Jean-Pierre Chapat

Synthesis and antiviral activity of imidazo[1,2-a]pyridines

Abstract Imidazo[1,2- a ]pyridines bearing a 3-(dithiolan-, dioxolan- or oxathiolan-2-yl) substituent were synthesized from the corresponding aldehydes. The dithiolanyl derivative 6a proved active against cytomegalovirus at an inhibitory concentration (IC 50 ) of 16 μM, whilethe oxathiolanyl compound 6c inhibited respiratory syncytial virus (IC 50 : 58 μM). The thioacetal 7 was active against cytomegalovirus at an IC 50 of 3.1 μM. None of the compounds had anti-HIV activity and were not inhibitory against other RNA and DNA viruses evaluated. Compounds 6a,c and 7 had in vitro selectivity indexes (ratio cytostatic concentration/antivirally active concentration) ranging between 8 and 10.

Heterocyclic enaminones: Photochemical synthesis of 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-9-ones

Abstract The synthesis of 6,7,8,9-tetrahydro-5 H -pyrido[2,3- b ]indol-9-ones from arylenaminones is described. Two “routes” have been investigated: a radical process through a photochemical reaction, and a catalytic process through an arylpalladium complex.

Carbon-nitrogen bond formation in cyclisations by deoxygenation, thermolysis, or photolysis of phenylimidazo[1,2-a]pyridine systems: access to pyrido[1′,2′ : 1,2]imidazo[4,5-b]indoles

Reductive cyclisation of 2-(2-nitrophenyl)imidazo[1,2-a]pyridine with triethyl phosphite gives the indolic structures (5) and (6). The latter are of interest because of preferential C insertion rather than reaction of the nitrene at N-1 of the imidazole ring. 2D N.m.r. confirms structure (5). Both thermolysis or photolysis of the representative 2-(2-azidophenyl)imidazo[1,2-a]pyridines (7) and (8) are also reported and shown to produce novel indole, cinnoline, and benzofuran structures in an extremely facile fashion.

Theophylline-like properties of xanthine analogs.

Theophylline and other methylxanthines display a large number of biological effects, some of which are clinically important. The effects of these compounds are commonly ascribed to an inhibition of cyclic AMP breakdown. However, it becomes actually evident that another mechanism, namely adenosine receptor antagonism, could be responsible for certain methylxanthine effects. It could be of interest to find new compounds displaying only one of these mechanisms, either phosphodiesterase inhibition or adenosine receptor antagonism. We have studied several synthetic imidazol[1,2a]pyrazines, some of which display theophylline-like pharmacological properties at lower doses than theophylline. We showed that some of these compounds inhibited mitogen-induced [3H]-thymidine uptake by human lymphocytes, which is consistent with increases in cyclic AMP levels: the most efficient compounds were those which were better phosphodiesterase inhibitors than theophylline and poorer adenosine receptor antagonists.

PREPARATION AND REACTIVITY OF 1-BENZYL-2,4-PIPERIDINEDIONE-3-CARBOXYLIC ACID DERIVATIVES

The preparation and structural determination of 2,4piperidinedione-3-carboxylic acid methyl ester 4. by a Dieckmann reaction was reported. Decarbomethoxylation and alkylation studies on A were also reported. The 4-piperidone framework has been used as synthetic intermediates specially in the synthesis of natural products and compounds with pharmacological interest (1), while synthetic applications of 2,4piperidinedione derivatives have been reported in the preparation of emetine-like antiepileptic, herbicide agents (2) and patented, for examples as therapeutic agents for liver disorders (3) . As a part of our program on the reactivity of heterocycles, we are now interested in the study of the reactivity of 2,4-piperidinedione-3-carboxylic acid ester. Methyl N-Benzyl-ß-alaninate 1 was obtained admixed with the tertiary amine 2 by Michael addition of methyl acrylate on benzylamine (52:38% yield respectively) in a mixture of methanol, water and triethylamine, according the procedure of Christie and Rapoport (4) . Finally, 1 was obtained in 86% yield in ethanol according the procedure of Huizenga and Pandit (5) . Compound 1 reacts with methyl malonyl chloride in dichloromethane-water in presence of potassium carbonate to give the amide 2 with 92% yield (6). The lH and 13C-NMR spectra were more complex due to the presence of two rotamers in the 60:40 ratio. In the case of acyclic amide, it was well established that the groupment in trans from the carbonyl resonate at a lower field Vol. 4, No. 4, 1998 Preparation and reactivity of l-benzyI-2,4-piperidinedione-3-carboxylic acid derivatives than the cis (7) . These results, in good agreement with the anisotropy diamagnetic model of amide described by Paulsen and Todt (8) led to the following assignments.

REACTIVITY OF 6,7,8,9-TETRAHYDROPYRIDO[1,2-a]BENZIMIDAZOL-9-ONE : SYNTHESIS OF PYRROLOPYRIDOBENZIMIDAZOLES

reactivity of 6,7,8,9-tetrahydropyrido[l,2-a]benzimidazol-9-ones 1 to give the 1,4 and 1,3-dicarbonyl compounds 2 and 3 is reported Further heterocyclisation of these derivatives is investigated in view of the obtention of the tetracyclic pyrrolic frameworks 4 and 5. Introduction As part of studies related to the biological activities of triand tetracyclic heterocycles with a bridghead nitrogen (1), we initiated a program aimed at examining the synthesis and cytotoxicity against resistant tumor cells of new tetracyclic derivatives of azacarbazoies. Since the pyrido[l,2-a]benzimidazole ring system has been found to exhibit anticancer properties by Badaway and co-workers (2), a number of studies have been directed toward this heterocycle. These investigations showed good activities for compounds substituted on ring A. As a first approach of modifications which should be integrated into ring C, we reported the regioselective synthesis of some pyrazolo derivatives and and their antitumor activities in vitro against some resistant cell lines (MDR+)(3). In order to determine the effect of the position of nitrogen atoms on such heterocyclic compounds, we describe now our investigations concerning the reactivity of the 6,7,8,9-tetrahydropyrido[l,2-a]benzimidazol-9-one 1 system in view of the synthesis of pyrrolo derivatives 4 and 5.

PHOTOCHEMISTRY OF POLYHALOGENATED HETEROCYCLIC ENAMINONES: COMPETITION BETWEEN CYCLIZATION AND DEHALOGENATION

Photochemistry of polvhalogenated enaminones is described under various conditions to give functionalized tetrahulroazacarbazolone (9, 15). Starting enaminones (2, 7, 14) also underwent competitive dehalogenations creating a sei o f .secondary products. Mechanistic aspect of the reactions are considered .