US 10,376,594 B2
Bio-orthogonal drug activation
Marc Stefan Robillard, Eindhoven (NL); Hendricus Marie Janssen, Eindhoven (NL); Wolter Ten Hoeve, Assen (NL); Ronny Mathieu Versteegen, Hegelsom (NL); and Raffaella Rossin, Eindhoven (NL)
Assigned to TAGWORKS PHARMACEUTICALS B.V., Eindhoven (NL)
Filed by TAGWORKS PHARMACEUTICALS B.V., Eindhoven (NL)
Filed on Dec. 30, 2015, as Appl. No. 14/983,858.
Application 14/983,858 is a continuation of application No. 14/117,655, previously published as PCT/IB2012/052446, filed on May 16, 2012.
Claims priority of provisional application 61/515,432, filed on Aug. 5, 2011.
Claims priority of provisional application 61/515,458, filed on Aug. 5, 2011.
Claims priority of application No. 11166241 (EP), filed on May 16, 2011; application No. 11166942 (EP), filed on May 20, 2011; application No. 11176736 (EP), filed on Aug. 5, 2011; application No. 11176741 (EP), filed on Aug. 5, 2011; application No. 11192572 (EP), filed on Dec. 8, 2011; and application No. 11192577 (EP), filed on Dec. 8, 2011.
Prior Publication US 2016/0106859 A1, Apr. 21, 2016
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 257/08 (2006.01); C07D 237/26 (2006.01); C07C 13/263 (2006.01); C07C 33/16 (2006.01); A61K 31/435 (2006.01); A61K 31/502 (2006.01); A61K 31/045 (2006.01); A61K 47/00 (2006.01); B82Y 5/00 (2011.01); A61K 47/68 (2017.01); A61K 31/704 (2006.01); A61K 38/05 (2006.01); A61K 39/395 (2006.01); A61K 47/22 (2006.01); A61K 31/444 (2006.01); A61K 47/54 (2017.01)
CPC A61K 47/6803 (2017.08) [A61K 31/435 (2013.01); A61K 31/444 (2013.01); A61K 31/704 (2013.01); A61K 38/05 (2013.01); A61K 39/3955 (2013.01); A61K 39/39558 (2013.01); A61K 47/22 (2013.01); A61K 47/545 (2017.08); A61K 47/555 (2017.08); A61K 47/558 (2017.08); A61K 47/6897 (2017.08); B82Y 5/00 (2013.01); C07C 33/16 (2013.01); C07D 237/26 (2013.01); C07D 257/08 (2013.01); Y02A 50/471 (2018.01)] 25 Claims
 
1. A prodrug kit comprising a prodrug compound and an activator compound, wherein the prodrug compound comprises a drug moiety DD linked to a trigger moiety TR either directly or via a linker LD, wherein the trigger moiety comprises a dienophile and the activator compound comprises a diene that can react with the dienophile, the dienophile comprising a structure according to formula (1a):

OG Complex Work Unit Drawing
wherein T and G each independently is H, or a substituent selected from the group consisting of alkyl, F, Cl, Br or I;
A and P each independently are CRa2 or CRaXD, provided that at least one is CRaXD;
wherein XD is (O—C(O)p-(LD)n-(DD), S—C(O)-(LD)n-(DD), O—C(S)-(LD)n-(DD), or S—C(S)-(LD)n-(DD), wherein p =0 or 1; wherein LD is a self-immolative linker, and n =0 or 1, wherein LD is linear or branched and linked to TR via S, N, NH, or O, wherein these atoms are part of the linker; wherein DD is one or more drugs, linked to LD, O—C(O), S—C(O), O—C(S), S—C(S) or CRa via S, N, NH, or O, wherein these atoms are part of the drug; and wherein when XD is (O—C(O))p-(LD)n-(DD) and p=0 and LD or DD is bound to TR via N or NH, these N and NH moieties are bound to an aromatic carbon of LD or DD;
Y, Z, Q, X together form a substituted or unsubstituted four-membered aliphatic moiety; wherein Y,Z,X,Q each independently are selected from the group consisting of CRa2, C═CRa2, C═O, with at most one of Y, Z, X, and Q being selected from the group consisting of C═CRa2 and C═O;
wherein each Ra independently is selected from the group consisting of H, alkyl, aryl, OR′, SR′, S(═O)R′″, S(═O)2R′″, S(═O)2NR′R″, F, Cl, , SO3H, SO4H, NO2, CN, CF3, CF2R′, NR′R″, C(═O)R′, C(═O)OH, C(═O)NR′R″, C(═S)NR′R″, NR′C(═O)—R′″, NR′C(═S)—R′″, NR′C(═OO—R′″, NR′C(═S)O—R′″, NR′C(═O)S—R′″, OC(═O)NR′—R″, SC(═O)NR′—R″, OC(═S)NR′—R″, SC(═S)NW′—R″, NR′C(═S)S—R′″, NR′C(═O)NR″—R″, NR′C(═S)NR″—R″, with each R′ and each R″ independently being H, aryl or alkyl and R′″ independently being aryl or alkyl;
wherein neither or at least one of the linker LD and the trigger moiety comprises a targeting agent TT or a masking moiety MM; wherein TT is an antibody, antibody fragment, protein, peptide, peptide mimetic, polymer, carbohydrate, or oligonucleotide targeting agent, and MM is a protein, peptide, polymer, polyethyleneglycol, or carbohydrate masking moiety;
wherein the drug moiety DD is selected from the group consisting of proteins, oligopeptides, oligonucleotides, oligosaccharides, peptides, peptoids and organic drug compounds;
wherein the activator comprises a diene selected from the dienes according to Formula (4)

OG Complex Work Unit Drawing
wherein R1 and R2 each independently are selected from the group consisting of H, alkyl, aryl, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S)NR′R″, SC(═S)NR′R″, NR′C(═O)NR″R″, NR′C(═S)NR″R″ with each R′ and each R″ independently being H, aryl or alkyl, and R′″ independently being aryl or alkyl; wherein A is N; B is N; X is N; and Y is N;
wherein neither or at least one of the substituents R1 and R2 on the diene is comprised in a binding to a polymer, protein, peptide, carbohydrate, dendrimer, heparin derivative, hyaluronic acid derivative, albumin, albumin-binding moiety, dye moiety, fluorescent moiety, imaging probe, chelate, liposome, polymer particle or polymersome.