FI90532B - A process for the preparation of new therapeutically useful octahydroindole derivatives - Google Patents

Description

1 90532

A process for the preparation of new therapeutically useful okahydroindole derivatives

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

U «N

nC0-NH-CH-CH-C00R-,

I I 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 R x and R 20 at the same time do not mean methyl. These compounds have an antihypertensive effect.

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, f Q-CH-C00R ~ -N \ r2

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 3 and R 2 are as defined above, P is hydrogen or one of the symbols P may also mean the same as R 3 as defined above, such as tert-butyl, is reacted with a compound of the formula ^ C00R4 3.5 II ΊΓ U_iXh wherein R4 is as defined above in the presence of a condensing agent 20, and if desired, one or both ester groups are converted into a carboxylic acid, or c) the compound of formula VI is reacted with a compound of formula VII, T = C-C00Ro f I 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 obtained compound of formula I is -35 is converted to salt.

li 3 90532

In the preparation of the compounds I, it is possible, for example, to start with 2-halocarboxylic acid derivatives II or III which react with nucleophilic compounds. 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 a suspension of alkali or alkaline earth carbonate as the base.

The starting material

C/o.

M

1 COOH

B

X

20 is prepared by catalytic hydrogenation, mainly with rhodium catalysts, of a compound of formula if; CCL

- · COOH

:.: 25 H

VIII

From this, 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, which is readily available from L-lactic acid.

4,90532

Intermediates 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 protecting group is cleaved off again after condensation is complete.

5 Suitable protecting groups are, for example, benzyloxycarbonyl.

The condensation can be performed not only with the DCC / HOBt combination (dicyclohexylcarbodiimide / 1-hydroxybenzotriazole) but also with another suitable condensing agent, e.g. the condensing agent described in Houben-Weyl, Band 15.

Process (b) starts 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, e.g. in the presence of dicyclohexylcarbodiimide, with an equivalent amount of a compound of formula V and R 4 is cleaved in a known manner. The reaction takes place via optionally isolatable anhydride XII, which is then opened with a compound of formula V.

B

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

XLI

30 R400Cv ^ CH2 ^ / ^ ^ \ / ch2 \ / coor4

HN-1 J V. J-N-CO-CH-N-CHt-COOH

. 35 I

B

v = 90532

If R 1 and R 2 in compound IV are different, preferably only one of the residues P is hydrogen, the other should be mainly R 3 or tert-butyl. 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 manner via Schiff bases, e.g. after reduction with sodium borohydride or sodium cyanoborohydride, catalytic hydrogenation or electrolytic reduction, for the formation of 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 mainly to the L-configuration. Crystallization can generally give 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 step, the diastereomers of the formula X can optionally be separated by crystallization or by a preparative HPLC method, so that products of the formula I having a uniform etheric order in all the centers of rotation 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 high blood pressure for a variety of reasons and can be used alone or in combination with other compounds that lower blood pressure, dilate blood vessels or increase urine output. Typical representatives of these classes of effects are described, for example, in Erhart-Rusching, Arzneimittel, 2. Auflage, Weinheim 1972.

6 90532

They can be used intravenously, subcutaneously or orally.

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

The compounds of formula I exist as their internal salts. In addition, if both carboxyl groups are free, alkali and alkaline earth metal salts and salts can be formed with physiologically innocuous amines. The free amino group still present can be reacted as a salt with an inorganic acid or an organic acid. Other compounds of formula I may also 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 30-5 ° C. Enzyme analysis is a variation of the publication

Biochem. Pharmacol. 20 (1971), p. 1673. 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 effected by adding 20 μΐ of the above enzyme solution. Incubate for 60 min at 37 ° C, then stop the reaction by adding 1 ml of 0.1 HCl. The (3-H) hippuric acid is then extracted with 1 ml of 5 ethyl acetate. After centrifugation for 10 minutes, take 150 to 200 μΐ of the acetic acid extract on top 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 of the invention have a long-lasting intense antihypertensive effect.

The following examples illustrate the invention.

The following abbreviations are used in the examples:

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

Idc 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

Unless otherwise stated,. The compounds described in the following examples are purified for analysis and bioassay by the HPLC purification method.

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 moles) 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 conc. HCl to pH 1. The separated oil is extracted into ethyl acetate. The ethyl acetate solution 15 is washed with water until the pH of the aqueous phase is 3.0. After drying over sodium sulfate, the product crystallizes from the ethyl acetate solution after concentration and trituration. 1.5 liters of diisopropyl ether are added to the crystal suspension and stirred for 1 hour at room temperature, filtered off with suction and the product is dried under high 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. The mixture is stirred for 5 hours at 0 [deg.] C. and the mixture is then allowed to stand for 9 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 oily. 286 g of product remain 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) dissolved in 3 liters of methanol, 15 g of 10% 15 Pd-barium sulphate catalyst are added and hydrogenated with hydrogen under normal pressure. The pH of the solution is maintained at 1-norm.

HCl in methanol by dropwise 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 hydrochloric acid instead of methanol during hydrogenation: ··: methanolic toluenesulfonic acid, or the hydrochloride is dissolved in water, a calculated amount of n-atrium tosylate is added and cooled by adding seed crystals and stirring to about 4 ° C. In this case, 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 carbobenzoxyalanine are added. g of N-hydroxybenzotriazole and 33 g of dicyclohexylcarbodiimide in 100 ml of dimethylformamide. Stir for one hour at 0 ° C, allow to stand overnight at + 4 ° C and then work up 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 portions of 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 oil.

e) L-alanyl-3-carboxy-1,2,3,4-tetrahydroiso-20-quinoline-tert-butyl ester hydrochloride (Ala-Tie-O-But) 15 g of carbobenzoxy-alanyl-3-carboxy-1, 2,3,4-: Tetrahydroisoquinoline tert-butyl ester

in 400 ml of methanol with 8 g of 10% Pd / ba-25 rium sulphate catalyst. Apparent pH of the solution

considered (glass electrode) 1-norm. by adding a methanolic solution of hydrochloric acid 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 residue is then digested with diisopropyl ether and dried in vacuo.

Melting point 110 ° (decomp.).

In the same way as Ala-Tic-OBut *. preparing compounds: i 90532 rv-ι XOOt-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 COO-t-C ^ Hg ^ ssi ^ '^ X ^ C-CK-NH - II I 2

O R

The following signals are common to the following compounds: 7.2 s (4H); 5.1-3.3m (3H); 3.9-3.0m (4H); 1.4s (9H) when R: H, 2s (4H); 3.9-3.0m (5H) 20 j: h2 ¢ /

B

13.1s (1H) and 7.5s (1H); 6.8s (1 H); 2.8m (2H) 25 CH-, 3'CH-CH-- 1.5m (3H); 0.9d (6H) •: X 2 •; CH 2 CH 2 F_ 5.1-4.3m (5H) 12 90532 / ~ Vs-CH 2 -CH 2 1,2-7, O (SH) 2.7-2, On 14E) CH, -CH, -CH - 1.5-1, On (9H)

3 * I

CH 3 δ δ CK 2 - 7.1s (5H) f 2.7d (2H) 10 - (CK 2 I J) 7.8-6.4n (9H)

B

HO-CH 2 -3,7d (2H) 15 / N 2 -CH 2 -O-C-NH-CH 2 -CH 2 -CH 2 -CH 2 - 7.1s (5H); 5.0s ({2H); 2.4m (2H); 1.8-1.3m (6H) 20 07, Is (5H); 5.0s -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 V ': (4H) I.

13 90532

Cy-CH2_O-C-KH-CH2 ~ 1 'ls (5H); 5.0s (2 H); 2.3m J O (2H)

5 H2N

·> C-NCH, CH, CH 2 - 8.3-7.6 m (2H); 2.9-1.6 m (6H) INN-N-CH2-O-C-NH-CH7 CH2-7.1s (5H); 5.0s (2 H); 2.4m (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 allow to 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 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 residual 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 to 7 with a solution of KOH in ethanol, and 6.2 g of 2-oxo-4-phenylbutyric acid ethyl ester are added and mixed in the presence of 9 g of ground molecular sieve 4 A , slowly 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 a methylene chloride / methanol mixture of 25 [mu] l (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 35. The residue is dissolved in water and dried by freeze-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 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 (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 in the presence of 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. The compound (oil) contains some dicyclohexylurea; it was chromatographed on silica gel for analysis with CHCl 3 / CH 2 OH 15: 1.

In the same manner as the condensation of fire grape acid with Tic-OBut, the following condensation products are prepared from Tie, Idc and the corresponding ketocarboxylic acid.

Il I · 7.3-6.5m (4H); 2.4s (3 H); 1, 4s 15 λ I 4 9 (9H) CO-CO-CH3 20 for the following compounds | T T j the following base body specific signals 7, 2s (4H) are uniformly detected; 5.1-4m (3H); 3.9-3.0m (2H); 1.4s (9H): 30 13, Is (1H); 7.5s (1 H); 6.8 s C 2 -L-Jh (1H); 3.9-3: Om (4H)

II

17 90532 -CH 2 -CH (CH 3) 2 2.4-1.0 m + d (9H) -CH 2 -S ->> 1.2-1.0 m (9H); 2.5m (2H) -CH 2 F 4,4s (2H) 10 -C → 2 -Q 7.15s (5H); 3.0ε (2H) -CHγ-CH-ClU-CH. * 2.4-1.9m (3H); 1.5-1.0m (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 pyruvyl-Tic-OBut and 394 mg. S-phenylcysteine is 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 pure 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, digest the residue with diisopropyl ether and dry over potassium hydroxide.

Yield 0.95 g of trifluoroacetate (hygroscopic). NMR: 7.4-7.1 (9H); 5.2-4.4m (3H); 3.9-3.0m (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 to a stirred mixture, if there is 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 of methanol are added. The reaction mixture is stirred for 24 hours at 0 [deg.] C. and then the sodium iodate is filtered off. The filtrate is extracted several times. with methylene chloride. Removal of the solvent remained. ,:. ·. 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 added. to 50 ml of water and 1 ml of perhydrol (30%) is added dropwise. 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 on 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); 3.9-3.0m (4H); 2.8m (2H); 1.5m (2H); 1.2d (3 H).

Example 9 N- (2-Amino-1-carboxypropyl) -L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2.2 g of N-N-Boc-o-N, N-diaminobutyric acid, made from the article Coll. czech. chem. Cortunun. 31, 2955 (1966) in the same manner as -Boc, 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 vigorously stirred 2 liters of diisopropyl ether. 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 used above. The resinous precipitates are combined and hand-rolled with hot ethyl acetate to dissolve only a portion. Add 1: 1 diethyl ether-diisopropyl ether to 3 liters with vigorous stirring to give a fluffy precipitate which is filtered off, washed with ether and dried. Yield: 234 g; by thin layer chromatography it is not uniform (diastereoisomeric mixture). Based on the UV spectrum and NMR, the aromatic substance is no longer present, The elemental analysis is impeccable.

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

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 at the same time. NaOH. This precipitates a thick precipitate. 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, whereupon an oil precipitates. 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 ice water, is filtered off and washed with a small amount of cold vinegar ester and then 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 with concentrated HCl until the pH is 1.5-2. After shaking, the ethyl acetate phase is separated, washed with a small amount of water and dried over sodium sulfate. Concentrate as above 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 eight times the amount of ethyl acetate. Melting point 197-198 ° C, = 7.5 ° (c = 1, in methanol). Elemental analysis is impeccable.

The Ca salt of 10 "B" is recrystallized from four times the amount 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 vinegar ester phases are washed with a small amount of water and evaporated to dryness. 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 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. Then stir for another 20 min. At 0 ° C and 5 hours at room temperature and the separated 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 / ^ SO 4 solution, sodium hydrogen carbonate (the unreacted Na salt of Z-Dic-OH precipitates and is filtered off) and water when dried. and evaporated to dryness in vacuo. Residual oily. Yield: 38.5 g = -17.3 ° (c = 1, in methanol). To obtain an analogous compound from compound "B", the procedure is the same. Yield 38.1 g, = + 6.7 ° (c = 1, in methanol).

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

27 g of 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, at pH 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. M.p .: 159-160 ° 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 substances are obtained which have a melting point of 162-164 ° C, -Q = -4.4 ° (c = 1, in methanol). Elemental analysis is impeccable.

e. N-Benzyloxycarbonyl-L-alanyl-L-decahydroisoquinoline-3-carboxylic acid tert-butyl ester (Z-Ala-Dic-OBu * ") 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 are added. N-ethylmorpholine and a solution of 6.6 g of dicyclohexylcarbodiimide (DCC) in 30 ml of methylene chloride are added dropwise with stirring at 0-4 [deg.] C. After 5 hours the mixture is filtered, the filtrate is evaporated to dryness and the residue is taken up in ethyl acetate. and washed at a temperature below 5 ° C with 23 90532 10% KHSO 4 / I 2 SO 4 (1: 2), 1 molar sodium hydrogen carbonate and water, dried over sodium sulfate and the solvent is distilled off. Residue of resin, readily soluble in all organic solvents Yield: 15.2 g In a similar manner, the isomeric mixture "B" y at this stage, which can be isolated at this stage using preparative HPLC 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 Z are catalytically hydrogenated according to Example 10d. After distilling off the solvent, the resinous residue initially crystallizes after some time or by trituration with ethyl acetate and recrystallizes for analysis from ethyl acetate.

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

In the same manner as H-Ala-Dic-OBu, alanyl-octahydroindole-2-carboxylic acid t-butyl ester (H-Ala-Oic-0Bu) 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).

K "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 hydrogenated for 24 hours at 40 ° C. Filter, acidify with conc. With HCl, the insoluble matter is filtered off and the aqueous phase is extracted several times with butanol. The organic phase is concentrated and chromatographed. (CHCl 3 / methanol / glacial 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 (3H); 1.4 s (9 H); 2,0-1,0m

Il I 2 (12H)

0 R

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

: H

..: r 25 CH 3 1.0-2.0 m. (15H); 0.9 d (6H) XCH'CH2- ·· / CH3. : 5.1-4.3 m (4H)

:: 30 -CH2F

Δ 7.2 s (5H); 2.7-2.0 m (4H) // V_s-ch2-ch-

Ii CH3-CH2-CH- 1.0-2.0 m (21H) CH3 90532

QcH2- 7.1 s (5H); 2.7 d (2H) / CH2-di I 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 (SH); 5.0 s (2H); Δ 2.4 m (2H); 2.0-1.0 m (18H) -CH2-CH2: -NH-CH2-CH2-CH2-? H2-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); 5.0s (2H); 0 2.4 m (2H), 2.0-1.0 m (16H) 26 90 532 VV) -CH0-O-C-NH-CH-7.1 s (5H); 5.0 s (2 H); \ == / O 2.3 m (2H) H2N \. C-NCH 9 CHCH 2 - 8.3-7.6 g (2H); 2.9-1.0 m 5 (18H) to C-NH-CH 2 - 8.3-7.6 ra (2H); 2.9-2.5 m H ".- (2H) 10 / -CH2-O-C-NH-CH2CH2- 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 ° (16H) 3

CH

Δ (NH-CH 2 7.4 s (1H); 2.5 m (2H); 2.3 s (6H) H 3 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-

Ui2

OR

30 R when H is 3.9-3.0 (4H) n-2 13.1 s (1H); 7.5 s (1H); Δ 6.8 s (1H); 2.8 m (2H)

B

27 90532

cb3V

.CH-CH 2 1,01.0-2.0 m (14H); 0.9 d (6H) c-c -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 2 -CH 2 -CH- 1.0-2.0 m (20H) 3 2 | ch 3 --CH 2 - 7.1 s (5H); 2.7 d (2H) 15 -CH2-7.8-6.4 m (5H); 2.8 m (2H)

B

HO-CH 2 - 3.7 d (2H) ft '' V 2 -C 2 -C-NH-C 2 -C 2 -C 2 -C 7 7.1 s (5H); 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); 7.0 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 m (177 H)

H Νχ H

x, C-N-CH - 8.3-7.6 m (2H); 2.9-2.5 m

HN '' Z

<2K) 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

h3c7 «* L1-NH-CH-— 7.4 s (1H); 2.5 m (2 H); y * '2.3 s, 6H, h3c 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 1-norm. With aqueous NaOH to 7.5.

.30 Add 200 mg of sodium cyanoborohydride and allow to react for 36 hours. Evaporate to dryness and recover by chromatography on a silica gel column (elution mixture: chloroform / methanol / water / glacial acetic acid 20 + 15 + 2 + 1). 1 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 for 30 minutes at room temperature. Evaporate to dryness in vacuo and triturate the residual oil with cold diisopropyl ether and petroleum ether.

Yield: 226 mg of amorphous substance.

NMR: 7.10 (s); 3.0-3.9 (m, broad); 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 a solution of KOH in ethanol and 6.2 g of 2-oxo-4-phenylbutyric acid ethyl ester are added and stirred, in the presence of 9 g of 4 A powdered molecular sieve, slowly adding 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- * 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 Dic-OBut and 630 mg of dicyclohexylcarbodiimide in 15 ml of anhydrous chloroform is mixed with a rapidly cooled and freshly distilled solution of 270 mg of pyruvic acid. In 5 ml of chloroform. The mixture is left in a deep-freezer (-20 ° C) for 16 hours and the precipitated 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 condensing 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 (UH); ΝΛ 2.4 s (3H); 1.4 s (9H) ·. * 25 | COO-t-C4H9 CO-CO-CH3 in the following compounds is uniformly observed for the parent compound. ...

1r the following signals: δ 5.1-4.8m (1H); 3.9-3.0m (2H); 1.4 s (9 H); 2.0-1.0 m (12H) I: 3i 90532 - CH 2 F 3 13.1 s (1H); 7.5 s (1 H); 6.8s 2 I-Ah (1H); 3.9-3.0 m (4H) -CH 2 -CH (CH 3) 2 2.4-1.0 ra (21H) CH 2 -S- ^ 7.2-7.0 m (5 H); 2.5 m (2H) 10 -CH 2 F 4.4 s (2H) -ch 2 F 3 7.15 (5h); 3.0 s (2h) δ-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) -alanine-L-decahydroisoquinol -carbon -25 acid tert-butyl ester 1.52 g of pyruvyl-Dic-OBut and 394 mg of phenyl-cysteine are dissolved in 5 ml of methanol and :; The pH is adjusted to 7.0 with 1-norm, NaOH (aq). Add 400 mg of sodium cyanoborohydride and the mixture. . 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 / CH3COOH / H2O 50/20/5/1).

329 O 5 S 2 NMR: 7.3 m (5H); 5.1-4.8 m (1H); 3.9-3.0 m (4H); 2.5 m (H H2H).

c.) N- (1-Carboxy-3-phenyl-3-thiapropyl) -alanyl-L-decahydro-isoquinoline-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, evaporate to dryness in vacuo, the residue is digested with diisopropyl ether and dried over potassium hydroxide. Yield: 0.95 g of trifluoroacetate (from hygroscopy).

NMR: 7.3 m (5H); 5.2-4.8 m (1 H); 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 with an equivalent amount of 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 ice-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 in the presence of 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 To a stirred mixture of 0.64 g of sodium periodate and 20 ml of water under ice-cooling is added 1.3 g of N- (1-Carbethoxy-2-benzyl-thioethyl) -L-alananyl-L-decahydro-isoquinoline-3-carboxylic acid dissolved in 20 ml of methanol. The reaction mixture is 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 following signals are observed in the NMR spectrum: 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 heated 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 sulfate, and when oxygen evolution has ceased, 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-diaminobutyric acid, prepared according to Coll. Czech, chem. Commun. 31, 2955 (1966) 15, is reacted with 2.4 grams of the compound 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, then adjust the pH with a small amount of HCl to 7-8 and distill off the solvent 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 on ice and filter off the precipitate after a short time, wash I.

35 90 532 with a small amount of ice-cold water and ether and dried in vacuo. The aqueous solution can also be converted to a zwitterion using a weakly basic ion exchanger and purified. The filtrate is then 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 water separation), 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 residue 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-butylis-30 blades and 45 ml triethylamine, are kept in tetrahydrofuran for 24 hours. The solvent is distilled off in vacuo, the residue is left 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 90532 The residue is chromatographed on silica gel with cyclohexane-ethyl acetate (4: 1), in which case, in addition to purification, the diastereoisomers also separate. After concentrating the corresponding fractions, keeping compound 5 in trifluoroacetic acid for 20 minutes cleaves the t-butyl ester. 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 cyclohexane-ethyl acetate (4: 1). The benzyl ester is chromatographically cleaved from the homogeneous compound by hydrogenation from a catalytic.

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 in the presence of 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 ο-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 by adding 1 ml of 1:37 90532 diisopropylethylamine 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 sulfate 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 residue is dried thoroughly in vacuo over KOH, the compound is in the form of 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 organic phase dried over anhydrous sodium sulfate is added 200 ml of dimethylacetamide (DMA) and evaporated to dryness at room temperature using 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, adjust the pH to 2-norm. with methanolic hydrochloric acid to 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 sulphate, 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 2 value of the S, S compound is lower and falls substantially heavier apart (48%). the oily substance is further processed 5 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 at normal pressure using 1 g of Pd / carbon 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 20 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 sulphate and evaporated to dryness, is chromatographed on silica gel. Elute with ethyl acetate / petroleum ether 4: 3 to give 2 fractions which evaporate to dryness in vacuo to give colorless oils.

39 90 532

Elemental analyzes: C H 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 hydrogenation of the catalyst at atmospheric pressure with 200 mg of Pd / carbon catalyst (10%). At the end of the hydrogen uptake (after about an hour), the catalyst is filtered off and the solution is evaporated to dryness in vacuo. Add a little pentane, heat to about 45 ° C and treat 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 Boc-Ala-OH are dissolved in 100 ml of DMF and 13 ml of N-ethylmorpholine, 13.5 g of HOBt and 29.6 g of octahydroindole-2-carboxylic acid benzyl ester hydrochloride are added. Cool in an ice bath, add 21 g of dicyclohexylcarbodiimide and stir 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).

5 b) Alanyl-octahydroindole-2-carboxylic acid benzyl ester trifluoroacetate 21.5 g of Boc-Ala-Oic-OBz1 are dissolved in 50 ml of trifluoroacetic acid. Evaporate to dryness in vacuo, digest the residue 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 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: h «90532

Method A;

Reduction amination of a condensation product prepared according to Example (6a or 12a) from Tie or Dic-OtC ^ Hg ester or benzyl ester or from Oic-OtC ^ Hg ester or benzyl ester and the corresponding «» ^ -ketocarboxylic acid with an 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 the corresponding ε-ketocarboxylic acid derivative according to Example (If, 10g, 11) and optionally cleavage of protecting groups according to Example (10h or 11) and / or optionally (13).

Method C:

The reduction amination according to Method A and, using a 20β-protected bifunctional amino acid, the cleavage of the protecting group from the amino acid derivative used.

Unless otherwise indicated, the following NMR values (cT values, ppm; TMS standard) apply to the compounds below: 4.9 m (2H); 4.5-3.0m (3H); 2.0-1.0m (11H).

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

42; π ς · 'k. » -S.

ον μ C Ό ε tN ° ε ε · ^

«° o ^ I

* I IS s - s. . - m CN CN '-' '_ T3 - Tl ..S ε S0' X X X r- · “° IN n IN ro“ ~ i zz 5 Ό ε X m ^ = * ^ r cn rr r- * ·. T-.

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1 to X

irj X <N

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U \ / XX

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• · / \ oj XX I <N

- '/ \ en xx es - \ / II X ^

\ _ / -in "cr u X

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Claims (2)

A process for the preparation of novel therapeutically useful octahydroindole derivatives of formula I and physiologically acceptable salts thereof, -COOH. J-N. (1) 10. in which formula R3 is CH3 or CH2F, R2 is alkyl of not more than 6 carbon atoms and which may be substituted by amino or hydroxy, and R3 is hydrogen or alkyl with 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, Q4-CH-COOR- f I3 L JN R 2 is CO-CH-Q (II) R 1 (III) in which formulas R 3, R 2 and R 3 are the same as above, one of the symbols Q is a nucleofugic group and the other is NH 2 and R 4 is H, methyl, ethyl, benzyl or tert-butyl, and, as desired, a obtained ester is converted to a carboxylic acid (R 2 and / or R 4 = hydrogen), or b) a compound of the formula POOC-CH-NH-CH-COOP ( IV) II R 2, R 2 46 90 532 where R 1 and R 2 are the same as above, P is hydrogen or one of the symbols P may also denote the same as R 3 defined above, such as tert-butyl, is reacted with a compound of formula 5 Where R4 represents the same as above, in the presence of a condensing agent, and, if desired, one or each of the ester group is converted to a carboxylic acid, or c ) a compound of 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 Rt, R2, R3 and R4 are the same as above 2 and one of the symbols T is hydrogen and NH2 and the other is an oxygen atom and the obtained Shiffs base is reduced, 3 and, if desired, the obtained compound is converted with the formula I to one site. 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.