Hiromichi Ogasawara

Structure–activity relationship studies with (±)-nantenine derivatives for α1-adrenoceptor antagonist activity

A series of (+/-)-nantenine derivatives of the natural aporphine alkaloids was synthesized and examined for a blocking action on alpha1-adrenoceptors in rat aorta and A10-cells. The potency of these derivatives was compared with that of an aporphine-related compounds (+)-boldine, an alpha1-adrenoceptor antagonist. Among nine (+/-)-nantenine derivatives having different substituents at N-6, C-1, or C-4 of the aporphine skeleton, (+/-)-domesticine had the most powerful alpha1-adrenoceptor-blocking action. The order of pA2 values was (+/-)-domesticine (8.06+/-0.06)>(+/-)-nordomesticine (7.34+/-0.03)>(+/-)-nantenine (7.03+/-0.03)>(+)-boldine (6.91+/-0.02)>other derivatives. Study of the structure-activity relationships showed that the replacement of a methoxy moiety at C-1 position of (plus minus)-nantenine with a hydroxyl group increased affinity for the receptor. In contrast, replacement of a methyl group with a hydrogen atom or an ethyl group at N-6 position in the (+/-)-nantenine structure decreased affinity for the receptor. These results suggest that a hydroxyl group at the C-1 position and a methyl group at the N-6 position in the (+/-)-nantenine structure are essential for the enhancement of affinity for the alpha1-adrenoceptor.

Synthetic studies on colchicine: reaction of homomorphinandienones

For the purpose of synthetic approaches toward colchicine (2) from O-methylandrocymbine (1a), reaction of homomorphinandienones (1a, b) was carried out. Oxidation of 1a, b with 35% aqueous hydrogen peroxide gave a separable diastereomeric mixture of N-oxides (5, 6). Polonovski reaction of the N-oxides (5) with acetic anhydride in CH 2 Cl 2 afforded N-demethyl-N-acetamide (7a), whereas that of 5 and 6 with acetic anhydride in the presence of triethylamine gave enamines (8a, b) together with N-demethyl-N-acetamides (7a, b). Furthermore, reaction of enamines (8a, b) with N-bromosuccinimide in dimethoxyethane-H 2 O or methanol produced α-bromo amides (9a, b)

Formation and reaction of p-quinol acetates of N-trifluoroacetyltetrahydroisoquinolin-7-ols

Lead tetraacetate oxidation of N-trifluoroacetyltetrahydro-isoquinolin-7-ols (13a, b) in AcOH gave stable p-quinol acetates (17a, b). Reaction of 17 with trifluoroacetic acid in CH 2 Cl 2 or MeCN gave morphinandienones (15) and aporphines (16), respectively. In contrast with o-quinol acetates (14), it was found that reaction of p-quinol acetates (17) in MeCN was considerably slower than that in CH 2 Cl 2 . A mechanistic pathway on the reaction is deduced

Formation of Morphinandienones via o-Quinol Acetates of N-Trifluoroacetyltetrahydroisoquinolin-7-ols

(±)-N-Trifluoroacetylnormorphinandienones (4a, b) were obtained by acid treatment of o-quinol acetates [o-QAs] (2a, b) in CH 2 Cl 2 or CH 3 CN at low temperature

Reaction of β-aminocrotonamide with dibasic acid derivatives

Reaction of β-aminocrotonamide (1) with succinic anhydride gave β-succinaminocrotonamide (3a), which was treated with base to cyclize to 3,4-dihydro-6-methyl-4-oxo-2-pyrimidinepropanoic acid (4a). Similarly, pyrimidinepentanoic acid derivative 4b was prepared from compound 1 and glutaric anhydride. Reaction of compound 1 with glutarate, adipate, and phthalate gave the corresponding pyrimidines 4b, 4c and 4d, while reaction of compound 1 with malonate gave 2-hydroxypyridine derivative 11 and dimethylpyrimidinone 4e. Reaction of dimethyl fumarate with compound 1 in the presence of methoxide gave a poor yield of pyrrolo[3,4-c]pyridine derivative 13.