`Gisvold's Textbook of
`
`E D
`
`ORGANIC MEDICINAL
`AND PHARMACEUTICAL
`CHEMISTRY
`E L E V E N T H
`
`I T
`
`I
`
`0 N
`
`Edited by
`John H. Block, Ph.D., R.Ph.
`Professor of Medicinal Chemistry
`Department of Pharmaceutical Sciences
`College of Pharmacy
`Oregon State University
`Corvallis, Oregon
`
`John M. Beale, Jr., Ph.D.
`Associate Professor of Medicinal Chemistry and
`Director of Pharmaceutical Sciences
`St. Louis College of Pharmacy
`St. Louis, Missouri
`
`~t· LIPPINCOTT WILLIAMS & WILKINS
`
`•
`
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`Page 1 of 18
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`viewed for current information, including contraindications, dosages, a,n<L-e~;~wons.
`:~
`
`A
`
`Printed in the United States of America
`
`First Edition, 1949
`Second Edition, 1954
`Third Edition, 1956
`Fourth Edition, 1962
`
`Fifth Edition, 1966
`Sixth Edition, 1971
`Seventh Edition, 1977
`
`1 .. ;. .. ._.}_/
`
`.
`
`{;.~~
`Elghth E iO 1982
`\ \.) \.. ' \J
`Ninth Ed i~ 991\ ~ .;
`Tenth Ed iW, 98
`
`nn\~
`
`'-.,
`~""'"l(f}("''.:' ..
`,~·1.i:.~~y;:·
`
`Library of Congress Cataloging-in-Publication Data
`Wilson and Gisvold's textbook of organic medicinal and pharmaceutical c
`ed. I edited by John H. Block, John M. Beale Jr.
`p.; em.
`Includes bibliographical references and index.
`ISBN - 13:978-0-7817-3481-3
`ISBN - 10:0-7817-3481-9
`I. Pharmaceutical chemistry. 2. Chemistry, Organic. I. Title: Textbook of organic medicinal
`and pharmaceutical chemistry. II. Wilson, Charles Owens, 1911 - 2002 III. Gisvold, Ole,
`1904- IV. Block, John H. V. Beale, John Marlowe.
`[DNLM: I. Chemistry, Pharmaceutical. 2. Chemistry, Organic. QV 744 W754 2004]
`RS403. T43 2004
`615'.19- dc21
`
`2003048849
`
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`07
`5 6 7 8 9 10
`
`Page 2 of 18
`
`
`
`84 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`The stereochemistry of the hydroxylated centers in the two
`metabolites has not been clearly established. Biotransforma(cid:173)
`tion of the antihypertensive agent minoxidil (Loniten) yields
`the 4'-hydroxypiperidyl metabolite. In the dog, this product
`is a major urinary metabolite (29 to 47%), whereas in hu(cid:173)
`mans it is detected in small amounts (~3%). 157· l58
`
`Oxidation Involving carbon-Heteroatom
`Systems
`Nitrogen and oxygen functionalities are commonly found in
`most drugs and foreign compounds; sulfur functionalities
`occur only occasionally. Metabolic oxidation of carbon(cid:173)
`nitrogen, carbon-oxygen, and carbon-sulfur systems prin(cid:173)
`cipally involves two basic types of biotransformation
`processes:
`
`Where X= N.O.S
`
`Usually Unstable
`
`Oxidative N-, 0-, and S-dealkylation as well as oxidative
`deamination reactions fall under this mechanistic pathway.
`
`2. Hydroxylation or oxidation of the heteroatom (N, S only, e.g.,
`N-hydroxylation, N-oxide formation, sulfoxide, and sulfone for(cid:173)
`mation).
`
`I. Hydroxylation of the ex-carbon atom attached directly to the
`heteroatom (N, 0, S). The resulting intermediate is often un(cid:173)
`stable and decomposes with the cleavage of the carbon-hetero(cid:173)
`atom bond:
`
`Several structural features frequently determine which
`pathway will predominate, especially in carbon-nitrogen
`systems. Metabolism of some nitrogen-containing com(cid:173)
`pounds is complicated by the fact that carbon- or nitrogen-
`
`0
`o
`II
`CH,---<( ~-~NHCH,CH,-o-so,Ni'!C'NH~
`
`4
`
`Glipizide
`
`H
`
`~N
`
`Phencyclidine
`
`OH
`
`H
`
`4-Hydroxycyclohexyl
`Metabolite
`
`+HO~
`
`H
`
`4-Hydroxypiperidyl
`Metabolite
`
`4' -Hydroxyminoxid il
`
`Page 3 of 18
`
`
`
`Chapter 4 • Metabolic Changes of Drugs and Related Organic Compounds 85
`
`hydroxylated products may undergo secondary reactions to
`form other, more complex metabolic products (e.g., oxime,
`nitrone, nitroso, imino). Other oxidative processes that do
`not fall under these two basic categories are discussed indi(cid:173)
`vidually in the appropriate carbon-heteroatom section. The
`metabolism of carbon-nitrogen systems will be discussed
`first, followed by the metabolism of carbon-oxygen and
`carbon-sulfur systems.
`
`OXIDATION INVOLVING CARBON-NITROGEN SYSTEMS
`
`Metabolism of nitrogen functionalities (e.g., amines, am(cid:173)
`ides) is important because such functional groups are found
`in many natural products (e.g., morphine, cocaine, nicotine)
`and in numerous important drugs (e.g., phenothiazines, anti(cid:173)
`histamines, tricyclic antidepressants, ,8-adrenergic agents,
`sympathomimetic phenylethylamines, benzodiazepines). 159
`The following discussion divides nitrogen-containing com(cid:173)
`pounds into three basic classes:
`
`1. Aliphatic (primary, secondary, and tertiary) and alicyclic (sec(cid:173)
`ondary and tertiary) amines
`2. Aromatic and heterocyclic nitrogen compounds
`3. Amides
`
`The susceptibility of each class of these nitrogen com(cid:173)
`pounds to either a-carbon hydroxylation or N-oxidation and
`the metabolic products that are formed are discussed.
`The hepatic enzymes responsible for carrying out a-car(cid:173)
`bon hydroxylation reactions are the cytochrome P-450
`mixed-function oxidases. TheN-hydroxylation or N-oxida(cid:173)
`tion reactions, however, appear to be catalyzed not only by
`cytochrome P-450 but also by a second class of hepatic
`mixed-function oxidases called amine oxidases (some(cid:173)
`times called N-oxidases). 160 These enzymes are NADPH(cid:173)
`dependent flavoproteins and do not contain cytochrome
`P-450. 161 · 162 They require NADPH and molecular oxygen
`to carry out N-oxidation.
`
`Tertiary Aliphatic and Alicyclic Amines.
`The oxida(cid:173)
`tive removal of alkyl groups (particularly methyl groups)
`from tertiary aliphatic and alicyclic amines is carried out by
`hepatic cytochrome P-450 mixed-function oxidase enzymes.
`This reaction is commonly referred to as oxidative N-deal(cid:173)
`kylation.163 The initial step involves a-carbon hydroxylation
`to form a carbinolamine intermediate, which is unstable and
`undergoes spontaneous heterolytic cleavage of the C-N
`bond to give a secondary amine and a carbonyl moiety (aide-
`
`hyde or ketone). 164· 165 In general, small alkyl groups, such
`as methyl, ethyl, and isopropyl, are removed rapidly. 163 N(cid:173)
`dealkylation of the t-butyl group is not possible by the carbi(cid:173)
`nolamine pathway because a-carbon hydroxylation cannot
`occur. The first alkyl group from a tertiary amine is removed
`more rapidly than the second alkyl group. In some instances,
`bisdealkylation of the tertiary aliphatic amine to the corre(cid:173)
`sponding primary aliphatic amine occurs very slowly. 163 For
`example, the tertiary amine imipramine (Tofranil) is mono(cid:173)
`demethylated to desmethylimipramine (desipramine). 166· 167
`This major plasma metabolite is pharmacologically active
`in humans and contributes substantially to the antidepressant
`activity of the parent drug. 168 Very little of the bisdemethy(cid:173)
`lated metabolite of imipramine is detected. In contrast, the
`local anesthetic and antiarrhythmic agent lidocaine is metab(cid:173)
`olized extensively by N-deethylation to both monoethylgly(cid:173)
`cylxylidine and glycyl-2,6-xylidine in humans. 169· 170
`Numerous other tertiary aliphatic amine drugs are metabo(cid:173)
`lized principally by oxidative N-dealkylation. Some of these
`include the antiarrhythmic disopyramide (Norpace), 171 · 172
`the antiestrogenic agent tamoxifen (Nolvadex), 173 diphenhy(cid:173)
`dramine(Benadry 1),174· 175 chlorpromazine (Thorazine ),176
`and ( + )-a-propoxyphene (Darvon). 178 When the tertiary
`amine contains several different substituents capable of
`undergoing dealkylation, the smaller alkyl group is removed
`preferentially and more rapidly. For example, in benzphe(cid:173)
`tamine (Didrex), the methyl group is removed much more
`rapidly than the benzyl moiety. 179
`An interesting cyclization reaction occurs with methadone
`on N-demethylation. The demethylated metabolite normeth(cid:173)
`adone undergoes spontaneous cyclization to form the en(cid:173)
`amine metabolite 2-ethylidene-1 ,5-dimethyl-3,3-diphenyl(cid:173)
`pyrrolidine (EDDP). 180 Subsequent N-demethylation of
`EDDP and isomerization of the double bond leads to 2-ethyl-
`5-methyl-3,3-diphenyl-1-pyrroline (EMDP).
`Many times, bisdealkylation of a tertiary amine leads to
`the corresponding primary aliphatic amine metabolite, whiCh
`is susceptible to further oxidation. For example, the bisdes(cid:173)
`methyl metabolite of the H1-histamine antagonist bromphe(cid:173)
`niramine (Dimetane) undergoes oxidative deamination and
`further oxidation to the corresponding propionic acid metab(cid:173)
`olite.181 Oxidative deamination is discussed in greater detail
`when we examine the metabolic reactions of secondary and
`primary amines.
`Like their aliphatic counterparts, alicyclic tertiary amines
`are susceptible to oxidative N-dealkylation reactions. For
`example, the analgesic meperidine (Demerol) is metabolized
`
`177
`•
`
`H
`I
`R -N-C---.
`1
`I"'
`I
`R2
`
`Tertiary Amine
`
`Carbinolamine
`
`R -NH +
`I
`R2
`
`1
`
`Secondary
`Amine
`
`Carbonyl Moiety
`(aldehyde or
`ketone)
`
`Page 4 of 18
`
`
`
`86 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`0
`II
`HCH
`~
`
`Imipramine
`
`Desmethylimipramine
`(desipramine)
`
`Bisdesmethylimipramine
`
`CH3 0
`
`/CH2CH3
`
`CH3 0
`
`CH3CHO ;=\_ II
`CH3CHO A._ II
`~ ~NHCCH 2N........_H ~ 0:-" NHC-CH2NH 2
`
`Lidocaine
`
`CH 3
`Monoethylglycylxylidine
`(MEGX)
`
`N
`
`CONH
`2
`I
`
`2
`
`2
`
`.
`
`o- C-CH CH N/
`......... 6
`
`"""-
`
`Disopyramide
`
`CH 3
`I
`.......,. CH-CH
`3
`
`CH-CH3
`I
`CH 3
`
`CH 3
`Glycyl-2 ,6-xylidine
`
`Diphenhydramine
`
`Chlorpromazine
`
`( + )-a-Propoxyphene
`
`Benzphetamine
`(N-demethylation
`and N-debenzylation)
`
`principally by this pathway to yield normeperidine as a major
`plasma metabolite in humans. 182 Morphine, N-ethylnormor(cid:173)
`phine, and dextromethorphan also undergo some N-dealkyl(cid:173)
`ation.183
`Direct N-dealkylation of t-butyl groups, as discussed
`above, is not possible by the a-carbon hydroxylation path(cid:173)
`way. In vitro studies indicate, however, that N-t-butylnor-
`
`to significant
`indeed, metabolized
`chlorocyclizine. is,
`amounts of norchlorocyclizine, whereby the t-butyl group
`is lost. 184 Careful studies showed that the t-butyl group is
`removed by initial hydroxylation of one of the methyl groups
`of the t-butyl moiety to the carbinol or alcohol product. 185
`Further oxidation generates the corresponding carboxylic .
`acid that, on decarboxylation, forms theN-isopropyl deriva-
`
`Page 5 of 18
`
`
`
`Chapter 4 • Metabolic Changes of Drugs and Related Organic Compounds 87
`
`Methadone
`
`Normethadone
`
`;fc6Hs
`A~.~CHCH3
`CH 3 ~1
`CH 3
`2-Ethylidene-1 ,5-dimethyl-
`3,3-diphenylpyrrolidine
`(EDDP)
`
`~C6Hs
`A. ,.)--cH2CH3
`
`CH3 N
`2-Ethyl-5-methyl-
`3,3-diphenyl-1-pyrroline
`(EMDP)
`
`y
`
`y
`
`~ Br-o-CHCH 2 COOH
`~ Br-o-CHCH 2CH 2NH 2 ~
`
`Brompheniramine
`
`Bisdesmethyl Metabolite
`
`3- ( p-Bromophenyl) -3-pyridyl(cid:173)
`propionic acid
`
`tive. TheN-isopropyl intermediate is dealkylated by the nor(cid:173)
`mal a-carbon hydroxylation (i.e., carbinolamine) pathway
`to give norchlorocyclizine and acetone. Whether this is a
`general method for the loss of t-butyl groups from amines
`is still unclear. Indirect N-dealkylation oft-butyl groups is
`not observed significantly. The N-t-butyl group present in
`many {3-adrenergic antagonists, such as terbutaline and sal(cid:173)
`butamol, remains intact and does not appear to undergo any
`significant metabolism. 186
`HOOOCH,CH,
`~ HOOOCH,CH,
`
`I
`CH 3
`Meperidine
`
`H
`
`Normeperidine
`
`Alicyclic tertiary amines often generate lactam metabo(cid:173)
`lites by a-carbon hydroxylation reactions. For example,
`the tobacco alkaloid nicotine is hydroxylated initially at the
`ring carbon atom a to the nitrogen to yield a carbinolamine
`intermediate. Furthermore, enzymatic oxidation of this
`cyclic carbinolarnine generates the lactam metabolite coti(cid:173)
`nine.I87. 188
`Formation of lactam metabolites also has been reported to
`occur to a minor extent for the antihistamine cyproheptadine
`(Periactin) 189· 190 and the antiemetic diphenidol (Vontrol). 191
`N-oxidation of tertiary amines occurs with several
`drugs. 192 The true extent of N-oxide formation often is com(cid:173)
`plicated by the susceptibility of N-oxides to undergo in vivo
`reduction back to the parent tertiary amine. Tertiary amines
`such as H1-histamine antagonists (e.g., orphenadrine, tripe(cid:173)
`lenamine), phenothiazines (e.g., chlorpromazine), tricyclic
`antidepressants (e.g., imipramine), and narcotic analgesics
`(e.g., morphine, codeine, and meperidine) reportedly form
`N-oxide products. In some instances, N-oxides possess phar(cid:173)
`macological activity. 193 A comparison of imipramine N(cid:173)
`oxide with imipramine indicates that the N-oxide itself pos(cid:173)
`sesses antidepressant and cardiovascular activity similar to
`that of the parent drug. 194· 195
`
`CH 30
`R = CH 3
`Morphine
`N-Ethylnormorphine R = CH 2CH 3
`
`CH 30
`Dextromethorphan
`
`Secondary and Primary Amines.
`Secondary amines
`(either parent compounds or metabolites) are susceptible to
`oxidative N-dealkylation, oxidative deamination, and N-oxi(cid:173)
`dation reactions: 163· 196 As in tertiary amines, N-dealkylation
`of secondary amines proceeds by the carbinolamine path-
`
`Page 6 of 18
`
`
`
`88 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`N-t-Butylnorchlorocyclizine
`
`1
`
`N-deisopropylation by
`a-carbon hyroxylation
`; (
`, carbinolamine pathway)
`
`Alcohol or Carbinol
`
`Carboxylic Acid
`
`N-lsopropyl Metabolite
`
`OH
`I_;H
`HOCDH2 c
`~ 'cH
`'- I
`I 2
`CH 3
`NH
`'c/
`I'CH
`3
`CH
`3
`
`HO
`
`Salbutamol
`
`Terbutaline
`
`[o-YaH1 Oxidation o~~
`
`~
`
`N
`
`CH 3
`
`N
`
`I
`CH 3
`
`o--o
`
`I
`CH 3
`N
`Nicotine
`
`Carbinol amine
`
`Cotinine
`
`OH
`
`Cyproheptadine
`
`Lactam Metabolite
`
`Diphenidol
`
`Page 7 of 18
`
`
`
`Chapter 4 • Metabolic Changes of Drugs and Related Organic Compounds 89
`
`H
`I
`-c~
`I
`NH 2
`
`a·Carbon
`
`I
`
`/H
`
`9J
`0
`II
`hydroxylation -c- --- -c- + NH 3
`I
`(NH 2
`
`way. Dealkylation of secondary amines. gives rise to the cor(cid:173)
`responding primary amine metabolite. For example, the a(cid:173)
`adrenergic blockers propranolol46· 47 and oxprenolol 197
`undergo N-deisopropylation to the corresponding primary
`amines. N-dealkylation appears to be a significant biotrans(cid:173)
`formation pathway for the secondary amine drugs metham(cid:173)
`phetamine198· 199 and ketamine,200· 201 yielding amphetamine
`and norketamine, respectively.
`The primary amine metabolites formed from oxidative
`dealkylation are susceptible to oxidative deamination. This
`process is similar to N-dealkylation, in that it involves an
`initial a-carbon hydroxylation reaction to form a carbino(cid:173)
`lamine intermediate, which then undergoes subsequent car(cid:173)
`bon-nitrogen cleavage to the carbonyl metabolite and am(cid:173)
`monia. If a-carbon hydroxylation cannot occur,
`then
`oxidative deamination is not possible. For example, deami(cid:173)
`nation does not occur for norketamine because a-carbon hy(cid:173)
`droxylation cannot take place. 200· 201 With methampheta(cid:173)
`mine, oxidative deamination of primary amine metabolite
`amphetamine produces phenylacetone. 198. 199
`In general, dealkylation of secondary amines is believed
`to occur before oxidative deamination. Some evidence indi(cid:173)
`cates, however, that this may not always be true. Direct de(cid:173)
`amination of the secondary amine also has occurred. For
`example, in addition to undergoing deamination through its
`desisopropyl primary amine metabolite, propranolol can
`undergo a direct oxidative deamination reaction (also by a(cid:173)
`carbon hydroxylation) to yield the aldehyde metabolite and
`isopropylamine (Fig. 4-9).202 How much direct oxidative de(cid:173)
`amination contributes to
`the metabolism of secondary
`amines remains unclear.
`
`Primary Amine
`
`Carbinolamine
`
`Carbonyl Ammonia
`
`Some secondary alicyclic amines, like their tertiary amine
`analogues, are metabolized to their corresponding lactam
`derivatives. For example, the anorectic agent phenmetrazine
`(Preludin) is metabolized principally to the lactam product
`3-oxophenmetrazine.203 In humans, this lactam metabolite
`is a major urinary product. Methylphenidate (Ritalin) also
`reportedly yields a lactam metabolite, 6-oxoritalinic acid,
`by oxidation of its hydrolyzed metabolite, ritalinic acid, in
`humans.204
`Metabolic N-oxidation of secondary aliphatic and alicy(cid:173)
`clic amines leads to several N-oxygenated products. 196 N(cid:173)
`hydroxylation of secondary amines generates the corre(cid:173)
`sponding N-hydroxylamine metabolites. Often, these hy(cid:173)
`droxylamine products are susceptible to further oxidation
`(either spontaneous or enzymatic) to the corresponding ni(cid:173)
`trone derivatives. N-benzylamphetamine undergoes metabo(cid:173)
`lism to both the corresponding N-hydroxylamine and the
`nitrone metabolites.205 In humans, the nitrone metabolite of
`phenmetrazine (Preludin), found in the urine, is believed
`to be formed by further oxidation of the N-hydroxylamine
`intermediate N-hydroxyphenmetrazine.203
`Importantly,
`
`Propranolol
`
`Oxprenolol
`
`Methamphetamine
`
`Amphetamine
`
`Phenylacetone
`
`Ketamine
`
`Norketamine
`
`Page 8 of 18
`
`
`
`90 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`Direcl
`Oxidative
`Deamination
`
`H2N-<
`t
`
`Propranolol
`
`1
`
`Carbinolamine
`
`Afdehyde Metabolite
`
`NH3
`t / Oxidative
`
`/
`
`Deamination
`Through Primary Amine
`
`OH
`I
`/CH
`
`0
`
`cxSCH 'CH
`
`2
`
`I 2
`NH 2
`
`/
`Primary Amine Metabolite
`(Desisopropyt Propranolol}
`
`Carbinolamine
`Figure 4-9 • Metabolism of propranolol to its aldehyde metabolite by direct deamination of the parent
`compound and by deamination of its primary amine metabolite, desisopropyl propranolol.
`
`1
`HsC6 0
`
`XNJ: -
`
`CH3 H
`
`[~'c}:),o~ l HsC6 0
`- ]),0
`
`CH3 H
`
`3 H
`3-0xophenmetrazine
`
`Phenmetrazine
`
`Carbinolamine
`Intermediate
`
`Hydrolysis
`
`Methylphenidate
`
`Ritalinic Acid
`
`6-0xoritalinic Acid
`
`much less N-oxidation occurs for secondary amines than
`oxidative dealkylation and deamination.
`
`-NH - -N - -N
`
`OH
`I
`\
`CH 3
`Hydroxylamine
`
`\
`CH3
`Secondary amine
`
`o-
`+I
`\
`CH 2
`Nitrone
`
`Primary aliphatic amines (whether parent drugs or metab-
`
`olites) are biotransformed by oxidative deamination
`(through the carbinolamine pathway) or by N-oxidation. In
`general, oxidative deamination of most exogenous primary
`amines is carried out by the mixed-function oxidases dis(cid:173)
`cussed above. Endogenous primary amines (e.g., dopamine,
`norepinephrine, tryptamine, and serotonin) and xenobiotics
`based on the structures of these endogenous neurotransmit(cid:173)
`ters are metabolized, however, via oxidative deamination by
`a specialized family of enzymes called monoamine oxidases
`(MA0s).206
`
`Page 9 of 18
`
`
`
`Chapter 4 • Metabolic Changes of Drugs and Related Organic Compounds
`
`91
`
`MAO is a flavin (FAD)-dependent enzyme found in two
`isozyme forms, MAO-A and MAO-B, and widely distrib(cid:173)
`uted in both the CNS and peripheral organs. In contrast,
`·cytochrome P-450 exists in a wide variety of isozyme forms
`and is an NADP-dependent system. Also the greatest variety
`of CYP isozymes, at least the ones associated with the me(cid:173)
`tabolism of xenobiotics, are found mostly in the liver and
`intestinal mucosa. MAO-A and MAO-B are coded by two
`genes, both on the X-chromosome and have about 70%
`amino acid sequence homology. Another difference between
`the CYP and MAO families is cellular location. CYP en(cid:173)
`zymes are found on the endoplasmic reticulum of the cell's
`cytosol, whereas the MAO enzymes are on the outer mito(cid:173)
`chondrial membrane. In addition to the xenobiotics illus(cid:173)
`trated in the reaction schemes, other drugs metabolized by
`the MAO system include phenylephrine, propranolol, timo(cid:173)
`lol and other ,8-adrenergic agonists and antagonists and a
`variety of phenylethylamines.Z06
`Structural features, especially the a substituents of the
`
`primary amine, often determine whether carbon or nitrogen
`oxidation will occur. For example, compare amphetamine
`with its a-methyl homologue phentermine. In amphetamine,
`a-carbon hydroxylation can occur to form the carbinolamine
`intermediate, which is converted to the oxidatively deami(cid:173)
`nated product phenylacetone.67 With phentermine, a-carbon
`hydroxylation is not possible and precludes oxidative deami(cid:173)
`nation for this drug. Consequently, phentermine would be
`expected to undergo N-oxidation readily. In humans, p-hy(cid:173)
`droxylation and N-oxidation are the main pathways for bio(cid:173)
`transformation of phentermine. 207
`Indeed, N-hydroxyphentermine is an important (5%) uri(cid:173)
`nary metabolite in humans.207 As discussed below, N-hy(cid:173)
`droxylamine metabolites are susceptible to further oxidation
`to yield other N-oxygenated products.
`Xenobiotics, such as the hallucinogenic agents mesca(cid:173)
`Iine208· 209 and 1-(2,5-dimethoxy-4-methylphenyl)-2-amino(cid:173)
`propane (DOM or "STP"),210· 211 are oxidatively deami(cid:173)
`nated. Primary amine metabolites arising
`from N-
`
`-
`
`( )
`
`CH 2 _.......CH 3
`'-....CH
`I
`_.......N ........
`HO
`
`CH 2C6 H5
`Hydroxylamine
`Metabolite
`
`Nitrone
`Metabolite
`
`H5Ce 0
`
`XN)--
`
`CH3 H
`Phenmetrazine
`
`H5Ce 0
`
`XN)
`CH3 I
`OH
`N-Hydroxyphenmetrazine
`
`-
`
`H5Ce 0
`
`XN)
`CH3 I.
`o-
`Nitrone
`Metabolite
`
`( )
`
`H
`CH 2 ;
`'-..., C _ CH
`a-Carbon
`al
`3 Hydroxylation
`NH 2
`Amphetamine
`
`Carbinolamine
`
`Phenylacetone
`
`CH CH3
`
`~ ........ <!-cH
`v
`al
`NH 2
`Phentermine
`
`3
`
`a-Carbon hydroxylation not possible; hence,
`~ do not see oxidative deamination
`
`~•tioo
`
`p-Hydroxyphentermine
`
`CH CH3
`
`~'-....?-CH3
`v
`
`NH
`'-.... OH
`N-Hydroxyphentermine
`
`Page 10 of 18
`
`
`
`92 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`OCH 3
`
`;yc.!:l?H CH,
`C~ NH2
`
`OCH 3
`1-(2 ,5-Dimethoxy-4-methylpheny\)-
`2-aminopropane
`DOM or "STP"
`
`CH ~CH3
`yY "c-H
`co2 HO
`;
`Enzymatid ~ I
`HO
`NH2
`S( + )-a-Methyldopamine
`
`Oxidative
`Deamination
`
`3,4-Dihydroxypheny\acetone
`
`dealkylation or decarboxylation reactions also undergo de(cid:173)
`amination. The example of the bisdesmethyl primary amine
`metabolite derived from bromopheniramine is discussed
`above (see section on tertiary aliphatic and alicyclic
`amines).181 In addition, many tertiary aliphatic amines (e.g.,
`antihistamines) and secondary aliphatic amines (e.g., pro(cid:173)
`pranolol) are dealkylated to their corresponding primary
`amine metabolites, which are amenable to oxidative deami(cid:173)
`nation. (S)( + )-a-Methyldopamine resulting from decarbox(cid:173)
`ylation of the antihypertensive agent (S)(-)-a-methyldopa
`(Aldomet) is deaminated to the corresponding ketone metab(cid:173)
`olite 3,4-dihydroxyphenylacetone.212 In humans, this ketone
`is a major urinary metabolite.
`TheN-hydroxylation reaction is not restricted to a-substi(cid:173)
`tuted primary amines such as phentermine. Amphetamine
`has been observed to undergo some N-hydroxylation in vitro
`to N-hydroxyamphetamine.213· 214 N-Hydroxyamphetamine
`is, however, susceptible to further conversion to the imine
`or oxidation to the oxime intermediate. Note that the oxime
`intermediate arising from this N-oxidation pathway can
`undergo hydrolytic cleavage to yield phenylacetone, the
`same product obtained by the a-carbon hydroxylation (carbi-
`
`nolamine) pathway.215· 216 Thus, amphetamine may be con(cid:173)
`verted to phenylacetone through either the a-carbon hydrox(cid:173)
`ylation or theN-oxidation pathway. The debate concerning
`the relative importance of the two pathways is ongo(cid:173)
`ing.217-219 The consensus, however, is that both metabolic
`pathways (carbon and nitrogen oxidation) are probably oper(cid:173)
`ative. Whether a-carbon or nitrogen oxidation predominates
`in the metabolism of amphetamine appears to be species
`dependent.
`In primary aliphatic amines, such as phentermine,207
`chlorphentermine (p-chlorphentermine),219 and amanta(cid:173)
`dine,220 N-oxidation appears to be the major biotransforma(cid:173)
`tion pathway because a-carbon hydroxylation cannot occur.
`In humans, chlorphentermine is N-hydroxylated extensively.
`About 30% of a dose of chlorphentermine is found in the
`urine (48 hours) as N-hydroxychlorphentermine (free and
`conjugated) and an additional 18% as other products of N(cid:173)
`oxidation (presumably the nitroso and nitro metabolites).219
`In general, N-hydroxylamines are chemically unstable and
`susceptible to spontaneous or enzymatic oxidation to the
`nitroso and nitro derivatives. For example, the N-hydroxyl(cid:173)
`amine metabolite of phentermine undergoes further oxida-
`
`Amphetamine
`
`N-Hydroxyamphetamine
`
`Imine
`
`Pheny\acetone
`
`Oxime
`
`Page 11 of 18
`
`
`
`Chapter 4 • Metabolic Changes of Drugs and Related Organic Compounds 93
`
`to the nitroso and nitro products.207 The antiviral and
`mu.~~~"""'"'""'ian agent amantadine (Symmetrel) reportedly
`--·"a•nr.l'•~ N-oxidation to yield the corresponding N-hy(cid:173)
`and nitroso metabolites in vitro.220
`
`mm1m.arnc Amines and Heterocyclic Nitrogen Com(cid:173)
`The biotransformation of aromatic amines
`the carbon and nitrogen oxidation reactions seen
`aliphatic amines.221 -223 For tertiary aromatic amines,
`as N,N-dimethylaniline, oxidative N-dealkylation as
`as N-o xi de formation take place. 224 Secondary aro(cid:173)
`amines may undergo N-dealkylation or N-hydroxyla-
`to give the corresponding N-hydroxylamines. Further
`wuctat10n of theN-hydroxylamine leads to nitrone products,
`in turn may be hydrolyzed to primary hydroxyl-
`225 Tertiary and secondary aromatic amines are
`1nc,om1te:red rarely in medicinal agents. In contrast, primary
`amines are found in many drugs and are often
`[enerated from enzymatic reduction of aromatic nitro com(cid:173)
`reductive cleavage of azo compounds, and hydrol-
`of aromatic amides.
`N-oxidation of primary aromatic amines generates the N(cid:173)
`ua.uu''"' metabolite. One such case is aniline, which
`'' ll''"'auu•·•"'"'u to the corresponding N-hydroxy product.223
`lli<lati:on of the hydroxylamine derivative to the nitroso
`ve also can occur. When one considers primary arc(cid:173)
`amine drugs or metabolites, N-oxidation constitutes
`a minor pathway in comparison with other biotransfor(cid:173)
`pathways, such as N-acetylation and aromatic by(cid:173)
`in humans. Some N-oxygenated metabolites
`been reported, however. For example, the antileprotic
`dapsone and its N-acetylated metabolite are metabo(cid:173)
`significantly to their corresponding N-hydroxylamine
`·ves.226 TheN-hydroxy metabolites are further conju(cid:173)
`with glucuronic acid.
`Methemoglobinemia toxicity is caused by several aro(cid:173)
`amines, including aniline and dapsone, and is a result
`the bioconversion of the aromatic amine to its N-hydroxy
`
`derivative. Apparently, the N-hydroxylamine oxidizes the
`Fe2+ form of hemoglobin to its Fe3+ form. This oxidized
`(Fe3+) state of hemoglobin (called methemoglobin or ferri(cid:173)
`hemoglobin) can no longer transport oxygen, which leads
`to serious hypoxia or anemia, a unique type of chemical
`suffocation. 227
`Diverse aromatic amines (especially azoamino dyes) are
`known to be carcinogenic. N-oxidation plays an important
`role in bioactivating these aromatic amines to potentially
`reactive electrophilic species that covalently bind to cellular
`protein, DNA, or RNA A well-studied example is the car(cid:173)
`cinogenic agent N-methyl-4-aminoazobenzene.228· 229 N-ox(cid:173)
`idation of this compound leads to the corresponding hydrox(cid:173)
`ylamine, which undergoes sulfate conjugation. Because of
`the good leaving-group ability of the sulfate csoi-) anion,
`this conjugate can ionize spontaneously to form a highly
`reactive, resonance-stabilized nitrenium species. Covalent
`adducts between this species and DNA, RNA, and proteins
`have been characterized. 230· 231 The sulfate ester is believed
`to be the ultimate carcinogenic species. Thus, the example
`indicates that certain aromatic amines can be bioactivated
`to reactive intermediates by N-hydroxylation and 0-sulfate
`conjugation. Whether primary hydroxylamines can be bioac(cid:173)
`tivated similarly is unclear. In addition, it is not known if
`this biotoxification pathway plays any substantial role in the
`to.xicity of aromatic amine drugs.
`N-oxidation of the nitrogen atoms present in aromatic het(cid:173)
`erocyclic moieties of many drugs occurs to a minor extent.
`Clearly, in humans, N-oxidation of the folic acid antagonist
`trimethoprim (Proloprim, Trimpex) has yielded approxi(cid:173)
`mately equal amounts of the isomeric I-N-oxide and 3-N(cid:173)
`oxide as minor metabolites.232 The pyridinyl nitrogen atom
`present in nicotinine (the major metabolite of nicotine)
`undergoes oxidation to yield the corresponding N-oxide me(cid:173)
`tabolite.233 Another therapeutic agent that has been observed
`to undergo formation of ari N-oxide metabolite is metronida(cid:173)
`zole.234
`
`Amantadine
`
`Chlorphentermine
`
`N-Hydroxychlorphentermine
`
`Nitroso Metabolite
`
`Nitro Metabolite
`
`Hydroxylamine
`
`Nitroso
`
`Nitro
`
`Page 12 of 18
`
`
`
`94 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`N-oxidation
`
`o- /CH 3
`
`N-Oxide
`
`N,
`CH3
`Carbon
`Tertiary Aromatic ~ ~;d-;;;~lation
`~
`Amine
`
`Carbinolamine
`
`Secondary
`Aromatic Amines
`
`Hydroxylamine
`(secondary)
`
`Nitrone
`
`Hydroxylamine
`(primary)
`
`NHOH
`
`N=O
`
`6 =6
`
`Hydroxylamine
`
`Nitroso
`
`Aniline
`(primary
`aromatic
`amine)
`
`RNH-o-S0 2 -o-NH 2 ---->RNH-o-80 2 -o-NHOH
`
`R = H
`Dapsone
`N-Acetyldapsone R = CCH 3
`II
`0
`
`N-Hydroxydapsone
`
`N-Acetyi-N -hydroxydapsone
`
`R=H
`· 0
`II
`R = CCH 3
`
`OH~o
`r
`
`N
`
`I
`CH 3
`
`Cotinine
`
`Metronidazole
`2-( 2-Methyl-5-nitro-imidazol- 1-yl )-ethanol
`
`Amides.
`Amide functionalities are susceptible to oxida(cid:173)
`tive carbon-nitrogen bond cleavage (via a-carbon hydroxyl(cid:173)
`ation) and N-hydroxylation reactions. Oxidative dealkyl(cid:173)
`ation of many N-substituted amide drugs and xenobiotics
`has been reported. Mechanistically, oxidative dealkylation
`proceeds via an initially formed carbinolamide, which is un(cid:173)
`stable and fragments to form the N-dealkylated product. For
`example, diazepam undergoes extensive N-demethylation to
`the pharmacologically active metabolite desmethyldi(cid:173)
`azepam? 35
`Various other N-alkyl substituents present in benzodiaze(cid:173)
`pines (e.g., flurazepam) 136- 138 and in barbiturates (e.g., hex(cid:173)
`obarbital and mephobarbital) 128 are similarly oxidatively N(cid:173)
`dealkylated. Alkyl groups attached to the amide moiety of
`some sulfonylureas, such as the oral hypoglycemic chlor(cid:173)
`propamide,236 also are subject to dealkylation to a minor
`extent.
`In the cyclic am ides or lactams, hydroxylation of the alicy-
`
`Page 13 of 18
`
`
`
`Chapter 4 • Metabolic Changes of Drugs and Related Organic Compounds 95
`
`CH 3
`
`I UNH
`
`C6H5N=N
`N-Methyl-4-aminoazobenzene
`
`Hydr