Dolastatin 15 derivatives
View Patent ↗Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, A-B-D-E-F-(G) r -(K) s -L (I), and acid salts thereof, wherein A, B, D, E, F, G and K are α-amino acid residues, and s and r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group. The present invention also includes a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.
1. A compound of the formula
A-B-D-E-F-(G) r -(K) s -L
wherein
r and s are 0;
A is
a proline derivative of Formula II a ,
wherein n a is 0 to 2; R a is hydrogen or unsubstituted normal or branched C 1 -C 3 -alkyl; R 1 a is hydrogen; or R a and R 1 a together form a propylene bridge; and R 2 a ,R 3 a , R 4 a , and R 5 a are each hydrogen; or
an α-amino acid derivative of Formula III a ,
wherein R a is hydrogen or unsubstituted C 1 -C 3 -alkyl; R 1 a is C 1 -C 3 -alkyl; R 6 a is methyl, hydroxyl- or methoxy-substituted C 1 -C 3 -alkyl, phenyl, or fluorine- or methoxy-substituted phenyl; and R 7 a is hydrogen or C 1 -C 3 -alkyl; or
an α-amino acid derivative of Formula IV a ,
wherein m a is 1 or 2; R 7 a is hydrogen or methyl; and R a is hydrogen or methyl; or
an α-amino acid of formula VII a ,
wherein R a is methyl; R 1 a is hydrogen; and R 2 a , R 3 a , R 4 a , and R 5 a are each methyl; or
an α-amino acid residue of formula X a ,
wherein n a is 2 or 3; R 7 a is methyl; and R a is methyl;
B is valyl, isoleucyl, or 2-tert-butylglycyl;
D is N-methylvalyl or N-methylisoleucyl;
E is prolyl, thiazolidinyl-4-carbonyl or 3,4-didehydroprolyl;
F is prolyl; and
L is N-benzylamide, N-methoxy-N-benzylamide, tert-butylamide, tert-butyl ester, N-methoxy-N-methylamide, isopropylamide, 5-phenyl isoxasolidinyl, isoxazolidinyl, pentylamide, (R) or (S) phenethylamide, -O-tert-butyl, isoxazolidinyl, 5-phenyl isoxazolidinyl,
2. The compound of claim 1 , wherein A is a proline derivative of Formula II a , wherein R a is hydrogen or unsubstituted normal or branched C 1 -C 3 -alkyl; R 1 a is hydrogen; or R a and R 1 a together form a propylene bridge; and R 2 a , R 3 a , R 4 a , and R 5 a are each independently hydrogen.
3. The compound of claim 1 , wherein A is an α-amino acid residue of Formula III a ,
wherein R a is hydrogen or unsubstituted C 1 -C 3 -alkyl; R 1 a is C 1 -C 3 -alkyl; R 6 a is methyl, hydroxyl- or methoxy-substituted C 1 -C 3 -alkyl, phenyl, or fluorine- or methoxy-substituted phenyl; and R 7 a is methyl, ethyl, or isopropyl.
4. The compound of claim 1 , wherein A is an α-amino acid residue of Formula IV a ,
wherein R 7 a is methyl; and R a is hydrogen or methyl.
5. The compound of claim 1 , wherein A is an α-amino acid residue of Formula VII a ,
wherein R a is methyl; R 1 a is hydrogen; and R 2 a , R 3 a , R 4 a , and R 5 a are each methyl.
6. The compound of claim 1 , wherein A is an α-amino acid residue of Formula X a ,
wherein R 7 a is methyl and R a is methyl.
7. The compound of claim 1 , wherein L is N-benzylamide, N-methoxy-N-benzylamide, tert-butylamide, N-methoxy-N-methylamide, isopropylamide, pentylamide, (R) and (S) phenethylamide,
8. The compound of claim 1 , wherein L is —O-tert-butyl.
9. The compound of claim 1 , wherein L is isoxazolidinyl or 5-phenyl isoxazolidinyl.
10. The compound of claim 1 , wherein A is an amino acid derivative selected from the group consisting of N-methyl-D-prolyl, N-methyl-L-prolyl, N-methyl-D-piperidine-2-carbonyl, N-methyl-L-piperidine-2-carbonyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl and N,N-dialkyl-L-2-ethyl-2-phenylglycyl; and B is valyl, isoleucyl, or 2-tert-butyl-L-glycyl.
11. The compound of claim 1 , wherein E is prolyl or 3,4-didehydroprolyl; and L is N-benzylamide, N-methoxy-N-benzylamide, tert-butylamide, N-methoxy-N-methylamide, isopropylamide, pentylamide, (R) and (S) phenethylamide,
12. The compound of claim 1 , wherein L is N-benzylamide, N-methoxy-N-benzylamide, tert-butylamide, N-methoxy-N-methylamide, isopropylamide, pentylamide, (R) and (S) phenethylamide,