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Substituted imidazo[1,2-b]pyridazine, imidazo[1,5-b]pyridazine, related compounds and uses thereof

A technology for compounds and compositions, applied in medical preparations containing active ingredients, metabolic diseases, drug combinations, etc.

Active Publication Date: 2022-07-15
BIAL R&D INVESTMENTS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs can produce significant side effects such as hallucinations, insomnia, nausea and constipation
In addition, patients often develop tolerance to these drugs, making the drugs ineffective in treating the symptoms of the disease, while sometimes producing movement-disordering side effects called dyskinesias

Method used

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  • Substituted imidazo[1,2-b]pyridazine, imidazo[1,5-b]pyridazine, related compounds and uses thereof
  • Substituted imidazo[1,2-b]pyridazine, imidazo[1,5-b]pyridazine, related compounds and uses thereof
  • Substituted imidazo[1,2-b]pyridazine, imidazo[1,5-b]pyridazine, related compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0430] Example 1 – Preparation of compounds

[0431] Substituted imidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazine compounds, related compounds were prepared based on the general procedures described below in Part I. Provided in Section II below for use in the preparation of certain substituted imidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazine compounds and / or related compounds Exemplary procedures for specific carboxylic acid compounds useful as intermediates for the synthesis. Specific substituted imidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazine compounds, and related compounds prepared according to general procedures are provided in Section III below.

[0432] PART I – GENERAL PROCEDURES

[0433] General Procedure A: Preparation of Amides by Coupling Carboxylic Acid Compounds with Amine Compounds

[0434] To a stirred solution of the carboxylic acid compound (1.0 equiv), HATU (1.5 equiv) and DIPEA ...

Embodiment 2

[0780] Example 2 – Preparation of additional compounds

[0781] Additional exemplary compounds were prepared based on the general procedures described in Section I below. Exemplary procedures for the preparation of specific compounds according to the general procedures are described in Section II below.

[0782] PART I – GENERAL PROCEDURES

[0783] General Procedure A: Preparation of Amide Compounds by Coupling of Carboxylic Acid Compounds with Amine Compounds

[0784] To a stirred solution of the carboxylic acid compound (1.0 equiv), HATU (1.5 equiv) and DIPEA (3.75 equiv) in DCM or DMF (~4 mL / 0.2 mmol) was added the amine (1.25-2.0 equiv). The reaction mixture was stirred at RT for 4-16 h, then washed with saturated NaHCO 3 Wash with aqueous solution (5 mL / 0.2 mmol), aqueous citric acid (5 mL / 0.2 mmol) and brine (5 mL / 0.2 mmol). The combined extracts were subjected to anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by ...

Embodiment 3

[1062] Example 3 – Evaluation of biological activity

[1063] The ability of exemplary compounds to activate glucocerebrosidase (Gcase) was measured. Experimental procedures and results are provided below.

[1064] Part I: Test Procedures

[1065] A 484 μL aliquot of a 1.0 mg / mL solution of phosphatidylserine (PS) (Sigma P7769) in chloroform was evaporated under nitrogen flow for 1 hour. The lipid membrane was dissolved in 40 mL of 176 mM K containing 7.5 μL of triton X-100 by vigorous vortexing for 4 min. 2 HPO 4 / 50 mM citric acid (pH 4.7), resulting in a mixed micellar formulation with a composition of 0.32 mM triton and 0.37 mol% PS. 4-Methylumbelliferyl-β-D-glucopyranoside (ACROS-337025000) was dissolved in the micelle solution to a final concentration of 2 mM and used as a reaction substrate.

[1066] Test compounds were diluted to the desired concentrations from a 10 mM stock in dimethyl sulfoxide (DMSO) and 0.41 μL of this DMSO compound mixture was added to 100 ...

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Abstract

The present invention provides substituted imidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazine compounds, related compounds, compositions containing such compounds, medical kits, and Such compounds or compositions are used in methods of treating medical disorders such as Gaucher disease, Parkinson's disease, Lewy body disease, dementia or multiple system atrophy in a patient. Exemplary substituted imidazo[1,2-b]pyridazine compounds described herein include substituted imidazo[1,2-b]pyridazine-3-carboxamide compounds and variants thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 62 / 332,151, filed May 5, 2016, the contents of which are incorporated herein by reference. technical field [0003] The present invention provides substituted imidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazine compounds, related compounds, compositions containing such compounds, medical kits, and Methods of treating medical disorders in patients using such compounds and compositions. Background technique [0004] Gaucher disease is a genetic disorder associated with a deficiency of the lysosomal enzyme, glucocerebrosidase. Gaucher disease has a reported incidence in the general population of approximately 1 in 20,000 live births and is a common lysosomal storage disorder. Current treatments for patients with the disease include often expensive enzyme replacement therapy, pain relievers to reliev...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/14C07D513/04C07D495/04C07D491/048C07D498/04A61K31/519A61P25/16A61P27/06A61P3/10A61P13/12A61P25/24A61P25/28A61P25/08A61P25/18A61P25/22A61P43/00
CPCC07D491/048C07D495/04C07D498/04C07D513/04C07D487/04A61P13/12A61P25/00A61P25/08A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P27/06A61P3/10A61P43/00A61K31/5025A61K31/4365
Inventor R·T·斯克尔杰E·M·J·布尔克W·J·格林利P·T·兰斯伯里
Owner BIAL R&D INVESTMENTS SA