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.     

Antiulcer agents. 2. Gastric antisecretory, cytoprotective, and metabolic properties of substituted imidazo[1,2-a]pyridines and analogues

The search for a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (27), a compound that exhibits gastric antisecretory and cytoprotective properties and has undergone clinical evaluation as an antiulcer agent, has culminated in the identification of four related compounds that exhibit pharmacologic profiles similar to that of 27. In three of these potential successors an amino group functions as a surrogate for the 3-cyanomethyl substituent of the prototype. The present work concerns, in addition to an evaluation of the structure-activity relationships of a series of analogues of 27, preliminary studies of the pharmacodynamics and metabolism of 27, performed with the aid of cyano carbon labeled versions of the drug (13C labeled; 28; 14C labeled, 29). These studies have shown that 27 is well-absorbed and extensively metabolized and that the major metabolite of 27 is the thiocyanate anion. A similar study performed on 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, labeled at the 3-position with carbon-13 (41) or carbon-14 (42), revealed that this compound, which has an antisecretory/cytoprotective profile comparable to that of 27, is also metabolized to thiocyanate anion, although this must occur via a different mechanism. The chemistry section includes a discussion of the potential sites of protonation of the pharmacologically similar 3-amino analogue 40 and the structurally related imidazo[1,2-a]pyrazine 67. Predictions based on charge density and protonation product stabilities are presented. That N1 is the site of protonation in these analogues has been definitively demonstrated by X-ray crystal structure analysis, which also unequivocally established the assigned imidazo[1,2-a]pyrazine ring structure.     

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.     

Benzimidazole condensed ring systems: New synthesis and antineoplastic activity of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo [4,5]imidazo[1,2-a]pyrinnidine derivatives

As part of an ongoing effort to develop new antineoplastic agents, a series of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo[4,5]imidazo[1,2-a]pyrimidine derivatives (5-19) were synthesized. 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine-2-one derivatives (5-7) were prepared via one-pot two-component thermal cyclization reaction of 2-aminobenzimidazole 1 and P-substituted methyl cinnamates (2-4). Vilsmir-Haack formylation of these derivatives (5-7) afforded the 2-chloro-3-carboxaldehyde targets (8-10) followed by nucleophilic displacement of the chloro atom in the 3-carboxaldehyde compounds (8-10) to yield the remaining final targets (11-19). The structures of the synthesized derivatives (5-19) were confirmed by means of IR, 1H NMR, MS and elemental analyses. The synthesized derivatives (5-19) were subjected to the National Cancer Institute (NCI) in vitro disease human cell screening panel assay. 2-Chloro-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxyaldehyde (8, NCI 722731) and 4-(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)-3,4-dihydrobenzo[4,5]imidazo [1,2-a]pyrimidine-3-carboxaldehyde (18, NCI 722739) showed a variable degree of antineoplastic activity against some of the cell lines tested. 2-Chloro-4-(4-nitrophenyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxyaldehyde (10, NCI 722743) exhibited good in vitro antineoplastic activity with subpanel disease selectivity against all the cell lines tested with log10 G150 (M), the concentration that inhibits 50% of cell growth, values ranging from -5.08 to < -8.00.     

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.     

Synthesis and hypoglycemic activity of substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines.

A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines were prepared using two approaches, the condensation of alpha-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a [(beta-hydroxyalkyl)amino]pyrazine. These imidazo[1,2-a]pyrazines were evaluated for their binding affinity to the alpha 1, alpha 2, beta 1, and beta 2 adrenergic receptors as well as their ability to lower blood glucose in insulin resistant hyperglycemic ob/ob mice. Modifications on 8-(1-piperazinyl)imidazo[1,2-a]pyrazine (4) reduced alpha 2 binding, lowered hypoglycemic potency, and showed variations in binding to the alpha 1, beta 1, and beta 2 adrenergic receptors. In addition to 4, the 2-methyl, 3-methyl, and 5-methyl 8-(1-piperazinyl)imidazo[1,2-a]pyrazines (16k, 25m, and 16f, respectively) displayed high affinity for the alpha 2 receptor and were potent hypoglycemic agents when compared to 2-amino-7,8-dihydro-4-(1-piperazinyl)-6H-thiopyrano[3,2- d]pyrimidine (MTP-1403, 2). Receptor binding was modified by use of a 4-methylpiperazine moiety which reduced alpha 1 and beta 1 binding while retaining some hypoglycemic activity. The structure-activity relationship for heterocyclic alkyl and halo substitution on biological activity is discussed.     

Piperazinylimidazo[1,2-a]pyrazines with selective affinity for in vitro alpha-adrenergic receptor subtypes

Regioselective syntheses of alkyl- and halogen-substituted piperazinylimidazo[1,2-a]pyrazines by novel oxidation-dehydration of [(beta-hydroxyalkyl)amino]pyrazines are described. Lanthanide shift reagent studies allowed correction of literature assignments of NMR chemical shifts and coupling constants for the imidazo[1,2-a]pyrazine ring system (e.g., J5,8 greater than J6,8). Equilibrium constants for displacement of specifically bound [3H]clonidine and [3H]prazosin from calf cerebral cortex homogenates in vitro are tabulated for reference and title compounds, and structure-affinity relationships for alpha 2- vs. alpha 1-adrenergic receptors are considered. Compound 2a, 8-(1-piperazinyl)imidazo[1,2-a]pyrazine, is equipotent with mianserin on the clonidine receptor (alpha 2) but ca. 70 times as selective as mianserin for this alpha 2-adrenergic receptor. Reduction of the imidazo ring (2,3-dihydro) lowers affinity for the alpha 2 receptor without affecting alpha 1-receptor affinity. Computer-assisted molecular modeling techniques are applied to the estimation of conformational energies of 2a and its 5-position isomer in relation to the semirigid molecule mianserin.     

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 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 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 some 7-phenylpyrrolo[1,2-a]pyrimidine derivatives. III

2-Amino-4-phenylpyrrolyl-3-carbonitrile (I) was reacted with ethyl formylacetate sodium salt affording 1,4-dihydro-4-oxo-7-phenylpyrolo[1,2-a]pyrimidin-8-carbonitrile (II), which was alkylated with EtI to give (III), which in turn was hydrolyzed to (IV). Treatment of both (III) and (IV) with 99% H3PO4 at approximately 200 degrees gave 1,4-dihydro-1-ethyl-7-phenylpyrrolo-[1,2-a]pyrimidin-4-one (V) whose structure was ascertained by an unequivocal synthesis starting from (I) and diethyl ethoxymethylenmalonate. Compound (V) was prepared in order to test its pharmacological properties in comparison with 4,7-dihydro-4-ethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-one, which showed an antiinflammatory activity comparable to that of phenylbutazone and indomethacine, and which was found devoid of ulcerogenic properties.     

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.     

Nitriles in Heterocyclic Synthesis: Synthesis of New Pyrazolo [1,5-a]pyrimidines,Pyrano[2,3-c]pyrazoles and Pyrano[3,4-c] pyrazoles

New pyrazolo[1,5-a]pyrimidines, pyrano[2,3-c]pyrazoles and pyrano[3,4-c]pyrazoles were synthesised by reaction of the α,β-unsaturated nitriles 1, 13 and 16 with 3-amino-2-pyrazolin-5-one (2) , 1-phenylpyrazolidine-3,5-dione (5) , and 5-amino-3-phenylpyrazole (10) .     

Structure-activity relationship of 4(5)-aryl-2-amino-1H-imidazoles, N1-substituted 2-aminoimidazoles and imidazo[1,2-a]pyrimidinium salts as inhibitors of biofilm formation by Salmonella typhimurium and Pseudomonas aeruginosa

A library of 112 4(5)-aryl-2-amino-1H-imidazoles, 4,5-diphenyl-2-amino-1H-imidazoles, and N1-substituted 4(5)-phenyl-2-aminoimidazoles was synthesized and tested for the antagonistic effect against biofilm formation by Salmonella Typhimurium and Pseudomonas aeruginosa. The substitution pattern of the 4(5)-phenyl group and the nature of the N1-substituent were found to have a major effect on the biofilm inhibitory activity. The most active compounds of this series were shown to inhibit the biofilm formation at low micromolar concentrations. Furthermore, the influence of 6 imidazo[1,2-a]pyrimidines and 18 imidazo[1,2-a]pyrimidinium salts on the biofilm formation was tested. These compounds are the chemical precursors of the 2-aminoimidazoles in our synthesis pathway. A good correlation was found between the activity of the imidazo[1,2-a]pyrimidinium salts and their corresponding 2-aminoimidazoles, supporting the hypothesis that the imidazo[1,2-a]pyrimidinium salts are possibly cleaved by cellular nucleophiles to form the active 2-aminoimidazoles. However, the imidazo[1,2-a]pyrimidines did not show any biofilm inhibitory activity, indicating that these molecules are not susceptible to in situ degradation to 2-aminoimidazoles. Finally, we demonstrated the lack of biofilm inhibitory activity of an array of 37 2N-substituted 2-aminopyrimidines, which are the chemical precursors of the imidazo[1,2-a]pyrimidinium salts in our synthesis pathway.     

Synthesis and antitumor activity of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin prepared via ring closure of a 1,2,4-triazine precursor

Several 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin were prepared and tested for their antitumor activity in cell culture. Dehydrative coupling of 3-amino-6-hydrazino-1,2,4-triazin-5(4H)-one (5) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6a) and further ring closure of the reaction product (7) provided 6-amino-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (8). Condensation of 5 with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid chloride (6b), followed by ring annulation, also gave 8 in good yield. Debenzoylation of 8 furnished the guanosine analogue 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)-one (4b). Thiation of 8 with P2S5, followed by debenzoylation of the thiated product (11a), afforded 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)- thione (11b). Methylation of the sodium salt of 11a gave the 8-methylthio derivative (10), which on ammonolysis furnished 6,8-diamino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazine (9). Diazotization of 10 with tert-butyl nitrite (TBN) and SbCl3 in 1,2-dichloroethane gave the corresponding 6-chloro derivative (12a). Reaction of 10 with TBN in THF in the absence of a halogen source gave 8-(methylthio)-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4- triazolo[3,4-f]-1,2,4-triazine (12b). Ammonolysis of 12b gave the azaformycin A analogue 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[3,4-f]-1,2,4-triazine (3), which on deamination afforded 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (4a). The azaformycin A analogue (3) showed pronounced inhibitory effects against L1210, WIL2, and CCRF-CEM cell lines with ID50 values ranging from 5.0 to 7.3 microM.     

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines (2 and 3) and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines (4 and 5) are described. The activity, shown by these compounds in the rat passive cutaneous anaphylaxis (PCA) test, is compared to the PCA data previously reported for a series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines. 10-Oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]pyri midine (2b), 10-oxo-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]py rimidine (4e), and 3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3, 4-d] pyrimidine (7e) gave a 100% inhibition in the rat PCA test at a dose of 5 mg/kg. The activity displayed by these compounds is comparable to that of the most active compounds in the 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine series.     

Antiulcer agents. 1. Gastric antisecretory and cytoprotective properties of substituted imidazo[1,2-a]pyridines

A novel class of antiulcer agents, the substituted imidazo[1,2-a]pyridines, is described. The present compounds are not histamine (H2) receptor antagonists nor are they prostaglandin analogues, yet they exhibit both gastric antisecretory and cytoprotective properties. The mechanism of gastric antisecretory activity may involve inhibition of the H+/K+-ATPase enzyme. Structure-activity studies led to the identification of 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, SCH 28080 (27), which was selected for further development and clinical evaluation.     

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.     

Formation of conjugate adducts in the reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde with guanosine

The reactions of guanosine with malonaldehyde in buffered aqueous solutions in the presence of acetaldehyde or formaldehyde were studied. The reaction mixtures were analyzed by RP-HPLC. Two adducts were formed in the reaction of malonaldehyde and acetaldehyde and one in the reaction of malonaldehyde and formaldehyde. The products were isolated and purified by preparative C-18 chromatography and structurally characterized by UV absorbance, 1H NMR, and 13C NMR spectroscopy and mass spectrometry. The adducts formed in the reaction of malonaldehyde and acetaldehyde were identified as 7-(2,2-diformyl-1-methylethyl)-3-(beta-D-ribofuranosyl)pyrimido[1,2-a]-purin-10(3H)-one (M2AA-Guo I) and 2-(3,5-diformyl-4-methyl-1,4-dihydro-1-pyridyl)-9-(beta-D-ribofuranosyl)-purin-6(9H)-one (M2AA-Guo II). In the reaction of malonaldehyde and formaldehyde, the major product was identified as 7-formyl-3-(beta-D-ribofuranosyl)pyrimido[1,2-a]purin-10(8H)-one (M1FA-Guo). The highest yields of M2AA-Guo I and M2AA-Guo II, 7 and 2 mol %, respectively, were obtained in the reaction performed at pH 7.4 and 37 degrees C for 6 days, while M1FA-Guo was produced at a yield of 0.3 mol % after 3 days of reaction at pH 7.4 and 37 degrees C. The products are formed by reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde condensation products with guanosine and are analogous to the previously identified condensation products formed with adenosine, cytidine, and proteins.     

Synthesis and anticonvulsant properties of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives.

A number of novel 1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives were prepared and their anticonvulsant properties evaluated. The new synthesized compounds proved to possess anticonvulsant effects depending on the nature of substituents at C-6, C-2, and C-3a positions of the polycyclic system. In particular, the 6-chloro-3a-(p-tolyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivative (22) displayed potency fivefold higher than unsubstituted compound (13).