A STUDY OF SELECTED DIBENZOCYCLOHEPTANE AND THIOXANTHENE DERIVATIVES BY CARBON-13 NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY (DOXEPIN, DOTHIEPIN, AMITRIPTYLINE, THIOTHIXENE, CHLORPROTHIXENE, NMR)

Carbon('13) nuclear magnetic resonance (NMR) chemical shift assignments are reported for Z- and E-doxepin hydrochloride (N,N-dimethyl-dibenz b,e oxepin-delta-11(6H), gamma-propylamine hydrochloride), Z- and E-dothiepin hydrochloride (N,N-dimethyldibenzo b,e thiepin-delta-11(6H), gamma-propylamine hydrochloride), Z and E-thiothixene (N,N-dimethyl-9- 3-(4-methyl-1-piperazinyl)propylidene thioxanthene-2-sulfonamide), Z and E-chlorprothixene (1-propanamine, 3-(2-chloro-9H-thioxanthen-9-ylidene)-N,N-dimethyl), amitriptyline hydrochloride (1-propanamine, 3-(10,11-dihydro-5H-diben-zo a,d cyclohepten-5-ylidene)-N,N-dimethyl-hydrochloride), and nortriptyline hydrochloride (1-propanamine, 3-(10,11-dihydro-5H-dibenzo a,d cyclohepten-5-ylidene)-N,N-dimethyl-hydrochloride). In addition to these latter pharmaceuticals, precursors and model compounds such as 5-methylene-5H-dibenzo a,d cycloheptane and 6H-dibenzothiepin-11-one were also studied. The pharmaceuticals under study are used in the treatment of anxiety, depression, and schizophrenia. They are believed to act by preventing reuptake inactivation of biogenic amines at the nerve endings thereby potentiating the amine action at postsynaptic receptors. Conformational variations between isomers in solution and predictably at the biogenic amine uptake jump may explain the greater biological activity of the Z- isomer. Conformation studies of nonisomeric drugs such as amitriptyline may also explain the biological activity of these dibenzocycloheptane derivatives. Current studies indicate that doxepin isomers differ in dibenz b,e oxepin ring conformation and that the alkylamino olefinic group is oriented above the most adjacent aromatic ring as in analogous studies of dibenzocycloheptane derivatives. Carbon('13) NMR studies of dothiepin indicate similar conclusions. The thioxanthene derivatives, thiothixene and chlorprothixene, do not differ in isomer ring conformation. Alkylamino olefinic group orientation agrees with previously reported X-ray crystallography data. This group is fully extended away from the thioxanthene ring. Carbon('13) NMR shift assignments for these compounds were made by comparison of model compound chemical shifts, off-resonance data, spin lattice relaxation time (T(,1)) determinations, homo- and heteronuclear shift-correlated 2D NMR spectroscopy, proton NMR, selective decoupling, and selective INEPT experiments.