Dolastatin 15 derivatives

• US 20010018422A1
• Filed: 01/08/2001
• Published: 08/30/2001
• Est. Priority Date: 07/08/1998
• Status: Abandoned Application

• Current Assignee: BASF AG (BASF SE)
• Original Assignee: BASF AG (BASF SE)
• Inventors: Ritter, Kurt, Amberg, Wilhelm, Kling, Andreas, Haupt, Andreas, Barlozzari, Teresa, Janssen, Bernd
• Application Number:
  US09/756,593
• Publication Number:
  US 20010018422A1
• Time in Patent Office: Days
• US Class Current: 514/17
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 5/101 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1024 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

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.

Claims

1. 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 II_a,

wherein n_a is 0 to 3;

R_a is hydrogen, or unsubstituted or fluorine-substituted normal, branched or cyclic C₁-C₃-alkyl;

R¹_a is hydrogen, C₁-C ₃-alkyl, phenyl, or substituted phenyl;

or R_a and R¹_a together form a propylene bridge; and

R²_a, R³_a, R⁴_a and R⁵_a are each, independently, hydrogen or alkyl;

or

an α

-amino acid derivative of Formula III_a,

wherein R_a is hydrogen or unsubstituted or fluorine-substituted C₁-C₃-alkyl;

R¹_a is hydrogen or C₁-C₄-alkyl;

R⁶_a is alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl;

or R¹_a is an alkyl group and R⁶_a is C₁-C₆-alkyl, cycloalkylmethyl, benzyl or substituted benzyl; and

R⁷_a is hydrogen or alkyl;

or

an α

-amino acid derivative of Formula IV_a,

wherein m_a is 1 or 2;

R⁷_a is hydrogen or alkyl;

R_a is hydrogen, or unsubstituted or fluorine-substituted alkyl;

or

an α

-amino acid derivative of Formula V_a,

wherein R⁷_a is hydrogen or alkyl and R_a is hydrogen, or unsubstituted or fluorine-substituted alkyl;

or

an α

-amino acid of Formula VI_a,

wherein R_a is hydrogen, or unsubstituted or fluorine-substituted alkyl;

R¹_a is hydrogen, alkyl, phenyl, or substituted phenyl;

or R_a and R¹_a together form a propylene bridge; and

X_a is hydroxy, alkoxy or fluorine;

or

an α

-amino acid of Formula VII_a,

wherein R_a is hydrogen, or unsubstituted or fluorine-substituted alkyl;

R¹_a is hydrogen, alkyl, phenyl, or substituted phenyl;

or R_a and R¹_a together form a propylene bridge; and

R²_a, R³_a, R⁴_a and R⁵_a are each, independently, hydrogen or alkyl;

or

an α

-amino acid residue of Formula VIII_a,

wherein R_a is hydrogen, or unsubstituted or fluorine-substituted alkyl;

or

a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IX_a,

wherein the 3-carbonyl moiety is in the endo or exo position, Z_a is a single bond or a double bond, and R_a is hydrogen or unsubstituted or fluorine-substituted alkyl;

or

an α

-amino acid residue of Formula X_a,

wherein n_a is 1, 2 or 3, and R⁷_a is hydrogen or alkyl and R_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 α

-amino acid residue of Formula II_b,

wherein R¹_b is hydrogen, and R²_b is alkyl or alkenyl;

or R¹_b and R²_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 α

-amino acid residue of Formula II_d,

wherein R_d is hydrogen, or unsubstituted or fluorine-substituted alkyl;

R¹_d is hydrogen; and

R²_d is alkyl, substituted alkyl or alkenyl;

or R¹_d and R²_d together form an isopropylidene group;

or

an α

-amino acid residue of Formula III_d,

wherein n_d is 1 or 2;

R³_d is hydrogen, alkyl or fluorine-substituted alkyl; and

X_d is hydrogen;

or n_d is 1 and X_d 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 II_e,

wherein n_e is 0, 1 or 2, R¹_e is hydrogen, or unsubstituted or fluorine-substituted alkyl;

R²_e and R³_e are each, independently, hydrogen or alkyl;

R⁴_e is hydrogen, hydroxy or alkoxy; and

R⁵_e is hydrogen or fluorine;

or n_e is 1 and R³_e and R⁴_e together form a double bond;

or n_e is 1 and R⁴_e and R⁵_e together form a double-bonded oxygen diradical;

or n_e is 1 or 2 and R¹_e and R²_e together form a double bond;

or

an aminocyclopentanecarboxylic acid residue of Formula III_e,

wherein R_e is alkyl and R¹_e is hydrogen, or unsubstituted or fluorine-substituted alkyl;

F is an aminobenzoyl derivative of Formula II_f,

wherein R_f is a hydrogen atom or an alkyl group;

the carbonyl group is ortho, meta, or para to the nitrogen atom;

R¹_f and R²_f 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 R¹_f and R²_f can together form a dioxymethylene group;

or

F is an aminocycloalkanecarboxylic acid residue of Formula III_f,

wherein R_f is a hydrogen atom or an alkyl group;

a_f 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.

2. The compound of

claim 1

wherein the pharmaceutically acceptable acid is hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid or acetylglycine.

3. The compound of

claim 1

wherein G is a monovalent radical of Formula II_g,

wherein

R¹_l is a hydrogen atom, a normal or branched, saturated or unsaturated C₁-C₁₈-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C₁-C₆-alkoxy group, a substituted or unsubstituted aryloxy-C₁-C₆-alkoxy group, wherein the aryl substituents comprise one or more halogen atoms or one or more C₁-C₄-alkyl, methoxy, ethoxy, trifluoromethyl, nitro or dioxymethylene groups;

or a heteroaryl-C₁-C₆-alkoxy group, wherein the heteroaryl group is derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine; and

R²_l is a hydrogen atom, a normal or branched C₁-C₁₈-alkyl group, a normal C₁-C₁₈ alkenyl group, a C₃-C₁₀-cycloalkyl group, an aryl group, or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more alkyl, alkoxy, dioxymethylene, trifluoromethyl or nitro groups;

or a heteroaryl or substituted heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine and the heteroaryl substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups;

or

a monovalent radical of Formula II_l,

wherein a_l is 0, 1, 2, 3, 4, or 5;

R³_l is a methyl, ethyl, normal propyl or isopropyl group;

R⁴_l is a saturated or partially unsaturated carbocyclic system which contains from 3 to 10 carbon atoms, an aryl group, or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, dioxymethylene, trifluoromethyl, nitro, cyanof C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups;

or a substituted or unsubstituted 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 group substituents comprise one or more C₁-C₆-alkyl, hydroxyl or phenyl groups;

or

a monovalent radical of Formula III_l,

—

(CH₂)₂-W_l-R⁵_l 

 

(III_l),

wherein W_l is an NR⁶_l group, an oxygen atom or a sulfur atom, R⁵_l and R⁶_l are each, independently, a hydrogen atom or a C₁-C₄-alkyl, C₃-C₇-cycloalkyl, aryl, arylmethyl or substituted aryl or arylmethyl group, wherein the aryl substituents comprise one or more halogen atoms or one or more alkoxy, dioxymethylene, trifluoromethyl, nitro, cyano, C₁-C₇-alkoxycarbonyl, C₁-C₇-alkylsulfonyl, amino, or C₁-C₇-dialkylamino groups;

or R⁶_l is a C₁-C₁₈-alkanoyl or benzoyl group;

or

a monovalent radical of Formula IV_l,

—

(CH₂)_bl-Z_l 

 

(IV_l),

b_l is 2, 3, or 4 and Z_l is a formyl, aminocarbonyl, hydrazinocarbonyl, cyclic acetal, cyclic thioacetal, acyclic acetal or acyclic thioacetal group;

or

a monovalent radical of Formula V_l,

b_l is 2, 3, or 4;

R⁷_l is a polyglycol group of the formula —

O—

(CH₂—

CH₂—

O)_dl—

CH₃; and

d_l is between about 2 and about 4, or between about 40 and about 90;

or

a monovalent radical of Formula VI_l,

wherein R⁸_l is a hydrogen atom, or a C₁-C₄ alkanoyl, C₁-C₄ alkyl, benzoyl, or benzyl group.

4. The compound of

claim 1

wherein G is a β

-hydroxy amino group of Formula III_g,

R⁹_l is a hydrogen atom, or a C₁-C₆-alkyl, aryl or 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; and

R¹⁰_l is a hydrogen atom, a methyl group or a phenyl group.

5. The compound of

claim 1

wherein G is a hydrazido group of Formula IV_g,

wherein R¹¹_l is a hydrogen atom and R¹²_l is a hydrogen atom, a normal or branched C₁-C₈-alkyl group, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group, an aryl-C₁-C₄-alkyl group, an aryl group, 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;

or a heteroaryl group, a heteroaryl-C₁-C₄-alkyl group or a 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.

6. The compound of

claim 1

wherein G is a monovalent radical of the formula —

O—

R¹³_l or of the formula —

S—

R¹³_l, and R¹³_l is a C₃-C₁₀-cycloalkyl, straight-chain or branched C₂-C₁₆-alkenylmethyl, C₁-C₁₆-alkyl or halogen-substituted C₁-C₁₆-alkyl group;

R¹³_l is a monovalent radical of the formula —

(CH₂)_el—

R¹⁴_l, e_l is 1, 2, or 3, and R¹⁴_l is a saturated or partially unsaturated C₃-C₁₀ carbocyclic group;

R¹³_l is a monovalent radical of the formula —

[CH₂—

CH═

C(CH₃)—

CH₂]_fl—

H, and f_l is 1, 2, 3, or 4;

R¹³_l is a monovalent radical of the formula —

[CH₂—

CH₂—

O]_gl—

CH₃, and g_l is between about 2 and about 4, or between about 40 and about 90;

R¹³_l is a monovalent radical of the formula —

(CH₂)_hl—

X, h_l is 0, 1, 2, or 3; and

X is an aryl or 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;

or 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;

R¹³_l is a monovalent radical of the formula —

(CH₂)_bl-W_l-R⁵_l, b_l is 2, 3, or 4, W_l is an oxygen atom, a sulfur atom or an NR⁶_l group;

R⁵_l is a saturated carbocyclic system which contains from about 3 to about 10 carbon atoms, a partially unsaturated carbocyclic system containing from about 3 to about 10 carbon atoms, an aryl or 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; and

R⁶_l is a hydrogen atom, or a C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₁-C₁₈-alkanoyl, benzoyl, arylmethyl, aryl or substituted aryl or arylmethyl 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.

7. The compound of

claim 1

wherein G is an aminoxy group of the formula —

O—

N(R¹⁶_l)(R¹⁵_l), wherein

R¹⁵_l and R¹⁶_l are each, independently, 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-C₁-C₄-alkyl group, an aryl group or a substituted aryl-C₁-C₄-alkyl or 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

R¹⁵_l and R¹⁶_l together with the nitrogen atom form a heterocyclic ring structure comprising 5, 6, or 7 atoms.

8. The compound of

claim 1

wherein G is a oximato group of the formula —

O—

N═

C(R¹⁵_l)(R¹⁶_l), wherein

R¹⁵_l and R¹⁶_l are each, independently, 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-C₁-C₄-alkyl group, an aryl group or a substituted aryl-C₁-C₄-alkyl or 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

R¹⁵_l and R¹⁶_l, together with the carbon atom, form a cyclic system, a cyclic system fused to an aromatic ring system or a cyclic system selected from the group consisting of;

9. The compound of

claim 1

wherein G 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, or a C₃-C₈-cycloalkyl-C₁-C₄-alkyl group.

10. The compound of

claim 1

wherein G is a monovalent radical of Formula V_g,

—

(CH₂)_ag—

R¹⁷_l 

 

(V_g)

a_g is 0, 1, or 2, and R¹⁷_l is 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;

or 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

11. The compound of

claim 1

wherein G is a monovalent radical of Formula VI_g,

b_g is 0, 1, 2, or 3;

e_g is 0 or 1;

R¹⁸_l is a hydrogen atom, a normal or branched C₁-C₈-alkyl group, a halogen substituted normal or branched C₁-C ₈-alkyl group, a C₃-C₈-cycloalkyl group, a C₃-C₈-cycloalkyl-C ₁-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.

12. The compound of

claim 1

wherein G is a monovalent radical of Formula VII_g,

d_g is 0, 1, 2, or 3;

eg is 0 or 1;

R¹⁹_l and R²⁰_l 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-C ₈-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 R¹⁹_l, R²⁰_l and the nitrogen atom form a ring system comprising 6 or fewer carbon atoms.

13. The compound of

claim 1

wherein G is an alkylene sulfoxide or an alkylene sulfone of Formula VIII_g,

g_g is 1 or 2, h_g is 1 or 2, and R²¹_l is a methyl, trifluoromethyl, ethyl or phenyl group.

20. A method for treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of

claim 1

.

14. A compound of the formula

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 C is a monovalent radical.

15. A compound of the formula

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

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

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.

18. A compound of the formula Me₂Val-Val-MeVal-Pro-F-G,

wherein F is of Formula II_f and R_f is a hydrogen atom or a methyl group, R¹_f and R²_f 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—

R¹³_l or —

S—

R¹³_l, and R¹³_l is an alkyl, aryl or alkylaryl group.

19. A compound of the formula Me₂Val-Val-MeVal-Pro-F-G,

wherein F is of Formula III_f, R_f is a hydrogen atom or a methyl group, a_f 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—

R¹³_l or —

S—

R¹³_l, and R¹³_l is an alkyl, aryl or alkylaryl group.

21. The method of claim 45 wherein the mammal is a human.