Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
First Claim
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1. A method for producing a maytansinoid having a disulfide moiety that bears a reactive ester comprising reacting the carboxyl group of N2′
- -deacetyl-N2′
-[3-(carboxyalkyldithio)-1-oxopropyl]-maytansine with a hydroxy compound to yield a maytansinoid having a disulfide moiety that bears a reactive ester.
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Abstract
The present invention discloses a one-step process for the production of cytotoxic conjugates of maytansinoids and cell binding agents. Maytansinoids having a disulfide linker that bears a reactive moiety are linked to cell binding agents, such as antibodies, without prior modification of the cell binding agent. These conjugates are useful as therapeutic agents which are delivered specifically to target cells and are cytotoxic.
312 Citations
27 Claims
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1. A method for producing a maytansinoid having a disulfide moiety that bears a reactive ester comprising reacting the carboxyl group of N2′
- -deacetyl-N2′
-[3-(carboxyalkyldithio)-1-oxopropyl]-maytansine with a hydroxy compound to yield a maytansinoid having a disulfide moiety that bears a reactive ester. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 26)
- -deacetyl-N2′
- 9. A method for producing a maytansinoid having a disulfide moiety that bears a reactive ester comprising performing a disulfide exchange reaction between a thiol-containing maytansinoid and the reactive disulfide moiety of a compound containing a reactive carboxylic acid ester.
- 13. A method for producing a maytansinoid having a disulfide moiety that bears a reactive ester comprising performing a disulfide exchange reaction between a thiol-containing maytansinoid and the reactive disulfide moiety of a compound containing a water soluble reactive carboxylic acid ester.
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17. A method for producing N2′
- -deacetyl-N2′
-[3-(3-carboxy-1-methyl-propyldithio)-1-oxopropyl]-maytansine (6);
comprising reacting a thiol-containing maytansinoid with 4-(2-pyridyldithio)-pentanoic acid (5);
- View Dependent Claims (18)
- -deacetyl-N2′
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19. A method for producing N2′
- -deacetyl-N2′
-[3-(3-carboxy-1-methyl-propyldithio)-1-oxopropyl]-maytansine (6)comprising the steps of; (a) combining N-methyl-N-(3-mercaptopropanoyl)-L-alanine and trimethylsilylethyl 4-mercaptopentanoate (9) to form a mixed disulfide compound, (b) coupling maytansinol to the product of (a) to produce a maytansinoid ester (10), and (c) deprotecting the maytansinoid ester (10). - View Dependent Claims (20)
- -deacetyl-N2′
- 21. A maytansinoid having a disulfide moiety that bears a reactive ester comprising the following formula 11:
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24. N2′
- -deacetyl-N2′
-[3-(3-carboxy-1-methyl-propyldithio)-1-oxopropyl]-maytansine comprising the following formula;
- -deacetyl-N2′
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25. The maytansinoid ester compound (10) comprising the following formula:
Specification