DK175111B1 - New substd. di:phenyl-methylamine derivs. - Google Patents

Abstract

Carboxyalkoxy-substd. diphenylmethylamine derivs. of formula (I) are also new. R1=1-8C alkyl or opt. substd. 6-14C aryl; R2=H or an aminoacid residue in which the amino gp. is protected by a weak acid or base-cleavable gp; R3=H or 1-4C alkyl; Y1-Y9=same or different H, 1-4C alkyl, 1-4C alkoxy or -O(CH2)n-COOH, provided one is -O (CH2)n-COOH; n=1-6. Diphenylmethanol deriv. intermediates of formula (II) are also new. Solid-phase synthesis of peptides of formula (XI) comprises: (i) coupling a cpd. (I; R2 other than H) with a resin; (ii) cleaving the protecting gp. of the aminoacid R2; (iii) coupling stepwise with q-p alpha-aminoacids temporarily protected with base- or weak acid-labile protecting gps. (opt. in activated deriv. form); and (iv) releasing the obtd. peptide P-R2a-NH-R3 (XI) (p=peptide residue from q less than or equal to p+1 amino acids; and R2a=aminoacid residue) from the resin with moderately strong acid, with simultaneous or separate cleavage of side-chain protecting gps.

Description

DK 175111 B1 i

The invention relates to a process for the preparation of peptidamides in a solid phase synthesis and to the use of diphenylmethane derivatives in the synthesis as spacers.

For the preparation of peptide amides by solid phase synthesis, benzhydrylamine or methylbenzhydrylamine resins such as those used in e.g. is described by J.P. Tam et al., Tetrahedron Lett. 22. »2851 (1981). A further method consists in ammonolysis of carrier-bound peptide-10 benzyl esters (C. Ressler et al., J. Am. Chem. Soc. 76, 3107 (1951)). Both methods are characterized by the strong acid required for decomposition of the spacer (liquid hydrogen fluoride or trifluoromethanesulfonic acid), side reactions or incomplete decomposition.

It is an object of the invention to provide a process for the preparation of peptide amides using spacers enabling a milder and better cleavage of peptide amides from the resin resin.

This is achieved according to the invention by using as spacers the diphenylmethane derivatives of the general formula I

R2 is Y5 γ9 γΐ γ2 (i) γ7 γ6 γ5 γ4 in which R1 is C1-6 alkyl or optionally substituted C6.14 aryl, R2 is an amino acid residue protected by a weakly acidic or base-leaving amino protecting group R 3 represents hydrogen or C 1-4 alkyl, Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7, Y 8 and Y 9 means hydrogen, C 1-4 alkyl, C 1-4 alkoxy or -O- (CH 2) n -COOH, wherein the groups 2 may be the same or different, with one group being, however, -0- (CH2) n -COOH, and n means an integer from 1 to 6.

The invention accordingly relates to the use of a diphenylmethane derivative of formula I in the solid phase synthesis of peptidamides of formula XI

P-R2-NH-R3 (XI) 10 in which P represents a peptide residue of q S p + 1 α-amino acids and R2 and R3 are as defined above.

The invention further relates to a process for the preparation of a peptide of formula XI, wherein P, R2 and R3 are as defined above, in a solid phase synthesis which is characterized by coupling a diphenylmethane derivative of formula I to the coupling reagents common in the peptide chemistry. a resin via -O- (CH2) n -COOH groups none, cleaves the protecting group for amino acid R2, incrementally connects qp α-amino acids, soro is temporarily protected by base-labile or weak acids labile amino-protecting groups, optionally in the form of their activated derivatives, and upon completion, the peptide of formula XI releases from the resin by treatment with a medium acid, while temporarily or subsequently, by appropriate measures 25, temporarily decomposing side chain protecting groups.

If necessary to prevent side reactions or to the synthesis of particular peptides, the functional groups in the amino acid side chain are further protected by suitable protecting groups (cf., for example, TW Greene, "Protective Groups in Organic Synthesis", New York , John Wiley & Sons, 1981), 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), Ser (But), Thr (Bzl), Thr (But).

3 DK 175111 B1

Preferred are compounds down to the general formula I, wherein R 1 is methyl and n is an integer of 1, 2 or 3.

Also preferred are compounds of this general Formula I in which R 2 represents an amino acid residue protected with a urethane protecting group, especially FmoC, and R 3 is hydrogen.

Furthermore, the groups Υ3-Υ9 mean especially methyl or methoxy, however, one group means -O- (CH2) n -COOH, and at least 10 4 of these groups mean hydrogen.

Preferably, Y1, Y3, Y5, Y7 or Y8 represent the group -O- (CH2) n-C00H.

Alkyl and alkoxy may be straight or branched. Cg_i4-Aryl is e.g. phenyl, naphthyl, biphenylyl or fluorenyl; preferably phenyl.

R 2 means the remainder of an amino acid, preferably an α-amino acid, which, if chiral, may be in the D or L form. Preferred are residues of naturally occurring amino acids and enantiomers, homologues, derivatives 20 and simple metabolites (cf. e.g., Wunsch et al., Houben-Weyl 15/1 and 2, Stuttgart, Thieme 1974). For example:

Aad, Abu, Tf Abu, ABz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, / 3Aib, Ala, / 3Ala, AAla, Alg, All, Ama, Amt, Ape, Apm, Apr, 25 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, Light, Ølys, ALys, Met, Mim, 'Min, nArg, Nle, Nva, Oly, Om, Pan, Pec, Pen, Phe, Phg, 30 Pic, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, See,

Sem, Ser, Thi, Øthi, Thr, Thy, Thx, Tia, Tle, Tly, Trp,

Trta, Tyr, Val and the residues of the corresponding enantiomeric 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, page 4 DK 175111 B1 14-23, and Bullesbach, Kontakte (Merck), 1980. No. 1, pages 23-35.

Basically labile or weakly acid labile protecting groups are especially urethane protecting groups such as Fmoc, 5 Ddz, Bpoc, Msc, Peoc, Pse and Tse, preferably Fmoc (cf. e.g. Hubbuch, Kontakte (Merck) 1979. No. 3, page 14 -23).

The diphenylmethane derivatives used in this process are prepared by:

a) a benzhydrol of formula II

10 YB γ9 γ1 γ2

γ7 γ6 γ5 γ A

15 in which R1, Y1, Y2, Υ3, Υ4, Υ5, Υ6, Υ7, Υ8 and Υ9 have the meaning given above,

react with a compound of formula III

R2 R3 / N (III)

25 I

H

in which R 2 represents hydrogen or an amino acid residue protected by a weakly acidic or basic leaving amino protecting group and R 3 represents hydrogen or C 1-4 alkyl, or

b) a benzophenone of formula IV

35 γΒ γ90 γΐ γ2 γ7 γ6 γδ γ4 (IV) 5 DK 175111 B1

is reacted with hydroxylamine to a compound of formula V

OH

YB γ9 In γΐ γ2 5 R1 Y7 γ6 γ5 γ4 in which R1, Υ1, Υ2, Υ3, Υ4, Υ5, Υ6, Υ7, Υ8 and Υ9 are defined as above, after which the oxime is reduced to an amine, preferably with zinc in glacial acetic acid. (S. Gaehde, G. Matsueda, Int. J. Peptide Protein Res. 18, 451 (1981)) and the amine optionally converted to derivatives thereof.

New diphenylmethane derivatives of formula I, wherein R 2, in addition to having the meaning given above, may also mean hydrogen, the process for their preparation and the novel benzhydrol derivatives of formula II are subject to claims in the parent application, DK No. 1893/88-A, wherein the method is also elucidated in more detail.

The resins used as the carrier material can be obtained commercially or are manufactured separately, such as alkoxybenzyl alcohol resins, aroinomethyl resins or benzhydrylamino resins. Preferred are benzhydrylamino (BHA) and methylbenzhydrylamino (MBHA) resins. The load is determined by amino acid analysis and / or elemental analysis.

As the coupling reagent for the diphenylmethane derivative of formula I and for the additional amino acid derivatives all possible activating reagents used in peptide synthesis can be used, cf. Houben-Weyl, The Method of Organic Chemistry, Vol. 15/2, especially, however, carbodiimides such as Μ, d'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide or N - ethyl-N '- (3-dimethylaminopropyl) carbodiimide . The coupling to the resin can thereby be effected directly by the addition of a 35 amino acid derivative with an activating reagent, and optionally with an addition which suppresses racemization, e.g. 4-6 DK 175111 B1 dimethylaminopyridine, 1-hydroxybenzotriazole (HOBt) (W. Konig, R. Geiger, Chein. Ber. 103. 708 (1970)) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt ) (W. Konig, R. Geiger,

Chen. Ber. 103. 2054 (1970)) or alternatively, the pre-activation of the amino acid derivative such as synnetic anhydride or HOBt or HOObt ester can be carried out separately and the solution of the activated materials in a suitable solvent is added to a coupled peptide resin.

The coupling or activation of a compound down the formula I and of the amino acid derivatives down one of the activation reagents mentioned above can be carried out in dimethylformamide or methylene chloride or a mixture of both. The activated amino acid derivative is generally used in a 1.5 to 4-fold excess. In cases where an incomplete coupling occurs, the coupling reaction is repeated without first performing the unblocking required of the subsequent amino acid by the α-amino acid group of the peptide resin.

The successful course of the coupling reaction can be investigated by means of the ninhydrin reaction, e.g. as described by E. Kaiser et al., Anal. Biochem. 5 »595 (1970). The synthesis can also be performed automatically, e.g. with a peptide synthesizer model 430A from Applied Biosystems, whereby either the synthesis programs established by the device maker or the user's own synthesis programs can be used. The latter is particularly used when using amino acid derivatives protected with the Fmoc group.

The cleavage of the peptide amides from the resin is effected by treatment with commonly used, medium-strong acids (e.g. trifluoroacetic acid) used in the peptide synthesis, using as cationic linkers such substances as phenol, cresol, thiocresol, anisole, thioanisole, ethanedithiol, dimethyldiol , ethyl methyl sulfide or the like, in the solid phase synthesis common cation binders, used singly or as a mixture of two or more of these excipients. The trifluoroacetic acid may also be used diluted with suitable solvents such as methylene chloride.

Upon splitting the spacer from the resin, the splitting of the side chain protecting groups is performed simultaneously.

The purification of the crude peptides thus obtained is carried out by chromatography on nSephadex® ion exchange resins or by HPLC.

The following examples serve to illustrate the invention described above.

Example 1 4- (4-Methoxybenzoyl) -phenoxyacetic acid ethyl ester.

Dissolve 64 g of aluminum chloride (anhydrous) in 160 ml of 1,2-dichloroethane, to which 71.6 g of 4-methoxybenzoyl chloride is added. To this, 57.6 ml of phenoxyacetic acid methyl ester 15 is slowly added with stirring and the reaction mixture is heated to 50 ° C for 4 hours. The mixture is dripped to ice water, which separates an oil. The aqueous phase is separated and the residue is stirred three times with water and crystallized with methanol. The precipitate is filtered off and recrystallized from 20 ethyl acetate.

Yield: 54.9 g (53% of theory).

Melting point: 146 ° C (148 ° C, ethyl acetate).

Example 2 4- (4'-Methoxybenzoyl) phenoxyacetic acid.

Dissolve 9.0 g of the methyl ester of Example 1 in 120 ml of 1,2-dimethoxyethane / water (4: 1, v: v) and add 15 ml of 2N NaOH. The mixture is stirred for 3 hours, then the pH is adjusted to 3 with 3 N HCl. The organic solvent 30 is evaporated under vacuum and the precipitated product is filtered off, then washed with water and dried under high vacuum.

Yield: 8.4 g (98% of theory).

Melting point: 181-182 ° C.

8 DK 175111 B1

Example 3 (4-Carboxymethoxyphenyl) -4'-methoxyphenylcarbinol.

Dissolve 11.2 g of 4- (4'-methoxybenzoyl) phenoxyacetic acid in 600 ml of 80% methanol (reflux) and to this add 4.4 ml of N-methylmorpholine. To the mixture, 6 g of sodium borohydride are added portionwise over 2 hours and the reaction is continued for 3 hours under reflux conditions. The mixture is cooled to room temperature and acidified with 3 N HCl to pH 2.5. The methanol is distilled off and the aqueous phase is extracted with ethyl acetate, then washed with a brine and dried over sodium sulfate. After distilling off the ethyl acetate, a white amorphous powder remains. The product is used directly for the next reaction. Yield: 9.3 g (83% of theory).

15

Example 4 2-Methylphenoxyacetic acid methyl ester.

Dissolve 108 g of 2-methylphenol in 500 ml of dry acetone and add 165.8 g of powdered potassium carbonate. To the stirred suspension is added 113 ml of bromoacetic acid ethyl ester and the mixture is further stirred at room temperature, excluding moisture. After completion of the reaction, the salt is filtered off by suction and washed with acetone and the filtrate is concentrated. It is taken up in ethyl acetate, then washed with water and the organic phase is dried over magnesium sulfate and concentrated.

Yield: 180 g of an oily liquid which is directly converted. 1 2 3 4 5 6

Example 5 2- 4- (4'-Methoxybenzoyl) -2-methylphenoxyacetic acid methyl ester.

3 146.6 g of anhydrous aluminum trichloride are dissolved in 500 4 ml of 1,2-dichloroethane. At 0 ° C, 5 187 g of 4-methoxybenzoyl chloride and 180 g of 2-methylphenoxyacetic acid methyl ester are added dropwise. To complete the reaction, heat to 50 ° C. The mixture is poured onto ice and the pH is adjusted to 2 with 2N HCl. The precipitated product is filtered off by suction and washed with water and some ether. The precipitate is dissolved under heat in ethyl acetate, with the addition of some activated carbon, then filtered and crystallized at -10 ° C. The product is filtered off by suction, washed with ether and dried under high vacuum. Yield: 172.8 g (55% of theory).

Melting point: 92-95 ° C.

Example 6 4- (4'-Methoxybenzoyl) -2-methylphenoxyacetic acid methyl ester.

50 g of 4-hydroxy-3-methyl-4'-methoxybenzophenone (R.

Martin et al., Monatsh. Chemie 110. 1057-1066 (1979)) is dissolved in 200 ml of dry DMF, and to this N2 is carefully added 9 g of a 55% sodium hydride dispersion in mineral oil. The mixture is then added dropwise with stirring 19.5 ml of bromoacetic acid methyl ester and the mixture is allowed to stand overnight at room temperature. The precipitated salt is filtered off by suction and the filtrate is concentrated under vacuum. The residue is taken up in ethyl acetate and washed with a sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulfate and the solvent is removed. The residue is triturated with ether, then filtered off with suction and dried.

Yield: 38.9 g (60% of theory).

Melting point: 96-98 ° C.

Example 7 4- (4'-Methoxybenzoyl) phenoxyacetic acid methyl ester.

29.1 g of 4-hydroxy-4'-methoxybenzophenone (R. Martin et al., Monatsh. Chemie 110. 1057-1066 (1979)) are dissolved in 400 ml of dry acetone. Then, with stirring, 19.3 g of finely powdered K2CO3 and 16 ml of bromacetic acid methyl ester are added to the mixture and it is stirred at room temperature. After 2 35 days, the reaction is complete. The precipitated salt-substance mixture is filtered off by suction, after which the filtrate is concentrated. Both residues are suspended in water and the pH is adjusted to 3 with 2 N HCl. Filtrate by suction, wash with water and dry in desiccator under high vacuum.

Yield: 35.7 g (98% of theory).

Melting point: 143-145 ° C.

Example 8 4- (4'-Methoxybenzoyl) -2-methylphenoxyacetic acid.

35.8 g of 4- (4'-methoxybenzoyl) -2-methylphenoxyacetic acid methyl ester are stirred with a mixture of 240 ml of dioxane and 240 ml of 0.5 N NaOH at room temperature. After the reaction, the organic solvent is removed and the aqueous phase is adjusted to pH 3 with 2N HCl, then extracted with ethyl acetate. Wash with water, then dry over magnesium sulfate and concentrate. Back there will be pale yellow crystals.

Yield: 30.2 g (83% of theory).

Melting point: 149-151 ° C.

20

Example 9 (4-Carboxymethoxy-3-methylphenyl) -4'-methoxyphenylcarbinol.

Dissolve 22.5 g of 4- (4 L -methoxybenzoyl) -2-methylphenoxyacetic acid in a mixture of 100 ml of dioxane and 200 ml of water while adding 1 N NaOH to pH 9. To the stirred solution is added portionwise 2.8 g of sodium borohydride. , and the mixture is allowed to stand overnight. Then the dioxane is removed and the aqueous phase is adjusted to pH 3 with 2N HCl and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. Back is a colorless foam which is rubbed off with n-hexane to an amorphous powder and then filtered off by suction. The product is used directly in the next reaction.

Yield: 19.2 g (84% of theory).

35 11 DK 175111 B1

Example 10 2.6- Dime thylphenoxyacetic acid methyl ester.

Dissolve 65 g of 2,6-dimethylphenol in 200 ml of dry DMF, and under N2, 23.2 g of a 55% suspension of sodium hydride in mineral oil are added portionwise to the mixture. Then, 50.4 ml of bromoacetic acid methyl ester is added dropwise with stirring to the mixture and allowed to stand overnight. The precipitated salt is filtered off by suction and the filtrate is concentrated. The residue is taken up in ethyl acetate and extracted with water. The organic phase is dried over magnesium sulfate and concentrated. Back becomes an oily liquid used directly in the following reaction.

Yield: 95.8 g (92% of theory).

Example 11 2.6- Dimethyl-4- (4'-methoxybenzoyl) phenoxyacetic acid methyl ester.

The synthesis is carried out analogously to Example 5 with 19.4 g of 2,6-dimethylphenoxyacetic acid methyl ester.

Yield: 17.4 g (53% of theory).

Example 12 (4-Carboxymethoxy-3,5-dimethylphenyl) -4'-methoxyphenylcarbinol.

16.4 g of 2,6-dimethyl-4- (4'-methoxybenzoyl) phenoxyacetic acid methyl ester are stirred in a mixture of 100 ml of 0.5 N NaOH and 100 ml of dioxane at room temperature. After completion of saponification of the methyl ester, 1.89 g of sodium borohydride is added to the mixture and allowed to react overnight.

Then, some undissolved material is filtered off and the filtrate is concentrated and the residual aqueous solution is acidified with 1 N HCl. Extract with ethyl acetate, then wash the organic phase with water and dry over magnesium sulfate, then concentrate the mixture.

35 Back there will be an amorphous powder used directly for the subsequent turnover.

12 DK 175111 B1

Yield: 11.3 g (71% of theory).

General Specification for the Preparation of Na-Fmoc-Amino Acid (4-Carboxymethoxy-Phenyl-4'-Methoxyphenyl) -methylamides and Ncr-Fmoc-Amino Acid (4-Carboxymethoxy-3-methylphenyl-4-methoxyphenyl) -methylamides and Na-Fmoc amino acid (4-carboxyl-3,5-boxymethoxy dimethylpheny1-4'-methoxyphenyl) -methylamider.

10 mmol of Να-Fmoc amino acid amide and 10 mmol of the corresponding carbinol are dissolved in the required amount of anhydrous 10 glacial acetic acid, to which are added 5-10 drops of concentrated sulfuric acid. To the mixture is added another 2 g of molecular sieve and the mixture is allowed to stand overnight. Then the molecular sieve is filtered off by suction and the filtrate is diluted with a lot of water, whereby the product partially precipitates. The aqueous phase is extracted with ethyl acetate, then the organic phase is shaken with water. The substance remaining after drying over sodium sulfate and concentration is recrystallized.

In accordance with the above conventional regulations, the following compounds are prepared:

Example 13

He-Pmoc-Glycine (4-carboxymethoxyphenyl-4 '-methoxyphenyl) methylamide.

Yield: 65%.

Melting point: 136-138 ° C.

Example 14 β-Fmoc-Phenylalanine (4-carboxymethoxyphenyl-4 '-methoxyphenyl) methylamide.

Yield: 65%.

Melting point: 159-162 ° C.

13 DK 175111 B1

Example 15 Να-Fmoc-Glycine (4-carboxymethoxy-3-methylphenyl-4'-methoxy-phenyl) methylamide.

Yield: 60%.

Melting point: 135-140 ° C.

Example 16

Ne-Fmoc-Valin- (4-carboxymethoxy-3-methylphenyl-4'-methoxyphenyl) methylamide.

Yield: 81%.

Melting point: 172-175 ° C.

Example 17? -Α-Fmoc-Glycine (4-carboxymethoxy-3,5-dimethylphenyl-4'-methoxyphenyl) methylamide.

Yield: 70%.

Melting point: 122-126 * 0.

Example 18 Synthesis of oxytocin H-Cys-Tyr-Ile-Gln-Asn-CYs-Pro-Leu-Gly-NHg using the anchor described in Example 13. The synthesis is carried out in a peptide synthesis organ from Fa. Labotec.

25 From 1.5 g of Boc-Val resin (loading 0.76 mmol / g), the protecting group with trifluoroacetic acid in methylene chloride is first removed. After washing with dichloromethane and ethyl diisopropylamine and again with dichloromethane, the resin is dried. Then 2.1 mmol of the 30 anchors prepared in Example 13 are added together with 3.15 mmol HOBt dissolved in 20 ml of dry DMF to the resin and 2.3 mmol diisopropylcarbodiimide added.

During slow mixing, the mixture is allowed to react overnight at room temperature. The completeness of the reaction is investigated by the ninhydrin reaction (Kaiser test).

35 The resin is then filtered off by suction and washed with DMF, and the peptide builds up on the resin, thereby cyclically passing through the following steps: 14 - The amino acid is coupled during in situ activation of 5 HOBt ester using diisopropylcarbodiinide as activation reagent (2.1 mnole of amino acid, 3.15 mnole of HOBt, 2.3 nnole of diisopropylcarbodiinide), - the resin is washed down DMF.

If the coupling is incomplete (Kaiser test), the coupling step is repeated.

Other side chain protecting groups are used tert.butyl for tyrosine and tert.butylthio for cysteine.

After completion of the synthesis, the Fmoc protecting group is first decomposed and then the resin is washed down in order of DMF, dichloromethane, isopropanol, dichloromethane and tert-butyl-methyl ether and then dried under high vacuum. 2.4 g of peptide resin are obtained. The decomposition is carried out at room temperature with a mixture of trifluoroacetic acid / thioanisole / ethanedithiol (80/15/5). After 2 hours, suction 20 is filtered off in tert.butyl methyl ether and the precipitated crude peptide is centrifuged and washed three times with tert.butyl methyl ether. The cleavage of the tert-butylthio protecting group is carried out by means of tributylphosphine in trifluoroethanol / water at pH 7.3. The S-H peptide is cyclized with iodine in a 60% aqueous acetic acid and the peptide is purified by chromatography on "Sephadex® LH 20" in methanol.

The oxytocin yield is 33%, where oxytocin is identical to an authentic comparison sample. 1 35 '

Claims (4)

Use of a diphenylroethane derivative of formula I R2 R3 5 XN / γΒ γ9 γΐ γ2 r1 "°" ^^ "ch" ^^ "y3 (I) γ7 γ6 γ5 γ4 10 in which R1 means C1-6 alkyl or optionally substituted C5-6 aryl, R 2 represents an amino acid residue protected by a weakly acidic or basic leaving amino protecting group, R 3 is hydrogen or C 1-4 alkyl, Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7, Y 8 and Y 9 represents hydrogen, C 1. 4-alkyl, C 1-4 alkoxy or -O- (CH 2 to 6, by solid phase synthesis of peptidamides of formula XI P-R 2 -NH-R 3 (XI), in which P represents a peptide residue of g <p + 1 α-amino acids, and R 2 and R 3 are as defined above. A process for the preparation of a peptidamide 30 of formula XI, wherein the P, R2 and R3 are defined as in claim 1, by a solid phase synthesis characterized by coupling a diphenylmethane derivative of formula I to a resin , the protecting group of the amino acid R by treatment with a medium-strong acid, while temporarily or subsequently, by appropriate measures, 5 side chain protecting groups are temporarily peeled off again. *