ABSTRACT
Mitsunobu inversion of the (S)-configurated lactate (S)-7, which is prepared in four steps starting from (S)-tyrosine, leads to the (R)-configurated lactate (R)-7. The key step in the transformation of the enantiomeric lactates (S)-7 and (R)-7 into the benzomorphan analogous tricycles (R,S)-16a,b, (S,R)-16a,b, (S,S)-22, and (R,R)-22 is an intramolecular Oxa-Pictet-Spengler reaction: The amides (S)-13, (R)-13, (S)-19 and (R)-19, in which the carbonyl moiety-masked as an acetal-is linked to the 2-phenylethanol moiety, are cyclized to give the tricyclic amides (R,S)-15, (S,R)-15, (S,S)-21, and (R,R)-21, respectively. In a concentration of 100 microM both enantiomers of 16a, 16b, and 22 are not able to compete with 3H-(+)-MK 801 for the phencyclidine binding sites of NMDA receptors. In vivo, only (R,S)-16b and (S,S)-22 exhibit weak sedative and analgesic activity.
Subject(s)
Central Nervous System Agents/chemical synthesis , Polycyclic Compounds/chemical synthesis , Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/pharmacology , Animals , Central Nervous System Agents/pharmacology , In Vitro Techniques , Mice , Polycyclic Compounds/pharmacology , Rats , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, Phencyclidine/drug effects , Receptors, Phencyclidine/metabolismABSTRACT
This paper deals with the synthesis and psychopharmacological effects of variations of the sedative and analgesic tricyclic amines 3a and 3b: Starting with the homochiral ketone 4 the amines 5 (primary amino group in equatorial position), 7 (axially oriented dimethylamino group), 9 (additional phenyl residue in position 7), 13b, and 14b (equatorially and axially arranged dimethylaminomethyl group) and 23 and 24 (axial amino group shifted to position 9) are prepared. BBr3 cleaves the phenolic ethers of the secondary amine (+/-)-3a to yield the aminodiphenol (+/-)-10. -Keeping mice under observation for behavioral anomalies (Irwin screen) and analgesic activity (writhing test) shows, that the amines 5, 7, 9, (+/-)-10, 13b, 14b, and 23 do not reach the sedative and analgesic effects of the amines 3a and 3b, described by us.
Subject(s)
Central Nervous System Agents/chemical synthesis , Polycyclic Compounds/chemical synthesis , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Behavior, Animal/drug effects , Central Nervous System Agents/pharmacology , Hypnotics and Sedatives/chemical synthesis , Hypnotics and Sedatives/pharmacology , Mice , Polycyclic Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
In an oxa-Pictet-Spengler reaction the methyl (S)-phenyllactate 6 and methyl levulinate (7a) are condensed to the 2-benzopyrans cis-8a and trans-8a, which react with CH3I to yield the dimethyl ethers cis-9a and trans-9a. Cis-9a and trans-9a can be separated by medium pressure liquid chromatography. In the subsequent Dieckmann-Cyclisation cis-9a is transformed to the laevorotatory beta-ketoester (-)-10a, while the dextrorotatory enantiomer (+)-10a is obtained from trans-9a after C-3-epimerisation. With Eu(hfc)3 the ketone (-)-11, prepared by saponification and decarboxylation of (-)-10a, proves to be enantiomerically pure. By reductive amination, ketone (-)-11 is transformed to the amines (-)-12a and (-)-12b. Symptoms typical for central damping are caused after i.p. application of (-)-12a and (-)-12b to mice. In the mouse writhing-test (-)-12a HCl affords an ED50-value of 7.0 mg/kg, comparable with the ED50-value of tramadol.
