Polycyclic N-hetero compounds. XXXV. Syntheses and anti-platelet aggregation activity of 5,6-Dihydro-4H-benzo[3,4]cyclohept[1,2-e]imidazo[1,2-c]pyrimidines with an oxygen function at the 1-position

Various 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d][pyrimidines bearing amino acid group at the 4-position of the skeleton were synthesized by the reaction of 4-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]-pyrimidine with some amino acid, which were cyclized to 5,6-dihydro-4H-benzo[3,4]cyclohept[1,2-e]imidazo-[1,2-c]pyrimidines, corresponding to B-homo-11,13,15-triazasteroids. Their inhibitory activities against platelet aggregation induced by collagen were also investigated.     

Synthesis of two new heterocyclic ring systems: Benzo[3,4] cyclohepta[1,2-d]-pyrimidines and benzo[3,4]cyclohepta[2,1-d] pyrimidines

Three 2,4-diamino-l(), 11-dihydro-9H-benzo[3,4]cyclohepta[ 1,2-d]pyrimidines (6a-6c) representing the first examples of a new ring system were synthesized from 2-benzosuberones and cyanoguanidine. Similarly, 2,4-diamino-6,7-dihydro-5H-benzo[3,4]cyelohepta[2,1-d]pyrimidine ( 24 ) was prepared from 1-benzosuberone. The ultraviolet spectral properties of these compounds were examined with reference to those of the analogs in which the central ring is five- and six-mernbered.     

N-Amino Derivatives of Condensed Imidazole Systems

The previously unknown 1-amino- and 3-aminonaphtho[1,2-d]imidazoles, 1-aminonaphtho[2,3-d]imidazole, 1-aminophenanthro[9,10-d]imidazole and the N-amino-N'-methylimidazolium picrates corresponding to them have been obtained by direct amination of a series of condensed imidazoles with O-picrylhydroxylamine. An X-ray structural investigation of 1-amino-3-methylnaphtho[1,2-d]imidazolium picrate showed that, in difference to 1-aminobenzimidazolium salts, a conformation exists in it in which the hydrogen atoms of the N-NH₂ group are directed to the side of the meso carbon atom.     

Synthesis of Precursors of Heterocyclic cis-β-Amino Alcohols by Intramolecular Amidoalkylation of 4-Hydroxyoxazolidin-2-ones

The reaction of intramolecular amidoalkylation of 4-hydroxyoxazolidin-2-ones leads to formation of novel and rare heterocyclic systems: substituted 1,5,6,10b-tetrahydro[1,3]oxazolo[4,3-a]isoquinolin-3-ones, 3a,4,5,10b-tetrahydro[1,3]dioxolo[4',5':6,7]naphtho[1,2-d][1,3]oxazol-2(1H)-ones, and 5,6,10,10a-tetrahydro-1H-di[1,3]oxazolo[3,4-d:4,3-g][1,4]diazepine-3,8-diones. Mild reaction conditions and the simplicity of isolation of the compounds formed make it possible to obtain the indicated heterocycles in high yields.     

Polycyclic N-Heterocyclic Compounds,Part 77: Synthesis of [1]Benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and Evaluation of Their Antiplatelet Aggregation Activity

Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[2′,3′:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Mutagenic heterocyclic nitrogen compounds related to protein pyrolysates. 1. Derivatives of dipyrido[1,2-a:3′,2′-d]imidazole

2-Amino-6-methyldipyrido[1,2-a:3′-2′-d]imidazole is one of the mutagenic principles of L-glutamic acid and casein pyrolysates. We prepared several isomeric amines of this compound, as well as their homologues methylated in different positions on the heterocyclic ring, either by nitration of the ring followed by reduction or from appropriate 4-azidodipyrido[1,2-a:3′,2′-d]imidazoles. The latter compounds, the heterocyclic ring itself and various functional derivatives (hydroxylated, carboxylated, hydrazinic) were synthesized from 2-aminoimidazo[1,2-a]pyridines via various reactions which are described herein.     

Synthesis of tricyclic and tetracyclic thieno[3,2-f]-1,4-thiazepines

Treatment of 5-methylthio-2,3-dihydrothieno[3,2-f]-1,4-thiazepine ( 9 ) with acylhydrazines gave 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepines 10, 11 , and that of 9 with ethyl anthranilate gave 5,6-dihydrothieno[3′,2′:6,7][1,4]thiazepino[5,4-b]quinazolin-8-one ( 14 ). Reaction of 9 with hydrazine hydrate or 4-chlorophenylhydrazine afforded 5-hydrazino compounds 12, 15 , which were subsequently cyclized to ethyl 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepine-3-carboxylate ( 13 ), 2-(4-chlorophenyl)-5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepin-3(2H)-one ( 16 ) and 2-(4-chlorophenyl)-6,7-dihydro-2H-thieno[3,2-f][1,2,4]triazino[4,3-d][1,4]thiazepine-3,4-dione ( 17 ). New thieno-anellated heterocycles were prepared with the aim of studying their affinity for the benzodiazepine receptors.     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

Benzofurano derivatives of coumarins as possible antifertility agents

Synthesis and medicinal importance of 4-methyl-6-nitro-8,9,10,11-tetrahydro-2H-benzofuro[2,3-b]-1-benzo-pyran-2-one (I), 4-ethyl-11-nitro-6,7,8,9-tetrahydro-2H-benzofuro[3,2-g]-1-benzopyran-2-one (II), and 6,7-di-hydro-4,13-dimethylbis-1-benzopyrano[6,7-d:7′,6′-d']-2H,11H-benzo[1,2-b:3,4-b']difuran-2,11-dione (III) is presented. The structures of these compounds were confirmed by elemental analysis and spectral studies.     

Thieno[2,3-d]pyrimidin-4-ones 1. Condensation of 2,3-dimethyl- and 2,3-tri-, 2,3-tetra-, and 2,3-pentamethylene-7,8-dihydro-pyrrolo[1,2-a]thieno[2,3-d]pyriminidin-4(6H)-ones with aromatic aldehydes and furfural

2,3-Dimethyl- and 2,3-tri-, 2,3-tetra-, and 2,3-pentamethylene-substituted 8-arylidene-6,7-dihydro-pyrrolo[1,2-a]thieno[2,3-d]pyrimidin-4-ones were synthesized by the reaction of 2,3-dimethyl- and 2,3-tri-, 2,3-tetra-, and 2,3-pentamethylene-7,8-dihydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-4(6H)-ones with benzaldehyde, its 4-dimethylamino-, 3,4-dimethoxy-, and 3,4-methylenedioxy derivatives and also furfural in the presence of NaOH.     

Synthesis of new fluorine-containing pyrazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]pyridinones as promising drug precursors

Methods for the synthesis of 4-R-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones (R = CF₂SAr and 4-CFHSAr) were developed. The derivatives with R = CF₂SAr were obtained by both heterocyclization of 1-substituted 5-aminopyrazoles with ethyl 4,4-difluoro-3-oxo-4-phenylsulfanylbutanoate and replacement of the Br atom in 4-bromodifluoromethyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones by sodium arenethiolates. The fragment 4-CF-HSAr was introduced by replacement of the Cl atom in 4-chlorofluoromethyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones by sodium arenethiolates. Oxidation of 4-CF₂SPh-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-ones gave the corresponding sulfoxides; their structures were confirmed by X-ray diffraction data.     

Heterocycles from Pyrazoloylhydroximoyl Chloride: Synthesis of Certain Quinoxaline,Benzothiadiazine, Benzoxadiazine,Quinazolinone, Imidazo[1,2-a]pyridine,Imidazo[1,2-a]pyrimidine,Isoxazole, Pyrazolo[3,4-d]pyridazine and Pyrrolidino[3,4-d]isoxazolin-4,6-dione Derivatives

3-Ethoxycarbonyl-5-methyl-1-(4-methylphenyl)-4-pyrazoloylhydroximoyl chloride (1) reacted with o-phenylenediamine, o-aminothiophenol, o-aminophenol and methyl anthranilate to afford 3-nitrosoquinoxaline, benzothiadiazine, benzoxadiazine, and 3-hydroxyquinazoline, respectively. Imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and isoxazole derivatives were obtained via the reaction of 1 with 2-aminopyridine, 2-aminopyrimidine and the appropriate active methylene compounds, respectively. Pyrazolo[3,4-d]pyridazines, and pyrrolidino[3,4-d]isoxazolines derivatives were also synthesized. The structures of the newly synthesized compounds were established on the basis of spectral data and alternate synthesis whenever possible.     

Reaction of sulfene with heterocyclic N,N-disubstituted α-aminomethyleneketones. X. Synthesis of thieno[2,3-h]-1,2-benzoxathiin derivatives

The polar 1,4-cycloaddition of sulfene to N,N-disubstituted (E)5-aminomethylene-6,7-dihydrobenzo[b]-thiophen-4(5H)ones II gave in excellent yield and only in the case of aliphatic N-substitution, N,N-disubstituted 4-amino-3,4,5,6-tetrahydrothieno[2,3-h]-1,2-benzoxathiin 2,2-dioxides III, which are derivatives of the new heterocyclic system thieno[2,3-h]-1,2-benzoxathiin. Dehydrogenation with DDQ of cycloadducts IIIa-d was successful only in the case of IIIa (NR₂ = dimethylamino) to give in low yield 4-dimethylamino-3,4-dihydrothieno[2,3-h]-1,2-benzoxathiin 2,2-dioxide.     

The synthesis and transformations of 2H-naphtho-[1,2-b]pyran-2-one derivatives. Naphtho[2′,1′:5,6]-pyrano[3,4-d][1,3]oxazines and naphtho[1′,2′:5,6]pyrano[3,4-d]-pyrimidines,derivatives of two new heterocyclic systems

1,4-Naphthoquinone ( 1 ) was transformed with alkyl 2-aminofumarates 2 into 2H-naphtho[1,2-b]pyran-2-ones 3 and 4 , which served as intermediates in the synthesis of 7, 8 and 13 , which are derivatives of two new heterocyclic systems: naphtho[2′,1′:5,6]pyrano[3,4-d][1,3]oxazine and naphtho[1′,2′:5,6]pyrano[3,4-d]pyrimidine.     

Polycyclic N-hetero compounds. XXXIII. Syntheses of 4-substituted 6,7-dihydro-5H-benzo[6,7]-cyclohepta[1,2-d]pyrimidines and their inhibitory activities on platelet aggregation and on reserpine-induced hypothermia

Various 4-substituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidines were synthesized by the reaction of 4-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine with amines. Their inhibitory activities against collagen-induced platelet aggregation and also against reserpine-induced hypothermia in mice were investigated.     

Synthesis of benzo[b]phenanthro[d]thiophenes

The synthesis of benzo[b]phenanthro[1,2-d]thiphene ( 1 ), benzo[b]phenanthro[4,3-d]thiophene ( 2 ), benzo-[b]phenanthro[2,1-d]thiophene ( 3 ) and benzo[b]phenanthro[3,4-d]thiophene ( 4 ) from appropriately substituted olefines by photochemical cyclodehydrogenation is described. The photolysis of olefin 9 gave a mixture of 4 and anthra[1,2-b]benzo[d]thiophene ( 5 ).     

Three New Arylnaphthalide Lignans from the Aerial Parts of Bupleurum marginatum Wall. ex DC.

Three new arylnaphthalide lignans, 5‐(4‐hydroxy‐3‐methoxyphenyl)furo[3′,4′: 6,7]naphtho[2,3‐d]‐1,3‐dioxol‐6(8H)‐one ( 1 ), 10‐(4‐hydroxy‐3‐methoxyphenyl)furo[3′,4′: 6,7]naphtho[1,2‐d]‐1,3‐dioxol‐9(7H)‐one ( 2 ), and 10‐(3,4‐dimethoxyphenyl)‐6‐hydroxyfuro[3′,4′: 6,7]naphtho[1,2‐d]‐1,3‐dioxol‐9(7H)‐one ( 3 ), together with two known ones, chinensin ( 4 ) and isodiphyllin ( 5 ), were isolated from the aerial parts of Bupleurum marginatum Wall . ex DC. The structures of the three new lignans were established by means of NMR spectroscopic studies, including HQSC, HMBC, and ROESY.     

Cyclic guanidines: Synthesis of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo[3′,4′:4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones

The synthesis of potential platelet aggregation inhibitors 4,6,7,8-tetrahydroimidazo[1,2-a]pyrazolo[3,4-d]-pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo[3′,4′:4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones derivatives is described starting from 4,6-dichloropyrazolo[3,4-d]pyrimidines.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Oxidation products of fused 2-hetarylimidazole derivatives

Oxidation of 5-(1-methyl-1H-benzimidazol-2-yl)thiophene-, and -selenophene-2-carbaldehydes with potassium dichromate in 20% aqueous sulfuric acid afforded the corresponding carboxylic acids. Analogous reaction with 5-(1-methyl-1H-benzimidazol-2-yl)furan-2-carbaldehyde led to the formation of 1-methyl-1H-benzimidazole as a result of decarboxylation of the primary oxidation product and subsequent decomposition of the furan ring. Probable factors responsible for instability of 5-(1H-benzimidazol-2-yl)-hetarene-2-carboxylic acids were considered. The oxidation of 2-furylnaphtho[2,3-d]- and 2-hetarylphenanthro-[9,10-d]imidazoles gave, respectively, an anthraquinone analog and 6,7-quinones. π-Electron-rich heterocycles in 2-furyl- and 2-pyrrolylphenanthro[9,10-d]imidazoles were oxidized completely, being replaced by hydrogen.