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Synthesis and Biological Evaluation of Novel Substituted-Imidazolidine Derivatives
Synthesis and Biological Evaluation of Novel Substituted-Imidazolidine Derivatives
Journal of the Korean Chemical Society. 2013. Apr, 57(2): 227-233
Copyright © 2013, Korea Chemical Society
  • Received : November 27, 2012
  • Accepted : March 05, 2013
  • Published : April 20, 2013
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About the Authors
Asif Husain
Rubina Bhutani
Deepak Kumar
Department of Chemistry, Changwon National University, Changwon 641-773, Korea.
Dong-Soo Shin
Department of Chemistry, Changwon National University, Changwon 641-773, Korea.

Abstract
A series of newer substituted-imidazolidine derivatives 3a-k were synthesized and assayed in vivo to investigate their anti-inflammatory, analgesic and antiulcer activity. The results of biological evaluation revealed that the three compounds, 4-[1,3-bis(4-hydroxy-3-methoxybenzyl)-2-imidazolidinyl]phenyldiethylamine ( 3g ), 4-[1,3-bis(3-Ethoxy-4-hydroxybenzyl)-2-imidazolidinyl] phenyldiethylamine ( 3h ) and 4-(1,3-bis(benzo[d][1,3]dioxol-5-ylmethyl)-4-methylimidazolidin-2-yl)- N,N -diethylbenzenamine ( 3j ) were good in their anti-inflammatory and analgesic actions. Additionally these derivatives showed superior GI safety profile as compared to that of the standard drug in terms of low severity index. The results are statistically treated for its significance.
Keywords
INTRODUCTION
Non steroidal anti-inflammatory drugs (NSAIDs) are used for the treatment of inflammatory conditions and pain by blocking the metabolism of arachidonic acid through the inhibition of cyclooxygenase enzyme (COX-1 and COX- 2) and thereby production of prostaglandins. 1 Commonly used NSAIDs show greater selectivity for COX-1 which provides cytoprotection in the gastrointestinal (GI) tract than COX-2 which mediates inflammation. Hence, they are associated with GI side effects like gastric irritation, ulceration and bleeding. 2 Highly selective COX-2 inhibitors have been developed and marketed as promising gastroprotective agents. 3 Later on, some potential limitations of long term COX-2 inhibitor therapy include ulcer exacerbation in high-risk patients, delayed gastroduodenal ulcer healing, thrombosis due to prostacyclin deficiency and kidney toxicity. 4 , 5 Thus COX-2 inhibitors have not eliminated the need for improved/safer drugs in the NSAIDs area.
Imidazolidines, a saturated imidazole (tetrahydroimidazole), have been reported to have important biological activities including potential α-adrenergic receptor agonist, 6 antimicrobial, antiparasitic, 7 , 8 oral hypoglycaemic, 9 antiarrhythmic, anticonvulsant, 10 , 11 anti-inflammatory and analgesic. 12 , 13 They have also been utilized as a versatile template for the synthesis of compounds with potential cyclooxygenase-2 inhibition activity. 14 Tetrahydroimidazoles have been termed as a promising group of NSAIDs with potential anti-inflammatory activities. 12 Literature survey revealed that not much work has been reported on biologically active tetrahydroimidazoles.
Since imidazolidine moiety seemed to be a possible pharmacophore in designing safer anti-inflammatory agents, 12 , 13 and in continuation of the work on the same nucleus. 15 In view of this we synthesize some new 4-[1,3−bis(substituted- benzyl)-2-imidazolidinyl]phenyl dialkylamines for their anti-inflammatory and analgesic actions. The compounds were also tested for their acute ulcerogenic activity.
MATERIALS AND METHODS
- Chemistry
All the chemicals were of synthetic grade and commercially procured from s.d Fine Chem. Ltd. Mumbai, India. Melting points were recorded on a Buchi capillary melting point apparatus and are uncorrected. The proton magnetic resonance spectra ( 1 H-NMR) were recorded on Bruker DPX-300 MHz in CDCl 3 using TMS as an internal standard. Mass spectra were recorded on LCMS/MS (Perkin–Elmer and LABINDIA, Applied Biosystem). Elemental analysis was performed for C, H and N using Perkin–lmer Model 240C. Dry solvents were used throughout. The protocol for the synthesis of title compounds is presented in 1 .
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Synthesis of N-substituted imidazolidine derivatives, 3a-k.
- General Procedure for Synthesis ofN1,N2-bis(substituted- benzylidene)ethane-1,2-diamines (1a−j).12,13,15
A mixture of an appropriate substituted aromatic aldehyde (0.005 mol), ethylenediamine/1,2-diaminopropane (0.006 mol) and dry benzene (15 mL) with a small quantity of molecular sieves (4Å) was refluxed azeotropically with Dean-Stark apparatus. After removal of water the reaction mixture was refluxed further for 6 h. After completion of the reaction, excess benzene was distilled off. A solid mass obtained which was recrystallised from methanol.
N1,N2-bis(4-Methylbenzylidene)ethane-1,2-diamine (1a): Yield 81%; m.p. 114–115 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 2.33 (s, 6H, CH 3 ), 3.84 (s, 4H, CH 2 ), 6.86 (d, 4H, H- 3,5, phenyl), 7.63 (d, 4H, H-2,6, phenyl), 8.18 (s, 2H, aldimine protons).
N1,N2-bis(3-Chlorobenzylidene)ethane-1,2-diamine (1b): Yield 61%; m.p. 103–105 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 3.96 (s, 4H, CH 2 ), 7.31 (dd, 2H, H-5), 7.48 (d, 2H, H-6), 7.53 (d, 2H, H-4), 7.74 (s, 2H, H-2), 8.26 (s, 2H, aldimine protons).
N1,N2-bis(4-Nitrobenzylidene)ethane-1,2-diamine (1c): Yield 74%; m.p. 134–135℃; 1 H-NMR (CDCl 3 ) δ ppm: 3.96 (s, 4H, CH 2 ), 7.88 (d, 4H, H-2,6), 8.23 (d, 4H, H-3,5), 8.16 (s, 2H, aldimine protons).
N1,N2-bis(4-Bromobenzylidene)ethane-1,2-diamine (1d): Yield 63%; m.p. 94–96 ℃; 1 H-NMR (CDCl 3 ) δ 3.99 (s, 4H, CH 2 ), 7.40 (d, 4H, H-2,6), 7.68 (d, 4H, H-3,5), 8.23 (s, 2H, aldimine protons).
N1,N2-bis(4-Fluorobenzylidene)ethane-1,2-diamine (1e): Yield 68%; m.p. 122–124 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 4.01 (s, 4H, CH 2 ), 6.98 (d, 4H, H-2,6), 7.36 (t, 4H, H-3,5), 8.27 (s, 2H, aldimine protons).
N1,N2-bis(4-Hydroxybenzylidene)ethane-1,2-diamine (1f): Yield 82%; m.p. 119–120℃; 1 H-NMR (CDCl 3 ) δ ppm: 3.90 (s, 4H, CH 2 ), 6.86 (d, 4H, H-3,5), 7.51 (d, 4H, H-2,6), 8.29 (s, 2H, aldimine protons), 10.32 (bs, 1H, OH).
N1,N2-bis(4-Hydroxy-3-Methoxybenzylidene)ethane- 1,2-diamine (1g): Yield 80%; m.p. 115–116 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 3.84 (s, 6H, OCH 3 ), 3.95 (s, 4H, CH 2 ), 6.84 (d, 2H, H-5), 7.12 (d, 2H, H-2x6), 7.45 (d, 2H, H-2), 8.16 (s, 2H, aldimine protons), 10.18 (bs, 1H, OH).
N1,N2-bis(4-Hydroxy-3-ethoxybenzylidene)ethane-1,2- diamine (1h): Yield 76%; m.p. 92–94℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.44 (t, 6H, CH 3 ), 3.95 (s, 4H, CH 2 ), 4.16 (q, 4H, OCH 2 ), 6.88 (d, 2H, H-5), 7.47 (d, 2H, H-6), 7.68 (s, 2H, H-2), 8.21 (s, 2H, aldimine protons), 9.83 (bs, 1H, OH).
N1,N2-bis(4-Diethylaminobenzylidene)ethane-1,2- diamine (1i): Yield 90%; m.p. 109–110 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.23 (t, 12H, N(CH 3 ) 2 ), 3.47 (q, 8H, N(CH 2 ) 2 ), 3.91 (s, 4H, 2xCH 2 ), 6.78 (d, 4H, H-3,5), 7.73 (d, 4H, 2xH-2,6), 8.25 (s, 2H, aldimine protons).
N1,N2-Bis(benzo[d][1,3]dioxol-5-ylmethyl)ethane-1,2- diamine (1j): Yield 86%; m.p. 85–86 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.33 (d, 3H, CH 3 ), 3.76 (bs, 3H, CH 2 +CH), 5.93 (s, 4H, OCH 2 O ), 6.87 (d, 2H, H-5), 6.95 (d, 2H, H- 6), 7.43 (dd, 2H, H-2), 8.05 & 8.15 (s, each, 2H, aldimine protons).
Reduction of N1,N2-bis(substituted-benzylidene)ethane- 1,2-diamines to get N1,N2-bis(substituted-benzyl)ethane- 1,2-diamines (2a–j). 12 , 13 , 15 The compound 1a–j (0.003 mol) was dissolved in a mixture of methanol (15 mL) and dichloromethane (10 mL). To this solution, a solution of sodium borohydride (0.013 mol) in sodium hydroxide solution (2N; 1 mL) was added dropwise with constant shaking and maintaining the temperature of the reaction mixture between 15–18 ℃ with stirring for 5 h. After completion of reaction, the solvent was distilled off and the residue diluted with water and extracted with ether. The organic layer was dried over sodium sulfate, filtered to remove inorganic salt and distilled off to get the desired compounds 2a–j .
N1,N2-bis(4-Methylbenzyl)ethane-1,2-diamine (2a): Pale yellow viscous oil; Yield 66%; 1 H-NMR (CDCl 3 ) δ ppm: ppm: 2.31 (s, 6H, 2xCH 3 ), 2.84 (s, 4H, CH 2 ), 3.68 (s, 4H, NCH 2 , benzyl), 6.83 (d, 4H, H-3,5), 7.55 (d, 4H, H- 2,6), 9.32 (bs, 2H, NH).
N1,N2-bis(3-Chlorobenzyl)ethane-1,2-diamine (2b): Yellow viscous oil; Yield 75%; 1 H-NMR (CDCl 3 ) δ ppm: 3.02 (s, 4H, CH 2 ), 3.74 (s, 4H, NCH 2 , benzyl), 7.71 (s, 2H, H-2), 7.53 (d, 2H, H-4), 7.31 (dd, 2H, H-5), 7.42 (d, 2H, H-6), 9.08 (bs, 2H, NH).
N1,N2-bis(4-Nitrobenzyl)ethane-1,2-diamine (2c): Light brown viscous oil; Yield 78%; 1 H-NMR (CDCl 3 ) δ ppm: 3.06 (s, 4H, CH 2 ), 3.88 (s, 4H, NCH 2 , benzyl), 8.16 (d, 4H, H-3,5), 7.81 (d, 4H, H-2,6), 9.41 (bs, 2H, NH).
N1,N2-bis(4-Bromobenzyl)ethane-1,2-diamine (2d): Dark yellow viscous oil; Yield: 70%; 1 H-NMR (CDCl 3 ) δ 2.87 (s, 4H, CH 2 ), 3.78 (s, 4H, NCH 2 , benzyl), 7.65 (d, 4H, H-3,5), 7.43 (d, 4H, H-2,6), 9.22 (bs, 2H, NH).
N1,N2-bis(4-Fluorobenzyl)ethane-1,2-diamine (2e): Pale yellow viscous oil; Yield 74%; 1 H-NMR (CDCl 3 ) δ ppm: 2.83 (s, 4H, CH 2 ), 3.79 (s, 4H, NCH 2 , benzyl), 7.32 (t, 4H, H-3,5), 6.95 (d, 4H, H-2,6), 9.14 (bs, 2H, NH).
N1,N2-bis(4-Hydroxybenzyl)ethane-1,2-diamine (2f): Pale yellow crystals; Yield 67%; m.p. 102–104℃; 1 H-NMR (CDCl 3 ) δ ppm: 2.81 (s, 4H, CH 2 ), 3.93 (s, 4H, NCH 2 , benzyl), 6.84 (d, 4H, H-3,5), 7.54 (d, 4H, H-2,6), 9.41 (bs, 2H, NH).
N1,N2-bis(4-Hydroxy-3-methoxybenzyl)ethane-1,2- diamine (2g): Yellow viscous oil; Yield 72%; 1 H-NMR (CDCl 3 ) δ ppm: 3.08 (s, 4H, CH 2 ), 3.82 (s, 6H, OCH 3 ), 3.96 (s, 4H, NCH 2 , benzyl), 6.88 (s, 2H, H-5), 7.16 (d, 2H, H-6), 7.78 (s, 2H, H-2), 9.04 (bs, 2H, 2xNH), 10.31 (s, 2H, 2xOH).
N1,N2-bis(4-Hydroxy-3-ethoxybenzyl)ethane-1,2-diamine (2h): Dark yellow viscous oil; Yield 65%; 1 H-NMR (CDCl 3 ) δ ppm: 1.46 (t, 6H, OCH 2 ), 3.03 (s, 4H, 2xCH 2 ), 3.91 (s, 4H, 2xNCH 2 , benzyl), 4.12 (q, 4H, OCH 3 ), 6.84 (d, 2H, H-5), 7.45 (d, 2H, 2H-6), 7.63 (s, 2H, H-2), 9.08 (bs, 2H, NH), 10.18 (s, 2H, OH).
N1,N2-bis(4-Diethylaminobenzyl)ethane-1,2-diamine (2i): Red viscous oil; Yield 68%; m.p. 102–104 ℃; 1 HNMR (CDCl 3 ) δ ppm: 3.07 (s, 4H, CH 2 ), 3.83 (s, 4H, NCH 2 , benzyl), 6.84 (d, 4H, H-3,5), 7.54 (d, 4H, H-2,6), 9.41 (bs, 2H, NH).
N1,N2-Bis(benzo[d][1,3]dioxol-5-ylmethylene)ethane- 1,2-diamine (2j): Dark yellow viscous oil; Yield 82%; 1 H-NMR (CDCl 3 ) δ 1.31 (d, 3H, CH 3 ), 3.73 (bs, 3H, CH 2 +CH), 3.88 (s, 4H, NCH 2 , benzyl), 5.95 (s, 4H, OCH 2 O ), 6.86 (d, 2H, H-5), 7.05 (dd, 2H, H-6), 7.53 (d, 2H, H-2), 10.05 (bs, 2H, NH).
- General Procedure for Synthesis of Substituted-imidazolidine Derivatives (3a–k).12,13,15
The compound 2a–j (2 mmol) was dissolved in absolute ethanol (15 mL) and to it was added p-diethyl/dimethylaminobenzaldehyde (in equimolar ratio). The reaction mixture was shaken for 5 h on a mechanical shaker and then left in a refrigerator for overnight. The reaction mixture was concentrated to half of its volume and was poured into ice cold water which gave a solid mass. It was filtered and recrystallized from methanol to get the compounds 3a–k .
4-[1,3-Bis (4-methylbenzyl)-2-imidazolidinyl]phenyldiethylamine (3a):
Yield: 70%; m.p. 100–102 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.13 (t, 6H, CH 3 ), 2.02 (s, 6H, CH 3 ), 3.29 (q, 4H, CH 2 ), 2.38 & 3.09 (m, each, CH 2 , imidazole ring), 3.13 & 3.74 (d, each, 4H, CH 2 , benzyl), 3.66 (s, 1H, CH, imidazole ring), 6.66 (d, 2H, H-3,5, p -diethylamino ring), 6.90 (d, 4H, H-3,5, p -tolyl),7.21 (d, 4H, H-2,6, p -tolyl), 7.39 (d, 2H, H-2,6, p -diethylamino ring); 13 C-NMR (CDCl 3 ) δ ppm: 14.68 [N(CH 3 ) 2 ], 22.40 (CH 3 ), 40.84 [N(CH 2 CH 3 ) 2 ], 50.27 (C-4/5), 56.28 (C-6/6 ' ), 88.65 (C-2), 112.15 (C-9/9 ' /11/ 11 ' ), 112.23 (C-3 '' /5 '' ), 127.07 (C-7/7 ' ), 127.88 (C-1 '' ), 129.46 (C-8/8 ' /12/12 ' ), 130.26 (C-2 '' /6 '' ), 141.91 (C-10/ 10 ' ), 149.64 (C-4 '' ); MS: m/z 427 (M + ); Anal. calcd. for C 29 H 37 N 3 : C, 81.45; H, 8.72; N, 9.83. Found: C, 81.20; H, 8.86; N, 9.69.
4-[1,3-Bis(3-chlorobenzyl)-2-imidazolidinyl]phenyldiethylamine (3b):
Yield 58%; m.p. 148–150 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.17 (t, 6H, CH 3 ), 2.45 & 3.17 (m, each, 4H, CH 2 , imidazole ring), 3.16 & 3.81 (d, each, 4H, CH 2 , benzyl), 3.31 (q, 4H, CH 2 ), 3.64 (s, 1H, CH, imidazole ring), 6.78 (d, 2H, H- 3,5, p -diethylamino ring), 7.08–7.24 (m, 8H, m -chlorophenyl), 7.26 (d, 2H, H-2,6, p -diethylamino ring); 13 C-NMR (CDCl 3 ) δ ppm: 14.52 [N(CH 3 ) 2 ], 40.49 [N(CH 2 ) 2 ], 50.25 (C-4/5), 56.21 (C-6/6 ' ), 88.67 (C-2), 112.12 (C-3 '' /5 '' ), 112.93 (C-8/8 ' ), 126.58 (C-12/12 ' ), 126.86 (C-7/7 ' ), 127.20 (C-1 '' ), 128.58 (C-9/9 ' ), 129.07 (C-11/11 ' ), 130.18 (C-2 '' / 6 '' ), 130.42 (C-10/10 ' ), 150.93 (C-4 '' ); Ms (m/z): 467 (M + ), 469, 471; Anal. calcd. for C 27 H 31 Cl 2 N 3 : C, 69.23; H, 6.67; N, 8.97. Found: C, 68.85; H, 7.58; N, 8.86.
4-[1,3-Bis(4-nitrobenzyl)-2-imidazolidinyl]phenyldiethylamine (3c):
Yield 53%; m.p. 168–170 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.15 (t, 6H, CH 3 ), 2.39 & 3.14 (m, each, 4H, CH 2 , imidazole ring), 3.33 (q, 4H, CH 2 ), 3.67 (s, 1H, CH, imidazole ring), 3.74 (m, 4H, CH 2 , benzyl), 6.68 (d, 2H, H-3,5, p -diethylamino ring), 7.01–7.40 (m, 8H, p -nitrophenyl), 7.42 (d, 2H, H-2,6, p -diethylamino ring); 13 C-NMR (CDCl 3 ) δ ppm: 14.49 [N(CH 3 ) 2 ], 40.56 [N(CH 2 ) 2 ], 50.24 (C-4/5), 56.26 (C-6/6 ' ), 88.62 (C-2), 112.20 (C-3 '' /5 '' ), 112.53 (C- 9/9 ' /11/11 ' ), 127.54 (C-7/7 ' ), 127.89 (C-1 '' ), 129.51 (C-8/ 8 ' /12/12 ' ), 130.26 (C-2 '' /6 '' ), 147.78 (C-10/10 ' ), 150.07 (C-4 '' ); Ms (m/z): 489 (M + ), 490, 491; Anal. calcd. for C 27 H 31 N 5 O 4 : C, 66.24; H, 6.38; N, 14.31. Found: C, 66.33; H, 6.16; N, 14.35.
4-[1,3-Bis(4-bromobenzyl)-2-imidazolidinyl]phenyldiethylamine (3d):
Yield 71%; m.p. 135–138 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.12 (t, 6H, CH 3 ), 2.42 & 3.16 (m, each, 4H, CH 2 , imidazole ring), 3.18 & 3.62 (d, each, 4H, CH2, benzyl), 3.31 (q, 4H, CH 2 ), 3.68 (s, 1H, CH, imidazole ring), 7.01–7.93 (m, 12H, Ar H); 13 C-NMR (CDCl 3 ) δ ppm: 14.57 [N(CH 3 ) 2 ], 40.78 [N(CH 2 ) 2 ], 50.53 (C-4/5), 56.29 (C-6/6 ' ), 88.02 (C- 2), 111.85 (C-9/9 ' /11/11 ' ), 112.08 (C-3 '' /5 '' ), 126.93 (C-7/ 7 ' ), 127.14 (C-1 '' ), 129.86 (C-2 '' /6 '' ), 130.78 (C-8/8 ' /12/ 12 ' ), 146.02 (C-10/10 ' ), 149.72 (C-4 '' ); Ms (m/z): 557 (M + , not observed); Anal. calcd. for C 27 H 31 Br 2 N 3 : C, 58.18; H, 5.61; N, 7.54. Found: C, 57.92; H, 5.65; N, 7.63.
4-[1,3-Bis(4-fluorobenzyl)-2-imidazolidinyl]phenyldiethylamine (3e):
Yield 56%; m.p. 143–145 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.15 (t, 6H, CH 3 ), 2.40 & 3.14 (m, 4H, CH 2 , imidazole ring), 3.19 & 3.78 (d, each, 4H, CH 2 , benzyl), 3.34 (q, 4H, CH 2 ), 3.64 (s, 1H, CH, imidazole ring), 6.87 (d, 2H, H- 3,5, p -diethylamino ring), 6.98–7.41 (m, 8H, p -fluorophenyl), 7.53 (d, 2H, H-3,5, p -diethylamino ring); 13 C-NMR (CDCl 3 ) δ ppm: 14.13 [N(CH 2 ) 2 ], 40.90 [N(CH 2 ) 2 ], 50.11 (C-4/5), 56.06 (C-6/6 ' ), 88.16 (C-2), 112.03 (C-9/9 ' /11/ 11 ' ), 112.57 (C-3 '' /5 '' ), 126.85 (C-1 '' ), 127.34 (C-7/7 ' ), 129.27 (C-2 '' /6 '' ), 130.26 (C-8/8 ' /12/12 ' ), 143.95 (C-10/ 10 ' ), 150.13 (C-4 '' ); Ms (m/z): 435(M + ), 436, 437; Anal. calcd. for C 27 H 31 F 2 N 3 : C, 74.46; H, 7.17; N, 9.65. Found: C, 74.28; H, 7.12; N, 9.71.
4-[1,3-Bis(4-hydroxybenzyl)-2-imidazolidinyl]phenyldiethylamine (3f):
Yield 68%; m.p. 136–138 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.13 (t, 6H, CH 3 ), 2.56 & 3.33 (m, each, 4H, CH 2 , imidazole ring), 3.21 & 4.01 (m, each, 4H, CH 2 , benzyl), 3.31 (q, 4H, CH 2 ), 3.63 (s, 1H, CH, imidazole ring), 6.63–7.37 (m, 12H, Ar H); 13 C-NMR (CDCl 3 ) δ ppm: 14.18 [N(CH 3 ) 2 ], 40.25 [N(CH 2 ) 2 ], 50.24 (C-4/5), 56.17 (C-6/6 ' ), 88.31 (C- 2), 112.34 (C-9/9 ' /11/11 ' ), 113.05 (C-3 '' /5 '' ), 127.01 (C- 1 '' ), 127.32 (C-7/7 ' ), 129.48 (C-8/8 ' /12/12 ' ), 130.58 (C-2 '' / 6 '' ), 149.68 (C-4 '' ), 157.71 (C-10/10 ' ); Ms (m/z): 431 (M + ); Anal. calcd. for C 27 H 33 N 3 O 2 : C, 75.14; H, 7.71; N, 9.74. Found: C, 74.88; H, 7.25; N, 9.80.
4-[1,3-Bis(4-hydroxy-3-methoxybenzyl)-2-imidazolidinyl] phenyldiethylamine (3g): Yield 65%; m.p. 133– 135 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.16 (t, 6H, 2xCH 3 ), 2.38 & 3.14 (m, each, 4H, CH 2 , imidazole ring), 3.07 & 3.76 (d, each, 4H, CH 2 , benzyl), 3.33 (q, 4H, CH 2 ), 3.72 (s, 6H, OCH 3 ), 3.63 (s, 1H, CH, imidazole ring), 6.67–7.39 (m, 10H, Ar H); 13 C-NMR (CDCl 3 ) δ ppm: 14.37 [N(CH 3 ) 2 ], 40.49 [N(CH 2 ) 2 ], 50.12 (C-4/5), 55.92 (OCH 3 ), 56.12 (C- 6/6 ' ), 88.68 (C-2), 111.07 (C-3 '' /5 '' ), 112.16 (C-8/8 ' ), 112.54 (C-11/11 ' ), 119.98 (C-12/12 ' ), 127.24 (C-1 '' ), 130.19 (C- 2 '' /6 '' ), 131.87 (C-7/7 ' ), 147.64 (C-9/9 ' ), 150.63 (C-4 '' ), 158.48 (C-10/10 ' ); Ms (m/z): 491 (M + ); Anal. calcd. for C 29 H 37 N 3 O 4 : C, 70.85; H, 7.59; N, 8.55. Found: C, 70.55; H, 7.72; N, 8.41.
4-[1,3-Bis(3-ethoxy-4-hydroxybenzyl)-2-imidazolidinyl] phenyldiethylamine (3h):
Yield: 53%; m.p. 121–123 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.14 (t, 6H, 2xCH 3 CH 2 ), 1.46 (t, 6H, OCH 3 ), 2.40 & 3.19 (m, each, 4H, CH 2 , imidazole ring), 3.12 & 3.77 (d, each, 4H, CH 2 , benzyl), 3.31 (q, 4H, CH 2 ), 3.68 (s, 1H, CH, imidazole ring), 4.14 (m, 4H, OCH 2 ), 6.63–7.43 (m, 10H, Ar H); 13 C-NMR (CDCl 3 ) δ 14.29 [N(CH 3 ) 2 ], 40.14 [N(CH 2 ) 2 ], 50.11 (C-4/5), 56.26 (C-6/6 ' ), 56.37 (OC 2 H 5 ), 88.47 (C- 2), 111.12 (C-3 '' /5 '' ), 112.53 (C-11/11 ' ), 112.91 (C-8/8 ' ), 119.82 (C-12/12 ' ), 127.28 (C-1 '' ), 130.06 (C-2 '' /6 '' ), 131.75 (C-7/7 ' ), 148.23 (C-9/9 ' ), 149.97 (C-4 '' ), 158.71 (C-10/10 ' ); Ms (m/z): 519 (M + ); Anal. calcd. for C 31 H 41 N 3 O 4 : C, 71.65; H, 7.95; N, 8.09. Found: C, 71.78; H, 7.69; N, 8.26.
4-[1,3-Bis (4-diethylamino-benzyl)-2-imidazolidinyl] phenyldiethylamine (3i):
Yield 72%; m.p. 125–127 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 1.16 (m, 18H, CH 3 ), 2.48–3.71 (m, 9H, CH 2 benzyl, CH 2 and CH of imidazole ring), 3.35 (m, 12H, CH 2 ), 6.63–7.44 (m, 12H, Ar H); 13 C-NMR (CDCl 3 ) δ 14.85 [N(CH 3 ) 2 ], 40.88 [N(CH 2 ) 2 ], 50.24 (C-4/5), 56.24 (C-6/6 ' ), 88.48 (C- 2), 112.21 (C-3 '' /5 '' ), 112.34 (C-9/9 ' /11/11 ' ), 127.46 (C-7/ 7 ' ), 127.86 (C-1 '' ), 129.52 (C-8/8 ' /12/12 ' ), 130.23 (C-2 '' / 6 '' ), 149.53 (C-4 '' ), 150.06 (C-10/10 ' ); Ms (m/z): 541 (M + ); Anal. calcd. for C 35 H 51 N 5 : C, 77.59; H, 9.49; N, 12.93. Found: C, 77.35; H, 9.56; N, 12.68.
4-(1,3-Bis(benzo[d][1,3]dioxol-5-ylmethyl)-4-methylimidazolidin- 2-yl)-N,N-diethylbenzenamine (3j):
Yield: 60%; m.p. 106–108 C; 1 H-NMR (CDCl 3 ) δ ppm: 0.96 (d, 3H, CH 3 ), 1.12 (t, 6H, CH 3 ), 2.48 (m, 2H, CH 2 , imidazole ring), 2.89 (m, 1H, CH of imidazole ring carrying methyl group), 3.31 (q, 4H, CH 2 ), 3.03 & 3.73 (d, 4H, CH 2 , benzyl), 3.82 (s, 1H, CH, imidazole ring), 5.86 (s, 4H, OCH 2 O), 6.57–6.69 (m, 6H, piperanyl rings), 6.83 & 7.41 (d, each, 4H, 2xA 2 B 2 , p -dethylamino phenyl ring); 13 C-NMR (CDCl 3 ) δ ppm: 14.68 [N(CH 2 ) 2 ], 22.51 (CH 3 ), 40.83 [N(CH 2 ) 2 ], 55.53 (C-6 ' ), 56.25 (C-6), 57.47 (C-4), 58.09 (C-5), 89.96 (C-2),101.08 (–O–CH 2 –O–), 106.87 (C-8/8 ' ), 109.15 (C-11/11 ' ), 113.03 (C-3 '' /5 '' ), 121.27 (C- 7/7 ' ), 121.40 (C-12/12 ' ), 127.49 (C-1 '' ), 130.22 (C-2 '' /6 '' ), 145.62 (C-9/9 ' ), 147.08 (C-10/10 ' ), 149.64 (C-4 '' ); Ms (m/ z): 501 (M + ); Anal. calcd. for C 30 H 35 N 3 O 4 : C, 71.83; H, 7.03; N, 8.38. Found: C, 71.75; H, 6.86; N, 8.71.
4-(1,3-Bis(benzo[d][1,3]dioxol-5-ylmethyl)-4-methylimidazolidin- 2-yl)-N,N-dimethylbenzenamine (3k):
Yield: 67%; m.p. 74–76 ℃; 1 H-NMR (CDCl 3 ) δ ppm: 0.92 (d, 3H, CH 3 ), 2.52 (m, 2H, CH 2 , imidazole ring), 2.85 (m, 1H, CH of imidazole ring carrying methyl group), 2.95 (s, 6H, CH 3 ), 3.06 & 3.67 (d, 4H, CH 2 , benzyl), 3.77 (s, 1H, CH, imidazole ring), 5.91 (s, 4H, OCH 2 O), 6.63– 6.71 (m, 6H, piperanyl rings), 6.77 & 7.45 (d, each, 4H, 2xA 2 B 2 , p -dimethylamino phenyl ring); 13 C-NMR (CDCl 3 ) δ 22.57 (CH 3 ), 40.09 [N(CH 3 ) 2 ], 55.52 (C-6 ' ), 56.05 (C- 6), 57.20 (C-4), 59.01 (C-5), 90.08 (C-2), 101.06 (-OCH2- O-), 107.53 (C-8/8 ' ), 109.48 (C-11/11 ' ), 112.50 (C- 3 '' /5 '' ), 121.26 (C-7/7 ' ), 122.4 (C-12/12 ' ), 127.47 (C-1 '' ), 130.56 (C-2 '' /6 '' ), 145.57 (C-9/9 ' ), 147.11 (C-10/10 ' ), 150.12 (C-4 '' ); Ms (m/z): 473 (M + ); Anal. calcd. for C 28 H 31 N 3 O 4 : C, 71.02; H, 6.60; N, 8.87. Found: C, 70.83; H, 6.48; N, 9.02.
- Pharmacological Evaluation
Male and female albino mice (Swiss) and rats (Wistar rats) were used as experimental animals. The animals were housed under standard conditions of temperature (24 ± 1 ℃), relative humidity (65 ± 10%) and 12 h light/dark cycle environment. During the study period, guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Institutional Animals Ethics Committee (IAEC) were followed for the maintenance of animals and the experimental protocol was approved by Institutional Animal Ethics Committee.
The in-vivo anti-inflammatory activity of the synthesized compounds was evaluated by carrageenan-induced rat paw edema method. 16 Indomethcin was taken as standard drug for comparison. All the compounds were administered orally and assayed at a dose of 20 mg/kg of body weight. The compounds that exhibited good anti-inflammatory activity (>50%) were further evaluated for their analgesic activity and ulcerogenic action. All this biological activities are represented in 1 .
- Anti-inflammatory Activity
The experiment was performed on Wistar rats of either sex, weighing 160–200 g. The animals were randomly divided into different groups comprising six rats in each group. One group was kept as control and received 0.5% carboxymethyl cellulose (CMC) solution. The other groups received standard drug (Indomethacin; 20 mg/kg, p.o.) and test compounds (20 mg/kg, p.o.). Carrageenan solution (0.1% in sterile 0.9% NaCl solution) in a volume of 0.1 mL was injected subcutaneously into the sub-plantar region of the right hind paw of each rat (control group also), 30 min after the administration of the test compounds and standard drugs. The paw volume was measured by glass Plethysmometer at 3 h after carrageenan injection. The percentage inhibition of edema was calculated using the following formula:
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where, Vc = edema volume of control group, Vt = edema volume in groups treated with test compounds.
Anti-inflammatory and analgesic activities along with ulcerogenic effect of the title compounds,3a–k
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*p < 0.05; **p<0.01; Standard 1 = Indomethacin; Standard 2 = Aspirin; nt = not tested; aRelative to the standard and data were analyzed by one-way ANOVA followed by Dunnett’ multiple comparison test for n = 6; bRelative to control and data were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test for n = 6.
- Analgesic Activity
Compounds which showed good anti-inflammatory activity (>50%) were also screened for their analgesic activity by acetic acid induce writhing method. 17 Swiss albino mice (20–30 g) of either sex were divided into groups comprising of six animals in each group. Aqueous acetic acid (i.p. injection; 0.10 mL of 1% solution) was used as writhing inducing agent. Mice were habituated for 30 min before acetic acid injection. Analgesic activity was evaluated after p.o. administration of test drugs at a dose of 20 mg/kg. One group was kept as control and received CMC suspension, another group received standard drug aspirin and rest of the groups were treated with test compounds (20 mg/kg) suspended in 1.0% CMC orally. After 1h of drug administration aqueous acetic acid was given to all mice i.p. Stretching movements consisting of arching of the back, elongation of body and extension of hind limbs were counted for 5–15 min of acetic acid injection. The analgesic activity was expressed in terms of percentage protection and calculated using following formula:
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where, Wc = mean number of writhes of control group, Wt = mean number of writhes of test group.
- Acute Ulcerogenic Activity
Acute ulcerogenesis test was done according to the reported method. 18 Albino rats (160–200 g) were divided into different groups consisting of six animals in each group. Ulcerogenic activity evaluated after p.o. administration of test compounds or indomethacin at the dose of 60 mg/kg (three times of the anti-inflammatory dose). Control rats received p.o. administration of vehicle (suspension of 1% CMC). Food but not water was removed 24 h before administration of the test compounds. After the drug treatment the rats were fed with normal diet for 17 h and then sacrificed. The stomach was removed and opened along the greater curvature, washed with distilled water and cleaned gently by dipping in normal saline. The mucosal damage was examined by means of a magnifying glass. For each stomach, the mucosal damage was assessed according to the following scoring system: 0.5: redness, 1.0: spot ulcers, 1.5: hemorrhagic streaks, 2.0: ulcers > 3 but < 5, 3.0: ulcers > 5. The mean score of each treated group minus the mean score of control group was regarded as severity index of gastric mucosal damage. No mucosal damage was found in control group with severity index of 0.00.
- Statistical Analysis
Data obtained from animal experiments were expressed as mean ± SEM. Statistical differences between the treatments and the standard were tested by one-way ANOVA followed by Dunnett’s multiple comparison test.
RESULTS AND DISCUSSION
- Chemistry
The title compounds, 4-[1,3-bis(substituted-benzyl)-2- imidazolidinyl]phenyldialkylamines ( 3a–k ), were successfully synthesized from N 1 , N 2 -bis(substituted-benzyl)ethane-1,2- diamines ( 2a–j ) which in turn was obtained by reduction of N 1 , N 2 -bis(substituted-benzylidene)ethane-1,2-diamines ( 1a–j ). 12 The steps of synthesis have been presented in 1 . In the first step, different aromatic aldehydes were reacted azeotropically with ethylenediamine/1,2- diaminopropane to obtain N 1 , N 2 -bis(substituted-benzylidene) ethane-1,2-diamines ( Ia–j ). In the second step, reduction of the compounds ( 1a–j ) in presence of sodium borohydride furnished N 1 , N 2 -bis(substituted-benzyl)ethane-1,2- diamines ( 2a–j ). These compounds were oily (viscous) in nature except the compound 2i , which was crystalline in nature. In the final step, the compounds 2a–j was condensed with p-diethyl/dimethyl-aminobenzaldehyde to obtain the title compounds 3a–k .
The chemical structures of the synthesized compounds were supported by spectral data and microanalysis data. 1 H-NMR spectra of the title compounds showed peaks of aromatic, diethyl/dimethyl, methylenes of imidazolidines ring and benzylic methylene protons. Triplet at δ 1.1 and quartet at δ 3.2 showed the presence of − N (CH 2 CH 3 ) 2 group. The multiplets at δ 2.4 & 3.1 and a singlet at δ 3.6 indicated the presence of 2×CH 2 and CH of imidazolidines ring. Two doublets each at δ 3.2 and 3.7 could be accounted for two benzylic methylenes. Protons of three phenyl rings appeared in the region of δ 6.5–7.9. It appears that the imidazolidines ring methylene protons as well as the benzylic methylene protons are non-equivalent and showed germinal coupling in proton magnetic resonance. In the 13 C NMR spectral data of the title compounds showed peaks around δ 14.2 for [ N (CH 2 ) 2 ] and δ 40.6 for [ N (CH 3 ) 2 ]. Other peaks were observed at appropriate places. Mass spectra of the compounds showed molecular ion peaks (M + ) in reasonable intensities. Microanalysis data were in range of ±0.4% for the theoretical values of the element analyzed (C, H, N).
- Pharmacology
Carrageenan induced rat paw edema method (CRPE) showed that compound 3g , 3h and 3j have good antiinflammatory action with 63.27, 60.08 and 58.17% inhibition, respectively. The activity of these compounds was comparable to that of the standard drug, Indomethacin, which showed 67.09% inhibition. Three more compounds, 3b , 3f and 3k , showed significant anti-inflammatory activity with 55.42, 53.72 and 55.21% inhibition, respectively. Other compounds showed moderate to low activity with % inhibition in the range of 27.61–47.77. An analysis of results revealed that disubstituted phenyl rings on the imidazolidine heterocyclic ring ( 3g 3h ) showed better activity as compared to that of the mono-substituted phenyl rings. Among the monosubstituted phenyl rings on the imidazolidine ring, presence of chloro-group ( 3b ) showed significant activity. Similar pattern of activity was observed in analgesic screening of the compounds.
Compounds ( 3b, 3f, 3g, 3h, 3j and 3k ) which showed good anti-inflammatory activity (>50%) were also screened for their analgesic activity. One compound, 3g , showed very good analgesic activity with 56.52% protection and its activity was comparable to that of the standard drug, Aspirin, which showed 58.71% protection. Rest of the compounds showed activity in the range of 30.07–49.64% protection ( 1 ).
In ulcerogenic test, the compounds ( 3b, 3f, 3g, 3h, 3j and 3k ) showed reduced ulcerogenic activity (severity index), ranging from 1.08 to 0.42, whereas the standard drug indomethacin showed high severity index of 2.08. The results indicated that the tested compounds were low in their GIT toxicity.
CONCLUSIONS
This study reports the synthesis and anti-inflammatory, analgesic and ulcerogenic activity of novel imidazolidines derivatives. The three compounds, 4-[1,3-bis(4-hydroxy- 3-methoxybenzyl)-2-imidazolidinyl]phenyldiethylamine ( 3g ), 4-[1,3-bis(3-ethoxy-4-hydroxybenzyl)-2-imidazolidinyl] phenyldiethylamine ( 3h ) and 4-(1,3-bis(benzo[d][1,3]dioxol- 5-ylmethyl)-4-methylimidazolidin-2-yl)- N , N -diethylbenzenamine ( 3j ), were good in their anti-inflammatory and analgesic activity. Additionally, these derivatives were also low in their GIT toxicity (ulcerogenic action) which is a common side effect with commonly used NSAIDs. The divergence in the activity of these compounds validates the significance of this study.
Acknowledgements
The authors are thankful to (late) Hakim Abdul Hameed Sahib (Founder and builder of Jamia Hamdard) and Mr A Mueed (President, Hamdard National Foundation) for providing facilities to carry out this work. And the publication cost of this paper was supported by the Korean Chemical Society.
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