The synthesis of a series of isoelectronic analogues of (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1) are described; included in this group are examples of thiazole, isothiazole, thiadiazole, pyrazine, and the structurally related naphthyridines. All of the compounds are similar to 1 in that they contain a cyano group ortho to the aminohydroxypropoxy side chain and meta to the nitrogen heteroatom. In addition, several related examples, having additional nuclear substituents and/or groups other than CN in the position adjacent to the aminohydroxypropoxy group, were prepared, and beta-adrenoceptor antagonist activity and vasodilating potency were determined. Three compounds, thiazole 2 and isothiazoles 3 and 27, effectively lowered mean arterial pressure in the SH rat at 5 mg/kg. Compounds 2, 3, and 27 increased iliac blood flow and exhibited beta-adrenergic blocking properties in the dog.
A series of compounds containing the 3-hydroxy-4H-pyran-4-one nucleus has been synthesized and tested as potential skeletal muscle relaxants. Reduction of 2-(azidomethyl)-5-hydroxy-4H-pyran-4-one (4) with HBr in HOAc--phenol yielded 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one (kojic amine, 3) in 81% yield. Reaction of 2-[(tosyloxy)-methyl]-5-(benzyloxy)-4H-pyran-4-one (5) with NH3 gave a 40% yield of the O-benzyl ether of kojic amine, which was N-acylated with a series of carbobenzyloxy-protected amino acids. Complete deprotection with HBr--HOAc gave the following amino acid amides of kojic amine: glycyl (23), alpha-alanyl (24), beta-alanyl (25), gamma-aminobutyryl (26), and glycylglycyl (27). Among the analogues of kojic amine prepared was a series of one-carbon homologues: 2-[(methylamino)methyl]-5-hydroxy-4H-pyran-4-one (7a), 2-(1-aminoethyl)-5-hydroxy-4H-pyran-4-one (8), 6-(aminomethyl)-3-hydroxy-2-methyl-4H-pyran-4-one (12), and 2-(2-aminoethyl)-5-hydroxy-4H-pyran-4-one (16). Kojic amine (3) has been found to possess certain of the properties to be expected in a gamma-aminobutyric acid mimetic agent, notably skeletal muscle relaxant activity. In the chronic spinal cat preparation, ED70 values for reduction of flexor spasms of 2.2 and 4.0 mg/kg by iv and po routes of administration, respectively, were observed for kojic amine, which was the most potent of the various hydroxypyrone derivatives investigated.
A series of 6,ll-dihydro-5R-pyrrolo [2,l-b][3]benzazepin-ll-ones, 4, has been prepared as intermediates for potential CNS drugs. Substituents in the pyrrole ring of 4 were introduced by Friedel-Crafts cyclization of pyrrole-substituted l-(2-phenethyl)pyrrole-2-carboxylic acid derivatives (6) and by electrophilic substitution on the parent ketone 4a. Substituents in the benzene ring of 4 were introduced by Friedel-Crafts cyclization of substituted 2-(2-pyrrol-l-ylethyl)benzoic acids (12). Novel and efficient photochemical reactions were discovered for the direct introduction of the cyano and trifluoromethyl groups into the pyrrole ring of 4a. The latter reaction was extended to yield a series of trifluoromethylated heterocycles. Pyrrolo[2,l-6][3]benzazepin-ll-ones Scheme I r4 *-fFX jsr' SOCl2 or CI2CHOMeI, total synthesis of the ring system; II, introduction of substituents into the parent ketone 4; and III, modification of substituents introduced in I or II. The major successes and difficulties encountered in these approaches are detailed below.1.1 Total Synthesis of Pyrrole-Substituted Ketones (4, X , Y = H). The synthesis of the requisite acid derivatives 6 was carried out by three methods as summarized in Scheme I. Method A has already been de-scribed7 and is quite satisfactory as long as the group X is resistant to catalytic hydrogenation. Method B, the alkylation of a substituted pyrrole-2-carboxylic ester with 2-phenethyl bromide, was also found to be a very satisfactory route to the esters 6.1, particularly when X was a strong electron-withdrawing group. When X was less electron withdrawing, it was advantageous to use phenethyl tosylate to minimize competitive elimination to form styrene.Method C was used to prepare ester 6.1h and, although quite satisfactory, was not used extensively. The preparation of the 4-substituted pyrrole-2-carboxylates was generally carried out by the recent method of Belanger8
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