GB2086390A

GB2086390A - 1-Carboxy-azaalkanoylindoline- 2-carboxylic acids, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application

Info

Publication number: GB2086390A
Application number: GB8132559A
Authority: GB
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1980-11-03
Filing date: 1981-10-29
Publication date: 1982-05-12
Also published as: HU185324B; ES516555A0; FI813422L; ES516556A0; ES8401026A1; PT73916A; EP0051301A1; NO813694L; DD201888A5; ES8303329A1; ES506784A0; AU7702281A; GR74689B; CA1172258A; IL64185A0; DK483681A; GB2086390B; ES8401025A1; PT73916B

Description

SPECIFICATION 1-Carboxy-azaalkanoylindoline-3-carboxylic acids, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application 1-Alkanoylindoline-2-carboxylic acids and their 5,6-dihyroxy-derivatives, i.e., N-acylated Cyclodopa-derivatives, are described in Nippon Kagaku Zassi 87, 760 (1966) and US-Patent 3,796,723 or Helv. Chim. Acta 53. 1701 (1970) respectively, e.g., as synthetical examples of 0- and/or Nacylations. Also 1-(carboxyazaalkanoyl or azaaralkanoyl)- (azetidine, pyrrolidine or piperidine)-2carboxylic acids and their functional derivatives are known, e.g., according to European Patent 0012401, as possessing antihypertensive activity. Surprisingly it was found that either by introduction of both a carboxy and aza moiety into the former indolines, or by extension of the latter pyrrolidines to the indoline ring-system, superior antihypertensive agents are obtained. The present invention concerns therefore the new 1-(carboxy-azaalkanoyl or azaaralkanoyl)indoline-2-carboxylic acids of the general Formula I

wherein Ph is unsubstituted 1,2-phenylene, or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogeno and trifluoromethyl; R1 is hydrogen, lower alkyl or amino-lower alkyl; R2 is lower alkyl or HPh-lower alkyl; and each of R3, R4 and R5 is hydrogen or lower alkyl; the amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy)-lower alkyl esters, or : salts, especially pharmaceutically acceptable salts thereof; process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application. The 1,2-phenylene group Ph and/or the phenyl group HPh, are preferably unsubstituted or monosubstituted, and their substituents are illustrated by the following groups; lower alkyl, e.g., methyl, ethyl, n- or i-propyl or -butyl; lower alkoxy, e.g., methoxy, ethoxy, n- or i-propoxy or -butoxy; lower alkylenedioxy, e.g., methylendioxy, 1,1- or 1,2-ethylenedioxy; hydroxy; halogeno, e.g., fluoro, chloro or bromo; or trifluoromethyl. A lower alkyl group R1 and/or R2 is preferably methyl, ethyl, n- or i-propyl or -butyl; the aminolower alkyl group R, is preferably a)-amino-(ethyl, propyl, butyl or pentyl); and the aryl-lower alkyl group R2 is also preferably HPh-methyl or w-HPh-(ethyl or propyl). Each of R3, R4 and R5 is preferably hydrogen, but also lower alkyl, advantageously methyl, or another of those mentioned previously. The term "lower", referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, and advantageously but one or two carbon atoms. Said functional derivatives, wherein either one or both carboxy groups are esterified or amidized, are preferably the mono- or bis- lower alkyl esters, e.g. the methyl, ethyl, n- or i-propyl or -butyl esters; the mono- or bis-amide, or the correspondingly N-alkylated amides, e.g. mono- or dimethylamide, or said substituted lower alkyl esters, preferably the half-esters with a free indoline-2-carboxy group, e.g.

Salts are preferably pharmaceutically acceptable salts, e.g. metal or ammonium salts of said acids, more particularly alkali or alkaline earth metal salts, e.g., the sodium, potassium, magnesium or calcium salt; or advantageously easily crystallizing ammonium salts derived from ammonia or organic amines, such as mono, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl)-amines, lower alkylenediamines or (hydroxy-lower alkyl or aryl lower alkyl)-lower alkylammonium bases, e.g., methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylendiamine, tris-(hydroxymethyl)-aminomethane or benzyl-trimethylammonium hydroxide.Said amphoteric compounds of Formula I form also acid addition salts, which are preferably such of therapeutically acceptable inorganic or organic acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, E malic, tartaric, citric, maleic, fumaric, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfonic acid; or ascorbic acid. The compounds of this invention exhibit valuable pharmacological properties, primarily hypotensive antihypertensive and cardioactive effects, inter alia due to their aniotensin converting enzyme inhibitory activity. These pharmacological properties are demonstrable by in vivo or in vitro animal tests, using advantageously mammals, e.g., rats, cats, dogs or isolated organs thereof, as test objects. The animals may either be normotensive or hypertensive e.g., genetically hypertensive rats, or renal hypertensive rats and dogs, and sodium-depleted dogs. Said compounds can be applied to them enterally or parenterally, advantageously orally or intravenously, for example within gelatin capsules or in the form of starchy suspensions or aqueous solutions respectively. The applied dosage may range between about 0.01 and 50 mg/kg/day, preferably between about 0.1 and 25 mg/kg/day, advantageously between about 1 and 10 mg/kg/day. The in vivo lowering effect on the blood pressure is recorded either directly by means of a catheter, for example placed in the dog's femoral artery, or indirectly by sphygamomanometry at the rat's tail, and a transducer, expressing the blood pressure prior and after dosing in mm Hg. Thus, for example, the representative members of the compounds of this invention, illustrated by the Examples herein, are very effective in hypertensive rats and dogs at p.o.-doses as low or lower than 10 mg/kg/day. They also inhibit the angiotensin I pressure response of normotensive rats. The enzyme renin normally causes specific hydrolysis of the circulating renin-substrate-protein. This hydrolysis generates angiotensin I, which is further hydrolyzed by the action of said converting enzyme to the potent vasoconstrictor angiotensin II. The inhibition of said enzyme prevents the generation of angiotensin II from I and, therefore, attenuates any pressure response following an angiotensin I challenge. The corresponding in vivo test is performed with male, normotensive rats, which are anesthetized with 100-120 mg/kg i.p. of sodium ethyl-(1-methylpropyl)-malonylthiourea. A femoral artery and saphenous vein are cannulated for direct blood pressure measurement and i.v. administration of angiotensin I and compounds of this invention. After the basal blood pressure is stabilized, pressor responses to 3 challenges of 0.33 Microg/kg of angiotensin I i.v., in 5 minutes intervals, are obtained. Pressure responses are again obtained 5, 10, 15, 30 and 60 minutes after either i.v., or p.o. administration (stomach tube) of the compounds to be tested, and compared with the initial responses.Any observed decrease of said pressor response is in indication of angioten I converting enzyme inhibition, ranging up to 80% after 10 mg/kg i.v., or 50 mg/kg p.o. doses, which decrease may be sustained up to 60 minutes. The in vitro inhibition of the angiotensin-converting enzyme by the compounds of this invention can be demonstrated analogous to Biochim. Biophys. Acta 293, 451 (1973). According to this method said compounds are dissolved at about 1 mM concentrations in phosphate buffer, externally cooled with

converting enzyme, which is freshly prepared from lungs of adult male rabbits in Tris buffer, containing potassium and magnesium chloride, as well as sucrose. Said solutions are incubated at 37[deg] for 30 minutes and combined with 0.75 ml of 0.6 N aqueous sodium hydroxide to stop further reaction. Then 100 Microl of o-phthalaldehyde are added at room temperature, and 10 minutes later 100 Microl of 6N hydrochloric acid. These samples are read against water in a spectrophotometer set at 360 nm, and the optical densities thereof estimated.They are corrected for the standard curve via a conversion factor expressing nanomoles of histidyl-leucine formed during said 30 minute incubation period. The results are plotted against drug concentration to determine the IC50, i.e., the drug concentration which gives half the activity of the control sample containing no drug. Again, said representative members of the compounds of this invention are very effective in this in vitro test system, down to IC50 values as low or lower than 6 nM. Accordingly, the compounds of this invention are valuable antihypertensive agents, especially useful for ameliorating hypertension (regardless of etiology) and/or heart-conditions, such as congestive heart failure, and/or other edemic or ascitic diseases, e.g. hepatic cirrhosis. They are also useful intermediates in the preparation of other valuable products, especially of corresponding pharmaceutical compositions. Particularly useful are those compounds of Formula I, wherein Ph is unsubstituted 1,2-phenylene, or 1,2-phenylene substituted by one or two identical or different members selected from lower alkyl, lower alkoxy, hydroxy and halogeno, or 1,2-phenylene substituted by one lower alkylenedioxy or

lower alkyl; and each of R3' R4 and R5 is hydrogen or lower alkyl; the amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy)lower alkyl esters, or salts, especially pharmaceutically acceptable alkali metal, alkaline earth metal, ammonium or acid addition salts thereof. More preferred are those compounds of Formula I, wherein Ph is 1,2-phenylene, unsubstituted or mono-substituted by lower alkyl, lower alkoxy, lower alkylendioxy, hydroxy, halogeno or trifluoromethyl;

R5 is hydrogen or methyl; the amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, monoor di-lower alkylamino, carboxy or carbo-lower alkoxy)-lower alkyl esters, or salts, especially pharmaceutically acceptable alkali metal, alkaline earth metal, ammonium or acid addition salts thereof. Especially valuable compounds of this invention are those of the general Formula II

more specifically the indoline-2S-chiral epimers thereof, wherein R is hydrogen, alkyl or alkoxy with up to 4 carbon atoms, hydroxy, halogeno or trifluoromethyl; m is an integer from 1 to 4; n is an integer from 1 to 3; R' is hydrogen or amino; and R" is hydrogen or R-phenyl; the mono- or bis-amide, the mono- or

metal, ammonium or acid addition salts thereof. The most preferred compounds are those of Formula II, wherein R is hydrogen, methyl, methoxy, hydroxy or chloro, advantageously in the 5-position, m is the integer 1, n is the integer 2, R' is hydrogen

and salts, especially pharmaceutically acceptable alkali metal, ammonium or acid addition salts thereof. The compounds of this invention are prepared according to conventional methods, advantageously by: 1) hydrogenating a Schiff's base of the general Formula III

or said functional derivatives thereof, wherein one of the integers p and q is 0 and the other is 1; or 2) condensing a compound of the general Formula IV

or said functional derivatives thereof, with a reactive functional derivative of a compound of the general Formula V

CO-CHR1-Z and one of Y and Z is amino and the other reactively esterified hydroxy, and converting said COORo group into hydrogen; or 3) hydrolysing or alcoholyzing a compound of the general Formula VI

wherein at least one of V and W is cyano, and the other is said free, amidized or esterified carboxy group;or 4) hydrogenating in a compound of the general Formula VII

or said function derivatives thereof, the indole moiety to the indoline moiety, and if desired, converting any resulting compound into another compound of the invention. The hydrogenation of compounds III is performed according to known methods, e.g. either with catalytically activated or nascent hydrogen, such as hydrogen in the presence of platinum, palladium or nickel catalysts, or generated electrolytically, or by the action of metals on acids or alcohols. Also reducing agents may be used, such as simple or complex light metal hydrides, e.g., boranes, or advantageously alkali metal borohydrides or cyanoborohydrides. Reactive functional derivatives of compounds V are preferably esterhalides, simple or mixed anhydrides, such as the lower alkyl half esters of said acid chlorides, the cyclic anhydride, or mixed acetic or cyanoacetic anhydrides. A reactively esterified hydroxy group Y or Z, is preferably halogeno, e.g., chloro, bromo or iodo; or aromatic sulfonyloxy, e.g., tosyloxy or brosyloxy. Said condensation of compounds IV and V occurs either spontaneously, or in the presence of condensing agents, such as organic or inorganic bases, e.g. said salt-forming amines or alkali metal carbonates, or disubstituted carbodiimides. Any resulting compound containing the aza-protecting group COORo, can be deprotected according to methods well known in peptide chemistry, advantageously by catalytic hydrogenation as shown above, or hydrolysis as shown below.Said starting materials are also known, of if new, may be prepared according to an analogous condensation step 2. The hydrolysis of the nitriles VI to the corresponding acids or amides is advantageously carried out with inorganic acids, such as hydrohalic or sulfuric acids, in known manner; and said alcoholysis is analogously performed in the presence of both said acids and the corresponding unsubstituted or _substituted lower alkanols. Finally, said hydrogenation of the indoles VII to the indolines I is also performed according to conventional hydrogenations of 1-acylindoles, for example, with catalytically activated or nascent hydrogen, e.g. hydrogen in the presence of platinum, palladium, rhodium or nickel catalysts, or hydrogen generated electrolytically, or by the action of metals on acids or alcohols. Also reducing agents may be used, such as simple or complex light metal hydrides, e.g. boranes, or advantageously alkali metal borohydrides or cyanoborohydrides. Preferred is the asymmetric hydrogenation to the indoline-2Scarboxylic acids, or said derivatives thereof, with chiral catalysts, as, for example, prepared from a rhodium salt with (R)-1,2-bis-(diphenylphosphino)-propane or (R)-1,2-bis(o-anisylphenylphosphino)ethane and 1,5-cyclooctadiene. Functional derivatives of carboxylic acids, e.g. of formulae III, IV, V, VII, R2CHNH2COOH or R2COCOOH are preferably esters, e.g. lower alkyl esters, such as ethyl, t-butyl, or aralkyl esters, such as benzyl esters. A reactive functional derivative of carboxylic acids within the meaning of this invention are preferably acid halides, reactive esters, simple or mixed anhydrides and the like known to the art, as previously described for compounds V. The starting materials are known or if new, they may be obtained according to methods known per se, for example analogously to the methods described in the examples herein. The new starting materials also constitute an object of the invention. The starting materials of formula III are prepared, preferably in situ, by condensing a compound of formula IV wherein X is ROCOCO with a compound R2CHNH2COOH or functional derivatives thereof; or by condensing a compound of formula IV wherein X is R1CHNH2CO with a compound of the formula R2COCOOH or functional derivatives thereof. Said condensations are carried out in inert organic solvents per se or in the presence of e.g. an anhydrous mineral or organic acid. (e.g. boron trifluoride, hydrogen chloride or acetic acid), an inorganic salt (e.g. magnesium sulfate) or molecular sieves. Intermediates of formula IV wherein X is R,COCO are known or are prepared by condensation of a compound of formula IV, or an ester thereof, wherein X is hydrogen, with an optionally protected (e.g. dithioketal) compound of the formula R COCOOH or a reactive functional derivative thereof. Intermediates of formula IV wherein X is R,CHNH2CO are in turn prepared by condensation of a compound of formula IV or an ester thereof wherein X is hydrogen with an optionally N-protected (e.g. the N-benzyloxycarbonyl or t-butyloxycarbonyl derivative) compound of the formula R1CHNH2COOH or a reactive functional derivative thereof, and if necessary deprotecting by methods known to the art and described hereafter. Condensations with reactive functional derivatives of carboxylic acids cited above or herein after occur either spontaneously or in the presence of condensing agents, e.g. inorganic or organic bases such as potassium carbonate, pyridine, or triethylamine. Condensations of the carboxylic acids per se may be carried out in the presence of coupling reagents, e.g. dicyclohexylcarbodiimide of 1(3-dimethylaminopropyl)-3-ethylcarbodiimide.

formula IV wherein X is hydrogen with a functional derivative of HOCOCHR Z wherein Z represents reactive esterified hydroxy (e.g. chloro or tosyloxy) or protected amino, e.g. t-butyloxycarbonylamino (tBOC-amino) or carbobenzyloxyamino (CBz-amino), and converting to the compound of formula IV wherein X is COCHR1NH2 by methods known to the art and described hereafter, e.g. hydrolysis under acidic conditions or catalytic hydrogenation.

prepared by: a) reacting an ester (e.g. a lower alkyl ester such as t-butyl ester) of a compound of the formula R1CHNH2COOH with an ester (e.g. a lower alkyl ester such as ethyl ester) of a compound of the

resulting Schiff base according to known methods, e.g. advantageously by hydrogenation in the presence of palladium or nickel catalysts or with a reducing agent e.g. sodium cyanoborohydride. c) Nprotecting the resulting azadiester with a known reactive functional derivative of RoCOOH; and d) hydrolyzing any resulting N-protected diester of a compound of formula V wherein Y is

Starting materials offormula VI wherein W is cyano may preferably be prepared from a compound

represents a reactively esterified hydroxy group. Starting materials of formula VII may be prepared by process 2) as previously described wherein a compound of formula IV is replaced by the corresponding indole derivative where R3 and R5 of formula IV are replaced by a single bond connecting carbon atoms bearing said R3 and R5 substituents. The compounds of the invention so obtained, can be converted into each other according to conventional methods. Thus, for example, resulting amides or esters may be further hydrolyzed or alcoholyzed (trans-esterified) according to process 3), or with aqueous alkalies, such as alkali metal carbonates or hydroxides, respectively. Resulting free acids may be esterified with said unsubstituted or substituted lower alkanols or diazoalkanes, or converted into said metal, ammonium or acid addition salts in conventional manner. Thus, for example, any resulting free (amphoteric) compound can be converted into a corresponding metal, ammonium or acid addition salt respectively, by reacting it with an equivalent amount of the corresponding base, basic salt, acid or ion exchange preparation, e.g. said acids with alkali metal or ammonium hydroxides or carbonates, or said acids, amides or esters with said inorganic or organic acids respectively. Any resulting salt may also be converted into the free compounds, by liberating the latter with stronger acids or bases respectively, advantageously at the pH-value between about 3 and 5. In view of the close relationship between the free compounds, and the salts thereof, whenever a compound of the invention, or intermediate thereof, is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances. In case mixtures of geometrical or optical isomers of the above compounds of Formulae I to VII are obtained, these can be separated into the single isomers by methods in themselves known, e.g., by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, such as according to J. Org. Chem. 43, 3803 (1978), e.g., by the fractional crystallization of d-or !-(tartrates, mandelates, camphorsulfonates, or 1-naphthyl-1-

quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts. The preferred starting material of Formula III is the 2S-optical isomer (epimer) thereof. The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, alkaline or acidic condensing or said other agents respectively, for example the standard peptide aminoprotecting agents, and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure. The invention further includes any variant of said processes, in which an intermediate product obtainable at any stage of the process is used as a starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form or their salts or optically pure antipodes. Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially valuable, e.g., those of Formula II, are being the following chiral isomers:

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral administration. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene-glycol, for tablets, also binders, e.g., magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or absorbents, colorants,flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively, and contain about 0.1 to 75%, preferably about 1 to 50% of the active ingredient. A unit dosage for a mammal of about 50-70 kg weight may contain between about 5 and 100 mg of the active ingredient. The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centrigrade, and all parts wherever given are parts by weight. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mmHg. EXAMPLE 1 The mixture of 1.0 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 3.8 of 4-phenyl-2-oxobutanoic acid and 30 ml of water is adjusted to the pH = 7.5 with aqueous sodium hydroxide at room temperature. It is combined with 0.8 g of sodium cyanoborohydride and stirred overnight at room temperature. Thereupon it is quenched with 5 ml of concentrated hydrochloric acid, filtered through a short column of a strong acidic ion exchange resin (Dowex 50W-X4) and the column eluted first with 50% aqueous ethanol to remove starting material, and then with 4% (by volume) aqueous ammonia.The latter eluate is evaporated, the residue slurried in 6 ml of water, the pH thereof adjusted to 3 with N hydrochloric acid and the precipitate collected, to yield the 1-[N-(1-carboxy-3-phenylpropyl)-S-alanyl]indoline-2S-carboxylic acid of Formula II, with R = R' = H, m = 1, n = 2 and R" = C6H5, melting at

The starting material is prepared as follows: 120 g of 1-acetylindoline-2-carboxylic acid [Nippon Kagaku Zasshi 87, 760 (1966)] and 172 g of 1-cinchonidine are dissolved in 1,200 ml of hot ethanol. The solution is allowed to stand at room temperature overnight and then at 0[deg] for 4 days. The white crystalline salt is filtered off and discarded. The filtrate is evaporated, 1,000 ml of water are added and the solution is adjusted to pH = 1 with concentrated hydrochloric acid. After 1 5 minutes the product is collected by filtration and washed thrice with 250 ml of 2N aqueous hydrochloric acid, twice with 500 ml of water and twice with 100 ml of ethanol, to give the 1-acetylindoline-2S-carboxylic acid melting

The suspension of 37.5 g thereof in 380 ml of 2N aqueous hydrochloric acid is deoxygenated by bubbling nitrogen through it for 5 minutes, followed by refluxing for 2 hours.It is cooled to room temperature, filtered through infusorial earth, the filtrate evaporated and the residue crystallized from diethyl ether-isopropanol, to yield the indoline-2S-carboxylic acid hydrochloride melting at 133[deg] (decomposition); [alpha ]D= 70.4[deg] (c = in ethanol). The solution of 34 g thereof in 350 ml of ethanol is saturated with dry hydrogen chloride without external cooling. The mixture is stirred for 2 hours at room temperature and the solvent removed until crystallization begins. The concentrate is poured into 400 ml of diethyl ether, cooled at 0[deg] for 1 hour and filtered, to yield the indoline-2S-carboxylic acid ester hydrochloride melting at 179-181 [deg];

To the mixture of 18.0 g thereof, 18.5 g of N-carbobenzyloxy-S-alanin, 11 ml of triethylamine and 300 ml of methylene chloride, 16.7 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added while stirring at 0[deg]. After one hour the temperature is allowed to rise to room temperature and stirring is continued overnight.The mixture is washed with water, 2N hydrochloric acid and saturated aqueous sodium bicarbonate, dried and evaporated, to yield the 1-(N-carbobenzyloxy-Salanyl)-indoline-2S-carboxylic acid ethyl ester. The mixture of 30.8 g thereof, 3.6 g of lithium hydroxide, 100 ml of dimethylformamide and 100 ml of water is stirred for 2 hours at room temperature, acidified with 200 ml of concentrated hydrochloric acid and extracted thrice with 100 ml of methylene chloride each. The combined extract is washed with water, dried and concentrated to 50 ml. The concentrate is diluted with 300 ml of diethyl ether, extracted thrice with 100 ml of saturated aqueous sodium bicarbonate each, the combined extract acidified with concentrated hydrochloric acid and reextracted with methylene chloride. This extract is dried and evaporated, to yield the 1-(N-carbobenzyloxy-Salanyl)-indoline-2S-carboxylic acid melting at 144-146[deg]. The mixture of 15 g thereof, 1.0 g of palladium-on-carbon and 150 ml of 90% aqueous ethanol is hydrogenated at room temperature and atmospheric pressure for 2 hours, filtered and evaporated to yield the 1-(S-alanyl)-indoline-2S-carboxylic acid melting at 205-207[deg], [alpha ]D=-141.8[deg] (c = 1.1 in water). EXAMPLE 2 The mixture of 0.50 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 0.66 g of ethyl 4-phenyl-2oxobutanoate, 0.43 g of triethylamine, 0.7 g of Raney-nickel, 2 g of 3A molecular sieves and 20 ml of ethanol, is hydrogenated at room temperature and 2.7 atm. for 18 hours. It is filtered, evaporated, the residue partitioned between 15 ml of ethylacetate and 30 ml of water, the mixture adjusted with 2N aqueous sodium hydroxide to the pH = 8.6, the aqueous phase separated and washed with 10 ml of ethyl acetate. It is acidified with 4N hydrochloric acid to the pH = 4.25, extracted thrice with 10 ml of ethyl acetate each, the combined extract dried and evaporated, to yield the 1-[N-(1-carboethoxy-3phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid showing IR-bands at 3210, 1745 and 1720cm-1, [alpha ]D= 103.4[deg] (c = 0.6 in ethanol). 0.6 g thereof are dissolved in 5 ml of diethyl ether and anhydrous hydrogen chloride is bubbled through the solution. The precipitate formed is filtered off, washed with diethyl ether and dried, to yield the corresponding hydrochloride melting at 176-180[deg]. EXAMPLE 3 Analogous to the methods disclosed herein the following 1 (carboxy-azaaralkanoyl)-indoline-2Scarboxylic acids of Formula II are prepared:

EXAMPLE 4 A mixture of 5.0 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 22.0 g of ethyl 2-oxo-4phenylbutanoate, 6.0 ml of triethylamine and 33.0 g of 3A molecular sieves in 75 ml of ethanol is stirred at room temperature for 30 minutes. A solution of 1.34 g of sodium cyanoborohydride in 25 ml of ethanol is added over a 3 hour period. The reaction mixture is stirred overnight at room temperature, filtered, and the filtrate is evaporated to dryness. The residue is partitioned between 30 ml of methylene chloride and 50 ml of water adding sufficient 2N aqueous sodium hydroxide solution to adjust the solution to pH9. The aqueous layer is separated and washed with 30 ml of methylene chloride.The aqueous solution is acidified to pH 1 with concentrated hydrochloric acid, stirred for 30 minutes, adjusted to pH 3 by the addition of 2N sodium hydroxide solution, and then extracted three times with 50 ml of methylene chloride. The methylene chloride extract is dried over magnesium sulfate and evaporated to dryness to give the product consisting mainly of the desired diastereoisomer. This is purified by preparative high pressure liquid chromatography on a silica gel column, using an 85:15 mixture of ethyl acetate; methanol as the eluent, to yield 1-[N-(1-carboethoxy-3-phenyl-propyl)-S-alanyl]indoline-2S-carboxylic acid.This product is dissolved in diethyl ether, anhdrous hydrogen chloride is added, and the resulting hydrochloride salt is collected to yield the 1-[N-(1-carboethoxy-3-phenylpropyl)-Salanyl]-indoline-2S-carboxylic acid hydrochloride melting at 140[deg] with decomposition, [alpha ]D= 77.5[deg] (c = 1.4 in ethanol). EXAMPLE 5 A mixture of 20.0 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 53.0 g of ethyl 2-oxo-4phenylbutanoate, 22 g of diisopropylethylamine and 130 g of 3A molecular sieves in 250 ml of ethanol is stirred at room temperature for 30 minutes. A solution of 6.7 g of sodium cyanoborohydride in 75 ml of ethanol is added over a 5 hour period. The reaction mixture is stirred for an additional hour, filtered, and evaporated under reduced pressure. An aqueous suspension of the residue is washed twice with 150 ml of ether. The pH is adjusted to 1.5 with concentrated hydrochloric acid and 100 ml of methylene chloride are added. After stirring for one hour the pH is adjusted to 2.9 with 10% aqueous sodium hydroxide solution, the methylene chloride layer is separated, and the aqueous portion is extracted two more times with 100 ml of methylene chloride.The combined methylene chloride extracts are dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting product is crystallized from 150 ml of ether to yield 1-[N-( 1 S-carboethoxy-3-phenylpropyl)-S-alanyl]-indoline-2Scarboxylic acid melting at 80[deg] with decomposition, [alpha ]D= 106[deg] (c = 0.8 in ethanol). EXAMPLE 6 A mixture of 5.0 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 13.2 g of ethyl 2-oxo-4phenylbutyrate and 6 ml of triethylamine in 115 ml of ethanol is hydrogenated at 2.7 atmospheres in the presence of 4.8 g of Raney nickel and 17 g of 3A molecular sieves. After 15 hours, the reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is partitioned between 75 ml of ethyl acetate and 50 ml of water to which is added sufficient 2N aqueous sodium hydroxide solution to bring pH to 8.6. The aqueous phase is separated, washed with 20 ml of ethyl acetate, acidified to pH 4.25 with 4N hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The combined three latter ethyl acetate extracts are dried over sodium sulfate and evaporated to dryness. The residue is treated with anhydrous hydrogen chloride in ethyl ether.The precipitated hydrochloride salt is collected and recrystallized from ethyl acetate to give 1-[N-(1-carboethoxy-3-phenylpropyl)-S-alanyl]indoline-2S-carboxylic acid hydrochloride melting at 207-8[deg], [alpha ]D= -109.6[deg] (c = 1.09 in ethanol). EXAMPLE 7 The mixture of 6.4 g of sodium 3-phenyl-2-oxopropanoate, 2.0 g of 1-(S-alanyl)-indoline-2Scarboxylic acid and 1.6 g of sodium cyanoborohydride in 50 ml of water at room temperature is adjusted to pH 7 with 1 N hydrochloric acid. The reaction mixture is stirred at room temperature for 2 days, quenched by the addition of 10 ml of concentrated hydrochloric acid and concentrated under reduced pressure. The resulting product is absorbed on a strong acid ion exchange column (Dowex 50, H+ form) and eluted with 4% aqueous ammonia to yield 1-[N-carboxy-2-phenyl-ethyl)-S-alanyl]indoline-2S-carboxylic acid melting at 140-3[deg], [alpha ]D=-92[deg] (c= 1.1 in ethanol) with NMR peaks at 1.35, 2.85 and 4.80 ppm. EXAMPLE 8 A mixture of 2.0 g of 1-(S-alanyl)-indoline-2S-carboxylic acid, 13.0 g of 3A molecular sieves, 2.4 ml of triethylamine and 5.0 g of ethyl pyruvate in 30 ml of ethanol is stirred at room temperature for 30 minutes. A solution of 0.54 g of sodium cyanoborohydride in 10 ml of ethanol is added over a 2 hour period, the reaction mixture is stirred at room temperature overnight and 4 ml of concentrated hydrochloric acid is added to quench the reaction. The reaction mixture is evaporated to dryness. The resulting product is absorbed on a strong acid ion exchange column (Dowex 50, H+ form) and the column is eluted with 4% aqueous ammonia to yield 1-[N-(1-carboethoxy-ethyl)-S-alanyl]-indoline-2Scarboxylic acid having NMR peaks in DMSO at 3.8, 1.6 and 1.2 ppm. EXAMPLE 9

in 25 ml of ethanol is saturated with ammonia at 0[deg] and stored in a pressure bottle at room temperature for 4 days. The solution is evaporated, the residue is taken up in water, the mixture is acidified with 3N hydrochloric acid at 0[deg] to pH 3.5 and extracted with methylene chloride to yield 1 -[N-

and 3220 cm-1. EXAMPLE 10 Preparation of 10,000 tablets each containing 5 mg of the active ingredient: Formula:

Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35[deg], broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected. EXAMPLE 11 Preparation of 10,000 capsules each containing 10 mg of the active ingredient: Formula

Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer first with the talcum, then with the lactose until homogenous. No 3 capsules are filled with 200 mg, using a capsule filling machine. Analogously tablets or capsules are prepared from the remaining compounds of the invention, e.g. those illustrated by other Examples. EXAMPLE 12 A mixture of 1-(S-Alanyl)-indoline-2S-carboxylic acid (100 g), anhydrous ethanol (2000 ml), acetic acid (29.9 g) and ethyl 4-phenyl-2-oxobutanoate (270 g) is stirred at room temperature for 2 h. Sodium cyanoborohydride (33.3 g) in anhydrous ethanol (300 ml) is then added at a constant rate over 5 h while maintaining the temperature between 20-24[deg]. After stirring overnight at ambient temperatures, the reaction mixture is cooled to 0[deg], 12N hydrochloric acid (100 ml) is added all at once, cooling is discontinued and the reaction mixture stirred for 1 h before the solvent is removed at 20-24[deg] and 3 mm Hg. The syrup which remains is added to a vigorously stirred mixture containing ice (0.6 kg), 6N sodium hydroxide solution (600 ml) and 1000 ml of ether. The aqueous portion is removed and is washed with 1000 ml of fresh ether.The aqueous solution (pH ca. 12.4) is combined with 1000 ml methylene chloride, cooled to 0 5[deg] and is acidified rapidly with 12N hydrochloric acid (ca. 93 ml) to pH 4.3. The methylene chloride portion is removed and the aqueous mixture is extracted with methylene chloride (2 x 500 ml). The combined organic portions are dried (anhydrous sodium sulfate), clarified by filtration and are concentrated at 20-24[deg] and 3 mm Hg to give 1-[N-(1 S-carboethoxy-3-

194 g of the obtained crude free base are dissolved in ethyl acetate (500 ml) and is added dropwise to a well-agitated cold (5[deg]) solution of phosphoric acid (42 g) in ethyl acetate (2300 ml).The mixture is stored overnight at 5[deg], is then stirred for 1 h and the solids are collected by filtration.The "cake" is washed with ethyl acetate (3 x 100 ml) and ether (3 x 100 ml) and dried at 24[deg] and 3 mm Hg to give crude phosphate salt. The product is recrystallized from absolute ethanol ethyl acetate and

carboxylic acid 1 :1 phosphate, m.p. 125-129[deg], [alpha ]23D=-87.2[deg] (c= 1 in methanol). EXAMPLE 13 To a solution of 3.67 g of sodium hydroxide in 100 ml of ethanol at room temperature is added a suspension of 16.0 g of 1-[N-(1 S-carboethoxy-3-phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid phosphoric acid salt in 100 ml of ethanol. The mixture is stirred for 30 minutes and then filtered. The filtrate is evaporated, the residue dissolved in 100 ml of diethyl ether, filtered and allowed to stand at room temperature overnight. The crystalline product is filtered, washed with diethyl ether and dried in

of methanol is added 1.6 g of sodium hydroxide in 50 ml of water. The reaction mixture is stirred 3 hours at room temperature and then evaporated. The residue in 100 ml of water is extracted with 2 x 50 ml od diethyl ether. The aqueous layer is adjusted to pH 3 with concentrated hydrochloric acid.The recipitated solid is collected by filtration and recrystallized from ethyl acetate to give 1-[N-(1 S-

(c = 0.6 in ethanol). EXAMPLE 15 A solution of 3.0 g of sodium 1-[N-(1 S-carboethoxy-3-phenylpropyl)-S-alanyl]-indoline-2Scarboxylate in 30 ml of methanol containing 100 mg of sodium carbonate is refluxed 10 hours and then evaporated. The residue is taken up in 150 ml of diethyl ether and filtered. The filtrate is concentrated to 50 ml and 50 ml of hexane is added. The precipitated product is collected by filtration to give sodium 1 [N-(1 S-carbomethoxy-3-phenylpropyl)-S-alanyl]-indoline-2S-carboxylate melting at 140 145[deg], [alpha ]D= -123.7[deg] (c = 0.8 in methanol). Starting material for Example 3/3 To a solution of 5.0 g of ethyl indoline -2S-carboxylate hydrochloride, 5.5 g of N-carbobenzyloxyL-valine and 3.0 ml of triethylamine in 200 ml of methylene chloride is added 4.4 g of 1-(3dimethylaminopropyl)-3-ethyl-carbodi mide hydrochloride. The reaction mixture is stirred overnight at room temperature and then washed with 75 ml of water, 75 ml of 2N aqueous hydrochloric acid and 75 ml of saturated aqueous sodium bicarbonate. The organic layer is dried over magnesium sulfate and evaporated to give ethyl 1-(N-carbobenzyloxy-L-valyl)-indoline-2S-carboxylate. To 9.3 of ethyl 1-(N-carbobenzyloxy-L-valyl)-indoline-2S-carboxylate in 75 ml of methanol is added 1.05 g of sodium hydroxide in 75 ml of water. The reaction mixture is stirred 3 hours at room temperature and then evaporated. The residue in 200 ml of water is washed with 75 ml of methylene chloride. The aqueous layer is acidified with 5 ml of concentrated hydrochloric acid and then extracted with 3 x 75 ml of methylene chloride. The latter combined organic extracts are dried over sodium sulfate and evaporated to give 1-(N-carbobenzyloxy-L-valyl)-indoline-2S-carboxylic acid. To 8.7 g of 1-(N-carbobenzyloxy-L-valyl)-indoline-2S-carboxylic acid in 100 ml of 85% aqueous ethanol is added 0.5 g of 10% palladium-on-carbon. The reaction mixture is hydrogenated at room temperature at atmospheric pressure for 3 hours, filtered and evaporated to yield 1-(L-valyl)-indoline2S-carboxylic acid melting at 194-196[deg], [alpha ]D= -63.2[deg] (c = 0.9 in 50% aqueous ethanol). Starting MaterialforExample 3/4 To 10.0 g of ethyl indoline-2S-carboxylate, 16.7 g of a-N-t-butoxycarbonyl-c-Nbenzyloxycarbonyl-L-lysine and 6.1 ml of triethylamine in 250 ml of methyl chloride is added 8.8 g of 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture is stirred overnight at room temperature, washed with 75 ml of water, 75 ml of 2N aqueous hydrochloric acid and 75 ml of saturated aqueous sodium bicarbonate. The organic layer is dried over magnesium sulfate and

2S-carboxylate in 150 ml of methanol is added a solution of 1.8 g of sodium hydroxide in 150 ml of water. The reaction mixture is stirred at room temperature for 3 hours and then evaporated. The residue in 300 ml of water is washed with 100 ml of methylene chloride.The aqueous layer is acidified by addition of 5 ml of concentrated hydrochloric acid and then extracted with 3 x 100 ml of methylene chloride. The combjned organic extracts are dried over magnesium sulfate and evaporated to give the 1-

13 ml of glacial acetic acid, 20 ml of methylene chloride and 13 ml of anisole at 0[deg] is added 40 ml of trifluoroacetic acid. The reaction mixture is allowed to warm to room temperature while stirring for 30 minutes and then evaporated. The residue is crystallized in diethyl ether to give the 1-(E-Nbenzyloxycarbonyl-L-lysyl)-indoline-2S-carboxylic acid trifluoroacetic acid salt. Cardiovascular pharmacology of compounds of the invention Testing of compounds is carried out by methods for evaluation of the inhibition of the angiotensin converting-enzyme (ACE). Biochemical assessment of in vitro ACE inhibition (ACEI) gauges the inhibition of peptidolytic activity of a compound in rabbit lung tissue. In in vivo studies angiotensin I (Al) pressor response inhibition of the compounds are conducted in rats. In the in vivo test method an increase in the blood pressure is first caused by administration of angiotensin I (Al) to the test animal. The inhibitory action of the individual compounds on this increase in blood pressure is then determined. Biochemical Testing Methodology A rabbit lung tissue preparation [Das and Saffer, J. Biol. Chem. 250 6762, (1975)] was used for assessment of ACE by the method of Cheung and Cushman [Cheung and Cushman, Biochim. Biophys. Acta 293: 451, (1973)]. This test system incorporates spectrophotometric evaluation of the amount of histidyl-leucine liberated from a synthetic substrate after 30 min. of 37[deg]C incubation. IC50 values for ACE inhibition were determined graphically as the concentration of test drug required to reduce the amount of histidyl-leucine formed to 50% of that generated in the absence of the test compound. Methodology of angiotensin / (AI) pressor response inhibition following intravenous administration of test compounds (%AI) In these studies catheters were placed in a femoral artery and a saphenous vein of anesthetized rats as described above. Arterial pressure was continuously recorded from the arterial catheter, while Al and the test compounds were injected through the venous catheter. AI pressor response inhibition was expressed as tabulated as the average inhibition recorded through 30 min. after test at several doses appropriate to determine the ID50 (i.v.) for AI pressor response inhibition. Results:

Claims

1. A compound of the general Formula I

wherein Ph is unsubstituted 1,2-phenylene, or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogeno and trifluoromethyl; R1 is hydrogen, lower alkyl or amino-lower alkyl; R2 is lower alkyl or HPh-lower alkyl; and each of R3. R4 and R5 is hydrogen or lower alkyl; the amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy)-lower alkyl esters thereof. 2. A compound of the formula I as shown in claim 1, wherein Ph is unsubstituted 1,2-phenylene, or 1,2-phenylene substituted by one or two identical or different members selected from lower alkyl, lower alkoxy, hydroxy and halogeno, or 1,2-phenylene substituted by one lower alkylenedioxy or

lower alkyl; and each of R3, R4 and R5 is hydrogen or lower alkyl; the amides mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy)lower alkyl esters thereof. 3. A compound of the general formula I shown in claim 1, wherein Ph is 1,2-phenylene, unsubstituted or mono-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogeno

each of R3, R4 and R5 is hydrogen or methyl; the amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy)-lower alkyl esters thereof.

4. A compound of the general Formula II

wherein R is hydrogen, alkyl or alkoxy with up to 4 carbon atoms, hydroxy, halogeno or trifluoromethyl; m is an integer from 1 to 4; n is an integer from 1 to 3; R' is hydrogen or amino; and R" is hydrogen or R-phenyl; the mono- or bis-amide, the mono- or bis-(lower alkyl or -amino-lower alkyl) esters thereof. 5. A compound of the formula II shown in claim 4, wherein R is hydrogen, methyl, methoxy, hydroxy or chloro, m is the integer 1, n is the integer 2, R' is hydrogen and R" is phenyl, the mono- or bis-amide, the mono- or bis-(lower alkyl or -amino-lower alkyl) esters thereof.

6. A compound as claimed in claim 4, in the form of its 2S-carboxyindoline chiral epimer. 7. A compound of the formula II shown in claim 4, defined in the Example 3, under a number from 1 to 9.

8. 1-[N-(1-carboxy-3-phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid.

9. 1-[N-(1-carboethoxy-3-phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid.

11. 1-[N-(1 R-carboethoxy-3-phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid.

12. 1-[N-(1-carboxy-2-phenyl-ethyl)-S-alanyl]-indoline-2S-carboxylic acid.

13. 1-[N-(1-carboethoxy-ethyl)-S-alanyl]-indoline-2S-carboxylic acid.

14. 1-[N-(1 S-carbamoyl-2-phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid.

15. 1-[N-(1 S-carboxy-3-phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid.

16.1-[N-(1 S-carbomethoxy-3-phenylpropyl)-S-alanyl]-indoline-2S-carboxylic acid.

17. A salt of a compound having a salt forming group, as claimed in any one of claims 1-8 and 10. 18. A salt of a compound having a salt forming group, as claimed in any one of claims 9 and 11-14.

19. A salt of a compound having a salt forming group, as claimed in any one of claims 15 and 16.

20. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in anyoneofclaims 1-8 and 10.

21. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in any one of claims 9 and 11 14.

22. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in any one of claims 15 and 16.

23. A pharmaceutical preparation comprising a compound claimed in anyone of claims 1-8, 10 and 20, in admixture or conjunction with a pharmaceutically suitable carrier. 24. A pharmaceutical preparation comprising a compound claimed in any one of claims 9, 11-14 and 21, in admixture or conjunction with a pharmaceutically suitable carrier.

25. A pharmaceutical preparation comprising a compound claimed in any one of claims 15, 16 and 22, in admixture or conjunction with a pharmaceutically suitable carrier. 26. Process for the manufacture of 1-(carboxy-azaalkanoyl or azaaralkanoyl)-indoline-2-carboxylic acids of the general Formula I

wherein Ph is unsubstituted 1,2-phenylene, or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogeno and . trifluoromethyl; R1 is hydrogen, lower alkyl or amino-lower alkyl; R2 is lower alkyl or HPh-lower alkyl; and each of R3' R4 and R5 is hydrogen or lower alkyl; the amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di-lower alkylamino, carboxy or carbo-lower alkoxy)-lower alkyl esters, or salts thereof, which consists in 1) hydrogenating a Schiff's base of the general Formula III

CO CHR1 Z and one of Y and Z is amino and the other reactively esterified hydroxy, and converting said COORo group into hydrogen; or 3) hydrolysing or alcoholyzing a compound of the general Formula VI

wherein at least one of V and W is cyano, and the other is said free, amidized or esterified carboxy group; or 4) hydrogenating in a compound of the general Formula VII

or said functional derivatives thereof, the indole moiety to the indoline moiety, and if desired, converting any resulting compound into another compound of the invention, and/or, if required, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and, if required, resolving a racemate obtained into the optical antipodes.

27. A process as claimed in claim 26 substantially as described in any one of Examples 1 and 3. 28. A process as claimed in claim 26 substantially as described in any one of Examples 2 and 4 to 9.

29. A process as claimed in claim 26 substantially as described in any one of Examples 12 to 15.

30. The compounds prepared according to either of claims 26 and 27.

31. The compounds prepared according to claim 28.

32. The compounds prepared according to claim 29.