[2-Methyl-4-Quinazolin-3-Yl] Acetamide Derivatives Sunil V
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Sunil V. Amrutkar et al. / Journal of Pharmacy Research 2011,4(8),2619-2621 Research Article Available online through ISSN: 0974-6943 http://jprsolutions.info Synthesis and anxiolytic activity of N-alkyl/aryl-2-[2-methyl-4-quinazolin-3-yl] acetamide derivatives Sunil V. Amrutkar*1, Sunil K. Mahajan1, Mahendra S. Ranawat2, Jayshree Patil1, Karvin K. Mehta1 *1Pharmaceutical Chemistry Department, M.G.V.’s Pharmacy College, Pune University, Nashik, India 2 B.N. College of Pharmacy, Udaipur, Rajasthan, India Received on: 17-05-2011; Revised on: 12-06-2011; Accepted on:16-07-2011
ABSTRACT A series of novel substituted N-alkyl/aryl-2-[2-methyl-4-quinazolin-3-yl] acetamide derivatives were synthesized and screened for anxiolytic activity by Elevated plus Maze Test and Light and Dark Test using Diazepam as standard. Structural elucidation of all the synthesized derivatives has been confirmed by FT-IR, 1HNMR and MS. It is observed that 2-(2-methyl-4-oxoquinazolin-3-ylamino)-N-phenylacetamide and 2-(2-methyl-4-oxoquinazolin-3-ylamino)-N morpholinoacetamide have shown potent anxiolytic activity as compared to standard.
Key words: Quinazolinone, acetamide, anxiolytic
1. INTRODUCTION O O Quinazolinone is fused bicycle compound first prepared in the laboratory by C H 3 1 C H 3 O Gabriel in 1903 . Chemistry of quinazolinone derivatives was stimulated in the O ( C H 3 C O ) 2 O early 1950s with the elucidation of a quinazolinone alkaloid, 3-keto-(3-hy- N H droxy-2-piperidyl)-propyl-4-quinazolone [febrifugine] from an Asian plant N H 2 Dichroa febrifuga, which is an ingredient of a traditional Chinese herbal rem- O C H 3 2 edy, effective against malaria . ( I )
Quinazoline exhibit potent central nervous system (CNS) activities like anti- anxiety, analgesic, anti-inflammatory6 and anticonvulsant7. Quinazolin-4-ones N H 2 - N H 2 with 2, 3-disubstitution is reported to possess significant analgesic, anti-in- 8,9,10,11 flammatory and anticonvulsant activities . Examples of quinazolinone O ring containing drugs are diproqualone, Mecloqualone, Flumazenil etc. O O H N H 2 N K C O N N O C H 2 3 Also the Arylacetamides are very well known pharmacophores and exhibit a 3 O C H N C H 10 11 C l 3 3 broad range of biological properties including analgesic , local anesthetic and N C H 3 12 O antiarthritic . In arylacetamides the nature of aromatic ring and its substitu- ( II I ) ( II ) ent is a primary determinant for its activity.
R /A r - N H 2 Thus on combining quinazolinone with arylacetamides, we could develop a novel class of anxiolytics which are potent than the currently commonly available drugs in the market. O O H N R / A r N N Chemistry H
We have synthesised 2-methyl-3-amino-4-Quinazolinone derivative by con- N C H 3 densation reaction between methyl anthranilate and acetic anhydride in pres- ence of catalyst amount of pyridine and hydrazine hydrate. The 2-methyl-3- I V ( a - k ) amino-4-Quinazolinone derivative(II) was reacted with ethyl chloracetate in presence of base potassium carbonate. The nucleophilic displacement of chlo- Figure 1: Scheme of synthesis of 2-Methyl-3-Amino-4-Quinazolinone rine from a-carbon produces an intermediate i.e. ethyl-2[(2-methyl quinazolin- acetamide Derivatives 4-one) amino] acetate(III). N-alkyl/aryl-2-[2-methyl-4-quinazolin-3-yl] ac- 2. MATERIALS AND METHODS etamide derivatives (IV) were synthesised by reaction of intermediate with various aliphatic and aromatic amines. 2.1. Chemistry 2.2.1. Synthesis of Methyl 2-Acetoamidobenzoate (I) Pharmacology In 100 ml RBF, a solution of Methyl Anthranilate (0.016 mol) in acetic anhy- Anxiety is a vague feeling of apprehension, worry, uneasiness, or dread, the dride (0.127 mol) was refluxed for 15 minutes. The reaction mixture was cooled, source of which is often nonspecific or unknown to the individual. Anxiety poured into cold water (50 ml) containing a drop of pyridine and stirred until the affects one-eighth of the total population world-wide and has become an oil solidified. Crude product was filtered, washed with cold water and dried it at important area of research interest in psychopharmacology during this de- 1000C. The product was recrystallised with ethanol. Yield 73.70%, mp 98- cade. According to biological theories, may biological abnormalities have been 1000C, and IR (KBr, cm-1): 1697.41 (C=O in ester), 1234.48 (C-O), 1593.25 associated with anxiety disorders, including obscured increase in brain neu- + rotransmitters. The locus ceruleus, a part of the brain located in the brainstem (C=O in amide), 1527.67 (N-H), 1089.82 (C-N). Mass spectrum [M ], m/z 193 may be responsible for many anxiety symptoms. Many patients with panic (100%). disorder are extremely sensitive to slight increases in carbon dioxide in the air12. 2.2.2. Synthesis of 3-amino-2-methyl-4-quinazolinone (II)
Method I (Conventional) *Corresponding author. In 100 ml RBF, a solution of hydrazine hydrate (10 ml) and Methyl 2- Acetamidobenzoate (2 gm) in ethanol was refluxed for 2 hours. The reaction Sunil V. Amrutkar mixture was cooled and stirred into cold water (50 ml). Crude product was Pharmaceutical Chemistry Department, filtered, washed with cold water and dried it at 1000C. Crude product was M.G.V.’s Pharmacy College, recrystallised from ethanol. Pune University, Nashik, India Method II (Microwave) In 100 ml RBF, a solution of hydrazine hydrate (10 ml) and 2 gm of Methyl 2-
Journal of Pharmacy Research Vol.4.Issue 8. August 2011 2619-2621 Sunil V. Amrutkar et al. / Journal of Pharmacy Research 2011,4(8),2619-2621 Acetoamidobenzoate (I) in ethanol was irradiated at 140 W for 3 min. The mp 130-1320C, IR (KBr, cm-1): 1656.91 (amide I), 1595.18 (amide II), 1199.76 reaction mixture was cooled and stirred into cold water (50 ml). Crude product (amide III), 3302.24 (N-H), 2985.91 (C-H alkyl), 3551.47 (N-H free amine). was filtered, washed with cold water and dried it at 1000C. The product was recrystallised from ethanol.Yield 66.54% (Conventional); 77.93% (Microwave) 2.2.14. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N’- mp 150-1520C, and IR (KBr, cm-1): 1666.91 (C=O), 1597.11 (N-H), 1257.63 phenylacetohydrazide (IVk) + 1 (C-N), 3300.31 (N-H str.); mass spectrum [M +2], m/z 177. H NMR (CDCl3, d, It was obtained from (III) and phenyl hydrazine in crystalline form. Yield 82%, 0 -1 ppm): 7.4-8.2 (Ar-H), 1.25 (s, 3H, CH3), 1.98 (s, 2H, NH2) mp 138-140 C, IR (KBr, cm ): 1658.84 (amide I), 1597.11 (amide II), 1197.83 2.2.3.Synthesis of Ethyl 2-(2-methyl-4-oxoquinazolin-3-ylamino)acetate (III) (amide III), 3302.24 (N-H), 2910.68 (C-H alkyl). The mixture of 3-amino-2-methylquinazolin-4(3H)-one (0.01 mole), ethyl 2.3. Pharmacology chloroacetate (0.01 mole) was irradiated under microwave at 700 W for 23-25 The Institutional Animal Ethics Committee approved the protocol adopted for minutes in presence of anhydrous K2CO3 using DMF as solvent. The reaction the experimentation of animals. The animals, male Swiss albino mice, weighing mixture was cooled and poured into ice-cold water. The resulting solid was 18-22 gm were procured from Bharat Serums and Vaccines Ltd., Thane, Mumbai, filtered, washed with water and recrystallised from ethanol/water. Yield 34.22%, India. All the animals were acclimatized for a week before use. One-way analysis mp 124-1280C, and IR (KBr, cm-1): 1728.28 (C=O), 1257.63 (C-O), 1197.83 (C-N), 3302.24 (N-H str.); mass spectrum [M+], m/z 246. 1H NMR (CDCl , d, of variance (ANOVA) was performed to ascertain the significance of all the 3 exhibited activities. ppm): 7.4-8.2 (Ar-H), 1.62 (s, 3H, CH3), 2.56 (s, 1H, NH), 2.71 (s, 2H, CH COO), 4.23 (q, 2H, COOCH CH ), 1.25 (t, 3H, COOCH CH ). 2 2 3 2 3 2.3.1. Anxiolytic Activity: 2.2.4. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino) acetamide (IVa) Anxiolytic activity was performed using Elevated plus maze (EPM) and Light It was obtained from (III) and ammonia in crystalline form. Yield 65%, mp 145- and dark model. Male Swiss albino mice weighing between 18-22 gm were divided 1460C, IR (KBr, cm-1): 1660.77 (amide I), 1599.04 (amide II), 1195.91(amide into 15 groups containing 5 animals each. The mice were treated with acetamide III), 3302.24 (N-H), 2949.26 (C-H alkyl). derivatives (30 mg/kg) 30 min before intraperitonial or 60 min before oral administration. The mice were placed centrally facing toward one of the closed 2.2.5. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N,N- diethylacetamide (IVb) arm of EPM and number of entries into open arms and time spent in open arms It was obtained from (III) and diethylamine in crystalline form. Yield 53%, mp were evaluated. Similarly time spent in the light area of light and dark paradigm 140-1420C, IR (KBr, cm-1):1658.84 (amide I), 1597.11 (amide II), 1141.90 was taken as a measure of anxiety. (amide III),3302.24 (N-H), 2951.19 (C-H alkyl). 3. RESULTS: 2.2.6.Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N-phenyl acetamide (IVc) It was obtained from (III) and aniline in crystalline form. Yield 72%, mp 147- 3.1 Chemistry 1480C, IR (KBr, cm-1): 1689.70 (amide I), 1600.97 (amide II), 1111.30 (amide III), 3311.98 (N-H), 2931.90 (C-H alkyl). Table 1: Physical Characteristics of synthesized Acetamide Derivatives 2.2.7. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N-(3-chlorophenyl) aceta- mide (IVd) Sr. No R/Ar IUPAC name Code mp (0C) % R It was obtained from (III) and m-chloroaniline in crystalline form. Yield 63%, F 0 -1 mp 156-158 C, IR (KBr, cm ): 1691.63 (amide I), 1599.04 (amide II), 1193.96 1. a 2-(2-methyl-4-oxoquinazolin-3- AA1 145-146 65 0.70 (amide III), 3306.10 (N-H), 2931.90 (C-H alkyl), 771.56 (C-Cl), 696.33, 771.56 ylamino)acetamide 2. b 2-(2-methyl-4-oxoquinazolin-3- AA2 140-142 53 0.50 (C-H bend m-substitution). ylamino)-N,N-diethylacetamide 3. c 2-(2-methyl-4-oxoquinazolin-3- AA3 147-148 72 0.53 2.2.8. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N-(4-chlorophenyl) aceta- ylamino)-N-phenylacetamide mide (IVe) 4. d 2-(2-methyl-4-oxoquinazolin-3- AA4 156-158 63 0.47 ylamino)-N-(3-chloro- phenyl)acetamide It was obtained from (III) and p-chloroaniline in crystalline form. Yield 65%, 5. e 2-(2-methyl-4-oxoquinazolin-3-ylamino)- AA5 142-144 65 0.52 mp 142-1440C, IR (KBr, cm-1): 1689.70 (amide I), 1600.97 (amide II), 1192.05 N-(4-chloro- phenyl)acetamide (amide III), 3311.89 (N-H), 2929.97 (C-H alkyl), 771.55 (C-Cl). 6. f 2-(2-methyl-4-oxoquinazolin-3-ylamino)- AA6 68-70 87 0.52 N-(3-nitrophenyl)acetamide 7. g 2-(2-methyl-4-oxoquinazolin-3- AA7 135-136 73 0.40 2.2.9. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N-(3- nitrophenyl) ac- ylamino)- N-p-tolylacetamide etamide (IVf) 8. h 2-(2-methyl-4-oxoquinazolin-3 AA8 144-146 64 0.41 It was obtained from (III) and m-nitroaniline in crystalline form. Yield 87%, mp -ylamino)- N-m-tolylacetamide 0 -1 9. i 2-(2-methyl-4-oxoquinazolin-3- AA9 132-134 87 0.39 68-70 C, IR (KBr, cm ): 1658.84 (amide I), 1597.11 (amide II), 1197.83 ylamino)-N-morpholinoacetamide (amide III), 3302.24 (N-H), 2985.91 (C-H alkyl), 875.71 (C-N Nitro-aro- 10. j 2-(2-methyl-4-oxoquinazolin- AA10 130-132 61 0.47 matic), 1475.59 (N=O symmetric), 1429.30 (N=O asymmetric). 3-ylamino) acetohydrazide 11. k 2-(2-methyl-4-oxoquinazolin-3- AA11 138-140 82 0.51 ylamino)-N’-phenylacetohydrazide 2.2.10. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N-p-tolylacetamide (IVg) It was obtained from (III) and p-toluidine in crystalline form. Yield 73%, mp CH3 H 0 -1 H N 135-136 C, IR (KBr, cm ): 1668.48 (amide I), 1602.90 (amide II), 1190.12 NH2 N N (amide III), 3309.96 (N-H), 2929.97 (C-H alkyl), 869.92 (C-H bend p- CH a 3 disubstituted). b c d Cl
H H 2.2.11. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N-m-tolylacetamide (IVh) N C l N H It was obtained from (III) and m-toluidine in crystalline form. Yield 64%, mp N CH3 0 -1 144-146 C, IR (KBr, cm ): 1691.63 (amide I), 1599.04 (amide II), 1196.91 NO (amide III), 3304.17 (N-H), 2931.90 (C-H alkyl), 696.33, 773.40 (C-H bend e f 2 g m-substituted). H N O 2.2.12. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino)-N-morpholinoacetamide NH-NH2 (IVi) N CH3 j It was obtained from (III) and morpholine in crystalline form. Yield 87%, mp h i 132-1340C, IR (KBr, cm-1): 1689.70 (amide I), 1599.04 (amide II), 1196.91 (amide III), 3304.17 (N-H), 2963.98 (C-H alkyl), 1031.95 (Symmetric C-O-C H H stretch). N N
2.2.13. Synthesis of 2-(2-methyl-4-oxoquinazolin-3(4H)-ylamino) acetohydrazide (IVj) k It was obtained from (III) and hydrazine hydrate in crystalline form. Yield 61%,
Journal of Pharmacy Research Vol.4.Issue 8. August 2011 2619-2621 Sunil V. Amrutkar et al. / Journal of Pharmacy Research 2011,4(8),2619-2621
pearance of a quartet COOCH2CH3 at d 4.2, triplet COOCH2CH3 at d 1.2, singlet 3.2 Pharmacology 1 CH2COO at d 2.7 in H NMR confirmed its formation. Further, reaction of Ethyl 2-(2-methyl-4-oxoquinazolin-3-ylamino) acetate ELEVATED PLUS MAZE TEST (III) with aliphatic/aromatic amines produced N-alkyl/aryl-2-[2-methyl-4- quinazolin-3-yl] acetamide Derivatives. From IR spectral studies, disappear- 200 ance of peak of ester functional group and appearance of characteristic peaks * 180 of amide I, amide II and amide III confirmed the acetamide derivatives. All 160 Physical characteristics of acetamide derivatives were given in table 1. 140 120 4.2 Pharmacology 100 * * * * * 80 * * In elevated plus maze model, QZN, AA1, AA2, AA3, AA4, AA6, AA11 showed 60 a anxiolytic profile at dose 30 mg/kg as that of the standard anxiolytic diaz- 40 epam. Among them QZN and AA3 has shown the potent activity. (Figure 1) TIME SPENT (SE C .) 20 .On the other hand AA5, AA7, AA8, AA9, AA10 failed to alter any behavioural 0 profile. The reason for the differences in the behavioural effects of these synthesized compounds is not clear. Std. QZN Qac AA1 AA2 AA3 AA4 AA5 AA6 AA7 AA8 AA9 AA10 AA11 Control In the light and dark Test, among acetamide library tested all compounds TREATED GROUPS QZN, QAc, AA1, AA2, AA3, AA4, AA5, AA6, AA7, AA8, AA9, AA10 and AA11 showed an anxiolytic profile at dose 30 mg/kg as that of the standard All values are expressed as mean ± SEM, n=5, *p<0.05 compared with control. Statistical anxiolytic diazepam. Among them QZN and AA9 has shown the potent activ- analysis was performed with One-way ANOVA followed by Dunnett’s test. p<0.05 was consid- ity. ered as statistical significant. Figure 1: Effect of synthesized compound in elevated plus-maze test 5. CONCLUSION We have developed a facile, rapid and environmentally benign microwave- assisted synthesis of N-alkyl/aryl-2-[2-methyl-4-quinazolin-3-yl] acetamide LIGHT-DARK TEST Derivatives. It is concluded that 2-(2-methyl-4-oxoquinazolin-3-ylamino)- N-phenylacetamideand2-(2-methyl-4-oxoquinazolin-3-ylamino)-N-morp 140 holinoacetamide have shown potent anxiolytic activity. It is also concluded 120 * that the highest anxiolytic activity will be observed with aromatic and * * * 100 * heteroaromatic acetamide compounds. * * * * * 80 * * * * 6. ACKNOWLEDGEMENT 60 The Authors are thankful to the management and Prof. V.M. Aurangabadkar, 40 Principal, M.G.V.’s Pharmacy College, Nasik and to Dr. Bal Subramanian for 20 TIME SPENT (SEC.) their support throughout the research project. 0 7. REFERENCES
Std. QZN Qac AA1 AA2 AA3 AA4 AA5 AA6 AA7 AA8 AA9 1. Daidon G., Raffa D., Plescia S., Mantione L., Microwave assisted synthesis of AA10 AA11 Control quinazolinone using different bases, Eur. J. Med. Chem, 36, 2001,737. TREATED GROUPS 2. El-Meligic S., El-Ansary A.K., Said M.M., Hussein M.M., Synthesis of ethyl 2-(2- methyl-4-oxoquinazolin-3(4H)-yl) acetate as important analog and intermediate of 2,3 disubstituted quinazolinones Indian J. Chem (Sect.B),2001,40-62. All values are expressed as mean ± SEM, n=5, *p<0.05 compared with control. Statistical 3. Reddy P.S., Reddy P.P., Vasantha T., Synthesis of ethyl 2-(2-methyl-4-oxoquinazolin- analysis was performed with One-way ANOVA followed by Dunnett’s test. p<0.05 was consid- 3 (4H)-yl) acetate as important analog and intermediate of 2, 3 disubstituted ered as statistical significant. quinazolinones, Heterocycles, 60, 2003,183. 4. Alagarsamy V., Revathi R., Vijay Kumar S., Ramseshu K.V., Synthesis and Figure 2: Effect of synthesized compound in light and dark test Pharmacological investigation of some novel 2, 3-disubstituted quinazolin-4(3H)- 4. DISCUSSION ones as analgesic and anti-inflammatory agents, Pharmazie, 58, 2003, 4-8. 5. Smith K., El-Hiti G.A., Abdo M.A., Abdel-Megeed M.F., Regiospecific electrophilic substitution of aminoquinazolinones: directed lithiation of 3-(pivaloylamino) and 4.1 Chemistry 3-(acetylamino)-2-methylquinazolin-4(3H)-ones, Journal of the Chemical During literature survey it was found that both quinazolin-4-one and Society,8,1995,1029-33. arylacetamides possess anxolytic activity. With this as reference, we have 6. Zappala M., Grasso S., Micale N., Zuccala G., Menniti F.S., Ferreri G., et al. 1- Aryl-6, designed and developed a scheme to synthesise N-alkyl/aryl-2-[2-methyl-4- 7-methylenedioxy-3H-quinazolin-4-ones as anticonvulsant agents, Bioorg Med quinazolin-3-yl] acetamide Derivatives. Chem Lett, 13, 2003,4427-30. 7. Padia J.K., Field M., Hinton J., Meecham K., Pablo J., Pinnock R.., Roth B.D., Singh It was also experimentally found out that the reaction to synthesise 3-amino- L., Suman-Chauhan N., Trivedi B.K., Webdale L., 41, 1998, J. Med. Chem,1042. 8. Srivastava V.K., Kumar A., Synthesis of newer thiadiazolyl and thiazolidinonyl 2-methyl-4-quinazolinone (III) gave better yields by using green chemistry quinazolin-4(3H)-ones as potential anticonvulsant agents, European Journal of approach i.e. microwave assisted synthesis(77.93%) as compared to conven- Medicinal Chemistry, 37, 2002, 873-82. tional method (66.54%)Mechanistically, the reaction proceeds via a methyl 9. Parmar S.S., Kishor K., Seth P.K., Arora R.C., Role of alkyl substitution in 2, 3 dis- 2-acetamidobenzoate (I) intermediate. Appearance of molecular ion m/z 193 ubstituted and 3-substituted 4-quinazolones on the inhibition of pyruvic acid oxi- (M+) in mass spectrum confirmed the intermediate (I). dation, Journal of Medicinal Chemistry, 12(1), 1969,138-41. 10. Coop A., MacKerell Jr. A.D., The Future of Opioid Analgesics., Am. J. Pharm. Educ., 66, 2003, 155. Encouraged by this result, reaction of 3-amino-2-methyl-4-quinazolinones 11. Harte A.J., Gunnlaugsson T., Synthesis of a-chloroamides in water, Tetrahedron Let- with ethyl chloroacetate in DMF in presence of potassium carbonate yielded ters, 47, 2006, 6321–6324. 34.22% Ethyl 2-(2-methyl-4-oxoquinazolin-3-ylamino) acetate (III). Ap- 12. Nishimura N., Koyano Y., Sugiura M., Maeba I., Heterocycles, 51, 1999, 803. Source of support: Nil, Conflict of interest: None Declared
Journal of Pharmacy Research Vol.4.Issue 8. August 2011 2619-2621