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Diastereomeric cis- and trans-tetrahydro-4-aryl-3-[(dimethylamino)methyl]-2H-pyranols derived from 3-[(dimethylamino)methyl]tetrahydro-4H-pyran-4-one (5), have been prepared and their configurations were established on the basis of ir data. The biologically more potent trans isomer 3 was resolved into its optical antipodes and the absolute stereochemistry of one of the enantiomers 14, was determined by X-ray crystallography. Some of the compounds showed analgesic activity comparable to codeine.

O-Demethylation of (9S,13S,14S)-3-methoxy-17- methylmorphinan-10-one (2) to (9S,13S,14S)-3-hydroxy-17-methylmorphinan- 10-one (3) and reduction of 3 to 10α- and 10β-hydroxylated morphinans 4 and 5, are described. The stereochemistry of these epimeric alcohols was established on the bases of 1 H nmr data

Reaction of 2-aminoethanethiol (3) with trans-3-(p-methoxyplienyl)glycidate (4) gave the rac.-cis-1,4-thiazepinone 5 and a by-product 6. The structure of 5 was proven by X-ray crystallography. The X-ray data revealed that this compound adopts the chair conformation in the solid state and the heterocyclic ring is sevenmembered. The structure of the by-product 6 was elucidated on the basis of spectral data. Compounds 9 and 10 were inactive as calcium channel blocking agents.

Reaction of 2-aminoethanethiol (3) with trans-3-(p-methoxyplienyl)glycidate (4) gave the rac.-cis-1,4-thiazepinone 5 and a by-product 6. The structure of 5 was proven by X-ray crystallography. The X-ray data revealed that this compound adopts the chair conformation in the solid state and the heterocyclic ring is sevenmembered. The structure of the by-product 6 was elucidated on the basis of spectral data. Compounds 9 and 10 were inactive as calcium channel blocking agents.

Oxidation of geranyl palmitate (3) with m-chloroperbenzoic acid in dichloromethane gave 6,7-epoxygeranyl palmitate (4) regioselectively, which was saponified to 6,7-epoxygeraniol (5).

Diastereomeric cis- and trans-tetrahydro-4-aryl-3-[(dimethylamino)methyl]-2H-pyranols derived from 3-[(dimethylamino)methyl]tetrahydro-4H-pyran-4-one (5), have been prepared and their configurations were established on the basis of ir data. The biologically more potent trans isomer 3 was resolved into its optical antipodes and the absolute stereochemistry of one of the enantiomers 14, was determined by X-ray crystallography. Some of the compounds showed analgesic activity comparable to codeine.

The base catalyzed reaction of 2-aminoethanethiol (3) with trans-3-(p-methoxyphenyl)glycidate (4) gave a mixture of isomeric lactams 5 and 6, and in addition, a by-product 7. The structures of these isomers were proven by X-ray crystallography. The data revealed that both isomers adopt the chair conformation in the solid state and the size of the heterocyclic ring in compound 5 is a six- and in compound 6 is a seven-membered ring.

O-Demethylation of (9S,13S,14S)-3-methoxy-17- methylmorphinan-10-one (2) to (9S,13S,14S)-3-hydroxy-17-methylmorphinan- 10-one (3) and reduction of 3 to 10α- and 10β-hydroxylated morphinans 4 and 5, are described. The stereochemistry of these epimeric alcohols was established on the bases of 1 H nmr data

The base catalyzed reaction of 2-aminoethanethiol (3) with trans-3-(p-methoxyphenyl)glycidate (4) gave a mixture of isomeric lactams 5 and 6, and in addition, a by-product 7. The structures of these isomers were proven by X-ray crystallography. The data revealed that both isomers adopt the chair conformation in the solid state and the size of the heterocyclic ring in compound 5 is a six- and in compound 6 is a seven-membered ring.

The base-catalyzed alkylation of rac.-trans-tetrahydro-6-hydroxy-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one (1) with dimethylaminoethyl chloride in dimethyl sulfoxide provided predominantly rac.-trans-tetrahydro-6-hydroxy-4-[(2-dimethylamino)ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one (2) and in addition, 2,3-dihydro-4-[2-(dimethylamino)-ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(4H)-one (3). A plausible mechanism is postulated for the dehydration of the rac.-trans-amide 2.

A series of novel 2- and 3-acylmorphinans (8-14) was synthesized in our search for a potent analgesic agent with low addiction potential. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, the levorotatory 3-acetyl-N-(cyclopropylmethyl)morphinan (12) was found to be an orally active analgesic, comparable in potency to morphine (1), yet only weakly able to substitute for morphine (1) in morphine-dependent rats.

The pharmacokinetic profile of (-)-2-hydroxy-N-cyclopropylmethylmorphinan (HCMM), a narcotic antagonist and analgesic, has been evaluated in man following administration of 25 to 50 mg of the drug orally and 10 to 15 mg intramuscularly. A specific radioimmunoassay procedure was developed for the determination of HCMM in plasma and urine. The drug had a mean "apparent" elimination half-life in plasma of about 11 hr following both routes of administration. A mean of 47% of the oral dose was excreted in the urine as unconjugated and conjugated HCMM and only 5% of the dose was excreted as intact HCMM. In one subject studied, the plasma levels of conjugated HCMM were as much as 5-fold higher than the levels of unconjugated drug. Although there was considerable intersubject variability following both routes of administration, the overall pharmacokinetic parameters suggest that oral and intramuscular doses are bioequivalent.

Antiserum against morphine was produced in rabbit immunized with morphine hapten conjugated to bovine serum albumin. The carrier protein was conjugated to the nitrogen atom of the opiate alkaloid in order to make the phenolic hydroxy group on C3 and the alcoholic group on C6 as determinant groups. The antibody does not recognize codeine or the major metabolite of morphine, 3-O-monoglucuronide. This antibody was used in conjunction with an antibody prepared against 3-O-carboxymethylmorphine to develop a radioimmunoassay which can measure codeine in the presence of morphine. The assay was used to follow both the plasma and brain levels of codeine and its biotransformation to morphine. Codeine when administered at a dose of 5 mg/kg i.v. showed a biphasic plasma decay curve the first phase of which had a t 1 2 of 26 min. Peak concentrations of morphine were detected in the plasma following that dose of codeine at 0.5 h. 30 min after the injection of 20 mg/kg i.p. codeine, the brain levels of morphine were only 2% that of codeine. Thereafter, the brain levels of morphine slowly declined.

A facile procedure for the preparation of cyclic imino ethers from thiocaprolactam and chloroformates is described.

The major metabolic pathway of the (-) enantiomer and the (+) enantiomer of 2-hydroxy-N-cyclopropylmethylmorphinan in dogs was shown to be conjugation with glucuronic acid and/or sulfate. Gas chromatography mass spectrometry, nuclear magnetic resonance spectroscopy and X-ray crystallography were used to identify additional metabolites of the two enantiomers in dog urine after hydrolysis with Glusulase. Metabolites of the (-) enantiomer were identified as 2-hydroxymorphinan and 2,7beta-dihydroxy-N-cyclopropropylmethylmorphinan. The major metabolites of the (+) enantiomer in hydrolyzed dog urine were identified as 2-hydroxymorphinan,2,3-dihydroxy-N-cyclopropylmethylmorphinan and 2-methoxy-3-hydroxy-N-cyclopropylmethylmorphinan. In addition, tentative or partial structures were postulated for three minor metabolites of the (+) enantiomer: 2-methoxy-3-hydroxymorphinan, a metabolite containing a hydroxyl group on either carbon 4, 5, 6 or 7 and a methylated catechol metabolite containing a hydroxyl group on carbon 4, 5, 6 or 7. Thus, the major oxidative pathways of the (-) enantiomer were N-dealkylation and aliphatic hydroxylation, while the (+) enantiomer mainly underwent N-dealkylation and aromatic hydroxylation, followed by phenolic methylation. Analysis of urine from a human subject administered the (-) enantiomer suggested that the metabolism of this isomer by man was similar to its metabolism by dog.

Preparation of (±)-3-methoxy-16-t-butylmorphinan (4) by reaction of t-butyl lithium with (±)-3-methoxy-N-chloromorphinan (1) is described. The structure of 4 was confirmed by X-ray crystallography.

A facile procedure for the preparation of methyl esters from carboxylic acids under neutral conditions is described.

1. The O-dealkylation of 3-O-tert.-butylmorphine, a new derivative of morphine, has been compared to the O-dealkylation of codeine by the rat. Rats were given either 3-O-tert.-butylmorphine or codeine intraperitoneally and 24 h urine samples were collected and analysed for morphine by a quantitative gas chromatographic procedure. With codeine, about 7% of the dose was excreted as morphine. In contrast, about 0.3% of a dose of 3-O-tert.-butylmorphine was recovered from urine as morphine. These results indicate that, unlike codeine, 3-O-tert.-butylmorphine is not O-dealkylated to any appreciable extent by the rat.2. Three metabolites of 3-O-tert.-butylmorphine have been recovered from rat urine, resolved by gas chromatography and identified by mass spectroscopy as 3-O-tert.-butylnormorphine, 3-O-(2-hydroxymethyl-2-propyl)morphine and 3-O-(2-hydroxymethyl-2-propyl)normorphine. The identities of the last two metabolites were confirmed by comparison of their mass spectra with the mass spectra of synthetic refe...

3-Methoxymorphinan (1) was converted to the corresponding N-chloro derivative 2 by treatment with aqueous sodium hypochlorite. Upon exposure to methanolic silver nitrate, 2 was rearranged to the carbinolamine ether 3. In addition, considerable amounts of the dechlorinated morphinan 1 were formed. The structure of 3 was secured by spectral analysis and its degradation to the hexahydroindoline derivative 4. The observed skeletal rearrangement of 2 which requires the migration of an alkyl group is discussed in terms of a nitrenium ion.

A new synthetic method for the preparation of N,N-dimethylformamide di-tert-butyl acetal by acid catalyzed transacetalization of readily available N,N-dimethylformamide dimethyl acetal is described.

A facile synthesis for the preparation of tert-butyl aryl ethers from phenols under basic conditions is described.

(+)6,7,7a,8,9,10,11,11a-Octahydro-2-methoxy-12-methyl-5H-7,11a-irninoethanodibenz[c, e]azepin-5-one (3) was prepared by Beckmann rearrangement of the oxime of (+)-3-methoxy-17-methylmorphinan-10-one (2) with polyphosphoric acid.

A series of novel O-aryl-N-methylmorphinans (7-19) were synthesized by the Ullmann reaction from levorphanol (4) in our search for a synthetic codeine (2) substitute with reduced addition liability. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, (-)-3-phenoxy-N-methylmorphinan (7) is an orally active analgesic comparable in potency to codeine (2), which exhibits decreased physical dependence liability and longer duration of action.

A series of novel 2- and 3-acylmorphinans (8-14) was synthesized in our search for a potent analgesic agent with low addiction potential. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, the levorotatory 3-acetyl-N-(cyclopropylmethyl)morphinan (12) was found to be an orally active analgesic, comparable in potency to morphine (1), yet only weakly able to substitute for morphine (1) in morphine-dependent rats.

Als Metabolit von Levallorphan (I) erhalt man die Hydroxy-Verbindung (II), die uber ihr Rontgenspektrum identifiziert wird.

(+)6,7,7a,8,9,10,11,11a-Octahydro-2-methoxy-12-methyl-5H-7,11a-irninoethanodibenz[c, e]azepin-5-one (3) was prepared by Beckmann rearrangement of the oxime of (+)-3-methoxy-17-methylmorphinan-10-one (2) with polyphosphoric acid.

The synthesis of 2-hydroxymethyl-2-propylmorphine (5) and 2-hydroxymethyl-2-propylnormorphine (7), the major rat urinary metabolites of 3-O-t-butylmorphine (3) are described.

This is a table indicating the characteristic NMR spectral positions for hydrogen in organic structures.