ANTINEOPLASTIC PEPTIDES

Abstract: Novel peptides of the following formula (I): R<1>R<2>N-CHX-CO-A-B-D-E-(G)s-K in which R<1>, R<2>, A, B, D, E, G, K, X, and s have the meanings stated in the description, and the preparation thereof are described. The novel peptides have an antineoplastic effect.

Description: ANTINEOP ASTIC PEPTIDES 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 (U.S. Patent Nos. 4,879,276 and 4,816,444) and the compounds described in WO 93/23424. Compounds of this invention include novel peptides of the for¬ mula I where R 1 is hydrogen, methyl, or ethyl; R 2 is methyl; or ethyl; or R 1 -N-R 2 together are a pyrrolidine ring; A is a vaiyl, isoleucyl, allo-isoleucyl, 2-tert-butylgly- cyl , 2-ethylglycyl, norleucyl or norvalyl residue; B is a N-methyl-valyl, N-methyl-norvalyl, N-methyl-leucyl, N-methyl-isoleucyl, N-methyl-2-tert-butylglycyl, N-methyl- 2-ethylglycyl, or N-methyl-norleucyl residue; D is a prolyl, homoprolyl, hydroxyprolyl, or thiazoli- dine-4-carbonyl residue; E is a prolyl, homoprolyl, hydroxyprolyl, thiazolidine-4- carbonyl, trans-4 -fluoro-L- rolyl, cis-4 -fluoro- -prolyl, trans-4 -chloro- -prolyl or cis-4 -chloro- -prolyl residue; X is ethyl, propyl, butyl, isopropyl, sec. butyl, tert.- butyl, cyclopropyl, or cyclopentyl; G is a -2-tert.butylglycyl, D-2-tert .butylglycyl , D-valyl, D-isoleucyl, D-leucyl, D-norvalyl, 1-aminopentyl-l- carbonyl, or 2 , 2 -dimethylglycyl residue; is 0 or l K is -NH-Ci-g-alkyl, -NH-C 3 . 8 -alkenyl , -NH-C 3 . 8 -alkinyl , -NH-C 6 -β-cycloalkyl, -NH-Cι- -alkene-C 3 .% • cycloalkyl, Cι- 4 -alkyl -N -Cι- 6 -alkyl , in which residues one CH group may be replaced by 0 or S, one H by phenyl or cyano, or 1, 2 or 3 H by F, except the N-methoxy-N-meth lamino, K ■ benzylamino, or N-methyl-N-benzylamino residue, or K is and the salts thereof with physiologically tolerated acids. Specifically K may be -NHCH 3 , -NHCH 2 CH 3 , -NH (CH 2 ) 2 CH 3 , -NH(CH 2 ) 3 CH 3 , -NH(CH 2 ) CH 3 , - NH (CH 2 ) 5 CH 3 , -NH (CH ) 6 CH 3 , -NHCH(CH 2 ) 7 CH 3 , -NHCH ,CH 3 ) 2 , - NHCH (CH 3 ) CH 2 CH 3 , -NHCH (C.rI 2 CH 3 ) 2 , -NHCH (CH 2 CH 2 CH 3 ) 2 , -NHC(CH 3 ) 3 , -NHCH (CH 2 CH 3 ) CH 2 CH 2 CH 3 , -NHCH(CH 3 )CH(CH 3 ) 2 , - HCH (CH 2 CH 3 ) CH (CH 3 ) 2 , "NHCH (CH 3 ) C (CH 3 ) 3 , -NH-cyclohexyl, -NH-cycloheptyl , -NH-cyclooctyl , -N (CH 3 ) OCH 2 CH 3 , -N(CH 3 )OCH 2 CH CH 3 , -N(CH 3 )OCH <CH 3 ) , -N(CH 3 )0 (CH 2 ) 3 CH 3 , -N(CH 3 )OCH 2 C 6 H 5 , -NH(CH 2 ) 2 C 6 H 5, -NH (CH 2 ) 3 C 6 H 5, -NHCH (CH 3 ) C 6 H 5 , -NHC (CH 3 ) 2 C 6 H 5 , -NHC (CH 3 ) 2 CH 2 CH 3 , -NHC (CH 3 ) (CH 2 CH 3 ) 2 , -NHCH[CH(CH 3 ) ] 2 . -NHC(CH 3 ) 2 CN, -NHCH(CH 3 ) CH (OH) C 6 H 5 , -NHCH 2 -cyclo- hexyl, -NHCH 2 C (CH 3 ) 3 , -NHCH 2 CH (CH 3 ) 2 , -N(CH 3 ) 2 , -N{CH 2 CH 3 ) , -N(CH 2 CH 2 CH 3 ) 2 , -NHCH 2 CF 3 , -NHCH(CH 2 F) 2 , -NHCH 2 CH 2 F, -NHCH 2 CH 2 OCH 3 , -NHCH 2 CH 2 SCH 3 , -NHCH 2 CHCH 2 , -NH-C (CH 3 ) 2 CH=CH 2 , -NHC (CH 3 ) 2 C ≡ CH, -NHC(CH 2 CH 3 ) 2 C≡CH, -NHC (CH 3 ) 2 CH 2 CH 2 OH, -NH(CH 2 CH 2 0) 2 CH CH 3 , -NHC (CH 3 ) 2 CH(CH 3 ) 2 , -NHC (CH 3 ) 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 CH 2 C 6 H 5 , -N(OCH 3 )CH(CH 3 ) 2 , -N(OCH 3 )CH 2 CH 3 , -N(OCH 3 )CH 2 CH 2 CH 3 , -N(OCH 3 )CH 2 C 6 H 5 , -N(OCH 3 )C 6 H 5 , -N(CH 3 ) OC 6 H 5 , -NHCH [CH (CH 3 ) 2 ] 2 , -N(OCH 3 )CH 2 CH 2 CH 2 CH 3 , or the special ring systems mentioned above. Preferred are compounds of the formula I where the substituents R 1 , R 2 , A, B, D, E, X, G and s have the following meanings: R 1 hydrogen, methyl, or ethyl, especially methyl; R 2 methyl or ethyl, especially methyl; A valyl, isoleucyl, 2-tert-butylglycyl, 2-ethylglycyl , nor- leucyl or norvalyl, especially valyl, isoleucyl, 2-tert- butylglycyl, 2-ethylglycyl, B N-methyl-valyl, N-methyl-norvalyl , N-methyl-isoleucyl, N-methyl-2- ert-butylglycyl , N-methyl-2-ethylglycyl, or N-methyl-norleucyl, especially N-methyl-valyl, N-methyl-2 -ethylglycyl, N-methyl-norleucyl, N- ethyl- isoleucyl, or N-methyl-2- ert.butyl -glycyl; D prolyl, homoprolyl or thiazolidine-4-carbonyl, especially prolyl or thiazolidine-4 -carbonyl; E prolyl, homoprolyl, thiazolidine-4-carbonyl, crans-4 -fluoro- -prolyl, cis-4 -fluoro-L-prolyl, trans-4-chloro-L-prolyl or cis-4-chloro-L-prolyl, especially prolyl, trans-4 -fluoro-prolyl, cis-4 -fluoro- prolyl, trans-4 -chloro-prolyl, or cis-4-chloro-prolyl; X ethyl, propyl, isopropyl, sec.butyl, tert.butyl or cyclo- propyl, especially ethyl, isopropyl, sec.butyl or ter .butyl; G L-2-tert.butylglycyl, D-2-tert .butylglycyl , D-valyl, D-isoleucyl, D-leucyl or 2, 2 -dimethylglycyl residue; 0 or 1 Preferred meanings for K are: -NH-Cj . -β-alkyl, -NH-Ce-β-cycloalkyl, -NH-CH 2 -cyclohexyl, Cι- 4 -alkyl -N -Cι- 6 -alkyl, in which residues one CH 2 group may be replaced by 0, one H by phenyl or 1 or 2 H by F, except the N-methoxy-N-methylamino, N-benzylamino, or N-methyl -N-benzylarrlno residue, or K is NH CO- NH- CH 2 CH 2 CH 3 More preferred K is -NHCH 3 -NHCH 2 CH 3 , -NH (CH 2 ) 2 CH 3 , -NH (CH 2 ) 3 CH 3 , -NH (CH 2 . 4 CH 3 , -NH(CH 2 ) 5 CH 3/ -NH(CH 2 ) 6 CH 3 , -NH (CH 2 ) 7 CH 3 , -NHCH(CH 3 ) 2 , -NHCH(CH 3 )CH 2 CH 3 , -NHCH (CH 2 CH 3 ) 2 , -NHCH (CH 2 CH 2 CH 3 ) 2 , -NHC(CH 3 ) 3 , -NHCH(CH 2 CH 3 )CH 2 CH 2 CH 3 , -NHCH (CH 3 ) CH (CH 3 ) 2 , -NHCH (CH 2 C3 3 ) CH (CH 3 ) - ; , -NHCH(CH 3 )C (CH 3 ) 3 , -NH-cyclohexyl , -NH-cycloheptyl , -NH-cyclooc- tyl, -N(CH 3 )OCH 2 CH 3 , -N (CH 3 ) OCH CH 2 CH 3 , -N (CH 3 ) OCH (CH 3 ) 2 , -N(OCH 3 )CH(CH 3 ) 2 , -N(CH 3 )OCH 2 C 6 H 5 , -NH (CH 2 ) 2 C 6 H 5 , -NH (CH 2 ) 3 C 6 H 5 , -NHCH(CH 3 )C 6 H 5 , -NHC(CH 3 ) 2 C 6 H 5 , -NHC (CH 3 ) CH 2 CH 3 , -NHC .CH 3 ) (CH 2 CK 3 ) 2 , -NHCH(CH 3 )CH(OH)C 6 H 5 , -NHCH 2 -cyclohexyl , -N(CH 3 ) 2 , -N;CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -NHCH(CH 2 F) 2 , -NHC (CH 3 ) 2 CH 2 CH 2 OH, -NH(CH 2 CH 2 0) 2 CH 2 CH 3 , -NHC (CH 3 ) 2 CH (CH 3 ) 2 , -NHC (CH 3 ) CH=CH , -NHC(CH 3 ) 2 CN, -NHC(CH 3 ) 2 C≡CH, -NHC (CH 3 ) 2 CONH 2 , -N (OCH 3 ) C 6 H 5 , -NHCH[CH(CH 3 ) 2 ] 2 . -N(OCH 3 )CH 2 C 6 H 5 , -N (OCH 3 ) CH 2 CH 3 , -N (OCH 3 ) CH 2 CH 2 CH 3 , -N (OCH 3 ) CH 2 CH 2 CH 2 CH 3 , Especially preferred are compounds of the formula I where R 1 and R 2 are methyl, A is a valyl, isoleucyl, or 2- ert. -butylglycyl residue is a N-methylvalyl, N-methyl-isoleucyl, or N- methyl-2-tert. -butylglycyl residue, D is a prolyl or thiazolidine-4-carbonyl residue, is a prolyl, cis-4-fluoro-L-prolyl, or cis- -chloro ■ L-prolyl residue, X is a isopropyl, sec. -butyl, or tert. -butyl residue, is 0, and -NHCH(CH 3 ) 2 , -NHCH(CH 3 )CH 2 CH 3 , -NHCH (CH 2 CH 3 ) 2 , -NHCH(CH 2 CH 2 CH 3 ) 2 , -NHC(CH 3 ) 3 , -NHCH (CH 2 CH 3 ) CH 2 CH 2 CH 3 , -NHCH(CH 3 )CH(CH 3 ) 2 , -NHCH (CH 2 CH 3 ) CH (CH 3 ) 2 , -NHCH (CH 3 )C(CH 3 ) 3 , -NH-cycloheptyl , -NH-cyclooctyl , -N(CH 3 )OCH 2 CH 3 , -N{CH 3 )OCH 2 CH CH 3 , -N (CH 3 ) OCH (CH 3 ) 2 , -N(OCH 3 )CH(CH 3 ) 2 , -N(CH )OCH C 6 H 5 , -NH (CH 2 ) 2 C 6 H 5 , -NH(CH 2 ) 3 C 6 H 5, -NHCH (CH 3 )C 6 H 5 , -NHC (CH 3 ) 2 C 6 H 5 , -NHC(CH 3 ) 2 CH 2 CH 3 , -NHC (CH 3 ) (CH 2 CH 3 ) 2 , -NHCH (CH 3 ) CH (OH) C 6 H 5 , -NHCH(CH 2 F) 2 , -NHC(CH 3 ) 2 CH 2 CH 2 OH, -NH (CH 2 CH 2 0) 2 CH 2 CH 3 , -NHC(CH ) 2 CH=CH 2 , -NHC (CH 3 ) 2 CH (CH 3 ) 2 , -N (OCH 3 ) CH 2 CH 3 , -N(OCH 3 )CH 2 CH 2 CH 3 , -N (OCH 3 ) CH 2 CH 2 CH CH 3 , -NHC (CH 3 ) 2 CN, ■ NHC(CH 3 ) 2 C≡CH, -NHCH[CH(CH 3 ) 2 ] 2 , -NHC(CH 3 ) 2 CONH 2 , -NHC(CH 3 ) 2 CH 2 C 6 H 5 , -N(OCH 3 )C 6 H 5 , -N(OCH 3 ) CH 2 C 6 H.,, CH 3 —NH- CO NH CH- CH-. CH 3 CH 3 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. 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, acet:.c 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 peptiάe 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 by forming an amide linkage. Erzy- rnatic and chemical methods are suitable for this. Chemical methods for forming the amide linkage are described in detail by Mueller, 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; The Practice of Peptide Synthesis, M. Bodanszky, A. Bodanszky, Springer-Verlag, 1994, 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, especially dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC ) , l-ethoxycarbonyl-2-ethoxy- 1, 2-dihydroquinoline (EEDQ) , pivaloylchloride, l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI), n-propan- ephosphonic anhydride (PPA) , N,N-bis (2-oxo-3-oxazolodinyl) -amido- phosphoryl chloride (BOP-CD, bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) , diphenylphosphoryl azide (DPPA) , Castro's reagent (BOP, PyBop) , O-benzotriazolyl-N,N,N' ,N' -tetra- methyluronium salts (HBTU) , O-azabenzotriazolyl-N,N, N' ,N' - tetra- methyluronium salts (HATU) , diethylphosphoryl cyanide (DEPCN) , 2, 5-diphenyl-2 , 3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and 1, 1' -carbonyldiimidazole (CDI) . The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP) , N-hydroxy-benzotriazole (HOBt) , N-hydroxybenzotriazine (HOOBt) , Azabenzotriazole, N-hydroxysuccinimide (HOSu) or 2-hydroxypyri - dine. 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 (Fmoc) techniques. Identified in each case is the protective group on the alpha- amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Mueller, Methoden der organischen Chemie Vol. XV/1, pp 20 to 906, Thieme Verlag, Stutt ¬ gart, 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. Che . Soc. 85 (1963) 2149. 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) , acetonitrile, dichloromethane (DCM) , ethyl acetate, 1,4-dioxane, tetrahydro- furan (THF) , N-methyl-2-pyrrolidone (N P) 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 complete, 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, especial Ly cleavage in liquid anhydrous hydrogen fluoride, in anhydrous tri - fluoromethanesulfonic acid, in dilute or concentrated trifluoro- acetic 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 :.n solution or on the polymeric support, by reductive alkylation of the res¬ in-bound peptide in DMF/1% acetic acid with NaCNBH 3 and the ap ¬ propriate aldehydes, by hydrogenation of the peptide in solution in the presence of aldehyde or ketone and Pd/C. 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 commercially-avail ¬ able materials using methods known in the art. For example, amino acids building blocks with R 1 and R 2 moieties can be prepared ec- cording to E. Wuensch, Houben Weyl, Meth. d. Org. Chemie, Bd. XV, 1, p. 306 following, Thieme Verlag Stuttgart 1974 and Literature cited therein. 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. leukemias, lymphomas) by administration of the compound to the mammal. It is a special advantage of the new compounds that they are very resistant to enzymatic degradation and can also be administered orally. Administration may be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means such as subcutaneously, intravenously, intramuscularly and intraperitoneally. The compounds may be administered alone or in the form of pharma¬ ceutical compositions containing a compound of formula I together with a pharmaceutically accepted carrier appropriate for the de¬ sired route of administration. Such pharmaceutical compositions may be combination products, i.e., may also contain other thera- peutically active ingredients. The dosage to be administered to the mammal will contain an ef¬ fective 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 0.05 to 50 milligrams per kilogram of body weight on oral administration and about 0.01 to 20 milli¬ grams per kilogram of body weight on parenteral administration. The novel compounds can be administered in conventional solid or liquid pharmaceutical administration forms, e.g. 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 disintegrants, flow regulators, plasticizers, 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. 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 abbreviations used: Me 2 Val = N,N-dimethylvaline, MeVal = N-methylvaline. A. General procedures I. The peptides claimed in claim 1 are either synthesized by classical solution synthesis using standard Z- and Boc- methodology as described above or by standard methods of solid-phase synthesis using Boc and Fmoc protective group techniques. In the case of solid phase synthesis, the N,N-dialkyl- penta- or hexapeptide acids are liberated from the solid support and further coupled with the corresponding C-ter- minal amines in solution. BOP-C1 and PyBrop were used as reagents for coupling of the amino acid following the N- methylamino acids. The reaction times were correspond- ingly increased. For reductive alkylation of the N-termi- nus, the peptide-resin was deprotected at the N terminus and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equiv¬ alents of NaCNBH 3 . After the reaction was complete (nega- tive Kaisertest) the resin was washed several times with water, isopropanol, DMF and dichloro ethane. In solution synthesis, the use of either Boc-protectec. amino acid NCAs (N- ert.-butyloxycarbonyl-amino acid-N- carboxy-anhydrides) , Z-protected amino acid NCAs (N-ben- zyloxycarbonyl-amino acid-N-carboxy-anhydrides) , or the use of pivaloylchloride as condensing agent respectively is most advantageous for coupling of the amino acid fol¬ lowing the N-methylamino acids. Reductive alkylation of the N terminus can e.g. be achieved by reaction of the N-terminally deprotected peptides or amino acids with the corresponding aldehydes or ketones using NaCNBH 3 or hy¬ drogen, Pd/C. II. Purification and characterization of the peptides Purification was carried out by gel chromatcgraphy (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) , me¬ dium pressure chro atography (stationary phase: HD-SIL C-18, 20-45 mikron, 100 Angstrom; mobile phase: gradient with A = 0.1% TFA/ MeOH, B = 0.1% TFA/water) , or prepara ¬ tive HPLC (stationary phase: Waters Delta-Pak C-18, 15 mikron, 100 Angstrom,- mobile phase: gradient with A = 0.1 % TFA/MeOH, B = 0.1 % TFA/water) . 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: acetonitrile-water gradient, buffered with 0.1% TFA, 40°C) . Characterization was by a ino-acid analysis and fast atom bombardment mass spectroscopy. B. Specific procedures EXAMPLE 1 (SEQ ID NO: 1) Me 2 Val-Val-MeVal-Pro-Pro-NHCH(CH 3 ) 2 a) Z-MeVal-Pro-OMe 66.25 g (250 mmol) Z-MeVal-OH were dissolved in 250 ml dry dichloromethane. After addition of 36.41 ml (262.5 mmol) triethylamine, the reaction mixture was cooled to -25° C and 32.27 ml (262.5 mmol) pivaloyl chloride were added. After stirring for 2,5 h, 41.89 g (250 mmol) H-Pro-OMe x HCl in 250 ml dichloromethane, neutralized with 36.41 ml (262.5 mmol) triethylamine at 0°C, were added to the reaction mixture. Stirring continued for 2 h at -25° C and overnight at room temperature. The reaction mixture was diluted with dichloro- rrethane and thoroughly washed with saturated aqueous NaHC0 3 solution (3x) , water (lx) , 5 % citric acid (3x) and saturated NaCl solution. The organic phase was dried over sodium sul- fate and evaporated to dryness. The residue (91.24 g) was stirred with petroleum ether overnight and filtered. 62.3 g of product were obtained. b) H-MeVal-Pro-OMe 48.9 g (130 mmol) Z-MeVal-Pro-OMe were dissolved in 490 ml rr.ethanol. After addition of 10.9 ml (130 mmol) concentrated hydrochloric acid and 2.43 g 10 % Palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 36.43 g of the product. Z-Val-MeVal-Pro-OMe 18.1 g (65 mmol) H-MeVal-Pro-OMe, 21.6 g (78 mmol) Z-Val- N-carboxyanhydride and 22.8 ml (130 mmol) diisopropylethyla- mine were stirred in 110 ml DMF at 40° C for 2 d. After evap¬ oration of DMF, dichloromethane was added and the organic pnase washed with saturated aqueous NaHC0 3 solution (3x) , water (lx) , 5 % citric acid (3x) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evapo¬ rated to dryness. The product (29.3 g) was obtained as a vis¬ cous oil. d) H-Val-MeVal-Pro-OMe 29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml ethanol. After addition of 1.15 g 10 % Palladium/ charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of the product. e) Z-Val-Val-MeVal-Pro-OMe 15.29 g (61 mmol) Z-Val-OH and 21.96 g (61 mmol) H-Val-MeVal- Pro-OMe were dissolved in 610 ml dichloromethane; and cooled to 0°C. After addition of 8.16 ml (73.2 mmol) N-Methylmorpho- line, 2.77 g (20.3 mmol) HOBt and 11.74 g (61 mmol) EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with satu¬ rated aqueous NaHC0 3 solution (3x) , water (lx) , 5 % citric acid (3x) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryr.ess to yield 31.96 g of the product. f) Z-Val-Val-MeVal-Pro-OH 31.96 g (57 mmol) Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml methanol. 102.6 ml of a 1 N LiOH solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml water, the aqueous phase was washed three times with ethyl acetate, adjusted to pH 2 at 0° C and ex ¬ tracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness yielding 30.62 g of the desired product as a white solid. g) Z-Val-Val-MeVal-Pro-Pro-NHCH (CH 3 ) 2 2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.664 g (3.35 mmol) H-Pro-NHCH (CH 3 ) 2 were dissolved in 34 ml of dry dichloromethane. After cooling to 0°C, 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHC0 3 solution (3x) , water (lx) , 5 % citric acid (3x) and saturated NaCl solution (lx) . The organic phase was dried over sodium sulfate and evaporated to dryness to yield 1.96 g of the product which was used in the next reaction without further purification. h) Me 2 Val-Val-MeVal-Pro-Pro-NHCH(CH 3 ) 1.96 g Z-Val-Val-MeVal-Pro-Pro-NHCH(CH 3 ) 2 were dissolved in 11 ml methanol. 0.054 g 10 % Pd/C were added under nitrogen at¬ mosphere and the reaction mixture hydrogenated at room temperature for 4 h. After addition of 0.86 ml (11.24 mmol) of a 37 % aqueous formaldehyde solution and 0.281 g 10 % Pd/C, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 2.77 g of crude product. Further purification was achieved by dissolving the peptide in water, adjusting the pH to 2 and extracting the aqueous phase three times with ethyl acetate. The aqueous phase was then adjusted to pH 8-9 and extracted four times with dichloromethane. The organic phase was dried over sodium sulfate to yield 1.37 g of purified product as a white foam. The compound was further purified using medium pressure liq¬ uid chromatography (10 - 50 % A in 10 min.; 50 - 90 % A in 320 min.) . Fractions containing the product were combined, lyophilized, redissolved in water and the pH adjusted to 9 with 1 N LiOH. After extraction with dichloromethane, the organic phase was dried over sodium sulfate and evaporated to dryness. Lyophilization led to 500 mg of pure product, which was characterized by fast atom bombardment mass spectrometry ( [M+H] + = 593) . EXAMPLE 2 (SEQ ID NO: 1) Me Val-Val-MeVal-Pro-Pro-NHC (CH 3 ) 3 i) Z-Val-Val-MeVal-Pro-Pro-NHC(CH 3 ) 3 2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.692 g (3.35 mmol) H-Pro-NHC (CH 3 ) 3 were dissolved in 34 ml of dry dichloro¬ methane. After cooling to 0°C, 1.35 ml (12.1 mmol) N-methyl- morpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHC0 3 solution (3x) , water (lx) , 5 % citric acid (3x) and saturated NaCl solution (lx) . The organic phase was dried over sodium sulfate and evaporated to dryness to yield 1.8 g of the product which was used in the next reaction without further purification. k) Me 2 Val-Val-MeVal-Pro-Pro-NHC (CH 3 ) 3 1.8 g Z-Val-Val-MeVal-Pro-Pro-NHC (CH 3 ) 3 were dissolved in 10 ml methanol. 0.049 g 10 % Pd/C were added under nitrogen at- 5 osphere and the reaction mixture hydrogenated at room temperature for 4 h. After addition of 0.86 ml (11.24 mmol) of a 37 % aqueous formaldehyde solution and 0.252 g 10 % Pd/C, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 1.82 g of crude 10 product. The compound was further purified using medium pres¬ sure liquid chromatography (10 - 50 % A in 10 min.; 50 - 90 . A in 320 min.). Fractions containing the product were com¬ bined, lyophilized, redissolved in water and the pH adjusted to 9 with 1 N LiOH. After extraction with dichloromethane, 15 the organic phase was dried over sodium sulfate and evapo¬ rated to dryness. Lyophilization led to 547 mg of pure product, which was characterized by fast atom bombardment mass spectrometry ( [M+H] + = 607). 20 The following compounds were prepared or can be prepared accord¬ ing to examples 1 and 2: 3. Xaa Val Xab Pro Xac 4. Xaa Val Xab Pro Xad 25 5. Xaa Val Xab Pro Xae 6. Xaa Val Xab Pro Xaf 7. Xaa Val Xab Pro Xag 8. Xaa Val Xab Pro Xah 9. Xaa Val Xab Pro Xai 30 10. Xaa Val Xab Pro Xak 11. Xaa Val Xab Pro Xal 12. Xaa Val Xab Pro Xam 13. Xaa Val Xab Pro Xan 14. Xaa Val Xab Pro Xao 35 15. Xaa Val Xab Pro Xap 16. Xaa Val Xab Pro Xaq 17. Xaa Val Xab Pro Xar 18. Xaa Val Xab Pro Xas 19. Xaa Val Xab Pro Xat 40 20. Xaa Val Xab Pro Xau 21. Xaa Val Xab Pro Xav 22. Xaa Val Xab Pro Xaw 23. Xaa Val Xab Pro Xax 24. Xdd Val Xab Pro Xay 45 25. Xaa Val Xab Pro Xaz 26. Xaa Val Xab Pro Xba 27. Xaa Val Xab Pro Xbb 28. Xaa Val Xbc Pro Xay 29. Xaa Val Xab Pro Xbd 30. Xaa Val Xab Pro Xbe 31. Xaa Val Xab Pro Xbf 5 32. Xaa Val Xab Pro Xbg 33. Xaa Val Xab Pro Xbh 34. Xaa Val Xab Pro Xbi 35. Xaa Val Xab Pro Xbk 36. Xaa Val Xab Pro Xbl 10 37. Xaa Val Xab Pro Xbm 38. Xaa Val Xab Pro Xbn 39. Xaa Val Xab Pro Xbo 40. Xaa Val Xab Pro Xbp 41. Xaa Val Xab Pro Xbq 15 42. Xaa Val Xab Pro Xbr 43. Xaa Val Xab Pro Xbs 44. Xaa Val Xab Pro Xbt 45. Xaa Val Xab Pro Xbu 46. Xaa Val Xab Pro Xbv 20 47. Xaa Val Xab Pro Xbw 48. Xaa Val Xab Pro Xbx 49. Xaa Val Xab Pro Xby 50. Xaa Val Xab Pro Xbz 51. Xaa Val Xab Pro Xca 25 52. Xaa Val Xab Pro Xcb 53. Xaa Val Xab Pro Xcc 54. Xaa Val Xab Pro Xcd 55. Xaa Val Xab Pro Xce 56. Xaa Val Xab Pro Xcf 30 57. Xaa Xdf Xab Pro Xay 58. Xaa Val Xab Pro Xch 59. Xaa Val Xab Pro Xci 60. Xaa Val Xab Pro Xck 61. Xaa Val Xab Pro Xcl 35 62. Xaa Val Xab Pro Xcm 63. Xaa Val Xab Pro Xcn 64. Xaa Val Xab Pro Xco 65. Xaa Val Xab Pro Xcp 66. Xaa Val Xab Pro Xcq 40 67. Xaa Val Xab Pro Xcr 68. Xaa Val Xab Pro Xcs 69. Xaa Val Xab Pro Xct 70. Xaa Val Xab Pro Xcu 71. xcw Val Xab Pro Xcv 45 72. Xcx Val Xab Pro Xcv 73. Xaa Val Xab Pro Pro Xcy 74. Xaa Val Xab Pro Pro Xcz 75. Xaa Val Xda Pro Xcv 76. Xaa Xdb Xab Pro Xcv 77. Xdc Val Xab Pro Xcv 78. Xaa He Xab Pro Xcv 5 79. Xdd Val Xab Pro Xcv 80. Xde Val Xab Pro Xcv 81. Xaa Xdf Xab Pro Xcv 82. Xaa Val Xab Pro Xcg 83. Xaa Val Xab Pro Pro Xdg 10 84. Xaa Val Xab Pro Pro Xdh 85. Xaa Val Xab Pro Pro Xdi 86. Xaa Val Xab Pro Pro Xdk 87. Xaa Val Xdl Pro Xcv 88. Xde Val Xab Pro Xay 15 89. Xaa Val Xdl Pro Xay 90. Xaa Val Xab Pro Xdm 91. Xaa Val Xab Pro Xdn 92. Xaa Val Xab Pro Xdo 93. Xaa Val Xab Pro Xdp 20 94. Xaa Val Xab Pro Xdq 95. Xaa Val Xab Pro Pro Xdr 96. Xaa Val Xab Pro Xds 97. Xaa Val Xbc Pro Xcv 98. Xaa He Xab Pro Xay 25 99. Xcw Val Xab Pro Xay 100. Xaa Val Xbc Pro Xal 101. Xaa Val Xdl Pro Xal 102. Xaa Xdf Xab Pro Xal 103. Xaa He Xab Pro Xal 30 104. Xdd Val Xab Pro Xal 105. Xde Val Xab Pro Xal 106. Xcx Val Xab Pro Xcy 107. Xcw Val Xab Pro Xal 108. Xcx Val Xab Pro Xal 35 109. Xcw Val Xab Pro Xav 110. Xcx Val Xab Pro Xav 111. Xcw Val Xab Pro Xaw 112. Xcx Val Xab Pro Xaw 113. Xab Val Xab Pro Xay 40 114. Xab Val Xab Pro Xcv 115. Xab Val Xab Pro Xal 116. Xab Val Xab Pro Xam 117. Xab Val Xab Pro Xan 118. Xab Val Xab Pro Xao 45 119. Xab Val Xab Pro Xav 120. Xab Val Xab Pro Xaw 121. Xab Val Xab Pro Xat 122. Xab Val Xab Pro Xau 123. Xab Val Xab Pro Xbf 124. Xab Val Xab Pro Xbm 125. Xab Val Xab Pro Xbn 5 126. Xab Val Xab Pro Xbo 127. Xab Val Xab Pro Xch 128. Xaa Val Xab Pro Xdt 129. Xaa Val Xab Pro Xdu 130. Xaa Val Xab Pro Xdv 10 131. Xaa Val Xab Pro Xdw 132. Xaa Val Xab Pro Xdx 133. Xaa Val Xab Pro Xdy 134. Xaa Val Xab Pro Xdz 135. Xaa Val Xab Pro Xea 15 136. Xaa Val Xab Pro Xeb 137. Xaa Val Xab Pro Xec 138. Xaa Val Xab Pro Xed 139. Xaa Val Xab Pro Xef 140. Xaa Val Xab Pro Xeg 20 141. Xaa Val Xab Pro Xeh 142. Xaa Val Xab Pro Xei 143. Xaa Val Xab Pro Xek 144. Xaa Val Xab Pro Xel 145. Xaa Val Xab Pro Xem 25 146. Xaa Val Xab Pro Xen 147. Xaa Val Xab Pro Xeo 148. Xaa Val Xab Pro Xep 149. Xaa Val Xab Pro Xeq 150. Xaa Val Xab Pro Xer 30 151. Xaa Val Xab Pro Xcg 35 0 5 Examples tor LUC .-id-characterization of the synciie_.___.t__u nuve-i compounds are given in the following table. EXAMPLE Fast atom bombardment MS analy¬ sis . [No.] [Mol. -Weight (measured)] 565 579 593 607 621 635 607 607 621 649 635 635 635 635 621 621 635 635 633 647 661 623 671 667 681 655 655 669 621 635 649 621 633 44. 667 EXAMPLE Fast atom bombardment MS analy¬ sis. 45. 607 46. 647 47. 668 48. 655 49. 669 50. 685 51. 629 52. 625 53. 721 55. 579 58. 623 61. 597 62. 621 63. 609 64. 625 65. 635 66. 591 67. 715 68. 685 69. 685 70. 591 71. 607 72. 621 74. 706 75. 579 76. 579 77. 579 78. 607 79. 607 80. 607 81. 607 82. 637 83. 692 84. 706 85. 706 86. 706 87. 607 90. 635 EXAMPLE Fast atom bombardment MS analy¬ sis. 92. 659 93. 617 5 94. 636 95. 678 128. 671 131. 625 10 1 9 625 151. 637 Table I - Sequence Identification of Compounds Prepared According 15 to Examples 1 and 2 Compound Number (s) Sequence ID Number 1-56, 58-72, 75, 77, 79, 80, 82, 1 87-94, 96, 97, 99-101, 104-151 20 73, 74, 83-86, 95, 2 57, 76, 81, 102 3 78, 98, 103 4 The symbols Xaa in the summary have the following meanings: 25 Xaa: N,N-Dimethylvaline Xab: N-Methylvaline 30 35 40 45 0 0 0 0 0 0 H 3 C O H 3 C 0 CH. 0 H 3 C O CH. Xbc: N-Methyl-isoleucine 0 0 0 O 0 0 H 3 C O 0 0 0 0 XCC: Proline adamantyl (1) amide 0 0 0 OH 0 CH 3 - 0 Xco: O 0 0 Xcw: N-Methyl -N-ethyl-valine Xcx: N,N-Diethyl aline O 0 Xda: N-Metnyι-2-aminobutyroyl Xdb: 2-aminobutyroyl Xde: N,N-Dimethyl-2-aminobutyroyl Xdd: N,N-Dimethy1-2-tert.butylglycine Xde: N,N-Dimethyl-isoleucine Xdf: 2-tert.butylglycine Xdg: H 3 C- -CH. -NH. -CH 3 • N- CH 3 CH 3 χdi: H 3 C- NH ^ ^CH 3 0 CH 3 0 CH 3 Xdl : N-Methyl-2-ter .butylglycine 0 CH 3 0 Cl O CH 3 Cl 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 was measured using a standard methodology for adherent cell lines such as the microculture tetrazolium assay (MTT) . Details of this assay have been published (Alley, MC et al, Cancer Research 48:589-601, 1988) . Exponen¬ tially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor are used to make micro- titer plate cultures. Cells are seeded at 3000 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 vary¬ ing from 10 ~4 M to 10 _1 ° M. Cells are then incubated for 72 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-di- methylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide in sa¬ line) . 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 replicated wells are calculated, using the for¬ mula % T/C (% viable cells treated/control). OD of treated cells x 100 = % τ /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 value. In vivo methodology Compounds of this invention were further tested in pre-clini- cal assay for in vivo activity which is indicative of clini¬ cal utility. Such assays were conducted with nude mice into which tumor tissue, preferably of human origin, had been transplanted (xenografted) , as is well known in this field. Test compounds were evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice. More specifically, human breast tumors (MX-1) which had been grown in athymic nude mice were transplanted into new recipi- ent mice, using tumor fragments which were about 50 mg in size. The day of transplantation was designated as day 0. Six to ten days later, mice were treated with the test compounds given as an intravenous injection or orally, in groups of 5-10 mice at each dose. Compounds were given every other day, for 3 weeks, at doses from 1-200 mg/kg body weignt. Tumor diameters and body weights were measured twice weekly. Tumor volumes were calculated using the diameters measured with Vernier calipers, and the formula (length x width 2 ) /2 = mm 3 of tumor volume Mean tumor volumes are calculated for each treatment group, and T/C values determined for each group relative to the un- treated control tumors. The new compounds possess good tumor inhibiting properties. 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: D-67056 (G) TELEPHONE: 0621/6048526 (H) TELEFAX: 0621/6043123 (I) TELEX: 1762175170 (ii) TITLE OF INVENTION: Novel peptides, the preparation and use chereof (iii) NUMBER OF SEQUENCES: 4 (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 (2) INFORMATION FOR SEQ ID NO: 1: (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: 1: Xaa Val Xaa Pro Xaa (2) INFORMATION FOR SEQ ID NO: 2: (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: 2: Xaa Val Xaa Pro Pro Xaa (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CEARACTERISTICS (A) LENGTH: 5 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Xaa Xaa Xaa Pro Xaa (2) INFORMATION FOR SEQ ID NO: 4: (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: 4: Xaa He Xaa Pro Xaa

Claims: laim: Novel peptides of the formula I R 1 R 2 N-CHX-CO-A-B-D-E- (G) s -K I where R 1 is hydrogen, methyl; or ethyl; P 2 is methyl; or ethyl; or R l -N-R 2 together are a pyrrolidine ring; A is a valyl, isoleucyl, allo-isoleucyl , 2-tert-butyl¬ glycyl, 2-ethylglycyl, norleucyl or norvalyl residue; B is a N-methyl-valyl, N-methyl-norvalyl, N-methyl-leucyl, N-methyl-isoleucyl, N-methyl-2-tert-butylglycyl, N-methyl-2-ethylglycyl or N-methyl-norleucyl residue; D is a prolyl, homoprolyl, hydroxyprolyl, or thiazoli- d ne-4-carbonyl residue; E is a prolyl, homoprolyl, hydroxyprolyl, thiazolid e- 4-carbonyl, trans-4 -fluoro-L-prolyl, cis-4 - fluoro-L prolyl, trans-4 -chloro-L-prolyl or cis-4 -chloro-L-prolyl residue; X is ethyl, propyl, butyl, isopropyl, sec.butyl, tert.butyl, cyclopropyl or cyclopentyl; G is a L-2-tert.butylglycyl, D-2-tert.butylglycyl, D-valyl, D-isoleucyl, D-leucyl, D-norvalyl, 1-ammopentyl-l- carbonyl or 2, 2-dimethylglycyl residue; is -NH-Ci 8 -alkyl, -NH-C 3 θ -alkenyl, -NH-C 3 8 alkmyl, NH-C 6 8 -cycloalkyl, -NH-Cx -alkene-C 3 8 - cycloalkyl , I Ci 4 -alkyl-N-Cχ 6 -alkyl, m which residues one CH group may be replaced by 0 or S, one H by phenyl or cyano, or 1, 2 or 3 H by F, except the N-methoxy-N-methylamino, N-benzylammo, or N-methyl-N-benzylammo residue, or K is 44 and the salts thereof with physiologically tolerated acids 2. Novel peptides of the formula I R_-R 2 N-CHX-CO-A-B-D-E- ( G) s -K where R 1 is hydrogen, methyl; or ethyl; R 2 is methyl; or ethyl; or R I_ N _ R2 together are a pyrrolidine ring; A is a valyl, isoleucyl, allo-isoleucyl, 2-tert-butyl¬ glycyl, 2-ethylglycyl, norleucyl or norvalyl residue; B is a N-methyl-valyl, N-methyl-norvalyl, N-methyl-leucyl, N-methyl-isoleucyl, N-methyl-2-tert-butylglycyl, N-methyl-2-ethylglycyl or N-methyl-norleucyl residue; D is a prolyl, homoprolyl, hydroxyprolyl or thiazoli- dine-4-carbonyl residue; E is a prolyl, homoprolyl, hydroxyprolyl, thiazolidine- 4-carbonyl, trans-4 - fluoro-L-prolyl, cis-4 -fluoro- L-prolyl, trans-4 -chloro-L-prolyl or cis-4 -chloro- L-prolyl residue; X is ethyl, propyl, butyl, isopropyl, sec.butyl, tert.butyl, cyclopropyl, or cyclopentyl; G is a L-2-tert.butylglycyl, D-2-tert.butylglycyl , D-valyl, D-isoleucyl, D-leucyl, D-norvalyl, 1-aminopentyl-l- carbonyl or 2, 2-dimethylglycyl residue; s is 0 or 1; K is -NHCH 3 , -NHCH 2 CH 3 -NH (CH 2 ) 2 CH 3 , -NH (CH 2 ) 3 CH 3 , -NH(CH 2 ) 4 CH 3 , -NH(CH 2 ) 5 CH 3 , -NH (CH 2 ) 6 CH 3 , -NHCH (CH 2 ) 7 CH 3 , -NHCH(CH 3 ) 2 , -NHCH(CH 3 )CH CH 3 , -NHCH (CH 2 CH 3 ) 2 , -NHCH(CH 2 CH 2 CH 3 ) 2 , -NHC(CH 3 ) 3 , -NHCH (CH 2 CH 3 ) CH 2 CH 2 CH 3 , -NHCH(CH 3 )CH(CH3) 2 , -NHCH (CH 2 CH 3 ) CH (CH 3 ) 2 , -NHCH(CH 3 )C(CH 3 ) 3 , -NH-cyclohexyl , -NH-cycloheptyl , -NH-cyclooctyl, - (CH 3 ) 0CH 2 CH 3 , - (CH 3 ) 0CH 2 CH 2 CH 3 , -N(CH 3 )0CH(CH 3 ) 2 , -N(CH 3 )0(CH 2 ) 3 CH 3 , -N (CH 3 ) 0CH 2 C 6 H 5 , -NH(CH 2 ) 2 C 6 H 5, -NH(CH 2 ) 3 C 6 H 5 , -NHCH (CH 3 ) C 6 H 5 , -NHC(CH 3 ) 2 C 6 H 5 , -NHC(CH 3 ) 2 CH 2 CH 3 , -NHC (CH 3 ) (CH 2 CH 3 ) 2 , -NHCH[CH(CH 3 ) 2 ] 2 , -NHC(CH 3 ) 2 CN, -NHCH (CH 3 ) CH (OH) C 6 H 5 , -NHCH 2 -cyclohexyl, -NHCH 2 C (CH 3 ) 3 , -NHCH 2 CH (CH 3 ) 2 , -NHCH 2 CF 3 , -NHCH(CH 2 F) 2 , -NHCH 2 CH 2 F, -NHCH 2 CH 2 OCH 3 , -NHCH 2 CH 2 SCH 3 , -NHCH 2 CHCH , -NH -C (CH 3 ) 2 CH=CH 2 , -NHC(CH 3 ) 2 C≡CH, -NHC(CH 2 CH 3 ) 2 C≡CH, -NHC(CH 3 ) 2 CH 2 CH 2 OH, -NH (CH 2 CH 0) 2 CH 2 CH 3 , -NHC (CH 3 ) 2 CH (CH 3 ) 2 , -NHC(CH 3 ) 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 CH 2 C 6 H 5 , -N (OCH 3 ) CH (CH 3 ) 2 , -N(OCH 3 )CH 2 CH 3 , -N(OCH 3 )CH 2 CH CH 3 , - N (OCH 3 ) CH 2 C 6 H 5 , -N(OCH 3 )C 6 H 5 , -N(CH 3 )OC 6 H 5 , -NHCH [CH (CH 3 ) 2 ] 2 , -N(OCH 3 ) CH 2 CH 2 CH 2 CH 3 , or K is 46 and the salts thereof with physiologically tolerated acids. 3. Novel peptides of the formula I R 1 R 2 N-CHX-CO-A-B-D-E- (G) s -K where R 1 is hydrogen, methyl; or ethyl; R 2 is methyl; or ethyl; A is a valyl, isoleucyl, 2-tert-butylglycyl, 2-ethylglycyl, norleucyl or norvalyl residue; 47 B is a N-methyl-valyl, N-methyl-norvalyl, i. c...^ ___ ^ leucyl, N-methyl-2-tert-butylglycyl, N-methyl-2-ethyl - glycyl or N-methyl-norleucyl residue; D is a prolyl or thiazolidine-4-carbonyl residue; E is a prolyl, homoprolyl, thiazolidine-4-carbonyl, trans-4 -fluoro-L-prolyl, cis-4 -fluoro-L-prolyl, trans-4 -chloro-L-prolyl or cis-4 -chloro-L-prolyl residue; X is ethyl, propyl, isopropyl, sec.butyl, tert.butyl or cyclopropyl; is a L-2-tert.butylglycyl, D-2-tert .butylglycyl, D-valyl, D-isoleucyl, D-leucyl or 2, 2-dimethylglycyl residue; is 0 or 1; is -NH-Cχ- 8 -alkyl, -NH-C 6 - 8 -cycloalkyl, -NH-CH 2 -cyclo- i hexyl, Cι- 4 -alkyl -N -Cχ- 6 -alkyl, in which residues one CH 2 group may be replaced by 0, one H by phenyl or 1 or 2 H by F, except the N-methoxy-N-methylamino, N-benzylamino or N-methyl-N-benzylamino residue, or K is 48 NH CO NH ¬ CH. CH 2 - CH. 4. Novel peptides of the formula I R 1 R 2 N-CHX-CO-A-B-D-E- (G) s -K I where R 1 is methyl; R 2 is methyl; A is a valyl, isoleucyl, 2-tert-butylglycyl or 2-ethyl¬ glycyl; B is a N-methyl-valyl, N-methyl-isoleucyl, N- ethyl-2- tert-butylglycyl, N-methyl-2-ethylglycyl or N-methyl- norleucyl residue; D is a prolyl or thiazolidine-4-carbonyl residue; E is a prolyl, trans- -fluoro-L-prolyl, cis-4 - fluoro-L- prolyl, trans-4 -chloro-L-prolyl or cis-4 -ch]oro-L-proLyl residue; X is ethyl, isopropyl, sec.butyl or tert.butyl; G is a L-2-tert.butylglycyl, D-2-tert.butylglycyl, D-valyl, D-isoleucyl, D-leucyl or 2, 2 -dimethylglycyl residue; s is 0 or 1; K is -NH-Cχ- 8 -alkyl, -NH-C 6 . 8 -cycloalkyl, -NH-CH 2 -cyclo- i hexyl, Cι- 4 -alkyl-N -Cι-6-alkyl, in which residues one CH 2 group may be replaced by 0, one H by phenyl or 1 or 2 H by F, except the N-methoxy-N-methylamino, N-benzylammo or N-methyl-N-benzylamino residue, or K is CO - NH ¬ CH-; CH- CH 3 or CH Novel peptides of the formula I R 1 R 2 N-CHX-CO-A-B-D-E- (G) S -K where R 1 is methyl; R 2 is methyl; A is a valyl, isoleucyl or 2-tert-butylglycyl residue; B is a N-methyl-valyl, N-methyl-isoleucyl or N-methyl- 2-tert-butylglycyl residue; D is a prolyl or thiazolidine-4-carbonyl residue; E is a prolyl, cis-4 -fluoro-L-prolyl or cis-4-chloro-L-pro- lyl residue; is isopropyl, sec.butyl or tert.butyl? is 0; is -NHC(CH 3 ) 3 , -NHCH(CH CH 2 )CH(CH ) 2 , -NHCH (CH 3 ) C (CH 3 ) . , -N(CH 3 )OCH CH 3 , -N(CH 3 )OCH 2 CH 2 CH 3 , -N (CH 3 ) OCH (CH 3 ) 2 , -N(CH 3 )0(CH 2 ) 3 CH 3 , -N(CH 3 )OCH 2 C 6 H 5 , -NHC (CH 3 ) ; C 6 H 5 , -NHC(CH 3 ) 2 CH 2 CH 3 , -NHC (CH 3 ) (CH 2 CH 3 ) 2 , -NHCH [CH (CH 3 ) 2 ] 2 , -NHC(CH 3 ) 2 CN, -NHCH(CH 3 )CH(OH)C 6 H 5 , -NH-C (CH 3 ) 2 CH=CH 2 , -NHC (CH 3 ) 2 C=CH, -NHC(CH 2 CH 3 ) 2 C__=CH, NHC (CH 3 ) 2 CH 2 CH 2 OH , -NHC(CH 3 ) 2 CH(CH 3 ) 2 , -NHC (CH 3 ) 2 CH 2 CH 2 CH 3 , -NHC ,CH 3 ) 2 CH 2 C 6 H 5 , -N(OCH 3 )CH(CH 3 ) 2 , -N(OCH 3 )CH 2 CH 3 , -N (OCH 3 ) CH 2 CH 2 CH 3 , -N(OCH 3 )CH 2 C 6 H 5 , -N(OCH 3 )C 6 H 5 , -N (CH 3 ) OC 6 H 5 , -N (OCH 3 ) CH 2 CH 2 CH 2 CH 3 , or Kis -NH CO NH CH 2 CH : CH and the salts thereof with physiologically tolerated acids. 6. Novel peptides of the formula I R 1 R 2 N-CHX-CO-A-B-D-E- (G) s -K where R 3 is methyl R 2 is methyl; is a valyl residue; is a N-methyl-valyl residue; D is a prolyl residue; is a prolyl residue; is isopropyl; is 0; is -NHC(CH 3 ) 3 , -NHCH(CH 2 CH )CH(CH 3 ) 2 , -NHCH (CH 3 ) C (CH 3 ) 3 , -N(CH 3 )OCH 2 CH 3 , -N(CH 3 )OCH 2 CH 2 CH 3 , - N (CH 3 ) OCH (CH 3 ) 2 , -N(CH 3 )0(CH 2 ) 3 CH 3 , -N(CH 3 )OCH 2 C 6 H 5 , -NHC (CH 3 ) 2 C 6 H 5 , -NHC(CH 3 ) 2 CH 2 CH 3 , -NHC (CH 3 ) (CH 2 CH 3 ) 2 , -NHCH [CH (CH 3 ) 2 ] 2 , -NHC(CH 3 ) 2 CN, -NHCH(CH 3 )CH(OH)C 6 H 5 , -NH- C (CH 3 ) 2 CH=CH 2 , -NHC(CH 3 ) 2 C≡≡CH, -NHC(CH 2 CH 3 ) 2 C_≡CH, NHC (CH 3 ) 2 CH 2 CH 2 OH, -NHC(CH 3 ) 2 CH(CH 3 ) , -NHC (CH 3 ) 2 CH 2 CH CH 3 , -NHC (CH 3 ) 2 CH 2 C 6 H 5 , -N(OCH 3 )CH(CH 3 ) 2 , -N(OCH 3 )CH 2 CH 3 , -N (OCH 3 ) CH 2 CH 2 CH 3 , -N(OCH 3 )CH C 6 H 5 , -N(OCH 3 )C 6 H 5 , -N (CH 3 ) OC 6 H 5 , - N ( 0CH 3 ) CH 2 CH 2 CH 2 CH 3 , or K is -NH CO NH CH 2 - CH- CH 3 and the salts thereof with physiologically tolerated acids. 7. Novel peptides of the formula I R 1 R 2 N-CHX-CO-A-B-D-E- (G) s -K I where R 1 is methyl; R 2 is methyl; A is a valyl, isoleucyl or 2-tert-butylglycyl residue; B is a N-methyl-valyl, N-methyl-isoleucyl or N-methyl-2- tert-butylglycyl residue; D is a prolyl or thiazolidine-4-carbonyl residue; E is a prolyl residue; X is isopropyl, sec.butyl or tert.butyl; G is a D-2-tert.butylglycyl, D-isoleucyl, 2 , 2 -dimethyl - glycyl residue, D-valyl or L-2 -ter .butylglycyl; s is 1; K is -NHCH 3 , -NHCH 2 CH 3 , -NH (CH 2 ) 2 CH 3 , -NH (CH 2 ) 3 CH 3 , -NH(CH 2 ) 4 CH 3 , -NH(CH 2 ) 5 CH 3 , -NHCH(CH 3 ) 2 , -NHCH(CH 3 ) CH 2 CH 3 , -NHCH(CH 2 CH 3 ) 2 , -NHC(CH 3 ) 3 , -NH-cyclohexyl, -NHC (CH 3 ) 2 C! ., -NCH(CH 3 ) 2 C≡CH or -NHC (CH 3 ) 2 CONH 2 ; or Kis and the salts thereof with physiologically tolerated acids. 8. Compounds of formula I or salts thereof for use in treating diseases. 9. The method or preparing compounds of formula I according to claim 1 characterized in that they are prepared according to known methods of peptide chemistry.

Inventors: AMBERG WILHELM, BARLOZZARI TERESA, BERNARD HARALD, BUSCHMANN ERNST, HAUPT ANDREAS, HEGE HANS-GUENTHER, JANSSEN BERND, KLING ANDREAS, LIETZ HELMUT, RITTER KURT, ULLRICH MARTINA, WEYMANN JUERGEN, ZIERKE THOMAS, AMBERG, WILHELM, BARLOZZARI, TERESA, BERNARD, HARALD, BUSCHMANN, ERNST, HAUPT, ANDREAS, HEGE, HANS-GUENTHER, JANSSEN, BERND, KLING, ANDREAS, LIETZ, HELMUT, RITTER, KURT, ULLRICH, MARTINA, WEYMANN, JUERGEN, ZIERKE, THOMAS
Applicants: AMBERG WILHELM, BARLOZZARI TERESA, BASF AG, BERNARD HARALD, BUSCHMANN ERNST, HAUPT ANDREAS, HEGE HANS GUENTHER, JANSSEN BERND, KLING ANDREAS, LIETZ HELMUT, RITTER KURT, ULLRICH MARTINA, WEYMANN JUERGEN, ZIERKE THOMAS, AMBERG, WILHELM, BARLOZZARI, TERESA, BASF AKTIENGESELLSCHAFT, BERNARD, HARALD, BUSCHMANN, ERNST, HAUPT, ANDREAS, HEGE, HANS-GUENTHER, JANSSEN, BERND, KLING, ANDREAS, LIETZ, HELMUT, RITTER, KURT, ULLRICH, MARTINA, WEYMANN, JUERGEN, ZIERKE, THOMAS
Application year: 1996
Main classification: C07K7
IPC codes: A61K31, A61K38, A61P35, C07K1, C07K7