CZ20003316A3 - Compounds and preparations inhibiting enzymes - Google Patents

Abstract

Substances, compositions and methods useful for prevention and treatment some health, skin, hair and oral disorders. These substances, compositions and compositions are also useful in personal care and health care, skin, hair, oral cavity, beauty. Formula I compounds and their compounds tautomers, acceptable salts and biohydrolizable amides, esters and imides, where A, Q, η, P, L], L2, L3, L4, Z, X, Bt and B2 have meaning.

Description

ENZYMES INHIBITING COMPOUNDS AND MEANS

TECHNICAL FIELD

The compounds, compositions and methods of the present invention are widely applicable in health care, skin, oral cavity and personal care products. Further disclosed are compositions, compositions and methods useful in washing and cleaning, washing rough surfaces, maintaining lawns and gardens, and surface coating applications and applications where the use of an enzyme inhibitor results in improved performance.

BACKGROUND OF THE INVENTION The present invention describes enzyme inhibitory substances that are involved in the course of certain disorders of health, skin, hair and oral cavity. These are especially enzymes of the lipases, serine proteases, metalloproteases, cysteine proteases and aspartic proteases. More specifically, it may be a lipase, carboxypeptidase A, chymotrypsin, elastase, trypsin, and leucine aminopeptidase. They are useful against a wide variety of disorders such as sore spots, acne, periodontal disease and obesity. They are also useful as contraceptives and drug delivery systems.

Sore spots are a common form of irritation and inflammation in children in diaper-covered areas. This irritation is also referred to as diaper dermatitis, or diaper rash. Although most commonly found in children, this disorder also occurs in adults. Anyone suffering from an excretion disorder to the extent that it is necessary to use an absorbent may develop this disorder. It can be anyone, from newborns to the oldest, and the rate of manifestation can vary.

Rash is a disorder in which contact dermatitis is evident in the early stages. Skin irritation in single sore spots is a consequence of increased skin contact with urine, faeces or both. Although it is well known that faeces lead to an outbreak of dermatitis, the particular urine component (s) and / or faeces responsible for skin irritation have not yet been satisfactorily identified. Among the most commonly considered candidates for causing sore spots are ammonia, enzymes present in feces, bacteria, bacterial products, urine pH, excessive hydration and Candida albicans.

There is direct evidence that proteolytic and lipolytic enzymes present in feces are important for skin irritation and inflammation under these conditions and the formation of, for example, sore spots. See, e.g., Buckingham, US Patent 4,556,560, 1985, Zimmerer, US Patent 4,657,537, 1987, Berg et al.

al., U.S. Patent 4,685,909, 1987, Jordan et al., U.S. Patent 4,842,593, 1989, Buckingham et al., " Ethiologic Factors in Diaper Dermatitis: The Role of Feces ", Pediatrics Dermatology, Vol. 3, s. 107-112 (1986) and Anderson et al., "Fecal Enzymes: In Vivo Human Skin Irritation", Contact Dermatitis, Vol. 30, s. 152-158 (1994). In addition, these effects are more noticeable when urine is present or when the skin is covered.

McFarlane et al., "Contribution of Microflora to Proteolysis in the Human Large Intestine", Journal of Applied Bacteriology, Vol. 64 (1988) s. 37-46, discloses that the faecal microflora contributes substantially to the proteolytic activity of human feces, suggesting that a number of bacterial enzymes including proteases, lipases, and other esterases may aid skin damage. A study with inhibitors developed to inhibit the enzymatic activity of different classes of proteases shows that serine proteases, cysteine proteases, and metalloproteases are most likely responsible for the proteolytic activity of feces. Unfortunately, the specific contribution of different types of enzymes to skin damage is largely unknown.

Several strategies for the prevention and / or treatment of sore spots are currently in use. Reducing skin hydration through frequent replacement of diapers, moisture absorbing powders, superabsorbent materials and improving diaper breathability are the most common procedures. Another common procedure is to use an artificial barrier. It is also typical to use cream, ointment, oil or milk to prevent irritation of the faeces or urine of the skin irrespective of their specificity. Unfortunately, such use of an artificial barrier, although it may prevent skin irritation, may be irritating in itself and may be aesthetically unacceptable. Although a number of factors seem to be necessary for the outbreak of a disorder such as sore spots, the course of the disorder itself will be caused by conventional mechanisms. For example, it has been shown that cytokine production by skin cells is a common response to the presence of irritants or breakdown of the skin barrier (stratum corneum). Some specific cell types, particularly keratinocytes, which are cells directly below the stratum corneum, are likely to be involved in cytokine production and are probably the first target of irritation. Keratinocytes have been shown to produce a variety of cytokines in response to irritation, including pro-inflammatory cytokines such as interleukin 1-alpha (IL-1α). These and other cytokines induce a cascade of events that may eventually lead to physiological manifestations such as redness, rash and skin ulcerations, collectively referred to as sore spots.

Although some prior art compositions for the treatment of sore sprays that contain inhibitors of faecal urease, lipase and / or protease activity have been described, the importance of an active regimen to prevent early stages of the cytokine response in keratinocytes leading to an inflammatory cascade has never been described. In particular, fecal enzymes were not known to play an important role

in inducing the cytokine response of keratinocytes to irritation, and thus that inhibition of fecal enzymes can be achieved by more specific prevention or treatment of sore blood than previously reported.

The compounds, compositions and methods of the present invention overcome the above-mentioned complications by inhibiting the enzymes described as supra under these conditions and causing skin disorders and inflammation such as sore spots. The inventors have surprisingly found that the compounds of the present invention inhibit enzymes that are involved in processes leading to the emergence of disorders such as sore spots. The proposed compounds have been found to have inhibitory activity against proteolytic and / or lipolytic enzymes including enzymes such as: lipase, carboxypeptidase A, chymotripsin, elastase, trypsin and / or leucine aminopeptidase. The proposed substances inhibit the activity of these enzymes and thereby reduce the irritability of the substances present in the feces.

Moreover, it has surprisingly been found that the compounds of the present invention are capable of penetrating the skin in limited amounts, which greatly reduces the potential for systemic side effects. Thus, the compounds of the present invention may be administered topically to the skin via, for example, the inner side of the diaper, ensuring their sufficiently close contact with the skin.

In addition, it has been found that the compounds of the present invention are useful in cases other than the treatment or prevention of sore spots. They are also useful in the treatment of obesity, where they can be used as an inhibitor of intestinal lipase. Thus, the proposed compounds, due to their inhibitory activity and polymer conjugated form, can be completely safe in their limited absorption upon oral administration.

In addition, the compounds of the present invention have been found to be useful for treating the skin in other inflammatory disorders such as acne. It is known from the theory that bacterial lipases cleave triglycerides in subcutaneous fat into free fatty acids known to irritate the follicular wall. Lipase inhibition by the compounds of the present invention prevents the formation of these fatty acids and skin irritation. In addition, inhibition of bacterial proteases by

«. The substances according to the invention also reduce the irritation of the inflamed follicle as they contain a poly (alkylene oxide) group which ensures their penetration into the subcutaneous fat.

Although some non-polymeric guanidine and amidine derivatives have already been described as protease inhibitors such as tripsin, chymotrypsin, plasmin, kallikrein, thrombin and acrosine, the compounds of the present invention have not yet been described. See, e.g., U.S. Patent No. 5,622,984 to Nkai et al., European Patent Application 0 486,702, Kabushiki et al., 1992, U.S. Patent No. 4,948,891 to Schnur et al., 1990, and U.S. Patent No. 4,454,338, Fuji et al., 1984. Although in the current state «9 9 · 9 · · · ·

Guanidino and amidino enzyme inhibitors are commonly found in the art, their use for reducing the effect or preventing sore spots is not mentioned anywhere.

Furthermore, it is known that conjugates of polymers to peptides, polypeptides, and some small molecules are useful in a variety of applications. For example, a copolymer of amino acid residues or peptide sequences with a poly (alkylene oxide) wherein the polymer is conjugated to a pharmaceutically active agent has been described. These substances have been developed to increase the functionality of poly (alkylene oxides). See. U.S. Patent No. 5,455,027 to Zalipsky et al., 1995. Another example is the conjugation of taxol with a polymer, particularly poly (ethylene oxide). In this case, the polymer is used to increase the water solubility and thus the usability of the drug. Taxol is controlled hydrolyzed from an implanted gel containing the conjugate. See. U.S. Patent No. 5,648,506, Desai et al., 1997. Another example is a conjugate of poly (ethylene oxide) with para-aminobenzamidine, which has been prepared for the purification of enzymes by an affinity reaction. French Patent Application No. 2,252,351, Segard et al., 1973 and Takerkart G., "Preparation and Propertiesof Organophylic Trypsin Macro-Inhibitors: Diamidino-α, o-DiphenylcarbamylPoly (Ethylene Glycol)", FEBS Letters, Vol. 42 pp. 214-217 (1974). See also U.S. Patent No. 5,162,307 to Digenis et al., 1992; Bernkop-Schnurch et al., Synthesis and Evaluation of a Modifed Mucoadhesive Polymer Protecting from acymotrypsinic Degradation, International Journal of Pharmaceutics, vol. 146, pp. 247-254 (1997); Bernkop Schnurch et al., Development and Analysis of a Polymer Protecting by Luminal Enzymatic Degradation Caused by α-Chymotrypsin, Drug Development acrd Industrial Pharmacy, vol. 23, pp. 733-740 (1997); and Bernkop-Schnurch et al., Development and In Vitro Evaluation of a Drug Delivery System Protecting from Trypsinic Degradation, International Journal of Pharmaceutics, vol. 157, pp. 17-25 (1997).

According to the present inventors, the compounds, compositions and methods of the present invention have a wide range of usefulness and enzymatic activities, particularly under conditions where the disorder is caused by the action of lipase and protease enzymes.

SUMMARY OF THE INVENTION

The present invention provides substances, compositions and methods useful for the prevention and treatment of undesirable medical, skin, hair and oral disorders. The compounds, compositions and methods of the present invention are also widely applicable for use in personal care and skin, hair and oral care compositions.

In particular, the present invention provides compounds of the general formula:

·· · 3 «·

• 4 4 4

4 «♦ · 4 · 4 4 ·

4 4 4 4 «« · 43 · * nh-b ₂

P — L — — 1/2 ~ L3 -L4

N - B,

And tautomers, acceptable salts and biohydrolizable amides, esters and imides thereof, wherein:

(a) Bi represents hydrogen, methyl, ethyl, propyl, methylene attached to B ₂ via a single covalent bond to form Bi and B _{2 to} form a five membered ring and methylene group attached to B ₂ via another methylene group so that Bi and B ₂ formed a six-membered cycle, (b) B ₂ represents hydrogen, methyl, ethyl, propyl, a methylene group attached to Bi via a single covalent bond so that Bi and B ₂ form a five-membered ring and a methylene group attached to Bi via another methylene group, so that Bj and _B2 form a six membered ring; (c) X is either a blank position or -CH ₂ -, -NH-, (d) Z is an aromatic, substituted or unsubstituted monocyclic or polycyclic, carbocyclic or heterocyclic ring (e Li, L ₂ and L ₃ are independently an empty position, or -NH-, -O-, -S-, -C (O) -, -CF ₂ -, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, -C (0) NH-, -NH-SO ₂ -R ¹ -, -C (O) -R ² -, C (O) -R ³ -O-, -C (O) -R ⁴ -S-, - C (O) -R ⁵ -NH-, -NH-R ⁶ -, -O-R ⁷ -, -C (O) O-R ⁸ -, -C (O) NH-R ⁹ -, -NHC ( O) -R ¹⁰ -, -0C (0) -R ⁿ -, -C (O) -CH (R ¹²⁾ -N (R ¹³⁾ -Y-, where R ^1, R ^2, R ^3, R ⁴ R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino group and wherein R ¹² is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino, and -AA wherein -AA is an amino acid side chain and R is hydrogen and R and R together form a monocyclic or polycyclic heterocyclic ring with the nitrogen to which R ^{13 is} attached and wherein Y is an empty position, or -C (O) -CH (R ¹⁴ ) -N (R ¹⁵ ) - wherein R ¹⁴ is hydrogen alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, alkylamino, chr an alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino group, and -AA wherein -AA is an amino acid side chain and R ¹⁵ is hydrogen and R ¹⁴ and R ¹⁵ taken together form another monocyclic or polycyclic heterocyclic ring with the nitrogen to which R is ^{) 5} linked.

(f) L4 is an empty position, or -C (0) -, • · · ·· ··

(g) P is a poly (alkylene oxide) polymer comprising linear poly (alkylene oxide), branched poly (alkylene oxide), star poly (alkylene oxide), (h) N is in the range of 1 to about 100 (i) Q is an empty position, or -0-,

NH- B ₂ '—L |' —L ₂ '—L}' - U *

NB, '(j) A is an empty position, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, Z', wherein Z 'is a saturated, unsaturated or aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring, -C (O) -Z ', and where Lf, L2', L3 ', Z', X ',

Bf and B2 'are the same as defined for L 1, L 2, L 3, Z, X, B, and B2;

wherein the substance is not of formula I and formula I is:

wherein m is in the range of from about 3 to about 500.

The compounds of the present invention are also optical isomers, diastereomers, enantiomers, tautomers, acceptable salts and biohydrolyzable amides, esters and imides of the above.

These substances have the ability to inhibit the activity of at least one enzyme, preferably a protease or lipase, in particular those responsible for the emergence of such disorders, for example sore spots. The present invention discloses substances having inhibitory activity against enzymes which are responsible for, for example, certain health disorders of the skin, hair and oral cavity. These enzymes may be, for example, a lipase, a serine protease, a metalloprotease, a cysteine protease and an aspartic protease. More specifically, it may be lipase, carboxypeptidase A, chymotrypsin, elastase, trypsin, and leucine aminopeptidase.

·· ····

The compounds of the present invention may also be used as intermediates for the preparation of other enzyme inhibitors. This means that the substances can be further modified to produce other active analogs.

As defined by infra and as used herein, substituents may be further substituted. They may be substituted by one or more substituents. These may be those listed in Hanch C., Leo A., "Substituent Constants for Corelation Analysis in Chemistry and Biology" (1979). Suitable substituents are, for example, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, alkylamino, cyano, halo, carboxy, alkoxyacyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

All references cited herein are hereby incorporated by reference. _t All percentages, ratios and proportions herein specified, are intended as weight percentages, unless otherwise indicated.

Definition of terms used

The term "acceptable salt" as used herein describes a cationic salt formed on any acidic (eg, carboxyl) group, or an anionic salt formed on any basic (eg, amino) group. Most of these salts are known in the art and are described in World Patent Application No. 87/05297, Johnston et al., filed Sep. 11, 1987. Suitable salts are, for example, alkali metal salts (such as sodium and potassium) and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Most preferred anionic salts are the halide (e.g., chlorides). These salts must of course be useful for administration to mammals.

"Alkenyl" is an unsubstituted or substituted hydrocarbon radical having from 2 to 15 carbon atoms, preferably from 2 to 10 carbon atoms, and most preferably from 2 to 8, except as indicated. Alkenyl substituents have at least one double bond (e.g., vinyl, allyl and butenyl).

<"Alkyl" is an unsubstituted or substituted saturated hydrocarbon radical having from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms

atoms and preferably from 1 to 4 carbon atoms. Most preferred alkyl groups are methyl, ethyl, propyl, isopropyl and butyl.

"Alkylamino" is an amino radical with one (secondary amine) or two (tertiary amine) alkyl substituents. For example, methylamino (-NHCH ₃ ), dimethylamino (-N (CH ₃ ) 2), methylethylamino (-N (CH ₃ ) CH ₂ CH ₃ ). Alkylamino can also be an alkyl radical bearing

9 9 9

9 9 9

9 9 9 amino. For example, CH 2 CH 2 CH 2 NH 2 or CH 2 CH 2 NH 2. Alkylamines may be substituted or unsubstituted.

"Alkylene" is an alkyl, alkenyl or alkynyl that is diradical, eg, methylene -CH 2 -.

"Amino acid side chain" is an R group derived from a natural or unnatural amino acid of the structure:

wherein T is hydrogen or is attached to R to form a ring (such as in the proline amino acid). This amino acid side chain may be substituted or unsubstituted and may have a D, L configuration or may be racemic.

"Aryl" is an aromatic carbocyclic or heterocyclic radical. The most preferred aryl group may be, for example, phenyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl, thienyl, furyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl and the like. These aryl groups may be substituted or unsubstituted.

"Arylalkenyl" is an alkenyl radical substituted with an aryl group or an aryl radical substituted with an alkenyl group. These arylalkenyls may be substituted or unsubstituted.

"Arylalkyl" is an alkyl radical substituted with an aryl group or an aryl radical substituted with an alkyl group. The most suitable arylalkyl group may be, for example, benzyl, phenylethyl and phenylpropyl. These arylalkyls may be substituted or unsubstituted. "Arylalkylamino" is an amino radical substituted with an arylalkyl group (eg, -NH-benzyl). The arylalkylamino group may also be an aminoalkyl radical substituted with an amino group. The arylalkylamino groups may be substituted or unsubstituted.

"Arylamino" is an amino radical substituted with an aryl group (eg, -NH-aryl). Arylamino may also be an aryl radical substituted with an amino group (eg, aryl-NH-). These arylamino groups may be substituted or unsubstituted.

"Biohydrolyzable amides" amides of the compounds of the present invention which do not necessarily interfere with the inhibitory activity of the formulations, or that are normally altered in vivo, by a human or animal subject to form an active inhibitor.

"Biohydrolyzable imides" are imides of the present invention that do not necessarily interfere with the inhibitory activity of the formulations, or that are routinely altered in vivo by a human or animal subject to produce an active inhibitor.

"Biohydrolyzable esters" are esters of the present invention that do not necessarily interfere with the inhibitory activity of the formulations, or that are routinely altered in vivo by a human or animal subject to produce an active inhibitor.

A "carbocyclic cycle" is a hydrocarbon cyclic radical. The carbocyclic cycles may be monocyclic or fusion, bridged, or form a spiropolycyclic system. The monocyclic carbocyclic cycles will contain a total of from 3 to 9 atoms, preferably from 4 to 7 atoms, and most preferably from 5 to 6 atoms. Polycyclic carbocyclic cycles contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably from 9 to 10 atoms.

"Cycloalkyl" is a saturated carbocyclic or heterocyclic radical. Most suitable cycloalkyl may be cyclopropyl, cyclobutyl and cyclopentyl.

A "heterocyclic cycle" is a cyclic radical containing in the ring chain carbon atoms and one or more heteroatoms. The heteroatom may be a nitrogen, sulfur, phosphorus or oxygen atom, preferably nitrogen, sulfur, or oxygen. The heterocyclic cycles may be monocyclic or fused, bridge-joined, or may form a spiropolycyclic system. The monocyclic carbocyclic cycles will contain a total of from 3 to 9 atoms, preferably from 4 to 7 atoms, and most preferably from 5 to 6 atoms. Polycyclic carbocyclic cycles contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably from 9 to 10 atoms.

A "lower" hydrocarbon group (eg, lower alkyl) is an alkyl having from 1 to 6, preferably from 1 to about 4, carbon atoms.

"Protected alkylamino" is an alkylamino group wherein the amino function is substituted with a protecting group, e.g., as disclosed in T. Greene, "Protecting Groups in Organic Synthesis" by John Wiley &amp; Sons 1981. The most suitable protecting group is N-tert-butoxycarbonyl (BOC). ) and Nbenzyloxycarbonyl (CBZ).

"Protected arylamino" is an arylamino group wherein the amino function is substituted with a protecting group, eg, as described in T. Greene, "Protecting Groups in Organic Synthesis" by John Wiley & Sons 1981. The most suitable protecting group is N-tert-butoxycarbonyl (BOC). ) and Nbenzyloxycarbonyl (CBZ).

"Protected arylalkylamino" is an arylalkylamino group wherein the amino function is substituted with a protecting group, e.g., as disclosed in T. Greene, &quot; Protecting Groups in Organic Synthesis &quot; by John Wiley &amp; Sons 1981. The most suitable protecting group is N-tertbutoxycarbonyl (BOC) and N-benzyloxycarbonyl (CBZ).

A "safe and effective amount" of the compounds (or compositions) of the present invention is an amount effective to inhibit the activity of at least one enzyme in a mammalian subject without any undesirable side effects (such as toxicity, irritation, or allergic reaction) to proportional profit / risk ratio within the meaning of the present invention.

A general representation of substances or parts thereof is used herein. In the general formula:

P-Lt — Lj-Lj-Li nh-b ₂

NB, and similar structures, pt-Q1 · ^L - * n does not represent a repeating monomer unit, since "A" contains only one bond for binding. Rather, this indicates a number of "AQ-" functional groups attached to the polymer and various functional units of the polymer. For example, if this value is n = 3, the general structure might look like this:

A-Q

AND

AND

nh-b ₂

N-Bj

Substances according to the invention

The compounds of the present invention are inhibitors of, for example, proteolytic and lipolytic enzymes. These enzymes may be lipases, serine proteases, metalloproteases, cysteine proteases and aspartic proteases.

The compounds of the present invention are described in essence of the invention. The present invention describes compounds of the general formula:

P-L, -L ^ -L3-L4 b-NH ₂

N —B |

And their tautomers, acceptable salts, biohydrolizable amides, esters and imides, wherein:

(a) Bi represents hydrogen, methyl, ethyl, propyl, methylene attached to B ₂ via a single covalent bond so that Bj and B ₂ form a five-membered ring and methylene group attached to B ₂ via another methylene group so that Bi and B ₂ formed a six-membered ring, preferably Bj represents hydrogen, or a methylene group attached to B ₂ via a single covalent bond, so that B 1 and B ₂ form a five-membered ring and a methylene group attached to B ₂ via another methylene group, so Bi and B ₂ formed a six-membered cycle, more preferably Bi represents hydrogen, or a methylene group attached to B ₂ via a single covalent bond to form Bi and B _{2 to} form a five membered ring, preferably Bi is hydrogen (b) B ₂ represents hydrogen, methyl, ethyl , propyl, a methylene group attached to Bi via a single covalent bond, so for B ₁ and B _{2 to} form a five-membered ring and a methylene group attached to Bi via another methylene group, so that Bi and B ₂ form a six-membered cycle, preferably B ₂ represents hydrogen, or a methylene group attached to Bi via a single covalent bond and B ₂ formed a five-membered ring and a methylene group attached to Bi via another methylene group so that Bi and B ₂ formed a six-membered cycle, more preferably B ₂ represents hydrogen, or a methylene group attached to Bi via a single covalent bond so that B | and B ₂ forms a five-membered ring, most preferably B ₂ is hydrogen (c) X is either an empty position or -CH ₂ -, -NH-, more preferably X is either an empty position, -NH-, more preferably X is either -NH-, (d) Z is an aromatic, substituted or unsubstituted monocyclic or polycyclic, carbocyclic or heterocyclic ring, more preferably Z is an aromatic, monocyclic, carbocyclic ring, more preferably Z is phenyl or naphthyl and most preferably Z is phenyl, preferably for L4 and X to be substituted at Z in the meta or para position, preferably L4 and X are substituted at Z at the para position, (e) L ₁ , L ₂ and L 3 are independently an empty position, or -NH-, -O-, -S-, -C (O) -, -CF ₂ -, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, -C (O) NH-, -NH-SO 2 -R ¹ -, -C (O) -R ² -, C (O) -R ³ -O-, -C (O) -R ⁴ -S-, -C (O) -R ⁵ -NH-, -NH-R ⁶ -, -O- R ⁷ -, -C (O) OR ⁸ -, -C (0) NH-R ⁹ -, -NHC (O) -R ¹⁰ -, -OC (O) -R ^U -, -C (O) - CH (R ¹² ) -N (R ¹³ ) -Y-, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl,

Φ · · · • • · · · · · · ·

Alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino, and wherein R ¹² is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl , arylalkenyl, alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino, and -AA wherein -AA is an amino acid side chain and R is hydrogen and R and R together form a monocyclic or polycyclic heterocyclic ring with the nitrogen to which R is ¹³ is attached to and wherein Y is a blank position or -C (O) -CH (R ¹⁴⁾ -N (R ¹⁵⁾ - wherein R ¹⁴ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, alkylamino, protected alkylamino , arylamino, protected arylamino, arylalkylamino, protected arylalkylamino, and -AA wherein -AA is an amino acid side chain and R ¹⁵ is hydrogen and R ¹⁴ and R ¹⁵ taken together form another monocyclic or polycyclic heterocyclic ring with nitrogen at where R ^{15 is} attached, preferably L ₁ , L 2 and L _{3 are} independently-ΝΗ-, -O-, -S-, -C (O) -, -CF 2 -, alkyl, aryl (preferably phenyl), -C ( O) NH-, -NHSO 2 -R ¹ -, -C (O) -R ² -, -C (O) -R ³ -O-, -C (O) -R ⁴ -S-, -C (O) ) -R ⁵ -NH-, -NH-R ⁶ -, -O-R ⁷ -, C (O) OR ⁸ -, -C (O) NH-R ⁹ -, -NHC (O) -R ¹⁰ - , -OC (O) -R ⁿ -, -C (O) -CH (R ¹⁰⁾ -N ^(R) -Y, wherein R ^1, R ^2, R ^3, R ^4, R ^5, R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently alkyl and aryl, and R ¹² is hydrogen, alkyl, aryl, arylalkyl, alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino, and -AA wherein -AA is the amino acid side chain and R is hydrogen, or R and R together form a monocyclic or polycyclic heterocyclic ring with the nitrogen to which R ^{13 is} attached and wherein Y is an empty position, R ¹² is preferably hydrogen, alkyl, cycloalkyl, aryl, arylalkyl and -AAA R ¹³ is preferably hydrogen, (f) L 4 is an empty position, or -C (O) -, more preferably L 4 is -C (O) -, (g) P is a poly (alkylene oxide) polymer containing linear p oly (alkylene oxide), branched poly (alkylene oxide), star poly (alkylene oxide), preferably P is linear poly (alkylene oxide) (wherein the linear poly (alkylene oxide) is preferably a poly (ethylene oxide) homopolymer or copolymer), or branched poly (alkylene oxide) ), preferably P is a linear poly (alkylene oxide) (wherein the linear poly (alkylene oxide) is preferably a poly (propyylene oxide) homopolymer or a poly (ethylene oxide) homopolymer and most preferably a poly (ethylene oxide) homopolymer) (h) n is in the range of 1 to about 100 wherein P is a linear poly (alkylene oxide), preferably is η 1 or 2, and most preferably 1, wherein P is a branched poly (alkylene oxide), n is more in the range of 2 to about 30, more preferably n is in the range of 2 to about 20, more preferably n is in the range of 2 to about 10, wherein P is a star poly (alkylene oxide), n is more in the range of 4 to about 100, (i) Q is an empty position, or -O-, better then Q -0-, • 4 ··· «4« · 4 • Λ · · ·· • β 4 · • · • • 4 »« ··· · • ·

4 β • 4 4 • 4 <

• 4 * 4 (j) A is an empty position, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, Z ', wherein Z' is a saturated, unsaturated or aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring, -C (O) -Z ', and -C (O) -R ¹⁵ -CF ₃ , wherein R ¹⁵ is an empty position or alkyl and:

_NH-B-2 '-lf-Y' - L3'- L4-4- X'- 2 4-n-B wherein L * / L ₂ \ ₃ L ', Z', X ', Bf and B _2' are the same as defined for L), L _2, L _3, Z, X, B and B _2; rather, A is alkyl (when A is alkyl, it is preferable that the methyl is a radical) or:

and most preferably when L ₁ '= L ₁ , L ₂ ' = L ₂ , L ₃ '= L ₃ , Z' = Z, X-X, Bj-BiaB ₂ '-B ₂ wherein the substance does not have the general formula Yippee:

wherein m is in the range of from about 3 to about 500.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

One of ordinary skill in the art can assume the existence of tautomeric forms for some of the compounds of the present invention. When tautomer A is shown, it is clear that other tautomeric conformations B and C need not necessarily be imaged. For illustration

HN N NH

Poly (alkylene oxides)

As used herein, P is a poly (alkylene oxide) based polymer, it may be from a linear, branched, or star-like polymer structure.

Linear poly (alkylene oxides)

The linear poly (alkylene oxides) may be homopolymers of alkylene oxide units or a copolymer of alkylene oxide units per se or copolymerized with one or more monomer units, the monomer units having a functional group other than that attached to the alkylene oxide unit. When the linear poly (alkylene oxide) copolymer can be composed of a different structure of monomer units. For example, it may comprise periodic repetitions (eg, A-B-A-B-A-B-A-B), irregular repetitions (eg, A-A-A-B-A-B-B-A-B-B), or a block copolymer (eg A-A-A-B-B-B-A-A-A).

When the P linear poly (alkylene oxide) compounds of the present invention have an average molecular weight of from about 350 daltons to about 20,000 daltons, more preferably from about 2,000 daltons to about 15,000 daltons, more preferably about 3,000 daltons to about 10,000 daltons. 000 daltons, preferably from about 3,000 daltons to about 5,000 daltons. The exception is when A is:

NH-b ₂ '-L' - _L2'-L3 '-L 4 - (- ^Z'

N-Bf 9 9 9 9 9 9 9 «« «----9 9 9 9 9 9 9 B B B · · ·····················

In this case, when P is a linear poly (alkylene oxide), the substances most preferably have an average molecular weight of from about 400 daltons to about 35,000 daltons, more preferably from about 1,500 daltons to about 20,000 daltons, more preferably about 3,400 daltons to about 10,000 daltons, preferably about 3,400 daltons to about 8,000 daltons.

Similarly, linear poly (alkylene oxides) typically contain from about 5 to about 1000 monomer units, more preferably from about 20 to 500 monomer units, more preferably from about 60 to 250 monomer units, and most preferably from about 60 to 200 monomer units.

Suitably, the poly (alkylene oxide) is composed of ethylene oxide and / or propylene oxide monomer units. In a most suitable particular variant of the present invention, the linear poly (alkylene oxide) homopolymer is composed of ethylene oxide or propylene oxide monomer units. A linear poly (ethylene oxide) homopolymer can be depicted

as follows:

wherein t is the number of repeating ethylene oxide monomer units. The poly (propylene oxide) linear homopolymer can be shown as follows:

wherein t is the number of repeating propylene oxide monomer units.

The linear poly (alkylene oxides) may be homopolymers of alkylene oxide units or a copolymer of alkylene oxide units per se or copolymerized with one or more monomer units, the monomer units having a functional group other than that attached to the alkylene oxide unit. When the linear poly (alkylene oxide) is a copolymer of alkylene oxide monomers, it is desirable that up to 20% to about 99% of the total number of monomer units comprise ethylene oxide monomers and from about 1% to about 80% propylene oxide monomers.

When the linear poly (alkylene oxide) is a copolymer of alkylene oxide monomers and other monomer units containing a functional group other than that attached to the unit

Of the alkylene oxide, it is preferred that up to about 50% to about 99% of the total number of monomer units comprise alkylene oxide monomers, more preferably, from about 70% to about 99% of the total monomer units are alkylene oxide monomers, and most preferably from about 80% to about 99% of the total monomer units are alkylene oxide monomers.

Examples of suitable linear poly (alkylene oxides) are propylamine-terminated bifunctional polyethylene glycols of 2000 molecular weight, available under the tradename Jeffamin® ED2003 from Huntsman Chemical Corp., Houston Texas. The following non-limiting examples merely illustrate the structure of linear poly (alkylene oxide) polymers:

where t, t and t are independently the number of repetitions of monomer units:

where t, t and t are independently the number of repeats of the monomer units.

The following non-limiting examples further illustrate examples of linear poly (alkylene oxides) copolymerized with another monomer unit containing a different functional group than that attached to the alkylene oxide unit:

99

(available from Sherwater Polymers, Inc.) wherein t, u and t are independently the number of repeating monomeric units,

(available from Gelest Inc). wherein t, u and t are independently the number of repeating monomer units,

(available from Gelest Inc). wherein t, u and t are independently the number of repeating monomer units.

Branched poly (alkylene oxides)

In order to increase the functionality of the P polymer, polymers with branched poly (alkylene oxide) chains are constructed. The branched poly (alkylene oxide) polymers comprise one to several linear poly (alkylene oxide) chains attached to one or more functional monomers. Functional monomers are defined as those which contain a reactive functional group. These reactive functional groups can be used to attach other functional groups, such as hydroxyl groups of linear poly (alkylene oxide) chains. Examples of such groups are carboxyl groups, alcohols and amines. When the branched poly (alkylene oxide) chain P polymer comprises from about 50% to about 99% of the total monomer units of the alkylene oxide monomer unit, more preferably from about 70% to about 99% of the total monomer units of the alkylene oxide monomer unit, and most preferably from about 80% to about 99% of the total number of monomer units of the alkylene oxide monomer unit.

If the P polymer is a branched poly (alkylene oxide) chain, its molecular weight should be from about 5,000 daltons to about 100,000 daltons, but rather its molecular weight

No. 4,994 should be from about 7,000 daltons to about 50,000 daltons and most preferably its molecular weight should be from about 10,000 daltons to about 50,000 daltons.

The following non-limiting examples show some examples of poly (alkylene oxides):

CH-CH ₂ ² ~ J va derivatives thereof, such as the hydrolysis product thereof, and wherein the tau independently represent the number of repeating monomer units,

where t, u and t are independently the number of repeating monomer units,

0 → 0 ° i

wherein t and u are independently the number of repeating monomer units and R is, for example, hydrogen or alkyl. This polymer resembles the following polymer where it occurred and alkoxylation (eg ethoxylation) and the result is the following example:

wherein t, u and u are independently the number of repeating monomer units and R is, for example

where t, u 'and u are independently the number of repeating monomer units:

where t and u represent independently the number of repeating monomer units:

° 3A-J »A» t .K NN

NH

Dewhere t, ť and t represent independently the number of repeating monomer units:

(ethoxylated trimethylpropane), wherein t, t and t represent independently the number of repeating monomer units.

Star poly (alkylene oxides)

Star poly (alkylene oxides), like branched polymers, are used to enhance polymer functionality. Various descriptions of methods for preparing poly (alkylene oxides) with a star-like structure are given in Gnana Y., Lutz P., Rempp P., "Synthesis of Star-Shaped Poly (ethylene oxide)", Macromolecular Chemistry, Vol. 189 (1988) pp. 2885-2892. Full range • 9 ·· ♦ · ♦ · 9

9 9 9

9 99 9 poly (alkylene oxides) with a star-like structure is commercially available. These star-type poly (alkylene oxides) may have a central core, which may or may not be polymerized to form a poly-core. Such cores contain a predetermined number of active sites to which linear or branched poly (alkylene oxide) chains can be attached to form a core with the desired number of arms. See also U.S. Patent 5,648,506, Desai et al., 1997. Examples of cores that can be used to prepare star-type poly (alkylene oxides) include, for example, divinylbenzene, polymerized divinylbenzene, sugars such as cyclodextrins and ethylenediamine. The number of arms may vary, but is in the range of from 4 to about 100. If the P is a star-type poly (alkylene oxide) it contains from about 80% to about 99% of the total monomer units of the alkylene oxide monomer unit, more preferably from about 90 % to about 99% of the total number of monomer units of the alkylene oxide monomer unit, and most preferably from about 95% to about 99% of the total number of monomer units of the alkylene oxide monomer unit.

If P is a poly (alkylene oxide) with a star-like structure, its molecular weight should be from about 10,000 daltons to about 500,000 daltons, but rather its molecular weight should be from about 10,000 daltons to about 100,000 daltons and most likely the molecular weight should be from about 10,000 daltons to about 50,000 daltons.

The poly (alkylene oxide) with a four-star star structure is shown below:

where t is the number of repeating monomer units.

The following are non-limiting examples of poly (alkylene oxides) with a star-like structure that contain an ethylenediamine core:

wherein t and u are independently the number of repeating monomer units.

Further examples of the compounds of the present invention

The following non-limiting examples serve only to illustrate the various compounds of the present invention:

• 4 44 • t · 4 • 4 4 4

Where R ¹² is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl and -AA, R ¹³ is hydrogen, D is -O-, -S- and -NH- and wherein m is in the range of from 5 to about 1000 monomer units, preferably then from 20 to about 500 monomer units, more preferably from 60 to about 250 monomer units, and most preferably from 60 to about 200 monomer units, and:

O o

• • • 9 9 9 9 99 9 9 9 • • · • 9 9 9 9 9 • ·· 9 • ·· * • 9 9 9 • 9 9 9 • • • • • 9 9 9 • · 9 9 9 ··· 99 99

O

R12 O nh ₂ • · ··· 9

9 9 • 9 ·

9 ·

9 9

NH

NH

NHj

O

NH

Process for the preparation of the substances according to the invention

The compounds of the present invention are prepared using techniques well known in the art. The starting materials used to prepare the compounds of the present invention are prepared using techniques well known in the art, or commercially available.

It goes without saying that a person skilled in the art in organic chemistry is able to carry out basic operations without detailed instructions.

Examples of these procedures are given in well-known publications such as J. March, "Advanced Organic Chemistry", John Wiley &amp; Sons, 1992.

One of skill in the art can appreciate that some reactions are better performed when certain functional groups are masked or protected, thereby increasing the yield of the reaction and / or avoiding certain undesired reactions. These side reactions are reported in the literature and are well known to any person skilled in the art. Examples of a variety of manipulations are given, for example, in T. Greene, iProtecting Groups in Organic Synthesis, John Wiley & Sons, 1981.

The compounds of the present invention may have one or more chiral centers. As a result, it is possible to prepare selectively different optical isomers, including diastereomer and enantiomer to a greater extent than others, for example using chiral starting materials, catalysts and solvents, or all stereoisomers or optical isomers including diastereomer and enantiomer can be prepared at once (racemic mixture). Thus, the compounds of the present invention may exist as a racemic mixture, a mixture of optical isomers, including a diastereomer and an enantiomer, or the stereoisomers may be separated by various techniques known in the art, such as chiral salts or chiral chromatography.

In addition, it is known that some optical isomer, including diastereomers and enantiomers, may have better properties than others. Thus, it is apparent in the claims that when a racemic mixture is claimed, it is understood that both optical isomers, including the diastereomer and the enantiomer, or stereomers substantially isolated, are intended as well.

The following is a basic technique for the synthesis of esters and amides of poly (alkylene oxide) polymers. Other non-limiting examples illustrate more specifically the process for preparing the various compounds of the present invention.

List of abbreviations

Ν, Ν-dimethylformamide DMF

DMA Ν, Ν-dimethylacetamide

1-Methyl-2-pyrrolidinone NMP

1,3-dicyclohexylcarbodiimide DCC

1,3-Diisopropylcarbodiimide DIC 1- (3-dimethylaminopropyl) -3-carbodiimide chloride EDCI

4-dimethylaminopyridine DMAP

-hydroxybenzotriazole hydrate HOBt · «* * * OB OB OB

Esterification of poly (alkylene oxides):

Poly (alkylene oxide) polymers having a methyl ether at one end of the polymer and containing at least one free hydroxyl are dissolved in a solvent suitable for esterification. Suitable solvents for esterification are acetonitrile, DMF, DMA, p-dioxane, NMP, dichloromethane and chloroform. More suitable solvents are acetonitrile, DMF, p-dioxane, NMP, dichloromethane. Most suitable solvents are acetonitrile, DMF, NMP, dichloromethane.

In an inert atmosphere, the polymer and the suitably protected carboxylic acid are dissolved in a suitable solvent at room temperature.

The initiator is then added. It can be DCC, DCI, EDCI. Esterification of poly (alkylene oxides) can be made more effective by adding, for example, 0.1 to 10.0 equivalents of DMAP.

The reaction proceeds with stirring at room temperature for 8 to 18 hours. The progress of the reaction can be monitored by TLC in silica gel and Dragendorff reagent (6.6 g barium chloride,

0.1 g of bismuth subnitrate, 2.7 g of potassium iodide in water (73 ml) and acetic acid (15 ml), the poly (alkylene oxide) derivatives are colored orange). Once the reaction is complete, the reaction solution is filtered and the filtrate is diluted with diethyl ether at a temperature between -10 ° C and about 25 ° C, preferably at a temperature between 0 ° C and about 4 ° C until a precipitate is formed. Alternatively, the filtrate is poured into excess diethyl ether with stirring at a temperature between -10 ° C and about 25 ° C, preferably at a temperature between 0 ° C and about 4 ° C until the esterified polymer falls out of solution. The solid phase is collected, washed with water and weighed. Further purification, if necessary, may be accomplished by recrystallization, for example, in hot ethanol.

The amides can be prepared under similar conditions to those described above, using appropriate starting materials, as will be apparent to one skilled in the art.

The following non-limiting examples serve only to illustrate the compositions of the present invention, including those specific variants wherein neither poly (alkylene oxide) ester nor amide is used.

EXAMPLES OF EMBODIMENTS OF THE INVENTION

EXAMPLE 1. N-4-guanidinobenzoyl-2-aminoethyl poly (ethylene glycol) monomethyl ether chloride:

2-aminoethyl poly (ethyleneglycol) monomethyl ether (M _n = 5000, 0.50 g, 0.1 mmol), the acid chloride of 4-guanidinobenzoic (0.22 g, 1 mmol) and HOBt (0.14 g, 1 mmol) are dissolved in a mixture of NMP and dichloromethane (1: 1) (3ml). 1,3-Dicyclohexylcarbodiimide (DDC) (0.21 g, 1 mmol) is added and the reaction is allowed to stir overnight at room temperature. The mixture is then filtered and the filtrate is poured into ice ether. The precipitate is collected washed with diethyl ether and • 444

4 44 444

4 4 4 4 »444 • · ♦ 44

Recrystallized from hot ethanol to give N-4-guanidinobenzoyl-2-aminoethylpoly (ethylene glycol) monomethyl ether chloride as a white powder.

DCC, HOBt CH ₂ Cl ₂ / NMP

EXAMPLE 2. N- [N- (4-Guanidinobenzoyl) -glycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether methanesulsonate

DCC, HOBt

NHBoc DMF

->.

cf ₃ every ₂ h

CH ₂ Cl 2

H

cf ₃ every ₂ h

NH NH ₂ y

NH

CH ₃ SO ₃ H · # # # # # # # # #

T ·· • t

Φ Φ ·

Φ φ Φ <Φ · ♦ φ φ φ ·

A. N- [N- (tert-butoxycarbonyl) glycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether: 2-aminoethyl poly (ethyleneglycol) monomethyl ether (M _n = 5000, 1.00 g, 0.2 mmol) N- (tert-butoxycarbonyl) -glycine (0.2 g, 5 eq.) And HOBt (0.14 g, 5 eq.) Are dissolved in 20 mL of DMF at room temperature under an argon atmosphere. After 10 minutes, DCC (0.2 g 5 eq.) Is added and the reaction is allowed to stir overnight at room temperature. The mixture is then filtered and the filtrate is poured into ice ether to form a white precipitate. The precipitate is collected recrystallized from hot ethanol to give N- [N- (tert-butoxycarbonyl) -glycyl] -2-aminoethylpoly (ethylene glycol) monomethyl ether.

B. N-glycyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether trifluoroacetate:

The product of Step A (0.93 g, 0.2 mmol) is dissolved in 12 mL of a 50% mixture of trifluoroacetic acid and dichloromethane and stirred at room temperature for 4 hours. The reaction mixture is diluted with ice-ether to give N-glycyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether trifluoroacetate as a white precipitate which is collected by filtration.

C. N- [N- (4-guanidinobenzoyl) glycyl] -2-aminoethyl poly (ethylene glycol) monomethyl ether methanesulsonate

The product of Step B (0.9 g, 0.19 mmol), 4-guanidinobenzoic acid metnasulfonate (0.5 g, 10 eq.), Triethylamine (1 eq.) And DMAP (0.2 g, 10 eq.) Are dissolved in 25 mL DMF. DCC (0.4 g, 10 eq.) Is added and the solution is incubated for 18 hours with stirring at room temperature, under an argon atmosphere. The mixture is then filtered and the filtrate is diluted with ice-ether to form a precipitate. The precipitate is collected and recrystallized from hot ethanol to give N- [N- (4-guanidinobenzoyl) -glycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether methanesulsonate as a white powder.

The following materials can be prepared by the procedure described in Example 2, using the appropriate starting materials:

MeO

MeO

MeO

CH3SO3H NH NH,

Y

NH

CH3SO3H

NH NH ₂ ¥

NH

CH ₃ SO ₃ H

NH NH ₂ ¥

NH

CH3SO3H

MeO '.O.

O

NH

NH

O

EXAMPLE 3. N- [N- (4-guanidinobenzoyloxy) -benzoylglycyl] -2-aminoethylpoly (ethylene glycol) monomethyl ether methanesulfonate:

₊ phi DCC,

- «η _NH2 H _{NHBoc DMF}

Meo {> / ^O L ^ -. _N ? NHBoc

CF ₃ CO ₂ H

CH ₂ Cfe

MeO '

NH,

DCC, HOBt Et ₃ N, DMF

CF ₃ CO ₂ H

A. N- [N- (tert-butoxycarbonyl) -glycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether: 2-aminoethyl poly (ethylene glycol) monomethyl ether (Mn-5000, 1.00 g, 0.2 mmol) N- (tert-butoxycarbonyl) -glycine (0.2 g, 5 eq.) And HOBt (0.14 g, 5 eq.) Are dissolved in 20 mL of DMF at room temperature under an argon atmosphere. After 10 minutes, DCC (0.2 g 5 eq.) Is added and the reaction is allowed to stir at room temperature for 18 hours. The mixture is then filtered and the filtrate is poured into ice ether to form a white precipitate. The precipitate is collected recrystallized from hot ethanol to give N- [N- (tert-butoxycarbonyl) -glycyl] -2-aminoethylpoly (ethylene glycol) monomethyl ether.

B. N-glycyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether trifluoroacetate:

The product of Step A (0.93 g, 0.2 mmol) is dissolved in 12 mL of a 50% mixture of trifluoroacetic acid and dichloromethane and stirred at room temperature for 4 hours. The reaction mixture is diluted with ice-ether to give N-glycyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether trifluoroacetate as a white precipitate which is collected by filtration.

C. N- [N- (4-Hydroxybenzoyl) -glycinyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether The product of Step B (0.2 g, 0.04 mmol) is dissolved in 10 mL of DMF and stirred at room temperature. One equivalent of triethylamine is added. HOBt (10 eq.) and 4-hydroxybenzoic acid (10 eq.) are then added. After 10 minutes, DCC (0.83 g, 10 eq.) Is added and the solution is incubated overnight with stirring. The mixture is then filtered and the filtrate is diluted with ice-ether to form a precipitate. The precipitate is collected and recrystallized from hot ethanol to give N- [N- (4-hydroxybenzoyl) glycinyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether methanesulsonate as a white powder.

D. N- [N- (4-guanidinobenzoyloxy) -benzoylglycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether methanesulfonate:

The product of Step C (0.15 g, 0.03 mmol), 4-guanidinobenzoic acid metnasulfonate (0.083 g, 03 mmol) and DMAP (0.05 g, 04 mmol) are dissolved in 10 mL of DMF. DCC (0.062 g, 03 mmol) is added and the solution is incubated with stirring at room temperature under argon atmosphere for 18 hours. The mixture is then filtered and the filtrate is diluted with ice-ether to form a precipitate. The precipitate is collected and recrystallized from hot ethanol to give N- [N (4-guanidinobenzoyloxy) -benzoylglycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether methanesulfonate as a white powder.

EXAMPLE 4. N- (4-guanidinobenzoyloxy) -glycyl-poly (ethylene glycol) monomethyl ether chloride:

MeO

n

H

NHBoc

MeO

MeO

HIM

CF3CO2H

DCC, HOBt Et ₃ N, DMF

A. N- (tert-butoxycarbonyl) -glycyl-poly (ethylene glycol) monomethyl ether:

Poly (ethylene glycol) monomethyl ether (M _n = 5000, 5.00 g, 1.0 mmol), N- (tert-butoxycarbonyl) glycine (1.75 g, 10 mmol) and DMAP (0.12 g, 1 mmol) are dissolved in 40 ml DMF. To this solution was added DCC (2.06 g, 10 mmol) and the reaction was allowed to stir at room temperature for 18 hours. The mixture is then filtered and the filtrate is poured into ice ether to form a white precipitate. The precipitate is collected, washed 3 times with ether and recrystallized from hot ethanol to give N- [N- (tert-butoxycarbonyl) -glycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether.

B. Glycyl-poly (ethylene glycol) monomethyl ether trifluoroacetate:

The product of Step A (1.03 g, 0.21 mmol) is dissolved in 20 mL of a 50% mixture of trifluoroacetic acid and dichloromethane and stirred at room temperature for 4 hours. The reaction mixture is diluted with ice-ether to give glycyl-poly (ethylene glycol) monomethyl ether trifluoroacetate as a white precipitate which is collected by filtration.

C. N- (4-guanidinobenzoyloxy) -glycyl-poly (ethylene glycol) monomethyl ether chloride:

To the product of Step B (0.2 g, 0.04 mmol) was added 4-guanidinobenzoic acid chloride (0.086 g, 0.4 mmol), HOBt (0.054 g, 0.4 mmol) and 10 mL of DMF. Triethylamine (6 μΐ) and DCC (0.083 g, 0.4 mmol) are added simultaneously and the solution is incubated overnight with stirring at room temperature. The mixture is then filtered and the filtrate is diluted with ice-ether to form a precipitate which is washed with ether. The precipitate is collected and recrystallized from hot ethanol to give N- (4-guanidinobenzoyloxy) -glycyl-poly (ethylene glycol) monomethyl ether chloride as a white powder.

EXAMPLE 5. N- [4- (4-Guanidinobenzoyloxy) -benzoyl] -glycyl-poly (ethylene glycol) monomethyl ether methanesulfonate:

MeO'P- ^'The Ah "· For DCC, DMF ^nH NHBoc

HIM ---- -

O

A. N- (4-hydroxybenzyloxy) -glycyl-poly (ethylene glycol) monomethyl ether:

Glycyl-poly (ethylene glycol) monomethyl ether trifluoroacetate (prepared as described in Example 4 A to B) (0.2 g, 0.038 mmol) is dissolved in 10 mL of DMF at room temperature and under argon atmosphere. Triethylamine (1 eq.), HOBt (0.06 g, 0.44 mmol) and 4-hydroxybenzoic acid (0.06 g, 0.43 mmol) were added sequentially to the reaction mixture. Finally, DCC (0.09 g, 10 eq.) Is added and the reaction is allowed to stir for 16 hours. The product is N- (4-hydroxybenzyloxy) -glycyl-poly (ethylene glycol) monomethyl ether as a white powder.

B. N- [4- (4-guanidinobenzoyloxy) -benzoyl] -glycyl-poly (ethylene glycol) monomethyl ether methanesulfonate:

The product of Step A (0.132 g, 0.03 mmol), 4-guanidinobenzoic acid methanesulfonate (0.09 g, 0.33 mmol), DMAP (0.05 g, 0.4 mmol) are dissolved in 10 mL of DMF. DCC (0.07 g, 0.032 mmol) is added and the solution is incubated for 18 hours with stirring at room temperature. The mixture is then filtered and the filtrate is diluted with ice-ether to form a precipitate. The precipitate is collected and recrystallized from hot ethanol to give N- [4- (4-guanidinobenzoyloxy) -benzoyl] -glycyl-poly (ethylene glycol) monomethyl ether methanesulfonate as a white powder.

EXAMPLE 6. (N ^and -4-Guanidinobenzoyl-N ^E -benzyloxycarbonyl-L-lysyl) -poly (ethylene glycol) monomethyl ether chloride:

444 44 44

MeO '

Boc-Lys (Z > OH .O.

DCC, DMAP DMF • NH

O

J- °

'NHBoc

CF ₃ CO ₂ H CH 2 Cl 2 • NH

O

NH H-Cl λ

H

O

N

AND

H class ·

A. (N ^tx - (tert-butoxycarbonyl) -N ^e -benzyloxycarbonyl-L-lysyl) -poly (ethylene glycol) monomethyl ether:

Poly (ethylene glycol) monomethyl ether (M _n = 5000, 2.00 g, 0.4 mmol) is transferred into the reaction vessel. Then N ^and -Boc-N ^E -benzyloxycarbonyl-L-lysine (1.522 g, 4.0 mmol) and DMAP (0.12 g, 1 mmol) dissolved in 15 mL of DMF are added. To this solution was added DCC (2.06 g, 10 mmol) and the reaction was allowed to stir at room temperature for 18 hours. The mixture is then filtered and the filtrate is washed with dichloromethane. The combined filtrates are concentrated in vacuo to about 10 mL and then poured into 150 mL of ether with vigorous stirring. The resulting precipitate is collected on a glass frit, washed with ether and dried under suction. The crude product is recrystallized from hot ethanol, again collected on a glass frit, washed with ether and dried under suction to give the (N '- (tert-butoxycarbonyl) -N ^with -benzyloxycarbonyl-L-lysyl) poly (ethylene glycol) monomethyl ether, in the form of a white powder.

B. Trifluoroacetate N ^E -benzyloxycarbonyl-L-lysyl) -poly (ethylene glycol) monomethyl ether: The product from Step A (1.03 g, 0.21 mmol) is dissolved in 10 mL of a 50% mixture of trifluoroacetic acid and dichloromethane and stirred at room temperature. temperature for 4 hours. The reaction mixture is diluted with 150 mL of ice-cold ether. The resulting precipitate is collected on a glass frit, washed with ether and dried under suction to give the trifluoroacetate ^£ N -benzyloxycarbonyl-L-lysyl) -poly (ethylene glycol) monomethyl ether as a white precipitate.

C. chloride ^(and N-4-guanidinobenzoyl-N ^e -benzyloxycarbonyl-L-lysyl) -poly (ethylene glycol) monomethyl ether:

The product of Step B (0.1 g, 0.02 mmol) is transferred to a reaction vessel equipped with a magnetic stirrer. 4-Guanidinobenzoic acid chloride (0.04 g, 0.2 mmol), HOBt (0.03 g, 0.2 mmol) is added and the mixture is dissolved in 2 mL of dichloromethane and 1 mL of NMP. Triethylamine (5.6 μΐ) and DCC (0.04 g, 0.2 mmol) are added simultaneously and the solution is incubated for 16 hours with stirring at room temperature under an argon atmosphere. The mixture is then filtered and the filtrate is washed with dichloromethane. The filtrates are mixed and poured into ether. . The resulting precipitate is collected on a glass frit, washed with diethyl ether to give (N '-4-guanidinobenzoyl-N ⁶ benzyloxycarbonyl-L-lysyl) -poly (ethylene glycol) mono-methyl ether chloride as a white powder.

EXAMPLE 7. Bis- [N- (4-guanidinobenzoyl) -glycyl] -poly (ethylene glycol) methanesulfonate:

starting PEG, _Mn = 3400

DEFEA DOC, HOBt CHYVNMP

ⁿ \

CHjSQjH

Bis-glycyl-poly (ethylene glycol) _(Mn ~ 3400, 0.4 g, 0.12 mmol), HOBt (0.318 g, 2.35 mmol) and the mesylate of 4-guanidinobenzoic acid (0.65 g, 2.35 mmol) is transferred to a reaction vessel and dissolved in 8 mL of dichloromethane. To this solution is added diisopropylethylenamine (45 μΐ) and 4 ml of NMP. DCC (0.49 g, 2.35 mmol) in 2 mL of dichloromethane is then added and the reaction is allowed to stir at room temperature under argon atmosphere for 40 hours. The mixture is then filtered and the filtrate is washed with diethyl ether to form a precipitate which is collected on a glass frit. The crude product is dissolved in hot ethanol filtered and transferred to a refrigerator (4 ° C). The resulting precipitate is collected on a glass frit, washed with ice-cold ethanol and diethyl ether, and dried under suction to give bis- [N- (4-guanidinobenzoyl) -glycyl] -poly (ethylene glycol) mesylate as a white powder.

99 99

EXAMPLE 8. Bis- [N- (4-guanidinobenzoyl) -glycyl] -poly (ethylene glycol) methanesulfonate:

HIM.

.HIM

Boc-Qy-OH

O

CF3CO2H

ILN

NBz

CF3CO2H

H

Ν NH2

Ύ

NH

CH3SO3H

H

A. Bis- (N- (tert-butoxycarbonyl) -glycyl) -poly (ethylene glycol):

Poly (ethylene glycol) (M + 8000, 10 g, 1.25 mmol), N- (tert-butoxycarbonyl) glycine (2.19 g, 12.55 mmol) and DMAP (0.092 g, 0.75 mmol) are transferred to a reaction vessel and dissolved in 100 mL DMF with stirring. DCC (2.58 g, 12.5 mmol) is then added and the reaction is allowed to stir overnight at room temperature under argon. The mixture is then filtered and the filtrate is poured into 900 ml of ice-cold ether to form a precipitate. The precipitate is collected on a glass frit, washed with 200 ml of diethyl ether and dried under suction to give bis (N- (tert-butoxycarbonyl) glycyl) -poly (ethylene glycol) as a solid.

B. Bis-glycyl-poly (ethylene glycol) trifluoroacetate:

9 · · · 9 9 9 9 • 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 ·· 99 9 9 99 9 9 9 9

The product of Step A is transferred to a reaction vessel and dissolved in 50 mL of a 50% mixture of trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 hour. The reaction mixture is diluted with 800 mL of diethyl ether and the precipitate is collected on a glass frit, washed with 200 mL of diethyl ether and dried under suction to give bis-glycyl-poly (ethylene glycol) trifluoroacetate.

C. Bis- [N- (4-guanidinobenzoyl) -glycyl] -poly (ethylene glycol) methanesulsonate:

The product of Step B (9.6 g, 1.2 mmol), 4-guanidinobenzoic acid metnasulfonate (3.30 g, 12 mmol) and HOBt (1.620 g, 12 mmol) are transferred to the reaction vessel and dissolved in 100 mL DMF with stirring. Triethylamine (350 μΐ) and DCC (2.48 g, 12 mmol) are added and the solution is incubated under argon for 16 hours. The mixture is then filtered and the filtrate is diluted with 800 mL of ether. The resulting precipitate is collected on a glass frit and transferred to a refrigerator (4 ° C) for 72 hours. The resulting crystals are collected on a glass frit, washed with ice-cold ethanol (200 mL) and ether (3 x 200 mL) and dried under suction to form bis- [N - (4guanidinobenzoyl) -glycyl] -poly (ethylene glycol) methanesulsonate as ethylene glycol. white powder.

EXAMPLE 9. N- [4- (4-Guanidinobenzoyloxy) -benzoyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether:

A. N- (4-hydroxybenzyloxy) -2-aminoethyl-poly (ethylene glycol) monomethyl ether:

2-aminoethyl-poly (ethylene glycol) monomethyl ether (M _n = 5000, 1 g, 0.2 mmol), 4-hydroxybenzoic acid (0.14 g, 1.00 mmol) and HOBt (0.14 g, 1.00 mmol) is dissolved in 12 ml DMF.

· * «*

DCC (0.206 g, 1 mmol) was added to the reaction mixture and the reaction was allowed to stir for 18 hours under argon. The mixture is then filtered and the filtrate is diluted with 200 mL of diethyl ether. The resulting precipitate is collected on a glass frit, washed with ether, and dried under suction to give N- (4-hydroxybenzyloxy) -2-aminoethyl-poly (ethylene glycol) monomethyl ether as a white powder.

B. N- [4- (4-guanidinobenzoyloxy) -benzoyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether methanesulfonate:

The product of Step A (0.89 g, 0.18 mmol), 4-guanidinobenzoic acid methanesulfonate (0.25 g, 0.89 mmol), DMAP (0.02 g, 0.15 mmol) are dissolved in 10 mL DMF. DCC (0.18 g, 0.89 mmol) is added and the solution is incubated with stirring at room temperature under argon for 20 hours. The mixture is then filtered and the filtrate is diluted with 200 mL of ether. The resulting precipitate is collected on a glass frit, washed with ether. The precipitate is dissolved in hot ethanol (75 mL), filtered and transferred to a refrigerator (4 ° C) for 72 hours. The resulting crystals are collected on a glass frit, washed with ice-cold ethanol and diethyl ether, and dried under suction to form N- [4- (4-guanidinobenzoyloxy) -benzoyl] -2-aminoethyl-poly (ethylene-glycol) monomethyl ether methanesulfonate white powder.

EXAMPLE 10. N- (4-Benzamidino) -2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide:

NH • 1 4 4 4 4

99

A. N- (4-cyanobenzoyl) -2-aminoethyl poly (ethylene glycol) monomethyl ether:

2-aminoethyl-poly (ethylene glycol) monomethyl ether (M _n = 5000, 0.10 g, 0.02 mmol) and triethylamine (1.1 eq.) Are dissolved into 10 ml of dichloromethane. While stirring under argon, 4-cyanobenzyl chloride (1.1 eq.) Is added. The reaction is allowed to stir for 1 hour and then the mixture is diluted with ice ether to give N- (4-cyanobenzoyl) -2-aminoethyl poly ( ethylene glycol) monomethyl ether, which is collected as a white powder by filtration.

B. N- (4-Benzamidino) -2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide:

The product of Step A (0.06 g, 0.012 mmol) is dissolved in 3 mL of pyridine. Triethylamine is then added. The solution is saturated with hydrogen sulfide and incubated for 18 hours at room temperature with stirring. The green-brown solution is purged with argon and diluted with 5 mL of dichloromethane. The solution is then diluted with ether until a precipitate is formed. The precipitate is collected and transferred to another reaction vessel in 4 mL of p-dioxane. 0.2 ml of methyl iodide is added to the yellowish solution and the solution is incubated with stirring overnight at room temperature. The reaction mixture is concentrated under vacuum and then redissolved in 3 ml of methanol. To the mixture is added ammonium acetate (0.02g) and the mixture is refluxed for 4 hours. The methanol is then removed and the residue is washed with ice-ether. The result is N- (4-benzamidino) -2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide.

EXAMPLE 11. N- [4- (Aminoiminomethyl) phenyloxy] -acetyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide:

O

NH 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

99 99 99 99 99

A. N-bromoacetyl-2-aminoethyl poly (ethylene glycol) monomethyl ether: 2-aminoethyl-poly (ethylene glycol) monomethyl ether (M _n = 5000, 0.4 g, 0.08 mmol) and HOBt (0.1 g, 0 (8 mmol) are dissolved with 3 ml of dichloromethane. Bromoacetic acid (0.1 µg, 0.8 mmol) and DCC (0.17 g, 0.8 mmol) are added sequentially. NMP (0.5 mL) is then added and the reaction is allowed to stir at room temperature for 1 hour. The mixture is then filtered and the filtrate is poured into iced diethyl ether. This gave N-bromoacetyl-2-aminoethyl poly (ethylene glycol) monomethyl ether which was usable without further purification.

B. N- (4-cyanophenoxy) acetyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether:

The product of Step A together with 4-cyanophenol (0.03 g, 0.24 mmol) is transferred to the reaction vessel and dissolved in anhydrous DMF (5 mL). Anhydrous cesium carbonate (0.1 g, 0.32 mmol) is then added and the reaction is allowed to stir at room temperature for 18 hours. The cloudy solution is then filtered and the filtrate is concentrated in vacuo. Ether is added to the resulting solution to form a yellow precipitate which is collected and washed with ether. The resulting precipitate is dissolved in dichloromethane (2 mL) and after filtration the solution is poured into ether. A precipitate formed which was collected and washed with 10% isopropanol in ether and then ether and dried under suction. The crude product is recrystallized from hot ethanol to give N- (4-cyanophenoxy) acetyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether as a white powder.

C. N- [4- (aminoiminomethyl) phenyloxy] -acetyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide:

The product of Step B (0.06 g, 0.012 mmol) is dissolved in a mixture of triethylamine (200 μΐ) and pyridine (2 mL). The solution is saturated with hydrogen sulfide and incubated for 18 hours at room temperature with stirring. The green-brown solution is purged with argon and diluted with 1 mL of dichloromethane. The solution is then poured into ice-cold diethyl ether to form a precipitate, which is washed with ether and dried under suction. The precipitate is collected and transferred to another reaction vessel in 2 mL of p-dioxane and 02 mL of methyl iodide. The mixture is heated under argon at 50 ° C for 1.5 hours. The vapors are aspirated in vacuo and the residue is dissolved in methanol (2 mL). Ammonium acetate (0.02g,

0.2 mmol) and the mixture is heated under reflux in an argon atmosphere for 3 hours, cooled to room temperature and stirred overnight. The vapors are suctioned off in vacuo and the residue is titrated with 2 ml of dichloromethane, filtered and the filtrate is taken up in iced diethyl ether. The resulting product is collected, recrystallized from hot ethanol to give N- [4- (aminoiminomethyl) phenyloxy] acetyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide as a white powder.

·· · «··· · ·· ·· · ·· ·· 4 9 4 4

4 4 9 ·

4 9 4 4 4 4 9 9 9

4 4 4 4 4 4 4 4

44 444 944

EXAMPLE 12. N- [4- (Aminoiminomethyl) benzoyl] -glycyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide:

A. [N- (4-cyanobenzoyl) -glycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether: trifluoroacetate N-glycyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether (M _n = 5000, 0, 2 g, 0.04 mmol), together with 4-cyanobenzoyl (0.03 g, 0.24 mmol), is transferred to a reaction vessel and dissolved in pyrrine (2 mL and triethylamine (0.2 mL)) and then stirred for 3 hours The resulting precipitate is dissolved in dichloromethane (2 mL) and poured into iced diethyl ether to give a precipitate which is collected and washed with ether and dried under constant suction.The crude product is recrystallized from hot ethanol so that [N- (4-cyanobenzoyl) -glycyl] -2-aminoethyl-poly (ethylene glycol) monomethyl ether formed.

B. N- [4- (aminoiminomethyl) benzoyl] -glycyl-2-aminoethyl-poly (ethylene glycol) monomethyl ether iodide:

The product of Step A (0.14 g, 0.03 mmol) is dissolved in a mixture of triethylamine (200 μΐ) and pyridine (2 mL). The solution is saturated with hydrogen sulfide and incubated for 18 hours at room temperature with constant stirring. The green-brown solution is purged with argon and diluted with 1 mL of methylene chloride. Then it is

4444

4 44 44 4444

444 4 4,444 ·

44 4444 * 44

4444 4 4444

44 444 444 44 44 Pour the solution into ice-cold ether to form a precipitate, which is washed with ether and dried under suction. The precipitate is collected and transferred to another reaction vessel in 2 mL of p-dioxane and 0.2 mL of methyl iodide. The mixture is heated under argon at 50 ° C for 1 hour. The vapors are aspirated in vacuo and the residue is dissolved in methanol (2 mL). Ammonium acetate (0.013g,

0.17 mmol) and the mixture is heated under reflux in an argon atmosphere for 3 hours, cooled to room temperature and stirred overnight. The vapors are suctioned off in vacuo and the residue is titrated with 2 ml of dichloromethane, filtered and the filtrate is transferred to ice-ether. The resulting product is collected, recrystallized from hot ethanol to give N- [4- (aminoiminomethyl) benzoyl] -glycyl-2-aminoethyl-poly (ethylene glycol) mono-methyl ether iodide as a white powder.

EXAMPLE 13. N- [4- (2-Amino-2-iminomethyl) benzoyl] glycyl-poly (ethylene glycol) monomethyl ether iodide:

MeO ^'n OAI C1

DCC, HOBt → Et ₃ N, NMP, CH 2 Cl

NaCN

DMF

CF ₃ CO ₂ H

-► MeO '.O-

NH

HI nh ₂ 4 4 9 9

4 4 4 9

9 · · · · ·

44

4 9

9 · • · ♦

4 4 4

94

A. N- (4-chloromethylbenzoyl) -glycyl-poly (ethylene glycol) monomethyl ether:

Trifluorooctane-glycyl-poly (ethylene glycol) monomethyl ether (0.2 g, 0.04 mmol), HOBt (0.27 g, 0.2 mmol) together with 4-chloromethylbenzoic acid (0.034 g, 0.2 mmol) ) was transferred to a reaction vessel and dissolved in dichloromethane (2 mL) and NMP (1 mL). Then DCC (0.04 g, 0.2 mmol) and triethylamine (5.5 μΐ) are added and the solution is stirred at room temperature for 18 hours. The solution is filtered and the filtrate is poured into ether. A precipitate is formed which is collected and washed with isopropanol / ether (1: 1), then washed with ether and dried under suction to give N- (4-chloromethylbenzoyl) -glycyl-poly (ethylene glycol) monomethyl ether as a white powder.

B. N- (4-cyanomethylbenzoyl) -glycyl-poly (ethylene glycol) monomethyl ether:

The product of Step A (0.16 g, 0.032 mmol) is transferred to the reaction vessel and dissolved in DMF (5 mL). Sodium cyanide (0.016 g, 0.32 mmol) is then added and the reaction is run at 50 ° C for 2 hours. The temperature is then raised to 100 ° C for 30 minutes. The reaction mixture is allowed to cool to room temperature for 18 hours with stirring. The solution is washed with dichloromethane (2 mL) and filtered. The filtrate is collected and transferred to ether, washed with isopropanol / ether (1: 1) then ether and dried under suction to give N- (4-cyanomethylbenzoyl) -glycylpoly (ethylene glycol) monomethyl ether as a white powder. .

C. N- [4- (2-Amino-2-iminomethyl) -benzoyl] -glycyl-poly (ethylene glycol) monomethyl ether iodide:

The product of Step B (0.15 g, 0.03 mmol) is dissolved in a mixture of triethylamine (200 μΐ) and pyridine (2 mL). The solution is saturated with hydrogen sulfide and incubated for 18 hours at room temperature with stirring. The solution is purged with argon and diluted with 1 mL of dichloromethane. The solution is then poured into ice ether to form a precipitate, which is washed with ether and dried under suction. The precipitate is collected and transferred to another reaction vessel in 2 mL of p-dioxane and 0.2 mL of iodomethane. The mixture is heated under argon at 50 ° C for 1 hour. The vapors are aspirated in vacuo and the residue is dissolved in methanol (2 mL). Ammonium acetate (0.014g, 0.18 mmol) is added and the mixture is heated under reflux in an argon atmosphere for 3 hours, cooled to room temperature and stirred overnight. The vapors are suctioned off in vacuo and the residue is titrated with 2 ml of dichloromethane, filtered and the filtrate is transferred to ice-ether. The resulting product is collected, recrystallized from hot ethanol to give N- [4- (2-amino-2-iminomethyl) benzoyl] glycyl-poly (ethylene glycol) monomethyl ether iodide as a white powder.

EXAMPLE 14.

9 9 9

9 9

HCl

DCC, DMAP, DMF

Poly- (ethylene glycol) -3-propionic acid monomethyl ether (0.18 g, 0.033 mmol) is taken up in DMF (15 mL). P-Aminobenzamidine dihydrochloride (0.08 g, 0.33 mmol), DMAP (0.04 g, 0.33 mmol) and DCC (0.08 g, 0.33 mmol) are added and the reaction mixture is incubated under stirring. stirring at room temperature overnight. The mixture is then filtered and the filtrate is diluted with ether to form a precipitate, melted, and washed with ether (3X) to give a hygroscopic substance which turns into a powder after lyophilization.

EXAMPLE 15.

Boc-gly-OH, DCC, DMAP, DMF

2nd TFA, CH ₂ C1 ₂

· • * * * * * * * * * * * * * * * * * * * · · · · · · · · ······························································ I ·

A. Tetronic 908 ® (BASF) (1g, 0.04 mmol, Mn = 25,000 Da), a 4-arm poly (alkylene oxide) copolymer formed by the reaction of propylene oxide with ethylene diamine followed by reaction with ethylene oxide, are transferred to a reaction vessel with N- (tert-butoxycarbonyl) -glycine (0.28 g,

1.16 mmol) and DMAP (0.02 g, 0.16 mmol). The mixture is then dissolved in 15 mL of DMF and DCC (0.33 g, 1.6 mmol) is added. The reaction mixture is incubated with stirring for 24 hours at room temperature, then the mixture is filtered and the filtrate is transferred to ice ether. The resulting precipitate is collected by filtration and washed with ether.

B. The product of A is dissolved in 20 mL of dichloromethane and trifluoroacetic acid (15 mL) is added and the mixture is incubated at room temperature for 1 hour. The solution is then poured into ice-ether and the resulting precipitate is filtered, washed with ether and dried under suction.

C. The product from B (0.79 g, 0.03 mmol) is transferred to the reaction vessel along with 4-guanidinobenzoic acid methanesulfate (0.18 g, 0.63 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (0, 09 g, 0.64 mmol). The mixture is dissolved in DMF (10 mL) and triethylamine (0.1 mL) is added. Once the mixture has dissolved, DCC (0.13 g, 0.63 mmol) is added and the reaction is allowed to stir overnight at room temperature. The reaction mixture is then filtered and the filtrate is poured into ice-ether. The resulting precipitate is collected, washed with ether and recrystallized from hot ethanol to give the desired product as a colorless powder.

in· • * 49 * · • * • • · • Φ • • • · • • • • 9 • • • · • • »· • · • a • • 4 « • • »· • ·· • • · ··

EXAMPLE 16.

NH

NH Ni

A. Pluronic® 10-R8 (BASF) (1g, 0.22 mmol, Mn ~ 4500 Da) is transferred to a reaction vessel with N- (tert-butoxycarbonyl) -glycine (Boc-glycine) (0.77 g, 4 , 4 mmol) and DMAP (0.08 g, 0.7 mmol). The mixture is then dissolved in dry DMF and DCC (0.91 g, 4.4 mmol) is added. The reaction mixture is incubated with stirring overnight at room temperature, then the mixture is filtered and the reaction mixture is filtered. The filtrate is transferred to 200 ml of a 1: 1 mixture of diethyl ether / pentane. . The resulting precipitate is collected by filtration and washed with pentane and dried under suction.

B. The product from A (0.75 g, 0.16 mmol) is dissolved in 10 mL of dichloromethane and trifluoroacetic acid (10 mL) is added and the mixture is incubated at room temperature for 1 hour. The solution is then poured into 200 mL of diethyl ether / pentane 1: 1. The resulting precipitate is collected by filtration and washed with pentane and dried under suction.

C. The product from B (0.5 g, 0.11 mmol) is transferred to the reaction vessel along with 4-guanidinobenzoic acid mesylate (0.61 g, 2.2 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (0, 3 g, 2.2 mmol). The mixture is dissolved in DMF and then DCC (0.45 g, 2.2 mmol) is added and the reaction is allowed to stir overnight at room temperature. The reaction mixture is then filtered and the filtrate is poured into 200 ml of diethyl ether / pentane 1: 1. The resulting precipitate is collected by filtration, dissolved in hot ethanol and cooled to 0 ° C to form a white precipitate. It is collected, washed with pentane and dried under suction

EXAMPLE 17.

O,; o

O

o> R .O

TFA cm · · · ·

A. Branched poly (ethylene glycol) (1g, 0.1 mmol, Mn ~ 10,000 Da), N- (tert-butoxycarbonyl) glycine (Boc-glycine) (0.7 g, 4.0 mmol) and DMAP (0 , 49 g, 4.0 mmol). are dissolved in DMF and DCC (0.83 g, 4.0 mmol) is added. The reaction mixture is incubated with stirring for 18 hours at room temperature under an argon atmosphere. The mixture is then filtered and the filtrate is transferred to ice-cold ether. The resulting precipitate is a star-shaped octa-N- (tert-butoxycarbonyl) -glycylpoly (ethylene glycol) which was collected by filtration and dried.

9

9

9 ·

9 ·

9 9

9999 9 9 9999

99 99 99 99 99

B. The product of A is dissolved in 50% trifluoroacetic acid (10 mL) in dichloromethane and the solution is incubated at room temperature for 3 hours. The solution is then poured into ice ether and the resulting star-octa-glycyl-poly (ethylene glycol) is filtered as the trifluoroacetate salt.

C. The product from B (0.5 g, 0.05 mmol) is transferred to the reaction vessel along with 4-guanidinobenzoic acid mesylate (1.1 g, 4.0 mmol), triethylamine (1 eq.) And 1- hydroxybenzotriazole hydrate (HOBt) (0.54 g, 4.0 mmol). The mixture is dissolved in DMF (25 mL) and DCC (0.83 g, 4.0 mmol) is added and the reaction is allowed to stir at room temperature for 18 hours. The reaction mixture is then filtered and the filtrate is poured into ice-ether. The resulting precipitate is collected, washed with ether to give the desired product.

Methods of using the present invention

The compositions and methods of the present invention are useful in medical and skin, hair, oral cavity and beauty care products. Furthermore, the compositions of the present invention are useful for detergents, rough surface cleaners, horticultural compositions, surface coating compositions, and other applications where inhibition of enzymes enhances process efficiency. Non-limiting examples of applications where the compositions of the present invention find use may include susceptibility, acne, periodontal disease, and obesity. These substances are also useful as contraceptives and in targeted drug delivery systems. These agents are enzyme inhibitors including lipases, serine proteases, metalloproteases, cysteine proteases, and aspartic proteases. More specifically, such as lipase, carboxypeptidase A, chymotrypsin, elastase, trypsin, and leucine aminopeptidase. The following substances, compositions and methods are not a limitation of the present invention, but merely show one skilled in the art how to use the substances, compositions and methods of the present invention.

Determination of the specificity of enzyme inhibitors for some particular enzymes is demonstrated by the ability of one of ordinary skill in the art. Corresponding techniques, both in vitro and in vivo, which are used to determine enzyme activity are well known in the art and can be found in the literature. The agents of the present invention can be tested for their inhibitory activity against, for example, lipase, carboxypeptidase A, chymotrypsin, elastase, trypsin, and leucine aminopeptidase. For the sake of clarity, examples of techniques for determining the inhibitory activity of these compounds against proteolytic and lipolytic enzymes are provided.

EXAMPLE A: Determination of Fecal Protease Inhibition

To illustrate the determination of inhibitory activity of the disclosed compounds to the fecal protease, the compounds of the present invention may be tested by standard enzyme technique for protease activity.

Rain feces are collected to prevent urine contamination and diluted 1: 4 with water. This mixture is then thoroughly mixed to form a homogeneous mixture by homogenization or sonication. Thereafter, the solution is diluted with the reaction buffer described below to obtain a feces concentration such that after addition of the protease substrate, the hydrolysis proceeds for 5 to 60 minutes. Using this technique, the activity of, eg, fecal trypsin at pH 8.2 in 50 nM Tris-HCl buffer with 20 mM CaCl 2 containing 0.3 mM test composition, fecal chymotrypsin at pH 7.6 in 50 mM Tris can be determined -HCl buffer with 20 mM CaCl 2 containing 0.05 mM test composition, fecal leucine aminopeptidase at pH 7.2 in 50 nM sodium phosphate containing the test composition. To test the effectiveness of the compositions, several different concentrations of each composition in doublets in the faecal extract and the appropriate reaction buffer should be tested and their inhibitory activity determined. Substances with an IC50 of 100 μΜ or less are the most suitable substances of the present invention. Substances with an IC50 of 90 μΜ or less are better, and substances with an IC50 up to IC90100 μΜ or less are best.

EXAMPLE B: In vitro skin assay to inhibit IL-1? Production

The in vitro technique for determining the efficacy of the compounds of the present invention in preventing skin inflammatory response to feces and enzymes present in feces may be as follows: Human keratinocytes are obtained from epidermal tissue and incubated in serum free medium on nylon cotton until uniformly grown. The nylon wadding is then lifted to the liquid-air interface, causing differentiation and formation of multilayered organized structures, similar to those found in tissue in vivo, including the stratum corneum barrier. Any other incubation tissue system that results in the growth and differentiation of keratinocytes can be used. Cell culture systems such as Epiderm ® (MatTek Corporation) are commercially available.

Baby feces are collected to prevent urine contamination and diluted in phosphate buffered saline (PBS) (pH 7.2 to 7.4). The mixture is then thoroughly mixed to obtain a homogeneous suspension by homogenization or sonication. An aliquot of the homogenate diluted with PBS is then applied to the surface of the control culture in a culture vessel. A predetermined amount of potential inhibitor (substance) is added to completely identical aliquots of the homogenate prior to addition to the surface of the test culture. Test cultures are incubated in a controlled atmosphere. At selected times, control cultures and cultures growing in the presence of test inhibitors and support culture are harvested and tested. The assay is performed using a standard technique for detecting the presence of IL-1α. A suitable technique for such an assay is an enzyme-linked immunosorbent assay (ELISA), commercially available as Quantikin ® from R&D Systems.

The rate of reduction of IL-1α production given by the presence of inhibitors of the present invention was calculated as follows:

% reduction = (IL-1α from control cultures - IL-1α from test cultures) IL-1α from test cultures

Use of the compounds of the present invention in absorbent pads

For example, the compounds of the present invention are useful for the prevention and treatment of disorders such as inflammation, irritation and / or skin injury along with disorders such as sore spots.

The substances according to the invention can be applied to the skin in the affected areas also in the form of so-called absorbent pads. As used herein, the term "absorbent pads" describes articles intended to absorb and absorb body fluids. Examples include feminine hygiene items, sanitary napkins, tampons, napkins, diapers, wetting briefs, diaper panties, sportswear components, and the like.

The most suitable absorbent pad is a diaper. The term &quot; diaper &quot; as used herein describes an absorbent pad commonly used by infants and those suffering from wetting, dressed on the lower body. The term includes all types of diapers, sanitary napkins, diapers for people suffering from wetting, and the like.

Substances useful for use in the present invention are described, for example, in U.S. Patent Applications 08 / 926,532 and 08 / 926,533, filed September 10, 2006. 1997, U.S. Patent 5,607,760, filed on March 4, 2003. 1997, U.S. Patent 5,609,587, filed March 11, 1997; 1997, U.S. Pat. No. 5,635,191, filed on Jun. 1997 and US Patent 5,643,588, filed Jul. 1997.

In a most preferred variant of the invention, the compositions of the invention comprise the substances of the invention and a carrier. In addition to its function as a vehicle to deliver an effective concentration of the compounds of the present invention to the affected skin, the composition may also contain components that reduce adherence of feces to the skin and thereby create a protective barrier while also having a therapeutic effect on the skin. improve skin health) and the like.

• · · ·

The compounds of the present invention may be applied to the absorbent pad either as a pure, dried powder, or may be incorporated as, for example, aqueous pharmaceutically and dermatologically acceptable solutions. By aqueous solutions are meant any solution in a hydrophilic vehicle, but not only in water, alcohol, polymer hydrogels, weak base, metal salt and / or the like, wherein the vehicle does not interfere to a detectable extent with the inhibitory activity of the compounds of the present invention. The substance of the present invention may also be diluted in a water-in-oil emulsion in a hydrophobic composition and / or as an aqueous component of an oil-in-water emulsion. It is desirable that the substance does not have a pH adjusted since the pH of the starting composition should be in the range of 3.5 to 9.5, depending on the intended location in the absorbent pad, it is desirable that the substance / composition of the present invention be in direct contact the skin has a pH of not less than 3.5 and not more than 7.5, preferably a pH in the range of 6.8 to 7.4. When the composition of the present invention is applied in the form of an absorbent pad, it contains a safe and effective amount of according to the present invention. In such a case, the composition of the present invention should contain from 0.01% to about 20%, preferably from 1% to about 10%, and most preferably about 10% of the substance of the present invention.

Obviously, of a variety of materials used as carriers in skin care compositions and applicable to the compounds of the present invention, those that are safe and effective are preferred. These are Category 1 materials, according to the US Federal Food and Drug Administrations (FDA) classification of substances intended for human skin protection products (21 CFR § 347), which currently includes: alantoin, aluminum hydroxide gel, calamine, cocoa butter, dimethicone, cod liver oil (in combination), glycerin, kaolin, petrolatum, lanolin, mineral oil, shark liver oil, white petrolatum, talc, surface starch, zinc acetate, zinc carbonate, zinc oxide and alike. Other useful materials are listed in Category 3 as defined by FD A, which currently includes: live yeast culture derivatives, aldioxa, aluminum acetate, microporous cellulose, cholecalciferol, colloidal oatmeal, cysteine chloride, dexpantenol, Peruvian balsam oil, protein hydrolyzate, racemic methionine, sodium bicarbonate, vitamin A and the like.

Many of the materials listed in FD A are currently used in commercially available skin care products such as A and D® Ointment, Vaseline® Petroleum Jelly, Desitin® Diaper Rash Ointment and Daily Care® Ointment, Gold Bond® Medicated Baby Powder , Aquaphor® Healing Ointment, Baby Mgic® Baby Lotion, and Johnson's Ultra Senzitive® Baby Cream. The effective concentration of the compounds of the present invention may be the same as those of these commercial products, but the compounds of the present invention may be applied in the form of an absorbent pad or applied directly to the skin. As discussed below, compositions useful for transferring the compounds of the present invention to the skin should have a melting point that is rather immobile and placed on a surface that is in contact with the skin at room temperature and is most easily transferable to the skin at body temperature and does not liquefy. unless they are exposed to extreme conditions. Suitably, the compositions of the present invention are transferable to the skin by normal contact, clothing movement and body heat. Because most of the compounds of the present invention remain tightly bonded to the composition, there is no need for too much of them to achieve the desired effect.

In a most preferred particular variant, the compositions of the present invention are oil solutions or water-in-oil emulsions. The compounds of the present invention may be solids per se or at least semi-solids at room temperature, but under certain conditions they may liquefy. This is due to the fact that while the compositions contain liquid substances in addition to solids. Suitably, the compounds of the present invention have a shear viscosity of from about 1.0 x 10 ⁶ centipose to about 1.0 x 10 centipose, more preferably from about 5.0 x 10 centipose to about 5.0 x 10 centipose. As used herein, "zero shear viscosity" means the viscosity measured at very low shear torque (e.g., 1.0 sec ') using a flat and conical viscometer (a suitable instrument is available from TA Instruments of New Castle, DE as model no. CSL 100

The most suitable compositions are maximally semi-liquid at room temperature to prevent their transfer. In addition, the compounds of the present invention should have a final melting point higher than the potential maximum storage temperature, i.e. greater than 45 ° C. Examples of such compositions are detailed in: US Patent 5,643,588, US Patent 5,607,760, US Patent 5,609,587, US Patent 5,635,191. In particular, the most suitable substances should have a melting profile of:

Characteristics Appropriate range The most suitable range % liquid at room temperature temperature (20 ° C) 2-50 3-25 % liquid at body temperature (36 ° C) 25-95 30-95 Melting point (° C) > 38 > 45

• * • · Β * Β Β

In order to increase the immobility of the proposed compositions, the viscosity of the compositions of the present invention should be as high as possible to prevent leakage of the compositions of the present invention to undesirable locations. Unfortunately, too high a viscosity prevents the passage of substances onto the skin. It is therefore necessary to achieve equilibrium such that the viscosity is high enough to keep the composition of the present invention on the surface of the pad, but not high enough to prevent the passage of the active ingredients into the skin. Thus, a suitable viscosity range is from about 5 to about 500 centipoise, more preferably from about 5 to about 300 centipoise, and most preferably from about 5 to about 100 centipoise, measured at 60 ° C using a rotary viscometer (e.g., a Lab Line Instrumens, Inc. Melrose Park, IL, Model 4537). The viscometer was operated at 60 rpm using rotor 2.

Compositions intended to provide therapeutic and / or protective benefit to the skin, in addition to the inhibitory properties due to the presence of an enzyme inhibitor, may contain other active skin care ingredients such as preservatives and skin softening agents. As used hereinafter, the term &quot; skin softener &quot; is a skin protecting agent against wetting, irritation, softening, softening, coating, moisturizing and cleansing. It is known that some of the above compositions are plasticizers. In the most suitable variation of the present invention, the plasticizer is either plastic or liquid at room temperature (i.e., about 20 ° C).

Examples of plasticizers useful in the compositions of the present invention are those based on petroleum derivatives, sucrose fatty acid esters, polyethylene glycol and derivatives thereof, certain fatty acid esters, alkyl ethoxylates, fatty acid ethoxylates, high unsaturated alcohols, polysiloxanes, propylene glycol and derivatives thereof , glycerine and derivatives thereof, including glyceride, acetoglycerides, and ethoxylated glycerides of C ₂ to C ₂ with fatty acids, triethylene glycol and derivatives thereof, spermaceti or other waxes, fatty acids, ethers of higher unsaturated alcohols, and particularly those having from about 12 to about 28 carbon atoms in the chain such as stearic acid, propoxylated high unsaturated alcohols, other fatty esters of polyhydroxylated alcohols, lanolin and its derivatives, kaolin and its derivatives, any other humectant mentioned above the monograph and mixtures thereof. Suitable petroleum derivative plasticizers are such hydrocarbons or hydrocarbon mixtures having a chain length of from about 16 to about 32 carbon atoms. Petroleum derivative plasticizers having such properties are mineral oils and petroleum (also known as mineral wax, petroleum gel and mineral gel). Suitable plasticizers based on esters of fatty acids are those which are derived from C ₂ to C ₂ -C 8 fatty acids, preferably from _CI6-C22 saturated fatty acids and monohydric ······ ·· · · · · · ·· * · »* * * ♦ · · · · · · * * * * * * * * * Short-chain alcohols (C1 to C8 preferably C1 to C3). Examples of such esters are methyl palmitate, methyl stearate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, ethylhexyl palmitate and mixtures thereof. Suitable humectants based on fatty acid esters may also be derived from high long chain unsaturated alcohols (C12 to C28 preferably C12 to C16) and short fatty acids such as lactic acid, lauryl lactate and cetyl lactate.

Suitable alkyl ethoxylate plasticizers are those derived from C12 to C22 high unsaturated alcohol ethoxylates having a degree of ethoxylation of from about 2 to about 30. Suitably, the high unsaturated alcohol ethoxylate plasticizers are lauryl, cetyl and stearyl ethoxylates and mixtures thereof with ethoxylation rates ranging from 2 to 23. Examples include laureth-3 (lauryl ethoxylate with an average ethoxylation degree of 3), laureth-23 (lauryl ethoxylate with an average degree of ethoxylation of 23), ceteth-10 (cetyl alcohol ethoxylate with an average degree of ethoxylation of 10) and stearetheth -10 (stearyl alcohol ethoxylate with an average degree of ethoxylation of 10). In use, these ethoxylate-based plasticizers are typically used in combination with petroleum derivative plasticizers, such as petrolatum, in a weight ratio of ethoxylate plasticizer with petroleum derivative plasticizers of from about 1: 1 to about 1: 5, preferably from about 1: 1 to about 1: 5. 1: 2 to 1: 4.

Suitable plasticizers based on high unsaturated alcohols are those derived from C12 to C22 high unsaturated alcohols, more preferably C16 to _C18 high unsaturated alcohols. Examples are cetyl alcohol and stearyl alcohol and mixtures thereof. In use, these high unsaturated alcohol softeners are typically used in combination with petroleum derivative plasticizers such as petrolatum in a weight ratio of high unsaturated alcohol plasticizers with petroleum derivative plasticizers from about 1: 1 to about 1: 5 preferably from 1: 1 to 1: 2.

Other suitable types of plasticizers useful in the compositions of the present invention are, for example, polysiloxane plasticizers. The polysiloxane plasticizers useful in the compositions of the present invention are those having a monomer of the general formula:

Where R ¹ and R ² for each independent siloxane monomer unit may be hydrogen, alkyl, aryl, alkenyl, cycloalkyl, halogenated hydrocarbon or other radical. Any of these radicals may or may not be substituted. R and R for each of the independent siloxane monomer units of the unit are: &lt; tb &gt;&lt; tb &gt; ______________________________________ &lt; tb &gt; may differ in corresponding structures relative to the following unit. In addition, the polysiloxane may be either a straight chain, a branched chain, or a ring structure. The radicals R ¹ and R ^2, for each independent siloxane monomeric unit can independently be other silicone structures such as siloxanes, polysiloxanes, silanes, and polysilanes. R ¹ and R ² may also contain a number of organic functional groups such as alcohol, carboxylic acid, phenyl and amine.

Exemplary alkyl radicals include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, octadecyl and the like. Examples of alkenyl radicals are vinyl allyl and the like. Examples of aryl radicals are phenyl, diphenyl, naphthyl and the like. Examples of arylalkyl radicals include benzyl, phenylethyl, phenylbutyl, tolyl, xylyl and the like. Examples of cycloalkyl radicals are cyclobutyl, cyclopentyl, cyclohexyl and the like. Exemplary halogenated radicals include chloromethyl, bromomethyl, tetrafluoroethyl, fluoroethyl, trifluoroethyl, triflorotolyl, hexafluoroxylyl and the like.

The viscosity of the polysiloxanes useful in the compositions of the present invention may vary as the viscosity of the polysiloxanes usually varies, but they need to remain fluid or must be prepared prior to application to the liner. That is, the viscosity could range from about 5 centistokes (measured at 37 ° C with a glass viscometer) to 20,000,000 centistokes. However, it is preferable that the polysiloxanes at 37 ° C have a viscosity in the range of from 5 to 5,000 centistokes, more preferably from 2 to 2,000 centistokes, and most preferably from 100 to about 1,000 centistokes. Highly viscous polysiloxanes that are not too fluid may be deposited on the liner by techniques such as the emuzification of polysiloxanes in a surfactant, or by deposition of polysiloxanes in a solvent such as hexane. A more detailed description of the polysiloxane deposition methods is discussed in detail below.

The most suitable polysiloxanes for use in the compositions of the present invention are described in U.S. Patent 5,059,282 to Amplulski et al., Filed in October 1991. The most suitable polysiloxanes for use in humectants in the compositions of the present invention are phenyl radical polymethylsiloxanes (e.g., DowCorning 556 Cosmetic). Grade Fluid: polyphenylmethylsiloxane) and cetyl or sterryl-linked dinethicones such as Dow 2502 and Dow 2503. In addition to these with phenyl or alkyl functions, amino, carboxy, hydroxy, ether, polyether, aldehyde, concrete, amide, ester and thiol groups. Of these substituent groups, phenyl, amino alkyl, carboxyl and hydroxyl groups are preferred, but more preferably phenyl.

99

9, 9, 9 • 9

9 9 9

9 9 ·

When used, the amount of emollient depends on a variety of factors, including the type of particular emollient used, the desired skin effect, other formulation components, and the like. The composition of the present invention should contain from 0% to 99.99% of the total weight of the plasticizer. Preferably, the composition comprises from 10% to 95%, more preferably from 20% to 80%, and most preferably from 40% to 75% of the total weight of the plasticizer.

Useful humectants are glycerin, propylene glycol, sorbitol, trihydroxystearin and the like.

Another optional component of suitable skin care compositions is an agent capable of immobilizing the composition (including substances, the most suitable emollient, and / or other therapeutic / protective components) at the desired location or insert. Since some useful plasticizers of the present invention have a liquid or semi-liquid consistency at 20 ° C, they tend to drain, especially when subjected to pressure. Once applied to a surface that is in direct contact with the skin, or when absorbed into the liner, especially in dissolved or molten form, the emollient will generally not be held in place. Instead, they begin to drain and leak into the undesirable places of the liner.

In particular, these plasticizers soak into the liner, which impairs their ability to absorb, since most plasticizers are highly hydrophobic in nature of the emollients and other substances used in the compositions of the present invention. This also means that a much higher amount of plasticizer needs to be applied to the liner to achieve the desired therapeutic and / or preventive effect. Increasing the amount of plasticizer will increase not only the cost but also the undesirable effect on the absorbent activity of the core of the liner and the unwanted transfer of the composition during manufacture and modification of the liner.

The purpose of the immobilizing agent is to prevent the emollient from moving by retaining it on the surface of the insert to which it has been applied. This is mostly because the immobilizing agent increases the melting point and / or viscosity of the composition to a higher value than the plasticizer. Since the immobilizing agent is usually miscible with the emollient (or soluble in the emollient with the addition of an emulsifier), the emollient will then retain the emollient at a predetermined location on the surface of the liner or at the site to which it is applied.

It is also an advantage to provide an immobilizing agent on the surface of the liner that comes into contact with the body to which it is initially applied. This can be achieved using an immobilizing agent that solidifies rapidly upon application to the surface of the liner. In addition, cooling of the coated inserts by means of fans, fans, etc. can be accelerated by crystallization of the immobilizing agent.

In addition to being miscible (or soluble) in the plasticizer, the immobilizing agent should have a melting point profile such that it behaves as a solid at room temperature. In this regard, it is preferred that the agent has a melting point of at least 35 ° C. This will ensure that 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 ttt ttt 99 99 the immobilizing agent will not in itself migrate to undesirable areas. More preferably, this agent has a melting point of at least 40 ° C. Typically, however, the agent will have a melting point of from about 50 ° C to about 150 ° C.

When used, the useful immobilizing agent may be selected from a list of substances commonly used for this purpose so as not to interfere with the primary role of the composition - by inhibiting enzymes and not adversely affecting the skin. The most suitable immobilizing agent will be, for example: Cm to C22 high unsaturated alcohol, C12 to C22 fatty acid and Cn to C22 high unsaturated alcohol ethoxylate with an average degree of ethoxylation of 2 to 30 and mixtures thereof. However, the most suitable immobilizing agent will be a Cm to C18 high unsaturated alcohol, more preferably a high melting point crystalline material such as: cetyl alcohol, stearyl alcohol, behenyl alcohol, and mixtures thereof. Mixtures of cetyl and stearyl alcohol are most preferred. Another preferred immobilizing agent is a C ₁₆ to C 18 fatty acid, such as: palmitic acid, stearic acid, and mixtures thereof. Mixtures of palmitic acid and stearic acid are most suitable. Another preferred immobilizing agent is the high unsaturated alcohol Cm to Cm ethoxylate with an average degree of ethoxylation of from 5 to 20. The most suitable high unsaturated alcohols, fatty acids and high unsaturated alcohol ethoxylates are linear. It is important that these suitable immobilizing agents such as Cm to Cg high unsaturated alcohols increase the crystallization rate of the composition of the present invention so that it crystallizes very rapidly on the surface of the substrate.

Of course, other types of immobilizing agents, such as polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and mixtures thereof may also be used. Most preferred esters and amides will contain three or more free hydroxy groups and are usually nonionic in nature.

Since the sensitivity of some individuals to these substances is documented, it is necessary to select such derivatives not to irritate the skin.

The polyhydroxy fatty acid esters suitable for use in the compositions of the present invention will have the following general formula:

Where R is a C 5 to C 31 carbon group, preferably C 7 to C 19 alkyl or alkenyl, more preferably linear C 9 to C 17 alkyl or alkenyl, and most preferably linear C 11 to C 17 alkyl or alkenyl, or mixtures thereof, Y is a polyhydroxyhydrocarbyl group having at least 2 free hydroxyls • · ··· ·

attached directly to the chain and n is at least 1. A suitable Y may be, for example, a polyol such as glycero, pentaerythrol, a sugar such as raffinose, maltodextrose, galactose and sucrose, glucose, fructose, maltose lactose mannose and erythros. , mannitol and sorbitol, and sugar alcohol anhydrides such as sorbitan.

One class of suitable polyhydroxy fatty acid esters useful in the compositions of the present invention are sorbitan esters, preferably C ₁₆ -C ₂₂ sorbitan esters. Due to the production method, these sorbitan esters usually contain mixtures of mono-, di-, etc. esters. Examples of suitable sorbitan esters are sorbitan palmitate (eg SPAN 40), sorbitan stearate (eg SPAN 60) and sorbitan behenate, which contain several mono-, di-, tri-, ester versions of such sorbitan, such as sorbitan mono- , di-, tri-palmitate, sorbitan mono-, di-, tristearate and sorbitan mono-, di-, tri-behenate. Mixtures of different sorbitan esters can also be used as sorbitan palmitate and sorbitan stearate. The most suitable sorbitan esters are sorbitan stearate esters, especially sorbitan mono-, di-, tri-stearate and some tetraesters such as SPAN 60 and sorbitan stearate sold under the tradename GLYCOMUL-S by Lonza, Inc. Although these sorbitan esters usually contain a mixture of mono-, di-, tri-esters and some tetraesters, mono-, di-, tri-esters are the major component of the mixture.

Another class of fatty acid esters useful in the compositions of the present invention are some glycerol monoesters, preferably glycerol monoesters of C 16 to C 22 saturated fatty acids such as glyceryl monostearate, glyceryl monopalmitate and glyceryl monobehenate. Furthermore, as with sorbitan esters, glyceryl monoesters usually contain a proportion of di- and tri-esters. The compositions useful in the present invention should contain a maximum proportion of glyceryl monoesters.

Another class of useful polyhydroxy fatty acid esters are sucrose fatty acid esters, preferably C 12 to C ₂₂ sucrose saturated fatty acid esters. Sucrose monoesters and diesters are most suitable and include sucrose mono- and di-stearate and sucrose mono- and di-laurate.

Suitable polyhydroxy fatty acid amides useful in the compositions of the present invention will have the following general formula:

O R

II I

N — Z

4 4 4 4 4 4

Where R ¹ is a C 1 -C 4 hydrocarbyl group, 2-hydroxyethyl, 2-hydroxypropyl, methoxyethyl, methoxypropyl or mixtures thereof, preferably C 1 -C 4 hydrocarbyl alkyl, methoxyethyl, or methoxypropyl, more preferably C 1 -C 2 alkyl or methoxypropyl, and most preferably C 1 -C 4 alkyl. alkyl (methyl) or methoxypropyl and wherein R ² is a C ₅ to C ₃ hydrocarbyl group, preferably a C 8 to C 8 alkyl or alkenyl, more preferably a linear C ₁₁ to C ₁₇ alkyl or alkenyl or mixtures thereof, Z is a polyhydroxyhydrocarbyl group with a linear chain containing at least 3 free hydroxyls attached directly to the chain and n is at least 1. See U.S. Patent 5,174,927, filed December 1992, Hosa, which describes polyhydroxy fatty acid amides and their preparation. The group Z is usually derived from a reducing sugar by a reductive amination reaction, preferably glycityl. Suitable reducing sugars are glucose, fructose, maltose, lactose, galactose, mannose, and xylose. Corn syrup containing high dextrans, Corn syrup containing fructose and Corn syrup containing high maltoses can also be used, as well as the individual sugars mentioned. These corn syrups give rise to a mixture of sugar components for the Z group.

Most preferred Z is: -CH 2 - (CHOH) _n -CH ₂ OH, -CH (CH ₂ OH) - [(CHOH) _{n -} ] - CH ₂ OH, CH ₂ OH-CH ₂ - (CHOH) 2 - (CHOR ³ ) - (CHOH) -CH ₂ OH, wherein n is in the range of from 3 to 5 and R is H or a cyclic or aliphatic monosaccharide. Most preferred are glycityls wherein n is 4, particularly -CH 2 - (CHOH) 4 -CH ₂ OH.

In the above general formula, R ^{1 can} be, for example, N-methyl, N-ethyl, N-propyl, Nisopropyl, N-butyl, N-2-hydroxyethyl, N-methoxypropyl or N-2-hydroxypropyl. R ² can be, for example, cacamides, stearamides, oleamides, lauramides, myristamides, capricamides, palmitamides, tallowamides etc. The group can be 1-deoxyglucityl, 2-deoxyfructityl, 2deoxymaltityl, 2-deoxylactityl, 1-deoxygalactityl, 2-deoxygalactityl deoxyfructityl, 2deoxymaltotriotityl etc.

The most preferred polyhydroxy fatty acid amide will have the following general formula:

OH I

CH - _CH2 OH - 4

Wherein R ^{1 is} methyl or methoxypropyl and wherein R ² is C 11 -C ¹⁸ linear alkyl or alkenyl. It can be N-lauryl-N-methylglucamide, N-cocoyl-N-methoxypropylglucamide, N-palmityl-N-methoxypropylglucamide, N-tallowyl-N-methylglucamide, N-tallowyl-N-methoxypropylglucamide.

OR ¹ Η I

-C ~ N ~ _CH2 ·

9 · 9 9 9 9 9 9 9 9

9 9 · · 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

99 99 99 99 99

As mentioned previously, some immobilizing agents may require an emulsifier to dissolve in the plasticizer. These are mostly some glucamides, such as N-alkyl-N-methoxypropylglucamides with an HLB value of at least 7. Suitable emulsifiers should have an HLB value of usually below 7. In this regard, the aforementioned sorbitan esters such as sorbitan stearate having HLB about 4.9 and less, are useful for dissolving glucamide-based immobilizing agents in tetrolate. Other useful emulsifiers are steareth-2 (polyethylene glycol ether of stearyl alcohol of the formula CH ₃ (CH 2) 17 (OCH ₂ CH ₂ ) _n OH, where n has an average value of 2, sorbitan tristearate, isosorbitan laurate and glyceryl monostearate. For example, an approximately 1: 1 mixture of N-cocoyl-N-methylglucamide and petrolatum which cannot be mixed under normal conditions, after adding 20% of a 1: 1 mixture of Steareth-2 and sorbitan tristearate, easily mix them into single phase.

Other ingredients that may also be useful as immobilizing agents, either alone or in combination with the above immobilizing agents, including wasps such as kamaub palm wax, ozokerite, beeswax, candelilla wax, paraffin, ceresin, cava wax Refractory, isioparaffin and other commonly used mineral waxes. The high melting point of these waxes helps to immobilize the compositions of the present invention at the desired location. Adding microcrystalline waxes is an effective immobilization strategy. Microcrystalline waxes are capable of immobilizing low molecular weight hydrocarbons at a desired location. The most suitable wax is paraffin. An example of a most suitable immobilizing agent is a paraffin wax such as Paraffin S.P. 434 from Strahl and Pitsch, Inc., West Babylon, NY.

The amount of useful immobilizing agents that can be used in the compositions of the present invention depends on a variety of factors including the emollient used, the immobilizing agent used, the other ingredients of the composition, the necessity of using an emulsifier to dissolve the immobilizing agent, and other factors. When used, the immobilizing agent will typically comprise from about 5% to about 90% of the composition, more preferably from about 5% to about 50%, and most preferably from about 10% to about 40%, by weight of the composition.

Suitably, at least the top of the insert is made of a hydrophilic material so that fluids (e.g., urine) can pass well through. It is also desirable that the composition be wettable enough that fluids pass rapidly through the topsheet. Another option is to use a hydrophobic skin care composition as long as the fluid changes the properties of the topsheet, the skin is maintained in order (as discussed below, non-uniform application of the composition to the pad surface is one way to achieve this effect). The bodily fluids to be absorbed pass through the topsheet into the core of the liner and the topsheet remains essentially • 4

44

4 ·

4 ·

4 4

4 4 4

44 dry and pleasant to the skin. If a hydrophobic composition is used, depending on the particular composition, a hydrophilic surfactant (or a mixture of hydrophilic surfactants) is required to increase wettability. For example, some immobilizing agents such as N-cocoyl-N-methoxypropylglucamide have an HLB of at least 7 and are sufficiently wettable even without the addition of a hydrophilic surfactant. Other immobilizing agents such as C16 to Cu high alcohols with an HLB value of less than 7 require the addition of a hydrophilic surfactant to increase the wettability of the composition after it is applied to the surface of the pad. Similarly, hydrophobic plasticizers, such as petrolatum, also require the presence of a hydrophilic surfactant if the resulting composition is to be hydrophilic. Of course, the wettability of the liner is not essential if the skin-contacting surface is different than the surface of the liner, or if the wettability is otherwise achieved (e.g., uneven application).

Suitable hydrophilic surfactants should be miscible with the skin care compositions so that they can form a homogeneous mixture. Due to the possible skin sensitivity of some individuals using the compositions of the present invention, these surfactants should be soft and non-irritating to the skin. These surfactants are usually non-polar and thus inert to the skin, but also to the other ingredients of the liner and composition of the present invention. An undesirable effect may be to break the tensile strength and reduce the adhesive bonds and the like.

Suitable non-polar surfactants are generally immovable after the composition is applied to the liner and their HLB value should be in the range of about 4 to 20, preferably 7 to about 20. To prevent their movement, the melting point should be higher than the normal temperature expected for proper storage, transport, sale and use of these products, i. higher than at least 30 ° C. Accordingly, the non-polar surfactants described herein should have a melting point similar to that discussed above for the immobilizing agent.

Suitable non-polar surfactants to be used in skin care compositions and compositions that are applied to the pads, at least in the area of liquid absorption, are, for example: alkyl glycosides, alkyl glycoside esters as described in U.S. Patent 4,011,389 filed 8.4. 1997, Langdom et al., Alkylpolyethoxylated esters such as Pegosperse 1000MS (available from Lonza Inc. Fair Lawn, NJ), ethoxylated sorbitan mono-, di- and / or tri-esters of C 12 to C 18 fatty acids with an average degree of ethoxylation of about 2 to about 20, preferably from 2 to 10, such as TWEEN 60 (sorbitan stearic esters with an average degree of ethoxylation of about 20) and TWEEN 61 (sorbitan stearic esters with an average degree of ethoxylation of about 4) and condensation products of aliphatic alcohols containing from 1 to 54 moles of ethylene oxide. Alkyl chain

9 • 99

9 9

9 9 9

9 9

99

9 9 9

9 9 ·

9 9 9

The aliphatic alcohol is usually linear and contains from 8 to about 22 carbon atoms. The condensation products of alcohols with an alkyl group containing from about 11 to 22 carbons and about 2 to 30 moles of ethylene oxide per mole of alcohol are also suitable. Examples of such ethoxylated alcohols are myristyl alcohol condensation products containing from 7 moles of ethylene oxide per mole of alcohol, coconut alcohol condensation products (a mixture of high alcohols with alkyl chains of 10 to 14 carbon atoms) containing from 6 moles of ethylene oxide per mole of alcohol. There are a number of suitable ethoxylated alcohols which are commercially available, such as TERGITOL 15-S-9 (condensation product of Cn to C15 linear alcohols containing 9 moles of ethylene oxide), sold by Union Carbide Corporation, KYRO EOB (condensation product of C13 to C15) linear alcohols containing 9 moles of ethylene oxide), sold by Procter & Gamble Co., as NEODOL, a series of surfactants from Shell Chemical Co., specifically NEODOL 25-12 (a condensation product of C12 to C15 linear alcohols containing 12 moles of ethylene oxide) and NEODOL 23-6.5T (a condensation product of C12 to C13 linear alcohols containing 6.5 moles of ethylene oxide which has been distilled to remove some impurities) and mainly PLURFAC referred to as a series of surfactants from BASF Corp., specifically PLURFAC A -38 (condensation product of C 18 linear alcohols containing 27 moles of ethylene oxide). Some surfactants of the ethoxylated alcohol type such as NEODOL 25-12 may also function as alkylethoxylated plasticizers. Other examples of suitable ethoxylated alcohol surfactants, such as the Idi class of Brij surfactants and mixtures thereof, wherein Brij 72 (steareth-2) and Brij 76 (steareth-10) are most suitable. Also mixtures of ethoxylated cetyl alcohols and stearyl alcohols for an ethoxylation degree between 10 and 20 may be used as hydrophilic surfactants.

Another example of a surfactant useful in the present invention is Aerosol OT, a dioctyl ester of sulfosuccinic acid sulfates sold by the American Cyanamid Company.

Other types of suitable surfactants for use in the skin care compositions of the present invention are silicone copolymers such as General Electric SF 1188 (copolymer of polydimethylsiloxane and polyoxyalkylene ether) and General Electric SF 1228 (silicone polyethylene copolymer). These silicone surfactants can also be used in combination with other surfactants listed above, such as ethoxylated alcohols. Silicone-based surfactants are effective at concentrations as low as 0.1%, preferably 0.25% to about 1%, of the total composition.

If the composition is to be hydrophilic, it is necessary to use an amount of hydrophilic surfactant which increases the wettability of the composition to the desired level and depends on the HLB value of the immobilizing agent, if used, on the HLB value of the surfactant and other

44 • 4 · 4

4 4

4 4

4 4 factors. The composition may contain from about 0.1% to about 50% of a hydrophilic surfactant if desired to increase the wettability of the composition. More preferably, the composition contains from 1% to 25%, and most preferably from 10% to 20%, of a hydrophilic surfactant to enhance the wettability of the composition of the present invention.

The skin care compositions and compositions of the present invention may contain other ingredients usually present in creams, ointments, oils, dusting powders, suspensions, and the like. These include water, viscosity modifying agents, perfuming agents, disinfectant antibacterial ingredients, antiviral agents, vitamins, pharmaceuticals, deodorants, brighteners, tighteners, solvents, preservatives and the like. In addition, a stabilizer may be added to prolong the action of the composition, such as cellulose derivatives, proteins, and lecithin. All of these materials are well known in the art as additives to these compositions and can be used in conventional concentrations.

If water-based formulations of the present invention are used, a preservative may be required. Suitable preservatives are, for example, propylparaben, methylparaben, benzyl alcohol, benzylalkonium, BHT, or acids such as citric, tartaric, maleic, lactic, benzoic, salicylic and the like. Suitable viscosity enhancers are those described above as an effective immobilizing agent. Other useful materials are, for example, alkylgalactomannan, silicon, talc, magnesium silicate, sorbitol, colloidal silicone dioxide, magnesium aluminum silicate, zinc stearate, wool wax alcohol, sorbiton, sesquioleate, cetyl hydroxyethylcellulose and other modified celluloses. Suitable solvents are, for example, propylene glycol, glycerin, cyclomethicone, polyethylene glycols, hexalenglycol, diol and polyhydroxylated solvents. Suitable vitamins are A, D-3, E, B-5 and E acetate.

Transport systems

The compounds of the present invention or compositions comprising them may be deposited on an absorbent pad in any transport system well known in the art that provides contact of the inhibitor with the feces mass to inhibit enzyme activity and / or ensure the transfer of the compounds or compositions of the present invention to the skin of the user of the liner so as to protect it from irritation by faecal enzymes at the point of contact of feces with the skin. The transport system may be a component of the portion or portions of the liner. These delivery systems are divided into those which deliver the transported substance clean and those which deliver it from the vehicle.

The delivery systems may be crushable or soluble microcapsules or "bubbles" containing the substances or compositions of the present invention. These transport systems can

Obsahovat φ obsahovat obsahovat «« φ φ obsahovat obsahovat * * obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat obsahovat due to the presence of urine or other bodily waste. These delivery systems are known to those skilled in the art.

Transport systems may also transfer a substance or composition as a structural component of some structural unit of the liner. For example, the compounds or compositions of the present invention may be incorporated directly by known techniques onto the surface or internal structure of the topsheet, the backsheet and / or the absorbent core, or other components of the pad during its manufacture, such as graphite or radical polymerization technique. The substances which are in powder form can be deposited on the surface of the liner by vapor deposition techniques and bonded by means of hydrogen bonds which disintegrate as soon as the surface becomes wet and thus releases the substance. Regardless of the transport system used, the substances of the present invention may change position, i. They may be washed away with urine into other areas of the liner, for example.

The substances and compositions of the present invention are then applied after use of the pad, at least a portion of which is transferred from the pad to the skin of the wearer. Thus, the composition of the present invention is applied directly to one or more sites on the user's body, or is applied to alternative locations to be available for transmission to one or more sites with user input. (Eg materials placed under the surface of the contact point, encapsulated devices, etc.). Suitable uses of the substances or compositions are spraying, imprinting (flexographic imprint), coverage (eg, contact coating, engraving), extrusion, or a combination of these techniques, eg spraying the skin care composition onto a rotating surface to deliver the composition to the desired location. liner. The agent-containing composition of the present invention can also be applied as a solid material using a variety of techniques, such as extrusion. The minimum amount of the substances or compositions containing the substance of the present invention to be applied to the skin of the wearer is that amount that provides a sufficient therapeutic, protective and / or healing effect once the composition of the present invention has been delivered to its destination. The amount of substances and composition used according to the present invention depends on various factors, such as the type of pad, the relative area of the pad to be treated with the composition, and the like. The delivery of an effective amount of the compounds of the present invention to the skin by means of an insert over a given period of time, the effective amount of applied or transferred composition to one or more sites on the skin of the user depends most of all on the composition used. The amount of the composition of the present invention at the site of contact with the user's skin should range from 0.05 mg / in (0.0078 mg / cm) to about 80 mg / in (12 mg / cm), preferably from 1 mg / in. in (0.16 mg / cm) to · at · r · t · r · t · t · do · 0,1 · t · t · a · · • «· · * · * * * * * * * * * *

About 40 mg / in (6 mg / cm), more preferably from 4 mg / in (0.6 mg / cm) to about 26 mg / in (4 mg / cm). However, these values are merely illustrative, and one of ordinary skill in the art will understand that the type of formulation as a determining parameter dictating concentration, and that sufficient substances should be applied and the ideal amount should be tested by specific tests.

Since the composition is substantially fixed to the surface, a relatively low amount of composition is needed to deliver an effective amount of the composition. The ability to use small amounts to benefit the skin is due to the fact that the composition is applied continuously and automatically as the pad is used. As noted, the possibility of using a relatively low amount of skin care composition allows the liner surface layer to retain the necessary water permeability characteristics.

The composition may be applied to the liner at any point of manufacture. For example, it is possible to apply the composition to the finished liner just prior to packaging. The composition may also be applied to a desired portion (eg, top, sides, sides, center, etc.) in manufacture, or by a material supplier, before it is assembled with other parts to form the desired product. The composition may be applied to other sites with the need to be introduced later in use during use.

The composition is typically applied to the liner in molten form. Since in the most suitable variations, the compositions have a much higher melting point than room temperature. The composition is typically heated to a temperature in the range of from 35 ° C to 150 ° C, preferably from about 40 ° C to about 100 ° C, before it is applied to the liner. The compounds of the present invention may be added to the compositions before or after heating. Once applied to the liner, it is cooled and allowed to solidify. The application process must be adapted to the proper solidification of the composition.

The most suitable way of applying the composition to the liner is by spraying, contact coating, engraving coating, extrusion coating technique and the like. One technique is to contact the top side of the insert with a means, then the insert is assembled with other parts of the product.

EXAMPLE C: Preparation of an absorbent pad with a top coated with a composition according to the present invention

A. Formulation Preparation: Formulation (Formulation A) is prepared by mixing the following molten (or liquid) ingredients together: petrolatum (such as White Protopet® from Witco Corp., Greenwich, CT), stearyl alcohol (such as CO 1897 from The Procter & Gambler Company) , Cincinnati, OH), aloe extract (Veragel Lipoid in Kaydol from Madis Botanicals, Inc., South

Hackensack, NJ), and the compound of Example 5 above. The percentage of each component is given in the table below:

Component % by weight Petrolatum 52.2 Stearyl alcohol 36.9 Aloe 0.9 The compound of Example 5 10.0

B. Preparing the liner containing the composition by contact coating: composition A is transferred to a reaction vessel heated to 170 ° F. The composition is then applied with a contact applicator (using, e.g., a Meltex EP45 five-hole adhesive melt applicator operating at 170 ° F) to the insert surface (commercially available as Pampers® Premium Size 4 diaper, from The Procter & Gambler Company, Cincinnati, OH) in a strip pattern with the stripes extending along the length of the diaper. Five strips are applied and each is 0.25 inches wide and 11.75 inches long and 1.19 mg / cm ² was administered. the gap between the bars was 0.31 inches.

EXAMPLE D: Method of improving skin health

A baby weighing 20 pounds, which showed typical signs of sore spots, was repacked for 21 days with diapers according to Example C. The diapers were changed as usual, (usually the diapers are changed every 3-4 hours during the day and the baby is repacked just before bedtime) . No protective skin moisturizer products were administered during this time. After 21 days, the occurrence of sore spots in the baby was greatly suppressed.

EXAMPLE E: A method of improving skin health

An adult 165 pounds of wetting, using absorbent pads and continuously suffering from mild skin irritation, used absorbent pads the same as the diaper of Example C for five days. He exchanged his inserts as usual. During this time he was not given any other protective and humidifying agents. After five days, the incidence of skin irritation was greatly suppressed or even disappeared.

EXAMPLE F: Method of improving skin health

A child weighing 20 pounds, who has no symptoms of sore spots with middle ear inflammation and prescribed antibiotic treatment. Based on the experience of the usual untreated sore spots, the caregiver assumed that the child would suffer from loose stools during treatment. During the antibiotic treatment, the infant was given the diapers of Example C. During this time, the child was not given any additional protective and moisturizing agents. The child did not develop any symptoms of sore spots during antibiotic treatment.

Use of the composition of the present invention in personal care products

The compounds and compositions described herein can also be used in skin applications that are suitable for treatment with an enzyme inhibitor, particularly in the presence of proteolytic and lipolytic enzymes. These compositions comprise an effective and safe amount of the compounds of the present invention and a conventional carrier thereof.

The compounds of the present invention can be used in both disposable and washable compositions against acne, facial lotions and conditioners, shower gels, foaming and non-foaming facial compositions, cosmetics, body oils, cream moisturizers, and cosmetic compositions. However, the most important remedy is acne remedies. These products are manufactured according to standard procedures using standard substrates known in the art. When used in personal care compositions, the compounds of the present invention (enzyme inhibitors) are generally applicable in an amount of greater than 0.001%, preferably greater than 0.01%, and most preferably greater than 0.1% and less than 20%, more preferably more than 10% and preferably 5%. Non-limiting examples of personal care compositions are given as references below where the compounds of the present invention can be delivered to achieve the desired inhibitory effect:

Skin cleansing compositions: U.S. Patent 5,641,479, Linares et al., Filed Jun. 24, 1997; U.S. Patent 5,599,549 to Wivell et al., Filed Feb. 4, 1997; U.S. Patent 5,585,104, Ha et al., Filed Dec. 17, 1996; U.S. Patent 5,540,852, Kefauver et al., Filed Jun. 30, 1996; and U.S. Patent 5,510,050, Dunbar et al., filed April 23, 1996.

Acne Facial: US Patent 5,612,324, Guang Lin et al., Filed Apr. 18, 1997; U.S. Patent 5,587,176, Warren et al., Filed Dec. 24, 1996; U.S. Patent 5,549,888, Venkateswaran, filed August 27, 1996, and U.S. Patent 5,470,884, Corless et al., Filed November 28, 1995.

Shower Gels: US Patent 5,650,384, Gordon et al., Filed Jun. 22, 1997; and US Patent 5,607,678, Moore et al., filed March 4, 1997.

• · · ·

Cosmetics: US Patent 5,641,493, Date et al., Filed Jun. 24, 1997; U.S. Patent 5,605,894, Blank et al., Filed Feb. 25, 1997; U.S. Patent 5,585,090, Yoshioka et al., Filed Dec. 17, 1996.

Hand, Face and Body Oils: U.S. Patent 4,939,179 to Cheney et al., Filed Jun. 3, 1990; and U.S. Patent 5,607,980, McAtee et al., filed March 4, 1997.

Cosmetic & Cleansing Tissues: US Patent 4,045,364, Richter et al., Filed Aug. 30, 1977; European Patent Application EP 0 619 074, Touchet et al., filed Oct. 12, 1994; U.S. Patent 4,975,217, Brown-Skrobot et al., Filed Dec. 4, 1990; U.S. Patent 5,043,155, Puchalski et al., Filed Aug. 27, 1991; and US Patent 5,648,083, Blieszner et al., filed June 15, 1997.

Use of the compounds of the present invention for pharmaceutical compositions

The agent of the present invention may also be used to treat certain disorders, such as obesity. Lipase inhibitors have been shown to be useful in the treatment of obesity by inhibiting the function of the lipase in the intestine, see US Patent 5,643,874 to Bremer et al., June 1, 1997. Accordingly, the compounds of the present invention are also useful for such treatment. The benefit of the compounds of the present invention is reduced absorption of the substances in the intestine as they prevent their decomposition. In addition to obesity, a variety of disorders and diseases, including those associated with obesity, can be treated or prevented with the compounds of the present invention, including: diabetes, high blood pressure, hyperlipidemia, and insulin resistance syndrome. The compounds of the present invention may also be used for the treatment of gingivitis and contraception.

Thus, the compounds of the present invention may take various dosage forms for treating and preventing the above disorders and diseases. Conventional procedures as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. (1990).

In addition to the active ingredient of the present invention, the composition also comprises a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein describes one or more compatible solid or liquid fillers, diluents or encapsulating substances that are useful for administration to mammals. The term "compatible" describes a substance that is miscible with the substances of the present invention and with each other in such a way that there are no interactions that would substantially reduce the pharmaceutical effect of the formulation under normal conditions Of course, pharmaceutically acceptable carriers must have sufficient purity and sufficiently low toxicity. , so that they can be administered to animals, especially mammals.

The compounds of the present invention may be in any dosage form suitable for oral, rectal, topical, nasal, ocular and parenteral administration. Depending on the desired route of administration, the appropriate pharmaceutically acceptable carrier well known in the art should be selected. It may be a solid or liquid filler, diluent, surfactant and encapsulating substance. Pharmaceutically active materials that do not affect the inhibitory activity of the compounds of the present invention may also be used. The amount of carrier used in conjunction with an effective amount of the active ingredients provides together the dose necessary for administration in a single administration. Methods and compositions for making dosage forms useful in the present invention are described in the following references: Modem Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds (1979), Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981) and Anse , Introduction to Pharmaceutical Dosage Forms, 2nd Edition (1976).

Examples of substances which may serve as a pharmaceutically acceptable carrier are sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose methyl cellulose, powdered tragacanth, malt, gelatin , talc, solid lubricants such as stearic acid and magnesium stearate, calcium sulphate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and thetheobroma oil, polyols such as propylene glycol, glycerin, sorbitol, mannitol and polypropylene glycol, alginate, emulsifiers such as TWWENs, humectants such as sodium lauryl sulfate, colorants, perfumes, tabletting agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic solutions and phosphate buffer solutions.

The choice of pharmaceutically acceptable carrier to be used in combination with the agents of the present invention depends on the type of agent and the mode of administration desired.

Suitable pharmaceutically acceptable carriers for systemic administration are sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyoyls, alginate, emulsifiers, pyrogen-free water, isotonic solutions and phosphate buffer solutions. Preferred pharmaceutically acceptable carriers for parenteral administration are propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. Suitably, the pharmaceutically acceptable carrier is present in the composition for parenteral administration in an amount of at least 90% of the total weight of the composition.

For oral administration, various dosage forms may be used, such as tablets, capsules, granules and coarse powder. These dosage forms contain a safe and effective amount of the compounds of the present invention, usually at least 5%, preferably from about 25% to 50%, of the compounds of formula I. Tablets may be compressed, comminuted, sugar coated, thin. · · · · · · · · · · · · · · · · · · ·

7A ··· · v ···· / v · · · · ······ · · · · · ············ multiply compressed, containing binders, lubricants, diluents, disintegrating agents, colorants, flavoring agents, solubilizers and melting agents. Liquid forms intended for oral administration are, for example, solutions, emulsions, suspensions, solutions and / or emulsions in non-effervescent tablets, effervescent tablets and contain suitable solvents, preservatives, emulsifiers, diluents, sweeteners, fluxing agents, coloring agents and flavoring agents.

Pharmaceutically acceptable carriers suitable for the preparation of dosage forms for oral administration are well known in the art. Tablets usually contain conventional pharmaceutically acceptable adjuvants such as an inert diluent such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose, binding components such as starch, gelatin and sucrose, disintegrants such as starch, alginate and croscarmellose, lubricants such as magnesium stearate , stearic acid and talc. Swallowing agents such as silicone dioxide. Dyes such as FD&C dyes, which may be added. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint and fruit flavors are useful as adjuvants in chewable tablets. The capsules usually contain one or more of the solid diluents mentioned above. The choice of carrier is dependent on taste requirements, cost, stability, which are not critical to the properties of the composition of the present invention and can be freely modified by any person skilled in the art.

Compositions intended for oral administration also include solutions, emulsions and suspensions, and the like. Pharmaceutically acceptable carriers suitable for these forms are well known in the art. Typical carriers are syrup, elixir, emulsions and suspensions such as ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate are the typical agents. The usual humectants are lecithin and polysorbate 80, the usual preservatives are methylparaben and sodium benzoate. Peropal dosage forms may also contain such ingredients as sweetening, flavoring and coloring agents as described above. These compositions may also be coated by conventional techniques, mostly pH or time-dependent coatings, such that the active agent of the present invention is released in the gastrointestinal tract of the subject at a desired location, or at different times, thereby enhancing its effect. Such dosage forms may be, for example, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit, waxes, and shellac. Other compositions useful for systemic administration of the compounds of the present invention are those intended for sublingual, oral and nasal dosage forms. These compositions typically comprise one or more soluble fillers such as sucrose, sorbitol and mannitol and ingredients such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.

9 9 9 9 9 9 9 9 9

Other swallowing agents, humectants, sweeteners, colorants, antioxidants and flavoring agents may also be added.

The compositions of the present invention may also contain other active ingredients.

Methods of application:

The compounds and compositions of the present invention may be administered topically or systemically. Systemic administration is a method of administering the compositions of the present invention to tissues of a patient's body, for example: intararticular, intrathecal, epidural, intramuscular, transdermal, intarvenous, intraperitoneal, subcutaneous, sublingual, rectal or oral. When used as a pharmaceutical, it is preferred that the compounds of the present invention be administered orally.

The particular dose of the agent administered, as well as the duration of treatment and its form, whether the agent is administered topically or systemically, are interdependent. The dose and method of treatment also depend on such factors as the type of agent administered, the indication of treatment, the inhibitory activity of the agent, the characteristics of the subject being treated, such as weight, treatment regimen, and the presence of eventual side effects. It is usually 5 to 3000 mg, but more preferably 5 to 1000 mg, and most preferably 10 to 100 mg of the compounds of the present invention, as a daily dose for systemic administration. It is clear that these doses are given by way of example only and that the daily dose may be adjusted depending on the above values.

For local disorders, topical application is preferred. For the treatment of skin inflammation, the composition is applied topically, in the form of a gel or paste, ointment or oil. Thus, the method of treatment depends on the nature of the disorder and the use of appropriate dosage forms depends on the state of the art.

For all of the above, the agent of the present invention may be administered alone or as a mixture and the composition may contain other active ingredients or carriers depending on the indication.

EXAMPLE G:

Tablets intended for oral administration according to the present invention comprising

Component amount the compound of Example 3 10 mg lactose 120 mg cornstarch 70 mg talc 4 mg magnesium stearate 1 mg

Other compounds of the present invention may also be used with substantially the same result.

Claims (10)

PATENT CLAIMS 1. A compound of the general formula: NH-B ₂ A - Q - P - L 1 - L 1 - L 3 - L 4 - fr Z j - X - Z ⁿ nb, and tautomers, acceptable salts and biohydrolizable amides, esters and imides thereof, wherein: (a) B) represents hydrogen, methyl, ethyl, propyl, methylene attached to B ₂ via a single covalent bond so that B) and B ₂ form a five-membered ring and a methylene group attached to B ₂ via another methylene group so that Bi and B ₂ formed a six-membered cycle, (b) B ₂ represents hydrogen, methyl, ethyl, propyl, methylene attached to Bi via a single covalent bond so that Bi and B ₂ formed a five-membered ring and methylene group attached to B _t via another methylene groups so that the Bi and _B2 form a six membered ring; (c) X is either a blank position or -CH ₂ -, -NH-, (d) Z is an aromatic, substituted or unsubstituted monocyclic or polycyclic, carbocyclic or heterocyclic ring, (e) Li, L ₂ and L 3 are independently an empty position, or -NH-, -O-, -S-, -C (O) -, -CF ₂ -, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl , -C (1) NH-, -NH-SO 2 -R ¹ -, -C (O) -R ² -, C (O) -R ³ -O-, -C (O) -R ⁴ -S-, -C (0) -R ⁵ -NH-, -NH-R ⁶ -, -O-R ⁷ -, -C (O) OR ⁸ -, -C (O) NH-R ⁹ -, -NHC (O) -R ¹⁰ - , -0C (0) -R ⁿ -, -C (O) -CH (R ¹²⁾ -N (R ¹³⁾ -Y-, where R ^1, R ^2, R ^3, R ^4, R ^5, R ⁶ R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected aryl alkyl amino, and wherein R is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino, and -AA wherein -AA is an amino acid side chain and R is hydrogen and R and R together form a monocyclic or polycyclic heterocyclic ring with the nitrogen to which R ^{13 is} attached and wherein Y is an empty position, or -C (O) -CH (R ¹⁴ ) -N (R ¹⁵ ) - wherein R ¹⁴ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, alkylamino, protected alkylamino, arylamino, protected arylamino, arylalkylamino, protected arylalkylamino, and -AA wherein -AA is an amino acid side chain and R ¹⁵ is hydrogen and R ¹⁴ and R ¹⁵ together form a further mono- or polycyclic heterocyclic ring with the nitrogen to which R ¹⁵ is bonded . * (Ί) L ₄ is an empty position, or -C (O) -, ( g) P is a poly (alkylene oxide) polymer comprising linear poly (alkylene oxide), branched poly (alkylene oxide), star poly (alkylene oxide), (h) N is in the range of 1 to about 100 (i) Q is an empty position, or - O-, (j) A is an empty position, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, Z ', wherein Z' is a saturated, unsaturated or aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring, -C (O) -Z ', -C (O) -R ¹⁵ -CF ₃ , wherein R 15 is an empty position or alkyl and wherein Lf, L ₂ ', L ₃ ', Z ', X', B _t 'and B ₂ are the same as defined for L ₁ , L ₂ , L ₃ , Z, X, Bi and B ₂ ; wherein the substance is not of formula I and formula I is: wherein m is in the range of from about 3 to about 500. A compound according to claim 1, wherein B ₁ and B ₂ are independently hydrogen, P is a linear poly (alkylene oxide) and is 1. A compound according to claims 1 or 2, wherein P is [M] _m wherein M is an ethylene oxide monomer, M is in the range of 5 to about 1000, and Q is -O-. A compound according to any preceding claim, wherein X is -NH- and A is alkyl. The compound of claim 1, wherein Q is -O-aA is: z — \ NH-B ₂ · —Li' — L2'— L3'— L4' — τ ^- Z 4 — X * - N-B, ’► 44 4 4 4 4 4 4 where L '= Li, L ₂ = L _2, L ₃ = L _3, L ₄ = L _4, Z' = Z, X '= X, Bf = biAb _2' = B _2nd A compound according to claim 1, wherein B ₁ and B ₂ are hydrogen and P is a branched poly (alkylene oxide). A compound according to claim 6, wherein P is: t Where u is in the range from 1 to about 10 and where t is in the range from 4 to 990 and wherein the substance has the following general formula: .O A — Q-O ' O.O-> ť NH-Bj x- ~ x ^r I-U-U-U4 z) -x-4 N-B, and where n is u + 1 and Q is the empty position. A compound according to claims 6 or 7, wherein A is: nh-b ₂ · • Lf — L2'— Ly — L4-I- ^z 4-x— NB (where L) - Li, - L ₂ , L ₃ '- L ₃ , L ₄ ' - L ₄ , Z'-Z, X'-X, B / = BiaB2 ^{, =:} B ₂ . The compound of claim 1, wherein P is a star poly (ethylene oxide) wherein Q is -O- and A is: nh-b ₂ · N-B, 98 9 · 9 9 9 «9 99 9 9 9999 999 9 9 9999 99 99 9 999999 9999 9 9 9999 99 99999999 99 99 where Li = Li, L2 '= L2, _L3' = L3, L4 = L4, Z '= Z, X' = X = Bf BjaB2 - B2. A composition comprising (I) a substance according to any preceding claim (II), a carrier which is a carrier customary in skin care compositions, a carrier customary in personal care compositions, and a pharmaceutically acceptable carrier.