Synthesis and oral antiallergic activity of carboxylic acids derived from imidazo[2,1-c][1,4]benzoxazines, imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles

4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxylic acid (3) was found to possess potent activity in the IgE-induced rat passive cutaneous anaphylaxis model which may be predictive of clinical antiallergic activity. Compared to disodium cromoglycate (DSCG, 1), 3 was less active following iv administration but unlike DSCG showed very significant oral activity. To explore the structural requirements for this activity, a range of tricyclic compounds was prepared and their activities were measured. Individual 2-carboxylic acids derived from imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles showed iv activities up to 10(3) times as potent as DSCG and many of them showed significant oral activity. From these, imidazo[1,2-a]quinoxaline-2-carboxylic acid 114 has been chosen for further development.     

Imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyrazines: the role of nitrogen position in inotropic activity

Congestive heart failure is a major medical problem for which existing medicaments have provided limited benefit. Recent new experimental drugs, including imidazo[4,5-b]- and imidazo[4,5-c]pyridines, have both inotropic and vasodilatory properties. Subtle changes in nitrogen position of these compounds have been shown to dramatically affect potency. We have synthesized a series of imidazo[4,5-b]- and -[4,5-c]pyridine analogues having an imidazo nitrogen relocated at the bridgehead position. The superior inotropic activity of the [4,5-c]pyridines as compared to [4,5-b]pyridines is reaffirmed by the activity of our analogues. The biological equivalence of imidazo[4,5-b]pyridines with imidazo[1,2-a]pyrimidines and imidazo[4,5-c]pyridines with imidazo[1,2-a]pyrazines is demonstrated. Further, 2-[2-methoxy-4-(methylsulfenyl)phenyl]imidazo[1,2-a]pyrazine and 2-[2-methoxy-4-(methylsulfonyl)phenyl]-imidazo[1,2-a]pyrazine are potent inotropic agents both in vitro and in vivo.     

Reactions with hydrazidoyl halides VIII: Synthesis of thiazolo [3,2-a] benzimidazoles,imidazo[2,1-b] thiazoles and imidazo[2,1-b] benzthiazoles

Hydrazidoyl halides were condensed with 2-mercaptobenzimidazole2 yielding4a-c which were cyclized to the corresponding 3-substituted 2-arylazothiazolo-[3,2-a] benzimidazole6a-c, respectively. Imidazo-[2,1-b] thiazoles9, 12, 15, and16 were obtained by the reaction of hydrazidoyl halides1 with 2-mercapto 4,5-dihydroimidazole3 and 2-aminothiazoles10. The structures of the products were established on the basis of their elemental analysis and spectral data studies.     

Reactions with hydroxamoyl halides: Synthesis of several isoxazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine and benz-1,2,4-triazine derivatives

Benzofuroylhydroxamoyl chloride ( 3 ) reacted with acrylonitrile, N-tolyl-maleimide and active methylene compounds to afford the isoxazoline 4 , the pyrrolidino[3,4-d]isoxazoline 5 and the isoxazole derivatives 6,7 , respectively. Nitrosoimidazo[1,2-a]pyridines 10 and the imidazo[1,2-a]pyrimidine 12 were obtained by the reaction of 3 with 2-aminopyridine and 2-aminopyrimidine, respectively. 3 reacted also with o-phenylenediamine and o-aminothiophenol to give the dihydrobenztriazine 13 and the benzothiadiazine 15 , respectively.     

Antiulcer agents. 3. Structure-activity-toxicity relationships of substituted imidazo[1,2-a]pyridines and a related imidazo[1,2-a]pyrazine

Investigation of the interrelationship between structure, antiulcer activity, and toxicology screening data derived from a series of compounds selected from structure-activity studies directed toward identifying a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1), has identified 3-(cyanomethyl)-2,7-dimethyl-8-(phenylmethoxy)imidazo[1,2 -a]pyridine (5), 3-amino-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine (6), and 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine (7). These analogues exhibit a combination of antisecretory and cytoprotective activity in animal models, while eliminating the adverse effects of the prototype 1. One of these, 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine, Sch 32651 (7), has a profile meeting all criteria.     

Novel dicationic imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines as antiprotozoal agents

2-[5-(4-Amidinophenyl)-furan-2-yl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-6-carboxamidine acetate salt (7) was synthesized from 2-[5-(4-cyanophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carbonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation in glacial acetic acid. Compound 4a was obtained in four steps starting with two successive brominations of 2-acetylfuran first with N-bromosuccinimide, and second with bromine to form alpha-bromo-2-acetyl-5-bromofuran (2) in a moderate yield. The product (3a), of the condensation reaction between 6-amino-nicotinonitrile and 2, undergoes Suzuki coupling with 4-cyanophenylboronic acid to furnish 4a in good yield. Acetate salt of 2-[5-(4-amidinophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carboxamidine (8a) was obtained from 4a, through the bis-O-acetoxyamidoxime followed by hydrogenation in a mixture of ethanol/ethyl acetate. N-Methoxy-2-(5-[4-(N-methoxyamidino)-phenyl]-furan-2-yl)-imidazo[1,2-a]pyridine-6-carboxamidine (6) was prepared via methylation of the respective diamidoxime 5a with dimethyl sulfate. By these approaches eight new diamidines and four potential prodrugs were prepared. All of the diamidines showed strong DNA affinities as judged by high DeltaT(m) values. Six of the eight diamidines gave in vitro IC(50) values of 63 nM or less vs T. b. rhodesiense with two exhibiting values of 6 nM and 1 nM. Also, six of the eight diamidines gave in vitro IC(50) values of 88 nM or less vs P. falciparum with two exhibiting values of 14 nM. Excellent in vivo activity in the trypanosomal STIB900 mouse model was found for five of the diamidines on ip dosage; these compounds gave 4/4 cures in this model. The oral activity of the prodrugs was modest with only one showing 2/4 cures in the same mouse model.     

Synthesis and antibacterial activity of some derivatives of imidazo[1,2-a]pyridine

Pharmaceutical Chemistry Journal -     

New heterocyclic ring systems--V synthesis and pharmacological activity of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b] indole derivatives and of 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido[5,4-b] indole

As a part of a study on analgesic and antiinflammatory active condensed heterocyclic compounds containing the pyrimidinic ring, a number of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b]indole and 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido [5,4-b] indole were synthesized and tested. The results of pharmacological assays are reported and discussed.     

Recent progress in the pharmacology of imidazo[1,2-a]pyridines

Imidazo[1,2-a]pyridine is a bicyclic system with a bridgehead nitrogen atom, of growing interest in medicinal chemistry. The paper deals with the recent progress realised in the comprehension of the pharmacological properties of this scaffold. From the many imidazo[1,2-a]pyridine analogues described in the literature, those discussed herein will be presented in three parts concerning first the enzyme inhibitors, then the receptor ligands and finally the anti-infectious agents.     

Synthesis of several new isoxazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,benzoxadiazine and benzothiazine derivatives from hydroximoyl halides

Furoylhydroximoyl chloride3 reacted with 2-aminopyridine, 2-aminopyrimidine,O-aminophenol,O-phenylenediamine and aminothiophenol to afford imidazo[1,2-a]pyridine6, imidazo[1,2-a]pyrimidine8, benzoxadiazine10, nitrosobenzopyrazine13a and nitrosobenzothiazine13b, respectively. Isoxazoline18 and pyrrolidino[3,4-d]isoxazolin-4,6-dione derivatives19a and19b obtained by the reaction of3 with acrylonitrile and N-arylmaleimide. Hydroximoyl chloride3 reacted with thiophenol and sodium benzenesulfinate to yield furylglyoxaloxime16a and16b, respectively. Hydroximoyl chloride3 reacted also with some active methylene compound to give isoxazole derivatives20–23, respectively.     

Synthesis and antiproliferative activity in vitro of new pyrido[1,4-b]diazepine derivatives and imidazo[4,5-b]pyridine

A novel series of esters 8-10 and hydrazones 4-6 was synthesized from 4-aryl-2-phenacylidene-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepine (1-3). Subsequent treatment of hydrazone 4 with p-chlorbenzaldehyde furnished azine 7. Long-standing heating of ester 8 with hydrazine hydrate afforded 3-[1-(p-chlorophenylene)-2-(5-phenyl-1H-pyrazol-3-yl)-ethyl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one (11). The structures of 4-6 and 8-10 were identified by the results of elemental analysis and their IR, 1H-NMR and MS spectra. Additionally, the structure of 11 was confirmed by X-ray diffraction method. Compounds 8-10 and 11 were examined for their antiproliferative activity in vitro against the cells of 5 human cancer cell lines, using SRB or MTT technique. Among tested compounds, only 11 revealed cytotoxic activity in vitro against all cell lines applied with ID50 (inhibitory dose 50%) values lower than 4 microg/mL, which is an international activity criterion for synthetic compounds. All compounds inhibit the proliferation of HL-60 human promyelocytic leukemia cell line.     

Synthesis and antiviral activity of novel erythrofuranosyl imidazo[1,2-a]pyridine C-nucleosides constructed via palladium coupling of iodoimidazo[1,2-a]pyridines and dihydrofuran

2,5,6-Trichloro-1-(beta-d-ribofuranosyl)benzimidazole (TCRB) and certain analogues have shown significant activity against human cytomegalovirus. The metabolic instability of the glycosidic linkage in TCRB prompted us to synthesize the structurally similar imidazo[1,2-a]pyridine erythrofuranosyl C-nucleosides. As an approach to the synthesis of polychlorinated imidazo[1,2-a]pyridine C-3-erythrofuranosides, a palladium-based methodology for coupling 2,3-dihydrofuran with chlorinated 3-iodoimidazo[1,2-a]pyridines was developed and optimized to give 80-90% yields of 2,6-dichloro- and 2,6,7-trichloro-3-(2,3-dideoxy-2,3-didehydro-d/l-erythrofuranosyl)imidazo[1,2-a]pyridine. Dihydroxylation of these didehydro derivatives with osmium tetroxide or with AD-mix alpha gave a mixture of erythrofuranosyl C-nucleosides that were separated by standard and then chiral chromatography. When screened for anti-HCMV and HSV-1 activity, the alpha-d anomer of 2,6,7-trichloro-3-(erythrofuranosyl)imidazo[1,2-a]pyridine proved to be the most active member of the series, while the beta-anomers all proved to be inactive.     

Synthesis of imidazo[1,2-a]pyridine derivatives as antiviral agents

The synthesis and antiviral activity of original dibromoimidazo[1,2-a]pyridines bearing a thioether side chain are reported. Molecular modeling was used to identify biophoric structural patterns that are common to 16 compounds. Structure-activity relationship (SAR) studies identified hydrophobicity (logP) as the most important factor for activity. From these SAR studies, the antiviral activity could be predicted.     

Synthesis and biological activity of 3-substituted imidazo[1,2-a]pyridines as antiulcer agents

New imidazo[1,2-a]pyridines substituted at the 3-position have been synthesized as potential antisecretory and cytoprotective antiulcer agents. The synthetic routes began with cyclization of aminopyridines 5a,b and chloro ketones 6a,b to give imidazo[1,2-a]pyridines 7-9. The side chain at the 3-position was elaborated to give primary amines 12a-c, which were treated with either butoxyaminocyclobutenedione 13 or methoxyaminothiadiazole 1-oxide (15) to give 14a,b and 16a-c, respectively. Thiadiazole 1-oxides 16a-c were converted to thiadiazoles 19a-c in a two-step process which involved extrusion of the sulfoxide in 16a-c to afford diimidamides 17a-c, which were subsequently treated with thiobisphthalimide (18). None of the compounds displayed significant antisecretory activity in the gastric fistula rat model, but several demonstrated good cytoprotective properties in both the EtOH and HCl models. 8-(Benzyloxy)-3-[1-[[2-[(4-amino-1,2,5-thiadiazol-3- yl)amino]ethyl]thio]ethyl]-2-methylimidazo[1,2-a]pyridine (19c) showed comparable cytoprotective activity to SCH-28080 (4).     

Synthesis and pharmacological activity of 6H-thiazolo [3',2': 1,2]-5-oxopyrimido[5,4-b]indole derivatives, a new heterocyclic ring system

In the outline of the investigations concerning the analgesic and antiinflammatory activity of new fused heterocyclic compounds containing the pyrimidine ring, a series of 6H-thiazolo[3',2': 1,2]-5-oxopyrimido[5,4-b]indole derivatives was synthesized. Pharmacological results are reported and discussed.     

Docking and quantitative structure–activity relationship studies for imidazo[1,2-a]pyrazines as inhibitors of checkpoint kinase-1

We have performed docking of imidazo[1,2-a]pyrazines complexed with checkpoint kinase1 (Chk1) to better understand the structural requirements and preferred conformations of these inhibitors. The study was performed on a selected set of 33 compounds with variation in structure and activity. In addition, the predicted inhibitor concentrations (IC₅₀) of the imidazo[1,2-a]pyrazines as Chk1 inhibitors were obtained by comparative molecular similarity analysis (CoMSIA). The best CoMSIA model included electrostatic and hydrophobic fields, had a good Q ² value of 0.589, and adequately predicted the compounds contained in the test set. Furthermore, plots of the CoMSIA fields allowed conclusions to be drawn for the selection of suitable inhibitors.