Abstract
The grouping X-(CH[2])[n] -N< is frequently found in pharmacodynamic agents, where X is OR, OH or O=C-O. By replacing X with sulphone and other sulphur-containing groups it was hoped to obtain novel substances with potential biological activity. The four groups of compounds prepared are depicted below:[chemical equation] - Most of the benzhydryl piperazine derivatives (l) were prepared by reacting the respective N'-benzhydrylpiperazine with the halogen-containing side-chain in a high boiling-point alcohol and in the presence of sodium carbonate. The sulphone (1X=SO[2]) and ether (1,X=0) groups produced the most active antihistamines, with the sulphoxides (1,X=SO) and thioethers (1,X=S) approximately equiactive. Pharmacological tests indicated that a straight chain of a certain minimum length is necessary for protection against histamine induced bronchospasm. Most of the n-fluorobutyrophenones (2,n=3) were prepared from the corresponding N'-gamma-(p-fluorobenzoyl)propylpiperazine and the halogen-containing side-chain. Either the ketone function was protected as a ketal or alternatively a hydrocarbon solvent was used. None of the compounds was an effective muscle relaxant. The ethylsulphone (2,n=3, XR=SO[2]Et) appeared to be the most active. All the p-fluoropropiophenone piperazines (2,n=2) were prepared by the Mannich reaction from the monosubstituted piperazine and p-fluoracetophenone. These propiophenones (2,n=2) appeared to be less active than the butyrophenones (2,n=3). Comparison of the activity of the butyrophenones and propiophenones slows some parallelismexists between the sulphones and the ethers of both series. [chemical equation] The chromans (3,n=1) and coumarans (3,n=0) were all prepared by reacting an aminomethyl heterocycle (5) with the corresponding. halosulphone or haloether. The 2-aminomethylchroman was prepared by a novel route from the previously unreported 2-hydroxymethylchroman and 2-chloromethylchroman. The 3-aminomethylchroman was prepared in a novel manner by the LiAlH[4] reduction in ether of 2H-chromene- 3-carboxamide. The pharmacological results indicated that whether X was SO[2] or O there was a common decreasing order of muscle relaxant activity: benzodioxane, 2-chroman, 3-chroman and coumaran. No correlation was observed between the muscle-relaxant activity of the compounds and their UV absorption characteristics. The Leuckart reaction was used for preparing the phenyltaurines (4;n=0, m=1, R=OH). The key reaction in the preparation of phenyl-GABA sulphones (4;n,m=1, R=Me) was the Micheal addition of a -sulphonyl esters to nitrostyrenes. The novel a-nitrosulphones were hydrogenated to sulphopyrrolidones (6). [chemical equation] None of the taurines, the phenyl-GABA sulphones or the sulphopyrrolidones were biologically active.