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1, 2, 4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents

a technology of benzotriazine oxide and radiosensitizer, which is applied in the direction of biocide, heterocyclic compound active ingredients, organic chemistry, etc., can solve the problems of only practical radiation treatment to destroy tumor cells, and difficult to achieve tumor cell selectivity

Inactive Publication Date: 2005-07-14
LEE WILLIAM W +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Of course, the use of radiation treatment to destroy tumor cells is only practical if damage to the surrounding normal tissue can be minimized or avoided.
Therefore, selectivity for tumor cells toward radiation is difficult to achieve—normal cells, in view of their oxygen supply, are generally more susceptible to radiation than the target tumor cells.
This, however, has proved difficult to do.
Hence, administration of “radiosensitizers” which operate according to this latter mechanism does not accomplish the desired purpose of selectively sensitizing the target tumor cells.

Method used

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  • 1, 2, 4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
  • 1, 2, 4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
  • 1, 2, 4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents

Examples

Experimental program
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Effect test

example 1

Preparation of 3-Hydroxy-1,2,4-Benzotriazine 1,4-Dioxide

[0217]

[0218] A stirred mixture of 1.50 g (9.25 mmole) of 3-amino-1,2,4-benzotriazine 1-oxide (1), 100.0 ml acetic acid, and 30.0 ml of 30% hydrogen peroxide was treated with 3.05 g (9.25 mmole) of Na2WO4 2H2O. The mixture was stirred in an oil bath at 60° C. for 4 days. The yellowish orange mixture was cooled to about 30° and filtered to remove a light yellow non-UV absorbing solid. The orange solution of hydrogen peroxide in acetic acid was evaporated to semi-dryness carefully with several additions of water and acetic acid to remove most of the peroxide. The concentrated solution was allowed to stand at room temperature to afford four crops of an orange solid, 0.87 g (42% yield of the sodium salt of 2). UVmax (20% CH3OH / H2O): 262.2 (ε 39,460); 477 (ε 7,030)., IR (neat): 3530μ, 3150μ, 2650μ, 2180μ and 1635μ. Anal. (calculated for the sodium salt): C7H4N3O3Na 1.25H2O, 223.64: C, 37.6; H, 2.93; N, 18.79. Found: C, 37.8; H, 2.75...

example 2

Preparation of 3-Amino-7-Trifluoromethyl-1,2,4-Benzotriazine 1-Oxide

[0219]

[0220] A mixture of 4-chloro-3-nitrobenzotrifluoride (Aldrich, 2.70 g, 12.9 mmole) and cyanamide dihydrochloride (2.75 g, 24 mmole) (previously prepared by treating an ether solution of cyanamide with HCl gas and collecting the precipitated solid) was heated at 140° C. for 1 h. The residue was treated with 2N NaOH (45 ml), heated for a further 5 min, and then allowed to cool. The precipitate was collected, washed with H2O, dried, and triturated with acetone-toluene to yield 1.32 g (45%) of 3 as a light yellow solid M.P. 301-302°, TLC: Rf 0.60 (9:1 methylene chloride:methanol on silica gel plates). Mass. Spec.: M+=230 (q=100).

example 3

Preparation of 3-Amino-7-Decyl-1,2,4-Benzotriazine 1-Oxide

[0221]

[0222] Preparation of 4-(1-decyl)-2-nitroaniline: Acetic anhydride (400 ml) was added over a 30-minute period to a stirred solution of 4-decylaniline (Aldrich, 80 g, 0.34 mole) in hexanes (2.41). After stirring for 1 h, the mixture was cooled and treated over 30 min. at 5-10° C. with 70% nitric acid (34 ml). Stirring was continued at 5-10° C. for 1 h and at 25° C. for 16 h. The mixture was diluted with H2O (11), stirred for 5 h, poured into an open dish and allowed to stand for 16 h. After further dilution with H2O (1.51), the solid was collected and recrystallized from an 85% ethanol solution (in water) to give 92 g (84%) of the intermediate as an orange solid, m.p. 64° C.

[0223] A solution (100 ml) of 85% KOH (19 g, 0.288 mole) in H2O was combined with a suspension of 4-(1-decyl)-2-nitroaniline (89 g, 0.28 mole), prepared above, in methanol (900 ml). The mixture was stirred for 6 h, neutralized to pH 7-8 with concent...

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Abstract

A method of using 1,2,4-benzotriazine oxides, some of which are novel compounds, as radiosensitizers and selective cytotoxic agents is disclosed. These compounds are shown to specifically radiosensitize hypoxic tumor cells. Some are additionally disclosed to be useful as specific cytotoxic agents for these cells. They also show an unexpected ability to radiosensitize aerobic cells following or preceding a hypoxic incubation of the cells with the drug. This provides a basis for selective radiosensitization of tumors compared to normal cells. A novel method for preparing the 1,2,4-benzotriazine oxides is also disclosed.

Description

[0001] This application is a continuation-in-part of U.S. application Ser. No. 356,602, filed 24 May 1989, which was a continuation of U.S. application Ser. No. 169,873, filed 18 Mar. 1988, now abandoned, which in turn was a continuation-in-part of U.S. application Ser. No. 911,906, filed 25 Sep. 1986, also abandoned.REFERENCE TO GOVERNMENT GRANT OR CONTRACT [0002] The invention described herein was made in the course of work under grant or contract from the Department of Health and Human Services. The Government has certain rights in this invention.TECHNICAL FIELD [0003] The invention relates to cytotoxic agents and radiotherapy effective against hypoxic cells. More specifically, the invention relates to certain novel 1,2,4-benzotriazine oxides, to methods of selectively killing tumor cells and / or sensitizing tumor cells to radiation using selected 1,2,4-benzotriazine oxides, and to novel synthetic methods. BACKGROUND ART [0004] Hypoxic cell radiosensitizers are compounds that sele...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/53A61K31/5377A61K41/00C07D253/10
CPCA61K31/53C07D253/10A61K41/0038A61K31/5377
Inventor LEE, WILLIAM W.BROWN, J. MARTINGRANGE, EDWARD W.MARTINEZ, ABELARDO P.TRACY, MICHAELPOLLART, DANIEL J.
Owner LEE WILLIAM W
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