Method of producing 6-substituted (s)-nicotine derivatives...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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Reexamination Certificate

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06747156

ABSTRACT:

The present invention relates to a method of producing enantiomerically pure 6-substituted (S)-nicotine derivatives and to new intermediate compounds for use in said method.
BACKGROUND OF THE INVENTION
There are several patent applications and published articles directed to vaccines/immunogens against nicotine dependency/harm reduction, but no such vaccines/immunogens are yet on the market.
One approach is directed to a vaccine/immunogen that in an individual can elicit antibodies which strongly bind to administered/inhaled nicotine and block its effect before it reaches the central nervous system. The desired result is that the individual will not experience the expected stimulating effect of nicotine administration/smoking, and therefore the interest in administering a tobacco product, such as moist snuff, or lighting a cigarette will cease (extinction/prevention).
A complementary approach is directed to an immunogen that in an individual can elicit antibodies which moderately or weakly bind to administered/inhaled nicotine and enhance/prolong its effect in the central nervous system. The desired result is that the individual will experience the expected stimulating effect of nicotine administration/smoking during a prolonged period of time, and therefore the interest in a renewed administration of a tobacco product, such as moist snuff, or lighting a cigarette will be postponed and the medical consequences of the tobacco product consumption will be reduced.
Both of the above mentioned approaches use immunogens which in an individual induces an immunological response which leads to harm reduction.
Papers disclosing active immunization to alter nicotine distribution was recently published (Hieda Y. et al, J. Pharmacol. Exp. Therap. 1997, 283, 1076-1081, Pentel, P. R. et al, Pharmacol. Biochem. Behav. 2000, 65, 191-198). The immunogens used in the Hieda and Pentel articles were (±)-6-(carboxymethyl-ureido)-nicotine conjugated to keyhole limpet hemocyanin and (±)-trans-3′-aminomethylnicotine conjugated to
Pseudomonas aerigunosa
exoprotein A via a succinic acid linker, respectively.
The international patent application WO 98/14216 claims a large number of hapten-carrier conjugates based on the nicotine molecule and the common structural feature of the compounds seems to be that all of the hapten molecules contain a terminal carboxylic acid group which is then conjugated to the carrier. No in vivo testing has been disclosed for the alleged drug abuse treatment.
Other nicotine derivatives useful in vaccines/immunogens are comprised by the present inventors' International patent application WO9961054A1 directed to nicotine immunogens comprising 5- or 6-nicotinyl-linker-carrier proteins.
All the published 6-nicotine derivatives are produced as racemates, and if an enantiomer is desired, the production is accomplished by procedures for separating racemic mixtures into optically pure fractions well known in the art (see for example U.S. Pat. No. 5,420,286) giving ≦50% of each enantiomer.
However, it should be noted that all tobacco products contain the (S)-nicotine enantiomer only. Therefore, it is desirable to use enantiomerically pure (S)-nicotine derivatives in the different prophylactic and therapeutic applications.


REFERENCES:
patent: 4155909 (1979-05-01), Sanders et al.
patent: 5502194 (1996-03-01), Rivadeneira et al.
patent: 0050428 (1982-04-01), None
patent: 0439745 (1991-08-01), None
patent: 0463464 (1992-01-01), None
patent: WO 9961054 (1999-12-01), None
J. Org. Chem, vol. 50, 1985, Dick A. de Bie et al., “On the Amination of Halogenonitropyridines”, pp. 484-487.

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