Dolastatin 15 derivatives
First Claim
1. A compound of the formula
or a salt thereof with a pharmaceutically acceptable acid, whereinA is a proline derivative of Formula IIa, ##STR45## 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 -C3 -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;
oran α
-amino acid derivative of Formula IIIa, ##STR46## 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;
oran α
-amino acid derivative of Formula IVa, ##STR47## wherein ma is 1 or 2;
R7a is hydrogen or alkyl;
Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
oran α
-amino acid derivative of Formula Va, ##STR48## wherein R7a is hydrogen or alkyl and Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
oran α
-amino acid of Formula VIa, ##STR49## 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;
oran α
-amino acid of Formula VIIa, ##STR50## 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;
oran α
-amino acid residue of Formula VIIIa, ##STR51## wherein Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
ora 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IXa, ##STR52## 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;
oran α
-amino acid residue of Formula Xa, ##STR53## 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;
oran α
-amino acid residue of Formula IIb, ##STR54## 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;
oran α
-amino acid residue of Formula IId, ##STR55## wherein Rd is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R1d is hydrogen; and
R2 d is alkyl, substituted alkyl or alkenyl;
or R1d and R2d together form an isopropylidene group;
oran α
-amino acid residue of Formula IIId, ##STR56## 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;
oran α
-amino acid residue of Formula IIe, ##STR57## 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;
oran aminocyclopentanecarboxylic acid residue of Formula IIIe, ##STR58## wherein Re is alkyl and R1e is hydrogen, or unsubstituted or fluorine-substituted alkyl;
F is an aminobenzoyl derivative of Formula IIf, ##STR59## 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;
orF is an aminocycloalkanecarboxylic acid residue of Formula IIIf, ##STR60## 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.
1 Assignment
0 Petitions
Accused Products
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 sulfoxide 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.
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Citations
21 Claims
- 1. A compound of the formula
- space="preserve" listing-type="equation">A--B--D--E--F--G,
or a salt thereof with a pharmaceutically acceptable acid, wherein A is a proline derivative of Formula IIa, ##STR45## 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 -C3 -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;
oran α
-amino acid derivative of Formula IIIa, ##STR46## 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;
oran α
-amino acid derivative of Formula IVa, ##STR47## wherein ma is 1 or 2;
R7a is hydrogen or alkyl;
Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
oran α
-amino acid derivative of Formula Va, ##STR48## wherein R7a is hydrogen or alkyl and Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
oran α
-amino acid of Formula VIa, ##STR49## 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;
oran α
-amino acid of Formula VIIa, ##STR50## 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;
oran α
-amino acid residue of Formula VIIIa, ##STR51## wherein Ra is hydrogen, or unsubstituted or fluorine-substituted alkyl;
ora 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IXa, ##STR52## 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;
oran α
-amino acid residue of Formula Xa, ##STR53## 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;
oran α
-amino acid residue of Formula IIb, ##STR54## 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;
oran α
-amino acid residue of Formula IId, ##STR55## wherein Rd is hydrogen, or unsubstituted or fluorine-substituted alkyl;
R1d is hydrogen; and
R2 d is alkyl, substituted alkyl or alkenyl;
or R1d and R2d together form an isopropylidene group;
oran α
-amino acid residue of Formula IIId, ##STR56## 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;
oran α
-amino acid residue of Formula IIe, ##STR57## 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;
oran aminocyclopentanecarboxylic acid residue of Formula IIIe, ##STR58## wherein Re is alkyl and R1e is hydrogen, or unsubstituted or fluorine-substituted alkyl; F is an aminobenzoyl derivative of Formula IIf, ##STR59## 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;
orF is an aminocycloalkanecarboxylic acid residue of Formula IIIf, ##STR60## 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; andG 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 20, 21)
- 11. The compound of claim 1 wherein G is a monovalent radical of Formula VIg,
- space="preserve" listing-type="equation">--(CH.sub.2).sub.b.sbsb.g --(C═
O).sub.c.sbsb.g --OR.sup.18.sub.l(VI.sub.g)
bg is 0, 1, 2, or 3;
eg is 0 or 1;
R18l is a hydrogen atom, a normal or branched C1 -C8 -alkyl group, a halogen substituted normal or branched C1 -C8 -alkyl group, a C3 -C8 -cycloalkyl group, a C3 -C8 -cycloalkyl-C1 -C4 -alkyl group, an aryl group or a substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C1 -C7 -alkoxycarbonyl, C1 -C7 -alkylsulfonyl, amino, or C1 -C7 -dialkylamino groups.
- eg is 0 or 1;
R19l and R20l are, independently, a hydrogen atom, a normal or branched C1 -C8 -alkyl group, a halogen-substituted C1 -C8 -alkyl group, a C3 -C8 -cycloalkyl group, a C3 -C8 -cycloalkyl-C1 -C4 -alkyl group, an aryl group or a substituted aryl group wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C1 -C7 -alkoxycarbonyl, C1 -C7 -alkylsulfonyl, amino, or C1 -C7 -dialkylamino groups;
a heteroaryl or substituted heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline and the heteroaryl substituents comprise one or more C1 -C6 -alkyl, hydroxyl or phenyl groups;
or R19l, R20l and the nitrogen atom form a ring system comprising 6 or fewer carbon atoms.
- space="preserve" listing-type="equation">--(CH.sub.2).sub.g.sbsb.g --S(O).sub.h.sbsb.g --R.sup.21.sub.L(VIII.sub.g),
- 14. A compound of the formula
- space="preserve" listing-type="equation">A--B--D--E--F--G
wherein A is N,N-dimethylvalyl, B is tertiary-leucyl, D is N-methylvalyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and G is a monovalent radical.
- 15. A compound of the formula
- space="preserve" listing-type="equation">A--B--D--E--F--G
wherein A is N,N-dimethylvalyl, B is valyl, D is N-methyl-tertiaryleucyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and G is a monovalent radical.
- 16. A compound of the formula
- space="preserve" listing-type="equation">A--B--D--E--F--G
wherein A is N-methyl-d-prolyl, B is valyl, D is N-methylvalyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and G is a monovalent radical.
- 17. A compound of the formula
- space="preserve" listing-type="equation">A--B--D--E--F--G
wherein A is N-methylhomoprolyl, B is valyl, D is N-methylvalyl, E is prolyl, F is an aminobenzoic acid residue or an aminocycloalkanecarboxylic acid residue and G is a monovalent radical.
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18. A compound of the formula Me2 Val-Val-MeVal-Pro-F-G, wherein F is of Formula IIf and Rf is a hydrogen atom or a methyl group, R1f and R2f are each a hydrogen atom, an alkyl group or an alkoxy group, and G is an amino group, an N-substituted amino group, a hydrazido, an alkyl, cycloalkyl, aryl, or alkylaryl, an alkylene ester, an alkylene amide, an alkylene sulfoxide or an alkylene sulfone group or a monovalent radical of the formula --O--R13l or --S--R13l, and R13l is an alkyl, aryl or alkylaryl group.
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19. A compound of the formula Me2 Val-Val-MeVal-Pro-F-G, wherein F is of Formula IIIf, Rf is a hydrogen atom or a methyl group, af is 1 or 2, and G is an amino group, an N-substituted amino group, a hydrazido, an alkyl, cycloalkyl, aryl, or alkylaryl, an alkylene ester, an alkylene amide, an alkylene sulfoxide or an alkylene sulfone group or a monovalent radical of the formula --O--R13l or --S--R13l, and R13l is an alkyl, aryl or alkylaryl group.
Specification