Positive allosteric modulators of the muscarinic acetylcholine receptor m4

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

Inactive Publication Date: 2019-07-19
VANDERBILT UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

[0315] Example 1. General Amine Synthesis

[0316] The following are exemplary syntheses of two of the amines used to prepare the compounds disclosed herein.

[0317]

[0318] 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..8...

example 2

[0322] Example 2. N-[(3-fluoro-4-methoxy-phenyl)methyl]-2,4-dimethyl-quinoline-6-carboxamide (Compound 1)

[0323]

[0324] 6-Bromo-2,4-dimethylquinoline (A). A 40 mL reaction vial equipped with a Teflon septum and a magnetic stir bar was charged with 6-bromo-2-methylquinoline (555.2 mg, 2.5 mmol, 1.0 eq.), Ir catalyst (22.9 mg, 0.030 mmol), p-Toluenesulfonic acid monohydrate (951 mg, 5.0 mmol, 2.0 eq.), DMSO (10.0 mL, 0.25M), and methanol (20.0 mL, 0.50M). The mixture was degassed for 10 minutes by passing nitrogen with an exit needle. Ethyl-2-mercaptopropionate (16.3 uL, 0.130 mmol, 0.05 eq.) was added. The mixture was illuminated with a blue LED at room temperature under a micro fan. Complete conversion to the desired product was complete after 5 days where ethyl-2-mercaptopropionate (16.3uL, 0.130mmol, 0.05eq.) was added 3 more times. 1M NaOH solution (10.0 mL) and DCM (100.0 mL) were added. The organic layer was separated and washed with brine, washed with Na 2 S...

example 3

[0331] Example 3. N-[1-(5-chloro-2-methoxy-4-pyridyl)azetidin-3-yl]-2,4-dimethyl-quinoline-6-carboxamide (compound 2)

[0332]

[0333] N-(azetidin-3-yl)-2,4-dimethylquinoline-6-carboxamide (D). To a solution of 2,4-dimethylquinoline-6-carboxylic acid (C) (185.9 mg, 0.924 mmol, 1.0 eq.) in DMF (5.0 mL, 0.185 M) was added HATU (738 mg, 1.94 mmol, 2.1 eq.) and DIEA (0.804 mL, 4.62 mmol, 5.0 eq.). After stirring for 5 minutes, 1-Boc-3-(amino)azetidine (398 mg, 2.31 mmol, 2.5 eq.) was added. The reaction mixture was allowed to stir for 1 h. Using reverse phase HPLC (MeCN / H 2 O / 0.1% TFA) purified the crude material to provide the Boc-protected compound. Desired fractions were concentrated at 50°C using an air concentrator. Once the material was concentrated to dryness, the desired product with complete Boc deprotection was evident. Use a HF bond Elut-SCX column and use NH in MeOH 3 The crude material was purified by solution (7N) elution to afford the title compound (235...

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Abstract

Disclosed herein are 2,4-dimethylquinoline-6-carboxamide compounds and 3,4- dimethylcinnoline-6-carboxamide compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4(mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to US Application Serial No. 62 / 435,426, filed December 16, 2016, the entire contents of which application is incorporated herein by reference. [0003] Statement of Government Interest [0004] This invention was made with government support under Grant No. 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 the binding of the endogenous orthosteric agonist acetylcholine (ACh). Conditions associated with co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/12C07D215/38
CPCC07D403/12C07D401/14C07D215/48C07D401/12C07D237/28C07D403/14A61P25/00A61P25/16A61P25/22A61P25/28A61P25/18
Inventor C·W·林斯利P·J·康恩D·W·恩格尔斯J·L·恩格尔斯M·F·朗
Owner VANDERBILT UNIV
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