Title of Invention	DOLASTATIN 15 DERIVATIVES
Abstract	5 Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, A-B-D-E-F- (G)r- (K)s-L (I), . 10 and acid salts thereof, wherein A, B, D, E, F, G and K are a-amino acid residues, and sand r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a 13- hydroxylamino group, a hydrazido group, an alkoxy group, a i~~ .15 thioalkoxy group, an amin~fy group, or an oximato group. The present invention also includes a method for treating , cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable 20 composition. 4

Title of Invention

DOLASTATIN 15 DERIVATIVES

Abstract

5 Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, A-B-D-E-F- (G)r- (K)s-L (I), . 10 and acid salts thereof, wherein A, B, D, E, F, G and K are a-amino acid residues, and sand r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a 13- hydroxylamino group, a hydrazido group, an alkoxy group, a i~~ .15 thioalkoxy group, an amin~fy group, or an oximato group. The present invention also includes a method for treating , cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable 20 composition. 4

Full Text	DOLASTATIN 15 DERIVATIVES BACKGROUND OF THE INVENTION 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. , Sioche.Ti. Pharmacology, 40: 1859-1364 (19S0) ; Beckwith et al., J. Natl. Cancer Inst., 85: 483-488 (1993) and references cited therein). These include Dolastatins 1-10 [U.S. Patent No. 4,8iS,444, Issued to Pettit et al.) and Dclastatin 15 (3uropean 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 . The exceedingly small amounts of the various Dolastatin peptides present in Dolabella auricularia (about 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 [of.: biorg. Med. Chem. Lett. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790; WO 93 23424] . 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 Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, and acid salts thereof, wherein A, B, D, E, F, G and K are a-amino acid residues, and s and r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a p-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group. Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. An additional embodiment of the present invention is a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition. DETAILED DESCRIPTION OF THE INVENTION 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. 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. Dolastatin 15 is also expensive to s"ynthesize 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 Dolastatin 10 and Dolastatin 15. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail. For the purposes cf 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, the unit -N(R)R", wherein R. and R" are each a monovalent radical, can, together with the nitrogen atom, form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom can together form a divalent radical, such as an oxygen atom or an alkylidene group, for example, a propylidene group. For the purposes of the present invention, the term "normal alkyl" refers to an unbranched, or straight chain, alkyl group, for example, normal propyl (rr-propyl, -CH2CH2CH3). The compounds of the present invention can be represented by Formula 1, wherein A, B, D, E, F, G, and K are a-amino acid residues; s and r are each, independencly, 0 or 1; and L is a monovalent radical such as an amino group, an N"-substituted amino group, a j3-hydroxy!amino group, a hydrazidc group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an cximato group. The peptides of Formula I are generally composed of L-amino acids but they can contain one or more D-amino acids. In the following discussion, reference to a particular amino acid includes both enantiomers unless a specific enantiomer is indicated. The present compounds 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. 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 Identity of A In one embodiment, A is a proline derivative of Formula II3, where n is an integer, preferably 0, 1, 2, or 3. Rg is a monovalent radical, such as a hydrogen atom or an unsubstitiited or fluorine-substituted alkyl group, for example a normal, branched or cyclic C1-C3-alkyl group which is, optionally, substituted by from 1 to about 3 fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2,2-trifluorcethyl, 1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropyl are preferred; In this embodiment, R1 a is a monovalent radical, such as a hydrogen atom, an alkyl group, such as a methyl, ethyl or propyl group, or a phenyl group. The phenyl group can be substituted; suitable substituents include one or mare halogen atoms, with fluorine, chlorine and bromine atoms preferred, C-C-alkyl groups, methoxy, ethoxy, trifluoromethyl or nitro groups. Rg and R1 together can also form a propylene bridge. fa" a" a a each, independently, a monovalent radical, such as a hydrogen atom or an alkyl, preferably, methyl, group. In another embodiment, A is a substituted glycine derivative of Formula Ilia, where R has the meaning stated for R in Formula IIa and, R- is a monovalent radical, for example, a hydrogen atom or a C,-Cg-alkyl group, preferably a methyl, ethyl or propyl group. In this embodiment, R is monovalent radical, such as an alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl group. Suitable examples include methoxymechyl, 1-methoxyethyl, 1,1-dimethyl-hydroxymethyl, 1-trifluoromethylethyl, 1-trifluoromethyl-2, 2,2-trifluoroethyl, vinyl, and 1-methylvinyl. Phenyl substituents can include one or more halogen atoms, preferably fluorine, chlorine or bromine atoms, and alkyl, methoxy, ethoxy, trifluororaethyl, and nitro groups. When R-g is an alkyl group, R can also be a Cj_-Cg-alkyl, cycloalkyl, unsubstituted benzyl or substituted benzyl group. Suitable benzyl substituents include one or more halogen atoms, such as fluorine, chlorine or bromine atoms, C1-C4-alkyl groups, and methoxy, ethoxy, trifluoromethyl and nitro groups. R"a is a monovalent radical, preferably a methyl, ethyl or isopropyl group. In anocher embodiment, A is an a-amino acid derivative of Formula IVg, where m is an integer, preferably 1 or 2, and Rg and R" have the meanings stated for these substituents in Formula III,. In another embodiment, A is an a-amino acid derivative of Formula V,, where Rg and R" have the meanings stated for Rg and R"a in Formula 111- In a further embodiment, A is a substituted proline derivative of Formula VI, where R and R have the meanings stated for Rg and R- in Formula IX, and X is a monovalent radical, preferably a hydroxyl, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. In another embodiment, A is a thiaprolyl derivative of Formula VII, where Rg has the meaning stated for Rg for Formula 11. In another embodiment, A is a 2-azabicyclo [2.2.1]heptane-3-carboxylic acid derivative of Formula IXg, where Z is a single or double bond and R has the meaning stated for Formula Ilg. The 3-carbonyl substituent can have either the exo or endo orientation. In another embodiment, A is an a-amino acid derivative of Formula X, where n has the meaning as stated for n for Formula llg, and R"" and R have the meanings as stated for R , and Rg for Formula Illg. Idencity of B B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue. B can also be an a-amino acid residue of Formula IIv preferably, a hydrogen atom and Rj is, for example, an alkyl, alkoxyalkyl or alkenyl group. In preferred smbodiments, R, is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a ■nethoxymethyl group, a l-methoxyethyl group or a 1-methylvinyl group. Additionally, R"" and Rj together can be an isopropylidene group. Identity of D D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkyl-norleucyl, N-alkyl-isoleucyl, W-alkyl-alio-isoleucyl or N-alkyl-norvalyl residue, where the N-alkyl group is preferably a methyl group or an ethyl group. In another embodiment, D is an a-amino acid residue of Formula IIQ, where R has the meaning stated for R in Formula Illgy Rd is a monovalent radical, preferably a hydrogen atom, and Rd is a monovalent radical, for example, an alkyl, alkoxyalkyl or alkenyl group. In preferred embodiments, Rd is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-raethylvinyl group, such as a cyclopropyl group, a methoxymethyl group, a l-methoxyethyl group or a 1-methylvinyl group. Additionally, R""" and R together can form an isopropylidene group. Alternatively, D can be a proline derivative of Formula III where n is an integer, for example, 1 or 2, and R has the meaning stated for R-"- in Formula Ilia- X is a monovalent radical, preferably a hydrogen atom, and, in the case where n equals 1, can also be a hydroxy or alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. Identity of E E is a prolyl, thia20lidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue, or a cyclic a-amino carboxylic acid residue of Formula Ilg, where ng is an integer, preferably 0, 1 or 2. R has the meaning stated for R""" in Formula III- Re " R"g are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group. R"" is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. Rg is a monovalent radical, preferably a hydrogen atom or a fluorine atom, In the case where ng is 1, Re snd R""g can together form a double bond, or R"g and R" can together be a double-bonded oxygen radical. In the case where n has the value 1 or 2, R-"-g and R can together form a double bond. In another embodiment, E is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula Illg, where Rg is an alkyl group, such as methyl or ethyl, and R-e has the meaning stated for R-" in Formula ril. Identity of F F is a prolyl, thiazolidinyl-4;-carbonyl, homoprolyl or hydroxyprolyl residue. F can also be a cyclic a-amino acid residue of Formula II;, where nf is an integer, preferably 0, 1 or 2. R has the meaning stated for R"- in Formula Illg. Rf and R-f are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group. Rf is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. RF is a monovalent radical, preferably a hydrogen atom or a fluorine atom. In the case where n has the value 1, R"f and Rf together can form a double bond or Rf and Rf can together be a double-bonded oxygen radical. In the case where n has the value 1 or 2, H and R= can together form a double bond. In another embociiment, F is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula Illf where Rf is a monovalent radical, such as a methyl or ethyl group, and Rf has the meaning stated for R in Formula Ilia- In another embodiment, F is an N-alkylglycyl or N- alkylalanyl residue, and the alkyl group is, preferably, a methyl group or an ethyl group. Identity of G G is an ci-amino acid residue of Formula Ilg, wherein B}g is a hydrogen atom, or an alkyl group, for example, methyl, ethyl or n-propyl. Rg can be, for example, a hydrogen atom, or an alkyl, arylalkyl, heteroarylalkyl or aryl group. Preferably, R is an ethyl; isopropyl, tertbutyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl- 2 -methyl, n-butyl, 2,2-dimethylpropyl, naphthylmethyl, or n-propyl group, or a substituted or unsubstituted phenyl group. Suitable phenyl substituents include ons or more halogen, preferably fluorine, chlorine or bromine, atoms, C-Cj-alkyl groups, methoxy, ethoxy, nitro or trifluoromethyl groups or a dioxomethylene group. Alternately, R"""g and Rg can, together with the a-carbon atom, form a cyclopentane or cyclohexane ring or a benzo-fused cyclopentane ring, such as, for example, the indanyl arQUD, where E"""j_ is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated Ci_-Ci3-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C-C-alkoxy group, or a substituted or unsubstituted aryloxy-C;;_-C5-alkoxy or heteroaryl-Cj_-Cg-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, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3- triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyriraidine, benzimidazole, benzopyran, benzothiazole, oxadiazole,thiadiazole or pyridine. Suitable aryi substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C]_-C4-alkyl groups, methoxy, ethoxy or trifluororaethyl groups, a dioxymethylene group or nitro groucs. Ri is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C]_-C;j_a-alkyl group, a C3-Cio-cycloalkyi group, a substituted or unsubstituted airyl group, or a substituted or unsubstituted heteroaryl 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, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3- triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quincline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole,thiadiazole or pyridine. Suitable aryl substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C1-C-alkyl groups, methoxy, ethoxy or trifluorom,ethyl groups, a dioxyraethylene group or nitro groups. Rj_ can, alternately, be of Formula II, monovalent radical, which can be a saturated or partially unsaturated carbocyclic system comprising from about 3 to about 10 carbon atoms, a substituted or unsubstituted aryl or heteroaryl group, with aryl and heteroaryl and preferred substituents having the meaning stated for Rj_ in Formula wherein Wj is an oxygen or sulfur atom or an N-R]_ group. Rx is a monovalent radical, such as a hydrogen atom, a C3_-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 Ri from Formula IIi- Ri is a monovalent radical, preferably a hydrogen atom, a C1-C-alkyl group or a C3-C7-cyGloalkyl group, a Cj_-Cig-alkanoyl group, a benzoyl group or a substituted or unsubscituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning where bi is an integer, preferably 2, 3 or 4. Zi can be a monovalent radical such as a formyl, aminocarbonyl or hydrazinccarbonyl group, or a cyclic or acyclic acatal or chioacetal group. in which h has the above-mentioned meaning. R; can be a monovalent radical, such as a polyglycol group of the formula -0-(CH2-CH2-O) j]_-CH3, where di is an integer, preferably in the range from about 2 to about 4 or from about 40 to about 90. R2_ can further be a carbohydrate of Formula VIj., where Ri is a monovalent radical, such as a hydrogen atom, a C1-C-alkanoyl or alkyl group, a benzoyl group or a a where R ]_ is a monovalent radical such as a hydrogen atom, a C1-Cg-alkyl group or a substituted or unsubstituted aryl group, with aryl and its preferred substituents having the meaning stated for R;_. R""" Is a monovalent radical, preferably a hydrogen atom, alkyl, for example, methyl, or and R""""! is a monovalent radical, preferably a hydrogen atom. R""! can be a monovalent radical such as a hydrogen atom, a normal or branched C-Cg-alkyl group, a- C2-C2-cycloalkyl group, a Cj-Cg-cycloalkyl-C1-C.-alkyl group or a substituted or unsubstituted aryl, heteroaryl, aryl-C;,-C-alkyl or heteroaryl-C1-C-alkyl group, where aryl, heteroaryl and their preferred substituents can be selected from among the options listed for R". When r and/or s is 1, R"-" can also be selected from among the options listed above for Ri, and the two radicals together can additionally form a propylene or butylene bridge. Another subclass of compounds of this invention includes peptides of Formula I wherein L is a monovalent radical of the formula -0-R--j or the formula -S-R~, where R-"-i_ is a monovalent radical, such as a C3-Cio-cycloalkyl group, a normal or branched Cj-Cig-alkenylmethyl group or a C1-CiQ-alkyl group which can be substituted by from l to about 5 halogen, preferably fluorine, atoms. Ri can also be the radical - (CH2) g-R"i, where e is an integer, preferably 1, 2 or 3. R2 monovalent radical, preferably a saturated or partially unsaturated C3-C2o-carbocycle. R"""i_ can further be the monvalent radical - [CH2-CH=C (CH3>-CK2] f-H, where f is an integer, preferably 1, 2, 3 or 4. R--3_ can also be the radical - [CH2-CH2-O] g-CH3, where g is an integer, preferably in the range from 1 to about 5. R-i can also be the radical - (CH2} h-ryl or - (CH2) h-iieteroaryl, where aryl and heteroaryl can also be substituted and, along with their preferred substituents, can be selected from the group listed for R i- h is an integer, preferably 0, 1, 2 or 3. R-"i can further be the radical - CCK;) t,-Wi-R"i. b, W and Ri can each be selected from am.ong the options described for Formula IVj, Another subclass of ccnipounds of this invention includes peptides of Formula I in which L is an aminoxy group of the formula -0-N (Ri_) {R-"-j,) , where Ri and R" are each a monovalent radical, which can independently be a hydrogen at om, a. norinal or branched Cj-Cg-alkyl group, which can be substituted by halogen, preferably fluorine, atoms, a C3-Ca-cycloalk:yl group, a Cs-Cg-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 R j_. R-"-""; can be selected from among the options listed for R. Additionally, Ri and R can together form a 5-, S- or 7-membered heterocycle. The compounds of the present invention further comprise the salts of the compounds described above with physiologically tolerated acids. Another subclass of compounds of this invention includes peptides of Formula I wherein L is an oximato group of the formula -0-N=C {R-j_) [R\) , Ri and RS can be selected from amiong 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. In or.e embodiment, the invention provides compounds of ■ormula I wherein A is an amino acid derivative selected :rom among N-alkyl-D-prolyl, N-alk:yl-L-prolyl, N-alkyl-D-)iperidine-2-carbonyl, N-alkyl-L-piperidine-2-carbonyl, 1, N-dialkyl-D-2-ethyl-2-phenylglycyl and N, N-dialkyl--L-2-;chyl-2-phenylglycyl, wherein alkyl is methyl, ethyl or .sopropyl; and B is a valyl, isoleucyl or 2-t-butyl-L-[lycyl res idue. Preferred compounds of the invention include compounds of Formula I wherein r and s are each 0. A is an amino acid derivative selected from among D-N-methyl-piperidine-2-carbonyl, L-N-methyl-piperidine-2-carbonyl, NN-dimethylamino-isobutyryl, N-methyl-L-prolyl, N-methyl-L-thiazolidine-4-carbonyl, N,N-dimethyIglycyl, L-prolyl, L-piperidine-2-carbon.yl, N~propyl-D-piperidine-2-carbonyl, D-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-methyl- [2,2,5,5-tetramethylj-L-thia20lidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropylglycyl , N,N-dimethyl-L-2-ethyl-2-phenylglycyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl, D-prolyl, N-methyl-D-prolyl, N,N-diraethyl-2-(2-fluorophenyl)glycyl, 1-aza-[3,3,0]bicyclooctyl-5-carbonyl, N,N-dimethyl-2- [4-fluoro]phenyl-glycyl, N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carbonyl, 2-(R,S}-ethyl-2-phenylglycyl, D,L-1-aminoindane-l-carbonyl, N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl, 2-[N,N-dimethylaminc]indane-2-carbcnyl, 5-[N, N-dimethylaminc]-5,6,7,8-tetrahydro-naphthalene-5-carbonyl, N"-isopropyl-2- (R, S) -ethyl-2-phenylglycyl, 1-[N,N-diraethylamino] indane-2-carbonyl, N,N-dimethyl- 2-propyl-2-phenylglycyl, N,N-dimethyl-2-[4-methoxy]phenyl-glycyl, N-methyl-3-hydroxy-D,L-valyl, N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl, N-methylpiperidine-2-carbcnyl, N-methyl-L-prolyl, N-methyl-1,2,3,4-tetrahydrcisoquinoline-l-carbonyl, N-methyla2et;idine-2-carbonyl, N-isopropylazetidine- 2-carbonyl, N,N-dimethyl- [0~meChyl]seryl, N,N-dimethyl-[0-methyl]threonyl, K-methyl-1, 2,3, 4-tetrahydrcisoguinoliiie-3-carbonyl, 1-[N,N-dimGthylamino]cyclohexyl-1-carbonyl, 1-[N,N-dimethylamino]cyclopenCyl-1-carbonyl and 1,2,3,4-tetrahydroisoquinoline-3-carbonyl. B is valyl, isoleucyl or 2-tert-butylglycyl. D is H-methylvalyl, N- methyl-2-t-butylglycyl or N-methylisoleucyl. E and F are each, independently, prolyl, thiaprolyl, homoprolyl, hydroxyprolyl, 3,4-didehydroprolyl, 4-fluoroprolyl, and 3- methylprolyl. L is an alkoxy group or an amino group of the formula R-j-N-R, wherein Ri_ and Rj_ are independently selected from the group consisting of hydrogen, alkoxy, hydroxy, alkyl and alkylaryl. In a particularly preferred subset of the compounds of the invention, r and s are each 0. A is an amino acid derivative selected from among D-N-methyl-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropyl-glycyl, N-methyl-D-prolyl, 1-aza-[3,3,0]bicyclocctyl-5-carbonyl, N-methyl-[2,2,5,5-tetramethyl] -thiazolidine-2-carbonyl, 2-(R,S)-ethyl-2-phenylglycyl, D,L-l-aminoindane-l-carbonyl, N,N-dimethyl-2-{R,S)-methyl- 2-phenylglycyl, 5-[N,N-dimethylamino] -5,S,7,8 -teCrahydro-naphthalene- 5 -carbonyl, 1- [N,N-diTtiethylaminc] indane-2-carbcnyl, N,N-dimethyl-2-propyl-2-phenylglycyl, N, N-dimethyl-L-2-ethyl-2-phenylglycyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl, N-meChyl-3-hydroxy-D,L-valyl, N,N-dimethyl-D,L-2-isoprcpyl-2-phenylglycyl, N-methyl-piperidine-2-carbonyl, N-methyl-D,L-prolyl, N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl, N"-methylazetidine-2-carfaonyl, N"isopropylazet:idine-2-carbonyl N,N-dimethyl-[0-methyI]seryl, 1-[N,N-dimQthylamino]cyclohexyl-1-carbcnyl and 1-[NjW-dimethylamino]cyclopentyl-l-carbonyl. B is valyl; D is N-methylvalyl; and E and F are each prolyl. L is a C1- Cg-alkoxy group or an amino group of the formula R-N-Ri, wherein R"i and Rj_ ars each independently selected from the group consisting of hydrogen, Cj-Cg-alkoxy, hydroxy, normal, cyclic or branched C1-Ci2-alkyl, and phenylalkyl. Synthetic Methods 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 hy linking suitable small peptide fragments. In sequen¬tial assembly, 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. In both sequential assembly 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 lin.kage ara described in detail in standard references on peptide chemistry, including Miiller, Methoden de?r praanischen Ch,emi> Vol, XV/2, 1-364, Thieme Verlag, Stuttgart, (1974); Stewart: and Young, Solid Phase Peptide Synthegj-s. 31-34 and 71-82, Pierce Chemical Company, Rockford, IL (1984); Eodanszky et ai. , Peptjie 5vnthe=;-i g. 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 prsformed 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) , l-ech.oxycarbcnyl-2-ethoxy-1,2-dihydroqiiinoline (EEDQ) , pivaloyl chloride, 1-ethyl-3 - {3-dimenhylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N",N"-bis (2-oxo-oxazolidinyl) amidophosphoryl chloride {BOP-Cl) , bromo-tris (pyrrolidine)phosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro"s reagent (SOP, PyBop), 0-benzotrlazolyl-N,N,N",N"-tetramethyluronium salts (HBTU), 0-azabenzotriazolyl-N,N,N",N"-tetramethyluronium salts (HATU) , diethylph.osphoryl cyanide (DEPCN) , 2,5-diphenyl-2,3- dihydro-3-oxo-4- hydroxythiophene dioxide (Steglich"s reagent; HOTDO), and 1,1"-carbonyldiimidasole (GDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMA.P) , N-hydroxy-benzotriazole (HOBt), N-hydroxyazabenzotriasole (KOAt), K-hydroxybenzotriazine (HOOEt), N-hydroxysuccinimide (HOSu) or 2-hycroxypyridine. Although the use of protecting croups is generally noc 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) technicrues. Identified in each case is the protective group on the 3(-amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Miiller, Methoden der oraanischp.n Chemie Vol. XV/l, 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: (1963) 2149. Solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, especially water, N,K-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THE), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents. 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, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents. Following synthesis, the pepnide 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 acenic 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. Partial deprotection of the peptide may also be necessary prior to certain derivatisaticn reactions. For example, peptides dialkylated at the N-cerminus can be prepared by coupling the appropriate N,N-di- alkylamino acid to Che peptide in solution or on the polymeric support, by reductive alkylation of the resin-bound peptide in DMF/l% acetic acid with NaCNBHj and the appropriate aldehyde or by hydrogenation of the peptide in solution in the presence of the appropriate aldehyde or ketone and Pd/carbon. The various non-naturally occurring amino acids as well as the various non-amino acid moieties disclosed herein can be obtained from commercial sources or synthesized from comm.ercially available staring materials using methods known in the art. For example, amino acid building blocks with R and R groups can be prepared according to the method described by Wuensch and Weyl, Methodp der OraanischR Chemie. vol. XV, Springer Verlag: Stuttgart, p. 306 (1974) and references cited therein. Methods of Use of the Claimed Compounds In another eTJDodiment, the present invention comprises a method for partially or zotally inhibiting formation of, or otherwise treating (e.g. , reversing or inhibiting the further development of} sclid tumors {e.g., tumors of the lung, breast, colon, prostane, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g., leukemias, lymphomas) in a mammal, for example, a hum.an, by administering to the mammal a therapeutically effective amount of a compound or a combination of compounds of Formula I. The compound(s) may be administered alone or in a pharmaceutical composition comprising the compound(s) and an acceptable carrier or diluent. Administration can 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 intraperitcneally, nasally or rectally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound or compounds of Formula I together with a pharmaceutically accepted carrier appropriate for the desired routs of administration. Such pharmaceutical compositions may be combination products, i.e., they may also contain other therapeutically active ingredients. 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 cf 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 cf the particular com.pound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the freq"j.ency at treatment; the administration of other therapies; and the effect desired. A typical daily dose will be from about 0.05 to about 50 milligrams per kilogram of body weight by oral administration and from about 0.01 to about 20 milligrams per kilogram of body //eight by parenteral administration. 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 ;onventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet iisintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sucker et al.: pharmazeutische Technologje, rhieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way typically contain from about 1 to ibout 90% by weight of the active substance. The present invencion will now be illustrated by the rollowing examples, which are not limiting. EXAMPLES 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 = dichlcromethane, DMSO = dimethylsulfoxide, Bu = butyl, Et = ethyl, Me = methyl, B2I = benzyl. In the compounds listed, all proteinogenous amino acids are L-amino acids unless otherwise noted. Other abbreviations used: Me2Val = N,N-dimethylvaline, MeVal = N-methylvaline, Bn = benzyl, MejAib = [2-N",N"-dimethylaraino] -isobutyric acid. General Procedures The peptides of the invention are synthesized either by classical solution synthesis using standard Z- and Boc-methodology as described above or by standard methods of solid-phase synthesis using Boo and Fm.oc protective group techniques. In the case of solid phase synthesis, the N,N-dialkyl-penta- or hexapeptide acids are liberated from the solid support and further coupled with the corresponding C-terminal amines in solution. BOP-CI and PyBrop were used as reagents for coupling of the amino acid following the N-methylarriinc acids. The reaction times were correspondingly increased. For reductive alkylation of the N-terminus, the peptide-resin was deprotected at the N Cerininus and then reacted wich a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNEKj. After the reaction was complete (negative Kaiser test) the resin was washed several times with water, isoprccanol, DM? and dichlcromethane. In solution synthesis, the use of either Boc-orotected amino acid NCAs (N-tert.-butyloxycarbonyl-amino acid-N-carboxy-anhydrides), Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) , or the use of pivaloyl chloride as condensing agent" respectively is most advantageous for coupling of the amino acid following the N-methylamino acids. Reductive alkylation of the N terminus can e.g. be achieved hy reaction of the N-terminally deprotected peptides or amino acids with the corresponding aldehydes or ketones using NaCNBHa or hydrogen-Pd/C. Valyl-N-methylvalyl-prolyl-prolylbenzylamide hydrochloride for example was prepared according to methods disclosed in German Patent Application No. DE 19527575 Al. Purification and characterization of the peptides Peptide purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% KOAc, SEPHADEX LH20/MeOH}, medium pressure chromatography (stationary phase; HD-SIL C-IS, 20-45 micron, 100 Angstrom; mobile phase: gradient with. A = 0.1% TFA/ MeOK, B = 0.1% TPA/water), preparative HPLC (stationary phase: Waters Delta-Pak C-IS, 15 micron, 100 Angstrom; mobile phase: gradient with A = 0.1 % TFA/MeOH, B = 0.1 % TFA/water), or by crystallization. The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 micron, 300 A; mobile phase: acetonitrile-water gradient, buffered with 0.1% TFA, 40°C; or 3.9 mm VYDAC C-18, 30°C}. Characterization was by fast atom bombardment mass spectroscopy and NMR-spectroscopy. Example 1 Synthesis of [N-Methyl"L-piperidine-2-carbonyll-Val-MeVal -Pro-Pro-NHBn (Compound 1} and [N-Methyl-D-piperidine-2-carbQnyl]-Val-MeVal -Pro-Pro-NHBn {Compound 2) "reparation of N-methyl-piperidine-2-carboxylic acid N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 r) was dissolved in a mixture of 100 ml methanol and 10 ml 7ater. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was :hen neutralized with hydrochloric acid, evaporated to iryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step. Preparation of [N-Methyl-piperidine-2-carbanyl]-Val-MeVal-Pro-Pro-NHBn The residue prepared as described above (5.05 g) and i-Val-MeVal-?ro-Pro-NHBn x HCl (4.88 g> were dissolved in SO ml dry DMF. After cooling the solution in an ice bath, L.52 g DEPCN and 2.S6 ml triethylamine were added. The treacticn mixture was stirred at 0°C for 2 h and then at room temperature overnight. The DMF was rem.oved by evaporation under reduced pressure. The residue was diluted with dichloromethane and the organic phase was cashed with aqueous hydrochloric acid (pH 2) and water, dried over sodium sulfate and evaporated to dryness. The diastereomeric mixture was then separated by flash chromatography with a gradient using heptane/ethyl acetate and dichlcrcmenhane/methanol. Under the HPLC conditions described in the previous section (C-18 reverse phase) isomer 1 has a retention time of 14.9 minutes, and isomer 2 has a retention time of 15.8 minutes. Both isomers were characterized by fast atom bombardment mass spectrometry ( [MTH]+ = 639) . Example 2 Preparation of MesAib-Val-MeVal-Pro-Pro-NHBn (Compound 3) Preparation of 2-[N,N-dimethylamino]-isobutyric acid 2"Amino-isobutyriG acid [10.3 g) was dissolved in 200 ml methanol. After addition of 25 ml aqueous formaldehyde and 1 g 10% Pd/C, the reaction mixture was hydrogenated overnight at room temperature. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was crystallized from isopropanol to give 4.8 g of the desired product. Preparation of MesAib-Val-MeVal-Pro-Prc-NHBn x HCl 2-[N,N-Dimethylamino]-isobutyric acid (1.3 g, 10 mmol) and 5.5 g (10 mmol) H-Val-MeVal-Pro-Pro-NHBn x HCl were dissolved in 50 ml dry DMF. After cooling to 0°C, 1.6 g DEPCN (10 mmol) and 2.9 ml triethylamine were added to the reaction mixture. The resulting mixture was stirred at 0°C for 2 h and at room temperature overnight. Ice water (50 mL) was then added, and the resulting mixture was extracted twice with diethyl ether. The ether extracts were washed with 1 N NaOK (Ix) and aqueous NaCl (3x) , then dried over sodium sulfate and evaporated to dryness under reduced pressure. The product was crystallized from 100 ml diethyl ether with HCl/ether, and recrystallized from acetone to give 1.2 g of the desired product, which was characterized by fas:; atom bombardment mass spectrometry ( [M-H] = 627) . Example 3 Preparation of [N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-Me Val-Pro-Pro-NHBn x HCl (Compound 4} Preparation of [N,N-dimethyl-2-ethyl-2-phenylglycyl] -Val-MeVal-Pro-Pro-NHBn X HCl 2.07 g (10 mmol) N,N-Dimechyl-2-ethyl-2-phenylglycine and 5.5 g (10 mmol) H-Val-MeVal-Pro-Pro-NHBn x HCl were dissolved in 100 ml dry DMF. After cooling to 0°C, l.e g DEPCW (10 mmol) and 2.9 ml triethylamine were added. The reaction mixture was stirred at 0°C for 2 h and at room temperature overnight, then worked up as described above. The crude product was crystallized from diethyl ether with HCl/ether to give 4 g of the desired product, which wag characterized by fast atom bombardment mass spectrometry { [M+H] + = 703) . Example 4 Preparation of [N-Methyl-D-Prc]-Val-MeVal-Pro-Pro-NHBn (Compound 5) Preparation of Z-D-Pro-Val-MeVal-Pro-Pro-NHBn 3.74 g Z-D-Pro-OH (15 mmol, EACHEM) and 8.25 g K-Val-MeVal-Pro-Pro-NHBn x HCl (15 mmol) were dissolved in 80 ml dry DMF. Afeer cooling to 0°C, 2.4 g DEPCN (2.25 ml, 15 mmcl) and 4.2 ml triethylamine (30 mmol) were added. The reaction mixture was scirred at 0°C for several hours and room temperature overnight, then the DMF was evaporated under reduced pressure. The residue was diluted with ethyl acetate and thoroughly washed with dilute aqueous HCl (pH 2), water, dilute aqueous NaOH (pH 9-10), and water. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 9.2 g o£ the desired protected pentapeptide. Preparation of D-Pro-Val-HeVal-Pro-?ro-NHBn x HCl 8.2 g (11 mmol) Z-D-Pro-Val-MeVal-Pro-Pro-NHBn was dissolved in 70 ml methanol. After addition of 0.7 ml concentrated hydrochloric acid and 0.3 g 10 % Palladium/charcoal to the solution, the resulting mixnure was hydrogenated. Filtration and evaporation of the solvent gave a residue which was dissolved in water, adjusted to pH 2 and extracted twice with ethyl acetate. The aqueous phase was adjusted to pH 9-10 and extracted twice with dichloromethane. The organic extracts were evaporated and the residue was redissolved in diethylether and crystallized by addition of HCl/e"ther as the hydrochloride salt to give 6.5 g of the desired product. Preparation of [N-methyl-D-Pro]-Val-MeVal-Pro-Pro-NH3n x HCl 1.94 g (3 mmol) of D-Pro-Val-?eVal-Pro-Pro-NHBn x HCl was dissolved in 30 ml methanol. To this solution was then added 0.3 g 10% Pd/charccal and 1.5 ml aqueous formaldehyde solution and the reaction mixture was hydrogenated. Following filtration and evaporation of the solvents, the resulting residue was dissolved in water, adjusted to pH 2 and extracted twice with diethyl ether and several additional times with dichloromethane. The aqueous phase was adjusted to pH 9-10 and extracted twice wi::h dichloromethane. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was crystallized as the hydrochloride salt to give 0.5 g of the desired product which was characterized by fast atom bombardment mass spectrometry ( [M+H]+ = 625). The compounds listed in Table 1 were prepared according to the methods described in Examples 1-4. Where compounds are referred to as "isomer 1" or "isomer 2", isomer 1 is the diastereomer with the shorter retention time on the reversed phase analytical HPLC system. Fast atom bombardment-mass spectrometry results for selected compounds are provided in Table 2. Table 1 Compound No. 6 Xah Val Xa.a Pro Xab 7 Xai Val Xaa Pro Xab 8 Xae Val Xaa Pro Xab 9 Xad Val Xaa Pro Xbr 10 Xam Val Xaa Pro Xab 11 Xaw lie Xaa Pro Xbx 12 Xao Val Xaa Pro Xab 13 Xad Val Xaa Pro Xap 14 Xaq Val Xaa Pro Xab 15 Xar Val Xaa Pro Xab 16 Xas Val Xaa Pro Xah 17 Xat Val Xaa Pro Xab isomer 1 18 Xat Val Xaa Pro Xab isomer 2 19 Xaf Val Xaa Pro Xab 20 Xav Val Xaa Pro Xab 21 Xag Val Xaa Pro Xab 22 Xax Val Xaa Pro Xab isomer 1 23 Xax Val Xaa Pro Xao isomer 2 24 Xay Val Xaa Pro Xab 25 Xaz Val Xaa Fro Xab isomer 1 26 Xaz Val Xaa Pro Xab isomer 2 27 Xba Val Xaa Pro Xab 2 3 Xbb Val Xaa Pro Xab 2 9 Xbc Val Xaa Pro Xab Table 1 Compound No. 3 0 Xbd Val Xaa Pro Xab isomer 1 31 Xbd Val Xaa Pro Xab isomer 2 3 2 Xbe Val Xaa Pro Xab isomer l 33 Xbe Val Xaa Pro Xsih isomer 2 34 Xbf Val Xaa Pro Xab isomer 1 35 Xbg Val Xa.a Pro Xab 3 5 Xbti Val Xaa Pro Xab isomer 1 3 7 Xbh Val Xaa Pro Xab isomer 2 38 Xbi Val Xaa Pro Xab isomer 1 3 9 Xbi Val Xaa Pro Xab isomer 2 4 0 Xbk Val Xaa Pro Xab isomer 1 41 Xbk Val Xaa Pro Xab isomer 2 42 Xbi Val Xaa Pro Xab 43 Xbf Val Xaa Pro Xab isomer 2 44 Xbm Val Xaa Pro Xab 45 Xaw Val Xaa Pro Xbn 45 Xbo Val Xaa Pro Xbn isomer 1 47 Xbo Val Xaa Pro Xbn isomer 2 4 3 Xaw Val Xaa Pro Xbp 4 9 Xbo Val Xaa Pro Xbp isomer l 50 Xbo Val Xaa Fro Xbp isomer 2 51 Xaw Val Xaa Pro Xbq 52 Xaw Val Xaa Pro Xbr 53 Xbs Val Xaa Pro Xbt isomer 1 54 Xbi Val Xaa Pro Xab isomer 1 55 Xbi Val Xaa Pro Xab isomer 2 56 Xbu Val Xaa Pro Xab isomer 1 57 Xbv Val Xaa Pro Xab 53 Xbw Val Xaa Pro Xab isomer 1 S9 Xbw Val Xaa Pro Xab isomier 2 50 Xbs Val Xaa Pro Xb" isomer 2 61 Xbu Val Xaa Pro Xab isomer 2 62 Xbo Val Xaa Pro Xbr isomer 1 S3 Xbo Val Xaa Pro Xbr isomer 2 64 Xbo Val Xaa Pro Xbq isomer 1 65 Xbo Val Xaa Pro Xbq isomer 2 66 Xaw Val Xaa Pro Xbx Table 1 Compound No. 67 Xby Val Xaa Pro Xab 68 Xbz Val Xaa Pro Xab 59 Xca Val Xaa Pro Xab isomer 1 70 Xca Val Xaa Pro Xab isomer 2 71 Xbo Val Xaa Pro Xbx isomer 1 72 Xbo Val Xaa Pro Xbx isomer 2 73 Xau Val Xaa Pro Xbp 74 Xau Val Xaa Pro Xbx 75 Xbi Val Xaa Pro Xbx isomer 2 76 Xau Val Xaa Pro Xab isomer 1 77 Xau Val Xaa Pro Xab isomer 2 78 Xau Val Xaa Pro Xcb 79 Xbi Val Xaa Pro Xcb isomer 1 SO Xbi Val Xaa Pro Xcb isomer 2 81 Xbi Val Xaa Pro Xcc isomer 1 82 Xbi Val Xaa Pro Xcc isomer 2 83 Xbi Val Xaa Pro Xcd 84 Xbk Val Xaa Pro Xcc isomer 1 85 Xbk Val Xaa Pro Xcc isomer 2 8 6 Xax Val Xaa Pro Xbp isomer 1 8 7 Xax Val Xaa Pro Xbp isomer 2 8 8 Xbk Val Xaa Pro Xcb isomer 1 8 9 Xbk Val Xaa Pro Xcb isomer 2 90 Xau Val Xaa Pro Xcc 91 Xau Val Xaa Pro Xcd 92 Xba Val Xaa Pro Xcb isomer 1 93 Xba Val Xaa Pro Xcb isomer 2 94 Xbo Val Xaa Pre Xbp isomer 1 9 5 Xbo Val Xaa Pro Xbp isomer 2 96 Xau Val Xaa Pro Xbp isomer 1 97 Xau Val Xaa Pro Xbp isomer 2 98 Xbi Val Xaa Pro Xcd isomer 2 9 9 Xbk Val Xaa Pro Xcd 100 Xba Val Xaa Pro Xbp isomer 1 101 Xba Val Xaa Pro Xbp isomer 2 102 Xba Val Xaa Pro Xcc iscm.er 1 Table 1 Compound Wo. 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 Xba Val Xaa Pro Xcc isomer 2 Xba Val Xaa Pro Xcd Xce Val Xaa Pro Xab Xcf Val Xaa Pro Xab Xcg Val Xaa Pro Xab isomer 1 Xcg Val Xaa Pro Xab isomer 2 Xaw Val Xaa Pro Xch Xaw Val Xaa Pro Xci Xaw Val Xaa Pro Xck Xaw Val Xaa Pro Xcl Xaw Val Xaa Pro Xcm Xaw Val Xaa Pro Xcn Xaw Val Xaa Pro Xco Xaw Val Xaa Pro Xcp Xaw Val Xaa Pro Xcq Xaw Val Xaa Pro Xcr Xad Val Xaa Pro Xch Xad Val Xaa Pro Xci Xad Val Xaa Pro Xck Xad Val Xaa Pro Xcl Xad Val Xaa Pro Xcm Xad Val Xaa Pro Xcn Xad Val Xaa Pro Xco Xad Val Xaa Pro Xcp Xad Val Xaa Pro Xcq Xad Val Xaa Pro Xcr Xad Val Xaa Pre Xbx Xau Val Xaa Pro Xch Xaj. Val Xaa Pro Xci Xau Val Xaa Pro Xck Xau Val Xaa Fro Xcl Xau Val Xaa Pro Xcm Xau Val Xaa Pro Xcn Xau Val Xaa Pro Xco Xau Val Xaa Pro Xcp Xau Val Xaa Pro Xcc Xau Val Xaa Pro Xcr Compound No. 140 Xau Val Xaa Pro Xbr 141 Xad Val Xaa Xal Xbx 142 Xau Val Xaa Xal Xbx 143 Xaw Val Xaa Xal Xbx 144 Xad Val Xaa Xal Xch 14 5 Xau Val Xaa Xal Xch 14 6 Xaw Val Xaa Xal Xch 147 Xad Val Xaa Xal Xcr 148 Xau Val Xaa Xal Xcr 14 9 Xaw Val Xaa Xal Xcr 150 Xad Val Xaa Xan Xbx 151 Xau Val Xaa Xan Xbx 152 Xaw Val Xaa Xan Xbx 153 Xad Val Xaa Xan Xch 154 Xau Val Xaa Xan Xch 155 Xaw Val Xaa Xan Xch 156"" Xad Val Xaa Xan Xcr 157 Xau Val Xaa Xan Xcr 158 Xaw Val Xaa Xan Xcr 159 Xau He Xaa Pro Xbx 160 Xad He Xaa Pro Xbx 161 Xaw He Xaa Pro Xch 162 Xad He Xaa Pro Xch 153 Xau He Xaa Pro Xch 164 Xaw Xcs Xaa Pro Xch 165 Xad Xcs Xaa Pro Xch 166 Xau Xcs Xaa Pro Xch 167 Xaw Xcs Xaa Pro Xbx 16a Xad Xcs Xaa Pro Xbx 169 Xau Xcs Xaa Pro Xbx 170 Xaw Val Xct Pro Xch 171 Xad Val Xct Pro Xch 172 Xau Val Xct Pro Xch 173 Xaw Val Xct Pro Xbx Table 1 Compound No. 174 Xad Val Xct Pro Xbx 175 Xau Val Xct Pro Xbx The symbols Xaa in Table 1 represent the following amino acids or residues thereof: Xaa: N-methyl-valine Xab: Prolyl N-benzylamide Xac: L-N-methyl-piperidine-2-carboxylic acid Xad: D-N-methyl-piperidine-2-carboxylic acid Xae: N-methyl-L-proline Xaf: N-methyl-L-thiazolidine-4-carboxylic acid Xag: N,N-diraethylglycine Xah: L-proline Xai; L-piperidine-2-carboxylic acid Xak: 2- [N, N-dimethylan\ino] -isobutyric acid Xal: L-thiazolidine-4-carboxylic acid Xam: N-propyl-D-piperidine-2-carboxylic acid Xan : tj-3 , 4 -didehydrcproline Xac: D-piperidine-2-carboxylic acid Xap: proline tert.butylester Xaq: N-ethyl-D-piperidine-2-carboxylic acid Xar: N-methyl- [2,2,5,5-teCramethyl] -L-thiazolidine-2- carboxylic acid Xas: N-isopropyl-D-piperidine-2-carboxylic acid Xat: N,N-dimethyl-2-cyclopropyl-glycine Xau; N,N"-dimeth,yl-2-ethyl-2-phenyl-glycine Xav: D-proline Xaw; N-methyl-D-proline Xax: N,N-dimethyl-2- [2-fluoro]phenyl-glycine Xay: 1-aza- [3,30]bicyclooctyl-5-carboxylic acid Xaz: N,N-dimethyl-2-[4-fluoro]phenyl-glycine Xba: N-methyl- [2,2,5,5-tetramethyl] -thiazolidine-2■ carboxylic acid Xbb: 2-(R,S)-ethyl-2-phenyl-glycine Xbc r D,L-l-aminoindane-l-carboxylic acid Xbd: N,N-dimethyl-2-(R,S)-methyl-2-phenyl-glycine Xbe : 2- [N,N-diinethylaminoj indane-2-carboxylic acid Xbf : 5-[N,N-dimethylamino]-5,6,7,8-tetrahydro- naphthalene-5-carboxylic acid Xbg; N-isopropyl-2-(R,S)-ethyl-2-phenyl-glycine Xbh: 1-[N,N-dimethylamino] indane-2-carboxylic acid Xbi : N,N-dimethyl-2-propyl-2-phenyl-glycine Xbk: N,N-dimethyl-2- [4-methoxy]phenyl-glycine Xbl: N-tnethyl-3 -hydroxy-D, L-valine Xbm; N, M-dimechyi-D, L-2-isopropyl-2-phenyl-glycine Xbn : prcline-N-methoxy-N-methyl-amide Xbc : N-methyl-piperidine-2-carboxylic acid Xbp; proline-isopropylamide Xbq; proline-isoxazolidinyl Xbr: proline-N-methoxy-N-benzylamide Xbs: N-methyl-D,L-proline Xbt: proline- [5--phenylI isoxazolidinyl Xbu: N-methyl-1,2,3,4-tetrahydrDisoquinoline-l- carboxylic acid Xbv: N-methyl-a2etidine-2-carboxylic acid Xbw: N-isopropyl-azetidine-2-carboxylic acid Xbx: proline-Cert-buCylamide Xby: N,K-dimethyl-[0-methyl] serine Xbz: N,N-dimethyl-[0-methyl] threonine Xca: N-methyl-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid Xob; proline-pentyl(3> amide Xcc; proline-(R)-phenethylamide Xcd: proline-(S)-phenethylamide Xce : 1- [Njlf-dimethyl amino] cyclohexyl-1-carboxyiic acid Xcf : 1- [N, N-dimethyl amino] cyclcpentyl -1-carboxylic acid Xcg : 1,2,3,4-cetrahydroisoquinoline-3-carboxylic acid Xch: In vitro Methodology 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: 539-601, (198S)). Exponentially growing cultures of HT-29 colon carcinoma cells were used to make raicrotiter 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 STC. Test compounds were added, in. 10-fold dilutions varying from 10"" M to 10"° M. Cells were then incubated for 4S 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-dimethylthia2ol-2-yl)-2,5-diphenyltetrazoliun bromide in saline). This mixture was incubated at 37 C for 5 hours, and then 50 mi 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 IC5Q, Table 3 presents the IC5Q values determined in the HT-29 assay for a series of compounds of the invention. 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. More specifically, human tumors grown in athymic nude mice can be transplanted into new recipient animals, using cumor rragmencs wnicn are aDOuc bu mg m size. The day of transplantation is designated as day 0. Six to ten days later, Che 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: Mean tumor weights are then calculated for each treatment group, and T/C values are determined for each group relative to the untreated control tumors. EQUIVALENTS Those skilled in the art will recognize or be able Co ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed in the scope of the following claims. We claim: 1. A compound of the formula A-B-D-E-F-{G}r-(K),-L, where in A is a proline derivative of Formula II,, unsubstituted or fluorine-substituted normal, branched or cyclic Ci-C1-allcyl; R2, is hydrogen, C1-C3-alkyl, phenyl, or substituted phenyl; or R, and R4, together form a propylene bridge; and R2, R3, R4, and R3, are each, independently, hydrogen or alkyl; or wherein R, is hydrogen or unsubstiCuted or fluorine-subscituted C1-C-alkyl/ R2, ia C1-C4-allcyl; R4. is alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl; or R1 is an alJcyl group and R", is C1-C,-alkyl, cycloalkylmethyl, bftnzyl or substituted benzyl; and R", is hydrogen or alkyl; or wherein R", ia hydrogen or alkyl and R, is hydrogen, or unsubacituted or fluorine-substituted alkyl; or wherein R, is hydrogen, or unsubstituted or fluorine-substituted alkyl; R2. is hydrogen, alkyl, phenyl, or substituted phenyl; or R. and R4-, together form a propylene bridge; and X is hydroxy, alkoxy or fluorine; or fluorine-aubacituted alkyl; R2, ia hydrogen, alkyl, phenyl, or euhatituted phenyl; or R. and R} together form a propylene bridge; and R4, R\, R4. and R", are each, independently, hydrogen or alkyl; or wherein the 3-carbonyl moiety is in the endo or exo poaition, z is a single bond or a doiible bond, and R, is hydrogen or unsubatituted or fluorine-siabstituted alkyl; or alkyl and R. is hydrogen, unsubstituted alkyl or fluorine-substituted alkyl; B ia a valyl, isoleucyl, allo-iSoleucyl, norvalyl, 2-tert-butylglycYl or 2-ethylglycyl residue; or D is an N-alkylvalyl, H-alk:yl-2-ethylglycyl, H- alkyl-2-tert-butylglycyl, N-allq/"lnorleucyl, N-alkylisoleucyl, N-allcyl-allo-iaoleucyl or N-alkylnorvalyl residue; or wherein n is 1 or 2; R2 is hydrogen, alkyl or fluorine-suhatituted al3cyl; and X is hydrogen; or n is 1 and X is fluorine, hydroxy. B}, and R", are each, independenCly, Hydrogen or alkyl; R4, ia hydrogen, hydroxy or altcoxy; and R2B is hydrogen or fluorine; or n, is l and R2 and R4, together form a double bond; or n, is 1 and R"g and R", together form a douhle-bonded oxygen diradical; or n. is 1 or 2 and R2, and R% together form a double bond; or an aminocyclopentanecarboxylic acid residue of Formula III,, F is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl reaidue; or imsubstituted or fluorine-siobstituted alkyl; R2j and R"( are each, independently, hydrogen or methyl; R4,. is hydrogen, hydroxy, alkoxy, or fluorine; R2j is hydrogen or fluorine; or n is 1 and R% and R4£ together form a doiible bond; or rif is 1 and R4j and R", together form a doable-bonded oxygen diradical; or n is i or 2 and R2, and R4, together form a double bond; or a 2- or 3-aininocyclopentanecarboxyXic acid residue of Formula Illf, wherein Ri is alkyl and R"" is hydrogen, or unsubatituted or fluorine-substituted alkyl; or an N-alkylglycyl or N-alkylalanyl residue; hydrogen, alkyl, arylalkyl, heteroarylalkyl, phenyl or substituted phenyl; or R" and R2, together with the a-carbon atom, form a C1-C8 ring or a benzo-fused C, ring; K is an a-amino acid of Formula 11,, wherein R\ is hydrogen, or alkyl; and R% is hydrogen, alkyl, arylalkyl, heteroarylalkyl, phenyl or substituted phenyl; or R2g and R\, together with the a-carbon atom, form a cyclopentane ring or a benzo-fuaed cyclopentane ring; IJ is a substituted or unsubstituted ainino, hydrazido, aminoxy or oximato group; and r and s are, independently, 0 or 1 provided that when s and r are each 0 and A is of formula ii, where n, isOorl andR2,, R%, R\, R\ and R", are each hydrogen, L is a substituted or unsubstituted amino or hydrazido group. 2. The compound as claimed in ciaim 1, wherein A is a proline derivative of Formula II,; R, is hydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, l-methyl-2-fluoroethyl, 1 - fluoromethyl ~2 - fluoroethyl, or 1 -En6thyl-2-fluoroethyl; R\ is hydrogen, methyl, ethyl, propyl, phenyl, or substituted phenyl, wherein the phenyl substituents coririae one or more alJcyl, alkoxy, trif luoromethyl or nitro groups; or Ra and Rla together form a propylene bridge; and R",, R2, R"", and R4. are each, independently, hydrogen or methyl. 3. The compound as claimed in claim 1, wherein A is an a-amino acid residue of Formula III,, wherein R, is hydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl, 2 -fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2 -fluoroethyl, 1-fluoromethyl-2 -fluoroethyl, or l-methyl-2-fluoroethyl; R2, ia a C~ C1-alkyl group; R", is methoxyniethyl, 1-methoxyethyl, vinyl, 1-methylvinyl, 1-trifluoromethylvinyl, 1-trifluoromethylethyl, 1-trifluororaethyl-2,2,2-tr±fluoroethyl, 1,1-dimethylhydroxymethyX, phenyl or substituted phenyl, wherein the phenyl substituenta coirr"ise one or more halogen atoms or one or more C-C,-alkyl, methoxy, trifluoromethyl or nxtro groups; or R2, is C1-C1-alkyl and R% is C1-C6-alkyl, cycloalkylmethyl, benzyl or substituted benzyl wherein the benzyl aubstituents comprise one or more halogen atoms, or one or more C1-C-alkyl, methoxy, ethoxy, trifluoromethyl or nitro groups,-and R", is methyl, ethyl or isopropyl. 4. The compound as claimed in claim 1, wherein A is an a-amino acid residue of Formula IV,, wherein R\ is methyl, ethyl or isopropyl; and R, ia hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2 -fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, l-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl. 3. The compound as claimed in claim 1, wherein A is an a-amino acid residue of Formula V,, wherein R", is methyl, ethyl or isopropyl and R, is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2 -fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, l-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluorQethyl. 6. The compound as claimed in claim 1, wlierein A is an a-aminoacid residue of Formula Via, wherein Rg is hydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropy 1, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1 -methyl-2-fluoroethyl, 1 -fIuoromethyi-2-fluoroethyl, or l-methyl-2-fluoroethyI; R"a is hydrogen, methyl, ethyl, propyl, phenyl, or substituted phenyl, wherein the phenyl substituents comprise one or more alkyl, alkoxy, trifluoromethyl or nitro groups; or R2 and R"a together form a propylene bridge; and Xg is a hydroxy, methoxy, or ethoxy group, or a fluorine atom. 7. The compound as claimed in claim 1, wherein L is a substituted or unsubstituted amino, or hydrazido. i. A pharmaceutical composition comprising a compound as claimed in claim 7, and a pharmaceutically acceptable carrier or diluent. ). The composition as claimed in claim 8, wherein L is an amino group of Formula II\|, R"I is a hydrogen atom, a normal or branched, saturated or unsaturated C1-Cig-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C1-C6-alkoxy group, a substituted or unsubstituted aryloxy-C1-C6-alkoxy group, wherein the aiyl substituents comprise one or more halogen atoms or one or more C1-C4-alkyl, methoxy, ethoxy, trifluoromethyl, dioxymethylene, or nitro groups; or a heteroaryl-C1-C3-alkoxy group; and R 1 is a hydrogen atom, a normal or branched C1-Cig-alkyl group, a normal or branched C1-Cig-alkenyl group, a C3-Cio-cycloalkyl group, an aryl group or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a Cf-C7-alkoxycarbonyl group, a dJoxymethylene group, a C1-C7-aIkylsulfonyl group, an amino group or a C1-Q-dialklamino group; a heteroaryl group or a substituted heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituents comprise one or more C1-C6-alkyl, hydroxyl or phenyl groups. R"i is methyl, ethyl, normal propyl or isopropyl; and R"*! is a saturated or partially unsaturated carbocyclic system comprising from about 3 to about 10 carbon atoms, an aryl group or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a CrCT-alkoxycarbonyl group, a dioxymethylene group, a C1-CT alkylsulfonyl group, an amino group or a C1-C6-dialkylamino group; a heteroaryl group or a substituted heteroaryl group derived from imidazole. isoxazoie, isothiazole, thiazole, oxazole, pyrazole, thiophene, ftiran, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazane, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituents comprise one or more CpC3-alkyl, hydroxyl or phenyl groups. Wi is an N(R2i) group, an oxygen atom or a sulfur atom; R"I and R4, are each, independently, a hydrogen atom or a C,-C4-alkyl, C3-C7-cycloalkyl, aryl, arylmethyl, substituted aryl, or substituted arylmethyl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a C1-C7-alkoxycarbonyl group, a dioxymethylene group, a C1-C7-alkylsuifonyl group, an amino group or a C1-C6-dialkylamino group; or R2i is a C1-Cig-alkanoyl group or a benzoyl group. aryl substituents comprise one or more halogen atoms, or one or more methoxy, ethoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C1-C7-alkoxycarbonyl, C1-C7-alkylsulfonyl, amino, or C1-C7-dialkylamino groups; or a heteroaryl-C]-C4 alkyl-group, wherein the heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4-or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazme, 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 R1 is a hydrogen atom, or r is 1, s is 1 or both r and s are 1, and R 1 is a normal or branched C1-C6-alkyl group, a C3-C8-cycloalkyl group, a C3-C6-cycloalky!-C1-C4-alkyt group, an aryl-C1-C4-alkyl group, an aryl group or a substituted aryl-C]-C4-alkyi or aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a C1-C7-alkoxycarbonyl group, a dioxymethylene group, a C1-C7-alkylsulfonyl group, an amino group or a C1-C6-dialkylamino group, a heteroaryl group, a heteroarlyl-C1-C4-alkyl group or a substituted heteroaryl or heteroaryl-C1-C4- alkyl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituents comprise one or more C1-C6-alkyl, hydroxy] or phenyl groups; or R1 and R2 together form a propylene bridge or a butylene bridge.

Full Text

DOLASTATIN 15 DERIVATIVES
BACKGROUND OF THE INVENTION
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. , Sioche.Ti. Pharmacology, 40: 1859-1364 (19S0) ; Beckwith et al., J. Natl. Cancer Inst., 85: 483-488 (1993) and references cited therein). These include Dolastatins 1-10
[U.S. Patent No. 4,8iS,444, Issued to Pettit et al.) and Dclastatin 15 (3uropean 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 .
The exceedingly small amounts of the various Dolastatin peptides present in Dolabella auricularia (about

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 [of.: biorg. Med. Chem. Lett. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790; WO 93 23424] .
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
Compounds of the present invention include cell growth inhibitors which are peptides of Formula I,

and acid salts thereof, wherein A, B, D, E, F, G and K are a-amino acid residues, and s and r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a p-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group.

Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
An additional embodiment of the present invention is a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.
DETAILED DESCRIPTION OF THE INVENTION
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.
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. Dolastatin 15 is also expensive to s"ynthesize 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 Dolastatin 10 and Dolastatin 15. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail.

For the purposes cf 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, the unit -N(R)R", wherein R. and R" are each a monovalent radical, can, together with the nitrogen atom, form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom can together form a divalent radical, such as an oxygen atom or an alkylidene group, for example, a propylidene group.
For the purposes of the present invention, the term "normal alkyl" refers to an unbranched, or straight chain, alkyl group, for example, normal propyl (rr-propyl, -CH2CH2CH3).
The compounds of the present invention can be represented by Formula 1,

wherein A, B, D, E, F, G, and K are a-amino acid residues; s and r are each, independencly, 0 or 1; and L is a monovalent radical such as an amino group, an N"-substituted amino group, a j3-hydroxy!amino group, a hydrazidc group, an

alkoxy group, a thioalkoxy group, an aminoxy group, or an cximato group.
The peptides of Formula I are generally composed of L-amino acids but they can contain one or more D-amino acids. In the following discussion, reference to a particular amino acid includes both enantiomers unless a specific enantiomer is indicated. The present compounds 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.
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
Identity of A
In one embodiment, A is a proline derivative of Formula II3,

where n is an integer, preferably 0, 1, 2, or 3. Rg is a monovalent radical, such as a hydrogen atom or an unsubstitiited or fluorine-substituted alkyl group, for example a normal, branched or cyclic C1-C3-alkyl group which is, optionally, substituted by from 1 to about 3 fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2,2-trifluorcethyl, 1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropyl are preferred;
In this embodiment, R1 a is a monovalent radical, such as a hydrogen atom, an alkyl group, such as a methyl, ethyl or propyl group, or a phenyl group. The phenyl group can be substituted; suitable substituents include one or mare halogen atoms, with fluorine, chlorine and bromine atoms preferred, C-C-alkyl groups, methoxy, ethoxy, trifluoromethyl or nitro groups. Rg and R1 together can also form a propylene bridge.
fa" a" a a each, independently, a monovalent radical, such as a hydrogen atom or an alkyl, preferably, methyl, group.
In another embodiment, A is a substituted glycine derivative of Formula Ilia,

where R has the meaning stated for R in Formula IIa and, R- is a monovalent radical, for example, a hydrogen atom

or a C,-Cg-alkyl group, preferably a methyl, ethyl or propyl group.
In this embodiment, R is monovalent radical, such as an alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl group. Suitable examples include methoxymechyl, 1-methoxyethyl, 1,1-dimethyl-hydroxymethyl, 1-trifluoromethylethyl, 1-trifluoromethyl-2, 2,2-trifluoroethyl, vinyl, and 1-methylvinyl. Phenyl substituents can include one or more halogen atoms, preferably fluorine, chlorine or bromine atoms, and alkyl, methoxy, ethoxy, trifluororaethyl, and nitro groups.
When R-g is an alkyl group, R can also be a Cj_-Cg-alkyl, cycloalkyl, unsubstituted benzyl or substituted benzyl group. Suitable benzyl substituents include one or more halogen atoms, such as fluorine, chlorine or bromine atoms, C1-C4-alkyl groups, and methoxy, ethoxy, trifluoromethyl and nitro groups.
R"a is a monovalent radical, preferably a methyl, ethyl or isopropyl group.
In anocher embodiment, A is an a-amino acid derivative of Formula IVg,

where m is an integer, preferably 1 or 2, and Rg and R" have the meanings stated for these substituents in Formula III,.
In another embodiment, A is an a-amino acid derivative of Formula V,,

where Rg and R" have the meanings stated for Rg and R"a in Formula 111-
In a further embodiment, A is a substituted proline derivative of Formula VI,

where R and R have the meanings stated for Rg and R- in Formula IX, and X is a monovalent radical, preferably a hydroxyl, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
In another embodiment, A is a thiaprolyl derivative of Formula VII,

where Rg has the meaning stated for Rg for Formula 11.
In another embodiment, A is a 2-azabicyclo [2.2.1]heptane-3-carboxylic acid derivative of Formula IXg,

where Z is a single or double bond and R has the meaning stated for Formula Ilg. The 3-carbonyl substituent can have either the exo or endo orientation.
In another embodiment, A is an a-amino acid derivative of Formula X,

where n has the meaning as stated for n for Formula llg, and R"" and R have the meanings as stated for R , and Rg for Formula Illg.

Idencity of B
B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue. B can also be an a-amino acid residue of Formula IIv

preferably, a hydrogen atom and Rj is, for example, an alkyl, alkoxyalkyl or alkenyl group. In preferred smbodiments, R, is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a ■nethoxymethyl group, a l-methoxyethyl group or a 1-methylvinyl group. Additionally, R"" and Rj together can be an isopropylidene group.
Identity of D
D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkyl-norleucyl, N-alkyl-isoleucyl, W-alkyl-alio-isoleucyl or N-alkyl-norvalyl residue, where the N-alkyl group is preferably a methyl group or an ethyl group.
In another embodiment, D is an a-amino acid residue of Formula IIQ,

where R has the meaning stated for R in Formula Illgy Rd is a monovalent radical, preferably a hydrogen atom, and Rd is a monovalent radical, for example, an alkyl, alkoxyalkyl or alkenyl group. In preferred embodiments, Rd is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-raethylvinyl group, such as a cyclopropyl group, a methoxymethyl group, a l-methoxyethyl group or a 1-methylvinyl group. Additionally, R""" and R together can form an isopropylidene group.
Alternatively, D can be a proline derivative of Formula III

where n is an integer, for example, 1 or 2, and R has the meaning stated for R-"- in Formula Ilia- X is a monovalent radical, preferably a hydrogen atom, and, in the case where n equals 1, can also be a hydroxy or alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
Identity of E
E is a prolyl, thia20lidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue, or a cyclic a-amino carboxylic acid residue of Formula Ilg,

where ng is an integer, preferably 0, 1 or 2. R has the meaning stated for R""" in Formula III- Re " R"g are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group. R"" is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. Rg is a monovalent radical, preferably a hydrogen atom or a fluorine atom, In the case where ng is 1, Re snd R""g can together form a double bond, or R"g and R" can together be a double-bonded oxygen radical. In the

case where n has the value 1 or 2, R-"-g and R can together form a double bond.
In another embodiment, E is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula Illg,

where Rg is an alkyl group, such as methyl or ethyl, and R-e has the meaning stated for R-" in Formula ril.
Identity of F
F is a prolyl, thiazolidinyl-4;-carbonyl, homoprolyl or hydroxyprolyl residue. F can also be a cyclic a-amino acid residue of Formula II;,

where nf is an integer, preferably 0, 1 or 2. R has the meaning stated for R"- in Formula Illg. Rf and R-f are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group. Rf is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. RF is a monovalent radical, preferably a hydrogen atom or a fluorine atom. In the case where n has the value 1, R"f and Rf together can form a double bond or Rf and Rf can together be a double-bonded oxygen radical. In the case where n has the value 1 or 2, H and R= can together form a double bond.
In another embociiment, F is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula Illf

where Rf is a monovalent radical, such as a methyl or ethyl group, and Rf has the meaning stated for R in Formula
Ilia-
In another embodiment, F is an N-alkylglycyl or N-
alkylalanyl residue, and the alkyl group is, preferably, a methyl group or an ethyl group.

Identity of G
G is an ci-amino acid residue of Formula Ilg,

wherein B}g is a hydrogen atom, or an alkyl group, for example, methyl, ethyl or n-propyl. Rg can be, for example, a hydrogen atom, or an alkyl, arylalkyl, heteroarylalkyl or aryl group. Preferably, R is an ethyl; isopropyl, tertbutyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl- 2 -methyl, n-butyl, 2,2-dimethylpropyl, naphthylmethyl, or n-propyl group, or a substituted or unsubstituted phenyl group. Suitable phenyl substituents include ons or more halogen, preferably fluorine, chlorine or bromine, atoms, C-Cj-alkyl groups, methoxy, ethoxy, nitro or trifluoromethyl groups or a dioxomethylene group. Alternately, R"""g and Rg can, together with the a-carbon atom, form a cyclopentane or cyclohexane ring or a benzo-fused cyclopentane ring, such as, for example, the indanyl arQUD,

where E"""j_ is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated Ci_-Ci3-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C-C-alkoxy group, or a substituted or unsubstituted aryloxy-C;;_-C5-alkoxy or heteroaryl-Cj_-Cg-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, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3- triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyriraidine, benzimidazole,

benzopyran, benzothiazole, oxadiazole,thiadiazole or pyridine. Suitable aryi substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C]_-C4-alkyl groups, methoxy, ethoxy or trifluororaethyl groups, a dioxymethylene group or nitro groucs.
Ri is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C]_-C;j_a-alkyl group, a C3-Cio-cycloalkyi group, a substituted or unsubstituted airyl group, or a substituted or unsubstituted heteroaryl 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, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3- triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quincline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole,thiadiazole or pyridine. Suitable aryl substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C1-C-alkyl groups, methoxy, ethoxy or trifluorom,ethyl groups, a dioxyraethylene group or nitro groups.
Rj_ can, alternately, be of Formula II,

monovalent radical, which can be a saturated or partially unsaturated carbocyclic system comprising from about 3 to about 10 carbon atoms, a substituted or unsubstituted aryl or heteroaryl group, with aryl and heteroaryl and preferred substituents having the meaning stated for Rj_ in Formula

wherein Wj is an oxygen or sulfur atom or an N-R]_ group. Rx is a monovalent radical, such as a hydrogen atom, a C3_-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 Ri from Formula IIi- Ri is a monovalent radical, preferably a hydrogen atom, a C1-C-alkyl group or a C3-C7-cyGloalkyl group, a Cj_-Cig-alkanoyl group, a benzoyl group or a substituted or unsubscituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning

where bi is an integer, preferably 2, 3 or 4. Zi can be a monovalent radical such as a formyl, aminocarbonyl or hydrazinccarbonyl group, or a cyclic or acyclic acatal or chioacetal group.

in which h has the above-mentioned meaning. R; can be a monovalent radical, such as a polyglycol group of the formula -0-(CH2-CH2-O) j]_-CH3, where di is an integer,
preferably in the range from about 2 to about 4 or from about 40 to about 90.
R2_ can further be a carbohydrate of Formula VIj.,

where Ri is a monovalent radical, such as a hydrogen atom, a C1-C-alkanoyl or alkyl group, a benzoyl group or a

a
where R ]_ is a monovalent radical such as a hydrogen atom, a C1-Cg-alkyl group or a substituted or unsubstituted aryl group, with aryl and its preferred substituents having the meaning stated for R;_. R""" Is a monovalent radical, preferably a hydrogen atom, alkyl, for example, methyl, or

and R""""! is a monovalent radical, preferably a hydrogen atom. R"*"! can be a monovalent radical such as a hydrogen atom, a normal or branched C-Cg-alkyl group, a- C2-C2-cycloalkyl group, a Cj-Cg-cycloalkyl-C1-C.-alkyl group or a substituted or unsubstituted aryl, heteroaryl, aryl-C;,-C-alkyl or heteroaryl-C1-C-alkyl group, where aryl, heteroaryl and their preferred substituents can be selected from among the options listed for R".

When r and/or s is 1, R"-" can also be selected from among the options listed above for Ri, and the two radicals together can additionally form a propylene or butylene bridge.
Another subclass of compounds of this invention includes peptides of Formula I wherein L is a monovalent radical of the formula -0-R--j or the formula -S-R~, where R-"-i_ is a monovalent radical, such as a C3-Cio-cycloalkyl group, a normal or branched Cj-Cig-alkenylmethyl group or a C1-CiQ-alkyl group which can be substituted by from l to about 5 halogen, preferably fluorine, atoms.
Ri can also be the radical - (CH2) g-R"i, where e is an integer, preferably 1, 2 or 3. R2 monovalent radical, preferably a saturated or partially unsaturated C3-C2o-carbocycle.
R"""i_ can further be the monvalent radical
- [CH2-CH=C (CH3>-CK2] f-H, where f is an integer, preferably
1, 2, 3 or 4.
R--3_ can also be the radical - [CH2-CH2-O] g-CH3, where g is an integer, preferably in the range from 1 to about 5. R-i can also be the radical - (CH2} h-ryl or
- (CH2) h-iieteroaryl, where aryl and heteroaryl can also be
substituted and, along with their preferred substituents,
can be selected from the group listed for R i- h is an
integer, preferably 0, 1, 2 or 3.
R-"i can further be the radical - CCK;) t,-Wi-R"i. b, W and Ri can each be selected from am.ong the options described for Formula IVj,
Another subclass of ccnipounds of this invention includes peptides of Formula I in which L is an aminoxy group of the formula -0-N (Ri_) {R-"-j,) , where Ri and R" are each a monovalent radical, which can independently be a

hydrogen at om, a. norinal or branched Cj-Cg-alkyl group, which can be substituted by halogen, preferably fluorine, atoms, a C3-Ca-cycloalk:yl group, a Cs-Cg-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 R j_. R-"-""; can be selected from among the options listed for R. Additionally, Ri and R can together form a 5-, S- or 7-membered heterocycle. The compounds of the present invention further comprise the salts of the compounds described above with physiologically tolerated acids.
Another subclass of compounds of this invention includes peptides of Formula I wherein L is an oximato group of the formula -0-N=C {R-j_) [R\) , Ri and RS can be selected from amiong 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.

In or.e embodiment, the invention provides compounds of ■ormula I wherein A is an amino acid derivative selected :rom among N-alkyl-D-prolyl, N-alk:yl-L-prolyl, N-alkyl-D-)iperidine-2-carbonyl, N-alkyl-L-piperidine-2-carbonyl, 1, N-dialkyl-D-2-ethyl-2-phenylglycyl and N, N-dialkyl--L-2-;chyl-2-phenylglycyl, wherein alkyl is methyl, ethyl or .sopropyl; and B is a valyl, isoleucyl or 2-t-butyl-L-[lycyl res idue.

Preferred compounds of the invention include compounds of Formula I wherein r and s are each 0. A is an amino acid derivative selected from among D-N-methyl-piperidine-2-carbonyl,
L-N-methyl-piperidine-2-carbonyl, NN-dimethylamino-isobutyryl, N-methyl-L-prolyl,
N-methyl-L-thiazolidine-4-carbonyl, N,N-dimethyIglycyl, L-prolyl, L-piperidine-2-carbon.yl, N~propyl-D-piperidine-2-carbonyl,
D-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-methyl- [2,2,5,5-tetramethylj-L-thia20lidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropylglycyl , N,N-dimethyl-L-2-ethyl-2-phenylglycyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl, D-prolyl, N-methyl-D-prolyl, N,N-diraethyl-2-(2-fluorophenyl)glycyl, 1-aza-[3,3,0]bicyclooctyl-5-carbonyl, N,N-dimethyl-2- [4-fluoro]phenyl-glycyl,
N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carbonyl, 2-(R,S}-ethyl-2-phenylglycyl, D,L-1-aminoindane-l-carbonyl, N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl, 2-[N,N-dimethylaminc]indane-2-carbcnyl, 5-[N, N-dimethylaminc]-5,6,7,8-tetrahydro-naphthalene-5-carbonyl, N"-isopropyl-2- (R, S) -ethyl-2-phenylglycyl, 1-[N,N-diraethylamino] indane-2-carbonyl, N,N-dimethyl- 2-propyl-2-phenylglycyl, N,N-dimethyl-2-[4-methoxy]phenyl-glycyl,
N-methyl-3-hydroxy-D,L-valyl, N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl, N-methylpiperidine-2-carbcnyl, N-methyl-L-prolyl, N-methyl-1,2,3,4-tetrahydrcisoquinoline-l-carbonyl,

N-methyla2et;idine-2-carbonyl, N-isopropylazetidine-
2-carbonyl, N,N-dimethyl- [0~meChyl]seryl,
N,N-dimethyl-[0-methyl]threonyl,
K-methyl-1, 2,3, 4-tetrahydrcisoguinoliiie-3-carbonyl,
1-[N,N-dimGthylamino]cyclohexyl-1-carbonyl,
1-[N,N-dimethylamino]cyclopenCyl-1-carbonyl and
1,2,3,4-tetrahydroisoquinoline-3-carbonyl. B is valyl,
isoleucyl or 2-tert-butylglycyl. D is H-methylvalyl, N-
methyl-2-t-butylglycyl or N-methylisoleucyl. E and F are
each, independently, prolyl, thiaprolyl, homoprolyl,
hydroxyprolyl, 3,4-didehydroprolyl, 4-fluoroprolyl, and 3-
methylprolyl. L is an alkoxy group or an amino group of
the formula R-j-N-R, wherein Ri_ and Rj_ are independently
selected from the group consisting of hydrogen, alkoxy,
hydroxy, alkyl and alkylaryl.
In a particularly preferred subset of the compounds of the invention, r and s are each 0. A is an amino acid derivative selected from among
D-N-methyl-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropyl-glycyl, N-methyl-D-prolyl, 1-aza-[3,3,0]bicyclocctyl-5-carbonyl,
N-methyl-[2,2,5,5-tetramethyl] -thiazolidine-2-carbonyl, 2-(R,S)-ethyl-2-phenylglycyl, D,L-l-aminoindane-l-carbonyl, N,N-dimethyl-2-{R,S)-methyl- 2-phenylglycyl, 5-[N,N-dimethylamino] -5,S,7,8 -teCrahydro-naphthalene- 5 -carbonyl,
1- [N,N-diTtiethylaminc] indane-2-carbcnyl, N,N-dimethyl-2-propyl-2-phenylglycyl, N, N-dimethyl-L-2-ethyl-2-phenylglycyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl, N-meChyl-3-hydroxy-D,L-valyl, N,N-dimethyl-D,L-2-isoprcpyl-2-phenylglycyl,

N-methyl-piperidine-2-carbonyl, N-methyl-D,L-prolyl,
N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl,
N"-methylazetidine-2-carfaonyl,
N"isopropylazet:idine-2-carbonyl
N,N-dimethyl-[0-methyI]seryl,
1-[N,N-dimQthylamino]cyclohexyl-1-carbcnyl and
1-[NjW-dimethylamino]cyclopentyl-l-carbonyl. B is valyl; D
is N-methylvalyl; and E and F are each prolyl. L is a C1-
Cg-alkoxy group or an amino group of the formula R-N-Ri,
wherein R"i and Rj_ ars each independently selected from the
group consisting of hydrogen, Cj-Cg-alkoxy, hydroxy,
normal, cyclic or branched C1-Ci2-alkyl, and phenylalkyl.
Synthetic Methods
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 hy linking suitable small peptide fragments. In sequen¬tial assembly, 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.
In both sequential assembly 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 lin.kage ara described in detail in standard references on peptide chemistry, including Miiller, Methoden de?r praanischen Ch,emi> Vol, XV/2, 1-364, Thieme Verlag, Stuttgart, (1974); Stewart: and Young, Solid Phase Peptide

Synthegj-s. 31-34 and 71-82, Pierce Chemical Company, Rockford, IL (1984); Eodanszky et ai. , Peptjie 5vnthe=;-i g. 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 prsformed 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) , l-ech.oxycarbcnyl-2-ethoxy-1,2-dihydroqiiinoline (EEDQ) , pivaloyl chloride, 1-ethyl-3 - {3-dimenhylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N",N"-bis (2-oxo-oxazolidinyl) amidophosphoryl chloride {BOP-Cl) , bromo-tris (pyrrolidine)phosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro"s reagent (SOP, PyBop),
0-benzotrlazolyl-N,N,N",N"-tetramethyluronium salts (HBTU), 0-azabenzotriazolyl-N,N,N",N"-tetramethyluronium salts (HATU) , diethylph.osphoryl cyanide (DEPCN) ,
2,5-diphenyl-2,3- dihydro-3-oxo-4- hydroxythiophene dioxide (Steglich"s reagent; HOTDO), and 1,1"-carbonyldiimidasole (GDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMA.P) , N-hydroxy-benzotriazole (HOBt), N-hydroxyazabenzotriasole (KOAt), K-hydroxybenzotriazine (HOOEt), N-hydroxysuccinimide (HOSu) or 2-hycroxypyridine.
Although the use of protecting croups is generally noc 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) technicrues. Identified in each case is the protective group on the 3(-amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Miiller, Methoden der oraanischp.n Chemie Vol. XV/l, 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: (1963) 2149.
Solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, especially water, N,K-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THE), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.
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, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents. Following synthesis, the pepnide 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 acenic 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.
Partial deprotection of the peptide may also be necessary prior to certain derivatisaticn reactions. For example, peptides dialkylated at the N-cerminus can be prepared by coupling the appropriate N,N-di- alkylamino acid to Che peptide in solution or on the polymeric support, by reductive alkylation of the resin-bound peptide in DMF/l% acetic acid with NaCNBHj and the appropriate aldehyde or by hydrogenation of the peptide in solution in the presence of the appropriate aldehyde or ketone and Pd/carbon.
The various non-naturally occurring amino acids as well as the various non-amino acid moieties disclosed herein can be obtained from commercial sources or synthesized from comm.ercially available staring materials using methods known in the art. For example, amino acid building blocks with R* and R groups can be prepared according to the method described by Wuensch and Weyl, Methodp der OraanischR Chemie. vol. XV, Springer Verlag: Stuttgart, p. 306 (1974) and references cited therein.
Methods of Use of the Claimed Compounds
In another eTJDodiment, the present invention comprises a method for partially or zotally inhibiting formation of, or otherwise treating (e.g. , reversing or inhibiting the further development of} sclid tumors {e.g., tumors of the lung, breast, colon, prostane, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g., leukemias, lymphomas) in a mammal, for example, a hum.an, by

administering to the mammal a therapeutically effective amount of a compound or a combination of compounds of Formula I. The compound(s) may be administered alone or in a pharmaceutical composition comprising the compound(s) and an acceptable carrier or diluent. Administration can 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 intraperitcneally, nasally or rectally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound or compounds of Formula I together with a pharmaceutically accepted carrier appropriate for the desired routs of administration. Such pharmaceutical compositions may be combination products, i.e., they may also contain other therapeutically active ingredients.
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 cf 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 cf the particular com.pound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the freq"j.ency at treatment; the administration of other therapies; and the effect desired. A typical daily dose will be from about 0.05 to about 50 milligrams per

kilogram of body weight by oral administration and from about 0.01 to about 20 milligrams per kilogram of body //eight by parenteral administration.
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 ;onventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet iisintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sucker et al.: pharmazeutische Technologje, rhieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way typically contain from about 1 to ibout 90% by weight of the active substance.
The present invencion will now be illustrated by the rollowing examples, which are not limiting.

EXAMPLES
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 = dichlcromethane, DMSO =
dimethylsulfoxide, Bu = butyl, Et = ethyl, Me = methyl, B2I = benzyl. In the compounds listed, all proteinogenous amino acids are L-amino acids unless otherwise noted. Other abbreviations used: Me2Val = N,N-dimethylvaline, MeVal = N-methylvaline, Bn = benzyl, MejAib = [2-N",N"-dimethylaraino] -isobutyric acid.
General Procedures
The peptides of the invention are synthesized either by classical solution synthesis using standard Z- and Boc-methodology as described above or by standard methods of solid-phase synthesis using Boo and Fm.oc protective group techniques.
In the case of solid phase synthesis, the N,N-dialkyl-penta- or hexapeptide acids are liberated from the solid support and further coupled with the corresponding C-terminal amines in solution. BOP-CI and PyBrop were used as reagents for coupling of the amino acid following the N-methylarriinc acids. The reaction times were correspondingly increased. For reductive alkylation of the N-terminus, the peptide-resin was deprotected at the N Cerininus and then reacted wich a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNEKj. After the reaction was complete (negative Kaiser test) the resin was washed several times with water, isoprccanol, DM? and dichlcromethane.

In solution synthesis, the use of either Boc-orotected amino acid NCAs (N-tert.-butyloxycarbonyl-amino acid-N-carboxy-anhydrides), Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) , or the use of pivaloyl chloride as condensing agent" respectively is most advantageous for coupling of the amino acid following the N-methylamino acids. Reductive alkylation of the N terminus can e.g. be achieved hy reaction of the N-terminally deprotected peptides or amino acids with the corresponding aldehydes or ketones using NaCNBHa or hydrogen-Pd/C.
Valyl-N-methylvalyl-prolyl-prolylbenzylamide hydrochloride for example was prepared according to methods disclosed in German Patent Application No. DE 19527575 Al.
Purification and characterization of the peptides
Peptide purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% KOAc, SEPHADEX LH20/MeOH}, medium pressure chromatography (stationary phase; HD-SIL C-IS, 20-45 micron, 100 Angstrom; mobile phase: gradient with. A = 0.1% TFA/ MeOK, B = 0.1% TPA/water), preparative HPLC (stationary phase: Waters Delta-Pak C-IS, 15 micron, 100 Angstrom; mobile phase: gradient with A = 0.1 % TFA/MeOH, B = 0.1 % TFA/water), or by crystallization.
The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 micron, 300 A; mobile phase: acetonitrile-water gradient, buffered with 0.1% TFA, 40°C; or 3.9 mm VYDAC C-18, 30°C}. Characterization was by fast atom bombardment mass spectroscopy and NMR-spectroscopy.

Example 1 Synthesis of
[N-Methyl"L-piperidine-2-carbonyll-Val-MeVal -Pro-Pro-NHBn (Compound 1} and [N-Methyl-D-piperidine-2-carbQnyl]-Val-MeVal -Pro-Pro-NHBn {Compound 2)
"reparation of N-methyl-piperidine-2-carboxylic acid
N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 r) was dissolved in a mixture of 100 ml methanol and 10 ml 7ater. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was :hen neutralized with hydrochloric acid, evaporated to iryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step.
Preparation of
[N-Methyl-piperidine-2-carbanyl]-Val-MeVal-Pro-Pro-NHBn
The residue prepared as described above (5.05 g) and i-Val-MeVal-?ro-Pro-NHBn x HCl (4.88 g> were dissolved in SO ml dry DMF. After cooling the solution in an ice bath, L.52 g DEPCN and 2.S6 ml triethylamine were added. The treacticn mixture was stirred at 0°C for 2 h and then at room temperature overnight. The DMF was rem.oved by evaporation under reduced pressure. The residue was diluted with dichloromethane and the organic phase was cashed with aqueous hydrochloric acid (pH 2) and water, dried over sodium sulfate and evaporated to dryness. The diastereomeric mixture was then separated by flash chromatography with a gradient using heptane/ethyl acetate and dichlcrcmenhane/methanol. Under the HPLC conditions

described in the previous section (C-18 reverse phase) isomer 1 has a retention time of 14.9 minutes, and isomer 2 has a retention time of 15.8 minutes. Both isomers were characterized by fast atom bombardment mass spectrometry
( [MTH]+ = 639) .
Example 2 Preparation of MesAib-Val-MeVal-Pro-Pro-NHBn (Compound 3)
Preparation of 2-[N,N-dimethylamino]-isobutyric acid
2"Amino-isobutyriG acid [10.3 g) was dissolved in 200 ml methanol. After addition of 25 ml aqueous formaldehyde and 1 g 10% Pd/C, the reaction mixture was hydrogenated overnight at room temperature. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was crystallized from isopropanol to give 4.8 g of the desired product.
Preparation of MesAib-Val-MeVal-Pro-Prc-NHBn x HCl
2-[N,N-Dimethylamino]-isobutyric acid (1.3 g, 10 mmol) and 5.5 g (10 mmol) H-Val-MeVal-Pro-Pro-NHBn x HCl were dissolved in 50 ml dry DMF. After cooling to 0°C, 1.6 g DEPCN (10 mmol) and 2.9 ml triethylamine were added to the reaction mixture. The resulting mixture was stirred at 0°C for 2 h and at room temperature overnight. Ice water (50 mL) was then added, and the resulting mixture was extracted twice with diethyl ether. The ether extracts were washed with 1 N NaOK (Ix) and aqueous NaCl (3x) , then dried over sodium sulfate and evaporated to dryness under reduced pressure. The product was crystallized from 100 ml diethyl ether with HCl/ether, and recrystallized from acetone to give 1.2 g of the desired product, which was characterized by fas:; atom bombardment mass spectrometry ( [M-H] = 627) .

Example 3 Preparation of
[N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-Me Val-Pro-Pro-NHBn x HCl (Compound 4}
Preparation of
[N,N-dimethyl-2-ethyl-2-phenylglycyl] -Val-MeVal-Pro-Pro-NHBn X HCl
2.07 g (10 mmol) N,N-Dimechyl-2-ethyl-2-phenylglycine and 5.5 g (10 mmol) H-Val-MeVal-Pro-Pro-NHBn x HCl were dissolved in 100 ml dry DMF. After cooling to 0°C, l.e g DEPCW (10 mmol) and 2.9 ml triethylamine were added. The reaction mixture was stirred at 0°C for 2 h and at room temperature overnight, then worked up as described above. The crude product was crystallized from diethyl ether with HCl/ether to give 4 g of the desired product, which wag characterized by fast atom bombardment mass spectrometry { [M+H] + = 703) .
Example 4 Preparation of
[N-Methyl-D-Prc]-Val-MeVal-Pro-Pro-NHBn (Compound 5)
Preparation of Z-D-Pro-Val-MeVal-Pro-Pro-NHBn
3.74 g Z-D-Pro-OH (15 mmol, EACHEM) and 8.25 g K-Val-MeVal-Pro-Pro-NHBn x HCl (15 mmol) were dissolved in 80 ml dry DMF. Afeer cooling to 0°C, 2.4 g DEPCN (2.25 ml, 15 mmcl) and 4.2 ml triethylamine (30 mmol) were added. The reaction mixture was scirred at 0°C for several hours and room temperature overnight, then the DMF was evaporated under reduced pressure. The residue was diluted with ethyl acetate and thoroughly washed with dilute aqueous HCl (pH 2), water, dilute aqueous NaOH (pH 9-10), and water. The

organic phase was dried over sodium sulfate and evaporated
to dryness to yield 9.2 g o£ the desired protected pentapeptide.
Preparation of D-Pro-Val-HeVal-Pro-?ro-NHBn x HCl
8.2 g (11 mmol) Z-D-Pro-Val-MeVal-Pro-Pro-NHBn was dissolved in 70 ml methanol. After addition of 0.7 ml concentrated hydrochloric acid and 0.3 g 10 % Palladium/charcoal to the solution, the resulting mixnure was hydrogenated. Filtration and evaporation of the solvent gave a residue which was dissolved in water, adjusted to pH 2 and extracted twice with ethyl acetate. The aqueous phase was adjusted to pH 9-10 and extracted twice with dichloromethane. The organic extracts were evaporated and the residue was redissolved in diethylether and crystallized by addition of HCl/e"ther as the hydrochloride salt to give 6.5 g of the desired product.
Preparation of [N-methyl-D-Pro]-Val-MeVal-Pro-Pro-NH3n x HCl
1.94 g (3 mmol) of D-Pro-Val-?eVal-Pro-Pro-NHBn x HCl was dissolved in 30 ml methanol. To this solution was then added 0.3 g 10% Pd/charccal and 1.5 ml aqueous formaldehyde solution and the reaction mixture was hydrogenated. Following filtration and evaporation of the solvents, the resulting residue was dissolved in water, adjusted to pH 2 and extracted twice with diethyl ether and several additional times with dichloromethane. The aqueous phase was adjusted to pH 9-10 and extracted twice wi::h dichloromethane. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was crystallized as the hydrochloride salt to give 0.5 g of the

desired product which was characterized by fast atom bombardment mass spectrometry ( [M+H]+ = 625).
The compounds listed in Table 1 were prepared according to the methods described in Examples 1-4. Where compounds are referred to as "isomer 1" or "isomer 2", isomer 1 is the diastereomer with the shorter retention time on the reversed phase analytical HPLC system. Fast atom bombardment-mass spectrometry results for selected compounds are provided in Table 2.
Table 1 Compound
No.
6 Xah Val Xa.a Pro Xab
7 Xai Val Xaa Pro Xab
8 Xae Val Xaa Pro Xab
9 Xad Val Xaa Pro Xbr
10 Xam Val Xaa Pro Xab
11 Xaw lie Xaa Pro Xbx
12 Xao Val Xaa Pro Xab
13 Xad Val Xaa Pro Xap
14 Xaq Val Xaa Pro Xab
15 Xar Val Xaa Pro Xab
16 Xas Val Xaa Pro Xah
17 Xat Val Xaa Pro Xab isomer 1
18 Xat Val Xaa Pro Xab isomer 2
19 Xaf Val Xaa Pro Xab
20 Xav Val Xaa Pro Xab
21 Xag Val Xaa Pro Xab
22 Xax Val Xaa Pro Xab isomer 1
23 Xax Val Xaa Pro Xao isomer 2
24 Xay Val Xaa Pro Xab
25 Xaz Val Xaa Fro Xab isomer 1
26 Xaz Val Xaa Pro Xab isomer 2
27 Xba Val Xaa Pro Xab
2 3 Xbb Val Xaa Pro Xab
2 9 Xbc Val Xaa Pro Xab

Table 1
Compound
No.
3 0 Xbd Val Xaa Pro Xab isomer 1
31 Xbd Val Xaa Pro Xab isomer 2
3 2 Xbe Val Xaa Pro Xab isomer l
33 Xbe Val Xaa Pro Xsih isomer 2
34 Xbf Val Xaa Pro Xab isomer 1
35 Xbg Val Xa.a Pro Xab
3 5 Xbti Val Xaa Pro Xab isomer 1
3 7 Xbh Val Xaa Pro Xab isomer 2
38 Xbi Val Xaa Pro Xab isomer 1
3 9 Xbi Val Xaa Pro Xab isomer 2
4 0 Xbk Val Xaa Pro Xab isomer 1

41 Xbk Val Xaa Pro Xab isomer 2
42 Xbi Val Xaa Pro Xab
43 Xbf Val Xaa Pro Xab isomer 2
44 Xbm Val Xaa Pro Xab
45 Xaw Val Xaa Pro Xbn
45 Xbo Val Xaa Pro Xbn isomer 1
47 Xbo Val Xaa Pro Xbn isomer 2
4 3 Xaw Val Xaa Pro Xbp
4 9 Xbo Val Xaa Pro Xbp isomer l
50 Xbo Val Xaa Fro Xbp isomer 2
51 Xaw Val Xaa Pro Xbq
52 Xaw Val Xaa Pro Xbr
53 Xbs Val Xaa Pro Xbt isomer 1
54 Xbi Val Xaa Pro Xab isomer 1
55 Xbi Val Xaa Pro Xab isomer 2
56 Xbu Val Xaa Pro Xab isomer 1
57 Xbv Val Xaa Pro Xab
53 Xbw Val Xaa Pro Xab isomer 1
S9 Xbw Val Xaa Pro Xab isomier 2
50 Xbs Val Xaa Pro Xb" isomer 2
61 Xbu Val Xaa Pro Xab isomer 2
62 Xbo Val Xaa Pro Xbr isomer 1
S3 Xbo Val Xaa Pro Xbr isomer 2
64 Xbo Val Xaa Pro Xbq isomer 1
65 Xbo Val Xaa Pro Xbq isomer 2
66 Xaw Val Xaa Pro Xbx

Table 1 Compound No.
67 Xby Val Xaa Pro Xab
68 Xbz Val Xaa Pro Xab
59 Xca Val Xaa Pro Xab isomer 1
70 Xca Val Xaa Pro Xab isomer 2
71 Xbo Val Xaa Pro Xbx isomer 1
72 Xbo Val Xaa Pro Xbx isomer 2
73 Xau Val Xaa Pro Xbp
74 Xau Val Xaa Pro Xbx
75 Xbi Val Xaa Pro Xbx isomer 2
76 Xau Val Xaa Pro Xab isomer 1
77 Xau Val Xaa Pro Xab isomer 2
78 Xau Val Xaa Pro Xcb
79 Xbi Val Xaa Pro Xcb isomer 1 SO Xbi Val Xaa Pro Xcb isomer 2

81 Xbi Val Xaa Pro Xcc isomer 1
82 Xbi Val Xaa Pro Xcc isomer 2
83 Xbi Val Xaa Pro Xcd
84 Xbk Val Xaa Pro Xcc isomer 1
85 Xbk Val Xaa Pro Xcc isomer 2 8 6 Xax Val Xaa Pro Xbp isomer 1 8 7 Xax Val Xaa Pro Xbp isomer 2 8 8 Xbk Val Xaa Pro Xcb isomer 1
8 9 Xbk Val Xaa Pro Xcb isomer 2
90 Xau Val Xaa Pro Xcc
91 Xau Val Xaa Pro Xcd
92 Xba Val Xaa Pro Xcb isomer 1
93 Xba Val Xaa Pro Xcb isomer 2
94 Xbo Val Xaa Pre Xbp isomer 1
9 5 Xbo Val Xaa Pro Xbp isomer 2
96 Xau Val Xaa Pro Xbp isomer 1
97 Xau Val Xaa Pro Xbp isomer 2
98 Xbi Val Xaa Pro Xcd isomer 2 9 9 Xbk Val Xaa Pro Xcd

100 Xba Val Xaa Pro Xbp isomer 1
101 Xba Val Xaa Pro Xbp isomer 2
102 Xba Val Xaa Pro Xcc iscm.er 1

Table 1
Compound
Wo.
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139

Xba Val Xaa Pro Xcc isomer 2
Xba Val Xaa Pro Xcd
Xce Val Xaa Pro Xab
Xcf Val Xaa Pro Xab
Xcg Val Xaa Pro Xab isomer 1
Xcg Val Xaa Pro Xab isomer 2
Xaw Val Xaa Pro Xch
Xaw Val Xaa Pro Xci
Xaw Val Xaa Pro Xck
Xaw Val Xaa Pro Xcl
Xaw Val Xaa Pro Xcm
Xaw Val Xaa Pro Xcn
Xaw Val Xaa Pro Xco
Xaw Val Xaa Pro Xcp
Xaw Val Xaa Pro Xcq
Xaw Val Xaa Pro Xcr
Xad Val Xaa Pro Xch
Xad Val Xaa Pro Xci
Xad Val Xaa Pro Xck
Xad Val Xaa Pro Xcl
Xad Val Xaa Pro Xcm
Xad Val Xaa Pro Xcn
Xad Val Xaa Pro Xco
Xad Val Xaa Pro Xcp
Xad Val Xaa Pro Xcq
Xad Val Xaa Pro Xcr
Xad Val Xaa Pre Xbx
Xau Val Xaa Pro Xch
Xaj. Val Xaa Pro Xci
Xau Val Xaa Pro Xck
Xau Val Xaa Fro Xcl
Xau Val Xaa Pro Xcm
Xau Val Xaa Pro Xcn
Xau Val Xaa Pro Xco
Xau Val Xaa Pro Xcp
Xau Val Xaa Pro Xcc
Xau Val Xaa Pro Xcr

Compound No.
140 Xau Val Xaa Pro Xbr
141 Xad Val Xaa Xal Xbx
142 Xau Val Xaa Xal Xbx
143 Xaw Val Xaa Xal Xbx
144 Xad Val Xaa Xal Xch
14 5 Xau Val Xaa Xal Xch
14 6 Xaw Val Xaa Xal Xch
147 Xad Val Xaa Xal Xcr
148 Xau Val Xaa Xal Xcr
14 9 Xaw Val Xaa Xal Xcr
150 Xad Val Xaa Xan Xbx
151 Xau Val Xaa Xan Xbx
152 Xaw Val Xaa Xan Xbx
153 Xad Val Xaa Xan Xch
154 Xau Val Xaa Xan Xch
155 Xaw Val Xaa Xan Xch
156"" Xad Val Xaa Xan Xcr
157 Xau Val Xaa Xan Xcr
158 Xaw Val Xaa Xan Xcr
159 Xau He Xaa Pro Xbx
160 Xad He Xaa Pro Xbx
161 Xaw He Xaa Pro Xch
162 Xad He Xaa Pro Xch
153 Xau He Xaa Pro Xch
164 Xaw Xcs Xaa Pro Xch
165 Xad Xcs Xaa Pro Xch
166 Xau Xcs Xaa Pro Xch
167 Xaw Xcs Xaa Pro Xbx
16a Xad Xcs Xaa Pro Xbx
169 Xau Xcs Xaa Pro Xbx
170 Xaw Val Xct Pro Xch
171 Xad Val Xct Pro Xch
172 Xau Val Xct Pro Xch
173 Xaw Val Xct Pro Xbx

Table 1
Compound
No.
174 Xad Val Xct Pro Xbx
175 Xau Val Xct Pro Xbx
The symbols Xaa in Table 1 represent the following amino acids or residues thereof:
Xaa: N-methyl-valine
Xab: Prolyl N-benzylamide
Xac: L-N-methyl-piperidine-2-carboxylic acid
Xad: D-N-methyl-piperidine-2-carboxylic acid
Xae: N-methyl-L-proline
Xaf: N-methyl-L-thiazolidine-4-carboxylic acid
Xag: N,N-diraethylglycine
Xah: L-proline
Xai; L-piperidine-2-carboxylic acid
Xak: 2- [N, N-dimethylan\ino] -isobutyric acid
Xal: L-thiazolidine-4-carboxylic acid
Xam: N-propyl-D-piperidine-2-carboxylic acid
Xan : tj-3 , 4 -didehydrcproline
Xac: D-piperidine-2-carboxylic acid
Xap: proline tert.butylester
Xaq: N-ethyl-D-piperidine-2-carboxylic acid
Xar: N-methyl- [2,2,5,5-teCramethyl] -L-thiazolidine-2-
carboxylic acid

Xas: N-isopropyl-D-piperidine-2-carboxylic acid
Xat: N,N-dimethyl-2-cyclopropyl-glycine
Xau; N,N"-dimeth,yl-2-ethyl-2-phenyl-glycine
Xav: D-proline
Xaw; N-methyl-D-proline
Xax: N,N-dimethyl-2- [2-fluoro]phenyl-glycine
Xay: 1-aza- [3,30]bicyclooctyl-5-carboxylic acid
Xaz: N,N-dimethyl-2-[4-fluoro]phenyl-glycine
Xba: N-methyl- [2,2,5,5-tetramethyl] -thiazolidine-2■
carboxylic acid
Xbb: 2-(R,S)-ethyl-2-phenyl-glycine
Xbc r D,L-l-aminoindane-l-carboxylic acid
Xbd: N,N-dimethyl-2-(R,S)-methyl-2-phenyl-glycine
Xbe : 2- [N,N-diinethylaminoj indane-2-carboxylic acid
Xbf : 5-[N,N-dimethylamino]-5,6,7,8-tetrahydro-
naphthalene-5-carboxylic acid
Xbg; N-isopropyl-2-(R,S)-ethyl-2-phenyl-glycine
Xbh: 1-[N,N-dimethylamino] indane-2-carboxylic acid
Xbi : N,N-dimethyl-2-propyl-2-phenyl-glycine
Xbk: N,N-dimethyl-2- [4-methoxy]phenyl-glycine
Xbl: N-tnethyl-3 -hydroxy-D, L-valine
Xbm; N, M-dimechyi-D, L-2-isopropyl-2-phenyl-glycine
Xbn : prcline-N-methoxy-N-methyl-amide
Xbc : N-methyl-piperidine-2-carboxylic acid
Xbp; proline-isopropylamide

Xbq; proline-isoxazolidinyl
Xbr: proline-N-methoxy-N-benzylamide
Xbs: N-methyl-D,L-proline
Xbt: proline- [5--phenylI isoxazolidinyl
Xbu: N-methyl-1,2,3,4-tetrahydrDisoquinoline-l-
carboxylic acid
Xbv: N-methyl-a2etidine-2-carboxylic acid
Xbw: N-isopropyl-azetidine-2-carboxylic acid
Xbx: proline-Cert-buCylamide
Xby: N,K-dimethyl-[0-methyl] serine
Xbz: N,N-dimethyl-[0-methyl] threonine
Xca: N-methyl-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic acid
Xob; proline-pentyl(3> amide
Xcc; proline-(R)-phenethylamide
Xcd: proline-(S)-phenethylamide
Xce : 1- [Njlf-dimethyl amino] cyclohexyl-1-carboxyiic acid
Xcf : 1- [N, N-dimethyl amino] cyclcpentyl -1-carboxylic
acid
Xcg : 1,2,3,4-cetrahydroisoquinoline-3-carboxylic acid

Xch:

In vitro Methodology
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: 539-601, (198S)). Exponentially growing cultures of HT-29 colon carcinoma cells were used to make raicrotiter 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 STC. Test compounds were added, in. 10-fold dilutions varying from 10"" M to 10"° M. Cells were then incubated for 4S 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-dimethylthia2ol-2-yl)-2,5-diphenyltetrazoliun bromide in saline). This mixture was incubated at 37 C for 5 hours, and then 50 mi 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 IC5Q,
Table 3 presents the IC5Q values determined in the HT-29 assay for a series of compounds of the invention.

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.
More specifically, human tumors grown in athymic nude mice can be transplanted into new recipient animals, using

cumor rragmencs wnicn are aDOuc bu mg m size. The day of transplantation is designated as day 0. Six to ten days later, Che 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:

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

EQUIVALENTS
Those skilled in the art will recognize or be able Co ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed in the scope of the following claims.

We claim:
1. A compound of the formula
A-B-D-E-F-{G}r-(K),-L, where in
A is a proline derivative of Formula II,,

unsubstituted or fluorine-substituted normal, branched or cyclic Ci-C1-allcyl; R2, is hydrogen, C1-C3-alkyl, phenyl, or substituted phenyl; or R, and R4, together form a propylene bridge; and R2, R3, R4, and R3, are each, independently, hydrogen or alkyl; or

wherein R, is hydrogen or unsubstiCuted or fluorine-subscituted C1-C-alkyl/ R2, ia C1-C4-allcyl; R4. is alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl; or R1 is an alJcyl group and R", is C1-C,-alkyl, cycloalkylmethyl, bftnzyl or substituted benzyl; and R", is hydrogen or alkyl; or

wherein R", ia hydrogen or alkyl and R, is hydrogen, or unsubacituted or fluorine-substituted alkyl; or

wherein R, is hydrogen, or unsubstituted or fluorine-substituted alkyl; R2. is hydrogen, alkyl, phenyl, or substituted phenyl; or R. and R4-, together form a propylene bridge; and X is hydroxy, alkoxy or fluorine; or

fluorine-aubacituted alkyl; R2, ia hydrogen, alkyl, phenyl, or euhatituted phenyl; or R. and R} together form a propylene bridge; and R4, R\, R4. and R", are each, independently, hydrogen or alkyl; or

wherein the 3-carbonyl moiety is in the endo or exo poaition, z is a single bond or a doiible bond, and R, is hydrogen or

unsubatituted or fluorine-siabstituted alkyl; or

alkyl and R. is hydrogen, unsubstituted alkyl or fluorine-substituted alkyl;
B ia a valyl, isoleucyl, allo-iSoleucyl, norvalyl,
2-tert-butylglycYl or 2-ethylglycyl residue; or

D is an N-alkylvalyl, H-alk:yl-2-ethylglycyl, H-
alkyl-2-tert-butylglycyl, N-allq/"lnorleucyl, N-alkylisoleucyl, N-allcyl-allo-iaoleucyl or N-alkylnorvalyl residue; or

wherein n is 1 or 2; R2 is hydrogen, alkyl or fluorine-suhatituted al3cyl; and X is hydrogen; or n is 1 and X is fluorine, hydroxy.

B}, and R", are each, independenCly, Hydrogen or alkyl; R4, ia hydrogen, hydroxy or altcoxy; and R2B is hydrogen or fluorine; or n, is l and R2 and R4, together form a double bond; or n, is 1 and R"g and R", together form a douhle-bonded oxygen diradical; or n. is 1 or 2 and R2, and R% together form a double bond; or
an aminocyclopentanecarboxylic acid residue of Formula III,,

F is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl reaidue; or

imsubstituted or fluorine-siobstituted alkyl; R2j and R"( are each, independently, hydrogen or methyl; R4,. is hydrogen, hydroxy, alkoxy, or fluorine; R2j is hydrogen or fluorine; or n is 1 and R% and R4£ together form a doiible bond;

or rif is 1 and R4j and R", together form a doable-bonded oxygen diradical; or n is i or 2 and R2, and R4, together form a double bond; or
a 2- or 3-aininocyclopentanecarboxyXic acid residue of Formula Illf,

wherein Ri is alkyl and R"" is hydrogen, or unsubatituted or fluorine-substituted alkyl; or an N-alkylglycyl or N-alkylalanyl residue;

hydrogen, alkyl, arylalkyl, heteroarylalkyl, phenyl or substituted phenyl; or R" and R2, together with the a-carbon atom, form a C1-C8 ring or a benzo-fused C, ring;
K is an a-amino acid of Formula 11,,

wherein R\ is hydrogen, or alkyl; and R% is hydrogen, alkyl, arylalkyl, heteroarylalkyl, phenyl or substituted phenyl; or R2g and R\, together with the a-carbon atom, form a cyclopentane ring or a benzo-fuaed cyclopentane ring;
IJ is a substituted or unsubstituted ainino,
hydrazido, aminoxy or oximato group; and
r and s are, independently, 0 or 1
provided that when s and r are each 0 and A is of formula ii, where
n, isOorl andR2,, R%, R\, R\ and R", are each
hydrogen, L is a substituted or unsubstituted amino or hydrazido group.
2. The compound as claimed in ciaim 1, wherein A is a proline
derivative of Formula II,; R, is hydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, l-methyl-2-fluoroethyl, 1 - fluoromethyl ~2 - fluoroethyl, or 1 -En6thyl-2-fluoroethyl; R\ is hydrogen, methyl, ethyl, propyl, phenyl, or substituted phenyl, wherein the phenyl substituents coririae one or more alJcyl, alkoxy, trif luoromethyl or nitro groups; or Ra and Rla together form a propylene bridge; and R",, R2, R"", and R4. are each, independently, hydrogen or methyl.
3. The compound as claimed in claim 1, wherein A is an a-amino
acid residue of Formula III,, wherein R, is
hydrogen, methyl, ethyl, normal propyl, isopropyl,
cyclopropyl, 2 -fluoroethyl, 2,2,2-trifluoroethyl,

1-methyl-2 -fluoroethyl, 1-fluoromethyl-2 -fluoroethyl, or l-methyl-2-fluoroethyl; R2, ia a C~ C1-alkyl group; R", is methoxyniethyl, 1-methoxyethyl, vinyl, 1-methylvinyl, 1-trifluoromethylvinyl, 1-trifluoromethylethyl, 1-trifluororaethyl-2,2,2-tr±fluoroethyl, 1,1-dimethylhydroxymethyX, phenyl or substituted phenyl, wherein the phenyl substituenta coirr"ise one or more halogen atoms or one or more C-C,-alkyl, methoxy, trifluoromethyl or nxtro groups; or R2, is C1-C1-alkyl and R% is C1-C6-alkyl, cycloalkylmethyl, benzyl or substituted benzyl wherein the benzyl aubstituents comprise one or more halogen atoms, or one or more C1-C-alkyl, methoxy, ethoxy, trifluoromethyl or nitro groups,-and R", is methyl, ethyl or isopropyl.
4. The compound as claimed in claim 1, wherein A is an a-amino acid residue of Formula IV,, wherein R\ is methyl, ethyl or isopropyl; and R, ia hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2 -fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, l-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluoroethyl.
3. The compound as claimed in claim 1, wherein A is an a-amino acid residue of Formula V,, wherein R", is methyl, ethyl or isopropyl and R, is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 2 -fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, l-fluoromethyl-2-fluoroethyl, or 1-methyl-2-fluorQethyl.

6. The compound as claimed in claim 1, wlierein A is an a-aminoacid residue of Formula Via, wherein Rg is hydrogen, methyl, ethyl, normal propyl, isopropyl, cyclopropy 1, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1 -methyl-2-fluoroethyl, 1 -fIuoromethyi-2-fluoroethyl, or l-methyl-2-fluoroethyI; R"a is hydrogen, methyl, ethyl, propyl, phenyl, or substituted phenyl, wherein the phenyl substituents comprise one or more alkyl, alkoxy, trifluoromethyl or nitro groups; or R2 and R"a together form a propylene bridge; and Xg is a hydroxy, methoxy, or ethoxy group, or a fluorine atom.
7. The compound as claimed in claim 1, wherein L is a substituted or unsubstituted amino, or hydrazido.
i. A pharmaceutical composition comprising a compound as claimed in claim 7, and a pharmaceutically acceptable carrier or diluent.
). The composition as claimed in claim 8, wherein L is an amino group of Formula II|,

R"I is a hydrogen atom, a normal or branched, saturated or unsaturated C1-Cig-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C1-C6-alkoxy group, a substituted or unsubstituted aryloxy-C1-C6-alkoxy group, wherein the aiyl substituents comprise one or more halogen atoms or one or more C1-C4-alkyl, methoxy, ethoxy, trifluoromethyl, dioxymethylene, or nitro groups; or a heteroaryl-C1-C3-alkoxy group; and

R 1 is a hydrogen atom, a normal or branched C1-Cig-alkyl group, a normal or branched C1-Cig-alkenyl group, a C3-Cio-cycloalkyl group, an aryl group or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a Cf-C7-alkoxycarbonyl group, a dJoxymethylene group, a C1-C7-aIkylsulfonyl group, an amino group or a C1-Q-dialklamino group; a heteroaryl group or a substituted heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituents comprise one or more C1-C6-alkyl, hydroxyl or phenyl groups.

R"i is methyl, ethyl, normal propyl or isopropyl; and
R"*! is a saturated or partially unsaturated carbocyclic system comprising from about 3 to about 10 carbon atoms, an aryl group or a substituted aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a CrCT-alkoxycarbonyl group, a dioxymethylene group, a C1-CT alkylsulfonyl group, an amino group or a C1-C6-dialkylamino group; a heteroaryl group or a substituted heteroaryl group derived from imidazole.

isoxazoie, isothiazole, thiazole, oxazole, pyrazole, thiophene, ftiran, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazane, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituents comprise one or more CpC3-alkyl, hydroxyl or phenyl groups.

Wi is an N(R2i) group, an oxygen atom or a sulfur atom;
R"I and R4, are each, independently, a hydrogen atom or a C,-C4-alkyl, C3-C7-cycloalkyl, aryl, arylmethyl, substituted aryl, or substituted arylmethyl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a C1-C7-alkoxycarbonyl group, a dioxymethylene group, a C1-C7-alkylsuifonyl group, an amino group or a C1-C6-dialkylamino group; or R2i is a C1-Cig-alkanoyl group or a benzoyl group.

aryl substituents comprise one or more halogen atoms, or one or more methoxy, ethoxy, trifluoromethyl, dioxymethylene, nitro, cyano, C1-C7-alkoxycarbonyl, C1-C7-alkylsulfonyl, amino, or C1-C7-dialkylamino groups; or a heteroaryl-C]-C4 alkyl-group, wherein the heteroaryl group derived from imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4-or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazme, 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
R1 is a hydrogen atom, or r is 1, s is 1 or both r and s are 1, and R 1 is a normal or branched C1-C6-alkyl group, a C3-C8-cycloalkyl group, a C3-C6-cycloalky!-C1-C4-alkyt group, an aryl-C1-C4-alkyl group, an aryl group or a substituted aryl-C]-C4-alkyi or aryl group, wherein the aryl substituents comprise one or more halogen atoms, or one or more C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl, cyano or nitro groups, a C1-C7-alkoxycarbonyl group, a dioxymethylene group, a C1-C7-alkylsulfonyl group, an amino group or a C1-C6-dialkylamino group, a heteroaryl group, a heteroarlyl-C1-C4-alkyl group or a substituted heteroaryl or heteroaryl-C1-C4-

alkyl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine, wherein the heteroaryl substituents comprise one or more C1-C6-alkyl, hydroxy] or phenyl groups; or R1 and R2 together form a propylene bridge or a butylene bridge.

Documents:

1605-mas-1998 abstract duplicate.pdf

1605-mas-1998 abstract.pdf

1605-mas-1998 claims duplicate.pdf

1605-mas-1998 claims.pdf

1605-mas-1998 correspondence others.pdf

1605-mas-1998 correspondence po.pdf

1605-mas-1998 description (complete) duplicate.pdf

1605-mas-1998 description (complete).pdf

1605-mas-1998 form-19.pdf

1605-mas-1998 form-2.pdf

1605-mas-1998 form-26.pdf

1605-mas-1998 form-4.pdf

1605-mas-1998 form-6.pdf

1605-mas-1998 petiiton.pdf

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Patent Number

227923

Indian Patent Application Number

1605/MAS/1998

PG Journal Number

10/2009

Publication Date

06-Mar-2009

Grant Date

27-Jan-2009

Date of Filing

17-Jul-1998

Name of Patentee

ABBOTT GmbH & Co. KG

Applicant Address

65205 WIESBADEN, MAX-PLANCK-RING 2,

Inventors:

#	Inventor's Name	Inventor's Address
1	BERND JANSSEN	114 APPLEBRIAR LANE, MARLBOROUGH, MASSACHUSETTS 01752,
2	TERESA BARLOZZARI	24 SOUTH WOODIDE AVENUE, WELLESLEY, MASSACHUSETTS 02181,
3	ANDREAS HAUPT	33 CATHEINE DRIVE, NORTHBOROOUGH, MASSACHUSETTS 01532,
4	THOMAS ZIERKE	AKAIENSTR 12, 67459 BOHL-IGGELHEIM,
5	ANDREAS KLING	RIEGELER WEG 14, 68239 MANNHEIM,

PCT International Classification Number

CO7K7/06

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	08/896,394	1997-07-18	U.S.A.