No abstract

The syntheses and the structural and stereochemical requirements for antagonism of (+)-amphetamine-induced sterotypy are described for a series of benzocycloheptapyridoisoquinoline derivatives. One of these compounds, (plus or minus)-(4a,13b-trans)[3(OH),13b(H)-trans[-3-tert-butyl-2,3,4,4a,8,9,13b,14-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3ol hydrochloride (butaclamol hydrochloride, USAN), is currently being studied in man. The relationship between structure and antiamphetamine activity in this class of compounds is discussed.

in experimental animals. Preliminary pharmacological res~llts have been described (1)and a fill1 paper is in preparation. In this report we describe the synthesis a n d stereochemistry of taclamine hydrochloride.T h e synthesis of taclamine.HC1 1 has been accomplislied through two independent pathways (see Scheme I). In the first, 10,1 I-dihydro-(2) (2) was condensed with 8-valerolactone t o give the hydroxyamide 3, which o n treatment with p h o s p h o r o~~s oxychloride undergoes a double cyclization to afford the pentacyclic pyridoisoquinolini~~m salt 4. R e d~~c t i o n of 4 with hydrogen and platinum, or, with sodium borohydride generates the 4a,13b-cis isomer of taclamine~free base which was converted to the hydrochloride salt 5. O n the other hand, reduction of 4 with zinc and hydrochloric acid affords predominately the 4a, l3b-trans isomer, 1. (See disc~lssion of stereochemistry below.) T h e isomeric nature of the two reduction products was confirmed by the oxidation of each, with 'Nonproprietary name selected by the U.S. Adopted Names Council. This compound has also been designated AY-22,214. (3). A mixt~lre o f the 4a,l3b-trar~s-and 4a, I3b-cis-pentacyclic aniino ketones 7 a and 80, respectively, were formed in a ratio of 6 : 1. The m i x t~~r e was readily separated into its components by column chromatography and the amino ketones 7 a and 8a were converted t o 1 and 5, respectively, through desulfi~rization of the corresponding ethylenethioketal derivatives, 76 and 86. T h e pure ethylenethioketal derivatives, 76 and 86 were also obtained by column chromatographic separation o f the m i x t~~r e o f 76 and 86 obtained by direct treatment of t h e amino ketone mixt~lre (7a a n d 8a) with ethaneditliiol and boron trifluoride etherate.Configurational assignments at the 4a and 13b centers o f 1 and 5 were made by interpretation of their n.m.r. spectra a n d , independently, by a consideration of the stereochemical controls operative in the reductions of the iminium salt 4. Thus, the isomer 5 obtained via catalytic hydrogenation of 4 is assigned a 4a,13b-cis relative configuration since examination of molecular models shows that the substrate for reduction, 4, contains an iminium center, which causes rings C, D, a n d E t o be virtually coplanar while the phenyl ring A is located on the cr-side at the Can. J. Chem. Downloaded from www.nrcresearchpress.com by 54.202.233.140 on 05/12/18For personal use only.

. Can. J. Chem. 54, 2715Chem. 54, (1976. The compound butaclamol hydrobromide crystallizes in space group P21/c with cell dimensions; a = 14.38(3), b = 13.31(3), c = 12.07(3) A, P = 101.64(8)". The structure was solved by Patterson methods and non-hydrogen atoms have been refined isotropically using a full-matrix least-squares to an R value of 0.17 for 779 observed reflections.The compound dexclamol hydrobromide crystallizes in space group P212121 with a = 8.412(2), b = 24.392(7), c = 10.465(2) A. Refinement of non-hydrogen atoms using isotropic thermal parameters and rigid aromatic rings converted at R = 0.090 using 1249 observed reflections, for the preferred enantiomorph, and R = 0.099 for the other enantiomorph.Both compounds have their hydroxy groups in the axial position, and both adopt conformations of the seven membered ring such that the C13b hydrogen atom experiences a flagpolebowsprit interaction with a hydrogen atom of C9. [Traduit par le journal]

Several analogues of the neuroleptic agent butaclamol, having modifications in the ring E region of the molecule, have been synthesized. Pharmacological evaluation identified two of the analogues as being equipotent to butaclamol, namely, anhydrobutaclamol (8) and deoxybutaclamol (9a). The molecular structures of both the active and inactive analogues were analyzed and the results have been used for mapping the central dopamine receptor. The existence of a previously proposed lipophilic accessory binding site on the receptor macromolecule has been confirmed. Its minimum dimensions, as well as its locus with respect to the primary binding sites, have been defined. A receptor model incorporating the above features is proposed.