Summary:
In the context of the present MSc dissertation a series of new hydrophobic
adamantane 2-imidazoline derivatives was synthesized. The design of these
molecules was based on their potential biological action as trypanocidals,
since compounds with similar skeletal features are known to act against
Trypanosoma brucei. Moreover, the introduction of lipophilic substituents was
expected to facilitate BBB crossing and hence their antiparasitic activity in
the CNS.
In brief, five different types of compounds were prepared and are as follows:
I. 5-(3-Cyclopentyl-1-adamantyl)-2-imidazolines (1)
This set of compounds (C3-cyclopentyl substituted adamantanes) was prepared by
reducing 3-cyclopentyl-1-adamantane carboxylic acid (11) to the respective
primary alcohol 12, which was oxidized to carboxaldehyde 13. The latter upon
Strecker reaction conditions using ammonia, methylamine and aniline was
converted to the aminonitriles 14a, 14b and 16, respectively, which were
catalytically reduced to the corresponding ethylenediamines 15a and 15b,
whilst, surprisingly, compound 16 was converted to N-cyclohexylethylenediamine
18. The desired product 17 was obtained from the reaction of 16 with BH3THF.
The target molecules 1 were prepared by reacting formamidine, acetamidine and
cyanogen bromide with the diamines 15a, 15b and 18, respectively.
II. 5-(3-Phenyl-1-adamantyl)-2-imidazolines (2)
The title compounds were prepared from 3-phenyl-1-adamantanecarboxylic acid
(21) by an analoguous, to imidazolines 1, reaction sequence.
III. 5-(3-Cyclohexyl-1-adamantyl)-2-imidazolines (3)
Hydrogenation of α-amino and α-methylamino-3-phenyl-1-adamantaneacetonitriles
(24a) and (24b) under pressure and at high temperature led to the concurrent
reduction of the benzene ring and the cyano-group, resulting to the formation
of 1-(3-cyclohexyl-1-adamantyl)ethylenediamines (26a) and (26b), which were
converted, as previously noted, to the respective 2-imidazolines 3.
IV. 5-[4-(1-adamantyl)phenyl]-1-methyl-2-imidazolines (4a-c)
4-(1-adamantyl)benzaldehyde (35), prepared via three different routes, was used
as starting material for the synthesis of 4a-c, following an analogous reaction
pathway to that previously described.
4
IV. 2-[4-(1-adamantyl)phenyl]-2-imidazoline (4d) and
2-(3-cyclopentyl-1-adamantyl)-2-imidazoline (4e)
The preparation of 2-imidazoline 4d involved the reaction of ethylenediamine
and iodine with benzaldehyde 35. By an analoguous, yet modified reaction,
imidazolines 4e was prepared from 3-cyclopentyl-1-adamantanemethanol (12).
The pharmacological data obtained as to the trypanocidal action of compounds
1-3, reveal that the introduction of lipophilic substituent, on C3 of
adamantane, enhances activity. In general, the cyclopentyl and cyclohexyl
substituted analogues show a satisfactory activity, whilst their C3-phenyl
substituted congeners are much less active. Last derivatives 4a-d (the phenyl
group is located between C1 of adamantane and the imidazolines ring) are
reasonably potent.