7V-Demethylation

To clarify the mechanism of reaction of P-450, it is crucial to characterize the reactive intermediates in the rate-determining step. Definitive evidence for an electron-transfer mechanism (C in Scheme 2) for the 7V-demethylation of N,N-dimethylanilines has been obtained by direct observation of the reduction of the high-valent species responsible for P-450 catalysis [96]. For peroxidase, an oxoferryl porphyrin 7r-radical cation, compound I ([(P)Fe =0] "), has been well characterized as the species equivalent to the proposed active intermediate of P-450 [97-103]. Compound I of horseradish peroxidase (HRP) can be readily generated by chemical oxidation of HRP [100-103]. The involvement of the electron-transfer process of compound I in the oxidation of several amines catalyzed by HRP was... 

It would seem that the metabolism (7V-demethylation) of caffeine is markedly reduced by some quinolones (notably pipemidic acid and enoxacin) resulting in greater levels and possibly greater effects. Other quinolones... 

Tobacco smoke contains polycyclic hydrocarbons, which act as inducers of the cytochrome P450 isoenzyme CYP1A2, and this results in a more rapid clearance of theophylline from the body. Both the 7V-demethylation and 8-hydroxylation of theophylline is induced. Ageing appears to offset the effects of smoking on theophylline metabolism. ... 

Plant. In strawberries, diphenamide was transformed via 7V-demethylation yielding A-methyl-2,2-diphenylacetamide (Golab et al., 1966). 

Drug-drug iuteractious Oxycodone In 11 healthy subjects telithromycin clearly reduced the 7V-demethylation of oxycodone to noroxycodone by inhibiting CYP3A4 [108 ]. Thus, telithromycin may increase the risk of opioid adverse effects in patients taking multiple doses of oxycodone for pain relief it may be appropriate to reduce the dose of oxycodone by 25-50%, followed by readjustment according to clinical response. 

In our experience, the most potent inhibition of oxidative metabolism has been achieved using the plant growth regulator tetcyclasis (24). Metabolism of chlortoluron was inhibited by 80% and 94% in cell suspension cultures of maize and cotton, respectively, following a 24-h pretreatment with tetcyclasis at a concentration of 10 (Table 10.1), ABT and 2,4-dichlorophenoxypropyne (2,4-DP) being considerably less potent both ring-methyl oxidation and 7V-demethylation were similarly susceptible. ... 

Irradiation rraws-2-[3-(7V-methylamino)propyl] stilbene 89 results in the formation of 7V-methyl-l-benzyltetrahydro-2-benzazepine 90 as the only significant primary photoproduct (equation 26), which in turn undergoes secondary photochemical N-demethylation. The final mixture contains 90 (38%) and 91 (25%) at high (>95%) conversion. Intramolecular photoadditions of these (equations 24-26) secondary (aminoalkyl)-stilbenes are highly regioselective processes24. 

Administration of 3 -amino-3 -deoxy-A,ALdimethyladenosine (the amino-nucleoside of puromycin) to rats produces a nephrotic syndrome that is clinically indistinguishable from the nephrotic syndrome of unknown origin frequently observed in children [365]. Rats, monkeys, and humans are susceptible to this nephrotoxicity and susceptibility has been related to specie ability to demethylate the aminonucleoside [213]. 7V -Methyladenosine prevents development of this syndrome [365a]. 

The acid-catalyzed cyclization of properly substituted aminoacetaldehyde dialkyl acetals was shown to be a suitable method in the construction of a homo-isopavine (Scheme 39) (132a,172). Treatment of 7V-[l,3-bis(3,4-dimethoxy-phenyl)propyl]aminoacetaldehyde dimethyl acetal (175) with concentrated hydrochloric acid afforded the 7V-norhomoisopavine 176 in 39% yield. This cyclization was also accompanied by some O-demethylation. Product 176 could be readily N-methylated using formaldehyde and sodium borohydride to afford the homoisopavine ( )-177 (772). 

A similar approach was used to establish the biosynthetic pathway in Cocculus laurifolius of cocsulinine (31), the first triply bridged dimer to be so studied. (S)-7V-Methylcoclaurine proved to be the precursor for both halves of the alkaloid. O-Demethylation was shown to be the final step in the biogenesis by the demonstration of efficient incorporation of tritiated O-methylcocsulinine (pre-... 

With methyl-3-nitropyridine 7V-oxides, use of selenium dioxide results in complete oxidative demethylation (80TL2433). In isoquinoline methyl groups at positions 1 and 3 are efficiently oxidized to the corresponding aldehyde with selenium dioxide. 

Disposition in the Body. Readily absorbed after oral administration but undergoes extensive first-pass demethylation to desipramine which is the principal active metabolite. It is also metabolised by 7V-oxidation, hydroxylation, and conjugation and is excreted in the urine mainly as metabolites a second active metabolite, 2-hydroxydesipramine, has been reported to be the major unconjugated urinary metabolite. 

Evidence in favor of the electron-transfer mechanism has also come from studies on substrates such as Ai-ethyl-7V-methylaniline which show a demethylation/... 

To distinguish between paths A and B in Scheme 2, Dinnocenzo and coworkers [78-80] determined intramolecular isotope effects for deprotonation from the radical cations (path A) and for hydrogen-atom abstraction from a series of substituted 7V,A-dimethylanilines (path B) these were compared with isotope effects for N-demethylation of the same series of 7V,7V-dimethylanilines. The deprotonation iso-tope-effect profile for the radical cations of A, iV-dimethylanilines were determined by monitoring electron-transfer reactions from A, A -dimethylanilines to [Fe(phen)3] ... 

The rate of initial electron transfer from A,7V-dimethylaniline to [Fe(phen)3] + is diffusion-limited. This is followed by the rate-determining proton transfer from the radical cation to pyridine to give the deprotonated a-amino radical which is rapidly oxidized by a second equivalent of [Fe(phen)3] + to yield the product iminium ion. Kinetic isotope effects [kii/kjf) for the proton transfer were determined from the J3/tfo ratios of the products derived from p-substituted A-methyl-A-trideuteromethylanilines. The k /kx) value first increases and then decreases with increasing pAa of p-substituted A,A-dimethylaniline. Such a bell-shaped isotope effect profile is typical of proton-transfer reactions [82, 85]. The maximum kn/fco value is determined as 8.8 which is much larger than the corresponding value for the demethylation of the same substrate by cytochrome P-450 (2.6) [79]. 

For a synthetic P-450 model system, however, an opposite eonclusion was drawn from similar analysis of kinetic isotope effects for AT-demethylation of / -substituted iV,7V -dimethylanilines by PhIO, catalyzed by iron /Me5o-tetrakis(2,3,4,5,6-penta-fluorophenyl)porphyrin chloride, (TPFPP)FeCl [89]. Intramolecular /ch/Zcd values obtained from the d /do ratios of the products derived from 4-X-7V-methyl-A-tri-deuteromethylanilines [2.0 (X = NO2), 2.0 (X = CN), 2.6 (X = Br), 3.1 (X = H), 3.2 (X = Me), and 3.3 (X = OMe)], decreased regularly on going from electron-donating to electron-withdrawing substituents. Such a trend is the complete oppo-... 

Shono [25] pointed out that the microsomal oxidation of tertiary amines and amides occurs via the same intermediates as the anodic oxidation in methanol solution. The dealkylation of 7V-methyl-7V,7V-dialkyl amines by both methods results in almost the same A -demethylation/A/ -dealkylation ratio. This method has been used in the pharmaceutical industry for the easy supply of metabolites of pharmaceuticals. 

The levo isomers of 3-hydroxy-7V-methyl-morphinan and of methadone are demethylated by rat hver 2-3 times more rapidly than the corresponding dextro antipodes. The S(+)-enantiomer of hexobarbital (Figure 26.4) is metabohzed almost twice as rapidly as the R(-)-enantiomer by allylic hydroxylation and, in the dog, the dextrorotatory isomer of 5-ethyl-5-phenyl-hydantoin affords 10 times more para-hydroxy-metabolite than the levorotatory isomer. ° Hydroxylation takes place alpha to a carbonyl in the dextrorotary enantiomer of glutethimide whereas the levorotamer is hydroxylated on the methylene group of the ethyl side chain. Numerous other examples are found in the literature. ... 

Benzylamino-2-(trimethylsilylmethyl)-but-l-ene cyclizes in the presence of acid to afford the azepine (138) <86TL5067>, and 7V-benzyl-6-(phenylsulfinyl)-hexanamide reacts with O-methyl-O-t-butyldimethylsilyl ketene acetal to afford the lactam (139) <90CPB1473>. Direct irradiation of ortho-(A -methylaminoethyl)stilbene in acetonitrile affords Af-methyl-2-phenyl-2,3,4,5-tetrahydro-benz[primary product but which undergoes demethylation upon further irradiation <92TL4249>. The demethylated product may also be obtained by irradiation of o-(3-amino-n-propyl)stilbene in the presence of w-dicyanobenzene as electron transfer agent. 

Pyrolysis of tetrahydroprotoberberine methiodides is reported to yield, in addition to the expected iV-demethylation product, 13-methyl tetrahydroprotoberberine via migration of the 7V-methyl group to C-13. This rearranged product possesses a rm -quinolizidine system with the 13-methyl group occupying the axial position. (For the base-catalyzed rearrangement of iV-methyltetrahydroprotoberberine salts to spirobenzylisoquinolines, see Sec. 25.2.7.)... 

Derivatives of istamycin B, including its 3-O-demethyl and various 2 -A -acyI and 7V-amidinyl derivatives, have been prepared in the search for compounds less toxic than the parent. Further analogues of 1,6-anhydro methyl acarviosin have been synthesized, particularly 2 -substituted compounds (OH->NH2,F). ... 

Reduction of 126 with Red-Al, followed by subsequent 7V-methylation and 0-demethylation, led to the formation of (-l-)-aphanorphine 124 in 13% overall yield (Scheme 40.26). 

---