DK175126B1 - Peptide aminoalkylamides, their preparation and use in the preparation of peptide hydrazides - 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

in DK 175126 B1

The invention relates to novel peptide aminoalkylamides, their preparation and use in the preparation of peptide hydrazides.

The introduction of an aminoalkylamide at the C-terminal end 5 of a biologically active peptide has in some cases positively affected the metabolic stability and activity. In the preparation of the peptides thus modified, the classical fragment coupling has been used in solution, cf. EP - A-179332.

10 In the solid phase synthesis of peptides (cf. Patchornik,

Cohen in Perspectives in Peptide Chemistry, pages 118-128 (Karger, Basel 1981)), the reactive chains are often not directly grafted onto the resin body, but they are connected to the support material by so-called spacers or connectors.

For example, from literature (e.g. Atherton, Sheppard in Peptide Chemistry, pages 101-117 (Karger, Basel 1981)) such spacers (so-called "linkage agents") having formulas VI, VII and VIII are known.

H0CH2-f> CH2 - CH2 - CO2H HOCH ^^ Q- OCH2-CO2H CO2H

(VI) (VII) (VIII) 1 In Chemical Abstracts 2JJ, 126602q, acidic spacers of formula are described

CH20H

\ (r = H 'OCH3) (Vila) OCH2COOH.

These spacers can only directly synthesize peptides in the solid phase which exhibit a C-terminal free carboxylic acid group. After cleavage of the peptide, the spacer remains unchanged, ie. that no spacer fragment transfer has occurred.

C-terminally with aminoalkylamide or hydrazide modified peptides are by means of those in Chemical Abstracts 98.

The spacers described using solid phase method 5 are not directly accessible, but only through a combined multistage process, having to connect a diaminoalkyl group to the solid phase peptide in solution.

The object of the invention is to provide spacers that enable, by solid phase synthesis, to produce 10 C-terminally with aminoalkylamide or hydrazide modified peptides. This object is achieved with the compounds of formula I.

Thus, the present invention relates to compounds of formula I 15 y in v2

(I) A- [B] p-NH- [X] m-NH.CO0-CH2 W-CO2-V

Y 3 y 4 in which A means hydrogen or a base labile or a weakly acid labile amino protecting group, B represents the same or different amino acid residues, X represents C1-12 arylene or C8-12 aryl-C1-C4 alkylene, Y3, Y2, Y3 and Y4 are the same or different and represent hydrogen, methyl, methoxy or nitro, where at least one of these symbols means hydrogen, V means hydrogen or a carboxyl protecting group, W means - [CH 2] n- or -O -ICH2] n-, 30 m means 0 or 1, rn means an integer from 0 to 6, and p means an integer from 0 to 5.

Such compounds of formula I are preferred where p = 0, 1 or 2, especially 0, and / or where m = 1.

Preferably, X is - [CH 2] q-, where q is 1-12, preferably 1-8.

DK 175126 B1 3

Preferably at least 2, especially at least 3 of the symbols Y1, Y2, Y3 and Y4, means hydrogen.

Basically labile or weakly acid labile protecting groups are especially urethane protecting groups such as Rnoc, 5 Ddz, Bpoc, Msc, Peoc, Pse and Tse, preferably Fmoc (cf. Hubbuch, Contacts (Merck) 1979. no. 3, pages 14-23) .

B means a residue of an amino acid, preferably an α-amino acid, which, if chiral, can be present in the D or L form. Preferred are residues of naturally occurring amino acids, their enantiomers, homologues, derivatives and simple metabolites (cf. e.g. Wunsch et al., Houben - Weyl 15/1 and 2, Stuttgart, Thieme 1974). For example, consider the following:

Aad, Abu, -rAbu, ABz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, 15 / 9Aib, Ala, ØAla, ÅAla, 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, Ile, Ise,

Iva, Gender, Borrowed, Len, Leu, Lsg, Lys, /? Lys, ALys, Met, Mim, 20 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 enatiomeric D-amino acids.

Functional groups in the side chains of said amino acid residues may be protected. Suitable protecting groups are described by Hubbuch, Kontakte (Merck) 1979. No. 3, pages 14-23 and by Bullesbach, Kontakte (Merck) 1980. No. 1, pages 23-35. Preferred are such groups that are stable to 30 bases and weak acids and which can be cleaved by strong acids.

The alkyl may be straight or branched. Cg_10-aryl is understood e.g. phenyl, tolyl or naphthyl, preferably phenyl.

A carboxyl protecting group V is e.g. C 1-6 alkyl or C 1-4 aralkyl, with methyl, ethyl, tert-butyl, benzyl 4-benzyl and modified benzyl such as p-chloro, p-bromo, p-nitro and p-methoxybenzyl and the N-analog picolyl is preferred. In a further sense, such protecting groups are understood to be activated ester groups such as ONSu, OBt, OObt or p-nitro-phenoxy.

The invention also relates to a process for preparing the compounds of the general formula I, which is characterized in that:

(a) a compound of formula II

10 ylv2 R-CO-O-CH2 ^ 3-W-CO2-V (II) γ3 Y * 15 in which R represents a removable nucleophilic leaving group,

V represents a carboxyl protecting group and 20 W, Y1, Y2, Y3 and Y4 are as defined in claim 1 reacted with a compound of formula III

A- [B] p-NH- [X] η ”ΝΗ2 (III), wherein A represents a base labile or a weak acid labile amino protecting group, and B, X, p and m are defined as in claim 1, and in the resulting protected compound of formula I, one or both of the protecting groups A and / or V are optionally cleaved to form the free radical (s) )2 and / or CO 2 H group (s), the preferred methods being: which V is selectively cleaved, e.g. by reductive cleavage with Zn / glacial acetic acid, or b) a compound of formula I in which A is hydrogen and B, X, Y1, Y2, Y3, Y4, V, W, m, n and p are defined

35 as in claim 1, is reacted with a compound of formula IV

A [B) 5.p-OH (IV) DK 175126 B1 wherein A, B and p are defined as above, however, A does not mean hydrogen, or its active ester, halide or azide, and, if V is not hydrogen , optionally a carboxyl protecting group V is cleaved to form the carboxyl group.

A removable nucleophile leaving group R is e.g. halogen such as chlorine, bromine and iodine, or activated aryloxy such as p-nitrophenoxy.

The reaction of a compound of formula II with a compound of formula III is preferably carried out in an aprotic solvent such as THF, DMF, CHCl 3 or CH 2 Cl 2, preferably in the presence of a base such as a tertiary amine, e.g. ethyl triisopropylamine, triethylamine or pyridine, obtaining an advantage by adding an acylation catalyst such as DMAP, HOObt or HOBt at a temperature between 0 ° C and the boiling point of the reaction mixture, preferably between 0 ° C and 40 ° C.

Compounds of general formula I (A = H) are reacted with compounds of formula IV, or active esters, halides or azides thereof, preferably in an organic solvent such as DMF, advantageously in the presence of a base such as a tertiary amine, at a temperature between -10 ° C and the boiling point of the reaction mixture, preferably at room temperature. Suitable active esters are e.g. The ONSu, OBt, OObt and 25 p-nitrophenoxy compounds.

Preferred halogen derivatives are the chlorides. To improve solubility, pyridinium perchlorate can be added.

Compounds of formula II are prepared, for example, by an ester of formula IX

γΐ Y2

ho- ch2-v ~ \ y W- C02- V

γ3 γ4 35 ix (IX)

Lm 1 / 9UODI

6 in which Y1, Y2, Y3, Y4, W and V are defined as above, but V does not mean hydrogen, is reacted with phosgene or phosgene derivatives, such as chloroformic acid nitrophenyl ester, in an aprotic polar solvent, e.g. THF or DMF, in admixture with a tertiary base such as a tertiary amine, e.g. pyridine, preferably in a ratio of 1: 1, at a temperature between -40 ° C and room temperature, preferably between -20 ° C and 0 ° C.

The invention further relates to the use of a compound of formula I, in which V means hydrogen and A does not mean hydrogen, in the solid phase synthesis of compounds of formula V

P-NH- [X] m-NH 2 (V) in which P represents a peptide residue q <p + 1 α-amino acids, and X, m and p are as defined above, as well as a process for preparing a peptide of the formula V, in which P, X, m and p are as defined above, by solid phase synthesis, which process is characterized in that a compound of general formula I in which A does not mean hydrogen and V means hydrogen is coupled to a resin, after which the protecting group A is cleaved and stepwise qp is coupled by means of base-labile or against weak 25 acids labile amino-protecting groups temporarily protected α-amino acids, optionally in the form of their activated derivatives, and upon completion of the construction of the peptide of formula V, it is released by treatment with an agent of strong to strong acid, temporarily introducing side chain protecting groups again at the same time or by appropriate measures.

If necessary to prevent side reactions or the synthesis of particular peptides, the functional groups in the amino acid side chains are further protected by suitable protecting groups (cf., for example, TW Greene, "Protective Groups in Organic Syntheses", New York, John Wiley & Sons , DK 175126 B1 7 19Bl), using primarily 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), With (O), Ser (Bzl), 5 Ser (But), Thr (Bzl), Thr (But).

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

The cleavage of the peptide of formula V is then carried out by treatment with the medium strengths commonly used in the peptide synthesis for strong acids (eg trifluoroacetic acid or HF), whereby the esterene protecting group contained in the spacer is cleaved.

As coupling reagent to the compound of formula I (V = H) and to the additional amino acid derivatives, all possible activation reagents used in peptide synthesis can be used, cf. Houben-Weyl, Methods der Organchen Chemie, Volume 15/2, but especially carbodiimides such as Ν, Ν'-dicyclohexylcarbodiimide, Ν, Ν'-diisopropylcarbodiimide or N-ethyl - N '- (3-dimethylaminopropyl) carbodiimide. The coupling can thereby be effected directly by the addition of an amino acid derivative with the activating reagent and optionally an additive which suppresses racemization, such as 1-hydroxybenzotriazole (HOBt) (W. Konig, R. Geiger, Chem. Ber. 103, 708 (1970)) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazin. (MAIN) (W.

Konig, R. Geiger, Chem. Ber. 103. 2054 (1970)), to the resin, or alternatively, the pre-activation of the amino acid derivative can be carried out separately as a symmetric anhydride or a HOBt or HOObt ester, and the solution of the activated materials in a suitable solvent is added to a coupling-capable peptide resin. .

The coupling or activation of the compound of formula 1 (V = H) and of the amino acid derivatives with one of the above activation reagents may be carried out in dimethyl formamide or methylene chloride or a mixture of both. The activated amino acid derivative is generally used in an excess of 1.5 to 4 times if an incomplete coupling occurs, the coupling reaction is repeated without first performing the unblocking of the subsequent amino acid α-α of the peptide resin. aroinogruppe.

The successful course of the coupling reaction can be controlled by the ninhydrin reaction, as described by E. Kaiser et al., Anal. Biochem 2 ± 595 (1970). The synthesis can also be performed automatically, e.g. with a peptide synthesizer, model 430Ά, Fa. Applied Biosystems, where either the synthesis programs established by the device manufacturer can be used or self-made programs can be used. The latter is particularly used when using amino acid derivatives protected with the Fmoc group.

In the cleavage of the peptide amides from the resin 15 by means of hydrogen fluoride and trifluoroacetic acid, in general, substances such as phenol, cresol, thiocresol, thioanisole, anisole, ethanedithiol, dimethyl sulfide, ethylmethyl sulfide or a mixture of two or more of these are added. Here, trifluoroacetic acid may also be used diluted with a suitable solvent such as methylene chloride.

Abbreviations used:

Fmoc 9-fluorenylmethyloxycarbonyl

Ddz α, α-dimethyl-3,5-dimethoxybenzyloxycarbonyl Bpoc 2- [biphenylyl- (4)] -propyl- (2) -oxycarbonyl

Msc methylsulfonylethyloxycarbonyl

Peoc pyridyl-ethyloxycarbonyl

Pse phenylsulfonyl-ethyloxycarbonyl

Tse tolylsulfonyl-ethyloxycarbonyl HONSu N-hydroxy-succinimide HOBt 1-hydroxybenzotriazole HOObt 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine THF tetrahydrofuran DMF dimethylformamide DMAP dimethylaminopyridine DK 175126 B1

The following examples serve to illustrate the present invention.

Example 1: 5 4-HydroxymethylPhenoxoacetic acid methyl ester.

Dissolve 18.2 g of 4-hydroxymethylphenoxyacetic acid together with 17.1 ml of Ν, Ν-diisopropylethylamine in 50 ml of DMF, and to the stirred solution 6.1 ml of methyl iodide. This causes the mixture to heat slightly. After 3 hours, the reaction is complete. The solvent is removed. The residue is taken up in ether and extracted once with 0.5 N hydrochloric acid. The aqueous phase is extracted three more times with ether, then the combined ether phases are washed with an aqueous sodium hydrogen carbonate solution and concentrated. The residue 15 is dissolved in ethyl acetate and filtered over a short column of silica gel. The slightly yellowish oil obtained after concentration crystallizes on standing.

NMR and mass spectroscopy are consistent with the structure indicated.

20

Example 2:

Fmoc-NH- (CH2) 4-NH-CO-O-CH2 O-CH2-COOCH3.

Dissolve 9.8 g of 4-hydroxymethylphenoxyacetic acid methyl ester in 200 ml of dried CH2 Cl2, after which 10.1 g of chloroformic acid p-nitrophenyl ester and 7 ml of triethylamine are added. The mixture is refluxed for approx. 6 hours, until the adduct is completely reacted. Then a suspension of 15.5 Fmoc-NH- (CH2) 4-NH2 (prepared by reaction of Boc-NH- (CH2) 4-NH2 with Fmoc-ONSu and then Boc) is dissolved in 100 ml of dried CH2Cl2 and further 7 ml of triethylamine and the mixture is refluxed. After completion of the reaction, the solvent is removed and the residue digested with ether, then filtered off by suction.

DK 175126 B1 10

The filter residue is washed with an aqueous 1 N Na 2 CO 3 solution and then with hot water, then dried under high vacuum in a desiccator.

Mp: 122-124 ° C, NMR and mass spectrum are in accordance with the indicated structure.

Example 3: H2N- (CH2) 4-NH-CO-O-CH2 ° ~ * 3 * 2 · C00H · 10 5.2 g of the ester of Example 2 are suspended in 100 ml of ethanol and 6 equivalents of an aqueous 1 N NaOH solution. After completion of reaction 15, the pH is adjusted to 3 with an aqueous 1 N HCl and the methanol is removed. The precipitate is filtered off with suction and washed with a little Η20, then digested in ether and filtered off again with suction.

Mp: from 196 ° C (decomposition), NMR and mass spectrum 20 are consistent with the structure indicated.

Example 4:

Fmoc-Phe-NH- (CH2) 4-NH-CO-O-CH2 V O-CH2-COOH.

25 \ = J

\ 1.5 g of the product of Example 3 is suspended in 50 ml of dried DMF. 0.9 g of pyridinium perchlorate (to improve solubility), 2.6 g of Fmoc-Phe-OObt and 0.5 ml of triethylamine are then added successively. The mixture is stirred at room temperature. After completion of the reaction, the solvent is removed and the residue partitioned between ethyl acetate and H 2 O. The aqueous phase is extracted once more with ethyl acetate and the combined organic phases are dried and concentrated. The residue is digested with a little CHCl 3 and filtered off by suction. The filter residue is washed with a little bit of ether and dried.

Snips: from 140 ° C (decomposition), NMR and mass spectroscopy are in accordance with the structure indicated.

Example 5:

Fmoc-Phe-NH- (CH2) 4-NH-CO-O-CH2 - / V O-CH2-CO- (4-methylbenzhydrylamine resin).

Dissolve 1.4 g of the Fmoc-phenyl-alanine spacer acid obtained in Example 4 together with 350 mg of HOBt in 40 ml of dry DMF and add the mixture to 3.66 g of 4-methylbenzhydrylamine resin (Nova Biochem, loading 0.4 mmol per g). Then add 0.6 ml of diisopropylcarbodiimide and allow the reaction to terminate under a continuous mixture. After completion of the reaction, it is filtered off with suction and washed with DMF, isopropanol, CH 2 Cl 2 and tert-butyl methyl ether and dried under high vacuum. Load according to elemental analysis (N-determination): 0.3 mmol per g.

20

Example 6:

Synthesis of rdes-Tvr ^ des-Ara ^ ll-r-atriopeptin-III-M-aminol butylamide. 1 2 3 4 5 6 7 8 9 10 11

The peptide synthesis is carried out on 1 g of the above-mentioned 2 resin using Fmoc amino acid oOBt esters by means of an automatic peptide synthesizer model 430A, from 4

Few. Applied Biosystems and self-modified synthesis programs.

5

For this, 1 mmol of the corresponding 6 amino acid derivative is weighed each time in the cartridge supplied by the manufacturer, 7

Fmoc-Arg (Mtr) -OH, Fmoc-Asn-OH and Fmoc-Gln-OH are weighed 8 together with 1.5 mmol HOBt in the cartridge. None of these amino acids despair 9

acids are carried directly into the cartridge by dissolving in 4 ml of DMF

10 and by adding 2 ml of a 0.55 M solution of diisopropylcarbodiimide in DMF. The HOObt ester is dissolved in 6 ml of DMF and then it is also pumped as the in situ pre-inactivated amino acids arginine, asparagine and glutamine on the precursor with 2 Ot piper idin in DMF of blocked resin. The in situ activated amino acids are doubly coupled.

Upon completion of the synthesis, the peptide-butyl amide 5 is cleaved from the resin while simultaneously removing the side-chain protecting groups with trifluoroacetic acid, thioanisole and m-cresol as cation scavengers. The residue obtained after removal of the trifluoroacetic acid is digested several times with ethyl acetate and centrifuged. The remaining crude peptide is treated to remove the cysteine protecting group with tributylphosphine in trifluoroethanol. After removing the solvent, it is again digested with ethyl acetate and centrifuged. The reduced crude peptide is then immediately oxidized with iodine in an 80% aqueous acetic acid solution, and the ₂2 excess is removed with ascorbic acid, and the reaction mixture is desalted after concentration to a small volume of Sepahdex G25 with aqueous 1 N acetic acid. The fractions containing the pure peptide are concentrated and lyophilized.

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

Example 7: 4-Hydroxymethylpheoxoacetic acid phosphene acyl ester. 1 2 3 4 5 6 7 8 9 10 11 182 g of 4-hydroxymethylphenoxyacetic acid and 199 g of α-2 bromoacetophenone are dissolved in 600 ml of dried DMF, and thereto 3 drops rapidly at 0 ° C 138 ml of triethylamine. It is allowed to warm to room temperature 4 and stir overnight 5. The DMF solution is poured into 3.5 liters of water and the aqueous 6 phase is extracted with ethyl acetate. The organic phase is washed 7 with water, then dried over sodium sulfate and 8 concentrated. Upon evaporation, the product precipitates. It is filtered off by suction, washed with ethyl acetate / n-10-hexane 1: 1 and dried under high vacuum.

11

Mp: 94-95 * 0, NMR is consistent with the indicated structure.

DK 175126 B1

Example 8; 13

° 2K ~ C3 "° ~ C0 ~ ° ~ ° - CH2-CO2-CH2-orO

Dissolve 30 g of 4-hydroxymethylphenoxyacetic acid phenacy ester under protective gas in 500 ml of a THF / pyridine 1: 1 mixture and cool to -20 ° C. Then 21 g of chloroformic acid p-nitrophenyl ester dissolved in 100 10 ml of THF are added dropwise. After stirring for 30 minutes at this temperature, it is heated to 0 ° C and the mixture is stirred in 1 liter of a semi-saturated aqueous NaCl solution of 0 ° C and stirred for 30 minutes. The precipitate is filtered off by suction and washed with ice water and, after drying, n-15 hexane is evaporated.

Mp: 142-145 ° C, NMR consistent with the indicated structure.

Example 9: 20

Fmoc-Phe-NH- {CH 2) 8 ** ® CO-O-CH 2 O-CH 2 -CO 2 -CH 2 -CO- (9.3 g of the compound of Example 8, 12.25 g Fmoc- Phe-NH- (CH 2) g-NH 2 'trifluoroacetate and 3.26 g HOObt are added as a solid to a flask and then poured into the mixture with 2.58 g of ethyl di isopropylamine in 100 ml of dried DMF. for another 3.5 hours at 40 ° C, then stir in 500 ml of a half-saturated aqueous NaCl solution. The precipitated precipitate is filtered off by suction and washed with ice-water and afterwards dried with ether / ethyl acetate. .

Mp: 147-150 ° C, NMR and MS are consistent with the formula given.

The following compounds (Examples 10-14) are prepared analogously to Example 9: LM \ 1/9120 Dl 14

Example 10;

Fmoc-Phe-NH- (CH2) 4-NH-CO-O-CH2 O-CH2-CO2-CH2-CO-

Mp: 144-147 * 0, HMR and MS correspond to the indicated formula.

Example 11; Fmoc-Ala-NH- (CH 2) 8-NH-CO-O-CH 2 O- CH 2 -CO 2 -CH 2 -CO 2

Mp: 179-181 * 0, NMR and MS correspond to the indicated formula.

Example 12:

Fmoc-NH- (CH2) 8-NH-CO-O-CH2 O-CH2 ~ CO2-CH2-CO- ^ t 20 Mp: 144-145 * 0, NMR and MS correspond to the formula given. Example 13:

Fmoc- NH- (CH2) 5- NH- CO- O- CH2 O-CH2-CO2-ra2-CO-

Mp: 172-175 * 0, NMR corresponds to the indicated formula.

Example 14: 30

Fmoc-NH- (CH2) 4-NH-CO-O-CH2 O-CT2-CO2-CH2-CO

Mp: 165-166 * 0, nmr corresponds to the stated formula.

Example 15; DK 175126 B1 15

Fmoc-Phe-NH- (CH2) 8-NH-CO-O-CH2 O-CH2-CO2H.

5

8.4 g Fmoc-Phe-NH- (CH2) 8-NH-CO-O-CH2 - O-O-CH2-CO2-CH2-CO

0 10 is suspended in a mixture of 150 ml glacial acetic acid and 50 ml dichloromethane, and to this is added portionwise 12 g of zinc powder previously activated by washing with 1 N HCl and dried ethanol. After a few minutes, the suspension under thick heat toning becomes thicker and difficult to stir. Therefore, an additional 80 ml of glacial acetic acid and 50 ml of dichloromethane are added thereto and stirred further overnight. Subsequently, it is filtered off by suction over a clear-layer filter and washed with glacial acetic acid and dichloromethane. The filtrate is concentrated and the residual oil of the residue is taken up in a little dichloromethane and stirred with ethyl acetate and ether. The precipitated product is filtered off by suction and dried under high vacuum.

Mp: from 160 ° C, decomposition, NMR and MS correspond to the indicated formula.

According to the method described in Example 15, the compounds of Examples 16 to 18 are also prepared:

Example 16: Fmoc-Phe-NH- (CH2) 4-KH-CO-O-CH2- ^ J ^ -O-CH2-CQ2H.

Mp: from 150 ° C, decomposition, NMR and MS correspond to the indicated formula.

35

fc / l \ I I V IfaV V I

16

Example 17i

Fmoc-Phe-NH- (CH 2> 8-NH-CO-O-CH 2 - ^^) - O-CH 2 -CO 2 H

Mp: from 160 ° C, decomposition, NMR and MS correspond to the formula given.

Example 18! 10

Fmoc-NH- (CH 2) 8-NH-CO-O-CH 2 -CO 2 H.

Mp: from 154 ° C, decomposition, NMR and MS correspond to the formula given.

Example 19:

Fmoc-NH- (CH2) 6-NH-CO-O-CH2 - / Vo-CH2-CO2CH3.

20

The synthesis occurs analogously to Example 2.

Mp: 115-118 ° C, NMR and MS correspond to the indicated formula.

25

Example 20: NH 2 - (CH 2) 6-NH-CO-O-CH 2 - ^ 3 ~ ° ~ CH 2 -CO 2 H.

30 is prepared according to the procedure described in Example 3.

Mp: 184-187 ° C, decomposition, NMR and MS correspond to the formula given.

35

Example 21: 17 DK 175126 B1

Frr.oc- Phe- NH- (CH2) 6- NH- CO- O- CH2- ^ ~ ^ -0- CH2-CO2H.

5

The synthesis occurs analogously to Example 4.

Mp: from 120 ° C, decomposition, NMR and MS correspond to the indicated formula.

Claims (8)

A compound characterized in that it has the general formula 5 yV_X2 (I) A- [B] p -NH- [X] m -NH-CO-O-CH2 W-CO2-V Y3 γ4 10 in which A means hydrogen or a base labile or to weak acids labile amino protecting group, B means the same or different residues of amino acids, 15. means C1-22 alkylene or C8-10 aryl-C1-12 alkylene, Y1, Y2, Y3 and Y4 are the same or different and hydrogen, methyl, methoxy or nitro, wherein at least one of these symbols means hydrogen, V means hydrogen or a carboxyl protecting group, 20. means “[CH2} n- or -O- [CH2] n-, m means 0 or 1, n means an integer from 0 to 6, and p means an integer from 0 to 5. Compound of the general formula 1 according to claim 25, characterized in that p - o, 1 or 2. A compound of formula I according to claim 1 or 2, characterized in that m * 1. Compound of the general formula I according to one of claims 1-3, characterized in that X means 30 - [CH 2 J q -, and g means an integer from 1 to 12. A compound of formula I according to any one of claims 1-4, characterized in that at least two of the symbols Y1, Y2, Y3 and Y4 mean hydrogen. Process for the preparation of a compound 35 according to any one of claims 1-5, characterized in that a) a compound of formula II R-CO-O-CH2 ^ W-CO2-V (11> 5) γ3γ4 in which R is a removable nucleophilic leaving group, V is a carboxyl protecting group, and 10 w, Y1, Y2, Y3 and Y4 are defined in claim 1, reacted with a compound of formula III A-CBJp-NH-IXDm -NHs (III), which A means a base labile or a weakly acid labile amino protecting group, and B, X, p and m are defined as in claim 1, and in the resulting protected compound of formula I, optionally one or both protecting groups A and / or V to form the free NH 2 and / or CO 2 H group (s), or b) a compound of formula I in which A means hydrogen and B, X, Y1, Y2 , Y3, Y4, V, W, m, n and p are defined as in claim 1, reacted with a compound of formula IV A [B) 5_p-OH (IV) which A, B and p are as defined above, except that A 2 does not mean hydrogen, or its active ester, halide or azide, and, if V is not hydrogen, is even decomposed e.g., a carboxyl protecting group V to form the carboxyl group. 3 Use of a compound of formula I according to one of claims 1-5, in which V means hydrogen and A does not mean hydrogen, in the solid phase synthesis of compounds of formula V 4 P-NH- [X] m-NH 2 (V) U1 / 0120 b1 in which P represents a peptide residue of g S p + 10 o-amino acids and X, n and p are defined as in claim 1. A process for preparing a peptide of formula V, wherein P, X, m and p are defined as in claim 5 7, by means of a solid phase synthesis, characterized in that a compound of formula I according to one of claims 1- 5, in which A does not mean hydrogen and V means hydrogen is coupled to a resin, the protecting group A is cleaved, stepwise gp is switched on by means of base-labile or against 10 weakly acid-labile amino-protecting groups, temporarily protected o-amino acids, optionally in the form of their activated derivatives, and upon completion, the peptide of formula V is released by treatment with a medium to strong acid from the resin, with temporarily introduced side chain protecting groups again being simultaneously cleaved or by appropriate measures.