HETEROCYCLES

Paper | Special issue | Vol. 77, No. 2, 2009, pp. 899-908
Received, 23rd July, 2008, Accepted, 24th September, 2008, Published online, 25th September, 2008.
DOI: 10.3987/COM-08-S(F)90

■ Transformations of Diethyl 2-[(Dimethylamino)methylene]-3-oxopentanedioate. A simple Synthesis of Substituted 2-Amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylates

Silvo Zupancic, Jurij Svete, and Branko Stanovnik*

Department of Organic Chemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O. Box 537, SI-1000 Ljubljana, Slovenia

Abstract

Diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate (2), prepared from acetone-1,3-dicarboxylates (1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) was, without isolation, transformed by treatment with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)pyrimidine-5-carboxylate (3). Compound 3 was transformed with DMFDMA first into intermediate 4 and with an excess of DMFDMA into ethyl 4-[1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyleneamino]pyrimidine-5-carboxylate (5). By treatment of compound 5 with ammonia, primary amines, hydrazine or hydroxylamine intermediates 6a-j were formed, which cyclized into 6-substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyridine-8- carboxylates (7a-j).

INTRODUCTION
There are many methods described in the literature for the synthesis of pyridopyrimidines.1-3 Recently, they have been prepared from 4-amino-6-chloro-5-phenyl-2-methylthiopyrimidine4 and from 4-amino-1- benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate.5 They are well-known pharmacophores,6,7 PDE- inhibitors,8 inhibitors of tyrosine kinase activity in the epidermal growth factor receptor.9,10
In connection with our interest in enaminones and related compounds, as building blocks for the preparation of various heterocyclic systems,11 including also some natural products,12,13 dialkyl acetone-1,3-dicarboxylates have been recently employed for the synthesis of heteroaryl substituted pyrimidines,14 dialkyl 1-substituted 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates,15 pyrazolo[4,3-d]- pyridine-7-carboxylates,16 pyrazolyl substituted pyridopyrimidines, pyranopyranediones, chromene- diones,17 and pyrazolo[4,3-d][1,2]diazepines.18,19 We recently reported an efficient method for the preparation and functionalisation of highly substituted 1-aminopyrroline, 1-aminopyrrole and oxazoline-pyrroline fused systems from 1,2-diaza-1,3-butadienes and 3-dimethylaminopropenoates,20 and the regio- and stereoselective one-pot synthesis of oxazoline-fused pyridazine via a “Michael addition-pyridazine-cyclisation-oxazoline cyclisation” cascade reaction.21 Many fused pyrimidines are formed by cyclisation of 3-heteroarylaminopropenoates, derived from 2-substituted 3-(dimethyl- amino)propenoates and heterocylic α-amino compounds.11,22

RESULTS AND DISCUSSION
Diethyl acetone-1,3-dicarboxylate (1) gave with N,N-dimethylformamide dimethyl acetal (DMFDMA) diethyl 2-[(2-dimethylamino)methylene]-3-oxopentanedioate (2), which was without isolation transformed with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)pyrimidine-5- carboxylate (3). When compound 3 was treated with one equivalent of DMFDMA in EtOH, amino group at 2 position was transformed into dimethylaminomethylene amino group to form intermediate 4. By further treatment with DMFDMA in n-propyl acetate as solvent under reflux also active methylene group at 6-position was transformed into dimethylaminomethylene group to give ethyl 4-[1-(dimethyl- amino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyleneamino]pyrimidine-5-carboxylate (5). In the reaction of compound 5 with ammonia, primary amines, or hydrazine first the dimethylaminomethylene group at 2-position was transformed into free amino group, followed by substitution of the dimethylamino group on the side chain to give intermediates 6a-j, which were without isolation cyclised into ethyl 6-substittued 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8- carboxylates (7a-i). Compound 5 was with hydroxylamine hydrochloride transformed into the corresponding 6-hydroxy derivative (7j) (Scheme 1, Table 1).

STRUCTURE DETERMINATION
The structures of new compounds were determined by spectroscopic methods (IR,1H and 13C NMR spectroscopy, MS) and by elemental analyses for C, H, and N. 1H NMR spectrum of compound 3 exhibits

two triplets at δ = 1.17 and 1.26 ppm and two quartets at δ = 4.07 and 4.20 ppm for two ester groups, a singlet at δ = 3.91 ppm for CH2 group, a singlet at δ = 7.52 ppm for NH2 and a singlet at δ = 8.71 ppm for H4. Compound 4 shows two triplets at δ = 1.25 and 1.38 ppm and two quartets at δ = 4.15 and 4.35 ppm for two ester groups, a singlet at δ = 4.15 ppm for CH2 group and a singlet at δ = 8.81 ppm for H4 two sinlets at δ = 3.22 and 3.25 ppm for NMe2 group and a singlet at δ = 9.01 ppm for the amidine proton. Compound 5 shows again two triplets at δ = 1.13 and 1.32 ppm and two quartets at δ = 4.05 and 4.27 ppm for two ester groups, a singlet at δ = 8.73 ppm for H4, a broad singlet at δ = 2.83 ppm for the NMe2 group and a singlet at δ = 7.62 ppm of the dimethylaminomethylene group, two singlets at δ = 3.16 and 3.29 ppm for NMe2 and a singlet at δ = 8.87 ppm for the amidine part of the molecule. 1H NMR spectra of compounds 7 exhibit two characteristic singlets for protons H4 and H7. While the signal for H4 appears for all bicyclic compounds at δH4 = 9.00 ppm, the signal for the H7 appears in the range of δH7 = 8.00-8.50 ppm, dependent on the group R attached at 6-position, and the signals characteristic for R group.

EXPERIMENTAL
Melting points were determined on a Kofler micro hot stage. The1H NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C nucleus, using DMSO–d6 and CDCl3, with TMS as the internal standard, as solvents (δ in ppm, J in Hz). All NMR experiments were carried out at 302 K. Mass spectra were recorded on an AutoSpecQ spectrometer and Q-TOF Premier spectrometer, IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (ν in cm-1). Microanalyses were performed on a Perkin-Elmer Series II CHN Analyser 2400. Column chromatography (CC) was performed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm).

Ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)pyrimidine-5-carboxylate (3)
To a solution of diethyl 1,3-acetonedicarboxylate (0.95, 5 mmol), in EtOH (10 mL), DMFDMA (0.72 mL, 5 mmol) was added and the mixture was stirred at rt for 45 min. Guanidine hydrochloride (478 mg, 5 mmol) was then added and the mixture was stirred under reflux for 1 h. The volatile components were evaporated and the crude product was recrystallized from EtOH to give 1. Yield 23% (290 mg), mp 125-127 °C. 1H NMR (DMSO-d6) δ: 1.17 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.26 (t, 3H: OCH2CH3, J = 7.2 Hz), 3.91 (s, 2H: CH2COOEt), 4.07 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.20 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.52 (s, 2H: NH2), 8.71 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.00, 43.03, 60.18, 60.29, 111.61 (C5), 161.12, 163.89, 164.48, 165.61, 169.19; IR (KBr) ν (cm-1): 3327, 3157, 1732, 1715, 1667, 1266; MS (M+) m/z: 253. Anal. Calcd for C9H11N3O4 (253.2): C 52.17, H 5.97, N 16.59. Found: C 51.95, H 6.24, N 16.37.

Ethyl 2-[(dimethylamino)methyleneamino]-4-(2-ethoxy-2-oxoethyl)pyrimidine-5-carboxylate (4)
2-Amino-5-ethoxycarbonyl-4-ethoxycarbonylmethylpirimidine (2; 253 mg, 1 mmol) was suspended in EtOH (3 mL), DMFDMA (0.14 mL, 1 mmol) was added and the mixture was stirred under reflux for 1 h. Then additional 0.07 mL DMFDMA (0.07 mL, 5 mmol) was added and the reaction mixture was heated under reflux for 1 h. The mixture was cooled and concentrated under reduced pressure to give an oily residue, to which Et2O (3 mL) was added and the precipitate was collected by filtration to give 4 Yield 83 % (255 mg), mp 99-101 oC (from t-BuOMe). 1H NMR (CDCl3) δ: 1.25 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.38 (t, 3H: OCH2CH3, J = 7.2 Hz), 3.22 (s, 3H: N(CH3)2), 3.25 (s, 3H: N(CH3)2), 4.15 (s, 2H: CH2COOEt), 4.15 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.35 (q, 2H: OCH2CH3, J = 7.2 Hz), 8.81 (s, 1H: H4), 9.01 (s, 1H: =CH); 13C NMR (CDCl3) δ: 14.11, 35.35, 41.36, 43.84, 60.85, 60.96, 116.84, 159.46, 161.07, 164.96, 165.85, 167.61, 169.66; IR (KBr) ν (cm-1): 2980, 1709, 1634, 1515; MS (M+) m/z: 308. Anal. Calcd for C14H20N4O4 (308.3): C 54.54, H 6.54, N 18.17. Found: C 54.91, H 6.76, N 18.30.

Ethyl 4-[1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyleneamino]py- rimidine-5-carboxylate (5)
To a solution of compound 2 (3.10 g, 10 mmol) in n-propyl acetate (25 mL) DMFDMA (2.1 mL, 15 mmol) was added. The mixture was stirred under reflux for 6 hours. Then the mixture was cooled and concentrated under reduced pressure to give an oily residue to which Et2O (5 mL) was added and the precipitate was collected by filtration to give 5. Yield 55 % (1.78 g), mp 142-144 oC (from tert-butyl methyl ether). 1H NMR (CDCl3) δ: 1.13 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.32 (t, 3H: OCH2CH3, J = 7.2 Hz), 2.83 (br s, 6H: C=CHN(CH3)2), 3.16 (s, 3H: N=CHN(CH3)2), 3.19 (s, 3H: N=CHN(CH3)2), 4.05 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.27 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.62 (s, 1H: C=CHN(CH3)2), 8.73 (s, 1H: H4), 8.87 (s, 1H: N=CHN(CH3)2); 13C NMR (CDCl3) δ: 14.17, 14.30, 35.22, 41.15, 43.93, 59.52, 60.63, 98.35, 119.35, 151.34, 158.77, 159.54, 165.76, 165.93, 166.63, 168.20; IR (KBr) ν (cm-1): 3420, 2984, 1690, 1600, 1563, 1426; MS (M+) m/z: 363. Anal. Calcd for C17H25N5O4 (363.4): C 56.19, H 6.93, N 19.27. Found: C 56.34, H 7.16, N 19.25.

6-Substituted ethyl 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7a-j). General procedure.
363 mg (1 mmol) of compound 3 was dissolved in 5 mL of EtOH and 3 mmol of the corresponding amine and one drop of concentrated HCl was added. The mixture was stirred under reflux for 5 h. Then the mixture was cooled on the ice bad and the product was filtered. The crude product was recrystallised from corresponding solvent.

Ethyl 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7a)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and 25 % NH4OH (0.20 mL, 3 mmol). Yield 97 % (225 mg), mp 289-291 oC (from DMF). 1H NMR (DMSO-d6) δ: 1.30 (t, 3H: OCH2CH3, J = 6.9 Hz), 4.22 (q, 2H: OCH2CH3, J = 6.9 Hz), 7.44(br s, 2H: NH2), 8.01 (s, 1H: H7), 8.97 (s, 1H: H4), 11.69 (br s, 1H: NH); 13C NMR (DMSO-d6) δ: 14.17, 60.08, 106.83, 109.59, 143.17, 158.67, 160.33, 161.22, 163.22, 164.19; IR (KBr) ν (cm-1): 3429, 3140, 1717, 1674, 1614, 1443; MS (M+) m/z: 234. Anal. Calcd. for C10H10N4O3 (234.2): C 51.28, H 4.30, N 23.92. Found: C 51.42, H 4.02, N 23.60; HRMS: Calcd. for C10H10N4O3: 234,075290, found: 234,076020.

Ethyl 2-amino-6-methyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7b)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and methylamine (aqueous sol. 11.8 M, 0.25 mL, 3 mmol) Yield 93 % (230 mg), mp 298-300 oC (from DMF). 1H NMR (DMSO-d6) δ: 1.31 (t, 3H: OCH2CH3, J = 7.2 Hz), 3.48 (s, 3H: CH3), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.43 (br.s, 2H: NH2), 8.40 (br s, 1H: H7), 9.00 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.22, 36.17, 60.15, 106.71, 108.96, 147.41, 157.82, 160.55, 160.84, 163.23, 163.99; IR (KBr) ν (cm-1): 3375, 3184, 1729, 1641, 1574; MS (M+) m/z: 248. Anal. Calcd for C11H12N4O3 (248.2): C 53.22, H 4.87, N 22.57. Found: C 53.17, H 4.92, N 22.63.

Ethyl 2-amino-6-(2-hydroxyethyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7c)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and ethanolamine (0.18 mL, 3 mmol). Yield 40 % (112 mg), mp 240-245 oC (from EtOH). 1H NMR (DMSO-d6) δ: 1.31 (t, 3H: OCH2CH3, J = 6.9 Hz), 3.65 (m, 2H: NCH2), 4.01 (m, 2H: CH2OH), 4.25 (q, 2H: OCH2CH3, J = 6.9 Hz) 4.93 (t, 1H: CH2OH, J = 5.7 Hz), 7.44 (br s, 2H: NH2), 8.30 (s, 1H: H7), 9.01 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.24, 50.96, 58.56, 60.16, 106.27, 109.07, 147.72, 157.87, 160.52, 160.66, 163.35, 164.03; IR (KBr) ν (cm-1): 3385, 3177, 1716, 1680, 1650, 1611, 1468; MS (M+) m/z: 278. Anal. Calcd for C12H14N4O4 (278.3): C 51.80, H 5.07, N 20.13. Found: C 52.09, H 5.33, N 20.07.

Ethyl 2-amino-6-isopropyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7d)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and isopropylamine (0.26 mL, 3 mmol). Yield 84 % (232 mg), mp 170-174 oC (from EtOH). 1H NMR (DMSO-d6) δ: 1.34 (m, 9H: OCH2CH3, CH(CH3)2), 4.26 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.01 (m, 1H: CH, J = 6.6 Hz), 7.44 (br s, 2H: NH2), 8.25 (s, 1H: H7), 9.02 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.19, 21.03, 46.83, 60.36, 107.90, 109.05, 141.86, 157.15, 160.14, 160.88, 163.60, 164.07; IR (KBr) ν (cm-1): 3430, 3175, 1735, 1630, 1574, 1188. Anal. Calcd for C13H16N4O3 (276.3): C 56.51, H 5.84, N 20.28. Found: C 56.60, H 5.94, N 20.06.

Ethyl 2-amino-6-cyclopropyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7e)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and cyclopropylamine (0.21 mL, 3 mmol). Yield 75 % (206 mg), mp 239-240 oC (from DMF). 1H NMR (DMSO-d6) δ: 0.85-0.92 (m, 2H: CH2 (cyclopropyl)), 0.96 - 1.06 (m, 2H: CH2 (cyclopropyl)), 1.31 (t, 3H: OCH2CH3, J = 7.2 Hz), 3.22.-.3.31 (m, 1H: CH (cyclopropyl)), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.44 (br s, 2H: NH2), 8.11 (s, 1H: H7), 8.99 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 6.35, 14.21, 31.86, 60.29, 106.96, 109.08, 145.90, 157.51, 160.60, 161.51, 163.27, 164.09; IR (KBr) ν (cm-1): 3414, 3163, 1723, 1670, 1634, 1574. Anal. Calcd for C13H14N4O3 (274.3): C 56.93, H 5.14, N 20.43. Found: C 57.01, H 5.25, N 20.34.

Ethyl 2-amino-6-benzyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7f)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and benzylamine (0.33 mL, 3 mmol). Yield 88 % (285 mg), mp 204-209 oC (from DMF). 1H NMR (DMSO-d6) δ: 1.30 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.19 (s, 2H: CH2Ph), 7.26 - 7.40 (m, 5H: Ph), 7.50 (br s, 2H: NH2), 8.50 (s, 1H: H7), 9.02 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.19, 50.81, 60.34, 107.75, 109.13, 127.55, 127.63, 128.66, 136.90, 146.30, 157.80, 160.44, 160.82, 163.28, 164.11; IR (KBr) ν (cm-1): 3475, 3175, 1640, 1579, 1456. Anal. Calcd for C17H16N4O3 (324.3): C 62.95, H 4.97, N 17.27. Found: C 63.23, H 4.87, N 17.28.

Ethyl 2-amino-6-(4-methoxybenzyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7g)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and 4-methoxybenzylamine (0.39 mL, 3 mmol). Yield 68 % (240 mg), mp 238-245 oC (from EtOH). 1H NMR (DMSO-d6) δ: 1.30 (t, 3H: OCH2CH3 , J = 7.2 Hz), 3.73 (s, 3H: OCH3), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.10 (s, 2H: CH2Ph), 6.91 (d, 2H: Ar, J = 9.0 Hz), 7.30 (d, 2H: Ar, J = 9.0 Hz), 7.48 (br s, 2H: NH2), 8.47 (s, 1H: H7), 9.01 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.18, 50.19, 55.09, 60.31, 107.65, 109.12, 144.05, 128.81, 129.34, 146.06, 157.71, 158.84, 160.41, 160.78, 163.32, 164.07; IR (KBr) ν (cm-1): 3398, 3190, 1727, 1677, 1632, 1568. Anal. Calcd for C18H18N4O4 (354.4): C 61.01, H 5.12, N 15.81. Found: C 60.69, H 5.21, N 15.82.

Ethyl 2-amino-6-(2-ethoxycarbonylmethyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7h)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and glycine ethyl ester hydrochloride (419 mg, 3 mmol). Yield 96 % (307 mg), mp 240-246 oC (from DMF). 1H NMR (DMSO-d6) δ: 1.22 (t, 3H: CH2COOCH2CH3, J = 7.2 Hz), 1.31 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.16 (q, 2H: CH2COOCH2CH3, J = 7.2 Hz), 4.23 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.79 (s, 2H: CH2COOCH2CH3), 7.55 (br s, 2H: NH2), 8.45 (s, 1H: H7), 8.99 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.02, 14.21, 49.51, 60.33, 61.22, 107.46, 108.69, 146.96, 158.08, 160.33, 160.67, 163.13, 164.20, 168.03; IR (KBr) ν (cm-1): 3501, 3170, 1750, 1687, 1663, 1631, 1576. Anal. Calcd for C14H16N4O5 (320.3): C 52.50, H 5.03, N 17.49. Found: C 52.78, H 5.08, N 17.29.

Ethyl 2,6-diamino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7i)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and hydrazine (0.094 mL, 3 mmol) Yield 94 % (234 mg), mp 278-290 oC (from DMF). 1H NMR (DMSO-d6) δ: 1.30 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.23 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.99 (s, 2H: NNH2), 7.46 (rs, 2H: NH2), 8.31 (s, 1H: H7), 9.04 (s, 1H: H4); 13C NMR (DMSO-d6) δ: 14.17, 60.18, 105.48, 108.69, 146.48, 157.17, 159.93, 160.58, 162.72, 163.93; IR (KBr) ν (cm-1): 3373, 3178, 1728, 1650, 1619, 1573, 1205; MS (M+) m/z: 249. Anal. Calcd for C10H11N5O3 (249.2): C 48.19, H 4.45, N 28.10. Found: C 47.96, H 4.72, N 28.05.

Ethyl 6-hydroxy-2-[(hydroxyamino)methyleneamino]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7j)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and hydroxylamine (50 % aqueous sol. 0.20 mL, 3 mmol). Yield 93 % (272 mg), mp 245-250 oC (from DMF). 1H NMR (DMSO-d6) δ: 11.33 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.29 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.94 (d, 1H: NHCH=NOH, J = 9.6 Hz), 8.63 (s, 1H: H7), 9.26 (s, 1H: H4), 9.69 (br d, 1H: NHCH=NOH), 10.61 (br s, 2H: OH, NHCH=NOH); IR (KBr) ν (cm-1): 3342, 1725, 1677, 1588, 1541; MS (M+) m/z: 293. Anal. Calcd for C11H11N5O5 (293.3): C 45,06, H 3,78, N 23,88. Found: C 44,88, H 4,01, N 23,62.

ACKNOWLEDGEMENTS
The financial support from the Slovenian Research Agency, Slovenia through grants P0-0502-0103, P1-0179, and J1-6689-0103-04 is gratefully acknowledged. Financial support by the pharmaceutical companies LEK-SANDOZ, Ljubljana, and KRKA, Novo mesto, is fully appreciated.


Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday

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13. For a review see: B. Stanovnik, J. Svete, Mini-Rev. Org. Chem., 2005, 2, 211. CrossRef
14. D. Bevk, U. Groselj, A. Meden, J. Svete, and B. Stanovnik, Helv. Chim. Acta, 2007, 90, 1737. CrossRef
15. S. Zupancic, J. Svete, and B. Stanovnik, Heterocycles, 2000, 53, 2033. CrossRef
16. a) D. Bevk, R. Jakse, A. Golobic, L. Golic, A. Meden, J. Svete, and B. Stanovnik, Heterocycles, 2004, 63, 609; CrossRef b) D. Bevk, R. Jakse, J. Svete, A. Golobic, L. Golic, and B. Stanovnik, Heterocycles, 2003, 61, 197. CrossRef
17. D. Bevk, L. Golic, A. Golobic, J. Svete, and B. Stanovnik, Heterocycles, 2005, 66, 207. CrossRef
18. D. Bevk, L. Groselj, A. Meden, J. Svete, and B. Stanovnik, Tetrahedron, 2006, 62, 8126. CrossRef
19. For a review see: D. Bevk, J. Svete, and B. Stanovnik, Enaminones and Related Compounds in the Synthesis of Pyrazoles, in: Modern Approaches to the Synthesis of O- and N-Heterocycles, ed. by T. S. Kaufman and E. L. Larghi, Trivandrum, 2007, Vol 3, pp. 73-88.
20. O. A. Attanasi, G. Favi, P. Filippone, A. Golobic, B. Stanovnik, and J. Svete, J. Org. Chem., 2005, 70, 4307. CrossRef
21. O. A. Attanasi, G. Favi, P. Filippone, A. Golobic, F. R. Perulli, B. Stanovnik, and J. Svete, Synlett, 2007, 2971. CrossRef
22. a) B. Stanovnik and J. Svete, Targets Heterocycl. Systems, 2000, 4, 105; b) R. Jakse, J. Svete, B. Stanovnik, and A. GolobiC, Tetrahedron, 2004, 60, 4601; CrossRef c) B. Japelj, S. Recnik, P. Cebasek, B. Stanovnik, and J. Svete, J. Heterocycl. Chem., 2005, 42, 1167 CrossRef