Search

A new convenient synthon for heterocyclic chemistry, namely 1H-pyrazolo[3,4-b]pyridin-3-ylguanidine was successfully prepared by selective guanylation of 1H-pyrazolo[3,4-b]pyridin-3-amine. A series of 3,4-dihydropyrido[2′,3′:3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amines was synthesized from 1H-pyrazolo[3,4-b]pyridin-3-ylguanidine using aldehydes or ketones as one-carbon inserting reagents. The tautomeric preferences of the products were determined using spectroscopic (e.g., 2D NOESY NMR) and single crystal X-ray diffraction data.

The substitution of hydrogen by fluorine as bioisosteric replacement has been practised widely in agricultural and medicinal chemistry. This has led to the discovery of many pesticides and therapeutically useful chemical entities. The 1,3,5-triazine heterocycle is found in many biologically active compounds that exhibit herbicidal, antimicrobial, antiparasitic and anticancer properties. The objective of the chapter is to present a review on the developments in the fields of fluorinated 1,3,5-triazines chemistry and aspects of their application in the last decade. The chapter is organized according to the structural and synthetic aspects of the fluorinated 1,3,5-triazines chemistry. Based on the structure of the heterocyclic nucleus and location of the fluoro substituent, the fluorinated 1,3,5-triazines are presented as three separate groups. Within the first group, 1,3,5-triazines bearing fluorinated substituent at carbon atom of the heterocyclic core are discussed with further structural discrimination by nature of the linkage between 1,3,5-triazine nucleus and the fluorinated substituent. Three types of the connections are categorized namely, C-C bond, C-X bond (X = N, O or S) and 1,3,5-triazines with fluorine atom directly attached to endocyclic carbon atom. Further classification within the subgroups is based on the synthetic methods used for the substituent at nitrogen atom are categorized into a second group, which includes 1,3,5-triazines without substitution at the ring carbon atoms, 1,3,5-triazinones and 1,3,5-triazinium salts. The third group includes the fluorinated fused heterocyclic compounds with 1,3,5-triazine nucleus, particularly azolo-1,3,5-triazines and azino-1,3,5-triazines. Special references are made to specific role of fluorine in the realization of useful chemical and biological properties of the compounds. The practical significance of fluorinated 1,3,5-triazines in organic chemistry and chemical engineering is emphasized. The fluorinated 1

THe 1,2,4-triazolo[1,5-a][1,3,5]triazine system in the title compound, C17H14FN7.2CH3OH, is essentially planar, with an r.m.s. deviation of 0.0215 A. The attached phenyl ring lies almost in the mean plane of the heterocyclic core [dihedral angle = 3.56 (4)deg]. In the crystal, centrosymmetric inversion dimers connected via intermolecular N=H...N hydrogen bonds between H atom of the primary amino group and the triazine N atom [R22(8) graph-set motif] form sheets parallel to (010). A second set of dimers connected via N=H...F hydrogen bonds between the other H atom of the primaryamino group and the F atom forms an R22(24) graph-set motif linking the sheets. Methanol solvent molecules are packed in channels running along the [010] direction.

From the reaction of biguanide with ethyl benzoylacetate, N-(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)guanidine and 6-benzoylmethyl-1,3,5-triazin-2,4-diamine were isolated.The structural evaluation of 6-benzoylmethyl-1,3,5-triazin-2,4-diamine was performed theoretically (DFT calculations) and experimentally (NMR spectroscopy and X-ray crystallography). The effects of solvents and temperature on keto-enol-enaminone tautomeric equilibrium were explored.

In the title compound, C16H13N7O, the 1,2,4-triazolo[1,5-a][1,3,5]triazine heterocyclic system is essentially planar (r.m.s. deviation = 0.0375 A). The attached benzene ring lies almost in the mean plane of 1,2,4-triazolo[1,5-a][1,3,5]triazine [dihedral angle = 1.36 (23) deg], while the pyridine ring is turned out of this plane by the aminomethyl bridge [dihedral angle = 69.22 (9) deg]. The amino group H atom is involved in intramolecular hydrogen bonding with a triazole N atom. In the crystal, molecules are connected via C(=O)NH...N hydrogen bonds into C(11) chains parallel to [100]. The amino group H atom acts as a hydrogen-bond donor, forming an NH...O C hydrogen bond with the carbonyl O atom,which links the molecules into C(6) chains running along [011] and [01-1].

In the title compound, C10H12N6.C2H5OH, the planarity of the heterocyclic system is slightly distorted at the triazine ring (r.m.s. deviation = 0.1191 A), which adopts a conformation best described as intermediate between a flattened twisted boat and a half-boat with the tertiary Csp3 atom at the bow. In the crystal, molecules form centrosymmetric dimers connected by N...H-O and O...H-N hydrogen bonds between the amino group H atom, the ethanol solvent molecule and the triazine N atom, making an R4 4(12) graph-set motif. The other H atom of the amino group and the H atom on the endocyclic N atom form N...H-N hydrogen bonds with the N atoms of the pyrazole and pyridine rings, respectively, linking the molecules into C(7)C(7) chains with the R2 2(8) binary graph-set motif running along [010].

The present review summarizes information on the synthetic approaches to compounds with pyrimido[1,2-a][1,3,5]triazines, 1,3,5-triazino[2,1-b]quinazolines (benzofused pyrimido[1,2-a][1,3,5]triazines), and other polyfused heterocyclic systems bearing these scaffolds. Data concerning potential applications of the pyrimido[1,2-a][1,3,5]triazines, particularly as biologically active agents, are also discussed.

In an attempt to study the optimal combination of a phenyl ring at the C2-position and different substituents at the N5- and N8-positions towards the selective modulation of human A3 adenosine receptors (hA3AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N8 and chains of variable length at N5. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA3AR in the low nanomolar range. Compound 16 possessed the best hA3AR affinity and selectivity profile (KihA3 = 1.33 nM; hA1/hA3 = 4880; hA2A/hA3 = 1100) in the present series of 2-(substituted)phenylpyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA3AR.

The present review summarizes information on the synthetic approaches to thiazolo[3,2-a][1,3,5]triazines and polyfused systems bearing this heterocyclic core since the first report on this structure in 1887. The methods allowing access to the heterocyclic systems comprising isomeric thiazolo[3,4-a][1,3,5]triazine scaffold are also included in the review. Data concerning potential applications of the thiazolo[1,3,5]triazines, particularly as biologically active agents are discussed.

The title compound, C12H13N5O2S, exists in the 3-phenyl-5-thioureido-1H-1,2,4-triazole tautomeric form stabilized by intramolecular hydrogen bonding between the endocyclic NH H atom and the thioureido S atom. The molecular structure is also stabilized by intramolecular N-H...O=C hydrogen bonds arranged in an S(6) graph-set motif within the carbethoxythiourea moiety. The mean planes of the phenyl and 1,2,4-triazole rings make a dihedral angle of 7.61 (11)deg. In the crystal, the molecules form two types of inversion dimers. Intermolecular hydrogen bonds are arranged in R22(6) and R22(8) graph-set motifs, together forming a network parallel to (111).

In the title compound, C7H12N6O.2H2O, the Z configuration of the hydrazone fragment is stabilized by an intramolecular N?H...N hydrogen bond involving one of the amino groups. In the crystal structure, the hydrazonamide molecules are connected via intermolecular N-H...O=C hydrogen bonds, forming C(7) chains running along [010]. The chains form sheets parallel to the (101). The chains are cross-linked by water molecules to form a three-dimensional hydrogen-bonded network.

Among the heterocyclic structures identified as potent human A3 (hA3) adenosine receptor’s antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C2-furyl ring, not only confer a good pharmacological profile (with significantly enhanced selectivity against other adenosine receptor subytpes) but also overcome the metabolic transformation of the furan ring into toxic intermediates. All the synthesized [2-(para-substituted) phenyl]-pyrazolo-triazolo-pyrimidines showed affinity at the hA3 receptor in the low nanomolar range. The most potent derivative of the series presented better affinity and excellent selectivity (compound 31, Ki hA3 = 0.108 nM; hA1/hA3 = 5200; hA2A/hA3 = 7200), in comparison to the C2-furyl counterpart. A receptor-driven molecular modeling investigation, based on a recently proposed model of A3 receptor derived from the crystallographic structure of human A2A receptor, has been carried out in order to support the experimental binding data and to justify the enhanced selectivity against the other receptor subtypes

A catalyst-free highly efficient synthesis of 3(5)-amino-5(3)-(het)aryl-1,2,4-triazoles in aqueous mediumwas performed using conventional heating and microwave irradiation. The tautomerism in the productswas investigated using NMR spectroscopy and X-ray crystallography. The effects of the substitution, temperature, solvents, and concentration on the tautomerism were studied. The triazoles were found to exist in 1H-forms, the 4H-form was not observed either in solid state or in solution. In general, 5-amino-1,2,4-triazoles were electronically preferred in the tautomeric equilibrium, but some exceptions from theestablished relationship were also identified.

The cyclocondensations of 3,4-dihydroquinazolin-2-yl guanidine with a variety of electrophilic reagents viz. aldehydes, ketones, triethyl orthoformate, diethyl ethoxymethylenemalonate, carbon disulfide and trichloroacetonitrile were found to afford 1,3,5-triazino[2,1-b]quinazolines. However, some unexpected reactions were also observed. The structural properties such as tautomerism and hinderance to conformational rotation were also investigated. The results of biological testing suggested that the 1,3,5-triazino[2,1-b]quinazoline nucleus could be a new promising scaffold for the development of potential anticancer agents.

Three-component condensation of veratrole, isobutylene oxide, and aliphatic omega-chloronitriles via the Ritter reaction leads to 1-(omega-chloroalkyl)-6,7-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinolines, the reduction of which with NaBH4 yields benzoannelated azabicyclo[m.n.0]alkanes. The synthesized compounds have been tested for hypotensive and antiaggregant activity.

The title compound, C12H16N12, is a centrosymmetric molecule which comprises of a hexaaza[14]annulene macrocyclic ring fused with two pyrazole rings. The macrocyclic ring is essentially planar, with an r.m.s. deviation of 0.0381 Å. The electron pairs of the amino groups are delocalized with the conjugated system of the macrocycle. Strong intramolecular N-H...N hydrogen bonds arranged in an S 2 2 (10) graph-set motif are present in the macrocyclic ring. In the crystal, theamino groups act as donors for intermolecular N-H...N interactions with the N atoms of the heterocyclic system, forming a network of two types of extended chains orientedparallel to the [101] and [011] directions. The crystal packing is also stabilized by weak intermolecular C-H...N hydrogen bonds formed between pyrazole C-H groups and N atoms of the macrocyclic ring, running in the [10] direction.

In the title compound, C8H8N4-C8H8N4, two tautomers, viz. 3-phenyl-1,2,4-triazol-5-amine and 5-phenyl-1,2,4-triazol-3-amine, are crystallized together in equal amounts. The 3-phenyl-1,2,4-triazol-5-amine molecule is essentially planar; the phenyl ring makes a dihedral angle of 2.3 (2)degrees with the mean plane of the 1,2,4-triazole ring. In the 5-phenyl-1,2,4-triazol-3-amine tautomer, the mean planes of the phenyl and 1,2,4-triazole rings form a dihedral angle of 30.8 (2)degrees. The electron delocalization of the amino group with the 1,2,4-triazole nucleus in the 3-phenyl-1,2,4-triazol-5-amine molecule is more extensive than that in the 5-phenyl-1,2,4-triazol-3-amine tautomer. The molecules are linked into a two-dimensional network parallel to (100) by N-H...N hydrogen bonds.

A practical synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines, which are key intermediates inthe preparation of adenosine receptor antagonists, is developed. The method allows introduction of avariety of aryl substituents at position 2 of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine systemvia cyclocondensation of 5-amino-4-iminopyrazolo[3,4-d]pyrimidine with benzaldehydes accompaniedwith oxidation by iodobenzene diacetate. Some unexpected reactions are observed and the structuresof the products are confirmed using NMR spectroscopy and X-ray crystallography.

The title compound, C13H9BrF3N5O, crystallizes with two independent molecules in the asymmetric unit. The pyrimidine rings of the molecules are planar [maximum deviations 0.053 (3) and 0.012 (3)Å], while the triazine rings adopt flattened half-boat conformations with the p-bromophenyl rings in the flagpole positions. The crystal packing is stabilized by a three-dimensional network of intermolecular N-H...N, N-H...O and N-H...F hydrogen bonds.

In the title compound, C7H7N5, the non-H atoms are almost coplanar (r.m.s. deviation = 0.050 Å), with the N atom of pyridine ring oriented to the N-N(H) side of the 1,2,4-triazole ring. The mean planes of the pyridine and 1,2,4-triazole rings form a dihedral angle of 5.58 (7)degrees. The N atom of the amino group adopts a pyramidal configuration. The molecules are linked into a two-dimensional network parallel to (10) by N-H...N hydrogen bonds.

The title compound, C6H8N6, crystallizes as an NH...N hydrogen-bond-linked dimer of two almost identical molecules in the asymmetric unit. Both of the molecules are almost planar (rms deviations of 0.0186 and 0.0296 Å in the two molecules) and their hydrazino groups are turned towards the pyrazole rings. The dimers are arranged into chains via intermolecular NH...N hydrogen bonds between the hydrazino groups and the N atoms of the pyrimidine rings of both types of the molecules, linking the molecules into a C(7) graph-set motif along [100]. The methyl groups and the N atoms of the pyrazole rings form weak CH...N hydrogen bonds, which connect chains of the dimers in a C(4) motif parallel to [100].

FIELD: medicine, pharmaceutics. SUBSTANCE: application of isonicotinoylhydrazide phthalate is proposed for lowering free fatty acids, cholesterol, and triglycerides levels. Decreasing of blood betalipoproteins concentration is shown in labanimals both intact and against diabetes background. EFFECT: finding the means for lowering free fatty acids, cholesterol, and triglycerides levels basing on isonicotinoylhydrazide phthalate.

In our lead finding program, 12 new fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines were prepared via a practical three-step procedure starting from (iso)nicotinic hydrazides. The fluorine substituted aryl fragment was introduced in the last step through cyclocondensation of N-(3-pyridyl-1,2,4-triazol-5-yl)guanidines and fluoro/trifluoromethyl substituted benzaldehydes. The structures of the compounds were confirmed by 1H and 13C NMR spectral data. The tautomeric preferences for the compounds were established using 2D NOESY experiments. The antiproliferative activity of the synthesized 1,2,4-triazolo[1,5-a][1,3,5]triazines was evaluated against breast, colon and lung cancer cell lines. The highest antiproliferative activity in the series was found for 2-(pyridine-3-yl)-7-(4-trifluoromethylphenyl)-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amine. The lack of inhibitory activity against bovine dihydrofolate reductase (DHFR) indicated that the antiproliferative activity was realized via other mechanisms.

The 2-amino-4-(het)aryl-4,6-dihydro-1(3)(11)H-[1,3,5]triazino[2,1-b]quinazolin-6-ones were prepared readily by cyclocondensation of anthranilic acid derived 4-oxo-3,4-dihydroquinazolinyl-2-guanidine with a variety of aldehydes. The structures of the compounds were confirmed by nmr spectroscopy, including 2D NOESY experiments.

7-Dimethylamino-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine crystallized with one molecule of methanol to give the title compound, C12H13N7CH3OH. The triazolo[1,5-a][1,3,5]triazine heterocyclic core is essentially planar as are both amino groups that are involved in -electron delocalization with the triazolo[1,5-a][1,3,5]triazine nucleus. The methyl groups of the dimethylamino fragment are involved in the formation of weak intramolecular C-H...N hydrogen bonds with the N atoms of the heterocyclic system. The crystal packing is stabilized by intermolecular N-H...N hydrogen bonds between the triazolo[1,5-a][1,3,5]triazine molecules. The methanol solvent molecule also participates in the formation of the crystal structure via intermolecular O-H...N, N-H...O and weak C-H...O hydrogen bonds, linking the layers of triazolo[1,5-a][1,3,5]triazine molecules.

The present review gives an account on the synthetic routes to pyrazolo[1,5-a][1,3,5]triazine system, which is an isostere of purine, and polyfused systems bearing this heterocyclic core. Data concerning biological activity of compounds with pyrazolo[1,5-a][1,3,5]triazine skeleton are also discussed.

A convenient and efficient synthesis of new 5-azapurine derivatives was developed. The regioisomeric 5-amino-6,7-dihydro- and 7-amino-4,5-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines were prepared in 3?4 steps from benzhydrazide via complementary and regiospecific routes as a part of our lead finding program. The molecular structures and tautomeric preferences of the compounds obtained were investigated using NMR spectral data and X-ray crystallography.

A synthesis of hitherto unknown heterocyclic system 1(5)H-1,5-diazacycl[3.3.2]azine-2,4-dione (5) is presented. The cyclocondensation of 2,6-diaminopyridine (1) with maleic anhydride yielded (5-amino-2-oxo-2,3-dihydroimidazo[1,2-a]pyridin-3-yl)acetic acid (2), which was converted to methyl (5-amino-2-oxo-2,3-dihydroimidazo[1,2-a]pyridin-3-yl) acetate hydrochloride (3). The ester (3) upon treatment with sodium carbonate solution underwent intramolecular cyclization to 2a,3-dihydro-1(5)H-1,5-diazacycl[3.3.2]azine-2,4-dione (4), which was oxidized in alkaline condition to provide 5.

Several 4-substituted 1,3,5-triazino[1,2-a]benzimidazol-2-amines were prepared via cyclization of 2-benzimidazolylguanidine with various reactants. The prototropic tautomerism in the obtained dihydro analogs was investigated. According to the NMR data, the 3,4-dihydro form was found to predominate in DMSO solutions. All tested compounds inhibited the activity of mammalian dihydrofolate reductase. The most active compound was 4,4-dimethyl-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazol-2-amine (IC50 = 10.9 microM).

The 5,7-diamino[1,2,4]triazolo[1,5-a][1,3,5]triazines were synthesized by cyclocondensation of 3(5)-amino-1,2,4-triazoles with cyanoguanidine. The substituted 3(5)-amino-1,2,4-triazoles were prepared from corresponding hydrazides and S-methylisothiourea via ring closure of the intermediate acylaminoguanidines. The 3,5-diamino-1,2,4-triazoles were prepared using partial aminolysis of dimethyl N-cyanodithiocarbonimidate followed by cyclization of the obtained N-substituted N’-cyano-S-methylisothioureas with hydrazine. The structures of the prepared compound were confirmed using NMR spectral data.

The substitution of hydrogen by fluorine as bioisosteric replacement has been practised widely in agricultural and medicinal chemistry. This has led to the discovery of many pesticides and therapeutically useful chemical entities. The 1,3,5-triazine heterocycle is found in many biologically active compounds that exhibit herbicidal, antimicrobial, antiparasitic and anticancer properties. The objective of the chapter is to present a review on the developments in the fields of fluorinated 1,3,5-triazines chemistry and aspects of their application in the last decade.The chapter is organized according to the structural and synthetic aspects of the fluorinated 1,3,5-triazines chemistry. Based on the structure of the heterocyclic nucleus and location of the fluoro substituent, the fluorinated 1,3,5-triazines are presented as three separate groups. Within the first group, 1,3,5-triazines bearing fluorinated substituent at carbon atom of the heterocyclic core are discussed with further structural discrimination by nature of the linkage between 1,3,5-triazine nucleus and the fluorinated substituent. Three types of the connections are categorized namely, C-C bond, C-X bond (X = N, O or S) and 1,3,5-triazines with fluorine atom directly attached to endocyclic carbon atom. Further classification within the subgroups is based on the synthetic methods used for the preparation of fluorinated 1,3,5-triazines.The 1,3,5-triazines bearing fluorinated substituent at nitrogen atom are categorized into a second group, which includes 1,3,5-triazines without substitution at the ring carbon atoms, 1,3,5-triazinones and 1,3,5-triazinium salts. The third group includes the fluorinated fused heterocyclic compounds with 1,3,5-triazine nucleus, particularly azolo-1,3,5-triazines and azino-1,3,5-triazines. Special references are made to specific role of fluorine in the realization of useful chemical and biological properties of the compounds. The practical significance of fluorinated 1,3,5-triazin

The title compound, C12H14N6, was synthesized via cyclocondensation of 5-guanidino-3-phenyl-1,2,4-triazole with acetone. Only one tautomeric form with the NH H atom vicinal to the methyl groups was observed in the crystal structure. The triazine ring adopts a flattened half-boat conformation. The dihedral angle between the triazole and phenyl rings is 9.99 (5). The crystal packing is stabilized by intermolecular N-H...N hydrogen bonds which link the molecules into a chain along the a axis.