EP1385821A2 - Nouveaux composes anti-adhesifs et leurs utilisations - Google Patents

Nouveaux composes anti-adhesifs et leurs utilisations

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Publication number
EP1385821A2
EP1385821A2 EP02725119A EP02725119A EP1385821A2 EP 1385821 A2 EP1385821 A2 EP 1385821A2 EP 02725119 A EP02725119 A EP 02725119A EP 02725119 A EP02725119 A EP 02725119A EP 1385821 A2 EP1385821 A2 EP 1385821A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
sulfonyl
methanesulfonyl
compounds
sulfonate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02725119A
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German (de)
English (en)
Other versions
EP1385821A4 (fr
Inventor
Randall S. Alberte
Robert D. Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cernofina LLC
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Cernofina LLC
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Filing date
Publication date
Application filed by Cernofina LLC filed Critical Cernofina LLC
Publication of EP1385821A2 publication Critical patent/EP1385821A2/fr
Publication of EP1385821A4 publication Critical patent/EP1385821A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/22—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings
    • C07C305/24—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/14—Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support

Definitions

  • Biologicales can contribute to fouling, including bacteria, fungi, algae, protozoans, and invertebrates. Fouling of surfaces may have damaging consequences for surfaces in a number of contexts, including surfaces submerged in liquids, exposed to aqueous vapors, or implanted in human or animal bodies. In a health-related environment, fouling can result in biofilm formation. Biofilm formation is understood to cause local contamination of an affected area with potential for invasive local infection and for systemic infection.
  • Microorganisms may damage tissues in at least three ways: 1) they can enter or contact host cells and directly cause cell death; 2) they can release endotoxins or exotoxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis; and 3) they can induce host-cellular responses that, although directed against the invader, may cause additional tissue damage, including suppuration, scarring and hypersensitivity reactions.
  • An infection whether local or systemic, represents the penetration of microorganisms into a host with the production of tissue damage or the elicitation of host defense mechanisms or both, leading to clinically identifiable symptoms. Common local symptoms can include pain, tenderness, swelling and interference with function. Common systemic symptoms can include fever, malaise and hyperdynamic cardiovascular effects. Massive bloodstream invasion by infectious agents can rapidly become fatal.
  • an infection When an infection has its origins in a biofilm surrounding an object in the body, whether a naturally occurring object or a foreign one, the infection often cannot be controlled without removing that object. If the object is naturally occurring, like devascularized or necrotic tissue, it is removed surgically via a process called debridement. If the object is a foreign one, such as a medical device, it is removed entirely. At times, a rim of tissue must be removed along with the contaminated object to ensure maximal removal of contaminating material. If the material being removed is essential for health, a similar article may need to be replaced in the same location; the replacement article will be especially prone to infection because of the residual microorganisms in the area.
  • Biofilm formation with health implications can involve those surfaces in all health- related environments, including surfaces found in medical environments and those surfaces in industrial or residential environments that are involved in functions essential to well- being like nutrition, sanitation and the prevention of disease.
  • implantable medical devices may be thrombogenic.
  • thrombogenesis is a form of abiologic fouling also amenable to treatment by the antifouling compositions of the invention described herein.
  • Adhesion of pathologic biologies to the surface of host cells is often a required step in the pathogenesis of disease. Such biologies adhere to cell surfaces through interactions involving surface-bound receptors.
  • Substances that preferentially bind to these receptors or otherwise block access to them by pathologic biologies may have use in preventing initiation of cellular infection.
  • Antifouling compounds such as the compositions of the instant invention, also have utility as environmentally benign crop protection agents by preventing attack of various fungi species upon seeds, seedlings, and mature crop plants, and bacteria.
  • antifouling agents may have broad applicability in effectively inhibiting a variety of organisms that contribute to the formation of bio films or are otherwise involved with biofouling. These compounds may also be environmentally safe, as they may naturally degrade into carbon dioxide and water, or simple organic acids.
  • the instant invention includes compounds having the structure 1 :
  • Y represents alkoxy, -OH, sulfonate, sulfate, sulfonyl, sulfoxido, -O-(aryl), -O- (acyl),
  • Ri is absent or present 1, 2, or 3 times;
  • Z represents alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R 80 ;
  • R 80 represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
  • Ri represents for each occurrence alkyl, alkynyl, alkynyl, halogen, formyl, acyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl, carboxamido, alkylamino, acylamino, hydroxyl, alkoxyl, acyloxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, thio, alkylthio, thioalkyl, (alkylthio)alkyl, carbamoyl, urea, thiourea, sulfonyl, sulfonate, sulfonamido, sulfonylamino, or sulfonyloxy; and m is an integer in the range 0 to 8 inclusive; and salts thereof.
  • Y represents sulfonate, sulfate, sulfonyl, sulfoxido, trifluoro- methanesulfonyl, or methanesulfonyl.
  • Ri is absent.
  • Z represents alkyl or alkenyl.
  • the instant invention relates to polymeric compounds which comprise a monomeric unit represented by structure 2:
  • Z represents alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R8o;
  • R 8 o represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
  • Ri represents for each occurrence alkyl, alkynyl, alkynyl, halogen, formyl, acyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl, carboxamido, alkylamino, acylamino, hydroxyl, alkoxyl, acyloxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, thio, alkylthio, thioalkyl, (alkylthio)alkyl, carbamoyl, urea, thiourea, sulfonyl, sulfonate, sulfonamido, sulfonylamino, or sulfonyloxy; and m is an integer in the range 0 to 8 inclusive; n is an integer from about 2 to about 1000; and the salts thereof.
  • Y represents sulfonate, sulfate, sulfonyl, sulfoxido, trifluoro- methanesulfonyl, or methanesulfonyl.
  • R ⁇ is absent.
  • Z represents alkyl or alkenyl.
  • the polymer of structure 2 further comprises a monomeric unit comprising a divalent organic group.
  • the instant invention features polymeric compounds comprising a monomeric unit represented by structure 3 :
  • Z represents alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R8o;
  • Ri represents for each occurrence alkyl, alkynyl, alkynyl, halogen, formyl, acyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl, carboxamido, alkylamino, acylamino, hydroxyl, alkoxyl, acyloxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, thio, alkylthio, thioalkyl, (alkylthio)alkyl, carbamoyl, urea, thiourea, sulfonyl, sulfonate, sulfonamido, sulfonylamino, or sulfonyloxy; and x, y, and n are independently integers from about 1 to about 1000; and the salts thereof.
  • the instant invention relates to compounds having the structure
  • Ri is absent or present 1, 2, or 3 times;
  • R 2 is absent or present 1, 2, or 3 times
  • Z represents optionally substituted alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R 80 ;
  • R 80 represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
  • the instant invention features medical devices and products comprised of a compound having the structure 1, 2, 3, 4,or 5.
  • the instant invention features antifouling compounds having the structure 1, 2, 3, 4 or 5.
  • Figure 3 a shows an example of a number of sulfoxy ester compounds in a combinatorial library.
  • Figure 3b shows examples of sulfoxy ester compounds in a combinatorial library.
  • Figure 4 shows a strategy for solid phase synthesis.
  • Figure 5 depicts a strategy for screening combinatorial libraries for novel non- adhesions.
  • novel anti-adhesive compounds for use on surfaces susceptible to adhesion by various biologies. Included among these compounds are esters of coumaric acid, mixed esters of coumaric acid and zosteric acid, and several other classes of compounds as described in the Examples. Such "antifouling" substances may be employed to prevent damage by biologies to such surfaces, prevent formation of biofilms on such surfaces, prevent infection by biologies of such surfaces, suppress thrombogenic properties of such surfaces, and other uses readily apparent to those skilled in the appropriate arts.
  • Another important property of the compounds of the instant invention is their ability to affect the agglutination of bacterial and mammalian cells.
  • the affects of these compounds on cell agglutination may involve the blocking of certain cell surface receptors and the activation of others - such as those involved in the attachment to extracellular surfaces and which thereby mediate fouling.
  • these compounds may possess many of the activities of naturally-occurring proteins and glycoproteins which bind to sites on the surface of a cell and thereby affect cell/cell interactions.
  • the instant compounds interfere with the attachment of organisms to surfaces, thereby having broad applicability in effectively inhibiting the attachment of a variety of organisms.
  • the compounds are relatively safe for wide-spread environmental use, as they may naturally degrade into carbon dioxide and water, or simple organic acids.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • exemplary heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like.
  • Exemplary electron- donating groups include amino, methoxy, and the like.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g.,
  • exemplary cycloalkyls have from 3-10 carbon atoms in their ring structure, and in another embodiment, have 5, 6 or 7 carbons in the ring structure.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
  • polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl
  • nitro means -NO2; the term “halogen” designates -F, -Cl,
  • R9, R ⁇ Q and R' JQ each independently represent a group permitted by the rules of valence.
  • R 9 is as defined above, and R' ⁇ ⁇ represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R8, where m and Rg are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • R9, RJO are as defined above.
  • of the amide will not include imides which may be unstable.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) m -R8, wherein m and Rg are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • R ⁇ ⁇ represents a hydrogen, an alkyl, an alkenyl, -(CH2) m -R8 or a pharmaceutically acceptable salt
  • R' ⁇ ⁇ represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R8, where m and Rg are as defined above.
  • alkoxyl or "alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, -O-alkynyl, -O-(CH2) m -R8, where m and R8 are described above.
  • sulfonate is art recognized and includes a moiety that can be represented by the general formula:
  • R4 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifiuoromethanesulfonyl, nonafluorobutanesulfonyl, -toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
  • sulfonyl refers to a moiety that can be represented by the general formula:
  • sulfoxido refers to a moiety that can be represented by the general formula:
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and traw.s-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • an “aprotic solvent” means a non-nucleophilic solvent having a boiling point range above ambient temperature, preferably from about 25°C to about 190°C, more preferably from about 80°C to about 160°C, most preferably from about 80°C to 150°C, at atmospheric pressure.
  • solvents are acetonitrile, toluene, DMF, diglyme, THF or DMSO.
  • Bioactivity or “bioactivity” or “activity” or “biological function”, which are used interchangeably, for the purposes herein means an effector or antigenic function that is directly or indirectly performed by a compound of the invention or a fragment thereof.
  • bioavailable is meant to refer to an appropriate location or orientation of a compound for performance of the compounds' bioactivity.
  • half- life refers to the amount of time required for half of a compound to be eliminated or degraded by natural processes
  • infectious microorganisms or “infectious agents” as used herein refers to disease causing or contributing bacteria (including gram-negative and gram-positive organisms, such as Staphylococci sps. (e.g. Staphylococcus aureus, Staphylococcus epidermis), Enter ococcus sp. (E. faecalis), Pseudomonas sp. (P. aeruginosa), Escherichia sp. (E. col ⁇ ), Proteus sp. (P.
  • Staphylococci sps. e.g. Staphylococcus aureus, Staphylococcus epidermis
  • Enter ococcus sp. E. faecalis
  • Pseudomonas sp. P. aeruginosa
  • Escherichia sp. E. col ⁇
  • Proteus sp. P.
  • a "pharmaceutically effective amount” refers to an appropriate amount to obtain a therapeutic effect. Toxicity and therapeutic efficacy of compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50
  • the effective amount may vary within a range depending upon the dosage form employed and the route of administration utilized.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • a "polar, aprotic solvent” means a polar solvent as defined above which has no available hydrogens to exchange with the compounds of this invention during reaction, for example DMF, acetonitrile, diglyme, DMSO, or THF.
  • a “polar solvent” means a solvent which has a dielectric constant ( ) of 2.9 or greater, such as DMF, THF, ethylene glycol dimethyl ether (DME), DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, t-butanol or 2-methoxyethyl ether.
  • Preferred solvents are DMF, DME, NMP, and acetonitrile.
  • solid support includes insoluble, functionalized, polymeric materials to which library members or reagents may be attached, with or without a linker, allowing them to be readily separated, for example by filtration, centrifugation, from, for example, excess reagents, soluble reaction by-products, or solvents.
  • a "sulfate binding moiety” refers to a moiety that is capable of binding or otherwise associating with a sulfate or sulfonate group.
  • the core material of a microcapsule containing a sulfate ester AF agent may be in the form of a liquid droplet, an emulsion, a suspension of solids, a solid particle, or a crystal.
  • the skilled artisan will be aware of numerous materials suitable for use as microcapsule coating materials, including, but not limited to, organic polymers, hydrocolloids, lipids, fats, carbohydrates, waxes, metals, and inorganic oxides. Silicone polymers are the most preferred microcapsule coating material for treatment of surfaces. Microencapsulation techniques are well known in the art and are described in the Encyclopedia of Polymer Science and Engineering, Vol. 9, pp. 724 et seq. (1989) hereby incorporated by reference.
  • a "plant pathogen” refers to an organism (bacteria, virus, protist, algae or fungi) that infects plants of plant components. Examples include molds, fungi and rot that typical use spores to infect plants or plant components (e.g fruits, vegetables, grains, stems, roots). Spores must recognize the host, attach, germinate, penetrate host tissues, and proliferate hyphae that will allow the fungus access to nutrients for growth and reproduction. Examples include: Botrytis sp. (B. cinerea), Penicillium sp. ( P. expansum, P. italicum, P. digitalum), Rhizopus sp. (R. sulonifer, R. nigricans), Alternaria sp.
  • Y represents alkoxy, -OH, sulfonate, sulfate, sulfonyl, sulfoxido, -O-(aryl), -O- (acyl), -O(sulfonyl) , trifluoro-methanesulfonyl, or methanesulfonyl;
  • Ri is absent or present 1, 2, or 3 times;
  • Z represents alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2)m-R 80 ;
  • Ri represents for each occurrence alkyl, alkynyl, alkynyl, halogen, formyl, acyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl, carboxamido, alkylamino, acylamino, hydroxyl, alkoxyl, acyloxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino) alkyl, thio, alkylthio, thioalkyl, (alkylthio)alkyl, carbamoyl, urea, thiourea, sulfonyl, sulfonate, sulfonamido, sulfonylamino, or sulfonyloxy; and m is an integer in the range 0 to 8 inclusive; and salts thereof.
  • Z represents alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R 8 o;
  • R 80 represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
  • the polymer of structure 2 further comprises monomeric units comprising a divalent organic group.
  • the instant invention features polymeric compounds comprising a monomeric unit represented by structure 3 :
  • Y represents alkoxy, -OH, sulfonate, sulfate, sulfonyl, sulfoxido, -O(aryl), -O(acyl), -O(sulfonyl), trifluoro-methanesulfonyl, or methanesulfonyl;
  • R ⁇ is absent or present 1,2, or 3 times;
  • Z represents alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R 80 ;
  • W represents alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R 80 ;
  • R 80 represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
  • m is an integer in the range 0 to 8 inclusive;
  • the polymers are comprised almost entirely, if not entirely, of the same subunit.
  • the polymers maybe copolymers, in which different subunits and/or other monomeric units are incorporated into the polymer.
  • the polymers are random copolymers, in which the different subunits and/or other monomeric units are distributed randomly throughout the polymer chain.
  • the polymer having units of formula 2 and 3 may consist of effectively only one type of such subunit, or alternatively two or more types of such subunits.
  • the polymer may contain monomeric units other than those subunits represented by formula 2 and 3.
  • the different types of monomeric units are distributed randomly throughout the chain.
  • random is intended to refer to the situation in which the particular distribution or incorporation of monomeric units in a polymer that has more than one type of monomeric units is not directed or controlled directly by the synthetic protocol, but instead results from features inherent to the polymer system, such as the reactivity, amounts of subunits and other characteristics of the synthetic reaction or other methods of manufacture, processing or treatment.
  • the subject polymers may be cross-linked.
  • substituents of the polymeric chain may be selected to permit additional inter-chain cross- linking by covalent or electrostatic (including hydrogen-binding or the formation of salt bridges), e.g., by the use of a organic residue appropriately substituted.
  • polymers may be composed almost entirely, if not entirely, of a single monomeric element, such as a subunit depicted in formula 2 and 3.
  • the polymers are effectively composed of two different subunits, in which the percentage of each subunit may vary from less than 1 :99 to more than 99:1, or alternatively 10:90, 15:85, 25:75, 40:60, 50:50, 60:40, 75:25, 85:15, 90:10 or the like.
  • a polymer may be composed of two different subunits that may be both represented by the generic formula 2 and 3, but which differ in their chemical identity.
  • the polymers may have just a few percent, or even less (for example, about 5, 2.5, 1, 0.5, 0.1 %) of the subunits having phosphorous- based linkages.
  • the present invention contemplates a range of mixtures like those taught for the two-component systems.
  • the instant invention relates to compounds having the structure
  • Y represents independently for each occurrence alkoxy, -OH, sulfonate, sulfate,sulfonyl, sulfoxido, -O(aryl), -O(acyl), -O(sulfonyl), trifluoro-methanesulfonyl, or methanesulfonyl.
  • Ri is absent or present 1, 2, or 3 times;
  • R 2 is absent or present 1, 2, or 3 times
  • Z represents optionally substituted alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or -(CH2) m -R 80 ;
  • R 80 represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
  • Ri and R 2 represent independently for each occurrence alkyl, alkynyl, alkynyl, halogen, formyl, acyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl, carboxamido, alkylamino, acylamino, hydroxyl, alkoxyl, acyloxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, thio, alkylthio, thioalkyl, (alkylthio)alkyl, carbamoyl, urea, thiourea, sulfonyl, sulfonate, sulfonamido, sulfonylamino, or sulfonyloxy; and m is an integer in the range 0 to 8 inclusive; and salts thereof.
  • Compounds of the invention have been shown to provide one or more plant and animal lectin-like activities.
  • Lectins bind to cell surface proteoglycans, which function in the attachment of pathogens such as viruses and bacteria. Accordingly the lectin-like activities of compounds of the invention are useful in treating and preventing infections and other receptor-mediated diseases and conditions.
  • the ability of the compounds to bind to certain cell surface sites is useful for agonizing or antagonizing certain cell surface interactions which are otherwise affected by animal or plant lectin proteins.
  • the extracellular polysaccharides produced by fouling organisms are often highly sulfated, and these sulfate esters play an important role in polymerization (e.g. glue/gel formation).
  • the instant invention is based, at least in part, on the finding that some compounds of the invention inhibit attachment of parasitic fungi spores to plants, as well as hyphal production from previously attached spores. Even after prolonged exposure, the presence of the compounds of the invention on the plants did not result in any toxic or growth inhibitory effect.
  • the compounds of the invention may provide a highly effective antifungal and antibacterial agent.
  • the compounds of the invention since essentially all fungal plant pathogens use spores to recognize the host plant, attach, germinate, penetrate the host plant tissue and proliferate hyphae that allows the fungus access to the plant's nutrients for growth and reproduction, the compounds are broad-based antifungal agents.
  • a compound of the invention can be varied as required to optimize the overall chemical properties of the particular compound for specific uses, while retaining the antifouling (AF) activity.
  • the length of an alkyl chain can be extended or shortened to control the rate of dissolution of the compound from a structure or a coating.
  • additional functional groups can be added to the alkyl chain to further vary the chemical nature of the molecule.
  • Implantable medical devices using artificial materials alone or in combination with naturally-derived materials, can be treated with compounds either by surface coating or by incorporation.
  • Metals may be suitably treated with surface coats while retaining their biological properties.
  • metals may be treated with paints or with adherent layers of polymers or ceramics that incorporate the compounds of the invention.
  • Certain embodiments treated in this manner may be suitable for orthopedic applications, for example, pins, screws, plates or parts of artificial joints.
  • Methods for surface treatment of metals for biological use are well-known in the relevant arts.
  • Other materials besides metals can be treated with surface coats of compounds according to the present invention as the medical application requires.
  • Examples include polymethylmethacrylate and related compounds, used for the affixation of orthopedic and dental prostheses within the body.
  • the presence of the compounds of the instant invention can decrease biofilm formation in those structures in contact with the glue, cement, or adhesive.
  • a compound of the invention can coat or can permeate the formed article.
  • the formed article allows diffusion of the compound, or functional portion thereof, into the surrounding environment, thereby preventing fouling of the appliance itself.
  • Microcapsules bearing compounds can also be imbedded in the material. Materials incorporating compounds are adaptable to the manufacture of a wide range of medical devices, some of which are disclosed below. Other examples will be readily apparent to those practitioners of ordinary skill in the art.
  • compounds of the invention can be applied to or incorporated in certain medical devices that are intended to be left in position permanently to replace or restore vital functions.
  • ventriculoatrial or ventriculoperitoneal shunts are devised to prevent cerebrospinal fluid from collecting in the brain of patients whose normal drainage channels are impaired. As long as the shunt functions, fluid is prevented from accumulating in the brain and normal brain function can continue. If the shunt ceases to function, fluid accumulates and compresses the brain, a complication. If the shunt becomes infected, it causes an infection to enter the central portions of the brain, another life- threatening complication.
  • These shunts commonly include a silicone elastomer or another polymer as part of their fabrication. Silicones are understood to be especially suited for combination with compounds according to the present invention.
  • Another shunt that has life-saving import is a dialysis shunt, a piece of polymeric tubing connecting an artery and a vein in the forearm to provide a kidney failure patient a means by which the dialysis equipment can cleanse the bloodstream. Even though this is a high-flow conduit, it is susceptible to the formation of biofilms and subsequent infection. If a shunt becomes infected, it requires removal and replacement. Since dialysis may be a lifelong process, and since there are a limited number of sites where shunts can be applied, it is desirable to avoid having to remove one due to infectious complications. Imbedding or otherwise contacting the compounds of the invention with the shunt material can have this desired effect.
  • Heart valves comprising artificial material are understood to be vulnerable to the dangerous complication of prosthetic valve endocarditis. Once established, it carries a mortality rate as high as 70%. Biofilms are integrally involved in the development of this condition. At present, the only treatment for established contamination is high-dose antibiotic therapy and surgical removal of the device. The contaminated valve must be immediately replaced, since the heart cannot function without it. Because the new valve is being inserted in a recently contaminated area, it is common for prosthetic valve endocarditis to affect the replacement valve as well. Artificial heart valves comprised of the compounds of the invention may reduce the incidence of primary and recurrent prosthetic valve endocarditis. Compounds of the invention can be applied to the synthetic portions or the naturally-derived portions of heart valves.
  • Pacemakers and artificial implantable defibrillators commonly comprise metallic parts in combination with other synthetic materials. These devices, which may be coated with a polymeric substance such as silicone are typically implanted in subcutaneous or intramuscular locations with wires or other electrical devices extending intrathoracically or intravascularly. If the device becomes colonized with microorganisms and infected, it must be removed. A new device can be replaced in a different location, although there are a finite number of appropriate implantation sites on the body. Devices comprising the compounds of the invention may inhibit contamination and infection, or substantially reduce the risk thereof. Devices implanted into the body either temporarily or permanently to pump pharmacological agents into the body can comprise metallic parts in combination with other synthetic materials.
  • Such devices can be entirely implanted or can be partially implanted.
  • the device may be partially or entirely covered with a polymeric substance, and may comprise other polymers used as conduits or tubes.
  • Incorporating AF agents according to the present invention into the coating materials imposed upon these devices or into the materials used for the devices themselves, their conduits or their tubing may inhibit their contamination and infection.
  • vascular grafting prostheses comprising compounds of the invention can resist infections, thereby avoiding these devastating complications.
  • Microsurgery typically involves vessels only one to four millimeters in diameter. It is understood that the sutures penetrating the vessel at the anastomosis are likely sites for clots to form. Microsurgical sutures comprising a compound of the invention would result in localized administration of an anticoagulant at the site most likely to be damaged by clotting.
  • Suture material used to anchor vascular grafting prostheses to normal blood vessels or to sew vessels or other structures together can also harbor infections.
  • Sutures used for these purposes are commonly made of prolene, nylon or other monofilamentous nonabsorbable materials.
  • An infection that begins at a suture line can extend to involve the vascular grafting prosthesis.
  • Suture materials comprising a compound of the invention would have increased resistance to infection.
  • a suture comprising a compound of the invention would be useful in other areas besides the vasculature.
  • Wound infections at surgical incisions may arise from microorganisms that lodge in suture materials placed at various levels to close the incision. General surgery uses both nonabsorbable and absorbable sutures. Materials for nonabsorbable sutures include prolene and nylon.
  • Absorbable sutures include materials like treated catgut and polyglycolic acid. Absorbable sutures retain tensile strength for periods of time from days to months and are gradually resorbed by the body. Fabricating an absorbable or a nonabsorbable suture comprising a compound of the invention and which retains the handling and tensile characteristics of the material is within the skill of artisans in the field.
  • Tissue expanders are sacs made of silicone elastomers adapted for gradual filling with a saline solution, whereby the filling process stretches the overlying tissues to generate an increased area of tissue that can be used for other reconstructive applications.
  • Tissue expanders can be used, for example, to expand chest wall skin and muscle after mastectomy as a step towards breast reconstruction. Tissue expanders can also be used in reconstructing areas of significant skin loss in burn victims.
  • a tissue expander is usually intended for temporary use: once the overlying tissues are adequately expanded, they are stretched to cover their intended defect. If a tissue expander is removed before the expanded tissues are transposed, though, all the expansion gained over time is lost and the tissues return nearly to their pre-expansion state. The most common reason for premature tissue expander removal is infection.
  • These devices are subjected to repeated inflations of saline solution, introduced percutaneously into remote filling devices that communicate with the expander itself. Bacterial contamination of the device is thought to occur usually from the percutaneous inflation process. Once contamination is established and a biofilm forms, local infection is likely. Expander removal, with the annulment of the reconstructive effort, is needed to control the infection. A delay of a number of months is usually recommended before a new tissue expander can be inserted in the affected area.
  • the silicone elastomer used for these devices is especially suitable for integrating with sulfate ester AF agents. Use of these agents in the manufacture of these articles may reduce the incidence of bacterial contamination, biofilm development and subsequent local infection.
  • Insertable devices include those objects made from synthetic materials applied to the body or partially inserted into the body through a natural or an artificial site of entry. Examples of articles applied to the body include contact lenses and stoma appliances.
  • An artificial larynx is understood to be an insertable device in that it exists in the airway, partially exposed to the environment and partially affixed to the surrounding tissues.
  • An endotracheal or tracheal tube, a gastrostomy tube or a catheter are examples of insertable devices partially existing within the body and partially exposed to the external environment. The endotracheal tube is passed through an existing natural orifice. The tracheal tube is passed through an artificially created orifice.
  • biofilm on the device permits the ingress of microorganisms along the device from a more external anatomic area to a more internal anatomic area.
  • the ascent of microorganisms to the more internal anatomic area commonly causes local and systemic infections.
  • biofilm formation on soft contact lenses is understood to be a risk factor for contact-lens associated corneal infection.
  • the eye itself is vulnerable to infections due to biofilm production.
  • Incorporating an antifouling agent in the contact lens itself and in the contact lens case can reduce the formation of biofilms, thereby reducing risk of infection.
  • Sulfate ester AF agents can also be incorporated in ophthalmic preparations that are periodically instilled in the eye.
  • biofilms are understood to be responsible for infections originating in tympanostomy tubes and in artificial larynxes. Biofilms further reside in tracheostomy tubes and in endotracheal tubes, permitting the incursion of pathogenic bacteria into the relatively sterile distal airways of the lung.
  • Biofilm formation in a vascular access device can lead to the development of a blood-borne infection as planktonic organisms disseminate from the biofilm into the surrounding bloodstream. Further, biofilm formation can contribute to the occlusion of the device itself, rendering it non- functional. If the catheter is infected, or if the obstruction within it cannot be cleared, the catheter must be removed. Commonly, patients with these devices are afflicted with serious medical conditions. These patients are thus poorly able to tolerate the removal and replacement of the device. Furthermore, there are only a limited number of vascular access sites. A patient with repeated catheter placements can run out of locations where a new catheter can be easily and safely placed.
  • a biliary drainage tube is used to drain bile from the biliary tree to the body's exterior if the normal biliary system is blocked or is recovering from a surgical manipulation. Drainage tubes can be made of plastics or other polymers.
  • a biliary stent commonly fabricated of a plastic material, can be inserted within a channel of the biliary tree to keep the duct open so that bile can pass through it.
  • Biliary sludge which forms as a result of bacterial adherence and biofilm formation in the biliary system is a recognized cause of blockage of biliary stents.
  • Pancreatic stents placed to hold the pancreatic ducts open or to drain a pseudocyst of the pancreas, can also become blocked with sludge.
  • Biofilms are furthermore implicated in the ascent of infections into the biliary tree along a biliary drainage tube. Ascending infections in the biliary tree can result in the dangerous infectious condition called cholangitis.
  • Incorporation of compounds of the invention in the materials used to form biliary drainage tubes and biliary stents can reduce the formation of biofilms, thereby decreasing risk of occlusions and infections.
  • a peritoneal dialysis catheter is used to remove bodily wastes in patients with renal failure by using fluids instilled into and then removed from the peritoneal cavity.
  • This form of dialysis is an alternative to hemodialysis for certain renal failure patients.
  • Biofilm formation on the surfaces of the peritoneal dialysis catheter can contribute to blockage and infection.
  • An infection entering the peritoneal cavity is termed a peritonitis, an especially dangerous type of infection.
  • Peritoneal dialysis catheters generally made of polymeric materials like polyethylene, can be coated with or impregnated with sulfate ester AF agents to reduce the formation of biofilms.
  • urological catheters exist to provide drainage of the urinary system. These catheters can either enter the natural orifice of the urethra to drain the bladder, or they can be adapted for penetration of the urinary system through an iatrogenically created insertion site. Nephrostomy tubes and suprapubic tubes represent examples of the latter. Catheters can be positioned in the ureters on a semipermanent basis to hold the ureter open; such a catheter is called a ureteral stent. Urological catheters can be made from a variety of polymeric products. Latex and rubber tubes have been used, as have silicones. All catheters are susceptible to biofilm formation.
  • a further complication encountered in urological catheters is encrustation, a process by which inorganic compounds comprising calcium, magnesium and phosphorous are deposited within the catheter lumen, thereby blocking it.
  • inorganic compounds are understood to arise from the actions of certain bacteria resident in biofilms on catheter surfaces. Reducing biofilm formation by the action of sulfate ester AF agents may contribute to reducing encrustation and subsequent blockage of urological catheters.
  • catheter-like devices exist that can be treated with AF agents.
  • surgical drains, chest tubes, hemovacs and the like can be advantageously treated with materials to impair biofilm formation.
  • Other examples of such devices will be familiar to practitioners in these arts.
  • Bandages, adhesive tapes and clear plastic adherent sheets are further examples where the incorporation of an AF agent in the glue or other adhesive used to affix the object, or incorporation of an AF agent as a component of the object itself, may be beneficial in reducing skin irritation and infection.
  • Embodiments of the present invention can be compatible for combination with currently employed antiseptic regimens to enhance their antimicrobial efficacy or cost-effective use. Selection of an appropriate vehicle for bearing a compound of the invention will be determined by the characteristics of the particular medical use. Other examples of applications in medical environments to promote antisepsis will be readily envisioned by those of ordinary skill in the relevant arts.
  • Antifouling coating compositions of the present invention can also contain a paint base such as vinyl, acrylic, and alkyd resin bases. They can also contain a pigment such as titanium dioxide, a thickener such as bentonite, fillers such as aluminum silicate and calcium silicate, and driers such as cobalt naphthenate and manganese naphthenate. They may also contain solvents or thinners such as mineral spirits, naphtha, benzene, toluene, methylethyl ketone, and the like.
  • compositions of the invention can be varied as required to optimize the overall chemical properties of the particular compound for specific uses, while retaining the AF activity.
  • the length of an alkyl chain can be extended or shortened to control the rate of dissolution of the compound from a structure or a coating.
  • additional functional groups can be added to the alkyl chain to further vary the chemical nature of the molecule.
  • a combinatorial library for the purposes of the present invention is a mixture of chemically related compounds which may be screened together for a desired property; said libraries may be in solution or covalently linked to a solid support.
  • the preparation of many related compounds in a single reaction greatly reduces and simplifies the number of screening processes which need to be carried out. Screening for the appropriate biological, pharmaceutical, agrochemical or physical property may be done by conventional methods. Diversity in a library may be created at a variety of different levels.
  • a library of substituted diversomers can be synthesized using the subject reactions adapted to the techniques described in the Still et al. PCT publication WO 94/08051, e.g., being linked to a polymer bead by a hydrolyzable or photolyzable group, e.g., located at one of the positions of substrate.
  • the library is synthesized on a set of beads, each bead including a set of tags identifying the particular diversomer on that bead.
  • the beads can be dispersed on the surface of a permeable membrane, and the diversomers released from the beads by lysis of the bead linker.
  • the diversomer from each bead will diffuse across the membrane to an assay zone, where it will interact with an enzyme assay.
  • MS mass spectrometry
  • a compound selected from a combinatorial library can be irradiated in a MALDI step in order to release the diversomer from the matrix, and ionize the diversomer for MS analysis.
  • the libraries of the subject method can take the multipin library format. Briefly,
  • Geysen and co-workers introduced a method for generating compound libraries by a parallel synthesis on polyacrylic acid-grated polyethylene pins arrayed in the microtitre plate format.
  • the Geysen technique can be used to synthesize and screen thousands of compounds per week using the multipin method, and the tethered compounds may be reused in many assays.
  • Appropriate linker moieties can also been appended to the pins so that the compounds may be cleaved from the supports after synthesis for assessment of purity and further evaluation (c.f, Bray et al. (1990) Tetrahedron Lett 31 :5811-5814; Valerio et al. (1991) Anal Biochem 197:168-177; Bray et al. (1991) Tetrahedron Lett 32:6163-6166).
  • a variegated library of compounds can be provided on a set of beads utilizing the strategy of divide-couple-recombine (see, e.g., Houghten (1985) PNAS 82:5131-5135; and U.S. Patents 4,631,211; 5,440,016; 5,480,971).
  • the beads are divided into separate groups equal to the number of different substituents to be added at a particular position in the library, the different substituents coupled in separate reactions, and the beads recombined into one pool for the next iteration.
  • the divide-couple-recombine strategy can be carried out using an analogous approach to the so-called "tea bag” method first developed by Houghten, where compound synthesis occurs on resin sealed inside porous polypropylene bags (Houghten et al. (1986) PNAS 82:5131-5135). Substituents are coupled to the compound- bearing resins by placing the bags in appropriate reaction solutions, while all common steps such as resin washing and deprotection are performed simultaneously in one reaction vessel. At the end of the synthesis, each bag contains a single compound.
  • a synthesis substrate is prepared for coupling through the covalent attachment of photolabile nitro veratryloxycarbonyl (NVOC) protected amino linkers or other photolabile linkers.
  • Light is used to selectively activate a specified region of the synthesis support for coupling. Removal of the photolabile protecting groups by light (deprotection) results in activation of selected areas. After activation, the first of a set of amino acid analogs, each bearing a photolabile protecting group on the amino terminus, is exposed to the entire surface. Coupling only occurs in regions that were addressed by light in the preceding step.
  • the reaction is stopped, the plates washed, and the substrate is again illuminated through a second mask, activating a different region for reaction with a second protected building block.
  • the pattern of masks and the sequence of reactants define the products and their locations. Since this process utilizes photolithography techniques, the number of compounds that can be synthesized is limited only by the number of synthesis sites that can be addressed with appropriate resolution. The position of each compound is precisely known; hence, its interactions with other molecules can be directly assessed.
  • the subject method utilizes a compound library provided with an encoded tagging system.
  • a recent improvement in the identification of active compounds from combinatorial libraries employs chemical indexing systems using tags that uniquely encode the reaction steps a given bead has undergone and, by inference, the structure it carries.
  • this approach mimics phage display libraries, where activity derives from expressed peptides, but the structures of the active peptides are deduced from the corresponding genomic DNA sequence.
  • the first encoding of synthetic combinatorial libraries employed DNA as the code.
  • a variety of other forms of encoding have been reported, including encoding with sequenceable bio-oligomers (e.g., oligonucleotides and peptides), and binary encoding with additional non-sequenceable tags.
  • the amine linking functionality on the bead was specifically differentiated toward peptide or oligonucleotide synthesis by simultaneously preincubating the beads with reagents that generate protected OH groups for oligonucleotide synthesis and protected NH2 groups for peptide synthesis (here, in a ratio of 1 :20).
  • the tags each consisted of 69-mers, 14 units of which carried the code.
  • the bead-bound library was incubated with a fluorescently labeled antibody, and beads containing bound antibody that fluoresced strongly were harvested by fluorescence-activated cell sorting (FACS).
  • FACS fluorescence-activated cell sorting
  • compound libraries can be derived for use in the subject method, where the oligonucleotide sequence of the tag identifies the sequential combinatorial reactions that a particular bead underwent, and therefore provides the identity of the compound on the bead.
  • oligonucleotide tags permits extremelyly sensitive tag analysis. Even so, the method requires careful choice of orthogonal sets of protecting groups required for alternating co-synthesis of the tag and the library member. Furthermore, the chemical lability of the tag, particularly the phosphate and sugar anomeric linkages, may limit the choice of reagents and conditions that can be employed for the synthesis of non-oligomeric libraries. In some embodiments, the libraries employ linkers permitting selective detachment of the test compound library member for assay.
  • Peptides have also been employed as tagging molecules for combinatorial libraries.
  • Two exemplary approaches are described in the art, both of which employ branched linkers to solid phase upon which coding and ligand strands are alternately elaborated.
  • orthogonality in synthesis is achieved by employing acid-labile protection for the coding strand and base- labile protection for the compound strand.
  • branched linkers are employed so that the coding unit and the test compound can both be attached to the same functional group on the resin.
  • a cleavable linker can be placed between the branch point and the bead so that cleavage releases a molecule containing both code and the compound (Ptek et al. (1991) Tetrahedron Lett 32:3891-3894).
  • the cleavable linker can be placed so that the test compound can be selectively separated from the bead, leaving the code behind. This last construct is particularly valuable because it permits screening of the test compound without potential interference of the coding groups. Examples in the art of independent cleavage and sequencing of peptide library members and their corresponding tags has confirmed that the tags can accurately predict the peptide structure. 2) Non-sequenceable Tagging: Binary Encoding
  • An alternative form of encoding the test compound library employs a set of non- sequencable electrophoric tagging molecules that are used as a binary code (Ohlmeyer et al. (1993) PNAS 90:10922-10926).
  • Exemplary tags are haloaromatic alkyl ethers that are detectable as their trimethylsilyl ethers at less than femtomolar levels by electron capture gas chromatography (ECGC). Variations in the length of the alkyl chain, as well as the nature and position of the aromatic halide substituents, permit the synthesis of at least 40 such tags, which in principle can encode 2 ⁇ 0 (e.g., upwards of 10 2) different molecules.
  • Some compounds disclosed herein are part of a combinatorial library.
  • a basis for the design of the combinatorial library will be to generate molecules containing functional groups derived from coumaric acid, zosteric acid, and other classes listed in the Examples linked to a spacer of varying structural lengths or conformations ( Figure 1).
  • a subset of the library may contain molecules with a single sulfooxy ester functional group attached to the spacer.
  • Another subset may contain similar coumaric acid substituents.
  • Functional groups may be derived from alcohol building blocks of varying structures (see figure 2) that are subsequently sulfonated to generate the sulfooxy ester moiety of zosteric acid (see figure 4).
  • Spacers will provide a site of attachment for functional groups as well as a linkage site to solid supports in order to facilitate solid phase synthesis of the combinatorial libraries.
  • An additional functional role of the spacer is to provide varying distances and orientations between the functional groups. It is expected these combinatorial libraries will yield novel molecules that more actively control bioadhesive mechanisms. (See figures 3 &
  • the first set of combinatorial libraries may be synthesized on solid supports using a cleavable linker (see figure 4). This would allow screening of library compounds to be carried out in solution (see figure 5). However, synthesis of combinatorial libraries in solution may also be carried out.
  • Combinatorial libraries of these compounds will be screened using a 96-well -based adhesion assay based on fluorescence tagging of bacteria or fungal spores. This screen may also be extended to include other organisms including viruses, yeast and invertebrate larvae. A summary of the screening approach is illustrated in figure 5 (Below).
  • the screening strategy includes both an adhesion and a viability assay in order to identify non-biocidile molecules with adhesion control properties. Active molecules identified through the above screening methods will then be advanced for further characterization. This will include structural determination, solubility properties, efficacy testing against a broad range of hosts and toxicity evaluations.
  • Compounds were packaged in 2-5 mg quantities in wells A02-D02 of a 96-deep well polypropylene microplate, tightly sealed with a plastic dimpled lid. The compounds were handled under slightly different conditions as they fell into two solubility classes. Compounds A02 and B02, insoluble in water, were dissolved in DMSO and tested at a final concentration of 0.5% with 5% DMSO, a concentration of DMSO that has no effect on any of the organisms used in the assays. Compounds C02 and D02, soluble in water, were dissolved in E-pure water, and tested at 0.5% after having been adjusted to the proper buffer condition for the assay.
  • LB growth media S. epidermidis (ATCC # 12228) is grown on nutrient agar plates from -70°C stock, a single colony should be picked and subcultured in LB media for overnight growth at 37°C shaking 200 rpm. Next day use 1/100 th volume of overnight culture to start new culture, this culture will need to grow for 4-5 hr which will be early log phase of growth.
  • Prep standard curve wells by adding 50 uL of 1XPBS in each well, 15 wells are needed for a 1 :1 dilution series starting at 0.5 - 0.03125 OD of cells in triplicate. Make dilutions and add the Syto 13 probe (luM final) fresh just before adding to the wells. The 9 wells below standards need to be saved for background controls, these also will need the probe as well. Working O.D. will be 0.0625 OD and Syto 13 probe is luM final, well volume is 100 uL. Once experimental samples have been incubated in the wells for a minimum of 10 min then add cells to each well according to final volume and concentrations.
  • Media and reagent preparation Marine broth (Defico 2216): make the medium according to the manufacture's instruction and autoclave for 20 min. There will be precipitation after cooling. Let sit for 1-2 days and transfer the clear part to a sterile bottle and store at RT. 80% seawater: It can be either filtered natural seawater (FSW) or artificial seawater (ASW, sigma S-9883). Autoclave to sterilize and store at RT PBS: see SOP PHY001 1 uM Syto-13: add 1 ul of 5mM stock (in DMSO) from Molecular Probe (Cat# 7575) to every 5 ml PBS. Preparation for cell material: Start culture in sterile marine broth late afternoon (ca.
  • Reagents Tap water 50/50 Oatmeal/PDA agar plates. C. acutatum is grown on 50/50 oatmeal PDA agar plates for 6-8 days. Seven days are optimal.
  • Compound D02 showed sufficient anti-adhesive activity in the Staphyloccocus assay to qualify for follow-up in a two-rate screen.

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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Structural Engineering (AREA)
  • Polymers & Plastics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Materials For Medical Uses (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne des composés présentant des propriétés anti-adhésives. Ces composés peuvent être des monomères ou des polymères. L'invention concerne également des méthodes de traitement de maladies induites par un récepteur au moyen des composés selon l'invention. L'invention concerne encore des procédés de protection des cultures, des dispositifs médicaux et des anti-parasites.
EP02725119A 2001-03-12 2002-03-12 Nouveaux composes anti-adhesifs et leurs utilisations Withdrawn EP1385821A4 (fr)

Applications Claiming Priority (3)

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US27522301P 2001-03-12 2001-03-12
US275223P 2001-03-12
PCT/US2002/007426 WO2002072020A2 (fr) 2001-03-12 2002-03-12 Nouveaux composes anti-adhesifs et leurs utilisations

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EP1385821A2 true EP1385821A2 (fr) 2004-02-04
EP1385821A4 EP1385821A4 (fr) 2006-03-08

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EP (1) EP1385821A4 (fr)
JP (2) JP4363850B2 (fr)
AU (1) AU2002255704A1 (fr)
CA (1) CA2441174A1 (fr)
WO (1) WO2002072020A2 (fr)

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US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
DE10246625A1 (de) 2002-10-07 2004-04-15 Basf Ag Verfahren zum Abtöten von Mikroorganismen
WO2008062466A2 (fr) * 2006-10-13 2008-05-29 Reliance Life Sciences Pvt. Ltd. Nouveaux agents chimiothérapeutiques contre l'inflammation et le cancer
CN103923243B (zh) * 2014-04-11 2016-06-01 东南大学 一种旋光聚乙炔红外低发射率材料及其制备方法
CN108367171A (zh) * 2015-12-24 2018-08-03 荷兰联合利华有限公司 用于生物膜控制的复合材料

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US5964794A (en) * 1996-03-21 1999-10-12 Biotronik Mess- Und Therapiegeraete Gmbh & Co. Ingenieurbuero Berlin Implantable stimulation electrode
WO2000016623A1 (fr) * 1998-09-23 2000-03-30 Phycogen, Inc. Agents antisalissures
WO2001074762A2 (fr) * 2000-04-03 2001-10-11 Phycogen, Inc. Generation de bibliotheques combinatoires synthetiques et criblage de nouvelles proadhesines et nonadhesines

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WO1992006127A1 (fr) * 1990-10-01 1992-04-16 Toppan Printing Co., Ltd. Polymere de cyclodextrine et film de cyclodextrine forme a partir de celui-ci
JPH04340960A (ja) * 1991-05-17 1992-11-27 Fuji Photo Film Co Ltd ハロゲン化銀カラー写真感光材料
DK137491D0 (da) * 1991-07-19 1991-07-19 Hempel Skibsfarve Fab S J Malingskomposition
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US4375461A (en) * 1980-07-25 1983-03-01 Johnson & Johnson Products, Inc. Sulfonated vinyl aromatic homopolymers and copolymers as dental plaque barriers
US5964794A (en) * 1996-03-21 1999-10-12 Biotronik Mess- Und Therapiegeraete Gmbh & Co. Ingenieurbuero Berlin Implantable stimulation electrode
WO2000016623A1 (fr) * 1998-09-23 2000-03-30 Phycogen, Inc. Agents antisalissures
WO2001074762A2 (fr) * 2000-04-03 2001-10-11 Phycogen, Inc. Generation de bibliotheques combinatoires synthetiques et criblage de nouvelles proadhesines et nonadhesines

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DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; FUJIMOTO, MASAHIKO ET AL: "Pesticidal wettable granules containing maleic acid-styrenesulfonic acid copolymer salts" XP002362386 retrieved from STN Database accession no. 1992:146192 & JP 03 236302 A2 (SANKYO CO., LTD., JAPAN) 22 October 1991 (1991-10-22) *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; OGAWARA, HIROSHI ET AL: "Tyrosine sulfate for inhibition of cancers" XP002362387 retrieved from STN Database accession no. 1995:94911 & JP 06 183963 A2 (NIPPON FLOUR MILLS, JAPAN) 5 July 1994 (1994-07-05) *
KINDNESS, G. ET AL: "Anticoagulant activity of polyanetholesulfonate in antithrombin III-deficient plasma" IRCS MEDICAL SCIENCE: LIBRARY COMPENDIUM , 7(12), 635 CODEN: IRLCDZ; ISSN: 0305-6651, 1979, XP008058194 *
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WANG, YONGMEI ET AL: "Intramolecular versus intermolecular formation of bityrosine upon photoreaction of poly(L-tyrosine) in dilute aqueous solution" POLYMER BULLETIN (BERLIN, GERMANY) , 28(3), 345-9 CODEN: POBUDR; ISSN: 0170-0839, 1992, XP008058100 *
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Also Published As

Publication number Publication date
EP1385821A4 (fr) 2006-03-08
JP2009149688A (ja) 2009-07-09
WO2002072020A2 (fr) 2002-09-19
CA2441174A1 (fr) 2002-09-19
WO2002072020A3 (fr) 2003-11-27
JP2004533416A (ja) 2004-11-04
JP4363850B2 (ja) 2009-11-11
AU2002255704A1 (en) 2002-09-24

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