Method for preparation of tripeptide derivatives or theirs pharmaceutically acceptable salts

专利摘要:
A tripeptide derivative represented by the following formula <CHEM> wherein R1 represents a C1-10 alkyl group, a C4-7 cycloalkyl or C5-7 cycloalkyl-lower alkyl group, a phenyl or phenyl-lower alkyl group in which the benzene ring may optionally be substituted by a substituent selected from halogen, lower alkyl, lower alkoxy, phenyl, methylenedioxy, ethylenedioxy, amino, di(lower alkyl)amino and hydroxy, a naphthyl or naphthyl-lower alkyl group in which the naphthalene ring may optionally be substituted by a substituent selected from halogen, lower alkyl, lower alkoxy and hydroxy, a heterocyclic or heterocyclic-lower alkyl group in which the heterocycle is a saturated or unsaturated 5- or 6-membered ring containing a nitrogen, oxygen or sulfur atom as the hetero atom, and may optionally be substituted by a substituent selected from halogen, lower alkyl, lower alkoxy, amino, di(lower alkyl)amino, hydroxy, oxo and saturated 5- or 6-membered nitrogen-containing heterocyclic group, and further may optionally be fused to a benzene ring, or an imidazolylvinyl group; R2 represents a hydrogen atom, a C1-10 alkyl group or a benzyl group; R3 represents a group of the formula <CHEM> in which <CHEM> represents a benzene, cyclopentane or cyclohexane ring, R4 represents a hydrogen atom, a C1-10 alkyl group or a benzyl group, p is 0 or 1, q is 1,2 or 3, and X represents a phenyl group which may optionally be substituted by a substituent selected from halogen, lower alkoxy and hydroxy, a C4-8 cycloalkyl group, or a C5-7 cycloalkyl group which is fused to a benzene, and Y represents a hydrogen atom or a lower alkyl group, or X and Y, together with the nitrogen and carbon atoms to which they are bonded, forms a 5- or 6-membered heterocyle which may contain a nitrogen, oxygen or sulfur atom,
公开号:SU1743356A3
申请号:SU874202607
申请日:1987-05-08
公开日:1992-06-23
发明作者:Саваяма Тадахиро；Тсукамото Масатоси；Сасадава Такаси；Нисимура Казия；Хосоки Каноо；Такеяма Кунихико
申请人:Дайниппон Фармасьютикал Ко., Лтд (Фирма)；
IPC主号:

专利说明:

are filtered, and the mother liquor is concentrated under reduced pressure. Ethyl acetate is added to the residue and the mixture is washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate to form 1.7 g of ethyl 1- (N-warm-butoxycarbonyl-1-lysyl -01-ethyl-ga mma-D-glutamyl) indolin-2 (5) -carboxylate (mp. 114-117 ° C). To a solution of 1.4 g of the product obtained and 0.4 g of urocanic acid in the dimethylformamide (DMF) -methylene chloride system, 1.17 g of water-soluble carbodiimide hydrochloride are added and the mixture is stirred overnight at room temperature. The solvent is evaporated under reduced pressure. The residue is recrystallized from a saturated aqueous solution of sodium bicarbonate, filtered. The crystals are washed with water, re-precipitated from a mixture of ether: ethanol. 1.4 g of a powdered product are obtained. It is purified by silica gel column chromatography. Elute with methanol: chloroform 1: 9. 1.0 g of powdered product is obtained. An aliquot (0.9 g) of the obtained powder was dissolved in 20 ml of dioxane, 3.8 ml of 1N was added. solution NaOH. The resulting mixture was stirred at room temperature for 3 hours, neutralized with an aqueous solution of potassium hydrogen sulphate, concentrated under reduced pressure. The residue obtained is dissolved in water. The pH of the solution is set to 5 with an aqueous solution of potassium hydrogen sulfate and subjected to chromatographic purification on a CHP 20 P column (acetonitrile – water gradient 0% - 60%) to form 0.65 g of powder. An aliquot (0.55 g) of the powder was left in 20 ml of trifluoroacetic acid for 30 minutes under ice cooling, then the trifluoroacetic acid was evaporated under reduced pressure, at room temperature. The residue is subjected to chromatographic purification on a column of CHP 20 P (acetonitrile – zod gradient), the resulting fractions are concentrated. The residue is lyophilized. 0.33 i of the expected product is obtained.
 - 43.5 ° (1 n. NaOH solution)
Calculated,%: C 52.52. H 6.44, N 14 13
S2bNz2№07-ZN20
Found,%: C, 52.38: H, 6.50; N 14.14.
Example 2. (2S, 3aS, 7a5) -1- (M2-nicotinoyl-lysyl-gamma-0-glutamyl) octahydro-1 H-indole-2-carboxylic acid.
To a mixture of 20 ml of THF and 3 ml of water was added 4.42 g of N-benzyl-oxycarbonyl-N-tertbutoxycarbonyl-lysine N-hydroxysuccinimide ester, 2.89 g (2S, 3aS, 7a5) -1- (gamma-0 -glutamyl) octahydro-1H-indus-2-carboxylic acid and 2.6 ml of triethylamine and the resulting mixture is stirred for 5 hours at room temperature. The reaction mixture is concentrated under reduced pressure. The residue is mixed with an aqueous saturated solution of sodium chloride and washed with ethyl acetate. The aqueous layer was acidified with 1% citric acid and extracted with ethyl acetate. The organic layer is washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure to form 5.19 g of residue. The residue is purified by the method of column chromatography (a column with CHP20P; gradient acetonitrile - water 0% - 60%). The resulting fractions are concentrated to dryness under reduced pressure. The residue is dissolved in the system dioxane - water is lyophilized to form 4, 7 g (2S, 3aS, 7a5) -1- (L6-benzenoxycarbonyl-L2-tert-butoxicrabonyl-L-lysyl-gamma-O-glutamyl) octahydro 1 N-Ndol-2-carboxylic acid. An aliquot (2.27.) Of the product is dissolved in 50 ml of trifluoroacetic acid and allowed to stand for 15 minutes while cooling the system with ice, after which it is concentrated to dryness under reduced pressure. The residue is dissolved in water, the pH is adjusted to 4 and subjected to chromatographic purification on a column of CHP 20 P (acetonitrile – water gradient 0%). The desired fractions are concentrated under reduced pressure to form 1.15 g (2S, 3aS, 7a3) -1 - (N6-benzyloxycarbonyl-1 - lysyl-gamma-0-glutamyl) octahydro-1H-in dol-2-carboxylic acid as a glassy substance. An aliquot (1.0 g) of such a glassy substance is dissolved in a mixture of H, 1M dimethylfoemoamide and tetrahydrofuran, and 0.5 ml of triethylamine and 0.39 g (nicotinoyloxy) succinimide are added. after which the resulting mixture is stirred over night at room temperature. Diluted hydrochloric acid is added to the reaction mixture and the resulting mixture is extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting glassy substance is dissolved in 25 ml of ethanol and 0.6 g of ammonium formate and 0.3 g of 10% palladium on carbon are added to the system. The mixture is stirred for 3 hours at room temperature. The catalyst is removed by filtration and the mother liquor is concentrated to dryness under reduced pressure. The residue is subjected to chromatographic purification on a column with CHP20P (acetonitrile gradient - water 0%). The desired fractions are concentrated to dryness under reduced pressure. The residue is lyophilized to obtain 0.5 g of the intended compound.
  - 27.2 ° (Н20).
Calculated,%: C 54.58; H 7.31; N 12.24.
S2bNz No. 07 2.25 H20
Found,%: C 54.62; H 7.25: N 12.20.
The following substances (examples 3-9) are synthesized in the same manner as in example 2.
Example 3. 1- (N-cyclohexylmethoxyxycarbonyl- -lysyl-gamma-O-glutamyl) indenine-2 (3) -crabonic acid.
The output of 0.34 g (46%). Parent compounds; 1 (N-benzyloxycarbonyl-lysyl-gamma-0-glutamyl) octahydro-1H-indole-2 (5) -carboxylic acid (compound I) and M- (cyclohexylmethoxycarbonyloxy) succinimide. M.p. 186-191 ° С
  -84.4 ° (1 n. NaOH solution).
Calculated. %: C 57.23: H 7.38: N 9.53.
C28H40M / | 08 1.5N20
Found,%: C 57.33; H 7.67: N 9.64.
Example 4. 1- (0 prolyl-1-lysyl-gamma-O-glutamyl) indolin-2 (5) -crabic acid. M.p. 209-216 ° C (decomposed).
  -66.3 ° (1 and. NaOH solution).
Yield 0.2.0 g (23%). Starting compounds: Compound I and (0-promyloxy) succinimide.
Calculated,%: C 51.71: H 7.29; N 12.06.
C23H35N507 3,5H20
Found,%: C 51.58: H 7.40: N 12.08.
Example 5. (2S. 3aS. 7a3) -1- (N-cyclobutane carbon and l-L-lysyl-gamma-O-glutamyl) octahydro-1H-indole-2-carboxylic acid.
Yield 0.51 g (67%). Starting compounds (2S, 3aS, 7a8) -1- (M6-benzyloxycarbonyl-1-lysyl-gamma-0-glutamyl) octahydro-1 H-indole-2-carboxylic acid (compound II) and M- (cyclobutanecarbonyloxy) succinimide.
No. 23 -46,8 ° (1 n, NaOH solution).
Calculated,%: C 55.11; H 8.18; N 9.89.
C25H4oN5Ov 2H20 0.25 GiHsOa.
Found,%: C 55.16: H 7.98; N 9.78.
Example 6. (2S. 3aS. 7aS) (nnpn-din-2-carbonyl) lysyl-gamma-0-glutamyl octahyd- H-indole-2-car6-inO5-aa acid.
The output of 0.35 g (23%). Starting compounds: Compound II and M- (pyridine-2-carbonyloxy) succinimide.
  -19.2 ° (in water). Calculated,%: C 55.45; H 7.25; N 12.44.
C26H37N50 1.75H20
Found,%: C 55.74; H 7.05; N 12.42.
Example 7. (2S, 3aS, (4-methoxybenzoyl) lysyl-gamma-0-glutamyl-octahydro-1H-indole-2-carboxylic acid.
Yield 0.05 g (3.5%). Starting compounds: Compound I and M- (4-methoxybenzoyloxy) succinimide. -15.2 ° (enter).
Calculated,%: C 53.92; H 7.60; N 8.98.
C28H4oN40a-3,5 Н20
Found,%: C 53.77; H 7.33; N 9.13.
Froze (2S, 3aS, 7a5) -1- (M6-benzylcarbamoyl) -, - lysyl-gamma-0-glutamyl) octagidro-1H-indole-2-crab acid.
0.56 g of (2S, 3aS, 7aS) -1- (N-benzyloxycarbonyl-i-lysyl-gamma-0-glutamyl) octahydro-1H-indace-2-carboxylic acid is dissolved in 5 ml of pyridine. and 0.14 g of benzyl isocyanate. The mixture is stirred overnight at room temperature. Sodium bicarbonate solution is added and the mixture is washed with ethyl acetate. The aqueous solution is acidified with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated to dryness under reduced pressure, to give 0.66 g of powder. The POWDER (0.65 g) obtained is dissolved in 15 ml of methanol and 0.3 g of ammonium formate and 0.1 g of catalyst — 10% palladium on carbon are added. The mixture was stirred at 60 ° C for 40 minutes. The catalyst is removed and the solvent is evaporated. The residue is purified on a chromatographic column CHP20P (gradient from 0 to 50% acetonitrile - water). The fractions containing the desired product were concentrated to dryness under reduced pressure, and the residue was freeze dried to give 0.109 g (yield 20%) of the title compound.
  -32.D ° (1 n. NaOH solution). Calculated. %: C 55.46; H 7.61; N 11.76.
C28H41N507-2H20
Found,% C56, O9; H 7.32; N 11.41.
The following compounds (Examples 9 and 10) were synthesized in the same manner as in Example 8.
Example 9. (2S, 3aS, 7a3) -1- 6-cyclohexylcarbamoyl-L-lysyl-gamma-0-glutamyl) octahydro-1H-indo / l-2-carboxylic acid.
The output of 0.46 g (43%). Starting compounds: Compound II and cyclohexylsocyanate.
“L29–31.1 ° (1N NaOH solution).
Calculated,%: C 56,41; H 8.37; N 11.75.
С27Н45№07.1,25 Н20-0,25 С.4Н802
Found %; 056.23; H 8.07; N 11.67.
Example 10. (25. Za5. 7a5) -1- (M2-phenylcarbamoyl-β-lysyl-gamma-O-glutamyl) octahydro-1H-indole-2-carboxylic acid.
The output of 0.65 g (64%). Starting compounds: Compound II and phenyl isocyanate.
“L -42 ° (1N NaOH solution).
Calculated,%: C 56.63; H 7.39; N 12.23.
C27H39N507-1,5H20
Found,%: C 56.80; H 7.23; N 12.03.
Example 11. (25. 3aS 7aS) -1- (N2-benzoyl-1-lysyl-gamma-D-glutamyl)-elktagidro-1 H-indole-2-carboxylic acid.
Sodium carbonate (2 0 g) is dissolved in 10 ml of water and 4 83 g of (25, 3aS. 7a5) -1- (gamma-0-glutamyl) octahydro-1H-indol-2-carboxylic acid are added. After formation of the solution, 40 ml of tetrahydrofuran are added. With vigorous stirring, 7.46 g of n-benzyloxycarbonyl-M-tert-butoxy-arbonyl-1.-lysine-n-i and hydroxysuccinimide ester are gradually added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to half the volume, acidified with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 9.17 g of (2S, 3aS, 7aS) -1- (N-benzyloxycarbonyl-N6-t -butoxycarbonyl-1-lysyl-gamma-0-glutamyl) octahydro-1H-indole-2-carboxylic acid are obtained.
The liquor (6.2 g) of the carboxylic acid obtained is dissolved in 60 ml of ethanol and 1.0 g of catalyst of 10% palladium on carbon is added. While mixing, 2.5 g of ammonium is added in small portions. The mixture was stirred for 4 hours. The catalyst was removed by filtration. The mother liquor is concentrated to dryness and ethyl acetate is added to the residue. The resulting powder was collected by filtration to obtain 3.9 g of (25, 3aS. 7a5) -1- (L6-tert-butoxycarbonyl- -lysyl-gamma-O-glutamyl) octagidro-1H-indole-2-carbon acid.
An aliquot of the resulting carboxylic acid (1.0 g) is dissolved in 7.0 ml of water and 0.55 g of sodium bicarbonate and 12 ml of tetrahydrofuran are added. With careful stirring, 0.46 g of M-benzoyl oxysuccinimide is added and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated to half volume, acidified with 10% citric acid, and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.
To the residue was added 20 ml of trifluoroacetic acid under ice-cooling, and the mixture was stirred for 15 minutes. Trifluoroacetic acid is evaporated under reduced pressure. The residue was separated by chromatography on a CHP20P column using acetonitrile and water (gradient from 0 to 50%). The fractions containing the desired product are concentrated to dryness under reduced pressure. The residue is lyophilized to obtain 0.50 g (46%) of the substance indicated in the preform.
“L25-23,1 ° (input).
Calculated,%: C 56.78; H 7.50; N 9.81 C27NzMM407 2.25 H20
Found,%: C 56.91; H 7.29; N 10.03.
The following substances (examples 12-31) are synthesized in the same manner as in example 11.
EXAMPLE 12 (4-methoxyphenylethoxy carbon and l) H-lysyl-gamma-0-glutamyl indolin-2 (5) -carboxylic acid.
The output of 0.26 g (31%). The starting compounds, compound I and M- (4-methoxyphenethyloxycarbonyloxy) succinimide.
Calculated,%: C 58.83; H 6.39; N 9,10.
C3N37N40g - H20
Found, ° /,: C 58/3; H 6.43; N 9.14.
Example 13. (25, Za5, 7a5) -1- (1 2-iso-nicotinoyl-1-lysyl-gamma-0-glutamyl) octahydro-1 H-indole-2-kaobonic acid
Yield: 0.29 g (47%). Starting compounds: Compound II and M- (isonicotinoyloxide) succinimide. -29.8 ° (in water).
Calculated. %: C 54.16; H 7.34; N 12.15.
S2bNz7№07 2,5N20
Found,%: C 54.25; H 7.06; N 12.23.
Example 14. (25 Za5, 7a5) -1- (M2-cyclopentyloxycaron 1l-b-lysyl-gamma-0-gl utamyl) octahydro-1 H- / shdol-2-carboxylic acid.
“L25 -37.1 ° (input).
Yield 0.42 g (39%). Starting material: Compound II and M- (cyclopentyloxycarbonyloxy) succinimide.
Calculated,%: C 55.21: H 8.02; N 9.90.
C26H42N408-1.5 H20
Found,%: C 55.05; H 7.77; N 10.05.
Example 15. (2S, 3aS, 7aS) -1- (N-cyclohexyloxycarbonyl-L-lysyl-gamma-O-glutamyl) octahydro-1H-indole-2-carboxylic acid.
  -31.9 ° (input).
Calculated,%: 055.51: H 8.20; N 9.59.
C27H44N408 1.75H20
Found,%: C 55.53; H 8.42: N 9.55.
Yield 0.50 g (56%). Starting compounds: Compound II and M- (cyclohexyloxycarbonyloxy) succinimide.
Example 16. (2S. 3aS, 7a5) -1- (1M2-cyclobutyloxycarbonyl -1 -lysyl-gamma-0-glutamyl) octahydro-1H-indole-2-carboxylic acid.
Yield 0.69 g (56%). Starting compounds: Compound II and M- (cyclobutyloxykeronyloxy) succinimide.
  -40.7 ° (in water).
Calculated,%: C 53.56: H, 7.91: N 9.99.
C25H40N408 2H20
Found,%: C 53.57; H 7.60; N 9.93.
Example 17.1- (N-cyclobutyloxycarbonyl-b-lysyl-gamma-O-glutamyl) -indolin-2 (5) -carboxylic acid.
Yield 0.50 g (63%). Starting compounds: Compound I and 1) - (cyclobutyloxycarbonyloxy) succinimide. M.p. 197-204 ° C.
G. “L27 -84.0 ° (1N NaOH solution).
Calculated,%: C 54.49: H 7.12: N 9.78.
C25H341 1 / -08 1.75 NaO
Found,%: C 54.67: H 7.40: N 9.53.
Example 18.1- (G-cyclohexylethoxycarbonyl-lysyl-gamma-D-glutamyl) indolin-2- (5) -carboxylic acid.
Yield 0.51 g (62%). Starting compounds: Compound I and M- (cyclohexylethoxycarbonyloxy) succinimid. M.p.
192-195 ° C.
  -78.8 ° (1 n. NaOH solution).
Calculated. % C 57.89: H 7.54: N9.31.
C29H42N408-1.5H20
Found%: C 57. 7.74: N 9.36.
Example 19. 1 - (- nicotinoyl-1-lysyl-gemma-O-glutamyl) indolin-2- (5) -carboxylic acid.
B) The yield of 0.58 g (70%). Starting compounds: Compound I and 1H- (nicotinoyloxy) succinimide. M.p. 218-222 ° C.
  -66,5 ° (1 n. NaOH solution).
Calculated. %: C 55.16 N 6.32: N 12.37.
S2bNz1№07 2.25N20
Found%: C 55.24: H 6.57: N 12.24.
Example 20. 1- (M2-cyclobutanecarbonyl-γ-lysyl-gamma-0-glutamyl) -indolin-2 (3) -carboxylic acid (Example 36).
Starting compounds: Compound I and (cyclobutanecarbonyloxy) succinimide. Mp 209-215 ° C.
  -96.6 ° (1N NaOH solution).
Calculated,%: C 56.70; H 7.04; N 10.58.
C25H34N407 "1.5 H20
Found,%: C 56.64; H 7.06; N 10.46.
Example 21. 1- 2-cyclopentyloxy-carbonyl-1-lysyl-gamma-0-glutamyl) indolin-2 (5) -carboxylic acid.
Yield 0.52 g (63%). Starting compounds: Compound I and M- (cyclopentyl or carbonyloxy) succinimide. M.p. 198-203 ° C.
  -79.3 (1 N. NaOH solution). Calculated. %: C 54.49; H 7.12; N 9.78. C26H36N40e 2.25H20
Found,%: C 54.67; H 7.40; N 9.53. Example 22. (2-nnpnflHH3TOKcn-carbonyl) - -lysyl-gamma-D-glutamyl indoline-2 (3) -carboxylic acid. The output of 0.23 g (23%). Starting compounds: Compound I and (2-pyridine ethoxycarbonyloxy) succinimide.
“L28 -69 3 ° (1N NaOH solution). Calculated,%: C 55,12; H 6.53: N 11.48. C28H35N40e 2.25H20
Found,%: 054.91; H 6.37; N 11.33.
Example 23. 1- 2-Benzoyl-1-lysyl-gamma-0-glutamyl) -indolin-2- (5) -carbonic acid.
Yield 0.44 g (44%). Starting compounds: Compound I and (benzoyloxy) succinimide. M.p. 202-208 ° C.
  -77.2 ° (1 n. NaOH solution). Calculated,%: C 57.85; H 6.47: N 9.99.
C27H32N407-2 H20
Found,%: C 57.97; H 6.32; N 10.20. Example 24. (2S, 3aS, 7aS) (4-chlorobenzyloxycarbonyl) -L-lysyl-gamma-D-glutamyl octahydro-1H-indole-2-carbonic acid.
Yield: 0.80 g (42%). Starting compounds: Compound II and (4-chlorobenzyloxycarbonyloxy) succinimide.
Calculated. %: C 54.06: H 6.81: N 9.01; CI 5.70.
C28H39CIN408-1.5 H20
Found,%: C 53,) 5: H 6.65; N 8.80: CI 5.56.
Example 25. (2S, 3aS, 7aS) (4-Methylbenzyloxycarbonyl) -L-lysyl-gamma-O-glutamyl octahydro-1H-indole-2-crabs and the acid.
  30.8 ° (1 n. NaOH solution).
The output of 0.13 g (81%). Starting compounds: Compound II and M- (4-methylbenzyloxycarbonyloxy) succinimide.
  -31.9 ° (1N. NaOH solution).
Calculated,%: C 57.46: H 7.57; N 9.24.
C29H42N408VU5H20
Found,%: C 57.37; H 7/51; N 9.07.
Example 26. (2S, 3aS, 7aS) (2-chlorobenzyloxycarbonyl) -L-lysyl-gamma-0-glutamyl octahydro-1H-indole-2-carboxylic acid.
Yield 0.94 g (59%). Starting compounds: Compound II and M- (2-chlorobenzyloxycarbonyloxy) succinimide.
 - -32.8 (1 N. NaOH solution).
Calculated,%: C 54.45; H 6.77; N 9.07; CI5J4.
C28H39CIN408 "1.25 H20
Found,%: C 54.55; H 6.81; N 8.90; CI 5.60.
Example 27. (2S, 3aS. 7aS) - (2-methylbenzyloxycarbonyl) -L-lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid - a acid.
The output of 0.82 g (55%). Starting compounds: Compound II and M- (2-methylbenzyloxycarbonyloxy) succinimide.
  -35.8 ° (1 n. NaOH solution).
Calculated,%: C 57.46; H 7.57; N 9.24.
C29H42N4O8-1.75 H20
Found,%: C 57.68; H 7.63; N 9.01.
Example 28. (2S, 3aS, 7aS) (2-fluorobenzyloxycarbonyl) -L-lysyl-gamma-0-glutamyl octahydro-1H-indole-2-carbonic acid.
The output of 0.35 g (28%). Starting compounds: Compound II and (2-fluorobenzyloxycarbonyloxy) succinimide.
“L32 -32.5 ° (1 n, NaOH solution).
Calculated,%: C 55.46; H 7.14: N 8.62; F 2.92.
C28H39FN408 1.5 C4H802
Found,%: C 55.63: H, 7.08; N 8.54; F3.01.
Example 29. (2S, 3aS, 7a3) (alpha-naphthylmethoxycarbonyl) - -lysyl-gamma-a-D-glutamyl octahydro-1H-indole-2-carboxylic acid.
Yield 0.40 g (34%). Starting compounds: Compound II and Y- (1-naphthylmethoxycarbonyloxy) succinimide.
 “L32 –36.30 ° (1N NaOH solution).
Calculated,%: C 60.08; H 7.18; N 8.49.
C32H42N408 "1.5, 25 C4H802
Found,%: C 59.78; H 7.41; N 8.37.
Example 30. (2S, ZAZ, 7a3) (alpha-naphthylethoxycarbonyl) - -lysyl-gamma-D-glutamyl octahydro-1H-indole-2-crabic acid.
The output of 0.37 g (29%). Starting compounds: Compound II and N- (L-naphthyl-ethoxycarbonyloxy) succinimide.
  -38.8 ° (1 n. NaOH solution). Calculated,%: C 59.64; H 7.44; N 7.95.
C33H44N408 2, 5 C4H802
Found,%: C 59.87; H 7.17; N 7.91.
Example 31. (2S, ZAZ, 7a3) (4-phenylbenzyloxycarbonyl) -L-lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxy-acid.
Yield 0.23 g (13%). Starting compounds: Compound II and (4-phenylbenzyloxycarbonyloxy) succinimide.
№27 -39.1 ° (1 n. NaOH solution). Calculated,%: C 61.09; H 7.26; N 7.92.
C34H44N408 O, 5 H20-0.5 C4H802
Found,%: C 61.23; H 7.26; N 7.85.
PRI me R 32. (23, ZAZ, 7aS) (4-mflroxybenzoyl) -1-lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid.
1.30 g is dissolved in 5 ml of water (23, ZAZ,
7aS) -1- (N-benzyloxycarbonyl-b-lysyl-g-amma-0-glutamyl) octahydro-1H-indole-2-carboxylic acid and 0.25 g of sodium carbonate and 10 ml of tetrahydrofuran are added. With vigorous stirring, 0.7 g of (4-hydroxybenzoyloxy) succinimide is added and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated to half the volume, acidified with 10% citric acid and
extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue is chromatographed.
column CHP20P (diameter 2.5 cm, length 40 cm), using as eluent a mixture of acetonitrile - water (gradient from 30 to 70%). The fractions containing the desired product are concentrated to dryness with reduced
pressure to give 0.6 g of residue. The residue is dissolved in a mixture of 25% HBr - acetic acid (10 ml) and the mixture is stirred at room temperature for 1 hour. Then 100 ml of ether are added and the white precipitate formed is collected by filtration and separated on a CHP20P column chromatography (diameter 2.5 cm, length 40 cm) using an acetonitrile-water mixture (gradient from 0 to 40%).
The fractions containing the desired product are concentrated to dryness under reduced pressure. The residue was freeze dried, to give 0.3 g (59%) of the title compound.
gf27 -17,4 ° (input).
Calculated,%: C 56.63. H 7.20: N 9.77.
C27H38N408 1.5H20
Found,%: C 56.71; H 7.09; N 9.95.
The following compounds are synthesized in the same manner as in Example 32.
Example 33. (2S, 3aS, 7aS) (2- ™ - ofencarbonyl) -.- lysyl-gamma-0-glutamyl octahydro-1H-carboxylic acid.
Yield 0.24 g (19%). Starting compounds: Compound II and M- (2-thiophenecarbonyloxy) succinimide.
  -23.1 ° (in water).
Calculated,%: C 54.14, H 6.91; N 10.10; S 5.78.
C25H36N407S-H20
Found,%: C 54.09; H 6.74; N 0.14; S 5.99.
Example 34. (2S, 3aS, 7aS) 2- (3-quinoline-carbonyl) lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid.
Yield 0.30 g (21%). Starting compounds: Compound U and M- (3-quinolinecarbonyloxy) succinimide.
MD -25.8 ° (1N NaOH solution).
Calculated,%: C 58.33: H 7.02 N 11.34.
SozNz9№07 2N20
Found,%: C 58.46; H 7.30; N 11.24.
Example 35. (2S, 3aS, 7aS) (2-chloronicotinoyl) lysyl-gamma-0-glutamyl-octahydro-1H-indole-2-carboxylic acid.
Yield 0.20 g (15%). Starting compounds: Compound II and M- (2-Chloronicotinoyloxy) succinimide.
“K6 -42.6 ° (in water).
Calculated,%: C 52.66; H 6.63; N 11.81; CI 5.98.
C26H38CN50 1.5H20
Found,%: C 52.75; H 6.68: N 11.76; CI 5.89.
Example 36. (2S, 3aS. 7aS) (4-chlorobenzoyl) -l-isyl-gamma-D-chloro-mil octahydro-1H-indole-2-cara lateral acid.
Yield 0.40 g (25%). Starting compounds: Compound II and (4-chlorobenzoyloxide) succinimide.
“L25 - -25.9 ° (1N NaOH solution).
Calculated,%: C 54.77: H 6.81; N 9.46: CI 5.99.
C27H37CIN407 1,5H20
Found,%: C 55.07: H 7.09; N 9.26; CI 5.79.
Example 37. (2S, 3aS, 7a5) -1- {M2-inolin-2- (5) -carboxyl-lysyl-gamma-0-glutamyl} octahydro-1H-intsol-2-carboxy- and acid .
Yield 0.25 g (18%). Starting compound: Compound II and L-indolin-2 (3) -carboniclosi-Succinimide.
  -64.3 ° (1 n. NaOH solution). Calculated,%: C 56.90; H 7.47; N 11.44.
C29H41N509-1,25H20
Found,%: C 56.99; H 7.61; N 11.15.
Example 38. (2S, 3aS, 7aS) (2- ™ - anaphtenecarbonyl) lysyl-gamma-O-gluta-0 mil octahydro-1H-indole-2-carboxylic acid.
Yield 0.3 g (31%). Starting compounds: Compound II and M- (2-tianaphthencarbonyloxy) succinimide. 5 -16,5 ° (1 n. NaOH solution).
Calculated,%: C 55.93; H 6.80; N 9.00; S 5.15.
C29h.j8N407.2H20
Found,%: C 56.08; H 6.63; N 8.87; S 0 4.94.
Example 39. (2S, 3aS, 7aS) (2-xn-naxolincarbonyl) lysyl-gamma-0-glutamyl-octagidro-1H-indole-2-crabonic acid.
5 Yield 0.30 g (21%). Starting compounds: Compound II and 1H- (2-quinoxaline-crabononyloxy) succinimide.
 -15.3 ° (1 n. NaOH solution).
Calculated,%: C 57.56; H 6.75; N 13.89. 0С29НзвМб07-1,25Н20
Found,%: C 57.48; H 7.00; N 13.96.
EXAMPLE 40. (2S, 3aS, 7aS) (2-isoquinolinecarbonyl) lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid 5.
Yield: 0.30 g (22%). Starting compounds: Compound II and - (2-isoquinoline carbonyloxy) succinimide.
  -51.8 ° (1N NaOH solution). 0Calculated,%: C 60.09; H 6.89; N 11.68.
C3H3gN507 1 H20
Found,%: C 59.89; H 6.66; N 11.61.
Example 41. (2S, 3aS, 7aS) (6-Methoxynicotinoyl) -.- lysyl-gamma-O-gluta-5 mil octahydro-1H-indole-2-Crabonic acid.
Yield 0.24 g (23%). parent compounds: Compound II and (6-methoxynicotin-yloxy) succinimide. 0 ab27 -18.0 ° (input).
Calculated,%: C 55.09; H 7.19; N 11.90.
С27Нзэ№08-1,5Н20
Found,%: C 55.09; H 7.44; N 11.77.
Example 42. (2S, 3aS, 7aS) (6-5 ethoxynicotinoyl) lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid.
Yield Q / I 5 g (14%). Starting compounds: Compound II and (6-ethoxy-nicotinoyl-oxy) succinimide.
  -16.4 ° (in water).
Calculated,%: 054.98; H 7.42; N 11.45.
С28Н41№ (У2 Н20
Found,%: C 55.00; H 7.70: N 11.27.
Example 43. (2S, 3aS, 7aS) (6-chloronicotinoyl) -1-lysyl-gamma-0-glutamyl-octahydro-1H- and ndol-2-carbon o wa acid.
Yield 2.0 g (55%). Starting compounds: Compound II and H- (6-chloronicotinoyloxy) succinimide.
  -21.4 ° (water).
Calculated,%: C, 51.87: H, 6.70; N 11.63: CI5.89.
S2bNzbS1 and-07 2 H20
Found,%: C 51.78; H 6.44: N 11.88; CI 6.05,
Example 44. (2S, 3aS, 7aS) - (6-n-propoxy-nicotinoyl) lysyl-gamma-D-glutamyl octahydro-1H-indole-2-carboxylic acid and a.
The output of 0.25 g (23%). Starting compounds: Compound II and K | - (6-n-propoxy-nicotinyloxy) succinimide.
  -25,2 ° (1 n. NaOH solution).
Calculated,%: C 56.48: H 7.52: N 11.36.
C29H43N508-1.5 H20
Found,%: C 56.56; H 7.22; N 11.36.
EXAMPLE 45. (2S, 3aS, 7aS) (2-H30-propoxinicotinoyl) - L-l from Il-ga mma-D-glutamyl octahydro-1H-indole-2-carboxylic acid - a.
Yield 0.20 g (18%). Starting compounds: Compound II and M- (2-isopropoxy-nicotinoyl-oxy) succinimide.
  -26.4 ° (1 n. NaOH solution).
Calculated,%: C 55.67: H 7.57: N 11.19.
S2dN43№08-2N20
Found,%: C 55.41; H 7.80; N 11.05.
EXAMPLE 46, (2S, 3aS. 7a3) (3-hydroxybenzoyl) lysyl-gamma-0-glutamyl octahydro-1H- and ndol-2-carbonone.
Yield 0.50 g (49%). Starting compounds: Compound II and M- (3-hydroxybenzoyloxy) succinimide.
Calculated,%: C 56.98; H 7.17; N 9.84.
C27H38N408-1.25 H20
Found,%: C 57.07; H 7.16: N 9.79.
EXAMPLE 47. (2S. 3aS. 7a3) (3-hydroxy-4-methoxybenzoyl) - -lysyl-gamma-0 -glutamyl octahydro-1H-indole-2-carboxylic acid.
Yield 0.30 g (27%). Starting compounds: Compound II and (3-hydroxy-methoxy-benzoyloxy) succinimide.
  -40.0 ° (1 n. NaOH solution).
Calculated,%: C, 52.95; H 7.38; N 8,82.
C28H4oN40g 3.25 H20
Found,%: C 52.86; H 7.07: N 8.97.
five
EXAMPLE 48. (2S, 3aS, 7aS) - (6-hydroxy-beta-naphthoyl) - -lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid.
The output of 0.35 g (31%). Starting compounds: Compound II and M- (6-hydroxy- (3-naphthyloxy) succinimide.
  -2.8 ° (1 N. NaOH solution). Calculated,%: C 58.02; N 7.07; N 8.73.
C3iH4oN408-2,5H20
Found,%: C 57.90; H 7.09; N 8.58, Example 49. 1- (N -pyrazinoyl-b-lysyl-gamma-O-glutamyl) -indolin-2 (3) -carboxylic acid.
5Dissolved 0.26 g of pyrazinic acid.
in a mixture of 3 ml of dimethylformamide and 20 ml of methylene chloride and 1.1 g of 1- (N-tert-butoxycarbonyl-L-lysyl-0-ethyl-gamma-0-glutamyl) ethyl ester are added
0 indolin-2 (5) -carboxylic acid and 0.84 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodium - mid-hydrochloride. The mixture is stirred overnight at room temperature. The reaction mixture is successively washed with a saturated aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a column of
0 silica gel, eluted with a mixture of (methanol - chloroform (2%), 0.8 g of 1- (N-tert-butoxycarbonyl-N-pyrazinoyl--lysyl-O-ethyl-gamma-D-glutamyl) indoline ethyl ester is obtained -2 (5) -carbon
5 acids in the form of a viscous oily substance.
The resulting material (0.8 g) was dissolved in dioxane and 3.5 ml of 1N was added. NaOH solution. The mixture is stirred under ice cooling for 1.5 hours. The reaction mixture is concentrated, acidified with 10% citric acid and separated on a CHP20P chromatographic column using acetonitrile-water (gradient from 0 to 60%). The fractions containing the desired product are concentrated to dryness under reduced pressure. The residue is re-precipitated from a mixture of petroleum ether and ethyl acetate. Filtration gives 0.55 g of 1- (N-tert-butoxycarbonyl-N-pyrazinoyl-1-lysyl-gamma-0-glutamyl) indoyl-2 (5) -carboxylic acid. 10 ml of trifluoroacetic acid is added to an aliquot (0.45 g) of the final compound and the mixture is stirred while cooling with ice for 20 minutes. The trifluoroacetic acid is evaporated and the residue is separated by chromatography on a CHP20P column, using acetonitrile-water as the eluent (gradient from 0 to 30%). The fractions containing the desired product are concentrated to dryness under reduced pressure. The residue was freeze dried to give 0.27 g of the title compound.
Mo25 -74.4 (1N NaOH solution).
Calculated,%: C 52.53: H, 6.17: N, 14.70.
С25НзоМ607 2,5Н20
Found,%: C 52.52; H 6.27; N 14.54.
Example 50. The monosodium salt of (2S, 3aS, 7a5) -1- (N2-nicotinoyl-1-lysyl-gamma-0-glutamyl) octahydro-1 H-indole-2-carboxylic acid.
In 5 ml of water, 0.57 g of (2S, 3aS, 7aS) -1- (N-nicotinoyl-L-lysyl-gamma-O-glutamyl) octahydro-1H-indole-2-carboxylic acid is dissolved and added 1 ml 1 n. NaOH solution. The resulting aqueous solution is separated on a CHP20P chromatographic column (gradient from 0 to 20% using an acetonitrile-water mixture). The fractions containing the desired product are concentrated to dryness under reduced pressure. The residue is freeze dried and 0.25 g of the compound indicated in the preform is obtained.
EDO26 -24,6 ° (in water).
Example 51 (2S, 3aS. 7a5) (2-methoxybenzoyl) lysyl-gamma-0-glutamyl octahydro-1H-indole-2-carboxylic acid.
1.0 g of ortho-anisic acid, 0.76 g of N-hydroxysuccinimide and 1.39 g of water-soluble crabodiimide hydrochloride are dissolved in 15 ml of methylene chloride and 1.38 g of solution are stirred overnight at room temperature. The precipitate is separated by filtration. The mother liquor was concentrated under reduced pressure and the residue was subjected to recrystallization from isopropanol, to obtain 1.47 g of M- (2-methoxybenzo-1-oxy) succinimide. M.p. 180-182 ° C.
(2S, 3aS, 7a5) -1- (L6-benzyloxy. Fabonyl-1-lysyl-gamma-0-glutamyl) octahydro-1 H-indole-2-carboxylic acid
is dissolved in 6 ml of water and sodium carbonate and 10 ml of tetrahydrofuran are added. With vigorous stirring, N- (2-methoxybenzoyloxy) succinimide is added. This mixture is stirred overnight at room temperature. The reaction mixture is acidified with 10% citric acid and extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was separated by chromatography on a CHP20P column, using acetonitride-water (gradient from
30 to 70%). The fractions containing the desired product are concentrated to dryness under reduced pressure, to give 1.0 g of (2S, 3aS, 7a5) -1-1b-benzyloxycarbonyl-L2- (2-methoxybenzoyl) -lysyl-gamma-0-glutamyl-oxy- tagidro-1 N-indole-2-carboxylic acid.
1.0 r (2S, 3aS, 7aS) benzyloxycarbonyl-N- (2-methoxybenzoyl) -1-lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid is dissolved in 10 ml of ethanol and 1.18 g of cyclohexene and 0.2 g of catalyst — 10% palladium-carbon are added. The mixture was stirred at 60 ° C for 2 hours. The catalyst was removed by filtration and the mother liquor was concentrated to dryness under reduced pressure. The residue is subjected to chromatographic separation on a CHP20P column (gradient from 0 to 50% using an acetonitrile-water mixture). The fractions containing the desired product are concentrated under reduced pressure. The residue was freeze dried to give 0.34 g of the compound indicated in the preform.
  -14.9 ° (input).
Calculated,%: C 56.36; H 7.43; N 9.39.
C28H40M408 2 H20
Found: C, 56.63 H, 7.1 N, 9.33.
Example 52 1- (N -cyclohexycarbonyl-1-lysyl-gamma-0-glutamyl) indolin-2 (5) -carboxylic acid.
The output of 0.28 g (42%). The starting compounds, compound II and M- (cyclohexylcarbonyloxy) succinimide. T. pl. 207-212 ° C.
“L -90.3 ° (1N NaOH solution).
Calculated,%: C 57.23; H 7.47; N 9.89.
C27H38N407 2H20
Found,%: C 57.42; H 7.52; N 9.94.
Example 53. (2S, 3aS, 7a3) (4-phenylbenzoyl) lysyl-gamma-0-glutamyl octahydro-1H-indoyl-2-carboxylic acid.
Yield 0.36 g (21%). Starting compounds: Compound II and M- (4-phenylbenzoyl-oxo) succinimide.
  -11.6 ° (1 n. NaOH solution).
Calculated,%: C 62.02; H 7.29; N 8.27.
SzzN421 and 07 1.5, 5 С4Нз02
Found,%: C 61.98; H 7.15; N 8.35.
Example 54. (2S, 3aS, 7aS) (4-fluorobenzoyl) -lysyl-gamma-O-glutamyl octahydro-1H-indole-2-carboxylic acid.
The output of 0.37 g (67%). Starting compounds: Compound II and (4-fluorobenzoyloxy) succinimide.
Calculated,% C 55.47: H 7.07; N 9.58; F 3.25.
C27H37N407F.2 H20
Found,%: C 55.59; H 7.36; N 9.46; F 3.03
Example 55. - (3,4-methylenedioxibenzyloxycarbonyl) - L-lysyl-gamma-O-glutamyl indolin-2 (5) -carboxylic acid.
2.5 g of N2-tert-butoxy-carbonyl-M6- (3-nitro-2-p-iridine sulphenyl) -1-lysine and 2.2 g of ethyl ester 1- (01-ethyl-gamma- O-glutam yl) indolin-2 (5) -carboxylic acid and 2.0 g of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride are added. This mixture is stirred overnight at room temperature. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate with a 5% aqueous solution of potassium bisulfate and an aqueous solution of sodium chloride. Dry over anhydrous sodium sulfate and concentrate to dryness under reduced pressure. The residue is recrystallized from ethanol to obtain 3.6 g of 1-S2-tert-butoxycarbonyl-1-N- (3-nitro-2-pyridine sulphenyl) lysyl-0-ethyl-gamma-0-glutamyl indoline ethyl ester -2- (3) -carboxylic acid.
  -28.2 ° (in dimethylformamide).
3.5 g of this ester is stirred with 30 ml of trifluoroacetic acid under ice cooling for 30 minutes. Trifluorus acid is evaporated and ethyl acetate and 5% potassium carbonate are added to the residue. The mixture is shaken vigorously. The organic layer is washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from a mixture of ether and ethanol to obtain 2.6 g of ethyl (3-nitro-2-pyridine sulphenyl) -L-lysyl-O-ethyl-gamma-O-glutamyl-indole in-2 (5) -carboxylic acid. T. pl. 95- 102 ° C.
 - -39.6 ° (in dimethylformamide).
An aliquot (1.0 g) of the ester formed is dissolved in 30 ml of methylene chloride, and 0.21 g of N-methyl morpholine and 1.07 g of M- (3,4-methylenedioxy benzyloxycarbonyloxy) succinimide and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate. 5% aqueous solution of potassium bisulfate and water. Dry over anhydrous sodium sulfate and concentrate to dryness under reduced pressure. The residue is recrystallized from a mixture of ethanol and methanol to obtain 1.1 g of ethyl ether - (3,4-methylene-dioxybenzyloxycarbonyl) - N - (3-nitro-2-pyridinesulphenyl) -lysyl
-01-ethyl-gamma-O-glutamyl indolin-2 (5) - carboxylic acid. M.p. 130-135 ° C.
Mo27 -23.2 ° (in dimethylformamide).
An aliquot (1.0 g) of this product is treated as in the second stage of Example 68, yielding 0.8 g of - (3,4-methylenedioxybenzyloxycarbonyl) -Y HZ-nitro-2-pyridine sulfenyl) -1 -lysyl-gamma -0-glutamyl indoline-2 (5) -carboxylic acid. T. pl. 100-110 ° C.
  -70,5 ° (1 n. NaOH solution).
An aliquot (0.74 g) of the product is dissolved in 10 ml of dioxane and 19 ml of dioxane and 10 ml of 0.5N are added. hydrochloric acid solution. The mixture was stirred at 45 ° C for 4 hours. The reaction mixture was neutralized and concentrated, and the residue was acidified with 1N. hydrochloric acid solution and chromatographically separated on a CHP20P column (gradient from 0 to 50% using a mixture of acetonitrile and water). The fractions containing the desired product were concentrated, and the precipitated crystals were collected by filtration, to give 4 mg (7.7%) of the title compound. M.p. 198-202 ° C.
  -67.3 ° (1 N. NaOH solution).
Calculated,%: C 54.88; H 6.04; N 8.83.
C2ENYM40-2 Noo
Found,%: C 55.16; H 6.14; N 8.83.
EXAMPLE 56. (2S. 3aS, 7a3) (2-hydroxy-3-methyl-benzoyl) -1 -lysyl-gamma-0-g lutamyl octahydro-1H-indole-2-carboxylic acid .
The output of 0.16 g (14%). Parent compounds; compound II and M- (2-hydroxy-3-methyl benzoyloxy) succinimide.
  + 45.2 ° (in 1 n. NaOH solution).
Calculated,%: C 57.71; H 7.54; N 9.11.
C2oH4oN40e-3 NgO
Found,%: C 54.78; H 7.46; N 8,82.
EXAMPLE 57. (2S. 3aS. 7aS) (2-rnfl-roxy-5-chlorobenzoyl) - -lysyl-gamma-0-glutamyl octahydro-1H-indole-2-carboxylic acid.
Yield 0.32 g (29%). Starting compounds: Compound II and (2-hydroxy-5-chlorobenzoyloxy) succinimide.
“L30 + 17.2 ° (1N NaOH solution).
Calculated,%: C 53.33; H 6.63; N 9.21; CI 5.83.
C27H37CIN4O8 1.5 NaO
Found,%: p. 53.21; H 6.75; N 9.23; CI 5.65.
Biological tests of the compounds obtained under the conditions of the described method were carried out.
Antihypertensive activity. Male Sprague Dawley rats (5 weeks old) under light anesthesia with ether were squeezed with a silver clamp (internal diameter 0.22 mm), the left renal artery. The right kidney and renal artery were intact. After 6-10 weeks after the clamp, rats with a blood pressure above 180 mm Nd were collected. Such rats were called double-spot real-hypertensive Goldblatt-type rats and were considered as a typical model of reninangiotensin-dependent hypertension.
Blood pressure was measured by the tail-cuff tail-cuff method using a programmed electrophygmomometer (PE-300, Narco Biosystems, USA) after heating for 10 minutes at 38 ° C in a heating chamber.
The antihypertensive activity of the tested compounds was evaluated after a single oral administration of these compounds in rats with renal hypertension (3-5 rats / group).
The results obtained are presented in the table.
In vitro ACE is an inhibitory activity against ACE in laboratory conditions. The assay medium contained the preparation ACE (rabbit lungs), a synthetic substrate (hippuryl-β-histidyl-β-leucine 5 mM), NaCI (300 mM) and phosphate buffer (100 mM, pH 8.3). The components were mixed to a final volume of 0.300 ml and incubated for 30 minutes at 37 ° C in the presence or absence of the compound used. After termination of the reaction as a result of the addition of 300 h 1 n. of the fxlaOH solution, the formed hippuric acid was extracted with 2 volumes / i of ethyl acetate-ia. After evaporation of ethyl acetate and the addition of distilled water, the hippuric acid was determined by its absorption in the 228 nm region using a spectrophotometer (Hitachi 100-41).
The degree of ACE is inhibition. ACE was calculated from the activities obtained in the presence and absence of the test compounds. The IGso value (molar concentration required for 50% inhibition of ACE activity) was obtained from the curve plotted in the dose – inhibition coordinates.
Toxicity. In the experiments, male mice of the TD-ddy strain weighing 22-25 g were used. It was found that the LDB value in oral use of the test compounds (Examples 15 and 51) in mice was more than 3,000 kg per 1 kg of body weight. The results show that the tested compounds are highly toxic.
m




ten
15
20
25
thirty
35
40
45
50
55
The tests carried out showed that the compounds obtained under the conditions of the described method have very low toxicity (3000 mg / kg), their therapeutic index of 300 or more, i.e. they are compounds of extremely low toxicity.
The table shows that structural analogs (the last 2 compounds), when injected into an animal, cause a decrease in blood pressure of only 3 and 2 mm Hg. at a dose of 30 mg / kg. An increase in the input quantity of these analogs does not lead to a significant decrease in blood pressure. These comparative compounds do not exhibit a therapeutically effective lowering of blood pressure.
Thus, the compounds obtained by the proposed method have a higher antihypertensive activity and belong to the category of practically non-toxic compounds.

权利要求:
Claims (1)
[1]
1. A method for preparing tripeptide derivatives of the general formula
(
CH2 SOOKg
RrW-CQ-M-CH-CQ-KH-CH- (CH2) rCO-S3 where RI is C4 Sat-Cycloalkyl group, cyclohexyl group - lower alkyl; a phenyl group optionally substituted with a substituent selected from halogen, methyl, methoxy, phenyl and hydroxy; phenyl-lower Cr-C2-alkyl groups, where the benzene ring is optionally substituted with a substituent selected from halogen, methyl, methoxy, phenyl and 3,4-methylenedioxy, ri / drox-substituted naphthyl group; a naphthyl group is a lower alkyl, pyridyl group, optionally substituted by a substituent selected from halogen and a lower alkoxy group of the C -C4 group, a pyrrolidinyl group. A 2-thienyl group, a 3-quinolyl group; A 2-indolyl group, a tianaphen-2-yl group, a quinoxalin-2-yl group, an isoquinolin-2-yl group, a 2-pyrazinyl group, a pyridyl-lower alkyl group or an imidazolyl group,
W is a single bond, -O- or -NH-;
R2 is hydrogen;
Pz - 2 (5) -carboxyindolyl group or 2-carboxy (2S, 3aS, 7a5) -octahydro-indolyl group, provided that if W is a single bond, then RI is a cyclo-C4 C-alkyl group, a phenyl group optionally substituted by halogen, methyl, methoxy, phenyl or hydroxy. hydroxy-substituted naphthyl group, pyridyl group, optionally substituted with halogen and lower alkoxy-St-Cz group, pyrrolidinyl group, 2-thienyl group; 3-quinolyl group, 2-indolyl group, tianaphen-2-il group, quinoxaline-2-il group, isoquinoyl-2-il group, 2-pyrazinyl group, imidazolyl vinyl group, or, if W - -0-, then RI is a cyclo-C4 C-alkyl group, a cyclohexyl group is a lower alkyl group, a phenyl-C, -C-alkyl group, and the benzene ring is optionally substituted by halogen, methyl, methoxy, phenyl, or 3,4-methylenedioxy, a naphthyl group - lower alkyl, a pyridyl group - lower alkyl, or. if, then RI is a cyclo-Cb-alkyl group, a phenyl-phenyl group, a phenyl-C-Ca-alkyl group, or a pharmaceutically acceptable salt thereof, characterized in that. that the compound of the general formula
Ri-W-COOH,
where FI and W have the indicated meanings, or its reactive derivative at the craboxyl group, such as an acid halide, isocyanate or activated amide, with a compound of the general formula -CH-Itz
SNG № g Shch-Shsho-MI-YsNog-CO-Xs
where is R2. R4 is hydrogen or an amino protecting group; 35 R2 and R4 are as defined.
0 5 0
five
0
five
or with its acid addition salt and, if necessary, a protecting group is removed, and the desired product is isolated in free form or as a salt.
Priority signs: 09.05.86 with Ri - cyclo-Cb-alkyl group,
a cyclohexyl group is a lower alkyl group, a phenyl group is a lower alkyl group in which the benzene ring may be optionally substituted by a methoxy group, a pyridyl group which may be optionally substituted by a substituent selected from a halogen and a lower alkoxy group, or an imidazolylvinyl group; R2 is hydrogen; Rz-2 (S) -craboxidinol or 2-carboxy (25, 3aS, 7aS) octahydroindoyl group; W is a single bond or -O.
03.07.86 when Ri is a cyclo-C-alkyl or pyrrolidinyl group; R2 is hydrogen; R3 is 2 (5) -carboxyindolyl or 2-carboxy (2S, 3aS, 7a3) octahydroindolyl group: W is a single bond or -0-.
26.01.87 when RI is a cyclo-Cb-alkyl group, a phenyl group, optionally substituted by a methoxy or hydroxy group, a phenyl group - a lower alkyl group in which the benzene ring is optionally substituted by a 3,4-methylenedioxy group, a 2-thienyl group, 3-quinolyl Group. 2-pyrazinyl group or pyridyl-lower alkyl group: R2 is hydrogen; R3 is 2 (5) -carboxyindolyl or 2-carboxy (2S, 3aS, 7a5) octahydroindolyl group; W is a single bond or -0-.
Table continuation
27
1743356
28 Continuation of the table

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US4320057A|1982-03-16|Aryl--pyrrolo--thiazepin--diones and aryl--piperidino--thiazepin--diones

---

DE19542189A1|1997-05-15|New cyclic alpha-imino:hydroxamic acid derivatives

---

SU1743356A3|1992-06-23|Method for preparation of tripeptide derivatives or theirs pharmaceutically acceptable salts

---

US4251444A|1981-02-17|Thiazepino-[4,3-b]-isoquinoline-1,5-dione derivatives and precursors

---

US4665055A|1987-05-12|Peptide renin inhibitors

---

CA1056818A|1979-06-19|Process for the manufacture of dipeptide derivatives

---

US4639451A|1987-01-27|Pyridazinone derivatives

---

DE19851184A1|2000-05-11|N-arylsulfonylamino acid omega amides

---

US4322436A|1982-03-30|Novel substituted phenylacetic acid amide compounds

---

CA1059994A|1979-08-07|Histidine derivatives

---

US4387049A|1983-06-07|Adamantyl containing peptides

---

PT100148B|1999-06-30|A process for the preparation of novel dipeptide derivatives containing a pyretin ring

---

US4678800A|1987-07-07|Gamma-r-glutamoyl derivatives

---

US4456594A|1984-06-26|N-Carboxyalkylproline-containing tripeptides

---

US4400511A|1983-08-23|2-Substituted octahydropyrrolo|-pyrazine-3-carboxylic acids

---

CA2166032A1|1996-06-24|1-oxo-2-|pentylpiperidine; process for preparing them and their use as therapeutic agents

---

HU192914B|1987-07-28|Process for producing new 3-/substituted amino/-5-phenyl-2/3h/-furanone derivatives and pharmaceutically acceptable salts

同族专利:

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公开号 | 公开日

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AU7241687A|1987-11-12|

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CA1318461C|1993-05-25|

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US4826814A|1989-05-02|

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DE3787042D1|1993-09-23|

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FI87794B|1992-11-13|

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DK171402B1|1996-10-14|

---

HU202884B|1991-04-29|

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EP0244836A2|1987-11-11|

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FI87794C|1993-02-25|

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DK235787D0|1987-05-08|

---

AU595309B2|1990-03-29|

---

ES2058074T3|1994-11-01|

---

DE3787042T2|1994-01-27|

---

EP0244836A3|1989-11-23|

---

EP0244836B1|1993-08-18|

---

JPS63295597A|1988-12-01|

---

CZ332387A3|1995-11-15|

---

FI872041A|1987-11-10|

---

FI872041A0|1987-05-08|

---

DK235787A|1987-11-10|

---

HUT45268A|1988-06-28|

---

MX174530B|1994-05-24|

---

SK278137B6|1996-02-07|

---

MX6424A|1993-09-01|

---

SK332387A3|1996-02-07|

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KR870011152A|1987-12-21|

---

NZ220173A|1990-01-29|

---

CZ280776B6|1996-04-17|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4215110A|1978-09-22|1980-07-29|Merck & Co., Inc.|Method of treating hypertension|

---

DE3381378D1|1982-01-23|1990-05-03|Ajinomoto Kk|DERIVATIVES OF AMINO ACIDS AND ANTI-HYPERTENSIVE MEDICINAL PRODUCTS CONTAINING THEM.|

---

JPS59227851A|1983-06-09|1984-12-21|Sankyo Co Ltd|Peptides having inhibitory action on renin|

---

US4678800A|1984-06-15|1987-07-07|Ciba-Geigy Corporation|Gamma-r-glutamoyl derivatives|

---

US4616002A|1984-11-09|1986-10-07|Ciba-Geigy Corporation|Dihydro pyridine compounds, compositions and use|

---

DE3619633A1|1986-06-11|1987-12-17|Hoechst Ag|PEPTIDES WITH INFLUENCE ON DIURESE AND NATURALSE, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THEIR USE|

---

DE3640535A1|1986-11-27|1988-06-01|Merck Patent Gmbh|PEPTIDE|

---

DK523288A|1987-10-06|1989-04-07|Hoffmann La Roche|AMINO ACID DERIVATIVES|WO1989004833A1|1987-11-16|1989-06-01|The Upjohn Company|Renin inhibiting peptides that contain amino and hydroxy dicarboxylic acids|

---

FR2649110B1|1989-06-29|1994-10-21|Adir|NOVEL PEPTIDE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|

---

US5391705A|1991-03-15|1995-02-21|Merrell Dow Pharmaceuticals Inc.|Polyfluorinated tripeptide thrombin inhibitors|

---

US6764693B1|1992-12-11|2004-07-20|Amaox, Ltd.|Free radical quenching composition and a method to increase intracellular and/or extracellular antioxidants|

---

US5925452A|1994-05-27|1999-07-20|Cubic Co., Ltd.|Decorated shaped product having source expression applied thereto, method for manufacturing same and shaped base material therefor|

---

WO1996034011A1|1995-04-27|1996-10-31|Dainippon Pharmaceutical Co., Ltd.|Purifying methods|

---

US6069232A|1995-10-02|2000-05-30|Hoechst Marion Roussel, Inc.|Polyfluoroalkyl tryptophan tripeptide thrombin inhibitors|

---

US5739354A|1996-03-26|1998-04-14|Hoechst Marion Roussel, Inc.|Process for the preparation of N-methyl-D-phenylalanyl-N- 1- 3- amino!propyl!-3,3-difluoro-2-oxohexyl!-L-prolinamide|

---

WO2003074048A1|2002-03-01|2003-09-12|Warner-Lambert Company Llc|Method of treating osteoarthritis|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP10739486|1986-05-09|

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JP15669386|1986-07-03|

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JP1636187|1987-01-26|

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