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Cytotoxic agents comprising new ansamitocin derivatives

A cell and binding agent technology, applied in the direction of antiviral agent, antifungal agent, non-central analgesic agent, etc., can solve the problem of unreported cancer cell killing activity and so on

Inactive Publication Date: 2013-08-28
IMMUNOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In vivo cell killing activity against cancer cells not reported

Method used

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  • Cytotoxic agents comprising new ansamitocin derivatives
  • Cytotoxic agents comprising new ansamitocin derivatives
  • Cytotoxic agents comprising new ansamitocin derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0348] Example 1. In Vitro Cytotoxicity

[0349]Cytotoxicity studies were performed using clonogen assays. The test cell lines (KB and SK-Br-3) were seeded in 6-well dishes at a constant number of 1000 cells per well. Cells were incubated with various concentrations (0 to 3 nM) of various ansamitocins or maytansines for 72 hours. The medium was then aspirated from the plate and replaced with fresh medium. The medium was allowed to grow, and colonies formed after a total of 7-10 days post inoculation. The medium was then fixed and stained with 0.2% crystal violet in 10% formalin / PBS, and colonies were counted. The seeding efficiency of untreated cells (medium only) was determined by dividing the number of counted colonies by the number of cells seeded. The fraction of drug-exposed cells survived was determined by dividing the number of drug-exposed colonies in wells by the number of colonies in control wells.

[0350] The results of in vitro cytotoxicity measurements of va...

Embodiment 2

[0351] Example 2. Preparation of derivatized carboxylic acids

[0352] Compound 28: 3-Mercaptopropionic acid was reacted with methyl S-methylthiosulfonate in ethanol to afford 28 as described previously. (Widdison, W.C., et al., J Med Chem, 2006.4, 4392-408).

[0353] Compound 30: Compound 30 was prepared by reacting methyl S-methylthiosulfonate with 4-mercapto-1-butanol.

[0354] Compound 32: Compound 32 was prepared by reacting methyl S-methylthiosulfonate with 1-amino-butan-4-thiol (Reineke, T.M. et al. Bioconjugate Chem., 2003 14, 247-254).

[0355] Compound 34: The furan-bearing carboxylic acid 34 was prepared as follows. 5-Hydroxymethyl-2-furoic acid methyl ester (33) (Moore, J.A et al., Journal of Polymer Science, Polymer Chemistry Edition (1984), 22(3) , 863-4) with methanesulfonyl chloride followed by thiourea and hydrolysis to give 33. 33 is then reacted with methylthiosulfonate.

[0356] Compound 37: Compound 37 was prepared by reacting 2,2'-dithiobipyridin...

Embodiment 3

[0359] Embodiment 3. Preparation of 4-nitro-phenol carbonate or 4-nitro-phenol carbamate

[0360] Reaction of 4-nitrophenyl chloroformate with compound 30 affords disulfide-bearing carbonate 43.

[0361] Reaction of 4-nitrophenyl chloroformate with compound 32 affords disulfide-bearing carbamate 44.

[0362] Preparation of Ansamitocin Derivatives

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Abstract

New ansamitocin derivatives bearing a linking group are disclosed. Also disclosed are methods for the synthesis of these new ansamitocin derivatives and methods for their linkage to cell-binding agents. The ansamitocin derivative- cell-binding agent conjugates are useful as therapeutic agents, which are delivered specifically to target cells and are cytotoxic. These conjugates display vastly improved therapeutic efficacy in animal tumor models compared to the previously described agents.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application Serial No. 61 / 409,831, filed November 3, 2010, the entire teachings of which are incorporated herein by reference. field of invention [0003] The present invention relates to a method for the preparation of a cytotoxic conjugate comprising an ansamicin derivative and a cell-binding agent. These conjugates have therapeutic utility when delivered in a targeted manner to specific cell populations. The present invention also relates to a process for the preparation of ansamitocin derivatives having a linker moiety, which can be used for the preparation of cytotoxic conjugates. The present invention further relates to novel ansamitocin derivatives. Background of the invention [0004] Antibody conjugates of cytotoxic drugs are being developed as target-specific therapeutics. Antibodies against various cancer cell-surface antigens have been conjugated to different cytotoxic ag...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00
CPCC07D498/18A61K47/68033A61K47/60A61K47/6849C07D498/16A61P1/18A61P13/12A61P17/00A61P19/00A61P19/02A61P19/08A61P21/00A61P25/00A61P29/00A61P31/00A61P31/10A61P31/12A61P35/00A61P37/06A61K45/06
Inventor R·V·J·查理W·C·威迪森S·D·威廉
Owner IMMUNOGEN INC
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