Synthesis and antinociceptive activity of pyrrolidinylnaphthalenes.

In this paper the synthesis of the racemates (2R,3S/2S,3R)-1,2-dimethyl-3-[2-(6-substituted naphthyl)]-3-hydroxypyrrolidine 1b-d [(2R,3S/2S,3R)-1b-d] are reported. Compounds 1b-d were prepared by reaction of the racemic 1,2-dimethyl-3-pyrrolidone 2 with the lithiation product obtained from 2-bromo-6-substituted naphthalene 3b-d. Pharmacological properties of (2R,3S/2S,3R)-1a-d are also described. Analgesic activity was investigated by the hot plate test and binding affinities towards mu, delta and kappa opioid receptors were evaluated. A preliminary evaluation of the in vivo side-effects was also accomplished using the rota-rod test. Interesting antinociceptive activity was shown by all compounds and in particular by 1d, which is the most active compound, since it is six-fold more potent than morphine and has lower side effects on the locomotory activity.

Dialkylaminoalkylnaphthalenes as novel opioid-like analgesics.

The study of dialkylaminoalkylnaphthalenes as novel opioid-like analgesics is reported. In particular, the synthesis of (1R,2R/1S,2S)-1-ethyl-1-[2-(6-hydroxynaphthyl)]-1-hydrox-2-m ethyl-2-dimethylaminoethane and its structural analogue (1R,2R/1S,2S)-1-ethyl-1-[2-(6-fluoronaphthyl)]-1-hydroxy-2-methyl- 2-dimethylaminoethane and the configurational analysis by X-ray and 1H NMR spectroscopy are described. Pharmacological profiles are discussed on the basis of the experimental results of analgesia tests (hot plate and writhing test) and rota-rod test, which was performed to distinguish analgesia from drug-induced motor changes. The compounds showed dose-dependent antinociception, with less potency than morphine. Motor coordination appeared to be less involved.

Synthesis of pyrrolinylnaphthalenes and evaluation of their antinociceptive activity.

In this paper the regioselective preparation of (R/S)-1,2-dimethyl-3-[2-(6-substituted naphthyl)]-2H,5H-pyrrolines 2a-d is reported. These compounds were prepared by thermal dehydration of the corresponding alcohols (2R,3S/2S,3R)-1,2-dimethyl-3-[2-(6-substituted naphthyl)]-3-hydroxy-pyrrolidines (2R,3S/2S,3R)-1a-d with anhydrous FeCl3-SiO2, under vacuum. Pharmacological properties of (R/S)-2a-d are also described. Analgesic activity was investigated by the hot plate test, also in the presence of selective antagonists of mu, delta and kappa opioid receptors. Preliminary analysis of the side-effects was also accomplished using the rota-rod test. Interesting antinociceptive activity was shown by all compounds and in particular by (R/S)-2a (AD50 = 0.31 mg/kg); delta opioid receptors were found to be mainly involved in the pharmacological process and, in general, it was found that the compounds influenced locomotory activity to a much lesser extent than did morphine.

Chiral resolution, configurational study and pharmacological profile of 2-phenoxypropionic acids.

The racemates and several enantiomers of 2-phenoxypropionic acids, bearing alkyl, acetyl, benzyl, benzoyl, phenyl, difluorophenyl, Cl, NO2 groups on the aromatic moiety, were investigated as potential analgesic-antiinflammatory drugs. The enantiomers, whose absolute configuration has been previously determined by us, were prepared by chiral resolution of the diastereoisomeric salts of the racemates with cynchonidine. The enantiomeric excess was determined by chiral chromatography. The chiroptical properties of the dextroisomers were investigated by CD. The pharmacological properties of the racemates and the enantiomers were monitored by analgesic-antiinflammatory activity tests as well as by gastrotolerability and acute toxicity tests. Some compounds were shown to be superior to ASA and ketoprofen because they have higher or similar analgesic properties, with less gastroulcerogenetic activity. Furthermore low acute toxicity was found for the compounds with high values of ED50. Correlations between the configuration of the enantiomers and their activity are not evident. For the most active compounds, the activity of one of the enantiomers is superior to that of the racemates. This is particularly true for (S)-3, (R)-15 and (S)-18.

Optical resolution of benzodiazepine esters by HPLC.

The separation of the enantiomers of 11-26 esters of oxazepam 1, temazepam 2, lorazepam 3 and lormetazepam 4 whith the acids benzoic 6, 2-methyl-3-nitrobenzoic 7, cynnamic 8 and hydrocynnamic 9 by HPLC on analytical columns with chiral stationary phases of (R)-N-(3,5-dinitrobenzoyl)phenylglycine (R)-DNBPG and (S)-N-(3,5-dinitrobenzoyl)leucine (S)-DNBL was described. The diastereoisomeric mixtures of esters 27-30 of the overmentioned benzodiazepines with (S)(+)-2-(6-methoxy-2-naphthyl)propionic acid have been also separated by HPLC on analytical column of SiO2. Some of the best separations have been repeated on semipreparative scale in order to isolate and characterize the optically pure enantiomers or diastereoisomers. Configurational assignment and elution order are established by a chiral recognition model. On the basis of the study by molecular models of the interaction between solute and chiral stationary phases, the conformers more interacting with these phases have been individuated and it has been possible to conclude that for any enantiomers couple the (S) isomer is always more retained by the chiral stationary phase of (R)-DNBPG and the (R) isomer by (S)-DNBL. Regarding to the interaction of diastereoisomeric esters 27-30 with SiO2, the esters more retained should result those of the benzodiazepines having (S) configuration.

Optical resolution and configuration of 2-(4-dimethylvinylphenyl)propionic acid.

Optical resolution of (+/-)-2-(4-dimethylvinylphenyl)propionic acid (I) was performed through fractional crystallization of its salts with (S)-(-)- and (R)-(+)-alpha-phenylethylamine. 2-(4-Dimethylvinylphenyl)propionic acid, in comparison to ibuprofen, has greater antiinflammatory, analgesic and antipyretic activities, as well as a higher therapeutic index. Absolute configuration was determined by comparison of the (S)-(-)-alpha-phenylethylamide 1H-N.M.R. spectra of the enantiomers of (I) and of the enantiomers of ibuprofen whose configuration was already known. Thus, the absolute configuration (S) was assigned to (+)-(I).

[Clathrates of unsaturated hydroxamic acids with antifungal acitivity]. / Clatrati di acidi idrossammici insaturi ad attività antifungina.

Urea complexes of 10-undecen-hydroxamic acid (III) and trans-2-dodecen-hydroxamic acid (IV) were prepared with the aim of testing antifungal activity. No significant difference of activity between the complexes and corresponding hydroxamic acids was demonstrated.

Circular dichroism studies of some aralkylamines.

Circular dichroism curves are reported for a number of aralkylamines having a general formula R--CH(NH2)--R' (in which R and R' are alkyl-, aryl- or aralkyl-groups) and for 1-aminobenzocyclobutene, 1-aminoindane, 1-amino-1,2,3,4-tetrahydronaphthalene and 2-amino-1,2,3,4-tetrahydronaphthalene. The Cotton effects due to aromatic chromophore 1Lb and 1La absorption bands are discussed and simple correlations between absolute configuration and the signs of Cotton effects are deduced.