Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof

A drug and compound technology, applied in the field of thrombopoietin mimics and thrombopoietin receptor agonists, can solve the problems of not specifying the form of the salt, reducing the bioavailability of the compound in vivo, and poor solubility of the compound

Active Publication Date: 2012-10-03
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the international application PCT / CN2009 / 000001 does not specifically describe the salt form of any one compound
[0010] The present inventors have found that the free acids of bicyclic substituted pyrazolone azo derivatives have poor solubility in conventional solvents, which is not conducive to being prepared into pharmaceutical dosage forms, and reduces the bioavailability of the compound in vivo, so it is urgent to develop bicyclic substituted pyrazoles A new form of ketoazo derivatives, which solves the problems of poor solubility and poor pharmacokinetic absorption of these compounds, and is suitable for conventional preparation processes

Method used

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  • Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof
  • Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof
  • Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] (Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) -hydrazino]-biphenyl -3-Carboxylic acid diethanolamine salt

[0114]

[0115]

[0116] first step

[0117] 2-Bromo-6-nitrophenol

[0118] Dilute 60mL of concentrated sulfuric acid into 186mL of water, add sodium nitrate (79.2g, 0.93mol) after cooling to room temperature, keep below 25°C, add o-bromophenol 1a (60mL, 0.52mol) dropwise, and react at room temperature for 2 hours. Add 320mL ethyl acetate to dissolve the separated solid, wash with water and saturated brine respectively, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel column chromatography to obtain 2-bromo-6-nitrate phenylphenol 1b (48.2 g, yellow solid). Yield: 42.8%.

[0119] MS m / z(ESI): 218[M+1]

[0120] 1 H NMR (400MHz, CDCl 3 ): δ11.18(s, 1H), 8.12-8.15(m, 1H), 7.89-7.91(m, 1H), 6.88-7.02(m, 1H)

[0121] second s...

Embodiment 2

[0160] (Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) -hydrazino]-biphenyl -2-Carboxylic acid bis(diethylamine) salt

[0161]

[0162] (Z)-2'-hydroxyl-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene )-hydrazino]-biphenyl-3-carboxylic acid 1j (150mg, 0.33mmol) was dissolved in 5mL tetrahydrofuran, and it was a dark red suspension. Diethylamine (48mg, 0.66mmol) was added dropwise under stirring, and it was purple Red solution, reacted at room temperature for 2 hours. A solid precipitated in the reaction solution, filtered, the filter cake was washed with tetrahydrofuran (1mL×3), and the obtained solid was dried under vacuum to obtain the title product (Z)-2′-hydroxyl-3′-[N′-(1- Indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-hydrazino]-biphenyl-3-carboxylic acid bis(diethylamine) Salt 2 (132 mg, red solid), yield: 66.7%.

[0163] HPLC: 99.2%

[0164] MS m / z(ESI): 452.9[M-1]

[0165] 1 H NMR (400MHz, CD 3...

Embodiment 3

[0167] (Z)-2'-Hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene) -hydrazino]-biphenyl -3-Carboxylic acid dipiperazine salt

[0168]

[0169] (Z)-2'-hydroxyl-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene )-hydrazino]-biphenyl-3-carboxylic acid 1j (150mg, 0.33mmol) was dissolved in 5mL tetrahydrofuran, and it was a dark red suspension, and piperazine (57mg, 0.66mmol) was added under stirring, and it was a purple-red solution , stirred at room temperature for 2 hours. A solid precipitated in the reaction solution, filtered, the filter cake was washed with tetrahydrofuran (1mL×3), and the obtained solid was dried under vacuum to obtain the title product (Z)-2′-hydroxyl-3′-[N′-(1- Indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-hydrazino]-biphenyl-3-carboxylic acid dipiperazine salt 3( 130 mg, dark red solid), yield: 62.8%.

[0170] HPLC: 98.5%

[0171] MS m / z(ESI): 452.8[M-1]

[0172] 1 H NMR (400MHz, CD 3OD): δ8.1...

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Abstract

The present invention relates to pharmaceutically acceptable salts of bicycle-substituted pyrazolon azo derivatives represented by the general formula (I), their preparation methods, 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 in the general formula (I) are the same as the description.

Description

technical field [0001] The present invention relates to a new pharmaceutically acceptable salt of bicyclic substituted pyrazolone azo derivatives, a preparation method thereof, a pharmaceutical composition containing the pharmaceutically acceptable salt, and its use as a therapeutic agent, especially as a platelet production agent. Use of TPO mimetic and thrombopoietin receptor agonist. Background technique [0002] Thrombopoietin (TPO), also known as megakaryocyte growth and development factor (MGDF), thrombocytopoiesis stimulating factor (TSF), c-Mpl ligand (c-myeloproliferative leukemia ligand , c-Mpl), the mpl ligand, megapoietin, is a glycoprotein associated with the production of platelets (Wendling, F., et.al., Biotherapy 10 (4): 269-77 (1998); Kuter D.J.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 rec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/655C07D231/46C07D405/12C07D409/12A61P7/00A61P7/04
CPCC07D405/12C07D409/12C07D231/46A61K31/4152A61K31/4155A61P7/00A61P7/04A61P43/00C07D295/027A61K45/06C07C211/05C07C211/27C07C215/08C07C215/10C07C215/40C07C279/14
Inventor 邓炳初吕贺军费洪博陈一千
Owner JIANGSU HENGRUI MEDICINE CO LTD
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