THAILANSTATIN ANALOGS
The invention provides novel cytotoxic compounds and cytotoxic conjugates comprising these cytotoxic compounds and cell-binding agents. More specifically, this invention relates to novel thailanstatin A analogs, useful as cytotoxic small molecule toxins in antibody-drug conjugates (ADCs). The present invention further relates to compositions including these cytotoxic compounds and ADCs, and methods for using these toxins and ADCs to treat pathological conditions including cancer.
1 . A compound of Formula (I):
wherein:
R is selected from the group consisting of: —(CH2) n —R 1 ; —C 5-6 heteroaryl, optionally substituted with one or more of halogen, —CF 3 , —C 1-6 alkyl, and —O—C 1-6 alkyl;
—C(R 2 )═N—R 3 ; —CH(CF 3 )NH(CH2) m CH 3 ; —C(R a R b )NH(CH 2 ) m CH 3 ;
—C(halogen)═CH(CH 2 ) m CH 3 ; —SO 2 —NH(CH 2 ) m CH 3 ; —O(CO)-aryl; —O(CO)— heteroaryl; —NR a R b ; and —NH-heteroaryl;
wherein R 1 is —O—CR a R b (CH 2 ) m CH 3 or —N—CR a R b (CH 2 ) m CH 3 ;
wherein R a and R b , together with the atoms to which they are joined, form a C 3-10 heterocyclyl ring;
R 2 is —CN or —NH(CH 2 ) m CH 3 ;
R 3 is —(CH 2 ) m CH 3 or —O—(CH 2 ) m CH 3 ;
X is —H or —CH 3 ;
each n is independently 1, 2, or 3; and
each m is independently 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 , wherein R is selected from the group consisting of:
3 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
4 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
L is a linker;
R is selected from the selected from the group consisting of: —(CH 2 ) n —R 1 ; —C 5-6 heteroaryl, optionally substituted with one or more of halogen, —CF 3 , —C 1-6 alkyl, and —O—C 1-6 alkyl;
—C(R 2 )═N—R 3 ; —CH(CF 3 )NH(CH 2 ) m CH 3 ; —C(R a R b )NH(CH 2 ) m CH 3 ;
—C(halogen)═CH(CH 2 ) m CH 3 ; —SO 2 —NH(CH 2 ) m CH 3 ; —O(CO)-aryl; —O(CO)— heteroaryl; —NR a R b ; and —NH-heteroaryl;
wherein R 1 is —O—CR a R b (CH 2 ) m CH 3 or —N—CR a R b (CH 2 ) m CH 3 ;
wherein R a and R b , together with the atoms to which they are joined, form a C 3-10 heterocyclyl ring;
R 2 is —CN or —NH(CH 2 ) m CH 3 ;
R 3 is —(CH 2 ) m CH 3 or —O—(CH 2 ) m CH 3 ;
each n is independently 1, 2, or 3; and
each m is independently 0, 1, 2, or 3.
5 . The compound according to claim 4 , wherein L is selected from the group consisting of Formula (A 1 ), Formula (A 2 ), Formula (A 3 ), Formula (A 4 ), and Formula (A 5 ):
wherein q is 3, 4, 5, 6, 7, 8, 9, or 10; and
Y is Br, I, or
6 . The compound according to claim 4 , wherein R is selected from the group consisting of:
7 . The compound according to claim 4 , having structure 10:
8 . A compound of Formula (III):
T-L′-Ab (III)
or a pharmaceutically acceptable salt thereof, wherein:
L is a linker moiety;
T is a radical of Formula (I′):
wherein:
R is selected from the group consisting of: —(CH 2 ) n —R 1 ; —C 5-6 heteroaryl, optionally substituted
with one or more of halogen, —CF 3 , —C 1-6 alkyl, and —O—C 1-6 alkyl;
—C(R 2 )═N—R 3 ; —CH(CF 3 )NH(CH 2 ) m CH 3 ; —C(R a R b )NH(CH 2 ) m CH 3 ;
—C(halogen)═CH(CH 2 ) m CH 3 ; —SO 2 —NH(CH 2 ) m CH 3 ; —O(CO)-aryl; —O(CO)— heteroaryl; —NR a R b ; and —NH-heteroaryl;
wherein R 1 is —O—CR a R b (CH 2 ) m CH 3 or —N—CR a R b (CH 2 ) m CH 3 ;
wherein R a and R b , together with the atoms to which they are joined, form a C 3-10 heterocyclyl ring;
R 2 is —CN or —NH(CH 2 ) m CH 3 ;
R 3 is —(CH 2 ) m CH 3 or —O—(CH 2 ) m CH 3 ;
each n is independently 1, 2, or 3;
each m is independently 0, 1, 2, or 3; and
Ab is an antibody.
9 . The compound or salt according to claim 8 , wherein R is selected from the group consisting of:
10 . The compound according to claim 8 , wherein L′ is selected from the group consisting of Formula (B 1 ), Formula (B 2 ), Formula (B 3 ), and Formula (B 4 ):
wherein q is 3, 4, 5, 6, 7, 8, 9, or 10.
11 . The compound or salt according to claim 8 , wherein the compound of Formula (III) is selected from the group consisting of:
wherein q is 3, 4, 5, 6, 7, 8, 9, or 10; and n is 1, 2, 3, or 4.
12 . The compound according to claim 8 , having structure 11:
wherein tras is trastuzumab.
13 . The compound or salt according to claim 8 , wherein the antibody is selected from the group consisting of trastuzumab, pertuzumab, gemtuzumab, and vadastuximab.
14 . The compound or salt according to claim 8 , wherein the antibody binds to one or more tumor-associated antigens or cell-surface receptors.
15 . The compound or salt according to claim 8 , wherein the antibody is selected from the group consisting of HER2, CD33, CD70, MUC1/CanAg, MUC16, CD151 and ITGaV.
16 . A pharmaceutical composition comprising a therapeutically effective amount of the compound or salt of claim 8 and a pharmaceutically acceptable diluent, carrier or excipient.
17 . A method for the treatment of cancer comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 16 .
18 . The method for the treatment of cancer of claim 17 wherein the cancer is selected from carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach and testes, leukemias and lymphomas.
19 . The method for the treatment of cancer of claim 17 , further comprising administering a therapeutically effective amount of a second therapeutic agent.
20 - 23 . (canceled)