Arabian Journal of Chemistry (2013) xxx, xxx–xxx King Saud University Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com ORIGINAL ARTICLE Synthesis and evaluation of antipsychotic activity of 11-(40-(N-aryl carboxamido/N-aryl-a-phenyl-acetamido)- piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives Manoj S. Jain *, Sanjay J. Surana Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur District, Dhule 425405, Maharashtra, India Received 14 January 2013; accepted 19 July 2013 KEYWORDS Abstract In the present study, a series of new substituted N-11-(40-N-aryl carboxamido/N-(aryl)- Dibenzoxazepine; a-phenyl-acetamido-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives were designed on a revised Antipsychotic; structural model, length and nature of linker and introduced aryl group. All the compounds Carboxamido/acetamido; (MJ1–MJ12) were synthesized by economical route and confirmed by IR, 1H NMR, and mass spec- Catalepsy tral analyses. The antipsychotic potentialities of the synthesized derivatives were evaluated in mice by catalepsy and foot sock induced aggression. The present study demonstrates significant antipsy- chotic activity for most of the compounds from series. Compounds MJ-1, MJ-3 and MJ-4 were found to be potent antipsychotic compounds of the series at 5 mg/kg dose level when compared with the reference drug clozapine. ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University. 1. Introduction observed that patients are liable to suffer from drug-induced extrapyramidal symptoms such as Parkinsonism, acute dys- Schizophrenia is one of the most widespread psychiatric disor- tonic reactions, akathisia, tardive dyskinesia and tardive dysto- ders and approximately 1.5–2% of the world’s population suf- nia (Chakrabarti et al., 1980; Work group on schizophrenia, fers from severe symptoms occupying more than half of the 1997). The introduction of the dibenzodiazepine antipsychotic beds in psychiatric clinics (The World Health Report, 2001). agent clozapine (8-chloro-11[4-methyl-1-piperazinyl]-5H- Currently many drugs are available for the treatment of psy- dibenzo-[b,e][1,4] diazepine) was an important development chosis. Ever since antipsychotics were introduced it has been in the pharmacotherapy of schizophrenia (Burki et al., 1975; Sayers et al., 1975). Preclinical and clinical investigations have shown that clozapine has properties different from those of * Corresponding author. Tel.: +91 9429459367; fax: +91 2563255189. classic neuroleptic agents, as well as a substantial therapeutic E-mail address: [email protected] (M.S. Jain). advantage (Kane et al., 1981; Lieberman et al., 1986; Peer review under responsibility of King Saud University. Lieberman et al., 1989). Clozapine was found to be one of the better choices for the treatment of refractory schizophrenia. Unlike classic neuroleptic agents, clozapine Production and hosting by Elsevier did not cause Parkinsonism, dystonia, or tardive dyskinesia, 1878-5352 ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University. http://dx.doi.org/10.1016/j.arabjc.2013.07.033 Please cite this article in press as: Jain, M.S., Surana, S.J. Synthesis and evaluation of antipsychotic activity of 11-(40-(N-aryl carboxamido/N-aryl-a-phenyl- acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.07.033 2 M.S. Jain, S.J. Surana nor did it elevate prolactin levels (Lieberman et al., 1989). De- chloride optics and are measured in cmÀ1. 1H NMR spectra spite the promise of clozapine, its use has been limited by its were recorded on Varian Mercury YH-300 MHZ (Gemini), propensity to cause agranulocytosis (Alvir et al., 1993). Bruker-500 MHz and Varian Unity-400 MHz spectrometer. The progress made in the area of QSAR and bioisosterism All experiments were carried out in CDCl3 as solvent and has opened an avenue to get better and safer drugs. Loxapine 1H chemical shift of the solvent was used as a secondary refer- and Clozapine belong to the class of dibenzoxazepine and dib- ence and referred to the TMS signal from the usual relation- enzodiazepine, respectively and they differ in pharmacody- ship; the values of the chemical shift (d) are given in ppm. namic profile (Wagh et al.,2007; Wagh et al., 2005). The Mass spectra were recorded on Jeol SX 102/Da-600 mass spec- Loxapine like drugs e.g. Clothiapine, Metiapine, and Zotepine; trometer, FAB gas at 10 kV accelerating voltage using a direct have an electronegative group at carbon-2 position that is rel- inlet system. FAB mass spectra were recorded at room temper- atively close to the side chain nitrogen and showed extrapyra- ature. Gas Chromatograms were recorded on Chemito-8610 midal side effects. On the other hand Clozapine like drugs e.g. HR using OV-101 column and B.P. 5 capillary column with Clozapine, Fluperlapine and Olanzapine all either lack a ring 0.5 l film thickness. substituent or have an electronegative group at C-8 position, much away from side chain nitrogen (Wagh et al., 2007). 3. Synthesis Therefore, Clozapine has thus inspired a search for additional, safer, ‘atypical’ agents with antipsychotic activity and low risk 3.1. Synthesis of 2-nitro-20-methyl diphenyl ether carboxylate of extrapyramidal side effects. Pharmacological investigation (3) of series of clozapine analogues revealed that optimal length of the hydrocarbon linker between N40 and the introduced aryl A mixture of o-Fluoro nitrobenzene (10 gm, 0.070 mol), anhy- system (phenyl) was two to four atoms (Capuano et al., 2003). drous potassium carbonate (14.7 g, 0.1066 mol) and methyl Both Clozapine and Loxapine on N-demethylation (at N4 of salicylate (16.2 g, 0.1066 mol) was transferred in a 500 ml piperazine) produce less active or toxic metabolite (Capuano round bottomed flask, equipped with a sealed mechanical stir- et al., 2003). Consequently, keeping the view of blocking the rer and a reflux condenser and contents were refluxed in diox- N-demethylation metabolism of Clozapine and Loxapine in ane for 10 h. The reaction was monitored by GC. The reaction our mind we have blocked N4 demethylation by substituting mixture was dumped in water, extracted with toluene, the ex- alkyl or aryl acetamido group at N4 of piperazine so as to in- tract washed with 5% solution of sodium hydroxide. Toluene crease half-life of drug and reduce side effects. Keeping this was then distilled off to give thick liquid of 2-nitro-20-methyl view in mind and continuation of our research toward devel- diphenyl ether carboxylate. Yield = 18 g (93%). opment of potent antipsychotic agents (Wagh et al., 2007), herein, we have incorporated an N-aryl carboxamido/N- 3.2. Synthesis of 2-amino-20-methyl diphenyl ether carboxylate (aryl)-a-phenyl-acetamido-piperazinyl substituted at N4 of (4) piperazine in dibenzoxazepine derivatives to improve their antipsychotic potential. Several synthetic routes were reported 0 for the synthesis of tricyclic ring, Stutton et al. reported syn- To a 2-nitro-2 -methyl-diphenyl ether carboxylate (3) (18 g, thesis using 2-chloro nitro benzene and phenol in the presence 0.066 mol) was added 100 ml of methanol followed by the of copper followed by reduction, phosgenation and cyclization addition of 1 g of Raney nickel, in a stainless steel hydrogena- (Stutton, 1969). In other route, 2-amino diphenyl ether was re- tion bottle and the reaction mixture was hydrogenated at acted with ethyl chloroformate followed by phosphorous oxy- 70 psi pressure, the reaction monitored by TLC. The catalyst chloride (Smits et al., 2006). We have tried for a new route of was filter and methanol was distilled-off under reduced pres- 0 synthesis using 2-fluoro nitrobenzene and methyl salicylate in sure to get the desired product, almost pure 2-amino-2 -meth- presence of potassium carbonate followed by reduction with yldiphenyl ether carboxylate, Yield = 13.5 g (82%). raney nickel and cyclization at 150 °C. In present work we have not only developed new route of synthesis using commer- 3.3. Synthesis of 11-Oxadibenz[b,f][1,4] oxazepine (5) cially available raw material but also achieve good yield with better antipsychotic potency of the target derivatives. In a 100 ml round bottomed flask, 2-amino-20-methyldiphenyl ether carboxylate (4) (10 g, 0.041 mol), 50 ml dimethyl form- 2. Methods and materials amide, and 0.5 ml sulfuric acid were added and refluxed for 15 h, the reaction was monitored by TLC. After the comple- All solvents and chemicals used in the synthesis were procured tion of reaction, it was cooled to room temperature and from commercial suppliers and purified whenever necessary. dumped in 200 ml water. Off-white colored precipitate was fil- Progress of the reaction was monitored by TLC using Chloro- tered and dried. m.p. 210–212 °C. Yield = 6.8 g (79%). form:acetone (9:1) system. The o-fluoro nitrobenzene, methyl salicylate, dioxane, potassium carbonate, methanol, pipera- 3.4. 11-chloro-dibenz[b,f][1,4] oxazepine (6) zine, xylene, phosphorus oxychloride and a-chloro phenylace- tic acid were procured from Rankem labs. Raney Ni and In a 500 ml round bottomed flask, 11-oxo-dibenzo [b,f][1,4] oxa- triphosgene were procured from sampro organic research zepine (5) (5 g, 0.023 mol), 50 ml POCl3 and 1 g N,N-dimethyl lab. Melting points (mp) were determined using Veego micro- aniline were mixed and refluxed for 18 h. The excess POCl3 processor based programmable melting point apparatus, in was distilled out under vacuum and the residue was extracted open capillaries and were uncorrected. Infrared spectra were with toluene (2 · 50 ml).