NZ198535A

NZ198535A - Substituted azabicycloalkanedicarboxylic acids and pharmaceutical compositions containing such

Info

Publication number: NZ198535A
Application number: NZ198535A
Authority: NZ
Inventors: M Vincent; G Remond; M Laubie
Original assignee: Adir
Priority date: 1980-10-02
Filing date: 1981-10-02
Publication date: 1984-09-28
Also published as: LU88262I2; IL63940A; FI77230B; SU1153827A3; NO160780B; FI77230C; AR242949A1; GEP19970943B; KR860001875B1; NO160780C; AU7594981A; DK157011C; ES8305723A1; FR2503155A2; JPS5791974A; NL930046I2; EG15361A; EP0049658A1; AU542611B2; MD381C2

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 98535 1 98535 "Q, © m p pfi fefe Id M a 'fci ifflEfc' y ^ A. J. P. & s. ir-i-n .dm?.. No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION afttds "SUBSTITUTED IMINO-DIACIDO, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM" SUBSTITUTICil OF APPLICANT UNCEB SECTION 24 AQlf^ kl We, SCIENCE UNION ET CIE, SOCIETE FRANCAISE DE RECHERCHE MEDICALE, a French company under the laws of France, of 14 rue du Val d"Or, 92150 Suresnes, France, hereby declare the invention for which ? / we pray that a patent may granted to jo^/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed bv Daae la) _now am ended - i«- 1 98 5 35 The present invention relates to new substituted imino-diacids, and more particularly to substituted aza- /' bicycloalkanedicarboxylic acids,/their preparation and pharmaceutical compositions ;which contain them. / The invention relates specifically to the compounds / having the general formula OOH CO - CH - (CH2)g - NH - CH - R. COOR wherein : the ring A is saturated and n = O^or 1, or the ring A is 10 a benzene ring and n = 1, R1 represents a lower ^allt-yl group having from 1 to 4 carbon atoms which can carry an amino group, R~ represents a h-^^rogen atom or an alkyl group having from 1 to 4 carbon atoms, / 15 R^ represents a straight or branched alkyl, a mono- or ^dicsycloalkylalley 1 or a^pGenylaDcyl group each having no more tji-an a total of 9 carbon atoms, or a substituted alkyl group of the formula: CH,) - Y - CH - R, 2 p 5 198535 "AS AMENDED - i«- The present invention relates to new substituted imino-diacids, and more particularly to substituted aza-bicycloalkanedicarboxylic acids, their preparation and pharmaceutical compositions which contain them. The invention relates specifically to the compounds having the general formula (ch2 OOH (I) 'CO - CH - (ch2)q - NH - CH - R- COOR- wherein : 10 15 the ring A is saturated and n = 0 or 1 , R1 represents a lower alkyl group having from 1 to 4 carbon atoms which can carry an amino group, R2 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R^ represents a straight or branched alkyl, a mono-or dicycloalkylalkyl each having no more than a total of 9 carbon atoms, or a substituted alkyl group of the formula: fcH-,) - Y - CH - R, 2 p 5 - 2 - 198 535 with = H, a lower alkyl (C1 to ) or a cyclo-alkyl (C^ to Cg) group, R^ = H, a lower alkyl (C1 to C^), a cycloalkyl (C^ to Cg) or an alkoxycarbonyl group, 5 Y = Sor>N-Q where Q = H, or an acetyl or benzyloxycarbonyl group, and p = 1 or 2, and q = O or 1. lO The compounds of the invention contain at least one carboxy group: two in the case where R2 = H; and at least one salt-forming amino group: two when Y=NH or R =NH2alk. The invention thus also relates to the salts of the compounds of the formula (I), especially those obtained with 15 a^therapeutically compatible inorganic or organic base. The invention also relates to the addition salts of the compounds -of formula (I), especially those obtained with a therapeutically compatible inorganic or organic acid. The compounds of formula (I) contain at least 3 20 asymmetric carbon atoms. Depending on the position of the substituents and the degree of hydrogenation, there are from 3 to 6 centres of asymmetry. The racemic compounds may be divided into their diastereoisomeric or epimeric mixtures, or resolved into their enantiomers in 25 a known manner. The various isomers form part of the invention, as do the racemic compounds. The invention comprises more particularly the derivatives of perhydroindole (formula I; A is saturated and n = O) corresponding to the general formula : >98535 ( I ' ) wherein the symbols , R^ and have the same meaning as in formula (I), in their racemic form or as optical isomers, and also the salts thereof obtained with thera-5 peutically compatible acids or bases. In addition, the compounds preferred are those corresponding to formula (I') in which R^ is a straight or branched (C^ to Cg)-alkyl group, a (C4 to Cg)-cyclo-alkylalkyl group, or a substituted alkyl group -CI^-S-CHR^R^ 10 with R^ = H or an alkyl group and R^ = an alkoxycarbony1 group, the alkyl and alkoxy groups having from 1 to 4 carbon atoms. In addition, R1 may usefully be a methyl radical, The compounds according to the invention, and also the salts thereof, have interesting pharmacological pro-15 perties. In particular, they have an inhibiting effect on certain enzymes, such as the carboxypolypeptidases, the encephalinases or kininase II. They inhibit particularly the transformation of the decapeptide angiotensin I to the octapeptide angiotensin II, which is responsible for 20 certain cases of arterial hypertension, by acting upon the converting enzyme. 1 98535 The therapeutic use of these compounds thus makes it possible to reduce or even eliminate the activity of these enzymes responsible for hypertension or cardiac insufficiency. The effect on kininase II results in an increase in the circulating bradykinin and also a reduction in the arterial pressure by this means. The invention also relates to the pharmaceutical compositions which contain as active ingredient at least one compound of the general formula I or one of its physiologically tolerable addition salts with an inorganic or organic base or acid, in conjunction with "an inert, non-toxic, pharmaceutically acceptable carrier. For therapeutic use, the compounds of the general formula I or the salts thereof are prepared in the form of pharmaceutical preparations suitable for intravenous or oral administration. In addition to the active ingredient, the pharmaceutical compositions according to the invention contain one or more inert, non-toxic carriers suitable for pharmaceutical use, and/or a binding agent, an aromatising agent, a disintegrating agent, a sweetener, a lubricant or a liquid excipient suitable for intravenous administration. The pharmaceutical compositions according to the invention may also contain another active ingredient having a synergistic or complementary effect. Among the latter active ingredients which may be mentioned are a diuretic and, in particular, a saliuretic, - 5 - jj_985^5 such as for example a thiazide, a dihydrothiazide, a chlorosulphamide, a dihydrobenzofuran 2-carboxylic acid or a derivative of phenoxyacetic acid. Examples of such compounds are N-( 3 1 -chloro-41 -sulphamoylbenzamido)-2-methylindoline, ethacrynic acid and furosemide. It is also possible to add a-adrenolytic substances such as prazosin or any other anti-hypertensive substance. The useful posology may vary widely, depending on the age and weight of the patient, the severity of the O symptoms and the method of administration. Oral administration is preferred, but intravenous administration is also perfectly suitable for the treatment of hypertension. In general terms, the unit dose will preferably range between 5 and 100 mg. 5 The invention includes a process for the preparation of the compounds of general formula I, which process comprises subjecting an azabicycloalkane carboxylic acid, or an alkyl ester thereof, of the general formula II: COR' (II) 20 wherein the meaning of the symbols A, n and a remains the same as that mentioned previously, - 6 - 1 98535 R* represents a lower alkyl radical or an aminoalkyl radical in which the amino function is protected by the usual radicals, such as for example benzyloxycarbonyl or tert.-butoxycarbonyl radicals, and R' represents a lower alkoxy or hydroxy radical, to a reductive alkylation reaction by means of a compound of the general formula III : O = C R3 ■COOR, (III) wherein the meaning of the substituents R2 and R^ remains the same as that mentioned previously, in order to obtain an amine of the general formula IV : CO - R' (IV) CH2^n ^CO - CH - (CH2) - NH - CH - R3 COOR. wherein R* and R* have the meaning given previously for formula II and the symbols R2< R^» A, n and c[ retain the meanings provided before, and after reductive alkylation the intermediate compound obtained is subjected, if necessary, to the usual depro-tection processes, such as for example total or partial saponification and/or hydrogenolysis, and if required to [now AMENDED] 7 J 9853 salt formation, and is thus converted into a compound of formula (I) or salt thereof. The compounds of the general formula if are described in or may be synthesised in accordance with the 5 European Patent Application published-under No. 0031741. / The above-mentioned reductive alkylation uses the pro- / / cess described by R.F. BORCH^M^.D. BERNSTEIN, and H. DUPONT DURST, JACS 93, 2897 (1971 ) . The process is preferably carried out^in an alcoholic medium and in the 10 presence of a neutral dehydrating agent and of an organic or inorganic cyanoborohydride. ..... /" y — The Examples-which follow illustrate the invention. 193335 rAS AMENDED - ~> - salt formation, and is thus converted into a compound of formula (I) or salt thereof. The compounds of the general formula II are described in or may be synthesised in accordance with the European Patent Application published under No. 0031741. The above-mentioned reductive alkylation uses the process described by R.F. BORCH, M.D. BERNSTEIN, and H. DUPONT DURST, JACS 93, 2897 (l97l). The process is preferably carried out in an alcoholic medium and in the presence of a neutral dehydrating agent and of an organic or inorganic cyanoborohydride. The Examples- which follow illustrate the invention. Examples 1 and 2 particularly illustrate the process of the invention but do not show the production of compounds of the invention. - 8 - 1 98535 EXAMPLE 1 (3S)-2-[N-(1-carboxyethyl)-(S)-alanyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline. Steo_A 5 Laevorotatory tetrahydroisoquinoline-3-carboxylic acid. 15 g of (S )-(3-phenylalanine are introduced into a three-necked flask surmounted by a condenser and then 34 ml of a 40 % solution of formaldehyde, and 105 ml of concentrated hydrochloric acid are added. lO The vessel is heated for 30 minutes over a boiling water-bath. A clear solution is thus obtained, the reaction medium is allowed to cool to room temperature, and then 15 ml of formaldehyde and 30 ml of concentrated hydrochloric acid are added thereto. The mixture is 15 then heated for 3 hours unqler reflux, and afterwards allowed to cool. The precipitate is then separated off by filtration. After drying without heat, it is taken up in 200 ml of boiling water and 400 ml of hot ethanol. The solutions are combined and neutralised by 20 adding a 10 % ammonia solution. Tetrahydroisoquinoline-3-carboxylic acid crystallises. The crystalline mixture is left to stand overnight in a refrigerator, and then the precipitate is separated off, suction filtered and washed with ethanol. 17.3 g of crude product 25 are thus obtained. The product is dried under vacuum over phosphoric acid. - 9 - >98 535 Calculated Found 5 Inf ra-red_sgectrurn NH2 + Band at 2800 - 2400 cm-1 COO Carbonyl band at 1630 cm-1 Rotatory_power aD = -108° (c = 2.2 normal NaOH) 10 Steg_B_ (3S)-methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride. In succession 5 g of tetrahydroisoquinoline 3-carboxylic acid and 30 ml of methanol are introduced into 15 a three-necked flask. 6 g of thionyl chloride are added to this suspension by pouring carefully, taking care that the temperature does not exceed 0, + 5°. The addition takes approximately 10 minutes. After the addition is completed, stirring is continued for 2 hours at room 20 temperature, and then the mixture is heated to reflux for 1% hours. Once the mixture has dissolved completely, heating is discontinued and the mixture is then evaporated to dryness. The residue is taken up three times in Analysis C^qH NO2 = 177 C% H% Wo 67.78 6.26 7.90 66.87 6.20 7.96 198535 - 10 - methanol and then evaporated to dryness. Finally, 8 g of colourless crystals are obtained and purified by trituration with ether. The crystals are separated off by filtration, suction filtered, washed with ether and dried. 5 6.4 g of methyl tetrahydroisoquinoline-3-carboxylate hydrochloride are thus obtained. Analysis C1C)Hl3N02ClH = 227.69 C H N Cl% Calculated 58.03 6.20 6.15 15.57 10 Found 57.79 6.46 6.38 15.67 Infra-red_spectrum Carbonyl band at 1735 cm-1 NH2+ band at 2800 - 2400 cm"1 Step_C 15 (3S)-2-[(S)-tert.butoxycarbonylalanylJ-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 water and the solution is rendered alkaline to pH 11 with NH^OH, 20 and then extracted with 2 x 50 ml of sulphuric ether. 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 dimethyl-formamide and this solution is added to a stirred solution -11- 1 98535 of 5 g (0.0264 mol) of (S)-tert.-butoxycarbonylalanine in 30 ml of dimethylformamide cooled to O, + 5°C. In succession 3.6 g (0.0264 mol) of 1-hydroxybenztriazole dissolved in 40 ml of dimethylformamide, and then 5.45 g 5 (0.0264 mol) of dicyclohexylcarbodiimide dissolved in 30 ml of chloroform are added to the solution obtained. The reaction mixture is stirred for 18 hours whilst being allowed to return to room temperature. The dicyclo-hexylurea which is formed is filtered and the filtrate, 10 evaporated to dryness under 0.1 mm Hg, leaves a residue which is redissolved in 50 ml of ethyl acetate and filtered again to separate off a second run of dicyclohexyl-urea. The filtrate is washed successively with 80 ml of a saturated aqueous solution of NaCl, 2 x 40 ml of 15 a 10 % aqueous solution of citric acid, again with 80 ml of a saturated aqueous solution of NaCl, 2 x 40 ml of a saturated aqueous solution of NaHCO^# and finally with a saturated aqueous solution of NaCl until neutial. The organic phase is dried over CaSO^, filtered 20 and evaporated to dryness under vacuum. The evaporation residue is the desired product : Weight : 9.1 g (95%) Melting point : 98-100° (Kofler) Analysis C-|9H26N2°5 25 C H N% Calculated 62.97 7.23 7.73 Found 63.15 7.05 7.97 1 98535 StegJD (3S)-2-[(S)-tert,butoxycarbonylalanyl]-3-carboxy-1 ,2,3,4-tetrahydroisoquinoline. 1.45 g of (0.004 mol) of the compound prepared 5 in the previous step are dissolved in 20 ml of methanol, and 4.4 ml (0.004 mol) of normal aqueous sodium hydroxide solution are added to the resulting solution. The solution is left for 20 hours at room temperature. The methanol is evaporated under vacuum by water 10 jet pump and the residue is taken up in 20 ml of water. After extraction of the unsaponified material by means of ethyl acetate, the aqueous phase is acidified with 4.4 ml of normal HC1. The precipitate which forms is extracted with 2 x 20 ml of ethyl acetate which is dried 15 over CaSO^, filtered and evaporated. The residue obtained is the desired product : Weight : 1.3 g (93 %) Analysis C18H24N2°5 C H N% 20 Calculated 62.05 6.94 8.04 Found 61.54 6.93 7.78 Step_E (3S)-2-[(S)-alanyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline. 1.1 g (0.00316 mol) of the derivative prepared in the 25 previous step are stirred at + 5°C with 4.5 ml of trifluoro-acetic acid whilst protected from humidity. 1 98535 The resulting solution is concentrated to dryness under O. 1 mm Hg. The crystalline, hygroscopic evaporation residue is the desired product, in the form of the trifluoroacetate solvated by means of 0.5 mol of tri-5 fluoroacetic acid : Weight : 1.3 g (98 %) AnalYsis C32H35F9N4°12 C% H% N% Calculated 45.83 4.21 6.68 10 Found 45.99 4.62 6.55 0.7 g (0.0019 mol) of the above trifluoroacetate are transformed into 0.45 g (94 %) of the corresponding free amino acid by being passed over 50 g of sulphonated resin (Dowex 50 W x 8 H+), followed by washing out with 15 500 ml of normal ammonia solution. Melting point : 17C°C (decomposition). Steg_F_ (3S)-2-[(S)-N—(1-carboxyethyl)-alanyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline. 20 0.849 g (0.0034 mol) of 2-[(£5)-alanyl]-3-carboxy- 1,2,3,4-tetrahydroisoquinoline are dissolved in the presence of 1.9 g (0.0216 mol) of pyruvic acid at 25°C in 22 rnl of normal sodium hydroxide solution and 50 ml of pH 7 buffer taken from a solution prepared from 50 ml of 25 o.1 molar solution of monosodium phosphate and 29.1 ml of N/10 sodium hydroxide solution. 0.45 g (0.0072 mol) - 14 - 198535 of sodium cyanoborohydride are added all at once. The reaction mixture is left at room temperature for 22 hours. The excess sodium cyanoborohydride is decomposed by the addition of 6 ml of concentrated hydrochloric acid. 5 The resulting solution is passed over an ion exchange resin (Dowex 50 H+). After washing out the resin with distilled water until there are no chlorine ions present, the product fixed on the resin is removed by washing out with 1 litre of normal aqueous ammonia solution. The 10 ammoniacal solution is concentrated to dryness under vacuum by water jet pump. The evaporation residue is the monoammonium salt of the desired product. Weight obtained : 0.8 g (69.7%). Analysis C-]6H23N3°5 15 C% H% N% Calculated 56.96 6.64 12.95 Found 57.79 6.69 12.70 EXAMPLE 2 (3S)-2-[(2RS) — 3—(1-carboxyethylamino)-2-methylpropanoyl]-20 3-carboxy-1,2,3,4-tetrahydroisoquinoline. Prepared as in Example 1 (Step C), starting from (2RS)-3-tert.butoxycarbonylamino-2-methylpropanoic acid and (3£[)-3-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline. The ( 3S> )-2-[ ( 2RS )-3-tert .butoxycarbonylamino-2-meihylpro-25 panoyl]-3-methoxycarboxyl-1,2,3,4-tetrahydroisoquinoline obtained is saponified with aqueous sodium hydroxide 1 98535 - 15 - solution, using the method described in Example 1 (Step D). The ( 3:S )-2-[ ( 2RS )-3-tert.butoxycarbonylamino-2-methylpropanoyl ]-3-carboxy-1 ,2,3,4-tetrahydroisoquinoline 5 obtained is treated with trifluoroacetic acid according to the method in Example 1 (Step E), providing (3S)-2-[(2RS)-3-amino-2-methylpropanoyl]-3-carboxy-l ,2,3 ,4*-tetra-hydroisoquinoline trifluoroacetate, which is transformed into the hydrochloride by being dissolved in an excess 10 of normal HC1 and concentrated to dryness. Analysis C^H^Cl ^O^ C H N Cl% Calculated 56.28 6.41 9.38 11 .87 Found 56.44 6.59 9.04 1 1 .94 15 56.94 6.62 8.97 11 .87 1.3 g (0.005 mol) of (3S )-2-[(2RS)-2-methyl-3-aminopro— panoyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline obtained in the previous step are dissolved in 20 ml of methanol containing 0.009 mol of HCl and 0.515 g of 94 % (0.0055 mol) 20 pyruvic acid. The solution is hydrogenated under a pressure of 0.5 bar in the presence of 1 g of 10 % palladinised charcoal. Approximately half of the theoretical amount of hydrogen is absorbed within 1 hour. The suspension is filtered, and 0.515 g of pyruvic acid are added to the 25 filtrate. It is then neutralised with triethylamine to pH 7-7.2. After the addition of 1 g of 10 % palladinised charcoal, the suspension is hydrogenated again under a 1 98535 pressure of 0.5 bar, until the starting primary amine has disappeared : this is checked by TLC revealing said amine by means of ninhydrin. The reaction mixture is filtered and the concentrated filtrate is dissolved in 25 ml of water and passed over 125 ml of ion exchange resin (Dowex 50 H+). The product fixed on the resin is washed out with 500 ml of normal aqueous ammonia solution, then 260 ml of distilled water. The combined washings are evaporated to dryness. The evaporation residue is the desired product in the form of the monoammonium salt. Weight obtained : O.6 g Analysis C'i7H25N3°5 C% H% N% Calculated 58.11 7.17 11.43 Found 58.91 6.93 11.96 EXAMPLE 3 1- £(S )-N-[(lRS)-1-carboxyethyl]-alanylJ-2-carboxyperhydro-indole. Steg_A (2RS)-2-carboxyindoline. 31.5 g of the above indoline (86 %) are obtained by saponification in 250 ml of normal sodium hydroxide solution and 150 ml of ethanol for "6 hours at room temperature of 43 g (0.224 mol) of the corresponding ethyl 198 535 - 17- ester prepared according to E.J. COREY et al. (J. Amer. Chem. Soc. 1970 92_, p. 2476). The aqueous alcoholic solution is concentrated to neutralised with 25 ml of 10N hydrochloric acid, 5 and the precipitate formed is filtered, washed with water, and dried. The crude acid is purified by being passed through an ion exchange resin column (Dowex 50 W x 8 H+) and washed out with 2N aqueous ammonia solution. The ammonium 10 salt obtained is dissolved in the minimum quantity of water and the acid precipitated by the theoretical amount of HC1. It is suction filtered, washed with water, and air-dried. Analysis (of ammonium salt) 021^2^02 C% Wo N/o 15 Calculated 59.99 6.71 15.54 Found 60.22 6.71 15.06 59.93 6.71 15.29 Steg_B (2S)-2-carboxyindoline. 20 60.5 g (0.37 mol) of (DL)-2-carboxyindoline pre pared 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 obtained is sucticn filtered and digested in 350 ml of anhydrous isopropanol under reflux. After cooling, 25 the suspension is filtered, and the precipitate is washed with a little isopropanol and dried. t 98535 - 18 - Weight of (L)-2-carboxyindoline, (+)-a-methyl-benzylamine salt obtained 29.8 g. = 5.3° (C = 1 % ethanol). The (2S)-2-carboxyindoline is prepared in a theo-5 retical yield by dissolving lO g of the above-mentioned salt (0.029 mol) in 50 ml of water and acidifying it with 29 ml of normal hydrochloric acid. The precipitate is suction filtered, washed with water, distilled, and dried. Optical purity : 96 % (VPC after 10 converting into the form of (-)-camphanic acid amide. The (2R)-2-carboxyindoline was obtained by the same process, starting from (RS)-carboxyindoline and (-)-a-methylbenzyl amine. The absolute configurations of the (S^) and (R) 15 acids were determined as follows: Analytical amounts (approx. 0.5 g) of each of the acids are converted into ethyl esters by treatment with thionyl chloride and ethanol according to the process described in Step C. 20 The esters are reduced by lithium aluminium hydride according to E. J. COREY (loc.cit.) to the corresponding primary alcohols, which are identified by their rotatory power with the alcohols described by E. J. COREY, the respective absolute configurations of which are known. 1 98535 - 19 - Steg_C_ (2S)-2-ethoxycarbonylperhydroindole. 11 g of (L)-2-carboxyindoline, (4 )-a-methylbenzyl-amine salt (0.032 mol) prepared in Step B are dissolved 5 in lOO ml of water and converted into the corresponding acid by the addition of 32 ml of N HCl. The acid is suction filtered, washed with water and dried in a desiccator over phosphoric anhydride, then suspended in 50 ml of anhydrous ethanol. At a temperature of O, + 5°, 3.9 ml of thionyl 10 chloride are added within lO minutes whilst stirring, and stirring is continued for 1 hour at 25°C, then 1 hour at 50°C. The mixture is left overnight at 25°, then concentrated to dryness under vacuum by water jet pump at 15 40° and taken up with 50 ml of anhydrous benzene and suction filtered. The (2S)-2-ethoxycarbonylindoline hydrochloride obtained is hydrogenated in solution in 150 ml of water in the presence of 2 g of palladinised charcoal for 8 20 hours at 45°C under 50 kg/cm^ pressure. After cooling and filtration of the catalyst, the filtrate is evaporated to dryness. The residue is the desired product in the form of the hydrochloride. Weight : 6.9 g (93%) 25 Analysis c^I^qci N02 C% H% N% Cl% Calculated 56.52 8.62 5.99 15.17 Found 55.52 8.53 5.96 15.16 - 20 - 1 98535 Steg_D (2 S) -N- [ (S)-t-Boc.-alanyl]-2-ethoxycarbonylperhydroindole. A solution comprising 3 g (0.0128 mol) of (2S)-2—ethoxycarbonylperhydroindole hydrochloride prepared 5 in the previous step (C), 15 ml of dried dimethylformamide (DMF) and 1.8 ml of triethylamine is added to a solution, cooled to + 5°C and stirred, of 2.42 g (0.0128 mol) of L-t-Boc.-alanine in 15 ml of DMF. To the resulting mixture there are then added in succession a solution of 1.7 g 10 (0.0128 mol) of N-hydroxybenz-triazole in 20 ml of DMF/ then a solution of 2.64 g (0.0128 mol) of dicyclohexyl-carbodiimide in 15 ml of dry chloroform. After 65 hours' stirring at 25°, the dicyclohexyl-urea formed is filtered and washed with ethyl acetate. 15 The combined filtrates are washed successively with 80 ml of a saturated aqueous solution of NaCl, 2 x 40 ml of concentrated citric acid solution, 2 x 40 ml of a saturated aqueous solution of NaHCO^, then again with 2 x 40 ml of NaCl solution. 20 The organic solution is dried over CaSO^, filtered, concentrated to dryness under vacuum by water jet pump, and the residue is taken up in TOO ml of ethyl acetate. The solution is filtered to eliminate the last traces of dicyclohexylurea, and the filtrate which is concentrated 25 to dryness leaves a residue which is the desired product in the form cf a very viscous oil. Weight : 3.8 g (81 %) - 21 - 1 98 5 3 Analysis C19H3 2N2°5 C% H% N% Calculated 61.93 8.75 7.60 Found 61.76 8.56 7.77 5 Step_E (2S)-N-[(S)-t-Boc-alanyl]-2-carboxyperhydroindole. 3.6 g (0.0098 mol) of ester obtained in Step D are dissolved in 30 ml of methanol in the presence of 11 ml of normal aqueous sodium hydroxide solution. 10 After 20 hours at 25°, the methanol is evaporated under vacuum by water jet pump and 60 ml of water are added. The solution is washed with 2 x 50 ml of ethyl acetate to eliminate the unsaponified material, then acidified with 11 ml of N hydrochloric acid. The white 15 precipitate formed is extracted with 2 x 50 ml of ethyl acetate, which are combined and washed with water, dried over CaSO^, filtered and concentrated to dryness. The residue is the desired product : Weight : 1.9 g (57 %) 20 Analysis C-|7H28N2°5 C% Wo N% Calculated 59.98 8.29 8.23 Found 59.10 8.16 7.81 198 535 - 22 - Step_F (2S)-1-[(S )-alanyl]-2-carboxyperhydroindole.. 1.6 g (0.0047 mol) of acid prepared in the previous step (E) are stirred at a temperature of 0, + 5°C in 5 solution in 10 ml of trifluoroacetic acid for 1 hour, and then for another 15 minutes at room temperature. After being evaporated to dryness under vacuum by vane pump, the residue dissolved in 15 ml of water is passed over an ion exchange resin column (Dowex 10 W + 8H+). The column is washed out with 1 litre of 2 N aqueous ammonia solution. The washings are concentrated to dryness under vacuum. The residue obtained is the desired product. Weight : 0.90 g (95 %) 15 Analysis Ci2H20N2°3 C% N% Calculated 59.98 8.39 11.10 Found 58.53 8.24 11.43 Step G 20 ( 2S^)-1 - £( S )-N-[ (1RS )-1 -carboxyethyl ]-alanyl^ -2-carboxy-perhydroindole . O.7 g (0.00291 mol) of (2S)-N-[(S)-alanyl]-2-carboxyperhydroindole prepared in the previous step (F) and 1.67 g (0.0183 mol) of pyruvic acid are dissolved in 25 18 ml of normal aqueous sodium hydroxide solution and 40 ml - 23 - 198 535 of pH 7 buffer, and the solution obtained is subjected to reduction with 0.400 g (0.0064 mol) of sodium cyanoborohydride as described in Example 1, Step F. After treatment with concentrated hydrochloric 5 acid and being passed over an ion exchange resin (Dowex 50 H+), the final ammoniacal washings, when evaporated to dryness, leave 0.76 g (79 %) of residue which is the desired product in the form of monoamraonium salt. Analysis Ci5H27N3^5 10 C% H% N% Calculated 54.70 8.26 12.76 Found 54.10 7.78 12.77 EXAMPLE 4 (2S)-1-£n-[2-((1RS)-1-ethoxycarbonylethylthio)-(IRS)-1-15 ethoxycarbonylethyl]-(S)-alanylJ-2-carboxyperhydroindole. 1 g (4.17 m mols) of (2S)-1-[(S)-alanyl]-2-carboxy-perhydroindole, prepared as described in Example 3, Step F, and 4.72 g (19 m mols) of ethyl [(1RS)-1-ethoxycarbonylethylthio ] -pyruvate are dissolved in 50 ml of 20 anhydrous ethanol in the presence of 15 g of molecular sieve 4 S. After 45 minutes' stirring at room temperature, 0.25 g of sodium cyanoborohydride in solution in 2.25 ml of anhydrous ethanol are added within 6 hours. After the molecular sieve has been separated off 25 by filtration, the filtrate is concentrated to dryness under reduced pressure and the residue is dissolved in 1 98535 - 24 - lOO ml of sulphuric ether. The solution is extracted with 2 x 100 ml of distilled water, then dried over calcium sulphate, filtered and chromatographed over 200 g of silica (Merck F 254), washing out with a 180/20 methylene 5 chloride/methanol mixture. 0.5 g (25 %) of the desired product are obtained in the form of the sodium salt. Analysis C22H35N2Na °7S C% H% N% S% Calculated 53. 43 7.13 5.66 6.48 lO Found 53. 28 7.09 5.19 5.92 The intermediate ethyl [(1RS)-1-ethoxycarbonylethyl-thio]-pyruvate is prepared by condensing ethyl bromo-pyruvate with (RS)-ethyl thiolactate in the presence of pyridine according to the process described for related 15 derivatives in the J. of Heter. Chem. (1973) 10/4 p. 679-681 ). b.p.^ = 165-170 Yield 67% EXAMPLE 5 20 ( 2£5) -1 - [ N- ( 2-ethoxycarbonylmethylthio-(l RS ) -1 -ethoxycar-bonylethyl)-()-alanyl]-2-carboxyperhydroindole. Prepared as in Example 4, starting from 1 g (4.17 m mols ) of (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole, 4.45 g (1.9 mols) of ethyl ethoxycarbonylmethylthiopyruvate 25 and 0.25 g of sodium cyanoborohydride. - 25 - 1 98535 After purification by chromatography, 0.26 g (14 %) of the desired product are obtained. Analysis 02^2^20^5 C% N% S% Calculated 55. OO 7.47 6.11 6.99 Found 54. 71 7.32 5.94 7.01 The intermediate ethyl ethoxycarbonylmethylthio-pyruvate is prepared by condensing ethyl bromopyruvate with ethyl thioglycolate according to the process described by the reference quoted in Example 4. *>.p.l5 = 165 - 175 Yield 50%. example 6 (2S)-1-£n-[3-(n-benzyloxycarbonyl-n-dicyclopropylmethyl-amino)-(IRS)-1-ethoxycarbonylpropyl]-(S^)-alanyl3-2-carboxyperhydroindole. Prepared as in Example 4, starting from 0.6 g of (2£)-1-[(S)-alanyl]-2-carboxyperhydroindole, 4.3 g of ethyl 4-[N-(benzyloxycarbonyl)-dicyclopropylamino]-2-oxobutyrate and 0.15 g of sodium cyanoborohydride. After purification by chromatography, 1 g (67 %) of the desired product is obtained. Analysis C% N% Calculated 66. 31 7.93 7 .03 Found 66. 11 7.83 7.22 198535 i i «» - 26 - The intermediate ethyl 4-fN- (benzyloxycarbonyl )-dicyclopropylamino]-2-oxobutyrate is prepared in 6 stages in the following manner : Stage 1 : condensation of bromoacetaldehyde diethylacetal 5 with ethyl 2-dithianylcarboxylate according to E.D. ELIEL, J. Org. Chem. (1972) vol. 3_7 3. p. 505-506. Yield : 57 % b.p. Q? = 130-135°C. Stage 2: the 2-( 2 , 2-diethoxy-1-ethyl )-2-ethoxycarbonyl-1 ,3—dithiane obtained is converted into a semicarbazone of 10 2-( 2-oxo-1-ethyl )-2-ethoxycarbonyl-l , 3-dithiane by stirring with a solution of seruicarbazide hydrochloride in water at room temperature for 24 hours. The semicarbazone, obtained in a yield of 88 %, has a melting point (Kofler) of 183°G. 15 Stage 3: the above semicarbazone is converted into the corresponding aldehyde by stirring with pyruvic acid in an aqueous acetic acid solution according to R.E. BEYLER et al.(j. Am. . Chem. Soc. (i960) 82_ p. 175). b.p.Q g = 140 - 145°C. 20 Yield : 50 %. Stage 4: the above-mentioned aldehyde is condensed with dicyclopropylmethylamine and the imine obtained is subjected to reduction according to the process described by J. W. LOWN and S. ITOH (Can. J. Chem. (1975) 53_ p. 960), i- providing 2-[ 2-(dicyclopropylmethylamino)-ethyl~j-2- c<0y' ethoxycarbonyl-1 ,3-dithiane in a yield of 65 %. Its o hydrochloride melts at 150 (K). 198535 j^QW AMENDED? 27 Stage 5: the derivative obtained in the prev^6us stage is subjected to the action of benzyl chloroformate according to the process described in "C^^mistry of the amino acids" vol. 2 p. 895 by GREENSTEIN and WINITZ C / (Wiley Editor). 2-<2-[N-(benzyloxycarbonyl)-dicyclo- propylmethylamino]-1-ethy 1^ -2-ethoxycarbonyl-1,3-dithiane is a viscous oil, obtained in/a yield of 93 %. / Stage 6: By the action/of N-bromosuccmimide in an / aqueous acetone ^solution, the derivative obtained / in the previous step is converted into ethyl 4—[N-(benzyl- / oxycarbonyl)-dicyclopropylamino]-2-oxobutyrate in a / / yield of 70 %, according to the process described by / y / E. J. COREY (J. Org. Chem. (l97l) 36, 3553-60). /■ / The compounds prepared in the preceding Examples, / ancKalso other compounds of formula (I) prepared in a / similar manner, have been collated in the Table which follows. For the sake of convenience, the symbols A and n are only mentioned for the values where A = a benzene ring and n = 1. For all the other compounds A means a saturated ring and n = 0 (perhydroindole of formula 11). The Table gives the characteristic values of the compounds with regard to infra-red (IR) and nuclear magnetic resonance (NMR) : s_ is for singlet, d is for doublet, c is for quadruplet, m is for multiplet. 193535 fAS AMENDED - 27 - Stage 5: the derivative obtained in the previous stage is subjected to the action of benzyl chloroformate according to the process described in "Chemistry of the amino acids" vol. 2 p. 895 by GREENSTEIN and V7INITZ 5 (Wiley Editor). 2-^2-[N-(benzyloxycarbonyl)-dicyclo- propylmethylamino]-1 -ethyl^ -2-ethoxycarbonyl-1 , 3-dithiane is a viscous oil, obtained in a yield of 93 %. Stage 6: By the action of N-bromosuccinimide in an aqueous acetone solution, the derivative obtained 10 in the previous step is converted into ethyl 4—[N-(benzyl-oxycarbonyl )-dicyclopropylamino]-2-oxobutyrate in a yield of 70 %, according to the process described by E. J. COREY (J. Org. Chem. (1971) 36, 3553-60). The compounds prepared in the preceding Examples, 15 and also other compounds of formula (I) prepared in a similar manner, have been collated in the Table which follows. For the sake of convenience, the symbols A and n are only mentioned for the values where A = a benzene ring and n = 1 . For all the other compounds A means a 20 saturated ring and n = 0 (perhydroindole of formula I* ). The Table gives the characteristic values of the compounds with regard to infra-red (IR) and nuclear magnetic resonance (NMR) : s_ is for singlet, d is for doublet, 2 is for quadruplet, <? m is for multiplet. Compounds 1 and 2 are not compounds of the present invention. Compound No. q R1 R2 P3 FORM (salt) 1 (EX. ]) (A™ benzene 0 CH 3 I! C" 3 amnioniitm salt n = 1) 2 (Ex. 2) (A * benzene? J CH3 H . C,,3 ammonium sn.lt n = 1) 3 (Ex. 3) O CH3 H ai3 ammonium salt 4 0 cm 3 C 21' 5 -cm^cii ( y / A acid mnlcate 5 0 CH3 C2H5 -ch2-s-ch (—<j) 6 0 CH3 C2H5 -CH2-CH2-CH(—(j)x acid malcate 7 0 CH3 C2H5 ch3 acid inn I onto 8 0 ch3 . C2»5 -CM2-S-CH(-Q);l sodium salt 9 (Ex.6) O ch3 C2H5 -CH2-CH2-N-CH (—<(j ^ COOCH_-CrHr (RS) 2 6 5 10 (Ex. 4) O tH3 C2n5 -CH.-S-CH-C00CoHr 2 | 2 5 6i3 (S) sodium salt i 1 0 CH3 C2M5 -ch--s-ch-cooc-, mr 2 | 2 5 ai3 acid malrate 1.2 o CH ^ <~'2^5 -CH2-CU (Cl\3) ? ."odium sail 13 0 J CH, c* C7'Ir, -ch7-ch7-nh-chC—^ acrtato t / o __1A Compound No. 14 (Ex.5) 15 16 17 18 19 20 21 2 2 23 24 25 26 (n « 1) 27 *2 ch3 c2h5 ch3 h ch3 c2h5 ch3 c2h5 ch3 c2h5 c»3 c2h5 CH 3 c2m5 C"3 c2h5 cii 3 c2n5 c»3 c2w5 ch3 c2h5 ch3 c2h5 ch3 c2h5 - (oy -nh2 c2h5 TABLE. (cont'd 1) . n 3 -ch2-s-ch2-cooc;?h5 -ch2ch2-nh-ch(-^J) 'Z n-c4H9 n-C3H? -ch2-(] i-c3n7 2 5 cooc0hr I 2 5 -c11-ch,-n-ch-ch, 2 2 I <S) J coch3 n_C5H11 n_C6H13 -cii2-cii2-n -cii coch3 n-C8Hl7 1 "c4h9 n-C3H7 form: (sait) sodium salt CII3COON3 sodium salt sodium snlt nodnitn salt sodium salt sodium salt nor!ium salt. sodium salt tri fluoroaceta te bis-trifluoroacotatc sC D> Cn G4 Cn a l¥. & tS o c • TABLE (cont.'f! 2) * — 1 Comp. I. n. ( Vr in cm ) NMR in CDC13 : chcmical shifts (ppm)/TMS 1 Nil : 3500-2300 C=0 : 1600 m. : 4H(7.4) 3H (5. 3-4 .1) d, : 211 (5.3) 611 (1. 8) s. : 211 (4.0) 2 Peaks : 511(3.5-3) 411(3.3) q^. : 311(1.2) 3H (4 .7) 111 (4-3. 5) d. : 311 (1.45) 3 NH : 3500-2500 C=0 : 1600 m. : 311(4.0-4) Peaks • 1011 (2.5-1. 3) 4 • Peaks : 611(4,6-3 7) 1911(2. 5-1) 211(2.5-3) s. : 511(7.3) 211(6.35) 5 Peak* : J.7H(1. 6-0. 0) 1011(0. 7-0 .1) 611(4.5-3. 311(3.2-1. 5) 211(5.7 9) -5.2) 6 Peaks : 2 111 (2. 7-1) llll({U8-0 .1) 611(4.6-3. 411(11.2) 7) s. : 2 H(6. 4) 7 Pcalts : 20H(2 „7-l .1) 611(4 .7-3 .9) 411(10,3) s. : 211(6.4) 0 NH3700-3200 CD ester 1730 Prnks s 011(4.7-3.2) d. : 211 (2.9) CO amide 1650- 3911(2.5-1) 1600 9 Hl35(j0—2300 CX) ester 1730- ..1690 COamide 1650- Prnks :39M(4 ,6-0.15) s. : 2M(5 .1) 511(7 .3) 1600 4H exchangeable (11.1) 10 Ml3300 CO ester 1725 Peaks : 11)1 (4 .5-2.6) s. : 211(6.5) CO amide 1620 V Peaks 2311(2.5-1) 11 : 911(4.7-3.2) 25M(2.5-1) 12 4H3600-2300 COester 1725 Ponies j : 611(3-4.5) d. : 6 H (1) COciniide 1630 \ ' \ Peaks V 2011(1. 2-2 .5) 13 NH * 3600-2300 COester 1730 COnmide 1650- ! 611 (4. 5-3. 3) q- ; 211 exchangeable (0.7-7.-7M 3511 (0 .3-2.5) .1550 TABLE (cont'd 1) Comp I. R. ( v in cm ) s NMR in CDC1. chcmical shifts (ppm)/TMS 14 15 16 17 10 19 20 21 22 23 2 4 25 26 27 NM3700-2500 C-0 ester 1720 C=0 amide 1625 NI13500-3000 C=0 1600-1550 NH3600-3100 C=0 ester 1725 C=0 amide 1620 hill 3300 NH 3300 Nil 3300 C=0 ester 172.5 C=0 amide 1620 C=0 ester 1725 C=0 amide 1610 C=0 ester 1725 C=0 amide NH 3600-2500 C=0 ester 1730 C=0 amide 1610 NH 3300 C=0 ester 1735 C=0 amide 1650-1600 NH 3300 C=0 ester 1725 C=0 amide 1610 NH* 3600-2100 C=0 ester 1730 C=0 amide 1650-l55f NH 3700 NH NH Nil C=0 ester 1730 C=0 amide 1600 V 3500-2300 C=0 ester 1740 C=0 amide 1650 3340-3200-3400 CO ester t72(j 00amide 1650* 3300-7.300 C=0 acide 1700 C=0 ester 1740 C=0 amide 1650 Panics : Peaks s Peaks : Peaks : Peaks : Peaks : Peaks : Peaks i Peaks : Peaks : Peaks : Peaks : Peaks : Peaks : 1811(2-1) • 211(2.5-2) g. 411(4.5-3.2) d. 1911 (2. 5-0. 9) 811(0,9-0, 1) 611(3-4,5) 2411(2.4-0 .7) 611(4.6-3 .4) 2511(2-5-0) 611(4.5-3) 511 (4 .5-3) 111 (2.9) 611(3-4,6) 2311(0.6-2-5) 1111(4-6-2,9) 2611(2.4-1) 711(3-5) 2011 (0.5-2. 6) 611(3-4.7) 3011 (0.0-2.6) 3211(2.6-0) 1011 (5-2.0) 611(3. 5-4 .6) 3411 (0. 6-2 .7) 2711 (2- 2-0 .7) 711(4.0-3) 2911 <2. 5-0 .7) 411(2 .5-3 .5) 711 (4 .5-2 ,5) 2711(0 .1 411(4.25) s. : 2H (3.4) 211(3) 211 oxchannenbl e : s. : 311(1.9) NMR in -2.5) n2o s. 2H(6.0) 25H (0 .7-2.5) s. : 3 H(2.1) 211 cxchnnnenble (5*9) 311 nxchangnable 211 exchangeable (5.0) 411 (4.5-3.5) NMR in n2° (0-9) » o CO ( n i U 1 98535 - 32 - Pharmacological study of the compounds of the invention. The compounds according to the invention were tested by i.v. or p.o. administration to dogs during consciousness . The blood pressure of the dogs was measured by means of a pressure detector (Statham P 23 Db) after catheterisa-tion of the aorta through the femoral artery. The findings were recorded by means of a recording apparatus (Brush 400). Angiotensin I and angiotensin II were injected into the animals intravenously at a dosage of 0.3 Y/kg. The compounds according to the invention were then administered orally or intravenously at a dosage of from 1 to 5 mg/kg. It was observed that there was inhibition of the hypertensive effect of angiotensin• I ranging from 50 to TOO % which occurred 30 to 90 minutes after administration and which remained at from 40 to 80 % more than 6 hours after administration. Certain compounds remained active after 24 hours, which is not the case with any compound known hitherto (particularly captopril, which is the only commercially available compound). In addition, the compounds of the invention seem to have no toxic effect (LDq 500 mg/kg i.p. in mice). </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 198535 - 33 - EXAMPLE OF FORMULATION ( 2S )-1 - tN~[ 2-(i 1S)-1-ethoxycarbonylethylthio)-( 1RS )-1 -ethoxycarbonylethyl]-(S)-alanyl3 -2-carboxyperhydroindole (maleate) 10 mg 5 wheat starch . 120 mg cornstarch 115 mg casein treated with formaldehyde 20 mg magnesium stearate 15 mg talc 20 mg 10 for 1 tablet. 1 98 53 now amended - 34 - Vv'ilAT^.^ OLMM io: g-=±i J=»=S

1. a compound having the general formula/: cooh co - ch - (ch0) / < °I (I) /r 1 - nh - ch - r. coor. 10 wherein the ring A is saturated and n = O or 1, or the ring A is a benzene ring and n = 1, R^ represents a lower alkyl group having from 1 to 4 carbon atoms which can carry an amino group, R2 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R^ represents a straight or branched alkyl, a mono- or di-cycloalkylalkyl or a phenylalkyl group each having no more than a total of 9 carbon^atoms, or a substi- 15 / tuted alkyl group of the formula : / - (CH2)o " Y " R5 A y r. / with r^ = h, a l^,wer alkyl (C1 to C^) or a cycloalkyl (C^ to / C6) group, r' R^ a lower alkyl (C1 to C^), a cycloalkyl (C^ to C^) or an alkoxycarbonyl group, rAS AMENDED - 34 - 198535 WiiAI>tfV72 CLAIM io_; Q-fr-a T

1. A compound having the general formula : R1 COOR2 wherein the ring A is saturated and n = 0 or 1, R^ represents a lower alkyl group having from 1 to 4 carbon atoms which can carry an amino group, R2 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, 0 R^ represents a straight or branched alkyl , a mono- or di-cycloalkylalkyl each having no more than a total of 9 carbon atoms, or a substituted alkyl group of the formula : - (CH.) - Y - CH - Rc I 5 R4 5 with R4 — H, a lower alkyl (C^ to C^) or a cycloalkyl (C^ to Cg) group, R^ = H, a lower alkyl (C1 to ), a cycloalkyl (C^ to 0^) or an alkoxycarbonyl group, 198535 - 35 - Y = S or ) N - Q where Q =* H, or an acetyl or benzyl- oxycarbonyl group, and p = 1 or 2, and q = 0 or 1 in racemic form or as an optical isomer.

2. A compound having the formula : (I1) ch - r, I COOR2 wherein the symbols , R2 and R^ have the same meaning as in formula (I) of claim 1, in racemic form or as optical isomer.

3. A compound according to claim 2, corresponding to the formula (I1) in which is a straight or branched (C^ to Cg) - alkyl group, a (C^ to Cg) - cycloalkylalkyl group, or a substituted alkyl group of the formula : - ch2 - s - chr4r5 with R^ = H or an alkyl group and R^ = an alkoxy-carbonyl group, the alkyl and alkoxy groups having from 1 to 4 carbon atoms.

4. A compound according to claim 2 or claim 3, corresponding to the formula (I') in which R^ is a methyl radical. J 98535 - 36 -

5. A salt of a compound according to any one of claims 1 to 4 with an inorganic or organic base or an addition salt of a compound according to any one of claims 1 to 4 with an inorganic or organic acid.

6. A salt according to claim 5 which is physiologically tolerable.

7. (2^)-1-£n-[2-((lRS)-1-ethoxycarbonylethylthio)- ( 1RS) — 1 —ethoxycarbonylethyl"}- (^)-alanyl^ -2-carboxyperhydroindole, or one of its (_S) isomers, or maleate of the compound or of one of its (S) isomers.

8. ( 2^)-1-£n-[ ( lRS)-1-ethoxycarbonyl-3-methylbutyl"|-(£)-alanyl|-2-carboxyperhydroindole, its (S) isomer or the sodium salt of the compound or its (S) isomer.

9. (2S)-1-^N-[(lRS)-1-ethoxycarbonylpentyll-(S)-alanylj -2-carboxyperhydroindole, its (S) isomer or the sodium salt of the compound or its (S^) isomer.

10. ( 2£3)-1-)N-[ ( lRS)-1-ethoxycarbonylbutyl"l-(Sj-alanylj-2-carboxyperhydroindole, its (S) isomer or the sodium salt of the compound or its (£) isomer.

11. (2S)-1-^N-[(lRS)-1-ethoxycarbonyl-2-cyclopropylethyl]-(S)-alanylj-2-carboxyperhydroindole, its (^) isomer or the sodium salt of the compound or its (_S) isomer.

12. A compound or salt according to claim 1 or claim 6, which is specified in the Table and/or in any one of the Examples herein.

13. A process for the preparation of the compounds or salts according to claim 1 or claim 5, which process is *f ' •' . *1 r-» i_ jy O 3 - 37 - characterized by subjecting an azabicycloalkane carboxylic acid, or an alkyl ester thereof, of the general formula II: OR' (II) CH2)n C° ~ CH " (CK2}q ' m: . R' wherein the meaning of the symbols A, n and g is the same as in claim 1 , R'.j represents a lower alkyl radical or an amino-alkyl radical in which the amino function is 10 protected by the usual radicals, and R* represents a lower alkoxy or hydroxy radical, to a reductive alkylation reaction by means of a compound of the general formula III : 15 (III) COOR- wherein the meaning of the symbols R£ and R^ is the same as in claim 1 , in order to obtain an amine of the general formula IV : tj ^ 1 98535 - 38 - wherein R' and R'^ have the meaning given previously for formula II and the symbols R^, A» H an<3 g retain the meanings given above, and, after reductive alkylation, the intermediate compound obtained is, if necessary, subjected to the usual de-protection process(es) and/or, if desired, a compound of the formula (I) is converted into a salt with a base or into an acid addition salt.

14. A process according to claim 13, wherein R'^ represents a lower alkyl radical or an aminoalkyl radical which is protected by a benzyloxycarbonyl or tert.-butoxycar-bonyl radical and after the reductive alkylation the intermediate compound obtained is if necessary subjected to total or partial saponification and/or hydrogenolysis .

15. A process according to claim 13, carried out substantially as described in any one of the Examples herein.

16. A compound according to claim 1, whenever prepared by a process according to any one of claims 13 to 15.

17. A salt of a compound according to claim 1, whenever prepared by a process according to any one of claims 13 to 15. - 39 - 198 535

18. A physiologically tolerable salt of a compound according to claim 1, whenever prepared by a process according to any one of claims 13 to 15.

19. A pharmaceutical composition containing as active ingredient at least one compound according to any one of claims 1 to 4, 6 to 12, 16 and 18, in admixture or conjunction with an inert, non-toxic therapeutically compatible carrier or excipient.

20. A pharmaceutical composition according to claim 19, which is in dosage unit form.

21. A pharmaceutical composition according to claim 20, which contains from 5 to 100 mg of active ingredient per dosage unit. *-t Q'*, ' , ^ /2«d£>t£rpt. e vtA tctu-e By Authorised Agents, A. J. PAf.X & SCN </div>