Chloro-substituted, sterically hindered 5,11-dicarbo analogs of clozapine as potential chiral antipsychotic agents

Abstract

Variable-temperature proton nuclear magnetic resonance studies have shown that 5-(2-propylidene)-10-(4-methylpiperazino)-5H-dibenzo[a,d] cycloheptene, a 5,11-dicarbo analogue of the atypical neuroleptic agent clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine], exists as thermally stable configurational isomers. The presence of the 2-propylidene group at C-5 on the 5H-dibenzo[a,d]cycloheptene moiety did not interfere greatly, as compared to clozapine, with the in vitro affinity of this 5,11-dicarbo analogue of clozapine for muscarinic and dopamine D-1 and D-2 binding sites in rat brain. Since the presence and position of a chloro substituent on the 5H-dibenzo[b,e][1,4]diazepine moiety have a marked influence on the respective binding affinities of 1,4-diazepines related to clozapine, chloro-substituted 5,11-dicarbo analogues of clozapine were prepared in order to further examine structure-activity relationships. Evaluation of these analogues for binding to muscarinic and dopamine binding sites in comparison with clozapine and other 5H-dibenzo[b,e][1,4]diazepine analogues of clozapine shows that the dopamine D-1 and D-2 receptor affinities of both the 5-(2-propylidene)-5,11-dicarbo analogue and its corresponding distal-chloro derivative, 2-chloro-5-(2-propylidene)-10-(4-methylpiperazino)-5H- dibenzo[a,d]cycloheptene, are retained. Because of the susceptibility to acid-catalyzed hydrolysis of these tertiary enamines, however, these compounds serve only as model compounds for their structure-activity evaluation. Since the proximal nitrogen atom of the piperazine ring is redundant for biological activity, 5-(2-propylidene)-10-(1-methyl-4-pyridyl)-5H-dibenzo[a,d]cycloh eptene and its 2-chloro derivative are excellent candidates for resolution into enantiomers as a means to separate antimuscarinic and antidopaminergic activity, respectively, associated with only a single stereoisomer.

Pyridobenzoxazepine and Pyridobenzothiazepine Derivatives as Potential Central Nervous System Agents: Synthesis and Neurochemical Study

“…16 Thus, for the isomers 10 and 16, we observed two different evolutions of the binding profile. The isomer -[1,5]-( 16) was more dopaminergic and serotonergic but less muscarinic than its isomer -[1,4]- (10). A similar evolution was noted for the oxazepine analogues 8 and 13 except for the D2 affinity.…”

“…After the solution had stirred for 30 min, the product was collected by filtration, washed with water, and dried at room temperature: yield 40-50%; mp 244-246 °C; IR (KBr) NMR (CDCI3/DMSO-d6) 10.76 (br s, HNCO), 8.41 (s, HC(1)), 8.21 (d, HC(3)), 7.65-7.31 (m, benzene and HC(4)). Anal.…”

Binding of 5H-Dibenzo[b,e][1,4]diazepine and Chiral 5H-Dibenzo[a,d]cycloheptene Analogs of Clozapine to Dopamine and Serotonin Receptors

“…As shown in Scheme 2, the preparation of the enantiomers of 5- (10). Reaction of the bromide 10 with n-butyllithium in ether formed the anion which reacted with 1-methyl-4-piperidone to give 10-(4-hydroxy-l-methyl-4-piperidinyl)-5-(2-propylidene)-5flr-dibenzo[a ,d]cycloheptene (11). Dehydration of 11 gave (±)-4c, and resolution of (±)-4c into (pSa,pRb)-(-)-4c and (pña,pSb)-(+)-4c was accomplished by fractional crystallization, respectively, of their (2S,3S)-0,0'-di-jD-toluoyl-and (2R,3R)-0,0'-di-ptoluoyltartrate hydrogen30-31 salts.…”

“…A hexane solution of the latter was passed through a gravity column of silica gel (180 g), and evaporation of the hexane gave a white solid residue. Recrystallization from hexane gave 10 (10.0 g, 76%) as a white solid: mp 94- (11). Under nitrogen, rc-butyllithium (1.6 M in hexane, 18 mL, 29 mmol) was added dropwise to a stirred solution of 10-bromo-5-(2-propylidene)-5H-dibenzo[o,d]cycloheptene (10; 8.50 g, 27.3 mmol) in ether (160 mL) at -78 °C.…”

Binding of 5H-Dibenzo[a,d]cycloheptene and Dibenz[b,f]oxepin Analogs of Clozapine to Dopamine and Serotonin Receptors

“…being10- bromodibenz[6,/]oxepin19(17), prepared by dehydrobromination of fraros-10,ll-dibromo-10,ll-dihydrodibenz[6,/]oxepin(16).The dibromide 16 was formed by bromination of dibenz[6 ,/]oxepin.19 This latter intermediate is available by a reduction and rearrangement from 9ff-xanthene-9-carboxylic acid.20 Reaction of the lithium derivative of 17 with 1-methyl-, 1-ethyl-, and l-(2-propenyl)-4-piperidone (10a-10c) gave, respectively, 10-[4-hydroxy-1 -methyl-, 10-[ 1 -ethyl-4-hydroxy-, and 10-[4-hydroxy-l-(2-propenyl)-4-piperidinyl]-dibenz[&/]oxepin (18a-18c). Dehydration with hydrochloric acid in ethanol formed 10-[l-methyl-, 1-ethyl, and l-(2-propenyl)-l,2,3,6-tetrahydro-4-pyridinyl]dibenz[6 /[oxepin (5a-5c…”