US 2001/0018422 A1 · 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 (I) and acid salts thereof, wherein A, D, and E are α-amino acid residues, B is an α-amino acid residue or an α-hydroxy acid residue, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue, and G is a monovalent radical, such as, for example, a hydrogen atom, an amino group, an alkyl group, an alkylene alkyl ether, an alkylene alkyl thioether, an alkylene aldehyde, an alkylene amide, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, an oximato group, an alkylene aryl group, an alkylene ester, an alkylene sultoxide or an alkylene sulfone. Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. An additional embodiment of the present invention is 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,
or a salt thereof with a pharmaceutically acceptable acid, wherein
A is a proline derivative of Formula IIa, 47
wherein na is 0 to 3;
Ra is hydrogen, or unsubstituted or fluorine-substituted normal, branched or cyclic C1-C3-alkyl;
R1a is hydrogen, C1-C 3-alkyl, phenyl, or substituted phenyl;
or Ra and R1a together form a propylene bridge;
and R2a, R3a, R4a and R5a are each, independently, hydrogen or alkyl;
or
an α-amino acid derivative of Formula IIIa, 48
wherein Ra is hydrogen or unsubstituted or fluorine-substituted C1-C3-alkyl;
R1a is hydrogen or C1-C4-alkyl;
R6a is alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl;
or R1a is an alkyl group and R6a is C1-C6-alkyl, cycloalkylmethyl, benzyl or substituted benzyl;
and R7a is hydrogen or alkyl;
or
an α-amino acid derivative of Formula IVa, 49
wherein ma is 1 or 2;
R7a is hydrogen or alkyl;
Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
or
an α-amino acid derivative of Formula Va, 50
wherein R7a is hydrogen or alkyl and Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
or
an α-amino acid of Formula VIa, 51
wherein Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R1a is hydrogen, alkyl, phenyl, or substituted phenyl;
or Ra and R1a together form a propylene bridge;
and Xa is hydroxy, alkoxy or fluorine;
or
an α-amino acid of Formula VIIa, 52
wherein Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R1a is hydrogen, alkyl, phenyl, or substituted phenyl;
or Ra and R1a together form a propylene bridge;
and R2a, R3a, R4a and R5a are each, independently, hydrogen or alkyl;
or
an α-amino acid residue of Formula VIIIa, 53
wherein Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
or
a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IXa, 54
wherein the 3-carbonyl moiety is in the endo or exo position, Za is a single bond or a double bond, and Ra is hydrogen or unsubstituted or fluorine-substituted alkyl;
or
an α-amino acid residue of Formula Xa, 55
wherein na is 1, 2 or 3, and R7a is hydrogen or alkyl and Ra 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 α-amino acid residue of Formula IIb, 56
wherein R1b is hydrogen, and R2b is alkyl or alkenyl;
or R1b and R2b 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 α-amino acid residue of Formula IId, 57
wherein Rd is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R1d is hydrogen;
and R2d is alkyl, substituted alkyl or alkenyl;
or R1d and R2d together form an isopropylidene group;
or
an α-amino acid residue of Formula IIId, 58
wherein nd is 1 or 2;
R3d is hydrogen, alkyl or fluorine-substituted alkyl;
and Xd is hydrogen;
or nd is 1 and Xd is fluorine, hydroxy, methoxy, or ethoxy;
E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl,or hydroxyprolyl residue;
or
an α-amino acid residue of Formula IIe, 59
wherein ne is 0, 1 or 2, R1e is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R2e and R3e are each, independently, hydrogen or alkyl;
R4e is hydrogen, hydroxy or alkoxy;
and R5e is hydrogen or fluorine;
or ne is 1 and R3e and R4e together form a double bond;
or ne is 1 and R4e and R5e together form a double-bonded oxygen diradical;
or ne is 1 or 2 and R1e and R2e together form a double bond;
or
an aminocyclopentanecarboxylic acid residue of Formula IIIe, 60
wherein Re is alkyl and R1e is hydrogen, or unsubstituted or fluorine-substituted alkyl;
F is an aminobenzoyl derivative of Formula IIf, 61
wherein Rf is a hydrogen atom or an alkyl group;
the carbonyl group is ortho, meta, or para to the nitrogen atom;
R1f and R2f are each, independently, a hydrogen atom;
a halogen atom;
a C1-C4-alkyl group;
a methoxy, ethoxy, trifluoromethyl, nitro, cyano, amino or dimethyalmino group;
or R1f and R2f can together form a dioxymethylene group;
or
F is an aminocycloalkanecarboxylic acid residue of Formula IIIf, 62
wherein Rf is a hydrogen atom or an alkyl group;
af is 0, 1 or 2;
and the carbonyl group is in position 2 or position 3 of the cycloalkane ring relative to the nitrogen atom;
and
G is a substituted or unsubstituted amino, hydrazido, aminoxy, oximato, arylalkyl, heteroarylalkyl, aryl, heteroaryl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonylalkyl, aminocarbonyl, alkylcarbonylalkyl, alkylcarbonyl, arylcarbonylalkyl, arylcarbonyl, alkylsulfinylalkyl, alkylsulfinyl, arylsulfinylalkyl, arylsulfinyl, alkylsulfonylalkyl, alkylsulfonyl, arylsulfonylalkyl or arylsulfonyl group.

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Dolastatin 15 derivatives

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Dolastatin 15 derivatives

Life of this patent

Abstract

Claims21