[Pyridazino(3,4-c)quinolines and pyridazino(4,5-c)quinolines--synthesis and investigation of lipoxygenase inhibition].
The cyclic hemiketone acetal 6 reacts with hydrazine in tert-butanol to yield the 1-amino-2,3-dihydro-2-hydroxy-pyrrole 7, while in acetic acid a mixture of the 1-amino-pyrrole 8 and the 1,4-dihydropyridazine 9 is obtained. The X-ray crystal structure of 9 shows a boat conformation flattened about N-1 with respect to nifedipine. Removing the boc-group of 9 gives the tautomeric 2,5-dihydropyridazine 13. The lactams 15 and 17 and the cyclic hydroxamic acids 16 and 18, respectively, are synthesized from 13 or from its oxidation product 14 using reductive conditions. The cyclic hemiacetal 21 reacts with hydrazine in a different manner from 6. In acetic acid the 1-aminopyrrole 22 is formed, while ethanol yields the 1,4-dihydropyridazine 23. The pyridazine 24, obtained by dehydrogenation of 23, gives the lactam 25 and the hydroxamic acid 26, respectively, when the nitro-group is reduced. The dihydropyridazines 9, 11 and 23 are transformed photochemically to give the nitrosophenyl-pyridazines 19, 20 and 27. The chloro-substituted hydroxamic acid 28 is isolated after treatment of 27 with hydrochloric acid. The stability of the partially saturated pyridazine compounds is discussed on the basis of half wave potentials measured by anodic oxidation by means of differential pulse voltammetry. The tricyclic hydroxamic acids 18 and 28 show only a weak inhibition of 5-lipoxygenase (5-LOX).
Institut für Pharmazeutische Chemie, Technischen Universität Braunschweig. k.goerlitzer@tu-bs.de
K
K
Görlitzer
J
J
Fabian
P G
PG
Jones
P
P
Frohberg
G
G
Drutkowski
D018360:Crystallography, X-Ray; D004563:Electrochemistry; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D011724:Pyridazines; D011804:Quinolines