8-chloro-(S)- and -(R)-10-((S)-and -(R)-3'-methylethylaminopyrrolidino)- 10,11-dihydrodibenzo(b,f)thiepins. Synthesis and pharmacological studies.
The synthesis for 8-chloro-(S)- and -(R)-10-[(S)- and -(R)-3'-methylethylaminopyrrolidino]-10,11-dihydrodibenzo[b,f]thiepins is presented. The absolute configuration at position 3' of the aminopyrrolidino side chain is known from synthesis and corresponds to the asymmetric carbon atom in (S)- or (R)-aspartic acid. The absolute configuration at C-10 of the dihydrodibenzo[b,f]thiepin ring system was deduced from ORD-CD analysis coupled with degradation of partially resolved (+)-8-chloro-10-amino-10,11-dihydrodibenzo[b,f]thiepin to (+)-(S)-1,2-diphenylethylamine. The four isomers were studied in mice for their ability to block conditioned avoidance responding, antagonize oxotremorine, and act as analgetics and anticonvulsants. These compounds were found to be nonselective antagonists of histamine, acetylcholine, and BaCl2 in vitro. The compounds exerted effects similar to those of chlorpromazine. Stereoselective differences in activity between diastereoisomers, rather than between enantiomorphs, were generally observed.
D000700:Analgesics; D000818:Animals; D000927:Anticonvulsants; D002942:Circular Dichroism; D003988:Dibenzothiepins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006168:Guinea Pigs; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D009905:Optical Rotatory Dispersion; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D011930:Reaction Time / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D000927:Anticonvulsants; D003988:Dibenzothiepins; D011759:Pyrrolidines