GB2498356A - Derivatised calixarenes as coatings for implantable medical devices - Google Patents

Abstract

Implantable medical devices, such as catheters, which comprise a calixarene-derived coating that resists adhesion and/or colonisation of bacteria, the calixarene being bonded to the surface of the device via one or more surface linker groups (preferably derived from acid chloride, chloroformate or silane functional groups) on the rim of the calixarene and comprising on the opposing rim one or more polyethylene glycol, polypropylene glycol or polytrimethylene glycol groups, or a mixture thereof; the glycol groups being attached to the calixarene via C3-16alkylene spacer groups; the glycol groups being either attached directly to the alkylene spacer group or via another linking group (such as a carbonate, carbamate, urea, phosphate or triazole group); said glycol groups having 2-250 repeating glycol units and being optionally terminated by hydrogen or C1â 4alkyl. The most preferred calixarene is of the form: The calixarene is preferably bonded to a device with a silicone surface. Calixarene-derived coating materials, intermediates useful in their manufacture, and to processes for the coating of the implantable devices are also claimed.

Description

Novel Medical Devices The present invention relates to implantable medical devices, such as catheters, which comprise a calixarene-derived coating that resists adhesion andior colonisation of bacteria, to calixarene-derived coating materials, intermediates useful in their manufacture, and to processes for their preparation and coating of said devices.

The use of implantable medical devices is prevalent in the healthcare sector, such devices being either totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and which are intended to remain after the procedure. Associated with the use of implanted devices is the problem of biofilm build up resulting in irritation, inflammation and infection. Biofilms are thin layers of microorganisms, usually protozoa and bacteria, which aggregate on the surfaces of implanted devices causing the problems described.

Catheters are one of the most commonly utilised implantable medical devices and it is estimated that 25% of all hospital admissions use urinary catheterisation to assist with bladder drainage. Catheter Acquired Urinary Tract Infections (CAUTI) develop quickly after insertion ( 3% per day) and are currently the major cause of hospital acquired infections, accounting for 40% of all cases.. Treatment of these infections involves a combination of medication and longer periods of hospitalisation, raising costs and not always providing a satisfactory outcome for the patients affected.

Current methods directed at reducing the incidence of catheter-associated infections include a range of catheters that utilise impregnated surfaces that elute toxic or therapeutic substances intended to kill organisms colonising the surfaces. in order to reduce biofilm formation and adherence of bacteria. Catheters are available that possess coatings such as chlorhexidine and silver sulfadiazine, heparin, benzalkonium chloride, or release anti-infective compounds, such as nitrofurazone.

United Kingdom Patent Application GB 2,448,153 is directed to coated implantable medical devices having a calixarene-derived surface coating that is both hydrophobic and oleophobic. International Patent Application WO 97/39077 refers to a method for imparting a water repellent surface to a hydrophilic substrate using calixarcne-dcrivcd compounds. United States Patent Application US 2002/0102405 refers to surfaces comprising self-assembled monolaycrs that rcsist the adsorption of biological species.

International Patent Application WO 2004/018402 refers to methods for changing the surface properties of a material with an oligomer or polymer comprising open-chain aldehyde-phenol condensates. United States Patent Application US 2005/0221072 refers to medical devices having nanofibre enhanced surfaces for the prevention of biofouling.

International Patent Application WO 02/083176 refers to vehicles for use in tissue engineering and surgical procedures comprising a melanocyte stimulating hormone, which may bc associated with the vehicle by coupling with polyethylene glycol linkers or via a calixarcnc treated surface. International Patent Application WO 2006/048649 refers to a plasma system and methods for treating substrates, including providing substrates with siloxane-based coatings using coating-forming compositions comprising silicon-containing materials. Krishna et al, Biomaterials, 2005, 26(34), 7115-7123, refers to a plasma polymerisation method for covalently grafling phospholipid monolayers on a silicone catheter surface for reduction in platelet aggregation.

Silver et al, Biomaterials, 1999, 20, 1533-143, is directed to a study of the surface properties and hemocompatibility of alkyl-siloxane monolayers supported on silicone rubber. Chaudhury et al, Science, 1992, 255, 5049, refers to self-assembled monolayers of siloxanes on elastomeric polydimethylsiloxane. Papra et al, Langmuir, 2001, 17, 4090-4095, refers to the preparation of wettable and protein-repellent surfaces by grafting a polyethylene glycol layer onto polydimethylsiloxanc, silicon and gold surfaces by means of a plasma oxidation process. Schilp et al, Langmuir, 2009, 25(17), 10077- 10082, relates to a study of the settlement and adhesion of algal cells to self-assembled monolayers of oligo(ethylene glycol) and poly(ethylene glycol) on gold surfaces.

Herrwerth et al, J. Am. Chem. Soc., 2003, 125, 9359-9366, relates to a study of the protein resistance of oligoether self-assembled monolayers on gold and silver surfaces.

Ferguson et al refers to a plasma oxidative process for preparing self-assembled monolayers on disordered, polymeric substrates. Roth et al, Langmuir, 2008, 24, 12603- 12611, refers to a plasma oxidative process for preparing polydimethylsiloxane layers on silicon wafers.

Rebelc et al; Chem. Commun., 2010, 46, 8630-8632, refers to the use of oligocthylcncglycol groups as pendant chains to confer water solubility on resoreinarenes and refers to a calixarene having a -(C)alkylene-O(CH2CH2O)4CI-L substituent useftil as an intermediate. Reinhoudt et al, Synthesis, 1995, 989, is directed to the synthesis of self-assembling resorcinarene tetrasulfide adsorbates and refers to a calixarene having a -Cs)alkylene-CH2CH2 substituent useftil as an intermediate.

Foster et al, Chem. Commun., 2007, 2512-2514 is directed to octavalent resorcinarene-derived cross linkers for stabilisation of protein-protein interactions. Mulawka et a!, May 9, 2007, (bmedesign.engr.isc.edu/websites/file.php?fi1e890&id237), "Polyethylene glycol applied to latex urinary catheters", refers to a photopolymerisation process for coating latex with a mierolayer of polyethylene glycol. Redl et a], December 3, 2006, (bmedesign.engr.wisc.edu/websites/filc.php?file=1343&id=134), "PEG hydrogel coating of medical devices", refers to the coating of urinary catheters with polyethylene glycol based hydrogels in order to limit infections.

There exists a need for alternative or improved products that address the problems associated with current implantable medical devices. In particular, there is a need for implantable medical devices having an increased resistance to the build up of biofilm, preferably leading to a reduction in cases of irritation, inflammation or infection. Such devices would ideally possess an increased resistance to the adhesion and/or eolonisation of bacteria. In the eatheterisation field, it is desirable for new devices to be less susceptible to the adhesion and/or colonisation ofbacteria that result in catheter-acquired urinary tract infections. In particular, catheters would have an improved resistance profile permitting their use for longer periods, reducing patient discomfort through reduced number of catheter changes, and reducing irritation, inflammation and infection rates. New medical devices, including catheters, that show even a modest reduction in infection rates would be welcomed and would have a great impact on efficacy and cost of healtheare systems.

It is therefore an object of the present invention to provide medical devices, in particular, catheters, comprising a surface coating that helps to overcome these problems associated with current devices. Ideally, such a catheter surface, or that of another device, would offer one or more of the following advantages: -Provide superior resistance to biofilm development and encrustation.

-Biologically inert; will not cause inflammation or other side-effects.

-Durability; will remain attached the device surface without leaching coating materials, effective for duration of the device's life-time.

-Form a smooth, thin surface minimising patient discomfort.

-Non-pharmacologic, avoiding drug-drug / drug-patient interactions, eliminating the need for delivery systems, dosing, and drug testing, and does not stimulate the emergence of resistant organisms.

-Localised effect, limited to the exposed surfaces (interior and/or exterior) of the catheter.

The present invention accordingly provides an implantable medical device having a coating comprising a calixarene bonded to the surface of the device via one or more surface-linker groups on one rim of the calixarene, wherein the opposing rim of the calixarene is substituted by one or more polyethylene glycol, polypropylene glycol or polytrimethylene glycol groups, or a mixture thereof, said surface-linker groups may be bonded to the surface of the device via covalent bonds, ionic bonds, hydrogen bonds, or Van der Waals forces, said glycol groups are attached to the calixarene via (C3 to Cio)alkylene spacer groups, said glycol groups, each independently, have from 2 to 250 repeating glycol units and may be optionally terminated by hydrogen or (Ci to C4)alkyl, said (C3 to Ciü)allcyl spacer groups may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds.

When the medical device is implanted into a patient, the coating will preferably resist adhesion and/or colonisation of bacteria onto the surface of the device. Preferred embodiments of the device may provide a coating that, either as an alternative to, or in addition to resisting adhesion and/or colonisation of bacteria, has an antimicrobial effect.

Said antimicrobial effect will ideally be exhibited at a surface concentration that also provides a safe pharmacological profile.

The present invention encompasses any implantable medical device and, in particular, covers a medical device, which is a stent, catheter, vascular graft, cardiac pacer lead, heart diaphragm, suture, needle, angioplasty device, artificial joint, heart valve, neurological stimulator, drug pump or surgical mesh implant as reinforcement or scaffolding. Medical devices having a surface, in whole or in part, which comprise silicone or a layer of silicone are preferred. Catheters are the most preferred medical device to which the invention is directed.

Catheters may be made of any suitable material including, fbr example, silicone, latex, polyurethane, such as polycatbonate or polyether based materials, polyamides, such as nylon II and nylon 12, fluoropolymers, such as polytetrafluomethylene, polyolefins, such as polyethylene, PVC, polyimides, or polyether etherketone.

Most preferred are catheters made fmm silicone or having a silicone coating thereon.

Calixarenes are macrocycic molecules based on the condensation product of a phenol and an aldehyde and whose general siructure is that of a molecular bowl on legs with the rim of the bowl lined by hydroxyl groups and the legs consisting of long-chain alkyl groups. A detailed review of the different types of calixarenes and their methods of manufteture is given by Bohmer, Angew. Chem. hit. Ed. EngL 1995, 34, 713-745. The surface properties of the calixarenes may be suitably modified to impart the desired properties by altering the substituents on either the rim or the legs.

There are three main types of calixarene, prepared respectively from phenols, from resorcinols (resorcinarene) and am pyrogallols and aldehydes. The present invention is applicable to all these types of calixarenes, and encompasses devices having a coating derived from any onc of them. Preferably, the invention covers a device wherein the calixarene is a resorcinarene.

Preferably, the calixarene is bonded to the surface of the device via 2 to 8 surface-linker groups. More preferably, the calixarene is bonded to the surface of the device via 2 to 6 surface-linker groups. Most preferably, the ealixarene is bonded to the surface of the device via 2 or 4 surface-linker groups. Preferably, said surface-linker groups are bonded to the surface of the device via covalent bonds.

In a preferred aspect of the invention, the calixarene is covalently bonded to the surface of a device made from silicone or having a silicone coating thereon, via 2 to 8, preferably 2 to 6, most preferably, 2 or 4 surface linker groups.

In a preferred embodiment, the implantable medical device according to each aspect of the invention, comprises a calixarene having a rim substituted by one or more polyethylene glycol groups.

The glycol groups of the invention (polyethylene glycol, polypropylene glycol or polytrimethylene glyeol groups, or a mixture thereof) may be attached to the alkylene spacer group directly via the oxygen of the glycol or via another viable linker group.

Other suitable linker groups include, for example, carbonate, glycol ether, glycolateether, carbamate, urea, a43-amino ether, a-hydroxyacetamide ether, amide, imide, thioether, phosphate, phosphonate, sulphate, sulphonate and triazole.

Suitable linker groups include, for example, the following groups of Scheme A and Scheme B, which can be prepared using the methods shown.

Scheme A 0-Linkers o 0 PEGOX + H0-C3-C1aIixarene -PEG-UU-C3-C1aIixarene OH OC3C16_CaIixarene + X-C3-C1alixarene

PEG-U PEG-U

PEG_Ox + H0-C3-C1aIixarene PEG-O O-C3-C16Calixarene N-Linkers

O U

PEG_OAx +H2N-C3-C1aIixarene PEGUNC3-CCaIixarene

H

O U

PEG-N1X +H2N-C3-C1aIjxarene -PEG_NAN_CsCmCalixarene

H H H

NH2 HNCaC16_CaIixarene + X-03-C16Qaljxarene

PEG-O PEG-U

PEG_Ox +H2N-C3-C1aIjxarene PEG-UJ N-C 3-C alixarene

H

P-Linkers o U

II

PEG-OH + XTh 0-CC 6calixarene * PEG-O0 -C3-C1aIixarene or

U

II

PEG-Ut-0 -C3-C1aIixarene PEG° o U

II

II

PEG-0'_C C1aIixarene PEG-OH + XJ'-_C C15Calixarene o x or

U

II

rEG-o-'--C C1aIixarene PEG° Where X is an appropriate leaving group Scheme B S-Linkers PEG-X + HS -03-Cl aIixarene -PEG-S-C3-C16calixarene o o PEG-N + HS-C3-Ci5Calixarene PEG-N o o 0 0 PEG + HS-C3-C1aIixarene -PEG N C3C16_CaIixarene

H H

PEG-O + HS-C3-C1aIixarene r PEGOt3C1e_CaIixarene O 0

II II

PEG-OH + XSC3CleCaIimne r PEG0 C3-CIe_Calixarene O 0 Cyclic Linkers

N

PEG-O-AIk4 fl + N3-C3-C1aIixarene j,NC3-CiaIixarene PEG-0-AlIwl Includes other cycIoaddion chemistries eg. Diels-Alder and photochemically inithted cycloadditions C-Linkers PEG-O-A1ks4--% + -C3-CCalixarene -PEG_O_AlkYl_%__CsCiahxarene / H 0 PEG-O-Alkyl---+ AIkYIo_CaCl6CaIrene 0 AlkylO

V

PEG-O-AlkyH "-C3-C1 alixarene Other Linkers

OH

PEG-Nuc + OC3-C16Calixarene Nuc -Calixarene

PEG O 0

COMe + N3C3C16_Calixarene N_C3CIO_Calixarene

PEG PEG

I I

R

Where X is an appropriate leaving group R is an appropriate aryl, alkyl, or PEG group Nue is 0, NH2, S Prcferably, thc glycol groups are linkcd dircctly via the oxygen of the glycol or via another linker group selected from carbonate, carbamate, urea, phosphate and triazole.

Most preferably, the glycol groups are attached to the alkylene spacer group via a carbonate linker.

The calixarenes of the present invention are preferably derived from phenols, resorcinols or pyrogallols, or mixtures thereof In a preferred cmbodiment, the present invention provides an implantabic mcdical device having a coating comprising a calixarene bonded to the surface of the device via oe or more surface-linker groups on one rim of the calixarene wherein said calixarene is derived from a compound of formula (I) x

Y Y

R R

Y Y z

X Z Z

-z / /

Y Y \ (I)

wherein X is H, (Ci-C4)alkyl, NH2, NH(Ci-C4)alkyl, N(Ci-C4)alkyl2 or Cl-12N1-1(Ci-C4)alkyl, and Y is OH, O(Ci-C4)alkyl or OCI-12C02(Ci-C4)alkyl; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)allcyl, and Y is H, (Ci-C4)alkyl, NH2, NH(C1 -C4)alkyl, N(Ci -C4)alkyl2 or CH2NH(C1 -C4alkyl; or X andY are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; Z is H, OH or methyl; nis 1,3or 5; and R is -(C3-C16)alkylenc-L1-G-R1 wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L is a bond or a linking group; G is 0(CH2CH2O)ni, -O(CH2CH(CH3)O)1-, -O(CH(CH3)CH2O)rn-, or -O(CH2CH2CH2O)m-; mis2to25O; R1 is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R' group may be the same or different.

Preferably, X is H and Y is OH.

Preferably, Z is H. Preferably, n is 1.

Preferably, R is -(Cio)alkylene-L1-G-R1. Preferably, L' is a linking group selected from those of Scheme A and Scheme B above. More preferably, L1 is a linking group selected from carbonate, carbamate, urea, phosphate and triazole. More preferably, L1 is carbonate.

Preferably, G is -O(CH2CH2O)111-. Preferably, m is 3 to 150. More preferably, mis 6 to 50. Mostpreferably,mis 15 to 25.

Preferably, R1 is H or methyl.

In a preferred aspect of the present invention said calixarene, which is derived from a compound of formula (I) or preferred embodiments thercoL is bonded to the surface of the device via surface linker groups substituted for any one or more of the X or Y substituents, or a combination thereof Preferably, the surface inker groups X or Y, or a combination thereof on the calixarene are derived from acid chloride, chloroformate or silane ftrnctional groups.

More preferably, the surface linker groups are derived from silane firnetional groups, which form one or more siloxane bonds with a device having a silicone surface.

Yet more preferably, the surface linker groups X and/or Y are L2-Si(R2), or X and an adjacent Y group together form calixarene L2 isaspacer group; R3 is (C2-Cio)alkylene-Si(R2)3, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; Si(R2)3 is selected from Si[O(Ci-C4)allcyl]3, SiCI3, Si[(Ci-C4)alkyl]2C1 and Si[(Ci-C4)alkyl]C12; each ailcyl and each surface linker group may be the same or different; and said silanc providing frmnctionality for bonding to the surface of the device.

Preferably, L2 is selected from OC2-Cio)alkylene, CH2NHC2-Cio)alkylene, OCI-12C02(C2-Cio)alkylene and OCFI2CONH(C2-Cio)alkylene, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds.

In a further aspect, the present invention provides a compound of formula (I) x

Y Y

R R

Y V z

X Z Z

-z / / \ x (I *) S wherein X is H, (Ci-C4)alkyl, NH2, NH(Cj-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4alkyl, and Y is OH, O(Cj-C4)aflcy or OCH2CO2(Cj-C4alky; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)allcyl, and Y is H, (Ci-C4)alkyl, NH2, NH(C1 -C4)alkyl, N(Ci -C4)alkyl2 or CH2NH(C1 -C4alkyl; or X and Y are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; Z is H, OH or methyl; n is 1,3 or 5; and R is -C5-Cio)allq'1ene-L'-G-R' wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 isa bond or a linking group; G is 0(CH2CH2O)m, 0(CH2CH(CH3)O)nr, 0(CH(CH3)CH2O)m, or -O(C1-12CH2CI-12O)1-; m is 2 to 250; R' is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R1 group may be the same or different; with the proviso that when X andY are OH; Z is H; and n is 1; R is not -(C)alkyIene-O(C H 2C H 2O)4C H3.

Preferably, X is H andY is OH.

Preferably, Z is H. Preferably, n isi.

Preferably, R is -(Cig)alkylene-L1-G-R1. Preferably, L' is a linking group selected from those of Scheme A and Scheme B above. More preferably, L' is a linking group selected from carbonate, earbamate, urea, phosphate and triazole. More preferably, L' is carbonate.

Preferably, G is -O(CI-I2CH2O)111-. Preferably, m is 3 to 150. More preferably, m is 6 to 50. Most preferably, mis 15 to 25.

Preferably, R' is H or methyl.

In a ifirther aspect, the present invention provides a compound of formula (II) x

Y Y

R R

Y Y

/\ \/X

IR R

Y Y (II)

wherein X is H, (Ci -C4)alkyl, NH2, NH(C -C4)alkyl, N(Ci -C4)alkyl2 or CH2NH(C -C4alkyl, and Y is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; or X is OH, O(Ci-C4)allq'l or OCH2CO2(Ci-C4)allcyl, and Y is H, (Ci-C4)alkyl, NH2, NH(Ci -C4)alkyl, N(C1 -C4)alkyl2 or CH2NH(Ci -C4)allyl; or X andY are each independently 01-1, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; and any one or more X or Y groups, individually or in combination, may be substituted for a surface linker group; Z is H, OH or methyl; n is 1, 3 or 5; and R is -(C3-Cio)alkylene-L1-G-R1 wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 is a bond or a linking group; G is -0(CH2CH20)1-, 0(CH2CH(CH3)0)nc 0(CH(CH3)CH2O)m, or -O(CH2CH2CH2O)m-; mis2to25O; R1 is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and Rl group, and each surface-linker group, may be the same or different.

Preferably, the surface-linker groups X or Y, or a combination thereof, on the calixarene are acid chloride, chloroformate or silane functional groups.

More preferably, the surface-biter groups X or Y, or a combination thereof, on the calixarene are silane functional groups, which may form one or more siloxane bonds with a device having a silicone surface.

Yet more preferably, the surface-linker groups X and/or Y are L2-Si(R2), or X and an adjacent Y group together form Calixarene Oh L2 is a spacer group; R3 is (C2-Cio)alkylene-Si(R2)3, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; Si(R2)3 is selected from Si[O(Ci-C4)alkyl]3, SiCI3, Si[(Ci-C4)alkyl]2C1 and Si[(Ci-C4)alkyl]C12; and each alkyl and each surface-linker group may be the same or different.

Preferably, L2 is selected from O(C2-Cio)alkylene, CH2NH(C2-Cio)alkylene, OCH2CO2C2-Cio)alkylene and OCH2CONHC2-Cio)alkylene, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds.

Preferably, X is H and Y is OH.

Preferably, Z is H. Preferably,nis 1.

Preferably, R is -(Cio)alkylene-L1-G-R1. Preferably, L1 is a linking group selected from those of Scheme A and Scheme B above. More preferably, L1 is a linking group selected from carbonate, earbamate, urea, phosphate and triazole. More preferably, L1 is carbonate.

Preferably, G is -OCH2CH2O)111-. Preferably, m is 3 to 150. More preferably, mis 6 to 50. Mostpreferably,mis 15 to 25.

Preferably, R1 is H or methyl.

In a preferred aspect, the compound of formula (II) is R3 P3

HO RR OH HO RR OH

HOHor HH wherein R is -(Cjo)alkylene-OC(O)O-(CH2CH2O)111-OH; and R is (C3)alkylenc-Si(OEt)3 or a combination thereof Preferably, m is 3 to 150. More preferably, mis 6 to 50. Most preferably, mis 15 to 25.

In a further aspect, the present invention provides a compound of formula (III) x

Y Y

R R Y 1

/\ \/X / (n I

K x (III)

S wherein X, Y, Z and n arc as defined herein including all aspccts and prcfcrrcd cmbodimcnts thereof; and R is -(C3-Cio)alkylene-OH or -(C2-C15)a&ylenc-CH2CH2 wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; and wherein each X, Y, Z and R group may be the same or different; with the proviso that when X is H, OH, CH3 or OCH; Y is OH; Z is H; and n is 1; R is not -(Cg)a&ylene-CH2CH2.

In a further aspect, the present invention provides a process for coating a silicone surface of an implantable medical device, as defined herein, which comprises plasma activation of the silicone surface of the device followed by reaction with a compound of formula (II) as defined herein.

In a frirther aspect, the present invention provides an implantable medical device preparable by a coating process as defined herein.

Included within the scope of the present invention are all stereoisomers, geometric isomers, tautomeric forms, and all medically acceptable isotopically-labellcd compounds of formula (I), (TI) and (III), and all implantable medical devices derived therefrom.

Processes The compounds and devices of the present invention as described herein may be prepared according to the following methods.

Formation of Protected Rcsorcinarcnc PEG acceptors' 1) -ii) -iii) -z c6-c13 z c6-c13 z c6-c13 1 2 3

OH

PG PG PG PG PG PG

iv) v) ;c;II:J:T1_ Z C6-C z C6-c Z C6-C3 Scheme 1-Compound 1 synthcsiscd according to Reinhoudt reference (Synthesis, 1995, 989) provided from suitable phenol and aldehyde or acetal in an alcoholic solvent such as ethanol under acid catalysis. ZH, OH, Me.

Compound 2; PG=Suitable protecting group, such as tButoxycarbonyl.

Compound 4; X Appropriate leaving group-halide, mesyl, tosyl or sulfonyl derivative such as 4-nitrophenylsulfonyl.

Conditions: 1) Appropriate protection sequence-representative is di-tertbutyl dicarbonate with a nuclcophilic catalyst (Ic. pyridine or 4-dimethylaminopyridine) in a suitable solvent, such as dichloromethane. Another common one is appropriate acetyl chloride eg.

trimethylacetyl chloride with suitable base, eg. triethylamine, diisopropylethylamine in suitable solvent eg. dichloromethane.

ii) Borane or suitable alkylborane, such as dieyclohexylborane at 0-3°C in a solvent such as tetrahydrofuran, followed by hydrogen peroxide and aqueous solution of suitable hydroxide base such as sodium hydroxide.

iii) Suitable phosphine eg. triphenylphosphine, halide donor such as carbon tetrabromide in dichloromethane or similar, or a sulfonyl chloride eg. p-toluenesulfonyl chloride, base such as triethylamine, pyridine, 4-dimethylaminopyridine in suitable solvent eg.

dichioromethane.

iv) Azide donor, such as sodium azide, trimethylsilyl azide in suitable solvent eg.

tetrahydrofliran.

v) Suitable phosphine eg. triphenylphosphine in appropriate solvent eg. dichloromethane, or hydrogen and palladium on carbon in appropriate solvent eg. ethanol.

PG PG PG PG

2 vi) viii) z c6-c13 z c6-c13 4> Ac

PG

z c6-c13

H s02c1

Scheme 2 Conditions: vi) thiolaeetic acid, suitable radical initiator such as azo(bisisobutyryl)nitrile, heated to 80°C or irradiated with a LV lamp in toluene or similar solvent vii) Suitable thioaeetate salt, such as potassium thioacetate in appropriate solvent eg. tetrahydrofuran.

viii) Suitable base, such as piperidine, pyrrolidine, ammonium hydroxide. Alternative is reductant such as lithium aluminium hydride in suitaNc sovcnt eg. tctrahydrofiiran. ix) N-ehlorosuecinimide, hydrochloric acid, appropriate solvent such as aeetonitrile.

PG PG PG PG

x) xii) -z c6-c13 z c6-c13

H H

STr 8 SI-I Scheme 3 Conditions: x) Suitable phosphine eg. triphenyiphosphine, suitable azodicarboxylate eg.

diethylazodicarboxylate, triphenylmethanethiol in suitable solvent such as dichioromethane or tetrahydrofttran. xi) triphenylmethanethiol, suitable base eg. sodium hydride or potassium tertbutoxide in suitable solvent eg. tetrahydroftiran. xii) trifluoroacetic acid, suitable silanc eg. triisopropylsilanc in appropriatc solvent cg.

dichloromethane.

PG PG O(O xHi) 3 I H

z c6-c13

H a. o

xiv) _tIIICT1._ xv)ithI.f!= z c6-c13 z c6-c13 z c6-c13

H H H

9=0 _P=O 12 J 13 14 Scheme 4: Compound 11: X2 = Appropriate halide, such as Cl, Br Compound 12: Y Appropriate substituent eg. alkoxy, trimethylsiloxy Compound 14: Y2= Appropriatc halidc cg. Cl, Br.

Conditions: xiii) phosphorus oxychloride (3 equivalents) or similar P(V) compound in suitable solveilt eg. diehloromethane, or phosphorus trichloride (3 equivalents) or similar then suitable oxidant eg. 12, and base such as pyridine in appropriate solvent eg.

acetonitrile. xiv) suitable phosphite eg. triethyiphosphite heated at 130-160°C. xv) An alkylsilyl halide, such as trimcthylsilylbromide in suitable solvent eg. dichioromethanc, followed by methanol. xvi) Appropriate halide donor, such as thionyl chloride.

PG PG xvii)

7 C6-C1 Scheme 5 Conditions: xvii) appropriate oxidant such as meta-chloroperbenzoic acid in suitable solvent eg. dichloromethane.

Formation of PEG-rcsorcinarcnc conjugates

-

PG PG A'R2

I I I O%_tO

xviii) tLfft xix) OH OH z 613 "PH [OH XX Z C-C 16 H OH z c6-c13 OH 17 Hz C6-C

OH OH A' R2

HOH n-rn

z C6C z O-fO OyO 0 0

I I

PEG PEG

PG PG PG PG HO.tOH 0(0 xx) xvi Z C-C xix) z c6-c13 z c6-c13 H H HNtO NH2 HNO R 6 19 1 20 PEG

PEG

-A' R2

OH OH

7 C6C13 Z Ce-Cia 21 HNtO HNtO

PEG PEG

Scheme 6: Compounds 17, 21; A= appropriate spacer group R2= Halide, alkoxy Compound 18, 20, 21; D= 0, NH, CH2 PEG= polyethylene glyco repeat unit >3, terminus OH, OAlkoxy Conditions: xviii) Suitable deprotection strategy ie. heating under vacuum to 130°C for PGCO2tBu. xix) 37% aq.formaldehyde (25 equivalents), suitable a,w-aminosilane eg.

3-(aminopropyl)triethoxysilane. Refluxed in an alcoholic solvent eg. ethanol. xx) suitable PEG-electrophile ie. PEG-chloroformate, PEG-isocyanate, appropriate amine base eg. triethylamine in a suitable solvent eg. dichloromethane, tetrahydrofuran.

PG PG HOH

xxi) z c6-c iH 6 xix) z c6c13

E

4 22 PEG 23 PEG sRR2 R2 6 6

E E

PEG PEG

Scheme 7: Compounds 22-24; E= 0, NH, S Conditions: xxi) Suitable nucleophile-terminated PEG, such as alcohol, amine or thiol-terminated PEG, appropriate base eg. sodium hydride or triethylamine in a suitable solvent ic. tetrahyclrofuran.

PG PG

I HO OH

°_iti xvhi z C5-1 N3 N3 25 xix) KR2 in n-rn z cGc:; z C61 26 N3 N3

-

A' R2 t!I-xxi) thiR2 A' R2 N OHOH (

OH -ft

in n-rn z c6cL; z c6cL; z c6cL; z CG-9:,; HN 0 NH F(O)(Y3)2 N SN (Y3)2(O)P OAc5

F F

I I

PEG PEG

27 PEG Scheme 8: Compound 27; suitable spacer group; ie. alkyl.

Compound 28; Y3= PEG, alkyl, aryl S Conditions: xxii) Appropriate alkyne-terminated PEG species, catalytic Cu(I) salt. (iOMe

PEGP

Suitable solvent. xxiii) , suitable solvent eg. 2:1 tetrahydrofuran: water wJTh

I S.

--C

N

NJ N\/

nI 0 0

NJ NJ ___ 3 p \)9

-___

I N*_ 4'= 9

C 9 00

o N r I In (A o

I In / >< S

S

N N

0 -z/o 0 0 2 NJNJ /\I , 9:

C

o 0;a I In 0 0 PG PG PG PG HOytOH oio xxvH xvhiç Z C69 xix)

H

SO2CI o==o PEG 9 9 3 PEG 5 A' R2 oH0oH z c6-c13 c6-c13

HH o=s=o

PEG PEG

Scheme 9 Conditions: xxiv) suitable maleimide-terminated PEG, appropriate s&vent eg.

dichioromethane. xxv) suitable a-haloamide-terminated PEG eg. a-bromoaeetamidyl PEG, suitable solvent eg. tetrahydrofliran. xxvi) appropriate olefin-terminated PEG, eg.

0-allyl PEG, suitable solvent eg. tetrahydroftiran. xxvii) appropriate PEG species, eg.

methoxyPEG-350, suitable base eg. triethylamine, pyridine, 4-dimethylaminopyridine, suitable solvent eg. diehioromethane.

PG PG PG PG HO-OH O%O

ii) iH) ___ Z C6 xix) Z xxvi -Z C5-C13.

O_ 0 O O Y4_ X2 Y4_ 38 PEG 37 PEG A' -

OH OH

OH

Hi " Inm Z e6c1 Z 0 0

I I

Y4-=O y(I'=O

PEG PEG

PG PG

I I HO-OH

PG PG o-o _______ xvih) _______ xxviii) _______ _______ z ca-cia ______ Z C6 013 xix) P=O Y4-_ I P0 V4 PEG z PEG 41 14 40 K R3

OH OH rn N

Z C6-C13 y4=O

PEG I

PEG

Scheme 10: Compounds 37-42; Ye0, OPEG.

Conditions: xxviii)suitable PEG eg. methoxyPEG-350, suitable base eg. triethylamine, appropriate solvent eg. dichioromethane.

PG PG

I I PG PG

O----O

Z C6C13 ZC6 -P=O xxix) A' R3

PG PG

OH 0 -0

xviii) xi Z CeCl3 x) m n-rn Z CsC13 CeC13

Z CC OPEG OPEGOPEG

xxxi)I 45 A' R3

PG PG HO

I I

xviii) .Ii1T Z 06-013 x) m n-rn Z CsC13 Z C6C13 z:OPEG OPEG OPEGOPEG Scheme 11 Conditions: xxix)appropriate aldehyde-terminated PEG eg. PEGOCH2CI-1O, suitable strong base 0g. potassium tertbutoxide, suitable solvent 0g. N,N-dimethylformamide.

xxx) Suitable olefin metathesis catalyst, eg. Grubb's 2nd generation catalyst, suitable solvent, eg. toluene. xxxi) appropriate reduction, eg. Lindlar's catalyst, hydrogen, suitable alcoholic solvent, 0g. ethanol.

PG PG PG PG HO OH

xxi) xviii) 706-013 xix) Z C,-C Z C,-C

I HO

E

o HO PEG

PEG P3 49 A' R3

OH OH

Z C6-C13 06-013 HOb HOb E..PEG EPEG Scheme 12: Compounds 49-51; E= 0, NH, S. Conditions: As previously described.

Methods for the preparation of the resorcinarene of formula (I) and processes for coating materials are disclosed in WO 97/39077 and at http://www.rsc.org/pdf/meg/shefcotes.pdf Other suitable methods for coating medical devices are known to those skilled in the art and include, e.g. methods described in WO 2005/112570, US 6702850, US 6602287, US 5053048, US 7070798 and US 2002/0102405. The surface of the medical devices may also be subject to treatment to modify the surface properties prior to coating such as disclosed in US 4445998 and Kim, Surface and Coatings Technology, 171, 2003, 312-316.

Experimental Details Instrumentation All NMR spectra were recorded on a Bruker AV400 spectrometer operating at 400MHz for 1-i and 101MHz for 13C, a Brulcer AV250 operating at 250MHz for H and 63MHz for 3C, or a Bruker DPX operating at 400MHz for H and 101MHz for 13C, with chemical shifts reported in parts per million (ppm). 1H spectra were referenced against the appropriate residual solvent signal; CDCb = 7.26ppm, Acetone = 2.O5ppm. 1t spectra were also referenced against the appropriate solvent signal; CDC13 = 77.1 6ppm.

Acetone = 206.2ôppm.

Mass spectra were obtained on a Waters LCT spectrometer for electrospray (ES) experiments, and a Bruker Reflex III for matrix-assisted laser desorption ionisation (MALDI) experiments.

Infrared (IR) spectra were obtained on either a Perkin Elmer Paragon 1000 spectrometer equipped with a SensIR Technologies DuroSampllR ATR accessory, or a Perkin Elmer Spectrum 1 00 spectromcter fitted with an ATR attachment.

Plasma treatment of samples was performed in a home-built plasma generator, operating at a pressure of 1x10'mbar, and at a forward power of approx. 100W at 13.5MHz.

Chemicals and Materials All reagents were purchased from Sigma-Aldrich, Alfa-Aesar or Fisher Scientific. Air-sensitive reactions were performed in flame-dried glassware, and under a N2 atmosphere.

Anhydrous solvents were obtained from a Grubbs solvent purification system except for acetone, which was purchased from Fisher Scientific. Flash column chromatography was performed using Davisil silica gel, and visualised on preeoated Merck F254 silica plates using IJV light or KIVInO4 dip.

Silastie catheters were obtained from Bard, USA, and sheet Silastie silicone was obtained from Dow Chemicals.

Deeenyl resoreinarene 1

HO H H H OH H H OH

To an ice-cold solution of resorcinol (10Mg, 90.82mmol.) in 3:1 EtOH:c.HCI, undecylenic aldehyde (18.87mL, 90.82mmol.) was added dropwisc under N2. Once addition was complete, to reaction was warmed to 25°C, then to 75°C, and stirred for 48h. The reaction was cooled, and any precipitate filtered off. The filtrate was poured into ice-water, and any further precipitate filtered off The combined solid was recrystallised twice from MeCN to yield the title compound (10.96g. 46%) as light orange/beige powder.

H (400MHz, Acetone) 8 (ppm) = 7.56 (s, 4H, Ar H), 6.25 (s, 4H, Ar H), 5.82 (ddt, J=17.0, 10.2, 6.7Hz, 41-1, CI-l2CHalkyl), 5.07 -4.86 (m, 8H, CH2CHaIkyI), 4.30 (t, J 7.9Hz, 4H, ArCHAr), 2.30 (dd, J 14.3, 7.6Hz, 8H, CH2CHCH2CH2), 1.45 -1.17 (m, 64H, alkyl H).

3C (101MHz, Acetone) 3 (ppm) = 152.69, 139.92, 125.52, 125.24, 114.78, 103.67, 34.62, 34.43, 34.37, 30.64, 30.53, 30.41, 29.98, 29.87, 29.11.

MS (ES) m'z = 1042 ([MH], 9%), 1059 ([M-{-NH4f, 100%).

HRMS(ES')nVz 1041.7233, C63H9708 requires 1041.7183.

JR (powder) v (cnf') = 3192.0 (br., str., OH stretch), 2923.6, 2853.0 (str., CH stretch), 1640.8 (C=C stretch), 1616.8, 1497.1 (Ar ring), 1443.6 (CH deformation).

Octa-Boc decenyl resorcinarene 2 Boc Boc Boc Boo Boc Boo 7'oIdBoc A stirred solution of 21 (2.OOg, 1.92mmol.), Boc2O (3.69g, 16.9Ommol.), and pyridine (0.lmL) in acetone (25mL) was heated under N2 for 15h at reflux. The reaction was concentrated in vacuo to give the title compound (3.20g. 90%) as viscous clear brown oil, which was used without ffirthcr purification.

H (400Mhz, CDCR) S (ppm) = 6.91 (br.s, 3M, Ar H), 5.78 (ddt, J= 16.9, 10.2, 6.7Hz, 4H, CH2CHaIkyI), 5.05 -4.83 (m, 8H, CH2CHaIIy1), 4.31 (t, J= 7.4Hz, 4H, ArCHAr), 2.07 -1.94 (m, 15H), 1.85 -1.80 (m, 8H), 1.48 (s, 72H, l'Ie3CO), 1.40-1.14 (m, 58H, alkyl H).

3C (63MHz, CDC13) S (ppm)= 184.33, 151.48, 147.37, 139.31, 132.66, 126.21, 116.76, 114.19,82.76,36.59,35.17,33.93,29.94,29.78,29.29,29.09,28.10, 27.80, 1.95.

MS (MALDE) m!z (arb. intensity units) = 1864 ([M+Na], 140), 1880 ([M--KI, 270).

JR (oil) v (cni') = 2983.0, 2926.7, 2852.5 (str., CH stretches), 1754 (str., C=O stretch), 1601.0, 1498.4 (Ar ring), 1461.2 (Cl-I deformations), 1396.0, 136S.3, 1241.7, 1139.6 (str., C-O stretch).

w-hydroxydecyl octa-Boc resorcinarene 3 Boo Boo Boo B0CB00 Boo 15;%/d'tBoG H To an ice-cold stirred solution of 2 (3.20g, 1.73mmol.) in THF (4OmL), BH.THF complex (9.69mL, 1M solution in THF) was added dropwise. The reaction was stirred at 0°C for 30mm under N2, then warmed to 25°C and stirred for 5 days. To the reaction H20 (2mL) was added slowly at 0°C, followed by H202 (5mL, lOOvol.) and IM NaOH (SmL). This was stirred at 25°C for lh, then at 50°C for 4h. The crude reaction mixture was poured into H20, and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo to yield the title compound (2.846g. 86%) as extremely viscous clear colourless oil.

H NMR (250 MHz, CDCI3) 6 = 6.82 (br.s, 4H, Ar H), 4.26 (t, J 7.1 Hz, 4H, ArCHAr), 3.49 (t, J 5.9 Hz, 8H, CH2OH), 1.44 (s, 72H, %Ie3CO), 1.18 (d, J 8.2 Hz, 76H, alkyl chain).

1 (101MHz, CDCI3) 6 (ppm) = 151.41, 107.96, 82.74, 63.00, 36.45, 32.78, 29.73, 29.66, 29.45, 29.14, 27.67, 25.77, 23.93, 1.03.

MS(MALDI)m/z(arb. intensity units) 1936 ([M+Na]',80).

JR (oil) v (cm1) = 3420.0 (br.w., OH stretch), 2980.3, 2927.9, 2854.0 (str., CH stretches), 1754.6 (str., C=O stretch), 1494.9 (Ar ring), 1459.3 (CH deformations), 1394.3, 1369.7, 1240.6 (str.,OH bending), 1138.8 (str., C-O stretch).

w-hydroxyd ecyl resorcinarene 4

OH OH

A flask containing 3 (2.89g, 1.Slmmol.) was heated at 130°C under vacuum until the molten resorcinarene re-solidified. This gave the title compound (1.29g, 77%) as a yellow/white powder once scratched from the flask.

H NMR (400 MHz, Acetone) 6 (ppm)= 8.48 (br. s, 8H, ArOH), 7.56 (s, 4H, Ark), 6.24 (s, 4H, ArH, 4.31 (t, J 7.9 Hz, 4H, ArCHAr), 3.54 (t, J 6.5 Hz, 8H, CH2OH), 2.95 (br. s, 4H, OH), 2.37 -2.22 (m, 8H, CH2CH2OH), 1.58 -1.44 (m, 8H, (Ar)2CHCH2), 1.43 -1.22 (m, 72H, alkyl chain).

3C NMR (101 MHz, Acetone) 6(ppm) = 152.84, 125.60, 125.37, 103.88, 62.69, 34.47, 34.38, 33.91, 30.70, 30.56, 30.53, 29.12, 26.90.

MS (MALDI) m/z (arb.intensity units) = 1120 ([M+Li] , 310), 1136 ([M+Na] , 270).

IR (solid)v (cm') = 3222.6 (br. str., OH stretch), 2923.1, 2852.4 (sh. str., CH stretches), 1619.4, 1495.0, 1444.0, 1293.8, 1155.5, 1085.9, 1049.9, 845.5.

Silane S (EtO)3Si\ rI_SI(OEt)3

H H H OH H H N

OH OH OH OH

A stirred solution of 4 (250mg, 0.22mmol.), formaldehyde (0.5OmL, 5.SOmmol., 37% aq.solution) and (3-aminopropyl)triethoxysilane (0.41 m L, I.76mmol.) in EtOI-I (5mL) was heated at reflux for 16h. The volatiles werc removed in vacuo, and the residue triturated in hexane twice, giving the title compound (4 19mg, 91%) as red/orange solid.

Partial H NMR (400 MHz, CDC13) 6 (ppm) = Characteristic signals at 4.70, 4.40 (s, ArCHN), 3.80 (q, OCH2CH,), 3.70 (s, OCH2N), 1.25 (t, OCH2CH).

JR (solid) v (eni1) = 3346.6 (hr. OH stretch), 2970.4, 2925.5, 2853.4 (str. CH stretches), 1598.9, 1468.7 (Ar ring), 1100.3, 1073.0 (sh.,str. C-O and Si-O stretches), 952.0, 882.8, 775.0 (br., str. C-Si stretch).

Monomethyl PEG-350 chloroformate 6 To a flask containing ice-cold phosgene solution (4.26mL, 20% in PhMe), PEG-350 (2.10g. 6.OOmmol.) was added slowiy. The mixture was stirred at 25°C under N2 for 4h, and then purged with a flow of N2 for 20mm to remove excess phosgene. The solvent was removed in vacuo to yield the title compound (2.35g, 95%) as clear colourless oil.

H (400MHz, CDC1,) 6 (ppm) = 4.46 -4.38 (m, 2H, CH2OCOC1), 3.78 -3.70 (m, 2H, OCH2CH2OCOCI), 3.67 -3.57 (m, 22H, OCH2), 3.51 (dd, 5.8, 3.6Hz, 2H, CH2OMe), 3.34 (s, 3H, OMe).

3C (101MHz, CDCh) 6 (ppm)= 150.81, 71.98, 70.83, 70.71,70.63,70.56, 68.31, SS.07.

MS (ES) m/z = 271,315,359,403,447,491,535,579, 623, 667, 711, 755, 799.

JR (oil) v (cni') = 2869.6 (br., str. CH stretch), 1775.1 (sh., str., C=O stretch), 1098.5 (br.,str. C-O stretch), 842.6 (str., C-Cl stretch).

PEG-350 carbonate 7 (1S1(OEt)3 (EtO)SS1\s at-0 ato at0 ofo i] i?i. LL h To a stirred ice-cold solution of 5 (419mg, O.2Ommol.) and triethylamine (0.l5mL, 0.84mmol.) in DCM (2OmL), 6 (413mg, 1.OOmmol.) in DCM (5mL) was added dropwisc. The reaction was stirred at 25°C for 16h, and then diluted with DCM. The organic phase was washed with H20, and then dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (702mg, 98%) as viscous clear orange oil, which solidified to a gel on standing.

Partial H NMR (400 MHz, CDCI3) ö (ppm) = Characteristic signals appear at 3.65 (m, OCH2CH2O), 3.4 (s, 0Cm).

IR (solid) v (cm') = 2970.9, 2923.7, 2886.0 (CH stretches), 1746.9 (sh, carbonate C=O stretch), 1682.5, 1467.6, 1389.9, 1348.5, 1251.6, 1073.7 (str., C-0 stretch), 950.6, 780.5 (sh. Si-0 stretch).

Surface Protocols Air plasma modification of silicone samples Sheet silicone was cut into lOxlOmm squares, peeled away from the PTFE backing, rinsed briefly with ethanol and dried under N2 to remove dust, and stored in 30 well plates until used.

Sections of silicone were pumped down in the plasma chamber to a base pressure of lxlO2mbar. The air inlet was then adjusted until a constant pressure of lxlO1mbar was achieved, and the signal generator gain increased until the plasma ignited. The signal was then optimised to a forward power of ca.IOOW, and then maintained for 120 s. The plasma chamber was evacuated to a pressure of lxlO2mbar prior to removal of the samples.

Surface Attachment of 7 to Oxidised Silicone A 5°A (w/v) stock solution of 7 was prepared in ethanol, with the solution heated under N2 at 60°C if dissolution was difficult. 0.5% (w!v) deposition solutions (5mL total volume) were prepared by diluting fresh 5% stock solution (0.50mL) with dd.H20 (0.25mL), ethanol (4.25mL) and glacial acetic acid (SRL).

Plasma-modified samples were immediately immersed in the freshly prepared deposition solutions, agitated briefly, and incubated for 120 mm. The samples were then rinsed thrice with ethanol, sonicated for 10 mm in clean ethanol, rinsed with ethanol, water, then ethanol and dried under a stream of nitrogen.

Biological Tests The coated catheter material was tested under laboratory conditions to assess effectiveness against relevant urinary tract microorganisms. The coating was demonstrated to modulate the adhesion and reproduction of the key organism responsible for urinary tract infections, Pr. Mirabibs: it does not appear to cause a reduction in the adherent cell number, but rather cellular attachment leads to the death of most cells in contact with the surface leading to a 90% reduction in colonization after four days.

Claims (13)

1. <claim-text>Claims 1. An implantable medical device having a coating comprising a calixarene bonded to the surface of the device via one or more surface-linker groups on one rim of the calixarene, wherein the opposing rim of the ealixarene is substituted by one or more polyethylene glycol, polypropylene glycol or polytrimethylene glycol groups, or a mixture thereof, said surface-linker groups may be bonded to the surface of the device via covalent bonds, ionic bonds, hydrogen bonds, or Van der Waals forces, said glycol groups arc attached to the calixarcnc via (C5 to Ci6)alkylcnc spacer groups, said glycol groups, each independently, have from 2 to 250 repeating glycol units and may be optionally terminated by hydrogen or (C1 to C4alkyl, said (C3 to C15)alkyl spacer groups may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds.</claim-text> <claim-text>2. An implantable medical device according to claim 1, which is a stent. catheter, vascular graft, cardiac pacer lead, heart diaphragm, suture, needle, angioplasty device, artificial joint, heart valve, neurological stimulator or drug pump.</claim-text> <claim-text>3. An implantable medical device according to claim 2, which comprises a silicone surface.</claim-text> <claim-text>4. An implantable medical device according to claim 3, which is a catheter.</claim-text> <claim-text>5. An implantable medical device according to any one of claims I to 4, wherein the calixarcnc is bonded to the surface of the device via 2 to 8 surface-linker groups.</claim-text> <claim-text>6. An implantable medical device according to claim 5, wherein the calixarene is bonded to the surface of the device via 2 or 4 surface-linker groups.</claim-text> <claim-text>7. An implantable medical device according to any one of claims 1 to 6, wherein said surface-linker groups are bonded to the surface of the device via covalent bonds.</claim-text> <claim-text>8. An implantable medical device according to any one of claims 1 to 7, wherein the rim of the calixarene is substituted by one or more polyethylene glycol groups.</claim-text> <claim-text>9. An implantable medical device according to according to any one of claims 1 to 8, wherein said glycol groups are attached to the alkylene spacer group directly via the oxygen of the glycol or via another linker group.</claim-text> <claim-text>10. An implantable medical device according to 9, wherein the glycol linker group is selected from carbonate, carbamate, urea, phosphate and triazole.</claim-text> <claim-text>11. An implantable medical device according to any one of claims 1 to 10, wherein said calixarene is derived from phenols, resorcinols or pyrogallols, or mixtures thereof 12. An implantable medical device according to claim 11, wherein said calixarene is derived from a compound of formula (I) xY YR RY Y zX Z Z - / (R R</claim-text> <claim-text>V (I)wherein X is H, (Ci-C4)alkyl, NH2, NH(Cj-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4)alkyl, and Y is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl, and Y is H, (Ci-C4)alkyl, NI-I2, NH(Ci-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4)alkyl; or X and Y are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; Z is H, OH or methyl; n is 1,3 or 5; and R is -(C3-C15)alkylene-L1-G-R1 wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 is a bond or a linking group; G is 0(CH2CH2O)1n, -O(CH2CH(CH3)O)111-, O(CH(CH3)CH2O)m, or -O(CFl2CH2CI-12O)-; mis2to250; R1 is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R1 group may be the same or different.</claim-text> <claim-text>13. An implantable medical device according to claim 12, wherein X is H and Y is OH.</claim-text> <claim-text>14. An implantable medical device according to either claim 12 or claim 13, wherein ZisH.</claim-text> <claim-text>15. An implantable medical device according to any one of claims 12 to 14, wherein n isi.</claim-text> <claim-text>16. An implantable medical device according to any one of claims 12 to 15, wherein R is -(Cjo)alkylene-L1-G-R1.</claim-text> <claim-text>17. An implantablc medical device according to any one of claims 12 to 16, wherein L1 is a linking group selected from carbonate, carbamate, urea, phosphate and triazole.</claim-text> <claim-text>18. An implantable medical device according to claim 17, wherein L' is carbonate.</claim-text> <claim-text>19. An implantable medical device according to any one of claims 12 to 18, wherein G is O(CHCH2O)mm 20. An implantable medical device according to any one of claims 12 to 19, wherein R1 is H or methyl.21. An implantable medical device according to any one of claims 12 to 20, wherein mis3tol50.22. An implantable medical device according to claim 21, wherein mis 6 to 50.23. An implantablc medical device according to claim 22, wherein m is 15 to 25.24. An implantable medical device according to any one of claims 12 to 23, wherein said calixarene is bonded to the surface of the device via surface-linker groups substituted for any one or more of the X or Y substituents, or a combination thereof.25. An implantable medical device according to claim 24, wherein the surface-linker groups X or Y, or a combination thereof, on the calixarene are derived from acid chloride, chloroformate or silane functional groups.26. An implantable medical device according to claim 25, wherein the surface-linker groups are derived from silane functional groups, which form one or more siloxane bonds with a device having a silicone surface.27. An implantable medical device according to claim 26, wherein the surface-linker groups X and/or Y are L2-Si(R2)3, or X and an adjacent Y group together form Calixarene L2 is a spacer group; R is (C2-Cio)alkylene-Si(R2)3, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; Si(R2)3 is selected from Si[O(Ci-C4)allcyl]3, SiCI3, Si[(Ci-C4)alkyl]2C1 and Si[(Ci-C4)alkyl]C12; each alkyl and each surface-linker group may be the same or different; and said silane providing frrnctionality for bonding to the surface of the device.28. An implantablc medical device according to claim 27, wherein L2 is selected from O(C2-Cio)alkylcnc, CH2NH(C2-Cio)alkylcnc, OCH2CO2(C2-C io)alkylcnc and OCH2CONH(C2-Cio)alkylene, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds.29. Acompoirnd of formula (I) xY YR RY Y zX Z Z-z / / fRY Y (I *)wherein X is H, (Ci-C4)alkyl, NH2, NH(Ci-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4)alkyl, and Y is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl, and Y is H, (Ci-C4)alkyl, NH2, NH(Ci-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4)alkyl; or X andY are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; -41 -Z is H, OH or methyl; n is 1,3 or 5; and R is -C5-Cio)alkylene-L'-G-R' wherein said alkylene may be optionally substithted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 isa bond or a linking group; G is 0(CH2CH2O)nr, 0(CH2CH(CH3)O)nç, -O(CH(CH3)CH2O)m-, or -O(CH2CH2CH2O)m-; m is 2 to 250; R' is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R1 group may be the same or different; with the proviso that when X and Y are OH; Z is H; and n is 1; R is not -(C3)alkylene-O(C H 2C H 2O)4C H3.30. A compound according to claim 29 as defined in any one of claims 13 to 23.31. A compound of formula (II) xY YR RV YK/\ \/ KRK(II *) whcrcin X is H, (Ci-C4)alkyl, NH2, NHCj-C4)alkyl, NCi-C4)aIkyl2 or CH2NHCi-C4)alkyl, and Y is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl, and Y is H, (Ci-C4)alkyl, NH2, NH(Ci-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4alkyl; or X and Y are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; and any one or more X or Y groups, individually or in combination, may be substituted for a surface-linker group; Z is H, OH or methyl; n is 1,3 or 5; and R is -(C3-Cio)a&ylcnc-L1-G-R1 wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 is a bond or a linking group; 13 is O(CH2CH2O)inm O(CH2CH(CH)O)m, O(CH(CHcz)CH2O)nr or -O(CH2CH2CH2O)m-; mis 2 to 250; R1 is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R' group, and each surface-linker group, may be the same or different.32. A compound according to claim 31, wherein the surface-linker groups X or Y, or a combination thereof, on the calixarene are acid chloride, chloroformate or silane functional groups.33. A compound according to claim 32, wherein the surface-linker groups X or Y, or a combination thereof, on the calixarene are silanc fhnctional groups, which may form one or more siloxane bonds with a device having a silicone surface.34. A compound according to claim 33, wherein the surface-linker groups X and!or Y are L2-Si(R2)3, or X and an adjacent Y group together form Calixarene L2 is a spacer group; R3 is (C2-Cio)alkylene-Si(R2)3, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; Si(R2)3 is selected from Si[O(Ci-C4)alkyl]3, SiCI3, Si[(Ci-C4)alkyl]2C1 and Si[(Ci-C4)alkyl]C12; and each alkyl and each surface-linker group may be the same or different.35. A compound according to claim 34, wherein L2 is selected from O(C2-Cio)alkylene, CH2NH(C2-Cio)alkylene, OCH2CO2(C2-Cjo)alkylene and OCH2CONH(C2-Cio)allcylene, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ctliyl groups arid may optionally contain one or more unsaturated bonds.36. A compound according to any one of claims 31 to 35 wherein the substituents X, Y, Z, n, R, L', 0 and R1 are as defined in any one of claims 13 to 23.37. A compound according to claim 31, which is R3 R3HO RR OH HO RR OHHOHor HH wherein R is -Cjo)alky1ene-OCO)O-(CH2CH2O)111-OH; and R3 is (C3)alkylene-Si(OEt)3 or a combination thereofS38. A compound according to either claim 36 or claim 37 wherein m is as defined in any one of claims 21 to 23.39. A compound of formula (III) xY YR RV V/\ \/X / fR RK (III)wherein X, Y. Z and n arc as defined in either claim 29 or claim 30; and R is -(C3-C15)alkylene-OH or -C2-Cis)a&ylene-CH2CH2 wherein said alkylene maybe optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; and wherein each X, Y, Z and R group may bc thc same or different; with the proviso that when Xis H, OH, CH3 or OCH3; Y is OH; Z is H; and n is 1; R is not -(g)allcylene-CH2=CH2.40. A process for coating a silicone surface of an implantable medical device, as defined in any one of claims 3 to 28, which comprises plasma activation of the silicone surface of the device followed by reaction with a compound of formula (II) as defined in any one of claims 31 to 38.41. An implantable medical device preparable by a coating process as defined in claim 40.Amendments to the claims have been filed as follows.CLAIMS: 1. An implantable medical device having a coating comprising a calixarene bonded to the surface of the device via one or more surface-linker groups on one rim of the calixarene, wherein the opposing rim of the ealixarene is substituted by one or more polyethylene glycol, polypropylene glycol or polytrimethylene glycol groups, or a mixture thereof, said surface-linker groups may be bonded to the surface of the device via covalent bonds, ionic bonds, hydrogen bonds, or Van der Waals forces, said glycol groups arc attached to the calixarene via (C5 to Ci6)alkylcnc spacer groups, said glycol groups, each independently, have from 2 to 250 repeating glycol units and may be optionally terminated by hydrogen or (C1 to C4alkyl, said (C3 to C15)alkyl spacer groups may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; and said glycol groups are attached to the (C3 to Cioalkylene spacer groups directly or via another linker group. rr
2. 2. An implantable medical device according to claim 1, which is a stent, catheter, vascular graft, cardiac pacer lead, heart diaphragm, suture, needle, angioplasty device, (\.J 20 artificial joint, heart valve, neurological stimulator or drug pump.
3. 3. An implantable medical device according to claim 2, which comprises a silicone surface.
4. 4. An implantable medical device according to claim 3, which is a catheter.
5. 5. An implantable medical device according to any one of claims 1 to 4, wherein the ealixarene is bonded to the surface of the device via 2 to 8 surface-linker groups.
6. 6. An implantable medical device according to claim 5, wherein the calixarene is bonded to the surface of the device via 2 or 4 surface-linker groups.
7. 7. An implantable medical device according to any one of claims I to 6, wherein said surface-linker groups are bonded to the surface of the device via covalent bonds.
8. 8. An implantable medical device according to any one of claims 1 to 7, wherein the rim of the calixarene is substituted by one or more polyethylene glycol groups.
9. 9. An implantable medical device according to according to any one of claims I to 8, wherein said glycol groups arc attached to the alkylcnc spacer group directly via the oxygen of the glycol or via another linker group.
10. 10. An implantabic medical device according to 9,herein the glycol linker group is selected from carbonatc, carbamate, urea, phosphate and triazolc.
11. 11. An implantable medical device according to any one of claims 1 to 10, wherein said calixarene is a condensation product of phenols and aldehydes, resorcinols and aldchydcs, or pyrogallols and aldchydcs, or mixtures thereof
12. 12. An implantable medical device according to any one of claims 1 to 11, wherein said calixarene is derived from a compound of formula (I) r r (0YR RV V zX Z Z / X -\ / (R RV V xwherein X is H, (Ci-C4)alkyl, NH2, NH(Cj-C4)alkyl, N(Ci-C4)alkyl2 or CH2NI-1(Ci-C4)alkyl, and Y is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl, and Y is H, (Ci-C4)alkyl, NH2, NH(Ci-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4alkyl; or X and Y are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; Z is H, OH or methyl; nisl,3or5;and R is -(C3-C16)alkylcne-L1-G-R1 wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 is a bond or a linking group; G is O(CH2CH2O)m, O(CH2CH(CH3)O)nç, -O(CH(CH3)CH2O)m-, or -O(CH2CH2CH2O)m-; mis 2 to 250; R1 is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R1 group may be the same or different; by substituting one or more of the X or Y substituents with said surface linker groups. rr
13. 13. An implantable medical device according to claim 12, wherein X is H and Y is OH. (\42014. An implantable medical device according to either claim 12 or claim 13, wherein ZisH.15. An implantable medical device according to any one of claims 12 to 14, wherein nisl.16. An implantable medical device according to any one of claims 12 to 15, wherein R is -(Cjo)alkylene-L1-G-R1.17. An implantable medical device according to any one of claims 12 to 16, wherein L1 is a linking group selected from carbonate, carbamate, urea, phosphate and triazole.18. An implantablc medical device according to claim 17, wherein L' is carbonate.19. An implantable medical device according to any one of claims 12 to 18, wherein 0 is -O(CH2CH2O%,-.20. An implantable medical device according to any one of claims 12 to 19, wherein R.'isHormethyL 21. An implantable medical device according to any one of claims 12 to 20, wherein mis3to 150.22. An implantablc mcdical dcvicc according to claim 21, whcrcin m is 6 to 50.23. An implantable medical device according to claim 22, wherein m isis to 25.24. An implantable medical device according to any one of claims 12 to 23, wherein said calixarene is bonded to the surface of the device via surface-linker groups ___ substituted 1kw any one or more of the X or Y substituents, or a combination thereof iii 25. An implantable medical device according to claim 24, wherein the surface-linker groups X or Y, or a combination thereof; on the calixarene are derived fivm acid (sJ 20 chloride, chloroformate or silane functional groups.26. An implantablc medical device according to claim 25, whcrcin thc su&cc-linker groups are derived fivm silane functional groups, which fbrm one or more siloxane bonds witha device havingasilicone surface.27. An implantable medical device according to claim 26, wherein the surface-linker groups X and/or Y are L2-Si(R2)3, or X and an adjacent Y group together ibrm Calixarene L2 is a spacer group; R3 is (C2-Cio)alkylene-Si(R2)3, wherein said alkylene may be optionally substitnted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; Si(R2)3 is selected from Si[O(Ci-C4)alkyl]3, SiCI3, Si[(Ci-C4)alkyl]2C1 and S i[(Ci -C4)alkyl] Cl2; each alkyl and each surface-linker group may be the same or different; and said silane providing functionality for bonding to the surface of the device.28. An implantable medical device according to claim 27, wherein L2 is selected from OC2-Cio)a1ky1ene, CH2NH(C2-Cio)allcylene, OCH2CO2(C2-Cio)a&ylene and OCI-I2CONFI(C2-Cio)alkylene, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds. (\J29. A compound of formula (I) r r C.oPY Y zX Z Z / X -\ /Y x (I)wherein X is H, (Ci-C4)alkyl, NH2, NHcC1-C4)alkyl, NCi-C4)aIkyl2 or CH2NHCi-C4)alkyl, and Y is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl, and Y is H, (Ci-C4)alkyl, NH2, NH(Ci-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4alkyl; or X and Y are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; Z is H, OH or methyl; nisl,3or5;and R is -(C3-Cio)alkylene-L'-G-R' wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 is a bond or a linking group; G is O(CH2CH2O)m, O(CH2CH(CH3)O)nç, -O(CH(CH3)CH2O)m-, or -O(CH2CH2CH2O)m-; mis 2 to 250; R1 is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R1 group may be the same or different; with the proviso that when X is H; Y is OH; Z is H; and n is 1; R is not -(C3)alkylene-O(CH2CHO)4CH3. rr 30. A compound accordmg to claim 29 as defined in any one of claims 13 to 23. (0(\,j 20 31. A compound of formula (II) xY YR RY V/\ Z:Z \/XV V (II)wherein X is H, (Ci-C4)alkyl, NH2, NH(Cj-C4)alkyl, N(Ci-C4)alkyl2 or CH2NH(Ci-C4)alkyl, and Y is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; or X is OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl, and Y is H, (Ci-C4)alkyl, NW, NH(C1 -C4)alkyl, N(Ci -C4)alkyl2 or CH2NH(C1 -C4alkyl; or X and Y are each independently OH, O(Ci-C4)alkyl or OCH2CO2(Ci-C4)alkyl; and any one or more X or Y groups, individually or in combination, is substituted for a surface-linker group; Z is H, OH or methyl; n is 1,3 or 5; and R is -(C-Cio)a&ylene-L'-G-R' wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; L1 is a bond or a linking group; U is OCH2CH2O)m, ocH2cH(cH3)o)111, 0(CH(CH3)CH2O)m, or -O(CH2CH2CH2O)m-; r r mis2to250; R1 is H or (Ci-C4)alkyl; and wherein each X, Y, Z, R and R' group, and each surface-linker group, may be the same or different.32. A compound according to claim 31, wherein the surface-linker groups X or Y, or a combination thereof, on the calixarene are acid chloride, chloroformate or silane functional groups.33. A compound according to claim 32, wherein the surface-linker groups X or Y, or a combination thereof, on the calixarene are silane functional groups, which may form one or more siloxane bonds with a device having a silicone surface.34. A compound according to claim 33, wherein the surface-linker groups X and/or Y are L2-Si(R2)3, or X and an adjacent Y group together form Calixarene L2 is a spacer group; R3 is (C2-Cio)alkylene-Si(R2)3, wherein said alkylene may be optionally substituted by one or more fluoro, methyl or ethyl groups and may optionally contain one or more unsaturated bonds; Si(R2)3 is selected from Si[O(Ci-C4)alkyl]3, SiCI3, Si[(Ci-C4)alkyl]2C1 and Si[(Ci-C4)alkyl]C12; and each alkyl and each surface-linker group may be the same or different.35. A compound according to claim 34, whcrcin L2 is selected from O(C2-Cio)alkylene, CH2NH(C2-Cio)alkylene, OCH2CO2(C2-Cjo)alkylene and OCH2CONH(C2-Cio)alkylene, wherein said alkylene may be optionally substituted by r one or more fluoro, methyl or ctliyl groups arid may optionally contain onc or more r unsaturated bonds. (036. A compound according to any one of claims 31 to 35 wherein the substituents X, Y, Z, n, R, L', 0 and R1 are as defined in any one of claims 13 to 23.37. A compound according to claim 31, which is P3 P3I IHO RR OH HO RR OHHjOHor HH wherein R is -Cjo)alkylene-OCO)O-(CH2CH2O)111-OH; and R3 is (C)alky1ene-Si(OEf)3 or a combination thereof r (Q 38. A compound according to either claim 36 or claim 37 wherein m is as defined in (\i any one of claims 21 to 23.39. A process for coating a silicone surface of an implantabic mcdical dcvice, as defined in any one of claims 3 to 28, which comprises plasma activation of the silicone surface of the device followed by reaction with a compound of formula (II) as defined in any one of claims 31 to 38.40. An implantable medical device preparable by a coating process as defined in claim 39.</claim-text>