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A series of 5-aryl-3-azabicyclo[3.2.0] heptan -6-one ketals 6 were synthesized by hydride reduction of 1-aryl-4, 4-dimethoxy-1,2- cyclobutanedicarboximides 5. Imides 5 were obtained as the sole, regioselective products of the [2 + 2] photocycloaddition of 1,1- dimethoxyethylene to 2- arylmaleimides . The m-methoxyphenyl-N-methyl analogue 6a was demethylated to phenol 7 with EtSNa -DMF. Both 6a and 7 were similar to morphine in analgesic potency in rats and mice and showed physiological effects that were identical with those of morphine and that were completely reversed by naloxone. Compound 7 was identical with morphine in its ability to displace [3H]naloxone from homogenates of rat brain minus cerebellum. A molecular mechanics analysis of the m-methoxyphenyl analogue 6a showed that the nitrogen atom, the methoxyphenyl group, and the methoxyl oxygen cis to the phenyl group can be superimposed on the corresponding features of the morphine molecule, and perhaps this accounts for the observed opiate-receptor binding properties of 7.

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A series of 1-aryl-3-azabicyclo[3.1.0]hexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides. Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa--DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediate 19 and 21. The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25. The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds. Bicifadine, 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man. Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis. The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive. Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.

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Several formamidine and acetamidine derivatives prepared from 3-amino-1,2,4-benzotriazine and 3-amino-1,2,4-benzotriazine-1-oxide displayed an aspirin-like anti-inflammatory and analgesic profile. The test systems include adjuvant-induced arthritis in rats, carrageenan-induced edema in rats, UV-induced erythema in guinea pigs, the analgesic gait test, the antipyretic test, and GI ulcer studies.

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100 analogs of gamma-oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) were prepared and tested using the carrageenin, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenyly)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as acetylsalicylic acid (ASA), phenylbutazone, and indometacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than ASA and at least as potent as phenylbutazone in all five tests.

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gamma-Oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) was shown to be an orally and parenterally effective nonsteroidal antiinflammatory, analgesic and antipyretic agent in a variety of animal species. Like other clinically active antiinflammatory drugs such as acetylsalicylic acid (ASA), indometacin and phenylbutazone, fenbufen has demonstrated potent activity in a variety of laboratory test systems including carageenin edema (rats), UV erythema (guinea pigs), adjuvant arthritis (rats), urate synovitis (dogs), phenylquinone writhing (mice), and yeast-induced pyresis (rats). In general, fenbufen was less potent than indomethacin and more potent than ASA, and appeared of special interest because of its high analgetic efficacy and long duration of antiinflammatory and analgetic action. While shown to have ulcerogenic potential in rats at toxic doses, fenbufen was less potent than indometacin in this respect and had a superior margin of gastrointestinal safety in treatment of dogs with urate synovitis. One of fenbufen's major metabolites, 4-biphenylacetic acid (BPAA), was found to be potent inhibitor of prostaglandin (PG) synthesis both in vitro and in vivo with a variety of tissues tested. Fenbufen itself was devoid of this anti-PG-synthetase activity although it interacted with prostaglandins in other ways. These results, coupled with the fact that only BPAA showed pharmacological activities when applied locally, led to the conclusion that BPAA was the principle responsible for fenbufen's antiinflammatory action. Fenbufen thus appears to be a pro-drug capable of circumventing at least some of the gastric toxicity usually incurred when compounds, which are themselves capable of inhibiting PG synthesis, are introduced directly into the stomach. Fenbufen's relatively low gastric toxicity in dogs and humans seems to substantiate this hypothesis. The pharmacological evidence indicates that fenbufen should be a highly effective and clinically useful antiinflammatory, analgetic and antipyretic drug.

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Amoxapine possesses a broad spectrum of psychotropic actions, including antidepressant and neuroleptic effects in animals. Antidepressant activity is characterized by its ability to inhibit tetrabenazine-induced depression, antagonize reserpine-induced hypothermia and enhance yohimbine lethality. Neuroleptic activity is demonstrated by the ability of amoxapine to decrease locomotor activity, induce ptosis and catalepsy, inhibit apomorphine gnawing and amphetamine stereotyped behavior and by characteristic changes in monkey discriminated avoidance behavior. The fact that punished responding in squirrel monkeys was present was present after repeated administration may indicate an anti-anxiety action of this drug. Evidence is offered that the conversion of the tertiary terminal nitrogen to a secondary amine may alter the pharmacologica properties of dibenzoxazepines in a similar way to the for the phenothiazines.

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One hundred analogs of fenbufen were prepared and tested using the carrageenan, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenylyl)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as aspirin, phenylbutazone, and indomethacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than aspirin and at least as potent as phenylbutazone in all five tests. Two related compounds were generally similar.

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Fenbufen [3-(4-biphenylylcarbonyl)propionic acid] was shown to be an orally and parenterally effective nonsteroidal antiinflammatory analgetic and antipyretic agent in animals. Like clinically useful drugs (aspirin, phenylbutazine and indomethacin) it has potent antiinflammatory activity in a wide spectrum of laboratory tests in mice, rats, guinea pigs, and dogs and was of particular interest since it appears to have high analgetic efficacy and a long duration of antiinflammatory and analgetic action. While shown to have ulcerogenic potential in rats at toxic doses, it appeared to have a superior margin of gastrointestinal safety in treatment of dogs with urate synovitis. Evidence was also presented to show that BPAA (4-biphenylacetic acid), a metabolite of fenbufen, has a similar profile of antiinflammatory activity, although appearing to produce slightly more gastrointestinal injury. It appears that BPAA may be the agent responsible for at least part of fenbufen's pharmacologic effects. The data presented suggest that fenbufen has the potential to be used safely and effectively to provide relief for patients with inflammatory disease.

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