FI90532C - A process for the preparation of new therapeutically useful octahydroindole derivatives - Google Patents

Description

Process for the preparation of new therapeutically useful octahydroindole derivatives 1,90532

Divided separated from application 812652 5

The invention relates to the preparation of new octahydroindole derivatives of the formula I and their physiologically tolerable salts.

-COOH

kJ—% nCO-CH-NH-CH-C00R-,

I and J

R 1 is R 15 wherein R x is CH 3 or CH 2 F, R 2 is alkyl of up to 6 carbon atoms which may be substituted by amino or hydroxy, and R 3 is hydrogen or alkyl of 1 to 6 carbon atoms, provided that Rx and R 20 does not simultaneously mean methyl. These compounds have an antihypertensive effect.

The compounds of the formula I and their physiologically tolerable salts can be prepared by a) reacting a compound of the formula II with a compound of the formula III, I Q-CH-C00R-K

CO-CH-Q

.30 i:. R 1 (11) (III) wherein R 1, R 2 and R 3 are as defined above, one of Q is a nucleofugic group and the other is NH 2 and R 4 is H, methyl, ethyl, benzyl or 2,90532 tert-butyl, and optionally obtained the ester is converted to a carboxylic acid (R 2 and / or R 4 = hydrogen), or b) a compound of formula POOC- (j: H-NH-CH-COOP (IV) R 1 R 2 wherein R 1 and R 2 are hinge as defined above, P is hydrogen or one of the symbols P may myOs mean the same as the above R3, such as tert-butyl, is reacted with a compound of the formula ^ C00R4 3.5 II ΊΓ wherein R4 is the same as above, with a condensing agent and, if desired, one or both ester groups are converted to a carboxylic acid, or c) a compound of formula VI is reacted with a compound of formula VII, T = C-C00R4 T = C-C00Ro II 3 L JN r9 \ λ

:. C = C 0 T

(VI) Rx (VII) 30 wherein n, Rx, R2, R3 and R4 are as defined above and one of the symbols T is hydrogen and NH2 and the other is an oxygen atom, and the resulting Schiff's base is reduced, and if desired, the resulting formula The compound of formula I is converted into a salt.

li 3 90532

In the preparation of compounds I, for example, 2-halocarboxylic acid derivatives II or III which react with nucleophilic compounds can be obtained. This reaction is carried out primarily in water-miscible organic solvents, optionally in the presence of water, with the addition of an inorganic or tertiary or quaternary organic base. If the reactants are soluble in aprotic organic solvents, such a solvent is preferred, in which case it is preferable to add trialkylamine, tetraalkylammonium hydroxide or tetramethylguanidine or an alkali or alkaline earth carbonate suspension as the base.

check-out

C/o.

1 COOH H

X

20 is prepared by catalytic hydrogenation of predominantly rhodium catalysts, a compound of formula ζΧλ

- · COOH

:.: 25 H

VIII

Esters with R4 are obtained in a known manner and are condensed with halocarboxylic acids. . 30 to compounds II (Q = halogen) either via acid chlorides, mixed anhydrides, active esters or by other methods thoroughly described in Houben-Weyl, Methoden der Organischen Chemie, Band 15.

When Rx = CH3, it is possible to start from, for example, D-2-chloropropionic acid readily available from L-lactic acid.

4,90532

Intermediate products of formula II (Q = NH 2) are obtained from carboxylic acid esters of general formula V by condensation with an N-protected 2-aminocarboxylic acid. The protection group is cleaved after the condensation has stopped.

Suitable protecting groups are, for example, benzyloxycarbonyl.

Condensation cannot be performed with DCC / HOBt combination alone (dicyclohexylcarbodiimide / 1-hydroxybenzotriazole) but with another suitable condensing agent, e.g. the condensing agent described in Houben-Weyl, Band 15.

Process (b) proceeds from compounds of formula IV.

If R 1 and R 2 are identical, then P can be ve-15 ty. The condensation is then carried out, for example, with dicyclohexylcarbodiimide in the presence of an equivalent amount of the compound of the formula V and R4 is cleaved in a known manner. The reaction takes place via an optionally isolatable anhydride XII which is opened with a compound of formula V in its fraction 20.

B

/ N \ '' 25 R.-HC CH-FL, 1 I I 2 + o = c c = o

XLI

R4OOCv ^ CH2 ^ / ^ ^ \ / CH2 \ / COOR4

HN-1 J k J-N-CO-CH-N-CHt-COOH

. 35 I

B

V

5,90532

If R 1 and R 2 in compound IV are different, primarily only one of the strokes P is hydrogen, the other should denote R 3 or tert-butyl at most. The condensation is then carried out as described with the compounds of the formula V5 and one or both ester groups are optionally converted into the carboxylic acid.

When in formulas VI or VII T = NH 2 and H, significant condensation with 2-ketocarboxylic acids or their esters according to method (c) results in a known reduction via Schiff's bases, e.g. sodium borohydride or sodium cyanoborohydride, by catalytic or reductive hydrogenation. electrolytically, to form the corresponding compounds of formula I in very pure form.

15 The new compounds have, among other things, 3 centers of rotation at α-C atoms. The order of the ligands corresponds to the L-configuration of the lå price. Crystallization countries can generally be obtained from sterically substantially uniform compounds of formula I. For enrichment of sterically more uniform forms, countercurrent distribution or preparative HPLC methods are preferred.

in the intermediate product step, the diastereomers of the formula X can optionally be separated by crystallization or by preparative HPLC methods so that products of the formula I having a uniform steric sequence can be obtained according to the method described above.

The new compounds of the formula I have a long-lasting, intense antihypertensive effect.

... 30 They can be used to control hypertension caused by various causes and can be used alone or in combination with other antihypertensive, vasodilator or urinary excretory compounds. Typical representatives of these classes of women are described, for example, in Erhart-Rusching, Arzneimittel, 2. Auflage, Weinheim 1972.

6 90532

They can be used intravenously, subcutaneously orally.

For oral administration, the dose is 20 to 200 mg per individual dose. In more severe cases, it 5 can be myds magnified because no toxic properties have been observed so far. Dose reduction of Myds is possible and is primarily applied when concomitant administration of substances that increase urinary excretion. When administered intravenously or subcutaneously, 10 single doses should be 0.01 to 10 mg.

The compounds of formula I exist as their internal salts. If both carboxyl groups are free, alkali and alkaline earth metal salts and salts can also be formed with physiologically innocuous amines. Further, the free amino group present may be reacted as a salt with an inorganic acid or an organic acid. Myds other compounds of formula I may be used in free form or as salts thereof.

The pharmacological activity of the compounds has been determined by ACE analysis. ACE is primarily responsible for the hydrolysis of angiotensin I to the vasopressor actapeptide angiotensin II. Its activity can be determined using hippuryl-1-histidyl-1-leucine (HHL) or hippurylglycidylglycine as a substrate.

The enzyme is prepared as follows: 10 g of rabbit lung powder are extracted for 10 min with 100 ml of potassium phosphate buffer (50 mol, pH 8.3) and then centrifuged for 40 min at 40,000 g. The supernatant is stored at 30 ° C. Enzyme analysis is a variation of the publication

Biochem. Pharmacol. 20 (1971), p. 1673 of a known method. The inhibitory effect of the compounds is investigated by adding 10 ml of inhibitor in distilled water or DMSO to 40 μl of buffer (750 nM, 115 mol potassium phosphate-35, pH 8.3) and 40 μl of (3-H) -HHL (500 pmol) 115 mol in potassium phosphate buffer, pH 8.3. The DMSO content of 7,90532 is kept below 1%. The reaction is carried out with an additional 20 μΐ of the above enzyme solution. Incubate for 60 min at 37 ° C, the residue of which is stopped by an additional 1 ml of 0.1 HCl. The (3-H) hippuric acid is then extracted with 1 ml of 5 ethyl acetate. Take 150 to 200 μΐ of the acetic acid extract on top of the centrifugation residue for 10 minutes and add it to 10 ml of scintillation fluid. The radioactivity is measured with a scintillation counter and the IC50 value is calculated from the result.

The compounds prepared according to the invention have a long-term intense antihypertensive effect.

The following examples illustrate the invention.

The following abbreviations are used in the examples:

Tic 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid 15 Decahydroisoquinoline-3-carboxylic acid

Ide indoline-2-carboxylic acid

Oic octahydroindole-2-carboxylic acid Z benzyloxycarbonyl

Boc tert-butyloxycarbonyl 20 tBu, Bu ", tert-C ^ Hg tert-butyl Nb 4-nitrobenzyl DCC dicyclohexylcarbodiimide DMF dimethylformamide 25 DMA dimethylacetamide NEM N-ethylmorpholine CA cyclohexylamine DCA dicycline

If no other method is mentioned,. The compounds described in the following examples are purified by analysis and biological determination by HPLC purification methods.

The compounds described in Examples 1-23 are not of formula I, but are evident from said examples. 35 methods used in the preparation of compounds of formula I.

8 '90532

Example 1 N- (1-Carboxy-3-phenylpropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid a) 2-Carbobenzoxy-3-carboxy-1,2,3,4-tetra - 5-hydroisoquinoline (Z-Tic) 188 g (1.05 mol) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline are added at 0 ° to 1050 ml of 1-norm. NaOH, and then 160 ml of chlorocarbon-10-acid benzyl ester and a further 1050 ml of 1-norm are added dropwise with stirring at this temperature. Na0H: a. It is then stirred for 2 hours at room temperature. Extract three times with ether and acidify the alkaline aqueous phase with ca. HCl to pH 1. The separated oil is extracted into ethyl acetate. The ethyl acetate solution is washed with water until the pH of the aqueous phase is 3.0. After drying over sodium sulfate, the product crystallizes out from the ethyl acetate solution after concentration and trituration. 1.5 liters of diisopropyl ether are added to the crystal suspension and the mixture is stirred for 1 hour at room temperature-20 / filtered off with suction, and the product is dried over a large vacuum over phosphorus pentoxide.

Yield: 256.7 g M.p. 138-139 ° C. ' b) 2-Carbobenzoxy-3-carboxy-1,2,3,4-tetrahydroisoquinoline tert-butyl ester To a solution of 248.8 g (0.8 moles) of 2-carbobenzoxy-3-carboxy-1 , 2,3,4-tetrahydroisoquinoline in 1600 ml of methylene chloride, 312 ml of tert-butanol and 8 g of 4-dimethylaminopyridine are added. Cool to -5 ° C and then add portionwise: a solution of 176 g of dicyclohexylcarbodiimide in 350 ml of methylene chloride. Stir for 5 hours at 0 ° and then allow to stand for 16 hours at room temperature. After suction of the dicyclohexylurea, the reaction solution is extracted three times with saturated sodium hydrogen carbonate solution. Dry over magnesium sulfate, concentrate in vacuo at room temperature to an oil. Give 286 g of product as a yellowish oil (97% of theory).

NMR: 7.30 s (5H); 7.20 s (4 H); 5.1-4m (3H); Δ, Os · (2H); 1.46 (9 H).

C) 3-Carboxy-1,2,3,4-tetrahydro-isoquinoline tert-butyl ester hydrochloride 284 g of 2-carbobenzoxy-3-carboxy-1,2,3,4-tetrahydroisoquinoline tert-butyl ester (0.775 moles) dissolve in 3 liters of methanol, add 15 g of 10% Pd-barium sulphate catalyst and hydrogenate with hydrogen under normal pressure. The pH of the solution is kept at 1-norm.

HCl in methanol dropwise by addition at 4.0 (glass electrode). The catalyst is filtered off and the solution is evaporated to dryness in vacuo at room temperature.

The crystalline product is triturated with anhydrous ether, filtered off with suction and dried in vacuo over phosphorus pentoxide.

: Yield: 156 g m.p. 180 ° (decomp.).

· .; : The tosylate can be obtained either by adding during the hydrogenation instead of a methanolic solution of hydrochloric acid: ··: a methanolic solution of toluenesulfonic acid, or by dissolving the hydrochloride in water, adding a calculated amount of sodium vinyl tosylate and cooling by adding seed crystals and stirring at about 4 ° C. Then the tosylate ’..1 30 precipitates apart in crystalline form. The crystals are filtered off, washed with water and dried.

Sp. 139-140 ° (dec.).

d) Carbobenzoxy-L-alanyl-3-carboxyl-12,3,4-tetrahydroisoquinoline tert-butyl ester 35 27 g (0.15 mol) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline tert-butyl ester .-butyl ester hydrochloride 10 90532 is suspended in 200 ml of dimethylformamide, cooled with stirring and protected from moisture to -5 ° C, and 19 ml (0.15 mol) of N-ethylmorpholine and a solution of 33.4 g of carbobenzoxalanine are added, 5 g of N-hydroxybenzotriazole and 33 g of dicyclohexylcarbodiimide in 100 ml of dimethylformamide. Stir for 1 hour at 0 ° C, allow to stand overnight at + 4 ° C and then work for one hour at room temperature after stirring. The separated dicyclohexylurea is filtered off and the reaction solution is evaporated to dryness under high vacuum at room temperature. The residual oil is dissolved in 1 liter of ethyl acetate and washed three times with 150 ml of various saturated sodium carbonate solution, 5% potassium hydrogen sulphate solution and once with water. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure at room temperature. Yield: 59 g of dljyM.

e) L-alanyl-3-carboxy-1,2,3,4-tetrahydroiso-20-quinoline-tert-butyl ester hydrochloride (Ala-Tic-O-But) 15 g of carbobenzoxy-alanyl-3-carboxy-1, 2,3,4-: Tetrahydroisoquinoline tert-butyl ester is hydrogenated in 400 ml of methanol with 8 grams of 10% Pd / ba-25 rumium sulfate catalyst. The apparent pH of the solution is kept (glass electrode) at 1-norm. methanolic hydrochloric acid was added at 4.0. After 8 hours, the catalyst is filtered off and the solution is evaporated to dryness in vacuo at room temperature. The solid is then digested with diisopropyl ether and dried in vacuo.

Melting point 110 ° (decomp.).

In the same way as the combined Ala-Tic-OBut *. preparing compounds: i 90532 rv-i XOO-t-C.Hn I 4 9 c = o K3C-CH-NH2 δ 7.3-6.5m (4H); 4.4t (1H); 3.8-3.0 m + d (3H); 1.4s (9H); 1,2d (3H) 10 Å COO-t-C; H9 ^ C-CK-NH, II I 2

O R

The following signals are common to the following compounds: 7, 2s (4H); 5.1-3.3m (3H); 3.9-3: Om (4H); 1.4s (9H) when R: H, 2s (4H); 3.9-3, Om (5H) 2 O: h2

Mi

B

13.1 (1H); 7.5s (1H); 6.8s (1H); 2.8m (2H) 25 CH-, 3'CH-CH-- 1.5m (3H); 0.9d (6H) •: X 2 •; CH 2 Cl 2 5.1-4.3m (5H) 12 90532 / ~ Vs-CH 2 -C32 7.2-7.0m (9H1 2.7-2.0m (4E> CH 2 -CH 2 - CH- 1.5-1, On (9H)

3 * I

CH 3 δ δ CK 2 - 7.1 S (5H) f 2,7d (2-H) 10 - (CH 2 Cl 2) 7.8-6.4 (9H)

B

HO-CH2- 3,7d (2H) 15 / N2-CH2-O-C-NH-CH2-CH2-CH2-CH2-7, Is (5H); 5, Os O (2H); 2.4m (2H); 1.8-1.3 m (6H) 2 O 7, Is (5H); 5, Os -ch2-o-c-kh-ch2-ck2-ch2-ch2-ch2- (2h); 2i4m; O (2H); 1.8-1.3 m (8H) 2 H -CH 2 -O-C-NH-CH-CH-CH 2 -Cl-7'ls (5') · 5's (2H); = 2.4 g (2H); 1.8-1.3m (4H) I, 13 90532

Cy-CH2_O-C-KH-CH2 ~ 1 'ls (5H); 5, Os (2 H); 2.3m J O (2H)

5 H2N

·> C-NCH, CH, CH 2 - 8.3-7.6 m (2H); 2.9-1.6m (6H) -IN-CH2-O-C-NH-CH7CH2-7.1s (5H); 5, Os <2H); 2.4m O (2H); 1.7-1.4 m (2H) f) N- (1-Carboxy-3-phenylpropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-but-15-style ester 305 mg of alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid butyl ester (Ala-Tic-OBut) and 445 mg of 4-phenyl-2-oxobutyric acid are dissolved in 4 ml of methanol and the pH is adjusted to 1-norm. With aqueous NaOH 20 to 7.5. Add 200 mg of sodium cyanoborohydride and react for 36 hours. Evaporate to dryness and recover by column chromatography on silica gel (elution mixture: chloroform / methanol / water / glacial acetic acid 20 + 15 + -2 + 1).

Yield: 382 mg; mp. From 120 °, decomp.

g) N- (1-Carboxy-3-phenylpropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 350 mg of the combined N- (1-carboxy-3-phenylpropyl) -Al- Tic-OBut is dissolved in 3 ml of anhydrous trifluoroacetic acid and allowed to stand for 30 minutes at room temperature. Evaporate to dryness in vacuo and triturate the oil with cold diisopropyl ether and petroleum ether.

14 90532

Yield: 276 mg of amorphous substance.

NMR: 7.20 μ. 7.10 (s); 4.3 (s, broad); 3.0-3.9 (m, broad); 1.23 u. 1.15 (d).

Example 2 N- (1-Carbethoxy-3-phenyl-propyl) -L-alanyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid 4.8 g of H-Ala-Tic-O-But. Tos-OH is dissolved in 40 ml of absolute ethanol, the pH is adjusted with an ethanolic solution of KOH. to 7 and 6.2 g of 10-oxo-4-phenylbutyric acid ethyl ester are added and the mixture is stirred in such a way that 9 g of powdered molecular sieve 4 Å are added slowly by adding a solution of 2 g of sodium cyanoborohydride in 15 ml of absolute ethanol.

After about 20 hours, filter and distill off the solvent in vacuo. The residue is partitioned between ethyl acetate and water, the ethyl acetate phase is separated off and evaporated to dryness in vacuo. The residue is chromatographed on silica gel using ethyl acetate / cyclohexane (1: 2 to 1: 4) as eluent.

The product is dissolved in 20 ml of trifluoroacetic acid and stirred for 30 min. at room temperature. Trifluoroacetic acid is distilled off in vacuo, then distilled with toluene and chromatographed on silica gel using methylene chloride / methanol-25 (10: 1).

Yield: 2.2 g.

Example 3 N- (1-Carboxy-5-aminopentyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 30 per 1.2 grams N- (1-carboxy-5-Boc-aminopentyl) -L -alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is poured into 10 ml of ice-cold trifluoroacetic acid and stirred for 1 hour at room temperature. It is then evaporated to dryness under vacuum. The residue is dissolved in water and dried using cooling drying.

Yield: 0.95 g.

Example 4 N- (1-Carboxy-3-phenyl-propyl) -L-alanyl-5,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid 880 mg of N- (1-carbethoxy-3-phenyl-propyl) - L-Alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is dissolved in 20 ml of dioxane / water (9: 1) and saponified at room temperature with 4.5 ml of 1-norm.

10 sodium hydroxide solution. After 1 hour, the solution is acidified with an equivalent amount of 1-norm, hydrochloric acid and most of the dioxane is evaporated off. The residue is extracted several times with ethyl acetate, and after removal of the solvent, the organic phase is chromatographed on a cation exchanger (DOWEX 50).

Yield: 630 mg.

Example 5 N- (1-Carbethoxy-3-aminopropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1.1 g of N- (1-carbethoxy-3-benzoxycarbonylaminopropyl ) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is dissolved in 150 ml of methanol and hyd-I; ; is run at 40 ° C under normal pressure so that the lane contains: 100 mg of palladium-on-carbon catalyst (10%).

After completion of the reaction, the catalyst is filtered off and the solvent is filtered off with suction.

Yield: 0.79 g.

Example 6 N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid a.) 2- (2-oxo-propionyl) -1,2 3,4-Tetrahydro-isoquinoline-3-carboxylic acid tert-butyl ester in a solution cooled to -50 ° C with 700 mg of Tic-OBut and 630 mg of dicyclohex-35-ylcarbodiimide in 15 ml of anhydrous chloroform, 16 90532 A rapidly distilled solution of 270 mg of pyruvic acid in 5 ml of chloroform is stirred rapidly. The mixture is allowed to stand for 16 hours in a freezer (~ 20 ° C) and the separated DC-urea is filtered off.

The solution is washed with KHSO 4 solution and then with KHCO 3 solution, dried over Na 2 SO 4 and concentrated in vacuo. Compound (dljya) contains some dicyclohexylurea; it was chromatographed on silica gel with CHCl 3 / CH 2 OH 15: 1.

In the same manner as the condensation of pyruvic acid with Tic-OBut, the following condensation products are prepared from Tic, Ide and the corresponding ketocarboxylic acid.

Il I · 7.3-6.5m (4H); 2.4s (3 H); 1,4s i 4 9 (9H) CO-CO-CH3 For the following compounds I T T j the following base-specific signals 7, 2s (4H) are uniformly observed; 5.1-4.3m (3H); 3.9-3: Om (2H); 1.4s (9H): 30 13, Is (1H); 7.5s (1H); 6.8 s C 2 -L-Jh (1H); 3.9-3, Om (4H) li 17 90532 -CH2-CH (CH3) 2 2.4-1.0 m + d (9H) -CH2-S -> 7.2-7, Om (9H ); 2.5m (2H) -CH 2 F 4,4s (2H) 10 -C → 2 -Q 7.15s (5H); 3, Os (2H) -CHγ-CH-ClU-CH. * 2.4-1.9m (3H); 1.5-1, Om (8H) / I Δ 3

CIU

3 "CH2" Tj {^] 7-, 8-6.4m (9H); 3.9-2.9m (4H)

B

B.) N- (1-carboxy-3-phenyl-3-thiapropyl) -alanyl-1,2,3,4-tetrahydro-isoquinoline-3-; carboxylic acid tert-butyl ester: 1.52 g of the compound pyruvyl-Tic-OBut and 394 mg of S-phenyl-cysteine are dissolved in 5 ml of methanol and the pH is adjusted to 1-norm. NaOH (aq) to 7.0. 400 mg of sodium cyanoborohydride are added and the mixture is allowed to stand for 24 hours at room temperature. Evaporate to dryness in vacuo, dissolve in chloroform, dry over sodium sulfate and evaporate to dryness.

The product is obtained by chromatography on silica gel (mixture CHCl3 / CH3OH / CH3C00H / H2O 50/20/5/1).

NMR: 7.3-7.0m (9H); 5.1-4m (3H); 3.9-3.0m (4H); 2.5m (2H).

is 90532 c.) N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid 1 g of the butyl ester of Example 6b is dissolved in 5 ml of 5-trifluoroacetic acid. . After 30 minutes, evaporate to dryness in vacuo, the residue is digested with diisopropyl ether and dried over potassium hydroxide.

Yield 0.95 g of trifluoroacetate (hygroscopic). NMR: 7.4-7.1 (9H); 5.2-4.4m (3H); 3.9-3: Om (4H); 2.5m (2H), 1.25m (3H).

Example 7 N- (1-Carbethoxy-2-benzylsulfinylethyl) -L-alanyl-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Under ice-cooling, a stirred mixture of 0.64 g of sodium periodate and 20 ml of water, 1.3 g of N- (1-carbethoxy-2-benzylthioethyl) -L-alanyl-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid dissolved in 20 ml are added. methanol. The reaction mixture is stirred for 24 hours at 0 ° C and then the sodium iodate is filtered off. The filtrate is extracted several times. with methylene chloride. After removal of the solvent. ,:. ·. 1.1 g of sulphoxide are obtained. The NMR spectrum shows the following signals: 7.3-7.0m (9H); 5.1-4.3m (3H); 4, Is (2H); 3.9-3.0m (4H); 2.6m (2H); 1.2d (3 H).

Example 8 N- (1-Carbethoxy-3-phenylsulfonyl-propyl) -L-alanyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid 260 mg of N- (1-carbethoxy-3-phenylthio-propyl) -L -30 alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and 20 mg of sodium tungstate dihydrate. to 50 ml of water and dropwise add 1 ml of perhydrol (30%). The mixture is heated at 80 ° C for 30 minutes and then stirred at 35 ° C for 1 hour. The excess peroxide li 19 90 532 is then destroyed with palladium 11a in barium sulphate and, when oxygen evolution has ceased, the palladium catalyst is filtered off from the solution, which is evaporated to dryness. The crude product is purified by ion exchange chromatography on DOWEX 50 H +.

Yield: 220 mg NMR: 7.7m (9H); 5.1-4m (3H); 3.9-3: Om (4H); 2.8m (2H); 1.5m (2H); 1.2d (3 H).

Example 9 10 N- (2-Amino-1-carboxypropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2.2 g of N-N-Boc-O-N-diaminobutyric acid, prepared Article Coll. czech. chem. Commun. 31, 2955 (1966) in the same manner as -Boc, 15 is reacted with 2.4 grams of pyruvyl-Tic-OBut, prepared according to Example 6a), as described in Example 6b). The Boc protecting group is then cleaved off as described in Example 3.

Yield: 2.6 g.

Example 10 N- (1-Carboxy-3-phenylpropyl) -L-alanyl-decahydroisoquinoline-3-carboxylic acid a. L-Decahydroisoquinoline-3-carboxylic acid (Die) 250 g of L1, 2,3,4-tetrahydroisoquinoline-3- the carboxylic acid is suspended in 2 liters of 90% acetic acid. 10 g of rhodium on carbon are added and the mixture is hydrogenated for 24 hours at 60-80 [deg.] C. and 120 bar. The filtered solution is evaporated to dryness, the residue is dissolved in 200 ml of ethyl acetate and added dropwise to 2 ml of diisopropyl ether with vigorous stirring. The solution is decanted from the resinous residue, evaporated to dryness in vacuo and the same treatment is repeated with about 1/3 of the amount of solvent previously used. The resinous precipitates are combined and hand-cured with hot ethyl acetate to dissolve only a portion. Additionally by vigorous stirring, stirring vigorously with 3 liters of a 1: 1 mixture of diethyl ether and diisopropyl ether, a precipitated precipitate is formed which is filtered off, washed with ether and dried. Yield: 234 g; by thin layer chromatography it is not uniform (mixture of diastereoisomers). Based on the UV spectrum and NMR, the aromatic substance is no longer present. The elemental analysis is impeccable.

10 The substance is used without further purification in the next step.

b. N-Benzyloxycarbonyl-L-decahydroisoquinoline-3-carboxylic acid (Z-Dic-OH) 58 g of L-decahydroisoquinoline-3-carboxylic acid 15 are dissolved in 315 ml of 1-norm. NaOH. With vigorous stirring at 0-5 ° C, 48 ml of benzyloxycarbonyl chloride and 370 ml of 1-norm are added dropwise over a period of one hour. NaOH. A thick precipitate then precipitates. At the end of the addition, the mixture is stirred for a further 20 hours, then extracted with ether and the precipitate is filtered off (= sodium salt of diastereoisomer "A"; yield 43 g). The pH of the filtrate is adjusted to 1.5-2 with concentrated HCl to precipitate an oil. It is dissolved in ethyl acetate. The aqueous phase is extracted with ethyl acetate, the combined ethyl acetate solutions are washed with water, dried over sodium sulfate and concentrated to a small volume (about 200 ml). Upon addition of 15-18 ml of cyclohexylamine (CA), a precipitate precipitates which, after cooling with water, is filtered off and washed with a small amount of cold acetic acid ester and dried. Yield: 48 g (CA salt of isomer mixture B).

The sodium salt of "A" is converted to the CA salt as follows: the compound is suspended in 500 ml of water, poured onto a layer of 200 ml of ethyl acetate and made into 21,90532 ha of potassium with concentrated HCl until the pH is 1.5-2. After shaking, the ethyl acetate phase is separated off, washed with a small amount of water and dried over sodium sulfate. Concentrate as before and add 16 ml of cyclohex-5-amylamine. The CA salt is isolated as above.

For purification, the CA salt of "A" is recrystallized from an eight-fold volume of ethyl acetate. Melting point 197-198 ° C, = 7.5 ° (c = 1, in methanol). Elemental analysis is impeccable.

The Ca salt of "B" is recrystallized from a quadruple volume of ethyl acetate. M.p .: 190 ° (sintered from 187 °) 1 = + 14.6 ° (c = 1, in methanol). Elemental analysis is impeccable.

The free acids are obtained in a known manner by suspending the CA salts in a water / ethyl acetate mixture and acidifying with citric acid. The ethyl acetate phase is washed with a small amount of water and evaporated to dryness. The combined Z-Dic-OH is obtained as an oily residue.

20 c. Benzyloxycarbonyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester (Z-Dic-OBu 2).

41 g of the combined Z-Dic-OH ("A") are dissolved in 350 ml of methylene chloride. 52 ml of t-butanol and 1.3 g of 4-dimethylaminopyridine are added, the mixture is cooled to 0 [deg.] C. and a solution of 29 g of dicyclohexylcarbodiimide (DCC) in 60 ml of methylene chloride is added dropwise with stirring. It is then stirred for a further 20 minutes. At 0 ° C and 5 hours at room temperature and separated, the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness in vacuo, the residue is dissolved in ethyl acetate, the solution is washed successively with KHSO 4 / i 2 SO 4 solution, sodium hydrogen carbonate (the unreacted Na salt of Z-Dic-OH precipitates and is filtered off) and water if -35 boiled and evaporated to dryness in vacuo. Jåånnds oljy-måistå. Yield: 38.5 g = -17.3 ° (c = 1, in methanol). To obtain an analogous compound from compound "B", proceed in the same manner. Yield 38.1 g, = + 6.7 ° (c = 1, in methanol).

d. L-decahydroisoquinoline-3-carboxylic acid tert-5-butyl ester tosylate (H-Dic-OBu * ".TosOH).

27 g of the compound "A" prepared according to Example 10c are catalytically hydrogenated in 250 ml of methanol by dropwise addition of 4-norm. A methanolic solution of TosOH, Pd / carbon catalyst, using a pH of 4.5 (pH-Stat). The filtered solution is then evaporated to dryness in vacuo, the crystalline residue is digested with ether and dried. Yield: 22.6 g. For analysis, a sample of the ethyl acetate is recrystallized. Sp. : 15 9-160 ° C; = -6.5 ° (C = 1, in methanol). Elemental analysis is impeccable. The compound is uniform by thin layer chromatography.

For the compound prepared according to Example 10c of the mixture of isomers "B", the procedure is the same. After recrystallization from the ethyl ester, 20 parts of a substance with a melting point of 162-164 ° C, -Q = -4.4 ° (c = 1, in methanol) are obtained. Elemental analysis is impeccable.

e. N-Benzyloxycarbonyl-L-alanyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester (Z-Ala-Dic-OBu 2) 12.4 g of H-Dic-O-But.TosOH, prepared according to Example 10d using compound "A" is dissolved in 250 ml of methylene chloride. 6.7 g of Z-Ala-OH and 4.05 ml of 1-hydroxybenzotriazole (HOBt) are added, 4.2 ml of N-ethylmorpholine are added and, with stirring at 0-4 ° C, a solution of 6.6 g of dicyclohexylcarbodiimide (DCC) in 30 ml of methylene chloride. After 5 hours, filter, evaporate the filtrate to dryness, dissolve the portion in ethyl acetate and wash at 5 ° C with 23 90532 in 10% KHSO 4/1 SO 4 (1: 2). ), With 1 molar sodium hydrogen carbonate and water, dried over sodium sulfate and the solvent is distilled off. A portion of a resin, readily soluble in all organic solvents. Yield: 15.2 g. The procedure is similar for isomer mixture "B", which can be isolated at this stage using preparative HPLC-kS treatment on silica gel eluting with chloroform / cyclohexane (9: 1).

10 f. L-Alanyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester tosylate (H-Ala-Dic-OBu * 1.TosOH) 8.5 g of the Z-compound are catalytically hydrogenated according to Example 10d. After distilling off the solvent, the resinous portion initially crystallizes after some time or trituration with ethyl acetate and recrystallizes from the ethyl acetate for analysis.

M.p .: 151-153 ° C (dec.), Mp = -28.8 ° (c = 1, in methanol). Elemental analysis is impeccable. The same procedure is followed for 2o for the isomer mixture "B". A crystalline resin is obtained; Elemental analysis is impeccable.

In the same manner as the compound H-Ala-Dic-OBu, the compound alanyl-octahydroindole-2-carboxylic acid t-butyl ester (H-Ala-Oic-OBu) and the following compounds are prepared and isolated primarily as tosylates (NMR values for the parent body). ): 4.9 t (1H); 4.5-3.0 m (2H); 1.4 s (9 H); 1.2 d (3 H); 2.0-1.0 m (11H), (H-Ala-Oic-OBufc).

: i '"CXk, ^ C00-t-C.Hq c = o H3C-CH-NH2 24 90532

The aminocarboxylic acid starting material octahydroindole-2-carboxylic acid is prepared as follows: 45 g of indole-2-carboxylic acid are dissolved in 500 ml of 4% sodium hydroxide solution. 20 g of Raney nickel-5 are added and the mixture is hydrogenated for 24 hours at 40 ° C. Filter, acidify with acid. With HCl, the insoluble matter is filtered off and the aqueous phase is extracted several times with butanol 11a. The organic phase is concentrated and chromatographed. (CHCl 3 / methanol / acetic acid 50: 20: 5).

Yield: 22 g. M.p .: 260 ° C.

In a similar manner, the following compounds are prepared. The NMR signals of the compounds are as follows: νmax COO-t-C4H8 5.1-4.3 m (2H); 3.9-3.0 m 15 L (2H); 1'4 s OH); 2.0-1, Om II I 2 (12H)

0 R

when R: H 3.9-3.0 m (4H) 20 · · s CH2 13.1 s (1H); 7.5 s (1H); jf Π 6.8 s (1H); 2.8 m (2H)

: H

.,: - 25 CH. 1.0-2.0 m. (15H); 0.9 d (6H) XCH'CH2- ·· / CH3. ; , n 5.1-4.3 m (4H)

:: 30 -CH2F

Δ 7.2 s (5H); 2.7-2.0 m (4H) // V_s-ch2-ch- 1 25532 CH3-CH2-CH- 1.0-2.0 m (21H) CH3

QcH2- 7.1 s (5H); 2.7 d (2H) CH - and 7.8-6.4 m (5H); 2.8 m (2H)

B

HO-CH2- 3.7 d (2H) --CH2-O - <: - NH-CH2-CH2-CH2-CH2- 7.1 s (BH); 5.0 s (2 H); Δ 2.4 m (2H); 2.0-1.0 m (18 H) -CH2-CH2: -NH-CH2-CH2-CH2-CH2-CH2- 7.1 s (5H); 5.0 s O (2H); 2.4 m (2 H); 2.0-1.0 m (20H) 25 (/ \ —ί: Η2-Ό - <: - ΝΗ-αΗ2-αΗ2- € Η2- 7.1 s (5H); 5, Os (2H); O 2.4 m (2H), 2.0-1.0 m (16H) 26 90 532 -CHO-O-C-NH-CH-7.1 s (5H), 5.0 s (2H); = / O 2.3 m (2H) H 2 N 2 .C-NCH 9 CH CH 3 - 8.3-7.6 m (2H); 2.9-1.0 m 5 (18H)

B

C-NH-CH 2 - 8.3-7.6 m (2H); 2, -9-2.5 m H ".- (2H) 10 / -CH 2 -O-C-NH-CH 2 CH 2 - 7.1 s (5H); 5.0 s (2 H); Δ 2.4 m (2H); 2.0-1.0 m (14H)

H C 3 "S — N

15 (NH) -CH2-CH2-CH- 7.4 s (1H); 2.5 m (2 H); 2.3 s (6 H); 2.0-1.0 in (16H) 3

CH

20 S (N) (NH-CH 2 7.4 s (1H); 2.5 ir, (2H); 2.3 s (6H) H 3 25 - 4.9 m (1H); 4.5-3 .0 m (2H); COO-t-C4H9 1.4 s (9H); 2.0-1.0 m (11H)

C-CH-NH-W 1 OR

30 when H: H 3.9-3.0 (4H)

Qjj - «-2 · 13.1 s (1H); 7.5 s (1H); 35 6.8 s (1H); 2.8 m (2H)

B

CH3V

.CH-CH 2 1,01.0-2.0 m (14H); 0.9 d (6H) 27,90532 cm-2 -CH-F 5.1-4.3 m (4H) D 1 -S-CHO-CH 2 - 7.2-7.0 m (5H); 2.7-2.0 m (4H) 10 CH - CH., - CH- 1.0-2.0 m (20H) 3 2 | ch 3 --CH 2 - 7.1 s (5H); 2.7 d (2H) 15X · CH2 - 7.8-6.4 m (5H); 2.8 m (2H)

B

HO-CH2- 3.7 d (2H) t 5.0 s (2 H); NC = 1 / 2.4 2.4 m (2H); 2.0-1.0 m (17 H) 012-O-C-NH-CH2-CH2-CH2-CH2-CH2 ~ 7.1 s 5.0 s (<2H); Δ 2.4 m (2H); 2.0-1.0 m'30 (19H) (/ Vy_CH.-O-C-NH-CHo-CH_-CH-- 7.1 s (5H); 5.0 s (2H); ^ == Δ 2.4 m (2H), 2.0-1.0 m (1 H) 28 90532 CH 2 OC-NH-CH 2 - 7.1 s (5H), 5.0 s (2H); O 2.3 m (2H)

H2N \ H

Δ C-N-CH 2 CH 2 CH-8.3-7.6 m (2H); 2.9-1.0 m (17H)

Νχ Νχ H

Δ C-N-CH- 8.3-7.6 m (2H); 2.9-2.5 m HN '' z <2H) 10 (/ n__ 0Η7-0-0-ΝΗ-0Η20Η2- 7.1 s (5H); 5.0 s (2H); N '== / O 2.4 m (2H), 2.0-1.0 m (13H)

HA

7.4 s (1H); 2.5 m (2 H); 2.3 s NH-CH2CH2CH2- (6H); 2.0-1.0 m (15H)

H3C

h3c7N * -NH-CH2 - 7.4 s (1H); 2.5 m (2H); 20 y * - 2.3 s (6H, g. N- (1-carboxy-3-phenylpropyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester 305 mg alanyl-decahydroisoquinoline-3- carboxylic acid t-butyl ester (Ala-Dic-OBut) and 445 mg of 4-phenyl-2-oxobutyric acid are dissolved in 4 ml of methanol and the pH is adjusted to 7.5 with 1N aqueous NaOH.

.30 200 mg of sodium cyanoborohydride are added and the mixture is allowed to react for 36 hours. Evaporate to dryness and recover by chromatography on a silica gel column (elution mixture: chloroform / methanol / water / ethyl acetate 20 + 15 + 2 + 1).

i 29 90 532

Yield: 376 mg; mp: from 123 °, decomp.

h. N- (1-Carboxy-3-phenylpropyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid 350 mg of N- (1-carboxy-3-phenylprop-5-yl) -Ala-Dic-OBut is dissolved in 3 ml of anhydrous trifluoroacetic acid and leave to stand for 30 minutes at room temperature. Evaporate to dryness in vacuo and triturate the residue with cold diisopropyl ether and petroleum ether.

Yield: 226 mg of amorphous substance.

NMR: 7.10 (s); 3.0-3.9 (m, broad S); 1.23 and 1.15 (d)? 2.0-1.0 (m, broad).

Example 11 N- (1-Carbethoxy-3-phenyl-propyl) -L-alanyl-15L-decahydro-isoquinoline-3-carboxylic acid 4.83 g of H-Ala-Dic-OBut.TosOH are dissolved in 40 ml of absolute ethanol, The pH is adjusted to 7 with an ethanolic solution of KOH and 6.2 g of 2-oxo-4-phenylbutyric acid ethyl ester are added and stirred to give 9 g of a 4 Å powdered molecular sieve. Slowly add a solution of 2 g of sodium cyanoboron. hydride in 15 ml of absolute ethanol. After about 20 hours, filter and distill off the solvent in vacuo. The residue is partitioned between ethyl acetate and water, the ethyl acetate phase is separated off and evaporated to dryness in vacuo. The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 2- to 1: 4).

The product is dissolved in 20 ml of 30 trifluoroacetic acid for 30 minutes. Trifluoroacetic acid is distilled off in vacuo, then distilled with toluene. Chromatograph on silica gel with methylene chloride / methanol (10: 1).

Yield: 1.8 g.

30 90 532

Example 12 N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-L-decahydroisoquinoline-3-carboxylic acid a.) 2- (2-Oxo-propionyl) -L-decahydro-isoquino-5-line-3-carboxylic acid tert-butyl ester To a solution cooled to -50 ° C of 700 mg of the compound Dic-OBut and 630 mg of dicyclohexylcarbodiimide in 15 ml of anhydrous chloroform is stirred rapidly a cooled and freshly distilled solution of 270 mg of paloryalic acid in 5 ml of chloroform. The mixture is left for 16 hours in a deep-freezing cabinet (-20 ° C) and the separated DC-urea is filtered off. The solution is washed with KHSO 4 and then with KHCO 3 solution, dried over Na 2 SO 4 and evaporated to dryness in vacuo. Compound 15 (oil) contains some dicyclohexylurea; For analysis, it was chromatographed on silica gel with CHCl 3 / CH 3 OH (15: 1).

In the same manner as condensation of pyruvic acid with Dic-OBut with the corresponding o <-eto-20 carboxylic acids, the following condensation products are prepared.

·· * 4.9 m (1H); 4.2-3.5 m -1 (1H); 3.0-1.2 m (11H); ΝΛ 2.4 s (3H); 1.4 s (9 H) ·. 25 I COO-t-C4H9 CO-CO-CH3 In the case of the following compounds, a total of 30 ^ ^ - is observed for the basic structure. ...

11 ^ the following signals: δ 5.1-4.8m (1H); 3.9-3.0m (2H); 1.4 s (9 H); 2.0-1.0m (12H) I: 31 90532H-ft 13.1 s (1H); 7.5 s (1H); 6.8s 2 I-Ah (1H); 3.9-3.0 m (4H) - 2.4-1.0 m (21H) CH 2 -S- (δ 7.2-7.0 m (5H); 2.5 m (2H) ) 10 -CH 2 F 4.4 s (2H) -ch 2 -? 3 7.15 (5h); 3.0 s (2h) 15 - CH 2 -β-CK 2 -CH 3 2.4-1.0 m (23H) CH 3 CH 21 -7.8-6.4 m (5H); 3.9-2.9 m (4H) 2 O: H · · b.) N- (1-carboxy-3-phenyl-3-thiapropyl) -Alanyl-L-decahydroisoquinol-3-carbon-25 acid-tert-butyl ester 1.52 g of the combined pyruvyl-Dic-OBut and 394 mg of phenyl-cysteine are dissolved in 5 ml of methanol and :; The pH is 1-norm. NaOH (aq) to 7.0. 400 mg of sodium cyanoborohydride and the mixture are added. . 30 is allowed to stand for 24 hours at room temperature. Evaporate to dryness in vacuo, dissolve in chloroform, dry over sodium sulfate and evaporate to dryness. The product is obtained pure by chromatography on silica gel (mixture of CHCl3 / CH3OH / CH3CO0H / H2O 50/20/5/1).

32 90532 NMR: 7.3 m (5H); 5.1-4.8 m (1H); 3.9-3.0 m (4H); 2.5 m (Η H2H).

c.) N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-L-decahydroisoquinoline-3-carboxylic acid 5 1 g of the butyl ester obtained in Example 12b is dissolved in 5 ml of trifluoroacetic acid. After 30 minutes it is evaporated to dryness in vacuo, the residue is digested with diisopropyl ether and dried over potassium hydroxide.

Yield: 0.95 g of trifluoroacetate (hygroscopic).

NMR: 7.3 m (5H); 5.2-4.8 ro (1H); 3.9-3.0 m (4H); 2.5 m (2 H); 1.25 m (3 H).

Example 13 N- (1-Carboxy-3-phenyl-propyl) -L-alanyl-L-15 decahydro-isoquinoline-3-carboxylic acid 880 mg of N- (1-carbethoxy-3-phenyl-propyl) -L-decahydro-isoquinoline-3- the carboxylic acid is dissolved in 20 ml of a dioxane / water mixture (9: 1) and saponified at room temperature with 4.5 ml of 1-norm. sodium hydroxide solution-20 ta. After 1 hour, the solution is acidified to the equivalent standard with 1-norm. hydrochloric acid and most of the dioxane are evaporated off. The residue is extracted several times with ethyl acetate, and after removal of the solvent, the organic phase is chromatographed on a cation exchanger 25 (DOWEX 50).

Yield: 630 mg.

Example 14 N- (1-Carboxy-5-aminopentyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid 30 per gram of N- (1-carboxy-5-Boc-aminopentyl) -L-alanyl -L-Decahydroisoquinoline-3-carboxylic acid is poured into 10 ml of cold trifluoroacetic acid and stirred for 1 hour at room temperature. It is then evaporated to dryness in vacuo. The residue is dissolved in water and dried by freeze-drying. Yield: 0.90 g.

33 90532

Example 15 N- (1-Carbethoxy-3-amino-propyl) -L-alanyl-L-decahydro-isoquinoline-3-carboxylic acid 1.1 g of N- (1-carbethoxy-3-benzoxycarbonylamino-5-propyl) -L-alanyl -L-Decahydroisoquinoline-3-carboxylic acid is dissolved in 150 ml of methanol and hydrated with a 100 mg portion of palladium / activated carbon (10%) at 40 ° C under normal pressure. After completion of the reaction, the catalyst is filtered off and the solvent is filtered off with suction. Yield: 0.79 g.

NMR: 5.1-4.8 m (1H); 3.9-2.5 m (6H); 2.0-1.0 m (14H); 1.2 d (3 H).

Example 16 N- (1-Carbethoxy-2-benzylsulfinylethyl) -L-15 alanyl-L-decahydroisoquinoline-3-carboxylic acid

While cooling to a stirred mixture of 0.64 g of sodium periodate and 20 ml of water, 1.3 g of N- (1-carbethoxy-2-benzyl-thioethyl) -L-alananyl-L-decahydroisoquinoline-3- carboxylic acid dissolved in 20 ml of 20 ml of methanol. The reaction mixture is stirred, stirred for 24 hours at 0 ° C and then filtered off from sodium iodate. The filtrate is extracted several times with methylene chloride. After removal of the solvent, 1.1 g of sulfoxide are obtained. The NMR spectrum shows the following signals: 7.3 m (5H); 5.1-4.8 m (1H); 4.1 s (1H); 3.9-3.0 m (4H); 2.6 m (2 H); 1.2 d (3 H).

Example 17 N- (1-Carbethoxy-3-phenylsulfonyl-propyl) -L-30-alanyl-L-decahydro-isoquinoline-3-carboxylic acid 260 mg of N- (1-carbethoxy-3-phenyl-thiopropyl) -L-alanyl-L- decahydroisoquinoline-3-carboxylic acid and 20 mg of sodium tungstate dihydrate are added to 50 ml of water and 1 ml of per-35 hydrol (30%) is added dropwise. The mixture is warmed for 30 min. At 80 ° C 34 90532 and then stirred for one hour at room temperature. The excess peroxide is then destroyed with palladium on barium sulphate and, on completion of the evolution of oxygen, the solution is filtered off from the palladium-5 catalyst and evaporated to dryness. The crude product is purified by ion exchange chromatography on DOWEX 50 H +. Yield: 220 mg.

NMR: 7.7 m (5H); 5.1-4.8 m (1H); 3.9-3.0 m (4H); 2.8 m (2 H); 1.5 m (2 H); 1.2 d (3 H).

Example 18 N- (2-Amino-1-carboxypropyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid 2.2 g of N / 5-Boc- [1] diaminobutyric acid, prepared according to Coll. Czech, chem. Commun. 31, 2955 (1966) 15, is reacted with 2.4 grams of combined pyruvyl-Dic-OBut, prepared according to Example 12a, as described in Example 12b. The Boc protecting group is then cleaved as described in Example 14. Yield: 2.6 g.

NMR: 5.1-4.8 m (1H); 3.9-3.0 m (5H); 2.0-1.0 m (15H); 1.2 d (3 H).

Example 19 LN- (1-Carbethoxy-5-aminopentyl) -L-alanyl-L-decahydroisoquinoline-3-carboxylic acid 25 a) 35 g of N, E-benzyloxycarbonyl-L-lysine ethyl ester hydrochloride and 30.6 g β-Bromopropionic acid is dissolved in a mixture of 350 ml of dioxane, 50 ml of ethanol and 75 ml of 4-norm. Na0H: a. Stir overnight at room temperature, keeping the pH constant at 8.8-9, using an autotitrator, after which the pH is adjusted to 7-8 with a small portion of HCl and the solvent is distilled off in vacuo. The residue is dissolved in as little water as possible and the pH of the solution is adjusted to 5-6 with hydrochloric acid. Cool with fractions and filter off the precipitate after a short standing, wash I.

35 90 532 in a small quantity must be cooled in cold water and ether and dried in vacuo. The aqueous solution can also be weakly converted to a zwitterion using a basic ion exchanger and purified. Thereafter, the filtrate is simply lyophilized. Yield: 12.9 g (52%).

b) The compound is dissolved in 100 ml of dimethylformamide and 23 g of H-Dic-OBzl are added successively at room temperature. TosOH (prepared in the usual way from an amino acid by boiling in benzyl alcohol-toluenesulfonic acid with separation of water), 6.5 ml of N-ethylmorpholine, 6.8 g of 1-hydroxybenzotriazole and 11 g of dicyclohexylcarbodiimide. After stirring for 4 hours, the urea is filtered off, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel with cyclohexane-ethyl acetate (4: 1).

In this case, the diastereoisomers are separated. The homogeneous fractions containing the title compound are combined, the solvent is distilled off in vacuo.

c) The residue is dissolved in methanol, catalytically hydrogenated with Pd / carbon catalyst, and after filtering off any catalyst, the conversion to the hydrochloride is carried out by adjusting the pH of the solution to 3. The solvent is distilled off and the portion is dried in vacuo.

Example 20 LN- (1-Carbethoxy-3-phenylpropyl) -L-alanyl-L-octahydroindole-2-carboxylic acid a) A mixture of 55 g of 2-bromo-4-phenyl-n-butyric acid ethyl ester, 14.5 g L-alanine-t-butyl-30 ter and 45 ml of triethylamine are kept in tetrahydrofuran for 24 hours. The solvent is distilled off in vacuo, the residue is taken up in parts soluble in water and ethyl acetate, the ethyl acetate phase is separated off, dried over sodium sulphate and the solvent is distilled off in vacuo.

36 90 532

The residue is chromatographed on silica gel with cyclohexane-ethyl acetate (4: 1), in addition to purification, the separation of diastereoisomers also takes place. After concentrating the corresponding fractions, keeping the compound in trifluoroacetic acid for 20 minutes, the t-butyl ester is cleaved. Trifluoroacetic acid is distilled off in vacuo and then distilled in vacuo with toluene.

b) 7 g of N- (1H-carbethoxy-3-phenylpropyl) -L-alanine, 11 g of octahydroindole-2-carboxylic acid benzyl-10-ester tosylate, 3.2 g of N-ethylmorpholine, 3.3 g of 1-hydroxybenzotriazole and 5.5 g of dicyclohexylcarbodiimide are then reacted according to Example 19b in dimethylformamide, the work-up is continued as described therein and the diastereomers are separated by chromatography on silica gel with a mixture of cyclohexane-ethyl acetate (4: 1). The benzyl ester is chromatographically cleaved from the homogeneous compound by catalytic hydrogenation.

Example 21 20 N- [1-Carbethoxy-4- (4,6-dimethyl-pyrimidyl-2-amino) -butyl] -N- (L-alanyl-L-decahydro-isoquinoline-3-carboxylic acid) a) 15.3 g of oi-bromopropionic acid and 41.1 g of H-Dic-OBut.TosOH are condensed in 300 ml of tetrahydrofuran to give 12.8 ml of N-ethylmorpholine and 1.35 g of 1-hydroxybenzotriazole using 22 g of dicyclohexylcarbodiimide. . After 4 hours, the urea is filtered off and the solvent is distilled off in vacuo. The residue is dissolved in ethyl acetate, the solution is washed with sodium hydrogencarbonate and citric acid solution and water, the ethyl acetate solution is dried over sodium sulfate and the solvent is distilled off under reduced pressure.

b) 3.75 g of the combined o-bromopropionyl-Dic-O-But are reacted at room temperature in 20 ml of tetrahydrofuran with 2.5 g of - (4,6-dimethylpyrimidin-2-yl) L-ornithine ethyl ester is added by adding 1 ml of diisopropylethylamine after 37 hours, after 24 hours the solvent is distilled off in vacuo, the residue is dissolved in ethyl acetate, the solution is washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. 20 b) the diastereoisomers are separated, the t-butyl ester is cleaved by dissolving the compound in dioxane / HCl, after 10-15 minutes the solvent is distilled off and the portion is dried thoroughly in vacuo over KOH, the compound is 10 as the hydrochloride.

Example 22 N- (1-S-Carbethoxy-3-phenyl-propyl) -5-alanyl-cis-octahydro-indole-2-S-carboxylic acid a) N- (1-S-carbethoxy-3-phenyl-propyl) -alanine Benzyl ester

Extraction with ethyl acetate from aqueous sodium carbonate solution containing 70 g of alanine benzyl ester toluenesulfonate gives the free base. To the dried organic phase dried over sodium sulfate, 200 ml of dimethylacetamide (DMA) are added and the mixture is evaporated to dryness at room temperature using a water-jet vacuum. After adding 90 g of d-bromo-phenyl-butyric acid ethyl ester and 40 ml of N-ethylmorpholine, the solution is allowed to stand for 4 days at room temperature. The progress of the reaction is monitored by thin layer chromatography on silica gel plates (mixture: cyclohexane / ethyl acetate 2: 1). Evaporate to near dryness in vacuo, the pH is adjusted to 2-norm. with methanolic hydrochloric acid to air 3 and add 10 ml of water. The excess bromoester and lipophilic product are extracted into petroleum ether, the methanol phase is evaporated to dryness, 3% sodium hydroxide solution (250 ml) is added and the reaction products are extracted into ethyl acetate / ether (1: 1). After drying over solid sodium sulfate, the mixture is evaporated to dryness and purified and the diastereomers are separated by chromatography on silica gel (cyclohexane / ethyl acetate 4: 1). The R 1 value of the S, S compound is lower and decreases more heavily (48%). (The oily substance is further processed immediately.

b) N- (1S-Carbethoxy-3-phenylpropyl) -S-alanine 37 g of benzyl ester are dissolved in 250 ml of ethanol and the benzyl is cleaved by catalytic hydrogenation for 2 hours under normal pressure using 1 g of Pd / carbon-10 catalyst ( 10% Pd). The catalyst is filtered off, the solution is evaporated to near dryness in vacuo and precipitation is carried out by adding petroleum ether.

Yield: 33 g; amorphous substance; NMR: 1.18 (d, 3H); 1.18 (t, 3 H); 1.5-2.1 (m. 2H); Δ 2.4-2.8 (m. 2H); 3.0-3.4 (2 m, 1H each); 4.07 (q, 2 H); 4.3-5.5 (b. 2H); 7.17 (s. 5H). DMSO-d.

c) N- (1S-Carbethoxy-3-phenyl-propyl) -S-alananyl-cis-octahydro-indole-2-R, S-carboxylic acid benzyl ester 5 g of N- (1S-carbethoxy-3-phenylpropyl) - The S-area is dissolved in 20 ml of DMF. 2.45 g of 1-hydroxybenzotriazole, 5.1 g of cis-octahydroindole-2-carboxylic acid benzyl ester hydrochloride, 1.5 ml of N-ethylmorpholine and 4 g of dicyclohexylcarbodiimide are added and the mixture is stirred for 3 hours at room temperature.

Dilute with 30 ml of ethyl acetate and filter off the urea. After evaporation to dryness in vacuo, the residue is dissolved in 100 ml of ether and extracted twice with aqueous hydrogen carbonate solution. The organic phase, dried over sodium sulfate and evaporated to dryness, is chromatographed on silica gel. Elute with ethyl acetate / petroleum ether 4: 3 to give 2 fractions which, on evaporation to dryness in vacuo, give colorless oils.

39 90 532

Elemental analyzes: C Η N

calculated for C 31 H 40 N 2 O 5 71.5 7.7 5.4 Yield °:

Fraction 1 71.3 7.8 5.3 3.3 g 5 Fraction 2 71.6 7.6 5.6 3.9 g d) N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl- 1'-cis-ctahydroindole-2-S-carboxylic acid 3 g of benzyl ester (fraction 2) are dissolved in ethanol and the benzyl is cleaved by catalytic hydrogenation under normal pressure with 200 mg of Pd / carbon catalyst (10%). After completion of the hydrogen uptake (after about an hour), the catalyst is filtered off and the solution is evaporated to dryness in vacuo. A little pentane is added, heated to about 45 ° C and treated under high vacuum. Forms an amorphous, solid foam.

Yield: 2.4 g.

NMR (CDCl 3): 1.20 (d, 3H); 1.23 (t, 3 H); multiplet 1.0-2.9 (11H); 3.0-4.5 (m. 3H); 4.12 (q, 2 H); 4.65 (b. 2H); 7.13 (s. 5H).

Example 23 N- (1-Carbethoxy-3-phenyl-propyl) -alanyl-octahydro-indole-2-carboxylic acid benzyl ester a) N-tert-Butyloxycarbonyl-alanyl-octa-hydroindole-2-carboxylic acid benzyl ester (Boc-Ala-Oic - 25 OBzl) 19 g of the combined Boc-Ala-OH are dissolved in 100 ml of DMF and 13 ml of N-ethylmorpholine, 13.5 g of the combined HOBt and 29.6 g of octahydroindole-2-carboxylic acid benzyl ester hydrochloride are added. After cooling in a triturate, 21 g of dicyclohexylcarbodiimide are added and the mixture is stirred for 15 hours at room temperature. The separated urea is filtered off with suction, the filtrate is evaporated to dryness in vacuo and the residue is dissolved in ethyl acetate. Extract 3 times with aqueous KHSO 4 and KHCO 3 and saturated NaCl solutions and evaporate the organic phase to dryness in vacuo.

Yield: 38.5 g.

NMR: 1.26 (d, 3H); 1.40 (s. 9H); 1.1-2.4 (m. 12H); 3.2-3.9 (m. 2H); 5.28 (s. 2H); 7.31 (s. 5H).

B) Alanyl octahydroindole-2-carboxylic acid benzyl ester trifluoroacetate 21.5 g of the combined Boc-Ala-Oic-OBz1 are dissolved in 50 [mu] l of trifluoroacetic acid. Evaporate to dryness in vacuo, digest the portion several times with diiso-10-propyl ether and dry in vacuo.

Yield: 21 g.

In NMR, the proton signal of the tert-butyl group is completely absent.

c) N- (1-Carbethoxy-3-phenyl-propyl) -alanyl-15-octahydro-indole-2-carboxylic acid benzyl ester

A mixture of 11.1 g of the compound Ala-Oic-OBzl. TFA, 7 g of o? -Bromo-phenylacetic acid ethyl ester and 3.3 ml of N-ethylmorpholine are stirred for 4 days at room temperature in 20 ml of dimethylacetamide. Evaporate to near dryness in vacuo, dissolve the residue in methanol, adjust the pH to 2-norm. With aqueous HCl to 2 and the lipophilic compounds are extracted with petroleum ether. The methanol phase is evaporated to dryness, 5% sodium hydroxide solution is added and the reaction product is extracted into ethyl acetate.

Chromatography on silica gel (mixture, ethyl acetate: petroleum ether 5: 3) gives the title compound as a colorless oil.

The following exemplified compounds were prepared by any of the following methods A-C, wherein the indicated methods can be characterized as follows: 90532

Method A;

A condensation product prepared according to Example (6a or 12a) from Tic or Dic-OtC ^ Hg ester or benzyl ester or from Oic-OtC ^ Hg ester or benzyl ester and the corresponding «» ^ -ketocarboxylic acid, reduction amination with the corresponding amino acid derivative according to Example (6b), cleavage of the protecting groups according to Example (6c or 12c or 22d) and possible saponification according to Example (13).

Method B;

Reduction amination of a dipeptide t-butyl ester prepared according to Example (Ie or 10e, f) with a corresponding cketketocarboxylic acid derivative according to Example (If, 10g, 11) and optionally cleavage of protecting groups according to Example (10h or 11) and / or optionally according to Example (13).

Method C:

Reduction amination according to Method A and using 20 W-protected bifunctional amino acids, cleavage of the protecting group from the amino acid derivative used

Unless otherwise indicated, the following NMR values (cT values, ppm; TMS standard) were observed for the compounds shown below: 4.9 m (2H); 4.5-3: Om (3H); 2.0-1: om (11H).

In the case of ethyl ester, the following additional signals occur: 4.2 q u HZ (2H) 30 1.2 t 7 Hz (3H).

42; π ς · 'k. » • ο · «. «-« «.

σ \ m C -ο ε tN ° ε ε · ^

«° °. ^ I

s ϊ I S s ~ i. . - m CN CN '-' '_ T3 - T!

.. S E

~ · O ™ · = == - · “° IN n IN m“ ~ i zz 5 Ό E = in £ = * ^ r cn rr ·. T-.

• * · * - ^ ^ c CN T- ΓΜ '-

: TRS

-η <m 0) ® υ u

rn C

= «O s 0 u 1 ΙΟ =

ITJ SC CN

O— = fv, CN U

xi * U

I = - O L'— = - - O I ”~ u u = o yx.c

CN

cn = x a ° \ / a x

\ _ / CN CN O U

/ \ cn xx cn - \ / II x ^

\ _ / -in t U X

u CN CN -

X X

u u

CN

X

u m m m Pk tc tc

& u υ D

o o o o c

-..- C \ J

c \ j n cn 00 ^ co ο v N- ^

Claims (2)

A process for the preparation of novel therapeutically usable octahydroindole derivatives of formula I and physiologically acceptable salts thereof, -COOH. J-Νχ (1) 10. in which formula R 1 is CH 3 or CH 2 F, R 2 is alkyl of not more than 6 carbon atoms and which may be substituted by amino or hydroxy, and R 1-6 carbon atoms, provided that Rx and R2 do not simultaneously denote methyl, characterized in that a) a compound of formula II is reacted with a compound of formula III, 20 \ 4 Q-CH-COOR 'II 3 L JN R \ K2 CO-CH-Q (II) R1 (III) in which formulas R3, R2 and R3 are the same as above, one of the symbols Q is a nucleofugic group and the other is NH2 and R4 are H, methyl, ethyl, benzyl or tert.-butyl, and, if desired, an obtained ester is converted to a carboxylic acid (R2 and / or R4 = vate), or b) a purification of the formula POOC-CH-NH-CH-COOP (IV) II 35. R 2 46 90 532 where R 1 and R 2 represent the same as above, P is wet or one of the symbols P may also denote the same as R 3 defined above, such as tert-butyl, reacted with a compound of formula 5 \ ^ C00R4 (1 2 3 4 5) -N \ H 10 wherein R 4 represents the same as above, in the presence of a condensing agent, and, if desired, one or each ester group is converted to a carboxylic acid, or c) a compound of the formula VI is reacted with a compound of formula VII, T = C-COOR 3 -N R2 Ss'C0-C = T (VI) r (VII) I; the formulas Rlr R2, R3 and R4 are the same as above 2 and one of the symbols T is wet and NH2 and the other 25 is an oxygen atom, and the resulting Shiff's base is reduced, 3 and, if desired, the resulting drain is converted by 4 to a salt. 5 2. A process according to claim 1, characterized in that a compound of formula I is prepared in which the two or three chiral centers at the carbon atoms have L-configuration.