Derivatives of dolastatin 10 and uses thereof
Derivatives of dolastatin 10 and uses thereof, the structures of which are shown as formula I, II, III and IV are provided.
1. A compound having the formula I:
or a pharmaceutically acceptable salt, solvate, or solvate of salt thereof, wherein
R 1 and R 2 are independently selected from H, —C 1 -C 8 alkyl, or R 1 and R 2 together form a heterocycle of the formula —(CR 14 R 15 ) n —Z—(CR 16 R 17 ) m —, wherein R 14 , R 15 , R 16 and R 17 are independently selected from H or —C 1 -C 8 alkyl; Z is selected from O, NR 18 or CR 19 R 20 , wherein R 18 , R 19 and R 20 are independently selected from H or —C 1 -C 8 alkyl; n and m are integers independently selected from 0 to 8;
R 3 , R 4 and R 6 are independently selected from H, —C 1 -C 8 alkyl, aryl, heterocycle, arylalkyl, or heteroarylalkyl; R 5 , R 9 , R 10 and R 11 are independently selected from H, or —C 1 -C 8 alkyl;
R 7 and R 8 are independently selected from H, —OH, —C 1 -C 8 alkyl, or —O—(C 1 -C 8 alkyl);
R 12 and R 13 are independently selected from H, —C 1 -C 8 alkyl, —OR 21 , —R 22 X, or R 12 and R 13 together form a heterocycle of the formula —(CR 23 R 24 ) p —W—(CR 25 R 26 ) q —, wherein W is selected from O, NR 27 , or CR 28 R 29 ; X is selected from —OH or —NR 30 R 31 ; p and q are integers independently selected from 0 to 8;
R 21 is selected from H, —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl;
R 22 is selected from alkylene, alkenlene, alkynlene, arylene, —(CH 2 CH 2 O) r —(CH 2 ) s —, or any combination thereof; r and s are integers independently selected from 0 to 8;
R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are independently selected from H or —C 1 -C 8 alkyl;
R 31 is selected from H, —C 1 -C 8 alkyl, or —OR 32 , wherein R 32 is selected from H, —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl.
2. The compound of claim 1 having the formula II:
wherein
R 1 and R 2 are independently selected from H or —C 1 -C 8 alkyl, or R 1 and R 2 together form a beterocycle of the formula —(CR 14 R 15 ) n —Z—(C R 16 R 17 ) m —, wherein R 14 , R 15 , R 16 and R 17 are independently selected from H or —C 1 -C 8 alkyl; Z is selected from O, NR 18 or CR 19 R 20 , wherein R 18 , R 19 , and R 20 are independently selected from H or —C 1 -C 8 alkyl; n and m are integers independently selected from 0 to 8:
R 12 and R 13 are independently selected from H, —C 1 -C 8 alkyl, —OR 21 , —R 22 X, or R 12 and R 13 together form a heterocycle of the formula —(CR 23 R 24 ) p —W—(CR 25 R 26 ) q —, wherein W is selected from O, NR 27 , or CR 28 R 29 ; X is selected from —OH or —NR 30 R 31 ; p and q are integers independently selected from 0 to 8;
R 21 is selected from H, —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl;
R 22 is selected from alkylene, alkenlene, alkynlene, arylene, —(CH 2 CH 2 O) r —(CH 2 ) s —, or any combination thereof: r and s are integers independently selected from 0 to 8:
R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are independently selected from H or —C 1 -C 8 alkyl:
R 31 is selected from H, —C 1 -C 8 alkyl, or —OR 32 , wherein R 32 is selected from H, —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl.
3. A compound of claim 2 , and its pharmaceutically acceptable salts, solvate, or solvate of salts, wherein its structure is shown as the following compounds 1-16
Num-
Compound
ber
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16.
4. A compound having the formula III:
or a pharmaceutically acceptable salt, solvate, or solvate of salt thereof, wherein
R 1 , R 2 , R 3 and R 4 are independently selected from H or —C 1 -C 8 alkyl;
m and n are integers independently selected from 2 m 4;
R 5 , R 6 and R 8 are independently selected from H, —C 1 -C 8 alkyl, aryl, heterocyclyl, Arylalkyl, heteroarylalkyl;
R 7 , R 11 and R 12 are independently selected from H or —C 1 -C 8 alkyl;
R 9 and R 10 are independently selected from H, —OH, —C 1 -C 8 alkyl, or —O—(C 1 -C 8 alkyl);
R 13 and R 14 are independently selected from H, —OH, —OR 16 , —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, heteroarylalkyl;
R 16 is selected from H or —C 1 -C 8 alkyl:
p is an integer ranging from 1 to 8;
R 15 is selected from —C 3 -C 8 alkyl, aryl, —C 3 -C 8 heterocyclyl, —COOH, or —C(═O)NR 17 R 18 ,
R 17 and R 18 are independently selected from H, —C 1 -C 8 alkyl, —OH, —OR 19 , or R 17 and R 18 together form a cycle of the formula —(CR 20 R 21 ) o —Z—(CR 22 R 23 ) q —, wherein R 19 , R 20 , R 21 , R 22 and R 23 are independently selected from H, —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl; Z is selected from O, NR 24 , or CR 25 R 26 , wherein R 24 , R 25 and R 26 are independently selected from H, or —C 1 -C 8 alkyl; o and q are integers independently selected from 0 to 8.
5. A compound of claim 4 and its pharmaceutically acceptable salts, solvate, or solvate of salts, wherein its structure is shown as formula IV
wherein
m and o are integers independently selected from 2 to 4;
R 12 is selected from H or —C 1 -C 8 alkyl;
R 13 and R 14 are independently selected from H, —OH, —OR 16 , —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, heteroarylalkyl;
R 16 is selected from H or —C 1 -C 8 alkyl;
p is an integer ranging from 1 to 8;
R 15 is selected from —C 3 -C 8 alkyl, aryl, —C 3 -C 8 heterocyclyl, —COOH, or —C(═O)NR 17 R 18 ;
R 17 and R 18 are independently selected from H, —C 1 -C 8 alkyl, —OH, —OR 19 , or R 17 and R 18 together form a cycle of the formula —(CR 20 R 21 ) o —Z—(CR 22 R 23 ) q —, wherein R 19 , R 20 , R 21 , R 22 and R 23 are independently selected from H, —C 1 -C 8 alkyl, aryl, heterocyclyl, arylalkyl, heteroarylalkyl; Z is selected from O, NR 24 , or CR 25 R 26 , wherein R 24 , R 25 and R 26 are independently selected from H, —C 1 -C 8 alkyl; o and q are integers independently selected from 0 to 8.
6. A compound of claim 5 , and its pharmaceutically acceptable salts, solvate, or solvate of salts, wherein its structure is shown as the following compounds 17-45
Num-
Compound
ber
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45.
7. A pharmaceutical composition comprising the compound in accordance with claim 1 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof and a pharmaceutically acceptable carrier.
8. An antibody-drug conjugate having the formula V:
L-(A-D) n V
wherein L is an antibody, antibody fragment, or protein; A is a linker part; D is the compound in accordance with claim 1 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof; n is an integer ranging from 1 to 8.
9. A method of treating cancer, wherein a patient is supplied with an effective amount of an antibody drug conjugate of claim 8 .
10. An antibody-drug conjugate having the formula VI:
L-(A-D) n VI
wherein L is an antibody, antibody fragment, or protein; A is a linker part; D is the compound in accordance with claim 2 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof; n is an integer ranging from 1 to 8.
11. A method of treating cancer, wherein a patient is supplied with an effective amount of an antibody drug conjugate of claim 10 .
12. An antibody-drug conjugate having the formula VII:
L-(A-D) n VI
wherein L is an antibody, antibody fragment, or protein; A is a linker part; D is the compound in accordance with claim 4 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof; n is an integer ranging from 1 to 8.
13. A method of treating cancer, wherein a patient is supplied with an effective amount of an antibody drug conjugate of claim 12 .
14. An antibody-drug conjugate having the formula VIII:
L-(A-D) n VIII
wherein L is an antibody, antibody fragment, or protein; A is a linker part; D is the compound in accordance with claim 5 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof; n is an integer ranging from 1 to 8.
15. A method of treating cancer, wherein a patient is supplied with an effective amount of an antibody drug conjugate of claim 14 .
16. A pharmaceutical composition comprising the compound in accordance with claim 2 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising the compound in accordance with claim 4 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising the compound in accordance with claim 5 , or a pharmaceutically acceptable salt, a solvate, or a solvate of salt thereof and a pharmaceutically acceptable carrier.