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Improved cytotoxic agents comprising new maytansinoids

A technology of maytansine and cells, which is applied in the direction of medical preparations containing active ingredients, antiviral agents, and medical preparations with non-active ingredients, which can solve problems such as instability

Inactive Publication Date: 2007-05-02
IMMUNOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the sulfur atom is in the beta position relative to the carbonyl group in this case, these maytansinoids and their disulfide-bonded conjugates with cell-binding agents were found to be unstable, which can be attributed to Due to their propensity to suffer from beta-elimination

Method used

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  • Improved cytotoxic agents comprising new maytansinoids

Examples

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preparation example Construction

[0450] Preparation of cell-binding agents

[0451] [171] The effectiveness of the compounds of the invention as therapeutic agents depends on careful selection of an appropriate cell-binding agent. Cell-binding agents can be of any type currently known, or becoming known, including peptide and non-peptide substances. Typically, they may be antibodies (especially monoclonal antibodies), lymphokines, hormones, growth factors, vitamins, nutrient transport molecules such as transferrin, or any other cell-binding molecule or substance.

[0452] [172] More specific examples of cell-binding agents that may be used include:

[0453] polyclonal antibodies;

[0454] Monoclonal antibodies;

[0455] Antibody fragments such as Fab, Fab' and F(ab') 2 , Fv (Parham, J.Immunol.131:2895-2902 (1983); Spring et al.J.Immunol.113:470-478 (1974); Nisonoff et al.Arch.Biochem.Biophys.89:230-244 ( 1960));

[0456] Interferons (eg, alpha, beta, gamma);

[0457] Lymphokines such as IL-2, IL-3, IL-...

Embodiment 1

[0526] Synthesis of maytansinoid 4b

[0527] [216] 4-Mercapto-4-methylpentanoic acid (7): A 500 ml flask was fitted with a stir bar and a 150 ml addition funnel. The system was placed under nitrogen atmosphere. 150 ml of anhydrous tetrahydrofuran (THF) and 75 ml of 2.5M n-BuLi in hexane (18.7 mmol) were added via cannula, and the solution was cooled in a dry ice / acetone bath at -78°C. Acetonitrile (7.3 g, 9.4 ml, 18 mmol) was added dropwise via syringe over a period of approximately 5 minutes. The reaction was stirred for 30 minutes when a white precipitate of lithium acetonitrile formed. Isobutenyl sulfide (15 g, 17 mmol) was dissolved in 100 mL dry THF and added dropwise via the addition funnel over approximately 30 minutes. The cooling bath was removed and the reaction was stirred for 3 hours. 38ml of 0.5M HCl was added dropwise while cooling the flask in an ice / water bath. The THF layer was retained, and the aqueous layer was washed twice with 75 ml of ethyl acetate. ...

Embodiment 2

[0536] Synthesis of Maytansinoid 4a

[0537] [222] 4-Methyldithio-pentanoic acid (13): In a 500 mL flask, a solution of 4-mercaptovaleric acid (12, 16.6 mg, 124 mmol) was dissolved in 350 mL of deionized water. The solution was magnetically stirred while sodium carbonate (19.7 g, 186 mmol) was added to the acid at a rate that did not cause excessive foaming. A 250 ml addition funnel was fitted to the flask containing a solution of methyl methanethiolsulfonate (23.4 g, 186 mmol) dissolved in 220 ml of glass distilled 100% ethanol. The flask was cooled in an ice / water bath and the system was maintained under an argon atmosphere. The methyl methanethiol sulfonate solution was added dropwise to the flask as quickly as possible, but at a rate that did not cause excessive foaming. The cooling bath was removed and the reaction mixture was stirred for an additional 2 hours. The solvent was removed by rotary evaporation under vacuum until approximately 250 ml remained. Subsequently...

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Abstract

New thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the alpha-carbon atom bearing the sulfur atom are disclosed. Also disclosed are methods for the synthesis of these new maytansinoids and methods for the linkage of these new maytansinoids to cell-binding agents. The maytansinoid-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] This application claims the benefit of Provisional Application No. 60 / 471,739, filed May 20, 2003, the disclosure of which is hereby incorporated by reference. technical field [0002] [01] The present invention relates to methods of preparing improved cytotoxic conjugates comprising maytansinoids and cell-binding agents. These conjugates are therapeutically useful when delivered to specific cell populations in a targeted manner. The present invention also relates to methods of preparing maytansinoids with thiol moiety, which can be used to prepare cytotoxic conjugates. The present invention further relates to novel maytansinoids, and novel intermediates in the synthesis of novel maytansinoids. Background technique [0003] [02] There are many reports trying to specifically target tumor cells with monoclonal antibody-drug conjugates (Sela et al., Immunoconjugates 189-216 (C.Vogel, ed.1987); Ghose et al, Targeted Drugs 1-22 (E.Goldberg, ed.1983); Diener et al, Antibo...

Claims

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Application Information

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IPC IPC(8): A61K31/5365C07D491/12A61K47/48C07D498/16
CPCA61K47/48561A61K47/48407C07D498/16A61K47/4863A61K47/6867A61K47/6809A61K47/6849A61P17/02A61P19/02A61P25/00A61P29/00A61P31/04A61P31/12A61P31/18A61P33/00A61P33/02A61P33/04A61P35/00A61P35/02A61P37/06A61P43/00C07D491/147C07D491/14A61K31/535
Inventor W·C·威迪逊R·V·J·沙利
Owner IMMUNOGEN INC
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