Novel Potassium Channel Activators. II. Synthesis and Pharmacological Evaluation of 3,4-Dihydro-2H-1,4-benzoxazine Derivatives: Modification of the Aromatic Part.

Abstract

Three new series of analogues related to 3,4-dihydro-2H-1,4-benzoxazine derivative 1a were synthesized and evaluated for their potassium channel activating activity. In the first series I, where the 6,7-positions were disubstituted, it was found that an electron-withdrawing substituent was preferable at the 6 position, but either an electron-withdrawing or releasing substituent without bulkiness was tolerated at the 7 position. In the second series II, where several heterocycles were introduced into the 6,7-positions, the oxadiazole derivative 6 showed more potent activity than cromakalim. In the third series III, where the benzene ring was replaced by a pyridine ring, borane complex 16 had equivalent activity to cromakalim. Especially, compound 6 showed a potent hypotensive effect with a long duration of action in the spontaneous hypertensive rat and had a lesser increasing effect on intracranial pressure in dogs than 1a and levcromakalim, showing a good profile as an antihypertensive agent.

Crystal structure of N-dichloroacetyl-3-methyl-6,8-dichloro-3,4-dihydro- 2H-1,4-benzoxazine, C11H9Cl4NO2

“…Moreover, benzoxazines were useful compounds as starting materials for the synthesis of larger structures with valuable biological activities [4][5][6]. N-Dichloroacetylb enzoxazines were used as herbicide safeners [7,8].…”

Recent Developments in the Synthesis and Applications of 1,2,5-Thia- and Selenadiazoles. A Review

“…12 A re-investigation of the synthesis of 1,2,5-thiadiazole-3,4-carbonitrile (10) from diaminomaleonitrile showed that the most probable intermediate is monosulfinylamine 11, which eliminates water by the action of hydrogen chloride formed in the first step of the reaction; 13 In many cases, employing an organic base allows the reaction temperature to be reduced to room temperature, or to 0 • C, avoiding undesirable side processes. Usually triethylamine [14][15][16][17][18][19] or pyridine [20][21][22][23][24][25] in inert solvents such as dichloromethane, benzene, or chloroform were used. Typical examples were given in Scheme 3.…”

From Cromakalim to Different Structural Classes of KATP Channel Openers

“…At Yamanouchi, Matzumoto et al have conducted extensive research on K ATP CO 1,4-benzoxazines by investigating the different positions of this new scaffold through a multi-step SAR study [89][90][91]. Similar to 50, these 1,4-benzoxazines lack a hydroxyl group at the C-3 position resulting in achiral compounds that can be considered as a structural simplification of CRK.…”

“…The presence of a C-6/C-7 fused oxadiazole was already known to enhance potency in the benzopyran class [101]. The aromatic portion of the 1,4-benzoxazine scaffold was also modified by replacing the benzene ring with a pyridine one, giving a few examples of pyrido-1,4-oxazines [90]. An in vitro vasorelaxant activity comparable to that of CRK was observed for pyrido[4,3-b]-1,4-oxazine derivative 56, which bears an unusual borane group at the N-6 position; Fig.…”

“…It should be noted that the 1,4-benzoxazine ring system structurally differs from that of benzopyran one. Comparative X-ray structural analyses [90,91] showed that the nitrogen atom has an approximately sp 2 -like planar bond configuration, while the atom at the C-4 position of the benzopyran in CRK has an sp 3 tetrahedral bond configuration. The relationship between activity and the bond angles needs further clarification.…”