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Indomethacin produces gastric corpus erosions in the fasted rat and small intestinal ulcers in the conventionally fed rat. We found that in rats fed chow pellets for 1 h after a 24-h fast, indomethacin given within 2 h after refeeding produced lesions in the gastric antrum, primarily along the lesser curvature, and also in the small intestine. The antral lesions reached a maximum size in 6–10 h, penetrated the muscularis mucosae within 3 days, and did not diminish for at least 7 days. The formation of the antral ulcer was prevented by prostaglandins or adrenalectomy, but was not affected by cimetidine, atropine, and/or vagotomy. In contrast, the gastric corpus erosions produced by indomethacin in the fasted rat were prevented by antisecretory drugs or vagotomy, and were aggravated by adrenalectomy. It is concluded that: (a) the chronic antral ulcers produced by indomethacin in the refed rat mimic human gastric ulcer with regard to location and histology; and (b) the mechanism of antral ulcer formation is different from corpus erosion formation, in that it was resistant to antisecretory drugs and vagotomy and was prevented by adrenalectomy. This experimental ulcer model could prove useful for studies of the etiology and therapy of gastric ulcer disease.

Changes in gastric mucosal haemoglobin concentration (mucosal blood volume), mucosal haemoglobin oxygenation, mucosal blood flow and gastric arterial blood flow caused by indomethacin, an ulcerogenic agent, and anti-ulcer agents were investigated in the stomach flap of anesthetized dogs. Indices of mucosal haemoglobin concentration and haemoglobin oxygenation, mucosal blood flow and arterial blood flow to the stomach flap were measured simultaneously. The intravenous injection of indomethacin (10 mg/kg) caused an immediate decrease in mucosal haemoglobin concentration with a gradual decrease in mucosal and arterial blood flow, and a slight decrease in mucosal haemoglobin oxygenation. The topical application of prostaglandin E2 (10 μg/ml) and spizofurone (a new anti-ulcer agent, 1 mg/ml) to the mucosa significantly increased these parameters, and remedied the decreases of these parameters caused by indomethacin. Cimetidine (20 mg/ml), pirenzepine (10 mg/ml) and proglumide (40 mg/ml) given topically did not significantly increase these parameters in the resting state or the indomethacin-induced ischaemic state. This study indicates that: indomethacin decreases gastric haemodynamics, and that improvement occurred with application of mucosal protective agents (i.e. prostaglandin E2 and spizofurone) and changes in mucosal blood concentration were closely correlated with those in mucosal blood flow and arterial blood flow, but correlated less well with those in the case of haemoglobin oxygenation.

2-Mono-and 2, 6-di-substituted cAMP (cAMP : adenosine 3', 5'-cyclic phosphate) were derived from the corresponding adenosine analogs via the 5'-phosphates. 2-Substituted cAMP and aristeromycin 3', 6'-cyclic phosphate were led to the 8-bromo derivatives. 8-(3, 5-Dimethylpyrazol-1-yl)-cAMP was derived from 8-hydrazinoadenosine. 8-(2-Hydroxypropyl-2)-cAMP was prepared by a γ-ray irradiation of cAMP in isopropanol. N6-Butyl-2-phenyl-cAMP was derived from 2-phenylinosine. 2-or 8-Substituted cAMP was led to its dibutyryl derivative. The activities of these new analogs were assessed with cAMP-dependent protein kinases (PK) and cAMP phosphodiesterases (PDE). 8-Bromo-2-chloro-, 2-chloro-, 2-bromo-, 2-phenylthio-, 8-carbamoyl- and 8-carboxy-cAMP were better activators of PK than cAMP, while 2-substituted analogs were significant substrates and inhibitors of PDE. 2-Phenyl-, benzyl-, phenoxy-, chloro- and bromo-cAMP or aristeromycin 3', 6'-cyclic phosphate had an inhibitory effect on the binding of cAMP to PK equal to or more than cAMP.

The protective effect of spizofurone (AG-629) on the rat gastric mucosa was studied in the presence of various stimuli. Spizofurone given orally markedly inhibited gastric lesions induced by ethanol (ED 50 = 6.5 mg/kg). Spizofurone inhibited ethanol-induced gastric lesions even when administered intraperitoneally (i.p.), but the onset of action after oral administration was shorter. Spizofurone given orally or i.p. in a dose range of 25–200 mg/kg inhibited indomethacin-induced gastric antral ulcers in re-fed rats. Furthermore, spizofurone potentiated the inhibitory effect of prostaglandin E 2 on indomethacin-induced gastric antral ulcers. Spizofurone given i.p. prevented a decrease in potential difference and the formation of gastric lesions induced by intragastric instillation of 30 mM aspirin in 0.1 N HCl. Spizofurone given i.p. inhibited the increase in net fluxes of H + and Na + caused by intragastric instillation of 15% ethanol in 0.1 N HCl. These findings indicate that spizofurone, like prostaglandin E 2 , exerts gastric mucosal protection and even potentiates the anti-ulcer effect of prostaglandin E 2 . The gastric mucosal protection by spizofurone is ascribed in part to preservation of the mucosal barrier.

The effect on guinea pig airways of the inhalation of leukotrienes, histamine or antigen was investigated by measuring changes in lung volume and analyzing the airway area on bronchograms with the Zeiss interactive image analysis system (IBAS). LTC 4 , LTD 4 , LTE 4 and histamine inhaled through an ultrasonic nebulizer caused inflation of the lung: LTD 4 was the most potent of the leukotrienes and was 100 times more potent than histamine on a molar basis. The results of analyses of areas of large and small bronchi and bronhioles on the bronchograms indicated that LTD 4 selectively decreased the area of the peripheral airways. Inhalation of an antigen in actively sensitized animals resulted in inflation of the lung and in a selective decrease in the area of the peripheral airways. Anaphylactic bronchoconstriction provoked by antigen inhalation was clearly inhibited by AA-861, a 5-lipoxygenase inhibitor but not significantly by mepyramine, an antihistamine. These observations indicate that LTD 4 is a potent constrictor of the peripheral airways in guinea pigs and that the anaphylactic bronchoconstriction provoked by antigen inhalation could be mediated by LTD 4 in actively sensitized guinea pigs.

The metabolites of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) (1), an orally effective antiallergic agent, and their analogues were synthesized to confirm the proposed structures and to determine their activity in the rat passive cutaneous anaphylaxis (PCA) test. A glucuronic acid metabolite (6) was assigned the structure 24b, 1-deoxy-1-[5-(6-ethylchromon-3-yl)tetrazol-1-yl]-beta-D-glucopyranuronate, by the comparison of 13C NMR, mass spectra, and TLC of isomeric compounds. In 13C NMR spectra, the shift difference of the tetrazole ring carbons between a pair of isomers was more remarkable than that of the glycosidic carbons. Therefore, the former is a useful criterion for distinguishing between such isomers. Some of the metabolities and analogues were active when administered intravenously, and two metabolites (2 and 3) were also effective upon oral administration.

The effect of spizofurone, a new anti-ulcer agent, on alkaline secretion was studied in an isolated sheet of bullfrog proximal duodenal mucosa mounted in an Ussing chamber. Spizofurone (10−4-10−3 M) as well as prostaglandin E2 (PGE2, 10−8-10−5 M) added to the nutrient solution increased alkaline secretion, transmucosal potential difference (PD) and short-circuit current (Isc), in a concentration-dependent manner. The maximum increases in alkaline secretion stimulated by spizofurone and PGE2 were much the same. Spizofurone also showed this effect when added to the secretory solution while PGE2 did not. Treatment with indomethacin partly but significantly inhibited the effect of spizofurone, but did not affect that of PGE2. These results indicate that the increase in alkaline secretion in bullfrog duodenal mucosa seen in the presence of spizofurone is mediated, at least in part, by stimulation of endogenous PGs synthesis.

Bromelain-induced edema in rats was studied and compared to carrageenin-induced edema. The edema reached a maximum 30 min after Bromelain was injected subcutaneously into the rat paw, then decreased slowly, and had almost disappeared 24 hr later. The bromelain-induced edema was obviously potentiated by the oral administration of captopril, a kininase II inhibitor, 1 hr before and after the bromelain was injected; the carrageenin-induced edema was moderately but not dose-dependently potentiated. Dexamethasone suppressed the bromelain-induced and carrageenin-induced edema, but onset of the effect was slow. Nonsteroidal acidic anti-inflammatory agents (indomethacin, piroxicam, phenylbutazone, mefenamic acid, timegadine, and benoxaprofen), except aspirin, exerted no effect on the bromelain-induced edema, whereas they significantly reduced the carrageenin-induced edema. Nonsteroidal nonacidic anti-inflammatory agents such as emorfazone, aminopyrine, tiaramide, perisoxal, and paracetamol, significantly inhibited both types of edema. Antihistamine, antiserotonin, and diuretic agents did not affect the bromelain-induced edema, but diuretic agents inhibited the carrageenin-induced edema. These results indicate that the bromelain-induced edema may be mediated mainly by bradykinin, but not by metabolites of the arachidonic acid cascade or not by biogenic amines, and that the carrageenin-induced edema is mediated predominantly by prostaglandins. The bromelain-induced edema appears to be a useful model to evaluate the effects of nonsteroidal nonacidic anti-inflammatory agents.

AA-2379 (methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl- 2H-pyrazolo [3,4-d]pyrimidine-2-carboxylate) has antiinflammatory, analgesic, and antipyretic activities, and inhibits the type III allergic (Arthus) reaction. In the studies reported here, we investigated the effect of AA-2379 on rat polymorphonuclear leukocyte (PMN) functions to clarify the mechanism of the antiinflammatory and antiallergic actions of AA-2379. AA-2379 at 10(-4) M inhibited lysozomal enzyme release. AA-2379 inhibits formyl methionyl-leucyl-phenylalanine (fMLP)- and C5a-induced arachidonic acid release; their 50% inhibitory concentrations were 2.8 x 10(-5) and 3.8 x 10(-5) M, respectively. Because dibutyryl cAMP, a cAMP analogue, and 3-isobutyl-1-methylxanthine, a cAMP phosphodiesterase inhibitor, inhibited fMLP-induced arachidonic acid release, and AA-2379 inhibited cAMP phosphodiesterase and increased cAMP content in PMNs, it is likely that AA-2379 inhibited arachidonic acid release by increasing cAMP content in rat PMNs. Furthermore, from the studies of fMLP-induced arachidonic acid release in Ca free medium it is suggested that AA-2379 inhibits the process which depends on Ca concentration in the medium. These results suggest that the inhibitory effect of AA-2379 on inflammation and allergic reactions such as the Arthus reaction is partly exerted by inhibiting PMN functions such as arachidonic acid and lysozomal enzyme release.

In studies of the role of leukotrienes in inflammatory reactions, the induction of rat reversed passive Arthus pleurisy (a type III allergic reaction) was employed. Increases of exudate volume, vascular permeability, and migration of inflammatory cells in the pleural cavity were observed. The vascular permeability was enhanced biphasically during 0–30 min (early response) and during 3–6 h (late response) after induction of the pleurisy. The infiltration of inflammatory cells, mainly polymorphonuclear leukocytes, into the cavity increased and reached a maximum 6 h after the pleurisy was induced. Leukotriene B4 (LTB4), 5-monohydroxyeicosatetraenoic acid (5-HETE), and slow-reacting substance of anaphylaxis (SRS-A), consisting of LTC4, LTD4 and LTE4, were detected in the exudate by reversed-phase high-performance liquid chromatography during the early response. The contents of LTC4 reached a maximum 10 min after the challenge, followed by a rapid decrease within 1 h. The rise and decay of LTC4 correlated with the increase in vascular permeability during the early phase. AA-861, a 5-lipoxygenase inhibitor, given intrapleurally inhibited the increase in vascular permeability, cell migration, and generation of leukotrienes during the early phase of the pleurisy. These results indicate that products of the 5-lipoxygenase pathway, such as LTC4 and LTB4, may play an important role as chemical mediators in the inflammatory reaction.

Amoxanox has potent antiallergic activity because it inhibits the release of chemical mediators such as histamine and leukotrienes. We studied the in vitro effect of amoxanox on arachidonic acid metabolism, including the lipoxygenase and cyclooxygenase pathways. Amoxanox inhibited calcium ionophore A23187-induced formation of 5-HETE, LTB4, SRS-A (LTC4, LTD4 and LTE4), and 12-HETE in rat peritoneal resident monocytes. These results indicate that amoxanox inhibits 5- and 12-lipoxygenases. The compound, however, did not affect the formation of TXB2 or 6-keto-PGF1α in guinea pig lung fragments and PGE2 or PGF2α in bovine seminal vesicles, suggesting that it did not inhibit cyclooxygenase. These results show that the antiallergic action of amoxanox is associated, at least in part, with the reduction of leukotrienes due to the inhibition of lipoxygenases.

The antiallergic action of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) was studied on isolated rat peritoneal mast cells. AA-344 clearly inhibited the IgE-mediated release of histamine caused by various concentrations of antigen and the 50% inhibitory concentration was 0.1 microM. On the IgGa-mediated release of histamine, a peak inhibition of AA-344 was observed at 10 microM. The histamine release induced by chemical agents such as concanavalin A, dextran and compound 48/80 was depressed by AA-344 at the range of 0.1--1 mM. The results obtained in this study indicate that the antiallergic action of AA-344 is due to selective inhibition on the immunological release of the chemical mediator from mast cells.

The spasmolytic action of 3-(2,4,5-triethoxybenzoyl)propionic acid (AA-149) on the biliary tract was investigated in anesthetized dogs. Intravenous administration of AA-149 at 2 mg/kg and higher doses produced a dose-dependent reduction in passage resistance through the choledochoduodenal junction and in gallbladder pressure, and a dose-dependent increase in bile flow. AA-149, like cholecystokinin, decreased biliary ductal pressure in spite of increasing the bile flow in dogs with ligation of the cystic duct of the gallbladder, whereas taurocholate increased the pressure as well as the bile flow. Moreover, the spasmic response of the choledochoduodenal junction to morphine was depressed strongly by AA-149, BUT NOT CONSISTENTLY BY ATROPINE. The effects of AA-149 were not influenced by pretreatment with atropine, phentolamine or propranolol. These findings strongly suggest that AA-149 relaxed the biliary tract and depressed the morphine-induced spasm by a mechanism different from those of anticholinergic and sympathomimetic agents.

We studied the effects of amoxanox (AA-673) on allergic asthma and spasmogen-induced bronchoconstnction in guinea pigs and rats. Amoxanox given orally or parenterally inhibited allergic asthma mediated by IgE, IgG1, or heterologous IgG in guinea pigs and by IgE in rats. This compound also reduced leukotriene D4- and platelet-activating factor-induced bronchoconstnction in guinea pigs, strongly suggesting an antagonistic activity against slow reacting substance of anaphylaxis (SRS-A). Histamine- or acetylcholine-induced bronchoconstnction was not significantly affected by amoxanox. These antiasthmatic effects of amoxanox seem to be associated with an inhibition of the release of chemical mediators such as histamine and SRS-A and with an antagonism against SRS-A.

Amlexanox markedly inhibits histamine release from rat mast cells. To clarify the mechanism of this inhibition, we investigated the effect of amlexanox on cAMP content, which, when increased, inhibits histamine release in rat peritoneal mast cells. At concentrations of 10––8––10––6M, amlexanox or isoproterenol increased the cAMP content of mast cells over that of control cells about 2-fold. When the mast cells were incubated with 10––8, 10––7 and 10––6M of amlexanox combined with 10––7M isoproterenol, the cAMP contents were synergistically increased 15-, 60- and 88-fold, respectively. 3-Isobutyl-1-methylxanthine (IBMX) at 10––6––10––4M increased the cAMP content 1.7––3.8-fold, and a combination of 10––4M IBMX and 10––7M isoproterenol synergistically increased the cAMP content 41-fold. A combination of amlexanox and IBMX synergistically increased the cAMP content 19-fold. The increase in cAMP content, when amlexanox and isoproterenol were combined, was transient; it peaked at 0.5 min after the drugs were administered, then decreased to 20–30% of the peak value about 2 min later. Pretreatment of mast cells with amlexanox reduced the effect of the combination of amlexanox and isoproterenol, indicating tachyphylaxis; pretreatment with IBMX had no such effect. The cAMP content of macrophages was also increased by amlexanox, but when combined with isoproterenol or PGE2, the effect was additive. Amlexanox inhibited cAMP phosphodiesterase in rat mast cells; its IC50 value was 1.4 × 10––5M, and its inhibitory activity was half that of IBMX. These results suggest that amlexanox inhibits histamine release by augmenting the cAMP content in mast cells, and that this augmentation is caused by enhancing the cAMP generation and, additively, by inhibiting cAMP phosphodiesterase.

The properties of K+-stimulated ATP hydrolysis (K+-ATPase) and vesicular accumulation of H+ (H+ accumulation) in hog gastric microsomes were investigated. The microsomes consisted of smooth surfaced vesicular particles, 70-300 nm in diameter. Both the activities of ATPase and the vesicular accumulation of H+ were stimulated by K+ in the presence of Mg2+, and enhanced by the K+-ionophore, valinomycin. However, there were differences in regulation of K+-ATPase and H+ accumulation by K+ ions, i.e. K+ at concentrations higher than 10 mM decreased K+-ATPase activity but further enhanced H+ transport. This observation suggests that the two reactions are partly independent. The H+ accumulation was inhibited by omeprazole, fenoctimine, spermine, and NaSCN, but not by cimetidine, prostaglandin E2, and atropine. The inhibitory effect of omeprazole on H+ accumulation paralleled the inhibition of K+-ATPase, while fenoctimine, spermine, and NaSCN suppressed H+ accumulation, without inhibiting K+-ATPase, under appropriate concentrations. In addition, the spontaneous diffusion of H+ across the microsomal membrane was markedly enhanced by fenoctimine, but not by the other agents used. These results indicate that omeprazole inhibits H+ accumulation by inhibiting K+-ATPase, fenoctimine suppresses H+ accumulation mainly by increasing the loss of accumulated H+ from the microsomal vesicles, spermine and NaSCN reduce H+ accumulation by inhibiting the transport of H+ into microsomal vesicles.

A newly synthesized compound, 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) given intravenously or orally inhibited considerably the 72-hr passive cutaneous anaphylaxis (72-hr PCA) induced by IgE in rats. The antiallergic action of AA-344 was neither due to the antihistamine or antiserotonin effect nor was it mediated via adrenergic mechanisms. The results obtained in a double sensitization with two IgE antibodies suggest that AA-344 may not impair antigen-antibody combination but probably prevents the release of chemical mediators including histamine. This assumption was supported by observation that AA-344 inhibited a reduction in the skin histamine content caused by the 72-hr PCA, without effect on the compound 48/80-induced histamine reduction. AA-344 also partially inhibited the IgGa-mediated 3-hr PCA in rats. These results indicate that the inhibitory action of AA-344 on the immediate hypersensitivity reactions is due to prevention of the release of chemical mediators from the mast cells, by acting on some process in sequential events leading to the mediator release following antigen-antibody combination.

The effects of injecting ATP, ADP, AMP, adenosine and adenine intrathecally on the pain response induced by the injection of substance P (10 ng/mouse) intrathecally were studied. All the compounds except adenine inhibited the pain response in a dose-related manner. The ED 50 values of ATP, ADP, AMP and adenosine were 2.10, 0.93, 0.88 and 0.48 μg/mouse, respectively. Pretreatment with theophylline at a dose of 100 mg/kg p.o. markedly diminished all the antinociceptive effects. The effect of adenosine was not affected by s.c. injection of naloxone. These results suggest the existence of adenosine receptors which modulate spinal nociceptive sensory processing, independently of the endogenous opiate system.

5-Acetylspiro [benzofuran-2 (3H), 1'-cyclopropan]-3-one (1a) shows potent gastric antisecretory and antiulcer activities in rats. In an attempt to improve the pharmacological profile of 1a, we synthesized positional isomers, as well as the prenyloxy and oxime derivatives. Evaluation of their antisecretory activities and protective activities against gastric lesions induced by water-immersion restraint stress in the rat indicated that the 7-acetyl derivative (1d) was equipotent to 1a.

— Synthetic substance P initially increased cyclic AMP levels and subsequently induced neurite extension in cultured neuroblastoma N 18 cells. The magnitude of these effects depended on the concentration of fetal calf serum (FCS) in the culture medium, being more evident in the presence of a lower (0.1%) concentration of FCS. In Eagle's medium containing 0.1% FCS, low concentrations of substance P (10−7-10−5 M) increased cyclic AMP levels and stimulated neurite extension. In Eagle's medium containing 5%FCS, both substance P at concentrations of 10−5-10−3M and dibutyryl cyclic AMP at concentrations of 10−4-10−2M increased cyclic AMP levels and stimulated neurite extension. The activities of acetylcholinesterase, (Na++ K+)-, HCO3− and Mg2+ -stimulated-ATPase were also increased. Cell growth was inhibited. Substance P at concentrations of 10-7-10−5M also stimulated the adenylate cyclase activity of a particulate fraction of N 18 in a concentration-dependent manner.

AA-344, which has been evidenced to inhibit selectively IgE-mediated allergic reactions, exhibited an inhibitory effect on cyclic AMP phosphodiesterase (PDase) in the homogenates of purified rat peritoneal mast cells (RMC). AA-344 showed synergistic effects with epinephrine, isoproterenol or prostaglandin E2 and F2α in increasing cyclic AMP level in RMC: the combinations caused an increase in cyclic AMP 30–160 times as much as that caused by the respective agent alone. In the latter effect, AA-344 was at least 1,000 times as potent as theophylline. On the other hand, histamine or serotonin with or without AA-344 had no effect on the RMC cyclic AMP. These results obtained in vitro suggest that AA-344 may exert antiallergic action by increasing cyclic AMP via an interaction with epinephrine or prostaglandins which might be endogenously involved in regulation of a function of RMC in allergic reactions.

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.

Amoxanox inhibited immunologically stimulated and LTD4-induced bronchoconstriction in laboratory animals. Amoxanox, like DSCG, inhibited rat IgE-mediated PCA and histamine release from rat peritoneal mast cells, and suppressed immunologically stimulated or calcium ionophore A23187-induced SRS-A generation in rat peritoneal cavity and guinea pig lung fragments. This compound also reduced the contractile response of guinea pig lung parenchymal and ileal strips to LTD4, but did not significantly affect the response of the ileum to either histamine or acetylcholine. Therefore, the antiallergic action of amoxanox seems to be associated with inhibition of chemical mediator release and antagonistic activity on SRS-A.

The slow-reacting substance of anaphylaxis (SRS-A) is generated in lung fragments of the actively sensitized guinea pig by an antigen-antibody reaction. The SRS-A generation in lung fragments was inhibited by its quinonyl acid (QS), and quinonyl-alcohol (QSA) derivatives of ubiquinone from a concentration as low as 10(-7) M. It was of interest that the C10 and C13 side chain length in the 6-position of ubiquinone provided the highest activity. These compounds showed no antagonistic activity towards the contractile response of guinea pig ileum to SRS-A, indicating that the compounds inhibit the biosynthesis of SRS-A.

Spiro [benzofuran-2 (3H), 1'-cyclopropan]-3-one (VI-1) and its derivatives (VI-2-VI-75) were synthesized in the same manner as described previously for the synthesis of spiro [cyclopropane-1, 2'-[2H] indol]-3'(1'H)-ones (I). These spiro [benzofuran-2 (3H), 1'-cyclopropan]-3-ones were evaluated for gastric antisecretory activity and protective activity against lesions induced by water-immersion restraint stress in the rat. The most potent antiulcer compounds (VI-17 and VI-55) were obtained by the introduction of an acetyl or dimethylamino group at the 5-position on the benzene ring. The most interesting member of the series, 5-acetylspiro [benzofuran-2 (3H), 1'-cyclopropan]-3-one (VI-17, AG-629), was selected as a candidate for clinical studies.

1. 1. Administration of theophylline and gastric acid stimulants, such as histamine, tetragastrin and carbachol, increased the adenosine 3′:5′-cyclic monophosphate (cyclic AMP) level 2–3-fold as comparred with the control. 2. 2. N 6 -2′-O- Dibutyryl cyclic AMP (dibutyryl cyclic AMP) stimulated gastric acid secretion and activity of carbonic anhydrase in rat gastric mucosa. 3. 3. In vitro addition of cyclic AMP ( 10 −5 −10 −7 M ) to the supernatant fraction (cytosol) of rat gastric mucosa caused a concentration dependent potentiation of carbonic anhydrase activity. It is considered that this activation was mediated through protein kinase activation.

General synthetic routes to quinone acids (8), quinone amides (9), quinone alcohols (10), and quinone methylketones (11) with polyprenyl side chains, in which allylic alcohols (3) are employed as the key intermediates, are described. The Claisen rearrangements and the Carrot reactions of the allylic alcohols (3) with ethyl orthoacetate and diketen produced the ethyl esters (4) and the methylketones (5), respectively. Quinone products (8), (10), and (11) were recovered by oxidative demethylation of hydroquinone dimethyl ethers (4), (5), and (7) or by acid hydrolysis of hydroquinone bis(methoxymethyl) ethers (4) and (5) followed by ferric chloride oxidation. Amidation of quinone acids (8) led to the formation of quinone amides (9). Inhibitory effects of these quinone derivatives on the generation of the slow reacting substance of anaphylaxis (SRS-A) in the lungs of sensitised guinea pigs are evaluated.