FI77230B - FOERFARANDE FOER FRAMSTAELLNING AV SUBSTITUERADE PERHYDROINDOLIMINODISYROR MED ANTIHYPERTENSIV AKTIVITET. - Google Patents

Description

77230

This invention relates to the preparation of novel substituted perhydroindole iminodic acid,

European Patent Application No. 0 012 401 describes certain monocyclic iminodic acids having antihypertensive properties. The most preferred compounds of said application have an arylalkyl group in the side chain. The present invention relates to novel imino-bicyclic diacids which do not have an arylalkyl group in the side chain: these new compounds have better activity and a longer duration of activity than the compounds according to EP patent application 0 012 401.

In particular, this invention relates to a process for the preparation of substituted perhydroindole imino acids of general formula I having antihypertensive activity. CO-CH-NH-CH-R 3 R, COOR 2 wherein R 1 is a lower alkyl group having 1 to 4 carbon atoms which may have an amino group, R 2 is hydrogen or an alkyl group having 1 to 4 carbon atoms, R3 is a straight-chain or branched alkyl group or a mono- or dicycloalkylalkyl group having a total of up to 9 carbon atoms, or a substituted alkyl group of the following formula 2,77230 - (CH2) pS- CH-R5 R4 wherein R4 is hydrogen or a lower alkyl group having 1 to 4 carbon atoms, R5 is a cycloalkyl group having 3 to 6 carbon atoms or an alkoxycarbonyl group having 1 to 4 carbon atoms, or R4 and R5 both represent a cycloalkyl group having 3 to 6 carbon atoms and p = 1 or 2.

The compounds of the invention contain at least one carboxy group or two when R 2 is NH 2 alkyl. Accordingly, the invention also relates to salts of the compounds of general formula I formed with pharmaceutically acceptable inorganic or organic bases.

The invention furthermore relates to addition salts of the compounds of the formula I which are formed with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I contain at least 3 asymmetric carbon atoms. Depending on the positions of the substituents, there are 3-6 asymmetric centers. Racemic compounds can be separated into diastereoisomeric or epimeric mixtures or enantiomers in a known manner. The various isomers and racemic compounds form part of this invention.

Further preferred are compounds of formula I wherein R 3 is a straight or branched chain alkyl group having 3 to 8 carbon atoms, a cycloalkylalkyl group having 4 to 8 carbon atoms or a substituted alkyl group -CH 2 -S-CHR 4 R 5 wherein R 4 is hydrogen or an alkyl group and R 5 is an alkoxycarbonyl group and the alkyl groups and alkoxy groups have 1 to 4 carbon atoms.

The compounds of the invention and their salts have interesting pharmacological properties. In particular, they inhibit certain enzymes, such as carboxypeptidases, enkephalinases or kininase II. By acting on the modifying enzyme, they inhibit in particular the conversion of angiotensin I, a decapeptide, to angiotensin II, 3,77230, which is an octapeptide, and which is responsible for certain excessive hypertension values.

These compounds can be used for therapeutic purposes to reduce or even eliminate the activity of these enzymes that cause hypertension or myocardial insufficiency. The effect on kininase II results in an increase in circulating bradykinin and thus a decrease in arterial blood pressure.

The compounds according to the invention can be formulated into pharmaceutical mixtures containing as active ingredient at least one compound of the general formula I or a salt formed with an inorganic or organic base or acid and an inert, non-toxic, pharmaceutically acceptable carrier.

For therapeutic use, the compounds of general formula I or their salts are formulated into pharmaceutical preparations which can be administered intravenously or orally. In addition to the active ingredient, the pharmaceutical compositions according to the invention contain one or more inert, non-toxic, pharmaceutically acceptable carriers and / or binders, flavoring agents, disintegrating agents, sweetening agents, lubricants or liquid diluents for intravenous administration.

The pharmaceutical compositions according to the invention may additionally contain another active ingredient which has a synergistic or complementary effect.

Among the latter active ingredients, mention may be made of diuretics and in particular saliuretics, such as thiazides, dihydrothiazides, chlorosulfamides, dihydrobenzofuran-2-carboxylic acids and phenoxyacetic acid derivatives. Such compounds include, for example, N- (3'-chloro-4'-sulfamoyl-benzamido) -2-methyl-indole, ethacrylic acid and furosemide.

It is also possible to add α-adrenolytic agents such as prazosin or other antihypertensive agents.

4,77230

The dosage of the active ingredient can vary greatly depending on the age and weight of the patient, the severity of the symptoms and the route of administration. Oral dosage forms are most preferred, but intravenous administration is also very suitable for the treatment of hypertension. In general, unit doses in the range of 5 to 100 mg are preferred.

Pharmacological testing of the compounds of the invention

The compounds of the invention were tested by administering them to awake dogs i.v. or p.o ..

Blood pressure in dogs was measured with a pressure gauge (Statham P 23 Db) by inserting a catheter into the aorta through the femoral artery. The results were recorded on a recording device (Brush 400).

Angiotensin I and angiotensin II were administered intravenously to animals at 0.3 γ / kg. Thereafter, 1-5 mg / kg of a compound of the invention was administered orally or intravenously.

It was found that there was a 50-100% inhibition of the antihypertensive effect of angiotensin I, which occurred 30-90 minutes after dosing and remained at 40-80% for more than 6 hours after administration of the compounds. Some compounds retained their activity for 24 hours, which is not typical of any compound known to date (and especially not captopril, which is the only commercially available compound). The compounds of the invention also do not appear to have a toxic effect (LD50> 500 mg / kg i.p. in mice).

The results are shown in Table I, captopril as a prior art compound.

5,77230

Table I:

Angiotensin-modifying enzyme inhibitory activity of the compounds of the invention.

Compound dose inhibition% inhibition% n; m_mq / kg route of administration after 1 h after 6 h captopril 5 i.v. 76 30 captopril 5 p.o. 87 30 2 5 i.v. 73 38 3 5 i.v. 65 35 5 5 i.v. 77 47 6 (e.g. 2) 5 i.v. 83 62 7 2 i.v. 100 48 1 p.o. 52 48 8 5 i.v. 92 67 5 p.o. 71 56 9 (e.g. 3) 5 i.v. 65 40 10 5 i.v. 100 83 1 i.v. 94 53 11 5 i.v. 100 68 1 p.o. 91 72 12 1 i.v. 84 46 15 1 i.v. 79 41 1 i.v. 90 38 16 1 i.v. 84 52 18_1_p.o._90_65_

Compounds of formula I may be prepared by reacting an alkyl ester of azabicycloalkanedicarboxylic acid of general formula II 6 77230 COR '

(XX

In which R 'is a lower alkyl group or an aminoalkyl group whose amino function is protected by a benzyloxycarbonyl group or a tert-butoxycarbonyl group, and R' is a lower alkyloxy group or a hydroxy group, is reductively alkylated with a compound of formula III O = c (III) COOR 2 wherein R 2 and R 3 are as defined above to give an amine of general formula IV - R * (IV)

VJ-V

^ CO-CH-NH-CH-R.

I I

R * 1 GOQR ^ where R 'and R * i have the same meaning as in the context of formula II and R2 and R3 have the same meaning as above, and the resulting product 7 77230 is, if necessary, completely or partially deprotected by complete saponification, partial saponification or hydrogenation, to give a compound of formula I.

The compounds of general formula II and their preparation methods are described in European Patent Application Publication No. 0031741. The above-mentioned reductive alkylation uses the method described in R. F. Borch, M. D. Bernstein and H. Dupont Durst, JAOS 93, 2897 (1971). The process is preferably carried out in an alcoholic solution in the presence of a neutral dehydrating agent and an organic or inorganic cyanoborohydride. The invention is illustrated by the following examples.

Example: Describes only the process of the invention, but does not give a compound of the invention.

(3S) -2- [N- (1-carboxyethyl) - (S) -alanyl] -3-carboxy-l, 2,

3,4-Tetrahydroisoquinoline Step A

Left-turning tetrahydroisoquinoline-3-carboxylic acid.

A three-necked flask equipped with a condenser is charged first with 15 g of (S) -β-phenylalanine and then with 34 ml of 40% formaldehyde solution and 105 ml of concentrated hydrochloric acid.

Heat the vessel for 30 minutes in a boiling water bath. This gives a clear reaction solution which is allowed to cool to room temperature and then 15 ml of formaldehyde and 30 ml of concentrated hydrochloric acid are added. Next, the mixture is refluxed for 3 hours and then allowed to cool to 8,77230. The precipitate is filtered off, dried without heating and dissolved in 200 ml of boiling water and 400 ml of hot ethanol. The solutions are combined and neutralized by the addition of 10% ammonia solution.

5 Tetrahydroisoquinoline-3-carboxylic acid crystallizes.

The crystalline mixture is left to stand overnight in the refrigerator and then the precipitate is filtered off and washed with ethanol. This gives 17.3 g of crude product. The product is dried in vacuo over phosphoric acid.

10 Analysis C 18 H 19 N 2 O 2 = 177

Calculated C% 67.78 H% 6.26 N% 7.90 Found 66.87 6.20 7.96

Infrared aspect NH9 + band in the range 2800-2400 cm ^ 15 C00 carbonyl band 1630 cm

Rotation αD = -108 ° (c = 2.2 N NaOH)

Step B

(3S) -Methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate-20-t-hydrochloride

To the three-necked flask are successively added 5 g of tetrahydroisoquinoline-3-carboxylic acid and 30 ml of methanol. 6 g of thionyl chloride are carefully poured into the suspension thus obtained so that the temperature does not rise above 0 to + 5 ° C. 25 The addition takes about 10 minutes. After the addition, stirring is continued for 2 hours at room temperature and then refluxed for 1.5 hours. When the mixture is completely dissolved, the heating is stopped and the solution is evaporated to dryness. The residue is extracted three times with methanol and evaporated to dryness. 8 g of colorless crystals are obtained, which are purified by trituration with ether. The crystals are filtered off, washed with ether and dried. 6.4 g of methyl tetrahydroisoquinoline-3-carboxylate hydrochloride are obtained. Analysis C1 () H13NO2ClH = 227.69 35 Calculated C% 58.03 H% 6.20 N% 6.15 Cl% 15.57

Found 57.79 6.46 6.38 15.67 9 77230

The infrared spectrum

Carbonyl band 1735 cm -1

NH2 + band 2800-2400 cm 1 Step C

5 (3S) -2 - ((S) -tert-butoxycarbonylalanyl) -3-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline 6.01 g (0.0264 mol) of the hydrochloride prepared in the previous step are dissolved in 50 ml of: The resulting solution is basified (pH 11) with ammonium hydroxide and then extracted with sulfuric acid ether (2 x 50 ml). The combined ether solutions are dried over calcium sulphate, filtered and evaporated to dryness. The residual amino ester (5.04 g) is dissolved in 30 ml of dimethylformamide and the solution thus obtained is stirred at 0 to + 5 ° C in a cooled solution of 5 g of (S) -tert-butoxycarbonylalanine. in ml of dimethylformamide. A solution of 3.6 g (0.0264 mol) of 1-hydroxybenzotriazole in 40 ml of dimethylformamide is successively dissolved in 30 ml of chloroform, followed by 5.45 g (0.0264 mol) of di-20-cyclohexylcarbodiimide and the solution thus obtained is added to the solution obtained above.

The resulting reaction mixture is stirred for 18 hours and at the same time allowed to warm to room temperature. When the dicyclohexylurea formed is filtered off and the filtrate is evaporated to dryness under a pressure of 0.1 mm Hg, a residue is obtained which is dissolved in 50 ml of ethyl acetate and a second portion of dicyclohexylurea is filtered off. The filtrate is washed successively with 80 ml of saturated aqueous sodium chloride solution, twice with 40 ml of 10% aqueous citric acid solution, 80 ml with 30 ml of saturated aqueous sodium chloride solution, twice with 40 ml of saturated aqueous sodium bicarbonate solution and finally with saturated aqueous sodium bicarbonate solution. .

The organic phase is dried over calcium sulphate, filtered and evaporated to dryness in vacuo. The evaporation residue is the desired product.

10 77230

Weight: 9.1 g (95%)

Melting point: 98-100 ° C (Kofler)

Analysis l c19h26n2o5

Calculated C% 62.97 H% 7.23 N% 7.73 5 Found 63.15 7.05 7.97

Step D

(3S) -2 - ((S) -tert-butoxycarbonylalanine) -3-carboxy-1,2,3,4-tetrahydroisoquinoline 1.45 g (0.004 mol) of the compound prepared in the previous step are dissolved in 20 ml of methanol. and 4.4 ml (0.004 mol) of a 1N aqueous solution of sodium hydroxide are added to the solution thus obtained.

The solution is left at room temperature for 20 hours. The methanol is evaporated off with a vacuum from a water jet pump and the residue is taken up in 20 ml of water. The unsaponifiables are extracted with ethyl acetate and the aqueous phase is acidified with 4.4 ml of 1N hydrochloric acid. The precipitate formed is extracted twice with 20 ml of ethyl acetate, dried over calcium sulphate, filtered and evaporated. The residue is the desired 20 product.

Weight: 1.3 g (93%)

Analysis for C 18 H 24 N 2 O 5

Calculated C% 62.05 H% 6.94 N% 8.04 Found 61.54 6.93 7.78

25 Step E

(3S) -2 - ((S) -alanyl) -3-carboxy-1,2,3,4-tetrahydroisoquinoline 1.1 g (0.00316 moles) of the derivative obtained in the previous step are stirred at + 5 ° C, protected from moisture. 30 in 4.5 ml of trifluoroacetic acid.

The solution obtained is evaporated to dryness under a pressure of 0.1 mm Hg. The crystalline hygroscopic evaporation residue is the desired product in the form of a trifluoroacetate solvate containing 0.5 moles of trifluoroacetic acid.

35 Weight: 1.3 g (98%)

Analysis for C 32 H 35 F 9 N 4 O 12

Calculated C% 45.83 H% 4.21 N% 6.68 Obtained 45.99 4.62 6.55 77230 0/7 g (0/0019 moles) of the trifluoroacetate obtained above are converted into 0.45 g ( 94%) of the corresponding amino acid by lowering the sulfonated resin (50 g, Dowex 50W x 8 H +) and then washing with 500 ml of 1N ammonia solution.

5 Melting point: 170 ° C (decomposes).

Step F

(3S) -2 - ((S) -N- (1-carboxyethyl) alanyl) -3-carboxy-1,2,3,4-tetrahydroisoquinoline 0.849 g (0.0034 mol) 2 - ((S) - alanyl) -3-carboxy-10 1,2,3,4-tetrahydroisoquinoline is dissolved at 25 ° C in the presence of pyruvic acid (1.9 g, 0.0216 mol) in a mixture of 22 ml of 1N sodium hydroxide solution and 50 ml of pH 7-buffer prepared by mixing 50 ml of 0.1 M monosodium phosphate solution and 29.1 ml of 0.1 N sodium 15 hydroxide solution. 0.45 g (0.0072 mol) of sodium cyanoborohydride are then added in one portion. The reaction mixture is left at room temperature for 22 hours.

Excess cyanoborohydride is decomposed by adding 6 ml of concentrated hydrochloric acid. The resulting solution is passed through an ion exchange resin (Dowex 50 H +). The resin is washed with distilled water until chloride ions are no longer present, and then the product attached to the resin is removed by washing with 1 liter of 1N aqueous ammonia solution. The ammonia solution is evaporated to dryness under vacuum with a water jet pump.

The evaporation residue is the monoammonium salt of the desired product. Weight: 0.8 g / 69.7%)

Analysis for C 16 H 23 N 3 O 5

Calculated C% 56.96 H% 6.64 N% 12.95

Found 57.79 6.69 12.70 77230 12

Example 1: 1 - {(S) -N - ((1RS) -1-carboxyethyl) -alanyl} -2-carboxyperhydroindole

Step A

5 (2RS) -2-Carboxyindoline 31.5 g (86%) of (2RS) -2-carboxyindoline are obtained by saponification of 43 g (0.224 moles) of the corresponding ethyl ester prepared by the method of E.J. Corey et al. (J.Amer.Chem. Soc. 1970, 92, p. 2476), for 8 hours at room temperature in a solution of 250 ml of 1N sodium hydroxide solution and 150 ml of ethanol.

The aqueous alcoholic solution is evaporated to half volume, neutralized with 25 ml of 10N hydrochloric acid and the precipitate formed is filtered off, washed with water and dried.

The crude acid is purified by passing through an ion exchange column (Dowex 50 W x 8H +) and washing with 2N aqueous ammonia. The ammonium salt obtained is dissolved in as little water as possible and the acid is precipitated with a theoretical amount of hydrochloric acid. The precipitate is dried, washed with water and air dried.

Analysis (ammonium salt) C 19 H 12 N 2 O 2

Calculated C% 59.99 H% 6.71 N% 15.54

Found 60.22 6.71 15.06 25 59.93 6.71 15.29

Step B

(2S) -2-carboxyindoline 60.5 g (0.37 mol) of (DL) -2-carboxyindoline prepared in step A are added to a solution of 44.9 g (0.37 mol) of (+) - a. -methylbenzylamine in 400 ml of anhydrous ethanol. The precipitate formed is filtered off and digested by refluxing in 350 ml of anhydrous isopropanol. The suspension is cooled and filtered and the precipitate is washed with a small amount of isopropanol and dried.

13.872 g of (+) -. Alpha.-methylbenzylanine salt of (L) -2-carboxyindoline are obtained.

otp1 = 5.3 ° (C = 1% ethanol).

(2S) -2-Carboxyindoline is prepared in theoretical yield by dissolving 10 g of the above salt (0.029 mol) in 50 ml of water and acidifying the solution by adding 29 ml of 1N hydrochloric acid.

The precipitate is filtered off, washed with water, distilled and dried. Optical purity 96% (gas chromatographic analysis after conversion to (-) - camphoric acid amide).

(2S) -2-Carboxyindoline was obtained by the same method starting from (RS) -carboxyindoline and (-) - α-methylbenzylamine.

The absolute configurations of (S) and (R) acids were determined as follows:

Analytical amounts (about 0.5 g) of each acid were converted to ethyl esters by treatment with thionyl chloride and ethanol as described in Step C.

The esters are reduced with lithium aluminum hydride E.J.

20 according to the method of Corey1 (see said reference) to the corresponding primary alcohols, which are identified on the basis of their circulating capacity by comparison with the alcohols mentioned in E.J.Corey's publication, the circulating capacity of which is known.

25 Step C

(2S) -2-Ethoxycarbonylperhydroindole 11 g (0.032 mol) of the (+) - α-methylbenzylamine salt of (L) -2-carboxyindoline prepared by the method of step B are dissolved in 100 ml of water and converted into the corresponding acid by adding 32 ml of 1N hydrochloric acid. The acid is dried, washed with water and dried in a desiccator over phosphoric anhydride and then suspended in 50 ml of anhydrous ethanol. 3.9 ml of thionyl chloride are added to the suspension over 10 minutes at a temperature between 0 and + 5 ° C with stirring, stirring is continued for a further 1 hour at 25 ° C and then for a further 1 hour at 50 ° C.

14 77230

The mixture is left to stand overnight at 25 ° C, then evaporated to dryness in a vacuum with a water jet pump at 40 ° C and the residue is taken up in 50% anhydrous benzene and filtered.

5 (2S) -2-Ethoxycarbonylindoline hydrochloride is dissolved in 150 g of water and hydrogenated for 8 hours at 45 ° C under 5000 kPa with the aid of 2 g of Pd / C catalyst.

The mixture is cooled, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is the desired product in the hydro-10 chloride form.

Weights 6.9 g (93%)

Analysis for C

Calculated C% 56.52 H% 8.62 N% 5.99 Cl% 15.17

Found 55.52 8.53 5.96 15.16

15 Step D

(2S) -N - ((S) -tert-butoxycarbonyl-alanyl) -2-Ethoxycarboxy-nyyliperhydroindoli

A solution of 3 g (0.0128 moles) of (2S) -2-ethoxycarbonylperhydroindo-20β-hydrochloride prepared in step C above in a mixture of 15 ml of dry dimethylformamide (DMF) and 1.8 ml of triethylamine is added + To a 5 ° C cooled and stirred solution of 2.42 g (0.0128 mol) of L-tert-butoxycarbonylalanine in 15 ml of dimethylformamide. To the resulting mixture is successively added a solution of 1.7 g (0.0128 moles) of N-hydroxybenztriazole in 20 ml of dimethylformamide and a solution of 2.64 g (0.0128 moles) of dicyclohexylcarbodiimide. In 15 ml of dry chloroform.

The mixture is stirred for 65 hours at 25 ° C, the di-cyclohexylurea formed is filtered off and washed with ethyl acetate.

The combined filtrates are washed successively with 80 ml of saturated aqueous sodium chloride solution, twice with 40 ml of concentrated citric acid solution, twice with 40 ml of saturated aqueous sodium bicarbonate solution and then twice with 35 ml of saturated sodium chloride solution.

The organic solution is dried over calcium sulphate, filtered, evaporated to dryness with a water-jet pump under reduced pressure and the residue is taken up in 100 ml of ethyl acetate. When the dicyclohexylurea residues are still filtered off and the filtrate is evaporated to dryness, the desired product is obtained as a very viscous oil.

5 Weight: 3.8 g (81%).

Analysis for C 18 H 32 N 2 O 5

Calculated C% 61/93 H% 8.75 N% 7.60

Found 61.76 8.56 7.77

Step E

(2S) -N - ((S) -tert-butoxycarbonylalanyl) -2-carboxyperhydroindole 3.6 g (0.0098 mol) of the ester obtained in step D are dissolved in a mixture of 30 ml of methanol and 11 ml of 1N aqueous sodium hydroxide solution.

The mixture is kept at 25 [deg.] C. for 20 hours and then the methanol is evaporated off under reduced pressure with a water-jet pump and 60 ml of water are added. To eliminate unsaponifiable material, the solution is washed twice with 50 ml of ethyl acetate and then acidified by adding 11 20 ml of 1N hydrochloric acid. The white precipitate formed is extracted twice with 50 ml of ethyl acetate, the extracts are combined, washed with water, dried over calcium sulphate, filtered and evaporated to dryness. The residue is the desired product.

Weight 1.9 g (57%).

25 Analysis

Calculated C% 59.98 H% 8.29 N% 8.23

Found 59.10 8.16 7.81

Step F

(2S) -1 - ((S) -alanyl) -2-carboxyperhydroindole 30 g (0.0047 mol) of the acid prepared in step E above are stirred at 0 to + 5 ° C in 10 ml of trifluoroacetic acid 1 hour and then another 15 minutes at room temperature.

The solution is evaporated to dryness under vacuum in a centrifugal pump, the residue is dissolved in 15 ml of water and passed through an ion exchange column (Dowex W + 8H +). The column is washed with 1 liter of 2N aqueous ammonia solution. The washing solutions 16 77230 are evaporated to dryness in vacuo. The residue obtained is the desired product.

Weight 0.90 g (95%).

Analysis for C 12 H 20 N 2 O 3 Calculated C% 59.98 H% 8.39 N% 11.10

Found 58.53 8.24 11.43

Step G

(2S) -1 - {(S) -N - ((1RS) -1-carboxyethyl) -alanyl} -2-carboxysiperhydroindole 0.7 g (0.00291 mol) of the (2S) prepared in step F above. ) -N - ((S) -alanyl) -2-carboxyperhydroindole and 1.67 g (0.0183 mol) of pyruvic acid are dissolved in a mixture of 18 ml of 1N aqueous sodium hydroxide solution and 40 ml of pH 7 buffer, and the resulting solution is reduced by adding 0.400 15 g (0.0064 mol) of sodium cyanoborohydride as described in Example 1, step F.

After treatment with concentrated hydrochloric acid, the mixture is passed through an ion exchange resin (Dowex 50 H +) and the final ammonia washings are evaporated to dryness to give 0.76 g of a residue (79%) which is the desired product in the form of the monoammonium salt.

Analysis for C 15 H 27 N 3 O 5

Calculated C% 54.70 H% 8.26 N% 12.76 Found 54.10 7.78 12.77 Example 2: (2S) -1 - {N- (2 - ((1 RS) -1- Ethoxycarbonylethylthio) - (1RS) -1-ethoxycarbonylethyl) - (S) -alanyl} -2-carboxyperhydroindole 1 g (4.17 mmol) of (2S) -1 - ((S)) prepared in Example 1, Step F. -alanyl) -2-carboxyperhydroindole and 4.72 g (19 mmol) of ethyl ((1 RS) -1-ethoxycarbonylethylthio) pyruvate are dissolved in 50 any anhydrous ethanol in the presence of a molecular sieve (15 g, 0.4 nm). The mixture is stirred for 45 minutes at room temperature and then a solution of 0.25 g of sodium cyanoborohydride in 2.25 ml of anhydrous ethanol is added over 6 hours.

The molecular sieve is filtered off, the filtrate is evaporated

dry under reduced pressure and the residue is dissolved in 100 ml of sulfuric acid ether. The solution is extracted with 2 x 100 ml of distilled water, dried over calcium sulphate, filtered and chromatographed on 200 g of silica gel (Merck F 254) using methylene chloride-methanol (180/20) as eluent. 0.5 g (25%) of the desired product is obtained in the form of the sodium salt. Analysis for C22H35N2Na O2S

Calculated C% 53.43 H% 7.13 N% 5.66 S% 6.48 Found 53.28 7.09 5.19 5.92 10 Intermediate ethyl - ((1 RS) -1-ethoxycarbonylethylthio ) pyruvate is prepared by condensing ethyl libromopyruvate and (RS) ethylthiolactate together in the presence of pyridine by the method described for the corresponding derivatives: J. of Heter.Chem. (1973) 10/4, pp. 679-681.

15 bp = 165-170 ° C, yield 67%.

Example 3: (2S) -1- (n- (2-Ethoxycarbonylmethylthio- (1 RS) -1-ethoxycarbonylethyl) - (S) -alanyl) -2-carboxyperhydroindole

The compound is prepared according to Example 2 using 1 g (4.17 mmol) of (2S) -1 - ((S) -alanyl) -2-carboxyperhydroindole and 4.45 g (1.9 moles) of ethyl ethoxycarbonylmethylthiopyruvate as starting materials and 0.25 g of sodium cyanoborohydride.

After chromatographic purification, 0.26 g (14%) of the desired product are obtained.

Analysis for C 21 H 34 N 2 O 7 S

Calculated C% 55.00 H% 7.47 N% 6.11 S% 6.99 Obtained 54.71 7.32 5.94 7.01 The intermediate ethyl ethoxycarbonylmethyl 30-thiopyruvate is prepared by condensing ethyl bromopyruvate and ethyl thioglycolate as described in Example 2. by the method specified in the reference.

mp δ = 165-175 ° C, yield 50%.

Example 4: 35 (2S) -1- {N- (3- (N-Benzyloxycarbonyl-N-dicyclopropylmethylamino) -1RS) -1-ethoxycarbonylpropyl) - (S) -alanyl} -2-carboxyperhydroindole 18,77230

The compound is prepared by the method of Example 2 using as starting materials 0.6 g of (2S) -1 - ((S) -alanyl) -2-carboxyperhydroindole, 4.3 g of ethyl 4- (n- (benzyloxycarbonyl) -dicyclopropylamino) - 2-oxobutyrate and 0.15 g of sodium cyanoborohydride.

After chromatographic purification, 1 g (67%) of the desired solvent is obtained.

Analysis for C 33 H 47 N 3 O 7

Calculated C% 66.31 H% 7.93 N% 7.03 10 Obtained 66.11 7.83 7.22 The intermediate ethyl 4- (n- (benzyloxycarbonyl) -dicyclopropylamino) -2-oxobutyrate is prepared in six as follows:

Step 1: Bromoacetaldehyde diethyl acetal and ethyl 2-dithianyl carboxylate are condensed together according to the method of E.D. Eliel, J.Org.Chem. (1972), Vol. 37, pp. 505-506. Yield 57%, m.p. = 130-135 ° C.

Step 2: The resulting 2- (2,2-diethoxy-1-ethyl) -2-ethoxycarbonyl-1,3-dithiane is converted to 2- (2-oxo-1-ethyl) -2-ethox-20-carbonyl-1 , 3-dithiane to semicarbazone by stirring in an aqueous solution of semicarbazide hydrochloride at room temperature for 24 hours. The yield of semicarbazone obtained is 88% and the melting point (Kofler) is 183 ° C.

Step 3: The semicarbazone obtained above is converted to the corresponding aldehyde by mixing with pyruvic acid in aqueous acetic acid according to the method of R.E.Beyler et al. (J. Ann. Chem. Soc. (1060), 82, p. 175). b.p. 0 = - U m -1 140-145 ° C, yield 50%.

Step 4: The aldehyde obtained above is condensed with dicyclo-30-propylmethylamine and the resulting imine is reduced according to the method of JWLown and S.Itoh (Can.J.Chem. (1975), 53, p. 960) to give the product 2- (2- (dicyclopropylmethylamino) ethyl) -2-ethoxycarbonyl-1,3-dithian in 65% yield. Its hydrochloride has a melting point of 150 ° C (K).

Step 5: The obtained derivative is reacted with benzyl chloroformate according to the method "Chemistry of the amino acids", vol. 2, pp. 895, Greenstein and Winitz (Wiley 19 77230

Editor). There is thus obtained 2- {2- [n- (benzyloxycarbonyl) -dicyclopropylmethylamino) -1-ethyl} -2-ethoxycarbonyl-1,3-dithian as a viscous oil in 93% yield.

Step 6: When the derivative 5 obtained in the previous step is reacted with N-bromosuccinimide in aqueous acetone, the product is 4- (n- (benzyloxycarbonyl) -dicyclopropylamino) -2-oxobutyrate in 70% yield (method: EJCorey, J. Org. Chem. (1971), 36, 3553-60).

The compounds prepared in the above examples and also other compounds of formula I prepared by the same methods are summarized in the following table.

The table shows the characteristic values obtained for the compounds in the infrared (IR) and nuclear magnetic resonance (NMR) assays: s is a singlet, d is a doublet, q is a quadruplet and m is a multiplet.

20 7 72 30

Table

Compound R2 R3 form (salt) 1 Eg 1 CH3 H CH3 ammonium salt 2 CH3 C2H5 -CH2-S-CH M), 3 CH3 C2H5 -CH2-CH2-CH acid maleate 4 CH3 C2H5 CH3 acid maleate 5 CH3 C2H5 -CH2-S- Ch (-Q) 2 sodium salt

! I (RS) I

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Claims (2)

77230 Claim: A process for the preparation of substituted perhydroindole imino acids of general formula I having antihypertensive activity L> - \ CO - CH - NH - CH - R 3 IIR, COOR 2 in which the formula has a lower alkyl group having 1 to 4 carbon atoms which may have an amino group , R 2 is hydrogen or an alkyl group having 1 to 4 carbon atoms, R 3 is a straight-chain or branched alkyl group or a mono- or dicycloalkylalkyl group having a total of up to 9 carbon atoms, or a substituted alkyl group of the following formula - (CH 2) d S- CH-R5, R4 wherein R4 is hydrogen or a lower alkyl group having 1 to 4 carbon atoms, R5 is a cycloalkyl group having 3 to 6 carbon atoms or an alkoxycarbonyl group having 1 to 4 carbon atoms, or R4 and R5 both represent a cycloalkyl group having 3 to 6 carbon atoms and p = 1 or 2, in racemic form or as optical isomers, and with pharmaceutically acceptable inorganic or organic bases of these compounds for the preparation of acid salts or addition salts thereof with pharmaceutically acceptable inorganic or organic acids, characterized in that the alkyl ester of azabicycloalkanedicarboxylic acid of the general formula II 77230 ^ COR 'rr2y ^ "N * - ch - nh2 R' R1 a lower alkyl group or aminoalkyl group whose amino group is protected by a benzyloxycarbonyl group or a tert-butoxycarbonyl group, and R 'is a lower alkyloxy group or a hydroxy group, is reductively alkylated with a compound of general formula III 0. C 1 (C 3) C 20 R 2 wherein R 2 and R 3 are as defined above to give the amine "R '(rv) of general formula IV. J 1 -CO-CH-NH-CH-R 2 -R * 1 COOR 3 wherein R1 and R'1 are as defined for formula II and R2 and R3 are as defined above, and the resulting intermediate is completely or partially deprotected, if necessary, by complete saponification, partial saponification or hydrogenation to give a compound of formula I. 2 3 0 For the preparation of substituents perhydro-indole-iminodisyror with antihypertensive activity and with all the compounds of formula I Li "\ CO - CH - NH - CH - R3 R, COOR2 and w / o 1-4 cholatom, wherein an amino group is present, R2 is an alkyl group having 1 to 4 colatomers, R3 is an alkyl group having a alkyl group or a mono- or dicycloalkylalkyl group, having a total of 9 colaters, or an alkyl group substituted with a form - (CH2) p —S-CH-R5 r4 1 vilken R4 is a hydrogen group having 1 to 4 colatomers, R5 is a cycloalkyl group having 3 to 6 colatomers or an alkoxycarbonyl group having 1 to 4 carbon atoms or R4 and R5 is a cycloalkyl group having 3 to 6 carbon atoms and p = 1 or 2, in racemic form or in an optical isomer, and in the case of a pharmaceutically acceptable organic or organic base or in the addition of a pharmaceutically acceptable organic or organic syrup, Formeln II