SYNTHESIS AND EVALUATION OF ANTIPSYCHOTIC ACTIVITY OF 11- (4-ARYL-1-PIPERAZINYL)-DIBENZ [b,f][1,4] OXAZEPINES AND THEIR 8-CHLORO ANALOGUES

Wagh, B.S.; Patil, Bhushan; Jain, Monish; Harak, Shilpa Sudhakar; Wagh, Sanjay B

doi:10.1515/hc.2007.13.2-3.165

Cited by 5 publications

(2 citation statements)

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“…Loxapine (Figure 1(a)) and clothiapine ( Figure 1(b)) are well known antipsychotic agents prescribed in schizophrenia, but they have major extrapyramidal side effects (EPSE) and motor side effects, which can be attributed mainly to the electronegative chlorine atom on carbon number 2 (C-2) of their tricyclic ring, which is responsible for greater affinity of these drugs towards D 2 receptors. To minimize the side effects of the aforementioned drugs, clozapine (Figure 1(c)), the structural analogue of loxapine, was synthesized, where the chlorine on C-2 is shifted to C-8 atom and the oxygen at position 5 of tricyclic ring is replaced with nitrogen [10]. These modifications certainly improved clozapines' pharmacokinetic and pharmacodynamic profile and proved to be effective in reducing both positive and negative symptoms of schizophrenia.…”

Section: Limitations Of Current Clinically Available Drugsmentioning

confidence: 99%

Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT_2A Antagonist

Jadhav

Kokil²,

Harak

et al. 2013

Journal of Chemistry

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Schizophrenia is a mental disorder manifested largely by disintegration of thought processes and emotional responsiveness. Given the therapeutic and toxic limitations of clinically available drugs, it is clear that there is still a need for the development of new generation antipsychotic agents with an improved clinical profile. Development of novel hybrid atypical tricyclic antipsychotic pharmacophore was achieved using direct (by measuring docking score of designed molecules on modelled 5- receptor) and indirect (current, clinically available therapeutic agents’ data) drug design approaches.

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Section: Limitations Of Current Clinically Available Drugsmentioning

confidence: 99%

Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT_2A Antagonist

Jadhav

Kokil²,

Harak

et al. 2013

Journal of Chemistry

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“…Previously reported synthetic approaches [9,10] to 11-substituted dibenzo[b,f] [1,4]oxazepines using 3 involve treating 3 with toxic phosgene or triphosgene to afford intermediate 1-(phenoxy)-2-isocyanatobenzene. We decided to avoid the use of phosgene or triphosgene by treating 3 with phenyl chloroformate under mild conditions, which afforded carbamate 4 in 98% yield.…”

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confidence: 99%

A novel synthetic approach to 11-substituted dibenzo[b,f][1,4]oxazepines

Zaware¹,

Ohlmeyer²

2014

Heterocyclic Communications

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A novel synthetic approach to 11-substituted dibenzo[b,f][1,4]oxazepinesAbstract: A novel protocol for the synthesis of 11-substituted dibenzo [b,f] [1,4]oxazepines is reported. Seven compounds were designed as analogs of the antipsychotic drug loxapine and antidepressant amoxapine. The key transformations include generation of a carbamate intermediate using phenyl chloroformate which avoids the use of harmful phosgene, a microwave-induced transformation of the carbamate intermediate into various urea derivatives, and a subsequent phosphorous oxychlorideinduced cyclocondensation. The simple reactions and wide substrate scope enhance the practical application of this methodology. Dibenzo[b,f][1,4]oxazepine derivatives possess diverse pharmacological activity [1-6]. Loxapine 1 and amoxapine 2 (Figure 1) are agents used for their antipsychotic and antidepressant action, respectively [7]. Both 1 and 2 bear the 11-substituted dibenzo[b,f][1,4]oxazepine scaffold.We report a new method for synthesis of seven fused 11-substituted dibenzo[b,f][1,4]oxazepines, namely compounds 19-25 (Scheme 1). The compounds were designed as analogs of 1 and 2.2-(4-Chlorophenoxy)aniline (3) was synthesized according to a reported method [8]. Previously reported synthetic approaches [9, 10] to 11-substituted dibenzo[b,f] [1,4]oxazepines using 3 involve treating 3 with toxic phosgene or triphosgene to afford intermediate 1-(phenoxy)-2-isocyanatobenzene. We decided to avoid the use of phosgene or triphosgene by treating 3 with phenyl chloroformate under mild conditions, which afforded carbamate 4 in 98% yield. Compound 4 was heated with amines 5-11 in a microwave reactor to yield the respective urea derivatives 12-18. The yields of these transformations ranged from 79% to 96%. A phosphorous oxychlorideinduced cyclocondensation of 12-18 furnished the target dibenzo[b,f][1,4]oxazepines 19-25, respectively, in yields ranging from 4% to 38%.In conclusion, we have developed a novel methodology for synthesis of 11-substituted dibenzo[b,f][1,4]oxazepines. The simplicity of the experiments, wide substrate scope, and avoidance of toxic phosgene, makes this methodology a useful addition in the collection of 11-substituted dibenzo[b,f][1,4]oxazepine syntheses. Experimental Phenyl [2-(4-chlorophenoxy)phenyl]carbamate (4) A solutionof 2-(4-chlorophenoxy)aniline (2.00 g, 9.10 mmol) and pyridine (0.83 mL, 10.0 mmol) in ethyl acetate (17.0 mL) at 0°C was treated dropwise with phenyl chloroformate (1.22 mL, 10.0 mmol).The resultant mixture was stirred for 3 h at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with 2% to 5% ethyl acetate-hexanes to afford phenyl [2-(4-chlorophenoxy)phenyl]carbamate 4 (3.02 g, 98%): 1 H NMR (600 MHz, CDCl 3 ) δ 8.26 (1H, bs), 7.56 (1H, bs), 7.41 (2H, t, J = 7.8 Hz), 7.35 (2H, d, J = 9.0 Hz), 7.31-7.30 (1H, m), 7.26 (1H, t, J = 7.2 Hz), 7.21 (2H, d, J = 7.8 Hz), 7.17 (1H, t, J = 7.8 Hz), 7.04 (1H, t, J = 7.2 Hz), 7.01 (2H, d, J = 8.4 Hz), 6...

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Synthesis of dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]benzoxazepin-10(11H)-one compounds based on o-nitrochloro derivatives of benzene and pyridine

Sapegin

Sakharov

Kalandadze³

et al. 2008

Mendeleev Communications

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SYNTHESIS AND EVALUATION OF ANTIPSYCHOTIC ACTIVITY OF 11- (4-ARYL-1-PIPERAZINYL)-DIBENZ [b,f][1,4] OXAZEPINES AND THEIR 8-CHLORO ANALOGUES

Cited by 5 publications

References 0 publications

Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT_2A Antagonist

Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT_2A Antagonist

A novel synthetic approach to 11-substituted dibenzo[b,f][1,4]oxazepines

Synthesis of dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]benzoxazepin-10(11H)-one compounds based on o-nitrochloro derivatives of benzene and pyridine

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SYNTHESIS AND EVALUATION OF ANTIPSYCHOTIC ACTIVITY OF 11- (4-ARYL-1-PIPERAZINYL)-DIBENZ [b,f][1,4] OXAZEPINES AND THEIR 8-CHLORO ANALOGUES

Cited by 5 publications

References 0 publications

Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT2A Antagonist

Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT2A Antagonist

A novel synthetic approach to 11-substituted dibenzo[b,f][1,4]oxazepines

Synthesis of dibenzo[b,f][1,4]oxazepin-11(10H)-one and pyrido[2,3-b][1,4]benzoxazepin-10(11H)-one compounds based on o-nitrochloro derivatives of benzene and pyridine

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Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT_2A Antagonist

Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5‐HT_2A Antagonist