New (Sulfonyloxy)piperazinyldibenzazepines as Potential Atypical Antipsychotics:  Chemistry and Pharmacological Evaluation

Abstract

A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.

Classics in Chemical Neuroscience: Clozapine

“…36,37 Other variations have been reported. 38,39 For example, the original patent also describes coupling Nmethylpiperazine to 13 to generate the corresponding amide prior to thermal condensation leading to 3 directly. En route to a tritiated version of 3, de Paulis and co-workers 39 first converted 14 to the thioamide, followed by methylation to provide an alternate leaving group for displacement by the tritiated N-methylpiperazine.…”

Synthesis of 2-aryl-1,2-dihydronaphtho[1,2-f][1,4]oxazepin-3(4H)-ones. Part I

“…The other regioisomer 2-aryl-2,3-dihydronaphto[1,2-f] [1,4]oxazepin-4(1H)-ones 8a-c, which could be formed from the nitrogen attack, were not isolated. …”

“…5,6 Additionally, benzo [1,4]oxazepines are crucial moieties in many psychoactive drugs. 7,8 It was found that dibenzo[b,f] [1,4]oxazepin-11(10H)-ones to be selective inhibitors of human immunodefiency virus (HIV) type 1 reverse transcriptase.…”

“…5,6 Additionally, benzo [1,4]oxazepines are crucial moieties in many psychoactive drugs. 7,8 It was found that dibenzo[b,f] [1,4]oxazepin-11(10H)-ones to be selective inhibitors of human immunodefiency virus (HIV) type 1 reverse transcriptase. 9 Known synthesis of benzoxazepines includes condensations of 2-aryloxyethylamines with 2-formylbenzoic acid, 10 rearrangement of methyl 2-(8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-yl)benzoate using Bischler-Napieralski conditions 11 and scandium or copper triflate catalyzed acylaminoalkylation of α-methoxyisoindolones with the formation of 1,4-benzoxazepines in moderate yields.…”

A new and convenient synthetic method for 1,2,3,5,6,11b-hexahydroimidazo [1,2-d][1,4]benzoxazepine and its derivatives

“…[1][2][3][4][5] Most syntheses of 2,3,4,5-tetrahydro-1,4-benzoxazepines involve the reduction of the carbonyl group(s) as for 5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine, 3-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine, and 3,5-dioxo-2,3,4,5-tetrahydro-1,4-benzoxazepine, or the reduction of a double bond as for 2,3-dihydro-1,4-benzoxazepine. 1,[6][7][8] Alternatively, 2,3,4,5-tetrahydro-1,4-benzoxazepines are accessible by one of the following known benzoxazepine syntheses: (i) condensation of 2-aryloxyethylamines with 2-formylbenzoic acid to form aminonaphthalides followed by cyclization: (ii) rearrangement of methyl 2-(8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-yl)benzoate using Bischler-Napieralski conditions; (iii) scandium or copper triflate-catalyzed acylaminoalkylation of α-methoxy-isoindolones with the formation of 1,4-benzoxazepines.…”