WO2021163520A1 - Biomatériaux polymères dérivés de monomères phénoliques et leurs utilisations médicales - Google Patents

Biomatériaux polymères dérivés de monomères phénoliques et leurs utilisations médicales Download PDF

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WO2021163520A1
WO2021163520A1 PCT/US2021/017898 US2021017898W WO2021163520A1 WO 2021163520 A1 WO2021163520 A1 WO 2021163520A1 US 2021017898 W US2021017898 W US 2021017898W WO 2021163520 A1 WO2021163520 A1 WO 2021163520A1
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formula
polymer
polymers
tyrosol
group
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PCT/US2021/017898
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Joachim B. Kohn
Durgadas Bolikal
Julian Chesterman
Jarrod Cohen
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Rutgers, The State University Of New Jersey
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Priority claimed from US16/791,133 external-priority patent/US11472918B2/en
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Priority to US17/904,248 priority Critical patent/US20230167238A1/en
Publication of WO2021163520A1 publication Critical patent/WO2021163520A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • the present invention relates to new classes of monomeric phenol compounds useful for preparation of biocompatible polymers and biocompatible polymers prepared therefrom, including novel biodegradable and/or bioresorbable polymers. These polymers, while not limited thereto, may be adapted for radio-opacity and are useful for medical device applications and controlled release therapeutic formulations.
  • polymers suitable for various bioengineering applications include those described in U.S. Patent Nos. 5,099,060; 5,665,831; 5,916,998 and 6,475,477, along with the polymers described in U.S. Patent Publication Nos. 2006/0024266 and 2006/0034769.
  • bioresorbable and/or biodegradable polymers are known, in most of these polymers diphenolic monomers are prepared by linking two suitably protected tyrosine molecules or tyrosine analogs via an amide linkage.
  • biocompatible polymers having desirable bioresorbability and biodegradability as well as good processibility under thermal conditions.
  • nontoxic polyarylates having a moderate rate of bioerosion, suitable for use as tissue-compatible materials for biomedical uses.
  • the present invention addresses the foregoing need by providing new monomers useful for the preparation of the desired biocompatible polymers and various types of such polymers useful for making the implantable medical devices.
  • the present invention broadly relates to diphenolic monomers and bioerodible polymers synthesized using such monomers.
  • the diphenolic monomers are derived from tyrosine and/or tyrosine analogs.
  • the present invention relates to bioerodible polycarbonates and polyarylates derived from the naturally occurring 4-(2-hydroxylethyl)phenol (or “tyrosol”) and phosgene and/or biocompatible dicarboxylic acids.
  • biocompatible polymers comprising a repeating structural unit of Formula (I):
  • A is a linking group selected from:
  • X 1 and X 2 are independently halogen (F, Cl, Br, or I); y 1 and y 2 have values independently selected from 0, 1, 2, 3 and 4; R 1 and R 2 are each independently selected from straight-chain or branched, saturated or unsaturated, substituted or unsubstituted, alkylene, alkenylene, alkylarylenoxy, heteroalkylene and heteroalkenylene containing up to 12 carbon atoms, said alkylene, alkenylene, heteroalkylene and heteroalkenylene optionally containing a pendant Z group and optionally comprising one, two or three heteroatoms independently selected from O, NR Z and S;
  • R 3 is selected from the group consisting of hydrogen, C1-C 30 alkyl, C1-C 30 heteroalkyl, C2-C 30 alkenyl, C2-C 30 alkynyl, C2-C 30 heteroalkenyl, and C2-C 30 heteroalkynyl;
  • R 4 is selected from the group consisting of a bond, C 1 -C 30 alkyl, C 2 -C 30 alkenyl, C 2 - C 30 alkynyl, C1-C 30 heteroalkyl, C2-C 30 heteroalkenyl, C2-C 30 heteroalkynyl, C 6 -C 30 aryl, C 7 - C 30 alkylaryl, C 8 -C 30 alkenylaryl, C 8 -C 30 alkynylaryl, and C2-C 30 heteroaryl;
  • R 4a is selected from the group consisting of C1-C 30 alkyl, C2-C 30 alkenyl, C2-C 30 alkynyl, C1-C 30 heteroalkyl, C2-C 30 heteroalkenyl, C2-C 30 heteroalkynyl, C 6 -C 30 aryl, C 7 -C 30 alkylaryl, C 8 -C 30 alkenylaryl, C 8 -C 30 alkynylaryl, and C 2 -C 30 heteroaryl;
  • the heteroatom in the heteroalkyl and/or heteroalkylaryl group is N in the form of a NR Z group, wherein R z is selected from the group consisting of H, Ci- C30 alkyl, and arylalkyl containing up to 30 carbon atoms.
  • R x in the definition of A and L in formula (I) is an alkyl group, e.g., a branched or unbranched C1-C6 alkyl.
  • R x in formula (I) is a methyl.
  • R 1 and R 2 are each independently -(demand -(CH 2 ) n -, respectively, where n and m are each independently integers in the range of one to 12.
  • R 1 is -(CH2) m - and R 2 is -(CH2) -, and n and m are each independently 1 or 2.
  • R 1 is -0-(CH2) m - or -0-C 6 H4-(CH2) m -, where the -C 6 H 4 - is optionally substituted phenyl (e.g., optionally substituted with 1 or 2 halogens such as Br and/or I) and n and m are each independently integers in the range of one to 12 (e.g., 1 or 2).
  • R 2 is independently -(CEh O- or - (CH 2 ) n -C 6 H 4 -0-, where the -C 6 H 4 - is independently optionally substituted phenyl (e.g., optionally substituted with 1 or 2 halogens such as Br and/or I) and n and m are each independently integers in the range of one to 12 (e.g., 1 or 2).
  • X 1 and X 2 in formula (I) can be independently selected to be any halogen atom.
  • X 1 and X 2 in formula (I) are each I.
  • X 1 and X 2 in formula (I) are each Br.
  • the X 1 and X 2 groups on the polymer comprising a recurring unit of formula (I) are iodine.
  • the polymer containing the repeating structural unit of Formula (I) can also contain one or more other repeating units.
  • the present invention provides polymers containing the repeating structural unit of Formula (I) and further containing recurring units represented by A 1 .
  • polymers examples include polycarbonates, polyarylates, polyiminocarbonates, polyphosphazenes and polyphosphoesters, comprising the repeating structure of Formula (II): wherein L, X 1 , X 2 , y 1 , and y 2 are defined as above; and A 1 is a linking group selected from: wherein R 8 is selected from a bond, C1-C 30 alkyl, C2-C 30 alkenyl, C2-C 30 alkynyl; Ci- C 30 heteroalkyl, C2-C 30 heteroalkenyl, C2-C 30 heteroalkynyl, C 7 -C 30 heteroalkylaryl, C 8 -C 30 heteroalkenylaryl, C 8 -C 30 heteroalkynylaryl, C 7 -C 30 alkylaryl, C 8 -C 30 alkenylaryl, C 8 -C 30 alkynyl aryl, and C2-C 30 heteroaryl; and
  • R 9 and R 10 are each independently selected from H, C 1 -C 30 alkyl, C 1 -C 30 heteroalkyl, C2-C 30 alkenyl, C2-C 30 alkynyl, C2-C 30 heteroalkenyl, and C2-C 30 heteroalkynyl.
  • the present invention provides diphenolic monomers having the following generic structure of Formula (III): (HI), wherein L, X 1 and X 2 , y 1 and y 2 are defined as above.
  • Such monomers are useful for making polymers that comprise repeating structural units of Formula (I) as described in greater detail below.
  • this invention provides diphenolic monomers derived from hydroxyalkylphenol having a generic structure of Formula (IV): (IV), wherein R 1 is defined as above.
  • R 1 is preferably a C 1 -C 12 alkylene, e.g., a C 1 -C 4 alkylene. More preferably R 1 is ethylene (-CH 2 -CH 2 -).
  • the hydroxyalkylphenol is 4-(2-hydroxyethyl)phenol or 2-(4-hydroxyphenyl)ethanol (or “tyrosol”) having the following structure: which is a natural product present in olive oil and white wine and has been shown to have both antioxidant and cardio-protective properties.
  • the phenyl ring of tyrosol can be halogenated, and those skilled in the art will understand that teachings herein regarding tyrosol can be applied to such halogenated forms as well.
  • Tyrosol can be converted into a diphenolic monomer, e.g., a diphenolic ester, in several ways. It can be esterified with desaminotyrosine (DAT) or N-protected tyrosine to form a diphenolic monomer with an ester linkage. It can also be esterified with 0.5 mole equivalents of dicarboxylic acids to provide a family of diphenolic diester monomers that can be introduced into polymers to control chain flexibility, as needed. Those skilled in the art will appreciate that use of ring halogenated compounds (e.g., halogenated tyrosol, halogenated DAT, etc.) results in the corresponding halogenated polymers.
  • DAT desaminotyrosine
  • DAT N
  • the present invention provides a new class of diphenolic monomers of the Formula (V): wherein L 1 is a bond, oxygen (-O-) or -R 4 -C(0)-0-, L 4 is a bond, oxygen (-O-) or optionally substituted phenoxy (-C6H4-O-), m and n are each independently integers in the range of one to 12, and X 1 , X 2 , yl, y2 and R 4 are as defined above.
  • R 4 is selected from saturated and unsaturated, substituted and unsubstituted, alkylene and alkylarylene groups containing up to 18 carbon atoms.
  • m and n are each independently 1 or 2.
  • an embodiment provides a monomer of the Formula wherein L 1 , X 1 , X 2 , yl, and y2 are as defined above.
  • Such monomers can be made from optionally halogenated tyrosol as described in greater detail below.
  • the present invention provides a class of diphenolic monomers of the Formula (VI): wherein X 1 , X 2 , yl, y2 and Z are as defined above.
  • Such monomers can be made from optionally halogenated 2-(4-hydroxyphenyl)ethanol as described in greater detail below.
  • the diphenolic monomers described herein can be polymerized using phosgene to form polycarbonates or with dicarboxylic acids to obtain polyarylates.
  • the diphenolic monomers can also be copolymerized with other diphenols (such as desaminotyrosyl tyrosine ethyl ester) and other dihydroxyl compounds such as poly(ethylene glycol), polycaprolactone-diol, poly(trimethylene carbonate), polylactide and/or polyglycolide.
  • the polymers can be made radio-opaque by introducing halogen, in particular iodine and/or bromine atoms, on the phenyl rings.
  • halogen in particular iodine and/or bromine atoms
  • Other optionally halogenated phenolic alcohols can be used in place of tyrosol, and other optionally halogenated aromatic carboxylic acids can be used in place of DAT.
  • Preferred biocompatible polymers that can be made using the monomers described herein include those comprising a recurring structural unit of the following Formula (VII), (Vila), (VIII), and/or (Villa): ( a) wherein L 2 is a bond or -R 8 -C(0)-, and m, n, L 1 , L 4 , X 1 , X 2 , yl, y2 and R 8 are defined above.
  • R 4 (in the definition of L 1 ) and R 8 are each independently selected from saturated and unsaturated, substituted and unsubstituted, alkylene and alkylarylene groups containing up to 18 carbon atoms.
  • Another aspect of this invention provides a polymer comprises repeating units of Formula XVIII Formula XVIII wherein:
  • A is CH2CH2
  • B is selected from the group consisting of -O-CO-CH2CH2, -O-CO- CH2CH2CH2, and -O-CO-CH2OCH2 and bonded to A via oxygen
  • the ester bond cleaves hydrolytically to produce water-soluble fragments, thus increasing the resorption rate of the polymer.
  • the present invention provides a polymer composition comprising a biocompatible polymer described herein.
  • the present invention provides a medical device comprising a biocompatible polymer described herein.
  • the medical device is a stent.
  • a method for making a polymer that comprises a recurring unit of formula (I) comprises attaching an N-substituent during the synthesis of a corresponding monomer. In an embodiment, the method of making the polymer comprises attaching an N-substituent during polymerization of a corresponding monomer. In an embodiment, the method of making the polymer comprises attaching an N-substituent after polymerization of a corresponding monomer. Methods of making a polymer comprising a recurring unit of the formula (I) are further discussed in detail below.
  • the present invention provides a polymer comprising a repeating structural unit of Formula (I) in which L is -R'-A-R 2 - and in which A is any one of the various linking groups set forth above.
  • L is -R'-A-R 2 -
  • A is any one of the various linking groups set forth above.
  • the present invention provides polymers, such as polycarbonates, polyarylates, polyiminocarbonates, polyphosphazenes and polyphosphoesters, comprising the repeating structure of Formula (II) as set forth above in which L is -R'-A-R 2 - and in which A and A 1 can be any combination of any of the various linking groups defined above for A and A 1 , respectively.
  • polymers such as polycarbonates, polyarylates, polyiminocarbonates, polyphosphazenes and polyphosphoesters, comprising the repeating structure of Formula (II) as set forth above in which L is -R'-A-R 2 - and in which A and A 1 can be any combination of any of the various linking groups defined above for A and A 1 , respectively.
  • L is -R'-A-R 2 -
  • a and A 1 can be any combination of any of the various linking groups defined above for A and A 1 , respectively.
  • Another aspect of the present invention provides diphenolic monomers that are capable of being polymerized to form polycarbonates or polyarylates.
  • the monomers provided by this aspect of the present invention are diphenolic compounds having the structure of Formula III set forth above, and in some embodiments can be considered to be tyrosine or tyrosol derivatives.
  • the present invention provides a polymer comprising the repeating structure of Formula (la):
  • X 1 , X 2 , y 1 , and y 2 are defined as above;
  • Q 1 and Q 2 are each independently hydrogen, halogen, or alternatively two adjacent Q*’s or Q 2 ’s form a bond;
  • L 3 is oxygen (O) or -NR X -, wherein R x is as defined above;
  • Z 1 is hydrogen, -C(0)OR 7 or -C(0)NR x R y , wherein R 7 , R x and R y are as defined above;
  • the present invention provides a polymer comprising the repeating structure of Formula (Ila): wherein i, j, y 1 , y 2 , X 1 , X 2 , Q 1 , Q 2 , Z 1 , Z 2 , L 3 and A 1 is as defined above.
  • the present invention provides a polymer comprising the repeating structure of Formula (lb): wherein i, j, y 1 , y 2 , X 1 , X 2 , Z 1 , Z 2 , and L 3 are as defined above.
  • the present invention provides a polymer comprising the repeating structure of Formula (lib): wherein i, j, y 1 , y 2 , X 1 , X 2 , Z 1 , Z 2 , L 3 and A 1 are as defined above.
  • the present invention incorporates the discovery that useful polyarylates can be prepared from tyrosol-derived diphenol compounds.
  • the present invention provides a polymer comprising the repeating structure of Formula (He): wherein i, j, y 1 , y 2 , X 1 , X 2 , Z, and A 1 are as defined above.
  • the present invention provides a polymer comprising the repeating structure of Formula (Ic): wherein i, j, y 1 , y 2 , X 1 , X 2 , Z 1 , Z 2 , and L 3 are as defined above.
  • the present invention provides a polymer comprising a recurring unit of structure (lid): wherein i, j, y 1 , y 2 , X 1 , X 2 , Z 1 , Z 2 , L 3 and A 1 are as defined above.
  • a 1 is any one of the A 1 linking groups set forth above; i is 1 or 2; and/or j is 1 or 2.
  • the present invention provides a polymer comprising a recurring unit of structure (Id): wherein X 1 , X 2 , y 1 , and y 2 are defined as above.
  • X 1 and X 2 are independently Br or I; and y 1 and y 2 are independently 0, 1, or 2.
  • the present invention provides a biocompatible polymer composition, comprising at least a first polymer component and a second polymer component.
  • the first polymer component comprises a number (n) of first recurring units of formula (Ic) as set forth above
  • the second polymer component comprises recurring units having a formula selected from the group consisting of the formula (EX), the formula (X), the formula (XI), and the formula (XII): wherein X 3 , X 4 , X 5 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 are independently selected from the group consisting of O, S and NR 11 , where R 11 is selected from hydrogen and an alkyl group containing from one to 30 carbon atoms;
  • Ar 1 and Ar 2 are phenyl rings optionally substituted with from one to four substituents independently selected from the group consisting of a halogen, a halomethyl, a halomethoxy, a methyl, a methoxy, a thiomethyl, a nitro, a sulfoxide, and a sulfonyl;
  • R 12 and R 13 contain from one to ten carbon atoms each and are independently selected from the group consisting of an optionally substituted alkylene, an optionally substituted heteroalkylene, an optionally substituted alkenylene, and an optionally substituted heteroalkenylene; g and h in formula (XII) are each independently integers in the range of about 1 to about 500; and
  • D and D 1 contain up to 24 carbon atoms and are independently selected from the group consisting of an optionally substituted alkylene, an optionally substituted heteroalkylene, an optionally substituted alkenylene and an optionally substituted heteroalkenylene; or D, X 8 and X 9 in formula (IX) are selected so that HX 8 — D — X 9 H defines a hydroxyl endcapped macromer, a mercapto endcapped macromer or an amino endcapped macromer; or D 1 , X 3 and X 4 in formula (XI) are selected so that HX 3 — D 1 — X 4 H defines a hydroxyl endcapped macromer, a mercapto endcapped macromer or an amino endcapped macromer.
  • the first polymer component comprises a recurring unit of formula (Id) as set forth above.
  • the present invention provides copolymers that comprise any two or more of the recurring units described herein.
  • the polymer comprises two or more recurring units selected from the group of recurring units represented by Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (lib), Formula (He), Formula (lid), Formula (VII), Formula (VIII), Formula (Villa), Formula (Vlllb), Formula (VIIIc), Formula (VUId), Formula (Vllle), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVIa), Formula (XVIb), and Formula (XVIc).
  • the polymer comprises at least two recurring units resulting from the polymerization of any two or more monomers described herein.
  • the polymer comprises two or more recurring units resulting from copolymerization of two or more monomers selected from the group of monomers represented by Formula (III), Formula (IV) (tyrosol), Formula (V), Formula (VI), tyrosine ethyl ester (TE), mono-iodinated TE (ITE), di-iodinated TE (I2TE), desaminotyrosine (DAT), mono-iodinated DAT (IDAT), di-iodinated DAT (I2DAT), desaminotyrosyl tyrosine ethyl ester (DTE), mono-iodinated DTE (IDTE), di-iodinated DTE (I2DTE), N-desaminotyrosyl mono-iodinated tyrosine ethyl ester (DITE), and N- desami
  • an embodiment provides a polymer that contains recurring units of the Formula (II) in which L is -R'-A-R 2 -, R 1 and R 2 are -(CH2)2-, A is as represented by the following Formula (XIII):
  • the polymer is a copolymer that contains tyrosol recurring units and recurring units of the Formula (II).
  • An example of a copolymer containing such recurring units is represented by the following Formulae (XHIa) and XHIb):
  • the polymer is characterized by Formula:
  • the polymer is characterized by Formula:
  • polymers containing the recurring units of Formulae (Xllla) and (Xlllb) contain a tyrosol recurring unit and a recurring unit of
  • tyrosol Given the unsymmetrical structure of tyrosol, it can be connected with a PrD-diUDAT unit using either its “head” (i.e., “phenoxy” moiety) or “tail” (i.e., the “ethylenoxy” moiety). Any two adjacent units formed from tyrosol itself can be in any of the “head-head”, “head-tail” and “tail-tail” arrangements.
  • the poly(PrD-dil2DAT-co-tyrosol carbonate) product is composed of mainly polymer molecules having randomly-ordered PrD-dibDAT and tyrosol recurring units connected through carbonate (-OC(O)O-) linkers.
  • any recurring units designated as -[A]-[B]- such as Formulae (XHIa) and (Xlllb) above and Formulae (XVIa), (XVIb) and (XVIc) below, encompass all possible such arrangements as hereby explained.
  • the polymer comprises a backbone which is not naturally occurring.
  • the polymer may comprise a backbone comprising at least one amino acid derivative.
  • a polymer comprising a recurring unit as described herein can be copolymerized with any number of other recurring units.
  • B in formula (XIV) is -0-((CHR) p -0) q -; each R is independently H or Ci to C3 alkyl; p and q are each independently an integer in the range of from about 1 to about 100; and
  • Various polycarbonates and polyarylates of the present invention employ diphenol compounds derived from tyrosol as a starting material.
  • Examples of tyrosol-derived diphenol monomer compounds suitable for the formation of polycarbonates or polyarylates have the structure depicted by Formula (III) defined as above.
  • the polymer is expected to hydrolyze to release the original diphenol and diacid, thus forming nontoxic degradation products, provided that the monomeric starting materials are nontoxic.
  • the toxicological concerns associated with polyarylates are met by using diphenols derived from tyrosol and phosgene or dicarboxylic acids that are either metabolites or highly biocompatible compounds.
  • Another aspect of the present invention provides molded articles prepared from the polymers of the present invention.
  • a 1 is a carbonyl group having a structure of , wherein the carbonyl group is derived from a phosgene starting material.
  • This method is essentially the conventional method for polymerizing diols into polycarbonates. Suitable processes, associated catalysts and solvents are known in the art and are taught in, for example, Schnell, Chemistry and Physics of Polycarbonates, (Interscience, New York 1964), the teachings of which are incorporated herein by reference. Other methods adaptable for use to prepare the poly-carbonate and other phosgene-derived polymers of the present invention are disclosed in U.S. Patent Nos. 6,120,491 and 6,475,477 the disclosures of which are incorporated by reference.
  • a 1 is a group having the structure: , which is a recurring unit derived from a carboxylic acid starting material or monomer.
  • the monomer used to form the polymer is a diphenol
  • the diphenol can be reacted with an aliphatic or aromatic dicarboxylic acid in the carbodiimide mediated process disclosed by US Patent No. 5,216,115 using 4-(dimethylamino) pyridinium-p-toluene sulfonate (DPTS) as a catalyst.
  • DPTS 4-(dimethylamino) pyridinium-p-toluene sulfonate
  • R 8 may be selected so that the dicarboxylic acids employed as starting materials are either important naturally-occurring metabolites or highly biocompatible compounds. Aliphatic dicarboxylic acid starting materials therefore include the intermediate dicarboxylic acids of the cellular respiration pathway known as the Krebs Cycle.
  • aliphatic dicarboxylic acid is adipic acid (R 8 is - (CH 2 ) 4 -), found in beet juice.
  • Still another biocompatible aliphatic dicarboxylic acid is sebacic acid (R 8 is -(CH 2 )s-), which has been studied extensively and has been found to be nontoxic as part of the clinical evaluation of poly(bis(p-carboxyphenoxy)propane-co-sebacic acid anhydride) by Laurencin et al., J. Biomed. Mater. Res., 24, 1463-81 (1990).
  • biocompatible aliphatic dicarboxylic acids include oxalic acid (R 8 is a bond), malonic acid (R 8 is -CH 2 -), glutaric acid (R 8 is -(CH 2 )3-), pimelic acid (R 8 is - (CH 2 ) 5 -), suberic acid (R 8 is -(CH 2 ) 6 -) and azelaic acid (R 8 is -(CH 2 )7-).
  • R 8 can thus represent -(CH 2 ) n -, where n is between 0 and 8, inclusive.
  • suitable aromatic dicarboxylic acids are terephthalic acid, isophthalic acid and bis(p-carboxy-phenoxy) alkanes such as bis(p-carboxy-phenoxy) propane.
  • Preferred polymers comprise a recurring unit as described herein, e.g., a recurring unit selected from the group of recurring units represented by Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (lib), Formula (He), Formula (lid), Formula (VII), Formula (VIII), Formula (Villa), Formula (Vlllb), Formula (VIIIc), Formula (VUId), Formula (Vllle), Formula (EX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVIa), Formula (XVIb), and Formula (XVIc).
  • Preferred polymers can contain combinations of derivatives of structural units selected from dicarboxylic acids, halogenated (e.g., iodinated or brominated) derivatives of desaminotyrosyl-tyrosine and poly(alkylene glycols), which exhibit desirable physicomechanical and physicochemical properties that are consistent with their use in fabrication of medical devices, including stents.
  • halogenated e.g., iodinated or brominated
  • the stents described in accordance with preferred embodiments of the present invention are sufficiently radiopaque to be visible by conventional X-ray fluoroscopy; (b) are of sufficient strength to support medically relevant levels of radial compression within an artery or surrounding tissue; and/or (c) have a desirable resorption profile that may be adjusted to account for the needs of a range of applications requiring the presence of a stent for different lengths of time or for the elution of therapeutics.
  • a medical device comprising an inherently radiopaque, biocompatible, bioresorbable polymer, including homogeneous polymers, copolymers and blends thereof, wherein the polymer comprises one or more recurring units of the Formula (XV):
  • X 1 , X 2 , yl, and y2 in Formula (XV) are selected so that X 1 and X 2 are present in an amount that is effective to render the polymer radiopaque.
  • the sum of yl and y2 in Formula (XV) is at least one.
  • B in Formula (XV) is an aliphatic linear or branched diol or a poly(alkylene glycol) unit.
  • Examples of preferred copolymers include those of the Formula (XVIa), (XVIb) and (XVIc), as follows:
  • Halogenation of the aromatic rings may be accomplished as described in the examples below, and by conventional methods as detailed in U.S. Pat. No. 6,475,477; herein incorporated in its entirety by reference and particularly for the purpose of describing methods of halogenating monomers.
  • Preferred polymers are sufficiently halogenated to render the resulting polymers radiopaque, e.g., yl and y2 in any of the formulas described herein may independently be 0, 1, 2, 3 or 4.
  • Halogenation of aromatic rings is preferred.
  • the sum of yl and y2 is at least one.
  • Various other groups within the polymer may also be halogenated.
  • the resulting polymer has a higher glass temperature and melting temperature. It is also unexpected that various polymers prepared from tyrosol-derived monomers are semi-crystalline and possess mechanical strength suitable for high strength applications.
  • polymers described herein including, e.g, polymers comprising a recurring unit selected from the group of recurring units represented by Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (lib), Formula (He), Formula (lid), Formula (VII), Formula (VIII), Formula (Villa), Formula (Vlllb), Formula (VIIIc), Formula (VHId), Formula (Vllle), Formula (EX), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVIa), Formula (XVIb) and Formula (XVIc)) may be synthesized by various conventional reactions known in the art.
  • the diphenolic monomer compounds can be reacted with aliphatic or aromatic dicarboxylic acids in a carbodiimide-mediated direct polyesterification using DPTS as a catalyst to form aliphatic or aromatic polyarylates.
  • dicarboxylic acids suitable for the polymerization to form polyarylates have the structure of Formula (XVII): o o
  • R 14 is selected from saturated and unsaturated, substituted and unsubstituted alkyl or alkylaryl groups containing up to 18 carbon atoms, and preferably from 2 to 12 carbon atoms.
  • R 14 is selected from aryl groups containing up to 18 carbon atoms and preferably from 6 to 12 carbon atoms.
  • R 14 is defined as above for R 8 .
  • R 14 is preferably selected so that the dicarboxylic acids employed as starting materials are either important naturally-occurring metabolites or highly biocompatible compounds. Examples of preferred aliphatic dicarboxylic acid starting materials are described elsewherein herein.
  • the polyarylates can also be prepared by the method disclosed by Higashi et al., J. Polym. Sci.: Polym. Chem. Ed., 21, 3233-9 (1983) using arylsulfonyl chloride as the condensing agent, by the process of Higashi et al., J. Polym. Sci.: Polym. Chem. Ed., 21, 3241-7 (1983) using diphenyl chlorophosphate as the condensing agent, by the process of Higashi et al., J. Polym. Sci.: Polym. Chem.
  • a particularly preferred polyesterification technique modifies the method of Moore to utilize an excess of the carbodiimide coupling reagent. This technique tends to produce aliphatic polyarylates having molecular weights greater than those obtained by Moore. Essentially any carbodiimide commonly used as a coupling reagent in peptide chemistry can be used as a condensing agent in the preferred polyesterification process.
  • carbodiimides are well-known and disclosed in Bodanszky, Practice of Peptide Synthesis (Springer- Verlag, New York, 1984) and include dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, N- cyclohexyl-N'-(2'-morpholinoethyl)carbodiimide-metho-p-toluene sulfonate, N-benzyl-N'-3'- dimethyl-aminopropyl-carbodiimide hydrochloride, 1 -ethyl-3-(3-dimethylaminopropyl)- carbodiimide methiodide, N-ethylcarbodiimide hydrochloride, and the like.
  • the preferred carbodiimides are dicyclohexyl carbodiimide and di
  • An esterification reaction mixture can generally be formed by contacting exactly equimolar quantities of the diphenol and the dicarboxylic acid in a solvent for the diphenol and the dicarboxylic acid.
  • suitable solvents include methylene chloride, tetrahydrofuran, dimethylformamide, chloroform, carbon tetrachloride and N-methyl pyrrolidinone. It is not necessary to bring all reagents into complete solution prior to initiating the polyesterification reaction, although the polymerization of slightly soluble monomers such as desaminotyrosyltyrosine ethyl ester and succinic acid will typically yield higher molecular weight polymers when the amount of solvent is increased.
  • the reaction mixture can also be heated gently to aid in the partial dissolution of the reactants.
  • the polyarylates can be worked up and isolated by known methods commonly employed in the field of synthetic polymers to produce a variety of useful articles with valuable physical and chemical properties, all derived from tissue compatible monomers.
  • the useful articles can be shaped by conventional polymer-forming techniques such as extrusion, compression molding, injection molding, and the like. Molded articles prepared from the polyarylates are useful, inter alia, as degradable biomaterials for medical implant applications. Such applications include the use of the molded articles as vascular grafts and stents, bone plates, sutures, implantable sensors, barriers for surgical adhesion prevention, implantable drug delivery devices and other therapeutic aids and articles which decompose harmlessly within a known period of time.
  • Another aspect of this invention provides a polymer comprises repeating units of Formula XVIII Formula XVIII wherein:
  • A is Ci - 3 alkyl
  • B is either a bond or -O-CO-C 2-5 alkyl, where B is bonded to A via the oxygen of the -O-CO-C2- 5 alkyl, and optionally two adjacent carbons of said C2- 5 alkyl have an oxygen inserted therebetween, and
  • Y is C 2-10 alkyl or C 2-10 alkenyl, wherein optionally two adjacent carbons of said C 2-10 alkyl or C 2-10 alkenyl have an oxygen inserted therebetween.
  • the polymer comprises repeating unit of Formula IX-a.
  • A is CH2 or CH2CH2.
  • the polymer comprises repeating unit of Formula EX-b.
  • B is selected from the group consisting of-0-CO-CH 2 CH 2 , -O-CO-CH2CH2CH2, and -O-CO-CH2OCH2.
  • Synthetic Schemes 1-4 illustrate the preparation of various types of phenolic monomers useful for the making polymers containing recurring units of the Formula (I).
  • One of ordinary skill in the art, guided by the disclosure herein, would understand that these synthetic schemes may be readily adapted to prepare phenolic monomers containing pendant side chains such as -N(R x )C( 0)R 5 , -N(R x )COOR 6 , -COOR 7 and/or -CONR x R y , as defined above.
  • X 1 , X 2 , yl, y2, R 4 , R 4a and R 8 are as defined above.
  • R 4 , R 4a and R 8 are each independently C1-C30 alkyl, e.g., C1-C6 alkyl, Ci-Cs alkyl, C1-C10 alkyl, etc.
  • variables e.g., X 1 and X 2 , and yl and y2, respectively
  • variables may be used interchangeably in the various formulae and schemes provided herein when the depicted structures are symmetrical.
  • X 1 (and X 2 ) may be a halogen, which at each occurrence independently may be selected from iodo, bromo, chloro, and fluoro.
  • the halogen is iodo or bromo.
  • Halogenation may be performed by conventional reactions known in the art. For instance, iodination may be performed on aryl rings by treatment with KI, ICI, IF, benzyltrimethylammonium dichloroiodate, or h in the presence of copper salts. Similarly, bromination may be performed on aryl rings by treatment with bromine in the presence of a catalyst, such as iron. Other brominating reagents include HOBr and bromo amides.
  • the above synthetic schemes are simplified for illustration purpose. Many variants can be obtained using similar synthetic strategies known to a person of skill in the art, for example, in Scheme 5:
  • the coupling of the acid and the alcohol may also be performed by conventional reactions known in the art.
  • Standard coupling reagents including EDCI, HBTU, HOBt, and the like, may be used for activation of the reactants. Examples of synthesis of these polymers are illustrated in the following synthetic Schemes 6-9:
  • the polymers described herein contain phosphorus.
  • the versatility of these polymers may come from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding may involve the 3p orbitals or various 3s- 3p hybrids; spd hybrids are also possible because of the accessible of orbitals.
  • the physico-chemical properties of the poly(phosphoesters) may be readily changed by varying either the R or R' group.
  • the biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the sidechain, a wide range of biodegradation rates are attainable.
  • X is Cl or Br
  • X 1 , X 2 , yl, y2, L, R 9 and R 10 are as defined above.
  • poly(phosphates) may be prepared by a dehydrochlorination between a phosphodichloridate and a diol according to the following synthetic Scheme 12:
  • Poly(phosphonates) may be prepared by a similar condensation between appropriately substituted dichlorides and diols.
  • Poly(phosphites) may be prepared from glycols in a two-step condensation reaction. A 20% molar excess of a dimethylphosphite is preferably used to react with the glycol, followed by the removal of the methoxyphosphonyl end groups in the oligomers by high temperature.
  • An advantage of melt polycondensation is that it avoids the use of solvents and large amounts of other additives, thus making purification more straightforward. It may also provide polymers of reasonably high molecular weight. Polymerization may also be carried out in solution.
  • a chlorinated organic solvent may be used, such as chloroform, dichloromethane, or dichloroethane.
  • the solution polymerization is preferably run in the presence of equimolar amounts of the reactants and, more preferably, a stoichiometric amount of an acid acceptor or a Lewis acid-type catalyst.
  • acid acceptors include tertiary amines such as pyridine or triethylamine.
  • useful Lewis acid-type catalysts include magnesium chloride and calcium chloride.
  • the product may be isolated from the solution by precipitation in a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those of ordinary skill in the art, such as by washing with an aqueous acidic solution, e.g., dilute HC1.
  • Halogenated phenolic monomers may also be polymerized to form polyiminocarbonates as illustrated in synthetic Scheme 13:
  • Polyiminocarbonates are structurally related to polycarbonates.
  • the polyiminocarbonates have imino groups in the places typically occupied by carbonyl oxygen in the polycarbonates.
  • linkages according to the formula:
  • the salts of the compounds described herein can be prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compound.
  • the polymer comprises poly(ether carbonate) wtih tyrosol- bioactive moiety.
  • a desaminotyrosyl-tyrosine dipeptide can be combined with the PEG in methylene chloride and phosgene can be added as a solution in toluene. The reaction would be completed in around 9 minutes. In some embodiments, this reaction is carried out for from 1-60 minutes.
  • the polymer comprises poly(tyrosine carbonate) pendant bioactive moiety groups.
  • the polymer comprises poly(ether carbonate) tyrosine-diol copolymer with a bioactive moiety in the backbone.
  • the polymer comprises poly(ether carbonate) tyrosine-diol copolymer with a pendant bioactive moiety. In some embodiments, the polymer comprises poly(ether ester) tyrosine-bioactive moiety-diacid copolymer. In some embodiments, the polymer comprises poly(imino carbonate) tyrosine-bioactive moiety-copoymer. In some embodiments, the polymer comprises poly(imono tyrosine) with pendant PEG groups. [0097] In another aspect the present invention provides a medical device that comprises a polymer and/or polymer composition as described herein. For example, an embodiment provides a stent that comprises a polymer composition as described herein. Another embodiment provides a method of treating a body lumen, comprising deploying the stent within the body lumen. These and other embodiments are described in greater detail below.
  • biodegradable refers to a property of polymer whose molecular weight goes down because of hydrolysis or enzymatic reactions under physiological conditions such that the polymer is transformed into lower molecular weight oligomers in a period not to exceed four (4) years.
  • oligomer refers to a hydrolyzed product of a polymer, whose molecular weight is less than 10% of the original polymer.
  • alkyl alkylene
  • Terminal alkyl groups e.g., of the general formula -CnEhn+i
  • linking alkyl groups e.g., of the general formula -(CH2) n -
  • alkylene alkylene
  • the alkyl group may have 1 to 50 carbon atoms (whenever it appears herein, a numerical range such as “1 to 50” refers to each integer in the given range; e.g., “1 to 50 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 50 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 30 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 5 carbon atoms.
  • the alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar designations.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-
  • alkylaryl is an aryl group connected, as a substituent, via an alkylene group.
  • the alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphtylalkyl.
  • the alkylene group is a lower alkylene group.
  • An alkylaryl group may be substituted or unstubstituted.
  • alkyl groups may link together other groups, and in that context may be referred to as alkylene groups.
  • Alkylene groups are thus biradical tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), and butylene (-(CH2)4-) groups.
  • An alkylene group may be substituted or unsubstituted.
  • alkenyl alkenylene
  • alkenylene alkenylene
  • similar terms have the usual meaning known to those skilled in the art and thus may be used to refer to an alkyl or alkylene group that contains in the straight or branched hydrocarbon chain containing one or more double bonds.
  • An alkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • An "amide” is a chemical moiety with formula -(R) n -C(0)NHR' or -(R) n - NHC(0)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.
  • An "amide linkage” is an amide group (-C(O)NH-) that links two chemical moieties to one another.
  • Any amine, hydroxy, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified.
  • the procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated by reference herein in its entirety.
  • aryl refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi- electron system.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C- carboxy, O-carboxy, iso
  • substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
  • heteroalkyl refers to an alkyl group where one or more carbon atoms has been replaced with a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroalkyl refers to an alkyl group or alkylene group as described herein in which one or more of the carbons atoms in the backbone of alkyl group or alkylene group has been replaced by a heteroatom such as nitrogen, sulfur and/or oxygen.
  • heteroalkenylene may be used to refer to an alkenyl or alkenylene group in which one or more of the carbons atoms in the backbone of alkyl group or alkylene group has been replaced by a heteroatom such as nitrogen, sulfur and/or oxygen.
  • heteroaryl refers to an aryl group where one or more carbon atoms has been replaced with a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • alkyl For convenience and conciseness, sometimes the terms “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “heteroaryl”, and “alkylaryl”, or the like, may be used to refer to the corresponding linking groups when they serve to connect two moieties of a molecule, either monomeric or polymeric, which should be readily understood by those skilled in the art. That is, on such occasions, “alkyl” should be interpreted as “alkylene”; “alkenyl” should be interpreted as “alkenylene”; “aryl” should be interpreted as “arylene”; and so on.
  • a "heavy atom” is an atom that, when attached to a polymer, renders the polymer easier to detect by an imaging technique as compared to a polymer that does not contain the heavy atom. Since many polymers contain relatively low atomic number atoms such as hydrogen, carbon, nitrogen, oxygen, silicon and sulfur, in most cases heavy atoms have an atomic number of 17 or greater. Preferred heavy atoms have an atomic number of 35 or greater, and include bromine, iodine, bismuth, gold, platinum tantalum, tungsten, and barium.
  • a "hydrocarbon” is an organic compound consisting entirely of hydrogen and carbon.
  • hydrocarbons include unsubstituted alkyl groups, unsubstituted aryl groups, and unsubstituted alkylaryl groups. Any substitution to an alkyl group, aryl group, or alkylaryl group in a hydrocarbon would only comprise carbon and/or hydrogen atoms.
  • macromers As used herein, the terms “macromer”, “macromeric” and similar terms have the usual meaning known to those skilled in the art and thus may be used to refer to oligomeric and polymeric materials that are functionalized with end groups that are selected so that the macromers can be copolymerized with other macromers or monomers. A wide variety of macromers and methods for making them are known to those skilled in the art.
  • suitable macromers include hydroxy endcapped polylactic acid macromers, hydroxy endcapped polyglycolic acid macromers, hydroxy endcapped poly(lactic acid-co-glycolic acid) macromers, hydroxy endcapped polycaprolactone macromers, poly(alkylene diol) macromers, hydroxy end-capped poly(alkylene oxide) macromers and hydroxy endcapped polydioxanone macromers.
  • polymer As used herein, the terms “polymer”, “polymeric” and similar terms have the usual meaning known to those skilled in the art and thus may be used to refer to homopolymers, copolymers (e.g., random copolymer, alternating copolymer, block copolymer, graft copolymer) and mixtures thereof.
  • copolymers e.g., random copolymer, alternating copolymer, block copolymer, graft copolymer
  • the repeating structural units of polymers may also be referred to herein as recurring units.
  • molecular weight has the usual meaning known to those skilled in the art and thus reference herein to a polymer having a particular molecular weight will be understood as a reference to a polymer molecular weight in units of Daltons.
  • molecular weights of polymers are further described herein using the terms “number average” molecular weight (Mn) and/or “weight average” molecular weight (Mw), both of which terms are likewise expressed in units of Daltons and have the usual meaning known to those skilled in the art.
  • substitutent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkylyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl,
  • radiopaque refers to polymer compositions that have been rendered easier to detect using medical imaging techniques (e.g., by X-ray and/or during fluoroscopy) being the incorporation of heavy atoms into the polymer composition.
  • medical imaging techniques e.g., by X-ray and/or during fluoroscopy
  • incorporation may be by mixing, e.g., by mixing an effective amount of a radiopacifying additive such as barium salt or complex, and/or by attachment of effective amounts of heavy atoms to one or more of the polymers in the polymer composition.
  • polymer compositions may be inherently radiopaque.
  • inherently radiopaque is used herein to refer to a polymer to which a sufficient number of heavy atoms are attached by covalent or ionic bonds to render the polymer radiopaque. This meaning is consistent with the understanding of those skilled in the art, see, e.g., U.S. Patent Publication No. 2006/0024266, which is hereby incorporated by reference for all purposes, including for the particular purpose of describing radiopaque polymeric materials.
  • substituent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carbox
  • ring-halogenated may be used to refer to a group that optionally contains one or more (e.g., one, two, three or four) halogen substituents on the aryl and/or heteroaryl ring.
  • the protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure or be stereoisomeric mixtures.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • TE stands for tyrosine ethyl ester
  • DAT stands for desaminotyrosine
  • DTE desaminotyrosyl tyrosine ethyl ester
  • PTE stands for hydroxy-phenoxy-l-oxoethyl tyrosine ethyl ester
  • Ty stands for tyrosol.
  • the polymer obtained by phosgenation of DTE is denoted as poly(DTE carbonate).
  • An "I" before the abbreviation shows mono-iodination (e.g. ITE stands for mono-iodinated TE) and an I2 before the abbreviation shows di-iodination (e.g. I2DAT stands for di-iodinated DAT).
  • DTE if the "I" is before D, it means the iodine is on DAT and if "I” is after D, it means the iodine is on the tyrosine ring (e.g. DI2TE stands for DTE with 2 iodine atoms on the tyrosine ring).
  • DI2TE stands for DTE with 2 iodine atoms on the tyrosine ring
  • halogen atom means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with bromine and iodine being preferred.
  • esters refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An “ester linkage” is an ester group that links two chemical moieties to one another.
  • purified refers to compounds disclosed herein being substantially free of other, dissimilar compounds with which the compounds of the invention are normally associated in their natural state, so that the compounds of the invention comprise at least 0.5%, 1%, 5%, 10%, or 20%, and most preferably at least 50% or 75% of the mass, by weight, of a given sample.
  • polymers described herein may be used in accordance with preferred aspects of the invention as a homogeneous polymer, as a copolymer, and/or as a polymer blend.
  • a polymer of the Formula (I) is understood to be a reference to a polymer that comprises a recurring unit of the Formula (I), which may be a homopolymer, copolymer or blend.
  • a polymer of the Formula (la) is understood to be a reference to a polymer that comprises a recurring unit of the Formula (la), which may be a homopolymer, copolymer or blend.
  • bioresorbable, inherently radiopaque stents disclosed in accordance with preferred embodiments of the present invention may be used, for example, to temporarily treat a blood vessel as in traditional applications which generally include delivery through a catheter.
  • polymers prepared from sufficient amounts of the the monomeric starting materials described herein and having at least one bromine- or iodine- substituted aromatic ring are radio-opaque, such as the polymers prepared from radiopaque diphenol compounds prepared according to the disclosure of U.S. Patent No. 6,475,477, as well as he disclosure of co-pending and commonly-owned U.S. Patent Application Serial No. 10/592,202, the disclosures of both of which are incorporated herein by reference.
  • the iodinated and brominated diphenol monomers of the present invention can also be employed as radio-opacifying, biocompatible non-toxic additives for other polymeric biomaterials.
  • Bromine and iodine substituted aromatic monomers of the present invention can be prepared by well-known iodination and bromination techniques that can be readily employed by those of ordinary skill in the art in view of the guidance provided herein without undue experimentation.
  • the halogenated aromatic compounds from which the halogenated aromatic monomers of the present invention are prepared typically undergo ortho-directed halogenation.
  • the term, “ortho-directed”, is used herein to designate orientation of the halogen atom(s) relative to the phenoxy alcohol group.
  • the polymers described herein include polymers prepared by polymerizing Formula III monomers having pendent free carboxylic acid groups. However, it is not possible to polymerize polymers having pendent free carboxylic acid groups from corresponding monomers with pendent free carboxylic acid groups without cross-reaction of the free carboxylic acid group with the co-monomer. Accordingly, polymers in accordance with the present invention having pendent free carboxylic acid groups are prepared from homopolymers and copolymers of benzyl and tert-butyl ester monomers of the present invention.
  • the benzyl ester homopolymers and copolymers may be converted to corresponding free carboxylic acid homopolymers and copolymers through the selective removal of the benzyl groups by the palladium catalyzed hydrogenolysis method disclosed by co-pending and commonly owned U.S. Patent No. 6,120,491, the disclosure of which is incorporated herein by reference.
  • the tert-butyl ester homopolymers and copolymers may be converted to corresponding free carboxylic acid homopolymers and copolymers through the selective removal of the tert-butyl groups by the acidolyis method disclosed by the above-referenced U.S. Patent Application Serial No. 10/592,202, also incorporated herein by reference.
  • the polymers in accordance with preferred embodiments of the present invention may be achieved by any of a variety of known methods commonly employed in the field of synthetic polymers to produce a variety of useful articles with valuable physical and chemical properties, all derived from tissue compatible monomers.
  • the useful articles can be shaped by conventional polymer- forming techniques such as extrusion, compression molding, injection molding, solvent casting, spin casting, wet spinning, combinations of two or more thereof, and the like. Shaped articles prepared from the polymers are useful, inter alia, as degradable biomaterials for medical implant applications. Such applications include the use of shaped articles as vascular grafts and stents.
  • Polymers according to the present invention also include polyethers, polyurethanes, poly(carbamates), poly(thiocarbonates), poly(carbonodithionates) and poly(thiocarbamates), which may be prepared from the diphenol compounds of the present invention in accordance with known methods.
  • Random or block copolymers of the polymers of the present invention with a poly(alkylene oxide) may be prepared according to the method disclosed in U.S. Pat. No. 5,658,995, the disclosure of which is also incorporated by reference.
  • the poly(alkylene oxide) is preferably a poly(ethylene glycol) block/unit typically having a molecular weight of less than about 10,000 per unit. More typically, the poly(ethylene glycol) block/unit has a molecular weight less than about 4000 per unit. The molecular weight is preferably between about 1000 and about 2000 per unit.
  • the molar fraction of poly(ethylene glycol) units in block copolymers may range from greater than zero to less than 1, and is typically greater than zero up to about 0.5, inclusive. More preferably, the molar fraction is less than about 0.25 and yet more preferably, less than about 0.1. In a more preferred variations, the molar fraction may vary from greater than about 0.001 to about 0.08, and most preferably, between about 0.025 and about 0.035.
  • the molar fractions reported herein are based on the total molar amount of poly(alkylene glycol) and non-glycol units in the polymers.
  • the polymers in accordance with preferred embodiments of the present invention may be achieved by any of a variety of known methods commonly employed in the field of synthetic polymers to produce a variety of useful articles with valuable physical and chemical properties, all derived from tissue compatible monomers.
  • the useful articles can be shaped by conventional polymer thermoforming techniques such as extrusion and injection molding when the degradation temperature of the polymer is above the glass transition or crystalline melt temperature, or conventional non-thermal techniques can be used, such as compression molding, injection molding, solvent casting, spin casting, wet spinning. Combinations of two or more methods can be used. Shaped articles prepared from the polymers are useful, inter alia, as degradable biomaterials for medical implant applications.
  • embodiments of the compounds described above can be a hydroxyphenyl-alkanoic acid, such as desaminotyrosyl tyrosine (DAT), or a hydroxyphenylalkenoic acid.
  • DAT desaminotyrosyl tyrosine
  • HX 3 — D 1 — X 4 H is a diol
  • the two compounds may be reacted in an acid catalyzed Fischer esterification reaction, illustrated generally as follows: Acid
  • X can be R 4a as defined above.
  • Polymer compositions as described herein also include polyethers, polyesters, poly-iminocarbonates, polyphosphoesters and polyphosphazines. Those skilled in the art can prepare these polymers using routine experimentation informed by the guidance provided herein. Polyesters, specifically poly(ester amides), may be prepared by the process disclosed by U.S. Patent 5,216,115, the disclosure of which is incorporated by reference, and particular-ly for the purpose of describing such processes. Polyiminocarbonates may be prepared by the process disclosed by U.S. Patent 4,980,449, the disclosure of which is incorporated by reference, and particularly for the purpose of describing such processes. Polyethers may be prepared by the process disclosed by U.S. Patent 6,602,497, the disclosure of which is incorporated by reference, and particularly for the purpose of describing such processes.
  • Various embodiments of the polymer compositions described herein may be used to produce a variety of useful articles with valuable physical and chemical properties.
  • the useful articles can be shaped by conventional polymer thermo-forming techniques such as extrusion and injection molding when the degradation temperature of the polymer is above the glass transition or crystalline melt temperature(s), or conventional non-thermal techniques can be used, such as compression molding, injection molding, solvent casting, spin casting, wet spinning. Combinations of two or more methods can be used. Shaped articles prepared from the polymers are useful, inter alia, as biocompatible, biodegradable and/or bioresorbable biomaterials for medical implant applications.
  • the medical device is a stent.
  • a stent may comprise many different types of forms.
  • the stent may be an expandable stent.
  • the stent may be configured to have the form of a sheet stent, a braided stent, a self-expanding stent, a woven stent, a deformable stent, or a slide-and-lock stent.
  • Stent fabrication processes may further include two-dimensional methods of fabrication such as cutting extruded sheets of polymer, via laser cutting, etch-ing, mechanical cutting, or other methods, and assembling the resulting cut portions into stents, or similar methods of three-dimensional fabrication of devices from solid forms.
  • the polymers are formed into coatings on the surface of an implantable device, particularly a stent, made either of a polymer as described herein or another material, such as metal.
  • a stent made either of a polymer as described herein or another material, such as metal.
  • Such coatings may be formed on stents via techniques such as dipping, spray coating, combinations thereof, and the like.
  • stents may be comprised of at least one fiber material, curable material, laminated material and/or woven material.
  • the medical device may also be a stent graft or a device used in embolotherapy.
  • the highly beneficial combination of properties associated with preferred embodiments of the polymers described herein means these polymers are well-suited for use in producing a variety of resorbable medical devices besides stents, especially implantable medical devices that are preferably radiopaque, biocompatible, and have various times of bioresorption.
  • the polymers are suitable for use in resorbable implantable devices with and without therapeutic agents, device components and/or coatings with and without therapeutic agents for use in other medical systems, for instance, the musculoskeletal or orthopedic system (e.g., tendons, ligaments, bone, cartilage skeletal, smooth muscles); the nervous system (e.g., spinal cord, brain, eyes, inner ear); the respiratory system (e.g., nasal cavity and sinuses, trachea, larynx, lungs); the reproductive system (e.g., male or female reproductive); the urinary system (e.g., kidneys, bladder, urethra, ureter); the digestive system (e.g., oral cavity, salivary glands, pharynx, esophagus, stomach, small intestine, colon), exocrine functions (biliary tract, gall bladder, liver, appendix, recto-anal canal); the endocrine system (e.g., pancreas/islets, pituitary, cor
  • the polymers described herein can thus be used to fabricate wound closure devices, hernia repair meshes, gastric lap bands, drug delivery implants, envelopes for the implantation of cardiac devices, devices for other cardiovascular applications, non- cardiovascular stents such as biliary stents, esophageal stents, vaginal stents, lung- trachea/bronchus stents, and the like.
  • the resorbable polymers are suitable for use in producing implantable, radiopaque discs, plugs, and other devices used to track regions of tissue removal, for example, in the removal of cancerous tissue and organ removal, as well as, staples and clips suitable for use in wound closure, attaching tissue to bone and/or cartilage, stopping bleeding (homeostasis), tubal ligation, surgical adhesion prevention, and the like.
  • Applicants have also recognized that preferred embodiments of the polymers described herein are well-suited for use in producing a variety of coatings for medical devices, especially implantable medical devices.
  • the present polymers may be advantageously used in making various resorbable orthopedic devices including, for example, radiopaque biodegradable screws (interference screws), radiopaque biodegradable suture anchors, and the like for use in applications including the correction, prevention, reconstruction, and repair of the anterior cruciate ligament (ACL), the rotator cuff/rotator cup, and other skeletal deformities.
  • Other devices that can be advantageously formed from preferred embodiments of the polymers described herein, include devices for use in tissue engineering. Examples of suitable resorbable devices include tissue engineering scaffolds and grafts (such as vascular grafts, grafts or implants used in nerve regeneration).
  • the resorbable polymers may also be used to form a variety of devices effective for use in closing internal wounds.
  • biodegradable resorbable sutures, clips, staples, barbed or mesh sutures, implantable organ supports, and the like for use in various surgery, cosmetic applications, and cardiac wound closures can be formed.
  • Preferred embodiments of the polymers described herein are also useful in the production of bioresorbable, inherently radiopaque polymeric embolotherapy products for the temporary and therapeutic restriction or blocking of blood supply to treat tumors and vascular malformations, e.g., uterine fibroids, tumors (i.e., chemoembolization), hemorrhage (e.g., during trauma with bleeding) and arteriovenous malformations, fistulas and aneurysms delivered by means of catheter or syringe.
  • tumors and vascular malformations e.g., uterine fibroids, tumors (i.e., chemoembolization), hemorrhage (e.g., during trauma with bleeding) and arteriovenous malformations, fistulas and aneurysms delivered by means of catheter or syringe.
  • Embolotherapy treatment methods are by their very nature local rather than systemic and the products are preferably fabricated from the radio-opaque polymers described herein, to permit fluoroscopic monitoring of delivery and treatment.
  • the polymers described herein are further useful in the production of a wide variety of therapeutic agent delivery devices.
  • Such devices may be adapted for use with a variety of therapeutics including, for example, pharmaceuticals (i.e., drugs) and/or biological agents as previously defined and including biomolecules, genetic material, and processed biologic materials, and the like.
  • pharmaceuticals i.e., drugs
  • biological agents as previously defined and including biomolecules, genetic material, and processed biologic materials, and the like.
  • Any number of transport systems capable of delivering therapeutics to the body can be made, including devices for therapeutics delivery in the treatment of cancer, intravascular problems, obesity, infection, and the like.
  • a medical device that comprises a polymeric material may include one or more additional components, e.g., a plasticizer, a filler, a crystallization nucleating agent, a preservative, a stabilizer, a photoactivation agent, etc., depending on the intended application.
  • a medical device comprises an effective amount of at least one therapeutic agent and/or a magnetic resonance enhancing agent.
  • preferred therapeutic agents include a chemotherapeutic agent, a non-steroidal anti- inflammatory, a steroidal anti-inflammatory, and a wound healing agent.
  • Therapeutic agents may be co-administered with the polymeric material.
  • at least a portion of the therapeutic agent is contained within the polymeric material.
  • at least a portion of the therapeutic agent is contained within a coating on the surface of the medical device.
  • Non-limiting examples of preferred chemotherapeutic agents include taxanes, tax- inines, taxols, paclitaxel, dioxorubicin, cis-platin, adriamycin and bleomycin.
  • Non-limiting examples of preferred non-steroidal anti-inflammatory compounds include aspirin, dexa- methasone, ibuprofen, naproxen, and Cox-2 inhibitors (e.g., Rofexcoxib, Celecoxib and Valdecoxib).
  • Non-limiting examples of preferred steroidal anti-inflammatory compounds include dexamethasone, beclomethasone, hydrocortisone, and prednisone. Mixtures comprising one or more therapeutic agents may be used.
  • Non-limiting examples of preferred magnetic resonance enhancing agents include gadolinium salts such as gadolinium carbonate, gadolinium oxide, gadolinium chloride, and mixtures thereof.
  • the amounts of additional components present in the medical device are preferably selected to be effective for the intended application.
  • a therapeutic agent is preferably present in the medical device in an amount that is effective to achieve the desired therapeutic effect in the patient to whom the medical device is administered or implanted. Such amounts may be determined by routine experimentation.
  • the desired therapeutic effect is a biological response.
  • the therapeutic agent in the medical device is selected to promote at least one biological response, preferably a biological response selected from the group consisting of thrombosis, cell attachment, cell proliferation, attraction of inflammatory cells, deposition of matrix proteins, inhibition of thrombosis, inhibition of cell attachment, inhibition of cell proliferation, inhibition of inflammatory cells, and inhibition of deposition of matrix proteins.
  • the amount of magnetic resonance enhancing agent in a medical devices is preferably an amount that is effective to facilitate radiologic imaging, and may be determined by routine experimentation.
  • pharmaceutical agent encompasses a substance intended for mitigation, treatment, or prevention of disease that stimulates a specific physiologic (metabolic) response.
  • biological agent encompasses any substance that possesses structural and/or functional activity in a biological system, including without limitation, organ, tissue or cell based derivatives, cells, viruses, vectors, nucleic acids (animal, plant, microbial, and viral) that are natural and recombinant and synthetic in origin and of any sequence and size, antibodies, polynucleotides, oligonucleotides, cDNA's, oncogenes, proteins, peptides, amino acids, lipoproteins, glycoproteins, lipids, carbohydrates, polysaccharides, lipids, liposomes, or other cellular components or organelles for instance receptors and ligands.
  • biological agent includes vims, serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or its derivatives (or any trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of diseases or injuries of man (per Section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)).
  • biological agent may include 1) “biomolecule”, as used herein, encompassing a biologically active peptide, protein, carbohydrate, vitamin, lipid, or nucleic acid produced by and purified from naturally occurring or recombinant organisms, antibodies, tissues or cell lines or synthetic analogs of such molecules; 2) “genetic material” as used herein, encompassing nucleic acid (either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), genetic element, gene, factor, allele, operon, structural gene, regulator gene, operator gene, gene complement, genome, genetic code, codon, anticodon, messenger RNA (mRNA), transfer RNA (tRNA), ribosomal extrachromosomal genetic element, plasmagene, plasmid, transposon, gene mutation, gene sequence, exon, intron, and, 3) “processed biologies”, as used herein, such as cells, tissues or organs that have undergone manipulation.
  • the thera-peutic agent may also include vitamin or mineral
  • the amount of the therapeutic agent is preferably sufficient to inhibit restenosis or thrombosis or to affect some other state of the stented tissue, for instance, heal a vulnerable plaque, and/or prevent rupture or stimulate endothelialization.
  • the agent(s) may be selected from the group consisting of antiproliferative agents, anti-inflammatory, anti-matrix metalloproteinase, and lipid lowering, cholesterol modifying, anti-thrombotic and antiplatelet agents, in accordance with preferred embodiments of the present invention.
  • the therapeutic agent is contained within the stent as the agent is blended with the polymer or admixed by other means known to those skilled in the art.
  • the therapeutic agent is delivered from a polymer coating on the stent surface.
  • the therapeutic agent is delivered by means of no polymer coating.
  • the therapeutic agent is delivered from at least one region or one surface of the stent.
  • the therapeutic may be chemically bonded to the polymer or carrier used for delivery of the therapeutic of at least one portion of the stent and/or the therapeutic may be chemically bonded to the polymer that comprises at least one portion of the stent body. In one preferred embodiment, more than one therapeutic agent may be delivered.
  • any of the aforementioned devices described herein can be adapted for use as a therapeutic delivery device (in addition to any other functionality thereof).
  • Controlled therapeutic delivery systems may be prepared, in which a therapeutic agent, such as a biologically or pharmaceutically active and/or passive agent, is physically embedded or dispersed within a polymeric matrix or physically admixed with a polymer described herein.
  • Controlled therapeutic agent delivery systems may also be prepared by direct application of the therapeutic agent to the surface of an implantable medical device such as a bioresorbable stent device (comprised of at least one of the polymers described herein) without the use of these polymers as a coating, or by use of other polymers or substances for the coating.
  • Therapeutic agent delivery compounds may also be formed by physically blending the therapeutic agent to be delivered with the polymers described herein using conven-tional techniques well-known to those of ordinary skill in the art.
  • polymer compositions described herein containing therapeutic agents are suitable for applications where localized delivery is desired, as well as in situations where a systemic delivery is desired.
  • the polymer conjugates and physical admixtures may be implanted in the body of a patient in need thereof, by procedures that are essentially conventional and well-known to those of ordinary skill in the art.
  • the polyarylates can also be formed into drug delivery implants that degrade to release pharmacologically or biologically active agents within a predictable controlled release time.
  • controlled drug delivery systems can be prepared by incorporating the active agents into the polymer chains as pendant side chains or by cross linking the pendant side chains to form a polymeric matrix into which the active agents are physically embedded or dispersed.
  • Controlled drug delivery system implants can also be formed by physically admixing the polyarylates with a biologically or pharmacologically active agent.
  • suitable biologically or pharmacologically active agents include in principle any active agent that has to be repeatedly administered over prolonged periods of time.
  • An advantage of using the radiopaque, bioresorbable polymers described herein in therapeutic agent delivery applications is the ease of monitoring release of a therapeutic agent and the presence of the implantable therapeutic delivery system. Because the radiopacity of the polymeric matrix is due to covalently attached halogen substituents, the level of radiopacity is directly related to the residual amount of the degrading therapeutic agent delivery matrix still present at the implant site at any given time after implantation. In preferred embodiments the rate of therapeutic release from the degrading therapeutic delivery system will be correlated with the rate of polymer resorption. In such preferred embodiments, the straight-forward, quantitative measurement of the residual degree of radioopacity will provide the attending physician with a way to monitor the level of therapeutic release from the implanted therapeutic delivery system.
  • the diphenolic monomers were prepared by Fisher-esterification of tyrosol with phenolic acids such as desaminotyrosine, 3,5-diiododesaminotyrosine or dicarboxylic acids (0.5 equivalents) by refluxing with catalytic amount of 4-toulenesulfonic acid in chloroform or 1 ,2-dichloroethane as the solvent. A modified Dean Stark trap was used to remove the water formed.
  • the diphenolic monomers in the pure form or as appropriate mixtures were polymerized to the corresponding polycarbonates using triphosgene. The polymers were compression molded into films. The films were tested for mechanical properties and they generally showed high modulus, tensile strength, and elongation at break. Further details are provided below.
  • Example 1 Synthesis of 4-hydroxyphenethyl 3-(4-hydroxyphenyl)propanoate (DTy) [00171] Into a 500 mL round bottomed flask fitted with an overhead stirrer, and a modified Dean-stark trap for solvents heavier than water were added 10 g (72 mmol) of tyrosol, 13 g (78 mmol) of desaminotyrosine (DAT), 0.65 g (3.4 mmol) of 4-toluenesulfonic acid monohydrate, and 200 mL of 1 ,2-dichloroethane (DCE).
  • DOTA desaminotyrosine
  • DCE desaminotyrosine
  • the reaction mixture was allowed to cool to room temperature while stirring was continued.
  • the product that precipitated was isolated by filtration and washed with 2 X 50 mL of DCE.
  • the solid was stirred with 150 mL of aqueous 5% NaHC03 for 3 h using overhead stirrer.
  • the product was isolated by filtration and washed with 3 X 50 mL of DI water and then dried in the vacuum oven for 24 h at 50 °C.
  • the product was dried under vacuum at 40 °C for 24 h and characterized by elemental analysis, HPLC, and 'H NMR spectroscopy.
  • the washing as above was repeated with two additional 100 mL portions of DI water.
  • the reaction mixture was then precipitated with 120 mL of IPA.
  • the resulting gel was ground twice with 150 mL portions of IPA in 1 L laboratory blender.
  • the product was isolated by vacuum filtration and dried in a vacuum oven at 80 °C for 24 h.
  • the polymer had a HPSEC polystyrene equivalent molecular weight of 160 Kda (THF as mobile phase).
  • THF HPSEC polystyrene equivalent molecular weight of 160 Kda
  • the polymer was semi-crystalline with a Tg of 51 °C and a Tm of 181 °C. On compression molding at 220 °C, it gave films which were transparent on rapid cooling and translucent when cooled slowly.
  • HPTy obtained in accordance with Example 1 was polymerized to obtain poly(HPTy carbonate) with an HPSEC polystyrene equivalent Mw of 140 Kda and a Tg of 55 °C.
  • Example 6 HPSEC polystyrene equivalent Mw of 140 Kda and a Tg of 55 °C.
  • the flask was heated using a heating mantle, while stirring with the overhead stirrer so that 1,2-dichloroethane and water distilled over into the Dean-Stark trap. The heating continued until the water collection stopped (about 1.45 mL of water was collected). The reaction mixture was allowed to cool to 50 °C and then evaporated to dryness. To the residue 175 mL of acetonitrile was added and stirred at room temperature for 4 h. The crystalline solid that separated was isolated by filtration and washed with acetonitrile. The Off-white crude product was collected and dried.
  • the poly(PrD-di LDAT-co-tyrosol carbonate) product is composed of mainly polymer molecules having randomly-ordered PrD-di I2DAT and tyrosol units connected through carbonate (-OC(O)O-) linkers. That is, two adjacent units could include PrD-di I2DAT and PrD-di I2DAT, PrD-di LDAT and tyrosol, or tyrosol and tyrosol.
  • tyrosol Given the unsymmetrical structure of tyrosol, it can be connected with a PrD-di LDAT unit using either “head” (i.e., “phenoxy” moiety) or “tail” (i.e., the “ethylenoxy” moiety). Any two adjacent units formed from tyrosol itself can be in any of the “head-head”, “head-tail” or “tail-tail” arrangements.
  • the PrD-di I2DAT since the PrD-di I2DAT was used in molar excess, the polymer molecules likely do not contain a large amount of long strings of “tyrosol- carbonate-tyrsol” units linked to each other. On the other hand, if there is a large excess of tyrosol relative to the PrD-di I2DAT in the reaction mixture, tyrosol may have more opportunity to link with each other to give relatively long strings of such linkages.
  • the washing was repeated with two additional 250 mL portions of DI water.
  • the reaction mixture was then precipita-ted with 300 mL of IPA.
  • the resulting gel was ground twice with 200 mL portions of IPA in 1 L laboratory blender.
  • the product was isolated by vacuum filtration and dried in a vacuum oven at 60 °C.
  • the polymer had a HPSEC polystyrene equivalent molecular weight of 126 Kda (THF as mobile phase) and glass transition temperature (Tg) of 58 °C. Compression molding at 195 °C gave a uniform transparent film which gave tensile modulus, tensile stress at yield, and elongation at break respectively of 191 ksi, 5 ksi and 450%.
  • Example 17 Preparation of Tyrosol or Analog-based Alternating Polycarbonates [00195] Alternating polymers having regular sequences of tail-tail, head-head, and/or head-tail configurations are disclosed. These polymers are distinctly different from random polymers having no specific order of tail-tail, head-head, and/or head-tail configurations. Specifically, polycarbonates derived from tyrosol, have three types of carbonate bonds: aromatic-aromatic (also referred to as head-head), mixed aromatic-aliphatic (also referred to as head-tail), and aliphatic-aliphatic (also referred to as tail-tail) as shown below:
  • aromatic-aromatic also referred to as head-head
  • mixed aromatic-aliphatic also referred to as head-tail
  • tail-tail aliphatic-aliphatic
  • R H (tyrosol) or OMe (homovanillyl alcohol)
  • Tyrosol was placed in a three-necked flask equipped with an overhead stirrer under inert atmosphere. Anhydrous tetrahydrofuran was added from a syringe and a solution was obtained while the mixture was stirred. The solution was constantly cooled with an ice/water bath. Triphosgene was dissolved in anhydrous tetrahydrofuran and added drop-wise to the reaction vessel. Aliphatic tyrosol chloroformate was obtained over the course of one hour. Most of the solvent was evaporated to prepare for the work-up. Methylene chloride was added to dissolve the residue and excess tyrosol was filtered off. The solution was cooled in an ice/water bath.
  • Dityrosol carbonate (x equivalents) and tyrosol carbonate (y equivalents) are dissolved in anhydrous tetrahydrofurane and cooled in dry ice/isopropanol bath. Pyridine is added drop-wise over the course of several hours in step 1. Then triphosgene dissolved in anhydrous tetrahydrofuran is added drop-wise into the reaction mixture.
  • the poly(tyrosol carbonate) with controlled composition of carbonate bonds is obtained through a standard work-up procedure.
  • Example 18 Preparation of poly(PrDl2DAT-co-9%tyrosol-co-l%PEGlK carbonate) [00203] In a 1 L 3-necked round-bottomed flask equipped with a mechanical stirrer, and a liquid addition device were placed 45 g (51 mmol) of PrD-di I2DAT, 4.5 g (33 mol) of tyrosol, 0.5 g (0.50 mmol) of PEG1000, 25 g (320 mmol) of pyridine, and 305 mL of DCM and stirred for 15 min to get a clear solution.
  • Triphosgene (8.6 g, 87 mmol of phosgene) was dissolved in 32 mL of DCM and the solution was introduced into the reaction flask over 2-3 hours. After the addition was complete, the reaction mixture was quenched with a mixture of 135 mL of THF and 15 mL of water. 350 mL of water was added to the reaction mixture and stirred for 5 min. After allowing the layers to separate, the top aqueous layer was removed and discarded. The washing was repeated with two additional 350 mL portions of DI water. The reaction mixture was then precipitated with 500 mL of acetone. The resulting gel was stirred with 500 mL of IPA when the gel broke up into fine particles.
  • the particles were ground twice, isolated by filtration and dried in a vacuum oven at 80 °C.
  • the polymer had a Mw of 400 Kda and glass transition temperature (Tg) of 92 °C.
  • Tg glass transition temperature
  • 'H NMR spectrum of the polymer was in agreement with the structure. Compression molding at 190 °C gave a uniform transparent film which gave tensile modulus, tensile stress at yield, and elongation at break of 240 ksi, 9.1 ksi, and 106% respectively.
  • Example 20 Preparation of PLLAdiol using ethylene glycol as initiator (EGPLLAD7K).
  • EGPLLAD7K ethylene glycol as initiator
  • the flask was maintained under a positive pressure of nitrogen and then immersed into an oil bath maintained at 110 °C and after heating for 1 h the lactide melted. The temperature was raised to 140 °C and heated with stirring for 4 h. The flask was then removed from the oil bath and allowed to cool to room temperature. To the flask 350 mL of DCM was added and stirred overnight to dissolve the polymer. The polymer solution was slowly added to 1 L of heptane with stirring. The polymer precipitated as white crystalline powder which was isolated by filtration. The precipitate was washed with 250 mL of acetonitrile to remove any unreacted lactide. The product was dried in a vacuum oven at 40 °C for 24 h.
  • PrDPLLAD7K was similarly prepared using 1,3 -propanediol as the initiator instead of ethylene glycol.
  • Example 21 Preparation of poly(PrD-di l 2 DAT-co-50%EGPLLAD7K carbonate).
  • a mechanical stirrer In a 1 L 3-necked round-bottomed flask equipped with a mechanical stirrer, and a liquid addition device were placed 30 g (0.034 mol) of PrD-di LDAT, 30 g (0.004 mol) of EGPLLAD7K, 11.4 g (0.145 mol) of pyridine, and 360 mL of chloroform and stirred for 15 min to get a clear solution (the solution was slightly cloudy).
  • Triphosgene (3.96 g, 0.04 mol of phosgene) was dissolved in 12 mL of chloroform and the solution was introduced into the reaction flask over 2-3 hours. After the addition was complete, the reaction mixture was quenched with a mixture of 135 mL of THF and 15 mL of water. 350 mL of water was added to the reaction mixture and stirred for 5 min. After allowing the layers to separate, the top aqueous layer was removed and discarded. The washing was repeated with two additional 350 mL portions of DI water. The reaction mixture was then precipitated with 700 mL of IPA. The resulting gel was ground with 550 mL twice in a 4 L blender. The product was isolated by filtration and dried in a vacuum oven at 80 °C. 'H NMR spectrum of the polymer was in agreement with the structure. Compression molding at 190 °C of the obtained 50% EGPLLAD polymer gave a uniform transparent film.
  • copolymers containing 20% and 65% EGPLLAD were also prepared.
  • the physical properties of the three polymer samples are set forth below.
  • Other polymers having different physical properties can be prepared by routine experimentation informed by the guidance provided herein, e.g., by appropriate selection of comonomer content, polymer molecular weight and film preparation procedures.
  • Example 22 Preparation of poly(l 2 DTy-co-50%EGPLLAD7K carbonate).
  • Example 23 Preparation of poly(l 2 DTy-co-50%DTy carbonate).
  • Iodination of tyrosol was carried out by adding 200 mL of KICh solution (2M) to 27.6 g (0.2 mol) of tyrosol in 140 mL of 95% ethanol and stirring the resulting solution for 1 h. When treated with 400 mL of water, an oil separated which was stirred with 100 mL of 2% sodium thiosulfate solution for 2 h. The brown solid obtained was dissolved in ethanol and treated with charcoal and filtered. The pure diiodotyrosol (4-(2-hydroxyethyl) 2,6,- diiodophenol) was obtained in 65% yield and was characterized by hplc and NMR.
  • Example 25 Synthesis of 4-hydroxyphenethyl 3-(4-(4-hydroxyphenoxy)phenyl)- propanoate.
  • the reaction is continued until approximately 1.4 mL of water collected in the modified Dean-stark trap above the DCE and the water collection essentially stopps (about 4 hours of reflux).
  • the reaction mixture is cooled to room temperature and the crude product is dissolved in 100 mL of ethyl acetate and washed twice with 100 mL portions of 5% sodium bicarbonate solution. After drying over magnesium sulfate the organic layer is concentrated and precipitated with hexane. The resulting white crystalline solid is collected by filtration and dried in a vacuum oven at 25 °C.
  • the product is characterized by elemental analysis, hplc, and *H NMR.
  • a 2 L 3-neck round bottom flask was attached to an overhead stirrer and a Dean- Stark apparatus with water-cooled condenser and a heating mantle was placed beneath the flask.
  • 4-hydroxyphenylacetic acid 157.4 g, 1.03 mol
  • Tyrosol 142.9 g, 1.03 mol
  • phosphoric acid 5.07 g, 51.7 mmol
  • 315 mL of toluene were added to the flask.
  • the reaction mixture was stirred and heated at reflux until no more water was collected by azeotropic distillation.
  • the reaction mixture was allowed to cool and phase separate and the upper layer was decanted leaving a thick syrup.
  • the syrup was dissolved in 600 mL of ethyl acetate and washed twice with 150 mL of 5% sodium bicarbonate solution and twice with 150 mL of brine solution.
  • the ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo to obtain a thick syrup.
  • the syrup was concentrated in vacuo several times with cold dichloromethane to obtain a white powdered residue.
  • the powder was recrystallized from a dichloromethane :hexane mixture, collected by vacuum filtration, and dried in a vacuum oven at 40 °C for 72 h. Yield: 223 g, 79%. Melting Point: 94 °C.
  • HTy 140 g, 0.514 mol, 1.00 eq
  • glutaric acid 65.9 g, 0.499 mol, 0.97 eq
  • DPTS 1,4-dimethylpyridinium p-toluenesulfonate
  • N,N'-diisopropylcarbodiimide (170 mL, 1.08 mol, 2.1 eq) was added slowly using an addition funnel. The reaction mixture was allowed to stir for 48 hours. The reaction mixture was transferred to a 10 L plastic beaker equipped with overhead stirring and precipitated by slowly adding isopropanol (5 L) using an addition funnel while stirring. The precipitate was collected by vacuum filtration, redissolved in DCM (1.5 L), and reprecipitated using isopropanol (3 L), twice. The final precipitate was collected by vacuum filtration and dried in a vacuum oven at 40 °C for 72 hours. Yield: 170 g, 92%.
  • DIC N,N'-diisopropylcarbodiimide
  • the glass transition temperature and melt temperature of polymers of the present invention are listed in Table 1 and Table 2.
  • the polymers of Table 1 contain repeating units of Formula XVIII -a.
  • A is CH 2 (HTy) or CH2CH2 (DTy).
  • Table 1 Glass transition temperature and melt temperature of polymers of Formula XVIII -a
  • Polymers of Formula XVIII -b has B defined as-O-CO-CFhCFhCFh (DiTyGlutarate) or -O-CO-CH 2 OCH 2 (DiTyDiglycolate).
  • B is defined as follows:

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Abstract

L'invention concerne de nouvelles classes de composés phénol, notamment celles dérivées du tyrosol et des analogues de celui-ci, utiles comme monomères pour la préparation de polymères biocompatibles, et des polymères biocompatibles préparés à partir de ces composés phénol monomères, notamment de nouveaux polymères biodégradables et/ou biorésorbables. Ces polymères ou compositions de polymères biocompatibles, qui présentent une biorésorbabilité et une aptitude au traitement améliorées, sont utiles dans diverses applications médicales, telles que dans des dispositifs médicaux et dans des formulations thérapeutiques à libération contrôlée. L'invention concerne également des procédés de préparation de ces composés phénol monomères et polymères biocompatibles.
PCT/US2021/017898 2012-02-03 2021-02-12 Biomatériaux polymères dérivés de monomères phénoliques et leurs utilisations médicales WO2021163520A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130203713A1 (en) * 2012-02-03 2013-08-08 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
US20140046018A1 (en) * 2008-10-10 2014-02-13 Polyactiva Pty Ltd. Biodegradable polymer - bioactive moiety conjugates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140046018A1 (en) * 2008-10-10 2014-02-13 Polyactiva Pty Ltd. Biodegradable polymer - bioactive moiety conjugates
US20130203713A1 (en) * 2012-02-03 2013-08-08 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JI SHEN, DUBE KOUSTUBH, CHESTERMAN JULIAN P., FUNG STEPHANIE L., LIAW CHYA-YAN, KOHN JOACHIM, GUVENDIREN MURAT: "Polyester-based Ink Platform with Tunable Bioactivity for 3D Printing of Tissue Engineering Scaffolds", BIOMATERIALS SCIENCE, vol. 7, no. 2, 29 January 2019 (2019-01-29), GB, pages 560 - 570, XP055847337, ISSN: 2047-4830 *
SOMMERFELD SVEN D., MURTHY N. SANJEEVA, COHEN JARROD, ZHANG ZHENG, KADUK JAMES A., KOHN JOACHIM: "Structural Investigations of Polycarbonates whose Mechanical and Erosion Behavior Can Be Controlled by Their Isomer Sequence", MACROMOLECULES, vol. 53, no. 22, 24 November 2020 (2020-11-24), US, pages 9878 - 9889, XP055847341, ISSN: 0024-9297, DOI: 10.1021/acs.macromol.0c01772 *

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