A. Rubtsov, R. Makhmudov, N. V. Kovylyaeva
Nov 1, 2002
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0
Influential Citations
16
Citations
Journal
Pharmaceutical Chemistry Journal
Abstract
Previously [1 – 3], we have reported on the derivatives of 4-aryl-2,4-dioxobutanoic (aroylpyruvic) acids (Ia – Ie, see scheme) possessing analgesic, antiinflammatory, anticonvulsant, and other pharmacological activities. In continuation of these investigations, we have attempted the synthesis of compounds combining the structures of pyruvic acid and 4-aminoantipyrine, the latter representing a base heterocycle in the series of non-narcotic analgesics [4]. Earlier [5], we obtained 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl amides, which exhibit complete enolization in solution and exist in the form of 4-antipyrylamides of 4-aryl2-hydroxy-4-oxo-Z-2-butenoic acids with intramolecular hydrogen bonds (IHBs) of the H-chelate type. It was established that the reactions of acids Ia – Ie with 4-aminoantipyrine (II) do not yield the anticipated salts III. Instead, we obtained 4-aryl-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylamino)-4-oxo-2acids IVa – IVe (see scheme and Tables 1 and 2). The IR spectra of acids IVa – IVe exhibit either two broadened absorption bands in the regions of 3458 – 3468 and 3415 – 3417 cm – 1 (compounds IVa and IVd) or a “shelf” within 3416 – 3467 cm – 1 (IVb, IVc, IVe) characteristic of the NH group, a band at 1733 – 1735 cm – 1 characteristic of the stretching vibrations of carboxy groups, and a series of bands in the interval from 1587 to 1669 cm – 1 characteristic of a lactam carbonyl in the heterocycle, C=O carbonyl in IHBs, C=N, and C=C (exact assignment being very difficult). The H NMR spectra of acids IVa – IVe contain two sets of signals suggesting the presence of two isomers (A and B): where Ant denotes the antipyrine residue. The existence of such isomers (A and B) was previously reported for structurally close 4-aryl-2-arylamino-4-oxo-2-butenoic acids [6]. The A form is characterized by the presence of a broadened signal due to the protons of COOH groups (13.1 – 13.3 ppm), a singlet due to the protons of NH groups involved in strong IHBs (11.52 – 11.63 ppm), and a singlet due to the protons of CH groups (6.39 – 6.44 ppm). In the spectrum of the B form, the signals from protons of the NH and CH groups are observed in a stronger field (9.56 – 9.71 and 6.08 – 6.39 ppm, respectively), while the signal from COOH groups in this form was not detected (probably because of considerable broadening). According to the relative signal intensity, the content of the B form ranges within 9 – 19%. Similarly to the reactions with acids Ia – Ie, 4-aminoantipyrine can interact with esters If – Ih to form methyl esters of 4-aryl-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylamino)-4-oxo-2-butenoic acids (Va – Vc). Judging by the H NMR spectra (Table 1), compounds Va – Vc exist in solution in the form of Z and E isomers (the content of the latter form amounting to 9 – 12%). The lower yields of compounds Va – Vc as compared to those of IVa – IVe are related to greater losses in the course of purification. 4-Aminoantipyrine also smoothly reacts with esters Ii – In to form 4-aryl-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-ylamino)-4-oxo-2-butenoic acid amides (VIa – VIg). According to the H NMR data (Table 1), compounds VIa – VIg also exist in solution in the form of Z and E isomers. We have established that acids IVa – IVe exhibit cyclization under the action of acetic anhydride, which leads to the formation of 2-aryl-1,5-dimethyl-4-(2-oxo-5-phenyl-2,3-dihydro-3-furanylideneamino)-1,2-dihydropyrazol-4ones (VIIa – VIIe) [7]. The H NMR spectra of compounds VIIa – VIIe exhibit no signals from protons of the NH groups present in the initial compounds (IVd – IVe); the IR spectra display (besides the absorption bands at 1651 – 1654 cm – 1