EP1212098A2

EP1212098A2 - Enzyme inhibitors

Info

Publication number: EP1212098A2
Application number: EP00960050A
Authority: EP
Inventors: Todd Laurence Underiner; Scott Edward Osborne; Timothy Bates; Garry Steven Garrett; Renae Dianna Fossum
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1999-09-10
Filing date: 2000-09-08
Publication date: 2002-06-12
Also published as: AR023272A1; AU7127000A; JP2003509538A; WO2001018181A2; WO2001018181A3; PE20010588A1

Abstract

The present invention relates to polymer conjugates which inhibit protease or lipase enzyme, said polymer conjugates comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme.

Description

ENZYME INHIBITORS

FIELD OF THE INVENTION The present invention relates to novel functional polymer conjugates which inhibit one or more proteolytic and/or lipolytic enzymes. The polymer conjugates described herein are suitable for use in any context wherein proteolytic and/or lipolytic enzyme inhibition is indicated; inter alia, treatment of diaper rash.

BACKGROUND OF THE INVENTION Diaper rash is ubiquitous. It was once believed that contacting the skin with urine produced diaper rash, however, it is now understood that the irritation of tissue which manifests itself in "diaper rash" is primarily caused by endogenic proteolytic and/or lipolytic enzymes, inter alia, trypsin, chymotrypsin, elastase, pancreatic lipase, which comprise human feces. However, skin irritation is not limited to enzymes which comprise feces, for example, menstrual fluids, nasal fluids, colostomy fluids, dandruff, wound healing may all provide a source of enzymes which produce irritation.

Proteolytic and lipolytic enzyme inhibitors are known. An example of effective inhibitors are "suicide inhibitors" which irreversibly react with the active site of the target enzyme thereby destroying the enzyme's ability to function. Reversible enzyme inhibitors, although not permanently inactivating the target enzyme, are also considered sufficiently effective to inhibit the effects of unwanted enzyme exposure. One drawback of low molecular weight enzyme inhibitors is their propensity to be readily absorbed through skin tissue, thereby entering into human cells wherein normal cell catabolism can be interrupted.

There is a long felt need to provide a barrier against the pernicious enzymes, which act to irritate human skin, especially enzymes which produce diaper rash.

SUMMARY OF THE INVENTION The present invention meets the aforementioned needs in that it has been surprisingly discovered that proteolytic and/or lipolytic enzyme inhibitors can be effectively delivered to human skin where said inhibitors can function as a barrier to enzyme activity thereby preventing diaper rash or other unwanted skin conditions. The enzyme inhibitors of the present invention are polymer conjugates which have an enzyme inhibitor component and a functionalized polymer component. The enzyme inhibitor component comprises an acyl unit which reversibly reacts with a protease or lipase enzyme. The inhibitor components of the present invention function as broadly specific enzyme inhibitors, that is the inhibitors do not bind so specifically to one type of enzyme that the inhibitors are not available for interaction with other enzymes which are present. It has been surprisingly discovered that non-specific protease inhibitors provide broader protection against skin irritation than enzyme-specific inhibitors, because these enzyme specific inhibitors are ineffective against other enzymes which may be present and which contribute to skin irritation.

A first aspect of the present invention relates to polymer conjugate which inhibits protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of one or more protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is attached thereto by a linking unit, said linking unit optionally capable of modulating the interaction between a target enzyme and said inhibitor component, and wherein further said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme. The inhibitor component is either bonded directly to said polymer component or connected by way of a linking unit, said linking unit also preferably capable of modulating the interaction between the target enzyme and said inhibitor component. When said linking unit also interacts with said enzyme, the polymer component also remains bonded to the inhibitor component.

The inhibitors of the present invention interact with the target enzymes by way of an acyl unit. However, this interaction between a target enzyme and acyl group does not result in the enzyme inhibitor portion being cleaved from the polymeric backbone to which it is attached. Instead, even after the enzyme inhibitor component and target enzyme have formed an enzyme/substrate pair, the inhibitor component remains linked to the polymer component.

The present invention further relates to a functionahzed polymer component comprising a moiety which acts as an anchoring template for one or more enzyme inhibitors while providing a means for delivering the conjugate molecule to human skin. The enzyme inhibitor component is optionally, but preferably, linked to the functionahzed polymer component by one or more linking groups.

The present invention further relates to a process for preventing the formation of skin irritation which is due to the presence of proteolytic and/or lipolytic enzymes, said process comprises the step of contacting an effective amount of a polymer conjugate as described herein below to human skin. These and other objects, features and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the prevention of pernicious and otherwise unwanted skin conditions, inter alia, rash, irritation, which is caused by the contact of proteolytic and/or lipolytic enzymes with skin. Among the conditions which the present invention seeks to ameliorate is diaper rash. The present invention achieves the desired result by applying to the skin by a suitable means a sufficient amount of a polymer conjugate which inhibits the activity of one or more enzymes which are the cause of said unwanted skin condition.

The polymer conjugates of the present invention comprise an enzyme inhibitor component and a functionahzed polymer component. The primary means by which the enzyme inhibitor component interacts with an enzyme is by way of an acyl unit, however, other moieties which comprise the conjugate can serve to modulate enzyme/substrate interaction. The acyl unit can be activated towards interaction with the enzyme or the acyl unit can be masked which results in reduced availability of the acyl unit and therefore reduced interaction with unwanted substrates. The enzyme inhibitors of the present invention are preferably broad spectrum in their ability to inhibit enzymes. The term "broad spectrum" is defined herein as "an inhibitor which will bind to more than one enzyme and which does not bind to one particular enzyme in so strongly a manner as to exclude the binding of said inhibitor with other enzymes which are present. "

As stated herein above the enzyme inhibitor component comprises a "target enzyme interacting acyl unit". The term "acyl unit" is defined herein as "a carbonyl comprising unit which may be in one or more precursor forms, inter alia, as a member of a ring, as an anhydride. " Preferred acyl units are esters and aldehydes, more preferably esters.

The enzyme inhibitor component of the present invention is bonded to a polymer component. The enzyme inhibitor component can be bonded directly to the polymer component or it can be bonded to the polymer component by means of a linking unit, preferably a linking unit which participates in the interaction of the inhibitor component with a target enzyme. Preferably the linking unit facilitates interaction of the enzyme and inhibitor by "modulating" the interaction between the enzyme and inhibitor. The terms "modulating" or "modulate" can have one or more meanings, however, one non-limiting example of this term is "facilitating the alignment of the inhibitor component into the enzyme active site". Another equally suitable meaning for these terms relates to "providing a means by which the interaction between the inhibitor component and a target enzyme is modified, inter alia, strengthened, weakened, abated, prolonged".

Preferably the enzyme inhibitor component of the present invention further comprises a unit or moiety which enhances the "broadness" or "range" of the enzyme inhibition or has the capacity to strengthen the interaction between the parent inhibitor and the target enzyme. The conjugates of the present invention further comprise a functionahzed polymer component which acts as a delivery template for one or more enzyme inhibitor components while serving other important function, inter alia, providing a means for anchoring the conjugate molecule to human skin, solublizing the conjugate into a carrier. The functionahzed polymer component is typically an amphiphilic polymer which is capable of being directly attached to the enzyme inhibitor component or of being attached thereto by a "selected" linking unit. A "selected" linking unit is one which when coupled with a particular enzyme inhibitor component, enhances the desired activity of said inhibitor.

The polymer component also provides the conjugate with a source of increased molecular weight which acts to inhibit the absoφtion of the enzyme inhibitor into skin tissue. The polymer component also acts to facilitate formulation of the enzyme inhibitor into carriers or facilitates deposition of the conjugate directly to skin or by way of a substrate, diaper top sheet, inter alia, to which the conjugate is applied.

The polymer conjugates of the present invention are utilized in an effective amount. For the puφoses of the present invention the term "effective amount" is defined herein as the amount necessary to provide a reduction in enzyme activity in at least one inhibition assay. Preferred assays which are described herein are, inter alia, "Fecal Protease Inhibition Assay", "Skin Test of Inhibition of IL-lα Production". Suitable tests also include tests which differentiate the specificity of said enzyme inhibitor, for example, which differentiate the particular proteases obstructed by said inhibitor.

POLYMER CONJUGATES Enzyme Inhibitor Component

The enzyme inhibitor component of the present invention comprises one or more units which have at least one acyl unit, preferably the acyl unit is a masked acyl unit. The preferred acyl units of the present invention are ester units and aldehyde units, more preferred are esters whether linear or part of a ring (cyclic esters). For the puφoses of the present invention the term "masked acyl unit" is understood to be an acyl unit which is reactive towards an enzyme, for example, the serine hydroxyl unit of protease enzyme active sites, but not to common substrates, inter alia, water, alcohol. Linear Enzyme Inhibitors

One embodiment of the present invention relates to "linear" enzyme inhibitors having the general formula:

[Inhibitor],, ^• (L)_z-[Poly] y wherein [Inhibitor] is an enzyme inhibiting functionality; L is a linking unit; [Poly] is a polymer component; the indices have the following values: x is from 1 to 50, y is from 1 to 10, z is 0 or 1. The polymer conjugates of the present invention may comprise a single enzyme inhibiting unit having multiple polymer units attached thereto, multiple inhibiting functionalities attached to a single polymer component, or mixtures thereof.

The preferred linear polymer conjugates of the present invention comprise an inhibitor wherein an acyl unit, [Acyl], is attached to a template, T. The template, T, may serve one or more functions as described herein below. The preferred linear polymer conjugates have the formula:

[Acyl]_w-T- ^■ (L)₂-[Poly] y wherein the index w is from 1 to 6. Preferred examples include polymer conjugates comprising one acyl unit (w = 1), bis-acyl unit conjugates (w = 2) , and tris-acyl unit conjugates (w = 3), preferably bis-acyl unit conjugates having one acyl unit tied back into the template as described herein below. Preferably the acyl units of the present invention comprise one or more enzyme modulating units [Mod]- which serve to modulate the reactivity of the acyl unit towards a target enzyme. A preferred example of a linear enzyme inhibitor acyl unit which does not comprise a [Mod] unit is -C0₂ ^" (carboxylate). Non-limiting examples of acyl units which also comprise a [Mod] unit include: a) esters; b) aldehydes; c) acetals; d) ketones; e) ketals; f) thioesters; g) thioacetals; h) anhydrides; i) and mixtures thereof.

The following is an example of a polymer conjugate wherein the enzyme inhibitor comprises an acyl unit which is an ester unit:

wherein [Mod] units are preferably C Cι₂ alkyl units, more preferably C C alkyl units. Further examples include polymer conjugates having the formula:

wherein [Mod] is hydrogen for aldehydes acyl units and [Mod] is an alkyl unit for ketone acyl units.

Other examples of acyl units include masked acyl units, inter alia, acetals, orthoesters having the formula:

[Mod]_b— C(H)_b.— T- (L)_z- [Poly]

wherein [Mod] is preferably a C₁-C₁₂ alkoxy unit; b has the value of 2 or 3 and b' has the value of 0 or 1 ; provided b + b' = 3.

The preferred linear polymer conjugates of the present invention have the formula:

X

[Mod]— (X)_a— C— (X)_a -T- (L)_z-[Poly] w

wherein each [Mod] is independently selected from: a) hydrogen; b) Ci-Cjg substituted or unsubstituted, linear or branched alkyl; preferably CpCg linear unsubstituted alkyl; more preferably C C₄ alkyl, inter alia, methyl and ethyl; c) C₃-C₁8 substituted or unsubstituted, cycloalkyl; preferably C₆-Cιo unsubstituted cycloalkyl; d) C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl; e) C₂-C₁₈ substituted or unsubstituted, linear or branched alkynyl; f) C₆-C₁₈ substituted or unsubstituted aryl; and g) a unit which is tied back to said T unit to form a ring comprising from 1 to 5 carbon atoms; and h) mixtures thereof; wherein X is CH₂, NH, O, S, CF₂

The inhibitor component, T, may comprise one or more units, as described herein below, which also serve to modulate the specificity of the inhibitor for a particular substrate. The polymer conjugates of the present invention may comprise one or more inhibitor components. When multiple inhibitors are present, they are preferably not suicide inhibitors, but reversible inhibitors. If an inhibitor irreversibly binds to an enzyme, the size of the bound enzyme may serve to occlude the binding of other enzymes to the remaining inhibitor components. Non-limiting examples of T units which comprise the linear polymer conjugates according to the present invention are selected from the group consisting of: a) substituted or unsubstituted, linear or branched C -C₂₂ alkylene; b) substituted or unsubstituted, linear or branched C -C₂₂ alkenylene; c) substituted or unsubstituted C6-C₂₂ cycloalkylene; d) substituted or unsubstituted C6-C₂₂ heterocyclic alkylene; e) substituted or unsubstituted C₆-C₂₂ arylene; f) substituted or unsubstituted C7-C₂₂ alkylarylene; g) esters, carbonates, amides, ureas, or carbamates having the formula:

O — R— (X)a-C— (X)_a-R² wherein R¹ is selected from the group consisting of: i) substituted or unsubstituted, linear or branched C₁-C ₂ alkylene; ii) substituted or unsubstituted, linear or branched C₂-C₂₂ alkenylene; iii) substituted or unsubstituted C -C₂₂ cycloalkylene; iv) substituted or unsubstituted C₆-C₂₂ heterocyclic alkylene; v) substituted or unsubstituted C₆-C₂₂ arylene; vi) substituted or unsubstituted C7-C₂₂ alkylarylene; R² is selected from the group consisting of: i) substituted or unsubstituted, linear or branched C C₂₂ alkyl; ii) substituted or unsubstituted, linear or branched C₂-C₂₂ alkenyl; iii) substituted or unsubstituted C₆-C₂₂ cycloalkyl; iv) substituted or unsubstituted C₆-C₂₂ heterocyclic alkyl; v) substituted or unsubstituted C₆-C₂₂ aryl; vi) substituted or unsubstituted C7-C₂₂ alkylaryl; X is O, S, NH, and mixtures thereof, each index a is independently 0 or 1.

However, the carbonyl unit of said ester, carbonate, amide, urea, or carbamate is not the acyl unit which comprises the [Acyl] unit which is the point of primary interaction with the target enzyme, but said carbonyl unit would have the capacity to provide enzyme interaction if designed to do so by the formulator.

Enzyme Inhibitor Dimers

The compounds of the present invention which are suitable for providing protection against skin irritation include "enzyme inhibitor dimers" having the formula:

O O

II II [Poly]— (L)_z— T-C-D-C-T— (L)_z-[Poly] wherein T is the same as for linear enzyme inhibitors, L and [Poly] are defined herein below, and D is a dimer linking unit.

In a preferred embodiment of the present invention, D is oxygen which when taken together with the two adjacent carbonyl units forms a linear anhydride which after interaction with a target enzyme, releases a second, un-associated, polymer conjugate. It is not necessary, nor is it a preferred embodiment, that each T, L, and [Poly] be the same for both polymer conjugates which form the dimer. The formulator can make use of the differential reactivity of enzymes and acyl units to deliver protease and/or lipase inhibitors of differing inhibition characteristics by using the linear "enzyme inhibition dimer" polymer conjugates of the present invention.

Polymer Conjugates Comprising an Acyl Unit as Part of a Ring

Protease and/or lipase inhibitors which have the acyl unit as part of a ring are a preferred embodiment of the present invention. For the puφoses of providing an example, an acyl unit which is part of a γ-lactone is used to exemplify "acyl unit-containing rings". A γ-lactone having the formula:

is an example of an acyl unit which is part of a ring. The units R', R", or R'" may represent a bond to the inhibitor component, a linking unit, or a polymer component. As is the case of the other embodiments listed herein above, the inhibitor component remains bound to the polymer component after the acyl unit has interacted with the target enzyme thereby providing a polymer component bonded enzyme inhibitor. For example, a γ-lactone polymer conjugate of the present invention having the general formula:

will have the general formula:

[enzyme] I OH C=0

after the ring-formed acyl unit interacts with a target enzyme.

Set forth as a contrasting example, is a polymer conjugate having the general formula:

which is capable by virtue of the 4-guanidinobenzyl moiety of reacting with a trypsin enzyme active site serine hydroxyl unit to displace the [Poly]-CH₂0- unit. The effect of this reaction is the acylation of the active site serine hydroxyl. However, in reacting with the enzyme, the inhibitor portion which comprises the 4-guanidinobenzoate moiety, is detached from the polymer component Once liberated from the enzyme, this inhibitor can potentially diffuse into human skin tissue with deleterious side-effects

This same 4-guanιdιnobenzoate enzyme inhibition unit can be suφπsingly incoφorated into a polymer conjugate according to the present invention wherein the inhibitor is free to interact with the enzyme via the acyl unit, but the inhibitor remains tethered to the polymer component For example, the inhibition unit can be formed into a heterocycle having the formula

wherein the enzyme inhibitor T is released by the opening of the 4H-benzoxazιn-4-one [b] ring but remains linked to the polymer component Without wishing to be limited by theory, once the enzyme has interacted with the conjugate acylating unit, the species which remains will have the proposed formula

one advantage of which is the polymer component remains linked to the enzyme inhibitor component

The formulator may make further use of this acyl unit containing ring Any T unit which comprises the ring system having the formula

Non-limiting examples of other fused rings wherein X is selected from the group consisting of X is CH₂, NH, O, S, CF₂, and mixtures thereof; and each D, E, F, and G is independently selected from the group consisting of CH, CH₂, N, NH, O, S, CF₂, and mixtures thereof include: i)

ϋ)

iii)

iv)

v)

vi)

vii) viii)

ix)

x) and mixtures thereof.

Preferred T units include: i)

ϋ)

iii)

iv) v) and mixtures thereof.

The T units may be linked to the polymer component in any manner which the formulator prefers, for example the most preferred units are the 4H-3,l-benzoxazin-4-one heterocycles having the formula:

which are preferably linked to the polymeric component via the 2 or 5 ring position. However, the formulator can equally well attach more than one polymer component to an inhibitor component, for example the polymer conjugate having the formula:

It will be noted by the formulator that only the exocyclic portion of the linking unit is rendered distinct from the heterocyclic ring system above. The examples herein above can effectively deliver a benzoic acid-like inhibitor, inter alia, 4-guanidinobenzoate, and part of the linking group is taken up as part of the benzoxazin-4-one ring system. Herein below only the exocyclic component of the linking groups are delineated, an the formulator is not restricted in using any part thereof to form other heterocycles which suitably deliver protease and/or lipase inhibitors.

Further non-limiting examples of acyl unit comprising ring systems which are suitable for use in the present invention include: i)

ϋ) iii)

iv)

The enzyme inhibition components of the present invention further comprises one or more enzyme differentiating units, R. R units are: a) hydrogen; b) C₁-C₁₈ substituted or unsubstituted, linear or branched alkyl; preferably -Cs linear unsubstituted alkyl, inter alia, methyl and ethyl, especially when the enzyme inhibitor component comprises a benzoxazin-4-one moiety. c) C₃-C₁₈ substituted or unsubstituted, cycloalkyl; preferably Cβ-Cio unsubstituted cycloalkyl; d) C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl; preferably Cjo and C₁₅ branched alkenyl units derived from teφenes or other isoprene derived units; e) C₂-C₁₈ substituted or unsubstituted, linear or branched alkynyl; f) Cβ-Cis substituted or unsubstituted aryl; preferably phenyl, biphenyl, naphthyl and the like; g) C₂-C₁₈ substituted or unsubstituted heterocyclic alkyl; h) C₃-Cι s substituted or unsubstituted heterocyclic alkenyl; i) alkylenearyl having the formula: (R')n-R² wherein R¹ is C₁- ₂ linear or branched alkylene, C₂-Cι₂ linear or branched alkenylene, or mixtures thereof; R² is C₆-Cιs substituted or unsubstituted aryl, C₃- Ci₈ heteroaryl, or mixtures thereof; n is from 1 to 16; a preferred alkylenearyl unit comprises substituted benzyl units; j) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently hydrogen, Cι-C₁₈ substituted or unsubstituted, linear, cyclic, or branched alkyl; m is from 0 to 10; k) a quaternary ammonium unit having the formula: (CH₂)_mN(R³)₃ Y ^" wherein each R³ is independently hydrogen, Cι-C]_S substituted or unsubstituted, linear, cyclic, or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; 1) a unit having the formula:

NHR⁴

^ ₅

NR⁵ wherein R⁴ is hydrogen, -C₄ alkyl, or mixtures thereof; R⁵ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferred is amidine; m) a unit having the formula:

NHR^b

-NH

NR' wherein R⁶ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁷ is hydrogen, C C₄ alkyl, or mixtures thereof; R⁶ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferred are guanidine units and cyclic units, inter alia, imidazolinyl; n) a unit having the formula:

— R⁸-R⁹ wherein R⁸ is: i) -(CH₂)_P-, wherein p is from 0 to 12; ϋ) -C(O)-; iii) -C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; iv) -C(X)R' 'C(X)-, wherein R¹ ' is C,-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; v) -C(X)NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vi) -C(X)NR¹⁰R"NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^u is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vii) -NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; viii) -NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; ix) -NR¹⁰C(X)R^πNR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^u is Cι-C_]2 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; x) -NR¹⁰R"C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xi) -NR¹⁰C(X)R^πC(X)O-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xii) -OC(X)R^πC(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xiii) -NR¹⁰C(X)NR¹⁰R¹ '-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R" is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xiv) -R¹¹NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; R¹ ' is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xv) -R^{1 1}NR¹⁰C(X)NR¹⁰R¹ '-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is - ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xvi) -NR¹⁰-, wherein R¹⁰ is hydrogen, C]-C₄ alkyl, or mixtures thereof; xvii) -O-; xviii) -(R^u)_tC(X)(Pv")_t-; wherein R^{1 1} is C Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xix) -(R^{1 1})_tOC(0)(R¹¹),-; wherein R^{1 1} is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xx) -(R")_tC(0)0(R")_r; wherein R^{1 1} is C,-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxi) alkyleneoxyalkylene having the formula: (R^,20)_qR¹³- wherein R . 12 is C₂-C linear or branched alkylene, substituted or unsubstituted phenylene; R¹³ is -(CH )_P-, wherein p is from 0 to 12; q is from 1 to 4; xxii) -S-; xxiii) -(R"),S(R")_r; wherein R¹¹ is C_rC₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxiv) -(R^u)_tS(0)(Rⁿ)_r; wherein R" is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxv) -(R¹¹)_tS0₂(R¹¹)_t-; wherein R¹¹ is Cι-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxvi) or mixtures thereof;

R⁹ is: i) hydrogen; ϋ) C₁-C₁₈ substituted or unsubstituted, linear or branched alkyl; iii) C₃-C₁₈ substituted or unsubstituted, linear or branched cycloalkyl iv) C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl; v) C₂-C₁₈ substituted or unsubstituted, linear or branched alkynyl; vi) Cβ-Cis substituted or unsubstituted aryl; vii) C₂-C₁₈ substituted or unsubstituted heterocyclic alkyl; viii) C₃-C₁₈ substituted or unsubstituted heterocyclic alkenyl; ix) -OH; x) -SO,M; xi) -OSO₃M; xii) -N0₂; xiii) halogen selected from fluorine, chlorine, bromine, iodine, or mixtures thereof; xiv) -C(Hal)₃, wherein each Hal is fluorine, chlorine, bromine, iodine, or mixtures thereof; xv) -COR¹⁴; wherein R¹⁴ is hydrogen, -OH, C,-C₁₂ alkyl, C,-C₁₂ alkoxy, or mixtures thereof; -N(R¹⁵)₂, or mixtures thereof; each R¹⁵ is independently hydrogen, -OH, C₁-C₄ alkyl, or mixtures thereof; xvi) -CH(OR¹⁴)₂ wherein R¹⁴ is hydrogen, C₁-C₁₂ alkyl, or two R¹⁴ units can be taken together to form a ring having from 3 to 5 carbon atoms; or mixtures thereof; xvii) a unit having the formula:

NHR⁴

^ ^ >5 NR >:^J> wherein R⁴ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁵ is hydrogen, C C alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xviii) a unit having the formula:

wherein R⁶ is hydrogen, CpC₄ alkyl, or mixtures thereof; R⁷ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R⁶ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xix) -NHOR¹⁶, wherein R¹⁶ is hydrogen; C₁- ₂ linear or branched alkyl; acyl having the formula -COR¹⁷, wherein R¹⁷ is C C₄ alkyl; or mixtures thereof; xx) a unit having the formula:

— CH=NOR 16 wherein R is hydrogen; CpCπ linear or branched alkyl; C7-C22 linear or branched alkylenearyl; acyl having the formula -COR¹⁷, R¹⁷ is C₁-C4 alkyl; or mixtures thereof; xxi) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently Cj-C₁₈ substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; xxii) a quaternary ammonium unit having the formula: (CH₂)_mN(R³)₃ Y - wherein each R³ is independently C Cιg substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; o) two R units on the same carbon atom can be taken together to form a carbonyl unit or carbonyl unit equivalent, inter alia, C=0, C=NH; and p) mixtures thereof.

Preferred R units according to the present invention include: a) hydrogen; b) Cj-Cs linear unsubstituted alkyl, for example, methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methyl hexyl, 2-ethyl, hexyl.

Methyl and ethyl are especially preferred when the enzyme inhibitor component comprises a benzoxazin-4-one moiety. c) Cβ-Cio unsubstituted cycloalkyl, for example cyclohexyl, 4-methylcyclohexyl, 4- isopropylcyclohexyl; d) Cio and C_l5 branched alkenyl units derived from teφenes or other isoprene derived units, for example, 3,7-dimethyl-6-octen-l-yl; 3,7-dimethyl-2,6- octadien- 1 -yl; 3,7-dimethyl- 1 ,6-octadien-3-yl; f) phenyl, naphthyl, 4-methoxyphenyl, 4-nitrophenyl, 4-(d-C₄ alkyl)phenyl; g) C₄-Cβ substituted or unsubstituted heterocyclic alkyl; non-limiting examples of which include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolindinyl, 3- pyrrolidinyl, 2-piperazinyl, N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- piperidinyl, N-moφholinyl, and mixtures thereof; h) C₃-C₁₈ substituted or unsubstituted heterocyclic alkenyl; 2-pyrrolyl, 3-pyrrolyl; i) alkylenearyl having the formula:

— CH₂- R² wherein R² phenyl, substituted phenyl, pyridinyl, substituted pyridinyl; j) an amino unit having the formula: — N(R^J)₂ wherein each R³ is independently hydrogen, methyl, ethyl, 2-hydroxyethyl, cyclopropyl; for example, methylamino, dimethylamino, ethylamino, diethylamino, dicyclopropyl; a unit having the formula:

NHR⁴

^

NR⁵ wherein R⁴ and R⁵ are each hydrogen, R⁴ and R⁵ is taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferably amidine, 2- pyridinyl, pyrimidinyl, imidazolyl; m) a unit having the formula:

H

n) a unit having the formula:

— R⁸-R⁹ wherein R⁸ is: i) -(CH₂)_P-, wherein p is from 0 to 12; ϋ) -C(O)-; xvi) -NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; xvii) -0-; xxi) alkyleneoxyalkylene having the formula: — (R¹²0)_qR¹³- wherein R¹² is C₂-C₆ linear or branched alkylene, substituted or unsubstituted phenylene; R¹³ is -(CH₂)_P-, wherein p is from 0 to 12; q is from 1 to 4; xxii) -S-; xxvi) or mixtures thereof;

R⁹ is: i) methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; preferably methyl when R⁸ is -0-; ii) cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 2,5-dimethylcyclopentyl; v) phenyl, 4-methoxyphenyl, 4-nitrophenyl, 3-chlorophenyl, 4- chlorophenyl, 3,5-dichlorophenyl, 4-aminobenzyl, 4-guanidinobenzyl; vi) N-aziridinyl, 2-pyrrolindinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl; viii) -OH, when the index p is from 1 to 4, preferably when p is 1 ; ix) -SO₃M when the index p is from 1 to 4, preferably when p is 1 ; x) -OSO₃M when the index p is from 2 to 4, preferably when p is 2; xi) -N0₂; xii) chlorine, bromine, or mixtures thereof; more preferably chlorine; xiii) -CF₃ ; xiv) -C0₂R¹⁴; wherein R¹⁴ is hydrogen, -NH₂, -N(CH )₂, or mixtures thereof; xvii) -NHOR¹⁶, wherein R¹⁶ is hydrogen; C₁-C₁₂ linear or branched alkyl; acyl having the formula -COR¹⁷, wherein R¹⁷ is C₁-C₄ alkyl; or mixtures thereof; xviii) a unit having the formula: CH=NOR¹⁶ wherein R¹⁶ is hydrogen, or methyl; and p) mixtures thereof.

For the puφoses of the present invention the term "substituted or unsubstituted, linear or branched" is defined herein as the following. Alkyl chains which comprise, for example, a -Cis alkyl unit will have any combination of carbon atoms arranged in linear form or with one or more branching chains provided the total number of carbons is from 1 to 18 carbon atoms. By the term "substituted" is meant any unit which suitably replaces a hydrogen atom of a linear or branched chain, non-limiting examples of which include halogen, hydroxyl, nitro, amino, cyano, -CO₂M, - SO₃M, -OSO₃M, wherein M is a water soluble cation. For alkenyl units, one or more double bonds may be present and said bonds may be conjugated or non-conjugated. Alkenyl units also include allenes. For aryl units, substituents may comprise alkyl units as will as halogen, etc.

R units can take any form which modulates the enzyme inhibition properties of the T unit. For example, R units under (i) above are alkylenearyl having the formula: — (^Rl)n^"R² wherein R¹ is C₁- ₂ linear or branched alkylene, C₂-C₁₂ linear or branched alkenylene, or mixtures thereof; R² C₆-Cι₈ substituted or unsubstituted aryl, C3-C₁₈ heteroaryl, or mixtures thereof; n is from 1 to 16. Non-limiting examples of suitable heteroaryl units are 5-member rings which have the formula: or a 6-member ring having the formula:

wherein said unit can be attached at any carbon atom.

Non-limiting examples of heterocyclic units suitable for use in the present invention include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, and mixtures. The heterocyclic ring can be substituted, for example, 2-pyridinecarboxylic acid (picolinyl) The heterocyclic ring can be incoφorated in any manner, for example, as a 2-pyridinyl unit (picolyl) or bonded to the heteroatom, for example, N-aziridinyl, N-pyrrolidinyl. Conjugates of the present invention which are salts or salt- forming compounds will preferably have counter ions which facilitate delivery or formulation. For example, preferred cations include sodium, potassium, lithium, ammonium, alkylammonium, and the like. Preferred anions include halogen, preferably chlorine, methylsulfate, and the like. However, di-basic acids, inter alia, oxalic, fumaric, succinic, may be used to form deliverable salts as well. Polymeric Component

The polymeric component of the present invention comprises units which provide the herein described conjugates with one or more properties which facilitate the delivery of the enzyme inhibitor to the required substrate.

The polymeric unit or the present invention, represented by [Poly]- can be bonded directly to the enzyme inhibiting component or can be attached by way of a linking unit. The polymeric materials of the present invention comprise: i) a polyalkyleneoxy unit having the formula:

R¹⁹(OR¹⁸)_x- wherein R¹⁸ is C₂-C₁₂ linear alkylene, C₃-C₁₂ branched alkylene, phenylene, C7- ₂ alkylenearylene, and mixtures thereof; R¹⁹ is hydrogen, Cι-Cι₈ substituted or unsubstituted, linear or branched alkyl; C₃-C₁₈ substituted or unsubstituted, linear or branched cycloalkyl; C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl; C₂-Ci₈ substituted or unsubstituted, linear or branched alkynyl; C₆-Cj₈ substituted or unsubstituted aryl; and mixtures thereof. The index x has the value of from about 10 to about 500. The polyalkyleneoxy unit may be a homopolymer, (e.g., all ethyleneoxy units), co-polymer (e.g., a mixture of ethyleneoxy and propyleneoxy units), or a block co-polymer. The average molecular weight of a polyalkyleneoxy polymeric unit according to the present invention is from about 400 daltons, preferably from about 1500 daltons, more preferably from about 3400 daltons to about 35,000 daltons, preferably to about 20,000 daltons, more preferably to about 10,000 daltons, most preferably to about 8000 daltons. ii) a co-polymeric polyalkyleneoxy unit having the formula: wherein R¹⁸ is C₂-C₁₂ linear alkylene, C₃-C₁₂ branched alkylene, phenylene, C₇-C₁₂ alkylenearylene, and mixtures thereof; R¹⁹ is hydrogen, -Cig substituted or unsubstituted, linear or branched alkyl; C₃-Cιs substituted or unsubstituted, linear or branched cycloalkyl; C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl; C₂-C₁₈ substituted or unsubstituted, linear or branched alkynyl; Cβ-Cis substituted or unsubstituted aryl; and mixtures thereof; R²⁰ is a unit selected from: a) a unit having the formula:

R'

I

— (CH)_Z—

wherein R' is hydrogen, methyl, allyl, hydroxyl, a linking group L which links an enzyme inhibiting component to the polymeric component as described herein below; -(CH₂)_Z-J wherein J is selected from the group consisting of hydrogen, -C0₂M, -OSO₃M, -S0₃M, -OPO₃M, -P0₃M, - N(R")₂, -C(0)N(R")₂, -NHC(=NH)NH₂, -CC1₃, -CF₃, and mixtures thereof, wherein R" is hydrogen, C₁-C₄ alkyl, or mixtures thereof; M is a water soluble cation, preferably ammonium, sodium, or potassium; z is from 1 to 12, z' is from 0 to 6; z + z' is preferably less than 7. The index x has the value of from about 10 to about 500. The index y has the value of from about 10 to about 100.

b) a unit having the formula:

wherein R" ' is C|-C₄ alkyl, Cj-C₄ alkoxy, phenyl, a continuation of the chain by branching, or mixtures or mixtures, u has the value of from about 3 to 100 The molecular weight of a polymeric component which comprises a co-polymeric polyalkyleneoxy unit is such that the desired viscosity and solubility of the entire molecule fits the needs of the formulator For example, units from (a) which comprise one or more linking units to enzyme inhibiting components may mcoφorate one or more hydrophilic units into the chain to increase the solubility of the final conjugate polymer However, any of the polymers described herein can be random co-polymers or block co-polymers in) a polysacchaπde unit having the formula

wherein R²¹ is hydrogen, C C₄ alkyl, and mixtures thereof, the indices r and s are each independently from 0 to 100 The polysacchaπde units of the present invention can be any mixture of 5 and 6-member ring sugar units, inter aha, sucrose, glucose, mannose, fructose in) a polyamine unit having the formula

H B

I I

[H₂N- R]_J+1 [N- R]_k [N- R]_j NH₂ R is C₂-C₁₂ linear alkylene, C₃- ₂ branched alkylene, and mixtures thereof, preferably R is ethylene, 1,3-propylene, and 1 ,6-hexylene, more preferred is ethylene The indices j and k are such that the molecular weight of said polyammes does not exceed about 30,000 daltons For example, for an entirely linear polyethyleneimme having a molecular weight of about 600 daltons, the index k is equal to 13 and j is equal to 0 For an entirely branched polyethyleneimme having a molecular weight of approximately 600 daltons, the index j is equal to 7 (This combination of indices results in a material having an average molecular weight of about 646 daltons, which, for the puφoses of the present invention is a low molecular weight polyalkyleneimine ) The enzyme inhibiting component may be linked or directly bonded to any of the backbone nitrogen units

The polymeric component of the present mvention may be a mixture of one or more of the polymeric units described herein above In addition, the formulator may attach to the polymeric component of the polymer conjugate as many linking units as necessary to deliver the required number of enzyme inhibiting components One preferred permutation of admixtures of different components are star polymers as described in "Synthesis of Star-Shaped Poly(ethylene oxide)", Y. Gnanou, et al, Makromolecular Chemistry, Vol. 189 (1988) pp. 2885-2892, U.S. 5,648,506 Desai et al., issued July 15, 1997, each of which is incoφorated herein by reference. The preferred polymer or copolymer unit [Poly] of the present invention are polyalkyleneoxy unit having the formula:

R¹⁹(OR¹⁸)_x- and co-polymeric polyalkyleneoxy units having the formula:

R^OR^MOR²⁰),- wherein R¹⁹ is preferably methyl for conjugates which comprise one enzyme inhibitor component, R¹ is preferably hydroxyethyl for conjugates comprising two enzyme inhibitor components. For the latter, the preferred [Poly] units have the formulae:

— OCH₂CH₂(OR¹⁸)— and — OCH₂CH₂(OR¹⁸)_x(OR²⁰)—

R¹⁸ is preferably ethylene and R²⁰ is preferably 2-propylene and when R¹⁸, OR¹⁹, and OR²⁰ are taken together the [Poly] unit has a molecular weight of from about 500 daltons, preferably from about 1000 daltons, more preferably from about 2000 daltons, most preferably from about 3000 daltons to about 10,000 daltons, preferably to about 8,000 daltons, more preferably to about 7500 daltons. Preferred

R¹⁹(OR¹⁸),_<(OR²⁰)_y- units are copolymer having random polymer units, for example, using EO for ethyleneoxy and PO for propyleneoxy, units having a formula:

CH₃(EO)_x.(PO)_y EO)_x"(POV.(EO)_x".(PO)_y".- wherein x' + x" + x'" + y' + y" + y'" represent a copolymer having a molecular weight of from about 500 daltons, preferably from about 1000 daltons, more preferably from about 2000 daltons, most preferably from about 3000 daltons to about 10,000 daltons, preferably to about 8,000 daltons, more preferably to about 7500 daltons.

Non-limiting examples of suitable polyalkyleneoxy polymers for use in the present invention include polyethyleneglycol having an average molecular weight of 1500 daltons (PEG 1500), 4000 daltons (PEG 4000), polyethyleneglycol having an average molecular weight of 5000 daltons (PEG 5000), polyethyleneglycol methyl ether having an average molecular weight of 1500 daltons (MPEG 1500), polyethyleneglycol methyl ether having an average molecular weight of 4000 daltons (MPEG 4000), polyethyleneglycol methyl ether having an average molecular weigh of 5000 daltons (MPEG 5000), block co-polymers of polyethylene glycol and polypropylene glycol (EO/PO co-polymers, wherein said PO unit can be 1 ,2-propylene, 1,3- propylene, or mixtures thereof), for example Pluronics^® available ex BASF. Also preferred are EO/PO/EO and PO/EO/PO co-polymers.

One important embodiment of the present invention relates to conjugates which comprise multiple enzyme inhibitor components. This can be done by the formulator to increase the relative amount of inhibitor on a per weight basis of conjugate or to deliver multiple inhibitors per conjugate. The following are non-limiting examples of polyhydroxy units which are suitable for this embodiment.

OH a) CH₃- (CH₂)₅-CH— (CH₂)₁₅— OH.

b) HO— (CH₂)₃₆— OH.

OH OH

I c) HO— (CH₂)₃- CH— (CH₂)₂₅— CH— (CH₂)₃— OH.

Linking Units

The enzyme inhibiting polymer conjugates of the present invention optionally, but preferably, comprise one or more linking units, L. When the polymer component is bonded to more than one enzyme inhibiting units, the conjugate may comprise more than one linking unit. In addition, more than one type of linking unit may be present. For example, one type of linking unit may be convenient for one particular inhibitor component whereas a second unit is more compatible with a second type of heterocyclic enzyme inhibiting unit.

The linking units of the present invention may comprise any units capable of linking the enzyme inhibitor component to the polymer backbone. If the backbone is formed by random copolymerization, the linking unit may be included. The linking group may be attached via "grafting" to the polymer backbone. Units which may conveniently serve as linking units are amino acids which have a carboxyl end and an amine end and which are capable of easy assembly into polymeric units (peptides). One or more amino acids taken together are a preferred means for linking the polymer unit and the enzyme inhibitor unit. Preferred linking units of the present invention have the formula:

-(R^{1 ,})_h{(X)_J[C(X)]_k(X)_J(R¹¹)_h(X)_J[C(X)]_k(X)_J}_f(R¹¹)h- wherein the unit having the formula:

{(X)_J[C(X)]_k(X)_J(R^{, 1})_h(X)_J[C(X)]_k(X)_J} — is preferably a repeatable unit, inter alia, amino acid, di-acid, wherein R^{1 1} is C Ci₂ substituted or unsubstituted alkylene; C₂-C₁₂ substituted or unsubstituted alkenylene; C3- ₂ cycloalkylene; substituted or unsubstituted aromatic; inter alia, 1 ,2-phenylene, 5-sulfo-l,3-phenylene, 1,4- phenylene; substituted or unsubstituted heterocyclic, non-limiting examples of which include benzimidazole, benzimidazolone, pyridine, piperazine, pyrroline, imidazoline, imidazole, moφholine, oxazole, tetrazole, lH-indenedione, oxazoline, quinoline, isoquinoline, thiazine, thiazole, benzothiophene, all of which can be linked either through a carbon atom or a heteroatom. The R¹ ' units can be substituted or unsubstituted with any of the herein above defined -R⁸R⁹ units. X is oxygen, sulfur, NR¹⁰ wherein R¹⁰ is hydrogen, C₁-C₄ alkyl, phenyl, or R¹⁰ can be taken as part of a ring bonded to another moiety in the linking group, for example, a propylene unit forming a ring between the nitrogen and R¹ ' as in the formula:

The indices h, j, and k are each independently 0 or 1. As indicated herein above, amino acids are a suitable and a preferred class of linking units, either alone, in combination with other amino acids, or other R^{1 1} units. The index f has the value from 0 to 10. An example of a linking unit comprising a repeatable unit (amino acid) wherein the index f greater than 1 is a linking unit having the general formula:

(R^π)_h{NHCH(CH₃)C(0)} {NHCH₂C(0)}(Rⁿ)_h— wherein a first repeatable unit is an alanine residue and a second repeatable unit is a glycine residue. However, depending upon the value of the index f, any combination of repeatable units can be taken together to form a linking unit, for example, a linking unit having the formula:

The preferred linking units of the present invention comprise one or more units selected from the group consisting of: i) -(CH₂)_P-, wherein p is from 0 to 12; ϋ) -C(O)-; iii) -C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; iv) -C(X)R' 'C(X)-, wherein R¹ ' is Cι-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; v) -C(X)NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vi) -C(X)NR¹⁰R' 'NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vii) -NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; viii) -NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; ix) -NR¹⁰C(X)R^UNR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; x) -NR¹⁰R' 'C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C_rC₄ alkyl, or mixtures thereof;

R¹¹ is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xi) -NR¹⁰C(X)R"C(X)O-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof;

R¹¹ is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xii) -OC(X)R^πC(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof;

R¹¹ is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xiii) -NR¹⁰C(X)NR¹⁰R^U-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof;

R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xiv) -R"NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof;

R¹ ' is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xv) -R"NR¹⁰C(X)NR¹⁰R"-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xvi) -NR¹⁰-, wherein R¹⁰ is hydrogen, -C₄ alkyl, or mixtures thereof; xvii) -0-; xviii) -(R^π)_tC(X)(R")_t-; wherein R¹¹ is C Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; wherein X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xix) -(R^{1 1}),OC(0)(R^{1 1}),-; wherein R^{1 1} is C_rC₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xx) -(R")_tC(0)0(R^{1 1}),-; wherein R¹¹ is Cι-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxi) -(R^{1 1}),OC(0)0(R^{1 1})_Γ; wherein t is 0 or 1 ; xxii) alkyleneoxyalkylene having the formula: (R¹²0)_qR¹³- wherein R¹² is C -C₆ linear or branched alkylene, substituted or unsubstituted phenylene; R¹³ is -(CH₂)_P-, wherein p is from 0 to 12; q is 1 or 2; xxiii) -S-; xxiv) -(R^{1 1}),S(R^{1 1})_t-; wherein R¹¹ is C Ci₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxv) -(R^u),S(0)(R^{I 1})_t-; wherein R¹¹ is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxvi) -(R¹¹)_tS02(R^{1 1})_t-; wherein R^{1 1} is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxvii) or mixtures thereof.

More preferred L units according to the present invention include: i) -C(O)-; ii) -C(0)NH-; iii) -C(0)R^uC(0)-, wherein R¹¹ is methylene, ethylene, propylene, butylene, or mixtures thereof; iv) -C(0)NHC(0)-; v) -C(0)NHR' 'NHC(O)- wherein R¹ ' is methylene, ethylene, propylene, butylene, or mixtures thereof; vi) -NHC(O)-; vii) -NHC(0)NH-; viii) -C(0)R^πNH-, R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; ix) -NHR^πC(0) -, R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; x) -NH-; xi) -0-; xii) -R^πOC(0)R^π-; wherein R^{1 1} is methylene, ethylene, propylene, butylene, or mixtures thereof; xiii) -R^πC(0) OR¹¹-; wherein R^{1 1} is methylene, ethylene, propylene, butylenes, or mixtures thereof; xiv) or mixtures thereof. The following are non-limiting examples of polymer conjugates according to the present invention.

An example of a preferred linear polymer conjugate is the ketothiazole polymer conjugate having the formula:

wherein the [Mod] unit having the formula: the [Acyl] unit having the formula:

O

II

the T unit having the formula:

the L unit having the formula:

and the polymer component being a random block copolymer of ethyleneoxy and propyleneoxy units.

A further example of a preferred linear polymer conjugate has the formula:

Another example of a linear polymer conjugate according to the present invention is the α-ketoester having the formula: HNk _^ NH₂

wherein the [Mod] unit having the formula:

the [Acyl] unit having the formula:

II o the T unit having the formula:

HN NH,

the L unit having the formula:

the [Poly] unit is an MPEG unit having the formula: wherein x has a value such that the molecular weight of the polymer component is from about 500 daltons to about 10,000 daltons.

The following is an example of a polymer conjugate wherein the acyl unit is an aldehyde ([Mod] is hydrogen), said conjugate having an open form and a closed form in equilibrium with each other having the formula:

Open form

Closed form The following is an example of a polymer conjugate comprising an acyl unit as part of a ring, said conjugate having the formula:

In the above example, the [Mod] unit comprises a unit having the formula: and the [Acyl] unit has the formula:

o

//

Y

An example of a preferred polymer conjugate having an ester acyl unit masked in a ring comprises a 4H-benzoxazin-4-one heterocyclic unit wherein each R unit is hydrogen which is linked by an ethyleneimine unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:

Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein each R unit is hydrogen which is linked by an N-ethylene-N'-phenylene urea unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:

Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein one R unit is guanidinyl which is linked by an N-ethylene-N'-phenylene urea unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:

Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein one R unit is methyl which is linked directly to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:

Another preferred polymer conjugate comprises a thieno[3,2- ][l,3]oxazine-4-one heterocyclic unit wherein one R unit is methyl which is linked directly to a polyethylene-glycol polymer component having an average molecular weight of about 5000 daltons having the formula

The following are non-limiting examples of polymer conjugates according to the present invention.

EXAMPLE 1 Synthesis of 2-(MPEG 5000V5-methyl-4H-3.1-benzoxazin-4-one

Methoxy polyethyleneglycol having an average molecular weight of about 5000 daltons (MPEG 5000) (50 g, 0.01 mol) is charged to a reaction vessel and dissolved in dichloromethane (125 mL). Under an inert atmosphere, a solution of phosgene in toluene (5.7 mL, 1.93 M) is added while cooling in ice. After addition, the ice bath is removed and the reaction mixture stirred for 12-18h under an inert atmosphere to form an MPEG 5000 chloroformate. In a separate flask, 2-amino-6-methylbenzoic acid (1.66 g, 0.011 mol) is dissolved in dichloromethane (100 mL) which is heated to 30°C. The heat source is removed and while still warm, polyfN- vinylpyridine) (10.23 g, 0.09 mol) is added to the solvent. With vigorous stirring, the MPEG 5000 chloroformate is added dropwise to the mixture. The reaction mixture is stirred for 12-24 h, then ethyl chloroformate (9.6 mL, 0.1 mol) is added at room temperature and stirred for another 12-24h. The solution is filtered to remove the poly(N-vinylpyridine) and the solution is precipitated onto 3.5 L of diethyl ether. The precipitate is filtered under nitrogen to yield 2- (MPEG 5000)-5-methyl-4H-3,l-benzoxazin-4-one as a white solid (33.3g, 67%) which is dried under vacuum.

EXAMPLE 2 Synthesis of 2-(MPEG 5000)-5-methyl-4H-3 -benzoxazin-4-one in toluene Methoxy polyethyleneglycol having an average molecular weight of about 5000 daltons

(MPEG 5000) (13.7g, 2.75mmol) is charged to a reaction vessel and dissolved in toluene (lOOmL) at 48°C. Under an inert atmosphere, a solution of phosgene in toluene (1.6mL, 1.93M) is added while cooling in ice. After the addition, the reaction mixture is stirred for 12-18h under an inert atmosphere at 48°C to form an MPEG 5000 chloroformate. In a separate flask, 2-amino- 6-methylbenzoic acid (457mg, 3.025mmol) is dissolved in toluene (70mL) that is heated to 75°C. Poly(N-vinylpyridine) (3.75 g, 0.033 mol) is added to the solution. The MPEG 5000 chloroformate is added dropwise to the anthranilate mixture. The reaction mixture is stirred for 12-24 h, then the temperature is raised to 80 °C and ethyl chloroformate (2.6 mL, 27.5mmol) is added and reaction mixture is stirred for another 12-24h. The solution is filtered to remove the polyfN-vinylpyridine) and the solution is precipitated onto 3.5 L of diethyl ether. The precipitate is filtered under nitrogen to yield 2-(MPEG 5000)-5-methyl-4H-3,l-benzoxazin-4-one as a white solid (12.4 g, 90%) which is dried under vacuum.

EXAMPLE 3 Synthesis of bis-2-(PEG 4000)-5-methyl-4H-3.1-benzoxazin-4-one

Polyethylene glycol having an average molecular weight of about 4000 daltons (PEG 4000) (5 g, 1.25 mmol) is charged to a reaction vessel and dissolved in dichloromethane (16 mL). Under an inert atmosphere, a solution of phosgene in toluene (1.6 mL, 1.93 M) is added. After addition, the reaction mixture is stirred for 12-18h to form the PEG-4000 bis chloroformate. In a separate flask, 2-amino-6-methylbenzoic acid (416 mg, 2.75 mmol) is dissolved in dichloromethane (25 mL) which is warmed to 30°C. The heat source is removed and while still warm, polyfN-vinylpyridine) (2.13 g, 18.75 mmol) is added to the anthranilate solution. The MPEG bis chloroformate is added dropwise to anthranilate mixture, and the reaction mixture stirred for 12-24h and ethyl chloroformate (1.8 mL, 18.75 mmol) is added at room temperature. The reaction mixture is stirred for 12-24h. The solution is filtered to remove the polyfN- vinylpyridine) and the solution is precipitated onto 3.5 L of diethyl ether. The precipitate is filtered under nitrogen to yield bis-2-(PEG 4000)-5-methyl-4H-3,l-benzoxazin-4-one as a white solid (4.3 g, 86%) which is dried under vacuum.

EXAMPLE 4 Preparation of 2-N-(PEG 5000)amino-4H-3,l-benzoxazine-4-one Methyl 2-isocyanatobenzoate (0.135 g, 0.76 mmol) is combined with PEG 5000 amine (2.5 g, 0.5 mmol) in dichloromethane (5 mL) and stirred 18 hours at room temperature. The reaction mixture is diluted with diethyl ether (200 mL) and the resulting precipitate of urea is recovered by filtration.

The PEG 5000 urea from step one (2.2 g, 0.41 mol) is treated with concentrated sulfuric acid (4 mL) and allowed to stand for 4 hours. The reaction mixture is diluted with excess saturated sodium bicarbonate and held at 0° C. Extraction with dichloromethane affords the 4H- benzoxazin-4-one linked by an N-ethylene-N'-phenylene urea moiety to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons.

EXAMPLE 5 Preparation of N-4-(^"7-guanidinyl-4H-3.1 -benzoxazine-4-one-2-yl)phenylene N'-PEG 5000 urea

2-(4-Amino)phenyl-7-bis(Boc)-guanidino-4H-3,l- benzoxazin -4-one (0.05 g, 0.101 mmol) is combined with N-methyl-moφholine (0.011 mL, 0.1 mmol) in TΗF (5 mL). A solution of 4-nitrophenyl chloroformate (0.02 g, 0.1 mmol) in TΗF ( mL) is added dropwise and the solution is stirred for 4 hours. PEG 5000 amine (0.25 g) is dissolved in TΗF (3 mL) and added to the reaction solution with is subsequently allowed to stand overnight. The reaction is diluted with diethyl ether (100 mL) and the resulting precipitate is collected by filtration.

The N-7- bis(Boc)-guanidino-2-(4-amino)phenyl-4H-3,l-benzoxazine-4-one-2-yl N' PEG 5000 urea from above (0.5 g, 0.1 mmol) is dissolved in glacial acetic acid (4 mL) and refluxed for 15 minutes The solvent is removed under reduced pressure to afford N-4-(7-guanidinyl-4H-3,l- benzoxazine-4-one-2-yl)phenylene N'-PEG 5000 urea.

EXAMPLE 6 Preparation of 2-PEG 5000-8-methyl-4H-3.1-benzoxazin-4-one PEG 5000 (1 g, 0.2 mmol) is dissolved in dichloromethane (25 mL) and a solution of 12.5% phosgene in toluene (93.3 mL, 6.37 mmol) is added dropwise at room temperature. After 30 minutes the solution is diluted with diethyl ether and the PEG 5000 chloroformate precipitate is collected by filtration.

6-Methyl anthranilic acid (0.15 g, 1 mmol) is dissolved in a mixture of 1% sodium bicarbonate (2.5 mL) and THF (0.5 mL). The PEG 5000 chloroformate from above (1 g, 0.2 mmol) is dissolved in THF and added dropwise to the reaction solution and is stirred for 18 hours. The reaction solution is extracted with dichloromethane, the extracts combined and the solvent removed under reduced pressure to yield the PEG 5000 benzoxazine carbamate.

The carbamate from above (0.05 g, 0.01 mmol) is dissolved in pyridine (3 mL) and ethyl chloroformate (0.004 mL, 4.0 mmol) is added followed by activated molecular sieves. After stirring 18 hours the solvent is removed under reduced pressure to afford the desired product.

EXAMPLE 7 Preparation of 2-PEG 5000-r2.3-dlthieno[T .31oxazin-4-one 2-Amino-3-thiophenecarboxylic acid (0.129 g, 1 mmol) is dissolved in 1% sodium bicarbonate (2.5 mL) and THF (0.5 mL). The PEG 5000 chloroformate from above (1 g, 0.2 mmol) is dissolved in THF and added dropwise to the reaction solution and is stirred for 18 hours. The reaction solution is extracted with dichloromethane, the extracts combined and the solvent removed under reduced pressure to afford the thiophenecarboxylic acid carbamate.

An admixture of trifluoroacetic acid (1 mL) and trifluoroacetic anhydride (0.0147 g, 0.07 mmol) are combined and cooled to 0° C to which is added portionwise over 30 minutes the thiophenecarboxylic acid carbamate (0.25 g, 0.05 mmol). After 90 minutes the solution is diluted with diethyl ether and the resulting 2-PEG 5000-[2,3-d]thieno[l,3]-oxazin-4-one precipitate is collected by filtration.

The polymer conjugates of the present invention are effective in treating and/or preventing one or more skin conditions, including irritation, resulting from the contact of enzymes with skin, inter alia, diaper rash. One effective means for delivering the stable conjugates to skin is via an article of manufacture, preferably an "absorbent article". Non-limiting examples of absorbent articles include sanitary napkins, panty liners, diapers, incontinence briefs, training briefs. Typically the polymer conjugates of the present invention are formulated into a skin- compatible carrier which serves to solublized the conjugate in addition to providing a vehicle for uniform delivery of the enzyme inhibitor to the skin surface. The formulator of articles of manufacture which employ the enzyme inhibiting conjugates of the present invention will recognize the vehicle may take any form, inter alia, aqueous, non-aqueous, dry powder. The amount of polymer conjugate which is present in the formulation depends upon the embodiment chosen by the formulator. In some instances, the polymer component of the conjugate itself may have properties which allow for the direct application of the conjugate without the need for a vehicle. However, when incoφorated as part of a composition, the conjugate will comprise from about 0.01%, preferably from about 1% to about 20%, preferably to about 10% by weight, of the delivery vehicle.

The following are non-limiting examples of assays which may be used to determine the effective levels of the polymer conjugates of the present invention.

Fecal Protease Inhibition Assay By way of illustration, to determine the activity of fecal protease inhibiting compounds, the compounds of the present invention may be tested in a standard enzyme assay for protease activity, as follows:

Infant feces are collected in a manner to keep them free from urine contamination and mixed with water to obtain a weight by weight (w/w) mixture (e.g., 1 :4 w/w). This mixture is then mixed thoroughly to obtain a homogeneous suspension by homogenization or sonication.

The feces are then diluted with a reaction buffer, described below, to obtain a fecal concentration which, when added to a protease substrate, hydrolyzes the substrate over a 5 to 60 minute period. Using such a method, for example, fecal trypsin activity may be determined at pH 8.2 in a 50 nM Tris-HCl buffer with 20 mM CaCl2, containing 0.3 mM of the composition to be tested; fecal chymotrypsin activity at pH 7.6 in a 50 mM Tris-HCl buffer with 20 mM CaCl2, containing 0.05 mM of the composition to be tested; and fecal leucine aminopeptidase activity at pH 7.2 in 50 mM sodium phosphate containing the composition to be tested. To test the efficacy of the compositions, several different concentrations of each putative inhibitory composition are added to duplicate feces-containing reaction buffers, and the inhibition of the enzyme activity is measured. Compounds having an IC50 of 100 μM or less are preferred compounds of the invention. More preferred are compounds having an IC50 to IC90, and most preferably an ICso to IC90, of 100 μM or less.

In Vitro Skin Test for Inhibition of IL-lα Production An in vitro method to determine the efficacy of the compounds of the present invention in preventing the proinflammatory response of the skin to feces and fecal enzymes may be performed as follows:

Human keratinocytes are obtained from epidermal tissue and cultured in serum-free medium in plastic culture vessels containing a nylon mesh surface for a period of time until they are confluent. The mesh surface is then raised to the liquid air interface in order to promote differentiation and formation of multilayered organized layers analogous to those found in vivo, including a well defined stratum corneum barrier. Any cell culture system that promotes the growth and differentiation of keratinocytes, as described, may be employed. A commercially

® available cell culture system suitable for use is Epiderm (MatTek Coφoration).

Infant feces are collected in a manner to keep them free of urine contamination and diluted with phosphate-buffered saline (PBS) (pH 7.2 - 7.4). The mixture is then mixed thoroughly to obtain a homogenous suspension by homogenization or sonication. To assay for

IL-lα production due to fecal enzyme activity, an aliquot of the homogenate is diluted with PBS and added to the surface of a control culture in a culture vessel. To assay for inhibition of IL-

1 α production due to protease activity, a predetermined quantity of a putative inhibitor (compound) is added to an otherwise identical diluted aliquot of the homogenate prior to adding it to the surface of a test culture. The cultures are allowed to incubate in a controlled atmosphere.

At selected times, the control cultures and inhibitor-treated test cultures, and the underlying culture media are harvested. The culture media are assayed for the presence of IL-lα by known methods. For example, a suitable assay for IL-lα is an enzyme-linked immunoabsorbent method

(ϊζ) commercially available as Quantikine from R&D Systems.

The percent reduction in IL- 1 α production due to the presence of the compound

(inhibitor) is calculated as follows:

(IL-l_α from control culture) - (IL-l_α from test culture)

% Reduction = x 100 (IL-l_α from control culture)

The polymer conjugates of the present invention are effective in treating and/or preventing one or more skin conditions, including irritation, resulting from the contact of enzymes with skin, inter alia, diaper rash. One effective means for delivering the stable conjugates to skin is via an article of manufacture, preferably an "absorbent article". Non-limiting examples of absorbent articles include sanitary napkins, panty liners, diapers, incontinence briefs, training briefs.

Adjunct biologically active ingredients

The formulator can add to the compositions of the present invention one or more "adjunct biologically active ingredients" to adjust the properties of the composition or to serve as an aid, inter alia, to healing of skin, booster to enzyme inhibition. A non-limiting example of a biologically active adjunct ingredient is hexamidine, 4,4'-

[1 ,6-hexanediylbis(oxy)]bisbenzenecarboximidamide. Hexamidine is preferred as an adjunct to the polymer conjugates of the present invention. Without being limited by theory or application, hexamidine has multiple properties ascribed thereto, inter alia, as a topical antiseptic: Bordeaux Med., M. J. Fenelon, 3, 867 (1 70); as an antibacterial: J. Int. Med. Res., G. Micheal et al., 14, 205 (1986). Hexamidine is preferably delivered as the diisethionate as Elestab HP 100^® available ex Rhone-Poulenc; inter alia, as RF 2535, Desomedine, Esomedine, Hexomedine, Ophtamedine.

FORMULATIONS

For topical administration to the epidermis, the conjugates of the present invention may be formulated as ointments, creams, lotions, etc. which can be directly applied or delivered via an article of manufacture, inter alia, a diaper. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colorizing agents.

Typically the polymer conjugates of the present invention are formulated into a skin- compatible carrier which serves to solublized the conjugate in addition to providing a vehicle for uniform delivery of the enzyme inhibitor to the skin surface. The formulator of articles of manufacture which employ the enzyme inhibiting conjugates of the present invention will recognize the vehicle may take any form, inter alia, aqueous, non-aqueous, dry powder.

The amount of polymer conjugate which is present in the formulation depends upon the embodiment chosen by the formulator. In some instances, the polymer component of the conjugate itself may have properties which allow for the direct application of the conjugate without the need for a vehicle. However, when incoφorated as part of a composition, the conjugate will typically comprise from about 0.01%, preferably from about 1% to about 20%, preferably to about 10% by weight, of the delivery vehicle.

The compositions of the present invention will preferably comprise one or more adjunct ingredients which include carriers. For the puφoses of the present invention the term "carriers" is used interchangeably with the term "emollients", "lotion base", etc. The formulator will recognize that certain carriers will have an emollient property or can serve more than one function. The compositions of the present invention comprise from about 1%, preferably from about 5%, more preferably from about 10% to about 99%, preferably to about 95%), more preferably to about 80%, most preferably to about 50% by weight, of one or more carriers. Non- limiting examples of carriers include petroleum-based emollients, sucrose ester fatty acids, polyethylene glycol and derivatives thereof, humectants, fatty acid ester type, alkyl ethoxylate type, fatty acid ester ethoxylates, fatty alcohol type, polysiloxane type, propylene glycol and derivatives thereof, glycerin and derivatives thereof, including glyceride, acetoglycerides, and ethoxylated glycerides of ₂-C₂₂ fatty acids, triethylene glycol and derivatives thereof, spermaceti or other waxes, fatty acids, fatty alcohol ethers, propoxylated fatty alcohols, other fatty esters of polyhydroxy alcohols, lanolin, kaolin, any of the Federally monographed commercially available skin care. Suitable petroleum-based emollients include C₁₆-C₃₂ hydrocarbons, including paraffins, include mineral oil and petrolatum (also known as "mineral wax", "petroleum jelly", and "mineral jelly").

The balance of the compositions of the present invention typically comprises, other than carriers, other adjunct ingredients. Non limiting examples of other preferred adjunct ingredients include water, viscosity modifiers, perfumes, disinfectant antibacterial actives, antiviral agents, vitamins, pharmaceutical actives, film formers, deodorants, opacifiers, astringents, solvents, preservatives, viscosity modifiers, and mixtures thereof. In addition, stabilizers can be added to enhance the shelf life of the composition such as cellulose derivatives, proteins and lecithin

Water-based skin care carriers and compositions may optionally comprise a preservative, non-limiting examples or which include propyl paraben, methyl paraben, benzyl alcohol, benzalkonium, tribasic calcium phosphate, BHT, or acids such as citric, tartaric, maleic, lactic, malic, benzoic, salicylic, and mixtures thereof.

A preferred use of the polymer conjugates of the present invention is for treatment or prevention of skin irritation from exposure to human feces as it relates to diaper rash and other articles of manufacture used to contain human waste. The polymer conjugates of the present invention inhibit proteolytic and/or lipolytic enzymes whether endogenous or exogenous.

Therefore the formulator can employ the conjugates of the present invention in any embodiment which has the puφose of modulating or prevent the effects of exposure to said enzymes. However, the formulations can have a variety of other uses, non-limiting examples of which include applying the compositions to cotton swabs wherein the compositions are applied to area where enzyme activity is to be inhibited or modulated (i.e., nasal canal, throat), applying the compositions to facial tissues or wipes for application to any skin surface or orifice, inter alia, nasal passage, ocular region.

The following are non-limiting examples of compositions according to the present invention: A composition for inhibiting enzymes on human skin comprising: a) from about 0.01%, preferably from about 0.5%, more preferably from about 1%, most preferably from about 1.5% to about 10%), preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; and b) the balance carriers and adjunct ingredients.

A composition for application to human skin, said composition inhibiting proteolytic and/or lipolytic enzymes on human skin comprising: a) from about 0.01%, preferably from about 0.5%, more preferably from about 1%, most preferably from about 1.5% to about 10%, preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; b) from about 0.01%, preferably from about 0.05%, more preferably from about 0.1% to about 5%, preferably to about 2%, more preferably to about 1% by weight, of an adjunct biologically active ingredient, preferably hexamidine; and c) the balance carriers and adjunct ingredients. A composition for application to human skin, said composition inhibiting proteolytic and/or lipolytic enzymes on human skin comprising: a) from about 0.01%, preferably from about 0.5%), more preferably from about 1%, most preferably from about 1.5% to about 10%, preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; b) from about 0.01%, preferably from about 0.05%, more preferably from about 0.1% to about 5%, preferably to about 2%, more preferably to about 1% by weight, of hexamidine; c) from about 0.01 % by weight, of a carrier alcohol, preferably a Cιo-C₂o linear or branched, saturated or unsaturated alkyl alcohol; d) from about 0.01% by weight, of a secondary benefit agent, preferably selected from the group consisting of vitamins, sun screens, depilatories, desiccants, astringents, and mixtures thereof; e) from about 0.01% by weight, of an aesthetic, said aesthetic selected from the group consisting of perfumes, fragrances, dyes, colorants, and mixtures thereof; and f) the balance carriers and emollients.

METHOD OF USE The present invention further relates to a method for inhibiting skin irritation comprising the step of contacting human skin with one or more enzyme inhibitor polymer conjugates according to the present invention. The present invention further relates to a method for inhibiting skin irritation comprising the step of contacting human skin with a composition which comprises: a) from about 0.01%, preferably from about 0.5%, more preferably from about 1%, most preferably from about 1.5% to about 10%, preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; and b) the balance carriers and adjunct ingredients.

The following is an example of a composition comprising a polymer conjugate according to the present invention which is suitable for use in an absorbent article. EXAMPLE 8

1. White Protopet available ex Witco.

2. CO 1897 available ex Procter & Gamble.

3. Veragel Lipid in Kaydol available ex Madis Botanicals.

4. Enzyme inhibitor according to Example 1.

EXAMPLE 9

1. White Protopet available ex Witco.

2. Enzyme inhibitor according to Example 1.

The compositions of the present invention can also be delivered to skin via compositions which provide other primary benefits. The following disclose compositions which can incoφorate the enzyme inhibiting polymer conjugates of the present invention and are each incoφorated herein by reference. Skin Cleansers

U S 5,641,479, Linares et al , issued June 24, 1997, U S 5,599,549, Wivell et al , issued February 4, 1997, U S 5,585,104, Ha et al , issued December 17, 1996, U S 5,540,852, Kefauver et al , issued July 30, 1996, and U S 5,510,050, Dunbar et al , issued April 23, 1996 Facial Acne Preparations

U S 5,612,324, Guang Lin et al , issued March 18, 1997, U S 5,587,176, Warren et al , issued December 24, 1996, U S 5,549,888, Venkateswaran, issued August 27, 1996, and U S 5,470,884, Corless et al , issued November 28, 1995 Shower gels U S 5,650,384, Gordon et al , issued July 22, 1997, and U S 5,607,678, Moore et al , issued March 4, 1997 Cosmetics

U S 5,641,493, Date et al , issued June 24, 1997, U S 5,605,894, Blank et al , issued February 25, 1997, U S 5,585,090, Yoshioka et al , issued December 17, 1996 Hand. Face, and Body Lotions

U S 4,939,179, Cheney et al , issued July 3, 1990, and U S 5,607,980, McAtee et al , issued March 4, 1997 Cosmetic and Cleansing Wipes

U S 4,045,364, Richter et al , issued August 30, 1977, European Patent Application, EP 0 619 074, Touchet et al , published October 12, 1994, U S Patent Number 4,975,217, Brown-

Skrobot et al , issued December 4, 1990, U S 5,043,155, Puchalski et al , issued August 27, 1991 , and U S 5,648,083, Bheszner et al , issued July 15, 1997

METHOD OF USE The present invention also comprises a method for the treatment and prevention of diaper rash and diaper dermatitis caused by the prolonged contact of human skin with body waste The present invention also ameliorates and serves as a prophylactic means to prevent the occurrence of said skin irritation by providing a barrier against unwanted protease or hpase enzymes

The method of the present invention comprises the step of contacting human skin with a composition comprising a) an effective amount, preferably from about 0 1 %, more preferably from about 1 % by weight, of a polymer conjugate according to the present invention, and b) the balance carriers and adjunct ingredients, wherein said composition is optionally, but preferably, applied to a substrate, inter alia, diaper topsheet, sanitary napkin. The methods of the present invention are carried out a pH which is compatible with the skin of the user.

Preferably the methods of the present invention also include contacting human skin with an ingredient which provides an additional benefit to the user, inter alia, provides conditioning to the exposed skin.

Normally the methods of the present invention deliver an "effective amount" of the compositions, which is the minimum inhibitory concentration of the selected enzyme inhibitor, to the skin. However, depending upon the formulation and the means for performing the methods of the present invention, any amount may be delivered by the formulator.

Claims

WHAT IS CLAIMED IS

1 A polymer conjugate which inhibits protease or lipase enzyme, said polymer con_jugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of one or more protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is attached thereto by a linking unit, said linking unit optionally capable of modulating the interaction between a target enzyme and said inhibitor component, and wherein further said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme

A compound according to Claim 1 having the formula

(L)₂-[Poly]

wherein said polymer component comprises a polymer unit [Poly] and optionally a linking unit, L, said inhibitor component comprises a template unit, T, an acyl unit having the formula [Mod](X)_aC(X)(X)_a, wherein [Mod] is a modulating unit independently selected from a) hydrogen, b) CpCis substituted or unsubstituted, linear or branched alkyl, c) C₃-C₁₈ substituted or unsubstituted, cycloalkyl, d) C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl, e) C₂-C₁₈ substituted or unsubstituted, linear or branched alkynyl, f) C₆-Cis substituted or unsubstituted aryl, g) a unit which is tied back to said T unit to form a ring comprising from 1 to 5 carbon atoms, and h) mixtures thereof,

X is CH₂, NH, O, S, CF₂, and mixtures thereof, each index a is independently 0 or 1 , w is from 1 to 6, x is from 1 to 50, y is from 1 to 10, z is 0 or 1 A compound according to either Claim 1 or 2 comprising an acyl unit having the formula

[Mod]-XC(O)-T wherein said unit is tied back to said T unit to form a ring comprising from 1 to 5 carbon atoms having the formula selected from the group consisting of: i)

ϋ)

iii)

iv)

v)

vi)

vii) viii)

ix)

x) and mixtures thereof; wherein each R is independently: a) hydrogen; b) C1-C i₁s substituted or unsubstituted, linear or branched alkyl; c) C3-C i1s substituted or unsubstituted, linear or branched cycloalkyl d) C2-C i1s substituted or unsubstituted, linear or branched alkenyl; e) C2-C i1s substituted or unsubstituted, linear or branched alkynyl; f) C-6-C i,s substituted or unsubstituted aryl; g) C2-C i₁s substituted or unsubstituted heterocyclic alkyl; h) C-3-C i,s substituted or unsubstituted heterocyclic alkenyl; i) aallkkyylleenearyl having the formula: (R')n-R² wherein R¹ is Ci-Cn linear or branched alkylene, C₂- ₂ linear or branched alkenylene, or mixtures thereof; R² Cβ-Cis substituted or unsubstituted aryl, or mixtures thereof; n is from 1 to 16; j) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently CpCis substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; k) a quaternary ammonium unit having the formula: (CH₂)_n^(R³)₃ Y ^" wherein each R³ is independently Ci- g substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; 1) a unit having the formula:

NHR⁴

NR⁵ wherein R⁴ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁵ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; m) a unit having the formula:

NHR⁶ ^■NH- ^

NR' wherein R⁶ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁷ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁶ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; n) a unit having the formula:

— R⁸-R⁹ wherein R⁸ is: i) -(CH₂)_P-, wherein p is from 0 to 12; ϋ) -C(O)-; iii) -C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; iv) -C(X)R' 'C(X)-, wherein R¹ ' is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; v) -C(X)NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vi) -C(X)NR¹⁰R^πNR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; vii) -NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; viii) -NR'°C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; ix) -NR¹⁰C(X)R¹ 'NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; x) -NR¹⁰R^UC(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xi) -NR¹⁰C(X)R"C(X)O-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xii) -OC(X)R' ¹C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xiii) -NR¹⁰C(X)NR¹⁰R¹ '-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xiv) -R^UNR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xv) -R¹¹NR¹⁰C(X)NR¹⁰R^{1 1}-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xvi) -NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; xvii) -0-; xviii) -(R¹¹)_tC(X)(R^{1 1}),-; wherein R¹¹ is Cι-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xix) -(R¹ ')_tOC(0)(R' '),-; wherein R¹ ' is C,-Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xx) -(R¹ ')_tC(0)0(R' '),-; wherein R¹ ' is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxi) alkyleneoxyalkylene having the formula: (R¹²0)_qR¹³— wherein R¹² is C₂-C6 linear or branched alkylene, substituted or unsubstituted phenylene; R¹³ is -(CH₂)_P-, wherein p is from 0 to

12; q is from 1 to 4; xxii) -S-; xxiii) -(R^U),S(R¹¹),-; wherein Rⁿ is C Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxiv) -(R"),S(0)(R¹¹),-; wherein R¹¹ is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxv) -(R^{1 1}),S0₂(R¹ ')(-; wherein R¹ ' is C_rCι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxvi) or mixtures thereof; R⁹ is: i) hydrogen; ii) C₁-C₁₈ substituted or unsubstituted, linear or branched alkyl; iii) C₃-C₁₈ substituted or unsubstituted, linear or branched cycloalkyl iv) C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl; v) C₂-C₁₈ substituted or unsubstituted, linear or branched alkynyl; vi) C₆-Ci₈ substituted or unsubstituted aryl; vii) C₂-C₁₈ substituted or unsubstituted heterocyclic alkyl; viii) C₃-C₁₈ substituted or unsubstituted heterocyclic alkenyl; ix) -OH; x) -SO₃M; xi) -OSO₃M; xii) -N0₂; xiii) halogen selected from fluorine, chlorine, bromine, iodine, or mixtures thereof; xiv) -C(Hal)₃, wherein each Hal is fluorine, chlorine, bromine, iodine, or mixtures thereof; xv) -COR¹⁴; wherein R¹⁴ is hydrogen, -OH, C,-C,₂ alkyl, C,-C,₂ alkoxy, or mixtures thereof; -N(R¹⁵)₂, or mixtures thereof; each

R¹⁵ is independently hydrogen, -OH, Cι-C alkyl, or mixtures thereof; xvi) -CH(OR¹⁴)₂ wherein R¹⁴ is hydrogen, C,-C₁₂ alkyl, or two R¹⁴ units can be taken together to form a ring having from 3 to 5 carbon atoms; or mixtures thereof; xvii) a unit having the formula:

NHR⁴

NR⁵ wherein R⁴ is hydrogen, Cι-C₄ alkyl, or mixtures thereof; R⁵ is hydrogen, Cι-C₄ alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xviii) a unit having the formula:

NHR^b

— NH-

NR' wherein R⁶ is hydrogen, C C₄ alkyl, or mixtures thereof; R⁷ is hydrogen, C C₄ alkyl, or mixtures thereof; R⁶ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xix) -NHOR¹⁶, wherein R¹⁶ is hydrogen; C,-Cι₂ linear or branched alkyl; acyl having the formula -COR¹⁷, wherein R¹⁷ is Cι-C₄ alkyl; or mixtures thereof; xx) a unit having the formula:

— CH=NOR 16 wherein R¹⁶ is hydrogen; -C12 linear or branched alkyl; C₇-C₂₂ linear or branched alkylenearyl; acyl having the formula -COR¹⁷, R is C₁-C₄ alkyl; or mixtures thereof; xxi) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently Ci- s substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; xxii) a quaternary ammonium unit having the formula:

wherein each R³ is independently Ci-Cjg substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; o) two R units on the same carbon atom can be taken together to form a carbonyl unit or carbonyl unit equivalent; and p) mixtures thereof;

D, E, F, and G are each independently selected from the group consisting of CH, CH₂, N, NH, O, S, CF₂, and mixtures thereof; L is selected from the group consisting of: i) -(CH₂)_P-, wherein p is from 0 to 12; ϋ) -C(O)-; iii) -C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; iv) -C(X)R' 'C(X)-, wherein R¹ ' is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; v) -C(X)NR'°C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vi) -C(X)NR¹⁰R' 'NR^,0C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vii) -NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; viii) -NR'°C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; ix) -NR¹⁰C(X)R' 'NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R is C1- 2 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; x) -NR¹⁰R^πC(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xi) -NR¹⁰C(X)R' 'C(X)0-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xii) -OC(X)R"C(X)NR'⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xiii) -NR¹⁰C(X)NR'°R¹ '-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xiv) -R¹¹NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; R¹¹ is C Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xv) -R^{1 1}NR'°C(X)NR¹⁰R¹ '-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xvi) -NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; xvii) -0-; xviii) -(R")_tC(X)(R")_r; wherein R^{1 1} is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; wherein X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xix) -(R^{1 1}),OC(0)(R^{1 1})_r; wherein R¹¹ is C C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xx) -(R")_tC(0)0(R")_r; wherein R" is C,-Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxi) -(R")_tOC(0)0(R' V; wherein t is 0 or 1 ; xxii) alkyleneoxyalkylene having the formula: (R¹²0)_qR¹³- wherein R¹² is C₂-C₆ linear or branched alkylene, substituted or unsubstituted phenylene; R¹³ is -(CH₂)_P-, wherein p is from 0 to 12; q is 1 or 2; xxiii) -S-; xxiv) -(R")_tS(R^{1 1})_r; wherein R¹' is C_rCι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxv) -(R")_tS(0)(R")_r; wherein R" is C_rC,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxvi) -(R¹¹)_tS0₂(R^{1 1})_t-; wherein R¹¹ is Cι-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxvii) or mixtures thereof; and

[Poly] units are selected from: i) a unit having the formula:

R¹⁹(OR¹⁸)_x- wherein R¹⁸ is C -Cι₂ linear alkylene, C3-C12 branched alkylene, phenylene, C₇- ₂ alkylenearylene, and mixtures thereof; R¹⁹ is hydrogen, -C₂₂ substituted or unsubstituted, linear or branched alkyl; C₃-C₂₂ substituted or unsubstituted, linear or branched cycloalkyl; C₂-C₂₂ substituted or unsubstituted, linear or branched alkenyl; C₂-C₂₂ substituted or unsubstituted, linear or branched alkynyl; C₆-C₂₂ substituted or unsubstituted aryl; and mixtures thereof; ii) a unit having the formula:

wherein R² is hydrogen, C C₄ alkyl, and mixtures thereof; x and y are each independently from 0 to 100; iii) a polyamine unit having the formula:

H B

I I

[H₂N- R]_j+, [N- R]_k [N- R]_j NH₂ wherein R is C₂-Cι₂ linear alkylene, C₃-C,₂ branched alkylene, and mixtures thereof; j and k are such that the molecular weight of said polyamine does not exceed 30,000 daltons; and iv) mixtures thereof.

A compound according to any of Claims 1-4 having a formula selected from: i)

wherein T is a template; [Mod] is C₁- ₂ alkyl, or a unit which is further attached to said T unit; L is a linking unit; [Poly] is a polymer component; X is X is CH₂, NH, O, S, CF₂, and mixtures thereof; w is from 1 to 6, x is from 1 to 50, y is from 1 to 10, z is 0 or 1 ; ϋ)

T- (L)_z- [Poly] wherein T is a template; [Mod] is hydrogen, CrC_]2 alkyl, or mixtures thereof; L is a linking unit; [Poly] is a polymer component; x is from 1 to 50, y is from 1 to 10, z is 0 or 1; iii)

[Mod]_b— C(H)_b.— T- ^■ (L)_z- [Poly]

wherein T is a template; [Mod] is -C₁₂ alkoxy unit; L is a linking unit; [Poly] is a polymer component; b has the value of 2 or 3 and b' has the value of 0 or 1; provided b + b' = 3, x is from 1 to 50, y is from 1 to 10, z is 0 or 1 ; iv) or mixtures thereof.

5. A compound according to any of Claims 1-4 comprising a [Mod]-XC(O)-T having the formula selected from the group consisting of: i) ϋ)

iii)

iv)

v)

vi)

vii)

viii)

ix)

R x)

xi)

xii)

xiii)

xiv) xv)

xvi)

xvii)

xviii)

xix)

xx) and mixtures thereof; wherein each R is independently: a) hydrogen; b) C₁-C₁₈ substituted or unsubstituted, linear or branched alkyl; c) C₃-C₁₈ substituted or unsubstituted, linear or branched cycloalkyl d) C2-C₁8 substituted or unsubstituted, linear or branched alkenyl; e) C₂-Ci8 substituted or unsubstituted, linear or branched alkynyl; f) C₆-Ci8 substituted or unsubstituted aryl; g) C₂-Ci8 substituted or unsubstituted heterocyclic alkyl; h) C3-C₁8 substituted or unsubstituted heterocyclic alkenyl; i) alkylenearyl having the formula: (R')n-R² wherein R¹ is Cι-C₁₂ linear or branched alkylene, C₂-C₁₂ linear or branched alkenylene, or mixtures thereof; R² C₆-Ci₈ substituted or unsubstituted aryl, or mixtures thereof; n is from 1 to 16; j) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently Ci- g substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; k) a quaternary ammonium unit having the formula:

(CH₂)_mN(R³)₃ Y ^■ wherein each R³ is independently Cj-Cis substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; 1) a unit having the formula:

NHR⁴

^

NR^J wherein R⁴ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁵ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; m) a unit having the formula:

NHR⁶

-NH-^

NR⁷ wherein R⁶ is hydrogen, C C alkyl, or mixtures thereof; R⁷ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁶ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; n) a unit having the formula: — R⁸-R⁹ wherein R^s is: i) -(CH₂)_P-, wherein p is from 0 to 12; ii) -C(O)-; iii) -C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; iv) -C(X)R^UC(X)-, wherein R" is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; v) -C(X)NR'°C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vi) -C(X)NR¹⁰R"NR'°C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is Cj-Cπ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; vii) -NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C C alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; viii) -NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; ix) -NR¹⁰C(X)R' 'NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; x) -NR¹⁰R' 'C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^u is C,-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xi) -NR¹⁰C(X)R' 'C(X)0-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xii) -OC(X)R' ' C(X)NR' °-, wherein R¹ ° is hydrogen, C ,- C₄ alkyl, or mixtures thereof; R¹¹ is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xiii) -NR¹⁰C(X)NR¹⁰R"-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xiv) -R"NR'°C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xv) -R"NR¹⁰C(X)NR'°R"-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R¹¹ is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xvi) -NR¹⁰-, wherein R¹⁰ is hydrogen, C C alkyl, or mixtures thereof; xvii) -0-; xviii) -(R")_tC(X)(R")_r; wherein R^{1 1} is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xix) -(R^{1 1})_tOC(0)(R^{1 1}),-; wherein R^{1 1} is C,-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xx) -(R")_tC(0)0(R"),-; wherein R^{1 1} is C_rC₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxi) alkyleneoxyalkylene having the formula: (R¹²0)_qR¹³- wherein R¹² is C₂-C₆ linear or branched alkylene, substituted or unsubstituted phenylene; R¹³ is -(CH₂)_P-, wherein p is from 0 to 12; q is from 1 to 4; xxii) -S-; xxiii) -(R^π)_tS(R")_t-; wherein R¹¹ is C C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxiv) -(R^{1 1}),S(0)(R^{1 1}),-; wherein Rⁿ is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxv) -(R¹¹),S0₂(R¹')t-; wherein R" is C,-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1; xxvi) or mixtures thereof; R⁹ is: i) hydrogen; ii) Cj-Cis substituted or unsubstituted, linear or branched alkyl; iii) C3-C₁₈ substituted or unsubstituted, linear or branched cycloalkyl iv) C₂-C₁₈ substituted or unsubstituted, linear or branched alkenyl; v) C₂-C₁₈ substituted or unsubstituted, linear or branched alkynyl; vi) C_δ-Cis substituted or unsubstituted aryl; vii) C₂-C₁₈ substituted or unsubstituted heterocyclic alkyl; viii) C₃-C₁₈ substituted or unsubstituted heterocyclic alkenyl; ix) -OH; x) -SO₃M; xi) -OSO₃M; xii) -N0₂; xiii) halogen selected from fluorine, chlorine, bromine, iodine, or mixtures thereof; xiv) -C(Hal)₃, wherein each Hal is fluorine, chlorine, bromine, iodine, or mixtures thereof; xv) -COR¹⁴; wherein R¹⁴ is hydrogen, -OH, C,-C,₂ alkyl, C,-C,₂ alkoxy, or mixtures thereof; -N(R¹⁵)₂, or mixtures thereof; each

R¹⁵ is independently hydrogen, -OH, C C₄ alkyl, or mixtures thereof; xvi) -CH(OR¹⁴)₂ wherein R¹⁴ is hydrogen, C_rCι₂ alkyl, or two R¹⁴ units can be taken together to form a ring having from 3 to 5 carbon atoms; or mixtures thereof; xvii) a unit having the formula:

NHR⁴

^

NR' wherein R⁴ is hydrogen, C C₄ alkyl, or mixtures thereof; R⁵ is hydrogen, C C₄ alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xviii) a unit having the formula:

wherein R⁶ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R⁷ is hydrogen, Cι-C alkyl, or mixtures thereof; R⁶ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xix) -NHOR¹⁶, wherein R¹⁶ is hydrogen; C Cι₂ linear or branched alkyl; acyl having the formula -COR¹⁷, wherein R¹⁷ is C,-C₄ alkyl; or mixtures thereof; xx) a unit having the formula: CH=NOR¹⁶ wherein R¹⁶ is hydrogen; C Cι₂ linear or branched alkyl; C7-C₂₂ linear or branched alkylenearyl; acyl having the formula -COR¹⁷, R¹⁷ is C C₄ alkyl; or mixtures thereof; xxi) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently Ci- s substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; xxii) a quaternary ammonium unit having the formula:

wherein each R³ is independently Cι-Cι₈ substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; o) two R units on the same carbon atom can be taken together to form a carbonyl unit or carbonyl unit equivalent; and p) mixtures thereof;

X is selected from the group consisting of CH₂, NH, O, S, CF₂, and mixtures thereof.

6. A compound according to any of Claims 1-6 wherein R is hydrogen, methyl, ethyl, amidinyl, guanidinyl, or mixtures thereof. A compound according to any of Claims 1 -6 wherein [Poly] units are selected from: i) a unit having the formula:

R^!9(OR¹⁸)_x- wherein R¹⁸ is C₂-Cι₂ linear alkylene, C3-C₁₂ branched alkylene, phenylene, C - C12 alkylenearylene, and mixtures thereof; R¹⁹ is hydrogen, Cι-C₂₂ substituted or unsubstituted, linear or branched alkyl; C3-C₂₂ substituted or unsubstituted, linear or branched cycloalkyl; C₂-C₂₂ substituted or unsubstituted, linear or branched alkenyl; C₂-C₂2 substituted or unsubstituted, linear or branched alkynyl; C₆-C₂₂ substituted or unsubstituted aryl; and mixtures thereof; ii) a unit having the formula:

wherein R² is hydrogen, Cι-C₄ alkyl, and mixtures thereof; x and y are each independently from 0 to 100; iii) a polyamine unit having the formula:

H B

I I

[H₂N- R]_j+1 [N- R]_k [N- R]_j NH₂ wherein R is C₂-C₁₂ linear alkylene, C₃-C₁₂ branched alkylene, and mixtures thereof; j and k are such that the molecular weight of said polyamine does not exceed 30,000 daltons; and iv) mixtures thereof.

A polymer conjugate which inhibits protease or lipase enzyme, said polymer conjugate comprising: a) a polymer component; b) at least one enzyme inhibiting component, said enzyme inhibiting component comprising: i) an acyl unit which interacts with at least one protease or lipase enzyme; ii) optionally an enzyme directing or enzyme activating unit; and c) optionally one or more linking units which link said polymer component to said enzyme inhibiting component and which is further capable of interacting with a target enzyme to modulate the interaction of said enzyme inhibiting component with said target enzyme.

9. A composition for inhibiting enzymes comprising: a) from 0.01% by weight, of one or more polymer conjugates which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; and b) the balance carriers and adjunct ingredients.

10. A compound according to either Claim 8 or 9 wherein said polymer conjugate has the formula:

(L)_z-[Poly] wherein T is an enzyme inhibitor component; L is a linking unit; [Poly] is a polymer component; [Mod]-OC(0)- is a unit which modulates the interaction of an acyl unit and a target enzyme; the indices have the following values: w is from 1 to 6, x is from 1 to 50, y is from 1 to 10, z is 0 or 1.

11. A composition according to any of Claims 8- 11 comprising a [Mod]-XC(O)-T having the formula selected from the group consisting of: i) ϋ)

iii)

iv)

v)

vi)

vii)

viii)

ix)

x)

xi)

xii)

xiii)

xiv) xv)

xvi)

xvii)

xviii)

xix)

xx) and mixtures thereof; wherein each R is independently: a) hydrogen; b) C₁-C₁₈ substituted or unsubstituted, linear or branched alkyl; c) C₃-C₁₈ substituted or unsubstituted, linear or branched cycloalkyl d) C₂-C, s substituted or unsubstituted, linear or branched alkenyl; e) C₂-C, s substituted or unsubstituted, linear or branched alkynyl; f) C₆-C, s substituted or unsubstituted aryl; g) C₂-C, s substituted or unsubstituted heterocyclic alkyl; h) C₃-C, s substituted or unsubstituted heterocyclic alkenyl; i) aallkkyylleenearyl having the formula: wherein R¹ is -C₁₂ linear or branched alkylene, C₂-Cι₂ linear or branched alkenylene, or mixtures thereof; R² Cβ-Cis substituted or unsubstituted aryl, or mixtures thereof; n is from 1 to 16; j) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently -Cis substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; k) a quaternary ammonium unit having the formula: (CH₂)_mN(R³)₃ Y ^" wherein each R³ is independently -Cis substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; 1) a unit having the formula:

wherein R⁴ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁵ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; m) a unit having the formula:

NHR⁶

— NH-

^

^' NR' wherein R⁶ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁷ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R^δ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; n) a unit having the formula: — R⁸-R⁹ wherein R⁸ is: i) -(CH₂)_P-, wherein p is from 0 to 12; ϋ) -C(O)-; iii) -C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; iv) -C(X)R^UC(X)-, wherein R^{1 1} is C,-Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; v) -C(X)NR'°C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; vi) -C(X)NR¹⁰R' 'NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R" is C Cι₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; vii) -NR¹⁰C(X)-, wherein R¹⁰ is hydrogen, Cι-C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; viii) -NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; ix) -NR¹⁰C(X)R' 'NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; x) -NR¹⁰R' 'C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^u is C₁-C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xi) -NR¹⁰C(X)R' 'C(X)0-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is C₁- ₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xii) -OC(X)R' 'C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R^{1 1} is -C₁₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xiii) -NR¹⁰C(X)NR'°R¹ '-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R" is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xiv) -R¹ 'NR¹⁰C(X)NR¹⁰-, wherein R¹⁰ is hydrogen, C C₄ alkyl, or mixtures thereof; R" is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xv) -R"NR'⁰C(X)NR'^OR" -, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R" is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur,

NR¹⁰, and mixtures thereof; xvi) -NR¹⁰-, wherein R¹⁰ is hydrogen, C,-C₄ alkyl, or mixtures thereof; xvii) -0-; xviii) -(R")_tC(X)(R' ')_r; wherein R¹ ' is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; X is oxygen, sulfur, NR¹⁰, and mixtures thereof; xix) -(R¹ '),OC(0)(R")_t-; wherein R¹ ' is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xx) -(R¹ ')_tC(0)0(R' '),-; wherein R¹ ' is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxi) alkyleneoxyalkylene having the formula: (R^I20)_qR¹³— wherein R¹² is C₂-C₆ linear or branched alkylene, substituted or unsubstituted phenylene; R¹³ is -(CH₂)_P-, wherein p is from 0 to

12; q is from 1 to 4; xxii) -S-; xxiii) -(R"),S(R")_r; wherein R¹' is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1; xxiv) -(R¹ ')_tS(0)(R' ')_r; wherein R¹ ' is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxv) -(R")_tS0₂(R"),-; wherein R" is C,-C,₂ alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxvi) or mixtures thereof;

R⁹ is: i) hydrogen; ϋ) C.-C substituted or unsubstituted, linear or branched alkyl; iii) C₃-C s substituted or unsubstituted, linear or branched cycloalkyl iv) C₂-C s substituted or unsubstituted, linear or branched alkenyl; v) C₂-C ₈ substituted or unsubstituted, linear or branched alkynyl; vi) C₆-C s substituted or unsubstituted aryl; vii) C₂-C s substituted or unsubstituted heterocyclic alkyl; viii) C₃-C ₈ substituted or unsubstituted heterocyclic alkenyl; ix) -OH; x) -S0₃M; xi) -OSO₃M; xii) -N0₂; xiii) halogen selected from fluorine, chlorine, bromine, iodine, or mixtures thereof; xiv) -C(Hal)₃, wherein each Hal is fluorine, chlorine, bromine, iodine, or mixtures thereof; xv) -COR¹⁴; wherein R¹⁴ is hydrogen, -OH, C,-C,₂ alkyl, C,-C₁₂ alkoxy, or mixtures thereof; -N(R¹⁵)₂, or mixtures thereof; each

R¹⁵ is independently hydrogen, -OH, C,-C alkyl, or mixtures thereof; xvi) -CH(OR¹⁴)₂ wherein R¹⁴ is hydrogen, C,-C₁₂ alkyl, or two R¹⁴ units can be taken together to form a ring having from 3 to 5 carbon atoms; or mixtures thereof; xvii) a unit having the formula:

wherein R⁴ is hydrogen, C,-C alkyl, or mixtures thereof; R⁵ is hydrogen, C,-C alkyl, or mixtures thereof; R⁴ and R⁵ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xviii) a unit having the formula:

NHR⁶ ^•NH

^

NR' wherein R⁶ is hydrogen, C,-C₄ alkyl, or mixtures thereof; R⁷ is hydrogen, C₁-C₄ alkyl, or mixtures thereof; R⁶ and R⁷ can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; xix) -NHOR¹⁶, wherein R¹⁶ is hydrogen; C,-C,₂ linear or branched alkyl; acyl having the formula -COR¹⁷, wherein R¹⁷ is C,-C₄ alkyl; or mixtures thereof; xx) a unit having the formula: CH=NOR¹⁶ wherein R¹⁶ is hydrogen; C,-C,₂ linear or branched alkyl; C₇-C₂₂ linear or branched alkylenearyl; acyl having the formula -COR¹⁷, R¹⁷ is C₁-C₄ alkyl; or mixtures thereof; xxi) an amino unit having the formula: (CH₂)_mN(R³)₂ wherein each R³ is independently C Ci₈ substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; xxii) a quaternary ammonium unit having the formula: (CH₂)_mN(R³)₃ Y - wherein each R³ is independently C Ci₈ substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10;

0) two R units on the same carbon atom can be taken together to form a carbonyl unit or carbonyl unit equivalent; and p) mixtures thereof;

X is selected from the group consisting of -CH₂-, -NH-, -0-, -S-, -CF -, and mixtures thereof.

12. A composition according to any of Claims 8-11 wherein [Poly] units are selected from: i) a unit having the formula:

R¹⁹(OR¹⁸)_x- wherein R is C -Cι₂ linear alkylene, C3- ₂ branched alkylene, phenylene, C₇- Cj₂ alkylenearylene, and mixtures thereof, R¹⁹ is hydrogen, -C₂₂ substituted or unsubstituted, linear or branched alkyl, C₃-C₂₂ substituted or unsubstituted, linear or branched cycloalkyl, C₂-C₂₂ substituted or unsubstituted, linear or branched alkenyl, C₂-C₂₂ substituted or unsubstituted, linear or branched alkynyl, C₆-C₂₂ substituted or unsubstituted aryl, and mixtures thereof,

11) a unit having the formula

wherein R is hydrogen, -C₄ alkyl, and mixtures thereof, x and y are each independently from 0 to 100,

111) a polyamine unit having the formula

H B

[H₂N- R]_J+ι [N- R]_k [N- R]_j NH₂ wherein R is C₂-C₁₂ linear alkylene, C3-C₁2 branched alkylene, and mixtures thereof, j and k are such that the molecular weight of said polyamine does not exceed 30,000 daltons, and iv) mixtures thereof

A composition according to any of Claims 8-12 wherein [Poly] units have the formulae

— OCH₂CH₂(OR¹⁸)— and — OCH₂CH₂(OR¹⁸)_x(OR²⁰)— R¹⁸ ethylene and R²⁰ is 2-propylene and when R¹⁸, OR¹⁹, and OR²⁰ are taken together said [Poly] unit has a molecular weight of from 500 daltons, to 10,000 daltons