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NAMPT/HDAC dual-target inhibitor and preparation method thereof

A technology of derivatives and amides, which is applied in the application field of drugs for the treatment of malignant tumors and diseases related to differentiation and proliferation, and can solve problems such as dose dependence

Active Publication Date: 2017-07-04
聚缘(上海)生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Clinical data show that both have dose-dependent thrombocytopenia and gastrointestinal side effects, which need further improvement

Method used

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  • NAMPT/HDAC dual-target inhibitor and preparation method thereof
  • NAMPT/HDAC dual-target inhibitor and preparation method thereof
  • NAMPT/HDAC dual-target inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Embodiment 1, N-(2-aminophenyl)-4-(3-(6-fluoropyridin-3-yl)methyl)thioureido)benzamide preparation (A1)

[0149] 1.1 Preparation of intermediate 2: 6-fluoro-3-aminomethylpyridine

[0150] Dissolve 6-fluoro-3-cyanopyridine (300mg, 2.46mmol) in 2mol / L ammonia / methanol solution (30mL), add Raney nickel (0.5g), H 2 The reaction was carried out at room temperature under atmosphere for 12 hours. After the reaction, the reaction solution was filtered with celite, rinsed with methanol (5mL×2), the filtrate was evaporated to dryness, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol=100:4) to obtain 262 mg of a yellow oily solid, which was collected as The rate is 85%. 1 H-NMR (DMSO-d 6 , 300MHz) δ: 8.11-6.84(m, 3H), 3.86(s, 2H), 1.47(s, 2H).

[0151] 1.2 Preparation of intermediate 4: 4-isothiocyanatobenzoic acid

[0152] Triethylamine (1.4mL, 194mmol) was dissolved in dichloromethane (12mL), and thiocarbonyldiimida...

Embodiment 2

[0158] Embodiment 2, N-(4-((2-aminophenyl) carbamoyl) phenyl) imidazo [1,2-a] pyridine-7-carboxamide Prepare (B7)

[0159] 2.1 Preparation of Intermediate 8: Methyl 4-((imidazo[1,2-a]pyridine-7-carboxamide)methyl)benzoate

[0160] Dissolve imidazo[1,2-a]pyridine-6-carboxylic acid (200mg, 1.00mmol), EDC (230mg, 1.20mmol) and DMAP (146mg, 1.20mmol) in dry DMF (5mL), and stir at room temperature 0.5 hours. Additional methyl 4-aminomethylbenzoate (165 mg, 1.00 mmol) was added and stirring was continued for 2 hours. After the reaction, the reaction solution was poured into ten times the amount of water, and solids were precipitated. The solid was filtered, and the filter cake was dried and then column chromatographed to obtain 120 mg of the intermediate, with a yield of 37%. 1 H-NMR (DMSO-d 6 , 300MHz) δ: 9.21(t, J=5.7Hz, 1H), 9.16(s, 1H), 8.08(s, 1H), 7.90(d, J=8.3Hz, 2H), 7.73-7.60(m, 3H ), 7.44(d, J=8.4Hz, 2H), 4.57(d, J=5.8Hz, 2H), 3.84(s, 3H).ESI-MS(m / s): 310.51[M+1],...

Embodiment 3

[0166] Example 3, N-(2-aminophenyl)-4-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzyl Amide Preparation (C1)

[0167] 3.1 Preparation of intermediate 15: methyl 4-azidomethylbenzoate

[0168] Methyl 4-bromomethylbenzoate (342 mg, 1.5 mmol) was dissolved in dry DMF (5 mL), and NaN3 (195 mg, 3 mmol) was added slowly with stirring at room temperature. Then, the reaction solution was placed in an oil bath at 80° C. for 8 hours. After the reaction, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL×3), and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness to obtain 310 mg of the intermediate methyl 4-azidomethylbenzoate with a yield of 85%. 1 H-NMR (DMSO-d 6 , 300MHz) δ: 7.90(d, J=8.3Hz, 2H), 7.43(d, J=8.3Hz, 2H), 3.83(s, 3H), 3.77(t, J=7.0Hz, 2H), 3.20( t, J=7.0Hz, 2H).ESI-MS (m / s): 206.35[M+1].

[0169] 3.2 Preparation of Intermediate 16: Methyl 4-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benz...

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Abstract

The invention discloses an NAMPT / HDAC dual-target inhibitor and a preparation method thereof. The dual-target inhibitor is an amide derivative and pharmaceutically acceptable salt thereof, wherein a structure general formula is represented as the formula (I). A pharmacological experiment proves that the derivative or the salt thereof have very strong inhibition activity on the nicotinamide phosphoribosyl transferase and the histone deacetylase, and have high in-vitro anti-tumor activity and excellent in-vivo tumor inhibiting effect. The invention also provides a preparation method of the derivative and the pharmaceutically acceptable salt thereof, and an application in preparation of an NAMPT inhibitor, a HDAC inhibitor, and anti-tumor medicines.

Description

technical field [0001] The invention belongs to the technical field of medicine; in particular, it relates to the application of a class of NAMPT / HDAC dual-target inhibitors with anti-tumor activity and their pharmaceutical preparations in the treatment of malignant tumors and drugs related to differentiation and proliferation. Background technique [0002] Multi-target drugs can simultaneously regulate multiple links in the tumor disease network system, and are not prone to drug resistance. The total effect on each target is greater than the sum of individual effects, achieving the best therapeutic effect. In addition, single molecules possess relatively simple absorption, distribution, metabolism and excretion processes, greatly reducing drug-drug interactions (Peters, J., et al. J. Med. Chem. 2013, 56, 8955-8971). The FDA has successively approved the marketing of multiple multi-target tyrosine kinase inhibitors, including sorafenib, dasatinib and lapatinib, etc., marking...

Claims

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Application Information

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IPC IPC(8): C07D213/61C07D213/40C07D213/56C07D213/73C07D213/75C07C335/22C07D317/58C07D235/14C07D495/04C07D471/04C07D401/04C07D249/06C07D409/04C07D401/12A61K31/44A61K31/4406A61K31/17A61K31/36A61K31/4184A61K31/4365A61K31/437A61K31/4439A61K31/4192A61P35/00
CPCC07C335/22C07D213/40C07D213/56C07D213/61C07D213/73C07D213/75C07D235/14C07D249/06C07D317/58C07D401/04C07D401/12C07D409/04C07D471/04C07D495/04
Inventor 盛春泉李宝力董国强
Owner 聚缘(上海)生物科技有限公司
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