Dolastatin 15 derivatives with carbonyl and heterocyclic functionalities at the C-terminus

A compound of the formula

• A-B-D-E-F-G,
• or a salt thereof with a pharmaceutically acceptable acid, wherein
• A is .alpha.-amino acid residue of Formula II.sub.l, ##STR31## wherein n.sub.a is 0 to 3;
• R.sub.a is hydrogen, or unsubstituted or fluorine-substituted normal, branched or cyclic C.sub.1 -C.sub.3 -alkyl;
• R.sup.1.sub.a is hydrogen, C.sub.1 -C.sub.3 -alkyl, phenyl, or substituted phenyl;
• or R.sub.a and R.sup.1.sub.a together form a propylene bridge;
• and R.sup.2.sub.a, R.sup.3.sub.a, R.sup.4.sub.a and R.sup.5.sub.a are each, independently, hydrogen or alkyl;
• or
• an .alpha.-amino acid residue of Formula III.sub.a, ##STR32## wherein R.sub.a is hydrogen or unsubstituted or fluorine-substituted C.sub.1 -C.sub.3 -alkyl;
• R.sup.1.sub.a is hydrogen or C.sub.1 -C.sub.4 -alkyl;
• R.sup.6.sub.a is alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl;
• or R.sup.1.sub.a is an alkyl group and R.sup.6.sub.a is C.sub.1 -C.sub.6 -alkyl, cycloalkylmethyl, benzyl or substituted benzyl;
• and R.sup.7.sub.a is hydrogen or alkyl;
• or
• an .alpha.-amino acid residue of Formula IV.sub.a, ##STR33## wherein m.sub.a is 1 or 2;
• R.sup.7.sub.a is hydrogen or alkyl;
• R.sub.a is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• or
• an .alpha.-amino acid residue of Formula V.sub.a, ##STR34## wherein R.sup.7.sub.a is hydrogen or alkyl and R.sub.a is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• or
• an .alpha.-amino acid of Formula VI.sub.a, ##STR35## wherein R.sub.a is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• R.sup.1.sub.a is hydrogen, alkyl, phenyl, or substituted phenyl;
• or R.sub.a and R.sup.1.sub.a together form a propylene bridge;
• and X.sub.a is hydroxy, alkoxy or fluorine;
• or
• an .alpha.-amino acid of Formula VII.sub.a, ##STR36## wherein R.sub.a is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• R.sup.1.sub.a is hydrogen, alkyl, phenyl, or substituted phenyl;
• or R.sub.a and R.sup.1.sub.a together form a propylene bridge;
• and R.sup.2.sub.a, R.sup.3.sub.a, R.sup.4.sub.a and R.sup.5.sub.a are each, independently, hydrogen or alkyl;
• or
• an .alpha.-amino acid residue of Formula VIII.sub.a, ##STR37## wherein R.sub.a is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• or
• an .alpha.-amino acid residue of Formula IX.sub.a, ##STR38## wherein the 3-carbonyl moiety is in the endo or exo position, Z.sub.a is a single bond or a double bond, and R.sub.a is hydrogen or unsubstituted or fluorine-substituted alkyl;
• or
• an .alpha.-amino acid residue of Formula X.sub.a, ##STR39## wherein n.sub.a is 1, 2 or 3, and R.sup.7.sub.a is hydrogen or alkyl and R.sub.a is hydrogen, unsubstituted alkyl or fluorine-substituted alkyl;
• B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue;
• or
• an .alpha.-amino acid residue of Formula II.sub.b, ##STR40## wherein R.sup.1.sub.b is hydrogen, and R.sup.2.sub.b is alkyl or alkenyl;
• or R.sup.1.sub.b and R.sup.2.sub.b together form an isopropylidene group;
• D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkylnorleucyl, N-alkylisoleucyl, N-alkyl-allo-isoleucyl or N-alkylnorvalyl residue;
• or
• an .alpha.-amino acid residue of Formula II.sub.d, ##STR41## wherein R.sub.d is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• R.sup.1.sub.d is hydrogen;
• and R.sup.2.sub.d is alkyl, substituted alkyl or alkenyl;
• or R.sup.1.sub.d and R.sup.2.sub.d together form an isopropylidene group;
• or
• an .alpha.-amino acid residue of Formula III.sub.d, ##STR42## wherein n.sub. d is 1 or 2;
• R.sup.3.sub.d is hydrogen, alkyl or fluorine-substituted alkyl;
• and X.sub.d is hydrogen;
• or n.sub.d is 1 and X.sub.d is fluorine, hydroxy, methoxy, or ethoxy;
• E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl, or hydroxyprolyl residue;
• or
• an .alpha.-amino acid residue of Formula II.sub.e, ##STR43## wherein n.sub.e is 0, 1 or 2, R.sup.1.sub.e is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• R.sup.2.sub.e and R.sup.3.sub.e are each, independently, hydrogen or alkyl;
• R.sup.4.sub.e is hydrogen, hydroxy or alkoxy;
• and R.sup.5.sub.e is hydrogen or fluorine;
• or n.sub.e is 1 and R.sup.3.sub.e and R.sup.4.sub.e together form a double bond;
• or n.sub.e is 1 and R.sup.4.sub.e and R.sup.5.sub.e together form a double-bonded oxygen diradical;
• or n.sub.e is 1 or 2 and R.sup.1.sub.e and R.sup.2.sub.e together form a double bond;
• or
• an aminocyclopentanecarboxylic acid residue of Formula III.sub.e, ##STR44## wherein R.sub.e is alkyl and R.sup.1.sub.e is hydrogen, or unsubstituted or fluorine-substituted alkyl;
• F is an azacycloalkanecarboxylic acid residue and
• G is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, aryl, arylalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, alkyl- or arylsulfinyl and alkyl- or arylsulfonyl;
• or
• F is an azacycloalkyl group and
• G is a heteroaryl group.