Studies on antiulcer drugs. III. Synthesis and antiulcer activities of imidazo[1,2-a]pyridinylethylbenzoxazoles and related compounds. A novel class of histamine H2-receptor antagonists.

A series of imidazo[1,2-a]pyridinylalkylbenzoxazole derivatives was synthesized and tested for histamine H2-receptor antagonist, gastric antisecretory and antiulcer activities. Some of 2-amino-6-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole derivatives were found to have good pharmacological activities. Among them, 2-amino-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl] benzoxazole (II-11) and 2-acetamido-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl] benzoxazole (II-38) showed potent antisecretory and cytoprotective activity. The structure-activity relationships of these compounds are discussed.     

Conformational analyses on histamine H2-receptor antagonists

Summary In a series of compounds with H₂-antihistaminic activity, a conformational analysis was performed based on force field calculations. The drugs studied were cimetidine, ranitidine, famotidine, roxatidine and the conformationally more restricted ICI127032. For the compounds containing a flexible chain, the local minima conformations and the global minimum conformation were calculated. These conformations were used for a systematic structural comparison with all energetically allowed conformations of the ICI derivative, with regard to the best fit of the common structural features. In this way a pharmacophore could be developed consisting of four parts: (1) a polar planar group, uncharged at physiological pH; (2) a hydrophobic part formed by aromatic systems or flexible chains; (3) an—under physiological conditions—protonated nitrogen atom; and (4) a substructure, which contains a hydrogen bond donor site and a hydrogen bond acceptor site in a specific spatial arrangement.     

Isomeric tropane analogues of histamine H2-receptor antagonists

In an attempt to investigate stereochemical requirements of antagonists of the histamine H₂-receptor, tropane analogues of cimetidine and metiamide have been synthesized possessing axial and equatorial N-methylthiourea and N-methyl-N-cyanoguanidine moieties at the 3-position of the tropane system. The tropane analogues of this study have been fully characterized with regard to configuration at C-3 and to conformation of the piperidine ring of the tropane nucleus.     

Studies on antiulcer drugs. I. Synthesis and antiulcer activities of imidazo[1,2-alpha]pyridinyl-2-oxobenzoxazolidines-3-oxo-2H-1,4-benzoxaz ines and related compounds.

A series of imidazo[1,2-alpha]pyridinyl-2-oxobenzoxazolidines (4a-i), -3-oxo-2H-1,4-benzoxazines (5a-q), their thio-analogues (4j-p and 5r-t) and 5,6,7,8-tetrahydroimidazo[1,2-alpha]pyridinyl derivatives (8 and 9) were synthesized and tested for anti-stress ulcer activity in rats. Several compounds were found to be more active than the reference compounds, zolimidine, cimetidine and sucralfate. Among them, compound 4e, 5i and 5l also exhibited potent protective activity against ethanol-induced gastric lesion. The synthesis and structure-activity relationships of these compounds are discussed.     

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.     

Studies on gastric antiulcer active agents. II. Synthesis of tetrazole alkanamides and related compounds

A series of tetrazole alkanamides was synthesized and tested for antiulcer activity against acetic acid-induced gastric ulcer in rats. These compounds were prepared by the reaction of tetrazole alkanoic acids and various amines by the mixed anhydride method or acid chloride method. Among them, 3-[(1-ethyl-5-tetrazolyl)methylthio]propionamide (IIn) was found to have the most potent activity. The structure-activity relationships are discussed.     

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.     

Studies on gastric antiulcer active agents. III. Synthesis of 1-substituted 4-(5-tetrazolyl)thio-1-butanones and related compounds

Many 1-substituted 4-(5-tetrazolyl)thio-1-butanones were synthesized and tested for antiulcer activity against acetic acid-induced gastric ulcer in rats. These compounds were prepared by the reaction of 5-mercaptotetrazoles and 4-halogeno-1-butanones. Among them, 1-cyclohexyl-4-(1-phenyl-5-tetrazolyl)thio-1-butanone (VIIIp) was found to have the most potent activity. The structure-activity relationships are discussed.     

Studies on proton pump inhibitors. II. Synthesis and antiulcer activity of 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolines and related compounds

Many 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolin e derivatives were synthesized and tested for their (H+ + K+)adenosine triphosphatase (ATPase)-inhibitory and antisecretory activities against histamine-induced gastric acid secretion in rats. These sulfinyl compounds were synthesized by the oxidation of the corresponding sulfides, which were obtained from the reaction of 8-chloromethyl-1,2,3,4-tetrahydroquinolines and 2-mercaptobenzimidazoles in the presence of potassium carbonate. All compounds tested were potent inhibitors of (H+ + K+)ATPase. Most of the compounds showed antisecretory activity. Among them, 8-[(2-benzimidazolyl)sulfinylmethyl]-1-ethyl-1,2,3,4-tetrahydro quinoline (IXa) was found to have the most potent activity. The structure-activity relationships are discussed.     

Absorption spectra of carbohydrates and related compounds in H2SO4

The possibility of modifying the Dreywood anthrone method for spectrophotometric determination of carbohydrates in order to increase the accuracy and reproducibility of the results was examined. The classical method and a developed modification were compared. The relative uncertainty in a determination by the modified method was less than 4%. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 218–220, May–June, 2006.     

Studies on antiatherosclerotic agents. Synthesis of 7-ethoxycarbonyl-4-formyl-6,8-dimethyl-1(2H)-phthalazinone derivatives and related compounds

Derivatives of 7-ethoxycarbonyl-4-formyl-6,8-dimethyl-1(2H)-phthalazinone and closely related compounds were synthesized using Wittig and epoxidation reactions. Ring opening amination of the epoxides were carried out using dimethylaluminum amide reagents under mild reaction conditions. beta-Keto ester and beta-diketone moieties were introduced through diazo derivatives. These moieties were reacted with hydrazine hydrate to produce 4-pyrazolyl derivatives. The derivatives were tested for their inhibitory effect on platelet aggregation, and their relaxing effect on blood vessels.