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The synthesis of N-substituted 1,7,7-trimethyl-2-piperidinobicyclo[2.2.1]hept-2-ene 3 carboxamides (II) by reaction of 1,7,7-trimethyl-2-piperidinobicyclo[2.2.1]hept-2-ene (I) with alkyl and aryl isocyanates, as well as the alkaline hydrolysis of (II) to N-substituted 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 3 carboxamides (III), are described. A number of compounds (II) and (III) showed strong hypotensive and bradycardiac activities in rats, as well as weak infiltration anesthesia and antiarrhythmic activity in mice. Antiacetylcholine activity in vitro is also reported.

A new series of aliphatic and aromatic amides of 5-trans-(3-aminopropoxy)-1,2,3,3-tetramethyl-2-azabicyclo[2.2.2] octane is described. A number of these compounds showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to that of lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

The synthesis of two series of N-substituted 4,7,7-trimethyl-3-(1-piperidinyl)bicyclo[2.2.1]hept-2-ene 2-carboxamides (I d-h) and 2-carbothioamides (I i-o), as well as of some N-aryl 4,7,7-trimethyl-3-(1-pyrrolidinyl)bicyclo[2.2.1]hept-2-ene 2-carboxamides (I a-c), by reaction of camphor piperidinoenamine and pyrrolidinoenamine with aryl isocyanates and isothiocyanates is described. On the whole compounds (I d-h) showed a weak hypotensive activity in rats.

Cyanoethylation of 1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octan-5-endo-ol, followed by LiAlH4 reduction and reaction with acyl chlorides, gave a series of amides derived from 5-endo-(3-aminopropoxy)-1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octane. The syntheses of N-methyl, N,N-dimethyl and N,N-dipropargyl derivatives of the afore mentioned amine, as well as of 5-endo-methylcarbamoyloxy- and 5-endo-phenylcarbamoyloxy-1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octane, are also described. Strong antiarrhythmic and local anesthetic activity was observed in two amides; an urethane showed antiarrhythmic activity only.

The synthesis of 6-cis-dimethylamino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-trans-ol (III) starting from 1,3,3-trimethyl-6-nitrimino-2-oxabicyclo[2.2.2]octane is described. Starting from aminoalcohol (III), a series of N-substituted urethanes (IV) and esters (V), as well as the rigid analogue of acetylcholine (VII), were prepared. A number of compounds (V) and particularly (IV) showed remarkable hypotensive and bradycardic activities in rats, whereas the p-aminobenzoate (V h) showed infiltration anesthesia in mice comparable to that of lidocaine. Antiarrhythmic activity in mice and antiacetylcholine activity in vitro are also reported.

The synthesis of three series of N-monosubstituted urethanes of 6-cis-dialkylamino-1,3,3-trimethyl-2-oxabicyclo [2.2.2] octan-5-transols (IV), (V) and (VI) (dialkylamino = pyrrolidino, piperidino, morpholino) by reaction of the corresponding aminoalcohols with alkyl or aryl isocyanates, is described. A number of compounds (IV) and (V) showed remarkable hypotensive and bradycardic activity in rats, whereas (IV c) showed infiltration anesthesia and (IV n) antiarrhythmic activity in mice comparable to those of lidocaine. Antiacetylcholine activity in vitro is also reported.

By reaction of secondary amines with 3-hydroxymethylene-exo-5,6-trimethylenenorbornan-2-one, synthesized from exo-5,6-trimethylenenorbornan-2-one and sodium/ethyl formate, a series of N,N-disubstituted 3-aminomethylene-exo-5,6-trimethylenenorbornan-2-ones has been obtained. These compounds gave N,N-disubstituted 3-aminomethyl-exo-5,6-trimethylenenorbornan-2-ones by LiAlH4 or catalytic reduction. Starting from the same alpha-hydroxymethyleneketone, pyrazole derivatives (V) and (VI) have been also synthesized; the former showed anticonvulsant activity in mice.

The synthesis of N-substituted 1-(2-aminoethyl)-3,5-diphenyl-1H-pyrazoles and their 4-bromo derivatives (V) by reaction of primary and secondary amines with the tosylates of 1-(2-hydroxyethyl)-3,5-diphenyl-1H-pyrazole and its 4-bromo derivative is described. Some of compounds (V) showed a remarkable analgesic activity in mice. Moreover, the above compounds usually exhibited moderate hypotensive, bradycardiac and antiinflammatory activities in rats, infiltration anesthesia in mice, as well as a weak platelet antiaggregating activity in vitro.

An unambiguous synthesis of 1-(2-diethylaminoethyl)-3,4-pentamethylenepyrazole (III) by acid cyclization of 2-(2-cycloheptanonyl)-1,3-dioxolane 2-diethylaminoethylhydrazone, and of N2-methyl and N2-(2-diethylaminoethyl)bornylenepyrazole (VIII) and (IX), by heating the hydrazones from 3-hydroxymethylene-2-bornanone and methylhydrazine or 2-diethylaminoethylhydrazine respectively, is described. (III) showed antiinflammatory activity and (VIII) an anticonvulsant action.

The synthesis of title compounds by reaction of camphor nitrimine with (5-norbornen-2-yl)methylamine, followed by NaBH4 reduction of the resulting imine to N-substituted isobornylamine (IV) and reaction of (IV) with alkyl and aryl isocyanates or acyl chlorides, is described. Some ureas and amides are endowed with antiarrhythmic activity in rats superior or comparable to that of quinidine, whereas benzamide (V o) showed an appreciable hypoglycemic activity in mice. Moreover, compounds (V) exhibited in general moderate hypotensive, bradycardic and antiinflammatory activities in rats, as well as a weak infiltration anesthesia in mice.

A series of N-substituted thioureas (II) and some ureas (III) were synthesized in excellent yields by reaction of 4,5,6,7-tetrahydro-7,8,8-trimethyl-3-phenylamino-4,7-methano-2H-indazole with alkyl, aryl isothiocyanates and isocyanates, respectively. On the whole compounds (II) and (III) showed hypotensive and in some cases hypoglycemic activity in rats. Effects on heart rate in rats, infiltration anesthesia in mice and antiacetylcholine activity in vitro are also reported.

The synthesis of a series of alkyl and aryl ureas (II) starting from 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane is described. Some of these compounds showed a moderate hypotensive activity in rats. Effects on heart rate in rats, infiltration anesthesia and antiarrhythmic activity in mice, as well as antiacetylcholine activity in vitro, are also reported.

Three series of esters of 6-cis-dialkylamino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-5-trans-ol (dialkylamino = pyrrolidino, piperidino, morpholino) are described. A number of these compounds showed strong hypotensive activity in rats, as well as infiltration anesthesia and antiarrhythmic activity in mice. The lowering effects on heart rate in rats are also described.

A synthesis of esters from 1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octan-5-endo-ol lithium slat and acyl chlorides is described. A number of these compounds showed strong antiarrhythmic, local anesthetic and hypotensive activities.

A new series of aliphatic and aromatic esters of 1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octan-5-trans-ol is described. A number of these compounds showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to that of lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

A series of aliphatic and aromatic esters of 1,7,7-trimethyl-2-exo-piperidinobicyclo[2.2.1]heptan-3-endo-ol is described. A number of these compounds showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice. Circulatory, cardiac and respiratory effects in dogs are also described.

Reaction of N,N-disubstituted 2-carboxyamido-2,6,6-trimethyltetrahydropyran-5-carboxylic acids with diphenyl phosphorazide in the presence of triethylamine and benzyl alcohol gave N,N-disubstituted 5-benzyloxycarbonylamino-2-carboxyamido-2,6,6-trimethyltetrahydr-pyrans, which in turn yielded N,-disubstituted 2-aminomethyl-5-methylamino-2,6,6-trimethyltetrahydropyrans by LiA1H4 reduction. 5-Benzyloxycarbonylamino-2-carboxypyrrolidino-2,6,6-trimethyltetrahydropyran gave 5-amino-2,6,6-trimethyl-2--pyrrolidinomethyltetrahydropyran by hydrogenolysis followed by LiA1H4 reduction. Among the amides prepared from the latter, the diphenylacetic acid amide showed antiarrhythmic and local-anesthetic activity.

The synthesis of title compounds by reaction of camphor nitrimine with 2-amino-2-methylpropanol, followed by NaBH4 reduction of the resulting imine to the aminoalcohol (III) and esterification of (III) with aliphatic and aromatic acyl chlorides in pyridine solution, is described. Phenyl carbamate (V) was also prepared by reaction of (III) with phenyl isocyanate. Some esters and (V) showed a moderate hypotensive activity in rats. Effects on heart rate and antiarrhythmic activity in rats, as well as infiltration anesthesia in mice, are also reported.

Two synthetic routes to (exo-5,6-trimethylenenorbornan-2-ylidene)acetonitrile starting from exo-5,6-trimethylenenorbornan-2-one are described. From the above-mentioned nitrile, 2-(exo-5,6-trimethylenenorbornan-2-ylidene)ethanamine and 2-(exo-5,6-trimethylenenorbornan-2-yl)ethanamine, as well as N,N-dimethyl and N,N-diethyl derivatives of the latter, were prepared.

Lithium aluminum hydride reduction of exo-5,6-trimethylenenorbornan-2-one oxime gave in good yield exo-5,6-trimethylenenorbornan-2-endo-amine, from which a number of amides were prepared by reaction with acyl chlorides. Lithium aluminum hydride reduction of the above-mentioned amides afforded N-substituted exo-5,6-trimethylenenorbornan-2-endo-amines in good yields. Some amides showed CNS depressant and anti convulsant activity, and an amine convulsant activity in mice.

The synthesis of alkyl and aryl ureas (II) derived from 5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2.]nonane (I), as well as hydrazides (V), (VI) and (VII) derived from 5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2]-nonan-3-amine (IV), is described. A number of theses compounds showed strong hypotensive and bradycardic activities in rats, as well as weak infiltration anesthesia and antiarrhythmic activity in mice. Antiacetylcholine activity in vitro is also reported.

The synthesis of three series of 3-acyl-, 3-alkyl- and 3-dialkylaminoacetyl-5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2]nonanes, (III), (IV) and (V), respectively, is described. A number of these compounds showed surface anesthesia in rabbits and infiltration anesthesia in mice, and antiarrhythmic activity in guinea pigs and mice, all effects being superior or similar to those of lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

The synthesis of 1-(2-hydroxyethyl)-3,5-diphenyl-1H-pyrazole (II) and its 4-bromo derivative (III) starting from chalcone epoxide, as well as of a series of esters and N-substituted carbamates derived from (II) and (III), is described. Some of these compounds showed remarkable depressant, antiarrhythmic and analgesic activities in mice and rats. Moreover, the above compounds usually exhibited moderate hypotensive, bradycardic and antiinflammatory activities in rats, infiltration anesthesia and hypoglycemic activity in mice, as well as a weak platelet antiaggregating activity in vitro.

The synthesis of a series of N-substituted 3-amino-2-hydroxypropyl ethers (III a-1) starting from (+)-1,3,3-trimethyl-2-oxabicyclo [2.2.2]-octan-6-hydroxyimine is described. Some of these compounds showed a remarkable hypotensive and a weak bradycardic activity in rats, as well as a moderate local anesthetic activity in mice. All compounds were found to be devoid of antiarrhythmic activity in rats and of beta-blocking activity in dogs.

The synthesis of ureas (IV) and amides (V) derived from the tricyclic terpenoid amine 5,7,7-trimethyl-6-oxa-3-azatricyclo[3.2.2.0(2.4)]nonane (III) is described. A number of these compounds showed hypotensive and bradycardic activity in rats, as well as infiltration anesthesia and antiarrhythmic activity in mice. In particular, the n-butylurea (IV b) was superior to lidocaine concerning the anesthetic effect, and the benzamide (V f) showed the same degree of local anesthetic and antiarrhythmic activity as lidocaine. Antiacetylcholine activity in vitro and antitumor activity against P388 lymphocytic leukemia in mice are also reported.

The synthesis of title compounds by reaction of fenchone nitrimine with 2-aminoethanol and 3-aminopropanol, followed by stereospecific NaBH4 reduction of the resulting imines, Eschweiler-Clarke reductive methylation and esterification with aliphatic and aromatic acyl chlorides is described. Some esters showed an appreciable hypotensive activity in rats. Effects on heart rate and antiarrhythmic activity in rats, as well as infiltration anesthesia in mice, are also reported.

The synthesis of (+/-)-1-(adamantan-2-yl)-2-propanamine (VI), its N,N-dimethyl derivative (VII) and other amines (VIII), (IX) and (X), starting from 2-adamantanone, is described. Some of these amines showed antiparkinson activity in mice.

The reaction of fenchone nitrimine (I) with benzamidine gave in good yield N,N-(1,3,3-trimethylbicyclo [2.2.1]hept-2-ylidene)benzamidine (II), which by acylation afforded N'-acyl-N,N-(1,3,3-trimethylbicyclo[2.2.1]hept-2-ylidene)benzam idines (III a-f) in excellent yields. Compounds (III) showed a moderate hypotensive activity in rats and a weak local anesthetic activity by infiltration in mice. Effects on heart rate and antiarrhythmic activity in rats are also reported.

The synthesis of beta-dialkylaminoethyl ethers (II a-f) and gamma-dialkylaminopropyl ethers (II g-i), as well as of aryl carbamates (III 1, m), starting from (+)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-hydroxyimine (I), is described. beta-Dimethylaminoethyl ether (II a) showed a remarkable hypotensive and bradycardic activity in rats; moreover, nearly all compounds (II) and (III) exhibited a weak antiarrhythmic activity in rats. Infiltration anesthesia in mice, beta-blocking activity in dogs and antiacetylcholine activity in vitro are also reported.

The synthesis of a series of alkyl and aryl thioureas (II) starting from 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane is described. Some of alkyl thioureas showed a moderate hypotensive activity in rats. Effects on heart rate and hypoglycemic activity in rats, infiltration anesthesia and antiarrhythmic activity in mice are also reported.

The synthesis of three series of glycinamides (IV), amides (V) and diamines (VI) starting from 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane is described. Some of compounds (IV), (V) and (VI) showed a moderate hypotensive activity in rats. Effects on heart rate in rats, infiltration anesthesia and antiarrhythmic activity in mice, as well as antiacetylcholine activity in vitro, are also reported.

By reaction of camphor enamine (I) with phenyl isothiocyanate, the N-phenyl thiocarboxamide (II) was obtained in excellent yield, and in turn gave 4,5,6,7-tetrahydro-7,8,8-trimethyl-3-phenylamino-4,7-methano-2H-indazole (III) in very good yield by reaction with hydrazine hydrate. A series of N-substituted ureas (IV) were synthesized in satisfactory yield by reaction of (III) with alkyl and aryl isocyanates. Ureas (IV) showed in general hypoglycemic and in some cases hypotensive activity in rats, whereas only hypotensive activity was present in the thiocarboxamide (II). Effects on heart rate, antiinflammatory and antipyretic activities in rats, infiltration anesthesia and antiarrhythmic activity in mice, as well as antiacetylcholine activity in vitro, are also reported.

The synthesis of N-phenyl-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-cis-amine (III) starting from 6-nitrimino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane, as well as of a series of amides (IV) and ureas (VI) derived from (III), is described. A number of compounds (IV) showed strong hypotensive and bradycardic activity in rats, whereas the urea (IVb) showed infiltration anesthesia in mice similar to that of lidocaine. Antiarrhythmic activity in mice and antiacetylcholine activity in vitro are also reported.

The synthesis of isonicotinic, nicotinic and clofibric esters (III a, b, c) and (IV a, b, c) starting from N-methyl-N-(2-hydroxyethyl or 3-hydroxypropyl)-1,3,3-trimethylbicyclo [2.2.1] heptan-2-endo-amine is described. In general these esters showed a normolipemic activity in rats; in particular, the isonicotinic ester (IV a) showed a hypocholesterolemic activity higher than that of clofibric acid.

A series of N,N-dialkyl 5-trans-carbamoyloxy-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octanes was prepared by reaction of 1,2,3,3-tetramethyl-2-azabicyclo [2,2,2]octan-5-trans-ol with phosgene, followed by aminolysis of the resulting chlorocarbonate with aliphatic secondary amines. 5-Chloro-1,2,3,3-tetramethyl-2-azabicyclo [2,2,2] octane (cis/trans mixture) was isolated as by-product of the reaction. A number of urethanes showed antiarrhythmic activity in guinea pigs and mice, as well as surface anesthesia in rabbits and infiltration anesthesia in mice, superior or similar to lidocaine. The circulatory, cardiac and respiratory effects in dogs and hens are also described.

The syntheses of (+/-)-1-(exo-5,6-trimethylenenorbornan--2-yl)2-propanamine (IV) starting from (exo-5-trimethylenenobornan-2-yl)acetic acid (I) or (exo-5,6-trimethylenenorbornan-2-yl)acetonitrile (II), as well as a series of amides (V) described. None of compounds (IV) and (V) showed amphetamine-like activity in mice.

The synthesis of 6-cis-dimethylamino-1,3,3-trimethyl-2-oxabicyclo [2.2.2] octan-5-cis-ol (III) starting from 6-cis-dimethylamino-1,3,3-trimethyl-2-oxabicyclo [2.2.2] octan-5-trans-ol (I) is described. Starting from aminoalcohol (II), a series of esters (IV) and N-substituted urethanes (V) was prepared. Benzoate (IV e) showed a remarkable hypotensive and bradycardic activity in rats, whereas acetate (IV a) showed infiltration anesthesia and antiarrhythmic activity in mice slightly inferior to those of lidocaine. Antiacetylcholine activity in vitro is also reported.

Synthesis of twelve N 1-nicotinoyl and isonicotinoylpyrazoles by reaction of 4,5-tetra-, penta-, hexamethylenepyrazoles, dihydronaphtopyrazole, bornylenepyrazole and cineolylenepyrazole with nicotinoyl and isonicotinoylchloride, is described. The structure of N 1-derivatives of these compounds was ascertained by comparison of N.M.R. spectra with those of 1-nicotinoyl and 1-isonicotinoyl-4,5-pentamethylene-5-hydroxy-2-pyrazoline, obtained by reaction of 2-hydroxymethylenecycloheptanone with nicotinoyl and isonicotinoylhydrazide, respectively. N 1-isonicotinoylbornylenepyrazole shows weak C.N.S. depression, muscle relaxation and anticonvulsant activity.

Lithium aluminium hydride reduction of N-phenoxycarbonyl-N,N-(1,3,3-trimethylbicyclo[2.2.1]-hept-2- yl)benzamidine (II), which afforded the N-acyl derivatives (III a-f) in good yields. Compounds (II) and (III) showed a moderate hypotensive activity in rats. Local anesthetic activity by infiltration in mice, effects on heart rate and antiarrhythmic activity in rats are also reported.