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Ro 22-3747 was orally active in two animal models of immediate hypersensitivity diseases mediated by immunoglobulin E: the rat passive cutaneous anaphylaxis test (ID50 of 0.65 mg/kg) and a model in which anaphylactic bronchospasm was studied in passively sensitized rats (ID50 of 0.022 mg/kg). In the latter model system Ro 22-3747 was also found efficacious by the aerosol route (Ro 22-3747 was 23-fold more potent than disodium cromoglycate by this route of administration). Like disodium cromoglycate (cromoglycate), Ro 22-3747 appears to act in these in vivo models by inhibition of allergic mediator release because it was a potent inhibitor of antigen-induced histamine release from passively sensitized rat peritoneal cells in vitro (IC50 values of 0.25 and 1.5 microM for Ro 22-3747 and cromoglycate, respectively) and did not exhibit end organ antagonism to histamine, serotonin or slow reacting substance of anaphylaxis. The mechanism by which Ro 22-3747 inhibits mediator release does not appear to involve inhibition of delta 5-lipoxygenase, phospholipase A2 or thromboxane synthase. Cromoglycate and Ro 22-3747 appear to have some similarities with regard to their mechanism of action, as they both exhibit a time-dependent loss of inhibitory activity when preincubated with peritoneal cells in vitro before antigen challenge. In addition, pretreatment with one prevented the subsequent inhibition of histamine release by the other. Unlike cromoglycate, however, Ro 22-3747 (10(-5) to 10(-3) M) also inhibited the release of histamine (3-59%), slow reacting substance of anaphylaxis (12-49%) and thromboxane (0-55%) from antigen-challenged (immunoglobulin G1-mediated) guinea-pig lung fragments.(ABSTRACT TRUNCATED AT 250 WORDS)

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A series of substituted (E)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenoic acids was prepared and evaluated in the rat passive cutaneous anaphylaxis (PCA) test for antiallergic activity. Alkoxy, alkylthio, and isopropyl substituents at the 6- or 8-positions provided highly potent compounds. Conversion to the Z isomer, reduction of the side chain double bond, or reduction of the quinazoline ring resulted in substantial loss of activity. Among the analogues that exhibited oral activity in the PCA test, (E)-3-[6-(methylthio)-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid (5i) was the most potent.

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3-O-tert-Butylmorphine (5) was prepared from 6-O-acetylmorphine (3) via alkylation with N,N-dimethylformamide di-tert-butyl acetal, followed by hydrolytic removal of the 3-(dimethylamino)-2-propenoate group. The same process was used to prepare the tert-butyl ether of levorphanol (6), (-)-3-tert-butoxy-N-methylmorphinan (8). Both 5 and 8 exhibited in vitro affinity for the opiate receptor comparable to codeine and had analgesic properties in the writhing test. Only 5 exhibited activity in the tail-flick procedure and neither compound showed significant antitussive activity.

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Ro 21-7634 was examined for oral antiallergic activity in two in vivo models commonly used to evaluate antiallergics. In the rat PCA test, this drug had an oral ID50 of 1.14 mg/kg and was found to be more potent than several other antiallergics including Disodium Cromoglycate (cromoglycate), Oxatomide, Doxanthrazole, Xanoxate, 2,6-bis (ethyoxyoxalylamino) pyridine, PRD-92-EA and M + B 22,948. In contrast to cromoglycate, Ro 21-7634 was found to be an orally active inhibitor of antigen-induced broncho-constriction in passively sensitized rats (ID50 = 0.2 mg/kg). In addition, Ro 21-7634 inhibited antigen-induced histamine release in an in vivo passive peritoneal anaphylaxis test system, following intraperitoneal administration. Ro 21-7634 demonstrated no end organ antagonism toward histamine, metacholine or serotonin in the guinea pig.

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A series of 8-substituted pyrido[2,1-]quinazoline-2-carboxylic acids was prepared by the nickel carbonyl mediated carboxylation of the corresponding bromides. The activities of these compounds in the rat PCA test are comparable to those of the corresponding 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids.

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The carbazole, C-5720, has the same order of analgesic, antipyretic and anti-inflammatory activity as indomethacin and is more potent than phenylbutazone and acetylsalicylic acid in the yeast inflamed paw, the carrageenin foot edema, the Mycobacterium butyricum-induced pyrexia, and the acute and chronic adjuvant arthritis tests. In chronic adjuvant arthritis in rats, C-5720 lowers the elevated serum mucopolysaccharide and plasma fibrinogen levels, and partially restores the depressed liver N-demethylase activity. C-5720 is 16 times less active than indomethacin in the production of gastric ulcers in rats and is about 70 times less active than indomethacin in blocking arachidonic acid-induced diarrhea in mice. C-5720 has a greater safety margin than indomethacin with respect to the production of gastric ulcers or the blockade of diarrhea and the reduction of inflammation in adjuvant-induced polyarthritis.

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This study compares the affects of a new non-steroidal anti-inflammatory drug, d,l-6-chloro-alpha-methyl-carbazole-2-acetic acid, its enantiomers, and indomethacin on platelet aggregation, prostaglandin synthetase, adjuvant arthritis, gastric ulceration and arachidonic acid induced diarrhea. In the adjuvant arthritic rat, doses producing anti-inflammatory activity were similar for all compounds with the exception of the l-isomer which was much less active. On the other hand, indomethacin was 10 to 25 times more potent with regard to inhibition of platelet aggregation, inhibition on prostaglandin synthetase, inhibition of arachidonic acid induced diarrhea, and induction of gastric ulceration than the racemate and its isomers. Such divergence of potencies suggests that the racemate, unlike indomethacin, would have no affect on platelet aggregation and, hence, produce no prolongation of bleeding time at doses possessing anti-inflammatory activity. The data also suggest that the racemate and d-isomer have greater specificity toward anti-arthritic acitvity and are less ulcerogenic than indomethacin. The d-isomer apparently is the more active component of the racemate in all the systems tested since: (a) the d-isomer has 2 to 3 times the inhibitory potency of the racemate and (b) the l-isomer, at high dosages or high concentrations had considerable less affect. Comparison of potencies relative to inhibition of platelet aggregation and of prostaglandin synthetase, are quite close; therefore, mechanistically, the anti-aggregatory affects of these drugs, or lack thereof, may be related to inhibition of prostaglandin synthetase.

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