Arch. Pharm. Pharm. Med. Chem. 2001, 334, 263–268
Sydnone derivatives 265
The characterization data of thiazoles 6a–x are given in
Table 1. The results of elemental analysis agree with the
theoretical values within the limits of experimental error.
The formation of 6 was supported by the disappearance of
IR bands corresponding to NH2 and C=S groups of 4. In a
typical example the IR spectrum of 6j shows the absence
of peak at 3454 cm–1 (NH2) and 1554 cm–1 and 1231 cm–1
(C=S attached to N atom). A peak at 1756 cm–1 typical o f
a carbonyl group clearly indicates the presence of a
sydnone moiety in compound 6j. The1H-NMR spectrum of
6l shows three singlets at δ = 2.31, 2.50, and 3.91, each
integrating for three protons corresponding to a methyl
group on phenyl, a methyl group of a pyrazole moiety, and
a methoxy group, respectively. The signal due to thiazole
proton appeared at δ = 7.68 as singlet[16]. The NH proton
appeared as a broad singlet at δ = 13.6. The aromatic
protons of p-anisyl group appeared as two doublets cen-
tered at δ = 6.97 and δ = 7.51 integrating for two protons
each. The p-tolyl protons appeared as multiplets at δ =
7.3–7.4, integrating for four protons. Similarly the 1H-NMR
spectra of few more compounds were recorded and the
signals are assigned as follows:
more active (Table 2). Similarly, among the compounds
tested for analgesic activity 6f, 6r, and 6u showed a marked
activity (Table 3). Most of the compounds tested showed
promising CNS depressant activity comparable with that of
standard drug pentobarbitone (Table 4).
Acknowledgement
The authors are thankful to Head, RSIC, Punjab University,
Chandigarh and Head, RSIC, CDRI, Lucknow for spectral and
analytical data.
Experimental section
All melting points were determined by the open capillary method
and are uncorrected. IR spectra (KBr disc) were recorded on a
JASCO FT IR 430 spectrophotometer. 1H-NMR spectra were
recorded on Bruker AC 300F (300 MHz) NMR spectrometer
using CDCl3/DMSO-d6 as solvent and tetramethylsilane as
internal standard. The chemical shifts are expressed in δ scale
downfield from TMS and proton signals are indicated s = singlet,
d = doublet, t = triplet, m = multiplet. Mass spectra were
recorded on a Jeol-JMS-D 300 mass spectrometer operating at
70 eV. UV spectra were recorded on UV-visible Anthelie spec-
trophotometer in quartz cell at room temperature. The purity of
the compounds was confirmed by TLC.
6c: 1H-NMR, CDCl3+DMSO-d6; δ = 2.5 (s, 3H, CH3), 7.79
(d, 2H,ortho protons of p-nitrophenyl), 8.28 (d, 2H, meta
protons of p-nitrophenyl), 7.6–7.7 (m, 5H, phenyl protons),
7.79 (s, 1H, thiazole 5H),and δ = 13.4 (s, 1H, NH).
6s: 1H-NMR, CDCl3+DMSO-d6: δ = 2.56 (s, 3H, CH3), 3.91
(s, 3H, OCH3), 7.1 (d, 2H, anisyl ortho protons), 7.61 (d,
2H, anisyl meta protons), 7.87 (s, 1H, thiazole 5H), 14.7 (br,
1H, NH), and δ = 7.9–8.1 (m, 4H, Ar-H).
6j: 1H-NMR, CDCl3+DMSO-d6: δ = 2.38 (s, 3H, CH3), 2.46
(s, 3H, CH3), 7.76 (d, 2H, ortho protons of p-nitrophenyl),
8.18 (d, 2H, meta protons of p-nitrophenyl), 7.28 (d, 2H,
ortho protons of p-tolyl), 7.46 (d, 2H, meta protons of
p-tolyl), 7.78 (s, 1H, thiazole 5H) and δ = 13.3 (br, 1H, NH).
General procedure for the preparation of ethyl-2-arylhydra-
zono-3-oxobutyrate 3
Appropriate amine 1 (0.01 mol) was dissolved in dilute hydro-
chloric acid (10 ml) and cooled to 0 °C in an ice bath. To this,
a cold solution of sodium nitrite (0.02 mol) was added. The
diazonium salt 2 solution was filtered into a cold solution of ethyl
acetoacetate (0.05 mol) and sodium acetate in ethanol. The
separated yellow solid was filtered, washed with water and
recrystallized from ethanol. The compounds prepared accord-
ing to this procedure are:
Ethyl-2-(4-chlorophenyl)hydrazono-3-oxobutyrate 3a
6g: 1H-NMR, CDCl3: δ = 2.4 (s, 3H, CH3), 7.4–7.8 (m, 10H,
Ar-H), 7.81 (s, 1H, thiazole 5H) and δ = 13.1 (br. 1H, NH).
Mp 94 °C (lit [9], 94 °C), yield 80%.
Ethyl-2-(4-tolyl)-hydrazono-3-oxobutyrate 3b
6f: 1H-NMR, DMSO-d6: δ = 2.31 (s, 3H, CH3), 3.86 (s, 3H,
OCH3), 6.91 (d, 2H, ortho protons of p-anisyl), 7.4 (d, 2H,
meta protons of p-anisyl), 7.6–7.8 (m, 5H, phenyl protons),
7.78 (s, 1H, thiazole 5H) and δ = 13.5 (br, 1H, NH)
Mp 62 °C (lit [9], 63 °C ), yield 69%.
Ethyl-2-(4-nitrophenyl)hydrazono-3-oxobutyrate 3c
Mp 123 °C, yield 78%. UV: λmax = 242 nm
The mass spectrum of 6p showed the molecular ion peak
at m/z, 509/511 consistent with the molecular formula
C22H16ClN7O4S. The peak at 451/453 is due to the loss of
(NO-CO) fragment which is typical of sydnone containing
molecules. Similarly the mass spectra of few more com-
pounds were recorded and are in conformity with the
assigned structure (Table 1).
IR: 3413cm–1(NH); 1686cm–1(C=O) & 1598cm–1(NH-N=C)
Ethyl-2-(2-carboxyphenyl)hydrazono-3-oxobutyrate 3d
Mp 142 °C, yield 70%.
Ethyl-2-(4-carboxyphenyl)hydrazono-3-oxobutyrate 3e
Mp 195 °C, (lit.[9], 196 °C). yield 70%.
Some selected compounds from this series were subjected
to anti-inflammatory[13], analgesic[14], and CNS depressant
activity[15] studies as per the procedures reported in the
literature. The screening studies indicated that compounds
6s, 6d, 6n, and 6u showed significant anti-inflammatory
activity in the 1st hour. However, at the end of the 3rd and
5th hours, compounds 6a, 6d, 6s, and 6u showed signifi-
cant activity. From observation it can be concluded that
compounds with chlorine and carboxylic substituents are
Ethyl-2-(4-anisyl)hydrazono-3-oxobutyrate 3f
Mp 55 °C, (lit.[9], 56 °C). yield 72%.
Ethyl-2-phenylhydrazono-3-oxobutyrate 3g
Mp 68 °C, yield 65%.