Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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

Active Publication Date: 2019-02-05
VANDERBILT UNIV
View PDF2 Cites 2 Cited by
  • 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 patients with Alzheimer's disease (Bodick et al., Arch. Neurol. [Archives of Psychiatry] 1997, 54, 465), However, treatment-induced side effects, such as gastrointestinal effects, severely limit the clinical utility of this compound

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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

[0742] Example 1. General Amine Synthesis

[0743] The following are exemplary syntheses of certain amines useful in the preparation of the compounds disclosed herein.

[0744]

[0745] 4-(1-methoxy-1-methyl-ethyl)benzonitrile (X1). To a solution of 4.34 mmol, 1.0 equiv) in DMF (16.4 mL) was added sodium hydride (60% in mineral oil, 260 mg, 6.51 mmol, 1.5 equiv). After 1 h at 5 °C, iodomethane (0.30 mL, 4.78 mmol, 1.1 equiv) was added. The mixture was allowed to warm to room temperature. After 2 h, water (20 mL) was added followed by EtOAc (30 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2 x 30 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 (0-50% EtOAc / hexanes) to afford the title compound (600 mg, 79% yield) as a viscous oil. ES-MS[M+1] + :176.6; 1 H NMR (400MHz, DMSO-d 6 ) δ 7.82 (ddd, J = 8.6, 1.8, 1.8H...

example 2

[0779] Example 2. N,N,3,4-Tetramethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazin-8-amine (Compound 1)

[0780]

[0781] Ethyl 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylate (A). To a 20 mL microwave vial was added 3-chloro-5,6-dimethyl- Pyridazine-4-carbonitrile (1.20 g, 7.16 mmol), potassium carbonate (1.98 g, 14.3 mmol), IPA (15 mL) and ethyl thioglycolate (0.87 mL, 7.88 mmol). After 20 min in the microwave reactor at 105 °C, the reaction was cooled to room temperature and added to water (150 mL). The solid was filtered and washed 3 times with water to give A (1.42 g, 79% yield) as a green powder. ES-MS[M+1] + :252.2; 1 H NMR (400MHz, CDCl 3 )δ 6.18 (s, 2H), 4.41 (q, J = 7Hz, 2H), 2.85 (s, 3H), 2.77 (s, 3H), 1.44 (t, J = 7.12Hz, 3H).

[0782] 3,4-Dimethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazin-8-ol (B). Heat A in an open vessel at 150°C (1.41 g, 5.61 mmol) in formamide (10 mL, 252 mmol). Formamidine acetate (1.75 g, 16.8 mmol) was added to the reaction. ...

example 3

[0785] Example 3. 2-[4-[[(3,4-Dimethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazin-8-yl)amino]methanol Base] phenyl] propan-2-ol (compound 76)

[0786]

[0787] 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxamide (A').To 5-amino-3,4-dimethyl-thieno[2, 3-c] Ethyl pyridazine-6-carboxylate (A, prepared as described in Example 2) (5.0 g, 19.9 mmol, 1.0 equiv) suspension in THF (33.0 mL) and MeOH (10.0 mL) Aqueous LiOH (1M, 99.5 mL, 5.0 equiv) was added to . After 16 hours at room temperature, LCMS confirmed loss of starting material. The reaction was cooled to 0 °C and the yellow solid was filtered off. The solid was dried in vacuo to afford lithium carboxylate (4.6 g) as a yellow powder. ES-MS[M+1] + :224.4; 1 H NMR (400MHz, DMSO-d 6 )δ6.37(s,2H),2.65(s,6). The filtrate was acidified with 4M HCl in dioxane to give the corresponding carboxylic acid (950 mg). ES-MS[M+1] + :224.3; 1 H NMR (400MHz, DMSO-d 6 )δ7.01 (bs, 2H), 2.73 (s, 3H), 2.71 (s, 3H).

[0788] To a...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

Disclosed herein are tricyclic compounds, including pyrimido[4',5':4,5]thieno[2,3-c]pyridazine-8-amine, pyrido[3',2M,5]thieno[3,2-d]pyrimidine-4-amine, pyrazino[2',3':4,5]thieno[3,2-d]pyrimidin-4-amine, pyrido[3',2':4,5]furo[3,2-d]pyrimidin-4- amine, and pyrimido[4',5':4,5]furo[2,3-c]pyridazin-8-amine compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholinereceptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating neurological and psychiatric disordersassociated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 353,447, filed June 22, 2016, U.S. Provisional Application No. 62 / 418,638, filed November 7, 2016, and U.S. Provisional Application No. 62 / 471,281, filed March 14, 2017 Priority of each of the above documents is hereby incorporated 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 ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): A61K31/395A61K31/5025C07D495/04
CPCC07D495/14C07D491/147A61P25/00A61P25/18C07D493/14C07D519/00A61P25/04A61P25/14A61P25/20A61P25/22A61P25/24A61P25/28A61P43/00A61K31/395A61K31/519A61K31/5025C07D495/04
Inventor C·W·林斯利P·J·康恩D·W·恩格尔斯S·博林杰J·C·塔尔P·斯皮林J·L·恩格尔斯M·郎T·M·布里奇斯
Owner VANDERBILT UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com