In one synthetic approach, the bicyclic isonitriles were cyclized with strong
bases to the corresponding tricyclic compounds [42]. A synthesis of dihydrolysergic acid starting from appropriately substituted 5-nitro-2-tetralones via a tricyclic isonitrile to the indole ring closure as the last step has been described [43].
In another strategy, the tricyclic ring has been formed in a single step from a
benzene derivative by tandem radical cyclizations to yield methyl 1-acetyl2,3,9,10-tetrahydrolysergate as an example [44].
The tricyclic system has also been constructed from an indole via electrophilic substitution reactions at positions 3 and/or 4. Synthesis of tricyclic
ergoline synthons from 5-methoxy-1H-indole-4-carboxaldehyde has been
described [45]. Sodium cyanoborohydride mediated reductive amination provided easy access to 1,3,4,5-tetrahydrobenz[cd]indole-4-amines, compounds
which show specificity for serotonin and dopamine receptors.
Various 4-substituted indoles were prepared and a synthetic method for
4-nitro-1,3,4,5-tetrahydrobenz[cd]-indole derivatives was carried out [46] and
also for 4,5-disubstituted 1H-1,3,4,5-tetrahydrobenz[cd]indole derivatives [47]
using intramolecular Michael addition. Furthermore, a method [48] was
published describing the successful syntheses of 4-nitro-1,3,4,5-tetrahydrobenz[cd]indole and its 1-hydroxy derivative.
It has recently been shown that Vicarious Nucleophilic Substitution (VNS)
can be a useful tool for the synthesis of biologically active compounds containing the 1,3,4,5-tetrabenz[cd]indole nucleus, such as 6-methoxy-1,3,4,5tetrahydrobenz[cd]indole-4-amine [49].
l-tryptophan has been used as a starting point for partial ergot structures
such as 1-benzoyl-4-(amino)-1,2,2a,3,4,5-hexahydrobenz[cd]indoles. An optically pure amine, a key intermediate, was prepared via a four-step sequence
employing an intramolecular Friedel-Crafts cyclization and a C-5 deoxygenation procedure [50].
2.1.5
Structure Activity Relationships
Structural analogies between the ergoline ring system and the several neurotransmitters (serotonin, dopamine, and noradrenaline) may give rise to the
diverse pharmacological properties of the different ergot alkaloids. It has been
shown that small changes in the chemical structure of the alkaloids results in
marked effects on their biological activity [2, 9].
Different 6-substituted tricyclic partial ergoline analogs which exhibited
strong serotonin agonist activity were synthesized [51]. A methoxy group at the
6-position greatly enhances activity and an electron-withdrawing group in the
6-position enhances both activity and stability. Some tricyclic partial ergoline
analogs were synthesized [52]. It was observed that the vascular 5HT 2 receptor
interactions for the partial ergolines, compared to amesergide, the parent ergoline, were dramatically reduced. The isopropyl tricyclic ergolines inhibited the
pressor response to serotonin like amesergide. The author concluded that the
isopropyl moiety on the indole nitrogen is important for vascular 5HT 2 receptor activity.
8
J. Mukherjee · M. Menge
bases to the corresponding tricyclic compounds [42]. A synthesis of dihydrolysergic acid starting from appropriately substituted 5-nitro-2-tetralones via a tricyclic isonitrile to the indole ring closure as the last step has been described [43].
In another strategy, the tricyclic ring has been formed in a single step from a
benzene derivative by tandem radical cyclizations to yield methyl 1-acetyl2,3,9,10-tetrahydrolysergate as an example [44].
The tricyclic system has also been constructed from an indole via electrophilic substitution reactions at positions 3 and/or 4. Synthesis of tricyclic
ergoline synthons from 5-methoxy-1H-indole-4-carboxaldehyde has been
described [45]. Sodium cyanoborohydride mediated reductive amination provided easy access to 1,3,4,5-tetrahydrobenz[cd]indole-4-amines, compounds
which show specificity for serotonin and dopamine receptors.
Various 4-substituted indoles were prepared and a synthetic method for
4-nitro-1,3,4,5-tetrahydrobenz[cd]-indole derivatives was carried out [46] and
also for 4,5-disubstituted 1H-1,3,4,5-tetrahydrobenz[cd]indole derivatives [47]
using intramolecular Michael addition. Furthermore, a method [48] was
published describing the successful syntheses of 4-nitro-1,3,4,5-tetrahydrobenz[cd]indole and its 1-hydroxy derivative.
It has recently been shown that Vicarious Nucleophilic Substitution (VNS)
can be a useful tool for the synthesis of biologically active compounds containing the 1,3,4,5-tetrabenz[cd]indole nucleus, such as 6-methoxy-1,3,4,5tetrahydrobenz[cd]indole-4-amine [49].
l-tryptophan has been used as a starting point for partial ergot structures
such as 1-benzoyl-4-(amino)-1,2,2a,3,4,5-hexahydrobenz[cd]indoles. An optically pure amine, a key intermediate, was prepared via a four-step sequence
employing an intramolecular Friedel-Crafts cyclization and a C-5 deoxygenation procedure [50].
2.1.5
Structure Activity Relationships
Structural analogies between the ergoline ring system and the several neurotransmitters (serotonin, dopamine, and noradrenaline) may give rise to the
diverse pharmacological properties of the different ergot alkaloids. It has been
shown that small changes in the chemical structure of the alkaloids results in
marked effects on their biological activity [2, 9].
Different 6-substituted tricyclic partial ergoline analogs which exhibited
strong serotonin agonist activity were synthesized [51]. A methoxy group at the
6-position greatly enhances activity and an electron-withdrawing group in the
6-position enhances both activity and stability. Some tricyclic partial ergoline
analogs were synthesized [52]. It was observed that the vascular 5HT 2 receptor
interactions for the partial ergolines, compared to amesergide, the parent ergoline, were dramatically reduced. The isopropyl tricyclic ergolines inhibited the
pressor response to serotonin like amesergide. The author concluded that the
isopropyl moiety on the indole nitrogen is important for vascular 5HT 2 receptor activity.
8
J. Mukherjee · M. Menge