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Synthesis and evaluation of antipsychotic activity of 11-(4′-(N-aryl carboxamido/N-aryl-α-phenyl-acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives
⁎Corresponding author. Tel.: +91 9429459367; fax: +91 2563255189. jainmanoj2712@gmail.com (Manoj S. Jain)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
In the present study, a series of new substituted N-11-(4′-N-aryl carboxamido/N-(aryl)-α-phenyl-acetamido-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives were designed on a revised structural model, length and nature of linker and introduced aryl group. All the compounds (MJ1–MJ12) were synthesized by economical route and confirmed by IR, 1H NMR, and mass spectral analyses. The antipsychotic potentialities of the synthesized derivatives were evaluated in mice by catalepsy and foot sock induced aggression. The present study demonstrates significant antipsychotic 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.
Keywords
Dibenzoxazepine
Antipsychotic
Carboxamido/acetamido
Catalepsy
1 Introduction
Schizophrenia is one of the most widespread psychiatric disorders and approximately 1.5–2% of the world’s population suffers from severe symptoms occupying more than half of the beds in psychiatric clinics (The World Health Report, 2001). Currently many drugs are available for the treatment of psychosis. Ever since antipsychotics were introduced it has been observed that patients are liable to suffer from drug-induced extrapyramidal symptoms such as Parkinsonism, acute dystonic reactions, akathisia, tardive dyskinesia and tardive dystonia (Chakrabarti et al., 1980; Work group on schizophrenia, 1997). The introduction of the dibenzodiazepine antipsychotic agent clozapine (8-chloro-11[4-methyl-1-piperazinyl]-5H-dibenzo-[b,e][1,4] diazepine) was an important development 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 classic neuroleptic agents, as well as a substantial therapeutic advantage (Kane et al., 1981; Lieberman et al., 1986; 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 did not cause Parkinsonism, dystonia, or tardive dyskinesia, nor did it elevate prolactin levels (Lieberman et al., 1989). Despite the promise of clozapine, its use has been limited by its propensity to cause agranulocytosis (Alvir et al., 1993).
The progress made in the area of QSAR and bioisosterism has opened an avenue to get better and safer drugs. Loxapine and Clozapine belong to the class of dibenzoxazepine and dibenzodiazepine, respectively and they differ in pharmacodynamic profile (Wagh et al.,2007; Wagh et al., 2005). The Loxapine like drugs e.g. Clothiapine, Metiapine, and Zotepine; have an electronegative group at carbon-2 position that is relatively close to the side chain nitrogen and showed extrapyramidal side effects. On the other hand Clozapine like drugs e.g. Clozapine, Fluperlapine and Olanzapine all either lack a ring substituent or have an electronegative group at C-8 position, much away from side chain nitrogen (Wagh et al., 2007). Therefore, Clozapine has thus inspired a search for additional, safer, ‘atypical’ agents with antipsychotic activity and low risk of extrapyramidal side effects. Pharmacological investigation of series of clozapine analogues revealed that optimal length of the hydrocarbon linker between N4′ and the introduced aryl system (phenyl) was two to four atoms (Capuano et al., 2003). Both Clozapine and Loxapine on N-demethylation (at N4 of piperazine) produce less active or toxic metabolite (Capuano et al., 2003). Consequently, keeping the view of blocking the N-demethylation metabolism of Clozapine and Loxapine in our mind we have blocked N4 demethylation by substituting alkyl or aryl acetamido group at N4 of piperazine so as to increase half-life of drug and reduce side effects. Keeping this view in mind and continuation of our research toward development of potent antipsychotic agents (Wagh et al., 2007), herein, we have incorporated an N-aryl carboxamido/N-(aryl)-α-phenyl-acetamido-piperazinyl substituted at N4 of piperazine in dibenzoxazepine derivatives to improve their antipsychotic potential. Several synthetic routes were reported for the synthesis of tricyclic ring, Stutton et al. reported synthesis using 2-chloro nitro benzene and phenol in the presence of copper followed by reduction, phosgenation and cyclization (Stutton, 1969). In other route, 2-amino diphenyl ether was reacted with ethyl chloroformate followed by phosphorous oxychloride (Smits et al., 2006). We have tried for a new route of synthesis using 2-fluoro nitrobenzene and methyl salicylate in presence of potassium carbonate followed by reduction with raney nickel and cyclization at 150 °C. In present work we have not only developed new route of synthesis using commercially available raw material but also achieve good yield with better antipsychotic potency of the target derivatives.
2 Methods and materials
All solvents and chemicals used in the synthesis were procured from commercial suppliers and purified whenever necessary. Progress of the reaction was monitored by TLC using Chloroform:acetone (9:1) system. The o-fluoro nitrobenzene, methyl salicylate, dioxane, potassium carbonate, methanol, piperazine, xylene, phosphorus oxychloride and α-chloro phenylacetic acid were procured from Rankem labs. Raney Ni and triphosgene were procured from sampro organic research lab. Melting points (mp) were determined using Veego microprocessor based programmable melting point apparatus, in open capillaries and were uncorrected. Infrared spectra were scanned on Shimadzu 8400S FTIR spectrometer with sodium chloride optics and are measured in cm−1. 1H NMR spectra were recorded on Varian Mercury YH-300 MHZ (Gemini), Bruker-500 MHz and Varian Unity-400 MHz spectrometer. All experiments were carried out in CDCl3 as solvent and 1H chemical shift of the solvent was used as a secondary reference and referred to the TMS signal from the usual relationship; the values of the chemical shift (d) are given in ppm. Mass spectra were recorded on Jeol SX 102/Da-600 mass spectrometer, FAB gas at 10 kV accelerating voltage using a direct inlet system. FAB mass spectra were recorded at room temperature. Gas Chromatograms were recorded on Chemito-8610 HR using OV-101 column and B.P. 5 capillary column with 0.5 μ film thickness.
3 Synthesis
3.1 Synthesis of 2-nitro-2′-methyl diphenyl ether carboxylate (3)
A mixture of o-Fluoro nitrobenzene (10 gm, 0.070 mol), anhydrous potassium carbonate (14.7 g, 0.1066 mol) and methyl salicylate (16.2 g, 0.1066 mol) was transferred in a 500 ml round bottomed flask, equipped with a sealed mechanical stirrer and a reflux condenser and contents were refluxed in dioxane for 10 h. The reaction was monitored by GC. The reaction mixture was dumped in water, extracted with toluene, the extract washed with 5% solution of sodium hydroxide. Toluene was then distilled off to give thick liquid of 2-nitro-2′-methyl diphenyl ether carboxylate. Yield = 18 g (93%).
3.2 Synthesis of 2-amino-2′-methyl diphenyl ether carboxylate (4)
To a 2-nitro-2′-methyl-diphenyl ether carboxylate (3) (18 g, 0.066 mol) was added 100 ml of methanol followed by the addition of 1 g of Raney nickel, in a stainless steel hydrogenation bottle and the reaction mixture was hydrogenated at 70 psi pressure, the reaction monitored by TLC. The catalyst was filter and methanol was distilled-off under reduced pressure to get the desired product, almost pure 2-amino-2′-methyldiphenyl ether carboxylate, Yield = 13.5 g (82%).
3.3 Synthesis of 11-Oxadibenz[b,f][1,4] oxazepine (5)
In a 100 ml round bottomed flask, 2-amino-2′-methyldiphenyl ether carboxylate (4) (10 g, 0.041 mol), 50 ml dimethyl formamide, and 0.5 ml sulfuric acid were added and refluxed for 15 h, the reaction was monitored by TLC. After the completion of reaction, it was cooled to room temperature and dumped in 200 ml water. Off-white colored precipitate was filtered and dried. m.p. 210–212 °C. Yield = 6.8 g (79%).
3.4 11-chloro-dibenz[b,f][1,4] oxazepine (6)
In a 500 ml round bottomed flask, 11-oxo-dibenzo [b,f][1,4] oxazepine (5) (5 g, 0.023 mol), 50 ml POCl3 and 1 g N,N-dimethyl aniline were mixed and refluxed for 18 h. The excess POCl3 was distilled out under vacuum and the residue was extracted with toluene (2 × 50 ml). The toluene extract was washed with cold water (2 × 100 ml) to remove the traces of POCl3 and dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure; residue was distilled under high vacuum and yielded the pale yellow liquid, 11-chloro dibenzoxazepine b.p.160–162 °C (2 mm/Hg). Yield = 3.25 g (60%).
3.5 Synthesis of 11-piperazinyl-dibenz[b,f][1,4] oxazepine (7)
In a 100 ml round bottomed flask, equipped with a condenser and mechanical stirrer, anhydrous piperazine (3.3 g, 0.038 mol), and 30 ml xylene were placed. Mixture was heated to 70–80 °C and a solution of 11-chloro dibenzoxazepine (6) (3 g 0.013 mol) in 20 ml xylene was added with stirring within 30 min and contents were further refluxed for 5 h, then the reaction mixture was cooled and dump in 100 ml water. Organic layer was separated and washed with water (2 × 50 ml) to remove excess of piperazine. Xylene was distilled off under vacuum; afforded, 11-piperazinyl dibenzoxazepine and was further purified by column chromatography. m.p. 184–186 °C. Yield = 3 g (92%) IR cm−1 3065 (–NH), 2893 (–CH), 1597 (C⚌N), 1244 (C–O–C). 1H NMR δ: 2.30 (s, 1H, NH), 3.80–3.50 (s, 8H, 4-CH2), 7.30–7.10 (m, 5H, Ar–H), 7.40–7.35(d, 1H, Ar-H), 7.50–7.44(t, 1H, Ar-H), M/S m/e: 279, 210, 194, 85.
3.6 Synthesis of aryl isocyanates (8a–e)
3.6.1 The following general procedure was adopted for the synthesis of all isocyanates
In a 250 ml round bottomed flask, equipped with a condenser and dropping funnel, a mixture of p-toludine hydrochloride (3 gm, 0.020 mol) and 50 ml xylene was heated. When the mixture boiled, a solution of triphosgene (6.16 gm, 0.020 mol) in 30 ml xylene was added slowly using dropping funnel with dip tube. As reaction was forwarded p-toludine hydrochloride dissolved, after the complete addition of triphosgene solution reflux was continued for further 30 min. Excess of toluene was distilled and p-tolyl isocyanate was obtained by high vacuum distillation (10 mm Hg). p-Tolyl isocyanate was packed in a bottle by flushing with nitrogen. Yield = 2.3 g (85%).
3.7 Synthesis of substituted N-aryl-α-chlorophenylacetamides (9a–e)
3.7.1 The following general procedure was adopted for the synthesis of all the N-aryl-α-chlorophenylacetamides
In a 100 ml round bottomed flask equipped with a stirrer and condenser, o-chloro aniline (2.25 gm, 0.02 mol), tri-ethyl amine (3.0 gm, mole) and 30 ml dioxane were placed and cooled to 0 °C. The solution of α-Chlorophenyl acetyl chloride (3.76 gm, 0.02 mol) in 20 ml dioxane was added drop wise with stirring (During addition the temperature was maintained between 0 °C and 10 °C). After complete addition the mixture was stirred for further 10 h at room temperature. The reaction mixture was dumped in cold water and solid was filtered and dried. m.p. 130–132 °C C, Yield = 3.7 g (78%).
3.7.2 Synthesis of 11-(4′-N-phenyl carboxamido)–piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ1)
In a 50 ml round bottomed flask, 11-(Piperazinyl)-dibenz[b,f][1,4]-oxazepine(7) (2.8 gm, 0.010 mol) was dissolved in 20 ml xylene and heated to 50 °C C. Phenylisocyanate (1.19 gm, 0.010 mol) was added drop wise, immediately product was precipitated out. After complete addition (30–45 min) the solid was filtered off and dried. The product was recrystallized from dilute hydrochloric acid (5%, 25 ml), solution was filtered and neutralized to pH 7 by dilute ammonia. Product was filtered and purified through alumina column eluted by chloroform. m.p. 172–174 °C. Yield = 2 g (51.70%). IR cm−1 3327 (–NH), 1678 (C⚌O), 1573(–NH), 1H NMR δ: 2.91 (t, 4H, 2CH2), 3.61 (t, 4H, 2CH2), 6.15 (s, 1H, NH), 7.3–6.8 (m, 11H, Ar-H), 7.53–7.45 (d, 2H, Ar-H), 13C NMR δ: 46.9, 50.2, 109.5, 117.4, 121.2, 124.8, 126.7, 129.4, 130.1, 136.9, 142.6, 148.7, 151.1, 155.2,171.2 m/z 398 (M+), 279, 209, 85.
3.7.3 Synthesis of 11-(4′-N-(2-methylphenyl)-carboxamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ2)
In a 50 ml round bottomed flask, 11-(Piperazinyl)-dibenz[b,f][1,4]-oxazepine(7) (2.8 gm, 0.010 mol) was dissolved in 20 ml xylene and heated to 50 °C C. Then, o-tolylisocyanate (1.33 gm, 0.010 mol) was added drop wise, immediately product was precipitated out. m.p. 164–66 °C. Yield = 2.4 g (58%). IR cm−1: 3273 (–NH), 1653 (C⚌O), 1593 (–NH), 1H NMR δ: 2.32 (s, 3H, CH3), 2.82 (t, 4H, 2CH2), 3.48 (t, 4H, 2CH2), 6.0 (s, 1H, NH), 7.1–6.8 (m, 7H, Ar-H), 7.35–7.2 (m, 3H, Ar-H), 7.58–7.42 (d, 2H, Ar-H), 13C NMR δ: 15.6, 48.2, 54.3, 105.2, 109.5, 115.3, 121.8, 123.1, 125.7, 128.3, 130.7, 146.5, 151.2, 155.8, 155.3, 172.9 m/z 413(M+1), 412(M), 307, 280, 194.
3.7.4 Synthesis of 11-(4′-N-(4-methylphenyl)-carboxamido)–piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ3)
In a 50 ml round bottomed flask, 11-(Piperazinyl)-dibenz[b,f][1,4]-oxazepine(7) (2.8 gm, 0.010 mol) was dissolved in 20 ml xylene and heated to 50 °C. Then p-tolylisocyanate (1.33 gm, 0.010 mol) was added drop wise, immediately product was precipitated out. m.p. 210–12 °C. Yield = 2.6 g (63.70%). IR cm−1: 3425 (–NH), 1680 (C⚌O), 1588 (–NH), 1H NMR δ: 2.14 (s, 3H, CH3), 2.91 (t, 4H, 2CH2), 3.61 (t, 4H, 2CH2), 6.2 (s, 1H, NH), 7.2–6.9 (m, 8H, Ar-H), 7.5–7.3 (m, 4H, Ar-H), 13C NMR δ: 22.5, 43.9, 47.8, 110.2, 115.3, 119.4, 125.8, 128.5, 129.9, 131.3, 138.2, 144.3, 149.1, 154.8, 158.3, 169.8 m/z 413(M+1), 412(M), 307, 280, 194.
3.7.5 Synthesis of 11-(4′-N-(4-chlorophenyl)-carboxamido)–piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ4)
In a 50 ml round bottomed flask, 11-(Piperazinyl)-dibenz[b,f][1,4]-oxazepine(7) (2.8 gm, 0.010 mol) was dissolved in 20 ml xylene and heated to 50 °C. Then p-chlorophenylisocyanate (1.53 gm, 0.010 mol) was added drop wise, immediately product was precipitated out. m.p. 234–36 °C. Yield = 2.39 g (55.30%). IR cm−1: 3358 (–NH), 1653 (C⚌O), 1593(–NH), 1H NMR δ: 2.95 (t, 4H, 2CH2), 3.66 (t, 4H, 2CH2), 6.32 (s, 1H, NH), 7.19–6.6 (m, 8H, Ar-H), 7.55–7.35 (m, 4H, Ar-H), 13C NMR δ: 45.7, 51.4, 108.5, 119.3, 122.3, 124.7, 126.3, 128.4, 130.9, 137.9, 146.3, 149.6, 154.1, 158.4, 174.2 m/z 434, 432(M), 307, 292, 237, 194.
3.7.6 Synthesis of 11-(4′-N-(4-methoxyphenyl)-carboxamido)–piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ5)
In a 50 ml round bottomed flask, 11-(Piperazinyl)-dibenz[b,f][1,4]-oxazepine(7) (2.8 gm, 0.010 mol) was dissolved in 20 ml xylene and heated to 50 °C. Then p-methoxyphenylisocyanate (1.49 gm, 0.010 mol) was added drop wise, immediately product was precipitated out. m.p. 202–04 °C. Yield = 2.9 g (67.5%). IR cm−1: 3385 (–NH), 1653 (C⚌O), 1593(–NH), 1H -NMR δ: 3.12 (s, 3H, CH3), 3.43 (t, 4H, 2CH2), 3.95 (t, 4H, 2CH2), 5.8 (s, 1H, NH), 7.3–6.5 (m, 8H, Ar-H), 7.57–7.48 (m, 4H, Ar-H), 13C NMR δ: 47.9, 49.3, 57.4, 110.4, 118.2, 122.4, 124.5, 127.7, 130.3, 132.1, 136.4, 138.7, 147.2, 148.8, 152.5, 155.8, 171.4 m/z 428(M), 307, 279, 210.
3.7.7 Synthesis of 11-(4′-N-(2,5-dichlorophenyl)-carboxamido)–piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ6)
In a 50 ml round bottomed flask, 11-(Piperazinyl)-dibenz[b,f][1,4]-oxazepine(7) (2.8 gm, 0.010 mol) was dissolved in 20 ml xylene and heated to 50 °C. Then 2, 5-dichlorophenylisocyanate (1.87 gm, 0.010 mol) was added drop wise, immediately product was precipitated out. m.p. 262–64 °C. Yield = 3.2 g (70.50%). IR cm−1: 3421 (–NH), 1604 (C⚌O), 1103(–NH), 1H NMR δ: 3.2 (t, 4H, 2CH2), 3.76 (t, 4H, 2CH2), 6.12 (s, 1H, NH), 7.33–6.5 (m, 7H, Ar-H), 7.58–7.46 (m, 4H, Ar-H), 13C NMR δ: 45.7, 47.8, 112.9, 117.8, 123.1, 124.8, 127.8, 131.5, 132.9, 135.2, 136.5, 138.2, 142.3, 148.4, 151.2, 156.7, 168.2 m/z 469, 467, 465(M), 307, 237, 194.
3.7.8 Synthesis of 11-(4′-(N-phenyl-α-phenyl acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ7)
In a 100 ml round bottomed flask equipped with reflux condenser, a solution of 11-(piperazinyl)-dibenz[b,f][1,4]-oxazepine(7) (2.8 gm, 0.010 mol) and tri-ethyl amine (1.5 gm, 0.015 mol) in 30 ml dioxane was taken. The reaction mixture was heated to reflux and a solution of N-phenyl-α-chlorophenyl acetamide (2.45 gm, 0.01 mol) in 20 ml dioxane was added with stirring. The mixture was refluxed for 6–8 h and the reaction was monitored by TLC. It was cooled to room temperature and dumped in 200 ml ice cold water. The precipitated product was filtered and dried. It was recrystallized from aqueous methanol. m.p. 180–82 °C. Yield = 2.80 g (57%). IR cm−1: 3410 (–NH), 1690 (C⚌O), 1588 (–NH), 1H -NMR δ: 2.2 (s, 1H, CH), 2.62 (s, 4H, 2CH2), 3.6 (s, 4H, 2CH2), 5.1(s, 1H, NH), 7–6.8 (m, 4H, Ar-H), 7.16 (s, 5H, Ar-H), 7.24–7.3 (d, 4H, Ar-H), 7.42–7.36 (m, 4H, Ar-H), 13C NMR δ: 47.4, 49.8, 67.4, 110.2, 115.7, 119.5, 121.8, 123.7, 124.7, 125.2, 127.4, 129.4, 131.5, 133.4, 135.1, 136.9, 138.2, 145.2, 151.4, 157.2, 159.3, 172.3, m/z 489(M+1), 368, 263, 194.
3.7.9 Synthesis of 11-(4′-(N-(2-methylphenyl)-α-phenyl acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ8)
A solution of 11-(piperazinyl)-dibenz[b,f][1,4]-oxazepine (7) (2.8 gm, 0.010 mol) and tri-ethyl amine (1.5 gm, 0.015 mol) in 30 ml dioxane was taken. The reaction mixture was heated to reflux and a solution of N-2-methylphenyl-α-chlorophenyl acetamide (2.59 gm, 0.01 mol) in 20 ml dioxane was added with stirring. m.p. 208–10 °C. Yield = 2.25 g (45%). IR cm−1: 3378 (–NH), 1680 (C⚌O), 1590 (–NH), 1H -NMR δ: 2.3 (s, 1H, CH), 2.45 (s, 3H, CH3), 2.75 (s, 4H, 2CH2), 3.7 (s, 4H, 2CH2), 5.3 (s, 1H, NH), 7.1–6.8 (m, 4H, Ar-H), 7.12 (s, 5H, Ar-H), 7.34–7.28 (d, 4H, Ar-H), 7.52–7.4 (m, 4H, Ar-H), 13C NMR δ: 16.3, 46.5, 50.4, 65.3, 111.5, 117.8, 120.5, 121.4, 123.2, 124.3, 125.1, 126.8, 127.3, 129.4, 133.9, 135.2, 136.4, 137.3, 138.8, 142.7, 149.1, 156.4, 160.1, 174.7, m/z 503(M+1), 368, 278, 263, 194.
3.7.10 Synthesis of 11-(4′-(N-(4-methylphenyl)-α-phenyl acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ9)
A solution of 11-(piperazinyl)-dibenz[b,f][1,4]-oxazepine (7) (2.8 gm, 0.010 mol) and tri-ethyl amine (1.5 gm, 0.015 mol) in 30 ml dioxane was taken. The reaction mixture was heated to reflux and a solution of N-4-methylphenyl-α-chlorophenyl acetamide (2.59 gm, 0.01 mol) in 20 ml dioxane was added with stirring. m.p. 202–04 °C. Yield = 2.75 g (55.40%). IR cm−1: 3368 (–NH), 1661 (C⚌O), 1589 (–NH), 1H NMR δ: 2.2 (s, 1H, CH), 2.23 (s, 3H, CH3), 2.67 (t, 4H, 2CH2), 3.63 (s, 4H, 2CH2), 5.7 (t, 1H, NH), 7.1–6.9 (m, 4H, Ar-H), 7.19 (s, 5H, Ar-H), 7.28–7.2 (d, 4H, Ar-H), 7.4–7.3 (m, 4H, Ar-H), 13C NMR δ: 26.2, 47.2, 51.5, 68.4, 112.8, 118.2, 120.4, 121.8, 122.9, 123.4, 125.5, 126.3, 127.3, 129.7, 132.4, 134.7, 136.8, 137.9, 139.2, 143.4, 148.2, 158.1, 160.4, 173.9, m/z 503(M+1), 502, 368, 278, 263, 194.
3.7.11 Synthesis of 11-(4′-(N-(4-chlorophenyl)-α-phenyl acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ10)
A solution of 11-(piperazinyl)-dibenz[b,f][1,4]-oxazepine (7) (2.8 gm, 0.010 mol) and tri-ethyl amine (1.5 gm, 0.015 mol) in 30 ml dioxane was taken. The reaction mixture was heated to reflux and a solution of N-4-chlorophenyl-α-chlorophenyl acetamide (2.80 gm, 0.01 mol) in 20 ml dioxane was added with stirring. m.p. 186–88 °C. Yield = 3.2 g (62.50%). IR cm−1: 3380 (–NH), 1693 (C⚌O), 1590 (–NH), 1H NMR δ: 2.15 (s, 1H, CH), 2.58 (t, 4H, 2CH2), 3.52 (t, 4H, 2CH2), 5.1 (s, 1H, NH), 6.8–6.7 (m, 4H, Ar-H), 7.1 (s, 5H, Ar-H), 7.25–7.14 (d, 4H, Ar-H), 7.38–7.3 (m, 4H, Ar-H), 13C NMR δ: 44.8, 48.7, 64.3, 111.3, 119.3, 120.8, 122.8, 123.7, 124.8, 125.9, 126.2, 127.4, 128.3, 130.4, 134.3, 135.8, 137.5, 139.5, 144.2, 149.3, 156.3, 159.8, 174.6, m/z 524(M), 522, 279, 263, 237, 223, 194.
3.7.12 Synthesis of 11-(4′-(N-(4-methoxyphenyl)-α-phenyl acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ11)
A solution of 11-(piperazinyl)-dibenz[b,f][1,4]-oxazepine (7) (2.8 gm, 0.010 mol) and tri-ethyl amine (1.5 gm, 0.015 mol) in 30 ml dioxane was taken. The reaction mixture was heated to reflux and a solution of N-4-methoxyphenyl-α-chlorophenyl acetamide (2.75 gm, 0.01 mol) in 20 ml dioxane was added with stirring. m.p. 240–42 °C. Yield = 3.10 g (61%). IR cm−1: 3428 (–NH), 1657 (C⚌O), 1598 (–NH), 1H NMR δ: 2.3 (s, 1H, CH), 3.25 (s, 3H, CH3), 2.82 (t, 4H, 2CH2), 3.7 (t, 4H, 2CH2), 5.32 (s, 1H, NH), 7.2–6.8 (m, 9H, Ar-H), 7.36–7.2.4 (d, 4H, Ar-H), 7.5–7.4 (m, 4H, Ar-H), 13C NMR δ: 46.1, 49.8, 53.8, 66.2, 110.4, 117.8, 121.2, 122.7, 123.6, 124.6, 126.3, 127.4, 128.7, 129.4, 134.3, 135.7, 136.9, 140.5, 143.8, 147.5, 154.3, 157.1, 159.7, 172.4, m/z 519 (M+1), 502, 397, 368, 278, 263,1 194, 121.
3.7.13 Synthesis of 11-(4′-(N-(2,5-dichlorophenyl)-α-phenyl acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives (MJ12)
A solution of 11-(piperazinyl)-dibenz[b,f][1,4]-oxazepine (7) (2.8 gm, 0.010 mol) and tri-ethyl amine (1.5 gm, 0.015 mol) in 30 ml dioxane was taken. The reaction mixture was heated to reflux and a solution of N-2,5-dichlorophenyl-α-chlorophenyl acetamide (3.15 gm, 0.01 mol) in 20 ml dioxane was added with stirring. m.p. 238–40 °C. Yield = 3.8 g (68.60%). IR cm−1: 3364 (–NH), 1659 (C⚌O), 1600 (–NH), 1H NMR δ: 2.19 (s, 1H, CH), 2.66 (t, 4H, 2CH2), 3.66 (t, 4H, 2CH2), 5.19 (s, 1H, NH), 7.19 (s, 5H, Ar-H), 7.28–7.2 (m, 4H, Ar-H), 7.5–7.4 (m, 2H, Ar-H), 7.79 (s, 1H, Ar-H), 13C NMR δ: 45.4, 48.9, 64.3, 109.8, 116.9, 120.9, 121.8, 123.2, 124.4, 126.1, 127.3, 128.4, 129.6, 131.4, 133.6, 135.3, 137.7, 139.8, 145.2, 148.9, 154.4, 158.3, 173.8, m/z 558 (M), 556, 368, 279, 263, 237, 223, 194.
3.8 Pharmacological screening
For pharmacological screening catalepsy and foot shock induced aggression model were used.
Catalepsy was induced by targeted compounds (MJ1–12) and haloperidol at a dose of 5 mg/kg (i.p.) to mice (n = 5). The duration of catalepsy was measured at 0, 30, 60, 90, 120, 150 and 180 min intervals by means of Bar test. Both the forepaws of mouse were placed on a horizontal bar raised 3 cm from the table, and time required to remove the forepaws from the bar was recorded as the duration of catalepsy. Foot shock induced aggression was used for the anti aggression activity, five pairs of mice were used to determine the activity of individual compound. Each pair of mice was dosed with 5 mg/kg (i.p.) and tested without previous exposure. Test compounds (MJ1–12) and standard compound (clozapine) were administered three min before the mice were placed in box with grid floor consisting copper wire with a distance of 6 mm. A constant current of 1.2 mA was supplied through grid by a constant current shocker. Latency for first attack and number of total attack were determined for the total duration of 5 min. All observations were given as mean ± SEM for each group. The data were analyzed by One-way ANOVA followed by Dunnett’s test, p < 0.05 was considered as significant.
4 Results and discussion
4.1 Chemistry
Synthesis of the titled compounds (MJ1–MJ12) has been carried out as being depicted in (Scheme 1). The condensation of O-fluoro nitro benzene with methyl salicylate in the presence of potassium carbonate in lead nucleus was found to be superior over Ulmman condensation as per the literature. Only slight excess of methyl salicylate was enough for the complete utilization of O-fluoro nitro benzene and after the completion of reaction the excess of methyl salicylate was removed by washing with cold 5% caustic solution. The reaction afforded 85–90% yield and product was sufficiently pure for next step. Scale up of this process was very easy due to controllable exothermicity of the reaction and no pressure requirement with much lesser reaction time. Catalytic hydrogenation process was utilized in next step to avoid hydrolysis of ester group. Nitro diphenyl ether (3) was hydrogenated to amino diphenyl ether (4) using raney-nickel as catalyst and methanol as solvent at 3 kg hydrogen pressure and subsequently the same material was used for next step of cyclization. The cyclization process was carried out in DMF and initiated by catalytic amount of sulfuric acid to get lactam (5). Activation of tricyclic lactam to the corresponding imino chloride was done by reaction with excess phosphorous oxychloride at reflux temperature for 8 h. Tricyclic imino chloride was purified by high vacuum distillation at 160–162 °C and 2 mmHg vacuum. To avoid dimerization the purified 11-chloro dibenzoxazepine is then condensed with excess of anhydrous piperazine. The excess of piperazine was removed by water washing to get lead nucleus 11-piperazinyl dibenzoxzepine.![Synthetic pathway for synthesis of dibenz-[b,f][1,4]-oxazepine derivatives (MJ1 - MJ12).](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.07.033-fig1.png)
While in side chain synthesis as per the literature report linker group between N4 and aryl moiety must be two to four atoms. The carboxamido analogues (MJ1–6) were furnished from highly reactive aryl isocynate and lead nucleus. In the synthesis of aryl isocyante derivatives the direct use of phosgene gas is highly dangerous, to avoid risk of phosgene gas handling triphogene was used which is in situ converted into phosgene gas by heating at 60 °C in the presence of substituted aniline hydrochoride to get aryl isocyanate in 55–75% yield.
The N-aryl-α-chlorophenyl acetamide analogues were synthesized by reacting lead nucleus with different N-aryl-α-chlorophenyl acetamides in xylene to get chiral molecules (MJ7–12) with 45–71% yield. Chirality in molecule is helpful to reduce enzymatic decomposition of one enantiomer. While the phenyl ring at α position creates steric hindrances which helps to reduce metabolic oxidation of molecule ultimately leading to better metabolic stability with prolonged biological half life.
The IR spectra of carboxamido derivative (MJ1–6) and N-aryl-α-chlorophenyl acetamide derivative (MJ7–12) revealed absorption bands in the region of 1700–1650 cm−1 corresponding to amide (NH–C⚌O) stretching vibration in IR region which is not present in lead nucleus conforming the formation of final compounds. In 1H NMR deuterium exchange confirms the formation of lead nucleus. Presence of amide proton in 1H NMR spectrum at 6.4–5.1 (δ ppm) confirms the formation of final compounds.
4.2 Antipsychotic activity
In pharmacological screening, all newly synthesized compounds showed reduction in number of fights and increase in latency to fight in foot shocked induced aggression model suggesting antipsychotic activity of the compounds (Fig. 1–4, Table 1). In addition all compounds were unable to produce catalepsy in mouse indicating compounds without extrapyramidal effect (Fig. 5, Table 2). It clearly demonstrated that, all newly synthesized compounds are like atypical antipsychotic drugs with decreased metabolic deactivation which is a prominent factor for bioavailability of drugs. Study showed that ring substitution is not required for antipsychotic activity. Strong electron withdrawing N-aryl carboxamido side chain showed better activity than sterically hindered N-aryl α-phenyl acetamido group. Para substitution on side chain aryl group showed better activity than ortho substitution and chloro group at para position (MJ4) showed better activity than methyl or methoxy group.
| Treatment (5 mg/kg, i.p.) | Latency to fight (s) | Number of fight |
|---|---|---|
| Vehicle | 16.4 | 56 |
| Clozapine | 189 | 13.4 |
| MJ1 | 167.4 | 12.8 |
| MJ2 | 78.2 | 33.8 |
| MJ3 | 173 | 14.2 |
| MJ4 | 181.8 | 8.4 |
| MJ5 | 144 | 29 |
| MJ6 | 75.2 | 28 |
| MJ7 | 136.4 | 13.2 |
| MJ8 | 94.2 | 18.8 |
| MJ9 | 111.6 | 22.2 |
| MJ10 | 84.2 | 23.2 |
| MJ11 | 92.4 | 23.6 |
| MJ12 | 120 | 16.4 |
| Treatment | 0 | 30 | 60 | 90 | 120 min | 150 | 180 min |
|---|---|---|---|---|---|---|---|
| Duration of catalepsy in secs (Mean ± SEM) | |||||||
| Haloperidol | 0.01 | 116.6 | 160.6 | 191.6 | 193.3 | 281.6 | 198.3 |
| MJ1 | 2.4 | 17.5 | 21.5 | 25 | 29.2 | 30.5 | 24.2 |
| MJ2 | 1.6 | 8.5 | 12.6 | 18.4 | 20.2 | 17.2 | 19.6 |
| MJ3 | 2.8 | 5.4 | 19.4 | 22.3 | 20.2 | 25.3 | 27.2 |
| MJ4 | 2.3 | 12.6 | 20.3 | 24.6 | 25 | 28.3 | 22.6 |
| MJ5 | 2.8 | 19.5 | 28.5 | 24.9 | 28.2 | 28.5 | 26.3 |
| MJ6 | 1.8 | 7.8 | 12.4 | 21.3 | 19.2 | 23.3 | 22.2 |
| MJ7 | 2.3 | 11.6 | 38.3 | 31.6 | 25 | 28.6 | 24.8 |
| MJ8 | 1.8 | 8.5 | 17.6 | 20.8 | 22.7 | 24.2 | 23.2 |
| MJ9 | 1.4 | 6.6 | 18.4 | 21.3 | 20.2 | 26.3 | 28.2 |
| MJ10 | 2.5 | 16.2 | 24.1 | 33.4 | 28.2 | 31.7 | 38.1 |
| MJ11 | 2.1 | 15.5 | 22.5 | 22.4 | 24.2 | 27.2 | 24.6 |
| MJ12 | 1.2 | 3.3 | 19.6 | 21.6 | 21.6 | 20.2 | 24.2 |
5 Conclusion
In summary, we have reported simple, high yielding synthesis of 11-(4′-(N-aryl carboxamido/N-aryl-α-phenyl-acetamido)-piperazinyl)-dibenz[b,f][1,4]-oxazepine derivatives. Antipsychotic evaluation was done for compounds by foot shock induced aggression in mice and shown good to equipotent activities. In future, receptor specific in vitro evaluation of these compounds can also be carried out for further study.
Acknowledgments
The authors duly acknowledge the support from Dr. Anil Tatiya, Dr. Bhavin Vyas, Sandesh Lodha and Pravin Patil for their valuable support during study period. Authors gratefully acknowledge NHRDF Nasik, Hikal Ltd Pune for spectral data.
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