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5-oxa-2-azaspiro [3.4] octane derivatives as M4 agonists

A technology of heterocycloalkyl and alkyl, applied in the field of 5-oxa-2-azaspiro[3.4]octane derivatives as M4 agonists, can solve the problems of indigestion, excessive salivation and the like

Pending Publication Date: 2022-05-27
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its treatment was associated with a number of side effects, including nausea, vomiting, excessive salivation, indigestion, and chills, which stopped its clinical studies

Method used

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  • 5-oxa-2-azaspiro [3.4] octane derivatives as M4 agonists
  • 5-oxa-2-azaspiro [3.4] octane derivatives as M4 agonists
  • 5-oxa-2-azaspiro [3.4] octane derivatives as M4 agonists

Examples

Experimental program
Comparison scheme
Effect test

example 1A

[0929] Example 1A: (S)-7-(4-(5-Fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-2-(1,3, 4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0930]

[0931] (S)-7-(4-(5-Fluoro-2-(oxetan-3-yloxy)phenyl)piperidin-1-yl)-5-oxa-2-aza Spiro[3.4]octane (Intermediate 7A, 540 mg, 1.49 mmol) was dissolved in 2% aqueous TPGS-750-M (2.6 mL) and THF (0.3 mL). Next, ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (329 mg, 1.49 mmol) and tripotassium phosphate (949 mg, 4.47 mmol) were added. The mixture was stirred at room temperature overnight, and then 2M LiOH (2.2 mL, 4.5 mmol) was added and the reaction was stirred at room temperature overnight. MeOH (6 mL) was added followed by 4N HCl solution to adjust the reaction to pH=2; then stirred at room temperature for 4 hours. The reaction was then adjusted to pH>8 and the aqueous layer was extracted with DCM and the combined organic layers were washed with MgSO 4 Dry, filter and concentrate in vacuo. The residue was purified by FCC (0%-10% MeO...

example 1B

[0934] Example IB: (S)-7-(4-(5-Fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-2-(1 ,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane

[0935]

[0936] (S)-7-(4-(5-Fluoro-2-(((R)-tetrahydrofuran-3-yl)methoxy)phenyl)piperidin-1-yl)-5-oxa-2 - Azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 6B, 217 mg, 0.442 mmol) was dissolved in DCM (4.4 mL) and TFA (0.68 mL, 8.85 mmol) was added. The reaction was stirred for 4 hours and then concentrated, and the residue was dissolved in DCM. The organic phase was washed with 1N NaOH and brine and concentrated. A portion of this material (97 mg, 0.248 mmol) was then dissolved in THF (0.05 mL) and 2% aqueous TPGS-750-M (0.45 mL) and 5-bromo-1,3,4-oxadiazole-2 was added - Ethyl formate (54 mg, 0.248 mmol) and K 3 PO 4 (52.7 mg, 0.248 mmol). The reaction was worked up analogously to Example 1A and the crude was passed through FCC (0%-7% MeOH / DCM) and by preparative HPLC (C18 OBD 30x50mm 5 μm column,...

example 1C

[0939]Example 1C: 5-((S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidine- 1-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)-1,3,4-oxadiazole-2-carboxylic acid ethyl ester

[0940]

[0941] (S)-7-(4-(2-(((R)-1,4-dioxan-2-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)- 5-oxa-2-azaspiro[3.4]octane (Intermediate 7C, 84 mg, 0.21 mmol) was dissolved in 2% aqueous TPGS-750-M (372 μL) and THF (41 μL). Ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (46 mg, 0.21 mmol) and tripotassium phosphate (44 mg, 0.21 mmol) were added and the reaction was worked up in a manner analogous to Example 1A. The crude product was purified by FCC (0%-7% MeOH / DCM) and by preparative HPLC (XBridge 30x50 mm 5 μm 25%-50% MeCN / H2O (5 mM NH4OH), 75 mL / min) to provide the title compound (28 mg, 0.058 mmol) ).

[0942] LCMS: Rt: 1.90 min (LCMS method 4); MS m / z 475.2 [M+H] + .

[0943] 1 H NMR (DMSO-d 6 )δ8.64(s,1H),7.02-6.92(m,3H),4.22(d,J=8.8Hz,1H),4.13(dd,J=8.3,3.9Hz,2H),4.04-3.89(m ,4H),3.81-3.88(m...

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Abstract

Provided herein are compounds according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5 and R7 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) and the use of such compounds as M4 receptor agonists.

Description

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of priority to US Provisional Application No. 62 / 912,986, filed October 9, 2019, the disclosure of which is incorporated herein by reference in its entirety. 2. Technical field [0003] Provided herein are novel 2-azaspiro[3.4]octane compounds that act as M4 receptor agonists, as well as pharmaceutical compositions thereof, for the treatment of M4 receptor-related conditions, diseases and disorders, including but not limited to Psychosis, hyperkinetic movement disorders, cognitive impairment, and substance use disorders. 3. Background technology [0004] Acetylcholine is the major neurotransmitter in the central and peripheral nervous systems, signaling by activating its ionotropic (nicotinic) receptors and G protein-coupled (muscarinic) receptors. Five muscarinic receptors (M1-M5) with differential expression and signaling have been identified. M1, M3 and M5 receptors are couple...

Claims

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Application Information

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IPC IPC(8): C07D491/107A61K31/454A61P25/18A61P25/00A61P25/24A61P25/28
CPCC07D491/107A61P25/18A61P25/00A61P25/24A61P25/28A61K45/06A61K31/454A61P25/30
Inventor A·卡尔霍恩陈昕K·M·伽丁尼尔E·C·霍尔K·珍德扎N·拉比-吉盖尔J·尼夫D·S·帕拉西奥斯钱明M·D·舒尔茨C·G·汤姆森K·Y·王杨凡
Owner NOVARTIS AG
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