Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo

a technology of indirubin and analogs, applied in the field of hyperproliferation diseases including oncology, can solve the problems of inability to meet preclinical testing and federal regulatory requirements for clinical evaluation, failure or disappointment of chemical agents in human clinical trials, and inability to rationally and successfully discover useful therapies, etc., to improve the utility of chemical agents with suboptimal performance, improve the effect of dose determination and schedule, and improve the therapeutic benefi

US20150087687A1Pending Publication Date: 2015-03-26BROWN DENNIS
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Patent Information

Authority / Receiving Office
US · United States
Current Assignee / Owner
Publication Date
2015-03-26

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Abstract

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutically active agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo.
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Description

CROSS-REFERENCES

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 61 / 614,724 by D. M. Brown, filed Mar. 23, 2012 and entitled “Compositions and Methods to Improve the Therapeutic Benefit of Indirubin and Analogs Thereof, Including Meisoindigo,” the contents of which are incorporated herein in their entirety by this reference.FIELD OF THE INVENTION

[0002] The present invention relates to the general field of hyperproliferative diseases including oncology with a focus on novel methods and compositions for the improved utility of chemical agents, compounds, and dosage forms previously limited by suboptimal human therapeutic performance including indirubin and analogs thereof, such as meisoindigo.BACKGROUND OF THE INVENTION

[0003] The search for and identification of cures for many life-threatening diseases that plague humans still remains an empirical and sometimes serendipitous process. While many advances have been made from basic scientific research to i...

Examples

example 1

Synthesis of Meisoindigo

[1056]Prior Process

[1057]To synthesis meisoindigo, typically, add equal molar amount of 2-hydroxyindole and N-methyl-indolinyl-diketone, glacial acetic acid (2.0 L of glacial acetic acid for one mole of the reaction substances), and hydrochloric acid (concentrated, 6.67 ml of HCl for one mole of the reaction substances) into three-neck flask, heat to 70-80° C., stir for 2 h, cool to room temperature. Bulk brown crystal precipitates are then formed. Filter, and sequentially wash with glacial acetic acid, dH2O, and ethanol. The melting point is measured. It should be between 235-237° C. Filter, and sequentially wash with glacial acetic acid, dH2O, and ethanol. Melt point is measured. It should be between 235-237° C.

[1058]Newly Developed Process

[1059]An outline of the process is shown in Table 1.

TABLE 1Reaction solution*Reaction ConditionsPurification ProcessAcetic acid (15v)70-80° C. for 3 hrsCool to 25-30° C., filter,Conc. HCl (0.05v)wash with acetic acid (5v)...

example 2

Effect of Meisoindigo on Viability of Cancer Cell Lines

[1077]FIG. 1 shows the viability of the AML cell line MV 4-11 (FLT-3 ITD) after meisoindigo treatments. Viability at 48 hours is shown by (♦); viability at 24 hours is shown by (▪). Results are shown for a control, 1% DMSO without meisoindigo, 0.1 μM meisoindigo, 1 μM meisoindigo, 10 μM meisoindigo, and 100 μM meisoindigo.

[1078]FIG. 2 shows the viability of a number of myeloid cell lines in terms of the percentage of viable cells after 24 hours of treatment with meisoindigo. Results are shown for a control, 1% DMSO without meisoindigo, 0.1 μM meisoindigo, 1 μM meisoindigo, 10 μM meisoindigo, and 100 μM meisoindigo.

[1079]FIG. 3 shows the viability of a number of additional myeloid cell lines in terms of the percentage of viable cells after 24 hours of treatment with meisoindigo. Results are shown for a control, 1% DMSO without meisoindigo, 0.1 μM meisoindigo, 1 μM meisoindigo, 10 μM meisoindigo, and 100 μM meisoindigo.

[1080]FIG. ...