DK2355853T3 - Bionedbrydelige polymer-bioaktivt fragmentkonjugater - Google Patents

Bionedbrydelige polymer-bioaktivt fragmentkonjugater Download PDF

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DK2355853T3
DK2355853T3 DK09818693.5T DK09818693T DK2355853T3 DK 2355853 T3 DK2355853 T3 DK 2355853T3 DK 09818693 T DK09818693 T DK 09818693T DK 2355853 T3 DK2355853 T3 DK 2355853T3
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bioactive
polymer
moiety
monomer
biodegradable polymer
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Michael Shane O'shea
Florian Hans Maximilian Graichen
Russell John Tait
Heng Chy Taing
Justine Leigh Jeffery
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Polyactiva Pty Ltd
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Claims (20)

1. Bionedbrydelig polymer omfattende en flerhed af frigivelige bioaktive fragmenter, hvor de frigivelige bioaktive fragmenter er vedhængende fra og kovalent bundet til det bionedbrydelige polymerskelet, hvor den bionedbrydelige polymer har en generel formel (I):
(I) hvor: A og B, der er det samme eller forskellige, repræsenterer det resterende af polymerskelettet og (i) omfatter en eller flere -X-R(ZD)-Y- som vist i formel (I), og (ii) er hver dannet af monomerenheder der er koblet via et bionedbrydeligt fragment, hvor hver X, Y, R, Z og D i et givet -X-R(ZD)-Y- fragment af den bionedbrydelige polymer er det samme eller forskellige; X og Y er hver uafhængigt et bionedbrydeligt fragment valgt fra et estereller karbamatfragment; R repræsenterer et lineært eller forgrenet eventuelt substitueret carbonhydrid; Z er et spacerfragment; og D er et frigiveligt bioaktivt fragment valgt fra fluoroquinolon antibiotika, hvor de bioaktive fragmenter (D) er i stand til at blive frigivet ved en hastighed lig med eller hurtigere end hastigheden af bionedbrydning af polymerskelettet.
2. Den bionedbrydelige polymer ifølge krav 1, hvor de bioaktive fragmenter (D) er valgt fra alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofoxacin, delafloxacin, dextrofloxacin, difloxacin, enoxacin, enrofloxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, tosulfloxacin og trovafloxacin.
3. Den bionedbrydelige polymer ifølge krav 1 eller krav 2, hvor A og B er valgt fra polyurethaner, polyestere, og copolymerer deraf.
4. Den bionedbrydelige polymer ifølge et hvilket som helst af kravene 1 til 3, hvilken omfatter mindre end 25 mol% af polymeriserede rester der er afledt fra en C2-diol, i forhold til det samlede antal mol af polymeriserede diolrester.
5. Den bionedbrydelige polymer ifølge et hvilket som helst af kravene 1 til 4, hvor D er koblet via Z til R af et ester-, amid-, thiol-, anhydrid-, imid-, karbonat-, peroxid-, peroxyester-, fosfatester-, thioester-, sulfatester-, karbamat-, azo- eller boronatesterfragment.
6. Den bionedbrydelige polymer ifølge krav 5, hvor Z er valgt fra gruppen bestående af oxy (-0-), alkyl, alkenyl, alkynyl, aryl, acyl (including -C(O)-), carbocyclyl, heterocyclyl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, acyloxy, carbocyclyloxy, heterocyclyloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkylacyloxy, alkyloxyacylalkyl, alkylcarbocyclyloxy, alkylheterocyclyloxy, alkylheteroaryloxy, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclylthio, alkylheterocyclylthio, alkylheteroarylthio, alkylalkenylalkyl, alkylalkynylalkyl, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylalkenylaryl, arylalkynylaryl, arylacylaryl, arylacyl, arylcarbocyclyl, arylheterocyclyl, arylheteroaryl, alkenyloxyaryl, alkynyloxyaryl, aryloxyaryl, arylacyloxy, arylcarbocyclyloxy, arylheterocyclyloxy, arylheteroaryloxy, alkylthioaryl, alkenylthioaryl, alkynylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclylthio, arylheterocyclylthio, og arylheteroarylthio, hvor når til stede den eller hver -CH2-gruppe i en hvilken som helst alkylkæde kan erstattes afen divalentgruppe uafhængigt valgt fra -O-, -0P(0)2-, -0P(0)20- -S-, -S(O)-, -S(0)20-, -0S(0)20-, -N = N-, -0Si(0Ra)20-, -Si(0Ra)20-, -0B(0Ra)0-, -B(0Ra)0-, -NRa-, -C(O)-, -C(0)0-, -0C(0)0-, -0C(0)NRa- og -C(0)NRa-, hvor den eller hver Ra kan være uafhængigt valgt fra hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, og acyl.
7. Den bionedbrydelige polymer ifølge krav 5 eller krav 6, hvor Z er valgt fra -O-; -C(O)-; og eventuelt substitueret: -0C(0)-Ci-i8alkylen-C(0)-; -C(0)0-Ci-i8alkylen-C(0)-; -NRaC(0)-Ci-i8alkylen-C(0)-; -C(0)0-Ci-i8alkylen-0-; -O-Ci-lealkylen-O-; -O-Ci-isalkylen-NR3-; -0C(0)-Ci-i8alkylen-NRa-; -C(0)-Ci-i8alkylen-NRa-; -0C(0)-Ci-i8alkylen-0-; -C(0)-Ci-i8alkylen-0-; og -C(0)NRa-Ci-i8alkylen-NRa- hvor Ra er valgt fra hydrogen, Ci-isalkyl, Ci-isalkenyl, Ci-isalkynyl, C6-isaryl, C3-i8carbocyclyl, C3-isheteroaryl, C3-i8heterocyclyl, og C7-isarylalkyl.
8. Den bionedbrydelige polymer ifølge et hvilket som helst af kravene 5 til 7, hvor Z er valgt fra -O-; -C(O)-; og -0C(0)-Ci-i8alkylen-C(0)-, såsom -0C(0)-C2-3alkylen-C(0)-.
9. Den bionedbrydelige polymer ifølge et hvilket som helst af kravene 1 til 8, hvor R er et lineært eller forgrenet eventuelt substitueret carbonhydrid med fra 1 til 12 kulstofatomer.
10. Den bionedbrydelige polymer ifølge et hvilket som helst af kravene 1 til 9, hvor R er aromatisk.
11. Den bionedbrydelige polymer ifølge krav 6, hvor, Z er aryloxy.
12. Den bionedbrydelige polymer ifølge krav 6, hvor Z er arylacyloxy.
13. Den bionedbrydelige polymer ifølge et hvilket som helst af kravene 1 til 10, opnåelig ved polymerisering af et monomer-bioaktivt fragmentkonjugat af formel (II):
(Π) hvor: X' og V er hver uafhængige funktionelle grupper der (a) er i stand til at undergå polymerisering med monomer med kompatibel kemisk funktionalitet, og (b) reagere med den kompatible kemiske funktionalitet for at give et bionedbrydeligt fragment, hvor X' og V er hver uafhængigt valgt fra hydroxyl, carboxylsyre, isocyanat, og carboxylsyrehalid; R repræsenterer et lineært eller forgrenet eventuelt substitueret carbonhydrid; Z er et spacerfragment; og D er et frigiveligt bioaktivt fragment valgt fra fluoroquinolon antibiotika; med mindst en monomer omfattende kompatibel kemisk funktionalitet.
14. Bionedbrydelig polymer ifølge krav 13, opnåelig ved polymerisering af det monomer-bioaktivt fragmentkonjugat af formel II, hvor substituenterne X' og Y' er hver hydroxyl, med et diisocyanat frembringende en polyurethan.
15. Bionedbrydelig polymer ifølge krav 13, opnåelig ved polymerisering af det monomer-bioaktive fragmentkonjugat af formel (II) hvor X' og Y' er hver hydroxyl med et polyisocyanat, en polysyre eller polyester, der kan finde sted i tilstedeværelsen af en eller flere andre typer af polyoler.
16. Bionedbrydelig polymer ifølge krav 15, hvor den ene eller flere andre typer af polyoler er polyesterpolyoler.
17. Bionedbrydelig polymer ifølge krav 15 eller krav 16, hvor polyisocyanatet er valgt fra m-phenylen diisocyanat, p-phenylen diisocyanat, 2,4-toluen diisocyanat, 2,6-toluen diisocyanat, 1,6-hexamethylen diisocyanat, 1,4-hexamethylen diisocyanat, 1,3-cyclohexan diisocyanat, 1,4-cyclohexan diisocyanat, hexahydro-toluen diisocyanat og dets isomerer, isophoron diisocyanat, dicyclo-hexylmethan diisocyanater, 1,5-napthylen diisocyanat, 4,4'-diphenylmethan diisocyanat, 2,4' diphenylmethan diisocyanat, 4,4'-biphenylen diisocyanat, 3,3'-dimethoxy-4,4'-biphenylen diisocyanat, 3,3'-dimethyl-diphenylpropan-4,4'-diisocyanat, 2,4,6-toluen triisocyanat, 4,4'-dimethyl-diphenylmethan-2,2',5,5,-tetraisocyanat, polymethylen polyphenyl-polyisocyanater og alkylestere af lysin diisocyanat.
18. Fremgangsmåde til at fremstille en bionedbrydelig polymer ifølge et hvilket som helst af kravene valgt fra 1 til 10 og 13 til 16, hvilken fremgangsmåde omfatter trinnet at polymerisere et monomer-bioaktivt fragmentkonjugat af formel (II):
(Π) hvor: X' og V er hver uafhængige funktionelle grupper der (a) er i stand til at undergå polymerisering med monomer med kompatibel kemisk funktionalitet, og (b) reagere med den kompatible kemiske funktionalitet for at give et bionedbrydeligt fragment, hvor X' og V er hver uafhængigt valgt fra hydroxyl, carboxylsyre, isocyanat, og carboxylsyrehalid; og R, Z og D er som defineret i et hvilket som helst af kravene valgt fra 1 til 10 og 13 til 17; med mindst en monomer omfattende kompatibel kemisk funktionalitet.
19. Monomer-bioaktivt fragmentkonjugat der er egnet til anvendelse i fremstilling af en bionedbrydelig polymer, hvor det monomer-bioaktive fragmentkonjugat har en struktur af general formel (II):
(Π) hvor: X' og V er hver uafhængige funktionelle grupper der (a) er i stand til at undergå polymerisering med monomer med kompatibel kemisk funktionalitet for at danne en bionedbrydelig polymer, og (b) reagere med den kompatible kemiske funktionalitet for at give et bionedbrydeligt fragment, hvor X' og V er hver hydroxyl og den kompatible kemiske funktionalitet er et diisocyanat og frembringer en polyurethan; R repræsenterer et lineært eller forgrenet eventuelt substitueret carbonhydrid; Z er et spacerfragment; og D er valgt fra fluoroquinolon antibiotika.
20. Monomer-bioaktivt fragmentkonjugat ifølge krav 19, hvor de bioaktive fragmenter (D) er valgt fra alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofoxacin, delafloxacin, dextrofloxacin, difloxacin, enoxacin, enrofloxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, tosulfloxacin og trovafloxacin.
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