Y. S. R. Reddy1*, MD. Afzal Azam, J. T. Leonard, B. Suresh and I. E. Chakravarthy2

J. S. S. College of Pharmacy, Rockland’s, Ootacamund-643 001
1G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad–500 028
2Department of Chemistry, S. K. U. P. G. Center, Kurnool-518 002, India.

*Corresponding Author:
Y. S. R. Reddy
G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad–500 028
Date of Submission 14 July 2005
Date of Revision 7 April 2006
Date of Acceptance 7 February 2007
Indian J Pharm Sci 2007, 69 (1): 112-114  

DOI: 10.4103/0250-474X.32120

Abstract

Starting chloropropane derivative (2) was prepared by the reaction of 2-methyl-8-hydroxyquinoline (1) with 1- bromo-3-chloropropane in presence of a base. Various new 1-(2-methyl-8-quinolyloxy)-3-propylamines (3a-3j) have been synthesized by the condensation of 1-(2-methyl-8-quinolyloxy)-3-chloropropane (2) with different amines. Compounds were screened for the possible central nervous system depressant activities. Some of them showed moderate central nervous system depressant activity.

Quinoline ring associated with various pharmacological activities [1]. An 8-substituted quinoline is a versatile lead molecule for designing potential bioactive agents. Due to the potent central nervous system depressant and hypotensive activities [2-4] exhibited by various aminopropanes, it was felt appropriate to synthesize 1-(2-methyl-8-quinolyloxy)-3-substitutedaminopropanes to evaluate their possible central nervous system depressant activities.

The required 1-(2-methyl-8-quinolyloxy)-3-chloropropane (2) was synthesized by condensation of 2-methyl-8-hydroxyquinoline (1) with 1-bromo-3-chloropropane in presence of anhydrous potassium carbonate and dry acetone. Condensation of compounds (2) with various amines yielded the title compounds 1-(2-methyl-8-quinolyloxy)-3-substituted-aminopropanes (3a-3j) as shown in Scheme 1.

Figure

Scheme 1: Synthesis of 2-methyl-8-quinolyloxypropylamines X=CH3, H; NRR’= morpholino, piperidino, 2-methyl piperidino, N-methyl piperazino, N-benzylpiperazino, anilino, 4-bromoanilino, 4-nitroanilino, 4-aminoanilino, N,N-diphenylamino

Melting points were determined in open capillaries and were uncorrected. The structures of these compounds were assigned on the basis of elemental analysis and spectral data. An IR spectrum was recorded on a Perkin-Elmer Infracord spectrophotometer and PMR on Varian EM-390 spectrophotometer in DMSO-d6 using TMS as internal reference. The mass spectra were recorded on Jeol 300 at 70 ev. All the compounds gave quite comparable C, H, N elemental analysis with their structures. Purity of the synthesized compounds checked on TLC using silica gel G as an adsorbent with suitable solvent system. The institutional animal ethics committee (IAEC) approved the animal experimentation protocols.

The required 1-(2-Methyl-8-quinolyloxy)-3-chloropropane (2) prepared from a mixture of 2-methyl-8-hydroxyquinoline (20.67 g, 0.13 mol), 1-bromo-3-chloro-propane (26.32 g, 0.167 mol) and anhydrous potassium carbonate (26 g, 0.195 mol) was refluxed in dry acetone (420 ml) for 40h, filtered and the solvent was removed under reduced pressure. The residue was recrystallized from ether. Yield: 23.57 g, 77%; mp: 84°; IR(KBr)cm-1: 2960 (C-C), 1610 (C=N), 1565-1590 (C=C) , 1220 (C-O) and 694 (C-Cl); 1H NMR (CDCl3) δ ppm: 1.84 (q, 2H, CH3H, CH3 ), 2.62 (m, 2H, CH2-Cl), 3.79 (m, 2H, OCH2), 7.14-7.41 (br m, 5H, Ar-H ); EI-MS (m/z): 236.103(M+) . The compound, 1-(2-methyl-8-quinolyloxy)-3-(1-morpholino) propane (3a) prepared from a mixture of 2a (2.35 g, 0.010 mol), morpholine (1.044 g, 0.012 mol), anhydrous sodium carbonate (7.42 g, 0.07 mol) and sodium iodide (0.44 g, 0.00 34 mol) was refluxed in dry acetone (40 ml) for 70 h. The reaction mixture was filtered and the filtrate on concentration gave oil, which was purified by column chromatography over silica gel using chloroform as an eluent. Yield: 68%; bp: 85°; IR (KBr) cm-1: 3412 (C-H), 1640 (C=N), 1542-1605 (C=C), 1261 (C-O); 1H NMR (CDCl3) δ ppm: 1.7 (q, 2H, CH2), 2.38 (s, 3H, CH3), 2.65 (t, 4H, CH2NCH2) , 3.52 (t, 2H, OCH2) 3.73 (t, 4H, CH2OCH2), 7.23 (m, 5H, Ar-H); EI-MS (m/z): 286.24 (M+). Similarly other compounds 3b-3j were prepared (Table 1).

Compound X Y NRR1 Molecular formula Yield (%) mp°
2 CH3 H - C13H14NOCl 77 84a
3a CH3 H morpholino C17H22N2O2 68 85b
3b CH3 H N-methylpiperazino C18H25N3O 45 54b
3c CH3 H N-benzylpiperazino C24H29N3O 55 53b
3d CH3 H piperidino C18H24N2O 63 oil
3e CH3 H 2-methylpiperidino C19H26N2O 59 60c
3f CH3 H anilino C19H20N2O 54 oil
3g CH3 H p-nitroanilino C19H19N3O3 74 123d
3h CH3 H p-aminoanilino C19H21N3O 59 235b
3i CH3 H p-bromoanilino C19H19N2OBr 73 135b
3j CH3 H N, N-diphenylamino C25H24N2O 50 oil

Table 1: Physical Data Of The Compounds

The antagonism of pentylenetetrazole-induced convulsions was carried out according to the method suggested by Barnes et al [5]. Adult albino mice of either sex weighing between 25-30 g were divided into seven groups of six mice each. Compounds 3a, 3b, 3c, 3e and 3g were given orally as a fine suspension of 0.5% w/v carboxymethylcellulose, 30 min before the administration of pentylenetetrazole at a dose of 0.2 LD50 for 2 to 6 groups and pentylenetetrazole (60 mg/kg) to the group 1. The time of onset of action and the time of death/recovery was noted. Diazepam (5 mg/kg) was used as a standard anticonvulsant drug and the results are recorded in Table 2.

Compound Onset of
Convulsions (min) 		Death (min) Recovery
Pentylenetetrazole 1.30 9.15 -
3a 10.42 ± 0.55* - All alive
3b 4.71 ± 0.34 15.5 -
3e 14.44 ± 0.29* - All alive
3g 17.44 ± 0.25* - All alive
Diazepam No convulsions - All alive

Table 2: Antagonism Of Pentylenetetrazole-Induced Convulsions

Antagonism of nikethamide-induced hyperactivity in an actophotometer was carried out according to the method of Piala et al [6]. Adult albino mice weighing 25-30 g were taken for this study and were divided into seven groups of six mice each. The compounds 3a, 3b, 3c, 3e and 3g were given orally at a dose of 0.2×LD50 mg/kg. After half an hour, nikethamide was given 10 mg/kg ip. Motor activity was measured for 15 min after 5 min of injection of the stimulant. Diazepam (5 mg/kg) was used as a standard drug and the results are recorded in Table 3.

Compounds  No. of movements observed (15 min) % reduction in hyperactivity
Nikethamide 48.23 -
3a 22.81 ± 1.13 50.00
3b 20.84 ± 0.88* 56.25
3c 22.46 ± 1.05 52.08
3e 21.27 ± 0.88* 56.42
3g 31.65 ± 0.89 35.42
Diazepam 14.88 ± 0.99* 68.72

Table 3: Antagonism of nikethamide-induced Hyperactivity

A newly synthesized five compounds were screened for biological activities. LD50 values and gross behavioral study of compounds 3a, 3b, 3c, 3e and 3g were studied by the method of Turner [7]. In general, the entire test compounds shown significant depressant action at a dose of 0.2 LD50 level. Compounds 3a, 3e and 3g have maximally increased the onset of pentylenetetrazole induced convulsions and also have protected the animals from death. Compounds 3b and 3c have moderate anticonvulsant activity (Table 2). Compounds 3a, 3b, 3c and 3e have significantly reduced nikethamide-induce hyperactivity to 50%, while compound 3g shown moderate reduction (Table 3). For anticonvulsant activity, piperazinyl group (3b and 3c) at 3-position of propane is not essential because p-nitroaniline derivative (3g) showed maximum activity. Compounds bearing substituted piperazinyl and piperidinyl groups at 3-position on propane exhibited maximum CNS depressant activity. In general all these compounds were found to be less active than diazepam.

Acknowledgements

Authors wish to place their regards to His Holiness Jagadguru Sri Sri Sri Shivarathri Deshikendra Mahaswamigalavaru of Sri Suttur Mutt, Mysore for providing facilities.

References