Desmethyl derivative

The sesquiterpene (+)-asteriscanolide 1 was first isolated from Asteriscus aquaticus L and characterized by San Feliciano in 1985.1 It has captured the attention of organic chemists mainly because of its uncommon bicyclo[6.3.0]undecane ring system bridged by a butyrolactone fragment. The only prior enantioselective synthesis of 1 has been described by Wender in 1988 featuring an Ni(0)-promoted [4 + 4]-cycloaddition.2 Booker-Milburn and co-workers described the sequential application of intramolecular [2 + 2]-photocycloaddition, Curtius rearrangement, and oxidative fragmentation to produce the 7-desmethyl derivative in 1997.3... 

Demethylation of trequinsin (3) with a 65 35 mixture of AcOH and 48% HBr at 115 °C for 3 h gave mainly 10-hydroxyl derivatives 148 (R = r = H), which was accompanied by traces of its 9-hydroxyl and 9,10-dihydroxy derivatives. In boiling 48% HBr for 2 h its 9,10-dihydroxy derivative formed in 63% yield (98IJC(B)1). 9-Methoxy group of 3 and that of its 2-[(2,6-dimethyl-4-carboxyphenyl)imino] derivative 178 (R = COOH) was selectively demethylated by the treatment with 60% NaOH and EtSH in HMPA. Treatment of 3 with pyridine HCl in boiling pyridine for 20 min afforded its 9,10-dihydroxy-3-desmethyl derivative in 65% yield. 4 -Hydroxymethyl... 

The optically active (2,5-dimethyl-6-fluorotetrahydroquinolin-l-yl)-methylenemalonates (131) were prepared in the reactions of optically active enantiomers of 2,5-dimethyl-6-fluorotetrahydroquinoline and EMME at 135-140°C for 1 hr (87JMC839). In a similar way, the 2-desmethyl derivative of 131 was prepared. 

Nuvole et al. stated that the cyclization of 974 and its desmethyl derivative gave tautomeric 9-hydroxy-1,2,3-triazolo[4,5-/]quinoline-8-carboxyl-ates (e.g., 975) or 9-oxo-6,9-dihydro-l,2,3-triazolo[4,5-/]quinoline-8-car-boxylates (e.g., 976, depending on the cyclization conditions (in xylene on the action of polyphosphoric acid (PPA) vs. in DMF on the action of PPA and in Dowtherm A under boiling vs. in polyphosphate (89FES609, 89FES619). 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

Pharmacokinetic properties Hydrocodone is metabolized by CYP2D6 to the O-desmethyl derivative hydromorphone (Otton et al., 1993). Further steps of metabolization include N-demethylation and glucuronidation. 

Pharmacokinetic properties About 40% of the drug is absorbed from the intestinal tract but nearly completely inactivated by first pass metabolism in the liver (Killinger et al., 1979). The main metabolites are N-desmethyl-loperamide and the di-desmethyl derivative (Yoshida et al., 1979). The elimination half life is about 10 h. 

Dihydro-5,6-dihydroxyconessine has been prepared by the action of aqueous nitrous acid on conessine (7a).7 Treatment of conessine with BrCN yields the 7V-cyano-iV-desmethyl derivative (7b).8 The latter has been converted (by standard methods) into derivatives (7c), (7d), and (7e).9... 

Animals. More than 90% excreted in urine and feces within 48 hr the major excreted metabolite was the O-desmethyl derivative. 

Turning now to derivatives with substituents adjacent to nitrogen, the racemic a-and /3-2-methyl-reversed esters prove to have similar activities (in contrast to the prodine diastereoisomers) and are somewhat less potent than the parent desmethyl derivative (see 17)/23 The /3-2-methylpropionate, with... 

Disposition in the Body. Slowly but completely absorbed following oral administration. It appears to undergo significant first-pass metabolism bioavailability about 70%. After intravenous administration, about 57% of a dose is excreted in the urine and 30% in the faeces over a period of 21 days less than 10% of the dose is excreted as unchanged drug. The principal metabolite is the desmethyl derivative, which has been shown to be active in animals, but hydroxylation also occurs to form phenolic derivatives which may be further converted to aromatic methoxy ethers or excreted as glucuronide conjugates A -oxidation also occurs and maprotiline A -oxide has been reported to be active numerous minor metabolites have been identified in urine. 

Disposition in the Body. Rapidly absorbed after oral administration and metabolised to the active A-desmethyl derivative. 

Disposition in the Body. Readily absorbed after oral administration and rapidly metabolised to the A -desmethyl derivative, which is active. About 27% of a dose is excreted in the urine in 48 hours, mostly as 4 -hydroxyphensuximide and its conjugate. 

The major alkaloid of these plants is cassythicine (XXX). The N-desmethyl derivative was also present in trace amounts. It is identical with actinodaphnine (45). 

It may be prepared by the aeetylation of oxymorphone to give 3,6-diacetate derivative which on treatment with cyanogen bromide yields the desmethyl derivative.This on hydrolysis, followd by alkylation with allyl bromide and finally treating with hydrochlorie aeid forms the official compound. 

A -Desmethyl derivatives 240-246 of RA-VII (166) were synthesized and evaluated using L1210 cells 168). Analogs 242, 2, 245, and 246 were found to be biologically inactive (IQo >10 /x.g/ml), whereas 240 and 241 were essentially equipotent with 166 (0.0007-0.002 /u.g/ml). ID and 2D H-NMR studies of these analogs revealed the role of N-methylation in the... 

Constitution. Frerichs and Stoepel (267, 268) had already shown that when berberine hydrochloride is heated with urea to 200° it loses one methoxyl group to yield a product to which they ascribed the name ber-berrubine and which they regarded as the 9-0-desmethyl derivative of berberine. Spath and Burger (232) showed that the free hydroxyl was as mooted and that tetrahydroberberrubine (m.p. 167°) has structure LXVII. 

To date there have been found only cularine and several of its 0- or N-desmethyl derivatives. The unique feature of this group is the presence of a seven-membered heterocycle containing an oxygen atom in a diphenyl ether linkage. The known occurrence of these alkaloids is restricted to the genera Dicentra and Corydalis. 

Most of the mescalin dose is excreted unchanged in the urine, but considerable amounts of 3,4,5-trimethoxyacetic acid are also present. The other products in urine, mainly N-acetylated O-desmethyl derivatives, are present in smaller quantities. 

After consumption of p-methoxyamphetamine (PMA), more than 80% of the amount of substance taken is excreted within a day via the urine, up to 15% unchanged, >25% in the form of the free 4-hydroxyamphetamine, and ca. 50% as conjugated 4-hydroxyamphetamine. The remainder, in analogy to amphetamine, is further metabolized [44]. In analogy to PMA, TMA undergoes a demethylation to form mono- and di-O-desmethyl derivatives. In methoxyamphetamines, two methoxy groups are located in the para position (DOB, DOM), so that demethylation to hydroquinone is also possible [51]. 

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