Heterocyclic quinones. XIV. Pharmacomodulation in a series of 11H-indolo[3,2-c]quinolinediones: synthesis and cytotoxicity of 8-substituted 11H-indolo[3,2-c]quinoline-7,10-diones

4-Chloro-8-methoxy-11H-indolo[3,2-c]quinoline could be obtained from 8-chloro-2,3-dihydro-1H-quinolin-4-one and 4-methoxyphenylhydrazine by applying Fischer's indole synthesis. Its nitration led to the 7-nitro derivative which was reduced to 7-amino-4-chloro-8-methoxy-11H-indolo[3,2-c]quinoline when Raney nickel was employed as a catalyst and to 7-amino-8-methoxy-11H-indolo[3,2-c]quinoline when palladium charcoal was used. Oxidation of the amines by potassium nitrosodisulfonate produced the corresponding 11H-indolo[3,2-c]quinoline-7,10-diones. Displacement of the methoxy group by (N,N-diethylamino)ethylamine or by N-methylpiperazine afforded the 8-aminoquinones. The quinones unsubstituted at the 4-position were more cytotoxic than the previously described 2-methoxy-11H-indolo[3,2-c]quinoline-1,4-diones.     

Synthesis of 1,2,4-triazolo[4,3-c]-, tetrazolo[1,5-c]-, and 1,2,4-triazino[5,6-c]pyrano[4'3':4,5]pyrrolo-[3,2-e]pyrimidine derivatives

4-Hydrazinopyrano[4',3':4,5]pyrrolo[2,3-d]pyrimidines served as precursors in the synthesis of new heterocyclic systems, namely, 1,2,4-triazolo[4,3-c]-, tetrazolo[1,5-c]-, and 1,2,4-triazino[5,6-c] pyrano[4',3':4,5]-pyrrolo[3,2-e]pyrimidines.A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Republic of Armenia, 375014 Yerevan. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 700-703, May, 1995. Original article submitted January 10, 1995; revision submitted April 20, 1995.     

Hapten synthesis for (+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tet rahydro-8H-pyrido[4',3':4,5]thieno[3,2-f] triazolo[4,3-a][1,4]diazepine (E6123).

(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4, 5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f]triazolo[4,3-a] [1,4]diazepine (E6123) is a very potent platelet-activating factor (PAF) receptor antagonist and shows potent anti-PAF activities at the microgram level in a variety of animal models. In order to examine the pharmacokinetics of E6123 at low doses, establishment of a radioimmunoassay is required. On the basis of the metabolic pattern of E6123, we synthesized 6-[2-chloro-4-(3-carboxypropyl) phenyl]-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H -pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 22 as a potential hapten. In the synthesis of 22, we developed butynyl carbamate as a piperidine ring N-protecting group to prevent possible side reaction, namely oxidation of the methylene at position 2. This protecting group is stable under usual basic and acidic conditions.     

Synthesis of 11H-indolo[3,2-c]quinolines by SnCl4-catalyzed cyclization of indole-3-carbaldehyde oximes

Russian Chemical Bulletin - A new method for synthesizing 11H-indolo[3,2-c]quinolines by SnCl4-catalyzed intramolecular electrophilic amination of 2-arylindole-3-carbaldehyde O-acetyl oximes was...     

Synthesis of new pyrrolo-[3,4-c]isoxazole, pyrrolo[2,3-d]-[1,2,3]triazole, triazolo[4,5-c]-pyridazine, and dipyrrolo-[3,2-b:3′,4′-d]pyran derivatives

New pyrrolo[3,4-c]isoxazole derivatives were synthesized from the key intermediates 4-cyanopyrrolidin-3-ones in two steps. Pyrrolo[2,3-d][1,2,3]triazoles and triazolo[4,5-c]pyridazine were obtained from 2-arylhydrazono-4-cyano-1-(4′-methoxyphenyl)-3-oxopyrrolidines by refluxing with phenylhydrazine in either ethanol or glacial acetic acid. Aldol self-condensation of 1-aryl-4-cyanopyrrolidin-3-ones afforded dipyrrolo-[3,2-b:3′, 4′-d]pyran derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1841–1848, December, 2007.     

Novel heterocyclic systems based on 8-R-4,5-dihydro-4,4-dimethyl-[1,2]dithiolo[3,4-c]quinoline-1-thiones

Based on the reaction of 8-R-4,5-dihydro-4,4-dimethyl[1,2]dithiolo[3,4-c]quinoline-1-thiones with oxalyl chloride followed by the reactions of 1,3-dipolar cycloaddition and diene synthesis with participation of acetylenedicarboxylic acid dimethyl ester, we have developed approaches to synthesis of novel polycondensed heterocyclic systems: [1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-4,5-dione, 6-(1,3-dithiol-2-ylidene)-1,2-dioxo-5-thioxo-7H-pyrrolo[3,2,1-ij]quinoline and 4,5-dioxospiro(pyrrolo)-[3,2,1-ij]thiopyrano[2,3-c]quinoline-11,2′-[1,3]dithiole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 610–615, April, 2006.     

Derivatives of Condensed Thienopyrimidimines. 13. Synthesis and Structure of Pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines

Methods for the synthesis of 5-substituted 10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines have been developed. An X-ray crystallographic study of 5-(2-ethoxymethylhydrazino)-10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidine has been carried out.     

Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.     

Formation of furo[3,2- c ]quinolone-2-carbonitriles and 4-oxo-4,5-dihydrofuro[3,2- c ]quinolone-2-carboxamides from reaction of quinoline-2,4-diones with 2-[bis(methylthio)methylene]malononitrile

Quinoline-2,4-diones reacted with 2-[bis(methylthio)methylene]malononitrile in DMF/Et3N to produce 3-(methylthio)-4-oxo-4,5-dihydrofuro[3,2-c]quinolone-2-carbonitriles and 3-(methylthio)-4-oxo-4,5-dihydrofuro[3,2-c]quinolone-2-carboxamides in state of 2-imino-substituted 4-(methylthio)-5,6-dihydro-2H-pyrano[3,2-c]quinolone-3-carbonitriles. The structures of all new products were proved using NMR, IR, and mass spectral data. The possible mechanism for the reaction is also discussed.     

Synthesis and Reactions of 4-Oxiranylmethylfuro[3,2-b]pyrroles and Their Benzo Derivatives

Methyl 4-oxiranylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylates 2a-c and methyl 1-oxiranylmethyl-1H-benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate (2d) were prepared by reaction of the appropriate starting compounds 1a-d with excess chloromethyloxirane. The compounds 2a-d undergo oxirane ring opening by heterocyclic amines (morpholine, pyrrolidine, piperidine or 4-methylpiperazine) giving N-2-hydroxy-3-heteroaminopropyl-substituted compounds 3a-f or substituted 4,5-dihydrofuro[2',3':4,5]pyrrolo[2,1-c][1,4]oxazin-8-ones 4a-e.     

A rapid stereocontrolled synthesis of the 3a-hydroxy-pyrrolo[2,3-b]indole skeleton, a building block for 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones

A two-step selenocyclisation-oxidative deselenaton sequence was used to establish the 3a-hydroxy-pyrrolo[2,3-b]indole core; these tricycles were used as effective precursors to 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones.     

1,4-Cycloaddition reactions. II. Preparation of p-dioxino[2,3-g]furo[3,2-c] quinolines,p-dioxino[2,3-f] furo[3,2-c] quinolines,and [1,3] dioxolo[4,5-g] furo[3,2-c] quinolines from 2,3-dihydro-5-methylfuran and schiff bases

The boron trifluoride catalyzed 1,4-addition of 2,3-dihydro-5-methylfuran to N-(p-methoxy-benzylidene)-1,4-benzodioxan-6-amine (II) gave 2 pairs of epimers, 2,3,3a,4,5,8,9,11b-octahydro-4-(p-methoxyphenyl)-11b-methyl-p-dioxino[2,3-g]furo[3,2-c]quinoline (IIIa and b) and 2,3,7,8,8a,9.10,1la-octahydro-8-(p-methoxyphenyl)-11a-methyl-p-dioxino[2,3-f]furo[3,2-c]quinoline (IVa and b). When N-(p-methoxybenzylidene)-3,4-methylenedioxyaniline (V) was condensed with 2,3-dihydro-5-methylfuran in an analogous manner, a mixture of 2 epimers of 2,3,3a,4,5,10b-hexahydro-4-(p-methoxyphenyl)-10b-methyl[1,3]dioxolo[4,5-g]furo[3,2-c]quinoline (VIa and b) was isolated. Treatment of this mixture with sulfur afforded 6-(p-methoxyphenyl)-8-methyl-1,3-dioxolo[4,5-g]quinoline-7-ethanol (VIII). Structural assignments for all of the products were made from NMR spectra. None of the compounds possessed appreciable biological activity.     

Microwave-Assisted Synthesis and Antifungal Activities of Polysubstituted Furo[3,2-c]chromen-4-ones and 7,8,9,10-Tetrahydro-6H-benzofuro[3,2-c]chromen-6-ones

An efficient and novel microwave-assisted synthesis of furo[3,2-c]chromen-4-ones and 7,8,9,10-tetrahydro-6H-benzofuro[3,2-c]chromen-6-ones via 4-hydroxycoumarins with α-chloroketones or α-bromocyclohexanone in the presence of acetic acid (AcOH)/ammonium acetate (NH₄OAc) using DMF as solvent under microwave irradiation is described. Systematically, antifungal biological tests showed that most of the compounds exhibited potent antifungal activity against Botrytis cinerea, Collecterichum capsica, Alternaria solani, Gibberella zeae, and Rhizoctorzia solani at the concentration of 50 µg/mL. The corresponding EC50 values of these analogues have been detected, and compound 4i showed better antifungal activity against tested fungi Botrytis cinerea and Collecterichum capsica than the reference Osthol.     

Synthesis of Hexa- and Octahydropyrido[3'2':4,5]thieno[3,2-d]pyrimidines

The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridine. Refluxing the latter with acyl chlorides in AcOH or heating in formic acid gave hexahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine.     

An alternative one-pot gold-catalyzed approach to the assembly of 11H-indolo[3,2-c]quinolines

A new one-pot approach was developed to construct the 11H-indolo[3,2-c]quinoline scaffold through a gold-catalysed reaction of 2-[(2-aminophenyl)ethynyl]phenylamine derivatives with aldehydes. The broad scope and the high regioselectivity of this new protocol as well as the mild and neutral reaction conditions make it a viable alternative to the previously reported procedures.     

Beiträge zur Chemie der Pyrrolo[3,2-c]azepine und der Pyrrolo [3,2-b]azepine

Some chemical transformations in the series of the pyrrolo [3,2-b]azepines and the pyrrolo[3,2-c]azepines are reported: alkylation at the pyrrolo nitrogen and/or the azepino nitrogen, reduction of the lactam group by means of LiAlH₄, preparation of lactim ethers and amidines, substitution in position 2 by MANNICH reaction, bromination and condensation with oxalyl chloride or chloral hydrate, and the cyclocondensation with dimethylmalonyl chloride. The structures of the 2-substitution products have been evaluated by NMR.-spectroscopy.     

Synthesis of isoindolo[2,1-a]quinoline derivatives and their effects on N2-induced hypoxia

A variety of isoindolo[2,1-a]quinoline derivatives as well as the following related heterocycles have been prepared: 11b,12-dihydro-5H-isoindolo[2,1-b][2]benzazepine-7,13-dione (8a), 7,8,14,14a-tetrahydroisoindolo[2,1-c][3]benzazocine-5, 13-dione (8b), 6a,7-dihydroisoquinolino[2,3-a]quinoline-5,12-dione (12), 2,3,3a-4-tetrahydropyrrolo[1,2-a]quinoline-1,5-dione (14), and pyrido[2',3':3,4]pyrrolo[1,2-a]quinoline-5,11(5H)-dione (17). The key synthetic step involves an intramolecular Friedel-Crafts reaction of acid chlorides such as isoindole-1-acetyl chlorides (4), the acids (3) of which were prepared starting with 2-arylisoindole-1,3(2H)-diones (2-arylphthalimides) (1). The protective effects of isoindolo[2,1-a]quinoline derivatives (19 and 20) against N2-induced hypoxia were examined. Among them, 6-(diethylaminomethyl)isoindolo[2,1-a]quinoline-5,11(5H)-dio ne (19b) showed the most potency.     

One-pot synthesis of 3-(sulfonyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridines through a cascade Michael/cyclization reaction

In this paper, a straightforward and valid three-component Michael/cyclization reaction of (E)-1-methyl-3-(arylidene)piperidin-4-ones, 2-(sulfonyl)acetonitriles, and aromatic aldehydes was explored for the preparation of potentially biologically active 3-(sulfonyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridines under mild reaction conditions. More diverse 3-(sulfonyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine derivatives were constructed in satisfactory yields (up to 97%). The chemical structure of newly synthesized 3-(sulfonyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridines were identified with ¹H-NMR, ¹³C-NMR, and mass spectrometry analysis. The recommendable method features a simple and direct workup, easy access to initial materials, high atom utilization efficiency, high final product yields, and a wide range of substrate adaptability.     

Synthesis of heterocyclic compounds possessing the 4H-thieno[3,2-b]pyrrole moiety

A series of novel heterocyclic combinatorial libraries containing 4H-thieno[3,2-b]pyrrole, thieno[2',3':4,5]-pyrrol[1,2-d][1,2,4]triazine and thieno[2',3':4,5]pyrrolo[1,2-a]pyrazine heterocyclic moieties were obtained by parallel solution-phase synthesis. Key steps include different reactions of initial alkyl 4H-thieno[3,2-b]-pyrrole-5-carboxylates, such as alkylation with alkylating agents; transformation of the carboxylate group into different reactive functionalities, followed by reactions with electrophilic species; intramolecular cyclizations; and amide bond formation. Simple manual techniques for parallel reactions were coupled with easy purification procedures to give high-purity final products.     

Mass-spectral investigation of pyrrolo[3,2-c]piperidines

The dissociative ionization of derivatives of pyrrolo[3,2-c]piperidines and their deutero analogs was studied. The successive elimination of the substituents in the piperidine ring, which leads to its aromatization, and cleavage of this ring via a retrodiene fragmentation mechanism are the principal pathways of fragmentation of these substances. The principles found make it possible to determine the position and character of the substituents in the piperidine ring of derivatives of pyrrolo[3,2-c]piperidines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 212–215, February, 1988.