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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: 2016-10-26
杨若一
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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

[0043] Example 1. Synthesis of compound 5e of the present invention

[0044] synthetic route:

[0045]

[0046] 1. Synthesis of compound 3 (5-methyl-2-(1H)-pyridone)

[0047] Add 3.40mL of 50% sulfuric acid (v / v) to the 25mL reaction flask, then add 1.00g (10mmol) of 2-amino-5-methylpyridine (compound 1), cool to below 10℃ in an ice salt bath, and stir for a while Minutes later, the reaction solution turned milky white; then slowly drop 1.72g (25mmol) NaNO 2 With 3mL H 2 The mixed solution composed of O, brownish-yellow gas with pungent odor is generated during the dropping process. After the addition, the reaction liquid turns to light yellow. Adjust the pH to 7-8 with 10% dilute sulfuric acid, reflux and stir the reaction for about 20 minutes. Remove most of the water, add an appropriate amount of 300 mesh silica gel to it, spin dry, pour it into a glass sand core funnel, rinse with ethyl acetate and filter with suction, spin the filtrate to dryness to obtain the crude product (co...

Embodiment 2

[0056] Example 2. Synthesis of compound 7a of the present invention

[0057] synthetic route:

[0058]

[0059] Using compound 1'(2-aminopyridine) as a raw material, according to a method similar to Example 1, compound 7a was prepared, and the single-step yield of the third step was 64%.

[0060] Compound 7a: 1-(4-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2-yl)phenyl)pyridine-2(1H)-one, yellow Solid, mp254-256℃;

[0061] 1 H NMR(400MHz,DMSO)δ8.07(d,J=8.6Hz,2H),7.83-7.69(m,3H),7.59-7.52(m,1H),6.51(d,J=9.3Hz,1H) ,6.38(td,J=6.7,1.1Hz,1H),3.50–3.37(m,1H),3.08(dd,J=14.5,7.2Hz,1H), 2.57(dd,J=11.1,6.1Hz,4H ),1.75(s,1H),1.44(dd,J=16.8,11.7Hz,4H);

[0062] 13 C NMR (101MHz, DMSO) δ163.61,160.91,145.35,141.14,138.39,129.26,127.76,122.32,120.64,106.21,56.01,53.84,31.94,25.33,23.97,18.45;

[0063] HRMS(ESI)calcd for C 18 H 19 N 3 O[M+H] + 294.1607, found 294.1604.

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Abstract

The invention relates to a pirfenidone derivative and a preparation method thereof, and discloses a compound represented by a formula I or a pharmaceutically acceptable salt, crystal form, hydrate or solvate of the compound, wherein R1, R2, R3, R4 and R5 are respectively or simultaneously selected from H, halogen, hydroxyl, nitryl, carbonyl or C1-C8 alkyl. Compared with pirfenidone, the novel compound disclosed by the invention has a different ring structure; furthermore, the fibrosis resistant activity of the novel compound is obviously higher than that of pirfenidone; particularly, the suppression rate of the novel compound to fibroblast proliferation is 95 percent or above, which is increased by 10 times or more when compared with the suppression rate (8.15 percent) of pirfenidone; meanwhile, the suppression effect of the novel compound to fibroblast secretory fiber connection proteins is obviously better than that of pirfenidone, so that the novel compound has a good industrialization prospect. The formula I is shown in the description.

Description

Technical field [0001] The invention relates to a pirfenidone derivative and a preparation method thereof. Background technique [0002] Fibrosis refers to a pathological process in which parenchymal cells in the patient's organs are reduced or necrosis caused by various pathogenic factors, and the extracellular matrix in the tissue increases and diffuse excessive deposition. Continued progress can lead to the destruction of organ structure and functional decline, until failure. Fibrosis can occur in a variety of organs. The most common clinical fibrosis mainly include: (1) pulmonary fibrosis; (2) liver fibrosis; (3) cardiac fibrosis; (4) renal fibrosis and (5) Pancreatic fibrosis; in addition, fibrosis of the eyes, blood vessels, and nervous system may also occur. [0003] Anti-fibrotic drugs refer to drugs used to treat and / or prevent fibrotic diseases, such as pirfenidone (marketed drug product). However, the compound's inhibition rate of fibroblast proliferation can only reach...

Claims

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Application Information

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IPC IPC(8): C07D401/10A61K31/4439A61P35/00A61P43/00
CPCC07D401/10
Inventor 杨若一胡冰霜黎勇曹婷婷杨子耀
Owner 杨若一
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