Tubulysin conjugates
The invention relates to novel tubulysin conjugates (e.g. of tubulysin A) and the use thereof in the treatment of cancer diseases.
1. A compound in the general formula U—V—W, wherein U refers to the Formula (I),
wherein
A has the following structure
X is CH 2 ;
Y is an oxygen atom;
R 1 and R 3 together are of the formula —(CH 2 ) 4 —;
R 2 is a C 1 -C 4 alkyl group;
R 4 , R 5 , R 6 , and R 19 are hydrogen atoms;
R 7 is an alkyl group;
R 8 is a hydrogen atom, an alkyl, alkenyl, or a heteroalkyl group
R 9 is an alkyl group;
R 11 is an acetyl group;
R 12 is a group of formula NHR 18 ;
R 18 has the following structures:
wherein R 19 is H or OH and R 20 is —V—W or
wherein R 19 is —V—W and R 20 is OH, NH 2 , or a heteroalkyl group;
V is an oxygen atom, a NH group, or a heteroalkylene group wherein the heteroatoms are selected from O, S, and N; and
W is polyethylene glycol (PEG) or a cyclodextrin comprising polyethylene glycol (PEG).
2. A method for treating a patient suffering from breast cancer, cervical cancer, ovarian cancer, colorectal cancer or non-small cell lung cancer, comprising administering to the patient one or more compounds of claim 1 .
3. A compound of claim 1 having the following formula:
wherein V is an oxygen atom; a NH group; a group of the formula —O—(CR a R b ) n —O— where R a and R b are independently C 1 -C 6 alkyl groups or together part of cycloalkyl group and n is 1 or 2; —NH—R c —NH—CO—CH 2 —O—; —O—R c —O—CH 2 —O—; or a group of the formula —O—R c —O— where R c is alkylene, arylene or a cycloalkylene group.
4. The compound of claim 3 wherein V is oxygen.
5. The method of claim 2 wherein a compound having the following formula is administered:
wherein V is an oxygen atom; a NH group; a group of the formula —O—(CR a R b ) n —O— where R a and R b are independently C 1 -C 6 alkyl groups or together part of cycloalkyl group and n is 1 or 2; —NH—R c —NH—CO—CH 2 —O—; —O—R c —O—CH 2 —O—; or a group of the formula —O—R c —O— where R c is alkylene, arylene or a cycloalkylene group.
6. The method of claim 5 wherein V is oxygen.
7. The method of claim 5 wherein V is a NH group.
8. The method of claim 5 wherein V is a group of the formula —O—(CR a R b ) n —O—.
9. The method of claim 5 wherein V is an oxygen atom; a NH group; a group of the formula —O—(CR a R b ) n —O— where R a and R b are independently C 1 -C 6 alkyl groups or together part of cycloalkyl group and n is 1 or 2; —NH—R c —NH—CO—CH 2 —O—; —O—R c —O—CH 2 —O—; or a group of the formula —O—R c —O— where R c is alkylene, arylene or a cycloalkylene group.
10. The method of claim 5 , wherein the polyethylene glycol has a molecular weight of 30 kDa.
11. The method of claim 5 , wherein the polyethylene glycol has a molecular weight of 35 kDa.
12. A compound, according to claim 1 , wherein R 2 is a methyl group.
13. A compound, according to claim 1 , wherein R 7 is a group of formula —CH(CH 3 )CH 2 CH 3 .
14. A compound, according to claim 1 , wherein R 8 is a hydrogen atom or a group of formula —CH 2 OC(═O)R 17 , wherein R 17 is a C 1 -C 6 alkyl or a C 2 -C 6 alkenyl group.
15. A compound, according to claim 1 , wherein R 9 is a group of formula —CH(CH 3 ) 2 .
16. A compound, according to claim 1 , wherein V is an oxygen atom, a NH group, or a group of the formula —O—(CR a R b ) n —O—, whereby R a and R b independently from each other are C 1 -C 6 alkyl groups, or, together, are part of a cycloalkyl group and n is 1 or 2; —NH—R c —NH—CO—CH 2 —O—, —O—R c —O—CO—CH2-O—, or a group of formula —O—R c —O—, whereby R c is an alkylene, arylene, or a cycloalkylene group.
17. A compound, according to claim 1 , wherein the compound of Formula (I) is Tubulysin A.
18. A compound, according to claim 1 , wherein the polymer is a polyethylene glycol (PEG).
19. A compound, according to claim 1 , wherein the polyethylene glycol has a molecular weight of more than 30 kDa to 100 kDa.