CS198060B1 - Biologically active peptides - Google Patents

Description

The invention relates to biologically active peptides of the formula I

O (I), wherein X is a residue of leucine or another aliphatic amino acid having 4 to 6 carbon atoms, especially lysine or arginine, Y is a residue of an aliphatic or aromatic amino acid having 2 to 10 carbon atoms, or a di- or tripeptide residue composed of these amino acids , R 1 and R ₂ , the same or different, are each independently hydrogen or C 1 -C 3 alkyl.

The peptides of formula (I) possess significant biological properties in the area of hypothalamo-pituitary function. An analysis of the known analeptic and amneetic effects of oxytoein and vasopresin and fragments thereof showed that these effects are localized in the C-terminal peptide, i.e. propyl-leucyl-glycinamide, respectively. prolyl-lysyl-glycine-amide. It follows that the N-terminal proline occupies an important place in the biological activity of these substances.

Surprisingly, it has been found that when proline is replaced by a 5-amidazolidone-1-carboxylic acid residue, new compounds of the formula I are obtained which have higher

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198,060 and more specific biological activity in the region.

Compounds of formula (I) may be prepared by methods conventional in peptide synthesis, e.g.

Further details are shown in the examples.

Examples

Example 1

5-Imidazolidone-1-carbonyl-L-leueine methyl ester

To a solution of L-leuein methyleether hydrochloride (5.46 g; 30 mmol) in methylene chloride (150 mL) was added N-ethylpiperidine (9.6 mL); After cooling the solution to -10 ° C, 5-iididolidone-1-carbonyl chloride (5.64 g) was added to the reaction solution in 3 portions over 20 minutes. After the whole batch was added, the solution was stirred for an additional 30 minutes at room temperature and evaporated. The residue was taken up in ethyl acetate-water and successively the organic phase was shaken with 1M hydrochloric acid, water, 5% sodium bicarbonate solution, water, dried over sodium sulfate and evaporated. The residue was crystallized from ethyl acetate (15 ml) and petroleum ether (150 ml). 3.6 g was obtained. The sample to be analyzed was crystallized similarly; mp 141-145 ° C (sintered at 130 ° C). [.Alpha.] D @ ²⁰ = 19.7 DEG (c = 0.3; methanol).

5-Imidazolidone-1-carbonyl-L-leueine amide

To a solution of 5-imidazolidone-1-carbonyl-L-leucine methyl ether (1.3 g; 5 mmol) in metband (5 mL) was added a 17% ammonia solution in methanol (5 µL). After standing at room temperature for 2 days, the solution was evaporated in vacuo and the residue was crystallized in benzene (20 ml). 830 mg (69%) of the product with m.p. Mp 151-153 ° C. The sample to be analyzed was crystallized from methanol and ether; m.p. Mp 177-180 ° C. [.Alpha.] D @ 20 + 5.6 DEG (e = 0.3, methanol).

Example 2

5-Imidazole-1-carhonyl-L-leucyl-glycine amide

To a solution of L-leueyl-glycine ethyleater hydrobromide obtained from the corresponding benzyloxycarbonyl derivative (3.5 g; 10 mmol) by treatment with 35 M hydrobromic acid in glacial acetic acid in methylene chloride (50 mL) was added N-ethylpiperidine (2.8 ml).

After cooling the reaction solution to -10 ° C, 5-imidazolidine-1-carbonyl chloride (1.49 g) was added in 3 portions over 30 minutes. After complete addition, the reaction mixture was stirred for an additional 30 minutes at room temperature, and the organic phase was successively shaken with 1 M hydrochloric acid, water, 5% sodium bicarbonate solution, water, dried over 9880 sodium sulfate and evaporated in vacuo. The residue was dissolved in methanol (5 mL) and 17% ammonia in methanol (5 mL) was added. After standing at room temperature for 2 days, the solution was evaporated in vacuo and the residue was crystallized from 2-propanol. 1.45 g of product was obtained. The sample to be analyzed was crystallized in a similar manner; m.p. M.p. 176-177 ° C.

[.Alpha.] D @ ²⁰ + 4.2 DEG (c = 0.3; methanol).

Example 3

5-Imidazolidone-1-carbonyl-N-benzyloxycarbonyl-L-lysine hydrazide

To a suspension of N -benzyloxycarbonyl-L-lysine methyl ester hydrochloride (6.6 g; 20 mmol) in methylene chloride (100 mL) was added N-ethylpiperidine (6.4 mL), after cooling the solution to -10 ° C over 30 min. 5-Imidazolidone-1-carbonyl chloride (3.8 g) was added in 3 portions.

After the addition was complete, the reaction mixture was stirred for an additional 30 minutes at room temperature and the organic phase was successively shaken with 1M hydrochloric acid, water, sodium bicarbonate solution, water, dried over sodium sulfate and evaporated. The non-crystals were dissolved in methanol (30 ml) and 80 dream hydrazine hydrate (5 ml) was added and after standing at room temperature for 2 days the reaction solution was evaporated; The residue was crystallized after stirring β with water (20 ml). The obtained hydrazide was crystallized from water (60 ml). 6.8 g of product with m.p. Mp 122-123 ° C. The sample to be analyzed was crystallized in a similar manner; m.p. Mp 117-120 ° C.

Ethyleater 5-L-imidazolidone-karbony1 ^Ν Σ-benzyloxycarbonyl-L-lysyl-glycine

To a solution of 5-imidazolidone-1-carbonyl-N-benzyloxycarbonyl-L-lysine hydrazide (1.22 g; 3 mmol) in dimethylformamide (40 mL) and horses. hydrochloric acid (1.2 mL), cooled to -15 ° C, was added sodium nitrite (210 mg) in water (0.84 mL). After stirring for 15 minutes and cooling (-10 ° C), the pH of the reaction solution was adjusted to 6.9 with N-ethylpiperidine, and the solution was mixed with a precooled (about -5 ° C) solution of glycine ethyl ester in dimethylformamide (20 ml) released in situ from its hydrochloride (420 mg; 3 mmol) by addition of N-ethylpiperidine (0.42 mL). After standing at 0 ° C for 12 hours, the reaction sample was evaporated in vacuo and the residue was dissolved in ethyl acetate-water and the organic phase was successively shaken with 1 L hydrochloric acid, water, washed with sodium bicarbonate solution, water, dried over sodium sulfate and evaporated. The residue was crystallized from a mixture of 2-propanol (3 ml) and petroleum ether (50 ml). Ethyl 910 mg of m.p. Mp 85-87 ° C. The sample to be analyzed was crystallized from benzene and ether, m.p. Mp 93-95 ° C. [.alpha.] D @ 20 = 3.6 DEG (c = 0.3; methanol).

Amide 5-L-imidazolidone-carbonyl-N ^£ -benzyloxycarbonyl-L-lyeyl-glycihu

To a solution of S-imidazolidone-1-carbonyl-N ' -benzyloxycarbonyl-L-lysyl-glycine ethyl ester (800 mg; 1.67 mmol) in methanol (5 mL) was added a 17N solution of ammonia in methanol (5 mL). the solution was left at room temperature for 3 days. The solution was then evaporated in vacuo and the residue was crystallized from methanol (30 ml) and ether (75 ml). It was obtained

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580 mg (77%) of the product with m.p. Mp 185-186 ° C. The sample to be analyzed was crystallized in a similar manner without changing the m.p. + 5.9 ° (c = 0.3, methanol).

5-Imidazolidone-1-carbonyl-L-lysyl-glycine amide

A solution of the 5-L-imidazolidone-carbonyl-N ^£ -benzyloxycarbonyl-L-lysyl-glycine (250 mg, 0.5 mmol) in methanol (30 mL) was hydrogenated over Pd black 30 minutes. The reaction solution was evaporated in vacuo, the residue was dissolved in methanol (0.5 mL) and the product was taken up in ether (50 mL) and petroleum ether (60 mL). 140 mg of chromatographically homogeneous material was obtained. Rj. 0.07 (butanol-acetic acid-water 4: 1: 1) and R? 0.43 (butanol-acetic acid-pyridine-water 15: 3: 10: 6).

Claims (1)

SUBJECT OF THE INVENTION Biologically active peptides of formula I Wherein X is a residue of leucine or another aliphatic amino acid having 4 to 6 carbon atoms, in particular lysine or arginine, Y is a residue of an aliphatic or aromatic amino acid having 2 to 10 carbon atoms or a di- or tripeptide residue consisting of these amino acids, R 6 and R ₂ is the same or different and independently of one another denotes hydrogen or C 1 -C 3 alkyl.