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Sulfonyl hydrazines as hypoxia-selective antineoplastic agents

A technology selected from and alkoxy groups, applied in the field of sulfonyl hydrazide prodrugs, can solve the problems of insufficient solubility and insolubility

Inactive Publication Date: 2007-08-22
VION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, KS119 is quite insoluble in aqueous solutions, and even does not have sufficient solubility (<5 mg / mL) in co-solubilization systems (such as polyethylene glycol (PEG) and ethanol) to meet the clinical needs of this drug

Method used

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  • Sulfonyl hydrazines as hypoxia-selective antineoplastic agents
  • Sulfonyl hydrazines as hypoxia-selective antineoplastic agents
  • Sulfonyl hydrazines as hypoxia-selective antineoplastic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-2

[0109] Phosphorylation of phenolic compounds

[0110] General Method A. To a stirred solution of the appropriate phenolic compound (10.0 mmol) in acetonitrile (15 mL) was added DMAP (1 mmol) and DIPEA (20 mmol) at room temperature. The reaction mixture was cooled to -13°C. A solution of dialkyl chlorophosphate (10 mmol) in acetonitrile (5 mL) was added dropwise to keep the internal temperature below -10°C. The reaction mixture was warmed to 0° C., then stirred continuously for 2 hours, and the completion was monitored by TLC. The reaction mixture was concentrated by rotary evaporation and washed with dichloromethane and 0.5M KHSO 4 aqueous solution to treat the oily residue. The organic layer was passed through anhydrous MgSO 4 Dry, then filter and concentrate to a brown viscous oil. The crude dialkylphosphine carboxy-aryl compound can be used without further purification.

[0111] 1-(3-Diethylphosphinecarboxy-4-nitrophenyl)ethanol (13). Following General Procedure A, ...

Embodiment 3

[0118] Grignard reaction of benzaldehydes

[0119]general method. To a solution of 4-nitrobenzaldehydes (4-nitrobenzaldehydes) (10 mmol) in anhydrous THF (30 mL) at -50 ° C for 45 minutes, slowly add a Grignard reagent, such as diethyl ether of methylmagnesium bromide (25 mmol ) solution. During the addition of the Grignard reagent, the temperature of the reaction mixture was kept below -40°C. The reaction mixture can be warmed to room temperature and stirred for 3.5 hours. The reaction mixture was cooled to -10 °C and quenched with 5% hydrochloric acid (25 mL). The reaction mixture was diluted with water (25 mL) and the product was extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with water to pH 5, passed through anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash chromatography on silica gel, eluting with 25% ethyl acetate in hexanes. After evaporation and drying in vacuo, α-alkyl 4-nitrobenzyl alcoho...

Embodiment 4

[0124] Reduction of acetophenones

[0125] general method. To a solution of chiral (R or S)-2-methyl-CBS-oxazaborlidine (oxazaborlidine) in A (1.0 M in toluene, 240 mL) was added 1.0 M BH 3 -THF solution (120 mL), and the resulting solution was cooled to -50°C. After 4 hours, slowly add 3'-hydroxy-4'-nitroacetophenone (100g) in THF / toluene (200mL / 800mL) solution and 1.0M BH to the above solution 3 - THF solution (1.0 L) while stirring vigorously. The reaction mixture was continuously stirred at -50°C for 2-3 hours, and the completion was monitored by HPLC. Acetone (200 mL) was then added dropwise to the reactor at -50°C. After stirring at -50 °C for 10 min, the reaction mixture was warmed to ambient temperature and stirred for 1.5 h. Concentrate by rotary evaporation on a 45°C bath, and the residue is saturated with Na 2 CO 3 Aqueous solution (2 L) was worked up. The mixture was heated at 50°C for 30 minutes and then cooled to room temperature. Tert-butyl methyl ether...

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Abstract

Novel phosphate-bearing prodrugs of sulfonyl hydrazines have the formulas (I), (II), (III) and (IV). Pharmaceutical compositions and uses thereof in the treatment of cancer are claimed. The aforementioned prodrugs include enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts or solvates and metabolites from all stages. The aforementioned prodrugs are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototheraphy or radiotherapy. Where R = C1-10 alkyl, or C1-10 haloalkyl (preferably containing no more than 5 halogen groups, preferably 2-chloroethyl); R' and R'' are independently C1-10 alkyl, or C5-20 aryl or heteroaryl (preferably methyl); R1 is H, C1-10 alkyl, C1-10 alkoxyl, C5-20 aryl or heteroaryl or C5-20 aroxyl or heteroaroxyl (preferably methyl and ethyl); X is O, NH, or NR (preferably O); Y is (CH2)n , where n = 1, 2, 3, 4 or 5 (preferably n = 2 and 3); or Y = aryl or heteroaryl (preferably para-phenyl); A = CH, or N (preferably CH); and B = CH=CH, O, S, NH, or NR (preferably CH=CH); or pharmaceutically acceptable salts, solvates, polymorphs or metabolites, thereof.

Description

field of invention [0001] The present invention relates to metabolically activated sulfonylhydrazide prodrugs (SHPs) that exhibit antitumor activity in mammals. Methods of treating neoplasia, including cancer in particular, are an additional part of the invention. [0002] related application [0003] This application claims priority from the following applications: U.S. Provisional Application No. US60 / 611,623, filed September 21, 2004; U.S. Provisional Application No. US60 / 615,419, filed October 1, 2004; Applied US Provisional Application No. US 60 / 616,500, any of which are incorporated herein by reference in their entirety. Background of the invention [0004] Eradication of solid tumors requires strategies to deal with viable populations of malignant cells in the hypoxic regions of these tumors. Inadequate and poorly organized vasculature is a major feature of rapidly growing tumor masses, resulting in hypoxic, high interstitial pressure, and a hypoxic, dormant, or sl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4196C07D249/08
Inventor 林旭伊凡·金迈克尔·F·贝尔考特特伦斯·W·多伊尔
Owner VION PHARMA INC
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