Compounds for fast and efficient click release
The invention disclosed herein relates to compounds, combinations, kits, and methods using same, for use in bioorthogonal release reactions. In particular, the compounds, combinations and kits of the invention can be used to achieve fast and efficient click release. Applications of the compounds, combinations, and kits of the invention include both in vitro and in vivo applications.
1 . A compound satisfying Formula (19):
and pharmaceutically acceptable salts thereof, wherein:
X 1 , X 2 , X 4 , and X 5 , are independently C(R 47 ) 2 or CR 47 Y T1 ;
X 3 is C(R 47 ) 2 , CR 47 Y T1 , or Y T3 ;
wherein at least one of conditions (a)-(b) is met:
(a) at least one of X 1 , X 2 , X 3 , X 4 , X 5 , is CR 47 Y T1 ; Y T1 is positioned cis relative to H a ; Y T1 is selected from the group consisting of OH, SH, and N(R 38 ) 2 ; and
(b) X 3 is Y T3 ; Y T3 is NR 38 and is not flanked by C(O), C(S), S(O), or S(O) 2 ;
R 48 is selected from the group consisting of —OC(O)—(S P ) k C A , —OC(S)—(S P ) k C A , —SC(O)(S P ) k C A , —SC(S)—(S P ) k C A , —O-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A , —S-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A , and —(S P ) k C A ;
r is an integer in range of from 0 to 2;
each s is independently 0 or 1;
each i is independently an integer in a range of from 0 to 4;
j is an integer in range of from 0 to 4;
each k is independently 0 or 1;
L C is a self-immolative linker and S′ is a spacer;
each C A and C B are independently selected from the group consisting of organic molecules and inorganic molecules;
wherein, when R 48 is —OC(O)—(S P ) k C A , —OC(S)—(S P ) k C A , —SC(O)—(S P ) k C A , or
—SC(S)—(S P ) k C A , then S P ˜, when k>0, or C A , when k=0, is bound to the —OC(O)—,
—OC(S)—, —SC(O)—, or —SC(S)— of R 48 via an atom selected from the group consisting of O, C, S, and N, wherein this atom is part of S P or C A ,
wherein, when R 48 is —O-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A or
—S-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A and r is 0, then S P , when k>0, or C A , when k=0, is bound to the —O— or —S— moiety of R 48 on the allylic position of the trans-cyclooctene ring of Formula (19) via a group selected from the group consisting of —C(O)—, and —C(S)—, wherein this group is part of S P or C A ,
wherein, when R 48 is —O-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A or
—S-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A and r is 1, then L C is bound to the —O— or —S— moiety on the allylic position of the trans-cyclooctene ring of Formula (19) via a group selected from the group consisting of —C(Y C2 )Y C1 —, and a carbon atom, wherein this group is part of L C ;
wherein Y C1 is selected from the group consisting of —O—, —S—, and —NR 36 —,
wherein Y C2 is selected from the group consisting of O and S,
wherein, when R 48 is —O-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A or —S-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A and r is 1, then S P , when k>0, or C A , when k=0, is bound to L C via a moiety selected from the group consisting of —O—, —S—, and —N—, wherein said moiety is part of S P or C A , wherein, when R 48 is —(S P ) k C A , then S P , when k>0, or C A , when k=0, is bound to the allylic position of the trans-cyclooctene of Formula (19) via an —O— or an —S— atom, wherein this atom is part of S P or C A ,
wherein each R 37 and R 36 is independently selected from the group consisting of hydrogen, —(S P ) i —C B with i independently being an integer in a range of from 0 to 4, C 1 -C 24 alkyl groups, C 2 -C 24 alkenyl groups, C 2 -C 24 alkynyl groups, C 6 -C 24 aryl groups, C 2 -C 24 heteroaryl groups, C 3 -C 24 cycloalkyl groups, C 5 -C 24 cycloalkenyl groups, C 12 -C 24 cycloalkynyl groups, C 3 -C 24 (cyclo)alkyl(hetero)aryl groups, C 3 -C 24 (hetero)aryl(cyclo)alkyl, C 4 -C 24 (cyclo)alkenyl(hetero)aryl groups, C 4 -C 24 (hetero)aryl(cyclo)alkenyl groups, C 4 -C 24 (cyclo)alkynyl(hetero)aryl groups, C 4 -C 24 (hetero)aryl(cyclo)alkynyl groups, C 4 -C 24 alkylcycloalkyl groups, and C 4 -C 24 cycloalkylalkyl groups;
wherein the R 37 and R 38 groups not being hydrogen are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OH, —NH 2 , —SO 3 H, —PO 3 H, —PO 4 H 2 , —NO 2 , —CF 3 , ═O, ═NH, and —SH, and optionally contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized,
wherein R 38 is independently selected from the group listed for R 37 and R 36 , with the proviso that R 38 is not attached to the remainder of the molecule via C(O), C(S), S(O), or S(O) 2 ;
wherein each R 47 is independently selected from the group consisting of hydrogen, —(S P ) i —C B , —F, —Cl, —Br, —I, —OR 37 , —N(R 37 ) 2 , —SO 3 , —PO 3 —, —NO 2 , —CF 3 , —SR 37 , —S(═O) 2 N(R 37 ) 2 , —OC(═O)R 37 , —SC(═O)R 37 , —OC(═S)R 37 , —SC(═S)R 37 , —NR 37 C(═O)—R 37 , —NR 37 C(═S)—R 37 , —NR 37 C(═O)O—R 37 , —NR 37 C(═S)O—R 37 , —NR 37 C(═O)S—R 37 , —NR 37 C(═S)S—R 37 , —OC(═O)N(R 37 ) 2 , —SC(═O)N(R 37 ) 2 , —OC(═S)N(R 37 ) 2 , —SC(═S)N(R 37 ) 2 , —NR 37 C(═O)N(R 37 ) 2 , —NR 37 C(═O)N(R 37 ) 2 , —C(═O)R 37 , —C(═S)R 37 , —C(═O)N(R 37 ) 2 , —C(═S)N(R 37 ) 2 , —C(═O)O—R 37 , —C(═O)S—R 37 , —C(═S)O—R 37 , —C(═S)S—R 37 , —S(O)R 37 , —S(O) 2 R 37 , —NR 37 S(O) 2 R 37 , —ON(R 37 ) 2 ,
—NR 37 OR 37 , C 1 -C 24 alkyl groups, C 2 -C 24 alkenyl groups, C 2 -C 24 alkynyl groups, C 6 -C 24 aryl groups, C 2 -C 24 heteroaryl groups, C 3 -C 24 cycloalkyl groups, C 5 -C 24 cycloalkenyl groups, C 12 -C 24 cycloalkynyl groups, C 3 -C 24 (cyclo)alkyl(hetero)aryl groups, C 3 -C 24 (hetero)aryl(cyclo)alkyl, C 4 -C 24 (cyclo)alkenyl(hetero)aryl groups, C 4 -C 24 (hetero)aryl(cyclo)alkenyl groups, C 4 -C 24 (cyclo)alkynyl(hetero)aryl groups, C 4 -C 24 (hetero)aryl(cyclo)alkynyl groups, C 4 -C 24 alkylcycloalkyl groups, and C 4 -C 24 cycloalkylalkyl groups;
wherein the alkyl groups, alkenyl groups, alkynyl groups, aryl, heteroaryl, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl groups, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, cycloalkylalkyl groups are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OR 37 , —N(R 37 ) 2 , —SO 3 R 37 , —PO 3 (R 37 ) 2 , —PO 4 (R 37 ) 2 , —NO 2 , —CF 3 , ═O, ═NR 37 , and —SR 37 , and optionally contain one or more heteroatoms selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized,
wherein two R 37 , R 38 , R 47 groups are optionally comprised in a ring,
wherein two R 37 , R 38 , R 47 groups are optionally comprised in a ring so as to form a ring fused to the eight-membered trans-ring.
2 . The compound according to claim 1 , wherein at most one of conditions (a) and (b) is met.
3 . The compound according to claim 1 selected from the group consisting of
and enantiomers thereof.
4 . The compound according to claim 1 selected from the group consisting of
5 . A combination comprising the compound according to claim 1 , and a diene.
6 . The combination according to claim 5 , wherein the diene is a tetrazine satisfying Formula (4) and pharmaceutically acceptable salts thereof:
wherein
each moiety Q 1 and Q 2 is independently selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —OR 37 , —N(R 37 ) 2 , —SO 3 , —PO 3 —, —NO 2 , —CF 3 , —SR 37 , —S(═O) 2 N(R 37 ) 2 , —OC(═O)R 37 , —SC(═O)R 37 , —OC(═S)R 37 , —SC(═S)R 37 , —NR 37 C(═O)—R 37 , —NR 37 C(═S)—R 37 , —NR 37 C(═O)O—R 37 , —NR 37 C(═S)O—R 37 , —NR 37 C(═O)S—R 37 , —NR 37 C(═S)S—R 37 , —OC(═O)N(R 37 ) 2 , —SC(═O)N(R 37 ) 2 , —OC(═S)N(R 37 ) 2 , —SC(═S)N(R 37 ) 2 , —NR 37 C(═O)N(R 37 ) 2 , —NR 37 C(═S)N(R 37 ) 2 , —C(═O)R 37 , —C(═S)R 37 , —C(═O)N(R 37 ) 2 , —C(═S)N(R 37 ) 2 , —C(═O)O—R 37 , —C(═O)S—R 37 , —C(═S)O—R 37 , —C(═S)S—R 37 , —S(O)R 37 , —S(O) 2 R 37 , —NR 37 S(O) 2 R 37 , —ON(R 37 ) 2 , —NR 37 OR 37 , alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, and cycloalkylalkyl groups;
wherein the Q 1 and Q 2 groups not being H, —F, —Cl, —Br, —I, —OH, —NH 2 , —SO 3 , —PO 3 —, —NO 2 , —CF 3 , are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OR 37 , —N(R 37 ) 2 , —SO 3 R 37 , —PO 3 (R 37 ) 2 , —PO 4 (R 37 ) 2 , —NO 2 , —CF 3 , ═O, ═NR 37 , and —SR 37 , and optionally contain one or more heteroatoms selected from the group consisting of O, S, NR 37 , P, and Si, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized,
wherein the Q 1 and Q 2 groups are optionally bound to —(S P ) D —R 87 ;
wherein D is 0 or 1, and each R 87 is individually selected from the group consisting of a biomolecule, polymer, peptoid, dendrimer, lipid, micelle, liposomes, polymersome, particle, bead, gel, metal complex, organic molecule, organometallic moiety, albumin-binding moiety, radionuclide-comprising moiety, dye moiety, a chelating moiety, and an imaging probe.
7 . The combination according to claim 6 , wherein Q 1 and Q 2 are selected from the group consisting of hydrogen, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-pyrimidyl, 2,5-pyrimidyl, 3,5-pyrimidyl, and 2,4-pyrimidyl.
8 . The combination according to claim 6 , wherein in Formula (4):
(a) Q 1 and Q 2 are selected from the group consisting of 2-pyridyl, 3-pyridyl, and 4-pyridyl; or
(b) Q 1 is selected from the group consisting of 2,6-pyrimidyl, 2,5-pyrimidyl, 3,5-pyrimidyl, and 2,4-pyrimidyl; and Q 2 is (hetero)alkyl; or
(c) Q 1 is phenyl and Q 2 is hydrogen.
9 . A non-therapeutic method for releasing a molecule from a compound according to claim 1 , said non-therapeutic method comprising the step of contacting a compound according to Formula (19) with a diene.
10 . A non-therapeutic method for imaging a compound according to claim 1 in a subject, said non-therapeutic method comprising the steps of
(a) administering the compound comprising a label, to the subject; and
(b) imaging the compound present in the subject; wherein the label is selected from the group consisting of radionuclides, fluorescent dyes, and phosphorescent dyes.
11 . A method for treating cancer, central nervous system (CNS) diseases, infection, inflammation, or cardiovascular diseases in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to claim 1 .
12 . The method according to claim 11 further comprising administering a diene.
13 . The combination according to claim 5 , wherein the diene is a tetrazine.
14 . The combination according to claim 6 , wherein at least one of moieties Q 1 and Q 2 is not hydrogen.
15 . The compound according to claim 1 , wherein each i and each j are independently 0 or 1.
16 . The compound according to claim 1 , wherein only condition (a) is met.
17 . The compound according to claim 16 , wherein group R 48 is in an axial position.
18 . The compound according to claim 17 , wherein X 1 and X 5 are —C(R 47 ) 2 —; and one of X 2 , X 3 , and X 4 is CR 47 Y T1 and two of X 2 , X 3 , and X 4 are —C(R 47 ) 2 —.
19 . The compound according to claim 18 , wherein Y T1 is OH.
20 . The compound according to claim 19 , wherein C A is a drug and C B is an antibody or a diabody.
21 . The compound according to claim 1 , wherein, when R 48 is —OC(O)—(S P ) k C A , —OC(S)—(S P ) k C A , —SC(O)—(S P ) k C A , or —SC(S)—(S P ) k C A , then S P , when k>0, or C A , when k=0, is bound to the —OC(O)—, —OC(S)—, —SC(O)—, or —SC(S)— of R 48 via a secondary or a tertiary N, wherein this group is part of S P or C A .
22 . The compound according to claim 1 , wherein, when R 48 is —O-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A or —S-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A and r is 1, then L C is bound to the —O— or —S— moiety on the allylic position of the trans-cyclooctene ring of Formula (19) via a group selected from the group consisting of —C(Y C2 )Y C1 —, and an aromatic carbon, wherein this group is part of L C .
23 . The compound according to claim 1 , wherein when R 48 is —O-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A or —S-(L C ((S P ) k C A ) s ((S P ) k C A ) s ((S P ) i —C B ) j ) r —(S P ) k C A and r is 1, then S P , when k>0, or C A , when k=0, is bound to L C via a moiety selected from a secondary or a tertiary N, wherein said moiety is part of S P or C A .
24 . The compound according to claim 1 , wherein at most three moieties C B are comprised in the structure of Formula (19).
25 . The compound according to claim 1 , wherein at most one moiety C B is comprised in the structure of Formula (19).
26 . The method according to claim 11 , wherein the subject is a human.
27 . The non-therapeutic method according to claim 9 , wherein the molecule is released in vitro.
28 . The method according to claim 10 , wherein the subject is a human.
29 . The method according to claim 10 , further comprising administering a tetrazine activator.
30 . The compound according to claim 20 , wherein X 1 and X 5 are —CH 2 —; and one of X 2 , X 3 , and X 4 is CR 47 Y T1 and two of X 2 , X 3 , and X 4 are —CH 2 —.