Wilson and
`Gisvold's Textbook of
`
`ORGANIC MEDICINAL
`AND PHARMACEUTICAL
`CHEMISTRY
`E L E V E N T H ED IT ION
`
`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
`
`•
`
`•
`
`LIPPINCOTT WILLIAMS & WILKINS
`A Wolters Kluwer Company
`Philadelphia • Baltimore • New York • London
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`
`SENJU EXHIBIT 2078
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`
`Page 1 of 18
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`

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`-
`viewed for current information, including contraindications, dosages, an1Lor~cllutions .
`•
`'V •.
`~ -~· /
`,.._ ·~> ~
`n~>\~
`,..~
`\\.)\.. t.U
`Eighth E iO 1982
`Ninth Ed i~~P~ 991\ ~ .}
`Tenth Ed iW,
`8
`
`Printed in the United States of America
`
`First Edition, 1949
`Second Edition, 1954
`Third Edition, 1956
`Fourth Edition, 1962
`
`Fifih Edition, 1966
`Sixth Edition, 1971
`Seventh Edition, 1977
`
`'A
`
`'
`
`i 4l
`<' A
`.. ~ :· :. \ ~.-.,;/
`, i' .14..'
`. ~\ '
`~.,-l.ll!i; .. ~"··
`~/'·
`
`Library of Congress Catalogiog-lo-Publicatioo 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 che mistry. II. Wilson, Charles Owens, 1911- 2002 lll. 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
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`2003048849
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`Page 2 of 18
`
`

`
`84 Wilson and Gisvold's Textbook of Organic Medicinal and PluJrmaceutical Chemistry
`
`R-X-t----" R-X' t) - R-XH + ~-
`1«
`
`l Hl
`
`0/
`
`I"
`
`0
`
`I
`
`H
`
`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· tss
`
`Oxidation Involving C.rbon-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 a-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)
`at<?m 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-
`
`Glipizide
`
`~N
`
`Phencyclidine
`
`OH
`
`H
`
`4-Hydroxycyclohexyl
`Melabolite
`
`+HO~N
`
`H
`
`4-Hydroxypiperidyl
`Metabolite
`
`NH2
`
`NH2
`
`N ~N ------. 0 _____. ~N ~N ------. 0
`~ N=<
`HO~ N=<
`NH2
`NH2
`
`•
`
`4
`
`Minoxidil
`
`4'-Hydroxyminoxldil
`
`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 faJI under these two basic categories are discussed indi(cid:173)
`vidually in the appropriate carbon-beteroatom 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 functionaJ 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:
`
`I. 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 ox.idases. The N-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 Alicydic 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)
`/cylation.163 The initial step involves a-carbon hydroxylation
`to form a carbinol amine 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 aJkyl 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)
`nolarnine 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 aJiphatic amine drugs are metabo(cid:173)
`Lized principaJly by oxidative N-dealkylation. Some of these
`include the antiarrhythmic disopyramide (Norpace), 171 • 172
`the antiestrogenic agent tamoxifen (Nolvadex), 173 diphenhy(cid:173)
`dramine(Benadryl),174·175chlorpromazine(Thorazine),176·177
`and ( + )-a-propoxyphene (Darvon). 178 When the tertiary
`amine contains severaJ different substituents capable of
`undergoing dealkylation, the smaJler alkyl group is removed
`preferentiaJly and more rapidly. For example, in benzphe(cid:173)
`tamine (Didrex), the methyl grouf is removed much more
`rapidly than the benzyl moiety.17
`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 dearnination 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 arnines.
`Like their aJiphatic counterparts, aJicyclic tertiary amines
`are susceptible to oxidative N-dealkylation reactions. For
`example, the analgesic meperidine (Demerol) is metabolized
`
`Terl•ary Amine
`
`Carbinolamine
`
`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
`..J...
`
`0
`II
`HCH
`~
`minot
`
`Imipramine
`
`Desmethytimiprarnine
`(desipramine)
`
`Bisdesmethylimiprarnine
`
`CH3 0
`
`CH3CHO r-(_ II
`~ <==<-" NHC-CH2NH 2
`CH3
`Glycyl-2 ,6-xylidine
`
`Tamoxilen
`
`Diphenhydramine
`
`CH3
`I
`.....,. CH-CH
`3
`
`'CH-CH
`I
`3
`CH3
`
`Disopyramide
`
`N
`
`CONH
`I
`2
`
`.
`
`o-C-CH CH 2N/
`6 2
`
`Chlorpromazine
`
`( + )-a·Propoxyphene
`
`Benzphetamine
`(N-demethylation
`and N·debeflZYiation)
`
`principally by this pathway to yield normeperidine as a major
`plasma metabolite in homans. 182 Morphine, N-ethylnorrnor(cid:173)
`phine, and dextromethorphan also undergo some N-dealkyl(cid:173)
`ation.183
`Direct N-dealkylation of /-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 norcblorocyclizine, whereby the /-butyl group
`is lost. 1 84 Careful studies showed that the /-butyl group is
`removed by initial hydroxylation of one of the methyl grou~s
`of the t-butyl moiety to the carbinol or alcohol product.' s
`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
`
`~CsHs
`A.)-CH2CH3
`CHaN
`2-Ethy1-5-melhyt-
`3,3-diphenyt-1-pyrrotine
`(EMOP)
`
`y
`
`---+ Br-o-CHCH2CH 2NH 2 ---+
`
`Brompheniramine
`
`Blsdesmelhyl Metabolite
`
`~CsHs
`AN~CHCH3
`I 1
`CH3
`CH 3
`2-Ethytidene-1 ,5-dimethyl-
`3,3-diphenytpyrrotidine
`(EDDP)
`
`y
`
`---+ Br-Q-CHCH2COOH
`
`3-(p-Bromophenyt)-3-pyndyt(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 arnines
`is still unclear. Indirect N-dealkylation oft-butyl groups is
`not observed significantly. The N-t-butyl group present in
`many ,8-adrenergic antagonists, such as terbutaline and sal(cid:173)
`butamol, remains intact and does not appear to undergo any
`significant metabolism. 186
`
`"OcoocH,cH,
`
`~ HOOCH,CH,
`
`I
`CH3
`Meperidine
`
`H
`
`Normeperidine
`
`:--cH3
`
`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 Jactam metabolite coti(cid:173)
`nine.187. 188
`Formation of Jactarn 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
`
`Secondary and Primary Amines.
`Secondary amines
`(either parent compounds or metabolites) are susceptible to
`oxidativeN-dealkylation, oxidative deamination, and N-oxi(cid:173)
`dation reactions. 163· 196 As in tertiary amines, N-dealkylation
`of secondary amines proceeds by the carbioolamine path-
`
`~ CH 30
`
`H
`CH30
`R : CH3
`Morphine
`N-Elhylnormorphine R ~ CH2CH3
`
`0
`Oextromethorphan
`
`Page 6 of 18
`
`

`
`88 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`---+ Cl
`
`CsHs
`
`/CH3
`NH + O=C,
`CH-N
`CH3
`\__/
`Norchlorocyclizine
`
`-o- 1 1 \
`! N-deisopwpy!ation by
`
`N-t -Butylnorchlorocycllzine
`
`1
`
`a-carbon hyroxylahon
`• carblnolamlne pathway)
`
`Alcohol or Carbinol
`
`Carboxylic Acid
`
`N-lsopropyl Metabolite
`
`OH
`I.;H
`HOCDH2 c
`'cH
`~ 1
`I 2
`CH3
`NH
`'c/
`I'CH
`3
`CH
`3
`
`HO
`
`Salbutamol
`
`Terbutaline
`
`----+
`
`o~Y
`
`CH3
`N
`Nicotine
`
`Oxidation
`
`Carbinofamane
`
`Cotinine
`
`OH
`
`----+ ---+
`
`Cyproheptadine
`
`Lactam Metabolite
`
`----+
`
`Page 7 of 18
`
`

`
`Chapter 4 • Metabolic Changes of Drugs and Related Organic Compounds 89
`
`way. Dealkylation of secondary a mines gives rise to the cor(cid:173)
`responding primary amine metabolite. For example, the a(cid:173)
`adrenergic blockers propranolo146
`47 and oxprenoloJ 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)
`phetamine 198· 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)
`201 With methampheta(cid:173)
`droxylation cannot take place. 200
`•
`mine, oxidative deamination of prim~ amine metabolite
`amphetamine produces phenyl acetone. 1 8. t99
`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
`isopropyl amine (Fig. 4-9).202 How much direct oxidative de(cid:173)
`amination contributes to the metabolism of secondary
`amines remains unclear.
`
`[ o;H] O
`H
`I
`II
`I
`-c~ --------+ -c- -- -c- + NH
`a·Carbon
`hydro<ylahon
`3
`1
`I
`(NH 2
`NH2
`
`Pnmary Amrne
`
`Carbinolamtne
`
`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.2°3 ln 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-ox.idation 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-bydroxylamine 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
`
`~0
`
`NOII<etamrne
`
`Ketamme
`
`Page 8 of 18
`
`

`
`90 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`D1recl
`Oxidauve
`Deamlnauon
`
`0
`
`cxSCH 'CH
`
`OH
`I
`/CH ~H
`I
`fH~ /CH 3
`\_ 'cH
`I
`CH3
`
`2
`
`0
`
`OH
`I
`CH
`
`2
`
`I
`H
`
`0
`
`o56i '-c9"
`
`Propranolol
`
`1
`
`Carbinolam1ne
`
`Aldehyde Metabolile
`
`NH3
`t / Ox1dal1ve
`Deamination
`Through Primary Amine
`
`/
`
`OH
`
`....... bH
`
`2
`
`I 2
`NH 2
`' Pnmary Amine Metabolite
`
`0
`II
`,.....c,
`CH3
`CH3
`~
`
`0
`
`cxSCH 'CH
`
`(Desisopropyt Propranolol)
`
`Carbtnolamine
`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.
`
`H,C:()'
`
`3
`
`CH N
`3 H
`Phenmetrazine
`
`[H,C, 0
`1
`~ cJ~lOH ------> cJ~l_o
`
`HsCs 0
`
`Carbinolamine
`Intermediate
`
`3-0xophenmetrazine
`
`Hydrolysis
`
`Methylphenidate
`
`Ritalinic Acid
`
`6-0xoritallnic Acid
`
`much less N-oxidation occurs for secondary amines than
`oxidative dealkylation and deamination.
`OH
`I
`~ -N
`\
`CH3
`Hydroxylamine
`
`o(cid:173)
`+1
`------> -N
`\
`CH2
`Nitrone
`
`- NH
`\
`CH3
`Secondary amine
`
`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 ,B-adrenergic agonists and antagonists and a
`variety of phenylethylamines.206
`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-bydroxyphentermine 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)
`line208· 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-
`
`_,
`
`crCH2 /CH 3
`
`'cH
`I
`/N,
`HO
`CH2C6H5
`Hydroxylamine
`Metabolite
`
`Nitrone
`Metabollte
`
`HsCe 0 XN) --
`
`CH3 H
`Phenmetrazine
`
`HsCs 0
`
`XN)
`
`CH3 I
`OH
`N-Hydroxyphenmetrazine
`
`---->
`
`HsCe 0 XN)
`
`CH3 I'
`o-
`Nitrone
`Metabolite
`
`v
`
`H
`~c~2;
`,.?-CH3
`NH2
`Amphetamine
`
`a-Carbon
`Hydroxylation
`
`Carbinolamine
`
`Phenytacetone
`
`a-Carbon hydroxylation not possible , hence.
`--> do not see oxidative deamination
`
`Phentermine ~a lion
`
`CH CH3
`
`~'?-CH3
`v
`NH
`'oH
`N-Hydroxyphentermine
`
`Page 10 of 18
`
`

`
`92 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`OCH3
`;yc~?,.( CH,
`C~ NH2
`OCH 3
`1-(2 .5-0imethoxy-4-methylphenyl)-
`2-aminopropane
`DOM or "STP"
`
`CH 2 /CH 3 D 'y- cooH
`
`HO
`
`HO
`
`NH2
`S( - )-a-Methyldopa
`
`J2 ' HOY'yC~c'-~ Oxkjative HOYyC~C/CH3
`
`CH
`
`Enzymatic ~ \
`HO
`NH2
`S( + )-a-Methyldopamine
`
`Deamination ~ 1\
`HO
`0
`
`3,4-Dihydroxyphenylacetone
`
`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 J'henterrnine,207
`chlorphentermine (p-chlorphenterrnine),21 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, chlorphenterrnine is N-hydroxylated extensively.
`About 30% of a dose of chlorphentermine is found in the
`urine (48 hours) as N-hydroxychlorphenterrnine (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
`
`Phenylacetone
`
`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
`PDJJw.•w"'v"'·,Q, agent amantadine (Symmetrel) reportedly
`N-oxidation to yield the corresponding N-hy-
`and nitroso metabolites in vitro.220
`
`Amines and Heterocyclic Nitrogen Com(cid:173)
`The biotransformation of aromatic amines
`the carbon and nitrogen oxidation reactions seen
`223 For tertiary aromatic amines,
`aliphatic amines?21
`-
`as N,N-dimethylaniline, oxidative N-dealkylation as
`as N-oxide formation take place.224 Secondary aro(cid:173)
`amines may undergo N-dealkylation or N-hydroxyla(cid:173)
`give the corresponding N-hydroxylamines. Further
`of theN-hydroxylamine leads to nitrone products,
`in tum may be hydrolyzed to primary hydroxyl-
`225 Tertiary and secondary aromatic amines are
`IICOUnl:ere:d rarely in medicinal agents. In contrast, primary
`are found in many drugs and are often
`from enzymatic reduction of aromatic nitro com-
`reductive cleavage of a.zo compounds, and hydrol(cid:173)
`aromatic arnides.
`.,~-.-vA•u"''u" of primary aromatic amines generates theN(cid:173)
`metabolite. One such case is aniline, which
`weusovu:t.CU to the corresponding N-hydroxy product.223
`of the hydroxylamine derivative to the nitroso
`also can occur. When one considers primary arc-
`amine drugs or metabolites, N-oxidation constitutes
`a minor pathway in comparison with other biotransfor(cid:173)
`u"'"w .. v:>. such as N-acetylation and aromatic hy(cid:173)
`PJI)'Iauion, in humans. Some N-oxygenated metabolites
`reported, however. For example, the antileprotic
`and its N-acetylated metabolite are metabo-
`~•~;mulo.;w.•uy to their corresponding N-hydroxylarnine
`TheN-hydroxy metabolites are further conju(cid:173)
`glucuronic acid.
`~.Mietliterrtog.lot>inc:Dllia toxicity is caused by several aro(cid:173)
`amines, including aniline and dapsone, and is a resuh
`bioconversion of the aromatic amine to its N-hydroxy
`
`derivative. Apparently, the N-hydroxylamine oxidizes the
`Fe2+ form of hemoglobin to its Pe3 + 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-mddation 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)
`229 N-ox(cid:173)
`cinogenic agent N-methyl-4-aminoazobenzene.228
`·
`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 (Sol-) 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 arnines can be bioactivated
`to reactive intermediates by N-hydroxylation and 0-sulfate
`conjugation. Whether primary hydroxylarnines 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 anN-oxide metabolite is metronida(cid:173)
`zole.234
`
`Amantadine
`
`Chlorphentermine
`
`N-Hydroxychlorphentermtne
`
`Nitroso Metabolite
`
`Nitro Metabolite
`
`Hydroxylamine
`
`Nltroso
`
`Nitro
`
`Page 12 of 18
`
`

`
`94 Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`N-oxidalion /
`/
`
`CH3 o- 1
`7 -+ O
`
`CH3
`
`N-Oxide
`
`o-N::CH3
`
`CH3
`Terliary Aromatic ~ ;;x--;;-~lalion
`~
`Amine
`
`Carbon
`
`Carbtnolamine
`
`Secondary
`Aromatic Amines
`
`Hydroxylamine
`(secondary)
`
`N~rone
`
`Hydroxylamine
`(primary)
`
`__.
`
`Aniline
`(pnmary
`aromatic
`amine)
`
`Hydroxylamine
`
`Nitroso
`
`R=- H
`Dapsone
`N-Acety1dapsone R - CCH3
`II
`0
`
`N-Hydroxyctapsone
`
`N-Acetyt-N-hydroxyctapsone
`
`R=H
`0
`II
`R = CCH3
`
`Cotinine
`
`/
`J:~
`I
`
`02N
`
`N
`
`CH3
`
`CH2CH20H
`
`Metronidazole
`2·(2-Methyt-5-nitro-imidazol- t -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.135
`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
`
`Hydroxylamine
`
`Sulfate Conrugate
`l-