Studies on antiulcer drugs. IV. Synthesis and antiulcer activities of imidazo[1,2-a]pyridinylethylbenzothiazoles and -benzimidazoles.

A series of 6-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]benzothiazoles (II) and benzimidazole analogues (III) was synthesized and tested for histamine H2-receptor antagonist, gastric antisecretory and anti-stress ulcer activity. A benzimidazole derivative (IIIa) exhibited strong antisecretory activity, whereas the corresponding benzothiazole derivative (IIb) lacked this potency in in vivo test. In contrast to compound IIIa, however, compound IIb demonstrated good inhibition against stress induced ulcer. The structure-activity relationships of these compounds are discussed.     

Reaction of β-lactam carbenes with 2-pyridyl isonitriles: a one-pot synthesis of 2-carbonyl-3-(pyridylamino)imidazo[1,2-a]pyridines useful as fluorescent probes for mercury ion

The one-pot reaction of β-lactam carbenes with 2-pyridyl isonitriles followed by an acidic hydrolysis was reported, which produced 2-carbonyl-3-(pyridylamino)imidazo[1,2-a]pyridines in moderate to good yields. Among the resulting novel imidazo[1,2-a]pyridine derivatives, 1-(6-chloro-3-(5-chloropyridin-2-ylamino)imidazo[1,2-a]pyridin-2-yl)-2-ethylbutan-1-one was demonstrated to be an efficient fluorescent probe for mercury ion both in acetonitrile and in buffered aqueous solution.     

Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives

A series of 1,2-dihydro-5-imidazo[1,2-a]pyridinyl-2(1H)-pyridonones was synthesized and evaluated for positive inotropic activity, 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2- oxo-3-pyridinecarbonitrile (11a) hydrochloride monohydrate (E-1020) was found to be a potent and selective inhibitor of phosphodiesterase III and a long-acting, potent, orally active positive inotropic agent. Additional imidazo[1,2-a]pyridin-2-yl (3a), -3-yl (16), -7-yl (20) and -8-yl (24a) compounds were also prepared. Altering the pyridine substitution from the 2-position to the 6-position produced a 2-fold increase in the i.v. cardiotonic potency (ED50) from 52 to 23 micrograms/kg, while substitution at the 3-, 7- or 8-position reduced potency. In the 2-positional isomers, introduction of halogen groups enhanced the activity and 3-chloro-1,2-dihydro-5-(6-fluoroimidazo[1,2-a] pyridin-2-yl)-6-methyl-2(1H)-pyridinone (3u) was the most potent (i.v. ED50 11 micrograms/kg) in this series. E-1020 is presently under development for the treatment of congestive heart failure.     

Synthesis of some new types of 3-coumarinyl-substituted pyrazolopyrimidines and imidazothiazoles

The treatment of 3-[3-(dimethylamino)-1-oxo-2-propenyl]chromen-2-ones with 3-amino-4-cyanopyrazole gives 7-(2-oxo-2H-chromen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitriles. The reaction of 3-(2-bromoacetyl)coumarins with 2-amino-4-(methoxycarbonylmethyl)thiazole and 2-amino-4-methylthiazole gives methyl 2-(6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b]thiazol-3-yl)acetate and 3-(2-methylimidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-ones, respectively. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 465–471, March, 2008.     

Studies on antiulcer drugs. V. Synthesis and antiulcer activity of aralkylbenzazoles.

A series of 2-alkylamino-5- or 6-aralkyl-substituted benzazoles were synthesized and tested for histamine H2-receptor antagonist and anti-stress ulcer activities. These new compounds showed little or no histamine H2-receptor antagonist activity in contrast to imidazo[1,2-a]pyridine analogues (I). On antiulcer assay, however, some pyridine derivatives (II) exerted higher activity than the reference compounds, sofalcone, sucralfate and cimetidine. The structure-activity relationships of these compounds are discussed.     

Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-alpha-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.     

Modification of biologically active amides and amines with fluoro-containing heterocycles 13.* Carbazoles and tetrahydrocarbazoles modified with 2-substituted (imidazo[1,2-a]pyridine-3-yl)propionamidic fragments

Russian Chemical Bulletin - An approach to modify biologically active carbazoles and tetrahydrocarbazoles with 2-trifluoromethyl and 2-methoxycarbonyl(imidazo[1,2-a]pyridin-3-yl)propionylamidic...     

One-pot synthesis of imidazo[1,2-b]pyrazole,imidazo[1,2-b]-1,2,4-triazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,imidazo[1,2-a]benzimidazole,and 1,2,4-triazolo[4,3-a]benzimidazole derivatives

Hydrazonoyl bromides 1a-c react with 5-amino-3-phenyl-1H-pyrazole, 5-amino-1H-1,2,4-triazole, 2-aminopyridine, and 2-aminobenzimidazole to afford the corresponding imidazol[1,2-b]pyrazoles 10, imidazo[1,2-b]-1,2,4-triazoles 11, imidazo[1,2-a]pyridines 16, imidazo[1,2-a]pyrimidines 17, and imidazo[1,2-a]benzimidazoles 20, respectively. Compounds 1a-c reacted also with 2-methylthiobenzimidazole to give 1,2,4-triazolo[4,3-a]benzimidazole derivatives 21. © 1997 John Wiley & Sons, Inc.     

Synthesis of azinoazole structural isomers by photocyclization

Irradiation of 2-chloro-N-(pyridin-2-yl)pyridin-3-amine and N-(2-chloropyridin-3-yl)-4,6-dimethyl-pyrimidin-2-amine in aqueous-alcoholic solution gave new azinoazole derivatives, 6-chlorodipyrido-[1,2-a:5′,4′-d]imidazole and 1,3-dimethylpyrido[3′,2′:4,5]imidazo[1,2-a]pyrimidine, respectively.     

An Improved Synthesis of 2-Chlorinated Imidazo[1,2-α]-pyridines and the Application of this Procedure for the Synthesis of Several New Polychlorinated Imidazo[1,2-α]Pyridnes.

Polychlorinated imidazo[1,2-α]pyridines were synthesized as analogs of certain chlorinated benzimidazoles. The imidazo[1,2-α]pyridines were obtained by a condensation of ethyl bromoacetate and chlorinated 2-aminopyridines. These condensation products were treated with an ion exchange resin to effect an exchange of hydrobromide salts with hydrochloride salts. These compounds were subsequently treated with POCl₃ to convert the imidazo[1,2-α]pyridin-2-ones into 2-chloroimidazo[1,2-a]pyridines.     

Reaction of 1-amino-, 2-amino-, and 1,2-diaminoimidazoles with β-diketones

1,2-Diamino-4-phenylimidazolium perchlorate condenses with 2 mole of β-diketones to give pyrimido[2′,1′:2,3]imidazo[1,5-b]pyridazinium derivatives, while, like 1-amino-2-mercapto-4-phenylimidazole, to give imidazo[1,5-b]pyridazine derivatives. Salts of 1-benzylideneamino- and 1-(2-thiazolyl)-2-aminoimidazoles react with β-diketones to give substituted imidazo[1,2-a]pyrimidinium derivatives.     

2-(1-Adamantyl)-7-methylimidazo-[1,2-α]pyridine and its reactions with N-bromosuccinimide

In reaction with equimolar amount or twice the amount of N-bromosuccinimide 2-(1-adamantyl)-7-methylimidazo[1,2-a]pyridine, obtained from 2-amino-4-methylpyridine and bromomethyl 1-adamantyl ketone, is converted into 2-(1-adamantyl)-3-bromo-7-methylimidazo[1,2-a]pyridine. With three times the amount of N-bromosuccinimide it gives 2-(1-adamantyl)-3-bromo-7-formylimidazo[1,2-a]pyridine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1791–1793, December, 2004.     

Preparation of new nitrogen-bridged heterocycles 72. A new approach to 1-acyl-3-(substituted methylthio)thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives. [corrected

The alkaline treatment of the pyridinium salts, readily available from the S-alkylations of 3-amino-4-(1-pyridinio)thiophene-5-thiolates with various alkyl halides, in chloroform at room temperature afforded the corresponding thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives in low to moderate yields via the intramolecular cyclization of the resulting 1,5-dipoles followed by the aromatization of the primary cycloadducts. Interestingly, the reactions using unsymmetrical 3-amino-4-[1-(3-methylpyridinio)]thiophene-5-thiolates afforded only 8-methylthieno[3',4':4,5]imidazo[1,2-a]pyridines and the other 6-methyl derivatives were not formed at all. In addition the isolation of a byproduct in the condensation reaction of pyridinium salt with the solvent (CHCl?) is also discussed.     

The Mannich reaction in the synthesis of N,S-containing heterocycles 3. Unexpected direction of the aminomethylation reaction of N-methylmorpholinium 1-amino-2,4-dicyano-4-ethoxycarbonyl-1,3-butadienethiolate. One stage cascade synthesis of new derivatives of pyrido[1,2-<Emphasis Type="Italic">a</Emphasis>][1,3,5]triazine

The interaction of N-methylmorpholinium 1-amino-2,4-dicyano-4-ethoxycarbonyl-1,3-butadienethiolate with primary amines and formaldehyde leads to the formation of ethyl esters of 7-cyano-6-thioxo-1,3,4,6-2H-pyrido[1,2-a][1,3,5]triazine-9-carboxylic acid in place of the expected derivatives of pyrido[2,1-b][1,3,5]thiadiazine. The structure of the ethyl ester of 7-cyano-3-phenyl-6-thioxo-1,3,4,6-2H-pyrido[1,2-a][1,3,5]triazine-9-carboxylic acid was demonstrated by X-ray structural analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1075–1081, July, 2007.     

Synthesis and molecular structure of 3,7-dimethyl-2-[N-(4-methylpyridyl-2)-4-hydroxy-3-methyl-5-oxopyrrolen-3-yl-2]imidazo[1,2-a]pyridine

Heterocyclization of 2-chloroepoxy-1,1-diethoxy-2.3-butane with 2-amino-4-methylpyridine occurred with participation of all three potential electrophilic centers to give 3,7-dimethyl-2-[N-(4-methylpyridyl-2)-4-hydroxy-3-methyl-5-oxopyrrolen-3-yl]imidazo[1,2-a]pyridine, the structure of which was determined by X-ray crystallography. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1089–1094, July 2006.     

Research on heterocyclic compounds. XXI. Synthesis of imidazo[2,1-b]benzothiazole and imidazo[2,1-b]thiazole derivatives

The reaction of some 2-aminobenzothiazoles and 2-aminothiazoles with ethyl 3-bromo-4-oxopentanoate was investigated with the aim to obtain the corresponding imidazo[2,1-b]benzothiazole and imidazo[2,1-b]-thiazole derivatives, respectively. In some cases, two unexpected side products were obtained together with the required compound and their structures were elucidated: e.g., 2-aminobenzothiazole reacted with ethyl 3-bromo-4-oxopentanoate to give ethyl 2-methylimidazo[2,1-b]benzothiazole-3-acetate together with ethyl imi-dazo[2,1-b]benzothiazole-2-propionate and ethyl 3-(benzothiazol-2-yl)amino-4-oxopentanoate.     

Efficient solid-phase synthesis of a library of imidazo[1,2-a]pyridine-8-carboxamides

A versatile method for the solid-phase synthesis of imidazo[1,2-a]pyridine-based derivatives, imidazo[1,2-a]pyridine-8-carboxamides, has been developed. They were obtained by treatment of the amino group of the polymer-bound 2-aminonicotinate with different alpha-haloketones, followed by halogenation at the 3-position of the polymer-bound imidazo[1,2-a]pyridine. The derived polymer-bound imidazo[1,2-a]pyridines 5, 6, and 7 were finally cleaved from the solid-support with an excess of primary or secondary amines. The final crude products were purified from excess amines by solid-supported liquid-liquid extraction (SLE).     

Imidazo[1,5-a]pyridine: a versatile architecture for stable N-heterocyclic carbenes

The imidazo[1,5-a]pyridine skeleton provides a versatile platform for the generation of new types of stable N-heterocyclic carbenes. Rh(I) mono- (6) and biscarbenes (7) from imidazo[1,5-a]pyridin-3-ylidenes (ImPy) and derivatives such as 13 from a mesoionic carbene were synthesized and characterized.     

Synthesis of (imidazo[1,2-C]pyrimidin-2-yl)phenylmethanones and 6-benzoylpyrrolo[2,3-D]pyrimidinones

4-Pyrimidinamines have been reacted with 3-bromo-1-phenylpropane-1,2-dione to give a series of (imidazo[1,2-c]pyrimidin-2-yl)phenylmethanones. The dione also reacted with ethyl amidinoacetate to yield ethyl 2-amino-5-benzoylpyrrole-2-carboxylate which was used to prepare a series of 6-benzoylpyrrolo[2,3-a]pyrimidines.     

Studies of imidazo[1,2-a]benzimidazole derivatives. 21. Synthesis of haloketones in the imidazo[1,2-a] benzimidazole series

Methods for the synthesis of imidazo[1,2-a]benzimidazole haloketone derivatives have been investigated. It has been found that -bromoketone derivatives of this heterocycle can be prepared either by bromination of 3-acylimidazo[1,2-a]benz-imidazoles with bromine in glacial acetic acid or by acylation of 3-unsubstituted imidazo[1,2-a]benzimidazoles with haloanhydride derivatives of -bromoalkanoic acids. Treatment of imidazo[1,2-a]benzimidazoles with 3-chloropropionyl chloride results in the formation of imidazo[1,2-a]benzimidazolyl-3-propionyl chloride and bis(imidazo[1,2-a]benzimidazolyl)propan-3-one derivatives as side products. Reaction of 2-phenylimidazo[1,2-a]benzimidazoles with 3-bromopropionic acid in polyphosphoric acid gives benzocyclohepten[5,6:4,5]imidazo[1,2-a]benzimidazole derivatives.For Communication 20, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 339–345, March, 1986.