Multi-substituted amine compounds and their preparation methods and uses

A technology of polysubstituted amines and compounds, applied in the field of medicine, can solve the problem of undetectable integrase and the like

Inactive Publication Date: 2018-04-17
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Normal levels of integrase mRNA but undetectable integrase in p75-deficient cell lines

Method used

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  • Multi-substituted amine compounds and their preparation methods and uses
  • Multi-substituted amine compounds and their preparation methods and uses
  • Multi-substituted amine compounds and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] Compound 1: tert-butyl 2-((((3-(2-cyanoethyl)pyridin-2-yl)methyl)(methyl)amino)methyl)-1H-benzimidazole-1-carboxylate ester

[0189]

[0190] Step a: 3-(2-Methylpyridin-3-yl)acrylonitrile

[0191] 3-Bromo-2-methylpyridine (1.72g, 10mmol), acrylonitrile (3.29mL, 50mmol), palladium acetate (244mg, 1mmol), tetra-n-butylammonium chloride (2.78g, 10mmol) and bicarbonate Sodium (4.2 g, 50 mmol) was dissolved in 15 mL of N,N-dimethylformamide (DMF). mixture in N 2Under the protection, it was placed in the microwave at 110°C for 5 hours. After cooling, the DMF was spin-dried, the residue was separated with water and dichloromethane (DCM), the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was column chromatographed to obtain the title compound as a white gum (1.33 g, recovered rate of 93%).

[0192] 1 H NMR (300MHz, CDCl 3 ,ppm):δ8.52-8.50(m,1.5H),8.18(d,0.5H,J=7.8Hz),7.72(d,1H,J=7.8Hz),7.63(d,1H,J=16.5 Hz),7.37(d,0...

Embodiment 2

[0217] Compound 2: 3-(2-((((1H-benzimidazol-2-yl)methyl)(methyl)amino)methyl)pyridin-3-yl)propionitrile

[0218]

[0219] Under stirring at 0°C, 3-(2-cyanoethyl)pyridin-2-yl)methyl)(methyl)amino)methyl)-1H-benzimidazole-1-carboxylic acid tert-butyl ester ( 42 mg, 0.104 mmol) in 5 mL of dichloromethane was added trifluoroacetic acid (119 μL, 1.55 mmol), and the mixture was stirred at room temperature for 2 h. The solvent and residual trifluoroacetic acid were spin-dried, and the residue was neutralized with saturated sodium carbonate solution. After the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was obtained by column chromatography. The compound was light yellow gum (28 mg, yield 90%).

[0220] 1 H NMR (300MHz, CDCl 3 )δ10.15(brs,1H),8.57(d,1H,J=4.5Hz),7.65-7.62(m,3H),7.32-7.23(m,3H),3.88(s,2H),3.80(s ,2H),3.06(t,2H,J=6.9Hz),2.77(t,2H,J=6....

Embodiment 3

[0222] Compound 3: 3-(2-(((isoquinolin-1-ylmethyl)(methyl)amino)methyl)pyridin-3-yl)propionitrile

[0223]

[0224]Under stirring, 1,2 - Acetic acid (10.6 μL, 0.183 mmol) and sodium triacetoxyborohydride (116 mg, 0.549 mmol) were successively added to 2 mL of dichloroethane solution, and the mixture was stirred at room temperature for 24 h. The solvent was evaporated to dryness, and the residue was subjected to column chromatography to obtain the title compound as a yellow oil (36 mg, yield 63%).

[0225] 1 H NMR (300MHz, CDCl 3 )δ8.94-8.91(m,2H),8.52(d,1H,J=8.1Hz),8.28(d,1H,J=7.8Hz),8.15-7.95(m,4H),7.67-7.63(m ,1H),4.72(s,2H),4.36(s,2H),3.19-3.17(m,2H),2.82-2.80(m,5H); 13 C NMR (100MHz, CDCl 3 , ppm): δ157.2, 156.0, 147.4, 141.4, 137.5, 136.2, 133.4, 130.1, 127.2, 125.4, 122.9, 120.7, 118.9, 62.1, 61.8, 43.1, 27.2, 18.0; EI-MS: 316 (M + );HRMS(EI): Calculated value: C 20 h 20 N 4 (M) + :316.1688; Measured value: 316.1685.

[0226] Wherein the preparation process...

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Abstract

The invention belongs to the technical field of medicines and specifically provides a multi-substituted amine compound as shown in a general formula I or an isomer thereof or a pharmaceutically acceptable salt, ester, pro-medicament or hydrate thereof or a pharmaceutical composition, as well as a preparation method and use thereof in preparation of medicaments for treating acquired immune deficiency syndrome. The compound or the pharmaceutical composition containing the compound can be used as an inhibitor for inhibiting the protein-protein interaction between HIV (human immunodeficiency virus) integrase and LEDGF / p75 and the dimerization of the HIV integrase, and further can be used for treating the acquired immune deficiency syndrome.

Description

technical field [0001] The invention belongs to the field of medical technology, in particular, the invention relates to multi-substituted amine compounds or their isomers or pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, their pharmaceutical compositions, and their preparation methods and its use in the preparation of drugs for the treatment of AIDS. The compound or the pharmaceutical composition comprising the compound can be used as an inhibitor to inhibit the protein-protein interaction between HIV integrase and LEDGF / p75 and the dimerization of HIV integrase, and then can be used for treating AIDS. Background technique [0002] Lens epithelium-derived growth factor (LEDGF) belongs to the liver cancer-derived growth factor (HDGF)-related protein (HRP) family, and it can be added to lens epithelial cells, fibroblasts, keratinocytes, etc. In the culture medium of cells, it can promote cell growth and prolong cell lifespan (Poeschla E M. Integrase...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D417/12C07D213/57C07D413/12C07D471/04C07D235/14A61K31/4439A61K31/4725A61K31/4709A61K31/444A61K31/4184A61K31/496A61K31/5377A61K31/437A61P31/18
CPCC07D213/57C07D235/14C07D401/12C07D413/12C07D417/12C07D471/04
Inventor 龙亚秋曹斌
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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