Synthesis of hypoglycemic compounds. I

Abstract

In order to develop a new type of hypoglycemic sulfonamide, the synthesis of sulfonamides whose p-amino groups are basic acylamido radicals are investigated. Piperidine (10 ml.) was treated with 5 g. p-acetamidobenzenesulfonyl chloride with vigorous stirring. The reaction mixt. was warmed 1 hr. on a water bath and cooled and the product filtered off and washed with water to give p-acetamidophenylsulfonylpiperidine (I), m. 171-2° (MeOH). I (10 g.) was heated with 50 ml. 15% HCl on a water-bath 3 hrs. and the mixt. chilled and neutralized with Na2CO3 to give p-aminophenylsulfonylpiperidine (II), m. 165-6° (EtOH). Chloroacetyl chloride (3 g.) in 10 ml. Me2CO was added to a soln. 5 g. II in 20 ml. Me2CO in the presence of a molar equiv. pyridine under stirring and the mixt. heated 1 hr. on a water bath, concd., and dild. with water to give p-chloroacetamidophenylsulfonylpiperidine (III), m. 131° (ligroine). A mixt. of 5 g. III and 3 g. piperidine in 20 ml. Me2CO was gently warmed on a water bath 2 hrs. to give p-piperidinoacetylphenylsulfonylpiperidine m. 147-8° (MeOH). Similarly, the following IV were synthesized (R, R1, and m.p. given): piperidino, NEt2, 89-90°; piperidino, NBu2, 114-15°; piperidino, 1-pyrrolidinyl, 132-4°; piperidino, morpholino, 171°; morpholino, NEt2, 96-8°; morpholino, NBu2 (VI), 149-51°; morpholino, 1-pyrrolidinyl (VII), 135-6°; morpholino, piperidino, 215-16°; morpholino, morpholino, 201-2°. Similarly prepd. were the following VIII (same data): piperidino, NEt2, 101-2°; piperidino, NBu2, 131-2°; piperidino, 1-pyrrolidinyl, 171°; piperidino, piperidino, 181-2°; piperidino, morpholino (IX), 162-3°; morpholino, NEt2, 216-17°; morpholino, NBu2, 125°; morpholino, 1-pyrrolidinyl, 162-3°; morpholino, piperidino, 215-16°; morpholino, morpholino, 222°. By the pharmacol. screening test, almost all these compds. have no hypoglycemic property; VI and VII showed weak actions, but IX unexpectedly had analgesic and local anesthesic activity. [on SciFinder(R)]