Sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents

J. Howard Rupard, Tomas De Paulis, Aaron Janowsky, Howard E. Smith

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Sterically hindered 5,11-dicarbo analogues of clozapine were prepared as potential chiral antipsychotic agents, with the possibility that for a particular analogue the antipsychotic activity of clozapine may reside in one enantiomer of the analogue whereas other unwanted biological effects of clozapine may be caused by the other enantiomer. Variable-temperature proton nuclear magnetic resonance studies showed that although 5-methylene-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene exists at room temperature as configurational enantiomers, the activation energy for thermal racemization is 19 kcal mol-1 at 105°C, and it is doubtful that the enantiomers of this analogue can be isolated under usual laboratory conditions. The (Z)-5-ethylidene and 5-isopropylidene analogues have activation energies greater than 23 kcal mol-1 at 160°C, and thus there is a possibility that the analogues can be obtained as their respective enantiomers. 5-Methyl-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene incorporates a chiral center which is not thermally racemized, but it exists at room temperature as two diasteromers with an activation energy for inversion of the 5H-dibenzo[a,d]cycloheptene ring of 21 kcal mol-1. When the 5,11-dicarbo analogues were tested in vitro for biological activity and their activities were compared to that of clozapine, the affinities for muscarinic and dopamine D-1 and D-2 sites were reduced but were still substantial. Thus the respective biological activities of the racemates indicate that the biological activities of the thermally stable enantiomers may be of importance in finding a clozapine derivative with fewer side effects than those shown by clozapine itself. Because of the susceptibility of the enamines to acid-catalyzed hydrolysis, resolution into respective enantiomers is not anticipated.

Original languageEnglish (US)
Pages (from-to)2261-2268
Number of pages8
JournalJournal of Medicinal Chemistry
Volume32
Issue number10
StatePublished - 1989

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Enantiomers
Clozapine
Antipsychotic Agents
Bioactivity
Activation energy
Temperature
Nuclear magnetic resonance
Cholinergic Agents
Protons
Dopamine
Hydrolysis
Magnetic Resonance Spectroscopy
Hot Temperature
Acids
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents. / Rupard, J. Howard; De Paulis, Tomas; Janowsky, Aaron; Smith, Howard E.

In: Journal of Medicinal Chemistry, Vol. 32, No. 10, 1989, p. 2261-2268.

Research output: Contribution to journalArticle

Rupard, J. Howard ; De Paulis, Tomas ; Janowsky, Aaron ; Smith, Howard E. / Sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents. In: Journal of Medicinal Chemistry. 1989 ; Vol. 32, No. 10. pp. 2261-2268.
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AB - Sterically hindered 5,11-dicarbo analogues of clozapine were prepared as potential chiral antipsychotic agents, with the possibility that for a particular analogue the antipsychotic activity of clozapine may reside in one enantiomer of the analogue whereas other unwanted biological effects of clozapine may be caused by the other enantiomer. Variable-temperature proton nuclear magnetic resonance studies showed that although 5-methylene-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene exists at room temperature as configurational enantiomers, the activation energy for thermal racemization is 19 kcal mol-1 at 105°C, and it is doubtful that the enantiomers of this analogue can be isolated under usual laboratory conditions. The (Z)-5-ethylidene and 5-isopropylidene analogues have activation energies greater than 23 kcal mol-1 at 160°C, and thus there is a possibility that the analogues can be obtained as their respective enantiomers. 5-Methyl-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene incorporates a chiral center which is not thermally racemized, but it exists at room temperature as two diasteromers with an activation energy for inversion of the 5H-dibenzo[a,d]cycloheptene ring of 21 kcal mol-1. When the 5,11-dicarbo analogues were tested in vitro for biological activity and their activities were compared to that of clozapine, the affinities for muscarinic and dopamine D-1 and D-2 sites were reduced but were still substantial. Thus the respective biological activities of the racemates indicate that the biological activities of the thermally stable enantiomers may be of importance in finding a clozapine derivative with fewer side effects than those shown by clozapine itself. Because of the susceptibility of the enamines to acid-catalyzed hydrolysis, resolution into respective enantiomers is not anticipated.

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