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Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof

A technology of derivatives and urea, which is applied in the field of medicine and can solve problems such as poor water solubility

Active Publication Date: 2014-04-09
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this compound also has disadvantages such as poor water solubility

Method used

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  • Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof
  • Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof
  • Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1: 1-[4-(4-tert-butoxycarbonyl-1-piperazinylsulfonyl)-phenyl]-3-(3-pyridylmethyl)thiourea

[0134] 4-(4-tert-butoxycarbonyl-1-piperazinylsulfonyl)aniline (0.34g, 1mmol, synthesized by general method 1), thiophosgene (0.14g, 1.2mmol) and 3-aminomethylpyridine (0.11 g, 1mmol) Synthesize 1-[4-(4-tert-butoxycarbonyl-1-piperazinylsulfonyl)-phenyl]-3-(3-pyridylmethyl)thiourea according to the general method to obtain a white solid 0.21g, yield 41%.

[0135] 1 H NMR(d-DMSO,600MHz)δ:1.34(s,9H),2.83-2.85(m,4H),3.37-3.39(m,4H),4.78(s,2H),7.37(dd,J=7.8 Hz,4.8Hz,1H),7.65(d,J=9.0Hz,2H),7.76(d,J=7.8Hz,1H),7.80(d,J=9.0Hz,2H),8.47(dd,J= 4.8Hz,1.2Hz,1H),8.57(d,J=1.8Hz,1H),8.61(s,1H),10.11(s,1H).ESI-MS(m / z):492.53[M+1] .

Embodiment 2

[0136] Example 2: 1-[4-(1-piperazinylsulfonyl)-phenyl]-3-(3-pyridylmethyl)thiourea

[0137] 1-[4-(4-tert-butoxycarbonyl-1-piperazinylsulfonyl)-phenyl]-3-(3-pyridylmethyl)thiourea (0.1g, 0.2mmol) was dissolved in dichloromethane: Trifluoroacetic acid (2:1) 20mL, stirred at room temperature for 1h. The solvent was evaporated to dryness, the residue was added with saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Then the solvent was concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane:methanol=100:5) to obtain 0.06 g of white solid with a yield of 75%.

[0138] 1 H NMR(d-DMSO,600MHz)δ:2.70-2.73(m,8H),4.76(s,2H),7.36(dd,J=7.2Hz,4.8Hz,1H),7.60(d,J=8.7Hz ,2H),7.75(d,J=7.8Hz,1H),7.85(d,J=8.7Hz,2H),8.46(m,1H),8.55(s,1H),9.20(s,1H),10.75 (s,1H).ESI-MS(m / z):392.12[M+1].

Embodiment 3

[0139] Embodiment 3: N-phenyl-4-[3-(3-pyridylmethyl)thioureido]benzenesulfonamide

[0140] 4-amino-N-phenylbenzenesulfonamide (0.25g, 1mmol, synthesized by general method 1), thiophosgene (0.14g, 1.2mmol) and 3-aminomethylpyridine (0.11g, 1mmol) were synthesized according to general method 1 N-phenyl-4-[3-(3-pyridylmethyl)thioureido]benzenesulfonamide was synthesized to obtain 0.16 g of white solid with a yield of 39%.

[0141] 1 H NMR(d-DMSO,600MHz)δ:4.75(d,J=5.3Hz,2H),7.00(t,J=7.3Hz,1H),7.10(d,J=7.8Hz,2H),7.22(t ,J=7.8Hz,2H),7.35(dd,J=7.8Hz,4.6Hz,1H),7.66-7.69(m,4H),7.74(d,J=7.8Hz,1H),8.46(dd,J =4.8Hz,1.7Hz,1H),8.54-8.55(m,2H),9.98(s,1H),10.20(s,1H).ESI-MS(m / z):399.61[M+1].

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Abstract

The invention belongs to the technical field of medicines. The invention provides a urea type derivative and a pharmaceutically acceptable salt thereof. The general structural formula of the compound is as shown in formula (I) in the specification. As proved by pharmacological experiments, the compound or salt mentioned in the invention not only has quite high inhibition activity on nicotinamide ribose phosphate transferase but also has high antitumor activity in vitro. The invention further provides a preparation method of the derivative and the pharmaceutically acceptable salt thereof, as well as an application of the derivative and the pharmaceutically acceptable salt thereof to preparation of a nicotinamide ribose phosphate transferase inhibitor or antitumor drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a urea derivative as an inhibitor of nicotinamide phosphoribosyltransferase, a preparation method thereof, and an application in preparation of antitumor drugs and the like. Background technique [0002] Nicotinamide phosphoribosyltransferase (nicotinamide phosphoribosyltransferase, Nampt) is also known as visfatin or pre-B cell clone enhancer factor (PBEF). Nampt catalyzes nicotinamide (NAM) to generate nicotinamide mononucleotide (nicotinaminde mononucleotide, NMN), which regulates the level of NAD, an essential energy substance in mammalian cells. Crucial role (Galli, U., et al. Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors, J Med Chem2013, 56, 6279-96.). Studies have shown that Nampt is closely related to the occurrence and development of tumors, and has become a very important new target in the research of anticancer drugs. Fi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/36C07D213/74C07D213/30C07D295/192C07D405/12C07D401/12C07D409/12A61P35/00
CPCC07D213/30C07D213/40C07D213/74C07D295/192C07D401/12C07D405/12C07D409/12
Inventor 缪朝玉盛春泉徐添颖董国强张赛龙
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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