Create 2syntheticdataset-smallparams.json

2syntheticdataset-smallparams.json

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+[
+    {
+        "name": "METHYLPHENIDATE",
+        "id": "11968",
+        "synthesis": "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]."
+    },
+    {
+        "name": "PERHEXILINE",
+        "id": "1216",
+        "synthesis": "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]."
+    },
+    {
+        "name": "PIPRADROL",
+        "id": "259",
+        "synthesis": "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."
+    },
+    {
+        "name": "MEFLOQUINE",
+        "id": "5370",
+        "synthesis": "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]."
+    },
+    {
+        "name": "MEPIVACAINE",
+        "id": "4176",
+        "synthesis": "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]."
+    },
+    {
+        "name": "ROPIVACAINE",
+        "id": "6847",
+        "synthesis": "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]."
+    },
+    {
+        "name": "BUPIVACAINE",
+        "id": "21293",
+        "synthesis": "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"
+    },
+    {
+        "name": "FLECAINIDE",
+        "id": "3638",
+        "synthesis": "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"
+    },
+    {
+        "name": "ENCAINIDE",
+        "id": "682",
+        "synthesis": "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)."
+    },
+    {
+        "name": "THIORIDAZINE",
+        "id": "6558",
+        "synthesis": "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."
+    },
+    {
+        "name": "RIMITEROL",
+        "id": "219",
+        "synthesis": "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)."
+    },
+    {
+        "name": "LOBELINE",
+        "id": "1914",
+        "synthesis": "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]."
+    },
+    {
+        "name": "ARGATROBAN",
+        "id": "2627",
+        "synthesis": "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"
+    },
+    {
+        "name": "ASCOMYCIN",
+        "id": "752",
+        "synthesis": ", 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]. REFERENCES [1] BusardoFP,KyriakouC,CipolloniL,ZaamiS,FratiP.Fromclinicalapplicationtocogni- tive enhancement: the example of methylphenidate. Curr Neuropharmacol 2016;14 (1):17(cid:1)27. [2] GadothN.Methylphenidate(ritalin):whatmakesitsowidelyprescribedduringthelast60 years?CurrDrugTherapy2013;8(3):171(cid:1)80. [3] DevosD,MoreauC,DelvalA,DujardinK,DefebvreL,BordetR.Methylphenidate.CNS Drugs2013;27(1):1(cid:1)14. [4] Patrick KS, Markowitz JS. Pharmacology of methylphenidat, amphetamine enantiomers andpemolineinattention-deficithyperactivitydisorder.HumanPsychopharmacol1997;12 (6):527(cid:1)46. [5] HartmannM,PanizzonL.Pyridineandpiperidinederivatives,US2507631;1950. [6] HuntleyCFM,KataistoEW,LaLumiereKD,ReischHA.Aprocessforthepreparationof methylphenidatehydrochloride,WO2012080834;2012. [7] StefanickSM,SmithBJ,BarrC,DobishMC.Aprocessforthepreparationofmethylphe- nidate,WO2015069505;2015. 2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 119 [8] DeutschHM,ShiQ,Gruszecka-KowalikE,SchweriMM.Synthesisandpharmacologyof potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring- substitutedmethylphenidateanalogs.JMedChem1996;39(6):1201(cid:1)9. [9] PrashadM,KimH-Y,LuY,LiuY,HarD,RepicO,etal.Thefirstenantioselectivesynthe- sisof(2R,20R)-threo-(1)-methylphenidatehydrochloride.JOrgChem1999;64(5):1750(cid:1)3. [10] RometschR.Stereoisomersofα-phenyl-α-(2-piperidyl)aceticacid,US2838519;1958. [11] RometschR.Conversionofstereoisomers,US2957880;1960. [12] Khetani V, Luo Y, Ramaswamy S. Resolution of piperidylacetamide stereoisomers, WO 9852921;1998. [13] Prashad M, Har D, Repic O, Blacklock TJ, Giannousis P. Enzymic resolution of (6)-threo-methylphenidate.Tetrahedron:Asymmetry1998;9(12):2133(cid:1)6. [14] RenalsonKS,KalambeAB,PanhekarDY.Efficientmethodforenantioselectivesynthesis ofdexmethylphenidatehydrochloride(Focalin).IntJResDevelopPharmLifeSci2014;3 (4):1066(cid:1)9. [15] Weisz I, Dudas A. Stereoisomeric 2-piperidylphenylacetic acid esters. The spatial struc- tureofa7-phenylazabicyclo[4.2.0]octane.MonatshChem1960;91:840(cid:1)9. [16] Shafi’eeA,HiteG.Absoluteconfigurationsofthepheniramines,methylphenidates,and pipradrols.JMedChem1969;12(2):266(cid:1)70. [17] Ashrafian H, Horowitz JD, Frenneaux MP. Perhexiline. Cardiovasc Drug Rev 2007;25 (1):76(cid:1)97. [18] HorowitzJD,ChirkovYY.Perhexilineandhypertrophiccardiomyopathy:anewhorizon formetabolicmodulation.Circulation2010;122(16):1547(cid:1)9. [19] Killalea SM, Krum H. Systematic review of the efficacy and safety perhexiline in the treatmentofischemicheartdisease.AmJCardiovascDrugs2001;1(3):193(cid:1)204. [20] HudakWJ,LewisRE,LucasRW,KuhnWL.Reviewofthecardiovascularpharmacology ofperhexiline.PostgraduateMedicalJSuppl1973;49(3):16(cid:1)25. [21] WinsorT.Clinicalevaluationofperhexilinemaleate.ClinPharmacolTherapeut1970;11 (1):85(cid:1)9. [22] HudakWJ,LewisRE,KuhnWL.Cardiovascularpharmacologyofperhexiline.JPharmacol ExpTherapeut1970;173(2):371(cid:1)82. [23] PalopoliFP,KuhnWL.1,1-Dicyclohexyl-2-(2-piperidyl)ethylene,US3038905;1962. [24] NoInventordataavailable,1,1-Dicyclohexyl-2-(2-piperidyl)ethane,GB1025578;1966. [25] BianchettiG,ViscardiR.1,1-Dicyclohexyl-2-(20-piperidyl)ethane,DE2643473;1977. [26] Horgan SW, Palopoli FP, Schwoegler EJ. 2-(2,2-Dicyclohexylethyl)piperidines, DE 2713500;1977. [27] HorganSW,PalopoliFP,WenstrupDL.DE2714081;1977. [28] Davies BJ, Herbert MK, Culbert JA, Pyke SM, Coller JK, Somogyi AA, et al. J ChromatogrBAnalytTechnolBiomedLifeSci2006;832(1):114(cid:1)20. [29] TsengC,GreigIR,HarrisonWTA,ZandaM.Asymmetricsynthesisandabsoluteconfigu- rationof(1)-and(2)-perhexiline.Synthesis2016;48(1):73(cid:1)8. [30] White MW,Archer JRH. Pipradroland pipradrolderivatives. In: Dargan PI,Wood DM, editors.Novelpsychoactivesubstances.Amsterdam:ElsevierInc.;2013.p.233(cid:1)59. [31] Tilford CH, Shelton RS, Van Campen Jr. MG. Histamine antagonists. Basically substi- tutedpyridinederivatives.JAmChemSoc1948;70:4001(cid:1)9. [32] WernerHW,TilfordCH.α,α-Diarylpiperidinemethanols,US2624739;1953. [33] Portoghese PS, PazdernikTL, Kuhn WL, Hite G, Shafi’ee A. Stereochemicalstudies on medicinal agents. V. Synthesis, configuration, and pharmacological activity of pipradrol enantiomers.JMedChem1968;11(1):12(cid:1)15. 120 Piperidine-BasedDrugDiscovery [34] Singh SK, Singh S. A brief history of quinoline as antimalarial agents. Int J Pharm Sci RevRes2014;25(1):295(cid:1)302. [35] WongsrichanalaiC,PrajakwongS,MeshnickSR,ShanksGD,ThimasarnK.Mefloquine- its 20 years in the Thai Malaria Control Program. Southeast Asian J Tropical Med Publ Health2004;35(2):300(cid:1)8. [36] WinstanleyP.Mefloquine:thebenefitsoutweightherisks.BritJClinPharmacol1996;42 (4):411(cid:1)13. [37] PalmerKJ,HollidaySM,BrogdenRN.Mefloquine:areviewofitsantimalarialactivity, pharmacokineticpropertiesandtherapeuticefficacy.Drugs1993;45(3):430(cid:1)75. [38] Lutz RE,Ohnmacht CJ, Patel AR. Antimalarials. 7. Bis(trifluoromethyl)-α-(2-piperidyl)- 4-quinolinemethanols.JMedChem1971;14(10):926(cid:1)8. [39] Bomches H, Hardegger B. High purity preparation of mefloquine hydrochloride, EP 92185;1983. [40] Carroll FI, Blackwell JT. Optical isomers of aryl-2-piperidylmethanol antimalarial agents. Preparation,opticalpurity,andabsolutestereochemistry.JMedChem1974;17(2):210(cid:1)19. [41] TagarielloV,CaporuscioA,DeTommasoO.Mepivacaine:updateonanevergreenlocal anaesthetic.MinervaAnestesiol2001;67(9Suppl.1):5(cid:1)8. [42] HelmyR,YoussefMH,RasheedMH,El-ShirbiniA,MandourA.Pharmacologicalprop- erties of a new local anesthetic drug (mepivacaine hydrochloride). J Egypt Med Assoc 1967;50(11(cid:1)12):688(cid:1)701. [43] EkenstamBT,EgnerBPH.AmidesofN-alkylpiperidinemonocarboxylicacidandN-alkyl- pyrrolidine-α-monocarboxylicacids,US2799679;1957. [44] RinderknechtH.Newlocalanesthetics.HelvChimActa1959;42:1324(cid:1)7. [45] Ekenstam BT, Egner B, Pettersson G. Local anesthetics. I. N-Alkylpyrrolidine and N-alkylpiperidinecarboxylicacidamides.ActaChemScand1957;11:1183(cid:1)90. [46] Pettersson BG. N-Methylpiperidine-2-carboxylic acid 2,6-xylidide hydrochloride, DE 2726200;1978. [47] TullarBF.Opticalisomersofmepivacaineandbupivacaine.JMedChem1971;14(9):891(cid:1)2. [48] McClureJH.Ropivacaine.BritJAnaesth1996;76(2):300(cid:1)7. [49] McClellanKJ,FauldsD.Ropivacaine:anupdateofitsuseinregionalanesthesia.Drugs 2000;60(5):1065(cid:1)93. [50] Simpson D, Curran MP, Oldfield V, Keating GM. Ropivacaine: a review of its use in regionalanaesthesiaandacutepainmanagement.Drugs2005;65(18):2675(cid:1)717. [51] Hansen TG. Ropivacaine: a pharmacological review. Exp Rev Neurotherapeut 2004;4 (5):781(cid:1)91. [52] WangRD,DanglerLA,GreengrassRA.Updateonropivacaine.ExpOpinPharmacother 2001;2(12):2051(cid:1)63. [53] BansalT,HoodaS.Ropivacaine-anovelandpromisinglocalanaestheticdrug.AsianJ PharmaceutClinRes2012;5(Suppl.1):13(cid:1)15. [54] Kuthiala G, Chaudhary G. Ropivacaine: a review of its pharmacology and clinical use. IndJAnaesth2011;55(2):104(cid:1)10. [55] OwenMD,DeanLS.Ropivacaine.ExpOpinPharmacother2000;1(2):325(cid:1)36. [56] MarkhamA,FauldsD.Ropivacaine:areviewofitspharmacologyandtherapeuticusein regionalanesthesia.Drugs1996;52(3):429(cid:1)49. [57] CasatiA,PutzuM.BestPractResClinAnaesthesiol2005;19(2):247(cid:1)68. [58] DeJongRH.Ropivacaine:whiteknightordarkhorse?RegAnesth1995;20(6):474(cid:1)81. 2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 121 [59] EkenstamBT,BovinC.L-N-n-Propylpipecolicacid2,6-xylidide,WO8500599;1985. [60] FederselHJ,JakschP,SandbergR.Anefficientsynthesisofanew,chiral20,60-pipecolox- ylididelocalanestheticagent.ActaChemScand1987;B41(10):757(cid:1)61. [61] TuominenM.Bupivacainespinalanaesthesia.ActaanaesthesiolScand1991;35(1):1(cid:1)10. [62] Chapman PJ. Review: bupivacaine -a long-acting local anaesthetic. Australian Dental J 1987;32(4):288(cid:1)91. [63] BabstCR,GillingBN.Bupivacaine:areview.AnesthesiaProgress1978;25(3):87(cid:1)91. [64] Gazzotti F, Bertellini E, Tassi A. Best indications for local anaesthetics: bupivacaine. Minervaanestesiologica2001;67(9Suppl.1):9(cid:1)14. [65] TullarBF,BolenCH.1-Butyl-20,60-pipecoloxylidide,GB1166802;1969. [66] No Inventor data available. Amides of N-alkylpiperidinemonocarboxylic acid and N- alkylpyrrolidine-α-monocarboxylicacids,GB775749;1957. [67] No Inventor data available. Amides of N-alkylpiperidinemonocarboxylic acid and N-alkylpyrrolidine-α-monocarboxylicacids,GB775750;1957. [68] BoforsA.N-Alkyl-andcycloalkylpiperidinecarboxylicacidamides,GB869978;1958. [69] Ekesntam BT, Pettersson BG. Synthesis of N-alkylpiperidine and N-alkylpyrrolidine- α-carboxylicacidamides,US2955111;1960. [70] Luduena FP, Tullar BF. Optical isomers of an aminoacyl xylidide, ZA 6802611; 1968. FromS.African(1968),ZA680261119681212. [71] Ivani G, Borghi B, van Oven H. Levobupivacaine. Minerva Anestesiologica 2001;67(9 Suppl. 1):20(cid:1)3. [72] McLeodGA,BurkeD.Levobupivacaine.Anaesthesia2001;56(4):331(cid:1)41. [73] AdgerB,DyerU,HuttonG,WoodsM.Stereospecificsynthesisoftheanestheticlevobu- pivacaine.TetrahedronLett1996;37(35):6399(cid:1)402. [74] Hudak JM, Banitt EH, Schmid JR. Discovery and development of flecainide. Am J Cardiol1984;53(5):17(cid:1)20. [75] Aliot E, Capucci A, Crijns HJ, Goette A, Tamargo J. Twenty-five years in the making: flecainideissafeandeffectiveforthemanagementofatrialfibrillation.Europace2011;13 (2):161(cid:1)73. [76] RodenDM,WoosleyRL.Flecainide:anewagentforthetreatmentofventriculararrhyth- mias.NEnglJMed1986;315(1):36(cid:1)41. [77] TamargoJ,LeHeuzeyJ,MaboP.Narrowtherapeuticindexdrugs:aclinicalpharmaco- logicalconsiderationtoflecainide.EurJClinPharmacol2015;71(5):549(cid:1)67. [78] ApostolakisS,OeffM,TebbeU,FabritzL,BreithardtG,KirchhofP.Flecainideacetate for the treatment of atrial and ventricular arrhythmias. Exp Opin Pharmacother 2013;14 (3):347(cid:1)57. [79] HolmesB,HeelRC.Flecainide:apreliminaryreviewofitspharmacodynamicproperties andtherapeuticefficacy.Drugs1985;29(1):1(cid:1)33. [80] Banitt EH, Coyne WE, Schmid JR, Mendel A. Antiarrhythmics. N-(Aminoalkylene)tri- fluoroethoxybenzamides and N-(aminoalkylene)trifluoroethoxynaphthamides. J Med Chem1975;18(11):1130(cid:1)4. [81] BanittEH,BronnWR,CoyneWE,SchmidJR.Antiarrhythmics.2.Synthesisandantiar- rhythmic activity of N-(piperidylalkyl)trifluoroethoxybenzamides. J Med Chem 1977;20 (6):821(cid:1)6. [82] BanittEH,BronnWR.Derivativesofpyrrolidineandpiperidine,US3900481;1975. [83] BanittEH,BronnWR.Derivativesofpyrrolidineandpiperidine,US4013670;1977. [84] BanittEH,BronnWR.Antiarrhythmicmethodutilizingfluoroalkoxy-N-piperidylandpyr- idylbenzamides,US4005209;1977. 122 Piperidine-BasedDrugDiscovery [85] WoosleyRL,WoodAJJ,RodenDM.Encainide.NEnglJMed1988;318(17):1107(cid:1)15. [86] Mitchell LB, Winkle RA. Encainide. New Drugs Annual: Cardiovasc Drugs 1983;1:93(cid:1)107. [87] Antonaccio MJ, Gomoll AW, Byrne JE. Encainide. Cardiovasc Drugs Ther 1989;3 (5):691(cid:1)710. [88] BrogdenRN,ToddPA.Encainide.Areviewofitspharmacologicalpropertiesandthera- peuticefficacy.Drugs1987;34(5):519(cid:1)38. [89] Somberg JC, Zanger D, Levine E, Tepper D. Encainide: a new and potent antiarrhyth- mic.AmHeartJ1987;114(4Pt1):826(cid:1)35. [90] Dykstra SJ, Minielli JL. Pharmacologically active substituted piperidin, DE 2210154; 1972. [91] DykstraSJ,MinielliJL.Substitutedpiperidines,US4000143;1976. [92] DykstraSJ,MinielliJL,LawsonJE,FergusonHC,DunganKW.Lysergicacidandquin- idineanalogs.2-(o-Acylaminophenethyl)piperidines.JMedChem1973;16(9):1015(cid:1)20. [93] Johnson PC, Covington RR. Synthesis of encainide-13C hydrochloride from 2- nitrobenzaldehyde-formyl-13C.JLabelledCompRadiopharm1982;19(8):953(cid:1)8. [94] No Inventor data available, Preparation of the antiarrhythmic encainide, BE 1000112; 1988. [95] Dillon JL, Spector RH. Process for the preparation of encainide hydrochloride, US 4675409;1987. [96] NoInventordataavailable,Encainide,NL8204775;1983. [97] Gold N. Experience with thioridazine (“Melleril”) therapy. J Mental Sci 1961;107:523(cid:1)8. [98] JonesAL,LewisDJ,MillerA.Useofthioridazine(mellaril)inavarietyofclinicalset- tings.CMAJ1960;83:948(cid:1)9. [99] Barsa JA, Saunders JC. Thioridazine (mellaril) in the treatment of chronic schizophre- nics.AmJPsychiatry1960;116:1028(cid:1)9. [100] Kirchner V, Kelly CA, Harvey RJ. Thioridazine for dementia. Cochrane Database Syst Rev2001;(3):CD000464. [101] Sultana A, Reilly J, Fenton M. Thioridazine or schizophrenia. Cochrane Database Syst Rev2000;(3):CD001944. [102] Fenton M, Rathbone J, Reilly J, Sultana A. Thioridazine for schizophrenia. Cochrane DatabaseSystRev2007;(3):CD001944. [103] Abdel-MoetyEM,Al-Rashood,KhalidA.Analyticalprofileofthioridazineandthiorida- zinehydrochloride.AnalProfilesDrugSubst1989;18:459(cid:1)525. [104] DuttaNK,KarakousisPC.Thioridazinefortreatmentoftuberculosis:promisesandpit- falls.Tuberculosis2014;94(6):708(cid:1)11. [105] AmaralL,MolnarJ.WhyandhowtheoldneurolepticthioridazinecurestheXDR-TB. Pharmaceuticals2012;5:1021(cid:1)31. [106] Thanacoody RHK. Thioridazine: the good and the bad. Rec Pat Anti-Infect Drug Disc 2011;6(2):92(cid:1)8. [107] Thanacoody HKR. Thioridazine: resurrection as an antimicrobial agent? Brit J Clin Pharmacol2007;64(5):566(cid:1)74. [108] Bourquin JP, Schwarb G, Gamboni G, Fischer R, Ruesch L, Guldimann S, et al. Syntheses in the phenothiazine family. II. N-Substituted phenothiazinethiol derivatives. HelvChimActa1958;41:1072(cid:1)108. [109] NoInventordataavailable.2-Mercaptophenothiazinederivatives,GB863550;1961. [110] NoInventordataavailable.2-Mercaptophenothiazinederivatives,GB863551;1961. 2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 123 [111] PinderRM,BrogdenRN,SpeightTM,AveryGS.Rimiterol:areviewofitspharmaco- logicalpropertiesandtherapeuticefficacyinasthma.Drugs1977;14(2):81(cid:1)104. [112] Muittari A. A brief review of sympathomimetic bronchodilators and a description of a newselectiveagent,rimiterolhydrobromide.Respiration1978;35(3):173(cid:1)80. [113] Carney I, Daly MJ, Lightowler JE, Pickering RW. Comparative pharmacology of WG 253 (rimiterol hydrobromide), a new bronchodilator. Arch Int Pharmacodyn, Therapie 1971;194(2):334(cid:1)45. [114] Griffin JP, Turner P. New bronchodilator (WG 253) in man. J Clin Pharmacol New Drugs1971;11(4):280(cid:1)7. [115] Bowman WC, Rodger IW. Actions of the sympathomimetic bronchodilator, rimiterol (R798), on the cardiovascular, respiratory, and skeletal muscle systems of the anesthe- tizedcat.BritJPharmacol1972;45(4):574(cid:1)83. [116] Palma-Carlos AG, Palma-Carlos GS. Beta-2-agonists of third generation. Allergie et Immunologie1986;18(4):31(cid:1)32,35. [117] LaiCK,TwentymanOP,HolgateST.Theeffectofanincreaseininhaledallergendose after rimiterol hydrobromide on the occurrence and magnitude of the late asthmatic response and the associated change in nonspecific bronchial responsiveness. Am Rev RespDis1989;140(4):917(cid:1)23. [118] Ydreborg SO, Svedmyr N, Thiringer G. Comparison of rimiterol and terbutaline, given byaerosol,inalong-termstudy.ScandJRespDiseases1977;58(2):117(cid:1)24. [119] Sankey GH, Whiting KDE. Cyclic adrenaline derivatives. Aryl-2-piperidylcarbinols. J HetChem1972;9(5):1049(cid:1)55. [120] SankeyGH,WhitingKDE.α-(Hydroxy-andalkoxy-substituted)phenyl-α-(2-piperidinyl) methanols,usefulasbronchodilators,DE2024049;1970. [121] SankeyGH,WhitingKDE.α-(Hydroxyandalkoxysubstituted)phenyl-α-(2-piperidinyl)- methanols,US3910934;1975. [122] KaiserC,RossST.Bronchodilatinghydroxyphenyl-2-piperidinylcarbinols,DE2047937; 1971. [123] AldaheffM.Lobelinesulfate.DrugsofToday1977;13(6):236(cid:1)9. [124] Damaj MI, Patrick GS, Creasy KR, Martin BR. Pharmacology of lobeline, a nicotinic receptorligand.JPharmacolExpTher1997;282(1):410(cid:1)19. [125] DwoskinLP,CrooksPA.Anovelmechanismofactionandpotentialuseforlobelineas atreatmentforpsychostimulantabuse.BiochemPharmacol2002;63(2):89(cid:1)98. [126] MillerDK,LeverJR,RodveltKR,BaskettJA,WillMJ,KrackeGR.Lobeline,apoten- tialpharmacotherapyfordrugaddiction,bindstoμopioidreceptorsanddiminishesthe effectsofopioidreceptoragonists.DrugAlcoholDepend2007;89(2(cid:1)3):282(cid:1)91. [127] Willyard C. Pharmacotherapy: quest for the quitting pill. Nature 2015;522(7557): S53(cid:1)5. [128] McCurdy CR, Miller RL, Beach JW. Lobeline:a naturalproduct with high affinity for neuronal nicotinic receptors and a vast potential for use in neurological disorders. In:CutlerSJ,CutlerHG,editors.Biologicallyactivenaturalproducts.BocaRaton,FL: CRCPress;2000.p.151(cid:1)62. [129] Stead LF, Hughes JR. Lobeline for smokingcessation. Cochrane Database SystemRev 2012;(2):CD000124. [130] Wieland H, Drishaus I. Lobelia alkaloids. IV. Synthesis of lobelia alkaloids. Just Lieb Ann1929;473:102(cid:1)18. [131] Scheuing G, Winterhalder L. Synthesis of lobelia alkaloids. Just Lieb Ann 1929;473:126(cid:1)36. 124 Piperidine-BasedDrugDiscovery [132] KlinglerF,SobottaR.Processformanufacturingofchirallobeline,US200600114791; 2006. [133] Klingler FD. Asymmetric hydrogenation of prochiral amino ketones to amino alcohols forpharmaceuticaluse.AccChemRes2007;40(12):1367(cid:1)76. [134] SchopfC,LehmannG.Synthesesandtransformationsofnaturalproductsunderphysio- logical conditions (modelexperiments onthe questionofthebiogenesisofnaturalpro- ducts). IV. Syntheses of tropinone, pseudopelletierine, lobelanine and related alkaloids underphysiologicalconditions.JustLiebAnn1935;518:1(cid:1)37. [135] Felpin F, Lebreton J. History, chemistry and biology of alkaloids from Lobelia inflate. Tetrahedron2004;60(45):10127(cid:1)53. [136] FelpinF,LebretonJ.Ahighlystereoselectiveasymmetricsynthesisof(-)-Lobelineand (-)-Sedamine.JOrgChem2002;67(26):9192(cid:1)9. [137] KlinglerFD.Developmentofefficienttechnicalprocessesfortheproductionofenantio- pureaminoalcoholsinthepharmaceuticalindustry,SynthesisofLobeline,Lobelaneand their Analogues. In: Blaser H, Federsel H, editors. A review, asymmetric catalysis on industrialscale.2ndEditionWeinheim:Wiley;2010.p.171(cid:1)85. [138] ZhengG,CrooksPA.Synthesisoflobeline,lobelaneandtheiranalogues.RevOrgPrep ProceduresInt2015;47(5):317(cid:1)37. [139] JeskeWP,FareedJ,HoppensteadtDA,LewisB,WalengaJM.Pharmacologyofargatro- ban.ExpRevHematol2010;3(5):527(cid:1)39. [140] McKeageK,PloskerGL.Argatroban.FromDrugs2001;61(4):515(cid:1)22. [141] Kondo LM, Wittkowsky AK, Wiggins BS. Argatroban for prevention and treatment of thromboembolism in heparin-induced thrombocytopenia. Ann Pharmacother 2001;35 (4):440(cid:1)51. [142] Jeske W, Walenga JM, Lewis BE, Fareed J. Pharmacology of argatroban. Exp Opin InvestDrugs1999;8(5):625(cid:1)54. [143] DhillonS.Argatroban.Areviewofitsuseinthemanagementofheparin-inducedthrom- bocytopenia.AmJCardiovascDrugs2009;9(4):261(cid:1)82. [144] BoggioLN,OzaVLM.Argatrobanuseinheparin-inducedthrombocytopenia.ExpOpin Pharmacother2008;9(11):1963(cid:1)7. [145] RiceL,HurstingMJ.Argatrobantherapyinheparin-inducedthrombocytopenia.ExpRev ClinPharmacol2008;1(3):357(cid:1)67. [146] Escolar G, Bozzo J, Maragall S. Argatroban: a direct thrombin inhibitor with reliable andpredictableanticoagulantactions.DrugsofToday2006;42(4):223(cid:1)36. [147] YehRW,JangI.Argatroban:update.AmHeartJ2006;151(6):1131(cid:1)8. [148] LewisBE,HurstingMJ.Argatrobantherapyinheparin-inducedthrombocytopenia.Fund ClinCardiol2004;47:437(cid:1)74. [149] FareedJ,JeskeWP.Small-moleculedirectantithrombins:argatroban.BestPracticeRes, ClinicalHaematol2004;17(1):127(cid:1)38. [150] WarkentinTE.Managementofheparin-inducedthrombocytopenia:acriticalcomparison oflepirudinandargatroban.ThrombRes2003;110(2(cid:1)3):73(cid:1)82. [151] Bambrah RK, Pham DC, Rana F. Argatroban in heparin-induced thrombocytopenia: rationaleforuseandplaceintherapy.TherapeutAdvChronicDisease2013;4(6):302(cid:1)4. [152] KathiresanS,ShiomuraJ,JangI,ArgatrobanJ.Thrombos.Thrombolys2000;13(1):41(cid:1)7. [153] Saugel B, Schmid RM, Huber W. Safety and efficacy of argatroban in the manage- ment of heparin-induced thrombocytopenia. Clin Med Insights: Blood Disorders 2011;4:11(cid:1)19. 2-Substitutedand1,2-DisubstitutedPiperidines Chapter | 3 125 [154] CossyJ,BelottiDA.Shortsynthesisofargatrobanapotentselectivethrombininhibitor. BioorgMedChem,Lett2001;11(15):1989(cid:1)92. [155] Okamoto S, Hijikata A, Kikumoto R, Tamao Y, Ohkubo K, Tezuka T, et al. N2- Arylsulfonyl-1-argininamides and pharmaceutically acceptable salts, US 4258192; 1981. [156] Kikumoto R, Tamao Y, Ohkubo K, Tezuka T, Tonomura S, Hijikata A, et al. α-(N- Arylsulfonyl-L-argininamides and pharmaceutical compositions containing these sub- stances,EP8746;1980. [157] CossyJ.Selectivemethodologiesforthesynthesisofbiologicallyactivepiperidiniccom- pounds.ChemRecord2005;5(2):70(cid:1)80. [158] Ermertcan AT, Ozturkcan S. Topical calcineurin inhibitors, pimecrolimus and tacroli- mus.AntiinflammAntiallergyAgentsMedChem2007;6(3):237(cid:1)43. [159] Bulusu MARC, Baumann K, Stuetz A. Chemistry of the immunomodulatory macrolide ascomycinandrelatedanalogues.ProgChemOrgNatProd2011;94:59(cid:1)126. [160] MollisonKW,FeyTA,GauvinDM,SheetsMP,SmithML,PongM,etal.Discoveryof ascomycin analogs with potent topical but weak systemic activity for treatment of inflammatoryskindiseases.CurrPharmDes1998;4(5):367(cid:1)79. [161] PaulC,GraeberM,StuetzA.Ascomycins:promisingagentsforthetreatmentofinflam- matoryskindiseases.ExpOpinInvestDrugs2000;9(1):69(cid:1)77. [162] Griffiths CEM. Ascomycin: an advance in the management of atopic dermatitis. Br J Dermatol2001;144(4):679(cid:1)81. [163] Hersperger R, Keller TH. Ascomycin derivatives and their use as immunosuppressive agents.DrugsFut2000;25(3):269(cid:1)77. [164] SimpsonD,NobleS. Tacrolimusointment:a reviewofitsusein atopicdermatitisand itsclinicalpotentialinotherinflammatoryskinconditions.Drugs2005;65(6):827(cid:1)58. [165] ZimmerR,BaumannK,SpernerH,SchulzG,HaidlE,GrassbergerMA.Syntheticmod- ifications of ascomycin. Part V. Access to novel ascomycin derivatives by replacement ofthecyclohexylvinylidenesubunit.CroatChemActa2005;78(1):17(cid:1)27. [166] ZimmerR,GrassbergerMA,BaumannK,HorvathA,SchulzG,HaidlE.Syntheticmod- ificationsofascomycin.II.Asimpleandefficientwaytomodifiediso-ascomycinderiva- tives.TetrahedronLett1995;36(42):7635(cid:1)8. [167] Ferraboschi P, Colombo D, De Mieri M, Grisenti P. First chemoenzymatic synthesis of immunomodulating macrolactam pimecrolimus. Tetrahedron Lett 2009;50 (30):4384(cid:1)8. [168] VezinaC,KudelskiA,SehgalSN.Rapamycin(AY-22,989),anewantifungalantibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot1975;28(10):721(cid:1)6. [169] KlawitterJ,NashanB,ChristiansU.Everolimusandsirolimusintransplantation-related butdifferent.ExpOpinDrugSafety2015;14(7):1055(cid:1)70. [170] MoesDJAR,GuchelaarH,deFijterJW.Everolimusandsirolimusinkidneytransplanta- tion.DrugDiscovToday2015;20(10):1243(cid:1)9. [171] AugustineJJ, Hricik DE. Experience witheverolimus,Transplant. Proc.,2004, 36 2S0, 500S-503S. [172] WebsterAC, LeeVW,ChapmanJR,CraigJC.Targetofrapamycininhibitors(TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipi- ents.CochraneDatabaseSystRev2006;(2):CD004290. [173] Schulze M, Stock C, Zaccagnini M, Teber D, Rassweiler JJ. Temsirolimus. Recent ResultsCancerRes2014;201:393(cid:1)403."
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+]