SE438152B - PROCEDURE FOR THE PREPARATION OF SUBSTITUTED PHENYLKETONS WITH SEDATIVE, MUSCLE RELAXING AND ANTI-CONVULSIVE EFFECTS - Google Patents

Description

Examples of compounds of formula I above are: L-phenylalanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, I glycyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, L-leucyl-N - (4-bromo-2-picolinoylphenyl) glycinamide, L-lysyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, L-isoleucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, LY-glutamyl- N- (4-bromo-2-picolinoylphenyl) glycinamide, L-alanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, L-arginyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, Ld-glutamyl -N- (4-bromo-2-picolinoylphenyl) glycinamide.

According to the process of the present invention, the above-mentioned substituted phenyl ketones (i.e. the compounds of formula I above and their acid addition salts) are prepared by cleavage according to methods known per se by the protecting group or groups in the group R20 in a compound of the general formula Wherein R and R 3 are as defined above and R is the acyl group of one of the above amino acids, wherein the amino group or amino groups present are in protected form and any other functional groups which may be present are in protected form, where required. (all such acyl groups containing an asymmetric carbon atom having an L or D, L configuration), if desired transferring a obtained free base into an acid addition salt or transferring an obtained acid addition salt into a free base or into another acid - adaitionssalt. The amino group or amino groups present in the acyl group R20 of formula II can be protected with any amino protecting group well known in peptide chemistry. Particularly suitable amino-protecting groups for the purpose according to the invention are aralkoxycarbonyl groups, especially the benzyloxycarbonyl group, and the tert-butoxycarbonyl group. The amino protecting group may also be formyl, trityl or trifluoroacetyl.

Any carboxy or hydroxy groups that may be present in the acyl group R20 in formula II may be protected with a conventional carboxy protecting or hydroxy protecting group.

For example, a carboxy group can be protected by transfer into an alkyl ester (eg a tert-butyl ester) or an aralkyl ester (eg a benzyl ester). For example, a hydroxy group may be protected by an aralkoxycarbonyl group (eg benzyloxycarbonyl), an alkanoyl group (eg acetyl, propionyl), an aroyl group (eg benzoyl), an alkyl group (eg tert.butyl) or an aralkyl group (eg benzyl). Other functional groups present in the acyl group R20 can be protected in a known manner.

The removal of the protecting group or groups in the acyl group R20 in a compound of formula II takes place according to methods known per se, i.e. methods used for or described in the literature on the removal of protecting groups. According to a preferred embodiment of the present invention, the acyl group R 20 carries a protecting group or protecting groups which can be removed by hydrolysis. Thus, for example, an aralkoxycarbonyl group (eg benzyloxycarbonyl) or a tert-butoxycarbonyl group can be removed by treatment with a mixture of hydrogen bromide and acetic acid. The tert-butoxycarbonyl group can also be removed with the aid of hydrogen chloride in an organic solvent (eg dioxane) or with the aid of trifluoroacetic acid. A benzyloxycarbonyl or tert-butoxycarbonyl group can also be removed by treatment with boron trichloride or boron tribromide in an inert organic solvent such as dichloromethane. A racemate of formula I above can be cleaved into its optical isomers according to known methods, for example by means of a suitable optically active acid. The desired L-isomer can be obtained by known methods, such as fractional crystallization of the resulting diastereoisomeric salts.

The starting materials of formula II above can be prepared in various ways. Thus, the starting materials of formula II can be prepared, for example, by condensation of 1 l of an amine of the general formula _ _ fi y _ JNH-cn-cn -Ä-NH i / 2 2. Wherein R 1 and R 2 are as defined above, with a suitably protected amino acid or a reactive derivative thereof.

The condensation can be carried out according to methods known in peptide chemistry, for example the method of mixed anhydride, azide, activated ester or acid chloride.

According to one method, a suitable amine of formula IV may be condensed with a suitably protected amino acid, wherein the terminal carboxy function is a mixed anhydride residue formed with an organic or inorganic acid. Suitably, such an amino acid bearing a free carboxy function is treated with a tertiary base such as tri (lower alkyl) amine (eg triethylamine) or N-ethylmorpholine in an inert organic solvent (eg tetrahydrofuran, dichloromethane or , 2-dimethoxyethane), and the resulting salt is reacted with a chloroformic acid ester (eg ethyl or isobutyl ester) at low temperature. The resulting mixed anhydride is then conveniently condensed in situ with the amine of formula IV.

According to another method, a suitable amine of formula IV may be condensed with a suitably protected amino acid, wherein the terminal carboxy group is in the form of an acid azide. This condensation preferably takes place in an inert organic solvent, such as dimethylformamide or ethyl acetate at low temperature.

In yet another method, a suitable amine of formula IV may be condensed with a suitably protected amino acid, wherein the terminal carboxy function is in the form of an active ester group (eg p-nitrophenyl, 2,4,5-trichlorophenyl or the n-hydroxysuccinimide ester group). This condensation preferably takes place at about -20 ° C in an inert organic solvent, such as dimethylformamide.

According to a further method, a suitable amine of formula IV may be condensed with a suitably protected amino acid, wherein the terminal carboxy function is in the form of an acid chloride. This condensation preferably takes place in the presence of a base and at a low temperature.

Alternatively, the starting materials of formula II may be prepared by condensation of a compound of the general formula 'PooR own 79 02.5 21-9 wherein R and R 3 are as defined above, with a suitably protected dipeptide or a reactive derivative thereof using one of the methods described above in connection with the condensation of an amine of formula IV with a protected amino acid or a reactive derivative thereof.

The amines of formula IV can be obtained, for example, by condensing a compound of formula V with a suitably protected amino acid or a reactive derivative thereof, after which the protected group is removed in the manner previously described.

Alternatively, the amines of formula IV can be obtained by hydrolysis of a 1,4-benzodiazpine of general formula 4 in the above-mentioned meaning, with a mineral acid. wherein R and R Thus, a 1,4-benzodiazepine of formula VI can be hydrolyzed with sulfuric acid, nitric acid, phosphoric acid or, preferably, a hydrohalic acid such as hydrochloric acid. The hydrolysis is preferably carried out at a temperature of about 20-30 ° C.

The compounds of formula I above are acid addition salts with inorganic acids (eg hydrohalic acids, such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid) and 7902521-9 with organic acids (eg acetic acid, succinic acid, glycolic acid, lactic acid , gluconic acid, tartaric acid, citric acid, maleic acid, malic acid, fumaric acid, methanesulfonic acid, paratoluenesulfonic acid, oxalic acid, ascorbic acid, benzoic acid, hydroxyethanesulfonic acid, 1,2-diethanesulfonic acid). The pharmaceutically acceptable acid addition salts are preferred. The acid addition salts can be prepared according to well known methods, for example by treating a base with a suitable acid. An acid addition salt can also be transferred to another acid addition salt using a suitable anion exchange resin (eg Amberlite IRA-401 in chloride form).

The compounds of formula I and their acid addition salts possess sedative, muscle relaxing and anticonvulsant properties.

Of particular interest are the pharmaceutically acceptable acid addition salts which are water soluble, as they can be easily administered by injection; for example in dentistry for the induction of anesthesia and in the treatment of acute convulsive diseases and epileptic conditions.

The anticonvulsant activity of the substituted phenyl ketones of the present invention is illustrated by their administration to mice, after which the mice so treated are subjected to the well-known pentatetramethylenetetrazole test.

The muscle relaxing activity can be demonstrated in the well-known rotary bar test.

The compounds of formula I and their pharmaceutically acceptable acid addition salts may be used as medicaments, for example in the form of pharmaceutical preparations containing them together with tolerable pharmaceutical carrier materials. This carrier material may be an organic or inorganic carrier material suitable for enteral or parenteral administration (eg water, lactose, gelatin, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycol, petroleum gels). The pharmaceutical preparations can be manufactured in solid form (eg as tablets, dragees, capsules) or in liquid form (eg solutions, suspensions or emulsions). PQQR QïššíLÉ 7902521-9. Pharmaceutical preparations = in a form adapted for pre-injection purposes are preferred. The pharmaceutical preparations may be subjected to conventional pharmaceutical procedures, such as sterilization, and / or may contain conventional pharmaceutical adjuvants, such as preservatives, stabilizers, wetting agents, emulsifying agents and buffering agents.

However, the doses at which the compounds of formula I and their pharmaceutically acceptable acid addition salts may be administered may vary depending on the needs of the patient and the instructions of the physician. However, a dose of 0.01 mg / kg / day to 1 mg / kg / day is preferred.

The invention is further illustrated by the following examples, in which the temperature refers to OC. The structure of all obtained products was confirmed according to standard procedures involving infrared and nuclear magnetic resonance spectroscopy. Example 1 (A) Preparation of the starting material: (I) 100 g of 7-bromo-1,3-dihydro-5- (2-pyridyl) -2H-1,4-benzodiazepin--2-one was dissolved in 750 ml of 2-N hydrochloric acid and allowed to stand at room temperature overnight. The solution was evaporated to an oil which was dissolved in water and evaporated again. The final traces of water were removed by shaking the oil with 50% methanol / / toluene, then evaporating. This treatment was repeated three times with 50% methanol / toluene and twice with toluene.

A light yellow to orange solid was obtained which was dried at 500 in vacuo. The product was characterized by its spectral data and was shown by titration to contain 2.5 moles of hydrogen chloride to one mole of 2-amino-N- (4-bromo-2-picolinoylphenyl) acetamide (13.5.5 g; 99%). After prolonged drying over sodium hydroxide, an analytical sample was obtained which was stoichiometric.

* In Analysis for C 14 H 14 BrCl 2 N 3 O 2 (407.11): Calculated: C: 41.31; H: 3.47; N: 10.32; Br: 19.63; Cl: 17.42. runner; c; 41.02; HRS; 3.61; N; 10.11; Br; 20.08; cl; 17.82. 7.24 g of N-benzyloxycarbonyl-L-phenylalanine-N-hydroxysuccinimide ester were dissolved in 80 ml of dimethylformamide, the solution was cooled to -200 and 8.48 g of the dihydrochloride, prepared as described under ( I), was added. 6.16 ml of N-ethylmorpholine were then added over 0.5 hours to the vigorously stirred suspension. The resulting mixture was then stirred for 1 hour at -200 and overnight at room temperature. The solvent was removed in vacuo and the residue was dissolved in a mixture of chloroform and water. The layers were separated and the aqueous layer was extracted with an additional portion of chloroform. The combined organic phases were washed five times with water, dried over magnesium sulphate and evaporated to an oil. Crystallization from hot ethanol gave 10.0 g (64%) of (N-benzyloxycarbonyl-L- -phenylalanyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide, m.p. 157-1830 (slow decomposition).

Analysis for C 1 H 11 N 4 O 5 (61.5.50): Calculated: C: 60.49; H: 4.42; N: 9.10.

Found: C: 60.44; H: 4.41; N: 8.90.

(B) Process: 4.0 g of (N-benzyloxycarbonyl-L-phenylalanyl) -N- (4-bromo-2-picolino-phenyl) glycinamide was stirred for 1 hour in a solution of 35% hydrogen bromide in glacial acetic acid. Dry diethyl ether was then added and the separated solid was filtered off, washed with diethyl ether and dried in vacuo. The crude product was dissolved in a minimal amount of dry methanol and treated with ethyl acetate, whereby the product was separated. 3.8 g (91%) of L-phenylalanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide dihydrobromide, m.p. 1820 (dec.), Were obtained; Åzífšo = + 28.4o (c = 1 in water).

Analysis for C 23 H 23 Br 3 N 4 O 3 (643.20): Calculated: C: 42.95; H: 3.60; N: 8.71; Br: 37.27.

Found: C: 42.53; H: 3.68; N: 8.35; Br: 37.04. 2.0 g of the above dihydrobromide was dissolved in 10 ml of water and dilute ammonium hydroxide solution was added slowly with stirring until the solution was basic. The yellow oil which separated on PooR about crystallization was allowed to stand. The product was filtered off, washed with water, dried in vacuo and recrystallized from ethanol / water. 1.18 g (79%) of the free base were obtained, L-phenylalanyl-N- (4-bromo-2-picolino-phenyl) -glycinamide, m.p. 600 (decomposition) and .alpha. = + 26.7 DEG (C = 1 and 1-N hydrochloric acid).

Analysis for C 23 H 21 BrN 4 O 3 (481.36): Calculated: C: 57.39; H: 4.40; N: 11.64; Br: 16.60.

Found: C: 56.96; H: 4.42; N: 11.48; Br: 16.42.

Example Gel 2 In an analogous manner to that described in Example 1, glycyl-N- (4-bromo-2-picolinoylphenyl) glycinamide was obtained, m.p. 97-1000.

Analysis for C 16 H 15 BrN 4 O 3 (391.23): Calculated: C: 49.11; H: 3.87; N: 14.32; Br: 20.42.

Found: C: 48.95; H: 3.92; N: 14.15; Br: 20.55.

Example Gel 3 In an analogous manner to that described in Example 1, L-lysyl- -N- (4-bromo-2-picolinoylphenyl) glycinamide trihydrobromide was obtained, m.p. 220 DEG (sonar); ¿Bg7š ° = + 1s, s ° (C = 1 1 water).

Analysis for C 20 H 27 Br 4 N 5 O 3 (70.5.11) = Calculated: C: 34.07; H: 3.86; N: 9.93; Br: 45.34; I Br ion: 34.00.

Found: C: 34.29; H: 4.25; N: 9.73; Br: 44.60; Br ion: 33.32; H 2 O: 0.96.

Anhydrous: C: 34.62; H: 4.18; N: 9.82; Br: 45.03; Br ion: 33.64.

Example Gel 4 (A) Preparation of starting material 3.18 g of N-benzyloxycarbonyl-L-isoleucine were dissolved in 25 ml of dry tetrahydrofuran and cooled to -100. 1.57 ml of isobutyl chloroformate and 1.52 ml of N-ethylmorpholine were added and the resulting solution was stirred at -100 for 20 minutes. 4.24 g of 2-amino-N- (4-7-bromo-2-picolinoylphenyl) acetamide dihydrochloride, prepared as described in part (A) (I) of Example 1, were added and the resulting suspension was cooled to -20 °. 3.13 ml of N-ethylmorpholine in 25 ml of dimethylformamide were added to the vigorously stirred suspension for 0.5 hours. The resulting mixture was stirred at -200 for an additional 40 minutes and allowed to stand at room temperature overnight. The product was worked up in an analogous manner as described in part (A) (II) of Example 1. Recrystallization from ethanol gave 4.2 g (60%) of (N-benzyloxycarbonyl-L-isoleucyl) -N- - (4-bromo-2). -picolinoylphenyl) glycinamide, m.p. 174 DEG-176 DEG.

Analysis for C 28 H 29 BrN 4 O 5 (581.48): Calculated: C: 57.84; H: 5.03; N: 9.64; Br: 13.74.

Found: C: 57.84; N: 5.02; N: 9.39; Br: 13.67.

(B) Process = 2.0 g of (N-benzyloxycarbonyl-L-isoleucyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide was stirred for 1 hour in a solution of 35% hydrogen bromide in glacial acetic acid. Dry diethyl ether was then added and the solid which separated was filtered off, washed with diethyl ether and dried in vacuo. Two precipitates of methanol / ethyl acetate gave 1.9 g (91%) of L-isoleucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide dihydrobromide, m.p. 1740 (dec.). 1.0 g of the above dihydrobromide was dissolved in 10 ml of water and dilute ammonium hydroxide solution was added with stirring until the solution was basic. The resulting oil was crystallized on standing, the crystals were filtered off, washed with water and dried in vacuo to give 0.65 g (89%) of the free base, L-isoleucyl-N- (4-bromo-2-picolinoylphenyl). ) glycinamide, m.p. 540 (slow decomposition); ÅÉQIÉO = + 29.6 ° (c = 1 in 1-N hydrochloric acid).

Analysis for C 20 H 23 BrN 4 O 3 (447.34): Calculated: C: 53.70; H: 5.18; N: 12.52; Br: 17.87 Found: C: 52.97; H: 5.23; N: 12.26; Br: 17.85; H20: 1.75 åvo fl ïi WRX L 7902521-9 1.9 _ _ av; Anhydrous: C: 53.37; H: 5.18; N: 12.35; Example 5 Br: 17.98.

In an analogous manner to that described in Example 4, but using N = in water).

Analysis for C 20 H 29 Br 4 N 7 O 4 (751.14): Calculated: C: 32.00; H: 3.89; N: 13.05; Found: C: 31.85; H: 3.88; N: 13.00; Exemgel 6 + 1.0 ° Br ion: 31.92.

Br ion: 32.20 In an analogous manner to that described in Example 4, but using N-benzyloxycarbonyl-L-glutamic acid - ') * - tert-butyl ester, C 1-4 glutamyl-N- (4-bromo-2-picolinoylphenyl) was obtained. ) glycinamide hydrobromide (1: 1.85), m.p. 153-1700 (slow decomposition); [ï fi jšo = + 20.0 ° (c = 1 in water).

Analysis for cl9H19BrN4o5. 1.85 HBr (612.98) = Calculated: C: 37.23; H: 3.43; N: 9.14; Found: C: 36.68; H: 3.69; N: 8.64; V H 2 O: 1.28.

Anhydrous: C: 37.16; H: 3.59; N: 8.75; Example Gel 7 (A) Preparation of the starting material: In an analogous manner to that described in Example 4 (A), (N ° phenyl) glycinamide was obtained, m.p. 135-1370.

Analysis for C 30 H 40 BrN 5 O 7 (662.59): Calculated: C: 54.38; H: 6.09; N: 10.57; Found: C: 54.33; H: 5.87; N: 10.34; (B) Process: 1.0 g (Nc *, b1-ditert.butoxycarbonyl-L-lysyl) -N- (4-bromo-Br: 37.15.

Br: 36.55; Br: 37.02.

I Br: 12.06.

Br: 12.24. 2-Picolinoyl-2-picolinoylphenyl) glycinamide was stirred for 1 hour in a solution of hydrogen chloride in dioxane (4-M). Diethyl ether was added and the solid which separated was filtered off, washed with diethyl ether and dried. The solid was dissolved in methanol and precipitated with ethyl acetate. The precipitate was dissolved in 20 ml of water and after extraction with chloroform the aqueous solution was lyophilized to give 0.7 g (88%) of L-lysyl-N- (4-bromo-2-picolinoylphenyl) glycine amide trihydrochloride 1.5 H 2 O; jëgfšo = + 20, 10 (c = 1 in water). ß Analysis for C20H27BrCl3N5O3. 1.5 H 2 O (598.76): Calculated: C: 40.12; H: 5.05; N: 11.70; Cl: 17.76.

Found: C: 40.27; H: 4.92; N: 11.57; Cl: 17.62.

Example 8 In an analogous manner to that described in Example 4, L-3'-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, m.p. 158-161 ° (dec.), Was obtained; Analysis for C 19 H 19 BrN 4 O 5 (463.30): Calculated: C: 49.26; H: 4.13; N: 12.09; Br: 17.25.

Found: C: 48.26; H: 4.40; N: 11.94; Br: 17.35; H 2 O: 1.24.

Anhydrous: C: 48.87; H: 4.31; N: 12.09; Br: 17.57.

Example Gel 9 In an analogous manner to that described in Example 1, L-alanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide was obtained, m.p. 76-780; ¿% &] Š0 = + 17.4 ° (C = 1.02s in methanol).

Analysis for C 17 H 17 BrN 4 O 3 (405.26): Calculated: C: 50.38; H: 4.23; N: 13.82; Br: 19.71.

Found: C: 50.43; H: 4.21; N: 13.56; Br: 19.74.

Example gel 10 (A) Preparation of the starting material: 6.56 g of tert-butoxycarbonyl-L-1eucyl-N-hydroxysuccinimide ester were dissolved in 80 ml of dimethylformamide, the solution was cooled to -200 and 8.48 g of 2-amino-N- (4-bromo -2-picolinoylphenyl) acetamide dihydro-, ...__ - ...__...-_ ~, _. __. ~ ----- ~ 'Poon QUAH 7902521-9 14 chloride was added. 6.16 ml of N-ethylmorpholine was then added over 30 minutes to the vigorously stirred suspension. The mixture was then stirred for 1 hour at -200 and overnight at room temperature.

The work-up was carried out in the same manner as in Example 1 (A) (II).

The resulting oil was crystallized from a mixture of ethanol and water and recrystallized from the same solvent mixture to give 5.1 g (47%) of pure (N-tert-butoxycarbonyl-L-leucyl) -N- (4-bromo-2-picolinoylphenyl). glycinamide, m.p. 129-1320.

Analysis for C 25 H 31 BrN 4 O 5 (547.46): Calculated: C: 54.85; H: 5.71; N: 10.23; Br: 14.60.

Found: C: 54.73; H: 5.83; N: 10.02; Br: 14.95.

(B) Process: 2.0 g of (N-tert-butoxycarbonyl-L-leucyl) -N- (4-bromo-2-picolinoyl-phenyl) glycinamide was stirred for 1 hour in a solution of hydrogen chloride in dioxane (4-M). Ethyl acetate was added and the solid which separated was filtered off, washed with ethyl acetate and dried in vacuo. The solid was dissolved in a minimal amount of methanol and the product, L-leucyl-N- (4-bromo-2-picolino-phenyl) glycinamide hydrochloride, was separated by the addition of ethyl acetate.

The hydrochloride was dissolved in 50 ml of water and dilute ammonium hydroxide solution was added slowly with stirring until the solution was basic. The yellow oil that separated was crystallized when allowed to stand. The product was filtered off, washed with water and dried in vacuo. 0.85 g (53%) of L-leucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide was obtained, m.p. 530 (dec.); j 26 / âo = + 26.0 ° (c = 1 in lrN hydrochloric acid).

Analysis for C H 23 BrN 4 O 3 (447.34): Calculated: C: 53.70; H: 5.18; N: 12.52.

Found: C: 53.35; H: 5.14; N: 12.21; H 2 O: 1.32. . Anhydrous: C: 54.06; H: 5.06; N: 12.37.

Claims (12)

7 90-25 2 1 - 9 15 _ PATENT REQUIREMENTS Process for the preparation of substituted phenyl ketones of the general formula - O NH-Icl-cnz-Nn-Rz f? / § /! \ T. In R :: O 1 R3 wherein R represents bromine; R 2 represents an acyl group derived from phenylalanine, glycine, lysine, isoleucine, arginine, glutamic acid, alanine, leucine, serine, methionine or proline; and R 3 represents 2-pyridyl; 7 and the acid addition salts thereof, characterized in that, according to methods known per se, the protecting group or groups in the group R20 are cleaved in a compound of the general formula. Hg-cH 'NH Rzo 2 "" _ II R ï: R 0 wherein R and R 3 are as defined above and R 20 represents the acyl group of one of the above amino acids, wherein the amino group or amino groups present are in protected form and any other functional groups which may be present are in protected form, where so required (all such acyl- ...__..._._- .. i »» V __.____._: _.... V »Poon QUALIT 7902521-9 16 groups containing an asymmetric carbon atom with L or D, L configuration), and if desired, transferring a obtained free base to an acid addition salt or transferring a obtained acid addition salt to a free base or to another acid addition salt. 2. A process according to claim 1, characterized in that a compound is prepared in which the acyl group R2 is derived from an L-amino acid, or an acid addition salt thereof. 3. A process according to claim 2, characterized in that the L-amino acid is L-phenylalanine or L-lysine. 4. A process according to claim 3, characterized in that L-phenylalanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. 5. A process according to claim 1, characterized in that glycyl-N- (4-bromo-2-picolino-phenyl) -glycinamide is prepared. 6. A process according to claim 2, characterized in that L-leucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. 7. A process according to claim 2, characterized in that L-lysyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. 8. A process according to claim 2, characterized in that L-isoleucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. 9. A process according to claim 2, characterized in that L - {- glutamyl-N- (4-bromo-2-fl-picolinoylphenyl) glycinamide is prepared. 7902521-9 17 10. A process according to claim 2, characterized in that L-alanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. 11. ll. Process according to Claim 2, characterized in that L-arginyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. 12. A process according to claim 2, characterized in that L-d-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. ._-.-> ~ ...-...-., .... _,. , ___ "iíøøa QUAL: