Compound, preparation method and uses thereof

A technology for compounds and compositions, applied in the fields of compounds and their preparation and use, can solve problems such as hidden safety hazards and ineffectiveness in disease development

Active Publication Date: 2019-07-19
MEDSPRING INT LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drugs used to treat allergic dermatitis mainly include antihistamines and bronchodilators, but they can only improve symptoms and have no effect on the development of the disease
In addition, corticosteroids also have a certain effect on allergic dermatitis, but there are potential safety hazards

Method used

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  • Compound, preparation method and uses thereof
  • Compound, preparation method and uses thereof
  • Compound, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1N-[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methoxy)-1H-indazol-1-yl]methyl} Preparation of phenyl)methyl]-2-hydroxy-2-methylpropionamide

[0059] Preparation of N-[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methoxy)-1H-indazol-1-yl of the following formula compound 6 ]methyl}phenyl)methyl]-2-hydroxy-2-methylpropionamide

[0060]

[0061] Step 1 Preparation of intermediate compound 1 4-(methoxy)-1H-indazol-3-amine

[0062]

[0063] 6-Fluoro-2methoxybenzonitrile (50g, 0.33mol) and hydrazine hydrate (50g, 0.99mol) were dissolved in 400ml of n-butanol, and refluxed for 20h under N2 protection. After the solution was cooled, 400ml of water was added and stirred evenly, the organic layer was separated, and the solid precipitated in the aqueous phase was collected. The solvent in the organic layer was removed under reduced pressure, and the residue was mixed with the aqueous phase and the precipitated solid in the aqueous phase, and extracted wit...

Embodiment 4

[0087] Embodiment 4 solubility test

[0088] The solubility of the compounds was determined according to the method established in the second part of the Pharmacopoeia of the 2010 edition. Accurately weigh the compound 6 prepared in Example 1, N-[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methoxy)-1H -Indazol-1-yl]methyl}phenyl)methyl]-2-hydroxy-2-methylpropionamide 10, 100, 1000 mg each, placed in a 500 ml volumetric flask at 25°C±2°C Add water to dilute to the mark, shake vigorously for 30 seconds every 5 minutes, observe the dissolution within 30 minutes, only 10 mg of the sample has no visible solute, and its solubility in water is 0.02 mg / ml.

[0089] Accurately weigh the formula II compound N-[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methoxy)-1H prepared in Example 2 -Indazol-1-yl]methyl}phenyl)methyl]-2-hydroxy-2-methylpropionamide sodium salt 10, 100, 1000, 2000 mg each, placed at 25°C±2°C In a 2ml volumetric flask, add water to dilute to the mark, shake...

Embodiment 5

[0095] Example 5 In vitro CCR4 antagonistic activity test

[0096] Antagonist potency was determined by radioligand [35S]-GTPyS competition assay. Briefly, CHO membranes expressing CCR4 were homogenized through a 23G needle. These membranes were then attached to WGA-coated LeadseekerSPA beads in assay buffer (20 mM HEPES, 10 mM MgCl, 100 mM NaCl, 0.05% BSA, 40 ug / ml saponin, pH adjusted to 7.4 using KOH 5M) to generate 3 μg / well final assay concentration (FAC) of membrane and 250 μg / well of FAC bead solution. After 60 min pre-coupling on ice, GDP was added to give 4.4uM FAC. [35S]-GTPyS prepared in assay buffer was then added to the bead / membrane solution to obtain 0.33 nM FAC. Addition of human MDCs to the bead / membrane / [35S]-GTPyS suspension resulted in FACs exhibiting 80% (EC80) of the maximal agonist response. The bead / membrane / [35S]-GTPyS / agonist suspension was dispensed into white Greiner polypropylene 384-well plates (45[mu]l / well) containing 0.5[mu]l of compound. ...

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Abstract

The invention relates to a compound represented by a formula I, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, wherein M is a monovalent alkali metal. The present invention further relates to a preparation method of the compound or the pharmaceutically acceptable salt, the solvate or the prodrug thereof, a pharmaceutical composition containing the compound, and uses in preparation of drugs, wherein the drugs are used for treating CCR4-mediated diseases.

Description

[0001] field of invention [0002] The present invention relates to novel compounds or pharmaceutically acceptable salts, solvates or prodrugs thereof. The present invention also relates to the preparation method of the compound or its pharmaceutically acceptable salt, solvate or prodrug, the pharmaceutical composition containing it and its use in the preparation of medicines for the treatment of CCR4-mediated leading diseases. Background technique [0003] CCR4 (Chemokine Receptor 4, Chemokine Receptor 4) was first discovered by Christine A.Power et al. in 1995 (Christine AP et al. J.Biol.Chem.1995,270(8):19495-19500), which belongs to chemotaxis One of the members of the factor receptor (CCR) family, it is a 7-transmembrane G-protein coupled receptor. It has two naturally occurring specific ligands: MDC (Macrophage-derived chemokine) and TARC (thymus and activation regulated chemokine) (Sadatoshi Maeda et al Veterinary Immunology and Immunopathology 2002(90):145-154). The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12A61K31/416A61P11/00A61P11/06A61P11/08A61P35/00A61P31/00A61P7/02A61P31/12A61P31/16A61P19/00A61P19/02A61P19/10A61P19/06A61P17/00A61P27/02A61P31/04A61P31/10A61P1/00A61P15/00
CPCC07D409/12A61K31/416A61P1/00A61P7/02A61P11/00A61P11/06A61P11/08A61P15/00A61P17/00A61P19/00A61P19/02A61P19/06A61P19/10A61P27/02A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P31/16A61P35/00A61P37/08
Inventor 赵海峰
Owner MEDSPRING INT LTD
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