric acid and malic acid.
4. 4. A process for the preparation of a compound of formula (II) as claimed in claim 1, comprising the steps of: Mixing 5-methylpyridine-2 (1H) -ketone, 2-chloro-3, 5, 6-trimethylpyrazine, cuprous iodide and anhydrous potassium carbonate into N, N-dimethylformamide, and carrying out reflux reaction to obtain a compound shown in a formula (II).
5. 5. The preparation method of the composition according to claim 4, wherein the molar ratio of the 5-methylpyridin-2 (1H) -one, the 2-chloro-3, 5, 6-trimethylpyrazine, the cuprous iodide and the anhydrous potassium carbonate is 1:1 (0.1-0.5): 2-3; or, the condition of the reflux reaction is 160 ℃ reflux reaction 5 h.
6. 6. The method of claim 4 or 5, wherein the method further comprises the steps of concentrating the reaction solution after the reflux reaction, dissolving the residual solution in methylene chloride, washing with water, and purifying by column chromatography to obtain white solid 5-methyl-1- (3, 5, 6-trimethyl pyrazin-2-yl) pyridin-2 (1H) -one.
7. 7. Use of a compound of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis and/or treatment of pulmonary fibrosis.
8. 8. A pharmaceutical composition for preventing and/or treating pulmonary fibrosis, comprising a compound represented by formula (II) or a pharmaceutically acceptable salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.
9. 9. The pharmaceutical composition according to claim 8, wherein the dosage form of the pharmaceutical composition is an oral solid preparation or a liquid preparation.

Description

Pirfenidone derivative and preparation method and application thereof Technical Field The invention belongs to the field of medicines, and particularly relates to a pirfenidone derivative, and a preparation method and application thereof. Background Pulmonary Fibrosis (IPF) is a chronic interstitial lung disease caused by unknown causes and characterized by pathological changes that are typical of normal interstitial pneumonia, the most common type of idiopathic interstitial pneumonia. IPF is commonly found in the ages of 40-70 years, the precise incidence of the disease is not confirmed by the current definite data, the incidence rate of the disease is estimated to be about 13-20 in every 10 thousands of people, the incidence rate is increased with the age, the average diagnosis age is 66 years, the death rate of the disease is increased with the age, the male is higher than the female, the 5-year survival rate is 20%, and the death rate is far higher than that of a plurality of cancers. The combination of corticosteroids with azathioprine and N-acetylcysteine can be used to treat mild to moderate pulmonary fibrosis, but such studies are less likely and have many side effects and lower clinical efficacy, and therefore such drugs remain highly limiting. Recent studies have demonstrated that IPF is caused by chronic epithelial cell damage and abnormal activation of fibroblasts. Therefore, the approach to treating IPF has shifted from the search for corticosteroids and immunosuppressants to anti-fibrotic drugs. Currently, no drug is approved by the FDA in the united states for the treatment of IPF. Pirfenidone is an oral pyridine drug capable of regulating a plurality of cytokines including transforming growth factor-beta (transforming growth factor-beta, TGF-beta), connective tissue growth factor (connective tissue growth factor, CTGF), platelet derived factor (PLATELET DERIVED growth factor, PDGF) and tumor necrosis factor (tumor necrosis factor, TNF-alpha), changing collagen expression synthesis and accumulation, inhibiting extracellular matrix proliferation and expression, and having anti-inflammatory, antioxidant and anti-fibrosis effects. Pirfenidone and nilamide are main drugs for treating idiopathic pulmonary fibrosis, and have similar action mechanisms, and target spots are fibroblasts and myofibroblasts. There is still the following significant difference between the two: 1. different targets in target cells, namely pirfenidone reduces cell proliferation, reduces the production of fibrosis related proteins and reduces inflammatory cell aggregation caused by stimulation by inhibiting targets such as transforming growth factor beta and the like. Nidamib inhibits proliferation, migration and transformation of fibroblasts by inhibiting various tyrosine kinases and affecting intracellular signaling. 2. The adverse reaction and the treatment effect are different, wherein the common adverse reaction of pirfenidone is liver enzyme elevation, and the common adverse reaction of Nidaminib is bronchitis and myocardial infarction. During the course of treatment, nifedipine shedding is more prevalent than pirfenidone, while pirfenidone withdrawal rates are less. Pirfenidone is more stable in stability than nilotica. 3. Although both nidulance and pirfenidone have been approved for the treatment of reduced lung function in IPF, none has significant advantages in reducing disease mortality. Although there is some improvement to IPF, the existing drugs do not meet clinical needs, so it is necessary to find more effective drugs for treating IPF. Disclosure of Invention In view of the above-mentioned drawbacks of the prior art, an object of the present invention is to provide a pirfenidone derivative which satisfies clinical needs and has a better effect in treating IPF. The pirfenidone derivative provided by the invention is a compound shown in a formula (I) or pharmaceutically acceptable salts, esters, solvates and prodrugs thereof: In the formula (I), R 1、R2、R3、R4 may be the same or different and are independently selected from any of the following groups ：-CH3、-CH2OH、-CH2NH2、-CF3、-CH2NR5R6; The R 5、R6 groups, which may be the same or different, are independently selected from any of the following-CH 3、-C2H5 groups. Further, the pharmaceutically acceptable salt of the compound shown in the formula (I) can be any salt selected from hydrochloride, nitrate, mesylate, phosphate, citrate, fumarate, sulfate, succinate, tartrate, citrate, hydrobromide, hydroiodide, acetate, lactate, benzoate, cinnamate, salicylate, malonate, glutarate and malate. Specifically, the compound represented by the formula (I) may be a compound represented by the following formula (II): Further, the pharmaceutically acceptable salt of the compound of formula (II) has a structural formula shown in formula (III): The X is selected from acid radical anions generated when any acid is ionized, such as hydrochloric acid, nitric acid, methanesulfonic a