DE2659154A1 - Compsn. for eliminating tumours and diseased tissue - contains a dehydro-oligopeptide of low toxicity - Google Patents

Abstract

Compsn. for causing the disappearance, without suppuration, of tumours and/or tissues contains >=1 dehydro-oligopeptide (I). (I) are pref. of formula: In (I) R1 is H, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, lower alkylsulphonyl or arylsulphonyl (all opt. substd.) or is alkoxycarbonyl, aralkoxycarbonyl or carbamoyl. R2, R7 and R12 are each H or lower alkyl, or R2, R7 or R12 together with R3 or R8, or R14 or adjacent C, form a 3-4C alkylene chain. R4 and R9 are each H or lower alkyl. R3, R8 and R13 are each H, opt. branched lower alkyl, aryl, aralkyl, aralkenyl, cycloalkyl cycloalkenyl or 4-7 membered heterocyclylmethyl with 1 or 2 heteroatoms (all opt. substd.), or indolylmethyl. R5 and R10 are each H or opt. substd. lower alkyl. R6 and R11 are each opt. substd. alkyl, aryl, 5-7 membered heterocyclyl with 1 or 2 heteroatoms, aralkyl or aralkenyl, or one or goth of them together with R5 or R10 are 3-7C opt. substd. alkylene or alkenylene. R14 is H, opt. substd. lower alkyl, or with R13 and C atom between them, complete a 4-7C alicyclic ring. R15 is OH, opt. substd. lower alkoxy, alkenyloxy, alkylthio, alkenylthio, arylthio or hydrazine, NH2 (opt. substd. by 1 or 2) opt. substd. alkyl), opt. substd. mono- or di-alkenylamino, alkynylamino, arylamino, mono- or di-aralkylamino, or an opt. substd. 4-7 membered N heterocycle which can have 1 or 2 other heteroatoms, amino substd. by opt. substd. 3-7 membered alicyclic rings, or aralkoxy amino. m, n, p and q are 0 or 1, but not all 1 at the same time). Their pharmaceutically acceptable salts can be used Used human and veterinary medicine for treating a wide range of tumours, pref. by topical application, and a variety of diseased tissues e.g. varicose ulcers, tubercular lesions, lesions caused by bacterial or fungal infections etc.

Description

Tumor- and tissue-dissolving drugs

The present invention relates to the use of some known Dehydrooligopeptides as tumor ur. »/ Czer tissue-dissolving drugs.

The dehydrooligopeptides are intended to be linked in peptide-like manner in the following and compounds consisting of two to ten amino acid units with at least a double bond (corresponding to at least one dehydroarninosäuregruppe) understood will.

The use of dehydrooligopeptides as drugs is not previously known.

It is known that one has a tumor and tissue dissolving effect Substances of various kinds can achieve.

However, the general toxicity of such compounds is usually so great that that therapeutically manageable options for action that the patient cannot harm even more, barely exist.

Substances chemically related to dehydrooligopeptides with a comparable one Effects are so far unknown. Commercial products for use with appropriate Indications are the cytostatics, with cyclophosfamide mentioned here as an example may be.

All means that have been used so far show an extremely large one General toxicity. This is often so pronounced that treatment has to be discontinued and therefore tumor diseases will often end fatally.

An example of the general toxic effect is that of cyclophosfamide mentioned. So report M.H.N. TATTERSALL and J.S.TOBIAS in The Lancet 1976 / II, No. 7994, page 1071: "Many anti-cancer drugs are twice the dose that 10% of the animals kill (LD10), fatal for 90% of the animals (LDgo) FREE and FREE (Advances in Chemotherapy 2 (1965), 269) were able to understand the importance of the application of agents such as cyclophosfamide in doses that correspond to the toxicity rate (LD10) approached to document. The key feature of these experiments lay in the observed exponential increase in cell death with a low (arithmetic) Dose increase. The LD10 dosage of the cyclophosfamide killed 99.999% of the tumor cells but one eighth of that dose (which was far less toxic) only killed 90% of the tumor cells and was therefore 5 log less clinically effective.

This observation is the basis for the widespread The view that chemotherapy of cancer is only effective if it is generally toxic is." the present invention now relates to the use of # Some known dehydrooligopeptides as drugs with tumor and tissue dissolving Effect5 which does not have the above-mentioned disadvantages of the general toxic effects have more; they are characterized by a strong tissue-dissolving effect, which is dose-dependent with good general tolerance.

It has been found that dehydrooligopeptides and their physiological compatible salts have a very good tumor- and / or tissue-dissolving effect.

In particular, it was found that dehydrooligopeptides of the general formula in which R1 represents a hydrogen atom, an optionally substituted alkanoyl group, an optionally substituted alkenoyl group, an alkoxycarbonyl group, an optionally substituted aroyl group, an optionally substituted aralkanoyl group or aralkenoyl group, an aralkoxycarbonyl group, a carbamoyl group, an optionally substituted heteroaroyl group, an optionally substituted lower alkylsulfonyl group an optionally substituted arylsulfonyl group, R2, R7 and R12 each represent a hydrogen atom, a lower alkyl group or in which R2, R7 or R12 together with the respectively adjacent substituent R3 or R8 or R12 form an alkylene chain with three to four carbon atoms, and R9 each represent a hydrogen atom or a lower alkyl group, R3, R8 and R13 each represent a hydrogen atom, a lower straight or branched-chain optionally substituted alkyl group, an optionally sub substituted aryl group, an optionally substituted aralkyl or aral = kenyl group, an indolylmethyl group, an optionally substituted Heterocyclusm.ethylgruppe with four to seven ring members and one to two heteroatoms, R5 and R10 each represent a hydrogen atom or an optionally substituted lower alkyl group, R6 and R11 each represent an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocycle with five to seven ring members and one to two heteroatoms, an optionally substituted aralkyl group, an optionally substituted aralkenyl group or in which R6 and / or R1l in Connection rit R5 resp.

R10 for an optionally substituted alkylene or. Alkenylene chain with three to seven carbon atoms, R14 for a hydrogen atom or in Compound with R13 and the carbon atom between them for an alicyclic with four to seven carbon atoms, R15 represents a hydroxyl group, one optionally substituted lower alkoxy or alkenyloxy group, one amino group, one lower optionally substituted alkylamino or dialkylamino group or -alkenylamino- or dialkenylamino group, for an optionally substituted arylamino group, an optionally substituted mono- or diaralkylamino group, a nitrogen containing heterocycle with four to seven ring members, in which another up to two further heteroatoms can be contained, or for one by alicyclics amino group substituted by three to seven ring members, m, n, p and q stand for the digits 0 or 1 with the proviso that not all four letters may be 1 at the same time, and their physiologically compatible Salts have strong turoric and tissue-dissolving properties.

It is new and completely surprising that dehydrooligopeptides are such show strong tumor and tissue dissolving effect.

The active ingredients according to the invention thus represent an enrichment of the Pharmacy.

In the general formula (I), the radicals R1 to R15 have the following Preferred meanings: The alkanoyl radical R1 is preferably a straight-chain one or branched alkanoyl radical with two to six carbon atoms. Exemplary may be mentioned: acetyl, propionyl, butyryl, pentanoyl.

The alkenoyl radical R1 is preferably a straight-chain or branched one Alkenoyl radical with three to six carbon atoms. The following may be mentioned by way of example: Crotonyl and acrylyl.

As substituents of R1 for the alkanoyl or

Alkenoyl radical R1 is preferred: one to three halogen atoms, preferred Fluorine and chlorine atoms, methoxy or ethoxy groups.

Examples include the chloroacetyl, trichloroacetyl or the trifluoroacetyl radical.

The lower straight- or branched-chain alkoxycarbonyl radical R1 is preferably for the methoxy, ethoxy, propoxy and butoxycarbonyl group, in particular for the tert-butoxycarbonyl group.

The optionally substituted aroyl radical R1 preferably denotes the benzoyl or t Ta? hthoyl radical.

The optionally substituted aralkanoyl or ralkenoyl radical R1 preferably means a best with eight to twelve carbon atoms, in particular eight to ten carbon atoms. Examples include Phen = acetyl-, Pher.propionyl-, Phenisopropionyl, cinnamoyl, - or ß-methylcinnamoyl or the phenylbutancyl radical.

As substituents in the aralkanoyl or aralkenoyl radical R1 come in question: one to three halogen atoms, alkyl or alkoxy groups with up to three carbon atoms, in particular the rteShoxy, the trifluoromethyl group, or a nitro group Hydroxy groups, which can also be acylated with lower organic acid residues.

The aralkoxycarbonyl radical R1 means in particular one with eight to ten carbon atoms, preferably the benzyloxycarbonyl group.

Under an optionally substituted heteroaroyl radical R1 is a heterocycle with five to seven ring members, the one to three nitrogen, May contain sulfur or oxygen atoms, with a carbonyl group attached Understood. Examples are the pyridinecarbyl, thiophenearbonyl, Furancarbonyl, pyrrole carbonyl, oxazole carbonyl, thiazole carbonyl and pyrazine carbonyl groups. These heterocycles can be substituted by one or more halogen atoms, preferably fluorine and chlorine atoms, alkoxy groups with one to four carbon atoms or alkyl groups of one to four carbon atoms.

The optionally substituted lower alkylsulfonyl radical R1 or Arylsulfonyl radical 1 preferably denotes methanesulfonyl, ethanesulfonyl, benzenesulfonyl or. Toluenesulfonyl radical.

A lower alkyl group in the radicals R2, R7 and R12 is preferably the ethyl and ethyl group.

If R2, R7 and P.12 together with the respectively adjacent R substituent R3, R8 and R14 form an alkylene chain with three to four carbon atoms, means this is that R2 with the associated nitrogen atom and the adjacent -CH group of the chain and R3 a pyrrolidine or. Form piperidine ring. The same applies to R7 and R8 or R12 and R13.

A lower alkyl group as a radical for Rq and Rg is preferably the methyl or the ethyl group.

An optionally substituted straight or branched chain lower Alkyl or alkenyl radicals R3, R8 and R13 denote a hydrocarbon radical with preferably one to six carbon atoms and optionally a double or Triple bond, such as a methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl radicals, the pentyl and fexyl radicals with their possible Isomers, also the vinyl, acetylene, propenyl, or the crotyl radical.

The following may be mentioned as substituents for the alkyl radical R3 or R8 or R13: one to three halogen atoms, hydroxyl groups, alkoxy groups with preferably one to four carbon atoms, alkyl = thio groups with preferably one to four carbon atoms, Sulfydryl groups, carbamido groups, carboxyl groups.

Examples of such substituted alkyl groups may be mentioned the carboxymethyl, carboxylethyl, orarbamoyl = methyl, methylmercaptoethyl, trifluoromethyl, Fluorine = methyl, chloromethyl and the hydroxymethyl group.

An optionally substituted aryl group for R3, R8 and; R13 in of the general formula I is preferably the phenyl radical. It can be substituted by one or more halogen atoms, trifluoromethyl groups, hydroxyl groups, lower Alkoxy groups with one to four carbon atoms, alkyl groups with one to four Carbon atoms, nitro groups or lower acyloxy groups with one to four carbon atoms An optionally substituted aralkyl benzene. Aralkenyl group for R3, R8 and R13 preferably denotes a phenylalkyl or -alkylene group with up to four carbon atoms and a double or triple bond in the side chain, in particular a CH2 group. The aralkyl or aralkenyl radical can be substituted by one or more halogen atoms, Nitro, hydroxyl, methoxy or alkyl groups with one to four carbon atoms.

An optionally substituted Heterocyclusmethy Igruppe means in particular the furfuryl, thenyl, pyrrolyl = methyl, thiazolylmethyl, oxazolylmethyl, Pyridine methyl, piperidine methyl, pyrazine methyl or morpholine methyl group.

They can optionally be substituted by one to three halogen atoms, Alkyl or alkoxy groups with one to three carbon atoms or a nitro group.

Optionally substituted, severre alkyl radicals for R1 and denote Alkyl radicals with preferably one to six 10, in particular one or two carbon atoms, which are substituted by halogen atoms, in particular chlorine or fluorine atoms can.

An optionally substituted alkyl group for R6 and R11 in the general formula I denotes a straight or branched chain alkyl group with preferably one to six carbon atoms, in particular one to three carbon atoms. It can be substituted by one to three halogen atoms, preferably Clilor- or fluorine atoms or by alkoxy groups having one to four carbon atoms, in particular Methoxy groups An optionally substituted aryl radical for P: and R11 denotes in particular the phenyl radical and the naphthyl radical. These can be substituted by halogen atoms, preferably fluorine and chlorine atoms, alkyl or alkoxy groups with one to four carbon atoms, methoxy and methyl groups being preferred, Nitro groups, hydroxy and lower acyloxy groups with one to four carbon atoms Amino, lower alkylamino or lower dialkylamino groups, preferably dimethylamino groups.

An optionally substituted heterocyclic radical for R6 and R11 denotes a heterocycle with five to seven ring members and one to two Heteroatoms, especially nitrogen, sulfur or oxygen atoms.

Examples include the thienyl, furyl, pyrrolyl, pyridyl, Imidazotyl, pyrazolyl, pyrimidyl, pyrazinyl and the morpholinyl radical. these can be substituted by halogen atoms, alkyl or alkoxy groups with one to four carbon atoms, hydroxyl, elitro and trifluoromethyl groups.

Optionally substituted aralkyl or aralkenyl groups for R6 and R11 are in particular those having seven to ten carbon atoms; preferred ind thienyl alkyl or phenylalkenyl groups with one to four carbon atoms in the aliphatic part. The cinnamenyl group and the phenethyl group may be mentioned by way of example.

They can be substituted by one or more halogen atoms, Alkyl or alkoxy groups with preferably one to four carbon atoms, nitro groups and trifluoromethyl groups.

In general formula I, the radicals R6 and R11 can be mixed with R5 or R10 and the carbon atom connecting them on the double bond is a cycloalkylidene ring or preferably form a cycloalkenylidene ring with three to seven carbon atoms, in particular the cyclohexylidene and the cyclohexenylidene ring.

An optionally substituted lower alkoxy or

Alkenyloxy radical for R15 in the general formula I means one straight or branched alkoxy or alkenyloxy radical with one to six carbon atoms, especially one to four carbon atoms. Examples include: d-ie methoxy, Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or the tert-butoxy group. They can be substituted by one or more halogen atoms or alkoxy groups with one to two carbon atoms. A. A lower one if necessary substituted monoalkylamino or. Monoalkenylamino or dialkenylamino or dialkylamino group R15 in each case denotes straight-chain or branched-chain alkyl or alkenyl substituents with preferably one to six carbon atoms, such as the ethyl: amino, Ethylamino, pentylamino and 1,1-D rethyl-2-pro = pynylamino group. You can be substituted be for example by halogen atoms, hydroxyl groups and alkoxy groups with or two carbon atoms.

An optionally substituted arylamino group R15 is preferred the phenylamino group, which can be substituted by one to three halogen atoms, Alkyl or alkoxy groups preferably each having one or two carbon atoms.

A mono- or di- optionally substituted -aralkyl = amino group for R15 is preferably a mono- or diphenylalkylamino group with one to four carbon atoms each in the aliphatic part. These can be substituted be through one to three halogen atoms, alkyl or alkoxy groups with each one to four carbon atoms.

One substituted by alicyclics with three to seven ring members Amino group means a cyclopropylamino, cyclobutylamino, cyclopentylamino, Cyclohexylamino and cycloheptylamino groups, preferably the cyclohexylamino group or the correspondingly disubstituted amino group.

The starting compounds for the preparation of the compounds according to the invention Compounds of the general formula I, the corresponding 2,4-disubstituted 5 (4H) -oxazolones are partly known from the literature. As far as they are not known, they decrease using the methods described in the literature.

The reaction of acetylglycine with benzaldehyde is described here as an example. The reaction takes place according to the equation The reaction is carried out by mixing the two components in equimolar proportions in the presence of a condensing agent, usually acetic anhydride, which also serves as a solvent, and a basic component such as sodium acetate. After standing for several hours, it is worked up by dilution with water and pecrystallization of the precipitated 4-benzylidene-2-methyl-5 (4H) -oxazolone from ethyl acetate / petroleum ether.

Further examples of starting compounds are: 2-methyl-4- (2-thenylidene) -5 (4H) -oxazolone, 2-methyl-4- (2-napthylmethylene) -5 (4H) -oxazolone, 4- (4-acetoxy-3-nitrobenzylidene) -2-methyl-5 (4H) -oxazolone, 4-ethoxymethylene-2-phenyl-5 (4H) -oxazolone, 4-cyclohexylmethylene-2-phenyl-5 (4H) -oxazolone, 4-benzylidene-2-trifluoromethyl-5 (4H) -oxazolone, 4- (1-methylpropylidene) -2-phenyl-5 (4H) -oxazolone, 2-phenyl-4- (2-thenylidene) -5 (4H) -oxazolone, 2- (3-pyridyl) -4- (2-thenylidene) -5 (4H) -oxazolone, 4- (ethyl-3-phenyl-2-propenylidene) -2-phenyl-5 (4H) -oxazolone, 2- (1-acetamido-2-phenylvinyl) -4- (4-dimethylamino = benzylidene) -5 (4H) -oxazolone, 4-thenylidene-2- (3-trifluoromethylphenyl) -5 (4H) -oxazolone, 4- (2-Cyclohexenylidene) -2-phenyl-5 (4H) -oxazolone, 4- (3-Phenyl-2-propylidene) -2-phenyl-5 (4H) -oxazolone, 4- (α-methylbenzylidene) -2-phenyl-5 (4H) -oxazolone, 4-cyclohexylidene-2-phenyl-5 (4H) -oxazolone, 4- (3-chlorobenzylidene) -2- (1-acetamido-2-phenylethyl) -5 (4H) -oxazolone, 4- (3-chlorobenzylidene) -2- (L-1-tert-butoxy carbonylariro-2-phenylethyl ) -5 (4H) -oxazolone, 2- (1-Acetamido-2-phenylvinyl) -4- (4-hydroxybenzyli = den) -5 (4H) -oxazolone.

A number of the active ingredients according to the invention are new, they can be used however, produce according to known methods (cf. D.G.DOHERTY et al., J.biol.Chem. 147 (1943), 617).

They are obtained, for example, either by alkaline hydrolysis of the corresponding 2,4-disubstituted 5 (4H) -oxazolones or by aminolysis of the oxazolones with the Alkali salts, esters or amides of amino acids.

Examples are the reactions in the synthesis of N-acetyldehydrophenylalanyldehydro- (3-chlorophenyl) alanine and N-acetyldehydrophenylalanyldehydro- (3-chlorophenyl) = alanyl-L-tyrosine: The reaction is usually carried out by stirring or

If the reactant is in diluents such as aqueous Acetone, tetrahydrofuran, dimethyl = formamide or alcohols normally at constant temperatures or slightly elevated temperature, the deactivation time depending on the reactivity (1/2 to twenty hours).

Working up is carried out by acidification with, for example, X, C1 and Evaporation of the organic solution, whereby the end product usually precipitates.

If the reaction times were extremely long, there is a partial racemization cannot be ruled out, as can be seen from the optical rotation values.

In some cases it was found for reasons of purity and yield as appropriate, instead of the free amino acid in the aminolysis, an amino acid ester use and hydrolyze this after the condensation.

Examples of the active ingredients according to the invention are: N-benzoyldehydro-ß- (2-thienyl) alanine methyl ester, N-acetyldehydro-ß- (2-thienyl) alanine ethyl ester, N-acetyldehydrophenylalanine, N-phenylacetyldehydro-ß- (thienyl) alanine -Acetyl-DL-phenylalanyldehydro- (3-chlorophenyl) alanine, N-tert-butoxycarbonyl-L-phenylalanyldehydro- (3-chlorophenyl) alanine, L-phenylalanyldehydro- (3-chlorophenyl) alanine, N-acetyldehydrophenylalanyl-L-proline , N-acetyldehydrophenylalanyl-D-proline, N-acetyldehydrophenylalanyl-D-tyrosine, N-acetyldehydrophenylalanyl-L-leucine, N-acetyldehydrophenylalanyl-L-methionine, N-acetyldehydrophenyl-gl-alanyl-L-amine, N-acetyldehydrophenyl-glalagetyl-Ldehyde, N-acetyldehydrophenyl-gl-asylamine-L-asrophenyldehydrophenyl-gl-asylamine, N-acetyldehydrophenyl-glalagetyl-L-aseptyldehyde, N-acetyldehydrophenyl-glalagetylamine Acetyldehydrophenylalanyl-DL-3-fluoroalanine, N-acetyldehydrophenylalanyl-L-serine, N-acetyldehydrophenylalanyl-L-tyrosine, N-acetyldehydrophenylalanylglycine, N-acetyldehydrophenylalanyl, N-acetyldehydrophenylalanyl) (nitrophenyl -chlorphenyl'alanine, N-trifluoroacetyldehydrophenylalanyl-L-tyrosine, N-acetyldehyde dro- (p-methylphenyl) alanyl-L-tyrcsine, N-benzoyl-2-cyclohexylideneglycyl-L-tyrosine, N-benzoyl-2- (2-cyclohexenylidene) glycyl-L-'yros r., N-acetyldehydro-3 - (2-furyl) alanyl-L-tyrosine, N-acetyldehydro-3-cinnamenylalanyl-L-tyrosine, N-acetyldehydro-3- (2-naphthyl) alanyl-L-tyrosine, N-benzoyldehydro-3-cyclohexylalanyl-L -tyrosine, N-benzoyldehydro-3-benzyl-3-methylalanyl-L-leucine, N-trifluoroacetyldehydrophenylalanyl-L-tyrosine tert-butyl ester, N-benzoyldehydro-3- (2-thienyl) alanyl-L-proline, N -Acetyldehydrophenylalanine- (1-carboxy-1-cyclopentyl) amide, N-acetyldehydro-3- (2-thienyl) alanyl-L-tyrosine, N-phenacetyldehydro-3- (2-thienyl) alanyl-L-tyrosintert.-butyl ester , N-phenylacetyldehydro-3- (2-thienyl) alanyl) -L-tyrosine, N-phenacetyldehydro-3- (2-thienyl) alanyl-L-leucine methyl = ester, N-phenacetyldehydro-3- (2-thienyl) alanyl -L-leucine, N-benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine, N-benzoyldehydro-3- (2-thienyl) alanyl-L- (p-nitrophenyl) = alanine, N-nicotinoyldehydro-3 - (2-thienyl) alanyl-L-tyrosine, N- (3-triflu oromethylbenzoyl) dehydro-3- (2-thienyl) alanyl-L-tyrosine, N-benzoyldehydro-3- (2-thienyl) alanyl-L-proline, N-nicotinoyldehydro-3- (2-thienyl) alanyl-L- ( p-nitro = phenyl) alanine, N-benzoyl-3-methyl-3- (2-thienyl) dehydroalanyl-L-tyrosine, N-acetyldehydro-3- (2-thienyl) alanyl-D-tyrosine, N-cinnamoyldehydrophenylalanylglycine, N-brenzoyldehydro-3- (2-thienyl) alanyl-L-phenylalanine, N-benzoyldehydro-3- (2-thienyl) alanyl-L-leucine, N-acetyldehydro-3- (2-thienyl) -L-phenylalanine, N-acetyldehydro-3- (2-thienyl) alanyl-L-leucine, N-benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine methyl ester, N-acetyldehydro-3- (2-thienyl) alanyl-L-tyrosine methyl ester , N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosinamide, N-benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine-N'-hexylamide, N-benzyldehydro-3- (2-thienyl ) alanyl-L-tyrosine-N'-cyclohexylamide, N-benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine-N ', N'-dinethylamide, N-benzoyldehydro-3- (2-thienyl) alanyl- L-tyrosi.Ll-.orphonld, N-acetyldehydrophenylalanyldehydrotyrosnn, N-acetyldehydrophenylalanyldeh ydro- (p-nitrophenyl) alanine, N-acetyldehydrophenylalanyndehydro- (p-fluorophenyl) alanine, N-acetyldehydrophenylalanyldehydro- (4-dimeta.ynam.inc = phenyl) alanine N-aetyldehydrophenylalanyndehydro- (3-chloroaldehyde-phenylalanyldehydro- (3-chloroaldehyde) 3-chloropheny1) = alanyl-L-tyrosine, N-acethydehydropehnylalanyl-3-phenylserine, N-benzoyldehydrophenylalanylglycine, N-benzoyldehydrophenylalanyl-3-phenylserine, N-acetyldehydroldehydroline, N-acetyldehydroldehyde, N-acetyldehyde-aldehyde, N-acetyldehyde-aldehyde, N-acetyldehyde-aldehyde, N-acetyldehyde-aldehyde, N-acetyl-aldehyde-aldehyde, N-acetyl-aldehyde-aldehyde-acetyl-aldehyde-l-acetyl-aldehyde-acetyl-aldehyde-l-acetyl-aldehyde-l-acetyl-aldehyde-acetyl-aldehyde-acetyl-aldehyde-aldehyde-aldehyde-3-phenylserine N-benzoyldehydrophenylalanyl L-phenlyalnin, N-acetyl-DL-N-phenylalnyldehydrophenylalanin Acetyldehydrophenylalanyldehydrophenylalanin N-Benzoyldehydrophenylalanyldehydrophenylalanin, N-Benzoyldehydrophenylalanyldehydrotyrosin, N-N-Acetyldehydroleucyldehydrophenylalanin Carboben ~ zoxyglycyldehydrophenylalanyl-L-glutaminsSure, N-Carbobenzoxyglycyldehydrophenylalanylphenylserin, --- L-alanine, glycine, -L-leucine, -L-phenylalanine, N-acetyldehydrophenylalanyldehydrophenylalanyl-L-tyrosine, -L-proline, 3-phenylserine, L-glutamic acid, -L-cys'in N-acetyldehydrophenylalanyl-D-glutamic acid, N-benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine benzyl ester, N-benzoyldehydro-3- (2-thienyl) -L-tyrosine-N-benzylamide, N-acetyldehydro-3 - (2-thienyl) alanine-N-methylam.id, N-acetyldehydro-3- (2-thienyl) alanine morpholide, I: -aetyldehydro-3- (2-thienyl) alanine, N-cinnamoyldehydrophenylalanyl-L-tyrosine, N -Benzoyldehydroisoleucyl-L-tyrosine, n-cinnamoyldehydrophenylalanine-N'-methylamide, N-cinnamoyldehydrophenylalanine-111-dimethyl-2-propynyl = amide, N-cinnamoyldehydrophenylalanine morpholide, N-benzoyl-3-cinnamenyl-3-methyl-3-tyrosine N-Benzoyl-3-methylphenyldehydroalanyl-L-leucine N-acetyldehydro-3- (2-thienyl) alanine-N'-methylamide, N-acetyldehydro-3- (2-thienyl) alanine-N'-1.1-dimethyl-2 propynylamide.

The compounds can be both in the racemate form and in the form of the isolated optical isoners are present with a defined absolute configuration. In addition, in the synthesis, for example of ST-2enzoyldeny = drophenylalanyl-L-leucine methyl ester, cis-trans isomers occur. In some cases, for example with N-acetyl = dehydro-3- (2-thienyl) alanyl-L-tyrosine, only one of the isomers is formed preferentially, as proven by 13C-NMR spectroscopy could be.

The active ingredients according to the invention have a dose-dependent tumor and tissue-dissolving effect, preferably when applied locally. Under local the following types of application are understood here: subcutaneous, intracutaneous, intratumoral, peritumorally, in the form of external agents in ointments, gels, lotions, creams, injection solutions and suspensions.

The necroses usually arise in the immediate area of the application sites, occasionally also far from it (lymphogenic). The necrotic area is after breaks open on the outside, free of putridem material even over a longer period of time, although in the experimental animals feed, feces, sawdust and other things with the open Wound came into contact.

However, the tumor tissue can also melt down if it is completely intact outer skin.

The activity of the third component of the immune hemolytic complement system is increased considerably.

The necrotic tissue is sharp from the surrounding healthy tissue delimited; Macroscopically and microscopically, it looks like it has been punched out.

The general behavior of the test animals is determined by the size of the Necrosis not affected. There is no poisoning of the entire organism.

The DL50 of the compounds according to the invention is moving ir, Intravenous injection experiment in rats of the order of magnitude 300 mg / kg.

The daily injection of 80 mg / kg to rabbits for 27 days was used tolerated completely unresponsive.

When used therapeutically, the dosages are in the range from 1 to 100 mg / kg of body weight, preferably 2 to 40 mg / kg.

The active compounds according to the invention can in a known manner in the formulations required for their mode of action are transferred, such as ointments, Pastes, creams, soluble powders, powders, emulsions, suspensions and injection solutions.

Examples of an injection solution are those according to the invention Active ingredients, if necessary with the aid of solubilizers in diluted form Dissolved physiologically compatible bases and added physiologically compatible ones Acids brought into an injectable orn of pH 6.8 to 8.0, especially 7 to 7.2.

Inorganic bases may be mentioned as examples as physiologically compatible bases Hydroxides, carbonates, hydrogen carbonates, especially those of sodium and potash.

Organic selenium mentioned as an example as physiologically compatible acids Acids such as citric acid, oxalic acid, lactic acid, benzoic acid, salicylic acid, acetic acid or also inorganic acids such as, for example, dilute hydrochloric or sulfuric acid.

The active compounds according to the invention can be used in the formulations Auxiliary materials are added. These are considered to be inert, non-toxic and pharmaceutical suitable solid, semi-solid and liquid carriers, emulsifiers and dispersants. Here, the therapeutically effective compound should in each case in one concentration from 1 to 90 percent by weight, preferably from 5 to 50 percent by weight be.

The present invention includes pharmaceutical preparations, the one in addition to non-toxic, inert pharmaceutically suitable carriers or contain several active ingredients according to the invention or which consist of one or more There are active ingredients according to the invention and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, zO3. Suppositories and ampoules are available, their active ingredient content lt a fraction or a multiple of a single dose. The dosage units can z.no 1,, m 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single base. A single dose preferably contains the narrow active ingredient - the one used in one application and which is usually a whole, half an egg, or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically suitable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are suppositories, Injection solutions, suspensions and enulsions, pastes, ointments, gels, creams, lotions, Powders and sprays called suppositories can be used in addition to the active ingredient or ingredients usual water-soluble or water-insoluble carrier substances, e.B. Polyethylene glycols, Fats, e.g.

Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or Mixtures of these substances.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers, e.g.

animal and vegetable fats, waxes, paraffins, starch, tragacanth, Cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

In addition to the active ingredient or ingredients, powders and sprays can contain the usual ones Contain carrier substances, e.g. lactose, talc, silica, aluminum hydroxide, Calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used the usual propellants e.g. contain chlorofluorocarbons.

Solutions and emulsions can be used in addition to the active substances customary carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular Cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the customary excipients such as liquid diluents, e.g.

Water, ethyl alcohol, propylene glycol, suspending agents, for example Ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures contain these substances.

The pharmaceutical preparations listed above can also be used the active ingredients according to the invention also contain further pharmaceutical active ingredients The pharmaceutical preparations listed above are produced in Usually by known methods, for example by mixing the or the Active ingredients with the carrier (s).

The present invention also includes the use of the invention Active ingredients and pharmaceutical preparations that contain one or more of the invention Contain active ingredients for the treatment of such tissues in human and veterinary medicine Areas that prevent and disrupt the normal biological functions.

They are for example: benign and malignant tumors more solid and tissue cystic nature, papillomas, adenomas, cyst adenomas; Including adenocarcinomas those of the cirrhotic type; Basal cell carcinoma; Sromas such as fibrosarcoma, Liposarcoma, myxoso, rhabdomyosarcoma, chondrosarcoma, lymphosarcoma, reticulum cell sarcoma, as well as Hodgkin's disease; embryonic tumors such as neuroblastoma, nephroblastoma, Teratoma, adamantinoma and retroblastoma, hemangioma, chordoma, odontoma and craniopharyngioma; Hemartomas such as lymphoangioma, exostoses, neurofibromatosis; Melanoma; Lymphomas; Hepatoblastomas; Nammacrcinoma, cervical carcinoma; Choriocarcinoma, adrenoacanthoma; Leiomyoma, androblastoma; Arrhenoblastoma; Sertoli cell tumor; Granulosa and theca cell tumor; Germinoma and seminoma, ovarian and vulvar cancer; Bladder, prostate and adenocarcinoma; tumors caused by schistosomiasis; Astrocytoma, ependymoglioma; Glioblastomas, Medulloblastoma; Oligodentroglioma, spongioblastoma; Meningioma and Schwann's tumors Vaginal cells; Pinealoma; Hemangioblastoma, osteoclastoma, Ewings tumor; multiplex Myeloma; Mucosis fungoides; Burkitt tumor; Leukemia such as acute and chronic lymphocytic leukemia, acute and chronic granulocyte leukemia, acute and chronic monocyte leukemia and stem cell leukemia; Basalioma, fibroma, Myoma and especially those with surgical intervention of a local injection accessible metastases of all tumor forms.

There are also therapeutically valuable effects in osteosarcoma of the compounds according to the invention; here, however, they have to be fitted with a special device can be injected under pressure of up to 600 atmospheres.

In addition, the compounds according to the invention can be used in fibrosing tissues of any kind, especially in the treatment of keloids, Leg ulcers, burn ulcers, decubital ulcers as well as clavi and onychomycoses, Scar tissue and for the therapy and prophylaxis of emboli and thrombosis.

The compounds according to the invention can also be used to dissolve birthmarks, atheromas and lipomas as well as to remove deep, possibly fistulous abscesses.

In addition, compounds according to the invention can be used for the regeneration of cavernomas and tuberculomas.

The compounds according to the invention can also be used for scar-free Regeneration of the substance defects in leprosy and other skin, scabs, or Epithelial defects of various origins, especially those caused by infections with Bacteria, fungi and pathogens of tropical diseases such as leishmaniasis, Fromboesia, Pinta and others are conditional.

In the examples given below, the measurement of the optical rotation with c = 2 in dimethylformamide.

The melting points were determined in a Tottoli device and are uncorrected.

For example 1 N-benzoyldehydro-β- (2-thienyl) alanine methyl ester 2 g of 2-phenyl-4- (2-thenylidene) -5 (4H) -oxazolone are dissolved in 50 ml of absolute methanol dissolved and stored for 16 hours at room temperature. Then the reaction solution evaporated, the residue taken up in glacial acetic acid / ethylene chloride, filtered and brought to crystallization by concentration. There are 2 g (88.8% of theory) N-Benzoyldehydro-ß- (2-thienyl) alanine methyl ester obtained from m.p. 1620 C.

C15H13NO3S calculated: C 62.70%, H 4.56%, N 4.87%, S 11.16%; found: C 62.81%, H 4.67%, N 4.85%, S 11.18%.

For example, 2 N-acetyldehydro-β- (2-thienyl) alanine ethyl ester is analogous Example 1 from 2-methyl-4- (2-thenylidene) -5 (4H) -oxazolone and absolute ethanol; Fp. 1Q9-11O00.

Yield 82%.

C11H13NIO3S # H2O calculated: C 51.42%, H 5.8%, N 5.4%, S 12.5%; found: C 51.80%, H 6.0%, N 5.4%, S 12.7%.

Example 3 N-acetyldehydrophenylalanine by saponification of 2-methyl-4-benzylidene-5t4H) -oxazolone (Literature preparation: Beilstein X, p.683); Mp. 188-190 ° C.

Example 4 N-phenylacetyldehydro-ß- (thienyl) alanine by saponification of 2-benzyl-4- (2-thenylidene) -5 (4H) -oxazolone; Mp 193-195 ° C; Yield 8.2% of the Theory.

C15H13NO3S calculated: C 62.70%, H 4.56%, N 4.88%, S 11.16%; found: C 62.68%, H 4.55%, N 4.96%, S 11.26.

Example 5 DL-N-acetylphenylalanyldehydro- (3-chlorophenyl) alanine 1.8 g (0.005 mol) of 2- (1-acetamido-2-phenylethyl) -4- (3-chlorobenzylidene) -5 (4H) -oxazolone are suspended in 7 ml of acetone and treated with 7.5 ml of 2N NaOH.

After stirring for half an hour, the reaction solution is quenched with citric acid acidified to pH 3, the resulting precipitate is filtered off and washed neutral.

Mp. 195-196 ° C, yield 1.6 g (84.2% of theory).

C20H19ClN2O4 calculated: C 62.10%, H 4.95%, Cl 9.17. %, N 7.24%; found: C 62.31%, H 4.77%, Cl 9.03%, N 7.31%.

Ex. 6 L-N-tert-butoxycarbonylphenylalanyldehydro- (3-chloro phenyl) alanine analogously to Example 5 from 2- (l-tert-butoxycarbonylamido-2-phenylethyl) -4- (3-chlorophenyl) -5 (4H) -oxazolone and recrystallization from aqueous acetone. M.p. 1730 C (dec.), [Α] D + 78.6 ° (c = 1; dimethylformamide), yield 83.3% of theory.

C23H25ClN2O5 calculated: C 62.09%, H 5.66%, Cl 7.97%, N 6.30%; found: C 62.26%, H 5.66%, Cl 7.95%, N 6.44%.

Ex. 7 L-phenylalanyldehydro- (3-chlorophenyl) alanine 2.5 g of the above compound by dissolving in 15 com anhydrous trifluoroacetic acid, Standing for one hour at room temperature, evaporating, taking up the residue in Water, adjust to pH 8 with NH3 and evaporate the solution until it starts Crystallization.

Mp 235-236 ° C; [α] D20 -31.50 (c = 1; dimethylformamide); yield 1.7 g (89.5% of theory).

C18H17ClN2O3 calculated: C 62.70%, H 4.97%, Cl 10.28%, N 8.13%; found: C 62.55%, H 5.35%, Cl 10.15%, N 8.19%.

Example 8 N-acetyldehydro-3- (2-thianyl) alanine analogously to Example 5 4-thenylidene-2-methyl-5 (4H) -oxazolone.

Mp 222-223 ° C; Yield 5.7% of theory.

C9H9NO3S calculated: C 51.17%, H 4.30%, N 6.63%, S 15.18%; found: C 51.21%, H 4.37%, N 6.65%, S 15.32%.

The following examples are based on the following general rule: 0, C25 mol of the amino acid to be condensed are suspended in 10 ml of acetone, 25 ml of 1N NaOH are added while stirring and the resulting solution is treated with a suspension of the correspondingly substituted 5 (4H) -oxazolone mixed in acetone. Depending on your ability to react the amino acid, the mixture is stirred at room temperature for 1/2 to 20 hours.

The filtered reaction solution is then mixed with 25 ml of 1NHCl added and the acetone distilled off in vacuo. Crystallized from the aqueous phase the desired end product, which is recrystallized from aqueous alcohol.

At 5 p i e l 9 N-acetyldehydrophenylalanyl-L-proline from 2-methyl-4-phenyl-5 (4H) -oxazolone and L-proline.

Mp 152-155 ° C; [α] D20 + 69.5 °; Yield 59% of theory.

C16H18N2O4 # 1/2 H2O calculated: C 61.72%, H 6.15%, N 9.00%; found: C 62.15%, H 6.3%, N 8.96%.

For example 1 10 N-acetyldehydrophenylalanyl-D-proline mp 151-153 ° C; [α] D20 -69.6 °; yield 55% of theory C16N18N2O4 calculated: C 61.72%, H 6.15%, N 9.0 %; found: C 61.75%, H 6.30%, N 8.94%.

EXAMPLE 11 NsAcetylaehgdrophenylalanyl-D-tyrosine mp 210 ° C; [α] 20 D -43.4 ° (c = 2; pyridine); Yield 61.3% of theory.

C20H20N2O5 calculated: C 65.21%, H 5.47%, N 7.60%; found: C 64.56 %, H 5.86%, N 7.77%.

Example 12 N-acetyldehydrophenylalanyl-L-leucine mp 206-207 ° C; [α] D20 22.50; Yield 65.7 »d.Th.

C17H22N2O4 calculated: C 64.13%, H 6.97%, N 8.80%; found: C. 64.26%, H 7.31%, N 8.78%.

B e i s p i e l 13 N-acetyldehydrophenyalanyl-L-methionine melting point 91-93 ° C, [α] D20 -74.4 °; Yield 70% of theory.

C16H20N2O4S calculated: C 57.12%, H 5.99%, N 8.33%, S 9.53%; found: C 57.02%, H 6.03%, N 8.40%, s 9.46%.

B e i s p i e 1 14 N-acetyldehydrophenylalanyl-L-aspartic acid m.p. 182-184 ° C; [α] D20 -46.65 °; Yield 63.5% of theory

C15H16N2O6 # H2O calculated: C. 53.25%, H 5S36%, N 8.28%; found: C 53.48%, H 4.92%, N 8.32%.

EXAMPLE 15 N-acetyldehydrophenylalanyl-L-glutamine, mp 188 ° C; [α] D20 -74.5 °; Yield 54% of theory.

C16H19N3O5 calculated: C 57.65%, H 5.75%, N 12.61%; found: C 58.17%, H 5.79%, IQ 13.16%.

EXAMPLE 16 N-acetyldehydrophenylalanyl-DL-3-fluoroanine m.p. 180 ° C (dec.); Yield 58.7% of theory.

C14H15FN2O4 calculated: C 57.14%, H 5.14%, F 6.46%, N 9.52%; found: C 57.22%, H 5.22%, F 6.30%, N 9.58%.

Ex. 17 N-acetyldehydrophenylalanyl-L-serine m.p. 17900 (dec.); [α] D20 +1.150; Yield 48.5% of theory

C14H16N2O5 calculated: C 57.53%, H 5.52%, N 9.58%; found: C, 57.48 %, H 5947%, N 9.66%.

B e i s p i e 1 18 N-acetyldehydrophenylalanyl-L-tyrosine melting point 219-220 ° C, Literature preparation.

B e i s ti e 1 19 N-acetyldehydrophenylalanylglycine m.p. 191-192 ° C; literature preparation.

Ex. 20 N-acetyldehydrophenylalanyl-L- (p-nitrophenyl) alanine Mp. 192-193 ° C (from ethanol / petroleum ether / isopropyl ether); [α] 20 D -110.7 °; yield 70.3% of theory.

C20H19N3O6 calculated: C 60.45%, H 4.82%, N 10.58%; found: C. 60.40%, H 4.90%, N 10.43%.

Ex. 1 21 N-acetyldehydroalanyl-DL- (p-chlorophenyl) alanine Mp 214-215 ° C (from ether / petroleum ether); Yield 66.9% of theory C20H19ClN2O calculated: C 62.10%, H 4.95%, Cl 9.17%, N 7.24%; found: C 62.39%, H 5.02%, Cl 9.14 %, N 7.11%.

B e i 5 p l e 1 22 N-acetyldehydro (p-methylphenyl) alanyl-L-tyrosine Mp 220-221 ° C; [α] D20 -38.5 °; Yield 47.6% of theory

C21H22N2O5 calculated: C 65.95%, H 5.80%, N 7.33%; found: C, 65.96 %, H 5.80%, N 7.16%.

B e i 5 p i e 1 N-benzoyl-2-cyclohexylidene glycyl-L-tyrosine mp 121 ° C; [alpha;] 20 D -0.5 °; Yield 75.8% of theory Th.

C24H26N2O5 calculated: C 68.23%, H 6.20%, N 6.63%; found: C, 68.16 %, H 6.18%, N 6.65%.

B e i 5 p i e 1 24 N-benzyl-2- (2-cyclohexenylidene) glyccyl-L-tyrosine Mp 126 ° C; [α] D20 -5.7 °; Yield 60% of theory.

C24H24N2O5 calculated: C- 68.56%, H 5.75%, N 6.66%; found: C, 68.46 %, H 5.70%, N 6.56%.

EXAMPLE 1 25 N-acetyldehydro-3- (2-furyl) alanyl-L-tyrosine mp. 2170C (ithanol / petroleum ether); [α] D20 -29.1 °; Yield 31% of theory.

C18H18N2O6 calculated: C 60.33, H 5.06%, N 7.82%; found: C, 60.37 %, H 5.11%, N 7.70%.

EXAMPLE 26 N-acetyldehydro-3-cinnamenylalanyl-L-tyrosine mp. 220-221 ° C: [α] 20 D -44.2 °; Yield 57.3% of theory C22H22N2O5 calculated: C 66.99%, H 5.62%, N 7.10%; found: C 66.80%, H 5.64%, N 7.06.

B e i s p 1 e 1 27 N-acetyldehydro-3- (2-naphthyl) alanyl-L-tyrosine Melting point 221-2220C (from ethyl acetate / isopropanol with petrol precipitate = ether); [α] D20 -11.6 ° (c- = 2; from methanol); Yield 55.7% of theory.

C24H22N2O5 calculated: C 68.89%, H 5.30%, N 6.70%; found: C 69.04 %, H 5.37%, N 6.65%.

EXAMPLE -1 28 N-Benzoyldehydro-3-cyclohexylalanyl-L-tyrcsine Mp 126-128 ° C; [α] 20 D + 0.8 ° (c = 1; dimethylformamide); Yield 60.3% of the Theory.

C25H28N2O calculated: C 68.79%, H 6.46%, N 6.42%; found: e 68.59 %, H 6.32%, N 6.24.

EXAMPLE 1 29 N-Bentzoyldehydro-3-benzyl-3-methylalanyl-L-leucine Mp 98-99 ° C; [α] D20 111.10; Yield 39% of theory.

C24H28N2O4 calculated: C 70.57%, H 6.915%, N 6.86%; found: C. 70.47%, H 6.74%, N 6.92%.

B e i s p i-e e N-benzoyldehydro-3- (2-thienyl) alanyl-L-proline m.p. 125 ° C (unsharp); [α] D20 + 2.0 °; Yield 52% of theory

C19H18N2O4S calculated: C 61.60%, H 4.90%, N 7.56%, s 8.66%; found: C 61.59%, H 4.80%, N 7.50%, s 8.79%.

Example 31 N-acetyldehydrophenylalanyl- (1-carboxy-1-cyclopentyl) amide M.p. 217 ° C (dec.); Yield 50.7% of theory.

C17H20N2O4 calculated: C64.54%, H 6.37%, N 8.86%; found: C, 64.85 %, H 6.55%, N 8.41%.

B e i s p 1 e 1 32 N-acetyldehydro-3- (2-thienyl) alanyl-L-tyrosine m.p. 227-228 ° C; [α] D20 -36.75 °; Yield 71.06% of theory

C18H18N2O5S calculated: C 57.74%, H 4.85%, N 7.48%, S 8.56%; found: C 57.61%, H 4.84%, N 7.49, S 8.62.

B e i s p 1 e 1 33 N-trifluoroacetyldehydrophenylalanyl-L-tyrosine tert-butyl ester The reaction takes place in dimethylformamide without NaOH.

M.p. 182-183 ° C; [α] 20 D -29.7 ° (c = 1; dimethylformamide); yield 84% of theory.

C24H25F3N2O5 calculated: C 60.24%, H 5.27%, 9 F 11.91%, N 5.86%; found: C 60.30%, H 5n30%, F 11.90%, N 5.93%.

B e i s p i e 1 ^ 34 N-trifluoroacetyldehydrophenylalanyl-L-tyrosine m.p. 165-1750C; 20-57.4 ° (c = 1; dimethylformamide); D20 -57.4 ° Yield 91% of theory.

C20H17F3N2O5 calculated: C 56.87, H 4.06, F 13-, 5%,%, N 6.63%; found: C 56.92%, H 4.05%, F 13.4%, N 6.61%.

Example 1 35 N-Phenacetyldehydro-3- (2-thienyl) alanyl-L-tyrosine tert-butyl ester made in dimethylformamide without NaOH.

M.p. 110-1200C (crude product); Yield 51.5% of theory.

This compound was further processed by stirring for 1/2 hour with trifluoroacetic acid N-phenacetyldehydro-3- (2-thienyl) alanyl-L-tyrosine M.p. 135-140 ° (dec.); [α] D20 -41 °; Yield 49% of theory

C24H22N2O5S calculated: C 63.98%, H 4.92%, N 6.22%, S 7.12%, found: C 63.79%, H 4.82%, N 6.29%, S 7.07%.

Ex. 36 N-phenylacetyldehydro-3- (2-thienyl) alanyl-L-leucine from 4.05 g (0.015 mol) of 2-benzyl-4- (2-thenylidene) -5 (4H) -oxazolone and 3 g (0.0165 Mol) L-leucine methyl ester hydrochloride in dimethyl form: lid in the presence of triethlamine by stirring for two hours and standing for twelve hours, diluting with water, etherifying, Wash out with dilute citric acid and evaporate the dried essential Solution forms N-phenylacetyldehydro-3- (2-thienyl) alanyl-L-leucine methyl ester. M.p. 160-1610C; Yield 4.75 g (76.3% of theory

4.66 g (0.011 mol) of the above compound were found at OOC in 50 ml of tetrahydrofuran dissolved, stirred with 11 ml of nNaOH for two hours at room temperature, the reaction solution extracted with chloroform, the aqueous phase acidified and then extracted with chloroform.

3.8 g (63.3% of theory) of N-phenacetyldehydro-3- (2-thienyl) alanyl-L-leucine were obtained obtained with m.p. 207-208 ° C.

[α] D20 -45.2 °.

C21H24N2O4S.

Calculated: C 62.98%> H 6.04%, N 6.99%, S 8.00%; found: C. 62.92%, H 6.02%, N 7.03%, S 7.92%.

EXAMPLE 1 37 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine M.p. 13500 (unsharp); Yield 41.2% of theory.

C23H20N2O5S calculated: C 63.29%, H 4.62%, N 6.43%, S 7.34%; found: C 63.25%, H 4.67%, N 6.37%, S 7.38%.

Ex. 1 38 N-Benzoyldehydrp-3- (2-thienyl) alanyl-L- (p-nitrophenyl) = alanine mp 125 ° C (unsharp); [α9D20 -67.3 °; Yield 60% of theory

C23H19N3O6S calculated: C 59.35%, H 4.11%, N 9.03%, S 6.89%; found: C 59.39%, H 4.36%, N 9.01%, S 6.71 S.

Ex. 39 N-nicotinoyldehydro-3- (2-thienyl) alanyl-L-tyrosine Mp 160 ° C (unsharp); [α] 20 D -8.35 °; Yield 50% of theory

C22H19N3O5S calculated: C 60.40%, H 4.38%, N 9.60%, S 7.33%; found: C 60.57%, H 4.58%, N 9.75%, S 7.32%.

For example 40 N- (3-trifluoromethylbenzoyl) dehydro-3- (2-thienyl) alanyl-L-tyrosine Mp 125 ° C (unsharp); [α] D20 -8.9 °; Yield 48% of theory

C24H19F3N2O5S calc .: C 57.14%, H 3.80%, F 11.30%, N 5.55%, S 6.36 %; Found: C 56.95%, H 3.81%, F 11.40%, N 5.45%, S 6.45%.

Example 41 N-nicotinyldehydro-3- (2-thienyl) alanyl-L- (p-nitrophenyl = alanine m.p. 197 ° C (dec.); [α] D20 -98 °; Yield 75% of theory Th.

C22H18N4O6S calculated: C 56.64%, H 3.89%, N 12.01%, S 6.87%; found: C 56.55, H 3.91%, N 12.05 ra, S 6.89%.

Ex. 42 N-Benzoyl-3-methyl-3- (2-thienyl) dehydroaianyl-L-tyrosine M.p. 1280C; [α] D20 +15.60; Yield 66.7% of theory.

C24H22N2O5S calculated: C 63.98%, H 4.92%, N 6.22%, S 7.12%; found: C 64.14%, H 4.93%, N 6.34%, S 7.03%. Example 1 N-acetyldehydro-3- (2-thienyl) alanyl-D-tyrosine Mp 221-222 ° C; [α] D20 + 36.8 °; Yield 51.49% of theory

C18H18N2O5S calculated: C 57.74%, H 4.85%, N 7.48%, S 8.56%; found: C 57.83%, H 4.89%, N 7.44%, S 8.67%.

For example 1 N-cinnamoyldehydrophenylalanylglycine m.p. 159-160; yield 75% of theory.

C20H18N20 H20 calculated: C 65.20%, H 5.47%, N 7.61%; found: C 65.27%, H 5.32%, N 7.76%.

Ex. 1 45 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-phenylalanine Mp 100 ° C; [α] 20 D -4.8 ° (c = 1; dimethyl sulfoxide); Yield: 80% of theory.

C23H20N2O4S calculated: C 65.70%, H 4.79%, N 6.66%, S 7.63%; found: C 65.64%, H 5.01%, N 6.50%, S 7.41%.

EXAMPLE 1 46 N-Benzoyldehyro-3- (2-thienyl) alanyl-L-leucine m.p. 110-100 ° C [α] 20 104-9 ° (c = 1; dimethyl sulfoxide); D yield 90% of theory.

C20H22N2O4S calculated: C 62.16%, H 5.74%, N 7.25%, S 8.29%; found: C 62.19%, H 5.84%, N 7.20%, S 8.23%. B e 1 s p i e 1 47 N-acetyldehydro-3- (2-thienyl) -L-phenylalanine Mp> 230 ° C; [α] 20 D -68.8 ° (c = 1; dimethyl sulfoxide); Yield: @ 90% the theory.

C18H18N2O4S calculated: C 60.32%, H 5.07 g, N 7.82%, S 8.93%; found: C 60.37%, H 5.04%, N 7.81%, S 8.96%.

EXAMPLE 1 N-Benzoyl-3-methylphenyldehydroalanyl-L-leucine, m.p. 102-104 ° C; [α] D20 -8.1 °; Yield 75% of theory

C23H26N2O4 calculated: C 70.03%, H 6.64 g, N 7.10%; found: C, 69.29 %, H 6.48 X, N 7.02%.

Example 49 N-cinnamoyldehydrophenylalanyl-L-tyrosine mp 172-174 ° C, [α] D20 -24 ° yield 30% of theory

C27H24N2O5 calculated: C 71.04%, H 5.3%, N 6.14%; found: C 70.85 %, H 5.39%, N 6.16%.

Example 50 N-acetyldehydro-3- (2-thienyl) alanine, melting point 230 ° C (dec.) Literature preparation.

Example 51 N-acetyldehydro-3- (2-thienyl) alanyl-L-leucine m.p. > 230 ° C; [α] 20 D -11.0 ° (c = 1; dimethyl sulfoxide); Yield: 90% of theory.

C15H20N2O4S calculated: C 55.54%, H 6.21%, N 8.64%, S 9.88%; found: C 55.72%, H 6.27%, N 8.59%, s 9.87%.

EXAMPLE 1 52 N-benzoyldehydroisoleucyl-L-tryosine m.p. 1070C; [α] D20 -12.1 °; Yield 31.5 1 of theory

C22H24N2O5 calculated: C 66.65%, H 6.10%, N 7.07%; found: C, 66.57 %, H 6.17%, N 6.90%.

EXAMPLE 1 53 N-Benzoyl-3-methyl-3-cinnamenyldehydroalanyl-L-tyrosine M.p. 130 ° C; [α] D20 -5.5 °; Yield 96% of theory

C28H26N2O5 calculated: C 71.47%, H 5.57%, N 5.95%; found: C. 71.60%, H 5.57%, N 5.87%.

B e i 5 p i e 1 N-acetyldehydrophenylalanyldehydro (3-chlorophenyl) alanyl-L-tyrosine by aninolysis of 4- (3-chlorobenzylidene) -2- (1-acet = amido-2-phenylethylene) -5 (4H) -oxazolone with L-tyrosine.

Mp 191-193 ° C; [α] 20 D -154.3 ° (c = 1; dimethylformamide); yield 78.5% of theory.

C29H26ClN3O6 calcd: C 63.56 S, H 4.78 S, Cl 6.47 S, N 7.67%; found: C 63.69%, H 4.76%, Cl 6.54, S, N 7.70%.

EXAMPLE 55 N-Acetyldehydrophenylalanyldehydrotyrosine 6.09 g (0.0175 mole) 2- (1-acetamido-2-phenylethylene) -4- (4-hydroxybenzylidene) -5 (4H) -oxazolone are mixed with 46.9 ml of NaOH and 40 ml of acetone for three hours at room temperature touched. After the acetone has been distilled off, the aqueous reaction solution is acidified with 47.6 ml of nHCl and recrystallization of the precipitate which has separated out and filtered off from ethanol / petroleum ether, 3.75 g (58.6% of theory) of N-acetyldehydrophenylalanyldehydrotyrosine are obtained obtained from melting point 202-206 ° C.

Literature preparation.

The following were prepared analogously from the corresponding oxazolones: B e i s p i e 1 56 N-acetyldehydrophenylalanyldehydro- (p-nitrophenylvalanine m.p. 1810 C; Yield 56.4% of theory.

C20H17N3O6 calculated: C 60.76%, H 4.33%, N 10.63%; found: C. 60.86%, H 4.51%, N 10.46%.

Eg 1 57 N-acetyldehydrophenylalanyldehydro (4-chlorophenyl) alanine M.p. 1770 C; Yield 60.9% of theory.

C20H17ClN2O4 calculated: C 62.42%, H 4.45%, N 7.28%, Cl 9.21%; found: C 62.49%, H 4.47%, N 7.37%, Cl 9.24%.

Ex. 58 N-acetyldehydrophenylalanyldehydro (p-fluorophenyl) alanine Mp 172 ° C; Yield 65.27% of theory.

C20H17FN2O4 # H2O calculated: C 62.17%, H 4.96% -, F 4.92%, N 7.25 Z; Found: C 62.30%, H 4.94 g, F 4.70 Z, N 7.25%.

B e i s p-i e 1 59 N-acetyldehydrophenylalanyldehydro (4-dimethylaminophenyl) -alanine Mp 153-155 ° C; Yield 36.2% of theory.

C22H23N304 calculated: C 67.16%, H 5.89%, N 10.68%; found: C. 67.03%, H 6.00%, N 10.52%.

Example 69 N-acetyldehydrophenylalanyldehydro (3-chlorophenyl) älanine Mp 183 ° C; Yield 88.4% of theory.

C20H17ClN2O4 calculated: C 62.42%, H 4.45%, Cl 9.21%, N 7.28%; found: C 62.54%, H 4.45%, Cl 9.23%, N 7.18%.

The following examples were carried out in tetrahydrofuran without NaOH.

Ex. 1 61 N-Benzyldehydro-3- (2-thienyl) alanyl-L-tyrosine methyl ester Mp 120 ° C (unsharp); [α] D20 -4.6 °; Yield 95% of theory

C24H22N205S calculated: C 63.98%, H 4.92%, N 6.22%, S 7.12%; found: 9 63.78%, H 4.93%, N 6.07%, S 7.02%.

B e i 5 p i e l 62 N-acetyldehydro-3- (2-thienyl) alanyl-L-tyrosine methyl ester Mp 243-245 ° C; [α] 20 D -78.1 ° (c = 1; dimethyl sulfoxide) C19H20N2O5S yield 65% of theory.

calculated: C 58.75%, H 5.19%, N 7.21%, s 8.26%; found: C, 58.45 %, H 5.35%, N 7.17%, S 8.47%.

EXAMPLE 1 63 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine benzyl ester is formed from the acid and benzyl alcohol by heating for 1/2 hour at 800C in Presence of hydrogen chloride.

Mp 95 ° C (unsharp); [α] D20 -2.0 °; Yield 79% of theory

C30H26N2O5S calculated: C 68.42%, H 4.98%, N 5.32%, S 6.09%; found: C 68.42%, H 4.96%, N 5.30%, S 6.02%.

B e i 5 p i e 1 64 N-acetyldehydro-3- (2-thienyl) alanine salt with morpholine 1.5 g of the dehydroamino acid are mixed with three times the amount of morpholine, diluted with methanol and evaporated to dryness.

Mp 173 ° (dec.); Yield 89% of theory.

C13H18N2O4S calculated: C 52.4%, H 6.0 g, N 9.4%, S 10.7%; found: C 52.8%, K 6.2%, N 9.4%, S 11.1%.

The following amides were made from the corresponding methyl esters by standing in a mixture with the corresponding amines (1 mol ester to 8 mol amine) in methanol cäcr tetrahydrofuran and working up by evaporation and purification Xiesel gel (reaction time 3 - 340 hours) produced.

Ex. 65 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine amide M.p. 2100C; [α] D20 -62.0 °; Yield 86% of theory.

C23H21N3O4S calculated: C 63.43%, H 4.86%, N 9.65%, S 7.36%; found: C 63.25%, H 4.96%, N 9.59%, S 7.38%.

Ex. 1 66 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine-N'-hexylamide Mp 115 ° C (unsharp); [α] D20 -63.4 °; Yield 80% of theory

C29H33N3O4S calculated: C 67.03%, H 6.40%, N 8.09%, S 6.17%; found: C 67.22%, H 6.51%, N 8.19%, S 6.08%.

Ex. 1 67 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine-N-methylamine M.p. 145 ° C (unsharp); [α] D20 -61.7 °; Yield 90.2% of theory

C24H23N3O4S calcd: C 64.12%, H 5.16 Z, N 9.35%, S 7.13%; found: e 64, o4%, H 4.99%, N 9.42%, S, 07%.

EXAMPLE 1 68 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine-N'-cyclohexylamide M.p. 1100C (unsharp); [α] D20 50.90; Yield 44% of theory

C29H31N3O4S calculated: C 67.29%, H 6.04%, N 8.12%, S 6.19%; found: C 67.38%, H 6.33%, N 8.09%, S 5.88%.

B e i s p i-e 1 69 N-Benzoyldehydro-3- (2-thienyl) alanyl-L-tyrosine-N ', N'-dimethyfamide M.p. 1300C (unsharp); [α] 20 D -2.2 °; Yield 13% of theory

C25H25N3O4S calculated: C 64.77%, H 5.44%, N 9.06%> s 6.92%; found: C 64.64%, H 5.41%, N 9.06%, -S 6.77%.

B e i 5 p i e 1 70 N-BenzOyldehydro-3- (2-thienyl) alanyl-L-tyrosine morpholide M.p. 1200C (unsharp); [α] D20 -0.7 °; Yield 22% of theory

C27H27N3O5S calculated: C 64.14%, H 4.38%, N 8.32%, S 6.34%; found: C 63.92%, H 5.53%, N 8.27%, S 6.09%.

Ex. 1 71 N-Benzoyldehydro-3- (2-thienyl) -L-tyrosine-N'-benzylamide Mp 133 ° C; [α] 20 D -69.83 °; Yield 68% of theory

C30H27N3O4S calculated: C 63.55%, H 5.18%, N 7.99%, S 6.10%; found: C 63.65%, H 5925%, N 8.13, a corresponding one instead of sodium hydroxide 5 (4H) -oxazolones the following are formed from the corresponding 5 (4H) -oxazolones Compounds: Example 1 72 N-acetyldehydro-3- (2-thienyl) alanine-N'-methylamide Mp. 183 ° C, yield 89% of theory

C10H12N2O2S found: C 53.55%, H 5.39%, N 12.52%, S 14.30%; found: C 53.66%, H 5.52%, N 12.52%, S 14.23%.

For example, N-acetyldehydro-3- (2-thienyl) alanine-N'-1,1-dimethyl-2-propionylamide Mp 197-200 ° C; Yield 36.2% of theory.

C14H16N2O2S calculated: C 60.85%, H 5.84%, N 10.14 S, 5 11.60 X, found: C 60.64%, H 6.06%, N 10.08%, S 11.38%.

EXAMPLE 74 N-acetyldehydro-3- (2-thienyl) alanine morpholide m.p. 159 ° C; Yield 82.7% of theory

C13H16N2O3S calculated: C 55.69%, H 5.75%, N 9.99%, s 11.4%; found: C 55.80%, H 5.73%, N 10.09%, S 11.22%, for example 1 75 N-cinnamoyldehydroalanine-N'-methylamide Mp 114-118 ° C; Yield 70% of theory

C19H18N2O2 calculated: C 74.5%, H 5.9%, N 9.1%; found: C. 74.4 %, H 6.0%, N 9.0%.

For example, 76 N-cinnamoyldehydroalanine-1,1-dimethyl-2-propynylamide Mp 200-203 ° C; Yield 40% of theory

C23H22N2O2 calculated: C 77.1%, H 6.2%, N 7.8%; found: C, 77.1 %, H 6.2%, N 8.0%.

Ex. 77 N-cinnamoyldehydroalanine morpholide mp 179-182 ° C; Yield 50 Xf of theory

C22H22N203 calculated: C 72.9%, H 6.1%, N 7.7%; found;. C 72.8 %, H 6.2%, N 7.5%.

Claims (6)

Claims 1) tumor and / or tissue-dissolving drug, characterized by a content of at least one dehydrooligopeptide. 2) Tumor- and / or tissue-dissolving medicament, characterized by a content of at least one dehydrooligopeptide of the general formula in which R1 represents a hydrogen atom, an optionally substituted alkanoyl group, an optionally substituted alkenoyl group, an alkoxycarbonyl group, an optionally substituted aroyl group, an optionally substituted aralkanoyl group or aralkenoyl group, an aralkoxycarbonyl group, a carbamoyl group, an optionally substituted heteroaroyl group, an optionally substituted lower alkylsulfonyl group substituted arylsulfonyl group, R2, R7 ur, d R12 in each case stands for a hydrogen atom, a lower alkyl group or in which R2, R7 or R12 together with the respectively adjacent substituents or R8 or R1. form an alkylene chain with three to four carbon atoms, R4 and Rg each represent a hydrogen atom or a lower alkyl group, R3, R8 and R13 each represent a hydrogen atom, a lower straight or branched chain optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl or aral = kenyl group, an indolylmethyl group, an optionally substituted Heterocyclusr.ethylgruppe with four to seven ring members and one to two heteroatoms, R5 and R10 each represent a hydrogen atom or an optionally substituted lower alkyl group, and R11 each represent a optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocycle with five to seven ring members and one to two heteroatoms, represents an optionally substituted aralkyl group, an optionally substituted aralkenyl group or in which R6 and / or R1l in connection with P5 resp. R10 for an optionally substituted alkylene or. Alkenylene chain with three to seven carbon atoms, R14 for a hydrogen atom or in Connection with P.13 and the carbon atom between them for an alicyclic with four to seven carbon atoms, R15 represents a hydroxyl group, one optionally substituted lower alkoxy or alkenyloxy group, one amino group, one lower optionally substituted alkylamino or dialkylamino group or alkenylamino or dialkenylamino group for an optionally substituted arylamino group, an optionally substituted mono- or diaralkylamino group, a nitrogen containing heterocycle with four to seven ring members, in which one more up to two further heteroatoms can be contained, or for one by alicyclics is an amino group substituted by three to seven ping members, m, n, p and q stand for the digits 0 or 1 with the proviso that not all four Letters may be 1 at the same time, or by the content of a corresponding one pharmaceutically acceptable salt. 3) Process for the production of a tumor- and / or tissue-dissolving Means, characterized in that dehydrooligopeptides with inert, non-toxic, pharmaceutically suitable carriers mixed. 4) Process for the production of a tumor- and / or tissue-dissolving Means, characterized in that dehydrooligopeptides according to claim 2 with inert, non-toxic, pharmaceutically suitable carriers mixed. 5) Methods for lysing human and / or animal tissues and / or tumors, characterized in that one dehydrooligopeptide humans or Applied to animals suffering from tissue damage and / or tumors. 6) Methods for lysing human and / or animal tissues and / or tumors, characterized in that dehydrooligopeptides according to the Formula in claim 2 applied to humans or animals suffering from tissue damage and / or Suffering from tumors.