S. V. Shorshnev

Study of the Products of Reaction of 5-Azauracil with Malondiamide and Aromatic C-Nucleophiles

As is known, hexamethylmelamine has been used in the USA for the treatment of lung carcinoma [1]. Another 1,3,5-triazine derivative, 5-azacytidine, was used for the treatment of acute lymphoblastic leukemia [2]. Apparently, the antitumor activity of some 1,3,5-triazine derivatives is related to the fact that these compounds, being antimetabolites of pyrimidine bases, are capable of accumulating in tumor cells and damaging these cells. At the same time, there are well-known chemical transformations of 5-azauracils with the formation of various pyrimidine derivatives. For example, 1,3-dimethyl-5-azauracil interacting with fluoracetamide in the presence of lithium diisopropylamide converts into the well-known antitumor drug 5-fluorouracil [3]. 5-Carboxamido and 5-cyano substituted uracil derivatives were obtained via interactions of 1,3-dimethyl-5-azauracil with malonamide and cyanamide, respectively, in the presence of sodium ethylate [4]. Previously, it was reported in a brief communication [5] that 5-azauracil (I), interacting with 1-phenyl-3-methyl-5-pyrazolone (IIa) without charge activation of the reagents, converted into a derivative of dipyrazolylmethane (IIIa) and biuret (IV). The same paper reported on the formation of stable 6-indolyl adducts of 5-azauracil. In continuation of the investigation of chemical transformations of 5-azauracil, we have studied the products of conversion of this compound upon interaction with some -dicarbonyl compounds representing heterocyclic and aromatic C-nucleophiles. It was found that 5-azauracil (I) can smoothly react not only with 1-phenyl-3-methyl-5-pyrazolone (IIa), but with some other 1-phenyl-5-pyrazolone derivatives (IIb – IId) as well. In these reactions, 5-azauracil acts as the donor of a one-carbon fragment; therefore, I can be used in preparative chemistry for the synthesis of dipyrazolylmethane derivatives III (see scheme and Table 1). The reaction of 5-azauracil with indoles (V) proceeds differently. This interaction (like that with pyrazolones) requires no charge activation of the reagents. The reaction products represent stable -adducts of 6-indolyl and 5-azauracil (VIa and VIb), the structure of which was confirmed by the data of H and C NMR spectroscopy and mass spectrometry [5]. In this study, we have synthesized for the first time a -adduct of 5-azauracil and -dicarbonyl compound. Heating 5-azauracil in butanol with malonamide (VII) leads to the formation of 1,2,3,4,5,6-hexahydro-6-(dicarbaminomethyl)-1,3,5-triazine-2,4-dione (VIII). The character and positions of proton signals in the H NMR spectrum of this compound confirm the proposed structure. Indeed, the doublet due to proton of the malonamide fragment is observed at 3.43 ppm; H-6 proton of triazine is manifested by a multiplet at 4.8 ppm (the splitting is caused by spin–spin coupling with the neighboring NH protons of the triazine ring and with proton of the malonamide fragment). The 1and 5-NH signals are observed in the region of 7.6 – 7.7 ppm. A broad singlet due to 3-NH proton is observed at 9.28 ppm. The singlets due to amino groups of the malonamide fragment are manifested at 7.27 and 7.30 ppm. It is interesting to note that adducts VI and VIII are formed even when reagents are mixed in DMSO at room temperature. The NMR spectrum measured upon keeping the mixture at this temperature reveals an increase in the adduct concentration. An original transformation was effected by interaction of 5-azauracil with o-phenylenediamine (IX): performed in the presence of hydrochloric acid, this reaction yielded 1,2,3,4,5,6-hexahydro-6-(3 ,4 -diaminophenyl)-1,3,5-triazine

Reactions of quinazoline and its 4-oxo- and 4-chloro-substituted derivatives with nucleophiles

Reaction of quinazoline (I) with 2-methylindole, pyrogallol, and 1-phenyl-3-methylpyrazol-5-one in the presence of acid led to the formation of C-4 adducts II, III, and V. Adduct IV was obtained by heating I with 1,3-dimethylbarbituric acid without acid catalysis. 1-Phenyl-3-methylpyrazol-5-one reacts with I without acid catalysis with the formation of dipyrazolylmethane VI. 4-Chloroquinazoline VIII reacts with 1-phenyl-3-methylpyrazol-5-one to yield 4-(1-phenyl-3-methyl-5-oxopyrazol-4-yl)quinazoline IX and dipyrazolylmethane VI. Heating VIII with 2-methylindole leads to formation of 4-(2-methylindol-3-yl)quinazoline X and tris(2-methylindol-3-yl)methane XI. The proposed structures were confirmed by NMR spectral data.

Cyanuric and Thiocyanuric Acid Esters: New Carriers of Boron-Containing Molecular Fragments

The class of s-triazine derivatives contains compounds possessing biological activity of various types. In particular, it was suggested to use hexamethylmelamine for the treatment of lung carcinoma [1]. Another 1,3,5-triazine derivative (5-azacytidine) is used for the treatment of acute lymphoblastic leukemia [2, 3]. It was suggested that the antitumor activity of some 1,3,5-triazine derivatives is related to the fact that these compounds represent antimetabolites of pyrimidine bases and are capable of accumulating in tumor cells [4]. A currently important task consists in the delivery of boron-containing molecular fragments to tumor tissues and the accumulation of these agents within the framework of boron neutron capture therapy (BNCT) [5]. We believe that a promising group of heterocyclic carriers of such boron-containing molecular fragments are s-triazines admitting multivariate chemical modification. For example, boron-containing derivatives can be synthesized using propargyl substituted s-triazines. This paper is devoted to the synthesis of propargyl derivatives of s-triazines and related boron-containing preparations. As is known, the substitution of amines for halogens in 2,4,6-tri-chloro-s-triazine (cyanuric chloride) proceeds in a stepwise manner (at different temperatures) and can be terminated at the stage of mono(0 – 5°C), di-(40 – 45°C), or triamino (> 100°C) derivatives. In order to provide for smooth conversion, it is necessary to use a base for binding liberated HCl [6, 7]. By the same token, cyanuric chloride exhibits stepwise reactions with alcohols. By varying the temperature, the relative amount of alcohol, and the acceptor of hydrogen chloride, it is also possible to obtain mono-, di-, and trialkoxy-s-triazines. However, if the initial alcohol contains electron-acceptor groups in the positions, the stepwise character is weakly pronounced and the reaction mixture contains various alkoxylation products and unreacted components, which art difficult to separate [8]. We have studied the reaction of cyanuric chloride (I) with propargyl alcohol in acetone in the presence of alkali and synthesized 2,4,6-tripropargyloxy-1,3,5-triazine (II) with a high yield using a method analogous to that described in [9]. The H NMR spectrum of compound II contains signals from the protons of CH groups of the propargyl fragment in the form of a triplet at = 3.62 ppm (J = 2.4 Hz), while protons of the CH2 groups are manifested by a doublet at 5.04 ppm (J = 2.4 Hz). Heating propargyl cyanurate II for a short time in diluted hydrochloric acid leads to the formation of cyanuric acid (III). At the same time, heating in a 5 % aqueous NaOH solution leads to a monooxy derivative (IV). The H NMR spectrum of this product displays a broadened signal from CH groups of propargyl fragments at 3.68 ppm and the signal from OCH2 groups at 4.99 ppm. In addition, the spectrum exhibits two weak-field signals at 11.13 and 12.76 ppm with a ratio of 1 : 5, which can be assigned to protons of the NH and OH groups. The equivalence of protons in the two propargyl groups is indicative of the symmetry of the molecule of compound IV. This H NMR spectrum is possible if the DMSO solution of compound IV comprises an equilibrium mixture of enole (A) and keto (B) isomers: Pharmaceutical Chemistry Journal Vol. 38, No. 4, 2004

New Conversions and Functionalization Possibilities in Pyrimido[4,5-e][1,2,4]triazine-6,8-diones

As is known, the pyrimido[4,5-e][1,2,4]triazine nucleus (7-azalumazine) is the base of a group of natural antibiotics including fervenulin, toxoflavin, MSD-92, and reumycin [1]. The most effective biological action is produced by the antibiotic reumycin, which is used in medicine as an antitumor agent [2]. The subgroup of isofervenulins, representing derivatives of pyrimido[4,5-e][1,2,4]triazine-6,8-diones (6-azalumazines), contains compounds possessing antiviral [3], antimicrobial [4], antiinflammatory, and analgesic properties [5]. Compounds of the 6-azalumazine system are most readily synthesized by condensation of alloxane with S-alkylisothiosemicarbazide as described in [6], where it was also demonstrated that various 3-amino derivatives of 6-azalumazine can be obtained by nucleophilic substitution of 3-alkylthio group. However, rigid reaction conditions sometimes result in destruction of the pyrimidine ring. For example, heating 3-ethylthio-6-azalumazine in benzylamine leads to the formation of 6-benzylamide-3,5-bis-benzylamino-as-triazinecarboxylic acid. Later [4], it was suggested to synthesize 3-substituted 6-azalumazines using 3-alkylsulfonyl derivatives obtained through oxidation of the corresponding 3-alkylthio compounds. It was shown that alkylsulfonyl groups can be replaced under mild conditions by oxy and azido groups, as well and by various amine residues, without decomposition of the uracil fragment. In this study, we have expanded the series of nucleophilic agents in order to obtain new 3-substituted 6-azalumazines. It was of both theoretical and practical interest to study reactions involving various types of C-nucleophiles, which can open ways to new series of pyrimidotriazine derivatives. Stirring sulfone Ia with a 3 – 5-fold excess of sodium sulfide leads to 7,9-dioxopyrimido[4,5-e][1,2,4]triazine-3thione (IIa) with a yield of 65 – 70% (Scheme 1). Similar reactions take place with dimethylpyrimidotriazine Ib. In particular, stirring sulfone Ib with a 2.5 – 3-fold excess of sodium sulfide leads to 6,8-dimethyl-7,9-dioxopyrimido[4,5-e][1,2,4]triazine-3-thione (IIb) (Scheme 1). The electron impact-excited mass spectra (EIMS) of thiones IIa and IIb contain the peaks of molecular ions and show a fragmentation pattern similar to that for 3-aryl and 3-heteryl substituted 6-azalumazines [7], whereby nitrogen molecule is detached from the triazine moiety of the molecule. Subsequently, RNCO fragment is detached from the uracil moiety of [M–N2] + ions, with the formation of species with m z = 126 (for IIa) and 140 (IIb), respectively. When a 5 – 6-fold excess of sodium sulfide is introduced into the reaction with sulfone Ib, the process yields 4-methylamino-5-methylcarbamoyl-1,2,4-trazine-3-thione (III) (instead of thione IIb). The proposed structure of thione III was confirmed by the data of H NMR spectroscopy and mass spectrometry. Indeed, the signals of methyl groups in the H NMR spectrum appear as doublets due to spin – spin coupling with protons of the NH groups. The mass of compound III determined from the mass spectrum coincides with the calculated value. The proposed structure is also confirmed by detachment of CH2NH and CH3NHCO fragments. The presence of [M–SH] peak in the mass spectrum indicates that the gas phase contains compound III in the thiol form. Alternatively, 1,2,4-triazinethione III was obtained by stirring thione IIb with a 5% aqueous alkali solution at room temperature. Conversions of the unsubstituted 6-azalumazine and a 3-methyl derivative in alkaline media were previously studied by H NMR [8]. It was established that the pyrimidine ring opens at pH 9 predominantly at the N5–C6 bond with the formation of carbamic acids A (Scheme 2). Upon subsequent alkalization of the reaction mass to pH > 10, these acids decompose to carbamoyltriazines B. It was also found that the reaction of triazine ring opening is reversible: Pharmaceutical Chemistry Journal Vol. 37, No. 5, 2003

Intramolecular Thermal Condensation of 3-Acetyl-5-Oxopyrazolo[1,5-a]quinoline-4-ethylcarboxylate: a Simple Pathway to the New Tetracyclic System Containing Fluoroquinolone Fragment

Synthetic antibiotics of the new class of fluoroquinolones are already widely used in medicine and veterinary as effective antibacterial drugs [1 – 6]. Previously [7], we described the synthesis of tricyclic fluoroquinolones (pyrazolo[1,5-a]quinolones) via cyclization of 7-substituted 1-amino-6-fluoro-1,4-dihydro-4-oxoquinoline-3-ethylcarbox ylates with -diketones. Investigations of the properties of these tricyclic derivatives showed that 3-acyl groups are subject to ipso-substitution under the action of bromine or sulfuric acid [8]. Chemical transformations and some possible mechanisms responsible for the conversion of pyrazoloquinolones were considered in [9]. Continuing our investigations into the properties of pyrazoloquinolones, we have found another transformation that opens the way to the new tetracyclic compounds containing fluoroquinolone fragments. After a 2-h treatment of 3-acetyl-7,8-difluoro-4-ethoxycarbonyl-2-methyl-5-oxo-1,5dihydropyrazolo[1,5-a] (I) in boiling ortho-dichlorobenzene, we obtained tetracyclic compound II. The H NMR spectrum of compound II id DMSO-d6, while displaying no signals of protons of the CH2 group, contained a one-proton singlet of the CH group at = 7.51 ppm. This is evidence that compound II occurs in solution predominantly in the enole form B. In addition, the spectrum contained a weak-field signal at 11.7 ppm indicative of participation of the oxy group in the formation of a stable intramolecular hydrogen bond.