US 6,143,721 A · Dolastatin 15 derivatives

Abstract

Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, A-B-D-E-F-(G).sub.r -(K).sub.s -L (I), and acid salts thereof, wherein A, B, D, E, F, G and K are .alpha.-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 .beta.-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.

A compound of the formula

A-B-D-E-F-(G).sub.r -(K).sub.s -L,
wherein
r and s are each independently, 0 or 1;
A is a proline derivative of Formula II.sub.a, ##STR37## 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 derivative of Formula III.sub.a, ##STR38## wherein R.sub.a is hydrogen or unsubstituted or fluorine-substituted C.sub.1 -C.sub.3 -alkyl;
R.sup.1.sub.a 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 derivative of Formula IV.sub.a, ##STR39## 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 derivative of Formula V.sub.a, ##STR40## 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, ##STR41## wherein R.sub.a is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R.sup.1.sub.a 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, ##STR42## 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, ##STR43## wherein R.sub.a is hydrogen, or unsubstituted or fluorine-substituted alkyl;
or
a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IX.sub.a, ##STR44## 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, ##STR45## 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, ##STR46## 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, ##STR47## 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, ##STR48## 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, ##STR49## 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, 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, ##STR50## wherein R.sub.e is alkyl and R.sup.1.sub.e is hydrogen, or unsubstituted or fluorine-substituted alkyl;
F is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue;
or
an .alpha.-amino acid residue of Formula II.sub.f, ##STR51## wherein n.sub.f is 0, 1 or 2, R.sup.1.sub.f is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R.sup.2.sub.f and R.sup.3.sub.f are each, independently, hydrogen or methyl;
R.sup.4.sub.f is hydrogen, hydroxy, alkoxy, or fluorine;
R.sup.5.sub.f is hydrogen or fluorine;
or n.sub.f is 1 and R.sup.3.sub.f and R.sup.4.sub.f together form a double bond;
or n.sub.f is 1 and R.sup.4.sub.f and R.sup.5.sub.f together form a double-bonded oxygen diradical;
or n.sub.f is 1 or 2 and R.sup.1.sub.f and R.sup.2.sub.f together form a double bond;
or
a 2- or 3-aminocyclopentanecarboxylic acid residue of Formula III.sub.f, ##STR52## wherein R.sub.f is alkyl and R.sup.1.sub.f is hydrogen, or unsubstituted or fluorine-substituted alkyl;
or an N-alkylglycyl or N-alkylalanyl residue;
G is an .alpha.-amino acid residue of Formula II.sub.g, ##STR53## wherein R.sup.1.sub.g is hydrogen or alkyl and R.sup.2.sub.g is hydrogen, alkyl, arylalkyl, heteroarylalkyl, phenyl or substituted phenyl;
or R.sup.1.sub.g and R.sup.2.sub.g, together with the .alpha.-carbon atom, form a C.sub.5 -C.sub.6 ring or a benzo-fused C.sub.5 ring;
K is an .alpha.-amino acid of Formula II.sub.k, ##STR54## wherein R.sup.1.sub.k is hydrogen, or alkyl;
and R.sup.2.sub.k is hydrogen, alkyl, arylalkyl, heteroarylalkyl, phenyl or substituted phenyl;
or R.sup.1.sub.g and R.sup.2.sub.g, together with the .alpha.-carbon atom, form a cyclopentane ring or a benzo-fused cyclopentane ring;
and
L is a substituted or unsubstituted amino, hydrazido, aminoxy or oximato group.

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Dolastatin 15 derivatives

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Dolastatin 15 derivatives

Life of this patent

Abstract

Claims39