DK2549276T3 - Reversibel, kovalent binding af funktionelle molekyler - Google Patents

Reversibel, kovalent binding af funktionelle molekyler Download PDF

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Publication number
DK2549276T3
DK2549276T3 DK12189317.6T DK12189317T DK2549276T3 DK 2549276 T3 DK2549276 T3 DK 2549276T3 DK 12189317 T DK12189317 T DK 12189317T DK 2549276 T3 DK2549276 T3 DK 2549276T3
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group
formula
compound
groups
protein
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DK12189317.6T
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Mark Smith
Stephen Caddick
James Baker
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Ucl Business Plc
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Priority claimed from GB0913967A external-priority patent/GB0913967D0/en
Priority claimed from GB0913965A external-priority patent/GB0913965D0/en
Priority claimed from GB0914321A external-priority patent/GB0914321D0/en
Application filed by Ucl Business Plc filed Critical Ucl Business Plc
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Publication of DK2549276T3 publication Critical patent/DK2549276T3/da

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Claims (15)

1. Anvendelse af en forbindelse med formlen (la) som et reagent for binding af en forbindelse med formlen RrH, der omfatter en første funktionel del med formlen F-ι, til en anden funktionel del med formlen F2
hvor: - X og X'hver repræsenterer oxygen; - Y er en elektrofil fraspaltelig gruppe; - R3 og R3' sammen danner en gruppe med formlen -N(R33·), hvor R33' repræsenterer et hydrogenatom eller en gruppe med formlen Y, Nu, -L(Z)n eller IG; - R2 repræsenterer et hydrogenatom eller en gruppe med formlen Y, Y, Nu, -L(Z)n eller IG; - hver gruppe med formlen Y er ens eller forskellig og repræsenterer en elektrofil fraspaltelig gruppe; - hver gruppe med formlen Nu er ens eller forskellig og repræsenterer en nukleofil udvalgt fra -OH, -SH, -NH2 og -NH(Ci-6-alkyl); - hver gruppe med formlen L er ens eller forskellig og repræsenterer en linker-gruppe; - hver gruppe med formlen Z er ens eller forskellig og repræsenterer en reaktiv gruppe bundet til en gruppe med formlen L, der er i stand til at blive omsat med en forbindelse, der indeholder en anden funktionel del som defineret i krav 1, således at den anden funktionelle del bindes til gruppen med formlen L; - n er 1,2 eller 3; og - hver gruppe med formlen IG er ens eller forskellig og repræsenterer en del der er en Ci-20-alkylgruppe, en C2.2o-alkenylgruppe eller en C2.20-alkynyl-gruppe, der er ikke-substitueret eller substitueret med én eller flere substituen-ter udvalgt fra halogenatomer og sulfonsyregrupper, og hvori (a) 0, 1 eller 2 carbonatomer er erstattet af grupper udvalgt fra C6-io-arylen, 5- til 10-leddet he-teroarylen, C3-7-carboclyclen og 5- til 10-leddet heterocyclylengrupper, og (b) 0, 1 eller 2 -CH2-grupper er erstattet af grupper udvalgt fra -O-, -S-, -S-S-, C(O)-og -N(Ci-6-alkyl)- grupper, hvor: (i) arylen-, heteroarylen-, carbocyclylen- og heterocyclylen-grupperne er ikke-substituerede eller substituerede med én eller flere substituenter, der er udvalgt fra halogenstomer og Ci-6-alkyl, Ci-6-alkoxy, Ci-6-alkylthiol, -N(Ci-6-al-kyl)(Ci-6-alkyl), nitro- og sulfonsyregrupper; og (ii) 0, 1 eller 2 carbonatomer i carbocyclylen- og heterocyclylengrupperne er erstattet af C(0)-grupper; og - enten: - den første funktionelle del eller den anden funktionelle del er et protein, der er et antistof eller antistoffragment, som kan binde til et specifikt antigen via en epitop på antigenet, og den anden af den første funktionelle del og den anden funktionelle del er et lægemiddel, eller - den første funktionelle del eller den anden funktionelle del er en polymerdel, der er udvalgt fra peptider, proteiner, polysaccharider, polyethere, poly-aminosyrer, polyvinylalkoholer, polyvinylpyrrolidoner, poly(meth)acrylsyre og derivater deraf, polyurethaner og polyphosphazener, og den anden af den første funktionelle del og den anden funktionelle del er et lægemiddel; hvor gruppen R-ι bindes til forbindelsen med formlen (la) via nukleofilt angreb af den første SH-gruppe i forbindelsen med formlen RrH ved 2-posi-tionen af forbindelsen med formlen (la), således at gruppen Y ved 2-positionen erstattes af gruppen Ri.
2. Anvendelse ifølge krav 1, hvor: (A) : Y er et halogenatom eller et triflat, tosylat, mesylat, N-hydroxysuccinimidyl, Nhydroxysulfosuccinimidyl, C-i-6-allcylthiol, 5- til 10-leddet heterocyclylthiol, C6-io-arylthiol, C3-7-carbocyclylthiol, -0C(0)CH3, -0C(0)CF3, phenyloxy, en -NRX-RyRz+- eller -PRxRyRz+-gruppe, hvori Rx, Ryog Rz er ens eller forskellige og er udvalgt fra hydrogenatomer og Ci-6-alkyl og phenylgrupper; og/eller (B) : L repræsenterer en del, der er en Ci-2o-alkylengruppe, en C2.20-alkenylen-gruppe eller en C2.2o-alkynylengruppe, der er ikke-substitueret eller substitueret med én eller flere substituenter, der er udvalgt fra halogenstomer og sulfonsy-regrupper, og hvori (a) 0, 1 eller 2 carbonatomer er erstattet af grupper udvalgt fra C6-io-arylen, 5- til 10-leddet heteroarylen, C3-7-carbocyclylen og 5- til 10-led-dede heterocyclylengrupper, og (b) 0,1 eller 2 -CH2-grupper er erstattet af grupper udvalgt fra -0-, -S-, -S-S-, C(O)- og -N-(i-e-alkyl)-grupper, hvor: (i) arylen-, heteroarylen-, carbocyclylen- og heterocyclylen-grupperne er ikke-substituerede eller substituerede med én eller flere substituenter, der er udvalgt fra halogenatomer og Ci-6-alkyl, Ci-6-alkoxy, Ci-6-alkylthiol, -N(Ci-6-al-kyl)(Ci-6-alkyl), nitro- og sulfonsyregrupper; og (ii) 0, 1 eller 2 carbonatomer i carbocyclylen- og heterocyclylengrupperne er erstattet af C(O)- grupper; og/eller (C): Z repræsenterer: (a) en gruppe med formlen -LG, -C(0)-LG, -C(S)-LG eller -C(NH)-LG, hvor LG er en elektrofil fraspaltelig gruppe; (b) en nukleofil Nu' udvalgt fra -OH, -SH, -NH2, -NH(Ci-6-alkyl) og -C(0)NH-NH2 grupper; (c) en cyklisk del Cyc, der er i stand til at foranledige en ringåbnende elektrofil reaktion med en nukleofil; (d) en gruppe med formlen -S(02)(Hal), hvor Hal er et halogenatom; (e) en gruppe med formlen -N=C=0 eller -N=C=S; (f) en gruppe med formlen -S-S(IG’), hvor IG' repræsenterer en gruppe med formlen IG som defineret i krav 2; (g) en gruppe AH, der er en C6-io-arylgruppe, der er substitueret med ét eller flere halogenatomer; (h) en fotoreaktiv gruppe, der kan aktiveres ved eksponering for ultraviolet lys; (i) en gruppe med formlen -C(0)H eller -C(0)(Ci-6-alkyl); (j) en maleimido-gruppe; (k) en gruppe med formlen -C(0)CHCH2; (l) en gruppe med formlen -C(0)C(N2)H eller -PhN2+, hvor Ph repræsenterer en phenylgruppe; eller (m) en epoxidgruppe; og/eller (D) : IG repræsenterer en del der er en ikke-substitueret Ci-6-alkylgruppe, C2.6-alkenylgruppe eller C2-6-alkynylgruppe, hvori (a) 0 eller 1 carbonatom erstattes af en gruppe udvalgt fra phenylen, 5- til 6-leddet heteroarylen, C5-6-carbocycly-len og 5- til 6-leddet heterocyclylengrupper, hvor phenylen-, heteroarylen-, car-bocyclylen- og heterocyclylen-grupperne er ikke-substituerede eller substituerede med én eller to substituenter, der er udvalgt fra halogenstomer og Ci-4-alkyl og Ci-4-alkoxygrupper, og (b) 0, 1 eller 2 -CH2- grupper er erstattet af grupper udvalgt fra -O-, -S- og C(O)- grupper; og/eller (E) : n er 1.
3. Anvendelse ifølge krav 1 eller 2, hvor forbindelsen med formlen (la) er en forbindelse med formlen (Ib)
(II) hvor: - X og X' hver repræsenterer et oxygenatom; - R33’ repræsenterer et hydrogenatom eller en Ci-6-alkylgruppe; - Y repræsenterer et halogenatom; og - R2 repræsenterer et hydrogen- eller halogenatom eller en Ci-6-alkyl-gruppe.
4. Anvendelse ifølge et hvilket som helst af de foregående krav, hvor: - Ri er en gruppe med formlen-Fi; - Fi er et peptid eller protein omfattende mindst en første cysteinrest; og - gruppen Ri bindes til forbindelsen med formlen (la) via nukleofilt angreb af thiolgruppen i den første cysteinrest ved 2-positionen af forbindelsen med formlen (la), således at gruppen Y erstattes af thiolgruppen i den første cysteinrest i gruppen R-i; og hvor eventuelt: - R2 er en gruppe med formlen Y; - R-ι endvidere omfatter mindst en anden cysteinrest; og - gruppen R-ι endvidere fastgøres til forbindelsen med formlen (la) via nukleofilt angreb af thiolgruppen i den anden cysteinrest ved 3-positionen af delen med formlen (la), således at gruppen R2 erstattes af thiolgruppen i den anden cysteinrest i gruppen R-i.
5. Fremgangsmåde til fremstilling af et konjugat, hvilken fremgangsmåde omfatter (i) omsætning af en forbindelse med formlen (la) med en forbindelse med formlen Ri-H, hvorved der frembringes en forbindelse med formlen (II)
(ii) efterfølgende binding af en del af formlen F2 til forbindelsen med formlen (II); hvor trin (i) involverer binding af gruppen R-ι via nukleofilt angreb af den første SFI-gruppe i forbindelsen med formlen R-i-H ved 2-positionen af forbindelsen med formlen (la), således at gruppen Y ved 2-positionen erstattes af gruppen Ri, og hvor X, X', Y, R-ι, R2, R3, R3, og F2 alle er som defineret i et hvilken som helst af kravene 1 til 4.
6. Fremgangsmåde ifølge krav 5, hvor: (A) : fremgangsmåden omfatter binding af F2 til forbindelsen med formlen (II) via en elektrofil additionsreaktion af F2 over carbon-carbon-dobbeltbindingen mellem 2-positionen og 3-positionen af formlen (II); eller (B) : R33' repræsenterer et hydrogenatom eller en gruppe med formlen Y, Nu eller -L(Z)n og fremgangsmåden omfatter binding af F2 til forbindelsen med formlen (II) via en reaktion mellem F2 og (i) nitrogenatomet af delen med formlen -N-(R33) eller (ii) gruppen med formlen Y, Nu eller -L(Z)n; eller (C) : R2 repræsenterer en gruppe med formlen Y, Nu eller -L(Z)n og fremgangsmåden omfatter binding af F2 til forbindelsen med formlen (II) via en reaktion mellem F2 og gruppen med formlen Y, Nu eller -L(Z)n.
7. Fremgangsmåde til fremstilling af et konjugat, hvilken fremgangsmåde omfatter omsætning af en forbindelse med formlen RrH med en forbindelse med formlen (Ila)
hvor: - R3a og R3a’ sammen danner en gruppe med formlen -N(R33a), hvor R33a’ repræsenterer en gruppe med formlen R33’ eller en gruppe med formlen F2 eller -L(F2)m(Z)n.m; - R2a repræsenterer en gruppe med formlen R2 eller en gruppe med formlen F2 eller --L(F2)m(Z)n-m; - m er et heltal med en værdi på fra nul til n; - forbindelsen med formlen (Ila) omfatter mindst én gruppe med formlen F2; - F2 er som defineret i krav 1; - X, X', R3, R3', R33', R2j L, Z og n alle er som defineret i et hvilket som helst af kravene 1 til 3 - Ri er som defineret i krav 1 eller 4 og - fremgangsmåden involverer binding af gruppen Ri via nukleofilt angreb af den første SH-gruppe i forbindelsen med formlen RrH ved 2-positionen af forbindelsen med formlen (Ila), således at gruppen Y ved 2-positionen erstattes af gruppen Ri.
8. Fremgangsmåde, der omfatter (i) tilvejebringelse af en forbindelse med formlen (III) eller (Illa); og (ii) spaltning af bindingen mellem gruppen Ri og carbonatomet ved 2-positionen af forbindelsen med formlen (III) eller (Illa)
(life) hvor: - R3a og R3a’ sammen danner en gruppe med formlen -N(R33), hvor R33a’ repræsenterer en gruppe med formlen R33, eller en gruppe med formlen F2 eller -L(F2)m(Z)n-m; - R2a repræsenterer en gruppe med formlen R2 eller en gruppe med formlen F2 eller —L(F2)m(Z)n.m, m er et heltal med en værdi på fra nul til n; - Ri er som defineret i krav 1 eller 4; - F2 er som defineret i krav 1; - X, X', R3, R3·, R33', R2, L, Z og n alle er som defineret i et hvilket som helst af kravene 1 til 3; og hvor, når fremgangsmåden involverer forbindelsen med formlen (Ilia): - Ri i forbindelsen med formlen (Illa) omfatter mindst en første thiolgrup-pe og en anden thiolgruppe, hvilken første thiolgruppe er bundet til 2-positionen i forbindelsen med formlen (I I la), og hvilken anden thiolgruppe er bundet til 3-positionen i forbindelsen med formlen (Illa); og - trin (ii) endvidere involverer spaltning af bindingen mellem gruppen Ri og carbonatomet ved 3-positionen af delen med formlen (Illa).
9. Forbindelse, hvilken forbindelse er: (A) en forbindelse med formlen (Ila) som defineret i krav 7; eller (B) en forbindelse med formlen (III) som defineret i krav 8, hvilken forbindelse omfatter mindst én gruppe med formlen F2, og hvori R2a ikke er et hydrogenatom.
10. Forbindelse med formlen (I I la) som defineret i krav 8.
11. Forbindelse ifølge krav 10, hvilken forbindelse omfatter mindst én gruppe med formlen F2.
12. Forbindelse ifølge krav 10 eller 11, hvor er et peptid eller protein, der mindst omfatter to cysteinrester, hvilke cysteinrester fortrinsvis danner en indre disulfidbro i peptidet eller proteinet, når peptidet eller proteinet ikke er bundet i forbindelsen med formlen (Illa).
13. Forbindelse med formlen (IVa) eller (IVb)
hvor - Ri er som defineret i krav 1 eller 4; - X, X', R2a, R3a og R3a’ er som defineret i krav 8; - R4 er et halogenatom, hydroxyl, Ci-6-alkoxy, thiol, Ci-6-alkylthio eller C1-e-alkylcarbonyloxygruppe, eller en gruppe med formlen F2; - mindst én af grupperne R2a og R4 omfatter en gruppe med formlen F2; og - F2 er som defineret i krav 1.
14. Forbindelse som defineret i (B) af krav 9, krav 11 eller krav 13 til anvendelse i en fremgangsmåde til behandling af menneske- eller dyrekroppen ved kirurgi eller terapi eller en diagnostisk metode, der praktiseres på menneske- eller dyrekroppen.
15. Fremgangsmåde som defineret i et hvilket som helst af kravene 5 til 7, hvor konjugatet omfatter en maleimidring og fremgangsmåden endvidere omfatter ringåbning af maleimidringen.
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