Drugs of the Future 1991, 16(5): 443-458
`Drugs of the Future 1991, 16(5): 443-458
`Copydg~l PROUS SCIENCE
`copyright PROUS SCIENCE
`
`Review Article
`Review Article
`
`Novel chemical approaches in prodrug deSign
`Novel chemical approaches in prodrug design
`
`Hans Bundgaard
`Hans Bundgaard
`Royal Danish School of Pharmacy,
`Royal Danish School of Pharmacy,
`Department of Pharmaceutical Chemist~
`Department of Pharmaceutical Chemistry,
`2 Universitetsparken, DK-2100 Copenhagen, Denmark
`2 Unlversitetsparken, DK-2100 Copenhagen, Denmark
`
`CONTENTS
`CONTENTS
`
`Inlroduction ...................................... 443
`Introduction . . • . • . . . . . . . . . . . . . . . . . . . . . • • • . . . . . • . .. 443
`Ester prodrugs ................................... 444
`Ester prod rugs .....•••...••....••.....•••.....•.. 444
`Double esters .................................. 444
`Double esters ..........•.•....•.......•.....••• 444
`Biolabile glycolamide esters ...................... 445
`Blolabile glycolamide esters •.•..•••••.•.••....••• 445
`Water-soluble ester prodrugs ...................... 446
`Water-soluble ester prodrugs . . . . . . • • . . . . . • . . • • . • •. 446
`Prodrug derivatives of amines ....................... 448
`Prodrug derivatives of amines ...•...••.............. 448
`Prodrug forms for an esler function ................... 448
`Prod rug forms for an ester function •..••.............. 448
`The double prodrug concept ......................... 450
`The double prodrug concept. . . . . . . . . . . . • . . • • .. . • .. .. 450
`Pilocarpine prodrugs ............................. 450
`Pilocarpine prod rugs .. . . . . . • . . . .. .. . . . .. .. . . . . ... 450
`Acyclovir prodrugs .............................. 450
`Acyclovir prod rugs ............••••.............. 450
`Prodrug derivatives of peplides ...................... 452
`Prodrug derivatives of peptides .....•..............•• 452
`Btorevemible dedvatization ol the peptide bond ........ 452
`Bloreversible derivatization of the peptide bond . . . . . . .. 452
`4-1mtdazolidino n e derivatives ...................... 454
`4-lmldazolidinonederivatives ......•..............• 454
`Prodrugs of TRH ................................ 455
`Prodrugs of TRH . . . . . • • . . . • • . . . . • • • . . . . . • . . . . . .. 455
`Conclusions ..................................... 456
`Conclusions ........•....................••••.... 456
`References ...................................... 456
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • • . . . . .. 456
`
`Introduction
`Introduction
`
`Prodrug design comprises an area of drug research that
`Prodrug design comprises an area of drug research that
`is concerned with the optimization of drug delivery. A pro-
`is concerned with the optimization of drug delivery. A pro-
`
`drug is a pharmacologically inactive derivative of a parent
`drug is a pharmacologically inactive derivative of a parent
`drug molecule that requires spontaneous or enzymatic
`drug molecule that requires spontaneous or enzymatic
`transformation within the body in'order to release the active
`transformation within the body inorder to release the actk, e
`drug, and that has improved delivery properties over the
`drug, and that has improved delivery propedies over the
`parent drug molecule.
`parent drug molecule.
`A molecule with optimal structural configuration and phy(cid:173)
`A molecule with optimal structural configuration and phy-
`sicochemical properties for eliCiting the desired therapeutic
`sicochemical properties for eliciting the desired therapeutic
`response at its target site does not necessarily possess the
`response at its target site does not necossadly possess the
`best moleCUlar form and properties for its delivery to its point
`best molecular form and properties for its delivery to its point
`of ultimate action. Usually, only a minor fraction of doses ad(cid:173)
`of ultimate action. Usually, only a minor fraction of doses ad-
`ministered reach the target area and since most agents in(cid:173)
`ministered reach lhe target area and since most agents in-
`teract with non-target sites as well, an inefficient delivery
`teract with non-target sites as well, an inefficient delivery
`may result in undesirable side effects. This fact of differ(cid:173)
`may result in undesirable side effects. This fact of differ-
`ences in transport and in situ effect characteristics for many
`ences in transpod and in situ effect characteristics for many
`drug molecules is the basic reason why bioreverslble chem(cid:173)
`drug molecules is the basic reason why bioreverstble chem-
`ical derivatization of drugs, i.e, prodrug formation, is a
`ical dedvatization of drugs, Le, prodrug formation, is a
`means by which a substantial improvement in the overall ef(cid:173)
`means by which a substantial improvement in the overall ef-
`ficacy of drugs can often be achieved.
`ficacy of drugs can often be achieved.
`Prod rugs are designed to overcome pharmaceutically
`Prodrugs are designed to overcome pharmaceutically
`andlor pharmacokinetically based problems associated
`and/or pharmacokinetically based problems associated
`with the parent drug molecule that would otherwise limit the
`with the parent drug molecule that would otherwise limit the
`clinical usefulness of the drug. The prodrug approach can
`clinical uselulness of the drug. The prodrug approach can
`
`+
`
`Pro-moiety
`Pro-moiety
`
`Enzyma1ic or
`Enzymatic or
`nonenzymatic
`nonenzymatic
`biotransformation
`.-_b-,iotranrormal.-io_n __ ....
`
`Drug
`
`Pro
`
`Drug
`
`Fig. 1. Schematic illustration of the prodrug concept as a means of improving drug absorption.
`Fig. 1. Schematic illustration of the prodrug concept as a means of improving drug absorption.
`
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`Novel chemical approaches in prodrug design
`Novel chemical approaches in prodrug design
`
`be illustrated as shown in Figure 1. The usefulness of a drug
`be illustrated as shown in Figure 1. The usefulness of a drug
`molecule is limited by its suboptimal physicochemical prop-
`molecule is limited by its suboptimal physicochemical prop(cid:173)
`erties, e.g., it shows poor biomembrane permeability. By at-
`erties, e.g., it shows poor biomembrane permeability. Byat(cid:173)
`tachment of a pro-moiety to the molecule or otherwise modi-
`tachment of a pro-moiety to the molecule or otherwise modi·
`lying the compound, a prodrug is formed that overcomes the
`fying the compound, a prodrug is formed that overcomes the
`barrier for the drug’s usetulness. Once past lhe barrier, the
`barrier for the drug's usefulness. Once past the barrier, the
`prodrug is reverted to the parent compound by a post-barri-
`prodrug is reverted to the parent compound by a post-barri(cid:173)
`er enzymatic or non-enzymatic process. Prodrug formation
`er enzymatic or non-enzymatic process. Prodrug formation
`can thus be considered as conferring a transient chemical
`can thus be considered as conferring a transient chemical
`cover to alter or eliminate undesirable properties of the par-
`cover to alter or eliminate undesirable properties of the par(cid:173)
`ent molecule.
`ent molecule.
`The prodnJg approach has been successfully applied to
`The prodrug approach has been successfully applied to
`a wide vadety of drugs. Most of the applications have in-
`a wide variety of drugs. Most of the applications have in(cid:173)
`volved: 1) enhancement of bioavailability and passage
`volved: 1) enhancement of bioavailability and passage
`through various biological barriers, 2) increased duration of
`through various biological barriers, 2) increased duration of
`pharmacological effects, 3) increased site-specificity, 4) de-
`pharmacological effects, 3) increased site-specificity, 4) de(cid:173)
`creased toxicity and adverse reactions, 5) improvement of
`creased toxicity and adverse reactions, 5) improvement of
`organoleptic properties, and 6)improvement ol stability and
`organoleptic properties, and 6) improvement of stability and
`solubility properties (1-6).
`solubility properties (1-6).
`A basic requisite for the prodrug approach to be useful in
`A baSic requisite for the prodrug approach to be useful in
`solving drug delivery problems is the ready availability of
`solving drug delivery problems is the ready availability of
`chemical derivative types satislying the prodrug require-
`chemical derivative types satisfying the prodrug require(cid:173)
`ments, the most prominent of these being reconversion of
`ments, the most prominent of these being reconversion of
`the prodrug to the parent drug in vivo. This prodrug-drug
`the prod rug to the parent drug in vivo. This prod rug-drug
`conversion may take place before absorption (e.g., in the
`conversion may take place before absorption (e.g., in the
`gastrointestinal tract), dudng absorption, after absorption or
`gastrointestinal tract), during absorption, after absorption or
`at the specific site of drug action in the body, all dependent
`at the specific site of drug action in the body, all dependent
`upon the specific goal for which the prodrug is designed.
`upon the specific goal for which the prodrug is designed.
`Ideally, the prodrug should be converted to the drug as soon
`Ideally, the prodrug should be converted to the drug as soon
`as the goal is reached. The prodrug per se is an inactive
`as the goal is reached. The prodrug per se is an inactive
`species and therefore, once its job is completed, intact pro-
`species and therefore, once its job is completed, intact pro(cid:173)
`drug represents unavailable drug. For example, prodrugs
`drug represents unavailable drug. For example, prodrugs
`designed to overcome solubility problems in formulating in-
`designed to overcome solubility problems in formulating in(cid:173)
`travenous injection solutions should preferably be con-
`travenous injection solutions should preferably be con(cid:173)
`verted immediately to drug following injection so that the
`verted immediately to drug following injection so that the
`concentration of circulating prodrug would rapidly become
`concentration of circulating prodrug would rapidly become
`insignificant in relation to that of the active drug. Conversely,
`insignificant in relation to that of the active drug. Conversely,
`if the objective of the prodrug is to produce a sustained drug
`if the objec1ive of the prod rug is to produce a sustained drug
`action through rate-limiting prodrug conversion, the rate of
`action through rate-limiting prodrug conversion, the rate of
`lhe conversion should not be too high.
`the conversion should not be too high.
`The necessary conversion or activation of prodrugs to the
`The necessary conversion or activation of prodrugs to the
`parent drug molecules in the body can take place by a vari(cid:173)
`parent drug molecules in the body can take place by a vad-
`ety of reactions. The most common prodrugs are those re(cid:173)
`ety of reactions. The most common prodrugs are those re-
`quiring a hydrolytiC cleavage mediated by enzymatic cataly(cid:173)
`quiring a hydrolytic cleavage mediated by enzymatic cataly-
`sis. Active drug speCies containing hydroxyl or carboxyl
`sis. Active drug species containing hydroxyl or carboxyl
`groups can often be converted to prodrug esters from which
`groups can often be converted to prodrug esters from which
`the active forms are regenerated by esterases within the
`the active forms are regenerated by esterases within the
`body, e.g., in the blood or liver. In other cases, active drug
`body, e.g., in the blood or liver. In other cases, active drug
`substances are regenerated trom their prodrugs by bio-
`substances are regenerated from their prodrugs by bio(cid:173)
`chemical reductive or oxidative processes.
`chemical reductive or oxidative processes.
`Besides usage of the various enzyme systems of the body
`Besides usage of thevadous enzyme systems of the body
`to carry out the necessary activation of prodrugs, the buff-
`to carry out the necessary activation of prod rugs. the buff(cid:173)
`ered and relatively constant value of the physiological pH
`ered and relatively constant value of the physiological pH
`(7.4) may be useful in triggering the release of a drug from
`(7.4) may be useful in triggering the release of a drug from
`a prodrug. In these cases, the prodrugs are characterized
`a prodrug. In these cases, the prodrugs are characterized
`by a high degree of chemical lability at pH 7.4, while prefer-
`by a high degree of chemical lability at pH 7.4, while prefer(cid:173)
`ably exhibiting a higher stability at, for example, pH 3-4. A
`ably exhibiting a higher stability at, for example, pH 3-4. A
`serious drawback of prodrugs requiring chemical (non-en-
`serious drawback of prod rugs requiring chemical (non-en(cid:173)
`zymatic) release of the active drug is the inherent lability of
`zymatic) release of the active drug is the Inherent lability of
`the compounds, raising some stability-formulation prob(cid:173)
`the compounds, raising some stability-formulation prob-
`lems at least in cases of solution preparations. As will be
`lems at least in cases of solution preparations. As will be
`shown later, such problems have, in particular cases, been
`shown later, such problems have, in particular cases, been
`
`overcome by using a more sophisticated approach involving
`overcome by using a more sophisticated approach involving
`pro-prodrugs or double prodrugs, where use is made of an
`pro-prod rugs or double prodrugs, where use is made of an
`enzymatic release mechanism prior to the spontaneous
`enzymatic release mechanism prior to the spontaneous
`reaction.
`reaction.
`In recent years several types of bioreversible derivatives
`In recent years several types of bioreversible derivatives
`have been exploited for utilization in designing prodrugs (7,
`have been exploited for utilization in deSigning prod rugs (7,
`8). An account of novel chemical approaches in the design
`8). An account of novel chemical approaches in the deSign
`of prodrugs is given in the following.
`of prodrugs is given in the following.
`
`Ester prod rugs
`Ester prodrugs
`
`The popularity of using esters as a prodrug type for drugs
`The popularity of using esters as a prodrug type for drugs
`containing carboxyl or hydroxyl functions stems pdmadly
`containing carboxyl or hydroxyl functions stems primarily
`from the fact that the organism is dch in enzymes capable
`from the fact that the organism is rich in enzymes capable
`of hydrolyzing esters. The distribution of esterases is ubiqui-
`of hydrolyzing esters. The distribution of esterases is ubiqui(cid:173)
`tous and several types can be found in the blood, liver and
`tous and several types can be found in the blood, liver and
`other organs or tissues. In addition, by appropriate esteriti-
`other organs or tissues. In addition, by appropriate esterifi(cid:173)
`cation of molecules containing a hydroxyl or caboxyl group
`cation of molecules containing a hydroxyl or caboxyl group
`it is feasible to obtain derivatives with almost any desirable
`it is feasible to obtain derivatives with almost any desirable
`hydro-or lipophilicity as well as in vivolabi/ity, the latter being
`hyd ro- or lipophilicity as well as in vivo lability, the lalter being
`dictated by electronic and steric factors. Accordingly, agreat
`dictated by electronic and steric factors. Accordingly, a great
`number of alcoholic or carboxylic acid drugs have been mo-
`number of alcoholic or carboxylic acid drugs have been mo(cid:173)
`dified for a multitude of reasons using the ester prodrug alp
`dified for a multitude of reasons using the ester prodrug ap(cid:173)
`proach (7).
`proach (7).
`Sometimes, however, many aliphatic or aromatic esters
`Sometimes, however, many aliphatic or aromatic esters
`are not sufficiently labile in vivo to ensure a sufficiently high
`are not sufficiently labile in vivo to ensure a sufficiently high
`rate and extent of prodrug conversion. For example, simple
`rate and extent of prodrug conversion. For example, simple
`alkyl and aryl esters of penicillins are not hydrolyzed to the
`alkyl and aryl esters of penicillins are not hydrolyzed to the
`active free penicillin acid in vivo and therefore have no thera(cid:173)
`active free penicillin acid in vivoand therefore have no thera-
`peutic potential (9). The reason for this is the highly stedcally
`peutic potential (9). The reason forthis is the highlysterically
`hindered environment about the carboxyl group in the peni-
`hindered environment about the carboxyl group in the peni(cid:173)
`cillin molecule which makes enzymatic attack on the acyl
`cillin molecule which makes enzymatic attack on the acyl
`group very difficult.
`group very difficult.
`
`Double esters
`Double esters
`
`This shortcoming can be overcome by preparing a double
`This shortcoming can be overcome by preparing a double
`ester type, (acyloxy)alkyl or [(alkoxycarbonyl)oxy]alkyl es-
`ester type, (acyloxy)alkyl or [(alkoxycarbonyl)oxy)alkyl es(cid:173)
`ters in which the terminal ester grouping is less sterically hin(cid:173)
`ters in which the terminal ester grouping is less stedcally hin-
`dered. The first step in the hydrolysis of such an ester is en(cid:173)
`dered. The first step in the hydrolysis of such an ester is en-
`zymatic cleavage of the terminal ester bond with formation
`zymatic cleavage o! the terminal ester bond with formation
`of a highly unstable hydroxymethyl ester which rapidly dis(cid:173)
`of a highly unstable hydroxymethyl ester which rapidly dis-
`sociates to the parent acidic drug and formaldehyde
`sociales to the parent acidic drug and formaldehyde
`(Scheme 1).
`(Scheme 1).
`This principle has been used successfully to improve the
`This principle has been used successfully to improve the
`oral bioavailability of ampicillin (1), and no fewer than three
`oral bioavailability of ampicillin (1), and no fewer than three
`ampicillin prodrug forms are now on the market, namely the
`ampicillin prodrug forms are now on the market, namely the
`pivaloyloxymethyl ester (2) (pivampicillin), the ethoxycarbo(cid:173)
`pivaloyloxymethyl ester (2) (pivampicillin), the ethoxycarbo-
`nyloxyethyl ester (3) (bacampicillin), and the phthalidyl ester
`nyloxyethyl ester (3) (bacampicillin), and the phthalidyl ester
`(4) (talampicillin) (for a review, see ref. 9). Bacampicillincon(cid:173)
`(4) (talampicillin) (Iora review, see ref. 9). Bacampiciilin con-
`tains a terminal carbonate ester moiety and releases etha-
`tains a terminal carbonate ester moiety and releases etha(cid:173)
`nol, carbon dioxide and acetaldehyde upon hydrolysis. In ta(cid:173)
`nol, carbon dioxide and acetaldehyde upon hydrolysis. In ta-
`lampicillin the pro-moiety released upon hydrolysis is
`lampicillin the pro-moiety released upon hydrolysis is
`2-carboxybenzaldehyde which is further metabolized to
`2-carboxybenzaldehyde which is further metabolized to
`2-hydroxymethylbenzoic acid.
`2-hydroxymethylbenzoic acid.
`In more recent years the applicability of this double ester
`In more recent years the applicability of this double ester
`concept in prodrug design has been further expanded.
`concept in prodrug design has been fudher expanded.
`Thus, similar esters have been prepared from various
`Thus, similar esters have been prepared from various
`non-steroidal antiinflammatory agents as well as Irom me-
`non-steroidal antiinflammatory agents as well as from me(cid:173)
`thyldopa (10), cromoglycic acid (11), furosemide (12) and
`thyldopa (10), cromoglycic acid (11), furosemide (12) and
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`Drugs Fut 1991, 16(5}
`Drugs Fut 1991, 16(5)
`
`Scheme 1
`Scheme I
`
`o
`0
`II
`If
`Drug- C- O- CH- O-C- P,2
`Orug-C-o-CH-o-C-~
`I
`I
`R,
`RI
`
`enzymic
`enzymic
`
`445
`445
`
`+ Rz-COOH
`+ ~-COOH
`
`o
`O
`II
`/I
`Drug-C-o-CHOH
`Drug- C- O- CHOH
`I
`I
`R1
`
`R, ! ~I
`
`last
`
`Drug- COOH
`Drug-COOH
`
`+ R,-CHO
`+ R1-CHO
`
`.
`
`membranes by passive diffusion and then revert by enzy-
`membranes by passive diffusion and then revert by enzy(cid:173)
`matic cleavage of the protective group to the parent phos-
`matic cleavage of the protective group to the parent phos(cid:173)
`phomonoester. Reports about the application of this pro-
`phomonoester. Reports about the application of this pro(cid:173)
`drug approach
`to biologically
`important nucleotides
`drug approach to biologically important nucleotides
`certainly may soon appear.
`certainly may soon appear.
`
`0
`
`H3C~~N~COOR
`I
`CH2CH3
`
`(5)
`(5)
`(6)
`(6)
`
`R=H
`R=H
`R = - CH20- fl- CH2CH2CH3
`R = - CH20- ICI- CH2CH2CH3
`o
`O
`
`OOR
`
`R=H
`R = - CH20-- ICI- C(CH3)3
`R .. -CH20-fl- C(CH3)3
`o
`0
`
`R = -«HO-fl-OCH2CH3
`CH3 0
`CH$ O
`
`(~)
`(1)
`(2)
`(2)
`
`(3)
`
`(4)
`(4)
`
`nalidixic acid (13). and found to be useful as prodrugs for en(cid:173)
`nalidixic acid (13}, and found to be useful as p rodrugs for en-
`hancement of the dermal or oral delivery of these acidic
`hancement of the dermal or oral delivery of these acidic
`drugs. The advantage of such esters in terms of enzymatic
`drugs. The advantage of such esters in terms of enzymatic
`lability can be illustrated with nalidixic acid (5). Whereas the
`lability can be illustrated with nalidixic acid (5). Whereas the
`methyl ester shows less than 5% hydrolysis upon incubation
`methyl ester shows less than 5% hydrolysis upon incubation
`in human plasma for 24 h. the butyryloxymethyl ester (6) is
`in human plasma for 24 h, the butyryloxymethyl ester (6) is
`rapidly hydrolyze~, the haH-life being 8 min (13).
`rapidly hydrolyzed, the half-life being 8 min (13),
`The applicability of cx-acyloxyalkyl esters as biologically
`The applicability of (x-acyloxyalkyl esters as biologically
`reversible transport forms has been extended to include the
`reversible transport forms has been extended to include the
`phosphate group and phosphonic acids (8). Both the chemi(cid:173)
`phosphate group and phosphonic acids (8). Both the chemi-
`cal and enzyme-mediated hydrolysis of bis(acyloxymethyl)
`cal and enzyme-mediated hydrolysis of bis(acyloxymethyl)
`esters of phosphomonoesters take place as shown in
`esters of phosphomonoesters take place as shown in
`Scheme2, with the intermediate formation of a monoacylox(cid:173)
`Scheme 2, with the intermediate formation of a monoacylox-
`ymethyl ester (14, 15). The D-hydroxymethyl derivatives
`ymethyl ester (14, 15). The O-hydroxymethyl derivatives
`formed upon ester hydrolysis have only a transitory exis(cid:173)
`formed upon ester hydrolysis have only a transitory exis-
`tence and spontaneously eliminate one molecule of formal(cid:173)
`tence and spontaneously eliminate one molecule of formal-
`dehyde. The bis(acyloxymethyl) ester derivatives are neu(cid:173)
`dehyde. The bis(acyloxymethyl)ester derivatives are neu-
`tral compounds, and they can conceivably traverse cell
`hal compounds, and they can conceivably traverse cell
`
`Biolabile glycol amide esters
`Biolabile glycolamide esters
`
`An alternative solution to the problem of obtaining enzy(cid:173)
`An alternative solution to the problem of obtaining enzy-
`matically labile ester prodrugs of carboxylic acid agents is
`matically labile ester prodrugs of carboxylic acid agents is
`provided by N,N-disubstituted glycolamide esters. Such es(cid:173)
`provided by N,N-disubstituted glycolamide esters. Such es-
`ters have recently been shown to be cleaved with remark(cid:173)
`ters have recently been shown to be cleaved with remark-
`able speed in human plasma, the responsible enzyme being
`able speed in human plasma, the responsible enzyme being
`pseudocholinesterase (Scheme 3) (16-18). As seen from
`pseudochotinesterase (Scheme 3) (16-18). As seen from
`the examples listed in Table I, such esters derived from vari(cid:173)
`the examples listed in Table I, such esters dedved lrom vad-
`ous carboxylic acids are hydrolyzed much more facilely than
`ous carboxylic acids are hydrolyzed much more facilely than
`the corresponding simple methyl or ethyl esters. The glyco(cid:173)
`the corresponding simple methyl or ethyl esters. The glyco-
`lamide esters combine a high susceptibility to undergo en(cid:173)
`lamide esters combine a high susceptibility to undergo en-
`zymatic hydrolysis in plasma with a high stability in aqueous
`zymatic hydrolysis in plasma with a high stability in aqueous
`solution and furthermore, this new ester prodrug type is
`solution and furthermore, this new ester prodrug type is
`characterized by providing ample possibilities for varying
`characterized by providing ample possibilities for varying
`the water and lipid solubilities of the derivatives with retain(cid:173)
`the water and lipid solubilities of the derivatives with retain-
`ment of the favorable enzymatic/nonenzymatic hydrolysis
`ment of the favorable enzymatic/nonenzymatic hydrolysis
`
`
`
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`
`Scheme 2
`Scheme 2
`
`Novel chemical approaches in prodrug design
`Novel chemical approaches in prodrug design
`
`HO-CH2~p?0
`R,-ft-O-CH20 'OR
`o
`
`Ia&t ! -CHzO
`
`ta= - CH=O
`
`HC\ ;l0
`p7
`He{ 'OR
`
`fasl
`fast
`.CH=O
`-c~o
`
`HO~ .0
`
`HO--CH~O OR
`
`Scheme 3
`Scheme 3
`
`o
`0
`0 0
`II
`R,
`1\
`11
`Drug- C-o- c~- c- (
`11 I,~1~
`R.!
`
`enzymic
`
`Orug-COOH + HOCH2- I~- KI~
`
`index. One obvious area of application of this ester prod rug
`index. One obvious area of application of this ester prodrug
`type concerns nonsteroid antiinflammatory drugs (19, 20).
`type concerns nonsteroid antiinflammatory drugs (19, 20).
`Esterification of these carboxylic acid agents is known to re·
`Estedfication of these carboxylic acid agents is known to re-
`duce their gastric ulcerogenic activity. However, simple alkyl
`duce their gastric ulcerogenic activity. However, simple alkyl
`esters of these agents are inefficiently cleaved in the organ·
`esters of these agents are inefficiently cleaved in the organ-
`ism and are often also highly insoluble in water. I n contrast,
`ism and are often also highly insoluble in water. In contrast,
`the glycolamide esters have a high capacity to release the
`the glycolamide esters have a high capacity to release the
`parent active drugs following absorption and possess physi(cid:173)
`parent active drugs following absorption and possess physi-
`cochemical properties favorable for peroral absorption (19).
`cochemical properties favorable for perorel absorption (19).
`
`Water-soluble ester prodrugs
`Water-soluble ester prodrugs
`
`Formation of water-soluble ester prodrugs has long been
`Formation of water-soluble ester prodrugs has long been
`recognized as an effective means of increasing the
`recognized es an effective means of increasing the
`aqueous solubility of drugs containing a hydroxyl group.
`aqueous solubility of drugs containing a hydroxyl group,
`aimed at developing improved preparations for parenteral
`aimed at developing improved preparations for parenteral
`or ophthalmic administration. The most commonly used es(cid:173)
`or ophthalmic administration. The most commonly used es-
`ters for increasing the aqueous solubility of hydroxyl-con·
`ters for increasing the aqueous solubility of hydroxy!-con-
`t~ning agents are esters containing an ionizable group, i.e.,
`t~ning agents are esters containing an ionizable group, i.e.,
`dicarboxylic acid hemiesters, phosphate esters and a-ami-
`dicarboxylic acid hemiesters, phosphate esters and (x-ami-
`
`Table I: Half-lives (t'l2) of hydrolysis of esters of various drugs and
`Table h Half-lives (t~/~) of hydrolysis of esters of vadous drugs and
`compounds containing a carboxylic acid function in 80% human
`compounds containing a carboxylic acid function in 80% I~uman
`plasma (pH 7.4, 37vC) (16, 19).
`pfasma (pH 7.4, 370(;) (16, 19).
`
`Acid
`Acid
`
`Methyl ester
`Methyl ester
`
`Salicylic acid
`Salicylic acid
`4-Aminobenzoic acid
`4·Aminobenzoic acid
`Ketoprofen
`Keloprofen
`Fenbufen
`Fenbufen
`Tolmetin
`Tolmetin
`Tolfenamic acid
`Tolfenamic acid
`Indomethacin
`Indomethacin
`Naproxen
`Naproxeo
`Furosemide
`Furosemide
`Tranexamic acid
`Tranexamic acid
`L·Tyrosine
`L-Tyrosine
`
`17.6 h
`17.6h
`>100 h
`>100h
`>20h
`>20 h
`4.7h
`4.7 h
`19 h
`19 h
`100h
`100 h
`150h
`150 h
`20h
`20 h
`>100 h
`>100 h
`4.0h
`4.0 h
`1.0 h
`1.0 h
`
`T112
`T1/2
`N, N-Diethylglycola-
`N. N-Diethylglycola-
`rnide ester
`mideester
`0.80 rain
`0.80 min
`0.6 rain
`0.6 min
`0.5 rain
`O.Smln
`3.8 min
`3.8 rain
`13.4 min
`13.4 min
`5.0 min
`5.0 rain
`25 min
`25 rain
`0.6 min
`0°6 mtn
`4.4h
`4.4 h
`1.2 min
`1.2 min
`0.5 min
`0.5 rain
`
`no acid esters (7). The ideal properties of such prodrugs are
`no acid esters (7). The ideal properties of such prodrugs are
`as follows: they should possess a high water solubility at the
`as follows: they should possess a high water solubility at the
`pH of optimal stability and sufficient stability in aqueous so(cid:173)
`pH of optimal stability and sufficient stability in aqueous so-
`lution to allow long·term storage (>2 years) of ready-la-use
`lution to allow long-term storage (>2 years) of ready-to-use
`solutions and yet they should be converted quantitatively
`solutions and yet they should be converted quantitatively
`and rapidly in vivo to the active parent drug. However. none
`and rapidly in vivoto the active parent drug. However, none
`of these derivatives may often fully satisfy all these require(cid:173)
`of these derivatives may often fully satisfy all these require-
`ments. Thus. whereas a-amino acid esters or related
`ments. Thus, whereas (x-amino acid esters or related
`short·chained aliphatic amino acid esters are in general
`short-chained aliphatic amino acid esters are in general
`readily hydrolyzed enzymatically, they exhibit a very poor
`readily hydrolyzed enzymatically, they exhibit a ve~j poor
`stability in aqueous solution, making it impossible to prepare
`stability in aqueous solution, making it impossible to prepare
`ready-to-use solutions (7).
`ready·to-use solutions (7).
`The major reason for the high instability’of (x-amino and
`The major reason for the high instability' of a·amino and
`short-chained aliphatiC amino acid esters in aqueous solu(cid:173)
`short-chained aliphatio amino acid esters in aqueous solu-
`tion at pH values affording their favorable waler·solubility
`tion at pH values affording their favorable water-solubility
`
`
`
`NPC02229595
`
`NOVARTIS EXHIBIT 2112
`Par v Novartis, IPR 2016-00084
`Page 4 of 16
`
`

`
`Drugs Fut 1991. 16(5)
`Drugs Fur lg91, 16(5)
`
`Scheme 4
`Scheme 4
`
`447
`447
`
`0
`0
`II
`II
`
`(C-OH
`
`N-
`I
`
`•
`-O~
`
`~O
`
`o~ arP
`
`•
`
`0
`lit":.,
`
`(rOR
`
`N-
`I
`
`(~
`C~OR
`9-H
`.(""'H
`N .......
`I
`
`~ OR
`H ""I
`
`('\0
`
`e ..... H
`N .......
`I
`
`(i.e., pH 3-5) is partly due to the strongly electron-withdraw(cid:173)
`(Le., pH 3-5) is partly due to the strongly electron-withdraw-
`ing effect of the protonated amino group which activates the
`ing effect of the protonated amino group which activates the
`ester linkage toward hydroxide ion attack and partly (and
`ester linkage toward hydroxide ion attack and partly (and
`predominantly) to intramolecular catalysis or assistance by
`predominantly) to intramolecular catalysis or assistance by
`the neighboring amino group of ester hydrolysis (21. 22).
`the neighboring amino group of ester hydrolysis (21, 22).
`The mechanisms involved include intramolecular nucleo(cid:173)
`The mechanisms involved include intramolecular nucleo-
`philic catalysis, intramolecular general-base catalysis or
`philic catalysis, intramolecular general-base catalysis or
`general-base specific base catalysiS. as depicted in
`general-base specific base catalysis, as depicted in
`Scheme 4.
`Scheme 4.
`It has recently been shown (23) that an effective and sim(cid:173)
`It has recently been shown (23) that an effective and sim-
`ple means to totally block the hydrolysis-facilitating effect of
`ple means to totally block the hydrolysis-facilitating effect of
`the amino group and yet retain a rapid rate of enzymatic es(cid:173)
`the amino group and yet retain a rapid rate o! enzymatic es-
`ter hydrolysis is to incorporate a phenyl group between the
`ter hydrolysis is to incorporate a phenyl group between the
`ester moiety and the amino group. By doing so the intramo(cid:173)
`ester moiety and the amino group. By doing so the intramo-
`lecular catalytic reactions of the amino group, as outlined in
`lecular catalytic reactions of the amino group, as outlined in
`Scheme 4, are no longer possible forsteric reasons and fur(cid:173)
`Scheme 4, are no longer possible for steric reasons and iur-
`thermore. the ester-Iabilizing effect of the protonated amino
`thermore, the ester-labilizing effect of the protonated amino
`group