Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof

A pharmacy and compound technology, applied in the field of bicyclic substituted pyrazolone azo derivatives, can solve problems such as lack of natural TPO sequence homology

Active Publication Date: 2011-06-08
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(WO96 / 40750, WO98 / 25965) These polypeptides can bind and activate TPO receptors, but do not have the sequence homology of natural TPO

Method used

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  • Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof
  • Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof
  • Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] 2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-hydrazino] -Biphenyl-3-carboxylic acid

[0093]

[0094] first step

[0095] 2-Bromo-6-nitrophenol

[0096]Dilute 60 mL of concentrated sulfuric acid into 186 mL of water, add sodium nitrate (79.2 g, 0.932 mol) after cooling to room temperature, keep below 25 °C, add o-bromophenol 1a (60 mL, 0.516 mol) dropwise, and react at room temperature for 2 hours. TLC tracked until the raw material disappeared, and added 320mL ethyl acetate to dissolve the separated solid, washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The title product 2-bromo-6-nitrophenol 1b was obtained (48.2 g, yellow solid). Yield: 42.8%.

[0097] MS m / z(ESI): 218[M+1]

[0098] 1 HNMR (400MHz, CDCl 3 ): δ6.88-7.02(m, 1H), 7.89-7.91(...

Embodiment 2

[0133] 5'-fluoro-2'-hydroxy-3'[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) -hydrazino]-biphenyl-3-carboxylic acid

[0134]

[0135] first step

[0136] 2-Bromo-4-fluoro-6-nitrophenol

[0137] 2-Bromo-4-fluoro-phenol 2a (8.0g, 41.9mmol) was dissolved in 10mL sulfuric acid solution (50%) under ice-salt bath, and sodium nitrate (7.1g, 83.5mmol) was added dropwise in 24mL sulfuric acid solution (25 %), reacted at room temperature for 1.5 hours. TLC tracked until the raw material disappeared, added 50mL of water, extracted with ethyl acetate (50mL×2), combined the organic phases, washed the ethyl acetate layer with water and saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and the filtrate was reduced to Concentrated under reduced pressure to obtain the title product 2-bromo-4-fluoro-6-nitrophenol 2b (8.0 g, red solid), which was directly used in the next reaction, yield: 80.8%.

[0138] second step

[0139] 1-Bro...

Embodiment 3

[0161] 2'-Hydroxy-3'-{N'-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalene-2-yl)-1,5-dihydropyridine Azol-4-ylidene]-hydrazino}-biphenyl-3-carboxylic acid

[0162]

[0163] first step

[0164] 2-hydrazino-5,6,7,8-tetrahydronaphthalene

[0165] Dissolve 3 g (3.68 g, 25.0 mmol) of 2-amino-5,6,7,8-tetrahydronaphthalene in 20 mL of concentrated hydrochloric acid under an ice bath, and stir for 10 minutes. 10 mL of sodium nitrite solution (1.72 g, 25.0 mmol) was added dropwise, and stirring was continued for 15 minutes under ice-cooling.

[0166] Dissolve stannous chloride dihydrate (22.6 g, 100 mmol) in 10 mL of concentrated hydrochloric acid in an ice-salt bath, add the spare intermediate solution, and react at room temperature for 1.5 hours. Adjust the pH to 9 with 40% sodium hydroxide solution in an ice bath, add 400 mL of ethyl acetate to extract, concentrate under reduced pressure, and dry to obtain the title product 2-hydrazino-5,6,7,8-tetrahydronaphthalene 3h (2.19 ...

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Abstract

The bicycle-substituted pyrazolon-azo derivatives of formula (I) or pharmaceutical acceptable salts, hydrates or solvates thereof, methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially as thrombopoietin (TPO) mimetics and their use as agonists of thrombopoietin receptor. The definitions of substituents of formula (I) are the same as the description.

Description

technical field [0001] The present invention relates to a new bicyclic substituted pyrazolone azo derivative represented by general formula (I), its preparation method and pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially a thrombopoietin (TPO) analog substances and their use as thrombopoietin receptor agonists. Background technique [0002] Thrombopoietin (TPO), also known as megakaryocyte growth and development factor (MGDF), thrombocytopoiesis stimulating factor (TSF), c-Mpl ligand (c-myeloproliferativeleukemia ligand, c-Mpl), mpl ligand, megapoietin is a glycoprotein related to platelet production (Wendling, F., et.al., Biotherapy 10 (4): 269-77 (1998); Kuter D.l.et al., The Oncologist; 1:98-106 (1996); Metcalf, Nature 369:519-520 (1994)). [0003] In certain instances, the activity of TPO results from the binding of TPO to the TPO receptor (also known as MPL). The TPO receptor has been successfully cloned and its ami...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4152A61K31/352C07D311/04C07D307/79A61P7/00A61K31/655C07D231/20A61K31/343
CPCC07D409/12C07D403/12C07D231/38C07D231/22C07D405/12C07D417/12C07D405/04A61P43/00A61P7/00A61P7/04A61P7/06C07D231/08C07D405/10
Inventor 邓炳初吕贺军郑浩陈一千费洪博王胜蓝王莉
Owner JIANGSU HENGRUI MEDICINE CO LTD
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