Wilson and Gisvold's
`Textbook of
`Organic Medicinal
`and Pharmaceutical
`Chemistry
`
`NINTH EDITION
`Edited by
`Jaime N. Delgado
`William A. Remers
`
`J.B. LIPPINCOTT
`
`NOVARTIS EXHIBIT 2038
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 4
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`

`

`Production Manager: Janet Greenwood
`Acquisitions Editor: Lisa McAllister
`Manuscript Editor: Marguerite Hague
`Production: Till & Till, Inc.
`Compositor: Science Typographers, Inc.
`Printer/Binder: The Murray Printing Company
`
`Ninth Edition
`
`1991, by J. B. Lippincott Company
`Copyright (cid:9)
`Copyright 1982 by J. B. Lippincott Company
`Copyright © 1977, 1971, 1966, 1962, 1956 by J. B. Lippincott Company
`Copyright © 1954 by J. B. Lippincott Company
`All rights reserved. No part of this book may be used or reproduced in any manner whatsoever without written
`permission except for brief quotations embodied in critical articles and reviews. Printed in the United States of
`America. For information write J. B. Lippincott Company, East Washington Square, Philadelphia, Pennsylvania 19105.
`
`6 5
`
`Library of Congress Cataloging in Publication Data
`
`Wilson and Gisvold's textbook of organic medicinal and pharmaceutical
`chemistry. — 9th ed. / edited by Jaime N. Delgado and William A.
`Remers : 17 contributors.
`p. cm.
`Includes bibliographical references.
`Includes index.
`ISBN 0-397-50877-8
`1. Chemistry, Pharmaceutical. 2. Chemistry, Organic. I. Wilson,
`. II. Gisvold, Ole, 1904 - (cid:9)
`III. Delgado,
`Charles Owens, 1911 - (cid:9)
`Jaime N. IV. Remers, William A. (William Alan), 1932 -
`V. Title: Textbook of organic medicinal and pharmaceutical
`chemistry.
`[DNLM: 1. Chemistry, Pharmaceutical. QV 744 W754]
`RS403.T43 1991
`615'. 19 — dc20
`DNLM / DLC
`for Library of Congress (cid:9)
`
`90-13652
`CIP
`
`The authors and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are
`in accord with current recommendations and practice at the time of publication. However, in view of ongodig research,
`changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions,
`the reader is urged to check the package insert for each drug for any change in indications and dosage and for
`added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently
`employed drug.
`
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`

`456 I CHOLINERGIC DRUGS AND RELATED AGENTS
`
`Products
`
`Physostigmine, USP is an alkaloid usually ob-
`tained from the dried ripe seed of Physostigma
`venenosum. It occurs as a white, odorless, micro-
`crystalline powder that is slightly soluble in water
`and freely soluble in alcohol, chloroform, and the
`fixed oils. This alkaloid as the free base is quite
`sensitive to heat, light, moisture, and bases, and
`readily undergoes decomposition. When used topi-
`cally to the conjunctiva it is better tolerated than its
`salts. Its lipid solubility properties permit adequate
`absorption from ointment bases.
`Physostigmine is a competitive inhibitor of AChE
`when ACh is simultaneously present. The mecha-
`nism proposed is one of a reversible competition for
`the active site on the enzyme. A noncompetitive
`inhibition is observed when the enzyme is preincu-
`bated with physostigmine.
`
`tral or slightly acidic and take on a red coloration
`after a period. The coloration may be taken as an
`index of the loss of activity of physostigmine solu-
`tions.
`Solutions of physostigmine salicylate are incom-
`patible with the usual reagents that precipitate alka-
`loids, alkalies, and with iron salts. Incompatibilty
`also occurs with benzalkonium chloride and related
`wetting agents because of the salicylate ion.
`Physostigmine in solution is hydrolyzed to methyl-
`carbamic acid and eseroline, neither of which in-
`hibits AChE. Eseroline is oxidized readily to a red
`compound rubreserine38 and is then converted to
`eserine blue and eserine brown. The addition of
`sulfite or ascorbic acid prevents the oxidation of the
`phenol, eseroline, to rubreserine. Hydrolysis does
`take place however and the physostigmine is inacti-
`vated. Solutions are most stable at pH 6 and should
`never be sterilized by heat, but rather by bacterio-
`logic filtration.
`
`0
`
`CH3NHCO
`
`HO
`
`OH -
`
`CH3 (cid:9)
`
`CH3
`
`(0)
`
`I
`I (cid:9)
`CH3 CH3
`Physostigmine
`
`N N
`
`CH3 CH3
`Eseroline
`
`N N
`
`CH3 CH3
`Rubreserine
`
`eserine
`blue
`
`eserine
`brown
`
`Physostigmine Salicylate, USP. Eserine sali-
`cylate. The salicylate of physostigmine may be pre-
`pared by neutralizing an ethereal solution of the
`alkaloid with an ethereal solution of salicylic acid.
`Excess salicylic acid is removed from the precipi-
`tated product by washing it with ether. The salicy-
`late is less deliquescent than the sulfate.
`
`0
`
`Physostigmine is a relatively poor carbamylating
`agent of AChE and is often considered a reversible
`inhibitor of the enzyme. It has a K i value (i.e.,
`k _ i /k +1) on the order of 10 -8 M and is considered
`as a potent inhibitor of the enzyme. Its cholinester-
`ase-inhibiting properties vary with pH (Fig. 12-12).
`The conjugate acid of physostigmine has a pKa of
`about 8 and as the pH is lowered more is in the
`protonated form. The inhibitory action is enhanced
`at lower pHs as shown in Figure 12-12; thus it is
`
`CH3NHC—O
`
`CH3
`
`H 2
`+J"
`-2
`H I H C H 0 -
`7 5 3
`CH3 CH3
`Physostigmine Salicylate
`
`N (cid:9)
`
`Physostigmine salicylate occurs as a white, shin-
`ing, odorless crystal, or white powder that is soluble
`in water (1 : 75), alcohol (1: 16), or chloroform (1: 6),
`but is much less soluble in ether (1 : 250). Upon
`prolonged exposure to air and light, the crystals
`turn red. The red may be removed by washing the
`crystals with alcohol, although this causes loss of
`the compound as well. Aqueous solutions are neu-
`
`100
`
`607-
`
`20—
`
`Neostigmine
`
`6 7 8 9
`pH
`
`10
`
`FIG. 12-12.
`
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`111
`
`obvious that the protonated or salt form makes a
`marked contribution to its activity.
`The ophthalmic effect (miotic) of physostigmine
`and related compounds is due to contraction of the
`ciliary body. This promotes drainage through the
`canal of Schlemm and decreases intraocular pres-
`sure. Hence, physostigmine is used in the treatment
`of glaucoma by direct instillation of a 0.1% to 1%
`solution in the eye. It is directly antagonistic to
`atropine in the eye, and it is sometimes used to help
`restore the pupil to normal size following atropine
`dilatation. Physostigmine also causes stimulation of
`the intestinal musculature and is used in conditions
`of depressed intestinal motility. In gaseous disten-
`tion of the bowel, physostigmine often aids in the
`evacuation of gas as well as restoring normal bowel
`movement. It is administered by injection for this
`purpose. Much research has been done to find syn-
`thetic drugs with a physostigminelike action. This
`has resulted in compounds of the 'neostigmine type
`that, at least for intestinal stimulation, are superior
`to physostigmine.
`Physostigmine Sulfate, USP occurs as a white,
`odorless, microcrystalline powder that is deliques-
`cent in moist air. It is soluble in water 1: 4, 1 : 0.4 in
`alcohol, and 1: 1,200 in ether. It has the advantage
`over the salicylate salt in that it is compatible in
`solution with benzalkonium chloride and related
`compounds.
`Neostigmine Bromide, USP. (m-Hydroxy-
`phenyl)trimethylammonium bromide dimethylcar-
`bamate; dimethylcarbamic ester of 3-hydroxyphenyl-
`trimethylammonium bromide (Prostigmin Bromide).
`A method of preparation is from dimethylcarbamyl
`chloride and the postassium salt of 3-hydroxyphen-
`yldimethylamine. Methyl bromide readily adds to
`the tertiary amine, forming the stable quaternary
`ammonium salt (see formula for neostigmine bro-
`mide). It occurs as a bitter, odorless, white crys-
`talline powder. It is soluble in water (1: 0.5) and in
`alcohol. The crystals are much less hygroscopic than
`are those of neostigmine methylsulfate and thus
`may be used in tablets. Solutions are stable and may
`be sterilized by boiling. Aqueous solutions are neu-
`tral to litmus.
`
`Neostigmine Bromide
`
`Use of physostigmine as a prototype of an indi-
`rect-acting parasympathomimetic drug led to the
`development of stigmine in which a trimethylamine
`
`CHOLINERGIC AGONISTS
`
`I 457
`
`group was placed para to a dimethyl carbamate
`group in benzene. Better inhibition of cholinesterase
`was observed when these groups were placed meta
`to each other, giving the drug neostigmine, a more
`active and useful agent. Although physostigmine
`contains a methyl carbamate functional group,
`greater chemical stability toward hydrolysis was ob-
`tained with, the dimethyl carbamate group in
`neostigmine.39'4°
`After oral or intravenous administration, neostig-
`mine has a half-life of about 50 minutes. About 80%
`of a single intramuscular dose of the drug is ex-
`creted in urine within 24 hours, approximately 40%
`as unchanged and the remainder as metabolities. Of
`the neostigmine that reaches the liver, 98% is me-
`tabolized in ten minutes to 3-hydroxyphenyltri-
`methyl ammonium, which has activity similar to,
`but weaker than, neostigmine. Its transfer from
`plasma to liver cells and then to bile is probably
`passive. Because cellular membranes permit the pas-
`sage of plasma proteins synthesized in the liver into
`the bloodstream through capillary walls or lym-
`phatic vessels, they may not present a barrier to the
`diffusion of quaternary amines such as neostigmine.
`Possibly the rapid hepatic metabolism of neostig-
`mine provides a downhill gradient for the continual
`diffusion of this compound.' A certain amount is
`hydrolyzed slowly by plasma cholinesterase.
`Neostigmine has a mechanism of action quite
`similar to that of physostigmine. Neogtigmine effec-
`tively inhibits cholinesterase at about 10-6 M con-
`centration. Its activity does not vary with pH, and
`at all ranges it exhibits similar cationic properties
`(see. Fig. 12-12). There may be a direct action of the
`drug on tissues innervated by cholinergic nerves,
`but this has not yet been confirmed.
`The uses of neostigmine are similar to those of
`physostigmine, but they differ in that there is greater
`miotic activity, fewer and less unpleasant local and
`systemic manifestations, and greater chemical sta-
`bility. The most frequent application of neostigmine
`is to prevent atony of the intestinal, skeletal, and
`bladder musculature. An important use is in the
`treatment of myasthenia gravis, a condition caused
`by an autoimmune mechanism that requires an in-
`crease in ACh in the neuromuscular junction to
`sustain normal muscular activity.
`Neostigmine Methylsulfate, USP. (m-Hy-
`droxphenyl)trimethylammonium methylsulfate di-
`methylcarbamate; dimethylcarbamic ester of 3-
`hydroxyphenyltrimethylammonium methylsulfate
`(Prostigmin Methylsulfate). Neostigmine is prepared
`as in the method previously described, and the qua-
`ternary ammonium salt is made with methyl sul-
`fate. This compound is a bitter, odorless, white crys-
`talline powder. It is very soluble in water and is
`
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