Preparation and configuration of racemic and optically active analgesic dialkylaminoalkylnaphthalenes.
The alkylaminoalkylnaphthalene 3 shows interesting opioid-like analgesic properties, mu-selective ligand competition, and enkephalin hydrolyzing enzyme inhibition. 3 possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with the receptor is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (1R,2R/1S,2S)- and (1R,2S/1S,2R)-racemates and the (1R,2R)- and (1S,2S)-enantiomers of the 1-ethyl-1-hydroxy-1-[2-(6-hydroxynaphthyl)]-2-methyl-3- dimethylaminopropane 3 is considered and the determination of absolute configuration is described. The (1R,2R/1S,2S)-3 and (1R,2S/1S,2R)-3 racemates and the (1R,2R)-3 and (1S,2S)-3 enantiomers were prepared by reaction of the racemic and optically active 1-dimethylamino-2-methylpentan-3-one 2, respectively, with the lithiation product obtained from 2-bromo-6-tetrahydropyranyloxynaphthalene and acidic hydrolysis. The optical resolution of aminoketone 2 was carried out via fractional crystallization of salts (+)- and (-)-dibenzoyltartrates. The configuration of the optically active compounds was determined by X-ray analysis of a crystal of (+)-(1R,2R)-3.HCl.H2O. Preliminary pharmacological tests showed that (+)-(1R,2R)-3 enantiomer is able to induce opioid-like analgesia with a relative potency 2.5 times that of (1R,2R/1S,2S)-3 and about 4 times that of morphine.
Ghislandi
V
V
Dipartimento di Chimica Farmaceutica, Università di Pavia, Italy.
Azzolina
O
O
Collina
S
S
Paroli
E
E
Antonilli
L
L
Giuseppetti
G
G
Tadini
C
C
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D009904:Optical Rotation; D010147:Pain Measurement / Q000187:drug effects; D013237:Stereoisomerism
D000700:Analgesics; D009281:Naphthalenes