A pirfenidone derivative, and a preparation method and application thereof

Abstract

The application discloses a pirfenidone derivative, a preparation method and application thereof. The pirfenidone derivative has a structural formula as shown in formula (I). In the formula (I), R1, R2, R3 and R4 can be the same or different, and are independently selected from any of the following groups: -CH3, -CH2OH, -CH2NH2, -CF3, -CH2NR5R6; R5 and R6 can be the same or different, and are independently selected from any of the following groups: -CH3, -C2H5. Compared with pirfenidone, the compound has a more optimal lung function improvement effect, and can meet the clinical requirement for treating pulmonary fibrosis (IPF).

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a pirfenidone derivative, its preparation method, and its application. Background Technology

[0002] Pulmonary fibrosis (IPF) is a chronic interstitial lung disease caused by unknown reasons, characterized by pathological changes resembling common interstitial pneumonia. It is the most common type of idiopathic interstitial pneumonia. IPF is most common in people aged 40 to 70. The exact incidence rate of this disease is currently not definitively confirmed, but it is estimated to be about 13 to 20 per 100,000 people, and the incidence rate increases with age, with an average age of diagnosis of 66 years. The mortality rate of this disease also increases with age, and is higher in men than in women. The 5-year survival rate is 20%, which is far higher than that of many cancers.

[0003] The combination of corticosteroids, azathioprine, and N-acetylcysteine ​​can be used to treat mild to moderate pulmonary fibrosis; however, research in this area is limited, and numerous side effects and low clinical efficacy exist, thus these drugs remain highly restrictive. Recent studies have demonstrated that IPF is caused by chronic epithelial cell damage and abnormally active fibroblasts. Therefore, treatment for IPF has shifted from searching for corticosteroids and immunosuppressants to antifibrotic drugs. Currently, the US FDA has not approved any drugs for the treatment of IPF.

[0004] Pirfenidone is an orally administered pyridine drug that can regulate many cytokines, including transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), and tumor necrosis factor (TNF-α), altering collagen expression, synthesis, and accumulation, and inhibiting extracellular matrix proliferation and expression. It has anti-inflammatory, antioxidant, and anti-fibrotic effects.

[0005] Pirfenidone and nintedanib are the main drugs for treating idiopathic pulmonary fibrosis. Both have similar mechanisms of action, targeting fibroblasts and myofibroblasts. However, they still have the following significant differences:

[0006] 1. Different intracellular targets: Pirfenidone reduces cell proliferation and the production of fibrosis-related proteins by inhibiting targets such as transforming growth factor β, thereby reducing the aggregation of inflammatory cells caused by stimulation. Nintedanib inhibits the proliferation, migration, and transformation of fibroblasts by inhibiting multiple tyrosine kinases and affecting intracellular signal transduction.

[0007] 2. Differences in adverse reactions and treatment efficacy: The common adverse reaction of pirfenidone is elevated liver enzymes; the common adverse reactions of nintedanib are bronchitis and myocardial infarction. During treatment, nintedanib shedding is more common than pirfenidone, while the discontinuation rate of pirfenidone is lower. In terms of stability, pirfenidone is more stable than nintedanib.

[0008] 3. Although both nintedanib and pirfenidone have been approved for the treatment of lung function decline in IPF, neither has a significant advantage in reducing disease mortality.

[0009] While existing drugs offer some improvement for IPF, they are still insufficient to meet clinical needs. Therefore, it is essential to find more effective drugs to treat IPF. Summary of the Invention

[0010] In view of the above-mentioned defects in the existing technology, the purpose of this invention is to provide a pirfenidone derivative that can meet clinical needs and has a better therapeutic effect on IPF.

[0011] The pirfenidone derivatives provided by this invention are compounds of formula (I) or their pharmaceutically acceptable salts, esters, solvates, or prodrugs:

[0012]

[0013] In the formula (I), R1, R2, R3, and R4 may be the same or different, and are independently selected from any of the following groups: -CH3, -CH2OH, -CH2NH2, -CF3, -CH2NR5R6;

[0014] R5 and R6 may be the same or different, and are independently selected from any of the following groups: -CH3, -C2H5.

[0015] Furthermore, the pharmaceutically acceptable salt of the compound represented by formula (I) may be any of the following salts: hydrochloride, nitrate, methanesulfonate, phosphate, citrate, fumarate, sulfate, succinate, tartrate, citrate, hydrobromide, hydroiodide, acetate, lactate, benzylsulfonate, cinnamate, salicylate, malonate, glutarate, malate.

[0016] Specifically, the compound represented by formula (I) can be a compound represented by formula (II) below:

[0017]

[0018] Furthermore, the pharmaceutically acceptable salt of the compound represented by formula (II) has the structural formula shown in formula (III):

[0019]

[0020] X is selected from the anions produced when any of the following acids ionize: 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, benzylsulfonic acid, cinnamic acid, salicylic acid, malonic acid, glutaric acid, and malic acid.

[0021] The pharmaceutically acceptable salt of the compound represented by formula (I) in this invention refers to a salt that, within the scope of reliable medical judgment, is suitable for contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable effect / risk ratio.

[0022] Furthermore, prodrugs based on compounds of Formula I are also within the scope of this invention. These prodrugs are metabolized in vivo to form compounds of Formula I, thereby exerting their therapeutic effect.

[0023] The present invention also provides a method for preparing the compound shown in formula (II) above.

[0024] The preparation method includes the following steps:

[0025] 5-methylpyridin-2(1H)-one, 2-chloro-3,5,6-trimethylpyrazine, cuprous iodide, and anhydrous potassium carbonate were mixed in N,N-dimethylformamide and subjected to reflux to obtain the compound shown in formula (II).

[0026] In the above method, the CAS number of the 5-methylpyridin-2(1H)-one is 1003-68-5, and its structural formula is shown below:

[0027]

[0028] In the above method, the CAS number of the 2-chloro-3,5,6-trimethylpyrazine is 68303-35-5, and its structural formula is shown below:

[0029]

[0030] In the above method, the molar ratio of 5-methylpyridin-2(1H)-one, 2-chloro-3,5,6-trimethylpyrazine, cuprous iodide, and anhydrous potassium carbonate is 1:1:(0.1-0.5):(2-3).

[0031] In the above method, the reflux reaction conditions are: reflux reaction at 160℃ for 5 hours.

[0032] The above method also includes the following steps: after the reflux reaction is completed, the reaction solution is concentrated, the residue is dissolved in dichloromethane, washed with water, and purified by column chromatography to obtain a white solid 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one.

[0033]

[0034] The present invention also provides the use of the compound of formula (I) above, or its pharmaceutically acceptable salt, ester, or solvate, in the preparation of medicaments for the prevention and / or treatment of pulmonary fibrosis.

[0035] The present invention also provides a medicament or pharmaceutical composition for the prevention and / or treatment of fibrosis, comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt, ester, solvate thereof, and a pharmaceutically acceptable carrier.

[0036] The drug can be introduced into the body, such as into muscles, intradermal tissues, subcutaneous tissues, veins, or mucous membranes, through oral administration, injection, spraying, penetration, absorption, or physical or chemical mediated methods; or it can be introduced into the body after being mixed with or encapsulated by other substances.

[0037] Preferably, the dosage form of the drug or pharmaceutical composition is an oral solid dosage form or a liquid dosage form. All of the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] The compound shown in formula (I) has a significant therapeutic effect on bleomycin-induced mouse pulmonary fibrosis model. At the same dose, ZONK2301-1 is more effective than pirfenidone in improving lung function indicators (lung compliance) and reducing the degree of lung tissue lesions. Attached Figure Description

[0040] Figure 1 Here is the synthetic route diagram for the compound shown in formula (II);

[0041] Figure 2 Images of HE staining and Masson staining of lung tissue from mice in the control and model groups. Detailed Implementation

[0042] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0043] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0044] Example 1: 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one (ZONK2301-1)

[0045]

[0046] 1) 2,3,5-Trimethylpyrazine 1-oxide

[0047]

[0048] 2,3,5-Trimethylpyrazine (20.0 g, 0.164 mol) was dissolved in acetic acid (100 mL), heated in an oil bath to 80 °C, and sodium perborate tetrahydrate (38.0 g, 0.247 mol) was added in portions. The mixture was stirred at a constant temperature for 20 h. The insoluble matter in the reaction solution was removed by filtration, and the solution was concentrated and purified by column chromatography to obtain a yellow transparent liquid, 2,3,5-trimethylpyrazine 1-oxide (18.3 g, 80.9%). 1 HNMR(DMSO-d6 400MHz)δ9.24(s,1H),2.45(s,3H),2.34(s,6H).ESI-MS m / z:139.1[M+H] + .

[0049] 2) 2-Chloro-3,5,6-Trimethylpyrazine

[0050]

[0051] Phosphorus oxychloride (90 mL) and a catalytic amount of concentrated sulfuric acid were added to a three-necked round-bottom flask. The flask was cooled to 10°C in an ice-water bath, and 18.0 g (0.130 mol) of 2,3,5-trimethylpyrazine 1-oxide was added dropwise. After the addition was complete, the mixture was slowly heated to 100°C and stirred at this temperature for 20 h. The reaction solution was distilled under reduced pressure, and the residue was poured into a saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane, concentrated, and purified by column chromatography to obtain a white solid 2-chloro-3,5,6-trimethylpyrazine (7.5 g, 37.0%). 1 HNMR(DMSO-d6 400MHz)δ2.56(s,3H),2.47(s,6H).ESI-MS m / z:157.6[M+H] + .

[0052] 3) 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one

[0053]

[0054] 5-Methylpyridin-2(1H)-one (4.87 g, 44.7 mmol), 2-chloro-3,5,6-trimethylpyrazine (7.0 g, 44.7 mmol), cuprous iodide (0.85 g, 4.47 mmol), and anhydrous potassium carbonate (12.3 g, 89.4 mmol) were mixed in N,N-dimethylformamide (100 mL) and refluxed at 160 °C for 5 h. The reaction solution was concentrated, and the residue was dissolved in dichloromethane, washed with water, and purified by column chromatography to obtain a white solid 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one (3.5 g, 34.2%). 1 HNMR(DMSO-d6 400MHz)δ7.96(s,1H),7.71(d,1H),7.03(d,1H),2.43(s,3H),2.32(d,3H),2.31(d,3H),2.25(d,3H).ESI-MS m / z:230.1[M+H]+.

[0055] Comparative Example 1: 5-Methyl-1-(pyrazin-2-yl)pyridin-2(1H)-one (ZONK2301-2)

[0056]

[0057] 5-Methylpyridin-2(1H)-one (2.86 g, 26.2 mmol), 2-chloropyrazine (3.0 g, 26.2 mmol), cuprous iodide (0.50 g, 2.62 mmol), and anhydrous potassium carbonate (7.23 g, 52.4 mmol) were mixed in N,N-dimethylformamide (50 mL) and refluxed at 160 °C for 5 h. The reaction solution was concentrated, and the residue was dissolved in dichloromethane, washed with water, and purified by column chromatography to obtain a white solid 5-methyl-1-(pyrazin-2-yl)pyridin-2(1H)-one (1.98 g, 40.5%). 1 HNMR (DMSO-d6 400MHz) δ8.40-8.35(m,3H),7.05-6.55(m,3H),2.21(s,3H).ESI-MS m / z:188.1[M+H]+.

[0058] Example 2: Preparation of 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one hydrochloride

[0059]

[0060] 0.1 g (0.44 mmol) of 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one was dissolved in 10 mL of ethyl acetate. A solution of 3 mmol / L hydrogen chloride in ethyl acetate was added at room temperature, precipitating a solid. The solid was filtered and dried to give 0.1 g (86.3%) of white solid 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one hydrochloride. ¹H NMR (DMSO-d₆ 400 MHz) δ 8.01 (s, 1H), 7.77 (d, 1H), 7.13 (d, 1H), 2.56 (s, 3H), 2.43 (d, 3H), 2.41 (d, 3H), 2.25 (d, 3H). ESI-MS m / z: 230.1 [M+H]⁺.

[0061] Example 3: 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one nitrate

[0062]

[0063] A white solid, 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one nitrate, was prepared according to the salt synthesis method in Example 2. ¹H NMR (DMSO-d6 400MHz) δ 8.05 (s, 1H), 7.78 (d, 1H), 7.15 (d, 1H), 2.55 (s, 3H), 2.43 (d, 3H), 2.40 (d, 3H), 2.26 (d, 3H). ESI-MS m / z: 230.1 [M+H]+.

[0064] Example 4: 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one methanesulfonate

[0065]

[0066] A white solid, 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one methanesulfonate, was prepared according to the salt synthesis method in Example 2. ¹H NMR (DMSO-d6 400MHz) δ 8.15 (s, 1H), 7.87 (d, 1H), 7.22 (d, 1H), 3.29 (s, 3H), 2.48 (s, 3H), 2.42 (d, 3H), 2.40 (d, 3H), 2.24 (d, 3H). ESI-MS m / z: 230.1 [M+H]+

[0067] Example 5: 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-ketophosphate

[0068]

[0069] A white solid, 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-ketophosphate, was prepared according to the salt synthesis method in Example 2. ¹H NMR (DMSO-d6 400MHz) δ 7.99 (s, 1H), 7.65 (d, 1H), 7.11 (d, 1H), 2.55 (s, 3H), 2.44 (d, 3H), 2.42 (d, 3H), 2.25 (d, 3H). ESI-MS m / z: 230.1 [M+H]+.

[0070] Example 6: 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one citrate

[0071]

[0072] A white solid, 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one citrate, was prepared according to the salt synthesis method in Example 2. ¹H NMR (DMSO-d6 400MHz) δ 7.97 (s, 1H), 7.56 (d, 1H), 7.13 (d, 1H), 3.38 (s, 1H), 2.76–2.63 (m, 4H), 2.56 (s, 3H), 2.42 (d, 3H), 2.40 (d, 3H), 2.22 (d, 3H). ESI-MS m / z: 230.1 [M+H]+.

[0073] Example 7, 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one fumarate

[0074]

[0075] A white solid, 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one fumarate, was prepared according to the salt synthesis method in Example 2. ¹H NMR (DMSO-d6 400MHz) δ 7.97 (s, 1H), 7.65 (d, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.23 (d, 1H), 2.54 (s, 3H), 2.42 (d, 3H), 2.40 (d, 3H), 2.25 (d, 3H). ESI-MS m / z: 230.1 [M+H]+.

[0076] Example 8: 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one sulfate

[0077]

[0078] A white solid, 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one sulfate, was prepared according to the salt synthesis method in Example 2. ¹H NMR (DMSO-d6 400MHz) δ 8.11 (s, 1H), 7.85 (d, 1H), 7.23 (d, 1H), 2.55 (s, 3H), 2.45 (d, 3H), 2.41 (d, 3H), 2.18 (d, 3H). ESI-MS m / z: 230.1 [M+H]+.

[0079] Example 9: 5-Methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one succinate

[0080]

[0081] A white solid, 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridin-2(1H)-one succinate, was prepared according to the salt synthesis method in Example 2. ¹H NMR (DMSO-d6 400MHz) δ 11.0 (s, 1H), 8.03 (s, 1H), 7.65 (d, 1H), 7.13 (d, 1H), 2.77–2.66 (m, 4H), 2.54 (s, 3H), 2.45 (d, 3H), 2.41 (d, 3H), 2.11 (d, 3H). ESI-MS m / z: 230.1 [M+H]+.

[0082] Example 10: Effects of pirfenidone derivatives on a bleomycin-induced mouse model of pulmonary fibrosis

[0083] 1. Test Methods

[0084] Ninety-six qualified SPF-grade BALB / c mice (half male and half female, weighing 18–22 g) were randomly divided into two groups according to body weight: a normal control group (n=12) and a model group (n=84). The model group mice were injected intravenously with 150 mg / kg bleomycin (20 mL / kg) to establish a mouse pulmonary fibrosis model. The normal control group mice were injected intravenously with an equal volume of physiological saline. Observations were conducted for 14 consecutive days. Before administration, two mice from each group were randomly selected for lung tissue pathological examination. The results showed mild inflammatory cell infiltration and mild collagen fibers in the alveoli. Sixty model mice were randomly divided into six groups according to sex and weight: model control group, pirfenidone group (250 mg / kg, molar dose 1.35 mmol / kg), ZONK2301-1 low-dose group (154.5 mg / kg, molar dose 0.675 mmol / kg), ZONK2301-1 high-dose group (309 mg / kg, molar dose 1.35 mmol / kg), ZONK2301-2 low-dose group (126 mg / kg, molar dose 0.675 mmol / kg), and ZONK2301-2 high-dose group (252 mg / kg, molar dose 1.35 mmol / kg), with 10 animals in each group. Before administration, the test substance (ZONK2301-1 or ZONK2301-2) or the reference substance (pirfenidone) was prepared into appropriate concentrations using pure water. Mice in each group were administered the corresponding drug orally at a dose of 20 mL / kg once daily for 14 consecutive days. The normal control group and the model control group were administered an equal volume of pure water orally. The day after the last administration, each group of animals was anesthetized by intraperitoneal injection of 20 mL / kg of Sutent 50, exposing the trachea, and lung function indicators of each group of animals were measured using a pulmonary function testing system.

[0085] 2. Test Results

[0086] 2.1 Model Validation

[0087] like Figure 2 As shown, no abnormal changes such as inflammatory cell infiltration and collagen fibers were observed in the lung tissue of mice in the normal control group; mild inflammatory cell infiltration and mild collagen fibers were observed in the alveoli of mice in the model group, indicating that the pulmonary fibrosis model was successfully constructed.

[0088] 2.2 Effects on lung function

[0089] As shown in Table 1, compared with the normal control group, the model control group rats showed the following differences in lung compliance (Cpyn), peak inspiratory flow rate (PIF), peak expiratory flow rate (PEF), tidal volume (Vt), forced vital capacity (FVC), and forced expiratory volume in 0.1 s (FEV1). 100All three parameters (P≤0.05 or P≤0.01) were significantly reduced, while Penh (airway resistance) was significantly increased (P≤0.01). Compared with the model control group, the pirfenidone group rats showed significantly reduced PIF, FVC, and FEV. 100 All significantly increased (P≤0.05 or P≤0.01), while Penh significantly decreased (P≤0.01). Compared with the pirfenidone group, the ZONK2301-1 low-dose group and the ZONK2301-1 high-dose group showed significantly better efficacy in improving lung function than the ZONK2301-2 low-dose and high-dose groups and the pirfenidone group.

[0090] Table 1. Effects of ZONK2301 on lung function in model mice.

[0091]

Claims

1. The compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salts of the compounds represented by formula (II) are any of the following: hydrochloride, nitrate, methanesulfonate, phosphate, citrate, fumarate, sulfate, succinate, tartrate, citrate, hydrobromide, hydroiodide, acetate, lactate, benzylsulfonate, cinnamate, salicylate, malonate, glutarate, and malate.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt of the compound represented by formula (II) has the structural formula shown in formula (III): X is selected from the anions produced when any of the following acids ionize: 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, benzylsulfonic acid, cinnamic acid, salicylic acid, malonic acid, glutaric acid, and malic acid.

4. A method for preparing the compound of formula (II) according to claim 1, comprising the following steps: 5-methylpyridin-2(1H)-one, 2-chloro-3,5,6-trimethylpyrazine, cuprous iodide, and anhydrous potassium carbonate were mixed in N,N-dimethylformamide and subjected to reflux to obtain the compound shown in formula (II).

5. The preparation method according to claim 4, characterized in that: The molar ratio of 5-methylpyridin-2(1H)-one, 2-chloro-3,5,6-trimethylpyrazine, cuprous iodide, and anhydrous potassium carbonate is 1:1:(0.1-0.5):(2-3). Alternatively, the reflux reaction conditions are: reflux reaction at 160°C for 5 h.

6. The preparation method according to claim 4 or 5, characterized in that: The method further includes the following steps: after the reflux reaction is completed, the reaction solution is concentrated, the residue is dissolved in dichloromethane, washed with water, and purified by column chromatography to obtain a white solid 5-methyl-1-(3,5,6-trimethylpyrazin-2-yl)pyridine-2(1H)-one.

7. The use of the compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or treatment of pulmonary fibrosis.

8. A pharmaceutical composition for the prevention and / or treatment of pulmonary fibrosis, comprising the compound of formula (II) of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, characterized in that: The dosage form of the pharmaceutical composition is an oral solid dosage form or a liquid dosage form.

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