Unlock instant, AI-driven research and patent intelligence for your innovation.

1-(3, 4-disubstituted phenyl) piperazine skeleton derivative and application thereof in medicine preparation

A halogenated, pharmaceutical technology, applied in the field of organic synthetic drugs, to achieve the effect of lowering blood sugar levels, excellent inhibitory effect, and regulating sugar metabolism

Pending Publication Date: 2021-12-17
SICHUAN UNIV
View PDF3 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, there are still few reports on SIRT6 inhibitors at present. Therefore, the research of more structurally novel SIRT6 inhibitors is of great significance for the development of drugs for the prevention and treatment of various diseases related to SIRT6 expression.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 1-(3, 4-disubstituted phenyl) piperazine skeleton derivative and application thereof in medicine preparation
  • 1-(3, 4-disubstituted phenyl) piperazine skeleton derivative and application thereof in medicine preparation
  • 1-(3, 4-disubstituted phenyl) piperazine skeleton derivative and application thereof in medicine preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Embodiment 1, the preparation of compound 1-methyl-4-phenylpiperazine (6a)

[0083]

[0084] Weigh compound N-methylpiperazine (3, 20mg, 0.2mmol), iodobenzene (4a, 44mg, 0.22mmol), palladium (II) acetate (ie Pd(OAc) 2 , 2.24mg, 0.01mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (ie Xant-phos, 29mg, 0.05mmol) and cesium carbonate (ie Cs 2 CO 3 , 97.5mg, 0.3mmol) was added to a 25mL double-necked round bottom flask, and then 6mL of anhydrous 1,4-dioxane solution was added. Under the condition of nitrogen protection, stir and heat to 100°C, and react for 12h. The reaction process was monitored by thin-layer chromatography, and the reaction solution was concentrated by a rotary evaporator after the reaction. The concentrated solution was purified by column chromatography to obtain compound 1-methyl-4-phenylpiperazine (6a) with a yield of 21%. 1 H NMR (400MHz, DMSO-d 6 )δ7.20(dd, J=8.6,7.3Hz,2H),6.92(d,J=7.8Hz,2H),6.76(t,J=7.2Hz,1H),3.15-3.07(m,4H), 2.48-2.40(...

Embodiment 2

[0085] Embodiment 2, the preparation of compound N-phenyl-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide (6b)

[0086]

[0087] N-methylpiperazine (3, 20mg, 0.2mmol) intermediate compound N-phenyl-5-fluoro-2-nitrobenzamide (4b, 70mg, 0.2mmol), Pd(OAc) 2 (2.24mg, 0.01mmol), Xant-phos (29mg, 0.05mmol) and Cs 2 CO 3 (97.5mg, 0.3mmol) was weighed into a 25mL double-necked round bottom flask, and 6mL of 1,4-dioxane solvent was added to dissolve it. Under the condition of nitrogen protection, the reaction was heated to 100° C., and the reaction was stirred for 12 h. The reaction process was monitored by thin-layer chromatography, and the reaction solution was concentrated by a rotary evaporator after the reaction. Then, the product was purified by column chromatography. The compound N-phenyl-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide (6b) was obtained with a yield of 31%. 1 H NMR (400MHz, DMSO-d 6 )δ9.35(d,J=8.5Hz,1H),7.99(d,J=9.3Hz,1H),7.41-7.30(m,8H),7.29-7.21(m,2H),7.04(dd...

Embodiment 3

[0088] Embodiment 3, the preparation of compound 5-(4-methylpiperazin-1-yl)-N-(naphthalene-1-yl)-2-nitrobenzamide (6c)

[0089]

[0090] Using the corresponding raw materials I-a and I-b shown in Table 1, according to the same synthesis method as compound 6b, compound 6c was prepared with a yield of 39%. 1 H NMR (400MHz, DMSO-d 6 )δ10.43(s,1H),8.23-8.16(m,1H),8.10(d,J=9.4Hz,1H),8.00-7.91(m,1H),7.83(d,J=7.8Hz,2H ),7.61-7.52(m,3H),7.18(d,J=2.8Hz,1H),7.11(dd,J=9.5,2.9Hz,1H),3.54(t,J=5.1Hz,4H),2.45 (t,J=5.1Hz,4H),2.24(s,3H). 13 C NMR(101MHz,DMSO)δ166.64,154.43,136.92,134.63,134.19,133.80,128.74,128.43,127.36,126.52,126.28,126.18,126.00,123.70,122.77,113.27,112.74,54.68,46.80,46.10.HRMS m / z(ESI)calcd for C 22 h 23 N 4 o 3 [M+H] + 391.1765 found: 391.1772, calcd for C 22 h 22 N4 o 3 Na[M+Na] + 413.1584found: 413.1593.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Equilibrium dissociation constantaaaaaaaaaa
Login to View More

Abstract

The invention relates to a 1-(3, 4-disubstituted phenyl) piperazine skeleton derivative and application thereof in medicine preparation. Specifically provided is a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a stereoisomer thereof, or an optical isomer thereof. The compound has a targeting and excellent inhibition effect on the deacetylation activity of SIRT6, and can increase the levels of H3K9ac and H3K18ac in pancreatic cancer cells, increase the expression level of glucose transporter GLUT-1 in pancreatic cancer cells and regulate glycometabolism; and the compound can also obviously reduce the blood sugar content of a type 2 diabetes mellitus mouse model. The 1-(3, 4-disubstituted phenyl) piperazine skeleton derivative provided by the invention has a good application prospect in preparation of an SIRT6 inhibitor and in preparation of medicines for preventing and / or treating SIRT6-related diseases (including cardiovascular and cerebrovascular diseases, tumors, metabolic diseases (such as diabetes, obesity and fatty liver), chronic obstructive pulmonary diseases, skeleton-related diseases and retinopathy).

Description

technical field [0001] The invention belongs to the field of organic synthetic medicines, and particularly relates to 1-(3,4-disubstituted phenyl)piperazine skeleton derivatives, a preparation method thereof and an application in medicine preparation. Background technique [0002] Epigenetics is a research hotspot in the field of life sciences. Epigenetic regulation of gene expression mainly involves DNA methylation, histone modification, chromatin remodeling and non-coding RNA regulation. Among them, histone acetylation modification was first found to be related to the regulation of gene transcription, and is closely related to the occurrence of many diseases. Enzymes involved in deacetylation, in addition to the classic class I and class II histone deacetylase (Histone deacetylase, HDAC), there is also class III HDAC, namely Sir2 (Silent information regulator 2, silent information regulatory protein 2) related Enzymes (Sir2-relateddenzymes, Sirtuins). Class III histone ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D295/033C07D295/155C07D295/135C07D295/073C07D295/096C07D215/50A61K31/5377A61K31/495A61K31/496A61P9/00A61P35/00A61P3/00A61P3/04A61P3/10A61P3/06A61P1/16A61P11/00A61P9/10A61P19/00
CPCC07D295/033C07D295/155C07D295/135C07D295/073C07D295/096C07D215/50A61P9/00A61P35/00A61P3/00A61P3/04A61P3/10A61P3/06A61P1/16A61P11/00A61P9/10A61P19/00
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV