Piperidine derivatives and compositions for the inhibition of nicotinamide phosphoribosyltransferase (nampt)

A compound and aryl technology, applied in the field of compounds and compositions for inhibiting nicotinamide phosphoribosyltransferase, can solve problems such as undetermined detailed mechanisms

Inactive Publication Date: 2014-06-18
FORMA TM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compound CHS-828 has been shown to potently inhibit cell growth of a wide range of tumor cell lines, but the detailed mechanism of this inhibitory effect of CHS-828 remains undetermined (Ravaud A, et al. Phase I study and guanidine kinetics of CHS-828 , a guanidine-containing compound, administered orally as a single dose every 3 weeks in solid tumors: an ECSG / EORTC study. Eur J Cancer2005; 41:702-707. [PubMed:15763645])

Method used

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  • Piperidine derivatives and compositions for the inhibition of nicotinamide phosphoribosyltransferase (nampt)
  • Piperidine derivatives and compositions for the inhibition of nicotinamide phosphoribosyltransferase (nampt)
  • Piperidine derivatives and compositions for the inhibition of nicotinamide phosphoribosyltransferase (nampt)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0459] N-(4-(1-benzoylpiperidin-4-yl)butyl)-1H-pyrrolo[32-c]pyridine-2-carboxamide

[0460]

[0461] 1H-Pyrrolo[3,2-c]pyridine-2-carboxylic acid (100mg, 0.617mmol) and (4-(4-aminobutyl)piperidin-1-yl)(benzene According to Galli U.; Ercolano, E.; Carraro, L.; Blasi Roman, C.R.; Sorba, G.; Canonico, P.L.; Genazzani, A.A.; Tron, G.C.; Billington, R.A. Synthesis and biologicalevaluation of isosteric analogues of FK866, an inhibitor of NAD salvation. ChemMedChem2008, 3, 771-779) was added to dimethylformamide (5.0ml) to obtain a light yellow suspension. Add O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (HATU) (220mg, 0.577mmol) and di Isopropylethylamine (0.089ml, 0.510mmol) and the suspension was stirred at room temperature overnight. The reaction mixture was then poured into a separatory funnel with water and ethyl acetate. The aqueous phase was separated and extracted three times with ethyl acetate. The combined organic phases were dried o...

Embodiment 2

[0464] N-(4-(1-benzoylazetidin-3-yl)butyl)-1H-pyrrolo[32-c]pyridine-2-carboxamide

[0465]

[0466] A. tert-butyl 4-(1-benzoylazetidin-3-yl)butylcarbamate:

[0467]

[0468] In a 250 mL round bottom flask, tert-butyl 4-(azetidin-3-yl)butylcarbamate (1 g, 4.38 mmol) and triethylamine (1.343 mL, 9.64 mmol) were added to dichloromethane ( volume 50 mL), then benzoyl chloride (0.508 mL, 4.38 mmol) was added dropwise. The reaction was monitored by TLC and when complete, the reaction mixture was diluted with dichloromethane and poured into a separatory funnel. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organics were separated and concentrated under reduced pressure and purified with Biotage to give 1.178 g of crude product. The material was again purified by Biotage to give 381 mg of product (26% yield). 1 H NMR (300MHz, DMSO-d6): δ7.59(m,2H),7.45(m,3H),6.77(t,1H),4.43(t,1H),4.09(t,1H),3.89(d...

Embodiment 3

[0479] N-(4-(1-benzoylpyrrolidin-3-yl)butyl)-1H-pyrrolo[32-c]pyridine-2-carboxamide

[0480]

[0481] Step A: To a solution of tert-butyl 4-(pyrrolidin-3-yl)butylcarbamate (0.993 g, 4.10 mmol) and triethylamine (1.343 mL, 9.64 mmol) in DCM (50 mL) at 0 °C Benzoyl chloride (0.476 mL, 4.10 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature over 16 hours. The mixture was diluted with water and DCM and the layers were separated. The organic layer was sequentially washed with saturated NaHCO 3 aqueous and brine washes with MgSO 4 dry. The residue was purified by Biotage (EtOAc / hexanes gradient) to give tert-butyl (4-(1-benzoylpyrrolidin-3-yl)butyl)carbamate (474 ​​mg, 33%) as colorless Oil.

[0482] Step B: To a solution of tert-butyl 4-(1-benzoylpyrrolidin-3-yl)butylcarbamate (474 ​​mg, 1.368 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at ambient temperature for 16 hours, then concentrated under redu...

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Abstract

The present invention relates to compounds and compositions for the inhibition of NAMPT, their synthesis, applications and antidotes. An illustrative compound of the invention is shown below: Formula (I)

Description

[0001] priority statement [0002] This application claims priority to U.S. Provisional Application 61 / 483,937, filed May 9, 2011, and U.S. Provisional Application 61 / 512,546, filed July 28, 2011, both of which are incorporated into this application in their entirety as refer to. technical field [0003] The present invention relates to compounds and compositions for inhibiting nicotinamide phosphoribosyltransferase ("NAMPT"), their synthesis, application and antidote. Background technique [0004] Nicotinamide adenine dinucleotide (NAD) plays a fundamental role in both cellular energy metabolism and cell signaling. In energy metabolism, the chemical properties of the pyridine ring make it easy for NAD to accept and donate electrons in hydride transfer reactions catalyzed by various dehydrogenases. [0005] The preparation of a class (including several subclasses) of compounds useful as inhibitors of nicotinamide adenine nucleotide formation and their use as antineoplasti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48C07D471/04C07D513/04C07D519/00A61K31/4523A61P35/00A61P31/12A61P31/18A61P11/00A61P11/06
CPCC07D471/04C07D215/48C07D513/04A61K45/06A61K31/4545A61K31/5377C07D519/00C07D491/048C07D495/04A61K31/437A61K31/4709A61K31/497A61P1/00A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P19/10A61P25/00A61P25/28A61P29/00A61P3/00A61P31/12A61P31/18A61P31/22A61P35/00A61P35/02A61P37/02A61P37/08A61P43/00A61P9/00A61P9/10A61P3/10A61K31/4365A61K31/4375
Inventor K.W.拜尔T.鲍梅斯特A.J.巴克梅尔特K.H.克洛德菲尔特B.韩J.D.昆茨J.林D.J.雷诺兹C.C.史密斯Z.王X.郑
Owner FORMA TM
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