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Application of pirfenidone derivative to pharmacy

A drug and pharmacy technology, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of no anti-fibrotic drugs, anti-tumor drugs, poor anti-fibrotic activity, etc., and achieve the effect of good industrialization prospects.

Inactive Publication Date: 2016-10-12
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
[0004] At present, there is no relevant report that the compound represented by formula I of the present invention or its pharmaceutically acceptable salt, crystal form, hydrate or solvate is used for the preparation of anti-fibrosis drugs and / or anti-tumor drugs

Method used

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  • Application of pirfenidone derivative to pharmacy
  • Application of pirfenidone derivative to pharmacy
  • Application of pirfenidone derivative to pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1, the synthesis of compound 5e of the present invention

[0041] synthetic route:

[0042]

[0043] 1. Synthesis of compound 3 (5-methyl-2-(1H)-pyridone)

[0044] 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

[0053] Embodiment 2, the synthesis of compound 7a of the present invention

[0054] synthetic route:

[0055]

[0056] Using compound 1' (2-aminopyridine) as a raw material, compound 7a was prepared according to a method similar to Example 1, and the single-step yield of the third step was 64%.

[0057] Compound 7a: 1-(4-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2-yl)phenyl)pyridin-2(1H)-one, yellow Solid, m.p.254-256°C;

[0058] 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);

[0059] 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;

[0060] HRMS (ESI) calcd for C 18 h 19 N 3 O[M+H] + 294.1607, found 294.1604.

Embodiment 3

[0066] Embodiment 3, the anti-fibrosis activity of the compound of the present invention

[0067] 1. Cell culture

[0068] Inoculate 3T3L1 cells in cell culture medium containing 10% FBS, add 100 IU / mL penicillin and streptomycin, place them in an incubator containing 5% carbon dioxide at 37°C and culture them. After the cells grow confluent, add 0.25% pancreatic Enzyme digestion and passage, the cells of passage 3-10 were used for experiments. Dissolve pirfenidone and the compound of the present invention in DMSO, filter and sterilize through a 0.22 μm filter membrane, store at -20°C, and thaw before use.

[0069] 2. Evaluation of cell proliferation rate / inhibition rate

[0070] 3T3L1 cells were inoculated in 96-well plates with DMEM medium containing 10% FBS, and the concentration was adjusted to 8×10 4 / hole, cultivated in an environment containing 5% carbon dioxide at 37°C for 24h, added three concentrations of the compounds of the present invention, 100, 200, and 400 μ...

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Abstract

The invention provides application of a pirfenidone derivative to pharmacy and discloses application of a compound as shown in a formula (I) (the formula can be seen in specification) or medically acceptable salt, the crystal form, aquo-complex or solvent thereof to preparation of anti-fibrosis drugs and / or antineoplastic drugs; wherein R1, R2, R3, R4 and R5 are separately or simultaneously selected from H, halogen, hydroxyl, nitro, carbonyl or a C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group, a C6 alkyl group, a C7 alkyl group or a C8 alkyl group. The invention provides application of the novel compound as shown in the formula (I) (the formula can be seen in specification) or medically acceptable salt, the crystal form, aquo-complex or solvent thereof to preparation of anti-fibrosis drugs and / or antineoplastic drugs, compared with pirfenidone, the novel compound has different ring structures, anti-fibrosis activity of the novel compound is remarkably better than that of pirfenidone, and the novel compound has good industrialized prospect.

Description

technical field [0001] The invention relates to the application of pirfenidone derivatives in pharmacy. 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 to fibrob...

Claims

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Application Information

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IPC IPC(8): A61K31/4439C07D401/10A61P35/00A61P11/00A61P1/16A61P9/00A61P13/12A61P1/18A61P27/02
CPCA61K31/4439C07D401/10
Inventor 杨若一胡冰霜黎勇曹婷婷杨子耀
Owner 杨若一
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