DERIVATIVES OF DOLASTATIN

Abstract: Novel derivates of dolastatin of formula (I) in which R<1>, R<2>, A, B, D, E, F, G, K, X, t, u, v, and w have the meanings stated in the description, and the preparation thereof are described. The novel substances have an antineoplastic effect.

Description: DERIVATIVES OF DOLASTATIN. Description The invention described herein provides novel peptides and deriv¬ atives thereof which offer potentially improved therapeutic uti¬ lities for the treatment of neoplastic diseases as compared to Dolastatin-10 and -15 (US Patent No 4,879,278, Nov. 7, 1989; US Patent No 4,816,444, Mar. 28, 1989). Furthermore, xinlike dolasta- tin-10 and -15 which must be laboriously purified from scarce natural sources, the compounds of this invention may be conve¬ niently synthesized as described in detail below. In addition, Dolastatin-10 is unstable to acid. It was described that even mi- nor 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 R-. N - CH - CO - A - B - (D) t - (E) u - (F) v - (G) w - K R2 / where R 1 is alkoxy, preferably Cι_ 4 ; alkyl, preferably Cι_ 7 ; cycloalkyl, preferably C3-6- alkylsulfonyl, prefer¬ ably Cι_ 6 ; fluoroalkyl, preferably fluoroethyl, di- fluoroethyl, trifluoroethyl, fluoroisopropyl, tri- fluoroisopropyl; trifluoroacetyl; amidino; ureyl; piperidinosulfonyl; morpholinosulfonyl; benzyloxycar- bonyl; alkyloxycarbonyl, preferably Cι_ ; aminosulfo- nyl which may be substituted by alkyl, preferably C 1 -5; hydroxy; arylsulfonyl which may be substituted by one or more substituents independently selected from alkyl (preferably Cι_ 4 ) , -N(CH 3 ) , nitro, halogen and CF3; benzyl which may be substituted by up to three substituents independently selected from alkyl (preferably Cι_ ) , alkoxy (preferably Cι_ 4 ) , nitro, halogen and CF3; or NR 3 R 4 where R 3 and R 4 may each be either hydrogen or alkyl, preferably Cι_ ; R 2 is hydrogen; alkyl,-preferably C; L _ 4 ; fluoroalkyl, preferably fluoroethyl, difluoroethyl, trifluoroe.- thyl, fluoroisopropyl, trifluoroisopropyl; cycloal¬ kyl, preferably C3- 7 ; acyl, preferably Cι_ 8 ; benzoyl or benzyl both of which may be substituted by up to three substituents independently selected from nitro, halogen, CF 3 , alkyl (preferably Cι_ ) and alkoxy (pre¬ ferably Cι_ 4 ) Ri-N-R 2 together may be phthalimido, a 5- or 6-membered het¬ erocycle which may be unsubstituted or substituted with one or more substituents independently selected from phenyl, benzyl, alkyl (preferably Cι_ ) , N{CH 3 )2, nitro, thienyl, CONH 2 and COOEt; A is a valyl, isoleucyl, leucyl, allo-isoleucyl, α-ami- noisob tanoyl, 3-tert-butylalanyl, 2-tert-butylgly- cyl, 3-cyclohexylalanyl, 2,4-diaminobutanoyl, ornithyl, lysyl, 2-ethylglycyl, 2-cyclohexylglycyl, lysyl or arginyl residue; B is a N-alkyl-valyl, -leucyl, -isoleucyl, -2-tert-bu- tylglycyl, -3-tert-butylalanyl, -3-cyclohexylalanyl, -phenylalanyl, -2-ethylglycyl, -norleucyl or -2-cy- clohexylglycyl residue where N-alkyl is preferably N-methyl or N-ethyl; D,E,F and G are independently selected from the group consisting of prolyl, homo-prolyl, hydroxyproly1, thiazolidi- nyl-4-carbony1, 1-aminopentyl-l-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexyla- lanyl, phenylalanyl, N-methylphenylalanyl, tetrahy- droisoguinolyl-2-carbonyl, 3-thiazolylalanyl, 3-thie- nylalanyl, histidyl, 1-aminoindyl-l-carbonyl, 2,4-diaminobutanoyl, arginyl, 3-pyridylalanyl, 3-tert-butylalanyl, 2-cyclohexylglycyl, lysyl, nor- leucyl and 3-naphthylalanyl residues X is hydrogen, alkyl (preferably linear or branched C-._ 5 ) . cycloalkyl (preferably cyclohexyl) , -CH 2 -cyclo- hexyl or arylalkyl (preferably benzyl or phenethyl) ; A and B together, F and G together, RiRN-CHX-CO and A together, E and F together, either alone or in pairs, may be where Y is hydrogen or lower alkyl (preferably methyl or ethyl); Z is hydrogen or lower alkyl (preferably Ci-s) ; n is 1, 2, or 3; V is oxygen or sulfur; M is hydrogen, lower alkyl (preferably Cι_ ), arylalkyl (preferably benzyl or phenethyl) , cyclohexyl, or - CH 2 -cyclohexyl; Q is hydrogen; R is hydrogen or lower alkyl (preferably C 1 - 3 ) ; or R and Q may together form a bond; U is hydrogen, lower alkyl (preferably C 1 -. 4 ) , phenyl, or cycloalkyl (preferably cyclohexyl); and is hydrogen, lower alkyl (preferably Cι_ 4 ) or phenyl; t,u,v, and w are independently 0 or 1; and K is hydroxy, alkoxy (preferably Cι_ 4 ) , phenoxy, benzy- loxy or a substituted or unsubstituted amino moiety; provided that where t, u, v and w are 0, K is not a hydroxy, alkoxy, benzoxy or phenoxy moiety; and further provided that where t, u and v are 0, K 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 co - pounds together with a pharmaceutically acceptable carrier and methods for using same for treating cancer in mammals. One subclass of compounds of thi.s invention includes compounds of formula I wherein R χ -N-R 2 is phthalimido or a 5- or 6-membered heterocycle of the formula which may be unsubstituted or substituted with one or more sub¬ stituents which may independently be selected from phenyl, ben¬ zyl, alkyl (preferably Cι_ 4 ) , N(CH 3 ) 2 , nitro, thienyl, oxo, CONH 2 and COOEt; Another subclass of compounds of this invention includes com¬ pounds of formula I wherein is an amino moiety of the formula R S -N-R 6 wherein R 5 is hydrogen, or hydroxy, or Cχ_ 7 -alkoxy, or benzyloxy. or Cι_-alkyl which may be substituted by one or more fluoro atoms, or C3_ 7 -cycloalkyl, or benzyl which may be substituted by up to three substituents which may independently be CF 3 , nitro, Cι--alkylsulfonyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, halo- gen or Cι- 4 -alkyl R 6 is hydrogen, or Cχ_ 7 -alkyl which may be substituted by one or more fluoro atoms, or C 3 _ 7 -c cloalkyl, or phenyl (which may be substituted by up to three substituents which may indepen- dently 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 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 naphthyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 / Ci_ 4 -alkyl, Cι_4~alkoxy, benzoxy, phenoxy, or Cι-.- 7 -alkyl-sul onyl) , or benzhydryl (which may be substituted by up to two substitu¬ ents which may independently be CF 3 , nitro, halogen, CONHBzl, C0N(Bzl)2, Cι_ 4 -alkyl, Cι- 4 -alkoxy, phenoxy, benzoxy, -or Cι_ 7 -alkyl-sulfonyl) , or biphenyl (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, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or triphenylmethyl (which may be substituted y up to three 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 benzhydrylethyl (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 benzhydrylmethyl (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 -alkox , phenoxy, benzoxy or Cι_ -alkyl-sulfonyl) , or naphthylmethyl (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 acenaphthyl (which may ' be substituted by up to two substitu¬ ents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cχ.- 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or acenaphthylmethyl (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_ -alkyl-sulfonyl) , or pyridyl (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 1 -- 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or picolyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_4-alkyl, Ci- 4 -alkoxy, pheno-xy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or benzothiazolyl (which may be substituted by up to two substi- tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Ci_ 4 -alkyl, C^-alkoxy, phenoxy, benzoxy, or Cι-7-alkyl-sulfonyl) , or benzisothiazolyl (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, C 1 _ 4 -alkoxy, phenoxy, benzoxy, or Cι-7-alkyl-sulfonyl) , or benzopyrazolyl (which may be substituted by up to two substi- tuents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cχ- 4 -alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or benzoxazolyl (which may be substituted by up to two substitu- ents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cι_ 4 -alkoxy, pheno^, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or fluorenyl (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, phenoxy, benzoxy, or Cι_-alkyl-sulfonyl) , or aminofluorenyl (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 pyrimidyl (which may be substituted by up to two substituents which may independently be CF 3 , nitro, halogen, COOEt, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl which may form a cyclic system, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_-alkyl-sulfonyl) , or 5-membered heteroaryl [which may be substituted by up to three substituents which may independently be CF 3 , nitro, halogen, cyano, COOMe, COOEt, thiomethyl, thioethyl, thiophe- nyl, picolyl,acetyl, -CH 2 -COOEt, CONH 2 CONHBzl, CON(Bzl) 2 . Cι_ 4 -alkyl, C 3 _ 6 -Qycloalkyl, C 3 _ 4 -alkylen group forming a bi- cyclic system with the heterocycle, Cι_ 4 -alkoxy, phenoxy, ben¬ zoxy, phenyl (which may be substituted by up to four substi¬ tuents which may independently be nitro, CF 3 , halogen, or Cι_ 4 -alkyl) , benzyl (which may be substituted by up to four substituents which may independently be nitro, CF 3 , halogen, C 1 - 4 -alkyl, naphthyl, Cι_ 7 -alkyl-sulfonyl, phenylsulfonyl, or Cι_ 4 -dialkylamino) 3 , or -CHR 7 -5-membered heteroaryl (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 , CONH 2 , COOBzl, C^-alkyl, Cι_ 4 -alkoxy, phenoxy, benzoxy, phenyl, ben¬ zyl, naphthyl, or Cι_ 7 -alkyl-sulfonyl [R 7 = hydrogen, linear or branched Cι_ 5 -alkyl, benzyl; or R 7 and R 5 together form a group -(CH 2 ) 3 - or -(CH 2 )4-])- This subclass includes compounds of formula I wherein t, u, v and w are independently 0 or 1; R 1 , R 2 and X are lower alkyl, A and F are lower alkyl amino acids, B is a N-loweralkylated lower alkyl amino acid; D, E, G and K are as previously defined. With the foregoing in mind, one set of such compounds can thus be depicted by the following formula II: R ! R 2 —CXH—CO—A—B Pro-Pro (F)~ (G) w —K II • and another by the following formula III R1R2N—CXH—CO—A—B Pro (F) v (G) w —K. Ill In another subclass of compounds of this invention R 5 -N-R 6 to¬ gether may form structures selected from the group consisting of 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 , Ci-e-alkyl, C;._ 6 -cycloalkyl, C 3 _ 4 -alkylen group forming a bicyclic system with the heterocycle, Cι-4-alkoxy, phenoxy, benzoxy, naphthyl, pyrimidyl, COOEf, COOBzl, C3-6 _ cycloalkyl, pyrolidinyl, piperidinyl, thienyl, pyrolyl, -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 se- lected from the group consisting of nitro, halogen, CF 3 , thiome- thyl 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, halo- gen, CF 3 , thiomethyl, thioethyl, Cι_ 4 -alkyl, and Cι- 4 -alkoxy) , Another subclass of compounds of this invention includes for ex¬ ample compounds of formula I wherein t, u, v, and w are zero and K is not an hydroxy, benzoxy, phenoxy or alkoxy moiety. Another subclass of compounds of this invention includes for ex¬ ample compounds of formula I wherein t, u, and v are zero and K is not an hydroxy or alkoxy moiety. Still another subclass of compounds of this invention includes for example compounds of formula I wherein t, u, v and w are 1 and is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. Yet another subclass of compounds of this invention includes for example compounds of formula I wherein t, u and v are 1, w is 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. Another subclass of compounds of this invention includes for ex¬ ample compounds of formula I wherein t and u are 1, v and w are 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. Preferred are compounds of formula I where the substituents have the following meanings: R 1 is ethyl, methyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroisopropyl, trifluoroisopropyl, isopropyl, propyl, butyl, pentyl, cyclopropyl, cyclopentyl, ureyl, mesyl, tosyl, naphtylsulfonyl, phenylsulfonyl, 2,4,6-trimethylsulfony1, benzyloxycarbonyl, tert.butyloxy- carbonyl, methyloxycarbonyl, morpholinosulfonyl, tert.butyla- minosulfonyl, methylaminosulfonyl, lactyl, trifluoroacetyl, NH 2 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2f N[CH(CH 3 ) 2 ] 2 , amidino, CH3O-, or one of the residues is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroisopropyl, trifluoroisopropyl, isopropyl, propyl, butyl, cyclopropyl, for yl, acetyl, pro- pionyl, (CH 3 ) 2 CHC0-, pivaloyl, benzoyl or one of the residues R 2 together is one of the following residues: A, B, D, E, F, G and X have the meanings as described above; t, u, v and w are independently 0 or 1; A and B together are F and G together are E and F together are R^N-CHX-CO and A together are 5 is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoroisopropyl, propyl, soproypyl, or R 6 is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoroethyl, trifluoroisopropyl, propyl, isopropyl, tert-bu- tyl, or COOBzl ONHBzl ONH 2 N -*N V _ N C(CH3h " O "" ε -γN OCH3 R 5 -N-CHR 7 - 5 -member ed heteroaryl -are R 5 -N-R 6 together are C(CH 3 ) 3 is a hydroxy, alkoxy (preferably Cι_ ) , phenoxy or benzoxy mo¬ iety. More preferred are compounds where the substituents have the fol¬ lowing meanings: R 1 is ethyl, methyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroisopropyl, trifluoroisopro¬ pyl, isopropyl, propyl, cyclopropyl, benzyloxycarbonyl, methyloxycarbonyl, lactyl, methylaminosulfonyl,tosyl, ureyl, mesyl, N(CH 3 ) , amidino. methoxy, benzyl, 4-pheno- xybenzyl, 4-benzyloxybenzyl, or 3, , 5-trimethoxybenzyl R 2 is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroe¬ thyl, 2,2,2-trifluoroethyl, isopropyl, propyl, butyl, cy¬ clopropyl, formyl, acetyl, propionyl, pivaloyl, benzoyl or benzyl, Ri-N-R 2 together are A, B, D, E, F, G and X have the meanings as described above; t, u, v and w are independently 0 or 1; A and B together are F and G together are E and F together are R1R2N-CHX-CO and A together are K is a hydroxy, Cι_ 4 -alkoxy or benzyloxy moiety; R= is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoro¬ ethyl, propyl, isoproypyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 4-phenoxybenzyl, 4-benzyloxybenzyl or 3,4,5-trimethoxybenzyl R ? is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-trifluoro¬ ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclo¬ pentyl, cyclohexyl, benzyl, 4-phenoxybenzyl, 4-benzyloxy- benzyl, 3,4,5-trimethoxybenzyl, phenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 3,4,5-trimethoxyphenyl or COOEt R S -N-CHR 7 -5-membered heteroaryl is COOEt R 5 -N-R 6 together are COOEt 30 35 40 45 These examples illustrate but do not limit the scope of the pres¬ ent invention. The peptides of the formula I are composed preferably of L-amino acids but they may contain one or more D-amino acids. The new compounds may be present as salts with physiologically tolerated acids such as: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, suc- cinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-as- partic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine. The novel compounds can be prepared by known methods of peptide chemistry. Thus, the peptides can be assembled sequentially from amino acids or by linking suitable small peptide fragments. In the sequential assemblage, starting at the C terminus the peptide chain is extended stepwise by one amino-acid each time. In frag¬ ment coupling it is possible to link together fragments of dif¬ ferent lengths, and the fragments in turn can be obtained by se¬ quential assemblage from amino acids or themselves by fragment coupling. Both in the sequential assemblage and in the fragment coupling it is necessary to link the units fcy forming an amide linkage. Enzymatic and chemical methods are suitable for this. Chemical methods for forming the amide linkage are described in detail by Mύller, 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 (activa¬ tors, especially dicyclohexylcarbodiimide (DCC) , diisopropylcar- bodiimide ( DIC) , l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline ( EEDQ) , l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlo- ride (EDCI) , n-propanephosphonic anhydride (PPA) , N,N- bis (2-oxo-3-oxazolidinyl)- midophosphoryl chloride (BOP-C1) , bromo-tris-pyrrolidinophosphonium hexa-fluorophosphate (PyBrop) , diphenylphosphoryl azide (DPPA) , Castro's reagent (BOP, PyBop) , 0-benzotriazolyl-N,N,N' ,N'-tetramethyluronium salts (HBTU) , die- thylphosphoryl cyanide (DEPCN) , 2,5-diphenyl-2,3-dihy- dro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and l,l'-carbonyldiimidazole (CDI) . The coupling reagents can be employed alone or in combination with additives such as N,N-dime- thyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (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 synthesis: the benzyloxycarbonyl (Z) , the t-butoxycarbo- nyl (Boc) and the 9-fluorenylmethoxycarbonyl (F oc) 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 Mύller, Methoden der organis- chen 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. A er. 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 en¬ tails 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 pro¬ cedure makes it possible to remove reagents and byproducts by filtration, and thus recrystallization of intermediates is un- necessary. The protected amino acids can be linked to any suitable polymers, which merely have to be insoluble in the solvents used and to have a stable physical form which makes filtration easy. The polymer must contain a functional group to which the first pro¬ tected amino acid can be firmly attached by a covalent bond. Suitable for this purpose are a wide variety of polymers, eg. cellulose, polyvinyl alcohol, polymethacrylate, sulfonated poly¬ styrene, chloromethylated styrene/divinylbenzene copolymer (Merrifield resin) , 4-methylbenzhydrylamine resin (MBHA-reεin) , phenylacetamidomethyl-resin (Pam-resin) , p-benzyloxy-benzyl-alco- hol-resin, benzhydryl-amine-resin (BHA-resin) , 4-(hydroxyme- thyl)benzoyloxy-methyl-resin, the resin of Breipohl et "al. (Tet¬ rahedron Letters 28 (1987) 565; supplied by BACHEM) , 4-(2,4-di- methoxyphenylaminomethyl)phenoxy-resin (supplied by Novabiochem) or o-chlorotrityl-resin (supplied by Biohellas) . Suitable for peptide synthesis in solution are all solvents 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. Peptide synthesis on the polymeric support can be carried out in all inert 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 peptide is cleaved off the polymeric support. The 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 trifluoromethanesulfonic acid, in dilute or concentrated trifluo- roacetic acid, palladium-catalyzed cleavage in THF or THF-DCM mixtures in the presence of a weak base such as morpholine or cleavage in acetic acid/dichloromethane/trifluoroethanol mix- tures. Depending on the chosen protective groups, these may be retained or likewise cleaved off under the cleavage conditions. Partial deprotection of the peptide may also be worthwhile when certain derivatization reactions are to be carried out. Peptides dialkylated at the N-terminus can be prepared either by coupling on the appropriate N,N-di-alkylamino acids in solution or on the polymeric support or by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH 3 and the appropriate aldehydes. The various non-naturally occurring amino acids as well as the various non-amino acid moieties disclosed herein may be obtained from commercial sources or synthesized from commer¬ cially-available materials using methods known in the art. For example, amino acids building blocks with R 1 and R 2 moieties can be prepared according to E. Wunsch, Houben Weyl, Meth. d. Org. Chemie, Bd. XV, 1, p. 306 following, Thieme Verlag Stuttgart 1974 and Literature cited therein. Peptides 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. Peptides with thiazole-, oxa- zol-, thiazolin- or oxazolin-containing dipeptide building blocks can be prepared by incorporating the appropriate dipeptidic units (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) into the peptide chain. 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 pharmaceu ical 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 ef- fec ive tumor-inhibiting amount of active ingredient which will depend upon conventional factors including the biological activ¬ ity of the particular compound employed; the means of administra¬ tion; the age, health and body weight of the recipient; the na¬ ture and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typ¬ ical daily dose will be about 5 to 250 milligrams per kilogram of body weight on oral administration and about 1 to 100 milligrams per kilogram of body weight on parenteral administration. The novel compounds can be administered in conventional solid or liquid pharmaceutical administration forms, eg. uncoated or (film-)coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conven- tional pharmaceutical aids such as tablet binders, fillers, pre¬ servatives, tablet disintegran s, flow regulators, plasticizers, wetting agents, dispersantε, emulsifiers, solvents, sustained re¬ lease compositions, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain 1-90% by weight of the active substance. 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 = methyl, Bzl = benzyl. A. General procedures 5 1. The peptides claimed in claim 1 are either synthesized by classical solution synthesis using standard Z- and Boc-methodol- ogy as described above or by standard methods of solid-phase syn¬ thesis on a completely automatic model 431A synthesizer supplied 0 by APPLIED BIOSYSTEMS. The apparatus uses different synthetic cycles for the Boc and Fmoc protective group techniques. a) Synthetic cycle for the Boc protective group technique 5 1. 30% trifluoroacetic acid " in DCM 2. 50% trifluoroacetic acid in DCM 3. DCM washing 4. 5% diisopropylethylamine in DCM 5. 5% diisopropylethylamine in NMP 0 6. NMP washing 7. Addition of preactivated protected amino acid (activation with 1 equivalent of DCC and 1 equivalent of HOBt in 5 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 30 9. Peptide coupling (2nd part) 1 x 16 min 10. Addition of 3.8 equivalents of diisopropylethylamine to the reaction mixture 11. Peptide coupling (3rd part) 1 x 7 min 35 12. DCM washing 3 x 1 min 13. if conversion is incomplete, repetition of coupling (back to 5.) 14. 10% acetic anhydride, 5% diisopropylethylamine in DCM 1 x 2 min 40 15. 10% acetic anhydride in DCM 1 4 min 16. DCM washing 4 x 1 min 17. back to 1. BOP-C1 and PyBrop were used as reagents for coupling of the 45 amino acid following N-methylamino acids. The reaction times were correspondingly increased. In solution synthesis, the use of ei¬ ther Boc-protected amino acid NCAs (N-tert.-butyloxycarbonyl- amino acid-N-carboxy-anhydrides) or Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) respec- . tively 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 6. DMF washing 7. if conversion is incomplete, repetition of coupling (back to 10% acetic anhydride in DMF 9. DMF washing 10. back to 2. BOP-Cl and PyBrop were used as reagents for coupling on the amino acid following the N-methylamino acids. The reaction times were correspondingly increased. 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 trans¬ ferred 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 ethane- dithiol (0.5 ml/g of resin), was followed by condensing in hydro¬ gen fluoride (10 ml/g of resin) while cooling with liquid N 2 . The mixture was left to warm to 0°C and stirred at this temperature for 45 min. The hydrogen fluoride was then stripped off under re¬ duced pressure, and the residue was washed with ethyl acetate in order to remove remaining scavenger. The peptide 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 coπ osition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985) . The suspension of the peptide-resin in the suitable TFA mixture was stirred at room temperature for the stated time and then the resin was filtered off and washed with TFA and DCM. The filtrate and the washings were concentrated, and the peptide was 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/trifluoroe- thanol/dichloromethane mixture (1:1:3) is stirred at room tem¬ perature for 1 h. The resin is then filtered off with suction and thoroughly washed with the cleavage solution. The combined filtrates are concentrated in acuo and treated with water. The precipitated solid is removed by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure. Q VI. Purification and characterization of the peptides 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 5 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; mo¬ bile phase: CH 3 CN/H 2 0 gradient, buffered with 0.1% TFA, 40°C) . Characterization was by amino-acid analysis and fast atom bom¬ bardment mass spectroscopy. B. Specific procedures EXAMPLE 1 (SEQ ID NO: 1) N,N-Dimethyl-Val-Val-N-methyl-Val-Pro-Pro-Val-Phe-NH 2 1.98 g of Fmoc-RINK-resin (substitution 0.46 mmol/g) , correspond¬ ing to a batch size of 0.84 mmol, were reacted as in Alb with 1.26 mmol each of Fmoc-Phe-OH Fmoc-N-methyl-Val-OH Fmoc-Val-OH Fmoc-Val-OH Fmoc-Pro-OH Fmoc-Val-OH Fmoc-Pro-OH The amino acid following the N-methylamino acid was coupled on with PyBrop as coupling reagent. After the iterative synthetic cycles were completed, the peptide-resin underwent N-terminal deprotection (steps 2-4 in Alb) , and was further reacted with aqueous formaldehyde solution as in All and then dried under re¬ duced pressure. The resulting resin was subjected to TFA cleavage as in AIV. The crude product (590 mg) was purified by gel filtration (SEPHADEX-LH-20) . The yield was 295 mg. EXAMPLE 2 (SEQ ID NO: 2 N, -Dimethy1-Val-Val-N-Me-Val-Pro —HN 4.11 g of Fmoc-Pro-p-alkoxybenzyl-alcohol-resin (substitution 0.73 mmol/g), corresponding to a batch size of 3 mmol, were reacted as in Alb with 4.5 mmol each of Fmoc-N-MeVal-OH Fmoc-Val-OH Fmoc-Val-OH. The amino acid following the N-methylamino acid was in this case reacted with double coupling using PyBrop or Bop-Cl with in¬ creased reaction times. After the synthesis was complete, the peptide-resin underwent N-terminal deprotection (steps 2-4 in 5 Alb) , and was further reacted with aqueous formaldehyde solution as in All and then dried under reduced pressure. The resin ob¬ tained in this way was subjected to TFA cleavage as in AIV. The crude product (750 mg) was employed directly for the next cou¬ pling. 100 mg of this compound were reacted with 45 mg of 0 (S)-2-[l-amino-2-phenylethyl]thiazole and 230 mg of PyBop with the addition of 192 μl of DIPEA in DMF at room temperature for 2 d. The reaction mixture was purified by gel chromatography (Se- phadex LH-20, methanol) and the product fractions were combined. 83 mg of product were obtained. 5 The following compounds were prepared and can be prepared accord¬ ing to examples 1 and 2: 3. Xaa Val Xan Pro Pro Val Phe 0 4. xaa Val Xan Pro Pro Val Xac 5. xaa Val Xan Pro Pro Val Xad 6. Xaa Val Xan Pro Pro Val Xae 7. Xaa Val Xan Pro Pro Val Xaf 8. Xaa Val Xan Pro Pro Val His-NH 2 25 9. Xbo Val Xan Pro Pro Val Phe-NH 2 10. Xaa Val Xan Pro Pro Val Xag-NH 2 11. Xaa Val Xan Pro Pro Val Xah 12. Xaa Xbe Xan Pro Pro Val Trp-NH 2 13. Xaa Val Xan Pro Pro Xai Phe-NH 2 30 14. Xae Val Xan Pro Pro lie Phe-NH 2 15. Xaa Val Xan Pro Xal Val Phe-NH 2 16. Xaa Val Xan Pro Xak Val Phe-NH 2 17. xaa Val Xan Xak Pro Val Phe-NH 2 18. Xaa Val Xan Xal Pro Val Phe-NH 2 35 19. Xaa Val Xao Pro Pro Val Phe-NH 2 20. Xaa Val Xam Pro Pro Val Phe-NH 2 21. xaa Xap Pro Pro Val Phe-NH 2 22. Xaa Xaq Pro Pro Val Phe-NH 2 23. Xaa He Xan Pro Pro Val Phe-NH 2 40 24. Xaa Xai Xan Pro Pro Val Phe-NH 2 25. Xaa Leu Xan Pro Pro Val Phe-NH 2 26. Xar Val Xan Pro Pro Val Phe-NH 2 27. xas Val Xan Pro Pro Val Phe-NH 2 28. Xat Val Xan Pro Pro Val Phe-NH 2 45 29. Xau Val Xan Pro Xal Val Phe-NH 2 30. Xav Val Xan Pro Pro Val Phe-NH 2 31. Xan Val Xan Pro Pro Val Phe-NH 2 32. Xaw Val Xan Pro Pro Val Phe-NH 2 33. Xax Val Xan Pro Pro Val Phe-NH 2 34. Xaa Val Xan Pro Pro Phe Phe-NH 2 35. Xaz Val Xan Pro Pro Val Phe-NH 2 5 36. Xba Val Xan Pro Pro Val Phe-NH 2 37. Xaa Val Xan Pro Pro Val-NH 2 38. Xaa Val Xan Pro Xbb 39. Xaa Val Xan Pro Xbc 40. Xaa Val Xan Pro Pro Xbd 10 41. Xax Val Xan Pro Pro Val-NH 2 42. Xaw Val Xan Pro Pro Val-NH 2 43. Xat Val Xan Pro Pro Val-NH 2 44. Xaa Xai Xan Pro Pro Val-NH 2 45. Xaa Val Xan Pro Pro Xai-NH 2 15 46. Xaa Val Xan Xak Pro Val-NH 2 47. Xaa val Xan Pro Xak Val-NH 2 48. Xaa Val Xan Pro Pro Val 49. Xav Val Xan Pro Pro Val-NH 2 50. Xaa Val Xan Pro Pro-NH 2 20 51. Xaa Val Xan Pro Pro 52. Xaa Val Xan Pro Xbf 53. Xaa Val Xan Xbb 54. xaa Val Xan Xbc 55. Xaa Val Xan Xbg 25 56. Xaa Val Xan Xbh 57. xaa Val Xan Xbi 58. Xaa Val Xan Xbk 59. Xaa Val Xan Xbl 60. Xaa Val Xan Xbm 30 61. Xaa Val Xan Xbn 62. Xax Val Xan Pro Pro-NH 2 63. Xaw Val Xan Pro Pro-NH 2 64. Xbo Val Xan Pro Pro-NH 2 65. Xat Val Xan Pro Pro-NH 2 35 66. Xaa Xai Xan Pro Pro-NH 2 67. xat Xai Xan Pro Pro-NH 2 68. Xaa Xap Pro Pro-NH 2 69. Xaa Xaq Pro Pro-NH 2 70. Xav Val Xan Pro Pro-NH 2 40 71. Xaa Xap Pro-NH 2 72. Xaa Xaq Pro-NH 2 73. Xaa Val Xan Pro 74. Xaa Val Xbp 75. xaa Val Xbq 45 76. Xaa Val Xbr 77. Xaa Val Xbs 78. Xaa Val Xan Xbf 79. Xaa Val Xbt 80. Xaa Val Xbu 81. Xaa Val Xbv 82. Xaa Val Xbw 5 83. Xax Val Xan Pro-NH 2 84. Xbo Val Xan Pro-NH 2 85. Xav Val Xan Pro-NH 2 86. Xaa Val Xan Pro Xbn 87. Xaa Val Xan Pro Xbg 10 88. Xaa Val Xan Pro Xbi 89. Xaa Val Xan Pro Xbl 90. Xbo Val Xan Pro Xbg 91. Xbo Val Xan Pro Xbl 92. Xbo Xbe Xan Pro Xbg 15 93. Xaa Val Xan Pro Xbx 94. Xaa Xbe Xan Pro Pro-NH 2 95. Xby Val Xan Pro Pro Val Phe NH 2 96. Xed Val Xan Pro Pro Val Phe NH 2 97. Xee Val Xan Pro Pro Val Phe NH 2 20 98. Xef Val Xan Pro Pro Val Phe NH 2 99. Xbz Val Xan Pro Pro Val Phe NH 2 100. Xeg Val Xan Pro Pro Val Phe NH 2 101. Xca Val Xan Pro Pro Val Phe NH 2 102. Xcb Val Xan Pro Pro Val Phe NH 2 25 103. Xcb Val Xao Pro Pro Val Phe NH 2 104. Xcc Val Xan Pro Pro Val Phe NH 2 105. Xce Val Xan Pro Pro Val Phe NH 2 107. xcg Val Xan Pro Pro Val Phe NH 2 108. Xch Val Xan Pro Pro Val Phe NH 2 30 109. Xci Val Xan Pro Pro Val Phe NH 2 110. Xck Val Xan Pro Pro Val Phe NH 2 111. Xci Val Xan Pro Pro Val Phe NH 2 112. Xc Val Xan Pro Pro Val Phe NH 2 113. Xcn Val Xan Pro Pro Val Phe NH 2 35 114. Xhn Val Xan Pro Pro Val Phe NH 2 115. Xho Val Xan Pro Pro Val Phe NH 2 116. Xhp Val Xan Pro Pro Val Phe NH 2 117. xhq Val Xan Pro Pro Val Phe NH 2 118. Xby Val Xan Pro Pro Val NH 2 40 119. Xed Val Xan Pro Pro Val NH 2 120. Xee Val Xan Pro Pro Val NH 2 121. Xef Val Xan Pro Pro Val NH 2 122. Xbz Val Xan Pro Pro Val NH 2 123. Xeg Val Xan Pro Pro Val NH 2 45 124. Xca Val Xan Pro Pro Val NH 2 125. Xcb Val Xan Pro Pro Val NH 2 126. Xcc Val Xan Pro Pro Val NH 2 127. Xce Val Xan Pro Pro Val NH 2 , 128. Xcg Val Xan Pro Pro Val NH 2 129. Xch Val Xan Pro Pro Val NH 2 130. Xci Val Xan Pro Pro Val NH 2 5 131. Xck Val Xan Pro Pro Val NH 2 132. Xci Val Xan Pro Pro Val NH 2 133. Xcm Val Xan Pro Pro Val NH 2 134. Xcn Val Xan Pro Pro Val NH 2 135. Xhn Val Xan Pro Pro Val NH 2 10 136. Xho Val Xan Pro Pro Val NH 2 137. Xhp Val Xan Pro Pro Val NH 2 138. Xhq Val Xan Pro Pro Val NH 2 139. Xby Val Xan Pro Pro NH 2 140. Xed Val Xan Pro Pro NH 2 15 141. Xee Val Xan Pro Pro NH 2 142. Xef Val Xan Pro Pro NH 2 143. Xbz Val Xan Pro Pro NH 2 144. Xeg Val Xan Pro Pro NH 2 145. Xca Val Xan Pro Pro NH 2 20 146. Xcb Val Xan Pro Pro NH 2 147. Xcc Val Xan Pro Pro NH 2 148. Xce Val Xan Pro Pro NH 2 149. Xcg Val Xan Pro Pro NH 2 150. Xch Val Xan Pro Pro NH 2 25 151. Xci Val Xan Pro Pro NH 2 152. Xck Val Xan Pro Pro NH 2 153. Xci Val Xan Pro Pro NH 2 154. Xcm Val Xan Pro Pro NH 2 155. Xcn Val Xan Pro Pro NH 2 30 156. Xhn Val Xan Pro Pro NH 2 157. Xho Val Xan Pro Pro NH 2 158. Xhp Val Xan Pro Pro NH 2 159. Xhq Val Xan Pro Pro NH 2 160. Xaa Val Xan Pro Pro Val Xei 35 161. Xaa Val Xan Pro Pro Val Xem 162. Xaa Val Xan Pro Pro Val Xeo 163. Xaa Val Xan Pro Pro Val Xep 164. Xaa Val Xan Pro Pro Val Xeq 165. Xaa Val Xan Pro Pro Val Xex 40 166. Xaa Val Xan Pro Pro Val Xey 167. Xaa Val Xan Pro Pro Val Xfb 168. Xaa Val Xan Pro Pro Val Xfe 169. Xaa Val Xan Pro Pro Val Xfh 170. Xaa Val Xan Pro Pro Val Xfu 45 171. Xaa Val Xan Pro Pro Val Xfv 172. Xaa Val Xan Pro Pro Val Xft 173. Xaa Val Xan Pro Pro Val Xfw 174. Xaa Val Xan Pro Pro Val Xfx 175. Xaa Val Xan Pro Pro Val Xga 176. Xaa Val Xan Pro Pro Val Xgd 177.xaa Val Xan Pro Pro Val Xgg 5 178. Xaa Val Xan Pro Pro Val xgh 179. Xaa Val Xan Pro Pro Val Xgi 180. Xaa Val Xan Pro Pro Val Xgl 181. Xaa Val Xan Pro Pro Val Xgs 182. Xaa Val Xan Pro Pro Val Xgv 10 183. Xaa Val Xan Pro Pro Val Xhe 184.Xaa Val Xan Pro Pro Val Xgy 185. Xaa Val Xan Pro Pro Val Xhd 186. Xaa Val Xan Pro Pro Val Xhb 187.xaa Val Xan Pro Pro Val Xhe 15 188.Xaa Val Xan Pro Pro Val Xhl 189. Xaa Val Xan Pro Pro Xeh 190. Xaa Val Xan Pro Pro Xen 191. Xaa Val Xan Pro Pro Xeo 192.Xaa Val Xan Pro Pro Xep 20 193.Xaa Val Xan Pro Pro Xeq 194.Xaa Val Xan Pro Pro Xer 195. Xaa Val Xan Pro Pro Xet 196. Xaa Val Xan Pro Pro Xeu 197. Xaa Val Xan Pro Pro Xes 25 18. Xaa Val Xan Pro Pro Xew 199. Xaa Val Xan Pro Pro Xez 200. Xaa Val Xan Pro Pro Xfc 201. Xaa Val Xan Pro Pro Xff 202. Xaa Val Xan Pro Pro Xfi 30 203. Xaa Val Xan Pro Pro Xfs 204.Xaa Val Xan Pro Pro Xfz 205. aa Val Xan Pro Pro Xgc 206. Xaa Val Xan Pro Pro Xgf 207. Xaa Val Xan Pro Pro Xgm 35208. Xaa Val Xan Pro Pro Xgr 209. Xaa Val Xan Pro Pro Xgu 210. Xaa Val Xan Pro Pro Xgs 211. Xaa Val Xan Pro Pro Xgx 212. Xaa Val Xan Pro Pro Xha 40 213. Xaa Val Xan Pro Pro Xhk 214. Xaa Val Xan Pro Xek 215. Xaa Val Xan Pro Xen 216.Xaa Val Xan Pro Xer 217.Xaa Val Xan Pro Xep 45 218. Xaa Val Xan Pro Xeq 219. Xaa Val Xan Pro Xer 220.Xaa Val Xan Pro Xet 221. Xaa Val Xan Pro Xeu 222. Xaa Val Xan Pro Xes 223. Xaa Val Xan Pro Xfa 224. Xaa Val Xan Pro Xfd 5 225. Xaa Val Xan Pro Xfg 226. Xaa Val Xan Pro Xfl 227. xaa Val Xan Pro Xfk 228. Xaa Val Xan Pro Xfm 229. xaa Val Xan Pro Xfn 10 230. Xaa Val Xan Pro Xfo 231. Xaa Val Xan Pro Xfp 232. Xaa Val Xan Pro Xfq 233. xaa Val Xan Pro Xfr 234. Xaa Val Xan Pro Xfy 15 235. Xaa Val Xan Pro Xgb 236. Xaa Val Xan Pro Xge 237. Xaa Val Xan Pro Xgk 238. Xaa Val Xan Pro Xgn 239. xaa Val Xan Pro Xhi 20 240. Xaa Val Xan Pro Xgo 241. Xaa Val Xan Pro Xgp 242. Xaa Val Xan Pro Xgq 243. Xaa Val Xan Pro Xgt 244. Xaa Val Xan Pro Xgw 25 245. Xaa Val Xan Pro Xgz 246. Xaa Val Xan Pro Xhm 247. xaa Xeo Pro Pro Val Phe NH 2 248. Xaa Xep Pro Pro Val Phe NH 2 249. Xaa Xeq Pro Pro Val Phe NH 2 30 250. Xaa Xer Pro Pro Val Phe NH 2 251. Xaa Xes Pro Pro Val Phe NH 2 252. Xaa Xet Pro Pro Val Phe NH 2 253. Xaa Xeu Pro Pro Val Phe NH 2 254. Xaa Xcw Pro Pro Val Phe NH 2 35 255. xaa Xcv Pro Pro Val Phe NH 2 256. Xaa Xcx Pro Pro Val Phe NH 2 257. Xaa Xey Pro Pro Val Phe NH 2 258. xaa Xda Pro Pro Val Phe NH 2 259. Xaa Xdb Pro Pro Val Phe NH 2 40 260. Xaa Xdc Pro Pro Val Phe NH 2 261. xaa Xdd Pro Pro Val Phe NH 2 262. Xaa Xdf Pro Pro Val Phe NH 2 263. Xaa Xdg Pro Pro Val Phe NH 2 264. Xaa Xdh Pro Pro Val Phe NH 2 45 265. Xaa Xeo Pro Pro Val NH 2 266. Xaa Xep Pro Pro Val NH 2 267. Xaa Xeq Pro Pro Val NH 2 Xaa Xer Pro Pro Val NH 2 Xaa Xcε Pro Pro Val NH 2 Xaa Xet Pro Pro Val NH 2 Xaa Xeu Pro Pro Val NH 2 Xaa Xcw Pro Pro Val NH 2 Xaa Xcv Pro Pro Val NH 2 Xaa Xcx Pro Pro Val NH 2 Xaa Xey Pro Pro Val NH 2 Xaa Xez Pro Pro Val NH 2 Xaa Xda Pro Pro Val NH 2 Xaa Xdb Pro Pro Val NH 2 Xaa Xdc Pro Pro Val NH 2 Xaa Xde Pro Pro Val NH 2 Xaa Xdf Pro Pro Val NH 2 Xaa Xdg Pro Pro Val NH 2 Xaa Xdh Pro Pro Val NH Xaa Xeo Pro Pro NH 2 Xaa Xep Pro Pro NH 2 Xaa Xeq Pro Pro NH 2 Xaa Xer Pro Pro NH 2 Xaa Xes Pro Pro NH 2 Xaa Xet Pro Pro NH 2 Xaa Xeu Pro Pro NH 2 Xaa Xcw Pro Pro NH 2 Xaa Xcv Pro Pro NH 2 Xaa Xcx Pro Pro NH 2 Xaa Xey Pro Pro NH 2 Xaa Xez Pro Pro NH 2 Xaa Xda Pro Pro NH 2 Xaa Xdb Pro Pro NH 2 Xaa Xdc Pro Pro NH 2 Xaa Xdd Pro Pro NH 2 Xaa Xdf Pro Pro NH 2 Xaa Xdg Pro Pro NH 2 aa Xdh Pro Pro NH 2 Xds Xan Pro Pro Val Phe NH 2 Xdt Xan Pro Pro Val Phe NH 2 Xdu Xan Pro Pro Val Phe NH 2 Xdv Xan Pro Pro Val Phe NH 2 Xdw Xan Pro Pro Val-Phe NH 2 Xdx Xan Pro Pro Val Phe NH 2 Xdy Xan Pro Pro Val Phe NH 2 Xdz Xan Pro Pro Val Phe NH 2 Xea Xan Pro Pro Val Phe NH 2 Xeb Xan Pro Pro Val Phe NH 2 Xee Xan Pro Pro Val Phe NH 2 Xds Xan Pro Pro Val NH 2 315. Xdt Xan Pro Pro Val NH 2 316. Xdu Xan Pro Pro Val NH 2 317. Xdv Xan Pro Pro Val NH 2 318. Xdw Xan Pro Pro Val NH 2 5 319. Xdx Xan Pro Pro Val NH 2 320. Xdy Xan Pro Pro Val NH 2 321. Xdz Xan Pro Pro Val NH 2 322. Xea Xan Pro Pro Val NH 2 323. Xeb Xan Pro Pro Val NH 2 10 324. Xee Xan Pro Pro Val NH 2 325. Xds Xan Pro Pro NH 2 326. Xdt Xan Pro Pro NH 2 327. Xdu Xan Pro Pro NH 2 328. Xdv Xan Pro Pro NH 2 15 329. Xdw Xan Pro Pro NH 2 330. Xdx Xan Pro Pro NH 2 331. Xdy Xan Pro Pro NH 2 332. Xdz Xan Pro Pro NH 2 333. Xea Xan Pro Pro NH 2 20 334. Xeb Xan Pro Pro NH 2 335. Xee Xan Pro Pro NH 2 336. Xds Val Pro Pro Val Phe NH 2 337. xds Val Pro Pro NH 2 338. Xdv Val Pro Pro NH 2 25 339. Xds Xan Pro Xfy 340. Xdv Xan Pro Xfy 341. Xaa Val Xhf Pro Pro Val Phe NH 2 342. Xaa Val Xhg Pro Pro Val Phe NH 2 343. Xaa Val Xhh Pro Pro Val Phe NH 2 30 344. Xaa Val Xhf Pro Pro Val NH 2 345. Xaa Val Xhg Pro Pro Val NH 2 346. Xaa Val Xhh Pro Pro Val NH 2 347. Xaa Val Xhf Pro Pro NH 2 348. Xaa Val Xhg Pro Pro NH 2 35 349. xaa Val Xhh Pro Pro NH 2 350. Xaa Val Xhf Pro Xfy 351. Xaa Val Xhg Pro Xfy 352. Xaa Val Xhh Pro Xfy 353. Xaa Val Xhf Pro Xgb 40 354. Xaa Val Xhg Pro Xgb 355. Xaa Val Xhh Pro Xgb 356. Xed Val Xan Pro Xfy 357. Xby Val Xan Pro Xfy 358. Xby Val Xan Pro Xhi 45 359. Xef Val Xan Pro Xfy 360. Xef Val Xan Pro Xhi 361. Xca Val Xan Pro Xfy 362. Xca Val Xan Pro Xhi 363. Xaa Val Xan Pro Xdp Phe NH 2 364. Xaa Val Xan Pro Xdq Phe NH 2 365. Xaa Val Xan Pro Xdr Phe NH 2 5 366. Xaa Val Xan Pro Xdp NH 2 367.Xaa Val Xan Pro Xdq NH 2 368. Xaa Val Xan Pro Xdr NH 2 369. Xaa Val Xan Pro Pro Xdi NH 2 370. Xaa Val Xan Pro Pro Xes NH 2 10 371. xaa Val Xan Pro Pro Xet NH 2 372. Xaa Val Xan Pro Pro Xeu NH 2 373. Xaa Xes Pro Pro Xdi NH 2 374. Xaa Xet Pro Pro Xdi NH 2 375. Xaa Xes Pro Xdp Phe NH 2 15 376. Xaa Xet Pro Xdp Phe NH 2 377. Xaa Xes Pro Xdp NH 2 378. Xaa Xet Pro Xdp NH 2 379. Xaa Xes Pro Xdq NH 2 380. Xaa Xet Pro Xdq NH 2 20 381. Xaa Xes Pro Xdr NH 2 382. Xaa Xet Pro Xdr NH 2 383.Xaa Val Xan Pro Pro Xdi NH 2 384. Xaa Val Xan Pro Pro Xdk NH 2 385. Xaa Val Xan Pro Pro Xdi NH 2 25 386. Xaa Val Xan Pro Pro Xdm NH 2 387. Xaa Val Xan Pro Pro Xdn NH 2 388. Xaa Val Xan Pro Pro Xdo NH 2 389. Xca Val Xan Pro Pro Phe Phe NH 2 390. Xby Val Xan Pro Pro Phe Phe NH 2 30 391. Xca Val Xan Pro Pro Phe Phe NH 2 392. Xef Val Xhf Pro Pro tLeu Phe NH 2 393. Xef Val Xhf Pro Pro tLeu Aic NH 2 394. Xef Val Xhf Pro Pro tLeu Tic NH 2 3 5. Xef Val Xan Pro Xfy 35 396. Xef Val Xan Pro Xbg 397. Xef Val Xan Pro Xbh 398. Xef Val Xan Pro Xgn 399. Xca Xet Pro Xfy 400. Xaa tLeu Xan Pro Pro Val Phe NH 2 40 401. Xaa Leu Xan Pro Pro Val Phe NH 2 402. Xaa He Xan Pro Pro Val Phe NK 2 403. Xaa Val Xan Pro Pro tLeu Phe NH 2 404. Xaa Val Xan Pro Pro Leu Phe NH 2 405. Xaa Val Xan Pro Pro lie Phe NH 2 45 406. Xaa Val Xan Pro Pro Val Dab NH 2 407. Xaa Val Xan Pro Pro Val Ala NH 2 408. Xaa Dab Xan Pro Pro Val Phe NH 2 409. Xaa Dab Xan Pro Pro Val NH 2 . 410. Xaa Dab Xan Pro Pro NH 2 411. Xht Val Xan Pro Pro Val Phe NH 2 412. Xhu Val Xan Pro Pro Val Phe NH 2 5 413. Xht Val Xan Pro Pro Val NH 2 413 (a) . Xhu Val Xan Pro Pro Val NH 2 414. Xht Val Xan Pro Pro NH 2 415. Xhu Val Xan Pro Pro NH 2 416. Xaa Val Xhy Pro Pro Val Phe NH 2 10 417. Xaa Val Xhz Pro Pro Val Phe NH 2 418. Xaa Val Xhy Pro Pro Val NH 2 419. Xaa Val Xhz Pro Pro Val NH 2 420. Xaa Val Xhy Pro Pro NH 2 421. Xaa Leu Xhz Pro Pro NH 2 15 422. Xaa Val Xhy Xfy 423. Xa Val Xhz Xfy 424. Xhv Val Xan Pro Pro Val Phe NH 2 425. Xhw Val Xan Pro Pro Val Phe NH 2 426. Xhx Val Xan Pro Pro Val Phe NH 2 20 427. Xhv Val Xan Pro Pro Val NH 2 428. Xhw Val Xan Pro Pro Val NH 2 429. Xhx Val Xan Pro Pro Val NH 2 430. Xhv Val Xan Pro Pro NH 2 431. Xhw Val Xan Pro Pro NH 2 25 432. Xhx Val Xan Pro Pro NH 2 433. Xaa Val Xan Pro Xia 434. Xaa Val Xan Pro Xib 435. Xaa Val Xan Pro Xic 436. Xaa Val Xan Pro Xid 30 437. xaa Val Xan Pro Xie 438. Xby Val Xan Pro Xia 439. Xby Val Xan Pro Xib 440. Xby Val Xan Pro Xic 441. Xby Val Xan Pro Xid 35 442. Xby Val Xan Pro Xie 443. Xca Val Xan Pro Xia 444. Xca Val Xan Pro Xib 445. Xca Val Xan Pro Xic 446. Xca Val Xan Pro Xid 40 447. Xca Val Xan Pro Xie 448. Xed Val Xan Pro Xia 449. Xed Val Xan Pro Xib 450. Xed Val Xan Pro Xic 451. Xed Val Xan Pro Xid 45 452. Xed Val Xan Pro Xie 453. Xby Leu Xan Pro Xia 454. Xby Leu Xan Pro Xib 455. Xby He Xan Pro Xic 456.Xby He Xan Pro Xid 457. Xby Leu Xan Pro Xie 458. Xca Leu Xan Pro Xia 5 459. Xca Val Xao Pro Xib 460. Xca Val Xao Pro Xic 461. Xat Val Xhf Pro Xak Leu Phe NH 2 462.Xat Val Xhf Pro Xhr Leu Phe NH 2 463. Xed Val Xhf Pro Xak Leu Phe NH 2 10 464. Xed Val Xhf Pro Xhr Leu Phe NH 2 465. Xat Val Xhf Pro Xak Val NH 2 466. Xat Val Xhf Pro Xhr Val NH 2 467. Xed Val Xhf Pro Xak Val NH 2 468. Xed Val Xhf Pro Xhr Val NH 2 15 469. Xat Val Xhf Pro Xak NH 2 470. Xat Val Xhf Pro Xhr NH 2 471. Xed Val Xhf Pro Xak NH 2 472. Xat Val Xhf Pro Xia 473. Xat Val Xhf Pro Xib 20 474. Xed Val Xhf Pro Xic 475.Xed Val Xhf Pro Xid 476. Xat Val Xhf Pro Xie 477. Xat Val Xhf Pro Xhs NH 2 478. Xed Val Xhf Pro Xhs NH 2 25 479. Xat Val Xhf Pro Xak Xfz 480. Xat Val Xhf Pro Xhr Xfz 481. Xed Val Xhf Pro Xak Xfz 482. Xed Val Xhf Pro Xhr Xfz 483. Xat Val Xhf Pro Xak Xbw 30 484. Xat Val Xhf Pro Xhr Xbw 485. Xed Val Xhf Pro Xak Xbw 486. Xed Val Xhf Pro Xhr Xbw 487. Xat Val Xhf Pro Xak Xer 488.Xat Val Xhf Pro Xhr Xer 35 489. Xed Val Xhf Pro Xak Xer 490. Xed Val Xhf Pro Xhr Xer 491. Xat Val Xhf Pro Xak Xgi 492. Xat Val Xhf Pro Xhr Xgi 493. Xed Val Xhf Pro Xak Xgi 40 494. Xed Val Xhf Pro Xhr Xgi 495. Xat Val Xhf Pro Xak Xif 496. Xat Val Xhf Pro Xhr Xif 497. Xed Val Xhf Pro Xak Xif 498. Xed Val Xhf Pro Xhr Xif 45 499. Xat Val Xhf Pro Xak Xig 500. Xat Val Xhf Pro Xhr Xig 501. Xed Val Xhf Pro Xak Xig 502. Xed Val Xhf Pro Xhr Xig 503. Xaa Val Xan Pro Pro Xif 504. Xaa Val Xan Pro Xig 505. Xca Val Xan Pro Pro Xif 5 506. Xca Val Xan Pro Xig 507. Xby Val Xan Pro Pro Xif 508. Xby Val Xan Pro Xig 509. Xed Val Xan Pro Pro Xif 510. Xed Val Xan Pro Xig 10 511. Xaa Leu Xan Pro Pro Xif 512. Xaa Leu Xan Pro Xig 513. Xca Leu Xan Pro Pro Xif 514. Xca Leu Xan Pro Xig 515. Xby Leu Xan Pro Pro Xif 15 516. Xby Leu Xan Pro Xig 517. Xed Leu Xan Pro Pro Xif 518. Xed Leu Xan Pro Xig 519. Xaa Lys Xan Pro Pro Val Phe NH 2 520. Xaa Lys Xan Pro Pro Val NH 2 20 521. Xaa Lys Xan Pro Pro NH 2 522. Xaa Lys Xan Pro Xfy 523. Xaa Chg Xan Pro Pro Val NH 2 524. Xaa Chg Xan Pro Pro NH 2 525. Xaa Chg Xan Pro Pro Val Phe NH 2 25 526. Xaa Val Xii Pro Pro Val Phe NH 2 527. Xaa Val Xii Pro Pro Val NH 2 528. Xaa Val Xii Pro Pro NH 2 529. Xaa Val Xan Pro Pro Val Lys NH 2 530. Xaa Val Xan Pro Xik 30 531. Xaa Val Xan Pro Pro Xii NH 2 532. Xaa Val Xbu 533. Xby Val Xbu 534. Xca Val Xbu 535. Xaa Val Xbv 35 536. Xby Val Xbv 537. Xca Val Xbv 538. Xaa Val Xan Pro Pro Xab 539. Xaa Val Xan Xab 540. Xim Val Xan Pro Pro Val Phe NH 2 40 541. Xin Val Xan Pro Pro Val Phe NH 2 542. Xio Val Xan Pro Pro Val Phe NH 2 543. Xip Val Xan Pro Pro Val Phe NH 2 544. Xiq Val Xan Pro Pro Val Phe NH 2 545. Xkd Val Xan Pro Pro Val Phe NH 2 45 546. Xim Val Xan Pro Pro Val NH 2 547. Xin Val Xan Pro Pro Val NH 2 548. Xio Val Xan Pro Pro Val NH 2 549.Xip Val Xan Pro Pro Val NH 2 550. Xiq Val Xan Pro Pro Val NH 2 551. Xkd Val Xan Pro Pro Val NH 2 552. Xim Val Xan Pro Pro NH 2 5 553. Xin Val Xan Pro Pro NH 2 554. Xio Val Xan Pro Pro NH 2 555. Xip Val Xan Pro Pro NH 2 556. Xiq Val Xan Pro Pro NH 2 557. Xkd Val Xan Pro Pro NH 2 10 558. Xaa Val Xan Pro Pro Val Xir 559. Xaa Val Xan Pro Pro Val Xis 560. Xaa Val Xan Pro Pro Val Xit 561. Xaa Val Xan Pro Pro Val Xiu 562. Xaa Val Xan Pro Pro Xiv 15 563--Xaa Val Xan Pro Pro Xiw " 564. Xaa Val Xan Pro Pro Xiy 565. Xaa Val Xan Pro Pro Xix 566. Xaa Val Xan Pro Xiz 567. Xaa Val Xan Pro Xka 20 568. Xaa Val Xan Pro Xkb 569. Xaa Val Xan Pro Xkc 570. Xke Val Xan Pro Pro Val Phe NH 2 571. Xkf Val Xan Pro Pro Val Phe NH 2 572. Xkg Val Xan Pro Pro Val Phe NH 2 25 573. Xkh Val Xan Pro Pro Val Phe NH 2 574. Xke Val Xan Pro Pro Val NH 2 575. Xkf Val xan Pro Pro Val NH 2 576. Xkg Val Xan Pro Pro Val NH 2 577. Xkh Val Xan Pro Pro Val NH 2 30 578. Xke Val Xan Pro Pro NH 2 579. Xkf Val Xan Pro Pro NH 2 580. Xkg Val Xan Pro Pro NH 2 581. Xkh Val Xan Pro Pro NH 2 582.Xaa Xez Pro Pro Val Phe NH 2 35 583. Xed Val Xhf Pro Xhr NH 2 Examples for the MS-characterization of the synthesized novel compounds are given in the following table. 40 45 Ta b le I - S equence Identification of Compounds Prepared - A ccording to Examples 1 and 2 Compound urnhpr . s . SeσuerirP- TD Wiimbpr 38, 39, 52, 86-91, 93, 214- 246, 350-362, 366-368, 395- 398, 433-452, 459, 460, 469- 478, 504, 506, 508, 510, 530, 566-569, 583 3, 9, 26-28, 30-33, 35, 36, 95-117, 341-343, 416, 417, 424-426, 526, 540-545, 570-573 4-7, 10, 11, 406, 558-561 12 13, 392, 403 14 15, 16, 29 17, 18 10 19, 20 11 21, 22, 247-264, 303-313, 582 12 23, 402 13 24, 400 14 25, 401 15 34 16 37, 118-138, 344-346 17 40, 45, 189-213, 369-372, 383- 18 388, 503, 505, 507, 509, 531, 538, 562-565 41-43, 48, 49, 527 19 44 20 46, 50, 51, 62-65, 70, 139- 21 159, 347-349, 414, 415, 420, 421, 430-432, 528, 552-557, 578-581 47 22 53-61, 78, 422, 423, 539 23 66, 67, 94, 410, 524 24 68, 69, 284-302, 325-335 25 The symbols Xaa in the summary have the following meanings: Xaa: N,N— Diraethylvaline Xag: Tetrahydroisoquinoline carboxylic acid Xah: 1 - Aminoindane- 1 - carboxylic acid Xai: tert-Leucine or 2-tert-butylglycine Xak: Homoproline or pipecolic acid Xal: 1 — aminopentane- 1 — carboxylic acid Xam: N- ethylisoleucine Xan: N— Methylvaline Xao: N-Methylleucine Xba: N-Benzylvaline Xbb: ' Xbk: Xbm: Xbo: N-Methyl-N-isopropylvaline Xby: N-N-Diethylvaline Xbz: N,N-Bis(2-fluoroethyl)valine Xcm: CH(CH 3 ) 2 Xdy: Xed: N,N-Diethyl-tert-leucin Xee: N,N-DitrifluoroethyI-tert-leucine Xef: N,N-Dipropyl- tert— leucine Xeg: N-Cyclopropyl-tert— leucine Xeh: COOEt Xeu: O o Xgi: O - Xgm: O Xgn: COOEt xgq: ( O Xgv: Xhf:N-Methyl-2-tert-butylglycine Xhg: N-Methyl-3-tert-butylalanine Xhh: N-Ethylvaline O Xhn: N—Ureyl— valine Xho: N,N— Dimethylphenylalamne Xhp: N,N— Diethylphenylalanine Xhq: N,N— Dipropylphenylalanine Xhr: Hydroxyproline Xhs: 3-Thienylalanine Xht: N,N-Dimethyl-3-cyclohexyl- alanine Xhu: N,N-Diethyl-3— cyclohexyl- alanine Xhv: N-Methyl-N-isopropyl- - tert. -leucine Xhw: N-Methyl-N-isopropyl- leucine Xhx: N-Methyl-N-isopropyl- isoleucine Xhy: N-Methyl-3-cyclohexyl- alanine Xhz: N- Methyl -phenylalanine Xih: 2- Cyclohexylglyάne Xii: N— Methyl— 2— cyclohexylglycine Xik: Xim: N - Methylaminosulf onyl -valine Xin N - ter butylaminosulf onyl -valine Xio N-Morpholinosulfonyl— valine Xip N - B enzyloxycarbonyl -valine Xiq: N - tert.Butyloxycarbonyl -valine Xir Phenylalanine - methylester Xis Phenylalanine — ethylester Xit: Phenylalanine - benzylester Xiu Phenylalanine - tertbutylester Xiv: Valin e — b en∑y lester Xiw: Valine — methylester Xix Valine- ethylester Xiy: Valine - tert.butylester Xiz Proline - benzylester Xka: Proline- methylester Xkb Proline - ethylester Xke: Proline- ter butylester Xkd: N-Lactyl -valine Xke: N-Methylsulfonyl— valine Xkf: N - Methyl - N - methylsulfonyl -valine Xkg: N-Tosyl -valine Xkh: N-Phthalyl-valine The ending -NH 2 has the meaning that the C-terminal amino acid is in its amide form. Compounds of this invention may be assayed for anti-cancer activ¬ ity 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-2 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 eye 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 +/- SO of data from rep¬ licated wells are calculated, using the formula % T/C (% viable cells treated/control) . 0D 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 indic¬ ative of clinical utility. Such assays are conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted ("xenografted' r ) , 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 doses 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 ) /2 = 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. The novel compounds of the present invention show good in vitro activity in the above mentioned assay systems and antitumor activity in the above mentioned in vivo system. SEQUENCE LISTING (1) GENERAL INFORMATION (i) APPLICANT: (A) BASF Aktiengesellschaft (B) STREET: Carl-Bosch-Strasse 38 (C) CITY: Ludwigshafen (E) COUNTRY: Bundesrepublik Deutschland (F) ZIP: -6700 (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: 57 (iv) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Diskette, 3,5 inch, 2 DD (B) COMPUTER: IBM AT-compatible, 80286 processor (C) OPERATING SYSTEM: MS-DOS version 5.0 (D) SOFTWARE: WordPerfect version 5.1 (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Xaa Val Val Xaa Val Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Xaa Val Xaa Pro Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B> TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Xaa Val Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Xaa Val Xaa Pro Pro Val Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: Xaa Val Xaa Pro Pro Val His 1 5 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: Xaa Xaa Xaa Pro Pro Val Trp 1 5 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: Xaa Val Xaa Pro Pro Xaa Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Xaa Val Xaa Pro Pro He Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9:. Xaa Val'.Xaa Pro Xaa Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: Xaa Val Xaa Xaa Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: Xaa Val Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: Xaa Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: Xaa He Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: Xaa Xaa Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: Xaa Leu Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Xaa Val Xaa Pro Pro Phe Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: Xaa Val Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: Xaa Val Xaa Pro Pro Xaa 1 5 (2) INFORMATION FOR SEQ "ID NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: Xaa Val Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20: Xaa Xaa Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: Xaa Val Xaa Xaa Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22: Xaa Val Xaa Pro Xaa Val 1 5 (2) INFORMATION FOR SEQ ID NO: 23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: a iiio acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peotide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: Xaa Val Xaa Xaa 1 (2) INFORMATION FOR SEQ ID NO: 24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: Xaa Xaa Xaa Pro Pro 1 5 (2) INFORMATION FOR SEQ ID NO: 25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25: Xaa Xaa Pro Pro 1 (2) INFORMATION FOR SEQ ID NO: 26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26: Xaa Val Xaa Pro 1 (2) INFORMATION FOR SEQ ID NO: 27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27: Xaa Xaa Xaa Pro Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28 Xaa Val Xaa Pro Pro Val Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29: Xaa Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: Xaa Val Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid - (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: Xaa Val Pro Pro 1 (2) INFORMATION FOR SEQ ID NO: 32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32: Xaa Xaa Pro Xaa 1 (2) INFORMATION FOR SEQ ID NO: 33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33: Xaa Val Xaa Pro Xaa Phe 1 5 1 17 (2) INFORMATION FOR SEQ ID NO: 34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34: Xaa Xaa Fro Pro Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY.: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35: Xaa Xaa Pro Xaa Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: Xaa Val Xaa Pro Pro Phe Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37: Xaa Val Xaa Pro Pro Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38: Xaa Val Xaa Pro Pro Leu Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 39: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39: Xaa Val Xaa Pro Pro He Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide Cxi) SEQUENCE DESCRIPTION: SEQ ID NO: 40: Xaa Val Xaa Pro Pro Val Ala 1 5 (2) INFORMATION FOR SEQ ID NO: 41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41: Xaa Xaa Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42: Xaa Xaa Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43: Xaa Val Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44 Xaa Val Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45 Xaa He Xaa Pro Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 46: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46: Xaa Val Xaa Pro Xaa Val 1 5 120 (2) INFORMATION FOR SEQ ID NO: 47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 47-: Xaa Val Xaa Pro Xaa Leu Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 48: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48: Xaa Val Xaa Pro Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 49: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49: Xaa Leu Xaa Pro Pro Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 50: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50; Xaa Leu Xaa Pro Pro Xaa 1 5 (2) INFORMATION FOR SEQ ID NO: 51: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51: Xaa Lys Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 52: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52: Xaa Lys Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 53: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53: Xaa Lys Xaa Pro Pro 1 5 (2) INFORMATION FOR SEQ ID NO: 54: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ' ID NO: 54: Xaa Lys Xaa Pro Xaa 1 5 -(2) INFORMATION FOR SEQ ID NO: 55: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55: Xaa Xaa Xaa Pro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO: 56: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56: Xaa Xaa Xaa Pro Pro Val Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 57: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7- amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57: Xaa Val Xaa Pro Pro Val Lys 1 5 —.

Claims: laim: R 1 is alkoxy; alkyl; cycloalkyl; alkylsulfonyl; fluoroalkyl; trifluoroacetyl; amidino; ureyl; piperidinosulfonyl; morpholinosulfonyl; benzyl¬ oxycarbonyl; alkyloxycarbonyl; aminosulfonyl which may be substituted by alkyl; hydroxy; arylsulfonyl which may be substituted by one or more substituents independently selected from alkyl, -N(CH 3 ) 2 , nitro, halogen and CF 3 ; benzyl which may be substituted by up to three substi¬ tuents independently selected from alkyl, alkoxy, nitro, halogen and CF 3 ; or NR 3 R 4 where R 3 and R 4 may each be either hydrogen or alkyl; R 2 is hydrogen; alkyl; fluoroalkyl; cycloalkyl; acyl; benzoyl or benzyl which may both be sub¬ stituted by up to three substituents indepen¬ dently selected from nitro, halogen, CF 3 , alkyl and alkoxy R i -N-R 2 together may be phthalimido, a 5- or 6-membered heterocycle which may be unsubstituted or sub¬ stituted with one or more substituents indepen- dently selected from phenyl, benzyl, alkyl, N(CH 3 ) 2 , nitro, thienyl, CONH 2 and COOEt A is a valyl, isoleucyl, leucyl, allo-isoleucyl, α-aminoisobutanoyl, 3-tert-butylalanyl, 2-tert- butylglycyl, 3-cyclohexylalanyl, 2,4-diaminobu- tanoyl, ornithyl, lysyl, 2-ethylglycyl, 2-cyclo- hexylglycyl, norleucyl, norvalyl or arginyl res¬ idue; B is a N-alkyl-valyl, -norvalyl, -leucyl-, -isoleu¬ cyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -3-cyclohexylalanyl, -phenylalanyl, or -2-cyclo- hexylglycyl residue; D,E,F and G are independently selected from the group con¬ sisting of prolyl, homo-prolyl, hydro-xyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl-l-carbo- nyl, valyl, 2-tert-butylglycyl, isoleucyl, leu- cyl, 3-cyclohexylalanyl, phenylalanyl, N-methyl- phenylalanyl, tetrahydroisoguinolyl-2-carbonyl, 3-thiazolylalanyl, 3-thienylalanyl, histidyl, 1-aminoindy1-1-carbonyl, 2,4-diaminobutanoyl, arginyl, 3-pyridylalanyl, 3-tert-butylalanyl, 2-cyclohexylglycyl, lysyl, norvalyl, norleucyl and 3-naphthylalanyl residues X is hydrogen, alkyl, cycloalkyl, -CH 2 -cyclohexyl or arylaltø-1 A and B together, F and G together, RiRN-CHX-CO and A to¬ gether, E and F together, either alone or in pairs, may be where Y is hydrogen or lower alkyl; Z is hydrogen or lower alkyl; n is 1, 2, or 3; V is oxygen or sulfur; M is hydrogen, lower alkyl, arylalkyl, cyclohexyl, or -CH 2 -cyclohexyl; Q is hydrogen; R is hydrogen or lower alkyl; or R and Q may to¬ gether form a bond; U is hydrogen, lower alkyl, phenyl, or cycloalkyl; and W is hydrogen, lower alkyl or phenyl; t,u,v,and w are independently 0 or 1; and K is hydroxy, alkoxy, phenoxy, benzyloxy or a sub¬ stituted or unsubstituted amino moiety; provided that where t, u, v and w are 0, K is not a hydroxy, alkoxy, benzoxy or phenoxy moiety; and further provided that where t, u and v are 0, K is not a hydroxy or alkoxy moiety; and the salts thereof with physiologically tolerated acids. 2. Compounds of formula I according to claim 1 wherein Ri-N-R 2 is phthalimido or 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, oxo, CONH 2 and COOEt; 3. Compounds of formula I according to claim 1 wherein K is an amino moiety of the formula R 5 -N-R δ wherein R 5 is hydrogen, or hydroxy, or Cι-7-alkoxy, or benzyloxy, or Cι_7-alkyl, or fluoroalkyl, or C 3 - 7 -cycloalkyl, or benzyl which may be substituted by up to three substituents which may independently be CF 3 , nitro, Cι_ 7 -alkylsulfonyl, Cχ_-j-alkoxy, phenoxy, benzoxy, halogen or Cι_ 4 -alkyl is H, or Cι-- 7 -alkyl t or C 3 _ 7 -cycloalkyl, or fluoroalkyl, or phenyl (which may be substituted by up to three sub¬ stituents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl which may form a cyclic system, Cι_-alkoxy, phenoxy, benzoxy, or Cι_ 7 -al_<yl-sul- fonyl) , or benzyl (which may be substituted by up to three substitu¬ ents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , C 3. _ 4 -al-.yl 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 substitu¬ ents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 , Cι_ 4 -alkyl, Cχ_ 4 -alkoxy, benzoxy, phenoxy, or Cι- 7 -alkyl-sulfonyl) r 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_ 4 -alkyl, C^-alkoxy, phenoxy, ben¬ zoxy, or Cι_ 7 -alkyl-sulfonyl) , or biphenyl (which may be substituted by up to two substitu¬ ents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2r Cι_ 4 -alkyl, C^-alkox , phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or triphenylmethyl (which may be substituted by up to three substituents 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 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, phe¬ noxy, benzoxy, or Cι_ 7 -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-- 4 -alkyl, Cι- 4 -alkoxy, phe¬ noxy, 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 , C 1 _ 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 , C 1 _ 4 -alkyl, C^-alkoxy, phenoxy, benzoxy, or Cι_-alkyl-sulfonyl) , or acenaphthylmethyl (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, C^-alkoxy, phenoxy, benzoxy, or Cι_ 7 -alkyl-sulfonyl) , or pyridyl (which may be substituted by up to two substitu- ents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 . Cι- 4 -alkyl, Cι- 4 -alkoxy, phenoxy, ben¬ zoxy, or Cι_ -alkyl-sulfonyl) , or picolyl (which may be substituted by up to two substitu¬ ents which may independently be CF 3 , nitro, halogen, CONHBzl, CON(Bzl) 2 . Cι_ 4 -alkyl, Cι- 4 -alkoxy, phenoxy, ben¬ zoxy, or Cι_ 7 -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 C_ . -. 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 -alkox , 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_4-alkyl, Cι- 4 -alkoxy, phenoxy, ben¬ zoxy, or Cι_ 7 -al-«yl-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, Cι- 4 -alkoxy, phenoxy, ben¬ zoxy, or Cι_ 7 -alkyl-sul onyl) , 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- 4 -alkoxy, phe- noxy, benzoxy, or Cι_ 7 -al-yl-sulfonyl) , or pyrimidyl (which may be substituted by up to two substi¬ tuents which may independently be CF 3 , nitro, halogen, COOEt, CONHBzl, CON(Bzl) 2 , C 1 _ 4 -alkyl which may form a cy¬ clic system, Cι_ 4 -alkoxy, phenoxy, benzoxy, or Cι_ 7 -al- kyl-sulfonyl) , or 5-membered heteroaryl [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 CONHBzl, CON(Bzl) 2 , Cι_ 4 -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-- 4 -alkyl) , benzyl (which may be substituted by up to four substituents which may independently be nitro, CF 3 , halogen, Cι_ 4 -al- kyl, naphthyl, Cι_ 7 -alkyl-sulfonyl, phenylsulfonyl, or C 1 _ 4 -dialkyla1rri.no) ] , or -CHR 7 -5-membered heteroaryl (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 , CONH 2 , COOBzl, Cι_ 4 -alkyl, Cι_ 4 -alkoxy, phe¬ noxy, benzoxy, phenyl, benzyl, naphthyl, or Cι_ 7 -alkyl- sulfonyl [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 ) 4 -]) . Compounds of formula I according to claim 1 wherein K is R 5 -N-R 6 which together may form structures selected from the group consisting of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of CF , nitro, halogen, oxo, cyano, N,N-dimethylamino, CONHBzl, CON(Bzl) 2 , Cι-6-alkyl, C 3 _ 4 -alkylen group forming an annelated ring system, C_ . - 4 -alkoxy, phenoxy, benzoxy, naph- thyl, pyrimidyl, COOEt, COOBzl, C 3 _ 6 -cycloalkyl, pyrolidinyl, piperidinyl, thienyl, pyrolyl, -CH 2 -CO-NCH(CH 3 ) 2 , -CH 2 -CO-N(CH 2 ) , -CH 2 -CO-N(CH 2 ) 4 θ, benzyl (which may be substi¬ tuted 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 cor¬ responding sulfoxide or sulfone, Cι_ 4 -alkyl, and Cι_ 4 -alkoxy) , and phenyl (which may be substituted by up to three substitu¬ ents independently selected from the group consisting of ni¬ tro, halogen, CF 3 , thiomethyl, thioethyl, Ci_ 4 -alkyl, and Cι_4-alkoxy) . Compounds of formula I according to claim 1 wherein t, u, v, and w are zero and is not an hydroxy, benzoxy, phenoxy or alkoxy moiety. 6. Compounds of formula I according to claim 1 wherein t, u, and v are zero and K is not an hydroxy or alkoxy moiety. 7. Compounds of formula I according to claim 1 wherein t, u, v and w are 1 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. 8. Compounds of formula I according to claim 1 wherein t, u and v are 1, w is 0 and is a hydroxy, alkoxy, phenoxy or benzy- loxy moiety. 9. Compounds of formula I according to claim 1 wherein t and u are 1, v and w are 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety. 10. Compounds of formula I or salts thereof for use in medicine in particular for treating oncological diseases. 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1. 12. A method of treating a tumor in a mammal comprising admini¬ stering to a mammal bearing such a tumor, a tumor-inhibiting amount of a compound of claim 1. 13. 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: EMLING FRANZ, HAUPT ANDREAS, ROMERDAHL CYNTHIA, EMLING, FRANZ, HAUPT, ANDREAS, ROMERDAHL, CYNTHIA
Applicants: BASF AG, EMLING FRANZ, HAUPT ANDREAS, ROMERDAHL CYNTHIA, BASF AKTIENGESELLSCHAFT
Application year: 1993
Main classification: C07K5
IPC codes: A61K38, A61P35, C07K5, C07K7