Antitumor peptides

Abstract

Novel compounds of the formulaR.sup.1 R.sup.2 N--CHX-CO-A-B-D-(E).sub.s -(F).sub.t -(G).sub.U -KIin which R.sup.1, R.sup.2, A, B, D, E, F, G, K, X, s, t, and u have the meanings stated in the description, and the preparation thereof are described. The novel substances have an antineoplastic effect.

Description

BACKGROUND OF THE INVENTION

It is known that peptides isolated from marine origin like Dolastatin-10 (U.S. Pat. No. 4,816,444) and Dolastatin-15 (EP-A-398558) show potent cell growth inhibitory activity (cf.: Biochem. Pharmacology 40, no. 8, 1859-64, 1990); J. Natl. Cancer Inst. 85, 483-88, 1993 and references cited therein). Based upon interesting results in experimental tumor systems in vivo, further preclinical evaluation of these natural products is currently under way in order to initiate clinical studies in cancer patients. However, the natural products have disadvantages, such as poor solubility in aqueous solvents and costly building blocks needed for synthesis. The invention described herein provides novel peptides and derivatives thereof which offer improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatin-10 and Dolastatin-15. Furthermore, the compounds of this invention may be conveniently synthesized as described in detail below.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of this invention include novel peptides of the formula I

R.sup.1 R.sup.2 N--CHX--CO--A--B--D--(E).sub.s --(F).sub.t --(G).sub.U --KI where R.sup.1 is alkoxy, preferably C.sub.1 -C.sub.4 ; alkyl, preferably C.sub.1-7 ; cycloalkyl, preferably C.sub.3-6 ; alkylsulfonyl, preferably C.sub.1-6 ; fluoroalkyl, preferably fluoroethyl, difluoroethyl, fluoroisopropyl, trifluoroisopropyl; aminosulfonyl which may be substituted by alkyl, preferably C.sub.1-5 ; hydroxy; or benzyl which may be substituted by up to three substitutents independently selected from alkyl (preferably C.sub.1-4), alkoxy (preferably C.sub.1-4), nitro, halogen and CF.sub.3 ; R.sup.2 is hydrogen; alkyl, preferably C.sub.1-4; fluoroalkyl, preferably fluoroethyl, difluoroethyl, fluoroisopropyl, trifluoroisopropyl; or cycloalkyl, preferably C.sub.3--7 ; R.sup.1 --N-R.sup.2 together may be a 5- or 6-membered heterocycle which may be unsubstituted or substituted with one or more substitutents independently selected from alkyl (preferably C.sub.1-4), N(CH.sub.3).sub.2, nitro, CONH.sub.2 and COOEt; A is a valyl, isoleucyl, leucyl, allo-isoleucyl, 2,2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl or norvalyl residue; B is a N-alkyl-valyl, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -2-ethylglycyl, -2-cyclopentylglycyl, -2-cyclopentylglycyl, norleucyl or -2-cyclohexylglycyl residue where N-alkyl is preferably N-methyl or N-ethyl; D is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue; E is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue; F and G are independently selected from the group consisting of prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl -1-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydroisoquinolyl -2-carbonyl, 3-thiazolylalanyl, 3-thienylalanyl, histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, tryptophanyl, glycyl, alanyl, .beta.-alanyl and 3-naphthylalanyl residues; x is hydrogen, alkyl (preferably C.sub.1-5), cycloalkyl (preferablyl C.sub.3-7), --CH.sub.2 -cyclohexyl or arylalkyl (preferably benzyl or phenethyl); s, t and u are independently 0 or 1; and K is hydroxy, alkoxy (preferably C.sub.1-4), phenoxy, benzyloxy or a substituted or unsubstituted amino moiety; and the salts thereof with physiologically tolerated acids.

This invention also provides methods for preparing the compounds of formula I, pharmaceutical compositions containing such compounds together with a pharmaceutically acceptable carrier and methods for using same for treating cancer in mammals.

One subclass of compounds of this invention includes compounds of formula I wherein R.sup.1 --N--R.sup.2 is a pyrrolidinyl or piperidinyl residue which may be unsubstituted or substituted with one or more substituents which may independently be selected from alkyl (preferably C.sub.1-4), N(CH.sub.3).sub.2, nitro, oxo, CONH.sub.2 and COOEt;

Another subclass of compounds of this invention includes compounds of formula I wherein K is an amino moiety of the formula R.sup.5 --N--R.sup.6 wherein

R.sup.5 is hydrogen, or hydroxy, or C.sub.1-7 alkoxy, or benzyloxy (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, phenoxy, benzoxy, halogen, C.sub.1-4 -alkyl, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or phenyloxy (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, phenoxy, benzoxy, halogen, C.sub.1-4 -alkyl, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or C.sub.1-12 -alkyl (which may be substituted by one or more fluoro atoms), or C.sub.3-7 -cycloalkyl, or benzyl (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, phenoxy, benzoxy, halogen, C.sub.1-4 -alkyl, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2); R.sup.6 is hydrogen, or C.sub.1-12 alkyl (which may be substituted by one or more fluoro atoms), or --(CH.sub.2).sub.v ,--C.sub.3-7 -cycloalkyl (v=0,1,2, or 3), or norephedryl, or norpseudoephedryl, or quinolyl, or pyrazyl, or --CH.sub.2 -benzimidazolyl, or adamantyl, or --CH.sub.2 -adamantyl, or alpha-methyl-benzyl, or alpha-dimethylbenzyl, or --(CH.sub.2).sub.v,-phenyl (v=0,1,2,or 3; which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, phenoxy, benzoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or --(CH.sub.2).sub.m -naphthyl (m=0 or 1; which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or --(CH.sub.2).sub.w -benzhydryl (w=0,1, or 2; which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or biphenyl (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or pyridyl (which may be substituted by up to two substitutents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH.sub.2), or picolyl (which may be substituted by up to two substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH.sub.2), or --CH.sub.2 --CH.sub.2 -pyridyl (which may be substituted by up to two substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH.sub.2), or benzothiazolyl (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or benzoisothiazolyl (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or benzopyrazolyl (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or benzoxazolyl (which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or --(CH.sub.2).sub.m -fluorenyl (m=0 or 1; which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or pyrimidyl (which may be substituted by up to two substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or --(CH.sub.2).sub.m,-indanyl (m=0 or 1; which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C1-4-alkyl which may form a cyclic system, cyano, hydroxy, N(CH.sub.3).sub.2, COOMe, COOEt, COOiPr, or COONH.sub.2), or --(CH.sub.2 CH.sub.2 O).sub.y --CH.sub.3 (y=0,1,2,3,4, or 5), or --(CH.sub.2 CH.sub.2 O).sub.y --CH.sub.2 CH.sub.3 (y=0,1,2,3,4, or 5), or --NH--C.sub.6 H.sub.5 (which may be substituted by up to two substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH.sub.2), or --NCH.sub.3 --C.sub.6 H.sub.5 (which may be substituted by up to two substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH.sub.2), or --NH--CH.sub.2 --C.sub.6 H.sub.5 (which may be substituted by up to two substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH.sub.2), or --NCH.sub.3 --CH.sub.2 --C.sub.6 H.sub.5 (which may be substituted by up to two substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, halogen, C.sub.1-4 -alkyl which may form a cyclic system, cyano, hydroxy, COOMe, COOEt, COOiPr, or COONH.sub.2), or 5-membered heteroaryl which may be substituted by up to three substituents which may independently be CF.sub.3, nitro, C.sub.1-7 alkylsulfonyl, C.sub.1-4 alkoxy, thiomethyl, thioethyl, picolyl, acetyl, C.sub.3-6 -cycloalkyl, thiophenyl, --CH.sub.2 --COOEt, C.sub.3-4 -alkylen group forming a bicyclic system with the heterocycle, phenyl (which may be substituted by up to three substituents which may independently be nitro, CF.sub.3, CN, halogen, or C.sub.1-4 -alkyl), benzyl (which may be substituted by up to three substituents which may independently be nitro, CF.sub.3, halogen, C.sub.1-4 -alkyl, C.sub.1-7 -alkylsulfonyl, cyano, hydroxy, C.sub.1-4 -dialkylamino), or --CHR.sup.7 -5-membered heteroaryl (which may be substituted by up to two subsituents which may independently be CF.sub.3, nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH.sub.2, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, phenyl, benzyl, naphthyl, or C.sub.1-7 -alkylsulfonyl �R.sup.7 =hydrogen, linear or branched C.sub.1-5 alkyl, benzyl; or R.sup.7 and R.sup.5 together form a group --(CH.sub.2).sub.3 --or --(CH.sub.2).sub.4 --!).

This subclass includes compounds of formula I wherein s, t and u are independently 0 or 1; R.sup.1, R.sup.2 and X are lower alkyl, A is a lower alkyl amino acid, B is a N-loweralkylated lower alkyl amino acid; D,E,F,G and K are as previously defined. With the foregoing in mind, three sets of such compounds can thus be depicted by the following formulas II, III, and IV:

R.sup.1 R.sup.2 N-CXH-CO-A-B-Pro-Pro-F-G-K II R.sup.1 R.sup.2 N-CXH-CO-A-B-Pro-Pro-F-K III R.sup.1 R.sup.2 N-CXH-CO-A-B-Pro-Pro-K IV --CHR.sup.7 -5-membered heteroaryl may for example be represented by one of the following residues: ##STR1## --NR.sup.5 CHR.sup.7 --5-membered heteroaryl may for example be represented by the following residues: ##STR2## 5-membered heteroaryl may for example be represented by the following residues: ##STR3##

In another subclass of compounds of this invention R.sup.5 --N--R.sup.6 together may form structures selected from the group consisting of ##STR4## which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of CF.sub.3, nitro, halogen, oxo, cyano, formyl, N,N-dimethylamino, C.sub.1-6 -alkyl, C.sub.3-6 -cycloalkyl, C.sub.3-4 -alkylen group forming a bicyclic system with the heterocycle, C.sub.1-4 -alkoxy, phenoxy, benzoxy, naphthyl, pyrimidyl, COOEt, pyrrolidinyl, piperidinyl, thienyl, pyrrolyl, CH.sub.2 --CO--NCH(CH.sub.3).sub.2, --CH.sub.2 --CO--N(CH.sub.2).sub.4, --CH.sub.2 --CO--N(CH2).sub.4 0, benzyl (which may be substituted by up to three substituents independently selected from the group consisting of nitro, halogen, CF.sub.3, thiomethyl or the corresponding sulfoxide or sulfone, thioethyl or the corresponding sulfoxide or sulfone, C.sub.1-4 -alkyl, and C.sub.1-4 -alkoxy).

Still another subclass of compounds of this invention includes for example compounds of formula I wherein s, t and u are 1 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.

Yet another subclass of compounds of this invention includes for example compounds of formula I wherein s and t are 1, u is 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.

Another subclass of compounds of this invention includes for example compounds of formula I wherein s is 1, t and u are 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.

These examples illustrate but do not limit the scope of the present 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, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.

The novel compounds can be prepared by known methods 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 fragment coupling it is possible to link together fragments of different lengths, and the fragments in turn can be obtained by sequential 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. Enzymatic 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 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 (activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC ), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis(2-oxo-3-oxazolldinyl)-amidophosphoryl chloride (BOP-Cl), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), 0-benzotriazolyl-N,N,N', N'-tetramethyluronium salts (HBTU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and 1,1'-carbonyldiimidazole (CDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), Azabenzotriazole, N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

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 conventional protective group techniques are preferred for the chemical peptide synthesis: the benzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques. Identified in each case is the protective group on the 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, Stuttgart, 1974. The units employed for assembling the peptide chain can be reacted in solution, in suspension or by a method similar to that described by Merrifield in J. Amer. Chem. Soc. 85 (1963) 2149. Particularly preferred methods are those in which peptides are assembled sequentially or by fragment coupling using the Z, Boc or Fmoc protective group technique, with one of the reactants in the said Merrifield technique being bonded to an insoluble polymeric support (also called resin hereinafter). This typically entails the peptide being assembled sequentially on the polymeric support using the Boc or Fmoc protective group technique, the growing peptide chain being covalently bonded at the C terminus to the insoluble resin particles (cf. FIG. 1 and 2). This procedure makes it possible to remove reagents and byproducts by filtration, and thus recrystallization of intermediates is unnecessary.

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 protected 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 polystyrene, chloromethylated styrene/divinylbenzene copolymer (Merrifield resin), 4-methylbenzhydrylamine resin (MBHA-resin), phenylacetamidomethyl-resin (Pam-resin), p-benzyloxy-benzyl-alcohol-resin, benzhydryl-amine-resin (BHA-resin), 4-(hydroxymethyl)-benzoyloxy-methyl-resin, the resin of Breipohl et al. (Tetrahedron 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), acetonitrile, 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 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, especially cleavage in liquid anhydrous hydrogen fluoride, in anhydrous trifluormoethanesulfonic acid, in dilute or concentrated trifluoroacetic 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 mixtures. 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.sub.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 commercially-available materials using methods known in the art. For example, amino acids building blocks with R.sub.1 and R.sub.2 moieties can be prepared according to E. Wuensch, Houben Weyl, Meth. d. Org. Chemie, Bd. XV, 1, p. 306 following, Thieme Verlag Stuttgart 1974 and Literature cited therein. Peptides with gamma- or delta-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-, oxazol-, 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 otherwise treat solid tumors (e.g. tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g. leukemias, lymphomas) by administration of the compound to the mammal. 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 pharmaceutical compositions containing a compound of formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical compositions may be combination products, i.e., may also contain other therapeutically active ingredients.

The dosage to be administered to the mammal will contain an effective tumor-inhibiting amount of active ingredient which will depend upon conventional factors including the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be about 0.05 to 100 milligrams per kilogram of body weight, preferably 0.1 to 10 milligrams, on oral administration and about 0.01 to 100 milligrams per kilogram of body weight, preferably 0.05 to 50 milligrams, 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 conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. 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=trifluoroacetic acid, Ac=acetic acid, Bu=butyl, Et=ethyl, Me=methyl, Bzl=benzyl, Nal=3-naphthylalanine, Cha=3-cyclohexylalanine, Npg=neopentylglycine, Abu=2-amino butyryl, Dab=2,4-diaminobutyryl. iPr=isopropyl.

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 on a completely automatic model 431A synthesizer supplied 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______________________________________1. 30% trifluoroacetic acid in DCM 1 .times. 3 min2. 50% trifluoroacetic acid in DCM 1 .times. 1 min3. DCM washing 5 .times. 1 min4. 5% diisopropylethylamine in DCM 1 .times. 1 min5. 5% diisopropylethylamine in NMP 1 .times. 1 min6. NMP washing 5 .times. 1 min7. Addition of preactivated protected amino acid (DCC and 1 equivalent of HOBt in NMP/DCM); Peptide coupling (1st part) 1 .times. 30 min8. Addition of DMSO to the reaction mixture until it contains 20% DMSO by volume Peptide coupling (2nd part) 1 .times. 16 min9. Addition of 3.8 equivalents of diisopropylethylamine to the reaction mixture Peptide coupling (3rd part) 1 .times. 7 min10. DCM washing 3 .times. 1 min11. if conversion is incomplete, repetition of coupling (back to 6.)12. 10% acetic anhydride, 5% diisopropylethylamine in DCM 1 .times. 2 min13. 10% acetic anhydride in DCM 1 .times. 4 min14. DCM washing 4 .times. 1 min15. back to 1.______________________________________

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

______________________________________b) Synthetic cycle for the Fmoc protective group technique______________________________________1. DMF washing 1 .times. 1 min2. 20% piperidine in DMF 1 .times. 4 min3. 20% piperidine in DMF 1 .times. 16 min4. DMF washing 5 .times. 1 min5. Addition of the preactivated protected amino acid (activation by 1 equivalent of TBTU and 5 equivalents of DIPEA in DMF); Peptide coupling 1 .times. 61 min6. DMF washing 3 .times. 1 min7. if conversion is incomplete, repetition of coupling (back to 5.)8. 10% acetic anhydride in DMF 1 .times. 8 min9. DMF washing 3 .times. 1 min10. 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 AIa or AIb was deprotected at the N terminus (steps 2-4 in AIb or 1-6 in AIa) 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.sub.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 Ia and II

The peptide-resin was dried under reduced pressure and transferred 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 ethanedithiol (0.5 ml/g of resin), was followed by condensing in hydrogen fluoride (10 ml/g of resin) while cooling with liquid N.sub.2. The mixture was left to warm to 0.degree. C. and stirred at this temperature for 45 min. The hydrogen fluoride was then stripped off under reduced pressure, and the residue was washed with ethyl acetate in order to remove remaining scavenger. The peptide was extracted with 30% acetic acid and filtered, and the filtrate was lyophilized.

IV. Work-up of the peptide-resins obtained as in Ib and II

The peptide-resin was dried under reduced pressure and then subjected to one of the following cleavage procedures, depending on the amino-acid composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985).

Cleavage conditions:

______________________________________TFA Scavenger Reaction time______________________________________1. 95% 5% water 1.5 h2. 95% 5% ethanethiol/ 1.5 h anisol (1:3)______________________________________

The suspension of the peptide-resin in the suitable TFA mixture was stirred at room temperature for the stated time and then the resin was filtered off and washed with TFA and DCM. The filtrate and the washings were concentrated, and the peptide was precipitated by addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered off, taken up in 30% acetic acid and lyophilized.

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

Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) with or without subsequent medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 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 l, 300 A; mobile phase: acetonitrile-water gradient, buffered with 0.1% TFA, 40.degree. C.).

Characterization was by amino-acid analysis and fast atom bombardment mass spectroscopy.

B. Specific procedures

EXAMPLE 1

(SEQ ID NO: 1)

N,N-Dimethyl-Val-Val-N-methyl-Val-Pro-Pro-Val-Phe-NH.sub.2

1.98 g of Fmoc-RINK-resin (substitution 0.46 mmol/g), corresponding to a batch size of 0.84 mmol, were reacted as in AIb with 1.26 mmol each of

Fmoc-Phe-OH Fmoc-Val-OH Fmoc-Pro-OH Fmoc-Pro-OH Fmoc-N-methyl-Val-OH Fmoc-Val-OH Fmoc-Val-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 AIb), and was further reacted with aqueous formaldehyde solution as in AII and then dried under reduced 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 1 can also be prepared via classical solution phase methodology. The synthesis of N,N-Dimethyl-Val-Val-N-Methyl-Val-Pro-Pro-Val-Phe-NH.sub.2 and its various intermediates is described in the following paragraph.

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.degree. 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.times.HCl in 250 ml dichloromethane, neutralized with 36.41 ml (262.5 mmol) triethylamine at 0.degree. C., were added to the reaction mixture. Stirring continued for 2 h at -25.degree. C. and overnight at room temperature. The reaction mixture was diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO.sub.3 solution (3.times.), water (1.times.), 5% citric acid (3.times.) and saturated NaCl solution. The organic phase was dried over sodium sulfate 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 methanol. 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.

c) 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) diisopropylethylamine were stirred in 110 ml DMF at 40.degree. C. for 2 d. After evaporation of DMF, dichloromethane was added and the organic phase washed with saturated aqueous NaHCO.sub.3 solution (3.times.), water (1.times.), 5% citric acid (3.times.) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness. The product (29.3 g) was obtained as a viscous oil.

d) H-Val-MeVal-Pro-OMe

29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml methanol. 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.degree. C. After addition of 8.16 ml (73.2 mmol) N-Methylmorpholine, 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 saturated aqueous NaHCO.sub.3 solution (3.times.), water (1.times.), 5% citric acid (3.times.) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness 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.degree. C. and extracted 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-Val-Phe-NH.sub.2

25 g (43.3 mmol) Z-Val-Val-MeVal-Pro-OH and 15.59 g (43.3 mmol) H-Pro-Val-Phe-NH.sub.2 were suspended in 430 ml of dry dichloromethane. After cooling to 0.degree. C., 5.81 ml (52 mmol) N-methylmorpholine, 1.97 g (15 mmol) HOBt and 8.33 g (43.3 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. The solvents were evaporated, the residue dissolved in 640 ml dichloromethane and thoroughly washed with saturated aqueous NaHCO.sub.3 solution (4.times.), water (1.times.), 5% citric acid (3.times.) and saturated NaCl solution. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 33.04 g of the product. The crude product was chromatographed on a silica gel column with 20% MeOH/Hexane. 18.32 g of the desired product were obtained.

h) N,N-Dimethyl-Val-Val-MeVal-Pro-Pro-Val-Phe-NH.sub.2

18.32 g Z-Val-Val-MeVal-Pro-Pro-Val-Phe-NH.sub.2 were dissolved in 80 ml methanol. 0.4 g 10% Pd/C were added under nitrogen atmosphere and the reaction mixture hydrogenated at room temperature for 4 h. After addition of 6.22 ml (81.24 mmol) of a 37% aqueous formaldehyde solution, hydrogenation was continued for 5 h. Filtration and evaporation of the solvent gave rise to 15.6 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 ethyl acetate. The organic phase was washed with water and dried over sodium sulfate to yield 11.3 g of purified product as a white powder. The compound was characterized by fast atom bombardment mass spectrometry (�M+H!.sup.+ =797).

EXAMPLE 2

(SEQ ID NO: 2)

N,N-Dimethyl-Val-Val-N-Me-Val-Pro-{1-�thiazol-(2)-yl!-2-phenyl}-ethylamide

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 AIb 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 increased reaction times. After the synthesis was complete, the peptide-resin underwent N-terminal deprotection (steps 2-4 in AIb), and was further reacted with aqueous formaldehyde solution as in AII and then dried under reduced pressure. The resin obtained in this way was subjected to TFA cleavage as in AIV. The crude product (750 mg) was employed directly for the next coupling. 100 mg of this compound were reacted with 45 mg of (S)-2-�l-amino-2-phenylethyl! thiazole and 230 mg of PyBop with the addition of 192 mikroL of DIPEA in DMF at room temperature for 2 d. The reaction mixture was purified by gel chromatography (Sephadex LH-20, methanol) and the product fractions were combined. 83 mg of product were obtained.

The following compounds were prepared and can be prepared according to examples 1 and 2:

3. Xaa Val Xan Pro Pro Val Phe 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.sub.2 9. Xbo Val Xan Pro Pro Val Phe NH.sub.2 10. Xaa Val Xan Pro Pro Val Xag NH.sub.2 11. Xaa Val Xan Pro Pro Val Xah 12. Xaa Xbe Xan Pro Pro Val Trp NH.sub.2 13. Xaa Val Xan Pro Pro Xai Phe NH.sub.2 14. Xae Val Xan Pro Pro Ile Phe NH.sub.2 15. Xaa Val Xan Pro Xal Val Phe NH.sub.2 16. Xaa Val Xan Pro Xak Val Phe NH.sub.2 17. Xaa Val Xan Xak Pro Val Phe NH.sub.2 18. Xaa Val Xan Xal Pro Val Phe NH.sub.2 19. Xaa Val Xao Pro Pro Val Phe NH.sub.2 20. Xaa Val Xam Pro Pro Val Phe NH.sub.2 21. Xaa Xap Pro Pro Val Phe NH.sub.2 22. Xaa Xaq Pro Pro Val Phe NH.sub.2 23. Xaa Ile Xan Pro Pro Val Phe NH.sub.2 24. Xaa Xai Xan Pro Pro Val Phe NH.sub.2 25. Xaa Leu Xan Pro Pro Val Phe NH.sub.2 26. Xar Val Xan Pro Pro Val Phe NH.sub.2 27. Xas Val Xan Pro Pro Val Phe NH.sub.2 28. Xat Val Xan Pro Pro Val Phe NH.sub.2 29. Xau Val Xan Pro Xal Val Phe NH.sub.2 30. Xav Val Xan Pro Pro Val Phe NH.sub.2 31. Xan Val Xan Pro Pro Val Phe NH.sub.2 32. Xaw Val Xan Pro Pro Val Phe NH.sub.2 33. Xax Vai Xan Pro Pro Val Phe NH.sub.2 34. Xaa Val Xan Pro Pro Phe Phe NH.sub.2 35. Xaz Val Xan Pro Pro Val Phe NH.sub.2 36. Xba Val Xan Pro Pro Val Phe NH.sub.2 37. Xaa Val Xan Pro Pro Val NH.sub.2 38. Xaa Val Xan Pro Xbb 39. Xaa Val Xan Pro Xbc 40. Xaa Val Xan Pro Pro Xbd 41. Xax Val Xan Pro Pro Val NH.sub.2 42. Xaw Val Xan Pro Pro Val NH.sub.2 43. Xat Val Xan Pro Pro Val NH.sub.2 44. Xaa Xai Xan Pro Pro Val NH.sub.2 45. Xaa Val Xan Pro Pro Xal NH.sub.2 46. Xaa Val Xan Xak Pro Val NH.sub.2 47. Xaa Val Xan Pro Xak Val NH.sub.2 48. Xaa Val Xan Pro Pro Val 49. Xav Val Xan Pro Pro Val NH.sub.2 50. Xaa Val Xan Pro Pro NH.sub.2 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 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 61. Xaa Val Xan Xbn 62. Xax Val Xan Pro Pro NH.sub.2 63. Xaw Val Xan Pro Pro NH.sub.2 64. Xbo Val Xan Pro Pro NH.sub.2 65. Xat Val Xan Pro Pro NH.sub.2 66. Xaa Xai Xan Pro Pro NH.sub.2 67. Xat Xai Xan Pro Pro NH.sub.2 68. Xaa Xap Pro Pro NH.sub.2 69. Xaa Xaq Pro Pro NH.sub.2 70. Xav Val Xan Pro Pro NH.sub.2 71. Xaa Xap Pro NH.sub.2 72. Xaa Xaq Pro NH.sub.2 73. Xaa Val Xan Pro 74. Xaa Val Xbp 75. Xaa Val Xbq 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 83. Xax Val Xan Pro NH.sub.2 84. Xbo Val Xan Pro NH.sub.2 85. Xav Val Xan Pro NH.sub.2 86. Xaa Val Xan Pro Xbn 87. Xaa Val Xan Pro Xbg 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 93. Xaa Val Xan Pro Xbx 94. Xaa Xbe Xan Pro Pro NH.sub.2 95. Xby Val Xan Pro Pro Val Phe NH.sub.2 96. Xed Val Xan Pro Pro Val Phe NH.sub.2 97. Xee Val Xan Pro Pro Val Phe NH.sub.2 98. Xef Val Xan Pro Pro Val Phe NH.sub.2 99. Xbz Val Xan Pro Pro Val Phe NH.sub.2 100. Xeg Val Xan Pro Pro Val Phe NH.sub.2 101. Xca Val Xan Pro Pro Val Phe NH.sub.2 102. Xcb Val Xan Pro Pro Val Phe NH.sub.2 103. Xcb Val Xao Pro Pro Val Phe NH.sub.2 104. Xcc Val Xan Pro Pro Val Phe NH.sub.2 105. Xce Val Xan Pro Pro Val Phe NH.sub.2 107. Xcg Val Xan Pro Pro Val Phe NH.sub.2 108. Xch Val Xan Pro Pro Val Phe NH.sub.2 109. Xci Val Xan Pro Pro Val Phe NH.sub.2 110. Xck Val Xan Pro Pro Val Phe NH.sub.2 111. Xcl Val Xan Pro Pro Val Phe NH.sub.2 112. Xcm Val Xan Pro Pro Val Phe NH.sub.2 113. Xcn Val Xan Pro Pro Val Phe NH.sub.2 114. Xhn Val Xan Pro Pro Val Phe NH.sub.2 115. Xho Val Xan Pro Pro Val Phe NH.sub.2 116. Xhp Val Xan Pro Pro Val Phe NH.sub.2 117. Xhq Val Xan Pro Pro Val Phe NH.sub.2 118. Xby Val Xan Pro Pro Val NH.sub.2 119. Xed Val Xan Pro Pro Val NH.sub.2 120. Xee Val Xan Pro Pro Val NH.sub.2 121. Xef Val Xan Pro Pro Val NH.sub.2 122. Xbz Val Xan Pro Pro Val NH.sub.2 123. Xeg Val Xan Pro Pro Val NH.sub.2 124. Xca Val Xan Pro Pro Val NH.sub.2 125. Xcb Val Xan Pro Pro Val NH.sub.2 126. Xcc Val Xan Pro Pro Val NH.sub.2 127. Xce Val Xan Pro Pro Val NH.sub.2 128. Xcs Val Xan Pro Pro Val NH.sub.2 129. Xch Val Xan Pro Pro Val NH.sub.2 130. Xci Val Xan Pro Pro Val NH.sub.2 131. Xck Val Xan Pro Pro Val NH.sub.2 132. Xcl Val Xan Pro Pro Val NH.sub.2 133. Xcm Val Xan Pro Pro Val NH.sub.2 134. Xcn Val Xan Pro Pro Val NH.sub.2 135. Xhn Val Xan Pro Pro Val NH.sub.2 136. Xho Val Xan Pro Pro Val NH.sub.2 137. Xhp Val Xan Pro Pro Val NH.sub.2 138. Xhq Val Xan Pro Pro Val NH.sub.2 139. Xby Val Xan Pro Pro NH.sub.2 140. Xed Val Xan Pro Pro NH.sub.2 141. Xee Val Xan Pro Pro NH.sub.2 142. Xef Val Xan Pro Pro NH.sub.2 143. Xbz Val Xan Pro Pro NH.sub.2 144. Xeg Val Xan Pro Pro NH.sub.2 145. Xca Val Xan Pro Pro NH.sub.2 146. Xcb Val Xan Pro Pro NH.sub.2 147. Xcc Val Xan Pro Pro NH.sub.2 148. Xce Val Xan Pro Pro NH.sub.2 149. Xcg Val Xan Pro Pro NH.sub.2 150. Xch Val Xan Pro Pro NH.sub.2 151. Xci Val Xan Pro Pro NH.sub.2 152. Xck Val Xan Pro Pro NH.sub.2 153. Xcl Val Xan Pro Pro NH.sub.2 154. Xcm Val Xan Pro Pro NH.sub.2 155. Xcn Val Xan Pro Pro NH.sub.2 156. Xhn Val Xan Pro Pro NH.sub.2 157. Xho Val Xan Pro Pro NH.sub.2 158. Xhp Val Xan Pro Pro NH.sub.2 159. Xhq Val Xan Pro Pro NH.sub.2 160. Xaa Val Xan Pro Pro Val Xei 161. Xaa Val Xan Pro Pro Val Xem 162. Xaa Val Xan Pro Pro Val Xeo 153. Xaa Val Xan Pro Pro Val Xep 164. Xaa Val Xan Pro Pro Val Xeq 165. Xaa Val Xan Pro Pro Val Xex 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 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 178. Xaa Val Xan Pro Pro Val Xgh 179. Xaa Val Xan Pro Pro Val Xgl 180. Xaa Val Xan Pro Pro Val Xgl 181. Xaa Val Xan Pro Pro Val Xgs 182. Xaa Val Xan Pro Pro Val Xgv 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 Xhc 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 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 198. 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 Xfl 203. Xaa Val Xan Pro Pro Xfs 204. Xaa Val Xan Pro Pro Xfz 205. Xaa Val Xan Pro Pro Xgc 206. Xaa Val Xan Pro Pro Xgf 207. Xaa Val Xan Pro Pro Xgm 208. 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 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 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 225. Xaa Val Xan Pro Xfg 225. Xaa Val Xan Pro Xfl 227. Xaa Val Xan Pro Xfk 228. Xaa Val Xan Pro Xfm 229. Xaa Val Xan Pro Xfn 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 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 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 245. Xaa Val Xan Pro Xgz 246. Xaa Val Xan Pro Xhm 247. Xaa Xco Pro Pro Val Phe NH.sub.2 248. Xaa Xcp Pro Pro Val Phe NH.sub.2 249. Xaa Xcq Pro Pro Val Phe NH.sub.2 250. Xaa Xcr Pro Pro Val Phe NH.sub.2 251. Xaa Xcs Pro Pro Val Phe NH.sub.2 252. Xaa Xct Pro Pro Val Phe NH.sub.2 253. Xaa Xcu Pro Pro Val Phe NH.sub.2 254. Xaa Xcw Pro Pro Val Phe NH.sub.2 255. Xaa Xcv Pro Pro Val Phe NH.sub.2 256. Xaa Xcx Pro Pro Val Phe NH.sub.2 257. Xaa Xcy Pro Pro Val Phe NH.sub.2 258. Xaa Xda Pro Pro Val Phe NH.sub.2 259. Xaa Xdb Pro Pro Val Phe NH.sub.2 260. Xaa Xdc Pro Pro Val Phe NH.sub.2 261. Xaa Xdd Pro Pro Val Phe NH.sub.2 262. Xaa Xdf Pro Pro Val Phe NH.sub.2 263. Xaa Xdg Pro Pro Val Phe NH.sub.2 264. Xaa Xdh Pro Pro Val Phe NH.sub.2 265. Xaa Xco Pro Pro Val NH.sub.2 266. Xaa Xcp Pro Pro Val NH.sub.2 267. Xaa Xcq Pro Pro Val NH.sub.2 268. Xaa Xcr Pro Pro Val NH.sub.2 269. Xaa Xcs Pro Pro Val NH.sub.2 270. Xaa Xct Pro Pro Val NH.sub.2 271. Xaa Xcu Pro Pro Val NH.sub.2 272. Xaa Xcw Pro Pro Val NH.sub.2 273. Xaa Xcv Pro Pro Val NH.sub.2 274. Xaa Xcx Pro Pro Val NH.sub.2 275. Xaa Xcy Pro Pro Val NH.sub.2 276. Xaa Xcz Pro Pro Val NH.sub.2 277. Xaa Xda Pro Pro Val NH.sub.2 278. Xaa Xdb Pro Pro Val NH.sub.2 279. Xaa Xdc Pro Pro Val NH.sub.2 280. Xaa Xde Pro Pro Val NH.sub.2 281. Xaa Xdf Pro Pro Val NH.sub.2 282. Xaa Xdg Pro Pro Val NH.sub.2 283. Xaa Xdh Pro Pro Val NH.sub.2 284. Xaa Xco Pro Pro NH.sub.2 285. Xaa Xcp Pro Pro NH.sub.2 286. Xaa Xcq Pro Pro NH.sub.2 287. Xaa Xcr Pro Pro NH.sub.2 288. Xaa Xcs Pro Pro NH.sub.2 289. Xaa Xct Pro Pro NH.sub.2 290. Xaa Xcu Pro Pro NH.sub.2 291. Xaa Xcw Pro Pro NH.sub.2 292. Xaa Xcv Pro Pro NH.sub.2 293. Xaa Xcx Pro Pro NH.sub.2 294. Xaa Xcy Pro Pro NH.sub.2 295. Xaa Xcz Pro Pro NH.sub.2 296. Xaa Xda Pro Pro NH.sub.2 297. Xaa Xdb Pro Pro NH.sub.2 298. Xaa Xdc Pro Pro NH.sub.2 299. Xaa Xdd Pro Pro NH.sub.2 300. Xaa Xdf Pro Pro NH.sub.2 301. Xaa Xdg Pro Pro NH.sub.2 302. Xaa Xdh Pro Pro NH.sub.2 303. Xds Xan Pro Pro Val Phe NH.sub.2 304. Xdt Xan Pro Pro Val Phe NH.sub.2 305. Xdu Xan Pro Pro Val Phe NH.sub.2 306. Xdv Xan Pro Pro Val Phe NH.sub.2 307. Xdw Xan Pro Pro Val Phe NH.sub.2 308. Xdx Xan Pro Pro Val Phe NH.sub.2 309. Xdy Xan Pro Pro Val Phe NH.sub.2 310. Xdz Xan Pro Pro Val Phe NH.sub.2 311. Xea Xan Pro Pro Val Phe NH.sub.2 312. Xeb Xan Pro Pro Val Phe NH.sub.2 313. Xec Xan Pro Pro Val Phe NH.sub.2 314. Xds Xan Pro Pro Val NH.sub.2 315. Xdt xan Pro Pro Val NH.sub.2 316. Xdu Xan Pro Pro Val NH.sub.2 317. Xdv Xan Pro Pro Val NH.sub.2 318. Xdw Xan Pro Pro Val NH.sub.2 319. Xdx Xan Pro Pro Val NH.sub.2 320. Xdy Xan Pro Pro Val NH.sub.2 321. Xdz Xan Pro Pro Val NH.sub.2 322. Xea Xan Pro Pro Val NH.sub.2 323. Xeb Xan Pro Pro Val NH.sub.2 324. Xed Xan Pro Pro Val NH.sub.2 325. Xds Xan Pro Pro NH.sub.2 326. Xdt Xan Pro Pro NH.sub.2 327. Xdu Xan Pro Pro NH.sub.2 328. Xdv Xan Pro Pro NH.sub.2 329. Xdw Xan Pro Pro NH.sub.2 330. Xdx Xan Pro Pro NH.sub.2 331. Xdy Xan Pro Pro NH.sub.2 332. Xdz Xan Pro Pro NH.sub.2 333. Xea Xan Pro Pro NH.sub.2 334. Xeb Xan Pro Pro NH.sub.2 335. Xec Xan Pro Pro NH.sub.2 336. Xds Val Pro Pro Val Phe NH.sub.2 337. Xds Val Pro Pro NH.sub.2 338. Xdv Val Pro Pro NH.sub.2 339. Xds Xan Pro Xfy 340. Xdv Xan Pro Xfy 341. Xaa Val Xhf Pro Pro Val Phe NH.sub.2 342. Xaa Val Xhg Pro Pro Val Phe NH.sub.2 343. Xaa Val Xhh Pro Pro Val Phe NH.sub.2 344. Xaa Val Xhf Pro Pro Val NH.sub.2 345. Xaa Val Xhg Pro Pro Val NH.sub.2 346. Xaa Val Xhh Pro Pro Val NH.sub.2 347. Xaa Val Xhf Pro Pro NH.sub.2 348. Xaa Val Xhg Pro Pro NH.sub.2 349. Xaa Val Xhh Pro Pro NH.sub.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 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 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.sub.2 364. Xaa Val Xan Pro Xdq Phe NH.sub.2 365. Xaa Val Xan Pro Xdr Phe NH.sub.2 366. Xaa Val Xan Pro Xdp NH.sub.2 367. Xaa val Xan Pro Xdq NH.sub.2 368. Xaa Val Xan Pro Xdr NH.sub.2 369. Xaa Val Xan Pro Pro Xdi NH.sub.2 370. Xaa Val Xan Pro Pro Xcs NH.sub.2 371. Xaa Val Xan Pro Pro Xct NH.sub.2 372. Xaa Val Xan Pro Pro Xcu NH.sub.2 373. Xaa Xcs Pro Pro Xdi NH.sub.2 374. Xaa Xct Pro Pro Xdi NH.sub.2 375. Xaa Xcs Pro Xdp Phe NH.sub.2 376. Xaa Xct Pro Xdp Phe NH.sub.2 377. Xaa Xcs Pro Xdp NH.sub.2 378. Xaa Xct Pro Xdp NH.sub.2 379. Xaa Xcs Pro Xdq NH.sub.2 380. Xaa Xct Pro Xdq NH.sub.2 381. Xaa Xcs Pro Xdr NH.sub.2 382. Xaa Xct Pro Xdr NH.sub.2 383. Xaa Val Xan Pro Pro Xdi NH.sub.2 384. Xaa Val Xan Pro Pro Xdk NH.sub.2 385. Xaa Val Xan Pro Pro Xdl NH.sub.2 386. Xaa Val Xan Pro Pro Xdm NH.sub.2 387. Xaa Val Xan Pro Pro Xdn NH.sub.2 388. Xaa Val Xan Pro Pro Xdo NH.sub.2 389. Xca Val Xan Pro Pro Phe Phe NH.sub.2 390. Xby Val Xan Pro Pro Phe Phe NH.sub.2 391. Xca Val Xan Pro Pro Phe Phe NH.sub.2 392. Xef Val Xhf Pro Pro Xai Phe NH.sub.2 393. Xef Val Xhf Pro Pro Xai Xah NH.sub.2 394. Xef Val Xhf Pro Pro Xai Xag NH.sub.2 395. Xef Val Xan Pro Xfy 396. Xef Val Xan Pro Xbg 397. Xef Val Xan Pro Xbh 398. Xef Val Xan Pro Xgn 399. Xca Xct Pro Xfy 400. Xaa Xai Xan Pro Pro Val Phe NH.sub.2 401. Xaa Leu Xan Pro Pro Val Phe NH.sub.2 402. Xaa Ile Xan Pro Pro Val Phe NH.sub.2 403. Xaa Val Xan Pro Pro Xai Phe NH.sub.2 404. Xaa Val Xan Pro Pro Leu Phe NH.sub.2 405. Xaa Val Xan Pro Pro Ile Phe NH.sub.2 406. Xaa Val Xan Pro Pro Val Dab NH.sub.2 407. Xaa Val Xan Pro Pro Val Ala NH.sub.2 408. Xaa Dab Xan Pro Pro Val Phe NH.sub.2 409. Xaa Xab Xan Pro Pro Val NH.sub.2 410. Xaa Dab Xan Pro Pro NH.sub.2 411. Xht Val Xan Pro Pro Val Phe NH.sub.2 412. Xhu Val Xan Pro Pro Val Phe NH.sub.2 413. Xht Val Xan Pro Pro Val NH.sub.2 413. (a). Xhu Val Xan Pro Pro Val NH.sub.2 414. Xht Val Xan Pro Pro NH.sub.2 415. Xhu Val Xan Pro Pro NH.sub.2 416. Xaa Val Xhy Pro Pro Val Phe NH.sub.2 417. Xaa Val Xhz Pro Pro Val Phe NH.sub.2 418. Xaa Val Xhy Pro Pro Val NH.sub.2 419. Xaa Val Xhz Pro Pro Val NH.sub.2 420. Xaa Val Xhy Pro Pro NH.sub.2 421. Xaa Leu Xhz Pro Pro NH.sub.2 422. Xaa Val Xhy Xfy 423. Xaa Val Xhz Xfy 424. Xhv Val Xan Pro Pro Val Phe NH.sub.2 425. Xhw Val Xan Pro Pro Val Phe NH.sub.2 426. Xhx Val Xan Pro Pro Val Phe NH.sub.2 427. Xhv Val Xan Pro Pro Val NH.sub.2 428. Xhw Val Xan Pro Pro Val NH.sub.2 429. Xhx Val Xan Pro Pro Val NH.sub.2 430. Xhv Val Xan Pro Pro NH.sub.2 431. Xhw Val Xan Pro Pro NH.sub.2 432. Xhx Val Xan Pro Pro NH.sub.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 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 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 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 Xld 452. Xed Val Xan Pro Xie 453. Xby Leu Xan Pro Xia 454. Xby Leu Xan Pro Xib 455. Xby Ile Xan Pro Xic 455. Xby Ile Xan Pro Xid 457. Xby Leu Xan Pro Xie 458. Xca Leu Xan Pro Xia 459. Xca Val Xao Pro Xib 460. Xca Val Xao Pro Xic 461. Xat Val Xhf Pro Xak Leu Phe NH.sub.2 462. Xat Val Xhf Pro Xhr Leu Phe NH.sub.2 463. Xed Val Xhf Pro Xak Leu Phe NH.sub.2 464. Xed Val Xhf Pro Xhr Leu Phe NH.sub.2 465. Xat Val Xhf Pro Xak Val NH.sub.2 466. xat Val Xhf Pro Xhr Val NH.sub.2 467. Xed Val Xhf Pro Xak Val NH.sub.2 468. Xed Val Xhf Pro Xhr Val NH.sub.2 469. Xat Val Xhf Pro Xak NH.sub.2 470. Xat Val Xhf Pro Xhr NH.sub.2 471. Xed Val Xhf Pro Xak NH.sub.2 472. Xat Val Xhf Pro Xia 473. Xat Val Xhf Pro Xib 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.sub.2 478. Xed Val Xhf Pro Xhs NH.sub.2 479. 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 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 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 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 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 Xlf 504. Xaa Val Xan Pro Xig 505. Xca Val Xan Pro Pro Xif 506. Xca Val Xan Pro Xlg 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 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 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.sub.2 520. Xaa Lys Xan Pro Pro Val NH.sub.2 521. Xaa Lys Xan Pro Pro NH.sub.2 522. Xaa Lys Xan Pro Xfy 523. Xaa Xih Xan Pro Pro Val NH.sub.2 524. Xaa Xih Xan Pro Pro NH.sub.2 525. Xaa Xih Xan Pro Pro Val Phe NH.sub.2 525. Xaa Val Xii Pro Pro Val Phe NH.sub.2 527. Xaa Val Xii Pro Pro Val NH.sub.2 528. Xaa Val Xii Pro Pro NH.sub.2 529. Xaa Val Xan Pro Pro Val Lys NH.sub.2 530. Xaa Val Xan Pro Xik 531. Xaa Val Xan Pro Pro Xil NH.sub.2 532. Xaa Val Xbu 533. Xby Val Xbu 534. Xca Val Xbu 535. Xaa Val Xbv 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.sub.2 541. Xin Val Xan Pro Pro Val Phe NH.sub.2 542. Xio Val Xan Pro Pro Val Phe NH.sub.2 543. Xip Val Xan Pro Pro Val Phe NH.sub.2 544. Xiq Val Xan Pro Pro Val Phe NH.sub.2 545. Xkd Val Xan Pro Pro Val Phe NH.sub.2 546. Xim Val Xan Pro Pro Val NH.sub.2 547. Xin Val Xan Pro Pro Val NH.sub.2 548. Xio Val Xan Pro Pro Val NH.sub.2 549. Xip Val Xan Pro Pro Val NH.sub.2 550. Xiq Val Xan Pro Pro Val NH.sub.2 551. Xkd Val Xan Pro Pro Val NH.sub.2 552. Xim Val Xan Pro Pro NH.sub.2 553. Xin Val Xan Pro Pro NH.sub.2 554. Xio Val Xan Pro Pro NH.sub.2 555. Xip Val Xan Pro Pro NH.sub.2 556. Xiq Val Xan Pro Pro NH.sub.2 557. Xkd Val Xan Pro Pro NH.sub.2 558. 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 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 568. Xaa Val Xan Pro Xkb 569. Xaa Val Xan Pro Xkc 570. Xke Val Xan Pro Pro Val Phe NH.sub.2 571. Xkf Val Xan Pro Pro Val Phe NH.sub.2 572. Xkg Val Xan Pro Pro Val Phe NH.sub.2 573. Xkh Val Xan Pro Pro Val Phe NH.sub.2 574. Xke Val Xan Pro Pro Val NH.sub.2 575. Xkf Val Xan Pro Pro Val NH.sub.2 576. Xkg Val Xan Pro Pro Val NH.sub.2 577. Xkh Val Xan Pro Pro Val NH.sub.2 578. Xke Val Xan Pro Pro NH.sub.2 579. Xkf Val Xan Pro Pro NH.sub.2 580. Xkg Val Xan Pro Pro NH.sub.2 581. Xkh Val Xan Pro Pro NH.sub.2 582. Xaa Xcz Pro Pro Val Phe NH.sub.2 583. Xed Val Xhf Pro Xhr NH.sub.2 584. Val Val Xan Pro Pro Val Phe 585. Xaa Val Xan Pro Pro Val 586. Xaa Val Xki Pro Pro Val Phe NH.sub.2 587. Xaa Val Xan Pro Pro Val Xhz NH.sub.2 588. Xaa Val Xan Pro Pro Val Xah NH.sub.2 589. Xaa Val Xan Pro Pro Val Tyr NH.sub.2 590. Xaa Val Xan Pro Pro Phe Phe NH.sub.2 591. Xaa Val Xan Pro Pro Val Xkj NH.sub.2 592. Xaa Val Xan Xbb 593. Xaa Val Xan Pro Pro Xab 594. Xaa Val Xan Xfp 595. Xaa Val Xan Xbg 596. Xaa Val Xan Xbx 597. Xaa Val Xan Pro Xbg 598. Xaa Val Xan Pro Pro Ile NH.sub.2 599. Xaa Val Xan Pro Pro Leu NH.sub.2 600. Xaa Val Xan Pro Pro Xlv NH.sub.2 601. Xaa Val Xan Xfo 602. Xaa Val Xan Pro Pro Xlw Phe NH.sub.2 603. Xaa Val Xan Pro Pro Xlx Phe NH.sub.2 604. Xaa Val Xan Pro Pro Val Xlw NH.sub.2 605. Xaa Val Xan Pro Xkr 606. Xar Val Xan Pro Xfy 607. Xat Xai Xan Pro Xfy 608. Xaa Val Xan Pro Pro Val Xlv NH.sub.2 609. Xaa Val Xan Pro Xkc 610. Xaa Val Xan Pro Xbm 611. Xaa Val Xan Pro Xka 612. Xaa Val Xan Pro Xks 613. Xaa Val Xan Pro Xiz 614. Xaa Val Xan Pro Xbk 615. Xaa Val Xan Pro Xen 616. Xaa Val Xan Pro Xhi 617. Xaa Val Xan Pro Xbh 618. Xaa Val Xan Pro Xfd 619. Xaa Val Xan Pro Xgn 620. Xbo Val Xan Pro Xfy 621. Xat Val Xan Pro Xfy 622. Xas Val Xan Pro Xfy 623. Xaa Val Xam Pro Xfy 624. Xcl Val Xan Pro Xfy 625. Xci Val Xan Pro Xfy 626. Xaa Val Xhz Pro Xfy 627. Xaa Val Xan Pro Xkt 628. Xaa Val Xan Pro Xku 629. Xaa Val Xan Pro Xkv 630. Xaa Val Xan Pro Xkw 631. Xaa Val Xhh Pro Xfy 632. Xaa Ile Xan Pro Xfy 633. Xaa Val Xan Xak Xfy 634. Xaa Val Xan Pro Xkb 635. Xat Val Xan Pro Xbg 636. Xar Val Xan Pro Xbg 637. Xar Val Xam Pro Xfy 638. Xaa Val Xan Pro Pro Xga 639. Xaa Val Xan Pro Xkx 640. Xaa Val Xan Pro Pro Leu Phe NH.sub.2 641. Xaa Val Xan Pro Pro Ile Phe NH.sub.2 642. Xaa Val Xan Pro Xky 643. Xaa Val Xan Pro Xkz 644. Xaa Val Xan Pro Xfr 645. Xaa Val Xam Pro Pro NH.sub.2 646. Xaa Val Xan Pro Xla 647. Xaa Val Xan Pro Xlb 648. Xaa Val Xan Pro Xlc 649. Xaa Val Xan Pro Xld 650. Xaa Val Xan Pro Xkk 651. Xaa Val Xan Pro Xek 652. Xaa Val Xan Pro Xle 653. Xaa Val Xan Pro Xlf 654. Xaa Val Xan Pro Xlg 655. Xaa Val Xan Pro Xkl 656. Xaa Val Xan Pro Xlh 657. Xkm Val Xan Pro Xfy 658. Xaa Val Xan Pro Xli 659. Xaa Val Xan Pro Xlk 660. Xkn Val Xan Pro Xfy 661. Xaa Val Xan Pro Xll 662. Xaa Val Xan Pro Xlm 663. Xaa Val Xan Pro Xfk 664. Xaa Xma Xan Pro Xfy 665. Xaa Val Xhg Pro Xfy 666. Xaa Val Xhy Pro Xfy 667. Xaa Val Xan Pro Xln 668. Xaa Xai Xan Pro Xfy 669. Xaa Val Xao Pro Xfy 670. Xaa Val Xan Pro Xlo 671. Xaa Val Xan Pro Xko 672. Xaa Val Xan Pro Xkp 673. Xaa Val Xan Pro Xlp 674. Xaa Val Xan Pro Xlq 675. Xaa Val Xan Pro Pro Xlr 676. Xaa Val Xhf Pro Xfy 677. Xaa Val Xan Pro Xls 678. Xaa Val Xan Pro Xlt 679. Xby Val Xan Pro Xfy 680. Xkq Val Xan Pro Xfy 681. Xaa Val Xan Pro Xlu

Examples for the MS-characterization of the synthesized novel compounds are given in the following table.

______________________________________EXAMPLE Fast atom bombardment MS analysis.�No.! �Mol.-Weight (measured)!______________________________________3. 79816. 81019. 81220. 81223. 81225. 81226. 81228. 81130. 82533. 88134. 84537. 64938. 73750. 55051. 55152. 73156. 55065. 56666. 56687. 63593. 704101. 853204. 740214. 619215. 845227. 649230. 691233. 717234. 641239. 579246. 595347. 566349. 566351. 669352. 656357. 669403. 811404. 812405. 812597. 635598. 665699. 665600. 749601. 594602. 852603. 826604. 804605. 677606. 655607. 670608. 848609. 608610. 627611. 565612. 633613. 642614. 642615. 731616. 657617. 647618. 648619. 663620. 669621. 655622. 655623. 655624. 681625. 667626. 689627. 565628. 579629. 593630. 594631. 659632. 655633. 655634. 580635. 648636. 648637. 669638. 788639. 647640. 812641. 812642. 668643. 709644. 717645. 566646. 684647. 657648. 684649. 634650. 630651. 619652. 699653. 608654. 655655. 680656. 590657. 670658. 655659. 669660. 627661. 607662. 621663. 649664. 627665. 669666. 695667. 628668. 655669. 655670. 607671. 646672. 660673. 685674. 628675. 754676. 656677. 635678. 621679. 669680. 656681. 667______________________________________ TABLE I______________________________________Sequence Identification of Compounds PreparedAccording to Examples 1 and 2Compound Number(s) Sequence ID Number______________________________________3, 9, 26-28, 30-33, 35, 36, 195-117, 341-343, 416, 417,424-426, 526, 540-545, 570-573, 58638, 39, 52, 86-91, 93, 214-246, 2350-362, 366-368, 395-398,433-452, 459, 460, 469-478,504, 506, 508, 510, 530,566-569, 583, 597, 606, 607, 609-611,613-626, 631, 633-637, 644, 650,651, 654, 655, 657, 660, 663, 665,666, 669, 671, 672, 676, 679, 680605, 612, 627, 628-630, 639, 642, 643,645-649, 652, 653, 656, 658, 659, 661,662, 667, 670, 673, 674, 677, 678, 6814-7, 10, 11, 160-188, 406, 558-561, 587, 3588, 591, 604, 6088 412 513, 392, 403, 602, 603 614, 641 715, 16, 29 817, 18 919, 20 1021, 22, 247-264, 303-313, 582 1123, 402 1224, 400 1325, 401 1434, 590 1537, 118-138, 344-346, 585 1640, 45, 189-213, 369-372, 383-388, 17503, 505, 507, 509, 531, 538, 563-565,593, 600, 638, 67541-43, 48, 49, 527 1844 1946, 50, 51, 62-65, 70, 139-159, 347-349 20414, 415, 420, 421, 430-432, 528,552-557, 578-58147 2153-61, 78, 422, 423, 539, 592, 594-596 2260166, 67, 94, 410, 524 2368, 69, 284-302, 325-335 2473, 83-85 2592, 664, 668 26265-283, 314-324 27336 28337, 338 29339, 340, 377-382, 399 30363-365 31373, 374 32375, 376 33389-391 34393, 394 35404, 640 36405 37407 38408 39409 40411, 412, 418, 419, 427-429, 41546-551, 574-577413, 413(a), 453, 454, 457, 42458, 512 514, 516, 518455, 456, 632 43465-468 44461-464 45479-502 46515, 517 47513 48519 49520 50521 51522 52523 53525 54529 55584 56589 57598 58599 59______________________________________

The symbols Xaa . . . in the summary have the following meanings: ##STR5##

The ending --NH.sub.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 activity 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). Exponentially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor are used to make microtiter plate cultures. Cells are seeded at 5000-20,000 cells per well in 96-well plates (in 150 .mu.l of media), and grown overnight at 370.degree. C. Test compounds are added, in 10-fold dilutions varying from 10.sup.-4 M to 10.sup.-10 M. Cells are then incubated for 48 hours. To determine the number of viable cells in each well, the MTT dye is added (50 .mu.l of 3 mg/ml solution of 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide in saline). This mixture is incubated at 370.degree. C. for 5 hours, and then 50 .mu.l 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 formula % T/C (% viable cells treated/control). ##EQU1## The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC.sub.50 value. The following results were obtained:

______________________________________COMPOUND OF EXAMPLE IC.sub.50 �M!______________________________________14 3 .times. 10.sup.-719 8 .times. 10.sup.-520 2 .times. 10.sup.-921 >10.sup.-423 2 .times. 10.sup.-525 2 .times. 10.sup.-426 6 .times. 10.sup.-827 5 .times. 10.sup.-629 >10.sup.-430 >10.sup.-452 5 .times. 10.sup.-555 2 .times. 10.sup.-656 4 .times. 10.sup.-757 4 .times. 10.sup.-658 10.sup.-562 3 .times. 10.sup.-565 4 .times. 10.sup.-766 2 .times. 10.sup.-768 6 .times. 10.sup.-773 2 .times. 10.sup.-586 10.sup.-787 4 .times. 10.sup.-888 2 .times. 10.sup.-993 5 .times. 10.sup.-994 >10.sup.-495 5 .times. 10.sup.-7102 10.sup.-4146 2 .times. 10.sup.-5157 2 .times. 10.sup.-4204 4 .times. 10.sup.-9214 10.sup.-9215 3 .times. 10.sup.-9227 10.sup.-8230 10.sup.-9233 10.sup.-9234 .sup. 3 .times. 10.sup.-10238 6 .times. 10.sup.-7239 6 .times. 10.sup.-8241 >10.sup.-6246 10.sup.-8247 >10.sup.-4284 6 .times. 10.sup.-7339 >10.sup.-6340 >10.sup.-6347 3 .times. 10.sup.-7349 6 .times. 10.sup.-7351 7 .times. 10.sup.-8352 2 .times. 10.sup.-8357 8 .times. 10.sup.-9361 >10.sup.-6400 2 .times. 10.sup.-4404 4 .times. 10.sup.-7405 3 .times. 10.sup.-7411 >10.sup.-5417 2 .times. 10.sup.-5521 >10.sup.-4______________________________________

Further compounds of this invention were assayed for anti-cancer activity by the crystal violet assay for cytotoxicity.

This assay was performed according to the method described by Flick H. and Gifford, G. E., J. Immunol. Meth. 68, 167-175 (1984). Proteins of surviving adherent cells are stained after exposure to a cytotoxic drug and quantitated calorimetrically. Test cells (CX-I; colon carcinoma, human) were plated in 96 flat bottom microtiter plates at a density of 2-3.times.10.sup.3 cells/well and incubated under standard culture conditions (RPMI 1640 with 10% fetal calf serum and 1% non-essential amino acids) at 37.degree. C. and 5% CO.sub.2 for one day. The cells were then exposed to several concentrations of the test compound. Controls were incubated in medium alone. After a further incubation period of 72 h, the culture medium was removed by flicking and 50 .mu.l of a crystal violet staining solution were added to each well. After a staining period of 20 min, the staining solution was removed and the plates were washed vigorously with water until all unbound dye was removed. The remaining insoluble dye crystals were dissolved by adding 100 .mu.l of a solution containing 50% ethanol and 0.1% acetic acid to each well. The absorbance of each well was determined using an ELISA microtiter plate reader at 540 nm (Titertec Multiscan, Flow Lab., Meckenheim).

The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC.sub.50. The following results were obtained:

______________________________________COMPOUND OF EXAMPLE IC.sub.50 �M!______________________________________1 9 .times. 10.sup.-82 4 .times. 10.sup.-83 6 .times. 10.sup.-78 5 .times. 10.sup.-69 4 .times. 10.sup.-810 6 .times. 10.sup.-813 2 .times. 10.sup.-716 9 .times. 10.sup.-728 3 .times. 10.sup.-831 10.sup.-533 2 .times. 10.sup.-534 4 .times. 10.sup.-836 2 .times. 10.sup.-537 4 .times. 10.sup.-738 .sup. 3 .times. 10.sup.-1048 4 .times. 10.sup.-750 2 .times. 10.sup.-751 5 .times. 10.sup.-759 8 .times. 10.sup.-6101 2 .times. 10.sup.-4406 4 .times. 10.sup.-7407 9 .times. 10.sup.-7408 2 .times. 10.sup.-6538 10.sup.-10______________________________________ B. In vivo methodology

Compounds of this invention were further tested in pre-clinical assay for in vivo activity which is indicative of clinical 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 recipient 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, in groups of 5-10 mice at each dose. Compounds were given every other day, for 3 weeks, at doses from 1-100 mg/kg body weight. Tumor diameters and body weights were measured twice weekly. Tumor volumes were calculated using the diameters measured with Vernier calipers, and the formula

(length.times.width.sup.2)/2=mm.sup.3 of tumor volume

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

In the second example as shown in FIG. 2., mice were treated with compound example #234, at 25 mg/kg 3 times a week for 3 weeks. All tumors in the treated group disappeared, while the control tumors grew so large the mice were sacrificed. No regrowth of the tumor was observed in the treated mice.

Representative Compounds Tested in Vivo

Additional compounds were also tested in the MX-1 model as described above. Compounds were administered i.v. Compounds which had good activity in the MX-1 model were also tested in additional in vivo models.

______________________________________EXAMPLE ACTIVITY* COMMENTS______________________________________2 + tumor growth delay37 ++ regressions, active in other models38 +++ cures, active in other models50 +++ cures, active in other models230 ++ regressions595 +++ cures, active in other models610 ++ regressions611 ++ regressions627 +++ cures, active in other models629 +++ cures, active in other models______________________________________ �*!: + tumor growth delay ++ regressions +++ cures other models P388 leukemia, OVCAR ovarian carcinoma, LOX human melanoma

These data show that the new compounds possess good tumor inhibiting properties.

__________________________________________________________________________SEQUENCE LISTING(1) GENERAL INFORMATION:(iii) NUMBER OF SEQUENCES: 59(2) INFORMATION FOR SEQ ID NO:1:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:XaaValXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:2:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:XaaValXaaProXaa15(2) INFORMATION FOR SEQ ID NO:3:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:XaaValXaaProProValXaa15(2) INFORMATION FOR SEQ ID NO:4:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:XaaValXaaProProValHis15(2) INFORMATION FOR SEQ ID NO:5:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:XaaXaaXaaProProValTrp15(2) INFORMATION FOR SEQ ID NO:6:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:XaaValXaaProProXaaPhe15(2) INFORMATION FOR SEQ ID NO:7:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:XaaValXaaProProIlePhe15(2) INFORMATION FOR SEQ ID NO:8:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:XaaValXaaProXaaValPhe15(2) INFORMATION FOR SEQ ID NO:9:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:XaaValXaaXaaProValPhe15(2) INFORMATION FOR SEQ ID NO:10:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:XaaValXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:11:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:XaaXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:12:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:XaaIleXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:13:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:XaaXaaXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:14:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:XaaLeuXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:15:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:XaaValXaaProProPhePhe15(2) INFORMATION FOR SEQ ID NO:16:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:XaaValXaaProProVal15(2) INFORMATION FOR SEQ ID NO:17:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:XaaValXaaProProXaa15(2) INFORMATION FOR SEQ ID NO:18:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:XaaValXaaProProVal15(2) INFORMATION FOR SEQ ID NO:19:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:XaaXaaXaaProProVal15(2) INFORMATION FOR SEQ ID NO:20:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:XaaValXaaXaaProVal15(2) INFORMATION FOR SEQ ID NO:21:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:XaaValXaaProXaaVal15(2) INFORMATION FOR SEQ ID NO:22:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:XaaValXaaXaa(2) INFORMATION FOR SEQ ID NO:23:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:XaaXaaXaaProPro15(2) INFORMATION FOR SEQ ID NO:24:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:XaaXaaProPro1(2) INFORMATION FOR SEQ ID NO:25:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:XaaValXaaPro1(2) INFORMATION FOR SEQ ID NO:26:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:XaaXaaXaaProXaa15(2) INFORMATION FOR SEQ ID NO:27:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:XaaXaaProProVal15(2) INFORMATION FOR SEQ ID NO:28:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:XaaValProProValPhe15(2) INFORMATION FOR SEQ ID NO:29:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:XaaValProPro1(2) INFORMATION FOR SEQ ID NO:30:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:XaaXaaProXaa1(2) INFORMATION FOR SEQ ID NO:31:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:XaaValXaaProXaaPhe15(2) INFORMATION FOR SEQ ID NO:32:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:XaaXaaProProXaa15(2) INFORMATION FOR SEQ ID NO:33:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:XaaXaaProXaaPhe15(2) INFORMATION FOR SEQ ID NO:34:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:XaaValXaaProProPhePhe15(2) INFORMATION FOR SEQ ID NO:35:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:XaaValXaaProProXaaXaa15(2) INFORMATION FOR SEQ ID NO:36:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:XaaValXaaProProLeuPhe15(2) INFORMATION FOR SEQ ID NO:37:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:XaaValXaaProProIlePhe15(2) INFORMATION FOR SEQ ID NO:38:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:XaaValXaaProProValAla15(2) INFORMATION FOR SEQ ID NO:39:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:XaaXaaXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:40:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:XaaXaaXaaProProVal15(2) INFORMATION FOR SEQ ID NO:41:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:XaaValXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:42:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:XaaValXaaProProVal15(2) INFORMATION FOR SEQ ID NO:43:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:XaaIleXaaProXaa15(2) INFORMATION FOR SEQ ID NO:44:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:XaaValXaaProXaaVal15(2) INFORMATION FOR SEQ ID NO:45:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:XaaValXaaProXaaLeuPhe15(2) INFORMATION FOR SEQ ID NO:46:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:XaaValXaaProXaaXaa15(2) INFORMATION FOR SEQ ID NO:47:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:XaaLeuXaaProProXaa15(2) INFORMATION FOR SEQ ID NO:48:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:XaaLeuXaaProProXaa15(2) INFORMATION FOR SEQ ID NO:49:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:XaaLysXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:50:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:XaaLysXaaProProVal15(2) INFORMATION FOR SEQ ID NO:51:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:XaaLysXaaProPro15(2) INFORMATION FOR SEQ ID NO:52:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:XaaLysXaaProXaa15(2) INFORMATION FOR SEQ ID NO:53:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:XaaXaaXaaProProVal15(2) INFORMATION FOR SEQ ID NO:54:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:XaaXaaXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:55:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:XaaValXaaProProValLys15(2) INFORMATION FOR SEQ ID NO:56:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:XaaValXaaProProValPhe15(2) INFORMATION FOR SEQ ID NO:57:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:XaaValXaaProProValTyr15(2) INFORMATION FOR SEQ ID NO:58:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:XaaValXaaProProIle15(2) INFORMATION FOR SEQ ID NO:59:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 6 amino acids(B) TYPE: amino acid(C) STRANDEDNESS:(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:XaaValXaaProProLeu15__________________________________________________________________________

Claims

1. A peptide of the formula I

R.sup.1 R.sup.2 N--CHX-CO-A-B-D-(E).sub.s -(F).sub.t -(G).sub.u -KI

where

R.sup.1 is alkoxy; alkyl; cycloalkyl; alkylsulfonyl; fluoroalkyl; aminosulfonyl, which may be substituted by alkyl; hydroxy; or benzyl, which may be substituted by up to three substituents independently selected from alkyl, alkoxy, nitro, halogen and CF.sub.3 ;

R.sup.2 is hydrogen, alkyl; fluoroalkyl; or cycloalkyl;

R.sup.1 --N--R.sup.2 together may form a 5-or 6-membered heterocycle which may be unsubstituted or substituted with one or more substituents independently selected from alkyl, N(CH.sub.3).sub.2, nitro, CONH.sub.2, and COOEt;

A is a valyl, isoleucyl, leucyl, allo-isoleucyl, 2,2-dimethylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl or norvalyl residue;

B is an N-alkyl-valyl, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -2-ethylglycyl, -norleucyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, or -2-cyclohexylglycyl residue;

D is a prolyl, homo-prolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

E is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;

F and G are independently selected from the group consisting of prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl-1- carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydroisoquinolyl-2-carbonyl, 3-thiazolylalanyl, 3-thienylalanyl, histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl norvalyl, norleucyl, tryptophanyl, neopentylglycyl, .beta.-alanyl and 3-naphthylalanyl residues;

X is hydrogen; alkyl; cycloalkyl; --CH.sub.2 -cyclohexyl or arylalkyl;

s, t, and u are independently 0 or 1; and

K is hydroxy, alkoxy, benzyloxy, phenyloxy or an amino moiety of the formula R.sup.5 --N--R.sup.6, wherein

R.sup.5 is selected from the group consisting of: hydrogen; hydroxy; alkoxy; substituted or unsubstituted benzyloxy; substituted or unsubstituted phenoxy; fluorine-substituted or unsubstituted, linear or branched alkyl; cycloalkyl; and substituted and unsubstituted benzyl; and

R.sup.6 is selected from the group consisting of: hydrogen; fluorine-substituted or unsubstituted, linear or branched alkyl; aryl; cycloalkylalkyl; arylalkyl; heteroarylalkyl; heteroaryl; (CH.sub.2 CH.sub.2 O).sub.y R, wherein y is 1 to 5 and R is an alkyl group; --CHR.sup.7 -5-membered heteroaryl, wherein the heteroaryl group is substituted or unsubstituted and R.sup.7 is hydrogen, linear or branched C.sub.1-4 -C.sub.5 -alkyl, or benzyl, or R.sup.5 and R.sup.7 together form a group --(CH.sub.2).sub.3 - or --(CH.sub.2).sub.4 -; and NR.sup.a R.sup.b, wherein R.sup.a is hydrogen or methyl and R.sup.b is a substituted or unsubstituted phenyl or benzyl group; or wherein

R.sup.5, R.sup.6 and N together form a heteroaryl- or substituted heteroaryl-substituted 5- or 6-membered ring; or wherein R.sup.5, R.sup.6 and N together form a ring system selected from the group consisting of: ##STR6## or a salt thereof with a physiologically tolerated acid.

2. A compound of formula I as defined in claim 1 wherein R.sup.1 --N--R.sup.2 together form a 5- or 6-membered heterocycle which may be unsubstituted or substituted with one or more substituents which may independently be selected from alkyl, N(CH.sub.3).sub.2, nitro, oxo, CONH.sub.2 and COOEt.

3. The compound of claim 1 wherein K is an amino moiety of the formula R.sup.5 --N--R.sup.6 wherein

R.sub.5 is hydrogen; hydroxy; C.sub.1-7 alkoxy; C.sub.3-7 -cycloalkyl;

benzyloxy, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; phenoxy; benzyloxy; halogen; C.sub.1-4 -alkyl; cyano; hydroxy; N(CH).sub.3).sub.2 ; COOMe; COOEt; COOiPr and COONH.sub.2 ;

phenyloxy, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; phenoxy; benzyloxy; halogen; C.sub.1-4 -alkyl; cyano; hydroxy; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr; and COONH.sub.2 ;

C.sub.1-7 -alkyl, optionally substituted by one or more fluorine atoms; or

benzyl, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; phenoxy; benzyloxy; halogen; C.sub.1-4 -alkyl; cyano; hydroxy; N(CH.sub.3); COOMe; COOEt; COOiPr and COONH.sub.2 ;

R.sup.6 is hydrogen; norephedryl; norpseudoephedryl; quinolyl; pyrazyl; --CH.sub.2 -benzimidazolyl; adamantyl; --CH.sub.2 -adamantyl; alpha-methyl-benzyl; alpha-dimethylbenzyl;

C.sub.1-12 -alkyl, optionally substituted by one or more fluorine atoms;

--(CH.sub.2).sub.v -C.sub.3-7 -cycloalkyl, wherein v=0,1,2, or 3;

--(CH.sub.2).sub.v -phenyl, wherein v=0,1,2, or 3, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; phenoxy; benzyloxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--(CH.sub.2).sub.m -naphthyl, wherein m=0 or 1, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxyl; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr; or COONH.sub.2 ; or

--(CH.sub.2).sub.w -benzhydryl, wherein w=0, 1, or 2, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr and COONH.sub.2 ;

biphenyl, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr and COONH.sub.2 ;

pyridyl, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

picolyl, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--CH.sub.2 --CH.sub.2 -pyridyl, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

benzothiazolyl, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

benzopyrazolyl, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 - alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

benzoxazolyl, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--(CH.sub.2).sub.m -fluorenyl, wherein m is 0 or 1, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C,.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr and COONH.sub.2 ;

pyrimidyl, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--(CH.sub.2).sub.m -indanyl, wherein m=0 or 1, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl, which may form a cyclic system; cyano; hydroxy; N(CH.sub.3).sub.2 ; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--(CH.sub.2 CH.sub.2 O).sub.y --CH.sub.3, wherein y=0,1,2,3,4, or 5;

--(CH.sub.2 CH.sub.2 O).sub.y --CH.sub.2 CH.sub.3, wherein y=0, 1,2,3,4, or 5;

--NH-C.sub.6 H.sub.5, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--NCH.sub.3 -C.sub.6 H.sub.5, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--NH--CH.sub.2 C.sub.6 H.sub.5, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

--NCH.sub.3 --CH.sub.2 C.sub.6 H.sub.5, optionally having up to two substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; halogen; C.sub.1-4 -alkyl which may form a cyclic system; cyano; hydroxy; COOMe; COOEt; COOiPr and COONH.sub.2 ;

5-membered heteroaryl, optionally having up to three substituents independently selected from the group consisting of CF.sub.3 ; nitro; C.sub.1-7 alkylsulfonyl; C.sub.1-4 alkoxy; thiomethyl; thioethyl; picolyl; acetyl; C.sub.3-6 -cycloalkyl; thiophenyl; --CH.sub.2 --COOEt; C.sub.3 -4 -alkylene group forming a bicyclic system with the heterocycle; phenyl; phenyl substituted by up to three substituents which may independently be nitro, CF.sub.3, CN, halogen, or C.sub.1-4 -alkyl; benzyl; or benzyl substituted by up to three substituents which may independently be nitro, CF.sub.3, halogen, C.sub.1-4 -alkyl, C.sub.1-7 -alkylsulfonyl, cyano, hydroxy or C.sub.1-4 -dialkylamino; or

--CHR.sup.7 -5-membered heteroaryl, wherein R.sup.7 is hydrogen; linear or branched C.sub.1-5 alkyl or benzyl; or R.sup.7 and R.sup.5 together form a group --(CH.sub.2).sub.3 - or --(CH.sub.2).sub.4 -, optionally having up to two substituents which may independently be CF.sub.3 ; nitro; cyano; halogen; COOMe; COOEt; COOiPr; CONH.sub.2 ; C.sub.1-4 -alkyl; C.sub.1-4 -alkoxy; phenyl; benzyl; naphthyl or C.sub.1-7 -alkylsulfonyl.

4. A compound of formula I as defined in claim 1 wherein K is R.sup.5 --N--R.sup.6 which together may form structures selected from the group consisting of ##STR7## which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of CF.sub.3, nitro, halogen, oxo, cyano, formyl, N,N-dimethylamino, C.sub.1-6 -alkyl, C.sub.3-6 -cycloalkyl, C.sub.3-4 -alkylene group forming a bicyclic system with the heterocycle, C.sub.1-4 -alkoxy, phenoxy, benzoxy, naphthyl, pyrimidyl, COOEt, pyrrolidinyl, piperidinyl, thienyl, pyrrolyl, CH.sub.2 -CO-NCH(CH.sub.3).sub.2, --CH.sub.2 --CO-N(CH.sub.2).sub.4, --CH.sub.2 -CO-N(CH.sub.2).sub.4 O, benzyl (which may be substituted by up to three substituents independently selected from the group consisting of nitro, halogen, CF.sub.3, thiomethyl or the corresponding sulfoxide or sulfone, thioethyl or the corresponding sulfoxide or sulfone, C.sub.1-4 -alkyl, and C.sub.1-4 -alkoxy).

5. A compound of formula I as defined in claim 1 wherein s, t and u are 1 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.

6. A compound of formula I as defined in claim 1 wherein s and t are 1, u is 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.

7. A compound of formula I as defined in claim 1 wherein s is 1, t and u are 0 and K is a hydroxy, alkoxy, phenoxy or benzyloxy moiety.

8. A compound of formula I as defined in claim 1 wherein K is an amino moiety of the formula R.sup.5 --N--R.sup.6.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I as defined in claim 1.

10. A method of treating a tumor in a mammal comprising administering to a mammal bearing such a tumor, a tumor-inhibiting amount of a compound of formula I as defined in claim 1.