Wilson and
`Gisv0ld’s Textbook of
`
`. ORGANIC MEDICINAL
`A AND PHARMACEUTICAL
`CHEMISTRY
`
`ELEVENTH EDITION
`
`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
`
`Q LIPPINCOTT WILLIAMS 5 \X/ILKINS
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`Wilson and Gisvold's textbook or organic medicinal and phannaceutical
`ed /edited by John H. Block, John M. Beale Jr.
`p. '. cm.
`Includes bibliographical references and index.
`ISBN-131978-0-7817-3481-3
`ISBN-l0:0-7817-34Bl-9
`l. Title: Textbook of organic medicinal
`l. Pharmaceutical chemistry. 2. Chemistry. Organic.
`and phannaceutical chemistry. 11. Wilson. Charles Owens. I91 l-2002 lll Gisvold, Ole.
`l904- IV. Block. John H. V. Beale. John Marlowe.
`IDNLM: 1. Chemistry. Pharmaceutical. 2. Chemistry, Organic. QV 744 W754 2004]
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`PAGE 2 OF 18
`
`

`
`
`
`34 Wilson and Gi.rvold'r Textbook of Organic Medirinal and Phannaceurical Chemistry
`
`The stereochemistry of the hydroxylated centers in the two
`metabolites has not been clearly established. Biotransforma-
`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-
`mans it is detected in small amounts (~3%)."7- ‘53
`
`Oxidation Involving Carbon-Helerootom
`Systems
`
`Nitrogen and oxygen functionalities are commonly found in
`most drugs and foreign compounds; sulfur functionalities
`occur only occasionally. Metabolic oxidation of carbon-
`nitrogen, carbon—oxygen, and carbon—sulfur systems prin-
`cipally involves
`two basic types of biotransformation
`processes:
`
`T
`
`H
`
`if
`
`ii
`
`Where X = NOS
`
`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. 5 only, c.g..
`N-hydroxylation. N-oxide formation. sulfoxide. and sulfone for-
`mation).
`
`I. Hydroxylation of the at-carbon atom attached directly to the
`heteroatom (N. 0. S). The resulting intermediate is often un-
`stable and decomposes with the cleavage of the carbon-hetero
`atom bond:
`
`Several structural features frequently determine which
`pathway will predominate, especially in carbon—niLrogen
`systems. Metabolism of some nitrogen-containing com-
`pounds is complicatcd by the fact that carbon- or nitrogen-
`
`o
`tli
`
`\NH M
`
`‘
`
`0 I
`
`I
`
`N
`cH,,—<__§—cNHcH2cH2—<;>—so2Nfi
`
`Glipiztde
`
` N —* H
`
`Phencyctidine
`
`4-Hydroxycyclohexyl
`Melamine
`
`HO
`
`H
`
`N
`
`4-Hydroxypiperidyl
`Metabolite
`
`NH2
`
`°“
`
`Minoxidil
`
`NH2
`
`N—/—<N —»O
`’
`HO} N=<
`
`NH?
`
`4’-Hydroxyminoxidil
`
`
`
`PAGE 3 OF 18
`
`

`
`
`
`Chapter 4 I 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-
`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—NlTROGEN SYSTEMS
`
`Metabolism of nitrogen functionalities (e.g., amines, am-
`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-
`histamines. tricyclic antidepressants, B-adrenergic agents,
`sympathomimetic phenylethylamines, benzodiazepines). ' 5°
`The following discussion divides nitrogen-containing com-
`pounds into three basic classes:
`
`1. Aliphatic (primary, secondary. and tertiary) and alicyclic (sec-
`ondary and teniary) amines
`2. Aromatic and heterocyclic nitrogen compounds
`3. Amides
`
`The susceptibility of each class of these nitrogen com-
`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-
`bon hydroxylation reactions are the cytochrome P-450
`mixed-function oxidases. The N-hydroxylation or N-oxida-
`tion reactions, however, appear to be catalyzed not only by
`cytochrome P-450 but also by a second class of hepatic
`mixed-function oxidascs called amine axidares (some-
`'~ times called N-oxidases).'°° These enzymes are NADPl-l-
`dependent flavoproteins and do not contain cytochrome
`P—4S0.'°" '57 They require NADPH and molecular oxygen
`to carry out N-oxidation.
`
`-
`
`The oxida-
`Tertiary Aliphatic and Alicydic Amines.
`tivc 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-
`kylation.'°3 The initial step involves or-carbon hydroxylation
`to form a carbinolamine intermediate, which is unstable and
`1 Z undergoes spontaneous heterolytic cleavage of the C—N
`_§ bond to give a secondary amine and a carbonyl moiety (alde-
`
`hyde or ketone).‘°"' '65 In general, small alkyl groups, such
`as methyl. ethyl, and isopropyl. are removed rapidly.‘°3 N-
`dealkylation of the t-butyl group is not possible by the carbi-
`nolarnine pathway because av-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-
`sponding primary aliphatic amine occurs vcry slowly. '63 For
`example, the tertiary amine imiprarnine (Tofranil) is mono-
`demethylated to desmethylimiprarnine (desipramine). ”’°'
`'67
`This major plasma metabolite is pharmacologically active
`in humans and contributes substantially to the antidepressant
`activity of the parent drug.'“ Very little of the bisdemethy-
`lated metabolite of irnipramine is detected. In contrast, the
`local anesthetic and antiarrhythmic agent lidocaine is metab-
`olized extensively by N-deethylation to both monoethylgly-
`cylxylidine and glycyl-2,6-xylidine in humans.'°°- ”°
`Numerous other tertiary aliphatic amine drugs are metabo
`lized principally by oxidative N-dealkylation. Some of these
`include the antiarrhythmic disopyramidc (Norpace).'7'- '72
`the antiestrogenic agent tamoxifen (Nolvadex),' 3 diphenhy-
`dramine(Benadryl).'7"' mchlorpromazine (Thorazine),'7°- '77
`and (+ )-a-propoxyphene (Darvon).'" 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-
`tamine (Didrex), the methyl group is removed much more
`rapidly than the benzyl moiety.'79
`An interesting cyclization reaction occurs with methadone
`on N-demethylation. The demethylated metabolite normeth-
`adone undergoes spontaneous cyclization to form the en-
`amine metabolite 2-ethylidene-l,5-dimethyl-3,3-diphenyl—
`pyrrolidine (EDDP).'3° Subsequent N-demcthylation of
`EDDP and isomerization of the double bond leads to 2-ethyl-
`5-methyl-3.3-diphenyl-l-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-
`methyl metabolite of the H.-histamine antagonist bromphe-
`niramine (Dimetane) undergoes oxidative deamination and
`further oxidation to the corresponding propionic acid metab-
`olite.'8' 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
`
`0 I
`
`I
`/ C\
`
`-——> R1 -—TH +
`Ft 2
`
`Secondary
`Amine
`
`Carbonyt Molety
`(aldehyde or
`kelone)
`
`‘E
`T
`“*‘t“‘F—' “'"'t“‘i‘-"
`R2
`R2
`
`Tertiary Amine
`
`Carbinoiamine
`
`PAGE 4 OF 18
`
`

`
`86 Wilson and Gisvoldlt Textbook of Organic Medicinal and Pharmaceutical Chcntislry
`
`0l
`
`l
`
`/
`CH2CH2CH,N\
`
`Imipramine
`
`CH3
`/
`CH,CH2CH2N\
`H
`
`Desmethytimipramine
`(desipramine)
`
`|
`CHZCHQCHQNHZ
`
`Bisdesrnethyiirnipramine
`
`CH3
`
`‘i
`NHCCH2N
`
`CH3
`
`/CHQCHS cH,cHo
`\
`_\.L,
`
`CHZCH3
`
`CH3 0
`NHCHECH N/CH2CH3 CH,CHo
`2 \H
`AL,
`
`CH3 0
`H
`NHC—CH2NH2
`
`CH 3
`Monoethytgiycytxytidine
`(MEGX)
`
`CH 3
`.
`.
`Gtycyl-2.6-xylndine
`
`CH3
`CONH2
`\, I
`|
`CH—CH3
`/
`®—c—cH2cH2N\
`_
`
`CH-—CH:,
`
`N
`
`H
`
`\
`/CH3
`CH0CH2CH2N\
`
`CH3
`
`I C
`
`H3
`
`Disopyyamide
`
`Tamoxifen
`
`Diphenhydramine
`
`S
`®: Ijx
`
`N
`/
`I
`CH2CH2CH2N\
`/\ CH3
`
`CH3
`
`O
`
`CH 3
`
`H 3C H
`
`o
`C H CH
`
`6
`
`5
`
`2
`
`\.
`/CH3
`
`CH3
`
`N\
`
`CH 3
`
`C}/\(
`/N\ Q
`
`\.
`
`/
`
`CH3
`
`2
`
`Chlotpromazine
`
`(+ )1:-Proooxyphene
`
`5e"Z°“e‘a"“f*e
`(N-demethytauon
`and N-debenmation)
`
`principally by this pathway to yield normepcridine asamajor
`plasma metabolite in humans”: Morphine, N-ethylnorrnor-
`phine, and dextromethorphan also undergo some N-dealkyl-
`ation.'”
`Direct N-dealkylation of I-butyl groups, as discussed
`above, is not possible by the a-carbon hydroxylation path—
`way. In vitro studies indicate, however. that N-i-butylnor-
`
`indeed. metabolized to significant
`is.
`chlorocyclizine.
`amounts of norchlorocyclizine, whereby the I-butyl group
`is lost.'‘“ Careful studies showed that the I-butyl group is
`removed by initial hydroxylation of one of the methyl grougs
`of the t-butyl moiety to the carbinol or alcohol product.‘ 5
`Funher oxidation generates the corresponding carboxylic
`acid that, on decarboxylation, forms the N-isopropyl deriva-
`
`PAGE 5 OF 18
`
`

`
`
`
`Chapter 4 I Metabolic Changes of Drugs and Related Organic Compounds
`
`87
`
`H C
`
`C 5&6/C5H5
`H7 _ \C€O
`Cfir—r\N_c CH2—CH,
`3
`H
`l
`3
`CH3
`Methadone
`
`o
`HJLH
`
`Z
`
`H C
`
`H C sis/CeH5
`C2
`\C\———O
`CfiH\NH
`CH2—CH3
`3
`l
`CH3
`Normethadone
`
`"20
`
`[
`
`/
`
`/
`
` 6H5
`
`CH CH
`2
`CH3 N
`2-Ethyl-5-methyl-
`3.3<iiphenyl- 1 -pyrroline
`(EMDP)
`
`3
`
`C
`H5 6C6H5
`CHCH
`
`3
`
`3
`
`N 2
`1
`CIDH3
`2-Ethyidene-1,5—dlmelhyl-
`3,3-diphenylpyrrolidine
`(EDDP)
`
`CH3
`
`N
`
`r
`N
`
`r
`N
`
`Br-@~CHCH2CH2N<C 3 —> —->Br—<:=_>-CHCH2CH,NH2 —~ —» Br—<;>—cHcH,cooH
`
`CH
`
`Ha
`
`Brompnentramtne
`
`Blsdesmethyt Metabolite
`
`3-tp-Bromophenyll-3-pyridyt
`oropionic acid
`
`.. tive. The N-isopropyl intennediate is dealkylated by the nor-
`" mal a—carbon hydroxylation (i.e., carbinolamine) pathway
`,‘ to give norchlorocyclizine and acetone. Whether this is a
`l general method for the loss of I-butyl groups from amines
`-; is still unclear. Indirect Ndealkylation of r-butyl groups is
`r not observed significantly. The N-t-butyl group present in
`i.- many B-adrenergic antagonists, such as terbutaline and sal-
`-_,'butamol, remains intact and does not appear to undergo any
`significant mct.abolism.'“
`
`H5C6 COOCHZCH3
`
`H5C5 COOCHQCH3
`
`N
`|
`
`N
`H
`
`Mepertdine
`
`Nmmepelldkle
`
`N\,R
`H
`H
`
`N\;CH3
`H
`H
`
`Alicyclic tertiary amines often generate lactam metabo-
`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-
`nine'l87.
`I88
`Formation of lactam metabolites also has been reported to
`occur to a minor extent for the antihistamine cyproheptadine
`(Periactin)'°9~ '9° and the antiemetic diphenidol (Vontrol).‘°‘
`N-oxidation of
`tertiary amines occurs with several
`drugs. '92 The true extent of N-oxide formation often is com-
`plicated by the susceptibility of N-oxides to undergo in vivo
`reduction back to the parent tertiary amine. Tertiary amines
`such as H.-histamine antagonists (e.g., orphenadrine. tripe-
`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-
`macological activity.'°3 A comparison of imipramine N-
`oxide with imiprarnine indicates that the N-oxide itself pos-
`sesses antidepressant and cardiovascular activity similar to
`that of the parent drug.'°" '95
`
`0
`
`CH3o
`v ° ' “"9
`Ethytnormorphine
`
`\3H
`R = CH3
`R = CH,CH3
`
`0
`CH3O
`Dextromethorphan
`
`Secondary amines
`Secondary and Primary Amines.
`(either parent compounds or metabolites) are susceptible to
`oxidative N-dealk lation. oxidative deamination, and N-oxi-
`dation reactions.‘ 1 '°" As in tertiary amines, N-dealkylation
`of secondary amines proceeds by the carbinolamine path-
`
`PAGE 6 OF 18
`
`

`
`88 Wilson and GisvoId's Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`CSHS
`/CH3
`|
`NH +O=C\
`CH—N
`\__/
`Noichlorocyctizme
`
`CH3
`
`
`
`Ndensopcopylabon by
`a-carbon hytoxylaxion
`(i .e._ carbinolamtne pathway)
`
`Cl
`
`CH3
`CGH5
`l
`\
`I
`'
`N—aC—CH3 —» CI
`CH—N
`\_/
`|
`C H 3
`
`N-I-Butylnorchlorocyclizine
`
`I
`
`COOH
`CH OH
`,cH3
`_cO2 \
`N I
`I
`2
`N~C—CH3 —. N—C—CH3 —- N—CH\
`_/
`I
`J I
`J
`CH3
`CH3
`Alcohol or Carbinol
`Carboxylic Acid
`
`N-Isopropyt MEIBDOIIIG
`
`CH3
`
`HO
`
`HO
`
`33” H
`‘.’“ H
`/
`c\
`C:
`HOCH2
`tw U tie
`Nflc/CH3
`HO
`NEG/CH3
`m
`~c.:<=w
`3
`
`3
`
`Terbutaline
`
`Saibutamoi
`
`/ «U\
`/iN>~(j T
`\N
`CH3
`Q I
`
`N
`
`CH3
`Nicotme
`
`Carbinolamine
`
`/
`N
`
`0
`
`t
`CH3
`
`Cotmine
`
`OH
`
` T
`
`0
`
`Cyprohepladine
`
`CH3
`Lactam Melabolile
`
`OH
`I
`C6H5—C|)—CH2CH2CH2—N
`CGH5
`
`Diphenidot
`
`_.
`
`2
`
`.
`
`OH
`|
`CsHs-<|3—CH2CH2CH2—N 2
`CsHs
`O
`2-Oxodiphenidol
`
`
`
`PAGE 7 OF 18
`
`

`
` H
`
`Chapter 4 I Metabolic Changes of Drugs and Related Organic Compounds
`
`89
`
`way. Dealkylation of secondary amines gives rise to the cor-
`responding primary amine metabolite. For example, the a-
`adrenergic blockers propranolol“"‘7 and oxprenolol'97
`undergo N-deisopropylation to the corresponding primary
`amines. N-dealkylation appears to be a significant biotrans-
`fonnation pathway for the secondary amine drugs metham-
`phetamine °’’' '”and ketamine,’°°'m' yielding amphetamine
`and norketamine, respectively.
`The primary amine metabolites fomied 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 carbine-
`lamine intermediate, which then undergoes subsequent car-
`bon—nitrogen cleavage to the carbonyl metabolite and am-
`monia.
`If a-carbon hydroxylation cannot occur,
`then
`oxidative deamination is not possible. For example. deami-
`nation does not occur for norketamine because a-carbon hy-
`droxylation cannot take place. ‘°°‘ 2°‘ With methampheta-
`mine. oxidative dearriination of prim
`amine metabolite
`amphetamine produces phenylacetone.' 3'
`'99
`In general, dealkylation of secondary amines is believed
`to occur before oxidative deamination. Some evidence indi-
`cates. however, that this may not always be true. Direct de-
`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-
`carbon hydroxylation) to yield the aldehyde metabolite and
`isopropylamine (Fig. 4-9).’°2 How much direct oxidative de-
`‘ amination contributes to the metabolism of secondary
`amines remains unclear.
`
`O
`o;jH
`..ae.;e:. _e- __t-.
`I
`hydvoxydation
`I
`NH2
`CNH2
`
`Primary Amine
`
`Carbinolamrne
`
`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°’ 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?“
`Metabolic N-oxidation of secondary aliphatic and alicy-
`clic amines leads to several N-oxygenated products.'9° N-
`hydroxylation of secondary amines generates the corre-
`sponding N-hydroxylamine metabolites. Often, these hy-
`droxylamine products are susceptible to further oxidation
`(either spontaneous or enzymatic) to the corresponding ni-
`trone derivatives. N-benzylamphetamine undergoes metabo-
`lism to both the corresponding N-hydroxylamine and the
`nitrone metabolites?” 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.’°’
`Importantly,
`
`
`
`2
`on
`\C/ ‘E3
`H
`
`0
`
`H2
`
`?“
`CH
`\ / \C
`CH2
`'
`HN\ /CH3
`‘EH
`CH3
`
`0
`
`\Cfi
`
`2
`
`Cf”
`CH
`\CH
`2
`I
`HN\ ,CH3
`f“
`CH3
`
`Propranolol
`
`Oxprenolol
`
`ii
`
`NH
`‘‘CH3
`Metna'npheta'nlne
`
`l
`NH
`
`2
`
`0
`
`Amphetamhe
`
`Phenylaoetone
`
`CI
`
`—9
`
`NHCH3
`0
`
`Cl
`
`NH2
`
`O
`
`Ketamine
`
`Norketamine
`
`‘PAGE8OF18
`
`

`
`90 Wilson and Gisvold'3 Textbook of Organic Medicinal and Pharmaceutical Chemistry
`
`.
`Stigma
`Deamnauon
`
`o
`
`OH
`I
`/CH /o‘—i—i
`,
`H2N—'<
`\CH2 \ $H
`HN\ /CH3 _£__.
`C|IH
`CH3
`
`Carbmolamlne
`
`NH3
`
`Aldehyde Metabolite
`
`/' Oxidalive
`
`Deaminatlon
`Through Primary Amine
`
`0
`
`éii
`
`Hr.
`\J\(|3<,\
`CH3
`
`Carbrnolamne
`
`3”“
`
`r*2
`NH2
`PmuqAmmeMaxum
`(oesisooropyl Proptanolol)
`
`Figure 4-9 I Metabolism of propranolol to its aldehyde metabolite by direct deamination of the parent
`compound and by deamination of its primary amine metabolite, desisopropyl propranolol.
`
`MID‘)?
`
`N
`CH3H
`Phenmetrazine
`
`3
`
`——>
`
`——>
`
`Hficffiol
`
`N
`OH
`CH3H
`Carbinolamine
`lntennediale
`
`O
`cH3[j
`3-Oxophenmelrazine
`
`COOH
`l
`
`CH
`:©
`
`COOH
`I
`
`_. _. H
`HN
`
`O
`
`Methylphenidate
`
`Rital~nic Acid
`
`6-Oxorilallnic Acid
`
`much less N-oxidation occurs for secondary amines than
`oxidative dealkylation and deamination.
`OH
`/
`_, _N
`\
`CH3
`Hyd,o,(y1am,ne
`
`O_
`J
`_. _N
`\\
`CH2
`Nmone
`
`_NH
`
`CH3
`Secondary amm
`
`Primary aliphatic amines (whether parent drugs or metab-
`
`PAGE 9 OF 18
`
`by oxidative deamination
`are biotransformed
`olites)
`(through the carbinolamine pathway) or by N-oxidation. In
`general._oxidative deamination of most exogenous primary
`amines 15 carried out by the mrxed—fu'nctron oxidases tins-
`cussed above. Endogenous primary amines (e.g., dopamine.
`norepinephnne. tryptamine. and serotonin) and xenobiotics
`based on the structures of these endogenous neurotransmit-
`ters are metabolized. however. via oxidative deamination by
`a specialized family of enzymes called monoamine oxidases
`(MAOs).2°°
`
`

`
`
`
`Chapter 4 I Metabolic Change: 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-
`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-
`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-
`zymes are found on the endoplasmic reticulum of the cell's
`cytosol, whereas the MAO enzymes are on the outer mito-
`chondrial membrane. In addition to the xenobiotics illus-
`trated in the reaction schemes, other drugs metabolized by
`the MAO system include phenylephrine, propranolol, timo-
`lol and other B-adrenergic agonists and antagonists and a
`variety of phenylethylamines.2°‘
`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 phentennine. ln amphetamine,
`ar-carbon hydroxylation can occur to form the carbinolamine
`intermediate, which is convened to the oxidatively deami-
`nated product phenylacetone.“ With phentcrrnine, a-carbon
`hydroxylation is not possible and precludes oxidative deami-
`nation for this drug. Consequently, phentermine would be
`expected to undergo N-oxidation readily. In humans, p-hy-
`droxylation and N-oxidation are the main pathways for bio-
`transformation of phentennine.’°"
`Indeed, N-hydroxyphentermine is an important (5%) uri-
`nary metabolite in humans.2°7 As discussed below, N-hy-
`droxylarnine metabolites are susceptible to further oxidation
`to yield other N-oxygenated products.
`Xenobiotics, such as the hallucinogenic agents mesca-
`line’°“"°° and l-(2,S-dimethoxy-4-methylphenyl)-2-amino-
`propane (DOM or “STP"),2'°' 1" are oxidatively deami-
`nated. Primary amine metabolites
`arising from N-
`
`_.
`
`°5efi‘’”3
`I
`NH
`\CH2C6H5
`-
`_
`N Benzyiamphemmm
`
`CH
`
`CH
`
`CH
`
`CH
`
`°
`3 — yea
`\€:fi
`,5,
`kg
`_ / \
`\CH2C5H5
`0
`\CHC5H5
`Ho/
`Hydroxylamine
`Nitrone
`Metabolite
`Metabolite
`
`H5C
`
`0
`
`I 1 ~
`crisfi
`Phenmetrazine
`
`H506 0
`
`I 1
`CH3?‘
`OH
`N-Hydroxyphenmetrazine
`
`H5O
`
`O
`
`—~ I]
`CH3
`
`O‘
`Nitlone
`Metabolite
`
`H
`CH2 /
`\_,C—CH3
`I
`NH2
`Amphetamine
`
`<--<=='b°'=
`Hvdroxvlarm
`
`,
`
`F
`O——H
`“"3
`CH2/
`\C—CH3 L,
`(I
`NH2
`Carbinolamine
`
`CH
`
`3
`
`CH2
`\C/
`II
`0
`Phenylacetone
`
`CH2 CH3
`.
`.
`\
`,C— CH3 _’ a-Carbon hydroxylation not possible: hence.
`fl“
`do not see oxidative deamination
`2
` tm
`CH
`cuu 3
`0/ (l3—CH3
`
`C”
`°{'g:,c°H,
`|
`
`p-Hydroxyphentermine
`
`\ OH
`N-Hydroxyphentermine
`
`PAGE 10 OF 18
`
`

`
`
`
`92 Wilson and Gi.tvold’s Textbook of Organic Medicinal and Phannaceutical Chemistry
`
`CH 0
`
`3
`
`cH2o
`
`CH2
`
`\(|:H2
`
`NH2
`
`CH3
`
`CH
`
`CH
`
`\E|:H/
`
`NH2
`
`3
`
`OCH3
`Mescaline
`
`1-(2.5-Dimethoxy-4-methylphenyl)-
`2-aminopropane
`DOM or "STP"
`
`Ho
`
`H0
`
`CH
`CH2;
`
`3
`
`co;
`
`j:j/ \C"COOH 2
`
`|
`NH2
`S( — )~a—Me-thytdopa
`
`Enzymatic
`
`,
`
`HO
`
`CH
`CH2 /
`\ :1
`C
`|
`HO
`NH2
`S( + )-a-Methyidopamine
`
`2
`3
`Oxidatvve
`H _:_,
`Deamination
`
`HO
`
`CH2
`\ X
`C
`
`CH3
`
`0
`HO
`3,4-Dihydroxyphenylacetone
`
`dealkylation or decarboxylation reactions also undergo de-
`amination. The example of the bisdesmethyl primary amine
`metabolite derived from bromopheniramine is discussed
`above (see section on tertiary aliphatic and alicyclic
`amines).'°' In addition, many tertiary aliphatic amines (e.g.,
`antihistamines) and secondary aliphatic amines (e.g.. pro-
`pranolol) are dealkylated to their corresponding primary
`amine metabolites, which are amenable to oxidative deami-
`nation. (S)( + )-oz-Methyldoparnine resulting from decarbox—
`ylation of the antihypertensive agent (S)(-)-at-methyldopa
`(Aldomet) is deaminated to the corresponding ketone metab-
`olite 3.4—dihydroxyphenylacetone.2'2 In humans, this ketone
`is a major urinary metabolite.
`The N-hydroxylation reaction is not restricted to cr-substi-
`tuted primary amines such as phentermine. Amphetamine
`has been observed to undergo some N-hydroxylation in vitro
`to N-hydroxyamphetamine.’"- 2"‘ 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.2'5‘ 2'6 Thus, amphetamine may be con-
`verted to phenylacetone through either the av-carbon hydrox-
`ylation or the N-oxidation pathway. The debate concerning
`the relative importance of the two pathways is ongo-
`ing.” 2" The consensus, however, is that both metabolic
`pathways (carbon and nitrogen oxidation) are probably oper-
`ative. Whether or-carbon or nitrogen oxidation predominates
`in the metabolism of amphetamine appears to be species
`dependent.
`207
`In primary aliphatic amines, such as phentermine,
`chlorphentermine
`(p-chlorphentemiine),"° and
`amanta-
`dine, 2° N—oxidation appears to be the major biotransforma—
`tion pathway because or-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-hydroxychlorphentennine (free and
`conjugated) and an additional 18% as other products of N-
`oxidation (presumably the nitroso and nitro metabolites)?”
`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-
`amine metabolite of phentennine undergoes further oxida-
`
`(FC“i“CH3—~©V
`
`NH2
`
`Amphetamine
`
`H 0
`
`NH
`
`lmine
`
`Nfl
`
`OH
`N-Hydroxyamphetamine
`
`\ fietion
`CS2: /CH3 H20
`Cflzc/CH3
`ll
`NH§OH
`l.
`2
`
`Pheriylacetone
`
`\ OH
`
`Oxime
`
`
`
`PAGE 11 OF 18
`
`

`
` .93
`Chapter 4 I Metabolic Changes of Drugs and Related Organic Compounds
`
`derivative. Apparently, the N-hydroxylamine oxidizes the
`Fe2+ form of hemoglobin to its Fe“ fonn. This oxidized
`(Fe3*) state of hemoglobin (called methemoglobin or ferri-
`hemoglobin) can no longer transport oxygen. which leads
`to serious hypoxia or anemia, a unique type of chemical
`suffocation?”
`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-
`cinogenic agent N—methyl—4—aminoazobenzene.m' 229 N-ox-
`idation of this compound leads to the corresponding hydrox-
`ylamine, which undergoes sulfate conjugation. Because of
`the good leaving—group ability of the sulfate (S042) anion,
`this conjugate can ionizc spontaneously to form a highly
`reactive, resonance—stabilized nitrenium species. Covalent
`adducts between this species and DNA, RNA, and proteins
`have been characterized.’3°' 23' 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-
`tivated similarly is unclear. In addition, it is not known if
`this biotoxification pathway plays any substantial role in the
`toxicity of aromatic amine drugs.
`N -oxidation of the nitrogen atoms present in aromatic het-
`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-
`mately equal amounts of the isomeric l-N-oxide and 3-N-
`oxide as minor metabolites?” The pyridinyl nitrogen atom
`present
`in Iiicotinine (the major metabolite of nicotine)
`undergoes oxidation to yield the corresponding N-oxide me-
`tabolitem Another therapeutic agent that has been observed
`to undergo formation of an N-oxide metabolite is metronida-
`zole.2"
`
`NH2
`
`CH
`
`
`
`‘(EV-CH3
`
`l
`NH2
`Phentermine
`
`I
`
`C52;-cits
`
`I
`NH2
`Chlorphentorrnine
`
`Nnanladne
`
`,/
`
`.
`
`CH
`
`Cfl-‘E://C:|‘_|3
`I
`NH,
`
`"’
`
`Cl
`
`CH
`
`CH3
`
`\2C/CH3 _’)
`I
`NQOH
`
`Cl
`
`CH
`
`CH3
`
`CH CH3
`
`\%//CH3 *. 0/ \2C//CH3
`I
`N§O
`CI
`N02
`
`Chlorphentermine
`
`N-Hydtoxychlorphentermine
`
`Nitroso Metabolite
`
`Nilfo Metabolite
`
`RCHQNHOH _.RcH,—N=o _.RCH2——rT:\
`Nitro
`Nitroso
`
`Hydroxylamine
`
`O
`
`PAGE 12 OF 18
`
`'1
`to the nitroso and nitro products.2°7 The antiviral and
`.,
`"parkinsonian agent amantadine (Symmetrel) reportedly
`- _. . goes N-oxidation to yield the corresponding N-hy-
`‘* xy and nitroso metabolites in vitro.”°
`
`,matic Amines and Heterocyclic Nitrogen Com-
`> nds.
`The biotransformation of aromatic amines
`' : lels the carbon and nitrogen oxidation reactions seen
`aliphatic arnines.22"223 For tertiary aromatic amines,
`" h as N,N-dimethylaniline_ oxidative N-dealkylation as
`as N-oxide formation take place?" Secondary aro-
`c amines may undergo N—dealkylation or N-hydroxyla-
`_
`to give the corresponding N-hydroxylamines. Further
`‘..
`, dation of the N-hydroxylamine leads to nitrone products,
`ch in turn may be hydrolyzed to primary hydroxyl-
`' . s.n5 Tertiary and secondary aromatic amines are
`. ntered rarely in medicinal agents. In contrast. primary
`_ u: amines are found in many drugs and are often
`_I’3‘. « ted from enzymatic reduction of aromatic nitro com-
`"_ . s, reductive cleavage of a_zo compounds, and hydrol-
`‘gm of aromatic amides.
`-oxidation of primary aromatic amines generates the N-
`in xylamine metabolite. One such case is aniline. which
`'~.
`tabolized to the corresponding N-hydroxy product?”
`‘dation of the hydroxylamine derivative to the nitroso
`‘-"vative also can occur. When one considers primary aro-
`'c amine drugs or metabolites, N-oxidation constitutes
`-it a minor pathway in comparison with other biotransfor-
`_on pathways, such as N-acetylation and aromatic hy-
`lation,
`in humans. Some N-oxygenated metabolites
`been reported, however. For example, the antileprotic
`--u dapsone and its N-acetylated metabolite are metabo-
`'§- significantly to their corresponding N-hydroxylamine
`°vatives.22° The N-hydroxy metabolites are further conju-
`with glucuronic acid.
`themoglobinemia toxicity is caused by several aro-
`- c amines, including aniline and dapsone, and is a result
`a - bioconversion of the aromatic amine to its N-hydroxy
`
`‘;
`
`CH
`
`I.
`
`

`
`94 Wilson and Gisvoldlt Textbook of Organic Medicinal and Pharmaceuliral Chemistry
`
`NHOH
`
`N=O
`
`@326 =o
`
`(primary
`aromatic
`amine)
`
`Hydroxyiamine
`
`Nitroso
`
`RNH0so,~©NH2 —»RNH SO2 NHOH
`
`R = H
`
`0l
`
`l
`R = CCH3
`
`N-Hydroxydapsone
`
`N-Acelyt-N-nydroxydapsone
`
`Dapsone
`N-Acetyldapsone
`
`R = H
`R = CCH,
`ll
`0
`
`Amide functionalitics are susceptible to oxida-
`Amides.
`tive carbon—nitrogen bond cleavage (via a-carbon hydroxyl-
`ation) and N-hydroxylation reactions. Oxidative dcall<yl-
`ation of many N—substituted amide drugs and xenobiotics
`has been reported. Mechanistically, oxidative dealkylation
`proceeds via an initially formed carbinolamide, which is un-
`stable and fragments to form the N—dealkylated product. For
`example, diazepam undergoes extensive N-demethylation to
`the pharmacologically
`active metabolite desmethyldi-
`azepam.2”
`Various other N-alkyl substituents present in benzodiaze-
`pines (e.g., f'|urazepain)'3“'” and in barbiturates (e.g.. hex-
`obarbital and mephobarbital)”8 are similarly oxidatively N-
`dealkylated. Alkyl groups attached to the amide moiety of
`some sulfonylureas. such as the oral hypoglycemic chlor-
`propamide.23° also are subject
`to dealkylation to a minor
`extent.
`
`In the cyclic amides or lactams, hydroxylation of the alicy-
`
`CH2CH20H
`Metronidazole
`2-(2»M9thyl.S—nitro—imzda7ol-1-y|)~ethanoI
`
`PAGE 13 OF 18
`
`

`
`
`
`Chapter 4 I Metabolic Changes of Drugs and Related Organic Compounds
`
`95
`
`rs
`rs
`N
`4 NH
`0 «~ 0 we 0
`
`3
`c6H5N=N
`N-Methyl-4—amunoazobenzene
`
`C5H5N=N
`Hydroxylamine
`
`C6H5N=N
`Sulfate Coniugate
`
`rs
`N
`
`C°"3'°‘“'Y DNA. RNA
`bound <—————-—
`addwts
`and proton
`
`~
`-2
`
`c H N=N
`6
`5
`
`re
`GjbQ”
`
`*
`_
`
`CsH5N=N
`
`1-$0.‘?
`
`re
`N1»
`
`U
`
`Nitrenium Ion
`
`OCH 3
`
`;.
`_. C}-I30
`:
`
`CH2
`
`Ni
`>—NH2 _.cH3o
`N 3
`
`‘
`
`OCH,
`
`H,N
`
`Trimelhoprim
`
`ocH3
`
`CH2
`
`OCH3
`
`H,N
`1 N~Oxide
`
`o
`;
`
`_ N
`>—NH2 + CH3
`N
`
`OCH3
`
`CH2
`
`N
`>—NH,
`N
`
`OCH3
`
`HZN
`3-N-Oxide
`
`\
`
`_ iclic carbon :2: to the nitrogen atom also leads to carbinolam-
`‘ides. An example of this pa