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Positive allosteric modulators of the muscarinic acetylcholine receptor m4

A C1-C4, compound technology, applied in the field of positive allosteric modulators of muscarinic acetylcholine receptor M4, can solve problems such as limiting clinical utility and the like

Pending Publication Date: 2020-07-10
VANDERBILT UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Further, xanomeline was shown to reduce psychotic behavioral symptoms such as delusions, suspiciousness, vocal outbursts and hallucinations in Alzheimer's disease patients (Bodick et al., Arch. Neurol. [Archives of Psychiatry] 1997, 54, 465) , however treatment-induced side effects, e.g., gastrointestinal effects, severely limit the clinical utility of this compound

Method used

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  • Positive allosteric modulators of the muscarinic acetylcholine receptor m4
  • Positive allosteric modulators of the muscarinic acetylcholine receptor m4
  • Positive allosteric modulators of the muscarinic acetylcholine receptor m4

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0294] Example 1. General Amine Synthesis

[0295] The following is an exemplary synthesis of one of the amines used to prepare the compounds disclosed herein.

[0296]

[0297] 4-(2-Hydroxypropan-2-yl)benzonitrile. To a solution of 4-iodobenzonitrile (10.0 g, 43.7 mmol, 1.0 equiv) in THF (218 mL) was added n-butyllithium (2.5 M in hexane, 22.7 mL) dropwise at -78 °C. 56.8 mmol, 1.3 eq) to keep the temperature below -70 °C. After 1 hour, acetone (32.0 mL, 436.6 mmol, 10.0 equiv) was added while maintaining the temperature below -70 °C. Remove the dry ice bath. After 16 h at room temperature, add saturated NH 4 Cl solution (100 mL), then EtOAc (250 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0%-60% EtOAc / hexanes) to afford the title compound (4...

example 2

[0299] Example 2.2-(4-(((3-(Difluoromethyl)-4-methylpyrimido[4',5':4,5]thieno[2,3-c]pyridazin-8-yl )amino)methyl)phenyl)propan-2-ol (2-(4-(((3-(Difluoromethyl)-4-methylpyrimido[4',5':4,5]thieno[2,3-c ]pyridazin-8-yl)amino)methyl)phenyl)propan-2-ol) (compound 1)

[0300]

[0301] Compound reference numbers in the following experiments correspond to those used in Scheme 1 in the Detailed Description section.

[0302] 3-Chloro-5,6-dimethyl-1-oxo-pyridazin-1-ium-4-carbonitrile (ii). To a solution of 3-chloro-5,6-dimethylpyridazine-4-carbonitrile (i) (10.0 g, 59.7 mmol, 1.0 equiv) in DCM (298 mL, 0.2 M) at 0 °C in small amounts 3-Chloroperoxybenzoic acid (40.1 g, 179 mmol, 3.0 equiv) was added in portions. The ice bath was removed, and the mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with DCM and washed with NaHCO 3 Wash with saturated solution (2x 200 mL). The organic layer was washed with brine, washed with Na 2 SO 4 Dry, fi...

example 3

[0317] Example 3. Biological Activity

[0318] A. Cell lines expressing muscarinic acetylcholine receptors

[0319] Use Lipofectamine2000 to human M 4 cDNA together with chimeric protein G qi5 Transfected into Chinese Hamster Ovary (CHO-K1) cells purchased from American Type Culture Collection. hM 4 -G qi5 Cells were cultured in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, 50 μg / mL G418 sulfate, and 500 μg / mL hygromycin B. will rM 4 -G qi5 Cells were cultured in DMEM containing 10% heat-inactivated FBS, 20 mM HEPES, 400 μg / mL G418 sulfate, and 500 μg / mL hygromycin B.

[0320] B. Cell-Based Functional Assays of Muscarinic Acetylcholine Receptor Activity

[0321] For high-throughput measurement of agonist-induced increases in intracellular calcium, stable expression of muscarinic Recipient CHO-K1 cells were plated in growth medium lacking G418 and hygromycin. at 37°C and 5% CO 2 , incubate the cells overnight. The next day...

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Abstract

Disclosed herein are tricyclic compounds, including 3-(difluoromethyl)-4-methylpyrimido[4',5':4,5]thieno[2,3-c]pyridazin-8-amine compounds, which may be useful as positive allosteric modulators of themuscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating neurologicaland psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 594,753, filed December 5, 2017, which is incorporated herein by reference in its entirety. [0003] Statement of Government Interest [0004] This invention was made with government support under Grant Numbers 5R01MH073676 and 1U19MH106839-01 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0005] The present disclosure relates to compounds, compositions and methods for the treatment of neurological and psychiatric disorders associated with abnormalities of muscarinic acetylcholine receptors. Background technique [0006] Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChR) or muscarinic acetylcholine receptors (mAChR) through binding of the endogenous orthosteric agonist acetylcholine (ACh). Conditions associated with cognitive impai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/14A61P25/00A61K31/51
CPCC07D495/14A61P25/00A61K31/519A61K45/06C07D519/00
Inventor C·W·林斯利P·J·康恩D·W·恩格尔斯J·L·恩格尔斯
Owner VANDERBILT UNIV
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