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Mol Divers (2012) 16:357–366DOI 10.1007/s11030-012-9372-3
FULL-LENGTH PAPER
Naturally occurring himachalenes to benzocycloheptene aminovinyl bromide derivatives: as antidepressant molecules
Abha Chaudhary · Pralay Das · Awanish Mishra ·Pushpinder Kaur · Bikram Singh · Rajesh K. Goel
Received: 21 December 2011 / Accepted: 16 April 2012 / Published online: 15 May 2012© Springer Science+Business Media B.V. 2012
Abstract A new series of benzocycloheptene amino vinylbromide derivatives (9a–9m) were synthesized from iso-meric mixture of himachalenes through two-step synthesis.The unusual structure of benzocycloheptene amino vinyl bro-mide derivative (9a) was confirmed by NMR and X-ray crys-tallography analyses. The newly synthesized amino vinylbromide derivatives of benzocycloheptene were further eval-uated for their antidepressant activities. The compound 9chad shown significant reduction in the immobility period.
Keywords Vinyl halide · Benzocycloheptene amino vinylbromide derivatives · Antidepressant · Himachalene
Introduction
The essential oil of Himalayan Cedar (Cedrus deodara) isan important raw material for the synthesis of fragrancesand pharmaceutical compounds. This oil is mainly com-posed of three sesquiterpenic bicyclic hydrocarbons: α- cis-,
Electronic supplementary material The online version of thisarticle (doi:10.1007/s11030-012-9372-3) contains supplementarymaterial, which is available to authorized users.
A. Chaudhary · P. Das (B) · P. Kaur · B. Singh (B)Division of Natural Plant Products, CSIR-Institute of HimalayanBioresource Technology, Palampur 176061, Himachal Pradesh,Indiae-mail: [email protected]
B. Singhe-mail: [email protected]
A. Mishra · R. K. Goel (B)Department of Pharmaceutical Sciences and Drug Research,Punjabi University, Patiala 147002, Punjab, Indiae-mail: [email protected]
β-, and γ -cis-himachalenes containing hexahydrobenzocy-cloheptene as basic skeleton. Benzocycloheptene derivativesare attractive biological targets in theoretical chemistry, phar-maceutical sciences, and coordination chemistry [1–3]. Thesecompounds have been synthesized by various methods suchas the enlargement of six-membered rings [4,5], cycliza-tion [6], and coupling reactions [7]. Organic and medici-nal chemists have produced substituted benzocycloheptenesfrom benzocycloheptanone [8,9]. Substituted benzocycloh-eptenes, SB-612111 (1) (ORL-1 receptor antagonist) may bea useful adjunct to chronic pain therapy and thermal hyper-algesia (Fig. 1) [10], and FK175 (2) as human β3 adren-ergic receptor agonists with good oral bioavailability [11].Amino benzocycloheptenes have been reported as antide-pressant [12], central analgesic agents and have a strongaffinity for opiate receptors [13], used for treatment of uri-nary bladder [9], neurodegenerative [14], cardiovascular dis-eases [16], sarcoma, carcinoma [15], and pain relief [17].Piperidine and piperazine derivatives of benzocyclohepten-e (3) exhibited antiarrhythmic effect [18]. Amino benzo-cycloheptenes can also act as melatonin receptor agonists[19], αv integrin antagonists [20], sphingosine 1-phosphatereceptor agonists [6], α-sympathomimetic, and anorexigenicagents [1]. Benzoimidazole benzocycloheptenes have beenused in pharmaceutical composition for modulationof small-conductance calcium-activated potassiumchannels [21].
Vinyl halides are also emerging as versatile substrates ina variety of chemical transformations and their importanceas valuable synthons is increasing accordingly. The role ofvinyl halides as precursors of vinyl anions [22] and as cou-pling components in a wide range of transition metal-cata-lyzed coupling reactions [23] has stimulated a great deal ofinterest in their synthesis. They are also present in a wide vari-ety of natural products, pharmaceuticals, and agrochemicals
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358 Mol Divers (2012) 16:357–366
N
N
HN
O
OEtO2C
HN
HO Cl
NX
O
O
Br
N
X=N/CH
1 2
3 9b
Fig. 1 Biologically active benzocycloheptene amine derivatives
[24]. In general, vinyl halides are synthesized from carbonylcompounds by reaction with traditional halogenating reagentsunder prolonged heating in high-boiling solvents or bymeans of multistep procedures [25,26]. These have beenalso synthesized by a suitable alkene precursor followedby the induction of the halide [27] or selective dehalogen-ation of vic-dihalides to vinyl halides [28,29]. The questfor new synthetic methods and development of milder andstraightforward reactions for the preparation of suchhalogenated derivatives represents a desirable goal.
The sequential functionalization of a simple moleculebearing multiple reaction sites may serve as a powerfulsynthetic strategy that should provide enormous opportu-nity for diversity as well as target-oriented synthesis. Forthese reasons and pursuing our research in the field, thisstudy focused on the synthesis and antidepressant activityof novel skeletons of benzocycloheptene amino vinylbromide derivatives starting from α-dehydro-aryl-himacha-lene which was produced from naturally occurringmixture of α-, β-, and γ -himachalenes using milderprocess.
Results and discussion
Chemistry
The conversion of benzocycloheptanone into theircorresponding amine derivatives has been reported in the lit-erature. This procedure involves oxime formation [1], reduc-tive amination [30], through azide formation, α-bromination[12], or cyanoboration [31]. Similarly, the fused ring systemsof himachalenes have been the subject of interest since lastfive decades.
For the valorization of himachalenes, the mixture ofα- (21 %),β- (55 %), andγ -himachalene (14 %) 4 was treatedwith DDQ in dry benzene under nitrogen at reflux conditionthat gave best results; yielding α-dehydro-ar-himachalene 5as major product (Scheme 1). Optimization of the bromin-ation of α-dehydro-ar-himachalene 5 with Br2/DCM, Br2/
AcOH and NBS all led to the formation of mixture of prod-ucts. Finally, bromination using KBr (4 equiv) and cericammonium nitrate (CAN, 3 equiv) in DCM:H2O (1:1, v/v)for 5 h at room temperature yielded dibromide 6 as the ma-jor product. This dibromide was found to be unstable duringits purification by column chromatography. Mechanistically,the alkene reacts with bromide radicals to form a dibromointermediate 6 or the rearranged product 7. The intermediatewas further treated with 1.5 equiv of morpholine and 2 equivof K2CO3 in DMF at 90 ◦ C for 15 h to produce benzocyclo-heptene amino vinyl bromide derivative 9a as major prod-uct. The structure of 9a (Fig. 2) was confirmed by NMR andX-ray crystallographic studies (CCDC No.: 836369) as singlecolorless crystals produced from DCM:hexane (1:1) mixture.
With the optimized reaction conditions at hand, the scopeof this reaction was investigated using different aromatic andaliphatic amines. Several secondary amines such as morpho-line, piperidine, piperazine, pyrrolidine, and diethyl aminewere used giving satisfactory yields (Table 1, entries 1–5). Tobroaden the scope of this method, different primary aminessuch as cyclohexyl-, benzyl-, isobutyl-, t-butyl-amine, andphenylethyl-amines were tested for the same reaction alsogiving good yields (Table 1, entries 6–10). No significantelectronic effect were observed for the reaction with
BrBr
Br
N R1
4 5 96
Br
Br
7
ora b
R2
c
Scheme 1 Synthetic protocol of benzocycloheptene amino vinyl bromide derivatives. Reagents and conditions: a DDQ, dry benzene, reflux, 24 h,N2; b CAN, KBr, DCM/H2O, rt, 5 h; c Amine (8), K2CO3, DMF, 80–90 ◦ C
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Mol Divers (2012) 16:357–366 359
Fig. 2 Structure confirmation of benzocycloheptene amino vinylbromide derivative 9a (No. CCDC 836369) by X-ray crystallography
aromatic primary amines considering the yields of the prod-uct. In case of diamines, the reaction of one amino group wasobserved while the other amino group remained unreacted(Table 1, entries 3). Sterically hindered amines,(Table 1, entries 14, 15) remain unaltered even when increas-ing the number.
Pharmacology
Physicochemical prediction
In this study, a series of synthesized compounds (9a–9m)was screened using Molinspiration property engine v2011.04to predict the physicochemical parameters, i.e., Log P(partition coefficient), TPSA (total polar surface area), MV(molecular volume), HBD (hydrogen bond donor), HBA(hydrogen-bond acceptor), and Lipinski score. The resultsrevealed that all compounds have good physicochemicalparameters except log P , which was satisfied by only fourcompounds (9a, 9c, 9d, and 9m).
Pharmacodynamic prediction
Among several substituted compounds only six compounds(9a, 9b, 9c, 9d, 9h, and 9j) were predicted with antidepres-sant activity in prediction of activity spectra for substances(PASS) program, either directly or indirectly (monoamineuptake inhibitor activity) (Table 2). Out of these six com-pounds, only four compounds (9a, 9b, 9c, and 9d) weredepicted with higher degree of predicted activity and there-fore were subjected to evaluate antidepressant activityin vivo.
Pharmacological study
The compounds with higher antidepressant score weresubjected to tail suspension test for the evaluation of anti-depressant effect. The antidepressant effect of samples wascompared with fluoxetine, a standard antidepressant drug,having selective serotonin (a monoamine) reuptake inhibi-tion property [32].
In tail suspension test vehicle control animals have shown260 s of immobility period while this immobility was signif-icantly reduced up to 160 s with fluoxetine (standard antide-pressant drug; 20 mg/kg) pretreatment. Pretreatment with 9a(5, 10, and 20 mg/kg) reduced the immobility period, how-ever significant reduction, as compared to vehicle control,was observed at 10 mg/kg dose. Pretreatment with 9b and9d was not found to reduce the immobility period. Whilethe treatment with 9c have exhibited significant reductionin the immobility period as compare to vehicle control at10 and 20 mg/kg dose (Fig. 3). This indicated that 9c hascomparative more potential antidepressant activity as sug-gested by PASS prediction. The antidepressant activity of9c may be due to its monoamine uptake inhibitor activity assuggested by PASS (Table 2).
Structure activity relationship
In this study, various benzocycloheptene amino vinyl bro-mide derivatives were synthesized using different amines, inorder to investigate the pharmacophoric substituent, respon-sible for better activity. The prospective biological activitiesof the synthesized compounds are the consequence of bothpharmacokinetic and pharmacodynamic properties that maybe differently affected by structural modifications indicatingthat there is a strict correlation between potency and struc-tural as well as conformational characteristics of the mole-cules. It has been suggested that tricyclic moiety (as in tri-cyclic antidepressants) is necessary for antidepressant effect.Virtually, if we fuse the third benzene ring in the benzocy-cloheptene moiety, that should increase the log P value ofthe synthesized compounds and limit its therapeutic efficacy.Furthermore, the tricyclic structure is not associated withaffinity for any particular receptor, rather, contributes to arange of multiple CNS pharmacodynamic (adverse) effectsbecause of increased lipophilicity [33]. Different substitu-tions at benzocycloheptene moiety have been reported fortheir antidepressant effect [12,34]. Therefore, in this syn-thetic design, the various substituents were introduced atunexplored 5th position of aryl himachalene moiety havinghigher probability of antidepressant activity.
Pharmacological results revealed that substitutions at 5thposition can also have antidepressant effect. Substitutionwith heterocyclic ring, having tertiary amine, have shownpotential activity as antidepressants though PASS (direct and
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Table 1 Description for thesynthesis of benzocyclohepteneamino vinyl bromide derivatives(9a–9m)
Entry Amine 8 Product 9 Yield (%)
2
1
HN 64
Br
N
9b
HN 62
Br
N
9d
HN O 76
Br
N
O
9a
4
NH
HN Br
N
NH
9c
3
5
6
63
75NH
Br
N
9e
72
NH2
Br
NH
9f
8
9
10
H2N
H2N
Br
HN
Br
NH
9h
9j
H2NBr
NH
9i
H2NBr
NH
H2NBr
NH
9k
9l
11
12
NH3
Br
NH2
9m
13
Entry Amine 8 Product 9 Yield (%)
H2N7 61
Br
NH
9g
14N
No reaction15
No reaction
NH
67
63
63
54
52
50
-
-
indirect effect). Among various substitutions morpholine,piperidine, piperazine, and pyrrolidine have shown betterphysicochemical and pharmacodynamic computationally pre-dicted profiles. However, piperazine substitution at the 5thposition produced a better in vivo antidepressant vs. morpho-
line, piperidine, and pyrrolidine substituents (Fig. 3). Substi-tutions with aliphatic and secondary amines did not satisfythe pharmacokinetic and pharmacodynamics criteria to beantidepressant as evidenced by computational and pharma-cological study.
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Mol Divers (2012) 16:357–366 361
Table 2 Computational database of benzocycloheptene amino vinyl bromide derivatives
Sample MW MV Log P TPSA HBD HBA Lipinski Antidepressant Monoamine uptakescore score inhibitory score
Pa Pi Pa Pi
9a 364.320 313.230 4.440 12.472 0 2 0 0.239 0.084 0.301 0.079
9b 362.347 321.047 5.502 3.328 0 1 1 0.238 0.084 0.278 0.095
9c 363.335 316.648 3.890 15.265 1 2 0 0.394 0.035 0.317 0.069
9d 348.320 304.245 4.996 3.238 0 1 0 0.240 0.083 0.296 0.082
9e 350.336 314.605 5.346 3.238 0 1 1 NP NP NP NP
9f 350.336 314.250 5.120 12.027 1 1 1 NP NP NP NP
9g 350.336 313.685 5.534 12.027 1 1 1 NP NP NP NP
9h 384.353 335.709 5.747 12.027 1 1 1 0.184 0.120 0.253 0.114
9i 398.379 352.511 5.802 12.027 1 1 1 NP NP NP NP
9j 376.374 337.493 6.254 12.027 1 1 1 0.152 0.147 NP NP
9k 370.326 318.907 6.046 12.027 1 1 1 NP NP NP NP
9l 384.353 335.468 6.495 12.027 1 1 1 NP NP NP NP
9m 294.230 246.384 3.368 26.023 2 1 0 NP NP NP NP
MW molecular weight, MV molecular volume, Log P partition coefficient, TPSA total polar surface area, HBD hydrogen-bond donor, HBA hydro-gen-bond acceptor, Lipinski score no of unmet criteria of Lipinski Rule of Five, Pa probable activity, Pi probable inactivity
aa a a
0
50
100
150
200
250
300
350
Imm
obili
ty P
erio
d (s
ec)
Fig. 3 Effect of different pharmacological interventions on immobil-ity period in tail suspension test; results were expressed as mean ± SEMof six animals; a significant as compare to vehicle
Conclusion
This method allowed the selective preparation of novel aminovinyl bromides as precursors for variety of biologicaltargets in good yields from readily available naturally occur-ring himachalenes mixture. We explored the antidepressantactivity for these synthons and observed that piperazine substi-tuted derivative had better activity. Thus, the piperazinederivative was considered as lead entity selected for furthermodifications to obtain more efficacious and potent antide-pressant drugs. This study was part of an ongoing programto develop appropriate methodologies for the synthesis ofhimachalene derivatives as potential pharmaceuticals, insec-ticides, and synthetic intermediates.
Experimental
General methods
All reagents and solvents were purchased from commer-cial sources (Sigma-Aldrich, Merck India Ltd). Reactionswere monitored by thin-layer chromatography plates coatedwith 0.2 mm silica gel 60 F254 (Merck). TLC plates werevisualized by the UV irradiation (254 nm) and iodine spray.The products were purified by the column chromatographyemploying silica gel 60 (Merck). All NMR spectra wererecorded on a Bruker Avance-300 instrument (300 MHz for1H, 75.46 MHz 13C) using CDCl3 and TMS as solvent andreference, respectively. IR spectra were obtained on a Nicolet5700 FTIR (Thermo, USA) spectrophotometer in the region4,000–400 cm−1 using KBr disks.
Procedure for synthesis of 2,9,9-trimethyl-5-methylene-6,7,8,9-tetrahydro-5H-benzocycloheptene (5)
To a solution of 4 (1 g, 4.902 mmol) in dry benzene (30 mL)was added DDQ (1.1 g, 9.804 mmol) and the mixture wasstirred at reflux for 24 h under N2. The solvent was removedunder reduced pressure. The reaction was then quenched byadding 5 % sodium bicarbonate solution and extracted withethyl acetate. The organic layer was evaporated and the re-sulting residue was chromatographed on silica gel elutingwith heptane (100 %) to afford 5 as colorless oil (490 mg,50 %). IR (KBr): 3051, 2976, 2955, 1573, 1266, 882 cm−1.
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362 Mol Divers (2012) 16:357–366
1H NMR (CDCl3, 300 MHz) δ 0.96–0.98 (m, 2H), 1.42(s, 6H), 1.80 (m 2H), 1.99 (m, 2H), 2.43 (s, 3H), 5.05 (s,1H), 5.13 (s, 1H), 7.05 (1H, m), 7.14 (m, 1H), 7.26 (m, 1H);13C NMR (CDCl3, 75 MHz) δ 21.9, 26.7, 30.9, 38.0, 39.3,41.2, 113.7, 127.0, 130.5, 135.4, 141.3, 146.9, 154.4. GC–MS (70 eV), tR = 33.528 min, m/z 200.
General procedure for the synthesis of compounds (9a–9m)
To a solution of 5 (101 mg, 0.505 mmol) in dichlorometh-ane (1.5 mL), KBr (241 mg, 2.02 mmol) and a solution ofCAN (831 mg, 1.515 mmol) in water (1.5 mL) were addedat room temperature and stirred for 5 h. After completionof the reaction, the dichloromethane layer was separated,washed with brine, and dried over sodium sulfate. The solventwas removed to get a yellowish oily liquid 6. This yellowishoil 6, morpholine (66 mg, 0.758 mmol), K2CO3 (139 mg,1.01 mmol), and anh. DMF (3 mL) were placed in a round-bottom flask and stirred at 90 ◦ C for 15 h. The reaction wasmonitored by TLC and the reaction mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with5 % aq. NaHCO3 and water. The organic layer was dried overanhydrous Na2SO4 and the solvent was removed in rotaryevaporator. Purification by silica gel column chromatographygave 9a (140 mg, 76 %) as light yellow crystals (hexane:ethylacetate, 97:3).
4-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-morpholine (9a)
White solid; m.p. 120 − −122 ◦ C; IR (KBr): 3455, 2939,2911, 2856, 2369, 1732, 1659, 1365, 834 cm−1; 1H NMR(CDCl3, 300 MHz) δ 1.38 (s, 6H), 2.09–2.15 (m, 2H), 2.41(s, 3H), 2.52–2.56 (m, 2H), 2.62 (m, 4H), 3.43 (s, 2H), 3.76(m, 4H), 7.11 (d, J = 8.03 Hz, 1H), 7.24 (s, 1H), 7.89 (d,J = 8.03 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.7, 32.1,37.6, 38.8, 47.4, 54.0, 63.8, 67.4, 126.6, 126.7 126.8, 128.8,134.6, 136.9, 137.4, 146.0. MS-EI: for C19H26BrNO, calcd364.3, found 364.5 m/z (M)+.
Crystal data for 9a
Orthorhombic crystal system, space group P212121 witha = 11.388(3) Å, b = 11.756(2) Å, c = 13.384 (3) Å, U =1791.8(7) Å
3, Dc = 1.351 mg/m−3, µ = 2.296 mm−1, Mo
Kα = 0.71073, R1 = 0.0276, wR2 = 0.0578, Z = 4.Crystallographic data for the structure in this paper have beendeposited with the Cambridge Crystallographic Data Centreas supplementary publication nos. CCDC 836369. Copiesof the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:+44 (0)1223 336033 or e-mail: [email protected]).
1-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-piperidine (9b)
Prepared as described for 9a; starting from 5 (102 mg,0.51 mmol), KBr (243 mg, 2.04 mmol), CAN (839 mg,1.53 mmol), piperidine (65 mg, 0.765 mmol), K2CO3
(141 mg, 1.02 mmol) and after purification with silica gelcolumn chromatography (hexane:ethyl acetate, 97.5:2.5) togive 9b (118 mg, 64 %) as light yellow semisolid; IR (KBr):3459, 2964, 2932, 2844, 2360, 1740, 16659, 1340, 863 cm−1;1H NMR (CDCl3, 300 MHz) δ 1.38 (s, 6H), 1.48 (m, 2H),1.63 (m, 4H), 2.18 (m, 2H), 2.41–2.44 (m, 4H), 2.55 (m,5H), 3.42 (br s, 2H), 7.10–7.12 (m, 1H), 7.23–7.34 (m, 1H),7.91–7.96 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.7, 24.5,26.2, 32.1, 38.1, 38.8, 47.1, 54.8, 64.0, 126.4, 126.6, 126.7,129.1, 135.1, 136.7, 137.5, 145.9. MS-EI: for C20H28BrN,calcd 362.4, found 362.7 m/z (M)+.
1-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-piperazine (9c)
Prepared as described for 9a; starting from 5 (105 mg,0.525 mmol), KBr (250 mg, 2.10 mmol), CAN (863 mg,1.575 mmol), piperazine (68 mg, 0.788 mmol) and K2CO3
(145 mg, 1.05 mmol) and after purification with silica gel col-umn chromatography (hexane:ethyl acetate, 95:5) to give 9c(120 mg, 63 %) as white solid; m.p. 147–150◦ C; IR (KBr):3451, 2955, 2917, 2847, 2362, 1735, 1662, 1336, 857 cm−1;1H NMR (CDCl3, 300 MHz) δ 1.31 (s, 6H), 2.04–2.08 (m,2H), 2.35 (s, 3H), 2.45–2.73 (m, 10H), 3.37 (s, 2H), 7.04 (d,J = 7.59 Hz, 1H), 7.17 (s, 1H), 7.83 (d, J = 7.86 Hz, 1H);13C NMR (CDCl3, 75 MHz) δ 21.8, 32.0, 38.1, 38.8, 47.4,51.8, 53.3, 63.4, 126.5, 126.7, 129.0, 134.9, 136.8, 137.1,145.9. MS-EI: for C19H27BrN2, calcd 363.3, found 363.5m/z (M)+.
1-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)pyrrolidine (9d)
Prepared as described for 9a; starting from 5 (106 mg,0.53 mmol), KBr (253 mg, 2.12 mmol), CAN (872 mg,1.59 mmol), pyrrolidine (57 mg, 0.795 mmol), and K2CO3
(146 mg, 1.06 mmol) and after purification with silica gelcolumn chromatography (hexane:ethyl acetate, 95:5) to give9d (115 mg, 62 %) as brown semisolid; IR (KBr): 3444, 2969,2907, 2840, 2365, 1755, 1650, 1345, 863 cm−1; 1H NMR(CDCl3, 300 MHz)δ 1.34 (s, 6H), 1.78–1.82 (m, 4H), 2.10–2.16 (m, 2H), 2.39 (s, 3H), 2.50–2.53 (m, 2H), 2.67 (m, 4H),
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Mol Divers (2012) 16:357–366 363
3.69 (s, 2H), 7.08–7.11 (m, 1H), 7.20–7.33 (m, 1H), 7.68–7.76 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.8, 23.8,32.1, 38.1, 38.8, 47.7, 54.5, 60.2, 125.9, 126.3, 126.8, 128.7,135.8, 136.9, 136.9, 146.2. MS-EI: for C19H26BrN, calcd348.3, found 348.8 m/z (M)+.
(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-diethyl-amine (9e)
Prepared as described for 9a; starting from 5 (101 mg,0.505 mmol), KBr (241 mg, 2.02 mmol), CAN (831 mg,1.515 mmol), diethylamine (55 mg, 0.758 mmol), and K2CO3
(139 mg, 1.01 mmol) and after purification with silica gel col-umn chromatography (hexane:ethyl acetate, 99:1) to give 9e(132 mg, 75 %) as brown semisolid; IR (KBr): 3461, 2962,2917, 2871, 2360, 1671, 1383, 823 cm−1; 1H NMR (CDCl3,300 MHz) δ 1.02 (t, J = 6.94 Hz, 6H), 1.34 (s, 6H), 2.05–2.09 (m, 2H), 2.36 (s, 3H), 2.46–2.51 (m, 2H), 2.55–2.62 (m,4H), 3.44 (s, 2H), 7.05 (d, J = 7.82 Hz, 1H), 7.18 (s, 1H),7.88 (d, J = 7.82 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
11.9, 21.8, 32.1, 38.1, 38.9, 46.7, 47.4, 59.2, 126.0, 126.5,129.2, 136.1, 136.6, 137.4, 146.0. MS-EI: for C19H28BrN,calcd 350.3, found 350.5 m/z (M)+.
(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-isobutyl-amine (9f)
Prepared as described for 9a; starting from5 (102 mg,0.51 mmol), KBr (243 mg, 2.04 mmol), CAN (839 mg,1.53 mmol), isobutylamine (56 mg, 0.765 mmol), and K2CO3
(141 mg, 1.02 mmol) and after purification with silica gel col-umn chromatography (hexane:ethyl acetate, 97:3) to give 9f(128 mg, 72 %) as brown semisolid; IR (KBr): 3463, 2960,2915, 2883, 2320, 1746, 1660, 1385, 923, 830 cm−1; 1HNMR (CDCl3, 300 MHz) δ 0.89–0.92 (m, 6H), 1.35 (s, 6H),1.70–1.81 (m, 1H), 2.04–2.11 (m, 2H), 2.35 (s, 3H), 2.43–2.48 (m, 4H), 3.64 (s, 2H), 7.06 (d, J = 7.76 Hz, 1H),7.19 (s, 1H), 7.45 (d, J = 7.82 Hz, 1H); 13C NMR (CDCl3,75 MHz) δ 20.9, 21.8, 28.2, 32.2, 38.1, 38.3, 48.1, 55.6, 58.6,123.8, 126.8, 126.9, 128.1, 136.9, 138.3, 146.6. MS-EI: forC19H28BrN, calcd 350.3, found 350.3 m/z (M)+.
(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)t-butylamine (9g)
Prepared as described for 9a; starting from 5 (102 mg,0.51 mmol), KBr (243 mg, 2.04 mmol), CAN (839 mg,1.53 mmol), t-butylamine (56 mg, 0.765 mmol), and K2CO3
(141 mg, 1.02 mmol) and after purification with silica gelcolumn chromatography (hexane:ethyl acetate, 95:5) to give9f (108 mg, 61 %) as yellowish brown semisolid; IR (KBr):
3460, 2970, 2875, 2315, 1665, 1390, 832 cm−1; 1H NMR(CDCl3, 300 MHz) δ 1.21 (s, 9H), 1.38 (s, 6H), 2.12–2.15 (m,2H), 2.52–2.54 (m, 2H), 3.66 (s, 3H), 2.39 (s, 3H), 7.10. (d,J = 7.69 Hz, 1H), 7.22 (s, 1H), 7.65 (d, J = 7.84 Hz, 1H);13C NMR (CDCl3, 75 MHz) δ 21.7, 28.9, 32.2, 38.1, 38.3,48.1, 49.0, 51.0, 123.9, 126.6, 126.9, 128.1, 137.4, 136.8,146.5, 138.3. MS-EI: for C19H28BrN, calcd 350.3, found350.7 m/z (M)+.
Benzyl-(6-bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)amine (9h)
Prepared as described for 9a; starting from5 (100 mg,0.5 mmol), KBr (238 mg, 2 mmol), CAN (822 mg, 1.5 mmol),benzylamine ((80 mg, 0.75 mmol), and K2CO3 (138 mg,1 mmol) and after purification with silica gel column chro-matography (hexane:ethyl acetate, 92:8) to give 9h (130 mg,67 %) as light yellowish semisolid; IR (KBr): 3477, 2932,2878, 2377, 2321, 1655, 1429, 1362, 1160, 824 cm−1; 1HNMR (CDCl3, 300 MHz) δ 1.39 (6H, s), 2.14–2.16 (2H, m),2.39 (3H, s), 2.50–2.52 (m, 2H), 3.75 (2H, s), 3.90 (2H, s),7.07–7.09 (m, 1H), 7.23–7.47 (7H, m); 13C NMR (CDCl3,75 MHz) δ 21.7, 32.2, 38.1, 38.4, 48.1, 54.4, 54.8, 124.1,126.9, 127.1, 128.2, 128.4, 136.7, 137.0, 138.0, 140.3, 146.8.MS-EI: for C22H26BrN, calcd 384.4, found 384.5 m/z (M)+.
(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-phenethyl-amine (9i)
Prepared as described for 9a; starting from 5 (103 mg,0.515 mmol), KBr (245 mg, 2.06 mmol), CAN (847 mg,1.545 mmol), phenethylamine (94 mg, 0.773 mmol), andK2CO3 (142 mg, 1.03 mmol) and after purification with silicagel column chromatography (hexane:ethyl acetate, 95:5) togive 9i (130 mg, 63 %) as light yellow semisolid; IR (KBr):3455, 2915, 2873, 2349, 2333, 1645, 1460, 1380, 1160, 830cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.34 (s, 6H), 2.07–2.12(m, 2H), 2.36 (s, 3H), 2.43–2.48 (m, 2H), 2.81–2.85 (m, 2H),2.92–2.95 (m, 2H), 3.73 (s, 2H), 7.03 (d, J = 7.82 Hz, 1H),7.20–7.22 (m, 3H), 7.26–7.29 (m, 2H), 7.33–7.36 (m, 1H);13C NMR (CDCl3, 75 MHz) δ 21.8, 32.2, 36.4, 38.1, 38.3,48.0, 51.7, 55.3, 124.0, 126.2, 126.9, 128.0, 128.5, 128.9,136.6, 136.9, 137.9, 140.2, 146.7. MS-EI: for C23H28BrN,calcd 398.4, found 398.3 m/z (M)+.
(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl) cyclohexylamine (9j)
Prepared as described for 9a; starting from 5 (106 mg,0.53 mmol), KBr (253 mg, 2.12 mmol), CAN (872 mg,1.59 mmol), cyclohexylamine (79 mg, 0.795 mmol), and
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K2CO3 (146 mg, 1.06 mmol) and after purification with silicagel column chromatography (hexane:ethyl acetate, 95:5) togive 9j (125 mg, 63 %) as yellow semisolid; IR (KBr): 3463,2922, 2850, 2360, 2327, 1641, 1458, 1376, 1177, 835 cm−1;1H NMR (CDCl3, 300 MHz) δ 11.29 (m, 4H), 1.34 (m, 4H),1.40 (s, 6H), 1.95 (m, 2H), 2.15–2.17 (m, 2H), 2.40 (s, 3H),2.52–2.54 (m, 3H), 3.76 (m, 2H), 7.11 (m, 1H), 7.22–7.31(m, 1H), 7.55–7.57 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ
21.7, 25.1, 26.3, 29.8, 32.1,33.1, 38.1, 38.4, 48.1, 52.5, 57.4,136.7, 124.4, 126.8, 127.0, 128.2, 137.0, 137.9, 146.7. MS-EI: for C21H30BrN, calcd 376.4, found 376.6 m/z (M)+.
(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)phenylamine (9k)
Prepared as described for 9a; starting from 5 (103 mg,0.515 mmol), KBr (245 mg, 2.062 mmol), CAN (847 mg,1.545 mmol), aniline (72 mg, 0.773 mmol), and K2CO3
(142 mg, 1.03 mmol) and after purification with silica gelcolumn chromatography (hexane, 100 %) to give 9k (125 mg,54 %) as yellowish brown semisolid; IR (KBr): 3466, 2945,2935, 2351, 2293, 1645, 1434, 1310, 1145, 821 cm−1; 1HNMR (CDCl3, 300 MHz) δ 1.33 (s, 6H), 2.09–2.12 (m, 2H),2.37 (s, 3H), 2.52 (m, 2H), 4.28 (s, 2H), 6.67–6.70 (m, 2H),6.75 (m, 1H), 7.05–7.11 (m, 2H), 7.17–7.20 (m, 1H), 7.22–7.24 (m, 1H), 7.30–7.32 (m, 1H); 13C NMR (CDCl3, 75MHz) δ 21.6, 32.1, 38.1, 38.4, 48.0, 50.0, 113.8, 116.2, 124.9,127.1, 128.0, 129.4, 135.6, 136.5, 137.4, 145.3, 147.1. ESI-MS m/z: 370.3. MS-EI: for C21H24BrN, calcd 370.3, found370.3 m/z (M)+.
(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-p-tolyl-amine (9l)
Prepared as described for 9a; starting from 5 (100 mg,0.50 mmol), KBr (238 mg, 2.00 mmol), CAN (822 mg,1.5 mmol), p-toluidine (80 mg, 0.75 mmol), and K2CO3
(138 mg, 1.5 mmol) and after purification with silica gel col-umn chromatography (hexane, 100 %) to give 9l (100 mg,52 %) as light yellow semisolid; IR (KBr): 3468, 2955, 2920,2360, 2299, 1678, 1447, 1313, 1126, 795 cm−1; 1H NMR(CDCl3, 300 MHz) δ 1.33 (s, 6H), 2.12 (t, J = 6.48, 7.22 Hz,2H), 2.24 (s, 3H), 2.36 (s, 3H), 2.50 (t, J = 6.47, 7.18 Hz,2H), 4.21 (s, 2H), 6.57 (d, J = 8.27 Hz, 2H), 6.95–7.05(m, 3H), 7.22 (s, 1H), 7.30–7.33 (d, J = 7.82 Hz, 1H); 13CNMR (CDCl3, 75 MHz) δ 21.8, 20.6, 32.2, 38.1, 38.4, 48.0,50.2, 113.5, 124.6, 127.0, 128.0, 29.8, 135.8, 136.9, 137.3,146.1, 147.1. MS-EI: for C22H26BrN, calcd 384.4, found384.5 m/z (M)+.
C-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-methylamine (9m)
Prepared as described for 9a; starting from 5 (101 mg,0.505 mmol), KBr (241 mg, 2.02 mmol), CAN (831 mg,1.515 mmol), ammonia (13 mg, 0.758 mmol), and K2CO3
(139 mg, 1.01 mmol) and after purification with silica gelcolumn chromatography (hexane:ethyl acetate, 98:2) to give9m (74 mg, 50 %) as light brown semisolid; IR (KBr): 3451,2962, 2924, 2850, 2358, 1610, 1461, 1369, 1091, 821 cm−1;1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 6H), 2.05–2.10 (m,2H), 2.35 (s, 3H), 2.43–2.47 (m, 2H), 3.71 (s, 2H), 7.02–7.05(m, 1H), 7.15–7.17 (s, 1H), 7.46–7.48 (m, 1H); 13C NMR(CDCl3, 75 MHz) δ 21.7, 32.2, 38.0, 39.3, 48.0, 60.5, 126.7,126.8, 127.8, 128.3, 135.8, 136.8, 136.9, 146.6. MS-EI: forC15H20BrN, calcd 294.2, found 294.2 m/z (M)+.
Computational study
Physicochemical prediction
For the prediction of physicochemical properties, Lipinskirule of five was performed using molinspiration online pro-gram (http://www.molinspiration.com/). “Lipinski Rule ofFive” is a rule of thumb to evaluate drug likeness or deter-mine if a chemical compound with a certain pharmacologi-cal or biological activity has properties that would make it alikely bioavailable to show activity of drug inhumans.
Pharmacodynamic prediction
The given basic moieties in the mol file format weresubjected to PASS program (version 10.1). This softwareestimates the predicted activity spectrum of a compound asprobable activity (Pa) and probable inactivity (Pi). Predic-tion of this spectrum by PASS is based on structure activityrelationship analysis of the training set containing more than205,000 compounds exhibiting approximately 3,750 kinds ofbiological activities. Being probabilities, the Pa and Pi val-ues vary from 0.000 to 1.000 and, in general, Pa + Pi �= 1,since these probabilities are calculated independently. ThePASS prediction results were interpreted and used in a flex-ible manner: (i) only activities with Pa > Pi are consid-ered as possible for a particular compound; (ii) if Pa > 0.7,the chance to find the activity experimentally is high; (iii) if0.5 < Pa < 0.7, the chance to find the activity experimen-tally is less, but the compound is probably not so similar toknown pharmaceutical agents; (iv) if Pa < 0.5, the chanceto find the activity experimentally is less, but the chance tofind a structurally new compound, i.e., NCEs (new chemicalentity) is more [35,36].
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Pharmacological studies
Experimental animals
The studies were carried out on Swiss Albino mice of eithersex and were obtained from the breeder (Chaudhary Cha-ran Singh Haryana Agricultural University, Hissar, Haryana,India). Swiss Albino mice weighing (22–28 g) were housedin groups of 6 mice/cage in standard cages at room tempera-ture (22 ± 2◦ C), under natural light/dark cycle and had freeaccess to water and food (standard laboratory pellets) beforethe experiments. The mice were acclimatized at lab condi-tions for 5 days before the start of experiment. Each experi-mental group consisted of ten animals. All the experimentalwork had been carried out from 9:00 to 16:00 h. The exper-imental protocol was duly approved by Institutional AnimalEthics Committee (IAEC) and care of the animals was car-ried out as per the guidelines of Committee for the Purpose ofControl and Supervision of Experiments on Animals (CPC-SEA), Ministry of Environment and Forest, Government ofIndia, vide Proposal No. 107/99/CPCSEA-2010-39.
Experimental protocol
Mice, of either sex, were divided into 14 groups (n = 5).For the evaluation of antidepressant activity, the animalswere suspended on tail suspension apparatus after 30 minof various pharmacological interventions. Group I vehiclecontrol group received vehicle treatment (10 % DMSO, i.p.,10 mL/kg), group II received standard drug treatment (Flu-oxetine 20 mg/kg, dissolved in water, i.p.), group III, IV, andV received 9a (5, 10, and 20 mg/kg; i.p.), group VI, VII, andVIII received 9b (5, 10, and 20 mg/kg; i.p.), group IX, X,and XI received 9c (5, 10, and 20 mg/kg; i.p.), and groupXII, XIII, and XIV received 9d (5, 10, and 20 mg/kg; i.p.)treatments, respectively.
Preparation of test samples and dose determination
Doses of the selected compounds were selected on the molec-ular weight basis in comparison with the standard drug (flu-oxetine) and three doses (5, 10, and 20 mg/kg) of theselected sample were tested in order to have dose response.The samples were dissolved in DMSO:H2O (1:9 v/v) andwere injected intraperitoneally (injection volume 10 mL/kg).
Tail suspension test
The method is based on the observations that a mouse sus-pended by the tail shows alternate period starting from agita-tion and immobility. The total duration of immobility inducedby tail suspension was measured according to the method
described earlier [32] with little modification. Mice were sus-pended 50 cm above the floor, via thread connected throughgallows. One end of the thread was tied with the tip oftail of the animal and other end of the thread was attachedto a kymograph for the proper determination of immobil-ity time (in seconds). Immobility time was recorded during6 min period. Animal was considered to be immobile whenit did not show any movement of body and appears to behanged passively. Animals in different treatment groups wereinjected with varying doses of test drugs/vehicle prior to30 min of behavioral assessment in tail suspension test.Immobility time in treatment groups was compared with thatof vehicle control group.
Statistical analysis
Statistical analysis was carried out using Sigma Stat Sta-tistical Software (version 3.5). Results were expressed asmean ± SEM. The significance of antidepressant effect wasdetermined using one way ANOVA (analysis of variance)followed by Tukey’s test. The results were regarded as sig-nificant at p < 0.05.
Acknowledgments Authors are thankful to the Director, CSIR-Institute of Himalayan Bioresource Technology for providing requiredfacilities and financial support. Authors (A.C. and P.K.) acknowledgeCSIR, Delhi for the awards of SRF. The authors are grateful toEr. Kiran Babu (CSIR-Institute of Himalayan Bioresource Technology)for providing himachalenes mixture from Cedarwood oil.
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