Hypotensive Agents. IX. 3-Azabicyclo[3.3.1]nonane Derivatives¹

Abstract

Series of nonane-2,4-diones have been prepared from cts-hexahydroisophthalic anhydride and the corresponding alkyl and dialkylaminoalkylamines. These imides have been reduced to the corresponding 3-alkyl and 3-dialkylaminoalkyl-3-azabicyclo[3.3.1]nonanes and hydrochloride and mono-and bis-quaternary salts prepared for screening as hypotensive agents. These compounds exhibited only a low degree of hypotensive activity or were inactive. When compared to the very active compounds encountered in the closely related isoindole, 2-azabicyclo-[4.3.0] nonane series, this was quite an unexpected result and illustrates again the difficulties and pitfalls frequently encountered in structural-physiological activity predictions and correlation. In this case just changing the bridging in the bicyclic ring from the [4.3.0] to the [3.3.1] structure resulted in marked reduction or almost complete loss of hypotensive activity.

Concise syntheses of bridged morpholines

“…Compound 8b was reduced to 2b, either electrolytically under strongly acidic conditions 18 or with lithium aluminium hydride. 19 This route to 2b was modified in the manner described below for 1a, again starting from cis-cyclohexane-1,3-dicarboxylic acid and proceeding via 6b and 7b (see Scheme 2 and Supplementary Information).…”

“…The developed methodology was also used to prepare [2,2,4,4-2 H4]8-oxa-3aza-bicyclo[3.2.1]octane 1b (Scheme 1), which is potentially useful for metabolic studies of drugs containing the bridged morpholine unit derived from 1a. The method described is versatile being applicable to both cycloalkane-1,3dicarboxylates 18,19 and oxacycloalkane-1,3-dicarboxylates.…”

Chemistry of 3-azabicyclo[3.3.1]nonanes

“…41 42 Hexahydroisophthalic acid (41) reacts with acetyl chloride and then with an amine to yield 42. The amine may be alkyl or dimethylaminoalkyl or an arylamine. 74 Similarly, hexahydroisophthalic anhydride reacts with TT,7V-dimethylcadaverine to form iV-(5-dimethylaminoamyl)-3-ABN. 75 All the substituted 3-ABN-2,4-diones have been reduced by using LiAlH4.…”

“…Diazaadamantanes with sulfur-containing substituents at 5,7 positions (63-65) are also cleaved by acetic anhydride91,92 to yield bispidine derivatives. iV-Tosylpiperidine-3,5-dicarboxylic acid (66) on conversion to the acid chloride and treatment with ammonia forms the diamide of 66, which on heating produces 67.91,93,94 The 1-cyano derivative 69 and 1- A mixture of acetone, a suitable aldehyde, and a primary amine in the ratio of 1:4:2 yields bispidine derivatives (74). Acetonedicarboxylic acid and its es-75 R=Me or Et ters may be employed in the place of acetone.…”

“…1.5-Diaryl-3,7-DABN-9-ones (74) and some simple 3,7-DABN-9-ones fail to react with carbonyl reagents except hydrazine.90,162 In the first case the reason seems to be the steric hindrance caused by the phenyl groups at bridgehead positions and not due to chair-boat conformation. In the second case the failure has been ascribed to an amide-like character.…”