Polycyclic N-heterocyclic compounds. XLI. Synthesis of 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines, 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines and their related compounds as a series of potential blood platelet aggregation inhibitors

As a series of polyheterocyclic compounds for exploitation as anti-platelet agents, tricyclic heterocyclic compounds, 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines 3–6, 9, 12–14 , and 16–26 , having nitrogen, oxygen, or sulfur containing functional groups at the 4-position, were prepared. In addition, tetra-cyclic heterocyclic compounds, 3-methyl-1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzaze-pinium chloride ( 7 ), 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines 10a-e , 2,3,6,7-tetrahydro-1H 5H-pyrimido[1′,2′:1,6]pyrimido[5,4-d][1]benzazepine ( 11 ), and 1,2,5,6-tetrahydro-4H-thiazolo-[3′,2′:1,6]pyrimido[5,4-d][1]benzazepinium chloride ( 15 ) via ring closure of 4-(hydroxyalkylamino)- 6, 9a-e , and 3c , and 4-(2-hydroxyethylthio)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine ( 14 ) with phosphoryl chloride or thionyl chloride, respectively, were also prepared. Their inhibitory activities against collagen-induced aggregation of rabbit blood platelets in vitro were investigated. Among them, compound 5 having a morpholino group at the 4-position on the tricyclic nucleus, which enhanced the activity more than 14-fold as compared with aspirin, was found to have the most satisfactory in inhibitory activity.     

Heterocyclic β-Enamino esters. 28. The reaction of heterocyclic β-Enamino esters and nitriles with cyclic amidines. A simple route to azolopyrimidines

Whereas 2-amino-3-ethoxycarbonyl-4,5-dihydrofurans Ia-c condense with 5-membered amidine derivatives, via elimination of ethanol to afford the azolopyrimidines IIIa,b, XI, and XIVa,b, the 2-amino-3-cyano-4,5-dihydrofurans Id,e give with the same reagents, under elimination of ammonia, the novel ring systems of furo-azolopyrimidines XVIII and XXa,b. 2-Amino-3-ethoxycarbonyl-5,6-dihydro-4H-thiopyrane (XXI) reacts with 5-amino-1,2,4-triazole (II) to yield the triazolo[1,5-a]pyrimidine XXII, and with 2-aminobenzimidazole to XXIII. The mechanism of these reactions is discussed. XIVb and VIIb are cyclized in a secondary step to give the novel furo[2,3-d]benzimidazo[1,2-a]pyrimidine XXVI, and furo[2,3-d]-1,2,4-triazolo[1,5-a]pyrimidine XXVIII respectively, besides the acetoxy derivatives XVII and XXIX.     

2-benzazepines. 10 [1]. New d-fused 2-benzazepines

Pyrano[3,2-d][2]benzazepines were synthesized by reaction of the beta-dimethylamino unsaturated ketone 1 with malonic ester or the anion of t-butyl acetate. Conversion of the pyrano derivative to the pyrido[3,2-d]-[2]benzazepine was achieved in low yield. A pyrrolo[3,2-d][2]benzazepine was prepared via an oxazepino-[6,7-d][2]benzazepine which was obtained by reaction of 1 with the anion of ethyl isocyanoacetate.     

Synthesis and properties of thiazolo[5,4-d]pyrimidine 1-oxides

Synthesis and properties of hitherto unknown thiazolo[5,4-d]pyrimidine 1-oxides are described. For example, the reaction of 6-chloro-1,3-dimethyl-5-nitrouracil (I) with methyl thioglycolate in the presence of excess triethylamine afforded 2-methoxycarbonyl-4,6-dimethylthiazolo[5,4-d]pyrimidine-5,7-(4H,6H)dione 1-oxide (IIIa), which is a versatile intermediate for the preparation of various thiazolo[5,4-d]pyrimidine derivatives.     

2-Alkyl-4-oxohexahydropyrimido[4,5-<Emphasis Type="Italic">d</Emphasis>]- and -[5,4-<Emphasis Type="Italic">d</Emphasis>]azocines

It has been established that 2-R-4-oxotetrahydropyrido[4,3-d]pyrimidines, under the action of activated alkynes in methanol, form a mixture of 2-R-4-oxohexahydropyrimido[4,5-d]azocines and products of decomposition of the tetrahydropyridine ring, the 2-R-5-methoxymethyl-4-oxo-6-vinylaminoethyl-pyrimidines. Tetrahydropyrido[3,4-d]pyrimidine, isomeric at the junction of the pyrimidine and tetrahydropyridine rings, forms only the corresponding pyrimido[5,4-d]azocine, the product of expansion, under the action of methyl propiolate.     

Synthesis and Reactions of Some Novel Triazolo‐, Azolo‐, Tetrazolo‐Pyridopyrimidine and Their Nucleoside Derivatives

Pyridopyrimidine reacted with aromatic aldehydes afforded the arylhydrazone 2a,b which could be cyclized into the pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidine 3a,b , with formic acid, and carbon disulphide to give pyrido[2,3‐d][1,2,4]traizolo[4,3‐a]pyrimidine 4, 5. Reaction of 1 with nitrous acid afforded tetrazolo[1,5‐a]pyrido[2,3‐d]pyrimidine 6 , which was reduced by zinc dust to give 2‐amino‐pyrido‐[2,3‐d]pyrimidine 7. Finally the reaction of 2‐hydrazino 1 with D‐xylose or D‐glucose afforded the acyclic N‐nucleoside 8, 11 which were converted into tetra/penta O‐acetate acyclic C‐nucleoside 9, 12 in acetic anhydride/pyridine. De‐acetylation of compounds 9, 12 afforded C‐nucleosides 10, 13.     

Polycyclic N‐Heterocyclic Compounds. Part 86: Synthesis and Evaluation of Antiplatelet Aggregation Activity of 2,4‐Disubstituted 9‐Chloro‐5,6‐dihydropyrimido[5,4‐d]benzazepine and Related Compounds

Libraries of tricyclic 2‐substituted 4‐alkylamino‐9‐chloro‐5,6‐dihydropyrimido[5,4‐d]benzazepines and tetracyclic 12‐substituted 8‐chloro‐1,2,5,6‐tetrahydro‐4H‐imidazo[1′,2′:1,6]pyrimido[5,4‐d]benzazepines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Utility of [4-(3-methoxyphenyl)pyrimidin-2-yl]cyanamide in synthesis of some heterocyclic compounds

N-[4-(3-Methoxyphenyl)pyrimidin-2-yl]cyanamide ( 1 ) was reacted with morpholine and respective binuclephilic reagents namely: ethylenediamine, o-phenylenediamine, o-aminothiophenol, or o-aminophenol to give the corresponding carboximidamide 2 , imidazolidine 3 , and benzazoles 4–6 . While its reaction with hydrazides in DMF at 90°C, gave the corresponding 1,2,4-triazols 7–11 . Also, treatment of cyanamide 1 with heterocycles having both nucleophilic and electrophilic groups (─NH₂/─COOEt) in iso-propanol in presence of catalytic amount of Conc. HCl, gave the corresponding thieno[2,3-d]pyrimidinone 12 and unexpected thieno[3,2-d]pyrimidine 13 instead of bis-thieno[3,2-d]pyrimidine 14 , respectively. While, its reaction with ethyl 5-amino-1,3-thiazole-4-carboxylate yielded the unexpected N-(pyrimidin-2-yl)urea 15 rather than the corresponding thiazolo[5,4-d]pyrimidine 16 . Unexpected N-(pyrimidin-2-yl)thiourea 17 was obtained, when cyanamide 1 reacted with potassium thiolates in iso-propanol with catalytic amount of Conc. HCl.     

Polyfunctional pyridines from nitroacetamidine and β-diketones. A useful synthesis of substituted imidazo [4,5-b] pyridines and related compounds

Nitroacetamidine undergoes a useful cyclocondensation with β-diketones to produce substituted 2-amino-3-nitropyridines. Use of an acylpyruvate generates hitherto unreported 2-amino-3-nitropyridine-4-carboxylates. These may be converted easily to functionalized imidazo[4,5-b]pyridines and oxazolo-[5,4-b]pyridines.     

Polycyclic N-hetero compounds. XXXVII. A convenient synthesis and evaluation of anti-platelet aggregation activity of 1,2,4,5-tetrahydro[1]- benzothiepino[4,5-e]imidazo[1,2-c]pyrimidine and its related compounds

A simple and highly efficient methodology for the synthesis of 1,2,4,5-tetrahydro[1]benzothiepino[4,5-e]-imidazo[1,2-c]pyrimidine ( XI ) having a novel ring system via 4-substituted 5,6-dihydro[1]benzothiepino-[5,4-d]pyrimidines VII-X is described. The anti-platelet aggregation activity for it and its related compounds against collagen-induced aggregation of rabbit blood platelets in vitro was found.     

Synthesis,in silico and in vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents

New potential bioactive oxazolopyrimidines have been synthesized using two main approaches: the pyrimidine ring annulation on a functionalized oxazole and the benzoyl bromide trimerization followed by rearrangement and formation of the oxazolo[5,4-d]pyrimidine scaffold. The docking analyzes have shown that 7-piperazine substituted oxazolo[4,5-d]pyrimidines 8a – 8c could be potential VEGFR2 inhibitors with high free energy of ligand–protein complex formation (ΔG: −10.1, −9.6, −9.8 kcal/mol, respectively). In vitro antitumor assays confirmed theoretical predictions that oxazolo[4,5-d]pyrimidines 8a – 8c containing positively charged piperazine moiety should demonstrate significantly higher cytotoxic effects. 4-[5-(4-Chlorophenyl)-2-phenyl[1,3]oxazolo[4,5-d]pyrimidin-7-yl]piperazin-1-ium trifluoroacetate ( 8c ) exhibited a slightly higher antiproliferative effect (IC₅₀=0.21 μm ) than doxorubicin (IC₅₀=0.36 μm ) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC₅₀=1.7 μm ) and HCT-116 (IC₅₀=0.24 μm ) cells.     

Construction of pyrimido[5,4-e]-as-triazine,purine, v-triazolo-[4,5-d]pyrimidine and pyrazolo[3,4-d]pyrimidine ring systems from 5-arylazo-6-arylidenehydrazino-1,3-dimethyluracils

Reaction of 5-arylazo-6-arylidenehydrazino-1,3-dimethyluracils (II), prepared by the treatment of 6-aryl-idenehydrazino-1,3-dimethyluracils (I) with diazotized arylamines, with dimethylformamide dimethylacetal resulted in the formation of pyrimido[5,4-e]-as-triazine (V) system, while the thermolysis of II resulted in the formation of purine (X), v-triazolo[4,5-d]pyrimidine (XII), and pyrazolo[3,4-d]pyrimidine (XIV, XIX) systems in lieu of the expected V. Reasonable mechanisms have been proposed for the formation of the various ring systems in these reactions.     

Synthesis and antiviral screening of 2-(propylthio)-7-substituted-thiazolo[5,4-d]pyrimidines as anti-bovine viral diarrhea virus agents

7-Chloro-2-(propylthio)thiazolo[5,4-d]pyrimidine 4 was prepared and used as a precursor for synthesizing new derivatives of thiazolo[5,4-d]pyrimidine through the nucleophilic displacement of the chlorine atom by different types of amino derivatives. Reaction of compound 4 with primary and secondary amines produced the corresponding substituted amino derivatives. Reaction of 4 with hydrazine hydrate then followed by condensation with aromatic aldehydes afforded hydrazone derivatives. Reaction of 4 with hydrazine hydrate then followed by reaction with isothiocyanates gave the disubstituted thiosemicarbazides. Finally, treatment of 4 with hydrazine derivatives afforded the novel disubstituted hydrazine derivatives. Preliminary antiviral screening on the bovine viral diarrhea virus (BVDV) was carried out, which was classified as a member of the same family of Hepatitis C virus. The results indicated that some of the tested compounds exhibited anti-BVDV activity which may be suitable for a new lead molecule to design more potent anti-BVDV agents.     

Polycyclic N-hetero compounds. XXXII Synthesis and antidepressive evaluation of B-homo-11,13,15-triazasteroids and their precursors

Synthesis of 4-(2-hydroxyethylamino)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine derivatives V and their cyclized products, B-homo-11,13,15-triazasteroidal compounds VI and VII , are described. These products were screened to evaluate the antidepressive activity.     

Cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine with hydroxylamine and hydrazine

The cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine (3) with hydroxylamine or hydrazine leads to 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenylisoxazolo-[5,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4a ) and 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenyl-1H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4b ), respectively. In the presence of methanolic hydrogen chloride, 4b undergoes a cleavage of the pyrimidine ring to yield (5-amino-1,2,4-triazol-1-yl)(3,5-dimethylpyrazol-4-yl)phenylmethane ( 5 ). The structure determination of the compounds obtained is based on ¹H and ¹³C nmr spectra including NOE measurements.     

Pyrazolopyrimidine nucleosides. Part VII. The synthesis of certain pyrazolo [3,4-d] pyrimidine nucleosides related to the nucleoside antibiotics toyocamycin and sangivamycin

The condensation of 4-acetamido-3-cyanopyrazolo[3,4-d]pyrimidine ( 5 ) with crystalline 2,3,5-tri-O-acetyl-β- D -ribofuranosyl chloride ( 6 ) has furnished a good yield of nucleoside material ( 7 ) which on treatment with sodium methoxide in methanol provided a high yield of nucleoside which was subsequently established as methyl 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]-pyrimidine-3-formimidate monohydrate ( 11 ). The formimidate function of 11 was found to be highly reactive and 11 was readily converted into the corresponding carhoxamidine ( 8 ), carboxamidoxime ( 14 ) and carboxamidrazone ( 15 ) when treated with the appropriate nucleophiles. Treatment of the imidate ( 11 ) with sodium hydrogen sulfide gave a high yield of the thiocarboxamide ( 12 ) which was then readily converted into 4-amino-3-cyano-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 16 ). Aqueous base transformed 11 into 4-amino-1-(β- D -ribofuranosyl)-pyrazolo[3,4-d]pyrimidine-3-carboxamide ( 10 ) while more vigorous basic hydrolysis provided the corresponding carboxylic acid ( 9 ) in nearly quantitative yield. Decarboxylation of 9 proceeded smoothly in hot sulfolane to provide the known 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 13 ) in 68% yield which unequivocally established the site of ribosylation and anomeric configuration for all nucleosides reported in this investigation.     

The synthesis and transformations of 2-ethoxycarbonyl-3-isothiocyanatopyridine. Pyrido[3,2-d]pyrimidines and some azolopyrido[3,2-d]pyrimidines

2-Ethoxycarbonyl-3-isothiocyanatopyridine ( 2 ), prepared from 3-amino-2-ethoxycarbonylpyridine ( 1 ) by the thiophosgene method, was converted with nucleophiles into pyrido[3,2-d]pyrimidine derivatives 6–11 and 25–30 either directly, or through thiourethane 3 . Tricyclic systems 18 and 19 were obtained from 3 , and tricyclic systems 12–17 from pyrido[3,2-d]pyrimidine derivative 11 . Pyrrole reacted with 2 at C₂ to give 20 , and by further cyclization 21 and 22 .     

New method for the synthesis of thieno[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidines

The reaction of 5-formyl-4-thiocyanatopyrimidines with nitromethane was studied under various conditions. The reaction was found unexpectedly to proceed with closure of a thiophene ring to give thieno[2,3-d]pyrimidines. The use of ammonium acetate as the catalyst leads to a side reaction involving closure of an isothiazole ring to give isothiazolo[5,4-d]pyrimidines. X-ray diffraction crystallographic analysis was used to confirm the structure of thieno[2,3-d]pyrimidine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1564–1571, October, 2004.     

Polycyclic N-heterocyclic compounds. 55. A novel reaction of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4-yl)amidine or its amide oxime derivatives with hydroxylamine

The reactions of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4-yl)amidines or its amide oxime derivatives with hydroxylamine hydrochloride under basic condition gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of [1,2,4]oxadiazole.     

Palladium-catalyzed oxidative C–H/C–H cross-couplings of thiazolo[5,4-d]pyrimidine with aromatic (hetero)cycles

A novel Pd(II)-catalyzed dehydrogenative cross-coupling reaction of thiazolo[5,4-d]pyrimidine with unactivated (hetero)arenes via C–H bond activation was achieved. This protocol provides a straightforward and operationally simple method for the synthesis of 2-arylsubstituted thiazolo[5,4-d]pyrimidines of interest in pharmaceutical sciences.