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Acyl-hydrazone and oxadiazole compounds, pharmaceutical compositions containing the same and uses thereof

A technology of compound and application, applied in the field of treatment of acute lymphoblastic leukemia, capable of solving problems such as low selectivity

Inactive Publication Date: 2014-11-19
UNIVERSIDADE FEDERAL DE SANTA CATARINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In a recent study, Wang and colleagues (Wang, Z.; Lu, Y.; Seibel, W.; Miller, D.D.; Li, W. Identifying Novel Molecular Structures for Advanced Melanoma by Ligand-Based Virtual Screening. Journal of Chemical Information and Modeling, 2009, 49, 1420-1427) evaluation of new antitumor compounds based on the structure of compound LY-1-100, which has a proven effect on microtubules (colchicine binding site) Mechanism of action and affinity, but low selectivity

Method used

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  • Acyl-hydrazone and oxadiazole compounds, pharmaceutical compositions containing the same and uses thereof
  • Acyl-hydrazone and oxadiazole compounds, pharmaceutical compositions containing the same and uses thereof
  • Acyl-hydrazone and oxadiazole compounds, pharmaceutical compositions containing the same and uses thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0114] Example 1: General procedure for the preparation of 3,4,5-trimethoxyphenyl-hydrazone 01-29

[0115] For the synthesis of 3,4,5-trimethoxyphenyl-hydrazone 01-29 we used the method described by Troeberg and col (Troeberg, L.; Chen, X.; Flaherty, T.M.; Morty, R.E.; Cheng, M. ; Hua, H.; Springer, C.; McKerrow, J.H.; Kenyon, G.L.; Lonsdale-Eccles, J.D.; Coetzer, T.H.T.; , 6, 660-669). In a 100mL / 1-mouth reaction flask, 3,4,5-trimethoxyphenyl-hydrazide (2mmol) prepared as described in Example 2 was put into an organic solvent: acetone, ethyl acetate, ether, ethanol, methanol (20mL) and the appropriate aldehyde (2mmol). The mixture was refluxed for 1 to 10 hours. Then, the solution was filtered and the solid was recrystallized in an organic solvent.

Embodiment 2

[0116] Example 2: General procedure for obtaining 3,4,5-trimethoxyphenyl-hydrazide for obtaining 3,4,5-trimethoxyphenyl-hydrazone 01-29

[0117] For the synthesis of 3,4,5-trimethoxyphenyl-hydrazides used in the preparation of acylhydrazones 01-29, we used methods already described (Chida, A.S.; Vani, P.V.S.N.; Chandrasekharam, M.; Srinivasan, R.; Singh, A.K. Synthesis of 2,3-dimethoxy-5-methyl-1,4-benzoquinone: a key fragment in coenzyme-Q series. Synthetic communications, 31, 657-660, 2001) in two steps:

[0118] Obtaining the ester: In a 1000mL / 1 neck reaction flask, combine gallic acid (50g, 0.294mol) with dimethyl sulfate (178.1g, 1.413mol), anhydrous potassium carbonate (175.5g, 1.293mol) and TBAI (tetrabutyl Ammonium iodide) (1 g) together in an organic solvent which can be ethanol, diethyl ether, ethyl acetate, acetone, petroleum ether (375 ml) and refluxed for 1 to 12 hours. The obtained solid was filtered and washed with the same organic solvent (3 x 50 mL). The es...

Embodiment 3

[0120] Example 3: General procedure for the preparation of phenyl-hydrazones 30-35

[0121] For the synthesis of phenyl-hydrazones 30-35 we used the method described by Troeberg and col (Troeberg, L.; Chen, X. ; Flaherty, T.M.; Morty, R.E.; Cheng, M.; Hua, H.; Springer, C.; McKerrow, J.H.; Kenyon, G.L.; and related amides kill cultured Trypanosoma brucei brucei. Molecular Medicine, 2000, 6, 660-669).

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Abstract

The present invention relates to acyl-hydrazone compounds, in particular 3,4,5-trimethoxyphenyl-hydrazide derivatives, as well as the oxadiazole analogs thereof and other similar compounds, and to the pharmaceutical use of the same for the treatment of various diseases associated with cell proliferation, such as leukemias, including acute lymphoblastic leukemia (ALL), tumours and inflammation. Acyl-hydrazones have been obtained having activity similar to that of the compound used as a standard in experiments (colchicine). The greater selectivity of the compounds according to the invention is an important feature, associated with fewer side effects than the pharmaceuticals used at present in clinical treatments. The synthetised acyl-hydrazones, more particularly the compounds 02 and 07, exhibited important anti-leukemic activity, which suggests 02 and 07 as candidates to pharmaceutical prototypes, or to pharmaceuticals for the treatment of leukemias, in particular acute lymphoblastic leukemia (ALL), tumours and other proliferative diseases, such as inflammation. The action mechanism of the most active compounds was determined by using DNA microarrays and subsequent tests indicated by the chip, besides selectivity studies in healthy human lymphocytes.

Description

field of invention [0001] The present invention relates to acyl-hydrazones derived from 3,4,5-trimethoxyphenylhydrazide for use in the treatment of diseases associated with cell proliferation such as leukemia, tumors, inflammation and other proliferative diseases. More specifically, the present invention relates to compounds having inhibitory activity on cyclin-dependent kinases (CDK) and topoisomerase I, which compounds are therefore useful in the treatment of acute lymphoblastic leukemia (ALL). The present invention also relates to novel acyl-hydrazones and oxadiazoles obtained from 3,4,5-trimethoxyphenyl-hydrazides. Background of the invention [0002] Cancer is a disease characterized by the proliferation and uncontrolled spread of abnormal human cell forms throughout the body. Tumor cells differ from normal cells in their high invasive capacity, loss of function, loss of differentiation and ability to metastasize due to lower adhesion between them (Rang, H.P.; Dale, M....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/86C07D271/107C07D233/54C07D333/02A61K31/166A61K31/4164A61K31/381A61P35/02
CPCC07D333/36C07D233/64C07C251/86C07D271/107C07D333/22A61P35/00A61P35/02A61K31/166A61K31/381A61K31/4164A61K31/4245C07D333/42C07C243/38
Inventor R·J·尼内丝A·马斯卡雷洛R·A·尤尼斯T·R·斯顿夫P·C·莱亚尔J·A·尤尼斯C·佩雷拉·德·索萨·梅洛R·R·卡内瓦罗洛L·多梅内吉尼·基亚拉迪亚A·博尔托利尼·西尔韦拉A·B·A·拉兰热拉
Owner UNIVERSIDADE FEDERAL DE SANTA CATARINA
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