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Synthesis of New Pyrimidine Derivatives with Evaluation of Their Anti-Inflammatory and Analgesic Activities

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Synthesis of New Pyrimidine Derivatives with Evaluation of Their Anti-Inflammatory and Analgesic Activities Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 68 No. 4 pp. 507ñ517, 2011 ISSN 0001-6837 Polish Pharmaceutical Society DRUG SYNTHESIS SYNTHESIS OF NEW PYRIMIDINE DERIVATIVES WITH EVALUATION OF THEIR ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES ZIENAB M. NOFAL1; HODA H. FAHMY1; EMAN S. ZAREA1 and WAFAA EL-ERAKY2 1Department of Therapeutical Chemistry, 2Department of Pharmacology, National Research Centre, Dokki, Cairo12311, Egypt Abstract: 5-Formyl-6-aminopyrimidine-2,4-(1H, 3H)-dione (2) has been previously prepared from compound 1. Cyclocondensation reaction of compound 2 with cyanoacetamide gave substituted pyridopyrimidine 3. Also, compound 2 was condensed with p-amino acetophenone and hydrazine derivatives to give 5-{[(4- acetylphenyl)imino]methyl}-6-aminopyrimidine (4) and 5-substituted carboaldehyde-6-amino pyrimidine derivatives (5a-d), respectively. Moreover, cyclocondensation reaction of compound 2 with thiosemcarbazide and semicarbazide hydrochloride gave 5-(5-thioxo or oxo-triazol-3-yl)-6-amino pyrimidine (6) and (7), respec- tively. Cyclocondensation reaction of compound 2 with thiourea and ethyl acetoacetate led to the formation of substituted ethyl bipyrimidine-5-carboxylate 8. Also, compound 2 was reacted with acetoacetic acid hydrazide and 2-cyanoacetohydrazide to give 5-(acetylpyrazol-6-aminopyrimidine 9 and 3-(6-aminopyrimidine-5-yl) pyrazole-4-carboxamide 10, respectively. Furthermore, compound 1 was diazotized to afford the diazonium salt 11. Its coupling with ethyl acetoacetate, ethyl cyanoacetate, acetylacetone, malononitrile, cyanoacetamide, diethylmalonate, in sodium acetate buffered solution afforded substituted hydrazonopyrimidines: ethylhydra- zono-3-oxobutanoate 12, ethylhydrazono-3-oxopropanoate 13, pentane-2,3,4-trione hydrazone 14, cyanohy- drazonoacetamide 15, diazenyl malonamide 16 and diethylhydrazonomalonate 17, respectively. Moreover, sub- stituted pyrazolediazenylpyrimidine derivatives 18a,b, 19a,b, 20, 21a-c, 22 were synthesized by the cyclization of substituted hydrazonopyrimidines 12, 17, 15, 14 and 13, respectively. The analgesic and anti-inflammatory activities of some of the synthesized compounds were evaluated. Compounds C18a, C20, C21b and C22 showed the most significant analgesic effects among synthesized moieties. All tested compounds, nonetheless, C18b showed significant anti-inflammatory effect in carrageenan induced paw edema model. Keywords: pyrimidine derivatives, cyclization, diazo-coupling reaction, condensation reaction, anti-inflamma- tory, analgesic activities Selective cyclooxygenase-2 (COX-2) inhibi- pyrimidine derivatives attracted organic chemists tors are a new kind of non-steroidal anti-inflamma- very much due to their biological and chemothera- tory drugs (NSAIDs). Due to their excellent thera- peutic importance (6). Pyrimidines represent a broad peutic effect on the treatment or alleviation of class of compounds, which have received consider- inflammation such as osteoarthritis (OA) and able attention due to their wide range of biological rheumatoid arthritis (RA) with little side effects to activities (7). Several patents have been reported on gastrointestinal tract, there is an increasing interest the preparation of these heterocycles, derivatives of in the research and development of selective COX- which are useful as bronchodilators, vasodilators, 2 inhibitors (1). In recent years, as some NSAIDs antiallergic, antihypertensive (8), anti-inflammato- including selective COX-2 inhibitors have been ry, and anticancer agents (9). In fact, there are many shown to be associated with cardiovascular events, pyrimidine derivatives with pharmacological activi- it has become a great challenge to explore novel ties (10).The pyrazole ring has attracted great atten- NSAIDs with reduced gastrointestinal tract and car- tion as it has become fairly accessible and it shows diovascular side effects (2). Some imidazo[1,2- diverse properties (11). Pyrazole based derivatives a]pyrimidine compounds have been reported to have have shown several biological activities as seen in significant anti-inflammatory and analgesic action COX-2 inhibitors (12). We perceived that when two in experimental animal models (3ñ5). Pyrazole and moieties, such as pyrazole and pyrimidine are joined * Corresponding author: e-mail: [email protected]; phone: +02 0104904250; fax: +2033370931 507 508 ZIENAB M. NOFAL et al. the new molecules might exhibit superior anti- 9.15, 10.80 (2s, 2H, 2NH, exchangeable with D2O). inflammatory activity. With this idea in mind the MS. m/z (%): 273 (M+ + 1, 9.42), 272.1 (M+, 30.25), present work was undertaken. 271 (M+ ñ 1, 12.48), 135 (59.91), 120 (100). Analysis: calcd. for C13H12N4O3 (272.260): C, 57.35; EXPERIMENTAL H, 4.44; N, 20.58%; found: C, 57.22; H , 4.33; N, 20.46%. All melting points are uncorrected and were determined in capillary tubes in Gallenkamp appara- General procedure for preparation of 6-amino- tus. IR spectra were recorded on a Beckman infrared 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-substi- spectrophotometer PU9712 using KBr discs. The tuted carbaldehyde derivatives (5a-d) 1H-NMR spectra were obtained on Joel EX270, 500 Mixture of compound 2 (0.155 g, 0.001 mol) MHz spectrometer using TMS as an internal stan- and hydrazine derivatives (0.001 mol) in absolute dard. Mass spectra were recorded on Finnigan ethanol (5 mL) was refluxed for three days. The SSQ7000 mass spectrometer at 70 eV. All reactions reactions mixtures were concentrated, cooled and were followed and checked by TLC using chloro- the solids formed were filtered, washed with ethanol form / methanol (9:3) as a mobile phase and spots and diethyl ether and then recrystallized from DMF were examined by UV lamp. The compounds to give 5a-d. throughout this work were named according to the IUPAC system using Chem Draw Ultra computer 6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- program version 8. 5-carbaldehyde hydrazone (5a) Yield 95%, m.p. >300OC. IR (KBr, cm-1): 3300, 7-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3- 3212.53 (NH, NH2), 1734.83 (2 CO), 1633.61 1 δ d]pyrimidine-6-carboxamide (3) (C=N), 1540.54 (C=C). H-NMR (DMSO-d6, , A mixture of compound 2 (0.155 g, 0.001 mol) ppm): 7.50 (br.s, 2H, NH2, exchangeable with D2O), and cyanoacetamide (0.001 mol) in glacial acetic 9.15 (s, 2H, NH2, exchangeable with D2O), 9.60 (s, acid (5 mL) was refluxed for two days. The solid 1H, CH=N), 10.70 (br.s. 2H, 2NH, exchangeable formed was filtered off, and recrystallized from with D2O). Analysis: calcd. for C5H7N5O2 (169.142): pyridine to give compound 3. C, 35.50; H, 4.17; N, 41.41%; found: C, 35.59; H, Yield 64%, m.p. 330OC. IR (KBr, cm-1): 4.21; N, 41.21%. 3440.11, 3342.56, 3145.55 (NH, NH2), 1710.43 (2 CO), 1642.83 (CO amide), 1558.95 (C=N, C=C). 6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 1 δ H-NMR (DMSO-d6, , ppm): 6.00 (br.s, 2H, NH2, 5-carbaldehyde phenyl hydrazone (5b) O -1 exchangeable with D2O), 7.85 (s, 1H, CH of pyri- Yield 75%, m.p. >300 C. IR (KBr, cm ): dine ring), 9.20 (s, 2H, NH2CO, exchangeable with 3286.36 (NH2, NH), 3000 (CH-aromatic), 1704.80 1 D2O), 10.70, 11.25 (2s, 2H, 2NH, exchangeable with (2 CO), 1619.95 (C=N, C=C). H-NMR (DMSO-d6, + δ D2O). MS: m/z (%): 220 (M ñ 1; 19.85), 127 (100). , ppm): 6.60ñ7.10 (m, 5H, Ar-H), 8.10 (s, 1H, Analysis: calcd. for C8H7N5O3 (221.17): C, 43.44; H, CH=N), 8.45 (br.s, 1H, NH, exchangeable with 3.19; N, 31.66%; found: C, 43.27; H, 3.20; N, D2O), 9.75 (s, 2H, NH2), 10.60 (s, 2H, 2NH, + 31.57%. exchangeable with D2O). MS: m/z (%): 247 (M + 2, 100). Analysis: calcd. for C11H11N5O2 (245.238): C, 5-{[(4-Acetylphenyl)imino]methyl}-6-aminopyr- 53.87; H, 4.52; N, 28.56%; found: C, 53.66; H, 4.34; imidine-2,4(1H,3H)-dione (4) N, 28.29%. To a solution of compound 2 (0.155 g, 0.001 mol) in glacial acetic acid (5 mL), p-aminoace- 6-Amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- tophenone (0.135 g, 0.001 mol) was added. The 5-carbaldehyde (3-chlorophenyl) hydrazone (5c) reaction mixture was refluxed for 20 h, the excess Yield 81%, m.p. >300OC. IR (KBr, cm-1): solvent was removed under reduced pressure and the 3410.17, 3350 (NH2, NH), 3000 (CH-aromatic), solid was collected by filtration and after recrystal- 1708.40 (2 CO), 1646.79 (C=N), 1536.39 (C=C), 1 δ lization from DMF/ H2O (1:1) yielded compound 4. 846.82, 764.68 (C-Cl). H-NMR (DMSO-d6, , Yield 83%, m.p. >330OC. IR (KBr, cm-1): ppm): 6.65ñ7.20 (m, 4H, Ar-H), 7.40 (s, 1H, NH, 3148.93 (NH, NH2), 1750, 1674, 1649.75 (3 CO), exchangeable with D2O), 8.15 (s, 1H, CH=N), 9.20 1 δ 1595.72 (C=N). H-NMR (DMSO-d6, , ppm): 1.80 (s, 2H, NH2, exchangeable with D2O), 10.60, 10.90 (s, 3H, CH3), 6.50, 7.65 (dd, 4H, Ar-H), 9.15 (s, 1H, (2s, 2H, 2NH, exchangeable with D2O). MS. m/z + CH=N), 7.35 (d, 2H, NH2, exchangeable with D2O), (%): 279 (M , 1.08), 142 (100). Analysis: calcd. for Synthesis of new pyrimidine derivatives with evaluation of... 509 C11H10ClN5O2 (279.68): C, 47.24; H, 3.60; N, C6H6N6O3 (210.15): C, 34.29; H, 2.88; N, 39.99%; 25.04%; found: C, 47.51; H, 3.59; N, 25.35%. found: C, 34.33; H, 3.09; N, 40.13%. N1-[(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrim- Ethyl-6í-amino-6-methyl-2í,4í-dioxo-2-thioxo- idin-5-yl)methylene]-N2-(4-methylbenzo)hydr- 1,1í,2,2í,3,3í,4,4í-octahydro-4,5í-bipyrimidine-5- azide (5d) carboxylate (8) Yield 60%, m.p.
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