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Heterocyclic compounds having activity as modulators of muscarinic M1 and/or M4 receptors in treatment of CNS diseases and pains

A technology of compounds and chemical bonds, applied in the fields of organic active ingredients, organic chemistry, nervous system diseases, etc.

Active Publication Date: 2019-07-09
HEPTARES THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in all clinical studies, normeline and other related mAChR agonists were less effective in cholinergic adverse events (including nausea, gastrointestinal pain, diarrhea, diaphoresis (excessive sweating), vomiting (excessive salivation), syncope and bradycardia) showed unacceptable margins of safety

Method used

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  • Heterocyclic compounds having activity as modulators of muscarinic M1 and/or M4 receptors in treatment of CNS diseases and pains
  • Heterocyclic compounds having activity as modulators of muscarinic M1 and/or M4 receptors in treatment of CNS diseases and pains
  • Heterocyclic compounds having activity as modulators of muscarinic M1 and/or M4 receptors in treatment of CNS diseases and pains

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1 to 25-1

[0588] The compounds of Examples 1-1 to 25-1 shown in Table 1 below have been prepared. Starting materials and intermediates are described in Table 2. The NMR and LCMS properties of the compounds of Examples 1-1 to 25-1 and the methods used to prepare them are listed in Table 3.

[0589] Table 1

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597] general method

[0598] Where preparative routes are not included, relevant intermediates are commercially available. Commercial reagents were used without further purification. Room temperature (rt) means about 20-27°C. 1 H NMR spectra were recorded at 400 MHz by Bruker or Jeol instruments. Chemical shift values ​​are expressed in parts per million (ppm) or (δ)-values. The following abbreviations are used for various NMR signals: s = singlet, br = broad, d = doublet, t = triplet, q = quartet, quint = quintet, td = triplet of doublets, tt = triplet Triplet, qd = quadruple doublet, ddd ...

preparation Embodiment 3-19

[0870] To prepare Example 3-19 that is 4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazacyclic Typical procedure for the preparation of cyclohexane via intermediate 32 and intermediate 44, exemplified by ethyl heptane-1-carboxylate

[0871]

[0872] Make 1-(5-methoxypyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.20 g, 0.87 mmol) and ethyl 1,4-diazepane-1-carboxylate Hydrochloride (0.18 g, 1.01 mmol) was dissolved in DCM (20 mL), and MeOH (2 mL) and acetic acid (5 drops) were added. The reaction mixture was stirred at room temperature for 4 h, then cooled to 0 °C. STAB (0.73 g, 3.47 mmol) was added in portions and the reaction mixture was stirred at room temperature overnight. Add NaHCO 3 (saturated solution, 40 mL), and the reaction mixture was stirred at room temperature for 1 h, then extracted with DCM (4 x 40 mL). The organic layers were combined and dried (MgSO 4 ). The solvent was removed in vacuo and separated by column chromatography (normal phase, [B...

preparation Embodiment 1-15

[0875] With Preparation Example 1-15, {(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrole Alk-3-yl}carbamate as an example for the preparation of substituted cyclohexyl derivatives via intermediates 15 and 28 typical process

[0876]

[0877] (3S)-Pyrrolidin-3-ylcarbamate tert-butyl ester (0.75 mL, 2.0 mmol) and 1-(5-chloropyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.83 mL, 2.2 mmol) was dissolved in DCM (7.5 mL), and acetic acid was added (5-10 drops). The reaction mixture was stirred at room temperature for 4 h, then cooled to 0 °C. STAB (0.64 g, 3.0 mmol) was added in portions and the reaction mixture was stirred at room temperature overnight. Add NaHCO 3 (saturated solution, 30 mL), and the reaction mixture was stirred at room temperature for 1 h, then extracted with DCM (4×30 mL), and the organic layers were combined and dried (MgSO 4 ). The solvent was removed in vacuo to give crude tert-butyl {(3S)-1-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexy...

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Abstract

The invention relates to compounds that are agonists of the muscarinic M1 receptor or M1 and M4 receptors and which are useful in the treatment of muscarinic M1 or M1 / M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula (Formula (I)) wherein Q4, Q5, R5, p, V, Q1, Q2, X1, X2and W are defined herein.

Description

[0001] The present invention relates to muscarinic M 1 receptor or M 1 and M 4 Agonists of the receptor and are useful in the treatment of muscarinic M 1 or M 1 and M 4 Receptor-mediated diseases. Also provided are pharmaceutical compositions comprising the compound and therapeutic uses of the compound. Background technique [0002] Muscarinic acetylcholine receptors (mAChRs), members of the G protein-coupled receptor superfamily, mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems. There are already five mAChR mAChR namely M 1 to M 5 been cloned. m 1 mAChR is mainly expressed in the postsynaptic cortex, hippocampus, striatum and thalamus; M 2 mAChRs are mainly located in the brainstem and thalamus, but also in the cortex, hippocampus and striatum where they are present on cholinergic synaptic terminals (Langmead et al., 2008 Br J Pharmacol). However, M 2 mAChRs are also expressed peripherally on cardiac tissue...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/08C07D403/08C07D243/08C07D471/04C07D471/10C07D487/10C07D207/42A61K31/551A61K31/401A61K31/437A61K31/4439A61K31/438A61K31/4353A61P25/00C07D413/12
CPCC07D401/08C07D403/08C07D413/12C07D243/08C07D471/04C07D471/10C07D487/10C07D207/42A61P25/00C07D207/14C07D209/96C07D213/57C07D271/06C07D295/205C07D403/04C07D409/08C07D413/04C07D413/14C07D487/04
Inventor 盖尔斯·艾伯特·布朗迈尔斯·斯图尔特·康格里夫马克·皮克沃斯本杰明·杰拉尔德·特汉
Owner HEPTARES THERAPEUTICS
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