Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof

a technology of benzylidenehydrazide and indole-2-carboxylic acid, which is applied in the field of substituted indole-2-carboxylic acid benzylidenehydrazide and analogs, can solve the problems of bone marrow toxicity, cancer cells lose the capacity to undergo cellular suicide, and cancer cells become cancerous, so as to prevent or ameliorate neoplasia and cancer. , to achieve th

Inactive Publication Date: 2002-09-12
CYTOVIA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become cancerous.
Thus, a drug like 6-mercaptopurine can cause bone marrow toxicity while remaining ineffective for a slow growing tumor.

Method used

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  • Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof
  • Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof
  • Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

5-Chloro-3-methyl-indole-2-carboxylic Acid (4-Methylbenzylidene)-hydrazide

[0188] A solution of 5-chloro-3-methyl-indole-2-carboxylic acid hydrazide (13 mg, 0.054 mmol), p-tolualdehyde (6.5 mg, 0.054 mmol) in ethanol (5 mL) was refluxed for 8 h. It was evaporated in vacuo and the residue was purified by column chromatography (silica gel, EtOAc / Hexane=4:1) to give 7.8 mg (42%) of the title compound. .sup.1H NMR (CD.sub.3OD): 8.26 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.62 (bs, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.28-7.21 (m, 3H), 2.58 (s, 3H), 2.39 (s, 3H).

example 2

5-Chloro-3-methyl-indole-2-carboxylic Acid (Benzylidene)-hydrazide

[0189] The title compound was prepared similar to Example 1. From 5-chloro-3-methyl-indole-2-carboxylic acid hydrazide (26 mg, 0.11 mmol) and benzaldehyde (11 mg, 0.11 mmol) was obtained 14 mg (39%) of the title compound. .sup.1H NMR (DMSO-d.sub.6): 11.56 (bs, 1H), 8.37 (bs, 1H), 7.73 (bs, 2H), 7.71 (bs, 1H), 7.55-7.44 (m, 3H), 7.23 (d, J=7.2 Hz, 1H), 4.40 (bs, 1H), 2.50 (s, 3H).

example 3

5-Chloro-3-methyl-indole-2-carboxylic Acid (4-Dimethylaminobenzylidene)-hy- drazide

[0190] The title compound was prepared similar to Example 1. From 5-chloro-3-methyl-indole-2-carboxylic acid hydrazide (24 mg, 0.1 mmol) and p-dimethylaminobenzaldehyde (14.9 mg, 0.1 mmol) was obtained 5 mg (21%) of the title compound. .sup.1H NMR (CD.sub.3OD): 10.9 (bs, 1H), 9.07 (bs, 1H), 8.2-6.6 (m, 6H), 3.06 (s, 6H), 2.70 (s, 3H).

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PUM

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Abstract

The present invention is directed to substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs thereof, represented by the general Formula I: 1 wherein X, Ar.sub.1, R.sub.2-R.sub.6 and R.sub.12 are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. The compounds of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

Description

BACKGROUND OF THE INVENTION[0001] 1. Field of the Invention[0002] This invention is in the field of medicinal chemistry. In particular, the invention relates to substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs, and the discovery that these compounds are activators of caspases and inducers of apoptosis. The invention also relates to the use of these compounds as therapeutically effective anti-cancer agents.[0003] 2. Description of Background Art[0004] Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis, et al., Dev. 112:591-603 (1991); Vaux, et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or other...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/341A61K31/381A61K31/404A61K31/4439A61K45/06
CPCA61K31/341A61K31/381A61K31/404A61K31/4439A61K45/06A61K2300/00
Inventor CAI, SUI XIONGDREWE, JOHN A.ZHANG, HAN-ZHONG
Owner CYTOVIA INC
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