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
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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 patients with Alzheimer's disease (Bodick et

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
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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...

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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

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Application Information

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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
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