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A series of 5-arylpyrrolo[3,2-b]pyridines 1 was synthesized by addition of 3-aminopyrroles to aryl enaminones. One example of a 7-arylpyrrolo[3,2-b]pyridine 2 was obtained as a minor product along with the 5-aryl isomer, by a modification of the reaction sequence.

The synthesis of the novel 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system has yielded several compounds which display activity in the reversal of cognition deficits in rats and mice as compared to existing reference agents. Activity was determined by improvements in Hypoxic Survival and Anoxic-Induced Amnesia tests. The synthesis and biological activity of the title compounds is described.

A series of 1-alkyl and 3-alkyl-2-benzoylamino-4-oxo-quinazolines has been prepared and found to have activity in tests for cognition enhancement in rats and mice.

A series of both symmetrical and unsymmetrical dibenzoyl guanidines containing a p-aminobenzamide moiety was studied for the reversal of cognition deficits in rats and mice.

The synthesis of the novel 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system has yielded several compounds which display activity in the reversal of cognition deficits in rats and mice as compared to existing reference agents. Activity was determined by improvements in Hypoxic Survival and Anoxic-Induced Amnesia tests. The synthesis and biological activity of the title compounds is described.

2-Aminobenzimidazoles were reacted with enaminones in acetic acid to give pyrimido[1,2-a]benzimidazoles. With a substituted enaminone only one regioisomer was obtained. Structural assignments based on nmr and uv spectroscopy are presented. Possible pathways leading to the products are discussed.

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.

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.

The novel compound, 2-(3-pyridyl)maleimlde, 7 was prepared by an efficient sequence involving the synthesis of ethyl 2-(3-pyridyl)-acrylate, 3 from ethyl 2-(3-pyridyl)acetate, 1 , followed by Michael-addition of HCN (via acetone cyanohydrin-MeOH) to give cyanoester 4 . Alternatively, 4 was prepared from the methyl ester 8 by alkylation with iodoacetonitrile. Acid hydrolysis gave amide-ester 5 which was then cyclized with NaOEt to 2-(3-pyridyl)succimide, 6 . Oxidation of 6 to maleimide 7 was achieved with N-chlorosuccinimide in pyridine, to give an overall,yield of 58%.

2-Aminobenzimidazoles were reacted with enaminones in acetic acid to give pyrimido[1,2-a]benzimidazoles. With a substituted enaminone only one regioisomer was obtained. Structural assignments based on nmr and uv spectroscopy are presented. Possible pathways leading to the products are discussed.

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.

Dimers (4) and (7) were obtained during the course of the Meerwein arylation reaction; a Diels–Alder reaction is proposed for the mechanism of the dimerization, and the X-ray structure of (4) is reported.