DOLOSTATIN ANALOG

Abstract: Novel peptides of formula (I) in which R<1>, R<2>, X, A, R<3>, B, D, E, R<7>, M, Q, a, b and d have the meanings stated in the description, and the preparation thereof are described. The novel substances have an antineoplastic effect.

Description: DOLOSTATIN ANALOG. Description The invention described herein provides novel peptides and derivatives thereof which offer potentially improved therapeutic utilities for the treatment of neoplastic diseases as compared to Dolastatin-10. Furthermore, unlike dolastatin-10 which must be laboriously purified from scarce natural sources, the compounds of this invention may be conveniently synthesized as described in detail below. In addition, Dolastatin-10 is unstable to acid. It was described that even minor changes in the structure can cause complete loss of activity (Biochemical Pharmacology, vol. 40, no. 8, 1859-64, 1990) . Compounds of this invention include novel peptides of the formula I I where R 1 is alkoxy, preferably Cι_ ; alkyl, preferably Cι_ 7 ; cyclo- alkyl, preferably C3-6. alkylsulfonyl, preferably C ± s ; trifluoroethyl; fluoroethyl; difluoroethyl; trifluoro- acetyl; amidino; ureyl; piperidinosulfonyl; morpholino- sulfonyl; benzyloxycarbonyl; alkoxycarbonyl, preferably C1-. 4 ; aminosulfonyl which may be substituted by alkyl, preferably Ci-s; hydroxy; phenylsulfonyl which may be sub¬ stituted by up to three substituents independently selected from alkyl (preferably Cι_ 4 ) , -N(CH 3 ) 2 , nitro, halogen and CF 3 ; or NR 8 R 9 where R 8 and R 9 may each be either hydrogen or alkyl, preferably C 1 - 4 ; R 2 is hydrogen; alkyl, preferably Cι_ 4 ; cycloalkyl, prefera- bly C3-7; acyl, preferably Ci-s; benzoyl or benzyl which may be substituted by up to three substituents indepen¬ dently selected from nitro, halogen, CF 3 , alkyl (prefera¬ bly C 1 -- 4 ) and alkoxy (preferably C 1 - 4 ) ; or R 1 - -R 2 together may be a 5- or 6-membered heterocycle which may be unsubstituted or substituted with one or more substi¬ tuents independently selected from phenyl, benzyl, alkyl (preferably Cι_ 4 ), N(CH 3 ) 2 , nitro, oxo, thienyl, CONH 2 , COOMe and COOEt; X is hydrogen, alkyl (preferably Cι_s) , cycloalkyl (pre- ferably cyclohexyl) , -CH 2 -cyclohexyl or benzyl; A is selected from the group consisting of valyl, iso- leucyl, leucyl, allo-isoleucyl, α-aminoisobutanoyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexyl- alanyl, 2-ethylglycyl or 2-cyclohexylglycyl residues; R 3 is hydrogen or alkyl (preferably Cι_ 5 ) ; B is hydrogen, alkyl (preferably C 1 -. 5 ) , cycloalkyl (pre- ferably cyclohexyl) , -CH 2 -cyclohexyl or benzyl; D is hydrogen, acetoxy, hydroxy, or alkoxy (preferably C1-5) ; E is hydrogen, or alkyl (preferably C 1 -. 5 ); or B and E together are -(CH 2 ) 3 -, -(CH 2 ) 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 CH 2 -, or -C(CH 3 ) 2 CH 2 -; R 7 is -NR -CHG-CHK-CHL-CO-, or where V is oxygen or sulfur; Y 1 is hydrogen; Z 1 is hydrogen or lower alkyl (preferably C 1 - 4 ) ; or Y 1 and Z 1 may together form a bond; W 1 is hydrogen, alkyl (pre¬ ferably Ci-ε) or phenyl; R 4 is hydrogen or alkyl (preferably C 1 -. 5 ) ; G is hydrogen, alkyl (preferably C 1 -. 5 ) , cyclohexyl, -CH 2 -cyclohexyl, or benzyl; K is hydrogen, acetoxy, hydroxy, or alkoxy (preferably Ci-s ) ; L is hydrogen, or alkyl (preferably Cι_ 5 ); or R 4 and G together are -(CH 2 ) -, -(CH 2 ) 3 -, or -CH 2 -CH(OH)-CH 2 -; M is selected from the group consisting of 1-amino- pentyl-1-carbonyl, valyl, 2-tert-butylglycyl, prolyl, hydroxyprolyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, tetrahydroisoquinoly1-2-carbonyl, 3-thiazolylalanyl, 3-thienylalanyl, histidyl, 2-amino- indyl-2-carbonyl, tyrosyl, 3-pyridylalanyl, 3-tert-butyl- alanyl, 2-cyclohexylglycyl, or 3-naphthylalanyl residues; or R1R2N-CHX-CO- and A together are where T is hydrogen or lower alkyl (preferably methyl or ethyl); U is hydrogen or lower alkyl (preferably C 1 -. 5 ) ; n is 1, 2, or 3; V is oxygen or sulfur; Y is hydrogen; Z is hydrogen or lower alkyl (preferably methyl) ; or Y and Z together may form a bond; W is hydrogen, lower alkyl (preferably C 1 -. 4 ) or phenyl; a, b, and d are independently 0 or 1; Q is hydroxy, alkoxy (preferably C 1 - 5 ) , phenoxy, benzyloxy or a substituted or unsubstituted amino group; provided that where b and d are 0, Q is not a hydroxy or alkoxy moiety; and the salts thereof with physiologically tolerated acids. This invention also provides methods for preparing the compounds of formula I, pharmaceutical compositions containing such compounds together with a pharmaceutically acceptable carrier and methods for using same for treating cancer in mammals. One subclass of compounds of this invention includes compounds of formula I wherein R-t-N-R 2 is a 5- or 6-membered heterocycle of the formula 15 which may be unsubstituted or substituted with one or more sub¬ stituents which may independently be selected from phenyl, benzyl, alkyl (preferably Cι_ ) , N(CH 3 ) 2 , nitro, thienyl, CONH 2 , COOEt or an oxo group; 20 Another subclass of compounds of this invention includes compounds of formula I wherein Q is an amino moiety of the formula R 5 -N-R 6 wherein 25 R 5 is H, or hydroxy, or Cι_ 7 -alkoxy, or benzyloxy, or Cι_7-alkyl, or fluoroethyl, or difluoroethyl, or tri- fluoroethyl, or C 3 _ 7 -cycloalkyl, R 6 is H, or Cι-7-alkyl, or phenyl (which may be substituted 30 by up to three substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl which may form a cyclic system, Cι- 4 -alkoxy, phenoxy, benzoxy, or Cι- 7 -alkyl-sulfonyl) , or benzyl (which may be substituted by up to three substi- 35 tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl which may form a cyclic system, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl- sulfonyl) , or naphthyl (which may be substituted by up to two sub- 40 stituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, benzoxy, phenoxy, or Cι_ 7 -alkyl-sulfonyl) , or benzhydryl (which may be substituted by up to two sub¬ stituents which may independently be CF3, nitro, halogen, 45 CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or biphenyl (which may be substituted by up to two sub¬ stituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl, Cι- 4 -alkoxy, phenoxy, ben¬ zoxy, or Cι- 7 -alkyl-sulfonyl) , or triphenylmethyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι- 4 -alkoxy, phenoxy, benzoxy, or Cι- 7 -alkyl-sulfonyl) , or benzhydrylethyl (which may be substituted by up to two substituents which may independently be CF3, nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phen¬ oxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or benzhydrylmethyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, C-- . _ 4 -alkoxy, phen¬ oxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or naphthylmethyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι- 4 -alkyl, Cι_ 4 -alkoxy, phen- oxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or acenaphthyl (which may be substituted by up to two sub¬ stituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) , Cι- 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or acenaphthylmethyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι-4-alkyl, Cχ_4-alkoxy, phenoxy, benzoxy, or Cι-7-alkyl-sulfonyl) , or pyridyl (which may be substituted by up to two substi- tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl} 2 , C 1 _ 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or picolyl (which may be substituted by up to two substi¬ tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or benzothiazolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, ha¬ logen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phen- oxy, benzoxy, or Cι- 7 -alkyl-sulfonyl) , or benzisothiazolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl,Cι_ 4 -alkoxy, phen¬ oxy, benzoxy, or Cι_7-alkyl-sulfonyl) , or benzopyrazolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, C0N(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι-7-alkyl-sulfonyl) , or benzoxazolyl (which may be substituted by up to two sub¬ stituents which may independently be CF 3 , nitro, halogen, CONHBzl, C0N(Bzl) 2 , Cι_ -alkyl, Cι-4-alkoxy, phenoxy, ben¬ zoxy, or Cι_ 7 -alkyl-sulfonyl) , or fluorenyl (which may be substituted by up to two sub- stituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or aminofluorenyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ -alkoxy, phenoxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or pyrimidyl (which may be substituted by up to two sub¬ stituents which may independently be CF 3 , nitro, halogen, COOEt, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl which may form a cy- clic system, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl- sulfonyl) , or 5-membered hetaryl [which may be substituted by up to three substituents which may independently be CF 3 , nitro, halogen, cyano, COOMe, COOEt, thiomethyl, thioethyl, thiophenyl, picolyl,acetyl, -CH 2 -COOEt, CONH 2 CONHBzl, CON(Bzl) 2 , Cι- -alkyl which may form a cyclic system, Cι_ 4 -alkoxy, phenoxy, benzoxy, phenyl (which may be sub¬ stituted by up to four substituents which may indepen¬ dently be nitro, CF 3 , halogen, or Cι_ -alkyl) , benzyl (which may be substituted by up to four substituents which may independently be nitro, CF 3 , halogen, Cι_ 4 -alkyl, naphthyl, Cι-7-alkyl-sulfonyl, phenylsulfonyl, or Cι-4-dialkylamino) ] , or -CHR 7 -5-membered hetaryl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , COOMe, COOEt, COOCH(CH 3 ) 2 , CONH2, COOBzl, d-4-alkyl, Cι_ 4 -alkoxy, phen¬ oxy, benzoxy, phenyl, benzyl, naphthyl, or Cι_ 7 -alkyl-sul- fonyl [R 7 = H, linear or branched Cι_ 5 -alkyl, benzyl; or R 7 and R 5 together form a group -(CH 2 ) 3 - or -(CH 2 ) -]). In another subclass of compounds of this invention R 5 -N-R 6 together may form structures selected from the group consisting of — N so 2 — N SO -o which may be unsubstituted or substituted with one or more sub¬ stituents independently selected from the group consisting of CF 3 , nitro, halogen, oxo, cyano, N,N-dimethylamino, CONHBzl, CON(Bzl) 2 , Cι_ 6 -alkyl (which may form a cyclic system) , Cι-4-alkoxy, phenoxy, benzoxy, naphthyl, pyrimidyl, COOEt,COOBzl, C 3 _ 6 -cycloalkyl, pyrrolidinyl, piperidinyl, thienyl, pyrrolyl, -CH 2 -CO-NCH(CH 3 ) 2 , -CH 2 -CO-N(CH 2 ) 4 , -CH 2 -CO-N(CH 2 ) 4 0, benzyl (which may be substituted by up to three substituents independently selected from the group consisting of nitro, halogen, CF 3 , thiomethyl or the corresponding sulfoxide or sulfone, thioethyl or the corresponding sulfoxide or sulfone, Cι_ 4 -alkyl, and Cι- 4 -alkoxy) , and phenyl (which may be substituted by up to three substituents independently selected from the group consisting of nitro, halogen, CF 3 , thiomethyl, thioethyl, Cι_ 4 -alkyl, and Cι_ 4 -alkoxy) . Another subclass of compounds of this invention includes compounds of formula I wherein b is zero. Yet another subclass of compounds of this invention includes compounds of formula I wherein d is zero, b is -NR-CHG-CHK-CHL-CO-, and Q is not a hydroxy or alkoxy group. Still another subclass of compounds of this invention includes compounds of formula I wherein b and d are zero, and Q is not a hydroxy or alkoxy group. Another subclass of compounds of this invention includes compounds of formula I wherein d is 0 and R 7 is Another subclass of compounds of this invention includes compounds of formula I wherein a is 0. Yet another subclass of compounds of this invention includes compounds of formula I wherein a and d are 0. Another subclass of compounds of this invention includes compounds of formula I wherein b and d are 1 and Q is a hydroxy, Cι- 4 -alkoxy or benzyloxy moiety. Preferred are compounds where the substituents have the following meanings: R 1 is ethyl, methyl, trifluoroethyl, fluoroethyl, difluoroethyl, isopropyl, n-propyl, n-butyl, n-pentyl, cyclopropyl, cycle- pentyl, ureyl, mesyl, tosyl, naphtylsulfonyl, phenylsulfonyl, 2,4, 6-trimethylsulfonyl, benzyloxycarbonyl, tert.butoxycarbo- nyl, methoxycarbonyl, morpholinosulfonyl, tert.butylaminosul- fonyl, methylaminosulfonyl, trifluoroacetyl, NH 2 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N[CH(CH 3 ) 2 ] 2 , amidino or CH 3 0-, R 2 is H, methyl, ethyl, isopropyl, n-propyl, n-butyl, cyclo- propyl, formyl, acetyl, propionyl, (CH 3 ) 2 CHCO-, pivaloyl, benzoyl or or R 1 -N-R 2 toget er are X is hydrogen, methyl, ethyl, isopropyl, -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , tert.butyl, -CH 2 -cyclohexyl, or benzyl; A is valyl, isoleucyl, leucyl, allo-isoleucyl, 3-tert- butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, or 2-cyclohexylglycyl; R 3 is hydrogen, methyl, or ethyl; ' " - * ' " 6 " is hydrogen, methyl, ethyl, isopropyl, -CH 2 CH(CH3) 2 , -CH(CH 3 )CH 2 CH 3 , tert.butyl, -CH 2 -cyclohexyl, or benzyl; D is hydrogen, hydroxy, methoxy, ethoxy, isopropyloxy or 5 tert-butyloxy; E is hydrogen, methyl, ethyl, isopropyl or tert-butyl; or B and E together may form a group -(CH 2 ) 2 -, -(CH 2 ) 3 -, 10 -CH(CH 3 )-CH 2 -, or -C(CH 3 ) 2 -CH 2 -; R 7 is -NR -CHG-CHK-CHL-CO-, or Z 1 20 where V is oxygen or sulfur; Y 1 is hydrogen; Z 1 is hydro¬ gen or methyl; or Y 1 and Z 1 may together form a bond; 1 is hydrogen, methyl, ethyl, isopropyl, 25 tert-butyl or phenyl; R 4 is hydrogen or methyl; G is hydrogen, methyl, ethyl, isopropyl, 30 -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , tert.butyl, -CH 2 -cyclohexyl, or benzyl; K is hydrogen, hydroxy, methoxy, ethoxy, iso¬ propyloxy or tert-butyloxy; 35 L is hydrogen, methyl, ethyl or isopropyl; or R 4 and G together are -(CH 2 ) 4 -, -(CH 2 ) 3 -, or - CH 2 -CH(OH)-CH 2 - 40 M is selected from the group consisting of valyl, 2-tert- butylglycyl, prolyl, hydroxyprolyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, tetrahydroisoquino- lyl-2-carbonyl, 3-thiazolylalanyl, 3-thienylalanyl, 45 2-aminoindyl-2-carbonyl, tyrosyl, 3-pyridylalanyl, 3-tert-butylalanyl, 2-cyclohexylglycyl, or 3-naphthyl- alanyl residues; a,b and d are independently 0 or 1; or R * * * R 2 N-CHX-CO and A together are R 2 Q is a hydroxy1, Cι- 5 -alkoxyl, benzyloxyl or a amino moiety - 15 NR 5 R 6 where R 5 is hydrogen, methyl, ethyl, trifluoroethyl, fluoroethyl, di- fluoroethyl, propyl, isopropyl, or 20 R 6 is hydr -ogen, meth -yl,oethyl, tr -iflouoroethyl, propyl, iso- 25 propyl, tert-butyl, or COOEt COOMe COOBzl COOEt COOMe ONHBzl COOMe COOEt CH3 20 45 or R 5 -N-R 6 together are More preferred are compounds where the substituents have the fol¬ lowing meanings: R 1 is ethyl, methyl, trifluoroethyl, fluoroethyl, difluoro¬ ethyl, isopropyl, propyl, cyclopropyl, benzyloxycarbonyl, methyloxycarbonyl, lactyl, methylaminosulfonyl, osyl, ureyl, mesyl, N(CH 3 )2, amidino or CH 3 0-; R 2 is H, methyl, ethyl, isopropyl, propyl, butyl, cyclo¬ propyl, formyl, acetyl, propionyl, pivaloyl, benzoyl or benzyl; or R 1 -N-R 2 together are X is hydrogen, methyl, isopropyl, -CH 2 CH(CH 3 )2, -CH(CH 3 )CH 2 CH 3 , tert-butyl, or benzyl; A is valyl, isoleucyl, leucyl, 2-tert-butylglycyl or 2-ethylglycyl; R 3 is hydrogen, methyl, or ethyl; B is hydrogen, methyl, isopropyl, -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH CH 3 , tert-butyl, or benzyl; D is hydrogen, hydroxy, methoxy or tert-butyloxy; E is hydrogen, methyl, isopropyl, tert-butyl, or ethyl; or B and E together are -(CH 2 ) 3 - or -(CH 2 ) 2 -; R7 IS M is selected from the group consisting of prolyl, hydroxy- prolyl, valyl, isoleucyl, 2-tert-butylglycyl, phenylala- nyl, tetrahydroisoquinolyl- 2-carbon 1, 2-aminoin- dyl-2-carbonyl, tyrosyl, 3-naphthylalanyl residues; a, b and dare independently 0 or 1; or R 1 R 2 N-CHX-CO- and A together are Q is a hydroxyl, Cι_ -alkoxyl, benzyloxyl or amino moiety 30 -NR 5 R 6 where R 5 is hydrogen, methyl, ethyl, trifluorethyl, fluoro¬ ethyl, difluoroethyl, propyl, isoproypyl, cyclo¬ 35 propyl, cyclopentyl, cyclohexyl; R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, tert- butyl, benzyl, 4-phenoxybenzyl, 4-benzyloxybenzyl, 3 ,4, 5-trimethoxybenzyl, phenyl, 4-phenoxyphenyl, 40 4-benzyloxyphenyl, 3 , 4, 5-trimethoxyphenyl or 45 COOEt CH, COOEt COOEt or R 5 -N-R 6 together are COOEt These examples illustrate but do not limit the scope of the present invention. The compounds of the formula I are composed preferably of L-amino acids or components derived from L-amino acids but they may contain one or more D-amino acids or components derived from D-amino acids. Particularly suitable physiologically tolerated acids are: 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 novel compounds can be prepared by known methods. Thus, the compounds can be assembled sequentially or by linking suitable small fragments. In the sequential assemblage, starting at the C terminus the peptide chain is extended stepwise by one amino acid or building block each time. In fragment coupling it is possible to link together fragments of different lengths, and the frag- ments in turn can be obtained by sequential assemblage from amino acids or building blocks. Both in the sequential assemblage and in the fragment coupling it is necessary to link the units by forming an amide linkage. Enzymatic and chemical methods are suitable for this. Chemical methods for forming the amide linkage are described in detail by Mϋller, Methoden der organischen Chemie Vol. XV/2, pp 1 to 364, Thieme Verlag, Stuttgart, 1974; Stewart, Young, Solid Phase Peptide Synthesis, pp 31 to 34, 71 to 82, Pierce Chemical Company, Rockford, 1984; Bodanszky, Klausner, Ondetti, Peptide Synthesis, pp 85 to 128, John Wiley & Sons, New York, 1976 and other standard works on peptide chemistry. Particular preference is given to the azide method, the symmetric and mixed anhydride method, in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents, espe¬ cially dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) , l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ) , l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis (2-oxo-3-oxa- zolidinyD-amidophosphoryl chloride (BOP-C1) , bromo-tris-pyrroli- dinophosphoniumhexa-fluorophosphate (PyBrop) , diphenylphosphoryl azide (DPPA) , Castro's reagent (BOP, PyBop) , O-benzotriazo- lyl-N,N,N' ,N'-tetramethyluronium salts (HBTU) , diethylphosphoryl cyanide (DEPCN) , 2,5-diphenyl-2,3-dihydro- 3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and 1, l'-carbonyldiimidazole (CDI) . The coupling reagents can be em¬ ployed alone or in combination with additives such as N,N-di- methyl-4-aminopyridine (DMAP) , N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuecinimide (HOSu) or 2-hydroxypyridine. Whereas it is normally possible to dispense with protective groups 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 conven¬ tional protective group techniques are preferred for the chemical peptide syntheses: the benzyloxycarbonyl (Z) , the t-butoxycarbo- nyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques. Identified in each case is the protective group on the α-amino group of the chain-extending unit. A detailed review of amino- acid protective groups is given by Mϋller, Methoden der organi¬ schen Chemie Vol. XV/1, pp 20 to 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 in J. Amer. Chem. Soc. 85 (1963) 2149. Particularly preferred methods are those in which peptides are assembled sequentially or by fragment coupling using the Z, Boc or Fmoc protective group technique, with one of the reactants in the said Merrifield technique being bonded to an insoluble poly¬ meric support (also called resin hereinafter) . This typically entails the peptide being assembled sequentially on the polymeric " ' * support using the Boc or Fmoc protective group technique, the growing peptide chain being covalently bonded at the C terminus to the insoluble resin particles (cf. Fig. 1 and 2). This proce¬ dure makes it possible to remove reagents and byproducts by fil- 5 tration, and thus recrystallization of intermediates is unneces¬ sary. The protected amino acids or building blocks can be linked to any suitable polymers, which merely have to be insoluble in the sol- 10 vents used and to have a stable physical form which makes filtra¬ tion easy. The polymer must contain a functional group to which the first protected amino acid can be firmly attached by a co- valent bond. Suitable for this purpose are a wide variety of polymers, eg. cellulose, polyvinyl alcohol, polymethacrylate, 15 sulfonated polystyrene, chloromethylated styrene/divinylbenzene copolymer (Merrifield resin) , 4-methylbenzhydrylamine resin (MBHA-resin) , phenylacetamidomethyl-resin (Pam-resin) , p-benzyl- oxy-benzyl-alcohol-resin, benzhydryl-amine-resin (BHA-resin) , 4-(hydroxymethyl)benzoyloxy-methyl-resin, the resin of Breipohl 20 et al. (Tetrahedron Letters 28 (1987) 565; supplied by BACHEM) , 4- (2,4-dimethoxyphenylaminomethyl)phenoxy-resin (supplied by Novabiochem) or o-chlorotrityl-resin (supplied by Biohellas) . Suitable for amide bond formation in solution are all solvents 25 which are inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , acetoni- trile, dichloromethane (DCM) , 1,4-dioxane, tetrahydrofuran (THF) , N-methyl-2-pyrrolidone (NMP) and mixtures of the said solvents. Synthesis on the polymeric support can be carried out in all in- 30 ert organic solvents in which the amino-acid derivatives used are soluble; however, preferred solvents additionally have resin- swelling properties, such as DMF, DCM, NMP, acetonitrile and DMSO,-and mixtures of these solvents. After synthesis is com¬ plete, the compound is cleaved off the polymeric support. The 35 conditions under which cleavage off the various resin types is possible are disclosed in the literature. The cleavage reactions most commonly used are acid- and palladium-catalyzed, especially cleavage in liquid anhydrous hydrogen fluoride, in anhydrous tri- fluoromethanesulfonic acid, in dilute or concentrated trifluoro- 40 acetic acid, palladium-catalyzed cleavage in THF or THF-DCM mix¬ tures in the presence of a weak base such as morpholine or cleavage in acetic acid/dichloromethane/trifluoroethanol mixtu¬ res. Depending on the chosen protective groups, these may be retained or likewise cleaved of under the cleavage conditions. 45 Partial deprotection of the peptide may also be worthwhile when certain derivatization reactions are to be carried out. Compounds dialkylated at the N-terminus can be prepared either by coupling of the appropriate N,N-di-alkylamino acids in solution or on the polymeric support, by reductive alleylation in solution (with e.g. NaCNBH 3 in MeOH) or by reductive alkylation of the resin-bound compound in DMF/1% acetic acid with NaCNBH 3 and the appropriate aldehydes. Compounds with γ- or δ-lactam bridges can be prepared by incorporating the appropriate lactam-bridged dipeptide units (R. Freidinger, J. Org. Chem. (1982) 104-109) into the peptide chain. Compounds with thiazole-, oxazol-, thiazolin- or oxazolin- containing dipeptide building blocks can be prepared by incorpo- rating the appropriate dipeptidic units (U. Schmidt et al., Synthesis (1987), 233-236; P. Jouin et al., Tetrahedron Letters (1992), 2807-2810; P. Wipf et al. , Tetrahedron Letters (1992), 907-910; W.R. Tully, J. Med. Chem. (1991), 2065; Synthesis (1987), 235; T. Shioiri et al., J. Org. Chem. (1987), 1252-1255; R. Pettit et al., J. Am. Chem. Soc. (1989), 5463-65) into the peptide chain. The building blocks having the structure -NR 3 -CHB- CHD-CHE-CO- and -NR -CHG-CHK-CHL-CO- can be prepared according to the literature by reacting for example the corresponding protec¬ ted amino acid aldehydes with the appropriate alkylating species like phosphonates, phosphorous ylides, Evans's reagent etc. (S. Shibuya et al., Heterocycles (1990), 1597-1600; M. Braun et al., Angew. Chem. (1987), 24-37; Angew. Chem. 1992, 104, No. 10; T. Shioiri et al., Peptide Chemistry 1989, N. Yanaihara (Ed.), 291-296; Pettit et al., J. Am. Chem. Soc. 1989, 111, 5463; T. Shioiri, Tetrahedron Letters 1991, 931-934; K. Koga, Tetrahedron Letters 1991, 2395-2398; The compounds of this invention may be used to inhibit or other¬ wise treat solid tumors (e.g. tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematologi- cal malignancies (e.g. leucemias, lymphomas) by administration of the compound to the mammal. Administration may be by any of the means-which are conventional for pharmaceutical, preferably onco¬ logical, agents, including oral and parenteral means such as sub- cutaneously, intravenously, intramuscularly and intraperito- neally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound of formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical composi- tions may be combination products, i.e., may also contain other therapeutically active ingredients. The dosage to be administered to the mammal will contain an effective tumor-inhibiting amount of active ingredient which will depend upon conventional factors including the biological activity of the particular compound employed; the means of ad¬ ministration; the age, health and body weight of the recipient; -'- * - 5 ,. , -- • - the nature and extent of the symptoms; the frequency of treat¬ ment; the administration of other therapies; and the effect desired. A typical daily dose will be about 5 to 250 milligrams per kilogram of body weight on oral administration and about 1 to 5 100 milligrams per kilogram of body weight on parenteral ad¬ ministration. Suitable dosage forms contain about 10 to 500 milligrams of active ingredient per unit. The active ingredient will thus ordi- 10 narily comprise about 1-90 % by weight based on the total weight of the composition. The novel compounds can be administered in conventional solid or liquid pharmaceutical administration forms, eg. uncoated or 15 (film-)coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conven¬ tional pharmaceutical aids such as tablet binders, fillers, pre¬ servatives, tablet disintegrants, flow regulators, plasticizers, 20 wetting agents, dispersants, emulsifiers, solvents, sustained re¬ lease compositions, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stutt¬ gart, 1978). The administration forms obtained in this way nor¬ mally contain 1-90% by weight of the active substance. 25 The following examples are intended to illustrate the invention. The proteinogenous amino acids are abbreviated in the examples using the known three-letter code. Other meanings are: TFA = tri- fluoroacetic acid, Ac = acetic acid, Bu = butyl, Et = ethyl, Me = 30 methyl, Bzl = benzyl, A. General procedures I. The compounds claimed in claim 1 are either synthesized by 35 classical solution synthesis using standard Z- and Boc-methodo- logy as described above or by standard methods of solid-phase synthesis either manually or on a completely automatic model 431A synthesizer supplied by APPLIED BIOSYSTEMS. The different synthe¬ tic cycles for the Boc and Fmoc protective group techniques are 40 as follows: a) Synthetic cycle for the Boc protective group technique 1. 30% trifluoroacetic acid in DCM 1 x 3 min 2. 50% trifluoroacetic acid in DCM l x l min 3. DCM washing 5 x 1 min 4. 5% diisopropylethylamine in DCM l x l min 5. 5% diisopropylethylamine in NMP l x l min 6. NMP washing 5 x 1 min 7. Addition of preactivated protected amino acid (activation with 1 equivalent of DCC and 1 equivalent of HOBt in NMP/DCM) ; Peptide coupling (1st part) 1 x 30 min 8. Addition of DMSO to the reaction mixture until it contains 20% DMSO by volume Peptide coupling (2nd part) 1 x 16 min Addition of 3.8 equivalents of diisopropyl¬ ethylamine to the reaction mixture Peptide coupling (3rd part) 1 x 7 min DCM washing 3 x 1 min if conversion is incomplete, repetition of coupling (back to 5. ) 14. 10% acetic anhydride, 5% diisopropyl¬ ethylamine in DCM 1 x 2 min 15. 10% acetic anhydride in DCM 1 x 4 min 16. DCM washing 4 x 1 min 17 . back to 1. BOP-Cl and PyBrop were used as reagents for coupling of the amino acid following N-methylamino acids or building blocks bearing an N-methyl group.. The reaction times were correspondingly in¬ creased. In solution synthesis, the use of either Boc-amino acid- NCAs (N-tert.-butyloxycarbonyl-amino acid-N-carboxy-anhydrides) or Z--amino acid-NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy- anhydrides) respectively is most advantageous for this type of coupling. b) Synthetic cycle for the Fmoc protective group technique 1. DMF washing 1 min 2. 20% piperidine in DMF 4 min 3, 20% piperidine in DMF 16 min 4. DMF washing 1 min 5. Addition of the preactivated protected amino acid (activation by 1 equivalent of TBTU and 1.5 equivalent of DIPEA in DMF); Peptide coupling 1 x 61 min DMF washing 3 x 1 min if conversion is incomplete, repetition of coupling (back to 5.) 8. 10% acetic anhydride in DMF 1 x 8 min 9. DMF washing 3 x 1 min 10 back to 2 BOP-Cl and PyBrop were used as reagents for coupling of the amino acid following the N-methylamino acid or building blocks bearing an N-methyl group. The reaction times were correspondingly in- creased. II. Reductive alkylation of the N terminus The peptide-resin prepared as in Ala or Alb was deprotected at the N terminus (steps 2-4 in Alb or 1-6 in Ala) and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH 3 . After reaction was complete (negative Kaiser test) the resin was washed several times with water, isopropanol, DMF and dichloromethane. III. Workup of the peptide-resins obtained as in la and II The peptide-resin was dried under reduced pressure and transfer¬ red into a reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA) . Addition of a scavenger, preferably anisole (1 ml/g of resin) , and in the case of tryptophan-containing peptides of a thiol to remove the indolic formyl group, preferably ethanedi- thiol (0.5 ml/g of resin), was followed by condensing in hydrogen fluoride (10 ml/g of resin) while cooling with liquid N 2 . The mix- ture was left to warm to 0°C and stirred at this temperature for 45 min. The hydrogen fluoride was then stripped off under reduced pressure, and the residue was washed with ethyl acetate in order to remove remaining scavenger. The compound was extracted with 30% strength acetic acid and filtered, and the filtrate was lyophilized. IV. Work-up of the peptide-resins obtained as in lb and II The peptide-resin was dried under reduced pressure and then sub- jected to one of the following cleavage procedures, depending on the amino-acid composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985) . The suspension of the peptide-resin in the suitable TFA mixture was stirred at room temperature for the stated time and then the resin was filtered off and washed with TFA and DCM. The filtrate and the washings were concentrated, and the compound was precipi¬ tated by addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered off, taken up in 30% acetic acid and lyophilized. V. When an o-chlorotrityl-resin (supplied by Biohellas) is used, the suspension of the peptide-resin in an acetic acid/trifluoro- ethanol/dichloromethane mixture (1:1:3) is stirred at room temperature for 1 h. The resin is then filtered off with suction and thoroughly washed with the cleavage solution. The combined filtrates are concentrated in vacuo and treated with water. The precipitated solid is removed by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure. VI. Purification and characterization of the compounds Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) with or without subse¬ quent-medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 μ, 100 A; mobile phase: gradient with A = 0.1% TFA/ MeOH, B = 0.1% TFA/H 2 0) . The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 1, 300 A; mobile phase: CH 3 CN/H 2 0 gradient, buffered with 0.1% TFA, 40°C) . Characterization was by fast atom bombardment mass spectroscopy and 1 H- or 13 C-spectroscopy. B. Specific procedures EXAMPLE 1 N,N-Dimethyl-Val- Val - 0.4 g phenylalaninamide hydrochloride (2 mmol) and 0.55 g Boc- N(CH 3 )-CH[CH(CH 3 ) 2 ]-CH(OCH 3 )-CH 2 -COOH (2 mmol; synthesized accor¬ ding to the literature: S. Shibuya et al., Heterocycles, vol. 31) no. 9, 1597-1600 (1990) were dissolved in DMF. After addition of 0.4 g DEPCN (2.2 mmol) and 1.4 ml Diisopropylamine (DIPEA) , the reaction mixture was stirred overnight at room temperature, the solvent evaporated under reduced pressure, and the residue taken up in ethylacetate and thoroughly washed with 5 % aqueous citric acid, water, 5 % NaHC0 3 , and NaCl solution. The organic layer was dried over Na 2 S0 , filtered, and evaporated to dryness. The resi- due (0.66 g) was dried in vacuo, deprotected with 5 ml TFA/DCM (1:1) for 2 hours and evaporated to dryness. The thus obtained deprotected fragment was dissolved in DMF and reacted with 0.44 g N-tert.butyloxycarbonyl-valine-N-carboxyanhydride (1.8 mmol) at 45°C. After stirring for 5 h the solvent was evaporated in vacuo, ethylacetate added, and the organic layer washed thoroughly with 5 % aqueous citric acid, 5 % aqu. NaHC0 3 , water, and aqu. NaCl, and dried over Na 2 S0 . The solvent was evaporated under reduced pressure and the residue (0.7 g, 1.3 mmol) treated with 5 ml TFA/ DCM (1:1) for 2 h. After evaporation of the solvent mixture and drying over KOH, the residue was dissolved in DMF and 0.19 g N,N-dimethylvaline (1.3 mmol; synthesized according to the lite¬ rature: see e.g. R.E. Bowmann, J. Chem. Soc. 1959, 1342), 0.25 g DEPCN- (1.5 mmol) and 0.7 ml DIPEA were added. The reaction mix¬ ture was stirred overnight at room temperature, evaporated to dryness and chromatographed on a SEPHADEX LH-20 column. Product fractions were collected and the solvent, evaporated, yielding 0.46 g of compound 1. EXAMPLE 2 0.29 g benzylamine (2 mmol) and 0.55 g Boc-N(CH 3 )-CH[CH(CH 3 ) 2 ]- CH(OCH 3 )-CH 2 -COOH (2 mmol; synthesized according to the litera¬ ture: S. Shibuya et al., Heterocycles, vol. 31, no. 9, 1597-1600 (1990)) were dissolved in DMF. After addition of 0.4 g DEPCN (2.2 mmol) and I.4 ml DIPEA, the reaction mixture was stirred over¬ night at room temperature, the solvent evaporated under reduced pressure, and the residue taken up in ethylacetate and thoroughly 5 washed with 5 % aqu. citric acid, water, 5 % NaHC0 3 , and NaCl so- ( lution. The organic layer was dried over Na S0 4 , filtered, and evaporated to dryness. The residue (0.51 g) was dried in vacuo, deprotected with 5 ml TFA/DCM (1:1) for 2 hours and evaporated to dryness. The thus obtained deprotected fragment was dissolved in 10 DMF and reacted with 0.4 g N-tert.-butyloxycarbonyl-valine-N- carboxyanhydride (1.6 mmol) at 45°C. After stirring for 5 h the solvent was evaporated in vacuo, ethylacetate added, and the organic layer washed thoroughly with 5 % aqu. citric acid, 5 % aqu. NaHCθ 3 , water, and aqu. NaCl, and dried over Na 2 S0 4 . The sol- 15 vent was evaporated under reduced pressure and the residue (0.51 g, 1.1 mmol) treated with 5 ml TFA/DCM (1:1) for 2 h. After eva¬ poration of the solvent mixture and drying over KOH, the residue was dissolved in DMF and 0.16 g N,N-dimethylvaline (1.1 mmol), 0.23 g DEPCN (1.4 mmol) and 0.7 ml DIPEA were added. The reaction 20 mixture was stirred overnight at room temperature, evaporated to dryness and chromatographed on a SEPHADEX LH-20 column. Product fractions were collected and the solvent evaporated, yielding 0.36 g of compound 1. 25 The following compounds were prepared and can be prepared accor¬ ding to examples 1 and 2: 3. xaa Val Xdm Xcx Xab 4. xaa Val Xdm Xcx Xac 30 5. Xaa Val Xdm Xcx Xat 6. xaa Val Xdm Xcx Xbp 7. xaa Val Xdm Xcx Xbt 8. Xaa Val Xdm Xcx Xbu 9. Xaa Val Xdm Xcx Xbv 35 10. Xaa Val Xdm Xcx Xbw 11. Xaa Val Xdm Xcx Xby 12. Xaa Val Xdm Xcx Xca 13. Xaa Val Xdh Xcx Xbq 14. Xaa Val Xdh Xcx Xbs 40 15. Xaa Val Xdm Xat 16. Xaa Val Xdm Xbp 17. Xav Val Xdm Xbq 18. xav Val Xdm Xbs 19. Xbo Val Xdm Xbt 45 20. Xbo Val Xdm Xbu 21. Xaa Xaf Xdm Xbv 22. Xaa Xaf Xdm Xbw 35 40 45 Table I Sequence Identification of Compounds Prepared According to Examples 1 and 2. The symbols Xaa... in the summary have the following meanings: Xaa: N,N-Dimethylvaline Xad: Tetrahydroisoquinoline carboxylic acid Xaf: tert-Leucine or 2-tert-butylglycine Xag: N-N-Dimethylisoleucine Xah: N,N-Dimethylleucine Xai : N, N-Dimethyl-tert-leucine Xak: N-amidino-valine Xai : N-Acetyl-N-methylvaline Xam: N-Methyl-N-benzylvaline OCH 3 Xas : N-Methyl-N-isopropylvaline O Xat : NH CH(CH 3 ) 2 Xav: N,N-Diethylvaline Xaw: N-Fluoroethylvaline Xax: N,N-Dipropylvaline Xay: N-Cyclopropylvaline Xbb: CH(CH 3 ) 2 CH(CH 3 ) 2 Xbo: N,N-Dipropyl-tert-leucine COOEt COOEt Xcs : N-Ureyl-valine Xct : N,N-Dimethylphenylalanine Xcu: 3-Thienylalanine Xcv: N-Methyl-N-isopropyl-tert.-leucine I Xda: •N' CO- CH 3 Xdb: — N' CO- k CH 3 CH, CH 3 CH 3 Xdo: Xdr : 3 -Napht hy 1 a 1 an ine CH 3 Xdv: N-Methylaminosulfonyl-valine Xdw: N-Methyl-N-methylsulfonyl-valine Xdx:N -Lactyl-N-methyl-valine The ending -NH 2 means that the C-terminal amino acid or building block is in the amide form. Compounds of this invention may be assayed for anti-cancer acti- vity by conventional methods, including for example, the methods described below. A. In vitro methodology Cytotoxicity may be measured using a standard methodology for ad¬ herent cell lines such as the microculture tetrazolium assay (MTT) . Details of this assay have been published (Alley, MC et al, Cancer Research 48:589-601, 1988). Exponentially growing cul¬ tures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor are used to make microtiter plate cultures. Cells are seeded at 5000-20,000 cells per well in 96-well plates (in 150 μl of media), and grown overnight at 37°C. Test compounds are added, in 10-fold dilutions varying from 10 -4 M to 10 -10 M. Cells are then incubated for 48 hours. To determine the number of viable cells in each well, the MTT dye is added (50 μl of 3 mg/ml solution of 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline) . This mixture is incubated at 37°C for 5 hours, and then 50 μl of 25 % SDS, pH2 is added to each well. After an overnight incubation, the absorbance of each well at 550 nm is read using an ELISA reader. The values for the mean +/- SD of data from re¬ plicated wells are calculated, using the formula % T/C (% viable cells treated/control) . OD of treated cells x 100 = % T/C OD of control cells The concentration of test compound which gives a T/C of 50 % growth inhibition was designated as the IC 50 B. In vivo methodology Compounds of this invention may be further tested in any of the various pre-clinical assays for in vivo activity which are indi¬ cative 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 which have been grown in athymic nude mice are transplanted into new recipient animals, using tu¬ mor fragments which are about 50 mg in size. The day of trans¬ plantation is designated as day 0. Six to ten days later, mice are treated with the test compounds given as an intravenous or intraperitoneal injection, in groups of 5-10 mice at each dose. Compounds were given daily for 5 days, 10 days or 15 days, at do¬ ses from 10-100 mg/kg body weight. Tumor diameters and body weights were measured twice weekly. Tumor volumes are calculated using the diameters measured with Vernier calipers, and the for¬ mula: ;length x width 2 ) 12 = mg of tumor weight Mean tumor weights are calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: BASF Aktiengesellschaft (B) STREET: Carl-Bosch-Strasse 38 (C) CITY: Ludwigshafen (E) COUNTRY: Federal Republic of Germany (F) POSTAL CODE (ZIP) : D-67056 (G) TELEPHONE: 0621/6048526 (H) TELEFAX: 0621/6043123 (I) TELEX: 1762175170 (ii) TITLE OF INVENTION: Novel peptides, the preparation and use thereof (iii) NUMBER OF SEQUENCES: 9 (iv) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.25 (EPO) (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Xaa Val Xaa Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: ---.»- ■> - * - * xaa Val Xaa Xaa Xaa 1 - 5 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Xaa Xaa Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Xaa Leu Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: Xaa Val Xaa Xaa Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid -,., . *. 70 (C) STRANDEDNESS: single (D) ' TOPOLOGY: 1inear (ii) MOLECULE TYPE: peptide ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 6: Xaa Xaa Phe Xaa 1 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: Xaa Val Xaa Phe 1 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Xaa Xaa Xaa Phe 1 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single ^ (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: Xaa Val Xaa Pro 1 Fig. 1 : The Boc protective group technique on a polymeric support Boc-NH-CH-CO-resin I PG-R Boc HF x H 2 N-CH-CO-[-NH-CH-CO-] n -NH-CH-COOH I I I R R R Boc = t-butyloxycarbonyl protective group PG= side-chain protective group R = amino-acid side chain Fig. The Fmoc protective group technique on a polymeric support Fmoc-NH-CH-CO-resin I PG-R Piperidine/DMF H 2 N-CH- CO -resin I PG-R Fmoc Activator Fmoc-NH-CH-CO-HN-CH-CO-resin I I PG-R PG-R TEA TFAx H 2 N-CH-CO-[-NH-CH-CO-] n -NH-CH-COOH I I I R R R Fmoc =9-fluorenylmethyloxycarbonyl protective group PG =side-chain protective group ~" R=amino-acid side chain

Claims: Claims 1. A peptide of the formula I I, where R 1 is alkoxy; alkyl; cycloalkyl; alkylsulfonyl; tri- fluoroethyl; fluoroethyl; difluoroethyl; trifluoro- acetyl; amidino; ureyl; piperidinosulfonyl; mor- pholinosulfonyl; benzyloxycarbonyl; alkoxycarbonyl; aminosulfonyl which may be substituted by alkyl; hydroxy; phenylsulfonyl which may be substituted by one or more substituents independently selected from alkyl, -N(CH 3 ) 2 , nitro, halogen and CF 3 ; or NR 8 R 9 where R 8 and R 9 may each be either hydrogen or alkyl; R 2 is hydrogen; alkyl; cycloalkyl; acyl; benzoyl or benzyl which may be substituted by up to three sub¬ stituents independently selected from nitro, halogen, CF 3 , alkyl and alkoxy (preferably Cι_ 4 ) ; or R 1 -N-R 2 together may be a 5- or 6-membered heterocycle which may be unsubstituted or substituted with one or more substituents independently selected from phenyl, benzyl, alkyl, N(CH 3 ) 2 , oxo, nitro, thienyl, CONH 2 , COOMe and COOEt; X is hydrogen, alkyl, cycloalkyl, -CH 2 -cyclohexyl or benzyl; A is selected from the group consisting of valyl, iso¬ leucyl, leucyl, allo-isoleucyl, α-aminoisobutanoyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexyl- alanyl, 2-ethylglycyl or 2-cyclohexylglycyl residues; R 3 is hydrogen or alkyl; B is hydrogen or alkyl, cycloalkyl, -CH 2 -cyclohexyl or benzyl; D is hydrogen, hydroxy, acetoxy, or alkoxy; E is hydrogen or alkyl; or B and E together are -(CH 2 ) 3 -, -(CH 2 ) 2 -. -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 CH 2 -, or -C (CH 3 ) 2 CH 2 -; R 7 is -NR 4 -CHG-CHK-CHL-CO- , or where V is oxygen or sulfur; Y 1 is hydrogen; Z 1 is hydrogen or lower alkyl; or Y 1 and Z 1 may together form a bond; W 1 is hydrogen, alkyl or phenyl; R 4 is hydrogen or alkyl; G is hydrogen, alkyl, cyclohexyl, -CH 2 -cyclohexyl, or benzyl; K is hydrogen, hydroxy, acetoxy, or alkoxy; L is hydrogen, or alkyl; or R 4 and G together are -(CH 2 ) -, -(CH 2 ) 3 -, or -CH 2 -CH(OH)-CH 2 -; M is selected from the group consisting of 1-amino- pentyl-1-carbonyl, valyl, 2-tert-butylglycyl, prolyl, hydroxyprolyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, tetrahydroisoquinolyl-2-carbonyl, 3-thiazolylalanyl, 3-thienylalanyl, histidyl, 2-aminoindyl-2-carbonyl, tyrosyl, 3-pyridylalanyl, 3-tert-butylalanyl, 2-cyclohexylglycyl, or 3-naph- thylalanyl residues; s ^ m.^^ 1 ^ 1 ^ *. ■ " • -• 75 or R R 2 N-CHX-CO- and A together are 10 15 where T is hydrogen or lower alkyl; U is hydrogen or lower alkyl; n is 1, 2, or 3; V is oxygen or sulfur; Y is 20 hydrogen; Z is hydrogen or lower alkyl; or Y and Z together may form a bond; W is hydrogen, lower alkyl or phenyl; a, b, and d are independently 0 or 1; 25 Q is hydroxy, alkoxy, phenoxy, benzyloxy or a sub¬ stituted or unsubstituted amino group; provided that where b and d are 0, Q is not a hydroxy or 30 alkoxy moiety; and the salts thereof with physiologically tolerated acids. 2. Compounds of formula I according to claim 1 wherein R-*~N-R 2 is 35 a 5- or 6-membered heterocycle of the formula which may be unsubstituted or substituted with one or more substituents which may independently be selected from phenyl, benzyl, alkyl, N(CH 3 ) 2 , nitro, thienyl, CONH 2 , COOEt or an oxo group; 3. Compounds of formula I according to claim 1 wherein Q is an amino moiety of the formula R 5 -N-R 6 wherein R 5 is H, or hydroxy, or Cι_ -alkoxy, or benzyloxy, or Cι-7-alkyl, or fluoroethyl, or difluoroethyl, or tri- fluoroethyl, or C 3 _ 7 -cycloalkyl, R 6 is H, or Cι- -alkyl, or trifluoroethyl, or phenyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl which may form a cyclic system, Cι_-alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or benzyl (which may be substituted by up to three substi¬ tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 Cι_ -alkyl which may form a cyclic system, Cι_ -alkoxy, phenoxy, benzoxy, or C^-al-yl- sulfonyl) , or naphthyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι- 4 -alkyl, Cι_ -alkoxy, benzoxy, phenoxy, or Cι_ -alkyl-sulfonyl) , or benzhydryl (which may be substituted by up to two substi¬ tuents which may independently be CF 3 , nitro,halogen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or biphenyl (which may be substituted by up to two substi¬ tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_-alkoxy, phenoxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or triphenylmethyl (which may be substituted by up to three substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or benzhydrylethyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halo- gen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or benzhydrylmethyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl, Cι_ -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or naphthylmethyl (which may be substituted by up to two substituents which may independently be CF 3/ nitro,halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι- 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or acenaphthyl (which may be substituted by up to two sub¬ stituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or acenaphthylmethyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or pyridyl (which may be substituted by up to two substi¬ tuents which may independently be CF / nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or picolyl (which may be substituted by up to two substi¬ tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι- 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or benzothiazolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι- 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or benzisothiazolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl,Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or benzopyrazolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or benzoxazolyl (which may be substituted by up to two sub¬ stituents which may independently be CF 3 , nitro,halogen, CONHBzl, CON(Bzl) 2 , Cι_ -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or fluorenyl (which may be substituted by up to two substi¬ tuents which may independently be CF 3 , nitro,halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, C-^-alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or aminofluorenyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halo¬ gen, CONHBzl, CON(Bzl) 2 , Cι- 4 -alkyl, Cι- 4 -alkoxy, phenoxy, benzoxy, or Cι_ -alkyl-sulfonyl) , or e*SV«ffli! * $S***«tø ** <*- " 78 pyrimidyl (which may be substituted " "r.y up " to two substi¬ tuents which may independently be CF 3 , nitro, halogen, COOEt, CONHBzl, C0N(Bzl) 2 , Cι_ 4 -alkyl which may form a cyclic system,Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or 5-membered hetaryl [which may be substituted by up to three substituents which may independently be CF 3 , nitro, halogen, cyano, COOMe, COOEt, thiomethyl, thioethyl, thiophenyl, picolyl,acetyl, -CH 2 -COOEt, CONH 2 CONHBzl, 10 CON(Bzl) 2 , Cι_ 4 -alkyl which may form a cyclic system, Cχ- 4 -alkoxy, phenoxy, benzoxy, phenyl (which may be sub¬ stituted by up to four substituents which may indepen¬ dently be nitro, CF 3 , halogen, or Cι_ -alkyl) , benzyl (which may be substituted by up to four substituents 15 which may independently be nitro, CF 3 , halogen, Cι_ 4 -alkyl, naphthyl, Cι_ 7 -alkyl-sulfonyl, phenylsulfonyl, or Cι- 4 -dialkylamino) ] , or -CHR 7 -5-membered hetaryl (which may be substituted by up to two substituents which may independently be CF 3 , 20 nitro, halogen, CONHBzl, CON(Bzl) 2 , COOMe, COOEt, COOCH(CH 3 ) 2 , CONH 2 , COOBzl, Cι_ 4 -alkyl,Cι_ 4 -alkoxy, phen¬ oxy, benzoxy, phenyl, benzyl, naphthyl, or Cι- 7 -alkyl-sul- fonyl [R 7 = H, linear or branched Cι_ 5 -alkyl, benzyl; or R 7 and R 5 together form a group -(CH 2 ) 3 - or -(CH 2 ) -]). 25 Compounds of formula I according to claim 1 wherein Q is an amino moiety of the formula R 5 -N-R 6 , which forms a structure selected from the group consisting of 30 35 40 45 45 #9 »&WfΦ≠ ι * :a ~ - -' ^ 80 which may be unsubstituted or substituted "" with one or more substituents independently selected from the group consisting of CF 3 , nitro, halogen, oxo, cyano, N,N-dimethylamino, CONHBzl, CON(Bzl) 2 , Cι-6-alkyl (which may form a cyclic 5 system), Cι- 4 -alkoxy, phenoxy, benzoxy, naphthyl, pyrimidyl, COOEt,COOBzl, C 3 _ 6 -cycloalkyl, pyrrolidinyl, piperidinyl, thienyl, pyrrolyl, -CH 2 -CO-NCH(CH 3 ) 2 , -CH 2 -CO-N(CH 2 ) 4 , -CH 2 -CO-N(CH 2 ) 0, benzyl (which may be substituted by up to three substituents independently selected from the group con- 10 sisting of nitro, halogen, CF 3 , thiomethyl or the correspon¬ ding sulfoxide or sulfone, thioethyl or the corresponding sulfoxide or sulfone, Cι_ 4 -alkyl, and Cι_ 4 -alkoxy) , and phenyl (which may be substituted by up to three substituents in¬ dependently selected from the group consisting of nitro, 15 halogen, CF 3 , thiomethyl, thioethyl, Cι_ -alkyl, and Cι-4-alkoxy) . 5. Compounds of formula I according to claim 1 wherein b is zero. 20 6. Compounds of formula I according to claim 1 wherein d is zero, b is -NR 4 -CHG-CHK-CHL-CO-, and Q is not a hydroxy or alkoxy group. 25 7. Compounds of formula I according to claim 1 wherein b and d are zero, and Q is not a hydroxy or alkoxy group. 8. Compounds of formula I according to claim 1 wherein d is 0 and R 7 is 30 9. Compounds of formula I according to claim 1 wherein a is 0. 40 10. Compounds of formula I according to claim 1 wherein a and d are 0. 11. Compounds of formula I according to claim 1 wherein b and d are 1 and Q is a hydroxy, Cι- 5 -alkoxy or benzyloxy moiety. 45 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1. 13. A method of treating a tumor in a mammal comprising administering to a mammal bearing such a tumor, a tumor- inhibiting amount of a compound of claim 1. 14. The method of preparing compounds of formula I according to claim 1 characterized in that they are prepared according to known methods of peptide chemistry.

Inventors: BARLOZZARI TERESA, HAUPT ANDREAS, JANSSEN BERND, KEILHAUER GERHARD, KLINGE DAGMAR, QIAN XIAO-DONG, RITTER KURT, ROMERDAHL CYNTHIA, BARLOZZARI, TERESA, HAUPT, ANDREAS, JANSSEN, BERND, KEILHAUER, GERHARD, KLINGE, DAGMAR, QIAN, XIAO-DONG, RITTER, KURT, ROMERDAHL, CYNTHIA
Applicants: BASF AG, BASF AKTIENGESELLSCHAFT
Application year: 1993
Main classification: C07K5
IPC codes: A61K38, A61P35, C07K1, C07K5, C07K7