3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds, preparation method thereof and application thereof

A ketone compound, Schiff base technology, applied in the field of medicinal chemistry

Active Publication Date: 2011-12-28
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the development of small-molecule protein kinase inhibitors is still in its infancy, and people are eager to obtain new drugs with high affinity for target kinases and good therapeutic effects on diseases related to abnormal cell proliferation and angiogenesis

Method used

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  • 3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds, preparation method thereof and application thereof
  • 3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds, preparation method thereof and application thereof
  • 3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds, preparation method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128]

[0129] 1A(E)-N-Phenyl-3-ethoxyacrylamide

[0130] Under cooling in an ice bath, dissolve aniline (9.3g, 0.1mol) and pyridine (16.2mL, 0.15mol) in anhydrous THF (150mL), and slowly add 3-ethoxyacryloyl chloride dropwise at a temperature of 0-5°C (15.0g, 0.11mol), after the dropwise addition, the temperature was naturally raised to room temperature, and the reaction was continued for 2h. Add 1N dilute hydrochloric acid (25mL) under ice-cooling, then add water (50mL) to dilute, concentrate under reduced pressure to a viscous oil, add toluene (70mL), stir at 50°C for 5min, cool to 0°C, and continue stirring for 1h. Filter, wash with water, and dry to obtain 15.3 g of solid, with a yield of 80.1%. MSI-MS: 192.1[M+H] + ; 1 H NMR (300Hz, CDCl 3 ) 1.29 (t, 3H, J=7.5Hz, CH 3 CH 2 ), 3.94(q, 2H, J=7.5Hz, CH 3 CH 2 ), 5.53(d, 1H, J=12.3Hz, =CH-CO), 7.30-7.33(m, 1H, Ar-H), 7.50-7.53(m, 2H, Ar-H), 7.55(d, 1H , J=12.3Hz,=CH-O), 7.63-7.66 (m, 2H, Ar-H), 9.67 (s, 1H, CONH...

Embodiment 2

[0136]

[0137] 2A(E)-N-(2-methyl-6-chlorophenyl)-3-ethoxyacrylamide

[0138] Referring to the synthetic method of 1A, the yield is 68.5%. MSI-MS: 240.1[M+H] + ; 1 H NMR (300Hz, CDCl 3 )

[0139] 1.28(t, 3H, J=7.5Hz, CH 3 CH 2 ), 2.16(s, 3H, Ph-CH 3 ), 3.94(q, 2H, J=7.5Hz, CH 3 CH 2 ), 5.59 (d, 1H, J=12.6Hz, =CH-CO), 7.08-7.24 (m, 2H, Ar-H), 7.32 (m, 1H, Ar-H), 7.49 (d, 1H, J =12.6Hz, =CH-O).

[0140] 2B 2-Amino-N-(2-methyl-6-chlorophenyl)thiazole-5-amide

[0141] Referring to 1B synthesis method, the yield is 86.7%. MSI-MS: 268.1[M+H] + ; 1 H NMR (300Hz, DMSO-d6)

[0142] 2.19(s, 3H, CH 3 ), 7.08-7.26(m, 2H, Ar-H), 7.30-7.43(m, 1H, Ar-H), 7.61(s, 2H, NH 2 ), 7.86 (s, 1H, thiozole-H), 9.69 (s, 1H, CONH).

[0143] I-2 2-(5-fluoroindol-2-one-3-methylene)amino-N-(2-methyl-6-chlorophenyl)thiazole-5-amide

[0144] Referring to the synthesis method of I-1, the yield is 21.0%. MSI-MS: 415.1[M+H] + ; 1 H NMR (300Hz, DMSO-d6)

[0145] 2.20(s, 3H, CH 3 ), 7.24-...

Embodiment 3

[0147]

[0148] 3A(E)-N-(4-fluorophenyl)-3-ethoxyacrylamide

[0149] Referring to the synthetic method of 1A, the yield is 70.3%. MSI-MS: 210.2[M+H] + ; 1 H NMR (300Hz, CDCl 3 )

[0150] 1.27(t, 3H, J=7.1Hz, CH 3 CH 2 ), 3.95 (q, 2H, J=7.1Hz, CH 3 CH 2), 5.50 (d, 1H, J=12.0Hz, =CH-CO), 7.07-7.16 (m, 2H, Ar-H), 7.48 (d, 1H, J=12.0Hz, =CH-O), 7.59 -7.66 (m, 2H, Ar-H), 9.74 (s, 1H, CONH).

[0151] 3B 2-Amino-N-(4-fluorophenyl)thiazole-5-amide

[0152] Referring to 1B synthesis method, the yield is 88.6%. MSI-MS: 238.1[M+H] + ; 1 H NMR (300Hz, DMSO-d6)

[0153] 7.10-7.19(m, 2H, Ar-H), 7.60(s, 2H, NH 2 ), 7.63-7.67 (m, 2H, Ar-H), 7.86 (s, 1H, thiozole-H), 10.11 (s, 1H, CONH).

[0154] I-3 2-(5-fluoroindol-2-one-3-methylidene)amino-N-(4-fluorophenyl)thiazole-5-amide

[0155] Referring to the synthesis method of I-1, the yield is 35.6%. MSI-MS: 385.1[M+H] + ; 1 H NMR (300Hz, DMSO-d6)

[0156] 7.15-7.19(m, 2H, Ar-H), 7.33-7.36(m, 1H, Ar-H), 7.63-7.71(m, 2H, Ar-H...

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Abstract

The invention discloses 3-heterocycle schiff base-5-fluorine-indole-2-ketone compounds represented by a general formula (I), pharmaceutical salts thereof, or solvent compounds thereof. R1, R2, R3, R4 and R5 are respectively independent unsubstituted C1-4 alkyl, unsubstituted C1-3 alkoxy, halogen, sulfamic, nitro, or hydrogen; or R1, R2, R3, R4 and R5 are respectively independent C1-4 alkyl substituted by 1 to 3 substituents selected from halogen, nitro, C1-3 alkyl, or C1-2 alkoxy; or R1, R2, R3, R4 and R5 are respectively independent C1-3 alkoxy substituted by 1 to 3 substituents selected from halogen, nitro, C1-3 alkyl, or C1-2 alkoxy. The halogen is fluorine, chlorine or bromine. X is S or NH. The invention also discloses a preparation method of the compounds, and an application of the compounds. The compounds provided by the invention assist in regulating the conduction of tyrosine kinase signals, and in inhibiting cacoethic cellular proliferation and blood vessel growth. The compounds provided by the invention provide substantial curative effects against diseases such as tumors, diabetes mellitus, dermatitis, and rheumatic arthritis.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a 3-heterocyclic Schiff base-5-fluoro-indol-2-one compound capable of inhibiting the activity of certain protein kinases, a preparation method and application thereof. Background technique [0002] Protein kinases are a class of enzymes that catalyze the phosphorylation of hydroxyl groups on specific tyrosine, valine, or threonine residues in proteins. This phosphorylation interferes with protein function and, as a result, protein kinases play key roles in the regulation of various cellular processes including metabolism, cell proliferation, cell differentiation, and cell survival, as well as blood vessel growth. These processes are associated with the development of tumors, diabetes, psoriasis, rheumatoid arthritis, etc., and are especially necessary for the growth of solid tumors. [0003] Since the 21st century, scientists have successively discovered m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D403/12A61K31/427A61K31/4178A61P35/00A61P3/10A61P17/00A61P19/02
Inventor 方正邹宝华杨照韦萍
Owner NANJING UNIV OF TECH
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