Tubulysins, method for producing the same and tubulysin preparations
View Patent ↗The invention relates to a compound of the following general formula (tubulysin) having the following meanings for R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , S, T, U, V, W, X, Y and Z: R=H, alkyl, aryl, OR1, NR1R2 or R 1 =H, C 1-6 alkyl or aryl R 2 =H, C 1-6 alkyl or aryl S=H, Hal, NO 2 or NHR 3 U=H, Hal, NO 2 or NHR 3 R 3 =H, HCO or C 1-4 alkyl-CO T=H or OR 4 R 4 =H, C 1-4 alkyl, aryl, COR 5 , P(O)(OR 6 ) 2 or SO 3 R 6 R 5 =C 1-6 alkyl, alkenyl, aryl or heteroaryl R 6 =H, alkyl or a metal ion V=H, OR 7 , Hal or (for W=O) O R 7 =H, C 1-4 alkyl or COR 8 R5=C 1-4 alkyl, alkenyl or aryl W=H or C 1-4 alkyl or (for V=O) O X=H, C 1-4 alkyl, alkenyl or CH 2 OR 9 R 9 =H, C 1-4 alkyl, alkenyl, aryl or COR 10 R 10 =C 1-6 alkyl, alkenyl, aryl or heteroaryl Y=(for Z=CH 3 or COR 11 ) free electron pair or (for Z=CH 3 )O R 11 =C 1-4 alkyl, CF 3 or aryl and/or Z=(for Y=O or free electron pair) CH 3 or (for Y=free electron pair) COR 11 .
1. A compound of formula I (tubulysin):
wherein R, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , S, T, U, V, W, X, Y and Z have the following meanings:
R=OR 1
R 1 =alkyl or aryl
S=H
U=H
T=H or OR 4
R 4 =H, alkyl, aryl, COR 5 , P(O)(OR 6 ) 2 or SO 3 R 6
R 5 =alkyl, alkenyl, or aryl
R 6 =H, alkyl or a metal ion
V=OR 7
R 7 =COR 8
R 8 =alkyl, alkenyl or aryl
W=H
X=H, alkyl, alkenyl or CH 2 OR 9
R 9 =H, alkyl, alkenyl, aryl or COR 10
R 10 =alkyl, alkenyl, or aryl
Y=free electron pair
R 11 =alkyl, CF 3 or aryl and/or
Z=CH 3 or COR 11 .
2. The compound according to claim 1 , wherein
R, R 1 , R 4 , R 5 , R 8 , R 9 , R 10 and/or R 11 =unsubstituted or substituted phenyl,
R 5 =C 1-4 alkyl or C 2-6 alkenyl
R 5 and/or X=C 2-4 alkenyl
R 6 =an alkali metal ion or an alkaline earth metal ion
R 8 and/or R 9 =C 2-4 alkenyl and/or
R 10 =C 2-6 alkenyl.
3. The compound according to claim 1 , wherein alkyl is branched, unbranched or cyclic C 1-20 alkyl.
4. The compound according to claim 1 , wherein alkenyl is branched, unbranched or cyclic C 2-20 alkenyl.
5. The compound according to claim 1 , wherein aryl is phenyl, naphthyl and biphenylyl.
6. The compound according to claim 1 , wherein alkyl, alkenyl, and aryl are unsubstituted or substituted.
7. The compound according to claim 2 , wherein R, R 1 , R 4 , R 5 , R 8 , R 9 , R 10 and/or R 11 =C 1-4 alkyl-substituted phenyl.
8. The compound according to claim 2 , wherein R 6 =an Na ion.
9. The compound according to claim 2 , wherein R 10 =C 2-4 alkenyl.
10. The compound according to claim 3 , wherein the alkyl is cyclic C 1-7 alkyl or C 1-8 alkyl.
11. The compound according to claim 10 , wherein the alkyl is cyclic C 1-4 alkyl.
12. The compound according to claim 11 , wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and cycloalkyl having from 3 to 8 carbon atoms in the ring.
13. The compound according to claim 4 , wherein the alkenyl is C 2-7 alkenyl or C 2-6 alkenyl.
14. The compound according to claim 13 , wherein the alkenyl is C 2-4 alkenyl.
15. The compound according to claim 14 , wherein the alkenyl is selected from the group consisting of vinyl, allyl propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-1-en-3-yl, but-1-en-4-yl, but-2-en-1-yl, but-2-en-2-yl, 2methyl-propen-1-yl, 2-methyl-propen-3-yl, and cycloalkenyl having from 3 to 8 carbon atoms in the ring and the number of double bonds in the alkenyl groups being from 1 to 3.
16. The compound according to claim 6 , wherein the alkyl, alkenyl, and aryl carry, in any position, from 1 to 3 substituents from the group formed by C 1-3 alkyl, C 1-3 alkoxy, hydroxy, amino (NH 2 ) and nitro (NO 2 ).