172

34Lactams and Imides

N-Unsubstituted imides are acidic (pKa of phthalimide in H2O: 8.30) but not enoughto undergo extensive deprotonation under physiological conditions. Lactams arealso more reactive than noncyclic amides because the cis conformation of theamide group in a lactam has higher energy than the trans conformer of an amide.Lactams and imides react with nucleophiles significantly faster than amides. Mostimide-containing drugs are five- or six-membered cyclic imides (Table 34.1), whichare more stable than open-chain imides (Scheme 34.1).

N

O

MeO

O

Aniracetamt1/2 0.6 h, F 0.2%

NH

N

O O

O

NH2

NH

N

O O

O

O

Lenalidomidet1/2 3−8 h, F 70%

Thalidomidet1/2 4−7 h, F high

NH

O O

Glutethimidet1/2 10−12 h, F low

NH

O O

Ethosuximidet1/2 45 h, F 93%

NN

HN

NH

O

OO

O Dexrazoxanet1/2 2−4 h

Scheme 34.1 Imides as drugs.

34.1Pyrazolone Antipyretics

Wilhelm Koenigs and Otto Fischer, working at the University of Munich in the1870s, believed that the antimalarial/antipyretic quinine had a tetrahydroquinolinesubstructure [1]. With the aim of discovering new antipyretic drugs, they prepared

Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and OrganicCompounds, First Edition. Florencio Zaragoza Dorwald. 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

34.2 Five-Membered Lactams as Nootropics 173

some tetrahydroquinolines and gave them to Wilhelm Filehne at the University ofErlangen, who found that one of them, kairine, had indeed antipyretic properties(Scheme 34.2). The compound was launched by Hoechst 1881 but turned out to betoo toxic. It was replaced by the antipyretics kairoline A and later by thalline, butthese compounds still had a low therapeutic index.

NOH

NNH

MeO

NN

O

NN

O

N

Kairine Kairoline A Thalline Phenazonet1/2 12 h, F 97%

Aminopyrinet1/2 2−3 h, F high

Scheme 34.2 Older antipyretic agents.

In 1883, Ludwig Knorr, also at the University of Erlangen, attempted to preparea new tetrahydroisochinoline by treating phenylhydrazine with an acetoacetate.The product turned out to be inactive in Filehnes assay, but he recommended toN-alkylate the compound because N-alkylation had reduced toxicity in kairine andkairoline. The resulting product, phenazone, turned out to be a potent and safeantipyretic. The correct pyrazolone structure was established by Knorr in 1887.This compound was marketed by Hoechst under the trade name antipyrine butwas later renamed phenazone. It became the best-selling drug worldwide and evenoutsold sodium salicylate because it tasted better and did not cause gastric irritation.Phenazone can, however, cause agranulocytosis, a drug-induced, often irreversibledepletion of neutrophilic granulocytes, which can be fatal. To improve potency andreduce toxicity, further analogs of phenazone were developed, such as aminopyrine,phenylbutazone, oxyphenbutazone, azapropazone, and sulfinpyrazone.

34.2Five-Membered Lactams as Nootropics

The first drugs for the treatment of epileptic seizures, bromide salts, were availableas early as 1857. Later, phenobarbital and phenytoin and a number of other, morepotent and selective antiepileptics were developed. In the early 1960s, variousγ-butyrolactams were prepared as cyclic γ-aminobutyric acid (GABA) analogs andtested in animal models, with the aim of discovering new sedatives. However,the compounds turned out to improve memory in rodents, and piracetam andother, related lactams, are used today to improve memory and cognitive function.In 1992, it was discovered at UCB that alkylated derivatives of piracetam hadan anticonvulsant effect in mice, which led to the development of the γ-lactamantiepileptics levetiracetam and brivaracetam [2].

174 34 Lactams and Imides

References

1. Sneader, W. (1996) Antipyretic analgesics. Drug News Perspect., 9, 61–64.2. Rogawski, M.A. (2008) Brivaracetam: a rational drug discovery success story. Br. J.

Pharmacol., 154, 1555–1557.

Table 34.1 Cyclic five-membered amides, carbamates, ureas, imides, and related compounds.V in l kg−1; CL in ml min−1 kg−1; Mwt in g mol−1.

t1/2 4 h V 0.8 PIDOTIMODF 45% CL 2.7 Immunomodulatorpb Mwt 244.3ur 82% PSA 112 A2

log P −2.38

HNN

O

OS

HO2C

t1/2 0.6 h V 2–4 ANIRACETAMF 0.2% CL 141 Nootropicpb – Mwt 219.2 Metabolites:ur – PSA 46.6 A2 N-(4-methoxybenzoyl)glycine,

log P 1.35 4-methoxybenzoic acid

N

OO

MeO

t1/2 18–28 h V – CROMAKALIMF – CL – Potassium channel opener,pb – Mwt 286.3 antihypertensive; Metabolism:ur – PSA 73.6 A2 glucuronidation, oxidation and

log P 1.27 hydrolysis of pyrrolidone tosuccinamide

N

O

OHNC

O

t1/2 4±2 h V 0.5–0.7 NEFIRACETAMF – CL 1.5–2.2 Nootropicpb – Mwt 246.3 Metabolism: hydroxylation ofur 5% PSA 49.4 A2 pyrrolidone (mainly at position 5),

log P 0.64 then ring fission

N

OHN

O

t1/2 5–7 h V 2–3 PRAMIRACETAMF – CL 4–5 Nootropicpb 30% Mwt 269.4ur – PSA 52.7 A2

log P −1.40

N

OHN

ON

t1/2 5±1 h V 0.6±0.1 PIRACETAMF 100% CL – Nootropicpb 0% Mwt 142.2 No metabolismur 80–100% PSA 63.4 A2

log P −1.75

N

OH2N

O

175

t1/2 3–8 h V 1–2 OXIRACETAMF 75±7% CL 1.8 Nootropicpb – Mwt 158.2 Almost no metabolitesur 50–84% PSA 83.6 A2 formed in rats

log P −2.48

N

OH2N

O

OH

t1/2 6–8 h V 0.6±0.1 LEVETIRACETAMF 100% CL 0.96 Antiepilepticpb <10% Mwt 170.2 Metabolism: hydrolysis ofur 70% PSA 63.4 A2 CONH2

log P −0.88

N

OH2N

O

t1/2 8±1 h V 0.5 BRIVARACETAMF 100% CL 0.8 Antiepilepticpb 18% Mwt 212.3 Metabolism: hydrolysis ofur 5–9% PSA 63.4 A2 CONH2

log P 0.88

N

OH2N

O

t1/2 8 h V 0.6 SELETRACETAMF >90% CL – Anticonvulsantpb <10% Mwt 232.2 Metabolism: hydrolysis ofur 30% PSA 63.4 A2 CONH2

log P 0.71

N

OH2N

O F

F

t1/2 3–5 h V – PHENYLPIRACETAMF 100% CL – Nootropicpb – Mwt 218.3ur 40% PSA 63.4 A2

log P 0.70

N

OH2N

O

t1/2 6–8 h V 0.5 ROLIPRAMF 74% CL 2–6 Antidepressant; Metabolism:pb – Mwt 275.3 O-dealkylation, 2- andur Low PSA 47.6 A2 3-hydroxylation of cyclopentyl,

log P 2.00 5-hydroxylation of pyrrolidone; PKof both isomers is similar,only R(−) isomer is active

HN

O

OMe

O

t1/2 12–16 h V 0.9 COTININEF 84–100% CL 0.9 Metabolite of nicotine; Metabolism:pb – Mwt 176.2 N-methylation and oxidation ofur 12% PSA 33.2 A2 pyridine, hydroxylation of

log P 0.08 pyrrolidinone, demethylation,glucuronidation

N

NO

H

(continued overleaf )

176 34 Lactams and Imides

t1/2 4–10 h (iv) V 0.5–1.1 3-HYDROXYCOTININEF – CL 1.1–2.6 Metabolite of cotininepb – Mwt 192.2ur – PSA 53.4 A2

log P −1.12N

NO

H

HO

t1/2 0.9–2.5 h V 1.1–1.6 TOLOXATONEF 50–62% CL 8–14 Antidepressant, MAO inhibitorpb 51% Mwt 207.2 Metabolism: glucuronidation,ur <1% PSA 49.8 A2 oxidation of CH3 to CO2H

log P 1.53

NO

O

HO

t1/2 9–16 h V 0.5–0.7 CIMOXATONEF – CL 0.4–0.8 Antidepressant, MAO inhibitorpb 93–96% Mwt 338.4 Active metabolite: O-desmethylur <1% PSA 71.8 A2 (t1/2 36 h)

log P 2.25

NO

O

MeO

O

CN

t1/2 11–22 h V – BEFLOXATONEF – CL – Antidepressant, MAO inhibitorpb 58% Mwt 349.3 Active metabolite: O-desmethylur <0.2% PSA 68.2 A2 (t1/2 22 h)

log P 1.91

NO

O

MeO

O

CF3

OH

t1/2 4–7 h V 0.6–0.9 LINEZOLIDF 80–100% CL 1.6–2.2 Antibacterialpb 31% Mwt 337.4 Metabolism: oxidative ringur 30–40% PSA 71.1 A2 opening of morpholine

log P 0.45NO

ON

O

HN

O F

t1/2 7–11 h V 0.8 RIVAROXABANF 80–100% CL 2.6 Factor Xa inhibitor, antithromboticpb 92–95% Mwt 435.9 Metabolism: oxidative degradationur 36% PSA 116 A2 of morpholinone to

log P 1.84 N-(2-hydroxyethyl)oxalamide,amide hydrolysis

NO

ON

O

O

HN

OSCl

177

t1/2 4–27 h V 0.17∗ APIXABANF 51%∗ CL 0.8–1.3 ∗chimpanzeepb 87% Mwt 459.5 Anticoagulant, factorur 13% PSA 111 A2 Xa inhibitor

log P 0.56 Metabolism: hydroxylation,O-demethylation, thenO-sulfation

ON

NO

ONN

MeO

NH2

O

t1/2 9–83 h V 0.31∗ ANACETRAPIBF 13%∗ CL 0.11∗ ∗monkeypb >99% Mwt 637.5 Cholesterol ester transferur <0.1% PSA 38.8 A2 protein inhibitor, antilipemic

log P 8.81 Metabolism: O-demethylation,hydroxylation

NO

O

CF3

F3C

CF3

OMe

F

t1/2 9±5 h V/F 12.3 METAXALONEF – CL 17 Muscle relaxantpb – Mwt 221.3 Metabolism: oxidation ofur 27% PSA 47.6 A2 CH3 to CO2H,

log P 1.18 O-dealkylation to phenol

O

NH

O

O

t1/2 14±2 h V 0.7±0.1 TRIMETHADIONEF – CL – Anticonvulsant, teratogenicpb 0% Mwt 143.1 Metabolism: N-demethylationur <3% PSA 46.6 A2 to dimethadione

log P 0.79

O

NO O

t1/2 6–13 d V 0.4–0.5 DIMETHADIONEF – CL – Metabolite of trimethadionepb Low Mwt 129.1ur – PSA 55.4 A2

log P 0.77

O

NH

O O

t1/2 45±8 h V 0.7±0.2 ETHOSUXIMIDEF 93±2% CL/F 0.19±0.04 Anticonvulsantpb 0% Mwt 141.2 Metabolism: hydroxylationur 25±15% PSA 46.2 A2 at ethyl (both carbons)

log P 0.25 and CH2CONH

O O

(continued overleaf )

178 34 Lactams and Imides

t1/2 7.8 h V – PHENSUXIMIDEF – CL – Anticonvulsantpb 21% Mwt 189.2 Metabolism: N-demethylation,ur Low PSA 37.4 A2 aromatic 4-hydroxylation

log P 0.04NO O

t1/2 2.5±1.5 h V – METHSUXIMIDEF – CL – Anticonvulsant; active metabolite:pb Low Mwt 203.2 N-desmethyl (t1/2 2–3 d; pb 50%)ur <1% PSA 37.4 A2 Further metabolism: aromatic and

log P 0.42 methyl hydroxylationNO O

t1/2 40–70 h V 0.8 SORBINILF – CL – Aldose reductase inhibitorpb – Mwt 236.2 Metabolites: 2-hydroxy,ur 26±7% PSA 67.4 A2 5-(2-hydroxyethyl)-5-(2-hydroxy-

log P 0.49 5-fluorophenyl)-imidazolidinedione

F

O

NHHN O

O

t1/2 1–2 h V – FIDARESTATF – CL – Aldose reductase inhibitor,pb – Mwt 279.2 treatment of diabetic neuropathyur – PSA 111 A2

log P −0.13

F

O

NHHN O

O

CONH2

t1/2 5–6 h V 0.25 PIOGLITAZONEF >80% CL – PPAR-γ agonist, insulin sensitizerpb >99% Mwt 356.4 Metabolism: thiazolidinoneur Low PSA 93.6 A2 hydrolysis, benzylic hydroxylation

log P 3.50 of ethyl, then oxidation to ketone(t1/2 16–23 h); withdrawn in 2011because of carcinogenicity

SNH

O

OH

O

N

t1/2 3.6–4.2 h V 0.19 ROSIGLITAZONEF 86–100% CL 0.6 PPAR-γ agonist, insulinpb 99.7% Mwt 357.4 sensitizer; Metabolism:ur 0% PSA 96.8 A2 N-demethylation, 3- and

log P 2.56 5-hydroxylation of pyridine, thensulfation and glucuronidation;withdrawn in 2010 in Europe forincreasing heart attack risk

SNH

O

O

ONN

179

t1/2 10–15 h V 0.14–0.17∗ RIVOGLITAZONEF 76%∗ CL 0.31–0.37∗ ∗monkey; PPAR-γ agonist,pb – Mwt 397.5 insulin sensitizerur 0.3%∗ PSA 103 A2 Metabolism (monkey): O- and

log P 2.95 N-demethylation, thiazolinehydroxylation,thiazoline ring opening

SNH

O

O

ON

N

MeO

t1/2 16–34 h V 2.5 TROGLITAZONEF 40–50% CL 8.5 PPAR-γ agonistpb >99% Mwt 441.5 Metabolism: O-sulfation,ur 0% PSA 110 A2 O-glucuronidation, oxidation to

log P 4.69 benzoquinone (chromane ringscission); withdrawn in 2000because of hepatotoxicity

SNH

O

O

OO

HO

t1/2 38–59 h V – NILUTAMIDEF 80–90% CL 2.5∗ ∗ratpb 84% Mwt 317.2 Antiandrogen, antineoplasticur <2% PSA 95.2 A2 Metabolism:

log P 3.35 CH3-hydroxylation, reduction ofNO2 to NH2, then aromatichydroxylation (ortho to NH2),reduction of C=O to CHOH

HNN

O

O

NO2

CF3

t1/2 8–14 h V – BMS-564929F – CL – Selective androgenpb – Mwt 305.7 receptor modulatorur – PSA 84.6 A2

log P 0.43

NN

O

O

CN

Cl

HHO

t1/2 15±9 h V 0.64±0.04 PHENYTOINF 90±3% CL – Anticonvulsant CYP2C9pb 89±23% Mwt 252.3 substrate, carcinogenur 2±8% PSA 58.2 A2 Metabolism: aromatic

log P 1.42 4-hydroxylation, thenglucuronidation

HN

NH

O

O

t1/2 8–15 min V 0.07–0.17 FOSPHENYTOINF Low CL – Prodrug of phenytoinpb 95–99% Mwt 362.3ur – PSA 126 A2

log P −1.06

HN

NO

OO

POHO

HO

(continued overleaf )

180 34 Lactams and Imides

t1/2 1.9 h (iv) V – MOFEBUTAZONEF >90% CL – Antiinflammatorypb 99% Mwt 232.3 Metabolism: glucuronidationur 8% PSA 49.4 A2

log P 2.26

N

HNO

O

t1/2 56±8 h V 0.1 PHENYLBUTAZONEF 90±10% CL 0.02 Antiinflammatorypb 96±1% Mwt 308.4 Metabolism: aromaticur 1% PSA 40.6 A2 4-hydroxylation

log P 3.38 (to oxyphenbutazone, see below),hydroxylation at CH2CH3

NNO

O

t1/2 27–64 h V 0.15 OXYPHENBUTAZONEF – CL 0.03 Active metabolite ofpb >98% Mwt 324.4 phenylbutazone; withdrawn inur <2% PSA 60.9 A2 1985 for causing blood dyscrasias

log P 2.74N

NO

O

OH

t1/2 22–33 h V 0.3–0.5 FEPRAZONEF – CL 0.1–0.2 Antiinflammatorypb 90% Mwt 320.4 Metabolism: hydroxylation ofur <1% PSA 40.6 A2 methyl and phenyl groups,

log P 3.05 C-glucuronidationN

N

O

O

t1/2 4±1 h V 0.74±0.23 SULFINPYRAZONEF 100% CL 2.4±0.6 Antithrombotic, uricosuricpb 98.3±0.5% Mwt 404.5 Metabolism: oxidation tour 39±9% PSA 76.9 A2 sulfone, reduction to sulfide

log P 1.89 (t1/2 14±5 h)N

N

O

O

SO

t1/2 10–24 h V 0.15 AZAPROPAZONE, APAZONEF 83±19% CL 0.14 Antiinflammatorypb 99.5% Mwt 300.4 Metabolism:ur 63% PSA 56.2 A2 aromatic hydroxylation

log P 1.78

N

NNO

O

N

181

t1/2 10–17 h V 1 MUZOLIMINEF – CL – Diureticpb 65% Mwt 272.1 Metabolism: hydrolysis ofur 5% PSA 58.7 A2 amide, then decarboxylation

log P 2.10

NN

O

H2N

Cl

Cl

t1/2 12 h (iv) V 0.77 ANTIPYRINE, PHENAZONEF 97% CL 0.64 Analgesicpb 7% Mwt 188.2 Metabolism: hydroxylation ofur – PSA 23.6 A2 vinylic methyl group

log P 0.44

NN

O

t1/2 1.0–1.5 h V 1.3–2.0 PROPYPHENAZONEF – CL 11 Analgesic, antipyreticpb Low Mwt 230.3 Metabolism: N-demethylation,ur 0.6% PSA 23.6 A2 hydroxylation of iPr

log P 1.72 and phenyl

NN

O

t1/2 2.1–3.2 h V 0.7 AMINOPYRINE, AMIDOPYRINEF High CL 2 Analgesic, antipyreticpb 15% Mwt 231.3 Metabolism: N-demethylation ofur 3–10% PSA 26.8 A2 NMe2, then N-acetylation and

log P 0.85 N-formylation; withdrawn in 1970because of bone marrowsuppression

NN

ON

t1/2 2.6–3.5 h V – METAMIZOL, DIPYRONEF 85%∗ CL 2.8 ∗metabolites onlypb 58% Mwt 311.4 Analgesic, antipyreticur 2–4% PSA 84.6 A2 Metabolites:

log P −1.50 4-(methylamino)antipyrine(t1/2 3.8 h),4-(formylamino)antipyrine(t1/2 10 h), 4-aminoantipyrinet1/2 4–6 h),4-(acetylamino)antipyrine(t1/2 11 h); withdrawn in1977 for causing agranulocytosis

NN

ON

HO3S

t1/2 4–12 h∗ V 0.5–0.9 CARBIMAZOLEF – CL 3.7 ∗prodrug of methimazolepb 40% Mwt 186.2 (see below); all values:ur 7% PSA 64.9 A2 methimazole on oral dosing of

log P 0.16 carbimazole; antihyperthyroid;complete absorption

NN

S

O

O

(continued overleaf )

182 34 Lactams and Imides

t1/2 3–6 h V 0.6–0.9 METHIMAZOLE, THIAMAZOLEF 95% CL 1.4–3.7 Antihyperthyroidpb – Mwt 114.2 Metabolite:ur 7% PSA 47.4 A2 3-methyl-2-thiohydantoin

log P −0.34 (t1/2 9 h)

NN

SH

t1/2 2–3 h (iv) V 0.3–0.4 AVIBACTAM, NXL-104F – CL 2–3 β-Lactamase inhibitor,pb – Mwt 265.2 antibacterialur – PSA 139 A2

log P −1.87

NN

O

OSNaO O

NH2

OO

t1/2 1–2 h V 1.8 ENOXIMONEF 45–70% CL 6.8–30 Cardiotonicpb 70–85% Mwt 248.3 Metabolism: reversibleur 0.5% PSA 83.5 A2 oxidation to sulfoxide

log P 3.72

NHHN

O

O

MeS

t1/2 1.3 h V 0.6–1.7 PIROXIMONEF >80% CL 7–9 Inotropicpb 85% Mwt 217.2 Metabolism (dog): reduction ofur 64% PSA 71.1 A2 ketone to alcohol, oxidative

log P 2.15 cleavage to isonicotinic acid

NHHN

O

O

N

t1/2 1.5 h V – NAFTAZONEF High CL – Hemostatic, vasoprotectantpb 0% Mwt 215.2 Metabolism: reduction of ketoneur – PSA 84.6 A2 to alcohol, glucuronidation

log P 0.95O

NNH

NH2O

t1/2 4–5 d V 26 AZIMILIDEF 85% CL 2.5 Antiarrhythmicpb 94% Mwt 458.0 Metabolism: oxidation to N-oxide,ur <10% PSA 72.6 A2 N-demethylation, hydrolysis of

log P 3.33 hydrazone and oxidation of CHOto CO2H, N-dealkylation andoxidation to butanoic acid

OCl N

N

NO

O

NN

183

t1/2 9 h V 0.54 DANTROLENEF 70–88% CL – Muscle relaxantpb High Mwt 314.3 Metabolism: reduction of NO2 tour 1–4% PSA 121 A2 NH2, then N-acetylation,

log P 1.07 hydroxylation of CH2NO

O2N NN

HNO

O

t1/2 1.0±0.2 h V 0.58±0.12 NITROFURANTOINF 90±13% CL 9.9±0.9 Antibacterialpb 62±2% Mwt 238.2 Metabolism: reduction of NO2

ur 47±13% PSA 121 A2

log P −0.47OO2N

NN

HNO

O

t1/2 5 h (cattle) V – NITROFURAZONEF – CL – Antibacterialpb – Mwt 198.1 Metabolism: reduction of NO2;ur – PSA 126 A2 withdrawn in 1974

log P 0.47 because of carcinogenicityOO2N

NNH

NH2O

t1/2 3±1 h V 12 NIFURTIMOXAntibacterialMetabolite: nitrite

F Low CL –pb – Mwt 287.3ur <1% PSA 117 A2

log P 0.73OO2N

NN

S OO

t1/2 12–15 h V – NIRIDAZOLEAnthelminticMetabolism: hydroxylation,oxidation to 4-ketoniridazole,hydrolysis of nitrothiazole to 1-thiocarbamoyl-2-imidazolidinone

F – CL –pb – Mwt 214.2ur <1% PSA 119 A2

log P 0.95N

SO2N N NH

O

t1/2 6 min∗ V 30∗ NITAZOXANIDE∗tizoxanide on oral administrationof prodrugProdrug of tizoxanide (t1/2 1.8 h);antiprotozoalMetabolism: deacetylation totizoxanide, then glucuronidation

F High∗ CLF 1.3–2.2∗

pb >99%∗ Mwt 307.3ur – PSA 142 A2

log P 2.74N

SO2NHN

O O O

t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchangeddrug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surfacearea; MAO, monoamine oxidase; PPAR, peroxisome proliferator-activated receptor.