Dolastatin 15 derivatives

Abstract

Compounds of the present invention include cell growth inhibitors which are peptides of Formula I

Description

RELATED APPLICATION(S)

[0001] This application is a continuation of International Application No. PCT/US99/14099, which designated the United States and was filed on Jun. 23, 1999, published in English, which is a continuation of, and claims priority to, Ser. No. 09/112,249, filed Jul. 8, 1998, the teachings of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] A number of short peptides with significant activity as inhibitors of cell growth have been isolated from the Indian Ocean sea hare Dolabella auricularia (Bai, et al., Biochem. Pharmacology 40: 1859-1864 (1990); Beckwith et al., J. Natl. Cancer Inst. 85: 483-488 (1993) and references cited therein). These include Dolastatins 1-10 (U.S. Pat. No. 4,816,444, issued to Pettit et al.) and Dolastatin-15 (European Patent Application No. 398558). Dolastatin 15, for example, markedly inhibits the growth of the National Cancer Institute's P388 lymphocytic leukemia (PS system) cell line, a strong predictor of efficacy against various types of human malignancies.

[0003] The exceedingly small amounts of the various Dolastatin peptides present in Dolabella auricularia (about 1 mg each per 100 kg sea hare) and the consequent difficulties in purifying amounts sufficient for evaluation and use, have motivated efforts toward the synthesis of these compounds (Roux et al., Tetrahedron 50: 5345-5360 (1994); Shioiri et al., Tetrahedron 49: 1913-24 (1993); Patino et al., Tetrahedron 48: 4115-4122 (1992) and references cited therein). Synthetic Dolastatin 15, however, suffers from drawbacks which include poor solubility in aqueous systems and the need for expensive starting materials for its synthesis. These, in turn, have led to the synthesis and evaluation of structurally modified Dolastatin 15 derivatives (see, for example, Bioorg. Med. Chem. Lett. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790).

[0004] However, there is a need for synthetic compounds with the biological activity of Dolastatin 15 which have useful aqueous solubility and can be produced efficiently and economically.

SUMMARY OF THE INVENTION

[0005] Compounds of the present invention include cell growth inhibitors which are peptides of Formula I

A-B-D-E-F-G (I)

[0006] and acid salts thereof, wherein A, D, and E are α-amino acid residues, B is an α-amino 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.

[0007] Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0008] 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.

[0009] The present invention provides compounds with antineoplastic activity as well as increased metabolic stability relative to Dolastatin 15.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to peptides having antineoplastic activity. It also includes pharmaceutical compositions comprising these compounds and methods for treating cancer in a mammal, including a human, by administration of these compositions to the mammal.

[0011] The invention is based on the discovery that Dolastatin 15, a peptide isolated from the sea hare Dolabella auricularia, is a potent inhibitor of cell growth. This compound, however, is present in trace quantities in the sea hare, and is, thus, difficult to isolate and expensive to synthesize and suffers from poor aqueous solubility. As shown herein, however, Dolastatin 15 can serve as a starting point for the development of compounds which overcome these disadvantages while retaining antineoplastic activity or exhibiting greater antineoplastic activity than the natural product. Applicants have discovered that certain structural modifications of Dolastatin 15 provide compounds with a surprisingly improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatins-10 and -15. The Dolastatin-15 derivatives exhibit activity even in multiple drug-resistant tumor systems and an unpredicted high solubility in aqueous solvents. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail.

[0012] For the purposes of the present invention, the term “monovalent radical” is intended to mean an electrically neutral molecular fragment capable of forming one covalent bond with a second neutral molecular fragment. Monovalent radicals include the hydrogen atom, alkyl groups, such as methyl, ethyl and propyl groups, halogen atoms, such as fluorine, chlorine and bromine atoms, aryl groups, such as phenyl and naphthyl groups, and alkoxy groups, such as methoxy and ethoxy groups. Two monovalent radicals on adjacent sigma-bonded atoms can also together form a pi bond between the adjacent atoms. Two monovalent radicals may also be linked together, for example, by a polymethylene unit, to form a cyclic structure. For example, in the unit —N(R)R′, R and R′ are each a monovalent radical, and can, together with the nitrogen atom, form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom can also together form a divalent radical, such as an alkylidene group, for example, a propylidene group, or an oxygen atom.

[0013] For the purposes of the present invention, the term “residue” refers to the molecular fragment remaining after the removal of the elements of a water molecule (one oxygen atom, two hydrogen atoms) from a molecule, such as an amino acid or a hydroxy acid.

[0014] For the purposes of the present invention the term “normal alkyl” refers to an unbranched, or straight chain, alkyl group, for example, normal propyl (n-propyl, —CH2CH2CH3).

[0015] The compounds of the present invention can be represented by Formula I,

A-B-D-E-F-G (I),

[0016] 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, such as an aminocyclobutanecarboxylic acid residue, an aminocylopentanecarboxylic acid residue, or an aminocyclohexanecarboxylic acid residue; and G is a monovalent radical.

[0017] The peptides of Formula I are generally composed of L-amino acids but they can contain one or more D-amino acids. They can also be present as salts with physiologically-compatible acids, including 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 and acetylglycine.

[0018] The following is a description of the present invention, including a detailed description of individual components and of methods of using the claimed compounds.

Compounds of the Present Invention

[0019] Identity of A

[0020] In one embodiment, A is an amino acid derivative of Formula IIa, 1

[0021] where na is an integer, preferably 0, 1, 2, or 3. Ra is a monovalent radical, such as a hydrogen atom or a C1-C3-alkyl group which can be normal, branched or cyclic and can be substituted by one or more, preferably 1 to about 3, fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropyl are preferred;

[0022] In this embodiment, R1a is a monovalent radical, such as a hydrogen atom or a methyl, ethyl, propyl or phenyl group. The phenyl group can be substituted; suitable substituents include one or more halogen atoms, with fluorine, chlorine and bromine being preferred, C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl or nitro groups.

[0023] R2a, R3a, R4a and R5a are each, independently, a monovalent radical, such as a hydrogen atom or a methyl group. Ra and R1a together can also form a propylene bridge.

[0024] In another embodiment, A is an amino acid derivative of Formula IIIa, 2

[0025] where Ra has the meaning stated for Formula IIa, R1a is a monovalent radical, for example, a hydrogen atom or a lower alkyl group, preferably a methyl, ethyl or propyl group.

[0026] In this embodiment, R6a is a monovalent radical, such as a hydrogen atom, a normal or branched C1-C8-alkyl group, which can he substituted by one or more halogen, preferably fluorine, atoms, or a C3-C8-cycloalkyl or C3-C8-cycloalkyl-C 1-C4-alkyl group, a C1-C4-oxoalkyl group such as a methoxymethyl, 1-methoxyethyl or 1,1-dimethylhydroxymethyl group, a C2-C5 alkenyl group, such as a vinyl or 1-methylvinyl group, or a substituted or unsubstituted phenyl group. Suitable phenyl substituents include one or more halogen atoms, preferably fluorine, chlorine or bromine atoms, and alkyl, methoxy, ethoxy, trifluoromethyl, or nitro groups. R7a is a monovalent radical, preferably a methyl group or an ethyl group.

[0027] In another embodiment, A is an amino acid residue of Formula IVa, 3

[0028] where ma is an integer, preferably 1 or 2. Ra and R7a have the meanings stated for Ra and R7a in Formula IIIa.

[0029] In another embodiment, A is an amino acid residue of Formula Va, 4

[0030] where Ra and R7a have the meanings stated for Ra and R7a in Formula IIIa.

[0031] In a further embodiment, A is a substituted proline derivative of Formula VIa, 5

[0032] where Ra and R1a have the meanings stated for Ra and R1a in Formula IIa, and Xa is a monovalent radical, preferably a hydroxyl, methoxy or ethoxy group or a fluorine atom.

[0033] In another embodiment, A is a thiaprolyl derivative of Formula VIIa, 6

[0034] where Ra, R1a, R2a, R3a, R4a and R5a have the meanings stated for these variables in Formula IIa.

[0035] In another embodiment, A is a 1,3-dihydroisoindole derivative of Formula VIIIa, 7

[0036] where Ra has the meaning stated for Ra in Formula IIa.

[0037] In another embodiment, A is a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IXa, 8

[0038] where Za is a single or double bond and Ra has the meaning stated for this variable in Formula IIa. The 3-carbonyl substituent can have either the exo or endo orientation.

[0039] Identity of B

[0040] B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue. B can also be a carboxylic acid derivative of Formula IIb, 9

[0041] wherein R1b and R2b are each a monovalent radical. R1b is, preferably, a hydrogen atom and R2b is, for example, a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group. Additionally, R1b and R2b together can be an isopropylidene group.

[0042] Identity of D

[0043] D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkyl-norleucyl, N-alkyl-isoleucyl, N-alkyl-allo-isoleucyl or N-alkyl-norvalyl residue, where the alkyl group is preferably methyl or ethyl.

[0044] In another embodiment, D is an α-amino carboxylic acid derivative of Formula IId, 10

[0045] where Rd has the meaning stated for Ra in Formula IIIa, R1d is a monovalent radical, preferably a hydrogen atom, and R2 is a monovalent radical such as a cyclopropyl group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group. Additionally, R1d and R2d together can form an isopropylidene group.

[0046] Alternatively, D can be a proline derivative of Formula IIId, 11

[0047] where nd is an integer, for example, 1 or 2. and R3d has the meaning stated for R1a in Formula IIIa. Xd is a monovalent radical, preferably a hydrogen atom, and, in the case where nd equals 1, can also be a hydroxyl, methoxy or ethoxy group or a fluorine atom.

[0048] Identity of E

[0049] E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue, or a cyclic α-amino carboxylic acid residue of Formula IIe, 12

[0050] where ne is an integer, preferably 0, 1 or 2. R1e has the meaning stated for R1a in Formula IIIa. R2e and R3e are each a monovalent radical, and can be, independently, a hydrogen atom or a methyl group. R4e is a monovalent radical, preferably a hydrogen atom, a hydroxyl, methoxy or ethoxy group or a fluorine atom. R5e is a monovalent radical, preferably a hydrogen atom. In the case where ne has the value 1, R3e and R4e together can form a double bond or R4e and R5e can together be a double-bonded oxygen radical. In the case where ne has the value 1 or 2, R1e and R2e can together form a double bond.

[0051] In another embodiment, E is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula IIIe, 13

[0052] where Re is a monovalent radical, such as a methyl or ethyl group and R1e has the meaning stated for R1a in Formula IIIa.

[0053] Identity of F

[0054] In one embodiment, F is an aminobenzoyl derivative of Formula IIf, 14

[0055] where Rf is a hydrogen atom or an alkyl group, preferably a methyl, ethyl or propyl group. The carbonyl group can be in position 1 (ortho), 2 (meta), or 3 (para) of the phenyl ring relative to the nitrogen atom. R1f and R2f are each, independently, a hydrogen atom; a halogen atom, for example, a fluorine, chlorine, bromine, or iodine atom; a C1-C4-alkyl group; a methoxy, ethoxy, trifluoromethyl, nitro, cyano, amino or dimethyalmino group. Additionally, R1f and R2f can together form a dioxymethylene group.

[0056] In another embodiment, F is an aminocycloalkanecarboxylic acid residue of Formula IIIf, 15

[0057] where Rf is a monovalent radical, such as a hydrogen atom or a lower alkyl group, preferably a methyl, ethyl or propyl group. af is an integer, for example, 0, 1 or 2. The carbonyl group is in position 2 or position 3 of the cycloalkane ring relative to the nitrogen atom at position 1. The stereogenic centers can be, independently of each other, R or S. For a five-membered ring (af=1) , the combinations R1,S2 and S1,R2 would be referred to as cis-pentacin derivatives, while the combinations R1,R2 and S1,S2 are trans-pentacin derivatives.

[0058] Identity of G

[0059] In one embodiment, G is an amino or substituted amino group of Formula IIg, 16

[0060] where R1l is a monovalent radical, such as 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, or a substituted or unsubstituted aryloxy-C1-C6-alkoxy or heteroaryl-C1-C6-alkoxy group. The aryl group is preferably a phenyl or naphthyl group. The heteroaryl group is a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system, such as, for example, imidazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, pyrazolyl, thiophenyl, furanyl, pyrrolyl, 1,2,4- or 1,2,3-triazolyl, pyrazinyl, indolyl, benzofuranyl, benzothiophenyl, isoindolyl, indazolyl, quinolinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzopyranyl, benzothiazolyl, oxadiazolyl, thiadiazolyl or pyridinyl group. Suitable aryl or heteroaryl substituents include one or more halogen atoms, preferably fluorine, bromine or chlorine; C1-C4-alkyl groups; methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group or a nitro group.

[0061] R2l is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C1-C18-alkyl group, a C3-C10-cycloalkyl group, a substituted or unsubstituted aryl group, where aryl is preferably phenyl or naphthyl. Suitable aryl substituents include one or more halogen, preferably fluorine, chlorine or bromine, atoms, C1-C4-alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group, nitro or cyano groups, a C1-C7-alkoxycarbonyl group, a C1-C7-alkylsulfonyl group, an amino or C1-C7-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle, or an unsubstituted or substituted heteroaryl group. The heteroaryl group can be a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system which can be fused to a benzene ring, such as, for example, imidazolyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyrazolyl, 1,2,4- or 1,2,3-triazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl or quinolinyl group, with preferred substituents being C1-C6-alkyl groups, or hydroxyl or phenyl groups.

[0062] R2l can additionally be of Formula IIl, 17

[0063] wherein al is an integer, preferably 0, 1, 2, 3, 4, or 5. R3l is a monovalent radical, such as a lower alkyl group, for example, a methyl, ethyl, propyl or isopropyl group. R4l is a saturated or partially unsaturated carbocyclic group containing from 3 to about 10 carbon atoms, or a substituted or unsubstituted aryl or heteroaryl group, where the preferred aryl and heteroaryl groups and suitable substituents are as stated for R2l in Formula IIg.

[0064] R2l can also be a monovalent radical of Formula IIIl, 18

[0065] wherein Wl is an oxygen or sulfur atom or an N—R6l group. R5l is a monovalent radical, such as a hydrogen atom, a C1-C4-alkyl or C3-C7-cycloalkyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R2l from Formula IIg. R6l is a monovalent radical, preferably a hydrogen atom, a C1-C4-alkyl group or a C3-C7-cycloalkyl group, a C1-C18-alkanoyl group, a benzoyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R2l in Formula IIg,

[0066] R2l can alternately be a substituent of Formula IVl, 19

[0067] where bl is an integer, preferably 2, 3 or 4. Zl is a monovalent radical, such as a formyl, aminocarbonyl or hydrazinocarbonyl group, or a cyclic or acyclic acetal or thioacetal group.

[0068] R2l can also be a substituent of Formula Vl, 20

[0069] in which bl is an integer, preferably 2, 3 or 4. R7l is a monovalent radical, such as a glycol oligomer of the formula

—O(CH2CH2O)dl—CH3,

[0070] where dl is an integer, preferably in the range from about 2 to about 4 or from about 40 to about 90.

[0071] R2l can further be a carbohydrate of Formula VIl, 21

[0072] where R8l is a monovalent radical, such as a hydrogen atom, a C1-C4-alkanoyl or alkyl group, a benzoyl group or a benzyl group.

[0073] In another embodiment, G is an β-hydroxy amine of Formula IIIg, 22

[0074] where R9l is a monovalent radical such as a hydrogen atom, a C1-C6-alkyl group or a substituted or unsubstituted aryl group, with aryl and its preferred substituents having the meaning stated for R2l in Formula IIg. R10l is a monovalent radical, preferably a hydrogen atom, alkyl, for example, methyl, or a phenyl group.

[0075] Another subclass of compounds of this invention includes peptides of Formula I wherein G is a hydrazido group of Formula IVg, 23

[0076] where R11l and R12l are each, independently, a monovalent radical such as a hydrogen atom, a normal or branched C1-C8-alkyl group, a C3-C8- cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group or a substituted or unsubstituted aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl group, where aryl, heteroaryl and their preferred substituents can be selected from among the options listed for R21 in Formula IIg. R11l and R12l can also together form a propylene or butylene bridge.

[0077] Another subclass of compounds of this invention includes peptides of Formula I wherein G is a monovalent radical of the formula —O—R13l or —S—R13l, where R13l is a monovalent radical, such as a C3-C10-cycloalkyl group, a normal or branched C2-C16-alkenylmethyl group or a C1-C16-alkyl group which can be substituted by from 1 to about 5 halogen, preferably fluorine, atoms.

[0078] R13l can also be the radical —(CH2)el—R14l where el is an integer, preferably 1, 2 or 3. R14l is a monovalent radical, preferably a saturated or partially unsaturated C3-C10-carbocycle.

[0079] R13l can further be the radical

—[CH2—CH═C(CH3)—CH2]fl—H,

[0080] where fl is an integer, preferably 1, 2, 3 or 4.

[0081] R13l can also be the radical

—[CH2—CH2—O]gl—CH3,

[0082] where gl is an integer, preferably from about 2 to about 4, or from about 40 to about 90.

[0083] R13l can also be the radical

—(CH2)hl-aryl or —(CH2)hl-heteroaryl,

[0084] where aryl and heteroaryl can also be substituted and, along with their preferred substituents, can be selected from the group listed for R2l in Formula IIg. hl is an integer, preferably 0, 1, 2 or 3.

[0085] R13l can further be the radical

—(CH2)bl-Wl-R5l,

[0086] where bl, Wl and R5l are each selected from among the options described for Formula IIIl.

[0087] Another subclass of compounds of this invention includes peptides of Formula I in which G is an aminoxy group of the formula

—O—N(R15l)(R16l),

[0088] where R15l and R16l are each a monovalent radical, and can independently be a hydrogen atom, a normal or branched C1-C8-alkyl group, which can be substituted by halogen, preferably fluorine, atoms, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted aryl-C1-C4-alkyl group. Aryl and heteroaryl groups and the preferred substituents thereof can be selected from the options listed for R2l in Formula IIg. Additionally, R15l and R16l can together form a 5-, 6- or 7-membered heterocycle.

[0089] Another subclass of compounds of this invention includes peptides of Formula I wherein G is an oximato group of the formula

—O—N═C(R15l)(R16l),

[0090] where R15l and R16l are selected from among the options listed above and, additionally, can together form a cyclic system comprising, preferably, from about 3 to about 7 ring atoms. This cyclic system can additionally be fused to one or more aromatic rings. Particularly preferred cyclic systems are shown below. 24

[0091] A further subclass of compounds of this invention includes peptides of Formula I wherein G is a hydrogen atom, a normal or branched C1-C8-alkyl group, which can be substituted by up to six halogen, preferably fluorine, atoms, a C3-C8-cycloalkyl group or a C3-C8-cycloalkyl-C 1-C4-alkyl group.

[0092] G can also be an arylalkyl, heteroarylalkyl, aryl or heteroaryl group of Formula Vg,

—(CH2)ag—R17l  (Vg)

[0093] where ag is an integer, such as 0, 1 or 2. R17l is a substituted or unsubstituted aryl or heteroaryl group. Preferred aryl groups include phenyl and naphthyl groups. Suitable aryl substituents include halogen, preferably fluorine, bromine or chlorine, atoms, C1-C4-alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group, a nitro or cyano group, a C1-C7-alkoxycarbonyl group, a C1-C7- alkylsulfonyl group, an amino group or a C1-C6-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle. R17l can also be a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system which can be fused to a benzene ring. Suitable heteroaryl groups include imidazolyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyrazolyl, 1,2,4- or 1,2,3-triazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl and quinolinyl groups. Preferred heteroaryl substituents are C1-C6-alkyl groups, a hydroxyl group or a phenyl group.

[0094] Another subclass of compounds of this invention includes compounds of Formula I wherein G is a monovalent radical of Formula VIg,

—(CH2)bg—(C═O)cg—OR18l  (VIg),

[0095] where bg is an integer, preferably 0, 1, 2 or 3, and cg is an integer, preferably 0 or 1. bg and cg are not both simultaneously 0. R18l is a monovalent radical, such as a hydrogen atom, a straight-chain or branched C1-C8-alkyl group which can be substituted by halogen, preferably fluorine, atoms, especially a CF2-moiety, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a substituted or unsubstituted aryl, preferably phenyl or naphthyl, group. Suitable aryl substituents are halogen, preferably fluorine, bromine or chlorine, atoms, C1-C4-alkoxy, trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a C1-C7-alkoxycarbonyl moiety, a C1-C7-alkylsulfonyl moiety, an amino group or a C1-C6-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle.

[0096] G can also be a monovalent radical of Formula VIIg 25

[0097] where dg is an integer, preferably 0, 1, 2 or 3, and eg is an integer such as 0 or 1. dg and eg cannot both simultaneously take the value 0. R19l and R20l are each, independently, a monovalent radical, such as a hydrogen atom, a straight-chain or branched C1-C8-alkyl group, which can further be substituted by halogen, preferably fluorine, atoms, especially a CF2-moiety, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a substituted or unsubstituted aryl, preferably phenyl or naphthyl group. Suitable aryl substituents include one or more halogen, referably fluorine, bromine or chlorine, atoms, C1-C4-alkoxy, trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a C1-C7-alkoxycarbonyl moiety, a C1-C 7-alkylsulfonyl group, an amino group or a C1-C6-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle. N(R19l)R20l can additionally form a ring system of the formula N(CH2)fg, where fg is an integer selected from among 4, 5 or 6.

[0098] Another subclass of compounds of this invention includes peptides of Formula I, wherein G is a monovalent radical of Formula VIIIg,

—(CH2)gg—S(O)hg—R21l  (VIIIg),

[0099] where gg is an integer, for example, 1 or 2, and hg is 1 or 2. R21l is a monovalent radical, preferably a methyl group, a trifluoromethyl group, an ethyl group or a phenyl group.

[0100] G can also be an alkyl- or arylcarbonylalkyl group of Formula IXg,

—(CH2)ig—(C═O)—R22l  (IXg),

[0101] where R22l is a monovalent radical, such as a hydrogen atom, a straight-chain or branched C1-C8-alkyl group which can be substituted by up to six halogen, preferably fluorine, atoms, especially a CF2-moiety, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a substituted or unsubstituted aryl, preferably phenyl or naphthyl, group. Suitable aryl substituents are halogen, preferably fluorine, bromine or chlorine, atoms, C1-C4-alkoxy, trifluoromethyl, nitro or cyano groups, a dioxymethylene moiety, a C1-C7-alkoxycarbonyl moiety, a C1-C7-alkylsulfonyl moiety, an amino group or a C1-C6-dialkylamino group, where the alkyl groups can, together with the nitrogen atom, also form a 5- or 6-membered heterocycle.

[0102] Synthetic Methods

[0103] The compounds of the present invention can be prepared by known methods of peptide synthesis. Thus, the peptides can be assembled sequentially from individual amino acids or by linking suitable small peptide fragments. In sequential assemblage, the peptide chain is extended stepwise, starting at the C-terminus, by one amino acid per step. In fragment coupling, fragments of different lengths can be linked together, and the fragments in turn can be obtained by sequential assembly from amino acids or by fragment coupling of still shorter peptides.

[0104] In both sequential assemblage and fragment coupling it is necessary to link the units by forming an amide linkage, which can be accomplished via a variety of enzymatic and chemical methods. Chemical methods for forming the amide linkage are described in detail in standard references on peptide chemistry, including Müller, Methoden der organischen Chemie Vol. XV/2, pages 1-364, Thieme Verlag, Stuttgart, Germany (1974); Stewart and Young, Solid Phase Peptide Synthesis, pages 31-34 and 71-82, Pierce Chemical Company, Rockford, Ill. (1984); Bodanszky et al., Peptide Synthesis, pages 85-128, John Wiley & Sons, New York, (1976). Preferred methods include the azide method, the symmetric and mixed anhydride method, the use of in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents, such as carboxylic acid activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA), N,N-bis(2-oxo-oxazolidinyl)imido-phosphoryl chloride (BOP-Cl), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenyl-phosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), O-benzotriazolyl-N,N,N′, N′-tetramethyluronium salts (HBTU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxy-thiophene dioxide (Steglich's reagent; HOTDO), and 1,1′-carbonyl-diimidazole (CDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

[0105] Although the use of protecting groups is generally not necessary in enzymatic peptide synthesis, reversible protection of reactive groups not involved in formation of the amide linkage is necessary for both reactants in chemical synthesis. Three conventional protective group techniques are preferred for chemical peptide synthesis: the benzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques. Identified in each case is the protective group on the α-amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Müller, Methoden der organischen Chemie Vol. XV/1, pp 20-906, Thieme Verlag, Stuttgart (1974). The units employed for assembling the peptide chain can be reacted in solution, in suspension or by a method similar to that described by Merrifield (J. Am. Chem. Soc. 85: 2149 (1963)). Particularly preferred methods are those in which peptides are assembled sequentially or by fragment coupling using the Z, Boc or Fmoc protective group technique, with one of the reactants in the said Merrifield technique being bonded to an insoluble polymeric support (also called resin hereinafter). This typically entails assembling the peptide sequentially on the polymeric support using the Boc or Fmoc protective group technique, with the growing peptide chain covalently bonded at the C terminus to the insoluble resin particles. This procedure allows the removal of reagents and byproducts by filtration, eliminating the need to recrystallize intermediates.

[0106] The protected amino acids can be linked to any suitable polymer, which must be insoluble in the solvents used and have a stable physical form which permits filtration. The polymer must contain a functional group to which the first protected amino acid can be covalently attached. A wide variety of polymers are suitable for this purpose, including cellulose, polyvinyl alcohol, polymethacrylate, sulfonated polystyrene, chloromethylated styrene/divinylbenzene copolymer (Merrifield resin), 4-methylbenzhydrylamine resin (MBHA-resin), phenylacetamidomethyl resin (Pam-resin), p-benzyloxy-benzyl-alcohol-resin, benzhydryl-amine-resin (BHA-resin), 4-(hydroxymethyl)-benzoyl-oxymethyl-resin, the resin of Breipohl et al. (Tetrahedron Letters 28 (1987) 565; supplied by BACHEM), 4-(2,4-dimethoxyphenylaminomethyl) phenoxy resin (supplied by Novabiochem) or o-chlorotrityl-resin (supplied by Biohellas).

[0107] Solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.

[0108] Peptide synthesis on the polymeric support can be carried out in a suitable inert organic solvent in which the amino acid derivatives starting materials are soluble. However, preferred solvents additionally have resin-swelling properties and include DMF, DCM, NMP, acetonitrile, DMSO, and mixtures of these solvents. Following synthesis, the peptide is removed from the polymeric support. The conditions under which this cleavage is accomplished for various resin types are disclosed in the literature. The cleavage reactions most commonly used are acid- or palladium-catalyzed, the former being conducted in, for example, liquid anhydrous hydrogen fluoride, anhydrous trifluoromethanesulfonic acid, dilute or concentrated trifluoroacetic acid, and acetic acid/dichloromethane/trifluoroethanol mixtures. The latter can be carried out in THF or THF-DCM-mixtures in the presence of a weak base such as morpholine. Certain protecting groups are also cleaved off under these conditions.

[0109] Partial deprotection of the peptide may also be necessary prior to certain derivatization reactions. For example, peptides dialkylated at the N-terminus can be prepared either by coupling the appropriate N,N-di-alkylamino acid to the peptide in solution or on the polymeric support or by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH3 and the appropriate aldehyde.

[0110] The two schemes which follow present a more detailed description of the synthesis of the compounds of the present invention. 26

[0111] The tetrapeptide A-B-D-E-OH is coupled with an amino-derivative F-G to give the final compound A-B-D-E-F-G using the methods for peptide coupling as described above. 27

[0112] Here, the N-terminal protected tetrapeptide A′-B-D-E-OH is coupled with an amino-derivative F-G to give an intermediate compound A′-B-D-E-F-G using the methods for peptide coupling as described above. Then, the N-protecting group is removed by conventional methods as described above. The groups RA and R7A can then be attached to the amino terminus via reductive alkylation as described above.

[0113] Building blocks of use in the synthesis of the claimed compounds (described in scheme I and II as F-G) can be prepared by the following general methods:

[0114] a) Synthesis of Amino-phenyl-ketones

[0115] The following schemes describe synthetic routes to aminophenyl-ketones which are not commercially available. 28

[0116] In scheme III.1, the synthesis starts with a nitrobenzaldehyde. Addition of organometallic compounds such as lithium or Grignard reagents led to the corresponding alcohols (Fürstner et al. Tetrahedron 52: 7329-7344 (1996); Fürstner et al., Tetrahedron 51, 773-786 (1995)). These alcohols can be oxidised to the ketones with known oxidation agents, such as chromium(VI) compounds (for example, pyridinium dichromate in dichloromethane, as described by Fürstner et al., supra) or the Dess Martin reagent. The nitrophenyl ketones are then reduced to the corresponding amino-phenyl-ketones either by hydrogenation in presence of a palladium catalyst, such as palladium on carbon, or by metal salts in presence of acids such as the combination of tin(II)chloride and hydrochloric acid (Nunn et al., J. Chem. Soc. 1952: 583-588). 29

[0117] A more direct route (see scheme III.2) is the reaction of nitrobenzoyl chlorides with an organometallic reagent such as a lithium or Grignard reagent (Fürstner et al., Tetrahedron 51, 773-786 (1995)). 30

[0118] 2-Amino-phenyl ketones can be obtained by reaction of the corresponding 2-fluorophenyl-ketone with sodium azide in a polar solvent, such as N,N-dimethylformamide, and subsequent reduction of the intermediate benzisoxazole (see scheme III.3). For example, the synthesis of 2-aminophenyl-(4-pyridazinyl)-ketone has been described by N. Haider et al. (Arch. Pharm. 325: 119-122 (1992)).

[0119] b) Synthesis of Amino-benzamides

[0120] The following schemes describe synthetic routes to aminobenzamides which are not commercially available. 31

[0121] In scheme IV.1, the steps are described starting from nitrobenzoic acids or substituted nitrobenzoic acids. These acids are coupled with primary or secondary amines (HNR1R2) by using coupling reagents. Preferred method is the use of coupling reagents such as carboxylic acid activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloylchloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propane-phosphonic anhydride (PPA), N,N-bis(2-oxo-3oxazolidinyl)-imidophosphoryl chloride (BOP-Cl), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), O-benzotriazolyl-N,N,N′,N′-tetramethyluronium salts (HBTU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl 2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and 1,1′-carbonyldiimidazole (CDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), azabenzotriazole, N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

[0122] In place of the acids, the corresponding nitro-benzoyl chloride can be used. These are either commercially available or could be synthesized from the corresponding acids with thionyl chloride. The amines react with the nitrobenzoylchlorides in the presence of a base such as pyridine, which can also be used as the solvent (N. S. Cho et al., J. Heterocycl. Chem. 33, 1201-1206 (1996)). The nitro-benzamides are then reduced to the corresponding amino-benzamides by reducing agents such as metal salts in presence of hydrochloride acids or by metal-catalysed hydrogenation using palladium on a solid such as palladium on charcoal as catalyst. This route is described in Example 1.

[0123] Another method involves transforming the amine to the trifluoroacetamide by treatment with trifluoroacetic anhydride. The amide is deprotonated with a base such as sodium hydride or potassium t-butanolate and then treated with the corresponding alkyl halide such as methyl iodide, ethyl iodide or isopropyl iodide. The trifluoroacetamide is easily cleaved in basic alcoholic solution such as potassium carbonate in methanol. 32

[0124] In scheme IV.2. the starting materials for the synthesis of amino-benzamides are the N-protected aminobenzoic acids. Different protecting groups for the nitrogen are compatible such as the above mentioned Z-, Boc- or Fmoc-protecting groups. The N-protected amino-benzoic acids are coupled with amines as described above for the nitro-benzoic acids using the above mentioned coupling conditions. This route is exemplified in Example 2. 33

[0125] A route for the preparation of 2-aminobenzamides is described in scheme IV.3. Opening of isatoic anhydride (substituted or unsubstituted at the nitrogen) by amines with evolution of carbon dioxide led to the corresponding 2-amino-benzamides, as described by Clark et al., J. Org. Chem. 9: 55-64 (1944).

[0126] c) Amino-cyclopentane- or Aminocyclohexane-carboxamides

[0127] Different routes have been described to the synthesis of cis-2-amino-cyclopentylcarboxylic acid (cispentacin) in racemic form or as pure enantiomer. Using an intramolecular nitrone-olefin cycloaddition cis-2-(t-butoxycarbonylamino)cyclopentane-1-carboxylic acid could be prepared in a few synthetic steps (Konosu et al., Chem. Pharm. Bull. 41: 1012 (1993)). Another route to enantiomerically pure cis-(1R, 2S)-2-amino-cyclopentylcarboxylic acid is the addition of chiral lithium (S)-(-methylbenzyl)benzylamide to t-butyl-1-cyclopentene-1-carboxylate with subsequent removal of the benzyl groups by hydogenation and removal of the t-butyl group by acid treatment (Davies et al., Synlett 1993, p. 461). The corresponding trans-epimer could be obtained by isomerisation with a base such as potassium t-butoxide. By using the lithium (R)-(-methylbenzyl)benzylamide in the Michael addition (1S, 2R)-2-amino-cyclopentylcarboxylic acid and (1S, 2S)-2-amino-cyclopentylcarboxylic acid can be obtained. This method is also applicable to the synthesis of cis-and trans-aminocyclohexane-1-carboxylic acid.

[0128] Resolution of racemic Boc-protected cis-2-aminocyclopentane carboxylic acid (Bernath et al., Acta Chim. 74: 479 (1972); Nativ et al., Isr. J. Chem. 10: 55 (1972)) can be achieved with (+)- and (−)-ephedrine in high enantiomeric excess (Nöteberg et al., Tetrahedron 53: 7975 (1997)). In this paper also the synthesis of the trans-enantiomers of Boc-protected trans-2-aminocyclopentane carboxylic methyl ester was described, starting with either trans-(3R, 4R)-bis(methoxycarbonyl)cyclopentanone or trans(3S,4S)-bis(methoxycarbonyl)-cyclopentanone.

[0129] Amides of Boc-protected 2-aminocyclopentylcarboxylic acid can be obtained by coupling the acid with the corresponding amine using the standard procedures as described above for the coupling of nitrobenzoic acid with amines or as described in D. Nöteberg et al., Tetrahedron 53: 7975 (1997). Deprotection of the amine function can be achieved by using Lewis acids, for example, a mineral acid such as hydrochloric acid in ether or dioxane or an organic acid, such as trifluoroacetic acid in methylene chloride.

[0130] Methods of Use of the Claimed Compounds

[0131] In another embodiment, the present invention comprises a method for partially or totally inhibiting formation of, or otherwise treating (e.g., reversing or inhibiting the further development of) solid tumors (e.g., tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g., leukemias, lymphomas) in a mammal, for example, a human, by administering to the mammal a therapeutically effective amount of a compound or a combination of compounds of Formula I. The agent may be administered alone or in a pharmaceutical composition comprising the agent and an acceptable carrier or diluent. Administration may be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means such as subcutaneously, intravenously, intramuscularly and intraperitoneally, nasally or rectally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound of Formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical compositions may be combination products, i.e., they may also contain other therapeutically active ingredients.

[0132] The dosage to be administered to the mammal, such as a human, will contain a therapeutically effective amount of a compound described herein. As used herein, “therapeutically effective amount” is an amount sufficient to inhibit (partially or totally) formation of a tumor or a hematological malignancy or to reverse development of a solid tumor or other malignancy or prevent or reduce its further progression. For a particular condition or method of treatment, the dosage is determined empirically, using known methods, and will depend upon factors such as the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be from about 5 to about 250 milligrams per kilogram of body weight by oral administration and from about 1 to about 100 milligrams per kilogram of body weight by parenteral administration.

[0133] The compounds of the present invention can be administered in conventional solid or liquid pharmaceutical administration forms, for example, uncoated or (film-)coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sücker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way typically contain from about 1 to about 90% by weight of the active substance.

[0134] The following examples are intended to illustrate the invention but are not to be considered limitations of the invention.

EXAMPLES

[0135] The proteinogenous amino acids are abbreviated in the examples using the known three-letter code. Other abbreviations employed are: TFA=trifluoroacetic acid, Ac= acetic acid, DCM=dichloromethane, DMSO= dimethylsulfoxide, Bu=butyl, Et=ethyl, Me=methyl, Bn= benzyl. In the compounds listed, all proteinogenous amino acids are L-amino acids unless otherwise noted.

[0136] General Materials and Methods

[0137] The compounds of the present invention are synthesized by classical solution synthesis using standard Z- and Boc-methodology as discussed above or by standard methods of solid-phase synthesis on a model 431A synthesizer supplied by APPLIED BIOSYSTEMS. This apparatus uses different synthetic cycles for the Boc and Fmoc protective group techniques, as described below.

Synthetic cycle for the Boc protecting group technique
	1.	30% trifluoroacetic acid in DCM	1 × 3 min
	2.	50% trifluoroacetic acid in DCM	1 × 1 min
	3.	DCM washing	5 × 1 min
	4.	5% diisopropylethylamine in DCM	1 × 1 min
	5.	5% diisopropylethylamine in NMP	1 × 1 min
	6.	NMP washing	5 × 1 min
	7.	Addition of preactivated	1 × 30 min
		protected amino acid
		(activation with 1 equivalent of
		DCC and 1 equivalent of HOBt in
		NMP/DCM);
		Peptide coupling (1st part)
	8.	Addition of DMSO to the reaction
		mixture until it contains 20% DMSO
		by volume
	9.	Peptide coupling (2nd part)	1 × 16 min
	10.	Addition of 3.8 equivalents of
		diisopropylethylamine to the reaction
		mixture
	11.	Peptide coupling (3rd part)	1 × 7 min
	12.	DCM washing	3 × 1 min
	13.	if conversion is incomplete,
		repetition of coupling (back to step 5)
	14.	10% acetic anhydride,
		5% diisopropylethylamine in DCM	1 × 2 min
	15.	10% acetic anhydride in DCM	1 × 4 min
	16.	DCM washing	4 × 1 min
	17.	back to step 1.

[0138] BOP-Cl and PyBrop were used as reagents for coupling an amino acid to an N-methylamino acid. The reaction times were correspondingly increased. In solution synthesis, the use of either Boc-protected amino acid NCAs (N-tert-butyloxycarbonyl-amino acid-N-carboxy-anhydrides) or Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) respectively is most preferable for this type of coupling.

Synthetic cycle for the Fmoc protective group technique
	1.	DMF washing	1 × 1 min
	2.	20% piperidine in DMF	1 × 4 min
	3.	20% piperidine in DMF	1 × 16 min
	4.	DMF washing	5 × 1 min
	5.	Addition of the preactivated	1 × 61 min
		protected amino acid (activation
		by 1 equivalent of TBTU and
		1.5 equivalent of DIPEA in DMF);
		Peptide coupling
	6.	DMF washing	3 × 1 min
	7.	If conversion is incomplete,
		repetition of coupling (back to 5.)
	8.	10% acetic anhydride in DMF	1 × 8 min
	9.	DMF washing	3 × 1 min
	10.	back to 2.

[0139] BOP-Cl and PyBrop were used as reagents for coupling an amino acid to an N-methylamino acid. The reaction times were correspondingly increased.

[0140] Reductive Alkylation of the N Terminus

[0141] The peptide-resin prepared as described above was deprotected at the N terminus and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH3. After reaction was complete (negative Kaiser test), the resin was washed several times with water, isopropanol, DMF and dichloromethane.

[0142] Workup of the Peptide-Resins

[0143] The peptide-resin obtained via the Boc protecting group technique was dried under reduced pressure and transferred into a reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA). A scavenger, usually anisole (1 mL/g of resin), was then added and additionally, in the case of tryptophan-containing peptides, a thiol (0.5 mL/g of resin), preferably ethanedithiol, to remove the indolic formyl group. This was followed by condensing in hydrogen fluoride (10 mL/g of resin) in a bath of liquid N2. The mixture was allowed to warm to 0° C. and stirred at this temperature for 45 min. The hydrogen fluoride was then stripped off under reduced pressure, and the residue was washed with ethyl acetate to remove any remaining scavenger. The peptide was extracted with 30% acetic acid and filtered, and the filtrate was lyophilized.

[0144] The peptide-resin formed by the Fmoc protecting group method was dried under reduced pressure and then subjected to one of the following cleavage procedures, depending upon the amino-acid composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985). The suspension of the peptide-resin in the suitable TFA mixture was stirred at room temperature for the stated time and then the resin was filtered off and washed with TFA and DCM. The filtrate and the washings were concentrated, and the peptide was precipitated by addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered off, taken up in 30% acetic acid and lyophilized.

[0145] When an o-chlorotrityl-resin (supplied by Biohellas) was used, the suspension of the peptide-resin in an acetic acid/trifluoroethanol/dichloromethane mixture (1:1:3) was stirred at room temperature for 1 h. The suspension was then filtered with suction and the peptide-resin was thoroughly washed with the cleavage solution. The combined filtrates were concentrated in vacuo and treated with water. The precipitated solid was removed by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure.

[0146] Purification and Characterization of the Peptides

[0147] Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) with or without subsequent medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 m, 100 Å; mobile phase: gradient with A=0.1% TFA/MeOH, B=0.1% TFA/H2O). The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 l, 300 Å; mobile phase: CH3CN/H2O gradient, buffered with 0.1% TFA, 40%C).

[0148] The polypeptides were characterized by amino-acid analysis and fast atom bombardment mass spectroscopy.

EXAMPLE 1

Synthesis of (2)-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CON(CH3)2 (Compound I-78)

[0149] Me2Val-Val-MeVal-Pro-OH and Z-Val-Val-MeVal-Pro-OH were prepared by the method disclosed in patent applications DE 4415998 and DE 19527575, the contents of which are incorporated herein by reference.

[0150] a) Synthesis of N,N-dimethyl-2-nitrobenzamide 34

[0151] To a solution of 2.0 g 2-nitrobenzoic acid and 0.98 g dimethylammonium chloride in dichloromethane at 0° C. were added 2.29 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.62 g N-hydroxy-benzotriazol and 6.05 g N-methyl-morpholine. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then washed sequentially with saturated sodium hydrogen carbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filteration the solvent was removed in vacuo yielding N,N-dimethyl-2-nitrobenzamide (2.13 g).

[0152] 1 H-NMR (DMSO, 270 MHz) d=2.7 (s, 3H), 3.0 (s, 3H), 7.5 (d, 1H), 7.7 (dd, 1H), 7.85 (dd, 1H), 8.15 (d, 1H) ppm

[0153] b) Synthesis of N,N-dimethyl-2-aminobenzamide 35

[0154] Palladium on charcoal (0.54 g, 10% Pd by weight) was added to a solution of 2.1 g N,N-dimethyl-2-nitrobenzamide in 150 mL methanol. The resulting suspension was hydrogenated at room temperature at atmospheric pressure for three hours. After filtration of the catalyst, the solvent was removed in vacuo affording N,N-dimethyl-2-aminobenzamide (1.8 g).

[0155] 1 H-NMR (DMSO, 270 MHz) d=2.9 (s, 6H), 5.1 (s, 2H), 6.5 (dd, 1H), 6.65 (d, 1H), 7.95 (d, 1H), 7.0 (dd, 1H) ppm

[0156] c) Synthesis of (2)-(Z-Val-Val-MeVal-Pro-NH)—C6H4—CON(CH3)2 36

[0157] To a solution of 2.0 g Z-Val-Val-MeVal-Pro-OH and 0.53 g N,N-dimethyl-2-amino-benzamide in dichloromethane was added 1.66 g bromo-tris-pyrrolidinophosphonium hexafluoro-phosphate (PyBrop) and 0.77 g N-ethyldiisopropylamine at 0° C. The mixture was stirred at room temperature overnight, and then washed sequentially with saturated sodium hydrogen carbonate, a 5% aqueous solution of citric acid, and brine. The organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (1:3 dichloromethane:ethyl acetate) to provide (2)-(Z-Val-Val-MeVal-Pro-NH)—C6H4—CON(CH3)2 (1.8 g).

[0158] FAB-MS 707.0 (M+H+d)

[0159] d) Synthesis of 2-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CON(CH3)2 37

[0160] Palladium on charcoal (58 mg, 10% Pd by weight) was added to a solution of 1.8 g 2-(Z-Val-Val-MeVal-Pro-NH)—C 6H4—CON(CH3)2 in 150 mL methanol. The resulting suspension was hydrogenated at room temperature at atmospheric pressure for three hours, then 1.5 mL of an aqueous formaldehyde solution (37% formaldehyde by weight) and 341 mg of palladium on charcoal were added. The mixture was hydrogenated at room temperature at atmospheric pressure overnight. After filtration over celite the solvent was removed in vacuo to give 1.30 g 2-(Me2Val-Val-MeVal-Pro-NH)—C 6H4—CON(CH3)2.

[0161] FAB-MS: 601.0 (M+H+)

[0162] 1 H-NMR (DMSO, 270 MHz) d=0.7 (s, 6H), 0.8-1.0 (m, 12H), 1.75 (m, 1H), 1.8- 2.2 (m, 6H), 2.2 (s, 6H), 2.6 (d, 1H), 2.8 (s, 3H), 2.9 (s, 3H), 3.05 (s, 3H), 3.55, 3.7 (m, 2H), 4.4 (m, 1H), 4.5 (m, 1H), 5.0 (d, 1H), 7.2 (dd, 1H), 7.25 (d, 1H), 7.4, dd, 1H), 7.6 (dd, 1H), 8.0 (d, 1H), 9.6 (s, 1H)

EXAMPLE 2

Synthesis of (2)-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CON(CH3)(OCH3) (Compound I-60)

[0163] a) Synthesis of N,O-dimethyl-(2-N-tert.butoxycarbonyl-amino)benzohydroxylamide 38

[0164] To a solution of 1.5 g 2-N-t-butoxy-carbonyl anthranilic acid and 0.68 g N,O-dimethylhydroxylamine hydrochloride in dichloromethane at 0° C., 1.33 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.94 g N-hydroxybenzotriazol and 3.20 g N-methylmorpholine were added. The mixture was stirred at room temperature overnight. The reaction mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filtration the solvent was removed in vacuo. Flash chromatography (silica gel, heptane:ethyl acetate 10:1) afforded N,O-dimethyl-(2-N-tert.Butoxycarbonyl-amino)benzohydroxylamide (1.18 g).

[0165] 1 H-NMR (CDCl3, 270 MHz) d=1.5 (s, 9H), 3.4 (s, 3H), 3.6 (s, 3H), 7.0 (dd, 1H), 7.2-7.4 (m, 2H), 8.1 (d, 1H), 8.4 (s, 1H)

[0166] b) Synthesis of N,O-dimethyl-(2-amino)benzohydroxylamide hydrochloride. 39

[0167] To a solution of 0.5 g N,O-dimethyl-(2-N-tert.butoxycarbonyl-amino)benzohydroxylamide in 15 mL dichloromethane at 0° C. was added 17 mL of a hydrogen chloride solution in ether and the resulting solution was stirred for 2 hours. The solvent was evaporated to give 0.41 g N,O-dimethyl-(2-amino)benzohydroxylamide hydrochloride.

[0168] 1 H-NMR (CDCl3, 270 MHz) d=3.4 (s, 3H), 3.6 (s, 3H), 7.3 (dd, 1H) , 7.5 (dd, 2H) , 7.6 (d, 1H), 7.9 (d, 1H)

[0169] c) Synthesis of (2)-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CON(CH3)(OCH3) 40

[0170] To a solution of 0.892 g Me2Val-Val-MeVal-Pro-OH and 0.234 g triethylamine in 10 mL dichloromethane at 0° C. was added 0.218 g formate. After stirring the resulting mixture for two hours, 0.41 g N,O-dimethyl-(2-amino)benzohydroxylamide hydrochloride and 0.234 g triethylamine were added and the mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with saturated sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate. After filtration the solvent was removed in vacuo. The residue was purified by chromatography (silica gel treated with 1% triethylamine, solvent: dichloromethane/3% isopropanol) to provide 0.28 g (2)-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CON(CH3)(OCH3).

[0171] FAB-MS: 617.5 (M+H+)

[0172] 1 H-NMR (DMSO, 270 MHz) d=0.7 (s, 6H), 0.8-1.0 (m, 12H), 1.7 (m, 1H), 1.8-2.2 (m, 6H), 2.2 (s, 6H), 2.6 (d, 1H), 3.0 (s, 3H), 3.2 (s, 3H), 3.5 (s, 3H), 3.5, 3.7 (m, 2H), 4.4 (m, 1H), 4.5 (m, 1H) , 5.0 (d, 1H), 7.2 (dd, 1H), 7.3-7.5 (m, 2H), 7.6 (dd, 1H), 8.0 (d, 1H), 9.65 (s, 1H)

EXAMPLE 3

Synthesis of Me2-Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic acid]-NHBn (Compound VII-2)

[0173] d) Synthesis of Racemic Cyclopentane-cis-1,2-dicarboxylic Acid Anhydride 41

[0174] 8.4 g (44.3 mmol) of commercially available cyclopentane-trans-1,2-dicarboxylic acid was refluxed for 20 h in 75 ml of acetic acid anhydride, then evaporated and the obtained residue distilled in a “Kugelrohr-apparatus” at 1.0 mbar. The fraction boiling at 165° was collected, yielding 5.8 g of the product as an oil.

[0175] 13 C-NMR (400 MHz; DMSO-d6) d (ppm): 25.3 (C-4), 30.6 (C-3,5), 45.7 (C-1,2), 175.6 (C-6,7).

[0176] b) Synthesis of Racemic Cis-2-carbamoylcyclopentanecarboxylic Acid 42

[0177] 1.1 g (7.85 mmol) of cyclopentane-cis-1,2-dicarboxylic acid anhydride were added to 8 ml of an aqueous NH3-solution and stirred until dissolution of the educt. The excess of ammonia was then evaporated, the remaining solution cooled to 0° C. and acidified with conc. HCl. The resulting precipitate was filtered off, washed with cold water and dried, yielding 0.7 g of cis-2-carbamoylcyclopentanecarboxylic acid with a melting point of 132-133° C. (lit.: 126-128° C.).

[0178] c) Synthesis of Racemic Cis-2-aminocyclopentanecarboxylic Acid 43

[0179] Under stirring at 0° C. 0.41 g (2.6 mmol) of Br2 were added to an aqueous solution (1.8 mL) of 0.48 g (12 mmol) NaOH. The mixture was cooled again and then 0.34 g (2.16 mmol) of cis-2-carbamoylcyclopentanecarboxylic acid added. After stirring for about 10 minutes again 0.35 g (8.65 mmol) NaOH—dissolved in 1.35 ml of water—were added, and then the whole mixture warmed to 75° C. for about 5 minutes. The mixture then was cooled again, neutralized by addition of conc. HCl, acidified with acetic acid and evaporated to dryness. The residue obtained was extracted five times with refluxing ethanol, and the combined ethanol-fractions evaporated again yielding 1.1 g of a white solid.

[0180] Purification was achieved by filtration of this residue over a column with Dowex 50 ion exchange resin. Therefore the column was washed with a solution of the solid in water, and then the product eluted by treatment with solid was dissolved in water and the column, absorbed on by washing the column with aqueous diluted NH3. After evaporation of the water the remaining crude product was recristallized from acetone yielding 0.14 g of pure cis-2-aminocyclopentanecarboxylic acid with a melting point of 200-202° C.

[0181] d) Synthesis of Racemic Cis-2-t-butyloxycarbonylaminocyclopentanecarboxylic Acid Benzylamide 44

[0182] To a solution of 1.5 g (11.6 mmol) of cis-2-aminocyclopentanecarboxylic acid in a mixture of acetonitrile/water 3:1 were added 3.3 g (15.1 mmol) of ditbutyldicarbonate, 0.5 g (12.2 mmol) of NaOH dissolved in 12 ml of H2O and 0.1 g (0.82 mmol) of DMAP. The mixture was stirred at ambient temperature for about 3 days, then diluted with water, extracted with ethylacetate. The combined organic phases were washed with a saturated aqueous NaCl-solution, dried over MgSO4 and evaporated to dryness leaving 1.3 g of the Boc-protected compound as an oil. A solution of the crude product and 0.65 g (6.1 mmol) benzylamine in a mixture of THF/DMF 10:1 was cooled to −10° C., then were added subsequently 0.9 g (5.86 mmol) of HOBT, 1.12 g (5.86 mmol) of EDC×HCl and 3 ml of NMM. The mixture was stirred for 2 h at −10° C., for 3 h at 0° C. and was then allowed to warm up to room temperature. After evaporation to dryness the remaining residue was dissolved in ethylacetate, washed with aqueous solutions of 5% citric acid, NaHCO3 and NaCl and dried over MgSO4. Evaporation yielded 1.3 g of cis-2-t-butyloxycarbonylaminocyclo-pentanecarboxylic acid benzylamide as an oil.

[0183] HPLC (gradient 2): Rt 10.5 min.

[0184] (Column: Machery & Nagel Nucleosil C18 PPN, 100×2.1, 5 m/100 A, acetonitrile/H2O+0.1% TFA; flow: 0.2 ml/min; temp. 40° C.).

[0185] 1 H-NMR (270 MHz; DMSO-d6) d (ppm): 1.35 (s, 9H), 1.35-1.95 (m, 6H), 2.82 (m, 1H), 4.03 (m, 1H), 4.25 (m, 2H), 6.35 (d, NH), 7.1-7.35 (m, 5H), 8.3 (m, 1H).

[0186] e) Synthesis of Racemic Cis-2-aminocyclopentanecarboxylic Acid Benzylamide Hydrochloride 45

[0187] To a solution of 0.7 g (2.2 mmol) of of cis-2-tert.butyloxycarbonylaminocyclo-pentanecarboxylic acid benzylamide in 30 ml CH2Cl2 were added 25 ml of saturated HCl in diethylether; the mixture was then stirred for 2 h at ambient temperature. Evaporation to dryness and coevaporation with toluene yielded 0.6 g of the deprotected amine as hydrochloride salt.

[0188] f) Synthesis of Me2-Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic Acid]-NHBn (Compound VII-2) 46

[0189] To a solution of 0.86 g (1.9 mmol) of the tetrapeptide Me2Val-Val-MeVal-Pro-OH and 0.56 g (2.2 mmol) aminocyclo-pentanecarboxylic acid benzylamide hydrochloride in 30 ml of THF/DMF 5:1 were added subsequently at −10° C. 0.29 g (1.9 mmol) of HOBT; 0.37 g (1.9 mmol) of EDC×HCl and 1.2 ml of NMM. The mixture was stirred for another at −10° C., then for 1-2 h at 0° C. and then allowed to warm up to ambient temperature. After evaporation the remaining residue was diluted with ethyl acetate, washed with an aqueous solution of NaCl, dried over MgSO4 and evaporated again. The remaining crude product (1.2 g) was purified by flash cromatography on silica gel (CH2Cl2/CH3OH) yielding 0.37 g of Me2Val-Val-MeVal-Pro-[cis-2-aminocyclopentanecarboxylic acid]-NHBn.

[0190] FAB-MS: 655 (M+H+).

[0191] The following compounds can be prepared as outlined in Schemes I-III and according to the above examples.

[0192] Table 1:

[0193] A is Me2Val, B is Val, D is MeVal, E is Pro, F is of Formula IIF and the group —C(═O)-G is in position 2 relative to the nitrogen atom. G is of Formula IIg or, IIIg or IVg.

No.	RF	R1F	R2F	—C(═O)—G
I-1	H	H	H	—NH—CH3
I-2	H	H	H	—NH—CH2—C6H5
I-3	H	H	H	—NH-isoC3H5
I-4	H	H	H	—NH—C6H5
I-5	H	H	H	1,3-Thiazol-2-yl-amide
I-6	H	4-OCH3	5-OCH3	—NH—CH3
I-7	H	3-cycloC5H9	H	—NH—CH3
I-8	H	H	H	—NH—C2H5
I-9	H	H	H	—NH-nC3H7
I-10	H	H	H	—NH-nC4H9
I-11	H	H	H	—NH-tertC4H9
I-12	H	H	H	—NH-cycloC3H5
I-13	H	H	H	—NH-cycloC4H7
I-14	H	H	H	—NH-cycloC5H9
I-15	H	H	H	—NH-cycloC6H11
I-16	H	H	H	—NH-cycloC7H12
I-17	H	H	H	—NH—CH3—O—CH3
I-18	H	H	H	—NH—CH2—CH2—O—CH3
I-19	H	H	H	—NH-1-adamantyl
I-20	H	H	H	—NH-(4-HO-C6H5)
I-21	H	H	H	—NH-(2-CF3—C6H4)
I-22	H	H	H	—NH-(3-CF3—C6H4)
I-23	H	H	H	—NH-(4-CF3—C6H4)
I-24	H	H	H	—NH-(2-OCH3—C6H4)
I-25	H	H	H	—NH-(3-OCH3—C6H4)
I-26	H	H	H	—NH-(4-OCH3—C6H4)
I-27	H	H	H	—NH-(2-SCH3—C6H4)
I-28	H	H	H	—NH-(3-SCH3—C6H4)
I-29	H	H	H	—NH-(4-SCH3—C6H4)
I-30	H	H	H	—NH-(2-N(CH3)2—C6H4)
I-31	H	H	H	—NH-(3-N(CH3)2—C6H4)
I-32	H	H	H	—NH-(4-N(CH3)2—C6H4)
I-33	H	H	H	—NH-(4-CN-C6H4)
I-34	H	H	H	—NH-(4-Cl-C6H4)
I-35	H	H	H	—NH-(4-Br-C6H4]
I-36	H	H	H	—NH-(4-F-C6H4]
I-37	H	H	H	—NH-(4-CH3—C6H4)
I-33	H	H	H	—NH-(2-NO2—C6H4)
I-39	H	H	H	—NH-(3-NO2—C6H4)
I-40	H	H	H	—NH-(4-NO2—C6H4)
I-41	H	H	H	—NH-(2,4-OCH3—C6H3)
I-42	H	H	H	—NH-(3,4-OCH3—C6H3)
I-43	H	H	H	—NH-(3,4,5-OCH3—C6H2)
I-44	H	H	H	—NH-(3,4-CH2OCH2—C6H3)
I-45	H	H	H	—NH-(2,3-CH2OCH2—C6H3)
I-46	H	H	H	—NH-2-pyridinyl
I-47	H	H	H	—NH-2-furanyl
I-48	H	H	H	—NH-2-thienyl
I-49	H	H	H	—NH-3-pyridinyl
I-50	H	H	H	—NH-3-furanyl
I-51	H	H	H	—NH-3-thienyl
I-52	H	H	H	—NH-4-pyridinyl
I-53	H	H	H	—NH-2-oxazolyl
I-54	H	H	H	—NH-3-isoxazolyl
I-55	H	H	H	—NH-4-isoxazolyl
I-56	H	H	H	—NH-5-isoxazloyl
I-57	H	H	H	—NH-2R-(but-2-yl)
I-58	H	H	H	—NH-2S-(but-2-yl)
I-59	H	H	H	—NH—O—CH3
I-60	H	H	H	—N(CH3) (OCH3)
I-61	H	H	H	—N(—(CH2)3—O—)
I-62	H	H	H	—NH—O—CH2—C6H5
I-63	H	H	H	—N(CH3)(O—CH2—C6H5)
I-64	H	H	H	—N(—(CH2)2—CH(C6H5)—O—)
I-65	H	H	H	—NH—O—C2H5
I-66	H	H	H	—N(C2H5)(OC2H5)
I-67	H	H	H	—N(CH2)(OC2H5)
I-58	H	H	H	—NH—O-isoC3H7
I-69	H	H	H	—N(CH3)(O-isoC3H7)
I-70	H	H	H	—NH—O—nC3H7
I-71	H	H	H	—N(CH3)(O—nC3H7)
I-72	H	H	H	—NH—O—nC4H9
I-73	H	H	H	—N(CH2)(O—nC4H9)
I-74	H	H	H	—NH-O-tertC4H9
I-75	H	H	H	—N(CH3)(O-tertC4H9)
I-76	H	H	H	—NH—O—C6H5
I-77	H	H	H	—N(CH3)(O—C6H5)
I-78	H	H	H	—N(CH3)2
I-79	H	H	H	—N(CH2—C6H5)2
I-80	H	H	H	—N(C2H5)2
I-81	H	H	H	—N(isoC3H7)2
I-82	H	H	H	—N(nC3H7)2
I-83	H	H	H	—N(nC4H9)2
I-84	H	H	H	—N(C6H5)2
I-85	H	H	H	—NH—CH2—CH2—OH
I-86	H	H	H	—NH—(CH2)3—OH
I-87	H	H	H	—NH(—(CH2)2CH(C6H5)OH)
I-88	H	H	H	—NH—(CH2)4—OH
I-89	H	H	H	—NH(—CH(CH3)—CH2—OH)
I-90	H	H	H	—NH(—CH2—CH(CH3)—OH)
I-91	H	H	H	—NH(CH(CH3)(CH2)2OH)
I-92	H	H	H	—NH(—(CH2)2CH(CH3)OH)
I-93	H	4-CH3	H	—NH—CH3
I-94	H	4-CH3	H	—NH—CH2—C6H5
I-95	H	4-CH3	H	—NH—isoC3H7
I-96	H	4-CH3	H	—NH—C6H5
I-97	H	4-CH3	H	—NH—C2H5
I-98	H	4-CH3	H	—NH-nC3H7
I-99	H	4-CH3	H	—NH—nC4H9
I-100	H	4-CH3	H	—NH-tertC4H9
I-101	H	4-CH3	H	—NH-cycloC3H5
I-102	H	4-CH3	H	—NH- cycloC4H7
I-103	H	4-CH3	H	—NH-cycloC5H9
I-104	H	4-CH3	H	—NH-cycloC6H11
I-105	H	4-CH3	H	—NH-1-adamantyl
I-106	H	4-CH3	H	—NH-2R-(but-2-yl)
I-107	H	4-CH3	H	—NH-2S-(but-2-yl)
I-108	H	4-CH3	H	—NH—O—CH3
I-109	H	4-CH3	H	—N(CH3)(OCH3)
I-110	H	4-CH3	H	—N(—(CH3—O—)
I-111	H	4-CH3	H	—N(CH3)2
I-112	H	4-CH3	H	—N(CH2—C6H5)2
I-113	H	4-CH3	H	—N(C2H5)2
I-114	H	4-CH3	H	—N(isoC3H7)2
I-115	H	4-CH3	H	—N(nC3H7)2
I-116	H	4-CH3	H	—N(nC4H9)2
I-117	H	4-CH3	H	—N(C6H5)2
I-118	H	5-CH3	H	—NH—CH3
I-119	H	5-CH3	H	—NH—CH2—C6H5
I-120	H	5-CH3	H	—NH-isoC3H7
I-121	H	5-CH3	H	—NH-C6H5
I-122	H	5-CH3	H	—NH-C2H5
I-123	H	5-CH3	H	—NH-nC3H7
I-124	H	5-CH3	H	—NH-nC4H9
I-125	H	5-CH3	H	—NH-tertC4H9
I-126	H	5-CH3	H	—NH-cycloC3H5
I-127	H	5-CH3	H	—NH-cycloC4H7
I-128	H	5-CH3	H	—NH-cycloC5H9
I-129	H	5-CH3	H	—NH-cycloC6H11
I-130	H	5-CH3	H	—NH-1-adamantyl
I-131	H	5-CH3	H	—NH-2R-(but-2-yl)
I-132	H	5-CH3	H	—NH-2S-(but-2-yl)
I-133	H	5-CH3	H	—NH—O—CH3
I-134	H	5-CH3	H	—N(CH3)(OCH3)
I-135	H	5-CH3	H	—N(—(CH3)3—O—)
I-136	H	5-CH3	H	—N(CH3)2
I-137	H	5-CH3	H	—N(CH2—C6H5)2
I-138	H	5-CH3	H	—N(C2H5)2
I-139	H	5-CH3	H	—N(isoC3H7)2
I-140	H	5-CH3	H	—N(nC3H7)2
I-141	H	5-CH3	H	—N(nC4H9)2
I-142	H	5-CH3	H	—N(C6H5)2
I-143	CH3	H	H	—NH—CH3
I-144	CH3	H	H	—NH—CH2—C6H5
I-145	CH3	H	H	—NH—isoC3H7
I-146	CH3	H	H	—NH-C6H5
I-147	CH3	H	H	—NH-C2H5
I-148	CH3	H	H	—NH-nC3H7
I-149	CH3	H	H	—NH-nC4H9
I-150	CH3	H	H	—NH-tertC4H9
I-151	CH3	H	H	—NH-cycloC3H5
I-152	CH3	H	H	—NH-cycloC4H7
I-153	CH3	H	H	—NH-cycloC5H9
I-154	CH3	H	H	—NH-cycloC6H11
I-155	CH3	H	H	—NH-1-adamantyl
I-156	CH3	H	H	—NH-2R-(but-2-yl)
I-157	CH3	H	H	—NH-2S-(but-2-yl)
I-158	CH3	H	H	—NH—O—CH3
I-159	CH3	H	H	—N(CH3)(OCH3)
I-160	CH3	H	H	—N(—(CH2)3—O—)
I-161	CH3	H	H	—N(CH3)2
I-162	CH3	H	H	—N(CH2—C6H5)3
I-163	CH3	H	H	—N(C2H5)2
I-164	CH3	H	H	—N(isoC3H7)2
I-165	CH3	H	H	—N(nC3H7)2
I-155	CH3	H	H	—N(nC4H9)2
I-167	CH3	H	H	—N(C6H5)2
I-168	H	4-OCH3	H	—NH—CH3
I-159	H	4-OCH3	H	—NH—CH2—C6H5
I-170	H	4-OCH3	H	—NH-isoC3H7
I-171	H	4-OCH3	H	—NH-C6H5
I-172	H	4-OCH3	H	—NH-C2H5
I-173	H	4-OCH3	H	—NH-nC4H7
I-174	H	4-OCH3	H	—NH-nC5H9
I-175	H	4-OCH3	H	—NH-tertC4H9
I-176	H	4-OCH3	H	—NH-cycloC3H5
I-177	H	4-OCH3	H	—NH-cycloC4H7
I-178	H	4-OCH3	H	—NH-cycloC5H9
I-179	H	4-OCH3	H	—NH-cycloC6H11
I-180	H	4-OCH3	H	—NH-1-adamantyl
I-181	H	4-OCH3	H	—NH-2R-(but-2-yl)
I-182	H	4-OCH3	H	—NH-2S-(but-2-yl)
I-183	H	4-OCH3	H	—NH—O—CH3
I-184	H	4-OCH3	H	—N(CH3)(OCH3)
I-185	H	4-OCH3	H	—N(—(CH2)3—O—)
I-186	H	4-OCH3	H	—N(CH3)2
I-187	H	4-OCH3	H	—N(CH2—C6H5)2
I-188	H	4-OCH3	H	—N(C2H5)2
I-189	H	4-OCH3	H	—N(isoC3H7)2
I-190	H	4-OCH3	H	—N(nC3H7)2
I-191	H	4-OCH3	H	—N(nC4H9)2
I-192	H	4-CH3	H	—N(C6H5)2
I-193	H	5-OCH3	H	—NH—CH3
I-194	H	5-OCH3	H	—NH—CH2—C6H5
I-195	H	5-OCH3	H	—NH-isoC3H7
I-196	H	5-OCH3	H	—NH—C6H5
I-197	H	5-OCH3	H	—NH—C2H5
I-198	H	5-OCH3	H	—NH-nC3H7
I-199	H	5-OCH3	H	—NH-nC4H9
I-200	H	5-OCH3	H	—NH-tertC4H9
I-201	H	5-OCH3	H	—NH-cycloC3H5
I-202	H	5-OCH3	H	—NH-cycloC4H7
I-203	H	5-OCH3	H	—NH-cycloC5H9
I-204	H	5-OCH3	H	—NH-cycloC6H11
I-205	H	5-OCH3	H	—NH-1-adamantyl
I-206	H	5-OCH3	H	—NH-2R-(but-2-y1)
I-207	H	5-OCH3	H	—NH-2S-(but-2-yl)
I-208	H	5-OCH3	H	—NH—O—CH3
I-209	H	5-OCH3	H	—N(CH3)(OCH3)
I-210	H	5-OCH3	H	—N(—(CH2)3—O—)
I-211	H	5-OCH3	H	—N(CH3)2
I-212	H	5-OCH3	H	—N(CH2—C6H5)2
I-213	H	5-OCH3	H	—N(C2H5)2
I-214	H	5-OCH3	H	—N(isoC3H7)2
I-215	H	5-OCH3	H	—N(nC4H9)2
I-216	H	5-OCH3	H	—N(nC4H9)2
I-217	H	5-OCH3	H	—N(C6H5)2

[0194] Table 2:

[0195] A is Me2Val, B is Val, D is MeVal, E is Pro and F is of Formula IIf, the group —C(O)-G is in position 3 relative to the nitrogen atom and G is of Formula IIg, IIIg or IVg.

No.	RF	R1F	R2F	—G
II-1	H	H	H	—NH—CH3
II-2	H	H	H	—NH—CH2—C6H5
II-3	H	H	H	—NH-isoC3H5
II-4	H	H	H	—NH—C6H5
II-5	H	H	H	1,3-Thiazol-2-yl-amide
II-6	H	4-OCH3	5-OCH3	—NH—CH3
II-7	H	3-cycloC5H9	H	—NH—CH3
II-8	H	H	H	—NH—C2H5
II-9	H	H	H	—NH-nC3H7
II-10	H	H	H	—NH-nC4H9
II-11	H	H	H	—NH-tertC4H9
II-12	H	H	H	—NH-cycloC3H5
II-13	H	H	H	—NH-cycloC4H7
II-14	H	H	H	—NH-cycloC5H9
II-15	H	H	H	—NH-cycloC6H11
II-16	H	H	H	—NH-cycloC7H12
II-17	H	H	H	—NH—CH3—O—CH3
II-18	H	H	H	—NH—CH2—CH2—O—CH3
II-19	H	H	H	—NH-1-adamantyl
II-20	H	H	H	—NH-(4-HO-C6H5)
II-21	H	H	H	—NH-(2-CF3—C6H4)
II-22	H	H	H	—NH-(3-CF3—C6H4)
II-23	H	H	H	—NH-(4-CF3—C6H4)
II-24	H	H	H	—NH-(2-OCH3—C6H4)
II-25	H	H	H	—NH-(3-OCH3—C6H4)
II-26	H	H	H	—NH-(4-OCH3—C6H4)
II-27	H	H	H	—NH-(2-SCH3—C6H4)
II-28	H	H	H	—NH-(3-SCH3—C6H4)
II-29	H	H	H	—NH-(4-SCH3—C6H4)
II-30	H	H	H	—NH-(2-N(CH3)2—C6H4)
II-31	H	H	H	—NH-(3-N(CH3)2—C6H4)
II-32	H	H	H	—NH-(4-N(CH3)2—C6H4)
II-33	H	H	H	—NH-(4-CN-C6H4)
II-34	H	H	H	—NH-(4-Cl-C6H4)
II-35	H	H	H	—NH-(4-Br-C6H4]
II-36	H	H	H	—NH-(4-F-C6H4]
II-37	H	H	H	—NH-(4-CH3—C6H4)
II-33	H	H	H	—NH-(2-NO2—C6H4)
II-39	H	H	H	—NH-(3-NO2—C6H4)
II-40	H	H	H	—NH-(4-NO2—C6H4)
II-41	H	H	H	—NH-(2,4-OCH3—C6H3)
II-42	H	H	H	—NH-(3,4-OCH3—C6H3)
II-43	H	H	H	—NH-(3,4,5-OCH3—C6H2)
II-44	H	H	H	—NH-(3,4-CH2OCH2—C6H3)
II-45	H	H	H	—NH-(2,3-CH2OCH2—C6H3)
II-46	H	H	H	—NH-2-pyridinyl
II-47	H	H	H	—NH-2-furanyl
II-48	H	H	H	—NH-2-thienyl
II-49	H	H	H	—NH-3-pyridinyl
II-50	H	H	H	—NH-3-furanyl
II-51	H	H	H	—NH-3-thienyl
II-52	H	H	H	—NH-4-pyridinyl
II-53	H	H	H	—NH-2-oxazolyl
II-54	H	H	H	—NH-3-isoxazolyl
II-55	H	H	H	—NH-4-isoxazolyl
II-56	H	H	H	—NH-5-isoxazloyl
II-57	H	H	H	—NH-2R-(but-2-yl)
II-58	H	H	H	—NH-2S-(but-2-yl)
II-59	H	H	H	—NH—O—CH3
II-60	H	H	H	—N(CH3) (OCH3)
II-61	H	H	H	—N(—(CH2)3—O—)
II-62	H	H	H	—NH—O—CH2—C6H5
II-63	H	H	H	—N(CH3)(O—CH2—C6H5)
II-64	H	H	H	—N(—(CH2)2—CH(C6H5)—O—)
II-65	H	H	H	—NH—O—C2H5
II-66	H	H	H	—N(C2H5)(OC2H5)
II-67	H	H	H	—N(CH2)(OC2H5)
II-68	H	H	H	—NH—O-isoC3H7
II-69	H	H	H	—N(CH3)(O-isoC3H7)
II-70	H	H	H	—NH—O—nC3H7
II-71	H	H	H	—N(CH3)(O—nC3H7)
II-72	H	H	H	—NH—O—nC4H9
II-73	H	H	H	—N(CH2)(O—nC4H9)
II-74	H	H	H	—NH-O-tertC4H9
II-75	H	H	H	—N(CH3)(O-tertC4H9)
II-76	H	H	H	—NH—O—C6H5
II-77	H	H	H	—N(CH3)(O—C6H5)
II-78	H	H	H	—N(CH3)2
II-79	H	H	H	—N(CH2—C6H5)2
II-80	H	H	H	—N(C2H5)2
II-81	H	H	H	—N(isoC3H7)2
II-82	H	H	H	—N(nC3H7)2
II-83	H	H	H	—N(nC4H9)2
II-84	H	H	H	—N(C6H5)2
II-85	H	H	H	—NH—CH2—CH2—OH
II-86	H	H	H	—NH—(CH2)3—OH
II-87	H	H	H	—NH(—(CH2)2CH(C6H5)OH)
II-88	H	H	H	—NH—(CH2)4—OH
II-89	H	H	H	—NH(—CH(CH3)—CH2—OH)
II-90	H	H	H	—NH(—CH2—CH(CH3)—OH)
II-91	H	H	H	—NH(CH(CH3)(CH2)2OH)
II-92	H	H	H	—NH(—(CH2)2CH(CH3)OH)
II-93	H	4-CH3	H	—NH—CH3
II-94	H	4-CH3	H	—NH—CH2—C6H5
II-95	H	4-CH3	H	—NH—isoC3H7
II-96	H	4-CH3	H	—NH—C6H5
II-97	H	4-CH3	H	—NH—C2H5
II-98	H	4-CH3	H	—NH-nC3H7
II-99	H	4-CH3	H	—NH—nC4H9
II-100	H	4-CH3	H	—NH-tertC4H9
II-101	H	4-CH3	H	—NH-cycloC3H5
II-102	H	4-CH3	H	—NH- cycloC4H7
II-103	H	4-CH3	H	—NH-cycloC5H9
II-104	H	4-CH3	H	—NH-cycloC6H11
II-105	H	4-CH3	H	—NH-1-adamantyl
II-106	H	4-CH3	H	—NH-2R-(but-2-yl)
II-107	H	4-CH3	H	—NH-2S-(but-2-yl)
II-108	H	4-CH3	H	—NH—O—CH3
II-109	H	4-CH3	H	—N(CH3)(OCH3)
II-110	H	4-CH3	H	—N(—(CH3—O—)
II-111	H	4-CH3	H	—N(CH3)2
II-112	H	4-CH3	H	—N(CH2—C6H5)2
II-113	H	4-CH3	H	—N(C2H5)2
II-114	H	4-CH3	H	—N(isoC3H7)2
II-115	H	4-CH3	H	—N(nC3H7)2
II-116	H	4-CH3	H	—N(nC4H9)2
II-117	H	4-CH3	H	—N(C6H5)2
II-118	H	5-CH3	H	—NH—CH3
II-119	H	5-CH3	H	—NH—CH2—C6H5
II-120	H	5-CH3	H	—NH-isoC3H7
II-121	H	5-CH3	H	—NH-C6H5
II-122	H	5-CH3	H	—NH-C2H5
II-123	H	5-CH3	H	—NH-nC3H7
II-124	H	5-CH3	H	—NH-nC4H9
II-125	H	5-CH3	H	—NH-tertC4H9
II-126	H	5-CH3	H	—NH-cycloC3H5
II-127	H	5-CH3	H	—NH-cycloC4H7
II-128	H	5-CH3	H	—NH-cycloC5H9
II-129	H	5-CH3	H	—NH-cycloC6H11
II-130	H	5-CH3	H	—NH-1-adamantyl
II-131	H	5-CH3	H	—NH-2R-(but-2-yl)
II-132	H	5-CH3	H	—NH-2S-(but-2-yl)
II-133	H	5-CH3	H	—NH—O—CH3
II-134	H	5-CH3	H	—N(CH3)(OCH3)
II-135	H	5-CH3	H	—N(—(CH3)3—O—)
II-136	H	5-CH3	H	—N(CH3)2
II-137	H	5-CH3	H	—N(CH2—C6H5)2
II-138	H	5-CH3	H	—N(C2H5)2
II-139	H	5-CH3	H	—N(isoC3H7)2
II-140	H	5-CH3	H	—N(nC3H7)2
II-141	H	5-CH3	H	—N(nC4H9)2
II-142	H	5-CH3	H	—N(C6H5)2
II-143	CH3	H	H	—NH—CH3
II-144	CH3	H	H	—NH—CH2—C6H5
II-145	CH3	H	H	—NH—isoC3H7
II-146	CH3	H	H	—NH-C6H5
II-147	CH3	H	H	—NH-C2H5
II-148	CH3	H	H	—NH-nC3H7
II-149	CH3	H	H	—NH-nC4H9
II-150	CH3	H	H	—NH-tertC4H9
II-151	CH3	H	H	—NH-cycloC3H5
II-152	CH3	H	H	—NH-cycloC4H7
II-153	CH3	H	H	—NH-cycloC5H9
II-154	CH3	H	H	—NH-cycloC6H11
II-155	CH3	H	H	—NH-1-adamantyl
II-156	CH3	H	H	—NH-2R-(but-2-yl)
II-157	CH3	H	H	—NH-2S-(but-2-yl)
II-158	CH3	H	H	—NH—O—CH3
II-159	CH3	H	H	—N(CH3)(OCH3)
II-160	CH3	H	H	—N(—(CH2)3—O—)
II-161	CH3	H	H	—N(CH3)2
II-162	CH3	H	H	—N(CH2—C6H5)3
II-163	CH3	H	H	—N(C2H5)2
II-164	CH3	H	H	—N(isoC3H7)2
II-165	CH3	H	H	—N(nC3H7)2
II-155	CH3	H	H	—N(nC4H9)2
II-167	CH3	H	H	—N(C6H5)2
II-168	H	4-OCH3	H	—NH—CH3
II-159	H	4-OCH3	H	—NH—CH2—C6H5
II-170	H	4-OCH3	H	—NH-isoC3H7
II-171	H	4-OCH3	H	—NH-C6H5
II-172	H	4-OCH3	H	—NH-C2H5
II-173	H	4-OCH3	H	—NH-nC4H7
II-174	H	4-OCH3	H	—NH-nC5H9
II-175	H	4-OCH3	H	—NH-tertC4H9
II-176	H	4-OCH3	H	—NH-cycloC3H5
II-177	H	4-OCH3	H	—NH-cycloC4H7
II-178	H	4-OCH3	H	—NH-cycloC5H9
II-179	H	4-OCH3	H	—NH-cycloC6H11
II-180	H	4-OCH3	H	—NH-1-adamantyl
II-181	H	4-OCH3	H	—NH-2R-(but-2-yl)
II-182	H	4-OCH3	H	—NH-2S-(but-2-yl)
II-183	H	4-OCH3	H	—NH—O—CH3
II-184	H	4-OCH3	H	—N(CH3)(OCH3)
II-185	H	4-OCH3	H	—N(—(CH2)3—O—)
II-186	H	4-OCH3	H	—N(CH3)2
II-187	H	4-OCH3	H	—N(CH2—C6H5)2
II-188	H	4-OCH3	H	—N(C2H5)2
II-189	H	4-OCH3	H	—N(isoC3H7)2
II-190	H	4-OCH3	H	—N(nC3H7)2
II-191	H	4-OCH3	H	—N(nC4H9)2
II-192	H	4-OCH3	H	—N(C6H5)2
II-193	H	5-OCH3	H	—NH—CH3
II-194	H	5-OCH3	H	—NH—CH2—C6H5
II-195	H	5-OCH3	H	—NH-isoC3H7
II-196	H	5-OCH3	H	—NH—C6H5
II-197	H	5-OCH3	H	—NH—C2H5
II-198	H	5-OCH3	H	—NH-nC3H7
II-199	H	5-OCH3	H	—NH-nC4H9
II-200	H	5-OCH3	H	—NH-tertC4H9
II-201	H	5-OCH3	H	—NH-cycloC3H5
II-202	H	5-OCH3	H	—NH-cycloC4H7
II-203	H	5-OCH3	H	—NH-cycloC5H9
II-204	H	5-OCH3	H	—NH-cycloC6H11
II-205	H	5-OCH3	H	—NH-1-adamantyl
II-206	H	5-OCH3	H	—NH-2R-(but-2-y1)
II-207	H	5-OCH3	H	—NH-2S-(but-2-yl)
II-208	H	5-OCH3	H	—NH—O—CH3
II-209	H	5-OCH3	H	—N(CH3)(OCH3)
II-210	H	5-OCH3	H	—N(—(CH2)3—O—)
II-211	H	5-OCH3	H	—N(CH3)2
II-212	H	5-OCH3	H	—N(CH2—C6H5)2
II-213	H	5-OCH3	H	—N(C2H5)2
II-214	H	5-OCH3	H	—N(isoC3H7)2
II-215	H	5-OCH3	H	—N(nC4H9)2
II-216	H	5-OCH3	H	—N(nC4H9)2
II-217	H	5-OCH3	H	—N(C6H5)2

[0196] Table 3:

[0197] A is Me2Val, B is Val, D is MeVal, E is Pro, F is of Formula IIf, the substituent —(C═O)-G is in position 4 relative to the nitrogen. G is of Formula IIg, IIIg or IVg.

No.	RF	R1F	R2F	—G
III-1	H	H	H	—NH—CH3
III-2	H	H	H	—NH—CH2—C6H5
III-3	H	H	H	—NH-isoC3H5
III-4	H	H	H	—NH—C6H5
III-5	H	H	H	1,3-Thiazol-2-yl-amide
III-6	H	4-OCH3	5-OCH3	—NH—CH3
III-7	H	3-cycloC5H9	H	—NH—CH3
III-8	H	H	H	—NH—C2H5
III-9	H	H	H	—NH-nC3H7
III-10	H	H	H	—NH-nC4H9
III-11	H	H	H	—NH-tertC4H9
III-12	H	H	H	—NH-cycloC3H5
III-13	H	H	H	—NH-cycloC4H7
III-14	H	H	H	—NH-cycloC5H9
III-15	H	H	H	—NH-cycloC6H11
III-16	H	H	H	—NH-cycloC7H12
III-17	H	H	H	—NH—CH3—O—CH3
III-18	H	H	H	—NH—CH2—CH2—O—CH3
III-19	H	H	H	—NH-1-adamantyl
III-20	H	H	H	—NH-(4-HO-C6H5)
III-21	H	H	H	—NH-(2-CF3—C6H4)
III-22	H	H	H	—NH-(3-CF3—C6H4)
III-23	H	H	H	—NH-(4-CF3—C6H4)
III-24	H	H	H	—NH-(2-OCH3—C6H4)
III-25	H	H	H	—NH-(3-OCH3—C6H4)
III-26	H	H	H	—NH-(4-OCH3—C6H4)
III-27	H	H	H	—NH-(2-SCH3—C6H4)
III-28	H	H	H	—NH-(3-SCH3—C6H4)
III-29	H	H	H	—NH-(4-SCH3—C6H4)
III-30	H	H	H	—NH-(2-N(CH3)2—C6H4)
III-31	H	H	H	—NH-(3-N(CH3)2—C6H4)
III-32	H	H	H	—NH-(4-N(CH3)2—C6H4)
III-33	H	H	H	—NH-(4-CN-C6H4)
III-34	H	H	H	—NH-(4-Cl-C6H4)
III-35	H	H	H	—NH-(4-Br-C6H4]
III-36	H	H	H	—NH-(4-F-C6H4]
III-37	H	H	H	—NH-(4-CH3—C6H4)
III-33	H	H	H	—NH-(2-NO2—C6H4)
III-39	H	H	H	—NH-(3-NO2—C6H4)
III-40	H	H	H	—NH-(4-NO2—C6H4)
III-41	H	H	H	—NH-(2,4-OCH3—C6H3)
III-42	H	H	H	—NH-(3,4-OCH3—C6H3)
III-43	H	H	H	—NH-(3,4,5-OCH3—C6H2)
III-44	H	H	H	—NH-(3,4-CH2OCH2—C6H3)
III-45	H	H	H	—NH-(2,3-CH2OCH2—C6H3)
III-46	H	H	H	—NH-2-pyridinyl
III-47	H	H	H	—NH-2-furanyl
III-48	H	H	H	—NH-2-thienyl
III-49	H	H	H	—NH-3-pyridinyl
III-50	H	H	H	—NH-3-furanyl
III-51	H	H	H	—NH-3-thienyl
III-52	H	H	H	—NH-4-pyridinyl
III-53	H	H	H	—NH-2-oxazolyl
III-54	H	H	H	—NH-3-isoxazolyl
III-55	H	H	H	—NH-4-isoxazolyl
III-56	H	H	H	—NH-5-isoxazloyl
III-57	H	H	H	—NH-2R-(but-2-yl)
III-58	H	H	H	—NH-2S-(but-2-yl)
III-59	H	H	H	—NH—O—CH3
III-60	H	H	H	—N(CH3) (OCH3)
III-61	H	H	H	—N(—(CH2)3—O—)
III-62	H	H	H	—NH—O—CH2—C6H5
III-63	H	H	H	—N(CH3)(O—CH2—C6H5)
III-64	H	H	H	—N(—(CH2)2—CH(C6H5)—O—)
III-65	H	H	H	—NH—O—C2H5
III-66	H	H	H	—N(C2H5)(OC2H5)
III-67	H	H	H	—N(CH2)(OC2H5)
III-58	H	H	H	—NH—O-isoC3H7
III-69	H	H	H	—N(CH3)(O-isoC3H7)
III-70	H	H	H	—NH—O—nC3H7
III-71	H	H	H	—N(CH3)(O—nC3H7)
III-72	H	H	H	—NH—O—nC4H9
III-73	H	H	H	—N(CH2)(O—nC4H9)
III-74	H	H	H	—NH-O-tertC4H9
III-75	H	H	H	—N(CH3)(O-tertC4H9)
III-76	H	H	H	—NH—O—C6H5
III-77	H	H	H	—N(CH3)(O—C6H5)
III-78	H	H	H	—N(CH3)2
III-79	H	H	H	—N(CH2—C6H5)2
III-80	H	H	H	—N(C2H5)2
III-81	H	H	H	—N(isoC3H7)2
III-82	H	H	H	—N(nC3H7)2
III-83	H	H	H	—N(nC4H9)2
III-84	H	H	H	—N(C6H5)2
III-85	H	H	H	—NH—CH2—CH2—OH
III-86	H	H	H	—NH—(CH2)3—OH
III-87	H	H	H	—NH(—(CH2)2CH(C6H5)OH)
III-88	H	H	H	—NH—(CH2)4—OH
III-89	H	H	H	—NH(—CH(CH3)—CH2—OH)
III-90	H	H	H	—NH(—CH2—CH(CH3)—OH)
III-91	H	H	H	—NH(CH(CH3)(CH2)2OH)
III-92	H	H	H	—NH(—(CH2)2CH(CH3)OH)
III-93	H	2-CH3	H	—NH—CH3
III-94	H	2-CH3	H	—NH—CH2—C6H5
III-95	H	2-CH3	H	—NH—isoC3H7
III-96	H	2-CH3	H	—NH—C6H5
III-97	H	2-CH3	H	—NH—C2H5
III-98	H	2-CH3	H	—NH-nC3H7
III-99	H	2-CH3	H	—NH—nC4H9
III-100	H	2-CH3	H	—NH-tertC4H9
III-101	H	2-CH3	H	—NH-cycloC3H5
III-102	H	2-CH3	H	—NH- cycloC4H7
III-103	H	2-CH3	H	—NH-cycloC5H9
III-104	H	2-CH3	H	—NH-cycloC6H11
III-105	H	2-CH3	H	—NH-1-adamantyl
III-106	H	2-CH3	H	—NH-2R-(but-2-yl)
III-107	H	2-CH3	H	—NH-2S-(but-2-yl)
III-108	H	2-CH3	H	—NH—O—CH3
III-109	H	2-CH3	H	—N(CH3)(OCH3)
III-110	H	2-CH3	H	—N(—(CH3—O—)
III-111	H	2-CH3	H	—N(CH3)2
III-112	H	2-CH3	H	—N(CH2—C6H5)2
III-113	H	2-CH3	H	—N(C2H5)2
III-114	H	2-CH3	H	—N(isoC3H7)2
III-115	H	2-CH3	H	—N(nC3H7)2
III-116	H	2-CH3	H	—N(nC4H9)2
III-117	H	2-CH3	H	—N(C6H5)2
III-118	H	3-CH3	H	—NH—CH3
III-119	H	3-CH3	H	—NH—CH2—C6H5
III-120	H	3-CH3	H	—NH-isoC3H7
III-121	H	3-CH3	H	—NH-C6H5
III-122	H	3-CH3	H	—NH-C2H5
III-123	H	3-CH3	H	—NH-nC3H7
III-124	H	3-CH3	H	—NH-nC4H9
III-125	H	3-CH3	H	—NH-tertC4H9
III-126	H	3-CH3	H	—NH-cycloC3H5
III-127	H	3-CH3	H	—NH-cycloC4H7
III-128	H	3-CH3	H	—NH-cycloC5H9
III-129	H	3-CH3	H	—NH-cycloC6H11
III-130	H	3-CH3	H	—NH-1-adamantyl
III-131	H	3-CH3	H	—NH-2R-(but-2-yl)
III-132	H	3-CH3	H	—NH-2S-(but-2-yl)
III-133	H	3-CH3	H	—NH—O—CH3
III-134	H	3-CH3	H	—N(CH3)(OCH3)
III-135	H	3-CH3	H	—N(—(CH3)3—O—)
III-136	H	3-CH3	H	—N(CH3)2
III-137	H	3-CH3	H	—N(CH2—C6H5)2
III-138	H	3-CH3	H	—N(C2H5)2
III-139	H	3-CH3	H	—N(isoC3H7)2
III-140	H	3-CH3	H	—N(nC3H7)2
III-141	H	3-CH3	H	—N(nC4H9)2
III-142	H	3-CH3	H	—N(C6H5)2
III-143	CH3	H	H	—NH—CH3
III-144	CH3	H	H	—NH—CH2—C6H5
III-145	CH3	H	H	—NH—isoC3H7
III-146	CH3	H	H	—NH-C6H5
III-147	CH3	H	H	—NH-C2H5
III-148	CH3	H	H	—NH-nC3H7
III-149	CH3	H	H	—NH-nC4H9
III-150	CH3	H	H	—NH-tertC4H9
III-151	CH3	H	H	—NH-cycloC3H5
III-152	CH3	H	H	—NH-cycloC4H7
III-153	CH3	H	H	—NH-cycloC5H9
III-154	CH3	H	H	—NH-cycloC6H11
III-155	CH3	H	H	—NH-1-adamantyl
III-156	CH3	H	H	—NH-2R-(but-2-yl)
III-157	CH3	H	H	—NH-2S-(but-2-yl)
III-158	CH3	H	H	—NH—O—CH3
III-159	CH3	H	H	—N(CH3)(OCH3)
III-160	CH3	H	H	—N(—(CH2)3—O—)
III-161	CH3	H	H	—N(CH3)2
III-162	CH3	H	H	—N(CH2—C6H5)3
III-163	CH3	H	H	—N(C2H5)2
III-164	CH3	H	H	—N(isoC3H7)2
III-165	CH3	H	H	—N(nC3H7)2
III-166	CH3	H	H	—N(nC4H9)2
III-167	CH3	H	H	—N(C6H5)2
III-168	H	2-OCH3	H	—NH—CH3
III-169	H	2-OCH3	H	—NH—CH2—C6H5
III-170	H	2-OCH3	H	—NH-isoC3H7
III-171	H	2-OCH3	H	—NH-C6H5
III-172	H	2-OCH3	H	—NH-C2H5
III-173	H	2-OCH3	H	—NH-nC4H7
III-174	H	2-OCH3	H	—NH-nC5H9
III-175	H	2-OCH3	H	—NH-tertC4H9
III-176	H	2-OCH3	H	—NH-cycloC3H5
III-177	H	2-OCH3	H	—NH-cycloC4H7
III-178	H	2-OCH3	H	—NH-cycloC5H9
III-179	H	2-OCH3	H	—NH-cycloC6H11
III-180	H	2-OCH3	H	—NH-1-adamantyl
III-181	H	2-OCH3	H	—NH-2R-(but-2-yl)
III-182	H	2-OCH3	H	—NH-2S-(but-2-yl)
III-183	H	2-OCH3	H	—NH—O—CH3
III-184	H	2-OCH3	H	—N(CH3)(OCH3)
III-185	H	2-OCH3	H	—N(—(CH2)3—O—)
III-186	H	2-OCH3	H	—N(CH3)2
III-187	H	2-OCH3	H	—N(CH2—C6H5)2
III-188	H	2-OCH3	H	—N(C2H5)2
III-189	H	2-OCH3	H	—N(isoC3H7)2
III-190	H	2-OCH3	H	—N(nC3H7)2
III-191	H	2-OCH3	H	—N(nC4H9)2
III-192	H	2-OCH3	H	—N(C6H5)2
III-193	H	3-OCH3	H	—NH—CH3
III-194	H	3-OCH3	H	—NH—CH2—C6H5
III-195	H	3-OCH3	H	—NH-isoC3H7
III-196	H	3-OCH3	H	—NH—C6H5
III-197	H	3-OCH3	H	—NH—C2H5
III-198	H	3-OCH3	H	—NH-nC3H7
III-199	H	3-OCH3	H	—NH-nC4H9
III-200	H	3-OCH3	H	—NH-tertC4H9
III-201	H	3-OCH3	H	—NH-cycloC3H5
III-202	H	3-OCH3	H	—NH-cycloC4H7
III-203	H	3-OCH3	H	—NH-cycloC5H9
III-204	H	3-OCH3	H	—NH-cycloC6H11
III-205	H	3-OCH3	H	—NH-1-adamantyl
III-206	H	3-OCH3	H	—NH-2R-(but-2-y1)
III-207	H	3-OCH3	H	—NH-2S-(but-2-yl)
III-208	H	3-OCH3	H	—NH—O—CH3
III-209	H	3-OCH3	H	—N(CH3)(OCH3)
III-210	H	3-OCH3	H	—N(—(CH2)3—O—)
III-211	H	3-OCH3	H	—N(CH3)2
III-212	H	3-OCH3	H	—N(CH2—C6H5)2
III-213	H	3-OCH3	H	—N(C2H5)2
III-214	H	3-OCH3	H	—N(isoC3H7)2
III-215	H	3-OCH3	H	—N(nC4H9)2
III-216	H	3-OCH3	H	—N(nC4H9)2
III-217	H	3-OCH3	H	—N(C6H5)2

[0198] Table 4:

[0199] A is Me2Val, B is Val, D is MeVal, E is Pro and F is of Formula IIf, the substituent —(C═O)-G is in position 2 relative to the nitrogen. G is of Formula Vg, VIg, VIIg, VIIIg or IXg.

No.	RF	R1F	R2F	-G
IV-1	H	H	H	—CH3
IV-2	H	H	H	—C2H5
IV-3	H	H	H	-nC3H7
IV-4	H	H	H	-isoC3H7
IV-5	H	H	H	-nC4H9
IV-6	H	H	H	-tertC4H9
IV-7	H	H	H	-cycloC3H5
IV-8	H	H	H	-cycloC4H7
IV-9	H	H	H	-cycloC5H9
IV-10	H	H	H	-cycloC6H11
IV-11	H	H	H	-cycloC7H12
IV-12	H	H	H	—CH2—O—CH3
IV-13	H	H	H	—CH2—CH2—O—CH3
IV-14	H	H	H	—CH2—C6H5
IV-15	H	H	H	—C6H5
IV-16	H	H	H	-(4-HO—C6H5)
IV-17	H	H	H	-(2-CF3—C6H4)
IV-18	H	H	H	-(3-CF3—C6H4)
IV-19	H	H	H	-(4-CF3—C6H4)
IV-20	H	H	H	-(2-OCH3—C6H4)
IV-21	H	H	H	-(3-OCH3—C6H4)
IV-22	H	H	H	-(4-OCH3—C6H4)
IV-23	H	H	H	-(2-SCH3—C6H4)
IV-24	H	H	H	-(3-SCH3—C6H4)
IV-25	H	H	H	-(4-SCH3—C6H4)
IV-26	H	H	H	-(2-N(CH3)2—C6H4)
IV-27	H	H	H	-(3-N(CH3)2—C6H4)
IV-28	H	H	H	-(4-N(CH3)2—C6H4)
IV-29	H	H	H	-(4-CN—C6H4)
IV-30	H	H	H	-(4-Cl—C6H4)
IV-31	H	H	H	-(4-Br—C6H4]
IV-32	H	H	H	-(4-F—C6H4]
IV-33	H	H	H	-(4-CH3—C6H4)
IV-34	H	H	H	-(2-NO2—C6H4)
IV-35	H	H	H	-(3-NO2—C6H4)
IV-36	H	H	H	-(4-NO2—C6H4]
IV-37	H	H	H	-(2,4-OCH3—C6H3)
IV-38	H	H	H	-(3,4-OCH3—C6H3)
IV-39	H	H	H	-(3,4,5-OCH3—C6H2)
IV-40	H	H	H	-(3,4-CH2OCH2—C6H3)
IV-41	H	H	H	-(2,3-CH2OCH2—C6H3)
IV-42	H	H	H	-2-pyridinyl
IV-43	H	H	H	-2-furanyl
IV-44	H	H	H	-2-thienyl
IV-45	H	H	H	-3-pyridinyl
IV-46	H	H	H	-3-furanyl
IV-47	H	H	H	-3-thienyl
IV-48	H	H	H	-4-pyridinyl
IV-49	H	H	H	-2-thiazolyl
IV-50	H	H	H	-2-oxazolyl
IV-51	H	H	H	-3-isoxazolyl
IV-52	H	H	H	-4-isoxazolyl
IV-53	H	H	H	-5-isoxazolyl
IV-54	H	H	H	—CF3
IV-55	H	H	H	—C2F5
IV-56	H	H	H	—CH3
IV-57	H	H	H	—C2H5
IV-58	H	H	H	-nC3H7
IV-59	H	H	H	-tertC4H9
IV-60	H	H	H	—CH2—C6H5
IV-61	H	H	H	—C6H5
IV-62	H	H	H	—CH2—COOCH3
IV-63	H	H	H	—CH2—COOC2H5
IV-64	H	H	H	—CF2—COOCH3
IV-65	H	H	H	—CF2—COOC2H5
IV-66	H	H	H	—CH2—CONH2
IV-67	H	H	H	—CH2—CONHCH3
IV-68	H	H	H	—CH2—CON(CH3)2
IV-69	H	H	H	—CH2—CONH—CH2—C6H5
IV-70	H	H	H	—CH2—CONH—C6H5
IV-71	H	H	H	—CH2—CONH(CH2—C6H5)2
IV-72	H	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—)
IV-73	H	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—CH2)
IV-74	H	H	H	—CH2—CH2—COOCH3
IV-75	H	H	H	—CH2—CH2—COOC2H5
IV-76	H	H	H	—CH2—CH2—CONH2
IV-77	H	H	H	—CH2—CH2—CONHCH3
IV-78	H	H	H	—CH2—CH2—CON(CH3)2
IV-79	H	H	H	—CH2—CH2—CONH—CH2—C6H5
IV-80	H	H	H	—CH2—CH2—CONH—C6H5
IV-81	H	H	H	—CH2—CH2—CONH(CH2—C6H5)2
IV-82	H	H	H	—CH2—CH2—CON(—CH2—CH2—
				CH2—CH2—)
IV-83	H	H	H	—CH2—CH2—CON(—CH2—
				(CH2)3—CH2)
IV-84	H	H	H	—CH2—COCH3
IV-85	H	H	H	—CH2—CH2—COCH3
IV-86	H	H	H	—CH2—COC2H5
IV-87	H	H	H	—CH2—CH2—COC2H5
IV-88	H	H	H	—CH2—CO—C6H5
IV-89	H	H	H	—CH2—CH2—CO—C6H5
IV-90	H	H	H	—CH2—CO—CH2—C6H5
IV-91	H	H	H	—CH2—CH2—CO—CH2—C6H5
IV-92	H	H	H	—CH2—SOC6H5
IV-93	H	H	H	—CH2—SOCH3
IV-94	H	H	H	—CH2SO(4-CH3—C6H4)
IV-95	H	H	H	—CH2—SO2C6H5
IV-96	H	H	H	—CH2—SO2CH3
IV-97	H	H	H	—CH2—SO2(4-CH3—C6H4)
IV-98	H	H	H	—CH2—CH2—SOC6H5
IV-99	H	H	H	—CH2—CH2—SOCH3
IV-100	H	H	H	—CH2—CH2—SO(4-CH3—C6H4)
IV-101	H	H	H	—CH2—CH2—SO2C6H5
IV-102	H	H	H	—CH2—CH2—SO2CH3
IV-103	H	H	H	—CH2—CH2—SO3(4-CH3—C6H4)
IV-104	CH3	H	H	—CH3
IV-105	CH3	H	H	—C2H5
IV-106	CH3	H	H	-nC3H7
IV-107	CH3	H	H	-isoC3H7
IV-108	CH3	H	H	-nC4H9
IV-109	CH3	H	H	-tertC4H9
IV-110	CH3	H	H	-cycloC3H5
IV-111	CH3	H	H	-cycloC4H7
IV-112	CH3	H	H	-cycloC5H9
IV-113	CH3	H	H	-cycloC6H11
IV-114	CH3	H	H	-cycloC7H12
IV-115	CH3	H	H	—CH2—O—CH3
IV-116	CH3	H	H	—CH2—CH3—O—CH3
IV-117	CH3	H	H	—CH2—C6H5
IV-118	CH3	H	H	—C6H5
IV-119	CH3	H	H	-(4-HO-C6H5)
IV-120	CH3	H	H	-(2-CF3—C6H4)
IV-121	CH3	H	H	-(3-CF3—C6H4)
IV-122	CH3	H	H	-(4-CF3—C6H4)
IV-123	CH3	H	H	-(2-OCH3—C6H4)
IV-124	CH3	H	H	-(3-OCH3—C6H4)
IV-125	CH3	H	H	-(4-OCH3—C6H4)
IV-126	CH3	H	H	-(2-SCH3—C6H4)
IV-127	CH3	H	H	-(3-SCH3—C6H4)
IV-128	CH3	H	H	-(4-SCH3—C6H4)
IV-129	CH3	H	H	-(2-N(CH3)2—C6H4)
IV-130	CH3	H	H	-(3-N(CH3)2—C6H4)
IV-131	CH3	H	H	-(4-N(CH3)2—C6H4)
IV-132	CH3	H	H	-(4-CN-C6H4)
IV-133	CH3	H	H	-(4-Cl—C6H4)
IV-134	CH3	H	H	-(4-Br—C6H4]
IV-135	CH3	H	H	-(4-F—C6H4]
IV-136	CH3	H	H	-(4-CH3—C6H4)
IV-137	CH3	H	H	-(2-NO2—C6H4)
IV-138	CH3	H	H	-(3-NO2—C6H4)
IV-139	CH3	H	H	-(4-NO2—C6H4]
IV-140	CH3	H	H	-(2,4-OCH3—C6H3)
IV-141	CH3	H	H	-(3,4-OCH3—C6H3)
IV-142	CH3	H	H	-(3,4,5-OCH3—C6H2)
IV-143	CH3	H	H	-(3,4-CH2OCH2—C6H3)
IV-144	CH3	H	H	-(2,3-CH2OCH2—C6H3)
IV-145	CH3	H	H	-2-pyridinyl
IV-146	CH3	H	H	-2-furanyl
IV-147	CH3	H	H	-2-thienyl
IV-148	CH3	H	H	-3-pyridinyl
IV-149	CH3	H	H	-3-furanyl
IV-150	CH3	H	H	-3-thienyl
IV-151	CH3	H	H	-4-pyridinyl
IV-152	CH3	H	H	-2-thiazolyl
IV-153	CH3	H	H	-2-oxazolyl
IV-154	CH3	H	H	-3-isoxazolyl
IV-155	CH3	H	H	-4-isoxazolyl
IV-156	CH3	H	H	-5-isoxazoyl
IV-157	CH3	H	H	—CF3
IV-158	CH3	H	H	—C2F5
IV-159	CH3	H	H	—CH3
IV-160	CH3	H	H	—C2H5
IV-161	CH3	H	H	-nC3H7
IV-162	CH3	H	H	-tertC4H9
IV-163	CH3	H	H	—CH2—C6H5
IV-164	CH3	H	H	—C6H5
IV-165	CH3	H	H	—CH2—COOCH3
IV-166	CH3	H	H	—CH2—COOC2H5
IV-167	CH3	H	H	—CF2—COOCH3
IV-168	CH3	H	H	—CF2—COOC2H5
IV-169	CH3	H	H	—CH2—CONH2
IV-170	CH3	H	H	—CH2—CONHCH3
IV-171	CH3	H	H	—CH2—CON(CH3)2
IV-172	CH3	H	H	—CH2—CONH—CH2—C6H5
IV-173	CH3	H	H	—CH2—CONH—C6H5
IV-174	CH3	H	H	—CH2—CONH(CH2—C6H5)2
IV-175	CH3	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—)
IV-176	CH3	H	H	—CH2—CON(—CH2—CH2—CH2—
				CH2—CH2)
IV-177	CH3	H	H	—CH2—CH2—COOCH3
IV-178	CH3	H	H	—CH2—CH2—COOC2H5
IV-179	CH3	H	H	—CH2—CH2—CONH2
IV-180	CH3	H	H	—CH2—CH2—CONHCH3
IV-181	CH3	H	H	—CH2—CH2—CON(CH3)2
IV-182	CH3	H	H	—CH2—CH2—CONH—CH2—C6H5
IV-183	CH3	H	H	—CH2—CH2—CONH—C6H5
IV-184	CH3	H	H	—CH2—CH2—CONH(CH2—C6H5)2
IV-185	CH3	H	H	—CH2—CH2—CON(—
				CH2—CH2—CH2—CH2—)
IV-186	CH3	H	H	—CH2—CH2—CON(—CH2—
				(CH2)3—CH2)
IV-187	CH3	H	H	—CH2—COCH3
IV-188	CH3	H	H	—CH2—CH2—COCH3
IV-189	CH3	H	H	—CH2—COC2H5
IV-190	CH3	H	H	—CH2—CH2—COC2H5
IV-191	CH3	H	H	—CH2—CO—C6H5
IV-192	CH3	H	H	—CH2—CH2—CO—C6H5
IV-193	CH3	H	H	—CH2—CO—CH2—C6H5
IV-194	CH3	H	H	—CH2—CH2—CO—CH2—C6H5
IV-195	CH3	H	H	—CH2—SOC6H5
IV-196	CH3	H	H	—CH2—SOCH3
IV-197	CH3	H	H	—CH2—SO(4-CH3—C6H4)
IV-198	CH3	H	H	—CH2—SO2C6H5
IV-199	CH3	H	H	—CH2—SO2CH3
IV-200	CH3	H	H	—CH2—SO2(4-CH3—C6H4)
IV-201	CH3	H	H	—CH2—CH2—SOC6H5
IV-202	CH3	H	H	—CH2—CH2—SOCH3
IV-203	CH3	H	H	—CH2—CH2—SO(4-CH3—C6H4)
IV-204	CH3	H	H	—CH2—CH2—SO2C6H5
IV-205	CH3	H	H	—CH2—CH2—SO2CH3
IV-206	CH3	H	H	—CH2—CH2—SO2(4-CH3—C6H4)

[0200] Table 5:

[0201] A is Me2Val, B is Val, D is MeVal, E is Pro and F is of Formula IIf, the substituent —(C═O)-G is in position 3 relative to the nitrogen. G is of Formula Vg, VIg, VIIg, VIIIg or IXg.

No.	RF	R1F	R2F	-G
V-1	H	H	H	—CH3
V-2	H	H	H	—C2H5
V-3	H	H	H	-nC3H7
V-4	H	H	H	-isoC3H7
V-5	H	H	H	-nC4H9
V-6	H	H	H	-tertC4H9
V-7	H	H	H	-cycloC3H5
V-8	H	H	H	-cycloC4H7
V-9	H	H	H	-cycloC5H9
V-10	H	H	H	-cycloC6H11
V-11	H	H	H	-cycloC7H12
V-12	H	H	H	—CH2—O—CH3
V-13	H	H	H	—CH2—CH2—O—CH3
V-14	H	H	H	—CH2—C6H5
V-15	H	H	H	—C6H5
V-16	H	H	H	-(4-HO—C6H5)
V-17	H	H	H	-(2-CF3—C6H4)
V-18	H	H	H	-(3-CF3—C6H4)
V-19	H	H	H	-(4-CF3—C6H4)
V-20	H	H	H	-(2-OCH3—C6H4)
V-21	H	H	H	-(3-OCH3—C6H4)
V-22	H	H	H	-(4-OCH3—C6H4)
V-23	H	H	H	-(2-SCH3—C6H4)
V-24	H	H	H	-(3-SCH3—C6H4)
V-25	H	H	H	-(4-SCH3—C6H4)
V-26	H	H	H	-(2-N(CH3)2—C6H4)
V-27	H	H	H	-(3-N(CH3)2—C6H4)
V-28	H	H	H	-(4-N(CH3)2—C6H4)
V-29	H	H	H	-(4-CN—C6H4)
V-30	H	H	H	-(4-Cl—C6H4)
V-31	H	H	H	-(4-Br—C6H4]
V-32	H	H	H	-(4-F—C6H4]
V-33	H	H	H	-(4-CH3—C6H4)
V-34	H	H	H	-(2-NO2—C6H4)
V-35	H	H	H	-(3-NO2—C6H4)
V-36	H	H	H	-(4-NO2—C6H4]
V-37	H	H	H	-(2,4-OCH3—C6H3)
V-38	H	H	H	-(3,4-OCH3—C6H3)
V-39	H	H	H	-(3,4,5-OCH3—C6H2)
V-40	H	H	H	-(3,4-CH2OCH2—C6H3)
V-41	H	H	H	-(2,3-CH2OCH2—C6H3)
V-42	H	H	H	-2-pyridinyl
V-43	H	H	H	-2-furanyl
V-44	H	H	H	-2-thienyl
V-45	H	H	H	-3-pyridinyl
V-46	H	H	H	-3-furanyl
V-47	H	H	H	-3-thienyl
V-48	H	H	H	-4-pyridinyl
V-49	H	H	H	-2-thiazolyl
V-50	H	H	H	-2-oxazolyl
V-51	H	H	H	-3-isoxazolyl
V-52	H	H	H	-4-isoxazolyl
V-53	H	H	H	-5-isoxazolyl
V-54	H	H	H	—CF3
V-55	H	H	H	—C2F5
V-56	H	H	H	—CH3
V-57	H	H	H	—C2H5
V-58	H	H	H	-nC3H7
V-59	H	H	H	-tertC4H9
V-60	H	H	H	—CH2—C6H5
V-61	H	H	H	—C6H5
V-62	H	H	H	—CH2—COOCH3
V-63	H	H	H	—CH2—COOC2H5
V-64	H	H	H	—CF2—COOCH3
V-65	H	H	H	—CF2—COOC2H5
V-66	H	H	H	—CH2—CONH2
V-67	H	H	H	—CH2—CONHCH3
V-68	H	H	H	—CH2—CON(CH3)2
V-69	H	H	H	—CH2—CONH—CH2—C6H5
V-70	H	H	H	—CH2—CONH—C6H5
V-71	H	H	H	—CH2—CONH(CH2—C6H5)2
V-72	H	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—)
V-73	H	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—CH2)
V-74	H	H	H	—CH2—CH2—COOCH3
V-75	H	H	H	—CH2—CH2—COOC2H5
V-76	H	H	H	—CH2—CH2—CONH2
V-77	H	H	H	—CH2—CH2—CONHCH3
V-78	H	H	H	—CH2—CH2—CON(CH3)2
V-79	H	H	H	—CH2—CH2—CONH—CH2—C6H5
V-80	H	H	H	—CH2—CH2—CONH—C6H5
V-81	H	H	H	—CH2—CH2—CONH(CH2—C6H5)2
V-82	H	H	H	—CH2—CH2—CON(—CH2—CH2—
				CH2—CH2—)
V-83	H	H	H	—CH2—CH2—CON(—CH2—
				(CH2)3—CH2)
V-84	H	H	H	—CH2—COCH3
V-85	H	H	H	—CH2—CH2—COCH3
V-86	H	H	H	—CH2—COC2H5
V-87	H	H	H	—CH2—CH2—COC2H5
V-88	H	H	H	—CH2—CO—C6H5
V-89	H	H	H	—CH2—CH2—CO—C6H5
V-90	H	H	H	—CH2—CO—CH2—C6H5
V-91	H	H	H	—CH2—CH2—CO—CH2—C6H5
V-92	H	H	H	—CH2—SOC6H5
V-93	H	H	H	—CH2—SOCH3
V-94	H	H	H	—CH2SO(4-CH3—C6H4)
V-95	H	H	H	—CH2—SO2C6H5
V-96	H	H	H	—CH2—SO2CH3
V-97	H	H	H	—CH2—SO2(4-CH3—C6H4)
V-98	H	H	H	—CH2—CH2—SOC6H5
V-99	H	H	H	—CH2—CH2—SOCH3
V-100	H	H	H	—CH2—CH2—SO(4-CH3—C6H4)
V-101	H	H	H	—CH2—CH2—SO2C6H5
V-102	H	H	H	—CH2—CH2—SO2CH3
V-103	H	H	H	—CH2—CH2—SO3(4-CH3—C6H4)
V-104	CH3	H	H	—CH3
V-105	CH3	H	H	—C2H5
V-106	CH3	H	H	-nC3H7
V-107	CH3	H	H	-isoC3H7
V-108	CH3	H	H	-nC4H9
V-109	CH3	H	H	-tertC4H9
V-110	CH3	H	H	-cycloC3H5
V-111	CH3	H	H	-cycloC4H7
V-112	CH3	H	H	-cycloC5H9
V-113	CH3	H	H	-cycloC6H11
V-114	CH3	H	H	-cycloC7H12
V-115	CH3	H	H	—CH2—O—CH3
V-116	CH3	H	H	—CH2—CH3—O—CH3
V-117	CH3	H	H	—CH2—C6H5
V-118	CH3	H	H	—C6H5
V-119	CH3	H	H	-(4-HO-C6H5)
V-120	CH3	H	H	-(2-CF3—C6H4)
V-121	CH3	H	H	-(3-CF3—C6H4)
V-122	CH3	H	H	-(4-CF3—C6H4)
V-123	CH3	H	H	-(2-OCH3—C6H4)
V-124	CH3	H	H	-(3-OCH3—C6H4)
V-125	CH3	H	H	-(4-OCH3—C6H4)
V-126	CH3	H	H	-(2-SCH3—C6H4)
V-127	CH3	H	H	-(3-SCH3—C6H4)
V-128	CH3	H	H	-(4-SCH3—C6H4)
V-129	CH3	H	H	-(2-N(CH3)2—C6H4)
V-130	CH3	H	H	-(3-N(CH3)2—C6H4)
V-131	CH3	H	H	-(4-N(CH3)2—C6H4)
V-132	CH3	H	H	-(4-CN-C6H4)
V-133	CH3	H	H	-(4-Cl—C6H4)
V-134	CH3	H	H	-(4-Br—C6H4]
V-135	CH3	H	H	-(4-F—C6H4]
V-136	CH3	H	H	-(4-CH3—C6H4)
V-137	CH3	H	H	-(2-NO2—C6H4)
V-138	CH3	H	H	-(3-NO2—C6H4)
V-139	CH3	H	H	-(4-NO2—C6H4]
V-140	CH3	H	H	-(2,4-OCH3—C6H3)
V-141	CH3	H	H	-(3,4-OCH3—C6H3)
V-142	CH3	H	H	-(3,4,5-OCH3—C6H2)
V-143	CH3	H	H	-(3,4-CH2OCH2—C6H3)
V-144	CH3	H	H	-(2,3-CH2OCH2—C6H3)
V-145	CH3	H	H	-2-pyridinyl
V-146	CH3	H	H	-2-furanyl
V-147	CH3	H	H	-2-thienyl
V-148	CH3	H	H	-3-pyridinyl
V-149	CH3	H	H	-3-furanyl
V-150	CH3	H	H	-3-thienyl
V-151	CH3	H	H	-4-pyridinyl
V-152	CH3	H	H	-2-thiazolyl
V-153	CH3	H	H	-2-oxazolyl
V-154	CH3	H	H	-3-isoxazolyl
V-155	CH3	H	H	-4-isoxazolyl
V-156	CH3	H	H	-5-isoxazoyl
V-157	CH3	H	H	—CF3
V-158	CH3	H	H	—C2F5
V-159	CH3	H	H	—CH3
V-160	CH3	H	H	—C2H5
V-161	CH3	H	H	-nC3H7
V-162	CH3	H	H	-tertC4H9
V-163	CH3	H	H	—CH2—C6H5
V-164	CH3	H	H	—C6H5
V-165	CH3	H	H	—CH2—COOCH3
V-166	CH3	H	H	—CH2—COOC2H5
V-167	CH3	H	H	—CF2—COOCH3
V-168	CH3	H	H	—CF2—COOC2H5
V-169	CH3	H	H	—CH2—CONH2
V-170	CH3	H	H	—CH2—CONHCH3
V-171	CH3	H	H	—CH2—CON(CH3)2
V-172	CH3	H	H	—CH2—CONH—CH2—C6H5
V-173	CH3	H	H	—CH2—CONH—C6H5
V-174	CH3	H	H	—CH2—CONH(CH2—C6H5)2
V-175	CH3	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—)
V-176	CH3	H	H	—CH2—CON(—CH2—CH2—CH2—
				CH2—CH2)
V-177	CH3	H	H	—CH2—CH2—COOCH3
V-178	CH3	H	H	—CH2—CH2—COOC2H5
V-179	CH3	H	H	—CH2—CH2—CONH2
V-180	CH3	H	H	—CH2—CH2—CONHCH3
V-181	CH3	H	H	—CH2—CH2—CON(CH3)2
V-182	CH3	H	H	—CH2—CH2—CONH—CH2—C6H5
V-183	CH3	H	H	—CH2—CH2—CONH—C6H5
V-184	CH3	H	H	—CH2—CH2—CONH(CH2—C6H5)2
V-185	CH3	H	H	—CH2—CH2—CON(—
				CH2—CH2—CH2—CH2—)
V-186	CH3	H	H	—CH2—CH2—CON(—CH2—
				(CH2)3—CH2)
V-187	CH3	H	H	—CH2—COCH3
V-188	CH3	H	H	—CH2—CH2—COCH3
V-189	CH3	H	H	—CH2—COC2H5
V-190	CH3	H	H	—CH2—CH2—COC2H5
V-191	CH3	H	H	—CH2—CO—C6H5
V-192	CH3	H	H	—CH2—CH2—CO—C6H5
V-193	CH3	H	H	—CH2—CO—CH2—C6H5
V-194	CH3	H	H	—CH2—CH2—CO—CH2—C6H5
V-195	CH3	H	H	—CH2—SOC6H5
V-196	CH3	H	H	—CH2—SOCH3
V-197	CH3	H	H	—CH2—SO(4-CH3—C6H4)
V-198	CH3	H	H	—CH2—SO2C6H5
V-199	CH3	H	H	—CH2—SO2CH3
V-200	CH3	H	H	—CH2—SO2(4-CH3—C6H4)
V-201	CH3	H	H	—CH2—CH2—SOC6H5
V-202	CH3	H	H	—CH2—CH2—SOCH3
V-203	CH3	H	H	—CH2—CH2—SO(4-CH3—C6H4)
V-204	CH3	H	H	—CH2—CH2—SO2C6H5
V-205	CH3	H	H	—CH2—CH2—SO2CH3
V-206	CH3	H	H	—CH2—CH2—SO2(4-CH3—C6H4)

[0202] Table 6:

[0203] A is Me2Val, B is Val, D is MeVal, E is Pro and F is of Formula IIf, the substituent —(C═O)-G is in position 4 relative to the nitrogen. G is of Formula Vg, VIg, VIIg, VIIIg or IXg.

No.	RF	R1F	R2F	-G
VI-1	H	H	H	—CH3
VI-2	H	H	H	—C2H5
VI-3	H	H	H	-nC3H7
VI-4	H	H	H	-isoC3H7
VI-5	H	H	H	-nC4H9
VI-6	H	H	H	-tertC4H9
VI-7	H	H	H	-cycloC3H5
VI-8	H	H	H	-cycloC4H7
VI-9	H	H	H	-cycloC5H9
VI-10	H	H	H	-cycloC6H11
VI-11	H	H	H	-cycloC7H12
VI-12	H	H	H	—CH2—O—CH3
VI-13	H	H	H	—CH2—CH2—O—CH3
VI-14	H	H	H	—CH2—C6H5
VI-15	H	H	H	—C6H5
VI-16	H	H	H	-(4-HO—C6H5)
VI-17	H	H	H	-(2-CF3—C6H4)
VI-18	H	H	H	-(3-CF3—C6H4)
VI-19	H	H	H	-(4-CF3—C6H4)
VI-20	H	H	H	-(2-OCH3—C6H4)
VI-21	H	H	H	-(3-OCH3—C6H4)
VI-22	H	H	H	-(4-OCH3—C6H4)
VI-23	H	H	H	-(2-SCH3—C6H4)
VI-24	H	H	H	-(3-SCH3—C6H4)
VI-25	H	H	H	-(4-SCH3—C6H4)
VI-26	H	H	H	-(2-N(CH3)2—C6H4)
VI-27	H	H	H	-(3-N(CH3)2—C6H4)
VI-28	H	H	H	-(4-N(CH3)2—C6H4)
VI-29	H	H	H	-(4-CN—C6H4)
VI-30	H	H	H	-(4-Cl—C6H4)
VI-31	H	H	H	-(4-Br—C6H4]
VI-32	H	H	H	-(4-F—C6H4]
VI-33	H	H	H	-(4-CH3—C6H4)
VI-34	H	H	H	-(2-NO2—C6H4)
VI-35	H	H	H	-(3-NO2—C6H4)
VI-36	H	H	H	-(4-NO2—C6H4]
VI-37	H	H	H	-(2,4-OCH3—C6H3)
VI-38	H	H	H	-(3,4-OCH3—C6H3)
VI-39	H	H	H	-(3,4,5-OCH3—C6H2)
VI-40	H	H	H	-(3,4-CH2OCH2—C6H3)
VI-41	H	H	H	-(2,3-CH2OCH2—C6H3)
VI-42	H	H	H	-2-pyridinyl
VI-43	H	H	H	-2-furanyl
VI-44	H	H	H	-2-thienyl
VI-45	H	H	H	-3-pyridinyl
VI-46	H	H	H	-3-furanyl
VI-47	H	H	H	-3-thienyl
VI-48	H	H	H	-4-pyridinyl
VI-49	H	H	H	-2-thiazolyl
VI-50	H	H	H	-2-oxazolyl
VI-51	H	H	H	-3-isoxazolyl
VI-52	H	H	H	-4-isoxazolyl
VI-53	H	H	H	-5-isoxazolyl
VI-54	H	H	H	—CF3
VI-55	H	H	H	—C2F5
VI-56	H	H	H	—CH3
VI-57	H	H	H	—C2H5
VI-58	H	H	H	-nC3H7
VI-59	H	H	H	-tertC4H9
VI-60	H	H	H	—CH2—C6H5
VI-61	H	H	H	—C6H5
VI-62	H	H	H	—CH2—COOCH3
VI-63	H	H	H	—CH2—COOC2H5
VI-64	H	H	H	—CF2—COOCH3
VI-65	H	H	H	—CF2—COOC2H5
VI-66	H	H	H	—CH2—CONH2
VI-67	H	H	H	—CH2—CONHCH3
VI-68	H	H	H	—CH2—CON(CH3)2
VI-69	H	H	H	—CH2—CONH—CH2—C6H5
VI-70	H	H	H	—CH2—CONH—C6H5
VI-71	H	H	H	—CH2—CONH(CH2—C6H5)2
VI-72	H	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—)
VI-73	H	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—CH2)
VI-74	H	H	H	—CH2—CH2—COOCH3
VI-75	H	H	H	—CH2—CH2—COOC2H5
VI-76	H	H	H	—CH2—CH2—CONH2
VI-77	H	H	H	—CH2—CH2—CONHCH3
VI-78	H	H	H	—CH2—CH2—CON(CH3)2
VI-79	H	H	H	—CH2—CH2—CONH—CH2—C6H5
VI-80	H	H	H	—CH2—CH2—CONH—C6H5
VI-81	H	H	H	—CH2—CH2—CONH(CH2—C6H5)2
VI-82	H	H	H	—CH2—CH2—CON(—CH2—
				CH2—CH2—CH2—)
VI-83	H	H	H	—CH2—CH2—CON(—CH2—
				(CH2)3—CH2)
VI-84	H	H	H	—CH2—COCH3
VI-85	H	H	H	—CH2—CH2—COCH3
VI-86	H	H	H	—CH2—COC2H5
VI-87	H	H	H	—CH2—CH2—COC2H5
VI-88	H	H	H	—CH2—CO—C6H5
VI-89	H	H	H	—CH2—CH2—CO—C6H5
VI-90	H	H	H	—CH2—CO—CH2—C6H5
VI-91	H	H	H	—CH2—CH2—CO—CH2—C6H5
VI-92	H	H	H	—CH2—SOC6H5
VI-93	H	H	H	—CH2—SOCH3
VI-94	H	H	H	—CH2SO(4-CH3—C6H4)
VI-95	H	H	H	—CH2—SO2C6H5
VI-96	H	H	H	—CH2—SO2CH3
VI-97	H	H	H	—CH2—SO2(4-CH3—C6H4)
VI-98	H	H	H	—CH2—CH2—SOC6H5
VI-99	H	H	H	—CH2—CH2—SOCH3
VI-100	H	H	H	—CH2—CH2—SO(4-CH3—C6H4)
VI-101	H	H	H	—CH2—CH2—SO2C6H5
VI-102	H	H	H	—CH2—CH2—SO2CH3
VI-103	H	H	H	—CH2—CH2—SO3(4-CH3—C6H4)
VI-104	CH3	H	H	—CH3
VI-105	CH3	H	H	—C2H5
VI-106	CH3	H	H	-nC3H7
VI-107	CH3	H	H	-isoC3H7
VI-108	CH3	H	H	-nC4H9
VI-109	CH3	H	H	-tertC4H9
VI-110	CH3	H	H	-cycloC3H5
VI-111	CH3	H	H	-cycloC4H7
VI-112	CH3	H	H	-cycloC5H9
VI-113	CH3	H	H	-cycloC6H11
VI-114	CH3	H	H	-cycloC7H12
VI-115	CH3	H	H	—CH2—O—CH3
VI-116	CH3	H	H	—CH2—CH3—O—CH3
VI-117	CH3	H	H	—CH2—C6H5
VI-118	CH3	H	H	—C6H5
VI-119	CH3	H	H	-(4-HO-C6H5)
VI-120	CH3	H	H	-(2-CF3—C6H4)
VI-121	CH3	H	H	-(3-CF3—C6H4)
VI-122	CH3	H	H	-(4-CF3—C6H4)
VI-123	CH3	H	H	-(2-OCH3—C6H4)
VI-124	CH3	H	H	-(3-OCH3—C6H4)
VI-125	CH3	H	H	-(4-OCH3—C6H4)
VI-126	CH3	H	H	-(2-SCH3—C6H4)
VI-127	CH3	H	H	-(3-SCH3—C6H4)
VI-128	CH3	H	H	-(4-SCH3—C6H4)
VI-129	CH3	H	H	-(2-N(CH3)2—C6H4)
VI-130	CH3	H	H	-(3-N(CH3)2—C6H4)
VI-131	CH3	H	H	-(4-N(CH3)2—C6H4)
VI-132	CH3	H	H	-(4-CN-C6H4)
VI-133	CH3	H	H	-(4-Cl—C6H4)
VI-134	CH3	H	H	-(4-Br—C6H4]
VI-135	CH3	H	H	-(4-F—C6H4]
VI-136	CH3	H	H	-(4-CH3—C6H4)
VI-137	CH3	H	H	-(2-NO2—C6H4)
VI-138	CH3	H	H	-(3-NO2—C6H4)
VI-139	CH3	H	H	-(4-NO2—C6H4]
VI-140	CH3	H	H	-(2,4-OCH3—C6H3)
VI-141	CH3	H	H	-(3,4-OCH3—C6H3)
VI-142	CH3	H	H	-(3,4,5-OCH3—C6H2)
VI-143	CH3	H	H	-(3,4-CH2OCH2—C6H3)
VI-144	CH3	H	H	-(2,3-CH2OCH2—C6H3)
VI-145	CH3	H	H	-2-pyridinyl
VI-146	CH3	H	H	-2-furanyl
VI-147	CH3	H	H	-2-thienyl
VI-148	CH3	H	H	-3-pyridinyl
VI-149	CH3	H	H	-3-furanyl
VI-150	CH3	H	H	-3-thienyl
VI-151	CH3	H	H	-4-pyridinyl
VI-152	CH3	H	H	-2-thiazolyl
VI-153	CH3	H	H	-2-oxazolyl
VI-154	CH3	H	H	-3-isoxazolyl
VI-155	CH3	H	H	-4-isoxazolyl
VI-156	CH3	H	H	-5-isoxazoyl
VI-157	CH3	H	H	—CF3
VI-158	CH3	H	H	—C2F5
VI-159	CH3	H	H	—CH3
VI-160	CH3	H	H	—C2H5
VI-161	CH3	H	H	-nC3H7
VI-162	CH3	H	H	-tertC4H9
VI-163	CH3	H	H	—CH2—C6H5
VI-164	CH3	H	H	—C6H5
VI-165	CH3	H	H	—CH2—COOCH3
VI-166	CH3	H	H	—CH2—COOC2H5
VI-167	CH3	H	H	—CF2—COOCH3
VI-168	CH3	H	H	—CF2—COOC2H5
VI-169	CH3	H	H	—CH2—CONH2
VI-170	CH3	H	H	—CH2—CONHCH3
VI-171	CH3	H	H	—CH2—CON(CH3)2
VI-172	CH3	H	H	—CH2—CONH—CH2—C6H5
VI-173	CH3	H	H	—CH2—CONH—C6H5
VI-174	CH3	H	H	—CH2—CONH(CH2—C6H5)2
VI-175	CH3	H	H	—CH2—CON(—CH2—CH2—
				CH2—CH2—)
VI-176	CH3	H	H	—CH2—CON(—CH2—CH2—CH2—
				CH2—CH2)
VI-177	CH3	H	H	—CH2—CH2—COOCH3
VI-178	CH3	H	H	—CH2—CH2—COOC2H5
VI-179	CH3	H	H	—CH2—CH2—CONH2
VI-180	CH3	H	H	—CH2—CH2—CONHCH3
VI-181	CH3	H	H	—CH2—CH2—CON(CH3)2
VI-182	CH3	H	H	—CH2—CH2—CONH—CH2—C6H5
VI-183	CH3	H	H	—CH2—CH2—CONH—C6H5
VI-184	CH3	H	H	—CH2—CH2—CONH(CH2—C6H5)2
VI-185	CH3	H	H	—CH2—CH2—CON(—
				CH2—CH2—CH2—CH2—)
VI-186	CH3	H	H	—CH2—CH2—CON(—CH2—
				(CH2)3—CH2)
VI-187	CH3	H	H	—CH2—COCH3
VI-188	CH3	H	H	—CH2—CH2—COCH3
VI-189	CH3	H	H	—CH2—COC2H5
VI-190	CH3	H	H	—CH2—CH2—COC2H5
VI-191	CH3	H	H	—CH2—CO—C6H5
VI-192	CH3	H	H	—CH2—CH2—CO—C6H5
VI-193	CH3	H	H	—CH2—CO—CH2—C6H5
VI-194	CH3	H	H	—CH2—CH2—CO—CH2—C6H5
VI-195	CH3	H	H	—CH2—SOC6H5
VI-196	CH3	H	H	—CH2—SOCH3
VI-197	CH3	H	H	—CH2—SO(4-CH3—C6H4)
VI-198	CH3	H	H	—CH2—SO2C6H5
VI-199	CH3	H	H	—CH2—SO2CH3
VI-200	CH3	H	H	—CH2—SO2(4-CH3—C6H4)
VI-201	CH3	H	H	—CH2—CH2—SOC6H5
VI-202	CH3	H	H	—CH2—CH2—SOCH3
VI-203	CH3	H	H	—CH2—CH2—SO(4-CH3—C6H4)
VI-204	CH3	H	H	—CH2—CH2—SO2C6H5
VI-205	CH3	H	H	—CH2—CH2—SO2CH3
VI-206	CH3	H	H	—CH2—CH2—SO2(4-CH3—C6H4)

[0204] Table 7:

[0205] A is Me2Val, B is Val, D is MeVal, E is Pro and F is of Formula IIIf, the substituent —(C═O)-G is in position 2 relative to the nitrogen and af is 1. G is of Formula IIg or IIIg. The compounds are mixtures of diasteromers, configuration in F is R, S (cis) or S,R (cis).

	No.	Rf	-G
	VII-1	H	—NH—CH3
	VII-2	H	—NH—CH2—C6H5
	VII-3	H	—NH-isoC3H7
	VII-4	H	—NH—C6H5
	VII-5	H	1,3-Thiazol-2-yl-amide
	VII-6	H	—NH—CH3
	VII-7	H	—NH—CH3
	VII-8	H	—NH—C2H5
	VII-9	H	—NH-nC3H7
	VII-10	H	—NH-nC4H9
	VII-11	H	—NH-tertC4H9
	VII-12	H	—NH-cycloC3H5
	VII-13	H	—NH-cycloC4H7
	VII-14	H	—NH-cycloC5H9
	VII-15	H	—NH-cycloC6H11
	VII-16	H	—NH-cycloC7H12
	VII-17	H	—NH—CH2—O—CH3
	VII-18	H	—NH—CH2—CH2—O—CH3
	VII-19	H	—NH-1-adamantyl
	VII-20	H	—NH-(4-HO—C6H5)
	VII-21	H	—NH-(2-CF3—C6H4)
	VII-22	H	—NH-(3-CF3—C4H4)
	VII-23	H	—NH-(4-CF3—C6H4)
	VII-24	H	—NH-(2-OCH3—C6H4)
	VII-25	H	—NH-(3-OCH3—C6H4)
	VII-26	H	—NH-(4-OCH3—C6H4)
	VII-27	H	—NH-(2-SCH3—C6H4)
	VII-28	H	—NH-(3-SCH3—C6H4)
	VII-29	H	—NH-(4-SCH3—C6H4)
	VII-30	H	—NH-(2-N(CH3)2—C6H4)
	VII-31	H	—NH-(3-N(CH3)2—C6H4)
	VII-32	H	—NH-(4-N(CH3)2—C6H4)
	VII-33	H	—NH-(4-CN—C6H4)
	VII-34	H	—NH-(4-Cl—C6H4)
	VII-35	H	—NH-(4-Br—C6H4]
	VII-36	H	—NH-(4-F—C6H4]
	VII-37	H	—NH-(4-CH3—C6H4)
	VII-38	H	—NH-(2-NO2—C6H4)
	VII-39	H	—NH-(3-NO2—C6H4)
	VII-40	H	—NH-(4-NO2—C6H4]
	VII-41	H	—NH-(2,4-OCH3—C6H3)
	VII-42	H	—NH-(3,4-OCH3—C6H3)
	VII-43	H	—NH-(3,4,5-OCH3—C6H2)
	VII-44	H	—NH-(3,4-CH2OCH2—C6H3)
	VII-45	H	—NH-(2,3-CH2OCH2—C6H3)
	VII-46	H	—NH-2-pyridinyl
	VII-47	H	—NH-2-furanyl
	VII-48	H	—NH-2-thienyl
	VII-49	H	—NH-3-pyridinyl
	VII-50	H	—NH-3-furanyl
	VII-51	H	—NH-3-thienyl
	VII-52	H	—NH-4-pyridinyl
	VII-53	H	—NH-2-oxazolyl
	VII-54	H	—NH-3-isoxazolyl
	VII-55	H	—NH-4-isoxazolyl
	VII-56	H	—NH-5-isoxazoyl
	VII-57	H	—NH-2R-(but-2-yl)
	VII-58	H	—NH-2S-(but-2-yl)
	VII-59	H	—NH—O—CH3
	VII-60	H	—N(CH3)(OCH3)
	VII-61	H	—N(—(CH2)3—O—)
	VII-62	H	—NH—O—CH2—C6H5
	VII-63	H	—N(CH3)(O—CH2—C6H5)
	VII-64	H	—N(—(CH2)2—CH(C6H5)—O—)
	VII-65	H	—NH—O—C2H5
	VII-66	H	—N(C2H5)(OC2H5)
	VII-67	H	—N(CH3)(OC2H5)
	VII-68	H	—NH—O-isoC3H7
	VII-69	H	—N(CH3)(O-isoC3H7)
	VII-70	H	—NH—O-nC3H7
	VII-71	H	—N(CH3)(O-nC3H7)
	VII-72	H	—NH—O-nC4H9
	VII-73	H	—N(CH3)(O-nC4H9)
	VII-74	H	—NH—O-tertC4H9
	VII-75	H	—N(CH3)(O-tertC4H9)
	VII-76	H	—NH—O—C6H5
	VII-77	H	—N(CH3)(O—C6H5)
	VII-78	H	—N(CH3)2
	VII-79	H	—N(CH2—C6H5)2
	VII-80	H	—N(C2H5)2
	VII-81	H	—N(isoC3H7)2
	VII-82	H	—N(nC3H7)2
	VII-83	H	—N(nC4H9)2
	VII-84	H	—N(C6H5)2
	VII-85	H	—NH—CH2—CH2—OH
	VII-86	H	—NH—(CH2)3—OH
	VII-87	H	—NH(—(CH2)2—CH(C6H5)—OH)
	VII-88	H	—NH—(CH2)4—OH
	VII-89	H	—NH(—CH(CH3)—CH2—OH)
	VII-90	H	—NH(—CH2—CH(CH3)—OH)
	VII-91	H	—NH(—CH(CH3)—(CH2)2—OH)
	VII-92	H	—NH(—(CH2)2—CH(CH3)—OH)
	VII-93	CH3	—NH—CH3
	VII-94	CH3	—NH—CH2—C6H5
	VII-95	CH3	—NH-isoC3H7
	VII-96	CH3	—NH—C6H5
	VII-97	CH3	—NH—C2H5
	VII-98	CH3	—NH-nC3H7
	VII-99	CH3	—NH-nC4H9
	VII-100	CH3	—NH-tertC4H9
	VII-101	CH3	—NH-cycloC3H5
	VII-102	CH3	—NH-cycloC4H7
	VII-103	CH3	—NH-cycloC5H9
	VII-104	CH3	—NH-cycloC6H11
	VII-105	CH3	—NH-1-adamantyl
	VII-106	CH3	—NH-2R-(but-2-yl)
	VII-107	CH3	—NH-2S-(but-2-yl)
	VII-108	CH3	—NH—O—CH3
	VII-109	CH3	—N(CH3)(OCH3)
	VII-110	CH3	—N(—(CH2)3—O—)
	VII-111	CH3	—N(CH3)2
	VII-112	CH3	—N(CH2—C6H5)2
	VII-113	CH3	—N(C2H5)2
	VII-114	CH3	—N(isoC3H7)2
	VII-115	CH3	—N(nC3H7)2
	VII-116	CH3	—N(nC4H9)2
	VII-117	CH3	—N(C6H5)2

[0206] Table 8:

[0207] A is Me2Val, B is Val, D is MeVal, E is Pro and F is of Formula IIIf, the substituent —(C═O)-G is in position 2 relative to the nitrogen and af is 1. G is of Formula IIg or IIIg.

[0208] The compounds are mixtures of diasteromers, configuration in F is either R, R (trans) or S,S (trans).

	No.	Rf	-G
	VIII-1	H	—NH—CH3
	VIII-2	H	—NH—CH2—C6H5
	VIII-3	H	—NH-isoC3H7
	VIII-4	H	—NH—C6H5
	VIII-5	H	1,3-Thiazol-2-yl-amide
	VIII-6	H	—NH—CH3
	VIII-7	H	—NH—CH3
	VIII-8	H	—NH—C2H5
	VIII-9	H	—NH-nC3H7
	VIII-10	H	—NH-nC4H9
	VIII-11	H	—NH-tertC4H9
	VIII-12	H	—NH-cycloC3H5
	VIII-13	H	—NH-cycloC4H7
	VIII-14	H	—NH-cycloC5H9
	VIII-15	H	—NH-cycloC6H11
	VIII-16	H	—NH-cycloC7H12
	VIII-17	H	—NH—CH2-O-CH3
	VIII-18	H	—NH—CH2—CH2—O-CH3
	VIII-19	H	—NH-1-adamantyl
	VIII-20	H	—NH-(4-HO-C6H5)
	VIII-21	H	—NH-(2-CF3—C6H4)
	VIII-22	H	—NH-(3-CF3—C6H4)
	VIII-23	H	—NH-(4-CF3—C6H4)
	VIII-24	H	—NH-(2-OCH3—C6H4)
	VIII-25	H	—NH-(3-OCH3—C6H4)
	VIII-26	H	—NH-(4-OCH3—C6H4)
	VIII-27	H	—NH-(2-SCH3—C6H4)
	VIII-28	H	—NH-(3-SCH3—C6H4)
	VIII-29	H	—NH-(4-SCH3—C6H4)
	VIII-30	H	—NH-(2-N(CH3)2—C6H4)
	VIII-31	H	—NH-(3-N(CH3)2-C6H4)
	VIII-32	H	—NH-(4-N(CH3)2-C6H4)
	VIII-33	H	—NH-(4-CN-C6H4)
	VIII-34	H	—NH-(4-Cl-C6H4)
	VIII-35	H	—NH-(4-Br-C6H4]
	VIII-36	H	—NH-(4-F-C-6H4]
	VIII-37	H	—NH-(4-CH3-C6H4)
	VIII-38	H	—NH-(2-NO2-C4H4)
	VIII-39	H	—NH-(3-NO2-C6H4)
	VIII-40	H	—NH-(4-NO2-C6H4]
	VIII-41	H	—NH-(2,4-OCH3-C6H3)
	VIII-42	H	—NH-(3,4-OCH3-C6H3)
	VIII-43	H	—NH-(3,4,5-OCH3-C6H2)
	VIII-44	H	—NH-(3,4-CH2OCH2-C6H3)
	VIII-45	H	—NH-(2,3-CH2OCH2-C6H3)
	VIII-46	H	—NH-2-pyridinyl
	VIII-47	H	—NH-2-furanyl
	VIII-48	H	—NH-2-thienyl
	VIII-49	H	—NH-3-pyridinyl
	VIII-50	H	—NH-3-furanyl
	VIII-51	H	—NH-3-thienyl
	VIII-52	H	—NH-4-pyridinyl
	VIII-53	H	—NH-2-oxazolyl
	VIII-54	H	—NH-3-isoxazolyl
	VIII-55	H	—NH-4-isoxazolyl
	VIII-56	H	—NH-5-isoxazoyl
	VIII-57	H	—NH-2R-(but-2-yl)
	VIII-58	H	—NH-2S-(but-2-yl)
	VIII-59	H	—NH—O—CH3
	VIII-60	H	—N(CH3) (OCH3)
	VIII-61	H	—N(—(CH2)3—O—)
	VIII-62	H	—NH—O—CH2—C6H5
	VIII-63	H	—N(CH3) (O—CH2—C6H5)
	VIII-64	H	—N(—(CH2)2—CH(C6H5)—O—)
	VIII-65	H	—NH—O—C2H5
	VIII-66	H	—N(C2H5) (OC2H5)
	VIII-67	H	—N(CH3) (OC2H5)
	VIII-68	H	NH—O-isoC3H7
	VIII-69	H	—N(CH3) (O-isoC3H7)
	VIII-70	H	—NH—O-nC3H7
	VIII-71	H	—N(CH3) (O-nC3H7)
	VIII-72	H	—NH—O-nC4H9
	VIII-73	H	—N(CH3) (O-nC4H9)
	VIII-74	H	—NH—O-tertC4H9
	VIII-75	H	—N(CH3) (O-tertC4H9)
	VIII-76	H	—NH—O—C6H5
	VIII-77	H	—N(CH3) (O—C6H5)
	VIII-78	H	—N(CH3)2
	VIII-79	H	—N(CH2—C6H5)2
	VIII-80	H	—N(C2H5)2
	VIII-81	H	—N(isoC3H7)2
	VIII-82	H	—N(nC3H7)2
	VIII-83	H	—N(nC4H9)2
	VIII-84	H	—N(C6H5)2
	VIII-85	H	—NH—CH2—CH2—OH
	VIII-86	H	—NH—(CH2)3—OH
	VIII-87	H	—NH(—(CH2)2—CH(C6H5) —OH)
	VIII-88	H	—NH—(CH2)4—OH
	VIII-89	H	—NH(—CH(CH3)—CH2—OH)
	VIII-90	H	—NH(—CH2CH(CH3) —OH)
	VIII-91	H	—NH(—CH(CH3)—(CH2)2OH)
	VIII-92	H	—NH(—(CH2)2—CH(CH3)—OH)
	VIII-93	CH3	—NH—CH3
	VIII-94	CH3	—NH—CH2—C6H5
	VIII-95	CH3	—NH-isoC3H7
	VIII-96	CH3	—NH—C6H5
	VIII-97	CH3	—NH—C2H5
	VIII-98	CH3	—NH-nC3H7
	VIII-99	CH3	—NH-nC4H9
	VIII-100	CH3	—NH-tertC4H9
	VIII-101	CH3	—NH-cycloC3H5
	VIII-102	CH3	—NH-cycloC4H7
	VIII-103	CH3	—NH-cycloC5H9
	VIII-104	CH3	—NH-cycloC6H11
	VIII-105	CH3	—NH-1-adamantyl
	VIII-106	CH3	—NH-2R-(but-2-yl)
	VIII-107	CH3	—NH-2S-(but-2-yl)
	VIII-108	CH3	—NH—O—CH3
	VIII-109	CH3	—N(CH3) (OCH3)
	VIII-110	CH3	—N(—(CH2)3—O—)
	VIII-111	CH3	—N(CH3)2
	VIII-112	CH3	—N(CH2—C6H5)2
	VIII-113	CH3	—N(C2H5)2
	VIII-114	CH3	—N(isoC3H7)2
	VIII-115	CH3	—N(nC3H7)2
	VIII-116	CH3	—N(nC4H9)2
	VIII-117	CH3	—N(C6H5)2

[0209] Mass spectrometry data of selected examples:

I-1   2-(Me2Val-Val-MeVal-Pro-NH)—C6H4C(O)NHCH3
      FAB-MS: 588 (M + H+)
I-2   2-(Me2Val-Val-MeVal-Pro-NH)—C6H4C(O)NHCH2C6H5
      FAB-MS: 664 (M + H+)
I-3   2-(Me2Val-Val-MeVal-Pro-NH)—C6H4C(O)NHCH(CH3)2
      FAB-MS: 616 (M + H+)
I-4   2-(Me2Val-Val-MeVal-Pro-NH)—C6H4C(O)NHC6H5
      FAB-MS: 650 (M + H+)
I-5   2-(Me2Val-Val-MeVal-Pro-NH)—C6H4C(O)NH(thiazol-2-yl)
      FAB-MS: 657 (M + H+)
I-6   2(Me2Val-Val-MeVal-ProNH)-4, 5-bis(methoxy)C6H2C(O)NHCH3
      FAB-MS: 649 (M + H+)
I-7   2-(Me2ValVal-MeVal-ProNH)-3-cyclopentanyl-C6H3C(O)NHCH3
      FAB-MS: 656 (M + H+)
I-64  2-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CO—N(—(CH2)2—
      CH(C6H5)O—)
      (mix. of diastereomers) FAB-MS: 706 (M + H+)
I-79  2-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CO—N(CH2C6H5)2
      FAB-MS: 754 (M +H+)
I-86  2-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CO—NH—(—(CH2)3 —
      OH)
      FAB-MS: 632 (M + H+)
I-87  2-(Me2Val-Val-MeVal-Pro-NH)—C6H4C(O)NH((CH2)2CH(C6H5)
      OH)
      FAB-MS: 708 (M + H+)
I-143 2-(Me2Val-Val-MeVal-Pro-N(CH3))—C6H4—CONHCH3
      FAB-MS: 601 (M + H+)
II-1  3-(Ne2Val-Val-MeVal-Pro-NH)—C6H4—CO—NHCH3
      FAB-MS: 588 (M + H+)
II-2  3-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CO—NH CH2C6H5
      FAB-MS: 664 (M + H+)
IV-1  2-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CO—CH3
      FAB-MS: 609 (M + H+)
IV-15 2-(Me2Val-Val-MeVal-Pro-NH)—C6H4—CO—C6H5
      FAB-MS: 635 (M + H+)

Evaluation of Biological Activity

[0210] In Vitro Methodology

[0211] Cytotoxicity was measured using a standard methodology for adherent cell lines, such as the microculture tetrazolium assay (MTT). Details of this assay have been published (Alley, M. C. et al., Cancer Research 48: 589-601, 1988). Exponentially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor were used to make microtiter plate cultures. Cells were seeded at 5000-20,000 cells per well in 96-well plates (in 150 mL of media), and grown overnight at 37° C. Test compounds were added, in 10-fold dilutions varying from 10−4 M to 10−10 M. Cells were then incubated for 48 hours. To determine the number of viable cells in each well, the MTT dye was added (50 mL of a 3 mg/mL solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline). This mixture was incubated at 37° C. for 5 hours, and then 50 mL of 25% SDS, pH 2, was added to each well. After an overnight incubation, the absorbance of each well at 550 nm was read using an ELISA reader. The values for the mean+/−SD of data from replicated wells were calculated, using the formula % T/C (% viable cells treated/control). The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC50.

Compound No. IC50 (mol/l)
I-1          4 × 10−7
I-2          >10−6
I-3          5 × 10−7
I-4          4 × 10−7
I-5          1.5 × 10−7
I-6          2 × 10−7
I-7          4 × 10−7
I-60         4 × 10−7
I-64         2.5 × 10−7
I-86         6 × 10−7
I-87         2 × 10−7
II-1         >10−6
II-2         >10−6
IV-1         >10−6
IV-15        7 × 10−8
VII-2        >10−6

[0212] In Vivo Methodology

[0213] Compounds of this invention may be further tested in any of the various preclinical assays for in vivo activity which are indicative of clinical utility. Such assays are conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted (“xenografted”), as is well known in this field. Test compounds are evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice.

[0214] More specifically, human tumors which have been grown in athymic nude mice are transplanted into new recipient animals, using tumor fragments which are about 50 mg in size. The day of transplantation is designated as day 0. Six to ten days later, the mice are treated with the test compounds given as an intravenous or intraperitoneal injection, in groups of 5-10 mice at each dose. Compounds are given daily for 5 days, 10 days or 15 days, at doses from 10-100 mg/kg body weight. Tumor diameters and body weights are measured twice weekly. Tumor masses are calculated using the diameters measured with Vernier calipers, and the formula:

(length×width2)/2=mg of tumor weight

[0215] Mean tumor weights are calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors.

[0216] The novel compounds of the present invention show good in vitro activity in the above-mentioned assay system.

Equivalents

[0217] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims.

Claims

1. A compound of the formula

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 IIg, 63

4. The compound of claim 1 wherein G is a β-hydroxy amino group of Formula IIIg, 67R9l 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 R10l 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 IVg, 68wherein R11l is a hydrogen atom and R12l 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—R13l or of the formula —S—R13l, and R13l is a C3-C10-cycloalkyl, straight-chain or branched C2-C16-alkenylmethyl, C1-C16-alkyl or halogen-substituted C1-C16-alkyl group; R13l is a monovalent radical of the formula —(CH2)el—R14l, el is 1, 2, or 3, and R14l is a saturated or partially unsaturated C3-C10 carbocyclic group; R13l is a monovalent radical of the formula —[CH2—CH═C(CH3)— CH2]fl—H, and fl is 1, 2, 3, or 4; R13l is a monovalent radical of the formula —[CH2—CH2—O]gl—CH3, and gl is between about 2 and about 4, or between about 40 and about 90; R13l is a monovalent radical of the formula —(CH2)hl—X, hl 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; R13l is a monovalent radical of the formula —(CH2)bl-Wl-R5l, bl is 2, 3, or 4, Wl is an oxygen atom, a sulfur atom or an NR6l group; R5l 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 R6l 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(R16l)(R15l), wherein R15l and R16l 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 R15l and R16l 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(R15l)(R16l), wherein R15l and R16l 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 R15l and R16l, 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: 69

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 Vg,

11. The compound of claim 1 wherein G is a monovalent radical of Formula VIg, 70bg 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-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 VIIg, 71dg is 0, 1, 2, or 3; 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-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 R19l, R20l 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 VIIIg, 72gg is 1 or 2, hg is 1 or 2, and R21l is a methyl, trifluoromethyl, ethyl or phenyl group.

14. A compound of the formula

15. A compound of the formula

16. A compound of the formula

17. A compound of the formula

18. A compound of the formula Me2Val-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.

19. A compound of the formula Me2Val-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.

20. A method for treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.

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