Troeger's base. An alternate synthesis and a structural analog with thromboxane A2 synthetase inhibitory activity

Abstract

The synthesis of 2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (Tröger's base) from p-toluidine and of two Tröger's base analogs from other anilines by reaction with hexamethylenetetramine in trifluoroacetic acid is described. 2,3,6,7-Tetrahydro-9-methyl-2,6-di-p-tolyl-1H,5H-pyrimido[5,6,1-ij] quinazoline is formed as a secondary product in the reaction of p-toluidine and hexamethylenetetramine. One of the Tröger's base analogs, 2,8-bis(3'-pyridylmethyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]d iazocine (5), is an effective inhibitor of the enzyme, thromboxane A2 (TxA2) synthase, with an ED50 of 30 ng/mL in a specified in vitro assay. Three analogs having substituents on the bridging methylene group of the bicyclic nucleus of the Tröger's base structure were prepared, but all were considerably less active than the aforementioned compound in the inhibition assay. The structures of these inhibitors of TxA2 synthase fall outside the classical structure-activity relationship that has been established for this class of enzyme inhibitors.

Synthesis of 5,6,11,12-tetrahydrodibenzo[b,f][1,5]diazocines and a demonstration of their reactivity to afford methano strap-modified Tröger’s base analogues

“…It has been previously shown that reactions of aldehydes, or a limited selection of ketones, with the two cyclic disecondary amines shown in Figure 2 results in the formation of Tröger's base analogues with the methylene strap either mono-or di-substituted. [35][36][37] H N N H H 3 C In light of the substituents that are now available on the aryl rings of Tröger's base analogues, in the present work we sought to develop a general methodology for the synthesis of functionalised cyclic disecondary amines (strap-clipped Tröger's base analogues) and demonstrate their use in a general approach toward methano-strap modified compounds. Initially, the generality of the literature methodology 35 (Method A) was explored, however, with the exception of compounds 1 and 2, these reaction conditions were found to be unsuccessful.…”

9-Methyl-2,6-di-p-tolyl-2,3,6,7-tetrahydro-1H,5H-pyrimido[5,6,1-ij]quinazoline

“…For related literature, see: Becker et al (1993); Bhuiyan et al (2007); Eisner & Wagner (1934); Farrar (1964); Johnson et al (1993); Maffei (1928Maffei ( , 1929; Smith & Schubert (1948) ;Walther & Bamberg (1906); Ibers & Hamilton (1974); Wagner & Eisner (1937 Data collection: CAD-4 (Schagen et al, 1989); cell refinement: CAD-4; data reduction: local program; program(s) used to solve structure: SIR92 (Altomare et al, 1994); program(s) used to refine structure: RAELS (Rae, 1996); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: local programs.…”

Introduction of Aromatic and Heteroaromatic Groups in the 2‐ and 8‐Positions of the Tröger’s Base Core by Suzuki, Stille and Negishi Cross‐Coupling Reactions – A Comparative Study

“…Due to these properties, the foremost applications of Tröger's base have been in the field of molecular recognition [3][4][5][6] although qualified for extensive usage in many other fields. [7][8][9][10] Since the synthesis of Tröger's base itself in 1887, more than 150 derivatives and analogues have been synthesized using various methods. The scope of this fascinating molecule could be even broader having access to a greater number of general methods for the synthesis of analogues and derivatives.…”

“…The yields are highly dependent on the aromatic substituents. [10,[18][19][20] A methodology based on first constructing the Tröger's base framework and then introducing the aryl groups as we propose in the present work, leads to greater synthetic flexibility, the tolerance to acid-sensitive groups on the aryl moiety and in general much higher yields.…”