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Propranolol, its 1"-mono-, di-, and trifluorinated analogs, and other related compounds were analyzed under electrospray ionization ion trap collision-induced dissociation (ESI-CID) and electron impact (EI) conditions. Interesting trends were observed in the fragment ions formed in both cases. Under ESI conditions, the abundances of product ions easily explained by protonation on the amine nitrogen decreased relative to the abundances of those formed from the ether-protonated species as the number of fluorines increased from zero to three. Under EI conditions, the distribution of fragment ions was shifted away from those arising from a nitrogen-centered cation radical and toward those arising from an ether oxygen-centered cation radical. The changes observed in apparent molecular sites of protonation and of ion radical formation in the mass spectra are consistent with the electron-withdrawing effects of the sequentially added fluorines. These effects are correlated with changes in solution phase pK( a)'s of the fluorinated amines.

Propranolol, deuterium- and 18O-labeled propranolol and related compounds were analyzed using an ion trap mass spectrometer equipped with a modified Finnigan API electrospray interface. Sequential product ion (MSn) experiments were used to elucidate fragmentation pathways for these compounds. The observed ions were compared to those observed under electron impact (EI) conditions. The electrospray ionization (ESI) ion trap spectra, as well as the EI spectra, afford useful information to allow assignments of most product ions, many of which retain portions of the aliphatic three-carbon side chain.

An improved laboratory scale synthesis of bufuralol (1) and 1″-oxobufuralol (4) was accomplished. The intermediate benzofurans were prepared via aromatization of 2,3-dihydrobenzofurans or by a one-step acidcatalyzed cyclization from 2,2-diethoxyethyl 4-bromo-6-ethyl-2-formylphenyl ether (23). Base-catalyzed cyclization of 3-(5-bromo-3-ethyl-2-hydroxyphenyl)-1.2-epoxypropane (16) provided the key intermediate, 5-bromo-7-ethyl-2-hydroxymethyl-2,3-dihydrobenzofuran (17). Selective functionalization of the C-2 and C-7 positions of the benzofuran ring system was accomplished to afford both 1 and 4.

Enantiomers of metoprolol containing six deuterium atoms in the isopropyl methyl groups were prepared in two steps from the sodium salt of 4-(2-methoxyethyl)phenol (3) and the commercially available (2R)- and (2S)-glycidyl 3-nitrobenzenesulfonates [(2R)-2 and (2S)-2]. The resulting (2R)- and (2S)-epoxides were opened using [2H6]-isopropylamine. The enantiomeric excesses were 93 and 95% for the deuterated (2R)- and (2S)-enantiomers of metoprolol [(2R)-1 and (2S)-1], respectively, as determined by chiral column HPLC.

During alkylation of 3-O-benzyl-6α-naltrexol (1) with large aralkyl halides like 2-bromomethylnaphthalene and 9-chloromethylanthracene under phase transfer catalysis conditions (potassium hydroxide, tetrabutylammonium bromide, methylene chloride), formation of a new 6α,14-epoxide-bridged isomorphinan (4) was noted. Chemical and spectral evidence, including nmr and mass spectral data, are presented to prove its structure. Its formation results from 6α-oxygen displacement of a 14-O-aralkyl ether intermediate under the phase transfer catalysis alkylation conditions.

Deuteration of disopyramide, 4-diisopropylamino-2-(2-pyridyl)-2-phenylbutyramide, was accomplished in an excess of 2H2SO4 at 125–135°C. Incorporation of 2-4 atoms of deuterium occurs with 65% recovery of disopyramide. At higher temperatures (150°C) greater incorporation of deuterium occurs, but substantial decomposition reduces the recovery of disopyramide to 25%.

Two 13C-labeled verapamil compounds were prepared. 2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-[2–(3,4-dimethoxyphenyl-1–[13C]-ethyl)methylamino]-valeronitrile was synthesized from 2–(3,4-dimethoxyphenyl)-1–[13C]-ethylamine, which was prepared from 3,4-dimethoxybenzyl chloride by displacement with 13C-labeled KCN followed by diborane reduction. 2-(3,4-Di-[13C]-methoxyphenyl)-2-isopropyl-5–[2–(3,4-di–[13C]-methoxyphenethyl)methylamino]-valeronitrile containing 50% incorporation of 13C in the N-methyl group was prepared via demethylation of verapamil and subsequent re-methylation with 13C-labeled CH3I.

Synthesis of furosemide. specifically labelled at the 2-furanylmethyl α-position with 2H or 3H is reported. This synthesis required reduction of N-[(2-furanyhethyl)amino]-4-chloro-5-(N-acetylaminosulfonyl)benzoia acid (2) with sodium 2H- or 3H-borohydride. followed by alkaline hydrolysis of the acetyl group.

Enantiomers of metoprolol (1) containing six deuterium atoms in the isopropyl methyl groups [(2R-2], two deuterium atoms at C-2 and C-6 of the aromatic ring [(2S)-3], and two deuterium atoms at C-3 of the propanolamine side chain [(2S)-4] were prepared. Chiral 2,2-dimethyl-1,3-dioxolane-4-methanols [(4R)-5 and (4S)-5] were key synthons. Sources of deuterium were [2H6]-isopropylamine, 4-(2-methoxyethyl)-2,6-[2H2]-phenol (12), prepared by 2HCl/2H2O exchange, and (4S)-2,2-dimethyl-1,3-dioxolane-4-[2H2]-4-methanol (19), prepared by LiAl2H4 reduction of (4S)-methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate. Enantiomeric excess was greater than 94% for each of the prepared enantiomers, as determined independently by 1H NMR spectroscopy on diastereomeric derivatives and by chiral column HPLC.

Syntheses of 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol-1,1,2,3,3-d5 (1), 3-(1-naphthyloxy)-1,2-propanediol-1,1,2,3,3-d5 (2) and 1-(isopropylamino)-3-(4-hydroxy-1-naphthyloxy)-2-propanol-1,1,2,3,3-d5 (3) from epichlorohydrin-d5 are described. Treatment of epichlorohydrin-d5 with 1-naphthol, in the presence of a catalytic amount of pyridine, afforded a mixture of 1-chloro-3-(1-naphthyloxy)-2-propanol-1,1,2,3,3-d5 (4) and 1,2-epoxy-(1-naphthyloxy)-propane-1,1,2,3,3-d5 which was converted to 4, with HCl or to 5 with 6N KOH. Reaction of 4 with isopropylamine afforded 1. Acid catalyzed hydrolysis of 5 afforded 2. A modification of the synthesis of 1 using 4-methoxy-1-naphthol, epichlorohydrin-d5 (1N NaOH) afforded epoxide 7, which was opened with isopropylamine. Ether cleavage with pyridine HCl completed synthesis of 1-(isopropylamino)-3-(4-hydroxy-1-naphthyloxy)-2-propanol-1,1,2,3,3-d5 (3).

Syntheses of 1-(isopropylamino)-3-(1-naphthoxy)-2-propanol-3,3-2H2 (propranolol-3,3-2H2) (1) and of 1-(isopropylamino)-3-(1-naphthoxy-180)-2-propanol (propranolol-180) (2) are described. Reaction of 1-naphthol (3) with glycerol-2,3-acetonide-1,1-2H2 tosylate (4) afforded, after hydrolysis, 3-(1-naphthoxy)propane-1,2-diol-3,3-2H2 (5). Tosylation afforded the primary tosylate (6) which was converted into 3-(1-naphthoxy)-1,2-epoxypropane-3,3-2H2 (7). Reaction of 7 with isopropylamine afforded 1 in 31% overall yield from 4. Reaction of 1-naphthol-180 (8) with epichlorohydrin (pyridine) afforded a mixture of 1-chloro-3-(1-naphthoxy-180)-2-propanol (9) and 1,2-epoxy-3-(1-naphthoxy-180)propane (10), which was converted to chlorohydrin 9 with HCl. Reaction of 9 with isopropylamine afforded 2 in 60% overall yield from 1-naphthol-180.

Deuterated (-)-verapamil, (2S)-(-)-2-(2,5,6-2H3-3,4-dimethoxyphenyl)-2-isopropyl-5-[(2,5,6-2H3-3,4-dimethoxyphenethyl)methylamino]valeronitrile, and its analog (-)-2H5-gallopamil, (2S)-(-)-2-(2,6-2H2-3,4,5-trimethoxyphenyl)-2-isopropyl-5-[(2,5,6-2H3-3,4-dimethoxyphenethyl)methylamino]valeronitrile, were prepared. (-)-Gallopamil readily incorporated five atoms of deuterium into the available positions in the aromatic rings. (-)-2H6-Verapamil was prepared from ring trideuterated 3,4-dimethoxyphenylacetic acid and (2S)-(+)-triphenyl-methoxy-2-[(methanesulfonyl)oxy]propane. Three additional atoms of deuterium were incorporated into the aromatic ring of the N-methyl-3,4-dimethoxyphenethylamine moiety incorporated as the the short N-alkyl side chain. N-13C-Methylverapamil was prepared from N-13C-methyl-3,4-dimethoxyphenethylamine.

Deuteration of verapamil, 5-[(3,4-dimethoxyphenylethyl)methyl-amino]-2-(3,4-dimethoxyphenyl)-2-isopropyvaleronitrile, an important calcium channel antagonist was accomplished by direct exchange in 25% 2H2SO4 in 2H2O. Refluxing for 140 hr incorporated 4–6 atoms of deuterium, which were distributed into both aromatic rings, but primarily in the ring attached through position 5 of the valeronitrile moiety.

Synthesis and stereochemistry of various endo-2- and exo-2-substituted-7-oxabicyclo[2.2.1]-hept-5-enes and -heptanes are described. The nmr spectra of several derivatives are reported and discussed. Use is made of this data to allow determination of the stereochemical integrity of the system. Facile chromatographic separation methods were found for endo- and exo-2-sub-stituted-7-oxabicyclo[2.2.1 ]hept-5-enes and -heptanes.

Evidence is presented confirming the formation of N-methyl-cis-bicyclo[2.2.2]octyl[2,3-d]-oxazolidine as the product of Eschweiler-Clarke reductive alkylation of cis-3-amino-bicyclo-[2.2.2]octan-2-ol.

Synthesis and opioid radioreceptor assay data on analogues closely related to 6-desoxy-6-spiro-alpha-methylene-gamma-lactone 5a, a compound with irreversible activity in this assay, are reported. Saturated lactones (7a,b), endocyclic alpha, beta-unsaturated gamma-lactones (8a,b and 9a), and 6 alpha,7 alpha-fused alpha-methylene-gamma-lactones (10a and 11a) were prepared. Related 6-desoxy-6-methylene 6 beta- and 6 alpha-oxides (12a,b and 13a) and glycidate esters 14a,b and 15a,b were also prepared with use of naltrexone (1a) and oxymorphone (1b) as starting material. Compounds in the N-cyclopropylmethyl (N-CPM) series were more potent than those in the N-Me series in displacing [3H]naltrexone in the opioid radioreceptor assay, usually by 2-16-fold in the absence of Na ion. The most potent N-CPM analogues were epoxides 12a and 13a and glycidate esters 14a and 15a, showing IC50's of 2-6 nM, similar to that of 5a. Of the N-Me analogues, 6 beta-oxide 12b was most active, with an IC50 of 8 nM in the absence of Na ion. For the N-CPM analogues, the Na ion ratios were generally less than 1, with two exceptions. The N-Me analogues showed expected larger Na ion effects of 7 or greater. None of the lactone analogues had irreversible effects when preincubated in the rat brain membrane preparation, even at 37 degrees C for 30 min, i.e., washing restored [3H]naltrexone binding to control levels. These results clearly show that the alpha-methylene-gamma-lactone moiety of 5a is required for irreversible effects, consistent with it serving as a conjugate addition acceptor of a nucleophilic group from a ligand at or near the receptor. The epoxides and glycidate esters also had no irreversible activity, indicating more electrophilic functional groups are needed and/or these electrophiles are not properly aligned to react with nucleophilic groups at or near the opioid receptor.

Reduction of 1 (verapamil) afforded amine 2, which was converted with thiophosgene to isothiocyanate 3, a chemoaffinity ligand for Ca2+ channels. Compound 3 showed concentration-dependent negative inotropic effects in rat right myocardial ventricular strips, EC50 = (4.56 +/- 3.40) X 10(-6) M (mean +/- SD), being slightly less potent than 4 (gallopamil), EC50 = (1.95 +/- 1.22) X 10(-6) M. It displaced [3H]gallopamil in rat myocardial membranes, IC50 = (3.42 +/- 2.51) X 10(-7) M, approximately equipotent with 1. It showed irreversible antagonism of [3H]gallopamil binding when preincubated at 10(-5) M; only 25% of [3H]gallopamil binding vs. control was observed. This agent may be a useful chemoaffinity ligand to aid in characterization of Ca2+ channels.

Two possible N-hydroxyamide metabolites of lidocaine were synthesized and characterized. A combined technique utilizing chemical-ionization mass spectrometry and stable isotope labeling demonstrated that these potentially carcinogenic N-hydroxyamides were neither present in human urine after oral lidocaine administration nor during intravenous infusion of lidocaine for the treatment of ventricular arrhythmias. However, small amounts of 2,6-dimethylphenylhydroxylamine were detected in the urine of all subjects. Mutagenesis assays using the Ames test showed that neither the N-hydroxyamides nor the N-hydroxyarylamine produced revertant colonies above background levels using the Salmonella tester strain TA-1538.

Six ring-fluorinated phenytoin analogs were synthesized, and their anticonvulsant activity in the maximal electroshock seizure and subcutaneous pentylenetetrazol assays was determined. 5-(4-Fluoro- phenyl)-5-phenylhydantoin, 5-(3-fluorophenyl)-5-phenylhydantoin, and 5,5-bis(4-fluorophenyl)hydantoin were active in the maximal electroshock seizure assay. The compounds were much less potent than phenytoin but showed an extremely long duration of action.

The 2R and 2S enantiomers of 4-isopropyl-2-(2-pyridyl)-2-phenylbutyramide [(2R)-2 and (2S)-2] were prepared from the respective 2R and 2S enantiomers of disopyramide [(2R)-1 and (2S)-1] by oxidation with peracid, Cope elimination, and subsequent zinc/HCl reduction of the resulting hydroxylamines (2R)-3 and (2S)-3. The enantiomers were tested as antagonists to the contraction of guinea pig ileum longitudinal muscle produced in response to electrically stimulated release of acetylcholine. The enantiomers showed IC50 values of 5.0 X 10(-6) and 14 X 10(-6) M for (2S)-2 and (2R)-2 respectively, about a 3-fold difference between enantiomers. Data are presented showing direct antagonism of acetylcholine in the guinea pig ileum assay. In a comparison of the anticholinergic effects of 2 and 1, the metabolite (2) was slightly less potent than disopyramide (1).

Amphetamine analogs 10(e)- and 10(a)-amino-1,2,3,4,4a,9,10,10a-(trans-4a,10a)-octahydrophenanthrene, I and II, respectively, were prepared. Hydrogenolysis (methanolic hydrochloric acid) of 9(a)-hydroxy-10(e)-amino-1,2,3,4,4a,9,10,10a-(trans-4a,10a)-octahydrophenanthrene afforded I. A similar procedure for the preparation of II from 9(a)-hydroxy-10(a)-amino-1,2,3,4,4a,9,10,10a-(trans,-4a,10a)-octahydrophenanthrene was followed, except the more drastic conditions of a mixture of acetic and perchloric acids were necessary. The compounds were inactive when assayed for amphetamine behavioral and hyperthermia effects.

Aus dem 1-Chlor-butin-carbamidat (I) erhalt man mit Dimethylamin und nachfolgender Quaternierung sowie spezifischer selektiver Hydrierung uber vergiftetem Pd das cis-Olefin (II).