Elsevier

Tetrahedron Letters

Volume 37, Issue 31, 29 July 1996, Pages 5479-5482
Tetrahedron Letters

Design and synthesis of a cocaine-diamide hapten for vaccine development

https://doi.org/10.1016/0040-4039(96)01170-7Get rights and content

Abstract

A cocaine-diamide hapten was designed in an effort to obtain a potent, long-lasting anti-cocaine immune response for the treatment of cocaine abuse. The analogue incorporated an amido linker functionality in place of the carbomethoxy group at C-2 and a benzoylamino replacement of the benzoyloxy group at C-3 of the cocaine framework. Compound 3 was synthesized in 6 chemical steps starting from (+)-2-carbomethoxy-3-tropinone.

A cocaine-diamide hapten was designed in an effort to obtain a potent, long-lasting anti-cocaine immune response for the treatment of cocaine abuse. The analogue 3 incorporated two amido linker functionalities was synthesized in 6 chemical steps starting from (+)-2-carbomethoxy-3-tropinone.

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      Amine 11 was prepared in 98% yield by the protection of the commercially available 6-aminohexanoic acid (10) with benzyl alcohol [74], while the benzoylecgonine (13) was furnished in its salt form (Scheme 2 - panel B) in 84% yield from the chemoselectivity hydrolysis of the methyl ester of cocaine (12) [75] (Scheme 2 - panel A). Subsequently, the carboxylic acid group of 13 was coupled with amine 11, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), furnishing amide 14 in 71% yield [44] (Scheme 2 - panel A). The benzyl ester group of 14 was then reductively cleaved by treatment with H2 and Pd/C to provide the hapten GNE in 52% overall yield (3 steps) from cocaine (12) [51] (Scheme 2 - panel A).

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      This substitution increases the capacity to hydrogen bond to antibodies [31], and increases humoral stability by removing a structurally labile esterase site thereby reducing degradation into cocaine metabolites. GNE was chosen as the PDD conjugate rather than cocaine or the analogs GNC or GND per se because this analog has an increased serum half-life and generates antibodies in greater concentration, leading to a greater immunogenicity and therefore cocaine sequestering ability [31–33]. PDD also increases the immunogenicity of GNE due to the presence of 2–3 PADRE molecules per dendrimer that target PDD to cells expressing MHC class II molecules on their surface, including APC cells necessary to process antigen for presentation and mount an effective antibody response (Fig. 1B).

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