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Pyrrolo-pyridazine derivatives as muscarinic m1 receptor positive allosteric modulators

A technology of pyridazine and pyrrole, which is applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., and can solve problems such as unreleased drugs

Pending Publication Date: 2021-07-23
SUVEN LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although several M1 PAMs have been disclosed in the literature to date, there are no drugs available on the market for use as M1 PAMs

Method used

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  • Pyrrolo-pyridazine derivatives as muscarinic m1 receptor positive allosteric modulators
  • Pyrrolo-pyridazine derivatives as muscarinic m1 receptor positive allosteric modulators
  • Pyrrolo-pyridazine derivatives as muscarinic m1 receptor positive allosteric modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] Example 1: N-[1-hydroxy-cyclohexylmethyl]4-(4-chlorobenzyl)-pyrrolo[1,2-b]pyridazine-2-carboxamide

[0268]

[0269] Step-1: To a stirred slurry of potassium tert-butoxide (4.31 g, 38.48 mmol) in anhydrous toluene (60.0 mL) cooled at 0° C. was added 1-(4-chlorophenyl) over a period of 15 minutes - A mixture of 2-propanone (5.0 g, 29.6 mmol) and diethyl oxalate (4.82 mL, 35.52 mmol). After stirring the reaction mixture at 0 °C for 2 hours, the reaction temperature was raised to RT and stirred for 16 hours. The reaction mass was cooled to ice bath temperature and quenched by adding aqueous acetic acid until the reaction pH reached 2.5. The reaction mass was diluted with EtOAc and the two layers were separated. The organic layer was washed with brine solution, washed with anhydrous Na 2 SO 4 Dry, and remove the solvent under reduced pressure to obtain the product of Step 1, ethyl 5-(4-chlorophenyl)-2,4-dioxopentanoate (7.6 g), in 96% yield.

[0270] 1 H-NMR (400MH...

Embodiment 2 to 18

[0277] Examples 2 to 18: The compounds of Examples 2 to 18 were prepared by following the experimental procedure as described in Example 1 with some non-critical changes.

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

Embodiment 19

[0284] Example 19: N-[2-Hydroxy-2-methyl-propyl]4-[4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-pyrrolo[1,2 -b]pyridazine-2-carboxamide

[0285]

[0286] Step-1: To a stirred slurry of potassium tert-butoxide (6.84 g, 61.01 mmol) in anhydrous toluene (93.0 mL) cooled at 0°C was added 1-(4-bromophenyl) over a period of 15 minutes - A mixture of 2-propanone (10.0 g, 46.93 mmol), diethyl oxalate (7.64 mL, 56.31 mmol) in toluene (93.0 mL). After stirring the reaction mixture at 0 °C for 2 hours, the reaction temperature was raised to RT and stirred at this temperature for 16 hours. The reaction mass was cooled to ice bath temperature and a solution of acetic acid (5.63 mL) and water (46.9 mL) was added until the reaction pH reached 5. The reaction mass was diluted with EtOAc and the two layers were separated. The organic layer was washed with brine solution, washed with anhydrous Na 2 SO 4 Dry and remove the solvent under reduced pressure to obtain the product of Step 1, ethyl 5-(...

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Abstract

The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers or pharmaceutically acceptable salt (s) thereof as muscarinic M1 receptor positive allosteric modulators (M1 PAMs). The present invention describes the preparation, pharmaceutical composition and the use of such compounds.

Description

technical field [0001] The present invention relates to a compound of formula (I) as a muscarinic M1 receptor positive allosteric modulator (M1 PAM) or its isotope form, stereoisomer, tautomer or its Pharmaceutically acceptable salt. The present invention describes the preparation, pharmaceutical compositions and uses of such compounds. Background technique [0002] Muscarinic acetylcholine receptors (mAChR) belong to the class A family of G protein-coupled receptors (GPCRs), and are widely expressed throughout the body. To date, five subtypes, termed M1 to M5, have been identified that respond to the endogenous neurotransmitter acetylcholine (ACh). They play a key role in regulating the activity of many important functions of the central and peripheral nervous systems, including cognitive functions. M1, M3 and M5 are coupled to Gq, while M2 and M4 are coupled to downstream signaling pathways and related effector systems through Gi / o (Critical Reviews in Neurobiology, 199...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P1/00A61P25/00A61P29/00A61K31/5025
CPCC07D487/04A61P25/00A61P29/00A61P1/00A61K31/5025A61K45/06A61P25/28A61P25/20A61K2300/00
Inventor 罗摩克里希纳·尼罗吉阿卜杜勒·拉希德·穆罕默德阿尼尔·卡巴里·欣德斯里尼瓦萨·拉奥·拉韦拉拉姆库马·苏布拉马尼安文卡特斯瓦卢·贾斯蒂
Owner SUVEN LIFE SCI LTD
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