Novel Ring Systems: Spiro[Cycloalkane] Derivatives of Triazolo- and Tetrazolo-Pyridazines

Abstract

In orderto synthesize new pyridazine derivatives anellated with different nitrogen heterocyclic moieties, spiro[cycloalkane]pyridazinones were transformed into the corresponding thioxo derivatives via a reaction with phosphorus pentasulfide. The reaction of the formed 2,3-diazaspiro[5.5] undec-3-ene-1-thiones with hydrazine provided the corresponding 1-hydrazono-2,3-diazaspiro[5.5] undec-3-ene, whose diazotization led to the desired spiro[cyclohexane-1,8'-tetrazolo[1,5-b]pyridazines. The reaction of dihydropyridazinethiones with benzhydrazide afforded the corresponding 7H-spiro[[1,2,4]triazolo[4,3-b]pyridazin-8,1'-cyclohexanes]. As a result of our work, seven new pyridazinethione intermediates were prepared, which served as starting materials for the synthesis of two kinds of new ring systems: tetrazolo-pyridazines and triazolo-pyridazines. The six new annulated derivatives were characterized by physicochemical parameters. The new N-heterocycles are valuable members of the large family of pyridazines.

Keywords: N-heterocycles; diazotization; pyridazine derivatives; tetrazolo-pyridazines; thionation; triazolo-pyridazines.

Figure 1

Pyridazine derivatives under clinical development: ensartinib, relugolix, talazoparib, and olaparib.

Scheme 1

Synthesis of spiro[cycloalkane]pyridazinones (4a–d and 5a,b) [24,25]; (a) 1a,b (1.0 mmol), Friedel–Crafts reaction: AlCl₃ (3.0 mmol), ArH derivative (3.0 mmol), 0 °C (30 min) -> room temperature (RT) (24 h); Grignardreaction: Grignard reagent (1.0 mmol), 0 °C (30 min) -> RT (24 h); (b) 2,3 (0.80 mmol), hydrazine hydrate (2.40 mmol), EtOH, reflux, (4 h); (c) 4a–d, 5a,b isolated yields after thin layer chromatography (TLC) purification: 35–97% [24,25].

Scheme 2

Thionation reaction of the spiro[cycloalkane]pyridazinones (4a–d and 5a,b); (a) 4a–d, 5a,b (1.0 mmol), P₂S₅ (3.0 mmol), PhMe, reflux, (6–8 h); (b) 6a–d, 7a,b isolated yields after TLC purification: 40–89%.

Scheme 3

Preparation of 1-(4-methoxyphenyl)-2,3-diazaspiro[5.5]undec-1-ene-4-thione (6e): (a) 1a (1.0 mmol), Friedel–Crafts reaction: AlCl₃ (3.0 mmol), anizole (3.0 mmol), 0 °C (30 min) -> RT (24 h); (b) 2a,e (0.80 mmol), hydrazine hydrate (2.40 mmol), EtOH, reflux, (4 h); (c) 2a,e (1.0 mmol), P₂S₅ (3.0 mmol), PhMe, reflux, (6–8 h); (d) 2e isolated yield after TLC purification: 14%.

Scheme 4

Synthesis of the hydrazono-pyridazinone (8a–c) and tetrazole derivatives (9a–c) (a) 6a–c (0.40 mmol), hydrazine monohydrate (1.20 mmol), tetrahydrofuran (THF), reflux, (5 h); (b) 8a–c (0.34 mmol), NaNO₂ (0.51 mmol), 0.5 N HCl, 5 °C, (2 h); (c) 8a–c isolated yields after TLC purification: 48–61%; (d) 9a–c isolated yields after TLC purification: 45–77%.

Scheme 5

Reaction of thioxo-derivatives (6a–c) with benzoic acid hydrazide (11) (a) 6a–c (0.73 mmol), 11 (2.20 mmol), n-BuOH, reflux, (84 h); (b) (c) 10a–c isolated yields after TLC purification: 14–42%.