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Ethylidene hydrazine carboxamide derivatives, preparation process and pharmaceutical use thereof

An alkyl and pharmacy technology, applied in the direction of pharmaceutical formulations, drug combinations, medical preparations containing active ingredients, etc., can solve the problem of lack of natural TPO sequence homology

Active Publication Date: 2013-07-10
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(WO96 / 40189, WO96 / 40750, WO98 / 25965) These polypeptides are designed to bind and activate TPO receptors, but do not have sequence homology to native TPO

Method used

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  • Ethylidene hydrazine carboxamide derivatives, preparation process and pharmaceutical use thereof
  • Ethylidene hydrazine carboxamide derivatives, preparation process and pharmaceutical use thereof
  • Ethylidene hydrazine carboxamide derivatives, preparation process and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103]

[0104] first step

[0105] Methyl 3-(hydrazinesulfonylamino)benzoate

[0106] Dissolve methyl 3-isothiocyanate benzoate 1a (3.0g, 15.5mmol) in 30mL of absolute ethanol, add 50% hydrazine hydrate solution (3mL, 30mmol) and 20mL of absolute ethanol while stirring, and heat to reflux 1 hour. The reaction was tracked by TLC until the raw materials disappeared, the reaction solution was cooled to room temperature, filtered, and the filter cake was dried under vacuum to obtain methyl 3-(hydrazinesulfonylamino)benzoate 1b (3.1 g, white solid). Yield: 88.8%.

[0107] MSm / z(ESI): 226[M+1]

[0108] 1 HNMR (400MHz, CD 3 OD-d 4): δ9.25(s, 1H), 8.35(s, 1H), 7.88(d, 1H, J=6.4Hz), 7.69(d, 1H, J=7.2Hz), 7.44(t, 1H, J= 8.4Hz), 4.76(br, 2H), 3.86(s, 3H)

[0109] second step

[0110] 1-m-tolyl-1,3-dihydroindolin-2-one

[0111] Using a known method [Bulletinde la Societe Chimique de France (1968), (3), 1090-1.], 1,3-dihydroindolin-2-one 1c (20g, 150mmol), m-bromotoluene (30....

Embodiment 2

[0130]

[0131] first step

[0132] 1-(3,4-Xylyl)-1,3-dihydroindolin-2-one

[0133] 1,3-indolin-2-one 2a (8.0g, 60.1mmol), 4-bromo-1,2-xylene (13.4g, 72.2mmol), cuprous iodide (2.29g, 12.0mmol ) and potassium carbonate (20.7g, 150mmol) were dissolved in 250mL of acetonitrile, N, N'-dimethyl-1,2-ethylenediamine (1.59g, 18mmol) was added under stirring, and heated to reflux for 2 hours. TLC followed the reaction until the raw materials disappeared, added 500mL of water, adjusted the pH=5 with 1N hydrochloric acid, extracted with ethyl acetate (100mL×3), dried over anhydrous magnesium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the obtained product by silica gel column chromatography The residue gave 1-(3,4-xylyl)-1,3-indolin-2-one 2b (8.0 g, yellow solid). Yield: 57.1%.

[0134] MSm / z(ESI): 238[M+1]

[0135] second step

[0136] (Z)-3-(1-Dimethylaminoethylene)-1-(3,4-xylyl)-1,3-dihydroindolin-2-one

[0137] Dissolve 1-(3,4-xylyl)-1,...

Embodiment 3

[0157]

[0158] first step

[0159] 1-(4-Methylphenyl)-1,3-dihydroindolin-2-one

[0160] Using a known method [Bulletinde la Societe Chimique de France (1968), (3), 1090-1.], 1,3-dihydroindolin-2-one 1c (13.3g, 100mmol), p-bromotoluene (20.5g, 120mmol) , cuprous iodide (3.8g, 20mmol) and potassium carbonate (30.36g, 220mmol) were dissolved in 150mL acetonitrile, and N, N'-dimethyl-1,2-ethylenediamine (2.67g, 30mmol) was added under stirring ), heated to reflux for 2 hours. TLC followed the reaction until the raw materials disappeared, added 500mL of water, adjusted the pH=5 with 1N hydrochloric acid, extracted with ethyl acetate (150mL×3), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography The residue gave the title product 1-(4-methylphenyl)-1,3-indolin-2-one 3a (16.0 g, pale yellow solid). Yield: 71.7%.

[0161] MSm / z(ESI): 224[M+1]

[0162] second step

[0163] (Z)...

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PUM

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Abstract

Ethylidene hydrazidecarboxamide derivatives of formula (I) or pharmaceutically acceptable salts, hydrate or solvation 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 in formula (I) are the same as the description.

Description

technical field [0001] The present invention relates to a novel ethylenehydrazine amide derivative represented by the general formula (I), its preparation method and a pharmaceutical composition containing the derivative, and it is used as a therapeutic agent, especially as a thrombopoietin (TPO) Mimetics and use as thrombopoietin receptor agonists. Background technique [0002] Thrombopoietin (TPO), also known as megakaryocyte growth and development factor (megakaryocyte growth and development factor, MGDF), thrombocytopoiesis stimulating factor (thrombocytopoiesis stimulating factor, TSF), c-Mpl ligand (c-myeloproliferativeleukemialigand, c-Mpl), mpl ligand The body, megapoietin, is a glycoprotein associated with the production of platelets (Wendling, F., et.al., Biotherapy 10(4):269-77 (1998); KuterD.l.etal., 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 TP...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/263C07D209/14C07D231/22C07D403/12C07C243/38C07D257/04A61K31/4015A61K31/4152A61K31/4155A61P7/04A61P43/00
CPCC07D207/263C07D231/22C07D403/12C07D257/04C07C335/40C07D209/14A61P7/00A61P7/04A61P43/00
Inventor 邓炳初吕贺军陈一千宋鹏王胜蓝
Owner JIANGSU HENGRUI MEDICINE CO LTD
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