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-name,id,synthesis
-METHYLPHENIDATE,11968,"Methylphenidate (3.1.6) (Ritalin) is a commonly prescribed central nervous
-system(CNS)stimulant.Methylphenidateisusedtotreatattentiondeficitdisor-
-der,attentiondeficithyperactivitydisorder,andnarcolepsy,achronicsleepdis-
-order. However, a growing number of young individuals misuse or abuse
-methylphenidatetosustainattention,enhanceintellectualcapacity,andincrease
-memory [1(cid:1)4]. Side effects of methylphenidate include trouble sleeping, loss
-ofappetite,weightloss,dizziness,nausea,vomiting,andheadache.
-Methylphenidate (3.1.6) has been synthesized via condensation of pheny-
-lacetonitrile (3.1.1) with a 2-chloropyridin (3.1.2) at 110(cid:1)112(cid:3)C in toluene
-in the presence of NaNH , which gave 2-phenyl-2-(pyridin-2-yl)acetonitrile
-2
-(3.1.3). The last was hydrolyzed to corresponding amide (3.1.4), which on
-treatment with HCl in methanol on heating gave methyl 2-phenyl-2-(pyridin-
-2-yl)acetate (3.1.5). Hydrogenation of the pyridine ring to a piperidine ring
-in the obtained product in acetic acid on the Pt or PtO catalyst gave the
-2
-desired methylphenidate (3.1.6)[5(cid:1)7](Scheme 3.1).
-N + NaNH 2 N N H 2SO 4 ONH 2 N CH 3OH OO N H 2-Pt OO N
-Cl N Toluene HCl H
-110–12°C
-3.1.1 3.1.2 3.1.3 3.1.4 3.1.5 Methylphenidate 3.1.6
-SCHEME3.1 Synthesisofmethylphenidate.
-Alternatively, 2-bromopyridine can be used instead of 2-chloropyridine
-[8]. A huge amount of chemical work is described on the separation and
-interconversion stereoisomers of methylphenidate [9(cid:1)14]. The absolute
-(2R,20R; threo) stereochemistry of the most active enantiomer, (2R,20R)-
-threo-methylphenidate,was proven [15,16]."
-PERHEXILINE,1216,"Perhexiline (3.1.11) was originally developed as an antianginal drug and was
-launched on the UK market as a racemate in 1975 under the trade name
-Piperidine-BasedDrugDiscovery.DOI:http://dx.doi.org/10.1016/B978-0-12-805157-3.00003-X
-Copyright©2017ElsevierLtd.Allrightsreserved. 103
-104 Piperidine-BasedDrugDiscovery
-Pexid. It rapidly gained a reputation for efficacy in the management of
-angina pectoris. However, hepatic and neurological adverse effects in a small
-proportionofpatientsled toamarkeddeclineinitsusein1985.The drugwas
-originally classified as a coronary vasodilator, and later as a calcium channel
-antagonist. Recent data suggests that it acts as a cardiac metabolic agent
-throughinhibitionoftheenzyme,carnitinepalmitoyltransferase-1[17(cid:1)22].
-Perhexiline (3.1.11) consists of a piperidine framework with a 2,2-dicy-
-clohexylethyl substituent at the 2-position. The synthesis of racemic perhexi-
-line is based on nucleophilic addition of lithiated 2-picoline (3.1.7) to
-dicyclohexyl ketone (3.1.8) to give the corresponding tertiary alcohol (3.1.9),
-which undergoes HCL mediated dehydration forming alkene (3.1.10), the
-subsequent hydrogenation of which catalyzed by PtO gives desired perhexi-
-2
-line (3.1.11) [23,24]. An alternative approach was demonstrated, using as
-starting ketone, bezophenone (3.1.12), which on reaction with lithiated 2-
-picoline gives tertiary alcohol (3.1.13), which after dehydration using hydro-
-chloric acid gives alkene (3.1.14), the hydrogenation of which catalyzed by
-PtO [25] or in presence Raney-Ni [26] or Rh-Al O [27] gives desired per-
-2 2 3
-hexiline(3.1.11) (Scheme3.2).
-O
-HO N HCl N H 2/PtO 2
-3.1.8
-BuLi O N
-N or PhLi 3.1.9 3.1.10 H/PtO, H
-3.1.7 or2 Rane2 y-Ni,
-3.1.12 HO N HCl N or Rh-Al 2O 3 Perhexiline 3.1.11
-3.1.13 3.1.14
-SCHEME3.2 Synthesisofperhexiline.
-Two enantiomers, (1)- and ((cid:1))-perhexiline have different pharmacody-
-namic profiles. It has been suggested that the ((cid:1))-enantiomer is primarily
-responsible for the therapeutic effects, whereas the (1)-enantiomer is primar-
-ily responsible for the toxic effects [17]. Optically enriched perhexiline has
-been obtained by resolution of the 1,10-binaphthyl-2,20-diyl(hydrogen)phos-
-phatediastereomeric salts of perhexiline[28].
-Synthesis of both enantiomers of perhexiline in high enantiomeric excess
-through a stereoselective catalytic hydrogenation of the 2-(oxazolidin-2-one)-
-substituted-pyridine and the elucidation of the absolute configurations of the
-twoenantiomersofperhexilinewhichwasunknown,wasrecentlyreported[29]."
-PIPRADROL,259,"Pipradrol (3.1.17) is a dopamine reuptake inhibitor and norepinephrine reup-
-take inhibitor, a mild amphetamine type psychostimulant with action similar
-2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 105
-to methylphenidate. Pipradrol was developed in the 1950s as an antidepres-
-sant and was used for treatment of obesity and dementia, but the adverse
-effects associated with its use and its abuse potential led to its withdrawal
-and international control [30].
-Pipradrol (3.1.17) was synthesized from pyridyl Grignard reagent prepared
-from 2-pyridyl bromide (3.1.15) and bezophenone (3.1.12), which gave diphe-
-nylpydinemethanol (3.1.16) reduced catalytically to desired pipradrol (3.1.17)
-[31,32]. Enantiomers of pipradrol were synthesized from (R)- and (S)- pipecolic
-acidethers(3.1.18)andtheprobableconformationofthebasewasdeduced.All
-ofthecentralstimulantactivityresidedin(R)-pipradrol,butboththe(R)and(S)
-isomerspossessedanticonvulsantproperties[33](Scheme3.3).
-Mg, EtMgBr OH OH
-Ether or
-Diethyl cellosolve N H 2/PtO 2 N PhMgBr
-N Br O 3.1.12 EtOH H Ether MeOOC N
-3.1.15 3.1.16 Pipradrol 3.1.17 3.1.18
-SCHEME3.3 Synthesisofpipradrol."
-MEFLOQUINE,5370,"Mefloquine(3.1.27),soldunderthebrandnameLariam,isanorallyadminis-
-tered very potent blood schizontocide that has been marketed since 1990 for
-both malaria prophylaxis and for acute treatment of falciparum malaria. It is
-a long-acting antimalarial drug known for its efficacy against chloroquine-
-and SP-resistant Plasmodium falciparum [34(cid:1)37]. Mefloquine can cause
-serious side effects that include nervous system changes.
-The synthesis of mefloquine (3.1.27) began with the synthesis quinolin-4-
-ol (3.1.21) obtained by polyphosphoric acid condensation of the ethyl 4,4,4-
-trifluoroacetoacetate (3.1.19) with O-trifluoromethylaniline (3.1.20). A further
-conversion of prepared (3.1.21) by POBr into the 4-bromoquinoline (3.1.22)
-3
-led to the transformation of the last 4-Li derivative (3.1.23) followed by CO
-2
-carboxylation gave cinclioninic acid (3.1.24). Addition of 2-pyridyllithium
-(3.1.25) gavethepyridyl ketone(3.1.26).Hydrogenationwith H -PtO gave a
-2 2
-goodyieldofdesiredmefloquine(3.1.27)[38,39](Scheme3.4).
-F 3CO O OEt+F 3C
-HN
-15P 0P °A
-C F
-3F C3C
-N OHP 1O 40B °r C3
-FF 3C3C
-N
-Br
-n E-B thu eL ri
-F
-3F C3C
-N
-LipC owO
-Ed2
-t
-e
-h(d
-r
-eer ry
-d)
-2
-3.1.19 3.1.20 3.1.21 3.1.22 3.1.23
-F 3C
-N Li
-F 3C F 3C
-N 3.1.25 N H 2/PtO 2 N
-F 3C COOH Ether F 3C
-O
-N EtOH F 3C OHN
-H
-3.1.24 3.1.26 Mefloquine 3.1.27
-SCHEME3.4 Synthesisofmefloquine.
-106 Piperidine-BasedDrugDiscovery
-None of the optically active forms of mefloquine (3.1.27) resolved via its
-hydrochloride salt with (1)- and ((cid:1))-3-bromo-8-camphorsulfonic acid
-ammonium salts showed any significant differences in antimalarial activity
-[40]."
-MEPIVACAINE,4176,"Many local anesthetics are presently available for clinical use, and among
-them many derivatives of 2-substituted piperidines. The choice of a particu-
-lar agent for a particular case is based mainly on its clinical and pharmaco-
-logical features.
-Mepivacaine(3.1.31),launchedonthemarketasCarbocaineandPolocaine,
-is a local anesthetic with a reasonably rapid onset and medium duration of
-action that became available in the 1960s. Mepivacaine exerts its local anes-
-thetic effect by blocking voltage-gated sodium channels in peripheral neurons,
-whichcreatestemporary anesthesia (lackoffeelingornumbness).Mepivacaine
-is used for causing numbness during surgical procedures, labor, or delivery
-[41,42].Itmaycausedizziness,drowsiness,orblurredvision.
-Two basic methods for the synthesis of mepivacaine are proposed. The first
-comprises the transformation of ethyl 1-methylpipecolate (3.1.30) to
-1-methylpiperidine-2-carboxylicacidamidewithmagnesium(2,6-dimethylphenyl)
-amidebromide(3.1.29)underrefluxinether.Amagnesiumderivative(3.1.29),in
-turn, was prepared via interaction of 2,6-xylidine (3.1.28) with ethylmagnesium
-bromide[43(cid:1)45].
-Inanothermethod,picolinicacidwasconvertedtoitsamide(3.1.32),hydro-
-genated over platinum on carbon catalyst, and alkylated at the piperidine ring
-nitrogenwithformalinusingpalladiumoncarbon[43,45,46](Scheme3.5).
-O
-N
-H OEt O N O N O N
-NH 2EtMgBr NMgBr 3.1.30 NH H 2/Pd-C NHH H 2/Pt-C NH
-Ether Ether CH 2O EtOH, HCl
-Reflux H 2O
-3.1.28 3.1.29 Mepivacaine 3.1.31 3.1.33 3.1.32
-SCHEME3.5 Synthesisofmepivacaine.
-(1)-Mepivacaine(cid:1)(S)-configuration is a longer-acting local anesthetic
-than the mixture enantiomers obtained during synthesis [47]."
-ROPIVACAINE,6847,"Ropivacaine (3.1.37) (Naropin) is the pure S((cid:1))-enantiomer of propivacaine
-releasedfor clinicaluse in1996.It is along-acting, well toleratedlocal anes-
-thetic agent and first produced as a pure enantiomer. Its effects and
-2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 107
-mechanism of action are similar to other local anesthetics working via
-reversible inhibition of sodium ion influx in nerve fibers. It may be a pre-
-ferred option among other drugs among this class of compounds because of
-its reduced CNS and cardiotoxic potential and its lower propensity for motor
-block inthe management ofpostoperative pain and labor pain [48(cid:1)58].
-Thesynthesisofropivacaine(3.1.37)wascarriedoutstartingwithL-pipeco-
-licacid(3.1.34),preparedbyaresolutionof(6)-pipecolicacidwith(1)-tartaric
-acid, which was dissolved in acetyl chloride and converted to acid chloride
-(3.1.35) with phosphorus pentachloride. The obtained compound (3.1.35) dis-
-solvedin toluenea solutionof2,6-xylidine(3.1.28) dissolved in themixture of
-equal volumes of acetone, and N-methyl-2-pyrrolidone was added at 70(cid:3)C to
-give (1)-L-pipecolic acid-2,6-xylidide (3.1.36). Reactionof this compoundwith
-propyl bromide in presence of potassium carbonate in i-PrOH/H O gave the
-2
-desiredropivacaine(3.1.37)[59](Scheme3.6).
-NH
-2
-PCl 3 3.1.28 O N PrBr O N
-O N AcCl O N Toluene, NH H K 2CO 3 NH
-OH H Cl H Acetone/NMP i-PrOH/HO
-2
-Ropivacaine
-3.1.34 3.1.35 3.1.36 3.1.37
-SCHEME3.6 Synthesisofropivacaine.
-Another approach for the synthesis of ropivacaine (3.1.37) was proposed
-via aresolution ofenantiomers ofchiral pipecolic acid-2,6-xylidide [60]."
-BUPIVACAINE (21293) AND LEVOBUPIVACAINE,1976,"Bupivacaine (3.1.41) (Marcaine) is a local anesthetic of great potency and
-long duration that has been widely used for years, but it has cardio and CNS
-toxicsideeffects. Formanyyearsitwasnearlytheonly localanestheticappli-
-cable to almost all kinds of loco-regional anesthetic techniques, and nowa-
-days,inmanyoccasions,itisstilltheonlyalternativeavailable[61(cid:1)64].
-Bupivacaine is currently used in racemic form. At high doses, however,
-the racemate is potentially hazardous dueto toxicity problems.
-Currently, racemic bupivacaine (3.1.41) is produced from picolinic acid
-(3.1.38) either by reduction to pipecolic acid (3.1.39) and then, after conver-
-sion to corresponding acid chloride (3.1.40) coupling with 2,6-xylidine to
-give pipecolic acid-2,6-xylidide (3.1.33), or by reducing the pyridyl amide
-(3.1.43) prepared from picolinic acid chloride (3.1.42) over platinum oxide.
-The amide intermediate (3.1.33), which can also be used to prepare the anes-
-thetics ropivacaine (3.1.37) and mepivacaine (3.1.31), was transformed to
-desired bupivacaine (3.1.41) either by direct alkylation using butyl bromide
-and potassium carbonate or by reductive amination using butyraldehyde
-[45,59,65(cid:1)69](Scheme3.7).
-108 Piperidine-BasedDrugDiscovery
-NH
-2
-H 2/PtO 2 PCl 3 3.1.28
-EtOH, AcOH O N AcCl O N Toluene,
-OHH Cl H Acetone/NMP
-3.1.39 3.1.40
-BuBr
-O N NH O N K 2CO 3or O N
-OH 2 NHH NH
-3.1.38 SOCl 2 3.1.28 O N H 2/PtO 2 P Hr CC OH OO H,
-Reflux O N Toluene NH H 2O/HCl 3.1.33 Bupivacaine3 .1.41
-Cl
-3.1.42 3.1.43
-SCHEME3.7 Synthesisofbupivacaine.
-Enantiomers of bupivacaine can be prepared via diastereomeric salt reso-
-lution with tartaric acid or by resolution of the amide (3.1.33) with O,
-O-dibenzoyltartaricacidfollowed by alkylation [47,70].
-One of enantiomers, S((cid:1)) isomer of the racemic bupivacaine (levobupiva-
-caine), has equal potency but less cardiotoxic and CNS effects in comparison
-with both R(1) bupivacaine and bupivacaine racemate. The reduced toxicity of
-levobupivacaine(3.1.48)givesawidersafetymargininclinicalpractice[71,72].
-Stereospecific synthesis of levobupivacaine from (S)-lysine have been
-proposed (Scheme3.8).
-NH
-2
-HO O
-O
-NN aa ONO Ac2,
-,
-HO O
-O 3.1.28
-H 2N N O AcOH AcO N O DCC
-H H
-3.1.44 3.1.45
-1. KCO, BuBr,
-HN OO 2M
-.
-e T2 O sCH I3
-,
-HN OO H 2/Pd-C O NHN
-H
-K P2 rC CO H3 Oo ,r O NHN
-AcO N O EtN TsO N O HCOOH
-H 3 H
-Levobupivacaine
-3.1.46 3.1.47 3.1.33 3.1.48
-SCHEME3.8 Synthesisoflevobupivacaine.
-Treatment of N-CBZ (S)-lysine (3.1.44) with sodium nitrite in acetic acid
-yields the acetate (3.1.45). The prepared acetate (3.1.45) was then coupled
-with dimethyl aniline using N,N0-dicyclohexylcarbodiimide to give the amide
-(3.1.46)ingoodyield.Theacetategroupwasthenconvertedintothetosylate
-(3.1.47), which was deprotected and cyclized stereospecifically in one-pot
-reaction to give the amide (3.1.33) in high yield. Alkylation is easily
-achieved using an alkyl bromide and K CO without any racemization.
-2 3
-Alkylation can also be carried out using butyraldehyde/formic acid although
-the former is amuchsimpler process[73] (Scheme3.8).
-2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 109"
-FLECAINIDE,3638,"Flecainide (3.1.54), sold under the trade name (Tambocor), is an antiarrhyth-
-micdrugusedtopreventandtreattachyarrhythmias,awidevarietyofcardiac
-arrhythmias including paroxysmal atrial fibrillation, paroxysmal supraventric-
-ular tachycardia and ventricular tachycardia, and has been used extensively
-worldwide over the last 25 years. It is a sodium channel blocker that is effec-
-tivemedicinefortachyarrhythmia,forwhichtheotherantiarrhythmicmedica-
-tion is not effective. Flecainide is also effective in the treatment of
-catecholaminergic polymorphic ventricular tachycardia but, in this condition,
-its mechanism of actionis contentious.It can be given either intravenously or
-orally and its pharmacokinetic properties allow for a relatively long (12
-hours) effect. Flecainide is an antiarrhythmic agent that has the potential to
-be considered an narrow therapeutic index drug that has a narrow window
-between its effective dose and a dose at which it can produce adverse toxic
-effects (dizziness, vision problems, shortness of breath, headache, nausea,
-vomiting, stomach pain, diarrhea, constipation, tremor or shaking, tiredness,
-weakness,anxiety,depression,numbness,ortingling)[74(cid:1)79].
-The original synthesis of flecainide is described on the Scheme 3.9,
-where a solution of 2,5-dihydroxybenzoic acid (3.1.49) in acetone was added
-to a suspension of KHCO in acetone followed by a solution of 2,2,2-tri-
-3
-fluoroethyl trifluoromethanesulfonate (3.1.50) and stirred under reflux for 72
-hours to give 2,2,2-trifluoroethyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate
-(3.1.51). The key step in this route is aminolysis. For that purpose obtained
-benzoate (3.1.51) was added to a stirred solution of 2-aminomethylpyridine
-(3.1.52) in glyme to give (3.1.53). Catalytic hydrogenation of the resultant
-N-(2-pyridylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide (3.1.54) was
-carried outinAcOH over PtO togive desired flecainide(3.1.54) [80(cid:1)83].
-2
-A significant simplification in the synthesis was achieved by the use of
-2-aminmethylpiperidine (3.1.55) [84] (Scheme 3.9).
-N
-O OH O O CF 3 H 2N N O NH
-OH +F 3C SO KHCO 3 O CF 3 3.1.52 O CF 3
-HO O O CF 3 RA efc lue xto 7n 2e
-h
-F 3C O Glyme F 3C O
-3.1.49 3.1.50 3.1.51 3.1.53
-H/PtO
-2 2
-AcOH
-N
-H 2N
-N
-O NHH
-H O CF
-3.1.55 3
-Glyme FC O
-3
-Flecainide 3.1.54
-SCHEME3.9 Synthesisofflecainide.
-110 Piperidine-BasedDrugDiscovery"
-ENCAINIDE,682,"Encainide (3.1.62), formerly marketed as Enkaid, is an antiarrhythmic drug
-with class IC activity and has been used in the treatment of life-threatening
-ventricular arrhythmias, symptomatic ventricular arrhythmias, and supraven-
-tricular arrhythmias. The most common noncardiac side effects were dizzi-
-ness and blurred vision and proarrhythmic effects. Encainide was associated
-with increased death rates in patients who had asymptomatic heart rhythm
-abnormalities after a recent heart attack and was withdrawn from the US
-market in 1991 [85(cid:1)89].
-The first step in practically all proposed methods for encainide synthesis
-is based on condensation of picoline (3.1.56) or picolinium salts (3.1.63)
-(methiodide, methsulfate) with 2-nitrobenzaldehyde (3.1.57). In some patents
-and papers a mixture of picoline as well as the aforementioned aldehyde was
-refluxed in acetic anhydride to give 2-[2-(2-Nitrophenyl)ethenyl-2]pyridine
-(3.1.57) [90(cid:1)93]. In others a mixture of previously prepared picolinium salts
-(3.1.63) and 2-nitrobenzaldehyde (3.1.57) was refluxed in methanol in the
-presence of a catalytic amount of piperidine to give product (3.1.64), which
-was dehydrated on reflux in the mixture of acetic acid, acetic anhydride and
-potassium acetateto give (3.1.65)[94,95].
-A solution of 2-[2-(2-nitrophenyl)ethenyl-2]pyridine (3.1.57) in ethanol
-was hydrogenated over Pd-C catalyst forming 2-[2-(2-aminophenyl)ethyl-2]
-pyridine (3.1.58). The obtained product was dissolved in pyridine and acyl-
-ated with 4-anisoyl chloride (3.1.59) at 70(cid:3)C to give amide (3.1.60). The last
-was dissolved in warm acetonitrile, treated with dimethyl sulfate (or methyl
-iodide), and heated to 70(cid:3)C. The resulted crystalline salt (3.1.61) was hydro-
-genatedinethanolusing platinum oxide togive desired encainide (3.1.62).
-In the method started from picolinium salts (3.1.63) (methiodide, meth-
-sulfate), the salt (3.1.65) obtained after dehydration of (3.1.64) was hydroge-
-nated over a platinum oxide catalyst to give 2-(2-(1-methylpiperidin-2-yl)
-ethyl)aniline (3.1.66), which was acylated with 4-anisoyl chloride 4- (3.1.59)
-inacetoneto give desired encainide (3.1.62) (Scheme 3.10).
-Another interesting method for the synthesis of encainide was proposed,
-according to which methyl anthranilate (3.1.67) was acylated with 4-anisoyl
-chloride (3.1.59) in dichloromethane solution to give amide (3.1.68). The
-obtained product on reaction with 2-pyridyllithium (3.1.69) formed product
-(3.1.70) underwent one-pot hydrogenation with Pt-C AcOH, followed by addi-
-tion of Pd-C catalyst, and reductive methylation with formalin in the presence
-ofPd-Ctogiveencainide(3.1.62)withgoodyield[96](Scheme3.11)."
-THIORIDAZINE,6558,"Thioridazine (3.1.73) (Mellaril), is one of the older, first-generation typical
-antipsychotic oral medications used not only for management of
-2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 111
-CHO
-O
-O
-3.1.N 5O 72 NO 2 H 2/Pd-C NH 2 3.1.59 Cl
-N Ac 2O N EtOH N Pyridine
-Reflux
-3.1.56 3.1.58
-O
-O O
-OO S OO H 2/PtO
-2 HN O
-HN O MeCN HN O + EtOH N
-3.1.60N 3.1.61N OO
-S
-OO-
-En 3c .1a .i 6n 2ide
-O
-O
-Cl
-Acetone
-CHO 3.1.59
-AcOH,
-N+ OO S OO- P Mip3 ee. t1 hri. adN 5 ni7O n oe l2 NO OH 2 N+ OO S OO- A RA Ecc etO O2 flO uN H x, a NO 2 N+ OO S OO- H E2 tO/P Ht NH 2 N
-3.1.63 3.1.64 3.1.65 3.1.66
-SCHEME3.10 Synthesisofencainide.
-O O O 1. H 2/Pt, AcOH O
-NH 2 COOCH 3O 3.1.59 Cl Li 3.1.6N 9 32 .. H H2 2/P /Pd d- -C C, CH 2O
-CH 2Cl 2 O NH THF O NHO HN O
-COOCH 3 N N
-3.1.67 3.1.68 3.1.70 Encainide 3.1.62
-SCHEME3.11 Synthesisofencainide.
-schizophrenia but is also widely used for the relief of anxiety, agitation,
-mania, manic depressive psychosis, and behavioral problems. However, evi-
-dence of cardiac complications led to the restriction of its use from 2000 and
-withdrawal worldwide in 2005 because it caused severe cardiac arrhythmias
-and excessive death rates associated with its use [97(cid:1)103].
-It has been shown recently that thioridazine has in vitro activity against
-multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of
-Mycobacterium tuberculosis, and is able to cure antibiotic-susceptible and
--resistant pulmonary tuberculosis infections. Under proper cardiac evalua-
-tion procedures, it is safe and does not produce any known cardiopathy
-[104(cid:1)107].
-The synthesis of thioridazine was achieved through reaction of 2-
-(methylthio)-10H-phenothiazine (3.1.71) and 2-(2-chloroethyl)-N-methylpi-
-peridine (3.1.72) in refluxing xylene in the presence of sodium amide to give
-desired thioridazine (3.1.73)[108(cid:1)110](Scheme3.12).
-112 Piperidine-BasedDrugDiscovery
-S NaNH 2 N N
-S N + Cl N Reflux S
-H
-S
-3.1.71 3.1.72 Thioridazine 3.1.73
-SCHEME3.12 Synthesisofthioridazine."
-RIMITEROL,219,"Rimiterol (3.1.82) is a third-generation, short-acting selective β2-adrenore-
-ceptoragonist used for the treatment of bronchospasm.
-It is not effective by the oral route of administration, but may be of value
-intheintravenoustherapyofsevereasthma.Rimiterolisavailableinpressur-
-ized aerosols. There have been no reports of significant subjective side
-effects following the acute administration of rimiterol by aerosol. There are
-no specific contraindications to rimiterol, but it should be given with care to
-patients with thyrotoxicosis, cardiovascular disease, diabetes mellitus, renal,
-or hepatic dysfunction [111(cid:1)118].
-Synthetic routes to rimiterol (3.1.82) are described. For that purpose 3,4-
-dimethoxyphenyl-2-pyridylcarbinol (3.1.77) was prepared by reaction
-between veratraldehyde (3.1.74) and picolinic acid (3.1.75) on reflux in p-
-cumene, or by treatment of the same aldehyde (3.1.74) with 2-pyridyllithium
-(3.1.76) prepared from 2-bromopyridine and n-butyllithium in ether.
-Obtained carbinol (3.1.77) was oxidized to the corresponding ketone (3.1.80)
-by potassium permanganate in water at 70(cid:3)C, or by dimetliylsulphoxide-
-acetic anhydride mixtures, or by air in boiling nitrobenzene. An alternative
-approach for the synthesis of ketone (3.1.81) was proposed via acylation of
-veratrole (3.1.78) with picolinic acid chloride (3.1.79) in nitrobenzene in the
-presence ofaluminum chloride.
-The protecting methoxy groups in (3.1.80) were changed to hydroxyl
-groups in boiling hydrobromic acid and the product (3.1.81) hydrogenated in
-methanol over platinum oxide to give desired rimiterol (3.1.82) [119(cid:1)122]
-(Scheme 3.13)."
-LOBELINE,1914,"Lobeline (3.1.90) is a plant alkaloid, the main constituent of the 20 known of
-Lobelia inflata, known as Indian tobacco because native Americans smoked
-the driedleavesasa substitutefor tobacco.
-Lobeline has a long history of therapeutic use and, and during the 19th
-century it was prescribed as an emetic or a respiratory stimulant used to treat
-asthma, collapse, and anesthetic accidents. Lobeline has multiple mechan-
-isms ofaction.
-2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 113
-N COOH KMnO/ HO
-4 2
-3.1.75
-p-Cumene O AcO, or
-O HO N AS ir, Nitro2 benzene O N N 3.1.7C 9OCl
-Nitrobenzene O
-O O 3N .1.7L 6i O O O O O
-3.1.74 Ether 3.1.77 3.1.80 3.1.78
-HBr
-HO N O N
-H H 2/PtO 2
-CHOH
-HO 3 HO
-OH OH
-Rimiterol 3.1.82 3.1.81
-SCHEME3.13 Synthesisofrimiterol.
-Lobeline is a high affinity compound for nicotinic acetylcholine recep-
-tors, and it is considered a promising candidate for pharmacotherapy of
-addiction and abuse (smoking, cocaine, amphetamines) and is used in tablets
-as asmoking cessation remedy.
-It has been classified as a compound having many nicotine-like effects
-working as both an agonist and an antagonist at nicotinic receptors, having
-many nicotine-like effects including hypertension, bradycardia and hypoten-
-sion, anxiolytic effects, enhancement of cognitive performance. Lobeline
-inhibits the function of vesicular monoamine and dopamine transporters and
-diminishes the behavioral effects of nicotine and amphetamines. Lobeline
-binds to μ-opiate receptors, blocking the effects of opiate receptor agonists.
-Lobeline esters was shown be useful for treating neurodegenerative diseases
-of the CNS, which include Alzheimer’s disease, Parkinson’s disease,
-Huntington’s disease, etc. [123(cid:1)129].
-Isolation from plants is uneconomical procedure, and many different
-routesof synthesis have been considered.
-The first synthesis of lobeline (3.1.90) started with a Claisen condensa-
-tion between ethyl glutarate (3.1.83) and acetophenone (3.1.84) to give tetra-
-ketone (3.1.85). The last on treatment with ammonia was cyclized to
-piperidine-2,6-diylidene derivative (3.1.86). The carbonyl groups in (3.1.86)
-were reduced by hydrogenation over platinum oxide giving a mixture of
-two diastereoisomers that were separated by crystallization to give
-β-norlobelanidiene (3.1.87). The double bonds in obtained compound
-(3.1.87) were reduced with aluminum amalgam to give (3.1.88), which was
-converted into its methylated derivative (3.1.89) by treatment with methyl
-tosylate.Theproducedcompound(3.1.89)wasconvertedinto(1/(cid:1))-lobeline
-by treatment withan oxidizing agent such aspermanganate, or chromium tri-
-oxide, and then was dissolved by D-tartaric acid giving ((cid:1))-lobeline (3.1.90)
-[130] (Scheme3.14).
-114 Piperidine-BasedDrugDiscovery
-O
-O
-OO
-O + N Ea tN hH er2 O
-OO
-O N 10H 03 °g Cas
-3.1.83 3.1.84 3.1.85
-O O 1.H 2/PtO 2 OH OH Al/Hg OH OH TsMe
-N H Pyridine N H Amalgam N H
-2. Crystal- Ether
-3.1.86 lization 3.1.87 3.1.88
-OH O
-OH OH 1. KMnO
-4 N
-N 2. D-tartaric
-3.1.89 acid Lobeline 3.1.90
-SCHEME3.14 Synthesisoflobeline.
-Another strategy for the synthesis of lobeline (3.1.90) was proposed the
-same year. For that purpose 2,6-lutidine (3.1.91) was condensed with benzal-
-dehyde (3.1.92) at high temperature in presence of zinc chloride to give 2,6-
-distyrylpyridine (3.1.93). Bromination of the last with an excess of bromine
-rand further dehydrobromination with potassium hydroxide gave dipheny-
-lethynylpyridine (3.1.95). Hydration of (3.1.95) with concentrated sulfuric
-acid furnished the diphenacylpyridine (3.1.96). Alkylation of the pyridine
-ring with methyl tosylate gave a quaternary salt (3.1.97) that was reduced to
-lobelanidine (3.1.98). A mild oxidation of (1/(cid:1))-lobelanidine (3.1.98) by
-potassium permanganate gave a mixture of the (1/(cid:1))-lobeline (3.1.90a)
-[131] Scheme 3.15.
-O
-Br Br
-N + H 2Z 3n 5C °Cl 2 N CB Cr 2 l 4 Br N Br K BO eH n/ zE et nO eH
-10h
-3.1.91 3.1.92 3.1.93 3.1.94
-H 2O O O TsMe O + O H 2/PtO 2
-N H 2SO 4 N Benzene N Ts– Methanol
-3.1.95 3.1.96 3.1.97
-OH OH KMnO OH O
-4
-N N
-3.1.98 (+/–)-Lobeline 3.1.90a
-SCHEME3.15 Synthesisof(1/-)-lobeline.
-Described synthetic routes might not be implemented for large scale pre-
-parationsas they are of lowefficiency.
-An efficient process for the preparation of ((cid:1))-lobeline (3.1.90) from
-lobelanine(3.1.99)onindustrialscalehavebeendevelopedusingasymmetric
-hydrogenation with a catalyst system consisting of cyclooctadiene rhodium
-2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 115
-chloride dimer ([RhCl(COD)] ) and (2R,4R)-4-(dicyclohexyl-phosphino)-2-
-2
-(diphenylphosphinomethyl)-N-methylaminocarbonyl pyrrolidine [132,133]
-(Scheme3.16).
-SCHEME3.16 Synthesisoflobeline.
-The chemical precursor for the biosynthesis of lobeline, 2,6-cis-lobelanine
-(3.1.99), was easily obtained by an elegant one-pot synthesis which involves
-Mannich condensation and a Robinson type biomimetic reaction of glutaric
-dialdehyde (3.1.100), benzoylacetic acid (3.1.101), and methylamine hydro-
-chloride(3.1.102)inacetoneandcitratebuffer[134](Scheme3.17).
-O O O O
-pH4, 25°C
-H OO H + 2 OH + CH 3NH 2 Acetone N
-Citrate
-3.1.100 3.1.101 3.1.102 buffer Lobelanine 3.1.99
-SCHEME3.17 Synthesisoflobelanine.
-Perfect reviews on synthesis and chemistry of lobeline are published
-[135(cid:1)138]."
-ARGATROBAN,2627,"Argatroban (3.1.111) (Arganova) is a highly selective direct thrombin inhibi-
-tor indicated for use as an anticoagulant for the treatment and prophylaxis of
-thrombosis in patients with heparin-induced thrombocytopenia (HIT), a dev-
-astating, life-threatening, immune-mediated complication of therapy with
-heparin and in patients undergoing percutaneous coronary intervention who
-have, orare at riskfor HIT.
-Argatroban does not generate antibodies, is not susceptible to degradation
-by proteasesand is cleared hepatically.
-It is a reversible antithrombin agent and therefore exhibits a considerably
-different pharmacological profile. Its mechanisms of action include several
-other processes that have not been explored fully to date. These include the
-inhibition of nonthrombin serine proteases, a direct effect on endothelial cells
-andthevasculature(generationofnitricoxide),anddownregulationofvarious
-116 Piperidine-BasedDrugDiscovery
-inflammatory and thrombotic cytokines. Argatroban is more effective than
-heparins and hirudins inthe antithrombotic managementof microvascular dis-
-orders (Heparin has historically been used as the anticoagulant of choice in
-themanagementofanumberofthromboticdiseases.)[139(cid:1)153].
-The improved synthesis of argatroban (3.1.111) started with prepara-
-tion of racemic (6)-trans-benzyl 4-methyl pipecolic acid ester (3.1.104),
-which was synthesized via α-lithiation and further benzyloxycarbonylation
-sequence of N-Boc-4-methylpiperidine (3.1.103) using for that purpose
-s-BuLi and tetramethylethylene-diamine in ether followed by addition of
-benzyl chloroformate, which yielded the afforded compound (3.1.104).
-After N-Boc deprotection (HCl, AcOEt), the desired benzyl 4-methyl pipe-
-colic acid ester (3.1.105) was obtained. The condensation of compound
-(3.1.105) with
-Nα -Boc-Nω
--nitro-L-arginine (3.1.106), two diastereomers
-(3.1.107a) and (3.1.107b) were obtained and separated by flash chroma-
-tography on silica gel to afford the desired (3.1.107a). After removal of
-the Boc group in (3.1.107a) by (HCl, AcOEt), the obtained compound
-(3.1.108) was transformed to (3.1.110) by treatment with 3-methyl-8-
-quinoline sulfonyl chloride (3.1.109) in dichloromethane in the presence
-of trimethylamine. The hydrogenation of the last over Pd/C catalyst in eth-
-anol/acetic acid mixture effected the debenzylation of the ester group, the
-cleavage of the nitro group, and the hydrogenation of the pyridine ring
-affording desired argatroban (3.1.111) [154] (Scheme 3.18). The first
-patents on the synthesis of argatroban are based on ethyl 4-methyl pipeco-
-lic acid ester [155(cid:1)157].
-NH
-2 COOH
-N N
-TM1 E. Ds A-B , u EL ti her HCl NO 2H Boc NH 3.1.106
-N 2. ClCHCOOCHPh N CHOOCHPh AcOEt N CHOOCHPh i-BuOCOCl
-Boc 2 2 Boc 2 2 H 2 2 EtN
-3
-3.1.103 3.1.104 3.1.105 THF
-NH
-2
-O COOCH 2Ph NH2 O COOCH2Ph
-N N N N N N
-NO 2H Boc NH NO2H BocNH
-3.1.107a 3.1.107b
-HCl
-AcOEt
-N
-NNH N2 O NCOOCH 2PhO CS lO 3.1.109 NNH N2 O NCOCH 2P Hh 2/Pd-C HNNH N2 O NCOOH
-NO 2H NH 2 Et 3N, CH 2Cl 2 NO 2H O 2SNH
-N
-EtOH, AcOH H O 2SNH H
-N
-3.1.108 3.1.110 Argatroban 3.1.111
-SCHEME3.18 Synthesisofargatroban.
-2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 117"
-ASCOMYCIN,752,", PIMECROLIMUS (1645),
-TACROLIMUS (32436), SIROLIMUS (22468), EVEROLIMUS
-(8972), AND TEMSIROLIMUS (2859)
-Series of Ascomycin (3.1.112) derivatives(cid:1)Pimecrolimus (3.1.113),
-Tacrolimus (3.1.114) as well as Sirolimus (3.1.115) and its derivatives
-Everolimus (3.1.116) and Temsirolimus (3.1.117)(cid:1)can formally be considered
-1,2-disubstitutedpiperidines(Fig.3.1).
-O O O
-OH Cl OH
-H H H
-O O O
-N N N
-HO
-O
-OO OH HO
-O
-OO OH HO
-O
-OO OH
-O O O
-O O O
-OHO OH
-O
-OH
-O
-Ascomycin 3.1.112 Pimecrolimus 3.1.113 Tacrolimus 3.1.114
-HO
-HO
-HO
-HO O HO O O O
-O
-N H O O OH N H O O OH N H O O OH
-O OO O O O OO O O O O O O O
-HO HO HO
-O O O
-H H H
-O O O
-Sirolimus 3.1.115 Everolimus 3.1.116 Temsirolimus 3.1.117
-FIGURE3.1 Ascomycin,pimecrolimus,tacrolimus,sirolimus,everolimus,andtemsirolimus.
-The 23-membered macrolactam Ascomycin (3.1.112) and 31-membered
-macrocyclic polyketide Sirolimus (3.1.115) are fermentation products origi-
-nally isolated from the cultured broth of Streptomyceshygroscopicus.
-Ascomycin and its derivatives are powerful calcium-dependent serine/
-threonine protein phosphatase (calcineurin (CaN), protein phosphatase 2B
-inhibitors and have been used therapeutically mainly as immunosuppressants
-in inflammatory skin diseases. Calcineurin inhibitors (CNIs) have been also
-proposed for the treatment of inflammatory and degenerative brain diseases.
-Ascomycin and its derivatives may be useful in preventing ischemic brain
-damage and neuronal death in the treatment of CNS and exhibit anticonvul-
-sant activity. Nonimmunosuppressantactivity of its derivatives as CNS drugs
-probablyshould befurther explored.
-Pimecrolimus (3.1.113) prepared by the substitution of 32-hydroxy group
-in ascomycin with a chlorine with an inversion of configuration and tacroli-
-mus (3.1.114), which was obtained by using the mutant Streptomyces
-118 Piperidine-BasedDrugDiscovery
-species. These compounds have been successfully introduced in the treat-
-ment of atopic dermatitis. They inhibit T cell proliferation, mast cell degran-
-ulation, production, and the release of IL-2, IL-4, IF-γ, and TNF-α. They do
-not effect endothelial cells and fibroblasts, so they do not induce skin atro-
-phy and consequentlyare well tolerated and safe.
-They have been used also for treatment of other inflammatory skin dis-
-eases including psoriasis, lichen planus, seborrheic dermatitis, allergic
-contact dermatitis, vitiligo, pyoderma gangrenosum, alopecia areata, graft-
-versus-host disease, akne rosacea, etc. The pharmacology, use, and modifica-
-tions ofAscomycin and its derivativesare reviewed[158(cid:1)167].
-Sirolimus (3.1.115) also known as Rapamycin, and its derivatives,
-Everolimus (3.1.116) and Temsirolimus (3.1.117), are a class of immunosup-
-pressive drugs approvedfor solid organ transplantation.
-Sirolimus, a mammalian target of rapamycin (mTOR) inhibitors, are a
-kind of macrolide antibiotics, producing by Streptomyces hygroscopicus in
-appropriate fermenting culture had been found to have also potent antiin-
-flammatory, antineoplasms, antiatherosclerosis, antiaging, neuroprotection
-properties.
-Sirolimus and its derivates, everolimus and temsirolimus, have a similar
-structure that inhibits the proliferation of T cells by interfering with a
-serine-threonine kinase, called mTOR. By inhibiting the ubiquitous mTOR
-pathway, they present a peculiar safety profile. Apart from their immuno-
-suppressive effects, these agents may also inhibit endothelial intimal prolif-
-eration, the replication of cytomegalovirus, and the development of certain
-cancers. They are used not only as immunosuppressants after organ trans-
-plantation in combination with CNIs but also as proliferation signal inhibi-
-tors coated on drug-eluting stents [168(cid:1)173].
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