JP2003508480A - Enzyme inhibitors - Google Patents

Abstract

The present invention relates to an enzyme-inhibiting polymer conjugate, preferably a polymer conjugate having formula (I), wherein R is a unit that acts to weaken the interaction between the saccharin inhibitor component and the target enzyme. L is a linking group; [poly] is a polymer unit; i indicates the number of the saccharin units constituting the complex, and has a value of 1 to 100; z is 0 or 1, The polymer conjugates described above are suitable for use in preventing skin irritation resulting from exposure of the skin to bodily fluids, especially feces, menstrual fluid. The composite of the present invention is useful for diapers, dressings, sanitary napkins, and the like. Embedded image

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION

The present invention relates to novel functional polymer conjugates that inhibit one or more proteolytic and / or lipolytic enzymes. The polymer composites described here are
It is suitable for use in situations where proteolytic and / or lipolytic enzyme inhibition, especially treatment of diaper rash, is required.

[0002]

BACKGROUND OF THE INVENTION

Diaper rash is commonplace. It was once thought that contacting the skin with urine causes diaper rash, however, the tissue irritation manifested by "diaper rash" is mainly due to endogenous proteolytic and / or lipolytic enzymes, especially in humans. It is now understood to be due to trypsin, chymotrypsin, elastase, and pancreatic lipase contained in feces. However, skin irritation is not limited to the enzymes contained in feces, and menstrual fluid, for example, can also provide a source of enzymes that cause irritation.

Proteolytic and lipolytic enzyme inhibitors are known. An example of an effective inhibitor is a "suicide inhibitor" that reacts irreversibly with the active site of the target enzyme, destroying the ability of the enzyme to function. Reversible enzyme inhibitors
It does not permanently inactivate the target enzyme, but is considered sufficiently effective in blocking the effects of unwanted enzyme exposure. One drawback of low molecular weight enzyme inhibitors is that they are easily absorbed from skin tissue and enter human cells, impeding normal cell catabolism. There has been a long felt need to provide a barrier against harmful enzymes that act to stimulate human skin, especially those that cause diaper rash.

[0004]

[Summary of Invention]

The present invention was surprisingly found that proteolytic and / or lipolytic enzyme inhibitors are effectively delivered to human skin, at which time they act as a barrier to enzyme activity and prevent diaper rash. And the above need is met. The enzyme inhibitor of the present invention is a polymer complex having an enzyme inhibitor component and a functional polymer component. The enzyme inhibitor component comprises a heterocyclic ring template and an enzyme targeting unit.
The functional polymer component comprises a moiety that provides a means for delivering the complex molecule to human skin while at the same time acting as an anchor template for one or more enzyme inhibitors. The enzyme inhibitor component is optionally, but preferably,
It is linked to the functional polymer component by a linking group. As described below, preferably the above linking unit interacts with the enzyme as a leaving group, which in particular exposes the electrophilic moiety at the enzyme active site and can irreversibly inhibit the target enzyme. Due to
Function.

A first aspect of the invention relates to an enzyme-inhibiting polymer conjugate having the formula: [poly]-(L) _z -T where T is a saccharin ring containing inhibitor component; L is a linking unit is there;
[Poly] is the polymer component; z is 0 or 1; preferably, the polymer conjugate has the formula:

[Chemical 21] In the above formula, preferably the linking group L is directly bonded to the heteroatom of the heterocyclic ring. In a preferred aspect of the invention, the linking unit L also acts as a leaving group that promotes irreversible binding to the target enzyme. The present invention further relates to a method for preventing the occurrence of skin irritation due to the presence of proteolytic and / or lipolytic enzymes, which method comprises administering an effective amount of a polymer conjugate as described below to human skin. Contacting.

These and other objects, features and advantages will be apparent to those skilled in the art from the following detailed description and appended claims. All percentages, ratios and proportions herein are by weight unless otherwise noted. All temperatures are degrees Celsius (° C) unless otherwise noted. All cited documents are incorporated herein by reference in relevant places.

[0007]

[Detailed Description of the Invention]

The present invention relates to the prevention of harmful and other undesired skin conditions, especially rashes, irritation caused by the contact of proteolytic and / or lipolytic enzymes with the skin. Among the symptoms that the present invention seeks to improve are diaper rash. The present invention achieves desirable results by applying a sufficient amount of a polymer conjugate that inhibits the activity of one or more enzymes responsible for the above-mentioned undesirable skin symptoms to the skin by a suitable means. There is.

The polymer conjugate of the present invention comprises a saccharin enzyme inhibitor component.
The saccharin component is substituted with one or more units that activate or inactivate enzyme inhibiting components for one or more proteolytic or lipolytic enzymes. One or more saccharin enzyme inhibiting components may be present in the polymer conjugates of the invention.

The complex of the present invention provides a means for tethering the complex molecule to human skin while at the same time acting as an anchor template for one or more enzyme inhibitors,
It further comprises a functional polymer component. The functional polymer component is typically an amphipathic polymer, which can be directly attached to the enzyme inhibitor component or attached to it by a linking unit. The polymeric component also provides the complex with a source of increasing molecular weight that acts to prevent absorption of the enzyme inhibitor into the skin tissue. Moreover, the polymer component serves to facilitate the formulation of the enzyme inhibitor in the carrier or promotes adhesion of the complex to the skin or substrate to which the complex is applied.

The conjugates of the invention optionally also comprise a linking unit that serves to tether the enzyme inhibitor portion of the conjugate to the polymeric component. The polymer may be attached directly to the enzyme-inhibited heterocycle, but preferably a linking group is present to facilitate the creation and attachment of the polymer. The linking group is preferably a unit that interacts with the target enzyme or other enzymes that are present, the interaction increasing the selectivity for the target enzyme or decreasing the affinity for the non-target enzyme. Work like.
The linking group thus plays a dual role; it provides a means for linking the enzyme inhibitor moiety to the polymer backbone, while acting to regulate the specificity of the polymer complex. Another aspect of the preferred linking group may, in some cases, interact with the enzyme before the inhibitor moiety of the polymer complex interacts with the target enzyme, eg, prior to directing the inhibitor moiety into the active site of the enzyme. The ability of the linking group. However, the linking unit may also serve a purpose independent of the enzymatic activity of the polymer complex. For example, the linking unit acts to hydrogen bond with the solvent, increasing the compatibility of the inhibitor moiety with the carrier.

The polymer conjugates of the present invention are utilized in effective amounts. For the purposes of the present invention, the term "effective amount" is defined herein as the amount required to bring about a reduction in enzyme activity in at least one inhibition assay. The preferred assays described here are in particular the "fecal protease inhibition assay", "a skin test for the inhibition of IL-1α production". Suitable tests also include tests that identify the specificity of the enzyme inhibitors described above, eg proteases are blocked by the inhibitors.

Polymer Complex Enzyme Inhibitor Component The enzyme inhibitor component of the present invention comprises a saccharin moiety having the formula:

[Chemical formula 22] The above polymer component is linked to the nitrogen of the saccharin moiety having a heterocyclic ring or the formula:

[Chemical formula 23] The polymer component is linked to the benzene ring. In the first embodiment where the polymer is linked to the nitrogen, it is preferred that there is a linking group that also acts as a leaving group. In the latter embodiment, R'is preferably a unit that acts as a leaving group that facilitates irreversible binding to the target enzyme. However, it is not a requirement for these inhibitors to irreversibly bind to the target enzyme, as the saccharin enzyme inhibitor components of later embodiments remain bound to the polymer component upon and after interaction with the target enzyme. For purposes of the present invention, the term "saccharin ring" is defined herein as a 1,2-benzisothiazol-3 (2H) -one 1,1-dioxide ring, or 2,3-dihydro-3- It is called oxobenzoisosulfonazole and is used interchangeably with each of these chemical names.

[0013]   The enzyme inhibiting component optionally further comprises one or more enzyme discriminating units R. R
The unit acts to weaken the interaction between the saccharin inhibitor component and the target enzyme.
Ku. The R units are:   a) hydrogen;   b) C₁-C₁₈Substituted or unsubstituted, straight chain or branched alkyl; preferably C ₁ -C₈Linear unsubstituted alkyl, especially benzoxazine-
Especially when containing a 4-one moiety, methyl and ethyl;   c) C_Three-C₁₈Substituted or unsubstituted cycloalkyl; preferably C₆-C₁₀ Unsubstituted cycloalkyl;   d) C_Two-C₁₈Substituted or unsubstituted, straight chain or branched alkenyl; preferably
, Derived from terpenes or other isoprene derived units₁₀And C₁₅ Branched alkenyl units;   e) C_Two-C₁₈Substituted or unsubstituted, linear or branched alkynyl;   f) C₆-C₁₈Substituted or unsubstituted aryl; preferably phenyl, biphe
Nil, naphthyl, etc .;   g) C_Two-C₁₈A substituted or unsubstituted heterocyclic alkyl;   h) C_Three-C₁₈A substituted or unsubstituted heterocyclic alkenyl;   i) an alkylene aryl having the formula:                             ‐ (R¹)_n-R^Two R in the above formula¹Is C₁-C₁₂Linear or branched alkylene, C_Two-C₁₂Straight chain
Is a branched alkenylene or mixture thereof; R^TwoIs C₆-C₁₈Replacement
Is unsubstituted aryl, C_Three-C₁₈Heteroaryl or a mixture thereof;
n is 1 to 16; preferred alkylene aryl units are substituted benzyl units.
Become;   j) Amino units having the formula:                             ‐ (CH_Two)_mN (R^Three)_Two Each R in the above formula^ThreeIndependently hydrogen, C₁-C₁₈Substituted or unsubstituted, straight chain, cyclic or
Or is branched alkyl; m is 0-10;   k) Quaternary ammonium units having the formula:                             ‐ (CH_Two)_mN⁺(R^Three)_ThreeY⁻ Each R in the above formula^ThreeIndependently hydrogen, C₁-C₁₈Substituted or unsubstituted, straight chain, cyclic or
Or is a branched alkyl; Y is an anion of sufficient charge to provide electrical neutrality.
M is 0-10;   l) A unit having the formula:

[Chemical formula 24] Wherein R ⁴ is hydrogen, C ₁ -C ₄ alkyl or a mixture thereof; R ⁵ is hydrogen, C ₁ -C ₄ alkyl or a mixture thereof; R ⁴ and R ⁵ are bonded together A heterocyclic ring having 3 to 5 carbon atoms may be formed; amidines are preferred; m) units having the formula:

[Chemical 25] R in the above formula⁶Is hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁷Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁶And R⁷Are together
To form a heterocyclic ring having 3 to 5 carbon atoms; guanidine
Units and cyclic units are preferred, especially imidazolinyl;   n) A unit having the formula:                             -R⁸-R⁹ R in the above formula⁸Is the following:     i)-(CH_Two)_p-(P is 0-12);     ii) -C (O)-;     iii) -C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or it
X is oxygen, sulfur, NR.¹⁰And their mixtures)
;     iv) -C (X) R¹¹C (X)-(R¹¹Is C₁-C₁₂Alkylene, substituted
Or unsubstituted phenylene or mixtures thereof; X is oxygen, sulfur, N
R¹⁰And mixtures thereof);     v) -C (X) NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixtures
);     vi) -C (X) NR¹⁰R¹¹NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-
C_FourAlkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene,
A substituted or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur
, NR¹⁰And mixtures thereof);     vii) -NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl or it
X is oxygen, sulfur, NR.¹⁰And their mixtures)
;     viii) -NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixture
It is a thing);     ix) -NR¹⁰C (X) R¹¹NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     x) -NR¹⁰R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     xi) -NR¹⁰C (X) R¹¹C (X) O- (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xii) -OC (X) R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xiii) -NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xiv) -R¹¹NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     xv) -R¹¹NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C _Four Alkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene
A substituted or unsubstituted phenylene or mixture thereof; X is oxygen, sulfur,
NR¹⁰And mixtures thereof);     xvi) -NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or mixtures thereof
It is a thing);     xvii) -O-;     xviii)-(R¹¹)_tC (X) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1 is; X is oxygen, sulfur, NR¹⁰And mixtures thereof);     xix)-(R¹¹)_tOC (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xx)-(R¹¹)_tC (O) O (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xxi) an alkyleneoxyalkylene having the formula:                             ‐ (R¹²O)_qR^Thirteen- R in the above formula¹²Is C_Two-C₆Linear or branched alkylene, substituted or unsubstituted phenol
Nylene; R^ThirteenIs- (CH_Two)_p-, Where p is 0-12;
q is 1 to 4;     xxii) -S-;     xxiii)-(R¹¹)_tS (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Alkylene
, Substituted or unsubstituted phenylene or mixtures thereof; t is 0 or 1
);     xxiv)-(R¹¹)_tS (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xxv)-(R¹¹)_tSO_Two(R¹¹)_t‐ (R¹¹Is C₁-C₁₂Arche
Phenyl, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
1);     xxvi) or mixtures thereof; R⁹Is the following:     i) hydrogen;     ii) C₁-C₁₈Substituted or unsubstituted, straight chain or branched alkyl;     iii) C_Three-C₁₈Substituted or unsubstituted, linear or branched cycloalkyl;     iv) C_Two-C₁₈Substituted or unsubstituted, straight chain or branched alkenyl;     v) C_Two-C₁₈Substituted or unsubstituted, linear or branched alkynyl;     vi) C₆-C₁₈Substituted or unsubstituted aryl;     vii) C_Two-C₁₈A substituted or unsubstituted heterocyclic alkyl;     viii) C_Three-C₁₈A substituted or unsubstituted heterocyclic alkenyl;     ix) -OH;     x) -SO_ThreeM;     xi) -OSO_ThreeM;     xii) -NO_Two;     xiii) a ha selected from fluorine, chlorine, bromine, iodine or mixtures thereof.
Rogen;     xiv) -C (Hal)_Three(Each Hal is fluorine, chlorine, bromine, iodine or its
A mixture of these);     xv) -COR¹⁴(R¹⁴Is hydrogen, -OH, C₁-C₁₂Alkyl, C₁-
C₁₂Alkoxy or a mixture thereof); -N (R¹⁵)_TwoOr it
A mixture of these (each R¹⁵Independently hydrogen, -OH, C₁-C_FourAlkyl or it
A mixture of these);     xvi) -CH (OR¹⁴)_Two(R¹⁴Is hydrogen, C₁-C₁₂Is it alkyl
, Or two R¹⁴The units are linked together to form a ring having 3 to 5 carbon atoms.
Can be formed or a mixture thereof);     xvii) A unit having the formula:

[Chemical formula 26] R ⁴ is hydrogen, C ₁ -C ₄ alkyl or a mixture thereof; R ⁵ is hydrogen, C ₁ -C ₄ alkyl or a mixture thereof; R ⁴ and R ⁵ are bonded together May form a heterocyclic ring having 3 to 5 carbon atoms; xviii) a unit having the formula:

[Chemical 27] R in the above formula⁶Is hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁷Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁶And R⁷Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;     xix) -NHOR¹⁶(R¹⁶Is hydrogen, C₁-C₁₂Straight or branched alkyl
, Formula-COR¹⁷Having an acyl (R¹⁷Is C₁-C_FourIs alkyl) or
A mixture thereof);     xx) Units with the following formula:                             -CH = NOR¹⁶ R in the above formula¹⁶Is hydrogen, C₁-C₁₂Linear or branched alkyl, C₇-C₂₂straight
Chain or branched alkylene aryl, formula-COR¹⁷Having an acyl (R¹⁷Is C ₁ -C_FourAlkyl) or mixtures thereof;     xxi) an amino unit having the formula:                             ‐ (CH_Two)_mN (R^Three)_Two Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; m is 0-10;     xxii) Quaternary ammonium units having the formula:                             ‐ (CH_Two)_mN⁺(R^Three)_ThreeY⁻ Each R in the above formula^ThreeIndependently hydrogen, C₁-C₁₈Substituted or unsubstituted, linear or
Is a heteroalkyl; Y is an anion of sufficient charge to provide electrical neutrality.
M is 0-10;   o) two R units on the same carbon atom are linked together to form a carbonyl unit or
May form carbonyl unit equivalents, especially C = O, C = NH; and   p) a mixture thereof.

[0014]   Preferred R units according to the invention include:   a) hydrogen;   b) C₁-C₈Straight chain unsubstituted alkyl such as methyl, ethyl, propyl, iso
Propyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl
2-methylhexyl, 2-ethylhexyl (especially if the enzyme inhibitor component is
Methyl and ethyl are featured when they comprise a benzoxazin-4-one moiety.
Preferred)   c) C₆-C₁₀Unsubstituted cycloalkyl, eg cyclohexyl, 4-methyl
Cyclohexyl, 4-isopropylcyclohexyl   d) C derived from terpenes or other isoprene derived units₁₀And C ₁₅ Branched alkenyl units such as 3,7-dimethyl-6-octen-1-yl,
3,7-Dimethyl-2,6-octadien-1-yl, 3,7-dimethyl-1,
6-octadiene-3-yl;   f) Phenyl, naphthyl, 4-methoxyphenyl, 4-nitrophenyl, 4-
(C₁-C_FourAlkyl) phenyl;   g) C_Four-C₆A substituted or unsubstituted heterocyclic alkyl; non-limiting examples of which are 2
-Furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolidinyl, 3-
Pyrrolidinyl, 2-piperazinyl, N-piperidinyl, 2-piperidinyl, 3-
Piperidinyl, 4-piperidinyl, N-morpholinyl and mixtures thereof
R;   h) C_Three-C₁₈Substituted or unsubstituted heterocyclic alkenyl; 2-pyrrolyl, 3
-Pyrrolyl;   i) an alkylene aryl having the formula:                             -CH_Two-R^Two R in the above formula^TwoIs phenyl, substituted phenyl, pyridinyl, substituted pyridinyl;   j) Amino units having the formula:                             -N (R^Three)_Two Each R in the above formula^ThreeIndependently hydrogen, methyl, ethyl, 2-hydroxyethyl,
Ropropyl, such as methylamino, dimethylamino, ethylamino, diethyla
Mino is dicyclopropyl;   l) A unit having the formula:

[Chemical 28] Wherein R ⁴ and R ⁵ are each hydrogen and R ⁴ and R ⁵ are bonded together,
A heterocyclic ring having 3 to 5 carbon atoms, which may form an amidine, 2-pyridinyl, pyrimidinyl, imidazolyl; m) a unit having the formula:

[Chemical 29] n) A unit having the formula: -R ⁸ -R ^{9 wherein} R ⁸ is: i)-(CH ₂ ) _p- (p is 0-12); ii) -C (O) -; Xvi) -NR ^10- (R ¹⁰ is hydrogen, C ₁ -C ₄ alkyl or mixtures thereof); xvii) -O-; xxi) alkyleneoxyalkylene having the formula:-(R ¹² O) _q R ¹³ - above wherein ^{R 12} is a _C 2 -C ₆ linear or branched alkylene, substituted or unsubstituted ^{phenylene; R 13} is - _{(CH 2) p} - a, where p is at 0-12 is there;
q is 1 to 4; xxii) -S-; xxvi) or mixtures thereof; R ⁹ is: i) methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
Preferably methyl (when R ⁸ is —O—); 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- Pyrrolidiyl, 3-pyrrolidiyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl; viii) OH (when index p is 1 to 4, preferably when p is 1); ix) -SO ₃ M (index when p is 1-4, preferably when p is 1); x) -OSO ₃ M (when index p is 2-4, preferably p is 2)
Xi) -NO ₂ ; xii) chlorine, bromine or a mixture thereof, more preferably chlorine; xiii) -CF ₃ ; xiv) -CO ₂ R ¹⁴ (R ¹⁴ is hydrogen, -NH ₂ ,- N (CH ₃ ) ₂ or a mixture thereof); xvii) -NHOR ¹⁶ (R ¹⁶ is hydrogen, C ₁ -C ₁₂ linear or branched alkyl, acyl having the formula —COR ¹⁷ (R ¹⁷ is C _1- C ₄ alkyl) or mixtures thereof); xviii) units having the formula: -CH = ^{NOR 16} above wherein ^{R 16} is hydrogen or methyl; and p) mixtures thereof.

[0015]   For the purposes of the present invention, the term "substituted or unsubstituted, linear or branched" refers to
Here, it is defined as follows. For example, C₁-C₁₈Al consisting of alkyl units
Kill chains are combinations of carbon atoms arranged in a straight line or having one or more branched chains.
With a total number of carbons of 1 to 18 carbon atoms. The term "replacement"
, A unit in which a straight-chain or branched-chain hydrogen atom is appropriately replaced, including non-limiting examples
Is halogen, hydroxyl, nitro, amino, cyano, -CO_TwoM-, -SO _Three M-, -OSO_ThreeThere is M-, where M is a water-soluble cation. Alkenyl
In the case of a unit, one or more double bonds may be present, the bonds may be conjugated or
It may be non-conjugated. The alkenyl unit also includes allenes. For aryl units, the
Substituents include alkyl units and halogens.

The R unit may take any form that regulates the enzyme inhibiting properties of the T unit. For example, the R unit in (i) above is an alkylenearyl having the formula:-(R ¹ ) _n -R ^{2 wherein} R ¹ is C ₁ -C ₁₂ straight or branched alkylene, C ₂ -C ₁₂ straight or branched alkenylene or mixtures thereof; R ² is C ₆ -C ₁₈ substituted or unsubstituted aryl, C ₃ -C ₁₈ heteroaryl or mixtures thereof;
n is 1-16. A non-limiting example of a suitable heteroaryl unit is a 5-membered ring having the formula:

[Chemical 30] Or a 6-membered ring having the formula:

[Chemical 31] The units may 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, thiazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl. , Fluorenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, indolizinyl,
There are indolyl, isoindolyl, purinyl, quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl and mixtures thereof. Heterocyclic rings are eg 2
-Substituted, such as pyridinecarboxylic acid (picolinyl). The heterocyclic ring may be incorporated in any form, eg as a 2-pyridinyl unit (picolyl), or may be attached to a heteroatom, eg N-aziridinyl, N-pyrrolidinyl.

The complex of the invention that is a salt or salt-forming compound preferably has a counterion that facilitates delivery or formulation. For example, a preferred cation is sodium,
Examples include potassium, lithium, ammonium, and alkyl ammonium. Preferred anions include halogen, preferably chlorine, methylsulfate and the like. However, dibasic acids, especially oxalic acid, fumaric acid, succinic acid may also be used to form deliverable salts.

Polymer Component The polymer component of the present invention comprises units that impart one or more properties to the conjugates described herein that facilitate delivery of the enzyme inhibitor to the required substrate. The polymer unit of the present invention represented by [poly] -may be directly bonded to the enzyme-inhibiting component or may be bonded via a linking unit.

The polymeric material of the present invention comprises: i) a polyalkyleneoxy unit having the formula: R ¹⁹ (OR ¹⁸ ) _x-wherein R ¹⁸ is C ₂ -C ₁₂ straight chain alkylene, C _3- C ₁₂ branched alkylene,
Phenylene, C ₇ -C ₁₂ alkylenearylene and mixtures thereof;
R ¹⁹ is hydrogen, C ₁ -C ₁₈ substituted or unsubstituted, linear or branched alkyl, C ₃ -C ₁₈ substituted or unsubstituted, linear or branched cycloalkyl, C ₂ -C ₁₈ substituted or unsubstituted, linear Or branched alkenyl, C ₂ -C ₁₈ substituted or unsubstituted, linear or branched alkynyl, C ₆ -C ₁₈ substituted or unsubstituted aryl and mixtures thereof. The index x has a value of about 10 to about 500. The polyalkyleneoxy units include homopolymers (eg all ethyleneoxy units), copolymers (eg a mixture of ethyleneoxy and propyleneoxy units) or block copolymers. The average molecular weight of the polyalkyleneoxy polymer units according to the present invention is about 400 Daltons, preferably about 1500 Daltons, more preferably about 3400 Daltons to about 35,000 Daltons, preferably about 20,000 Daltons.
0 daltons, more preferably about 10,000 daltons, most preferably about 800
It is 0 Dalton. ii) Copolymer polyalkyleneoxy units having the formula: R ¹⁹ (OR ¹⁸ ) _x (OR ²⁰ ) _y-wherein R ¹⁸ is C ₂ -C ₁₂ straight chain alkylene, C ₃ -C ₁₂ branched alkylene,
Phenylene, C ₇ -C ₁₂ alkylenearylene and mixtures thereof;
R ¹⁹ is hydrogen, C ₁ -C ₁₈ substituted or unsubstituted, linear or branched alkyl, C ₃ -C ₁₈ substituted or unsubstituted, linear or branched cycloalkyl, C ₂ -C ₁₈ substituted or unsubstituted, linear Or branched alkenyl, C ₂ -C ₁₈ substituted or unsubstituted, linear or branched alkynyl, C ₆ -C ₁₈ substituted or unsubstituted aryl and mixtures thereof. R ²⁰ is a unit selected from: a) a unit having the formula:

[Chemical 32] In the above formula, R'is hydrogen, methyl, allyl, hydroxyl, and the following polymer components
A linking group L for linking the enzyme inhibitory component to_Two)_z-J; where J is
Hydrogen, -CO_TwoM-, -OSO_ThreeM-, -SO_ThreeM-, -OPO_ThreeM-, -PO _Three M-, -N (R ")_Two-, -C (O) N (R ")_Two-, -NHC (= NH) N
H_Two‐ 、 ‐ CCl_Three, -CF_ThreeAnd selected from the group consisting of
R'is hydrogen, C₁-C_FourAlkyl or a mixture thereof; M is a water-soluble carboxylic acid
Thione, preferably ammonium, sodium or potassium; z is 1
12, z'is 0-6; z + z 'is preferably less than 7. index
x has a value of about 10 to about 500. The index y has a value of about 10 to about 100.
Have.     b) A unit having the formula:

[Chemical 33] In the above formula, R ″ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, a continuous part of a branched chain or a mixture thereof; u has a value of about 3-100. The molecular weight of the polymer component composed of the copolymer polyalkyleneoxy unit is
The desired viscosities and solubilities for all molecules are such that they meet the needs of the trader.
For example, the unit from (a) containing one or more linking units to the enzyme inhibitory component is
One or more hydrophilic units may be incorporated into the chain to increase the solubility of the final composite polymer. However, the polymers described herein may be random or block copolymers.

[0021]   iii) a polysaccharide unit having the formula:

[Chemical 34] Wherein R ²¹ is hydrogen, C ₁ -C ₄ alkyl and mixtures thereof; indices r and s are each independently 0-100. The polysaccharide unit of the present invention is 5
And 6-membered ring sugar units, especially any mixture of sucrose, glucose, mannose, fructose.

[0022]   iii) a polyamine unit having the formula:

[Chemical 35] R is _C 2 _{-C 12} linear _alkylene, C 3 _{-C 12} branched alkylene, and mixtures thereof; preferably R is ethylene, 1,3-propylene and 1,6-hexylene, more preferably ethylene. The indices j and k are such that the molecular weight of the polyamine does not exceed about 30,000 daltons. For example, for an entirely linear polyethyleneimine having a molecular weight of about 600 Daltons, the index k is 13 and j is 0. For a fully branched polyethyleneimine having a molecular weight of about 600 Daltons, the index j is 7 (this combination of indices yields a material with an average molecular weight of about 646 Daltons, which for the purposes of the present invention. It is a low molecular weight polyalkyleneimine). The enzyme inhibiting component may be linked to any backbone nitrogen unit or may be directly linked.

The polymer component of the present invention may be a mixture of one or more of the polymer units described above. In addition, the manufacturer may attach as many linking units to the polymer component of the polymer conjugate as needed to deliver the required number of enzyme inhibiting components. One preferred structure of a mixture of different components is the "Synthesis of Star-Shaped Poly (et
hylene oxide) ”, Y. Gnanou, et al., Makromolecular Chemistry, Vol.189 (1988) pp.
2885-2892, Desai et al., US 5,648,5, issued July 15, 1997.
06 star polymers, each of which is incorporated herein by reference.

Preferred polymer or copolymer units [poly] of the present invention include polyalkyleneoxy units having the formula: R ¹⁹ (OR ¹⁸ ) _x- and copolymer polyalkyleneoxy units having the formula: R ¹⁹ (OR ¹⁸ ). _x (OR ²⁰ ) _y −; wherein R ¹⁹ is preferably methyl in the case of a complex containing one enzyme inhibitor moiety and R ¹⁹ is of a complex containing two enzyme inhibitor moieties. In this case, it is preferably hydroxyethyl. In the latter case, it has a preferred [poly] unit ^{_{formula: -OCH 2 CH 2 (OR 18}} ) x - and ^{_{-OCH 2 CH 2 (OR 18)}} x (OR 20) y - R 18 is preferably Is ethylene, R ²⁰ is preferably 2-propylene, and when R ¹⁸ , OR ¹⁹ and OR ²⁰ are linked together, the [poly] unit is about 500 Daltons, preferably about 1000 Daltons, and Preferably about 200
It has a molecular weight of 0 daltons, most preferably about 3000 daltons to about 10,000 daltons, preferably about 8000 daltons, and more preferably about 7500 daltons. Preferred R ¹⁹ (OR ¹⁸ ) _x (OR ²⁰ ) _y- units are those having the formula: with a copolymer having random polymer units, such as EO for ethyleneoxy and PO for propyleneoxy: CH ₃ (EO _{^{) x '(PO) y'}} (EO) x "(PO) y" (EO) x '''(PO)y''' - above wherein x '+ x "+ x''' + y '+ y" + y' ″ Is a copolymer having a molecular weight of about 500 Daltons, preferably about 1000 Daltons, more preferably about 2000 Daltons, most preferably about 3000 Daltons to about 10,000 Daltons, preferably about 8000 Daltons, more preferably about 7500 Daltons. Represents

Non-limiting examples of polyalkyleneoxy polymers suitable for use in the present invention include 150
Polyethylene glycol having an average molecular weight of 0 daltons (PEG 1500), 4000 daltons (PEG 4000), polyethylene glycol having an average molecular weight of 5000 daltons (PEG 5000), polyethylene glycol methyl ether having an average molecular weight of 1500 daltons (MPEG 1500), 4000
Polyethylene glycol methyl ether (MPE) having an average molecular weight of Dalton
G4000), block copolymers of polyethylene glycol methyl ether (MPEG5000), polyethylene glycol and polypropylene glycol having an average molecular weight of 5000 Daltons (EO / PO copolymers; the PO units being 1,2-propylene, 1,3-propylene or their A mixture), for example Pluronics ^{R from} BASF. EO / PO / EO and PO / EO / P
O copolymers are also preferred. One important aspect of the present invention relates to a complex comprising a number of enzyme inhibitor components. This can be done by one of skill in the art to increase the relative amount of inhibitor per weight basis of the complex or to deliver multiple inhibitors per complex. The following are non-limiting examples of polyhydroxy units suitable for this embodiment.

[Chemical 36]

Linking Unit The enzyme-inhibiting polymer conjugate of the present invention optionally, but preferably, comprises one or more linking units L. When the polymer component is attached to more than one enzyme inhibiting unit, the complex may include more than one linking unit. In addition, there may be more than one type of linking unit. For example, one type of linking unit is convenient for one particular inhibitor component, while the second unit is more compatible with the second type of heterocyclic enzyme inhibiting unit.

The linking unit of the present invention is capable of linking the enzyme inhibitor component to the polymer backbone,
Any unit may be used. Linking units may be included if the backbone is formed by random copolymerization. The linking group may be attached to the polymer backbone by "grafting". The units that work well as linking units are amino acids with carboxyl and amine ends that can be easily assembled into polymer units (peptides).
One or more amino acids linked together is the preferred means for linking the polymer unit and the enzyme inhibitor unit.

[0028]   Preferred linking units of the present invention have the formula: ‐ (R¹¹)_h[(X)_j[C (X)]_k(X)_j(R¹¹)_h(X)_j[C (X)]_k(X)_j]_f(R¹¹)_h-
A unit having the following formula in the above:   -[(X)_j[C (X)]_k(X)_j(R¹¹)_h(X)_j[C (X)]_k(X)_j]- Are preferably repeating units, especially amino acids, diacids; R¹¹Is C₁-C₁₂Setting
Substituted or unsubstituted alkylene, C_Two-C₁₂Substituted or unsubstituted alkenylene, C_Three -C₁₂Cycloalkylene, substituted or unsubstituted aromatic, especially 1,2-phenylene
5-sulfo-1,3-phenylene, 1,4-phenylene, substituted or unsubstituted
Telocyclic (non-limiting examples of which include benzimidazole, benzimidazoline,
Gin, piperazine, pyrroline, imidazoline, imidazole, morpholine, oki
Sazole, tetrazole, 1H-indendione, oxazoline, quinoline, a
Soquinoline, thiazine, thiazole, benzothiophene) and they
All may be linked via a carbon atom or a heteroatom. R¹¹Unit is -R above ⁸ R⁹It may be substituted or unsubstituted with any of the units. X is oxygen and sulfur
, NR¹⁰And where R¹⁰Is hydrogen, C₁-C_FourAlkyl, phenyl
Or R¹⁰May exist as part of a ring joined to another moiety by a linking group
For example, nitrogen and R¹¹Propylene mono-forms a ring with
It can be:

[Chemical 37] The indices h, j and k are each independently 0 or 1. as mentioned above,
Amino acids, alone, in combination with other amino acids or other R ¹¹ units, are a suitable and preferred class of linking units. The index f has a value of 0-10.
Examples of linking units index f comprises a larger repeating unit than 1 (amino acid) is a linking unit having the following general formula: - (R ¹¹⁾ _h [NHCH (CH ₃₎ C (O)] [ NHCH ₂ C (O)] (R ¹¹⁾ _h - the first repeat unit is an alanine residue, the second repeat unit is glycine residues. However, depending on the value of the index f, any combination of repeating units may be joined together to form a linking unit, for example a linking unit having the formula:

[Chemical 38]

[0029]   The preferred linking unit of the present invention is one or more units selected from the group consisting of
Consists of:   i)-(CH_Two)_p-(P is 0-12);   ii) -C (O)-;   iii) -C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or them
X is oxygen, sulfur, NR¹⁰And mixtures thereof);   iv) -C (X) R¹¹C (X)-(R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);   v) -C (X) NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl again
Is a mixture thereof; X is oxygen, sulfur, NR¹⁰And in their mixtures
is there);   vi) -C (X) NR¹⁰R¹¹NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C _Four Alkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene
A substituted or unsubstituted phenylene or mixture thereof; X is oxygen, sulfur,
NR¹⁰And mixtures thereof);   vii) -NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl or them
X is oxygen, sulfur, NR¹⁰And mixtures thereof);   viii) -NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixtures
);   ix) -NR¹⁰C (X) R¹¹NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourArchi
R or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR¹⁰ And mixtures thereof);   x) -NR¹⁰R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourArchi
R or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR¹⁰ And mixtures thereof);   xi) -NR¹⁰C (X) R¹¹C (X) O- (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);   xii) -OC (X) R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);   xiii) -NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);   xiv) -R¹¹NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourArchi
R or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR¹⁰ And mixtures thereof);   xv) -R¹¹NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C_Four Alkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Or unsubstituted phenylene or mixtures thereof; X is oxygen, sulfur, N
R¹⁰And mixtures thereof);   xvi) -NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or mixtures thereof
);   xvii) -O-;   xviii)-(R¹¹)_tC (X) (R¹¹)_t-(T is 0 or 1; X is
Oxygen, sulfur, NR¹⁰And mixtures thereof);   xix)-(R¹¹)_tOC (O) (R¹¹)_t-(T is 0 or 1);   xx)-(R¹¹)_tC (O) O (R¹¹)_t-(T is 0 or 1);   xxii) an alkyleneoxyalkylene having the formula:                             ‐ (R¹²O)_qR^Thirteen- R in the above formula¹²Is C_Two-C₆Linear or branched alkylene, substituted or unsubstituted phenol
Nylene; R^ThirteenIs- (CH_Two)_p-, Where p is 0-12;
q is 1 or 2;   xxii) -S-;   xxiii)-(R¹¹)_tS (R¹¹)_t-(T is 0 or 1);   xxiv)-(R¹¹)_tS (O) (R¹¹)_t-(T is 0 or 1);   xxv)-(R¹¹)_tSO_Two(R¹¹)_t-(T is 0 or 1);   xxvi) or mixtures thereof.

Further preferred L units according to the invention are: i) -C (O)-; ii) -C (O) NH-; iii) -C (O) R ¹¹ C (O)-(R ¹¹ is Methylene, ethylene, propylene, butylene or mixtures thereof); iv) -C (O) NHC (O)-; v) -C (O) NHR ¹¹ NHC (O)-(R ¹¹ is methylene, ethylene, Propylene, butylene or a mixture thereof); vi) -NHC (O)-; vii) -NHC (O) NH-; viii) -C (O) R ¹¹ NH- (R ¹¹ is C ₁ -C ₁₂ Alkylene, substituted or unsubstituted phenylene or mixtures thereof); ix) -NHR ¹¹ C (O)-(R ¹¹ is C ₁ -C ₁₂ alkylene, substituted or unsubstituted phenylene or mixtures thereof); x ) -NH-; xi) -O ^{; Xii) -R 11 OC (O} ) R 11 - (R 11 is methylene, ethylene, propylene, butylene or mixtures ^{thereof); xiii) -R 11 C (} O) OR 11 - (R 11 is methylene, Ethylene, propylene, butylene or mixtures thereof); xiv) or mixtures thereof.

The following are non-limiting examples of polymer composites according to the present invention. A preferred enzyme inhibiting unit is a derivative of N-hydroxymethylsaccharin. Without wishing to be bound by theory, the following is the mechanism proposed as the first step in the reaction of the polymer conjugate of the present invention with the target enzyme. In the example below, the L unit acts as a leaving group, which remains bound to the polymer component after the saccharin inhibitor component begins a series of reactions and irreversibly binds to the target enzyme.

[Chemical Formula 39]

For the purposes of this invention, PEG 5000 is used to represent a methoxy capped polyethylene glycol homopolymer having an average molecular weight of about 5000 daltons. A preferred polymer conjugate having the IUPAC name N- (PEG5000) -terephthalamic acid 1,1,3-trioxo-1,3-dihydro-1λ ⁶ -benzo [d] isothiazol-2-ylmethyl ester is about 5000 To the polyethylene glycol polymer component having an average molecular weight of Daltons, the (xi) linking unit -NR ¹⁰ C (X) R ¹¹ C (X) O- (R ¹⁰ is hydrogen; R ¹¹ is unsubstituted phenylene; each X is oxygen) and consists of N-methylenesaccharin enzyme inhibiting components linked by the above, and the above polymer conjugate has the formula:

[Chemical 40]

Another preferred polymer conjugate, exemplifying a preferred R unit, comprising similar linking units and polymer components has the formula:

[Chemical 41]

IUPAC name PEG5000-carbamic acid 4- [5- (1,1,3-trioxo-1,3-dihydro-1λ ⁶ -benzo [d] isothiazol-2-ylmethylsulfanyl) tetrazol-1-yl Another preferred polymer conjugate having a phenyl ester comprises a phenyl moiety and a tetrazole moiety as R ¹¹ units, the above polymer conjugate having the formula:

[Chemical 42]

IUPAC name N- (PEG5000 propanoyl) tranexamic acid 1,1,3
-Trioxo-1,3-dihydro-1λ ⁶ -benzo [d] isothiazole-2-
Another preferred polymer conjugate with ylmethyl ester comprises a combination of cyclohexylene and methylene moieties as R ¹¹ units, said polymer conjugate having the formula:

[Chemical 43]

The following is another example of a polymer conjugate according to the present invention comprising phenylene R ¹¹ units:

[Chemical 44] The following is an example of a polymer conjugate according to the present invention comprising an amino acid R ¹¹ unit:

[Chemical formula 45] The following is another preferred polymer conjugate according to the present invention:

[Chemical formula 46]

The following is a non-limiting method of making a polymer composite according to the present invention. Example 1 N-(PEG5000) - terephthalamide acid 1,1,3-trioxo-1,3 - dihydro llambda ⁶ - benzo [d] isothiazol-2-yl methyl ester of preparation PEG5000 amine (0.5 g, 0 0.1 mmol) is mixed with terephthalic acid (0.083 g, 0.5 mmol) and hydrated hydroxybenzotriazole (0.069 g, 0.5 mmol) in DMF (6 ml). Dicyclohexylcarbodiimide (0.103 g, 0.5 mmol) is added to the stirred mixture and the reaction is stirred for 18 hours.
The solid obtained is filtered off and the filtrate is diluted with ether. The obtained precipitate is filtered to obtain mono-PEG amide terephthalate. The above mono-PEG 5000 hemiamide (0.27 g, 0.05 mmol) was added to N-bromomethyl saccharin (0.14 g, 0.5 mm) in acetonitrile (10 ml).
ol). Triethylamine (0.11 g, 1 mmol) was added, and the reaction solution was added to 2
Gently heat to 40 ° C. over time, then stir at room temperature for 18 hours. The reaction solution is diluted with ether, and the obtained solid substance is collected by filtration. Recrystallization from ethanol gives the desired terephthalate amide-ester, which is used without further formation.

[0038] Example 2 5000- 4 carbamic acid [5- (1,1,3-trioxo-1,3 Jihido Russia llambda ⁶ - benzo [d] isothiazol-2-yl methylsulfanyl) Tet Razoru -1 Preparation of 1- (4-hydroxyphenyl) -1H-tetrazole-5-thiol (0.- yl] phenyl ester
15 g, 0.8 mmol), N-bromomethylsaccharin (0.2 g, 0.72 mmol)
) And acetonitrile (6 ml) were mixed and triethylamine (0.82 g,
0.8 mmol) and the reaction is stirred for 18 hours. The solvent is removed under reduced pressure, the residue is partitioned between ethyl acetate and water and the organic phase is concentrated to give the saccharin tetrazole condensation product. The product obtained from the previous step (0.34 g, 0.85 mmol), triethylamine (0.09 g, 0.85 mmol) is mixed in methylene chloride (6 ml).
Monomethoxy PEG 5000 isocyanate (1.0 g, 0.2 mmol) is dissolved in methylene chloride and added dropwise to the reaction solution. The reaction is stirred for 18 hours, then cold ether is added and the resulting precipitate is filtered off. Recrystallization from ethanol yields the desired saccharin polymer conjugate.

[0039] Example 3 N- (PEG5000 propanoyl) tranexamic acid 1,1,3-trioxo - 1,3-dihydro llambda ⁶ - benzo [d] isothiazol-2-Irumechiruesu ether To a solution of N- bromo-methyl saccharin (0 .28 g, 1 mmol), N-Boc-tranexamic acid (0.26 g, 1 mmol) and acetonitrile (6 ml) were mixed in a reactor, DMF (1 ml) and triethylamine (0.15 ml) were added, and the reaction solution was added to 18 Stir for hours. The solvent is removed under reduced pressure, the residue is partitioned between ethyl acetate and water and the organic phase is concentrated to give the saccharin tranexamic acid condensation product. The condensate from the previous step was treated with a 25% solution of trifluoroacetic acid in methylene chloride (
5 ml) and stir for 2 hours. The solvent was removed under reduced pressure and the resulting oil was converted to H
Decomposition in Cl / ether solution gives the deprotected condensation product. Deprotected condensation product as HCl salt (0.035 g, 0.1 mmol), PEG50
00 propionic acid (1 g, 0.2 mmol) and DMF (5 ml) are mixed with triethylamine (0.015 ml, 0.011 g, 0.11 mmol) in a reactor. Dicyclohexylcarbodiimide (0.021 g, 0.1 mmol) is added. The reaction is stirred for 18 hours, then cold ether is added and the resulting precipitate is filtered off. Recrystallization from ethanol yields the desired saccharin polymer conjugate.

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

Typically, the polymer conjugates of the present invention will provide a vehicle for the uniform delivery of enzyme inhibitors to the skin surface, as well as in a skin compatible carrier that helps dissolve the conjugates. Is prescribed to. Those skilled in the art of products using the enzyme-inhibiting complexes of the present invention will take into account any form of vehicle, especially vehicles that are aqueous, non-aqueous, dry powders.

The amount of polymer conjugate present in the formulation depends on the embodiment selected by the person skilled in the art. In some cases, the polymeric component of the composite itself may have the property of being capable of direct application of the composite without the need for a vehicle. However, when formulated as part of a composition, the complex comprises about 0.01% of the delivery vehicle,
It is preferably about 1% to about 20%, preferably about 10% by weight. The following are non-limiting examples of assays 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 inhibitor compounds, the compounds of the invention are tested in a standard enzyme assay for protease activity as follows: Free from urine contamination. Collect the infant's feces, mix with water, weight / weight (w / w
) Obtaining a mixture (eg 1: 4 w / w). This mixture is then well mixed by homogenization or sonication to obtain a homogeneous suspension. The stool is then diluted with a reaction buffer as described below to obtain a stool concentration that, when added to the protease substrate, allows the substrate to hydrolyze for 5-60 minutes. Using such a method, for example, fecal trypsin activity was measured in 20 mM CaCl ₂ containing 0.3 mM of the composition being tested.
In 50 nM Tris-HCl buffer at pH 8.2; fecal chymotrypsin activity
PH 7.6 in 50 mM Tris HCl buffer with 20 mM CaCl ₂ containing 0.05 mM of the composition being tested; and fecal leucine aminopeptidase activity at pH 7.2 in 50 mM sodium phosphate containing the composition being tested. Be examined. To test the efficacy of the composition, several different concentrations of each putative inhibitory composition are added to the same fecal-containing reaction buffer and inhibition of enzyme activity is measured.
Compounds with an IC ₅₀ of 100 μM or less are preferred compounds of the invention.
Further preferred are compounds having an IC ₅₀ to IC _{90 of} 100 μM or less, most preferably IC ₈₀ to IC ₉₀ .

In Vitro Skin Test for Inhibition of IL-1α Production An in vitro method to determine the efficacy of the compounds of the invention in preventing the proinflammatory response of the skin to feces and fecal enzymes is performed as follows: Human keratinocytes are obtained from epidermal tissue and cultured in serum-free medium in a plastic incubator containing a nylon mesh surface until they become confluent. The mesh surface is then lifted to the liquid-air interface in order to promote the formation and differentiation of multi-layered layers similar to those found in vivo, such as a clear stratum corneum barrier. Any cell culture system that promotes keratinocyte proliferation and differentiation as described can be used. A commercially available cell culture system suitable for use is Epiderm ^R (MatTek Corporation).

Feces of infants were collected so that urine was not mixed and phosphate buffer (PBS) (pH 7.
Dilute with 2-7.4). This mixture is then well mixed by homogenization or sonication to obtain a homogeneous suspension. To assay for IL-1α production by fecal enzyme activity, a portion of the homogenate is diluted with PBS and added to the surface of control cultures in an incubator. To assay for inhibition of IL-1α production by protease activity, a predetermined amount of putative inhibitor (compound) is added to another identical dilution of homogenate before it is added to the surface of the test culture. The culture is incubated under a controlled atmosphere. At selected times, control and inhibitor-treated test cultures and substratum are harvested. The medium is assayed for the presence of IL-1α by known methods. For example, a suitable assay for IL-l [alpha] is an enzyme-linked immunosorbent Abuzo over vent method commercially available as Quantikine ^R from R & D Systems.

The percent reduction in IL-1α production due to the presence of the compound (inhibitor) is calculated as follows:% reduction = [(IL-1α from control cultures) − (IL from test cultures
-1α) / (IL-1α from control cultures)] × 100

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

[0048] Auxiliary bioactive component artisan, either adjust the properties of the composition, or act as auxiliaries, especially in the case of skin treatments enhance enzyme inhibition, the present invention one or more "auxiliary bioactive ingredient" Can be added to the composition. When present, the ancillary bioactive ingredient is present in about 0.
01%, preferably about 0.05%, more preferably about 0.1% to about 5%, preferably about 2%, more preferably about 1% by weight. A non-limiting example of a bioactive co-ingredient is hexamidine, i.e. 4,4 '-[1,6-hexanediylbis (oxy)] bisbenzenecarboximidamide. Hexamidine is preferred as an adjunct to the polymer composites of the present invention. Without being limited to theory or use, hexamidine is particularly suitable for topical preservatives: Bordeaux Med., MJFe.
nelon, 3,867 (1970); Antibacterial agent: J.Int.Med.Res., G.Micheal et al., 14,205 (1986)
As, it has many properties. Hexamidine is preferably Rhone-Poulen
c As a diisethionate, such as the commercially available Elestab HP 100 ^R , especially RF2535
, Desomedine, Esomedine, Hexomedine, Ophtamedine.

Formulation For topical administration to the epidermis, the complex of the invention may be formulated as an ointment, cream, lotion, etc., which can be applied or delivered directly from the product, especially diapers, facial tissues. Ointments and creams are, for example, formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions are 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 coloring agents.

[0050] Typically, the polymer conjugates of the invention are in a skin compatible carrier that helps to dissolve the conjugate in addition to providing a vehicle for uniform delivery of the enzyme inhibitor to the skin surface. Is prescribed to. Those skilled in the art of products using the enzyme-inhibiting complexes of the present invention will take into account any form of vehicle, especially vehicles that are aqueous, non-aqueous, dry powders.

The amount of polymer conjugate present in the formulation depends on the embodiment selected by the person skilled in the art. In some cases, the polymeric component of the composite itself may have the property of being capable of direct application of the composite without the need for a vehicle. However, when formulated as part of a composition comprising only the polymer conjugate and the delivery vehicle, the conjugate will typically be about 0.01% of the delivery vehicle, preferably about 1% to about 20%. %, Preferably about 10% by weight.

The composition of the present invention preferably comprises one or more auxiliary ingredients including a carrier. For the purposes of the present invention, the term "carrier" is used interchangeably with the terms "emollient", "lotion base" and the like. Those of skill in the art will appreciate that certain carriers may be emollient or may perform more than one function.
The composition of the present invention comprises about 1%, preferably about 5%, more preferably about 10% to about 9%.
It comprises 9%, preferably about 95%, more preferably about 80%, most preferably 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 its derivatives, humectants, fatty acid ester types, alkyl ethoxylate types, fatty acid ester ethoxylates, fatty alcohol types, polysiloxane types, propylene. Glycol and its derivatives, glycerin and its derivatives, such as glycerides, acetoglycerides and ethoxylated glycerides of C ₁₂ -C ₂₂ fatty acids, triethylene glycol and its derivatives, spermaceti or other waxes, fatty acids, fatty alcohol ethers, propoxylated There are fatty alcohols, other fatty esters of polyhydroxy alcohols, lanolin, kaolin, and federal standard commercial skin care. Suitable petroleum-based emollients, C ₁₆ -C ₃₂ hydrocarbons, including paraffins, mineral oil and petrolatum there is ( "mineral wax", also known as "petroleum jelly" and "mineral jelly").

The balance of the composition of the present invention typically comprises, in addition to the carrier, other adjunct ingredients. Non-limiting examples of other preferred adjunct ingredients include water, viscosity modifiers, fragrances, antiseptic antibacterial actives, antivirals, vitamins, pharmaceutically active agents, film formers, deodorants, opacifiers, astringents, solvents, There are preservatives, viscosity modifiers and mixtures thereof. In addition, stabilizers such as cellulose derivatives, proteins and lecithin may be added to increase the shelf life of the composition.

Water-based skin care carriers and compositions may optionally include preservatives, non-limiting examples of which are propylparaben, methylparaben, butylparaben, benzyl alcohol, benzalkonium chloride, tribasic calcium phosphate, BHT.
, Or acids such as citric acid, tartaric acid, maleic acid, lactic acid, malic acid, benzoic acid, salicylic acid and mixtures thereof.

A preferred use of the polymer conjugates of the present invention, such as in connection with diaper rash, is
It relates to the treatment or prevention of skin irritation due to exposure to human feces, and other products used to incorporate human waste. The polymer conjugates of the invention, whether endogenous or exogenous, inhibit proteolytic and / or lipolytic enzymes. Therefore, a person skilled in the art can use the complex of the present invention in any manner with the purpose of controlling or preventing the exposure action to the above-mentioned enzyme. However, the practitioner has a variety of other uses, including, by way of non-limiting example, applying the composition to a swab to the site (ie, nasal canal, throat) where enzyme activity is to be inhibited or modulated. The composition is applied or applied to a facial tissue or wipe and applied to the skin surface or holes, especially the nasal passages, the eye area.

The following are non-limiting examples of compositions according to the invention: Compositions for inhibiting enzymes in human skin are: a) about 0.01%, preferably about 0.5%, more preferably About 1%, most preferably about 1.5% to about 10%, preferably about 7.5%, more preferably about 5% by weight of one or more polymer conjugates having the formula: T- (L ) _Z- [poly] In the above formula, T is a saccharin ring-containing enzyme inhibitor component; L is a linking unit; [poly] is a polymer component; z is 0 or 1; and b) the remaining carrier. And an auxiliary ingredient.

A composition for human skin application; said composition for inhibiting proteolytic and / or lipolytic enzymes in human skin is: a) about 0.01%, preferably about 0.5%, more preferably about 1 %, Most preferably about 1.5% to about 10%, preferably about 7.5%, more preferably about 5% by weight of one or more polymer conjugates having the formula: T- (L) _z -[Poly] In the above formula, T is a saccharin ring-containing enzyme inhibitor component; L is a linking unit; [poly] is a polymer component; z is 0 or 1; b) about 0.01%; Preferably about 0.05%, more preferably about 0.1% to about 5%, preferably about 2%, more preferably about 1% by weight auxiliary bioactive ingredient, preferably hexamidine; and c) the balance of the carrier. And an auxiliary ingredient.

A composition for human skin application; said composition for inhibiting proteolytic and / or lipolytic enzymes in human skin is: a) about 0.01%, preferably about 0.5%, more preferably about 1 %, Most preferably about 1.5% to about 10%, preferably about 7.5%, more preferably about 5% by weight of one or more polymer conjugates having the formula: T- (L) _z -[Poly] In the above formula, T is a saccharin ring-containing enzyme inhibitor component; L is a linking unit; [poly] is a polymer component; z is 0 or 1; b) about 0.01%; Preferably about 0.05%, more preferably about 0.1% to about 5%, preferably about 2%, more preferably about 1% by weight hexamidine; c) about 0.01% by weight or more carrier alcohol, preferably _C 10 _{-C 20} linear the A branched, saturated or unsaturated alkyl alcohol; d) about 0.01% by weight or more, preferably a secondary benefit agent selected from the group consisting of vitamins, tanning agents, depilatories, desiccants, astringents and mixtures thereof. E) about 0.01% by weight or more of an esthetic agent; the esthetic agent being selected from the group consisting of fragrances, fragrances, dyes, colorants and mixtures thereof; and f) the balance carrier and emollients. The auxiliary ingredients are petroleum-based emollients,
Sucrose ester fatty acid, polyethylene glycol and its derivatives, moisturizer, fatty acid ester, alkyl ethoxylate, fatty acid ester ethoxylate,
Fatty alcohols, polysiloxanes, propylene glycol and its derivatives, glycerin, glycerides, acetoglycerides and ethoxylated glycerides of C ₁₂ -C ₂₂ fatty acids, triethylene glycol and its derivatives, waxes, fatty acids,
Selected from the group consisting of fatty alcohol ethers, propoxylated fatty alcohols, fatty esters of polyhydroxy alcohols, lanolin, kaolin and mixtures thereof.

Compositions for inhibiting enzymes in human skin include: a) about 0.01%, preferably about 0.5%, more preferably about 1%, most preferably about 1.5% to about 10. %, Preferably about 7.5%, more preferably about 5% by weight of one or more polymer conjugates having the formula: T- (L) _z- [poly] wherein T is a saccharin ring containing enzyme. Is an inhibitor component; L is a linking unit; [poly] is a polymeric component; z is 0 or 1; b) comprises the remainder of the delivery vehicle.

The following is an example of a composition comprising a polymer composite according to the present invention suitable for use in absorbent articles. Example 4 Ingredient% petrolatum ¹ 52.2 Stearyl alcohol ² 36.9 Aloe ³ 0.9 polymer composite ⁴ 10.0 1. White Protopet ^R commercially available from Witco 2. Procter & Gamble Commercial CO1897 3. Veragel Lipid in Madis Botanicals commercial Kaydol 4. Enzyme inhibitor according to Example 1

The compositions of the present invention may be delivered to the skin via compositions that exert other primary effects. The following discloses compositions that may incorporate the enzyme-inhibiting polymer conjugates of the present invention, each incorporated herein by reference. Skin Cleanser , Linares et al., US 5,641,479, issued June 24, 1997;
Wivell et al., US 5,599,549; 199, issued February 4, 1997.
Ha et al., US 5,585,104, issued December 17, 2006; July 1996.
Kefauver et al. US 5,540,852 issued March 30; Dunbar et al US 5,510,050 facial acne preparation issued April 23, 1996 Guang Lin issued March 18, 1997 US 5,612,324
Warren et al., US 5,587,176, published December 24, 1996;
Venkateswaran US Pat. No. 5,549,888 issued August 27, 1996.
Corless et al., US 5,470,884, published November 28, 1995, shower gel Gordon et al., US 5,650,384, issued July 22, 1997; 1
Moore et al US 5,607,678 cosmetics issued March 4, 997 Date et al US 5,641,493; 19 issued June 24, 1997;
Blank et al., US 5,605,894; 1996, issued February 25, 1997.
Yoshioka et al., US 5,585,090 Hand, Face and Body Lotion , issued December 17, 2010, Cheney et al., US 4,939,179, 19 issued July 3, 1990;
McAtee et al. US 5,607,980 cosmetics and cleansing wipes issued March 4, 1997 Richter et al. US 4,045,364 issued August 30, 1977;
European patent application EP 0,61 of Touchet et al., Published October 12, 1994.
Brown-Skrobot et al., US Patent 4,975,217, issued December 4, 1990; Puchalski et al., US, August 27, 1991.
5,043,155; US of Blieszner et al., Issued July 15, 1997.
5,648,083

Methods of Use The present invention also relates to methods for the treatment and prevention of diaper rash and diaper dermatitis resulting from prolonged contact of human skin with body exudates. The present invention acts as a preventive measure to improve the skin irritation and prevent its occurrence by providing a barrier to unwanted protease or lipase enzymes. The method of the present invention comprises: a) an effective amount, preferably about 0.1% by weight or more, more preferably about 1% or more;
A polymer conjugate according to the invention; and b) contacting human skin with a composition comprising the balance carrier and auxiliary ingredients, said composition optionally, but preferably, a substrate, especially a diaper topsheet, Applied to sanitary napkins. The method of the present invention is carried out at a pH compatible with the skin of the user. Preferably, the method of the invention contacts human skin with a component that has an additional effect on the user, in particular conditioning on exposed skin. Generally, the method of the present invention is a minimum inhibitory concentration of a selected enzyme inhibitor,
Deliver an "effective amount" of the composition to the skin. However, depending on the formulation and means for carrying out the method of the invention, any amount may be delivered by the trader.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 7/00 A61K 7/00 K 31/795 47/04 31/795 47/10 47/04 47/12 47/10 47/14 47/12 47/24 47/14 47/34 47/24 47/44 47/34 A61P 17/00 47/44 17/16 A61P 17/00 43/00 111 17/16 C08G 85 / 00 43/00 111 A61F 13/18 B C08G 85/00 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU , MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K) E, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Todd, Lawrence, Andalinar Cincinnati, Ohio, USA , Cyler, Drive, 6262 (72) Inventor Timothy, Bates Cincinnati, Ohio, USA, Forrester, Drive, 1589 F-term (reference) 4C003 HA00 4C076 AA06 AA11 AA16 AA71 BB31 CC18 DD28A DD34A DD37A DD38A DD39A DD44A AC1112 AC111 AC072 AC111 AC072 AC211 AC4211 AC072 AC4211 AC072 AC4411 AC072 AC4411 AC072 AC4412 AC4411 AD112 AD511 BB60 DD12 DD23 DD31 EE12 4C086 AA01 AA03 FA04 MA01 MA04 MA63 NA14 ZA89 ZC20 4J031 AA02 AA53 AF03 BA22 BB01 BB02 BD03

Claims (18)

[Claims] 1. A polymer complex having the following formula: T- (L) _z- [poly] In the above formula, T is a saccharin ring-containing enzyme inhibitor component; L is a linking unit; [poly] is a polymer component. Wherein z is 0 or 1; the polymer conjugate as described above. 2.   The following formula: [Chemical 1] Or the following formula: [Chemical 2] Has the saccharin inhibitor component of: In the above formula, the R unit is:   a) hydrogen;   b) C₁-C₁₈Substituted or unsubstituted, straight chain or branched alkyl;   c) C_Three-C₁₈Substituted or unsubstituted, linear or branched cycloalkyl;   d) C_Two-C₁₈Substituted or unsubstituted, straight chain or branched alkenyl;   e) C_Two-C₁₈Substituted or unsubstituted, linear or branched alkynyl;   f) C₆-C₁₈Substituted or unsubstituted aryl;   g) C_Two-C₁₈A substituted or unsubstituted heterocyclic alkyl;   h) C_Three-C₁₈A substituted or unsubstituted heterocyclic alkenyl;   i) an alkylene aryl having the formula:                             ‐ (R¹)_n-R^Two R in the above formula¹Is C₁-C₁₂Linear or branched alkylene, C_Two-C₁₂Straight chain
Is a branched alkenylene or mixture thereof; R^TwoIs C₆-C₁₈Replacement
Is unsubstituted aryl or a mixture thereof; n is 1-16;   j) Amino units having the formula:                             ‐ (CH_Two)_mN (R^Three)_Two Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; m is 0-10;   k) Quaternary ammonium units having the formula:                             ‐ (CH_Two)_mN⁺(R^Three)_ThreeY⁻ Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; Y is an anion of sufficient charge to provide electrical neutrality; m
Is 0-10;   l) A unit having the formula: [Chemical 3] R in the above formula^FourIs hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁵Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R^FourAnd R⁵Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;   m) A unit having the formula: [Chemical 4] R in the above formula⁶Is hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁷Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁶And R⁷Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;   n) A unit having the formula:                             -R⁸-R⁹ R in the above formula⁸Is the following:     i)-(CH_Two)_p-(P is 0-12);     ii) -C (O)-;     iii) -C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or it
X is oxygen, sulfur, NR.¹⁰And their mixtures)
;     iv) -C (X) R¹¹C (X)-(R¹¹Is C₁-C₁₂Alkylene, substituted
Or unsubstituted phenylene or mixtures thereof; X is oxygen, sulfur, N
R¹⁰And mixtures thereof);     v) -C (X) NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixtures
);     vi) -C (X) NR¹⁰R¹¹NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-
C_FourAlkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene,
A substituted or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur
, NR¹⁰And mixtures thereof);     vii) -NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl or it
X is oxygen, sulfur, NR.¹⁰And their mixtures)
;     viii) -NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixture
It is a thing);     ix) -NR¹⁰C (X) R¹¹NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     x) -NR¹⁰R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     xi) -NR¹⁰C (X) R¹¹C (X) O- (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xii) -OC (X) R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xiii) -NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xiv) -R¹¹NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     xv) -R¹¹NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C _Four Alkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene
A substituted or unsubstituted phenylene or mixture thereof; X is oxygen, sulfur,
NR¹⁰And mixtures thereof);     xvi) -NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or mixtures thereof
It is a thing);     xvii) -O-;     xviii)-(R¹¹)_tC (X) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1 is; X is oxygen, sulfur, NR¹⁰And mixtures thereof);     xix)-(R¹¹)_tOC (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xx)-(R¹¹)_tC (O) O (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xxi) an alkyleneoxyalkylene having the formula:                             ‐ (R¹²O)_qR^Thirteen- R in the above formula¹²Is C_Two-C₆Linear or branched alkylene, substituted or unsubstituted phenol
Nylene; R^ThirteenIs- (CH_Two)_p-, Where p is 0-12;
q is 1 to 4;     xxii) -S-;     xxiii)-(R¹¹)_tS (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Alkylene
, Substituted or unsubstituted phenylene or mixtures thereof; t is 0 or 1
);     xxiv)-(R¹¹)_tS (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xxv)-(R¹¹)_tSO_Two(R¹¹)_t‐ (R¹¹Is C₁-C₁₂Arche
Phenyl, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
1);     xxvi) or mixtures thereof; R⁹Is the following:     i) hydrogen;     ii) C₁-C₁₈Substituted or unsubstituted, straight chain or branched alkyl;     iii) C_Three-C₁₈Substituted or unsubstituted, linear or branched cycloalkyl;     iv) C_Two-C₁₈Substituted or unsubstituted, straight chain or branched alkenyl;     v) C_Two-C₁₈Substituted or unsubstituted, linear or branched alkynyl;     vi) C₆-C₁₈Substituted or unsubstituted aryl;     vii) C_Two-C₁₈A substituted or unsubstituted heterocyclic alkyl;     viii) C_Three-C₁₈A substituted or unsubstituted heterocyclic alkenyl;     ix) -OH;     x) -SO_ThreeM;     xi) -OSO_ThreeM;     xii) -NO_Two;     xiii) a ha selected from fluorine, chlorine, bromine, iodine or mixtures thereof.
Rogen;     xiv) -C (Hal)_Three(Each Hal is fluorine, chlorine, bromine, iodine or its
A mixture of these);     xv) -COR¹⁴(R¹⁴Is hydrogen, -OH, C₁-C₁₂Alkyl, C₁-
C₁₂Alkoxy or a mixture thereof); -N (R¹⁵)_TwoOr it
A mixture of these (each R¹⁵Independently hydrogen, -OH, C₁-C_FourAlkyl or it
A mixture of these);     xvi) -CH (OR¹⁴)_Two(R¹⁴Is hydrogen, C₁-C₁₂Is it alkyl
, Or two R¹⁴Units linked together form a ring having 3 to 5 carbon atoms
Can be formed or a mixture thereof);     xvii) A unit having the formula: [Chemical 5] R in the above formula^FourIs hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁵Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R^FourAnd R⁵Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;     xviii) A unit having the formula: [Chemical 6] R in the above formula⁶Is hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁷Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁶And R⁷Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;     xix) -NHOR¹⁶(R¹⁶Is hydrogen, C₁-C₁₂Straight or branched alkyl
, Formula-COR¹⁷Having an acyl (R¹⁷Is C₁-C_FourIs alkyl) or
A mixture thereof);     xx) Units with the following formula:                             -CH = NOR¹⁶ R in the above formula¹⁶Is hydrogen, C₁-C₁₂Linear or branched alkyl, C₇-C₂₂straight
Chain or branched alkylene aryl, formula-COR¹⁷Having an acyl (R¹⁷Is C ₁ -C_FourAlkyl) or mixtures thereof;     xxi) an amino unit having the formula:                             ‐ (CH_Two)_mN (R^Three)_Two Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; m is 0-10;     xxii) Quaternary ammonium units having the formula:                             ‐ (CH_Two)_mN⁺(R^Three)_ThreeY⁻ Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; Y is an anion of sufficient charge to provide electrical neutrality; m
Is 0-10;   o) two R units on the same carbon atom are linked together to form a carbonyl unit or
May form a carbonyl unit equivalent; and   p) a mixture thereof; L is a linking group; R'targets R or the saccharin enzyme inhibitor component
Is a unit that acts to irreversibly bind to an enzyme; [poly] is a polymer unit
I is the number of the saccharin units forming the complex, and a value of 1 to 100
The compound of claim 1, wherein z is 0 or 1. 3. R is: a) hydrogen; b) C ₁ -C ₈ straight chain unsubstituted alkyl; c) C ₆ -C ₁₀ unsubstituted cycloalkyl; d) C ₁₀ and C ₁₅ branched alkenyl units; e) Phenyl, naphthyl, 4-methoxyphenyl, 4-nitrophenyl, 4-
An aryl unit selected from the group consisting of (C ₁ -C ₄ alkyl) phenyl and mixtures thereof; f) a C ₄ -C ₆ substituted or unsubstituted heterocyclic alkyl; g) a C ₃ -C ₁₈ substituted or unsubstituted Heterocyclic alkenyl; h) an alkylenearyl having the formula: —CH ₂ —R ^{2 where} R ² is selected from the group consisting of phenyl, substituted phenyl, pyridinyl, substituted pyridinyl and mixtures thereof; i) An amino unit having the formula: —N (R ³ ) ₂ wherein each R ³ is independently hydrogen, methyl, ethyl, 2-hydroxyethyl, cyclopropyl or mixtures thereof; j) a unit having the formula: : [Chemical 7] Wherein R ⁴ and R ⁵ are each hydrogen and R ⁴ and R ⁵ are bonded together,
Forming a heterocyclic ring having 3 to 5 carbon atoms; k) a unit having the formula: units having the l) the following formula: ^-R 8 -R ⁹ In the formula ^{R 8} are as _{follows: i) - (CH 2)} p - (p is 0~12); ii) -C (O ) -; Iii) -NR ^10- (R ¹⁰ is hydrogen, C ₁ -C ₄ alkyl or mixtures thereof); iv) -O-; v) Alkyleneoxyalkylene having the formula:-(R ¹² O) _q R ¹³ - above wherein ^{R 12} is a _C 2 -C ₆ linear or branched alkylene, substituted or unsubstituted ^{phenylene; R 13} is - _{(CH 2) p} - a, where p is at 0-12 is there;
q is 1-4; vi) -S-; vii) or mixtures thereof; R ⁹ is: i) an alkyl unit selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; ii) cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 2,5
-A cycloalkyl unit selected from dimethylcyclopentyl; iii) selected from phenyl, 4-methoxyphenyl, 4-nitrophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-aminobenzyl, 4-guanidinobenzyl Vi) a heterocyclic unit selected from N-aziridinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl; v) -OH (index p is 1 to 4) Vi) -SO ₃ M (when index p is 1 to 4); vii) -OSO ₃ M (when index p is 2 to 4); viii) -NO ₂ ; ix) chlorine , bromine or mixtures ^{_{thereof; x) -CF 3; xi)}} -COR 14 (R 14 is _-OH, -NH 2, -N ( H _{3) 2} or mixtures ^{thereof); xii) -NHOR 16 (R} 16 is _hydrogen, C 1 _{-C 12} straight or branched alkyl, acyl ^{(R 17} having the formula -COR ¹⁷ is _C 1 -C ₄ alkyl as) or mixtures thereof); xiii) units having the formula: -CH = NOR ¹⁶ above wherein R ¹⁶ is hydrogen or methyl; a and m) mixtures thereof, to claim 2 The described compound. 4. R is: a) hydrogen; b) methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n.
An alkyl unit selected from the group consisting of: -pentyl, isopentyl, n-hexyl, 2-methylhexyl, 2-ethylhexyl and mixtures thereof; c) consisting of cyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl and mixtures thereof A cycloalkyl selected from the group; d) 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazinyl, N-piperidinyl, 2-piperidinyl, 3-piperidinyl, A heterocyclic alkyl selected from the group consisting of 4-piperidinyl, N-morpholinyl and mixtures thereof; e) selected from the group consisting of methylamino, dimethylamino, ethylamino, diethylamino, dicyclopropyl and mixtures thereof. amino Position; f) amidine, 2-pyridinyl, pyrimidinyl, imidazolyl and heterocycle is selected from the group consisting of a mixture thereof; units having g) formula: ^-R 8 -R ⁹ above wherein ^{R 8} is -O- And R ⁹ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and mixtures thereof; and h) a compound thereof. 5. L has the formula:-(R ¹¹ ) _h [(X) _j [C (X)] _k (X) _j (R ¹¹ ) _h (X) _j [C (X )] _K (X) _j ] _f (R ¹¹ ) _h ‐
In the above formula, R ¹¹ is C ₁ -C ₁₂ substituted or unsubstituted alkylene, C ₂ -C ₁₂ substituted or unsubstituted alkenylene, substituted or unsubstituted C ₃ -C ₁₂ cycloalkylene,
Is a substituted or unsubstituted aromatic, substituted or unsubstituted heterocyclic; X is oxygen, sulfur, NR ¹⁰ , wherein R ¹⁰ is hydrogen, C ₁ -C ₄ alkyl, phenyl, or R ¹⁰ May be present as part of a ring joined to another moiety by a linking group; indices h, j and k are each independently 0 or 1 and index f is 0-10. 4. The compound according to any one of 4 above. 6.   The connection unit L is:   i)-(CH_Two)_p-(P is 0-12);   ii) -C (O)-;   iii) -C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or them
X is oxygen, sulfur, NR¹⁰And mixtures thereof);   iv) -C (X) R¹¹C (X)-(R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);   v) -C (X) NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl again
Is a mixture thereof; X is oxygen, sulfur, NR¹⁰And in their mixtures
is there);   vi) -C (X) NR¹⁰R¹¹NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C _Four Alkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene
A substituted or unsubstituted phenylene or mixture thereof; X is oxygen, sulfur,
NR¹⁰And mixtures thereof);   vii) -NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl or them
X is oxygen, sulfur, NR¹⁰And mixtures thereof);   viii) -NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixtures
);   ix) -NR¹⁰C (X) R¹¹NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourArchi
R or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR¹⁰ And mixtures thereof);   x) -NR¹⁰R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourArchi
R or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR¹⁰ And mixtures thereof);   xi) -NR¹⁰C (X) R¹¹C (X) O- (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);   xii) -OC (X) R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);   xiii) -NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);   xiv) -R¹¹NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourArchi
R or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR¹⁰ And mixtures thereof);   xv) -R¹¹NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C_Four Alkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, substituted
Or unsubstituted phenylene or mixtures thereof; X is oxygen, sulfur, N
R¹⁰And mixtures thereof);   xvi) -NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or mixtures thereof
);   xvii) -O-;   xviii)-(R¹¹)_tC (X) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Archi
Len, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Is 1; X is oxygen, sulfur, NR¹⁰And mixtures thereof);   xix)-(R¹¹)_tOC (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Archi
Len, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Is 1);   xx)-(R¹¹)_tC (O) O (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Archi
Len, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Is 1);   xxi)-(R¹¹)_tOC (O) O (R¹¹)_t-(T is 0 or 1)
;   xxii) an alkyleneoxyalkylene having the formula:                             ‐ (R¹²O)_qR^Thirteen- R in the above formula¹²Is C_Two-C₆Linear or branched alkylene, substituted or unsubstituted phenol
Nylene; R^ThirteenIs- (CH_Two)_p-, Where p is 0-12;
q is 1 or 2;   xxiii) -S-;   xxiv)-(R¹¹)_tS (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Alkylene,
Substituted or unsubstituted phenylene or mixtures thereof; t is 0 or 1
is there);   xxv)-(R¹¹)_tS (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Arche
Phenyl, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
1);   xxvi)-(R¹¹)_tSO_Two(R¹¹)_t‐ (R¹¹Is C₁-C₁₂Arche
Phenyl, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
1);   xxvii) or mixtures thereof The compound according to any one of claims 2 to 5, selected from the group consisting of: 7. The [poly] unit has a molecular weight of 1000 to 8000 daltons.
7. The compound according to any one of items 6 to 6. 8. Having the formula: embedded image The compound according to claim 2, wherein x is 50 to 250 in the above formula. 9. Having the formula: embedded image The compound of claim 2 wherein x has a value such that the [poly] unit has a molecular weight of 5000 Daltons. 10. The compound has the formula: embedded image The compound according to claim 2, wherein x is 50 to 250 in the above formula. 11. Has the formula: embedded image The compound according to claim 2, wherein x is 50 to 250 in the above formula. 12. Having the formula: embedded image The compound according to claim 2, wherein x is 50 to 250 in the above formula. 13. Having the formula: embedded image The compound according to claim 2, wherein x is 50 to 250 in the above formula. 14. A) 0.01% by weight or more of one or more polymer conjugates having the formula: T- (L) _z- [poly] wherein T is a saccharin ring-containing enzyme inhibitor component. L is a linking unit; [poly] is a polymeric component; z is 0 or 1; and b) a composition for inhibiting an enzyme, comprising the balance carrier and auxiliary components. 15.   The following formula: [Chemical 15] Or the following formula: [Chemical 16] Has the saccharin inhibitor component of: In the above formula, the R unit is:   a) hydrogen;   b) C₁-C₁₈Substituted or unsubstituted, straight chain or branched alkyl;   c) C_Three-C₁₈Substituted or unsubstituted, linear or branched cycloalkyl;   d) C_Two-C₁₈Substituted or unsubstituted, straight chain or branched alkenyl;   e) C_Two-C₁₈Substituted or unsubstituted, linear or branched alkynyl;   f) C₆-C₁₈Substituted or unsubstituted aryl;   g) C_Two-C₁₈A substituted or unsubstituted heterocyclic alkyl;   h) C_Three-C₁₈A substituted or unsubstituted heterocyclic alkenyl;   i) an alkylene aryl having the formula:                             ‐ (R¹)_n-R^Two R in the above formula¹Is C₁-C₁₂Linear or branched alkylene, C_Two-C₁₂Straight chain
Is a branched alkenylene or mixture thereof; R^TwoIs C₆-C₁₈Replacement
Is unsubstituted aryl or a mixture thereof; n is 1-16;   j) Amino units having the formula:                             ‐ (CH_Two)_mN (R^Three)_Two Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; m is 0-10;   k) Quaternary ammonium units having the formula:                             ‐ (CH_Two)_mN⁺(R^Three)_ThreeY⁻ Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; Y is an anion of sufficient charge to provide electrical neutrality; m
Is 0-10;   l) A unit having the formula: [Chemical 17] R in the above formula^FourIs hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁵Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R^FourAnd R⁵Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;   m) A unit having the formula: [Chemical 18] R in the above formula⁶Is hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁷Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁶And R⁷Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;   n) A unit having the formula:                             -R⁸-R⁹ R in the above formula⁸Is the following:     i)-(CH_Two)_p-(P is 0-12);     ii) -C (O)-;     iii) -C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or it
X is oxygen, sulfur, NR.¹⁰And their mixtures)
;     iv) -C (X) R¹¹C (X)-(R¹¹Is C₁-C₁₂Alkylene, substituted
Or unsubstituted phenylene or mixtures thereof; X is oxygen, sulfur, N
R¹⁰And mixtures thereof);     v) -C (X) NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixtures
);     vi) -C (X) NR¹⁰R¹¹NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-
C_FourAlkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene,
A substituted or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur
, NR¹⁰And mixtures thereof);     vii) -NR¹⁰C (X)-(R¹⁰Is hydrogen, C₁-C_FourAlkyl or it
X is oxygen, sulfur, NR.¹⁰And their mixtures)
;     viii) -NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl
Or a mixture thereof; X is oxygen, sulfur, NR¹⁰And their mixture
It is a thing);     ix) -NR¹⁰C (X) R¹¹NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     x) -NR¹⁰R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     xi) -NR¹⁰C (X) R¹¹C (X) O- (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xii) -OC (X) R¹¹C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xiii) -NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C_FourA
Rukiru or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene, also substitution
Or unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR ¹⁰ And mixtures thereof);     xiv) -R¹¹NR¹⁰C (X) NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAl
Kills or mixtures thereof; R¹¹Is C₁-C₁₂Alkylene, if substituted
Is unsubstituted phenylene or a mixture thereof; X is oxygen, sulfur, NR^{1 0} And mixtures thereof);     xv) -R¹¹NR¹⁰C (X) NR¹⁰R¹¹‐ (R¹⁰Is hydrogen, C₁-C _Four Alkyl or a mixture thereof; R¹¹Is C₁-C₁₂Alkylene
A substituted or unsubstituted phenylene or mixture thereof; X is oxygen, sulfur,
NR¹⁰And mixtures thereof);     xvi) -NR¹⁰‐ (R¹⁰Is hydrogen, C₁-C_FourAlkyl or mixtures thereof
It is a thing);     xvii) -O-;     xviii)-(R¹¹)_tC (X) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1 is; X is oxygen, sulfur, NR¹⁰And mixtures thereof);     xix)-(R¹¹)_tOC (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xx)-(R¹¹)_tC (O) O (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xxi) an alkyleneoxyalkylene having the formula:                             ‐ (R¹²O)_qR^Thirteen- R in the above formula¹²Is C_Two-C₆Linear or branched alkylene, substituted or unsubstituted phenol
Nylene; R^ThirteenIs- (CH_Two)_p-, Where p is 0-12;
q is 1 to 4;     xxii) -S-;     xxiii)-(R¹¹)_tS (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Alkylene
, Substituted or unsubstituted phenylene or mixtures thereof; t is 0 or 1
);     xxiv)-(R¹¹)_tS (O) (R¹¹)_t‐ (R¹¹Is C₁-C₁₂Al
Xylene, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
Or 1);     xxv)-(R¹¹)_tSO_Two(R¹¹)_t‐ (R¹¹Is C₁-C₁₂Arche
Phenyl, substituted or unsubstituted phenylene or mixtures thereof; t is 0 or
1);     xxvi) or mixtures thereof; R⁹Is the following:     i) hydrogen;     ii) C₁-C₁₈Substituted or unsubstituted, straight chain or branched alkyl;     iii) C_Three-C₁₈Substituted or unsubstituted, linear or branched cycloalkyl;     iv) C_Two-C₁₈Substituted or unsubstituted, straight chain or branched alkenyl;     v) C_Two-C₁₈Substituted or unsubstituted, linear or branched alkynyl;     vi) C₆-C₁₈Substituted or unsubstituted aryl;     vii) C_Two-C₁₈A substituted or unsubstituted heterocyclic alkyl;     viii) C_Three-C₁₈A substituted or unsubstituted heterocyclic alkenyl;     ix) -OH;     x) -SO_ThreeM;     xi) -OSO_ThreeM;     xii) -NO_Two;     xiii) a ha selected from fluorine, chlorine, bromine, iodine or mixtures thereof.
Rogen;     xiv) -C (Hal)_Three(Each Hal is fluorine, chlorine, bromine, iodine or its
A mixture of these);     xv) -COR¹⁴(R¹⁴Is hydrogen, -OH, C₁-C₁₂Alkyl, C₁-
C₁₂Alkoxy or a mixture thereof); -N (R¹⁵)_TwoOr it
A mixture of these (each R¹⁵Independently hydrogen, -OH, C₁-C_FourAlkyl or it
A mixture of these);     xvi) -CH (OR¹⁴)_Two(R¹⁴Is hydrogen, C₁-C₁₂Is it alkyl
, Or two R¹⁴Units linked together form a ring having 3 to 5 carbon atoms
Can be formed or a mixture thereof);     xvii) A unit having the formula: [Chemical 19] R in the above formula^FourIs hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁵Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R^FourAnd R⁵Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;     xviii) A unit having the formula: [Chemical 20] R in the above formula⁶Is hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁷Is
Hydrogen, C₁-C_FourAlkyl or a mixture thereof; R⁶And R⁷Are together
To form a heterocyclic ring having 3 to 5 carbon atoms;     xix) -NHOR¹⁶(R¹⁶Is hydrogen, C₁-C₁₂Straight or branched alkyl
, Formula-COR¹⁷Having an acyl (R¹⁷Is C₁-C_FourIs alkyl) or
A mixture thereof);     xx) Units with the following formula:                             -CH = NOR¹⁶ R in the above formula¹⁶Is hydrogen, C₁-C₁₂Linear or branched alkyl, C₇-C₂₂straight
Chain or branched alkylene aryl, formula-COR¹⁷Having an acyl (R¹⁷Is C ₁ -C_FourAlkyl) or mixtures thereof;     xxi) an amino unit having the formula:                             ‐ (CH_Two)_mN (R^Three)_Two Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; m is 0-10;     xxii) Quaternary ammonium units having the formula:                             ‐ (CH_Two)_mN⁺(R^Three)_ThreeY⁻ Each R in the above formula^ThreeIs independently C₁-C₁₈Substituted or unsubstituted, straight or branched chain
Kill; Y is an anion of sufficient charge to provide electrical neutrality; m
Is 0-10;   o) two R units on the same carbon atom are linked together to form a carbonyl unit or
May form a carbonyl unit equivalent; and   p) a mixture thereof; L is a linking group; R'targets R or the saccharin enzyme inhibitor component
Is a unit that acts to irreversibly bind to an enzyme; [poly] is a polymer unit
I is the number of the saccharin units forming the complex, and a value of 1 to 100
15. The composition of claim 14, wherein z is 0 or 1. 16. A) 0.01% by weight or more of one or more polymer conjugates having the following formula and capable of inhibiting one or more proteolytic enzymes: T- (L) _z- [poly]. In the above formula, T is a saccharin ring-containing enzyme inhibitor component; L is a linking unit; [poly] is a polymer component; z is 0 or 1; b) 0.01% by weight or more of auxiliary bioactivity And c) a composition for human dermal application, comprising the balance of carriers and adjunct ingredients. 17. A) 0.01% by weight or more of one or more polymer conjugates having the following formula and capable of inhibiting one or more proteolytic enzymes: T- (L) _z- [poly]. In the above formula, T is a saccharin ring-containing enzyme inhibitor component; L is a linking unit; [poly] is a polymer component; z is 0 or 1; b) comprises the balance carrier and auxiliary components. A method for preventing human skin irritation, comprising the step of contacting the composition with human skin. 18. The auxiliary component is a petroleum-based emollient, sucrose ester fatty acid, polyethylene glycol and its derivative, humectant, fatty acid ester, alkyl ethoxylate, fatty acid ester ethoxylate, fatty alcohol, polysiloxane, propylene glycol and its. Derivatives, glycerin, glycerides, acetoglycerides and ethoxylated glycerides of C ₁₂ -C ₂₂ fatty acids, triethylene glycol and its derivatives, waxes, fatty acids, fatty alcohol ethers, propoxylated fatty alcohols, fatty esters of polyhydroxy alcohols, lanolin, 18. The method of claim 16 or 17, selected from the group consisting of kaolin and mixtures thereof.