Swern oxidation of chromanol 1 led to ketone 3 with concomitant chlorination of the adjacent 4-position. Using Leuckarl conditions, chromanone 2 was converted to enamine 5. -4-Bromochromene-3-carbaldehyde 8, which was obtained by Vilsmeier-Arnold reaction from 7, turned out to be a suitable intermediate for the insertion of the pyridone residue. 3-Chloro derivatives 16 and 19 resulted on heating the mesylate or tosylate with LiCl in DMF. Brornination of chromene 20 led to 21. -All compounds were tested for oral antihypertensive activity in spontaneously hypenensive rats with a dose of 1 m@g.
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Substituenten in der 3-Stellung auf die Wirksarke von Kaliumkanalaktivatoren vom Chromantyp Swern-Oxidation von Chromanol 1 fiihrte unter gleichzeitiger Chlorierung der benachbarten 4-Stellung zum Keton 3. Unter Bedingungen der Leuckart-Reaktion wurde das Chromanon 2 in das Enamin 5 iibergefiihrt. Als geeignetes Zwischenprodukt fur die Einfuhrung des Pyridonrests envies sich der 4-Bromchromen-3-carbaldehyd 8, der durch Vilsmeier-Arnold Reaktion aus 7 erhalten wurde. Die 3-Chlorderivate 16 und 19 resultienen aus dem Mesylat bzw. Tosylat durch Erhitzen mit LiCl in DMF. Die Bromierung des Chromens 20 fiihrte zu 21. -Die blutdrucksenkende Aktivitat der Verbindungen wurde an spontan hypertensiven Ratten nach oraler Gabe mit einer Dosierung von 1 m@g getestet.
Potassium channel openers which relax smooth muscles by activating potassium channels have attracted increasing attention, since they have a high potential in the treatment of diseases') caused by smooth muscle contraction such as hypertension, angina pectoris, bronchial asthma, and urinary incontinence. In particular the 2H-1 -benzopyrans have proved to be of great interest within the different structural classes of K+ channel activators. Since their discovery the lead compound cromakalim has been modified in many ways'). Replacement of the 4-(2-oxo-I -pyrrolidinyl) group with an a-pyridone (1, emakalim) and with heterocyclyloxy groups (e.g. 17, EMD 57 283) as well as the unsaturated chromene structure (bimakalim) represented some early alterations displaying higher potency in preclinical studies.