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Aromatic ring or aromatic heterocyclic imidazole compound, its preparation method and pharmaceutical use

A compound and pharmaceutical technology, applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve problems such as changes in the hematopoietic system, instability of natural ligand molecules, cyclic dinucleosides, and poor druggability

Active Publication Date: 2022-07-22
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] STING protein has obvious species selectivity, and the natural ligand molecules of human STING protein, cyclic dinucleosides (CDNs), are unstable, easily degraded by various nucleases and phosphodiesterases, and have poor druggability; moreover, activating interferon The synthetic pathway also brings a series of side effects, such as skin allergic reaction, flu-like syndrome, changes in the hematopoietic system, etc.

Method used

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  • Aromatic ring or aromatic heterocyclic imidazole compound, its preparation method and pharmaceutical use
  • Aromatic ring or aromatic heterocyclic imidazole compound, its preparation method and pharmaceutical use
  • Aromatic ring or aromatic heterocyclic imidazole compound, its preparation method and pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] N-(5-carbamoyl-7-methoxy-1-propyl-1H-benzo[d]imidazol-2-yl)quinoline-2-amide

[0047]

[0048] (1) Preparation of 4-chloro-3-methoxy-5-nitrobenzamide

[0049]

[0050] Methyl 3-methoxy-4-propylamino-5-nitrobenzenecarboxylate (1 g, 4.1 mmol), 50 ml of ammonia water (28%, 50 ml) were added to the bottle in turn, and heated to 50 ° C under argon protection for the reaction 5h. The reaction was cooled to room temperature, filtered under reduced pressure after a large amount of light yellow solid was precipitated, and the filter cake was washed with ether and dried to obtain 0.715 g of light yellow solid, yield 75.6%, melting point 215-217°C.

[0051] 1 H NMR (400MHz, DMSO-d 6 )δ8.29(s,1H),8.05(d,J=1.64Hz,1H),7.88(d,J=1.56Hz,1H),7.78(s,1H),4.02(s,3H).

[0052] MS(ESI) m / z 231.0(M+H) + .

[0053] (2) Preparation of 3-methoxy-5-nitro-4-propylaminobenzamide

[0054]

[0055] 4-Chloro-3-methoxy-5-nitrobenzamide (1 g, 4 mmol), propylamine (0.715 ml, 8.7 mmol), pot...

Embodiment 2

[0072] N-(5-carbamoyl-7-methoxy-1-propyl-1H-benzo[d]imidazol-2-yl)isoquinoline-1-amide

[0073]

[0074] (1) Preparation of the title compound

[0075] 2-Amino-7-methoxy-1-propyl-1H-benzo[d]imidazole-5-amide (0.2 g, 0.81 mmol), isoquinoline-1-carboxylic acid (0.168 g, 0.97 mmol) ), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.368g, 0.97mmol), N,N-diisopropylethyl acetate The amine (0.54ml, 3.25mmol) was dissolved in 10ml N,N-dimethylformamide, and the reaction was stirred at room temperature for 5h. After the reaction, 30 ml of saturated ammonium chloride solution was added, and a large amount of light orange solid was precipitated, which was filtered under reduced pressure, and the filter cake was washed with ether and dried to obtain 0.149 g of light orange solid, yield 45.5%, melting point 251-252 ° C.

[0076] 1 H NMR (400MHz, DMSO-d 6 )δ8.57–8.51(m,1H),8.37(d,J=5.7Hz,1H),7.89(d,J=8.2Hz,1H),7.74(d,J=1.2Hz,1H),7.70– 7.66(m, 2H), 7.54(t,...

Embodiment 3

[0079] 7-Methoxy-2-(2-pyridylamido)-1-propyl-1H-benzo[d]imidazole-5-amide

[0080]

[0081] (1) Preparation of the title compound

[0082]2-Amino-7-methoxy-1-propyl-1H-benzo[d]imidazole-5-amide (0.2 g, 0.81 mmol), pyridine-2-carboxylic acid (0.120 g, 0.97 mmol), 2-(7-Benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.368g, 0.97mmol), N,N-diisopropylethylamine ( 0.54ml, 3.25mmol) was dissolved in 10ml N,N-dimethylformamide, and the reaction was stirred at room temperature for 8h. After the reaction, 30 ml of saturated ammonium chloride solution was added, and a large amount of white solid was precipitated, which was filtered under reduced pressure, the filter cake was washed with ether, and dried to obtain 183 mg of white solid, yield 64.1%, melting point>300°C.

[0083] 1 H NMR (400MHz, DMSO-d 6 )δ8.65(d,J=4.0Hz,1H),8.40(d,J=7.8Hz,1H),7.88(t,J=7.8Hz,1H),7.83(s,2H),7.50–7.37( m, 1H), 7.19(s, 1H), 7.13(s, 1H), 4.36(t, J=6.7Hz, 2H), 3.94(s, 3H), 1.80–1....

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Abstract

The present invention relates to a class of compounds containing an aromatic ring or an aromatic heterocyclic imidazole structure or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and the medicinal use of the compound. The compound of the present invention has the effect of specifically stimulating the STING protein, and can be used to prepare a medicine for treating diseases related to the function of the STING protein, such as malignant tumor and virus infection.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to a class of compounds containing an aromatic ring or an aromatic heterocyclic imidazole structure or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing such compounds, and the preparation of such compounds in the treatment of Drug application in diseases related to STING protein function. Background technique [0002] The innate immune system plays an important role in recognizing pathogens and eliciting acquired immune protection. Various pattern recognition receptors (PRRs) are used to recognize pathogen-associated molecular patterns (PAMPs) to defend against foreign invaders. The invasion of pathogenic microorganisms constitutes the body's first line of defense against pathogens, which includes a series of cellular functions and related mechanisms. [0003] Stimulator of interferon genes (STING) is a transmembrane p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D403/12C07D235/30C07D471/04A61P35/00A61P31/12A61K31/4709A61K31/4439A61K31/501A61K31/4184A61K31/454A61K31/437A61K31/5377
CPCC07D401/12C07D403/12C07D235/30C07D471/04A61P35/00A61P31/12
Inventor 汪小涧奚秋牡金晶王明晋贾文强扈金萍陈晓光
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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