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Pirfenidone derivative and preparation method thereof

A compound and hydrate technology, applied in the field of pirfenidone derivatives and its preparation, can solve the problems of poor anti-fibrosis activity and achieve good industrialization prospects

Inactive Publication Date: 2016-11-09
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Anti-fibrotic drugs refer to the medicines for the treatment and / or prevention of fibrotic diseases, such as: pirfenidone (pharmaceutical product listed on the market), however, the inhibitory rate of this compound to fibroblast proliferation can only reach 8.15%, anti-fibrotic poor activity

Method used

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  • Pirfenidone derivative and preparation method thereof
  • Pirfenidone derivative and preparation method thereof
  • Pirfenidone derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1, the synthesis of compound 5b of the present invention

[0050] synthetic route:

[0051]

[0052] 1. Synthesis of compound 3 (5-methyl-2-(1H)-pyridone)

[0053] First add 3.40mL of 50% sulfuric acid (v / v) to a 25mL reaction flask, then add 1.00g (10mmol) of 2-amino-5-picoline (compound 1), cool to below 10°C in an ice-salt bath, and stir for several After 10 minutes, the reaction solution turned milky white; then slowly added dropwise 1.72g (25mmol) NaNO 2 with 3mL H 2 The mixed solution composed of O has brown-yellow gas with pungent odor during the dropwise addition process. After the addition, the reaction solution turns light yellow. Use 10% dilute sulfuric acid to adjust the pH to 7-8, reflux and stir for about 20 minutes, and spin Most of the water was removed, an appropriate amount of 300 mesh silica gel was added thereto, spin-dried, poured into a glass sand core funnel, rinsed with ethyl acetate and suction-filtered, and the filtrate was spi...

Embodiment 2

[0062] Embodiment 2, the synthesis of compound 5c of the present invention

[0063] According to the method similar to Example 1, in step 3, ethylenediamine was used as a raw material to prepare compound 5c, and the single-step yield of step 3 was 69%.

[0064]

[0065] Compound 5c: 1-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-5-methylpyridin-2(1H)-one, yellow solid, m.p.252-254°C;

[0066] 1 H NMR (400MHz, DMSO) δ8.01 (d, J = 8.5Hz, 2H), 7.68 (d, J = 8.5Hz, 2H), 7.55–7.31 (m, 2H), 6.45 (d, J = 9.3Hz ,1H),4.02–3.25(m,4H),2.05(s,3H),1.86(dd,J=12.6,9.6Hz,1H);

[0067] 13 C NMR (101MHz, DMSO) δ164.04, 160.29, 144.87, 143.66, 135.37, 129.01, 127.50, 125.22, 123.22, 120.32, 114.84, 69.80, 45.61, 16.42;

[0068] HRMS (ESI) calcd for C 15 h 15 N 3 O[M+H] + 254.1294, found 254.1289.

Embodiment 3

[0069] Embodiment 3, the synthesis of compound 5d of the present invention

[0070] According to the method similar to Example 1, using 1,3-propylenediamine as raw material in step 3, compound 5d was prepared, and the single-step yield of step 3 was 54%.

[0071]

[0072] Compound 5d: 1-(4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl)-5-methylpyridin-2(1H)-one, yellow solid, m.p.265-267℃ ;

[0073] 1 H NMR (400MHz, DMSO) δ7.83 (d, J = 8.5Hz, 2H), 7.68 (d, J = 8.5Hz, 2H), 7.51–7.40 (m, 2H), 6.45 (d, J = 9.3Hz ,1H),3.51(m,6H),2.93(dd,J=14.7,7.4Hz,1H),2.05(d,J=13.5Hz,3H);

[0074] 13 C NMR (101MHz, DMSO) δ160.21, 158.66, 144.51, 143.61, 135.29, 128.51, 127.95, 127.39, 120.27, 114.62, 45.76, 17.60, 16.37, 11.06;

[0075] HRMS (ESI) calcd for C 16 h 17 N 3 O[M+H] + 268.1451, found 268.1449.

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Abstract

The invention discloses a compound shown in the formula I or pharmaceutically acceptable salt or a pharmaceutically acceptable crystal form or pharmaceutically acceptable hydrate or pharmaceutically acceptable solvate thereof. R1, R2, R3, R4 and R5 are selected from H, halogen, hydroxyl, nitryl and carbonyl or C1-C8 alkyl respectively or simultaneously; R6 and R7 are selected from H or C1-C8 alkyl respectively or simultaneously, and R6 and R7 are connected to form a five-membered ring or a six-membered ring containing 3-17 carbon atoms. Compared with pirfenidone, the novel compound has different ring structures, the anti-fibrosis activity of the novel compound is remarkably superior to that of pirfenidone, and especially, the inhibition ratio of the novel compound for fibroblast proliferation is increased by at least 30% compared with pirfenidone; meanwhile, the inhibition effect of the novel compound on fibroblast secretory fibronectin is remarkably superior to that of pirfenidone, and good industrial prospects are achieved. The formula I is shown in the specification.

Description

technical field [0001] The present invention relates to pirfenidone derivatives and a preparation method thereof. Background technique [0002] Fibrosis refers to the pathological process of reduction or necrosis of parenchymal cells in patients' organs, increase of extracellular matrix in tissues and diffuse excessive deposition caused by various pathogenic factors. Continuous progress can lead to destruction of organ structure and functional decline, until failure. Fibrosis can occur in many organs, and the most common clinical fibrosis mainly includes: (1) pulmonary fibrosis; (2) liver fibrosis; (3) cardiac fibrosis; (4) renal fibrosis and (5) Fibrosis of the pancreas; in addition, fibrosis of the eye, blood vessels, and nervous system may also occur. [0003] Anti-fibrotic drugs refer to the medicines for the treatment and / or prevention of fibrotic diseases, such as: pirfenidone (pharmaceutical product listed on the market), however, the inhibitory rate of this compound...

Claims

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Application Information

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IPC IPC(8): C07D401/10A61K31/4439A61K31/506A61P35/00
CPCC07D401/10
Inventor 尹述凡黎勇曹婷婷杨子耀
Owner SICHUAN UNIV
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