Compositions and methods of use thereof achiral analogues of CC-1065 and duocarmycins

A compound and chloride technology, which is applied to the composition of CC-1065 and the new achiral analogs of Docamex and its application field, can solve the problems of low efficiency and the like

Inactive Publication Date: 2003-12-10
SPIROGEN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While these methods are feasible, at least on a small scale, they are inefficient because during the chemical resolution step, all undesired enantiomers must be discarded
Moreover, only mi

Method used

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  • Compositions and methods of use thereof achiral analogues of CC-1065 and duocarmycins
  • Compositions and methods of use thereof achiral analogues of CC-1065 and duocarmycins
  • Compositions and methods of use thereof achiral analogues of CC-1065 and duocarmycins

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 12 Preparation of 2-(2-amino-4-hydroxyphenyl)ethyl bromide and 2-(2-amino-4hydroxyphenyl)ethyl chloride

[0061] Add EtOH (45mL) and 10% NaOH (60mL) to the round bottom containing diethyl 2-(4-benzyloxy-2-nitrophenyl)malonate (4c) (2.00g, 5.17mmol) In the flask, a dark brown solution was produced. The solution was refluxed for 3 hours and passed TLC (CHCl 3 ) Check that the solution is light yellow and clear at this time. The EtOH was removed under reduced pressure to form a yellow suspension, and enough THF (30 mL) was added to produce a clear yellow solution, which was placed in an ice bath and stirred. 6M HCl (30 mL) was slowly added to the solution to reach pH 1. The light orange solution was refluxed for another 1 hour, at which time two layers formed. Collect the upper THF layer and use CHCl 3 (100 mL) The aqueous solution was extracted. The organic layers were combined and dried over anhydrous sodium sulfate. The solution was then filt...

Embodiment 2

[0068] Example 2 N-(2-(2-chloroethyl)-4-hydroxyphenyl)-1-methyl-4-(1-methyl-4-butyramidopyrrole-2-amido)pyrrole-2 -Preparation of amides and their derivatives

[0069] Add cold methanol (100mL) to N-methyl-4-(N-methyl-4-nitropyrrole-2-amide)pyrrole-2-carboxylic acid methyl ester (3.00g, 9.8mmol) and 5% Pd / C (1.2g) mixture. The reaction mixture was hydrogenated for 18 hours and passed TLC (10% MeOH / CHCl 3 )an examination. After the reduction was completed, the amine was suction filtered with Celite and a sintered funnel, the filtrate was rotary evaporated to dryness and co-evaporated twice.

[0070] Using a syringe, distilled dichloromethane (30 mL) and butyryl chloride (1.00 mL, 10.8 mmol) were added to the dropping funnel through the septum. Then dissolve the amine in anhydrous THF (75mL) and add Et 3 N (1.5 mL, 10.8 mmol). The amine mixture was stirred in an ice bath for 5 minutes, and then the butyryl chloride mixture was slowly dropped. A light peach-c...

Embodiment 3

[0075] Example 34-(2-Chloroethyl)-3-[[5-(4-bis-(2-chloroethyl)amino)benzamide]indole-2-amide]phenol and its derivatives Preparation

[0076] A suspension of 2-(2-amino-4-hydroxyphenyl)ethyl chloride (310 mg, 1.81 mmol), 10% Pd-C (233 mg) was hydrogenated in dry THF (10 mL) at room temperature and atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated to obtain the amine as a white solid. Add 5-nitroindole-2-carboxylic acid (372 mg, 1.81 mmol), EDCI (1.04 g, 5.42 mmol) and dry DMF (10 mL). The reaction mixture was stirred for two days under a nitrogen atmosphere at room temperature. Use Kugelrohr device (0.1mmHg, 60□) to remove the solvent, and use CHCl 3 Distribute the residue with water. The aqueous layer was extracted with ethyl acetate (twice). Dry the combined organic extracts (Na 2 SO 4 ). The brown oily residue was purified by silica gel chromatography (0->50% ethyl acetate: chloroform per 50 mL) to isolate 4-(...

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PUM

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Abstract

The present invention relates to novel achiral seco-analogues of the DNA minor groove and sequence-selective alkylating agents (+)-CC1065 and the duocarmycins, depicted as general class (I), (II), (III), (IV) and (V) wherein X is a good leaving group, such as chloride, a bromide, an iodide, a mesylate, a tosylate, an acetate, a quaternary ammonium moiety, a mercaptan, an alkylsulfoxyl, or an alkylsulfonyl group, preferably either a chloride, a bromide, or an iodide group. R1 is a suitable minor groove binding agent to enhance the interactions of the achiral seco-cyclopropaneindole (CI) or an achiral seco-duocarmycin with specific sequences of DNA. R and R2-R5 are defined in claim 1.

Description

[0001] Related application [0002] This application is a partial continuation application of US Patent Application 09 / 666,160, which is incorporated herein by reference. Technical field [0003] The present invention relates to new (+)-CC1065 and duocarmycins achiral seco-analogs and pharmaceutical compositions containing the achiral analogs. (+)-CC1065 and Docamixin achiral analogues are used as anticancer drugs. Background technique [0004] A class of compounds that have received much attention recently are DNA minor groove binders (1a) that exert their anticancer activity by alkylating specific DNA sequences. Minor groove interaction agents are more attractive than intercalators and major groove binders, because the minor groove is generally only occupied by spine of hydration, and therefore the anticancer drugs are more accessible. In addition, covalent modifications in the minor groove are generally more toxic to cells than their major groove alkylation counterparts, such a...

Claims

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Application Information

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IPC IPC(8): C07D235/18A61K31/167A61K31/4025A61K31/404A61K31/4184A61K31/496A61P35/00C07C215/76C07C231/10C07C233/24C07C235/38C07C271/28C07C271/30C07D207/34C07D207/40C07D207/416C07D209/42C07D213/64C07D213/69C07D235/24C07D405/12C07D405/14
CPCC07D235/24C07C235/38C07C215/76C07D405/12C07D213/64C07D213/69C07C271/28C07C271/30C07D207/416C07D209/42Y02P20/55A61P35/00
Inventor 摩西·李
Owner SPIROGEN
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