Anilides related to substituted benzamides. Potential antipsychotic activity of N-(4-amino-5-chloro-2-methoxyphenyl)-1-(phenylmethyl)-4-piperidinecarboxamide

Abstract

The substituted benzamides are used clinically both as antipsychotics and as stimulants of gastric motility. The antipsychotic effects are considered to be a consequence of their central dopamine antagonist properties, but there is evidence that the gastric stimulatory effects may be mediated by other mechanisms. Clebopride (3) is a substituted benzamide that although marketed for its stimulatory effects on gastric motility, is also a potent central dopamine antagonist. The corresponding anilide, BRL 20596 (4a), where the amide bond has been reversed, has been synthesized and found to lack gastric stimulatory activity. However, the potent central dopamine antagonist activity is retained, suggesting that benzamides and anilides have similar affinities for central dopamine receptors. The implications of the conformations adopted by benzamides and anilides at such receptors are discussed. Evidence is also presented that there is a further lipophilic binding site on such receptors for which the N-benzyl group is an optimal fit.

Synthesis of Substituted Piperidines from N,N-Bis[(benzotriazol-1-yl)methyl]amines

“…Thus, starting from readily available 1 , 4-chloropiperidines 2a − e were prepared via a [3 + 3] cycloaddition under mild reaction conditions while avoiding the use of trifluoroacetic acid. 4-Chloropiperidines 2a − e are useful building blocks for many biologically active compounds, e.g., antihistaminic N-heterocyclic 4-piperidinamines 2a and fentanyl analogues. 2b,c …”

“…Syntheses of piperidines are well documented, 1a-d due to their physical and biological properties and their presence in numerous natural products. 2a-d N , N -Bis[(benzotriazol-1-yl)methyl]amines 1 , readily prepared from 1-(hydroxymethyl)benzotriazole and amines or from benzotriazole, aqueous formaldehyde, and amines, 3a,b are useful (Scheme ) in the preparation of the following: (i) Secondary and tertiary amines (R 1 = alkyl, H), 4a,b N , N -disubstituted hydroxylamines (R 1 = OH), and 1,1-disubstituted hydrazines and their 2-acyl derivatives (R 1 = NHCOR) via displacement by Grignard reagents or NaBH 4 reduction of benzotriazole; (ii) isoxazolidines (R 1 = OH) by conversion of bis[(benzotriazol-1-yl)methyl]hydroxylamine to the nitrone and 1,3-dipolar additions; (iii) julolidines (R 1 = Ph), through elimination of benzotriazole, formation of methylene immonium cation, and subsequent reaction with two molecules of vinyl ether or vinyl amide; and (iv) pyrrolidines (R 1 = Ar, alkyl) by reductive cleavage of the Bt−C bond by SmI 2 to generate dianion and reaction with alkenes. We now report the application of 1 for the synthesis of piperidines.…”

Arylcarbamate Derivatives of 1-Piperidineethanol as Potent Ligands for 5-HT4Receptors

“…The carbamates 7 , structurally closely related to benzoates derived from 4-amino-5-chloro-2-methoxybenzoic acid, were prepared according to the synthetic pathway described in Scheme . 5-Chloro- o -anisidine was acetylated and transformed into the corresponding nitro amine derivative 10 according to the process described by Hadley . It was treated with phosgene in a toluene solution to give 5-chloro-2-methoxy-4-nitrophenyl isocyanate ( 11 ) which reacted with the different amino alcohols, easily synthesized by the reaction of 2-bromoethanol and the secondary amines in the presence of NaOH, to give compounds 12 .…”

“…5-Chloro-o-anisidine was acetylated and transformed into the corresponding nitro amine derivative 10 according to the process described by Hadley. 13 It was treated with phosgene in a toluene solution to give 5-chloro-2-methoxy-4nitrophenyl isocyanate (11) which reacted with the different amino alcohols, easily synthesized by the reaction of 2-bromoethanol and the secondary amines in the presence of NaOH, to give compounds 12. The nitro group of compounds 12 was reduced into the amino derivatives 7a-g by the reaction of Na 2 S 2 O 4 in a MeOH/ H 2 O 14 mixture with a moderate yield.…”

The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro

“…The interaction of substituted benzamides with brain BDZ binding sites does not appear to be related to their antagonist activity at dopamine D2-receptors. It is interesting to note that BRL 20596, which is the anilide derivative of clebopride where the amide bond has been reversed, retains potent central dopamine receptor antagonist properties (Blaney et al, 1983), but is inactive at BDZ binding sites (Table 1).…”