IE60864B1 - The synthesis of peptide aminoalkylamides and peptide hydrazides by the solid-phase method - Google Patents

Abstract

Compounds of the formula I <IMAGE> in which A is hydrogen or an amino protective group, B is an amino acid residue, X is alkylene or aralkylene, Y<1>, Y<2>, Y<3> and Y<4> are identical or different and are hydrogen, methyl, methoxy or nitro, V is hydrogen or a carboxyl protective group, W is -[CH2]n- or -O-[CH2]n-, m is 0 or 1, n is 0 to 6 and p is 0 to 5, are prepared as described and used in the solid-phase synthesis.

Description

The introduction of an aminoalkylamide into the C-terminal end of a biologically active peptide has in some cases had beneficial effects on the metabolic stability and activity. The preparation of the peptides 5 modified in this way has made use of the classical coupling of fragments in solution (EP-A-179 332).

In the solid-phase synthesis of peptides (see Patchornik, Cohen in Perspectives in Peptide Chemistry, pages 118 128 (Karger, Basle 1981)) the reactive chains are often not grafted directly onto the synthetic resin material, but are bonded to the carrier material by what are called spacers or links. The literature (for example Atherton, Sheppard in Perspectives in Peptide Chemistry, pages 101 - 117 (Karger, Basle 1981)) discloses, for example, such spacers (called linkage agents) which have the formulae VI, VII and VIII.

H0CH2 /yCR2~CH2· C02H HOCH2-/A- OCH2- C02H HOCH^Z CO2H (VI) (VII) (VIII) CA 98: 126602 q describes acid-labile spacers of the formula Vila (Vila) 0CH,C0,H Only peptides which have a free C-terminal carboxylic acid group are amenable to direct solid-phase synthesis with the aid of these spacers. After elimination of the peptide, the spacer is present unchanged, that is to say no spacer fragment transfer has taken place.

Peptides with C-terminal modification by aminoalkylamide or hydrazide are obtainable by the solid phase method with the aid of the spacers described in CA 98: 126602 g not directly but only by a combined multistage process, it having been necessary to couple a diaminoalkyl radical onto the peptide in solution after prepared in the solid phase.

The object of the invention is to provide spacers which make it possible to prepare peptides with C-terminal modification by aminoalkylamide or hydrazide directly by means of solid-phase synthesis. This object is achieved by the compounds of the formula I.

Thus the present invention relates to compounds of the formula I A- [B]p-NH- [X]m-NH-C0-0-CH2 yl y2 in which A ι denotes hydrogen or an amino protective group which is labile to bases or labile to weak acids, represents identical or different amino acid residues, denotes (Cj-Cij)-alkylene or (Ce-C10)-aryl-(C1-C12)alkylene, 73 and Y* are identical or different and denote hydrogen, methyl, methoxy or nitro, at least one of these radicals denoting hydrogen, V denotes hydrogen or a carboxyl protective group, W denotes -[CH2]„- or -O-[CH2]n-, m is 0 or 1, n is an integer from 0 to 6, and p is an integer from 0 to 5.

Preferred compounds of the formula I are those in which p is 0, 1 or 2, in particular 0, and/or in which m is 1.

X is preferably -[CH2]q-, it being possible for g to be 1-12, preferably 1-8, Preferably at least 2, in particular at least 3, of the radicals Υ1, Y2, Y3 and Y* denote hydrogen.

Protective groups which are labile to bases or labile to weak acids are, in particular, urethane protective groups, such as Fmoc, Ddz, Bpoc, Msc, Peoc, Pse and Tse, preferably Fmoc (see, for example, Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 - 23).

B represents the residue of an amino acid, preferably of an α-amino acid, which, if chiral, can be present in the D or L form. Preference is given to residues of naturally occurring amino acids, their enantiomers, homologs, derivatives and simple metabolites (see, for example, Wunsch et al., Houben-Weyl 15/1 and 2, Stuttgart, Thieme 1974). Thus, for example, the following are suitable, Aad, Abu, 7Abu, ABz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, 0Aib, Ala, 0Ala, AAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, hCys, His, hSer, Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, 0Lys, ALys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, £Thi, Thr, Thy, Thx, Tia, Tie, Tly, Trp, Trta, Tyr, Val and the residues of the corresponding enantiomeric D-amino acids.

Functional groups in the side chains of the said amino acid residues can be in protected form. Suitable protective groups are de.Wem, scribed in Hubbuch, Kontakte (Merck) 1979. No. 3, pages 14 - 23, and in Bullesbach, Kontakte (Merck) 1980. No. 1, pages 23 - 35. The preferred groups are those which are stable to bases and weak acids and can be eliminated using strong acids.

Alkylene can be straight-chain or branched. Examples of definitions of (C6-C10) -aryl are phenyl, tolyl or naphthyl; phenyl is preferred.

A carboxyl protective group V is, for example, (Ci-Cg)-alkyl or (C7-Cu)-aralkyl; preference is given to methyl, ethyl, tert.butyl, benzyl and modified benzyl, such as p-chloro-, ρ-bromo-, p-nitro- and p-methoxybenzyl and the nitrogen analog picolyl. In the wider sense, such protective groups include activated ester groups such as ONSu, OBt, OObt or p-nitrophenoxy.

The invention also relates to a process for the preparation of the compounds of the formula I, which comprises a) reaction of a compound of the formula II Y3 y4 R-CO-O-CH2-C y-w-co2-v (II) in which R represents a leaving group which can be detached nucleophilically, V represents a carboxyl protective group, and W, Y1, Y2, Y3 and Y* are as defined in claim 1, with a compound of the formula III A-[ Β ] p—NH-[ X ] D-NH2 (III) in which A represents an amino protective group which is labile to bases or labile to weak acids, and Β, X, p and m are as defined in claim 1, and elimination of, where appropriate, one or both of the protective groups A and/or V in the resulting protected compound of the formula I, with the formation of the free NH2 and/or CO2H group(s), the preferred processes being those in which V is selectively eliminated, for example by reductive cleavage with Zn/glacial acetic acid, or b) reaction of a compound of the formula I in which A denotes hydrogen, and Β, X, Y1, Y2, Y3, YA, V, W, m, n and p are as defined in claim 1, with a compound of the formula IV A-[B]5.p-OH (IV) in which A, B and p are as defined above, but A does not denote hydrogen, or its active ester, halide or azide, and, if V is not hydrogen, where appropriate elimination of a carboxyl protective group V with the formation of the carboxyl group.

A leaving group R which can be detached nucleophilically is, for example, halogen, such as chlorine, bromine and iodine, or activated aryloxy, such as p-nitrophenoxy.

The reaction of a compound of the formula II with a compound of the formula III is preferably carried out in an aprotic solvent such as, for example, THF, DMF, CHC13 or CH2C12, advantageously in the presence of a base such as, for example, a tertiary amine, for example ethyl triisopropylamine, triethylamine or pyridine, the addition of an acylation catalyst such as, for example, DMAF, HOObt or HOBt having an advantageous effect, at a temperature between 0°C and the boiling point of the reaction mixture, preferably between 0°C and 40°C.

Compounds of the formula I (A = hydrogen) are reacted with compounds of the formula IV, their active ester, halide or azide preferably in an organic solvent, such as DMF, advantageously in the presence of a base such as, for example, a tert.amine, at a temperature between -10°C and the boiling point of the reaction mixture, preferably at room temperature. Examples of suitable active esters are the ONSu, CBt, OObt and p-nitrophenoxy compounds. Preferred halogen derivatives are the chlorides. Pyridinium perchlorate can be added to improve the solubility.

Compounds of the formula II are prepared by, for example, reacting esters of the formula IX yl γ2 w Y3 γ4 co2-v (XX) in which Y1, Y2, Y3, Y*, W and V are as defined above, but V does not denote hydrogen, with phosgene or phosgene derivatives such as, for example, nitrophenyl chloroformate in an aprotic polar solvent, for example THF or DMF, mixed with a tert, base, for example a tert, amine such as pyridine, preferably in the ratio 1 : 1, at a temperature between -40°C and room temperature, preferably between -20°C and 0°C.

The invention also relates to the use of a compound of the formula I, in which V denotes hydrogen and A does not denote hydrogen, in the solid-phase synthesis of compounds of the formula V P-NH-[X ]m-NH2 (V) in which P represents a peptide residue comprising g < p+1 α-amino acids, and X, m and p are as defined above, and to a process for the preparation of a peptide of the formula V, in which Ρ, X, m and p are as defined above, by solid-phase synthesis, which comprises coupling a compound of the formula I, in which A does not denote hydrogen, and V represents hydrogen, to a resin, eliminating the protective group A, stepwise coupling on q-p α-amino acids which are, where appropriate, in the form of their activated derivatives and which have been temporarily protected by amino protective groups which are labile to bases or labile to weak acids and, after construction is complete, liberating the peptide from the resin by treatment with a moderately strong to strong acid, the temporarily introduced side-chain protective groups being eliminated again at the same time or, by suitable measures, subsequent thereto.

If necessary to prevent side reactions or for the synthesis of specific peptides, the functional groups in the side chain of amino acids are additionally protected by suitable protective groups (see, for example, T.W. Greene, Protective Groups in Organic Syntheses, New York, John Wiley & Sons, 1981), those primarily used being Arg(Tos), Arg(Mts), Arg(Mtr), Asp(OBzl), Asp(OBut), Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(OBzl), Glu(OBut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-2), Lys(Boc), Met(O), Ser (Bzl), Ser(But), Thr (Bzl), Thr(But).

The resins used as carrier material are commercially available. BHA and MBHA resins are preferred.

The peptide of the formula V is then cleaved off by treatment with the moderately strong to strong acids customarily used in peptide synthesis (for example trifluoroacetic acid and HF), there being cleavage of the urethane protective group contained in the spacer.

It is possible to use as coupling reagent for the compound of the formula I (V = H) and the other amino acid derivatives all possible activating reagents used in peptide synthesis, see, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of organic chemistry), volume 15/2, but in particular carbodiimides such as, for example, N,N'-dicyclohexylcarbodiimide, Ν,Ν'-diisopropylcarbodiimide or N-ethyl-N'-(3-dimethylaminopropyl) carbodiimid. This coupling can be carried out directly by addition of the amino acid derivatives with the activating reagent and, where appropriate, an additive which suppresses racemization, such as, for example, 1-hydroxybenzotriazole (HOBt) (W. KSnig, R. Geiger, Chem. Ber. 102. 708 (1970)) or 3-hydroxy-4-oxo-3,4-dihydroxybenzotriazine (HOOBt) (W. Konig, R. Geiger, Chem. Ber. 103. 2054 (1970)) to the resin, or the preactivation of the amino acid derivative can be carried out separately as the symmetric anhydride or HOBt or HOObt ester, and the solution of the activated species in a suitable solvent can be added to the peptide-resin which is ready for coupling.

The coupling and activation of the compound of the formula I (V = H) and of the amino acid derivatives with one of the abovementioned activating reagents can be carried out in dimethylformamide or methylene chloride or a mixture of the two. The activated amino acid derivative is normally used in a 1.5- to 4-fold excess. In cases where incomplete coupling occurs, the coupling reaction is repeated, without previously carrying out the deblocking of the α-amino group of the peptide-resin which is necessary for coupling the next amino acid in the sequence.

Successful completion of the coupling reaction can be checked using the ninhydrin reaction as described, for example, by E. Kaiser et al. Anal. Biochem. 34, 595 (1970). The synthesis can also be carried out automatically, for example using an Applied Biosystems model 430A peptide synthesizer, it being possible to use either the synthesis programs provided by the apparatus manufacturer or those constructed by the user himself. The latter are particularly employed when amino acid derivatives protected with the Fmoc group are used.

When the peptide amides are cleaved off the resin with hydrogen fluoride and trifiuoroacetic acid, it is customary to add substances as cation traps, such as phenol, cresol, thiocresol, thioanisole, anisole, ethanedithiol, dimethyl sulfide, ethyl methyl sulfide or a mixture of two or more of these auxiliaries. In this connection, the trifiuoroacetic acid can also be used diluted by suitable solvents such as, for example, methylene chloride.

Abbreviations used: Fmoc 9-fluorenylmethyloxycarbonyl Ddz a, a-dimethyl- 3,5-dimethoxybenzy loxycarbonyl Bpoc 2-[4-biphenyl]-2-propyloxycarbonyl Msc methylsulfonylethyloxycarbonyl Peoc pyridylethyloxycarbonyl Pse phenylsulfonylethyloxycarbonyl Tse tolylsulfonylethyloxycarbonyl HONSu N-hydroxysuccinimide HOBt 1-hydroxybenzotriazole HOObt 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine THF tetrahydrofuran DMF dimethylformamide DMAP dimethylaminopyridine The examples which follow serve to illustrate the present invention without intending to confine it to them.

Example 1: Methyl 4-hydroxymethylphenoxyacetate 18.2 g of 4-hydroxymethylphenoxyacetic acid are dissolved together with 17.1 ml of Ν,Ν-diisopropylethylamine in ml of DMF, and then 6.1 ml of methyl iodide are added to the stirred solution. The mixture warms slightly during this. The reaction is complete after 3 h. The solvent is removed in vacuo. The residue is taken up in ether, and the solution is extracted once with 0.5 N hydrochloric acid. The aqueous phase is then extracted three times with ether, and the combined ether phases are washed with aqueous sodium bicarbonate solution and concentrated. The residue is dissolved in ethyl acetate and filtered through a short silica gel column. The pale yellowish oil which is obtained after concentration crystallizes on being left to stand.

NMR and mass spectrum are consistent with the indicated structure.

Example 2: Fmoc-NH- (CH2)4-NH-CO-O-CH2 O-CH2-COOCH3 9.8 g of methyl 4-hydroxymethylphenoxyacetate are dissolved in 200 ml of dry CH2C12, and then 10.1 g of p15 nitrophenyl chloroformate and 7 ml of triethylamine are added. The mixture is boiled under reflux for about 6 h, until the precursor has completely reacted. Then a suspension of 15.5 g of Fmoc-NH-(CH2)4-NH2 (prepared by reaction of Boc-NH-(CH2)4-NH2 with Fmoc-ONSu followed by elimination of Boc) in 100 ml of dry CH2C12 and a further 7 ml of triethylamine are added, and the mixture is boiled under reflux. After the reaction is complete, the solvent is removed in vacuo, and the residue is digested with ether and filtered off with suction. The residue on the filter is washed with agueous 1 N Na2CO3 solution and then with hot water, and is dried under high vacuum in a desiccator.

Melting point 122-124 °C, NMR and mass spectrum are consistent with the indicated structure.

Example 3 .2 g of the ester obtained as in Example 2 are suspended in 100 ml of methanol, and 6 equivalents of an agueous 1 N NaOH solution are added. After the reaction is complete, the pH is adjusted to 3 with agueous 1 N HCl, and the methanol is removed in vacuo. The precipitate is filtered off with suction, washed with a little H2O, and then digested in ether and again filtered with suction. Melting point starts at 196°C (decomposition), NMR and mass spectrum are consistent with the indicated structure.

Example 4: Fmoc-Ph·-NH- ((¾)4-10-CO-O-CH2 -COOH 1.5 g of the product obtained as in Example 3 are suspended in 50 ml of dry DMF. Then, successively, 0.9 g of pyridinium perchlorate (to improve the solubility) and 2.6 g of Fmoc-Phe-OObt and 0.5 ml of triethylamine are added. The mixture is stirred at room temperature. After the reaction is complete, the solvent is removed in vacuo, and the residue is partitioned between ethyl acetate and H2O. The agueous phase is extracted once more with ethyl acetate, and the combined organic phases are dried and concentrated. The residue is digested with a little CHCI3 and is filtered off with suction. The residue on the filter is washed with a little ether and is dried. Melting point starts at 140°C (decomposition), NMR and mass spectrum are consistent with the indicated structure.

Example 5: Fmoc-Ph·-NH-(CH2)4-NH (4-methylbenzhydrylamine resin) O~ C&2~ CO1.4 g of the Fmoc-phenylalanine spacer acid obtained as in Example 4 are dissolved together with 350 mg of HOBt in 40 ml of dry DMF, and the solution is added to 3.66 g of 4-methylbenzhydrylamine resin (Nova Biochem, loading 0.4 mmol/g). Then 0.6 ml of diisopropylcarbodiimide is added, and the reaction is allowed to go to completion, mixing continuously. After the reaction is complete, the product is filtered off with suction, washed with DMF, isopropanol, CH2C12 and tert.-butyl methyl ester and is dried under high vacuum. Loading according to elemental analysis (nitrogen determination): 0.3 mmol/g.

Example 6: Synthesis of [des-Tyr2*, des-Arg23]-r-atriopeptin III-(4-amino)butylamide The peptide synthesis is carried out on 1 g of the abovementioned resin using OOBt esters of Fmoc-amino acids with an Applied Biosystems model 430A automatic peptide synthesizer and synthesis programs modified by ourselves.

For this, 1 mmol of each of the appropriate amino acid derivatives is weighed into the cartridges supplied by the manufacturer, Fmoc-Arg(Mtr)-OH, Fmoc-Asn-OH and FmocGln-OH are weighed together with 1.5 mmol of HOBt into the cartridges. These amino acids are preactivated directly in the cartridges by dissolving in 4 ml of DMF and adding 2 ml of 0.55 M solution of diisopropylcarbodiimide in DMF. The HOObt esters are dissolved in 6 ml of DMF and then pumped, in the same way as the amino acids arginine, asparagine and glutamine which are preactivated in situ, onto the resin which has previously been deblocked with 20% piperidine in DMF. The amino acids which are activated in situ are coupled twice.

After the synthesis is complete, the peptide butylamide is cleaved off the resin, simultaneously removing the side-chain protective groups with trifluoroacetic acid which contains thioanisole and m-cresol as cation traps. The residue obtained after removal of the trifluoroacetic acid in vacuo is subjected to digestion with ethyl acetate and centrifugation several times. The remaining crude peptide is treated with tributylphosphine in trifluoroethanol to remove the cysteine protective group. After the solvent has been removed, the residue is again digested with ethyl acetate and centrifuged. The reduced crude peptide is immediately oxidized with iodine in 80% strength agueous acetic acid, the excess I2 is removed with ascorbic acid, and the reaction mixture is concentrated to a small volume and then salt is removed on ®Sephadex G25 with agueous 1 N acetic acid. The fractions containing the pure peptide are combined and freeze-dried.

According to amino acid analysis, the amino acid composition of the peptide corresponds to the indicated formula.

Example 7: Phenylacyl 4-hydroxymethylphenoxyacetate 182 g of 4-hydroxymethylphenoxyacetic acid and 199 g of α-bromoacetophenone are dissolved in 600 ml of dry DMF, and then, at 0°C, 138 ml of triethylamine are rapidly added dropwise. The mixture is allowed to reach room temperature, and is stirred overnight. The DMF solution is poured into 3.5 1 of water, and the agueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated. The product precipitates out on evaporation. It is filtered off with suction, washed with ethyl acetate/nhexane 1:1 and dried under high vacuum.

Melting point: 94-95°C, NMR is consistent with the indicated structure.

Exemple 8s 0- CH2-CO£- CH2- CO g of phenacyl 4-hydroxymethyIphenoxyacetate are dissolved, under protective gas, in 500 ml of a 1:1 mixture of THF and pyridine, and the solution is cooled to -20’C. Then 21 g of p-nitrophenyl chloroformate dissolved in 100 ml of THF are added dropwise. After the mixture has been stirred at this temperature for 30 minutes, it is allowed to warm to 0°C and stirred into 1 1 of a half-saturated agueous NaCl solution at O’C, and the mixture is then stirred for 30 minutes. The precipitate is filtered off with suction, washed with ice-water and, after drying, triturated with n-hexane. Melting point: 142-145’C, NMR is consistent with the indicated structure.

Example 9: Fmoc-Phe-NH- (CH2)s-NH 9.3 g of the compound prepared in Example 8, 12.25 g of Fmoc-Phe-NH-(CH2)8-NH2 tri fluoroacetate and 3.26 g of HOObt are placed as the solid substances in a flask, and then a mixture of 2.58 g of ethyl diisopropylamine in 100 ml of dry DMF is poured over. The mixture is then stirred at 40’C for 3.5 hours and then stirred into 500 < ml of half-saturated agueous NaCl solution. The precipitate which separates out is filtered off with * suction, washed with ice-water and, after drying, triturated with ether/ethyl acetate.

Melting point: 147-150’C, NMR and MS are consistent with the indicated formula.

The following compounds (Examples 10 to 14) are prepared in analogy to Example 9: Example 10 Fmoc-Phe-NH-(CH2)4NR* CO-O Melting point 144-147‘C, NMR and MS correspond to the 5 indicated formula.

Example 11 Fmoc-Ala-NH-(CH2)8-NH-CO-O-CH2 °* CH2- CO2- CB2- CO-^~^ Melting point 179-181eC, NMR and MS correspond to the indicated formula.

Example 12 Fmoc-NH-(CH2)8-NH-CO Melting point 144-145eC, NMR and MS correspond to the indicated formula.

Example 13: Fmoc-NH-(CH2)5-NH Melting point 172-175°C, NMR corresponds to the indicated formula.

Example 14: Fmoc-NH- (CH2)4-NH-CO-O-CH2 O-CH2-CO2-CH2-CO-^^ Melting point 165-166°C, NMR corresponds to the indicated formula.

Example 15: Fmoc-Phe-NH 8.4 g of Fmoc-Phe-NH-(CH2)8NH-CO-0 are suspended in a mixture of 150 ml of glacial acetic acid and 50 ml of dichioromethane, and 12 g of zinc powder which has previously been activated by washing with 1 N HCl and dry ethanol are added in portions. After a few minutes, the suspension becomes more viscous and difficult to stir, while there is a slight evolution of heat. Hence a further 80 ml of glacial acetic acid and 50 ml of dichioromethane are added, and stirring is continued overnight. The mixture is then filtered with suction through a filter with a clarifying layer, washing with glacial acetic acid and dichioromethane. The filtrate is concentrated, and the oil which remains as residue is taken up in a little dichioromethane and stirred with ethyl acetate and ether. The precipitated product is filtered off with suction and dried under high vacuum.

Melting point: decomposition above 160°C, NMR and MS are consistent with the indicated formula.

In addition, the compounds of Examples 16 to 18 are prepared by the method described in Example 15: Example 16: Fmoc-Phe-NH-(CH2)4-NH-CO-O-CH2-^\Ϋθ-ΟΗ2-002Η Melting point: decomposition above 150°C, NMR and MS are consistent with the indicated formula.

Example 17: Fmoc-Phe-NH-(CH2)4-NH-CO-0 O-CH2-CO2H Melting point: decomposition above 160°C, consistent with the indicated formula.

Example 18: Fmoc-NH-(CH2)8-NH-CO-O-CH2-C NMR and MS are y O-CH2-CO2H Melting point: decomposition above 154°C, NMR and MS are consistent with the indicated formula.

Example 19: Fmoc-NH-(CH2)g-NH-CO-O-CH2 O-CH2-CO2CH3 The synthesis is carried out in analogy to Example 2. Melting point: 115-118*C, NMR and MS are consistent with the indicated formula.

Example 20: NH2-(CH2)fe-NH-CO-0-CH2 was prepared by the method described in Example 3.

Melting point: 184-187°C decomposition, NMR and MS are consistent with the indicated formula.

Example 21: Fmoc-Phe-NH (CH2)fe-NH-CO-0-CH2 O-CH2-CO2H The synthesis is carried out in analogy to Example 4.

Melting point: decomposition above 120°C, NMR and MS are consistent with the indicated formula.

Claims (11)

1. A compound of the formula I (I) A-[B] p -NH-[X] m -NH-CO-O-CH 2 in which A denotes hydrogen or an amino protective group which is labile to bases or labile to weak acids, B represents identical or different amino acid residues, X denotes (Cx-C^)-alkylene or (C 6 -C 10 )-aryl(Ci-C u ) -alkylene, Y 1 , Y 2 , Y 3 and Y* are identical or different and denote hydrogen, methyl, methoxy or nitro, at least one of these radicals denoting hydrogen, V denotes hydrogen or a carboxyl protective group, W denotes -[CH 2 ] n - or -O-[CH 2 ] n -, m is 0 or 1, n is an integer from 0 to 6, and p is an integer from 0 to 5.

2. A compound of the formula I as claimed in claim 1, in which p is 0, 1 or 2.

3. A compound of the formula I as claimed in claim 1 or 2, in which m is 1.

4. A compound of the formula I as claimed in one of claims 1 - 3, in which X denotes -[CH^-, and q denotes an integer from 1-12.

5. A compound of the formula I as claimed in one of claims 1-4, in which at least 2 of the radicals Y 1 , Y 2 , Y 3 and Y* denote hydrogen.

6. A process for the preparation of a compound as claimed in one of claims 1-5, which comprises a) reaction of a compound of the formula II yl γ2 R-CO-O-CH 2 a W-CO2-V γ3 γ4 (II) in which R represents a leaving group which can be detached nucleophilically, V represents a carboxyl protective group, and W, Y 1 , Y 2 , Y 3 and Y* are as defined in claim 1, with a compound of the formula III A- [B] p -NH-[X]„-NH 2 (III) in which A represents an amino protective group which is labile to bases or labile to weak acids, and Β, X, p and m are as defined in claim 1, and elimination of, where appropriate, one or both of the protective groups A and/or V in the resulting protected compound of the formula I, with the formation of the free NH 2 and/or CO 2 H group(s) or b) reaction of a compound of the formula I in which A denotes hydrogen, and Β, X, Y 1 , Y 2 , Y 3 , Y*, V, W, m, n and p are as defined in claim 1, with a compound of the formula IV A-[B] 5 . p -OH (IV) in which A, B and p are as defined above, but A does not denote hydrogen, or its active ester, halide or azide, and, if V is not hydrogen, where appropriate elimination of a carboxyl protective group V with the formation of the carboxyl group. The use of a compound of the formula I as claimed in one of claim» 1-5, in which V denotes hydrogen, and A does not denote hydrogen, in the solid-phase synthesis of compounds of the formula V P-NH-[X] b -NH 2 (V) in which P represents a peptide residue comprising q έ p + 1 α-amino acids, and X, m and p are defined as in claim 1. A process for the preparation of a peptide of the formula V, in which Ρ, X, m and p are defined as in claim 7, by solid-phase synthesis, which comprises coupling a compound of the formula I, as claimed in one of claims 1-5, in which A does not denote hydrogen, and V represents hydrogen, to a resin, eliminating the protective group A, stepwise coupling on of g-p α-amino acids which are, where appropriate, in the form of their activated derivatives and which have been temporarily protected by amino protective groups which are labile to bases or labile to weak acids and, after construction is complete, liberating the peptide of the formula V from the resin by treatment with a moderately strong to strong acid, the temporarily introduced sidechain protective groups being eliminated again at the same time or, by suitable measures, subsequent thereto. -229. A compound of the formula 1 given and defined in claim 1, which is any one of those specifically hereinbefore mentioned.

7. 10. A process for the preparation of a compound of the formula I given and defined in claim 1, substantially as hereinbefore described and exemplified.

8. 11. A compound of the formula I given and defined in claim 1, whenever prepared by a process claimed in claim 6 or 10.

9. 12. Use according to claim 7 of a compound of the formula I as defined in the solid-phase synthesis of a compound of the formula V as given and defined, substantially as hereinbefore described and exemplified.

10. 13. A process for the preparation of a peptide of the formula V given and defined in claim 7, substantially as hereinbefore described and exemplified.

11. 14. A peptide of the formula V given and defined in claim 7, whenever prepared by a process claimed in claim 8 or 13.