Victor Ghislandi

PREPARATION AND CONFIGURATION OF RACEMIC AND OPTICALLY ACTIVE ANALGESIC CYCLOAMINOALKYLNAPHTHALENES

Cycloaminoalkylnaphthalene 3 shows interesting opioid-like analgesic properties. It possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with receptors is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (2R,3S/2S,3R) racemate and the (2R,3S) and (2S,3R) enantiomers of the 1,2-dimethyl-3-[2-(6-hydroxynaphthyl)]-3-hydroxypyrrolidine 3 is considered and the determination of absolute configuration is described. The (2R,3S/2S,3R)-3 racemate and the (2R,3S)-3 and (2S,3R)-3 enantiomers were prepared by reaction of the racemic and optically active 1,2-dimethyl-3-pyrrolidone 2, respectively, with the lithiation product obtained from 2-bromo-6-tetrahydropyranyloxy-naphthalene 1 and acidic hydrolysis. The above-mentioned enantiomers of 3 were also obtained by optical resolution via fractional crystallization of the salts with D- and L-tartaric acids. The configuration of the optically active compounds was determined by X-ray analysis of a crystal of (-)-(2S,3R)-3.HCl.H2O. The pharmacological test HPT showed that (-)-(2S,3R)-3.HCl.H2O enantiomer is able to induce opioid-like analgesia with a relative potency 1.5 times that of (2R,3S/2S,3R)-3 and approximately 1.5 times that of morphine.

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.

Chemical and biological profile of racemic and optically active dialkylaminoalkylnaphthalenes with analgesic activity

The racemic mixtures and the enantiomers of dialkylaminoalkylnaphthalenes are described here as novel analgesic agents with potencies similar, or superior to that of morphine. The synthesis and isolation of the pure enantiomers and a study of the absolute configuration are reported. The resolution of racemates was accomplished by preparative liquid chromatography using a Chiralpak AD column. The configurational assignment was performed on the basis of the X-ray crystallographic analysis of (+)-benzyl-(3-hydroxy-3-naphthalen-2-yl-butyl)dimethylammonium bromide and by comparative study of CD and NOESY 1 H NMR spectra of the resolved enantiomers. Pharmacological evaluation of the analgesic activity by means of the hot plate test is described.

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.

(Z)- and (E)-3-Alkyldine-1,3-dihydroindol-2-ones : influence of configuration on the transmission of the inductive effect to the carbonyl group

A series of (Z-) and (E-)-3-alkylidene-1,3-dihydroindol-2-ones has been prepared and their i.r. spectra in the carbonyl region recorded. Good correlations were obtained between the carbonyl stretching frequency of the E-isomers and the polar parameter σ*, indicating that the inductive effect of the alkyl group is transmitted to the carbonyl group and that the variation in frequency in the series is a function of this effect only. The Z-isomers do not give a linear correlation and it is suggested that this is due to the steric interactions of the alkyl group with the oxygen of the carbonyl group which twists the CC–CO system to a certain extent with consequent variation in conjugation.

Synthesis and pharmacological evaluation of new N-methyl-arylpyrrolidinols with analgesic activity

In the present paper, we report on the synthesis and antinociceptive activity of a new series of N-methyl-arylpyrrolidinols that we designed for a rational structure-activity relationship (SAR) study. The antinociceptive properties were investigated in vivo by the hot plate and formalin tests in mice and control on the locomotory activity was also monitored by the rota rod test. With this aim, the evaluation of the lipophilicity of all compounds was performed by the Daylight computational method in order to better understand the SAR. Interesting properties were proven for the compounds of the entire series.

ON THE ENANTIOMERS OF 2-DIMETHYLAMINO-3-PENTANONE, KEY INTERMEDIATES IN THE SYNTHESIS OF ANALGESIC ALKYLAMINOALKYLNAPHTHALENES

Abstract 2-Dimethylamino-3-pentanone 1 is the key intermediate in the synthesis of alkylaminoalkylnaphthalenic analgesics. In this paper the resolution of this compound with l - and d -dibenzoyltartaric acids is described. The behavior of the diastereomeric dibenzoyltartrates and of the enantiomers in solution is investigated by NMR spectroscopy, polarimetry and chiral gas-chromatographic analysis.