Synthesis and Pharmacological Evaluation of K<SUB>ATP</SUB>-channel Openers Related to Cromakalim: Introduction of Arylsulphonylurea Moieties

Abstract

A series of 4‐(arylsulphonylaminocarbonylamino)‐3,4‐dihydro‐2,2‐dimethyl‐2 H‐1‐benzo‐pyran derivatives were prepared and evaluated as potential ATP‐sensitive potassium‐channel activators. Pharmacological studies showed that some compounds expressed vasodilator efficacy on vascular smooth muscle. The compounds had no inhibitory activity on insulin secretion from pancreatic β‐cells.

Design, Synthesis, and Pharmacological Evaluation of R/S-3,4-Dihydro-2,2-dimethyl- 6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans: Toward Tissue-Selective Pancreatic β-Cell KATP Channel Openers Structurally Related to (±)-Cromakalim

“…Convenient starting materials for the synthesis of the original R/ S -3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2 H -1-benzopyrans ( 13 − 42 ) are R/S -4-amino-3,4-dihydro-2,2-dimethyl-6-fluoro-2 H -1-benzopyran ( 12a ), R/ S -4-amino-6-chloro-3,4-dihydro-2,2-dimethyl-2 H -1-benzopyran ( 12b ), and R/ S -4-amino-6-bromo-3,4-dihydro-2,2-dimethyl-2 H -1-benzopyran ( 12c ). These compounds were prepared according to the methods previously reported. , …”

“…These compounds were prepared according to the methods previously reported. 21,22 R/S-3,4-Dihydro-2,2-dimethyl-6-fluoro-4-(phenylaminocarbonylamino)-2H-1-benzopyran (13). Phenyl isocyanate (0.26 mL, 2.4 mmol) was added to a solution of 12a 22 (0.4 g, 2 mmol) in…”

“…Chemistry. The key intermediates for the synthesis of compounds 13 − 42 , R/ S -4-amino-3,4-dihydro-2,2-dimethyl-6-fluoro-2 H -1-benzopyran ( 12a ), R/ S -4-amino-6-chloro-3,4-dihydro-2,2-dimethyl-2 H -1-benzopyran ( 12b ), and R/ S -4-amino-6-bromo-3,4-dihydro-2,2-dimethyl-2 H -1-benzopyran ( 12c ) were obtained, as described previously, in six steps starting from the appropriate p -halogenophenols , (Scheme ).

1 Synthesis of Cromakalim Analogues a a Reagents: (i) (CH 3 CO) 2 O, H 2 SO 4 ; (ii) AlCl 3 ; (iii) acetone, pyrrolidine; (iv) NaBH 4 , CH 3 OH; (v) CH 3 CN, H 2 SO 4 ; (vi) HCl 37%; (vii) RNCO, CH 2 Cl 2 ( 13 − 42 ).

…”

“…Chemistry. The key intermediates for the synthesis of compounds 13-42, R/S-4-amino-3,4-dihydro-2,2-dimethyl-6fluoro-2H-1-benzopyran (12a), R/S-4-amino-6-chloro-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (12b), and R/S-4-amino-6bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (12c) were obtained, as described previously, in six steps starting from the appropriate p-halogenophenols 21,22 (Scheme 1).…”

“…Treatment of acetophenones 8a-c with acetone in the presence of pyrrolidine led to chromanone intermediates 9a-c, which were reduced to chromanols 10a-c with sodium borohydride in methanol. The 4-acetylaminobenzopyrans 11a-c were prepared by the Ritter reaction 22 from chromanols 10a-c. This reaction occurred in acetonitrile supplemented with concentrated sulfuric acid.…”