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Carbamate compounds and methods of making and using same

A technology of compounds and formate esters, applied in the field of carbamate compounds and their preparation and use, can solve the problems of lack of selectivity of MAGL regulatory compounds

Inactive Publication Date: 2017-06-09
ABIDE THERAPEUTICS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, MAGL-modulating compounds to date generally lack the selectivity that is widely used as pharmaceutically acceptable agents in vivo, especially relative to fatty acid amide hydrolase (FAAH), a major N-arachidonoyl ethanol Amide (AEA) hydrolases - required for selective agents

Method used

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  • Carbamate compounds and methods of making and using same
  • Carbamate compounds and methods of making and using same
  • Carbamate compounds and methods of making and using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0274] Example 1: 2,5-dioxopyrrolidin-1-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piper pyridine-1-carboxylate

[0275]

[0276] From bis(benzo[d][1,3]dioxol-5-yl)(piperidin-4-yl)methanol (27 mg, 0.075 mmol), DSC (19 mg, 0.075 mmol) and NMM ( 0.025 mL, 0.23 mmol) Follow Procedure A to synthesize the title compound. Purification of the crude product by flash chromatography (6:3:1 EtOAc:Hexane:MeOH) afforded the title compound (31 mg, 84%) as a white solid: 1 HNMR (400MHz, CDCl 3 )δ6.92(s,2H),6.90(d,J=8.30Hz,2H),6.74(d,J=8.34Hz,2H),5.92(s,4H),4.27–4.09(m,2H), 3.02(t,J=12.13Hz,1H),2.89(t,J=12.29Hz,1H),2.80(s,4H),2.44(t,J=11.60Hz,1H),2.19(s,1H), 1.66–1.56(m,2H),1.56–1.36(m,2H); 13 C NMR (101MHz, CDCl 3 )δ170.25, 150.65, 148.13, 146.66, 139.94, 119.15, 108.26, 107.06, 101.45, 79.62, 46.06, 45.24, 44.40, 26.65, 26.40, 25.86; for C 25 h 24 N 2 o 9 [M+Na] + Calculated HRMS (ESI-TOF+) m / z: 519.1374, found 519.1384.

Embodiment 2

[0277] Example 2: 2,5-dioxopyrrolidin-1-yl 4-[bis(4-chlorophenyl)methyl]piperazine-1-carboxylate

[0278]

[0279] The title compound was synthesized following Procedure A from 1-(bis(4-chlorophenyl)methyl)piperazine (160 mg, 0.5 mmol), DSC (130 mg, 0.50 mmol) and NMM (0.16 mL, 1.5 mmol). Purification of the crude product by flash chromatography (50% EtOAc / hexanes) afforded the title compound (180 mg, 78%) as a colorless oil: 1 H NMR (500MHz, CDCl 3 )δ7.33–7.29(m,4H),7.28–7.25(m,4H),4.24(s,1H),3.63(bs,2H),3.51(bs,2H),2.79(s,4H),2.42 (d,J=4.8Hz,3H); 13 C NMR (126MHz, CDCl 3 )δ170.14, 150.70, 140.44, 133.60, 129.42, 74.76, 51.45, 51.38, 45.54, 45.04, 25.89; for C 22 h 21 Cl 2 N 3 o 4 [M+H] + Calculated HRMS (ESI-TOF+) m / z: 462.0987, found 462.0979.

Embodiment 3

[0280] Example 3: 2,5-dioxopyrrolidin-1-yl 4-[bis(4-bromophenyl)methyl]piperazine-1-carboxylate

[0281]

[0282] The title compound was synthesized following Procedure A from 1-(bis(4-bromophenyl)methyl)piperazine (45 mg, 0.11 mmol), DSC (28 mg, 0.11 mmol) and NMM (0.036 mL, 0.33 mmol). The crude product was purified by flash chromatography (50% EtOAc / hexanes) to afford the title compound (50 mg, 83%) as an off-white crystalline solid: 1 H NMR (600MHz, CDCl 3 )δ7.42(d,J=8.32Hz,4H),7.25(d,J=8.30Hz,4H),4.21(s,1H),3.64(bs,2H),3.52(bs,2H),2.81( s,4H),2.44(bs,4H); 13 C NMR (151MHz, CDCl 3 )δ169.71, 150.26, 140.45, 131.98, 129.32, 121.32, 74.50, 51.04, 50.97, 45.11, 44.60, 25.46; for C 22 h 21 Br 2 N 3 o 4 [M+H] + Calculated HRMS (ESI-TOF+) m / z: 549.9977, found 549.9963.

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Abstract

Provided herein are carbamate compounds useful in the treatment of, eg, pain, solid tumors, and / or obesity.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of and priority to US Provisional Patent Application Serial No. 61 / 685,511 filed March 19, 2012, which is hereby incorporated by reference in its entirety. Background technique [0003] Monoacylglycerol lipase (MAGL) is the main enzyme in the nervous system responsible for the hydrolysis of endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate-based lipid. enzyme. The endocannabinoid system regulates a range of physiological processes including, for example, appetite, pain perception, inflammation and memory. Furthermore, conditions such as obesity, chronic pain, anxiety and depression have been linked to modulation of the signaling activity of the endocannabinoid system. [0004] For example, MAGL-modulating compounds can be used to stimulate 2-AG-mediated signaling, and conditions associated with such signaling, including pain, inflammation, metabolic disease, an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D405/14C07D491/08C07D401/12C07D413/12C07D487/04C07D491/107C07D207/36C07D207/40C07D498/08A61K31/535A61K31/495A61K31/40A61P25/00A61P35/00
CPCC07D207/46C07D209/48C07D233/80C07D401/12C07D401/14C07D403/12C07D403/14C07D405/14C07D413/12C07D413/14C07D417/12C07D471/04C07D471/10C07D487/04C07D491/08C07D491/107C07D498/08A61P3/04A61P25/00A61P25/28A61P29/00A61P35/00A61P43/00
Inventor 贾斯汀·S·奇萨谢丽尔·A·格莱斯托德·K·琼斯东-辉·王奥利维亚·韦伯本杰明·F·克拉瓦特迈卡·J·尼普哈基斯阿曼德·康格尼塔杰·尹·昌
Owner ABIDE THERAPEUTICS INC