Pyridazinones. 1. Synthesis and antisecretory and antiulcer activities of thio amide derivatives

In an effort to develop new types of antiulcer agents, a series of novel 3(2H)-pyridazinone derivatives and related analogues was synthesized. Substituted 3(2H)-pyridazinones and their 4,5-dihydro analogues were alkylated by omega-haloalkyl cyanides at the N-2 position under phase-transfer catalytic reaction, and the nitrile group was converted to the thio amide group by treatment with hydrogen sulfide alone or with the appropriate primary or secondary amines. Various substituents were introduced on the nitrogen of thio amide, on the carbon in the side chains, and on the 3(2H)-pyridazinone ring. The synthesized compounds were evaluated for gastric antisecretory activity in the pylorus-ligated rat, and selected compounds were applied to experimental ulcer models, such as Shay's, aspirin-induced, and stress-induced ulcers in the rat. Structure-activity relationships are discussed. 3(2H)-Pyridazinones with a C-6 phenyl group and an N-2 alkyl side chain with a terminal thio amide group (48, 49, 51, and 52) were the most potent among the compounds tested.     

Synthesis and evaluation of the analgesic and anti-inflammatory activity of new 3(2H)-pyridazinone derivatives

A series of 6-substituted-3(2H)-pyridazinone derivatives were synthesized and evaluated for analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. Analgesic and anti-inflammatory activities of the title compounds have been evaluated. Four of the ten tested compounds possessed significant analgesic effects in the phenylbenzoquinone-induced writhing test (PBQ test). The most active derivatives 8a, 8b, 8d, 8e were void of gastric ulcerogenic effect or acute toxicity at the maximal dose (200 mg/kg p.o.). In the carrageenan-induced paw edema model, compound 8d (6- [4- (2-fluorophenyl) piperazin-1-yl]-3(2H)-pyridazinone) showed anti-inflammatory activity similar to that of the standard drug indometacin (CAS 53-86-1). A significant dependence of the anti-inflammatory effect on the substituents was observed; The pharmacological study of these compounds confirms that modification of the chemical group at position 6 of the 3(2H)-pyridazinone ring influences analgesic and anti-inflammatory activities.     

Synthesis and antiulcer activity of N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas: histamine H2-receptor antagonists with a potent mucosal protective activity.

As an aim toward developing new antiulcer agents, new N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas were synthesized and evaluated for histamine H2-receptor antagonistic, gastric antisecretory, and gastric mucosal protective activities. A QSAR study showed that the most favorable N-substituents were electron-donating straight-chain alkyl groups of short length such as ethyl group from the viewpoint of dual action, i.e., gastric antisecretory and mucosal protective actions. Among the ureas studied, compounds 4, 5, and 8-10 were selected as candidates for further study.     

Synthesis and antisecretory and antiulcer activities of derivatives and analogues of 2-(2-pyridyl)tetrahydrothiophene-2-carbothioamide

New thioamide derivatives of 2-(2-pyridyl)tetrahydrothiophene-2-carbothioamide (29) and related compounds (in which the tetrahydrothiophene ring was replaced by tetrahydrothiopyran, tetrahydrofuran, 1,3-dithiane, or 1,3-oxathiane and where the pyridine ring was replaced by other nitrogen heterocycles) were synthesized and tested for their antisecretory and antiulcer activities. These thioamides were prepared according to one of the following methods: reaction of an isothiocyanate with the carbanion of the corresponding cyclic precursor (for secondary thioamides); reaction of ammonia or an amine with the dithio ester prepared from the same precursor (for primary, secondary, and tertiary thioamides). These thioamides were evaluated by the Shay method to measure their antisecretory activity and by the stress-induced-ulcer method to test their antiulcer activity. Structure-activity relationships are discussed. N-Methyl-2-(2-pyridyl)tetrahydrothiophene-2-carbothioamide (R.P. 40749, 30) exhibited activities that were at least 10 times higher than those reported for cimetidine.     

Potential antisecretory antidiarrheals. 2. Alpha 2-adrenergic 2-[(aryloxy)alkyl]imidazolines

Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine in vivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity. Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a. A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-Methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive. Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compound. Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive. Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33. The more active compounds in the rat cholera toxin assay (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited central nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneously hypertensive rats at 50 mg/kg. A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups. Regression analysis showed no correlation of antisecretory ED50 to the calculated log P. The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.     

Synthesis and analgesic activity of some 4,6-disubstituted-3(2H)-pyridazinone derivatives

A series of 6-morpholino-4-aryl-3(2H)-pyridazinone alkanoic acids, their ester and amide derivatives were prepared and tested for their in vivo analgesic activity by using the p-benzoquinone-induced writhing test. The analgesic activity of the compounds 6-morpholino-4-aryl-3(2H)-pyridazinone (6a-b) were comparable but little lower than that of acetyl-salicylic acid (CAS 50-78-2) as an analgesic agent. The 6-morpholino-4-aryl-3(2H)-pyridazinones having a propanoic acid (10a-b), ester (7a) and amides (12a-b, 12d and 12g) as side chains at the position 2 of the pyridazinone ring showed higher activity than the reference compound without gastric ulceration forming potential. All other compounds generally showed higher activity but caused gastric ulceration in the animals.     

Studies on the synthesis of antiulcer agents. VI. Synthesis and antiulcer activity of dihydrobenzofuranone derivatives

The derivatives (2) of 3-(2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl) acrylic acid (2b) were synthesized. The compounds (3a-g) in which bromo, methoxy, nitro, amino or acetamido group was introduced on the benzene ring of the derivatives (2) and the compounds (3h-k) in which acryloyl moiety was introduced on the 6- or 7-position of the benzofuranone skeleton also synthesized. Furthermore, propionic acid derivatives (4a-c), acetic acid derivatives (4d-g), formic acid derivatives (4h-k) and oxyacetic acid derivatives (5) were prepared by converting the acryloyl moiety of the derivatives (2) into propionyl, acetyl, formyl and oxyacetyl groups. These compounds were tested for antiulcer activities. Among these compounds, 1-[3-(2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl)acryloyl]piperidine (2d) and 4-[3-(2,3-dihydro-2,2-dimethyl-3-oxo-5-benzofuranyl)acryloyl] morpholine (2g) were found to have stronger antiulcer activities.     

Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives

In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.     

Some pyridazinone and phthalazinone derivatives and their vasodilator activities

In this study, 6-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone and 4-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-1(2H)-phthalazinone derivatives were synthesized by reacting 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone or 4-(4-aminophenyl)-1(2H)-phthalazinone compound with different 4-arylidene-2-phenyl-5(4H)-oxazolone derivatives. The vasodilator activities of the compounds were examined both in vitro and in vivo. Some pyridazinone derivatives showed appreciable activity.     

Synthesis and analgesic and antiinflammatory activity of methyl 6-substituted-3(2h)-pyridazinone-2-ylacetate derivatives

A series of methyl 6-substituted-3(2H)-pyridazinone-2-ylacetates 9 were synthesized and their analgesic and anti-inflammatory effects were evaluated in the phenylbenzoquinone-induced writhing test (PBQ test) and carrageenan-induced paw edema method, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. Methyl 6-(4-(4-fluorophenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9e was found to be more active than acetylsalicylic acid (ASA). Methyl 6-(4-(2-ethoxyphenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9c has shown an anti-inflammatory activity as compared to the standard compound indometacin at the carrageenan-induced paw edema method.A significant dependence of the anti-inflammatory effect on the substituents has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at the position 6 of the 3(2H)-pyridazinone system influences analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and (1)H-NMR spectra and elemental analysis.     

Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914)

A series of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones was synthesized and evaluated for positive inotropic activity. Only compounds with two small alkyl groups at C-4 showed significant activity. The structure-activity relationships for optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The phosphodiesterase inhibitory activity is also reported and correlated with the substitution pattern at C-4 in the pyrazolone ring.     

Bicyclic compounds with potential antiulcer and/or antisecretory activity. I. 4,5,6,7-Tetrahydrobenzimidazoles

The remarkable antiulcer and antisecretory activity of some previously described 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine derivatives prompted us to further investigate related bicyclic systems. Accordingly, a series of 5-amino- and 5-aminomethyl-4,5,6,7-tetrahydrobenzimidazoles, regiospecifically alkylated in position 1, were synthesized and tested. Only a few 1-ethyl-5-amino derivatives displayed a reasonable antiulcer activity in comparison with our former class of compounds.     

Synthesis and pharmacological study of a series of 3(2H)-pyridazinones as analgesic and antiinflammatory agents

The synthesis and the pharmacological evaluation of some 3(2H)-pyridazinone derivatives are reported. The compounds were screened for analgesic, antiinflammatory and antipyretic activities. All tested derivatives showed a higher analgesic activity than phenylbutazone, while being devoid of ulcerogenic action.     

Studies on the synthesis of antiulcer agents. V. Synthesis and antiulcer activity of dihydrobenzofuranone derivatives

In the preceding paper, we reported that 1-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]piperidine(1a) and 4-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]morpholine(1b) have potent antiulcer activities. In this paper, propionic acid derivatives (2,3) and oxyacetic acid derivatives (4, 5, 10) were prepared by converting the acryloyl moiety into propionyl and oxyacetyl groups, and tested for antiulcer activities. As a result, [3-oxospiro[benzofuran-2(3H),1'-cyclopropan]5-yloxy]-a cetamide(4j) exhibited significant antiulcer activities.     

Studies on histamine H2 receptor antagonists. 2. Synthesis and pharmacological activities of N-sulfamoyl and N-sulfonyl amidine derivatives

A series of N-sulfamoyl and N-sulfonyl amidines have been prepared and tested in vitro for H2 antihistamine activity on guinea pig atrium. In addition, several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Structure-activity relationship studies showed that those compounds containing 2-[(diaminomethylene)amino]thiazole exhibited potent H2-receptor antagonist activity. Introduction of alkyl or aralkyl groups to the terminal nitrogen of the sulfamoyl moiety reduced biological activities. Sulfamoyl amidines were more potent in both tests than sulfonyl amidines. Of these compounds, 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]- N2-sulfamoylpropionamidine (2e, famotidine) showed extremely high potency in both assays and was selected for clinical trials as an antiulcer agent. Acid-catalyzed hydrolysis of famotidine gave the sulfamoyl amide 6 at room temperature and the carboxylic acid 7 at elevated temperatures. 15N NMR spectrum showed that famotidine in solution existed in only one of several possible tautomers derived from the amidine and the guanidine moieties. Nitrosation of famotidine was performed under mild condition and proved to occur on the 5-position of the thiazole ring.     

Synthesis and bioactivity of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone derivatives

A series of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone derivatives was prepared and examined for cardiotonic activity The structures of these new pyridazinone derivatives were confirmed by IR, 1H-NMR and mass spectrum. The cardiotonic activities of these compounds were studied on isolated perfused toad heart and compared with the activity of levosimendan (CAS 141505-33-1). Compound 5a emerged as the mostinteresting compound in this series with potential cardiotonic activity.     

Potential histamine H2-receptor antagonists. Synthesis, conformational studies and activity of novel 3-oxo-1,2,5-thiadiazole 1,1-dioxide derivatives

New histamine H2-receptor antagonists bearing a novel "urea equivalent", the 3-oxo-1,2,5-thiadiazole 1,1-dioxide ring, have been synthesized in a transamination reaction. Open chain derivatives have also been obtained. Theoretical conformational analysis of the compounds has been carried out using a molecular modelling program. Semiempirical CNDO/2 calculations have also been performed. The antisecretory and cytoprotective activities of the compounds have been evaluated.     

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.     

Bronchodilator Activity of Theophylline Derivatives Substituted at the 7-Position

Theophylline derivatives with several groups linked at the 7-position were synthesized and their pharmacological activities were studied on guinea pig. Relaxant action in the tracheal muscle was increased in comparison with that of theophylline when the 3(2H)-pyridazinone system was linked to 7-(2-ethyl)-theophylline through the piperazine ring, but decreased when the 7-(2-ethyl)-theophylline was linked to 3(2H)-pyridazinone ring through an amino group.     

Synthesis and antiulcer activity of novel 5-(2-ethenyl substituted)-3(2H)-furanones.

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.