R. R. Makhmudov

Synthesis, Antiinflammatory and Analgesic Activity of 4-Antipyrine Derivatives

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

Synthesis And Analgesic Activity Of 4-Aryl-2-Arylamino-4-OXO-2-Butenoic Acid Hetarylamides

4-Aryl-2-arylamino-4-oxo-2-butenoic acid hetarylamides were synthesized by the reaction of 4-aryl-2-hydroxy-4-oxo-2-butenoic acid hetarylamides with aromatic amines and also by ring opening of 5-aryl-3-arylamino-3H-furan-2-ones by heterocyclic amines. Their analgesic activity was studied. Compounds with activity comparable to and exceeding that of the reference drugs and with low toxicity were found.

Synthesis and Analgesic Activity of 5-Aryl-4-Heteroyl-3-Hydroxy-1-(2-Thiazolyl)-3-Pyrrolin-2-Ones and their Derivatives

The three-component reaction of methyl 2-heteroylpyruvates with aromatic aldehydes and 2-aminothiazole was used to synthesize 5-aryl-4-(2-heteroyl)-3-hydroxy-1-(2-thiazolyl)-3-pyrrolin-2-ones. The corresponding 3-amino derivatives were obtained from the synthesized compounds by nucleophilic substitution with o-aminophenol, m-phenylenediamine, hydroxylamine, and urea; the corresponding pyrrolo[3, 4]pyrazoles, with hydrazine hydrate and phenylhydrazine. The structures of the new compounds were established using IR, PMR, and mass spectra and qualitative reactions. The acute toxicity and analgesic activity of the synthesized compounds were studied.

Synthesis and Study of the Antibacterial and Analgesic Activity of 3-Acyl-1,2,4,5-tetrahydro-[1,2-a]quinoxaline-1,2,4-triones

As is known, derivatives of 1,2,3,4-tetrahydro-2-quinoxalones possess pronounced anticonvulsant and analgesic properties [1]. It was of interest to broaden the spectrum of pharmacological activity of compounds belonging to this class by modifying the base structure by annelation with a pyrrole cycle via the 1 – 2 bond of quinoxalone. For this purpose, we synthesized a series of 3-acyl-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones (X – XVIII) using reactions of 3-alkoxycarbonylmethyleneand 3-phenacylidene-1,2,3,5-tetrahydro-2-quinoxalones (I – IX) with oxalyl chloride in anhydrous chloroform conducted by the method developed in [2].

Synthesis and Analgesic Activity of Substituted 4-(Het)aryl-4-oxo-2-thienylaminobut-2-enoic Acids

A series of 4-aryl-4-oxo-2-thienylaminobut-2-enoic acids was synthesized by interaction of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids with Gewald 2-aminothiophenes. All the compounds synthesized were found to have analgesic activity at or above the levels of the reference compounds.

Synthesis and analgesic activity of the products of the interaction between 3-aroylpyrrolo[1,2-a]-quinoxaline-1,2,4(5H)-triones with benzoic acid hydrazides

The synthesis, properties, structure, and analgesic activities of the products of the interaction of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with benzoic acid hydrazides are described. The significance of the structure-function relationship is discussed.

Substituted amides and hydrazides of acylpyruvic acids. Part 11. Synthesis and biological activity of 4-aryl-2-hydroxy-4-oxo-2-butenoic acid n-(1,3-thiazol-2-yl)amides

As is known, alkyl-, aryl-, and heterylamides of acylpyruvic (or 4-substituted 2-hydroxy-4-oxo-2-butenoic) acid exhibit a broad spectrum of pharmacological properties, including antimicrobial [2 – 14], anticonvulsant [8, 9, 12, 15, 16], antiinflammatory [7, 10, 11, 17 – 23], and analgesic [2, 3, 7 – 20, 22, 23] activity at a low toxicity [3 – 5, 7 – 11, 15, 17 – 21, 23]. It was reported [17] that the group of aroylpyruvic acid thiazolyl amides not containing substituents in the thiazole cycle also includes compounds possessing analgesic and antiinflammatory properties. According to our previous data, N-(1,3-thiazol-2-yl)amide of pivaloylpyruvic acid exhibits a moderate bacteriostatic effect [9] and pronounced analgesic and anti-inflammatory properties [3, 23]. In continuation of the search for new biologically active compounds among acylpyruvic acid thiazolyl amides, we have synthesized a series of 4-aryl-2-hydroxy-4-oxo-2-butenoic acid N-(1,3-thiazol-2-yl)amides (Ia – Iz) substituted at the thiazole ring and studied some pharmacological properties of the obtained compounds. Amides Ia – Iz were synthesized using a well-known method [9, 17, 24] based on the reactions of 5-arylfuran-2,3-diones (IIa – IIg) with 4-ethyl-, 4-aryl-, and 4,5-dimethyl-2-amino-1,3-thiazoles. Amides Ia – Iz appear as readily crystallizable substances of a light-yellow or yellow color, which are insoluble in water and hexane, sparingly soluble in ethanol, acetonitrile, ethyl acetate, dioxane, and benzene, and soluble in DMSO and DMF. For Ar, R, and R see Table 1.

Substituted Amides and Hydrazides of Acylpyruvic Acids. Part 9. Synthesis, Antimicrobial and Analgesic Activity of Substituted 4-Aryl-3-halogen-2,4-dioxobutanoic Acid Amides

As is known, aroylpyruvic acid esters (Ix, Iy) and amides (IIx, IIy) exhibit a broad spectrum of pharmacological properties, including anticonvulsant [2 – 4], antiinflammatory [2, 5], analgesic [2, 5, 6], and antimicrobial [3, 5, 7] activity, at a low toxicity [2 – 6]. It was reported that halogenation of aroylpyruvic acid esters (I) leads to the formation of 3-substituted halogen derivatives (III) not enolized at the -dicarbonyl fragment. In comparison with the initial acid esters (I), the 3-halogen-substituted analogs (III) exhibit higher bacteriostatic [8, 9] and analgesic [10] activity. According to our data, chlorination of some aroylpyruvic acid arylamides II leads (with preparative yield) to the formation of biologically active 4-aryl-2,4-dioxo-3-chlorobutanoic acid amides (IV, Hal = Cl) [11]. In continuation of our previous investigations of the biological activity of halogen-containing amides IV, we have reacted substituted aroylpyruvic acid amides II with bromine and chlorine under mild conditions, isolated a series of new 4-aryl-3-halogen2,4-dioxobutanoic acid amides (IVa – IVo) [12 – 14], and studied their pharmacological properties. Compound R R Hal

Antinociceptive Activity of Dimethyl 7-aryl-2-(2-rimino)-8-[(3-aryl)quinoxalin-2-yl]-9-oxo-1,6-dioxaspiro[4.4]non-3,7-diene-3,4-dicarboxylates

The antinociceptive activity of dimethyl 7-aryl-2-(2-R-imino)-8-[(3-aryl)quinoxalin-2-yl]-9-oxo-1,6-dioxaspiro[4.4]non-3,7-diene-3,4-dicarboxylates was studied.

Synthesis and analgesic and antimicrobial activities of 2-(3,3-dialkyl-1,2,3,4-tetrahydroisoquinolin-1-idene)ethanoic acid ureides

A series of 2-(3,3-dialkyl-1,2,3,4-tetrahydroisoquinolin-1-idene)ethanoic acid ureides were synthesized via cyclocondensation of dialkylbenzylcarbinols and cyanoacetylurea. Experiments showed that hydrochlorides of the synthesized compounds exhibited an analgesic effect that surpassed that of metamizole sodium. It was established that four (of a total of seven) synthesized compounds possessed minimum inhibiting concentrations of about 31.2 μg/mL against Staphylococcus aureus.