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Inhibiting the transient receptor potential A1 ion channel

A C1-C6 compound technology, applied in the field of inhibition of transient receptor potential A1 ion channel, can solve problems such as paroxysmal pain

Active Publication Date: 2017-04-19
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, gain-of-function mutations in TRPA1 cause familial paroxysmal pain syndrome; patients with this disorder have episodic pain that may be induced by cold

Method used

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  • Inhibiting the transient receptor potential A1 ion channel
  • Inhibiting the transient receptor potential A1 ion channel
  • Inhibiting the transient receptor potential A1 ion channel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0526] Example 1 (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2' - (2,2-Dimethylpyrrolidin-1-yl)-[2,5'-bipyrimidine]-4-yl)propionamide

[0527]

[0528] To 2'-(2,2-dimethylpyrrolidin-1-yl)-[2,5'-bipyrimidine]-4-amine (4.2g, 15.5mmol) and (S)-2-( 1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid (3.56 g, 14.1 mmol) in DCM (72 mL) To the mixture was added HOAT (1.92 g, 14.1 mmol). The reaction was cooled to 0 °C and pyridine (2.23 g, 28.2 mmol) and DIC (2.67 g, 21.2 mmol) were added. The reaction was warmed to 25-28 °C and stirred overnight. The reaction mixture was quenched with 0.5N HCl. The mixture was added dropwise to n-hexane and the formed precipitate was collected and washed with MeOH to give (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H -Purin-7(6H)-yl)-N-(2'-(2,2-dimethylpyrrolidin-1-yl)-[2,5'-bipyrimidinyl]-4-yl)propionamide ( 3 g, 19%). 1 H NMR (CDCl 3 )δ9.78(s, 1H), 9.14(s, 2H), 8.54(d, J=5.6Hz, 1H), 7.91(s, 1H), 7....

Embodiment 2

[0529] Example 2 (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2' - ((S)-2-(trifluoromethyl)pyrrolidin-1-yl)-[2,5'-bipyrimidinyl]-4-yl)propionamide (Compound 2 )

[0530]

[0531] To (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propionic acid (2.44g, 9.67mmol) and (S)-2'-(2-(trifluoromethyl)pyrrolidin-1-yl)-2,5'-bipyrimidin-4-amine (3.3g, 10.6mmol) in DCM (48mL ) was added HOAT (1.3 g, 9.67 mmol). The mixture was cooled to 0 °C. Pyridine (1.5 g, 19.3 mmol) was added dropwise over 30 minutes, followed by DIC (1.8 g, 14.5 mmol). The reaction was stirred at 35 °C for 16 h; it was then diluted with DCM (100 mL). The mixture was saturated with NH 4 Cl (50mL, pre-cooled to 0°C) and brine extraction, with Na 2 SO 4 Dry and concentrate. The residue was purified by chromatography, eluting first with EA:PE (3:2), then DCM:MeOH (30:1 ), then recrystallized from EtOH to give the title compound (4.5 g, 78%), It is a white solid. 1 H NMR (DM...

Embodiment 3

[0533] Example 3 (R)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2' - ((S)-2-(Trifluoromethyl)pyrrolidin-1-yl)-[2,5'-bipyrimidinyl]-4-yl)propionamide

[0534]

[0535] The mother liquor from Example 2 after recrystallization in EtOH was concentrated. The residue was loaded for chiral preparative HPLC purification to give (R)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purine-7 (6H)-yl)-N-(2'-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)-[2,5'-bipyrimidinyl]-4-yl)propionamide , which is a white solid. 1 H NMR (DMSO-d 6 )δ11.48(s, 1H), 9.25(s, 2H), 8.69(d, J=5.6Hz, 1H), 8.33(s, 1H), 7.83(d, J=5.6Hz, 1H), 5.81( q, J=7.2Hz 1H), 5.13(t, 1H), 3.71(m, 2H), 3.69(s, 3H), 3.17(s, 3H), 2.14(m, 4H), 1.88(d, J= 7.2Hz, 3H).MH + 545.de: 99%. *

[0536] *Chiral HPLC method conditions: column: CHIRALPAK IB, 150*4.6mm, 5μm; mobile phase: A: hexane (HPLC grade); B: EtOH (HPLC grade); flow rate: 0.8mL / min; gradient: 30% B kept for 25 minutes.

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Abstract

The present invention relates to compounds of the Formula (I), or a pharmaceutically acceptable salt, pharmaceutical preparation, or pharmaceutical composition thereof, and their use for the treatment of pain, inflammatory disease, neuropathy, dermatological disorders, pulmonary conditions, and cough, as well as inhibiting the Transient Receptor Potential Al ion channel (TRPA1).

Description

[0001] priority claim [0002] This application claims priority to US Provisional Application No. 61 / 983,223, filed April 23, 2014, and US Provisional Application No. 61 / 987,272, filed May 1, 2014, both of which are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical preparations or pharmaceutical compositions, and their uses for treating pain, inflammatory diseases, neuropathy, skin diseases, lung diseases and cough, and inhibiting Use of the Transient Receptor Potential Al Ion Channel (TRPA1). Background technique [0004] Transient receptor potential Al (referred to herein as "TRPA1") is a non-selective cation channel involved in the sensation of pain in humans. TRPA1 is found in sensory neurons and functions as a detector to help correlate the detection of noxious chemicals, tissue damage and inflammation with pain. Activatio...

Claims

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Application Information

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IPC IPC(8): C07D473/08A61K31/522A61P11/00A61P11/06
CPCC07D473/08A61P11/00A61P11/06A61P11/14A61P17/00A61P25/02A61P25/04A61P29/00C07B2200/13
Inventor B.S.利帕Q.李I.弗罗纳A.J.杰克逊C.M.刘G.梁M.F.贝弗斯基R.A.厄尔L.麦奎因J.斯密特B.科万斯X.吴B.L.切纳德
Owner ELI LILLY & CO
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