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Universi^ Micrwilms International aoO N .Zeeb Road Ann Arbor, Ml 48106 8513651 Wyatt, Dorothy Katharine A STUDY OF SELECTED DIBENZOCYCLOHEPTANE AND THIOXANTHENE DERIVATIVES BY CARBON-13 NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY The American University Ph.D. 1985 University Microfilms I nternetionelSOO N. Zeeb Road, Ann Arbor, Ml 48106 Copyright 1985 by Wyatt, Dorothy Katharine All Rights Reserved PLEASE NOTE: In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark V 1. Glossy photographs or pages. 2. Colored illustrations, paper or print _____ 3. Photographs with dark background _____ A. Illustrations are poor copy ______ 5. Pages with black marks, not original copy. 6. Print shows through as there is text on both sides of page. 7. Indistinct, broken or small print on several pages 8. Print exceeds margin requirements ______ 9. 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WYATT 1985 ALL RIGHTS RESERVED A STUDY OF SELECTED DIBENZOCYCLOHEPTANE AND THIOXANTHENE DERIVATIVES BY CARBON^^ NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY by Dorothy K. Wyatt ABSTRACT Carbon^^ nuclear magnetic resonance (NMR) chemical shift assignments are reported for Z~ and ^-doxepin hydrochloride (N,N,-dimethyl-dibenz[b,e]oxepin-de1ta- 11(6H), gamma-propylamine hydrochloride), Z- and E- dothiepin hydrochloride ( N , N-d ime thy Id i benzo[ b , e ] th ie- pin-delta-ll(6H), gamma-propylami ne hydrochloride), Z- and E- thiothixene (N ,N-dimethy 1-9-[3-(4-methy 1-1-piper- aziny1)propy1 idene]thioxanthene-2-su Ifonamide), 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-hydrochlor- ide), and nortriptyline hydrochloride (1-propanamine, 3- (10,11-d ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)- N ,N-diraethyl-hydrochloride). In addition to these latter pharmaceuticals, precursors and model compounds such as 5-methy 1ene-5H-dibenzo[a,d]eyeloheptane and 6H- ii d ibenzothiepin-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 inacti­ vation 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 7^- iso­ mer. Conformation studies of non isomer ic 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 a Iky 1 amino o 1e f in ic group is oriented above the most adjacent aromatic ring as in analogous studies of d ib enzoc yc lo hep tane derivatives. Carbon^^ NMR studies of dothiepin indicate similar conclusions. The thio- xanthene derivatives, thiothixene and chlorprothixene, do not differ in isomer ring conformation. Alkylamino o 1e f in ic group orientation agrees with previously re­ ported X-ray crystallography data. This group is fully extended away from the thioxanthene ring. IQ Carbon NMR shift assignments for these compounds 111 were made by comparison of model compound chemical shifts, off-resonance data, spin lattice relaxation time (Tj) determinations, homo - and heteronuc1 ear shift- correlated 2D NMR spectroscopy, proton NMR, selective decoupling, and selective INEPT experiments. iv ACKNOWLEDGEMENTS I wish to express deepest appreciation to my advisors without whose encouragement and support this work would not have been possible. I wish to especially thank Dr. Nina M. Roscher whose untiring encouragement and assistance made possible the completion of this effort. She not only provided the financing necessary for access to the more sophisticated NMR instrumentation as well as necessary chemicals and supplies, but gave extensively of her time to provide encouragement as well as assistance in planning and organizing access to these instruments. I wish to thank Dr. Lee T. Grady, who suggested this topic and who encouraged me throughout this project as well as gave me the opportunity to develop and grow as a research chemist and later, as a supervisor under his direction, for the use of the Varian FT 80-A NMR spectrometer which has been used extensively throughout this endeavor, for providing drug samples for analysis, and for providing the introduc­ tions necessary for the acquisition of the dothiepin samples. I also wish to thank Dr. Mary Aldridge without whose encouragement I would not have entered and con­ tinued my graduate school efforts at American University which resulted in the completion of this Ph.D. In addition, I wish to acknowledge the support of the U.S. Department of Education under the Graduate and Profes­ sional Opportunities Fellows program. I wish to express great appreciation to Dr. Mike Geek 1e and Bruker Instruments, Inc., Billerica, Massachu­ setts for their assistance and the use of their Bruker AM-400 NMR spectrometer and instruction in the use of 2D NMR techniques. I wish also to thank Dr. Ad Bax of the National Institutes of Health for use of the Nicolet NT- 270 NMR spectrometer and instruction in the use of selective INEPT experiments. I wish to also acknowledge the support of the NSF Northeast Regional NMR Facility at Yale University, which was funded by Grant Number CHE-7916210, from the Chemistry Division of NSF. I wish to further acknowledge the assistance of Dr. Ann Turner of Howard University who provided use of a Nicole t NT-200 NMR spectrometer as well as Dr. Cecil Dubrowski of the University of Delaware who provided use of their Bruker AM-250 NMR spectrometer. I wish to thank Mr. Johnny Johnson and Dr. Islam of the British Pharmacopoeia as well as Dr. Spooner of Boots Chemical Co. for their assistance and courtesy and for providing dothiepin hydrochloride and 6H-d ibenzo- VI [ b , e ] th i epln-11-one reference standards and E^- and dothlepln hydrochloride samples, respectively, that were used in this analysis. Their kindness and generosity while visiting their laboratory facilities in England will always be remembered. I wish also to thank Dr. Y . Segal1 of the Israeli Institute for Biological Research for providing the 5-methy1ene-5H-dibenzo[a,d]eyelohep­ tane sample used in the analysis. I wish to especially thank my husband, William K. Wyatt who not only encouraged and supported me in this endeavor but shared my travails as his own. He not only kept the same erratic schedule necessitated by my off-hour use of NMR instrumentation but also travelled with me whenever possible to remote NMR locations. I wish also to thank my dear friend Mrs. Ann Ferguson who not only endeavored to assist and encourage me whenever possible on this effort but who frequently gave of her own time toward that end.

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