Synthesis and calcium ion antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines

Abstract

As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines (3) and evaluated their Ca2+ antagonistic activities. Ca2+ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum. On the basis of their potent Ca2+ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity. Among these six compounds, the key compound 15 [3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[3,4- (methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo- 2H-1,4-benzothiazine hydrogen fumarate] was recognized as having the lowest cardioselectivity. Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means of X-ray crystallography of a synthetic precursor (+)-4a. The Ca2+ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15). The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem. This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.

Photochemical Identification of Transmembrane Segment IVS6 as the Binding Region of Semotiadil, a New Modulator for the L-type Voltage-dependent Ca2+ Channel

“…Using photoaffinity labeling and antibody mapping techniques, all three drugs have been shown to bind to different regions in more than one motif. Several other Ca 2ϩ antagonists have different chemical structures and somewhat different pharmacological actions than DHP, PAA, and BTZ (3)(4)(5). Semotiadil (SD-3211) is a novel Ca 2ϩ antagonist with a unique 1,4-benzothiazine ring structure (3) (Fig.…”

Ionic liquid [omim][NO3], a green medium for room-temperature synthesis of benzothiazinone derivatives in one pot

“…The identity of the known products was confirmed by the comparison of their melting points and their NMR data with those available in the literature. New products were characterized by their 1 H NMR, 13 C NMR, IR and mass spectra and their purity was confirmed by elemental analyses.…”

A Novel and Facile One-Pot Synthesis of 3-Aryl-4H-benzo[1,4]thiazin-2-amine

“…In conclusion, we have described a highly efficient procedure for the preparation of 3-aryl-4H-benzo [1,4]thiazin-2-amines by a three-component condensation using PTSA as a catalyst, furnishing the products in good yield without further purification in moderate to good yields. All products were characterized by mp, IR, 1 H NMR, and GC-MS. Melting points were measured by using the capillary tube method with an electrothermal 9200 apparatus.…”

“…4 Benzothiazines have been reported as calcium channel blockers, 5 phosphodiesterase inhibitors, 6 5-HT3 antagonists, 7 anticataract agents, 8 dopamine D 4 , 9 Na + /H + exchange inhibitors, 10 coagulation factor Xa inhibitors, 11 and matrix metalloproteinase inhibitors. 12 Therefore, a wide range of studies for the synthetic development of benzothiazine derivatives has been carried out.…”