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 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;
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 1c 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 and R 1d , at each occurrence, are independently hydrogen or C 1-4 alkyl;
R 1e 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 selected from the group consisting of auristatin and monomethyl auristatin E;
-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 pharmaceutically acceptable 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 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.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1a 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 1a 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 pharmaceutically acceptable 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 4 , or a pharmaceutically acceptable salt thereof, wherein -L 2 - is —C(O)—.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
-L 1 - is
-L 3 - is a bond or C 1-6 alkylene;
-L 4 - is a bond, —N(R 12 )—C 2-3 alkylene-N(R 13 )C(O)—, —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 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, C 1-4 alkoxy, cyano, and nitro.
7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
m is 1;
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.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein p is 0.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein -L 2 - is —C(O)—;
is
R D is hydrogen or C 1-4 alkyl on a nitrogen atom of the payload; and
D′ is a payload moiety.
11 . The compound of claim 10 , or pharmaceutically acceptable salt thereof, wherein
is
12 . The compound of claim 11 , or pharmaceutically acceptable salt thereof, wherein the compound is
13 . A pharmaceutical composition comprising the compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14 . A method of treating a cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a therapeutic support composition, the therapeutic support composition comprising a biocompatible support and a tetrazine-containing group of formula
wherein
R 20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′R″, 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)R′R″, SC(═S)R′R″, NR′C(═O)NR″R″, and NR′C(═S)NR″R″;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl;
R′″ at each occurrence is independently selected from aryl and alkyl;
R 30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; halalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R a , R 31a and R 31b are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; and
t is 0, 1, 2, 3, or 4;
wherein the biocompatible support is a hyaluronic acid, or a salt thereof.
15 . The method of claim 14 , wherein the therapeutic support composition comprising the hyaluronic acid, or salt thereof, and the tetrazine-containing group comprises substituted hyaluronic acid units of formula (II),
wherein G 2 is
and
R 22 is a linker of 1 to 100 linking atoms.
16 . The method of claim 15 , wherein G 2 is
and R 20 is hydrogen or C 1-4 alkyl.
17 . The method of claim 16 , wherein R 20 is methyl.
18 . The method of claim 17 , wherein the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
19 . The method of claim 17 , wherein the cancer is a solid tumor.
20 . The method of claim 17 , wherein the cancer is a soft tissue sarcoma.
21 . The method of claim 20 , wherein the soft tissue sarcoma is a fibrosarcoma, rhabdomyosarcoma, or Ewing's sarcoma.
22 . The method of claim 17 , wherein the cancer is a diffuse intrinsic pontine glioma.
23 . A kit comprising the compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a therapeutic support composition, the therapeutic support composition comprising a biocompatible support and a tetrazine-containing group of formula
wherein
R 20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′R″, NR′R″, 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)R′R′″, SC(═S)R′R″, NR′C(═O)NR″R″, and NR′C(═S)NR″R″;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl;
R′″ at each occurrence is independently selected from aryl and alkyl;
R 30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; halalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R a , R 31a and R 31b are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; and
t is 0, 1, 2, 3, or 4;
wherein the biocompatible support is a hyaluronic acid, or a salt thereof.
24 . The kit of claim 23 , wherein the therapeutic support composition comprising the hyaluronic acid, or salt thereof, and the tetrazine-containing group comprises substituted hyaluronic acid units of formula (II),
wherein G 2 is
and
R 22 is a linker of 1 to 100 linking atoms.
25 . The kit of claim 24 , wherein G 2 is
and R 20 is hydrogen or C 1-4 alkyl.
26 . The kit of claim 25 , wherein R 20 is methyl.