3-Substituted 1-methyl-3-benzazepin-2-ones as 5-HT_2C receptor agonists

Abstract

In search of potent and selective 5-HT_2C receptor agonists, a series of novel 3-substituted 1-methyl-3-benzazepin-2-ones and 8-chloro-1-methyl-3-benzazepin-2-ones have been synthesized and evaluated for their 5-HT_2C receptor agonistic potential. 5-HT_2C receptor agonist activity was established with the despair swim test, plus maze test and the compounds' ability to decrease DA and 5-HT levels in rat brains similar to m-CPP. Selectivity was established with 5-HT_2C mediated penile erection and hypophagic responses in the presence of RS-102221 (a selective 5-HT_2C antagonist). The study established the selective 5-HT_2C receptor agonist response of compounds 7, 12–14, 24, 30, and 38 which could act as potential lead molecules for the treatment of pathological conditions associated with 5-HT_2C receptors.

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1. Introduction

The 5-hydroxytryptamine (5-HT, serotonin) neurotransmitter and modulator system controls the functioning of the gastrointestinal tract,¹ platelets² and central nervous system (CNS).³ Nearly 80% of 5-HT is synthesized in the enterochromaffin cells located in the gastrointestinal tract and in serotonergic neurons present in the CNS.^4,5 5-HT receptors are classified according to their structural, functioning and transduction-coupling properties. 5-HT, a ubiquitous neurotransmitter, mediates its action via fourteen different membrane bound receptor subtypes^6,7 which are broadly classified into seven major families i.e. 5-HT_1–7. All 5-HT receptor families are G-protein coupled receptors except for the 5-HT₃ receptor which is a ligand gated ion channel.⁸

The 5-HT₂ receptors comprise of three members 5-HT_2A, 5-HT_2B and 5-HT_2C, all belonging to the super family of G-protein-coupled receptors.⁹ The 5-HT₂ receptor subtype after activation stimulates the phospholipase C, a second messenger pathway, resulting in the hydrolysis of phosphoinositide which leads to increase in intracellular calcium levels.¹⁰ Apart from the conventional phospholipase C pathway, some studies have reported that the 5-HT₂ receptor subtypes can also activate phospholipase A2, leading to release of arachidonic acid.¹¹

5-HT_2C regulates a wide variety of physiological and behavioural functions, proving to be an attractive target for the treatment of a number of conditions like obesity, psychiatric disorders, sexual dysfunction, urinary incontinence, cardiovascular regulation, muscle contraction, body temperature, and also memory and learning.^12,13 Selective binding to 5-HT_2C receptor is an important criterion because 5-HT_2A agonists can have potentially hallucinogenic and cardiovascular (CV) side effects¹⁴ while 5-HT_2B agonism is linked with heart valvulopathy and pulmonary hypertension.¹⁵ 5-HT_2A, 5-HT_2B and 5-HT_2C receptors exhibit 46–50% overall sequence similarity as they are homologous in nature. To avoid side effects, a potential drug candidate should show its selectivity for 5-HT_2C receptor and should be devoid of intrinsic activity to 5-HT_2A and 5-HT_2B receptors, present predominantly in the thoracic aorta and fundus respectively.^16,17

Efforts have been made by researchers in the past for the discovery of potent and selective 5-HT_2C agonists, which led to the discovery of lorcaserin (1, APD-346, Arena) an anti-obesity agent. Vabicaserin (2, SCA-136; Pfizer) is another selective 5-HT_2C agonist which was used earlier to treat psychosis, but it has been discontinued due to non significant clinical effects.¹⁸

Recently we reported some novel 3-benzazepines possessing the scaffold present in lorcaserin (1), as potentially selective 5-HT_2C agonists.¹⁹ In a continuing research work on the series, we further report synthesis of some 1-methyl-3-benzazepin-2-one derivatives possessing selective 5-HT_2C agonist activity. Based on the results of preliminary screening, some chosen compounds (Schemes 1 and 2) have been evaluated further in animal model for depression, anxiety, obesity and penile erection.

Scheme 1 Regents and conditions: (a) NaH, 1.2 eq., dry THF : DMF, 80 °C, alkyl halides, substituted benzyl halides or cyclomethyl halides (R-X).

Scheme 2 Regents and conditions: (a) triphenylmethanol, p-Ts-OH·H₂O, dry toluene, 65–80 °C (b) NaH, dry THF : DMF, 80 °C (c) trifluoroacetic acid : DCM (70 : 30), room temp.

2. Results and discussion

2.1. Chemistry

1-Methyl-3-benzazepin-2-one²⁰ (5) was synthesized by the reported procedure.²⁰ Treatment of compound (5) with equimolar quantities of NaH and different alkyl/alkynyl/cyclohexylmethyl/arylmethyl halides resulted in the formation of 3-substituted derivatives (7–37). Some 8-chloro derivatives (38–44) were also prepared similarly from 8-chloro-1-methyl-3-benzazepin-2-one²⁰ (6) which was synthesized as per the reported method²⁰Scheme 1. The free acid derivative (37) was obtained on saponification of the ester (36).

Compound (48) having N-acetamide group was prepared from 2-bromoacetamide (45) and the benzazepine derivative (5). Direct reaction of 2-bromoacetamide (45) with 3-benzazepin-2-one (5) failed to provide the desired product, so it was thought to protect the amide function in 2-bromoacetamide (45) using some suitable protecting group. 2-Bromoacetamide (45) was reacted with triphenylmethanol using tosic acid as a catalyst to obtained N-trityl derivative (46) which was treated with NaH and 3-benzazepin-2-one (5) to obtain the desired derivative (47). Treatment of the derivative (47) with trifluoroacetic acid : DCM (70 : 30) resulted in the formation of compound (48) as shown in Scheme 2.

2.2. In vitro 5-HT_2A and 5-HT_2B receptors bioassays using rat thoracic aorta and rat fundus preparations

All of the synthesized compounds (7–44 and 48) were evaluated in vitro for 5-HT_2A and 5-HT_2B sensitivity by using rat thoracic aorta and rat fundus preparations to determine activity of the compounds on 5-HT_2A and 5-HT_2B receptors respectively (Table 1). Initially, all test compounds (7–44 and 48) were evaluated at 2 × 10⁻⁵ M concentration in both of the in vitro experiments to determine their 5-HT_2A/5-HT_2B agonist/antagonist activity. In case any compound showed agonist and/or antagonist activity on either of the preparations, it became evident by their pD₂ and/or pA₂ values respectively. pD₂ value is the negative logarithm of the EC₅₀ of an agonist which indicates its potency while pA₂ depicts the negative logarithm of the molar concentration of the antagonist that necessitates doubling of the concentration of the agonist needed to produce the original response. None of the compounds showed affinity for 5-HT_2A receptor on rat thoracic aorta preparation. However, compounds (16, 18, 19–22, 25–27, 33–35, 41 and 43) were found to be 5-HT_2B receptor agonists, which was evident by their pD₂ values while compounds (15 and 40) were shown to possess 5-HT_2B receptor antagonistic property offering pA₂ values greater than 6 (Table 1). Only those compounds which did not show 5-HT_2A and 5-HT_2B affinities in the isolated tissue preparations were taken up further for in vivo study on 5-HT_2C receptor. Thus, compounds (7–14, 17, 23, 24, 28–32, 36–39, 42, 44, and 48) were selected for 5-HT_2C receptor affinity studies since all these compounds were found to be inactive in the in vitro studies on both the tissues, suggesting their lack of affinity for the 5-HT_2A and 5-HT_2B receptors. These compounds could be active or inactive on 5-HT_2C receptor.

Table 1 In vitro assessment of the test compounds (7–44 and 48) for 5-HT_2A and 5-HT_2B receptors' actions using isolated rat thoracic aorta and rat fundus preparations respectively^a

Comp.	5-HT2A		5-HT2B		Comp.	5-HT2A		5-HT2B
	Agonist	Antagonist	Agonist	Antagonist		Agonist	Antagonist	Agonist	Antagonist
	pD2 value	pA2 value	pD2 value	pA2 value		pD2 value	pA2 value	pD2 value	pA2 value
a Results are expressed as mean ± SEM *compounds were found inactive at 2 × 10^−5 M concentration. Those compounds which showed activity at this concentration were later used for determining their pD2/pA2 values.
7	*	*	*	*	27	*	*	6.99 ± 0.36	—
8	*	*	*	*	28	*	*	*	*
9	*	*	*	*	29	*	*	*	*
10	*	*	*	*	30	*	*	*	*
11	*	*	*	*	31	*	*	*	*
12	*	*	*	*	32	*	*	*	*
13	*	*	*	*	33	*	*	6.81 ± 0.13	—
14	*	*	*	*	34	*	*	8.47 ± 0.19	—
15	*	*	—	6.95 ± 0.25	35	*	*	7.70 ± 0.33	—
16	*	*	8.46 ± 0.39	—	36	*	*	*	*
17	*	*	*	*	37	*	*	*	*
18	*	*	7.21 ± 0.24	—	38	*	*	*	*
19	*	*	7.76 ± 0.22	—	39	*	*	*	*
20	*	*	6.73 ± 0.41	—	40	*	*	—	8.38 ± 0.19
21	*	*	7.84 ± 0.34	—	41	*	*	8.59 ± 0.20	—
22	*	*	8.39 ± 0.28	—	42	*	*	*	*
23	*	*	*	*	43	*	*	7.44 ± 0.14	—
24	*	*	*	*	44	*	*	*	*
25	*	*	7.03 ± 0.10	—	48	*	*	*	*
26	*	*	6.48 ± 0.29	—

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2.3. Despair swim test

There are evidences demonstrating that overactivation of 5-HT_2C receptor may develop depressive and anxiety symptoms in a certain population of patients. 5-HT mediated activation of 5-HT_2C receptor is responsible for the negative side effects associated with selective serotonin re-uptake inhibitor (SSRI) medication.²¹ The despair swim test model was adopted for the assessment of depression.²² Rajkumar et al. has demonstrated the ability of m-CPP to induce depressogenic behaviour in rodents due to its 5-HT_2C receptor agonist activity. Compounds (7–14, 17, 23, 24, 28–32, 36–39, 42, 44, and 48) were screened for the despair swim test. As expected for a positive control, m-CPP (4) showed significant increase in the immobility time, indicative of the depressive effect (Fig. 1, p < 0.001). Compounds (7, 12–14, 24, 30, and 38) showed significant increase in the immobility time as compared to the saline control (Fig. 1, p < 0.001) which was possibly due to their 5-HT_2C receptor agonist activity. These compounds showed 5-HT_2C agonist mediated depressogenic response similar to the standard m-CCP (4). Rest of the compounds (8–11, 17, 23, 28, 29, 31, 32, 36, 37, 39, 42, 44, and 48) did not show significant effects in this test suggesting their inactivity for 5-HT_2C receptor. Compounds (7, 12–14, 24, 30, 38) demonstrating activity in this test were proceeded for further evaluation.

Fig. 1 Effect of m-CPP (2 mg kg⁻¹, p.o.) and the test compounds (10 mg kg⁻¹, p.o.) in despair swim test. Values represent the immobility time. Data are expressed as mean ± SEM. ***p < 0.001, **p < 0.01 indicate the level of significance vs. vehicle-treated control group (N = 6).

2.4. Elevated plus maze test

Anxiety is regulated mainly by the amygdala region of the brain with high levels of 5-HT_2C receptor expression. Previous report²³ demonstrated that activation of amygdala by a 5-HT_2C receptor agonist is strongly associated with the anxiety state. Thus antagonism of 5-HT_2C receptor might be beneficial for the treatment of anxiety.^24,25 Thus, the chosen compounds (7, 12–14, 24, 30, and 38) were evaluated on the anxiety model. The elevated plus maze test was adopted to assess the anxiety like condition. In the elevated plus maze test, m-CPP (4) showed significant anxiogenic response in mice (Fig. 2A, p < 0.001). Compounds (7, 12–14, 24, 30, and 38) showed significant decrease in the exploration (Fig. 2A.) as well as time spent (Fig. 2B.) in the open arm (p < 0.001), demonstrating their anxiogenic effect like the one showed by m-CPP (4), substantiating their activity on 5-HT_2C receptor.

Fig. 2 Effect of m-CPP (2 mg kg⁻¹, p.o.) and the test compounds (10 mg kg⁻¹, p.o.) on the elevated plus maze test (A) represents time spent in open arm while (B) represents number of open arm entries. Data are expressed as mean ± SEM. ***p < 0.001, **p < 0.01 indicate level of significance vs. vehicle-treated control group (N = 6).

2.5. Hypophagic response

Tecott et al.²⁶ demonstrated that 5-HT_2C receptor knockout mice developed obesity and remained hyperphagic throughout their life. Pro-opiomelanocortin (POMC) neurons express predominantly 5-HT_2C receptor mRNA wherein 5-HT_2C agonism leads to increased production of α-melanocyte stimulating hormone (MSH) which ultimately enhances MC4 receptor signalling^26–29 resulting in reduced food intake. 5-HT_2C receptor agonists also increase satiety resulting in reduced food intake.^28,30 The test compounds (7, 12–14, 24, 30, and 38) were assessed for their 5-HT_2Creceptor mediated hypophagic response. In accordance with the above cited findings, compounds (7, 12–14, 24, 30, and 38) significantly decreased the amount of food intake (Fig. 3A, p < 0.001). Their hypophagic effects were significantly reversed by pre-treatment of the animals with RS-102221 (3) a selective 5-HT_2C receptor antagonist, (Fig. 3A, p < 0.001) confirming their 5-HT_2C receptor agonistic activity. m-CPP (4) also showed a significant hypophagic effect (Fig. 3A, p < 0.001) in this model.

Fig. 3 Effect of m-CPP (2 mg kg⁻¹, p.o.) and the test compounds (10 mg kg⁻¹, p.o.) on hypophagic and penile erection models. (A) Represents amount of food intake upon test compound administration alone and with pretreatment of the animals with RS-102221 (2 mg kg⁻¹, i.p.). (B) Represents number of penile lickings upon test compound administration alone and with pretreatment of the animals with RS-102221 (2 mg kg⁻¹, i.p.). Data are expressed as mean ± SEM. ***p < 0.001, **p < 0.01 indicate level of significance vs. vehicle-treated control group (N = 6). ###p < 0.001, ##p < 0.01, ##p < 0.05 indicates significant difference from respective test compound treated group (only compound) (N = 6).

2.6. Penile erection

Compounds (7, 12–14, 24, 30, and 38) were also evaluated for the 5-HT_2C receptor mediated penile erection in the absence and in the presence of RS-102221 (3), a 5-HT_2C antagonist. m-CPP (4) induces penile erection, excessive grooming and increased levels of oxytocin, prolactin and corticosterone in rats. Paraventricular nucleus is believed to control sexual behaviour and neuroendocrine responses.³¹m-CPP (4) significantly induced penile erection and engorged penis (Fig. 3B, p < 0.001) in the test. Compounds (7, 12–14, 24, 30, and 38) also showed similar effects (Fig. 3B, p < 0.001) which were significantly suppressed by pre-treatment of the animals with RS-102221 (3) (Fig. 3B, p < 0.001). These results substantiated selective antagonism of the test compounds towards 5-HT_2C receptor.

2.7. Estimation of monoamines

Previous studies³² revealed that 5-HT_2C receptors have an influence on the firing of monoamine neurotransmitters. 5-HT_2C agonists negatively regulate the firing of dopamine (DA) and 5-HT neurons in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA), respectively.^33,34 A significant decrease in the brain concentrations of DA (Fig. 4A, p < 0.001) and 5-HT (Fig. 4B, p < 0.001) was observed in the animals exposed to the test compounds (7, 12–14, 24, 30, and 38). Pre-treatment of the animals with RS-102221 (3) at a dose of 2 mg kg⁻¹, p.o. significantly reversed the decreased levels of DA (Fig. 4A, p < 0.001) and 5-HT (Fig. 4A, p < 0.001) which further supported our above described observations. This study reaffirmed that the test compounds, which were found to be 5-HT_2C agonists in different in vivo models as described above, significantly decreased the DA and 5-HT levels in the brain similar to those caused by m-CPP (4). Thus, these results have demonstrated that the evaluated compounds (7, 12–14, 24, 30, and 38) are selective 5-HT_2C receptor agonists.

Fig. 4 Effect of m-CPP (2 mg kg⁻¹, p.o.) and the test compounds (10 mg kg⁻¹, p.o.) on DA and 5-HT levels in the rat brain. Values represent the % fold change of in (A) DA and (B) 5-HT levels in the rat brain after treatment of compounds alone and in presence of RS-102221. Data are expressed as mean ± SEM. ***p < 0.001 indicates level of significance vs. vehicle-treated control group (N = 6). ###p < 0.001, ##p < 0.01 indicates significant difference from respective test compound treated group (only compound) (N = 6).

2.8. Structure activity relationship (SAR)

Different 3-substituted benzazepin-2-ones were synthesized maintaining 1-methyl group as a constant structural feature in all of the compounds like lorcaserine (1). But unlike lorcaserine (1), the synthesized compounds were racemic mixtures. It was not tried to resolve the racemic mixtures or to synthesize optically pure isomers because the primary aim of the study was to identify compounds with some degree of selective agonist activity for 5-HT_2C receptors. Structural optimization on the basis of stereoisomerism of the active compounds would be part of subsequent phase of development as it is a cost and time intensive process. It was observed that variations in groups at position 3 altered the activity and selectivity on 5-HT₂ receptors. Interestingly, none of these derivatives were found to be active on 5-HT_2A receptors as seen from the Table 1, as no compound gave an adequate response on isolated rat thoracic aorta preparation. Many of these derivatives showed agonist (16, 18–22, 25–27, 33–35, 41 and 43) or antagonist (15 and 40) activity on 5-HT_2B receptors. Among the alkyl substituents, when the chain length or branching was increased, the resulting compounds either became inactive (8–11) towards all the receptors or became 5-HT_2B responsive [agonists (16 and 20) or antagonists (15 and 40)]. Substitution with cycloalkylmethyl also did not cause enhancement in activity as these compounds were either inactive (32) on 5-HT₂ receptors or proved agonist (34) for 5-HT_2B receptors. Ethyl (7) and isopropyl (14) were the only alkyl groups which offered good selectivity as seen from all of the in vivo experiments.

Substituted benzyl derivatives showed much more responsiveness towards the 5-HT₂ receptors. Majority of them were found to be 5-HT_2B agonists (18, 19, 21, 22, 25–27, 33, 35 and 43), some totally inactive (23, 28, 29, 31, 36, 37 and 44) while some others showed a good level of selectivity (12, 13, 24 and 30) for 5-HT_2C receptors. It seems that 2- and 4- positions of the benzene ring are more suited for a compound to show 5-HT_2C receptor affinity. It could not become very clear whether electron withdrawing or donating groups favor binding of the compounds to 5-HT_2C receptors, but electronegative atoms in these positions (12, 13 and 30) favour binding to the 5-HT_2C receptors while alkyl groups (21, 22 and 33) at 2- or 4-positions and electron withdrawing groups at position 3 or 2 and/or 5 in the benzyl moiety (26–28) make the compounds 5-HT_2B agonists. Although, there are certain exceptions (19, 25, 29, 31 and 35) to the above observations.

Substitution of the chloro group at position 8 in the 3-substituted 3-benzazepin-2-one ring system with simple ethyl group (38) offered 5-HT_2C selectivity, but other groups at 3-position make the compounds (40, 41 and 43) more responsive towards 5-HT_2B receptors. It seems 8-chloro substitution does not favour 5-HT_2C selectivity. Polar groups are also not desired at position 3 as both the compounds (37 and 48) were found to be inactive on 5-HT receptors.

3. Conclusion

Nonselective binding to the homologous 5-HT_2A and 5-HT_2B receptors is an important hurdle in the search for a selective 5-HT_2C agonist. We synthesized a series of 3-substituted 1-methyl-3-benzazepin-2-ones with alkyl/cycloalkylmethyl/benzyl groups at this position. Some 8-chloro derivatives were also synthesized. All the synthesized compounds were evaluated in vitro on the rat thoracic aortic strip and isolated rat fundus for their 5-HT_2A and 5-HT_2B receptors' sensibilities. Compounds found inactive on these isolated tissue preparations were further evaluated using despair swim test and elevated plus maze test to determine their in vivo 5-HT_2C receptor activity. The selected compounds (7, 12–14, 24, 30 and 38) also caused a decrease in DA and 5-HT levels in the brains of the treated animals similar to that caused by m-CPP (4). The selectivity issue was resolved by 5-HT_2C mediated penile erection and hypophagic response shown by these compounds in the treated animals. The study established 5-HT_2C receptor selective agonist activity of compounds (7, 12–14, 24, 30 and 38) which could act as lead molecules for development of drugs for selective 5-HT_2C receptor actions.

4. Experimental procedure

4.1. Chemical synthesis

All the reagents and solvents required for synthesis of the compounds were purified by general laboratory³⁵ techniques before use. Melting points were determined using silicon oil bath type (Veego) and heating block type (Lab India) melting point apparatus and are uncorrected. Completion of the reactions was monitored by thin layer chromatography (TLC) using silica gel pre-coated plates (60 F254, Merck, 0.25 mm thickness) visualizing in ultraviolet light (254 nm) or iodine vapours. Yields reported here are un-optimized. The IR spectra (wave numbers in cm⁻¹) were recorded on a BRUKER ALPHA-T (Germany) FT-IR spectrophotometer using potassium bromide discs. ¹H NMR and ¹³C NMR spectra were recorded using Bruker Advance-II 400 MHz spectrometer in CDCl₃ or DMSO-d₆ solvents; chemical shift has been expressed as δ ppm and coupling constant (J) in Hz. Mass spectra were recorded using a Thermo Fisher mass spectrometer with EI as ion source or Advion mass spectrometer with ESI as ion source and also using AB Sciex 3200 Q Trap mass analyzer for the compounds.

HPLC analysis was performed using Shimadzu prominence system (Kyoto, Japan) consisting of LC-20AT Pump, and SPD 20 A detector. The chromatographic column used was phenomenex C-18, 250 mm length × 4.6 mm diameter with 0.5 μ particle sizes and the column temperature was maintained at 25–28 °C. Separation of analytes was performed under isocratic conditions at a flow-rate of 0.5–1.0 ml min⁻¹. The mobile phase consisted of acetonitrile/water (60 : 40). The purity of the compounds was found to be greater than 98%. Chromatographic separations were performed on columns using silica gel (100–200) or neutral alumina, activity grade I. All reagents used were of analytical reagent grade obtained from S. d. fine chemicals, Spectrochem, Qualigens or Sigma-Aldrich Avera chemicals.

4.1.1. 1-Methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one²⁰ (5). 2-Chloro-N-phenylethylpropanamide³⁶ (2 g, 0.094 mmol) was melted to a tan oil with bubbling at 91 °C, in a 100 ml RBF. Anhydrous aluminum chloride (6 g) was added to this and the reaction mixture was heated up to 180 °C for 10–15 min, cooling to room temperature and quenching with 10% HCl solution. Stirring was carried out for further 20 min. The resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was dried over sodium sulphate and the solvent removed to get a semi solid compound which was purified by column chromatography using silica gel as stationary phase and n-hexane–ethyl acetate (70 : 30%) as eluent to get pure product (5). (1 g, 62%); mp = 151–153 °C; R_f 0.35 (n-hexane : ethyl acetate 20%); IR, (KBr): 3321, 3061, 2940, 1645, 1544, 753; ¹H NMR (CDCl₃): δ 7.20–7.16 (m, 4H), 7.14 (bs, 1H), 4.24–4.22 (q, 1H, J = 6.9 Hz), 3.74 (m, 1H), 3.35 (m, 1H), 3.32 (m, 1H), 2.95 (m, 1H), 1.50–1.48 (d, 3H, J = 6.9 Hz); MS (m/z): 175.38 (M)⁺.

4.1.2. 8-Chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one²⁰ (6). Compounds (6) was prepared from N-(4-chlorophenylethyl)-2-chloropropanamide using a procedure similar to that described for compound (5) to get a white solid (6); 50%; mp = 155–160 °C; R_f: 0.15 (n-hexane : ethyl acetate 20%); IR (KBr): 3321, 3061, 2940, 1644, 1544, 753; ¹H NMR (CDCl₃): δ 7.44 (bs, 1H), 7.19–7.15 (m, 2H), 7.12 (s, 1H) 4.30–4.24 (q, 1H, J = 6.8 Hz), 3.78–3.72 (m, 1H), 3.25–3.12 (m, 2H), 3.01–2.94 (m, 1H), 1.38–1.36 (d, 3H, J = 6.8 Hz); MS (m/z): 209.41 (M)⁺.

4.2. General procedure (A) for preparation of 3-substituted-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (7–37)

To a mixture of NaH (60% dispersion in mineral oil; 75 mg, 3.43 mM) in dry THF (9 ml) and DMF (1 ml) (4.5 : 0.5), 3-benzazepin-2-one (5) (500 mg, 2.85 mmol) was added in 100 ml two neck RBF and stirred for half an hour. Solution of the halide in dry THF (4.5 ml) and DMF (0.5 ml) was added drop wise to the above slurry and the resulting mixture was heated up to 60–80 °C in an oil bath in presence of dry N₂. On cooling to the room temperature, the reaction mixture was treated with ice-water (20 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over sodium sulphate and the solvent removed to get a semi solid compound which was purified by column chromatography using silica gel as stationary phase and n-hexane–ethyl acetate as eluant.

4.2.1. 3-Ethyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (7). Synthesized as per the general procedure (A) using ethyl iodide (0.45 ml) to get a semi solid (7), (150 mg, 61%); R_f 0.39, (n-hexane : ethyl acetate 20%); IR, (KBr): 3131, 2927, 1639, 1401, 727; ¹H NMR (CDCl₃): δ 7.17–7.09 (m, 4H), 4.41–4.36 (q, 1H, J = 6.9 Hz), 4.20–4.13 (m, 1H), 3.49–3.22 (m, 4H), 3.15–3.08 (m, 1H), 1.45–1.43 (d, 3H, J = 6.9 Hz), 1.07–1.03 (t, 3H, J = 7.1 Hz); ¹³C NMR (CDCl₃): 175.58, 137.67, 129.62, 128.95, 127.61, 126.96, 125.93, 41.85, 40.89, 32.92, 18.35, 14.69; MS (m/z): 203.88 (M)⁺.

4.2.2. 3-Butyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (8). Synthesized as per the general procedure (A) using butyl bromide (0.4 ml) to get a semi solid (8), (200 mg, 76%); R_f 0.42, (n-hexane : ethyl acetate 20%); IR, (KBr): 3130, 2932, 2870, 1658, 1401, 1097, 799; ¹H NMR (DMSO-d₆): δ 7.18–7.08 (m, 4H), 4.43–4.38 (q, 1H, J = 6.8 Hz), 4.22–4.16 (m, 1H), 3.43–3.41 (m, 2H), 3.38–3.36 (m, 1H), 3.32–3.28 (m, 1H), 3.27–3.25 (m, 1H), 1.44–1.43 (d, 3H, J = 6.8 Hz), 1.41–140 (m, 2H), 1.26–1.16 (m, 2H), 0.88–0.85 (t, 3H, J = 7.3 Hz); ¹³C NMR (CDCl₃): 175.63, 137.65, 137.13, 129.99, 128.95, 125.86, 47.60, 46.49, 41.47, 32.99, 30.33, 29.72, 20.10, 14.70; MS (m/z): 231.28 (M)⁺.

4.2.3. 3-Allyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (9). Synthesized as per the general procedure (A) using allyl bromide (0.37 ml) to get a semi solid (9), (200 mg, 73%); R_f 0.36, (n-hexane : ethyl acetate 20%); IR, (KBr): 3129, 2935, 1656, 1404, 797, 744; ¹H NMR (DMSO-d₆): δ 7.20–7.09 (m, 4H), 5.74–5.55 (m, 1H), 5.07–5.06 (d, 2H), 4.46–4.41 (q, 1H, J = 6.8 Hz), 4.16–4.09 (m, 1H), 4.04–4.00 (m, 1H), 3.90–3.89 (m, 1H), 3.37–3.28 (m, 1H), 3.20–3.10 (m, 1H), 3.08–3.05 (m, 1H), 1.4–1.44 (d, 3H, J = 6.8Hz); MS (m/z): 215.79 (M)⁺.

4.2.4. 3-Propyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (10). Synthesized as per the general procedure (A) using n-propyl bromide (0.33 ml) to get a semi solid (10), (195 mg, 79%); R_f 0.32, (n-hexane : ethyl acetate 20%); IR, (KBr): 3130, 2968, 2933, 1655, 1401 745; ¹H NMR (DMSO-d₆): δ 7.19–7.08 (m, 4H), 4.40–4.38 (q, 1H, J = 6.8 Hz), 4.21–4.17 (m, 1H), 3.44–3.41 (m, 2H), 3.31–3.29 (m, 2H), 3.22–3.21 (m, 1H), 1.52–1.48 (m, 2H), 1.46–1.43 (d, 3H, J = 6.8 Hz), 0.82–0.78 (t, 3H, J = 7.3 Hz); ¹³C NMR (CDCl₃): 173.79, 137.29, 136.13, 130.02, 126.70, 126.71, 125.95, 49.48, 46.57, 40.49, 33.05, 21.47, 14.84, 11.32; MS (m/z): 217.66 (M)⁺.

4.2.5. 3-Dodecyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (11). Synthesized as per the general procedure (A) using 1-bromododecane (0.83 ml) to get a semi solid (11), (200 mg, 78%); R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3111, 2923, 1641, 1463, 1402, 945, 732; ¹H NMR (CDCl₃): δ 7.26–7.23 (d, 1H, J = 8.7 Hz), 7.20–7.13 (m, 2H), 7.09–7.06 (d, 1H, J = 8.7 Hz), 4.36–4.30 (q, 1H, J = 6.9 Hz), 4.13–4.06 (m, 1H), 3.45–3.32 (m, 3H), 3.22–3.17 (m, 1H), 3.13–3.10 (m, 1H), 1.55–1.47 (d, 3H, J = 6.9 Hz), 1.50–1.47 (q, 2H, J = 7.2 Hz), 1.31–1.22 (m, 18H), 0.84–0.86 (t, 3H, J = 7.2 Hz); ¹³C NMR (CDCl₃): 173.70, 137.30, 130.14, 129.99, 126.69, 125.92, 47.94, 46.56, 40.49, 33.06, 31.97, 29.68, 29.61, 29.59, 29.46, 29.40, 28.27, 26.91, 22.74, 14.81, 14.17; MS (m/z): 343.14 (M)⁺.

4.2.6. 3-(4-Bromobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (12). Synthesized as per the general procedure (A) using 4-bromobenzyl bromide (0.85 g) to get a white solid (12), (210 mg, 81%); mp = 90-92 °C; R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3129, 1647, 1401, 791; ¹H NMR (DMSO-d₆): δ 7.40–7.37 (d, 2H, J = 8.3 Hz), 7.22–7.13 (m, 3H), 7.07–7.05 (m, 3H), 4.58–4.43 (m, 3H), 4.41–4.10 (m, 1H), 3.33–3.31 (m, 1H), 3.20–3.15 (m, 1H), 2.99–2.93 (m, 1H), 1.48–1.47 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.01, 137.12, 136.86, 136.12, 131.64, 129.87, 129.70, 126.90, 126.81, 125.67, 121.22, 50.24, 46.39, 40.30, 32.45, 14.59; MS (m/z): 343.22 (M)⁺; anal. calcd for C₁₈H₁₈BrNO: C, 62.8; H, 5.27; N, 4.07. Found: C, 62.65; H, 5.01; N, 3.72%.

4.2.7. 3-(2,6-Difluorobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (13). Synthesized as per the general procedure (A) using 2,6-difluorobenzyl bromide (0.70 g) to get a white solid (13), (290 mg, 85%); mp = 133–135 °C; R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3116, 2984, 2944, 1662, 1401, 1032, 836; ¹H NMR (DMSO-d₆): δ 7.35–7.31 (m, 1H), 7.18–7.10 (m, 3H), 7.03 (d, 1H, J = 6.6 Hz), 6.97–6.93 (m, 2H), 4.79–4.76 (d, 1H, J = 14.1 Hz), 4.54–4.45 (d, 1H, J = 14.1 Hz), 4.45–4.43 (q, 1H, J = 6.8 Hz), 4.20–4.12 (m, 1H), 3.41–3.37 (m, 1H), 3.17–3.12 (m, 1H), 2.99–2.92 (m, 1H) 1.45–1.43 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 172.55, 162.16, 159.68, 135.74, 135.01, 128.88, 128.55, 125.66, 124.82, 112.34, 110.46, 44.57, 39.29, 37.28, 31.43, 13.67; MS (m/z): 301.64 (M)⁺; anal. calcd for C₁₈H₁₇F₂NO: C, 71.75; H, 5.69; N, 4.65. Found: C, 71.52; H, 5.45; N, 4.41%.

4.2.8. 3-Isopropyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (14). Synthesized as per the general procedure (A) using isopropyl iodide (0.54 ml) to get a semi solid (14), (145 mg, 59%); R_f 0.40, (n-hexane : ethyl acetate 20%); IR, (KBr): 3276, 3129, 1639, 1548, 1401, 1262, 763; ¹H NMR (DMSO-d₆): δ 7.46–7.43 (m, 2H), 7.36–7.34 (m, 1H), 7.24–7.22 (m, 1H), 7.18–7.16 (m, 1H), 7.13–7.7.09 (m, 1H), 5.65–5.60 (m, 1H), 5.32–5.29 (m, 1H), 3.94–3.83 (m, 2H), 1.32–1.30 (d, 3H, J = 7.0 Hz), 1.09–1.07 (d, 3H, J = 6.6 Hz), 1.02–1.01 (d, 3H, J = 6.6 Hz); MS (m/z): 216.46 (M)⁺.

4.2.9. 1-Methyl-3-pentyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (15). Synthesized as per the general procedure (A) using iodopentane (0.45 ml) to get a semi solid (15), (210 mg, 73%); R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3128, 3024, 2932, 1641, 1401, 733; ¹H NMR (CDCl₃): δ 7.26–7.24 (d, 1H, J = 8.3 Hz), 7.20–7.13 (m, 2H), 7.09–7.07 (d, 1H, J = 8.3 Hz), 4.36–4.31 (q, 1H, J = 6.8 Hz), 4.14–4.06 (m, 1H), 3.45–3.27 (m, 4H), 3.17–3.10 (m, 1H), 1.56–1.50 (d, 3H, J = 6.8 Hz), 1.48–1.46 (m, 2H), 1.31–1.16 (m, 4H), 0.86–0.83 (t, 3H, J = 7.1 Hz); ¹³C NMR (CDCl₃): 173.66, 137.29, 136.12, 129.96, 126.66, 126.58, 125.88, 47.85, 46.51, 40.43, 33.02, 29.02, 27.89, 22.14, 14.77, 14.01; MS (m/z): 245.79 (M)⁺.

4.2.10. 3-Isopentyl-1-methyl-4,5-dihydro-1H-benzo[d]azepine-2(3H)-one (16). Synthesized as per the general procedure (A) using 1-bromo-3-methylbutane (0.42 ml) to get a semi solid (16), (200 mg, 71%); R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3133, 2960, 2873, 1645, 1401, 735; ¹H NMR (DMSO-d₆): δ 7.19–7.18 (d, 1H, J = 8.4 Hz), 7.13–7.06 (m, 2H), 7.02–7.00 (d, 1H, J = 8.4 Hz), 4.28–4.23 (q, 1H, J = 6.8 Hz), 4.06–3.99 (m, 1H), 3.40–3.27 (m, 3H), 3.22–3.15 (m, 1H), 3.07–3.01 (m, 1H), 1.48–1.44 (d, 3H, J = 6.8 Hz), 1.40–1.36 (m, 1H), 1.32–1.27 (m, 2H), 0.82–0.80 (d, 6H, J = 6.6 Hz); ¹³C NMR (CDCl₃): 172.52, 136.15, 135.06, 128.90, 125.61, 125.53, 124.78, 45.42, 45.28, 39.26, 35.92, 31.95, 25.01, 21.54, 13.66; MS (m/z): 245.39 (M)⁺.

4.2.11. 1-Methyl-3-(3-propargyl)-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (17). Synthesized as per the general procedure (A) using 3-bromo-1-propyne (0.30 ml) to get a white solid (17), (180 mg, 74%), mp = 122–124 °C; R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3129, 1664, 1401, 800; ¹H NMR (CDCl₃): δ 7.24 (m, 1H), 7.22–7.15 (m, 2H), 7.13–7.10 (m, 1H), 4.41–4.36 (dd, 2H, J₁ = 2.5 Hz and J₂ = 17.4 Hz), 4.34–4.30 (q, 1H, J = 6.6 Hz), 4.16–4.11 (m, 1H), 3.65–3.58 (m, 1H), 3.36–3.29 (m, 1H), 3.24–3.16 (m, 1H), 2.19–2.18 (t, 1H, J = 2.5 Hz), 1.58–1.56 (d, 3H, J = 6.6 Hz); ¹³C NMR (CDCl₃): 173.21, 136.96, 136.42, 129.77, 126.91, 126.79, 125.79, 79.26, 71.78, 46.31, 40.50, 36.25, 32.49, 14.05; MS (m/z): 213.46 (M)⁺; anal. calcd for C₁₄H₁₄NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.58; H, 6.93; N, 6.48%.

4.2.12. 1-Methyl-3-(1-naphthylmethyl)-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (18). Synthesized as per the general procedure (A) using 1-chloromethylnaphthalene (0.34 ml) to get a semi solid (18), (300 mg, 87%); R_f 0.37, (n-hexane : ethyl acetate 20%); IR, (KBr): 3132, 2924, 1651, 1484, 1401, 792; ¹H NMR (CDCl₃): δ 7.81–7.80 (d, 1H, J = 8.2 Hz), 7.74–7.69 (dd, 2H, J = 8.2 Hz), 7.36–7.15 (m, 5H), 7.12–7.08 (m, 1H), 7.00–6.96 (m, 1H), 6.71–6.69 (d, 1H, J = 8.0 Hz), 5.03–5.00 (d, 1H, J = 14.8 Hz), 4.98–4.94 (d, 1H, J = 14.8 Hz) 4.35–4.30 (q, 1H, J = 6.8 Hz), 3.88–3.81 (m, 1H), 3.30–3.24 (m, 1H), 2.94–2.88 (m, 1H), 2.61–2.53 (m, 1H), 1.56–1.54 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.88, 136.75, 136.03, 133.73, 133.07, 131.80, 129.99, 128.52, 128.45, 127.10, 126.75, 126.55, 126.38, 125.97, 125.68, 125.12, 123.87, 48.07, 44.60, 40.38, 32.19, 14.67; MS (m/z): 315.67 (M)⁺.

4.2.13. 3-(2-Chloro-4-fluoro)benzyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (19). Synthesized as per the general procedure (A) using 2-chloro-4-fluorobenzyl bromide (0.8 g) to get a semi solid (19), (240 mg, 66%); R_f 0.39, (n-hexane : ethyl acetate 20%); IR, (KBr): 3130, 2930, 1658, 1400, 1041, 903; ¹H NMR (CDCl₃): δ 7.30–7.28 (d, 1H, J = 7.5 Hz), 7.24–7.19 (m, 2H), 7.11–6.99 (m, 3H), 6.85–6.83 (d, 1H, J = 8.2 Hz), 4.74–4.64 (dd, 2H, J₁ = 15.5 Hz, and J₂ = 21.44 Hz), 4.43–4.38 (q, 1H, J = 6.8 Hz), 4.11–4.03 (m, 1H), 3.44–3.38 (m, 1H), 3.27–3.20 (m, 1H), 3.01–2.94 (m, 1H), 1.61–1.59 (d, 3H, J = 6.8 Hz);¹³C NMR (CDCl₃): 174.21, 162.91, 137.18, 136.81, 134.05, 133.95, 131.21, 130.67, 129.92, 127.00, 125.76, 116.88, 114.52, 47.60, 46.93, 40.41, 32.55, 14.59; MS (m/z): 317.73 (M)⁺.

4.2.14. 3-(sec Butyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (20). Synthesized as per the general procedure (A) using 2-bromobutane (0.38 ml) to get a semi solid (20), (210 mg, 82%); R_f 0.39, (n-hexane : ethyl acetate 20%); IR, (KBr): 3122, 2965, 1637, 1453, 802; ¹H NMR (CDCl₃): δ 7.44–7.41 (m, 1H), 7.26–7.17 (m, 3H), 6.94–6.86 (m, 1H), 5.59–5.54 (m, 1H), 5.30–5.27 (m, 1H), 3.82–3.73 (m, 2H), 1.45–144 (d, 3H, J = 7.2 Hz), 1.34–1.10 (m, 3H), 0.99–0.88 (d, 3H, J = 6.6 Hz), 0.75–0.63 (t, 3H, J = 7.4 Hz); MS (m/z): 231.64 (M)⁺.

4.2.15. 1-Methyl-3-(4-methylbenzyl)-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (21). Synthesized as per the general procedure (A) using 4-methylbenzyl bromide (0.49 ml) to get a white solid (21), (290 mg, 88%); mp = 93–95 °C; R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3267, 3129, 3021, 1672, 1402, 802; ¹H NMR (CDCl₃): δ 7.28–7.26 (d, 1H, J = 7.6 Hz), 7.22–7.20 (d, 1H, J = 7.5 Hz), 7.16–7.12 (d, 1H, J = 7.5 Hz), 7.07–7.00 (m, 5H), 4.63–4.59 (d, 1H, J = 14.6 Hz), 4.53–4.49 (d, 1H, J = 14.6 Hz), 4.40–4.35 (q, 1H, J = 6.8 Hz), 4.01–3.93 (m, 1H), 3.39–3.33 (m, 1H), 3.16–3.11 (m, 1H), 2.95–2.86 (m, 1H), 2.30 (s, 3H), 1.69–1.59 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.95, 137.19, 136.99, 136.31, 134.71, 129.93, 129.23, 128.08, 126.75, 126.65, 125.78, 50.33, 45.90, 40.41, 32.51, 21.13, 14.78; MS (m/z): 279.26 (M)⁺; anal. calcd for C₁₉H₂₁NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.42; H, 7.44; N, 4.83%.

4.2.16. 3-(4-Isopropylbenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (22). Synthesized as per the general procedure (A) using 4-isopropylbenzyl bromide (0.60 ml) to get a white solid (22), (300 mg, 81%); mp = 75–77 °C; R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3131, 3013, 2961, 1644, 1403, 1097, 800; ¹H NMR (CDCl₃): δ 7.30–7.28 (d, 1H, J = 7.6 Hz), 7.23–7.12 (m, 4H), 7.09–7.07 (d, 2H, J = 8.2 Hz), 7.03–7.01 (d, 1H, J = 7.2 Hz), 4.69–4.65 (d, 1H, J = 14.7 Hz), 4.51–4.47 (d, 1H, J = 14.7 Hz), 4.40–4.39 (q, 1H, J = 6.9 Hz), 4.00–3.96 (m, 1H), 3.41–3.35 (m, 1H), 3.18–3.13 (m, 1H), 2.93–2.86 (m, 2H) 1.62–1.61 (d, 3H, J = 6.9 Hz), 1.24–1.22 (d, 6H, J = 6.9 Hz); ¹³C NMR (CDCl₃): 172.86, 146.94, 136.16, 135.26, 133.99, 128.86, 126.98, 125.69, 125.63, 125.53, 124.71, 49.29, 44.94, 39.34, 32.73, 31.41, 22.97, 13.71; MS (m/z): 307.65 (M)⁺; anal. calcd for C₂₁H₂₅NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 81.72; H, 7.92; N, 4.44%.

4.2.17. 3-(4-Trifluoromethylbenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (23). Synthesized as per the general procedure (A) using 4-trifluoromethylbenzyl bromide (1.55 ml) to get a white solid (23), (300 mg, 79%); mp = 79–81 °C; R_f 0.22, (n-hexane : ethyl acetate 20%); IR, (KBr): 3130, 2931, 1658, 1326, 1117, 817; ¹H NMR (CDCl₃): δ 7.51–7.49 (d, 2H, J = 8.1 Hz), 7.31–7.29 (d, 1H, J = 7.6 Hz), 7.25–7.16 (m, 4H), 7.05–7.03 (d, 1H, J = 7.6 Hz), 4.70–4.60 (dd, 2H, J₁ = 15.2 Hz and J₂ = 13.1), 4.42–4.37 (q, 1H, J = 6.8 Hz), 4.07–4.00 (m, 1H), 3.40–3.33 (m, 1H), 3.25–3.18 (m, 1H), 2.98–2.90 (m, 1H), 1.63–1.61 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.08, 141.96, 137.23, 136.12, 129.83, 129.48, 128.22, 126.92, 125.68, 125.58, 125.47, 122.81, 50.62, 46.83, 40.41, 32.44, 14.56; MS (m/z): 333.78 (M)⁺; anal. calcd for C₁₉H₁₈F₃NO: C, 68.46; H, 5.44; N, 4.20. Found: C, 68.19; H, 5.25; N, 3.96%.

4.2.18. 3-(3,5-Difluorobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (24). Synthesized as per the general procedure (A) using 3,5-difluorobenzyl bromide (0.44 ml) to get a semi solid (24), (280 mg, 82%); R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 3129, 2984, 1657, 1446, 1596, 1116, 761; ¹H NMR (CDCl₃): δ 7.31–7.29 (d, 1H, J = 7.3 Hz), 7.26–7.24 (d, 1H, J = 7.3 Hz), 7.19–7.17 (m, 1H), 7.08–7.06 (d, 1H, J = 7.3 Hz), 6.69–6.60 (m, 3H), 4.62–4.58 (d, 1H, J = 15.3 Hz), 4.54–4.50 (d, 1H, J = 15.3 Hz), 4.42–4.37 (q, 1H, J = 6.8 Hz), 4.07–4.00 (m, 1H), 3.39–3.33 (m, 1H), 3.28–3.23 (m, 1H), 3.03–2.94 (m, 1H), 1.62–1.61 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.06, 164.41, 161.93, 141.96, 141.78, 137.15, 129.79, 127.04, 125.62, 110.57, 103.01, 50.30, 46.86, 40.30, 32.32, 14.48; MS (m/z): 301.23 (M)⁺.

4.2.19. 3-(2-Chloro-6-fluoro)benzyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (25). Synthesized as per the general procedure (A) using 2-chloro-6-fluorobenzyl bromide (0.48 ml) to get a white solid (25), (290 mg, 80%); mp = 147–149 °C; R_f 0.28, (n-hexane : ethyl acetate 20%); IR, (KBr): 3140, 2933, 1663, 1531, 1402, 781; ¹H NMR (CDCl₃): δ 7.27–7.12 (m, 5H), 7.00–6.96 (m, 2H), 5.02–4.98 (d, 1H, J = 14.3 Hz) 4.73–4.69 (d, 1H, J = 14.3 Hz), 4.40–4.35 (q, 1H, J = 6.8 Hz), 4.01–3.93 (m, 1H), 3.37–3.31 (m, 1H), 3.15–3.09 (m, 1H), 2.96–2.88 (m, 1H), 1.59–1.57 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 172.66, 162.47, 135.67, 135.17, 135.02, 128.96, 128.58, 125.65, 124.83, 124.52, 122.06, 121.89, 113.29, 43.61, 39.95, 39.33, 31.45, 13.72; MS (m/z): 317.03 (M)⁺; anal. calcd for C₁₈H₁₇FClNO: C, 68.03; H, 5.39; N, 4.41. Found: C, 67.79; H, 5.14; N, 4.18%.

4.2.20. 3-(2,5-(Bistrifluoro)benzyl)-1-methy-4,5-dihydro-1-benzo[d]azepin-2(3H)-one (26). Synthesized as per the general procedure (A) using 2,5-bistrifluoromethylbenzyl bromide (0.65 ml) to get a white solid (26), (300 mg, 66%); mp = 110–112 °C, R_f 0.35, (n-hexane : ethyl acetate 20%); IR, (KBr): 2981, 2932, 1657, 1491, 1286, 1117, 706; ¹H NMR (CDCl₃): δ 7.73 (s, 1H), 7.48 (s, 2H), 7.32–7.30 (d, 1H, J = 7.3 Hz), 7.26–7.24 (d, 1H, J = 7.4 Hz), 7.20–7.18 (d, 1H, J = 7.4 Hz), 7.07–7.05 (d, 1H, J = 7.3 Hz), 4.84–4.80 (d, 1H, J = 15.5 Hz), 4.60–4.56 (d, 1H, J = 15.5 Hz), 4.43–4.38 (q, 1H, J = 6.8 Hz), 4.12–4.06 (m, 1H), 3.40–3.35 (m, 2H), 3.00–2.92 (m, 1H), 1.63–1.55 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.25, 140.67, 137.26, 135.77, 132.41, 131.75, 129.73, 127.65, 127.23, 125.40, 124.55, 121.43, 121.39, 121.35, 121.31, 50.42, 47.37, 40.24, 32.27, 14.16; anal. calcd for C₂₀H₁₇F₆NO: C, 59.85; H, 4.27; N, 3.49. Found: C, 59.48; H, 4.03; N, 3.18%.

4.2.21. 3-(2-Cyanobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (27). Synthesized as per the general procedure (A) using 2-bromomethylbenzonitrile (0.68 g) to get a white solid (27), (290 mg, 80%); mp = 141–143 °C; R_f 0.33, (n-hexane : ethyl acetate 20%); IR, (KBr): 3143, 2978, 2225, 1650, 1490, 1357, 1165, 770; ¹H NMR (CDCl₃): δ 7.67–7.61 (m, 1H), 7.45–7.41 (m, 1H), 7.34–7.30 (m, 2H), 7.21–7.17 (m, 3H), 7.06–7.04 (d, 1H), 4.87–4.77 (dd, 2H, J₁ = 15.6 Hz and J₂ = 19.08 Hz), 4.45–4.39 (q, 1H, J = 6.8 Hz), 4.14–4.08 (m, 1H), 3.52–3.42 (m, 1H), 3.30–3.23 (m, 1H), 3.02–2.93 (m, 1H), 1.65–1.60 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.16, 141.72, 137.02, 136.08, 133.19, 132.71, 129.82, 128.88, 127.79, 126.97, 125.62, 117.64, 111.67, 49.11, 47.37, 40.24, 32.41, 14.45; MS (m/z): 291.1 (M + 1)⁺; anal. calcd for C₁₉H₁₈N₂O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.22; H, 5.98; N, 9.32%.

4.2.22. 3-(3-Nitrobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (28). Synthesized as per the general procedure (A) using 3-nitrobenzyl bromide (0.73 g) to get a white solid (28), (250 mg, 80%); mp = 120–122 °C; R_f 0.24, (n-hexane : ethyl acetate 20%); IR, (KBr): 3130, 2979, 2930, 1655, 1525, 1348, 1091, 811; ¹H NMR (CDCl₃): δ 8.10–8.07 (dd, 1H, J = 7.3 Hz), 7.96 (s, 1H), 7.43–7.41 (m, 2H), 7.31–7.29 (d, 1H, J = 7.2 Hz), 7.26–7.24 (m, 1H), 7.21–7.19 (d, 1H, J = 7.2 Hz), 7.06–7.04 (d, 1H, J = 7.2 Hz), 4.71–4.69 (d, 1H, J = 14.9 Hz), 4.68–4.66 (d, 1H, J = 14.9 Hz), 4.42–4.40 (q, 1H, J = 6.8 Hz), 4.09–4.07 (m, 1H), 3.42–3.38 (m, 1H), 3.24–3.20 (m, 1H), 2.97–2.87 (m, 1H), 1.63–1.61 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.08, 147.30, 139.00, 136.07, 134.88, 132.94, 128.75, 128.59, 126.03, 125.95, 124.55, 121.40, 121.38 49.42, 46.08, 39.22, 31.30, 13.36; MS (m/z): 311.00 (M + 1)⁺; anal. calcd for C₁₈H₁₈N₂O₂: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.45; H, 5.58; N, 8.78%.

4.2.23. 3-(4-Chlorobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (29). Synthesized as per the general procedure (A) using 4-chlorobenzyl bromide (0.45 ml) to get a white solid (29), (290 mg, 82%); mp = 102–104 °C; R_f 0.24, (n-hexane : ethyl acetate 20%), IR, (KBr): 3133, 3028, 2977, 1649, 1403, 1093, 816; ¹H NMR (CDCl₃): δ 7.20–7.14 (m, 5H), 7.05–7.00 (m, 3H), 4.62–4.50 (dd, 2H, J₁ = 14.9 Hz and J₂ = 21.26 Hz), 4.40–4.38 (q, 1H, J = 6.8 Hz), 4.00–3.96 (m, 1H), 3.37–3.30 (m, 1H), 3.19–3.12 (m, 1H), 2.94–2.85 (m, 1H), 1.60–1.59 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.98, 137.16, 136.12, 133.14, 129.84, 128.68, 126.87, 125.69, 50.21, 46.37, 40.40, 32.46, 14.60; MS (m/z): 300.01 (M + 1)⁺; anal. calcd for C₁₈H₁₈ClNO: C, 72.11; H, 6.05; N, 4.67. Found: C, 71.85; H, 5.85; N, 4.35%.

4.2.24. 3-(4-Methoxybenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (30). Synthesized as per the general procedure (A) using 4-methoxybenzyl bromide (0.47 ml) to get a semi solid (30), (290 mg, 82%); R_f 0.24, (n-hexane : ethyl acetate 20%); IR, (KBr): 3108, 3065, 2935, 1649, 1247, 1034, 821; ¹H NMR (CDCl₃): δ 7.23–7.18 (m, 1H), 7.15–7.11 (d, 1H, J = 7.2 Hz), 7.09–7.06 (d, 1H, J = 7.2 Hz), 7.00–6.99 (m, 2H), 6.94–6.92 (d, 1H, J = 7.3 Hz), 6.74–6.71 (m, 2H), 4.55–4.52 (d, 1H, J = 14.6 Hz), 4.48–4.42 (d, 1H, J = 14.6 Hz), 4.32–4.30 (q, 1H, J = 6.8 Hz), 3.95–3.88 (m, 1H), 3.70 (s, 3H), 3.33–3.27 (m, 1H), 3.20–3.08 (m, 1H), 2.86–2.82 (m, 1H), 1.65–1.60 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.92, 158.91, 137.14, 136.27, 129.93, 129.87, 129.41, 126.73, 126.64, 125.76, 113.91, 55.28, 50.01, 45.78, 40.40, 32.52, 14.74; MS (m/z): 296.01 (M + 1)⁺.

4.2.25. 3-(4-Fluorobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (31). Synthesized as per the general procedure (A) using 4-fluorobenzyl bromide (0.42 ml) to get a semi solid (31), (240 mg, 70%); R_f 0.24, (n-hexane : ethyl acetate 20%); IR, (KBr): 3130, 2964, 2928, 1653, 1403, 1262, 798; ¹H NMR (CDCl₃): δ 7.29–7.14 (m, 3H), 7.12–7.08 (m, 2H), 7.03–7.02 (m, 1H), 6.96–6.91 (m, 2H), 4.60–4.52 (dd, 2H, J₁ = 14.8 Hz and J₂ = 18.14 Hz), 4.40–4.35 (q, 1H, J = 6.8 Hz), 4.04–3.96 (m, 1H), 3.39–3.32 (m, 1H), 3.19–3.12 (m, 1H), 2.29–2.85 (m, 1H), 1.61–1.59 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.03, 163.44, 137.22, 136.21, 133.65, 130.07, 129.93, 127.69, 126.82, 125.77, 115.69, 50.16, 46.27, 40.48, 32.60, 14.69; MS (m/z): 284.01 (M + 1)⁺.

4.2.26. 3-Cyclopropylmethyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (32). Synthesized as per the general procedure (A) using bromomethylcyclopropane (0.34 ml) to get a semi solid (32), (110 mg, 70%); R_f 0.29, (n-hexane : ethyl acetate 20%); IR, (KBr): 3128, 3010, 1650, 1401; ¹H NMR (CDCl₃): δ 7.26–7.24 (m, 1H), 7.19–7.15 (m, 2H), 7.08–7.07 (m, 1H), 4.39–4.34 (q, 1H, J = 6.8 Hz), 4.21–4.13 (m, 1H), 3.57–3.50 (m, 1H), 3.37–3.16 (m, 4H), 1.57–1.51 (d, 3H, J = 6.8 Hz), 0.98–0.91 (m, 1H), 0.49–0.41 (m, 2H), 0.26–0.17 (m, 2H); ¹³C NMR (CDCl₃): 173.80, 137.06, 136.20, 130.03, 126.64, 126.52, 125.93, 51.72, 46.32, 40.33, 33.02, 14.81, 9.96, 3.56. MS (m/z): 230.00 (M + 1)⁺.

4.2.27. 3-(4-t-Butylbenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (33). Synthesized as per the general procedure (A) using 4-t-butylbenzyl bromide (0.64 ml) to get a white solid (33), (310 mg, 87%); mp = 101–103 °C; R_f 0.28, (n-hexane : ethyl acetate 20%); IR, (KBr): 3133, 2961, 2869, 1645, 1407, 1038, 813; ¹H NMR (CDCl₃): δ 7.20–7.18 (m, 3H), 7.13–7.04 (m, 2H), 7.00–6.98 (d, 2H, J = 8.2 Hz), 6.93–6.91 (d, 1H, J = 7.3 Hz), 4.59–4.53 (d, 1H, J = 14.7 Hz), 4.39–4.36 (d, 1H, J = 14.7 Hz) 4.31–4.26 (q, 1H, J = 6.8 Hz), 3.93–3.85 (m, 1H), 3.31–3.25 (m, 1H), 3.08–3.01 (m, 1H), 2.97–2.87 (m, 1H), 1.52–1.50 (d, 3H, J = 6.8 Hz), 1.20 (s, 9H); ¹³C NMR (CDCl₃): 172.85, 149.19, 136.16, 135.27, 133.60, 128.86, 126.68, 125.69, 125.60, 124.71, 124.39, 49.22, 44.99, 39.35, 33.44, 31.40, 30.32, 13.72; MS (m/z): 322.1 (M + 1)⁺; anal. calcd for C₂₂H₂₇NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 81.89; H, 8.25; N, 4.11%.

4.2.28. 3-Cyclohexylmethyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (34). Synthesized as per the general procedure (A) using cyclohexyl bromide (0.50 ml) to get a white solid (34), (289 mg, 76%), mp = 92–94 °C; R_f 0.32, (n-hexane : ethyl acetate 20%); IR, (KBr): 2926, 2851, 1637, 1439, 770; ¹H NMR (CDCl₃): δ 7.92–7.85 (m, 1H), 7.23–7.08 (m, 2H), 6.99–6.94 (m, 1H), 5.67–5.62 (m, 1H), 4.15–4.05 (q, 1H), 3.74–3.65 (m, 1H), 3.35–3.28 (m, 1H), 3.06–3.00 (m, 3H), 1.75–1.74 (d, 3H), 1.62–1.54 (m, 6H), 1.51–1.38 (m, 4H), 0.96–0.87 (m, 1H); ¹³C NMR (CDCl₃): 176.00, 141.45, 134.39, 130.01, 128.11, 127.22, 126.89, 56.53, 47.56, 36.73, 33.97, 32.74, 30.96, 30.96, 30.67, 26.36, 25.88; MS (m/z): 272.1 (M + 1)⁺; anal. calcd for C₁₈H₂₅NO: C, 79.66; H, 9.28; N, 5.16. Found: C, 79.46; H, 9.12; N, 4.93%.

4.2.29. 3-[(2-Cyano)-4-biphenyl]-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (35). Synthesized as per the general procedure (A) using 4-bromomethyl-2-biphenylcarbonitrile (0.93 g) to get a semi solid (35), (310 mg, 86%); R_f 0.29, (n-hexane : ethyl acetate 20%); IR, (KBr): 3063, 2961, 2855, 2220, 1647, 1360, 1102, 846; ¹H NMR (CDCl₃): δ 7.77–7.74 (d, 1H, J = 7.9 Hz), 7.65–7.61 (d, 1H, J = 7.9 Hz), 7.49–7.41 (m, 5H), 7.31–7.29 (d, 1H, J = 7.4 Hz), 7.24–7.20 (m, 2H), 7.17–1.15 (m, 1H), 7.07–7.05 (d, 1H, J = 7.4 Hz), 4.73–4.70 (d, 1H, J = 15.1 Hz), 4.65–4.61 (d, 1H, J = 15.1 Hz) 4.45–4.40 (q, 1H, J = 6.8 Hz), 4.11–4.03 (m, 1H), 3.46–3.40 (m, 1H), 3.24–3.18 (m, 1H), 2.99–2.94 (m, 1H), 1.64–1.62 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.10, 144.08, 173.38, 136.15, 135.19, 132.72, 131.82, 129.01, 128.95, 127.93, 127.21, 126.53, 125.85, 125.70, 124.60, 117.71, 110.12, 49.42, 45.41, 39.25, 31.36, 28.67, 13.56; MS (m/z): 367.01 (M + 1)⁺.

4.2.30. Methyl 4-(1-methyl-2-oxo-1,3,4,5-tetrahydrobenzo[d]azepinyl)methylbenzoate (36). Synthesized as per the general procedure (A) using methyl (4-bromomethyl)benzoate (0.78 g) to get a white solid (36), (240 mg, 70%); mp 92–95 °C; R_f 0.28, (n-hexane : ethyl acetate 20%); IR, (KBr): 3126, 2928, 2854, 1707, 1678, 1402, 1289, 738; ¹H NMR (CDCl₃): δ 7.85–7.83 (d, 2H, J = 7.9 Hz), 7.23–7.21 (d, 1H, J = 7.9 Hz), 7.18–7.14 (m, 1H), 7.12–7.09 (m, 3H), 6.96–6.94 (d, 1H, J = 7.4 Hz), 4.64–4.60 (d, 1H, J = 15.2 Hz), 4.56–4.52 (d, 1H, J = 15.2 Hz) 4.36–4.30 (q, 1H, J = 6.8 Hz), 4.00–3.92 (m, 1H), 3.83 (s, 3H), 3.31–3.25 (m, 1H), 3.15–3.08 (m, 1H), 2.88–2.80 (m, 1H), 1.55–1.53 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.07, 166.89, 143.10, 137.12, 136.09, 129.87, 129.85, 127.76, 126.93, 126.83, 125.65, 52.11, 50.01, 46.59, 40.28, 32.41, 14.55; MS (m/z): 324.7 (M + 1)⁺; anal. calcd for C₂₀H₂₁NO₃: C, 74.28; H, 6.55; N, 4.33. Found: C, 73.88; H, 6.36; N, 4.05%.

4.2.31. 4-(1-Methyl-2-oxo-1,3,4,5-tetrahydrobenzo[d]azepinyl)methylbenzoic acid (37). Compound (36) (50 mg) was taken in a two neck round bottom flask. To this 5% solution of KOH (5 ml) and methanol (4 ml) was added. The reaction got completed in half an hour which was confirmed by TLC. The reaction mixture was poured into ice-cold water (50 ml), acidified with dil. HCl and extracted with dichloromethane. The solvent was removed and the compound was purified over a column of silica gel using n-hexane and ethyl-acetate to get a white solid (37), (45 mg, 98%); mp = 197–200 °C; R_f 0.36, (n-hexane : ethyl acetate 20%); IR, (KBr): 3069, 2969, 2854, 1700, 1652, 1486, 1297, 750; ¹H NMR (CDCl₃): δ 8.00–7.97 (d, 2H, J = 7.8 Hz), 7.31–7.21 (d, 1H, J = 7.8 Hz), 7.26–7.16 (m, 4H), 7.05–7.03 (d, 1H, J = 7.2 Hz), 4.74–4.70 (d, 1H, J = 15.3 Hz), 4.67–4.63 (d, 1H, J = 15.3 Hz) 4.44–4.39 (q, 1H, J = 6.8 Hz), 4.09–4.01 (m, 1H), 3.41–3.34 (m, 1H), 3.25–2.18 (m, 1H), 2.98–2.90 (m, 1H), 1.64–1.62 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.19, 170.99, 143.96, 137.14, 136.07, 130.50, 129.83, 128.43, 127.82, 126.97, 126.88, 125.71, 50.77, 46.70, 40.43, 32.41, 14.59; MS (m/z): 310 (M + 1)⁺; anal. calcd for C₁₉H₁₉NO₃: C, 73.77; H, 6.19; N, 5.53. Found: C, 73.65; H, 5.99; N, 5.42%.

4.3. General procedure (B) for the preparation of 3-substitued 8-chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (38–44)

To a stirred suspension of 8-chloro-3-benzazepin-2-one (6) (500 mg, 2.38 mmol) and NaH (63.00 mg, 2.61 mmol) in a mixture (2 ml) of dry THF and DMF (4.5 : 0.5) was added a solution of desired halide in dry THF and DMF (2 ml) and the mixture was heated under a stream of dry N₂ at 60–80 °C on an oil bath. The reaction mixture on cooling to room temperature was treated with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and concentrated to get semi solid of the compound which was further purified by column chromatography using silica gel as stationary phase and n-hexane: ethyl acetate as eluent.

4.3.1. 8-Chloro-3-ethyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (38). Prepared according to general procedure (B) using ethyl iodide (0.24 ml) to get a white solid (38), (120 mg, 65%); mp = 74–76 °C. R_f: 0.29 (n-hexane : ethyl acetate; 20%); IR (KBr): 3130, 2977, 2933, 1643, 1429, 812; ¹H NMR (CDCl₃): δ 7.26–7.21 (m, 1H), 7.16–7.11 (m, 1H), 7.08–7.00 (m, 1H), 4.31–4.26 (q, 1H, J = 6.8 Hz), 4.12–4.04 (m, 1H), 3.53–3.36 (m, 3H), 3.25–3.11 (m, 1H), 3.09–3.05 (m, 1H), 1.54–1.52 (d, 3H, J = 6.8 Hz), 1.12–1.08 (t, 3H); ¹³C NMR (CDCl₃): 172.94, 139.19, 135.90, 132.49, 129.80, 127.48, 126.60, 46.00, 42.66, 40.14, 33.02, 14.78, 13.29; MS (m/z): 238.10 (M + 1)⁺; anal. calcd for C₁₃H₁₆ClNO: C, 65.68; H, 6.78; N, 5.89. Found: C, 65.39; H, 6.54; N, 5.68%.

4.3.2. 3-Butyl-8-chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (39). Prepared according to general procedure (B) using n-butyl iodide (3.3 ml) to get a semi solid (39), (210.10 mg, 73%), R_f 0.36 (n-hexane : ethyl acetate 20%); IR (KBr): 3136, 2960, 2869, 1656, 1402, 1107, 805; ¹H NMR (CDCl₃): δ 7.21–6.91 (m, 3H), 4.31–4.25 (q, 1H, J = 6.8 Hz), 4.15–4.06 (m, 1H), 3.44–3.31 (m, 3H), 3.24–3.16 (m, 1H), 3.08–3.05 (m, 1H), 1.55–1.53 (d, 3H), 1.48–1.44 (m, 2H), 1.33–1.20 (m, 2H), 0.93–0.86 (t, 3H); ¹³C NMR (CDCl₃): 173.26, 139.08, 135.78, 132.40, 129.80, 127.43, 126.75, 47.65, 46.25, 40.00, 32.92, 30.38, 20.12, 14.74, 13.89; MS (m/z): 266.1 (M + 1)⁺.

4.3.3. 3-Allyl-8-Chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (40). Prepared according to general procedure (B) using allyl bromide (0.25 ml) to get a semi solid (40), (150.10 mg, 78%), R_f 0.35 (n-hexane : ethyl acetate 20%); IR (KBr): 3081, 2980, 2934, 1658, 1409, 1368, 1054, 927; ¹H NMR (CDCl₃): δ 7.19–6.92 (m, 3H), 5.70–5.60 (m, 1H), 5.07–5.00 (m, 2H), 4.26–4.20 (q, 1H, J = 6.8 Hz), 3.99–3.92 (m, 3H), 3.35–3.27 (m, 1H), 3.16–3.08 (m, 1H), 3.03–2.95 (m, 1H), 1.48–1.45 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.15, 138.03, 135.07, 133.49, 132.41, 131.20, 129.70, 127.33, 126.81, 117.49, 50.01, 45.70, 39.81, 32.55, 14.64; MS (m/z): 250.1 (M + 1)⁺.

4.3.4. 8-Chloro-3-propyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (41). Prepared according to general procedure (B) using n-propyl bromide (0.28 ml) to get a pale yellow solid (41), (190 mg, 68%), mp = 83–85 °C, R_f 0.39 (n-hexane : ethyl acetate 20%); IR (KBr): 2965, 2930, 1646, 1455, 803; ¹H NMR (CDCl₃): δ 7.26–6.99 (m, 3H), 4.31–4.26 (q, 1H, J = 6.8 Hz), 4.15–4.07 (m, 1H), 3.44–3.28 (m, 3H), 3.25–3.05 (m, 2H), 1.53–1.51 (d, 3H, J = 6.8 Hz), 1.50–1.48 (m, 2H), 0.94–0.81 (t, 3H); ¹³C NMR (CDCl₃): 173.42, 139.36, 135.78, 134.49, 132.34, 129.03, 126.74, 50.63, 46.26, 39.89, 32.51, 21.06, 20.03, 14.74; MS (m/z): 252.10 (M + 1)⁺; anal. calcd for C₁₄H₁₈ClNO: C, 66.89; H, 7.21; N, 5.56. Found: C, 66.65; H, 6.99; N, 5.32%.

4.3.5. 8-Chloro-3-dodecyl-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (42). Prepared according to general procedure (B) using a solution of 1-bromododecane (0.7 ml) to get a semi-solid (42), (170.10 mg, 66%), R_f 0.38 (n-hexane : ethyl acetate 20%); IR (KBr): 3136, 2960, 1655, 1402, 1191, 855; ¹H NMR (CDCl₃): δ 7.18–7.15 (m, 2H), 7.07 (s, 1H), 4.29–4.27 (q, 1H, J = 6.8 Hz), 4.11–4.08 (m, 1H), 3.48–3.35 (m, 3H), 3.20–3.19 (m, 1H), 3.13–3.09 (m, 1H), 1.53–1.46 (m, 3H), 1.48–1.46 (m, 2H), 1.31–1.22 (m, 18H), 0.89–0.83 (t, 3H); ¹³C NMR (CDCl₃): 173.27, 137.98, 135.85, 132.41, 129.83, 127.46, 126.65, 47.97, 46.19, 39.95, 32.98, 32.00, 29.71, 29.63, 29.49, 29.43, 28.43, 26.93, 22.77, 14.75, 14.19; MS (m/z): 378.30 (M + 1)⁺.

4.3.6. 3-(4-Bromobenzyl)-8-chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (43). Prepared according to general procedure (B) using 4-bromobenzyl bromide (0.78 g) to get a semi solid (43), (220.20 mg, 76%), R_f 0.32 (n-hexane : ethyl acetate 20%); IR (KBr): 3130, 2980, 1657, 1402, 1011, 760; ¹H NMR (CDCl₃): δ 7.40–7.37 (m, 2H), 7.22–7.13 (d, 1H), 7.19–7.17 (m, 1H), 7.15–7.11 (m, 1H), 7.02–6.98 (m, 1H), 6.94–6.92 (d, 1H), 4.58–4.43 (m, 2H), 4.37–4.30 (q, 1H), 4.06–3.97 (m, 1H), 3.36–3.29 (m, 1H), 3.15–3.07 (m, 1H), 2.99–2.93 (m, 1H), 1.58–1.56 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.57, 138.89, 137.95, 136.71, 135.59, 134.51, 132.59, 131.73, 129.74, 126.94, 121.40, 50.27, 46.05, 39.96, 32.36, 14.62; MS (m/z): 380.00 (M + 1)⁺.

4.3.7. 8-Chloro-3-(2,6-difluorobenzyl)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (44). Prepared according to general procedure (B) using 2,6-difluorobenzyl bromide (0.60 g) to get a white solid (44), (210 mg, 88%), mp = 98–101 °C, R_f 0.36 (n-hexane : ethyl acetate 20%); IR (KBr): 3130, 2977, 1643, 1429, 812; ¹H NMR (CDCl₃): δ 7.28–7.20 (m, 2H), 7.16–7.09 (m, 1H), 6.98 (s, 1H), 6.91–6.83 (m, 2H), 4.94–4.82 (m, 1H), 4.63–4.56 (m, 1H), 4.32–4.27 (q, 1H), 4.15–4.02 (m, 1H), 3.50–3.39 (m, 1H), 3.14–3.08 (m, 1H), 2.96–2.86 (m, 1H) 1.45–1.43 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 173.17, 163.18, 160.70, 138.74, 135.36, 132.39, 131.23, 129.70, 128.03, 127.35, 126.75, 113.21, 111.53, 45.34, 39.98, 32.37, 30.53, 14.81; MS (m/z): 336.10 (M + 1)⁺; anal. calcd for C₁₈H₁₆ClF₂NO: C, 64.39; H, 4.80; N, 4.17. Found: C, 64.18; H, 4.56; N, 3.95%.

4.4. 3-(2-Acatamido)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (48)

4.4.1. Step-I: 2-bromo-N-tritylacetamide (46). 2-Bromo-N-tritylacetamide (46) was synthesized from 2-bromoacetamide (45). A solution of the amide (45) (0.864 mmol), triphenylmethanol (0.576 mmol, 0.67 equiv.) and p-toluene-sulphonic acid (0.288 mmol) in dry toluene (15 ml) was refluxed under nitrogen with the help of Dean Stark apparatus.³⁷ The reaction was monitored by TLC using ethyl acetate and n-hexane. The reaction mixture was cooled to room temperature, quenching with 2% aqueous sodium bicarbonate solution, and extracted with ethyl acetate (3 × 5 ml). The organic layer was washed with water, brine and dried to get a pure white solid (46), (1 g, 88%); mp 197–199 °C (literature mp 204–211 °C);³⁸R_f 0.35, (n-hexane : ethyl acetate 20%), IR, (KBr): 3265, 3052, 2852, 1664, 1491, 736.

4.4.2. Step-II: 3-(2-acatamido)-1-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (48). To a stirred suspension of 3-benzazepin-2-one (5) (200 mg) and NaH (60% dispersion in mineral oil; 68.46 mg) in a mixture (2 ml) of dry THF and DMF (4.5 : 0.5), a solution of the 2-bromo-N-tritylacetamide (46) (228.74 mg) in the same solvent (2 ml) as mentioned above was added. The reaction mixture was heated in a stream of dry N₂ at 60–80 °C in an oil bath. The reaction mixture was cooled to room temperature and treated with cold water and extracted with ethyl acetate. The resulting organic layer was dried over sodium sulphate to get an intermediate (47) which was stirred with trifluoroacetic acid : DCM (70 : 30) for half an hour. As soon as the reaction got completed, the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulphate to a get a compound which was purified by column chromatography using silica gel as stationary phase and n-hexane : ethyl acetate as solvent and to get white solid (48) (210 mg, 67.40%); mp 138–140 °C, R_f 0.28, (n-hexane : ethyl acetate 20%); IR, (KBr): 3397, 3197, 1682, 1642, 1394, 742; ¹H NMR (CDCl₃): δ 7.28–7.13 (m, 4H), 6.08 (s, 1H), 5.24 (s, 1H), 4.40–4.35 (q, 1H, J = 6.8 Hz), 4.23–4.17 (m, 1H), 4.09–4.03 (d, 1H, J = 15.5 Hz), 3.99–3.90 (d, 1H, J = 15.5 Hz), 3.55–3.49 (m, 1H), 3.37–3.30 (m, 1H), 3.21–3.13 (m, 1H), 1.59–1.57 (d, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃): 174.56, 171.62, 136.90, 129.88, 127.22, 127.04, 125.52, 52.51, 48.98, 40.11, 32.15, 14.20; MS (m/z): 255.1 (M + Na)⁺; anal. calcd for C₁₃H₁₆N₂O₂: C, 67.22; H, 6.94; N, 12.06. Found: C, 66.99; H, 6.84; N, 11.97%.

4.5. Materials

5-Hydroxytryptamine creatinine sulphate was purchased from Hi-Media. m-CPP, and RS-102221 were procured from Sigma Aldrich.

4.6. Animals

Male Wistar rats (200–250 g) and female Swiss Albino mice (25–30 g) were used for the studies with free access of food and water ad libitum during the course of the study. Animals were maintained on 12 h light/dark cycle. After 15 days acclimatization, animals were used for the studies. All the protocols were approved by the Institutional Animal Ethics Committee (IAEC) and were conducted as per the guidelines of CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals) with approval no: MSU/PHARM/IAEC/2013/02.

4.7. In vitro 5-HT_2A bioassay using isolated rat thoracic aorta strip

Wister rats (200–250 g) were used for the study. The animals were sacrificed by an overdose of sodium pentobarbital (50 mg kg⁻¹). After dissecting the thoracic aorta, the helical strips were mounted as described earlier³⁹ in the Kreb's solution aerated with 95% O₂ and 5% CO₂ at 37 °C under 1 g of resting tension. For each determination at least six arterial strips were utilized. Isometric contractions were recorded using a force transducer (UGO BASILE, Italy) coupled to a Gemini 7070 recorder (UGO BASILE, Italy). All the test compounds were checked for their 5-HT_2A receptor agonist and antagonist actions at a single concentration of 2 × 10⁻⁵ M before determining their pA₂ or pD₂ values. 5-HT (10⁻⁸ to 10⁻⁵ M) was used as standard agonist to determine 5-HT_2A antagonism by the test compounds.

4.8. In vitro 5-HT_2B bioassay using an isolated rat fundus preparation

Wistar rats weighing 200–250 g, fasted for 48 h, were sacrificed by an overdose of sodium pentobarbital (50 mg kg⁻¹). The fundus strips were prepared as described earlier⁴⁰ and mounted in a 25 ml organ tube containing Kerb's solution at 37 °C, well aerated with 95% O₂ and 5% CO₂ with initial resting tension of 2 g. At least 6 longitudinal and 6 horizontal strip preparations were used for each test substance. The contractile responses were recorded on a 2-channel recorder using a force transducer coupled to a Gemini 7070 recorder (UGO Basile, Italy). Initially the test compounds were assessed to check their 5-HT_2B receptor activity at 2 × 10⁻⁵ M concentration. The compounds showing contractile responses were further evaluated (at 10⁻⁶ to 10⁻⁴ M) in the presence of SB-206553 (10⁻⁶ and 10⁻⁷ M) (5H_2B receptor antagonist) to confirm their 5-HT_2B agonism which was evident by their pD₂ values. Similar to the previous experiment, the antagonistic activity of the selected compounds was determined using 5-HT (10⁻⁸ to 10⁻⁵ M) as agonist.

4.9. In vivo rodent models for 5-HT_2C receptor agonistic activity

After the in vitro screening of the compounds for evaluating 5-HT_2A and 5-HT_2B receptor agonist/antagonist actions, the inactive compounds in both the studies were further evaluated using different in vivo rodent models as described below for their 5-HT_2C receptor agonistic potentials. m-CPP (4) (2 mg kg⁻¹, p.o.) was used as standard, while the test compounds were administered at a dose of 10 mg kg⁻¹, p.o. Dose of the test compounds were decided after dose-deciding pilot study (data not shown). For all in vivo experiments, six animals per group were utilized.

4.10. Despair swim test

Swiss Albino mice were forced to swim inside a vertical Plexiglas cylinder (45 cm height × 20 cm diameter) filled with water up to 30 cm height and maintained at 25 °C to assess their depression state. After the 15 min training period, animals were randomly divided into different experimental groups. Next day, 1 h after the drug administration, the animals were again placed in the cylinder and total duration of immobility was measured during a 5 min test period.⁴¹

4.11. Elevated plus maze test

Anxiety was assessed on elevated plus maze apparatus using Swiss Albino mice. Animals were acclimatized to the apparatus for 10 min before performing the experiment. One hour after the drug treatment, animals were individually placed at the centre of the maze facing their heads towards open arm and allowed to explore all the arms for 5 min. Number of entries and time spent in open arms were recorded.⁴²

4.12. Hypophagic response

Food deprived Wistar rats were housed individually for 24 h. Next day, after the treatment, animals were supplemented with weighed amounts of the normal food pellets. Amount of food remaining after 2 h was measured. 5-HT_2C receptor selectivity was also assessed by the administration of RS-10222 (3) (selective 5-HT_2C receptor antagonist) (2 mg kg⁻¹, i.p.)^43,44 to the animals 30 min prior to administration of the test compounds.⁴⁵

4.13. Penile erection model

Immediately after the treatment, rats were placed in Plexiglas observation cages. A mirror was placed behind the cages to observe penile erection over a 2 hour period. To assess the 5-HT_2C receptor selectivity, the animals were administered with RS-102221 (3) (2 mg kg⁻¹, i.p.), 30 min prior to the test compound. Number of lickings of the penis were observed.³³

4.14. Estimation of monoamines

5-HT_2C receptor agonists negatively regulate the monoamine firing in the brain.^34,46,47 It was confirmed by the estimation of DA and 5-HT levels in the rat brain using HPLC. After demonstrating the hypophagic response of compounds (7, 12–14, 24, 30 and 38), their 5-HT_2C selectivity was confirmed in the presence of RS-102221 (3). At the end of the study, all the rats were sacrificed by an overdose of sodium pentobarbital (50 mg kg⁻¹). The brains were dissected out, weighed and homogenized in 10% w/v 0.17 M perchloric acid to extract the monoamines. Homogenates were allowed to stand for 15 min and the supernatants were decanted in separate Eppendorf tubes and were centrifuged at 4 °C for 20 min at 15 000 rpm. After centrifugation, the supernatants were separated and analyzed immediately or stored at −70 °C until assayed. Brain concentrations of DA and 5-HT were assessed by RP-HPLC coupled with electrochemical detector (Model no. Waters 2465) (Waters Corporation, Milford, USA). Estimation was performed as per previously described method with minor modifications.^48,49 Briefly, a Sunfire® C18 column (4.6 mm × 150 mm, particle size 5 μm) was used and separation was carried out using mobile phase containing methanol (15% v/v) in a solution (pH 4.2) of 32 mM citric acid, 12.5 mM disodium hydrogen orthophosphate, 0.5 mM sodium octyl sulphate, 0.5 mM EDTA and 2 mM KCl, at a flow rate of 1.2 ml min⁻¹, an operating pressure of 3000 psi and an operating potential of 0.61 V. The internal standards were prepared by spiking known amounts of mixed standards (10, 20, 40, 80 and 160 ng ml⁻¹ of each 5-HT and DA) in 1 ml of pooled brain homogenates. The standard curves were used to quantify the amount of 5-HT and DA in each sample by calculating the area under the curve (AUC). The limit of detection (LOD) for 5-HT and DA were found 0.83 ± 0.06 ng ml⁻¹ and 0.11 ± 0.03 ng ml⁻¹, respectively while the limit of quantification (LOQ) was found to be 2.53 ± 0.12 ng ml⁻¹ and 0.34 ± 0.03 ng ml⁻¹ respectively.

4.15. Statistical analysis

All the observed data were analyzed using GraphPad Prizm-5. Comparison within groups was made by repeated measures ANOVA and comparison among groups was made by factorial ANOVA followed by Bonferroni test. Data were expressed as mean ± SEM. A value of p < 0.05 was considered significant.

Acknowledgements

Prof. M. R. Yadav is thankful to UGC, New Delhi for the award of ‘UGC-BSR One time research grant’ [F.19-147/2015 (BSR)]. The study was also supported by UGC-BSR-RFMS fellowship to MS and MB. JM, thanks UGC project (F. No. 41-716/2012-SR). The authors acknowledge the analytical facilities provided by Dr Vikram Sarabhai Research Center, The M. S. University of Baroda, Vadodara, India.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra17718a

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