Bioorthogonal compositions
Cyclooctene conjugates of therapeutic or diagnostic agents have improved aqueous solubility and can release the agents upon contact with a tetrazine-containing biomaterial. The cyclooctene conjugates provide site-selective delivery of agents at the location of the tetrazine-containing biomaterial in a subject. The compositions and methods have applications in the treatment of various diseases or conditions including cancer, tumor growths, and bacterial infections.
1. A compound of formula (I-A), or a salt thereof wherein
R 1a is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 1b is selected from the group consisting of G 1 , OH, —NR 1c —C 1-4 alkylene —G 1 , —NR 1c —C 1-4 alkylene —N(R 1d ) 2 , —N(R 1c )CHR 1e CO 2 H, —N(R 1c )—C 1-6 alkylene —CO 2 H, —N(R 1f )—C 2-4 alkylene —(N(C 1-4 alkylene —CO 2 H)—C 2-4 alkylene) n —N(C 1-4 alkylene —CO 2 H) 2 , —N(R 1c )CHR c C(O)OC 1-6 alkyl, —N(R 1c )—C 1-6 alkylene —C(O)OC 1-6 alkyl, and —N(R 1f )—C 2-4 alkylene —(N(C 1-4 alkylene —C(O)OC 1-6 alkyl)—C 2-4 alkylene) n —N(C 1-4 alkylene —C(O)OC 1-6 alkyl) 2 ;
R 1c c and R 1d , at each occurrence, are independently hydrogen or C 1-4 alkyl;
R 1c is —C 1-4 alkylene —CO 2 H, —C 1-4 alkylene —CONH 2 , or —C 1-4 alkylene —OH;
R 1f is hydrogen, C 1-6 alkyl, or C 1-4 alkylene —CO 2 H;
D, at each occurrence, is independently a payload comprising a therapeutic agent or a diagnostic agent;
-L 1 - is a linker;
-L 2 - is selected from the group consisting of —C(O)—and C 1-3 alkylene;
G 1 is an optionally substituted heterocyclyl;
m is 1, 2, or 3
n is 0, 1, 2, or 3; and
p is 0, 1, or 2.
2. The compound of claim 1 , or a salt thereof, wherein
R 1b is selected from the group consisting of G 1 , OH, —NR 1c —C 1-4 alkylene —G 1 , —NR 1c —C 1-4 alkylene —N(R 1d ) 2 , —N(R 1c )CHR 1c CO 2 H, —N(R 1c )CH 2 CO 2 H, and —N(R 1f )—CH 2 CH 2 —(N(CH 2 CO 2 H)CH 2 CH 2 ) n —N(CH 2 CO 2 H) 2 ;
R 1e is —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 OH, or —CH(CH 3 )OH; and
R 1f is hydrogen or CH 2 CO 2 H.
3. The compound of claim 1 , or a salt thereof, wherein
R 1a a is C 1-4 alkyl;
R 1b is selected from the group consisting of G 1 , OH, —NR 1c —C 1-4 alkylene —G 1 , —NR 1c —C 1-4 alkylene —N(R 1d ) 2 , —N(R 1c )CHR 1c CO 2 H, —N(R 1c )CH 2 CO 2 H, and —N(R 1f )—CH 2 CH 2 —(N(CH 2 CO 2 H)CH 2 CH 2 ) n —N(CH 2 CO 2 H) 2 ;
R 1e is —C 1-4 alkylene —CO 2 H;
R 1f is hydrogen or C 1-4 alkylene —CO 2 H;
G 1 is a 4- to 8-membered monocyclic heterocyclyl containing a first nitrogen and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, G 1 being attached at the first nitrogen and optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halo, cyano, OH, —OC 1-4 alkyl, and oxo; and
n is 0, 1, or 2.
4. The compound of claim 3 , or a salt thereof, wherein
R 1a is CH 3 ;
R 1e is —CH 2 CO 2 H;
R 1f is hydrogen or CH 2 CO 2 H; and
G 1 is a piperazinyl, morpholinyl, piperidinyl, azepanyl, or pyrrolidinyl, attached through a ring nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, halo, cyano, OH, —OC 1-4 alkyl, and oxo.
5. The compound of claim 1 , or a salt thereof,
wherein - L 2 - is —C(O)—.
6. The compound of claim 5 , or a salt thereof, wherein R 1b is selected from the group consisting of OH, N(H)CH 2 CO 2 H, —N(H)CHR 1c CO 2 H, —N(H)—CH 2 CH 2 —(N(CH 2 CO 2 H)CH 2 CH 2 ) n —N(CH 2 CO 2 H) 2 , and —N(CH 2 CO 2 H)—CH 2 CH 2 —N(CH 2 CO 2 H) 2 ; and
R 1c is —CH 2 CO 2 H.
7. The compound of claim 6 , or a salt thereof, wherein R 1b is OH.
8. The compound of claim 6 , or a salt thereof, wherein R 1b is N(H)CH 2 CO 2 H.
9. The compound of claim 1 of formula (I), or a pharmaceutically acceptable salt thereof
wherein
R 1a is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
-L 2 - is selected from the group consisting of —C(O)— and C 1-3 alkylene;
R 1b is selected from the group consisting of G 1 , OH, —NR 1c —C 1-4 alkylene —G 1 , and —NR 1c —C 1-4 alkylene —N(R 1d ) 2 ;
G 1 is an optionally substituted heterocyclyl; and
R c and R id , at each occurrence, are independently hydrogen or C 1-4 alkyl.
10. The compound of claim 1 , or a salt thereof, wherein:
-L 1 - is
or —O—;
-L 3 - is a bond or C 1-6 alkylene;
-L 4 - is a bond, —NHN:,—N(R 10 ) —C 2-6 alkylene-N(R 11 )—, —N(R 12 )—C 2-3 alkylene —N(R 13 )C(O)—, —N(R 10 )—C 1-6 alkylene —C(O)NHN:, —NHNHC(O)C 1-6 alkylene-C(O)NHN:, —CH(NHC(O)R 14 )C 1-4 alkylene-S—S—C 1-4 alkylene —OC(O)—, —NHNHC(O)CH(NHC(O)R 15 )CH 2 C(O)—, —C 1-6 alkylene —CH(G x )OC(O)—,
R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 19 are each independently hydrogen or C 1-4 alkyl;
R 16 is hydrogen, C 1-4 alkyl, —C 1-4 alkylene —OH, —C 1-4 alkylene —OC 1-4 alkyl, —C 1-4 alkylene —CO 2 H, or —C 1-4 alkylene —CONH 2 ;
R 17 , at each occurrence, is independently hydrogen or —CH 2 OC(O)—; and
G X is phenyl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, C1-4alkoxy, cyano, and nitro.
11. The compound of claim 1 , or a salt thereof, wherein:
is
R 18 at each occurrence, is independently hydrogen or —CH 2 OC(O)NHD′;
R D is hydrogen or C 1-4 alkyl on a nitrogen atom of the payload; and
D′ is a payload moiety.
12. The compound of claim 1 , or a salt thereof, wherein
13. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the payload is a therapeutic agent.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is an antibiotic agent, antifungal agent, antiviral agent, anticancer agent, cardiovascular agent, CNS agent, anti-inflammatory/anti-arthritic agent, anti-TB/anti-leprosy agent, anti-histaminic/respiratory disorder agent, a corticosteroid agent, immunosuppressant agent, or anti-ulcer agent.
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is selected from at least one of paclitaxel, doxorubicin, daunorubicin, etoposide, irinotecan, SN-38, docetaxel, gemcitabine, podophyllotoxin, carmustine, ixabepilone, patupilone, cyclosporin A, rapamycin, amphotericin, vancomycin, daptomycin, doxycycline, ceftriaxone, trimethoprim, sulfamethoxazole, acyclovir, nystatin, amphotericin B, flucytosine, emtricitabine, gentamicin, colistin, L-dopa, oseltamivir, cefalexin, 5-aminolevulinic acid, cysteine, celecoxib, and nimodipine.
16. The compound or pharmaceutically acceptable salt thereof of claim 15 , wherein the compound is
17. A pharmaceutical composition comprising the compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A method of enhancing or eliciting an immune response comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount enhances or elicits an immune response against a cancer in the subject.
19. A kit comprising the compound of claim 13 , or a pharmaceutically acceptable salt thereof, and instructions for use thereof.
20. The compound of any of claim 1 , or a salt thereof, wherein the payload is a diagnostic agent.
21. A diagnostic composition comprising the compound of claim 20 , or a salt thereof, and a pharmaceutically acceptable carrier.
22. A kit comprising the compound of claim 20 , or a salt thereof, and instructions for use thereof.
23. The compound of claim 20 , or a salt thereof, wherein the diagnostic agent is a fluorescein or a rhodamine.
24. The compound of claim 1 , or a salt thereof, wherein:
R 1b is selected from the group consisting of OH, —NR 1c —C 1-4 alkylene—N(R 1d ) 2 , —N(R 1c )CHR 1e CO 2 H, —N(R 1c )—C 1-6 alkylene—CO 2 H, —N(R 1f )—C 2-4 alkylene—(N(C 1-4 alkylene—CO 2 H)—C 2-4 alkylene) n —N(C 1-4 alkylene—O 2 H) 2 , —N(R 1c )CHR 1e C(O)OC 1-6 alkyl, —N(R 1c )C 1-6 alkylene—C(O)OC 1-6 alkyl, and —N(R 1f )—C 2-4 alkylene—N(C 1-4 alkylene—C(O)OC 1-6 alkyl)—C 2-4 alkylene) n —N(C 1-4 alkylene—C(O)OC 1-6 alkyl) 2 ; and
—L 2 —is —C(O)—.
25. The compound of claim 24 , or a salt thereof, wherein:
R 1b is selected from the group consisting of OH, —NR 1c—C 1-4 alkylene—N(R 1d ) 2 , —N(R 1c )CHR 1e CO 2 H, —N(R 1c )CH 2 CO 2 H, and —N(R 1f )—CH 2 CH 2 —(N(CH 2 CO 2 H)CH 2 CH 2 ) n —N(CH 2 CO 2 H) 2 ;
R 1e is —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 OH, or —CH(CH 3 )OH; and
R 1f is hydrogen or CH 2 CO 2 H.
26. The compound of claim 24 , or a salt thereof, wherein:
R 1a is C 1-4 alkyl;
R 1b is selected from the group consisting of OH, —NR 1c —C 1-4 alkylene—N(R 1d) 2 , —N(R 1c )CHR 1e CO 2 H, —N(R 1c )CH 2 CO 2 H, and —N(R 1f )—CH 2 CH 2 —(N(CH 2 CO 2 H)CH 2 CH 2 ) n —N(CH 2 CO 2 H) 2 ;
R 1e is —C 1-4 alkylene—CO 2 H;
R 1f is hydrogen or C 1-4 alkylene—CO 2 H; and
n is 0, 1, or 2.
27. The compound of claim 26 , or a salt thereof, wherein:
R 1a is CH 3 ;
R 1e is —CH 2 CO 2 H; and
R 1f is hydrogen or CH 2 CO 2 H.